Several KRASG12D inhibitors (KRASG12Di) are under clinical evaluation for pancreatic ductal adenocarcinoma (PDAC). However, as seen with other first generation KRAS inhibitors, resistance may limit th Show more
Several KRASG12D inhibitors (KRASG12Di) are under clinical evaluation for pancreatic ductal adenocarcinoma (PDAC). However, as seen with other first generation KRAS inhibitors, resistance may limit their long-term efficacy, necessitating combination strategies to enhance therapeutic outcomes. Exportin 1 (XPO1), a nuclear transport protein overexpressed in PDAC, represents a therapeutic vulnerability in KRAS-mutant cancers. Here, we demonstrate that the second-generation XPO1 inhibitor Eltanexor synergizes with MRTX1133 to enhance its efficacy in multiple PDAC models. We generated KRASG12Di-resistant PDAC cells and assessed their response to Eltanexor. The antiproliferative effects of MRTX1133 and Eltanexor combinations were evaluated in 2D and 3D Eltanexor sensitized MRTX1133-resistant PDAC cells to growth inhibition. In both 2D and 3D culture models, the combination of Eltanexor and MRTX1133 significantly reduced cell viability. Mechanistically, the combination treatment suppressed key KRAS downstream signaling molecules, including p-ERK, mTOR, p-4EBP1, DUSP6, and cyclin D1. Kinome analysis further revealed reduced MAPK-related kinase activity. Combining subtherapeutic doses of Eltanexor and MRTX1133 resulted in significant tumor regression and prolonged survival in PDAC xenograft and immunocompetent orthotopic allograft models. Moreover, maintenance therapy with Eltanexor prevented tumor relapse, yielding a durable antitumor response. This study demonstrates that Eltanexor overcomes resistance to MRTX1133 and enhances its efficacy in PDAC. The combination regimen may provide a durable therapeutic response while reducing the required dose of KRASG12D inhibitors, potentially delaying resistance and improving patient outcomes. Show less
B cells express many protein ligands, yet their regulatory functions are incompletely understood. We profiled ligand expression across murine B sublineage cells, including those activated by defined r Show more
B cells express many protein ligands, yet their regulatory functions are incompletely understood. We profiled ligand expression across murine B sublineage cells, including those activated by defined receptor signals, and assessed their regulatory capacities and specificities through in silico analysis of ligand-receptor interactions. Consequently, we identified a B cell subset that expressed cytokine interleukin-27 (IL-27) and chemokine CXCL10. Through the IL-27-IL-27 receptor interaction, these IL-27/CXCL10-producing B cells targeted CD40-activated B cells in vitro and, upon induction by immunization and viral infection, optimized antibody responses and antiviral immunity in vivo. Also present in breast cancer tumors and retained there through CXCL10-CXCR3 interaction-mediated self-targeting, these cells promoted B cell PD-L1 expression and immune evasion. Mechanistically, Show less
Macrophages play a crucial role in coordinating the skeletal muscle repair response, but their phenotypic diversity and the transition of specialized subsets to resolution-phase macrophages remain poo Show more
Macrophages play a crucial role in coordinating the skeletal muscle repair response, but their phenotypic diversity and the transition of specialized subsets to resolution-phase macrophages remain poorly understood. Here, to address this issue, we induced injury and performed single-cell RNA sequencing on individual cells in skeletal muscle at different time points. Our analysis revealed a distinct macrophage subset that expressed high levels of Gpnmb and that coexpressed critical factors involved in macrophage-mediated muscle regeneration, including Igf1, Mertk and Nr1h3. Gpnmb gene knockout inhibited macrophage-mediated efferocytosis and impaired skeletal muscle regeneration. Functional studies demonstrated that GPNMB acts directly on muscle cells in vitro and improves muscle regeneration in vivo. These findings provide a comprehensive transcriptomic atlas of macrophages during muscle injury, highlighting the key role of the GPNMB macrophage subset in regenerative processes. Our findings suggest that modulating GPNMB signaling in macrophages may represent a promising avenue for future research into therapeutic strategies for enhancing skeletal muscle regeneration. Show less
The highly organized structures of the immunological synapse (IS) are crucial for T cell activation. PDZ domains might be involved in the formation of the IS by serving as docking sites for protein in Show more
The highly organized structures of the immunological synapse (IS) are crucial for T cell activation. PDZ domains might be involved in the formation of the IS by serving as docking sites for protein interactions. In this study, we investigate the role of the PALS1-associated tight junction protein (PATJ), which contains 10 PDZ domains, in the formation of IS and its subsequent impact on T cell activation. To elucidate the function of PATJ, we generated murine models with conditional T cell-specific knockout of We observed a rapid increase in PATJ expression during T cell activation. Conditional knockout of Our study reveals an important role of PATJ in the formation of IS and provides an approach to improve the efficacy of CAR-T therapy. 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 Show more
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
It remains controversial whether lipids affect osteoporosis (OP) or bone mineral density (BMD), and causality has not been established. This study aimed to investigate the genetic associations between Show more
It remains controversial whether lipids affect osteoporosis (OP) or bone mineral density (BMD), and causality has not been established. This study aimed to investigate the genetic associations between lipids, novel non-statin lipid-lowering drug target genes, and OP and BMD. Mendelian randomization (MR) method was used to explore the genetic associations between 179 lipid species and OP, BMD. Drug-target MR analysis was used to explore the causal associations between angiopoietin-like protein 3 (ANGPTL3) and apolipoprotein C3 (APOC3) inhibitors on BMD. The IVW results with Bonferroni correction indicated that triglyceride (TG) (51:3) (OR = 1.0029; 95% CI: 1.0014-1.0045; P = 0.0002) and TG (56:6) (OR = 1.0021; 95% CI: 1.0008-1.0033; P = 0.0011) were associated with an increased risk of OP; TG (51:2) (OR = 0.9543; 95% CI: 0.9148-0.9954; P = 0.0298) was associated with decreased BMD; and ANGPTL3 inhibitor (OR = 1.1342; 95% CI: 1.0393-1.2290; P = 0.0093) and APOC3 inhibitor (OR = 1.0506; 95% CI: 1.0155-1.0857; P = 0.0058) was associated with increased BMD. MR analysis indicated causal associations between genetically predicted TGs and OP and BMD. Drug-target MR analysis showed that ANGPTL3 and APOC3 have the potential to serve as novel non-statin lipid-lowering drug targets to treat or prevent OP. Show less
Pork serves as a significant meat commodity, with intramuscular fat (IMF) content being a critical determinant of its quality. However, the epigenetic mechanism of porcine IMF deposition is still uncl Show more
Pork serves as a significant meat commodity, with intramuscular fat (IMF) content being a critical determinant of its quality. However, the epigenetic mechanism of porcine IMF deposition is still unclear. This study integrated proteomics and lactylation profiles from the longissimus thoracis (LT) muscles of pigs with extremely high (IMF_H) and extremely low (IMF_L) IMF content to clarify the association between lactylation and porcine fat deposition. Furthermore, an intramuscular preadipocyte induction and differentiation model was conducted to elucidate the changes in lactylation during adipocyte differentiation. Finally, the regulatory role of lactylation in adipocyte differentiation was explored by modulating lactate production during the induction and differentiation of preadipocytes. Proteomic analysis revealed significantly increased expression of key lipid metabolism related proteins (FASN, APOA4, FABP4, ACLY, PLIN1) in IMF_H pig muscle tissues compared with IMF_L tissues, along with substantial activation of lipid metabolism pathways. Lactylation profiling identified 95 differential lysine sites across 56 proteins, with most showing lower lactylation levels in the IMF_H group. The integrative omics analysis revealed differences in lactylation profiles in porcine LT tissues with varying efficiencies of IMF deposition, highlighted PGK1, PKM, and PYGM as central lactylation-modified proteins in porcine fat deposition regulation. Further in vitro study proved that lactate-mediated lactylation inhibited adipogenic differentiation of porcine intramuscular preadipocytes through PPARγ signaling pathway. This study clarified the changes in the lactylation profile in porcine LT tissues with varying efficiencies of IMF deposition, and demonstrated that lactate-mediated lactylation inhibits the PPARγ signaling pathway and the adipogenic differentiation of porcine intramuscular preadipocyte. This study provided a new insight to understanding the epigenetic regulation mechanisms of lipid deposition in pigs. Show less
Polycystic ovary syndrome (PCOS) is frequently accompanied with metabolic dysfunctions, yet the causal relationships between metabolic factors and PCOS remain to be conclusively established and etiolo Show more
Polycystic ovary syndrome (PCOS) is frequently accompanied with metabolic dysfunctions, yet the causal relationships between metabolic factors and PCOS remain to be conclusively established and etiology-based therapies are lacking. To comprehensively identify the metabolic causal factors and potential drug targets for PCOS. This genetic association study was conducted using bidirectional two-sample Mendelian Randomization (MR), multivariable MR (MVMR) and drug-target MR. Considering metabolic sexual dimorphism, female-specific genome-wide association studies (GWASs) for metabolic factors were obtained. To ensure the robustness of the findings, an additional independent PCOS GWAS dataset was utilized for replication. The PCOS cohort included 10,074 PCOS cases (mean age 28 to 45 years) and 103,164 controls (mean age 27 to 60 years) of European ancestry. All participants were female. Employing two-sample MR analysis, we found that genetically proxied body mass index (BMI) (OR = 3.40 [95 % CI, 2.65-4.36]), triglyceride (TG) (OR = 1.54 [95 % CI, 1.17-2.04]), low-density lipoprotein cholesterol (LDL-c) (OR = 1.37 [95 % CI, 1.07-1.76]), and type 2 diabetes (T2D) (OR = 1.24 [95 % CI, 1.09-1.41]) were significantly associated with an increased risk of PCOS, whereas genetically predicted high-density lipoprotein cholesterol (HDL-c) (OR = 0.61 [95 % CI, 0.47-0.80]) decreased the odds of PCOS. Stepwise MVMR established a hierarchy of interactions among these metabolic factors, identifying BMI and HDL-c as the most prominent causal factors. Notably, drug-target MR analysis identified incretin-based therapeutics, PCSK9 inhibitors, LPL gene therapy, sulfonylureas, and thiazolidinediones as potential therapeutics for PCOS. All these findings were validated in an independent dataset. This study offered insights into the roles of obesity, diabetes, and dyslipidemia in PCOS etiology and therapeutics, underscoring the necessity for managing metabolic health in women and paving the way for tailored therapeutic strategies for PCOS based on its metabolic underpinnings. Show less
Lipid profiles are largely determined by genetic variants, and lipid metabolism plays a crucial role in Alzheimer's disease. To investigate whether lipid profile variability in response to diverse sta Show more
Lipid profiles are largely determined by genetic variants, and lipid metabolism plays a crucial role in Alzheimer's disease. To investigate whether lipid profile variability in response to diverse statins could be affected by cholesterol metabolism-related genetic variants in Alzheimer's disease.. This prospective observational pharmacogenetic study was conducted at the Universidade Federal de São Paulo (Unifesp), Brazil. Consecutive outpatients were prospectively followed for lipid profile variations over one year, estimated by the associations between statin therapy and the following variants: rs2695121 (NR1H2), rs3846662 (HMGCR), rs11669576 (LDLR8), rs5930 (LDLR10), rs5882 and rs708272 (CETP), rs7412 and rs429358 (APOE), and ACE insertion/deletion polymorphism. All polymorphisms in the 189 patients were in Hardy-Weinberg equilibrium. Statins resulted in lower total cholesterol and LDL cholesterol levels, whereas the effects on HDL cholesterol varied according to the statin used. Atorvastatin resulted in lower triglyceride level variations than simvastatin. APOE-ε4 carriers showed a better response to atorvastatin in elevating HDL-cholesterol than APOE-ε4 non-carriers. Carriers of the ACE insertion allele had cumulatively lower total cholesterol and LDL-cholesterol levels, regardless of statin therapy, but lower triglyceride levels when using atorvastatin. Carriers of rs11669576-G had lower total cholesterol and LDL-cholesterol levels when using simvastatin, and lower total cholesterol and triglycerides when using atorvastatin. Concerning CETP haplotypes, carriers of rs5882-A and rs708272-A benefitted the most from statins, which lowered total cholesterol and increased HDL-cholesterol levels, and from atorvastatin lowering triglycerides; however, the effects of atorvastatin lowering total cholesterol and LDL-cholesterol were more pronounced for carriers of rs5882-GG/rs708272-GG. Lipid profile variations may be pharmacogenetically mediated in Alzheimer's disease, thus, confirming their high heritability. Show less
Colorectal cancer (CRC) constitutes a significant public health burden in both China and the United States of America (USA), with low physical activity (LPA) identified as a key modifiable risk factor Show more
Colorectal cancer (CRC) constitutes a significant public health burden in both China and the United States of America (USA), with low physical activity (LPA) identified as a key modifiable risk factor. This study aimed to characterize temporal trends in CRC burden attributable to LPA in these 2 nations from 1990 to 2021. Using data from the 2021 global burden of disease database, age and sex-specific disparities in CRC burden attributed to LPA were evaluated in both countries. Trend analyses of age-standardized mortality rates and age-standardized disability-adjusted life year rates were performed using joinpoint regression. Decomposition analysis was applied to disentangle contributions from demographic aging, population growth, and epidemiological transitions. The age-period-cohort model was employed to quantify the independent effects of age, period, and birth cohort. Bayesian age-period-cohort modeling was utilized to project future CRC burden attributed to LPA through 2036. In 2021, LPA-attributable CRC mortality cases in China reached 16,698 (95% uncertainty interval: 10,065-24,626), exhibiting a 191.16% increase from 1990. The number of disability-adjusted life years attributed to LPA totaled 3,20,464 (95% uncertainty interval: 1,92,275-4,74,070), reflecting a 149.67% rise over the same period. Conversely, the USA reported more moderate increases of 18.26% in LPA-attributable CRC deaths and 20.28% in disability-adjusted life years. The age-period-cohort model revealed that the disease burden in both countries is shifting towards younger age groups. Further analysis of each state in the USA revealed that in 2021, the burden on low-income groups was heavier. The Bayesian age-period-cohort model predicts that the burden of CRC caused by LPA in the 2 countries will show a significant upward trend by 2036. As the burden of CRC caused by LPA becomes increasingly severe in China and the USA, there is an urgent need to raise public awareness about how physical activity can help prevent CRC and for policymakers to create targeted public health policies to lower this disease burden. Show less
Mutations in LRRK2, a leading genetic cause of Parkinson's disease (PD), are linked to immune dysregulation, but the immune profiles in the periphery and central nervous system (CNS) remain incomplete Show more
Mutations in LRRK2, a leading genetic cause of Parkinson's disease (PD), are linked to immune dysregulation, but the immune profiles in the periphery and central nervous system (CNS) remain incompletely defined. This study utilized a large cohort of serum samples (n = 651) and matched CSF samples (n = 129) from LRRK2 mutation carriers and non-carriers, with and without PD, to assess immune regulators using Luminex immunoassay. After correction for multiple comparisons, LRRK2 mutations were associated with significantly elevated serum levels of SDF-1 alpha and TNF-RII, while CSF markers such as BAFF, CD40L, and IL-27 were nominally reduced. Regardless of LRRK2 status, PD was associated with nominally lower levels of inflammatory analytes in CSF, with minimal changes observed in serum. Correlation analyses revealed distinct immune profiles between serum and CSF, suggesting compartmentalized immune responses. These findings highlight immune alterations in LRRK2 mutation carriers and PD, providing potential serum markers for monitoring immune responses and avenues for mechanistic studies. Show less
Xueli Chen, Li Dai · 2025 · Biochemical genetics · Springer · added 2026-04-24
Asthma is a common chronic respiratory disease in children, the incidence rate of which has increased in recent years. Wilms tumour 1-associated protein (WTAP) is an N6-methyladenosine (m6A) methyltra Show more
Asthma is a common chronic respiratory disease in children, the incidence rate of which has increased in recent years. Wilms tumour 1-associated protein (WTAP) is an N6-methyladenosine (m6A) methyltransferase. The purpose of this study was to explore the specific mechanism of WTAP in asthma progression, and clarify the intricate interplay between m6A modifications, WTAP, AXIN1, and their collective impact on airway smooth muscle cells (ASMCs) proliferation in asthma. Platelet-derived growth factor-BB (PDGF-BB)-treated ASMCs were used to establish an asthma model in vitro. The cell phenotype was tested using CCK-8, transwell, and wound healing assays. The expression of the Wnt signalling pathway was detected by western blotting. In addition, the relationship between WTAP/YTDHF2 and AXIN1 was assessed by a double luciferase reporter assay. Actinomycin D treatment and RT‒qPCR assays were performed to determine the mRNA stability of AXIN1. We found that WTAP was significantly increased in PDGF-BB-treated ASMCs. Knockdown of WTAP inhibited the excessive cell viability and migration of ASMCs induced by PDGF-BB. Furthermore, WTAP knockdown increased AXIN1 levels and inhibited the Wnt signalling pathway. Furthermore, WTAP knockdown decreased the m6A levels and enhanced the mRNA stability of AXIN1. WTAP overexpression showed the opposite effect. In addition, YTHDF2 was demonstrated to be the reader that recognizes the WTAP-mediated m6A modification of AXIN1. YTHDF2 knockdown enhanced the mRNA stability of AXIN1 and reversed the effect of WTAP overexpression on PDGF-BB-treated ASMCs. WTAP knockdown inhibited the excessive cell viability and migration of ASMCs by enhancing the m6A levels of AXIN1, which was further recognized by YTHDF2. The upregulation of AXIN1 mediated by the WTAP/YTHDF2 axis further inhibited the Wnt signalling pathway. Our study provides a new method for the treatment of asthma. This work not only deepens our understanding of the molecular underpinnings of asthma but also identifies potential therapeutic targets for the development of novel treatments aimed at inhibiting ASMC proliferation and alleviating asthma symptoms. Show less
Gastrointestinal (GI) cancers exhibit aberrant lipid metabolism, yet the causal mechanisms remain elusive. Here, we integrated Mendelian randomization (MR) and multi-omics data to dissect metabolic dr Show more
Gastrointestinal (GI) cancers exhibit aberrant lipid metabolism, yet the causal mechanisms remain elusive. Here, we integrated Mendelian randomization (MR) and multi-omics data to dissect metabolic drivers of 20 GI diseases. Focusing on colorectal (CC) and esophageal cancer (EC), we identified five metabolites (e.g., 1,2-di-palmitoyl-sn-glycero-3-phosphocholine) and arachidonic acid ethyl ester as causal drivers. Summary-data-based MR and colocalization analysis (PP.H4 > 0.75) revealed FADS1 as a master regulator of these metabolites, with genetic variants exhibiting tissue-specific lipidomic effects. Functional validation using FADS1-knockout cell lines and mouse models demonstrated that FADS1 inhibition suppresses tumor cell proliferation, migration, and invasion while promoting apoptosis. In vivo, FADS1 deletion reduced chemically induced CC/EC tumor burden by 62-75%, accompanied by decreased Ki-67/MMP-9 expression and inflammatory infiltration. Mechanistically, FADS1 ablation disrupted lipid metabolism (reduced linoleic acid and arachidonic acid) and attenuated PI3K/AKT and MAPK signaling. Multi-omics integration further corroborated FADS1-mediated epigenetic regulation (e.g., mQTL-driven DNA methylation). This study establishes FADS1 as a pivotal orchestrator of GI carcinogenesis via metabolic reprogramming and signaling dysregulation, offering a compelling therapeutic target for precision oncology in CC and EC. Regulatory mechanisms of FADS1 in CC and EC. Show less
Injectable hydrogel implants represent a promising therapeutic approach for ischemic heart failure; but their efficacy is often limited by low bioactivity, poor durability, and inadequate injection te Show more
Injectable hydrogel implants represent a promising therapeutic approach for ischemic heart failure; but their efficacy is often limited by low bioactivity, poor durability, and inadequate injection techniques. Herein, a unique hydrogel incorporating extracellular matrix from fish swim bladder (FSB-ECM), which has distinct advantages over mammalian derived ECM, such as low antigenicity, bioactivity, and source safety, is developed. It consists of collagen, glycoproteins, and proteoglycans, including 13 proteins common in the myocardial matrix and three specific proteins: HSPG, Col12a1, and vWF. This hydrogel enhances cardiac cell adhesion and stretching while promoting angiogenesis and M2 macrophage polarization. In addition, its storage modulus (G') increases over time, reaching about 1000 Pa after 5 min, which facilitates transcatheter delivery and in situ gelling. Furthermore, this hydrogel provides sustained support for cardiac contractions, exhibiting superior longevity. In a rat model of ischemic heart failure, the ejection fraction significantly improves with FSB-ECM treatment, accompanied by increased angiogenesis, reduced inflammation, and decreased infarct size. Finally, RNA sequencing combined with in vitro assays identifies ANGPTL4 as a key protein involved in mediating the effects of FSB-ECM treatment. Overall, this new injectable hydrogel based on FSB-ECM is suitable for transcatheter delivery and possesses remarkable reparative capabilities for treating heart failure. Show less
Uterine corpus endometrial carcinoma (UCEC) is one of the most common gynecologic tumors. Due to the high recurrence and metastasis of UCEC, it is crucial for patients to find new biomarkers for diagn Show more
Uterine corpus endometrial carcinoma (UCEC) is one of the most common gynecologic tumors. Due to the high recurrence and metastasis of UCEC, it is crucial for patients to find new biomarkers for diagnosis and therapy. In this study, R software and the TCGA database were used to screen candidate UCEC predictive markers. Western blot and RT-qPCR were performed to detect protein and mRNA expression of EXT1 in UCEC cell lines. In addition, MTT assay, flow cytometry, transwell assay, and wound healing assay were conducted to assess the cell viability, apoptosis, invasion, and migration in UCEC cells. Overlap-extension PCR technique was employed to construct the vector targeting the deletion of the methylated segment of EXT1. The results showed that a total of 11 candidate genes were obtained and EXT1 was identified as a potential target. The expression and methylation levels of EXT1 were both increased in UCEC tissues and cell lines, as well as elevated EXT1 was closely related to the poor prognosis of patients. Besides, the knockdown of EXT1 significantly inhibited the malignant biological behaviors in UCEC cells. Additionally, the current study also found that the deletion of 1559-2146 bp CpG island segment upregulated EXT1 expression and promoted malignant biological behaviors in UCEC cells. Furthermore, the presence of m7G RNA methylation in UCEC cells also was found. In conclusion, the methylation of EXT1 influenced the gene expression, thereby affecting the malignant biological behaviors in UCEC cells and regulating the pathological progression of UCEC. Show less
Many patients are suffering from atherosclerosis without typical risk factors, which can cause severe cardiovascular complications. Trimethylamine N-oxide (TMAO), derived from gut microbes, is a key u Show more
Many patients are suffering from atherosclerosis without typical risk factors, which can cause severe cardiovascular complications. Trimethylamine N-oxide (TMAO), derived from gut microbes, is a key unconventional contributor to the development of atherosclerosis. Here we present a strategy performed by orally administered nano-functionalized probiotics (PDMF@LGG) to inhibit TMAO through the gut microbiota-trimethylamine (TMA)-TMAO axis. PDMF@LGG, composed of polydopamine-coated Lacticaseibacillus rhamnosus GG and nanoparticles based on a reactive oxygen species (ROS)-responsive polymeric prodrug of fluoromethylcholine (FMC), can promote the retention of probiotics and nanoparticles in the intestine to persistently scavenge elevated ROS and release drugs. This process suppresses TMA production and absorption, lowering plasma TMAO levels. The therapeutic effects on male ApoE Show less
Diabetes mellitus and dyslipidemia are major risk factors for atherosclerosis. Hypoechoic plaques, which indicate vulnerable or unstable plaques, may rupture and lead to ischemic stroke, cognitive imp Show more
Diabetes mellitus and dyslipidemia are major risk factors for atherosclerosis. Hypoechoic plaques, which indicate vulnerable or unstable plaques, may rupture and lead to ischemic stroke, cognitive impairment, increased adverse cardiac events, and even death. This study aimed to investigate the correlation between plasma lipid levels and the characteristics of atherosclerotic plaques in adult patients with type 2 diabetes mellitus. A retrospective analysis was conducted on adult patients with type 2 mellitus who were hospitalized in the Department of Endocrinology at Affiliated Hospital of Hebei University between January 2017 and December 2021.Patients were categorized into two groups based on arterial ultrasound results. Statistical analyses were performed to compare plasma lipid levels and plaque characteristics across the groups. 1) Statistically significant differences were observed among the two groups in terms of gender, hypertension, age, duration of diabetes mellitus, plaque location, triglycerides (TG),total cholesterol (TC), Apolipoprotein A1 (Apo A1),very-low-density lipoprotein (VLDL), VLDL/apolipoprotein B(ApoB), high-density lipoprotein cholesterol (HDL)/ApoA1 ( In clinical practice, the characteristics of atherosclerotic plaques and lipid profiles should be jointly evaluated to guide targeted treatment and effectively reduce the risk of atherosclerotic cardiovascular disease. Show less
The treatment of functional tricuspid regurgitation (TR) is still controversial. Characterizing the cellular composition of the tricuspid valve and identifying the molecular alterations of each cell t Show more
The treatment of functional tricuspid regurgitation (TR) is still controversial. Characterizing the cellular composition of the tricuspid valve and identifying the molecular alterations of each cell type in valves with TR will advance our understanding of the mechanisms of TR and guide improvements in treatment. The authors aimed to investigate the changes in cellular composition and gene expression patterns of cells in regurgitant tricuspid valves and shed light on the mechanisms of functional TR. To improve our understanding of the pathogenesis of functional TR, we performed single-cell RNA sequencing of tricuspid valve from 10 patients, including 5 patients with moderate-to-severe functional TR and 5 nondiseased control subjects. Multiplexed fluorescence was used to detect the spatial distributions of valvular cell states and validated the cell-cell interaction. We assessed the transcriptional profiles of 84,102 cells and identified 6 major cell clusters, along with 25 cell subtypes, in the specimens. Valve interstitial cells (VICs) were the largest population. VICs and lymphoid cells exhibited more heterogeneity in TR patients. VICs exhibited higher transcriptional activity toward matrifibrocyte-like cells and myofibroblast-like cell differentiation, myeloid cells activated immune response, and lymphoid cells promoted fibrosis. In TR, the alternation of COMP-CD47 and FGF2-FGFR1 interaction may occur in TR specimens, which may serve as promising therapeutic targets for TR. Our single-cell atlas highlights the transcriptomic heterogeneity underlying the cell functions and interactions in human tricuspid valves and defines molecular and cellular perturbations in functional TR. We identified VIC clusters with fibrosis activation accumulated in TR valves. Show less
Adenylate cyclase 3 (Adcy3) has been linked to both obesity and major depressive disorder. We identified a protein-coding variant in the transmembrane (TM) helix of Adcy3 in rats; similar obesity vari Show more
Adenylate cyclase 3 (Adcy3) has been linked to both obesity and major depressive disorder. We identified a protein-coding variant in the transmembrane (TM) helix of Adcy3 in rats; similar obesity variants have been identified in humans. This study investigates the role of a TM variant in adiposity and behavior. We mutated the TM domain of Adcy3 (Adcy3 Adcy3 The ADCY3 TM domain plays a role in protein function via p-AMPK and CREB signaling. Adcy3 may contribute to the relationship between obesity and major depressive disorder, and sex influences the relationships between Adcy3, metabolism, and behavior. Show less
Sepsis arises from a dysregulated host response to infection, leading to multiorgan inflammatory injury. Early diagnosis and treatment necessitate the identification of reliable immune biomarkers. Thi Show more
Sepsis arises from a dysregulated host response to infection, leading to multiorgan inflammatory injury. Early diagnosis and treatment necessitate the identification of reliable immune biomarkers. This study investigated the relationship between aging, immunity, and sepsis by analyzing six human aging-related gene sets (656 genes). We identified 16 aging-related differentially expressed genes (DEGs) in sepsis. Among these, ATP11B, RBBP7, DOCK10, and NUP160 demonstrated the strongest connectivity with other genes and exhibited significant predictive power. Functional enrichment analysis (GO and KEGG) revealed distinct signaling pathway profiles between high-risk and low-risk sepsis groups (stratified based on risk scores). These dysregulated pathways, associated with multiple immune cells, were primarily linked to transcriptional dysregulation in cellular processes and cancer-related pathways. Experimental validation assays corroborated the roles of ATP11B and RBBP7. Collectively, our bioinformatic and experimental findings indicate that ATP11B, RBBP7, DOCK10, and NUP160 are implicated in the pathogenesis and progression of sepsis. But their potential for sepsis biomarkers still requires further verification. Show less
In recent years, there has been a steady increase in professionals engaged in radioactive work. The biological impacts of long-term exposure to low dose-rate radiation remain elusive, as there is a de Show more
In recent years, there has been a steady increase in professionals engaged in radioactive work. The biological impacts of long-term exposure to low dose-rate radiation remain elusive, as there is a dearth of systematic research in this field. BEAS-2B cells were used to establish a cell model with continuous passaging after radiation exposure, which was subsequently subjected to in vivo tumorigenesis assays and in vitro malignant phenotype experiments. By scRNA-seq, we conducted copy number variation analysis, cell trajectory analysis, and cell communication analysis. Furthermore, we used FACS, molecular docking, multiplex immunohistochemistry, qRT-PCR, and co-immunoprecipitation to validate and further explore the molecular mechanisms driving tumor evolution. Long-term low dose-rate exposure is associated with a higher degree of malignancy, as evidenced by the induction of more CNV and EMT events, as well as the delayed activation of DNA repair pathways, which trigger increased genomic instability. The long-term low dose-rate specific ligand-receptor pair, ANGPTL4-SDC4, enhances cell malignancy by promoting angiogenesis in newly formed lung tumor cells. This study not only provides the first evidence and mechanistic explanation that long-term low dose-rate radiation leads to increased cellular malignancy but also offers valuable theoretical insights into the dynamic processes of early tumor evolution in lung cancer within the realm of tumor biology. Show less
Mubalake Abudoureyimu, Ni Sun, Weiwei Chen+3 more · 2025 · International journal of immunopathology and pharmacology · SAGE Publications · added 2026-04-24
This study aimed to investigate whether the dysregulation of Aurora-A is involved in lenvatinib resistance in hepatocellular carcinoma. Bioinformatics tools and drug sensitivity assays were used to in Show more
This study aimed to investigate whether the dysregulation of Aurora-A is involved in lenvatinib resistance in hepatocellular carcinoma. Bioinformatics tools and drug sensitivity assays were used to investigate the association between Aurora-A expression level and lenvatinib resistance in hepatocellular carcinoma cell lines. Cell function experiments had performed after treatment with lenvatinib and/or a selective Aurora-A inhibitor (MLN-8237). CircRNA microarray, RIP, RNA pull-down, and dual-luciferace reporter assay were performed to identify the downstream molecular mechanism of Aurora-A dysregulation. Aurora-A expression was positively correlated with lenvatinib resistance in hepatocellular carcinoma cells. The Aurora-A selective inhibitor MLN-8237, in combination with lenvatinib, synergistically inhibited hepatocellular carcinoma cell proliferation in vitro and vivo, suggesting the Aurora-A might be a potential therapeutic target for lenvatinib resistance. Mechanistically, Aurora-A induced FGFR1 expression through the hsa-circ-0058046/miR-424-5p/FGFR1 axis. Aurora-A promotes lenvatinib resistance through hsa-circ-0058046/miR-424-5p/FGFR1 axis in hepatocellular carcinoma cells. The simultaneous inhibition of FGFR1 by the Aurora-A inhibitor MLN-8237 and lenvatinib overcame lenvatinib resistance in hepatocellular carcinoma cells. Collectively, our findings indicate that Aurora-A promotes lenvatinib resistance through the hsa-circ-0058046/miR-424-5p/FGFR1 axis in hepatocellular carcinoma (HCC) cells. These results suggest that Aurora-A may serve as a therapeutic target for HCC patients exhibiting lenvatinib resistance. Furthermore, the combination of lenvatinib and MLN-8237 shows potential for clinical trials aimed at overcoming lenvatinib resistance. Show less
Aplastic anemia, characterized by pancytopenia and hypoplastic bone marrow, is associated with various acquired cytogenetic abnormalities, including trisomy 8, in 4%-15% of patients. Constitutional mo Show more
Aplastic anemia, characterized by pancytopenia and hypoplastic bone marrow, is associated with various acquired cytogenetic abnormalities, including trisomy 8, in 4%-15% of patients. Constitutional mosaic trisomy 8 notably increases the risks for cytopenia and myeloid malignancies. Duplications near chromosome 8 centromere are associated with developmental delays, autism, and trisomy 8p11.21q11.21 correlates with hematologic disorders. We report a 19-year-old female with constitutional mosaic pericentromeric trisomy 8 presenting with menorrhagia, vitamin B12 deficiency, familial short stature, pancytopenia, and bone marrow aplasia. G-banded chromosome and FISH analyses of her bone marrow and blood samples revealed constitutional mosaic pericentromeric trisomy 8. Chromosomal microarray analysis confirmed mosaic duplications in the 8p12q11.21 region spanning 51 OMIM genes, with 16 identified as OMIM morbid genes, and including 9 genes with autosomal dominant inheritance patterns. FGFR1, ASH2L, ANK1, KAT6A, IKBKB, PLAT, and CEBPD are implicated in hematologic disorders, with FGFR1, ASH2L, KAT6A, and IKBKB showing notable triplosensitivity scores. These regions overlap with 13 published cases (12 papers), of which three displayed hematologic disorders, including neutropenia and juvenile myelomonocytic leukemia. Our case underscores the 8p12q11.21 region as a potential causal region for aplastic anemia, emphasizing the need for further investigation of this patient for possible progression to hematologic malignancy. Show less
Lung adenocarcinoma (LUAD) is a leading cause of cancer deaths. Given that traditional pathologic features to diagnose LUAD do not fully reflect the biological differences in patients, the search for Show more
Lung adenocarcinoma (LUAD) is a leading cause of cancer deaths. Given that traditional pathologic features to diagnose LUAD do not fully reflect the biological differences in patients, the search for novel biomarkers is necessary. In this study, we obtained immune-related genes (IRGs) from ImmPort and performed cluster analysis on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) to mine LUAD subtypes with different immune characteristics. Quantitative analysis of IRGs was performed by single-sample gene set enrichment analysis (ssGSEA). Based on the univariate cox and LASSO regression methods, we screened the characteristic genes that significantly affected LUAD and built the model based on the RiskScore coefficients. The relative expressions of characteristic genes in LUAD were determined using qRT-PCR. Transwell and wound healing assays were utilized to verify the practical regulation of these genes on the migration and invasion levels of LUAD. Correlations were established between RiskScore and LUAD drug sensitivity by oncoPredict. We acquired three LUAD subtypes and demonstrated heterogeneous IRGs scores and clinical features. The molecular subtypes were differentially enriched in bile acid metabolism, fatty acid metabolism, and ECM-receptor interaction. This study identified seven genes (MS4A1, EXO1, CPS1, ZNF750, S100P, NT5E, KCNN4) as a signature affecting prognosis, from the differentially expressed genes (DEGs) among the molecular subtypes, and constructed a RiskScore for the prognosis of LUAD. Cellular experiments verified that 6 of 7 characteristic genes were expression dysregulation in LUAD cell line. Silencing of EXO1 significantly suppressed the migration and invasion of LUAD cell lines. RiskScore and immune checkpoints such as CD276, TNFSF4, and TNFSF9 showed a positive correlation. This study identified three LUAD subtypes with distinct immune characteristics and constructed a seven-gene prognostic model. This model correlates with immune checkpoint and chemotherapy sensitivity, providing new targets and strategies for clinical diagnosis and treatment. Show less
Gastroesophageal reflux disease (GERD) and asthma are commonly co-occurring conditions, with shared genetic factors identified. However, the specific loci and the influence of common genetic architect Show more
Gastroesophageal reflux disease (GERD) and asthma are commonly co-occurring conditions, with shared genetic factors identified. However, the specific loci and the influence of common genetic architecture remain undefined. We obtained genome-wide association study (GWAS) summary statistics for GERD (71 522 cases and 261 079 controls) and asthma (56 167 cases and 352 255 controls). Using linkage disequilibrium score regression (LDSC), we assessed genetic correlations between GERD and asthma. Bidirectional Mendelian randomization (MR) was performed to investigate potential causal relationships, followed by cross-trait GWAS meta-analysis and colocalization analysis to identify shared risk loci. Additionally, summary-data-based MR and transcriptome-wide association study were conducted to pinpoint common functional genes. Finally, we analyzed gene expression profiles in both healthy individuals and GERD patients using esophageal single-cell RNA sequencing (scRNA-seq) data. We identified a significant genetic correlation between GERD and asthma ( rg = 0.37, P = 6.19 × 10 -38 ) and a significant causal effect of GERD on asthma [odds ratio (OR) = 1.22, P = 1.54 × 10 -5 ]. Cross-trait meta-analyses revealed 56 shared risk loci between GERD and asthma, including 51 loci that were newly identified. Three loci (rs61937247, rs7960225, and rs769670) exhibited evidence of colocalization. Gene-level analyses pinpointed three novel shared genes ( RBM6, SUOX , and MPHOSPH9 ) between GERD and asthma. scRNA-seq analysis uncovered heightened expression of these genes in immune cells of patients diagnosed with GERD. Our study has discovered novel shared genetic loci and candidate genes between GERD and asthma, providing further insights into the genetic susceptibility of comorbidity and potential mechanisms of the two diseases. 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 Show more
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
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease globally, yet it lacks any approved pharmacological therapies. Dual glucagon-like peptide-1 Show more
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease globally, yet it lacks any approved pharmacological therapies. Dual glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) agonists have shown clinical promise, but their causal effect on MASLD remains unestablished. This study uses genetic evidence to evaluate the causal role of dual GLP-1R/GIPR agonists on MASLD and to explore its underlying mechanisms. Using a novel approach combining Mendelian randomization (MR) and Bayesian colocalization, we constructed a high-confidence genetic proxy for dual GLP-1R/GIPR agonists based on five genetic variants strongly associated with both mRNA expression and HbA1c levels. We then performed two-sample MR to assess the causal effect of this genetically proxied effect on MASLD and related metabolic risk abnormalities. Genetically proxied dual GLP-1R/GIPR agonists was causally associated with a substantially reduced risk of MASLD (OR: 0.24, 95 % CI: 0.08-0.75, P = 0.01). This protective effect was accompanied by significant improvements in systemic metabolic health, including increased high-density lipoprotein cholesterol (Beta: 0.39, 95 % CI: 0.13-0.66, P = 3.40 × 10 This study provides causal evidence that dual GLP-1R/GIPR agonists protects against MASLD. The mechanism likely involves broad improvements in lipid metabolism and insulin sensitivity. These findings offer strong genetic validation for this therapeutic strategy and provide a compelling rationale for its continued clinical development for the treatment of MASLD. Show less
The AMPK/SIRT1/PGC-1α pathway serves as a central regulator of cellular energy homeostasis, coordinating metabolic stress responses, epigenetic modifications, and transcriptional programs. Its dysfunc Show more
The AMPK/SIRT1/PGC-1α pathway serves as a central regulator of cellular energy homeostasis, coordinating metabolic stress responses, epigenetic modifications, and transcriptional programs. Its dysfunction is implicated in the pathogenesis of a wide spectrum of complex modern diseases, spanning neurodegeneration, metabolic syndromes, and chronic inflammatory conditions. This review examines the pathway's role as an integrative hub and its potential as a therapeutic target. We synthesize current mechanistic evidence from molecular, cellular, and preclinical studies to elucidate the pathway's operational logic and the consequences of its dysregulation. The analysis is structured around key disease paradigms-including Alzheimer's disease, Parkinson's disease, diabetes, cardiovascular injury, stroke, and chronic kidney disease-to dissect its tissue-specific pathophysiological impacts. The AMPK/SIRT1/PGC-1α axis operates through a core positive feedback loop: AMPK activation elevates NAD+, thereby activating SIRT1, which in turn deacetylates and activates PGC-1α to drive mitochondrial biogenesis and function, further reinforcing SIRT1 activity. Disruption of this cascade manifests in disease-specific mechanisms: promoting Aβ production via BACE1/γ-secretase in Alzheimer's; impairing α-synuclein clearance in Parkinson's; disrupting GLUT4 translocation and insulin signaling in diabetes; exacerbating oxidative damage and mitochondrial dysfunction in cardiovascular and neuronal injury; and accelerating fibrosis and sustained inflammation in renal and pulmonary diseases via NLRP3 and TGF-β/Smad3 signaling. The AMPK/SIRT1/PGC-1α pathway represents a cornerstone target at the intersection of metabolism, aging, and disease. Current therapeutic strategies-including pharmacological activators (e.g., metformin, SRT1720), natural compounds (e.g., resveratrol), lifestyle interventions (e.g., exercise, caloric restriction), and emerging technologies (e.g., gene editing, exosomal miRNAs)-offer multidimensional avenues for intervention. Future research must prioritize elucidating tissue-specific regulatory mechanisms, such as AMPK isoform diversity and PGC-1α interactome dynamics, to enable precision therapeutics and successful clinical translation for a range of complex disorders. Show less