Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (MLN-TK) are rare hematologic malignancies defined by recurrent kinase gene rearrangements.
To establish the reference interval for the serum lipid index in pregnant women and to explore the relationship between lipid metabolism levels and pregnancy outcomes. Data were derived from 446 pregn Show more
To establish the reference interval for the serum lipid index in pregnant women and to explore the relationship between lipid metabolism levels and pregnancy outcomes. Data were derived from 446 pregnancy women and 317 healthy non-pregnant women. Serum levels of total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), lipoprotein (a) [Lp(a)], and hypersensitive C-reactive protein (hs-CRP) were measured in both groups. The mean and standard deviation of each index were calculated to establish the reference range of normal serum lipid levels in pregnant women in mid-to-late pregnancy. The associations between serum lipid levels and perinatal outcomes were assessed statistically. There were no significant differences in age, pregnancy, or parity between the adverse outcome and normal delivery groups, but the caesarean section rate was significantly higher in the adverse outcome group. The levels of hs-CRP, TG, TC, HDL-C, LDL-C, and ApoA1 were significantly higher in the adverse outcome group. Elevated hs-CRP, TG, and HDL-C levels were risk factors for adverse pregnancy outcomes. According to the receiver operating characteristic curve, the optimal threshold of the combined diagnosis of these three indicators to predict adverse pregnancy outcomes was 0.534, and the area under the curve was 0.822. The establishment of lipid reference intervals in the second and third trimesters of pregnancy can effectively evaluate lipid metabolism in pregnant women, and the measurement of lipid metabolism in pregnant women is helpful in predicting adverse pregnancy outcomes. Show less
Understanding the adaptive evolution of brain function in extreme environments remains a central challenge in evolutionary biology. This study investigates the molecular mechanisms underlying cave ada Show more
Understanding the adaptive evolution of brain function in extreme environments remains a central challenge in evolutionary biology. This study investigates the molecular mechanisms underlying cave adaptation by comparing brain transcriptomes of sympatric cave-dwelling ( Show less
Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by hyperglycemia and insulin resistance, Migraine is a common chronic neurological disease caused by increased excitability of the Show more
Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by hyperglycemia and insulin resistance, Migraine is a common chronic neurological disease caused by increased excitability of the central nervous system, both exerting substantial health burdens. However, the shared genetic basis and underlying molecular mechanisms remain largely unexplored. This study integrates single-cell data and Mendelian randomization (MR) analysis to identify comorbidity-associated genes and elucidate potential mechanistic links between these two conditions. Single-cell datasets from T2DM and migraine were analyzed to identify differentially expressed genes (DEGs). MR analysis was employed to prioritize key causal genes, followed by network-based functional characterization, disease-drug association analysis, cell annotation, and pseudo-time trajectory modeling. Analysis of single-cell data identified 2,128 migraine-associated and 3,833 T2DM-associated genes, with 714 genes shared between the two diseases. MR analysis highlighted AP4E1 and HSD17B12 as key regulators implicated in both conditions. Network analysis further linked these genes to lipid metabolism and vesicle transport pathways. Computational predictions revealed common comorbidities, including metabolic dysregulation and chemical-induced liver injury, as well as potential therapeutic agents such as valproic acid and bisphenol A. Single-cell annotation identified six major immune cell types in T2DM (T cells, NK cells, B cells, CD14 monocytes, CD16 monocytes, and dendritic cells), with T cells emerging as central players. In migraine, five immune cell types were identified (CD4 T cells, CD8 T cells, B cells, NK cells, and monocytes), with monocytes being the predominant cell type. Pseudo-time analysis delineated seven subpopulations of T cells and four subpopulations of monocytes, suggesting distinct functional trajectories in disease pathogenesis. However, due to the use of peripheral blood-derived single-cell data, genes primarily expressed in the central nervous system, such as CALCA and RAMP1, could not be detected, limiting the identification of certain migraine-specific pathways. This single-cell data and MR analysis investigation identifies AP4E1 and HSD17B12 as pivotal genetic determinants in T2DM-migraine comorbidity, shedding light on their molecular interplay and potential therapeutic relevance. Show less
Inflammation is crucial in regulating coagulation and hemostasis. While prior research shows that apolipoprotein A-IV (ApoA-IV) has anti-inflammatory and antiplatelet effects, its specific impact on c Show more
Inflammation is crucial in regulating coagulation and hemostasis. While prior research shows that apolipoprotein A-IV (ApoA-IV) has anti-inflammatory and antiplatelet effects, its specific impact on coagulation remains unclear. To investigate the effects of ApoA-IV on the coagulation system, including its interactions with potential targets and the underlying mechanisms. Plasma ApoA-IV levels in deep vein thrombosis patients were tested by enzyme-linked immunosorbent assay. The effects of ApoA-IV on coagulation were assessed through thromboelastography. Potential interactions and mechanisms were analyzed using surface plasmon resonance and AlphaFold 3. Mice bleeding and stroke models were employed to evaluate the effects on hemostasis and thrombosis. ApoA-IV levels were reduced in deep vein thrombosis patients and correlated with increased thrombotic risk. Thromboelastography showed that ApoA-IV treatment delayed clot reaction and kinetic times while decreasing thrombus generation angle and maximum amplitude, highlighting its crucial role in inhibiting coagulation and platelet aggregation. We identified ApoA-IV as a functional activator of activated protein C (APC), with critical interactions occurring at residues 144 to 148 within the exosite loop of the APC protease domain. In animal models, anti-ApoA-IV antibody administration shortened bleeding time but exacerbated ischemic stroke outcomes. Notably, inhibitory peptide HE5, which inhibits ApoA-IV-APC interaction, effectively counteracted the anticoagulant activity of ApoA-IV. These findings establish ApoA-IV as a pivotal regulator of coagulation and hemostasis, primarily through enhancing APC activity. This research advances our understanding of the interplay between inflammation, lipid metabolism, and thrombosis, offering insights for developing novel antithrombotic therapies. Show less
Sijie Gu, Haoran Feng, Xiaomei Li+10 more · 2025 · Molecular therapy : the journal of the American Society of Gene Therapy · Elsevier · added 2026-04-24
Preventing the progression from acute kidney injury (AKI) to chronic kidney disease (CKD) remains a considerable clinical challenge. In this study, we elucidate the role of WNT5A in accelerating the A Show more
Preventing the progression from acute kidney injury (AKI) to chronic kidney disease (CKD) remains a considerable clinical challenge. In this study, we elucidate the role of WNT5A in accelerating the AKI-to-CKD transition and its underlying mechanisms. Renal biopsies from patients with AKI showed marked upregulation of WNT5A and its receptor, CD146, in proximal tubules, with higher expression in patients with CKD progression. In murine AKI models, Wnt5a knockdown attenuated CKD progression. Conversely, proximal tubular overexpression of Wnt5a exacerbated renal fibrosis in ischemia-reperfusion injury (IRI) mice, which was alleviated by Box5, a specific WNT5A antagonist. In vitro, WNT5A overexpression in transforming growth factor β (TGF-β)-stimulated HK-2 cells promoted CD146 upregulation, activated JNK phosphorylation, and enhanced SNAI1 expression. The genetic silencing of WNT5A/CD146 and JNK inhibition suppresses SNAI1 expression and attenuates fibrotic responses. Mechanistically, JNK-mediated c-JUN phosphorylation promoted its interaction with KLF5 at the SNAI1 promoter, driving renal fibrosis. Elevated serum levels of soluble CD146 correlated with renal function in patients with AKI and were higher in patients exhibiting CKD progression. Inhibition of WNT5A could serve as a therapeutic target for delaying renal fibrosis in AKI progression. Show less
Accumulation of amyloid-β (Aβ) peptides and hyperphosphorylated tau proteins in the hippocampus triggers cognitive memory decline in Alzheimer's disease (AD). The incidence and mortality of sporadic A Show more
Accumulation of amyloid-β (Aβ) peptides and hyperphosphorylated tau proteins in the hippocampus triggers cognitive memory decline in Alzheimer's disease (AD). The incidence and mortality of sporadic AD were tightly associated with diabetes and hyperlipidemia, while the exact linked molecular mechanism is uncertain. Here, the present investigation identified significantly elevated serum Kallistatin levels in AD patients concomitant with hyperglycemia and hypertriglyceridemia, suggesting potential crosstalk between neuroendocrine regulation and metabolic dysregulation in AD pathophysiology. In addition, the constructed Kallistatin-transgenic (KAL-TG) mice defined its cognitive memory impairment phenotype and lower long-term potentiation in hippocampal CA1 neurons accompanied by increased Aβ deposition and tau phosphorylation. Mechanistically, Kallistatin could directly bind to the Notch1 receptor and thereby upregulate BACE1 expression by inhibiting PPARγ signaling, resulting in Aβ cleavage and production. Besides, Kallistatin could promote the phosphorylation of tau by activating GSK-3β. Fenofibrate, a hypolipidemic drug, could alleviate cognitive memory impairment by downregulating Aβ and tau phosphorylation of KAL-TG mice. Collectively, the experiments clarified a novel mechanism for Aβ accumulation and tau protein hyperphosphorylation regulation by Kallistatin, which might play a crucial role in linking metabolic syndromes and cognitive memory deterioration, and suggested that fenofibrate might have the potential for treating metabolism-related AD. Show less
NRBF2, a component of autophagy-associated PIK3C3/VPS34-containing phosphatidylinositol 3-kinase complex, plays a crucial role in learning and memory processes, yet its specific impact on memory and t Show more
NRBF2, a component of autophagy-associated PIK3C3/VPS34-containing phosphatidylinositol 3-kinase complex, plays a crucial role in learning and memory processes, yet its specific impact on memory and the underlying molecular mechanisms remains unclear. Here, we utilized NRBF2 knockout mice to examine its influence on the time course of fear memory. Employing quantitative PCR, Western blot analysis, behavioral tests, and electrophysiology, we investigated the mechanisms through which NRBF2 affects memory processing. We observed an increase in This study offer new insights into the role of NRBF2 and highlight the potential of targeting NRBF2 as a therapeutic strategy for addressing cognitive deficits associated with various disorders. Show less
Long noncoding RNAs (lncRNAs), non-protein-coding transcripts exceeding 200 nucleotides, are critical regulators of gene expression through chromatin remodeling, transcriptional modulation, and post-t Show more
Long noncoding RNAs (lncRNAs), non-protein-coding transcripts exceeding 200 nucleotides, are critical regulators of gene expression through chromatin remodeling, transcriptional modulation, and post-transcriptional modifications. While ionizing radiation (IR) induces cellular damage through direct DNA breaks, reactive oxygen species (ROS)-mediated oxidative stress, and bystander effects, the functional involvement of lncRNAs in the radiation response remains incompletely characterized. Here, through genome-wide CRISPR activation (CRISPRa) screening in non-small cell lung cancer (NSCLC) cells, we identified LOC401312 as a novel radiosensitizing lncRNA, the stable overexpression of which significantly enhanced IR sensitivity. Transcriptomic profiling revealed that LOC401312 transcriptionally upregulates carbamoyl-phosphate synthase 1 (CPS1), a mitochondrial enzyme involved in pyrimidine biosynthesis. Notably, CPS1 overexpression recapitulated the radiosensitization phenotype observed with LOC401312 activation. Mechanistic investigations revealed that CPS1 suppresses the phosphorylation of ATM kinase (Ser1981) protein, which is a key mediator of DNA damage checkpoint activation. This study established the LOC401312-CPS1-ATM axis as a previously unrecognized regulatory network governing radiation sensitivity, highlighting the potential of lncRNA-directed metabolic rewiring to impair DNA repair fidelity. Our findings not only expand the functional landscape of lncRNAs in DNA damage response but also provide a therapeutic rationale for targeting the LOC401312-CPS1 axis to improve radiotherapy efficacy in NSCLC. Show less
Accurate and generalizable prediction of drug-target interactions (DTIs) remains a critical challenge for drug discovery, particularly when addressing underexplored targets and compounds. Recent advan Show more
Accurate and generalizable prediction of drug-target interactions (DTIs) remains a critical challenge for drug discovery, particularly when addressing underexplored targets and compounds. Recent advances in graph neural networks and large-scale pre-trained models offer new opportunities to capture rich structural and functional features essential for DTI prediction while enhancing the generalization ability. We present GS-DTI, a graph structure-based DTI prediction framework that integrates molecular graph transformers, protein language models, and protein tertiary structure. Our method achieved robust and interpretable DTI predictions. GS-DTI extracts drug features from SMILES-derived molecular graphs using a knowledge-guided pre-trained transformer, while protein features are derived from both sequence and predicted 3D structure for comprehensive representation. A multi-task loss function equipped with contrastive learning is adopted to enhance generalization and functional interpretability. Extensive experiments on the benchmarks and challenging cross-domain settings demonstrate that GS-DTI achieves state-of-the-art performance. Notably, our model improves the MCC by over 10% compared to previous methods in the drug-target pair cold start test. The model can pinpoint the binding pockets of the targets, offering robust interpretability, and case studies show GS-DTI's promising potential in virtual screening for new candidate drugs of BACE1. The GS-DTI source code and processed datasets are available at https://github.com/purvavideha/GSDTI. All experimental data are derived from public sources. Show less
Yolk percentage is a critical index in the egg product industry, reflecting both nutritional value and economic benefits. To elucidate the underlying mechanisms that contribute to variations in egg yo Show more
Yolk percentage is a critical index in the egg product industry, reflecting both nutritional value and economic benefits. To elucidate the underlying mechanisms that contribute to variations in egg yolk percentage, we performed integrated transcriptome and metabolome analyses on the liver, ovary, and magnum tissues of Rhode Island Red chickens with high and low yolk percentages. A total of 322 differentially expressed genes (DEGs) and 128 significantly differential metabolites (SDMs) (VIP>1, P < 0.05) were identified in the liver, whereas 419 DEGs and 215 SDMs were detected in the ovary, and 238 DEGs along with 47 SDMs were found in the magnum. In the liver, genes such as HMGCR, DHCR7, MSMO1, and CYP7A1 were linked to cholesterol metabolism, essential for steroid hormone synthesis and yolk formation, while ACACB, ACSL1, ACSL4, LPL, and SGPP2 were involved in fatty acid biosynthesis, a key process for supplying energy and structural components of the yolk. In the ovary, COL6A6, COMP, CHAD, ITGA7, THBS2, and TNC contributed to extracellular matrix-receptor interactions, which are fundamental for follicle development and oocyte maturation. In the magnum, UGT1A1, MAOB, and ALDH3B2 participated in drug metabolism-cytochrome P450 and amino acid metabolism, ensuring a proper environment for egg white formation and potentially influencing nutrient allocation to the yolk. Metabolic pathway enrichment revealed that steroid hormone biosynthesis, glycerophospholipid metabolism, and betaine metabolism were predominant in the liver; pyruvate, taurine, and hypotaurine metabolism in the ovary; and phenylalanine metabolism in the magnum. Moreover, integrated analysis highlighted key metabolites and genes potentially regulating yolk deposition, including 7,8-dihydroneopterin and Pg 38:4 in the liver (related to immune modulation and lipid metabolism, respectively), thalsimine in the ovary, as well as DL-glutamine in the magnum, all of which may be crucial for maintaining metabolic homeostasis and supporting egg formation. Collectively, these findings deepen our understanding of how distinct molecular and metabolic pathways in the liver, ovary, and magnum orchestrate yolk proportion and deposition. Such insights may advance future strategies to improve egg quality and productivity in poultry breeding programs. Show less
This study focuses on the impacts of polystyrene/polylactic acid microplastics (PS/PLA-MPs) on ovarian reserve and oocyte maturation in female mice, along with the underlying mechanisms. 1 μm PS-MPs a Show more
This study focuses on the impacts of polystyrene/polylactic acid microplastics (PS/PLA-MPs) on ovarian reserve and oocyte maturation in female mice, along with the underlying mechanisms. 1 μm PS-MPs and PLA-MPs were prepared, with PLA-MPs having a rougher surface and broader size distribution. In vitro, PLA-MPs showed higher cytotoxicity to granulosa cells compared to PS-MPs. In vivo, MPs exposure disrupted the estrous cycle, and damaged ovarian reserve. Granulosa cell apoptosis and cytokine activation led to transzonal projection retraction, oocyte oxidative stress, meiotic abnormalities, and reduced oocyte retrieval and polar body extrusion rate, thus reducing litter size. PS-MPs induced more severe intestinal and ovarian impairment. Analysis of feces 16S rRNA, serum metabolomics, and ovarian RNA sequencing revealed that lipoprotein lipase (LPL) was suppressed by both MPs, linking gut microbiota, lipid metabolism, and ovarian injury. Fecal microbiota transplantation as a rescue strategy in MPs exposed mice upregulated LPL, alleviating ovarian reserve decline. In PLA-MPs exposed mice, ovarian reserve related indicators partially recovered after a two-week exposure cessation. These results clarify the similarities and differences in how PS-MPs and PLA-MPs impair ovarian function via gut-ovary axis and lipid metabolism dysregulation. Show less
Colorectal cancer (CRC) is a prevalent digestive system malignancy accompanied by peritoneal metastasis occurring in 7% of cases. Methyltransferase-like 3 (METTL3) promoted the progression of CRC wher Show more
Colorectal cancer (CRC) is a prevalent digestive system malignancy accompanied by peritoneal metastasis occurring in 7% of cases. Methyltransferase-like 3 (METTL3) promoted the progression of CRC whereas its function in peritoneal metastasis was incompletely understood. Here, we found that METTL3 was upregulated in peritoneal metastasis tissues of CRC patients compared with CRC tissues. By sequencing the mRNA of above tissues, we discovered that METTL3-mediated N6-methyladenosine (m6A) modification regulated the downstream target Show less
To identify distinct sleep quality profiles among patients undergoing maintenance hemodialysis (MHD) using latent profile analysis (LPA), and examine differences in perceived stigma across these sleep Show more
To identify distinct sleep quality profiles among patients undergoing maintenance hemodialysis (MHD) using latent profile analysis (LPA), and examine differences in perceived stigma across these sleep quality subtypes. From December 2024 to March 2025, a total of 334 MHD patients were recruited via convenience sampling from the nephrology departments of two tertiary hospitals in Xinjiang, China. Data were collected using structured questionnaires, including the Pittsburgh Sleep Quality Index (PSQI), the Self-Rating Depression Scale (SDS), and the Social Impact Scale (SIS), along with sociodemographic and clinical information. LPA was employed to identify latent subgroups of sleep quality based on PSQI components. Multinomial logistic regression was used to determine predictors of sleep profile membership. Differences in stigma scores across sleep profiles were analyzed using non-parametric equivalents. Three distinct sleep profiles were identified: Class 1 - "overall better sleep", Class 2 - "short sleep duration and low efficiency", and Class 3 - "poor sleep quality with high medication use". Multinomial logistic regression identified comorbid heart failure (OR=2.867, Patients with MHD exhibit heterogeneous patterns of sleep disturbance, which are associated with varying levels of perceived stigma. Those with the poorest sleep quality and highest reliance on medication experience the most pronounced stigma. Tailored interventions addressing sleep-related issues and psychosocial factors may help reduce stigma and improve patient well-being. Show less
Lipid overaccumulation in the liver predisposes ducks to metabolic disorders. The molecular mechanism of oleic acid (OA)-induced hepatic steatosis in ducks is not fully elucidated. A cellular model of Show more
Lipid overaccumulation in the liver predisposes ducks to metabolic disorders. The molecular mechanism of oleic acid (OA)-induced hepatic steatosis in ducks is not fully elucidated. A cellular model of steatosis was established by treating primary duck hepatocytes with OA. Transcriptome sequencing was performed to identify key signaling pathways and candidate genes. The role of Apolipoprotein A1 (APOA1) was investigated through overexpression and knockdown experiments. Intracellular triglycerides (TGs) were quantified commercially; lipid droplets were visualized by Oil Red O staining. Intracellular TG accumulation was induced by OA treatment in a dose-dependent manner. Through transcriptome analysis, 1045 differentially expressed genes (DEGs) were identified, with APOA1 being recognized as a key candidate within the peroxisome proliferator-activated receptor (PPAR) signaling pathway. The content of TGs and lipid droplets was increased by APOA1 overexpression, whereas these effects were suppressed by APOA1 knockdown. The expression of acetyl-CoA carboxylase alpha (ACACA) and fatty acid synthase (FASN) was upregulated by APOA1. Conversely, the expression of carnitine O-palmitoyltransferase 1 (CPT1), acyl-CoA oxidase 1 (ACOX1), and apolipoprotein B (APOB) was downregulated. This study demonstrates that OA upregulates APOA1, suggesting the involvement of the PPAR pathway and providing a theoretical basis for modulating hepatic fat deposition. Show less
The Kruppel-like factor 15(KLF15) gene functions as a crucial transcriptional modulator involved in numerous cellular processes such as differentiation, proliferation, growth, and programmed cell deat Show more
The Kruppel-like factor 15(KLF15) gene functions as a crucial transcriptional modulator involved in numerous cellular processes such as differentiation, proliferation, growth, and programmed cell death. The epithelial-to-mesenchymal transition (EMT) provides malignant cells with the adaptability and movement necessary for tumor advancement and spread, with zinc finger E-box binding homeobox 1(ZEB1) playing a pivotal role as a transcriptional factor in EMT. This investigation initially examined the association between the KLF15 protein and EMT associated transcription factors such as ZEB1, Slug, and Snail, along with marker proteins like E-cadherin and β-catenin in bladder cancer. Furthermore, we explored their connections with clinicopathological attributes and conducted prognostic analyses. Immunohistochemical techniques were utilized to ascertain the presence of KLF15 protein and EMT-associated transcription factor proteins, along with their marker proteins in 110 specimens of bladder cancer tissues. Concurrently, clinicopathological data and postoperative survival statistics were amassed. The rates of KLF15 and Slug protein expression were linked with pathological differentiation, lymphatic involvement, and pTNM staging. The protein expression rates of ZEB1, Slug, Snail, E-cadherin, and β-catenin also showed associations with lymphatic metastasis and pTNM stages. Notably, the expression of KLF15, the coexpression of KLF15 and ZEB1, and lymphatic metastasis emerged as independent prognostic indicators for the overall survival rates in bladder cancer cases. EMT enhances the risk of tumor recurrence and reduces overall survival durations in bladder cancer cases. Furthermore, KLF15 is a significant contributor to the EMT pathway in bladder cancer, primarily through its interaction with the transcription factor ZEB1. KLF15 and ZEB1 might serve as key biomarkers for metastasis and prognosis, offering potential new targets for therapeutic intervention in bladder cancer. Show less
The malignant transformation of odontogenic keratocysts (OKC) into cancerous odontogenic keratocysts (COKC) is exceedingly rare, and its mechanisms remain poorly understood. Studies exploring the cell Show more
The malignant transformation of odontogenic keratocysts (OKC) into cancerous odontogenic keratocysts (COKC) is exceedingly rare, and its mechanisms remain poorly understood. Studies exploring the cellular heterogeneity, molecular pathways, and clinical features of COKC are limited. In this study, we performed single-cell RNA sequencing (scRNA-seq) on three COKC samples and integrated the data with a public OKC dataset, identifying 22,509 single cells. Two COKC-specific epithelial subpopulations, Basal-C0-EXT1 and Basal-C3-HIST1H3B, were identified. These subpopulations exhibited enhanced stemness and invasive potential, respectively, suggesting their roles as key drivers of OKC carcinogenesis. Fibroblasts underwent phenotypic transitions, particularly from inflammation-associated fibroblasts (IFBs) to myofibroblasts (MFBs). Similarly, macrophage phenotypic transformation may also play a role in OKC carcinogenesis. Clinical observations of severe lesion-area pain in COKC patients suggest potential neuroinvasiveness, Supported by single-cell transcriptomic data, imaging findings, and histopathological evidence. A review of clinical data revealed that none of the COKC patients exhibited cervical lymph node metastasis. Single-cell transcriptomics suggests that this phenomenon may be associated with an active immune microenvironment in COKC, reduced epithelial-mesenchymal transition (EMT) activity, lower VEGFC expression, and upregulated MAST4 expression as a potential regulator of lymphatic metastasis. In conclusion, COKC exhibits distinct molecular, cellular, and clinical characteristics compared to OKC, featuring potent neuroinvasiveness and low lymph node metastatic potential. These findings provide important insights into the mechanisms underlying COKC development and may guide novel diagnostic and therapeutic strategies. Show less
As a chronic lipid driven arterial disease, dyslipidemia is one of the most critical risk factors for atherosclerosis (AS). The gut microbiota plays an important role in regulating host lipid metaboli Show more
As a chronic lipid driven arterial disease, dyslipidemia is one of the most critical risk factors for atherosclerosis (AS). The gut microbiota plays an important role in regulating host lipid metabolism disorders. Studies have shown that the herb "Gualou-Xiebai" (GLXB) can effectively regulate the blood lipid levels of ApoE Show less
The mediation effect of 24-hour physical activities on the association between type 2 diabetes and mortality is unclear. Additionally, Little evidence was found on the isotemporal substitution effect Show more
The mediation effect of 24-hour physical activities on the association between type 2 diabetes and mortality is unclear. Additionally, Little evidence was found on the isotemporal substitution effect of 24-hour physical activities components on changing Life expectancy among patients with type 2 diabetes diagnosed. To address the abovementioned research gap, the study has a two-fold aims: first, to examine the mediation effect of 24-hour physical activities in type 2 diabetes and mortality; and second, to address how reallocating time on different daily activities would affect life expectancy. Analysis was conducted on the accelerometer data of 103,359 participants in the UK Biobank, with a median age of 57 years (range 39 to 70). Compositional mediation cox model was conducted to analyze the mediating effects of 24-hour physical activities. Additionally, the cohort Life table method was utilized to estimate the changes of Life-years over the next 10 years resulting from the substitution effect of different physical activities. During a mean follow-up of 13.95 (range 2.95-16.28) years, 2,649 deaths were recorded. Diabetes was significantly associated with increased time spent engaging in sedentary behavior (SB), and reduced time spent on moderate-to-vigorous physical activity (MVPA) and light-intensive physical activity (LPA), thereby demonstrating an association with higher mortality risk. The indirect effect of physical activity (HR = 1.27, 95% CI 1.23-1.30) accounted for 41.9% of the total effect of diabetes on mortality. Furthermore, the Life expectancy gains with a maximum of 1.32 years over the next 10 years was found when reallocating SB time to MVPA. The results revealed that 24-hour physical activities might mediate the association between diabetes and mortality. Therefore, promoting participation in MVPA and reducing sedentary activities among diabetes patients was expected to have a positive effect on Life expectancy over the next 10 years. Show less
SANET-ep (NCT02588170) and SANET-p (NCT02589821) demonstrated the efficacy and safety of surufatinib versus placebo in patients with advanced extra-pancreatic and pancreatic neuroendocrine tumours (NE Show more
SANET-ep (NCT02588170) and SANET-p (NCT02589821) demonstrated the efficacy and safety of surufatinib versus placebo in patients with advanced extra-pancreatic and pancreatic neuroendocrine tumours (NETs). Here, we present a pooled analysis of final overall survival (OS) from two randomised phase 3 studies. The SANET studies were randomised, placebo-controlled, double-blind, phase 3 studies in China, comparing the efficacy and safety of oral 300-mg surufatinib (n = 265) versus placebo (n = 133) in patients with unresectable/metastatic, well-differentiated NETs (grade 1/2). After progression of disease or study unblinding, patients receiving placebo crossed over/switched to open-label surufatinib. By pooling the data from the two studies, OS analysis was completed using Kaplan-Meier methodology and a Cox proportional hazards model in the intention-to-treat population. Exploratory analyses were performed using different models to correct the confounding effect introduced by crossover. Long-term safety was assessed. At study termination, 69 % of the placebo group had crossed over/switched to surufatinib. Median OS was 50.1 versus 46.8 months for patients initially on surufatinib versus those initially on placebo (stratified hazard ratio [HR] 0.935, 95 % confidence interval [CI] 0.684-1.278; p = 0.6727). After correcting the confounding effect introduced by crossover/switching, the HR ranged from 0.558 to 0.825. Commonly (≥10 %) reported treatment-related adverse events (grade 3/4) included hypertension and proteinuria. OS of patients initially on surufatinib was not significantly longer versus patients initially on placebo, likely due to the high amount of crossover from placebo to surufatinib. No new safety signals were observed. SANET-ep (NCT02588170) and SANET-p (NCT02589821). Show less
To explore the influence related factors of endoscopic assistant in gasless transaxillary endoscopic thyroidectomy by using machine learning and nomogram, and construct an endoscopic assistant system. Show more
To explore the influence related factors of endoscopic assistant in gasless transaxillary endoscopic thyroidectomy by using machine learning and nomogram, and construct an endoscopic assistant system. A skilled endoscopic assistant(Group A, The learning curve coefficient of goodness of fit R It is necessary to train endoscopic assistant to build an endoscopic assistant system, and improve the surgical process by shortening CET, TRT and reduce LWT times. The importance of experience accumulation to improve the efficiency of surgery should be emphasized. Show less
The high mortality rate of severe heat stroke is mainly related to multiple organ dysfunction syndrome (MODS), and respiratory failure caused by acute lung injury (ALI) is a significant factor in the Show more
The high mortality rate of severe heat stroke is mainly related to multiple organ dysfunction syndrome (MODS), and respiratory failure caused by acute lung injury (ALI) is a significant factor in the development of MODS during the course of severe heat stroke. Previous research has demonstrated that severe heat stroke-induced acute lung injury (sHS-ALI) is associated with an increase in reactive oxygen species (ROS) in vascular endothelial cells (VECs), but the specific initiating factors and intermediate mechanisms involved are unclear. In this study, the mRNA profiles of mouse lung tissues were analysed using high-throughput sequencing. Genome-wide knockout was performed using CRISPR-Cas9 technology to identify a cohort of differentially expressed genes that promote human umbilical vein endothelial cells survival after heat stress. The expression of key proteins [fibroblast growth factor 23 (FGF23), phosphorylated fibroblast growth factor receptor-1 (p-FGFR-1), FGFR-1, phosphorylated phospholipase C-γ2 (p-PLC-γ2), PLC-γ2, p-p47 In this study, we first screened sHS-ALI target genes by cross-comparison This study confirmed that FGF23/FGFR1 signalling, as an upstream priming factor, mediated NOX2-ROS activation in VECs after heat stress, thus participating in the sHS-ALI process. FGFR-1 Y766 phosphorylation is essential for FGF23/FGFR-1 signalling activation in VECs, which is involved in sHS-ALI. These findings further clarify the mechanism underlying sHS-ALI and contribute to reducing the mortality and morbidity of severe heat stroke. Show less
Acute rejection (AR) is a significant complication in liver transplantation, impacting graft function and patient survival. Kupffer cells (KCs), liver-specific macrophages, can polarize into pro-infla Show more
Acute rejection (AR) is a significant complication in liver transplantation, impacting graft function and patient survival. Kupffer cells (KCs), liver-specific macrophages, can polarize into pro-inflammatory M1 or anti-inflammatory M2 phenotypes, both of which critically influence AR outcomes. Angiopoietin-like 4 (ANGPTL4), a secretory protein, is recognized for its function in regulating inflammation and macrophage polarization. This study investigates the effects of ANGPTL4 on KC polarization through cellular interactions between hepatocytes (HCs) and KCs. Using a rat orthotopic liver transplantation model, we observed reduced ANGPTL4 expression during AR, whereas increased ANGPTL4 levels were linked to immune tolerance. Administration of ANGPTL4 recombinant protein improved liver function, suppressed inflammation, and promoted M2 polarization of KCs. Co-culture experiments demonstrated that hepatocyte-derived ANGPTL4 significantly modulates KC polarization and inflammatory responses, mainly by inhibiting the NF-κB signaling pathway. The results emphasize the promise of ANGPTL4 as a therapeutic target to reduce AR and improve liver transplant outcomes by influencing hepatocyte-KC interactions. Show less
As a novel member of the interleukin(IL)-1 family, IL-38 has shown therapeutic effects in various chronic inflammatory diseases. However, its role and underlying mechanisms in cardiovascular diseases, Show more
As a novel member of the interleukin(IL)-1 family, IL-38 has shown therapeutic effects in various chronic inflammatory diseases. However, its role and underlying mechanisms in cardiovascular diseases, particularly atherosclerosis, remain unclear. This study aimed to explore the effects of IL-38 on atherosclerosis progression and its mechanisms in regulating macrophage function during the atherosclerotic process. To evaluate the therapeutic potential of IL-38 in atherosclerosis, we performed histopathological examinations and biochemical analyses in vivo. In vitro, we used primary bone marrow-derived macrophages (BMDMs) stimulated with oxidized low-density lipoprotein (ox-LDL) to assess the anti-inflammatory effects of IL-38 and quantified its impact on ox-LDL-induced macrophage polarization. To further elucidate the specific mechanisms by which IL-38 regulates macrophage function, we conducted mRNA sequencing and validated downstream regulatory signaling pathways. IL-38 exhibited therapeutic potential in atherosclerosis by reducing atherosclerotic plaque formation, modulating plaque composition, suppressing the production of proinflammatory cytokines within plaques, and potentially regulating macrophage cholesterol metabolism. Moreover, IL-38 exerted significant anti-inflammatory effects on macrophages both in vivo and in vitro. Notably, it inhibited the polarization of macrophages toward the proinflammatory M1-like phenotype in both settings. Additionally, IL-38 impeded the phosphorylation and nuclear translocation of p65 in BMDMs and reduced ox-LDL-induced macrophage apoptosis. IL-38 holds therapeutic potential for atherosclerosis, as it alleviates disease progression, inhibits macrophage polarization toward the M1-like phenotype, suppresses nuclear factor-κB (NF-κB) signaling activation, and reduces macrophage apoptosis. This study provides new insights into the anti-inflammatory mechanisms by which IL-38 mitigates atherosclerosis. Show less
Liver X receptor α (LXRα) plays an important role in inflammatory immune response induced by hepatic ischemia-reperfusion injury (IRI) and acute rejection (AR). Macrophage M1-polarization play an impo Show more
Liver X receptor α (LXRα) plays an important role in inflammatory immune response induced by hepatic ischemia-reperfusion injury (IRI) and acute rejection (AR). Macrophage M1-polarization play an important role in the occurrence and development of AR. Although the activation of LXR has anti-inflammatory effects, the role of LXRα in AR after liver transplantation (LT) has not been elucidated. We aimed to investigate LXRα anti-inflammatory and macrophage polarization regulation effects and mechanisms in acute rejection rat models. LXRα anti-inflammatory and liver function protective effects was initially measured in primary Kupffer cells and LT rat models. Subsequently, a flow cytometry assay was used to detect the regulation effect of LXRα in macrophage polarization. HE staining, TUNEL and ELISA were used to evaluate the co-treatment effects of TO901317 and tacrolimus on hepatic apoptosis and liver acute rejection after LT. In this study, we found that LPS can inhibit the expression of LXRα and activate MAPK pathway and PI3K/AKT/mTOR. We also found that LXRα agonist (TO901317) could improve liver function and rat survival after LT by activating the level of ABCA1 and inhibiting MAPK. TO901317 could inhibit macrophage M1-polarization by activating PI3K/AKT/mTOR signal pathway to improve the liver lesion of AR rats after liver transplantation. Additionally, co-treatment with TO901317 and tacrolimus more effectively alleviated the damaging effects of AR following LT than either drug alone. Our results suggest that the activation of LXRα can improve liver function and rat survival after LT by regulate ABCA1/MAPK and PI3K/AKT/mTOR signaling axis in macrophages. Show less
MicroRNAs (miRNAs) are a class of endogenous non-coding small RNAs that are widely found in organisms and play an important regulatory role in various biological processes, especially immune and infla Show more
MicroRNAs (miRNAs) are a class of endogenous non-coding small RNAs that are widely found in organisms and play an important regulatory role in various biological processes, especially immune and inflammatory responses. However, the function of miR-320b in the inflammatory responses of bovine mammary epithelial cells (bMECs) remains to be elucidated. In this study, we examined the miR-320b mimic transduction group (miR-320b_mimic) and negative control mimic transduction group (NC_mimic) of lipopolysaccharide-treated bMECs using data-independent acquisition (DIA) proteomics and untargeted metabolomics. Subsequently, we performed a joint analysis of the sequencing data. Proteomic analysis identified 330 differentially abundant proteins (DAPs) primarily related to PPAR, ferroptosis, arachidonic acid metabolism, IL-17, and complement and coagulation cascades. Metabolome analysis identified 128 and 66 differentially accumulated metabolites (DAMs) in the positive and negative ion mode primarily involved in linoleic acid metabolism, cholesterol metabolism, AMPK, MAPK, and chemokine. Integrated metabolomics and proteomics analysis revealed the co-enrichment of DAPs and DAMs in choline metabolism in cancer, endocrine resistance, glycerophospholipid metabolism, primary bile acid biosynthesis, and the ferroptosis signaling pathways. The results of quantitative real-time PCR (RT-qPCR) showed that compared with the NC_mimic group, mRNA expression levels of COX-2, IL-12 A, iNOS, MAPK1, and MAPK14 genes were significantly down-regulated, and the mRNA expression levels of PPARγ, CEBPα, CEBPβ, FABP4, and LPL genes were significantly up-regulated in the miR-320b_mimic group. These results provide crucial insights into the molecular regulatory functions of miR-320b and offer valuable data for further research on molecular breeding aimed at enhancing mastitis resistance in bovine animals. Show less
Colorectal cancer (CRC) metastasis remains a major cause of mortality, driven by epithelial-to-mesenchymal transition (EMT) and invasion. Programmed cell death 4 (Pdcd4), a tumor suppressor, is known Show more
Colorectal cancer (CRC) metastasis remains a major cause of mortality, driven by epithelial-to-mesenchymal transition (EMT) and invasion. Programmed cell death 4 (Pdcd4), a tumor suppressor, is known to inhibit translation via interaction with eukaryotic initiation factor 4A (eIF4A). Previous studies have established that Pdcd4 suppresses stress-activated protein kinase 1-interacting protein 1 (Sin1) translation through the mTORC2-Akt axis, thereby downregulating Snail expression and EMT in CRC cells. However, whether Pdcd4 directly regulates Slug, another critical EMT transcription factor, remains unexplored. PDCD4 shRNA and SLUG siRNA were used to knock down Pdcd4 and Slug in colorectal cancer cells, respectively. The sucrose gradient fractionation was performed to determine SLUG translation. A luciferase reporter assay was used to determine the role of the SLUG 5' untranslated region (5'UTR) on Pdcd4 inhibition. The effect of Slug on promoting invasion was determined by Matrigel invasion assays. Knockdown of Pdcd4 in colorectal cancer cells increased Slug protein levels without altering SLUG mRNA abundance. Sucrose gradient fractionation revealed that Pdcd4 knockdown elevated the proportion of SLUG mRNA in polysome fractions, demonstrating Pdcd4-mediated suppression of SLUG translation. To validate the mechanism, the SLUG 5'UTR was cloned and fused to a luciferase reporter and named SLUG-5'UTR-Luc. Pdcd4 knockdown markedly enhanced SLUG-5'UTR-Luc activity; whereas, ectopic Pdcd4 expression suppressed it, indicating that the SLUG 5'UTR is critical for Pdcd4-mediated translational repression. Treatment with the eIF4A inhibitor silvestrol substantially reduced Slug protein levels and SLUG-5'UTR-Luc activity. In addition, Pdcd4 overexpression decreased Slug protein abundance and restored E-cadherin expression. Notably, Slug knockdown in Pdcd4-deficient cells rescued E-cadherin expression and abrogated the invasive phenotype. These findings suggest that up-regulation of Slug translation by Pdcd4 knockdown contributes to enhanced invasion. Pdcd4 suppresses colorectal cancer invasion by translationally downregulating Slug expression. Show less
Cardiovascular diseases (CVDs) are the leading global cause of mortality and disability, with prevalence increasing due to aging and risk factors like obesity and hypertension. The retina, rich in mic Show more
Cardiovascular diseases (CVDs) are the leading global cause of mortality and disability, with prevalence increasing due to aging and risk factors like obesity and hypertension. The retina, rich in microvasculature, provides a unique opportunity to investigate microvascular dysfunction linked to CVDs and other systemic vascular diseases. This study used a multifaceted approach to assess the genetic correlation and causal relationship between retinal characteristics and CVDs. Linkage disequilibrium score regression (LDSC) and Mendelian randomization (MR) analyses were conducted using genome-wide association study (GWAS) data from the UK Biobank and FinnGen datasets. A cross-sectional study was also conducted to validate the findings, collecting optical coherence tomography (OCT) images from 124 eyes (89 with CVDs and 35 healthy controls). A prediction model is based on least absolute shrinkage and selection operator (LASSO) regression to assess the risk of CVD. Using LDSC and two-sample MR, we found genetic evidence consistent with a causal effect whereby genetically proxied thinner retinal nerve fiber layer (RNFL) was associated with higher risks of hypertension and myocardial infarction (MI), while genetically proxied thicker photoreceptor inner segment/outer segment (PR-IS/OS) was associated with coronary heart disease and MI (false discovery rate [FDR] thresholds as reported). Genetically proxied thinner retinal pigment epithelium (RPE) showed an inverse association with stroke risk. Several circulating biomarkers-including lipoprotein(a) [Lp(a)], low-density lipoprotein cholesterol (LDL-C), and ApoB-exhibited MR evidence of association with multiple CVDs. In a cross-sectional cohort, retinal layer differences and their relationships with lipids were directionally consistent with the genetic findings. Retinal structural traits measured by OCT-particularly RNFL, PR-IS/OS, and RPE thickness-are best interpreted as non-invasive markers that reflect systemic vascular biology. Our MR analyses support shared etiologic pathways between retinal microstructure and CVDs rather than implying that retinal damage clinically causes cardiovascular events. Findings warrant validation in larger and more diverse populations and should not be considered definitive proof of causality. Show less