Endocrine, metabolic & immune disorders drug targets最新文献

Background: Hypercalcemia is an electrolyte imbalance with multiple etiologies, the most common being primary hyperparathyroidism (PHPT). The diagnostic workup of PHPT is relatively straightforward, as elevated serum calcium levels in the presence of elevated or inappropriately normal parathyroid hormone (PTH) immediately raise the suspicion for PHPT. However, this typical presentation can be unhinged by the presence of severe vitamin D deficiency, which may mask hypercalcemia. Furthermore, vitamin D deficiency itself can contribute to PTH increase.

Case presentation: We report the case of a 53-year-old man presenting with markedly elevated PTH levels (639 pg/ml) with only borderline-elevated serum calcium (10.8 mg/dl) and severe vitamin D deficiency (5 ng/ml). Once the vitamin D level was restored to normal range with cholecalciferol supplementation, the patient developed severe hypercalcemia (14.4 mg/dl) requiring specific management.

Conclusion: This case report offers an interesting insight into the potential for cholecalciferol replacement therapy to unmask significant hypercalcemia in PHPT patients and underscores the need for caution in such a context.

Background: Neuroinflammation is a key driver of cognitive deficits after surgical menopause, a state commonly triggered by oophorectomy for oncological purposes. This intervention is routinely performed in premenopausal patients with hormone receptor-positive (HR+) breast cancer, constitutes foundational therapy for epithelial ovarian carcinoma, and is indicated for risk reduction in carriers of hereditary mutations such as breast cancer susceptibility gene 1/2 (BRCA1/2). As highly efficient immune cells, microglia play a central role in the onset of neurodegenerative diseases. Our study explored the role of thioredoxin-1 (Trx-1) in suppressing microglial activation and its potential for ameliorating postmenopausal cognitive decline.

Methods: Female C57BL/6J mice underwent ovariectomy (OVX) to model tumor-therapeutic oophorectomy. They were intraperitoneally injected with recombinant human Trx-1 (rhTrx-1) at a dose of 200 μg/30 g or PBS once weekly for five weeks following OVX. A Y-maze active avoidance task and trace fear conditioning were used to assess cognitive function. Levels of neuroinflammation were evaluated through immunofluorescence, enzyme-linked immunosorbent assay (ELISA), and real-time polymerase chain reaction (PCR). Trx-1 levels in the hippocampus of OVX mice were measured by western blot and immunohistochemical analysis. Furthermore, the impact of Trx-1 on microglial activation was assessed in vitro.

Results: OVX induced the production of inflammatory factors and microglial activation in the brain, resulting in cognitive deficits in mice. However, intraperitoneal injection of rhTrx-1 inhibited these effects by improving cognitive function, reducing inflammatory cytokines, and promoting microglial polarization. In vitro studies also showed that rhTrx-1 attenuated lipopolysaccharide (LPS)-stimulated microglial activation through mitogen-activated protein kinase (MAPK) pathway signaling.

Discussion and conclusion: Due to its inhibitory effect on neuroinflammation and microglial activation, Trx-1 may represent a promising therapeutic candidate for managing cancer therapy-related cognitive impairment, particularly in patients undergoing estrogen-deprivation therapies such as oophorectomy.

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.