Endocrine, metabolic & immune disorders drug targets最新文献

Gestational Diabetes Mellitus (GDM) is a common endocrine condition associated with adverse pregnancy outcomes. In recent years, a growing number of risk factors associated with gestational diabetes mellitus have been defined. GDM poses a serious threat to maternal health. The etiology is complex and multifactorial and can be divided into inherent and modifiable factors. The inherent factors have been described in other literature, while the modifiable factors are mainly the risk of lifestyle habits. In this study, we performed a narrative review of the progress of risk factors associated with gestational diabetes mellitus.

Background: The recognition of epicardial adipose tissue (EAT) as a cardiac risk factor has increased the interest in strategies that target cardiac adipose tissue.

Aim: The effect of bariatric and metabolic surgery (BMS)-induced weight loss on EAT volume was evaluated in this study.

Methods: Fifteen bariatric patients, with (MS) or without (wMS) Metabolic Syndrome, underwent magnetic resonance imaging (MRI) using an open-bore scanner to assess EAT volume, visceral adipose tissue (VAT) thickness, and other cardiac morpho-functional parameters at baseline and 12 months after BMS. Nine patients underwent laparoscopic sleeve gastrectomy (LSG), and 6 patients underwent Roux-en-Y Gastric Bypass (RYGBP).

Results: EAT volume significantly decreased in all the patients 12 months post-BMS from 91.6 cm³ to 67.1 cm³; p = 0.0002 in diastole and from 89.4 cm³ to 68.2 cm³; p = 0.0002 in systole. No significant difference was found between the LSG and RYGBP group. Moreover, EAT volume was significantly reduced among wMS compared with MS. In particular, EAT volume in diastole was significantly reduced from 80.9 cm³ to 54.4 cm³; p = 0.0156 in wMS and from 98.3 cm³ to 79.5 cm³; p = 0.031 in MS. The reduction was also confirmed in systole from 81.2 cm³ to 54.1 cm³; p = 0.0156 in wMS and from 105.7 cm³ to 75.1 cm³; p = 0.031 in MS. Finally, a positive correlation was found between EAT loss, BMI (r = 0.52; p = 0.0443) and VAT (r = 0.66; p = 0.008) reduction after BMS.

Conclusion: These findings suggest that EAT reduction may be a fundamental element for improving the cardio-metabolic prognosis of bariatric patients. Moreover, this is the first study performed with an open-bore MRI scanner to measure EAT volume.

Multiple Sclerosis (MS), a debilitating inflammatory disorder of the central nervous system characterized by demyelination, is significantly influenced by polygenic variations. Although the precise cause of MS remains unclear, it is believed to arise from a complex interplay of genetic and environmental factors. Recent investigations have focused on the polygenic nature of genetic alterations linked to MS risk. This review highlights the critical role of these genetic variants in shaping disease susceptibility and progression. Specific Human Leukocyte Antigen (HLA) alleles, such as HLA-DRB1*15:01, HLA-DRB50*101, HLA-DR2+, HLA-DQ6, DQA 0102, and DQB1 0602, are implicated in immune modulation, significantly increasing the risk of developing MS. Additionally, Genome-wide Association Studies (GWAS) have identified non-HLA genetic variants that contribute to MS susceptibility, including IL-2RA (rs2104286), IL-7R (rs6897932), CD40 (rs1883832 T), CD58 (rs2300747), and others, each playing a role in immune regulation and disease progression. Dysfunctions in genes regulating myelin integrity, such as MOG (Myelin Oligodendrocyte Glycoprotein), MAG (Myelin-associated Glycoprotein), and PLP1 (Proteolipid Protein 1), further drive MS pathogenesis. Moreover, viral infections, notably Epstein-Barr Virus (EBV), Human Herpesvirus 6 (HHV-6), and measles virus, may exacerbate the development of MS by triggering immune responses. Understanding the contribution of these genetic and viral factors may shed light on the complex etiology of MS. Polygenic Risk Scores (PRS) provide a valuable tool for estimating MS susceptibility based on the cumulative effect of genetic variants. However, translating these genetic insights into clinical practice requires further validation, including environmental considerations. Investigating MS polygenicity could lead to personalized therapies, enhancing diagnosis, prognosis, and treatment, ultimately improving outcomes for MS patients.

Background: Recurrent Miscarriage (RM) is a chronic and heterogeneous autoimmune disease. Platelet factor 4 (PF4) has been found to be involved in the pathogenesis of RM.

Objective: We aimed to explore the role and mechanism of PF4 on trophoblasts in RM in vitro.

Methods: In this study, the expression of PF4 and PF4 receptor CXC chemokine receptor 3 (CXCR3) in the placentas of patients with RM were analyzed by RT-qPCR and western blotting. Serum PF4 level was tested by ELISA. Following PF4 silencing and SOCS3 overexpression in HTR-8/SVneo cells, cell proliferation was detected by CCK-8, colony formation, and EDU assays. Wound healing and transwell assays separately evaluated cell migration and invasion. Immunofluorescence assay determined E-cadherin expression. Tube formation assay was used to measure the angiogenesis. Western blotting examined the expression of metastasis, epithelial-mesenchymal transition (EMT) and suppressor of cytokine signaling 3 (SOCS3)/signal transducer and activator of transcription 3 (STAT3) signaling-associated proteins.

Results: The results revealed that PF4 displayed increased expression in placental villus tissues of RM patients. Serum PF4 level was also elevated in RM patients. PF4 silencing promoted the proliferation, migration, invasion, EMT, and angiogenesis of HTR-8/SVneo cells. Additionally, PF4 knockdown downregulated SOCS3 expression to activate STAT3 signaling. SOCS3 overexpression countervailed the effects of PF4 deficiency on HTR-8/SVneo cells.

Conclusion: In summary, PF4 participated in the proliferation, migration, invasion, EMT and angiogenesis of trophoblast cells by modulating the SOCS3/STAT3 signaling pathway, indicating that targeting the PF4/SOCS3/STAT3 pathway could be a novel therapy for RM.

Metabolic dysfunction-associated steatohepatitis (MASH) is a major cause of a worldwide clinical and financial burden. Despite the tremendous efforts for untangling the molecular mechanisms, there is still a need for defining specific therapeutic targets. In this editorial, the author will focus on the role of erythrocyte death and hepatic erythrophagocytosis in MASH. Evidence indicates that erythrolysis prior to erythrophagocytosis protects against the development of MASH, while phagocytosis of intact erythrocytes culminates in hepatic inflammation. Furthermore, understanding the balance between erythrolysis and intact erythrocyte engulfment could lead to the development of new strategies for the treatment of MASH.

Background: Denosumab, a fully humanized monoclonal neutralizing antibody inhibiting the RANK/RANKL/OPG signaling pathway, is widely used for treating patients with bone metastases. However, its use in cancer patients with bone metastases is burdened by the risk of all grades of hypocalcemia, with the severe grade being rare. In the literature, several cases of severe symptomatic hypocalcemia have been reported, particularly in patients with breast and prostate cancers. In this report, we present a rare case of asymptomatic hypocalcemia in a 78 years-old patient with sigmoid cancer and bone metastases.

Case presentation: Hypocalcemia was detected two weeks after the first denosumab administration, during routine biochemical evaluation. The patient reported only a mild nonspecific paresthesia after medical questioning, without relevant clinical symptoms. Despite the severity of the hypocalcemia, serum calcium levels began to improve after a short period of low-dose calcium and calcitriol therapy, though complete stabilization and normalization occurred after several weeks.

Conclusion: This case highlights the importance to consider severe paucisymptomatic or asymptomatic hypocalcemia as a possible side effect in bone-metastatic patients treated with denosumab. It is advisable to monitor serum calcium levels even in the absence of typical hypocalcemia-related symptoms.

Background: The significance of circular RNAs (circRNAs) in diabetic complications has been established. However, their role in basal and diabetic states, as well as cognitive dysfunction, requires further investigation.

Methods: BV-2 microglial cells were exposed to high glucose (50mM) and insulin (2μM) for 48 hours. The levels of interleukin-1beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factoralpha (TNF-α) were assessed through quantitative polymerase chain reaction (qPCR), western blot, and ELISA. CircRNA and messenger RNA (mRNA) sequencing were performed, and the data were analyzed. Differentially expressed circRNAs and mRNAs were identified using qPCR. The circRNA-miRNA interaction was predicted using Miranda and TargetScan software, and their levels were quantified by qPCR.

Results: The results demonstrated a significant increase in mRNA and protein levels of IL-1β, IL-6, and TNF-α in BV2 cells treated with glucose and insulin. Five circRNAs (four upregulated and one downregulated) were identified in both glucose and insulin groups compared to the control. Further qPCR analysis revealed marked increases in the levels of chr17:40159331- 40159711+ and chr2:72800499-72801858- (mmu_circ_0010164) in both treatment groups. Competitive endogenous RNA networks showed significant upregulation of mRNA levels of mitochondrial transcription termination factor 1b (Mterf1b) and G protein subunit gamma 4 (Gng4), accompanied by a decrease in mmu-miR-6918-3p and mmu-miR-7043-3p levels in the glucose and insulin groups compared to the control. Knockdown of mmu_circ_0010164 significantly inhibited the inflammatory response induced by glucose and insulin in BV-2 microglial cells.

Conclusion: These findings indicate that both glucose and insulin can elicit inflammatory responses in BV2 cells through the modulation of mmu_circ_0010164 levels. The underlying mechanism may involve potential downstream targets of mmu_circ_0010164, specifically mmu-miR-7043-3p/Gng4 and mmu-miR-6918-3p/Mterf1b. This provides novel insights into the treatment of glucose-induced neuroinflammation.

Background: The ketogenic diet, known for its high-fat, low-carbohydrate composition, has been extensively studied in endocrine and metabolic diseases. This study carried out bibliometric analysis to examine the research trends in this field over the past 20 years, aiming to provide insights for future studies.

Methods: We searched the Web of Science Core Collection for all relevant papers. VOSviewer was used for network visualization, the bibliometrix package of R software (version 4.3.0) was utilized for data analysis, and CiteSpace was employed for mapping and trend analysis.

Results: This study encompassed 508 relevant articles spanning from 2003 to 2023, authored by 2827 researchers from 887 institutions across 57 countries/regions. The total number of publications increased from 3 in 2003 to 508 in 2023, showing a steady growth trend. The United States emerged as the predominant contributor in this field, followed by Italy and China. Notably, SAJOUX I consistently exhibited high activity in this field, according to the analysis, with an h-index of 13. The journal Nutrients has consistently made substantial contributions to this field, accounting for 19% of all publications. The keywords "obesity," "ketogenic diet," and "weight loss" appeared most frequently, with "obesity" occurring 163 times.

Conclusion: This study used a bibliometric method to analyze the impact of the ketogenic diet on the endocrine metabolic system. The research identifies recent frontiers and trending directions, providing valuable references for scholars in this field.

Aims and objectives: The purpose of this study was to comprehensively evaluate the association of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) with neurological adverse events using the US Food and Drug Administration Adverse Event Reporting System (FAERS) database, with the aim of guiding the rational use of statins.

Methods: The number and clinical characteristics of adverse events (AEs) to statins in the FAERS database between 2012 and March, 2023, were extracted. Neurological AEs were defined by the system organ classes (SOCs) of "Nervous System Disorders (10029205)" and the corresponding PT. Disproportionality was calculated using the reporting dominance ratio (ROR), proportional reporting ratio (PRR), and information component (IC025).

Results: Between January, 2012 and March, 2023, a total of 90,357 AEs were reported for the three statins (atorvastatin, resuvastatin, and simvastatin). The majority of reports on AEs came from the United States (n = 7284). A total of 8409 reports described neurological AEs following the use of the three statins, with atorvastatin accounting for more than half of the reports (n = 4430). The mean age of patients who developed neurological AEs was 55 years and older. The prevalence was similar in female patients (2230/4480) and male patients (1999/4480). Disproportionate analyses showed that at the SOC level, only the correlation between atorvastatin and neurological AEs suggested a positive signal (ROR: 9.77 (9.56-9.99); IC025: 3.28; PRR (χ2): 9.76 (16.07)) and in total, there were 32 PTs with a positive signal. The median time for neurological AEs was 71 days (IQR: 14-559 days), and the most common AEs were other serious effects (important medical event) (OT) (n = 2283) and hospitalization (HO) (n = 715).

Conclusion: This study suggests that atorvastatin may be associated with an increased risk of neurological AEs. This study provides realistic evidence of the potential risk of statin-related adverse events.