👤 Kai Hu

Chronic ketamine exposure results in psychotic and cognitive symptoms that resemble those found in patients with schizophrenia. Emerging evidence suggests that patients with schizophrenia exhibit gut microbiota dysbiosis and decreased levels of short-chain fatty acids (SCFAs) and BDNF, which are related to the severity of psychotic and cognitive symptoms. Dietary inulin can regulate gut microbiota, SCFAs, and BDNF. However, the role of gut microbiota, SCFAs, and BDNF in chronic ketamine-induced schizophrenia-like behaviors is unclear. In this study, we found that chronic ketamine exposure for 28 days caused gut microbiota dysregulation, reduced the expression of SCFAs in serum, hippocampus, and feces, elevated gut permeability, downregulated the BDNF-TrkB-ERK1/2-CREB signaling pathway, caused neuronal damage, and decreased the expression of synaptic proteins Syn and PSD-95, which may lead to anxiety-like behaviors, prepulse inhibition (PPI) deficits, and spatial learning and memory deficits. In addition, inulin intervention reversed gut microbiota dysbiosis by decreasing the abundance of Show less

Prenatal stress (PS) significantly influences the neurodevelopment of offsprings, potentially resulting in deficits in learning and memory. Mangiferin (MGF) is a naturally occurring flavonoid compound found in many plants, exhibits various pharmacological effects. The study investigates the potential molecular mechanisms of MGF in improving learning and memory deficits in offspring exposed to PS. Animal model of PS offspring and ACR-induced PC12 cell model were used to investigate the effects of MGF. Synaptic plasticity-related proteins and the BDNF signaling pathway were studied, as well as MGF's potential to alleviate endoplasmic reticulum stress (ERS). MGF can mitigate learning and memory impairments and enhance the density of hippocampal neurons, as well as increase the expression of neuronal markers Neurogranin (Ng), DLG4 and activity marker c-fos in the offspring of PS mice. Meanwhile, MGF significantly increased BDNF signaling pathway and synaptic plasticity-related proteins in PS offspring. MGF also efficiently alleviated ERS. Additionally, MGF significantly up-regulated the reduced viability, DLG4 protein expression and synaptic plasticity-related proteins in ACR-induced PC12 cells. MGF can improve endoplasmic reticulum morphology and down regulated the expression of key molecular proteins in the endoplasmic reticulum signaling pathway. MGF could improve the cognitive and memory impairments in the PS offspring mice. The underlying mechanisms involved the alleviation of ERS and improvement of synaptic plasticity-related proteins. The study indicated that MGF holds promise as an effective intervention for ameliorating learning and memory deficits associated with PS, and it offers potential therapeutic effect for neurological disorders linked to ACR dysfunction. Show less

Dual GIP/GLP-1 receptor agonists have gained significant attention in clinical applications because of their remarkable efficacy in reducing obesity and type 2 diabetes. However, the mechanisms by which these dual agonists affect systemic metabolism remain elusive. To investigate the effects of a novel dual-receptor agonist, THDBH120, on systemic metabolism in obese individuals and the specific roles of GIPR and GLP-1R in modulating systemic and adipose tissue metabolism. To evaluate the intrinsic properties of THDBH120, we conducted a potency assay by using HEK293 cell lines overexpressing either human GIPR or GLP-1R and measured the accumulation of cAMP as a downstream second messenger following receptor activation. To evaluate the efficacy of THDBH120 on systemic metabolism, we used obese rodents and nonhuman primate species that received various doses and frequencies of THDBH120. To determine the metabolic roles of GLP-1R and GIPR in mediating the beneficial effects of THDBH120, we used GLP-1R- and GIPR-knockout mouse models treated with THDBH120, the GLP-1R agonist semaglutide, or the GIPR agonist LAGIPRA and performed transcriptomic sequencing analyses of adipose tissues. THDBH120 is a novel long-acting dual GIPR/GLP-1R agonist that has superior weight loss and metabolic improvement effects in rodents and mammals. The activation of GLP-1R by semaglutide or THDBH120 improved lipid metabolism, whereas the activation of GIPR by LAGIPRA or THDBH120 alleviated inflammation. THDBH120 improved lipid metabolism via GLP-1R-mediated pathways and mitigated inflammation by activating GIPR-associated pathways in the adipose tissues of obese mice. Both GLP-1R and GIPR are important in mediating the beneficial effects of dual receptors on systemic metabolism. THDBH120 is a novel long-acting dual GIPR/GLP-1R agonist that has potential clinical applications. Show less

The induction of nausea and emesis represents a significant barriers to optimizing weight loss medications for the treatment of obesity. Identifying mechanisms that improve tolerability and/or enhance efficacy without induction of emetic neurocircuitry could provide substantial therapeutic benefits. Candidate peptide YY (PYY)-based approaches for obesity treatment are no exception, as PYY-based therapeutics are uniformly associated with nausea and emesis. Recently, interest in glucose-dependent insulinotropic polypeptide receptor (GIPR)-based therapeutics has resurfaced, with some paradoxical findings from several preclinical studies showing that both GIPR agonism and antagonism, when combined with glucagon-like peptide-1 receptor (GLP-1R) agonists, result in greater body weight loss and superior glycemic control compared to GLP-1R agonism alone. Here, we investigated the effects of pharmacological modulation of the GIPR system on the actions of PYY. We found that systemic GIPR agonism attenuated PYY-induced malaise while preserving its anorectic and body weight-lowering effects in rats. Interestingly, GIPR antagonism enhanced PYY-induced hypophagia and body weight loss without compromising its malaise tolerability profile. Furthermore, inhibition of GIPR signaling significantly reduced PYY-induced c-Fos expression in the area postrema (AP) of the hindbrain. Since both NPY2R and GIPR are expressed in the same AP neurons, this suggests a potential neuronal pathway by which GIPR modulates the effects of PYY. Overall, our findings underscore the multifaceted actions of the GIPR system and highlight the therapeutic potential of both GIPR agonism and antagonism in enhancing and improving the effects of PYY-based obesity treatments. Show less

To investigate the metabolic mechanisms underlying weight regain (WR) after semaglutide withdrawal in females with obesity, focusing on gut microbiota, bile acid metabolism, and central nervous system regulation. In a prospective, single-arm interventional study, 28 women with obesity finished 36-week semaglutide treatment (2.4 mg/week) followed by 12-week withdrawal. Parallel animal studies used HFD-fed female rats with 4-week semaglutide intervention and 4-week withdrawal. Measurements included body weight, metabolic parameters, gut microbiota composition, bile acid profiles, and hypothalamic gene expression. During treatment, patients achieved significant weight loss (-16.9 ± 4.8 kg), but 71.4% exhibited WR (+5.1 ± 1.6 kg) post-withdrawal, with 78.5% reporting appetite rebound (≥30% increase in VAS score and a sustained ≥300 kcal/day rise). Animal studies showed post-withdrawal gut microbiota dysbiosis (increased Firmicutes/Bacteroidota ratio, reduced Clostridium sensu stricto 1), decreased ursodeoxycholic acid levels, and downregulated hypothalamic TGR5 expression. Hypothalamic orexigenic signaling (AgRP/NPY) rebounded while anorexigenic pathways (POMC/MC4R) attenuated. Improvements in hepatic and adipose lipid metabolism partially persisted through maintained AMPK/SIRT1 activation and AKT/mTOR suppression. The recurrence of WR and increased appetite after semaglutide withdrawal coincided with reversals in gut microbiota and related metabolic profiles. This pattern of changes may implicate gut-derived signals in the reactivation of central appetite pathways, providing a basis for investigating strategies to sustain weight loss. Show less

Genome-wide association studies (GWASs) have identified hundreds of obesity-associated SNPs, but establishing their causality remains challenging. Here, we demonstrate that rs11676272, located in the ADCY3 gene, is a functional causal variant for obesity susceptibility. Bioinformatic analyses and dual-luciferase reporter assays indicate that the rs11676272 region may act as a human-gained enhancer regulating ADCY3 expression. In HEK293T cells, CRISPR-Cas9-mediated single-nucleotide editing of rs11676272 (T > C) reduces ADCY3 expression. Moreover, the rs11676272-T allele is preferentially bound by the transcription factor E2F3 to upregulate ADCY3 expression, whereas the rs11676272-C risk allele loses this binding. In vivo, the rs11676272 T > C variant in human ADCY3 (hADCY3) knock-in mice accelerates weight gain under high-fat diet conditions and shortens primary cilia in the ventromedial hypothalamus (VMH). CRISPRa-mediated activation of the hADCY3 promoter region rescues ciliary length in both the VMH and hypothalamic arcuate nucleus of Mut-hADCY3 mice. Our data reveal a causal role for rs11676272 in obesity, offering insight into potential therapeutic strategies. Show less

Human genetic analyses have identified numerous single-nucleotide polymorphism (SNP) loci in noncoding regions associated with obesity-related traits; however, the functional contributions of such SNP loci to obesity are largely unknown. The noncoding variant rs713586, with its risk allele C, is linked to two candidate genes, DNAJC27 and ADCY3, potentially implicated in obesity. However, whether rs713586 primary targets ADCY3 or DNAJC27 gene to regulate body weight and what molecular mechanisms underlie this process remain unclear. We conducted bioinformatics analyses using BMI data from the UK biobank and GIANT consortium, and prioritised functional variants on chromosome 2 linked to ADCY3 gene for experimental validation. The variant rs713586 was identified as a functional regulator of ADCY3 and DNAJC27 expression. We investigated the molecular mechanisms by which rs713586 participates in obesity through epigenetic regulation. Dual-luciferase reporter assay and genome-editing in cell lines were conducted to assess the impacts of the rs713586-C risk allele or a proximal enhancer (Enh) on ADCY3 and DNAJC27 promoter activity and expression levels. CRISPR/Cas9-mediated knockout of Dnajc27 was performed in mice to evaluate its role in obesity. Mechanistic studies examined the interactions between the rs713586-T or -C alleles and the transcription factor ZFP42. Additionally, we assessed the DNA methylation patterns within the Enh and promoter regions of ADCY3 to evaluate their impact on ADCY3 expression. First, the rs713586-C risk allele significantly reduced the promoter activity of ADCY3 and DNAJC27 and thus reduced their expression levels. However, Dnajc27 knockout mice did not develop obesity, thereby excluding DNAJC27 as the target gene through which rs713586 mediates obesity. Further, we demonstrate that the rs713586-C allele impaired ZFP42 binding, leading to decreased TET1 recruitment and increased DNA methylation in the Enh and promoter regions of ADCY3, ultimately suppressing its expression. Given that ADCY3 is a well-established gene involved in obesity, we conclude that the rs713586-C risk allele may associated with obesity susceptibility, concomitant with downregulated ADCY3 expression. Our findings establish the rs713586-ZFP42-TET1-ADCY3 epigenetic regulatory axis, providing insights into the mechanism of rs713586-mediated obesity pathogenesis. National Natural Science Foundation of China and Natural Science Foundation of Hebei Province of China (32470645, 32070567, 32202840), and Priority-Funded Postdoctoral Research Project, Zhejiang Province (ZJ2025118). Full funding details are provided in the Acknowledgements. Show less

Naringenin (NGN), a flavonoid widely utilized in agricultural and pharmaceutical applications, has increasingly become a source of environmental concern. This study systematically evaluated the developmental toxicity of NGN in zebrafish embryos. Our results showed that NGN exposure caused dose-dependent increases in embryonic mortality and induced a range of developmental malformations, including reduced body length, impaired eye and ear development, and cardiac dysfunction. Behavioral analyses revealed significant deficits in locomotor activity and sensory responses at concentrations of 5 and 10 mg/L. Molecular assessments via RT-qPCR demonstrated that NGN disrupted the expression of multiple genes critical for cardiac (kcnh2a, kcnh2b, hand2, has2, myh7, tnnt2a), otic (col2a1a, sox9a, sox9b), liver (hhex, leg1.1), visual (gnat1, gnat2), apoptotic (bax, casp9, casp3), and neurodevelopmental (pomca, bdnf, gfap, mbpa, s100b) pathways. Notably, NGN at 10 mg/L inhibited apoptosis and altered liver function, whereas a concentration of 15 mg/L promoted apoptosis, and these results suggest that NGN may interfere with the developmental processes of zebrafish embryos through different mechanisms at low and high concentrations, exhibiting a non-monotonic dose-response relationship. These findings highlight the potential ecological hazards of NGN contamination in aquatic environments, emphasizing the need for stricter management and further research into its long-term and combined effects with other pollutants. Our research offers new perspectives into the molecular and phenotypic mechanisms of NGN toxicity and underscores the importance of comprehensive risk assessment for emerging environmental contaminants. Show less

Gestational intermittent hypoxia (GIH), which serves as a model for obstructive sleep apnea (OSA), is associated with adverse maternal and neonatal outcomes, especially cognitive impairments in offspring. Growing evidence supports that the anti-inflammatory actions of melatonin significantly influence the peripartum environment and contribute to the mitigation of neurodegeneration. However, the full impact of GIH on offspring cognition and the molecular mechanisms by which melatonin modulates these effects remain uncertain. Thus, in this study, we explored the neurobiological changes in GIH-exposed offspring and the mechanism underlying maternal melatonin supplementation in preventing these alterations using a murine model. C57BL/6J mice were exposed to GIH between gestational Days 15 and 21. Concurrently, dams received either vehicle or melatonin. The Morris water maze test was employed to evaluate offspring cognitive function, after which the offspring were euthanized at 2 months of age. The hippocampal levels of glial markers (ionized calcium-binding adapter molecule 1 [Iba-1], glial fibrillary acidic protein [GFAP]), NOD-like receptor thermal protein domain-associated protein 3 [NLRP3], nuclear factor-kappa B [NF-κB], tight-junction proteins (zonula occludens-1 [ZO-1], occludin), and synaptic plasticity-related proteins (brain-derived neurotrophic factor [BDNF], tropomyosin receptor kinase B [TrkB], postsynaptic density protein 95 [PSD-95], synaptophysin [SYN]) were quantified by enzyme-linked immunosorbent assay and western blot. Maternal melatonin supplementation significantly attenuated learning and memory impairments, reduced the protein levels of Iba-1 and GFAP by suppressing NLRP3/NF-κB signaling, and elevated those of ZO-1, occludin, BDNF, TrkB, PSD-95, and SYN. Additionally, melatonin mitigated inflammatory responses, glial cell activation, blood-brain barrier (BBB) leakage, and synaptic dysfunction induced by GIH in mice. Our results demonstrated that GIH-exposed mice exhibit cognitive deficits, alongside neuroinflammatory responses, leading to inflammasome activation, glial reactivity, BBB breakdown, and synaptic deficits. However, melatonin exerted significant protective effects against these deleterious effects. Show less

There is a significant association between depressive episodes of bipolar disorder and non-suicidal self-injury (NSSI). Mindfulness-based cognitive therapy (MBCT) represents an evolution of cognitive behavioural therapy and serves as a comprehensive psychological intervention. Preliminary research suggests that MBCT may enhance cognitive flexibility and attentional adjustment in patients with depressive episodes of bipolar disorder by modulating brain activity. The aim of this study was to explore the effects of MBCT on behaviour, cognitive function, and serum precursor of brain-derived neurotrophic factor (proBDNF) levels in adolescents with depressive episodes of bipolar disorder. A total of 149 adolescent patients with bipolar disorder and depression with NSSI were randomly assigned. The Chinese version of the Adolescent Non-suicidal Self-Injury Assessment Questionnaire (ANSAQ) was used to measure NSSI symptoms. One group received MBCT in addition to treatment as usual (TAU) (n = 75), while the other group received TAU alone (n = 74). At baseline and at weeks 4 and 8 after treatment initiation, participants were assessed using the Barratt Impulsiveness Scale (BIS), the Hamilton Anxiety Scale (HAMA), the Repeatable Battery for the Assessment of Neuropsychological Status, and the Hamilton Depression Scale (HAMD). In addition, serum precursor Brain-Derived Neurotrophic Factor (proBDNF) levels were determined using an enzyme-linked immunosorbent assay. After 4 and 8 weeks of treatment, the MBCT group showed significantly greater improvement than the control group across the three BIS dimensions (motor impulsiveness, cognitive impulsiveness, and non-planning impulsiveness) (P < 0.001). HAMD scores in the MBCT group were significantly lower than those in the TAU group (4 weeks: MBCT:16.89 ± 1.45 vs TAU:17.27 ± 1.47, P < 0.05; 8 weeks: MBCT:9.24 ± 1.43 vs TAU:11.01 ± 1.84, P < 0.001). Similarly, HAMA scores were lower in the MBCT group (4 weeks: MBCT:13.14 ± 1.30 vs TAU:14.13 ± 1.65, P < 0.05; 8 weeks: MBCT:7.16 ± 1.68 vs TAU:8.17 ± 1.40, P < 0.001). Regarding cognitive function, the MBCT group demonstrated significantly higher scores in immediate memory (4 weeks: MBCT:72.31 ± 11.08 vs TAU:68.31 ± 9.36 P < 0.05; 8 weeks:MBCT:74.80 ± 13.06 vs TAU:71.87 ± 13.64, P < 0.05), delayed memory (4 weeks: MBCT:74.46 ± 11.50 vs TAU:70.20 ± 11.76, P < 0.05; 8 weeks: MBCT:76.54 ± 13.07 vs TAU:71.90 ± 12.60, P < 0.001), attention (4 weeks: MBCT:77.53 ± 11.41 vs TAU: 73.01 ± 13.21, P<0.05; 8 weeks: MBCT:84.56 ± 12.77 vs TAU:76.87 ± 11.38, P < 0.001), language ability (4weeks: MBCT:76.47 ± 12.17 vs TAU:72.13 ± 13.25 P < 0.05;8 weeks: MBCT:79.89 ± 15.02 vs TAU:74.83 ± 12.97, P < 0.05) and visuospatial ability (4 weeks:MBCT:89.04 ± 10.92 vs TAU:84.01 ± 12.67 P < 0.05;8 weeks:MBCT:90.23 ± 13.62 vs TAU:87.67 ± 12.74 P < 0.05) . In addition, serum proBDNF levels in the MBCT group were significantly lower than those in the TAU group at both 4 weeks (MBCT:1.34 ± 0.09 ng/mL vs TAU:1.40 ± 0.06 ng/mL, P < 0.05) and 8 weeks (MBCT:1.27 ± 0.07 ng/mL vs TAU:1.31 ± 0.04 ng/mL, P < 0.05). MBCT can effectively reduce impulsive behaviour, alleviate depressive and anxiety symptoms related to self-injurious behaviour in adolescents with bipolar depression, and decrease serum proBDNF levels. Additionally, immediate memory, delayed memory, attention, language, and visuospatial ability were significantly improved following treatment. Show less

Acute hepatitis is a major pathological process underlying acute liver injury (ALI) and acute liver failure (ALF), both of which are associated with high mortality. Yet, no effective treatment is currently available, underscoring the pressing need for novel therapeutic targets. By integrating multiple transcriptomic datasets, this study finds that the expression of brain-derived neurotrophic factor (BDNF) is consistently downregulated in hepatocytes across various ALI/ALF models. Mechanistically, this downregulation is attributed to transcriptional repression of BDNF by RE1-silencing transcription factor. Restoration of endogenous BDNF or exogenous administration of recombinant BDNF significantly alleviates LPS/DGal-induced ALI/ALF. Correlation analysis and proteomic profiling reveal that BDNF exerts potent anti-inflammatory effects by directly binding to and antagonizing Toll-like receptor 4 (TLR4) on macrophages. Structural analysis identifies amino acids 233-244 of BDNF as the key functional domain responsible for this effect. A synthetic 12-mer peptide derived from this region, termed BDP12, retains TLR4-antagonizing ability, demonstrating strong anti-inflammatory efficacy and a favorable safety profile in cultured macrophages and mouse ALI/ALF models. In conclusion, this study identifies hepatocyte-derived BDNF as an endogenous antagonist of TLR4 and a critical immune checkpoint in acute hepatitis. BDNF and its mimetic peptide BDP12 represent promising therapeutic candidates for treating acute hepatitis-mediated ALI/ALF. Show less

Epilepsy is increasingly linked to neurodegeneration, yet the cellular drivers of the neuron-microglia interplay remain unclear. Herein, we present "EpiNeuroid", a 3D-bioprinted human neural organoid that incorporates barium titanate piezoelectric nanoparticles to generate an on-demand, ultrasound-triggered electrostimulatory microenvironment that induces a hyperexcitable state, recapitulating key electrophysiological signatures indicative of a trend toward epileptiform discharges. EpiNeuroid recapitulates neuronal DAMPs release (HMGB1, TLR4, NF-κB), microglial activation (Iba1, TNF-α, IL-1β, IL-6, iNOS), heightened neuronal Ca Show less

Post-cardiac surgery anxiety or depression (PCPAD) is a common neuropsychiatric complication following cardiovascular interventional procedures, which significantly increases the risk of adverse cardiovascular events and long-term mortality. Existing treatment strategies have limitations, and clinical needs remain unmet. The gut-brain axis (GBA) serves as a core network regulating neuroimmune and endocrine responses, and its imbalance involves key links such as intestinal flora dysbiosis and neuroimmune crosstalk disorders. It is closely related to the pathogenesis of this complication, providing a novel perspective for targeted interventions. This review aims to systematically clarify the mechanism of GBA in PCPAD, comprehensively explore therapeutic strategies targeting this axis, and focus on the intervention value and application potential of natural products. The study was designed and conducted in strict accordance with the PRISMA 2020 guidelines. Relevant literatures were searched from PubMed, Web of Science Core Collection, ScienceDirect, Embase, Cochrane Library, and CNKI databases from their inception to December 2025. Literatures focusing on GBA-related mechanisms of PCPAD or investigating the mechanisms and clinical applications of natural products targeting GBA for PCPAD treatment were included. Conference abstracts, case reports, duplicate publications, and other ineligible literatures were excluded. Through quality control strategies including double independent screening and verification, priority inclusion of high-credibility evidence, and data cross-validation, 168 eligible literatures were finally included. The composition and functions of GBA, its imbalance mechanisms, and the basic and clinical evidence of natural product-based interventions were systematically analyzed. Studies have shown that GBA imbalance is the core pathogenesis of PCPAD, among which the inflammatory cascade initiated by intestinal flora dysbiosis, abnormal activation of the neuroendocrine axis, disorder of immune-nerve crosstalk, and abnormal gene and epigenetic regulation are key pathological links. In summary, GBA imbalance, especially gut microbiota dysbiosis and neuroimmune interactions, plays a critical role in the pathogenesis of PCPAD. Natural products (including traditional Chinese medicine (TCM) monomers, TCM compound prescriptions, patented TCM drugs, and natural products from other plant sources worldwide) can exert therapeutic effects by synergistically regulating GBA homeostasis through multiple targets. Specifically, they include increasing the abundance of beneficial bacteria such as Bifidobacterium and Lactobacillus, promoting the production of anti-inflammatory metabolites such as short-chain fatty acids, repairing intestinal barrier function, inhibiting pro-inflammatory pathways such as NF-κB and NLRP3 inflammasome, and regulating the levels of neurotransmitters and neurotrophic factors such as 5-HT and BDNF. Basic and clinical studies have confirmed that these natural products have high biocompatibility and low toxic side effects, and are compatible with the safe medication needs of patients during the organ function recovery period after cardiac surgery. Several natural products have been proven to modulate GBA dysfunction, with potential for clinical therapeutic application. This review systematically elucidates a new paradigm of precise intervention for PCPAD via natural products that regulate GBA through multiple targets, addressing the limitation of traditional single-target therapies and providing a low-cost, easily promotable solution for clinical translation. Additionally, natural product-based interventions offer a novel approach for treating post-cardiac surgery complications. In the future, it is necessary to further conduct large-sample, multicenter clinical trials to clarify their mechanisms of action and standardized dosage regimens, strengthen toxicological research, facilitate the translation from basic research to clinical practice, and provide more precise therapeutic strategies for patients. Show less

Alzheimer's disease (AD) is one of the most common forms of neurodegenerative disorder characterized by extracellular Aβ accumulation and intracellular tau hyperphosphorylation. Currently, there are no effective therapeutic drugs available for AD. Regular exercise training has emerged as a promising physical intervention strategy for mitigating both the risk and progression of AD, but different types of exercise interventions show varied and conflicting results in AD treatment, with their differential effects and mechanisms still unelucidated. Using an Aβ oligomer-induced AD mouse model, we investigated therapeutic effects of voluntary wheel running, forced treadmill running, and combined exercise (voluntary combined with forced running) on AD pathologies. For depressive-like behavior, we conducted forced swimming test and tail suspension test; for cognition, Novel object recognition test (object recognition ability) and Morris water maze test (spatial learning and memory) was used respectively. We applied BrdU-DCX/NeuN/GFAP immunofluorescence co-staining to measure neurogenesis, Western blot to examine proteins associated with synapses, neurons, astrocytes, apoptosis, and BDNF signaling key components, serum metabolomics to identify exercise-induced metabolites. Furthermore, a clinical trial involving healthy subjects and patients with AD implemented an acute exercise intervention and utilized portable functional near-infrared spectroscopy to assess cortical activation and functional connectivity under conditions of both voluntary and forced exercise. Voluntary, forced, and combined exercise alleviated depressive-like phenotypes and short-term cognitive deficits in AD mice, while only forced exercise conferred sustained long-term memory benefit. All exercises boosted hippocampal neurogenesis by enhancing newborn cell (BrdU Our findings reveal distinct neuroprotective profiles of long-term voluntary, forced, and combined exercise interventions against Aβ oligomer neurotoxicity in an AD mouse model, and different acute exercise modalities also demonstrate distinct effects on cortical activation and functional connectivity in patients with AD. Our study provides novel insights into exercise modalities' therapeutic effects in ameliorating AD neuropathology. Show less

Chronic pain (CP) is increasingly recognized not only as a sensory and emotional condition but also as a significant contributor to cognitive dysfunction. Growing evidence indicates that CP-induced cognitive dysfunction arises from a cascade of neurobiological processes, including persistent neuroinflammation, neurotransmitter dysregulation, and impaired synaptic plasticity. These mechanisms particularly affect the hippocampus and medial prefrontal cortex (mPFC)-regions essential for memory, attention, and executive function. Neuroimaging studies have documented structural atrophy and disrupted network connectivity in these brain areas in CP patients. At the molecular level, pro-inflammatory cytokines such as interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) impair glutamatergic and GABAergic signaling, disrupt long-term potentiation (LTP), and inhibit neurogenesis. Additionally, dysregulation of brain-derived neurotrophic factor (BDNF) signaling exacerbates synaptic vulnerability, contributing to cognitive decline. These mechanistic overlaps are particularly relevant in aging populations and in Alzheimer's disease (AD), where CP may act as a risk factor. This review integrates clinical and preclinical findings on CP-related cognitive dysfunction, outlines key molecular mechanisms, and explores emerging therapeutic strategies targeting inflammation, neurotransmitter systems, and synaptic repair. Understanding the interaction between chronic pain and cognition is critical for developing precision treatments that address both nociceptive and neurodegenerative pathways. Show less

Retigabine (RTG) shows notable neuroprotective efficacy in multiple brain injury models; however, its interplay with endoplasmic reticulum stress (ERS) is poorly understood. This study was designed to explore the therapeutic potential of RTG against CRS-induced depression-like behaviors and cognitive deficits in mice and to uncover the associated molecular mechanisms. A depression-like and cognitive impairment model was established in C57BL/6 male mice using chronic restraint stress (CRS). Six-week-old C57BL/6 male mice were randomly assigned to the following groups: control (Con), model (CRS), RTG (10 mg/kg), XE-991 (2 mg/kg) or tunicamycin (Tm, 2 mg/kg). Behavioral tests were conducted to assess depression-like behaviors and cognitive function. Hippocampal neuronal morphology was examined by H&E and immunofluorescence staining, while changes in endoplasmic reticulum stress (ERS)-related signaling pathways were analyzed by Western blot. Retigabine treatment reduced hippocampal neuronal damage and the expression of ERS-related factors (GRP78, CHOP) and the pro-apoptotic factor BAX in CRS-induced mice, while it increased the levels of BDNF. These effects were antagonized by XE-991 and the ERS agonist tunicamycin (Tm). Retigabine may alleviate CRS-induced depressive-like behaviors and cognitive impairment by inhibiting ERS-mediated apoptosis, suggesting its potential as a novel therapeutic strategy for depression. Show less

To investigate the therapeutic mechanisms of miR-9-5p-overexpressing human umbilical cord mesenchymal stromal cells (hUC-MSCs) in neonatal rat models of hypoxic-ischemic brain damage (HIBD). Fresh neonatal umbilical cords were collected to isolate and culture human umbilical cord mesenchymal stromal cells (hUC-MSCs). Recombinant adenovirus was used to amplify miR-9-5p and transduce hUC-MSCs, generating miR-9-5p-overexpressing cells. Functional assessments included: ELISA to evaluate secretory function (e.g., neurotrophic and anti-inflammatory factors), real-time cell analysis to measure proliferation capacity, Transwell and Dunn chamber assays to assess chemotactic migration ability. Healthy 7-day-old Sprague-Dawley (SD) rats of both sexes were randomly allocated into four groups (n = 12/group, with 4 rats per group assigned to TTC staining, Western blot, or Morris water maze assay, respectively): Sham-operated control group (mock surgery), Hypoxic-ischemic brain damage (HIBD) model group, miR-9-5p-hUC-MSCs treatment group, and Adenovirus-transduced hUC-MSCs (Ad-hUC-MSCs) treatment group. The HIBD model was induced in groups 2-4. At 24 h post-modeling, 1×10 Spindle-shaped and polygonal adherent cells emerged within 3-5 days following umbilical cord tissue block inoculation, with flow cytometric analysis confirming their identity as mesenchymal stromal cells (MSCs). Compared to the Ad-hUC-MSCs treatment group, miR-9-5p enhanced the secretion of neuroreparative and anti-inflammatory factors (e.g., NGF, BDNF, IL-6) in hUC-MSCs while suppressing pro-inflammatory cytokines (e.g., IL-1, IL-2) (p < 0.05). Furthermore, miR-9-5p significantly promoted hUC-MSCs proliferation and augmented the chemotactic migratory capacity of miR-9-5p-hUC-MSCs. At 48 h post-transplantation in the miR-9-5p-hUC-MSCs group, the sham-operated controls showed no detectable cerebral infarction, whereas the model group exhibited distinct pale infarct foci occupying 33.15% ± 4.38% of total brain volume (vs. controls, p < 0.05), indicating severe cerebral injury. Both miR-9-5p-hUC-MSCs and Ad-hUC-MSCs treatments markedly reduced infarct volumes to 14.85% ± 2.79% and 19.11% ± 4.57%, respectively, with the miR-9-5p-hUC-MSCs group demonstrating a statistically superior therapeutic effect compared to Ad-hUC-MSCs (p < 0.05). Transplantation of either Ad-hUC-MSCs or miR-9-5p-hUC-MSCs significantly improved short- and long-term neurobehavioral outcomes in hypoxic-ischemic brain damage (HIBD) rats. At 48 h post-HIBD induction, upregulated expression of Beclin-2 and Caspase-3 proteins was observed in brain tissue. Notably, these elevated protein levels were attenuated following treatment with miR-9-5p-hUC-MSCs or Ad-hUC-MSCs. MiR-9-5p enhances the secretion of immunomodulatory factors and improves the migratory and proliferative capacities of hUC-MSCs. Overexpression of miR-9-5p promotes in vivo homing of hUC-MSCs, which mitigate cerebral injury and exert neuroprotective and reparative effects through dual mechanisms: modulating immune responses and providing neurotrophic support. Furthermore, hUC-MSCs significantly reduce cerebral infarct volume in hypoxic-ischemic brain damage (HIBD) rats and downregulate levels of apoptotic proteins (Beclin-2 and Caspase-3) in brain tissue, demonstrating potent cerebroprotective effects. Show less

Alzheimer's disease (AD) is a common dementia in the elderly population, typically manifested through symptoms of cognitive impairment (CI) and memory loss. Pathologically, it is characterized by abnormally elevated levels of amyloid-β (Aβ) deposition and tau phosphorylation. Given the rapid rate of population aging, many scientists are investigating AD, focusing on its pathogenic mechanisms and potential treatments. Unfortunately, to date, no highly effective therapeutic strategies have emerged. Intriguingly, multiple studies have revealed alterations in the gut microbiome of individuals with AD, suggesting it may serve as a novel avenue for investigating AD pathogenesis. Show less

Alzheimer's disease (AD) is increasingly recognized as a multisystem disorder shaped not only by central neurodegeneration but also by peripheral metabolic and immune dysregulation. Growing evidence highlights the gut microbiota and its metabolites as key modulators of amyloid accumulation, tau phosphorylation, neuroinflammation, and microglial dysfunction. This review aims to synthesize current advances on how plant-derived bioactive compounds modulate AD pathophysiology through microbiota-dependent metabolic and neuroimmune mechanisms, and to establish a systems-level framework linking botanical interventions to gut microbiota remodeling and metabolite signaling. A comprehensive literature survey was conducted using PubMed, Web of Science, ScienceDirect, and Google Scholar, covering publications from 2010 to 2026. Studies investigating gut microbiota, microbial metabolites, and plant-derived bioactive compounds in AD-related metabolic, immune, and neurodegenerative pathways were systematically reviewed and integrated. Plant-derived bioactive compounds, including phytochemicals, polysaccharides, and multi-herb formulations, interact extensively with the gut microbiota, undergoing microbial biotransformation to yield more active metabolites while simultaneously reshaping microbial community structure and metabolite profiles. These bidirectional interactions position the microbiota as a central mediator of plant-derived therapeutic activity. We summarize current evidence on how plant-derived compounds influence AD pathophysiology through microbiota-dependent metabolic and neuroimmune pathways. Major microbial metabolites, including short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO), bile acids (BAs), and indole derivatives, are discussed, together with their regulatory roles in signaling networks such as nuclear factor κB (NF-κB), phosphatidylinositol 3-kinase/Akt (PI3K/Akt), cAMP response element-binding protein/brain-derived neurotrophic factor (CREB/BDNF), and triggering receptor expressed on myeloid cells 2 (TREM2)-associated microglial states. We further summarize evidence for synergistic strategies combining plant bioactives with probiotics and highlight advances in microbial biotransformation, precision metabolite modulation, and engineered microbial systems. Finally, future directions integrating multi-omics, personalized microbiota-guided interventions, and synthetic biology are outlined to support the development of targeted, mechanism-based therapies. By framing AD through a gut microbiota-centered perspective, this review provides a unified mechanistic foundation for the development of next-generation interventions based on plant-derived compounds and microbiota regulation. Show less

Social context modulates stress physiology and resilience, yet preclinical rat paradigms vary widely in stressor type, timing of social exposure, contact modality, and endpoint definitions. We synthesized rat studies to quantify directional and, where feasible, standardized effect-size evidence for social buffering and to outline translational implications. PubMed, Scopus, and Web of Science were searched (2008-2025) for in vivo rat studies comparing conspecific (pair/group housing or conspecific presence) versus solitary conditions across validated stress and PTSD-like paradigms (e.g., fear conditioning/extinction, CUS/CMS, social defeat, predator threat). Data extraction and reporting followed PRISMA 2020 and SYRCLE guidance. Synthesis followed a two-tier approach: (i) all eligible contrasts were direction-coded as beneficial, neutral/mixed, or detrimental under conspecific conditions based strictly on reported statistical contrasts; and (ii) for domains with sufficient coded contrasts, the proportion of beneficial comparisons was estimated with exact binomial tests and 95% confidence intervals. Standardized mean-difference meta-analysis (Hedges' g; random-effects REML) was conducted only for predefined outcomes with adequate numerical reporting. Forty studies met inclusion criteria, yielding 89 extracted comparisons. Overall, 69/89 comparisons (≈78%) favored conspecific conditions. Domain-level directional syntheses supported predominance of beneficial outcomes for hormonal (0.72; 95% CI 0.50-1.00; p = 0.048) and neurotrophic/plasticity markers (0.89; 95% CI 0.57-1.00; p = 0.020), whereas inflammatory/oxidative outcomes were more variable (0.71; 95% CI 0.39-0.94; p = 0.227). For predefined behavioral endpoints with sufficient data, effect-size pooling showed a large reduction in conditioned fear (Hedges' g = -1.22 [-1.53; -0.91], p < 0.0001). Social buffering is robust at behavioral and neuroendocrine levels and often aligns with neurotrophic/plasticity markers, while peripheral immune/redox readouts are more context-dependent. Show less

While mindfulness has demonstrated efficacy in enhancing executive function in non-athletes through improved present-moment awareness and acceptance of current experiences, particularly regarding attention regulation and cognitive control, its neurocognitive mechanisms and the effects and underlying mechanisms of mindfulness-based intervention (MBI) on different executive functioning skills in athletic populations remain poorly understood. The purpose of this randomized controlled trial tackles a novel and important topic by investigating the beneficial effects of 12-week MBI on executive functioning skills in baseball players-a population that faces unique cognitive and physical demands, and the associated neurophysiological and biochemical regulation mechanisms. Thirty-four baseball players were randomly divided into the MBI group (11M/6F) and the control group (11M/6F). Executive functioning skills (N-back task for working memory, Stroop task for inhibitory control, and Switching task for cognitive flexibility) were tested before and after the intervention. Functional near-infrared spectroscopy (fNIRS) was used to record quantified hemodynamic responses in the prefrontal cortex through oxygenated hemoglobin concentration (Oxy-Hb) monitoring during the performance of executive function tasks. Biomarkers of cognitive function, including BDNF, IL-6, TNF-α, and Cortisol, were measured using enzyme-linked immunosorbent assays (ELISA). MBI partially improved all three executive function skills, with increased Oxy-Hb level in L-FPA during the task of working memory, increased Oxy-Hb level in R-VLPFC during the task of inhibitory control, and decreased Oxy-Hb level in R-FPA, M-FPA, and L-DLPFC during the task of cognitive flexibility. Furthermore, MBI increased circulating BDNF level and decreased IL-6 and Cortisol levels. In addition, our correlation analyses showed that improvement in executive function (improved behavioral performances and changes in Oxy-Hb levels) were associated with changes in Cortisol and inflammatory cytokines (TNF-α and IL-6). A 12-week MBI partially improved three components of executive function in baseball players. This enhancement may be attributed to the MBI-induced reductions in Cortisol and inflammatory cytokines (such as TNF-α and IL-6), which altered blood oxygen contents in specific brain regions, thereby promoting executive function. Show less

The high global prevalence of anxiety disorders, coupled with the limitations of existing treatments, constitutes a severe public health challenge. Chronic stress, as a core environmental trigger, has garnered increasing attention for its mechanism of mediating brain-derived neurotrophic factor (BDNF) imbalance through neuroinflammation. BDNF dysregulation may contribute to anxiety disorders, particularly in subtypes with heightened neuroinflammation. The objective of this review is to comprehensively and methodically explores the potential role of the "M1-like microglia-A1-like astrocyte axis (M1-A1 axis)" in linking chronic stress to BDNF dysregulation in anxiety disorders, and to provide a theoretical basis for intervention strategies targeting this axis. By synthesizing recent relevant clinical and preclinical evidence, this review integrates evidence from molecular to systems levels, focusing on the activation mechanisms of neuroinflammation under chronic stress, the crosstalk between glial cells, and their regulatory network on BDNF. Chronic stress is associated with peripheral and central cascades through hypothalamic-pituitary-adrenal (HPA) axis activation and gut microbiota disruption. Within the central nervous system (CNS), stress induces microglial polarization toward the pro-inflammatory microglial subpopulations (hereinafter referred to as M1-like microglia). The signals released by M1-like microglia, such as Interleukin-1 alpha (IL-1α), Tumor Necrosis Factor-alpha (TNF-α), and Complement Component 1q (C1q) (ITC), drive astrocytes to transform into the neurotoxic astrocyte states (hereinafter referred to as A1-like astrocyte), forming the "M1-A1 axis". This axis contributes to BDNF dysregulation through the following mechanisms: (1) Release of pro-inflammatory cytokines inhibits BDNF transcription and translation; (2) Induction of astrocytic lactate metabolism disruption, which impairs neuronal energy supply and acidifies the microenvironment, further amplifying inflammation and affecting BDNF expression; (3) Compromise of the blood-brain barrier(BBB)enables peripheral immune cells to penetrate into the CNS, and these cells work in synergy with central glial cells to amplify inflammation. The reduction in BDNF and the imbalance in the ratio of its precursor to mature form ultimately lead to impaired synaptic plasticity in brain regions like the hippocampus (HIP) and amygdala, precipitating anxiety-like behaviors. Existing pharmacological interventions are inadequate to reverse this pathological process. The M1-A1 axis may serve as a key node linking chronic stress to BDNF dysregulation and anxiety disorders. Targeting the phenotypic transformation of glial cells, repairing the BBB, or modulating glial cell metabolism (e.g., lactate shuttle) may represent potential strategies requiring further validation. Future research should focus on the spatiotemporal dynamics of this axis and its clinical translation. Show less

Depression is a major global health burden, and current treatments are limited by delayed onset and incomplete efficacy, highlighting the need for novel, mechanism-based therapies. Chronic restraint stress (CRS) induces behavioral, hormonal, and synaptic changes relevant to depression, but the role of adiponectin signaling remains unclear. Here, we examined whether the adiponectin receptor agonist AdipoRon exerts antidepressant-like effects via brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signaling in mice subjected to 14 days of CRS. CRS produced anxiety- and depression-like behaviors, elevated plasma corticosterone, reduced circulating adiponectin, and selectively decreased hippocampal adiponectin and adiponectin receptor 2 (AdipoR2), accompanied by reduced PSD-95 and GluA1 in CA3 and the dentate gyrus (DG). AdipoRon treatment (20 mg/kg, days 8-14) prevented behavioral deficits, normalized corticosterone and adiponectin levels, and restored hippocampal AdipoR2, PSD-95, and GluA1 expression in CA3 and DG. AdipoRon also reversed CRS-induced decreases in hippocampal phosphorylated AMPK (p-AMPK), PPARα, BDNF, and phosphorylated TrkB (p-TrkB), with p-AMPK/AMPK and PPARα levels positively correlating with BDNF. Immunofluorescence confirmed BDNF recovery in CA3 and DG. Importantly, pretreatment with the TrkB antagonist ANA-12 abolished the behavioral, hormonal, and molecular effects of AdipoRon, indicating that its actions require BDNF-TrkB activation. These findings suggest that AdipoRon mitigates CRS-induced deficits via hippocampal AdipoR2-AMPK-PPARα-BDNF-TrkB signaling and highlight AdipoR2 as a promising target for depression therapy under chronic stress. Show less

PIK3CA is one of the most frequently mutated genes in cervical cancer (CC). However, its clinical utility is hampered by paradoxical treatment-dependent outcomes, restricting its application in precision oncology. To address this issue, we constructed a high-resolution single-cell transcriptomic atlas of the CC tumor microenvironment. It was found that PIK3CA mutations induce a dichotomous TME, simultaneously associated with marked T-cell inflammation and resistance to adaptive immune responses. Malignant epithelial subsets induce CD8 Show less

Protein feed resource shortage is a major constraint to the sustainable development of the livestock industry and a bottleneck problem hindering the growth of the Tibetan pig industry in China's Qinghai-Tibet Plateau region. Walnut meal, rich in protein, holds promise as a substitute for soybean meal. However, the effects and underlying mechanisms of walnut meal substitution on Tibetan pigs in Diqing remain unclear. The study showed that substituting 50% of soybean meal with walnut meal in the diet of Diqing Tibetan pigs significantly reduced backfat thickness and increased intramuscular fat content ( This study reveals that walnut meal can serve as a substitute for soybean meal, and a 50% substitution ratio is conducive to intramuscular fat deposition in Diqing Tibetan pigs. The findings provide valuable insights for the development and application of unconventional protein feed resources, and offer new perspectives for the production of marbled pork. Show less