👤 Jihai Peng

Despite the known impacts of weaning on animal health, the underlying molecular mechanisms remain unclear, particularly how psychological and nutritional stress differentially affect gut health and immune function over time. This study hypothesized that early weaning exerts distinct short- and long-term effects on lamb stress physiology, immunity, and gut health, mediated by specific molecular pathways. Twelve pairs of full-sibling male Hu sheep lambs were assigned to control (CON) or early-weaned (EW) groups. Plasma stress/immune markers were dynamically monitored, and intestinal morphology, antioxidant capacity, apoptosis, and transcriptomic profiles were analyzed at 5 and 28 days post-weaning. Early weaning triggered transient psychological stress, elevating hypothalamic-pituitary-adrenal (HPA) axis hormones (cortisol, catecholamines) and inflammatory cytokines (TNF-α) within 1 day ( Show less

Cholesterol is an essential molecule for tumor cell growth and proliferation, and dysregulated cholesterol metabolism has been widely implicated in cancer pathogenesis. However, the specific role and underlying molecular mechanisms of cholesterol metabolism alterations in diffuse large B-cell lymphoma (DLBCL) remain poorly understood. We retrospectively analyzed clinical data from 200 DLBCL patients and 185 healthy controls, focusing on lipid and lipoprotein levels, including triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), and apolipoprotein E (ApoE). Univariate and multivariate Cox proportional hazard models were used to evaluate the prognostic value of these markers, and Kaplan-Meier analysis assessed their associations with overall survival (OS). Bioinformatics analysis predicted associations between lipid markers and cholesterol metabolism. Cellular experiments further investigated the expression of cholesterol metabolism-related proteins and the effect of the cholesterol-depleting agent Methyl-β-cyclodextrin (MβCD) on DLBCL cells. We confirmed significant alterations in metabolic markers (such as TC and ApoA1) between the healthy control group and patients, which were significantly associated with patient prognosis and overall OS. Bioinformatics analysis revealed a strong correlation between these markers and elevated CD36 expression. In addition, DLBCL cells exhibited increased expression of cholesterol uptake and synthesis proteins (CD36, SREBP2, and HMGCR) and decreased expression of efflux proteins (APOA1, NR1H2 and ABCG1), consistent with cholesterol metabolic reprogramming. Treatment with MβCD disrupted CD36 expression and cholesterol metabolism, leading to reduced DLBCL cell survival. These findings underscore the pivotal role of cholesterol metabolic reprogramming in DLBCL progression. CD36 and related metabolic markers represent promising therapeutic targets, opening novel avenues for the treatment of this malignancy. Show less

The spleen is essential for immunity, mediating host defense against pathogens and regulating immunological homeostasis. Western-style diets commonly cause the aggregation of body fat and the emergence of obesity. This state might lead to damage to the spleen's functions. However, the effects of Western-style diets on gene expression and metabolic regulation in the spleen have not yet been fully explored. In this study, Show less

Thrombosis is a life-threatening complication in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. This study aims to conduct a statistical analysis of the incidence of blood clots and lipid concentrations, and to examine the networks of oxylipins in hospitalised patients with SARS-CoV-2. Serum samples of 1731 hospitalised patients with SARS-COV-2 were used to measure six lipid parameters: total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A (apoA), and apolipoprotein B (apoB). Additionally, the lipid profiles and oxidative lipidomics characteristics were examined via liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-MS/MS) in SARS-COV-2-positive patients with and without thrombosis. The mortality rate in the SARS-COV-2 thrombosis group was significantly higher at 29.6% compared to the SARS-COV-2 non-thrombosis group at 12.1% (P < 0.0001). The levels of the lipid parameters were closely associated with both thrombosis and SARS-COV-2 severity. Patients with SARS-COV-2 admitted to the hospital exhibited significant changes in oxidative lipid metabolites, specifically in the arachidonic acid (ARA) and docosahexaenoic acid (DHA) classes, compared with those in the control group. Among the thrombus group, 28 oxidative lipid metabolites were found to be differentially expressed compared to the non-thrombus group, and with the most notable variations observed in 20-hydroxyPGF2α and 14(15)-EpETE. Enrichment analysis using KEGG revealed that differential oxidized lipid metabolites mainly concentrated in the ARA and serotonergic synapses metabolism signaling pathway. Our findings indicate a close association between lipid mediators and both SARS-COV-2 and thrombi. Specifically, ARA and serotonergic synapses metabolism signaling pathway may be an important pathogenic factor for thrombosis caused by SARS-COV-2. Furthermore, 20-hydroxyPGF2α and 14(15)-EpETE show promise as potential biomarkers for SARS-CoV-2-induced thrombosis. Show less

The association between low-density lipoprotein (LDL) cholesterol and increased mortality risk has been well-documented, yet apolipoprotein B (apoB) is regarded as a more precise risk indicator. However, a comprehensive analysis integrating both markers in relation to mortality risk remains unreported. This study aimed to investigate the relationship between LDL cholesterol levels and mortality across varying apoB concentrations within the general population. Data from 15,380 participants in the 2005-2016 National Health and Nutrition Examination Survey (NHANES) were utilized to construct Cox regression models and apply restricted cubic splines, assessing the association between LDL cholesterol and mortality across distinct apoB stratifications. The study cohort had a median (IQR) age of 46.0 (32.0, 60.0) years, with 7949 (51.8%) males. During a median follow-up of 101.0 months (IQR: 67-137), 1771 (8.8%) all-cause mortality events were observed; 443 (2.1%) deaths were attributed to cardiovascular diseases, while 109 (0.5%) resulted from cerebrovascular diseases. Low apoB and LDL-cholesterol levels were independently linked to an elevated risk of all-cause and cardiovascular mortality. Compared with participants having apoB <90 mg/dL and LDL-cholesterol levels between 100-129 mg/dL, those with LDL-cholesterol <70 mg/dL (HR, 1.81; 95%CI: 1.39-2.36) and 70-99 mg/dL (HR, 1.28; 95%CI: 1.01-1.62) demonstrated a higher risk of all-cause mortality. Additionally, reduced apoB levels contributed to an increased risk of cardiovascular mortality among individuals with low LDL-cholesterol levels. Low apoB and LDL-cholesterol levels were associated with heightened all-cause and cardiovascular mortality risk in the general population. Conversely, high apoB and low LDL-cholesterol levels did not correlate with increased mortality risk. Show less

Central obesity poses a significant health threat. Lutein-rich fruits and vegetables may help manage obesity. Limited evidence suggests that lutein exerts health effects by inhibiting advanced glycation end products (AGEs), but data on its effects in centrally obese individuals are sparse. Thus, we aimed to investigate the effects of lutein supplementation in subjects with central obesity. A double-blind, randomized controlled trial was conducted involving patients with central obesity. Anthropometric indices, dietary intake, metabolic parameters, carotenoid and AGEs levels were compared between those receiving a 32-week intervention of 10 mg d Show less

Apolipoprotein C3 (APOC3) and angiopoietin-like protein 8 (ANGPTL8) genes are related to lipid metabolism. The relationships between single nucleotide polymorphisms (SNPs) in the APOC3 and ANGPTL8 genes with metabolic dysfunction-associated steatotic liver disease (MASLD) remain controversial. This study aimed to investigate the associations between specific SNPs in the APOC3 and ANGPTL8 genes and MASLD risk, with a particular focus on the mediating role of triglycerides (TG). A total of 440 participants were enrolled and categorised into MASLD and control groups. Genotyping of APOC3 SNPs (rs5128, rs2854116 and rs2854117) and ANGPTL8 SNP (rs2278426) was conducted using polymerase chain reaction-restriction fragment length polymorphism or Sanger sequencing methods. Multivariate logistic regression was employed to estimate the associations between these SNPs and MASLD risk, and mediation analysis was performed to assess the potential mediating effect of TG. We found that APOC3 SNPs were associated with MASLD risk, with increased odds ratios (ORs) indicating a higher risk of MASLD: rs5128 CG + GG genotype (OR = 1.8, 95% CI = 1.1-2.8), rs2854116 TC + CC genotype (OR = 1.9, 95% CI = 1.1-3.1) and rs2854117 CT + TT genotype (OR = 1.9, 95% CI = 1.2-3.2). No association was found between ANGPTL8 rs2278426 and MASLD (p > 0.05). Mediation analysis revealed that TG significantly mediated these relationships, accounting for 80.25% of the effect for rs5128, 64.61% for rs2854116 and 62.59% for rs2854117. In summary, polymorphisms in APOC3 (rs5128, rs2854116 and rs2854117) were associated with MASLD risk, with TG serving as a potential mediating factor. In contrast, ANGPTL8 rs2278426 polymorphism did not show any association with MASLD. Show less

This study aims to investigate the anti-atherosclerotic mechanism of Maiguan Fukang Tablets(MGFK) by integrating ultra-high-performance liquid chromatography-quadrupole orbitrap mass spectrometry(UHPLC-QE-MS), network pharmacology, and animal experiments. UHPLC-QE-MS identified 131 compounds in MGFK. Network pharmacology databases were utilized to retrieve drug targets and disease-related targets, and a "component-target-disease" network was constructed, yielding 418 overlapping potential therapeutic targets. These targets were further analyzed via protein-protein interaction(PPI) network, Gene Ontology(GO) enrichment, and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment, which revealed significant associations primarily with inflammatory response, negative regulation of apoptotic process, and the phosphatidylinositol-3-kinase(PI3K)/protein kinase B(AKT) signaling pathway. Molecular docking demonstrated strong binding affinities between protein kinase B1(AKT1) and core active compounds including luteolin, liquiritigenin, apigenin, and kaempferol. An atherosclerosis(AS) model was established in ApoE~(-/-) mice by feeding a high-fat diet for 14 weeks, and mice were randomly divided into a model group, MGFK high-dose group, MGFK low-dose group, and atorvastatin group. Experimental results confirmed that MGFK significantly reduced aortic plaque area, decreased lipid and foam cell proportion within plaques, lowered serum total cholesterol(TC), and reduced the expression levels of tumor necrosis factor-α(TNF-α), interleukin(IL)-1β, and IL-6. Furthermore, MGFK decreased the apoptosis rate within plaques, upregulated B-cell lymphoma-2(BCL-2) expression, downregulated BCL-2-associated X protein(BAX) and cleaved caspase-3, and promoted the phosphorylation of PI3K and AKT. These findings suggest that MGFK exerts anti-atherosclerotic effects potentially by regulating the PI3K/AKT signaling pathway, thereby reducing apoptosis within plaques, lowering levels of inflammatory cytokines and blood lipids, and attenuating plaque size, lipid content, and foam cell formation. Show less

Increasing evidence suggests that familial hypercholesterolemia (FHC) exacerbates myocardial infarction (MI). This study aimed to identify possible candidate biomarkers for patients with FHC and MI. The data were obtained from Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were screened using Limma, while module genes were identified through Weighted Gene Co-expression Network Analysis (WGCNA) in GSE48060. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analysis, protein-protein interaction (PPI) network and CIBERSORT methods were performed to explore the intersection genes. A receiver operating characteristic (ROC) curve were employed to evaluate the diagnostic effectiveness, with validation conducted using datasets GSE61144 and RT-qPCR. The FHC datasets included 656 DEGs, while there were 956 DEGs and 90 module genes in MI datasets. There were 49 overlapping DEGs between FHC and MI, which were associated with immune functions. Additionally, immune infiltration analysis revealed disturbances in immune cell populations. There were 13 candiate hub genes were screen after PPI network analysis. Show less

The ocular surface microbiome (OSM) in patients with meibomian gland dysfunction (MGD) differs from that of healthy individuals. However, the precise role of OSM in MGD remains unknown. Therefore, we aimed to investigate the mechanism of OSM in the inflammation of MGD and the effects of topical sodium butyrate (SB) treatment in ApoE ApoE Five-month-old ApoE ApoE Show less

Aortic dissection (AD) involves complex interactions among amino acid, glucose, and lipid metabolism, exacerbating aortic inflammation and extracellular matrix (ECM) degradation, coupled with smooth muscle cell (SMC) dysfunction (phenotypic alteration, aging, apoptosis). To explore AD pathogenesis, we integrated single-cell RNA sequencing (scRNA-seq), metabolomics, machine learning, and Mendelian randomization to investigate SMC changes and gene-metabolite interactions. ScRNA-seq data (GSE213740, GSE155468) were analyzed for cell clustering and pseudo-time trajectories via Seurat and Monocle2. Metabolomics (9 samples: 6 AD, 3 controls) and machine learning validated key genes/metabolites, with Mendelian randomization assessing causal links. Nine cell subsets and 2000 variable genes were identified, with SMCs central to AD via cholesterol metabolism. APOE and PLTP were key genes; metabolomics highlighted cholesterol esters (CEs) and triglycerides (TGs) as critical metabolites. Machine learning confirmed APOE/PLTP's high predictive accuracy (AUC: 0.796-0.989). Mendelian randomization linked elevated CEs and TGs to increased AD risk (IVW: P = .04 and P = .02, respectively). This study establishes a gene-metabolite network where APOE and PLTP regulate CEs/TGs, influencing SMC function and AD progression, offering potential therapeutic targets. Show less

Atherosclerosis (AS) is a chronic inflammatory disorder characterized by foam cell formation and persistent inflammation as central pathological drivers. Although colchicine (Col) exhibits potent anti-inflammatory activities, its clinical application is limited by a narrow therapeutic window. In the present study, we developed phosphatidylserine-exposing nanovesicles (Col@PSVs) that leverage the innate phagocytic capacity of macrophage-derived foam cells by presenting surface "eat-me" signals, thereby enabling targeted immune modulation. The synergistic collaboration between Col and PSVs allows low-dose Col to retain robust anti-inflammatory efficacy while mitigating dose-dependent toxicity. Mechanistically, Col@PSVs potently suppress CCR7-mediated NF-κB signaling activation in foam cells, leading to a marked downregulation of pro-inflammatory cytokine and disruption of inflammatory cascades. In ApoE Show less

Alzheimer's disease (AD) is a neurodegenerative disease characterized by abnormal accumulation of β-amyloid (Aβ) and hyperphosphorylation of the Tau protein. Currently, there is a lack of effective and safe therapeutic approaches. In Traditional Chinese medicine (TCM), Gandou Decoction has shown significant efficacy in improving cognitive decline and dementia-related symptoms, but its specific mechanism remains unclear. This study systematically analyzed the active components and anti-AD mechanism of Modified Gandou Decoction (MGD) by integrating network pharmacology, machine learning, molecular docking, molecular dynamics (MD) simulation, and A total of 21 potential active molecules of MGD and 68 intersection targets were screened out. Among them, 8 core targets (EIF2AK2, PPARG, BACE1, ESR1, GSK3B, ACE, CASP3, MAPK14) were confirmed to be significantly associated with AD pathology by gene expression difference analysis (P ≤ 0.05). KEGG enrichment analysis showed that MGD mainly intervenes in the amyloid production pathway, the MAPK pathway, and the IL-17 pathway. Molecular docking demonstrated that the majority of the 21 potential active compounds exhibited strong binding affinities to the 8 core targets. Moreover, some potential active molecules exhibited better binding energy and similar binding modes compared with known inhibitors when binding to the corresponding target proteins. Molecular dynamics simulation showed that Alisol B, a potential active component of MGD, could stably bind to BACE1, EIF2AK2, and CASP3. MGD exerts its anti-AD effect through its potential active component Alisol B, which binds to target proteins BACE1, EIF2AK2, and CASP3, and synergistically inhibits Aβ production, Tau phosphorylation, and neuroinflammatory processes through multiple pathways. This study provides a foundation for developing MGD-derived natural products for AD treatment, although the precise mechanisms require further experimental validation. Show less

The increased prevalence of opioid use disorder (OUD) makes it imperative to disentangle the biological mechanisms contributing to individual differences in OUD vulnerability. OUD shows strong heritability, however genetic variants contributing to vulnerability remain poorly defined. We performed a genome-wide association study using over 850 male and female heterogeneous stock (HS) rats to identify genes underlying behaviors associated with OUD such as nociception, as well as heroin-taking, extinction and seeking behaviors. By using an animal model of OUD, we were able to identify genetic variants associated with distinct OUD behaviors while maintaining a uniform environment, an experimental design not easily achieved in humans. Furthermore, we used a novel non-linear network-based clustering approach to characterize rats based on OUD vulnerability to assess genetic variants associated with OUD susceptibility. Our findings confirm the heritability of several OUD-like behaviors, including OUD susceptibility. Additionally, several genetic variants associated with nociceptive threshold prior to heroin experience, heroin consumption, escalation of intake, and motivation to obtain heroin were identified. Tom1, a microglial component, was implicated for nociception. Several genes involved in dopaminergic signaling, neuroplasticity and substance use disorders, including Brwd1, Pcp4, Phb1l2 and Mmp15 were implicated for the heroin traits. Additionally, an OUD vulnerable phenotype was associated with genetic variants for consumption and break point, suggesting a specific genetic contribution for OUD-like traits contributing to vulnerability. Together, these findings identify novel genetic markers related to the susceptibility to OUD-relevant behaviors in HS rats. Show less

Atherosclerosis (AS) is a serious threat to human health. Although glucose balance, lipid metabolism, inflammation and hypertension are closely related to AS, whether methyltransferase-like (METTL) family members are involved in the occurrence and development of AS remains elusive. Differentially expressed genes of METTLs in AS and normal blood vessels in GSE43292 and GSE100927 databases were analyzed. Random forest screening was used to screen marker genes, and the intersection genes in the two databases were selected. GSE28829/GSE41571 and clinical tissue samples were used for verification. The databases were further used to analyze marker genes' tissue and cellular localization and their correlation with lipid metabolism and efferocytosis. 7 and 17 differentially expressed METTL genes were obtained from GSE43292 and GSE100927 databases, respectively. METTL7B and METTL5 were verified as the intersection marker genes. Compared with the control group, the expression of METTL7B was significantly increased in advanced AS, AS ruptured plaque and clinical heavy-load plaque tissues. ROC curve analysis showed that the AUC of METTL7B in GSE28829 and GSE41571 was greater than 0.9. In addition, it was found that METTL7B was significantly correlated with lipid metabolism-related genes and promoted the formation of lipid droplets. METTL7B was positively correlated with atherosclerosis and macrophage-mediated efferocytosis. RNA-seq and targeted lipidomics results also confirmed that METTL7B is closely related to lipid metabolism and atherosclerosis. And further analysis also indicated that METTL7B could regulate 104 kinds of lipids, such as Lipid-n-0041, Lipid-n-0056, Lipid-n-0057, Lipid-n-0098, Lipid-n-0099 and Lipid-n-0169, mediated by AKR1C1, CETP and RORA. This study reveals a new mechanism for the occurrence and development of AS, thereby providing a potential target for the treatment of AS. In conclusion, METTL7B can be used as a predictor and therapeutic target for AS. Show less

Mitochondrial unfolded protein response (UPR The data were sourced from the cancer genome atlas (TCGA) and GSE31210 dataset and MRGs were retrieved to identify those with prognostic relevance, which were applied to recognize the molecular clusters in LUAD. The cluster-specific differentially expressed genes (DEGs) were identified for the functional enrichment analysis. The independent differentially expressed MRGs were sorted out to develop a risk model. Besides, the tumor immune microenvironment was analyzed using the ESTIMATE, TIMER, MCP-counter, and ssGSEA algorithms. The data were processed with Mutect2 to evaluate the genetic mutation landscape, while the IMvigor210 cohort and pRRophetic package were utilized to predict immunotherapeutic responses and drug sensitivity. Finally, in vitro validation was performed via quantitative real-time PCR (qRT-PCR), cell counting kit-8 (CCK-8), wound healing, and Transwell assays. Most MRGs were higher expressed in LUAD, and CREB binding protein (CREBBP), lysine demethylase 6B (KDM6B) and leucine rich pentatricopeptide repeat containing (LRPPRC) were the top 3 genes with mutation frequency. 8 MRGs were applied to identify 2 molecular clusters, with the worst prognosis seen in cluster C1. The clusters-specific DEGs were mainly enriched in cell proliferation-related pathways and the established risk model based on 4 hub genes (ANLN, FAM83A, CPS1 and KRT6A) showed satisfying efficacy in predicting the prognosis and was negatively correlated with most immune cells. Besides, the tumor mutation burden tended to be stronger in high risk group with high gene mutation frequency. In IMvigor210 cohort, higher RiskScore was seen in patients with progressive disease and stable disease and related to a worse survival. 3 drug candidates, including Roscovitine, Rapamycin and PHA.665752 were positively correlated with RiskScore. Besides, all 4 MRGs were highly expressed in LUAD cells and the silencing of ANLN repressed the LUAD cell proliferation, migration and invasion. The established 4-MRGs signature not only serves as a robust prognostic indicator but also highlights the significant involvement of mitochondrial unfolded protein response in shaping tumor microenvironment and influencing immunotherapy outcomes in LUAD. The 4 MRGs may contribute to the understanding on UPR Show less

Frailty and sarcopenia are age-related conditions linked to mitochondrial dysfunction, but their causal mechanisms remain poorly defined. This study aimed to identify mitochondrial-related genes causally associated with frailty and sarcopenia using comprehensive multi-omics approaches. We performed summary-data-based Mendelian randomization using genome-wide association study summary statistics for the frailty index and sarcopenia-related traits. Quantitative trait loci data for DNA methylation, gene expression, and plasma protein abundance were analyzed across 1136 mitochondrial-related genes. Colocalization analysis was applied to confirm shared causal variants. For frailty, GRPEL1 showed tissue-specific associations at methylation and expression levels (protective in blood: β = -.15, false discovery rate (FDR) = 1.5e-02; adverse in brain/muscle), while LRPPRC demonstrated consistent protective effects across tissues (β = -.05 to -.13, PPH4 > 0.93). For sarcopenia-related traits, GATM was associated with appendicular lean mass (ALM) across all omics levels with opposing tissue effects (negative in blood: β = -.03, FDR = 1.9e-09; positive in muscle), and ETFDH showed positive associations with ALM (β = .03, FDR = 1.4e-06). Additional genes included CPS1 and MMAB for frailty, NTHL1 and MTCH2 for grip strength, and TOMM70, BNIP3, TUFM for walking pace. Complete regulatory pathways were identified for GRPEL1 and GATM, linking methylation to expression to phenotype. This multi-omics study identified distinct mitochondrial genetic signatures for frailty and sarcopenia, with key genes including GRPEL1, LRPPRC, GATM, ETFDH, and others showing tissue-specific causal associations. These findings advance understanding of mitochondrial mechanisms in age-related functional decline and identify multiple therapeutic targets. Show less

Hereditary multiple exostoses (HME) is an autosomal dominant skeletal disorder primarily linked with mutations in Exostosin-1 (EXT1) and Exostosin-2 (EXT2) genes. However, not all HME cases can be explained by these mutations, and its pathogenic mechanisms are not fully understood. Herein, utilizing whole-exome sequencing and genetic screening with a family trio design, we identify two novel rare mutations co-segregating with HME in a Chinese family, including a nonsense mutation (c.204G>A, p.Trp68*) in EXT1 and a missense mutation (c.893T>G, p.Phe298Cys) in FUT7. Functional assays reveal that the FUT7 mutation affects the cellular localization of FUT7 protein and regulates cell proliferation. Notably, the simultaneous loss of fut7 and ext1 in a zebrafish model results in severe chondrodysplasia, indicating a functional link between FUT7 and EXT1 in chondrocyte regulation. Additionally, we unveil that FUT7 p.Phe298Cys reduces EXT1 expression through IL6/STAT3/SLUG axis at the transcription level and through ubiquitination-related proteasomal degradation at the protein level. Together, our findings not only identify novel germline mutations in FUT7 and EXT1 genes, but also highlight the critical interaction between these genes, suggesting a potential 'second-hit' mechanism over EXT1 mutations in HME pathogenesis. This insight enhances our understanding of the mechanisms underlying HME and opens new avenues for potential therapeutic interventions. Show less

Age-related Macular Degeneration (AMD) is widely acknowledged as a principal cause of vision loss in the elderly. Currently, the therapeutic interventions available in clinical practice fail to achieve satisfactory outcomes. Therefore, it is imperative that we approach the progress of AMD from novel perspectives in order to explore new therapeutic strategies. We obtained transcriptomic data from the macular and the peripheral retina from patients with AMD and a control group from the Gene Expression Omnibus (GEO) database. Through Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, we identified differentially expressed genes (DEGs) that were significantly enriched in functions associated with ferroptosis. Subsequent application of machine learning techniques enabled the identification of key hub genes, whose diagnostic potential was further validated. Additionally, the expression of these hub genes was corroborated in both animal and cellular models. Finally, we performed a functional enrichment analysis of these hub genes. In the macula of patients with AMD, 452 DEGs were identified, while in the peripheral retina, 222 DEGs were discovered. Within the macula, 19 genes were associated with ferroptosis, compared to 3 in the peripheral retina. Consequently, the macular was selected as the primary focus of the study. Subsequent screening of these 19 genes using LASSO regression, Support Vector Machine (SVM), and Random Forest algorithms identified four hub genes: FADS1, TFAP2A, AKR1C3, and TTPA. Consequently, we utilized cigarette smoke extract (CSE) to either stimulate retinal pigment epithelial (RPE) cells in vitro or administer it via intravitreal injection, thereby establishing in vitro and in vivo models of AMD. Results from RT-PCR and Western blot analyses revealed an upregulation of FADS1, AKR1C3, and TTPA, while TFAP2A exhibited decreased expression. Finally, we investigated the infiltration of immune cells within the macular and performed a functional enrichment analysis of the hub genes. We identified four key ferroptosis-related genes (FRGs)-FADS1, AKR1C3, TFAP2A, and TTPA-that possess diagnostic relevance for AMD and correlate with immune cell infiltration. Moreover, significant changes in both mRNA and protein expression levels of these genes have been observed in in vitro experiments and mice models. Show less

Kidney renal clear cell carcinoma (KIRC), the predominant subtype of renal cell carcinoma, poses significant health risks. The rapid progression and resistance to targeted therapies highlight the need for new tumor markers and therapeutic targets. FADS1, part of the fatty acid desaturase family, regulates fatty acid synthesis and participates in lipid metabolism. However, its role in KIRC is not well-studied. The study utilized bioinformatics analysis through the TCGA database and other platforms to identify FADS1 expression levels in KIRC. Twenty pairs of KIRC clinical tissue samples were used for qPCR verification. Meanwhile, eight pairs of KIRC clinical tissue samples were used for Western blot verification. Conduct statistical evaluation, including Wilcoxon rank sum test and Kaplan-Meier analysis, to explore the correlation between FADS1 expression and clinical pathological features and immune infiltration. In addition, in vitro experiments were conducted to confirm the biological function of FADS1. The findings indicated that FADS1 is highly expressed in KIRC and contributes to tumor development. FADS1's role in lipid metabolism leads to lipid accumulation within tumor cells, which may influence the occurrence and progression of KIRC. TIMER analysis revealed a correlation between FADS1 expression and the infiltration levels of various immune cells, indicating its potential role in modulating immune characteristics. FADS1 could serve as a prognostic biomarker associated with immunity in KIRC, highlighting its potential as a diagnostic and therapeutic target. The study underscores the importance of further research into FADS1's role in lipid metabolism and immune infiltration to develop effective therapeutic strategies. Show less

Fatty Acid Desaturase 1 (FADS1) is a rate-limiting enzyme controlling the bioproduction of long-chain polyunsaturated fatty acids (PUFAs). Increasing studies suggest that FADS1 is a potential cancer target. Our previous research has demonstrated the significant role of FADS1 in cancer biology and patient survival, especially in kidney cancers. We aim to explore the underlying mechanism in this study. We found that pharmacological inhibition or knockdown of the expression of FADS1 significantly reduced the intracellular conversion of long-chain PUFAs, effectively inhibits renal cancer cell proliferation, and induces cell cycle arrest. The stable knockdown of FADS1 also significantly inhibits tumor formation in vivo. Mechanistically, we showed that while FADS1 inhibition induces endoplasmic reticulum (ER) stress, FADS1 expression is augmented by ER-stress inducer, suggesting a necessary role of PUFA production in response to ER stress. FADS1-inhibition sensitized cellular response to ER stress inducers, leading to cell apoptosis. Also, FADS1 inhibition-induced ER stress leads to activation of the PERK/eIF2α/ATF4/ATF3 pathway. Inhibiting PERK or knockdown of ATF3 rescued FADS1 inhibition-induced ER stress and cell growth suppression, while ATF3-overexpression aggravates the FADS1 inhibition-induced cell growth suppression and leads to cell death. Metabolomic analysis revealed that FADS1 inhibition results in decreased level of UPD-N-Acetylglucosamine, a critical mediator of the unfolded protein response, as well as impaired biosynthesis of nucleotides, possibly accounting for the cell cycle arrest. Our findings suggest that PUFA desaturation is crucial for rescuing cancer cells from persistent ER stress, supporting FADS1 as a new therapeutic target. Show less

The abnormal accumulation of lipid droplets in clear cell renal cell carcinoma (ccRCC) is related to metabolic reprogramming. However, the mechanism between metabolic reprogramming and tumor progression in ccRCC remains to be explored. Utilize multiple omics technologies to predict the relationship between fatty acid metabolism and tumor progression, and identify the key regulatory proteins and mechanisms. The role of proteins in influencing tumor progression and fatty acid metabolism was explored from both in vivo and in vitro. The mechanism of the regulatory protein was analyzed and verified by co-immunoprecipitation and mass spectrometry. Multimodal analysis revealed that fatty acid desaturase 3 (FADS3), as a key molecule connecting fatty acid metabolism and Epithelial-mesenchymal transition (EMT), was upregulated in clinical samples of ccRCC and participated in the immune regulation, and was positively correlated with clinical stage and poor prognosis. Functionally, FADS3 promoted cell proliferation and EMT in vivo and in vitro as well as sunitinib resistance, and induced fatty acid synthesis and lipid droplet storage. Mechanistically, FADS3 activates the phosphorylation of Smad2/3 through autocrine Transforming Growth Factor-β (TGF-β). The lipid droplets induced by FADS3 could act as a reservoir of acetyl-CoA, promoting the acetylation of Smad2 and inducing the upregulation of TGF-β receptors, thereby promoting the proliferation and EMT. Our study confirmed FADS3 as a key intermediate protein regulating fatty acid metabolism and tumor progression, which was expected to be a potential diagnostic and prognostic biomarker for ccRCC. Show less

Pathological retinal angiogenesis drives vision loss in diseases like proliferative diabetic retinopathy (PDR) and retinal vein occlusion (RVO). Erdafitinib, a pan-fibroblast growth factor receptor (FGFR) inhibitor, has shown therapeutic potential in FGFR-mutated urothelial carcinoma. This study aimed to determine whether erdafitinib suppresses pathological retinal angiogenesis beyond its canonical FGFR inhibition, and to dissect its potential mechanisms through multi-model validation. We employed zebrafish developmental angiogenesis and oxygen-induced retinopathy (OIR) mouse models, combined with in vitro endothelial cell assays. In zebrafish, erdafitinib dose-dependently inhibited intersegmental vessel (ISV) formation and disrupted retinal angiogenesis, with confocal microscopy revealing truncated vascular length (by 62% at 4 µM vs. controls). The OIR model demonstrated erdafitinib's efficacy in reducing neovascular density (35% decrease) and pathological tuft formation. Mechanistically, erdafitinib impaired human umbilical vein endothelial cell (HUVEC) tube formation and migration, accompanied by downregulation of VEGFR2 expression (2.1-fold reduction) and inhibition of AKT/ERK phosphorylation. Molecular docking confirmed erdafitinib's binding to VEGFR2 kinase domain (binding energy: -7.8 kcal/mol), albeit with lower affinity than FGFR1 (-10.2 kcal/mol). These findings establish that erdafitinib exerts off-target anti-angiogenic effects by blocking VEGFR2 phosphorylation and downstream signaling, supporting its repurposing potential for anti-VEGF-resistant retinal vascular diseases. Further studies should address its intraocular pharmacokinetics and long-term safety. Show less

Osimertinib (OSI) therapy, a cornerstone in treating non-small cell lung cancer (NSCLC), has been severely limited by rapidly developing acquired resistance. Inhibition of bypass activation using a combination strategy holds promise in overcoming this resistance. Biguanides, with excellent anti-tumor effects, have recently attracted much attention for this potential. The current study investigated whether novel biguanide compounds developed by our team could overcome OSI resistance and the underlying mechanisms were explored. A comprehensive screening assay using OSI-resistant cells identified the optimal combination of biguanide compounds with OSI. Proteomics, co-immunoprecipitation mass spectrometry, RNA sequencing, and homologous recombination assays were used to elucidate the molecular mechanisms underlying combination therapy. NSCLC tumor tissues, especially OSI-resistant tissues, obtained from our clinic were used to assess the correlations between key proteins and OSI resistance. SMK-010, a highly potent biguanide compound, effectively overcame OSI resistance These findings highlight the crucial role of the BMI1/FGFR1 axis in OSI resistance and provide a rational basis for the future clinical application of the biguanide, SMK-010, in combination with OSI. Show less

This article aims to analyze the safety and efficacy of Erdafitinib in the treatment of patients with advanced solid tumors harboring FGFR1-4 mutations. Search for relevant articles in databases such as PubMed, Embase, The Cochrane Library, Web of Science, and CNKI, covering the period from their establishment to October 25, 2024. Summarize the adverse drug reaction (AE) data, overall survival (OS), median progression-free survival (PFS), objective response rate (ORR), and other relevant data for patients with advanced solid tumors treated with Erdafitinib for FGFR1-4 mutations. Conduct a meta-analysis on the corresponding summarized data using the software Stata 18.0. Through our search, we identified a total of 10 articles involving 1019 patients. In urothelial carcinoma, the most prevalent adverse reactions are hyperphosphatemia (78.5%), diarrhea (56.5%), and stomatitis (51.1%). The most frequently reported adverse reactions in other solid tumors are hyperphosphatemia (66.5%), dry mouth (48.5%), and diarrhea (44.9%). Patients with urothelial carcinoma treated with Erdafitinib exhibit higher median progression-free survival (PFS) and objective response rate (ORR) compared to those treated with other solid tumor therapies. Current evidence indicates that Erdafitinib exhibits certain therapeutic efficacy in the treatment of advanced solid tumors harboring FGFR1-4 mutations, with the most pronounced therapeutic effect observed in urothelial carcinoma. The efficacy of Erdafitinib in treating other solid tumors requires further confirmation through larger-scale studies involving a broader range of FGFR1-4 mutant tumors. Show less

Diabetic cardiomyopathy (DCM) in type 2 diabetes (T2D) may lead to heart failure and patient death. Fibroblast growth factor 21 (FGF21) is a therapeutic candidate for treating this disease. However, one impediment to its clinical use is its weak ability to activate downstream signaling pathways. In this study, based on our in-depth understanding of the binding properties of fibroblast growth factor receptor 1c (FGFR1c) with paracrine FGF1 and endocrine FGF21, we engineered a novel FGF21 analog named FGF21 Show less

Pesticides increase agricultural productivity, but with the widespread use of pesticides, concerns have arisen about their potential negative impacts on human health and aquatic organisms. Pydiflumetofen (PYD) is a novel chiral fungicide, and the potential environmental and health hazards of PYD and its chiral isomers are not sufficiently understood. In this work, zebrafish were employed as a model organism to study the toxicity of PYD, specifically investigating the developmental and cardiovascular toxicities in zebrafish exposed to 0.2 μg/mL of PYD for 72 h. The results showed that PYD severely impeded the development of zebrafish embryos, resulting in abnormal hatching rates, enlarged yolk sacs and shortened body length. In addition, PYD resulted in morphological and functional abnormalities of the embryonic heart and blood vessels, such as pericardial edema, linearization of the heart, impeded vascular production, slowed heart rate, and reduced erythrocyte flow rate. Mechanistically, we found that PYD caused oxidative stress, lipid accumulation and apoptosis in zebrafish. Simultaneously, the expression of genes associated with cardiac (nkx2.5, gata4, tbx5, hand2, has2) and vascular (vegfc, dll4, cdh5, hey2, and notch3) development was altered. Notably, our results indicate that (+)-R-PYD exhibits higher developmental and cardiovascular toxicity than (-)-S-PYD. This paper first reveals the cardiovascular toxicity of PYD and opens new avenues for assessing the environmental and health hazards caused by chiral fungicides. Show less

Coronary artery disease (CAD) is an immune-mediated disorder driven by dysregulated T cell responses. Interleukin-27 (IL-27) has immunoregulatory properties, but its role in CAD remains unclear. This study is the first to investigate the effects of IL-27 on CD4⁺LAP⁺ T cells in CAD and to explore its interaction with interleukin-2 (IL-2) in modulating immune imbalance. CAD severity was quantified by the Gensini score. Plasma IL-27 and oxidized low-density lipoprotein (ox-LDL) were measured by ELISA. Flow cytometry assessed CD4⁺ T cell subsets, while qRT-PCR and Western blot evaluated lineage-specific transcription factors. IL-27 levels were elevated in acute coronary syndrome and correlated with ox-LDL and Gensini scores. Patients with severe CAD showed a Th1/Th17-dominant profile and reductions in Th2, CD4⁺LAP⁺, and Tregs. In vitro, IL-27 promoted Th1 differentiation via T-bet/IFN-γ upregulation and suppressed Th2, Th17, and regulatory subsets, counteracting IL-2-induced expansion of Tregs and CD4⁺LAP⁺ cells. These effects were dose dependent and favored pro-inflammatory responses. IL-27 drives immune imbalance in CAD by reinforcing Th1 polarization and antagonizing IL-2-mediated regulation. Beyond mechanistic insights, these findings identify IL-27 as a potential biomarker for disease severity and a candidate therapeutic target in CAD. Show less