Obesity is one of the most prevalent health conditions in humans and companion animals across the world. Obesity is associated with multiple health conditions across species including premature mortality. It is therefore of importance across the fields of medicine and veterinary medicine. The regulation of body weight is a homeostatic process vulnerable to disruption by genetic and environmental factors. It is well established that the heritability of obesity is high in humans and laboratory animals, with ample evidence that the same is true in companion animals. In this review, we provide an overview of how genes link to obesity in humans, drawing on a wealth of information from laboratory animal models, and summarising the mechanisms by which obesity causes related disease. Throughout, we focus on how large-scale human studies and niche investigations of rare mutations in severely affected patients have improved our understanding of obesity biology and can inform our ability to interpret results of animal studies. For dogs, cats and horses, we review the similarities in obesity pathophysiology to humans and review those genetic studies that have been done to investigate them. Finally, we discuss how veterinary genetics may learn from humans about studying precise, nuanced phenotypes and implementing large-scale studies, but also how veterinary studies may be able to look past clinical findings to mechanistic ones and demonstrate translational benefits to human research.

The risk factors associated with COVID-19 related severity, morbidity, and mortality, i.e., obesity (often associated with NAFLD), hyperglycemia, hypertension and dyslipidemia all cluster together as metabolic syndrome (MetS). Instead of studying association of these risk factors with COVID-19, it makes sense studying the association between MetS on one hand and COVID-19 on the other. This study explores a molecular basis underpinning the above association. Severity of COVID-19 patients with MetS could be due to functional alterations of host proteins due to their interactions with viral proteins. We collected data from Enrichr (https://amp.pharm.mssm.edu/Enrichr/), DisGeNET (https://www.disgenet.org/) and others and carried out enrichment analysis using Enrichr. Various biological processes and pathways associated with viral protein interacting partners are known to involve in metabolic diseases. The molecular pathways underlying insulin resistance, insulin signaling and insulin secretion are not only involved in diabetes but also in CVD and obesity (associated with non-alcoholic fatty liver disease; NAFLD). Lipid metabolism/lipogenesis, fatty acid oxidation and inflammation are associated with MetS. Viral interacting host proteins are associated and enriched with terms like hyperglycemia, coronary artery disease, hypertensive disease related to CVD and liver diseases in DisGeNET. Association of viral interacting proteins with disease-relevant biological processes, pathways and disease-related terms suggests that altered host protein function following interaction with viral proteins might contribute to frequent occurrence and/or severity of COVID-19 in subjects with MetS. Such analysis not only provides a molecular basis of comorbidity but also incriminates host proteins in viral replication, growth and identifies possible drug targets for intervention.

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.

In Newtonian mechanics, time as well as space are perceived as absolute entities. In 2 Einstein’s special relativity, time is frame dependent. Time is also affected by gravitational field 3 and as the field varies in space, time also varies throughout space. In the present article, a 4 thermodynamic-based time is investigated. The entity is called "irreversibility", which is generated 5 when availability (also known as exergy) is destroyed. Since each thermodynamic system may 6 generate different amount of irreversibility, this quantity is system dependent. The time’s arrow is 7 automatically satisfied, since irreversibility generation always proceeds in one direction (toward 8 future). We have demonstrated that, like common time, irreversibility is frame dependent, and 9 affected by gravity in the similar manner as the common time. For this reason, we propose to 10 assign the entity irreversibility of the system as thermodynamic time. A possible application of the 11 thermodynamic time is an interpretation and managing of the aging of biological systems. The 12 metabolic efficiency is related to the irreversibility of the chemical processes and affect the aging of 13 the system. Our sensation of time-flow may be attributed to the flow of availability and destruction 14 of it through the living system. It is shown by other authors that entropy generation (equivalent to 15 irreversibility) is a parameter for the human life span. Since the thermodynamic time is based on a 16 concept of thermodynamics that is universal, further applications to other subjects, such as biological 17 clock, telomere, and cosmology are possible.

Fatty acids play a major role in determining membrane biophysical properties. Staphylococcus aureus produces branched-chain fatty acids (BCFAs) and straight-chain fatty acids (SCFAs), and can incorporate exogenous SCFAs and straight-chain unsaturated fatty acids (SCUFAs). Many S. aureus strains produce the triterpenoid pigment staphyloxanthin, and the balance of BCFAs, SCFAs and staphyloxanthin determines membrane fluidity. Here, we investigated the relationship of fatty acid and carotenoid production in S. aureus using a pigmented strain (Pig1), its carotenoid-deficient mutant (Pig1ΔcrtM) and the naturally non-pigmented Staphylococcus argenteus that lacks carotenoid biosynthesis genes and is closely related to S. aureus. Fatty acid compositions in all strains were similar under a given condition indicating that staphyloxanthin does not influence fatty acid composition. Strain Pig1 had decreased membrane fluidity as measured by fluorescence anisotropy than the other strains under all conditions indicating that staphyloxanthin helps maintain membrane rigidity. We could find no evidence for correlation of expression of crtM and fatty acid biosynthesis genes. Supplementation of medium with glucose increased SCFA production and decreased BCFA and staphyloxanthin production, whereas acetate-supplementation also decreased BCFAs but increased staphyloxanthin production. We believe that staphyloxanthin levels are influenced more through metabolic regulation than responding to fatty acids incorporated into the membrane.

Diabetes complications appear with the severity of hyperglycemia and the age of the disease. In type 2 diabetes mellitus (T2DM), herbal medicines are also effective in reducing hyperglycemia and can be used for this purpose to manage complications. This study aimed to prove the effectiveness of Amaranthus spinosus root extract on type 2 diabetes (T2D) and its microvascular complications. A high-fat diet and low-dose streptozocin were used for 20 days to induce T2D syndrome and complications in rats. The validated animal models were treated orally with the dried hydroethanolic extract of A. spinosus for three weeks; then the hematological, biochemical, and histological markers were evaluated. The results showed that the extract at a dose of 500 mg/kg bw was effective against diabetes and its complications. This effectiveness was linked to a significant reduction (p < 0.0001) in basal blood glucose, tissue oxidative stress, serum cardiovascular and hepato-renal markers, and an improvement in insulin secretion and utilization. The protective activity of the extract against macular edema and renal fibrosis was confirmed by histopathological examinations. These findings prove that A. spinosus root extract contains bioactive compounds that may be useful in preventing or reversing diabetic retinopathy and renal fibrosis.

Obesity is a major public health concern globally, significantly increasing the risk of numerous metabolic and cardiovascular diseases. While lifestyle interventions remain the primary strategy for weight management, pharmacotherapy is increasingly recognized as an essential component for patients with obesity, especially when lifestyle modifications alone are insufficient. Glucagon-like peptide-1 (GLP-1) receptor agonists, originally developed for the management of type 2 diabetes, have emerged as effective agents in promoting weight loss in both diabetic and non-diabetic populations. This literature review examines the efficacy, safety, and mechanisms of action of GLP-1 receptor agonists, focusing on liraglutide and semaglutide, in obesity treatment. Furthermore, it discusses the impact of GLP-1 receptor agonists on obesity-related comorbidities, their comparison with other pharmacological treatments, and future perspectives.

Overconsumption of an unbalanced diet and overweight, leading to insulin resistance, dyslipidemia, hepatic steatosis, cardiovascular diseases and obesity, is nowadays a worldwide health issue, with different patterns of metabolic disturbances in the young and adult popula-tions, in both gender. Preclinical models that closely mimic the gradual weight gain that occurs in humans upon consumption of a “western-type” diet (WD) are of great interest. In particular, the diet-induced obesity (DIO) model in the C57BL/6J mouse sub-strain is often used in biomed-ical research, considering that it is prone to metabolic disorders and obesity, and is widely used to generate genetically modified mice. This study aimed to phenotypically characterize the C57BL/6J mouse strain fed a WD-like diet, using high-frequency ultrasound imaging (HFUS) as a complementary tool to longitudinally monitor morphofunctional changes in the liver, heart and kidney associated with DIO. Long term WD feeding increased mice body weight (BW), liver/BW ratio and body condition score (BCS), serum transaminases, glucose and insulin, as well as Homeostasis model assessment (HOMA) indexes, and caused dyslipidemia and insulin resistance. According to the 3Rs, ultrasound imaging has enabled a comprehensive study of metabolic syndrome in mice, in vivo and non-invasive, improving the identification of early stages of diseases.

Hyperuricemia (HU), characterized by elevated uric acid (UA) levels in the blood, represents a global health concern associated with various conditions, including cardiovascular diseases, gout, hypertension, metabolic syndrome, renal dysfunction, and neurodegenerative diseases. This review offers a contemporary analysis of HU, encompassing its causes, associated health risks, diagnosis, treatment, and future outlook. Recent studies have underscored the multifaceted origin of HU, implicating genetic predisposition, dietary patterns, lifestyle choices, and environmental influences. Genetic variations affecting enzymes and transporters involved in purine metabolism and UA excretion have been identified, laying the groundwork for personalized treatment strategies. Advances in diagnostic imaging and omics technologies provide enhanced precision in the detection and evaluation of risks. While pharmacological interventions remain central to managing HU, persistent challenges such as treatment resistance prompt exploration of novel drug targets and lifestyle modifications. Chinese herbal medicines offer a potentially alternative approach with fewer side effects. Emerging research on the impact of gut microbiota on UA metabolism opens new therapeutic avenues. Despite progress, challenges such as optimizing treatment duration and understanding long-term effects persist. Collaborative efforts are crucial to address these challenges and advance our comprehension of HU. The integration of precision medicine and holistic patient care approaches holds promise for improving outcomes and enhancing quality of life for individuals with HU.

Background: The pandemic caused by the SARS-CoV-2 virus demonstrated the importance of prevention through a healthy diet and lifestyle, the most vulnerable people being those with severe chronic conditions, those who are overweight, and those with an unbalanced immune system. Methods: The evaluation of the eating habits and lifestyle of the Romanian population in the post-pandemic period was carried out based on a cross-sectional observational study with the help of a questionnaire. Results: 4704 valid answers were registered (3136 female and 1568 male respondents). Among the respondents, most of them belong to the young population, 2892 between the ages of 18 and 40, i.e., 61.5%. Most male respondents are overweight (1400) and obese (780). Most respondents indicated a tendency to consume 1-2 meals per day irregularly (p=0.6167). Only 974 respondents adopted a healthy diet, and 578 a healthy lifestyle. Conclusion: The present study reports low adherence to a healthy diet (20.7%) and healthy lifestyle (12.28%), especially among the young population (< 30 years). In the current context, it reports a reduced tendency to consume vegetables and fruits among the population, below the daily average recommended by the nutrition guidelines, a tendency towards sedentary behavior, and even deficient hydration of some of the respondents; these negative aspects can create a long term a series of nutritional and psycho-emotional imbalances. Our results evidence that complex surveys among the population are regularly required to investigate nutritional or lifestyle deficiencies; moreover, it could be helpful in further educational measures in nutrition, food, and environmental safety.

Purpose of Review Multipotent Mesenchymal stromal cells (MSCs) have recently risen to prominence in regenerative medicine for their powerful intrinsic properties of self-regeneration, immunomodulation, and multi-potency. They exhibited an excellent safety profile in early-phase clinical trials. Nevertheless, MSCs-based therapy suffers reduced efficacy in randomized clinical trials due to a poor understanding of their proper delivery modalities. Here, we intend to explore the current application of MSCs after tissue injuries. We specifically focus on tissue source, delivery routes, metabolic fitness, and cell dose. We further discuss potential approaches to optimize in vivo engraftment. Recent findings MSCs therapeutic effect mediates by paracrine and contact factors, which are cells' intrinsic physiological processes. The cell culture expansion process does not destroy MSCs' intrinsic properties. In vivo persistence of administered MSCs determines their therapeutic potency. Cell viability, fitness, immune match, and delivery route meticulously regulate their in vivo persistency. Different genetic or chemical modification strategies are currently applied to extend their in vivo lifespan and boost their pharmaceutical effect. Summary Improving the in vivo persistence of implanted MSCs could facilitate its clinical translation. This review highlights the pros and cons of different MSCs’ delivery strategies used in clinical or preclinical studies, emphasizing various modification approaches. These can promote prolonged graft cell survival.

Type 2 diabetes mellitus (T2DM) is a common metabolic disease characterised by insulin resistance and elevated blood glucose levels, affecting millions of people worldwide. T2DM patients with dyslipidaemia have an increased risk of cardiovascular disease (CVD). A complex interplay of risk factors such as hyperglycaemia, dyslipidaemia, hypertension, obesity, inflammation and oxidative stress favour the development of atherosclerosis, a central mechanism in the pathogenesis of cardiovascular disease. Dyslipidaemia, a hallmark of T2DM, is characterised by elevated triglycerides, decreased high-density lipoprotein (HDL) cholesterol and the presence of small, dense low-density lipoprotein (LDL) particles, all of which promote atherosclerosis. In this article, we have attempted to present various treatment strategies that include pharmacological interventions such as statins, ezetimibe, PCSK9 inhibitors, fibrates and omega-3 fatty acids. We have also tried to highlight the pivotal role of lifestyle modifications, including physical activity and dietary changes, in improving lipid profiles and overall cardiovascular health in T2DM patients. We have also tried to present the latest clinical guidelines for the management of dyslipidaemia in T2DM patients. In conclusion, the treatment of dyslipidaemia in T2DM patients is of great importance as it lowers lipid particle levels, slows the progression of atherosclerosis and ultimately reduces susceptibility to cardiovascular disease.

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.

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.

Aging is a major risk factor for Alzheimer's disease (AD). AD mouse models are frequently used to assess pathology, behavior, and memory in AD research. While the pathological characteristics of AD are well established, our understanding of the changes in the metabolic phenotypes with age and pathology is limited. In this work, we used the Promethion cage systems® to monitor changes in physiological metabolic and behavioral parameters with age and pathology in wild-type and 5xFAD mouse models. Then, we assessed whether these parameters could be altered by treatment with oleocanthal, a phenolic compound with neuroprotective properties. Findings demonstrated metabolic parameters such as body weight, food and water intake, energy expenditure, dehydration, and respiratory exchange rate, and the behavioral parameters of sleep patterns and anxiety-like behavior are altered by age and pathology. However, the effect of pathology on these parameters was significantly greater than normal aging, which could be linked to amyloid-β deposition and blood-brain barrier (BBB) disruption. In addition, and for the first time, our findings suggest an inverse correlation between sleep hours and BBB breakdown. Treatment with oleocanthal improved the assessed parameters and reduced anxiety-like behavior symptoms and sleep disturbances. In conclusion, aging and AD are associated with metabolism and behavior changes, with the changes being greater with the latter, which were rectified by oleocanthal. In addition, our findings suggest that monitoring changes in metabolic and behavioral phenotypes could provide a valuable tool to assess disease severity and treatment efficacy in AD mouse models.

Aims: Medical Nutritional Treatment (MNT) can be complex and associated to potential meta-bolic complications, which has been recently described as Nutritrauma. There is no data on the effect of applying this strategy in clinical practice. The aim of our work is to describe if applica-tion of Nutritrauma concept in real live is useful to detect metabolic complications associated to the prescription of MNT in critically ill patients. Methods: In this descriptive prospective study at a single center, we enrolled 30 consecutive crit-ical ill patients of a 14 beds medical – surgical Intensive Care Unit. The Nutritrauma strategy implementation was based in four M steps: Metabolic screening, MNT prescription, Biochemical Monitoring and Nutritional Management. The primary endpoint was to describe the metabolic complications of the MNT detected with Nutritrauma strategy. Secondary endpoint was to de-scribe the most frequent causes of inappropriate prescription. Results: We analysed 28 patients (mean age 69,7 ± 11,3 years; APACHE II 18,1 ± 8,1, SOFA 7,5 ± 3,7; Nutric Score modified 4,3 ± 2,01 and mean BMI 27,2 ± 3,8). The most frequent disease on admission was sepsis (46,4%). Length of ICU stay was 20,6 ± 15,1 days and 39,3% died during the ICU stay. Enteral nutrition (82,1%) was more frequent than parenteral nutrition (17,9%). During nutritional monitoring 54 specific analytical determinations were made. Hyperglycemia was the most frequent metabolic alteration (83,3% of the determinations). Electrolyte disturbance were hypocalcemia (50%), hypophosphatemia (29,6%) and hypokalemia (27,8%). The most frequent lipid profile abnormality were hypocholesterolemia (64,8%) and hypertriglyceridemia (27,8%). Furthermore, nutritional prescription was modified in the 53,6% of patients: increase protein dosage (25%), increase caloric dosage (21,4%) and change to an organ-specific diet (17,8%). Conclusions: The application of Nutritrauma strategy facilitate the detection of metabolic com-plications and the evaluation of the appropiate prescription of the MNT.

It was found that patients with comorbidities of obesity and diabetes have a high risk of breast cancer occurrence and face worse breast cancer outcomes. Though several reports showed the reinforced link between obesity, diabetes, and prediabetes with breast cancer, the underlying molecular mechanism is still unknown. The present study aimed to investigate the underlying molecular link between increased risks of breast cancer due to coincident diabetes or obesity using a spontaneous obese rat model with impaired glucose tolerance (WNIN/GR-Ob rat). A single dose of solubilized DMBA suspension (40 mg/kg body weight) was orally administered to the animals at the age of 60 days to induce breast tumors. The tumor incidence, latency period, tumor frequency, and tumor volume were measured. Histology, immunohistochemistry, and immunoblotting were performed to evaluate the tumor morphology and expression levels of signal molecules. It was observed that the onset of breast tumor and latency period per tumor development were early in GR-Ob rats compared to respective lean rats. It was found that 62% of obese rats were bearing tumors, and in comparison, only 21% of the lean animals developed breast tumors. Overexpression of ER, PR, Ki67, and p53 markers was observed in tumor tissues of obese rats in comparison with lean rats. The levels of the hallmarks of cell proliferation and angiogenesis involved in IGF-1/PI3K/Akt/GSK3β/β-catenin signaling pathway molecules were upregulated in obese rat breast tumors compared to lean rats. Furthermore, obesity with prediabetes is associated with changes in IGF-1 signaling and acts on PI3K/Akt/GSK3β/β-catenin signaling, which results in quick cell proliferation and development of breast tumors in obese rats than the lean rats. These results indicate that the onset of the tumor and its development was faster in a spontaneous obese rat model with impaired glucose tolerance than their lean counterparts, with a higher percentage of tumor incidence.

Alzheimer's disease (AD) is an incurable neurodegenerative disorder. Early screening, particularly in blood has been regarded as an effective approach for AD diagnosis and prevention. In addition, metabolic dysfunction has been demonstrated to be closely related to AD, which might be reflected in whole blood transcriptome. Hence, we hypothesized that establishment of diagnostic model based on metabolic signatures of blood is a workable strategy. To the end, we initially constructed metabolic pathway pairwise (MPP) signatures to characterize the interplay among metabolic pathways. Then, a series of bioinformatic methodologies, e.g., differential expression analysis, functional enrichment analysis, and network analysis, etc. were used to investigate the molecular mechanism behind AD. Moreover, an unsupervised clustering analysis based on the MPP signature profile via Non-Negative Matrix Factorization (NMF) algorithm was utilized to stratify AD patients. Finally, aimed at distinguishing AD patients from non-AD group, a metabolic pathway-pairwise scoring system (MPPSS) was established using multi-machine learning methods. As a result, many metabolic pathways correlated to AD were disclosed, including oxidative phosphorylation and fatty acid biosynthesis, etc. NMF clustering analysis divided AD patients into two subgroups (S1 and S2), which exhibit distinct activities of metabolism and immunity. Typically, oxidative phosphorylation in S2 exhibits a lower activity than that in S1 and non-AD group, suggesting the patients in S2 might possess a more compromised brain metabolism. Additionally, Immune infiltration analysis showed that the patients in S2 might have phenomena of immune suppression, compared with S1 and non-AD group. These findings indicated that S2 probably have a more severe progression of AD. Finally, MPPSS could achieve an AUC of 0.73 in training dataset, 0.71 in testing dataset and an AUC of 0.82 on weighted average in five external validation datasets. Overall, our study successfully established a novel metabolism-based scoring system for AD diagnosis using blood transcriptome, and provided new insight into the molecular mechanism of metabolic dysfunction implicated in AD.

Indirect calorimetry (IC) is a widely used method to study animal energy metabolism by measuring gas exchange. The accuracy of IC depends on detecting variations in signals reflecting the metabolic response, which can be challenging due to measurement noise and external factors. In this study, we propose a methodology to validate IC systems, including an easy-to-use spreadsheet for data computing, to verify accuracy and detect whole-system leaks. We conducted a re-covery test using a simulation of CO2 dynamics in MS Excel and injecting a known CO2 concentration into four respirometry chambers. The clearance rate of CO2 was observed and compared to the expected clearance rate from the simulation. The results from the recovery test in our system show that the proposed methodology is accurate and precise. The proposed methodology and recovery test can be used to standardize the validation of IC systems, providing accurate measurements of animal energy metabolism in different environmental conditions and energy utilization from feeds.

Obesity is characterized by chronic low-grade inflammation. Caveolin-1 (CAV1), a structural and functional protein found in adipose tissues (AT), is augmented in obese individuals. We aimed to define the inflammatory mediators that influence CAV1 gene regulation and associated mechanism in obesity. Using subcutaneous AT from 27 (7 lean/20 obese) normoglycemic individuals, in vitro human adipocyte models, and in vivo mice models, we found elevated CAV1 expression in obese AT and a positive correlation between the gene expression of CAV1, tumor necrosis factor alpha (TNF-α), and the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB). CAV1 gene expression was associated with that of proinflammatory cytokines/chemokines, and their cognate receptor (r ≥ 0.447, p ≤ 0.030) but not with anti-inflammatory markers. CAV1 expression was correlated with CD163, indicating a prospective role for CAV1 in adipose inflammatory microenvironment. Unlike wild-type animals, mice lacking TNF-α exhibited reduced levels of CAV1 mRNA/proteins, which were elevated by administering exogenous TNF-α. Mechanistically, TNF-α induces CAV1 gene transcription by mediating NF-kB binding to its two regulatory elements located in the CAV1 proximal regulatory region. The interplay between CAV1 and TNF-α signaling pathway is interesting and has potential as a target for therapeutic interventions in obesity and metabolic syndromes.

The global threat of COVID-19 has led to the increasing use of metabolomics to study SARS-CoV-2 infection in humans and animals. Despite this, understanding SARS-CoV-2's metabolome during infection remains difficult and incomplete. Here, metabolic responses were characterized from sampled nasal washes collected from an asymptomatic ferret model (n = 20) at different time points before and after the SARS-CoV-2 challenge using an LC-MS-based metabolomics approach. Multivariate analysis of the nasal wash metabolome data resulted in several statistically significant features being observed. Despite no effects of gender or interaction between gender and time on the time course of SARS-CoV-2 infection, 16 metabolites were significantly different at every time point post-infection. Among these altered metabolites, the relative abundance of taurine was elevated post infection which could be an indication of hepatotoxicity, while the accumulation of sialic acids could indicate SARS-CoV-2 invasion. The pathway analysis identified several pathways influenced by SARS-CoV-2 infection. Of these, sugar, glycan, and amino acid metabolisms were the key altered pathways in the upper respiratory channel during infection. These findings provide some new insights into the progression of SARS-CoV-2 infection in ferrets at the metabolic level which could be useful for the development of early clinical diagnosis tools and new or repurposed drug therapies.

Increasingly, systems biology is gaining relevance in basic and applied research. The combination of computational biology with wet lab produces a synergy that results in an exponential increase in knowledge of biological systems. The study of microorganisms such as Staphylococcus epidermidis RP62A enables the researcher to understand better its metabolic network, which allows the design of effective strategies to treat infections caused by this species or others. S. epidermidis is the second cause of infection in patients with joint implants, so treating its proliferation seems vital for public health. There are different approaches to the analysis of metabolic networks. Flux Balance Analysis (FBA) is one of the most widespread streams. It allows the study of large metabolic networks, their structural properties, the optimization of metabolic flux, and the search for intervention strategies to modify the state of the metabolic network. This work presents the validation of the Staphylococcus epidermidis RP62A metabolic network model elaborated by Díaz-Calvo et al.. Then, we elaborate further on the network analysis’s essential reactions, classifying them. Finally, we introduce some proposals to intervene in the network and design knock-outs.

In proteomics, it is essential to quantify proteins in absolute terms if we wish compare results among studies and integrate high-throughput biological data into genome-scale metabolic models. While labeling target peptides with stable isotopes allows protein abundance to be accurately quantified, the utility of this technique is constrained by the low number of quantifiable proteins that it yields. Recently, label-free shotgun proteomics has become the “gold standard” for carrying out global assessments of biological samples containing thousands of proteins. However, this tool must be further improved if we wish to accurately quantify absolute levels of proteins. Here, we used different label-free quantification techniques to estimate absolute protein abundance in the model yeast Saccharomyces cerevisiae. More specifically, we evaluated the performance of seven different quantification methods, based either on spectral counting (SC) or extracted-ion chromatogram (XIC), which were applied to samples from five different proteome backgrounds. We also compared the accuracy and reproducibility of two strategies for transforming relative abundance into absolute abundance: a UPS2-based strategy and the total protein approach (TPA). This study mentions technical challenges related to UPS2 use and proposes ways of addressing them, including utilizing a smaller, more highly optimized amount of UPS2. Overall, three SC-based methods (PAI, SAF, and NSAF) yielded the best results because they struck a good balance between experimental performance and protein quantification.

Background: Nonalcoholic fatty liver disease (NAFLD) is regarded as a component of metabolic syndrome, which has insulin resistance (IR) as the primary physiopathological event. The aim of study was to establish the association between IR, assessed using triglyceride and glucose index (TyG), and histopathological features of NAFLD lesions. Methods: The study included patients with metabolic syndrome. Fasting plasma glucose (FPG), fasting lipid profiles and liver enzymes were measured. IR was assessed by TyG index. Liver biopsy was performed for assessment steatosis and fibrosis. Results: TyG index had a mean value of 8.93 ± 1.45, with a higher value in the patients with overweight (p=0.002) and obesity (p=0.004) than in the patients with normal weight. TyG index mean value of 8.78 ± 0.65 in subjects without NASH, 8.91 ± 0.57 in patients with borderline NASH and 9.13 ± 0.55 in patients with definite NASH. Significant difference was found between subjects without NASH and the ones with definite NASH (p=0.004). The analysis of the area under the ROC curve proved that TyG index is a predictor for NASH (p=0.043). Conclusion: TyG index is a facile tool used to identify individuals at risk for NAFLD, but not for the progression of liver lesions.

Members of the DUF34 (domain of unknown function 34) family, also known as the NIF3 protein superfamily, are ubiquitous across superkingdoms. Proteins of this family have been widely annotated as “GTP cyclohydrolase I type 2” through electronic propagation based on one study. Here, the annotation status of this protein family was examined through comprehensive literature review and integrative bioinformatic analyses that revealed varied pleiotropic associations and phenotypes. This analysis combined with functional complementation studies strongly challenges the current annotation and suggests that DUF34 family members may serve as metal ion insertases, chaperones, or metallocofactor maturases. This general molecular function could explain how DUF34 subgroups participate in highly diversified pathways such as cell differentiation, metal ion homeostasis, pathogen virulence, redox and universal stress responses.

One of the major challenges in the post-genomic era is elucidating the genetic basis of human diseases. In recent years, studies have shown that polygenic risk scores (PRS), based on aggregated information from millions of variants across the human genome, can estimate individual risk for common diseases. In practice, the current medical practice still predominantly relies on physiological and clinical indicators to assess personal disease risk. For example, caregivers mark individuals with high body mass index (BMI) as having an increased risk to develop type 2 diabetes (T2D). An important question is whether combining PRS with clinical metrics can increase the power of disease prediction in particular from early life. In this work we examined this question, focusing on T2D. We show that an integrated approach combining adult BMI and PRS achieves considerably better prediction than each of the measures on unrelated Caucasians in the UK Biobank (UKB, n=290,584). Likewise, integrating PRS with self-reports on birth weight (n=172,239) and comparative body size at age ten (n=287,203) also substantially enhance prediction as compared to each of its components. While the integration of PRS with BMI achieved better results as compared to the other measurements, the latter are early-life measurements that can be integrated already at childhood, to allow preemptive intervention for those at high risk to develop T2D. Our integrated approach can be easily generalized to other diseases, with the relevant early-life measurements.

Background: There is a strong comorbidity between mood disorders and metabolic syndrome (MetS). Increased levels of reactive oxygen and nitrogen species (RONS) and nitro-oxidative stress toxicity (NOSTOX) partially underpin this comorbidity.Aims: To examine the associations of RONS/NOSTOX biomarkers with MetS after adjusting for the significant effects of mood disorders (major depression, and bipolar type 1 and 2), generalized anxiety disorder (GAD), tobacco use disorder (TUD), and male sex.Methods: The study included subjects with (n=65) and without (n=107) MetS and measured levels of superoxide dismutase 1 (SOD1), lipid hydroperoxides (LOOH), nitric oxide metabolites (NOx), malondialdehyde (MDA), and advanced oxidation protein products (AOPP) and computed z unit-weighted composite scores which reflect RONS/NOSTOX. The study included 105 patients with mood disorders, 46 with GAD, and 95 with TUD.Results: MetS was associated with increased levels of MDA and AOPP, independently from mood disorders, TUD, sex and GAD. Atherogenicity and insulin resistance (IR) were significantly associated with a NOSTOX composite score. Mood disorders, TUD, GAD, male sex and MetS independently contribute to increased RONS/NOSTOX. The RONS/NOSTOX profile of MetS was different from that of GAD, which showed increased SOD1 and NOx levels. TUD was accompanied by increased SOD1, LOOH and MDA, and male sex by increased LOOH and AOPP.Conclusions: MetS is characterized by increased lipid peroxidation with aldehyde formation and chlorinative stress, and atherogenicity and IR are strongly mediated by RONS/NOSTOX. Partially shared RONS/NOSTOX pathways underpin the comorbidity of MetS with mood disorders, GAD, and TUD.

Non-alcoholic fatty liver disease (NAFLD) continues to rise and has become the most common cause of chronic liver disease among all ages and ethnicities. Metabolic disorders such as obesity and insulin resistance are closely associated with sarcopenia and NAFLD. Sarcopenic obesity is a clinical disorder characterized by the simultaneous loss of skeletal muscle and gain of adipose tissue. It is associated with worse outcomes in individuals with NAFLD. It is projected that NAFLD and sarcopenia will rise as the prevalence of obesity continues to increase at an unparallel rate. Recently, sarcopenia and sarcopenic obesity have gained considerable interest, but we still lack a well-defined definition and a management approach. Therefore, it is imperative to continue shining the light on this topic and better understand the underlying mechanism as well as treatment options. In this review article, we aimed to address the pathophysiology, impact, and outcomes of sarcopenic obesity on NAFLD.

Fibroblasts, the most abundant cells in the connective tissue, are key modulators of the extracellular matrix (ECM) composition. These spindle-shaped cells are capable of synthesizing various extracellular matrix proteins and collagen. They also provide the structural framework (stroma) for tissues and play a pivotal role in the wound healing process. While they are maintainers of the ECM turnover and regulate several physiological processes, they can also undergo transformations responding to certain stimuli and display aggressive phenotypes that contribute to disease pathophysiology. In this review, we focus on the metabolic pathways of glucose and highlight metabolic reprogramming as a critical event that contributes to the transition of fibroblasts from quiescent to activated and aggressive cells. We also cover the emerging evidence that allows us to draw parallels between fibroblasts in autoimmune disorders and more specifically in rheumatoid arthritis and cancer. We link the metabolic changes of fibroblasts to the toxic environment created by the disease condition and discuss how targeting of metabolic reprogramming could be employed in the treatment of such diseases. Lastly, we discuss Systems Biology approaches, and more specifically, computational modelling, as a means to elucidate pathogenetic mechanisms and accelerate the identification of novel therapeutic targets.

This purpose was to compare the ability of body shape index (ABSI) and body roundness index (BRI) with waist circumference (WC), body mass index (BMI), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR) and body adiposity index (BAI) to predict metabolic risk. The cross-sectional study was conducted in 17,360 Chinese subjects (were aged 18-95 years old) who escaped cardiovascular disease (CVD) or diabetes. Biochemical and anthropometric variables were measured by trained staff. Receiver operating characteristic curve (ROC) and optimal cutoff values of obesity indices were recruited to compare the predictive ability for metabolic risk factors. The mean age of subjects was 53.7(13.1) years, 41.6 % were males. Within young group (<60 years), the areas under the curve (AUC) demonstrated that WC, BMI, WHR, WHtR and BRI were able to similarly predict high metabolic risk in males (0.74 vs. 0.74 vs. 0.73 vs. 0.73 vs. 0.73) and in females (0.73 vs. 0.73 vs. 0.71 vs. 0.73 vs. 0.73), while the approximate predictive ability were only acquired in males (0.73 vs. 0.73 vs. 0.70 vs. 0.73 vs. 0.73) within elder group (≥60 years). The optimal cut-off values of BRI for high metabolic risk were calculated in males (<60 y: 3.49 vs. ≥60 y: 3.46) and females (<60 y: 3.47 vs. ≥60 y: 3.60). Meanwhile, BRI displayed a strong prediction to elevated BP and elevated TG in males (AUC = 0.64; AUC = 0.70) and to elevated BP, elevated TG and elevated SUA in females (AUC = 0.67; AUC = 0.69; AUC =0.70). BRI was able to similarly predict high metabolic risk compared to WC, BMI, WHR, WHtR and BAI, while ABSI was not. Moreover, BRI revealed specific predictive ability for elevated BP, elevated TG and elevated SUA.

Introduction. The use of probiotics demonstrate efficacy against obesity and metabolic syndrome (MetS). Detection effective probiotic strains for hyperglycemia and immunity associated with is important task. The aim of the study was to evaluate an influence of Lactobacillus casei IMV B-7280 separately and composition L. casei IMV B-7280 / Bifidobacterium animalis VKB / B. animalis VKL on the levels of blood glucose and immunity in obese mice. Meterials and methods. Obesity was induced by fat-enriched diet (FED) in male BALB/c mice. Obese mice were transferred to standard diet and received per os probiotic strains daily during 10 days. We measured tumor necrosis factor-a (TNF-a) in blood serum using enzyme-linked immunosorbent assay and functional activity of peritoneal exudate macrophages (PEMs). Glucose levels in blood was defined with glucometer. Results. We ascertained that all probiotic strains induced reducing mice weight and visceral fat, normalization of TNF-a production and functional activity of PEMs. Treatment with L. casei IMV B-7280 was associated with decreasing blood glucose levels. No normalization of glucose and TNF-a levels in obese mice, transferred to standard diet without probiotic treatment, although we revealed decreasing their weight and visceral fat and partial recover of functional activity of PEMs. Conclusions. Probiotic strain L. casei IMV B-7280 (separately) and composition L. casei IMV B-7280 / B. animalis VKB / B. animalis VKL can re-equilibrate metabolic and inflammation indices in mouse obesity model. L. casei IMV B-7280 alone was more efficient in decreasing glucose levels than composition of strains.

The aim of this article is to summarize recent bioinformatic and statistical developments applicable to NMR-based metabolomics. Extracting relevant information from large multivariate datasets by statistical data analysis strategies may be of considerable complexity. Typical tasks comprise for example classification of specimens, identification of differentially produced metabolites, and estimation of fold changes. In this context it is of prime importance to minimize contributions from unwanted biases and experimental variance prior to these analyses. This is the goal of data normalization. Therefore, special emphasize is given to different data normalization strategies. In the first part, we will discuss the requirements and the pros and cons for a variety of commonly applied strategies. In the second part, we will concentrate on possible solutions in case that the requirements for the standard strategies are not fulfilled. In the last part, very recent developments will be discussed that allow reliable estimation of metabolic signatures for sample classification without prior data normalization. In this contribution special emphasis will be given to techniques that have worked well in our hands.

Metabolic disorders have become among the most serious threats to human health, leading to severe chronic diseases such as obesity, type 2 diabetes, non-alcoholic fatty liver disease, as well as cardiovascular diseases. Interestingly, despite the fact that each of these maladies has different physiological and clinical symptoms, they appear to share certain pathological traits such as intracellular stress and inflammation induced by metabolic derangements stemmed from over nutrition frequently aggravated by modern sedentary life style. These modern ways of living inundate cells and organs with saturating levels of sugar and fat, leading to glycotoxicity and lipotoxicity that induce intracellular stress signaling ranging from oxidative to ER stress response to cope with the metabolic insults [1]. In this review, we discuss the roles played by cellular stress and its responses in shaping metabolic disorders. We have summarized here current mechanistic insights explaining the pathogenesis of these disorders. These are followed by a discussion of the latest therapies targeting the stress response pathways.

Carbonic anhydrases (CAs) are metalloenzymes that are omnipresent in nature. The CAs catalyze the basic reaction of reversible hydration of CO₂ to HCO₃⁻ and H⁺ in all living organisms. Photosynthetic organisms contain six evolutionarily different classes of CAs, namely, α-CAs, β-CAs, γ-CAs, δ-CAs, ζ-CAs, and θ-CAs. Many of the photosynthetic organisms contain multiple isoforms of each CA family. Model alga, Chlamydomonas reinhardtii contains fifteen CAs belonging to three different CA gene families. Out of the fifteen CAs, three belong to α-CA gene family, nine to β-CA gene family, and three are γ-CAs. The multiple copies of the CAs in each gene family may be due to gene duplications within the particular CA gene family. The CAs of Chlamydomonas reinhardtii are localized in different subcellular compartments of this unicellular alga. The presence of a large number of CAs and their diverse subcellular localization within a single cell suggests the importance of these enzymes in metabolic and biochemical roles they perform in this unicellular alga. In the present review, we update the information on molecular biology of all the fifteen CAs and their metabolic and biochemical roles in Chlamydomonas reinhardtii. We also present a hypothetical model showing the known functions of CAs and predicting the functions of CAs for which precise metabolic roles are yet to be discovered.

Ferroptosis, a form of regulated cell death characterized by lipid peroxidation and iron accumulation, has been implicated in the progression of metabolic dysfunction-associated steatohepatitis (MASH) in obesity. This study investigated the role of ferroptosis in the development of hepatic steatosis and MASH in obese mice and assessed the therapeutic potential of ferrostatin-1, a ferroptosis inhibitor. C57BL/6J wild-type mice (n = 8) and ob/ob (n = 16) were maintained on a standard chow diet. Mice were divided into three groups that included C57BL/6 (n = 8), ob/ob (n = 8), and ob/ob + ferrostatin-1 (FER) (n = 8), with the latter group receiving an intraperitoneal injection of 5 μM/kg ferrostatin three times per week for eight weeks. Following treatment, serum and tissue samples were collected for analysis. Significant hepatic steatosis and increased lipogenesis markers were observed in ob/ob mice, and this was normalized in the ob/ob + FER group treated with ferrostatin-1. Elevated oxidative stress was indicated by increased reactive oxygen species (ROS) and Malondialdehyde (MDA) levels in the ob/ob group, while glutathione peroxidase 4 (GPX4) activity was significantly reduced. Ferrostatin-1 treatment decreases MDA levels and restores GPX4 activity. Additionally, ferrostatin mitigates iron overload and promotes macrophage polarization from M1 to M2, thereby reducing liver inflammation and fibrosis. Ferrostatin treatment reversed mitochondrial dysfunction in ob/ob mice Our findings revealed that ferroptosis plays a significant role in the progression of obesity to hepatic steatosis and MASH. Inhibiting ferroptosis using ferrostatin-1 effectively improves liver histology, reduces oxidative stress, normalizes lipogenesis, and modulates macrophage polarization. This study highlights the potential of targeting ferroptosis as a therapeutic strategy for obesity-related liver diseases, warranting further investigation in clinical settings.

Anthocyanins are well known as colorants of flowers, but many other invisible functions might have been more important during the evolution of complex biosynthesis networks in plants. The number of anthocyanin decorating enzymes, the subtle control of structural genes by numerous transcription factors, and routes of intracellular anthocyanin transport are reviewed here. Various ecological functions of anthocyanins hold the key to understanding evolutionary trajectories that lead to the success of these pigments. Proposed functions include carbon sinks that prevent excessive sugar levels, sun blockers protecting the photosynthesis apparatus, antioxidants scavenging reactive oxygen species, providing camouflage, and attraction of pollinators and seed dispersers. Anthocyanins clearly fulfill different functions in different plant organs. It is currently believed that protective functions in leaves gave rise to the biosynthesis network and that flower and fruit coloration evolved later.

The aim of this study was to investigate the differentially expressed genes associated with intramuscular fat deposition in the longissimus dorsi muscle of Xinjiang Brown Bulls. The longissimus dorsi muscles of 42 Xinjiang Brown Bulls were selected under the same feeding conditions. The intramuscular fat content of muscle samples were determined by Soxhlet extraction method, from which 5 samples with high intramuscular fat content (HIMF group) and 5 samples with low intramuscular fat content (LIMF group) were selected. It was found that the intramuscular fat content of HIMF group was 46.054% higher than that of LIMF group. Muscle samples produced by paraffin section for morphological observation. It was found that the fat richness of the HIMF group was better than that of the LIMF group. Transcriptome sequencing technology was used to analyze the gene expression differences of longissimus dorsi muscle. Through in-depth analysis of the longissimus dorsi muscle by transcriptome sequencing technology, we screened a total of 165 differentially expressed genes. The results of Gene Ontology (GO) enrichment analysis showed that the differentially expressed genes in the two groups were mainly clustered in biological pathways related to carbohydrate metabolic processes, redox processes and oxidoreductase activities. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that the differentially expressed genes were significantly clustered in 15 metabolic pathways, which mainly covered fatty acid metabolism (related to lipid metabolism and glucose metabolism), pentose phosphate pathway, Peroxisome Proliferator-Activated Receptors (PPAR) signalling pathway and other important metabolic processes. The three genes that were predominantly enriched in the glycolipid metabolic pathway by analysis were SCD5, CPT1C, and FBP2, all of which directly or indirectly affect intramuscular fat deposition. In summary, the present study investigated the differences in gene expression between high and low intramuscular fat content in the longissimus dorsi muscle of Xinjiang Brown Bulls by transcriptome sequencing technology, and revealed the related signalling pathways. Therefore, we hypothesized that SCD5, CPT1C, and FBP2 were the key genes responsible for the significant differences in intramuscular fat content of the longissimus dorsi muscles in a population of Xinjiang Brown Bulls. We expect that these findings will provide fundamental support for subsequent studies exploring key genes affecting fat deposition characteristics in Xinjiang Brown Bulls.

Carbamate insecticides have been used for over four decades to control brown planthopper, Nilaparvata lugens, but resistance has been reported in many countries, including Korea. The test results on resistance to fenobucarb showed that the LC₅₀ values were 3.08 for the susceptible strain, 10.61 for the 2015 population, and 73.98 for the 2019 population. Compared to the susceptible strain, the 2015 and 2019 populations exhibited resistance levels 3.4 and 24.2 times higher, respectively. To elucidate the reason for the varying levels of resistance to fenobucarb in these populations, mutations in the ace1 gene, the target site of carbamate, were investigated, but no previously reported mutations were confirmed. Through RNAseq analysis focusing on the expression of detoxification enzyme genes as an alternative resistance mechanism, it was found that the carboxylesterase gene Nl-EST1 was overexpressed 2.4 times in the 2015 population and 4.7 times in the 2019 population compared to the susceptible strain. This indicates a strong correlation between the level of resistance development in each population and the expression level of Nl-EST1. Previously, Nl-EST1 was reported in an organophosphorus insecticide-resistant strain of Sri Lanka 2000. Thus, Nl-EST1 is crucial for developing resistance to organophosphorus and carbamate insecticides. Resistance-related genes such as Nl-EST1 could serve as expression markers for resistance diagnosis, and it can apply to integrated resistance management of N. lugens.

Metabolic syndrome (MS), a complex pathology with features like abnormal body fat distribution, insulin resistance, and dyslipidaemia, contributes to higher cardiovascular (CV) risk. A cross-sectional study including 87 individuals, assessed CV risk in elderly patients with type 2 diabetes and MS in Algarve, Portugal. The 10-year CV risk was estimated using the ADVANCE risk score calculator. The reductions in CV risk were estimated by adjusting the data inputted on the online tool to achieve systolic blood pressure (SBP) <130 or <120 mmHg, and LDL-cholesterol <70 mg/dL. Beyond waist circumference, the mean number of clinical features of MS was 3.14±0.84, without significant sex differences. The mean CV risk was 22.5% (CI: 20.3-24.7). Sex-specific analysis showed higher risk in males (24.2%, CI: 21.3-27.0) vs. females (19.7%, CI: 16.2-23.3; p=0.028). Hypothetical risk reductions show that lowering SBP to <130 mmHg could significantly lower the risk by an average of 9.2% (CI: 7.7-10.7), whereas 34.5% of the participants would be out of the diagnostic criteria for MS. When comparing each potential intervention with current risk, all interventions significantly reduce the 10-years CV risk. The study highlights the potential of blood pressure control in reducing CV risk and the importance of multifaceted risk reduction strategies.

Abstract Background: Metabolic syndrome (MetS) is a complex disorder characterized by insulin resistance (IR), central obesity, atherogenic dyslipidemia and higher glucose levels. It increases the risk of cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM), imposing an economic burden on the healthcare system. However, the historical origins of MetS as well as the development and evolution of its definitions have not been conclusively documented in the literature. Aim: This study seeks to enhance the understanding of the developmental trends of MetS during the preceding two decades, placing particular emphasis on the definition, diagnosis and prevalence. Methods: An extensive search was performed from 1920 to 2023 across prominent scientific research engines, including Scopus, PubMed, MDPI, and others. Results: Despite advancements, many aspects of MetS remain inadequately understood. As the understanding of the nature and pathophysiology of MetS progresses, the development and refinement of its diagnostic criteria, and assessment and treatment guidelines will continue. Additionally, there exists significant variation in the global prevalence of metabolic syndrome, ranging from 14 to 39%. This prevalence is projected to increase due to the adoption of less healthy dietary patterns and sedentary lifestyles. The observed disparities in metabolic syndrome prevalence can be attributed to multiple factors, including demographic characteristics. Furthermore, the lack of a standardized definition across studies also contributes to the variation in reported prevalence rates. Conclusion: Further studies focusing on the standardization of the MetS definition across different research are crucial. The establishment of consistent criteria would enhance the reliability and validity of research findings, enabling more meaningful comparisons and interpretations.

We report the case of a four-year-old male patient with a complex medical history born prematurely as the result of intrauterine growth restriction due to placental insufficiency. His clinical manifestations include severe neurodevelopmental deficits, global developmental delay, Pierre-Robin sequence, and intractable epilepsy with both generalized and focal features. The proband’s low levels of citrulline and lactic acidosis provoked by administration of depakoke are evocative of a mitochondrial etiology. However, the genotype-phenotype correlation remains undefined in the absence of nuclear and mitochondrial pathogenic variants detected by deep sequencing of both genomes. However, live-cell mitochondrial metabolic investigations provide evidence of a deficient oxidative phosphorylation pathway responsible for ATP synthesis, leading to chronic energy crisis in the proband. In addition, our metabolic analysis reveals metabolic plasticity in favor of glycolysis for ATP synthesis. Our mitochondrial morphometric analysis by transmission electron microscopy confirms the suspected mitochondrial etiology, as the proband’s mitochondria exhibit an immature morphology with poorly developed and rare cristae. Thus, our results support the concept that sub-optimal levels of intrauterine oxygen and nutrients alter fetal mitochondrial metabolic reprogramming toward OXPHOS leading to a deficient postnatal mitochondrial energy metabolism. In conclusion, our collective studies shed light on the long-term postnatal mitochondrial pathophysiology caused by intrauterine growth restriction due to idiopathic placental insufficiency and its negative impact on the energy-demanding development of fetal and postnatal brain.

Osteoarthritis (OA) is a pathology of great impact worldwide which its physiopathology is not completely known and usually diagnosed by imaging techniques performed at advanced stages of the disease. The aim of this study was to evaluate early serum metabolome changes and identify the main metabolites involved in an inflammatory OA animal model. The study was performed with thirty rats, OA in all animals was induced by intra-articular injection of monoiodoacetate into the knee joint. Blood samples were taken from all animals and analyzed by mass spectrometry before OA induction, and 28, 56 and 84 days following induction. Histological study confirmed OA in all samples. The results of this study allow the identification of several changes in the serum metabolome over time, including organic acids, benzenoids, heterocyclic compounds and lipids at T28, organic acids at T56 and lipid classes at T84. We conclude that OA induces serological changes in the metabolome and, more specifically, 18 metabolites which could serve as potential biomarkers. However, it was not possible to establish a relationship between the identified metabolites and the time at which the samples were taken. Therefore, these findings should be confirmed in future OA studies.

Increasing evidence of sexual dimorphism in pathophysiology of metabolic complications caused by sex steroids is under investigation. The gut microbiota represents a complex microbial ecosystem involved in energy metabolism, immune response, nutrition acquisition, and health of host organisms. Gender-specific differences in composition are present between females and males. The purpose of this study was to use cross-sex fecal microbiota transplantation (FMT) for the detection of sex-dependent metabolic, hormonal, and gut microbiota changes in female and male recipients. Healthy non-obese female and male Wistar rats were divided into donor, same-sex, and cross-sex recipient groups. After a 30-day period of FMT administration, biochemical markers (glucose and lipid metabolism) and sex hormones were measured and gut microbiota was analyzed. Cross-sex male recipients displayed significantly lower testosterone concentration compared to males that received same-sex FMT. Sex-dependent changes caused by cross-sex FMT were detected, while several bacterial taxa correlated with plasma testosterone levels. This study represents the first to study the effect of cross-sex changes in the gut microbiome concerning metabolic and hormonal changes/status in adult non-obese Wistar rats. Herein, we present the cross-sex FMT as a potential tool to modify sex-specific pathologies.

Soil improvement methods can result in changes in the microbial community in blueberry soil. However, there have been few reports on the impacts of different soil improvement methods on the microbial function, particularly on endophytic microbe. In this study, we analyzed the response of microbial community composition, microbial function and nitrogen (N) cycle to different improvement methods using high throughput sequencing. We aimed to investigate the best soil improvement method from a microbial perspective. The results showed that the highest microbial diversity was observed in the T4 treatment (peat combined with mushroom bran), followed by the T2 treatment (peat combined with acidified rice husk) both in the rhizosphere and roots. The dominant phyla were Proteobacteria and Actinobacteria, which were most abundance in the T4 and T1 (peat combined with sulfur) treatments in the rhizosphere soil, respectively, but showed the opposite trend in the root endophytic bacterial community. Interestingly, Acidobacterium and Paludibaculum, belonging to the Acidobacteria phylum, were found to have the highest influence according to the correlation network analysis. And these bacteria were most abundant in the T2 treatment in the rhizosphere soil. The rhizosphere soil microbial communities were clustered into two categories: one for T1 and T2 treatments, and another for T3 (mushroom bran) and T4 treatments. Compared to the other treatments, the T1 treatment had the most significant impact on microbial functional pathways in the blueberry roots. T2 treatment promoted the growth of N fixation functional bacteria both in the rhizosphere soil and roots. At the module level, the T2 treatment increased the relative abundance of N fixation and decreased the relative abundance of assimilating nitrate reduction reaction (ANRA), dissimilating nitrate reduction reaction (DNRA), denitrification and completed nitrification in the blueberry rhizosphere soil. Additionally, the T2 treatment increased the abundance of root endophytic microbes involved in N fixation. Overall, our findings suggest that the addition of peat combined with acidified rice husk is the optimal soil improvement method for blueberry cultivation.

Recently, we isolated and characterized a new pool of mesenchymal stem cells- HPC (Hoof Progenitor Cells), which reside in the coronary corium of equine hooves. We hypothesize, that due to their location, HPC may be involved in the pathogenesis of laminitis, and could possibly be utilized in its treatment. The aim of this study was to compare the newly described HPC to a well-established cell pool-ASC (Adipose Stem Cells). The two cell populations were maintained either in standard culture conditions or under a hyperinsulinemic milieu as hyperinsulinemia is often observed alongside laminitis. Cell cycle dynamics, mitochondrial membrane potential and oxidative stress were analyzed with microcapillary cytometry. Furthermore, the expression of key markers of mitochondrial metabolism, oxidative stress, apoptosis, immunomodulation and insulin signalling were analyzed with the RT-qPCR method. Additionally, a selected panel of miRNA was analyzed with the RT-qPCR method. In standard culture conditions, ASC exhibit higher proliferation than HPC while in hyperinsulinemia a shift towards S phase was observed in both populations. As for the mitochondrial membrane potential, in standard culture conditions, HPC was characterized by a higher percent of live cells. Hyperinsulinemia did not strongly affect the mitochondrial membrane potential of the analyzed populations. Our findings indicate that HPC are characterized by higher activity in terms of mitochondrial dynamics, mitophagy, and mitochondrial biogenesis under standard culture conditions. Yet in both populations, a diminished mitochondrial dynamic and metabolism was observed in hyperinsulinemia. The analysis of oxidative stress revealed, that HPC might possess somewhat higher resistance towards oxidative stress than ASC. Minimal change was observed in the expression of key markers of apoptosis in ASC and HPC under hyperinsulinemia. The analysis of key immunomodulatory markers indicated that HPC may help the cytokine storm for a more effective phenotype change to an immunosuppressing pool of cells with better migratory and healing abilities under hyperinsulinemia than ASC. As for insulin signalling, the obtained data suggests that HPC might be more resistant to hyperinsulinemia and may have greater therapeutic potential in reducing laminitis. Obtained results demonstrated that HPC possesses better potential to modulate the PTEN-AKT pathway by miR-21 and reverse high glucose and high insulin-induced insulin resistance. Taken together, the obtained results indicate that HPC may be a very promising cell pool with therapeutic potential in laminitis treatment, and could be more effective than ASC.

Polycystic ovary syndrome (PCOS) is increasingly being viewed as an evolutionary mismatch disorder that manifests in women after exposure to a range of lifestyle and environmental factors. Although there is ongoing debate regarding the pathogenesis, international guidelines recommend lifestyle treatment, with diet and exercise, as the first line of management in all women with PCOS. In addition, accumulating evidence suggests that environmental factors such as endocrine disrupting chemicals (EDC) may be involved in the pathogenesis of PCOS due to their known hormonal and metabolic effects. As a result, international professional bodies have recommended that all pregnant women be advised of the risks of EDC and that education programs be developed to inform health professionals. Microparticulate air pollution (MAP) is also a significant environmental exposure that has been associated with a variety of chronic diseases, including PCOS. We performed a systematic review of studies examining the relationship between MAP and PCOS using the PRISMA methodology. The review identified 214 records from PubMed, Cochrane, and Scopus databases, and 4 studies that met the inclusion criteria for qualitative assessment. Preliminary data suggest that MAP may contribute to the pathogenesis of PCOS via a number of mechanisms. This review highlights the need for greater awareness and further research on the effects of MAP in women with PCOS.

Adenylosuccinic acid (ASA) is a small molecule dicarboxylate that could be a strong clinical development candidate for inherited myopathies involving dysregulated purine nucleotide metabo-lism. Currently, there are no published pharmacokinetic/dynamic or toxicology data available, albeit 10-year clinical trial data in Duchenne muscular dystrophy patients suggests a chronically safe drug. In this study, we tested the toxicity of ASA to cultured myoblasts in vitro and acute systemic toxicity in mice. ASA is a non-toxic small molecule with an LD50> 5000mg/kg. Some background necrotic foci in the liver, kidney and gastrointestinal tract were shown that are likely incidental but warrant follow-up sub-/chronic oral exposure studies.

An impaired healing response underlies diabetic foot wounds chronicity, frequently translating in amputation, disability, and early mortality. In addition, diabetics frequently suffer of the underappreciated episode of post-epithelization ulcer recurrence. Recurrence epidemiological data are alarmingly high; so that the ulcer is considered in “remission” and not healed for the time it remains epithelialized. Recurrence may result from the conspiracy of behavioral and biological factors. Although the damaging role of behavioral, clinical predisposing factors is undebatable, the role of endogenous biological signalers that prime the residual scar tissue to recurrence has remained elusive. We propose that ulcer recurrence is deeply impinged by chronic hyperglycemia and its downstream biological effectors, which originate epigenetic drivers that enforce abnormal pathologic phenotypes to dermal fibroblasts, and keratinocytes as memory cells. Hyperglycemia-derived cytotoxic reactants accumulate and modify dermal proteins, reduce scar tissue mechanical tolerance, and disrupt fibroblasts-secretory activity. Accordingly, the combination of epigenetic and local and systemic cytotoxic signalers, induce the onset of “at-risk phenotypes” as premature skin cells aging, dysmetabolism, inflammatory, pro-degradative, and oxidative programs that may ultimately converge to scar cells demise. Unfortunately, post epithelialization recurrence rates data are missing in clinical studies of accepted ulcer healing therapies during follow-up periods. Intra-ulcer infiltration of epidermal growth factor exhibits the most consistent remission data with the lowest recurrences during 12-month follow-up. Recurrence data should be regarded as a valuable clinical endpoint during the investigational period for each emergent healing candidate.

Background: Hepatic erythrophagocytosis is augmented in NASH and amplifies inflammation and fibrosis. Although various pro-phagocytic signals have been identified on erythrocytes of NASH patients, the role of bound thrombospondin-1 (TSP-1), which acts as an “eat-me” signal, arginase-1, which regulates the levels of nitric oxide in erythrocytes, and phosphatidylethano-lamine (PE) which can amplify erythrophagocytosis and hepatic inflammation have not been explored. Hence, we sought to investigate the levels of arginase-1 and TSP-1 in erythrocyte lysate and PE in erythrocyte membranes of NASH patients. Methods: Twenty-four patients and 14 healthy controls participated in our study. The levels of TSP-1 and arginase were quantified by ELISA in erythrocyte lysates, and the levels of PE in erythrocyte membranes by thin layer chro-matography. Results: Erythrocytes of NAFLD patients exhibit lower levels of arginase-1 and TSP-1 (p<0.01). Erythrocyte-bound TSP-1 levels correlated with the levels of erythrocyte surface CD47. Phosphatidylethanolamine was increased in erythrocytes of NASH patients and was accompanied by increased release, indicating exposure. Conclusion: Our results imply reduced TSP-1 binding by erythrocytes which could allow free TSP-1 molecules to act on macrophages, enhancing erythrophagocytosis. Increased PE which could amplify inflammation after efferocytosis, while downregulation of arginase-1 could lead to defective efferocytosis.

Apicomplexan infections, such as giardiasis and cryptosporidiosis, negatively impact a considerable proportion of human and commercial livestock populations. Despite this, the molecular mecha-nisms of disease, particularly the effect on the body beyond the gastrointestinal tract, are still poorly understood. To highlight host-parasite-microbiome biochemical interactions, we utilised integrated metabolomics-16S rRNA genomics and metabolomics-proteomics approaches in a C57BL/6J mouse model of giardiasis and compared these to Cryptosporidium and uropathogenic Escherichia coli (UPEC) infections. Comprehensive samples (faeces, blood, liver, and luminal contents from duo-denum, jejunum, ileum, caecum and colon) were collected 10 days post infection and subjected to proteome and metabolome analysis by liquid and gas chromatographic mass-spectrometry, re-spectively. Microbial populations in faeces and luminal washes were examined using 16S rRNA metagenomics. Proteome-metabolome analyses indicated that 12 and 16 key pathways were sig-nificantly altered in the gut and liver, respectively, during giardiasis with respect to other infections. Energy pathways including glycolysis and supporting pathways of glyoxylate and dicarboxylate metabolism, and redox pathway of glutathione metabolism, were upregulated in small intestinal luminal contents and the liver during giardiasis. Metabolomics-16S rRNA genetics integration in-dicated that populations of three bacterial families –Autopobiaceae (Up), Desulfovibrionaceae (Up) and Akkermanasiaceae (Down) – were most significantly affected across the gut during giardiasis, causing upregulated glycolysis and short-chained fatty acid (SCFA) metabolism. In particular, the perturbed Akkermanasiaceae population seemed to cause oxidative stress responses along the gut-liver axis. Overall, the systems biology approach applied in this study highlighted that the effects of host-parasite-microbiome biochemical interactions extended beyond the gut ecosystem to the gut-liver axis. These findings form the first steps in a comprehensive comparison to ascertain the major molecular and biochemical contributors of host-parasite interactions and contribute towards the development of biomarker discovery and precision health solutions for apicomplexan infections.

Each individual has a unique gut microbiota; therefore the genes in our microbiome outnumber the genes in our genome by about 150 to 1. Perturbation in host nutritional status influences gut microbiome composition and vice versa. The gut microbiome can help in producing vitamins, hormones, and other active metabolites that support the immune system; harvest energy from food; aid in digestion; protect against pathogens; improve gut transit and function; send signals to the brain and other organs, oscillating the circadian rhythm and coordinate with host metabolism through multiple cellular pathways. Gut microbiota can be influenced by host genetics, medications, diet, and lifestyle factors from preterm to aging. So before prescribing a customized treatment, it is crucial to monitor and count the gut flora as a focused biomarker. Many nutritional approaches that have been developed help in maintaining and restoring an optimal microbiome such as specific diet therapy, nutrition interventions and customized eating patterns. One of these approaches is time-restricted feeding/eating (TRF/E), a type of intermittent fasting (IF) in which a subject abstains from food intake for a specific time window. Such a dietary modification might alter and restore the gut microbiome for proper alignment of cellular and molecular pathways throughout the lifespan. In this review, we have highlighted that gut microbiota would be a targeted biomarker and TRF/E would be a targeted approach for restoring the gut microbiome associated molecular pathways like hormonal signaling, the circadian system, metabolic regulators, neural responses, and immune-inflammatory pathways. Consequently, modulation of gut microbiota through TRF/E could contribute in proper utilization and availability of the nutrients and in this way confer protection against diseases for harnessing personalized nutrition approaches to improve human health.

Cytochrome P450 oxidoreductase (POR) is the redox partner of steroid and drug-metabolizing cytochromes P450 located in the endoplasmic reticulum. Mutations in POR cause a broad range of metabolic disorders. The POR variant rs17853284 (P228L) identified by genome sequencing has been linked to lower testosterone levels and reduced P450 activities. We expressed POR wild type and the P228L variant in bacteria, purified the proteins, and performed protein stability and catalytic functional studies. Variant P228L affected the stability of the protein as evidenced by lower unfolding temperatures and higher sensitivity to urea denaturation. A significant reduction of small molecule metabolism was observed with POR P228L while activities of CYP3A4 were reduced by 25%, and activities of CYP3A5, and CYP2C9 were reduced by more than 40% compared to WT POR. The 17,20 lyase activity of CYP17A1 responsible for production of main androgen precursor dehydroepiandrosterone, was reduced to 27% of WT in presence of P228L variant of POR. Based on in silico and in vitro studies we predict that the change of proline to leucine may change the rigidity of the protein, causing conformational changes in POR, leading to altered electron transfer to redox partners. A single amino acid change can affect protein stability and cause a severe reduction in POR activity. Molecular characterization of individual POR mutations is crucial for a better understanding of the impact on different redox partners of POR.

The Metabolic Food Waste [MFW (kg of food)], first time developed in 2016 as a new indicator by Serafini and Toti, indicates the amount of food consumed over the nutritional requirements and the impact of this overconsumption on the environment. It is necessary to identify the causes and to develop potential methods to prevent and reduce MFW, at the same time with increasing consumer awareness about unsustainable diets and changing diet habits toward more environmentally conscious consumption patterns. By analysing and corroborating external data available for food waste, nutritional requirements, environmental impact of food waste and consumer behaviour, we identified as primary causes for MFW the lack of nutritional education and little understanding of the nutritional requirements amongst all categories of consumers, no access to appropriate food resources or reduced availability of fresh produced food. We conclude that for the quantification of the negative impact of MFW on both the environment and human health, we need a decisive action to raise consumer awareness for healthy and sustainable diets, together with an uniform worldwide distribution of the nutritious food.

Olfactory Receptors (ORs) are a large family of G protein coupled receptors predominantly expressed by the main olfactory epithelium at nasal level and are responsible for the generation of smelling sense. Microarray and deep sequencing analyses, however, have demonstrated that ORs are ectopically expressed in various human tissues including testis, kidneys, adipose tissue and liver and their biological functions become to be unrevealed. Molecular and pharmacological approaches have shown that some of these ORs modulate glucose and lipid metabolism at multiple interfaces, suggesting that ORs might be part of the large family of nutrient sensors. i.e. molecular/ cellular machines that respond to a specific nutrient component. By using nutrients- derived agonists it has been shown that ORs effectively modulates glucose and lipid metabolism raising interest on their possible therapeutic application in the treatment of metabolic disorders including dyslipidemia, obesity and metabolic syndrome.

Staphylococcus aureus is a high-priority pathogen causing severe infections with high morbidity and mortality worldwide. Many S. aureus strains are methicillin-resistant (MRSA) or even multi-drug resistant. It is one of the most successful and prominent modern pathogens. An effective fight against S. aureus infections requires novel targets for antimicrobial and antistaphylococcal therapies. Recent advances in whole-genome sequencing and high-throughput techniques facilitate the generation of genome-scale metabolic models (GEMs). Among the multiple applications of GEMs is drug-targeting in pathogens. Hence, comprehensive and predictive metabolic reconstructions of S. aureus could facilitate the identification of novel targets for antimicrobial therapies. This review aims at giving an overview of all available GEMs of multiple S. aureus strains. We downloaded all 114 available GEMs of S. aureus for further analysis. The scope of each model was evaluated, including the number of reactions, metabolites, and genes.Furthermore, all models were quality-controlled using Mᴇᴍᴏᴛᴇ, an open-source application with standardized metabolic tests. Growth capabilities and model similarities were examined. This review should lead as a guide for choosing the appropriate GEM for a given research question. With the information about the availability, the format, and the strengths and potentials of each model, one can either choose an existing model or combine several models to create models with even higher predictive values. This facilitates model-driven discoveries of novel antimicrobial targets to fight multi-drug resistant S. aureus strains.

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and the third-leading cause of cancer-related mortality. Currently, the global burden of nonalcoholic fatty liver disease (NAFLD) has dramatically overcome both viral and alcohol hepatitis thus becoming the main cause of HCC incidence. NAFLD pathogenesis is severely influenced by lifestyle and genetic predisposition. Mitochondria are highly dynamic organelles which may adapt in response to environment, genetics and epigenetics in the liver (“mitochondrial plasticity”). Mounting evidence highlighted that mitochondrial dysfunction due to loss of mitochondrial flexibility, may arise before overt NAFLD and since the early stages of liver injury. Mitochondrial failure not only promotes hepatocellular damage, but also release signals (mito-DAMPs) which trigger inflammation and fibrosis, generating an adverse microenvironment in which several hepatocytes select anti-apoptotic programs and mutations that may allow survival and proliferation. Furthermore, one of the key events in malignant hepatocytes is represented by remodeling of glucidic-lipidic metabolism combined to reprogramming of mitochondrial functions, optimized to deal with energy demand. In sum, this review will discuss how mitochondrial defects may be translated into causative explanations of NAFLD-driven HCC, emphasizing future directions for research purposes and for development of potential preventive or curative strategies.

The present study was designed to investigate the bioactive compound in Rumextunetanus extracts (polygonaceae), a plant growing in GarâaSejnane region (NW-Tunisia). Hydro-methanol extracts of flowers and stems of Rumextunetanus were analyzed by RP-UHPLC-ESI-QTOF-MS in the negative mode to identify the maximum of bioactive compounds. Applied the aforementioned method, a total of 60 bioactive compounds were characterized for the first time in Rumextunetanus between them, 18 photochemical were firstly identified in the Polygonaceae family in negative ionization mode. Quantification of the identified compounds revealed that quercetin-3-O-glucuronide and (-)-epicatechingallate were the most abundant phenolic compounds in flowers and stems, respectively. Moreover, positive correlations were found between the antioxidant activity measured by DPPH and FRAP assays with the total phenolic compounds (r = 0.98; r = 0.99, respectively) and the abundance of some phenolic subfamilies such as hydroxycinnamic acids, hydroxybenzoic acids, flavonols and flavones with r > 0.86. The compounds displaying significant (P < 0.01) and good correlations with the antioxidant activity (r > 0.93) were hydroxybenzoic acid, rutin, quercetin-3-O-glucuronide, quercetin-3-O-glucoside, quercetin and luteolin-7-O-rutinoside. In addition, the flowers and stems of Rumex tunetanus showed different bioactive compound profiles and significant antioxidant properties of extracts. These results highlight the potential of the RP-UHPLC-ESI-QTOF-MS and MS/MS system to identify untargeted metabolic profiling of Rumex tunetanus. Overall, these results contribute to the clear explanation of the past and current usage of genus Rumex in folk medicine. Future investigations are necessary to develop purified antioxidant extracts, with the application of more selective extraction techniques.

Insulin resistance is the most important underlying cause of obesity and type 2 Diabetes (T2DM), and insulin sensitizing treatments have proved effective in preventing diabetes and inducing weight loss. Obesity and T2DM are also associated with increased inflammation. Mangosteen is a tropical tree, whose fruits, widely known for their antioxidant properties, have been recently suggested having a possible further role in the treatment of obesity and T2DM. The objective of this pilot study has been to evaluate safety, compliance and efficacy of mangosteen on insulin resistance, weight management, and inflammatory status in obese female patients with insulin resistance. 22 patients were randomized 1:1 to behavioral therapy alone or behavioral therapy and mangosteen and 20 completed the 26-week study. The mangosteen group reported a significant improvement in insulin sensitivity (HOmeostatic Model Assessment-Insulin Resistance, HOMA-IR -53.22% vs -15.23%, p=.0037), and a trend decrease in inflammation markers serum levels, together with trend greater weight loss and trend increased HDL levels. No side effect attributable to treatment was reported. Given the positive preliminary results we report and the excellent safety profile, we suggest a possible role of mangosteen in the treatment of obesity, insulin resistance and inflammation.

Alzheimer’s disease (AD) is a predominant and incurable chronic debilitating neuro-degenerative disorder occupying more than 60% of all types of dementias. It is inaugurating by a cascade of events initiating from amnesic-type memory impairment and by gradually loss of cognitive and executive capacities, which is an intolerable problem for the patients and their familiars. Pathologically, there is overwhelming evidence that clumps of misfolded amyloid-β (Aβ) and hyperphosphorylated Tau protein aggregate in the brain. These pathological processes leading to synapse loss, neuronal loss, brain atrophy and gliosis culminating in neurodegeneration and fuelling AD. Thus, at a basic level, abnormality in brain proteins function is observed, causing disruption in the brain network and loss of neural connectivity. Nevertheless, AD is a multifactorial disorder, caused by a combination of age-related changes, genetic, environmental and lifestyle factors that affect the brain over time, its mysterious pathology seems non limited to senile plaques (Aβ) and neurofibrillary tangles (tau), but plethora of substantial and biological processes have been also emerged in its pathogenesis such as — breakdown and/or dysfunction of the blood–brain barrier (BBB); patients’ carriers of the gene variant APOE4; and the immunosenescence of the immune system. Furthermore, type 2 diabetes (T2DM) and metabolic syndrome (MS) whose have also observed as early markers that may provoke pathogenic pathways that lead or aggravate AD progression and pathology. Notwithstanding, of various pathological pathways, there are numerous substantial AD features that require shedding light on, such as chronic neuroinflammation, decrease glucose utilization and energy metabolism as well as brain insulin resistance (IR). Herein, we come to broadened our understanding & to connect the dots of the multiple comorbidities and their cumulative impact that may have synergistic effects on BBB dysfunction and AD pathology. We shed light on the path-physiological modifications in the cerebral vasculature that may contribute to AD pathology and cognitive decline prior to clinically detectable changes in amyloid beta (Aβ) and tau pathology, diagnostic biomarkers of AD, neuroimmune involvement and the role of APOE4 allele and AD-IR pathogenic link - the shared genetics and metabolomics biomarkers between AD and IR disorders. Investment in the future researches brings us closer to know the pathogenesis of AD, and paves the way to build preventive and treatment strategy.

Background: Extra virgin olive oil is a fundamental component of the Mediterranean diet. It contains several molecules that sustain human well-being by modulating cellular metabolism and exerting antioxidant, anti-inflammatory, anti-ageing effects to protect normal tissues and can exert anti-angiogenic, and pro-apoptotic effects on cancer cells. Metabolites found in different parts of the olive tree, including leaves, also possess properties that might help in cancer prevention and promote wellness in aging. Olive mill wastewater (OMWW), a liquid residue produced during olive oil extraction, represents an environmental issue. However, it is enriched in phytochemicals with potential beneficial properties. Dietary supplements based on OMWW can be produced for nutritional supplementation with advantages to the ecology. Purpose: This work aims to measure hematochemical, anthropometric and metabolomic parameters in volunteers assuming an OMWW dietary supplement, OliphenoliaⓇ (OMWW-OL). Methods: The supplementation of OMWW-OL 25 mL twice daily for 30 days was tested on a pilot cohort of volunteers with characteristics close to metabolic syndrome. Hematochemical, anthropometric, and metabolomic parameters were analyzed before the intervention, at 30 days and 30 days after stopping consumption. Results: 29 volunteers were enrolled and 23 completed the study. The participants’ parameters at baseline were measured, and then twice daily at 30 days of treatment and 30 days after assumption discontinuation. Although treatment was with an olive derivative, weight and body mass index instead of increasing slightly decreased, particularly in women. Also, hydration increased, especially in women, while blood pressure, glycemia and insulin decreased. Cholesterol, low-density and high-density lipoproteins and triglycerides were stable while vitamin D levels, alongside calcium, sensibly increased. Albumin also increased and parameters related to sarcopenia displayed promising, although not statistically significant, trends toward positive effects. All the values were in support of an equilibrium with no damaging effects. By mass spectrometry analysis, we also found favorable changes in the vitamin D/histamine and homocysteine/methionine ratios, an increase in a new metabolite of unknown formula, and vitamin D/unknown metabolite ratio. Conclusions: Supplementation of OMWW-OL has no detrimental effects and, although with limited potency of a pilot study, might imply the beneficial modulation of several biological parameters, being potentially valuable for people at risk of metabolic syndrome. Some of these parameters could also be relevant as anti-ageing and in cancer prevention.

In the text, the synthesis and characteristics of the novel ONS-type vanadium(V) complexes with thioanilide derivatives of amino acids are described. They have shown inhibition of human protein tyrosine phosphatases (PTP1B, LAR, SHP1 and SHP2) in the submicromolar range, as well as inhibition of non-tyrosine phosphatases (CDC25A and PPA2) similar to bis(maltolato)oxovanadium(IV)(BMOV). The ONS complexes increased [14C]-deoxy-D-glucose transport into C2C12 myocytes, and one of them, VC070, also enhanced this transport in 3T3-L1 adipocytes. These complexes inhibited gluconeogenesis in hepatocytes HepG2, but none of them decreased lipid accumulation in the non-alcoholic fatty liver disease model using the same cells. Compared to the tested ONO-type vanadium complexes with 5-bromosalicylaldehyde and substituted benzhydrazides as Schiff base ligand components, the ONS complexes revealed stronger inhibition of protein tyrosine phosphatases, but the ONO complexes showed greater activity in the cell models in general. Moreover, the majority of the active complexes from both groups showed better effects than VOSO4 and BMOV. Complexes from both groups activated AKT and ERK signaling pathways in hepatocytes to a comparable extent. One of the ONO complexes, VC068, showed activity in all of the above models, also including glucose utilization in the myocytes and glucose transport in insulin-resistant hepatocytes. The discussion section explicates the results within the wider scope of the knowledge about vanadium complexes.

Objective: To analyze the relation between alterations in the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis during the first 6 months of life and weight in children born in the Lower Middle São Francisco region. Methods: This is an analytical cohort, with a quantitative approach and a translational perspective. Thirty children with low and normal birth weight were initially identified in a hospital and reapproached at 3 and 6 months of age. Birth weight and alterations in GH/IGF-1 curves at birth, third month, and sixth month of life. Results: Weight gain during the 6 months of follow-up in newborns with low birth weight was greater compared to newborns with normal birth weight. All children who were born with low birth weight had an altered GH/IGF-1 curve at birth (p = 0.002). Most newborns with low birth weight maintained the alteration in the GH/IGF-1 curve at the third month of life (p = 0.027). Regarding the GH/IGF-1 curve at the sixth month, alteration persisted in greater proportion among children with low birth weight. Conclusion: Alterations in insulin resistance markers, demonstrated by increased GH without a proportional increase in IGF-1, were observed to be significant in children with low birth weight, with greater adiposity in this group, which may increase the risk of metabolic diseases in later life.

Metabolic-dysfunction associated steatotic liver disease (MASLD) is a chronic liver disease that affects more than a quarter of the global population, and is increasing worldwide, due to the pandemic of obesity. Insulin resistance is closely associated with the development and progression of MASLD. Hepatic entry of increased fatty acids (FA) released from adipose tissue, increase in FA synthesis and reduced FA oxidation in the liver, and hepatic overproduction of triglyceride (TG)-rich lipoproteins may induce the development of MASLD. Since insulin resistance also induces atherosclerosis, the leading cause for death in MASLD patients is cardiovascular disease (CVD). Considering that the development of CVD determines the prognosis of MASLD patients, the ideal therapeutic interventions for MASLD should reduce body weight, improve coronary risk factors, in addition to an improvement in liver functiom. Lifestyle modification such as diet and exercise and surgical interventions such as bariatric surgery and intragastric balloons have shown to improve MASLD by reducing body weight. Sodium glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have been shown to improve coronary risk factors and to suppress the occurrence of CVD. Both SGLT2i and GLP-1 have been reported to improve liver enzymes, hepatic steatosis and fibrosis. We recently reported that the selective peroxisome proliferator-activated receptor-alpha (PPARα) modulator, pemafibrate, improved liver function. PPARα agonists have multiple anti-atherogenic properties. Here, we consider the pathophysiology of MASLD and the mechanisms of action of such drugs, and consider whether such drugs and the combination therapy of such drugs could be the ideal treatments for MASLD.

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

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

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

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

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

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

Cryptococcus neoformans is a pathogenic fungus that causes cryptococcosis, a significant secondary infection in immunocompromised individuals with immune-suppressive related symptoms from HIV infection and organ transplants. Fungaemia occurs via the respiratory route and spreads by tissue invasion into other body parts. Enzymes and membrane-associated permeases/transporters are accessory proteins deployed to enhance the survival, adaptation, and infection caused by Cryptococcus species. The nutrient bioavailability determines the functional turnover rate of these proteins in the immediate fungal environment. Low oxygen levels in the internal organs, essential micro-elements locked in the storage proteins, catabolite repression, phagolysosomal low glucose level and pH, tight junction, and extracellular matrixes are challenges to the survival of this pathogen in the host. This review identifies key hydrolytic and metabolic enzymes and permeases/transporters as essential weapons of virulence in addition to survival, tolerance, resistance, adaptation, and infection in humans. Under the regulation of different transcription factors, these proteins are released in response to nutrient sensors designed to siphon the host nutrients and induce infection in predisposed individuals. The extracellular secretory vesicles called “exosomal virulence bag” also harbour cryptococcal urease, laccase, phosphatase, and capsular components as additional secretory protein weapons for immune evasion, tissue invasion and persistence.

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

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

Systemic hypertension has been recognized as a modifiable traditional cardiovascular risk factor and influenced by many factors such as eating habits, physical activity, diabetes and obesity. The objective of this study was to identify cardiometabolic factors that predict changes in blood pressure induced by a one-year lifestyle intervention in primary care settings involving a collaboration between family physicians, dietitians, and exercise specialists. Patients with metabolic syndrome diagnosis were recruited by family physicians participating in primary care lifestyle intervention among several family care clinics across Canada. Participants for whom all cardiometabolic data at the beginning (T0) and the end (T12) of the intervention were available were included in the present analysis (n=101). Patients visited the dietitian and the exercise specialist weekly for the first three months and monthly for the last nine months. Diet quality, exercise capacity, anthropometric indicators, and cardiometabolic variables were evaluated at T0 and at T12. The intervention induced a significant decrease in waist circumference (WC), systolic (SBP) and diastolic (DBP) blood pressure, and plasma triglycerides and an increase in cardiorespiratory fitness (estimated VO2max). Body weight (p<0.001), body mass index (BMI) (p<0.001), and plasma glucose (p=0.006) reduction and VO2max increase (p=0.048) were all related to changes in SBP. WC was the only variable for which changes were significantly correlated with those in both SBP (p<0.0001) and DBP (p=0.0004). Variations in DBP were not associated with changes in other cardiometabolic variables to a statistically significant extent. Twelve participants were identified as adverse responders in both SBP and DBP and displayed less favorable changes in WC. The beneficial effects of a lifestyle intervention on blood pressure were significantly associated with cardiometabolic variables, especially WC. These findings suggest that a structured lifestyle intervention in primary care can help improve cardiometabolic risk factors in patients with metabolic syndrome.

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

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

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

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

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

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

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

Background/aims: Prior research identified a significant association between heart disease and metabolic dysfunction-associated liver steatohepatitis (MASLD), but the mechanisms are unclear. This study aims to search predictive biomarkers for grade I left ventricular diastolic dysfunction (LVDD), an early stage of heart failure (HF), in type 2 diabetes mellitus (T2DM) patients. Methods: This single-center, prospective observational study screened 73 T2DM patients for grade 1 LVDD and MASLD using 2D echocardiography, tissue analysis, spectral color Doppler, and Fibromax. Results: The study analyzed 50 patients (mean age 58±11.3 years) with a median diabetes duration of 7 years, abdominal obesity (mean BMI 34.4±5.9 kg/m2), and a mean HbA1c of 7.9±1.5%. The prevalence of grade I LVDD, fibrosis, mild steatosis, moderate to severe liver steatosis, mild MASLD, and moderate MASLD was 54%, 44%, 14%, 80%, 43%, and 34%, respectively. Regression analysis revealed that grade 1 LVDD was positively associated with age, Fibrotest, ɑ2-macroglobulin, epicardiac adipose tissue (EAT), and negatively associated with lateral s`, E wave, E/e`, E/A, medium E`, and septal e` (p&lt; 0.05 for all). ɑ2-macroglobulin &gt; 1.92 g/L (AUROC= 0.782, sensitivity 70.4%, specificity 81.2%) and fibrotest score &gt; 0.11 (AUROC 0.766, sensitivity 92.6%, specificity 56.2%) were significant predictors of grade I LVDD. Conclusion: HF is a multifaceted disorder associated with multisystem organ damage, including nonalcoholic MASLD. Although the underlying mechanisms remain unclear, innovative non-invasive biomarkers, such as ɑ2-macroglobulin or fibrotest, could concurrently indicate liver stiffness and the likelihood of grade I LVDD, an early, asymptomatic HF stage in T2DM patients.

Probiotics, known for regulating gut microbiota, may aid those with overweight or obesity, but their mechanisms require more research. This study involved 75 overweight or obese young adults, randomly assigned to either a Bifidobacterium brevis BBr60 group or a placebo group. Both groups received diet guidance and took either BBr60 (1×1010 CFU/day) or a placebo for 12 weeks. Re-searchers analyzed body composition, serum glucose, lipids, liver and kidney function, comprehensive metabolome, and intestinal homeostasis before and after the intervention. After 12 weeks, BBr60 significantly reduced weight and BMI compared to pre-treatment levels and outperformed the placebo. The BBr60 group also showed improved blood biochemistry, with notably lower fasting blood glucose (FBG) levels than the placebo group (p < 0.05). Additionally, BBr60 influenced vital serum and fecal metabolites related to three amino acid metabolic pathways and regulated the bacteria Dialister, Klebsiella, and Bacteroides, which correlated strongly with serum metabolites. These findings indicate that BBr60 can safely and effectively regulating BMI, body weight, serum glucose, lipids, and liver function markers, which may involve BBr60's impact on key gut bacteria, which influence metabolites related to the valine, leucine, and isoleucine biosynthesis; glycine, serine, and threonine metabolism; and alanine, aspartate, and glutamate metabolism.

Portal myofibroblasts (PMF) are known to be critical in bile duct injury, but their role in liver fibrogenesis remains underexplored. Thy-1, an adhesion molecule integral to fibroblasts, relevant in fibrogenesis and detectable in serum as soluble Thy-1 (sThy-1), is expressed by PMF but not hepatic stellate cells in vitro. This study aimed to elucidate the correlation between Thy-1 expression in liver histology and sThy-1 levels in serum with the degree of liver fibrosis in patients with primary biliary cholangitis (PBC) and metabolic dysfunction associated steatotic liver disease (MASLD). Liver histology samples were stained for Thy-1 and sThy-1 was measured using an enzyme-linked immunosorbent assay (ELISA). In patients with PBC and MASLD, portal Thy-1 expression significantly correlated with increased fibrosis. The sinusoidal Thy-1 expression also significantly correlated with increased fibrosis in patients with PBC (p

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

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

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

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

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

The clinical relationship between diabetes and inflammation is well-established. Various branches of science independently have confirmed that disrupting oxidant-antioxidant equilibrium and elevated lipid peroxidation could be a potential mechanism for chronic kidney disease associated with Type 2 diabetes mellitus (T2DM). Under diabetic condition, hyperglycemia, especially inflammation, and increased reactive oxygen species generation are bidirectionally associated. Inflammation, oxidative stress and tissue damage are believed to have a role in the development of diabetes. Although the exact mechanism underlying the oxidative stress and its impact on diabetes progression remains uncertain, the hyperglycemia-inflammation-oxidative stress interaction clearly plays a significant role in onset and progression of vascular disease, kidney disease, hepatic injury, pancreas damage and, therefore holds promise as a therapeutic target. Evidence strongly indicates that the use of multiple antidiabetic medications therapy fails to achieve the normal range for glycated hemoglobin target, signifying treatment resistant diabetes. Antioxidants with polyphenols are considered useful as adjuvant therapy for their potential anti-inflammatory effect and antioxidant activity. We aimed to analyze the current major points reported in preclinical in vivo and clinical studies of antioxidants in the prevention or treatment of inflammation in T2DM. Then, we will share our speculative vision of the future diabetes clinical trials.

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

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

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

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

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

Metabolomics analysis generates vast arrays of data, necessitating comprehensive workflows involving expertise in analytics, biochemistry and bioinformatics, in order to provide coherent and high-quality data that enables discovery of robust and biologically significant metabolic findings. In this protocol article, we introduce NoTaMe, an analytical workflow for non-targeted metabolic profiling approaches utilizing liquid chromatography–mass spectrometry analysis. We provide an overview of lab protocols and statistical methods that we commonly practice for the analysis of nutritional metabolomics data. The paper is divided into three main sections: the first and second sections introducing the background and the study designs available for metabolomics research, and the third section describing in detail the steps of the main methods and protocols used to produce, preprocess and statistically analyze metabolomics data, and finally to identify and interpret the compounds that have emerged as interesting.

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

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

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

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

Suboptimal nutrition is a leading cause of cardiometabolic disease and mortality. Biological sex is a variable that can play a role in individual response to nutritional factors and may modulate the impact of nutrition on disease. This narrative review explores the intricate interplay between sex, nutrition, and health outcomes, and the consequent importance of considering sex in nutrition research, dietary recommendations, and disease management. We examine the impact of sex on how various dietary patterns, including the Mediterranean diet, macronutrient content and quality, Western diet, and energy restriction associate with or affect metabolic health and disease risk. Understanding how sex influences the response to the diet can inform precision nutrition interventions and approaches for disease prevention and management.