👤 Li-Qiu Ma

Atherosclerotic vascular diseases remain the leading cause of death despite the use of lipid-lowering drugs. The development of more efficacious therapies targeting endothelial inflammation and endothelial-to-mesenchymal transition (EndMT) is an essential endeavor, aiming for better treatment outcomes. The increased mutation frequency of the The results of liquid chromatography-mass spectrometry, immunostaining, RNA sequencing, and Western blot in mouse and human arteries with atherosclerotic plaques identified TBK1 as one of the key mediators of EndMT and atherogenesis. Its role was then investigated in endothelium-specific TBK1 knockdown An increased expression of TBK1 was observed by liquid chromatography-mass spectrometry analysis in the aortas of The interaction between activated TBK1 and PAK1IP1 inhibits the binding of PAK1IP1 to PAK1, which, in turn, increases the phosphorylation of PAK1 and ERK1/2 in endothelial cells. This process drives EndMT. Endothelium-specific TBK1 knockdown or GSK8612 treatment inhibits EndMT and plaque formation. Safe TBK1 inhibitors could be developed into effective agents for the treatment of atherosclerotic vascular disease. Show less

Hypertensive heart disease (HHD) and hypertrophic cardiomyopathy (HCM) are characterized by left ventricular hypertrophy and diastolic dysfunction. Despite overlapping remodeling features, their distinct mechanisms and therapeutic responses remain unclear. This study integrated genetic, imaging, and proteomic data to identify key mediators underlying β1-adrenergic receptor blockers (β1-blockers)-related therapeutic heterogeneity between HHD and HCM. Genetic instruments for β1-blockers were derived from two genome-wide association studies and integrated with cardiac magnetic resonance radiomic traits and plasma proteomic data from the UK Biobank, along with disease outcomes from FinnGen. A refined two-stage network Mendelian randomization framework with pleiotropy-robust estimators identified mediators of treatment response. To further elucidate their biological and clinical significance, additional analyses were performed, including drug-target profiling, molecular docking, adverse events (AEs) assessment, and drug prediction. We identified three types of imaging features and ten mediator proteins that contributed to therapeutic responses in HHD and HCM. These mediators were categorized as either mediating (aligned with therapeutic outcomes) or suppressing (opposing therapeutic outcomes). Left ventricular regional radial strain acted as a suppressing factor in HHD but a mediating factor in HCM, whereas end-diastolic and end-systolic volumes consistently showed suppressing effects in both. Regional myocardial wall thickness also exerted a suppressing role in HCM. Among protein mediators, APOE, CGREF1, ITGA5, LSP1, NOS3, and NPPB were linked to HHD, whereas DUSP13, ITGA11, NID1, and SERPINA4 were related to HCM. Specifically, APOE, ITGA5, NOS3, NPPB, DUSP13, and ITGA11 acted as mediating factors, while CGREF1, LSP1, NID1, and SERPINA4 served as suppressing ones. These findings remained robust after pleiotropy adjustment and other genetic analyses. Molecular docking revealed interactions between ADRB1, the β1-blockers target, and downstream proteins, while drug prediction identified eight potential compounds linked to these mediators. Additionally, AE analyses indicated that some targets, such as DUSP13, could both mitigate and aggravate common AEs while contributing to cardiac therapy. This integrative multi-omics analysis revealed distinct imaging and proteomic mechanisms of genetically proxied β1-blockers in HHD and HCM, providing genetic evidence for differential therapeutic responses and highlighting molecular targets for precision cardiovascular therapy. Show less

Toll-like receptor 9 (TLR9), expressed in both microglia and neurons of the CNS, represents a promising therapeutic target for Alzheimer's disease (AD). While either microglial or neuronal TLR9 activation exerts neuroprotective effects that ameliorate AD pathology and preserve cognitive function, CpG oligodeoxynucleotides (ODNs), the synthetic agonists, cannot cross the blood-brain barrier (BBB). To overcome this, we developed tNCpG, an apolipoprotein E (ApoE)-functionalized polymersome nanocarrier for brain-targeted delivery of CpG ODNs. APP/PS1 transgenic mice, which overexpress human mutant APP/PS1 and are widely used in AD mouse models for preclinical studies, were administered tNCpG intravenously biweekly for 3 months, starting at 4 months of age. tNCpG achieved efficient brain delivery while specifically targeting microglia and neurons. tNCpG treatment enhanced microglial recruitment to and phagocytosis of Aβ plaques, suppressed Aβ production while promoting its degradation, and improved BBB integrity and Aβ efflux. Collectively, these effects significantly reduced cerebral Aβ burden, neuroinflammation, and neurodegeneration, leading to the rescue of cognitive deficits. Our study establishes targeted TLR9 activation via tNCpG as a disease-modifying therapeutic strategy for AD. Show less

This study aimed to identify risk factors and develop statistical models to predict cerebral amyloid angiopathy (CAA). Associations between demographic, cognition, cardiovascular, and AD-related neuropathology and CAA were analyzed using data from three longitudinal cohorts of aging and dementia. Logistic regression with LASSO was used for feature selection. Predictive performance was assessed using ROC-AUC and decision curve analysis (DCA). Predictor importance was quantified using Shapley Variable Importance Cloud (ShapleyVIC), which provides a robust estimate of individual feature contribution in prediction. Stratified analyses showed that the strength of association between episodic memory or tau pathology and CAA was greater in males, while the amyloid pathology-CAA association was stronger in females. Among APOE ε4 carriers, the amyloid/tau pathology-CAA associations were pronounced. Episodic memory and amyloid/tau pathology were identified as key factors in our predictive model. DCA demonstrated the model’s clinical utility, and SHAP values confirmed the importance of individual features. We identified sex- and APOE-specific risk factors for CAA and developed models to support CAA risk stratification. The online version contains supplementary material available at 10.1186/s13195-025-01948-8. Show less

Extracorporeal cardiac shock wave (ECSW) therapy enhances the function of endothelial colony-forming cells (ECFCs), but whether it can serve as a preconditioning strategy to enhance myocardial infarction (MI) therapy remains unclear. This study investigated the efficacy and mechanism of intravenously delivered ECSW-preconditioned ECFCs (SW-ECFCs) in a rat MI model. ECFCs were isolated from the bone marrow of ApoE Transcriptomic analysis revealed significant enrichment of the PI3K/AKT pathway in SW-ECFCs. Functionally, ECSW enhanced ECFCs migration, tube formation, proliferation, and VEGF-A secretion, while reducing apoptosis; these effects were largely abolished by PI3K inhibition. In vivo, serum levels of CK, CK-MB, and LDH were significantly elevated in all MI groups compared to the Sham group (P < 0.01), indicating comparable initial injury. However, no significant differences were observed among treatment groups (P > 0.05). SW-ECFCs transplantation significantly improved cardiac function, reduced infarct size, fibrosis, and apoptosis, and enhanced angiogenesis (P < 0.05). These benefits were associated with increased levels of p-AKT, p-eNOS, and BCL-2 protein as well as nitric oxide content, while suppressing the expression of cleaved caspase-3 (P < 0.05). Crucially, all these therapeutic benefits were largely abolished by PI3K inhibition. In conclusion, this study demonstrates that preconditioning ECFCs with ECSW significantly enhances their therapeutic efficacy for myocardial infarction, improving both cardiac function and structural repair. These benefits are mediated primarily through activation of the PI3K/AKT signaling pathway, which augments cell homing, paracrine activity, and survival, thereby providing a novel and promising strategy for cardiac regeneration. Show less

Conventional nanocarriers are readily cleared by macrophages in the liver, with only a minimal fraction reaching hepatocytes. This limitation has been effectively overcome in clinically approved lipid nanoparticles (LNPs) through the incorporation of ionizable lipids. Inspired by this property, we explored whether incorporating ionizable lipids into the lipid bilayer membrane of mesoporous silica nanoparticles (silicasomes) could similarly enhance their hepatic cellular uptake. We developed ionizable silicasomes (I-silicasomes) and systematically compared them with ionizable liposomes (I-liposomes), as well as their conventional counterparts (C-silicasomes and C-liposomes). Surprisingly, I-silicasomes did not enhance hepatocyte uptake Show less

Chronic stress is associated with inflammatory activation and oxidative stress responses leading to endothelial dysfunction, which promotes the development of atherosclerosis (AS). SGLT2 inhibitors, such as Dapagliflozin (DAPA), exhibit a protective effect against cardiovascular diseases. However, the effects and mechanisms of DAPA on chronic stress-induced AS are largely unknown. The aim of this study was to determine whether DAPA confers a protective effect against chronic stress-induced AS and to elucidate its further molecular mechanisms. The combined high-fat diet-fed and chronic unpredictable mild stress in ApoE-/- mice and lipopolysaccharides- and corticosterone-induced human umbilical vein endothelial cells (HUVECs) were employed to evaluate the antiatherosclerotic effect of DAPA under chronic stress in vivo and in vitro. Histological staining, western blot analysis, siRNA transfection, reactive oxygen species (ROS) staining, and apoptosis assessment were used to investigate the potential mechanisms of DAPA against AS under chronic stress. The results indicate that DAPA significantly improved plaque size and increased plaque stability in the aorta under chronic stress and reduced inflammation and oxidative stress and inhibited apoptosis in the aorta and HUVECs. Chronic stress upregulated regulated in development and DNA damage response 1 (REDD1) expression, which exacerbated cellular inflammation, oxidative stress, and apoptosis levels, leading to endothelial dysfunction. In contrast, DAPA downregulated REDD1 expression and activated the AKT/FoxO1 pathway. In addition, p53 was a transcriptional regulator of REDD1 under chronic stress. More importantly, p53 agonists prevented DAPA from downregulating REDD1 and inhibited AKT/FoxO1 activation, thereby exacerbating chronic stress-induced endothelial dysfunction. These results suggest that DAPA effectively attenuates chronic stress-induced endothelial dysfunction and AS by downregulating REDD1 to activate the AKT/FoxO1 pathway. Show less

Epigenetic clocks associate with neuropathology and Alzheimer's disease (AD) clinical risk, but findings are mixed regarding whether clocks associate with blood-based biomarkers and in non-European populations. We calculated biological age and age acceleration from blood methylation data in 704 older Hispanic adults and tested associations with clinical diagnosis and antemortem biomarker levels. Age acceleration was significantly associated with sex, clinical diagnosis, and levels of eight plasma biomarkers, including P-tau217 levels. Additionally, biomarker associations trended more significantly among APOE-ε4 non-carriers. We also identified that methylation levels in CD4 and CD8 T-cell types are associated with age acceleration. We demonstrated that biological age acceleration, measured in blood, in a Hispanic cohort enriched for preclinical individuals, can stratify clinical AD risk and is associated with plasma AD biomarker levels. Blood-based aging clocks associate with Alzheimer's disease plasma biomarker levels. Biological aging appears relevant to pathological aging in apolipoprotein E (APOE) -ε4 non-carriers. Immune T-cell composition relates to biological aging. Show less

Vascular smooth muscle cell senescence contributes critically to vascular remodeling and atherosclerosis, with mitochondrial dysfunction and impaired mitophagy recognized as major contributors. SRC, a stress-responsive tyrosine kinase, has been linked to aging, yet its role in vascular aging remains unclear. Here, we examined the role of SRC in regulating autophagy/mitophagy using in vitro and in vivo models. An accelerated vascular aging model was established using a high-fat diet and streptozotocin injection in ApoE Show less

Glycolysis-derived lactate serves as a substrate for lysine lactylation, an epigenetic modification playing critical transcriptional regulatory roles in inflammatory diseases. Endothelial inflammation, characterized by upregulated glycolysis, initiates atherosclerosis, yet the contribution of histone lactylation remains undefined. Although narciclasine exhibits anti-inflammatory and antioxidant properties, its impact on endothelial inflammation in atherosclerosis is unknown. Connectivity Map (CMap) analysis predicted narciclasine as an inhibitor of oscillatory shear stress and TNF-α-induced endothelial inflammation. In vitro, treatment of human umbilical vein endothelial cells (HUVECs) with 20 nM narciclasine significantly suppressed ox-LDL-induced expression of VCAM1, ICAM1, SELE, and CCL2, reduced reactive oxygen species (ROS) production, and inhibited monocyte adhesion and migration. In vivo, administration of narciclasine (0.02 mg/kg) attenuated carotid artery endothelial inflammation and macrophage infiltration, consequently reducing early atherogenesis in partial carotid ligation model in ApoE Show less

Gynostemma pentaphyllum (GP) is known as the "elixir of life" in Guizhou Province, China, as it has been widely consumed by the elderly. Numerous studies have shown that gypenosides (GPS) extracted from GP are involved in lipid metabolism. Apolipoprotein E (ApoE) is a polymorphic protein with multiple biological functions, such as regulating lipid transport and iron metabolism. The deficiency of ApoE can lead to disorders in both lipid and iron metabolism. Therefore, ApoE knockout (ApoE We randomly divided C57BL/6 mice were randomly divided into blank group (WT), apolipoprotein E knockout group (ApoE KO/ApoE The results demonstrate that gypenosides reduce ApoE deficiency-induced iron accumulation by downregulating TfR1 (a cellular iron import protein) and upregulating Fpn1 (an iron export protein). In the spleen of ApoE Gypenosides can reduce tissue iron accumulation in the liver and spleen of ApoE-deficient mice, suggesting that, based on its function in regulating lipid metabolism, gypenosides also possess the potential ability to regulate iron metabolism. 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

Vascular senescence is a fundamental driver of age-related cardiovascular diseases, yet the epigenetic mechanisms controlling this process remain poorly understood. This study investigated the role and underlying mechanisms of lysine acetyltransferase 8 (KAT8), a key histone acetyltransferase, in maintaining endothelial cell homeostasis and preventing vascular senescence. We found that KAT8 expression is consistently downregulated in human aged vessels, senescent rats and mice, and cellular models of aging. Using CRISPR-Cas9-based loss-of-function and gain-of-function approaches in endothelial cells, C57BL/6J mice, and ApoE Show less

Cognitive impairment is a significant health concern in aging populations, but the interplay between biological aging, lifestyle factors, and genetic susceptibility remains unclear. This study examined whether accelerated biological aging is associated with cognitive impairment, whether lifestyle modifies this association, and how genetic background influences these relationships in Chinese older adults. In this cross-sectional study (2022-2023), 7033 participants from southwestern China were included. Accelerated biological aging was calculated as the residual difference between biological age (based on 10 biomarkers) and chronological age. Lifestyle was assessed via a composite index (smoking, alcohol, physical activity, diet, sleep). Cognitive function was measured using the Chinese Mini-Mental State Examination (C-MMSE), and genetic risk was evaluated through polygenic scores and APOE ε4 status. Linear and logistic regression models assessed associations between accelerated aging and cognition. Accelerated biological aging was associated with lower MMSE scores ( β = -0.243, 95% CI: -0.354, -0.133) and higher cognitive impairment prevalence (OR = 1.098, 95% CI: 1.040, 1.158). An unhealthy lifestyle exacerbated cognitive impairment in biologically older individuals (RERI = 0.25). Those with both accelerated aging and unhealthy lifestyle had the lowest MMSE scores ( β = -1.424, 95% CI: -1.846, -1.003) and highest odds of cognitive impairment (OR = 1.467, 95% CI: 1.194, 1.803). These effects were consistent across all genetic background subgroups. Accelerated aging was associated with lower cognitive function, especially in individuals with unhealthy lifestyles, regardless of genetic susceptibility. This highlights lifestyle modification as a potential intervention target for aging-related cognitive impairment. Show less

Atherosclerosis (AS), a major cardiovascular disease driver, can be caused by high levels of serum cholesterol. Eggs are the main source for dietary cholesterol, and although epidemiological studies reported no association between egg intakes and cardiovascular diseases, dietary cholesterol intake is still restricted for individuals with dyslipidemia. This study evaluated the effects of egg yolk lipids isolated from low-cholesterol (LC) and normal eggs (NC) on the progression of AS using the ApoE Show less

The coordinated development of skeletal muscle and intramuscular adipose tissue in animals essentially determines meat yield and quality, a process co-regulated by multiple genes. Using a co-culture model of bovine skeletal muscle cells (SMCs) and intramuscular adipocytes (IMAs), integrated with transcriptomic sequencing and bioinformatic analyses, key candidate genes coregulating muscle development and fat deposition were identified. Three potential coregulators-WNT5A, APOE, and BDKRB2-were selected. Protein-protein interaction (PPI) network analysis, along with tissue and cellular expression profiling, indicates that WNT5A potentially interacts with key protein markers of adipogenesis and myogenesis. Furthermore, it is highly expressed in both adipose and muscle tissues. Pathway enrichment analysis revealed significant enrichment of WNT5A in the Wnt signaling pathway. These findings suggest that WNT5A plays a dual regulatory role in the development of both skeletal muscle and intramuscular fat (IMF). This finding lays a solid theoretical foundation for deciphering the molecular mechanisms of muscle-fat deposition in beef cattle and for improving meat quality. Show less

Vascular smooth muscle cells (VSMCs) contribute to atherosclerotic foam cell formation, but mechanisms regulating their phenotypic switching and programmed cell death remain unclear. O-GlcNAcylation, a nutrient-sensitive post-translational modification implicated in vascular calcification, lacks defined roles in VSMC foam cell biology. Inducible smooth muscle-specific Ogt knockout mice on an Apoe OGT expression and global O-GlcNAcylation were reduced in VSMCs during atherogenic progression. Ogt deletion in VSMCs promoted foam cell formation with enhanced lipid accumulation but paradoxically reduced atherosclerotic lesion area concurrent with increased intraplaque cell death. Both genetic and pharmacological OGT inhibition recapitulated this duality in vitro, simultaneously accelerating lipid accumulation while triggering PANoptosis, as evidenced by concurrent activation of cleaved caspase-3, phosphorylated MLKL, and cleaved GSDMD. Individual inhibition of apoptosis, necroptosis, or pyroptosis provided only partial rescue. OGT acts as a dual regulator of VSMC fate, attenuating plaque burden through PANoptosis induction while promoting foam cell formation, revealing its complex role in atherosclerosis pathogenesis and suggesting context-dependent therapeutic implications. Show less

Defective Wnt/β-catenin signaling is closely associated with the pathogenesis of Alzheimer's disease (AD), thus validating this pathway as a therapeutic target for AD. ISX9 is a potent agonist of the Wnt/β-catenin pathway. However, it remains unknown whether ISX9 exerts anti-AD effects by enhancing the Wnt/β-catenin signaling pathway. We therefore explored the neuroprotective potential of ISX9 using both hippocampal neuron-derived HT22 cells and 5×FAD transgenic mouse model of AD. In HT22 cells, we employed the SuperTOPFlash reporter gene, Co-IP and Western blot assays to investigate the mechanism by which ISX9 activates the Wnt signaling pathway. The effects of ISX9 on the biological behavior of HT22 cells were further evaluated through MTT, BrdU and IF staining. To study the therapeutic effect of ISX9 on AD, six-month-old 5×FAD transgenic mice were randomly divided into four groups: WT, WT/ISX9, AD and AD/ISX9. The mice were intraperitoneally injected with ISX9 or vehicle at an interval of one day for 2 months. Behavioral tests were conducted to evaluate the cognitive and learning abilities of mice, while the expression levels of Aβ peptides, Tau-related proteins, neuroinflammatory factors, blood-brain barrier (BBB)-related proteins and the components of Wnt/β-catenin signaling were investigated. Our results demonstrated that ISX9 potently activated Wnt/β-catenin signaling by promoting the association of LRP6 with AXIN1, and increased the viability and proliferation of hippocampal cells. At the behavioral level, ISX9 improved learning and memory abilities in 5×FAD mice, and ameliorated hippocampal neuronal damage. Furthermore, ISX9 treatment effectively reduced the expression of Aβ peptides, total Tau, and phosphorylated Tau (S404) proteins in the AD mice. Mechanistically, ISX9 exhibited its neuroprotective effects, activating the Wnt/β-catenin signaling pathway via potentiating the interaction of LRP6 with AXIN1, upregulating the expression of BBB-related proteins and downregulating neuroinflammatory factors in AD mice. Our findings indicate that ISX9 potently activates the Wnt/β-catenin signaling pathway and confers cognitive protection in hippocampal cells and AD mice. This compound may serve as a promising therapeutic agent for the treatment of AD. Show less

Alzheimer's disease (AD) is characterized by a complex pathophysiology, involving abnormal aggregation of amyloid b (Ab) and tau proteins, neuroinflammatory responses, and significant synaptic dysfunction, which collectively contribute to cognitive decline. This review offers a novel perspective by focusing on the pivotal role of synaptic plasticity in the pathogenesis of AD, underscoring its potential as a therapeutic target. The study uniquely synthesizes current molecular and clinical research to illustrate how Ab and tau pathologies disrupt synaptic signaling and structure, further exacerbated by neuroinflammation. We explore both pharmacological interventions, such as BACE1 inhibitors and tau stabilizers, and non-pharmacological strategies, including cognitive therapy and neuromodulation techniques, which have shown promise in modulating synaptic plasticity and slowing cognitive deterioration. Despite these advancements, the field faces significant challenges, including the complexity of AD's underlying mechanisms and limitations in early diagnosis. This review not only highlights the significance of synaptic plasticity in AD but also proposes future research directions that could lead to innovative therapeutic approaches, offering new hope for effective treatment strategies. Show less

Electroacupuncture (EA) has been widely used in the clinical treatment of cognitive impairment after cerebral ischemia (CI) in China, but the specific molecular mechanism is not fully understood yet. In this study, permanent middle cerebral artery occlusion (pMCAO) model mice were administrated with EA therapy, Morris water maze (MWM) test was used for evaluation of cognitive function, Nissl staining was employed to quantify surviving neurons in the hippocampus, and enzyme-linked immunosorbent assay (ELISA) was utilized to detect the levels of amyloid beta (Aβ). The results showed that EA treatment obviously improved learning and memory abilities in the mice with pMCAO, inhibited neuronal loss in the hippocampus, and reduced the levels of Aβ40 and Aβ42. Meanwhile, we observed that METTL3 expression and total N6-methyladenosine (m6A) levels were significantly increased in the hippocampal tissues of pMCAO mice, which were reduced by EA therapy. Then, hippocampal neuronal cell line HT22 was induced by oxygen-glucose deprivation (OGD) to verify the molecular regulatory mechanism in vitro, and we found that METTL3 upregulated BACE1 expression in OGD-induced HT22 cells through promoting m6A enrichment on BACE1 mRNA, thus facilitating Aβ production and cell apoptosis of OGD-induced HT22 cells. Finally, through in vivo functional recovery experiments, we demonstrated that EA therapy restrained the METTL3/BACE1 axis to alleviate Aβ accumulation and cognitive dysfunction in pMCAO model mice. In summary, our data reveals that the m6A-modified BACE1 pathway is one of the molecular targeting mechanisms for EA treatment in cognitive impairment after CI. Show less

FURIN cleaves a subset of proproteins into functional mature fragments. Evidence suggests that FURIN is involved in brain development and the associated diseases, whereas the potential mechanisms remain incompletely understood. Here, we report that cerebral FURIN-deficient mice exhibit cognitive decline and neurodegeneration. Lipid droplets (LDs) that are preferentially accumulated in astrocytes correlate with an increase of the LD markers PLIN2 and PLIN3, and conversely a decreased level of autophagic proteins including ATG5, BECN1 and MAP1LC3/LC3 as well as LAMP1. Accordingly, silencing of Show less

Chronic cerebral hypoperfusion (CCH), a subclinical state underlying mild cognitive impairment (MCI), triggers multiple pathological changes associated with Alzheimer's disease (AD) and vascular dementia (VaD), including amyloid-β (Aβ) deposition, tau phosphorylation, microglial activation and neural circuit dysfunction. Developing multitarget therapeutics to effectively prevent the transition from MCI to AD and/or VaD remains an urgent challenge. Herein, we engineered a brain-targeted dual-modified PEGylated nanoliposome (LipTM@miR-195), incorporating mannose (MAN) and the trans-activating protein of HIV type 1 (TAT), which encapsulates polyethyleneimine (PEI) complesed microRNA-195 (miR-195). In a CCH rat model, tail-vein administration of LipTM@miR-195 (0.112 mg/kg) efficiently crossed the blood-brain barrier (BBB) without detectable side effects. Treatment reversed CCH-induced spatial learning and memory deficits, rescued neural circuit dysfunction, and suppressed elevated APP, BACE1, AT8 and CD68 levels. Collectively, these findings provide compelling evidence that LipTM@miR-195 nanoliposome holds therapeutic potential for CCH-induced cognitive impairment, thereby preventing the progression from MCI to AD and/or VaD. Show less

Beta-site APP-cleaving enzyme 1 (BACE1), a critical rate-limiting enzyme that synthesizes β-amyloid peptide (Aβ), is an important marker of early pathological changes in Alzheimer's disease (AD). Early small plaques cannot be accurately detected using traditional Magnetic resonance imaging (MRI) probes. Therefore, magnetic resonance tuning (MRET) and susceptibility weighted imaging (SWI)-based smart responsive MR nanoprobes are designed to achieve the sensitive detection of BACE1 and Aβ plaques. This probe is modified with a blood-brain barrier-penetrating targeting peptide that enables its reach to the AD microenvironment. The enhancement of T1WI signals owing to the MRET effect caused by the separation of probes in response to BACE1 is used to reflect real-time BACE1 changes. When Aβ plaques are present, the remaining probes that bound around Aβ plaques underwent in situ thiol cross-linking under the action of peroxynitrite (ONOO Show less

Huanshaodan (HSD) is a Traditional Chinese Medicine Compound Prescription, traditionally used in the clinical treatment of Alzheimer's disease (AD) in China. Nevertheless, its bioactive constituents and mechanistic basis remain poorly understood. To identify the components derived from HSD that inhibit SIRT2 and investigate the underlying mechanisms in mitigating AD pathogenesis. A luciferase reporter gene assay was employed to screen HSD for components that downregulate SIRT2 expression. The neuroprotective effects and the mechanisms of the screened component, ferulic acid (FA), was evaluated both in SAMP8 mice and HT22-APPswe cell using behavioral tests, H&E, immunohistochemistry, transmission electron microscopy, ELISA, MTT, Western blot, RT-qPCR, immunofluorescence and Co-immunoprecipitation, to assess its effect on SIRT2 expression, SIRT2-APP interaction, as well as the expression of proteins associated with APP proteolytic processing. SIRT2-overexpressing plasmids were transfected to assess FA's neuroprotection via SIRT2 modulation. As a component in HSD, FA inhibited SIRT2 promoter-driven transcription, ameliorated cognitive deficits, protected neuronal and synaptic structures, reduced Aβ deposition in SAMP8 mice and Aβ level in HT22-APPswe cells. FA suppressed SIRT2 expression, inhibited SIRT2-APP interaction, modulated the expression levels of proteins involved in APP proteolytic processing, namely ADAM10, sAPPα, BACE1, sAPPβ, and CTFα in vitro and in vivo. Notably, the regulatory effects of FA on APP proteolytic processing in HT22-APPswe cells were completely abolished upon SIRT2 overexpression. This study demonstrates that FA is an active component in HSD that mitigates AD pathology, potentially by modulating APP proteolytic processing through SIRT2 downregulation. Show less

Pancreatic cancer (PC) is a common gastrointestinal malignancy whose initiation and progression may be closely linked to the gut microbiota. Previous research indicates that Scutellaria barbata D. Don and Scleromitrion diffusum (Willd.) R.J. Wang (SB-SD) exhibit diverse biological activities, such as anti-inflammatory, antioxidant, and antitumor effects, though their precise regulatory mechanisms are not fully elucidated. Here, we treated PC cells with SB-SD to assess its impact on cell viability, apoptosis, migration, and cell cycle progression, while Western blotting analyzed the expression of HSP90AA1, MAPK3, p53, CDK1, and p21. We also established a pancreatic cancer xenograft model in nude mice to evaluate the in vivo inhibitory effect of SB-SD on tumor growth. Furthermore, we employed metagenomic sequencing, untargeted metabolomics, and quantitative proteomics to comprehensively profile changes in the gut microbiota, serum metabolites, and differentially expressed proteins, with Western blotting subsequently validating BCKDK, GATM and p53 expression. The results show that SB-SD significantly inhibited PC cell proliferation, promoted apoptosis, and induced S/G2 phase cell cycle arrest, potentially via modulation of the HSP90AA1/MAPK3 signaling pathway. Measurements of tumor volume and weight, complemented by histopathological analysis, confirmed that SB-SD effectively suppressed the growth of PANC-1 xenograft tumors. Integrated multi-omics analyses suggest that the antitumor effects of SB-SD may involve the modulation of key gut microbes like Bacteroides caccae and Lactobacillus, the promotion of choline metabolism, and the regulation of BCKDK and GATM. Together, these findings not only corroborate the direct antitumor activity of SB-SD against pancreatic cancer but also offer novel mechanistic insights by constructing a microbiota-metabolite-protein interaction network. Show less

Congenital heart disease (CHD) is the most common birth defect worldwide, with over half of cases lacking a defined etiology. Maternal metabolic dysregulation has been implicated in CHD risk, but the specific metabolites and mechanisms involved in embryonic heart development remain poorly understood. Carbamoyl phosphate (CP), a key urea cycle intermediate, has not previously been linked to cardiac morphogenesis. This study aimed to identify maternal metabolites associated with offspring CHD risk and to elucidate the role of CP in regulating cardiac development. Untargeted metabolomic profiling was performed on early-pregnancy serum from 98 mothers of CHD offspring and 50 age-matched controls. Functional validation was performed using two pregnant mouse models: pharmacological inhibition of glutamine metabolism via BPTES and Cps1 heterozygous knockout (Cps1 Maternal serum CP levels were significantly reduced in CHD cases and negatively correlated with upstream nutrient levels. In mice, both BPTES treatment and maternal Cps1 knockdown increased CHD incidence in offspring. Conversely, NCG supplementation reduced CHD risk in Cps1 Maternal CP deficiency increases offspring CHD risk by disrupting TET2-mediated DNA demethylation through impaired lysine carbamylation. These findings highlight maternal CP and TET2 carbamylation as potential metabolic-epigenetic targets for CHD prevention. Show less

Coronary heart disease (CHD) remains a leading cause of morbidity and mortality worldwide. Mitochondria-associated endoplasmic reticulum membranes (MAMs) have recently emerged as critical mediators in cardiovascular pathophysiology; however, their specific contributions to CHD pathogenesis remain largely unexplored. This study aimed to identify and validate MAM-related biomarkers in CHD through integrated analysis of transcriptomic sequencing data and Mendelian randomization, and to elucidate their underlying mechanisms. We analyzed two gene expression microarray datasets (GSE113079 and GSE42148) and one genome-wide association study (GWAS) dataset (ukb-d-I9_CHD) to identify differentially expressed genes (DEGs) associated with CHD. MAM-related DEGs were filtered using weighted gene co-expression network analysis (WGCNA). Functional enrichment analysis, Mendelian randomization, and machine learning algorithms were employed to identify biomarkers with direct causal relationships to CHD. A diagnostic model was constructed to evaluate the clinical utility of the identified biomarkers. Additionally, we validated the two hub genes in peripheral blood samples from CHD patients and normal controls, as well as in aortic tissue samples from a low-density lipoprotein receptor-deficient (LDLR-/-) atherosclerosis mouse model. We identified 4174 DEGs, from which 3326 MAM-related DEGs (DE-MRGs) were further filtered. Mendelian randomization analysis coupled with machine learning identified two biomarkers, DHX36 and GPR68, demonstrating direct causal relationships with CHD. These biomarkers exhibited excellent diagnostic performance with areas under the receiver operating characteristic (ROC) curve exceeding 0.9. A molecular interaction network was constructed to reveal the biological pathways and molecular mechanisms involving these biomarkers. Furthermore, validation using peripheral blood from CHD patients and aortic tissues from the Ldlr-/- atherosclerosis mouse model corroborated these findings. This study provides evidence supporting a mechanistic link between MAM dysfunction and CHD pathogenesis, identifying candidate biomarkers that have the potential to serve as diagnostic tools and therapeutic targets for CHD. While the validated biomarkers offer valuable insights into the molecular pathways underlying disease development, additional studies are needed to confirm their clinical relevance and therapeutic potential in larger, independent cohorts. Show less

RNA G-quadruplexes (rG4s), formed through guanine self-recognition into stacked tetrads, serve as critical regulators of gene expression, yet their comprehensive mapping and dynamic regulation in physiological contexts remain technically challenging. Here, we develop Ultra-low-input rG4-seq (ULI-rG4-seq), enabling precise rG4 detection enabling precise rG4 detection with ∼140 bp resolution in samples as small as 100 oocytes, and reveal notable enrichment of rG4s near crucial regulatory regions, particularly transcription start sites and end sites. This technological advance, combined with Trim-away or oocyte-specific knockout of DHX36 (also known as G4R1 or RHAU), an rG4-specific helicase, reveals acute and chronic loss of DHX36 leads to opposing effects on rG4 levels. This observation extends beyond the traditional view of helicases as unwinding enzymes and suggests sophisticated cellular mechanisms maintaining RNA structural homeostasis. Through integrated analysis of rG4 landscapes and DHX36-binding profiles, we demonstrate coordination between cytoplasmic rG4 regulation and nuclear gene expression, revealing how RNA structure dynamics orchestrate RNA stability and translation, thereby influencing transcriptional elongation, genome stability, and alternative splicing. Finally, we show that deletion of DHX36 resulted in decreased oocyte quality, premature ovarian failure and complete female infertility due to transcriptional defects and genome instability related to R-loop accumulation. These technological and conceptual advances not only deepen our understanding of RNA-based regulation but also open new therapeutic possibilities for diseases involving RNA structure. Show less