Wei Wang

Midlife obesity is an established independent risk factor for age-related cognitive decline, yet direct causal experimental evidence and underlying gut microbial mechanisms remain poorly defined. Using a mouse model of high-fat diet (HFD)-induced obesity restricted to the midlife period (6–12 months of age) in male wild-type C57BL/6J mice, we characterized the temporal and causal relationship between midlife weight gain and cognitive deterioration, and investigated the mediating function of Akkermansia muciniphila (Akk). Longitudinal body weight tracking across the lifespan revealed a stage-specific dynamic pattern, with sustained adipose tissue accumulation occurring during the midlife period (6–12 months of age). Midlife HFD exposure triggered multi-dimensional cognitive deficits accompanied by significant depletion of intestinal Akk, while oral supplementation of Akk effectively attenuated HFD-induced weight gain and ameliorated spatial, recognition and contextual memory impairments. Mechanistically, Akk suppressed hippocampal glial hyperactivation and proinflammatory factor upregulation, attenuated neuronal loss, and preserved hippocampal synaptic integrity. Serum metabolomics further identified midlife-specific metabolic remodeling characterized by dysregulated lipid metabolism and depleted microbiota-derived indole metabolites. Our findings establish a causal link between midlife obesity and accelerated cognitive aging, and identify Akk as a promising early intervention target for age-related cognitive decline.

Background: Inflammatory bowel disease (IBD) is closely and epidemiologically linked to long-term high-fat diet (HFD) exposure. Transient receptor potential vanilloid 1 (TRPV1) is critically involved in IBD pathogenesis and significantly downregulated in the intestinal mucosa of obese populations. Nevertheless, whether TRPV1 mediates HFD-exacerbated chronic IBD remains poorly defined. Results: Myeloid-cell-specific Trpv1 knockout ( Trpv1 ^{∆ Mye} ) mice were used to investigate the roles of macrophage Trpv1 in dextran sulfate sodium-induced chronic colitis with long-term HFD exposure. Single-cell RNA sequencing, bulk RNA sequencing, and in vitro cell line experiments were conducted to elucidate the mechanism through which Trpv1 downregulation exacerbates HFD-related colitis. Quantitative reverse transcription-polymerase chain reaction and Western blot assays were performed for mechanistic validation and molecular verification. Results showed that Trpv1 ^{∆ Mye} mice subjected to long-term HFD developed exacerbated intestinal inflammation, prominent intestinal fibrosis, and impaired intestinal barrier integrity. Mechanistically, myeloid-cell-specific Trpv1 deletion promoted macrophage pro-inflammatory and pro-fibrotic polarization and uncovered a novel miR-31/Wnt16 axis associated with the activation of non-canonical Wnt signaling, which in turn was associated with epithelial barrier dysfunction and stromal fibrogenesis. Conclusions: Together, our findings unveil a cell-type-specific role of macrophage Trpv1 in diet-exacerbated IBD and delineate a precise miR-31/Wnt16 signaling pathway, which may provide novel insights for the clinical management of IBD patients with metabolic comorbidities.

Background: Stroke is a severe cerebrovascular disease characterized by narrow time windows and complications. This study aimed to identify novel drug targets and repurposed drugs for stroke. Methods: This study used expression quantitative trait loci data from druggable genes in brain and blood as instrumental variables. Mendelian randomization, colocalization, and phenome‐wide Mendelian randomization were applied to evaluate causal relationships and potential side effects, with stroke and ischemic stroke as primary outcomes. Preclinical validation used oxygen–glucose deprivation/reperfusion and middle cerebral artery occlusion/reperfusion models. Pharmacological and behavioral assessments evaluated the therapeutic potential of candidate targets and drugs. Additionally, proteomic sequencing was performed following GGCX (γ‐glutamyl carboxylase) overexpression to explore its biological functions. Results: Elevated GGCX expression in brain and blood was potentially causally associated with reduced risk of stroke and ischemic stroke, supported by colocalization evidence, although potential cardiovascular risks could not be excluded. Drug repositioning identified ifenprodil as a candidate agent that reduced infarction volume, improved motor and cognitive functions, and reversed GGCX downregulation in mice. Ifenprodil treatment and GGCX overexpression alleviated oxygen–glucose deprivation/reperfusion–induced injury and upregulated GGCX expression. Mechanistically, GGCX conferred neuroprotection by regulating protein homeostasis, suppressing inflammation, promoting metabolic recovery, and modulating nuclear transcriptional regulation. Conclusions: This study established a potential causal link between GGCX and stroke risk, particularly ischemic stroke. GGCX represents a promising therapeutic target for ischemic stroke. Targeted GGCX expression upregulation and drug repurposing, particularly ifenprodil, may offer novel therapeutic avenues. Further validation is warranted to assess clinical efficacy and safety.

The consensus molecular subtype 4 (CMS4) of colorectal cancer (CRC) represents an aggressive, mesenchymal phenotype associated with the poorest clinical prognosis. Although angiogenesis is fundamental to CRC progression, current anti-VEGF therapies are frequently compromised by primary or acquired resistance, creating an urgent need to identify alternative vascular drivers. NOTCH3 is significantly enriched in CMS4 CRC, yet its direct role in modulating the tumor vasculature remains elusive. Here, integrating multi-center transcriptomic datasets with clinical validation, we identified NOTCH3 as a critical engine of CRC angiogenesis. In Stage IV clinical samples, NOTCH3 expression correlated significantly with microvessel density (MVD). Functionally, overexpression of the NOTCH3 intracellular domain (NICD3) dramatically enhanced endothelial tube formation and migration in vitro, while driving robust tumor vascularization in xenograft models. Through transcriptomic profiling, we identified the secreted factor transforming growth factor-beta-induced protein (TGFBI) as the essential downstream effector. Mechanistically, we demonstrate that NICD3 physically interacts with and upregulates SMAD3, thereby facilitating the direct transcriptional activation of TGFBI. Crucially, to translate these mechanistic insights, we utilized molecular docking and drug screening to identify the flavonoid Hesperidin (HES) as a potent binder of TGFBI. HES treatment effectively abolished NICD3-driven angiogenesis and suppressed tumor progression in vivo. Collectively, our findings characterize a novel NICD3/SMAD3/TGFBI signaling axis as a key vulnerability in CRC and propose HES as a promising precision therapeutic strategy for CRC patients with features of CMS4.

Major depressive disorder (MDD) ranks as a primary contributor to global ill health and disability, with treatments often proving insufficient. Recent study has increasingly found a strong correlation between gut microbiome diversity and mood-related behaviors, including MDD. Depression can alter gut microbiota (GM) composition, while intentional modulation of the GM may conversely influence depressive symptoms. This phenomenon arises from dynamic bidirectional interactions between the gut and brain, although the exact pathways are not yet fully elucidated. Proposed pathways include, but are not limited to, neural circuits, the endocrine system, immune responses, and metabolic regulation. Clinical data have also shown that regulating the GM through probiotics and prebiotics has the potential to alleviate depressive symptoms. This review summarizes contemporary research on the composition and modulatory functions of GM in MDD, and explores the predictive potential of GM for depression as well as the therapeutic prospects of probiotics, aiming to provide insights and directions for future research.

Neurodegeneration is a chronic, progressive process initiated by early neurite retraction, a pathological hallmark preceding neuronal death in neurodegenerative disorders such as Parkinson’s disease (PD). Cleavage of gasdermin E (GSDME) releases its N-terminal domain (GSDME-N), which has been shown to mediate mitochondrial dysfunction and the onset of neurodegeneration. However, the therapeutic potential of targeting GSDME-N for early intervention in PD, and whether nicotine, a tobacco component with neuroprotective properties, acts through GSDME modulation remain unexplored. The SH-SY5Y cells, primary neurons and C57BL mice were treated with rotenone to model neurodegeneration in PD. Mitochondrial accumulation of GSDME-N and activation of autophagy were assessed via immunoblotting and immunostaining. Mitochondrial membrane potential was evaluated using JC-1 and TMRM fluorescent dyes, while mitochondrial reactive oxygen species were detected with MitoSOX™ Red superoxide indicator. For morphological analysis, immunofluorescence staining was performed using antibodies against microtubule-associated protein 2 (MAP2) to visualize neurites, along with MitoTracker to label mitochondria within neurites. In vivo, C57BL/6 mice were administered rotenone and provided with nicotine supplementation in their drinking water. Motor function was assessed using rotarod, hanging wire and pole tests. Tyrosine hydroxylase (TH)-positive neurons and fibers were detected using immunohistochemistry. We demonstrated that GSDME-N accumulation on mitochondria during early neurodegeneration was suppressed by nicotine, thereby maintaining mitochondrial homeostasis and preventing neurite retraction. Mechanistically, nicotine activated autophagic pathway to promote GSDME-N clearance, which maintained mitochondrial membrane potential, reduced reactive oxygen species (ROS) production, and specifically rescued mitochondrial function. This protective mechanism significantly attenuated early pathological changes, including neurite retraction and loss. In a rotenone-induced PD model, nicotine treatment effectively reduced GSDME-N accumulation and decelerated neurodegenerative progression. These findings reveal the critical role of GSDME-N in early-stage mitochondrial damage in PD and propose a novel therapeutic strategy targeting the nicotine-autophagy axis to counteract GSDME-N-mediated neurodegeneration.