👤 Lili Tian

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

Anorexia nervosa (AN) is a complex psychiatric disorder with both psychiatric and metabolic underpinnings. This study aims to explore the genetic architecture of AN and the interplay between its psychiatric and metabolic components. Through a meta-analysis of AN GWAS data from European and Finnish populations, we identified a novel genome-wide significant locus near the SOX5 gene. Genetic correlation and Mendelian randomization analyses revealed shared and potentially causal relationships between AN and multiple psychiatric and metabolic traits. Local genetic correlation analysis identified 185 significant genomic regions contributing to shared heritability between AN and correlated phenotypes, with 100 loci demonstrating pleiotropic effects across multiple traits. The MTAG analyses identified 86 significant loci (34 overlapping with local genetic correlation results), including 25 novel loci such as brain-relevant VAMP2 (17p13.1) and metabolic-neurological hubs LPL (8p21.3) and BDNF (11p14.1). Gene Co-expression Network Analysis (WGCNA) further identified key gene modules associated with both metabolic and neurological pathways, particularly highlighting synaptic signaling and lipid metabolism. Single-cell transcriptomic analysis further resolved this genetic risk to the cellular level, confirming its concentration in limbic and striatal GABAergic neurons and extending the implicated circuitry to include cortical regions involved in motor function. These findings collectively demonstrate the intricate genetic interplay between psychiatric and metabolic pathways in AN, underscoring the necessity of an integrated approach to understanding its pathogenesis. Show less

Given the limitations of current treatments for Alzheimer's disease (AD), this study aims to comprehensively evaluate the therapeutic efficacy of human umbilical cord mesenchymal stem cells (hUCMSCs) in AD mouse models through a systematic review and meta-analysis. Additionally, we explore the impact of transplantation dose and route on treatment outcomes to identify the optimal window for clinical application. In accordance with the PRISMA guidelines, we systematically searched four major databases to identify randomized controlled trials involving hUCMSCs in AD mouse models. We used the standardized mean difference (SMD) to synthesize effect sizes and performed subgroup analyses based on pre-defined transplantation routes and doses. A total of 13 studies were included in the analysis. The meta-analysis revealed that hUCMSCs transplantation significantly improved spatial learning and memory in AD model mice, with a marked reduction in escape latency (SMD = -2.55; 95% CI: -3.34 to -1.75; Human umbilical cord mesenchymal stem cells can improve behavioral and pathological outcomes in AD mouse models via multiple mechanisms of action. The intravenous route using medium to high doses emerges as a critical factor for achieving optimal effects, providing important evidence and informing future experimental design and clinical translational research. 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

(1) Background: The increasing environmental concentration of polystyrene nanoplastics (PS-NPs) may pose a risk of human exposure and health threats. Previous studies have demonstrated that exposure to PS-NPs poses a threat to neural synaptic plasticity, yet the underlying mechanisms remain unclear. (2) Methods: Hippocampal astrocytes and neurons were co-cultured, exposed to PS-NPs at concentrations of 10, 50, and 100 μg/mL, and cytotoxicity was assessed. We investigated PS-NP-induced impairment of synaptic plasticity by regulating the brain-derived neurotrophic factor (BDNF). (3) Results: Calmodulin-dependent protein kinase II (CaMKII) is a central molecular organizer of synaptic plasticity, learning, and memory, and its activity is intrinsically linked to intracellular calcium ion concentration. Our research indicates that PS-NPs may interfere with calcium ion signaling and CaMKIIα activity, thereby reducing CaMKIIα activity. This subsequently downregulates the expression of cAMP response element-binding protein (CREB), modulates BDNF expression, and impacts synaptic plasticity. (4) Conclusions: In summary, this study primarily focused on the effects of PS-NPs exposure on hippocampal synaptic plasticity. 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

Puerarin is a flavonoid bioactive component extracted from the Chinese herb radix puerariae, which has been reported to have anti-inflammatory and neuroprotective effects and is a potential drug for the treatment of neuroinflammatory diseases. There is increasing evidence that the gut-liver-brain axis is closely related to neurological disorders. However, studies on the use of puerarin for the treatment of depression based on gut-liver-brain axis-mediated inflammatory injury have not been reported. In the present study, a 4-week chronic restraint stress (CRS) mouse depression model was established. Place the mice in 50 mL centrifuge tubes for restraint. The tubes should be perforated with 15-20 small holes to ensure adequate ventilation. The restraint period is from 9:00 a.m. to 1:00 p.m. daily, during which food and water are withheld. Based on the results of previous studies, the better antidepressant dose of puerarin, 100 mg/kg, was chosen, and fluoxetine was used as a positive control to investigate the intervention effect and potential mechanism of puerarin on depression. All of the aforementioned drugs were administered via oral gavage. Sucrose preference test (SPT), tail suspension test (TST), open field test (OFT), novelty suspended feeding test (NSFT) and forced swimming test (FST) were used to observe the behavioral changes in mice to assess the antidepressant effects. The microbial composition of the intestinal tract was analyzed using 16S rRNA gene sequencing. Histopathological changes in colon and liver were also observed by HE staining method. The levels of lipopolysaccharide (LPS) in colon, serum, liver and prefrontal cortex (PFC) and the levels of 5-hydroxytryptamine (5-HT) in prefrontal cortex were detected by enzyme-linked immunosorbent assay (ELISA). The method was developed for the detection of 5-HT in the prefrontal cortex. The serum levels of glutamate transaminase (AST) and alkaline phosphatase (ALP) were measured by microplate assay. Finally, the expression of brain-derived neurotrophic factor (BDNF), TLR4, MYD88, p-IκB-α, and p-p65 proteins were determined by immunoblotting assay (Western Blot, WB) in mice with PFC. Puerarin was effective in alleviating CRS-induced depression-like behaviors measured in SPT, TST, FST and NSFT in mice. Compared with the CRS model group, puerarin increased the rate of sugar-water preference in the SPT and shortened the cumulative immobility time in the TST and FST as well as the ingestion latency in the NSFT in depressed mice. In addition, puerarin administration ameliorated CRS-induced gut microbiota dysbiosis in mice, elevating the abundance of Lactobacillaceae, Lactobacillus spp. Decreased the relative abundance of Ruminococcaceae, Ruminococcus, Desulfovibrionaceae, and Prevotella spp. Puerarin also reduced LPS, AST and ALP levels, improved damaged colon and liver tissues, inhibited neuroinflammatory damage mediated by the TLR4/MYD88/NF-κB signaling pathway, and up-regulated the levels of 5-HT and BDNF in the prefrontal cortex of the mice, thereby reversing CRS-induced depressive-like behaviors in depressed mice. Puerarin can improve CRS-induced depression in mice by regulating the gut-liver-brain axis and its related molecules. For example, it can regulate CRS-induced intestinal flora disorders and intestinal permeability, thereby reducing systemic LPS levels and the relative levels of AST and ALP, inhibiting the activation of the TLR4/MYD88/NF-κB signaling pathway by LPS, thereby reducing neuroinflammatory damage, and ultimately improving the depressive symptoms of CRS mice. Show less

To investigate the effect of pterostilbene (PTE), a natural dimethyl ether analog of resveratrol with higher bioavailability, on cognitive recovery after cerebral ischemia reperfusion (IR) injury and its potential mechanisms. Mice were subjected to middle cerebral artery occlusion and assigned to Sham, IR, PTE+IR, and PTE+Zinc Protoporphyrin (ZnPP)+IR groups. Cognitive function was assessed using the Morris water maze. Cerebral infarct volume was evaluated by 2,3,5-triphenyltetrazolium chloride (TTC) staining, and neuronal apoptosis was determined via TUNEL assay. The protein levels of postsynaptic density protein 95 (PSD-95), phosphorylated cAMP response element-binding protein (p-CREB), brain-derived neurotrophic factor (BDNF), and histone deacetylases (HDACs) in the hippocampus were measured by western blot. PTE treatment significantly reduced cerebral infarct volume, alleviated cognitive deficits, and inhibited neuronal apoptosis in the hippocampus. At the molecular level, PTE up-regulated the expression of PSD-95, p-CREB, and BDNF, while down-regulating HDAC (1, 2, 3, 4, 7) levels. The beneficial effects of PTE were partially reversed by the HO-1 inhibitor ZnPP. PTE ameliorates cognitive impairment induced by cerebral IR injury, potentially through activating the BDNF/CREB pathway and inhibiting HDAC expression. This suggests PTE as a promising neuroprotective agent for post-stroke cognitive recovery. Show less

Breast cancer patients frequently experience debilitating cancer-related fatigue (CRF) during chemotherapy. Emerging evidence implicates the gut microbiota (GM) and the gut-brain axis in CRF pathogenesis, yet whether pre-chemotherapy GM profiles can predict CRF remains unclear. This prospective cohort study enrolled 100 breast cancer patients initiating chemotherapy. GM profiling and fatigue assessment (Visual Analogue Fatigue Scale, Cancer Fatigue Scale) were performed at baseline and the third chemotherapy cycle. Serum levels of neuroimmune-endocrine markers were also measured. Multivariate logistic regression was used to build a predictive model for moderate-to-severe CRF. Patients experiencing moderate-to-severe CRF at the third chemotherapy cycle demonstrated higher baseline Baseline GM characteristics predict the risk and severity of chemotherapy-induced CRF, potentially through modulation of neuroimmune-endocrine pathways via gut-brain axis. These findings underscore the potential role of GM as a predictive biomarker and a therapeutic target for chemotherapy-induced CRF. Show less

Aurantii Fructus (AF)is a traditional Chinese medicine historically used to regulate Qi and alleviate emotional distress, suggesting potential psychotropic effects. This study investigates its therapeutic value for depression based on this traditional indication. To evaluate the rapid antidepressant-like effect of a single acute dose of AF extract in a chronic unpredictable mild stress (CUMS) mouse model and elucidate its underlying molecular mechanisms through integrated transcriptomic and metabolomic analyses. AF flavonoid content was quantified by HPLC. Male mice underwent a 4-week CUMS protocol. A single oral dose of AF was administered 2 h prior to behavioral testing (NSF, TST, SPT, and OFT), with ketamine serving as a positive control. Hippocampal transcriptome analysis was performed by RNA sequencing, and serum metabolites were profiled via LC-MS in both positive and negative ion modes. Pearson correlation analysis assessed relationships between key targets and behavioral outcomes. Pathway involvement was functionally validated in a separate experiment using a hypoxanthine synthesis inhibitor. AF contained narirutin (1.32 mg/g), hesperidin (3.19 mg/g), neohesperidin (22.89 mg/g), naringenin (0.03 mg/g), and nobiletin (0.08 mg/g). Acute AF administration rapidly reversed CUMS-induced depressive-like behaviors, significantly decreasing latency to feed and increasing food consumption in the NSF test, reducing immobility time in the TST, and elevating sucrose preference in the SPT, without altering locomotor activity. Transcriptomic analysis revealed specific downregulation of hippocampal caspase-4 expression by AF. Metabolomic profiling showed AF normalized elevated serum hypoxanthine levels. Serum hypoxanthine levels negatively correlated with hippocampal caspase-4 expression and behavioral improvements, whereas caspase-4 expression positively correlated with behavioral deficits. Pharmacological inhibition of hypoxanthine synthesis abolished AF's antidepressant effects and prevented its normalization of hippocampal caspase-4, NF-κB, GDNF, and BDNF expression. Acute AF produces rapid, ketamine-like antidepressant effects by targeting the hypoxanthine-caspase-4 pathway. This study reveals a novel purinergic mechanism underlying AF's traditional use for emotional disorders and offers a promising therapeutic strategy for rapid-acting antidepressant development. Show less

Lilium brownii is a plant that can be used for medicinal and food purposes. 1-O-p-coumaroyl-3-O-feruloyl glycerol (CF) is a phenolic acid glycerol dimer isolated from Lilium brownii. This study aims to evaluate the neuroprotective effects of CF and elucidate the possible molecular mechanisms underlying its neuroprotective effects through in vivo and in vitro models of Parkinson's disease. 1-methyl-4-phenylpyridinium ions (MPP Following CF administration, the apoptosis rate and reactive oxygen species (ROS) levels in PC12 cells were significantly reduced. CF markedly upregulated the expression of proteins including dopamine, tyrosine hydroxylase, brain-derived neurotrophic factor (BDNF), while simultaneously downregulating the expression of proteins such as α-synuclein. Molecular docking results demonstrated favorable affinity between CF and proteins including p62. This compound not only ameliorated motor and cognitive impairments in Parkinson's disease mice but also markedly increased neuronal numbers within the substantia nigra region of these animals. CF exerts a neuroprotective effect in Parkinson's disease by modulating the p62-Keap1-Nrf2 signalling pathway. Show less

The global aging population has led to a rising prevalence of cognitive impairment, posing a significant public health challenge. Resistance training (RT) is a non-pharmacological intervention that has been increasingly investigated for its potential to support cognitive function in older adults. Clinical evidence suggests that RT may be associated with benefits in certain cognitive domains, including memory, executive function, processing speed, and visuospatial ability. However, findings across studies remain heterogeneous, with several trials reporting neutral outcomes. Most intervention studies involve structured RT programs conducted at moderate to high intensity and performed multiple times per week. However, optimal training parameters have not yet been clearly established due to variability in study design and the absence of formal dose-response analyses. Emerging evidence suggests that the cognitive effects of RT may be mediated, at least in part, through muscle-brain axis signaling involving exercise-induced myokines. Factors such as irisin, brain-derived neurotrophic factor, interleukin-6, interleukin-15, and insulin-like growth factor-1 have been implicated in processes related to neuroplasticity, neuroinflammatory regulation, and neurovascular function, primarily based on preclinical and translational research. This review synthesizes current evidence on RT-related molecular mechanisms and clinical findings to provide an integrative perspective on the potential role of resistance training in mitigating age-related cognitive decline. 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

The comparative efficacy and safety profiles of PCSK9 inhibitors in familial hypercholesterolemia (FH), including genotype-dependent treatment responses, remain unclear. This systematic review was conducted in accordance with the Preferred Reporting Items for Meta-Analyses guidelines. A network meta-analysis of randomized clinical trials evaluating the use of PCSK9 inhibitors for the treatment of FH patients, including subgroup analyses of efficacy, was performed. Fifteen randomized clinical trials (n = 2954 patients) were included. All PCSK9 inhibitors significantly improved lipid parameters compared to control. In heterozygous FH (HeFH) populations, ongericimab showed the greatest reductions in LDL-C (mean difference [MD]: -74.98 %), ApoB (MD: -64.64 %), and Lp(a) (MD: -59.66 %), with SUCRA rankings of 68.7 %, 63.6 %, and 95.0 %, respectively. However, these results are based on a single trial and require further validation. No significant lipid-lowering effects were observed in HoFH patients. In terms of safety, lerodalcibep showed the most favorable profile for injection-site reactions and ALT >3 × ULN, with SUCRA values of 98.5 % and 96.7 %, respectively. Inclisiran was associated with a significantly higher risk of injection-site reactions. PCSK9 inhibitors generally show favorable efficacy and safety in FH patients. However, comparative rankings and point estimates should be interpreted with caution due to funnel plot asymmetry for LDL-C and imbalances in trial data. Ongericimab demonstrated promising results in HeFH, but further validation is required. Inclisiran's efficacy may be underestimated due to short-term follow-up. Monotherapy with PCSK9 inhibitors has limited efficacy in HoFH patients, highlighting the need for combination therapies. Show less

Sepsis is a syndrome caused by the host's inflammatory response to an infection with an unknown mechanism. This study aimed to identify differentially expressed genes (DEGs) potentially involved in the development and recovery of tracheal injury from septic shock. Nine New Zealand white rabbits were randomized to control (CON), septic shock model (SS), and septic shock norepinephrine treatment (SSNE) groups (each group n = 3). The SS and SSNE groups were injected with lipopolysaccharide to induce septic shock. The SSNE group was administered Ringer lactate with norepinephrine to maintain normal blood pressure. All animals underwent cuffed endotracheal intubation for 2 h. The injured tracheal segment was harvested. RNA sequencing was performed to identify the DEGs, followed by bioinformatics analysis, and pathological staining (both HE and Masson) was performed for pathological evaluation. Bioinformatics analysis included principal component analysis (PCA), gene set enrichment analysis (GSEA), and protein-protein interaction (PPI) network construction. Key findings were validated by qRT-PCR and immunohistochemistry. We obtained 124 upregulated and 28 downregulated DEGs in SS vs. CON groups, along with 60 upregulated and 178 downregulated DEGs in SSNE vs. SS groups. The pathological score showed that trachea tissue in the SS group had the highest score. The protein-protein interaction (PPI) prediction identified APOB and CD36 as the hub genes. The molecular experiments further confirmed that at mRNA and protein levels, APOB was significantly upregulated, while CD36 was significantly downregulated. Subsequent qRT-PCR and immunohistochemical analyses confirmed that APOB expression was significantly upregulated while CD36 was downregulated in the septic shock group, a trend partially reversed by norepinephrine treatment. Our study results suggest that APOB and CD36 may be involved in the pathogenesis of tracheal injury recovery in septic shock patients treated with NE. Not applicable. Show less

Chronic obstructive pulmonary disease (COPD) is a systemic condition with comorbidities beyond the lung (eg, cardiovascular and metabolic disorders), and gastrointestinal (GI) disorders are also common. The shared genetic basis of COPD-GI comorbidity and its mediating factors remain unclear. We hypothesized that COPD and GI diseases share pleiotropic genetic architecture implicating lipid-metabolic pathways, with smoking mediating part of the association. We analyzed publicly available European-ancestry GWAS summary statistics for COPD (Global Biobank Meta-analysis Initiative), 15 GI diseases (FinnGen), and smoking phenotypes (UK Biobank). Genetic correlation was estimated using linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL). Multi-trait analysis of GWAS (MTAG) boosted COPD discovery by leveraging genetically correlated GI traits. We integrated locus-to-gene mapping with multi-tissue expression quantitative trait loci (eQTL) and plasma protein quantitative trait loci (pQTL) evidence to prioritize shared loci, genes, and proteins. Bidirectional two-sample Mendelian randomization (MR) tested causal directions, and two-step mediation MR evaluated smoking. COPD showed significant genetic correlation with nine GI diseases. We identified six comorbidity-associated loci (three with CADD > 12.37) and 13 unique candidate pleiotropic genes; APOE was supported by proteomic evidence. Enrichment analyses highlighted lipid-metabolism pathways. MR suggested COPD increases risk of gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), acute appendicitis, and gastric ulcer, while diverticular disease showed reverse causality toward COPD. Smoking partially mediated the COPD effect on GERD, acute appendicitis, and gastric ulcer. COPD and multiple GI disorders share a distributed pleiotropic genetic basis within the broader systemic comorbidity spectrum of COPD. Multi-omics evidence supports a genomic pulmonary-intestinal axis in which lipid metabolism and smoking-related mechanisms contribute to COPD and GI comorbidity, providing targets for risk stratification and potential intervention. Show less

Sodium perfluorononenoxybenzene sulfonate (OBS), a substitute for perfluorooctane sulfonate (PFOS), has been frequently detected in the environment and human blood. Although OBS exposure has been identified as a novel risk factor for atherosclerosis associated with endothelial dysfunction, the underlying molecular mechanisms remain unclear. In this study, in vitro experiments using human umbilical vein endothelial cells (HUVECs) demonstrated that OBS exposure induced oxidative stress, activated the PERK-eIF2α-ATF4 axis of endoplasmic reticulum stress (ERS) and triggered NF-κB signaling. Pharmacological inhibition with N-acetylcysteine (NAC, an antioxidant), 4-phenylbutyric acid (4-PBA, an ERS inhibitor), and BAY 11-7082 (an inhibitor for NF-κB signaling pathway) revealed a sequential pathogenic cascade, in which oxidative stress acts upstream to initiate ERS and compromise endothelial barrier function, leading to NF-κB activation, which drives inflammatory responses, monocyte adhesion, and impaired endothelial migration. Consistent with these findings, in vivo experiments in ApoE Show less

N6-methyladenosine (m6A) RNA modification can govern cell fate by co- or post-transcriptionally regulating gene expression. VSMCs can undergo phenotypic switching, contributing to other cells within atherosclerotic plaques, including foam cell- and macrophage-like cells. However, the role of VSMC m6A in atherosclerosis development remains unclear. While PPAR-α and PPAR-γ have been extensively studied in macrophages for their roles in atherosclerosis, the epigenetic regulation of these nuclear receptors under high cholesterol conditions remains poorly understood. We utilized murine and human atherosclerotic aortas, along with VSMC-specific Mettl3 and Mettl14 knockout mice, to evaluate the role of VSMC m6A in atherosclerosis. Lineage tracing was used to assess macrophage-like VSMCs. The epigenetic regulation of Ppara and Pparg transcription by Methyltransferase-like 14 (METTL14) was investigated through a variety of methods, including histological, cellular, genomic, transcriptomic, metabolomic, lipidomic, computational, and pharmacological approaches. The therapeutic potential of VSMC Mettl14 in atherosclerosis was analyzed using adeno-associated virus-mediated expression in ApoE-/- mice.We showed that the METTL3/METTL14 methyltransferase complex was reduced in both murine and human atherosclerotic VSMCs. The levels of METTL3, and consequently m6A, were regulated by METTL14, which was in turn influenced by ox-LDL. Notably, while VSMC METTL3 or m6A did not contribute to atherosclerosis, VSMC-specific Mettl14 knockout mice exhibited accelerated foam cell formation, enhanced vascular inflammation, and exacerbated atherosclerosis. These effects were driven by impaired beta-oxidation and reduced mitochondrial oxidative phosphorylation (OXPHOS). Replenishment of Mettl14 significantly attenuated these adverse effects. Specifically, METTL14 regulated phenotypic switching of VSMCs and modulated the number of VSMC-derived macrophage-like cells, rather than infiltrating macrophages, within atherosclerotic plaques. Furthermore, we demonstrated that METTL14 regulates the transcription of Ppara and Pparg, master regulators of lipid metabolism that promote cholesterol efflux, by enhancing SETD1A-mediated H3K4 trimethylation in an m6A-independent manner. Activation of PPAR-γ with rosiglitazone restored impaired mitochondrial OXPHOS in Mettl14-deficient VSMCs, leading to reduced lipid accumulation. Lastly, recapitulating Mettl14 expression in atherosclerotic vessels through AAV gene therapy effectively inhibited atherosclerosis progression without compromising liver function. We have unveiled that METTL14 promotes lipid metabolism and inhibits atherogenesis through activating PPAR-α/γ expression. These experiments highlight the therapeutic potential of the endogenous METTL14/PPAR-α/γ axis for treating atherosclerotic and metabolic diseases. Show less

White matter (WM) is a key substrate for interregional neural communication and cognitive function but the role of WM glucose metabolism in cognitive aging has been understudied. Using multimodal neuroimaging (MRI, FDG-PET, amyloid-PET) from 3142 participants (15,287 visits) across two studies, we examined the contribution of WM to cognition and identified divergent WM signatures. Higher glucose metabolism in expected WM (EWM; corpus callosum and cingulum) was associated with better cognition, whereas increased metabolism in atypical WM (AWM; corona radiata) was linked to worse cognition, indicating a compensatory mechanism. EWM metabolism declined with aging, Alzheimer's disease (AD) progression (amyloid-β and APOE-ε4 carrier), and white matter hyperintensities, while AWM metabolism increased with aging and vascular risk but was partially weakened by AD neuropathology. Longitudinally, higher EWM and lower AWM metabolism predicted slower cognitive decline. Divergent WM metabolic patterns shed light on the dynamic role of WM in maintaining cognitive function. This study emphasizes the complementary information provided by WM metabolism for predicting future cognitive decline and identifying cognitive resilience. Show less

Elucidating effective components and mechanisms of traditional Chinese medicine (TCM) formulas remains a critical challenge for modernization. ErShiWei RouDouKou Pills (ESWRDK), a Tibetan formula with cardiovascular potential, lacks systematic exploration of its anti-atherosclerotic (AS) material basis and mechanisms. A novel six-stage cascade focused strategy integrating three-dimensional filtering mode, qualitative characterization, multi-component quantification, anti-AS efficacy, multi-lipidomics and bioactive compounds evaluation was proposed, advancing TCM research by holistic and multi-layered approach. UHPLC-MS combined with mass defect-ion intensity filtering (MD-ITF), DPIs, Nl and FBMN employed for profiling. Nine characteristic components were quantitated. A 12-week high-fat diet was fed to ApoE Firstly, the MD-ITF method and structural classification was established for complicated matrix. Secondly, 426 chemical components including 74 low-abundance were characterized. Thirdly, 9 characteristic components were quantified, and content distribution were profiled. Fourthly, ESWRDK reduced lipids, inflammation, and aortic plaques in AS mice. Fifthly, a total of 38, 23 and 48 differential biomarkers were identified predominantly linked to glycerophospholipids (GP) metabolism. WB confirmed ESWRDK downregulated hepatic PLA2, upregulated p-AMPK/AMPK and PPAR-α, and suppressed SREBP-1, orchestrating and mitigating lipid dysregulation. Finally, dehydrodiisoeugenol and agarotetrol bound PLA2, formed stable 1:1 static quenchingand inhibited PLA2 activity in vitro. A novel six-stage cascade-focused strategy was successfully established to elucidate ESWRDK's anti-AS mechanisms, offering feasible paradigm for advancing modernization of TCM. Show less

Alzheimer' s disease (AD) is a progressive neurodegenerative disorder characterized by a spectrum of cognitive impairments, ranging from mild memory loss to severe cognitive decline and, ultimately, death. The global incidence of AD is projected to increase significantly, with late-onset AD being predominantly sporadic in nature. Over the past three decades, the Apolipoprotein E (APOE) gene has been recognized as the most important single genetic determinant of sporadic AD risk. The APOE4 allele is a major risk factor for AD and is known to exacerbate the pathological process for AD. Identifying protective variants that may reduce the risk or delay the onset of AD is of great significance for the development of effective treatments. This review comprehensively examines the protective effects of APOE and its related protective mutations. It also explores the impact of these unique protective variants at the cellular level during the pathological progression of AD. Furthermore, the review compiles new insights for AD treatment offered by these protective mutations, exploring the potential applications of APOE and its related protective variants in advanced therapeutic strategies, including gene editing, RNA editing, and stem cell therapy. Show less

Diabetic atherosclerosis (DA), characterized by disordered glucose and lipid metabolism, represents a significant metabolic vascular complication. Tangzhiqing (TZQ) has traditionally been used to treat diabetes and its complications. However, its material basis and mechanism for DA remain require further investigation. This research aimed to systematically elucidate the pharmacological material basis and underlying mechanism of the traditional Chinese medicine TZQ in diabetic atherosclerosis model mice. This study established UPLC-MS/MS and UPLC-Q-TOF/MS methods to detect composition and content of TZQ in vivo and in vitro, with pharmacokinetic analysis determining plasma concentration changes of representative components. DA model was induced by western diet and streptozotocin injection in ApoE 118 compounds were identified from TZQ. It contains categories such as organic acids, quinones, flavonoids, alkaloids, and terpenoids. Among them, 39 compounds were absorbed into bloodstream. Pharmacokinetic analysis demonstrated that 18 compounds were effectively absorbed into plasma with appropriate bioavailability. Pharmacodynamic results demonstrated that TZQ significantly alleviated hyperglycemia, hyperlipidemia, and aortic pathology in DA mice. Metabolomics and network pharmacology suggested the anti-DA effects were associated with bile acid metabolism. Targeted analysis confirmed TZQ restored high-fat-diet-induced bile acid metabolic imbalance. 16S rRNA sequencing revealed TZQ modulated gut microbiota dysbiosis, specifically regulating bile acid metabolism-related genera (e.g., Desulfovibrio, Bacteroides, Lactobacillus). The WB results showed that TZQ enhanced the expression of FXR, SHP and CYP7A1 in liver. Molecular docking proved that the bioactive compounds of TZQ exhibits favorable affinity for both FXR and CYP7A1. The study provided a comprehensive detection of in vitro and in vivo constituents and pharmacokinetic profile of TZQ, establishing a foundation for further exploration of its pharmacologically active components. TZQ alleviated DA by regulating the gut microbiota and bile acid metabolism. These results created a new perspective for the management of DA. Show less

Atherosclerosis (AS) is a chronic vascular disease with complex pathological mechanisms, characterized primarily by the formation of aortic plaques. Calenduloside E (CE), a compound isolated from Aralia elata, exhibits beneficial cardiovascular activities. Our previous studies have shown that CE can protect human umbilical vein endothelial cells (HUVECs) from damage induced by oxidized low-density lipoprotein (ox-LDL) through binding to the target protein HSP90AB1 in cell lysate. However, there is currently no direct research demonstrating the anti-atherosclerotic effect of CE in vivo, and its mechanism of action and direct targets in cell remain unclear. This study demonstrates that CE exhibits potent anti-atherosclerotic activity. In vivo, CE shows significant anti-atherosclerotic activity by inhibiting plaque formation in ApoE Show less

Lecanemab has been approved for the treatment of mild cognitive impairment due to Alzheimer's disease (AD) and mild AD dementia based on the efficacy in slowing cognitive decline and preliminary safety data from the phase Ⅲ Clarity AD trial. However, this trial excluded patients with high risk of cerebral hemorrhage, such as individuals with intracranial aneurysms or > 4 microhemorrhages. A 70-year-old male with mild AD, intracranial aneurysm, microhemorrhages, and APOE ε3/ε4 genotype received lecanemab after multidisciplinary evaluation and informed consent. Over six months of intensive monitoring, cognitive function stabilized with no deterioration, daily activities were preserved, microhemorrhages remained stable (with one new small lesion noted at 3 months), and no aneurysm rupture or severe adverse events (including amyloid-related imaging abnormalities) occurred. This case suggests that, despite hemorrhage risks, lecanemab may have a manageable risk-benefit profile in selected real-world AD patients under intensive monitoring and multidisciplinary care, with its application beyond clinical trial criteria requiring more nuanced and individualized consideration. Show less

Perirenal fat deposition significantly impacts sheep carcass quality and economic efficiency. To elucidate the underlying genetic regulation, we performed a genome-wide association study (GWAS) on 556 Hu sheep and a comparative transcriptome analysis on 24 Hu sheep (12 with high- and 12 with low-perirenal fat deposition), all with accurate phenotypic records. Furthermore, hub genes and tissue-specific genes (TSGs) were discerned through weighted gene co-expression network analysis (WGCNA) and by leveraging RNA-Seq data from 12 tissues, respectively. qRT-PCR is used to validate the accuracy of RNA-Seq data. GWAS identified significant SNPs near genes including SETD4, TIMP2, SOCS3, and DNAH17. Comparative transcriptome analysis of HPF and LPF groups identified 2072 differentially expressed genes (DEGs), which were significantly associated with lipid storage (LPL), fatty acid homeostasis (APOE, GOT1), and biosynthesis (ACACA). A total of 2333 differential alternative splicing events were identified in 1169 genes, with skipped exons (SE, 30.65 %) being the most common. GO analysis of these SEs showed links to RNA splicing and lipid metabolism, with genes like BSCL2, DGAT1, PLIN5, and PNPLA2 involved in lipid droplet organization and triglyceride storage. WGCNA revealed key modules that were positively and negatively correlated with perirenal fat deposition, emphasizing hub genes (SAR1B, THRSP, ACSS2, KIF5B) associated with lipid droplet organization and metabolism. The integrated analysis of GWAS and RNA-seq identified TIMP2, SOCS3, and DNAH17 as potential key genes involved in regulating perirenal fat deposition in sheep. An association analysis of 372 Hu sheep populations identified significant links (P < 0.05) between perirenal fat deposition traits and mutations in the TIMP2 (g.9759169 G > A) and DNAH17 (g.9494469C > T) genes. Crucially, tissue-specific gene analysis across 12 tissues identified 448 perirenal fat TSGs, of which 75 were also differentially expressed genes (e.g., LPL, THRSP, LEP, ADRB3). In conclusion, our multi-omics study identified key genes influencing perirenal fat deposition in sheep. Notably, mutations in TIMP2 and DNAH17 could serve as candidate markers for enhancing carcass quality through marker-assisted selection. Show less

Purinergic receptor P2X7 has been considered as a potential new target for detecting and treating high-risk plaque. Nanobodies are the smallest antibody fragments with high antigen binding ability and specificity, which are well-suited for radionuclide imaging. The present study aimed to develop a novel P2X7-targeted nanobody SPECT tracer and to investigate its potential for identification of atherosclerotic plaque (AP). The anti-P2X7 nanobody 1c81 was site-specifically conjugated with [ Show less

Atherosclerosis, a key pathological basis of cardio-cerebrovascular diseases, is closely associated with aging and endothelial cell senescence. The role of microRNAs (miRNAs) in regulating endothelial cell senescence and atherosclerosis remains incompletely understood. In this study, we discovered that miR-375-3p expression was significantly elevated in the serum of both aged and atherosclerotic mice. Overexpression of miR-375-3p induced endothelial cell senescence, evidenced by increased senescence-associated β-galactosidase (SA-β-gal) staining, upregulation of p15, IL6, and IL8, and inhibited cell colony formation. In vivo inhibition of miR-375-3p in ApoE Show less