Validate the clinical utility of exosome cargo (miRNAs/proteins) and NLRP3/BDNF as key regulatory molecules for acupuncture-mediated spinal cord injury (SCI) recovery. From the establishment of the da Show more
Validate the clinical utility of exosome cargo (miRNAs/proteins) and NLRP3/BDNF as key regulatory molecules for acupuncture-mediated spinal cord injury (SCI) recovery. From the establishment of the database to May 2025, a literature search was conducted on PubMed, and Embase, using keywords ["exosome cargo" or "exosome"], ["acupuncture" or "acupuncture and moxibustion" or "electroacupuncture" or "EA"], ["spinal cord injury" or "SCI"], ["immune regulation"], ["inflammatory reaction"], ["neuroregeneration" or "nerve"]. Including peer-reviewed studies on human/animal models, articles that do not meet the requirements are excluded. Preclinically, MSC-exosomal miR-145-5p suppressed TLR4/NF-κB signaling, reducing spinal IL-1β by 47% in SD rats. Schwann cell-exosomal MFG-E8 activated SOCS3/STAT3, increasing M2 macrophage CD206 by 63% and raising rat BBB scores by 3.8 points; Treg-exosomal miR-2861 upregulated tight junction proteins (occludin/ZO-1) to repair the blood-spinal cord barrier. Acupuncture (EA at GV14/GV4) upregulated spinal BDNF by 72% and NGF by 58% via Wnt/β-catenin, while EA at GV6/GV9 downregulated NLRP3 by 42-58% and TNF-α by 35-47%. Clinically, EA at EX-B2 increased ASIA scores by 3.2±1.1 points (Guo et al). Besides, 5x/week EA improved ASIA vs 3x/week (+6.4 points). EA+exercise reduced MAS by 1.6-2.9 points, with outcomes correlated to peripheral NLRP3 reduction, BDNF elevation, and MBI/WISCIII increases. Exosome cargo (miR-145-5p/MFG-E8) and NLRP3/BDNF are key regulatory molecules underlying acupuncture-mediated SCI recovery. However, limitations (small RCT samples, heterogeneous acupuncture protocols, unstandardized exosome isolation) hinder translation. Future work should focus on standardized biomarker detection, exosome engineering, and large-scale clinical trials. Show less
Apolipoprotein E (APOE) alleles are well-established genetic risk factors for Alzheimer's disease (AD), but their effects on AD biomarkers (amyloid beta [Aβ]42/40, phosphorylated tau [p-tau]181, neuro Show more
Apolipoprotein E (APOE) alleles are well-established genetic risk factors for Alzheimer's disease (AD), but their effects on AD biomarkers (amyloid beta [Aβ]42/40, phosphorylated tau [p-tau]181, neurofilament light chain [NfL], and glial fibrillary acidic protein [GFAP]) may vary across populations due to ancestry-, age-, and sex-related differences. We hypothesized that these effects vary across Hispanic/Latino background groups with distinct ancestral admixture. We analyzed ε2 and ε4 allele associations with AD biomarkers using survey-weighted linear regression models, adjusting for demographic covariates. Secondary analyses examined genetic analysis group- and ancestry-specific effects. ε4 was associated with lower Aβ42/40 and higher p-tau181and GFAP levels, but not with NfL, suggesting its role in Aβ and tau deposition and neuroinflammation. ε4 associations were stronger in those with higher European and lower African ancestry. These findings expand on prior studies suggesting that genetic ancestry modifies APOE-associated AD risk in Hispanic/Latino populations and highlight the importance of capturing ancestry-based heterogeneity in AD biomarker research. Show less
Current in vitro enzyme inhibition assays often involve subjective data analysis based on the researcher's experience. In this study, we developed a multi-dimensional quantitative integration platform Show more
Current in vitro enzyme inhibition assays often involve subjective data analysis based on the researcher's experience. In this study, we developed a multi-dimensional quantitative integration platform (MDQIP) that uses a model to objectively calculate and rank compound activities, addressing the limitations of traditional "experience-driven" evaluations, accelerates the screening and evaluation of potential AChE inhibitors from Red Gastrodia elata, offering a more efficient approach to drug discovery. Ultrafiltration-LC screening identified parishin A as having the most stable binding, with binding degree and recovery rates of 98.85% and 99.39%, respectively. Molecular docking revealed that parishins A and C were the strongest AChE inhibitors, exhibiting stable binding through hydrogen bonds, π-alkyl, and π-π interactions. Molecular dynamics simulations confirmed the stability of these compounds, with binding energies of -82.65 ± 4.24 and - 80.69 ± 4.19 kcal/mol. Enzyme kinetics showed that parishins A and C are mixed-type inhibitors, with IC Show less
Timosaponin AIII (Tim-AIII), a steroidal saponin derived from Anemarrhena asphodeloides, has emerged as a promising antitumor agent, yet its precise molecular targets and mechanisms in breast cancer r Show more
Timosaponin AIII (Tim-AIII), a steroidal saponin derived from Anemarrhena asphodeloides, has emerged as a promising antitumor agent, yet its precise molecular targets and mechanisms in breast cancer remain poorly defined. Here, we identify fibroblast growth factor 2 (FGF2) as a direct binding target of Tim-AIII using a combination of network pharmacology, CETSA, and surface plasmon resonance assays. Mechanistically, Tim-AIII exhibits a dual therapeutic mode of action. First, it induces reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress, activating the eIF2α-ATF4-CHOP axis and initiating apoptosis. Second, it dampens the FGF2-FGFR1-PI3K/AKT signaling cascade, thereby inhibiting epithelial-mesenchymal transition (EMT) and suppressing cell migration and invasion. RNA sequencing and enrichment analyses confirm that Tim-AIII regulates critical oncogenic pathways, including ER stress, calcium signaling, and PI3K/AKT. In vivo evaluations demonstrate that Tim-AIII significantly reduces tumor growth without detectable systemic toxicity in breast cancer-bearing mice. This study not only elucidates the molecular basis of Tim-AIII's antitumor efficacy but also positions it as a potential targeted therapeutic for breast cancer, with dual action on ERS-induced apoptosis and EMT suppression. Show less
This first-in-human Phase I study evaluated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of KN069, a novel dual Glucagon-like peptide-1 receptor agonist (GLP-1RA)/Glucose- Show more
This first-in-human Phase I study evaluated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of KN069, a novel dual Glucagon-like peptide-1 receptor agonist (GLP-1RA)/Glucose-dependent insulinotropic polypeptide receptor (GIPR) antagonist in Chinese men with overweight/obesity. This randomised, double-blind trial included a single ascending dose (SAD; 12-120 mg, N = 36, 3:1 active-to-placebo) and a multiple ascending dose (MAD; N = 12, dose escalation 15-60 mg) phase. Safety was assessed via adverse events (AEs) and compliance. PK was analysed using a sandwich enzyme-linked immunosorbent assay (ELISA) for Intact and Total KN069. PD included measurements of body weight, waist circumference, body mass index (BMI) and metabolic parameters. Immunogenicity was assessed by detecting anti-drug antibodies (ADA). KN069 was well tolerated, with predominantly mild-to-moderate gastrointestinal adverse events. PK showed dose-proportional exposure (12-90 mg) with a long half-life for Total KN069 (899.74-1099.01 h). In the SAD part, preliminary dose-dependent weight reductions were observed, with maximum early changes at Day 7 (90 mg: -4.71% vs. placebo: -0.41%) and sustained for up to 133 days. In the MAD part, Group B (60 mg) achieved a -2.57% mean weight reduction from baseline at Day 25, alongside a significant decrease in waist circumference (p = 0.0446). Metabolic improvements included lower fasting glucose, triglycerides, uric acid and elevated insulin/C-peptide. KN069 exhibits favourable safety, long-acting PK and preliminary dose-dependent weight reduction alongside expected pharmacologic metabolic effects, supporting further clinical development. gov Identifier: NCT06547775. Show less
The global obesity epidemic necessitates therapies that enhance energy expenditure. Non-shivering thermogenesis (NST) in brown/beige adipose tissue represents a promising target, with fibroblast growt Show more
The global obesity epidemic necessitates therapies that enhance energy expenditure. Non-shivering thermogenesis (NST) in brown/beige adipose tissue represents a promising target, with fibroblast growth factor 21 (FGF21) emerging as a critical regulator linking environmental stimuli to adipose plasticity and mitochondrial function. However, the precise mechanisms of FGF21 secretion and its specific role in adipose tissue browning and subsequent NST potentiation remain incompletely elucidated. FGF21 regulates NST via distinct spatiotemporal mechanisms. Acute cold exposure triggers hepatic FGF21 secretion through a β FGF21 exhibits dual regulation: hepatic (acute lipid mobilization) and adipose-based (chronic browning); adipose-targeted FGF21 delivery is essential for therapeutic efficacy, and future studies should integrate FGF21 with UCP1-independent pathways (e.g., creatine/succinate cycles) to advance obesity treatment. Show less
Atherosclerosis (AS) is a prevalent typical chronic inflammation disease characterised by lipid deposition, immune cell infiltration and inflammatory response in the arterial intima. The long-term tre Show more
Atherosclerosis (AS) is a prevalent typical chronic inflammation disease characterised by lipid deposition, immune cell infiltration and inflammatory response in the arterial intima. The long-term treatments of the existing drugs suffered safety concerns. Show less
This study investigated the neuroprotective effects and mechanisms of cycloastragenol (CAG) on oxidative stress and neurological function in cerebral ischemia-reperfusion injury (CIRI) and oxygen-gluc Show more
This study investigated the neuroprotective effects and mechanisms of cycloastragenol (CAG) on oxidative stress and neurological function in cerebral ischemia-reperfusion injury (CIRI) and oxygen-glucose deprivation/reoxygenation (OGD/R) models. In vivo, rats were given oral CAG daily for 28 days before CIRI induction. Cerebral infarction and hippocampal injury were assessed using TTC, Nissl, and HE staining. Neurological scores, morris water maze, grip strength tests, and brain water content were used to evaluate functional outcomes. Oxidative stress was determined by biochemical assays, DHE staining, and transmission electron microscopy, while Western blotting was performed to measure neuroprotective proteins. In vitro, primary neurons were treated with CAG and subjected to OGD/R. Cell viability was tested by CCK-8 assay, apoptosis and mitochondrial membrane potential were analyzed by flow cytometry, ROS levels were quantified, and MDA, SOD, and GSH were measured biochemically. Western blot further evaluated BDNF and NeuN expression to confirm in vivo findings. In vivo, CAG reduced infarct volume and edema, improved neurological deficits, preserved the structural integrity of neurons in the hippocampal CA1 region. CAG also promoted motor function recovery, markedly reduced MDA levels, increased SOD and GSH activity, and upregulated BDNF and NeuN expression. In vitro, CAG enhanced cell viability in the OGD/R model, reduced apoptosis, restored mitochondrial membrane potential, and significantly suppressed oxidative stress induced by ischemia-reperfusion. CAG effectively alleviated injury caused by cerebral and cellular ischemia-reperfusion by maintaining redox homeostasis, inhibiting oxidative stress, and promoting the expression of neuroprotective proteins, demonstrating promising neuroprotective potential. Show less
Diabetic foot ulcers (DFU) are a major complication of diabetes, and its pathogenesis remains incompletely elucidated. Converging evidence indicates that oxidative stress and dysregulated mitochondria Show more
Diabetic foot ulcers (DFU) are a major complication of diabetes, and its pathogenesis remains incompletely elucidated. Converging evidence indicates that oxidative stress and dysregulated mitochondrial polarization participate in DFU progression, nominating these processes as therapeutically actionable targets. This study integrates bulk and single-cell transcriptomic data with machine learning to reconstruct cross-scale, cell type-resolved molecular atlases and regulatory networks. Macrophages and fibroblasts emerged as communication hubs, dominating pathway enrichment and ligand-receptor programs such as macrophage migration inhibitory factor signaling pathway (MIF), ANNEXIN signaling pathway, and COMPLEMENT signaling pathway. Peptidylprolyl isomerase F (PPIF), which encodes cyclophilin D (CypD) and apolipoprotein E (APOE) were further prioritized as putative drivers within macrophages and fibroblasts, and a five-gene classifier was derived with robust performance (internal/external AUC = 0.833/0.933). Within DFU lesions, under the control of non-coding RNA circuitry, SOX5 may shape the inflammatory microenvironment, APOE may participate in lipid-metabolic remodeling, and PPIF (CypD) likely links reactive oxygen species (ROS) accumulation to a p53-dependent mitochondrial death pathway (necroptosis/apoptosis). Orthogonal validation showed significantly increased CypD in diabetic foot ulcer skin (DFUS) and diabetic foot ulcer tendon (DFUT) relative to diabetic foot skin (DFS) and DFT (Diabetic foot tendon), with up-regulated p53 and Cytc and down-regulated ApoE in DFUS; in primary foot-skin fibroblasts, a high-glucose plus tert-butyl hydroperoxide (HG+TBHP) model reproduced elevated ROS, loss of mitochondrial Δψm (mitochondrial membrane potential), growth restriction, and apoptosis, supporting a ROS-CypD/mPTP (mitochondrial permeability transition pore)-Δψm depolarization-p53/Cytc apoptosis axis. The delineated PPIF-centered regulatory network includes upstream transcription factors CEBPB/REL/SPI1 and a downstream ceRNA axis comprising miR-128-3p/miR-23a-3p-long non-coding RNA OIP5-AS1. Additionally, the significant role of polarization-specific reprogramming in regulating macrophage function highlights therapeutic strategies focused on metabolic reprogramming and inhibition of the PPIF/mPTP pathway. Collectively, a cell type-resolved molecular map of DFU is provided, healing-relevant cell populations and regulatory circuits are prioritized, and a translational, testable intervention framework is proposed. Show less
Autophagy supports clear cell renal cell carcinoma (ccRCC) progression, yet its upstream regulatory mechanisms remain to be fully defined. Integrating bulk, single-cell, and spatial transcriptomics, w Show more
Autophagy supports clear cell renal cell carcinoma (ccRCC) progression, yet its upstream regulatory mechanisms remain to be fully defined. Integrating bulk, single-cell, and spatial transcriptomics, we identify a regulatory axis wherein the transcription factor ZBED6 activates the expression of the autophagy-initiating kinase PIK3C3 via the repression of IGF2, thereby driving pro-tumorigenic autophagy. Spatial analysis confirms the co-localization of ZBED6 and PIK3C3 in tumor tissues. Using genes associated with this axis, we develop a six-gene prognostic signature that stratifies patients with distinct survival outcomes and differential responses to immunotherapy and targeted therapy. Functional assays show that ZBED6 promotes ccRCC cell proliferation, migration, and invasion. This work elucidates a pathway governing autophagy in ccRCC and provides a framework for prognostic assessment and precision therapy. Show less
Elevated lipoprotein(a) [Lp(a)] is a genetically determined, causal risk factor for atherosclerotic cardiovascular disease, but effective therapies remain limited. Proprotein convertase subtilisin/kex Show more
Elevated lipoprotein(a) [Lp(a)] is a genetically determined, causal risk factor for atherosclerotic cardiovascular disease, but effective therapies remain limited. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are primarily used to lower low-density lipoprotein cholesterol (LDL-C), yet their effects on Lp(a) have been inconsistently reported. This umbrella review synthesizes meta-analytic evidence on PCSK9 inhibitors and Lp(a). We systematically searched PubMed, Embase, Web of Science, and Cochrane Library through April 2025 for meta-analyses of randomized controlled trials (RCTs) comparing PCSK9 inhibitors (alirocumab, evolocumab, inclisiran) with placebo or standard therapy. The primary outcome was mean percentage change in Lp(a). Methodological quality was assessed using the Assessment of Multiple Systematic Reviews 2 (AMSTAR-2), and evidence certainty was graded with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Overlap of primary trials was quantified using the Corrected Covered Area (CCA), and sensitivity analyses were performed to account for overlapping evidence. Twenty-one meta-analyses (116 RCTs; 231,796 participants) were included. The PCSK9 inhibitors consistently reduced Lp(a): evolocumab (29.68-46.68%; high certainty), alirocumab (18.55-26.46%; high certainty), and inclisiran (18.00%; high certainty). Higher biweekly doses yielded larger decreases (e.g., alirocumab 150 mg: 24.6%; evolocumab 140 mg: 26.8%, high certainty). Reductions were dose-dependent and broadly consistent across populations, comparators, follow-up durations, and baseline Lp(a). The Lp(a) reductions correlated modestly with LDL-C (β = 0.28; 95% CI 0.07-0.49) and apolipoprotein B (apoB) (β = 0.33; 95% CI 0.03-0.63). Concomitant reductions in LDL-C, apoB, and major adverse cardiovascular events were supported by high and moderate certainty evidence. Safety was favorable, with injection-site reactions being the most common adverse event. Sensitivity analyses confirmed robustness of findings after accounting for overlapping trials. The PCSK9 inhibitors, particularly evolocumab 140 mg every 2 weeks, significantly lower Lp(a) alongside LDL-C and apoB. These findings highlight the consistent Lp(a)-lowering effect of PCSK9 inhibitors. However, the observed cardiovascular benefits are largely attributable to concomitant LDL-C reduction, and the incremental contribution of Lp(a) lowering remains uncertain. Confirmation from outcome trials specifically designed to target Lp(a) is required. PROSPERO CRD420251048597. Show less
Dual GIP/GLP-1 receptor agonists have gained significant attention in clinical applications because of their remarkable efficacy in reducing obesity and type 2 diabetes. However, the mechanisms by whi Show more
Dual GIP/GLP-1 receptor agonists have gained significant attention in clinical applications because of their remarkable efficacy in reducing obesity and type 2 diabetes. However, the mechanisms by which these dual agonists affect systemic metabolism remain elusive. To investigate the effects of a novel dual-receptor agonist, THDBH120, on systemic metabolism in obese individuals and the specific roles of GIPR and GLP-1R in modulating systemic and adipose tissue metabolism. To evaluate the intrinsic properties of THDBH120, we conducted a potency assay by using HEK293 cell lines overexpressing either human GIPR or GLP-1R and measured the accumulation of cAMP as a downstream second messenger following receptor activation. To evaluate the efficacy of THDBH120 on systemic metabolism, we used obese rodents and nonhuman primate species that received various doses and frequencies of THDBH120. To determine the metabolic roles of GLP-1R and GIPR in mediating the beneficial effects of THDBH120, we used GLP-1R- and GIPR-knockout mouse models treated with THDBH120, the GLP-1R agonist semaglutide, or the GIPR agonist LAGIPRA and performed transcriptomic sequencing analyses of adipose tissues. THDBH120 is a novel long-acting dual GIPR/GLP-1R agonist that has superior weight loss and metabolic improvement effects in rodents and mammals. The activation of GLP-1R by semaglutide or THDBH120 improved lipid metabolism, whereas the activation of GIPR by LAGIPRA or THDBH120 alleviated inflammation. THDBH120 improved lipid metabolism via GLP-1R-mediated pathways and mitigated inflammation by activating GIPR-associated pathways in the adipose tissues of obese mice. Both GLP-1R and GIPR are important in mediating the beneficial effects of dual receptors on systemic metabolism. THDBH120 is a novel long-acting dual GIPR/GLP-1R agonist that has potential clinical applications. Show less
Jingbo Lu, Runhao Xu, Tinghua Li+2 more · 2026 · Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition · added 2026-04-24
To investigate changes in serum lipid profile parameters combined with tumor markers in gastric cancer (GC) patients and their value in GC screening. A total of 100 patients diagnosed with GC at Renji Show more
To investigate changes in serum lipid profile parameters combined with tumor markers in gastric cancer (GC) patients and their value in GC screening. A total of 100 patients diagnosed with GC at Renji Hospital (West) between May and September 2025 were consecutively enrolled as the GC group (54 cases in stage Ⅰ/Ⅱ and 46 cases in stage Ⅲ/Ⅳ). Additionally, 100 age- and sex-matched healthy individuals undergoing routine physical examinations were included as the healthy control (HC) group. The serum levels of nine lipid indicators (high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], total cholesterol [TC], triglycerides [TG], small and dense low-density lipoprotein cholesterol [sdLDL-C], apolipoprotein [Apo] A1, ApoB, ApoC2, and ApoC3) and five tumor markers (carcinoembryonic antigen [CEA], carbohydrate antigen [CA] 19-9, CA50, CA242, and CA72-4) were measured using an automatic biochemical analyzer and an electrochemiluminescence instrument. Intergroup differences were analyzed using the Mann-Whitney Compared with the HC group, the GC group showed significantly lower levels of ApoA1, ApoC3, TC, HDL-C, LDL-C, and sdLDL-C ( The combined panel of ApoA1, ApoC3, HDL-C, LDL-C, TC, sdLDL-C, CEA, CA50 and age offers a potential auxiliary tool for detecting gastric cancer. Show less
The role of efferocytosis in chronic rhinosinusitis (CRS), particularly CRS with nasal polyps (CRSwNP), remains poorly understood. We comprehensively characterized efferocytosis in CRS and determined Show more
The role of efferocytosis in chronic rhinosinusitis (CRS), particularly CRS with nasal polyps (CRSwNP), remains poorly understood. We comprehensively characterized efferocytosis in CRS and determined its association with inflammatory endotypes and clinical outcomes in CRSwNP. Efferocytosis-related marker expression between nasal polyps and healthy nasal mucosa was detected by quantitative real-time PCR and immunohistochemistry. Public single-cell RNA sequencing profiles of CRS were reanalyzed to dissect efferocytosis at single-cell resolution. Associations between efferocytosis and tissue inflammation were evaluated by Spearman correlation. Regression models and receiver operating characteristic analyses assessed the predictive capability of efferocytosis for CRSwNP recurrence. Compared with controls, CRSwNP exhibited widespread efferocytosis deficiency, including "find me" signals (CX3CR1, S1PRs, P2RY2, GPR132), "eat me" signals (ITGAV, MerTK, Tim1, ADGRB1), "don't eat me" signal CD300a, postengulfment signals (ABCA1, NR1H3/2, PPARδ/γ), and bridging molecule MFGE8. Macrophages, the principal efferocytic cells, shifted from homeostatic C3 Insufficient phagocytosis and increased antiphagocytosis activity are hallmarks of efferocytosis deficiency in CRS and are associated with the severity of inflammation and the clinical outcome of CRSwNP. Show less
Depression is a debilitating psychiatric disorder with high prevalence and suicide risk, imposing significant burdens on global health. Against this global health burden, the active ingredients of Gek Show more
Depression is a debilitating psychiatric disorder with high prevalence and suicide risk, imposing significant burdens on global health. Against this global health burden, the active ingredients of Gekko gecko Linnaeus (AIGG), a traditional Chinese medicine (TCM), have shown empirical antidepressant effects. However, their specific pharmacological mechanisms remain unclear. This study systematically elucidated the antidepressant mechanisms of AIGG by integrating GC-MS-based component analysis, network pharmacology, molecular docking, and a corticosterone (CORT)-induced depressive mouse model. GC-MS identified 10 bioactive compounds (including fatty acids) in AIGG. Network pharmacology screening of 51 potential targets revealed significant enrichment in synaptic transmission and cAMP pathways. Molecular docking confirmed strong binding affinities between AIGG-derived compounds and key targets. In vivo experiments demonstrated that AIGG significantly reversed depression-like behaviors in both forced swim and tail suspension tests, suppressed Interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), and elevated β-nerve growth factor (β-NGF) levels, attenuated neuroinflammatory infiltration and neuronal apoptosis in brain tissue, and upregulated protein expression of protein kinase cAMP-activated catalytic subunit alpha (PRKACA), brain-derived neurotrophic factor (BDNF), and postsynaptic density protein 95 (PSD95). The study confirmed that AIGG alleviates depression by activating the cAMP-PRKACA-BDNF axis to restore synaptic plasticity, providing a novel natural product-based strategy for treatment of the resistant depression. Show less
Keratoconus (KC) is a progressive disorder of corneal thinning characterized by responses in the extracellular matrix and cellular interactions. This study used bioinformatics methods to identify key Show more
Keratoconus (KC) is a progressive disorder of corneal thinning characterized by responses in the extracellular matrix and cellular interactions. This study used bioinformatics methods to identify key genes involved in KC development and in anoikis and endoplasmic reticulum (ER) stress. KC and control datasets from the GEO database were analyzed to identify differentially expressed genes (DEGs). These were cross-referenced with anoikis and ER stress-related genes from Genecards. Functional enrichment, immune infiltration analysis, and machine learning techniques (LASSO, Random Forest) were used to identify candidate molecular signatures, which were then validated in an animal model. We identified 46 DEGs associated with anoikis and 41 DEGs related to ER stress. Functional analysis linked them to apoptosis and IL-17 signaling. Five key molecular signatures were identified: CDKN1A, MCL1, PTGS2, PTHLH, and ANGPTL4. The expression of ANGPTL4, CDKN1A, and MCL1 was consistent in the animal model. These genes are associated with inflammatory and oxidative stress responses. Twelve potential therapeutic drugs were predicted. This study identifies five candidate molecular signatures for KC related to anoikis and ER stress, offering insights into KC pathogenesis and potential targeted therapies. Show less
Fibroblast growth factor receptor 2 (FGFR2) has gained recognition as a compelling therapeutic target in oncology. We present LHQ766, a novel orally bioavailable FGFR2 inhibitor demonstrating exceptio Show more
Fibroblast growth factor receptor 2 (FGFR2) has gained recognition as a compelling therapeutic target in oncology. We present LHQ766, a novel orally bioavailable FGFR2 inhibitor demonstrating exceptional potency and selectivity, through optimization of our previously reported FGFR2 inhibitor 7. The structures and purity of all target compounds were confirmed by Show less
High-dose methotrexate for pediatric cancer treatment is frequently associated with mucositis, which can lead to delayed or discontinued treatment and impact survival. While individual genetic variant Show more
High-dose methotrexate for pediatric cancer treatment is frequently associated with mucositis, which can lead to delayed or discontinued treatment and impact survival. While individual genetic variants have been implicated, the cumulative impact of genetic variation within relevant biological pathways remains unexplored. We evaluated single nucleotide polymorphisms across 18 pathways previously identified as relevant to mucositis in 278 pediatric patients with acute lymphoblastic leukemia from six academic health centers across Canada. Pathway enrichment was assessed using the Joint Association of Genetic variants tool, and a predictive model was developed using XGBoost, a supervised machine learning algorithm based on gradient-boosted decision trees. Pathway enrichment identified significant associations in IL6 (P = 0.04) and WNT/β-catenin (P = 0.048) signaling pathways. The predictive model (area under the curve [AUC] = 0.76) highlighted single nucleotide polymorphisms associated with inflammation- and mucosa-related genes, including PRKCD, IL17B, MAST3, and CAPN9, with both risk and protective effects. Model performance dropped by 0.15 in AUC (from 0.76 to 0.61) after removing single nucleotide polymorphism features, underscoring their predictive value. This pathway-informed approach identifies genetic contributors to methotrexate-induced mucositis and supports polygenic risk prediction. Our findings provide a foundation for individualized toxicity risk profiling and suggest potential therapeutic targets to mitigate treatment-limiting mucositis in pediatric oncology. Show less
As a result of individual genetic variations, some patients show no response to initial antidepressant medications. This study aims to investigate the association between specific genetic polymorphism Show more
As a result of individual genetic variations, some patients show no response to initial antidepressant medications. This study aims to investigate the association between specific genetic polymorphisms and the efficacy of antidepressant drugs and to improve the accuracy and effectiveness of treatment under the guidance of genetic testing. A retrospective screening was conducted on medical records from, Suixian People's Hospital between January 2022 and December 2024. A total 202 patients with depression carrying the CYP2C19 gene were selected after the application of exclusion criteria. They were assigned to three groups in accordance with their genetic metabolism types: the rapid metabolism group (Group A, n = 65), the intermediate metabolism group (Group B, n = 94) and the poor metabolism group (Group C, n = 43). All three groups were treated with sertraline for a six-week treatment cycle. The observation indicators included scores on the Hamilton Depression Scale (HAMD); onset time of drug effect; rates of response and remission; scores on the Clinical Global Impression-Improvement (CGI-I) scale; levels of the neurotransmitter factors 5-hydroxytryptamine (5-HT), γ-aminobutyric acid (GABA) and brain-derived neurotrophic factor (BDNF); incidence of adverse events; and scores on the Morisky Medication Adherence Scale-8 (MMAS-8). The baseline data of the three groups of patients were comparable before medication (p > 0.05). Compared with those in Groups A and B, patients in Group C showed a significantly greater reduction in HAMD scores (all p < 0.05), along with higher response rates (all p < 0.05) and remission rates (all p < 0.05). Amongst the three groups, Group C had a shorter onset time of drug effect (all p < 0.05); more significant improvement in CGI-I scores (all p < 0.05); and more prominent upregulation of neurotransmitter factors, namely, 5-HT (all p < 0.05), GABA (all p < 0.05) and BDNF (all p < 0.05). Regarding the incidence of adverse events, Group C had the highest rate, whereas Group A had the lowest (10.8% vs. 24.5% vs. 41.9%). Compared with other groups, Group B exhibited a more significant increase in MMAS-8 scores (all p < 0.05). Metabolic phenotype exerts substantial effects on the therapeutic outcome of sertraline in patients with depression carrying the CYP2C19 gene. Amongst groups, Group C showed better therapeutic efficacy but an elevated incidence of adverse events and lower medication adherence; Group A had relatively poor efficacy; and Group B demonstrated superior adherence. In clinical practice, individualised treatment can be implemented on the basis of CYP2C19 metabolic typing to improve therapeutic efficacy and reduce adverse events and medical burden. Show less
One important element impacting meat quality is fat metabolism, which mainly affects meat features through intramuscular fat deposition. Chinese native yellow-feathered broilers and white-feathered br Show more
One important element impacting meat quality is fat metabolism, which mainly affects meat features through intramuscular fat deposition. Chinese native yellow-feathered broilers and white-feathered broilers differ significantly in intramuscular fat concentration. This study used transcriptomic and metabolomic sequencing technologies to identify a total of 173 differentially expressed genes and 259 differential metabolites in the pectoral muscles of Chahua Chicken No. 2 and Cobb broiler in order to explore the genetic mechanisms by which lipid metabolism influences meat quality in Chinese indigenous yellow-feathered and white-feathered broilers. These included differentially expressed genes like FABP1, LPL, ELOVL7, SLC27A1, MOGAT1, and ULK2, which were enriched in pathways relevant to lipid metabolism and showed strong associations with γ-linolenic acid and palmitaldehyde, two distinct metabolites. In order to develop local chicken germplasm resources and breed superior indigenous chicken varieties, these candidate genes could serve as the genetic foundation for the variations in meat quality and lipid metabolism between Chinese native yellow-feathered and white-feathered broilers. Show less
Pancreatic cancer (PC) is a common gastrointestinal malignancy whose initiation and progression may be closely linked to the gut microbiota. Previous research indicates that Scutellaria barbata D. Don Show more
Pancreatic cancer (PC) is a common gastrointestinal malignancy whose initiation and progression may be closely linked to the gut microbiota. Previous research indicates that Scutellaria barbata D. Don and Scleromitrion diffusum (Willd.) R.J. Wang (SB-SD) exhibit diverse biological activities, such as anti-inflammatory, antioxidant, and antitumor effects, though their precise regulatory mechanisms are not fully elucidated. Here, we treated PC cells with SB-SD to assess its impact on cell viability, apoptosis, migration, and cell cycle progression, while Western blotting analyzed the expression of HSP90AA1, MAPK3, p53, CDK1, and p21. We also established a pancreatic cancer xenograft model in nude mice to evaluate the in vivo inhibitory effect of SB-SD on tumor growth. Furthermore, we employed metagenomic sequencing, untargeted metabolomics, and quantitative proteomics to comprehensively profile changes in the gut microbiota, serum metabolites, and differentially expressed proteins, with Western blotting subsequently validating BCKDK, GATM and p53 expression. The results show that SB-SD significantly inhibited PC cell proliferation, promoted apoptosis, and induced S/G2 phase cell cycle arrest, potentially via modulation of the HSP90AA1/MAPK3 signaling pathway. Measurements of tumor volume and weight, complemented by histopathological analysis, confirmed that SB-SD effectively suppressed the growth of PANC-1 xenograft tumors. Integrated multi-omics analyses suggest that the antitumor effects of SB-SD may involve the modulation of key gut microbes like Bacteroides caccae and Lactobacillus, the promotion of choline metabolism, and the regulation of BCKDK and GATM. Together, these findings not only corroborate the direct antitumor activity of SB-SD against pancreatic cancer but also offer novel mechanistic insights by constructing a microbiota-metabolite-protein interaction network. Show less
Focal articular cartilage defects often progress to osteoarthritis, imposing a substantial global health burden. Current neglect of cartilage developmental regulation and cartilage microenvironment co Show more
Focal articular cartilage defects often progress to osteoarthritis, imposing a substantial global health burden. Current neglect of cartilage developmental regulation and cartilage microenvironment compromises therapeutic efficacy. We developed an innovation CE-SKP/CPH/P2G3 scaffold which effectively repairs focal cartilage defects and emulates native cartilage ontogeny: the superficial CE-SKP hydrogel layer recruits SMSCs and promotes chondrogenesis; the middle CPH hydrogel layer induces chondrocyte hypertrophic calcification, forming cartilage calcified layer; and the basal P2G3 nanofiber membrane isolates subchondral cells, enforcing a top-down developmental sequence and preserving a localized hypoxic niche. Show less
Although glass-based long-persistent luminescence (LPL) materials offer superior transparency and integration capability compared with conventional phosphors, their emission has been predominantly res Show more
Although glass-based long-persistent luminescence (LPL) materials offer superior transparency and integration capability compared with conventional phosphors, their emission has been predominantly restricted to the blue-green region, leaving warm-color LPL largely unexplored. In this work, Mn Show less
Diabetic retinopathy (DR) is a leading cause of vision loss in working-age adults and often progresses to proliferative diabetic retinopathy (PDR) with irreversible complications. Anti-vascular endoth Show more
Diabetic retinopathy (DR) is a leading cause of vision loss in working-age adults and often progresses to proliferative diabetic retinopathy (PDR) with irreversible complications. Anti-vascular endothelial growth factor (VEGF) therapy remains the first-line treatment; however, resistance poses a significant challenge, necessitating alternative therapeutic targets. This study explores the role of angiopoietin-like protein 4 (ANGPTL4) in PDR pathogenesis, emphasizing vascular-immune-lymphatic interactions. We found significantly elevated ANGPTL4 and VEGF-C levels in the vitreous humor of patients with PDR, which were not affected by anti-VEGF therapy. In vivo, full-length ANGPTL4 and its C-terminal fragment promoted pathological angiogenesis and lymphatic-like remodeling in diabetic murine retinas, characterized by increased lymphatic vessel endothelial hyaluronan receptor 1, prospero homeobox 1, and VEGF receptor 3 (VEGFR3) expression. Single-cell sequencing further revealed ANGPTL4-driven immune dysregulation, with abnormal infiltration of CD4+ T cells and dendritic cells. Knockdown of ANGPTL4 in mice with oxygen-induced retinopathy alleviated retinal hypoxia, neovascularization, and vascular leakage. Mechanistically, retinal hypoxia markedly increased ANGPTL4 expression levels in the retina, which activated the activator protein-1 (AP-1) transcription factor complex and promoted Cd83 transcription in mouse heart microvascular endothelial cells. Additionally, ANGPTL4 bound to neuropilin-1 (NRP1)/VEGFR3, driving human lymphatic endothelial cell proliferation and lymphatic vessel ingrowth from the optic nerve sheath into the retina, a finding that suggests a novel pathway independent of angiopoietin-Tie signaling. These findings establish ANGPTL4 as a key mediator of immune-vascular interactions in PDR and a potential therapeutic target to address both pathological angiogenesis and lymphatic dysfunction. Some patients with proliferative diabetic retinopathy (PDR) have poor responses to anti-vascular endothelial growth factor (anti-VEGF) therapy. This situation highlights the need for additional therapeutic approaches. In proliferative diabetic retinopathy, what is the role of ANGPTL4 that differs from VEGF? We found that ANGPTL4 is elevated in the vitreous humor of patients with PDR who are poorly responsive to anti-VEGF therapy. ANGPTL4, particularly its C-terminal fragment, causes retinal lymphatic-like remodeling in diabetic mice. This study provides novel insights into the complex interplay between immune activation, neovascularization, and lymphatic-like remodeling in PDR. Our findings deepen our understanding of PDR pathophysiology and propose a promising therapeutic target. Show less
According to existing research findings, dihydroartemisinin effectively regulates bone metabolism balance, while ferroptosis is closely related to the occurrence of steroid-induced osteonecrosis of th Show more
According to existing research findings, dihydroartemisinin effectively regulates bone metabolism balance, while ferroptosis is closely related to the occurrence of steroid-induced osteonecrosis of the femoral head. As the exact biological mechanism among the three is still unclear, Mendelian randomization, computer-aided drug design, and transcriptomics sequencing were used to explore the specific mechanism of action. The study validated the specific signaling pathways through which dihydroartemisinin may treat steroid-induced osteonecrosis of the femoral head using animal experiments and transcriptomics sequencing. Data were obtained from public databases for Mendelian randomization analysis, and a two-sample Mendelian randomization was used to determine the intermediary role of core pathway-related targets. Computer-aided drug design was employed to assess the binding affinity between dihydroartemisinin and core targets. Transcriptome sequencing determined that dihydroartemisinin may treat steroid-induced osteonecrosis of the femoral head by regulating ferroptosis. We obtained 564 ferroptosis-related targets that met the analysis criteria and 1812 plasma proteins from the UK Biobank, and analyzed finngen_R11_OSTEON_DRUGS in the Finnish database as outcome. The results showed that there were two quantitative trait loci that had a causal relationship with ferroptosis targets. There were 110 protein quantitative trait loci causally associated with plasma proteins from the UK Biobank, and none of these loci had an inverse causal relationship with SONFH. Through mediation analysis, 7 mediating pathways were identified, yielding eight targets including ZP3, CCL17, APOE, C7ORF50, SPINK4, SPINK2, FTMT, and PRDX6. Computer-aided drug design revealed that CCL17 and PRDX6 exhibited the best docking effects. The study determined that CCL17 and PRDX6 have a significant causal relationship with SONFH. It also clarified the specific mechanism by which DHA may regulate ferroptosis to treat SONFH, which will provide a reference for the discussion of the prevention and treatment mechanisms of SONFH. Show less
Prior studies indicate that allyl isothiocyanate (AITC) alleviates metabolic dysfunction-associated steatotic liver disease (MASLD). The vitamin D receptor (VDR) is known to exert protective effects i Show more
Prior studies indicate that allyl isothiocyanate (AITC) alleviates metabolic dysfunction-associated steatotic liver disease (MASLD). The vitamin D receptor (VDR) is known to exert protective effects in MASLD; however, whether AITC alleviates MASLD through VDR remains unclear. To clarify the function and underlying mechanisms of AITC in MASLD AML-12 cells were exposed to 300 μM palmitate acid (PA) for 24 hours to establish an To establish an AITC provides a robust molecular basis for improving MASLD by activating hepatic VDR and driving the downstream HNF-4α/MTTP/ApoB signaling pathway. This pathway reduces hepatic lipid accumulation, promotes FA β-oxidation, and improves insulin resistance, establishing AITC as a promising treatment for MASLD. Show less