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.

Mucinous breast carcinoma is a rare subtype of mammary neoplasm encountered in medical practice. It represents approximately 1-6% of all breast cancers and is more common in postmenopausal women. There are two subtypes of mucinous breast carcinoma: pure and mixed. We report the case of a 73-year-old Caucasian woman diagnosed with mucinous pancreatic cystadenoma in 2007. She underwent a surgical procedure involving pancreatectomy of the body and tail, along with multiple known cardiovascular and metabolic comorbidities. In November 2019, during a clinical-biological evaluation for associated diseases, a mucinous carcinoma of the right breast was accidentally detected and later confirmed through further investigations. For treatment, a surgical procedure was performed involving lower right quadrantectomy with right axillary lymph node dissection. The postoperative clinical course was favorable. In conclusion, we present the case of a patient diagnosed with mixed mucinous breast carcinoma, without axillary lymph node invasion. Postmenopausal women with diabetes, overweight, and obesity have an increased susceptibility to breast cancer, with our patient having all these risk factors. To date, no study has demonstrated the genetic or radiation implication in the occurrence of mucinous carcinomas, nor the possible development of mucinous carcinomas in series in the same patient. Current data are insufficient to provide recommendations for the screening of malignant mucinous tumors in subjects with significant cardiometabolic risk factors.

Hepatitis B Virus (HBV) is a challenge for global health services, affecting millions and leading hundreds to end-stage liver disease each year. This comprehensive review explores the interactions between HBV and the host, examining their impact on clinical outcomes. HBV infection encompasses a spectrum of severity, ranging from acute hepatitis B to chronic hepatitis B, which can potentially progress to cirrhosis and hepatocellular carcinoma (HCC). Occult hepatitis B infection (OBI), characterized by low HBV DNA levels in hepatitis B surface antigen-negative individuals, can reactivate and cause acute hepatitis B. The identification of diverse HBV genotypes reveals distinct geographical distributions and associations with clinical outcomes. Moreover, single nucleotide polymorphisms (SNPs) within the host genome have been linked to several clinical outcomes, including cirrhosis, HCC, OBI, hepatitis B reactivation, and spontaneous clearance. The immune response plays a key role in controlling HBV infection by eliminating infected cells and neutralizing HBV in the bloodstream. Furthermore, HBV can modulate host metabolic pathways involved in glucose and lipid metabolism and bile acid absorption, further influencing disease progression. HBV clinical outcomes correlate with three levels of viral adaptation. In conclusion, the clinical outcomes of HBV infection could result from complex immune and metabolic interactions between the host and HBV. These outcomes can vary among populations and are influenced by HBV genotypes, host genetics, environmental factors, and lifestyle. Understanding the degrees of HBV adaptation is essential for developing region-specific control and prevention measures.

Sphingolipids play an important role in the development of diabetes both type 1 and type 2 diabetes as well as in the development of both micro- and macro-vascular complications. Several reviews have been published concerning the role of sphingolipids in diabetes but most of the emphasis has been on the possible mechanisms by which sphingolipids, mainly ceramides, contribute to the development of diabetes. Research on circulating levels of the different classes of sphingolipids in serum and in lipoproteins and their importance as biomarkers to predict not only the development of diabetes but also of its complications has only recently emerged and it is still in its infancy. This review summarizes the previously published literature concerning sphingolipid-mediated mechanisms involved in the development of diabetes and its complications focusing on how circulating plasma sphingolipid levels and the relative content carried by the different lipoproteins may impact their role as possible biomarkers both in the development of diabetes and mainly in the development of diabetic complications. Further studies in this field may open new therapeutic avenues to prevent or arrest/reduce both the development of diabetes and progression of its complications.

Calcium (Ca2+) ions act as second messenger, regulating several cell functions. Mitochondria are critical organelles for the regulation of intracellular Ca2+. Mitochondrial calcium (mtCa2+) uptake is ensured by the presence in the inner mitochondrial membrane (IMM) of the mitochondrial calcium uniporter (MCU) complex, a macromolecular structure composed of pore-forming and regulatory subunits. MtCa2+ uptake plays a crucial role in the regulation of oxidative metabolism and cell death. Many evidences demonstrate that dysregulation of mtCa2+ homeostasis can have serious pathological outcomes. In this review, we briefly discuss the molecular structure and the function of the MCU complex and then we focus our attention on human diseases in which a dysfunction in mtCa2+ has been showed.

Polycystic ovary syndrome (PCOS) usually comes along with metabolic disturbances attributed to androgen excess and obesity, but the contribution of each has not been defined, and the occurrence of metabolic disturbances is frequently not investigated. We evaluated 99 PCOS and 41 non-PCOS women. Clinical biomarkers of glucose-, liver-, and endothelial-related metabolic alterations were measured; participants were categorized into four groups according with obesity (OB) and hyperandrogenemia (HA) statuses: Healthy (no-HA, lean), HA (HA, lean), OB (no-HA, OB), and HAOB (HA, OB). Metabolic disturbances were highly frequent in PCOS women (70%). BMI correlated with all biomarkers, while free testosterone (FT) only with glucose- and hepatic-related indicators. Despite insulin sensitivity and liver enzymes were associated with FT, women with obesity exhibited lower M [coeff = 8.56 – 0.080(FT) –3.71(Ob); p <0.001)] and higher aspartate aminotransferase (coeff = 26.27 + 0.532(FT) + 8.08(Ob); p = 0.015)] than lean at the same level of FT. Women with obesity exhibited greater risk of metabolic disorders than lean, independently of hyperandrogenemia. Clinicians are compelled to search for metabolic alterations in PCOS women; obesity must be handled in all cases, but hyperandrogenemia needs to be managed also in those with glucose- or liver-related disturbances.

Bibliometric studies on inherited metabolic diseases(IMDs) didn't exist in the literature.Our research aims to conduct a bibliometric study to determine the current status,trending topics,and missing points of publications on IMDs.Between 1968-2023, we conducted a literature search with keyword "inherited metabolic disease" in the SCOPUS-database.We included research articles in medicine written in English,published in the final section.We created our data pool using VoSviewer, SciMAT, and Rstudio software programs for bibliometric parameters of the articles that met the inclusion criteria.We performed bibliometric analysis of the data with R-package "bibliometrix" and BibExcel programs.We included 2702 research articles published on IMDs.Top three countries that have written the most articles in this field are; USA(n= 501), United Kingdom(n=182), and China(n= 172).The most preferred keywords by the authors were;newborn screening(n=54), mutation(n=43), phenylketonuria(n=42), children(n=35), genetics(n= 34) and maple syrup urine disease(n=32).Trending topics were osteoporosis, computed tomography, bone marrow transplantation in the early years of the study, chronic kidney disease, urea cycle disorders, next-generation sequencing, newborn screening, and familial hypercholesterolemia in the final years of the study. This study provides clinicians with a new perspective showing that molecular and genetic studies in inherited metabolic diseases will play an essential role in diagnosis and treatment in the future.

Over the last decades, the increased incidence of metabolic disorders such as type 2 diabetes and obesity has motivated researchers to investigate new enzyme inhibitors. In this study, the inhibitory effects of synthetic amino acid derivatives (PPC80, PPC82, PPC84, PPC89, and PPC101) on the activity of digestive enzymes was assessed by in vitro assays. The inhibitory effect was determined by the inhibition percentage and the 50% inhibitory concentration (IC50), and the mechanism of action was investigated by Lineweaver–Burk plots. PPC80, PPC82, and PPC84 inhibited pancreatic lipase (IC50 of 1.67–10.23 x 10-1 mmol/L). The activity of pancreatic α-amylase was suppressed by PPC80, PPC82, PPC84, PPC89, and PPC101 (IC50 of 1.62–5.19 x 10-1 mmol/L). Finally, PPC84, PPC89, and PPC101 also showed a potent inhibitory effect on α-glucosidase (IC50 of 0.51–3.53 x 10-1 mmol/L). PPC80 and PPC82 followed a non-competitive inhibition mechanism against pancreatic lipase, while PPC84 acted through competitive inhibition. The inhibition of pancreatic α-amylase by the derivatives was non-competitive, as well as for PPC84, PPC89 and PPC101 against α-glucosidase. The results suggest that these synthetic amino acid derivatives have inhibitory potential against digestive enzymes and may be used as therapeutic agents to control metabolic disorders.

The model of obesity induced by monosodium glutamate cytotoxicity on the hypothalamic nuclei is widely used in the literature. However, MSG promotes persistent muscle changes and there is a significant lack of studies that seek to elucidate the mechanisms by which damage refractory to reversal is established. This study aimed to investigate the early and chronic effects of MSG in-duction of obesity upon systemic and muscular parameters of Wistar rats. Animals were exposed to MSG subcutaneously (4 mg.g-1 b.w.) or saline (1.25 mg.g-1 b.w.) daily from PND01 to PND05 (n = 24). After, in PND15, 12 animals were euthanized to determine the plasma and inflammatory profile and to assess muscle damage. In PND142, the remaining animals were euthanized, and samples for histological and biochemical analyses were obtained. Our results suggest that early exposure to MSG reduced growth, and increased adiposity, induction hyperinsulinemia, and a pro-inflammatory scenario. In adulthood were found, peripheral insulin resistance, reduced muscle mass, oxidative capacity, neuromuscular junctions, increased fibrosis, and oxidative distress. Thus, we can conclude that the condition found in adult life and the difficulty in restoring the muscle profile are related to the metabolic damages established early.

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.

Purpose: Obstructive sleep apnoea (OSA) affects patients’ quality of life and health. Magnesium (Mg) is an essential mineral and a potent antioxidant. Mg deficiency can worsen oxidative stress caused by sleep deprivation or disorders. The impact of OSA on serum Mg levels and its health consequences remain unclear. Methods: This study systematically reviewed clinical studies investigating the serum Mg levels of OSA patients and the potential relationships with other biomarkers.Results: Six articles were included for qualitative synthesis; five were used in quantitative analysis. Two out of four studies that compared OSA patients to healthy controls found them to have significantly lower serum Mg levels. Our meta-analysis with three studies shows that patients with OSA had significantly lower serum Mg with an effect size of -1.22 (95% CI: -2.24, -0.21). However, the mean serum Mg level of OSA patients (n=251) pooled from five studies (1.90 mg/dL, 95% CI: 1.77, 2.04) does not differ significantly from the normal range. OSA severity appears to affect serum Mg negatively. Serum Mg levels generally improve after treatment, coincide with the improvement of OSA severity. Low serum Mg levels correlate with worsening of cardiovascular risk biomarkers of C-reactive protein, ischaemia-modified albumin, and carotid intima-media thickness. The serum Mg levels also potentially correlate with biomarkers for lipid profile, glucose metabolism, calcium and heavy metals. Conclusions: Sleep deprivation appears to deplete Mg levels of OSA patients, making them at risk of Mg deficiency, which potentially increases systemic inflammation and the risk of cardiovascular and metabolic diseases.

Patients with schizophrenia (SCZ) are at high risk of cardiovascular disease (CVD) due to an inherited predisposition, a sedentary life style and the use of antipsychotic medications. Several approaches have been taken to minimize this risk but results continue to be unsatisfactory. A potential alternative is prescribing Selective Serotonin Reuptake Inhibitors (SSRIs). SSRIs decrease platelet aggregation and reduce the risk of coronary heart disease in patients with depression. We therefore aim to investigate whether there is evidence that supports the use of SSRIs to reduce the risk for CVD in SCZ. A systematic review of the literature revealed five published reports relating to the impact of SSRIs on CV risk in SCZ. Three trials assessed the influence on metabolic parameters of fluvoxamine when combined with clozapine. Two of those studies found improvements with fluvoxamine. Of the other two reports, one indicates SSRIs as a group caused minimal but statistically significant increments in total cholesterol, LDL and triglyceride. The second report suggests that when SSRIs are combined with antipsychotics, the metabolic impact depends on the antipsychotic prescribed. While there are promising results, further studies are needed to establish the impact of SSRIs on CV risk in SCZ.

Microbes do not live in isolation but in microbial communities. The relevance of microbial communities is increasing due to the awareness about their biotechnological influences in a huge number of environmental, health and industrial processes. Hence, being able to control and engineer the output of both natural and synthetic communities would be of great interest. However, most of the available methods and biotechnological applications (both in vivo and in silico) have been developed in the context of isolated microbes. In vivo microbial consortia development, i.e. to reproduce the community life conditions in the wet-lab, is extremely difficult and expensive requiring of computational approaches to advance knowledge about microbial communities, mainly with descriptive modelling, and further with engineering modelling. In this review we provide a detailed compilation of available examples of engineered microbial communities as a launch pad for an exhaustive and historical revision of those computational methods devoted so far toward the better understanding, and rational engineering of natural and synthetic microbial communities.

Multi-step evolution characterizes the carcinogenesis of GI malignancies, where the disease progresses through the accrual of genetic mutations, co-option of multiple host cellular factors and the acquisition of increasingly aggressive pathological features. Ensuing cancer complexity and plasticity are challenges for therapeutic approaches. On the other hand, disease inception is often triggered by a defined oncogenic event, which leads to escalating effects on gene expression, cellular metabolism, chromatin organization and ultimately cell identity. Decoding this molecular cascade of events is crucial to design strategies for early diagnosis as well as to tackle tumor onset. To this aim, the in vitro culture of non-transformed epithelial cells represents a major technical challenge. Genetic studies, combined with lineage-tracing experiments demonstrated that pancreatic cancerous lesions originate from acinar cells, a specialized cell type in the pancreatic epithelium, following mutations of the KRAS oncogene. Ex vivo culture of pancreatic acinar cells has allowed the identification of early mutant KRAS-driven alterations. Primary acinar cells survive in vitro in organoid-like 3D spheroids, which can recapitulate histological and molecular features of disease initiation. Here, we will discuss the isolation and culture of primary mouse pancreatic acinar cells, providing and historical and technical perspective. Impact for pancreatic cancer research will also be debated; in particular we will dissect the role of KRAS signaling in driving oncogenic transformation and highlight differences with canonical 2D culture of established cancer cell lines.

The Maximum Entropy Theory of Ecology, or METE, is a theoretical framework of macroecology that makes a variety of realistic ecological predictions about how species richness, abundance of species, metabolic rate distributions, and spatial aggregation of species interrelate in a given region. In the METE framework, "ecological state variables" (representing total area, total species richness, total abundance, and total metabolic energy) describe macroecological properties of an ecosystem. METE incorporates these state variables into constraints on underlying probability distributions. The method of Lagrange multipliers and maximization of information entropy (MaxEnt) lead to predicted functional forms of distributions of interest. We demonstrate how information entropy is maximized for the general case of a distribution, which has empirical information that provides constraints on the overall predictions. We then show how METE’s two core functions are derived. These functions, called the "Spatial Structure Function" and the "Ecosystem Structure Function" are the core pieces of the theory, from which all the predictions of METE follow (including the Species Area Distribution, the Species Abundance Distribution, and various metabolic distributions). Primarily, we consider the discrete distributions predicted by METE.We also explore the parameter space defined by the METE’s state variables and Lagrange multipliers. We aim to provide a comprehensive resource for ecologists who want to understand the derivations and assumptions of basic mathematical structure of METE.

The increased consumption of high fat-containing foods has been linked to the prevalence of obesity and abnormal metabolic syndromes. Rhizopus oligosporus, a fungus in the family Mucoraceae, is widely used as a starter for homemade tempeh. Although R. oligosporus can prevent the growth of other microorganisms, it grows well with lactic acid bacteria (LAB). Lactobacillus plantarum can produce β-glucosidase, which catalyzes the hydrolysis of glucoside isoflavones into aglycones (with greater bioavailability). Therefore, the development of a soybean-based functional food by the co-inoculation of R. oligosporus and L. plantarum is a promising approach to increase the bioactivity of tempeh. In this study, the ameliorative effect of L. plantarum in soy tempeh on abnormal carbohydrate metabolism in high-fat diet (HFD)-induced hyperglycemic rats was evaluated. The co-incubation of L. plantarum with R. oligosporus during soy tempeh fermentation reduced the homeostatic model assessment of insulin resistance, HbA1c, serum glucose, total cholesterol, triglyceride, free fatty acid, insulin, and low-density lipoprotein contents and significantly increased the high-density lipoprotein content in HFD rats. It also increased the LAB counts as well as the bile acid, cholesterol, triglyceride, and short-chain fatty acid contents in the feces of HFD rats. Our results suggested that the modulation of serum glucose and lipid levels by LAB occurs via alterations in the internal microbiota, leading to the inhibition of cholesterol synthesis and promotion of lipolysis. Tempeh, produced with both L. plantarum and R. oligosporus, may be a beneficial dietary supplement for individuals with abnormal carbohydrate metabolism.

Evidence shows that weightloss improves insulin sensitivity but few studies have examined the effect of macronutrient composition independently of weight loss on direct measures of insulin sensitivity. We randomised 89 overweight or obese women to either a standard diet (StdD) that was intended to be low in fat and relatively high in carbohydrate (n=42) or to a relatively high protein (up to 30% of energy), relatively high fibre (>30g/day) diet (HPHFib) (n=47) for 10 weeks. Advice regarding strict adherence to energy intake goals was not given. Insulin sensitivity and secretion was assessed by a novel method - the Dynamic Insulin Sensitivity and Secretion Test (DISST). Although there were significant improvements in body composition and most cardiometabolic risk factors on HPHFib, insulin sensitivity was reduced by 19.3% (95% CI: 31.8, 4.5%; p=0.013) in comparison with StdD. We conclude that the reduction in insulin sensitivity after a diet relatively high in both protein and fibre, despite cardiometabolic improvements, suggests insulin sensitivity may reflect metabolic adaptations to dietary composition for maintenance of glucose homeostasis, rather than impaired metabolism.

Chronic kidney disease (CKD) and cardiovascular disease (CVD) are highly prevalent conditions, each significantly contributing to the global burden of morbidity and mortality. CVD and CKD share a great number of common risk factor, such as hypertension, diabetes, obesity, and smoking among others. Their relationship extends beyond these factors, encompassing intricate interplay between the two systems. Within this complex network of pathophysiological processes, vitamin D has emerged as a potential linchpin, exerting influence over diverse physiological pathways implicated in both CKD and CVD. In recent years, scientific exploration has unveiled a close connection between these two prevalent conditions and vitamin D, a crucial hormone traditionally recognized for its role in bone health. This article aims to provide an extensive review of vitamin D's multifaceted and expanding actions concerning its involvement in CKD and CVD.

Lower limb exoskeletons have the potential to reduce the prevalence of work-related musculoskeletal disorders; however, they often lack user-oriented control strategies. Human-in-the-loop (HITL) controls can adapt an exoskeleton’s assistance in real-time, to optimize the user-exoskeleton interaction. This study presents a HITL control for a knee exoskeleton to minimize the users’ physical effort, a parameter innovatively evaluated by their interaction torque with the exoskeleton (a muscular effort indicator) and metabolic cost. This work innovates by estimating the user’s metabolic cost within the HITL control through a machine-learning model. The regression model was able to estimate the metabolic cost, in real-time, with a root-mean-squared error of 0.66 W/kg and a mean absolute percentage error of 26%, making faster (10s) and less noisy estimations than a respirometer (K5, Cosmed) device. The HITL reduced the user’s metabolic cost and interaction torque by 7.3% and 32.3%, respectively, when compared to a zero-torque control. The developed HITL control surpassed both a non-exoskeleton and a zero-torque condition regarding the user’s physical effort, even for a simple task such as slow walking. Furthermore, the user-specific control enabled a lower metabolic cost than the non-user-specific assistance. This proof-of-concept demonstrated the potential for HITL controls in assisted working.

Punica granatum L., commonly known as pomegranate, is a typical fruit of Asia, Mediterranean countries, Middle East and USA areas. While in the ancient time pomegranate was considered an ornamental plant, nowadays numerous scientific studies have highlighted its antioxidant and anti-radical activities, up to consider pomegranate as a “superfood”. Pomegranate presents a high content of natural bioactive compounds (NBCs) and its consumption appears to exert numerous healthy beneficial effects, in particular, in several pathological conditions, namely in patients affected by metabolic syndrome, cancer, nephrolithiasis, urinary tract infections and neurodegenerative diseases. Moreover, recent studies pointed out the possible beneficial action of pomegranate on oral health. For these reasons, the utility of pomegranate in internal medicine and in dentistry represents a promising field, as it could permit the development of innovative natural adjuvant therapies, able to empower the standard pharmaceutical therapies.

As yin and yang, cancer and diabetes are metabolic disorders characterized by deregulated, yet opposing, metabolic alterations. These metabolic shifts reflect a complex network of defective underlying signaling pathways, which ultimately orchestrate both disease pathogenesis and progression. The Warburg effect portrays the chief metabolic phenotype in cancer and is reflected by the dominance of aerobic glycolysis over minimal-to-no viable oxidative phosphorylation in cancer. Conversely, during the pathogenesis of type 2 diabetes (T2D), oxidative phosphorylation is constantly heightened. In advanced insulin resistance and T2D, the metabolic landscape becomes more complex, with exacerbating metabolic alterations affecting oxidative phosphorylation in a tissue-specific manner. Promising nutritional adjuvants, such as alpha-lipoic acid and flavonoids, can reprogram metabolism and exert antitumor and antidiabetic effects. Other pharmacological agents, such as metformin, have therapeutic effects on cancer and T2D. Herein, we discuss the molecular mechanisms and signaling pathways involved in the metabolic shifts in cancer and T2D, and explore the therapeutic strategies under investigation that aim to reverse the metabolic shift in both disease scenarios.

Hyperhomocysteinemia (HHcys) is recognized as an independent risk factor for various significant medical conditions, yet controversy persists around its assessment and management. The diagnosis of disorders affecting homocysteine (Hcys) metabolism faces delays due to insufficient awareness of its clinical presentation and unique biochemical characteristics. In cases of arterial or venous thrombotic vascular events, particularly with other comorbidities, it is crucial to consider moderate to severe HHcys. A nutritional approach to HHcys management involves implementing dietary strategies and targeted supplementation, emphasizing key nutrients like vitamin B6, B12, and folate crucial for Hcys conversion. Adequate intake of these vitamins, along with betaine supplementation, supports Hcys remethylation. Lifestyle modifications, such as smoking cessation and regular physical activity, complement the nutritional approach to enhance Hcys metabolism. For individuals with HHcys, maintaining a plasma Hcys concentration below 50 μmol/L consistently is vital to lower the risk of vascular events. Collaboration with healthcare professionals and dietitians is essential for developing personalized dietary plans addressing specific needs and underlying health conditions. This integrated approach aims to optimize metabolic processes and reduce the associated health risks.

HIV-associated cognitive dysfunction during combination antiretroviral therapy (cART) involves mitochondrial dysfunction, but the impact of contemporary cART on chronic metabolic changes in the brain and in latent HIV infection is unclear. We interrogated mitochondrial function in a human microglia (hμglia) cell line harboring inducible HIV provirus, and in SH-SY5Y cells, after exposure to individual antiretroviral drugs or cART, using the MitoStress assay. cART-induced changes in protein expression, reactive oxygen species (ROS) production, mitochondrial DNA copy number, and cellular iron were also explored. Finally, we evaluated the ability of ROS scavengers or plasmid-mediated overexpression of the antioxidant iron-binding protein, Fth1, to reverse mitochondrial defects. Contemporary antiretroviral drugs, particularly bictegravir, depressed multiple facets of mitochondrial function by 20-30%, with most pronounced effects in latently infected-HIV+ hμglia and SH-SY5Y cells. Latently HIV-infected hμglia exhibited upregulated glycolysis. Increases in total and/or mitochondrial ROS, mitochondrial DNA copy number, and cellular iron accompanied mitochondrial defects in hμglia and SH-SY5Y cells. In SH-SY5Y cells, cART reduced mitochondrial iron-sulfur-cluster-containing supercomplex and subunit expression and increased Nox2 expression. Fth1 overexpression or pre-treatment with N-acetylcysteine prevented cART-induced mitochondrial dysfunction. Contemporary cART impairs mitochondrial bioenergetics in hμglia and SH-SY5Y cells, partly through cellular iron accumulation; some effects differ by HIV latency.

Obesity is a troubling public health problem worldwide as it increases risks of respiratory complications, systemic arterial hypertension, type 2 diabetes mellitus, sleep disorders, cardiovascular diseases, and metabolic syndrome (MetS). As a measure to counteract comorbidities associated with severe obesity, bariatric surgery stands out. This study aimed to investigate the adiponectin/leptin ratio in women with severe obesity with and without MetS undergone Roux-en-Y Gastric Bypass (RYGB) and to characterize the biochemical, glucose, and inflammatory parameters of blood in women with severe obesity before and after RYGB. Were enrolled female with severe obesity undergoing RYGP with MetS (n=11) and without (n=39). Anthropometric data and blood samples were obtained before and 6 months after RYGB to analyze total cholesterol, low-density lipoprotein (LDL), high- density lipoprotein (HDL), non-HDL total cholesterol, and glucose; and circulating levels of adiponectin and leptin. Significant reductions in weight, body mass index, and glucose, total cholesterol, LDL, and leptin were observed after surgery, with higher levels of HDL, adiponectin, and adiponectin/leptin ratio observed after surgery compared to preoperative values. This study demonstrated that weight loss induced by RYGB in patients with severe obesity with or without MetS improved biochemical and systemic inflammatory parameters, particularly the adiponectin/leptin ratio.

BACKGROUND. Two sequelae of non-alcoholic steatohepatitis (NASH), ESLD and HCC, have become the leading causes for liver transplantation in the Western. The present study aims to approach the cellular metabolic disturbances involved in NASH progression that are associated with microbiota community changes. METHODS. Metabolic effects and microbiota community changes were explored in the murine with NASH progression by blocking the Na/K-ATPase/Src/reactive oxygen amplification loop using the synthetic targeting peptide pNaKtide. DNA from the terminal ileum microbiota habitat was obtained and amplified by PCR to develop DNA bacterial phylogenic sequence analysis of wild type and treated animals at 12, 24 and 48 weeks. Induced changes by pSrc normalization at 24 weeks were correlated with liver morphological changes, intestinal CD4+/CD8+ ratio, and liver macrophage CD14+ expression. Differences among groups were evaluated by ANOVA/t-test and Principal Component Analysis (PCA). RESULTS. Microbiota communities varied significantly at all time points (12, 24 and 48 weeks), with an increase of Verrucomicrobia and a decrease of Bacteroidetes and Firmicutes in the HFD group. Microbiota community changes regressed to their wild-type state at 24 weeks on treated animals, and those changes were associated with a decrease in liver inflammation and senescence, lower ileum CD4+/CD8+ T cells and higher liver CD14+ cells (p<0.05). Concomitantly, the metabolic disturbances in our diet-induced NASH model were normalized by NKA/Src signaling blockage and exercise with a paucity of apoptotic activity, mitigation of cell senescence, and regression of liver fibrosis (p<0.01). CONCLUSIONS. pSrc inhibition at caveolar α1-Na/K-ATPase rescinded NASH-related metabolic disturbances establishing resident physiological microbiota communities with concomitant paucity on apoptotic activity and regression of liver fibrosis; effects that were associated with both gut and liver T-lymphocyte responses.

Chinese Taihe Black-bone silky fowl (TBsf) is the homology of medicine and food and has high nutritional and medical value all over the world. However, the nutritional compositions and specific metabolite advantages of Taihe silky fowl muscle are still poorly understood. In this study, we investigated the differences of nutritional components between TBsf and another similar breed (Black Feathered chicken and laid green-shelled eggs, BF-gsc). Meanwhile, we also explored the divergences in muscle characteristics of Taihe silky fowl fed with two different diets, that is normal chicken feed (TBsf-ncf) and Broussonetia papyrifera-fermented feed (TBsf-bpf). Firstly, the growth performance and biochemical index of Taihe silky fowl was significantly different compared with black-feathered chicken. Secondly, we identified the metabolic alterations in Taihe silky fowl by performing an un-targeted UHPLC-Q-TOF-MS/MS analysis. Our results suggested that the whole metabonomic characteristics had obvious separation between TBsf-ncf, TBsf-bpf and BF-gsc groups both in the positive and negative ion mode by PCA analysis. Next, OPLS-DA multivariate analysis revealed that 57 metabolites (in positive mode) and 49 metabolites (in negative mode) were identified as differential metabolites between TBsf-ncf and BF-gsc group. These differential metabolites were mainly enriched to ABC transporters, biosynthesis of amino acids and aminoacyl-tRNA biosynthesis. Besides, there were 47 metabolites (in positive) and 13 metabolites (in negative) were differentially regulated between TBsf-ncf and TBsf-bpf group, which were majorly involved in histidine metabolism and linoleic metabolism. Furthermore, the integrated network analysis suggested that DL-arginine, DL-isoleucine, linoleoylcarnitine, stearoylcarnitine (positive) and ricionleic acid, D-proline, uric acid (negative) were the significantly metabolic biomarkers in Taihe silky fowl. Moreover, the metabolites of primaquine, ticlpoidine, riboflavin, acetylcarnitine (positive) and salicylic acid, acetaminophen sulfate, glutamic acid (negative) were markedly changed in the Taihe silky fowl fed with BP-fermented feed. In summary, a global survey of the nutritional components and metabolite differences were performed in muscle tissues of Taihe silky fowl between various breeds and feeds. The comprehensive expression profiles of the metabolites in Taihe silky fowl affected by genetic and environmental factors were acquired. This study provided valuable evidence fo breed and feed-induced putative biomarkers as well as improved the economic value of Taihe silky fowl through targeted metabolite regulation.

The main aim of the present study was to explore health professionals’ reported experiences and approaches to managing children who receive a designation of cystic fibrosis transmembrane conductance regulator-related metabolic syndrome/cystic fibrosis screen positive inconclusive diagnosis following a positive NBS result for cystic fibrosis. An online questionnaire was distributed via Qualtrics Survey Software and circulated to a purposive, international sample of health professionals involved in managing children with this designation. In total, 101 clinicians completed the online survey; 39 from the US, six from Canada and 56 from Europe (including the UK). Results indicated that while respondents reported minor deviations in practice, they were cognizant of recommendations in the updated guidance and for the most part, attempted to implement these into practice consistently internationally. Where variation was reported, the purpose of this appeared to be to enable clinicians to respond to either clinical assessments or parental anxiety in order to improve outcomes for the child and family. Further research is needed to determine if these findings are reflective of both a wider audience of clinicians and actual (rather than reported) practice.

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.

Short chain quinones (SCQs) have been identified as potential drug candidates against mitochondrial dysfunction, which is largely dependent on their reversible redox characteristics of the active quinone core. We recently synthesized a SCQ library of > 148 naphthoquinone derivatives and identified 16 compounds with enhanced cytoprotection compared to the clinically used benzoquinone idebenone. One of the major drawbacks of idebenone is its high metabolic conversion in the liver, which significantly restricts is therapeutic activity. Therefore, this study assessed the metabolic stability of the 16 identified naphthoquinone derivatives 1-16 using hepatocarcinoma cells in combination with an optimized reverse-phase liquid chromatography (RP-LC) method. Most of the derivatives showed significantly better stability than idebenone over 6 hours (p < 0.001). By extending the side-chain of SCQs, increased stability for some compounds was observed. Metabolic conversion from the derivative 3 to 5 and reduced idebenone metabolism in the presence of 5 were also observed. These results highlight the therapeutic potential of naphthoquinone-based SCQs and provide essential insights for future drug design, prodrug therapy and polytherapy, respectively.

The modification the gut microbiota in metabolic syndrome and associated chronic diseases is among leading tasks of microbiome research and needs for clinical use of probiotics. Evidence lack for the implications for microbiome modification to improve metabolic health in particular when applied impersonalized. Probiotics have tremendous potential in personalized nutrition and medicine to develop healthy diets. The aim was to to conduct comprehensive overview of recent updates of role of microbiota on human health and development of metabolic syndrome and efficacy of microbiota modulation considering specific properties of probiotic strain and particular aspects of metabolic syndrome and patient`s phenotype to fill the gap between probiotic product and individual to facilitate development of individualized / personalized probiotic and prebiotic treatments. We discuss the relevance of using host phenotype-associated biomarkers, those based on imaging and molecular and patrient`s history, reliable and accessible to facilitate person-specific appication of probiotics and prebiotic substances. Microbiome phenotypes can be parameters of predictive medicine to recognize patient`s predispositions and evaluate treatment responses; the number of phenotype markers can be effectively involved to monitor microbiome modulation. The studied strain-dependent properties of probiotic strains are potentially relevant for individualized treatment for gut and distant sites microbiome modulation. The evidence regarding probiotic strains properties can be taken to account via pathophysiology-based approach for most effective individualized treatment via gut, oral and vaginal and other sites microbiome modulation according to phenotype of the patient providing individualized and personalized medical approaches. Preventive potential of probiotics is strong and well-documented. Recommendations for individualized clinical use of probiotics, and for probiotic studies design have been suggested.

The peroxiredoxin (PRDX) family, a new family of proteins with a pivotal antioxidative function, is ubiquitously synthesized and abundantly identified in various organisms. In contrast to the intracellular localization of other family members (PRDX1/2/3/5/6), PRDX4 is the only known secretory form and protects against oxidative damage by scavenging reactive oxygen species in both the intracellular (especially the endoplasmic reticulum) compartments and the extracellular space. Recently, we generated unique human PRDX4 (hPRDX4) transgenic (Tg) mice on a C57BL/6J background and investigated the critical and diverse protective roles of PRDX4 against diabetes mellitus, atherosclerosis, insulin resistance, and nonalcoholic fatty liver disease (NAFLD) as well as evaluated its role in the intestinal function in various animal models. Our published data have shown that PRDX4 helps prevent the progression of metabolic syndrome by reducing local and systemic oxidative stress and synergistically suppressing steatosis, inflammatory reactions, and/or apoptotic activity. These observations suggest that Tg mice may be a useful animal model for studying the relevance of oxidative stress on inflammation and the dysregulation of lipid/bile acid/glucose metabolism upon the progression of human metabolic syndrome, and that specific accelerators of PRDX4 may be useful as therapeutic agents for ameliorating various chronic inflammatory diseases.

Background: Metabolic flux analysis (MFA) is an indispensable tool in metabolic engineering. The simplest variant of MFA relies on an overdetermined stoichiometric model of the cell’s metabolism under the pseudo-steady state assumption, to evaluate the intracellular flux distribution. Despite its long history, the issue of model error in the overdetermined MFA, particularly misspecifications of the stoichiometric matrix, has not received much attention. Method: We evaluated the performance of statistical tests from linear least square regressions, namely Ramsey RESET test, F-test and Lagrange multiplier test, in detecting model misspecifications in the overdetermined MFA, particularly missing reactions. We further proposed an iterative procedure using the F-test to correct such an issue. Result: Using Chinese hamster ovary and random metabolic networks, we demonstrated that: (1) a statistically significant regression does not guarantee high accuracy of the flux estimates, (2) the removal of a reaction with a low flux magnitude can cause disproportionately large biases in the flux estimates, (3) the F-test could efficiently detect missing reactions, and (4) the proposed iterative procedure could robustly resolve the omission of reactions. Conclusion: Our work demonstrated that statistical analysis and tests could be used to systematically assess, detect and resolve model misspecifications in the overdetermined MFA.

Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses metabolic dysfunction-associated fatty liver (MASL) and metabolic dysfunction-associated steatohepatitis (MASH), with MASH posing a risk of progression to cirrhosis and hepatocellular carcinoma (HCC). The global prevalence of MASLD is estimated at approximately a quarter of the population, with significant healthcare costs and implications for liver transplantation. The pathogenesis of MASLD involves intrahepatic liver cells, extrahepatic components, and immunological aspects, particularly the involvement of macrophages. Hepatic macrophages are a crucial cellular component of the liver and play vital roles in liver function, contributing significantly to tissue homeostasis and swift responses during pathophysiological conditions. Recent advancements in technology have revealed the remarkable heterogeneity and plasticity of hepatic macrophage populations and their activation states in MASLD, challenging traditional classification methods like the M1/M2 paradigm and highlighting the coexistence of harmful and beneficial macrophage phenotypes that are dynamically regulated during MASLD progression. This complexity underscores the importance of considering macrophage heterogeneity in therapeutic targeting strategies, including their distinct ontogeny and functional phenotypes. This review provides an overview of macrophage involvement in MASLD progression, combining traditional paradigms with recent insights from single-cell analysis and spatial dynamics. It also addresses unresolved questions and potential therapeutic targets in this area.

The gastrointestinal tract is colonized by trillions of different microorganisms, named the gut microbiota, which is key to degrade undigested food such as dietary fibers. The fermentation of these food components leads to the production of short-chain fatty acids (SCFA) acetate, propionate, and butyrate, which exploit several beneficial roles for the host’s health. Their production and absorption happen in different ways in the human intestine and depend on the type of dietary fiber reaching the gut and the microorganisms involved in the fermentation. The supplementation of SCFAs, mostly butyrate, in treating gastrointestinal, metabolic, cardiovascular, and gut-brain-related diseases has been reported in the medical literature. This review aims to give an overview of the production and absorption dynamics of acetate, propionate, and butyrate in the human gut, with a final focus on the role played by these SCFAs on gastrointestinal and metabolic health and the present therapeutic implications.

Salidroside, a valuable phenylethanoid glycoside, is obtained from plants belonging to the Rhodiola genus, known for its diverse biological properties. At present, salidroside is still far from large-scale industrial production due to the lower titer and higher process cost. In this study, we constructed a biosynthetic pathway from L-tyrosine to salidroside in Saccharomyces cerevisiae. To increase sali-droside production, we for the first time constructed an in vivo UDP-glucose regeneration system that sucrose synthase GmSUS worked in conjunction with UDP-glucose transferase RrUGT33 to improve the UDP-glucose availability with inexpensive sucrose as the consumed substrate. Finally, the molar conversion rate of L-tyrosine could reach 95%. To further reduce the cost, co-culture with E. coli that synthesized L-tyrosine de novo resulted in an 81% reduction in the final substrate cost per 1 kg of salidroside compared to the initial cost. The final titer of salidroside obtained 3.8 g/L and was the highest titer achieved at the Shake-Flask-Level in the existing reports. And this marked the first successful synthesis of salidroside in an in situ enhanced UDP-glucose system using sucrose. This accomplishment laid a robust groundwork for further investigations into the synthesis of other notable glycosides and natural compounds.

Long-term storage may reduce the nutritional quality of brown rice, so the present study was aimed to evaluate the nutritive values and application in pig diets. In Exp.1, 18 Landrace × Yorkshire (L × Y) barrows with initial body weight (IBW) of 25.48 ± 3.21 kg were randomly assigned to three treatments, which included corn diet, one-year stored brown rice (BR1) diet and six-year stored brown rice (BR6) diet, to determine the digestible energy (DE) and metabolisable energy (ME) value of stored brown rice. In Exp. 2, 24 barrows (L × Y; IBW: 22.16 ± 2.42 kg) fixed with ileal T-cannula were randomly allotted to four dietary treatments, including corn diet, two stored brown rice diets and nitrogen-free diet, to evaluate the amino acid (AA) digestibility of stored brown rice. In Exp. 3 and 4, 108 crossbred weaned piglets (L × Y; IBW: 9.16 ± 0.89 kg) and 90 crossbred growing pigs (L × Y; IBW: 48.28 ± 3.51 kg) were allotted to 3 treatment diets, including control diet and two stored brown rice diets, respectively, to investigate the application of stored brown rice in weaned piglet and growing-finishing pig diets. Results showed that: 1) The DE and ME of corn and stored brown rice showed no significant differences (P > 0.05), while the apparent ileal digestibility (AID) of arginine, histidine, aspartic acid, and the standardized ileal digestibility (SID) of arginine and histidine were higher in stored brown rice compared to corn (P < 0.05). 2) Compared with the control diet, the stored brown rice diets showed no significant effects on growth performance, nutrient apparent total tract digestibility (ATTD) and serum biochemical indices (P > 0.05), but decreased digestive enzymes activities in duodenum, jejunum and ileum of piglets (P < 0.05). 3) Compared with the control diet, the stored brown rice diets showed no significant effects on growth performance, carcass traits, meat quality, fatty acids profiles in the longissimus dorsi muscle of growing-finishing pigs (P > 0.05). In conclusion, the brown rice stored for 6 years under good conditions has no obvious changes in available energy and nutrient values. Although it may reduce digestive enzyme activity in small intestine of the piglets, the stored brown rice showed no obvious adverse effect on growth performance and meat quality, and can be effectively used in pig diet.

Metabolic surgery can promote comprehensive physiological improvements to alleviate metabolic disorders, particularly for patients with type 2 diabetes. Nevertheless, the therapeutic scope has been limited owing to unexpectedly inconsistent surgical outcomes. Therefore, this study to overcome these obstacles by determining the fundamental mechanism underlying the conflicting outcomes. The surgical anatomy, clinical course, and outcomes of various metabolic surgeries, including modified duodenal-jejunal bypass (DJB) procedures, were compared to understand the specific surgical patterns from different perspectives comprehensively. Patients in the nonobese group were exclusively included to prevent confounding effects from overweight patients with type 2 diabetes. Following intestinal anastomosis, the epithelial identity of the succeeding intestine was replaced by that of the proximal epithelium owing to altered crosstalk between the epithelium and opposing mesenchymal cells. Subsequent intestinal compensatory proliferation and rapid turnover rate accelerate the spread of the replaced epithelium. The main factors contributing to inconsistent outcomes of metabolic surgery are inadequate duodenal exclusion and inappropriate biliopancreatic limb length. Replacement of enteroendocrine cells during regeneration can lead to inconsistent outcomes in metabolic surgery. The type and density of enteroendocrine cells distributed at the terminal end of the proximal intestine play a significant role in diverse outcomes of metabolic surgery.

Porphyrinic photosensitizers (PSs) and their nano-sized polymer-based carrier systems are required to exhibit low dark toxicity, avoid side effects, and ensure high in vivo tolerability. Yet, little is known about the intracellular fate of PSs during the dark incubation period and how it is af-fected by nanoparticles. In a systematic study, high resolution magic angle spinning NMR spectroscopy combined with statistical analyses was used to study the metabolic profile of cultured HeLa cells treated with different concentrations of the PS chlorin e4 (Ce4) alone or encapsulated in carrier systems. For the latter, either polyvinylpyrrolidone (PVP) or the micelle forming polyethylene glycol (PEG)-polypropylene glycol triblock copolymer Kolliphor P188 (KP) were used. Diffusion edited spectra indicated Ce4 membrane localization evidenced by Ce4 concentration dependent chemical shift perturbation of the cellular phospholipid choline resonance. The effect was also visible in the presence of KP and PVP, but less pronounced. The appearance of the PEG resonance in the cell spectra pointed towards cell internalization of KP whereas no conclusion could be drawn for PVP that remained NMR-invisible. Multivariate statistical analyses of the cell spectra (PCA, PLS-DA and oPLS) revealed a concentration-dependent metabolic response upon exposure to Ce4 that was attenuated by KP and even more by PVP. Significant Ce4-concentration dependent alterations were mainly found for metabolites involved in the tricarboxylic acid cycle and the phosphatidylcholine metabolism. The data underline an important protective role of the polymeric carriers following cell internalization. Moreover, the current study allowed - to our knowledge for the first time - to trace the intracellular PS localization on an atomic level by NMR methods.

Polycystic ovary syndrome (PCOS) is a common endocrinopathy of reproductive-aged women characterized by hyperandrogenism, oligo-anovulation and insulin resistance closely linked with preferential abdominal fat accumulation. As an ancestral primate trait, PCOS was likely further selected in humans when scarcity of food in hunter-gatherers of the late Pleistocene additionally programmed for enhanced fat storage to meet the metabolic demands of reproduction in later life. As an evolutional model for PCOS, healthy normal-weight women with hyperandrogenic PCOS have subcutaneous (SC) abdominal adipose stem cells that favor fat storage through exaggerated lipid accumulation during development to adipocytes in vitro. In turn, fat storage is counterbalanced by reduced insulin sensitivity and preferential accumulation of highly-lipolytic intra-abdominal fat in vivo. This metabolic adaptation in PCOS balances energy storage with glucose availability and fatty acid oxidation for optimal energy use during reproduction; its accompanying oligo-anovulation allowed PCOS women from antiquity sufficient time and strength for childrearing of fewer offspring with a greater likelihood of childhood survival. Heritable PCOS characteristics are now affected by today’s contemporary environment through epigenetic events that predispose to lipotoxicity with excess weight gain and pregnancy complications, calling for an emphasis on preventive healthcare to optimize the long-term, endocrine-metabolic health of PCOS women in today’s obesogenic environment.

The co-occurrence of depression and obesity has become a significant public health concern worldwide. Recent studies have shown that metabolic dysfunction, which is commonly observed in obese individuals and characterized by inflammation, insulin resistance, leptin resistance, and hypertension, is a critical risk factor for depression. This dysfunction may induce structural and functional changes in the brain, ultimately contributing to depression's development. Given that obesity and depression mutually increase each other's risk of development by 50-60%, there is a need for effective interventions that address both conditions. The comorbidity of depression with obesity and metabolic dysregulation is thought to be related to chronic low-grade inflammation, characterized by increased circulating levels of pro-inflammatory cytokines, and C-reactive protein (CRP). As pharmacotherapy fails in at least 30-40% of cases to adequately treat major depressive disorder, a nutritional approach is emerging as a promising alternative. Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are a promising dietary intervention that can reduce inflammatory biomarkers, particularly in patients with high levels of inflammation, including pregnant women with gestational diabetes, patients with type 2 diabetes mellitus, and overweight individuals with major depressive disorder. Further effort directed to implement these strategies in clinical practice could contribute to improved outcomes in patients with depression and comorbid obesity and/or metabolic dysregulation.

Drought events are predicted to become more prevalent in the future. Evaluating the performance of herbicide-resistant and susceptible weed ecotypes to progressive drought can provide insights into whether resistance trait(s) increased or reduced the fitness of a resistant population. Two experiments were conducted in the greenhouse between January and May 2021 to evaluate drought tolerance differences between Palmer amaranth accessions resistant to S-metolachlor or glyphosate and their susceptible counterparts. The accessions used were: S-metolachlor-resistant (17TUN-A), a susceptible standard (09CRW-A), and glyphosate-resistant (22 to 165 EPSPS copies) and glyphosate-susceptible (3 to 10 EPSPS copies) plants from accession 16CRW-D. Daily transpiration of each plant was measured. The daily transpiration rate was converted to normalized transpiration ratio (NTR) using a double-normalization procedure. The daily soil water content was expressed as a fraction of transpirable soil water (FTSW). The threshold FTSW (FTSWcr), after which NTR decreases linearly, was estimated using a two-segment linear regression analysis. The data showed differences between S-metolachlor- resistant and -susceptible accessions (P ≤ 0.05). The FTSW remaining in the soil at the breakpoint for the S-metolachlor-susceptible accession (09CRW-A) was 0.17±0.007. The FTSW remaining in the soil at the breakpoint for the S-metolachlor-resistant accession (17TUN-A) was 0.23±0.004. Although the mechanism endowing resistance to S-metolachlor might have contributed to increased drought tolerance, follow-up experiments are needed to verify this finding. Increased EPSPS copy number did not improve drought tolerance of Palmer amaranth.

Background: Nutritional rickets is still considered as a global health problem especially in low-resource countries and immigrant societies of developed countries. Generalized skeletal deformities including angular knee deformities as genu varum and genu valgum are prominent features of nutritional rickets. Angular knee deformities can cause gait difficulties. However, the true remodelling potential of the healed knee deformities is largely unknown to the pediatric and orthopedic community. Aims: The primary objective of this study protocol is to investigate the natural history of disease in regard to the remodelling potential of angular knee deformities in children and adolescents with healed nutritional rickets. And determine the potential patient- and deformity-related factors that are associated with a favorable deformity remodelling as age and sex of patients and type, severity, laterality of deformities etc. Methods: This will be a prospective observational analytical cohort natural history of disease study. A minimum of at least 140 knees with healed nutritional rickets and angular knee deformities will be observed at regular three-monthly intervals over a period of at least one year. We will report two outcome variables namely; clinical and radiological tibio-femoral angle. And independent patient and deformity-related variables as age, sex, deformity type, severity and laterality. Inferential statistics namely bivariate and multivariate analysis will be employed accordingly to identify the relation between outcome variables and the different independent variables. Ethics and dissemination: This protocol study has been approved by the institutional research ethics committee. Results will be presented at conferences and submitted to relevant international and society publications. Authors will also communicate the results to their scholarly networks and post them on scholarly networking sites. Conclusions: This study has the potential for improving the decision-making process as to which patients deserve conservative treatment and which deserve surgical deformity correction. Results are expected to have an impact on the clinical practice of pediatricians, orthopedic surgeons and family physicians alike.

Over the recent years, non-alcoholic fatty liver disease (NAFLD) has become the most common liver disorder in the developed world, accounting for 20% to 46% of liver abnormalities. Steatosis is the hallmark of NAFLD and is recognized as an important risk factor for complication and death after general surgery, and even more so after liver resection. Similarly, liver steatosis also impacts the safety of live liver donation and transplantation. We aim to review surgical outcomes after liver resection for colorectal-metastases in patients with steatosis, and discuss the most common pre-operative strategies to reduce steatosis. Finally, as illustration, we report the favourable effect of a low-caloric, hyper-protein diet during a two-stage liver resection for colorectal metastases in a patient with severe steatosis.

Metabolic disorders, metabolic syndrome and non-alcoholic fatty liver disease, and depression are those of the most common and debilitating disorders worldwide that often coexist further increasing mortality risks. Although the exact mechanisms underlying this association are poorly known, several hypotheses have been proposed: antipsychotic medication and antidepressants use, diet and physical activity or any other lifestyle factors. However, the high co-occurrence rate of depression and metabolic disorders suggests a possible pathophysiological overlap. In this paper I review several raised mechanisms for this overlap which are the hypothalamic-pituitary-adrenal axis dysregulation, immune alterations with chronic inflammation, as well as oxidative stress. In my view, there is one common thread running through all the aforementioned areas of pathophysiology which is microbiota alteration. So far, several possible interventions in our microbiota have been introduced into clinical practice - dietary and other lifestyle changes, supplementation with prebiotics or probiotics, fecal microbiota transplantation – but with vague indications. A better characterization of the above associations may represent a critical step at phenotyping, and a more targeted approach to the treatment of both depressive and metabolic disorders. At the end of the paper, I give several practical applications for future studies.

Studies in animal models have suggested that the ketogenic diet may be effective in the treatment of cancer. However, human cohort studies on the ketogenic diet have, thus far, failed to show benefits in cancer survival or in any other hard clinical endpoints of the disease. This paper presents a case report of a patient with glioblastoma multiforme. The patient had initially been treated with standard oncotherapy including surgery, radiotherapy and chemotherapy. Despite standard treatment, the patient experienced a recurrence of the glioblastoma seven months later. Subsequently, the patient refused radiotherapy and chemotherapy and opted to use the paleolithic ketogenic diet (PKD) as a stand-alone therapy. Following the adoption of the PKD, progression of the disease has been completely halted. At the time of writing, the patient has remained in remission for 48 months, is without side-effects and experiences an excellent quality of life without the use of any drugs.

There is a strong anticipated future for human pluripotent stem cell-derived hepatocytes (hiPS-HEP), but so far their use has been limited due to insufficient functionality. We investigated the potential of hiPS-HEP as an in vitro model for metabolic diseases by combining transcriptomics with multiple functional assays. The transcriptomics analysis revealed that 86% of the genes were expressed at similar levels in hiPS-HEP as in human primary hepatocytes (hphep). Adult characteristics of the hiPS-HEP were confirmed by the presence of important hepatocyte features, e.g. Albumin secretion and expression of major drug metabolizing genes. Normal energy metabolism is crucial for modeling metabolic diseases, and both transcriptomics data and functional assays showed that hiPS-HEP were similar to hphep regarding uptake of glucose, LDL and fatty acids. Importantly, the inflammatory state of the hiPS-HEP was low under standard conditions, but in response to lipid accumulation and ER stress the inflammation marker TNFα was upregulated. Furthermore, hiPS-HEP could be co-cultured with primary hepatic stellate cells both in 2D and in 3D spheroids, paving the way for using these co-cultures for modeling NASH. Taken together, hiPS-HEP have the potential to serve as an in vitro model for metabolic diseases. Furthermore, differently expressed genes identified in this study can serve as targets for future improvements of the hiPS-HEP.

Epigenetic changes are a hallmark of short- and long-term transcriptional regulation, and hence instrumental in the control of cellular identity and plasticity. Epigenetic mechanisms leading to changes in chromatin structure, accessibility for recruitment of transcriptional complexes, and interaction of enhancers and promoters all contribute to acute and chronic adaptations of cells, tissues and organs to internal and external perturbations. Similarly, the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is activated by stimuli that alter the cellular energetic demand, and subsequently controls complex transcriptional networks responsible for cellular plasticity. It thus is of no surprise that PGC-1α is under the control of epigenetic mechanisms, and constitutes a mediator of epigenetic changes in various tissues and contexts. In this review, we summarize the current knowledge of the link between epigenetics and PGC-1α in health and disease.

Hippocrate, the father of medicine, already said:"Wine is a thing wonderfully appropriate to man if, in health as in disease, it is administered with appropriate and just measure according to the individual constitution." wine has always accompanied humanity, for religion or for health. Christians and Jews need wine for the liturgy. For Platon the wine was an indispensable element in society and took all its importance in the symposium. In this second part of the banquet, mixed with water, the wine gave the word. If the french paradox made a lot of ink flow; it was the wine that was originally responsible for it. Many researchers have tried to share the alcohol and polyphenols in order to solve the mystery. Beyond its cardiovascular effects, there are also effects on longevity, metabolism, cancer prevention and neuroprotection, and the list goes on. The purpose of this work is to make an analysis of current knowledge on the subject. Indeed, if the paradigm of the antioxidants is seductive, it is perhaps by their prooxidant effect that the polyphenols could act, by an epigenetic process mediated by nrf2. Wine is a preserve of antioxidants for the winter and it is by this property that the wine acts, in alcoholic solution. A wine without alcohol is pure heresy. By the way, we were not talking about elixir to design all this millennial pharmacopee that made the man was able to heal and prosper on the planet. From Alvise Cornaro to Serge Renaud, nutrition was the key to health and longevity, whether Cretan or Okinawa diet, it is the small dose of alcohol (wine or sake) that allows the bioavailability of polyphenols. Moderate drinking give a protection for diseases and a longevity potential. In conclusion, let’s drink fewer, but drink better to live older.

Compelling epidemiologic data support the critical role of dietary fructose in the epidemic of obesity, metabolic syndrome and nonalcoholic fatty liver disease (NAFLD). The metabolic effects of fructose on the development of metabolic syndrome and NAFLD are not completely understood. High fructose intake impairs copper status, and copper-fructose interactions have been well documented in rats. Altered copper-fructose metabolism leads to exacerbated experimental metabolic syndrome and NAFLD. A growing body of evidence has demonstrated that copper levels are low in NAFLD patients. Moreover, hepatic and serum copper levels are inversely correlated with the severity of NAFLD. Thus, high fructose consumption and low copper availability are considered two important risk factors in NAFLD. However, the causal effect of copper-fructose interactions as well as the effects of fructose intake on copper status remain to be evaluated in humans. The aim of this review is to summarize the role of copper-fructose interactions in the pathogenesis of the metabolic syndrome and discuss the potential underlying mechanisms. This review will shed light on the role of copper homeostasis and high fructose intake and point to copper-fructose interactions as novel mechanisms in the fructose induced NAFLD.

Since coffee has been shown to influence positively the metabolism of subjects with metabolic syndrome (MetS), we aimed to evaluate the short- and long-term effects of a coffee-based supplement on different features of diet-induced MetS. 24 Sprague Dawley rats were divided into control or nutraceuticals groups to receive a high-fat/high fructose diet with or without a mixture of caffeic acid (30 mg/day), trigonelline (20 mg/day), and cafestol (1 mg/day) for 12 weeks. An additional 11 rats were assigned to an acute crossover study. In the chronic experiment, nutraceuticals did not alter body weight or glycemic control but improved fed hyperinsulinemia and HOMA-IR, and plasma adiponectin levels. The impact of nutraceuticals on post-prandial glycemia tended to be more pronounced after acute administration than at the end of the chronic study. Circulating and intrahepatocellular alanine transaminase activity, assessed by hyperpolarized-¹³C NMR spectroscopy, were reduced by coffee nutraceuticals at endpoint. There was also a tendency towards lower liver triglyceride content and histological steatosis score in the intervention group. In conclusion, a mixture of coffee nutraceuticals improved insulin sensitivity and exhibited hepatoprotective effects in a rat model of MetS. Higher dosages with or without caffeine deserve to be studied in the future.

Prolylcarboxypeptidase (PRCP, PCP, Lysosomal Pro-X-carboxypeptidase, Angiotensinase C) controls angiotensin - and kinin- induced cell signaling. Elevation of PRCP appear to be activated in chronic inflammatory diseases (cardiovascular disease (CVD), diabetes) in proportion to severity. Vascular endothelial cell senescence and mitochondrial dysfunction have consistently been shown in models of CVD in aging. The cellular senescence, a driver of age-related dysfunction, can differentially alter the expression of lysosomal enzymes due to lysosomal membrane permeability. There is a lack of data demostrating the effect of age-related dysfunction on the expression and function of PRCP. To explore the changes in PRCP, PRCP-dependent prekallikrein (PK) pathway was charcterized in early – and late-passage human pulmonary artery endothelial cells (HPAECs). Detailed kinetic analysis of cells treated with high molecular weight kininogen (HK), a precursor of bradykinin (BK), and PK revealed a mechansim by which senescent HPAECs activate the generation of kallikrein upon the assembly of the HK-PK complex on HPAECs in parallel with an upregulation of PRCP and endothelial nitric oxide (NO) synthase (eNOS) and NO formation. The NO production and expression of both PRCP and eNOS increased in early-passage HPAECs while decreased in late-passage HPAECs. Low activity of PRCP in late passage HPAECs was associated with rapid decreased telomerase reverse transcriptase mRNA levels. We also found that, with an increase in the passage number of HPAECs, reduced PRCP altered respiration rate. These results indicated that aging dysregulates PRCP protein expression, and further studies will shed light into the complexity of PRCP-dependent signling pathway in aging.

The modification of GFP-CaaL sensor proteins by geranylgeranyl groups in plants requires an active plastidial mevalonate (MVA)-independent pathway. As a consequence, fosmidomycin, a specific inhibitor of 1-deoxy-D-xylulose (DX)-5 phosphate reductoisomerase/DXR, the second enzyme in this so-called methylerythritol phosphate (MEP) pathway, impedes protein prenylation, which results in GFP-labeling of nuclei instead of the plasma membrane. In tobacco cells, a visual screen of conditions that allowed membrane localization of GFP-CaaL proteins in the presence of fosmidomycin, pinpointed jasmonic acid methyl esther (Me-JA) as a chemical able to overcome the inhibition in a gradual manner. Using Arabidopsis protein prenyltransferase loss-of-function mutant lines expressing GFP-CaaL proteins, we demonstrated that Me-JA induces a modification in protein substrate recognition by protein farnesyltransferase (PFT). Similar to Me-JA, farnesol and MVA also alter the protein substrate specificity of PFT, whereas DX and geranylgeraniol have limited or no effect. Our data indicate that stimulation of the MVA pathway adjusts the protein substrate specificity of PFT, which is corroborated with metabolic cross-talk of the origin of the prenyl group used to modify the protein. To illustrate how activation of the MVA pathway impacting PFT substrate specificity benefits a plant under stress conditions, a model is proposed.

This review is focused on synephrine, the principal phytochemical found in bitter orange and other medicinal plants, and widely used as a dietary supplement for weight loss/body fat reduction. We examine different aspects of synephrine biology, delving into its established and potential molecular targets, as well as its mechanisms of action. We present an overview of the origin, chemical composition, receptors, and pharmacological properties of synephrine, including its anti-inflammatory and anti-cancer activity in various in vitro and animal models. Additionally, we conduct a comparative analysis of the molecular targets and effects of synephrine with those of its metabolite, selective glucocorticoid receptor agonist (SEGRA) Compound A (CpdA), which shares a similar chemical structure with synephrine. SEGRA, including CpdA, have been extensively studied as glucocorticoid receptor activators that have a better benefit/risk profile than glucocorticoids due to the reduced adverse effects. We discuss the potential of synephrine usage as a template for the synthesis of new generation of non-steroidal SEGRA. The review also provides insights into the safe pharmacological profile of synephrine.

Background: Depression, a multifaceted mental health condition, necessitates a multidimensional approach to treatment. This study aimed to elucidate the potential efficacy of various mitochondrial interventions, ranging from pharmacological treatments to lifestyle modifications, in alleviating depressive symptoms and enhancing overall mental well-being and assess the diverse range of mitochondrial assessments for managing depression by synthesizing findings from selected studies. Methods: A systematic compilation of studies, employing observational, interventional, and animal-based designs, was undertaken to elucidate the intricate relationship between mitochondrial function and depression as well as depressive signs and symptoms. The PRISMA guidelines were employed for conducting this review and a specific set of selection criterion were formulated by a team of reviewers for selection of relevant papers. Results: The synthesized results from the 21 selected papers highlighted the potential of these interventions to target diverse aspects of depression. Hyperbaric oxygen therapy and psychotherapy demonstrated significant reductions in depression and anxiety scores, with hyperbaric oxygen therapy particularly effective in improving nerve function and daily living activities. Whole-body cryotherapy displayed substantial improvements in depressive symptoms and quality of life. Frequent sauna bathing exhibited a lower risk of depressive symptoms in males. Dietary patterns, including Paleolithic and Mediterranean diets, showcased potential protective effects against depression, anxiety, and stress. The ketogenic diet revealed promise in ameliorating depression and psychosis symptoms alongside positive metabolic changes. Fasting interventions, though challenging, were associated with lower anxiety and depression levels without increased fatigue. Bright white light therapy enhanced remission rates and reduced depression scores in bipolar depression. Probiotic supplementation exhibited potential in reducing depression scores and improving metabolic markers, although further investigation is warranted. Conclusion: The diverse array of interventions explored in this study underlines the multifaceted nature of depression treatment. While these findings offer hope for more personalized and effective approaches, it is imperative to consider the variability in study designs, sample sizes, and methodologies among the selected papers. The mechanisms underlying the observed effects remain partially understood, emphasizing the need for continued mechanistic research. This study sets the stage for future investigations and clinical practices, showcasing the potential of various interventions in mitigating the challenges posed by depression and paving the way for more effective treatment strategies.

Nuclear receptors (NRs) constitute a superfamily of ligand-activated transcription factors with a paramount role in ubiquitous physiological functions such as metabolism, growth, and reproduction. Owing to their physiological role and druggability, NRs are deemed attractive and valid targets for medicinal chemists. Pentacyclic triterpenes (PTs) represent one of the most important phytochemical classes present in higher plants, where oleanolic acid (OA) is the most studied PTs representative owing to its multitude of biological activities against cancer, inflammation, diabetes, and liver injury. PTs possess a lipophilic skeleton that imitates the NRs endogenous ligands. Herein, we report a literature overview on the modulation of metabolic NRs by OA and its semi-synthetic derivatives, highlighting their health benefits and potential therapeutic applications. Indeed, OA exhibited varying pharmacological effects on FXR, PPAR, LXR, RXR, PXR, and ROR in a tissue-specific manner. Owing to those NRs modulation, OA exhibited prominent hepatoprotective properties comparable to ursodeoxycholic acid (UDCA) in a bile duct ligation mice model and antiatherosclerosis effect as simvastatin in a model of New Zealand white (NZW) rabbits. It also demonstrated a great promise in alleviating non-alcoholic steatohepatitis (NASH) and liver fibrosis, attenuated alpha-naphthol isothiocyanate (ANIT)-induced cholestatic liver injury, and controlled blood glucose levels, making it a key player in the therapy of metabolic diseases. We also compiled OA semi-synthetic derivatives and explored their synthetic pathways and pharmacological effects on NRs, showcasing their structure-activity relationship (SAR). To the best of our knowledge, this is the first review article to highlight OA activity in terms of NRs modulation.

In the last decade, an increasing awareness was directed to the role of Vitamin D in non-skeletal and preventive roles for chronic diseases. Vitamin D is a key hormone involved in the regulation of calcium/phosphorous balance and it has been implicated in the pathogenesis of inflammation, insulin resistance and obesity. Cholecalciferol (Vitamin D3) and Ergocalciferol (Vitamin D2) are the main form of vitamin D: the active form (1,25-dihydroxyvitamin D) is the result of two hydroxylations that take place in liver, kidney, pancreas and immune cells. Some anti-inflammatory cytokines are produced at higher levels by vitamin D, while some pro-inflammatory cytokines are released at lower levels. Toll-Like Receptor (TLR) expression is increased and a pro-inflammatory state is also linked to low levels of vitamin D. Regardless of how it affects inflammation, various pathways suggest that vitamin D directly improves insulin sensitivity and secretion. The level of vitamin D in the body may change the ratio of pro- to anti-inflammatory cytokines, which would impact insulin action, lipid metabolism, and the development and function of adipose tissue. Many studies have demonstrated an inverse relationship between vitamin D concentrations and pro-inflammatory markers, insulin resistance, glucose intolerance, metabolic syndrome, obesity and cardiovascular disease. It's interesting to note that several long-term studies also revealed an inverse correlation between vitamin D level and the occurrence of diabetes mellitus. Vitamin D supplementation in people has controversial effects, in fact while some studies demonstrated improvements in insulin sensitivity, glucose and lipid metabolism, others revealed no significant effect on glycemic control and inflammation. The aim of this review is to provide insight into the molecular basis of the relationship between vitamin D, insulin-resistance, metabolic syndrome, type 1 and 2 diabetes, gestational diabetes, and cardiovascular diseases.

This article explores the relationship between metabolic syndrome and cardiovascular disease, providing a comprehensive overview of its risk factors and prevalence. Metabolic syndrome, characterized by a cluster of interconnected risk factors, significantly increases the likelihood of developing cardiovascular disease and type II diabetes. The study, conducted over a one-year period, involved 117 patients with ages between 30 to 79 years old. Various elements such as gender, age, education level, background, smoking, alcohol consumption, dietary aspects, physical activity, and their contribution in developing the metabolic syndrome, were analysed.Central adiposity and high blood pressure emerged as prominent elements of the condition. The findings underscore the importance of a healthy lifestyle in the prevention and management of metabolic syndrome. Encouraging regular physical activity, maintaining a balanced diet, rich in fresh vegetables and fruits, and avoiding harmful behaviours, such as smoking or alcohol consumption, are essential in reducing the risk of metabolic syndrome and its associated cardiovascular complications. The study highlights the need for public health initiatives, as well as individualized preventive strategies to combat the rising prevalence of metabolic syndrome. Through promoting awareness of its risk factors and implementing effective interventions, healthcare professionals can contribute to better cardiovascular health worldwide. Further research in this area will continue to enhance our understanding of the metabolic syndrome and refine preventive and therapeutic approaches for its management.

Piriform fossa and/or esophageal injuries caused by calibration tubes are relatively rare and re-main unelucidated. Herein, we report the case of a 36-year-old woman with morbid obesity, sleep apnea, and menstrual abnormalities who was scheduled to undergo laparoscopic sleeve gastrectomy (LSG). We inserted a 36-Fr Nelaton catheter made of natural rubber as a calibration tube during the surgery. However, excessive resistance was observed. We confirmed a submuco-sal layer detachment of approximately 5 cm from the left piriform fossa to the esophagus using intraoperative endoscopy. Additionally, LSG was performed using an endoscope as the guiding calibration tube. We inserted a nasogastric tube under endoscopy with a guidewire before com-pleting the surgery, hoping for a guiding effect on saliva flow. After 17 months, the patient suc-cessfully lost weight postoperatively without complaints of neck pain or discomfort during swallowing. Therefore, if the damage is limited to the submucosal layer, as in this case, conserva-tive therapy should be considered, which is similar to the concept of not requiring suture closure in endoscopic submucosal dissection. This case highlights the risk of iatrogenic injuries to the pi-riform fossa and/or esophagus during LSG and the importance of careful calibration tube inser-tion to prevent them.

Plants have evolved tightly regulated strategies to adapt and acclimate to a changing environment to ensure their survival. Various environmental factors affect plant distribution, growth and yield. Low temperature belongs to those abiotic factors which significantly constrain range boundaries of plant species. Exposing plants to low but non-freezing temperature induces a multigenic processes termed cold acclimation, which finally results in an increased freezing tolerance. Cold acclimation comprises reprogramming of the transcriptome, proteome and metabolome and affects communication and signaling between subcellular organelles. Reprogramming of the central carbohydrate metabolism plays a key role in cold acclimation. This review summarizes current knowledge about the role of carbohydrate metabolism in plant cold acclimation. A focus is laid on subcellular metabolic reprogramming, its thermodynamic constraints under low temperature and mathematical modelling of metabolism.

1) Background: A population-based cross-sectional study was conducted to understand how green cover and accessibility of common public open spaces in compact urban areas affect physical activeness of resident. 2) Methods: A total of 554 residents completed a structured questionnaire on quality-of-life, physical activity level, and healthy eating practice. 3) Results: The sampled population lived with green cover averaged 10.11 ± 7.95% (ranged 1.56–9.88), whereas majority (90%) of the residents performed physical activities at medium and high levels. Metabolic Equivalent of Task (MET)-minutes/week was associated with the green cover percentage (Pearson r = 0.092; p < 0.05). Irrespective of age and physical activity level, active residents commonly used public open spaces within district for performing exercise, especially parks and promenade were mostly used by older residents while sports facilities by the younger groups. 4) Conclusions: Current findings suggested promotion of exercise could be achieved by the design or redesign of built environment to include more parks accessible to the residents with the increase of vegetation.

Literature is inconsistent as to how coffee affects the features of the metabolic syndrome (MetS), and which bioactive compounds are responsible for its metabolic effects. We aimed to compare the in-vivo effects of unfiltered coffee with a selected mixture of its compounds on diet-induced MetS. 24 male Sprague-Dawley rats were fed a high-fat (35% W/W) food plus 20% W/W fructose in drinking water for 14 weeks, and were randomized into three groups: control, coffee, or nutraceuticals (5-O-caffeoylquinic acid, caffeic acid, and trigonelline). Coffee or nutraceuticals were provided in drinking water in a dosage equal to 4 cups/day in a human. Compared to the controls, only coffee supplementation decreased total food intake, weight gain, and estimated average plasma glucose. Surrogate measures of insulin resistance (fasting insulin, HOMA-IR, and oral glucose tolerance) were improved at endpoint in the coffee group. Circulating triglyceride levels were also reduced by coffee. Histopathological and quantitative measurements indicated lower grades of liver steatosis after long-term coffee consumption. In conclusion, a combination of phenolic acids and trigonelline was not as effective as coffee per se in improving the components of the MetS. This points to the role of other coffee chemicals and a potential synergism between compounds.

Mosquitoes have distinct developmental and adult life history, and the vectorial capacity of females has been shown to be affected by the larval nutritional environment. However, little is known about the effect of developmental nutrition on insulin-signaling and nutrients storage. In this study, we used Aedes aegypti, the yellow fever mosquito, to determine whether larval nutrition affects insulin gene expression. We also determined the traits regulated by insulin signaling, such as stored-nutrients levels and fecundity. We raised mosquito larvae on two different diets, containing either high protein or high carbohydrates. Development on a high-carbohydrate diet resulted in several life-history phenotypes indicative of suboptimal conditions, including increased developmental time and decreased fecundity. Additionally, our data showed that insulin transcript levels are affected by a high-carbohydrate diet during development. Females, not males, reared on high-carbohydrate diets had much higher transcript levels of insulin-like peptide 3 (ILP3), a mosquito equivalent of human insulin, and these females more readily stored sugar from the meal into lipids. We also found that AaILP4, not AaILP3, transcript levels were much higher in the males after a sugar meal, suggesting sex-specific differences in insulin-signaling pathway. Our findings suggest a conserved mechanism of carbohydrate-mediated hyperinsulinemia in animals.

This review focuses on the emerging evidence for the association between estimated cardiorespiratory fitness (eCRF) and metabolic risk factors. Given the challenges associated with directly measuring cardiorespiratory fitness (CRF) in large populations, eCRF presents a practical alternative for predicting metabolic health risks. A literature search identified six relevant cohort studies from 2021 to 2024 that investigated the association of eCRF with hypertension, hyperglycemia, dyslipidemia, and obesity. The review findings highlight a consistent inverse relationship between higher eCRF and lower incidence of metabolic risks in line with CRF cohort studies. This review highlights the importance of low eCRF as a primordial indicator for metabolic risks and underscores the need for broader application. Future research directions should include exploring eCRF's predictive accuracy across diverse populations and health outcomes and testing its real-world applicability in healthcare and public health settings.

Prediabetes, a pivotal phase in glucose metabolism between normalcy and diabetes, exerts a profound influence on the aging process and the risk of age-related diseases. This comprehensive review delves into the intricate web of blood-based biomarkers that collectively expedite senescence, marking the transition from a state of health to age-related complications. Key findings underscore the significance of diverse biomarkers, such as telomere length, p16INK4a, senescence-associated secretory phenotype (SASP) factors, DNA methylation clocks, advanced glycation end products (AGEs), inflammatory and oxidative stress markers, circulating hormones, and additional factors like folate, B12, osteocalcin, and more. Not only do these biomarkers serve as indicators of senescence, but they actively fuel chronic inflammation, oxidative stress, and metabolic dysregulation, all of which contribute to accelerated aging. The implications of this understanding are profound, as prediabetes emerges as a critical period in an individual's life, influencing various physiological systems, including the vascular and neural systems, metabolic functions, hormonal regulation, and bone health. Recognizing the profound influence of prediabetes on senescence provides a foundation for personalized intervention strategies to mitigate age-related complications and promote healthy aging. Future research directions call for a more diverse array of biomarkers, in-depth exploration of their roles, and the development of tailored precision medicine strategies to ensure a holistic understanding and effective management of prediabetes-induced senescence and its implications for aging. This knowledge has far-reaching implications for public health and clinical practice, emphasizing the need for early detection and intervention in prediabetic individuals to enhance the quality of life in an aging population with diverse needs.

Dynamic variables in the non-equilibrium systems of life are determined by catalytic activities. These relate to the expression of the genome. The extent to which such a variable depends on the catalytic activity defined by a gene has become more and more important in view of the possibilities to modulate gene expression or intervene with enzyme function through the use of medicinal drugs. With all the complexity of cellular systems biology, there are still some very simple principles that guide the control of variables such as fluxes, concentrations, and half-times. Using time-unit invariance we here derive a multitude of laws governing the sums of the control coefficients that quantify the control of multiple variables by all the catalytic activities. We show that the sum of the control coefficients of any dynamic variable over all catalytic activities is determined by the control of the same property by time. When the variable is at a maximum, minimum or steady, this limits the sums to simple integers like 0, -1, 1, and -2, depending on the variable under consideration. Some of the implications for biological control are discussed as is the dependence of these results on the precise definition of control.

Microbial production is a promising method that can overcome major limitations in conventional methods of lycopene production, such as low yields and variations in product quality. Significant efforts have been made to improve lycopene production by engineering either the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway or mevalonate (MVA) pathway in microorganisms. To further improve lycopene production, it is critical to utilize metabolic enzymes with high specific activities. Two enzymes, 1-deoxy-D-xylulose-5-phosphate synthase (Dxs) and farnesyl diphosphate synthase (IspA), are required in lycopene production using MEP pathway. Here, we evaluated the activities of Dxs and IspA of Vibrio sp. dhg, a newly isolated and fast-growing microorganism. Considering that the MEP pathway is closely related to the cell membrane and electron transport chain, the activities of the two enzymes of Vibrio sp. dhg were expected to be higher than the enzymes of E. coli. We found that Dxs and IspA in Vibrio sp. dhg exhibited 1.08-fold and 1.38-fold higher catalytic efficiencies, respectively. Consequently, the heterologous overexpression improved the specific lycopene production by 1.88-fold. Our findings could be widely utilized to enhance production of lycopene and other carotenoids.

Alkyl moieties—open chain or cyclic—are common in drug molecules and can be internal or terminal. The open-chain alkyls can be linear or branched; the cyclic alkyls may be substituted. Usually, the branches in open-chain alkyls and substituents in cycloalkyls influence both the pharmacokinetics and pharmacodynamics of a drug molecule. The hydrophobicity of alkyl moieties in drug molecules is modified by metabolic hydroxy functionalization via free-radical intermediates to give primary, secondary, or tertiary alcohols depending on the class of the substrate carbon. The hydroxymethyl groups resulting from the functionalization of methyl groups are mostly oxidized further to carboxyl groups to give carboxy metabolites. As observed from the surveyed cases in this review, hydroxy functionalization leads to loss, attenuation, or retention of pharmacologic activity with respect to the parent drug. On the other hand, carboxy functionalization leads to a loss of activity with the exception of only a few cases in which activity is retained. The exceptions are those groups in which the carboxy functionalization occurs at a position distant from a well-defined primary pharmacophore. Some parent-drug equiactive hydroxy metabolites have been developed into metabolite ester prodrugs, while some of the parent-drug carboxy metabolites have been developed into metabolite drugs. In this review, we present and discuss the above state of affairs for a variety of drug classes, using selected drug members to show the effect on pharmacologic activity as well as dependence of the metabolic change on drug molecular structure. Some subtexts found to manifest from the hydroxy and carboxy functionalization of alkyl moieties in drug molecules are presented and discussed. The review provides basis for informed predictions of (i) structural features required for metabolic hydroxy and carboxy functionalization of alkyl moieties in existing or planned small drug molecules; and (ii) whether the resulting metabolites will possess pharmacologic activity or be devoid of it.

A growing body of research has identified fetal risk factors associated with adult diseases that form the basis for the Developmental Origins of Health and Disease (DOHaD) hypothesis. This theory proposes a critical developmental period during which the fetus is highly susceptible to specific environmental influences that significantly impact health from short to long term. Maternal stress and T2DM during pregnancy are among these influences, likely leading to fetal overexposure to glucocorticoids and suggesting a shared pathway between maternal dysregulated HPA axis and fetal environmental insults. Studies demonstrate that prenatal glucocorticoid exposure alters fetal HPA axis function, affecting brain function, tissue glucocorticoid availability, and fetal growth in utero. These programmed changes, such as altered HPA axis function and reduced fetal growth, contribute to metabolic disorders persisting into adulthood. T2DM is preceded by a prediabetic state, often asymptomatic, which shares similar pathophysiological complications with T2DM, including HPA axis dysregulation observed in animals. Therefore, investigating prediabetes during pregnancy alongside maternal HPA axis function and its effects on fetal outcomes is crucial, as these areas remain understudied. This review aims to synthesize existing literature on pre-existing T2DM during pregnancy, its links to fetal programming via HPA axis changes, and possible links to pregestational prediabetes.

Secondary movement disorders (SMDs) represent a heterogeneous group of neurological conditions characterized by abnormal, involuntary movements resulting from various underlying causes. This comprehensive review aims to thoroughly understand SMDs, including their epidemiology, pathophysiology, clinical manifestations, diagnostic approach, and management strategies. SMDs encompass a spectrum of movement abnormalities, including dystonia, chorea, athetosis, myoclonus, tics, and tremors. They can arise from a multitude of etiologies, such as drug-induced effects, post-infectious processes, metabolic disturbances, and structural brain lesions. The epidemiology of SMDs varies depending on the underlying cause, with some conditions being more prevalent in specific populations or age groups. Understanding the pathophysiology of SMDs is crucial for accurate diagnosis and targeted management. Diagnosing SMDs requires a comprehensive approach, including a detailed history, physical examination, laboratory investigations, neuroimaging studies, and sometimes electrophysiological studies. Management of SMDs is multifaceted and may involve pharmacological, non-pharmacological, and surgical interventions. Individualized treatment plans are essential, considering the underlying cause, severity of symptoms, and patient preferences. Emerging concepts in the field of SMDs include advancements in genetic research, identification of biomarkers, and development of novel therapeutic approaches. There is a growing focus on patient-centered care and improving the quality of life for individuals with SMDs. In conclusion, SMDs pose diagnostic and therapeutic challenges, requiring a multidisciplinary approach for optimal management. Continued research and collaboration are essential for advancing our understanding and treatment of these complex disorders.

Methylglyoxal (MGO) is the major compound belonging to reactive carbonyl species (RCS) responsible for the generation of advanced glycation end products (AGEs). Its upregulation followed by deleterious effects at the cellular and systemic level is associated with metabolic disturbances (hyperglycemia/hyperinsulinemia/insulin resistance/hyperlipidemia/inflammatory processes/carbonyl stress/oxidative stress/hypoxia). Therefore, it is implicated in a variety of disorders including metabolic syndrome, diabetes mellitus and cardiovascular diseases. In this review an interplay between pathways leading to MGO generation and scavenging is addressed, in regard to this system’s impairment in pathology. The issues associated with mechanistic MGO involvement in pathological processes, as well as the discussion on its possible causative role in cardiometabolic diseases are enclosed. Finally, the main strategies aimed at MGO and its AGEs downregulation with respect to cardiometabolic disorders treatment are addressed. Potential glycation inhibitors and MGO scavengers are discussed, as well as the mechanisms of their action.

Abstract: The brain endothelial cell (BEC) glycocalyx (ecGCx) is a BEC surface coating consisting of a complex interwoven polysaccharide (sweet husk) mesh-like network of membrane-bound proteoglycans, glycoproteins, and glycosaminoglycans (GAGs) covering the apical luminal layer of the brain endothelial cells. The ecGCx may considered as the 1st barrier of a tripartite blood-brain barrier (BBB) consisting of 1) ecGCx; 2) BECs; (3) extravascular compartment of pericytes, extracellular matrix, and perivascular astrocytes, Perturbations of this barrier allow for increased permeability in the postcapillary venule that will be permissive to both fluids, solutes, and proinflammatory peripherally-derived leukocytes into the perivascular spaces (PVS) to result in enlargement as well as increased neuroinflammation. The ecGCx is known to have multiple functions, which include its physical and charge barrier, mechanical transduction, regulation of vascular permeability, modulation of inflammatory response, and anticoagulation functions. This review discusses each of the listed functions in detail and utilizes multiple transmission electron micrographs and illustrations to allow for a better understanding of the ecGCx structural and functional roles as it relates to enlarged perivascular spaces (EPVS). This is the 5th review of a series quintet that discuss the importance of EPVS from the perspective of the cells of brain barriers. Attenuation and/or loss of the ecGCx results in brain barrier disruption with increased permeability to proinflammatory leukocytes, fluids and solutes, which accumulate in the postcapillary venule perivascular spaces. This accumulation results in obstruction and results in EPVS with impaired waste removal of the recently recognized glymphatic system. Importantly, EPVS are progressively being regarded as a marker of cerebrovascular and neurodegenerative pathology.

Previous studies reported the physical, transcriptomics and metabolomics changes in in-vitro acute heat stressed bovine granulosa cells. Granulosa cells exhibited transient proliferation senescence, oxidative stress, increased rate of apoptosis, and decline in steroidogenic activity. This study performs joint integration and network analysis of metabolomics and transcriptomics data to further narrow down and elucidate the role of differentially expressed genes, important metab-olites and relevant cellular and metabolic pathways in acute heat-stressed granulosa cells. Among significant (Raw P-value <0.05) metabolic pathways where metabolites and genes did converge, this study found Vitamin B6 metabolism, Glycine, serine and threonine metabolism, Phenylalanine metabo-lism, Arginine biosynthesis, Tryptophan metabolism, Arginine and proline metabolism, Histidine metabolism, and Glyoxylate and dicarboxylate metabolism. Important significant convergent bio-logical pathways included, ABC transporters and Protein digestion and absorption, while func-tional signaling pathways included cAMP, mTOR, and AMPK signaling pathways together with Ovarian steroidogenesis pathway. Among caner pathways, the most important pathway was Central carbon metabolism in cancer. Through multiple analysis query, Progesterone, Serotonin, citric acid, Pyridoxal, L-Lysine, Succinic acid, L-Glutamine, L-Leucine, L-Threonine, L-Tyrosine, Vitamin B6, Choline, and CYP1B1, MAOB, VEGFA, WNT11, AOX1, ADCY2, ICAM1, PYGM, SLC2A4, SLC16A3, HSD11B2 and NOS2 appeared to be important enriched metabolites and genes, respectively. These genes, metabolites, metabolic, cellular and cell signaling pathways com-prehensively elucidate the mechanisms underlying the intricate fight between death and survival in acute heat-stressed bovine granulosa cells, and essentially help further our understanding and future quest of research in this direction.

Among non-conventional yeasts of industrial interest, the dimorphic oleaginous yeast Yarrowia lipolytica appears as one of the most attractive for a large range of white biotechnology applications, from heterologous proteins secretion to cell factories process development. The past, present and potential applications of wild type, traditionally improved or genetically modified Yarrowia lipolytica strains will be resumed, together with the wide array of molecular tools now available to genetically engineer and metabolically remodel this yeast. The present review will also provide a detailed description of Yarrowia lipolytica strains and highlight the natural biodiversity of this yeast, a subject little touched upon in most previous reviews. This work intends to fill this gap by retracing the genealogy of the main Yarrowia lipolytica strains of industrial interest, by illustrating the search for new genetic backgrounds and by providing data about the main publicly available strains in yeast collections worldwide. At last, it will focus on exemplifying how advances in engineering tools can leverage a better biotechnological exploitation of the natural biodiversity of Yarrowia lipolytica and of other yeasts from the Yarrowia clade.

Background Telomere shortening is related to aging and unfavourable health outcomes. Obesity and metabolic diseases are important factors for accelerating aging. This study aimed to find out the association between obesity, metabolic disease, and telomere length in metabolically healthy adults. Methods 237 adults were enrolled with written consents at a health promotion centre of a tertiary hospital from February 2014 to March 2015. After excluding 99 subjects who met the exclusion criterion, a total of 130 metabolically healthy subjects were selected for final analysis. The subjects were divided into quartile groups according to the telomere lengths of their oral mucosal cells. Results The subjects consisted of 66 (50.8%) males with a mean age of 58.59 years. The body mass index (BMI, kg/m2) increased significantly along with the quartile groups (Q1, 23.00; Q2, 23.96; Q3, 23.70; Q4, 25.20; P-for trend=0.008). Waist circumference (WC, P-for trend=0.022), waist-to-hip ratio (WHR, P-for trend=0.005), and waist-to-height ratio (WHtR, P=0.001) also increased along with the quartile groups. Obesity prevalence (BMI ≥25 kg/m2), abdominal obesity (WC ≥90 cm for men, ≥85 cm for women), WHR 〉1.0 for men or 〉0.85 for women, and WHtR ≥0.5 increased significantly as the telomere length increased (P-for trend <0.05). After adjusting for covariates, the ORs for each obesity markers increased as the telomere length increased (P-for trend <0.05); and the ORs of WHtR were especially meaningful (Q1, 1.00; Q2, 2.53; Q3, 2.97; Q4, 7.81; P-for trend = 0.001). There were no significant trends for metabolic syndrome and its components along with the prevalence of fatty liver disease. Conclusion Obesity markers and telomere length had significant positive correlation despite the established theory. The obesity paradox may exist in metabolically healthy adults with regard to telomere length, However, further studies with larger sample sizes for the association between obesity and telomere length are needed.

Abstract: Astrocytes (ACs) are the most abundant human cell in the brain and importantly, are the master connecting and communicating cells that provide structural and functional support of brain cells at all levels of organization. Further, they are recognized to be the guardians and housekeepers of the brain. Protoplasmic perivascular astrocyte endfeet and their basal lamina form the delimiting outermost barrier (glia limitans) of the perivascular spaces in postcapillary venules and are important for the clearance of metabolic waste and comprise the glymphatic system, which is critically dependent on the proper waste removal by the pvACef polarized aquaporin 4 water channels. Also, the protoplasmic perisynaptic astrocyte endfeet (psACef) are important in cradling the neuronal synapses that serve to maintain homeostasis and serve a functional and supportive role for synaptic transmission. Enlarged perivascular spaces (EPVS) are emerging as important aberrant findings on magnetic resonance imaging (MRI) and associate with white matter hyperintensities, lacunes, aging, accepted to be biomarkers for cerebral small vessel disease, increased in obesity, metabolic syndrome, and type 2 diabetes. Knowledge is exponentially expanding regarding EPVS along with the glymphatic system, since EPVS are closely associated with impaired glymphatic function and waste removal from the brain to the cerebrospinal fluid and systemic circulation. This review intends to focus on how the pvACef play a crucial role in the development of EPVS.

Metabolic pathways provide key information to achieve a better understanding of life and all its processes; this is useful information for the improvement of medicine, agronomy, pharmacy, and other similar areas. The main analysis tool used to study these pathways is based on the idea of pathway comparison, using graph data structures. Metabolic pathway comparison has been defined as a computationally complex task \cite{ay2011submap,abaka2013campways}. In previous work from 2017, two different approaches that simplify the problem of comparing pathways represented as graphs were introduced. The first algorithm consists of the transformation of a two-dimensional graph structure, representing a metabolic pathway, to a one-dimensional structure and thus aligning the corresponding data using a reduced 1 dimension string. The second algorithm consists of performing a paired analysis between reactions in pathways and thus eliminating all similarities, finally, showing these differences to the user. The suggestion is to use the information provided by these algorithms as a previous analysis to a deeper, more expensive, comparison tool use. Here we provide an extension of this work with more data and deeper analysis. These methods have shown to be an effective way to treat the problem of metabolic pathway comparison as listed in the discussion and results section. Our results show evidence of a quick, simple and effective way to resolve the described problem.

As Chronic Non-Communicable Diseases (CNCD) increase, preventive approaches become more crucial. In this review, Calorie Restriction (CR) effects on human beings were evaluated, comparing benefits and risks of different CR diets: classic CR vs ketosis-inducing diets, including Intermittent Fasting (IF), Classic Ketogenic Diet (CKD), Fasting Mimicking Diet (FMD), Very-Low-Calorie Ketogenic Diet (VLCKD) and Spanish Ketogenic Mediterranean Diet (SKMD). Special emphasis on Insulin Resistance (IR) was placed, as it mediates Metabolic Syndrome (MS), a risk factor for CNCD, and predicts MS diagnosis. CR is the most robust intervention known to increase lifespan and health span, with high evidence and known biochemical mechanisms. CR improves cardiometabolic risk parameters, boosts exercise insulin sensitivity response, and there may be benefits of implementing moderate CR on healthy young and middle-aged individuals. However, there is insufficient evidence to support long-term CR. CKD is effective for weight and MS management, and may have additional benefits such as prevention of muscle loss and appetite control. SKMD has extreme significance benefits for all the metabolic parameters studied. Studies show inconsistent benefits of IF compared to classic CR. More studies are required to study biochemical parameters, reinforce evidence, identify risks, and seek effective and safe nutritional CR approaches.

Research with deuterium-depleted water (DDW) in the last two decades proved that deuterium/hydrogen ratio has a key role in cell cycle regulation and cellular metabolism. The present study aimed to investigate the possible effect of deuterium-depleted organic compounds (DDOC) alone and in combination with DDW on cancer growth in two in vivo mouse models. To produce DDOC, drinking water of laying hens was replaced with DDW (25 ppm) for 6 weeks, resulting in 60 ppm D level in dried egg yolk that was used as deuterium-depleted food additive. In one model, 4T1, a cell line with high metastatic capacity to the lung, was inoculated in the mice’s mammary pad. After three weeks of treatment with DDW and/or DDOC, the tumor volume in the lungs was smaller in all treated groups vs. controls with natural D level. Tumor growth and survival in mice transplanted with MCF-7 breast cancer cell line showed that the anticancer effect of DDW was enhanced by food containing the deuterium-depleted yolk. The study confirmed the importance of D/H ratio not only in consumed water but also in metabolic water produced by the mitochondria while oxidizing nutrient molecules. This is in line with the concept that initiation of cell growth requires the cells to generate a higher D/H ratio, but DDW, DDOC, or the naturally low-D lipids in a ketogenic diet, have significant effect on tumor growth by preventing the cells from raising D/H ratio to the threshold.

FLH 13-11 is an F1 interspecific hybrid muscadine grape genotype that was developed to produce new anthocyanins for pigment color stability. This hybrid resulted from a cross between ‘Marsh’ (Vitis munsoniana) and ‘Magoon’ (V. rotundifolia). This report characterizes the anthocyanins produced in fully ripe berries, and reveals a significant difference in total anthocyanin contents from two continuous cropping seasons. High-performance liquid chromatography with a diode array detector (HPLC-DAD) and HPLC-quadrupole time-of-flight tandem mass spectrometry (HPLC-qTOF-MS/MS) were used to profile anthocyanins in berries. The resulting data showed that fourteen anthocyanins were detected, six from 2011 and nine from 2012, with only one produced in both seasons. However, the anthocyanidin profiles of berries were the same. Five anthocyanins were annotated as diglucosides of anthocyanidins based on MS/MS features, including delphinidin 3,5-diglucoside produced in both seasons, cyanidin 3,5-diglucoside mainly formed in 2011, petunidin 3,5-diglucoside, malvidin 3,5-diglucoside, and peonidin 3,5-glucoside only detected in 2012. Also, three anthocyanidin-diglucoside like anthocyanins and three monoglucosides including peonidin 3- glucoside, delphinidin 3- glucoside like, and pelargonidin 3- glucoside like anthocyanins, were detected in 2011 and 2012, respectively. These results indicate that FLH 13-11 can produce both anthocyanidin-diglucosides and -monoglucosides, and their biosynthesis is closely dependent on cropping years.

The pathophysiology of Nonketotic Hyperglycinemia (NKH), a rare neuro-metabolic disorder associated with severe brain malformations and life-threatening neurological manifestations, remains incompletely understood. Therefore, a valid human neuronal model is essential. We aimed to investigate the impact of GLDC gene variants, which cause NKH, on cellular fitness during the differentiation process of human induced pluripotent stem cells (iPSCs) into iPSC-derived astrocytes and to identify sustainable mechanisms capable of overcoming GLDC deficiency. We developed the GLDC27-FiPS4F-1 line and performed metabolomic, mRNA abundance and protein analyses. The study showed that although GLDC27-FiPS4F-1 maintained the parental genetic profile, it underwent a metabolic switch to an altered serine-glycine-one-carbon metabolism with a coordinated cell growth and cell cycle proliferation response. We then differentiated the iPSCs into neural progenitor cells (NPCs) and astrocyte-lineage cells. Analysis showed that GLDC-deficient NPCs had shifted towards a more heterogeneous astrocyte lineage with increased expression of the radial glial markers GFAP and GLAST and the neuronal markers MAP2 and NeuN. In addition, we detected changes in other genes related to serine and glycine metabolism and transport, all consistent with the need to maintain glycine at physiological levels. These findings improve our understanding of the pathology and offer new perspectives for therapeutic options.

The architecture, organization and functioning of biocatalytic reaction networks, which are coded in the cell specific genome and which work together in the small space of biological cells, are a fascinating feature of life evolved over more than 3 billion years. The knowledge about the diversity of biocatalytic functions and metabolic pathways sustaining life on our planet is highly important, especially as the currently occurring loss of biodiversity is considered a planetary boundary which is at high risk, and knowledge about the life of current biological organisms should be gained before they become extinct. In addition to the well-known enzymatic reactions involved in biochemical pathways, the enzyme universe offers numerous opportunities for discovering novel functions and pathways. Maintaining thousands of molecules and reactions functioning properly within biological cells, which may be exposed to various kinds of external hazards, environmental stress, enzymatic side reactions or non-enzymatic chemical reactions, is key for keeping cellular life healthy. This review aims at outlining advances in assigning enzyme functions to protein sequences and the discovery of novel biocatalytic functions and pathways.

Quantitative biomarkers derived from positron-emission tomography/computed tomography (PET/CT) have been suggested as prognostic variables in immune-checkpoint inhibitor (ICI) treated non-small cell lung cancer (NSCLC). As such data for first-line ICI therapy and especially for chemotherapy-ICI combinations are still scarce, we retrospectively evaluated baseline 18F-FDG-PET/CT of 85 consecutive patients receiving first-line pembrolizumab with chemotherapy (n=70) or as monotherapy (n=15). Maximum and mean standardized uptake value, metabolic tumor volume (MTV), total lesion glycolysis and bone marrow-/ spleen to liver ratio (BLR/SLR) were calculated. Kaplan-Meier analyses and Cox-regression models were used to assess progression-free/overall survival (PFS/OS) and their determinant variables. Multivariate selection for PFS/OS revealed MTV as most relevant PET/CT biomarker (p<0.001). Median PFS/OS were significantly longer in patients with MTV≤70mL versus >70mL (PFS: 10 months (M; 95% confidence interval 4-16) vs. 4M (3-5), p=0.001; OS: not reached vs. 10M (5-15), p=0.004). Disease control rate was 81% vs. 53% for MTV≤/>70mL (p=0.007). BLR ≤1.06 versus >1.06 was associated with better outcomes (PFS: 8M (4-13) vs. 4M (3-6), p=0.034; OS: 19M (12-/) vs. 6M (4-12), p=0.005). In patients with MTV>70mL, concomitant BLR≤1.06 indicated a better prognosis. Higher MTV is associated with inferior PFS/OS in first-line ICI treated NSCLC, with BLR allowing additional risk stratification.

Ever since Varela and Maturana proposed the concept of autopoiesis as the minimal requirement for life, there has been a focus on cellular systems that erect topological boundaries to separate themselves from their surrounding environment. Here we reconsider whether the existence of such a spatial boundary is strictly necessary for self-producing entities. This work presents a novel computational model of a minimal autopoietic system inspired by dendrites and molecular dynamics simulations in three-dimensional space. A series of simulation experiments where the metabolic pathways of a particular autocatalytic set are successively inhibited until autocatalytic entities that could be considered autopoietic are produced. These entities maintain their distinctness in an environment containing multiple identical instances of the entities without the existence of a topological boundary. This gives rise to the concept of a metabolic boundary which manifests as emergent self-selection criteria for the processes of self-production without any need for unique identifiers. However, the adoption of such a boundary comes at a cost, as these autopoietic entities are less suited to their simulated environment than their autocatalytic counterparts. Finally, this work showcases a generalized metabolism-centered approach to the study of autopoiesis that can be applied to both physical and abstract systems alike.

Intratumoral immune cytolytic activity (CYT), measured as the geometric mean of the expression of Granzyme-A (GZMA) and Perforin-1 (PRF1), has emerged as a critical factor in cancer immunotherapy, with significant implications for patient prognosis and treatment outcomes. Here, we review how different immune checkpoint pathways, the composition of Tumor Microenvironment (TME), antigen presentation and metabolic pathways, all regulate CYT. We also discuss the various methods through which CYT can be assessed. The detection and analysis of tumor-infiltrating lymphocytes using flow cytometry or immunohistochemistry provide important information on the immune cell populations within the TME. Gene expression profiling and spatial analysis techniques, such as multiplex immunofluorescence and imaging mass cytometry, allow researchers to study CYT in the context of the TME. We further report the significant clinical implications that CYT has, as its increased levels are associated with positive clinical outcomes and a favorable prognosis. Moreover, CYT can be used as a prognostic biomarker and aid in patient stratification. Measuring CYT through different methods offers promising paths for improving treatment responses. Overall, we highlight that the understanding and modulation of CYT levels is critical for improving cancer immunotherapy. Research into CYT and the factors that influence it has the potential to transform cancer treatment and improve patient outcomes.

Metabolic dysfunction-associated fatty liver disease (MAFLD) has now affected nearly one third of global population and became the number one cause of chronic liver disease in the world because of the obesity pandemic. Chronic hepatitis resulting from hepatitis B virus (HBV) and hepatitis C virus (HCV) also remain significant challenges to liver health even in the 21st century. The coexistence of MAFLD and chronic viral hepatitis can markedly alter the disease course of individual diseases and can complicate the management of each of these disorders. Thorough understanding of the pathobiological interlink and interactions between MAFLD and these two chronic viral hepatitis infections are crucial for appropriate management of patients. We update these interlinks in this comprehensive clinical review.

Type 2 diabetes mellitus (T2DM) and late-onset Alzheimer’s disease-dementia (LOAD) are increasing in global prevalence and current predictions indicate they will only increase over the coming decades. These increases may be a result of the concurrent increases of obesity and aging. T2DM is associated with cognitive impairments associated with metabolic factors and increases the cellular vulnerability to develop the age-related increased risk of LOAD. This review addresses possible mechanisms due to obesity, aging, multiple intersections between T2DM and LOAD and mechanisms for the continuum of progression. Multiple ultrastructural images in female diabetic db/db models are utilized to demonstrate marked cellular remodeling changes of mural and glia cells and provide for the discussion of functional changes in T2DM. Throughout this review multiple endeavors to demonstrate how T2DM increases the vulnerability of the brain’s neurovascular unit (NVU), neuroglia and neurons are presented. Five major intersecting links are considered: i. aging (chronic age-related diseases); ii. metabolic (hyperglycemia - advanced glycation end-products and its receptor (AGE/RAGE) interactions and hyperinsulinemia – insulin resistance (a linking linchpin); iii. oxidative stress (reactive oxygen-nitrogen species); iv. inflammation (peripheral macrophage and central brain microglia); v. vascular (macrovascular accelerated atherosclerosis - vascular stiffening and microvascular NVU/neuroglial remodeling) with resulting impaired cerebral blood flow.

Restricted feeding is well known to affect expression profiles of both clock and metabolic genes. However, it is unknown whether these changes in metabolic gene expression result from changes in the molecular clock or in feeding behavior. Here we eliminated the daily rhythm in feeding behavior by providing 6-meals evenly distributed over the light/dark-cycle. Animals on this 6-meals-a-day feeding schedule retained the normal day/night difference in physiological parameters including body temperature and locomotor activity. The daily rhythm in respiratory exchange ratio (RER), however, was significantly phase-shifted through increased utilization of carbohydrates during the light phase and increased lipid oxidation during the dark phase. This 6-meals-a-day feeding schedule did not have a major impact on the clock gene expression rhythms in the master clock but did have mild effects on peripheral clocks. By contrast, genes involved in glucose and lipid metabolism showed differential expression. Concluding, eliminating the daily rhythm in feeding behavior in rats does not affect the master clock and only mildly affects peripheral clocks, but disturbs metabolic rhythms in liver, skeletal muscle and brown adipose tissue in a tissue-dependent manner. Thereby a clear daily rhythm in feeding behavior strongly regulates timing of peripheral metabolism, separately from circadian clocks.

The current SARS-CoV-2 pandemic is still threatening humankind. Despite first successes in vaccine development and approval, no antiviral treatment is available for COVID-19 patients. The success is further tarnished by the emergence and spreading of mutation variants of SARS-CoV-2, for which some vaccines are not effective anymore. This highlights the urgent need for antiviral therapies even more. This article describes how the Genome-Scale Metabolic Model (GEM) of the host-virus interaction of human alveolar macrophages and SARS-CoV-2 was refined by incorporating the latest information about the virus’s structural proteins and the mutant variants B.1.1.7 and B.1.351. We confirmed the initially identified guanylate kinase as a potential antiviral target with this refined model and identified further potential targets from the purine and pyrimidine metabolism. The model was further extended by incorporating the virus’ lipid requirements. This opened new perspectives for potential antiviral targets in the altered lipid metabolism. Especially the phosphatidylcholine biosynthesis seems to play a pivotal role in viral replication. The guanylate kinase is even a robust target in all investigated mutation variants currently spreading worldwide. These new insights can guide laboratory experiments for the validation of identified potential antiviral targets. Only the combination of vaccines and antiviral therapies will effectively defeat this ongoing pandemic.

We aimed to develop a non-linear regression model that could predict the fat fraction of the liver (USFF), similar to magnetic resonance imaging proton density fat fraction (MRI-PDFF), based on quantitative ultrasound (QUS) parameters. We measured and retrospectively collected the ultrasound attenuation coefficient (AC), backscatter-distribution coefficient (BSC-D), and liver stiffness (LS) using shear wave elastography (SWE) in 90 patients with clinically suspected non-alcoholic fatty liver disease (NAFLD) and 51 patients with clinically suspected metabolic-associated fatty liver disease (MAFLD). The MRI-PDFF was also measured in all patients within a month of the ultrasound scan. In the linear regression analysis, only AC and BSC-D showed a significant association with MRI-PDFF. Therefore, we developed prediction models using non-linear least-squares analysis to estimate MRI-PDFF based on the AC and BSC-D parameters. We fitted the models on the NAFLD dataset and evaluated their performance in 3-fold cross-validation repeated five times. We decided to use the model based on both parameters to estimate the ultrasound fat fraction (USFF). The correlation between USFF and MRI-PDFF was strong in NAFLD and very strong in MAFLD. According to a receiver operating characteristics (ROC) analysis, USFF could differentiate between <5% vs. ≥ 5% and < 10% vs. ≥ 10% MRI-PDFF steatosis with excellent, 0.97 and 0.91 area under the curve (AUC) accuracy in the NAFLD and with AUCs of 0.99 and 0.96 in the MAFLD groups. In conclusion, USFF calculated from QUS parameters is an accurate method to quantify liver fat fraction and to diagnose ≥ 5% and ≥ 10% steatosis in both NAFLD and MAFLD. Therefore, USFF can be an ideal non-invasive screening tool for patients with NAFLD and MAFLD risk factors.

Fatty acids (FAs) represent an important class of metabolites, impacting on membrane building blocks and cellular regulatory networks. In nature, prokaryotes are characterized with the most impressing FA structural diversity and the highest relative contents of free fatty acids (FFAs). Thereby, nitrogen-fixing bacteria (order Rhizobiales), often found in symbiosis with legumes, attract a special interest. Indeed, FAs impact on the structure of rhizobial nodulation factors, required for successful infection of plant root. Although the FA patterns can be addressed by GC- and LC-MS, these methods are time-consuming and suffer from compromised sensitivity, low stability of derivatives and artifacts. In contrast, MALDI-TOF-MS represents an excellent platform for high-efficient metabolite fingerprinting, also applicable to FFAs. Therefore, here we propose a simple and straightforward protocol for high-throughput relative quantification of FFAs in rhizobia by the combination of Langmuir technology and MALDI-TOF-MS, which is featured with high sensitivity, accuracy and precision of quantification. Here we propose a step by step procedure comprising rhizobia culturing, pre-cleaning, extraction, sample preparation, mass spectrometric analysis, data processing and post-processing. To demonstrate the analytical potential of the protocol we illustrate it by a case study – comparison the FFA metabolomes of two rhizobia species - Rhizobium leguminosarum and Sinorhizobium meliloti.

Microsamples (collections usually less than 50 µL) have been introduced in pre-clinical, clinical, and research settings to overcome obstacles in sampling via traditional venipuncture. However, venipuncture remains the sampling gold standard for metabolic phenotyping of blood. This pre-sents several challenges in metabolic phenotyping workflows: accessibility for individuals in ru-ral and remote underserved areas (due to the need for trained personnel), the unamenable nature to frequent sampling protocols in longitudinal research (for its invasive nature), and sample col-lection difficulty in the young and elderly. Furthermore, venous sample stability may be compro-mised when temperate conditions necessary for cold-chain transport are beyond control. Alter-natively, research utilising microsamples extends phenotyping possibilities to inborn errors of metabolism, therapeutic drug monitoring, nutrition, as well as sport and anti-doping. Although the application of microsamples in metabolic phenotyping exists, it is still in its infancy, with whole blood being overwhelmingly the primary biofluid collected through the collection method of dried blood spots. Research into metabolic phenotyping of microsamples is limited; however, with advances in commercially available microsampling devices, common barriers such as volumetric inaccuracies and the ‘haematocrit effect’ in dried blood spot microsampling can be overcome. In this review, we provide an overview of the common uses and workflows for mi-crosampling in metabolic phenotyping research. We discuss the advancements in technologies, highlighting key considerations and remaining knowledge gaps for employment of microsamples in metabolic phenotyping research. Supporting the translation of research from the ‘bench to the community’.

The pH-related metabolic paradigm has rapidly grown in cancer research and treatment. In this contribution, this recent oncological perspective has been laterally for the first time in order to integrate neurodegeneration within the energetics of the cancer acid-base conceptual frame. At all levels of study, molecular, biochemical, metabolic and clinical, the intimate nature of both processes appears to be opposite mechanisms occurring at the far ends of a physiopathological intracellular pH/extracellular pH (pHi/pHe) spectrum. This wide-ranged original approach now permits an increase in our understanding of these opposite processes, cancer and neurodegeneration, and, as a consequence, allows to propose new avenues of treatment based upon the intracellular and microenvironmental hydrogen ion dynamics regulating and deregulating the biochemistry and metabolism of both cancer and neural cells. Under the same perspective, the etiopathogenesis and special characteristics of multiple sclerosis (MS) becomes an excellent model for the study of neurodegenerative diseases and, utilizing this pioneering approach, we find that MS appears to be a metabolic disease even before an autoimmune one. Also within this paradigm, several important aspects of MS, from mitochondrial failure to microbiota functional abnormalities, are analyzed in depth.

COVID-19 is one of the deadliest respiratory diseases, and its emergence caught the pharmaceutical industry off guard. While vaccines have been rapidly developed, treatment options for infected people remain scarce, and COVID-19 poses a substantial global threat. This study presents a novel workflow to predict robust druggable targets against emerging RNA viruses using metabolic networks and information of the viral structure and its genome sequence. For this purpose, we implemented pymCADRE and PREDICATE to create tissue-specific metabolic models, construct viral biomass functions and predict host-based antiviral targets from more than one genome. We observed that pymCADRE reduces the computational time of flux variability analysis for internal optimizations. We applied these tools to create a new metabolic network of primary bronchial epithelial cells infected with SARS-CoV-2 and identified enzymatic reactions with inhibitory effects. The most promising reported targets were from the purine metabolism, while targeting the pyrimidine and carbohydrate metabolisms seemed to be promising approaches to enhance viral inhibition. Finally, we computationally tested the robustness of our targets in all known variants of concern, verifying our targets’ inhibitory effects. Since laboratory tests are time-consuming and involve complex readouts to track processes, our workflow focuses on metabolic fluxes within infected cells and is applicable for rapid hypothesis-driven identification of potentially exploitable antivirals concerning various viruses and host cell types.

The investigation by the integrated approach newly introduced for this study indicates that insulin resistance (IR) would develop first preferentially in the muscle tissue with a relatively low cell turnover and then progress in sequence to the subcutaneous adipose tissue, to the visceral adipose tissue, and to the liver with higher cell turnovers. Moreover, metabolic disruptions due to IR vary widely from tissue to tissue, contrary to the conventional notion that IR merely impairs glucose uptake in the whole body. This warrants that IR be divided better into four distinct tissue specific IRs: muscle insulin resistance (MIR), subcutaneous adipose insulin resistance (s-AIR), visceral adipose insulin resistance (v-AIR), and hepatic insulin resistance (HIR). Tissue-specific IRs developing in the order of MIR, s-AIR, v-AIR, and HIR – producing tissue specific metabolic disruptions – would amount to nothing but the whole body insulin resistance (WBIR) evolving in four distinctively insulin resistant stages. The four stage metabolic evolution from rapid weight gain to visceral obesity to rapid weight loss to full blown diabetes not only complies well with the natural development history of diabetes but also resolves most of the controversies regarding obesity or diabetes, including visceral obesity, obesity paradox, and dawn phenomenon that have long remained metabolic puzzles. In addition, the four-stage WBIR evolution model refutes the entrenched notion of the lipid-induced insulin resistance (LIIR) but supports instead the glycation-induced insulin resistance (GIIR) proposed in this study. A speculation is that the glycation reaction activated ever more with WBIR evolving may serve as the common thread connecting each other a cluster of disorders or diseases that are often collectively referred to as the metabolic syndrome, such as obesity, diabetes, cardio/cerebral vasculopathy, nephropathy, neuropathy, and retinopathy.