The development of anti-pain technologies in the complex treatment of pain syndromes is one of the most urgent tasks of modern medicine. We have undertaken a placebo-controlled experimental study of the therapeutic potential of low-intensity laser radiation when applied to acupuncture points, which are directly related to the autonomic nervous system. The adaptation effect of puncture photobiomodulation on the induction of stress-mediated autonomic reactions, oxidative metabolism and microcirculation in animals during the acute phase of pain stress was revealed. The data obtained are of interest for use in the complex rehabilitation of patients with pain syndrome.

Calcium signaling and lipid metabolism are crucial in the infection processes of Apicomplexans parasites. Thus, enzymes involved in these processes can be drug targets against Apicomplexans. For example, in malaria infection, in-depth research into lipid metabolic pathways is crucial in understanding the parasite's infection cycle, particularly during its erythrocytic infection cycle, which has been demonstrated to be a critical stage during the disease progression. Most enzymes that play critical roles in lipid synthesis and calcium signaling have been extensively studied; nonetheless, a vast knowledge gap still exists, especially on specific enzymes and their roles in the transmission and progression of the Apicomplexan parasites. Many types of infections caused by Apicomplexans are life-threatening and hard to treat. These intracellular parasites proliferate within parasitophorous vacuoles in their host cells. As the parasites multiply, they need to meet their high demand for nutrients such as amino acids and lipids. They can acquire nutrients through scavenging and biosynthesis. This review summarizes a few interesting, unique pathways in selected Apicomplexa and how such unique pathways can be targets for drugs.

Healthcare systems are mindful of the importance of proper diet and nutrition in reducing the risk of various chronic diseases resulting in hospitalizations. In this regard, they are focusing on promoting the intake of foods comprising various diets with health benefits, such as the ketogenic diet. In this meta-analysis, a total of 20 research studies on the effect of the ketogenic diet on the immune system were analyzed. The research studies were obtained from three databases: Google Scholar, PubMed, and Science Direct. From the meta-analysis, the odd ratio of a similar outcome of an improvement in the strength of immunity between the intervention and control group was 0.76. On the other hand, the p-value for the studies was 0.09, with 15 out of the 20 being considered statistically significant. The heterogeneity between the studies was I2 = 15%, signifying a low variability in the findings that is not by chance. The Ketogenic diet indeed has positive effects on immunity. Nonetheless, it can also result in negative effects that may harm human health.

In insects, Adipokinetic hormone is the primary hormone responsible for the mobilization of stored energy. While a growing body of evidence has solidified role of Adipokinetic hormone (AKH) in modulating the physiological and behavioral responses to metabolic stress, little is known about the upstream endocrine circuit that directly regulates AKH release. We evaluated the AKH-producing cell (APC) transcriptome to identify potential regulatory elements controlling APC activity, and found that a number of receptors show consistent expression levels, including all known dopamine receptors and the Pigment Dispersing Factor receptor (PDFR). We tested the consequences of targeted genetic knockdown and found that AKH expression of RNAi elements corresponding to each dopamine receptor caused a significant reduction in survival under starvation. In contrast, PDFR knockdown significantly extended lifespan under starvation whereas expression of a tethered PDF in APCs resulted in a significantly shorter lifespan. These manipulations caused various changes in locomotor activity under starvation. We used live-cell imaging to evaluate the acute effects of the ligands for these receptors on APC activation. Dopamine application led to a transient increase in intracellular calcium in a sugar-dependent manner. Furthermore, co-application of dopamine and ecdysone led to a complete loss of this response, suggesting that these two hormones act antagonistically. We also found that PDF application led to an increase in cAMP in APCs, and that this response was dependent on expression of the PDFR in APCs. Together these results suggest a complex circuit in which multiple hormones act on APCs to modulate metabolic state.

The objective of this study was to identify key transcription factors involved in lipid metabolism and immune response related to the differentially expressed genes (DEG) from the liver samples of 35 pig model for metabolic diseases fed diets containing either 1.5 or 3.0% soybean oil (SOY1.5 or SOY3.0). A total of 281 DEG between SOY1.5 and SOY3.0 diets (log2fold-change ≥ 1 or ≤ −1; FDR-corrected p-value < 0.1) were identified, in which 129 were down-regulated and 152 were up-regulated in SOY1.5 group. The functional annotation analysis detected transcription factors linked to lipid homeostasis and immune response, such as RXRA, EGFR, and SREBP2 precursor. These findings demonstrated that key transcription factors related to lipid metabolism could be modulated by dietary inclusion of soybean oil. It could contribute to nutrigenomics research field that aims to elucidate dietary interventions in animal and human health, as well as to drive the food technology and science.

Energy metabolism, including alterations in energy intake and expenditure, is closely related to aging and longevity. Metabolomics studies have recently unraveled changes in metabolite composition in plasma and tissues during aging and have provided critical information to elucidate the molecular basis of aging process. However, the metabolic changes in tissues responsible for food intake and lipid storage have remained unexplored. In this study, we aimed to investigate aging-related metabolic alterations in these tissues. To fill this gap, we employed NMR-based metabolomics in several tissues, including different parts of the intestine (duodenum, jejunum, ileum) and brown/white adipose tissues (BAT, WAT) of young (9-10 weeks) and old (96-104 weeks) wild-type (mixed genetic background of 129/J and C57BL/6) mice. We further included plasma and skeletal muscle of the same mice to verify previous results. Strikingly, we found that duodenum, jejunum, ileum, and WAT do not metabolically age. In contrast, plasma, skeletal muscle, and BAT show a strong metabolic aging phenotype. Overall, we provide first insights into the metabolic changes of tissues essential for nutrient uptake and lipid storage and have identified biomarkers for metabolites that could be further explored to study the molecular mechanisms of aging.

Despite a large amount of data on the association of folate metabolism disturbances with different aspects of schizophrenia, the role of the MTHFD1 1958 G>A polymorphism in this disorder is barely studied. The aim of this study was to assess the distribution of alleles and genotypes frequencies of MTHFD1 1958 G>A in patients with schizophrenia and healthy controls and to study the association of allele/genotype carriage of this SNP with biochemical markers of one-carbon metabolism and with the severity of schizophrenia symptoms. Methods: In 57 patients with schizophrenia and 37 healthy volunteers the carriage of alleles/genotypes of the MTHFD1 1958 G>A and biochemical markers of folate metabolism disturbances were evaluated. Clinical symptoms of schizophrenia and the severity of extrapyramidal side effects of therapy were assessed in patients. Results: an association of the wild GG genotype with schizophrenia was shown (GG versus AG / AA: χ2 = 7.31; p = 0.007). The serum folate level in carriers of the wild genotype GG is lower (in all participants p = 0.024, in patients p = 0.10), and the level of cobalamin in this subgroup is higher (in all participants p = 0.047, in patients p = 0.091) than in carriers of other genotypes. Patients carrying the G allele had less severe negative symptoms (p = 0.0041) and extrapyramidal side effects of antipsychotics (p = 0.054), than patients with AA genotype. The age of psychosis manifestation is the later, the more wild alleles G are present in the genotype (p = 0.00195).

Animal studies have shown that developmental exposures to polybrominated diphenyl ethers (PBDE) permanently affect blood/liver balance of lipids. No human study has evaluated associations between in utero exposures to persistent organic pollutants (POPs) and later life lipid metabolism. In this pilot, maternal plasma levels of PBDEs (BDE-47, BDE-99, BDE-100, and BDE-153) and polychlorinated biphenyls (PCB-138, PCB-153, and PCB-180) were determined at delivery in participants of GESTation and Environment (GESTE) cohort. Total cholesterol (TCh), triglycerides (TG), low and high density lipoproteins (LDL-C and HDL-C), total lipids (TL), and PBDEs were determined in serum of 147 children at ages 6-7. General linear regression was used to estimate the relationship between maternal POPs and child lipid levels with adjustment for potential confounders, and adjustment for childhood POPs. In utero BDE-99 was associated with lower childhood levels of TG (p=0.003), and non-significantly with HDL-C (p=0.06) and TL (p=0.07). Maternal PCB-138 was associated with lower childhood levels of TG (p=0.04), LDL-C (p=0.04), and TL (p=0.02). Our data indicate that in-utero exposures to POPs may be associated with long-lasting decrease in circulating lipids in children, suggesting increased lipid accumulation in the liver, a mechanism involved in NAFLD development, consistent with previously reported animal data.

The liver is a key node of whole-body nutrient and fuel metabolism and is also the principal site for detoxification of xenobiotic compounds. As such, hepatic metabolite concentrations and/or turnover rates inform the status of both hepatic and systemic metabolic diseases as well as the disposition of medications. As a tool to better understand liver metabolism in these settings, in vivo magnetic resonance spectroscopy (MRS) offers a non-invasive means of monitoring hepatic metabolic activity in real time both by direct observation of concentrations and dynamics of specific metabolites as well as by observation of their enrichment by stable isotope tracers. This review summarizes the applications and advances in human liver metabolic studies by in vivo MRS over the past 35 years and discusses future directions and opportunities that will be opened by the development of ultra-high field MR systems and by hyperpolarized stable isotope tracers.

Animal communication signals are regulated by multiple hormonal axes that ensure appropriate signal targeting, timing, and information content. The regulatory roles of steroid hormones and many peptide hormones are well understood and documented across a wide range of vertebrate taxa. Two recent studies have reported a novel function for leptin, a peptide hormone central to energy balance regulation: regulating communication signals of weakly electric fish and singing mice. With only limited evidence available at this time, a key question is just how widespread leptinergic regulation of communication signals is within and across taxa. A second important question is what features of communication signals are subject to leptinergic regulation. Here we consider the functional significance of leptinergic regulation of animal communication signals in the context of both direct and indirect signal metabolic costs. Direct costs arise from metabolic investment in signal production, while indirect costs arise from the predation and social conflict consequences of the signal’s information content. We propose a preliminary conceptual framework for predicting which species will exhibit leptinergic regulation of their communication signals and which signal features leptin will regulate. This framework suggests a number of directly testable predictions within and across taxa. Accounting for additional factors such as life history and reproductive strategies will likely require modification or elaboration of this model.

Esters constitute a wide family of volatile compounds impacting the organoleptic properties of many beverages including wine and beer. They can be classified according to their chemical structure. Higher Alcohols Acetate differ from Fatty Acids Ethyl Esters whereas a third group, Substituted Ethyl Esters, contributes to the fruitiness of red wines. Derived from yeast metabolism, the biosynthesis of Higher Alcohols Acetates and Fatty Acids Ethyl Esters has been widely in-vestigated at the enzymatic and genetic level. In this work, we confirmed their effective contri-bution in the fruity perception in young red wines by evaluating the effect of their depletion by chemical and sensorial analyses. As previously reported, two pairs of esterases respectively en-coded by the paralogue genes (ATF1, ATF2) and (EEB1 and EHT1) are mostly involved in the bi-osynthesis of Acetate of Higher alcohols and Fatty Acids Ethyl Esters. However, those esterases have a moderate effect on the biosynthesis of Substituted Ethyl Esters that depends to another pair of genes, MGL2 and YJU3 encoding for mono-acyl lipases. These new findings complete our un-derstanding of esters metabolism in the context of wine alcoholic fermentation. In order to evaluate the sensorial impact of esters we attempted to produce a red wine without esters by generating a multiple deletion strain. Surprisingly, we failed to abolish all the esterase activities revealing unsuspected physiological consequences of ester biosynthesis routes. A preliminary RNA-seq analysis depicted the overall impact of the multiple deletion of ATF1, ATF2, EEB1 and EHT1 that triggers the expression shift of 1124 genes involved in nitrogen and lipid metabolism but also chromatin organization and histone acetylation, suggesting an unsuspected regulatory role of ester metabolism

Hyperuricemia is a risk factor for gout. It has been well observed that a large proportion of hyperuricemia individuals have never had a gout attack(s), while some patients with gout can have a normuricemia. This raises a puzzle of the real role of serum uric acid (SUA) in the occurrence of gout attacks. As the molecule of uric acid has its dual effects in vivo with antioxidant property as well as being an inflammatory promoter, it has been placed in a delicate position in balancing metabolisms. Gout seems to be a multifactorial metabolic disease and its pathogenesis should not rely solely on hyperuricemia or MSU crystal. This critical review aims to unfold the mechanisms of the SUA role participating in gout development. It also discusses some key elements which are prerequisite for the formation of gout in association with the current therapeutic regime. The compilation should be helpful in precisely fighting for a cure of gout clinically and pharmaceutically.

Thesis Statement: The consumption of externally fermented foods acted as the initial metabolic trigger enabling hominid brain expansion. Because brain tissue is metabolically expensive, it is thought that the evolution of humans’ large brains was only possible through a concomitant reduction in the size of another expensive organ system, the gut. However, this gut reduction must have itself been made possible by dietary changes, the nature of which are still unclear. Here, we propose that the initial metabolic trigger of hominid brain expansion may have been the consumption of externally fermented foods. We define “external fermentation” as occurring outside the body, as opposed to the internal fermentation that occurs through the gut microbiome. This practice could have begun accidentally and with limited understanding, but over time, fermentation technologies may have become increasingly intentional, socially-transmitted, and culturally-reinforced. We detail the mechanisms by which external fermentation can mediate the evolution of increased brain size, as well as a reduction in gut size, by increasing the bioavailability of macro- and micronutrients while reducing digestive energy expenditure. Importantly, we calculate that the reduction in human gut size relative to modern apes is mainly due to a reduction in the colon, the site of internal fermentation. We also discuss the explanatory power of our hypothesis relative to others, including realistic plausibility in hominids with brains roughly the size of modern chimpanzees. Finally, we survey external fermentation practices across human cultures to demonstrate its viability across a huge range of environments, temperatures, and food sources. We close with suggestions for empirical tests.

Although diet interventions are mostly related to metabolic disorders, nowadays they are used in wide variety of pathologies. From diabetes and obesity to cardiovascular diseases, through cancer or neurological disorders and stroke, nutritional recommendations applied to almost all diseases. Among those disorders, metabolic disturbances and brain function and/or diseases have recently been shown to be linked. Indeed, numerous neurological functions are often associated with perturbations of whole-body energy homeostasis. In this regard, specific diets are used in various neurological conditions such as epilepsy, stroke, or seizure recovery. In addition, Alzheimer’s disease or Autism Spectrum Disorders are also considered as putatively improved by diet intervention. Glycemic index diets are a novel developed indicator expected to anticipate the changes in blood glucose induced by specific foods, and how they can affect various physiological function. Several results provide indications of efficiency of low glycemic index diets in weight management, insulin sensitivity, but also cognitive function, epilepsy treatment, stroke, or neurodegenerative diseases. Overall, studies involving glycemic index could provide new insight in the relationship between energy homeostasis regulation and brain function or related disorders. Therefore, in this review we will summarize main evidences on glycemic index involvement in brain mechanisms of energy homeostasis regulation.

The molecular interaction between the nematode and the host plant cells is complex and sophisticated. Initial contact with the plant parasitic nematodes (PPNs) triggers immune response in the host plant system which includes the release of toxic molecules. To put a bridle on this immune response, PPNs trigger pivotal cytoprotective mechanisms, such as antioxidant and detoxification pathways. Mechanisms of these pathways have been studied in PPNs and the specific genes involved have been targeted for gene silencing research in view of developing novel control measures. However, one of the important group of proteins involved in detoxification pathways known as ABC-transporters are not being studied until recently in PPNs. This opinion article focusses on the current knowledge and future prospects of ABC transporters in PPNs.

To reduce the risk factors for mortality, the paper has focused on the assessment of the socioeconomic, clinical, physical, biophysiological, and biochemical characteristics of Down's syndrome which can be affected by the type of nutrition system, toxicity, and ecological footprint. Patients were males with trisomy 21 diagnosed by karyotype test and assessed by clinical examinations. Samples were collected from different biofluids. The physicochemical analyses of the biomatrix samples were performed and these properties had compared to findings of healthy males and age-matched controls. Duraphat application was proved effective for their oral treatment and saliva was the optimum biomarker for detecting malnutrition. Patients were hypersensitive to Cu while the Mn content in blood and hair was considered an expression to the degree of epileptic condition and chronic seizure development. The ecological footprint was 5.6 gha and carbon footprint was recognised in food poverty habits. These can be reduced by eating more plant-based proteins and fibre-rich foods with low saturated fats and sodium. The findings provide an up-to-date reference for expected developmental outcomes in children with DS in terms of biophysicochemistry. The genetically sensitive intervention is affected by heredity factor and sensitivity to toxics. Down's syndrome is encouraged to live green-hipster life.

In the modern world, the problem of antibiotic therapy is acute. Despite the diversity of existing antibiotic drugs, their efficacy decreases as new, resistant forms of pathogenic microorganisms emerge. It is extremely difficult to control such processes and even more difficult to treat severe bacterial infections. In such situations, an individual approach to each patient is required and physicians need parameters to estimate the efficacy of antibiotic therapy. This review discusses the significance of monitoring the content of antibiotics in the blood for this purpose, in combination with the content of inflammatory markers, such as C-reactive protein and procalcitonin. The basic principles of antibiotic therapy, and factors in the resistance of microorganisms to antibiotics, are examined. Approaches to assess the efficacy of antibiotic therapy, as well as methods to detect antibiotics and inflammatory markers in the blood of patients, and comparative assessment of their capabilities and limitations, are described.

Perturbation in the microbial population/colony index has harmful consequences on human health. Both biological and social factors influence the composition of the gut microbiota and promote gastric diseases. Changes in the gut microbiota manifest in disease progression owing to epigenetic modification in host which influences differentiation and function of immune cells adversely. Uncontrolled use of antibiotics; chemotherapeutic drugs and change in the diet pattern usually contribute to the changes in the colony index of sensitive strains known to release microbial content in the tissue micromillieu. Ligands released from dying microbes induce TLR mimicry on interaction with TLR abnormally which skew hypoxia and sterile inflammation contributing to severity of disease like IBD autoimmunity and cancer. Various modalities/interventions practiced across the globe and future strategies for microbiota based therapeutic approaches with special emphasis on tumor and inflammatory diseases are reviewed here. Therefore the major aim and scope of this manuscript is to both discuss various modalities/interventions across the globe and to design future microbiota based therapeutic approaches for mitigating the burden with special emphasis on tumor and Inflammatory diseases.

Pyruvate kinase M2 (PKM2) is essential for aerobic glycolysis and is highly expressed in various cancer tissues. Although high PKM2 expression is observed in prostate cancer tissues, its functional role in cancer metabolism is unclear. Here, we investigated the role of PKM2 in regulating autophagy and its associated pathways in prostate cancer cells. PKM2 expression was silenced using various PKM2 small interfering RNAs (siRNAs) and then we measured PKM2-related cellular pathways associated with autophagy. PKM2 siRNA-transfected prostate cancer cells showed significantly reduced viability. Acridine orange staining and immunoblotting analysis showed that PKM2 downregulation markedly increased autophagic cell death. Results of western blotting analysis showed that PKM2 knockdown affected protein kinase B/mechanistic target of rapamycin 1 pathway, which consequently downregulated the expression of glycolytic enzymes lactate dehydrogenase A and glucose transporter 1. To the best of our knowledge, this is the first study to show that PKM2 inhibition alters cancer cell metabolism and induces autophagy. Thus, the present study provides a strategy for the development of PKM2-targeted novel anticancer drugs for the treatment of prostate cancer.

During the last decade, essential polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) derived from marine sources have been investigated as nonpharmacological dietary supplements to improve different pathological conditions, as well as aging. The aim of this study was to determine the effects of dietary n-3 PUFA monoacylglycerides (MAG, both EPA and DHA) on the mitochondrial metabolism and oxidative stress of a short-lifespan model, Drosophila melanogaster, sampled at five different ages. Our results showed that diets supplemented with MAG-EPA and MAG-DHA increased median lifespan by 14.6% and decreased mitochondrial proton leak resulting in an increase of mitochondrial coupling. The flies fed on MAG-EPA also had higher electron transport system capacity and mitochondrial oxidative capacities. Moreover, both n-3 PUFAs delayed the occurrence of lipid peroxidation, but only flies fed the MAG-EPA diet showed maintenance of superoxide dismutase activity during aging. Our study therefore highlights the potential of n-3 PUFA monoacylglycerides as nutraceutical compounds to delay the onset of senescence by acting directly or indirectly on the mitochondrial metabolism, and suggests that Drosophila could be a relevant model for the study of the fundamental mechanisms linking the effects of n-3 PUFAs to aging.

The energy sensor AMP-activated protein kinase (AMPK) is a key player in the control of energy metabolism. AMPK regulates hepatic lipid metabolism through the phosphorylation of its well-recognized downstream target acetyl CoA carboxylase (ACC). Although AMPK activation is proposed to lower hepatic triglyceride (TG) content via the inhibition of ACC to cause inhibition of de novo lipogenesis and stimulation of fatty acid oxidation (FAO), its contribution to the inhibition of FAO in vivo has been recently questioned. We generated a mouse model of AMPK activation specifically in the liver achieved by expression of a constitutively active AMPK using adenoviral delivery. Indirect calorimetry studies revealed that liver-specific AMPK activation is sufficient to induce a reduction in the respiratory exchange ratio and an increase in FAO rates in vivo. This led to a more rapid metabolic switch from carbohydrate to lipid oxidation during the transition from fed to fasting. Finally, mice with chronic AMPK activation in the liver display high fat oxidation capacity evidenced by increased [C14]-palmitate oxidation and ketone body production leading to reduced hepatic TG content and body adiposity. Our findings suggest a role for hepatic AMPK in the remodeling of lipid metabolism between the liver and adipose tissue.

In the context of the development of bioprocesses for the production of biofuels and bulk chemicals, microbial cells are rationally engineered to produce such molecules at high yield and titres in order to develop new biological methods that satisfy economic constraints. The redox and energetic balances of such strains play crucial roles in performance. Processes performed in strict anaerobes have a limited amount of energy available compared to that in aerobic organisms. This energy is obtained through fermentation and/or ion gradient-driven phosphorylation. Such anaerobic organisms have developed energy conservation mechanisms to increase ATP yields. This paper presents the properties of one of these mechanisms catalysed by the Rnf complex, an ion-translocating membrane complex with a ferredoxin NAD+ oxidoreductase activity. The Rnf complex performs the transfer of electrons from reduced ferredoxin to NAD+ coupled with an ion-motive transport. Ferredoxin is a common electron carrier for anaerobic bacteria and, with NAD+, is involved in several pathways of interest for the production of biofuels. This complex was first identified in Rhodobacter capsulatus and found to be involved in nitrogen fixation. It was then found to be involved in energy conservation in multiple anaerobic organisms, from acetobacteria such as Acetobacterium woodii to sulfate-reducing bacteria such as Desulfovibrio alaskensis and autotrophic bacteria such as Clostridium ljungdahlii and Clostridium aceticum. The Rnf complex triggers two types of ion transports: it can be either a sodium or a proton transporter. Both of these transports create a gradient of ions, generating a membrane potential that is then used by ATPase to produce ATP and thus serving as an energy conservation mechanism. In this review, the available information on the Rnf complex from genetic organization up to its in vivo and in vitro activities in several microorganisms is summarized, with a special focus on the proton-motive Rnf complex.

We report the application of a recently proposed approach for modeling biological systems using a maximum entropy production rate principle in lieu of having in vivo rate constants. The method is applied in four steps: (1) a new ODE-based optimization approach based on Marcelin’s 1910 mass action equation is used to obtain the maximum entropy distribution, (2) the predicted metabolite concentrations are compared to those generally expected from experiment using a loss function from which post-translational regulation of enzymes is inferred, (3) the system is re-optimized with the inferred regulation from which rate constants are determined from the metabolite concentrations and reaction fluxes, and finally (4) a full ODE-based, mass action simulation with rate parameters and allosteric regulation is obtained. From the last step, the power characteristics and resistance of each reaction can be determined. The method is applied to the central metabolism of Neurospora crassa and the flow of material through the three competing pathways of upper glycolysis, the non-oxidative pentose phosphate pathway, and the oxidative pentose phosphate pathway are evaluated as a function of the NADP/NADPH ratio. It is predicted that regulation of phosphofructokinase (PFK) and flow through the pentose phosphate pathway are essential for preventing an extreme level of fructose 1, 6-bisphophate accumulation. Such an extreme level of fructose 1,6-bisphophate would otherwise result in a glassy cytoplasm with limited diffusion, dramatically decreasing the entropy and energy production rate and, consequently, biological competitiveness.

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.

Although migraine belongs to the main causes of disability worldwide the mechanisms of its pathogenesis are poorly known, which is among the reasons that this disease is underdiagnosed and undertreated. As migraine diagnosis is based on the subjective assessment of symptoms, there is a need to establish objective markers of its occurrence and severity. Tryptophan (TRP) metabolism has been associated with the pathogenesis of neurological and psychiatric disorders. In the present work, we investigated an association between migraine and the urine concentration of TRP and its metabolites 5-hydroxyindoleacetic acid (5-HIAA), kynurenine (KYN), kynurenic acid (KYNA) and quinolinic acid (QA) in 21 low-frequency episodic migraine patients and 32 controls. Migraine patients displayed lower urinary levels of 5-HIAA and KYNA, but KYN and QA were enhanced as compared with the controls. Consequently, the patients were characterized by different values of the 5-HIAA/TRP, KYN/TRP, KYNA/KYN, and KYNA/QA ratios. Furthermore, urinary concentration of 5-HIAA was negatively correlated with Migraine Disability Assessment score, monthly migraine, and monthly headache days. A negative correlation between Patient Health Questionnaire 9 scores assessing depression. In conclusion, the urinary 5-HIAA level may be an easy-to-determine marker of migraine occurrence and severity and may contribute to the identification of migraine patients with depression.

The aim of our study was a comprehensive comparative assessment of the effect of consumption of 1 and 2% cholesterol as part of a standard diet with and without regular moderate physical activity on the main biomarkers of lipid and cholesterol metabolism, as well as the intestinal microbiota of male Wistar rats. The animals were randomly divided into 5 groups according to body weight and Open Field test results: Control (n=10), 1% Chol (n=10), 2% Chol (n=10), 1% Chol + RUN (n=10) and 2% Chol + RUN. The cholesterol was additionally added in the amount of 1g or 2g/100g, respectively, to the diet of animals. The rats of experimental groups 1% Chol + RUN and 2% Chol + RUN were subjected to regular (2 days a week) physical activity on a Treadmill. In rats of four experimental groups, when compared to the Control, a response of 39 indicators was revealed. The largest number of changes in biomarkers - 29 (statistically significant, p

The increase in hypoxia events, a result of climate change in coastal and fjord ecosystems, impacts the health and survival of mussels. These organisms deploy physiological and molecular responses as an adaptive mechanism to maintain cellular homeostasis under environmental stress. However, the specific effects of hypoxia on mussels of socioeconomic interest, such as Mytilus chilensis, are unknown. Using RNA-seq, we investigated the transcriptomic profiles of the gills, digestive gland, and adductor muscle of M. chilensis under hypoxia (10 days at 2 mg L-1) and reoxygenation (10 days at 6 mg L-1). There were 15,056 differentially expressed transcripts identified in gills, 11,864 in the digestive gland, and 9,862 in the adductor muscle. The response varied among tissues, showing chromosomal changes in Chr1, Chr9, and Chr10 during hypoxia. Hypoxia regulated signaling genes in the Toll-Like, mTOR, citrate cycle, and apoptosis pathways in gills, indicating metabolic and immunological alterations. These changes suggest that hypoxia-induced a metabolic shift in mussels, reducing reliance on aerobic respiration and increasing reliance on anaerobic metabolism. Furthermore, hypoxia appeared to suppress the immune response, potentially increasing disease susceptibility, with negative implications for the mussel culture industry and natural bed populations. This study provides pivotal insights into metabolic and immunological adaptations to hypoxia in M. chilensis, offering candidate genes for adaptive traits.

Europium is one of the most reactive lanthanides and humans use it in many different applica-tions, but we still know little about its potential toxicity and cellular response to its exposure. Two strains of the eukaryotic microorganism model Tetrahymena thermophila adapted to high concentrations of two Eu(III) compounds (EuCl3 or Eu2O3) were obtained and compared to a control strain and cultures treated with both compounds. In this ciliate, EuCl3 is more toxic than Eu2O3. LC50 values show that this microorganism is more resistant to these Eu(III) compounds than other microorganisms. Oxidative stress originated mainly by Eu2O3 is minimized by overexpression of genes encoding important antioxidant enzymes. The overexpression of metallothionein genes under treatment with Eu(III) compounds supports the possibility that this lanthanide may interact with the -SH groups of the cysteine residues from metallothi-oneins and/or displace essential cations of these proteins during their homeostasis function. Both lipid metabolism (lipid droplets that fuse with europium-containing vacuoles) and au-tophagy are involved in the cellular response to europium stress. Bioaccumulation, together with a possible biomineralization to europium phosphate, seems to be the main mechanism of Eu(III) detoxification in these cells.

To investigate the effect of prohexadione-calcium (Pro-Ca) primed on seed germination and seedling growth of oilseed rape under salt stress, to alleviate the inhibition of soil salinization on the growth of oilseed rape, and to improve the sustainability of agricultural production. Using Huayouza 158R and Huayouza 62 as test materials, the regulation of seed germination and seedling growth under the stresses of 0, 100, and 150 mM NaCl (S0, S100, and S150) was investigated after the primed of Pro-Ca. We conducted six treatments, S0: non-primed + 0 mM NaCl, PCS0: Pro-Ca primed + 0 mM NaCl, S100: non-primed + 100 mM NaCl, PCS100: Pro-Ca primed + 100 mM NaCl, S150: non-primed + 150mM NaCl, Pro-Ca+S150: Pro-Ca primed + 150 mM NaCl. The results showed that salt stress inhibited seed germination and seedling growth, and Pro-Ca primed significantly increased the germination index and vigor index of oilseed rape seeds. The average germination time and malondialdehyde (MDA) content were significantly reduced, which resulted in the optimal initiation fiddling concentration of 8mg·L-1. The morphological parameters of oilseed rape decreased significantly under salt stress, with leaf area decreasing by 70.69% and 75.03% and total chlorophyll content decreasing by 18.55% and 18.68% at S150. With the rise of salt stress, the changes of each photosynthetic parameter were somewhat similar, and Pn, Gs, Ci, and Tr continued to decline, indicating that the effects of salt stress on photosynthesis in oilseed rape might be mainly attributed to stomatal restriction and inhibition of photosynthetic pigment synthesis. While Na+ and MDA contents increased significantly, reaching a peak at S150, indicating that Na+ content increased significantly under salt stress, which resulted in the slow growth of oilseed rape and weak plants under the influence of Na+ salt damage. After Pro-Ca primed, leaf area and photosynthetic pigment synthesis increased, and the initiation treatment promoted the rise of Pn, Gs, Ci, and Tr under salt stress. The Na+ content decreased by 7.29% and 6.96% in PCS100 compared with S100, decreased by 9.23% and 25.02% in PCS150 compared with S150, and increased in K+ and Mg2+ after Pro-Ca primed. At this time, the antioxidant enzyme activities increased, and the MDA content and relative conductivity decreased. It was concluded that Pro-Ca primed improved the photosynthetic capacity of oilseed rape by promoting leaf growth, stomatal opening, and photosynthetic pigment synthesis. At the same time, reducing Na+ content and promoting K+ and Mg2+ absorption and antioxidant enzyme activities together alleviate salt damage and improve salt tolerance of oilseed rape.

Background: RNA helicase DHX15 plays a significant role in vasculature development and lung metastasis in vertebrates. In addition, several studies have demonstrated the overexpression of DHX15 in the context of hepatocellular carcinoma. Therefore, we hypothesized that this helicase may play a significant role in liver regeneration, physiology and pathology. Methods: Dhx15 gene deficiency was generated by CRISPR/Cas9 in zebrafish and by TALEN-RNA in mice. FANA Antisense-Oligonucleotides were used to silence Dhx15 in wild-type mice. The hepatocellular carcinoma tumor induction model was generated by subcutaneous injection of Hepa 1-6 cells. Results: Homozygous Dhx15 gene deficiency was lethal in zebrafish and mouse embryos. Dhx15 gene deficiency impaired liver organogenesis in zebrafish embryos and liver regeneration after partial hepatectomy in mice. Also, heterozygous mice presented decreased number and size of liver metastasis after Hepa 1-6 cells injection compared to wild-type mice. Dhx15 gene silencing with FANA Antisense-Oligonucleotides in wild-type mice resulted in 80% reduced expression in the liver and a significant reduction in other major organs. In addition, Dhx15 gene silencing significantly hindered primary tumor growth in the hepatocellular carcinoma experimental model. Regarding the potential use of DHX15 as a diagnostic marker for liver disease, patients with hepatocellular carcinoma showed increased levels of DHX15 in blood samples compared with subjects without hepatic affectation. Conclusion: Dhx15 is a key regulator of liver physiology and organogenesis, is increased in the blood of cirrhotic and hepatocellular carcinoma patients and has a key role in controlling hepatocellular carcinoma tumor growth and expansion in experimental models.

(1) Background: Ferric carboxymaltose (FCM) is an intravenous (IV) high-dose iron that is effective in the treatment of iron deficiency anemia. This study was to determine if preoperative IV FCM administration could improve recovery from postoperative anemia in patients undergoing revision total joint arthroplasty. (2) Methods: This prospective randomized controlled study analyzed 82 patients undergoing revision total joint arthroplasty during a single hospitalization. Patients in the iron group (n = 41) were administered 1000 mg of IV FCM two weeks preoperatively, while those in the control group (n = 41) were not. Moreover, patients with anemia defined as a preoperative suboptimal Hb concentration <13.0 g/dl were compared according to IV FCM administration. The absolute Hb levels and changes in Hb levels, iron profiles, transfusion rate, and EuroQOL 5-dimension (EQ-5D) scores were compared. (3) Results: There were no significant differences in recovery of Hb levels at each timepoint between the two groups; however, the changes in Hb levels from baseline to four weeks postoperatively showed marginally significant differences favoring the iron group (p = 0.052). However, for preoperatively anemic patients, the change in hemoglobin (Hb) levels between baseline and four weeks postoperatively was significantly better in the iron group than in the control group (iron group [n = 26], −0.3 ± 0.7 g/dL vs. control group [n = 27], −0.9 ± 0.8 g/dL; p = 0.040), although the absolute Hb levels, transfusion rates, and patient quality of life were comparable (all p > 0.05). The iron group showed improved iron metabolite levels including serum ferritin and transferrin saturation four weeks postoperatively, and no adverse events associated with IV FCM administration occurred in either group. (4) Conclusions: Preoperative IV FCM in anemic individuals undergoing revision joint arthroplasty was effective in accelerating recovery from surgery-related anemia by improving Hb levels without any adverse events, despite similar actual Hb levels between the groups. Our findings are clinically relevant and can facilitate determination of the suitability of IV FCM as a safe and reliable protocol for iron supplementation for anemia correction.

The need to carry different items, which become an extra load, is a characteristic of trail running. The aim of this study is to determine physiological-metabolic changes produced by running with extra load. Four male well-trained trail runners completed three treadmill maximal metabolic tests carrying different loads (0% (L0), 5% (L5), and 10% (L10) of their body mass) in a weighted vest. Gasses exchange was monitored to assess ventilatory thresholds 1 (VT1), and 2 (VT2), zone of maximal fat oxidation, and peak oxygen consumption (VO2peak). Heart rate (HR), power and velocity (V) were tracked for comparing their behavior. A repeated measures ANOVA showed significant differences in V (p<.001; ηp2= 0.910) as a limitation for reaching peak velocity (Vpeak) with L10 respect to L0 (p=0.001), and L5 (p=0.011). Power expression showed differences (p=0.068; ηp2= 0.592). It tended to be greater with L10 than L0 (p=0.057), despite achieving lower V. VT2 tended to occur at different %VO2peak (p=0.069; ηp2= 0.591). L5 VT2 was reached at higher %VO2peak than L0 (p=0.062), and L10 (p=0.071). ANOVA also showed a tendency to signification for V at this point (p= 0.098; ηp2= 0.538). In conclusion, L10 seems to limit Vpeak while L5 may delay VT2 expression.

Current treatments in patients with pancreatic cancer offer limited benefits. In this report, we applied “alkalization therapy”, which was efficacious for other solid tumors at our clinic, to stage 4 pancreatic cancer patients, and investigated its effect on disease prognosis. Patients with metastatic pancreatic cancer who were treated at Karasuma Wada Clinic in Kyoto, Japan, between 2011 and 2022 were included in the study. All patients received alkalization therapy (combination of an alkaline diet, bicarbonate, and citric acid administration), alongside standard chemotherapy. Urine samples were collected to assess urine pH as a marker for whole-body alkalization. In the 98 patients analyzed, the median overall survival (OS) from the time of diagnosis was 13.2 months. Patients with a mean urine pH of 7.5 or greater had a median OS of 29.9 months, compared with 15.2 months for those with a mean urine pH of 6.5 to 7.5, and 8.0 months for those with a mean urine pH of less than 6.5, which suggests a trend of a longer OS in patients with a higher urine pH. Conclusions: Alkalization therapy may offer a viable approach to enhance the survival of stage 4 pancreatic cancer patients, who typically have an unfavorable prognosis.

Abstract Plant uptake and assimilation of essential nitrogen compounds from the soil are mainly in the form of nitrate and ammonium ions. Plant nitrate transporters (NRTs) play a crucial role in nitrate uptake from the soil into the roots. NRT structural analysis reveals the mechanisms by which these transporters function. Similarly, plant ammonium transporters (AMTs) mediate the uptake of ammonium ions, and their structural analysis has provided valuable information on their mechanisms. After nitrogen uptake by plant roots, the nitrogen metabolism pathway involves the incorporation of nitrogen into organic compounds. Glutamine synthetase (GS) and glutamate synthase (GoGAT) are the master players in this pathway. They work together to convert ammonium ions into glutamine and glutamate, respectively. Different isoforms of GS and GoGAT exist, enabling plants to fine-tune nitrogen metabolism based on environmental cues. Under severe abiotic stress conditions, nitric oxide (NO) has been found to enhance plant survival under drought. Furthermore, the interaction between salinity stress and nitrogen availability in plants has been studied, with NO identified as a potential mediator of responses to salt stress. On the other hand, excessive use of nitrate fertilizers can lead to health and environmental issues. Therefore, alternative strategies, such as establishing nitrogen fixation in plants through diazotrophic microbiota, have been explored to reduce reliance on synthetic fertilizers. Ultimately, genomics can identify new genes related to nitrogen fixation, which could be harnessed to improve plant productivity. By deciphering the genetic basis of nitrogen-fixing traits, researchers aim to develop crops that efficiently utilize nitrogen from the environment.

Chinese pepper rust is a live parasitic fungal disease caused by Coleosporium zanthoxyli, which seriously affects the cultivation and industrial development of Z. armatum. Cultivating and planting resistant cultivars is considered the most economical and environmentally friendly strategy to control this disease. Therefore, the mining of excellent genes for rust resistance and analysis of the mechanism of rust resistance are the key strategies to achieve the targeted breeding of rust resistance. However, there is no relevant report on pepper rust resistance at present. The aim of the present study was to further explore the resistance mechanism of pepper by screening the rust-resistant germplasm resources in the early stage. Combined with the analysis of plant pathology, transcriptomics, and metabolomics, we found that the genes and metabolites related to phenylpropanoid metabolism were highly enriched in resistant varieties after pathogen infection, which indicated that phenylpropanoid metabolism might mediate the resistance of Z. armatum. This finding was further confirmed by real-time quantitative polymerase chain reaction analysis, which revealed that the expression levels of core genes involved in phenylpropane metabolism in disease-resistant varieties were high. In addition, the difference in flavonoid content in the leaves between resistant and susceptible varieties further supported the conclusion that the flavonoid pathway is one of the main pathways involved in resistance formation in Chinese pepper, and MeJA is involved in the formation of resistance. Our research results not only help to better understand the resistance mechanism of Z. armatum rust but also contribute to the breeding and utilization of resistant varieties.

Much evidence suggests a correlation between degeneration and mitochondrial impairment. Typical cases of degeneration can also be observed in physiological phenomena (aging) as well as in neurological neurodegenerative diseases and cancer. All these pathologies have as a common denominator the dyshomeostasis of mitochondrial bioenergy. Even neurodegenerative diseases show a bioenergetics imbalance in their pathogenesis or progression. Huntington's chorea and Parkinson's disease are both neurodegenerative diseases, but while Huntington's disease is a genetic, and progressive disease with early manifestation and severe penetrance, Parkinson's disease is a pathology with a multifactorial aspect. Indeed, there are different types of Parkinson/Parkinsonism. Many forms are early onset diseases linked to gene mutation, others can appear in young adults and senescent only post-injury, and a final group is idiopathic. Huntington's was defined as a hyperkinetic disorder, while Parkinson's is a hypokinetic disorder; but in the middle, there are a lot of similarities as well as neuronal excitability, the loss of striatal function, psychiatric comorbidity, etc. In the review, we would embrace the theories that both diseases start and develop in light of mitochondrial dysfunction. These dysfunctions act on energy metabolism and reduce the vitality of neurons in many different brain areas.

Much evidence suggests a correlation between degeneration and mitochondrial impairment. Typical cases of degeneration can also be observed in physiological phenomena (aging) as well as in neurological neurodegenerative diseases and cancer. All these pathologies have as a common denominator the dyshomeostasis of mitochondrial bioenergy. Even neurodegenerative diseases show a bioenergetics imbalance in their pathogenesis or progression. Huntington's chorea and Parkinson's disease are both neurodegenerative diseases, but while Huntington's disease is a genetic, and progressive disease with early manifestation and severe penetrance, Parkinson's disease is a pathology with a multifactorial aspect. Indeed, there are different types of Parkinson/Parkinsonism. Many forms are early onset diseases linked to gene mutation, others can appear in young adults and senescent only post-injury, and a final group is idiopathic. Huntington's was defined as a hyperkinetic disorder, while Parkinson's is a hypokinetic disorder; but in the middle, there are a lot of similarities as well as neuronal excitability, the loss of striatal function, psychiatric comorbidity, etc. In the review, we would embrace the theories that both diseases start and develop in light of mitochondrial dysfunction. These dysfunctions act on energy metabolism and reduce the vitality of neurons in many different brain areas.

Prostate Cancer (PCa) is still ranked as the first cancer in male population and evidences have suggested an alteration of glycemic and lipidic metabolism that are related to its progression and prognosis. Aim of the study is to investigate associations between enzymes’ expression, especially involved in the lipidic pathway, and PCa aggressiveness. We retrospectively analyzed data from 390 patients with PCa or benign prostatic hyperplasia (BPH) at the Department of Urology, University of Catania. Immunohistochemical slides were evaluated for the expression of proteins related to glucose and lipidic metabolism. A total of 286 were affected by PCa while 104 by BPH. We demonstrated that ATP-lyase (odds ratio [OR]: 1.71; p<0.01), fatty acide sinthase (OR: 4.82; p<0.01), carnitine palmitoyl transferase-1a (OR: 2.27; p<0.05) were associated with androgen receptor (AR) expression. We found that steaoryl Co-A desaturase expression in PCa patients with total cholesterol ≥ 200 mg/dl was independently associated with ISUP ≥4 (OR: 4.22; p=0.049). We found that CPT-1a+ was associated with biochemical recurrence (hazard ratio: 1.94; p=0.03]). Our results support the evidences that the manipulation of lipidic metabolism could serve in the future to contrast PCa progression.

Background: Omega-3 polyunsaturated fatty acids (PUFAs) are increasingly reported to improve chronic neuroinflammatory diseases in peripheral and central nervous systems. Specifically, docosahexaenoic acid (DHA) protects nerve cells from noxious stimuli in vitro and in vivo. Recent reports link PUFA supplementation to improving painful diabetic neuropathy (pDN) symptoms. However, the molecular mechanism behind omega-3 PUFAs ameliorating pDN symptoms is lacking. Therefore, we sought to determine the distinct cellular pathways that omega-3 PUFAs dietary supplementation promotes in reducing painful neuropathy in type 2 diabetes mellitus (DM2) patients. Methods: Forty volunteers diagnosed with type 2 diabetes were enrolled in the "En Balance-PLUS" diabetes education study. The volunteers participated in weekly lifestyle/nutrition education and daily supplementation with 1,000 mg DHA and 200 mg eicosapentaenoic acid. The Short-Form McGill Pain Questionnaire validated clinical determination of baseline and post-intervention pain complaints. Laboratory and untargeted metabolomics analyses were conducted using blood plasma collected at baseline and after three months of participation in the dietary regimen. The metabolomics data was analyzed using random forest, hierarchical cluster, ingenuity pathway analysis, and metabolic pathway mapping. Results: We found that metabolites involved in oxidative stress and glutathione production shifted significantly to a more anti-inflammatory state post supplementation. Example of these metabolites include cystathionine (+90%), S-methylmethionine (+9%), glycine cysteine-glutathione disulfide (+157%) cysteinylglycine (+19%), glutamate (-11%), glycine (+11%) and arginine (+13.4%). In addition, the levels of phospholipids associated with improved membrane fluidity such as linoleoyl-docosahexaenoyl-glycerol (18:2/22:6) (+253 %) were significantly increased. Ingenuity pathway analysis suggested several key bio functions associated with omega-3 PUFA supplementation such as formation of reactive oxygen species (p = 4.38 × 10-4, z-score = -1.96), peroxidation of lipids (p = 2.24 × 10-5, z-score = -1.944), Ca2+ transport (p = 1.55 × 10-4, z-score = -1.969), excitation of neurons (p = 1.07 ×10-4, z-score = -1.091), and concentration of glutathione (p = 3.06 × 10-4, z-score = 1.974). Conclusion: The reduction of pro-inflammatory and oxidative stress pathways following omega-3 PUFAS supplementation is consistent with using omega-3 PUFAs as a complementary dietary strategy as part of the overall treatment of painful diabetic neuropathy.

Obesity represents a major public health problem with a prevalence increasing at an alarming rate worldwide. Continuous intensive efforts to elucidate the complex pathophysiology and improve clinical management have led to a better understanding of biomolecules like gut hormones, an-tagonists of orexigenic signals, stimulants of fat utilization, and/or inhibitors of fat absorption. In this article, we will review the pathophysiology and pharmacotherapy of obesity including inter-section points to the new generation of antidiabetic drugs. We provide insight into the effective-ness of currently approved anti-obesity drugs and other therapeutic avenues that can be explored.

In the present study, the potential of ethylene as ethephon (an ethylene source) was investigated individually or with a combination of the split dosage of nitrogen (N) and sulfur (S) soil treatments for the removal of damaging effects of salt stress (100 mM NaCl) in mustard (Brassica juncea L.). Plants were grown with 50 mg N plus 50 mg S kg−1 soil at sowing time and an equivalent dosage at 20 days after sowing ([N50 + S50]0d + [N50 + S50]20d). Ethephon at 200 μL L‒1 was applied to combined split dosage of N and S with or without NaCl. Plants subjected to NaCl showed a deceased in growth and photosynthetic characteristics as well as N and S assimilation, though, proline metabolism and antioxidants increased. The application of ethephon to plants grown with split N and S dosages significantly enhanced the photosynthetic efficiency by increasing the assimilation of N and S, improving the content of proline and induction of the antioxidant system with or without NaCl. The regulation of ethylene and/or split form N and S application may be the potential tools for overcoming salt stress effects in this species and in related Brassicaceae.

The concerning worldwide increase of obesity and chronic metabolic diseases such as T2D, dyslipidemia, and cardiovascular disease motivates further investigations into preventive and alternative therapeutic approaches. Over the past decade, there is growing evidence that the formation and activation of thermogenic adipocytes (brown and beige) may serve as therapy to treat obesity and its associated diseases owing to its capacity to increase energy expenditure and to modulate circulating lipids and glucose levels. Thus, understanding the molecular mechanism of brown and beige adipocytes formation and activation will facilitate the development of strategies to combat metabolic disorders. Here, we provide a comprehensive overview of pathways and players involved in the development of brown and beige fat as well as the role of thermogenic adipocytes in energy homeostasis and metabolism. Also, we discuss the alterations in brown and beige adipose tissue function during obesity and, explore the therapeutic potential of thermogenic activation to treat metabolic syndrome.

Glyceraldehyde 3–phosphate dehydrogenase (GAPDH) is a key glycolytic enzyme, which is crucial for the breakdown of glucose to provide cellular energy. Over the past decade, GAPDH has been reported to be one of the most prominent cellular targets of post-translational modifications (PTMs), which divert GAPDH towards different non-glycolytic functions. Hence, it is termed a moonlighting protein. During metabolic and oxidative stress, GAPDH is a target of different oxidative PTMs (oxPTM), e.g. sulfenylation, S-thiolation, nitrosylation and sulfhydration. These modifications alter the enzyme’s conformation, subcellular localization and regulatory interactions with downstream partners, which impact its glycolytic and non-glycolytic functions. In this review, we discuss the redox regulation of GAPDH by different redox writers, which introduce the oxPTM code on GAPDH to instruct a redox response; the GAPDH readers, which decipher the oxPTM code through regulatory interactions and coordinate cellular response via the formation of multi-enzyme signaling complexes; and the redox erasers, which are the reducing systems that regenerate the GAPDH catalytic activity. Human pathologies associated with the oxidation-induced dysregulation of GAPDH are also discussed, featuring the importance of the redox regulation of GAPDH in neurodegeneration and metabolic disorders.

Burn-induced cardiac dysfunction is thought to involve mitochondrial dysfunction although the mechanisms responsible are unclear. In this study, we used our established model of in vivo burn injury to understand the genetic evidence of burn-induced mitochondrial metabolism confusion by describing cardiac mitochondrial metabolism-related gene expression after burn. Cardiac tissue was collected at 24 hours after burn injury. An O2K respirometer system was utilized to measure cardiac mitochondrial function. Oxidative phosphorylation complex activities were determined using enzyme activity assays. RT Profiler PCR array was used to identify differential regulation of genes involved in mitochondrial biogenesis and metabolism. Quantitative qPCR and Western Blotting were applied to validate differentially expressed genes. Burn-induced cardiac mitochondrial dysfunction was supported by the finding of decreased state 3 respiration and decreased mitochondrial electron transport chain activity in complex I, III, IV, and V following burn injury. Eighty-four mitochondrial metabolism-related gene profiles were measured. The mitochondrial gene profile showed that one third of genes related to mitochondrial energy and metabolism was differentially expressed. Of these 28 genes, 15 were more than 2-fold upregulated and 13 were more than 2-fold downregulated. All genes were validated using qPCR; 4 genes had a protein level which correlated with the observed change in gene expression. This study provides preliminary evidence that a large percentage of mitochondrial metabolism-related genes in cardiomyocytes were significantly affected by burn injury.

The autonomic regulation of hepatic metabolism offers a novel target for the treatment of non-alcoholic fatty liver disease (NAFLD). However, the molecular characteristics of neurons that regulate the brain-liver axis remain unclear. Since mice lacking neuronal lipoprotein lipase (LPL) develop perturbations in neuronal lipid-sensing and systemic energy balance, we reasoned that LPL might be a component of pre-autonomic neurons involved in the regulation of hepatic metabolism. Here we show that despite obesity, mice with reduced neuronal LPL (NEXCreLPLflox [LPL KD]) show improved glucose tolerance and reduced hepatic lipid accumulation with aging compared to WT controls (LPLflox). To determine the effect of LPL deficiency on neuronal physiology, liver-related neurons were identified in the paraventricular nucleus (PVN) of the hypothalamus using the transsynaptic retrograde tracer PRV-152. Patch-clamp studies revealed reduced inhibitory post-synaptic currents in liver-related neurons of LPL KD mice. Fluorescence Lifetime Imaging Microscopy (FLIM) was used to visualize metabolic changes in LPL-depleted neurons. Quantification of the free vs. bound Nicotinamide Adenine Dinucleotide (NADH) and Flavin Adenine Dinucleotide (FAD) revealed increased glucose utilization and TCA cycle flux in LPL-depleted neurons compared to controls. Global metabolomics from hypothalamic cell lines either deficient in, or over-expressing, LPL recapitulated these findings. Our data suggest that LPL is a novel feature of liver–related preautonomic neurons in the PVN. Moreover, LPL loss is sufficient to cause changes in neuronal substrate utilization and function, which may precede changes in hepatic metabolism.

Recent COVID-19 outbreak has come into prominence the pathogenetic mechanisms underlying the Biology and Biochemistry of viral infections. COVID-19 illness is brought about by infection with the severe acute respiratory syndrome coronavirus SARS-CoV-2 [1,2], an enveloped positive single stranded RNA virus (ssRNA+). From a lipidomics viewpoint, there is a variety of mechanisms involving virus infection that encompass virus entry, disturbance of host cell lipid metabolism, and the role played by diverse lipids in regard to the infection effectiveness. All these aspects have currently been tackled separately as independent issues and focusing on the function of proteins. Here we review the role of cholesterol and other lipids in in ssRNA+ and SARS-COV-2 infection.

Carvacrol has long been studied for its natural antifungal potential and food preservative. But the exact mode of its action remained highly complex as a general, but especially for Penicillium digitatum (P. digitatum) largely remained unexplored. Herein, a 1H-NMR-based metabolomic technique was used to investigate the antifungal mechanism of carvacrol. The metabolomic profiling data showed that alanine, aspartate, glutamate and glutathione metabolism were imbalanced in the fungal hyphae. A strong positive correlation was seen between aspartate, glutamate, alanine and glutamine, while negative correlation among glutathione and lactate. These metabolic changes revealed that carvacrol-induced oxidative stress had disturbed the energy production and amino acid metabolism of P. digitatum. Current study will improve the understanding of the metabolic changes posed by plant-based fungicides in order to control citrus fruit green mold caused by P. digitatum. Moreover, the study will provided certain experimental and theoretical basis for the development of novel citrus fruit preservatives.

Near-Infrared Spectroscopy (NIRS) has been used to measure muscle mitochondrial capacity. The current method requires as many as 22 short ischemic occlusions to generate a recovery curve for mitochondrial capacity. PURPOSE: To determine the effectiveness of using a 6-occlusion analysis protocol to study muscle mitochondrial capacity. METHOD: Two independent, unidentified data sets were analyzed (bicep n=48, forearm n=41) from previous studies using a NIRS device (Artinis, Ltd.). Both data sets had two recovery tests that included 22 ischemic occlusions. A recovery rate used to indicate mitochondrial capacity was calculated two different ways (simultaneously). Each sample was analyzed with a MATLAB program; with a curve-fit for the 22 ischemic occlusions and curve matching for the first six ischemic cuffs and an end resting value. The two resulting rate constants were compared using correlations, both for the two data sets, good and bad fitting data, using the best 5 of 6 points for the 6 cuff approach. RESULTS: The rate constants were not significantly different between the 22 cmuff and 6 cuff for the total data sets: bicep (1.43+0.32min^-1, 1.44+0.35min^-1, p=0.56), forearm (1.94+0.42min^-1, 1.95+0.44min^-1, p=0.76). The average bicep rate constants, when compared to each other, had an equation of y=1.07x-0.09, R²=0.90. The average forearm rate constants, when compared to each other, had an equation of 0.98x+0.02, R²=0.93. CONCLUSIONS: The 6-Cuff analysis provided the same results as the longer 22-cuff. The 6-cuff approach is both shorter in time and uses less ischemic occlusion periods, increasing the practicality of the NIRS mitochondrial capacity test.

Chronic unpredictable environmental stress (CUES) may induce predisposition to diabetes mellitus. This study investigates the role of CUES on impaired homeostasis. Stressed group mice (n = 20) were exposed to CUES for 16 weeks. Weekly body weight, feed consumption, feed efficiency ratio, fasting blood glucose were monitored. Plasma HbA1c, plasma cortisol, plasma epinephrine and plasma insulin, serum lipids, antioxidants and carbohydrate metabolizing enzymes activity were assessed along with DNA damage and histopathological examination of liver, kidney, pancreas, spleen and skeletal muscles. Fasting blood glucose levels & HbA1c in the stressed were significantly higher compared to control (p < 0.001). Serum lipids were found insignificantly higher in stressed mice compared to control. Body weights of the stressed mice and feed efficiency ratio were found significant (p < 0.001). Plasma corticosterone, plasma epinephrine, HOMA-IR was found to be significantly higher in the stressed group (p < 0.001). Plasma insulin level was found to be significantly lower in the stressed group (p < 0.001). Significant changes were observed in antioxidants level, carbohydrate metabolizing enzymes activity, peripheral tissues and DNA integrity. CUES initiates pathogenesis of diabetes.

Green Tea Catechins (GTCs) are a family of chemically related compounds usually classified as antioxidant molecules. Epidemiological evidences, supported by interventional studies, highlighted a more than promising role for GTCs in human Prostate Cancer (PCa) chemoprevention.In the last decades many efforts have been made to gain new insights into the mechanism of action of GTCs. Now it is clear that GTCs anticancer action can no longer be simplistically limited to their direct antioxidant/pro-oxidant properties. Recent contributions to the advancement of knowledge in this field have shown that GTCs specifically interact with cellular targets including, cell surface receptors, lipid rafts and endoplasmic reticulum, modulate gene expression through direct effect on transcription factors or indirect epigenetic mechanisms, interfere with intracellular proteostasis at various levels. Many of the effects observed in vitro are dose and cell context dependent and take place at concentration that cannot be achieved in vivo.Poor intestinal absorption together with an extensive systemic and enteric metabolism influence GTCs bioavailability through still poor understood mechanisms. Recent efforts to develop delivery systems that increase GTCs overall bioavailability, by mean of biopolymeric nanoparticles, represent the main way to translate preclinical results in a real clinical scenario for PCa chemoprevention.

The genome sequencing of Botrytis cinerea has supplied a general overview of the map of genes involved in secondary metabolite synthesis. B. cinerea genomic data have revealed that this phytopathogenic fungus has seven sesquiterpene cyclase (Bcstc) genes that encode proteins involved in the farnesyl diphosphate cyclization. Three sesquiterpene cyclases (BcStc1, BcStc5 and BcStc7) have been characterized, related to the biosynthesis of botrydial, abscisic acid and (+)-4-epi-eremophilenol, respectively. However, the role of the other four sesquiterpene cyclases (BcStc2, BcStc3, BcStc4 and BcStc6) remains unknown. BcStc3 is a well-conserved protein with homologues in many fungal species, and here, we have undertaken its functional characterization in the life cycle of the fungus. A null mutant ΔBcstc3 and an overexpressed–Bcstc3 transformant (OvBcstc3) were generated, and both strains show deregulation of those other sesquiterpene cyclase-encoding genes (Bcstc1, Bcstc5, Bcstc7). These results suggest a co-regulation of the expression of the sesquiterpene cyclase gene family in B. cinerea. Phenotypic characterization of both transformants revealed that BcStc3 is involved in oxidative stress tolerance, production of reactive oxygen species and virulence. The metabolomic analysis allowed the isolation of characteristic polyketides and eremophilenols from the secondary metabolism of B. cinerea, although no sesquiterpenes different from those already described were identified.

This study investigates the metabolic parallels between stimulated pancreatic beta cells and cancer cells, emphasizing glucose and glutamine metabolism. Addressing the significant public health challenges of Type 2 Diabetes Mellitus (T2DM) and cancer, we aim to deepen understanding of the mechanisms driving insulin secretion and cellular proliferation. Our analysis of anaplerotic cycles and NADPH's role in biosynthesis elucidates their vital functions in both processes. Additionally, we find that both cell types share an antioxidative response mediated by the Nrf2 signaling pathway, glutathione synthesis, and UCP2 upregulation. Notably, UCP2 facilitates the transfer of C4 metabolites, enhancing reductive TCA cycle metabolism. We also uncover that hypoxic responses are transient in beta cells post-stimulation but persistent in cancer cells. By synthesizing these insights, our research suggests novel therapeutic targets for T2DM, highlighting the shared metabolic strategies of stimulated beta cells and cancer cells. This comparative analysis not only illuminates the metabolic complexity of these conditions but also emphasizes the crucial role of metabolic pathways in cell function and survival, offering fresh perspectives for tackling T2DM and cancer challenges.

Peritoneal dialysis (PD) is a home-based efficacious modality for replacement of renal function in end-stage kidney failure patients but is still under-prescribed. A major limitation is the durability of the dialytic technique. Continuous exposure of the peritoneum to bioincompatible conventional glucose-based solutions is thought to be the main cause of long-term morpho-functional peritoneal changes eventually resulting in ultrafiltration failure. Poor PD solution biocompatibility is primarily related to the high glucose content, which is not only detrimental to the peritoneal membrane but has many potential metabolic side effects. To improve the clinical outcome and prolong the survival of the treatment, PD-related bioincompatibility urgently needs to be overcome. However, combining dialytic and osmotic efficacy with a satisfactory biocompatible profile proves quite difficult. New approaches targeting the composition of the PD solution include replacement of glucose with other osmotic agents and the addition of cytoprotective or osmo-metabolic compounds. Other strategies include infusion of mesenchymal cells or the administration of orally active agents. In the present article we review the current evidence on efforts to improve the biocompatible and functional performance of PD, focusing on studies performed in vivo (animal models of PD, human subjects on PD).

To investigate the effect of nitrogen (N) application on carbon metabolism and yield of flag leaves and grains of spring wheat under drip irrigation in Xinjiang, a split - plot design was adopted from 2020 to 2021, with strong gluten wheat Xinchun 37 (XC37) and medium gluten wheat Xinchun 6 (XC 6) as the main plot factor and different nitrogen application rates as subplot factor. Four nitrogen application rates of 0, 210, 255 and 300 kg·hm-2 (CK2, B1, A1 and CK1, respectively) were set to analyze and compare the nitrogen response of key enzyme activity, soluble sugar, sucrose and starch content in flag leaves and grains to control yield formation. The results showed that with the increase of nitrogen application, Sucrose phosphate synthetase (SPS) and sucrose synthetase (SS) in flag leaves, SS in seeds, activities of adenosine diphosphate pyrophosphorylase (ADPG - PPase), soluble starch synthase (SSS), bound starch synthase (GBSS) and starch branching enzyme (SBE) in seeds, contents of soluble sugar and sucrose and yield in flag leaves increased first increasing and then decreasing. The A1 treatment (255 kg·hm-2) showed significant differences compared to other treatments, with increases of 7.95–158.33%, 8.69–155.12%, 7.65–53.25%, 5.41–62.83%, 2.85–85.52%, 3.08–57.30%, 8.87–79.16%, 9.33–196.55%, 9.43–112.78%, and higher levels of amylose, amylopectin, and total starch content than other treatments by 1.86–30.38%, 10.58–83.69%, and 7.96–63.09%, respectively. Correlation and stepwise regression analysis indicate highly significant positive correlation between yield and solube sugar and sucrose of flag leaves and grains, as well as their key emzymes and starch. Among them, soluble sugar in grains, amylopectin, and sucrose in grains have the greatest impact on the yield of XC37, determining 84.5% of its yield. SSS, soluble sugars in grains, amylopectin, and SBE have the greatest impact on the yield of XC 6, determining 80.4% of its yield. The starch shows a highly significant positive correlation with ADPG - PPase, SSS, GBSS, and SBE. There is a significant interaction effect between nitrogen application rate and variety, with better performance observed in Xinchun 37 compared to Xinchun 6. Under drip irrigation conditions in arid areas, nitrogen application of 255 kg·hm-2 can effectively regulate the metabolism of sucrose to starch in flag leaves and grains of spring wheat, which is conducive to the accumulation of starch in grains and the formation of yield.

Obesity entails metabolic alterations across multiple organs, highlighting the role of inter-organ communication in its pathogenesis. Extracellular vesicles (EVs) are communication agents in physiological and pathological conditions and although they have been associated with obesi-ty-comorbidities, their protein cargo in this context remain largely unknown. To decipher the messages encapsulated in EVs, we isolated plasma derived EVs from diet induced obese murine models. Obese plasma EVs exhibited a decline in protein diversity while control EVs revealed significant enrichment in protein folding functions, highlighting the importance of proper folder in maintaining metabolic homeostasis. Previously, we revealed that gut derived EVs proteome holds particular significance in obesity. Here, we compared plasma and gut EVs and identified four proteins exclusively present in the control state of both EVs, revealing the potential for a non-invasive assessment of gut health by analyzing blood derived EVs. Given the relevance of post-translational modifications (PTMs), we observed a shift in chromatin-related proteins from glycation to acetylation in obese gut EVs, suggesting a regulatory mechanism targeting DNA transcription during obesity. This study provides valuable insights into novel roles of EVs and protein post-translational modifications in the intricate mechanisms underlying obesity, shed-ding light on potential biomarkers and pathways for future research.

Colorectal cancer is a high-incidence tumor that has a high mortality rate due to its frequent metastasis to the liver. The difference in genes, proteins, and immune microenvironment between the primary and metastatic sites causes them to show different responses to treatment. Colorectal cancer liver metastasis patients also tend to show poorer treatment response and prognosis. Therefore, in this paper, we summarize the heterogeneity exhibited after colorectal cancer liver metastasis from five aspects (gene, transcriptome, protein, metabolism, and immunity), and we found that except for the genetic heterogeneity, the other four aspects exhibite significant heterogeneity, which might serve as a new therapeutic direction and a prognostic marker for patients with liver metastasis. Finally, the therapeutic modalities regarding tumors are rapidly evolving, and we have also summarize the new clinical therapeutic modalities currently proposed based on these heterogeneities, aiming to provide new therapeutic ideas for the clinical treatment of patients with colorectal cancer liver metastases.

Aluminum (Al) toxicity is the most common factor limiting the growth of alfalfa in acidic soil conditions. Melatonin (MT), a significant pleiotropic molecule present in both plants and animals, has shown promise in mitigating Al toxicity in various plant species. This study aims to elucidate the underlying mechanism by which melatonin alleviates Al toxicity in alfalfa through a combined physiological and transcriptomic analysis. The results reveal that 5 μM MT significantly alleviates Al-induced growth inhibition and preserves the morphology of root tip cells. Moreover, MT application reduces Al accumulation in alfalfa roots and shoots by 28.6% and 27.6%, respectively. Additionally, MT plays a crucial role in scavenging Al-induced excess H2O2 by enhancing the activities of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT), consequently reducing malondialdehyde (MDA) levels. The RNA-seq results reveal that MT application significantly upregulates the expression of xyloglucan endotransglucosylase/hydrolase (XTH) and carbon metabolism-related genes, including those involved in the glycolysis process, as well as sucrose and starch metabolism, suggesting that MT application may mitigate Al toxicity by facilitating the binding of Al to the cell walls, thereby reducing intracellular Al accumulation, and by improving respiration and the content of sucrose and trehalose. Taken together, our study demonstrates that MT alleviates Al toxicity in alfalfa by restoring redox homeostasis, enhancing Al binding to the cell wall, and modulating carbon metabolism. This research advances our understanding of the mechanisms underlying MT's effectiveness in mitigating Al toxicity, offering potential strategies for reducing Al accumulation in alfalfa.

Worldwide, hypoxia-related conditions, including cancer, COVID-19, and neuro-degenerative diseases, often lead to multi-organ failure and significant mortality. Oxygen, crucial for cellular function, becomes scarce as levels drop below 10 mmHg (<2% O2), triggering mitochondrial dysregulation and activating hypoxia-induced factors (HiFs). Herein, Oxygen nanoBubbles (OnB), an emerging versatile oxygen de-livery platform, implies to offer a novel approach to address hypoxia-related pathologies. This review explores OnB oxygen delivery strategies and systems, including diffusion, ultrasound, photodynamic, and pH-responsive nanobubbles. It delves into the nanoscale mechanisms of OnB, elucidating their role in mitochondrial metabolism (TFAM, PGC1alpha), hypoxic responses (HiF-1alpha), and their interplay in chronic pathologies including cancer and neurodegenerative disorders, amongst others. By understanding these dynamics and underlying mechanisms, this article aims to contribute to our accruing knowledge of OnB and the developing potential in ameliorating hypoxia- and metabolic stress-related conditions and fostering innovative therapies.

In recent years, there has been a notable rise in the incidence of breast cancer among young patients, who exhibit worse survival outcomes and distinct characteristics compared to the intermediate and elder patients. Therefore, it’s imperative to identify identify the specific features unique to young patients, which could offer insights into potential therapeutic strategies and improving survival outcomes. In our study, we performed an integrative analysis of bulk transcriptional and genomic data from extensive clinical cohorts to identify prognostic factors. Additionally, we analyzed the single-cell transcriptional data and conducted in vitro experiments. Our work confirmed that young patients exhibited higher grading, worse disease-free survival (DFS), a higher frequency of mutations in TP53 and BRCA1, a lower frequency of mutations in PIK3CA, and upregulation of eight metabolic pathways. Notably, galactose metabolism pathway showed upregulation in young patients and was associated with worse DFS. Further analysis and experiments indicated that galactose metabolism pathway may regulate the stemness of cancer cells and ultimately contribute to worse survival outcomes. In summary, our finding identified distinct clinicopathological, transcriptional, and genomics features and revealed a correlation between galactose metabolism pathway, stemness, and poor disease-free survival of breast cancer in young patients.

Ribosomal proteins (RPs) mediate protein synthesis and stability of the ribosomal complex. RPs and rRNA form ribosomal subunits and ri-bosomes, the cellular machinery for protein synthesis, a fundamental biological process related to cell growth and proliferation. The differ-ences between paralogs within the same RP family have led them to ac-quire extraribosomal functions involved in plants' growth, develop-ment, and biotic and abiotic stresses. From transcriptomic analysis, it has been revealed that ribosomal proteins have a crucial role during MTs development. The RPLs; RPL11, RPL29 and RPL40 interact with PEBP family members (Phosphatidylethanolamine-binding proteins), poten-tial activators in the MTs development. In potatoes, genome editing is a promising technology to introduce crop breeding traits. Recently, the edition of the genome through the CRISPR/Cas9 system has made it the most efficient and powerful genetic modification method. Based on this, the gene modulation by overexpression and silencing in RPL11, RPL29 and RPL40 will guide us to understand the effect on the microtuberiza-tion process and produce improved potato plants with the capability of growing under adverse environments (biotic and abiotic stresses). By understanding the molecular biology mechanisms that RPs govern, we can improve crops under today's changing climatic conditions.

Abstract: (1) Background: Cancer immune escape is associated with the metabolic reprogramming of TME, and combining metabolic targets with immunotherapy has great potential to improve clinical outcomes. Among all metabolic processes, lipid metabolism, especially fatty acid (FA) metabolism, has a huge role in cancer cell survival, migration, and proliferation, but its mechanism and role in the tumor immune microenvironment remain to be investigated. (2) Methods: We comprehensively analyzed 309 fatty acid-related genes, screened 121 different genes, and used one-way COX regression to select 15 genes with prognostic impact. Systematically evaluated the correlation between FMGs modification patterns and Tumor Microenvironment Infiltration, prognosis, and Immunotherapy. The FMGs-Score was constructed to quantify the FMGs modification patterns using principal component analysis. (3) Results: Three clusters based on FMGs-related genes were demonstrated in breast cancer, with three patterns of distinct immune cell infiltration and biological behavior. An FMGsScore signature was constructed to reveal that patients with a low FMGsScore had higher immune checkpoint expression, higher immune checkpoint inhibitor (ICI) scores, increased immune microenvironment infiltration, better survival advantage, and were more sensitive to immunotherapy than those with a high FMGsScore. Finally, the expression and function of the signature key gene NDUFAB1 were examined by in vitro experiments. (4) Conclusions: This study significantly demonstrates the non-negligible role of FMGs in the immune microenvironment of breast cancer, and that FMGsScores can be used to guide the prediction of immunotherapy in breast cancer patients. In in vitro experiments, knockdown of the NDUFAB1 gene resulted in reduced proliferation and migration of MCF-7 cell lines.

The importance of PAs for CNS functions are well known. Less clear is, however, where PAs in the brain are derived from. Principally, there are three possibilities: (i) intake by nutrition, release into the bloodstream, and subsequent uptake from CNS capillaries, (ii) products of parenchymatous organs as the liver, and again uptake from CNS capillaries, and (iii) uptake of precursors such as arginine from the blood and subsequent local biosynthesis of polyamines within the CNS.The present investigation aimed to unequivocally answer the question, whether PAs, especially the higher ones like SPD and SPM can or cannot be taken up into the brain from the bloodstream. For this purpose a biotin-labelled analogue of SPM was synthesized, characterized, and used to visualize its uptake into brain cells subsequent to application to surviving brain slices, to the intraventricular space, or to the bloodstream.In surviving slices uptake of B-X-SPM is massive into protoplasmic and absent in fibrous type astrocytes. It is also taken up by neurons but to a lesser degree. Under in-vivo conditions astrocyte uptake of biotinylated SPM also is massive from the brain interstitial fluid subsequent to intraventricular application. In contrast, following intracardial injection there is no uptake from the bloodstream, indicating that the brain is completely dependent on the local synthesis of polyamines.

Vitamin B9(folate)/B12 deficiency is known to induce brain structural and/or functional retardations. Besides neural tube defects in case of major consequences, several mild deregulations also lead to deleterious effect after birth, and folate supplementation recommended in some countries usually stop at the end of the first trimester. Various hormonal receptors were shown to be deregulated in brain tissue under this context. The glucocorticoid receptor (GR) is particularly sensitive to epigenetic regulation and post-traductional modifications. In a mother-offspring rat model of vitamin B9/B12 deficiency, we investigated whether a prolonged folate supplementation could restore the GR signalization in the hypothalamus. Our data showed that a deficiency in folate and vitamin B12 during the in-utero and the early postnatal periods was associated with reduced GR expression inn the hypothalamus. We also described for the first time a new post-traductional modification of GR that impaired ligand binding and GR activation, leading to decreased the expression of one of the GR targets in the hypothalamus, AgRP. Moreover, this brain-impaired GR pathway was associated with behavioral perturbations during offspring growth. Importantly, perinatal and postnatal supplementation with folic acid helped restore GR mRNA level and activity in hypothalamus cells and improved behavioral deficits.

It was the aim of this study to compare the ratio of salbutamol and its major metabolite salbutamol-4’-O-sulfate as well as the quantity excreted renally after oral and inhalative administration. Additionally, the excretion pattern after application of racemic salbutamol opposed to the pure enantiomer levosalbutamol was evaluated. For quantitation of the sulfonated metabolite of salbutamol, reference material was synthesized and characterized by NMR and HRMS. Urine samples were analyzed by ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Salbutamol is mainly metabolized by sulfotransferase 1A3 (SULT1A3), which is most abundantly found in the jejunum. A high first pass effect occurs upon oral administration, which leads to a higher amount of salbutamol-4’-O-sulfate in urine compared to unchanged salbutamol excreted within the first hour post administration. Thus, when administered orally, the proportion of metabolite to total salbutamol was higher than for inhalative administration in the early urinary excretion. Levosalbutamol is the favored enantiomer of SULT1A3 and therefore metabolized at a higher rate whereas racemic salbutamol shows a reduced proportion between metabolite and parent compound. The amount of sulfoconjugate was found higher than that of the parent compound for all urine samples except for those excreted in the first hour after inhalative administration.

ATP and other nucleoside phosphates have specific receptors named purinergic receptors. Purinergic receptors and ectonucleotidases regulate various signaling pathways that play a role in physiological and pathological processes. Extracellular ATP in the tumor microenvironment (TME) has a higher level than in normal tissues and plays a role in cancer cell growth, survival, angiogenesis, metastasis, and drug resistance. In this review, we investigated the role of purinergic receptors in the development of resistance to therapy through changes in tumor cell metabolism. When a cell transforms to neoplasia, its metabolic processes change. The metabolic reprogramming modified metabolic feature of the TME, that can cause impeding immune surveillance and promote cancer growth. The purinergic receptors contribute to therapy resistance by modifying cancer cells' glucose, lipid, and amino acid metabolism. Limiting the energy supply of cancer cells is one approach to overcoming resistance. Glycolysis inhibitors which reduce intracellular ATP levels, may make cancer cells more susceptible to anti-cancer therapies. The loss of the P2X7R through glucose intolerance and decreased fatty acid metabolism reduces therapeutic resistance. Potential metabolic blockers that can be employed in combination with other therapies will aid in the discovery of new anti-cancer immunotherapy to overcome therapy resistance. Therefore, therapeutic interventions that are considered to inhibit cancer cell metabolism and purinergic receptors simultaneously can potentially reduce resistance to treatment.

Background: Evidence supports a causal relationship between circadian disturbance and impaired glucose homeostasis. Method: To determine the effect of a nursing educational intervention on improving healthy sleep, a parallel, open-label clinical trial in subjects with Impaired Fasting Glucose (IFG) or Type 2 Diabetes Mellitus (T2DM) and 18 and older was performed. Study variables were sex, age, fasting glucose, glycated hemoglobin A1c (HbA1c), Pittsburgh Sleep Quality Index (PSQI), sleep duration and efficiency, BMI, antidiabetic treatment and diet and physical exercise. An individual informative educational intervention was carried out following a bidirectional feedback method. It was intended to develop skills to improve sleep through 9 simple tips. An analysis of covariance was performed on all the mean centered outcome variables controlling for the respective baseline scores. Results: After the intervention, in the experimental group, PSQI dropped, the duration and quality of sleep increased. Further, a decrease in fasting glucose and in HbA1c levels was observed. Conclusion: The proposed intervention has proven to be effective to improve sleep quality, time, and efficiency and in only 3 months, to achieve a decrease in fasting glucose and HbA1c levels. These findings support the importance of sleep and circadian rhythms education focused on improving in T2DM or IFG.

Genome-scale metabolic models (GEMs) have been widely used for phenotypic prediction of microorganisms. However, the lack of other constraints in the stoichiometric model often leads to a large metabolic solution space inaccessible. Inspired by previous studies that take allocation of macromolecule resources into account, we developed a simplified Python-based workflow for constructing enzymatic constrained metabolic network model (ECMpy) and constructed an enzyme-constrained model for Escherichia coli (eciML1515) by directly adding a total enzyme amount constraint in the latest version of GEM for E. coli (iML1515), considering the protein subunit composition in the reaction, and automated calibration of enzyme kinetic parameters. Using eciML1515, we predicted the overflow metabolism of E. coli and revealed that redox balance was the key reason for the difference between E. coli and Saccharomyces cerevisiae in overflow metabolism. The growth rate predictions on 24 single-carbon sources were improved significantly when compared with other enzyme-constrained models of E. coli. Finally, we revealed the tradeoff between enzyme usage efficiency and biomass yield by exploring the metabolic behaviors under different substrate consumption rates. Enzyme-constrained models can improve simulation accuracy and thus can predict cellular phenotypes under various genetic perturbations more precisely, providing reliable guidance for metabolic engineering.

Abstract: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder with extensive genetic and aetiological heterogeneity. While the underlying molecular mechanisms involved remain unclear, significant progress has been facilitated by recent advances in high-throughput transcriptomic, epigenomic and proteomic technologies. Here, we review recently published ASD proteomic data and compare proteomic func-tional enrichment signatures to those of transcriptomic and epigenomic data. We iden-tify canonical pathways that are consistently implicated in ASD molecular data and find an enrichment of pathways involved in mitochondrial metabolism and neurogenesis. We identify a subset of differentially expressed proteins that are supported by ASD tran-scriptomic and DNA methylation data. Furthermore, these differentially expressed proteins are enriched for disease phenotype pathways associated with ASD aetiology. These proteins converge on protein-protein interaction networks that regulate cell pro-liferation and differentiation, metabolism and inflammation which demonstrates a link between canonical pathways, biological processes and the ASD phenotype. This review highlights how proteomics can uncover potential molecular mechanisms to explain a link between mitochondrial dysfunction and neurodevelopmental pathology.

Disruption of the in utero environment can have dire consequences on fetal growth and development. Intrauterine growth restriction (IUGR) is a pathological condition by which the fetus deviates from its expected growth trajectory, resulting in low birth weight and impaired organ function. The developmental origins of health and disease (DOHaD) postulates that IUGR has lifelong consequences on offspring well-being, as human studies have established an inverse relationship between birth weight and long-term metabolic health. While these trends are apparent in epidemiological data, animal studies have been essential in defining the molecular mechanisms that contribute to this relationship. One such mechanism is cellular stress, a prominent underlying cause of the metabolic syndrome. As such, this review considers the role of oxidative stress, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and inflammation in the pathogenesis of metabolic disease in IUGR offspring. In addition, we summarize how uncontrolled cellular stress can lead to programmed cell death within the metabolic organs of IUGR offspring.

Helicases are proteins that use the energy of ATP to unwind nucleic acids and to remodel protein-nucleic acid complexes. They are involved in almost every aspect of the DNA and RNA metabolisms and participate in numerous repair mechanisms that maintain cellular integrity. Helicases are classified into 6 superfamilies (SF1-6). The archaeal Lhr-type proteins are SF2 helicases that are mostly uncharacterized. They have been proposed to be a DNA helicase that acts in DNA recombination and repair processes in Sulfolobales and Methanothermobacter. In parallel, a protein annotated as an Lhr2 protein was also found in the network of proteins involved in RNA metabolism in Thermococcales. To this respect, we performed in-depth phylogenomic analyses to report the classification and taxonomic distribution of Lhr-type proteins in Archaea, and to better understand their relationship with bacterial Lhr. Furthermore, with the goal of envisioning the role(s) of aLhr2 in archaeal cells, we deciphered the enzymatic activities of aLhr2 from Thermococcus barophilus (Tbar). We showed that Tbar-aLhr2 is a DNA/RNA helicase acting on DNA:RNA and RNA:RNA duplexes and proposed that aLhr2 helicases are involved in processes dependent of DNA and RNA transactions.

Metabolic syndrome, diabetes and ischemic heart disease are among the leading causes of death and disability in Western countries. Diabetic cardiomyopathy is responsible for the most severe signs and symptoms. An important strategy for reducing the incidence of cardiovascular disease is regular exercise. Remote ischemic conditioning has some similarity with exercise, and can be induced by short periods of ischemia and reperfusion of a limb, and it can be performed in people who cannot exercise. There is abundant evidence that exercise is beneficial in diabetes and ischemic heart disease, but there is a need to elucidate the specific cardiovascular effects of emerging and unconventional forms of exercise in people with diabetes. Also, remote ischemic conditioning may be considered among the options to induce beneficial effects in these patients. The characteristics and interactions of diabetes and ischemic heart disease, and the known effects of exercise and remote ischemic conditioning in the presence of metabolic syndrome and diabetes, are analyzed in this brief review.

RNA epigenetics is perhaps the most recent aspect of interest for translational epigeneticists. RNA modifications create such an extensive network of epigenetically driven combination whose role in physiology and pathophysiology is still far from being elucidated. Not surprisingly, some of the players determining changes into RNA structure are in common with those involved in DNA and chromatin structure regulation, while other molecules seem very specific to RNA. It is envisaged, then, that new small molecules, acting selectively on RNA epigenetic changes, will be reported soon, opening new therapeutic interventions based on the correction of the RNA epigenetic landscape. In this review, we shall summarize some aspects of RNA epigenetics limited to those in which the potential clinical translatability to cardiovascular disease is emerging.

In intermediary metabolism, enzymes are mainly for the specific provision of one small molecule from another, B from A, for its further use. But there are also decades of work relating to another evolved purpose, which is to prevent untoward effects of odd compounds of various origins, and of ordinary intermediates, whose improper concentrations may be avoided by hydrolases and other activities of metabolic correction.

The angiotensin-converting enzyme (ACE) is a peptidase that is involved in the synthesis of Angiotensin II, the bioactive component of the renin-angiotensin system. A growing body of literature argues for a beneficial impact of ACE inhibitors (ACEi) on age-associated metabolic disorders, mediated by cellular changes in reactive oxygen species (ROS) that improve mitochondrial function. Yet, our understanding of the relationship between ACEi therapy and metabolic parameters is limited. Here, we used three genetically diverse strains of Drosophila melanogaster to show that Lisinopril treatment reduces thoracic ROS levels and mitochondrial respiration in young flies, and increases mitochondrial content in middle-aged flies. Using untargeted metabolomics analysis, we also showed that Lisinopril perturbs the thoracic metabolic network structure by affecting metabolic pathways involved in glycogen degradation, glycolysis, and mevalonate metabolism. The Lisinopril-induced effects on mitochondrial and metabolic parameters, however, are genotype-specific and likely reflect the drug’s impact on nutrient-dependent fitness traits. Accordingly, we found that Lisinopril negatively affects survival under nutrient starvation, an effect that can be blunted by genotype and age in a manner that partially mirrors the drug-induced changes in mitochondrial respiration. In conclusion, our results provide novel and important insights into the role of ACEi in cellular metabolism.

Production of energy is a main task of cancer cells metabolism, since costs of duplicating are enormous. Although energy is derived in cells by dismantling carbon to carbon bonds of any macronutrient, cancer nutritional needs for energetic purposes have been studied primarily as dependent on glycolysis. Since the end of the last century, awareness of dependence of cancer metabolism on amino acids not only for protein syntheses but also for matching energy needs has grown. The roles of specific amino acids, like glutamine, glycine and serine have been explored in different experimental conditions and reviewed. Moreover, there are epidemiological evidences that some amino acids used as supplement for therapeutic reasons (the branched chain ones) may reduce incidence of liver cancer, and some molecular mechanism has been proposed as functional to their protective action. On the contrary, metabolic signature of some pathology connected with increased risk of cancer, like prolonged hyperinsulinemia in insulin resistant patients, is signed by plasma elevated levels of the same branched chain amino acids, posing puzzling questions to clinicians. Most recently, peculiar formulations of amino acids, deeply different if compared to amino acids compositions normally present in foods, have shown the power to master epigenetics slowing growth or driving cancer cells to apoptotic death, while being even beneficial for normal cells and for animals health and life span. In this review, we will analyze and try to disentangle some of the many knots dealing with complexities of amino acids biology and linked to cancer metabolism.

Coordinated sets of extremely numerous digital data, on a given social or economic event, are treated by Artificial Intelligence tools to obtain reasonably accurate, valuable predictions. The same approach, applied to biomedical issues, as how to choose the right drug to completely cure a given cancer patient, does not reach satisfactory results. It is the “organized biological complexity”, which requires a different systems approach, to integrate, in an Augmented Intelligence strategy, statistical computations of digital data, network construction of “omics” findings, well-designed mathematical models and new experiments in an iterative pathway to reconstruct the “logic” beneath the “organized complexity”, as shown here for Systems Metabolomics of cancer. On this basis new diagnostic approaches, able to identify precision drug treatments, as well as new discovery strategy for more effective anti-cancer drugs are described.

The present study examined and compared the effects of high- and low-molecular weight (MW) chitosan, a nutraceutical, on intestinal and liver lipid metabolism in rats fed with high-fat diet. Both high- and low-MW chitosan decreased liver weight, elongated small intestine, improved the dysregulation of blood lipids and liver fat accumulation, and increased fecal lipid excretion in high-fat diet-fed rats. Supplementation of both high- and low-MW chitosan significantly inhibited the decreased phosphorylated AMP-activated protein kinase (AMPK)α and peroxisome proliferator-activated receptor (PPAR)α protein expressions and the increased lipogenesis/cholesterogenesis-associated protein expressions (sterol regulatory element binding protein (SREBP)1c, SREBP2, and PPARγ) and the decreased apolipoprotein (Apo)E and microsomal triglyceride transfer protein (MTTP) protein expressions in the livers of high-fat diet-fed rats. Both high and low-MW chitosan supplementation could also suppress the increased MTTP protein expression and the decreased angiopoietin-like protein (Angptl)4 protein expression in the intestines of high-fat diet-fed rats. Comparison between high and low-MW chitosan, high-MW chitosan has a higher efficiency than low-MW chitosan on the inhibition of intestinal lipid absorption and the increase of hepatic fatty acid oxidation, which can improve liver lipid biosynthesis and accumulation.

Keywords: Adrenergic signaling in cardiomyocytes; cardiac muscle contraction; Chagas disease; diabetic cardiomyopathy; dilated cardiomyopathy; glycerolipid metabolism; glycolisis/glucogenesis; hypertrophic cardiomyopathy; purine metabolism; steroid hormone biosynthesis.

Mitochondria are semiautonomous organelles, which are pivotal for the energy metabolism of eukaryotic cells. These organelles contain their own genetic system (mtDNA, mitogenome) that encodes to some structural RNAs and organellar proteins. The biogenesis and function of mitochondria is tightly regulated by nuclear-encoded protein cofactors. The mtDNAs of land plants are characteristically large, with a complex mode of gene organization and expression, in particularly at the post-transcriptional level. To become functional, the primary organellar transcripts undergo extensive maturation steps, which include endo- and exo-nucleolytic cleavage, RNA-base editing, and both ‘cis’- and ‘trans’-splicing events. These essential processing steps rely on the activities of a large set of nuclear-encoded factors. Among these, the RNA helicases serve as key players in organellar (mt-)RNA metabolism. This review summarizes the important roles played by these factors in regulating the highly dynamic processes of transcription, RNA processing, and translation within the mitochondria of land plants. We further discuss recent advancements in understanding how dysregulation of mitochondrial RNA helicases affects the organellar gene expression, respiratory functions, and hence the growth, development and physiology of land plants.

Fruit cracking or splitting, a severe physiological disease that highly affects appearance and quality, compromise the commodity value of fruit and also causes huge economical losses to the producers of several fleshy fruit crops. The growth-promoting phytohormone gibberellic acid (GA) and growth-inhibiting phytohormone abscisic acid (ABA) antagonistically regulate numerous developmental processes throughout the plant life cycle. Homeostasis of endogenous GA and ABA play a significant role in the normal growth of fruits, and its imbalance may lead to the occurrence of cracking or splitting during the process of fruit growth, development, ripening and postharvest storage. The pathways of GA and ABA metabolism and signaling have been studied widely, and the major components were well characterized, which including the genes encoding major biosynthesis and catabolism enzymes and the key signaling components. Nevertheless, our knowledge of the mechanisms of GA and ABA governing fruit cracking is not comprehensive enough. In this review, we not only focus on the scenarios of effects of endogenous GA and ABA contents in the fruit and exogenous plant growth regulators GA and ABA treatments, but also endeavor to provide some genetic cues on the function of GA and ABA responsible for fruit cracking modulation. Information from this review aims to strengthen the understanding of potential molecular bases underlying GA and ABA in fruit cracking control and provide guidance in breeding of fruit cultivars with cracking-resistant ideotypes, and also make great theoretical significance in guiding the establishment of integrated prevention and control measures to fruit cracking or splitting.

Cytochrome P450 oxidoreductase (POR) is an essential redox partner for steroid and drug-metabolizing cytochromes P450 located in the endoplasmic reticulum. Mutations in POR lead to metabolic disorders, including congenital adrenal hyperplasia, and affect the metabolism of steroids, drugs, and xenobiotics. In this study, we examined approximately 450 missense variants of the POR gene listed in the Genome Aggregation Database (gnomAD) using eleven different in silico prediction tools. We found that 64 novel variants were consistently predicted to be disease-causing by most tools. To validate our findings, we conducted population analysis and selected two variations in POR for further investigation. The human POR wild type, along with the R268W and L577P variants, were expressed in bacteria and subjected to enzyme kinetic assays using model substrate. We also examined the activities of several cytochrome P450 proteins in the presence of POR (WT or variants) by combining P450 and reductase proteins in liposomes. We observed a decrease in enzymatic activities (ranging from 35% to 85%) of key drug metabolizing enzymes, supported by POR variants R288W and L577P compared to WT-POR. These results validate our approach of curating a vast amount of data from genome projects and provide an updated and reliable reference for diagnosing POR deficiency.

A key response to glucose stress is an increased production of unsaturated fatty acids to balance the increase of saturated fatty acids in the membrane. The C. elegans homolog of stearoyl-CoA desaturase, FAT-7, introduces the first double bond into saturated C18 fatty acids yielding oleic acid and is a critical regulatory point for surviving cold and glucose stress. Here, we incorporated 13C stable isotopes into the diet of nematodes and quantified the 13C-labelled fatty acid by GC-MS and HPLC/MS-MS to track the metabolic response to various concentrations of glucose. Previous work has analyzed membrane composition of C. elegans when responding to mild glucose stress and showed few alterations in overall fatty acid composition in the membrane. Here, in nematodes exposed to higher concentrations of glucose, a specific reduction of oleic acid and linoleic acid was observed. Using time courses and stable isotope tracing, the response of fatty acid me-tabolism to increasing levels of glucose stress has been characterized, revealing a funneling of monounsaturated fatty acids to preserve polyunsaturated fatty acid abundance. Taken together, higher levels of glucose unveil a specific reduction of oleic and linolenic acid in the metabolic re-wiring required to survive glucose stress.

The accumulation of loss of function mutations in the uricase gene well explains the high urate levels in hominoids (apes and humans) compared to other mammals. The loss of human uricase activity may have allowed humans to survive environmental stressors, evolution bottlenecks, and life-threatening pathogens. While high urate levels may contribute to developing cardiometabolic disorders such as hypertension and insulin resistance, low urate levels may increase the risk for neurodegenerative diseases. The double-edged sword effect of uric acid has resurrected a growing interest in the antioxidant role of urate and the role of the uricase gene in modulating the risk of obesity. Characterizing both the effect of uric acid levels and the uricase gene in different animal models may provide new insights into the potential therapeutic benefits of uric acid and novel uricase-based therapy.

Background: Abdominal migraine (AM) is a clinical diagnosis specified by Rome IV and ICHD III as a functional gastrointestinal disease (FGID) and a migraine associated syndrome, respectively. AM is undiagnosed and undertreated, and thus far the FDA has not approved any drug for AM treatment. We and others showed that changes in the kynurenine (KYN) pathway of tryptophan (TRP) metabolism played an important role in the pathogenesis and treatment of FIGDs. Changes in the KYN pathway were shown in migraine. Findings: Abdominal migraine reflects impairments in communication within the gut-brain axis. Treatment approaches have not been sufficiently documented and are based on experience of physicians, presenting personal rather than evidence-based practice and including efficacy of some drugs used in adult migraine. Non-pharmacological treatment of AM is aimed preventing or ameliorating AM triggers. Modulations within the KYN pathway of TRP metabolism induced by changes in TRP content in the diet, may ameliorate FGIDs and support their pharmacological treatment. Pharmacological manipulations of brain KYNs in animals have brought promising results for clinical applications. Conclusions: In conclusion, controlled placebo-based clinical trials with dietary manipulation to adjust the amount of the product of the KYN pathway of TRP metabolism are justified in children and adolescents with AM. Further preclinical studies are needed to establish details of these trials.

The epidemiological and clinical pathological aspects of polioencephalomalacia (PEM) in five buffaloes (buffaloes 01 to 05) in the amazon biome are described. Epidemiological data were obtained during the clinical visit in which the animals with clinical signs compatible with polioencephalomalacia were submitted to a general and specific clinical examination of the nervous system. During the necropsy of the five animals, the intensity and location of the lesions were evaluated and fragments from different organs were collected and fixed in 10% buffered formalin and sent to the Pathological Anatomy Sector of the Federal Rural University of Rio de Janeiro for histopathological examination. Of the five studied animals, all were of the Murrah breed, four male and one female, with ages ranging from two months to one year. Two buffaloes (buffalo 01 and 02) were from the municipality of Castanhal, Pará, kept in an extensive breeding system on Urochloa brizantha pasture. Buffaloes 03 and 04 belonged to a property located in the municipality of Cachoeira do Arari, Marajó Island, Pará, and buffalo 05 was from a property located in the municipality of Itaubal, state of Amapá, all of them were raised in an extensive system in flooded of native pasture. At the clinical examination, all buffaloes had a body score between 2.5 and 3 (scale from 1 to 5), and there was noted decreased alertness, postural changes, marked hypermetria when stimulated to move, total or partial blindness demonstrated by colliding to the corral structures, head pressing and circumduction of the hindquarters when supported on the forelimbs, opisthotonos, muscle tremors, convulsions, paddling movements, sialorrhea, decrease in palpebral and pupillary reflexes and eyeball rotation placing the pupillary slit in a vertical position. At necropsy, mild lesions characterized by edema and flattening of the cerebral convolutions were observed. Histopathological examination showed laminar necrosis of the cerebral cortex. The diagnosis of polioencephalomalacia was based on epidemiological, clinical-pathological, and histopathological findings, similar to findings in other ruminants. The cause of polioencephalomalacia in the studied buffaloes was not established, which indicates the need for further studies to elucidate this disease in the species, mainly in the Amazon region.

Canine mammary tumors (CMTs) are among the most common disease in female dogs and share similarities with human breast cancer, which have placed these animals as a model of study in comparative oncology. Metabolic reprogramming is one of them and is known as a hallmark of carcinogenesis whereby cells undergo adjustments to supply the high bioenergetic and biosynthetic demands of rapidly proliferating cells. However, such alterations are also vulnerabilities that may serve as therapeutic strategies which have been tested mostly in human clinical trials, but poorly explored in CMTs. In this dedicated review, we compilated the metabolic changes described for CMTs emphasizing the metabolism of carbohydrates, amino acids, lipids, and mitochondrial function. We observed here key factors associated with the presence and aggressiveness of CMTs, such as the increase in glucose uptake followed by enhanced anaerobic glycolysis via upregulation of glycolytic enzymes, changes in glutamine catabolism due to overexpression of glutaminases, raise in fatty acid oxidation and distinct effects depending on the lipid saturation, in addition to mitochondrial DNA which is a hotspot for mutations. Therefore, more attention should be paid to this topic given that targeting metabolic fragilities could improve the outcome of CMTs.

Barth Syndrome, a rare X-linked disorder affecting 1:300,000 live births, results from defects in Tafazzin, an acyltransferase that remodels cardiolipin and is essential for mitochondrial respiration. Barth Syndrome patients develop cardiomyopathy, muscular hypotonia and cyclic neutropenia during childhood, rarely surviving to middle age. At present, no effective therapy exists and downstream transcriptional effects of Tafazzin dysfunction are incompletely understood. To identify novel, cell-specific, pathological pathways that mediate heart dysfunction, we performed single-nucleus RNA-sequencing (snRNA-seq) on wild-type (WT) and Tafazzin-knockout (Taz-KO) mouse hearts. We determined differentially expressed genes (DEGs) and inferred predicted cell-cell communication networks from these data. Surprisingly, DEGs were distributed heterogeneously across the cell types, with fibroblasts, cardiomyocytes, endothelial cells, macrophages, adipocytes and pericytes exhibiting the greatest number of DEGs between genotypes. One differentially expressed gene was detected for the lymphatic endothelial and mesothelial cell types, while no significant DEGs were found in the lymphocytes. A Gene Ontology (GO) analysis of these DEGs showed cell-specific effects on biological processes such as fatty acid metabolism in adipocytes and cardiomyocytes, increased translation in cardiomyocytes, endothelial cells and fibroblasts, in addition to other cell-specific processes. Analysis of ligand-receptor pair expression, to infer intercellular communication patterns, revealed the strongest dysregulated communication involved adipocytes and cardiomyocytes. For the knockout hearts, there was a strong loss of ligand-receptor pair expression involving adipocytes, and cardiomyocyte expression of ligand-receptor pairs underwent reorganization. These findings suggest that adipocyte and cardiomyocyte mitochondria may be most sensitive to mitochondrial Tafazzin deficiency and that rescuing adipocyte mitochondrial dysfunction, in addition to cardiomyocyte mitochondrial dysfunction, may provide therapeutic benefit in Barth Syndrome patients.

Alzheimer’s disease (AD) is characterized by the formation of senile plaques consisting fibrillated amyloid-β (Aβ), dystrophic neurites, and the neurofibrillary tangles of tau. The oligomers/fibrillar Aβ damages the neurons or initiate an intracellular signaling cascade for neuronal cell death leading to Aβ toxicity. The Aβ is a 4 kDa molecular weight peptide originating from the C-terminal region of the amyloid precursor protein via proteolytic cleavage. Apart from the typical AD hallmarks, certain deficits in metabolic alterations have been identified. This study describes the emerging features of AD from the aspect of alternation in the main pathway of carbohydrate metabolism in the human brain. Particularly, the neurons in patients with AD favor glycolysis despite a normal mitochondrial function indicating a Warburg-like effect. In addition, certain dietary patterns are well known for their properties in preventing AD. Among those, a ketogenic diet may substantially improve the symptoms of AD. An effective therapeutic method in the treatment, mitigation, and prevention of AD has not yet been established. Therefore, the researchers pursue the development and establishment of novel therapies effective in suppressing AD symptoms and the elucidation of their underlying protective mechanisms against neurodegeneration aiming for AD therapy in near future.

Amyloids were conventionally referred to as extracellular and intracellular accumulation of Aβ42 peptide which causes the formation of plaques and neurofibrillary tangles inside the brain leading to the pathogenesis in Alzheimer’s disease. Subsequently, amyloid-like deposition was found in the etiology of Prion diseases, Parkinson disease, Type II Diabetes and Cancer which was attributed to the aggregation of Prion protein, α-Synuclein, Islet Amyloid Polypeptide Protein and p53 protein respectively. Hence, traditionally amyloids were considered as aggregates formed by the proteins or peptides exclusively. However, since the last decade it has been discovered that other metabolites like single amino acids, nucleobases, lipids, glucose derivatives etc. have propensity to form amyloid-like toxic assemblies. Several studies suggest direct implications of these metabolite assemblies in the patho-physiology of various Inborn errors of metabolisms like Phenylketonuria, Tyrosinemia, Cystinuria and Gaucher’s disease to name a few. In this review, we present a comprehensive literature overview which suggests amyloid-like structure formation as a common phenomenon for the disease progression and pathogenesis in multiple syndromes. The review on this topic is urgently required to create awareness about the understanding of fundamental molecular mechanism behind the origin of diseases from an amyloid perspective and possibly look for a common therapeutic strategy for the treatment of these maladies by designing generic amyloid inhibitors.

Studies on the neurobiological causes of anxiety disorders suggest that the GABA system in-creases synaptic concentration and enhances the affinity of GABAA (type A) receptors for ben-zo-diazepine ligands. Flumazenil antagonizes the benzodiazepine binding site of the GABA (γ-aminobutyric acid) type /benzodiazepine receptor (BZR) complex in the central nervous sys-tem (CNS). The integration of the metabolites of flumazenil by LC-tandem mass spectrometry will complete understanding of the in vivo metabolism of flumazenil and accelerate radio-pharmaceutical inspection and registration. The main goal of our study was to investigate using reversed-phase HPLC (PR-HPLC) coupled with electrospray ionization triple quadrupole tan-dem mass spectrometry (ESI-QqQ MS) for the identification of flumazenil and its metabolites in a hepatic matrix. And a carrier-free nucleophilic fluorination with automatic synthesizer for [18F]flumazenil which applied to in vivo nano-positron emission tomography (Nano-PET)/computed tomography (CT) imaging and ex vivo bio-distribution used to analyze in normal rats. The study showed that 50% of the flumazenil was bio-transformed at 60 min by the rat liver homogenate, while one metabolite (M1) was a methyl transesterification product of flumazenil. In a rat liver microsomes system, two metabolites were identified (M2 and M3) as its carboxylic acid and hydroxylated ethylester forms, respectively. [18F]flumazenil in vivo nanoPET/CT imag-ing and ex vivo bio-distribution assay also showed significant effects on GABAA receptor availa-bility in the amygdala, prefrontal cortex, cortex, and hippocampus in the rat brain, worriless about the formation of metabolites. We showed completion of the bio-transformed course of flumazenil by the hepatic system; and [18F]flumazenil can be a good ligand and serve as a PET agent for determination of GABAA/BZR complex for multiplex neurological syndromes in the clinical stage.

Metformin, the treatment of first choice in type 2 diabetes (T2D), is known to mainly act by decreasing endogenous glucose production (EGP) in the liver. Paradoxically, in the last decade several reports documented increased EGP after metformin treatment. This increase, was often attributed to pronounced rises in glucagon, consistent with counter-regulatory response to the glucose lowering effect of metformin. However, considering that hyperglucagonemia, but not hypoinsulinemia, is a main driver of EGP in T2D, increased EGP should have been a common finding. This observation, together with the finding that metformin antagonizes glucagon effects on energy expenditure and protein synthesis, concurrently to its effects on EGP and the emerging evidences demonstrating increased branched chain and gluconeogenic amino acids in response to metformin treatment may points to a liver alpha-cell skeletal muscle cross talk similar to that observed in the liver-alpha cell axis. Here, we provide a mechanistic perspective to this latter possibility, based on mechanistic studies of metformin’s transcriptional targets; retaining thus its glucagon antagonistic and presumably anti-gluconeogenic effects on liver and attributing the increase in EGP to renal gluconeogenesis. We finally discuss how increased EGP might reflect an adverse response to metformin treatment, providing support from clinical and epidemiological data.

Because of the need to replace the current clinical artemisinins in artemisinin combination therapies, we are evaluating fitness of amino-artemisinins for this purpose. These include the thiomorpholine derivative artemiside obtained in one scalable synthetic step from dihydroartemisinin (DHA) and the derived sulfone artemisone. We have recently shown that artemiside undergoes facile metabolism via the sulfoxide artemisox into artemisone and thence into the unsaturated metabolite M1; DHA is not a metabolite. Artemisox and M1 are now found to be approximately equipotent with artemiside and artemisone in vitro against asexual P. falciparum (Pf) blood stage parasites (IC50 1.5 – 2.6 nM). Against Pf NF54 blood stage gametocytes, artemisox is potently active (IC50 18.9 nM early-stage, 2.7 nM late-stage). Comparative drug metabolism and pharmacokinetic (DMPK) properties were assessed via po and iv administration of artemiside, artemisox and artemisone in a murine model. Following oral administration, the composite Cmax value of artemiside plus its metabolites artemisox and artemisone formed in vivo is some 2.6-fold higher than that attained following administration of artemisone alone. Given that efficacy of short half-life rapidly-acting antimalarial drugs such as the artemisinins is associated with Cmax, it is apparent that artemiside will be more active than artemisone in vivo, due to additive effects of the metabolites. As is evident from earlier data, artemiside indeed possesses appreciably greater efficacy in vivo against murine malaria. Overall, the higher exposure levels of active drug following administration of artemiside coupled with its synthetic accessibility indicate it is much the preferred drug for incorporation into rational new artemisinin combination therapies.

Sphingosine-1-phosphate (S1P) synthesized by sphingosine kinase (SPHK) is a signaling molecule, involved in cell proliferation, growth, differentiation, and survival. Indeed, a sharp increase of S1P was linked to the pathological outcome with inflammation, cancer metastasis or angiogenesis etc. In this regard, the SPHK/S1P axis regulation has been a specific issue in anticancer strategy to turn accumulated sphingosine (SPN) into cytotoxic ceramides (Cers). For these purposes, there have been numerous chemicals synthesized for SPHK inhibition. In this study, we investigated the comparative efficiency of dansylated PF-543 (DPF-543) on the Cers synthesis along with PF-543. DPF-543 deserved attention in strong cytotoxicity, due to the cytotoxic Cers accumulation by ceramide synthase (CerSs). DPF-543 exhibited dual actions on Cers synthesis by enhance the serine palmitoyltransferase (SPT) activity, and by inhibiting SPHKs which eventually induced an unusual environment of the high amount of 3-ketosphinganine and sphinganine (SPA). SPA in turn was consumed to synthesize Cers via de novo pathway. Interestingly, PF-543 increased only the SPN level, but not for SPA. In addition, DPF-543 mildly activates acid sphingomyelinase (aSMase) that contributes a partial increase on Cers. Collectively, a dansyl-modified DPF-543 relatively en-hanced Cers accumulation via de novo pathway which was not observed in PF-543. Our results demonstrated that the structural modification on SPHK inhibitors is still an attractive anticancer strategy by regulating sphingolipid metabolism.

Apoptosis, the programmed and intentional death of senescent, damaged, or otherwise superfluous cells, is the natural end-point for most cells within multicellular organisms. Apoptotic cells are not inherently damaging, but if left unattended they can lyse through secondary necrosis. The resulting release of intracellular contents drives inflammation in the surrounding tissue and can lead to autoimmunity. These negative consequences of secondary necrosis are avoided by efferocytosis—the phagocytic clearance of apoptotic cells. Efferocytosis is a product of both apoptotic cell and efferocyte mechanisms, which cooperate to ensure the rapid and complete removal of apoptotic cells. Herein, the processes used by apoptotic cells to ensure their timely removal, and the receptors, signaling, and cellular processes used by efferocytes to identify, remove, and process the apoptotic cells, are reviewed.

Amyotrophic Lateral Sclerosis (ALS) is an irreversible neurodegenerative disease with no known cure. Recent studies suggest a strong metabolic component in ALS pathogenesis and have shown an inverse relationship between leptin levels and ALS progression, although the effects of leptin as a treatment have not yet been studied. Therefore, we aim to examine whether the acute treatment with leptin has beneficial effects on brain pathology and cognitive function in the transgenic TDP43A315T line of ALS. Mice were treated intranasally (IN) with 0.03mg/kg of leptin or vehicle (VH) daily for 7 days. Data showed a progressive decline in body weight and motor coordination in TDP43A315T mice. Moreover, Lep-treated TDP43A315T mice showed an earlier disease onset, along with an improvement in motor performance. Altered levels of some of the adipokines and metabolic proteins studied were found in TDP43A315T mice, which were differently expressed among Lep-treated and VH-treated animals. Furthermore, some correlations were found among the serum levels of this proteins in WT and TDP43A315T mice. As far as we know, this is the first pilot study to provide evidence of the therapeutic effect of leptin treatment in a mice model of ALS, although further studies are needed to expound on the underlying mechanisms.

The mangrove plant Acanthus ilicifolius and its relative, A. mollis, have been previously proved to possess diverse pharmacological effects. Therefore, evaluating the differentially expressed proteins of these species under tidal flooding stress is essential to fully exploit and benefit from their medicinal values. The roots of A. ilicifolius and A. mollis were exposed to 6 h of flooding stress per day for 10 days. The dry weight, hydrogen peroxide (H2O2) content, anatomical characteristics, carbon and energy levels, and two-dimensional electrophoresis coupled with MALDI-TOF/TOF MS technology were used to reveal the divergent flooding resistant strategies. A. ilicifolius performed better under tidal flooding stress, which was reflected in the integrity of the morphological structure, more efficient use of carbon and energy, and a higher percentage of up-regulated proteins associated with carbon and energy metabolism. A. mollis could not survive in flooding conditions for a long time, as revealed by incomplete cell structures of the roots, less efficient use of carbon and energy, and a higher percentage of down-regulated proteins associated with carbon and energy metabolism. Energy provision and flux balance played a role in the flooding tolerance of A. ilicifolius and A. mollis.

Polycyclic aromatic hydrocarbons (PAHs), which consist of low-molecular-weight PAHs (LMW-PAHs) and high-molecular-weight PAHs (HMW-PAHs), form an important class of pollutants. Pyrene and benzo[a]pyrene (BaP) are the main pollutants belonging to HMW-PAHs, and their degradation by microorganisms remains an important strategy for their removal from the environments. Extensive studies have been carried out on the isolation and characterisation of microorganisms that actively degrade LMW-PAHs, and to a certain extent, the HMW-PAH pyrene. However, so far, limited work has been carried out on BaP biodegradation. BaP consists of five fused aromatic rings, which confers this compound a high stability, rendering it less amenable to biodegradation. The current review summarizes the emerging reports on BaP biodegradation. More specifically, work carried out on BaP bacterial degradation and current knowledge gaps that limit our understanding of BaP degradation are highlighted. Moreover, new avenues of research on BaP degradation are proposed, specifically in the context of the development of “omics” approaches

Mitochondria are constantly subjected to stressful conditions due to their unique physiology and organization. The resulting damage leads to mitochondrial dysfunction, which underlies many pathophysiological conditions. Hence, constant surveillance is required to closely monitor mitochondrial health for sound maintenance of cellular metabolism and thus, for viability. In addition to internal mitochondrial chaperones and proteases, mitochondrial health is also governed by host cell protein quality control systems. The Ubiquitin-Proteasome System (UPS) and autophagy constitute the main pathways for removal of damaged or superfluous proteins in the cytosol, nucleus, and from certain organelles such as the ER and mitochondria. Although stress-induced ubiquitin-dependent degradation of mitochondrial outer membrane proteins has been widely studied, mechanisms of intramitochondrial protein ubiquitination have remained largely elusive due to the predominantly cytosolic nature of UPS components, separated from internal mitochondrial proteins by a double membrane. However, recent research has illuminated examples of intramitochondrial protein ubiquitination pathways and highlighted their importance under basal and stressful conditions. Owing to the dependence of mitochondria on the error-prone process of protein import from the cytosol, it is imperative that the cell eliminate any accumulated proteins in the event of mitochondrial import deficiency. Apparently, a significant portion of this activity involves ubiquitination in one way or another. In the present review article, following a brief introduction to mitochondrial protein quality control mechanisms, we discuss our recent understanding of intramitochondrial protein ubiquitination, its importance for the basal function of mitochondria, metabolic implications, and possible therapeutic applications.

Iron and zinc are essential micronutrients required for growth and health. Deficiencies of these nutrients are highly prevalent among populations, but can be alleviated by supplementation. Cross-sectional studies in humans showed positive association of serum zinc levels with hemoglobin and markers of iron status. Dietary restriction of zinc or intestinal specific conditional knock out of ZIP4 (SLC39A4), an intestinal zinc transporter, in experimental animals demonstrated iron deficiency anemia and tissue iron accumulation. Similarly increased iron accumulation has been observed in cultured cells exposed to zinc deficient media. These results together suggest a potential role of zinc in modulating whole body iron metabolism. Studies in intestinal cell culture models demonstrate that zinc induces iron uptake and transcellular transport via induction of divalent metal iron transporter-1 (DMT1) and ferroportin (FPN) expression, respectively. It is interesting to note that intestinal cells are exposed to very high levels of zinc through pancreatic secretions, which is a major route of zinc excretion from the body. Therefore, zinc appears to be modulating the iron metabolism possibly via regulating the DMT1 and FPN1 levels. Herein we critically reviewed the available evidence to hypothesize novel mechanism of Zinc-DMT1/FPN axis in regulating intestinal iron absorption and tissue iron accumulation to facilitate future research aimed at understanding the yet elusive mechanisms of iron and zinc interactions.

Physical frailty and sarcopenia (PF&S) are hallmarks of aging that share a common pathogenic background. Perturbations in protein/amino acid metabolism may play a role in the development of PF&S. In this preliminary study, 68 community-dwellers aged 70 years and older, 38 with PF&S and 30 non-sarcopenic, non-frail controls (nonPF&S), were enrolled. A panel of 37 serum amino acids and derivatives was assayed by UPLC-MS. Partial Least Squares Discriminant Analysis (PLS-DA) was used to characterize the amino acid profile of PF&S. The optimal complexity of the PLS-DA model was found to be three latent variables. The proportion of correct classification was 76.6 ± 3.9% (75.1 ± 4.6% for enrollees with PF&S; 78.5 ± 6.0% for controls). Older adults with PF&S were characterized by higher levels of asparagine, aspartic acid, citrulline, ethanolamine, glutamic acid, sarcosine, and taurine. The profile of nonPF&S individuals was defined by higher levels of α-aminobutyric acid and methionine. Distinct profiles of circulating amino acids and derivatives characterize older individuals with PF&S. The dissection of these patterns may provide novel insights into the role played by protein/amino acid perturbations in the disabling cascade and possible new targets for interventions.