Endocrine, metabolic & immune disorders drug targets最新文献

Introduction: Metabolic syndrome (MetS) is a significant public health issue. The role of genetic versus environmental factors in MetS remains debated. The Caveolin1 (CAV1) gene, which encodes the caveolin protein, has been reported to be associated with several diseases. This study aims to elucidate the connection and underlying mechanisms between the CAV1 gene variant and MetS.

Methods: Following the PROSPERO-registered protocol (CRD42024452093), we performed extensive searches in PubMed, Web of Science, and Embase through April 2024. Ten cross-sectional studies, encompassing 3545 participants, were included, focusing on the association between the CAV1 gene variant and three core components of MetS: obesity, dyslipidemia, and hypertension. Associations were evaluated using standardized mean differences (SMDs) and 95% confidence intervals (CIs) for AA or AG genotypes versus GG.

Results: Robust associations between the CAV1 rs3807992 polymorphism and indicators of obesity, body mass index (95% confidence interval (CI) = 0.063 to 0.467, p = 0.010), body fat mass (95% CI = 0.052 to 0.247, p = 0.003), and fat mass index (95% CI = -0.004 to 0.319, p = 0.056) were found. Furthermore, inverse correlations were observed with lipid profiles: high-density lipoprotein (95% CI = -0.493 to -0.154, p < 0.001), low-density lipoprotein (95% CI = -0.296 to -0.101, p < 0.001), and total cholesterol (95%CI = -0.186 to -0.027, p = 0.008) showed significant relationship, while no significant associations were found with triglycerides or diastolic blood pressure.

Discussion: The CAV1 rs3807992 variant may play a role in MetS, suggesting its potential as a genetic marker and therapeutic target, while our study also provides insights into the underlying mechanisms.

Conclusion: CAV1 rs3807992 polymorphism is significantly associated with metabolic syndrome, particularly obesity and adverse lipid profiles. The A allele may contribute to increased obesity while negatively affecting cholesterol levels. These findings support the potential use of rs3807992 as a genetic biomarker for MetS risk assessment and personalized prevention.

Introduction: Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are chronic autoimmune diseases characterized by inflammation and tissue damage. Emerging evidence suggests vitamins D, C, and K may influence disease activity. The aim of this study is to assess serum vitamin levels in Jordanian RA and SLE patients and their association with disease activity.

Methods: This case-control study included 156 participants recruited at the University of Jordan Hospital (January-September 2023): 99 patients with RA, 11 patients with SLE, and 46 healthy controls. Serum vitamin levels were measured by ELISA; inflammatory markers were extracted from medical records. Statistical analysis was performed using SPSS with significance set at p<0.05.

Results and discussion: RA and SLE patients showed significantly lower vitamin D (RA: 17.5 ±16.4 ng/ml, adjusted p=0.003; SLE: 13.7 ±8.3 ng/ml, adjusted p=0.044) and vitamin C (RA: 14.7 ± 5.3 mg/ml, adjusted p=0.003; SLE: 13.5 ± 3.5 ng/ml, adjusted p=0.003) levels versus controls (D: 33.3 ±20.9 ng/ml; C: 38.8 ±33.4 ng/ml). Vitamin K levels were reduced but remained within the reference range (RA: 2.2±1.1 ng/ml, adjusted p=0.003; SLE: 2.9±1.0 ng/ml, adjusted p=0.003). Deficiencies in vitamins D and C were found to be positively associated with elevated inflammatory markers, particularly ESR. No significant associations were found between vitamin levels and anti-CCP, ANA, joint involvement, or skin rash in RA and SLE patients; however, vitamin C levels were significantly associated with anti-CCP antibody expression in RA patients.

Conclusion: In Jordanian RA and SLE patients, lower serum levels of vitamin D and C are associated with increased inflammation, underscoring the need for further research to explore the therapeutic potential of supplementation.

Introduction: Cryptorchidism, a common congenital malformation in male newborns due to abnormal testicular descent, is closely linked to male infertility and germ cell tumors. The study suggested that estrogen response contributes to its occurrence.

Methods: Data were collected from Gene Expression Omnibus (GEO). Enrichment scores were calculated by single-sample gene set enrichment analysis (GSEA), while pathway analysis was performed using GSEA. Key modules were identified through weighted gene co-expression network analysis (WGCNA), followed by the screening of differentially expressed genes (DEGs) using the limma package. The intersection genes were further screened by LASSO and Support Vector Machine-Recursive Feature Elimination (SVM-RFE). Potential transcription factors (TFs) were predicted using hTFtarget, and related microRNAs were analyzed using the Encori database. The TF regulatory network was visualized using Cytoscape 3.8.0.

Results: Patients with cryptorchidism exhibited significantly higher early estrogen response scores compared to controls, with a notable enrichment of the early estrogen response pathway. This study identified 2 biomarkers, PRR15 and SRPX, which were both regulated by the TF SPI1. PRR15 gene expression was significantly related to early estrogen response. Additionally, these two biomarkers were primarily involved in cell division pathways; in particular, PRR15 was closely linked to progesterone-mediated oocyte maturation.

Discussion: PRR15 and SRPX, which SPI1 potentially regulated, were identified as genes associated with early estrogen response in cryptorchidism and were enriched in estrogen-related and cell division pathways.

Conclusion: This study provided translational insights, enhancing the current understanding of testicular pathogenesis and contributing to the diagnosis and treatment of cryptorchidism.

Introduction: Dapagliflozin, an SGLT2 inhibitor developed for Type 2 Diabetes Mellitus (T2DM), has shown multiple cardiovascular benefits. This study evaluated its effects on lipid profile and IR pattern in South Indian patients with T2DM and Heart Failure (HF).

Methods: This randomized trial was conducted over 180 days in 58 patients with T2DM and HF, assigned in a 1:1 ratio to standard therapy or standard therapy plus dapagliflozin 10 mg daily. Lipid, glycemic, and IR parameters were assessed at baseline, 12 weeks, and 24 weeks.

Results: Dapagliflozin group showed marked improvements in BMI (p = 0.01), TC (p = 0.02), TG (p = 0.01), HDL (p = 0.001), LDL (p = 0.002), and VLDL (p = 0.01), FPG (p = 0.0001), PPG (p = 0.002) and HbA1c (p = 0.01), HOMA-IR (p = 0.002), HOMA2%B (p = 0.003), and decreased insulin levels (p = 0.001) by 24 weeks. In contrast, significant changes were noted only in LDL (p = 0.01), HDL (p = 0.03), and TG (p = 0.01) in the standard group. A positive correlation was observed between the mean change in TG and HOMA-IR after 24 weeks of dapagliflozin treatment.

Discussion: Dapagliflozin improved lipid profile and reduced IR, demonstrating benefits in T2DM and HF patients, which aligned with the findings from the larger SGLT2i trials. Study limitations included the small sample size, single-center setting, and an open-label design.

Conclusion: Dapagliflozin improved lipid and IR, highlighting its potential as an adjunctive therapy in patients with co-morbid T2DM and HF.

Clinical trial number: CTRI/2024/01/06208.

Introduction: This study aimed to investigate the potential relationship between live microbe intake and advanced liver fibrosis in patients with Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD).

Methods: Individuals with complete Vibration-Controlled Transient Elastography (VCTE) and dietary data from the National Health and Nutrition Examination Survey (NHANES) 2017-2020 were included. Generalized Additive Models (GAMs) were constructed to evaluate the relationship between live microbe intake and severity of hepatic steatosis and fibrosis, adjusting for potential confounders. Subgroup analyses and interaction tests assessed potential modifying effects of sex, age, Body Mass Index (BMI), liver enzymes, and alcohol consumption. Sensitivity analyses were performed to confirm robustness.

Results: A total of 2,533 individuals with MASLD were analyzed. GAM analyses showed no significant association between dietary live microbe intake and hepatic steatosis severity measured by Controlled Attenuation Parameter (CAP) (p = 0.779). However, there was a significant inverse relationship between live microbe intake and Liver Stiffness Measurement (LSM), indicating reduced liver fibrosis severity with higher microbe intake (p = 0.004). Subgroup and interaction analyses consistently supported this association across different age groups, sexes, BMI categories, and liver enzyme levels.

Discussion: These findings highlight a significant association between higher dietary intake of live microbes and reduced severity of liver fibrosis, emphasizing the potential role of dietary modification in managing liver fibrosis in MASLD.

Conclusion: Higher dietary intake of live microbes is significantly associated with reduced liver fibrosis severity in MASLD, suggesting a potential protective role of dietary microbes in liver health.

Background: The causal relationship between gut microbiota and puerperal sepsis (PS) remains unclear, and there is a lack of in-depth research regarding the potential mediating role of immune cells in this context.

Objective: This study aims to investigate the causal relationship between gut microbiota and PS using Mendelian randomization (MR) analysis and to assess the mediating effects of immune cells on the risk of PS onset through mediation analysis.

Materials and methods: We selected data from large-scale genome-wide association studies (GWAS) involving 473 gut microbiota species, 731 immune cell phenotypes, and PS datasets. Univariate MR (UVMR) analysis was employed to explore the causal relationship between gut microbiota and PS, with the primary statistical method being inverse variance weighting (IVW). Multiple statistical models were applied for sensitivity analysis to minimize the confounding effects of horizontal pleiotropy and heterogeneity. Subsequently, a two-step mediation MR analysis was conducted to evaluate whether immune cells mediate the relationship between gut microbiota and PS.

Results and discussion: Analysis using various statistical models indicated that 11 gut microbiota species (e.g., Azorhizobiume, Bacillus velezensis, CAG-245 sp000435175, Lentimicrobiaceae, and Providencia) exhibited a causal relationship with PS. Further reverse causal analysis between PS and gut microbiota ruled out the possibility of reverse causality. The two-step mediation MR analysis demonstrated that the percentage of IgD-CD27- B cells (10.26%) and CD62L- monocytes (17.29%) partially mediated the effect of CAG-245 sp000435175 on PS risk.

Conclusion: This study provides evidence of a causal relationship between the abundance of certain gut microbiota species and PS, while also revealing a potential mediating role of immune cells. These findings offer valuable theoretical insights into personalized treatment strategies and the development of novel diagnostic biomarkers for PS.

Introduction: Diabetes mellitus (DM) induces systemic vascular dysfunction and leads to life-threatening complications, including diabetic cardiomyopathy (DCM) and diabetic kidney disease (DKD), whose shared mechanisms remain elusive. In this study, we performed an in- -depth bioinformatics analysis to identify shared therapeutic targets and key molecular players in DKD and DCM.

Methods: Integrated computational and experimental approaches were employed. Bioinformatics analysis of GEO datasets (GSE30122 and GSE197850) identified differentially expressed genes (DEGs). Hub genes were extracted via protein-protein interaction networks and functional enrichment. In vitro validation was performed using AGE-stimulated cardiomyocytes and podocytes analyzed by qPCR, complemented by in vivo studies in rat models. Additionally, protein-chemical interactions and drug repurposing analyses were performed.

Results: We identified 48 common DEGs (P-adj< 0.05 and |log2FC| > 1.0) and prioritized 7 hub genes (CD200, CRHBP, DHRS3, EMCN, HPGD, PDGFRB, and SULF1), which were validated as dysregulated in in vitro and in vivo models. Computational screening revealed 10 promising therapeutic candidates (P-adj < 0.05) targeting core pathogenic networks.

Discussion: Our study is one of the first to simultaneously investigate the molecular underpinnings of DKD and DCM by integrating bioinformatics data with experimental validation. Meanwhile, the relatively small sample sizes may limit the statistical power and generalizability of the identified DEGs.

Conclusion: This study uncovers novel shared mechanisms between DCM and DKD, providing a framework for dual-organ protective therapies to advance the management of diabetic complications.

Introduction: Mitochondrial diseases refer to a group of hereditary disorders involving damage to high-energy-consuming tissues, such as muscles, nerves, and the heart. Mitochondrial DNA (mtDNA) mutations account for most cases, but the timely identification and treatment of these conditions remain challenging.

Case presentation: This report describes a case of a 36-year-old male patient who was diagnosed with diabetes in 2017 and subsequently experienced recurrent diabetic ketoacidosis and seizures. On May 20, 2022, he presented with cognitive impairment, unsteady gait, and an elevated blood lactate level. Brain MRI and mitochondrial gene sequencing on peripheral blood cells revealed destructive neuronal lesions and a mutation of m.3243A>G in the MT-TL1 gene with a ratio of 6.04%, which supported the diagnosis of mitochondrial encephalomyopathy associated with lactic acidosis and stroke-like episodes (MELAS) and mitochondrial diabetes mellitus (MDM). Treatment with insulin, fluid replacement, ketoacidosis correction, diazepam, and phenobarbital relieved most symptoms. However, his blood glucose was poorly controlled. Four months after discharge, the patient suffered a relapse. Although therapies to combat infection, reduce blood glucose, and correct ketoacidosis improved his condition, the patient died in 2023 due to cerebral infarction.

Conclusion: This case embodies the typical manifestations of mitochondrial diseases, emphasizing the urgency of prompt diagnosis and symptom management, which largely depends on effective genetic screening.

Introduction: The role of immune cells in type 2 diabetes mellitus (T2DM) development is well-studied, but their interactions with the gut microbiota and the mediating role in this process remain unclear.

Methods: We analyzed 731 immune cell phenotypes (3,757 Europeans), 473 gut microbiota traits (5,959 Finns), and T2DM data (over 400,000 Finns). Mendelian randomization (MR) was based on three assumptions: the instrumental variable (IV) is associated with exposure, IV is not influenced by confounding, and IV affects the outcome only through exposure. We selected single-nucleotide polymorphisms (SNPs) from genome-wide association studies as instrumental variables (IVs) to infer causal effects in two-sample MR analysis.

Results: We identified 36 immune cell phenotypes associated with T2DM, including 29 protective factors and seven risk factors, as well as 10 gut microbiota significantly linked to T2DM, with eight protective factors and two risk factors. MR revealed that five gut microbiota mediated the relationship between immune cells and T2DM. For example, the effects of CD3 on resting Treg (OR: 1.0136), CD3 on CM CD4+ (OR: 1.0180), and CD3 on naive CD4+ cells (OR: 1.0150) in T2DM were found to be partially mediated by the species Bacillus AY. The corresponding mediation effect proportions were 8.99%, 11.8%, and 11.4%.

Discussion: MR analysis identified multiple gut microbiota mediators in the relationship between immune cells and T2DM, addressing previous observational evidence. Limitations included the European ancestry bias, among others.

Conclusion: This study has highlighted the gut microbiota as a mediator between immune cells and T2DM, offering new insights for its early prevention and intervention.

Introduction: Only a few studies have investigated the prevalence and safety of oral quadruple regimens for treating type 2 diabetes (T2D), and evidence regarding combinations that include glucagon-like peptide-1 receptor (GLP-1R) agonists remains limited.

Methods: A descriptive, retrospective, cross-sectional study was conducted to collect information on the use of four non-insulin drug combinations in patients with T2D over a 12-month period.

Results: A total of 1,463 patients with T2D were evaluated during the study period, of whom 13.7% met the inclusion criteria and were enrolled. The mean duration of quadruple therapy was 37.0 ± 23.3 months. Sodium-glucose co-transporter-2 (SGLT2) inhibitors were the most common add-on therapy to a prior triple-drug regimen (32.3%), followed by pioglitazone (30.4%), sulfonylureas (21.9%), and GLP-1R agonists (12.9%). The mean reduction in glycated hemoglobin A1c (A1C) during quadruple therapy was 0.98 ± 0.88% compared to baseline values (p < 0.001), with no significant adverse effects or safety concerns reported. Notably, the addition of GLP-1R agonists as the fourth drug resulted in greater weight loss than any other oral antidiabetic medication.

Discussion: Despite the limitations inherent to a retrospective design, this study demonstrates that quadruple regimens can achieve significant reductions in A1C levels while maintaining a favorable safety profile.

Conclusion: In this study, 13.7% of patients with T2D received quadruple non-insulin drug combinations. Larger randomized controlled trials are needed to further evaluate their safety, efficacy, limitations, and potential role in T2D management.