Endocrine, metabolic & immune disorders drug targets最新文献

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.

Background: Hirschsprung disease (HD) is a congenital disorder associated with specific missense mutations in the RET proto-oncogene. This study aimed to demonstrate the incidence of Hirschsprung disease and its clinical and pathological aspects in an Iraqi pediatric cohort from a major referral hospital in Baghdad.

Methods: A retrospective analysis was conducted over a ten-year period, reviewing the clinical and surgical records of patients diagnosed with Hirschsprung disease. Pathological sections were re-evaluated, and patient medical histories, prior surgeries, and other relevant clinical data were confirmed.

Results: A total of 106 cases of Hirschsprung disease were identified. The mean age at diagnosis was 2.4 ± 3.0 years, with 40.6% of cases diagnosed within the first year of life. The male-to-female ratio was 2.6:1. The most commonly affected anatomical sites were the colon (35.8%) and rectum (23.6%). Pathological evaluation revealed the absence of ganglion cells in 57.5% of cases. Rectal biopsy was the most frequently performed diagnostic procedure (64.2%), and colon resection was required in 35.8% of cases. A significant association was found between disease presence and anatomical site involvement (P = 0.010) and surgical intervention (P = 0.046).

Conclusion: The study highlights a male predominance in Hirschsprung disease, with the majority of cases diagnosed within the first year of life. The rectum and colon were the most commonly affected sites. Significant associations were observed between disease presence and anatomical site involvement, as well as surgical interventions, emphasizing the importance of early diagnosis and appropriate management strategies.

Introduction: PCOS is a common endocrine disorder in women of reproductive age, with granulosa cells playing a key role in its development. This study aims to identify shared differentially expressed genes (DEG) in granulosa cells and blood from PCOS patients, offering potential biomarkers and therapeutic targets.

Methods: Transcriptomic data were obtained from the Gene Expression Omnibus (GEO) database: GSE95728 (granulosa cells; 7 PCOS, 7 controls) and two blood-based datasets, GSE85932 and GSE54248 (12 PCOS, 12 controls). In silico tools were employed to identify DEG, hub genes, and protein-protein interactions and to explore predicted drug targets.

Results: DEG analysis revealed that Vanin-2 (VNN2) and Interleukin-1 receptor type 2 (IL1R2) were consistently dysregulated in PCOS patients. Dysferlin (DYSF), Carbonic Anhydrase 4 (CA4), and Solute Carrier Family 2 Member 14 (SLC2A14) were differentially expressed between the blood datasets, while Aquaporin 9 (AQP9), C-X-C Motif Chemokine Receptor 1 (CXCR1), and Annexin A3 (ANXA3) were dysregulated in GSE95728 (granulosa cells) and GSE54248 (blood). Functional enrichment highlighted immune and metabolic pathways. Protein-protein interaction analysis identified AQP9 as a hub gene. Drug prediction analysis suggested that IL1R2 could be targeted by anakinra, while VNN2 was predicted to interact with pantothenic acid.

Discussion: The dysregulation of VNN2 and IL1R2 across tissue types suggests their involvement in immune-inflammatory processes in PCOS. The expression of AQP9 and other metabolism-related genes indicates possible immune-metabolic crosstalk, aligning with known PCOS pathophysiology.

Conclusion: VNN2 and IL1R2 show potential as biomarkers or therapeutic targets in PCOS. Further validation is needed to confirm their clinical significance and roles.

Background: Acromegaly associated with Morris syndrome has never been reported in the literature.

Case presentation: We present the case of a 49-year-old woman with Morris syndrome, diagnosed in 1992, who has undergone gonadectomy and hormone replacement therapy for about 15 years. The patient was referred to our centre for the clinical suspicion of acromegaly in June 2022, for the enlargement of the acral extremities and the development of prognathism in the last 10 years. The patient underwent mandibular reduction surgery and removal of a tubular adenoma of the colon in 2010. In June 2021, the patient performed random GH, IGF-I, and prolactin (PRL) dosages that confirmed the diagnosis of acromegaly. A contrasted pituitary MRI showed the presence of an 8 mm intrasellar pituitary adenoma. Therefore, a transsphenoidal resection of the pituitary tumor was conducted in September 2021. The histological examination proved the diagnosis of somatotropinoma. At the last follow-up at our center in June 2024, the patient presented in a fair general clinical condition, with recovery of related acromegaly symptoms, normalized IGF-I levels, and a negative pituitary MRI for signs of somatotropinoma recurrence.

Conclusion: Our clinical case describes for the first time the association between Morris syndrome and acromegaly. Due to the singularity of this case, we decided to conduct more in-depth genetic analyses through a clinical exome study and CGH Array evaluation, which, however, did not lead to the discovery of a genetic association between the two conditions. Although this condition is rare, further genetic studies are needed to demonstrate a genetic association between these two conditions.