Search Results (124)

Background: Immune checkpoint inhibitors (ICIs) have transformed cancer treatment, yet severe immune-related adverse events (irAEs) often necessitate immunotherapy discontinuation and cause life-threatening complications. Circulating plasma proteins, dynamically accessible and functionally linked to immunity, may predict and offer novel targets for irAEs. Methods: Leveraging multi-omics integration, we conducted bidirectional two-sample Mendelian randomization (MR) using protein quantitative trait loci (pQTLs) from 4998 plasma proteins and genome-wide association data of irAE phenotypes. A causal inference framework combining colocalization analysis, multivariable MR (MVMR) adjusting for body mass index (BMI) confounding, and mediation MR elucidated BMI-independent pathways. Systems biology approaches including tissue-specific expression profiling, pathway enrichment, and protein interaction network analysis revealed spatial and functional drivers of irAE pathogenesis. Results: Proteome-wide MR mapping identified eight plasma proteins (CCL20, CSF1, CXCL9, CD40, TGFβ1, CLSTN2, TNFSF12, TGFα) causally associated with all-grade irAEs, and five (CCL20, CCL25, CXCL10, ADA, TGFα) with high-grade irAEs. Colocalization prioritized CD40/TNFSF12 (all-grade) and ADA/CCL25 (high-grade) as therapeutic targets (PPH4 > 0.7). CXCL9/TNFSF12 (all-grade) and CCL25 (high-grade) exerted BMI-independent effects, suggesting intrinsic immune dysregulation mechanisms. Tissue-specific gene expression patterns, CSF1, TGFβ1 in lung, TNFSF12 in the ileum may explain organ-specific irAE vulnerabilities. High-grade irAEs correlated with compartmentalized immune dysregulation and IL-17/immunodeficiency pathway activation. Conclusions: This study establishes the causal atlas of plasma proteins in irAE pathogenesis, bridging biomarker discovery with actionable therapeutic targets. These advances align with next-generation immunotherapy goals: maximizing efficacy while taming the immune storm. Full article

Background/Objectives: Wool is an important product in sheep production, but the genetic mechanisms underpinning variation in wool growth are not fully understood. Identifying the genes and genomic variants that play a role in increasing fleece weight may allow for increased selection accuracy and improved economic return to producers. Methods: A genome-wide association study (GWAS) was conducted to investigate genetic associations with lifetime fleece weight, average fleece weight and average post-lambing ewe weight for Rambouillet, Polypay, Suffolk and Columbia ewes (N = 1125). Weir–Cockerham F_ST and runs of homozygosity (ROH) analyses were conducted to improve detection of putative wool-related signatures. Results: Twenty-four SNPs were identified through GWAS for lifetime fleece weight, average fleece weight and average post-lambing ewe weight. Chromosomes 2 and 6 contained ROH islands in Rambouillet, and chromosomes 2, 3 and 10 contained ROH islands in Suffolk. The F_ST analysis identified 18 SNPs in proximity to 37 genes of interest. Conclusions: Many of the SNPs and signatures of selection reported in this study are near or within current candidate genes for wool production and wool quality, including ADAR, KCNN3, NTN1, SETBP1, TP53 and TNFSF12. The significant SNPs implicated by GWAS may be used to predict ewes’ potential for lifetime wool production and are suggested as candidates for further study to continue to elucidate the genetic mechanisms underlying wool production traits in United States sheep breeds. Full article

Background: Marantodes pumilum var. alata (MPva) has been reported to promote fracture repair. This study investigates the role of MPva leaf extract on biochemical markers and bone-repair genes in a postmenopausal rat model to understand its fracture-healing properties. Methods: Thirty female Sprague Dawley rats were grouped into sham-operated (Sham), ovariectomized control (OVXC), estrogen treatment (ERT), and plant treatment (MPv20 and MPv100) groups. After ovariectomy, the right tibiae of rats were fractured. The ERT group was treated with 64.5 μg/kg/day of estrogen, while the MPv20 and MPv100 groups received 20 and 100 mg/kg/day doses of MPva leaf extract, respectively, for 8 weeks. Sham and OVXC acted as untreated controls. Blood samples collected before and after treatment were assayed for pro-inflammatory cytokines (IL-6 and TNF-α), while bone samples were assayed for bone-turnover markers: osteocalcin and pyridinoline, oxidative-status markers (GPx, SOD, and MDA), and bone-repair genes (Bglap, Spp1, Dkk1, Igf1, Tnfsf11, and Fgf23). Results: IL-6, GPx, and SOD levels were significantly increased in both MPv groups (p < 0.05). IGF1 was significantly upregulated in both MPv groups, while Tnfsf11 was downregulated in the MPv20 group (p < 0.05). Conclusions: MPva leaf extract may promote bone repair by stimulating pro-inflammatory and antioxidant responses, which are associated with its regulation of Igf1 and Tnfsf11 genes. Full article

Background: Colonic diverticulosis is a common condition, particularly in the elderly population. While dietary habits, obesity, smoking, and physical inactivity contribute to its pathogenesis, emerging evidence highlights a genetic predisposition affecting extracellular matrix (ECM) remodeling, inflammation, and connective tissue integrity. The aim of this systematic review was to summarize genetic determinants of colonic diverticulosis. Methods: The PubMed^® database was searched for original studies in humans. The inclusion criteria were named genetic factor and confirmed diverticulosis. Patients with diverticulitis and diverticular diseases were excluded from this review. Results: Out of 137 publications, 10 articles met the inclusion criteria: six large association studies (GWAS) and four cross-sectional studies. The genes regulating ECM turnover, including TIMP1, MMP3, and MMP9, are involved in diverticulosis development. The TIMP1 (rs4898) T allele has been associated with increased susceptibility, potentially due to its role in ECM remodeling. Similarly, MMP3 (rs3025058) and MMP9 (rs3918242) polymorphisms contribute to altered collagen degradation. The COL3A1 (rs3134646) variant coding modified collagen type III may promote diverticular formation. Other genes, such as ARHGAP15 (rs4662344, rs6736741), affect cytoskeletal dynamics. Identified in GWAS studies, gene candidates may be grouped into blood group and immune system-related genes (ABO, HLA-DQA1, HLA-H, OAS1, TNFSF13, FADD), extracellular matrix and connective tissue genes (COL6A1, COLQ, EFEMP1, ELN, HAS2, TIMP2), signaling and cell communication (BMPR1B, WNT4, RHOU, PHGR1, PCSK5), nervous system and neurodevelopment (BDNF, CACNB2, GPR158, SIRT1, SCAPER, TRPS1), metabolism and transporters (SLC25A28, SLC35F3, RBKS, PPP1R14A, PPP1R16B), lipids and cholesterol (LDAH, LYPLAL1, STARD13), transcription and gene regulation (ZBTB4, UBTF, TNRC6B), apoptosis (FADD, PIAS1), and poorly characterized genes (C1TNF7, ENSG00000224849, ENSG00000251283, LINC01082, DISP2, SNX24, THEM4, UBL4B, UNC50, WDR70, SREK1IP1). Conclusions: There are a number of gene variants that probably predispose to colonic diverticulosis. Detailed characterization of the multigene background of diverticulosis will enable appropriate therapeutic or preventive interventions in the future. Full article

Glioma is the most common primary malignant intracranial tumor with limited treatment options and a dismal prognosis. This study aimed to develop a robust gene expression-based prognostic signature for GBM using the Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) datasets. Using WGCNA and LASSO algorithms, we identified four MHC-related genes (TNFSF14, MXRA5, FCGR2B, and TNFRSF9) as prognostic biomarkers for glioma. A risk model based on these genes effectively stratified patients into high- and low-risk groups with distinct survival outcomes across TCGA and CGGA cohorts. This signature correlated with immune pathways and glioma progression mechanisms, showing strong associations with immune function and tumor microenvironment infiltration patterns. The risk score reflected tumor microenvironment remodeling, suggesting its prognostic relevance. We further propose I-BET-762 and Enzastaurin as potential therapeutic candidates for glioma. In conclusion, the four-gene signature we identified and the corresponding risk score model constructed from it provide valuable tools for the prognosis prediction of glioblastoma multiforme (GBM) and may guide personalized treatment strategies. The least absolute shrinkage and selection operator (LASSO) risk score has demonstrated significant prognostic evaluation utility in clinical GBM patients, bringing potential implications for patient stratification and the optimization of treatment regimens. Full article

Curcumin, a major phytochemical derived from Curcuma longa, has been shown to enhance the efficacy of chemotherapeutic agents such as doxorubicin, 5-fluorouracil, and cisplatin by overcoming drug resistance, making it a promising adjunct in the treatment of glioblastoma. However, the global gene-expression changes triggered by curcumin in glioblastoma remain underexplored. In this study, we investigated the effects of curcumin on human glioblastoma (U87 MG) cells, where it significantly reduced cell viability and proliferation in a dose- and time-dependent manner and induced apoptosis without affecting senescence. Transcriptomic analysis revealed 5036 differentially expressed genes, with pathway enrichment identifying 13 dysregulated cancer-associated pathways. Notably, curcumin modulated several key regulators involved in MAPK, Ras, TGF-β, Wnt, Cytokine, and TNF signaling pathways. Several apoptosis and cell cycle-associated genes, including PRKCG, GDF7, GDF9, GDF15, GDF5, FZD1, FZD2, FZD8, AIFM3, TP53AIP1, CRD14, NIBAN3, BOK, BCL2L10, BCL2L14, BNIPL, FASLG, GZMM, TNFSF10, TNFSF11, and TNFSF4, were significantly altered. Several pro-apoptotic and anti-BCL, cell-cycle-regulated genes were modulated following curcumin treatment, emphasizing its potential role in curcumin-mediated anti-tumor effects. This study provides insight into the molecular mechanisms underlying curcumin’s action against glioblastoma. Full article

Sepsis is a life-threatening condition driven by dysregulated immune responses, resulting in organ dysfunction and high mortality rates. Identifying key genes and pathways involved in sepsis progression is crucial for improving diagnostic and therapeutic strategies. This study analyzed transcriptomic data from 49 samples (37 septic patients across days 0, 1, and 8, and 12 healthy controls) using weighted gene co-expression network analysis (WGCNA) and multi-algorithm feature selection approaches. Differential expression analysis, pathway enrichment, and network analyses were employed to uncover potential biomarkers and molecular mechanisms. WGCNA identified modules such as MEbrown4 and MEblack, which strongly correlated with sepsis progression (r > 0.7, p < 0.01). Differential expression analysis highlighted up-regulated genes like CD177 and down-regulated genes like LOC440311. KEGG analysis revealed significant pathways including neuroactive ligand–receptor interaction, PI3K-Akt signaling, and MAPK signaling. Gene ontology analysis showed involvement in immune-related processes such as complement activation and antigen binding. Protein–protein interaction network analysis identified hub genes such as TNFSF10, IGLL5, BCL2L1, and SNCA. Feature selection methods (random forest, LASSO regression, SVM-RFE) consistently identified top predictors like TMCC2, TNFSF10, and PLVAP. Receiver operating characteristic (ROC) analysis demonstrated high predictive accuracy for sepsis progression, with AUC values of 0.973 (TMCC2), 0.969 (TNFSF10), and 0.897 (PLVAP). Correlation analysis linked key genes such as TNFSF10, GUCD1, and PLVAP to pathways involved in immune response, cell death, and inflammation. This integrative transcriptomic analysis identifies critical gene modules, pathways, and biomarkers associated with sepsis progression. Key genes like TNFSF10, TMCC2, and PLVAP genes show strong diagnostic potential, providing novel insights into sepsis pathogenesis and offering promising targets for future therapeutic interventions. Among these, TNFSF10 and PLVAP are known to encode secreted proteins, suggesting their potential as circulating biomarkers. This enhances their translational relevance in clinical diagnostics. Full article

Transforming growth factor beta (TGF-β), a master regulator of renal fibrosis, is the hallmark of chronic kidney disease (CKD) progression, and CKD worsens bone remodeling. However, the effects of the dysregulation of TGF-β signaling on bone remodeling during CKD have not been investigated. Here, we determined the effects of TGF-β receptor I (TβRI) overexpression under the control of Mx1-Cre on bone remodeling in CKD mice (Mx1;TβRI^CA-CKD mice). Our results demonstrated that kidney fibrosis and serum urea nitrogen levels were elevated in Mx1;TβRI^CA-CKD mice compared to WT-CKD, indicating that TβRI overexpression exacerbated renal injury during CKD. Serum calcium was decreased, while PTH was enhanced, in Mx1;TβRI^CA-CKD mice. Mx1;TβRI^CA-CKD mice displayed severe osteopenia as assessed by uCT in both femurs and mandibles. An histomorphometric analysis showed that tibial cancellous bone volume was decreased in Mx1;TβRI^CA-CKD. Likewise, mRNA expression levels of an osteoclastogenesis marker, Tnfsf11/Tnfrsf11b, was increased, and osteoblast marker genes Runx2 and Sp7 were decreased in Mx1;TβRI^CA-CKD mice. Mx1;TβRI^CA-CKD mice displayed increased inflammatory cytokines levels. Together, our results indicated that in the setting of CKD, TβRI overexpression induced both CKD progression and the dysregulation of bone remodeling, leading to severe bone loss. As such, these data provide an avenue for the future development of therapeutics for CKD-induced osteoporosis. Full article

Background: Among the various forms of root resorption, External Apical Root Resorption (EARR) has garnered particular attention due to its prevalence and potential complications associated with orthodontic interventions. Methods: An electronic search of literature was performed between September 2024 and December 2024 to identify all articles investigating the Role of Genetic Polymorphisms in External Apical Root Resorption Among Orthodontic Patients: Implications for Treatment Outcomes. The search was conducted using MEDLINE (National Library of Medicine)-PubMed with restrictions concerning the date of publication. In particular, we focused on the period 2014–2024 using the following keywords: gene polymorphisms AND orthodontic treatment AND apical root resorption OR external apical root resorption. This was followed by a manual search, and references were used to identify relevant articles. Results: The review showed that certain variations of the following genes may be positively associated with OIEARR: Osteopontin gene, P2RX7, IL-1β, IL-6, IL1RN, OPG, RANK, STAG2, RP1-30E17.2, SSP1, SFRP2, TNFSF11, TNFRSF11A, TNFRSF11B, VDR, CYP27B1, ACT3N, TSC2, WNT3A, LRP1, LRP6. Conversely, the IRAK1 gene has a protective function against the development of OIEARR. Conclusions: Despite these advancements, it is still not feasible to establish new guidelines and clinical protocols based on the existing research findings. The integration of genetic considerations into orthodontic practice has the potential to revolutionize treatment strategies, ensuring that they are not only effective but also respectful of each patient’s unique biological landscape. Full article

Long-term geographic isolation and breeding programs both influence population characteristics. Leiqiong cattle, a native breed from the southernmost region of China, are renowned for disease and heat resistance, with two subgroups on Hainan Island and the Leizhou Peninsula. However, the genomic differences between them remain unexplored. In this study, we conducted genomic comparisons using whole-genome sequencing data from the two subgroups of Leiqiong cattle and three commercial breeds to assess their population structures. Leiqiong cattle in Hainan exhibited lower genetic diversity and a pure ancestral content due to their isolation from the mainland. In contrast, the subgroup in Guangdong displayed higher genetic diversity and mixed ancestry, influenced by the intrusion of commercial breeds. The genetic divergence between them was evaluated by estimating a genetic distance of 0.08 and a split time of 3400 to 4250 years ago, highlighting the role of geographical barriers in speciation. Notably, two candidate genes were identified through selection sweeps, including PIP4K2A, potentially related to immunity, and TNFSF4, possibly involved in hair follicle development. Our findings reveal the different genetic structures and genomic characteristics in the two subgroups of Leiqiong cattle, providing valuable insights into their evolutionary history and establishing a foundation for future breeding strategies. Full article

Background/Objectives: This study aimed to construct a risk score (RS) based on necroptosis-associated genes to predict the prognosis of patients with advanced epithelial ovarian cancer (EOC). Methods: EOC data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) series 140082 (GSE140082) were used. Based on known necroptosis-associated genes, clustering was performed to identify molecular subtypes of EOC. A least absolute shrinkage and selection operator (LASSO)–Cox regression analysis identified key genes related to prognosis. The expression of one of them, RIPK3, was analyzed via immunohistochemistry in an EOC cohort. Results: An RS made from ten genes (IDH2, RIPK3, FASLG, BRAF, ITPK1, TNFSF10, ID1, PLK1, MLKL and HSPA4) was developed. Tumor samples were divided into a high-risk group (HRG) and low-risk group (LRG) using the RS. The model is able to predict the overall survival (OS) of EOC and distinguish the prognosis of different clinical subgroups. Immunohistochemical verification of the receptor-interacting serine/threonine-protein kinase (RIPK) 3 confirmed that high nuclear expression is correlated with a longer OS. In addition, the score can predict the response to a programmed death ligand 1 (PD-L1) blockade treatment in selected solid malignancies. Patients from the LRG seem to benefit more from it than patients from the HRG. Conclusions: Our RS based on necroptosis-associated genes might help to predict the prognosis of patients with advanced EOC and gives an idea on how the use of immunotherapy can potentially be guided. Full article

The Chinese soft-shelled turtle (Pelodiscus sinensis), a type of warm-water reptile, is frequently chosen as the model animal to understand how organisms respond to environmental stressors. However, the responsive mechanism of P. sinensis to natural cold stress is unclear, especially in terms of metabolic pattern and molecular pathways. Herein, plasma biochemical, hepatic morphological, apoptotic, transcriptomic, and metabolomic detection methods were performed to investigate the response of P. sinensis to acute cold stress. A consistent increase in plasma AST and ALT activities with a decline in ALP activity was found following 14 °C and 7 °C cold stress compared with the control group. Plasma GLU, TG, CHO, and HDL contents, reflecting energy metabolism, were decreased to lower levels from 2 to 16 days post cold stress (dps). Histological and TUNEL detection in the liver demonstrated that the 14 °C and 7 °C cold stress caused severe morphological damage and cell apoptosis in a time-dependent manner. DEGs in the biosynthesis of fatty acids (Acsbg2, Acsl3, Acsl4, Acsl5, Mcat, and Acacb), as well as unsaturated fatty acids (Hsd17b12, Elovl7, Scd, and Baat), starch and sucrose metabolism (Pgm1, Pgm2, and Treh), and apoptosis (Ddit3, Gadd45a, Lmnb1, Tuba1c, Tnf, Tnfsf10, Fos, Itpr1, and Ctso) were discovered in the transcriptome under cold stress. The metabolomic data showed that metabolites, including chenodeoxycholic acid, oleoylethanolamide, uric acid, fructose 1,6-bisphosphate, CMP, and S-(Hydroxymethyl)-glutathione, were remarkably altered in the cold stress groups. Combined transcriptomic and metabolomic data revealed that pyrimidine metabolism, amino acid metabolism, and pyruvate metabolism were the most significant pathways regulated by the low-temperature exposure. Overall, this work suggests that 14 °C and 7 °C cold stress could induce obvious morphological damage and apoptosis in the liver at 4 dps. Moreover, energy metabolism and amino acid metabolism were the main signaling pathways in response to cold stress for P. sinensis. Full article

This study characterizes the evolution of the tumor necrosis factor superfamily (TNFSF) across vertebrate lineages, both cyclostomes and gnathostomes, by combining sequence similarity and synteny data for the genes from 23 model species. The available evidence supports a simple model in which most of the diversity found in living species can be attributed to the expansion of four genes found in an ancestor of all vertebrates before the first of the genome duplications that occurred in the vertebrate lineages. It is inferred that the ancestor of all cyclostomes possessed only six TNFSF genes. A cyclostome-specific genome triplication had little effect on the total number of these genes. The ancestor of all gnathostomes, due to the effect of a second genome duplication plus additional single-gene duplications, already had 21 TNFSF genes. In several gnathostome lineages, particularly in some tetrapods, the TNF superfamily has significantly contracted due to numerous gene losses. This evolutionary model provides a framework for exploring functional data, showing that the descendants of different ancestral genes have acquired distinct roles, most prominently in the innate and adaptive immune systems, which led to a species-specific refinement of which TNFSF genes were conserved or lost. Several data hitherto difficult to interpret (the interactions of very different TNFSF ligands with the same receptors; the ability of the same ligands to bind alternative receptors, with or without death domains; and the cooperation of different ligands in specific functions) can be explained as consequences of the evolutionary history of the TNF superfamily. Full article

The genetic improvement of beef cattle breeds is crucial for the advancement of the beef cattle industry. Whole-genome resequencing technology has been widely applied in genetic breeding as well as research on selection signatures in beef cattle. In this study, 20× whole-genome resequencing was performed on 282 Angus cattle from the Ningxia region, and a high-quality dataset encompassing extensive genomic variations across the entire genome was constructed. The iHS test identified 495 selection signal regions, which included pregnancy-associated glycoprotein (PAG) family genes and immune-related genes such as UL16-binding protein 21 (ULBP21), CD1b molecule (CD1B), and tumor necrosis factor ligand superfamily member 11 (TNFSF11). A quantitative trait locus (QTL) enrichment analysis revealed that several economic traits, including longissimus muscle area, marbling score, carcass weight, average daily gain, and milk yield, were significantly enriched in cattle with these selection signatures. Although the enrichment of QTLs for health traits was low, immune-related genes may indirectly contribute to improvements in production performance. These findings show the genetic basis of economic and adaptive traits in Ningxia Angus cattle, providing a theoretical foundation and guidance for further genetic improvement and breeding strategies. Full article

Polycyclic aromatic hydrocarbons (PAHs) are known to have toxic effects on fish. In this study, we examined the effects of benz[a]anthracene (BaA), a type of PAH, on fish liver metabolism. Nibbler fish (Girella punctata) were intraperitoneally injected with BaA (10 ng/g body weight) four times over a 10-day period. BaA significantly decreased known bone metabolism-related plasma factors such as calcium and inorganic phosphorus. Moreover, significant reductions were observed in the plasma levels of known liver metabolism-related factors, including ferrous ions, total bile acids, total bilirubin, free bilirubin, aspartate aminotransferase, and alkaline phosphatase. Interestingly, mono-hydroxylated metabolites of BaA, such as 3 hydroxylbenz[a]anthracene (3-OHBaA), were detected in the bile of BaA-injected nibbler fish. This hydroxylated form of BaA was found in its free form, rather than conjugated with glucuronic acid or sulfuric acid. Due to the lack of whole-genome sequence data for the nibbler fish, two nibbler fish-specific apoptosis-related factors (TNF receptor superfamily member 1A: tnfrsf1a and TNF superfamily member 10: tnfsf10) were isolated by De novo RNA sequencing. In a liver tissue culture, 3-OHBaA (10⁻⁶ M) significantly upregulated the expression of tnfrsf1a and tnfsf10 in the liver. These results provide the first evidence that 3-OHBaA metabolites exhibit toxic effects on the liver in teleost. Full article