Endocrine, metabolic & immune disorders drug targets最新文献

Introduction: Lipid metabolism and endoplasmic reticulum stress (ERS) are crucial in coronary artery disease (CAD) pathogenesis, but the exact mechanisms remain unclear. This study aims to systematically investigate the molecular interplay between lipid metabolism and ERS in CAD.

Methods: Lipid metabolism-related genes (LRGs), ERS-related genes (ER-RGs), and the bulk RNA-seq dataset were collected related to CAD. Machine learning algorithms and receiver operating characteristic (ROC) analysis were then integrated to identify key genes. Subsequent analyses included gene set enrichment analysis (GSEA), immune cell infiltration profiling, regulatory network construction, and drug prediction. The causal relationship between key genes and CAD was analyzed by Mendelian randomization. Finally, the mRNA expression levels of key genes in clinical samples were verified with the help of qPCR experiments.

Results: 12 candidate genes were identified by integrating LASSO, SVM-RFE, and Boruta algorithms. The ROC analysis prioritized three high-confidence diagnostic key genes (NFKB1, LPIN1, and SEC24B). Furthermore, these key genes exhibited significant associations with the CAD immune microenvironment; notably, NFKB1 demonstrated a strong positive correlation with memory-activated CD4+ T cells. Furthermore, MR analysis showed SEC24B polymorphisms conferred reduced CAD risk (OR = 0.85), consistent with its protective expression pattern. The qPCR results show significant downregulation of both LPIN1 and NFKB1 in CAD patients.

Discussion: Our findings suggest that NFKB1, LPIN1, and SEC24B play pivotal roles in CAD by linking lipid metabolism with endoplasmic reticulum stress and modulating immune responses. The downregulation of NFKB1 and LPIN1 in CAD patients, together with the protective effect of SEC24B polymorphisms, highlights a complex interplay between metabolic and inflammatory pathways. These insights not only improve our understanding of CAD pathogenesis, but also point to potential molecular targets for precise therapeutic interventions.

Conclusion: This study elucidates the pathogenic mechanisms of L-ER RGs in CAD development, identifying NFKB1, LPIN1, and SEC24B as key molecular mediators. It not only reveals their roles in immune regulation and metabolic pathways but also provides actionable targets for precision therapeutics in CAD management.

Introduction: Monoclonal gammopathy, or paraproteinemia, involves monoclonal immunoglobulins in the blood and ranges from benign monoclonal gammopathy of undetermined significance (MGUS) to malignant multiple myeloma. Hemostatic abnormalities affect 15-30% of cases but are often under-recognized. This study presents three cases of Immunoglobulin A (IgA) monoclonal gammopathy with hemostatic dysfunction to enhance understanding of its pathophysiology and clinical impact.

Case presentation: This report presents a retrospective review of three patients with IgA monoclonal gammopathy at Changhua Christian Hospital, including two with lymphoplasmacytic lymphoma and one with plasma cell myeloma, each exhibiting hemostatic dysfunction. Despite the same underlying IgA monoclonal gammopathy, the etiologies, clinical presentations, and laboratory findings varied significantly among the patients. Two patients experienced clinically significant bleeding episodes associated with acquired von Willebrand syndrome (AvWS) and platelet dysfunction. Conversely, one patient exhibited multiple coagulation factor deficiencies and platelet dysfunction but did not have clinically significant bleeding episodes.

Conclusion: This case series highlights the diverse hemostatic manifestations of IgA monoclonal gammopathy, including AvWS, platelet dysfunction, and multiple clotting factor deficiencies. Despite having the same class of monoclonal protein, patients exhibited distinct clinical and laboratory findings, suggesting heterogeneous mechanisms of coagulation impairment. Awareness of these presentations in hematologic and immunologic practice is crucial for diagnosis and individualized management. Further research is needed to elucidate the molecular mechanisms underlying these hemostatic defects and develop targeted management strategies.

Introduction: Observational research has indicated a link between regulatory T-cells (Tregs) and the risk of acute respiratory distress syndrome (ARDS). However, establishing a definitive causal relationship has been challenging. This study aimed to clarify this connection using a two-sample Mendelian randomization (MR) approach.

Method: The summary datasets of genome-wide association studies (GWAS) were utilized, identifying 716 instrumental variables (IVs) related to Tregs. The inverse-variance weighted (IVW) method served as the primary analysis, supplemented by weighted median, MR-Egger, and weighted mode methods. Sensitivity analyses included Cochran's Q, leave-one-out analysis, MR-Egger intercept, and MR pleiotropy residual sum and outlier (MR-PRESSO) tests.

Results: A genetically-predicted 1-SD increase in the absolute count of CD39+ CD4+ Tregs was associated with a 23.2% reduction in the odds of ARDS (OR = 0.768, 95% CI: 0.612 - 0.963, P = 0.022). Conversely, a 1-SD increase in the absolute count of CD127- CD8br Tregs was associated with a nearly threefold increase in the odds of developing ARDS (OR = 2.894, 95% CI: 1.511 - 5.543, P = 0.001). Sensitivity tests revealed no heterogeneity or horizontal pleiotropy.

Discussion: Our findings suggested a dual and opposing role for Treg subtypes in ARDS. The protective effect of CD39+ CD4+ Tregs is biologically plausible, likely mediated by the immunosuppressive adenosine pathway. In contrast, the unexpected risk-increasing effect of CD127- CD8br Tregs may reflect their functional plasticity or a dysregulated, insufficient response within the severe inflammatory lung microenvironment, rather than a direct pathogenic role.

Conclusion: This study has provided compelling evidence for a genetic causal link between specific Tregs subtypes and ARDS risk, highlighting their potential as biomarkers for ARDS diagnosis and treatment.

Introduction: Pancreatic cancer (PC) presents unique challenges to traditional immunotherapy due to its immunosuppressive microenvironment and low mutation burden. Research into antibody-mediated immune responses, which has been extensively applied in various cancer types, is also applicable to the study of pancreatic cancer.

Methods: Using public Genome-wide association study (GWAS) data and genetic instruments, we conducted a two-sample Mendelian randomization (MR) analysis to explore causal relationships between 46 antibody-mediated immune responses and PC. We employed five MR methods. Cochran's Q statistic and corresponding p-values from the MR Egger and Inverse Variance Weighted methods assessed instrument heterogeneity. Egger intercept and MR pleiotropy residual sum and outlier (MR-PRESSO) methods detected potential horizontal pleiotropy, ensuring the robustness of our findings.

Results: Our study identified causal links between five antibody-mediated immune responses and pancreatic cancer risk. Chlamydia trachomatis momp A antibody levels were inversely correlated, while Anti-helicobacter pylori IgG seropositivity, Polyomavirus 2 JC VP1 antibody levels, and Merkel cell polyomavirus VP1 antibody levels showed positive correlations. Notably, Anti- Merkel cell polyomavirus IgG seropositivity exhibited strong positive associations across Inverse variance weighting (IVW), weighted median, and MR-Egger analyses (p < 0.05).

Discussion: These results suggest that specific Antibody-Mediated Immune Responses may modulate pancreatic carcinogenesis through immune activation or chronic inflammation. The protective association for Chlamydia trachomatis momp A contrasts with the risk-enhancing effects observed for anti-helicobacter pylori IgG and polyomaviruses, highlighting heterogeneous immunobiological pathways that warrant mechanistic investigation.

Conclusion: Our study demonstrated a randomized causal effect between antibody-mediated immune responses and pancreatic cancer, offering a new perspective for clinical diagnosis and treatment of the disease.

Introduction: The high global prevalence of diabetes and treatment noncompliance is a great clinical challenge. Thus, the need for anti-diabetic medications is critical. In this regard, in vivo antidiabetic potential of the synthesized dichloroindolinone (C1 and C2) was investigated.

Methods: Different animal models were used for the oral glucose tolerance test and the alloxan-induced mice model at 25mg, 50mg, and 75mg/kg po. Various biomarkers were examined for glycemic effects, followed by histological analysis.

Results: The test compounds showed marked safety in the acute toxicity test up to 2000 mg/kg. In the oral glucose tolerance test, compounds elicited significant (*P< 0.05) effects at 25mg, 50mg, and 75mg/kg. Similarly, the blood glucose levels were lowered at various test doses and pioglitazone 10 mg/kg when observed at 0, 7, 14, and 21 days of treatment in alloxan-induced diabetic mice. The hepatic biomarkers, ALT and AST, were significantly regulated in test mice. Total Cholesterol (TC) and Triglycerides (TG) were significantly (*P< 0.05) modulated at various doses. The renal biomarkers, urea and serum creatinine, were also significantly (*P< 0.05) regulated. To strengthen the biochemical analysis, the histopathological examination of C1 and C2 in the pancreas revealed a prominent improvement in the morphological changes.

Discussion: The C1 and C2 showed significant antidiabetic effects and significantly lowered ALT and AST levels, according to the results. The results of the biochemical profile showed that the test doses had considerably lowered TG and TC.

Conclusion: In short, both compounds exhibit acute safety, oral glucose tolerance, and antidiabetic effects in biochemical and histological amelioration.

Introduction: Polycystic ovary syndrome (PCOS) is a complex endocrine disorder characterized by hyperandrogenism, ovarian dysfunction, and metabolic abnormalities. It affects between 4% and 21% of females of fertile age. The present review provides a comprehensive analysis of PCOS, covering pathophysiology, diagnostic criteria, prevalence, biochemical markers, and demographic influences. It examines genetic, hormonal, and lifestyle variables, contributing to the conditions, highlighting ethnic disparities in prevalence.

Methods: To systematically analyse current data and refine evidence-based diagnosis and management guidelines, published in 2018, a global team was assembled. A systematic literature search was conducted across major academic databases, including PubMed, Scopus, Web of Science, and Google Scholar, to identify relevant studies on PCOS pathophysiology, diagnosis, and emerging therapies. Based on the global team's view, our generalised narrative review explores metabolic implications such as glucose intolerance, obesity, and type-2 diabetes, as well as hormonal imbalances involving androgens, luteinizing hormone, and prolactin.

Results: Lifestyle factors, socioeconomic status, and ethnicity significantly influenced PCOS expression. Advancements in diagnosis, including AI-driven evaluation and precision medicine approaches, are discussed, alongside improvements in biochemical testing and treatment strategies.

Discussion: PCOS expression varies by lifestyle, ethnicity, and socioeconomic status. Emerging diagnostics like AI and precision medicine enhance detection, treatment, and understanding of its metabolic complexity.

Conclusion: The review emphasizes the importance of personalized interventions and integrated healthcare approaches to enhance PCOS management and patient outcomes.

Congenital hyperinsulinemia (CHI) is a clinically heterogeneous disorder that is the leading cause of persistent and recurrent hypoglycemia in infancy and childhood. There are 39 pathogenic genes associated with CHI. The forkhead box A2 (FOXA2) gene variants that induce forkhead box A2 hyperinsulinemia (FOXA2-HI) are extremely rare. This review describes the genetic pathogenesis and treatment progress of FOXA2-HI to improve clinicians' understanding of the disease.

Background: Diabetes mellitus is a global health issue, affecting over 6.2% of the population. Effective management of type II diabetes mellitus (DM II) depends largely on patients' knowledge, attitudes, and practices (KAP). This study has examined how demographic and clinical factors influence KAP among DM II patients in Punjab, India, aiming to identify knowledge gaps and behavioral trends.

Methods: A cross-sectional study was conducted from February 2023 to July 2024 across three outpatient clinics in Punjab. A total of 500 patients were recruited using non-probability purposive sampling. Data were collected using a pre-validated questionnaire and analyzed through SPSS software. KAP scores were assessed and categorized into poor, fair, or good, with multiple linear regression used to identify significant predictors.

Results: Among the 500 participants (197 females, 303 males), demographic and clinical factors significantly influenced KAP scores (p<0.05). Higher scores were associated with males, married individuals, those with higher educational attainment, health insurance, and regular clinic visits. Education was a key predictor of improved KAP across all domains. Conversely, poor scores were linked to lower education levels, absence of health insurance, and limited physical activity. Gender disparities were observed, with males displaying better knowledge and attitudes, while females exhibited higher practice scores.

Conclusion: This study has highlighted disparities in KAP among DM II patients in Punjab, emphasizing the critical role of education, healthcare access, and physical activity. Targeted interventions, community-based educational programs, and policy-driven improvements in healthcare accessibility are essential to bridge knowledge gaps, reshape attitudes, and foster positive practices. These findings can guide the development of tailored strategies for diabetes management, ultimately improving health outcomes and quality of life for affected individuals.

Introduction: Cancer-associated fibroblasts (CAFs) can promote gastric cancer (GC) progression through regulating the tumor microenvironment (TME). This study explored cell-to-fibroblast communication based on the single-cell data of GC, identified CAF-related genes linked to GC using high-dimensional weighted gene co-expression network analysis (hdWGCNA), and conducted functional mining, drug prediction, and molecular docking for these genes.

Materials and methods: Single-cell data were preprocessed using the Seurat package. The communication network between cell subpopulations and fibroblasts was analyzed using CellChat. Key hub genes were initially identified through hdWGCNA, while differentially expressed genes (DEGs) between cancer and control groups were obtained using DESeq2. Subsequently, the overlapping genes between the hub genes and DEGs were subjected to LASSO regression (via the glmnet package) and SVM-RFE (implemented in e1071) to select biomarkers for GC. Immune cell infiltration was assessed using the CIBERSORT package, and functional enrichment analysis was performed on the background gene set by GSEA_4.2.2 software. Finally, drugs targeting the biomarkers were predicted by employing the DSigDB database.

Results: Single-cell analysis identified eight major cell subpopulations, with fibroblasts distinctly marked by DCN and LUM expression. Cell communication analysis revealed that HLA-ECD94: NKG2A and HLA-E-KLRC1 were the main interactions through which other cell clusters exerted influence on fibroblasts. COL1A1 and SERPINH1 were identified as CAF-related biomarkers that promoted GC progression through macrophage-mediated immune infiltration. High co-expression of the two genes was significantly enriched in epithelial-mesenchymal transition (EMT).

Discussion: COL1A1 and SERPINH1 may promote GC progression via regulating EMT and forming an immunosuppressive microenvironment through ECM remodeling and macrophage polarization. Additionally, chitosamine was screened as a potential COL1A1-targeting drug for GC treatment.

Conclusion: These findings have deepened our current understanding of CAF-mediated mechanisms in GC, contributing to the development of precision diagnostics and therapeutics in GC.