👤 Xiaojie Quan

Ambient air pollution aggravates cardiovascular-kidney-metabolic (CKM) disorders and sarcopenia, yet the shared genetic and epigenetic mechanisms that underlie their frequent co-occurrence remain poorly understood. We integrated genome-wide association study (GWAS) data for CKM components (cardiovascular disease [CVD], chronic kidney disease [CKD], metabolic syndrome), CKM-related cardiovascular events, and sarcopenia diagnostic criteria from European-ancestry cohorts, and conducted meta-analyses harmonizing each phenotype across at least three studies. We employed Mendelian Randomization (MR) to assess potential causal links and genetic correlation analyses (global and local) to quantify shared heritability. Multi-omics analyses included two sequential phases: Phase 1 identified and validated novel shared CKM-sarcopenia genes through integrated methylation (n = 1980) and expression (n = 31,684) analyses, followed by cross-validation using two complementary transcriptome-wide association studies (TWAS). Phase 2 prioritized druggable targets through proteomic analysis across five independent cohorts (deCODE, n = 35,559; UK Biobank Pharma Proteomics Project (UKB-PPP), n = 54,219; Fenland, n = 10,708; FinnGen Olink, n = 619; FinnGen Somascan, n = 828) and integrated colocalization. MR suggested genetically predicted associations between sarcopenia and CKM; genetically slower walking pace was associated with higher CVD risk (OR = 0.85, P = 9.56 × 10 Ambient air pollution likely promotes CKM-sarcopenia comorbidity chiefly via inflammatory signaling and epigenetic modifications. Our multi-omics integration reveals convergent pathways, candidate driver genes, and differential methylation sites that link these conditions. We propose these targets for environmental mitigation and molecular intervention, which require validation in diverse populations. Show less

The incidence of osteoarthritis (OA) is strongly correlated with aging. It has been shown that the accumulation of senescent cells in the synovium precedes chondrocyte senescence and cartilage degradation, suggesting that synovial cell senescence plays a key role in OA pathogenesis. This study aimed to investigate the mechanisms underlying synovial cell senescence and its influence on intercellular communication within the joint. Using multiplex immunofluorescence, gene regulatory network reconstruction, and single-cell RNA sequencing analyses, we identified senescent cells and characterized the senescence-associated secretory phenotype in the synovium. A series of in vivo and in vitro functional experiments is conducted to elucidate the mechanisms of fibroblast senescence and its effects on macrophages and chondrocytes. We found that synovial intimal fibroblasts (SIF) display more marked premature senescence compared to other synovial cell types. A specific senescent subpopulation within SIF is identified, and we demonstrated that the transcription factors EGR1 and ATF3 regulate senescence-related pathways in these cells. Furthermore, we showed that senescent SIF promote M1 macrophage polarization and cartilage degeneration through paracrine secretion of ANGPTL4. Additionally, senescent SIF may facilitate OA progression through direct cell-cell contact with macrophages. Show less

In recent years, except for the well-known heart failure with reduced ejection fraction (HFrEF), the incidence of heart failure with preserved ejection fraction (HFpEF) and heart failure with mildly reduced ejection fraction (HFmrEF) among the classification of heart failure (HF) has been increasing. However, due to their complex mechanisms, current research remains insufficient to address clinical needs. Utilizing wild-type (WT), miR-30a-5p knockout (KO), and overexpression (OE) murine models combined with estrogen modulation and ovariectomy (OVX), this study delineates sex-specific regulatory networks in HF pathogenesis. Female KO mice lost the inherent resistance of WT females to HFpEF induction via 24-week HFD/L-NAME, whereas males exhibited comparable HFpEF susceptibility regardless of genotype, developing hallmark phenotypes including diastolic dysfunction (E/E'), myocardial hypertrophy (heart weight/tibia length), cardiac fibrosis, and hepatic steatosis. Particularly, due to the reduced ejection fraction in KO mice, combined with HFD/L-NAME, the HF phenotype was ultimately manifested as impaired diastolic function and slightly reduced ejection fraction (with the characteristics of HFpEF and HFmrEF). Mechanistically, KO-HF females displayed significant estrogen axis disruption (plasma estradiol and the expression of ERα, ERβ, ESRRA, and PELP1 expression). OVX in WT females validated the importance of estrogen for HFpEF resistance. Transcriptomic profiling identified convergent targets across cardiac (ITGAD, ITGAM, FGA, and FGB) and hepatic tissues (APOA1 and APOB), revealing miR-30a-5p's orchestration of extracellular matrix remodeling (via ITGAD/ITGAM mechanotransduction),fibrinogen-mediated microvascular homeostasis, and APOB-driven metabolic dysregulation. Notably, OE intervention failed to mitigate OVX-induced cardiac/hepatic pathology, implicating estrogen-dependent miR-30a-5p functionality. These findings establish miR-30a-5p as a crucial sex-specific regulator of HF (mainly HFpEF), operating through estrogen signaling to balance cardiac compliance and metabolic adaptation. Show less

The triglyceride-glucose (TyG) index, an insulin resistance marker linked to the progression of metabolic dysfunction-associated steatotic liver disease (MASLD), underscores the redox imbalance-mediated crosstalk between MASLD and cardiovascular-liver-metabolic health (CLMH), although its causal mechanisms and molecular drivers remain unresolved. We employed a multi-omics framework to integrate Mendelian randomization (MR) and transcriptome-wide association studies (TWAS). MR leveraged 192 genome-wide significant single-nucleotide polymorphisms for TyG from the UK Biobank, employing inverse-variance weighted (IVW) and generalized summary-data MR (GSMR). Transcriptomic integration utilized four approaches: Multi-marker Analysis of GenoMic Annotation for gene-set enrichment; Joint-Tissue Imputation PrediXcan (JTI-PrediXcan) for tissue-specific expression; Sparse Multi-Tissue Imputation Xcan (SMulTiXcan) for cross-tissue meta-analysis; and Fine-mapping of Causal Gene Sets (FOCUS) for Bayesian fine-mapping. Comorbid genes were validated using Functional Summary-based Imputation (FUSION) and prioritized based on the Polygenic Priority Score (PoPS). Single-cell spatial transcriptomics (sc-ST) in embryonic mice (E16.5) mapped tissue-specific expression via genetically informed spatial mapping (gsMap). The MR analysis demonstrated a causal effect of TyG on MASLD risk [IVW: odds ratio (OR) = 1.58, 95% CI = 1.04-2.38, P = 0.030; GSMR: OR = 1.43, 95% CI = 1.27-1.61, P = 5.20 × 10 -9 ]. TWAS identified 12 comorbid genes (C2orf16/SPATA31H1, FNDC4, GCKR, GMIP, HAPLN4, LPAR2, MAU2, MEF2B, NDUFA13, NRBP1, TM6SF2, and ZNF513). Independent validation using the FUSION framework confirmed nine TyG-MASLD comorbid genes with genome-wide significant false discovery rate-adjusted associations. Notably, TM6SF2 (TyG-PoPS = 7.2491) and GCKR (TyG-PoPS = 6.7102) showed strong positive associations in TyG, whereas NDUFA13 exhibited negative scores in MASLD (PoPS = -0.5028). Spatial mapping revealed conserved enrichment of APOA1, APOB, and APOC4 (sc-ST, P < 0.001) in murine liver and vascular tissues. Organ-specific analysis showed significant MASLD signals including the liver (sc-ST, P = 6.43 × 10 -5 ), adrenal gland (Cauchy P = 0.0064), and connective tissue (sc-ST, P = 3.29 × 10 -5 ). This study establishes TyG as a causal MASLD driver mediated by redox-sensitive hubs and evolutionarily conserved apolipoproteins, linking hepatic lipid peroxidation to systemic metabolic dysregulation. Targeting these pathways may mitigate dual hepatic-cardiovascular risks, advancing precision therapies for CLMH. 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

This study examined the heterogeneous nature of dual-career stress and its asymmetric associations with on adolescent athletes, aiming to: (1) identify distinct stress profiles based on academic, training, and role-conflict stressors; (2) assess whether stress associations vary across levels of athletic burnout and academic performance; and (3) test whether stress profiles moderate these relationships. A two-wave longitudinal study included 843 adolescent male football players in China. Latent Profile Analysis (LPA) categorized participants using three stressor subscales at Time 1. Quantile Regression (QR) at Time 2 (6 months later) analyzed the association between total stress and athletic burnout and academic performance across five quantiles (τ = 0.10-0.90), with stress profile as moderator, controlling for social support, time management, and demographics. LPA revealed four profiles: Balanced Moderates (37.2%), Academically Overwhelmed (28.1%), Sport-Centric Strained (22.0%), and Dual-Track Distressed (12.7%). QR showed the positive association between stress and burnout increased across quantiles (β = 0.41 at τ = 0.10 to 0.78 at τ = 0.90), with the strongest association observed among already burnt-out athletes most. For academic performance, the negative association between stress and performance was strongest at lower quantiles (β = -0.71 at τ = 0.10) and weaker at higher quantiles (β = -0.29 at τ = 0.90). Stress profiles significantly moderate these relationships: the Dual-Track Distressed profile showed the strongest association with on burnout (β = 0.89), while Academically Overwhelmed and Dual-Track Distressed profiles showed the strongest negative association with on academic performance (β = -0.79 and -0.92, respectively). Dual-career stress experiences and impacts are highly heterogeneous. Adolescents cluster into meaningful stress profiles, and stress is most strongly associated with negative outcomes among those already at extremes of burnout or poor academic performance. Findings underscore the need for personalized interventions tailored to athletes' specific stress profiles and outcome levels, supporting holistic development in dual-career contexts. Show less

The differential diagnosis between Tuberculosis (TB) and Non-tuberculous Mycobacteria (NTM) has historically been constrained by the inadequate sensitivity and specificity of current diagnostic methods. Furthermore, distinguishing between Active Tuberculosis (ATB) and Latent Tuberculosis Infection (LTBI) poses significant challenges. This study aims to develop a molecular differentiation system for ATB, LTBI, and NTM by integrating plasma proteomics with multi-dimensional analytical techniques, while also exploring key biomarkers associated with disease progression and treatment response. Using label-free quantitative technology, we conducted a plasma proteomics analysis across five groups: ATB, LTBI, NTM, Cured Patients (CPs), and Healthy Donors (HD). Differentially Expressed Proteins (DEPs) were identified through screening (FC > 1.5 or <0.67, P < 0.05), followed by Gene Ontology/KEGG pathway enrichment, STRING interaction network, and Mfuzz dynamic clustering analysis to systematically elucidate molecular characteristics. Experimental data were validated through a multidimensional quality control system (Pearson correlation coefficient, peptide distribution, molecular weight distribution, etc.). Enzyme-linked immunosorbent assay (ELISA) was employed to detect the plasma expression levels of target proteins across the groups and to facilitate comparisons. This study identified 1,338 non-redundant proteins across five cohorts. Comparative analysis revealed 142 DEPs across the three comparative groups (ATB, LTBI, and NTM), which were primarily localized in the extracellular domain. Key findings include: 27 DEPs in the ATB-LTBI group, primarily enriched in inflammatory responses (such as A2M, IL-1R2) and epithelial barrier functions (TGM3, KRT3); 69 DEPs in the ATB-NTM group, characterized by significant changes in immunoglobulin light chains (IGLV2-11) and innate immune effector molecules (S100A8); 46 DEPs in the NTM-LTBI group, closely related to lipid metabolism (APOC3) and extracellular matrix remodeling (FN1). KEGG pathway analysis revealed that DEPs in the ATB-LTBI group were enriched in nitrogen metabolism pathways, those in the ATB-NTM group were associated with thyroid hormone synthesis, and the NTM-LTBI group was involved in phagosome function. Dynamic clustering results showed six treatment response modules: Cluster 1/2 (riboflavin metabolism, complement coagulation pathway) were activated post-treatment, Cluster 3/4 (proteasome, cardiac signaling pathway) exhibited partial reversal in expression, and Cluster 5/6 (platelet activation, cytoskeleton) showed delayed regression. Research confirmed 10 differential proteins between the ATB-CPs and ATB-HD groups, including S100A8, LTA4H, and DEFA1B, which constitute a molecular fingerprint specific to ATB. ELISA validation confirmed significantly elevated S100A8 and GPX3 in ATB group, while NTM group showed higher FGB and lower ATRN levels. This study systematically reveals the plasma proteomic characteristics under infection statuses caused by different mycobacteria. A discrimination framework for ATB/LTBI/NTM was constructed based on disease-specific differential proteins, overcoming the limitations of traditional diagnostic techniques in distinguishing infection states. Through dynamic analysis of six temporal therapeutic modules, the reprogramming patterns of the host protein network during tuberculosis treatment were elucidated. This research lays a multidimensional molecular foundation for the precise typing, personalized treatment, and prognostic evaluation of mycobacterial infections. Show less

Alzheimer's disease (AD) is a neurodegeneration driven by beta-amyloid (Aβ) deposits in the brain involving autophagy dysfunction. Ginsenoside Rg1, a pharmacologically active compound found in ginseng, has possible therapeutic effects for AD. This study discovered that FGR proto-oncogene (FGR) was a therapeutic target of Rg1 in AD and it was possibly involved in autophagy. C57BL/6 J mice were injected with 5 μL (1 μg/mL) Aβ Show less

Obesity is a chronic inflammatory disorder, which promotes the progression of metabolic disorders. MicroRNA (miR)-6838-5p is dysregulated and participates in the progression of several disorder models. To explore the role and mechanism of miR-6838-5p in insulin resistance. Mice were fed with high-fat diet (HFD) to construct an obesity animal model. The role of miR-6838-5p was evaluated by insulin tolerance test (ITT), glucose tolerance test (GTT), homeostasis model assessment of insulin resistance (HOMA-IR) analysis, enzyme-linked immunosorbent assay (ELISA) and western blot assays. The potential target of miR-6838-5p was screened through the starBase online website and confirmed by the luciferase assay. HFD supply induced a prominent increase in the body weight, white adipose tissue (WAT) weight, the area under the curve (AUC) of GTT and ITT, HOMA-IR, the serum level of insulin and the serum concentrations and relative protein levels of interleukin (IL)-1β, IL-6 and monocyte chemoattractant protein-1 (MCP-1) accompanied with reduced levels of IL-10 in mice. The level of miR-6838-5p was reduced in HFD-fed mice. Upregulation of miR-6838-5p partly reversed the above-mentioned indicators. Moreover, miR-6838-5p directly targeted to β-site amyloid precursor protein cleaving enzyme1 (BACE1) and negatively regulated the BACE1 expression. Downregulation of BACE1 improved insulin sensitivity and inflammatory mediators release involving in AKT/GSK3β signaling pathway in HFD-fed mice. Besides, overexpression of BACE1 counteracted the depressant role of miR-6838-5p overexpression in insulin resistance and inflammatory factors release in HFD-fed mice. MiR-6838-5p/BACE1 axis regulated insulin resistance and inflammatory factors release in HFD-fed mice. Show less

Advanced renal cell carcinoma (RCC) primarily relies on targeted and immune-based therapies, yet these treatments often face limitations due to inefficacy and drug resistance. Branched-chain α-keto-acid dehydrogenase kinase (BCKDK) has been implicated in promoting RCC metastasis, but its specific substrates and the mechanisms underlying its regulation of RCC progression remain poorly understood. This study uncovers a novel mechanism whereby BCKDK-mediated AKT phosphorylation drives RCC tumorigenesis and drug resistance. Elevated BCKDK expression correlates with poor prognosis in RCC clinical samples. BCKDK deficiency inhibits RCC cell proliferation and tumorigenesis both in vitro and in vivo. Mechanistic investigations reveal that BCKDK directly binds to and regulates the phosphorylation of AKT. BCKDK-mediated phosphorylation of AKT decreases ubiquitin-mediated AKT protein degradation, and promotes tumorigenesis via activation of the AKT/mTOR signaling pathway. RNA sequencing identifies BCKDK's involvement in the drug metabolism network and apoptotic signaling pathways. The BCKDK/AKT/ABCB1 axis mediates doxorubicin resistance. Targeting BCKDK/AKT inhibits the growth of RCC patient-derived organoids (PDOs), enhances doxorubicin-induced apoptosis in RCC cells, and suppresses tumor growth in vivo. These findings identify a previously unrecognized phosphorylation substrate of BCKDK and highlight the critical role of the BCKDK/AKT signaling axis in RCC progression, offering a promising target for therapeutic intervention. Show less

Membrane lipids play a crucial role in brain function and cell signalling, and they serve as key biological substrates in inflammatory responses, thrombosis, and energy metabolism. Multiple clinical and molecular evidences suggest that membrane lipids are probably involved in the pathogenesis of ischemic stroke (IS). However, current knowledge about the membrane lipid landscape and its involvement in IS pathophysiology is limited. We performed untargeted lipidomic analysis on erythrocyte membranes from 56 IS patients and 55 healthy controls. Integrated with gene expression and weighted gene co-expression network analysis, we identified dysregulated lipid signalling pathways and their contributions to IS pathophysiology. A total of 1392 erythrocyte membrane lipids were detected and quantified. Our results revealed significant impairment of membrane lipid homeostasis in IS patients, characterized by a marked reduction in glycerophospholipids (GPLs) and lysophospholipids (LPLs). Further analysis indicated that the impaired lipids were primarily concentrated in three disturbed signalling pathways, including the phospholipase A2-mediated GPL-LPL pathway, the phospholipase C-mediated inositol 1,4,5-trisphosphate/diglyceride pathway, and the sphingosine-1-phosphate (S1P)-S1P receptors pathway. Gene expression results indicated that these pathways were inhibited during the subacute phase of IS. Furthermore, these lipid signalling pathways form a highly interconnected network that collaboratively contributes to inflammation and thrombosis in IS, thereby influencing the progression and prognosis of the disease. Our findings reveal impaired erythrocyte membrane lipid homeostasis in IS, which implicates inflammatory processes and thrombosis in IS. This research offers new insights into the role of membrane lipids in IS pathogenesis, potentially informing future monitoring and therapeutic strategies. Show less

Fel d1, the major cat allergen responsible for over 90% of human IgE-mediated allergies, has an incompletely defined physiological role. To explore its function and assess the feasibility of producing hypoallergenic cats, we knocked out the CH2 domain of Fel d1 using CRISPR/Cas9 in feline skin cells. An optimized sgRNA introduced a frameshift mutation, with knockout efficiency validated by sequencing, qRT-PCR, and Western blot. Transcriptomic alterations were profiled by RNA-seq, and functional consequences were investigated via GO, KEGG, and GSEA analyses. Key findings were confirmed by qPCR, and phenotypes were assessed using CCK-8, EdU, and flow cytometry. The approach successfully generated a three-base insertion, resulting in near-complete loss of CH2 mRNA and Fel d1 protein. RNA-seq identified 3,469 differentially expressed genes (DEGs), with significant enrichment in pathways for hypertrophic cardiomyopathy (HCM) and rheumatoid arthritis (RA). Key genes in these pathways (e.g., Show less

Type 2 diabetes mellitus (T2DM) is a metabolic disorder that is characterized by insulin resistance and hyperglycemia. It is also known to be a risk factor for Alzheimer's disease (AD). Insulin plays a crucial role in regulating the body's metabolism and is responsible for activating the Phosphoinotide-3-Kinase (PI3K)/Protein Kinase B (Akt) signaling pathway. This pathway is activated when insulin binds to the insulin receptor on nerve cells, and it helps regulate the metabolism of glucose and lipids. Dysfunction in the insulin signaling pathway can lead to a decrease in brain insulin levels and insulin sensitivity, thereby inducing disruptions in insulin signal transduction and leading to disorders in brain energy metabolism. Moreover, these dysfunctions also contribute to the accumulation of β-amyloid (Aβ) deposition and the hyperphosphorylation of Tau protein, both of which are characteristic features of AD. Therefore, this article focuses on insulin resistance to reveal the complex mechanism between brain insulin resistance and AD occurrence in T2DM. On this basis, this article further summarizes the biological effects and mechanisms of antidiabetic drugs on the two diseases, aiming to provide new ideas for the discovery of drugs for the treatment of T2DM combined with AD. Show less

Altered expression and activity of solute carrier family 4 member 4 (SLC4A4) could affect the growth, survival and metastasis of tumor cells. Currently, the role of SLC4A4 in lung adenocarcinoma (LUAD) immunotherapy and prognosis was not entirely clear. We analyzed SLC4A4 expression in LUAD tissues and cell lines using quantitative reverse transcription-polymerase chain reaction, Western blotting, and immunohistochemistry. The effects of SLC4A4 overexpression on angiogenesis, cell migration, invasion, and epithelial-mesenchymal transition were examined. Public databases helped construct a risk model evaluating SLC4A4's expression on LUAD prognosis and immunotherapy response. Additionally, a xenograft model, flow cytometry, and enzyme-linked immunosorbent assay further explored SLC4A4's role in tumor immune microenvironment infiltration. Upregulation of SLC4A4 promoted apoptosis in the LUAD cell line and significantly inhibited the migration and invasive ability of cancer cells (P<0.01). A total of 10 key genes (including SIGLEC6, RHOV, PIR, MOB3B, MIR3135B, LPAR6, KRT8, ITGA2, CPS1, and C6) were screened according to SLC4A4 expression, immune score and stromal score, and a prognostic model with good outcome was constructed (AUC values of which in the training cohort at 1,3, and 5 years reached 0.73, 0.73, and 0.72, respectively). Importantly, we demonstrated that high expression of SLC4A4 was able to increase the proliferation level and cytokine secretion of CD8+ T cells for the purpose of promoting the immune system response to LUAD. Our study revealed that SLC4A4 can serve as a prognostic indicator for LUAD, providing new insights into the treatment and diagnosis of LUAD. Show less

Vps34 is the unique member of the class III phosphoinositide 3-kinase family that performs both vesicular transport and autophagy. Its role in natural killer (NK) cells remains uncertain. In this study, a model without Vps34 (Vps34 Show less

In Alzheimer's disease (AD) brain, inflammatory activation regulates protein levels of amyloid-β-peptide (Aβ) and phosphorylated tau (p-tau), as well as neurodegeneration; however, the regulatory mechanisms remain unclear. We constructed APP- and tau-transgenic AD mice with deletion of IKKβ specifically in neurons, and observed that IKKβ deficiency reduced cerebral Aβ and p-tau, and modified inflammatory activation in both AD mice. However, neuronal deficiency of IKKβ decreased apoptosis and maintained synaptic proteins (e.g., PSD-95 and Munc18-1) in the brain and improved cognitive function only in APP-transgenic mice, but not in tau-transgenic mice. Additionally, IKKβ deficiency decreased BACE1 protein and activity in APP-transgenic mouse brain and cultured SH-SY5Y cells. IKKβ deficiency increased expression of PP2A catalytic subunit isoform A, an enzyme dephosphorylating cerebral p-tau, in the brain of tau-transgenic mice. Interestingly, deficiency of IKKβ in neurons enhanced autophagy as indicated by the increased ratio of LC3B-II/I in brains of both APP- and tau-transgenic mice. Thus, IKKβ deficiency in neurons ameliorates AD-associated pathology in APP- and tau-transgenic mice, perhaps by decreasing Aβ production, increasing p-tau dephosphorylation, and promoting autophagy-mediated degradation of BACE1 and p-tau aggregates in the brain. However, IKKβ deficiency differently protects neurons in APP- and tau-transgenic mice. Further studies are needed, particularly in the context of interaction between Aβ and p-tau, before IKKβ/NF-κB can be targeted for AD therapies. Show less

South Asians (SAs) represent ∼25% of the world's population and account for >50% of global cardiovascular (CV) deaths, yet they continue to be underrepresented in contemporary clinical trials. The REDUCE-IT study demonstrated in a high-risk and predominantly White population that icosapent ethyl (IPE) lowered major adverse cardiovascular events by 25%. We sought to determine the generalizability of these results to a high-risk population of SAs with established CV disease living in Canada. This was a cross-sectional observational study of 200 statin-treated SAs (≥45 years) with atherosclerotic CV disease (ASCVD) (NCT05271591). SA ethnicity was self-identified as being of Anglo-Indian, Bangladeshi, Bengali, Bhutanese, Goan, Gujarati, Indian, Jatt, Kashmiri, Maharashtrian, Malayali, Nepali, Pakistani, Punjabi, Sindhi, Sinhalese, Sri Lankan, Tamil, Telugu, or other SA. ASCVD was defined as the presence of coronary, carotid, or peripheral atherosclerosis. Mean age of the cohort was 67 years, where 82% were men and 57% had diabetes. The predominant ASCVD phenotype was coronary artery disease (94%). Mean (SD) baseline LDL-C and triglycerides were 1.70 (0.8) mmol/L and 1.42 (1.0) mmol/L, respectively. Three-quarters were on high-intensity statin therapy. According to the Health Canada/Canadian Cardiovascular Society Guidelines and FDA-approved indication, 33% and 25% of the participants were, respectively, eligible for IPE. A large proportion of high-intensity, statin-treated, high-risk patients with ASCVD and of self-reported SA ethnicity are eligible for IPE. These data have important translational implications for SAs who are at a disproportionately higher risk of CV morbidity and mortality. This study was funded by an unrestricted grant provided by HLS Therapeutics Inc, Canada. Show less

Rab proteins are important components of small GTPases and play crucial roles in regulating intracellular transportation and cargo delivery. Maintaining the proper functions of Rab proteins is essential for normal cellular activities such as cell signaling, division, and survival. Due to their vital and irreplaceable role in regulating intracellular vesicle transportation, accumulated researches have shown that the abnormalities of Rab proteins and their effectors are closely related to human diseases. Here, this review focused on Rab21, a member of the Rab family, and introduced the structures and functions of Rab21, as well as the regulatory mechanisms of Rab21 in human diseases, including neurodegenerative diseases, cancer, and inflammation. In summary, we described in detail the role of Rab21 in human diseases and provide insights into the potential of Rab21 as a therapeutic target for diseases. Show less

Fascin actin-bundling protein 1 (FSCN1), an actin-bundling protein associated with cell migration and invasion, is highly expressed in various tumor tissues. FSCN1 has also been reported to be a marker of increased invasive potential in cervical cancers. However, the functions of FSCN1 are still not fully understood in cervical cancers. Here, the gene expression profile of HeLa cells transfected with FSCN1 shRNA (shFSCN1) was compared with that of cells transfected with empty vector (shCtrl). The results showed that shFSCN1 extensively affected the transcription level of 5,043 genes in HeLa cells. In particular, Gene Ontology (GO) analysis showed that a large number of upregulated genes were annotated with terms including transcription regulation and DNA binding. The downregulated genes were enriched in some cancer pathways, including angiogenesis and cell adhesion. qPCR validation confirmed that FSCN1 knockdown significantly affected the expression of selected genes in HeLa cells either negatively or positively. Expression analysis in TCGA (The Cancer Genome Atlas) revealed that FSCN1 had negative correlations with several transcription factors and a positive correlation with an angiogenic factor (angiopoietin like 4, Show less

Rab21 is a GTPase protein that is functional in intracellular trafficking and involved in the pathologies of many diseases, such as Alzheimer's disease (AD), glioma, cancer, etc. Our previous work has reported its interaction with the catalytic subunit of gamma-secretase, PS1, and it regulates the activity of PS1 via transferring it from the early endosome to the late endosome/lysosome. However, it is still unknown how Rab21 protein itself is regulated. This work revealed that Rab21 protein, either endogenously or exogenously, can be degraded by the ubiquitin-proteasome pathway and the autophagy-lysosome pathway. It is further observed that the ubiquitinated Rab21 is increased, but the total protein is unchanged in AD model mice. We further observed that overexpression of Rab21 leads to increased expression of a series of genes involved in the autophagy-lysosome pathway. We speculated that even though the ubiquitinated Rab21 is increased due to the impaired proteasome function in the AD model, the autophagy-lysosome pathway functions in parallel to degrade Rab21 to keep its protein level in homeostasis. In conclusion, understanding the characters of Rab21 protein itself help explore its potential as a target for therapeutic strategy in diseases. Show less

To determine the prevalence of Melanocortin-4 Receptor (MC4R) mutations in a cohort of children and adolescents with overweight or obesity and to determine whether treatment responses differed between carriers and noncarriers. Using target region capture sequencing, an MC4R mutation screen was performed in 1261 Danish children and adolescents enrolled at a tertiary multidisciplinary childhood obesity treatment center. Measurements of anthropometrics, blood pressure, fasting blood biochemistry including lipid and hormone levels, and dual-energy X-ray absorptiometry were performed at baseline and throughout treatment. Of 1209 children and adolescents that met all criteria to be included in the described analyses, 30 (2.5%) carried damaging or unresolved MC4R mutations. At baseline, mutation carriers exhibited higher concentrations of plasma thyroid-stimulating hormone (p = 0.003), and lower concentrations of plasma thyroxine (p = 0.010) compared to noncarriers. After a median of 1 year of treatment (range 0.5-4.0 years), body mass index (BMI) standard deviation score (SDS) was reduced in noncarriers but not in carriers, and this difference in treatment response was statistically significant (p = 0.005). Furthermore, HDL cholesterol was reduced in carriers, a response significantly different from that of noncarriers (p = 0.017). Among Danish children and adolescents with overweight or obesity entering a tertiary lifestyle intervention, 2.5% carried damaging or unresolved MC4R mutations. In contrast to noncarriers, carriers of damaging or unresolved MC4R mutations failed to reduce their BMI SDS during obesity treatment, indicating a need for personalized treatment based on the MC4R genotype. Show less

Exposure to the antibacterial agent triclosan (TCS) is associated with abnormal placenta growth and fetal development during pregnancy. Peroxisome proliferator-activated receptor γ (PPARγ) is crucial in placenta development. However, the mechanism of PPARγ in placenta injury induced by TCS remains unknown. Herein, we demonstrated that PPARγ worked as a protector against TCS-induced toxicity. TCS inhibited cell viability, migration, and angiogenesis dose-dependently in HTR-8/SVneo and JEG-3 cells. Furthermore, TCS downregulated expression of PPARγ and its downstream viability, migration, angiogenesis-related genes Show less

Adenomyosis (ADS) is an estrogen-dependent gynecological disease with unspecified etiopathogenesis. Local hyperestrogenism may serve a key role in contributing to the origin of ADS. Talin1 is mostly identified to be overexpressed and involved in the progression of numerous human carcinomas through mediating cell proliferation, adhesion and motility. Whether Talin1 exerts an oncogenic role in the pathogenesis of ADS and puts an extra impact on the efficacy of estrogen, no relevant data are available yet. Here we demonstrated that the adenomyotic eutopic and ectopic endometrial stromal cells (ADS_Eu_ESC and ADS_Ec_ESC) treated with β-estradiol (β-E Show less

Tetraspanin CD63 has been widely implicated in tumour progression of human malignancies. However, its role in the tumorigenesis and metastasis of hepatocellular carcinoma (HCC) remains unclear yet. In the present study, we aimed to investigate the specific function and underlying mechanisms of CD63 in HCC progression. CD63 expression in HCC tissues was detected using immunohistochemistry and quantitative real-time PCR analyses; effects of CD63 on HCC cell proliferation and migration were investigated by CCK-8 assay, colony formation assay, transwell assay and a xenograft model of nude mice. RNA-sequencing, bioinformatics analysis, dual-luciferase reporter assay and Western blot analysis were performed to explore the underlying molecular mechanisms. Results of our experiments showed that CD63 expression was frequently reduced in HCC tissues compared with adjacent normal tissues, and decreased CD63 expression was significantly associated with larger tumour size, distant site metastasis and higher tumour stages of HCC. Overexpression of CD63 inhibited HCC cell proliferation and migration, whereas knockdown of CD63 promoted these phenotypes. IL-6, IL-27 and STAT3 activity was regulated by CD63, and blockade of STAT3 activation impaired the promotive effects of CD63 knockdown on HCC cell growth and migration. Our findings identified a novel CD63-IL-6/IL-27-STAT3 axis in the development of HCC and provided a potential target for the diagnosis and treatment of this disease. Show less

Branched-chain α-keto acid dehydrogenase kinase (BCKDK), the key enzyme of branched-chain amino acids (BCAAs) metabolism, has been reported to promote colorectal cancer (CRC) tumorigenesis by upregulating the MEK-ERK signaling pathway. However, the profile of BCKDK in metastatic colorectal cancer (mCRC) remains unknown. Here, we report a novel role of BCKDK in mCRC. BCKDK is upregulated in CRC tissues. Increased BCKDK expression was associated with metastasis and poor clinical prognosis in CRC patients. Knockdown of BCKDK decreased CRC cell migration and invasion ex vivo, and lung metastasis in vivo. BCKDK promoted the epithelial mesenchymal transition (EMT) program, by decreasing the expression of E-cadherin, epithelial marker, and increasing the expression of N-cadherin and Vimentin, which are mesenchymal markers. Moreover, BCKDK-knockdown experiments in combination with phosphoproteomics analysis revealed the potent role of BCKDK in modulating multiple signal transduction pathways, including EMT and metastasis. Src phosphorylated BCKDK at the tyrosine 246 (Y246) site in vitro and ex vivo. Knockdown and knockout of Src downregulated the phosphorylation of BCKDK. Importantly, phosphorylation of BCKDK by Src enhanced the activity and stability of BCKDK, thereby promoting the migration, invasion, and EMT of CRC cells. In summary, the identification of BCKDK as a novel prometastatic factor in human CRC will be beneficial for further diagnostic biomarker studies and suggests novel targeting opportunities. Show less

BACKGROUND Alzheimer disease (AD) is a typical progressive and destructive neurodegenerative disease that has been studied extensively. However, genetic features and molecular mechanisms underlying AD remain unclear. Here we used bioinformatics to investigate the candidate nuclear genes involved in the molecular mechanisms of AD. MATERIAL AND METHODS First, we used Gene Expression Omnibus (GEO) database to obtain the expression profiles of the mRNAs from hippocampus microarray and identify differentially expressed genes (DEGs) the plier algorithm. Second, functional annotation and visualization of the DEGs were conducted by the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Finally, BioGRID, IntAct, STRING, and Cytoscape were utilized to construct a protein-protein interaction (PPI) network. Hub genes were analytically obtained from the PPI network and the microRNA (miRNA)-target network. RESULTS Two hippocampus microarrays (GSE5281 and GSE48350) were obtained from the GEO database, comprising 161 and 253 cases separately. Among these, 118 upregulated genes and 694 downregulated genes were identified. The upregulated DEGs were mainly involved in positive regulation of transcription from RNA polymerase II promoter, positive regulation of cartilage development, and response to wounding. The downregulated DEGs were enriched in chemical synaptic transmission, neurotransmitter secretion, and learning. By combining the results of PPI and miRNA-target network, 8 genes and 2 hub miRNAs were identified, including YWHAZ, DLG4, AGAP2, EGFR, TGFBR3, PSD3, RDX, BRWD1, and hsa-miR-106b-5p and hsa-miR-93-5p. These target genes are highly enriched in various key pathways, such as amyloid-beta formation, regulation of cardiocyte differentiation, and actin cytoskeleton reorganization. CONCLUSIONS In this study, YWHAZ, DLG4, AGAP2, EGFR, TGFBR3, PSD3, RDX, and BRWD1 were identified as candidate genes for future molecular studies in AD, which is expected to improve our understanding of its cause and potential molecular mechanisms. Nuclear genes, DEGs, and related networks identified by integrated bioinformatics analysis may serve as diagnostic and therapeutic targets for AD. Show less

Neuroplasticity and connectivity in the central nervous system (CNS) are easily damaged after hypoxia. Long-term exposure to an anoxic environment can lead to neuropsychiatric symptoms and increases the likelihood of depression. Demyelination is an important lesion of CNS injury that may occur in depression. Previous studies have found that the RhoA/ROCK pathway is upregulated in neuropsychiatric disorders such as multiple sclerosis, stroke, and neurodegenerative diseases. Therefore, the chief aim of this study is to explore the regulatory role of the RhoA/ROCK pathway in the development of depression after hypoxia by behavioral tests, Western blotting, immunostaining as well as electron microscopy. Results showed that HIF-1α, S100β, RhoA/ROCK, and immobility time in FST were increased, sucrose water preference ratio in SPT was decreased, and the aberrant activity of neurocyte and demyelination occurred after hypoxia. After the administration of Y-27632 and fluoxetine in hypoxia, these alterations were improved. Lingo1, a negative regulatory factor, was also overexpressed after hypoxia and its expression was decreased when the pathway blocked. However, fluoxetine had no effect on the expression of Lingo1. Then, we demonstrated that demyelination was associated with failures of oligodendrocyte precursor cell proliferation and differentiation and increased apoptosis of oligodendrocytes. Collectively, our data indicate that the RhoA/ROCK pathway plays a vital role in the initial depression during hypoxia. Blocking this pathway in the early stage of hypoxia can enhance the effectiveness of antidepressants, rescue myelin damage, and reduce the expression of the negative regulatory protein of myelination. The findings provide new insight into the prophylaxis and treatment of depression. Show less