ARTICLE | doi:10.20944/preprints202309.1314.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: MC4R; Monogenic Obesity; Severe Obesity; childhood obesity; Qatar
Online: 20 September 2023 (08:11:32 CEST)
The leptin-melanocortin pathway is pivotal in appetite and energy homeostasis. Pathogenic variants in genes involved in this pathway lead to severe early-onset monogenic obesity (MO). The MC4R gene plays a central role in leptin-melanocortin signaling, and variants predominantly heterozygous in this gene are the most common cause of MO. We identified two novel heterozygous variants c,253A>G p.Ser85Gly and c.802T>C p.Tyr268His in the MC4R gene in two unrelated patients with morbid obesity and evaluated the functional impact of these variants. A targeted gene panel consisting of 52 obesity-related genes was undertaken. Variants were analyzed and filtered to identify potential disease-causing and validated using Sanger sequencing. The impact of the variants on the MC4R gene using in silico prediction tools and molecular dynamics simulation was assessed. To further study the pathogenicity of the identified variants, GT1-7 cells were transfected with plasmid DNA encoding either wild-type or mutant MC4R variants. The effects of allelic variations in MC4R gene on cAMP synthesis, MC4R protein level, and activation of ERB and CREB signaling pathways in both stimulated and unstimulated ɑ-MSH paradigms were determined for their functional implications. In-silico analysis suggested that the variants destabilized the MC4R structure and affect the overall dynamics of the MC4R protein, possibly leading to intracellular receptor retention. In-vitro analysis of the functional impact of these variants showed a significant reduction in cell surface receptor expression and impaired extracellular ligand binding activity, leading to reduced cAMP production. In-vitro analysis assays and in silico analysis revealed the pathogenicity of the two novel MC4R variants identified. Our analysis shows that the variants do not affect total protein expression; however, they are predicted to affect the post-translational localization of MC4R protein to the cell surface and impair downstream signaling cascades. This finding might help our patients to benefit from the novel therapeutic advances for monogenic forms of obesity.
REVIEW | doi:10.20944/preprints202309.1062.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: cardiovascular disease; fatty acids; insulin resistance; metabolic-dysfunction associated steatotic liver disease; pemafibrate; triglyceride
Online: 18 September 2023 (08:37:02 CEST)
Metabolic-dysfunction associated steatotic liver disease (MASLD) is a chronic liver disease that affects more than a quarter of the global population, and is increasing worldwide, due to the pandemic of obesity. Insulin resistance is closely associated with the development and progression of MASLD. Hepatic entry of increased fatty acids (FA) released from adipose tissue, increase in FA synthesis and reduced FA oxidation in the liver, and hepatic overproduction of triglyceride (TG)-rich lipoproteins may induce the development of MASLD. Since insulin resistance also induces atherosclerosis, the leading cause for death in MASLD patients is cardiovascular disease (CVD). Considering that the development of CVD determines the prognosis of MASLD patients, the ideal therapeutic interventions for MASLD should reduce body weight, improve coronary risk factors, in addition to an improvement in liver functiom. Lifestyle modification such as diet and exercise and surgical interventions such as bariatric surgery and intragastric balloons have shown to improve MASLD by reducing body weight. Sodium glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have been shown to improve coronary risk factors and to suppress the occurrence of CVD. Both SGLT2i and GLP-1 have been reported to improve liver enzymes, hepatic steatosis and fibrosis. We recently reported that the selective peroxisome proliferator-activated receptor-alpha (PPARα) modulator, pemafibrate, improved liver function. PPARα agonists have multiple anti-atherogenic properties. Here, we consider the pathophysiology of MASLD and the mechanisms of action of such drugs, and consider whether such drugs and the combination therapy of such drugs could be the ideal treatments for MASLD.
ARTICLE | doi:10.20944/preprints202308.1602.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: estrogens; proprotein convertase subtilisin/kexin type 9; lipoprotein; low-density lipoprotein cholesterol; cholesterol; lipids; in vitro fertilization
Online: 23 August 2023 (09:18:30 CEST)
Background: The mechanisms underlying the effect of estradiol (E2) on low-density lipoprotein cholesterol (LDL-C) levels are not completely understood, although a role for proprotein con-vertase subtilisin/kexin type 9 (PCSK9) has been proposed. We aimed to investigate the association between levels of E2, PCSK9 and lipid parameters in premenopausal women undergoing in vitro fertilization (IVF). Methods: Healthy women undergoing IVF in the Department of Obstetrics and Gynecology of the University General Hospital of Ioannina were recruited. Levels of E2, pro-protein convertase subtilisin/kexin type 9 (PCSK9), total cholesterol (TCHOL), high-density lip-oprotein cholesterol (HDL-C), LDL-C, and triglycerides (TGs) were measured 10 days after ovarian depression (E2min) and 7 days after ovarian stimulation (E2max). Results: A total of 34 consecutive healthy women aged 38 (26-46) years old who underwent a full IVF cycle were included. E2 levels increased by 329.6% from E2min to E2max (108 [47-346] to 464 [241-2471] pg/mL, p<0.05). At the same time, serum PCSK9 levels significantly decreased by 30.8% (245 ± 80 to 170 ± 64 ng/mL, p<0.05). No significant changes in TCHOL, LDL-C, TGs and HDL-C were found (-0.4%, -3.8%, -2.2%, and +5.3%, p >0.05). Conclusions: The increase in endogenous E2 production during an IVF cycle was associated with a significant decrease in serum PCSK9 levels during a 7-day period.
REVIEW | doi:10.20944/preprints202308.1470.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Growth hormone receptor (GHR); Human growth hormone; Deletion of exon 3 (d3GHR); Polymorphism; Growth and development; Hormone deficiency
Online: 21 August 2023 (11:59:26 CEST)
Growth hormone (GH) is a peptide hormone that plays a crucial role in controlling growth, development, and lifespan. Molecular regulation of GH is accomplished via the GH receptor (GHR) gene, which is the main factor influencing human development and is essential to optimal functioning of the GH/IGF-I axis. Two GHR isoforms have been studied, according to the presence (flGHR) or absence (d3GHR) of exon 3. The d3GHR variant, which has recently been related to longevity, is associated with enhanced signal transduction and higher receptor function. Many of these studies indicated that the growth response to GH treatment may be affected. Individuals carrying the d3GHR isoform have higher receptor activity, improved signal transduction, and alterations in the treatment response and efficacy compared with those carrying the WT isoform. Further, studies performed in patients with acromegaly, Prader-Willi syndrome, Turner syndrome, small for gestational age (SGA), and growth hormone deficiency (GHD) suggested that the d3GHR variant may have an impact on the relationship between GH and IGF-I levels, height, weight, BMI, and other variables. Other research, however, revealed inconsistent results, which might have been caused by confounding factors, including limited sample sizes and different experimental methods. In this review, we lay out the complexity of the GHR isoforms and provide an overview of the major pharmacogenetic research conducted on this ongoing and unresolved subject.
REVIEW | doi:10.20944/preprints202307.1807.v2
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: polycystic ovary syndrome (PCOS); ovary; uterus; placenta; mitochondria; biogenesis; mtDNA; metabolism; mitochondrial dynamics; oxidative stress
Online: 21 August 2023 (10:16:55 CEST)
Polycystic ovary syndrome (PCOS) is a complex, but relatively common endocrine disorder associated with chronic anovulation, hyperandrogenism, and micro-polycystic ovaries . In addition to reduced fertility, people with PCOS have a higher risk of obesity, insulin resistance, and metabolic disease , all comorbidities that are associated with mitochondrial dysfunction. This review summarizes human and animal data that report mitochondrial dysfunction and metabolic dysregulation in PCOS to better understand how mitochondria impact reproductive organ pathophysiology. This in-depth review considers all the elements regulating mitochondrial quantity and quality, from mitochondrial biogenesis under transcriptional regulation of both the nuclear and the mitochondrial genome, to the ultrastructural and functional complexes that regulate cellular metabolism and reactive oxygen species production, to dynamics which regulate subcellular interactions that are key to mitochondrial quality control. When any of these mitochondrial functions are disrupted the energetic equilibrium within the cell changes, cell processes can fail, and cell death can occur. If this process is ongoing, it affects tissue and organ function to cause disease. The objective of this review is to consolidate and classify a broad number of PCOS studies to understand how various mitochondrial processes impact reproductive organs including the ovary (oocyte and granulosa cell), uterus, placenta, and circulation to cause reproductive pathophysiology. A secondary objective is to uncover the potential role of mitochondria in transgenerational transmission of PCOS and metabolic disorders.
ARTICLE | doi:10.20944/preprints202308.0779.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: bile acids; colesevelam; enterohepatic circulation; liver; humanized mouse model
Online: 10 August 2023 (04:16:37 CEST)
Bile acids (BAs) and their signalling pathways have been identified as therapeutic targets for liver and metabolic diseases. We generated Cyp2c70-/- (KO) mice that are not able to convert chenodeoxycholic acid into rodent-specific muricholic acids (MCAs) and, hence, possess a more hydrophobic, human-like BA pool. Recently, we have shown that KO mice display cholangiopathic features with development of liver fibrosis. The aim of this study was to determine whether BA sequestration modulates liver pathology in Western type-diet (WTD)-fed KO mice. The BA sequestrant colesevelam was mixed into the WTD (2% w/w) of male Cyp2c70+/+ (WT) and KO mice and the effects were evaluated after 3 weeks of treatment. Colesevelam increased fecal BA excretion in WT and KO mice and reduced the hydrophobicity of biliary BAs in KO mice. Colesevelam ameliorated diet-induced hepatic steatosis in WT mice, whereas KO mice were resistant to diet-induced steatosis and BA sequestration had no additional effects on liver fat content. Total cholesterol concentrations in livers of colesevelam-treated WT and KO mice were significantly lower than those of untreated controls. Of particular note, colesevelam treatment normalized plasma levels of liver damage markers in KO mice and markedly decreased hepatic mRNA levels of fibrogenesis-related genes in KO mice. Lastly, colesevelam did not affect glucose excursions and insulin sensitivity in WT or KO mice. Our data show that BA sequestration ameliorates liver pathology in Cyp2c70-/- mice with a human-like bile acid composition without affecting insulin sensitivity.
REVIEW | doi:10.20944/preprints202308.0710.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: diabetes; mitochondrial dynamics; glucose-stimulated insulin secretion; pancreatic beta cell; fusion; fission
Online: 9 August 2023 (08:22:26 CEST)
Mitochondria are involved in the regulation of cellular energy metabolism, calcium homeostasis, and apoptosis. For mitochondrial quality control, dynamic processes, such as mitochondrial fission and fusion, are necessary to maintain shape and function. Disturbances of mitochondrial dynamics lead to dysfunctional mitochondria which contribute to the development and progression of numerous diseases, including Type 2 Diabetes (T2D). Compelling evidence put forward that mitochondrial dynamics play a significant role in the metabolism-secretion coupling of pancreatic β cells. The disruption of mitochondrial dynamics is linked with defects in energy production and increased apoptosis, ultimately impairing insulin secretion and β cell death. This review provides an overview of altered mitochondrial dynamics in pancreatic β cells using ge-netic/pharmacologic approaches, and how these affect insulin secretion.
ARTICLE | doi:10.20944/preprints202308.0640.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Type 2 Diabetes Mellitus (T2DM); Intermittent Fasting; Machine Learning
Online: 8 August 2023 (11:54:50 CEST)
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by elevated blood glucose levels. Despite the availability of pharmacological treatments, dietary plans, and exercise regimens, T2DM remains a significant global cause of mortality. Consequently, there is a growing interest in exploring lifestyle interventions, such as Intermittent Fasting (IF). This study aims to identify underlying patterns and principles for effectively improving T2DM risk parameters through IF. By analyzing data from multiple randomized clinical trials investigating various IF interventions in humans, a machine learning algorithm was employed to develop a personalized recommendation system. This system advises pre-diabetic and diabetic individuals on the most suitable IF interventions to improve T2DM risk parameters. With a success rate of 95%, this recommendation system offers highly tailored guidance, optimizing intermittent fasting's benefits for diverse population subgroups. The results of this study allow us to conclude that weight is the crucial feature for females, while age is the determining factor for males to reduce glucose levels in blood. By revealing patterns in diabetes risk parameters among individuals, this study not only provides practical guidance but also sheds light on the underlying mechanisms of T2DM, contributing to a deeper understanding of this complex metabolic disorder.
ARTICLE | doi:10.20944/preprints202308.0610.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: type 1 diabetes; high-intensity interval exercise; glycaemic control; hypoxia; inflammation
Online: 8 August 2023 (10:18:30 CEST)
Type 1 diabetes (T1D) is associated with hyperglycaemia-induced hypoxia and inflammation. The study assessed the effects of a single high-intensity interval exercise (HIIE) on glycaemia (BG) and serum level of pro-inflammatory cytokines and an essential mediator of adaptive response to hypoxia in T1D patients. The macronutrients intake was also evaluated. Nine patients suffering from T1D for about 12 years and nine healthy individuals (CG) were enrolled and completed one session of HIIE at the intensity of 120% lactate threshold and duration of 4 x 5 min intermittent with 5 min rest after each bout of exercise. Capillary and venous blood was withdrawn at rest, immediately after and at the 24 h post-HIIE for analysis of BG, hypoxia-inducible factor alpha (HIF-1α), tumour necrosis factor alpha (TNF-α) and vascular-endothelial growth factor (VEGF). Pre-exercise BG was significantly higher in the T1D compared to the CG (p = 0.043). HIIE led to a significant decline in T1D patients’ BG (p = 0.027) and to a tendency for a lower BG at 24-h post-HIIE vs pre-HIIE. HIF-1α was significantly elevated in the T1D compared to CG and there was a trend for HIF-1α to decline, and VEGF, TNF-α to increase in response to HIIE in the T1D group. Both groups consumed higher and lower than recommended amounts of protein and fat, respectively. In T1D group, a tendency for a higher digestible carbohydrate intake and more frequent hyperglycaemic episodes on the day after HIIE were observed. HIIE was effective in reducing T1D patients’ glycaemia and improving the short-term glycaemic control. HIIE has the potential to improve adaptive response to hypoxia by elevating the serum level of VEGF. Patients’ diet and level of physical activity should be screened on a regular basis, and they should be educated on the glycaemic effects of digestible carbohydrates.
REVIEW | doi:10.20944/preprints202307.1451.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Non-alcoholic fatty liver; Extracellular vesicles; Biomarkers; Surface proteins
Online: 21 July 2023 (10:05:15 CEST)
Non-alcoholic fatty liver disease (NAFLD) is a liver disorder that has become a global health concern due to its increasing prevalence. Currently, there is a need for reliable biomarkers to aid in the diagnosis and prognosis of NAFLD. Extracellular vesicles (EVs) are promising candidates in biomarker discovery, as they carry proteins that reflect the pathophysiological state of the liver. In this review, we developed a list of EV proteins that could be used as diagnostic biomarkers for NAFLD. We employed a multi-step strategy that involved reviewing and comparing various sources of information. Firstly, we reviewed papers that have studied EVs proteins as biomarkers in NAFLD, as well as papers that have studied circulating proteins as biomarkers in NAFLD. To further identify potential candidates, we utilized the EV database Vesiclepedia.org to qualify each protein. Finally, we consulted the Human Protein Atlas to search for candidates' localization, focusing on membrane proteins. By integrating these sources of information, we developed a comprehensive list of potential EVs membrane protein biomarkers that could aid in the diagnosis and monitoring of NAFLD. In conclusion, our multi-step strategy for identifying EV-based protein biomarkers for NAFLD provides a comprehensive approach that can also be applied for other diseases. The protein candidates identified through this approach could have significant implications for the development of non-invasive diagnostic tests for NAFLD and improve the management and treatment of this prevalent liver disorder.
ARTICLE | doi:10.20944/preprints202307.1077.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: aerobic exercise training; metabolic programming; DOHaD; adolescence
Online: 17 July 2023 (10:58:52 CEST)
The purpose of this study was to examine the impact of fructose consumption during the peri-pubertal period on the later onset of metabolic syndrome in rats. Additionally, the study sought to explore the potential of moderate-intensity physical training as a non-pharmacological approach to mitigate the fructose effects. Male rats, 30 days old, received 10% fructose, and were submitted to concomitant moderate-intensity training until 60 days old. They were divided into 4 groups: sedentary control (SC), sedentary fructose (SF), trained control (TC), and trained fructose (TF). Fructose consumption mainly affected adult animals, resulting in glucose intolerance, increased periepididymal fat, and increased total cholesterol, triglycerides, and insulin levels. Furthermore, these rats exhibited reduced sympathetic nerve activity. The moderate running led to a decrease in periepididymal and retroperitoneal adipose tissue, as well as a reduction in total cholesterol and improved glucose tolerance. Peri-pubertal rats that received combination treatments exhibited lower levels of glucose and insulin during an intraperitoneal glucose tolerance test. The results indicate that 10% fructose supplementation during peripuberty predisposes to metabolic syndrome in adulthood. However, simultaneous moderate-intensity exercise training attenuates these effects and induces positive changes in glycemic homeostasis, lipid metabolism, and autonomic nervous system activity.
REVIEW | doi:10.20944/preprints202307.0959.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Diabetes mellitus; silent pandemic; existential risk; heterogeneity; Insulin gene; health, genetic; anthropogenics; hyperglycemia
Online: 14 July 2023 (09:55:58 CEST)
Life is supported by metabolism, a vital physiological activity. It guarantees enough energy available to power every cellular activity. The primary cellular substrate, glucose, is where the majority of the energy needed by the cell to support all other life activities and the growth of living creatures is derived. The quality of life is greatly impacted by any disease or flaw that alters the metabolism of glucose. There is no known cure for the metabolic illness known as diabetes. As diabetes is so varied, the only effective treatments would be based on precision medicine and a molecular strategy. This review covers a wide range of topics, including the ability to recognize the various forms of diabetes, the anthropogenic and genetic influence of the cause of diabetes, the severity of the various forms of diabetes, its potential existential risk, the disease burden, and clinical methods for diagnosing them. The most recent research goes on to recommend ways to ameliorate the disease, including diet-based management, biotherapies, and other individual lifestyle choices. Futuristic therapy using molecular biology approach was suggested. Recent research found a direct correlation between an individual's lifestyle and the rate of gene mutation in diabetes. There is an existential risk associated with the sickness as the rate of the spread of the disease among population globally is faster than the world's population growth rate. It is possible to think of diabetes as a silent pandemic.
REVIEW | doi:10.20944/preprints202306.1724.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: canine mammary tumors; metabolism, cancer; mitochondria; metabolic reprogramming; glucose; amino acids; lipids
Online: 25 June 2023 (08:00:35 CEST)
Canine mammary tumors (CMTs) are among the most common disease in female dogs and share similarities with human breast cancer, which have placed these animals as a model of study in comparative oncology. Metabolic reprogramming is one of them and is known as a hallmark of carcinogenesis whereby cells undergo adjustments to supply the high bioenergetic and biosynthetic demands of rapidly proliferating cells. However, such alterations are also vulnerabilities that may serve as therapeutic strategies which have been tested mostly in human clinical trials, but poorly explored in CMTs. In this dedicated review, we compilated the metabolic changes described for CMTs emphasizing the metabolism of carbohydrates, amino acids, lipids, and mitochondrial function. We observed here key factors associated with the presence and aggressiveness of CMTs, such as the increase in glucose uptake followed by enhanced anaerobic glycolysis via upregulation of glycolytic enzymes, changes in glutamine catabolism due to overexpression of glutaminases, raise in fatty acid oxidation and distinct effects depending on the lipid saturation, in addition to mitochondrial DNA which is a hotspot for mutations. Therefore, more attention should be paid to this topic given that targeting metabolic fragilities could improve the outcome of CMTs.
REVIEW | doi:10.20944/preprints202306.1390.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Very low density lipoproteins; biogenesis; dyslipidemia
Online: 20 June 2023 (05:24:45 CEST)
The production and secretion of very-low density lipoproteins (VLDL) by hepatocytes has a direct impact on liver fat content as well as the concentration of cholesterol and triglycerides in the circulation and thus affects liver and cardiovascular health, respectively. Importantly, excess caloric intake and lack of physical activity are associated with overproduction of VLDL, hepatic steatosis, and increased levels of atherogenic lipoproteins. Cholesterol as well as triglycerides in remnant particles after VLDL lipolysis are risk factors for atherosclerotic cardiovascular disease (ASCVD) and have garnered increasing attention over the last few decades. To date, however, increased risk of ASCVD is not the only concern when considering today’s cardiometabolic patients, as they often also suffer from hepatic steatosis. This notion highlights the importance of understanding the molecular regulation of VLDL biogenesis. Fortunately, there has been a resurgence of interest in the intracellular assembly, trafficking, degradation, and secretion of VLDL by hepatocytes, that has led to many exciting new molecular insights, the topic of this review. We think that increasing our understanding of the biology of this pathway will help improve the health of the cardiometabolic patient in the long term.
ARTICLE | doi:10.20944/preprints202306.1340.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: CBS deficiency; homocystinuria; homocysteine; simplified diet; methionine portioning; fruits, vegetables
Online: 19 June 2023 (09:45:30 CEST)
The main treatment for pyridoxine nonresponsive cystathionine-β-synthase deficiency is a strict diet. Most centers prescribe low-protein diets based on gram-protein exchanges, and all protein sources are weighed. The purpose of this study is to investigate the effects of a more liberal methionine (Met)-based diet with relaxed consumption of fruits and vegetables on metabolic outcomes and dietary adherence. Ten patients previously on a low-protein diet based on a gram-protein exchange list were enrolled. The natural protein exchange lists were switched to a "Met portion exchange list". Foods containing less than 0.005 g methionine per 100 g of the food were accepted as exchange-free foods. A questionnaire was conducted to assess the effects of the new dietary approach on dietary compliance. The switch to Met portioning had no adverse effects on the control of plasma homocysteine levels in terms of metabolic outcomes. It resulted in a significant reduction in patients' daily betaine dose. The questionnaire results indicated significantly increased dietary compliance, and all patients preferred to continue with this modality. In conclusion, methionine portion-based medical nutrition therapy with relaxed consumption of fruits and vegetables seems to be a good and safe option to achieve good metabolic outcomes and high treatment adherence.
ARTICLE | doi:10.20944/preprints202306.0420.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: diabetes; anaerobic exercise; glut4 gene expression; streptozocin
Online: 6 June 2023 (08:52:56 CEST)
Diabetes is a chronic condition that worsens living conditions and causes significant problems, particularly in the vascular system. Many different treatment options are used to prevent these negative effects of diabetes. The most important of these is changing living conditions and exercising regularly.This study aimed todetermining the impacts of a 6-week anaerobic exercise protocol on the blood glucose levels and Glut4 gene expression in the muscle tissues of streptozocin (STZ)-induced diabetic rats. A total of 45 rats were separate control, sedentary, and exercise groups (n=15 each). The STZ used to induce diabetes in rats was applied once with a single intraperitoneal injection. No diabetes was created in the control group, and no exercise was performed, whereas in the sedentary group, diabetes was induced, and no exercise was applied. It was determined that the Glut4 gene expression in the muscle tissue of the exercise group was importantly increased when compared with the sedentary diabetes group.Glut4 gene is an important gene involved in blood glucose regulation and anaerobic exercise significantly increased the expression level of this gene in our study.
REVIEW | doi:10.20944/preprints202305.1788.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: adipose tissue; corin; hepsin; matriptase-2; type II transmembrane serine protease; thermogenesis
Online: 25 May 2023 (09:51:58 CEST)
Adipose tissue is a crucial organ in energy metabolism and thermoregulation. Adipose tissue phenotype is controlled by various signaling mechanisms under pathophysiological conditions. Type II transmembrane serine proteases (TTSPs) are a group of trypsin-like enzymes anchoring on the cell surface. These proteases act in diverse tissues to regulate physiological processes, such as food digestion, salt-water balance, iron metabolism, epithelial integrity, and auditory nerve development. More recently, several members of the TTSP family, namely, hepsin, matriptase-2, and corin, have been shown to play a role in regulating lipid metabolism, adipose tissue phenotype, and thermogenesis, via direct growth factor activation or indirect hormonal mechanisms. In mice, hepsin deficiency increases adipose browning and protects from high-fat diet-induced hyperglycemia, hyperlipidemia, and obesity. Similarly, matriptase-2 deficiency increases fat lipolysis and reduces obesity and hepatic steatosis in high-fat diet-fed mice. In contrast, corin deficiency increases white adipose weights and cell sizes, suppresses adipocyte browning and thermogenic responses, and causes cold intolerance in mice. These findings highlight an important role of TTSPs in modifying cellular phenotype and function in adipose tissue. In this review, we provide a brief description about TTSPs and discuss recent findings regarding the role of hepsin, matriptase-2, and corin in regulating adipose tissue phenotype, energy metabolism, and thermogenic responses.
ARTICLE | doi:10.20944/preprints202305.1481.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: atherosclerosis; 20(S)-PPT; PCSK9; LDLR; Panax notoginseng
Online: 22 May 2023 (09:02:18 CEST)
Atherosclerosis (AS) is a chronic progressive disease caused by various factors, and causes various cerebrovascular and cardiovascular diseases (CVDs). Reducing the plasma levels of low-density lipoprotein-cholesterol (LDL-C) is the primary goal in preventing and treating AS. Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) plays a crucial role in regulating LDL-C metabolism. Panax notoginseng has potent lipid-reducing effects and protects against CVDs, and its saponins induce vascular dilatation, inhibit thrombus formation, and are used in treating CVDs. However, the anti-AS effect of the secondary metabolite, 20(S) -protopanaxatriol (20(S)-PPT), remains unclear. In this study, the anti-AS effect and molecular mechanism of 20(S)-PPT were investigated in vivo and in vitro by western blotting, real time-polymerase chain reaction (RT-PCR), Enzyme-linked Immunosorbent Assay (ELISA), immunofluorescence staining, and other assays. The in vitro experiments revealed that 20(S)-PPT reduced the levels of PCSK9 in the supernatant of HepG2 cells, upregulated low density lipoprotein receptor (LDLR) protein levels, promoted LDL uptake by HepG2 cells, and reduced PCSK9 mRNA transcription by upregulating the levels of FoxO3 protein and mRNA and decreasing the levels of HNF1α protein and mRNA. The in vivo experiments revealed that 20(S)-PPT upregulated aortic αSMA expression, increased the stability of atherosclerotic plaques, and reduced aortic plaque formation induced by a high-cholesterol fed in ApoE-/- mice (HCF group). Additionally, 20(S)-PPT reduced the aortic expression of CD68, reduced inflammation in the aortic root, and alleviated the hepatic lesions in the HCF group. The study revealed that 20(S)-PPT inhibited LDLR degradation via PCSK9 to alleviate AS.
ARTICLE | doi:10.20944/preprints202305.1240.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: DNP; PNS; Diabetic neuropathic pain; Peripheral pain; Distal symmetric polyneuropathy; diabetic neuropathy; diabetes mellitus; DM; T1D; T2D; DPN; DPNP; Diabetic peripheral neuropathic pain; Diabetic peripheral neuropathy
Online: 17 May 2023 (10:55:11 CEST)
Diabetes mellitus is the global epidemic of the 21st century affecting millions worldwide. Usually, patients with long-standing type one diabetes (T1D) or type two diabetes (T2D) tend to develop complications. A common complication is the degenerative of the nerves in the peripheral nervous system (PNS). This complication is known as distal symmetric polyneuropathy or just diabetic neuropathy. A variety of symptoms can be experienced with this complication, including pain and numbness. One characterization of this complication is the sensory loss that begins in the lower extremities and spreads substantially to the fingers and hand. There is no clear mechanism for how this happens in diabetic patients. Studies have shown that nerve damage from this complication can be due to oxidative stress, sorbitol accumulation, and advanced glycation end products (AGEs). Some of the most common medications being provided for diabetic neuropathic pain (DNP) include amitriptyline and desipramine. Other medications also include gabapentin and duloxetine. There are noninvasive options, such as acupuncture, that could provide beneficial data if rigorous studies are conducted. A number of new studies are being completed to identify more effective treatments for this condition.
ARTICLE | doi:10.20944/preprints202305.0685.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Kidney cancer; Metabolic syndrome; Age; Young adults
Online: 10 May 2023 (04:38:19 CEST)
The aim of this study was to determine the association of metabolic syndrome (MetS) with kidney cancer and the impact of age and gender on such association. Using Korean National Health Insurance Service database, 9,932,670 subjects who had check-up in 2009 were followed up until the diagnosis of kidney cancer or death or until 2019. Kidney cancer was significantly associated with MetS (HR 1.56). This association was higher in the younger age group (HR: 1.82, 1.5, and 1.37 in 20-39 years, 40-64 years, and ≥65 years, respectively). In terms of the association of kidney cancer with obesity and central obesity, young-aged males showed higher HR for kidney cancer than old-aged ones (HR of obesity: 1.96, 1.52, and 1.25; HR of central obesity: 1.94, 1.53, and 1.3 in 20-39 years, 40-64 years, ≥65 years, respectively), while young-aged females showed lower HR. Kidney cancer was associated with obesity and MetS. The association was higher in younger aged population than in older ones. Regarding gender, MetS, obesity, and central obesity showed higher associations with kidney cancer in younger aged male population, while there was no significant difference in such association according to age in females.
REVIEW | doi:10.20944/preprints202305.0130.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Obesity; hypothalamus; appetite; glucose homeostasis; weight-loss drugs; AGRP; POMC; NTS; incretins
Online: 3 May 2023 (10:22:49 CEST)
Keywords: Obesity; hypothalamus; appetite; glucose homeostasis; weight-loss drugs; AGRP; POMC; NTS; incretins.
REVIEW | doi:10.20944/preprints202305.0041.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: endothelial dysfunction; chronic kidney disease; heart failure; sodium-glucose cotransporter 2 inhibitors
Online: 2 May 2023 (02:18:51 CEST)
Beyond plasma glucose-lowering in patients with type 2 diabetes, sodium- glucose cotransporter 2 inhibitors (SGLT2i) significantly reduced the hospitalization for heart failure (HF) and retarded the progression of chronic kidney disease (CKD). Endothelial dysfunction is not only involved in the development and progression of cardiovascular disease (CVD), and is also associated with the progression of CKD. In patients with type 2 diabetes, hyperglycemia, insulin resistance, hyperinsulinemia and dyslipidemia induce the development of endothelial dysfunction. SGLT2i have shown an improvement in endothelial dysfunction, as assessed by flow-mediated vasodila-tion, in individuals at high risk for CVD. Along with an improvement of endothelial dysfunction, SGLT2i showed improvements in oxidative stress, inflammation, mitochondrial dysfunction, glucotoxicity such as advanced glycation end products signaling and nitric oxide bioavailability. The improvements in endothelial dysfunc-tion and such endothelium-derived factors may play an important role in preventing the development of coronary artery disease, coronary microvascular dysfunction and diabetic cardiomyopathy which cause HF and in retarding CKD. The suppression of the development of HF and the progression of CKD achieved by SGLT2i might have been largely induced by the improvement of vascular endothelial function by SGLT2i.
REVIEW | doi:10.20944/preprints202304.1189.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Functional role of GABA in insulin secretion stimulation; GABA metabolism in pancreatic islets; GABA and insulin secretion; interaction of glucose and GABA metabolism in pancreatic islets; GABA shunt
Online: 29 April 2023 (02:51:09 CEST)
The stimulus-secretion coupling of glucose-induced release is generally attributed to the metabolism of the hexose in the β-cells in the glycolytic pathway and the citric acid cycle. Glucose metabolism generates an increased cytosolic concentration of ATP and of the ATP/ADP ratio that closes the ATP-dependent K+-channel at the plasma membrane by the interaction of ATP with the regulatory Kir6.2 channel subunit The resultant depolarization of the β-cells opens voltage-dependent Ca2+-channels at the plasma membrane that allow an increase of the cytosolic cation concentration that triggers the exocytosis of insulin secretory granules. The resultant secretory response evolves in time as a biphasic secretion with a first and transient peak of approximately 10 minutes duration followed by a sustained phase of secretion lasting as long as the stimulus. Whereas the first transient peak can be reproduced by a simple depolarization of β-cells with high extracellular KCl maintaining the KATP-channels open with diazoxide, the sustained phase is agreed to depend on the participation of some metabolic signal that remains to be determined Our group has been investigating for several years the participation of β-cell GABA metabolism, together with that of glucose (the β-cell “specific” nutrient secretagogue) and some other “metabolic” secretagogues (branched-chain alpha-ketoacids and a mixture of L-Leucine + L-glutamine, at supraphysiological concentrations) in their mechanism of stimulation of insulin secretion. All three types of stimuli promote the flux in the GABA shunt of rat islets by different metabolic pathways that end in the production of α-ketoglutarate. This citric acid cycle intermediary is preferentially derived to the GABA shunt instead of its continuous oxidation in the citric acid cycle. Islet content of GABA is significantly suppressed by all the stimuli and blocking the GABA shunt with gabaculine, or ϒ-vinyl-GABA (GABAT inhibitors), diminish the insulin secretory responses as well as total ATP and the ATP/ADP ratio. It is concluded that GABA metabolism is increased in parallel to glucose metabolism and is significantly contributing to the magnitude of the insulin secretory response. Its possible implication in β-cells degradation in type-2 (perhaps also in type 1) diabetes is suggested.
ARTICLE | doi:10.20944/preprints202304.1133.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Non-alcoholic fatty liver disease; magnetic resonance imaging; amino acids; metabolomics; inflammation
Online: 28 April 2023 (07:20:14 CEST)
Background & Aims: Non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) have been linked to changes in amino acid (ΑΑ) levels. The current observational study sought to investigate the relationship between plasma AA concentrations in a NAFLD population and MRI parameters reflecting inflammation and fibrosis, inflammatory and oxidative stress markers, and disease-related anthropometric and biochemical indicators. Approach & Results: Plasma AA levels were quantified with liquid chromatography in 97 NAFLD patients from the MAST4HEALTH study. Medical, anthropometric and lifestyle characteristics were collected and biochemical parameters, as well as inflammatory and oxidative stress biomarkers were measured. In total, males and subjects with higher MRI-proton density fat fraction (MRI-PDFF) exhibited higher plasma AA levels compared to females and subjects with lower PDFF respectively. Several associations of AAs with disease related markers were revealed, with the more prominent ones being those of aromatic amino acids with log-PDFF (beta: 1.190E-02, p-Value: 0.001) and log-ALT (beta: 7.55E-03, p-Value: 0.001), of branched amino acids with log-insulin (beta: 1.97E-03, p-Value: 1.16E-04) and of ethanolamine (beta: 0.036, p-Value: 3.65E-04) and L-ornithine (beta: 5.4E-04, p-Value: 0.021) with log-total antioxidant status (TAS). Conclusions: Plasma AA levels varied according to sex, BMI, and several MRI clinical factors. Furthermore, significant relationships were demonstrated between AA and several disease indicators, such as MRI parameters, biochemical and oxidative stress indices, showing the potential utility of AAs as diagnostic dis-ease-related indicators activity.
REVIEW | doi:10.20944/preprints202304.1102.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Maternal obesity; placenta; environmental adaptation; sex specificities; reproduction
Online: 28 April 2023 (04:06:35 CEST)
Maternal obesity is increasingly prevalent and is associated with elevated morbidity and mortality rates in both mothers and children. As the interface between the mother and fetus, the placenta has mediates the impact of the maternal environment on fetal development. Most of the literature data on the effects of maternal obesity on placental functions do not exclude potential confounding factors like metabolic diseases (e.g. gestational diabetes). Moreover, it is now clear that the placental response to maternal environment depends on the fetal sex. In this context, we reviewed how maternal obesity (in the absence of gestational diabetes) affects the human placenta in terms of (i) endocrine function, (ii) morphological characteristics, (iii) nutrient exchanges and metabolism, (iv) inflammatory/immune status, (v) oxidative stress, and (vi) transcriptome, with a focus on fetal sex specificities. A better understanding of sex-specific placental responses to maternal obesity is crucial for improving pregnancy outcomes and the health of mothers and children.
ARTICLE | doi:10.20944/preprints202304.0602.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Thyroid hormones; thyroid hormone transporters; MCT8; OATP1C1; human; monkey; basal ganglia; motor thalamus; MSN cells; nucleus basalis of Meynert
Online: 20 April 2023 (03:25:07 CEST)
Monocarboxylate transporter 8 (MCT8) and organic anion-transporting polypeptide 1C1 (OATP1C1) are thyroid hormones (TH) transmembrane transporters relevant for the availability of TH in neural cells, crucial for their proper development and function. Mutations in MCT8 or OATP1C1 result in severe disorders with dramatic movement disability related to alterations in basal ganglia motor circuits. Mapping the expression of MCT8/OATP1C1 in those circuits is necessary to explain their involvement in motor control. We studied the distribution of both transporters in the neuronal subpopulations that configure the direct and indirect basal ganglia motor circuits using immunohistochemistry and double/multiple labeling immunofluorescence for TH transporters and neuronal biomarkers. We found their expression in the medium-sized spiny neurons of the striatum (the receptor neurons of the corticostriatal pathway), and in various types of its local microcircuitry interneurons, including the cholinergic. We also demonstrate the presence of both transporters in projection neurons of intrinsic and output nuclei of the basal ganglia, motor thalamus and nucleus basalis of Meynert, suggesting an important role of MCT8/OATP1C1 for modulating the motor system. Our findings suggest that a lack of function of these transporters in the basal ganglia circuits would significantly impact motor system modulation, leading to clinically severe movement impairment.
ARTICLE | doi:10.20944/preprints202304.0208.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Obesity, Succinate, Glucose Tolerance, Lipolysis, Lipogenesis, High-Fat Diet
Online: 11 April 2023 (08:03:02 CEST)
The number of obese people worldwide is rising dramatically, with 51% of the global population expected to be obese or overweight by 2035. And it is usually involved in a variety of chronic diseases, including diabetes, hypertension, cardiovascular and cerebrovascular diseases. In the process of obesity, adipose tissue expands indefinitely, which induces metabolic dysfunction. Here, we confirm the role of succinate in the intervention of obesity. Through adding succinate to drinking water, high-fat diet induced obese mice were associated with the lower fat mass, and improved glucose tolerance and energy expenditure. These metabolic changes are accompanied by increased expression of lipolysis genes and decreased lipogenesis genes, especially in subcutaneous adipose tissue. In summary, supplement of succinate improves lipid deposition and metabolic health in obese mice.
ARTICLE | doi:10.20944/preprints202212.0045.v8
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: emergent dimensionality; imaginary dimensions; Planck units; fine-structure constant; black holes; neutron stars; white dwarfs; complex energy; complex force; Buchdahl's theorem; photon sphere; holographic principle; mathematical physics
Online: 20 March 2023 (09:55:20 CET)
Imaginary dimensions in physics require an imaginary set of base Planck units and some negative parameter cn corresponding to the speed of light in vacuum c. Fresnel coefficients for the normal incidence of electromagnetic radiation on monolayer graphene introduce the second, negative fine-structure constant α2−1≈−140.178 as a fundamental constant of nature and this constant introduces these imaginary base Planck units along with this negative parameter cn≈−3.06×108 [m/s]. Neutron stars and white dwarfs, considered as objects emitting perfect black-body radiation, are conjectured to possess energy exceeding their mass-energy equivalence ratios, wherein the imaginary parts of two complex energies inaccessible for direct observation make storing excess of these energies possible. With this assumption, black holes are fundamentally uncharged; charged micro neutron stars and white dwarfs with masses lower than 5.7275×10−10 [kg] cannot be observed; and the radii of white dwarfs' cores are limited to RWD<6.7933 GMWD/c2. A black-body object is in the equilibrium of complex energies of mass, charge, and electromagnetic radiation if its radius Req≈2.7665 GMBBO/c2.
REVIEW | doi:10.20944/preprints202303.0211.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: metabolic syndrome; glucose tolerance; pathophysiology; hyperglycemia; diet
Online: 13 March 2023 (03:58:55 CET)
The metabolic syndrome, first introduced by Hermann Haller in 1975, was sometimes also known as insulin resistance syndrome, syndrome X, and plurimetabolic syndrome. In 1989 it was rechristened by Kaplan as "Deadly Quartet" based on a consolidation of central obesity, impaired glucose tolerance, dyslipidemia, and systemic hypertension. Metabolic syndrome is positively associated with a pro-inflammatory and pro-thrombotic state, attributed to increased pro-thrombotic and inflammatory markers activity. Moreover, Metabolic syndrome is frequently associated with increased atherosclerotic cardiovascular disease, impaired glucose tolerance, hyperuricemia, obstructive sleep apnea, and chronic kidney disease. Despite concerted endeavors worldwide, the complexity of the pathophysiology of metabolic syndrome is still not clearly understood. Currently, therapeutic possibilities are confined to individual therapy of hyperglycemia, hypertension, hypertriglyceridemia, hyperuricemia, regular physical exercise, and a restricted diet.
REVIEW | doi:10.20944/preprints202303.0004.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: gut microbiota; metabolomics; metagenomics; liver fat; NAFLD; diet; metabolic pathways
Online: 1 March 2023 (02:40:16 CET)
The frequency of non-alcoholic fatty liver disease (NAFLD) has exacerbated setting diagnostic challenges, which increases the need for reliable non-invasive diagnostic tools. Due to the importance of gut-liver axis in the progression of NAFLD, studies try to reveal microbial signatures in NAFLD, evaluate them as diagnostic biomarkers and to predict the disease progression. The gut microbiome affects human physiology by processing the ingested food to bioactive metabolites. These molecules can penetrate the portal vein and the liver to promote or prevent hepatic fat accumulation. Here findings of human fecal metagenomic and metabolomic studies in relation to NAFLD are reviewed. The studies present mostly distinct and even contradictory findings on microbial metabolites and functional genes in NAFLD. The most reproducing microbial biomarkers are increased lipopolysaccharides and peptidoglycan biosynthesis, enhanced degradation of lysine, increased levels of branched chain amino acids as well as altered lipid and carbohydrate metabolism. Among other causes, the discrepancies between the studies may be related to the obesity status of the patients and severity of NAFLD. In none of the studies except one, diet was considered, though it is an important factor driving the gut microbiota metabolism. The future studies should consider diet in the analyses.
REVIEW | doi:10.20944/preprints202302.0482.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Rats; Biological research; Environmental conditions; Stress; Handling
Online: 28 February 2023 (02:04:49 CET)
Rat is one of the most commonly used model animals for biological research. The organs and systems of human being are somewhat similar to that of rat in structure as well as functions, making it a valuable choice for research experimentation in biological sciences. A number of studies have been conducted to evaluate the potential risks and toxicity of different elements on the physiology and histology of rats. There is need to address certain environmental factors affecting rats condition during experimentation. Reproduction along with its pathologies is under investigation on larger scale throughout the world, being central for the existence of a species. These studies focus on the major factors that influence reproductive function. Review of literature clearly indicated the unwanted consequences of over nutrition, malnutrition, high or low temperature, non-enriched housing, improper handling, intense or poor light exposure and environmental pollution on histology and hormonal profile of reproductive system of rats.
REVIEW | doi:10.20944/preprints202302.0223.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Obesity; Hyperpalatability; Adipose tissue; Hormonal imbalance
Online: 14 February 2023 (02:17:02 CET)
Obesity is characterized by surplus buildup of body lipids primarily in adipose tissue. Prevalence and incidence of obesity are ascending persistently at an alarming rate. Unusual eating behaviors like compulsion to eat (food addiction) and excessive consumption are the premier contributors to obesity. Both are under influence of a variety of stimuli, mainly being stress, emotions, dietary restrictions, sweetness, hyperpalatability, neural pathways, hormonal imbalance and genetics. This review summarizes the potential driving factors behind overeating and food addiction for understanding and exploring obesity linked novel agents and processes as an endeavor to advance treatment approaches. Obesity has been studied extensively throughout the world due to high incidence and association with several metabolic disorders including cardiovascular disorders. The food addition has considered one of potential key factor of obesity and excessive weight gain. Sedentary life style and availability of food also induce obesity.
REVIEW | doi:10.20944/preprints202302.0015.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: movement disorders; mitochondria; energy metabolism; synaptic plasticity; basal ganglia; calcium
Online: 1 February 2023 (11:53:47 CET)
Much evidence suggests a correlation between degeneration and mitochondrial impairment. Typical cases of degeneration can also be observed in physiological phenomena (aging) as well as in neurological neurodegenerative diseases and cancer. All these pathologies have as a common denominator the dyshomeostasis of mitochondrial bioenergy. Even neurodegenerative diseases show a bioenergetics imbalance in their pathogenesis or progression. Huntington's chorea and Parkinson's disease are both neurodegenerative diseases, but while Huntington's disease is a genetic, and progressive disease with early manifestation and severe penetrance, Parkinson's disease is a pathology with a multifactorial aspect. Indeed, there are different types of Parkinson/Parkinsonism. Many forms are early onset diseases linked to gene mutation, others can appear in young adults and senescent only post-injury, and a final group is idiopathic. Huntington's was defined as a hyperkinetic disorder, while Parkinson's is a hypokinetic disorder; but in the middle, there are a lot of similarities as well as neuronal excitability, the loss of striatal function, psychiatric comorbidity, etc. In the review, we would embrace the theories that both diseases start and develop in light of mitochondrial dysfunction. These dysfunctions act on energy metabolism and reduce the vitality of neurons in many different brain areas.
ARTICLE | doi:10.20944/preprints202212.0578.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Type 1 diabetes; mental-health; COVID-19; adolescents; qualitative research; narratives; NVivo
Online: 30 December 2022 (09:16:21 CET)
Background: The global prevalence of anxiety and depressive symptoms in adolescents has increased considerably during the COVID-19 pandemic. Mental health problems may compromise glycemic control in young people with type 1 diabetes; however, evidence of improved glycemic control in adolescents with T1D appeared early during the pandemic. This qualitative study aimed to provide a more in-depth understanding of how the COVID-19 pandemic affected adolescents with type 1 diabetes routines, experiences, T1D management, behaviors, and mental health. Methods: 24 adolescents, aged 15-18 years, with DM1, joined the discussion of focus groups in the context of the summer camp for diabetes. Word frequency and thematic analysis were conducted on adolescents’ narratives. Results: The word Frequency Analysis identified 'friends', 'family', and 'home' as the most frequent terms. Seven themes were identified: (1) COVID-19 and T1D; (2) emotional reactions to the COVID-19 pandemic; (3) changes in daily life; (4) feelings of loss; (5) coping with the COVID-19 pandemic; (6) the COVID-19 pandemic as an opportunity; (7) return to (new) normality. Conclusions The COVID-19 pandemic may have represented a more stressful condition for adolescents with DM1, facing additional challenges compared to their healthy peers. The results offer directions to the diabetes care team for a customized intervention while the consequences of the pandemic on adolescents’ health continue.
ARTICLE | doi:10.20944/preprints202212.0526.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: hyperglycemia; dyslipidemia; oxidative stress; Gymnema Sylvestre
Online: 28 December 2022 (03:31:07 CET)
The effect of Gymnema Sylvestre supplementation on beta cell and hepatic activity was explored in an alloxan-induced hyperglycemic rat model. Adult rats were made hyperglycemic via a single inj. (i.p) of Alloxan (120mg/kg b.w). Gymnema Sylvestre was supplemented @250mg/kg and 500mg/kg b.w. Blood glucose levels were constantly monitored. After 21 days, rats were euthanized, and blood and tissues (pancreas and liver) were collected for biochemical, expression, and histological analysis. One-way ANOVA was used to compare the means of different treatment groups. Gymnema Sylvestre significantly reduced blood glucose levels with a subsequent increase in plasma insulin levels in a dosage-dependent manner. Total oxidant status (TOS), malondialdehyde, LDL, VLDL, ALT, AST, triglyceride, total cholesterol, total protein, C-reactive protein, and cortisol levels were reduced significantly in alloxan-treated hyperglycemic rats supplemented with Gymnema Sylvestre as compared to control. Significantly raised paraoxonase, arylesterase, albumin, and HDL levels were also observed in Gymnema Sylvestre supplemented hyperglycemic rats. Increased mRNA expression of Ins-1, Ins-2, Gck, Pdx1, Mafa, and Pax6 were observed, while decreased expression of Cat, Sod1, Nrf2, and NF-kB was observed in the pancreas. Whereas increased mRNA expression of Gck, Irs1, SREBP1c, and Foxk1 and decreased expression of Irs2, ChREBP, Foxo1, and FoxA2 were observed in the liver. The current study indicates the potent effect of Gymnema Sylvestre on the transcription modulation of the insulin gene in the alloxan-induced hyperglycemic rat model. Enhanced plasma insulin levels further help to improve hyperglycemia-induced dyslipidemia through transcriptional modulation of hepatocytes.
ARTICLE | doi:10.20944/preprints202212.0213.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Chagas Disease; Laron Syndrome; Growth Hormone; Trypanosoma cruzi; GHR-/- mice; bGH mice
Online: 13 December 2022 (01:15:59 CET)
Chagas disease (CD) is one of the most devasting parasitic diseases in the Americas affecting 7 to 8 million people worldwide. In vitro and in vivo experiments have demonstrated that decreased growth hormone (GH) serum levels occur as CD progresses. Interestingly, inactivating mutations in the GH receptor in humans induce Laron syndrome (LS), a clinical entity characterized by increased GH and decreased insulin growth factor-1 (IGF-1) serum levels. The largest cohort of LS subjects lives in the southern provinces of Ecuador. Remarkably, CD prevalence in these individuals is diminished despite living in highly endemic areas. In the current ex vivo study, we employed serum from GHR -/- mice, also known as LS mice (a model of GH resistance with high GH and low IGF-1 levels), and serum from bovine GH (bGH) transgenic mice (high GH and IGF-1), to test the effect on T. cruzi infection. We infected mouse fibroblast L-cells treated with serum from each type of mouse with metacyclic trypomastigotes from Trypanosoma cruzi (etiological CD infectious agent). Treatment with GHR-/- serum (LS mice) significantly decreased infection by 28% compared to 48% seen in control wild-type mouse serum (WT). Treatment with bGH mouse serum significantly decreased infection by only 41% compared to 54% from WT controls. Our results suggest that high GH and low IGF-1 in blood circulation, as typically seen in LS individuals, confers partial protection against T. cruzi infection.
ARTICLE | doi:10.20944/preprints202212.0194.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Caveolin 1; Obesity; Adipose tissue; Metabolic inflammation; Cytokines; TNF-α; NF-κB
Online: 12 December 2022 (06:02:18 CET)
Obesity is characterized by chronic low-grade inflammation. Caveolin-1 (CAV1), a structural and functional protein found in adipose tissues (AT), is augmented in obese individuals. We aimed to define the inflammatory mediators that influence CAV1 gene regulation and associated mechanism in obesity. Using subcutaneous AT from 27 (7 lean/20 obese) normoglycemic individuals, in vitro human adipocyte models, and in vivo mice models, we found elevated CAV1 expression in obese AT and a positive correlation between the gene expression of CAV1, tumor necrosis factor alpha (TNF-α), and the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB). CAV1 gene expression was associated with that of proinflammatory cytokines/chemokines, and their cognate receptor (r ≥ 0.447, p ≤ 0.030) but not with anti-inflammatory markers. CAV1 expression was correlated with CD163, indicating a prospective role for CAV1 in adipose inflammatory microenvironment. Unlike wild-type animals, mice lacking TNF-α exhibited reduced levels of CAV1 mRNA/proteins, which were elevated by administering exogenous TNF-α. Mechanistically, TNF-α induces CAV1 gene transcription by mediating NF-kB binding to its two regulatory elements located in the CAV1 proximal regulatory region. The interplay between CAV1 and TNF-α signaling pathway is interesting and has potential as a target for therapeutic interventions in obesity and metabolic syndromes.
ARTICLE | doi:10.20944/preprints202211.0512.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Thyroid hormones; Mixture; Neurodevelopment; Xenopus laevis; EDC
Online: 28 November 2022 (10:44:37 CET)
Thyroid hormones (THs) are essential for normal brain development, influencing neural cell differentiation, migration, and synaptogenesis. Multiple endocrine-disrupting chemicals (EDCs) are found in the environment, raising concern for their potential effects on thyroid hormone signaling and the consequences on neurodevelopment and behavior. While most research on EDCs investigates the effects of individual chemicals, human health may be adversely affected by a mixture of chemicals. Many compounds belonging to a wide range of chemical classes have been identified as EDCs, notably those affecting thyroid hormone signaling. We hypothesized that embryonic exposure to a mixture of chemicals (containing phenols, phthalates, pesticides, heavy metals, perfluorinated -, polychlorinated, and polybrominated compound) commonly found in the human amniotic fluid could lead to altered brain development to assess its effect on thyroid hormone signaling and neurodevelopment in an amphibian model (Xenopus laevis), highly sensitive to thyroid disruption. Newly hatched tadpoles were exposed for eight days to either TH (thyroxine, T4 10nM) or the amniotic mixture (1x concentration) and gene expression was analyzed in the brains of exposed tadpoles using both RT-qPCR and RNA sequencing. Results indicate that whilst some overlap on TH-dependent genes exist, T4 and the mixture have different gene signatures. Immunohistochemistry showed increased proliferation in the brains of T4-treated animals whereas no difference was observed for the amniotic mixture. Further, we demonstrated diminished tadpoles’ motility in response to T4 and mixture exposure. As the individual chemicals composing the mixture are considered safe, these results highlight the importance of examining the effects of mixtures to improve risk assessment
ARTICLE | doi:10.20944/preprints202211.0403.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: cardiovascular diseases; physical activity; physical exercise; sedentarism; quality of life
Online: 22 November 2022 (03:39:54 CET)
Obesity is related to the establishment of chronic inflammation and metabolic diseases, but it can be positively influenced by the regular practice of physical activity. The study aimed to compare the anthropometric, metabolic, and inflammatory parameters of physically active Military Police Officers (MPOs) with those who are less physically active. Sixty male MPOs, low activity (n=28) and physically active (n=32) participated. The following parameters were measured: plasma cytokine levels, C-reactive protein (CRP) levels, circulating glucose triglyceride (TAG) and high-density lipoprotein cholesterol (HDL-C) levels, and plasma glutamic oxalacetate transaminase (GOT), glutamic-pyruvate transaminase (GPT), and gamma-glutamyl transferase (GGT) activities. The physically active group presented lower body fat and reduced TAG and IL-8 levels compared to the low activity group. Moreover, a negative correlation between SPE and SBP, DBP, BPM was detected for the physically active group (p<0.05) but not in the low activity group. Furthermore, the physically active group's work time (WT) values were not correlated with the important metabolic markers SBP, DBP, BPM, GLU, TAG (p>0.05) but could be in the low activity group (p<0.05). These findings highlight the fundamental protective role of physical activity in controlling body composition, subclinical inflammation, and cardiovascular risk in MPOs.
BRIEF REPORT | doi:10.20944/preprints202211.0168.v2
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: autoantibodies; type I interferon; interferon-ω; interferon-α2; multiplex assay; protein microarray; cell-based autoantibody assay; ELISA
Online: 22 November 2022 (02:20:41 CET)
Autoantibodies against type 1 interferons (IFN-I) are highly specific marker for type 1 autoimmune polyglandular syndrome (APS-1). Moreover, determination of antibodies to IFN-ω and IFN-α2 allows a short-term diagnosis in patients with isolated and atypical forms of APS-1. In this study, a comparison of three different methods, namely, multiplex microarray-based, cell-based and enzyme-linked immunosorbent assays for detection of antibodies against omega-interferon and alpha2-interferon was carried out. A total of 206 serum samples from adult patients with APS-1, APS-2, isolated autoimmune endocrine pathologies, non-autoimmune endocrine disorders and healthy individuals were analyzed. In the APS-1 patient cohort (n=18), there was good agreement between the results of anti- IFN-I antibody tests performed by three methods, with 100% specificity and sensitivity for microarray-based assay. Although only the cell-based assay can determine the neutralizing activity of autoantibodies, the microarray-based assay can serve as a highly specific and sensitive screening test to identify anti- IFN-I antibody positive patients.
REVIEW | doi:10.20944/preprints202211.0263.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Thin Endometrium; stem cells; Granulocyte colony-stimulating factor; Acupuncture treatment; Physical therapy
Online: 15 November 2022 (01:12:22 CET)
The endometrium is an important part of the uterus. The human endometrium is a complex and dynamic tissue that goes through phases of growth and regression during any menstrual cycle. A thin endometrium might be relevant to a lower rate of implantation as well as a higher rate of miscarriage. Several treatments have been developed for thin endometrium, such as granulocyte colony-stimulating factor, stem cell therapy, acupuncture and physical therapy, among others. These approaches have been shown to have effects on the endometrium related to reducing the area of fibrosis, increasing the number of glands, promoting angiogenesis, increasing endometrial thickness, improving tissue structure, and increasing pregnancy rates. This review summarizes the key role of these treatments in repairing thin endometrium and improving clinical pregnancy rates
REVIEW | doi:10.20944/preprints202210.0065.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: preeclampsia; neonatal outcome; vitamin D; 25(OH)D, 1,25(OH)2D; diabetes; pregnancy complication; vitamin D deficiency; vitamin D supplementation
Online: 6 October 2022 (12:16:11 CEST)
Vitamin D plays an essential role in embryogenesis and the course of intra- and postnatal periods and is crucially involved in the functioning of the mother-placenta-fetus system. Low quantity of Vitamin D during pregnancy can lead to the elevated risk for preeclampsia occurence. Despite the numerous studies on the association of Vitamin D deficiency and preeclampsia development, the current research on this theme is contradictory. In this review we summarize and analyze study data on the effects of vitamin D deficiency and supplementation on pregnancy, labor, fetal and neonatal outcomes.
ARTICLE | doi:10.20944/preprints202209.0481.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: diabetes status; prediabetes; type 2 diabetes; breast cancer; NHANES
Online: 30 September 2022 (08:40:03 CEST)
Abstract Objectives: The purpose of this study was to determine whether breast cancer and diabetes status are related in adult Americans. Methods: We conducted a cross-sectional study of 7,599 individuals from the National Health and Nutrition Examination Survey (NHANES). Diabetes was classified as type 2 diabetes and pre-diabetes. Both prediabetes and diabetes were diagnosed according to ADA 2014 guidelines. Multiple logistic regression analysis was used to explore the relationship between diabetes status and breast cancer. Results: We found that prediabetes (OR = 0. 60, 95% CI:(0. 40, 0. 88), P= 0. 009613) and non-diabetes (OR = 0.05.3,95% CI: (0.34, 0.83), P = 0. 006014) were associated with a reduced risk of breast cancer in comparison to Type 2 diabetes (literature). Prediabetes in non-Hispanic blacks was associated with a reduced risk of breast cancer (OR=0. 55,95%CI:0. 40-0. 75, P<0. 001). Using two segmented linear regression models to fit the relationship between BMI and breast cancer, we found that the relationship between BMI and breast cancer was nonlinear, but there was a threshold effect. The threshold effect analysis found that BMI affcted breast cancer at an inflection point 26. 3 Kg/m2. Adjusted OR (95% CI) on both sides of the turning point was 1. 0799 ( 1. 0029, 1. 1629 ) and 0. 9873 ( 0. 9638, 1. 0115 ), respectively. Conclusions: Diabetes status is associated with the risk of breast cancer development. Moreover, the risk of developing breast cancer steadily increased from nondiabetes to prediabetes and type 2 diabetes. In addition, the prevalence of breast cancer showed a gradual increase withincreasing BMI up to 26. 3 Kg/m2 with the highest prevalence of breast cancer. There was an inverse U-shaped relationship between BMI and the breast cancer prevalence.
ARTICLE | doi:10.20944/preprints202209.0180.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: endometriosis; multi-omics; expression profile; menstrual blood; MenSCs
Online: 13 September 2022 (12:32:56 CEST)
Given the importance of menstrual blood in the pathogenesis of endometriosis and the multifunctional roles of menstrual mesenchymal stem cells (MenSCs) in regenerative medicine, this issue has gained prominence in the scientific community. Moreover, recent reviews highlight how robust the integrated assessment of omics data is for endometriosis. To our knowledge, no study has applied the multi-omics approaches to endometriosis MenSCs. It is a case-control study at a university-affiliated hospital. MenSCs transcriptome and proteome data were obtained by RNA-seq and UHPLC-MS/MS detection. Among the differentially expressed proteins and genes, we emphasize ATF3, ID1, ID3, FOSB, SNAI1, NR4A1, EGR1, LAMC3, and ZFP36 genes and MT2A, TYMP, COL1A1, COL6A2, and NID2 proteins that were already reported in the endometriosis. Our functional enrichment analysis reveals integrated modulating signaling pathways such as epithelial-mesenchymal transition (↑) and PI3K signaling via AKT to mTORC1 (↓in proteome), mTORC1 signaling, TGF beta signaling, TNFA signaling via NFkB, and response to hypoxia via HIF1A targets (↑in transcriptome). Our findings highlight primary changes in the endometriosis MenSCs, suggesting that the chronic inflammatory endometrial microenvironment can modulate these cells, providing opportunities for endometriosis etiopathogenesis. Moreover, they identify challenges for future research leveraging knowledge for regenerative and precision medicine in endometriosis.
REVIEW | doi:10.20944/preprints202209.0146.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: central obesity; waist circumference; physical activity; basal metabolic rate; body composition
Online: 12 September 2022 (11:36:37 CEST)
This article aims to systematically review the available evidence concerning the relationship between basal metabolism (BM), body composition (BC), and physical activity (PA) with central obesity. The search strategy was carried out using Web of Science, PubMed, Google Scholar, and SciELO following the PRISMA guidelines. The STROBE checklist and the Jadad scale for quality assessment were also used. A total of 1382 studies were initially identified being 25 publications eligible for systematic data extraction. Individual studies showed that adults with waist circumference (WC) above 88 cm in women and above 102 in men had a higher risk of metabolic alterations related to high absolute energy expenditure and less maximum oxygen consumption (VO2 max). Participants with central obesity presented a high percentage of body fat (BF%) between 30.6% and 41.6%. Most of the PA intervention studies reported reductions in WC between 1.3 and 5.8 cm. In conclusion, there is a direct relationship between the components of BM with central obesity and a direct association between central obesity and BF%. PA is a protective factor that needs to be promoted to reduce WC and control central obesity as a public health problem. PROSPERO ID registration: CRD42021232917.
ARTICLE | doi:10.20944/preprints202209.0019.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: enzyme-constrained model; Corynebacterium glutamicum; metabolic engineering
Online: 1 September 2022 (09:54:55 CEST)
Genome-scale metabolic model (GEM) is a powerful tool for interpreting and predicting cellular phenotypes under various environmental and genetic perturbations. However, GEM only consid-ers stoichiometric constraints, and the simulated growth and product yield values will show a monotonic linear increase with increasing substrate uptake rate, which deviates from the experi-mentally measured values. Recently, the integration of enzymatic constraints into stoichiometry-based GEMs was proven to be effective in making novel discoveries and predicting new engineer-ing targets. Here we present the first genome-scale enzyme-constrained model (eciCW773) for Corynebacterium glutamicum reconstructed by integrating enzyme kinetic data from various sources using ECMpy workflow based on the high-quality GEM of C. glutamicum (obtained by modifying the iCW773 model). The enzyme-constrained model improved the prediction of pheno-types and simulated overflow metabolism, while also recapitulating the trade-off between biomass yield and enzyme usage efficiency. Finally, we used eciCW773 to identify several gene modifica-tion targets for L-lysine production, most of which agree with previously reported genes. This study shows that incorporating enzyme kinetic information into the GEM enhances the cellular phenotypes prediction of C. glutamicum, which can help identify key enzymes and thus provide reliable guidance for metabolic engineering.
ARTICLE | doi:10.20944/preprints202208.0436.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: tryptophan metabolites; microbiome; obesity; enzymatic landscape
Online: 25 August 2022 (13:21:39 CEST)
Indole and indole-3-lactate are known dominant microbial tryptophan catabolites (MICT). In obesity, the fecal indole concentration corresponds to the normal one, and that of indole-3-lactate significantly decreases along with other MICT, while it increases in blood plasma. During the analysis of the «enzymatic landscape» of the intestinal microbiota we find an almost twofold increase in the correlation between the concentrations of fecal MICT and the «enzymatic landscape», with indole-3-lactate having the closest relationships with the “enzymatic landscape” of all MICT. Here, we report statistically significant correlations of indole-3-lactate and the gut microbial enzymes for fructose, amino sugars, nucleotides, polyamines metabolism, and sulfoglycolysis. We also demonstrate that indole-3-lactate producing microbiota representatives increase three-fold in obesity. The phenotype of the microbiotic population is thus represented by completely different genera and species of microorganisms in obese individuals compared to healthy donors.
ARTICLE | doi:10.20944/preprints202208.0317.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Cytochrome P450; POR; Congenital adrenal hyperplasia; metabolic disorders; CYP3A4; protein stability; drug metabolism
Online: 17 August 2022 (10:02:51 CEST)
Cytochrome P450 oxidoreductase (POR) is the redox partner of steroid and drug-metabolizing cytochromes P450 located in the endoplasmic reticulum. Mutations in POR cause a broad range of metabolic disorders. The POR variant rs17853284 (P228L) identified by genome sequencing has been linked to lower testosterone levels and reduced P450 activities. We expressed POR wild type and the P228L variant in bacteria, purified the proteins, and performed protein stability and catalytic functional studies. Variant P228L affected the stability of the protein as evidenced by lower unfolding temperatures and higher sensitivity to urea denaturation. A significant reduction of small molecule metabolism was observed with POR P228L while activities of CYP3A4 were reduced by 25%, and activities of CYP3A5, and CYP2C9 were reduced by more than 40% compared to WT POR. The 17,20 lyase activity of CYP17A1 responsible for production of main androgen precursor dehydroepiandrosterone, was reduced to 27% of WT in presence of P228L variant of POR. Based on in silico and in vitro studies we predict that the change of proline to leucine may change the rigidity of the protein, causing conformational changes in POR, leading to altered electron transfer to redox partners. A single amino acid change can affect protein stability and cause a severe reduction in POR activity. Molecular characterization of individual POR mutations is crucial for a better understanding of the impact on different redox partners of POR.
ARTICLE | doi:10.20944/preprints202208.0159.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: metabolomics; NMR; PEMT; knockout; aging; mice; liver; intestine; white/brown adipose tissue
Online: 8 August 2022 (13:36:04 CEST)
Phospholipid metabolism, including phosphatidylcholine (PC) biosynthesis, is crucial for various biological functions and is associated to longevity. Phosphatidylethanolamine N-methyltransferase (PEMT) is a protein that catalyzes the biosynthesis of PC, the levels of which change in various organs such as brain and kidney during aging. However, the role of PEMT for systemic PC supply is not fully understood. To address how PEMT affects aging-associated energy metabolism in tissues responsible for nutrient absorption, lipid storage and energy consumption, we employed NMR-based metabolomics to study liver, plasma, intestine (duodenum, jejunum, ileum), brown/white adipose tissues (BAT, WAT), and skeletal muscle of young (9–10 weeks) and old (96–104 weeks) wild-type (WT) and PEMT knockout (KO) mice. We found that the effect of PEMT-knockout was tissue-specific and age-dependent. Deficiency of PEMT affected the metabolome of all tissues examined, among which the metabolome of BAT from both young and aged KO mice was dramatically changed in comparison to WT mice, whereas the metabolome of jejunum was only slightly affected. As for aging, the absence of PEMT increased the divergence of metabolome during aging of liver, WAT, duodenum and ileum and decreased the impact on skeletal muscle. Overall, our results suggest that PEMT plays a previously unexplored critical role in both aging and energy metabolism.
ARTICLE | doi:10.20944/preprints202208.0073.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: extravillous trophoblast; placenta; saturated fatty acid; in-utero environment; MRP1
Online: 3 August 2022 (04:21:58 CEST)
Normal function of placental extravillous trophoblasts (EVTs), which are responsible for uteroplacental vascular remodeling, is critical for adequate delivery of oxygen and nutrients to the developing fetus and normal fetal programming. Proliferation and invasion of spiral arteries by EVTs depends upon adequate levels of folate. Multidrug resistance-associated protein 1 (MRP1), which is an efflux transporter, is known to remove folate from these cells. We hypothesized that palmitic acid increases MRP1-mediated folate removal from EVTs, thereby interfering with EVTs’ role in early placental vascular remodeling. HTR-8/SVneo and Swan-71 cells, first trimester human EVTs, were grown in the absence or presence of 0.5 mM and 0.7 mM palmitic acid, respectively, for 72 h. Palmitic acid increased ABCC1 gene expression and MRP1 protein expression in both cell lines. The rate of folate efflux from the cells into the media increased with a decrease in migration and invasion functions in the cultured cells. Treatment with N-acetyl cysteine (NAC) prevented the palmitic acid mediated upregulation of MRP1 and restored invasion and migration in the EVTs. Finally, in an ABCC1 knockout subline of Swan-71 cells, there was a significant increase in invasion and migration functions. The novel finding in this study that palmitic acid increases MRP1-mediated folate efflux provides a missing link that helps to explain how maternal consumption of saturated fatty acids compromises the in-utero environment.
ARTICLE | doi:10.20944/preprints202208.0045.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: sideroflexin; SFXN1; mitochondria; ATAD3A; 17beta-HSD10; TIM50
Online: 2 August 2022 (07:46:32 CEST)
Sideroflexins (SFXN) are evolutionarily conserved mitochondrial carriers belonging to the SCL56 family. Until recently, the metabolites transported by SFXN were unknown and they were thought to be transporters of a metabolite involved in iron homeostasis. SFXN1 is now known as the mitochondrial serine transporter. Because little is known about SFXN1 interactome, we launched a high-throughput search of SFXN1 binding partners with the aim to better understand its mitochondrial functions. Using a large-scale identification of SFXN1 physical partners based on co-immunoprecipitation followed by shotgun mass spectrometry (coIP-MS), we identified 96 putative SFXN1 interactants in the MCF7 human cell line. Our in-silico analysis of the SFXN1 interactome highlights biological processes linked to mitochondrial organization, electron transport chain and transmembrane transport. Among SFXN1 potential physical partners, ATAD3A and 17-HSD10, two proteins associated with neurological disorders and neurodegeneration, were further confirmed as interactants using different human cell lines. Further work will be needed to investigate the significance of these interactions in neurological disorders.
ARTICLE | doi:10.20944/preprints202207.0311.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: glucose; cortisol; corticosterone; stress; early life adversity
Online: 21 July 2022 (07:53:13 CEST)
External stressors strongly increase cardiovascular activity and induce metabolic changes that ensure the availability of glucose and oxygen as part of a co-ordinated stress response. Exposure to stress during early life appears to have an exaggerated long-term effect on this response, leading to an increased risk or cardiometabolic disorders. Here we demonstrate that acute stress induced glucose release is impacted by the early life environment in rodent maternal deprivation and early-life infection models and this was validated in our EpiPath human early-life adversity cohort. In all three models differences in baseline blood glucose levels after ELA exposure were sex dependent. The human ELA model showed higher levels of basal glucose in females, similar to the mouse infection and rat maternal deprivation models. We anticipated that the stress induced glucose rise would be a GC dependent process. However, the kinetics of stress-induced glucose release, peaking 15-28 minutes before cortisol suggest that it is a GC-independent process. We confirmed this by administering an escalating dose of cortisol to a health human cohort, and the inability of an intravenous GC bolus induce a glucose rise in man confirms that it is a rapid, GC independent, process.In conclusion, we provide a novel perspective on the mechanisms behind stress related metabolic changes and highlights the importance of collecting early life data as a measure to understand an individual’s metabolic status in a better light.
ARTICLE | doi:10.20944/preprints202207.0275.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: blood pressure; cardiorespiratory fitness; waist circumference; lifestyle intervention; primary care; adverse responders; metabolic syndrome
Online: 20 July 2022 (05:59:58 CEST)
Systemic hypertension has been recognized as a modifiable traditional cardiovascular risk factor and influenced by many factors such as eating habits, physical activity, diabetes and obesity. The objective of this study was to identify cardiometabolic factors that predict changes in blood pressure induced by a one-year lifestyle intervention in primary care settings involving a collaboration between family physicians, dietitians, and exercise specialists. Patients with metabolic syndrome diagnosis were recruited by family physicians participating in primary care lifestyle intervention among several family care clinics across Canada. Participants for whom all cardiometabolic data at the beginning (T0) and the end (T12) of the intervention were available were included in the present analysis (n=101). Patients visited the dietitian and the exercise specialist weekly for the first three months and monthly for the last nine months. Diet quality, exercise capacity, anthropometric indicators, and cardiometabolic variables were evaluated at T0 and at T12. The intervention induced a significant decrease in waist circumference (WC), systolic (SBP) and diastolic (DBP) blood pressure, and plasma triglycerides and an increase in cardiorespiratory fitness (estimated VO2max). Body weight (p<0.001), body mass index (BMI) (p<0.001), and plasma glucose (p=0.006) reduction and VO2max increase (p=0.048) were all related to changes in SBP. WC was the only variable for which changes were significantly correlated with those in both SBP (p<0.0001) and DBP (p=0.0004). Variations in DBP were not associated with changes in other cardiometabolic variables to a statistically significant extent. Twelve participants were identified as adverse responders in both SBP and DBP and displayed less favorable changes in WC. The beneficial effects of a lifestyle intervention on blood pressure were significantly associated with cardiometabolic variables, especially WC. These findings suggest that a structured lifestyle intervention in primary care can help improve cardiometabolic risk factors in patients with metabolic syndrome.
ARTICLE | doi:10.20944/preprints202207.0081.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: adolescents; high sensitivity C-reactive protein; Interleukin 6; Leucine-rich α-2 glycoprotein 1; obesity; TNF-α
Online: 6 July 2022 (03:25:10 CEST)
Leucine-rich α-2 glycoprotein1 (LRG1) is a member of the leucine-rich repeat (LRR) family that was implicated in multiple diseases including cancer, aging and heart failure as well as diabetes and obesity. LRG1 plays a key role in diet-induced hepatosteatosis and insulin resistance by mediating the crosstalk between adipocytes and hepatocytes. LRG1 also promotes hepatosteatosis by upregulating de novo lipogenesis in the liver and suppressing fatty acid β oxidation. In this study, we investigated the association of LRG1 with obesity markers including leptin and other adipokines in adolescents (11-14 years; n=425). BMI-for-age classification based on WHO growth charts was used to define obesity. Plasma LRG1 was measured by ELISA while other markers were measured by multiplexing assay. Median (IQR) of LRG1 levels was higher in obese [30 (25, 38) µg/mL] and overweight [30 (24, 39) µg/mL] adolescents, compared to normal-weight participants [27 (22, 35) µg/mL]. The highest tertile of LRG1 had an OR [95%CI] of 2.55 [1.44, 4.53] for obesity. LRG1 was positively correlated to plasma levels of HsCRP (R=0.2), Leptin (R=0.2) and Chemerin (R=0.24) with p<0.001. Additionally, it was positively associated with plasma level of IL6 (R=0.17) and IL10 (R=0.14) but not TNF-α. In conclusion, LRG1 levels are increased in obese kids and associate with increased levels of adipogenic markers. These results suggest the usefulness of LRG1 as an early biomarker for obesity and its related pathologies in adolescents.
ARTICLE | doi:10.20944/preprints202206.0129.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Diabetic retinopathy; Oxidative stress; Advanced glycation end products (AGEs); Antioxidant enzymes; Vascular endothelial growth factor; B-vitamins; Vitamin-C; Vitamin- E
Online: 8 June 2022 (12:40:07 CEST)
Excessive intracellular glucose in insulin independent tissues including nerve, nephron, lens and retina invites mishandling of metabolism of glucose resulting in a background of increased oxidative stress, advanced glycation end products (AGE) formation, lipid peroxidation and failure of antioxidant defense systems in type 2 diabetes mellitus (T2DM). All these detrimental biochemical anomalies ultimately attack biological membranes and especially capillary beds of retina and glomerulus of kidney, resulting in break-down of inner blood-retinal i.e. initiation of diabetic retinopathy (DR). If these disarrays are corrected to a large extent, development of DR can be avoided or delayed. In this prospective clinical trial, 185 patients with T2DM who received B-vitamins, vitamin-C, and E along with anti-diabetic medication for five years, demonstrated a slower rate of the development of DR and reduced abnormal biochemical mediators like reactive oxygen species (ROS), malondialdehyde (MDA), AGE, and vascular endothelial growth factor (VEGF) compared to 175 T2DM individuals who were treated with only anti-hyperglycemic drugs.
ARTICLE | doi:10.20944/preprints202206.0085.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Ranolozine; Insuline; astrocytes; inflammation; antioxidants
Online: 6 June 2022 (10:14:05 CEST)
Ranolazine (Rn) is a drug used to treat persistent chronic coronary ischemia. It has also been shown to have therapeutic benefits on the central nervous system and an anti-diabetic effect by lowering blood glucose levels and however, no effects of Rn on cellular sensitivity to insulin (Ins) have been demonstrated yet. The present study aimed to investigate the permissive effects of Rn on the actions of Ins in astrocytes in primary culture. Ins at 10-8 M, Rn (10-6 M) and Ins+Rn (10-8 M and 10−6 M respectively) were added to astrocytes during 24 h. In comparison to control cells, Rn and/or Ins caused modifications in cell viability and proliferation. p-AKT, p-ERK, p-eNOS, Mn-SOD, COX-2, and the anti-inflammatory protein COX-2 were all upregulated by ins. On the contrary, no significant changes were found in the protein expression of Cu/Zn-SOD, NF-κB and IκB. The presence of Rn produced an increase in p-ERK protein and a significant decrease in COX-2 protein expression. Furthermore, Rn significantly increased the effects of Ins on the expression of p-AKT, p-eNOS, p-ERK, Mn-SOD, and PPAR-γ. On the other hand, Rn+Ins produced a significant decrease in COX-2 expression. In conclusion, Rn facilitated the effects of insulin on the p-AKT, p-eNOS, p-ERK, Mn-SOD and PPAR-γ, signaling pathways, as well as on the anti-inflammatory and antioxidant effects of the hormone.
ARTICLE | doi:10.20944/preprints202204.0052.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Carbohydrates; keto diet; IRS; C-peptide
Online: 7 April 2022 (04:03:54 CEST)
Abstract: Carbohydrates form the major source of energy in Asian diets. A lower carbohydrate diet became the recommended golden standard for healthy lifestyle. However, the effects of low-carbohydrates diet on health in apparently healthy individuals have been poorly studied, especially in relation to insulin resistance syndrome (IRS). A total of 120 healthy weight participants with no previous history of a major medical condition and an average BMI of ≤ 25kg/m2 were recruited. Self-reported dietary intake and objective physical activity by accelerometry were tracked for seven days. Participants were divided into three categories according to their dietary intake of carbohydrates. Blood samples were collected for metabolic markers analysis. HOMA of insulin resistance (HOMA-IR), β-cell function (HOMA-B) and C-peptide were used to evaluate glucose homeostasis. The consumption of low carbohydrates (less than 45% of total energy) significantly correlated with higher HOMA-IR, Lower HOMA-β % compared to moderate carbohydrate intake (between 45% to 65%). However, only the HOMA-β % was significantly influenced by carbohydrates intake. Moreover, low carbohydrates intake was significantly associated with elevated C-peptide secretion. The substitution of carbohydrates with other macronutrients, such as fat and proteins in the Atkins/ketogenic diet, resulted in a pronounced induction of IRS-related inflammatory markers; FGF2, IP-10, IL-6, IL-17A, MDC and reduction of IL-13. Overall, the presented data highlight, for the first time, that low carbohydrate intake results in significant glucose homeostasis imbalance that may be driven by a heightened state of inflammatory response.
REVIEW | doi:10.20944/preprints202202.0353.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Diabetic; Chronic Kidney Disease; Metformin; Acidosis Lactate
Online: 28 February 2022 (09:28:33 CET)
Background: Diabetes Mellitus is a metabolite disorder with parameters of high blood sugar levels. In the management of diabetes can be used the drug metformin is the gold of choice to achieve a therapeutic effect and rarely causes side effects of the drug, but it still has debate view. However, if used in excessive doses for patients with kidney disease, it will be contraindicated with side effects such as lactic acidosis. Objective: This study aims to evaluate the side effect of Metformin for diabetic kidney diseases (DKD) patients. Method: This study used the Narrative Review Method that was obtained from 2011 to 2021, in the English language from PubMed, Google Scholar, and Cochrane Library. Results: Metformin is at the forefront of the treatment of type 2 diabetes mellitus (DM2). Metformin is likely to have lactic acidosis-related adverse effects in chronic kidney disease (CKD) patients, such as increased arterial lactate. Lactic acidosis is defined as an increase in arterial lactate with an indicator of more than five mmol/L and an arterial blood pH of less than 7.35. Metformin-induced lactate levels are considered to be below the parameters. DKD risk factors can be conceptually classified as several susceptibility factors, initiation factors, and developmental factors. The two most prominent risk factors are hyperglycemia and hypertension. Conclusion: Metformin can increase lactate levels in CKD patients but is still below the parameters of lactic acidosis. This study may have some weaknesses and requires further prospective research to validate the results.
ARTICLE | doi:10.20944/preprints202202.0097.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Captive breeding; endangered; red panda; reproductive hormone; stress hormone; welfare
Online: 7 February 2022 (16:07:29 CET)
Animals in human care are affected by stressors that can ultimately reduce fitness. When reproduction is affected, endangered species’ conservation programmes can be severely compromised. Thus, understanding factors related to stress and reproduction, and measures of related hormones, are important to ensure captive breeding success. Red pandas are endangered and populations in the wild are threatened with extinction. A global captive breeding programme has been launched to conserve the species with the goal of reintroduction. However there is little informaiton on how stressors impact reproductive aspects of the species. This study measured fecal glucocorticoid (fGCM), fecal progestagen (fPM) and fecal androgen (fAM) metabolite concentrations in 12 female and 8 male red pandas (Ailurus fulgens fulgens) at three zoos in northeastern India to determine predictors of adrenal and gonadal steroid activity and the influence of fGCM on reproduction. Results indicated that fGCM concentrations were higher in males than females, and positively correlated with number of visitors, while negatively related to frequency of feedings and enclosure area. Sex, visitor number, frequency of feeding, and enclosure area explained 67% of the variations in fGCM concentrations in the study population. Concentrations of fPM were positively associated with tree density in the enclosure, explaining 47% of the variation among females. For fAM, positive associations were found with frequency of feeding, but concentrations were negatively related to age and number of visitors; these three covariates explained 45% of the variation in fAM concentration among males. Comparison of fGCM with fPM showed a negative trend, indicating increasing adrenal hormones may decrease reproductive function among female red pandas. The study thus suggests that zoo management should consider increasing feeding frequency, providing larger enclosures with more trees, and regulating visitor numbers to reduce stress and increase reproductive fitness among red pandas.
ARTICLE | doi:10.20944/preprints202201.0357.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: predictive modeling; biomarker; cerebrospinal fluid; cross-sectional study; neurodegenerative disease
Online: 24 January 2022 (12:59:55 CET)
In recent years, metabolomics has been used as a powerful tool to better understand the physiology of neurodegenerative diseases and identify potential biomarkers for progression. We used targeted and untargeted aqueous, and lipidomic profiles of the metabolome from human cerebrospinal fluid to build multivariate predictive models distinguishing patients with Alzheimer’s disease (AD), Parkinson’s disease (PD), and healthy age-matched controls. We emphasize several statistical challenges associated with metabolomic studies where the number of measured metabolites far exceeds sample size. We found strong separation in the metabolome between PD and controls, as well as between PD and AD, with weaker separation between AD and controls. Consistent with existing literature, we found alanine, kynurenine, tryptophan, and serine to be associated with PD classification against controls, while alanine, creatine, and long chain ceramides were associated with AD classification against controls. We conducted a univariate pathway analysis of untargeted and targeted metabolite profiles and find that vitamin E and urea cycle metabolism pathways are associated with PD, while the aspartate/asparagine and c21-steroid hormone biosynthesis pathways are associated with AD. We also found that the amount of metabolite missingness varied by phenotype, highlighting the importance of examining missing data in future metabolomic studies.
ARTICLE | doi:10.20944/preprints202112.0237.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: religious fasting; daytime dry fasting; energy expenditure; body composition; microdialysis
Online: 14 December 2021 (13:06:26 CET)
Each year in March, adherents of the Bahá’í faith abstain from eating and drinking from sunrise to sunset for 19 days. Thus, Bahá’í fasting (BF) can be considered as a form of daytime dry fasting. We tested if BF decreases energy expenditure after a meal and improves anthropometric measures, and systemic and tissue-level metabolic parameters. This was a self-controlled cohort study with 11 healthy men. We measured anthropometric parameters, metabolic markers in venous blood, and pre- and postprandial energy metabolism at systemic (indirect calorimetry) and tissue (adipose tissue and skeletal muscle microdialysis) level, both before and during BF. During BF, we found reduced body weight, body mass index, body fat and blood glucose. Postprandial increase in energy expenditure was lower, diet-induced thermogenesis tended to be lower. In adipose tissue, perfusion, glucose supply and lipolysis were increased. In skeletal muscle, tissue perfusion did not change. Glucose supply and lipolysis were decreased. Glucose oxidation was increased, indicating an improved insulin sensitivity. BF may be a promising approach to losing weight and improving metabolism and health. However, outside the context of religiously-motivated fasting, skipping a meal rather in the evening (dinner cancelling) might be recommended, as metabolism appears to be reduced in the evening.
ARTICLE | doi:10.20944/preprints202112.0120.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: aging; NMR spectroscopy; mice; energy metabolism; fat; intestine; metabolomics
Online: 8 December 2021 (12:03:07 CET)
Energy metabolism, including alterations in energy intake and expenditure, is closely related to aging and longevity. Metabolomics studies have recently unraveled changes in metabolite composition in plasma and tissues during aging and have provided critical information to elucidate the molecular basis of aging process. However, the metabolic changes in tissues responsible for food intake and lipid storage have remained unexplored. In this study, we aimed to investigate aging-related metabolic alterations in these tissues. To fill this gap, we employed NMR-based metabolomics in several tissues, including different parts of the intestine (duodenum, jejunum, ileum) and brown/white adipose tissues (BAT, WAT) of young (9-10 weeks) and old (96-104 weeks) wild-type (mixed genetic background of 129/J and C57BL/6) mice. We further included plasma and skeletal muscle of the same mice to verify previous results. Strikingly, we found that duodenum, jejunum, ileum, and WAT do not metabolically age. In contrast, plasma, skeletal muscle, and BAT show a strong metabolic aging phenotype. Overall, we provide first insights into the metabolic changes of tissues essential for nutrient uptake and lipid storage and have identified biomarkers for metabolites that could be further explored to study the molecular mechanisms of aging.
ARTICLE | doi:10.20944/preprints202112.0073.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: MicroRNAs; miR-126; mir-197; mir-223; Cardiometabolic Disease; Diabetes; Cardiovascular disease; Atherosclerosis; Inter Media Thickness
Online: 6 December 2021 (12:52:25 CET)
We aim to investigate if serum levels of microRNAs: miR-126, mir-197 and mir-223, previously implicated in cardiometabolic disease, are reproducibly associated with incident-diabetes (inc-DM), incident-cardiovascular disease (inc-CVD) and with carotid atherosclerosis (measured for the maximum thickness of the intima-media of the carotid bulb (IMT)). The microRNAs were measured, one: in serum of 553 subjects from the baseline exam of the Swedish prospective cohort, Malmö Diet and Cancer Study (MDC-CC), with 169 subjects who developed CVD and 140 DM (16 years follow-up) and, two: in 1221 subjects from the Malmö Offspring Study (MOS), with 14 de-veloped CVD and 12 DM (3.7 years follow-up). Multivariate logistic and linear regression models were used to investigate the relationship of serum-concentrations of the microRNAs and inc-DM, inc-CVD, IMT-bulb respectively. In MDC-CC, miR-126 showed significant positive association with inc-DM (p= 0.01) whereas in fully adjusted model, the association was borderline significant (p= 0.05). The results were not replicated in MOS. There was no consistent significant association between the microRNAs with IMT or inc-CVD in any cohort. Our results do not support previous reports on significant associations between these microRNAs and the risk of CMD, as they were not reproducible in our cohorts. In addition, the directionality of any associations found were not consistent with those previously reported.
ARTICLE | doi:10.20944/preprints202111.0285.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: depression; serum levels; phthalates; bisphenols
Online: 16 November 2021 (09:53:20 CET)
Public concern has emerged about the effects of endocrine disruptor compounds (EDCs) on neuropsychiatric disorders. Preclinical evidence suggests that exposure to EDCs is associated with the development of the major depressive disorder (MDD) and could result in neural degeneration. The interaction of EDCs with hormonal receptors is the best-described mechanism of their biological activity. However, the dysregulation of the hypothalamic-pituitary-gonadal adrenal axis has been reported and linked to neurological disorders. On the other hand, at a worldwide level and in Mexico, the incidence of MDD has recently been increasing. Of note, in Mexico, there are no clinical associations on blood levels of EDCs and the incidence of the MDD. Methodology: Thus, we quantified for the first time the serum levels of parent compounds of two bisphenols and four phthalates in patients with MDD. Results: The levels of di-ethyl-hexyl-phthalate (DEHP), butyl-benzyl-phthalate (BBP), di-n-butyl phthalate (DBP), and di-ethyl-phthalate (DEP), bisphenol A (BPA), and bisphenol S (BPS) were determined with a gas chromatograph-mass spectrometer. Results/ conclusion: We found significant differences between concentrations of BBP between controls and patients with MDD.
ARTICLE | doi:10.20944/preprints202110.0291.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Succinate; SUCNR1; GDM; Placenta; Endothelial cells, Angiogenesis
Online: 20 October 2021 (12:35:18 CEST)
Placental hypervascularization has been reported in pregnancy-related pathologies such as gestational diabetes mellitus (GDM). Nevertheless, the underlying causes behind this abnormality are not well understood. In this study, we addressed the expression of SUCNR1 (cognate succinate receptor) in human placental endothelial cells and hypothesized that succinate-SUCNR1 axis might play a role in the placental hypervascularization reported in GDM. We measured significantly higher succinate levels in placental tissue lysates from women with GDM relative to matched controls. In parallel, SUCNR1 protein expression was upregulated in GDM tissue lysates as well as in isolated diabetic fetoplacental arterial endothelial cells (FpECAds). A positive correlation of SUCNR1 and vascular endothelial growth factor (VEGF) protein levels in tissue lysates indicated a potential link between succinate-SUCNR1 axis and placental angiogenesis. In our in-vitro experiments, succinate prompted hallmarks of angiogenesis in human umbilical vein endothelial cells (HUVECs) such as proliferation, migration and spheroid sprouting. These results were further validated in fetoplacental arterial endothelial cells (FpECAs), where succinate induced endothelial tube formation. VEGF gene expression was increased in response to succinate in both HUVECs and FpECAs. Yet, knockdown of SUCNR1 in HUVECs led to suppression of VEGF gene expression and abrogated the migratory ability and wound healing in response to succinate. In conclusion, our data underline SUCNR1 as a promising metabolic target in human placenta and as a potential driver of enhanced placental angiogenesis in GDM.
REVIEW | doi:10.20944/preprints202110.0005.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Brown adipose tissue; beige adipose tissue; obesity; cold exposure; uncoupling protein-1, beta-adrenergic receptor; energy expenditure; adipose browning; micro-RNA
Online: 1 October 2021 (11:30:39 CEST)
Obesity-associated metabolic abnormalities comprise of a cluster of conditions including dyslipidemia, insulin resistance, diabetes, and cardiovascular diseases that has affected more than 650 million people all over the globe. Obesity results from accumulation of white adipose tissues mainly due to the chronic imbalance of energy intake and energy expenditure. Variety of approaches to treat or prevent obesity, including lifestyle interventions, surgical weight loss procedures and pharmacological approaches to reduce energy intake and increase energy expenditure have failed to substantially decrease the prevalence of obesity. Brown adipose tissue (BAT), the primary source of thermogenesis in infants and small mammals may represent a promising therapeutic target to treat obesity by promoting energy expenditure through non-shivering thermogenesis mediated by mitochondrial uncoupling protein 1 (UCP1). Since the confirmation of functional BAT in adult humans by several groups, approximately a decade ago and its association with a favorable metabolic phenotype, intense interest on the significance of BAT in adult human physiology and metabolic health has emerged within the scientific community to explore its therapeutic potential for the treatment of obesity and metabolic diseases. Substantially decreased BAT activity in individuals with obesity indicates a role for BAT in setting of human obesity. On the other hand, BAT mass and its prevalence has been reported to correlate with lower body mass index (BMI), decreased age and glucose levels, leading to lower incidence of cardio metabolic diseases. Increased cold exposure in adult humans with undetectable BAT was associated with decreased body fat mass and increased insulin sensitivity. Deeper understanding of the role of BAT in human metabolic health and its inter-relationship with body fat distribution and deciphering proper strategies to increase energy expenditure by either increasing functional BAT mass, or inducing white adipose browning holds the promise for possible therapeutic avenues for the treatment of obesity and associated metabolic disorders.
ARTICLE | doi:10.20944/preprints202109.0268.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: flavan-3-ols; adipose; browning; catecholamine; sympathetic nerve
Online: 15 September 2021 (15:16:21 CEST)
We previously found increases in uncoupling protein (Ucp)-1 transcription in brown adipose tissue (BAT) of mice following a single oral dose of flavan 3-ols (FL), a fraction of catechins and procyanidins. It was confirmed that these changes were totally reduced by co-treatment of adrenaline blockers. According to these previous results, FL possibly activates sympathetic nervous system (SNS). In this study, we confirmed the marked increase in urinary catecholamine (CA) s projecting SNS activity following a single dose of 50 mg/kg FL. In addition, we examined the impact of the repeated administration of 50 mg/kg FL for 14 days on adipose tissues in mice. In BAT, FL tended to increase the level of Ucp-1 along with thermogenic transcriptome factors, such as peroxisome proliferator-activated receptor γ coactivator (PGC)-1α and PR domain-containing (PRDM)1. Transcription of browning markers, such as CD137 and transmembrane protein (TMEM) 26 in addition to PGC-1α were increased in epididymal adipose (eWAT) by FL. A multilocular morphology with cell size reduction was shown in the inguinal adipose (iWAT), together with increasing the level of Ucp-1 following administration of FL. These results suggest that FL produces browning in adipose through activation of the SNS.
ARTICLE | doi:10.20944/preprints202108.0536.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: interferon gamma; cancer immunotherapy; viral vectors; alphavirus; bone marrow-derived macrophages; spheroids; CD38; Pam3CSK4
Online: 30 August 2021 (10:18:08 CEST)
Interferon gamma (IFNg) is a pleiotropic cytokine that can potentially reprogramme the tumour microenvironment. However, the antitumour immunomodulatory properties of IFNg still need to be validated due to variable therapeutic outcomes in preclinical and clinical studies. We developed a replication-deficient Semliki Forest virus vector expressing IFNg (SFV/IFNg) and evaluated its immunomodulatory antitumour potential in vitro in a model of 3D spheroids and in vivo in immunocompetent 4T1 mouse breast cancer model. We demonstrated that SFV-derived IFN-g stimulated bone marrow macrophages to acquire the tumoricidal M1 phenotype in 3D nonattached conditions. Coculturing SFV/IFNg-infected 4T1 spheroids with BMDMs inhibited spheroid growth. In the orthotopic 4T1 mouse model, intratumoural administration of SFV/IFNg virus particles alone or in combination with the Pam3CSK4 TLR2/1 ligand led to significant inhibition of tumour growth compared to the administration of the control SFV/Luc virus particles. Analysis of the composition of intra-tumoural lymphoid cells isolated from tumours after SFV/IFNg treatment revealed an increase in CD4+ and CD8+ and a decrease in T-reg (CD4+/CD25+/FoxP3+) cell populations. Furthermore, a significant decrease in the populations of cells bearing myeloid cell markers CD11b, CD38 and CD206 was observed. In conclusion, the SFV/IFNg vector induces a therapeutic antitumour T-cell response and inhibits myeloid cell infiltration in treated tumours.
ARTICLE | doi:10.20944/preprints202108.0235.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Pancreatic Ductal Adenocarcinoma; metabolites; cholestatic (obstructive) jaundice; lipoprotein; inflammation; tumour stages
Online: 10 August 2021 (14:08:27 CEST)
Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a characteristic dysregulated metabolism. Abnormal clinicopathological features linked to defective metabolic and inflammatory response pathways can induce PDAC development and progression. In this study, we investigated the metabolites and lipoproteins profiles of PDAC patients of African ancestry. Nuclear Magnetic Resonance (NMR) spectroscopy was conducted on serum obtained from consenting individuals (34 PDAC, 6 Chronic Pancreatitis, and 6 healthy participants). Seventy-five signals were quantified from each NMR spectrum. The Liposcale test was used for lipoprotein characterization. Spearman’s correlation and Kapan Meier tests were conducted for correlation and survival analyses respectively. In our patient cohort, the results demonstrated that levels of metabolites involved in the glycolytic pathway increased with the tumour stage. Raised ethanol and 3-hydroxybutyrate were independently correlated with a shorter patient survival time, irrespective of tumour stage. Furthermore, increased levels of bilirubin resulted in an abnormal lipoprotein profile in PDAC patients. Additionally, we observed that the levels of a panel of metabolites (such as glucose, lactate) and lipoproteins correlated with those of inflammatory markers. Taken together, the metabolic phenotype can help distinguish PDAC severity and be used in predicting patient survival and in informing treatment intervention.
REVIEW | doi:10.20944/preprints202108.0123.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: metabolic syndrome; caffeinated coffee; decaffeinated coffee; green coffee extract; chlorogenic acid
Online: 4 August 2021 (22:04:19 CEST)
Coffee is rich in phenolic acids, such as caffeic acid and chlorogenic acid (CGA). Polyphenol-rich diets have been shown to reduce the risk of metabolic syndrome (MeTS). Background and Objectives: This systematic review and meta-analysis discusses the effects of coffee consumption and its dose-response on MeTS parameters. Materials and Methods: PubMed and Scopus® were searched for relevant articles published between 2015 and 2020. This review focused on randomised controlled trials (RCTs) investigating the effect of coffee consumption on anthropometric measurements, glycaemic indices, lipid profiles, and blood pressure. Data from relevant studies were extracted and analysed using random, fixed, or pooled effects models with 95% confidence intervals (CIs). Results: Green coffee extract (GCE) supplementation (180 to 376 mg) was found to reduce waist circumference (weighted mean difference (WMD) = -0.39; 95% CI: -0.68, -0.10), triglyceride levels (WMD = -0.27; 95% CI: -0.43, -0.10), high-density lipoprotein-cholesterol levels (WMD = 0.62; 95% CI: 0.34, 0.90), systolic blood pressure (WMD = -0.44; 95% CI: -0.57, -0.32), and diastolic blood pressure (WMD = -0.83; 95% CI: -1.40, -0.26). Decaffeinated coffee (510.6 mg) reduced the fasting blood glucose levels (WMD = -0.81; 95% CI: -1.65, 0.03). The meta-analysis showed that the intake of GCE containing 180 to 376 mg of CGA (administered in a capsule) and liquid decaffeinated coffee containing 510.6 mg of CGA improved the MeTS outcomes in study participants. Conclusions: The findings of the review suggested that the effect of coffee on MeTS parameters varies depending on the types and doses of coffee administered. A more detailed RCT on specific coffee doses (with adjustment for energy and polyphenol intake) and physical activity is needed to further confirm the observed outcomes.
REVIEW | doi:10.20944/preprints202106.0464.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Antioxidants; Free radicals; Fructose; Oxidative stress
Online: 17 June 2021 (14:40:02 CEST)
An imbalance in any metabolic system can be traced to its homeostasis. When homeostatic environment is not attainable then there will be a response from the body. A new shift has emerged, “the negative feedback effect of high fructose consumption;” more pain than gain. The human metabolic system daily combat fructose sugar metabolism which emanates from high consumption. This inadvently lead to a chronological series of complications arising from the feedback. These feedbacks play pivotal roles in skeletal muscle damage and other body frameworks, it also fosters toxic advanced glycation end products (AGEs), factors that impose and inflict damaging effects to the body`s energy currency and serious threat to health. These damages are missed or overlooked because of early nonspecific physiological symptoms. High level of fructose has both long- and short-term effects on human metabolic processes. These effects which are majorly through the production of reactive oxygen species (ROS) and other free radicals, are felt in the disruption of biomolecules such as causing DNA mutation, lipid peroxidation etc. these effects in turn lead to various diseases such as cancer, diabetes, atherosclerosis, and other health issues. In this review, we will focus on the damaging effects this sugar has on human health and the present solutions being applied. We will also look at the next step in combatting and controlling these negative feedbacks.
ARTICLE | doi:10.20944/preprints202104.0655.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Meteorin-like hormone, irisin, adipomyokines, bone markers, Osteoactivin , Syndecan, OPG, Osteonectin, type 2 diabetes, obesity.
Online: 26 April 2021 (10:57:31 CEST)
The musculoskeletal system consisting of bones and muscles have been recognized as endocrine organs secreting hormones that are involved in regulating metabolic and inflammatory pathways. Obesity and type 2 diabetes (T2D) are associated with several musculoskeletal system complications. We hypothesized that an interaction exists between adipomyokines namely, irisin and METRNL, and various bone markers in individuals with obesity and T2D. A total of 228 individuals were enrolled in this study, including 124 non-diabetic and 104 T2D. A Multiplex assay was used to assess the level of various bone markers namely Osteoactivin, Syndecan, osteoprotegerin (OPG) and osteonectin/SPARC. Our data shows elevated levels of Osteoactivin, Syndecan, OPG and SPARC in T2D as compared to non-T2D individuals (p ≤ 0.05). Using Spearman’s correlation, irisin was positively correlated only with Osteoactivin and OPG (p < 0.05). Similarly, a positive association was observed between METRNL and Osteoactivin (p < 0.05). The strong positive association shown in our study between irisin, METRNL and various bone markers emphasises the strong interaction between these organs. This suggests that a dysregulation in the functional interaction between these molecules could play a possible role in the development of bone and muscle related complications that are associated with obesity and T2D.
ARTICLE | doi:10.20944/preprints202103.0273.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: testicular germ cell tumors (TGCTs); human seminoma; p75 neurotrophin receptor (p75NTR); p75NTR -signaling.
Online: 9 March 2021 (14:52:34 CET)
Several studies have demonstrated that the p75NTR low-affinity receptor of Nerve Growth Factor (NGF), is produced in abnormally large amounts in several human cancer types. However, the role of p75NTR varies substantially depending on cell context, so that a dual role of this receptor protein in tumor cell survival and invasion, as well as cell death, has been supported in recent studies. Herein we explored for the first time the expression of p75NTR in human specimens (nr=40) from testicular germ cell tumors (TGCTs), mostly seminomas. Nuclear overexpression of p75NTR was detected by immunohistochemistry in tumor tissue as compared to normal tissue, whereas neither NGF nor its high-affinity TrkA receptor was detected. An increased nuclear staining of phospho-JNK, belonging to the p75NTR signaling pathway, and its pro-apoptotic target gene, p53, was concomitantly observed. Interestingly, our analysis revealed that decreased expression frequency of p75NTR, p-JNK, and p53 was related to staging progression, thus suggesting that p75NTR may represent a specific marker of differentiation in TGCTs.
ARTICLE | doi:10.20944/preprints202101.0601.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: menopause, women, phytoestrogens, bread, soy
Online: 29 January 2021 (06:05:18 CET)
Menopause is the last step in the reproductive history of a woman. The ovaries stop producing hormones and the body reacts by lowering its functions, including the neuronal one. Phytoestrogens are plant products with estrogen-like activity able to affect many body functions. The aim of the present experiment was to study the effects of 30 days of regular consumption of a soy-enriched bread containing a known amount of phytoestrogens (genistein and daidzein). Women at climacteric, within 5 years or more than 5 years of menopause, were asked to include in their diet 200 g/day of a bread containing 40 mg of phytoestrogens. The effect on common menopausal symptoms and neurophysiological, hormonal and antioxidant parameters were determined before and after 30 days through questionnaires and experimental tests. Phytoestrogens were measured in the urine. In all groups, there was a significant increase of phytoestrogens in the urine and a decrease of the classical symptoms of menopause as well as a significant improvement in attentional performance tests, the quality of life index and pain intensity. Phytoestrogens present in the soy-enriched bread, are an important supplement in aging women due to their ability to induce estrogen-like effects without the potential side effects of estrogens.
ARTICLE | doi:10.20944/preprints202011.0474.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Breast cancer, genome-scale metabolic models, constraint-based analysis, divergence analysis, gene expression, metabolism, drug targets, personalized metabolic networks.
Online: 18 November 2020 (12:29:02 CET)
Cancer cells are adept at reprogramming energy metabolism and the precise manifestation of this metabolic reprogramming exhibits heterogeneity across individuals (and from cell to cell). In this study, we analyzed the metabolic differences between interpersonal heterogeneous cancer phenotypes. We used divergence analysis on gene expression data of 1156 breast normal and tumor samples from The Cancer Genome Atlas (TCGA) and integrated this information with a genome-scale reconstruction of human metabolism to generate personalized, context-specific metabolic networks. Using this approach, we classified the samples into four distinct groups based on their metabolic profiles. Enrichment analysis of the subsystems indicated that amino acid metabolism, fatty acid oxidation, citric acid cycle, androgen and estrogen metabolism and ROS detoxification distinguished these four groups. Additionally, we developed a workflow to identify potential drugs that can selectively target genes associated with the reactions of interest. MG-132 (a proteasome inhibitor) and OSU-03012 (a celecoxib derivative) were the top-ranking drugs identified from our analysis and known to have anti-tumor activity. Our approach has the potential to provide mechanistic insights into cancer-specific metabolic dependencies, ultimately enabling the identification of potential drug targets for each patient independently, contributing to a rational personalized medicine approach.
REVIEW | doi:10.20944/preprints202011.0069.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Fibroblasts; Rheumatoid Arthritis; Cancer; Metabolic Reprogramming; Glycolytic Switch; Systems Biology; Computational Modelling
Online: 2 November 2020 (19:28:02 CET)
Fibroblasts, the most abundant cells in the connective tissue, are key modulators of the extracellular matrix (ECM) composition. These spindle-shaped cells are capable of synthesizing various extracellular matrix proteins and collagen. They also provide the structural framework (stroma) for tissues and play a pivotal role in the wound healing process. While they are maintainers of the ECM turnover and regulate several physiological processes, they can also undergo transformations responding to certain stimuli and display aggressive phenotypes that contribute to disease pathophysiology. In this review, we focus on the metabolic pathways of glucose and highlight metabolic reprogramming as a critical event that contributes to the transition of fibroblasts from quiescent to activated and aggressive cells. We also cover the emerging evidence that allows us to draw parallels between fibroblasts in autoimmune disorders and more specifically in rheumatoid arthritis and cancer. We link the metabolic changes of fibroblasts to the toxic environment created by the disease condition and discuss how targeting of metabolic reprogramming could be employed in the treatment of such diseases. Lastly, we discuss Systems Biology approaches, and more specifically, computational modelling, as a means to elucidate pathogenetic mechanisms and accelerate the identification of novel therapeutic targets.
ARTICLE | doi:10.20944/preprints202009.0185.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: eel luteinizing hormone receptor; constitutively activating mutation; inactivating mutation; cyclic adenosine monophosphate response; cell surface loss of receptor
Online: 8 September 2020 (10:56:48 CEST)
We analyzed signal transduction of three constitutively activating mutants (M410T, L469R, and D590Y) and two inactivating mutants (D417N and Y558F) of the eel luteinizing hormone receptor (eel LHR), known to occur in human LHR. The objective of this study was to assess the functional effects of these mutations in signal transduction and cell surface loss of receptor. Mutant receptors were transiently expressed in Chinese hamster ovary (CHO-K1) cells. Eel LH-stimulated accumulation of cyclic adenosine monophosphate (cAMP) was measured by homogeneous time-resolved fluorescence (HTRF) assays. The loss of receptors from the cells surface was measured using an enzyme-linked immunosorbent assay (ELISA) in human embryonic kidney (HEK) 293 cells. The cAMP response in cells expressing the wild type eel LHR was increased in a dose-dependent manner using eel LH ligand stimulation. Compared with the wild type, cells expressing the activating mutants (M410T, L469R, and D590Y), exhibited a 4.0-, 19.1-, and 7.8-fold increase in basal cAMP response without agonist stimulation, respectively. Their maximal responses to agonist stimulation were approximately 65%, 52%, and 98%, respectively, of those of the wild type. The inactivating mutants (D417N and Y558F) did not completely impair signal transduction, and their maximal responses were only 33% and25 % of those of wild type. These data clearly showed that the eel LHR-L469R and D590Y, activating mutants enhanced the rate of the loss of cell surface receptors following treatment with eel LH. Thus, the loss of cell surface receptors in cells expressing mutant eel LHRs was consistent with the eel LH agonist-induced production of cAMP. Our results suggested that the activation of the eel LHR requires appropriate loss of LHR-ligand complexes from the cell surface.
REVIEW | doi:10.20944/preprints202009.0004.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: metabolomics; vaccines; infections; integrative metabolomics; systems biology; diagnosis; response detection
Online: 1 September 2020 (10:25:03 CEST)
Approaches to identification of metabolites have progressed from early biochemical pathway evaluation to modern high dimensional metabolomics which is a powerful tool to identify and characterize biomarkers of health and disease. While traditionally considered relevant in the context of classic metabolic diseases, immunometabolism has emerged as an important area of study as leukocytes generate key metabolites important to innate and adaptive immunity. Herein we discuss the metabolomic signatures and pathways perturbed during infection as well as vaccination. For example, changes in lipid and amino acid pathways (e.g., tryptophan, serine, and threonine) have been noted during infection while carbohydrate and bile acid pathways have shift upon vaccination. Metabolomics holds substantial promise to provide fresh insight into the molecular mechanisms underlying host response to infection and vaccination, and its integration with other systems biology platforms will add further impact to our studies of health and disease.
REVIEW | doi:10.20944/preprints202008.0685.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: vitamin D; muscle; parathyroid hormone; vitamin D-binding protein
Online: 30 August 2020 (18:31:44 CEST)
Vitamin D, unlike the micronutrients, vitamins A, E and K, is largely obtained, not from food, but by the action of solar UV light on its precursor, 7-dehydrocholesterol, in skin. With the decline in UV light intensity in winter, most skin production of vitamin D occurs in summer. Because no defined storage organ or tissue has been found for vitamin D, it has been assumed that adequate vitamin D status in winter can only be maintained by oral supplementation. Skeletal muscle cells have now been shown to incorporate the vitamin D-binding protein (DBP) from blood into the cell cytoplasm where it binds to cytoplasmic actin. This intracellular DBP provides an array of specific binding sites for 25-hydroxyvitamin D (25(OH)D) which diffuses into the cell from the extracellular fluid. When intracellular DBP undergoes proteolytic breakdown, the bound 25(OH)D is then released and diffuses back into blood. This uptake and release of 25(OH)D by muscle, accounts for the very long half-life of this metabolite in the circulation. As 25(OH)D concentration in blood declines in winter, its cycling in and out of muscle cells appears to be upregulated. Parathyroid hormone is the most likely factor enhancing the repeated cycling of 25(OH)D between skeletal muscle and blood. This mechanism appears to have evolved to maintain adequate vitamin D status in winter.
ARTICLE | doi:10.20944/preprints202008.0580.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Aminobenzoic acid; cinnamic acid; gene clusters; hydroxybenzoic acid; resveratrol; SLC25 subfamily 44; para-coumaric acid; ubiquinone
Online: 26 August 2020 (10:43:03 CEST)
The solute carrier family 25 (SLC25) participates in the transport of metabolites and cofactors across the membranes of mitochondria, plastids, peroxisomes, and endoplasmic reticulum. By calling for genomic blocks involved in adjacent metabolic reactions, this report introduces gene clusters of the Slc25 subfamily 44, stilbene and chalcone synthases, and subunits of the mitochondrial electron transfer complexes. The Slc25A44 gene was found ubiquitously expressed and transcriptionally co-regulated with energy metabolism genes in human, mouse, and Arabidopsis thaliana. The Slc25A44s also had no homozygous missense mutation and were highly conserved at intra-species level with the majority of polymorphism present in the non-coding regions. When expressed in oocytes, AdSlc25A44 from Arachis duranensis showed transport activity for the common precursors of flavonoids, stilbenoids, and ubiquinone. Accordingly, AdSLC25A44 and its human orthologue HsSLC25A44 elevated the production of para-coumaric, 4-aminobenzoic, and 4-hydroxybenzoic acids in Saccharomyces cerevisiae strains designed to produce para-coumaric acid via different pathways. Moreover, the engineered SLC25 subfamily specific signature, i.e., AdSLC25A44LWW206IQF, had a stronger effect on para-coumaric acid secretion than the native variant. Importantly, the aerobic growth-rate of S. cerevisiae was significantly higher when expressing the AdSLC25A44, HsSLC25A44, or AdSLC25A44LWW206IQF. These results suggest that SLC25A44 is an essential mitochondrion-ER-nucleus zone transporter associated with metabolism of secondary metabolites and energy.
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Glycine soja seed; Type 2 diabetes mellitus; Antidiabetic; AMPK; Akt; PPAR-γ
Online: 25 August 2020 (11:47:20 CEST)
Anti-diabetic effects of Glycine soja seed extract (GS) on Type 2 diabetes mellitus mouse model and human hepatocytes induced insulin resistance were investigated. 3 weeks old db/db mice were divided into 5 groups (n = 6) including two control groups and 3 GS treated groups with different doses. Oral administration of GS for 6 weeks to diabetic db/db mice reduced blood glucose level significantly in a dose dependent manner by 44.7% (300 mg/kg/day), 30.9% (150 mg/kg/day) and 21.1% (75 mg/kg/day). GS treatment also lowered significantly plasma level of HbA1c, insulin, IGF-1 and leptin, and increased that of adiponectin. GS treatment activated AMPK, and down-regulated GLUT2 in liver tissues of mice while up-regulated GLUT4 in muscle tissues of mice. In in vitro study with insulin resistance induced human hepatocyte, GS treatment increased glucose uptake and increased the activities of Akt and PPAR-γ in response to insulin. Treatment of GS appears to reduce blood glucose level by regulating energy metabolism positively through various metabolic pathways and reducing insulin resistance in Type 2 diabetes mellitus.
REVIEW | doi:10.20944/preprints202008.0417.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: hepatic fibrosis; hepatocullar carcinoma; vibration controlled transient elastography
Online: 19 August 2020 (13:00:28 CEST)
The prevalence of obesity or metabolic syndrome is increasing worldwide (“Globally metabodemic”). Approximately 25% of adult general population is suffering from nonalcoholic fatty liver disease (NAFLD) which has become serious health problem. Hepatic fibrosis is the most significant determinant of all cause and liver -related mortality in NAFLD. Noninvasive test (NIT) should be urgently required to evaluate hepatic fibrosis in NAFLD. Fibrosis-4 (FIB-4) index is the 1st triaging tool for excluding advanced fibrosis because of its accuracy, simplicity, and cheapness especially for general physicians or endocrinologists, although FIB-4 index has several drawbacks. Accumulating evidence has suggested that vibration controlled transient elastography (VCTE) and the enhanced liver fibrosis (ELF) test may become useful as the 2nd step after triaging by FIB-4 index. The leading cause of mortality in NAFLD is cardiovascular disease (CVD), extrahepatic malignancy, and liver-related diseases. NAFLD often complicates chronic kidney disease (CKD), resulting in increased simultaneous liver kidney transplantation (SLKT). FIB-4 index could be a predictor of not only liver-related mortality and incident hepatocullar carcinoma (HCC) but also prevalent and incident CKD, CVD, and extrahepatic malignancy. Although NITs as milestones for evaluating treatment efficacy have never been established, FIB- 4 index is expected to reflect histological hepatic fibrosis after treatment in several longitudinal studies. We here review the role of FIB-4 index as 1st step NIT in management of NAFLD.
CONCEPT PAPER | doi:10.20944/preprints202005.0211.v2
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Thermoregulation; microbial metabolism; overflow metabolism; biofilms; public goods; social evolution; ecological competition; fever; bacteriophage defense
Online: 17 July 2020 (09:35:22 CEST)
Many microbes live in habitats below their optimum temperature. Retention of metabolic heat by aggregation or insulation would boost growth. Generation of excess metabolic heat may also provide benefit. A cell that makes excess metabolic heat pays the cost of production, whereas the benefit may be shared by neighbors within a zone of local heat capture. Metabolic heat as a shareable public good raises interesting questions about conflict and cooperation of heat production and capture. Metabolic heat may also be deployed as a weapon. Species with greater thermotolerance gain by raising local temperature to outcompete less thermotolerant taxa. Metabolic heat may provide defense against bacteriophage attack, by analogy with fever in vertebrates. This article outlines the theory of metabolic heat in microbial conflict and cooperation, presenting several predictions for future study.
REVIEW | doi:10.20944/preprints202007.0314.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: hepatic fibrosis; Mac-2 binding protein glycated isomer; apoptosis inhibitor of macrophage; patatin-like phospholipase domain-containing protein 3; α-fetoprotein; PIVKA-II
Online: 14 July 2020 (13:55:16 CEST)
Nonalcoholic fatty liver disease (NAFLD) is becoming the leading cause of hepatocellular carcinoma (HCC), liver-related mortality, and liver transplantation. There is reasonable epidemiological cohort data to recommend surveillance of patients with NAFLD based upon the incidence of HCC. The American Gastroenterology Association (AGA) expert review published in 2020 recommend that NAFLD patients with cirrhosis or advanced fibrosis estimated by non-invasive tests (NITs) should consider HCC surveillance. NITs include fibrosis-4 (FIB-4) index, the enhanced liver fibrosis (ELF) test, FibroScan, and MR elastography. The recommended surveillance modality is abdominal ultrasound (US) given that it is cost effective and noninvasive with good sensitivity. However, US is limited in obese patients and those with NAFLD. In NAFLD patients with a high likelihood of having an inadequate US or if US is attempted but inadequate, CT or MRI may be utilized. The GALAD score, consisting of age, gender, AFP, lens culinaris-agglutinin-reactive fraction of AFP (AFP-L3), and protein induced by vitamin K absence or antagonist-II (PIVKA-II), can help to identify high risk of incident HCC in NAFLD patients. Innovative parameters including Mac-2 binding protein glycated isomer , type IV collagen 7S, free apoptosis inhibitor of macrophage, combination of single nucleoside polymorphisms are expected to be established. Considering a large number of NAFLD population, optimal screening tests must meet several criteria including high sensitivity, cost effectiveness and availability.
ARTICLE | doi:10.20944/preprints202007.0227.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Data integration; Metabolomics; Multi-tissue; Multiblock; Joint and unique multiblock analysis (JUMBA), OnPLS; Multiblock Orthogonal Component Analysis (MOCA)
Online: 11 July 2020 (04:01:03 CEST)
Data integration has been proven to provide valuable information. The information extracted using data integration in the form of multiblock analysis can pinpoint both common and unique trends in the different blocks. When working with small multiblock datasets the number of possible integration methods is drastically reduced. To investigate the application of multiblock analysis in cases where one has few number of samples, we studied a small metabolomic multiblock dataset containing six blocks (i.e. tissue types), only including common metabolites. We used a single model multiblock analysis method called Joint and unique multiblock analysis (JUMBA) and compare it to a commonly used method, concatenated PCA. These methods were used to detect trends in the dataset and identify underlying factors responsible for metabolic variations. Using JUMBA, we were able to interpret the extracted components and link them to relevant biological properties. JUMBA shows how the observations are related to one another, the stability of these relationships and to what extent each of the blocks contribute to the components. These results indicate that multiblock methods can be useful even with a small number of samples.
ARTICLE | doi:10.20944/preprints202007.0211.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Ionotropin; Steroid phosphocholine esters; pre-eclampsia; endogenous ouabain; DLM; PTSD
Online: 10 July 2020 (09:55:05 CEST)
Cardiotonic glycoside toxins, originally isolated from plants or amphibians, have been proposed as mammalian cardiotonic hormones. This paper is a review and update of the discovery of [i] a new class of steroid hormones, [ii] the path for their biosynthesis and [iii] some preliminary data on their function. The compounds are phosphoester conjugates and share a characteristic structural feature, a lactone ring, with [a] one class of synthetic potassium sparing diuretics and with [b] plant and amphibian cardiotonic steroids. Purification was initially monitored by cross reaction with steroid sulfate assays and later with digoxin-specific assays. Six compounds were purified by HPLC to near homogeneity and characterized by Tandem mass spectroscopy (MS-MS) and 31P-NMR. Three were digoxin-like materials (DLM) with 23 carbon atoms. The two extra carbon atoms form a spiral lactone E-ring. Several additional spiral lactones have been identified by MS-MS. In a pilot study, based on MS analysis, we evaluated phosphocholine steroid levels in individual serum samples in patients with pre-eclampsia (n=20). The control group of normotensive pregnant women (n=20) was used to estimate the mean and standard deviation. Twelve of the women with pre-eclampsia had a z-score over 2 for at least one of the four phosphocholine steroids. In contrast, only 1 sample from the normotensive women had a z-score over 2. The observation that there are two patterns, one with elevated phosphocholine steroid levels and one without the elevation, suggests that there may be two different underlying causes of pre-eclampsia. We now need to extend the study to determine which pattern predicts progression to life-threatening hypertension in pregnant women. This pilot study illustrates that it is possible to evaluate individual endogenous cardiotonic hormones without relying on antibodies developed to plant or amphibian toxins.
ARTICLE | doi:10.20944/preprints202006.0245.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: COVID-19; Metabolic syndrome; Comorbidity; Enrichment analysis; biological processes and pathways
Online: 21 June 2020 (09:52:10 CEST)
The risk factors associated with COVID-19 related severity, morbidity, and mortality, i.e., obesity (often associated with NAFLD), hyperglycemia, hypertension and dyslipidemia all cluster together as metabolic syndrome (MetS). Instead of studying association of these risk factors with COVID-19, it makes sense studying the association between MetS on one hand and COVID-19 on the other. This study explores a molecular basis underpinning the above association. Severity of COVID-19 patients with MetS could be due to functional alterations of host proteins due to their interactions with viral proteins. We collected data from Enrichr (https://amp.pharm.mssm.edu/Enrichr/), DisGeNET (https://www.disgenet.org/) and others and carried out enrichment analysis using Enrichr. Various biological processes and pathways associated with viral protein interacting partners are known to involve in metabolic diseases. The molecular pathways underlying insulin resistance, insulin signaling and insulin secretion are not only involved in diabetes but also in CVD and obesity (associated with non-alcoholic fatty liver disease; NAFLD). Lipid metabolism/lipogenesis, fatty acid oxidation and inflammation are associated with MetS. Viral interacting host proteins are associated and enriched with terms like hyperglycemia, coronary artery disease, hypertensive disease related to CVD and liver diseases in DisGeNET. Association of viral interacting proteins with disease-relevant biological processes, pathways and disease-related terms suggests that altered host protein function following interaction with viral proteins might contribute to frequent occurrence and/or severity of COVID-19 in subjects with MetS. Such analysis not only provides a molecular basis of comorbidity but also incriminates host proteins in viral replication, growth and identifies possible drug targets for intervention.
REVIEW | doi:10.20944/preprints202006.0200.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: exosomes; micro vesicles; extracellular vesicles; mesenchymal stromal cells (MSC); miRNA; cell therapy; artificial nano particles
Online: 16 June 2020 (07:57:00 CEST)
Extracellular vesicles (EV) such as exosomes, are newly recognized fundamental, natural and physiologic particles of life that seemingly are involved all biologic processes and clinical diseases. Due to their universal involvements, understanding the nature and the potential therapeutic uses of these nano-vesicles requires innovative experimental approaches, in virtually every field. Of the EV group, exosome nano-vesicles and larger companion extracellular micro vesicles (MV) can mediate completely new phenomena dependent on intercellular transfer of proteins and selected RNAs; particularly miRNAs, between donor and targeted cells to elicit epigenetic alterations inducing functional cellular changes. These recipient acceptor cells are nearby (paracrine transfers) or far away after distribution via the circulation (endocrine transfers). The major properties of such vesicles seem to have been conserved over eons, suggesting that they may have ancient evolutionary origins arising perhaps even before cells in the primordial soup from which life evolved. Their potential ancient evolutionary attributes may be responsible for the ability of some modern day exosomes to withstand unusually harsh conditions; perhaps due to unusual membrane lipid compositions. This is exemplified by maternal milk exosome survival of the neonatal acid/enzyme rich stomach. It is postulated that this also applies to their durable presence in phagolysosomes; suggesting unique intracellular release of contents. A major issue discussed is the generally poorly realized superiority of these naturally evolved nano vesicles to therapies compared human engineered artificial nanoparticles; say for treatment of cancers.
ARTICLE | doi:10.20944/preprints202005.0341.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: AGEs; aortic calcification; type 2 diabetes mellitus; diabetes-related complications
Online: 21 May 2020 (09:46:56 CEST)
The aim of this study was to evaluate the relationship between serum levels of advanced glycation end products (AGEs) and abdominal aortic calcification (AAC) in patients with type 2 diabetes mellitus (DM2). This was a prospective cross-sectional study conducted from January 2017 to June 2018. One-hundred and four consecutive patients with DM2 were given lateral lumbar X-rays in order to quantify aortic abdominal calcification AAC. Circulating levels of AGEs and classical cardiovascular risk factors were determined. Clinical history was also registered. Patients with higher AGEs values had higher grades of aortic calcification and higher number of diabetic related complications. Multivariate logistic regression analysis showed that being older, male and having high levels of AGEs and triglycerides were the independent risk factors associated to moderate-severe AAC when compared to no-mild AAC. Our results suggest that AGEs plays a role in the pathogenesis of aortic calcifications. In addition, the measurement of AGEs levels may be useful for assessing the severity of AAC in the setting of diabetic complications.
ARTICLE | doi:10.20944/preprints202004.0466.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: COVID-19; coronavirus; ACE2; bioinformatics analysis; drug prediction
Online: 26 April 2020 (03:14:50 CEST)
Recently, the outbreak of coronavirus disease 2019 (COVID-19) is threatening human health globally. There is a dire need to find potential therapeutic agents. Angiotensin converting enzyme 2 (ACE2), as an entry receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is considered as potential therapeutic target in COVID-19 pandemic. Here, our bioinformatics analysis revealed that the biological function of ACE2 was correlated with regulation of blood pressure and mediation of SARS-CoV-2 entry into host cells. Ten ACE2 cooperative proteins were identified by using STRING with a high score. ACE2 expressed highly in the small intestine, testis, and kidney. The level of ACE2 expression in tumor tissues varies in different types of cancers compared with that in normal tissues. It was worth noting that the expression level of ACE2 in the tumor has no effect on patient survival. MiRNA hsa-miR-942-5p, and three transcription factors (TFs) including Signal transducer and activator of transcription 4 (STAT4), Estrogen related receptor α (ESRRA), and Signal transducer and activator of transcription 3 (STAT3) were selected as novel ACE2 regulators. Moreover, nine potential therapeutic drugs were predicted by two online databases. Thus, our research may expand the overall view of ACE2 in COVID-19 treatment.
ARTICLE | doi:10.20944/preprints202003.0148.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: osteosarcoma; cancer; tumor; vitamin D; vitamin D deficiency; vitamin D receptor; vdr; mitochondria; ROS; SOD; SOD1; SOD2; superoxide; superoxide dismutase
Online: 9 March 2020 (02:40:08 CET)
Superoxide, a form of reactive oxygen species (ROS), is catabolized by superoxide dismutase (SOD) and contributes to carcinogenesis via the oxidative damage it inflicts on cells. The aim of this research was to analyze the potential vitamin D-mediated regulation of the antioxidative “SOD1-to-SOD2 switch” within the human MG-63 osteosarcoma model. For this study; real-time PCR analysis was performed using MG-63 cells exposed to metabolically active 1,25(OH)2D3. Frist; a sustained statistically significant >2-fold suppression of proliferating cell nuclear antigen (PCNA) transcripts was observed after 10nM but not at 100nM of 1,25(OH)2D3 treatment; suggesting a cytostatic effect. In order to assess regulators of mitochondrial oxidative phosphorylation; gene expression of COX2 and COX4l1 of the mitochondrial complex IV and antioxidative enzymes (SOD1; SOD2 and Catalase (CAT)) were monitored. For COX2 and COX4l1; no changes in gene expression were observed. However; a concomitant decrease in CAT and SOD1 mRNA; and increase in SOD2 mRNA after 24 hours of 10nM 1,25(OH)2D3 treatment were observed. A ~8-fold increase in SOD2 mRNA was apparent after 48 hours. The significant increase in SOD2 activity in the presence of vitamin D indicates an antioxidant potential and sensitization of vitamin D during osteosarcoma transformation and mitochondrial detoxification over time.
ARTICLE | doi:10.20944/preprints201909.0103.v2
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: PORD; congenital adrenal hyperplasia; POR; CY19A1; CYP21A2, CYP17A1
Online: 12 February 2020 (02:57:08 CET)
Context: Mutations in Cytochrome P450 oxidoreductase (POR) cause a form of congenital adrenal hyperplasia (CAH). We are reporting a novel R550W mutation in POR identified in a 46, XX patient with signs of aromatase deficiency. Objective: Analysis of aromatase deficiency from R550W mutation in POR. Design, Setting, and Patient: Both the child and the mother had signs of virilization. Ultrasound revealed the presence of uterus and ovaries. No defects in CYP19A1 were found, but further analysis with a targeted Disorders of Sexual Development NGS panel (DSDSeq.V1, 111 genes) on a NextSeq (Illumina) platform in Madrid and Barcelona, Spain, revealed compound heterozygous mutations c.73_74delCT/p.L25FfsTer93 and c.1648C>T/p.R550W in POR. WT and R550W POR were produced as recombinant proteins and tested with multiple cytochrome P450 enzymes at University Children’s Hospital, Bern, Switzerland. Main Outcome Measure and Results: R550W POR showed 41% of the WT activity in cytochrome c and 7.7% activity for reduction of MTT. Assays of CYP19A1 showed a severe loss of activity and CYP17A1, as well as CYP21A2 activities, were also lost by more than 95%. Loss of CYP2C9, CYP2C19, and CYP3A4 activities was observed for the R550W-POR. Predicted adverse effect on aromatase activity as well as a reduction in binding of NADPH was confirmed. Conclusions: Pathological effects due to POR R550W were identified, expanding the knowledge of molecular pathways associated with aromatase deficiency. Screening of the POR gene may provide a diagnosis in CAH without defects in genes for steroid metabolizing enzymes.
ARTICLE | doi:10.20944/preprints202002.0019.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: metabolomics; LC-MS; mass spectrometry; metabolic profiling; computational; statistical; unsupervised learning; supervised learning; pathway analysis
Online: 3 February 2020 (05:54:14 CET)
Metabolomics analysis generates vast arrays of data, necessitating comprehensive workflows involving expertise in analytics, biochemistry and bioinformatics, in order to provide coherent and high-quality data that enables discovery of robust and biologically significant metabolic findings. In this protocol article, we introduce NoTaMe, an analytical workflow for non-targeted metabolic profiling approaches utilizing liquid chromatography–mass spectrometry analysis. We provide an overview of lab protocols and statistical methods that we commonly practice for the analysis of nutritional metabolomics data. The paper is divided into three main sections: the first and second sections introducing the background and the study designs available for metabolomics research, and the third section describing in detail the steps of the main methods and protocols used to produce, preprocess and statistically analyze metabolomics data, and finally to identify and interpret the compounds that have emerged as interesting.
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Angelica gigas Nakai; triglycerides; VLDL-C; TG/HDL-C; atherogenic index
Online: 22 December 2019 (13:56:42 CET)
Background: Angelica gigas Nakai, Korean dang-gui, has long been widely used in traditional treatment methods. There have been a number of studies of the health effects of A. gigas and related compounds, but studies addressing effects on blood triglycerides (TG) are lacking. To investigate the effects of A. gigas Nakai extract (AGNE) on TG in Korean subjects, we carried out a 12-week, randomized, double-blind, placebo-controlled clinical trial. Methods: Subjects who met the inclusion criterion (130 mg/dL ≤ fasting blood TG ≤ 200 mg/dL) were recruited for this study. One hundred subjects were assigned to the AGNE group (n=50) or the placebo group (n=50), who were given 1g/day of AGNE (as a gigas Nakai extract 200mg/d) in capsules, and the control group for 12 weeks. Outcomes were efficacy TG, lipid profiles, atherogenic index, and safety parameters were assessed initially for a baseline measurement and after 12 weeks. Results: After 12 weeks of supplementation, TG and very low-density lipoprotein cholesterol (VLDL-C) concentration and TG/HDL-C ratio in the AGNE group were significantly reduced compared to the placebo group (p <0.05). No significant changes in any safety parameter were observed. Conclusions: These results suggest that ingestion of AGNE may improve TG and be useful to manage or prevent hypertriglyceridemia.
ARTICLE | doi:10.20944/preprints201911.0343.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: anti-apoptosis; anti-oxidant; curcumin; hyperglycemia; hyperlipidemia
Online: 27 November 2019 (09:57:14 CET)
Curcumin is the main secondary metabolites of Curcuma longa and other Curcuma spp, and has been reported to have some potential in preventing and treating some physiological disorders. This study investigated the effect curcumin in inhibiting high-fat diet and streptozotocin (STZ)-induced hyperglycemia and hyperlipidemia in rats. Twenty-six male Sprague-Dawley (SD) rats (170-190 g) were randomly divided into a standard food pellet diet group (Control group), a high-fat diet and streptozotocin group (HF+STZ group), and a high-fat diet combined with curcumin and STZ group (HF+ Cur +STZ group). Compared with the HF+STZ group, the HF+Cur+STZ group exhibited significantly reduced fasting blood glucose (FBG), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), alanine aminotransferase (AST) and aspartate transaminase (ALT) levels, and liver coefficients; in the livers of these rats, the expression of malondialdehyde (MDA) and Bax was downregulated, whereas that of superoxide dismutase (SOD) and Bcl-2 was upregulated. Moreover, the liver histology of these rats was improved and resembled that of the control rats. These results suggest that curcumin prevents high-fat diet and STZ-induced hyperglycemia and hyperlipidemia, mainly via anti-oxidant and anti-apoptotic mechanisms in the liver.
ARTICLE | doi:10.20944/preprints201911.0042.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: olivo-ponto-cerebellar atrophy (OPCA); amyotrophic lateral sclerosis (ALS); tauopathy; leukodystrophy; mass spectrometry; RT-qPCR; Ceramide Synthase (CERS2/CERS1); Serine Palmitoyltransferase 2 (Sptlc2); neutral Sphingomyelinase (Smpd3); neutral Ceramidase (Asah2); Fatty Acid Elongase (Elovl1/4/5); SCA34; SCA38; acid Sphingomyelinase (ASMase, Smpd1)
Online: 5 November 2019 (03:04:02 CET)
Ataxin-2 (ATXN2) acts during stress-responses, modulating mRNA translation and nutrient metabolism. Atxn2 knockout mice exhibit progressive obesity, dyslipidemia and insulin resistance. Conversely, the progressive ATXN2 gain-of-function due to polyGlutamine (polyQ) expansions leads to a dominantly inherited neurodegenerative process named spinocerebellar ataxia type 2 (SCA2), with early adipose tissue loss and late muscle atrophy. We tried to understand lipid dysregulation in a SCA2 patient brain and in an authentic mouse model. Thin layer chromatography of a patient cerebellum was compared to the lipid metabolome of Atxn2-CAG100-KnockIn (KIN) mouse spinocerebellar tissue. The human pathology caused deficits of sulfatide, galactosylceramide, cholesterol, C22/24-sphingomyelin and gangliosides GM1a/GD1b, despite quite normal levels of C18-sphingomyelin. Cerebellum and spinal cord from the KIN mouse showed a consistent decrease of various ceramides, with a significant elevation of sphingosine in the more severely affected spinal cord. Deficiency of C24/26-sphingomyelins contrasted with excess C18/20-sphingomyelin. Spinocerebellar expression profiling revealed consistent reductions of CERS protein isoforms, of Sptlc2 and Smpd3, but upregulation of Cers2 mRNA, as prominent anomalies in the ceramide-sphingosine metabolism. Reduction of Asah2 mRNA correlated to deficient S1P levels. In addition, downregulations for the elongase Elovl1, Elovl4, Elovl5 mRNAs and ELOVL4 protein explain the deficit of very-long-chain sphingomyelin. Reduced ASMase protein levels correlated to the accumulation of long-chain sphingomyelin. Overall, a deficit of myelin lipids was prominent in SCA2 nervous tissue at prefinal stage, not compensated by transcriptional adaptation of several metabolic enzymes. Myelination is controlled by mTORC1 signals, so our human and murine observations are in agreement with the known role of ATXN2 yeast, nematode and mouse orthologs as mTORC1 inhibitors and autophagy promoters.
ARTICLE | doi:10.20944/preprints201909.0125.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: adults; dietary pattern; fast food; KNHANES; obesity
Online: 11 September 2019 (14:59:00 CEST)
Background: Few studies have examined multifaceted aspects of fast food consumption and dietary patterns for their effects on obesity. We examined the independent associations of obesity with fast food consumption and dietary pattern in Korean adults. Methods: A total of 19,017 adults aged 19–64y participated from KNHANES 2010-2014. Fast food items were removed from diet and then dietary patterns were generated. Multivariate logistic regression analysis was used to examine the odds for overweight/obesity and central obesity according to fast food consumption and dietary patterns. Results: Fast food consumers were about 10% of Korean adults. Both of White rice and kimchi pattern and Meat and alcohol pattern were associated with low intakes of fiber, calcium, vitamin C, grains, fruit, and milk(p<0.05). Fast food consumers had higher the Meat and alcohol pattern and the Grains, fruit, and milk pattern, and they had lower the White rice and kimchi pattern than non-fast-food-consumers. Fast food consumer were not associated with overweight/obesity, whereas the participants with Meat and alcohol pattern had 14% higher overweight/obesity(95%CI:1.01,1.28) and 16% higher central obesity(95%CI:1.00,1.34). Conclusions: Fast food consumption was not directly associated with obesity, whereas the Meat and alcohol pattern had independent associations with overweight/obesity and central obesity among Korean adults.
ARTICLE | doi:10.20944/preprints201907.0180.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: GPETAFLR peptide; protein hydrolysate; liver; hepatic steatosis; high-fat diet
Online: 15 July 2019 (06:09:04 CEST)
Bioactive peptides are related to the prevention and treatment of many diseases. GPETAFLR is an octapeptide which was isolated from lupine (Lupinus angustifolius L.) and showed anti-inflammatory properties. The aim of this study was to evaluate the potential activity of GPETAFLR to prevent non-alcoholic fatty liver disease (NAFLD) in high-fat diet (HFD)-induced obese mice. C57BL/6J mice were fed a standard diet or an HFD. Two of the groups fed the HFD diet were treated with GPETAFLR in their drinking water at 0,5 mg/kg/d or 1 mg/kg/d. To determine the ability of GPETAFLR to improve the onset and progression of NAFLD, histological studies, hepatic enzyme profile, inflammatory cytokine and lipid metabolism-related genes and proteins were analyzed. Our results suggest that HFD-induced inflammatory metabolic disorders were alleviated by treatment with GPETAFLR. In conclusion, dietary lupine consumption could repair HFD-induced hepatic damage, possibly via modifications in the liver’s lipid signalling pathways.
ARTICLE | doi:10.20944/preprints201907.0117.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: eel luteinizing hormone receptor, constitutively activating mutation, inactivating mutation, cAMP responses.
Online: 8 July 2019 (12:38:11 CEST)
Luteinizing hormone receptor (LHR) is a member of the seven-transmembrane (TM) receptor family. Several mutations in LHR have been identified in many mammalian species, leading to either constitutive activation or inactivation of the receptor. Mutations in highly conserved regions of the TM domain have been reported. In this study, we analyzed signal transduction by three constitutively active mutants (designated M410T, L469R, and D590Y) and two inactivating mutants (D383N and Y546F) of eelLHR known as naturally occurring in human LHR . To directly assess the functional effects of these mutations, site-directed mutant receptors were transiently expressed in CHO-K1 cells and cAMP accumulation stimulated by recombinant eelLH (rec-eelLH) was measured by homogeneous time-resolved fluorescence (HTRF) assays. The cAMP response in cells expressing eelLHR wild-type (eLHR-WT) increased in a dose-dependent manner with rec-eelLH ligand stimulation. Cells expressing the activating eelLHR mutants, M410T, L469R, and D590Y, exhibited a 4.0-, 19.1-, and 7.8-fold increase in basal cAMP response, respectively. However, their maximal responses were approximately 73, 53, and 92%, respectively, of the maximal response of LHR-WT. The L469R mutant exhibited a particularly marked increase in cAMP production in the absence of agonist. The maximal responses of the inactivating mutants, D383N and Y546F, were 32 and 24% of LHR-WT, respectively. However, the inactivating mutations did not completely impair signal transduction. Thus, we report here the first characterization of activating and inactivating mutations in eelLHR and we show that these mutations have similar effects as those reported for mammalian LHRs. Moreover, eelLHR with activating mutations showed constitutive cAMP responses. These results provide important data on the signal transduction of constitutively active and inactive LHR mutants. Further studies should aim to identify the mechanism responsible for the significant increase in basal cAMP response in the constitutively activated eelLHR mutants.
ARTICLE | doi:10.20944/preprints201907.0089.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: type 2 diabetes; KCNJ11; RFLP; SNP
Online: 5 July 2019 (04:53:09 CEST)
Type 2 diabetes mellitus (T2DM) is a polygenic metabolic disease described by hyperglycemia, which is caused by insulin resistance or reduced insulin secretion. Interaction between various genetic variants and environmental factors triggers T2DM. The main aim of this study was to find the risk associated with genetic variant (rs5210) of KCNJ11gene in the development of T2D in Indian Population. A total number of 300 cases of T2D and 100 control samples were studied to find the polymorphism in KCNJ11 through PCR-RFLP. The genotype and allele frequencies in T2DM cases were significantly different from the control population. We found a significant association of KCNJ11 (rs5210) gene polymorphism with T2DM in North Indian patients indicating the role of this variant in developing risk for T2DM.