👤 Ye Pan

The gut microbiota influences host immunity and metabolism, and changes in its composition and function have been implicated in several non-communicable diseases. Here, comparing germ-free (GF) and specific pathogen-free (SPF) mice using spatial transcriptomics, single-cell RNA sequencing, and targeted bile acid metabolomics across multiple organs, we systematically assessed how the gut microbiota's absence affected organ morphology, immune homeostasis, bile acid, and lipid metabolism. Through integrated analysis, we detect marked aberration in B, myeloid, and T/natural killer cells, altered mucosal zonation and nutrient uptake, and significant shifts in bile acid profiles in feces, liver, and circulation, with the alternate synthesis pathway predominant in GF mice and pronounced changes in bile acid enterohepatic circulation. Particularly, autophagy-driven lipid droplet breakdown in ileum epithelium and the liver's zinc finger and BTB domain-containing protein (ZBTB20)-Lipoprotein lipase (LPL) (ZBTB20-LPL) axis are key to plasma lipid homeostasis in GF mice. Our results unveil the complexity of microbiota-host interactions in the crosstalk between commensal gut bacteria and the host. Show less

Our previous studies have shown that miR-130b can significantly inhibit subcutaneous fat deposition in pigs. This study aims to further investigate its effect on lipid accumulation at early-stage (24 and 48 h) and late-stage (7 d) adipogenic differentiation and to clarify potential mechanisms using primary rat intramuscular preadipocytes (IMAs). Results showed that at 24 h and 48 h, miR-130b overexpression significantly reduced lipid deposition by inhibiting proliferation and inducing apoptosis. Furthermore, miR-130b overexpression significantly inhibited the expression of cell cycle and apoptosis marker genes. Specifically, the mRNA expression of Show less

Phenotypic heterogeneity is apparent among individuals with putative monogenic disease, such as familial hypertrophic cardiomyopathy. Genome sequencing (GS) allows interrogation of the full spectrum of inborn genetic variation in an individual and RNA profiling provides a snapshot of the cardiac-specific pathogenic effects on gene expression. Identify candidate genetic modifiers of hypertrophic cardiomyopathy phenotype. We performed GS of 48 individuals with variants in GS identified the Evaluation of the whole genome, even in the case of alleged monogenic disease, leads to important new insights. The identified variants, regions, and genes are candidates to modify disease presentation in cardiomyopathy. Show less

Lung squamous cell carcinoma (LUSC) is a highly aggressive malignancy with limited targeted therapies and poor clinical outcomes. Ferroptosis, an iron-dependent form of regulated cell death, plays a crucial role in tumor progression, metabolic reprogramming, and immune modulation. Increasing evidence suggests that dysregulation of ferroptosis contributes to therapeutic resistance and immune escape in various cancers. MYO19, a mitochondrial trafficking protein, has recently been implicated in oxidative stress and metabolic control, but its role in ferroptosis and tumor immunity remains unclear. Meanwhile, microRNAs (miRNAs) are recognized as key post-transcriptional regulators in cancer biology. Among them, hsa-miR-520a-3p has been reported to exhibit tumor-suppressive functions in several malignancies. However, the interplay between hsa-miR-520a-3p and MYO19, and their potential involvement in ferroptosis regulation and immune modulation in LUSC, has not been systematically investigated. Data were collected from TCGA, UCSC XENA, ENCORI, HPA, and UALCAN public database. Differential expression, prognostic, correlation analyses and miRNA analyses were performed using bioinformatics tools including TIMER, TISIDB, Kaplan-Meier Plotter, and ENCORI. Ferroptosis-related analysis utilized Ze-Xian Liu's dataset. Functional assays, including CCK-8 viability, Transwell migration, and MDA/GSH measurements, were performed in NCI-H226 and NCI-H2170 cells after transfection with miR-520a-3p mimics/inhibitors or MYO19 knockdown/overexpression constructs. Ferroptosis sensitivity was further tested under RSL3 treatment, and ferroptosis protein markers as well as rescue experiments were analyzed by Western blotting. The result revealed that MYO19 was significantly upregulated in multiple tumor types and correlated with unfavorable prognosis. Especially in LUSC, elevated MYO19 expression was associated with advanced stage, reduced immune infiltration, and enrichment of ferroptosis-resistant transcriptional programs, whereas hsa-miR-520a-3p showed opposite patterns. Overexpression of hsa-miR-520a-3p in NCI-H226 and NCI-H2170 cells increased lipid peroxidation (MDA increased), reduced intracellular GSH, and enhanced RSL3-induced cytotoxicity, indicative of ferroptosis activation. Conversely, MYO19 knockdown elevated ACSL4 and reduced SLC7A11, changes that were partially reversed by MYO19 re-expression. These findings suggest that the hsa-miR-520a-3p/MYO19 axis is associated with ferroptosis susceptibility and may influence the immunosuppressive tumor microenvironment. Show less

Impaired excretion of lipid deposits within vascular smooth muscle cell-derived foam cells (VSMC-FCs) contributes to the ongoing expansion of the plaque necrotic core. This study aims to explore the effects and underlying mechanisms of exosomes secreted by M2 macrophage (M2-exos) on lipid metabolism of VSMC-FCs and plaque stability. First, immunofluorescence was used to detect the expression levels of CD45 (a recognized differentially-expressed molecule of myeloid and VSMC-FCs) and the key proteins of cholesterol efflux pathway, ABCA1 and ABCG1, in human early and late plaques. Next, an in vitro foam cell model was used to assess the effect and mechanism of M2-exos on lipid metabolism in vascular smooth muscle cells by western blot, Oil red O staining and cell total cholesterol assays. RNA-seq and quantitative real-time PCR were employed to characterize the miRNA profiles within M2-exos. The dual-luciferase reporting system and gene silencing approaches were utilized to assess the regulatory effect of candidate miRNA on target genes and signaling pathways. Subsequently, the effect of M2-exos on plaque progression and stability in ApoE Immunofluorescence revealed that compared to early plaques, VSMC-FCs (CD45 M2-exos exerted an obvious atherosclerotic protective effect, and the underlying mechanism was closely related to MiR-7683-3p, which targeted the 3'UTR of HOXA1 mRNA and activated the PPARγ-LXRα-ABCG1 mediated cholesterol efflux in VSMC-FCs. Show less

The Kirgiz, a Turkic-speaking ethnic group with a rich nomadic heritage, represent a pivotal population for understanding human migration and adaptation in Central Asia. However, their genetic origins and admixture history remain largely unexplored. Here, we present the first comprehensive genomic study of Kirgiz populations from Xinjiang, China (XJ.KGZ, n = 36) and their counterparts in Kyrgyzstan (KRG), integrating genome-wide data of 2,406 global individuals. Our analyses reveal four primary ancestry components in XJ.KGZ: East Asian (41.7%), Siberian (25.6%), West Eurasian (25.2%), and South Asian (7.6%). Despite close genetic affinity (FST = 0.13%), XJ.KGZ and KRG diverged ∼447 years ago, with limited gene flow post-split. A two-wave admixture model elucidates their demographic history: an initial East-West Eurasian mixture ∼2,225 years ago, likely reflecting west-east contacts during the period of the Warring States and the Qin Dynasty, followed by secondary admixture events (∼875 to 425 years ago) linked to historical migrations under Mongol and post-Mongol rule. Local adaptation signatures implicate genes critical for cellular tight junction (e.g. PATJ), pathogen invasion (e.g. OR14I1), and cardiac functions (e.g. RYR2) with allele frequency deviations suggesting ancestry-specific selection. While no classical high-altitude adaptation genes (e.g. EPAS1) showed selection signals, RYR2 and C10orf67-implicated in hypoxia response in Tibetan fauna-displayed Western ancestry bias, hinting at convergent adaptation mechanisms. This study advances our understanding of the genetic makeup and admixture history of the Kirgiz people and provides novel insights into human dispersal in Central Asia. Show less

Colorectal cancer (CRC) is a globally prevalent malignancy associated with high mortality rates. Despite the existence of various treatment modalities, the prognosis for CRC remains relatively poor. This study aims to explore the role of RNA-binding proteins (RBPs) in CRC progression and their potential as prognostic biomarkers and therapeutic targets. We first identified 166 prognosis-related RBPs, including LIN28B, PPARGC1A, RBM47, and AFF3, by performing univariate Cox regression analysis on bulk transcriptomic and clinical data from The Cancer Genome Atlas (TCGA). Next, single-cell RNA sequencing data from normal, adenoma, and CRC tissues of four patients were analyzed to determine cell type-specific expression patterns of RBPs. Ten upregulated RBPs (HSPB1, RBM47, HMGN2, BRD2, BST2, RBM6, YBX3, CANX, PLEC, and RNASET2) were identified as CRC-associated. Among them, HSPB1, RBM47, HMGN2, BRD2, BST2, and PLEC were predominantly expressed in epithelial cell subsets, whereas RNASET2, RBM6, YBX3, and G3BP2 showed higher expression in T cell subpopulations. Aberrant expression of these RBPs was significantly associated with clinical features such as age, cancer stage, and overall survival ( The online version contains supplementary material available at 10.1038/s41598-025-29678-9. Show less

Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone secreted by K cells in the small intestine and is considered an obesity-promoting factor. In this study, we systematically investigated the anti-obesity effects of intragastric safflower yellow (SY)/hydroxysafflor yellow A (HSYA) and the underlying mechanism for the first time. Our results showed that intragastric SY/HSYA, rather than an intraperitoneal injection, notably decreased serum GIP levels and GIP staining in the small intestine in diet-induced obese (DIO) mice. Moreover, intragastric SY/HSYA was also first found to significantly suppress GIP receptor (GIPR) signaling in both the hypothalamus and subcutaneous White adipose tissue. Our study is the first to show that intragastric SY/HSYA obviously reduced food intake and body weight gain in leptin sensitivity experiments and decreased serum leptin levels in DIO mice. Further experiments demonstrated that SY treatment also significantly reduced leptin levels, whereas the inhibitory effect of SY on leptin levels was reversed by activating GIPR in 3 T3-L1 adipocytes. In addition, intragastric SY/HSYA had already significantly reduced serum GIP levels and GIPR expression before the serum leptin levels were notably changed in high-fat-diet-fed mice. These findings suggested that intragastric SY/HSYA may alleviate diet-induced obesity in mice by ameliorating hyperleptinemia via dual inhibition of the GIP-GIPR axis. Show less

To explore the prevalence and associated factors of obesity in Tibetan adults in Qinghai, China, and to determine the association between the FTO (rs1121980 and rs17817449) and MC4R gene (rs17782313 and rs12970134) polymorphisms with obesity. A cross-sectional survey was conducted in 2015 in Qinghai to selected Tibetan adults aged 20 to 80 years. Prevalence of obesity (BMI ≥ 28 kg/m A total of 1741 Tibetan adults were enrolled. The age- and sex- standardized prevalence of obesity and overweight was 18.09% and 31.71%, respectively. Male sex, older age, heavy level of leisure-time exercise, current smoke, and heavy level of occupational physical activity were associated with both obesity and overweight. MC4R gene polymorphisms were associated with obesity in Tibetan adults. No significant gene-environment interaction was detected. The prevalence of obesity and overweight in Tibetan adults was high. Both environmental and genetic factors contributed to the obesity prevalent. Show less

It is crucial to understand the glucose control within our bodies. Bariatric/metabolic surgeries, including laparoscopic sleeve gastrectomy (LSG) and Roux-en-Y gastric bypass (RYGB), provide an avenue for exploring the potential key factors involved in maintaining glucose homeostasis since these surgeries have shown promising results in improving glycemic control among patients with severe type 2 diabetes (T2D). For the first time, a markedly altered population of serum proteins in patients after LSG was discovered and analyzed through proteomics. Apolipoprotein A-IV (apoA-IV) was revealed to be increased dramatically in diabetic obese patients following LSG, and a similar effect was observed in patients after RYGB surgery. Moreover, recombinant apoA-IV protein treatment was proven to enhance insulin secretion in isolated human islets. These results showed that apoA-IV may play a crucial role in glycemic control in humans, potentially through enhancing insulin secretion in human islets. ApoA-IV was further shown to enhance energy expenditure and improve glucose tolerance in diabetic rodents, through stimulating glucose-dependent insulin secretion in pancreatic β cells, partially via Gαs-coupled GPCR/cAMP (G protein-coupled receptor/cyclic adenosine monophosphate) signaling. Furthermore, T55-121, truncated peptide 55-121 of apoA-IV, was discovered to mediate the function of apoA-IV. These collective findings contribute to our understanding of the relationship between apoA-IV and glycemic control, highlighting its potential as a biomarker or therapeutic target in managing and improving glucose regulation. Show less

The impact of lipid-lowering medications on chronic kidney disease (CKD) remains a subject of debate. This Mendelian randomization (MR) study aims to elucidate the potential effects of lipid-lowering drug targets on CKD development. We extracted 11 genetic variants encoding targets of lipid-lowering drugs from published genome-wide association study (GWAS) summary statistics, encompassing LDLR, HMGCR, PCSK9, NPC1L1, APOB, ABCG5/ABCG8, LPL, APOC3, ANGPTL3, and PPARA. A Mendelian randomization analysis was conducted targeting these drug-related genes. CKD risk was designated as the primary outcome, while estimated glomerular filtration rate (eGFR) and blood urea nitrogen (BUN) were assessed as secondary outcomes. Additionally, mediation analysis was performed utilizing 731 immune cell phenotypes to identify potential mediators. The meta-analysis revealed a significant association between ANGPTL3 inhibitors and a reduced risk of CKD (OR [95% CI] = 0.85 [0.75-0.96]). Conversely, LDLR agonists were significantly linked to an increased risk of CKD (OR [95% CI] = 1.11 [1.02-1.22]). Regarding secondary outcomes, lipid-lowering drugs did not significantly affect eGFR and BUN levels. Mediation analysis indicated that the reduction in CKD risk by ANGPTL3 inhibitors was mediated through modulation of the immune cell phenotype, specifically HLA-DR on CD14+ CD16+ monocytes (Mediated proportion: 4.69%; Mediated effect: -0.00899). Through drug-targeted MR analysis, we identified a causal relationship between lipid-lowering drug targets and CKD. ANGPTL3 and LDLR may represent promising candidate drug targets for CKD treatment. Show less

Frailty is an emerging global burden of disease, characterized as an age-related clinical syndrome. Recent studies have suggested a potential link of circulating protein levels with the onset of frailty. This study aims to analyze the potential causal relationships of plasma proteins with frailty using a Mendelian Randomization (MR) study design. Associations of plasma proteins with frailty were assessed using inverse variance weighted (IVW), MR-Egger regression, weighted median, maximum-likelihood method, and MR-PRESSO test. Protein-protein interaction network construction and gene ontology functional enrichment analysis were conducted based on MR-identified target proteins. After false discovery rate (FDR) correction, MR analysis identified five plasma proteins, including BIRC2 [OR = 0.978, 95%CI (0.967-0.990)] and PSME1 [OR = 0.936, 95%CI (0.909-0.965)], as protective factors against frailty, and 49 proteins, including APOB [OR = 1.053, 95%CI (1.037-1.069)] and CYP3A4 [OR = 1.098, 95%CI (1.068-1.128)], as risk factors. Network analysis suggested BIRC2, PSME1, APOE, and CTNNB1 as key intervention targets. This study employed MR design to investigate the association of circulating plasma proteins with frailty, identified five proteins negatively associated with frailty risk and 49 proteins positively associated with frailty. Show less

Stable angina pectoris, resulting from coronary artery atherosclerosis, significantly affects quality of life and carries a high risk of cardiovascular events. Despite modern therapies, managing this condition remains challenging. Traditional Chinese medicine (TCM) views it as a syndrome of heart meridian obstruction by phlegm and blood stasis, necessitating improved circulation and phlegm resolution. This study aims to evaluate the efficacy of Jiangzhi Mai'an Granules, a TCM formulation, in treating stable angina pectoris and carotid atherosclerosis, with the goal of integrating TCM with Western medicine to enhance clinical outcomes and patients' quality of life. A total of 120 patients diagnosed with stable angina pectoris and carotid atherosclerotic plaques of the phlegm and blood stasis types were randomly divided into 2 groups. The control group (n = 60) received standard Western medical treatment, whereas the treated group (n = 60) received JZMA in addition to the standard regimen. The treatment duration in both the groups was 3 months. The outcomes measured included carotid intima-media thickness (CIMT), carotid plaque dimensions, TCM syndrome scores, and serum lipid profiles (total cholesterol [TC], triglycerides [TG], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], apolipoprotein B [Apo B], and non-HDL-C) and lipoprotein phospholipase A2 (Lp-PLA2) levels before and after treatment. The treated group achieved a total efficacy rate of 93.3% (56/60), which surpassed the control group rate of 78.3% (47/60). The CIMT, carotid plaque thickness, and area in the treated group were significantly reduced posttreatment compared to baseline (P < .05) and were also lower than those in the control group (P < .05). Serum lipid levels, including TC, TG, LDL-C, ApoB and non-HDL-C were significantly decreased in both groups posttreatment (P < .05), and the treated group showed a further increase in HDL-C levels (P < .05). The treated group exhibited lower serum lipid levels than the control group posttreatment (P < .05). The TCM syndrome scores improved significantly in both groups after treatment (P < .05), with the treated group demonstrating a more pronounced reduction in scores than the control group (P < .05). The incidence of adverse events did not differ significantly between the 2 groups. JZMA combined with standard treatment effectively reduced CIMT, plaque size, and serum lipid levels, thereby enhancing clinical outcomes in patients with stable angina and carotid atherosclerosis. Show less

Despite the exploration of the connections between serum low-density lipoprotein cholesterol (LDL-C) levels and aneurisms in epidemiological studies, causality remains unclear. Therefore, this study aimed to assess the causal impact of LDL-C-lowering targets (HMGCR, PCSK9, NPC1L1, CETP, APOB, and LDLR) on various forms of aneurisms using Mendelian Randomization (MR) analysis. Two genetic instruments acted as proxies for exposure to LDL-C-lowering drugs: expression quantitative trait loci of drug target genes and genetic variants linked to LDL-C near drug target genes. Summary-data-based MR (SMR), inverse-variance-weighted MR (IVW-MR), and multivariable MR (MVMR) methods were employed to compute the effect estimates. The SMR analysis revealed substantial associations between increased HMGCR expression and a heightened risk of aortic aneurism (odds ratio [OR] = 1.603, 95% confidence interval [CI] = 1.209-2.124), thoracic aortic aneurism (OR = 1.666, 95% CI = 1.122-2.475), and abdominal aortic aneurism (OR = 1.910, 95% CI = 1.278-2.856). Likewise, IVW-MR analysis demonstrated positive correlations between HMGCR-mediated LDL-C and aortic aneurism (OR = 2.228, 95% CI = 1.702-2.918), thoracic aortic aneurism (OR = 1.751, 95% CI = 1.191-2.575), abdominal aortic aneurism (OR = 4.784, 95% CI = 3.257-7.028), and cerebral aneurism (OR = 1.993, 95% CI = 1.277-3.110). Furthermore, in the MVMR analysis, accounting for body mass index, smoking, and hypertension, a significant positive relationship was established between HMGCR-mediated LDL-C levels and the development of aortic aneurisms, encompassing both thoracic and abdominal subtypes. Similarly, consistent positive associations were observed for PCSK9 and CETP genes, as well as PCSK9-mediated and CETP-mediated LDL-C levels, with the occurrence of aortic aneurism and abdominal aortic aneurism. Nonetheless, the evidence for potential associations between APOB, NPC1L1 and LDLR with specific subtypes of aortic aneurisms lacked consistent support from both SMR and IVW-MR analyses. Our MR analysis offered compelling evidence of a plausible causal link between HMGCR and an increased risk of aortic aneurism, encompassing both thoracic and abdominal types. These groundbreaking findings further bolster the case for the deployment of HMGCR inhibitors in the treatment of aortic aneurisms, including both thoracic and abdominal variants. Show less

The relationship between atherogenic lipoproteins and subclinical coronary atherosclerosis has not been thoroughly evaluated in low-risk adults. The purpose of this study was to assess the association of low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (HDL-C), and apolipoprotein B (apoB) with coronary atherosclerosis in adults without traditional risk factors. We assessed atherosclerosis on coronary computed tomography angiography among asymptomatic adults in the Miami Heart Study not taking lipid-lowering therapy and without hypertension, diabetes, or active tobacco use. Prevalence of atherosclerosis was evaluated based on serum LDL-C, non-HDL-C, and apoB, and multivariable logistic regression with forward selection was used to assess variables associated with coronary plaque. Among 1,033 adults 40 to 65 years of age, 55.0% were women and 86.3% had estimated 10-year atherosclerotic cardiovascular disease risk <5%. Coronary atherosclerosis prevalence was 35.9% (50.6% in men; 23.8% in women) and 3.4% had ≥1 high-risk plaque feature. Atherosclerosis prevalence increased with LDL-C, ranging from 13.2% in adults with LDL-C <70 mg/dL up to 48.2% with ≥160 mg/dL. Higher LDL-C (adjusted OR [aOR]: 1.13 [95% CI: 1.08-1.18] per 10 mg/dL), age (aOR: 1.43 [95% CI: 1.28-1.60] per 5 years), male sex (aOR: 3.81 [95% CI: 2.86-5.10]), and elevated lipoprotein(a) (aOR: 1.46 [95% CI: 1.01-2.09]) were associated with atherosclerosis. Higher serum non-HDL-C and apoB were similarly associated with atherosclerosis. In adults with optimal risk factors, 21.2% had atherosclerosis with greater prevalence at higher lipoprotein levels. Among asymptomatic middle-aged adults without traditional risk factors, coronary atherosclerosis is common and increasingly prevalent at higher levels of atherogenic lipoproteins. These findings emphasize the importance of lipid-lowering strategies to prevent development and progression of atherosclerosis regardless of risk factors. Show less

Despite centuries of traditional use of silymarin for hepatoprotection, current randomized controlled trial (RCT) studies on the effectiveness of silymarin in managing metabolic dysfunction-associated steatotic liver disease (MASLD) are limited and inconclusive, particularly when it is administered alone. The low bioavailability of silymarin highlights the possible influence of gut microbiota on the effectiveness of silymarin; however, no human studies have investigated this aspect. To determine the potential efficacy of silymarin in improving MASLD indicators and to investigate the underlying mechanisms related to gut microbiota. In this 24-week randomized, double-blind, placebo-controlled trial, 83 patients with MASLD were randomized to either placebo (n = 41) or silymarin (103.2 mg/d, n = 42). At 0, 12, and 24 weeks, liver stiffness and hepatic steatosis were assessed using FibroScan, and blood samples were gathered for biochemical detection, while faecal samples were collected at 0 and 24 weeks for 16S rRNA sequencing. Silymarin supplementation significantly reduced liver stiffness (LSM, -0.21 ± 0.17 vs. 0.41 ± 0.17, P = 0.015) and serum levels of γ-glutamyl transpeptidase (GGT, -8.21 ± 3.01 vs. 1.23 ± 3.16, P = 0.042) and ApoB (-0.02 ± 0.03 vs. 0.07 ± 0.03, P = 0.023) but had no significant effect on the controlled attenuation parameter (CAP), other biochemical indicators (aminotransferases, total bilirubin, glucose and lipid parameters, hsCRP, SOD, and UA), physical measurements (DBP, SBP, BMI, WHR, BF%, and BMR), or APRI and FIB-4 indices. Gut microbiota analysis revealed increased species diversity and enrichment of Oscillospiraceae in the silymarin group. These findings suggest that silymarin supplementation could improve liver stiffness in MASLD patients, possibly by modulating the gut microbiota. The trial was registered at the Chinese Clinical Trial Registry (ChiCTR2200059043). Show less

Apolipoprotein C3 (APOC3) plays a critical role in regulating triglyceride levels and serves as a key predictor of cardiovascular disease (CVD) risk, particularly in patients with diabetes. While APOC3 is known to inhibit lipoprotein lipase, recent findings reveal its broader influence across lipoprotein metabolism, where it modulates the structure and function of various lipoproteins. Therefore, this review examines the complex metabolic cycle of APOC3, emphasizing the impact of APOC3-containing lipoproteins on human metabolism, particularly in patients with diabetes. Notably, APOC3 affects triglyceride-rich lipoproteins and causes structural changes in high-, very low-, intermediate-, and low-density lipoproteins, thereby increasing CVD risk. Evidence suggests that elevated APOC3 levels-above the proposed safe range of 10-15 mg/dL-correlate with clinically significant CVD outcomes. Recognizing APOC3 as a promising biomarker for CVD, this review underscores the urgent need for high-throughput, clinically feasible methods to further investigate its role in lipoprotein physiology in both animal models and human studies. Additionally, we analyze the relationship between APOC3-related genes and lipoproteins, reinforcing the value of large-population studies to understand the impact of APOC3 on metabolic diseases. Ultimately, this review supports the development of therapeutic strategies targeting APOC3 reduction as a preventive approach for diabetes-related CVD. Show less

Dyslipidemia is a recognized risk factor for type 2 diabetes (T2D), yet the genetic basis and causal nature remain unclear, particularly in Chinese populations. The authors investigated the causal effects of genetically predicted lipid levels on T2D risk and explored the potential effects of lipid-modifying drugs. Leveraging data from the Kunshan Community cohort in China, we analyzed the associations between low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides (TGs) with T2D risk using genetic risk scores, 1-sample univariable, multivariable, and nonlinear Mendelian randomization (MR) analyses. Two-sample MR using summary-level data from Global Lipid Genetics Consortium and Biobank Japan was used for validation. Drug-target MR was used to examine the impact of lipid-modifying drug targets on T2D. Lower genetic risk scores of LDL-C (OR per SD: 0.97 [95% CI: 0.95-0.99]; Our findings suggested potential adverse effects of lower LDL-C, TG levels, as well as long-term use of APOC3 inhibitors on T2D risk in Chinese populations. These findings highlight the need for cautious lipid management strategies in T2D prevention. Show less

Mixed hyperlipidemia represents a substantial public health issue and a considerable burden on healthcare systems. Although the introduction of statins and LDL-cholesterol lowering agents have significantly reduced the incidence of atherosclerotic cardiovascular diseases (ASCVD), a significant portion of the population continues to exhibit ASCVD progression due to elevated triglyceride-rich lipoprotein (TRL) levels. This persistent risk has catalyzed the development of novel pharmacological interventions targeting these lipoproteins. Our special report commenced with a targeted PubMed search using keywords such as 'plozasiran,' 'zodasiran,' and terms related to APOC3 and ANGPTL3. As the review progressed, emergent research questions guided further searches, allowing for the inclusion of additional relevant articles to comprehensively illustrate the linkage between TRLs and cardiovascular disease, discuss the roles of APOC3, ANGPTL3, and the pharmaceutical agents that target these proteins, and provide a comparison on the ARCHES-2 and MUIR trials. The ARCHES-2 and MUIR trials demonstrated effective triglyceride reduction by these therapies, yet it is uncertain if this correlates with significant clinical benefits. Advances in antisense oligonucleotide technology, especially the GalNAc delivery platform, show promise for personalized lipid management, though challenges such as cost and safety concerns remain. Show less

Links have been reported between the airflow limitation and both metabolic syndrome (MetS) and fatty liver (FL). Additionally, associations between genetic factors and risks of MetS, FL, and airflow limitation have been identified separately in different studies. Our study aims to simultaneously explore the association between specific single nucleotide polymorphisms (SNPs) of certain genes and the risk of the three associated diseases. In this retrospective cross-sectional nationwide study, 150,709 participants from the Taiwan Biobank (TWB) were enrolled. We conducted a genotype-phenotype association analysis of nine SNPs on seven genes (ApoE-rs429358, MBOAT7-rs641738, LEPR-rs1805096, APOC3-rs2854116, APOC3-rs2854117, PPP1R3B-rs4240624, PPP1R3B-rs4841132, TM6SF2-rs58542926, and IFNL4-rs368234815) using data from the TWB1.0 and TWB2.0 genotype dataset. Participants underwent a series of assessments including questionnaires, blood examinations, abdominal ultrasounds, and spirometry examinations. MetS was associated with FL and airflow limitation. ApoE-rs429358, LEPR-rs1805096, APOC3-rs2854116, APOC3-rs2854117, PPP1R3B-rs4240624, PPP1R3B-rs4841132, and TM6SF2-rs58542926 were significantly associated with the risk of MetS. The cumulative impact of T alleles of ApoE-rs429358 and TM6SF2-rs58542926 on the risk of FL was observed (p-value for trend < 0.001). Individuals without MetS and airflow limitation carrying LEPR-rs1805096 G_G genotype exhibited a reduction in the forced expiratory volume in 1 s percentage prediction (Coefficient -35, 95 % confidence interval (CI) -69.7- -0.4), low forced vital capacity percentage prediction (Coefficient -41.6, 95 % CI -82.6- -0.6), and low vital capacity percentage prediction (Coefficient -42.2, 95 % CI -84.2- -0.1). MetS significantly correlated with FL and airflow limitation. Multiple SNPs were notably associated with MetS. Specifically, T alleles of ApoE-rs429358 and TM6SF2-rs58542926 cumulatively increased the risk of FL. LEPR-rs1805096 shows a trend-wise association with pulmonary function, which is significant in patients without MetS or airflow limitation. Show less

Dual specificity protein phosphatase 6 (DUSP6) was recently identified as a key hub gene in a causal To investigate the role of DUSP6 in AD, we stereotactically injected AAV5-DUSP6 or AAV5-GFP (control) into the dorsal hippocampus (dHc) of both female and male 5xFAD or wild type mice, to induce overexpression of DUSP6 or GFP. Barnes maze testing indicated that DUSP6 overexpression in the dHc of 5xFAD mice improved memory deficits and was associated with reduced amyloid plaque load, Aß In summary, DUSP6 overexpression in dHc reduced amyloid deposition and memory deficits in male but not female 5xFAD mice, whereas reduced neuroinflammation and microglial activation were observed in both males and females, suggesting that DUSP6-induced reduction of microglial activation did not contribute to sex-dependent improvement in memory deficits. The sex-dependent regulation of synaptic pathways by DUSP6 overexpression, however, correlated with the improvement of spatial memory deficits in male but not female 5xFAD. Show less

Microsomal glutathione transferase 3 (MGST3) regulates eicosanoid and glutathione metabolism. These processes are associated with oxidative stress and apoptosis, suggesting that MGST3 might play a role in the pathophysiology of Alzheimer's disease. Here, we report that knockdown (KD) of MGST3 in cell lines reduced the protein level of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and the resulting amyloidogenesis. Interestingly, MGST3 KD did not alter intracellular reactive oxygen species level but selectively reduced the expression of apoptosis indicators which could be associated with the receptor of cysteinyl leukotrienes, the downstream metabolites of MGST3 in arachidonic acid pathway. We then showed that the effect of MGST3 on BACE1 was independent of cysteinyl leukotrienes but involved a translational mechanism. Further RNA-seq analysis identified that regulator of G-protein signaling 4 (RGS4) was a target gene of MGST3. Silencing of RGS4 inhibited BACE1 translation and prevented MGST3 KD-mediated reduction of BACE1. The potential mechanism was related to AKT activity, as the protein level of phosphorylated AKT was significantly reduced by silencing of MGST3 and RGS4, and the AKT inhibitor abolished the effect of MGST3/RGS4 on phosphorylated AKT and BACE1. Together, MGST3 regulated amyloidogenesis by controlling BACE1 protein expression, which was mediated by RGS4 and downstream AKT signaling pathway. Show less

Staufen-1 (STAU1) is a double-stranded RNA-binding protein (RBP) involved in a variety of pathological conditions. In this study, we investigated the potential role of STAU1 in Alzheimer's disease (AD), in which two hallmarks are well-established as cerebral β-amyloid protein (Aβ) deposition and Tau-centered neurofibrillary tangles. We found that STAU1 protein level was significantly increased in cells that stably express full-length APP and the brain of APP/PS1 mice, an animal model of AD. STAU1 knockdown, as opposed to overexpression, significantly decreased the protein levels of β-amyloid converting enzyme 1 (BACE1) and Aβ. We further found that STAU1 extended the half-life of the BACE1 mRNA through binding to the 3' untranslated region (3'UTR). Transcriptome analysis revealed that STAU1 enhanced the expression of growth arrest and DNA damage 45 β (GADD45B) upstream of P38 MAPK signaling, which contributed to STAU1-induced regulation of Tau phosphorylation at Ser396 and Thr181. Together, STAU1 promoted amyloidogenesis by inhibiting BACE1 mRNA decay, and augmented Tau phosphorylation through activating GADD45B in relation to P38 MAPK. Targeting STAU1 that acts on both amyloidogenesis and tauopathy may serve as an optimistic approach for AD treatment. Show less

The metabolic patterns of human placental-derived mesenchymal stem cell (hP-MSC) treatment for primary sclerosing cholangitis (PSC) remain unclear, and therapeutic effects significantly vary due to individual differences. Therefore, it is crucial to investigate the serological response to hP-MSC transplantation through small molecular metabolites and identify easily detectable markers for efficacy evaluation. Using Mdr2 Collectively, the results of the liver histology, serum liver enzyme levels, and inflammatory factors supported the therapeutic efficacy of hP-MSC treatment. Based on significant differences, 41 differentially expressed metabolites were initially identified; these were enriched in bile acid, lipid, and hydroxyproline metabolism. After treatment, bile acid transport was accelerated, whereas bile acid production was reduced; unsaturated fatty acid synthesis was upregulated overall, with increased FADS2 and elongase expression and enhanced fatty acid β-oxidation; hepatic proline 4-hydroxylase expression was decreased, leading to reduced hydroxyproline production. Correlation analysis of liver enzymes and metabolites, combined with time trends, identified eight potential biomarkers: 2-aminomuconate semialdehyde, L-1-pyrroline-3-hydroxy-5-carboxylic acid, L-isoglutamine, and maleamic acid were more abundant in model mice but decreased after hP-MSC treatment. Conversely, 15-methylpalmitic, eicosenoic, nonadecanoic, and octadecanoic acids were less abundant in model mice but increased after hP-MSC treatment. This study revealed metabolic regulatory changes in PSC model mice after hP-MSC treatment and identified eight promising biomarkers, providing preclinical evidence to support therapeutic applications of hP-MSC. Show less

Structural variations (SVs) have significant impacts on complex phenotypes by rearranging large amounts of DNA sequence. We present a comprehensive SV catalog based on the whole-genome sequence of 1060 pigs (Sus scrofa) representing 101 breeds, covering 9.6% of the pig genome. This catalog includes 42,487 deletions, 37,913 mobile element insertions, 3308 duplications, 1664 inversions, and 45,184 break ends. Estimates of breed ancestry and hybridization using genotyped SVs align well with those from single nucleotide polymorphisms. Geographically stratified deletions are observed, along with known duplications of the KIT gene, responsible for white coat color in European pigs. Additionally, we identify a recent SINE element insertion in MYO5A transcripts of European pigs, potentially influencing alternative splicing patterns and coat color alterations. Furthermore, a Yorkshire-specific copy number gain within ABCG2 is found, impacting chromatin interactions and gene expression across multiple tissues over a stretch of genomic region of ~200 kb. Preliminary investigations into SV's impact on gene expression and traits using the Pig Genotype-Tissue Expression (PigGTEx) data reveal SV associations with regulatory variants and gene-trait pairs. For instance, a 51-bp deletion is linked to the lead eQTL of the lipid metabolism regulating gene FADS3, whose expression in embryo may affect loin muscle area, as revealed by our transcriptome-wide association studies. This SV catalog serves as a valuable resource for studying diversity, evolutionary history, and functional shaping of the pig genome by processes like domestication, trait-based breeding, and adaptive evolution. Show less

Infigratinib, an FGFR1-3 selective oral tyrosine kinase inhibitor, has shown clinical activity in cancers with FGFR alterations. The pharmacokinetics (PK) of infigratinib and its major metabolites have been characterized in global populations. This study examined the PK profile of infigratinib and its metabolites in Chinese patients. In this phase II, open-label, single-arm study in China, patients with advanced gastric cancer (GC) or gastroesophageal junction adenocarcinoma (GEJ) harboring FGFR2 gene amplification received 125 mg infigratinib orally once daily in a "3 weeks on, 1 week off" schedule for 28-day cycles. Plasma PK parameters were calculated with a non-compartmental model. Data were available from 21 patients (19 GC and two GEJ). After a single dose, peak infigratinib plasma concentration was reached at a median time of 3.1 h, with geometric mean C Show less