Endocrine, metabolic & immune disorders drug targets最新文献

Introduction: Although Gamma-Glutamyl Transferase (GGT) has been implicated in metabolic disorders, its association with male reproductive hormones in type 2 diabetes mellitus (T2DM) remains unclear.

Methods: In this cross-sectional study, 971 men with T2DM were recruited from Shandong Provincial Hospital. Serum GGT levels were measured as the primary exposure variable, while male reproductive hormones-including total testosterone (TT), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and sex hormone-binding globulin (SHBG)-served as outcome variables. Multivariable linear regression, threshold effect models, and subgroup analyses were used to assess associations, adjusting for age, BMI, glycemic control, and other confounders.

Results: The mean age of participants was 56.37 ± 12.49 years. After full adjustment, men in the highest GGT tertile exhibited a 0.44 ng/mL reduction in TT levels compared to the lowest tertile (P < 0.01). A nonlinear relationship was identified, with a saturation effect at GGT = 118 IU/L. Below this threshold, each 10-IU/L increase in GGT corresponded to a 0.13 ng/mL decrease in TT (95% CI: -0.21 to -0.05). Unadjusted inverse associations with SHBG (β=-14.87, 95%CI:-26.47 to -3.28) and LH (β=-1.34, 95%CI:-2.14 to -0.54) became nonsignificant after adjustment (P>0.05). No FSH associations were detected.

Discussion: Our findings reveal a novel dose-dependent relationship between GGT and testosterone in T2DM, with effects plateauing beyond 118 IU/L. This threshold may reflect the point where oxidative stress overwhelms gonadal compensatory mechanisms.

Conclusion: The nonlinear relationship suggests GGT may help identify androgen deficiency risk, though SHBG/LH links appear confounder-dependent. Monitoring GGT could aid T2DM male health management.

Background: Esketamine has shown promise in mitigating tissue damage caused by ischemia- reperfusion injury, making it a potential therapeutic candidate for acute lung injury (ALI) induced by limb ischemia-reperfusion (LIR-ALI).

Objective: This study sought to explore the role and mechanism of esketamine in the LIR-ALI rat model.

Methods: The effects of esketamine on the LIR-ALI rats model were evaluated through histopathological examination, assessment of pulmonary edema, measurement of MDA and SOD levels, and analysis of inflammatory cytokine levels (IL-1β, etc.) in the bronchoalveolar fluid (BALF) and serum. Western blot analysis was used to assess the expressions of TLR4, NF-κB, and NLRP3. TLR4 agonist, LPS, was used to validate the role of NF-κB/NLRP3 pathway in LIRALI.

Results: Esketamine significantly alleviated LIR-induced ALI by reducing pulmonary edema, inflammatory cell infiltration, and oxidative stress. Elevated MDA content and suppressed SOD activity were significantly reversed by esketamine, along with inactivity of the TLR4/NF-κB/NLRP3 pathway. Esketamine treatment reduced inflammatory response in BALF and serum. TLR4 activation by LPS reversed the ameliorative effects of esketamine on LIR-ALI.

Conclusion: Esketamine protected against LIR-induced ALI by mitigating oxidative stress and suppressing the TLR4/NF-κB/NLRP3 axis. These findings highlight the potential therapeutic value of esketamine for ALI.

Background: Atrial Fibrillation (AF) is the most prevalent form of cardiac arrhythmia, with a complex etiology that implicates lipid metabolism. This study employs Mendelian Randomization (MR) to dissect the causal relationships between lipidomic profiles and AF, utilizing comprehensive genetic data to clarify these associations.

Methods: Summary statistics for 179 lipid species across 13 classes were retrieved from the GWAS Catalog, encompassing 7,174 Finnish individuals from the GeneRISK study. For AF, data were synthesized from six major studies comprising over one million subjects. Our Two-Sample MR (TSMR) approach was implemented using Inverse Variance Weighting (IVW), MR-Egger, and MR-PRESSO for sensitivity analysis. Additionally, we uniquely integrated the Mendelian Randomization-Bayesian Model Averaging (MR_BMA) method to robustly prioritize the most likely causal lipid determinants of AF, and performed bidirectional MR analysis to assess potential reverse causality.

Results: The TSMR analysis, reinforced by MR_BMA, revealed significant causal associations between specific lipid species and AF risk. In particular, Phosphatidylcholine (17:0_18:2) was associated with a decreased risk of AF (OR = 0.96, 95% CI 0.93-0.99, P<0.05), whereas Phosphatidylcholine (16:0_20:5) and Phosphatidylcholine (17:0_20:4) were linked to increased risks (OR = 1.04, 95% CI 1.01-1.07, P<0.01; and OR = 1.02, 95% CI 1.00-1.05, P<0.05, respectively). Furthermore, elevated levels of Phosphatidylethanolamine (18:0_20:4) (OR = 1.03, 95% CI 1.01-1.06, P<0.01) and Triacylglycerol (50:4) (OR = 1.04, 95% CI 1.00-1.07, P<0.05) were also associated with increased AF risk. In addition, Sphingomyelin (d34:2), Sterol ester (27:1/18:0), and Sterol ester (27:1/18:3) emerged as further risk factors, thereby expanding the spectrum of lipidomic determinants implicated in AF. The bidirectional MR analysis provided no evidence of reverse causation, reinforcing the directionality of the lipid-driven association. Sensitivity analyses demonstrated robust findings with no indication of pleiotropy or heterogeneity.

Conclusion: This study provides strong evidence for the causal role of specific lipid species in the development of AF. Our comprehensive MR analysis not only deepens our understanding of AF pathophysiology but also highlights the therapeutic potential of targeting these lipid alterations. Notably, the absence of reverse causation supports a unidirectional relationship wherein altered lipid species drive AF risk.

Background: Heart failure with preserved ejection fraction (HFpEF) represents a challenging cardiovascular condition characterized by normal systolic function but impaired diastolic performance. Despite its increasing prevalence, therapeutic options remain limited. This study investigated the metabolic effects of canagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on cardiac function and energy metabolism in HFpEF.

Methods: We established a rat model of HFpEF using Dahl salt-sensitive rats and evaluated three experimental groups: control (A), HFpEF (B), and canagliflozin-treated HFpEF (C). This study carried out comprehensive analyses of cardiac structure and function, metabolomic profiling, and detailed assessment of myocardial energy metabolism, including mitochondrial respiratory capacity and ATP synthesis. Additionally, we validated our findings using H9C2 cardiomyocytes under controlled conditions.

Results: Canagliflozin treatment significantly improved cardiac remodeling markers, including reduced myocardial volume and fibrosis area, while enhancing diastolic function (E/A ratio). Metabolomic analysis revealed normalization of hypermetabolic states, with significant reductions in key metabolites, including L-lysine, D-glucose, and uridine. The treatment restored balance in multiple metabolic pathways, particularly affecting β-alanine metabolism, pyrimidine metabolism, and the citrate cycle. Notably, canagliflozin enhanced mitochondrial respiratory function, increased ATP synthesis, and optimized fatty acid utilization, as evidenced by reduced free fatty acid content.

Conclusion: Our findings demonstrated that canagliflozin exerts cardioprotective effects through multiple metabolic pathways, suggesting its potential as a therapeutic option for HFpEF. The ability of the drug to optimize energy metabolism and improve mitochondrial function represents a novel mechanism for treating this challenging condition.

20α-hydroxyprogesterone [(20S)-20-hydroxypregn-4-en-3-one, 20α-DHP] is one of the endogenous metabolites of progesterone (Pregn-4-ene-3,20-dione, P4) and a steroid hormone. The literature related to 20α-DHP mainly concentrates on the years from the 1950s to 1970s, and a review of 20α-DHP has not been conducted. In this work, the endogenous and exogenous sources of 20α-DHP are introduced, and methods for determining 20α-DHP in biological samples are described. The biological activities of 20α-DHP are summarized in detail, including the maintenance of pregnancy, endometrial protection, regulation of hormone secretion, ovulation promotion, uterine epithelial cell proliferation, antagonism of breast cancer, and as a diagnostic indicator for psoriasis and polycystic ovarian syndrome. Finally, the pharmacokinetic characteristics of 20α- DHP are briefly introduced to provide a reference for the further development and utilization of 20α-DHP.

Background: Staphylococcus aureus is one of the most frequent human infections, which triggers various infectious diseases like soft tissue infection, lethal pneumonia, endocarditis, and bacteremia. The most common pathogen responsible for simple cystitis is E.coli; however, it also causes pneumonia, bacteremia, and abdominal infections, such as spontaneous bacterial peritonitis.

Objective: Chinese medicines have been used effectively in the treatment of infectious disorders; thus, this study aimed to investigate the efficiency of Chinese medicine against S. aureus.

Methods: An extract of traditional Chinese medicine was prepared using nine compounds: tongcao, talc, red peony root, fennel, guangui, lychee core, dry sunflower, dianthus, and purslane, to evaluate its antibacterial activity against Staphylococcus aureus RN450RF.

Results: The minimum inhibitory concentration (MIC) of the Chinese medicine measured by the consecutive double dilution technique was 200g/L. The drug-resistant plasmid was transferred equally well under controlled laboratory conditions with a median conjugation frequency of 1.1x106. The maximum activity of conjugated transfer of resistant drug plasmid of E. coli CP9 (R45) was observed at 2/1 MIC (100 g/L drug concentration), 32h time interval, with a bacterial concentration 108 CFU/ml.

Conclusion: These results suggest that the secondary inhibitory concentration (1/2 MIC) of the Chinese medicine solution can promote the combination and transfer of the resistance plasmid of Chinese medicine (R45) between different strains. The drug concentration, binding time, and initial bacterial concentration have different degrees of positive promotion effects on the conjugation and transfer of drug-resistant plasmids. Traditional Chinese medicine might be a potentially huge disease management and infection control resource.

Introduction: Anemia has been linked to an increased risk of coronary heart disease (CHD), yet the underlying causal relationship remains unclear. This study aimed to investigate the bidirectional associations between anemia and CHD using a multi-method approach.

Methods: Data were obtained from the European FinnGen biobank and the Gene Expression Omnibus (GEO) database. Mendelian Randomization (MR) analysis was performed with instrumental variables (IVs). The study assessed causal robustness using MR methods and sensitivity analysis, followed by differential expression analysis and weighted gene co-expression network analysis (WGCNA) to screen for core genes. Further, machine learning algorithms, such as least absolute shrinkage and selection operator (LASSO), random forest (RF), and support vector machine (SVM) algorithms, were applied to screen for key diagnostic genes. Additionally, the CIBERSORT algorithm was used to analyze immune cell infiltration, and validation was conducted using an in vitro oxidized low-density lipoprotein (ox-LDL)-induced endothelial cell model and western blot experiments.

Results: MR analysis revealed a positive causal link among vitamin B12 deficiency anemia, hemolytic anemia, and coronary heart disease, while cardiovascular events appeared to have a negative association with hemolytic anemia. Integrated bioinformatics analysis identified six core genes involved in immune response, inflammation, and lipid metabolism. To improve the accuracy of key gene screening and avoid bias from a single method, this study combined multiple machine learning algorithms for comprehensive analysis, ultimately identifying IFIH1 and APBB2 as potentially valuable diagnostic biomarkers, and revealing affected macrophages, mast cells, and T cells infiltration. In vitro experiments confirmed altered expression of IFIH1 and APBB2 upon ox-LDL treatment, supporting their role in CHD pathogenesis.

Conclusion: This study, through the integration of MR, transcriptomics, and machine learning methods, has for the first time revealed the causal role of vitamin B12 deficiency anemia and hemolytic anemia in the occurrence of CHD, and identified IFIH1 and APBB2 as potential biomarkers. This research study has provided a new theoretical basis and research direction for understanding the molecular link between anemia and CHD and for improving clinical early warning systems.

Background: Perineal necrotizing fasciitis, or Fournier's gangrene, is a rare but rapidly progressing condition characterized by fascial necrosis. It is a severe, potentially life-threatening infection requiring prompt diagnosis and standardized treatment to optimize patient outcomes.

Case presentation: A 48-year-old woman with poorly controlled type 2 diabetes developed necrotizing fasciitis of the right perineum secondary to an ischial tuberosity pressure ulcer. She had a prior spinal cord injury resulting in sensory dysfunction in the lower limbs, which masked significant pain. Management included surgical debridement, open wound care, antimicrobial therapy, and a free skin graft for wound closure.

Conclusion: Effective treatment of necrotizing fasciitis relies on aggressive debridement and appropriate antimicrobial therapy. This case highlights the importance of early recognition and intervention to improve clinical diagnostic and management strategies.

Introduction: Previous studies suggest a link between Basal Metabolic Rate (BMR) and obstetrical disorders; however, causality remains unclear. We investigated the causal effects of BMR on 14 obstetric disorders and evaluated the potential mediating effects of blood metabolites in these relationships.

Methods: Using Genome-Wide Association Study (GWAS) summary data, we conducted both univariate and multivariable Mendelian Randomization (MVMR) analyses. The primary causal inference was based on Inverse Variance Weighted (IVW), MR-Egger, weighted median, and sensitivity analyses (Cochran's Q, MR-PRESSO). Mediation analysis was employed to quantify the proportion of effects operating through metabolite-regulated pathways.

Results: BMR was inversely associated with hyperemesis gravidarum (OR=0.73, 95%CI: 0.59-0.90, P=0.008), Intrahepatic Cholestasis of Pregnancy (ICP) (OR=0.67, 95%CI: 0.56-0.80, P<0.001), poor fetal growth (OR=0.80, 95%CI:0.71-0.90, P=0.001), and preterm delivery (OR=0.78, 95%CI:0.70-0.87, P<0.001). MVMR identified elevated BMR and mannose levels as protective against ICP, with BMR showing a positive correlation with mannose. Mediation analysis revealed that BMR reduced ICP risk partly through increased mannose (OR = 1.38, 95% CI: 1.19-1.59, P = 2.03 × 10^-5), accounting for 29.93% of the effect.

Discussion: Elevated BMR significantly reduced risks of intrahepatic cholestasis (HR=0.67), fetal distress (HR=0.80), and preterm birth (HR=0.78), mediated partly by mannose levels. Mendelian randomization established causality, linking metabolic adaptation to improved pregnancy outcomes. However, these findings, based on European genetic data, limit generalizability, and unmeasured confounders may persist despite MR methods.

Conclusion: Higher BMR may lower risks of hyperemesis gravidarum, ICP, poor fetal growth, and preterm delivery. Mannose mediates the protective effect of BMR on ICP, highlighting potential metabolic pathways for intervention.