👤 Wenliya Dong

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

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

Atherosclerosis (AS), a chronic inflammatory process driven largely by macrophage-mediated plaque formation, remains poorly understood in mitochondrial-macrophage crosstalk. While CYBA polymorphisms correlate with cardiovascular risk, the functional role of CYBA in connecting mitochondrial dysfunction to macrophage phenotypic alteration and functional modulation remains largely unknown. In this study, we integrated multi-omics profiling of AS immune microenvironments with mitochondrial-associated gene sets. Machine learning and single-cell RNA sequencing identified CYBA as a key oxidative stress regulator. CYBA expression was significantly upregulated both in oxidized low-density lipoprotein (ox-LDL)-stimulated THP-1 macrophages and in atherosclerotic lesions, with immunofluorescence confirming macrophage enrichment. Show less

High levels of circulating interleukin (IL)-16 are associated with a reduced incidence of cardiovascular events. The disruption of atherosclerotic plaques commonly causes myocardial infarction and stroke. In this study, we investigated the effects of IL-16 on phenotypic modification of plaques. Mice with deficiencies in IL-16 and apolipoprotein E (IL16 IL-16 deficiency increased the necrotic core and reduced fibrous cap thickness in the plaques. IL-16 deletion accelerated the degradation of intraplaque collagen and elastin, increased matrixmetalloproteinase activity, and reduced TIMP-3 expression. Transplantation of wild-type IL-16 bone marrow into IL-16 knockout mice successfully attenuated the plaque instability caused by IL16 deficiency. Furthermore, hematopoietic-derived IL-16 activated the CD4/JAK2/STAT6 pathway and increased the binding of STAT6 to the coactivator cAMP-response element-binding protein (CBP)/p300 at the TIMP-3 promoter in smooth muscle cells (SMCs). Consequently, acetylation of STAT6 and histone H3 increased more than 2-fold, which caused a 2.2-fold upregulation of TIMP-3. Moreover, the anti-atherosclerotic effects of IL-16 on plaque stability were abrogated by the SMC-specific deletion of CD4, and the plaque vulnerability caused by IL-16 defects was reversed by SMC-specific overexpression of TIMP-3. IL-16/CD4/JAK2/STAT6 upregulates TIMP-3 expression in SMCs to remodel the intraplaque extracellular matrix toward a stable phenotype. Our findings suggest that IL-16 is a novel factor in vascular remodeling and atherosclerotic plaque phenotype modulation and is a potential target for intervention in the later stages of atherosclerosis. Show less

Lecanemab is an anti-Aβ antibody approved in China for mild cognitive impairment (MCI) and mild dementia. Real-world application requires comprehensive assessment beyond MMSE scores, considering factors like ARIA risk. This single-center, real-world study aims to evaluate its efficacy in an expanded population, observe biomarker changes, and assess its safety profile in clinical practice. We recruited adults aged 40-90 with early AD from the PUMCH Dementia Cohort. A total of 42 patients received lecanemab treatment, of whom 29 completed the 6-month treatment evaluation. Participants had confirmed amyloid and tau pathology and met clinical criteria (CDR ≤ 1, CDR-SB ≤ 8and MMSE ≥ 18). Comprehensive assessments included neuropsychological testing, CSF and plasma biomarkers (Lumipulse G1200), multi-sequence 3T MRI (volumetric and ALPS index analysis), and amyloid/tau PET imaging (Centiloid quantification). All were monitored for adverse reactions. Matched control groups (matched for sex, age, APOE genotype, disease severity, and baseline therapy) were established for comparison of longitudinally changes in cognitive function, daily living ability and structure MRI. Treatment was effective even for patients with lower MMSE scores but still classified as having mild dementia by CDR. A significant median Centiloid reduction of 30.9 was observed, with a 24.1% amyloid PET negativity rate after six months. While scores on cognitive and functional scales (CDR-SB, ADL) significantly worsened, indicating disease progression, the rate of progression was significantly slower compared to the control group. Structural MRI showed significant volume reduction in multiple brain regions and increased ventricular volume post-treatment, with no statistically significant change in the ALPS value. The rate of brain volume reduction is faster than that in the control group. Plasma biomarker dynamics (Aβ This study confirms the clinical efficacy, biomarker changes, and safety profile of lecanemab treatment over a 6-month period, demonstrating its positive therapeutic value and a favorable safety profile in the Chinese population with AD. Show less

We sought to examine the cross-sectional associations of social support and depressive symptoms with cognitive function in dementia-free rural older adults. This population-based cross-sectional study included 4719 participants (age ≥ 60 years) living in rural China. Social support and depressive symptoms were measured using the Social Support Rating Scale and the 15-item Geriatric Depression Scale, respectively. Global cognition, memory, verbal fluency, attention, and executive function were assessed using a neuropsychological test battery. Mild cognitive impairment (MCI) was defined following Petersen's criteria. Data were analyzed using general linear and logistic regression models. Greater social support was associated with lower likelihood of MCI and greater z-scores of global cognition, memory, verbal fluency, and executive function (all P < 0.05). Having depressive symptoms was associated with increased likelihood of MCI and lower z-scores of global cognition, memory, verbal fluency, attention, and executive function (all P < 0.05). Greater social support was associated with higher global cognitive z-score in men, higher memory z-score in APOE ε4 non-carriers, and higher executive function z-score in participants with school education (all P < 0.01). The association of depressive symptoms with lower z-scores of global cognition and attention was stronger among people with formal schooling than those without (P < 0.01). Furthermore, depressive symptoms could significantly mediate 46.97 % of the cross-sectional association between social support and global cognition. Late-life social support and having no depressive symptoms are associated with a reduced likelihood of MCI and better cognitive function in a rural Chinese older population, with the associations varying by sex, education, and APOE genotype. 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

Precise identification of vulnerable plaque (VAP) is essential for the prevention of acute cardiovascular diseases, yet current molecular probes are hampered by poor VAP lesion penetration and high background. Here, the innate tropism of circulating inflammatory monocytes for VAP, and their differentiation-driven expression of legumain (Lgmn) in response to the VAP microenvironment is exploited. A monocyte differentiation-activated fluorescent (MDAF) probe is conceived that hitchhikes monocytes to precisely migrate to VAP and is activated by Lgmn during monocyte differentiation. This activation triggers in situ self-assembly, resulting in spatiotemporally controlled aggregation-induced emission (AIE) fluorescence signals, and turning the monocyte itself into an on-site "scout" that reports plaque instability. In Apoe Show less

Primary resistance to chimeric antigen receptor (CAR) T-cell therapies has limited their widespread application. Our prior genome-wide CRISPR/Cas9 screening revealed that the loss of CD58, a crucial intrinsic resistance factor in tumors, resulted in insufficient immune synapse formation and impaired CAR T-cell activation and cytotoxicity. However, the specific signaling pathway and transcriptional changes associated with CAR T-cell dysfunction have not been addressed. Here, we revealed that AP-1-mediated activation was attenuated in CAR T cells impaired by tumor CD58 loss, driving a decrease in mitochondrial biogenesis, metabolic kinetic impairment, mitochondrial membrane potential loss and ROS accumulation. Moreover, this AP-1 attenuation triggered death receptor-independent apoptosis through the intrinsic mitochondrial pathway. In seeking therapeutic strategies, we pharmacologically and genetically blocked three distinct inhibitory phosphatases positioned upstream of AP-1 signaling. Multifaceted validation has demonstrated that dual specificity phosphatase 6 (DUSP6) blockade is an effective approach to supplement AP-1 signaling while notably reducing CAR T-apoptosis and enhancing mitochondrial fitness, proliferation and long-term cytotoxicity. The transcriptomic profiles of DUSP6-ablated CAR T cells revealed markedly upregulated T-cell activation signatures and enriched metabolic pathways. Clinically, bulk and single-cell RNA-seq analyses revealed that DUSP6 was downregulated in patients who responded to T-cell-based immunotherapy, implying its relevance to patient outcomes. Our findings repositioned CD58 not merely as an immune synapse component but also a metabolic checkpoint in CAR T-cell biology, the loss of which triggers AP-1-dependent mitochondrial derangement and creates a permissive landscape for intrinsic apoptosis, which can be ameliorated by ablation of the inhibitory phosphatase DUSP6. Crucially, DUSP6 ablation represents a promising engineering target to potentiate CAR T-cell efficacy in broader applications. Show less

Ovarian cancer (OC) is an aggressive gynecological malignancy with poor prognosis, largely due to late-stage diagnosis and high metastatic potential. However, the functional role and regulatory mechanisms of fibroblast growth factor receptor 1 (FGFR1) in OC remain incompletely understood. In this study, we investigated the expression pattern and biological function of FGFR1 in OC and explored its underlying molecular mechanisms. FGFR1 expression was analyzed using TCGA, GTEx, and tissue microarray datasets, and its prognostic significance was evaluated by Kaplan-Meier survival analysis. Functional assays were performed in OVCAR-3 and SK-OV-3 cells following FGFR1 knockdown or overexpression to assess cell proliferation, migration, invasion, and metabolic activity, including extracellular acidification rate (ECAR) and oxygen consumption rate (OCR). Lactate production and histone lactylation were measured by biochemical assays and Western blotting. Protein interaction between FGFR1 and SIRT3 was examined by co-immunoprecipitation and immunofluorescence, and rescue experiments were conducted to determine SIRT3 dependency. In vivo subcutaneous xenograft models were used to evaluate the role of FGFR1 in tumor growth. We found that FGFR1 expression was significantly reduced in OC tissues and that low FGFR1 levels were associated with unfavorable clinical outcomes. Functionally, FGFR1 silencing promoted OC cell proliferation, migration, invasion, and metabolic activity, whereas FGFR1 overexpression exerted inhibitory effects. Mechanistically, FGFR1 interacted with SIRT3 and stabilized its protein expression. Importantly, SIRT3 knockdown abrogated the FGFR1-mediated reductions in lactate production, glycolytic enzyme expression, ATP levels, and histone lactylation, indicating that FGFR1 regulates metabolic reprogramming through a SIRT3-dependent mechanism. Consistently, FGFR1 knockdown promoted the formation of larger and more invasive tumors in vivo. Collectively, these findings demonstrate that FGFR1 functions as a context-dependent tumor suppressor in OC by modulating SIRT3-mediated metabolic reprogramming and histone lactylation, suggesting that targeting the FGFR1-SIRT3 axis may represent a potential therapeutic strategy for ovarian cancer. Show less

Esophageal squamous cell carcinoma (ESCC) remains a major health burden, particularly in Asia, with poor patient prognosis despite advancements in radiotherapy, chemotherapy, and immunotherapy. The marked inter-patient and intra-tumor heterogeneity of ESCC underscores the need for molecularly informed diagnostic and therapeutic strategies. Recent high-throughput omics technologies, including genomics, transcriptomics, proteomics, and metabolomics, have substantially advanced our understanding of ESCC biology. Genomic profiling has revealed recurrent alterations such as TP53 and NOTCH1 mutations, as well as actionable targets including PIK3CA, FGFR1, and SOX2 amplifications, which provide new opportunities for precision therapy. Epigenomic and transcriptomic analyses have identified methylation-based early detection markers (e.g., PAX9, SIM2) and immune-related transcriptomic subtypes associated with prognosis and immunotherapy responsiveness. Proteomic and metabolomic studies have further uncovered cell cycle and spliceosome pathway activation and altered lactate metabolism, offering additional biomarker and therapeutic insights. In this review, we synthesize these multi-omics advances and highlight how they collectively inform improved diagnostic, prognostic, and therapeutic strategies for ESCC. Despite these developments, the clinical translation of multi-omics findings remains limited due to the lack of standardized analytical pipelines, insufficient multi-center validation, and the high cost and technical complexity of integrating multi-omics data into routine clinical workflows. Future research integrating artificial intelligence with multi-omics data holds promise for enhancing diagnostic accuracy and enabling more precise therapeutic decision-making in ESCC. Show less

Nurses' voice behavior is critical for patient safety and organizational improvement. However, its manifestation is not uniform among nurses. This study aimed to identify latent profiles of nurses' voice behavior using Latent Profile Analysis (LPA) to understand this heterogeneity and explore its influencing factors, with a specific focus on differences across work motivation dimensions (rooted in Self-Determination Theory, SDT). A multicenter cross-sectional design was adopted. Data from 701 clinical nurses across six hospitals in Guangxi Province were analyzed: LPA identified four distinct profiles, and Multinomial Logistic Regression was used to examine predictors. Work motivation was measured by the Multidimensional Work Motivation Scale (MWMS), and voice behavior by the Voice Behavior Scale (VBS). LPA identified four distinct profiles (Conservative, 5.42%; Balanced Risk-Taker, 26.39%; Transitional, 34.38%; Challenging, 33.8%), and Multinomial Logistic Regression was used to examine predictors. Work motivation was measured by the Multidimensional Work Motivation Scale (MWMS), and voice behavior by the Voice Behavior Scale (VBS). Results showed autonomous motivation (e.g., intrinsic drive) strongly predicted active voice behavior, while amotivation predicted conservative profiles. Nurses exhibited high work motivation (MWMS: 93.02 ± 21.09) and moderately high voice behavior (VBS: 39.27 ± 8.736). The research found that nurses exhibited high work motivation and moderately high voice behavior, with autonomous motivation being a pivotal predictor. Differentiated strategies targeting intrinsic motivation enhancement are critical for fostering nursing innovation and improving care quality. Show less

Acute ischemic stroke (AIS) poses a substantial risk of permanent disability and death globally, with neuroinflammation being a key driver of secondary brain damage post-stroke. Proprotein convertase subtilisin/kexin type 9 (PCSK9), beyond its well-accepted role in cholesterol metabolism through low-density lipoprotein receptor (LDLR) degradation, has emerged as an important mediator of neuroinflammation, making it an attractive new therapeutic target. This has sparked broader discussions about the potential pleiotropic effects of PCSK9 inhibitors on brain function. Proprotein convertase subtilisin/kexin type 9 mediates inflammation post-ischemia directly and indirectly by disrupting mTOR pathways. This stimulates signaling cascades associated with inflammation. For example, the nuclear factor-κB (NF-κB), toll-like receptor 4 (TLR4), and mitogen-activated protein kinase (MAPK) pathways in microglia activation. It also brings about reaction in astrocytes and increases the release of cytokines like interleukin-1β, interleukin-6, and tumor necrosis factor-α. Proprotein convertase subtilisin/kexin type 9 interacts with apolipoprotein E receptor 2 (ApoER2) present on neurons cells, leading to further inflammatory effects. Proprotein convertase subtilisin/kexin type 9 indirectly increases lipoprotein(a) [Lp(a)], which promotes inflammation through the Lp(a)-TLR4 axis and induces endothelial dysfunction. Monoclonal antibodies (evolocumab, alirocumab) and small interfering RNA (siRNA) agents (inclisiran) are examples of PCSK9 inhibitors. According to preclinical studies, these inhibitors can mitigate neuroinflammation by blocking the M1 polarization of microglia and downregulating key pro-inflammatory factors while preserving the blood-brain barrier (BBB). They also inhibit neuronal apoptosis via the Bcl-2/Bax-caspase cascade and reduce the aggregation of β-amyloid (Aβ). Evidently, the findings from cardiac ischemia-reperfusion models show that pretreatment with PCSK9 inhibitors is effective with optimal neuroprotection. Recent clinical data support these mechanisms: PCSK9 inhibitors not only lower LDL-C and Lp(a) but also reduce systemic inflammatory markers (e.g., high-sensitivity C-reactive protein [hs-CRP], interleukin-6). Early adjunctive use of evolocumab in AIS is associated with reduced early neurological deterioration, highlighting that its effects extend beyond lipid lowering to modulating immune pathways in both the central and peripheral systems. As a promising multitarget therapeutic strategy for AIS, PCSK9 inhibitors target the interconnected pathways of lipid metabolism and neuroinflammation. Future studies should address critical challenges such as defining the optimal therapeutic time window, improving BBB penetrability, and refining patient stratification to translate their neuroprotective effects into clinical benefits for stroke patients. Show less

Serum lipoprotein(a) [Lp(a)] is recognized as an independent risk factor for cardiovascular disease. However, whether hypertension modifies the association between Lp(a) and adverse outcomes in acute decompensated heart failure (ADHF) remains unclear. We investigated how hypertension status influences the relationship between Lp(a) and all-cause mortality in ADHF. We conducted a single-center retrospective observational study including 2610 patients hospitalized with ADHF. We normalized the distribution of Lp(a) by a logarithmic transformation and assessed the risk of all-cause mortality with Lp(a), using Cox regression with adjustment for potential confounders. Among 2610 patients (39.0% women; mean age, 68.8 years), 1606 (61.5%) had hypertension. Over 4.1 years (median), 1287 deaths occurred. In all patients, log-transformed Lp(a) was significantly associated with mortality (adjusted HR 1.21; 95% CI, 1.05-1.39; Increased admission Lp(a) levels were associated with a higher risk of all-cause mortality in ADHF patients with hypertension. Further studies are needed to explore the mechanistic links among Lp(a), hypertension and ADHF. Show less

Major depressive disorder (MDD) in adolescents is a critical public health concern, yet objective diagnostic biomarkers remain lacking. We conducted an integrative lipidomics study across human cohorts and a chronic unpredictable mild stress (CUMS) rat model. Targeted UPLC-MS/MS profiling was applied to a training cohort (95 MDD, 40 controls), and untargeted UPLC-HRMS profiling to an independent cohort (56 MDD, 37 controls). Candidate biomarkers were identified using univariate tests, partial least squares discriminant analysis, and three feature-selection methods (Boruta, LASSO, RFE), with predictive performance evaluated by cross-validation and external replication. Translational relevance was examined in CUMS rats through behavioral assays and lipidomic profiling of serum and brain tissues. Pathway enrichment and regression models explored metabolic context and clinical associations. In the training cohort, we found that 244 lipids were significantly altered, highlighting altered glycerophospholipid, glycerolipid, and sphingolipid metabolism. A 29-lipid panel achieved 90.4% cross-validation accuracy, while a reduced 7-lipid subset reached 94.8%. In the validation cohort, an 8-lipid panel achieved 71.2% accuracy, and a minimal 2-lipid set-LPA(18:2) and SPH(d16:1)-reached 72.1%. Cross-species analysis confirmed consistent downregulation of SPH(d16:1) in serum of both humans and rats, and of LPC(0:0/16:0) specifically in the rat prefrontal cortex. Regression analyses linked sex, age, and anxiety severity to lipid alterations. This cross-platform, cross-species study identifies reproducible lipid signatures of adolescent MDD, highlights SPH(d16:1) and LPC(0:0/16:0) as translational biomarkers, and implicates glycerophospholipid metabolism in MDD pathophysiology, providing a foundation for biomarker-guided diagnostics and therapeutics. Show less

TyHGB is a novel insulin resistance (IR)-related indicator, and its association with coronary heart disease (CHD) remains unclear. Additionally, studies have shown a close correlation between the diagonal earlobe crease (DELC) and CHD, yet it has not been fully applied in clinical practice to date. Therefore, this study constructed and validated a diagnostic model for CHD by combining TyHGB and DELC. A total of 1664 patients suspected of CHD who underwent coronary angiography (CAG) in the Department of Cardiology, Chengde Central Hospital from September 2021 to April 2025 were recruited for this study. Participants were categorized into a CHD group ( Age, sex, hypertension, diabetes, CR, Lp(a), TyHGB, and DELC were identified as independent risk factors for CHD through multivariate logistic regression analysis ( Both TyHGB and DELC have been identified as independent risk factors for CHD, with a linear relationship observed between TyHGB levels and CHD risk. A diagnostic model for CHD, developed by integrating TyHGB, DELC, and traditional risk factors, demonstrates strong diagnostic efficacy. The online version contains supplementary material available at 10.1186/s12944-026-02880-y. Show less

MYBPC3 mutations are the leading cause of hypertrophic cardiomyopathy. Here, to study the pathogenesis of hypertrophic cardiomyopathy, we created a MYBPC3 knockout (KO) model using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). MYBPC3-deleted hiPSC-CMs revealed the characteristics of heart failure, which exhibited increased contractility at 30 days but decreased at 40 days. Furthermore, at 40 days, it also shows abnormal calcium handling, increased ROS levels, and mitochondrial damage. Further RNA sequencing revealed that the oxidative stress pathway was aberrant, in addition to alterations linked to hypertrophic cardiomyopathy. Moreover, after adding melatonin to hiPSC-CMs at 30 days, MYBPC3-deleted hiPSC-CMs showed restored calcium handling capacity, decreased ROS levels, and improved myocardial contractility. In summary, reducing ROS can improve the phenotype of hypertrophic cardiomyopathy. Show less

Congenital myasthenic syndromes (CMS) are often underdiagnosed due to phenotypic overlap with other neuromuscular disorders. Limited epidemiological data and low awareness hinder early diagnosis, which is key for effective treatment. Early recognition of CMS is important as symptomatic treatments often specific for genetic subtypes exist and emerging therapies are in the pipeline. This study aims to estimate the prevalence of genetically confirmed CMS in the United Kingdom and explore geographical variations. Prevalence was calculated as of 31 December 2023, including genetically confirmed CMS patients residing in the United Kingdom and known to be alive. Patients with missing geographic or living status data were excluded. Prevalence was estimated overall and compared between UK regions served by a highly specialized neuromuscular service (hsNMS) and those without such services (non-hsNMS). A cohort of 442 genetically confirmed CMS patients was identified. CHRNE deficiency, DOK7, RAPSN were the most common subtypes. The UK prevalence was 6.5 cases per million overall and 8.5 cases per million in the pediatric population. The overall prevalence was statistically higher in hsNMS (8.8 cases per million) compared to non-hsNMS regions (5.9 cases per million). Homozygous patients had a more clustered distribution particularly around urban area. Our results suggest there is likely underdiagnosis of CMS in many areas of the United Kingdom and hsNMS may play an important diagnostic role. Variations may also be related to other cultural clustering and founder effects. Further research should explore how healthcare access, ethnicity, and consanguinity contribute to regional variation and diagnostic rates. Show less

Cisplatin resistance remains a major challenge in bladder cancer. Although the tumor suppressor ASPP2 is a critical co-factor for TP53-mediated apoptosis, its role in metabolic reprogramming and cisplatin response remains unclear. This study aimed to delineate the mechanism by which ASPP2 regulates cisplatin sensitivity through metabolic reprogramming. We first assessed the clinical significance of ASPP2 using patient tissues and public databases, finding that its downregulation in bladder cancer is associated with poor patient survival. Through gain- and loss-of-function studies in vitro and in vivo, we further demonstrated that ASPP2 inhibits the mevalonate (MVA) pathway independently of TP53 status, thereby sensitizing cells to cisplatin-induced DNA damage and apoptosis. This chemosensitizing effect was specifically reversed by the addition of MVA pathway metabolites. Moreover, WWP2 was identified as the E3 ubiquitin ligase responsible for ASPP2 degradation via K48-linked ubiquitination. Finally, WWP2 silencing was shown to stabilize ASPP2, suppress the MVA pathway, and synergize with cisplatin to impede tumor growth in mouse models. Overall, the WWP2-ASPP2-MVA pathway axis is identified as a novel driver of cisplatin resistance in bladder cancer. These results establish a mechanistic basis for targeting this axis to restore chemosensitivity, offering a promising therapeutic strategy for recalcitrant disease. Show less

Ulcerative colitis (UC) is a prevalent chronic gastrointestinal disease. Gene plays an important role in UC pathogenesis. Therefore, we aim to identify UC susceptibility genes and specific cell types expressing these genes. We conducted a cross-tissue transcriptome-wide association study by integrating UC GWAS with 49 tissues gene expression matrix from the Genotype-Tissue Expression project. Subsequently, we employed Functional Summary-based Imputation to verify candidate genes within colon tissue. Conditional and Joint Analysis was utilized to filter out genes potentially influenced by linkage disequilibrium. Multimarker Analysis of Genomic Annotation was then applied to pinpoint genes relevant to UC. Validation of the selected genes was performed using Mendelian randomization. GeneMANIA analysis was conducted to elucidate biological functions of identified genes. Finally, single-cell RNA sequencing was employed to ascertain cell types in which these genes are enriched. The cross-tissue transcriptome-wide association study, Functional Summary-based Imputation and Multimarker Analysis of Genomic Annotation analyses identified a total of 5 genes, of which 3 genes, ADCY3, ITGB6, and MTMR3, were retained after Mendelian randomization. These genes were found to be implicated in several functional pathways, including the cyclic AMP metabolic process and phosphorus-oxygen lyase activity. Furthermore, we observed ADCY3 predominantly enriched in B cells, while ITGB6 and MTMR3 enriched in epithelial cells. Our study has identified 3 genes associated with UC susceptibility. These findings not only enhance our understanding of the genetic underpinnings of UC, but also offer novel avenues for exploring molecular mechanisms and potential therapeutic targets for UC. Show less

Excessive adipose tissue accumulation adversely impacts the health of both humans and livestock. Adenylyl cyclase 3 (ADCY3) is a promising anti-obesity target, yet its regulatory role in adipogenesis remains incompletely understood. Our findings revealed a dynamic pattern of ADCY3 expression during adipogenesis and lipid droplet (LDs) accumulation. Functional analyses demonstrated that ADCY3 overexpression impaired adipogenesis by downregulating adipogenic transcription factors CEBPα and PPARγ. Furthermore, it reduced both the number and size of LDs through suppressing triglyceride synthesis and fatty acid metabolism, concomitantly downregulating key genes involved in LDs formation (PLIN1, CIDEC, FIT2, and Seipin), as well as factors mediating glycerol ester synthesis and fatty acid metabolism (DGAT1, DGAT2, ACC, SCD, FASN, and ACSL1). Transcriptomic profiling revealed that ADCY3 overexpression suppressed PPARγ signaling, leading to the downregulation of oxidative phosphorylation genes encoded by both the nuclear and mitochondrial genomes. Our results implicate ADCY3 in the regulation of lipid metabolism, with the speculative involvement of mitochondrial metabolic remodeling. This perspective offers a framework for developing future interventions against excessive lipid deposition. Show less

Polycystic ovary syndrome (PCOS) is a prevalent metabolic and reproductive endocrine disorder with strong heritability. However, the independent role of oocytes in mediating this heritability remains unclear. Utilizing in vitro fertilization-embryo transfer and surrogacy, we demonstrated that oocytes from androgen-exposed mice (F1) transmitted PCOS-like traits to F2 and F3 generations. Notably, caloric restriction (CR) in F1 or F2 effectively prevented this transmission by restoring disrupted DNA methylation in oocyte genes related to insulin secretion and AMPK signaling pathways. Further detection in adult tissues of offspring revealed dysregulated DNA methylation and expression of those genes (e.g., Adcy3, Gnas, and Srebf1) were reversed by maternal CR. Moreover, similar benefits of CR were observed in aberrant embryonic methylome of women with PCOS. These findings elucidate the essential role of CR in preventing PCOS transmission via methylation reprogramming, emphasizing the importance of preconception metabolic management for women with PCOS. Show less

In this study, to achieve more effective blood sugar lowering and weight-loss effects, eight glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic peptide (GIP)/glucagon (GCG) triple receptor agonists were designed and synthesized. Their sixteen related conjugates were obtained through Cys alkylation and Lys esterification modifications with two fatty acid side chains, respectively. After chemical structure confirmation using high-resolution mass spectrometry and peptide mapping, in vitro and in vivo biological effects of TRA01-24 were assessed. The structure-activity relationship (SAR) data on the amino acids, fatty acids, linkers and biological effects in vitro and in vivo of TRA01-24 have been summarized. Furthermore, peptide-protein molecular docking elucidated the structural basis for the biased agonist activity of TRA22 at GLP-1R, characterized by strong GLP-1R activation but weak GCGR and GIPR activation. In conclusion, a lead compound with excellent efficacy in vitro and in vivo, TRA24, was screened, which had better in vivo efficacy than tirzepatide in both normal and db/db mice. Show less

The pervasiveness and versatility of G protein-coupled receptors (GPCRs) in virtually all physiological processes is based on the receptors' capability to activate intracellular signal transduction pathways in response to diverse extracellular stimuli. While the importance of GPCRs makes them the largest group of drug targets (comprising about one-third of marketed medicines), more than half of GPCRs lack preclinical drug candidates because of high structural conservatism of their orthosteric sites. Recognizing that the mechanisms of GPCR function and regulation are chiefly allosteric in nature, we explore their allosteric control and the potential for developing allosteric drugs with high specificity. First, we obtained a picture of allosteric signaling in 280 non-olfactory GPCRs in human and explored archetypal structure-based patterns and sequence-determined variations of allosteric communication. We showed how the causality of allosteric effects due to ligand binding can be quantified, using the β Show less

Angiogenesis, a meticulously regulated process essential for both normal development and pathological conditions, necessitates a comprehensive understanding of the endothelial mechanisms governing its progression. Leveraging the zebrafish model and NgAgo knockdown system to identify target genes influencing angiogenesis, our study highlights the significant role of gastric inhibitory polypeptide (GIP) and its receptor (GIPR) in this process. While GIP has been extensively studied for its insulinotropic and glucagonotropic effects, its role in angiogenesis remains unexplored. This study demonstrated that GIPR knockdown induced developmental delays, morphological abnormalities, and pronounced angiogenic impairments in zebrafish embryos. Conversely, exogenous D-Ala2-GIP administration enhanced blood vessel formation in the yolk sac membrane of chick embryos. Consistent with these findings, D-Ala2-GIP treatment promoted microvessel formation in the tube formation assays and rat aortic ring models. Further investigation revealed that D-Ala2-GIP facilitated human umbilical vein endothelial cell (HUVEC) migration, a key step in angiogenesis, through the cyclic adenosine monophosphate (cAMP)-mediated activation of the Epac/Rap1/Cdc42 signaling pathway. This study provides novel insights into the angiogenic functions of GIP and its potential implications for cardiovascular biology. Show less

Previous experiments have demonstrated that BGM0504, a GLP-1R/GIPR dual agonist drug by molecular dynamics-guided optimization, had enhanced agonistic activity compared to tirzepatide. This study aims to investigate its safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) in Chinese healthy volunteers. A randomized, double-blind, placebo-controlled and dose-escalation Phase I study was conducted as follows: a single dose (2.5 mg) and once-weekly administration for 2 weeks to reach target doses (5, 10 and 15 mg) by titration. A total of 40 volunteers received at least one dose of BGM0504 or placebo. The PK profile of BGM0504 was investigated over a wide dose range and supported once-weekly administration. It was observed that C BGM0504 was generally safe and well tolerated with favourable PK profile and potential role in weight loss was also confirmed. These findings support subsequent development of BGM0504 for type 2 diabetes mellitus (T2DM) and obesity. Show less