Search Results (212)

Background: To investigate the effect of angiotensin-(1-7) [Ang-(1-7)] on serum metabolomics in obese type 2 diabetic (T2DM) mice. Methods: Four-week-old male C57BL/6 mice were fed a high-fat diet and intraperitoneally injected with streptozotocin (35 mg/kg) to establish an obese T2DM model. Mice were randomized into control, T2DM and T2DM+Ang-(1-7) groups (n = 6). Body weight and blood glucose were recorded weekly. At 10 weeks, blood glucose, serum inflammatory factors, lipid profiles, and pancreatic β-cell insulin secretion were detected; serum metabolite alterations were analyzed via untargeted metabolomics. Results: 1. Ang-(1-7) intervention decreased blood glucose (p < 0.05) and CRP levels (p < 0.01), and alleviated dyslipidemia (p < 0.05 or p < 0.01), as well as β-cell morphology and insulin expression in obese T2DM mice. 2. Non-targeted metabolomics analysis suggested that Ang-(1-7) may alleviate abnormal amino acid metabolic pathways by regulating levels of metabolites such as L-valine, L-proline, L-histidine, and glutamic acid. This intervention also tended to reduce multiple lipid metabolites, including Omega-3 Arachidonic Acid Ethyl Ester, phosphatidylcholine, and glycerophosphocholine, thereby participating in the modulation of lipid metabolism balance. KEGG enrichment analysis further indicated that Ang-(1-7) was involved in the regulation of protein digestion and the absorption pathway, as well as the HIF-1 signaling pathway related to oxidative stress, bile acid metabolism pathway, and other signaling pathways, and improving the insulin secretion pathway, pyrimidine metabolism, and TCA cycle energy metabolism pathway. Conclusions: Ang-(1-7) may partially improve metabolic disturbances in obese T2DM mice, which is potentially associated with the modulation of multiple metabolic processes, including amino acid metabolism, lipid metabolism, insulin secretion, and TCA cycle energy metabolism. Full article

Objective: In this study, Dehydroepiandrosterone (DHEA-induced Polycystic Ovary Syndrome (PCOS) mice were used as models to evaluate the improvement effect of Vitexin (Vit) on ovarian fibrosis and explore the mechanism of action of the NR4A1/NLRP3 signaling pathway. Method: Sixty 4-week-old female ICR mice of the same batch number were selected and their systems were divided into 6 groups (n = 10): normal (Control, Ctrl) group, model (Polycystic Ovary Syndrome, PCOS) group, treatment (Vitexin, The Vit group, normal NR4A1 gene silencing group (Ctrl NR4A1^-/-), NR4A1 gene silencing model group (PCOS NR4A1^-/-), and NR4A1 gene silencing treatment group (Vit NR4A1^-/-). Silencing gene modeling was performed by tail vein injection of adeno-associated virus (serotype AAV-8), and the mouse genotypes were detected by qRT-PCR technology 14 days after injection. After the genotype was determined, the PCOS group and the PCOS NR4A1^-/- group were administered dehydroepandrosterone (6 mg/100 g/d) by gavage for 28 consecutive days for modeling, while the Vit group and the Vit NR4A1^-/- group were treated with dehydroepandrosterone + vitexin (10 mg/kg/d) by gavage for 28 consecutive days. All mice were raised with pure water and regular maintenance food. After 4 weeks of drug intervention, the mice were euthanized and samples were collected. The pathological changes in ovarian tissue were observed by H&E staining, and the degree of ovarian tissue fibrosis was observed by Masson staining. The levels of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), malondialdehyde (MDA), total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) in mouse serum were detected by biochemical kits. The levels of inflammatory factors (IL-1β, IL-6, IL-18, TNF-α) in mouse serum were determined by enzyme-linked immunosorbent assay. Real-time fluorescence quantitative PCR (qRT-PCR) was used to detect oxidative kinase (Gsta4, Prdx3, Mgst1, Gpx3, Gsr), inflammatory factors (Nlrp3, Caspase-1, Asc, Il-1β, Il-18, Tnf-α) and fibrotic pathway-related genes (Tgf-β1, Smad3, Collagen1, CTGF, α-SMA, Mmp-13, and β-catenin) in ovarian tissues. The levels of inflammatory factors (NLRP3, Caspase-1, ASC, IL-1β, IL-18, TNF-α, IκBα) and fibrosis in mice were determined by Western blot method, and statistical description and analysis were performed using SPSS software. Result: In the wild-type genotype group, compared with the PCOS group, Vit treatment could effectively regulate the metabolic abnormalities of PCOS mice, including inhibiting excessive weight gain, restoring normal glucose tolerance, and reducing body fat content. After Vit treatment, the levels of MDA, TC, TG, LDL, IL-1β, IL-6, IL-18 and TNF-α in the serum of PCOS mice were significantly reduced, while the levels of SOD and HDL in the serum of PCOS mice were increased. The staining results indicated that Vit treatment could significantly inhibit the process of ovarian fibrosis in PCOS mice. The results of WB and PCR demonstrated that after Vit gavage treatment in mice, inflammatory and fibrotic factors such as Nlrp3, Caspase-1, Asc, Il-1β, Il-18, Tgf-β1, Smad3, Collagen1, CTGF, and α-SMA in ovarian tissues could be significantly down-regulated, and the fibrotic level of ovarian tissues could be reduced. Among the same measurement indicators, the silenced NR4A1 group showed a certain degree of increase compared with the wild genotype group, but there was no significant difference. Conclusions: Vit intervention can restore the sex hormone levels and follicular development in ovarian tissues of PCOS mice, regulate reproductive endocrine disorders and abnormal lipid metabolism levels, and regulate the expression of Collagen I, a-SMA and CTGF in the ovaries by inhibiting the NR4A1/NLRP3 signaling pathway, thereby improving the ovarian fibrosis level of PCOS mice. It is suggested that it may play a key role in the treatment of PCOS and the prevention and delay of its long-term complications. Full article

Postprandial variability in glucose and protein levels is one of the elements of insulin resistance (IR) and prediabetes, which is an area precursor to type 2 diabetes mellitus (DM). The objective of the study was a comprehensive proteomic analysis according to glucose tolerance in the general population who did not self-report DM or other diseases. We used Olink^® Reveal, a novel, high-throughput platform by Olink Proteomics based on their Proximity Extension Assay (PEA), to identify levels of 1034 circulating proteins in small volumes (4 µL) of plasma samples. The study enrolled 508 participants (mean age 52 ± 10.5 years, 47.2% men) from the population-based study, Bialystok PLUS Polish Longitudinal University Study. The study population was categorized according to glucose metabolism in comparison to impaired fasting blood glucose (IFG), impaired glucose tolerance (IGT), and newly diagnosed DM. Analysis of variance (ANOVA) adjusted for age, weight, fat mass, lean mass, and body mass index (BMI), identified 19 proteins significantly associated with categories of glucose tolerance. Of the five markers with the greatest ability to distinguish newly diagnosed diabetes from non-diabetic participants, paralemmin 2 performed best (AUC = 0.81; 77% sensitivity, 75% specificity), whereas furin was the most accurate for detecting any abnormal glucose regulation (AUC = 0.69). A linear regression model adjusted for the same confounding factors showed statistically significant associations between Hb_A1c levels and 37 proteins. Our findings highlight multiple proteins with significantly different levels across categories of glucose tolerance, especially between the healthy controls and the group with newly diagnosed DM. The consistent patterns of protein level differences, independent of body composition, suggest potential involvement in the progression of glucose metabolism disturbances and provide unique insights into pathomechanisms. These findings identify PALM2, FURIN, PDZK1, ACAA1, and IL18R1 as potential biomarkers of early dysglycemia. Full article

Leucine-rich repeat kinase 2 (LRRK2) is a multidomain serine/threonine kinase and a major genetic contributor to Parkinson’s disease (PD). Although LRRK2 has been extensively studied in neurodegeneration, emerging evidence indicates that it also plays a critical role in systemic metabolism. LRRK2 regulates glucose homeostasis through modulation of insulin signaling, vesicle trafficking, mitochondrial function, and inflammatory responses. Studies using LRRK2 knockout and knock-in models, including the pathogenic G2019S mutation, have revealed abnormalities in insulin sensitivity, adipose tissue inflammation, hepatic glucose production, and skeletal muscle metabolism. Mechanistically, LRRK2 phosphorylates Rab GTPases, thereby controlling insulin receptor trafficking and GLUT4 translocation. In addition, LRRK2 influences mitochondrial dynamics and reactive oxygen species production, linking metabolic stress to inflammatory signaling. Importantly, LRRK2 also regulates innate immune pathways, including TLR4–NFκB signaling and inflammasome activation, thereby connecting peripheral metabolic dysfunction to neuroinflammation. Here, we propose an integrated metabolic–neuroinflammatory crosstalk model in which LRRK2 functions as a molecular coordinator linking peripheral metabolic dysfunction to central neurodegeneration. In this framework, systemic metabolic stress—characterized by insulin resistance, chronic inflammation, advanced glycation end product (AGE) accumulation, and blood–brain barrier disruption—drives microglial activation and neurodegenerative processes. Understanding this systemic axis may provide new therapeutic opportunities targeting both metabolic dysfunction and neurodegeneration in PD. Full article

The metabolism of the four major substances—glucose, lipids, amino acids, and nucleotides—constitutes the most prominent metabolic phenotype of schizophrenia. The pathological axis shared by these substances involves energy pathway imbalances, redox stress, immune-inflammatory activation, and abnormalities in neurotransmitter synthesis/degradation. Existing research confirms that key metabolites within these pathways hold potential as biomarkers for diagnosis or progression monitoring. In recent years, electroconvulsive therapy (ECT) has been shown to improve psychotic symptoms while exerting broad regulatory effects on neurogenesis, immune homeostasis, and the hypothalamic–pituitary–target gland axis, though its precise mechanisms remain unclear. Recent studies indicate that ECT treatment can also regulate changes in brain and peripheral metabolism. We propose an integrated “metabolism-immunity-neuroendocrine” hypothesis to systematically elucidate how metabolic reprogramming during ECT treatment cascades sequentially to the immune, neural, and endocrine systems, thereby revealing the molecular basis of its antipsychotic effects. Furthermore, we conduct a comparative analysis of the effects of antipsychotic drugs on the same metabolic network and explore the universality and specificity of metabolic regulation in other physical therapies (such as rTMS, tDCS) and psychiatric disorders like depression and bipolar disorder. This research aims to provide novel biomarkers and intervention targets for the precision diagnosis and treatment of schizophrenia. Full article

Background/Objectives: Reduced serotonin transporter (SERT) function is associated with increased vulnerability to emotional and metabolic dysregulation, particularly in elderly women. Most preclinical studies relied on young male rodents with complete Sert deficiency; the Western diet (WD) acerbates these abnormalities. However, complete Sert loss does not fully reflect the human condition of partial SERT dysfunction. Here, we examined the effects of WD in aged female Sert^+/− mice on metabolic, biochemical, molecular, and behavioral outcomes. Methods: Wild-type (WT) and Sert^+/− mice were fed WD or a control diet. Emotionality, cognition, glucose tolerance (GT), plasma ¹HNMR spectroscopy metabolome and biochemical parameters were studied. Gene expression analyses of nitric oxide (NO)-related markers were performed in the hypothalamus, dorsal raphe, and liver. Results: WD-exposed WT mice showed impaired GT and reduced plasma lactate and branched-chain amino acid levels; metabolome changes were more pronounced in mutants, while GT was unchanged. Naïve Sert^+/− mice exhibited lower lactate and alanine levels compared with WT controls. WD increased leptin and cholesterol levels in both genotypes, whereas triglyceride concentrations were reduced in Sert^+/− mice. Both WD and Sert deficiency increased Nos expression, while arginase expression was differentially regulated by genotype and diet. Malondialdehyde levels were elevated in the prefrontal cortex of Sert^+/− mice regardless diet. WD also impaired object recognition memory and induced anxiety- and depression-like behaviors, with more pronounced effects in Sert^+/− mice, except marble test behavior. Conclusions: Partial Sert deficiency aggravates some but not all WD-induced metabolic alterations, enhances oxidative stress, dysregulates arginine–NO signaling, and modifies behavior, highlighting the translational relevance of Sert^+/− mice for modeling SERT dysfunction. Full article

Background/objectives: Metabolic abnormalities, independent of excess weight, may contribute to cancer risk even among individuals of normal weight, though their role remains unclear. This study sought to ascertain if metabolically unhealthy normal-weight (MUNW) individuals, generally characterized by a normal body mass index alongside the presence of metabolic abnormalities, have higher cancer risk than metabolically healthy peers, to analyze variations in risk across obesity-related cancer types, and to examine which single specific metabolic components can predict cancer independently in normal-weight individuals. Methods: Two authors systematically searched the PubMed, EMBASE, and Web of Science databases for longitudinal studies, published from inception to July 2025, that included normal-weight adults, classified participants by metabolic health status, and reported incident cancer outcomes in metabolically unhealthy versus healthy normal-weight groups. Hazard ratio (HR) estimates were extracted from each study and were pooled using random-effects inverse-variance model with empirical Bayes variance estimator. Results: Thirty-five studies involving 18,210,858 participants (56.0% females, mean age = 53.8 years) were included. A total of 280,828 new cancer cases were diagnosed during follow-up (mean = 10.6 years). In comparison with metabolically healthy normal-weight individuals, MUNW individuals had a 20% higher risk of cancer (HR = 1.20, 95% confidence interval [CI]: 1.13–1.28). Increased risks were observed for gastric cancer (HR = 1.40, 95% CI: 1.04–1.87), pancreatic cancer (HR = 1.37, 95% CI: 1.21–1.54), and colorectal cancer (HR = 1.34, 95% CI: 1.14–1.57), which were the cancer types showing statistically significant associations in subgroup analyses. Normal-weight participants presenting specific metabolic factors like central adiposity or glucose metabolism abnormalities had a 20% (HR = 1.20, 95% CI: 1.13–1.37) and 23% (HR = 1.23, 95% CI: 1.06–1.41) increased cancer risk, respectively. Conclusions: MUNW individuals are at higher risk of cancer, with specific metabolic abnormalities, particularly central adiposity and impaired glucose regulation, emerging as the factors most strongly associated with increased risk in normal-weight individuals. Routine metabolic screening and detailed phenotyping are crucial to identify these risks. Full article

Metabolic reprogramming is a fundamental hallmark and a key driver of malignant tumors. By reshaping glucose, lipid, and amino acid metabolism, as well as mitochondrial function, it sustains the abnormal proliferation and survival of tumor cells, making it a crucial target for anti-tumor therapy. Curcumin, a natural multi-target compound, exhibits unique advantages in intervening in tumor metabolic reprogramming due to its low toxicity and broad-spectrum regulatory properties. In various tumor models, it can directly modulate the activity of key glycolytic enzymes, such as hexokinase 2, lactate dehydrogenase A, and pyruvate kinase M2, as well as transporters like glucose transporter 1. Furthermore, it inhibits the expression of proteins related to lipid metabolism, including fatty acid synthase and stearoyl-CoA desaturase 1, while also intervening in amino acid metabolic networks, such as glutaminase and branched-chain amino acid transaminase. Additionally, curcumin targets mitochondrial function and reactive oxygen species balance, creating multi-dimensional intervention effects through various pathways, including the induction of ferroptosis by regulating the SLC7A11/GPX4 axis and modulating gut microbiota metabolism. Its mechanism of action involves the synergistic regulation of key signaling pathways, including phosphoinositide 3-kinase/Akt, NF-κB, AMP-activated protein kinase, and hypoxia-inducible factor-1alpha. Furthermore, its specific effect profile demonstrates significant dependency on cell type and tumor model. This article systematically reviews the regulatory effects of curcumin on these critical metabolic processes and pathways in tumor metabolic reprogramming, revealing its molecular mechanisms in disrupting tumor growth and progression by targeting energy and biosynthetic metabolism. These findings provide a significant theoretical foundation and a preclinical research perspective for the development of natural antitumor drugs based on metabolic regulation, as well as for optimizing combination therapy strategies. Full article

Background: Metabolic syndrome (MetS), a cluster of cardiometabolic abnormalities including elevated blood pressure, impaired glucose regulation, dyslipidemia, and increased waist circumference is increasingly recognized as a condition linked to both physical and psychological health risks. This study aims to investigate genotype-specific differences in psychological distress between healthy individuals and those with metabolic disorders, as well as to examine potential gene metabolic status interactions. Methods: This study is a cross-sectional analysis conducted in Turkistan city in the Southern region of Kazakhstan. Participants (healthy and those with metabolic syndrome) were invited to take part in the study by random sampling from the Khoja Akhmet Yassawi Kazakh-Turkish International University Medical Center. Consenting individuals provided a genetic analysis. Psychosomatic indicators were assessed using the Perceived Stress Questionnaire (PSQ) and the Depression, Anxiety, and Stress Scale (DASS-21). Results: A total of 200 individuals participated, with an approximately 3:1 ratio of women to men. The mean age in years was 50.4 ± 9.5 and 48.8 ± 7.7 for men and women, respectively. Preliminary analyses showed variations in cognitive and psychosomatic measures among individuals with metabolic syndrome, but no associations with genetic variants, and no significant group differences across key psychosomatic indicators when stratified by metabolic or genetic factors. However, a significant difference in LPL-Anxiety between genotypes GA-GG (p < 0.05) was found. Conclusions: Variations in metabolic and genetic factors within the studied population were not associated with measurable differences in stress or depressive symptoms. Full article

Eurotium cristatum (EC), a fungus derived from Fu brick tea, exhibits anti-obesity potential, but its mechanisms regulating intestinal gluconeogenesis (IGN) remain unclear. This study aimed to elucidate whether EC alleviates obesity and glucolipid metabolic disorders by modulating the gut microbiota and activating the IGN pathway. The 8-week EC administration at low (10⁴ CFU/mL), medium (10⁶ CFU/mL), and high doses (10⁸ CFU/mL) ameliorated high-fat-diet (HFD)-induced metabolic abnormalities, including aberrant weight gain, dyslipidemia, glucose intolerance and hepatic injury with effects showing a dose-dependent trend. EC treatment significantly activated IGN, as indicated by increased colonic levels of short-chain fatty acids (SCFAs) and succinate (key IGN substrates) and the upregulation of IGN-key enzymes (PEPCK, FBPase, and G6Pase). In addition, EC treatment significantly alleviated the HFD-induced gut dysbiosis by reducing the Firmicutes/Bacteroidetes ratio and enriching beneficial bacteria such as Lachnospiraece_NK4A136_group, Bacteroidota and Alloprevotella. Non-targeted metabolomics analysis revealed that EC significantly altered the linoleic acid metabolism, specifically decreasing the relative levels of bile acid and chenodeoxycholic acid (p < 0.01) while increasing those of linoleic acid and ricinoleic acid (p < 0.05). EC treatment reshaped the gut microbiome, promoted the production of beneficial metabolites (e.g., SCFAs), and consequently activated the IGN pathway, ultimately ameliorating host glucose and lipid metabolic disorders. Our findings provide mechanistic insights into the anti-obesity effects of EC, suggesting its potential for further investigation as a dietary intervention for metabolic diseases. Full article

Objectives: Erhuang Quzhi Formula (EQF) has been used for the treatment of non-alcoholic fatty liver disease (NAFLD). However, its active components and mechanistic basis remain unclear. This study aims to systematically identify the therapeutic material basis of EQF and to elucidate its potential mechanisms of action against NAFLD through an integrated multi-omics strategy. Methods: An integrated strategy combining UPLC-Q-TOF-MS and network pharmacology was applied to characterize serum components of EQF and construct a compound–target network. Core targets were screened and validated by molecular docking. A NAFLD model was established in C57BL/6 mice through high-fat diet feeding. To evaluate the therapeutic effects, mice were treated with EQF and assessed by measurements of serum biochemical parameters, liver histopathology, and glucose tolerance. UPLC-Q-TOF-based lipidomic and metabolomic analyses of liver tissue were conducted to clarify EQF’s regulatory effects on global lipid profiles and endogenous metabolites. Key genes and proteins involved in relevant signaling pathways were verified by RT-qPCR and Western blot. Results: A total of thirty-one prototype compounds were identified in the EQF-containing serum. Network pharmacology analysis predicted that EQF may alleviate NAFLD by acting on core targets such as TNF, JUN, and STAT3. In vivo experiments demonstrated that EQF administration significantly improved liver function, attenuated dyslipidemia, and reduced inflammation in model mice. Furthermore, metabolomic and lipidomic analyses indicated that EQF effectively reversed abnormal glycerophospholipid and sphingolipid levels and restored their metabolic homeostasis. Conclusions: EQF exerts therapeutic effects in a NAFLD mouse model through multi-component, multi-target, and multi-pathway mechanisms, primarily associated with the regulation of lipid metabolism, improvement of liver function, and suppression of inflammatory responses. This study provides mechanistic insights and a pharmacodynamic basis for the future clinical investigation of EQF. Full article

Background/Objectives: Non-alcoholic steatohepatitis (NASH) is a progressive liver condition closely associated with gut microbial dysbiosis and hepatic metabolic abnormalities. Poria cocos polysaccharide (PCP), a bioactive component derived from the medicinal fungus Poria cocos, possesses hepatoprotective properties, yet the therapeutic mechanisms of PCP in NASH, particularly those involving microbial and metabolic regulation, remain incompletely elucidated. This study aimed to investigate the effects of PCP on improving NASH and explore its mechanisms related to prebiotic activity. Methods: Mice were induced to develop NASH using a Western diet, followed by PCP intervention for 12 weeks. Hepatic function, including liver enzymes and lipids, glucose metabolism, and liver histopathological changes, was assessed. Fatigue and neurobehavioral alterations were evaluated via rotarod, open field, and tail suspension tests. Hepatic pro-inflammatory cytokines were measured using RT-qPCR. Gut microbiota were analyzed through 16S RNA gene sequencing, and metabolites of liver tissue were analyzed through untargeted metabolomics. Results: PCP decreased blood glucose and hepatic lipid levels in NASH mice, alleviating liver inflammation, ballooning degeneration, and fibrosis. It also improved fatigue-like performance on rotarod test and reduced the hepatic expression of IL-6, IL-1β, TNF-α, and IL-18. Microbiota analysis revealed that PCP restored gut microbial diversity, promoted the growth of beneficial taxa such as Alistipes and Butyricoccaceae_UCG-009, and inhibited harmful bacteria, including Romboutsia ilealis. Liver metabolomics showed that PCP normalized key metabolites like taurocholate and regulated taurine and hypotaurine metabolism, which were correlated with reduced inflammation, fatigue-like performance, and fibrosis. Conclusions: PCP, as a promising edible agent, alleviates hepatic damage, metabolic disorders, and fatigue-like performance on rotarod test in NASH mice, probably by reshaping gut microbiota and modulating hepatic taurine and hypotaurine metabolism. Full article

Diabetes, a metabolic disorder characterized by hyperglycemia resulting from insulin insufficiency or impaired insulin sensitivity, is one of the major global health challenges. Persistent hyperglycemia in diabetes affects microcirculation, eyes, kidneys, liver, pancreas, muscle, and adipose tissue, which consequently leads to irreversible health issues such as retinopathy, nephropathy, neuropathy, cardiovascular complications, abnormalities of lipoprotein metabolism, and gastrointestinal dysfunction. Although available therapies are effective to some extent, they remain limited in efficacy and are often associated with side effects, underscoring the urgent need for novel treatment options. Traditionally, plant extracts and natural compounds have been used for centuries to treat diabetes and its complications. Plant extracts from the Gentianaceae family have emerged as a particularly promising source of bioactive compounds proven to be useful for the treatment of various diseases, including diabetes. This review provides a comprehensive overview of the most studied plant extracts and isolated compounds from the Gentianaceae family, with a focus on their use in diabetes treatment as well as their action in managing hyperglycemia, antioxidant activity, protection of pancreatic beta cells and associated complications. Numerous in vitro and in vivo studies have demonstrated their great potential to regulate blood glucose levels, reduce oxidative stress, alleviate tissue and organ damage—primarily in the liver and kidney—and improve lipid metabolism. To fully achieve this potential, future research should prioritize well-designed clinical trials to verify safety and efficacy in humans, conduct detailed molecular and cellular studies, standardize extraction and characterization methods to ensure reproducibility, and incorporate conservation biology principles into pharmacognostic investigations. Full article

Background: As a chronic threat to human and animal health, diabetes impairs cognition and synaptic plasticity through mechanisms that remain unresolved. This study aims to explore whether mitochondria-associated endoplasmic reticulum membrane (MAM)-mediated mitochondrial Ca²⁺ overload and endoplasmic reticulum stress plays an important role in high-glucose-induced synaptic plasticity damage in hippocampal neurons. Methods and Results: In diabetic mice, cognitive dysfunction was tightly linked to the synaptic plasticity impairment, manifesting as significant reductions in both mRNA and protein levels of PSD-95, GAP-43, and SYP. Concomitantly, aberrant increases in MAM number and structural alterations, along with pronounced up-regulation of Mfn2, were observed in hippocampal tissue from diabetic mice and cultured hippocampal neurons exposed to high glucose. High glucose also elevated MAM-located Ca²⁺ transporters (IP3R, GRP75, MCU, and VDAC1), provoking mitochondrial Ca²⁺ overload and activating ERS, particularly via the IRE1α pathway. Knockdown of Mfn2 ameliorated these high-glucose-induced MAM abnormalities, suppressed mitochondrial Ca²⁺ overload and ERS, and exerted a protective effect against high-glucose-induced synaptic plasticity damage. Application of the inhibitor MCU-i4 to block Ca²⁺ transport within MAM reduced high-glucose-induced mitochondrial Ca²⁺ overload, relieved ERS, and improved high-glucose-induced synaptic plasticity impairment. Application of the inhibitor 4μ8C to suppress the IRE1α pathway of ERS alleviated mitochondrial Ca²⁺ overload and improved high-glucose-induced synaptic plasticity impairment. Conclusions: High glucose elicits MAM dysregulation, which precipitates reciprocal mitochondrial Ca²⁺ overload and ER stress, jointly driving hippocampal synaptic plasticity impairment. Full article

Diabetes mellitus (DM) encompasses a group of metabolic diseases characterised by abnormal glucose levels. The pathophysiology of DM involves intricate disruptions in glucose metabolism and immune regulation. The gut microbiome is known to play a crucial role in human health and disease, and changes in its composition have been reported in numerous conditions, including DM. In this review, we discuss recent findings on the intricate relationship between the gut microbiome and DM, including its complications. We highlight the involvement of gut microorganisms in inflammation and metabolic processes, and we summarise current evidence on how antidiabetic therapies influence microbiome composition and activity. Finally, we explore the potential role of microbiome monitoring in predicting treatment response. Full article