👤 Meilan Jin

Despite advances in acute ischemic stroke (AIS) research, identifying reliable biomarkers and regulatory mechanisms remains challenging. We first identified AIS-related genes via extensive literature review, retrieved dataset GSE16561 from the Gene Expression Omnibus (GEO, https://ncbi.nlm.nih.gov/geo/), and performed differential/enrichment analyses. Bioinformatics verified N6-methyladenosine (m Show less

With population aging, the incidence of osteoporosis continuously elevates worldwide, resulting in increased fracture risks and clinical demand for orthopedic fixation. However, under osteoporotic conditions, the stability and longevity of implants are severely compromised by the pathological microenvironment, thus developing effective therapeutic interventions to achieve successful osteoporotic osseointegration remains a critical challenge in the regenerative medicine field. Herein, the parathyroid hormone (PTH) is encapsulated in Sr Show less

Anshen Bunao Syrup (ABS), a traditional Chinese medicinal formula, is widely used to treat neurological disorders such as insomnia, dizziness, and neurasthenia. However, its antidepressant effect and underlying mechanisms remain insufficiently characterized. This study aims to comprehensively evaluate the antidepressant effect of ABS in a rat model, and to elucidate the underlying mechanism. Chronic unpredictable mild stress (CUMS) induced depressive rats were used to evaluate the antidepressant effect of ABS. Histopathological alterations in the hippocampus and colonic mucosa were examined using Nissl and H&E staining. Microglial activation was evaluated by Iba-1 immunohistochemical staining. Gut microbiota composition and metabolic profiles were analyzed using 16S rRNA sequencing and untargeted metabolomics. Differential gene expression and pathway regulation were investigated by transcriptomics and confirmed by Western Blot (WB). ABS significantly ameliorated depressive-like behaviors and elevated dopamine and 5-Hydroxytryptamine levels in cortical regions. Furthermore, ABS mitigated hippocampal neuronal damage, suppressed microglial overactivation and reduced oxidative stress in the cortex. 16S rRNA sequencing analysis showed that ABS exerted antidepressant effects via modulation of the "microbiota-gut-brain" axis, particularly by altering intestinal microbiota composition, enhancing gut function, and suppressing HPA axis hyperactivity. Metabolomics revealed that ABS corrected metabolic disturbances, and alleviated inflammation-related metabolic disturbances, while transcriptomics indicated regulation of the Npas4-BDNF-PI3K/AKT signaling pathway, which was further confirmed by WB. ABS significantly ameliorated depression in a CUMS rat model, primarily through coordinated regulation of gut microbiota, metabolic homeostasis, and the Npas4-BDNF-PI3K/AKT signaling pathway, providing integrative mechanistic insights into its antidepressant effects. 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

Alzheimer's disease (AD) is characterized by progressive synaptic failure, neuroinflammation, amyloid and tau pathology, yet effective disease-modifying therapies remain limited. Cannabidiol (CBD) has shown neuroprotective potential in AD, but its direct molecular targets and signaling mechanisms remain unclear. Here, we demonstrate that CBD ameliorates cognitive and emotional deficits in 3×Tg-AD mice by restoring synaptic integrity and plasticity. At the mechanistic level, CBD activated TrkB signaling independently of BDNF, leading to suppression of tau hyperphosphorylation via the PI3K/AKT/GSK3β pathway and attenuation of neuroinflammation and amyloid pathology through inhibition of the JAK2/STAT3/SOCS1 axis. Using isothermal shift assays combined with biophysical binding analyses, we identified FRS2, a core adaptor protein of TrkB, as a direct molecular target of CBD. Molecular dynamics simulations further revealed that CBD stabilizes the FRS2-TrkB interface, thereby facilitating TrkB activation. Importantly, genetic knockdown of FRS2 abolished CBD-induced TrkB signaling and its downstream neuroprotective effects in both cellular and in vivo AD models. Together, these findings identify FRS2 as a critical signaling node mediating BDNF-independent TrkB activation by CBD and establish a mechanistic framework linking CBD to disease-modifying pathways in AD. Show less

Perineural invasion (PNI) represents a uniquely distinctive pathway for tumor metastasis, but its underlying molecular mechanisms and therapy remain unclear. Bioinformatics analysis and transcriptomic sequencing were first employed to investigate the involvement of the BDNF/TrkB axis in the ESCC PNI, which was validated with ESCC cells co-cultured with a dorsal root ganglia system (ESCC/DRG model), a mouse PNI model, and ESCC tissues, mainly using microscopic imaging, IVIS Spectrum The BDNF/TrkB axis is closely associated with the PNI in ESCC. This pathway plays a pivotal role in driving PNI progression via Akt signaling. Deguelin was identified as an effective inhibitor of PNI in ESCC. Mechanistically, BDNF was revealed to be a key binding target of Deguelin, which disrupts PNI development by modulating the BDNF/TrkB/Akt axis. Notably, overexpression of BDNF can counteract Deguelin's inhibitory effects on ESCC growth and PNI progression. The BDNF/TrkB axis promotes the progression of ESCC PNI, and Deguelin inhibits ESCC PNI by targeting this axis, enhancing the understanding of PNI's molecular mechanisms and offering new therapeutic options. Show less

This study aimed to investigate the effect of different preferences of food-derived odors (common food flavors/spices) on the appetite, immune system, and CNS of mice through 15 days of olfactory exposure. According to the ranking of sniffing duration, beef essence was chosen as a pleasant odor, while garlic essence was chosen as an unpleasant odor. Results showed that food intake and body weight gradually increased in all groups, with the lowest values observed in the garlic odor group. Unpleasant garlic odor suppressed the mRNA transcription levels of agouti-related protein (AgRP) and neuropeptide Y (NPY) in the hypothalamic arcuate nucleus, along with elevated leptin levels, thereby inhibiting food intake and causing body weight loss. In addition, the serum TNF-α, IL-2, and IL-6 levels in the garlic odor group were significantly higher than those in the beef and control groups, which indicated that the immune system may be impaired by the exposure to unpleasant garlic odor. Furthermore, pleasant beef odors could promote the differentiation of hippocampal neurons and the levels of brain-derived neurotrophic factors and glial cell line-derived neurotrophic factor, which may have great potential in improving neurological disorders. Conclusively, unpleasant odors may suppress immune function or modulate the CNS by establishing an odor-CNS-immune pathway, while pleasant food odors affect only the CNS. The present study preliminarily provides novel insights that different preferences for food odors could affect the body weight, immune system, and CNS. It may serve as a reference for further research and development of aromatherapy as an adjuvant medicine and therapeutic method. Show less

This study investigated the expression of brain-derived neurotrophic factor (BDNF) signaling components (BDNF-TrkB-AKT1) and apoptosis-related factors (Bcl-2 and Bax) in yak brain regions at different altitudes. The cerebral cortex, cerebellum, hippocampus, thalamus, and medulla oblongata were collected from 3-year-old yaks living at low and high altitudes. The relative mRNA expression of BDNF, TrkB, AKT1, Bcl-2, and Bax was assessed by qRT-PCR. Protein abundance and cellular localization of BDNF, TrkB, AKT1, Bcl-2, and Bax were evaluated by Western blotting and immunohistochemistry, with immunoreactivity quantified by optical density analysis. Within each altitude group, BDNF, TrkB, AKT1, and Bcl-2 mRNA expression and the corresponding protein levels (BDNF, TrkB, AKT1, and Bcl-2) were significantly higher in the cerebral cortex and hippocampus than in the cerebellum, thalamus, and medulla oblongata (P < 0.05). In contrast, Bax mRNA and Bax protein levels did not differ significantly among the five regions. Compared with low-altitude yaks, high-altitude yaks showed significantly higher BDNF, TrkB, AKT1, and Bcl-2 mRNA expression and higher BDNF, TrkB, AKT1, and Bcl-2 protein levels in brain tissues (P < 0.05), whereas Bax protein expression did not differ between altitude groups. Immunohistochemistry revealed immunoreactivity for BDNF, TrkB, AKT1, Bcl-2, and Bax in both altitude groups, with prominent labeling in cortical pyramidal neurons and across the pyramidal cell layer in the hippocampal CA region. Immunoreactivity was also detected in large neurons of the thalamus and medulla oblongata. In the cerebellum, labeling was strongest in Purkinje cells, with weaker signals in the granule cell layer and molecular layer. BDNF-TrkB-AKT1 pathway components and Bcl-2 showed relatively higher expression in the cerebral cortex and hippocampus within each altitude group, whereas Bax expression did not vary across regions. These patterns are consistent with an association between BDNF-TrkB-AKT1 signaling and increased Bcl-2 expression without a corresponding increase in Bax, which may support neuronal adaptation in the cerebral cortex and hippocampus. Elevated expression of BDNF, TrkB, AKT1, and Bcl-2 at high altitude suggests enhanced adaptation to hypoxia in high-altitude yaks; the underlying mechanisms require further investigation. Show less

Neuroplasticity is the core process by which the brain responds to aging, learning, and injury. Reporting positive non-pharmacological intervention approaches to promote neural plasticity is a core focus of contemporary neuroscience and rehabilitation medicine. Tai Chi (TC), as a traditional Chinese physical and mental practice that deeply combines soothing body movements, breathing regulation, and spiritual focus, is increasingly attracting attention from the scientific community for its role in facilitating brain health. Our review seeks to combine recent evidence, elucidate how TC promotes neural plasticity via multi-level mechanisms, discuss its advantages in promoting cognitive, motor, and emotional functions, and investigate its clinical utilization prospects and future research challenges in neurorehabilitation. According to reviewing recent literature, we combined evidence from cross-sectional studies, randomized controlled trials, systematic reviews, and meta-analyses, with a center on citing research findings utilizing multimodal neuroimaging techniques (such as fMRI, fNIRS, EEG) and molecular biology techniques to construct a complete chain of evidence from molecules to systems. TC drives multi-level neural plasticity modifications via its unique physical and mental combination properties. At the macro level, it can enhance the gray matter volume of the hippocampus and prefrontal cortex, and promote the organizational effectiveness of large-scale functional networks in the brain. At the micro molecular level, TC establishes a favorable microenvironment for neuronal survival, synaptic plasticity, and neural repair by upregulating BDNF, increasing endogenous antioxidant defense, modulating inflammatory balance, and improving mitochondrial energy metabolism. These structural, functional, and molecular level changes collectively form the neurobiological basis for TC to promote memory and executive function, increase balance and motor management, and promote emotional regulation ability. Our review further assesses the clinical effectiveness of TC in the rehabilitation of neurological diseases, such as Parkinson's disease (PD), stroke, and mild cognitive impairment, determining that it not only decreases symptoms, but may also have the possible role to decrease disease development. Ultimately, our review delve into the challenges and future perspectives experienced by this range in the context of standardization of research paradigms, causal reasoning of mechanisms, and individualized interventions. Show less

Substance use disorders (SUDs) present a global health challenge with high relapse rates. Emerging evidence implicates gut microbiota dysbiosis in SUD pathophysiology via the gut-brain axis. This 24-week randomized controlled trial investigated whether precision exercise interventions could modulate the gut microbiota-emotion axis to improve psychological outcomes in individuals undergoing compulsory drug rehabilitation. Thirty male participants were randomized to a precision exercise group (n = 15; individualized aerobic + resistance training, 4-5 sessions/week) or control group (n = 15; standard rehabilitation activities). Multi-dimensional assessments included weekly fecal (16S rRNA sequencing), urine (SCFAs via GC-MS), and saliva samples (cortisol, serotonin, BDNF via ELISA), alongside psychological evaluations (SCL-90-R, POMS) and physiological measures. The exercise group exhibited significant increases in gut microbial diversity (Shannon index: +18.2%, p < 0.001; Cohen's d = 2.14) and enrichment of beneficial taxa (e.g., Faecalibacterium, Bifidobacterium; LDA >3.5). Urinary SCFAs increased markedly (butyrate: 3.12-fold, p < 0.001), correlating with elevated salivary BDNF (+82%, p < 0.001) and reduced cortisol (-41.1%, p < 0.001). Psychological outcomes improved substantially: SCL-90-R Global Severity Index decreased by 43.3% (p < 0.001), and 78.6% of exercise participants achieved clinically meaningful improvement. Machine learning models predicted treatment response (AUC = 0.91) using baseline microbiome features. Precision exercise restores gut microbiota homeostasis, enhances neuroactive metabolite production, and improves emotional regulation in SUD recovery. The gut microbiota-emotion axis represents a viable target for non-pharmacological interventions, with microbiome profiles enabling personalized treatment strategies. Show less

The neurotrophic factor (NTF) family has recently expanded its role beyond neurological conditions, but its involvement in acute inflammatory lung diseases remains largely unclear. Using well-established acute lung injury (ALI) and sepsis models, we demonstrate that brain-derived neurotrophic factor (BDNF), a key NTF, is impaired in pulmonary epithelial cells and negatively correlates with the inflammatory response. Raising the BDNF level alleviates inflammatory lung injury, but these effects are absent in macrophage-deleted mice. Both in vivo and in vitro results show BDNF inhibits macrophage inflammation, and further proteomics analysis identifies macrophage TLR4 as a receptor that BDNF antagonizes via direct binding. The BDNF fragment (aa 104-115) is critical for BDNF-TLR4 interaction, and the corresponding synthetic BDNF-derived dodecapeptide (BDP-12) retains TLR4-antagonistic and anti-inflammatory effects both in vitro and in vivo, without pro-proliferative side effects. In conclusion, our findings reveal that epithelial-derived BDNF prevents macrophage inflammation by directly targeting TLR4 and highlights BDP-12 as a potential therapeutic agent for acute inflammatory diseases. Show less

The roots of Platycodon grandiflorus (Jacq.) A. DC. (Campanulaceae), known as Platycodi Radix (PR), have long been used as a traditional medicine for respiratory ailments and for relieving chest oppression, a symptom associated with qi stagnation and emotional imbalance resembling depressive states. However, the molecular mechanisms underlying this ethnopharmacological effect and neuroplastic signaling remain to be elucidated. This study aimed to investigate the antidepressant-like activities of PR and its triterpenoid saponins, platycodin D (PD) and platycodin D2 (PD2), and their underlying molecular mechanisms. In a chronic restraint stress (CRS) mouse model, antidepressant efficacy was evaluated using behavioral assessments, including open field tests and forced swimming tests. Hippocampal microarray and pathway enrichment analyses, as well as the compound combination-oriented natural product database unified terminology (COCONT) database, were used to explore signaling pathways and active components, respectively. The molecular mechanisms underlying brain-derived neurotrophic factor (BDNF) expression and secretion were investigated in N2a cells and hippocampal tissues. The activation of BDNF-related signaling pathways was examined using neurite outgrowth assays, quantitative PCR, immunoblotting, and immunofluorescence analysis. PR extract (PRE), PD, and PD2 significantly improved depressive-like behavioral deficits induced by CRS and restored the expression of hippocampal neuroplasticity markers, including BDNF, neurofilament light, and PSD95. These effects were accompanied by enhanced activities in ERK/cAMP-response element binding protein (CREB) and Akt/mechanistic target of rapamycin (mTOR) signaling pathways. These compounds promoted neurite outgrowth and triggered α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs)-dependent Ca PR and its triterpenoid saponins, PD and PD2, could alleviate stress-induced depressive symptoms and modulate BDNF-centered neuroplasticity signaling, supporting their potential relevance as phytotherapeutic candidates for depressive disorders. Show less

Neuroinflammation is a key pathogenic process in multiple central nervous system (CNS) disorders. It can lead to neuronal injury and cognitive decline through excessive glial activation and aberrant engagement of the programmed cell death protein-1/programmed death-ligand 1 (PD-1/PD-L1) checkpoint axis. To address these pathologies, we engineered a PD-1-enriched macrophage-membrane, lactoferrin-modified, PEGylated, glycyrrhizic-acid-loaded biomimetic hybrid liposome (PMLpGL) for dual, precise modulation of the neuroinflammatory microenvironment. PMLpGL alleviates neuronal inhibitory signaling by reversibly sequestering excess PD-L1 via membrane-anchored PD-1, while its cargo GA suppresses high-mobility group box-1 (HMGB1)-driven inflammatory cascades, thereby returning inducible PD-1/PD-L1 expression and glial activation toward homeostasis. Physicochemical characterization showed a hydrodynamic diameter of 165 ± 3 nm and a zeta potential of -10.2 ± 0.2 mV. Engineered macrophage membranes displayed marked PD-1 overexpression, and ligand-depletion saturation assays demonstrated specific, saturable PD-1/PD-L1 binding. In a Transwell blood-brain barrier (BBB) model, PMLpGL achieved a 24-h permeability of 22.86 ± 0.14 %, indicating robust in-vitro BBB traversal. In vivo fluorescence imaging showed peak brain accumulation at 24 h with retention to 48 h; liquid chromatography-tandem mass spectrometry further confirmed brain targeting and persistence-at 12 h, brain GA with PMLpGL was ∼48-fold higher than free drug and remained quantifiable at 48 h. Pharmacodynamic evaluations in cells and mice demonstrated that PMLpGL suppresses glial activation and normalizes inducible checkpoint expression; reshapes the cytokine milieu by lowering IL-6, IL-1β, TNF-α, and HMGB1 while increasing IL-10, TGF-β, and brain-derived neurotrophic factor; and restores the synaptic protein synapsin-1. Correspondingly, PMLpGL significantly improved cognition in open-field, novel object recognition, and Morris water maze tests. Collectively, PMLpGL combines PD-1 decoy sequestration with GA-mediated upstream immunomodulation to attenuate neuroinflammatory cascades, protect neurons, and reverse cognitive deficits. By pairing BBB compatibility with microenvironment-precise regulation, this platform offers a promising therapeutic strategy for CNS diseases associated with cognitive decline. Show less

The integrated stress response (ISR) has been implicated in cognitive decline associated with ageing and neurodegenerative diseases. Pharmacological inhibition of the ISR using the small-molecule ISRIB has demonstrated promising neuroprotective effects in several preclinical models. However, its potential therapeutic value in vascular cognitive impairment (VCI) remains largely unexplored. Here, we established a modified permanent bilateral carotid occlusion (2-VO) rat model of VCI and investigated the therapeutic potential of the ISRIB via microinjection in hippocampal dentate gyrus (DG). VCI rats exhibited elevated expression of vascular endothelial growth factor (VEGF), cluster of differentiation 34 (CD34), ionized calcium-binding adapter molecule 1 (Iba1), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6), indicating successful establishment of the model. Behavioral assessments revealed that VCI rats exhibited impaired spatial, working, and recognition memory. Bioinformatic analysis highlighted ISR pathway activation in VCI. Furthermore, elevated phosphorylated eukaryotic initiation factor 2 alpha (p-eIF2α) and activating transcription factor 4 (ATF4) protein levels in the DG confirmed ISR activation in the DG of VCI rats. VCI also reduced neuronal integrity, as evidenced by decreased Nissl body density. ISRIB treatment significantly improved cognitive performance, suppressed ATF4 expression, enhanced puromycin-labeled protein synthesis, and restored phosphorylated cAMP response element-binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) signaling. Notably, ISRIB increased c-fos activation and upregulated synaptophysin and postsynaptic density protein 95 (PSD95) expression in the DG of VCI rats, indicating enhanced neuronal activity and synaptic function. Our results indicate that ISR activation contributes to hippocampal-dependent memory impairment in VCI. ISRIB effectively restores synaptic function and cognition, underscoring its therapeutic value and translational potential in treating VCI. 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

Atherosclerosis is the pathological basis of cardiovascular diseases. Dingxin Recipe III (DXRIII), a traditional Chinese herbal formula, has shown therapeutic effect for atherosclerosis, though its mechanisms remain unclear. This study aimed to investigate the effects and molecular mechanisms of DXRIII on atherosclerosis progression. Male ApoE DXRIII significantly reduced aortic plaque areas, improved lipid profiles (decreased triglycerides, total cholesterol, and low-density lipoprotein-C), and alleviated hepatic steatosis. Integrated multi-omics revealed modulation of lipid metabolism pathways, including steroid hormone biosynthesis and arachidonic acid metabolism pathways. Steroidogenic acute regulatory-related lipid transfer protein 4 (Stard4) was identified as a key target, with expression positively correlated with gamma-linolenic acid and negatively correlated with corticosterone. Direct binding between DXRIII components and Stard4 was observed. Stard4 overexpression reduced lipid accumulation, while knockdown aggravated lipid deposition and negated the effect of DXRIII. Hepatic Stard4 knockdown aggravated atherosclerosis and lipid-related genes expression (Angptl4, Apob, Soat2, Scarb1, Lepr). DXRIII attenuates atherosclerosis by upregulating hepatic Stard4 expression to restore lipid homeostasis and reduce lipid accumulation. Show less

Breast cancer is the most frequently diagnosed cancer, with metastasis accounting for the majority of cancer-related deaths. The mechanisms of early-stage breast cancer metastasis to regional immune sites like lymph nodes remain elusive. Here, we performed an in-depth proteomic and phosphoproteomic analysis of a substantial series of breast cancer samples, alongside genomic and transcriptomic evaluations. This cohort encompasses 195 specimens: 65 primary breast tumors, their corresponding normal tissues, and metastatic axillary lymph nodes. We offer an overview of the molecular alterations at the transcriptomic, proteomic, and phosphoproteomic levels during lymph node metastasis. Notably, the findings indicate that regional lymph node metastasis is primarily influenced by proteomic and phosphoproteomic alterations, rather than genomic or transcriptomic changes. We found the ANGPTL4 and HMGB1 could serve as the biomarker of lymph node metastasis. Data analysis and cell experiments involving silencing of the alternative splicing factor HNRNPU demonstrated that alternative splicing plays a significant role in modulating protein expression, phosphorylation profiles and cell proliferation. The key phosphorylation sites, including MARCKSL1-S104 and FKBP15-S320, as well as the upstream kinase PRKCB, were identified as playing crucial roles in breast cancer lymph node metastasis. Targeted intervention of the kinase PRKCB resulted in effectively suppressing the proliferation and metastasis of breast cancer tumor cells. Immune profiling analysis and experimental validation of breast cancer cell cocultured with CD8+ T cell reveals correlations between phosphorylation of MARCKSL1-S104 and FKBP15-S320 with immune checkpoint PD-L1 expression, and their impact on tumor cell apoptosis, suggesting a potential mechanism of immune evasion in metastasis. This study systematically characterizes the molecular landscape and features of primary breast tumors and their matched metastatic lymph nodes. These insights enhance our understanding of early-stage breast cancer metastasis and may pave the way for improved diagnostic tools and targeted therapeutic strategies. Show less

Clinical application of mesenchymal stem cells for endometrial repair has been hampered by variability in cell quality, large-scale production, and uncertainty regarding the optimal delivery route. In this study, we investigated the therapeutic potential of clinical-grade human embryonic stem cell-derived immunity-and-matrix-regulatory cells (IMRCs) for treating refractory moderate-to-severe intrauterine adhesion (IUA). In a rabbit IUA model, sub-endometrial injection of IMRCs significantly reduced fibrosis and enhanced endometrial angiogenesis, outperforming uterine perfusion. Transcriptomic analysis revealed distinct pro-angiogenic gene expression profiles between the two delivery routes. In vitro, IMRCs co-cultured with endometrial stromal cells (ESCs) markedly enhanced angiogenic potential compared to either cell type alone. Protein array analysis of the co-culture supernatant showed elevated levels of angiogenic factors, with functional assays confirming that inhibition of ANGPTL4, a non-canonical pro-angiogenic mediator, impaired angiogenesis. In a first-in-human, single-center, phase 1 dose-escalation trial involving 18 patients with refractory IUA, high-dose sub-endometrial IMRC injection promoted angiogenesis, reduced uterine scarring, and improved pregnancy outcomes, with no safety concerns observed over 3 years of follow-up. These findings highlight the translational promise of IMRCs as a novel therapeutic strategy for endometrial regeneration in severe IUA. Show less

Rising global temperatures lead to a continuous increase in the frequency and intensity of extreme weather events, such as droughts and floods, posing serious threats to terrestrial homeotherms. However, adaptive changes in respiratory metabolism and molecular mechanisms in lung tissues of small mammals under extreme water shortage conditions remain unclear. This study hypothesized that small desert mammals can adapt to extreme water shortage environments by regulating the plasticity of lung tissue gene expression and respiratory metabolism. Using 29 wild-caught Siberian jerboas ( Show less

AllergoOncology has emerged as an interdisciplinary field exploring the interaction between allergic diseases and cancer; however, the lack of stable in vivo models has limited mechanistic investigations. This study aimed to establish an experimental animal model to explore the impact of systemic allergic responses on tumor progression and to provide preliminary insights into the regulatory role of allergy in cancer development. An ovalbumin (OVA)-induced systemic allergy tumor-bearing mouse model (OVA-TM) was established by OVA sensitization followed by subcutaneous implantation of CT26 colon cancer cells. Tumor growth, immune responses, and behavioral changes were systematically evaluated. Tumor immune microenvironment alterations were assessed using immunological and histological analyses. Transcriptomic profiling and mass spectrometry imaging (MSI) were integrated to investigate immune-related metabolic alterations. Human tumor survival datasets were used to validate the prognostic relevance of differentially expressed genes (DEGs), and enrichment analyses of allergy- and cancer-associated genes were performed using humanized databases. OVA-induced systemic allergy significantly suppressed tumor growth and promoted immune cell infiltration, particularly CD3 This study establishes a practical in vivo model for AllergoOncology and demonstrates that systemic allergic responses can modulate tumor progression through immune activation, apoptosis, and inflammation-metabolism axis reprogramming, providing a foundation for future mechanistic and therapeutic studies. Show less

Biomarkers that capture the dynamic transition from obesity to metabolic dysfunction and subsequent cardiorenal disease remain insufficient. This study evaluated stage-specific associations of lipid-inflammation indices across this continuum. We included 109,442 obese adults (UK Biobank) across four stages, obesity (Stage 1), metabolic disorders (Stage 2), cardiorenal disease (Stage 3), and death (Stage 4). Five baseline indices (ApoB/A1-CRP, RCII, NHR, lymphocyte-to-HDL-C, monocyte-to-HDL-C) were evaluated. Markov multistate models were used to estimate transition-specific risks, with Cox regression and restricted cubic spline (RCS) analyses as complementary approaches. During a median follow-up of 15.73 years, 11.14% of participants progressed from Stage 1 to 2, and 25.88% from Stage 2 to 3. In fully adjusted model, ApoB/A1-CRP (HR, 1.07, 95% CI, 1.00-1.14, P = 0.048) and RCII (HR, 1.08, 95% CI, 1.01-1.15, P = 0.017) were significantly associated with Stage 2 to 3 progression. Upon Stage 3 stratification, NHR was primarily associated with mortality following cardiorenal disease onset. RCS analyses indicated significant non-linear associations for ApoB/A1-CRP, RCII, and NHR. RCII demonstrates robustness in sensitivity analysis. RCII is independently associated with the progression from metabolic disorders to cardiorenal diseases in obesity. It may serve as a clinically biomarker for early risk stratification. Show less

The effects of lipid traits on colorectal cancer (CRC) risk and the extent to which obesity may modify these effects remain unclear. To examine the associations between lipid traits and CRC risk using an observational study and Mendelian randomization (MR) analyses, and the role of weight status in the potential associations. In the Guangzhou Biobank Cohort Study (GBCS), lipid profiles were measured during 2003-2008, and CRC events were identified through record linkage with the cancer registry. MR analyses assessed the causal effects of lipid traits on CRC using a genome-wide association study meta-analysis of 185,616 Europeans. Among 28,576 GBCS participants followed until 2020, 599 CRC events occurred. Participants in the highest quartile of apolipoprotein B (apoB) had a higher CRC risk (hazard ratio [HR] 1.43, 95% CI 1.02-2.01). This association remained in those with overweight/obesity (HR 2.21, 95% CI 1.28-3.83). MR analyses supported a detrimental effect of apoB on CRC (odds ratio 1.12 per 1 SD, 95% CI 1.02-1.22). MR analyses also showed positive associations for total cholesterol and the apoB/apolipoprotein A-I ratio, which were not significant in the observational study. Higher apoB levels were associated with an increased CRC risk in both observational and MR analyses, suggesting a potential role of apoB in CRC prevention, especially among participants with overweight/obesity. However, the limitations of single-time lipid measurements and the use of different ancestries across study designs indicate the need for further research to confirm the robustness and generalizability of the findings. Show less

We hypothesized that the Hemopexin-Apolipoprotein B product (Hpx·apoB), a composite biomarker integrating lipid dysregulation and oxidative stress pathways, would improve coronary artery disease (CAD) diagnosis and risk stratification. This single-center cross-sectional study included 460 participants (350 CAD patients, 110 non-significant CAD controls). Plasma hemopexin (Hpx) was measured by liquid chromatography - tandem mass spectrometry, and the Hpx·apoB product was calculated. Multivariate logistic regression analyzed its CAD association, while area under the curve (AUC), net reclassification index (NRI), and integrated discrimination improvement (IDI) assessed its incremental predictive value over conventional risk factors and established models (Framingham, SCORE2). The Hpx·apoB product was significantly elevated in CAD patients compared to controls (median [IQR]: 2.35 [1.80-3.15] vs. 1.72 [1.30-2.25] mg The Hpx·apoB biomarker, combining oxidative stress and lipid metabolism, independently predicts CAD presence and severity while improving existing risk models' accuracy, enhancing clinical risk stratification. Show less

The genetic and clinical factors influencing the rate of brain structure change in cognitive decline remain poorly understood. This study aimed to identify genetic variants and risk factors contributing to these changes and explore potential causal relationships. We analyzed data from 2036 individuals across three longitudinal cohorts to assess change rates in 17 brain regions associated with cognitive decline. Genome-wide association studies (GWASs) were followed by phenome-wide association studies (PheWASs), Mendelian randomization (MR), and independent replication. We identified loci associated with brain structure change, including known Alzheimer's disease genes (apolipoprotein E, APOC1) and novel signals (BEAN1, SDHC). PheWAS and MR analyses in large biobanks suggested potential causal links between brain atrophy and anemia-related traits as well as type 2 diabetes. Our findings highlight genetic contributors and clinical traits associated with brain structure change in cognitive decline. Larger studies with broader cognitive assessments are needed to validate these findings. Show less

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disorder characterized by progressive aortic wall degeneration, inflammation, and vascular smooth muscle cells (VSMCs) loss. Despite extensive research, no effective pharmacological treatment is currently available to prevent or halt AAA progression. This study aimed to discover effective therapeutic agents for AAA and identify potential natural compounds with pharmacological efficacy against the disease by targeting matrix metalloproteinase-2 (MMP2), a key enzyme involved in extracellular matrix degradation and aneurysm progression. An integrated screening strategy combining cytotoxicity evaluation, high-content immunofluorescence imaging, and molecular docking was applied to an angiotensin II (Ang II)-stimulated rat aortic smooth muscle cells (RASMCs) model. A total of 138 natural products were systematically assessed. The anti-aneurysmal efficacy of the identified compound was further validated in both CaCl₂-induced and Ang II-infused ApoE Salvianolic acid B (Sal B), a major polyphenol from Salvia miltiorrhiza, was identified as a potent anti‑AAA candidate. It suppressed aneurysm formation, reduced elastin degradation, and attenuated inflammatory infiltration in vivo, while preserving the contractile phenotype, lowering ROS, and inhibiting MMP activity in Ang II‑stimulated RASMCs in vitro. Mechanistically, Ang II suppresses NRF2, leading to downregulation of the System Xc⁻-GPX4 axis and promoting lipid peroxidation and VSMC ferroptosis. This ferroptosis then activates the AGE-RAGE pathway, amplifying inflammation and MMP‑driven matrix degradation. Sal B counteracts this cascade by restoring NRF2 activity, improving lipid metabolism, and inhibiting MMPs, thereby blocking ferroptosis‑initiated inflammation and preserving aortic integrity. Salvianolic acid B exerts protective effects against AAA by attenuating oxidative stress, ferroptosis, and inflammation. These findings highlight Sal B as a promising natural therapeutic candidate for the prevention and treatment of abdominal aortic aneurysm. Show less

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by hepatic steatosis with cardiometabolic disorders. Due to the complicated pathophysiological processes, current therapeutic strategies for MASLD remain limited. Previous studies revealed that miR-320 was a regulator of systemic lipid metabolism with multi-targets. However, whether treatments against miR-320 would be benefit to MASLD was unclear. Mice with MASLD were induced by high-fat diet (HFD) treatment. Tough Decoy or sponge against miR-320 was delivered by recombinant adeno-associated virus (serotype 8) vectors in vivo. Hepatic steatosis and plasma lipids were assessed by histopathology, biochemical assays and LC-MS. Moreover, LC-MS, Western blotting, real-time PCR, immunofluorescence and luciferase reporter were performed to investigate the underlying mechanisms. Knockdown of miR-320 attenuated HFD-induced MASLD by alleviating hepatic lipid accumulation and hyperlipidemia. Mechanistically, palmitic acid (PA) combined with oleic acid (OA) treatment promoted the translocation of miR-320 from the cytoplasm into the nucleus of hepatocytes. Especially, increased nuclear miR-320 activated the transcription of APOE by targeting its promoter, which in turn aggravated triglyceride accumulation and secretion in hepatocytes. Our study revealed that treatments against miR-320 attenuated hepatic steatosis and hyperlipidemia simultaneously, which might be a potential strategy of MASLD. Show less

Alzheimer's disease (AD) is one of the most pressing public health challenges in an aging world. However, effective therapeutic strategies are still lacking. Imbalance in lipid homeostasis is a key driver of AD. Given the established link between dysregulated lipid metabolism and amyloid-beta (Aβ) aggregation, we investigated whether chicoric acid (CA), a dietary polyphenol with reported lipid-modulating properties, could mitigate Aβ pathology by modulating lipid metabolism in 5xFAD transgenic mice. In the brain, we found that CA upregulated the expression of liver X receptor Beta (LXR-β) and ATP-binding cassette transporter A1 (ABCA1) in 5xFAD mice. Through this pathway, it promoted apolipoprotein E (ApoE) lipidation and enhanced the expression of Aβ-clearance proteins (IDE and LRP1). Notably, in the periphery, CA reshaped the gut microbiota in 5xFAD mice, which reduced serum neurotoxic bile acid levels and preserved the integrity of the peripheral Aβ clearance system. Together, our study first demonstrated that CA globally regulated lipid homeostasis to alleviate Aβ pathology by coordinating cerebral cholesterol efflux with peripheral bile acid metabolism. The findings facilitated exploring active compounds from traditional Chinese medicine that may reduce Aβ deposition by targeting lipid metabolism pathways. Show less

Atherosclerosis (AS), a chronic inflammatory disorder initiated by vascular endothelial dysfunction (ED), is prominently triggered by hemodynamic low-shear stress (LSS). Interferon regulatory factor 6 (IRF6) is a transcription factor that regulates the inflammatory response following injury. In this work, the LSS-induced AS model was induced by the partial ligation of the left carotid artery in high-fat diet-fed ApoE Show less