Chronic antipsychotic use is associated with neuronal damage and cognitive impairment, with the gut microbiome increasingly implicated. However, the specific microbial metabolites and mechanisms involved remain unknown. Here, we demonstrate that chronic olanzapine treatment induces gut microbial dysbiosis, compromises intestinal barrier integrity, and causes cognitive deficits in mice. Multi-omics analyses reveal profound depletion of the microbiota-associated metabolite ergothioneine in blood and brain, a finding validated in the blood of olanzapine-treated patients and risperidone- and clozapine-treated mice. This deficiency correlates with a loss of ergothioneine-producing bacteria (Cyanobacteria and subordinate taxa). Fecal microbiota transplantation from olanzapine-treated mice confers cognitive impairment, while ergothioneine supplementation mitigates it. Mechanistically, ergothioneine attenuates hippocampal oxidative stress and inhibits the redox-sensitive phosphatase protein tyrosine phosphatase 1B (PTP1B). Furthermore, hippocampal neuronal-specific PTP1B deletion abolishes olanzapine-induced synaptic and cognitive deficits. Our findings identify depletion of microbiota-derived ergothioneine as a mechanism underlying antipsychotic-induced cognitive impairment, highlighting therapeutic strategies to mitigate this side effect.

ARTICLE HIGHLIGHTS:The present study reveals a previously unknown molecular mechanism linking prediabetes to neurodegeneration, addressing a critical gap in understanding metabolic-neurological interplay. We investigated whether PTP1B mediates prediabetes-induced cognitive impairment. PTP1B impaired synaptic signaling and synaptic ultrastructure in hippocampal neurons, contributing to cognitive decline in prediabetes. PTP1B is a novel therapeutic target for prediabetes-associated neurodegeneration.

BackgroundObesity is an epidemic and systemic metabolic disease that seriously endangers human health. This study aimed to understand the transcriptomic characteristics of the blood of metabolically unhealthy obesity (MUO) and provide insight into the target genes of differently expressed microRNAs in the occurrence and development of MUO.MethodsThe GSE146869, GSE145412, GSE23561, and GSE169290 datasets were analyzed to understand the transcriptome characteristics of the blood of MUO and provide insights into the target genes of differently expressed microRNAs (DEMs) in MUO. Functional and pathway enrichment analyses and gene interaction network analyses were performed to profile the function of differentially expressed genes (DEGs). In addition, miRNet 2.0, TransmiR v2.0, RNA22, TargetScan 7.2, miRDB, and miRWalk databases were used to predict the target genes of effective microRNAs.ResultsA total of 189 co-DEGs were identified in at least two datasets. The 156 co-upregulated genes were enriched into 29 biological process (BP) terms and 12 KEGG pathways. Among the 29 BP terms, the immune- and metabolism-related BP terms were enriched. The 33 co-downregulated genes were enriched into two BP terms, including apoptotic process and regulation of the apoptotic process, with no KEGG pathway. The hub genes EGF, STAT3, IL1B, PF4, SELP, and ITGA2B in the gene interaction network might play important roles in abnormal BP in MUO. Among the 19 DEMs identified in the blood of the MUO group by the GSE169290 dataset, 18 microRNAs targeted 85 genes as risk factors in MUO.ConclusionA network consisting of 18 microRNAs and 85 target genes might serve as a risk factor for metabolically unhealthy obesity.

Chronic infection with Toxoplasma gondii (T. gondii) emerges as a risk factor for neurodegenerative diseases in animals and humans. However, the underlying mechanisms are largely unknown. We aimed to investigate whether gut microbiota and its metabolites play a role in T. gondii-induced cognitive deficits. We found that T. gondii infection induced cognitive deficits in mice, which was characterized by synaptic ultrastructure impairment and neuroinflammation in the hippocampus. Moreover, the infection led to gut microbiota dysbiosis, barrier integrity impairment, and inflammation in the colon. Interestingly, broad-spectrum antibiotic ablation of gut microbiota attenuated the adverse effects of the parasitic infection on the cognitive function in mice; cognitive deficits and hippocampal pathological changes were transferred from the infected mice to control mice by fecal microbiota transplantation. In addition, the abundance of butyrate-producing bacteria and the production of serum butyrate were decreased in infected mice. Interestingly, dietary supplementation of butyrate ameliorated T. gondii-induced cognitive impairment in mice. Notably, compared to the healthy controls, decreased butyrate production was observed in the serum of human subjects with high levels of anti-T. gondii IgG. Overall, this study demonstrates that gut microbiota is a key regulator of T. gondii-induced cognitive impairment.

JOURNAL/nrgr/04.03/01300535-202409000-00042/figure1/v/2024-01-16T170235Z/r/image-tiff Parkinson's disease is a neurodegenerative disease characterized by motor and gastrointestinal dysfunction. Gastrointestinal dysfunction can precede the onset of motor symptoms by several years. Gut microbiota dysbiosis is involved in the pathogenesis of Parkinson's disease, whether it plays a causal role in motor dysfunction, and the mechanism underlying this potential effect, remain unknown. CCAAT/enhancer binding protein β/asparagine endopeptidase (C/EBPβ/AEP) signaling, activated by bacterial endotoxin, can promote α-synuclein transcription, thereby contributing to Parkinson's disease pathology. In this study, we aimed to investigate the role of the gut microbiota in C/EBPβ/AEP signaling, α-synuclein-related pathology, and motor symptoms using a rotenone-induced mouse model of Parkinson's disease combined with antibiotic-induced microbiome depletion and fecal microbiota transplantation. We found that rotenone administration resulted in gut microbiota dysbiosis and perturbation of the intestinal barrier, as well as activation of the C/EBP/AEP pathway, α-synuclein aggregation, and tyrosine hydroxylase-positive neuron loss in the substantia nigra in mice with motor deficits. However, treatment with rotenone did not have any of these adverse effects in mice whose gut microbiota was depleted by pretreatment with antibiotics. Importantly, we found that transplanting gut microbiota derived from mice treated with rotenone induced motor deficits, intestinal inflammation, and endotoxemia. Transplantation of fecal microbiota from healthy control mice alleviated rotenone-induced motor deficits, intestinal inflammation, endotoxemia, and intestinal barrier impairment. These results highlight the vital role that gut microbiota dysbiosis plays in inducing motor deficits, C/EBPβ/AEP signaling activation, and α-synuclein-related pathology in a rotenone-induced mouse model of Parkinson's disease. Additionally, our findings suggest that supplementing with healthy microbiota may be a safe and effective treatment that could help ameliorate the progression of motor deficits in patients with Parkinson's disease.

Obesity has reached pandemic proportions and is a risk factor for neurodegenerative diseases, including Alzheimer's disease. Chronic inflammation is common in obese patients, but the mechanism between inflammation and cognitive impairment in obesity remains unclear. Accumulative evidence shows that protein-tyrosine phosphatase 1B (PTP1B), a neuroinflammatory and negative synaptic regulator, is involved in the pathogenesis of neurodegenerative processes. We investigated the causal role of PTP1B in obesity-induced cognitive impairment and the beneficial effect of PTP1B inhibitors in counteracting impairments of cognition, neural morphology, and signaling. We showed that obese individuals had negative relationship between serum PTP1B levels and cognitive function. Furthermore, the PTP1B level in the forebrain increased in patients with neurodegenerative diseases and obese cognitive impairment mice with the expansion of white matter, neuroinflammation and brain atrophy. PTP1B globally or forebrain-specific knockout mice on an obesogenic high-fat diet showed enhanced cognition and improved synaptic ultrastructure and proteins in the forebrain. Specifically, deleting PTP1B in leptin receptor-expressing cells improved leptin synaptic signaling and increased BDNF expression in the forebrain of obese mice. Importantly, we found that various PTP1B allosteric inhibitors (e.g., MSI-1436, well-tolerated in Phase 1 and 1b clinical trials for obesity and type II diabetes) prevented these alterations, including improving cognition, neurite outgrowth, leptin synaptic signaling and BDNF in both obese cognitive impairment mice and a neural cell model of PTP1B overexpression. These findings suggest that increased forebrain PTP1B is associated with cognitive decline in obesity, whereas inhibition of PTP1B could be a promising strategy for preventing neurodegeneration induced by obesity.

Background: Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease in clinical practice. It is mainly due to cardiovascular hypoplasia during embryonic development. The study aimed to find the etiology of TOF. Methods: Through the mRNA expression profile analysis of the GSE35776 dataset, differentially expressed genes (DEGs) were found, and the functional analysis and protein-protein interaction (PPI) network analysis were then performed on DEGs. Likewise, the hub genes and functional clusters of DEGs were analyzed using the PPI network. Differentially expressed miRNAs were analyzed from the GSE35490 dataset, followed by miRNet predicted transcription factors (TFs) and target genes. The key TF-miRNA-gene interaction mechanism was explored through the found significant difference between genes and target genes. Results: A total of 191 differentially expressed genes and 57 differentially expressed miRNAs were identified. The main mechanisms involved in TOF were mitochondria-related and energy metabolism-related molecules and pathways in GO and KEGG analysis. This discovery was identical in TFs and target genes. The key miRNAs, hsa-mir-16 and hsa-mir-124, were discovered by the Venn diagram. A co-expression network with the mechanism of action centered on two miRNAs was made. Conclusion: Hsa-mir-16 and hsa-mir-124 are the key miRNAs of TOF, which mainly regulate the expression of NT5DC1, ECHDC1, HSDL2, FCHO2, and ACAA2 involved in the conversion of ATP in the mitochondria and the metabolic rate of fatty acids (FA). Our research provides key molecules and pathways into the etiology of TOF, which can be used as therapeutic targets.

Introduction: This study aimed to understand the transcriptome characteristics of the skeletal muscle of elderly (EL) men with metabolic syndrome (MS) and to find the hub genes and insight into the molecular mechanisms of skeletal muscle in the occurrence and development of MS. Methods: In this study, the limma package of R software was used to analyze the differentially expressed genes in the skeletal muscle of healthy young (YO) adult men, healthy EL men, and EL men diagnosed with MS (SX) for at least 10 years. Bioinformatics methods, such as GO enrichment analysis, KEGG enrichment analysis, and gene interaction network analysis, were used to explore the biological functions of differentially expressed genes, and weighted gene coexpression network analysis (WGCNA) was used to cluster differentially expressed genes into modules. Results: Among the YO group, EL group, and SX group, 65 co-differentially expressed genes were found maybe regulated by age factor and MS factor. Those co-differentially expressed genes were enriched into 25 biological process terms and 3 KEGG pathways. Based on the WGCNA results, a total of five modules were identified. Fifteen hub genes may play an essential role in regulating the function of skeletal muscle of EL men with MS. Conclusions: 65 differentially expressed genes and 5 modules may regulate the function of skeletal muscle of EL men with MS, among which fifteen hub genes may play an essential role in the occurrence and development of MS.

Obesity is a risk factor for neurodegenerative disease associated with cognitive dysfunction, including Alzheimer's disease. Low-grade inflammation is common in obesity, but the mechanism between inflammation and cognitive impairment in obesity is unclear. Accumulative evidence shows that quinolinic acid (QA), a neuroinflammatory neurotoxin, is involved in the pathogenesis of neurodegenerative processes. We investigated the role of QA in obesity-induced cognitive impairment and the beneficial effect of butyrate in counteracting impairments of cognition, neural morphology, and signaling. We show that in human obesity, there was a negative relationship between serum QA levels and cognitive function and decreased cortical gray matter. Diet-induced obese mice had increased QA levels in the cortex associated with cognitive impairment. At single-cell resolution, we confirmed that QA impaired neurons, altered the dendritic spine's intracellular signal, and reduced brain-derived neurotrophic factor (BDNF) levels. Using Caenorhabditis elegans models, QA induced dopaminergic and glutamatergic neuron lesions. Importantly, the gut microbiota metabolite butyrate was able to counteract those alterations, including cognitive impairment, neuronal spine loss, and BDNF reduction in both in vivo and in vitro studies. Finally, we show that butyrate prevented QA-induced BDNF reductions by epigenetic enhancement of H3K18ac at BDNF promoters. These findings suggest that increased QA is associated with cognitive decline in obesity and that butyrate alleviates neurodegeneration.

Obesity is a risk factor for cognitive dysfunction and neurodegenerative disease, including Alzheimer's disease (AD). The gut microbiota-brain axis is altered in obesity and linked to cognitive impairment and neurodegenerative disorders. Here, we targeted obesity-induced cognitive impairment by testing the impact of the probiotic Clostridium butyricum, which has previously shown beneficial effects on gut homeostasis and brain function. Firstly, we characterized and analyzed the gut microbial profiles of participants with obesity and the correlation between gut microbiota and cognitive scores. Then, using an obese mouse model induced by a Western-style diet (high-fat and fiber-deficient diet), the effects of Clostridium butyricum on the microbiota-gut-brain axis and hippocampal cognitive function were evaluated. Finally, fecal microbiota transplantation was performed to assess the functional link between Clostridium butyricum remodeling gut microbiota and hippocampal synaptic protein and cognitive behaviors. Our results showed that participants with obesity had gut microbiota dysbiosis characterized by an increase in phylum Proteobacteria and a decrease in Clostridium butyricum, which were closely associated with cognitive decline. In diet-induced obese mice, oral Clostridium butyricum supplementation significantly alleviated cognitive impairment, attenuated the deficit of hippocampal neurite outgrowth and synaptic ultrastructure, improved hippocampal transcriptome related to synapses and dendrites; a comparison of the effects of Clostridium butyricum in mice against human AD datasets revealed that many of the genes changes in AD were reversed by Clostridium butyricum; concurrently, Clostridium butyricum also prevented gut microbiota dysbiosis, colonic barrier impairment and inflammation, and attenuated endotoxemia. Importantly, fecal microbiota transplantation from donor-obese mice with Clostridium butyricum supplementation facilitated cognitive variables and colonic integrity compared with from donor obese mice, highlighting that Clostridium butyricum's impact on cognitive function is largely due to its ability to remodel gut microbiota. Our findings provide the first insights into the neuroprotective effects of Clostridium butyricum on obesity-associated cognitive impairments and neurodegeneration via the gut microbiota-gut-brain axis.

Background:Gut homeostasis, including intestinal immunity and microbiome, is essential for cognitive function via the gut-brain axis. This axis is altered in high-fat diet (HFD)-induced cognitive impairment and is closely associated with neurodegenerative diseases. Dimethyl itaconate (DI) is an itaconate derivative and has recently attracted extensive interest due to its anti-inflammatory effect. This study investigated whether intraperitoneal administration of DI improves the gut-brain axis and prevents cognitive deficits in HF diet-fed mice. Results:DI effectively attenuated HFD-induced cognitive decline in behavioral tests of object location, novel object recognition, and nesting building, concurrent with the improvement of hippocampal RNA transcription profiles of genes associated with cognition and synaptic plasticity. In agreement, DI reduced the damage of synaptic ultrastructure and deficit of proteins (BDNF, SYN, and PSD95), the microglial activation, and neuroinflammation in the HFD-fed mice. In the colon, DI significantly lowered macrophage infiltration and the expression of pro-inflammatory cytokines (TNF-alpha, IL-1 beta, IL-6) in mice on the HF diet, while upregulating the expression of immune homeostasis-related cytokines (IL-22, IL-23) and antimicrobial peptide Reg3 gamma. Moreover, DI alleviated HFD-induced gut barrier impairments, including elevation of colonic mucus thickness and expression of tight junction proteins (zonula occludens-1, occludin). Notably, HFD-induced microbiome alteration was improved by DI supplementation, characterized by the increase of propionate- and butyrate-producing bacteria. Correspondingly, DI increased the levels of propionate and butyrate in the serum of HFD mice. Intriguingly, fecal microbiome transplantation from DI-treated HF mice facilitated cognitive variables compared with HF mice, including higher cognitive indexes in behavior tests and optimization of hippocampal synaptic ultrastructure. These results highlight the gut microbiota is necessary for the effects of DI in improving cognitive impairment. Conclusions:The present study provides the first evidence that DI improves cognition and brain function with significant beneficial effects via the gut-brain axis, suggesting that DI may serve as a novel drug for treating obesity-associated neurodegenerative diseases.

The lifespan of schizophrenia patients is significantly shorter than the general population. Olanzapine is one of the most commonly used antipsychotic drugs (APDs) for treating patients with psychosis, including schizophrenia and bipolar disorder. Despite their effectiveness in treating positive and negative symptoms, prolonged exposure to APDs may lead to accelerated aging and cognitive decline, among other side effects. Here we report that dysfunctional mitophagy is a fundamental mechanism underlying accelerated aging induced by olanzapine, using in vitro and in vivo (Caenorhabditis elegans) models. We showed that the aberrant mitophagy caused by olanzapine was via blocking mitophagosome–lysosome fusion. Furthermore, olanzapine can induce mitochondrial damage and hyperfragmentation of the mitochondrial network. The mitophagosome–lysosome fusion in olanzapine‐induced aging models can be restored by a mitophagy inducer, urolithin A, which alleviates defective mitophagy, mitochondrial damage, and fragmentation of the mitochondrial network. Moreover, the mitophagy inducer ameliorated behavioral changes induced by olanzapine, including shortened lifespan, and impaired health span, learning, and memory. These data indicate that olanzapine impairs mitophagy, leading to the shortened lifespan, impaired health span, and cognitive deficits. Furthermore, this study suggests the potential application of mitophagy inducers as therapeutic strategies to reverse APD‐induced adverse effects associated with accelerated aging.

The microbiota–gut–liver axis has emerged as an important player in developing nonalcoholic steatohepatitis (NASH), a type of nonalcoholic fatty liver disease (NAFLD). Higher mushroom intake is negatively associated with the prevalence of NAFLD. This study examined whether lentinan, an active ingredient in mushrooms, could improve NAFLD and gut microbiota dysbiosis in NAFLD mice induced by a high-fat (HF) diet. Dietary lentinan supplementation for 15 weeks significantly improved gut microbiota dysbiosis in HF mice, evidenced by increased the abundance of phylum Actinobacteria and decreased phylum Proteobacteria and Epsilonbacteraeota. Moreover, lentinan improved intestinal barrier integrity and characterized by enhancing intestinal tight junction proteins, restoring intestinal redox balance, and reducing serum lipopolysaccharide (LPS). In the liver, lentinan attenuated HF diet-induced steatohepatitis, alteration of inflammation–insulin (NFκB-PTP1B-Akt-GSK3β) signaling molecules, and dysregulation of metabolism and immune response genes. Importantly, the antihepatic inflammation effects of lentinan were associated with improved gut microbiota dysbiosis in the treated animals, since the Spearman's correlation analysis showed that hepatic LPS-binding protein and receptor (Lbp and Tlr4) and pro- and antiinflammatory cytokine expression were significantly correlated with the abundance of gut microbiota of phylum Proteobacteria, Epsilonbacteraeota and Actinobacteria. Therefore, lentinan supplementation may be used to mitigate NAFLD by modulating the microbiota–gut–liver axis.

目的 分析代谢异常型肥胖(metabolically unhealthy obesity,MUO)和代谢正常型肥胖(metabolically healthy obesity,MHO)儿童的全血转录组特征,探讨MUO的生物标志物.方法 采用Gene Expression Omnibus(GEO)数据库的GSE146869数据集,包括27例肥胖儿童的全血转录组测序数据,其中13例MHO儿童,14例MUO儿童.利用R软件的"Limma"包,分析全血细胞中的差异表达基因.使用基因本体论(gene ontology,GO)富集分析、京都基因与基因组百科全书(Kyoto encyclopedia of genes and genomes,KEGG)富集分析、蛋白互作(protein-protein interaction,PPI)网络分析等生物信息学方法,探索差异表达基因的生物学功能.使用加权基因共表达网络分析(weighted gene co-expression network analysis,WGCNA),将差异表达基因聚类为模块,探索MUO的生物标志物或潜在治疗靶点.使用R软件进行生物信息分析和统计学分析.结果 MHO组与MUO组儿童的性别、年龄、体质量指数、收缩压、舒张压、空腹血糖、胰岛素含量和胰岛素抵抗指数比较,差异均无统计学意义(P值均>0.05).MUO组血清三酰甘油、白细胞介素-6和肿瘤坏死因子-α含量高于MHO组(P值均<0.05).与MHO组相比,MUO组上调109个基因,下调77个基因.186个差异表达基因富集到46个GO条目和3条KEGG通路.其中,细胞分裂周期5样蛋白(cell division cycle 5 like,CDC5L)、CTP合酶1(CTP synthase 1,CTPS1)和主要组织相容性复合体ⅠC(major histocompatibility complex classⅠ-C,HLA-C)基因为PPI网络图的枢纽基因.WGCNA将186个差异表达基因聚类生成5个模块,在青色模块中,切割和聚腺苷酸化特异因子7(cleavage and polyadenylation specific factor 7,CPSF7)处于核心位置,为枢纽基因.结论 186个差异表达基因和5个模块可以作为儿童MUO的潜在靶标,其中CDC5L、CTPS1、HLA-C和CPSF7基因可能在MUO发生、发展中扮演重要的角色.

BackgroundDietary fiber is fermented in the lower gastrointestinal tract, potentially impacting the microbial ecosystem and thus may improve elements of cognition and brain function via the gut-brain axis. β-glucans, soluble dietary fiber, have different macrostructures and may exhibit different effects on the gut-brain axis. This study aimed to compare the effects of β-glucans from mushroom, curdlan and oats bran, representing β-(1,3)/(1,6)-glucan, β-(1,3)-glucan or β-(1,3)/(1,4)-glucan, on cognition and the gut-brain axis.MethodsC57BL/6J mice were fed with either control diet or diets supplemented with β-glucans from mushroom, curdlan and oats bran for 15 weeks. The cognitive functions were evaluated by using the temporal order memory and Y-maze tests. The parameters of the gut-brain axis were examined, including the synaptic proteins and ultrastructure and microglia status in the hippocampus and prefrontal cortex (PFC), as well as colonic immune response and mucus thickness and gut microbiota profiles.ResultsAll three supplementations with β-glucans enhanced the temporal order recognition memory. Brain-derived neurotrophic factor (BDNF) and the post-synaptic protein 95 (PSD95) increased in the PFC. Furthermore, mushroom β-glucan significantly increased the post-synaptic thickness of synaptic ultrastructure in the PFC whilst the other two β-glucans had no significant effect. Three β-glucan supplementations decreased the microglia number in the PFC and hippocampus, and affected complement C3 and cytokines expression differentially. In the colon, every β-glucan supplementation increased the number of CD206 positive cells and promoted the expression of IL-10 and reduced IL-6 and TNF-α expression. The correlation analysis highlights that degree of cognitive behavior improved by β-glucan supplementations was significantly associated with microglia status in the hippocampus and PFC and the number of colonic M2 macrophages. In addition, only β-glucan from oat bran altered gut microbiota and enhanced intestinal mucus.ConclusionsWe firstly demonstrated long-term supplementation of β-glucans enhanced recognition memory. Comparing the effects of β-glucans on the gut-brain axis, we found that β-glucans with different molecular structures exhibit differentia actions on synapses, inflammation in the brain and gut, and gut microbiota. This study may shed light on how to select appropriate β-glucans as supplementation for the prevention of cognitive deficit or improving immune function clinically.

ScopeHepatic steatosis is a major health issue that can be attenuated by a healthy diet. This study investigates the effects and molecular mechanisms of butyrate, a dietary fiber metabolite of gut microbiota, on lipid metabolism in hepatocytes.Methods and resultsThis study examines the effects of butyrate (0–8 mM) on lipid metabolism in primary hepatocytes. The results show that butyrate (2 mM) consistently inhibits lipogenic genes and activates lipid oxidation‐related gene expression in hepatocytes. Furthermore, butyrate modulates lipid metabolism genes, reduces fat droplet accumulation, and activates the calcium/calmodulin‐dependent protein kinase II (CaMKII)/histone deacetylase 1 (HDAC1)‐cyclic adenosine monophosphate response element binding protein (CREB) signaling pathway in the primary hepatocytes and liver of wild‐type (WT) mice, but not in G‐protein‐coupled receptor 41 (GPR41) knockout and 43 (GPR43) knockout mice. This suggests that butyrate regulated hepatic lipid metabolism requires GPR41 and GPR43. Finally, the study finds that dietary butyrate supplementation (5%) ameliorates hepatic steatosis and abnormal lipid metabolism in the liver of mice fed a high‐fat and fiber‐deficient diet for 15 weeks.ConclusionThis work reveals that butyrate improves hepatic lipid metabolism through the GPR41/43‐CaMKII/HDAC1‐CREB pathway, providing support for consideration of butyrate as a dietary supplement to prevent the progression of NAFLD induced by the Western‐style diet.

Background Chinese medical postgraduates (CMPs) are a special subpopulation that has a great risk of mental health due to high workload, and heavy academic and clinical pressure during the COVID-19 pandemic. Physical activity has been demonstrated to be positive for the mental health of human being. However, little is known about the risks to mental health among CMPs as well as the potential effects of physical activity on mental health in CMPs during the COVID-19 pandemic. Aims In the present study, the aims are to (1) investigate the levels of PA and mental health that CMPs had; (2) to identify the potential factors that contribute to mental health among CMPs; (3) to explore the potential effects of PA on the mental health in CMPs. Methods The survey was conducted online across 25 provinces of mainland China in 28 medical colleges or universities with structured questionnaires. Physical Activity Rating Scale-3 (PARS-3), Depression, Anxiety, Stress Scales (DASS-21), and General Self-Efficacy Scale (GSES) were employed to assess the levels of PA, Negative emotional states, and self-efficacy of the participants, respectively. Resilience was evaluated using Connor-Davidson Resilience Scale (CD-RISC). The chi-square and Wilcoxon rank-sum tests were used to compare inter-group differences in demographic data and mental health conditions. Spearman's rank correlation test and partial correlation analysis were used to assess associations between exercise scores and mental health. Results We found some socio-demographic variables such as the location, education levels of parents and the levels of degrees they are training had potential effects on outcomes of mental health among 2,217 CMPs ( P < 0.05); furthermore, we also found that PA was negatively correlated with the negative emotion ( r = −0.045, P < 0.05) such as depression ( r = −0.052, P < 0.05), anxiety and stress, ( r = −0.051, P < 0.05) but positively correlated with the self-efficacy ( r = 0.143, P < 0.001) and resilience ( r = 0.192, P < 0.001) among Chinese postgraduate medical students. Conclusion We concluded that for Chinese postgraduate medical students, taking part in physical activity would depress negative emotions such as depression, anxiety, and stress, but improve their self-efficacy and resilience, which will benefit them in completing their studies and training.

Background: Neurodegenerative diseases, such as Alzheimer's disease patients (AD), Huntington's disease (HD) and Parkinson’s disease (PD), are common causes of morbidity, mortality, and cognitive impairment in older adults. Objective: We aimed to understand the transcriptome characteristics of the cortex of neurodegenerative diseases and to provide an insight into the target genes of differently expressed microRNAs in the occurrence and development of neurodegenerative diseases. Methods: The Limma package of R software was used to analyze GSE33000, GSE157239, GSE64977 and GSE72962 datasets to identify the differentially expressed genes (DEGs) and microRNAs in the cortex of neurodegenerative diseases. Bioinformatics methods, such as GO enrichment analysis, KEGG enrichment analysis and gene interaction network analysis, were used to explore the biological functions of DEGs. Weighted gene co-expression network analysis (WGCNA) was used to cluster DEGs into modules. RNA22, miRDB, miRNet 2.0 and TargetScan7 databases were performed to predict the target genes of microRNAs. Results: Among 310 Alzheimer's disease (AD) patients, 157 Huntington's disease (HD) patients and 157 non-demented control (Con) individuals, 214 co-DEGs were identified. Those co-DEGs were filtered into 2 different interaction network complexes, representing immune-related genes and synapse-related genes. The WGCNA results identified five modules: yellow, blue, green, turquoise, and brown. Most of the co-DEGs were clustered into the turquoise module and blue module, which respectively regulated synapse-related function and immune-related function. In addition, human microRNA-4433 (hsa-miR-4443), which targets 18 co-DEGs, was the only 1 co-up-regulated microRNA identified in the cortex of neurodegenerative diseases. Conclusion: 214 DEGs and 5 modules regulate the immune-related and synapse-related function of the cortex in neurodegenerative diseases. Hsa-miR-4443 targets 18 co-DEGs and may be a potential molecular mechanism in neurodegenerative diseases' occurrence and development.

Background Long-term high fat (HF) diet intake can cause neuroinflammation and cognitive decline through the gut-brain axis. (1, 3)/(1, 6)-β-glucan, an edible polysaccharide isolated from medical mushroom, Lentinula edodes ( L. edodes ), has the potential to remodel gut microbiota. However, the effects of L. edodes derived β-glucan against HF diet-induced neuroinflammation and cognitive decline remain unknown. This study aimed to evaluate the neuroprotective effect and mechanism of dietary L edodes β-glucan supplementation against the obesity-associated cognitive decline in mice fed by a HF diet. Methods C57BL/6J male mice were fed with either a lab chow (LC), HF or HF with L. edode s β-glucan supplementation diets for 7 days (short-term) or 15 weeks (long-term). Cognitive behavior was examined; blood, cecum content, colon and brain were collected to evaluate metabolic parameters, endotoxin, gut microbiota, colon, and brain pathology. Results We reported that short-term and long-term L. edodes β-glucan supplementation prevented the gut microbial composition shift induced by the HF diet. Long-term L. edodes β-glucan supplementation prevented the HF diet-induced recognition memory impairment assessed by behavioral tests (the temporal order memory, novel object recognition and Y-maze tests). In the prefrontal cortex and hippocampus, the β-glucan supplementation ameliorated the alteration of synaptic ultrastructure, neuroinflammation and brain-derived neurotrophic factor (BDNF) deficits induced by HF diet. Furthermore, the β-glucan supplementation increased the mucosal thickness, upregulated the expression of tight junction protein occludin, decreased the plasma LPS level, and inhibited the proinflammatory macrophage accumulation in the colon of mice fed by HF diet. Conclusions This study revealed that L. edodes β-glucan prevents cognitive impairments induced by the HF diet, which may occur via colon-brain axis improvement. The finding suggested that dietary L. edodes β-glucan supplementation may be an effective nutritional strategy to prevent obesity-associated cognitive decline.

Background: Cognitive impairment, an increasing mental health issue, is a core feature of the aging brain and neurodegenerative diseases. Industrialized nations especially, have experienced a marked decrease in dietary fiber intake, but the potential mechanism linking low fiber intake and cognitive impairment is poorly understood. Emerging research reported that the diversity of gut microbiota in Western populations is significantly reduced. However, it is unknown whether a fiber-deficient diet (which alters gut microbiota) could impair cognition and brain functional elements through the gut-brain axis. Results: In this study, a mouse model of long-term (15 weeks) dietary fiber deficiency (FD) was used to mimic a sustained low fiber intake in humans. We found that FD mice showed impaired cognition, including deficits in object location memory, temporal order memory, and the ability to perform daily living activities. The hippocampal synaptic ultrastructure was damaged in FD mice, characterized by widened synaptic clefts and thinned postsynaptic densities. A hippocampal proteomic analysis further identified a deficit of CaMKIId and its associated synaptic proteins (including GAP43 and SV2C) in the FD mice, along with neuroinflammation and microglial engulfment of synapses. The FD mice also exhibited gut microbiota dysbiosis (decreased Bacteroidetes and increased Proteobacteria), which was significantly associated with the cognitive deficits. Of note, a rapid differentiating microbiota change was observed in the mice with a short-term FD diet (7 days) before cognitive impairment, highlighting a possible causal impact of the gut microbiota profile on cognitive outcomes. Moreover, the FD diet compromised the intestinal barrier and reduced short-chain fatty acid (SCFA) production. We exploit these findings for SCFA receptor knockout mice and oral SCFA supplementation that verified SCFA playing a critical role linking the altered gut microbiota and cognitive impairment. Conclusions: This study, for the first time, reports that a fiber-deprived diet leads to cognitive impairment through altering the gut microbiota-hippocampal axis, which is pathologically distinct from normal brain aging. These findings alert the adverse impact of dietary fiber deficiency on brain function, and highlight an increase in fiber intake as a nutritional strategy to reduce the risk of developing diet-associated cognitive decline and neurodegenerative diseases.