👤 Yunlang Dai

Harnessing the simultaneous activation of GLP-1R, GIPR, and GCGR has emerged as a highly promising therapeutic paradigm for obesity and related metabolic diseases, including nonalcoholic steatohepatitis (NASH). Here, we report the discovery of TPM003, a novel unimolecular GLP-1R/GIPR/GCGR triple agonist engineered by using a long-acting PEG-fatty acid (PEG-FA) stapling technology. TPM003 exhibits balanced triple receptor agonism and demonstrates an extended systemic half-life across multiple species. In obese mice, TPM003 induced robust and durable weight loss, accompanied by broad improvements in metabolic parameters, outperforming current GLP-1RA standards. Importantly, TPM003 also effectively reversed hepatic steatosis and improved markers of liver function in multiple NASH models. Furthermore, TPM003 is compatible with SNAC-based absorption enhancement, enabling oral delivery in a tablet formulation. Collectively, these findings highlight the therapeutic advantages of balanced GLP-1R/GIPR/GCGR agonism for obesity and NASH and support TPM003 as a promising preclinical candidate with translational potential. Show less

Cellular and synaptic plasticity in ventral tegmental area (VTA) play a key role in alcohol use disorder (AUD). Here, we first delineated the in vivo dynamics of dopamine (DA) neuron activity in VTA during chronic intermittent ethanol exposure: initial sensitization was followed by a phase of attenuated and dysregulated response upon the first high-concentration exposure, culminating in stable hyper-responsiveness. Chronic ethanol exposure impaired long-term potentiation of GABAergic synapses (LTP Show less

Neuroinflammation driven by dysfunctional microglial responses represents a critical early pathogenic process, particularly in the context of Alzheimer's disease (AD). The natural flavonoid fisetin possesses anti-inflammatory characteristics; however, the exact mechanisms via which it mitigates microglial dysfunction in AD are not fully elucidated. This work employed a combination of in vivo and in vitro approaches, utilizing male APP/PS1 mice and ADDL-stimulated primary microglia. Behavioral tests, immunohistochemistry, molecular profiling, and mitochondrial function assays were conducted. This research combines network pharmacology, molecular docking, and cellular thermal shift assays (CETSA) to offer predictive insights. Fisetin treatment improved cognitive performance in APP/PS1 mice, concurrently reducing amyloid pathology and plaque-associated microglial clustering. In primary microglia, fisetin potently inhibited ADDL-induced pro-inflammatory activation, mitochondrial ROS overproduction, and membrane depolarization. PI3K was identified as a signaling node potentially involved in fisetin-mediated regulation of microglial inflammatory responses. Accordingly, fisetin constrained microglial inflammatory signaling, at least in part through modulation of the PI3K-Akt-NF-κB axis, thereby limiting NF-κB nuclear translocation and pro-inflammatory cytokine release in both the mouse hippocampus and cultured primary microglia. Furthermore, conditioned medium from fisetin-treated microglia alleviated neuronal damage and restored the expression of BDNF and PSD95 in primary neurons. The collective findings, along with experimental studies utilizing the PI3K inhibitor (LY294002), indicate that PI3K may act as a molecular target of fisetin, underscoring its potential therapeutic significance in regulating early inflammatory processes in AD. Show less

This study explored the molecular mechanisms by which T7 peptide-modified liposomal irisin (T7@Lipo@Irisin) alleviates perioperative neurocognitive disorders (PND) via regulation of the AMPK/PGC-1α metabolic pathway. T7@Lipo@Irisin nanoparticles were prepared by thin-film hydration and ultrasonic dispersion and showed favorable physicochemical performance, with an encapsulation efficiency of approximately 85%. Serum analysis of healthy donors (n = 10) and PND patients (n = 6) showed higher IL-6 and TNF-α and lower brain-derived neurotrophic factor (BDNF) in PND. In vitro, T7@Lipo@Irisin restored mitochondrial membrane potential, reduced reactive oxygen species (ROS) accumulation, enhanced Neuro-2a hippocampal neuron viability, and activated the AMPK/PGC-1α axis under oxidative stress. In a PND mouse model, it improved Garcia neurological scores, preserved neuronal morphology, and decreased apoptosis. Multi-omic integration of scATAC-seq/scRNA-seq and TMT-based proteomics demonstrated enhanced neuro-glial crosstalk, epigenetic activation of metabolic/antioxidant genes (e.g., Sirt1, Nfe2l2), and upregulated pathways (mitochondrial function, NAD-dependent metabolism, synaptic homeostasis). Proteomics confirmed upregulation of SIRT1, NDUFS2, and BDNF, forming a network linked to energy metabolism and neural repair. Collectively, T7@Lipo@Irisin mitigates PND by activating AMPK/PGC-1α to enhance mitochondrial function and stabilize the neuro-microenvironment. Show less

The pituitary gland plays a pivotal role in regulating puberty and reproductive physiology; however, the precise cellular and molecular mechanisms driving the pubertal transition in large animal, such as ewes, remain poorly understood. Here, we generated a comprehensive single-cell transcriptomic atlas of the ovine anterior pituitary, specifically comparing the pre-pubertal (3 month) and post-pubertal (6 month) stages. We identified 30 335 cells classified into ten distinct clusters. Comparative analysis revealed a global transcriptional reprogramming during puberty, characterized by a marked upregulation of genes associated with ribosome biogenesis, unfolded protein response, and hormone secretion across endocrine cells, reflecting an expanded biosynthetic capacity. Specifically, we identified SCG2 as a critical regulator of gonadotroph maturation. Functional validation demonstrated that SCG2 facilitates the biogenesis of secretory granules, thereby promoting FSH synthesis and secretion. Furthermore, intercellular communication analysis uncovered a distinct shift in the pituitary microenvironment: the 6 month pituitary exhibited enhanced regulatory networks, including IGF signaling mediated by non-endocrine cells and NT signaling (e.g., BDNF-NTRK2) driven by multiple cell types. These findings suggest that the onset of puberty relies on a coordinated "endocrine-to-endocrine" and "non-endocrine-to-endocrine" crosstalk. This study provides a high-resolution molecular blueprint of the pubertal transition, highlighting the key roles of biosynthetic machinery upgrades and microenvironmental remodeling in establishing the high reproductive performance of Hu sheep. Show less

Endometriosis-associated ovarian cancer (EAOC), encompassing subtypes like ovarian clear cell (OCCC) and endometrioid (OEC) carcinoma, represents a distinct Type I malignancy arising from endometriotic lesions. These tumors are characterized by a specific molecular landscape, including high-frequency driver mutations in genes such as ARID1A, PIK3CA, and PTEN. Within this setting, the role of estrogen receptor β (ERβ), whose expression is progressively upregulated during malignant transformation, requires a nuanced re-evaluation. This review repositions ERβ not as a primary oncogenic driver, but as a critical, spatiotemporal modulator. Its principal function appears to be potentiating pro-survival signaling, such as the PI3K/AKT pathway, within a cellular environment already primed by constitutive genetic alterations. Furthermore, ERβ appears to couple apoptosis resistance with microenvironmental remodeling and metastatic programming. We further dissect the role of the downstream ERβ–brain-derived neurotrophic factor (BDNF)/Tropomyosin receptor kinase B (TrkB) signaling axis, proposing it as a key cooperative network that provides parallel and compensatory survival signals. The central thesis is that the significance of this axis is profoundly context-dependent, and its roles should be interpreted alongside the tumor’s underlying genomic status. Finally, we outline translational prospects, arguing that targeting this pathway will require precision medicine strategies, including composite biomarkers and rational combination therapies. These strategies should be tailored to the specific molecular subtype of each patient’s tumor. Show less

The efficacy of antidepressants is influenced by a combination of genetic, individual, and environmental factors. This study aimed to investigate the association between the miR-182 rs76481776 polymorphism and the response to antidepressant treatment in major depressive disorder (MDD) patients, and its underlying molecular mechanisms. This study enrolled 180 MDD patients and 180 healthy controls. The rs76481776 genotype was determined using TaqMan-based qPCR. The severity of depression and treatment response were assessed using the Hamilton Depression Rating Scale (HAMD). The expression of miR-182 and The T allele of rs76481776 was a significant risk factor for MDD (OR = 2.182, 95% CI: 1.424-3.345, The T allele of rs76481776 diminished the therapeutic efficacy of antidepressants by up-regulating miR-182 expression and subsequently suppressing Show less

The activation of glial cells in the central nervous system plays an important role in the neural signaling of chronic pain and pruritus. However, their involvement in the neural signaling of chronic pain and pruritus in ACD remains to be investigated. To determine the effect of spinal glial cell activation in the coexistence of chronic pain and pruritus in the ACD model, we observed spinal glial cell activation in a mouse model of ACD induced by SADBE. Square acid dibutyl ester (SADBE) was employed to establish ACD model mice and monitor the activation of spinal cord glial cells. Additionally, the Gene Expression Omnibus (GEO) database was utilized to analyze potential mechanisms. In the ACD model, the behaviors of licking and biting within 35 days after modeling were significantly increased. The expression levels of Iba-1, BDNF, LCN2, GRPR, and GFAP differed significantly from those of the control group. In addition, through GEO data analyses, a strong correlation has been found between pain and IFN-γ. Similarly, in vitro experiments revealed that IFN-γ increased the expression of Iba-1, CD16, and BDNF in BV2 cells and the release of LCN2 in primary astrocytes, thus activating spinal cord glial cells. IFN-γ also induced the phosphorylation of JAK1/STAT1 and the expression of IFNGR1 in BV2 cells and primary astrocytes. Collectively, the above findings suggest that the coexistence of chronic pain and pruritus in the ACD model is associated with the activation of spinal microglia and astrocytes. The underlying mechanism involves the binding of IFN-γ to its receptor IFNGR1, which is accompanied by the upregulation of JAK1/STAT1 signaling pathway phosphorylation. Show less

This study aimed to evaluate the association between the LDL-c/ApoB ratio (LAR) and the prevalence of gallstones in regional Chinese adults. We conducted a cross-sectional study involving patients with gallstones who underwent surgical treatment at our hospital from March 2021 to September 2023, as well as e-cases from our medical check-up center during the same period. Participants were divided into gallstone and non-gallstone groups. Data on routine blood and biochemical tests, hypertension, and diabetes mellitus history were collected. The differences between the two groups were analyzed using the chi-square test or Kruskal-Wallis rank sum test. Logistic regression analysis, subgroup analysis, and propensity-matched analysis were performed to assess the relationship between LAR and the prevalence of gallstones. The study included 801 participants aged over 18 years, of whom 259 had gallstones. After adjusting for relevant confounders, LAR was found to be negatively associated with gallstone prevalence (OR = 0.67, 95% CI: 0.48, 0.95). Propensity-matched analyses confirmed that an elevated LAR remained negatively associated with gallstone prevalence (OR = 0.65, 95% CI: 0.43, 0.98). The dose-response curve indicated a linear negative correlation between LAR and gallstone prevalence. LAR is negatively associated with the prevalence of gallstones. Although a causal relationship cannot be established, these findings may provide preliminary insights for gallstone prediction in regional Chinese adult populations. Show less

Ischemic stroke is a heterogeneous disease influenced by inflammation, coagulation dysfunction, and metabolic disturbances. However, integrated analysis incorporating these biological domains for patient stratification remain limited. A retrospective study of 132 ischemic stroke patients was conducted. Clinical, coagulation, inflammatory, and metabolic parameters were collected. Principal component analysis (PCA) was applied for dimensionality reduction and visualization. PCA revealed underlying heterogeneity among patients. Validated Data driven clustering identified biologically distinct ischemic stroke subtypes based on inflammation, coagulation, and metabolic profiles. This stratification highlights the heterogeneity of ischemic stroke and may inform future personalized approaches to risk assessment and management. Show less

As an important interface between the peripheral environment and the central nervous system, the gut microbiota varies greatly between patients or animals with Alzheimer's disease (AD) and their respective non-AD counterparts; however, it remains unexplored whether the apolipoprotein E (APOE) genotype, age, and sex may interactively influence the characteristics of gut microbiota in AD animals. APOE genotype, age, and sex were enrolled as independent variables, with genotype distinguished into APOE3 and APOE4, age into 3 and 10 months, and sex into female and male. The composition, structure, and potential functions of gut microbiota were systematically analyzed by 16S rRNA gene amplicon sequencing to evaluate the individual and interactive effects of APOE genotype, age and sex. Significant interactions were observed among APOE genotypes, ages, and sexes, with different factor combinations exhibiting distinct effect on microbiotic composition and functional potential. APOE genotype exerted the most significant influence on gut microbiota, followed by age and sex with a relatively minor effect, highlighting the dominant role of host genetic background. Functional prediction analysis indicated that the functional profiles were mainly concentrated in basic metabolic pathways, including the biosynthesis of secondary metabolites and amino acids, and carbon metabolism. APOE genotype, age, and sex are jointly associated with the structure and potential function of the gut microbiota in AD model mice. These findings provide a perspective of multi-factor interaction into the alterations in gut microbiota in AD and offer new microecological evidence for understanding APOE4-related AD susceptibility, as well as a conceptual basis for future stratified microecological intervention studies. Show less

Atherosclerosis is a chronic inflammatory condition marked by the deposition of lipids within the arterial wall and the infiltration of inflammatory cells, culminating in the development of atherosclerotic plaques. Ubiquitin-specific protease 18, USP18, a specific deubiquitinating enzyme, has been demonstrated to exert protective effects on the cardiovascular system. Pathological studies were performed utilizing human coronary arteries obtained from the Forensic Medical Examination Center of Guizhou Medical University, in conjunction with the aorta from experimental ApoE knockout mice. The ApoE knockout mice underwent intervention with adenovirus carrying USP18-RNAi and a control adenovirus containing hU6-MCS-CMV-EGFP, after which pathological analyses were conducted. In vitro, THP-1 cells, induced with phorbol ester, were subjected to treatment with si-USP18 or si-NC, followed by exposure to oxidized low-density lipoprotein. The expression levels of USP18 and proteins associated with the TAK1/NF-κB signaling pathway, as well as the interaction between USP18 and TAK1, were assessed using Western blotting, RT-PCR, and immunofluorescence techniques.The interaction between USP18 and TAK1 was confirmed using molecular docking techniques, co-immunoprecipitation assays, and immunofluorescence analysis. The purpose of this study is to explore the role of USP18 on atherosclerosis and the underlying mechanism. The expression of USP18 is elevated in early-stage human coronary atherosclerotic plaques but decreases in advanced lesions. Treatment of macrophages derived from THP-1 cells and bone marrow-derived macrophages (BMDMs) with lipopolysaccharide (LPS) results in reduced USP18 expression. In ApoE USP18 modulates TAK1 to suppress the activation of the NF-κB signaling pathway in macrophages, consequently exerting an anti-atherosclerotic effect and offering a potential therapeutic strategy for atherosclerosis treatment. Show less

Following spinal cord injury (SCI), neuroinflammation driven by lipid-laden macrophage foam cells is a key pathology, yet how these cells manage their lipid homeostasis is unclear. We delineate a neuroprotective axis in which macrophages deploy apolipoprotein E (APOE) to transfer intracellular lipids to neighboring cells, especially fibroblasts. Genetic ablation of The online version contains supplementary material available at 10.1186/s12974-026-03756-9. Show less

Moutan Cortex, a traditional Chinese medicine, has been used to treat cardiovascular diseases. Paeonol (Pae), a key bioactive compound, is responsible for its anti-atherosclerotic effects. Although CD8 We investigated whether Pae inhibits atherosclerosis by targeting the spleen tyrosine kinase (SYK)/nuclear factor of activated T-cells c1 (NFATc1) pathway, thereby reducing CD8 High-fat diet-fed apolipoprotein E-deficient (ApoE Pae attenuated plaque formation and T-cell activation in ApoE SYK in CD8 Show less

Apolipoprotein E (ApoE) is a key regulator of lipid metabolism that binds to lipid nanoparticle (LNP) surfaces to mediate cellular interactions. However, the ApoE-LNP behavior is highly dependent on the LNP composition, and the underlying mechanisms remain unclear. Here, we show that subtle alterations in LNP surface lipids profoundly reshape the ApoE-LNP structure and intracellular trafficking. Using cryogenic electron microscopy and live-cell imaging, we demonstrate that replacing 10 mol % 1,2-distearoyl- Show less

C1q/TNF-related proteins (CTRPs) belong to the adipokine family. Here, we aimed to assess the relation of CTRP4 levels in serum and perivascular adipose tissue (PVAT) with coronary artery disease (CAD), and investigate the effect of CTRP4 on atherosclerosis and the underlying mechanisms. CTRP4 levels were examined in serum and epicardial adipose tissue (a major PVAT) from patients with CAD. Atherosclerotic lesions were analysed in CTRP4 CTRP4 levels were lower in serum and epicardial adipose tissue of patients with CAD compared to non-CAD controls. CTRP4 knockout promoted atherosclerosis in ApoE Decreased CTRP4 levels in serum and epicardial adipose tissue are associated with CAD in patients. CTRP4 deficiency promotes the development of atherosclerosis in ApoE Show less

Alport syndrome (AS) is the most common inherited glomerular disease among patients with chronic kidney disease. With exome sequencing now widely used in clinical practice, pathogenic variants in Alport-related genes (COL4A3/COL4A4/COL4A5) are increasingly identified in patients with diverse phenotypes, including proteinuria‑predominant disease and kidney failure of unknown etiology. Diagnostic complexity further increases when COL4A3/COL4A4/COL4A5 variants are co‑inherited with pathogenic variants associated with other genetic kidney disorders. We reported a 31‑year‑old male presenting with kidney failure, significant proteinuria, familial hematuria and hyperlipidemia. Whole‑exome sequencing (WES) identified two pathogenic variants: a hemizygous COL4A5 variant (c.2105G > A; p.Gly702Asp) and a heterozygous APOE Kyoto variant (c.127C > T; p.Arg43Cys). Given the potential dual diagnosis of AS and lipoprotein glomerulopathy (LPG), a kidney biopsy was performed. Histologic examination revealed uneven thickness of the glomerular basement membrane consistent with the diagnosis of AS, but no LPG-related lesions were observed, indicating incomplete penetrance of APOE Kyoto variant. Cascade family screening detected APOE Kyoto variant in the patient's father and elder sister, both of whom lacked proteinuria until follow-up period. This case highlights the complementary role of kidney biopsy alongside WES in AS with complex genetic mechanisms. It also illustrates the incomplete penetrance of APOE Kyoto, common among Chinese carriers. Show less

Endothelial to mesenchymal transition (EndMT), the transformation of endothelial cells into a mesenchymal-like state, is regulated by various factors, including transcription factors such as activator protein 1 (AP-1). While recent studies have confirmed the role of EndMT in atherosclerosis, the involvement of AP-1 in EndMT, particularly in the context of human diabetes, remains unclear. This study aimed to elucidate the role of the AP-1 transcription factor complex in EndMT associated with atherosclerosis in diabetes, utilising both an in vivo preclinical model and an ex vivo model using patient-derived serum for translational relevance. Additionally, it sought to profile gene expression changes following AP-1 inhibition in an EndMT model under high glucose conditions. Serum from patients with and without type 2 diabetes mellitus (T2DM) was used to assess EndMT in primary human aortic endothelial cells (HAECs) in the presence and absence of the AP-1 inhibitor T-5224. EndMT was evaluated through immunofluorescent staining of these cells and of aortic sections from a murine model of diabetes-associated atherosclerosis in a preclinical early intervention study. Furthermore, HAECs were used to explore the effects of AP-1 inhibition on the transcriptional signature of EndMT. Patient-derived serum induced EndMT in HAECs, which T-5224 effectively prevented, as confirmed by immunofluorescent staining. Immunofluorescent analysis of the aortic sinus also revealed that T-5224 treatment inhibited EndMT, leading to reduced atherosclerosis in Apoe This study identifies AP-1 inhibition with T-5224 as a potential therapeutic approach for EndMT resulting in reduced atherosclerosis in diabetes. The use of human serum underscores the translational relevance of these findings. Show less

Cancer-associated fibroblasts (CAF) are abundant stromal cells in the tumor microenvironment (TME) that play a vital role in promoting tumor progression and drug resistance. The mechanisms regulating heterogeneity of CAFs in renal cell carcinoma (RCC) could represent potential targets for reprogramming the TME. In this study, we conducted single-cell RNA sequence and flow cytometry analyses that identified a CAF subset overexpressing apolipoprotein E (ApoE), which was correlated with poor survival in patients with RCC. Mechanistically, NRF1 activation in CAFs induced formation of ApoEhigh CAFs and secretion of NRG1. ApoEhigh CAFs potentiated stemness properties in the surrounding RCC cells by secreting NRG1 and subsequently activating the HER2/NF-κB pathway. Interfering with NRG1 expression or inhibiting NF-κB signaling reduced ApoEhigh CAF-induced stemness of RCC cells. Furthermore, neutralizing NRG1 enhanced the efficacy of sunitinib in RCC models in vivo. Together, these findings highlight targeting the tumor-promoting functions of ApoEhigh CAFs as a promising approach for treating advanced RCC. NRF1 drives formation of ApoEhigh cancer-associated fibroblasts that secrete NRG1 to stimulate stemness of renal cell carcinoma, revealing a stromal-mediated mechanism that can be inhibited to improve treatment of advanced kidney cancer. Show less

Anti-inflammatory colchicine therapy has emerged as a new era for atherosclerotic cardiovascular diseases. However, the therapeutic benefit of colchicine has not been clearly defined. Herein, we present a double coordination-driven approach to fabricate a stable metal-organic nano-assembly of colchicine (COL-TA-Zn) by uniting the tropolone ring of colchicine (COL), phenolic groups of tannic acid (TA), and Zn Show less

Pro-inflammatory macrophage function is linked to an increase in mitochondrial fission. Melatonin has a positive impact on atherosclerosis and has a significant effect on the control of mitochondrial fission and fusion. Nevertheless, it is still unclear how melatonin contributes to slowing the advancement of atherosclerosis. The ApoE The study found that melatonin treatment decreased the area of atherosclerotic plaque, decreased lipid deposition, suppressed inflammatory cytokine levels, inhibited macrophage pro-inflammatory differentiation, inhibited mitochondrial fragmentation, increased the level of Sirt3, and decreased Drp1 expression in atherosclerosis (AS) mice. However, Sirt3 inhibition abolished the protective affects of melatonin in AS mice. Melatonin therapy upregulated Sirt3 expression in RAW264.7 cells subjected to ox-LDL, blocked Drp1-mediated mitochondrial fission, and reduced inflammatory cytokine levels. On the other hand, melatonin's inhibitory effects on Drp1 expression and mitochondrial fission were lessened by Sirt3 inhibition. Additionally, DRP1 siRNA knockdown inhibited mitochondrial fission and pro-inflammatory differentiation of macrophages induced by ox-LDL. Melatonin inhibits the growth of atherosclerosis and the pro-inflammatory differentiation of macrophages by blocking the Sirt3-Drp1 pathway, which prevents mitochondria from fission. Melatonin's suppression of mitochondrial fission may be a viable strategy for postponing cardiovascular problems in atherosclerosis patients. 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

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

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) plaque deposition, neurofibrillary tangles of hyperphosphorylated tau protein, and chronic neuroinflammation, leading to synaptic dysfunction and cognitive decline. Current diagnostic methods rely on clinical symptoms and limited biomarkers, while available treatments only provide symptomatic relief without halting disease progression. MicroRNAs (miRNAs), small non-coding RNAs of 19-22 nucleotides, have emerged as crucial regulators of gene expression through post-transcriptional mechanisms and show distinct dysregulation patterns in AD patients' blood, cerebrospinal fluid (CSF), and brain tissues. Key miRNAs such as miR-132, miR-146a, miR-34a, and miR-125b demonstrate consistent alterations in expression levels, correlating with disease progression and offering potential as non-invasive diagnostic tools. This review comprehensively examines the dual role of miRNAs as diagnostic biomarkers and therapeutic targets for AD. We also provide an analysis of specific miRNA signatures in different biofluids (plasma, serum, CSF) and brain regions that correlate with disease stages, highlighting their potential for early and non-invasive diagnosis. Therapeutically, miRNAs modulate multiple AD-related pathways, including neuroinflammation via NF-κB signaling, Aβ production through BACE1 inhibition, and tau phosphorylation via GSK3β regulation. miRNAs also influence synaptic plasticity, mitochondrial function, and autophagy, presenting multifaceted opportunities for intervention. However, challenges, including miRNA heterogeneity, stability, and targeted delivery, remain critical impediments. Advances in nanocarriers, exosomal miRNAs, and viral vectors show promise in overcoming these obstacles, enabling precise miRNA modulation. In addition, we underscore the need for standardized protocols, further validation in clinical cohorts, and the development of cost-effective detection methods to translate miRNA-based approaches into practical diagnostics and therapies. By integrating miRNA biomarkers with existing diagnostic tools and exploring combinatorial therapeutic strategies, researchers can harness the potential of miRNAs to revolutionize AD intervention, paving the way for early detection and effective treatment of this devastating disease. Show less

Hepatotoxicity induced by environmental pollutants can be regulated at the transcriptional, translational, and post-translational levels. However, few studies have investigated the changes in liver acetylomics caused by pollutant exposure. In the present study, we demonstrated that perfluorooctanoate (PFOA) and its potential alternative, perfluoro-(3,5,7,9-tetraoxadecanoic) acid (PFO4DA), modified the liver acetylation profile in male mice exposed to 10 mg/kg/d PFOA or PFO4DA for 28 days. Relative to the control group, liver proteins in the exposed mice exhibited altered acetylation patterns, with 1508 and 498 differentially acetylated sites identified in the PFOA- and PFO4DA-exposed groups, respectively. These modifications were not confined to lipid metabolism, but also extended to the urea cycle and hyperammonemia. Furthermore, in vitro and in silico experiments revealed that mutation of CPS1-1168K to CPS1-1168R restored enzymatic activity under PFOA/PFO4DA exposure, while mutation to CPS1-1168Kac reduced the adenosine triphosphate (ATP) binding capacity, suggesting that CPS1-1168K may be a key acetylation site for PFOA and PFO4DA disruption of the urea cycle. Additionally, both chemicals exhibited the potential to compete with ATP for the ATP-binding site, which is essential for CPS1 activity. These findings contribute to understanding the mechanisms underlying PFAS toxicity and support the establishment of an adverse outcome pathway framework. Show less