Endocrine, metabolic & immune disorders drug targets最新文献

Introduction: Intracranial aneurysm (IA) is a cerebrovascular disease that lacks effective methods for early diagnosis and risk prediction. Considering the pivotal roles of senescence and inflammation in many diseases, this study aimed to identify related biomarkers for IA and explore their underlying mechanisms.

Methods: The GSE122897 and GSE75436 datasets were obtained from the Gene Expression Omnibus (GEO) database. Senescence and inflammation scores were calculated using single-sample GSEA (ssGSEA), and weighted gene co-expression network analysis (WGCNA) was performed to identify relevant modules and hub genes. Differentially expressed genes (DEGs) were determined with the DESeq2 package, followed by conducting LASSO regression and support vector machine-recursive feature elimination (SVM-RFE) to screen key genes. Immune infiltration was analyzed using CIBERSORT and ESTIMATE algoritms, and correlations between key genes and immune cells were assessed. Finally, transcription factor (TF)-miRNA regulatory networks were constructed using the JASPAR package and ENCORI database.

Results: IA samples exhibited significantly higher senescence and inflammation scores in comparison to the controls. A total of 858 hub genes identified by WGCNA were intersected with the DEGs for further refinement by LASSO and SVM-RFE, ultimately yielding PTCH1, ACACB, DRD1, and SLC25A21-AS1 as the candidate genes for IA. Immune infiltration analysis showed that the expression of these genes was associated with several immune cells, including NK cells. Moreover, IA samples had higher ESTIMATEScore, ImmuneScore, and StromalScore, which were all negatively correlated with the expression of the four genes. TF-miRNA network analysis revealed 67, 71, and 76 potential TF regulators for PTCH1, ACACB, and SLC25A21-AS1, respectively.

Discussion: These findings indicated that senescence and inflammation contributed to IA pathogenesis and may regulate disease progression by modulating the immune microenvironment, highlighting their dual role in IA.

Conclusion: PTCH1, ACACB, and SLC25A21-AS1 were identified as potential biomarkers associated with senescence and inflammation in IA, providing novel insights into its molecular mechanisms and potential diagnostic or therapeutic targets.

Background: Patients with GAD65 antibody-associated autoimmune encephalitis who also have diabetes are usually considered to have type 1 diabetes mellitus (T1DM). However, previous reports often lacked β-cell function assessments, relying solely on anti-GAD65 positivity for diagnosis, which is insufficient for accurate classification.

Case presentation: We present a 30-year-old Chinese woman diagnosed with GAD65-associated autoimmune encephalitis, hyperthyroidism, and diabetes. Her peak C-peptide level was 3.99 ng/mL, inconsistent with the β-cell dysfunction typical of classic T1DM. The combination of high GAD65 antibody titers and preserved β-cell function made it challenging to determine her diabetes type.

Conclusion: This case suggests that clinicians should pay more attention to assessing and monitoring β-cell function when GAD65-associated autoimmune encephalitis is accompanied by diabetes.

Neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, ischemic stroke, and other related conditions, significantly impact the quality of life, particularly in low-income nations. The pathogenesis of these diseases is driven by neuroinflammation, oxidative stress, apoptosis, mitochondrial dysfunction, and regulation of autophagy. To date, no therapies or medications can fully reverse the progression of these diseases. Natural polysaccharides have demonstrated significant therapeutic potential in the treatment of neurodegenerative diseases. Lycium barbarum polysaccharide, derived from the traditional Chinese medicine Lycium barbarum L., has attracted considerable attentionfor its diverse biological activities, biodegradability, ease of modification, and low toxicity. This review aims to systematically evaluate the neuroprotective effects of Lycium barbarumpolysaccharides and their mechanisms in various neurodegenerative disease models. For this study, we used multiple scientific databases, including PubMed, Scopus, Web of Science, and Google Scholar. We verified the correct plant name through the website plantlist.org. The search results were interpreted and documented based on the retrieved bibliographic information. Lycium barbarum polysaccharide has shown significant therapeutic potential for the treatment of neurodegenerative diseases. Experimental evidence reveals its neuroprotective effects through various mechanisms, including reducing neuroinflammation, alleviating oxidative stress, inhibiting apoptosis, improving mitochondrial function, and regulating autophagy. The current review established that Lycium barbarum polysaccharide holds promise as a therapeutic agent for neurodegenerative diseases. However, further research is required to address the limitations identified in previous studies and to guide future experimental investigations and clinical applications.

Introduction: Sarcopenia is a degenerative musculoskeletal disease affecting the elderly, significantly impairing patients' quality of life and challenging modern medicine. This study innovatively combines Traditional Chinese Medicine (TCM) theories with modern medical research to explore the mechanisms by which Gushukang granules address sarcopenia.

Methods: The research integrated multi-dimensional research methods, including network pharmacology, metabolomics, and animal experiments, to comprehensively investigate the scientific mechanisms of Gushukang granules' intervention in sarcopenia.

Results: Network pharmacology analysis identified multiple potential targets related to muscle growth and repair. UPLC-Q-TOF MS technology tracked metabolic pathways, while animal experiments verified that Gushukang granules precisely regulate muscle metabolic balance by modulating key signaling pathways involved in protein synthesis and degradation.

Discussion: The findings demonstrate the potential of integrating traditional and modern medical approaches in addressing age-related muscle degradation, providing scientific validation for TCM treatment of sarcopenia.

Conclusion: This study establishes a model for modernizing TCM research, offering solid scientific evidence for comprehensive intervention of chronic diseases in the elderly and highlighting the TCM concept of "preventing disease before its onset" in modern medical translation.

Introduction: Irritable Bowel Syndrome (IBS) and hypothyroidism are both common conditions that significantly affect patient health. This study examines the link between IBS and hypothyroidism, focusing on how IBS impacts hypothyroidism.

Methods: A retrospective cohort study using data from the UK Biobank (UKB) and a cross-sectional analysis from the National Inpatient Sample (NIS) were conducted. Propensity score matching was applied to control for confounding factors. Cox proportional hazards models (UKB) and logistic regression models (NIS) were used to evaluate the association between IBS and hypothyroidism. Subgroup analyses by age and sex were performed.

Results: The UKB cohort included 22,970 IBS patients (mean age 56.1 ± 7.94 years, 72.2% female) with a hypothyroidism prevalence of 4.1%, compared to 438,094 non-IBS participants (mean age 56.4 ± 8.12 years, 51.9% female) with a prevalence of 2.9%. In the NIS, 183,738 IBS patients had a hypothyroidism prevalence of 20.6%, compared to 10.3% in 20,298,589 non-IBS participants. After PSM, the hazard ratio (HR) for hypothyroidism in IBS patients was 1.21 (95% CI: 1.12-1.30, P < 0.001) in the UKB, and the odds ratio (OR) was 1.25 (95% CI: 1.23-1.27, P < 0.001) in the NIS. Subgroup analyses showed a higher risk for hypothyroidism in IBS patients, particularly those aged ≤65 years and females.

Conclusions: IBS is associated with an increased risk of hypothyroidism. Clinicians should consider screening for thyroid dysfunction in IBS patients to improve patient outcomes.

Introduction: The interplay between LncRNA MALAT1 and hsa-miR-1 plays a crucial role in Myocardial Ischemia-Reperfusion Injury (MIRI), offering insights into the molecular mechanisms underlying cardiovascular pathologies. This study sought to elucidate their regulatory relationship and functional impact on MIRI progression.

Materials and methods: Using an H9C2 cardiomyocyte cell line subjected to ischemia-reperfusion (I/R) modeling, we analyzed alterations in LncRNA MALAT1 and hsa-miR-1 expression and their downstream effects on apoptosis, reactive oxygen species (ROS) accumulation, and myocardial injury markers.

Results: Our findings demonstrated that siRNA-mediated knockdown of MALAT1 or modulation of hsa-miR-1 (via mimics and inhibitors) effectively attenuated oxidative stress and reduced cardiomyocyte apoptosis. Furthermore, in vivo experiments using a murine MIRI model corroborated the regulatory roles of MALAT1 and hsa-miR-1, identifying them as potential therapeutic targets for mitigating reperfusion injury.

Discussion: Our findings highlight the importance of the MALAT1/miR-1 axis in MIRI pathogenesis. The observed reduction in ROS and apoptosis upon modulation of these molecules suggests their involvement in key cellular stress responses. These results align with previous studies on lncRNA- miRNA interactions in cardiovascular diseases.

Conclusion: These results not only highlight the significance of the MALAT1/miR-1 axis in MIRI but also propose novel molecular intervention strategies for the treatment of cardiovascular disease.

Introduction: This study investigated the hepatoprotective effects and mechanisms of 17β-estradiol (E2) in a mouse model of type 2 diabetes mellitus (T2DM) with non-alcoholic fatty liver disease (NAFLD).

Methods: Male C57BL/6J mice (n = 6/group) were fed a high-fat diet for 8 weeks and injected with streptozotocin (60 mg/kg for 3 days) to induce T2DM + NAFLD. Animals were randomized into control, model, E2 (20 μg/kg/day, i.p., 8 weeks), E2 + siNC, and E2 + siPGC-1α groups. Metabolic indices, liver enzymes, body weight, liver index, and pre-specified cholestasis-related safety endpoints (alkaline phosphatase [ALP], total bile acids [TBA], total bilirubin [TBil]) were quantified. H&E and Oil Red O staining were used to assess hepatic injury and steatosis. PGC-1α/ERRα signaling was evaluated by Western blotting, immunofluorescence, and ChIPqPCR.

Results: Compared with the model group, E2 reduced fasting blood glucose by 54.7%, insulin by 36.3%, HOMA-IR by 71.1%, cholesterol by 25.9%, triglycerides by 46.2%, LDL-C by 36.6%, ALT by 47.2%, and AST by 39.9% (all P < 0.05). Body weight, liver index, hepatocyte injury, and lipid deposition were also decreased. E2 restored hepatic PGC-1α and ERRα expression and their co-localization; ChIP-qPCR confirmed ~7-fold enrichment of ERRα promoter regions by PGC-1α. For cholestasis-related indices, ALP and TBA exhibited only small, non-concerted changes while TBil remained stable; all values stayed within reference limits, indicating no cholestatic phenotype under our dosing paradigm. PGC-1α knockdown (E2 + siPGC-1α) blunted or abolished these metabolic, histological, and signaling benefits.

Discussion: The study demonstrates that 17β-estradiol exerts hepatoprotective and metabolic regulatory effects in diabetic fatty liver via modulation of the PGC-1α/ERRα pathway.

Conclusion: This study demonstrates that E2 alleviates metabolic dysfunction and hepatic injury in T2DM-NAFLD mice by activating the PGC-1α/ERRα axis, while preserving cholestatic safety, as evidenced by non-concerted ALP/TBA/TBil changes within reference limits. PGC-1α is essential for mediating these effects, highlighting the PGC-1α/ERRα pathway as a promising therapeutic target for metabolic liver disease.

Background: Anti-LGI1 antibody-associated encephalitis is a rare autoimmune neurological disorder, and primary Sjögren's syndrome is a systemic autoimmune disease with multisystem involvement. The coexistence of these conditions with acute cerebral infarction is extremely rare and highlights complex interactions between autoimmune and vascular mechanisms.

Case presentation: This case report describes a middle-aged female patient diagnosed with LGI1 antibody-associated encephalitis, complicated by Sjögren's syndrome and acute cerebral infarction. The patient presented with an acute onset of symptoms, including delayed response, cognitive impairment, and right-sided weakness. Brain MRI revealed a fresh infarction in the left basal ganglia region. Blood and cerebrospinal fluid tests confirmed the presence of LGI1 antibodies, with blood anti-SS-A antibody levels at +++ and anti-SS-B antibody levels at +, as well as anti- Ro-52 antibody levels at +++.

Conclusions: This report emphasizes the importance of recognizing the overlap between these conditions, as timely diagnosis and intervention can lead to better outcomes in similar cases. By examining the relationship between anti-LGI1 antibody-associated encephalitis, primary Sjögren's syndrome, and acute cerebral infarction, this paper aims to expand the understanding of the complex interactions between autoimmune encephalitis and systemic disorders.

Introduction: Lipid metabolism and endoplasmic reticulum stress (ERS) are crucial in coronary artery disease (CAD) pathogenesis, but the exact mechanisms remain unclear. This study aims to systematically investigate the molecular interplay between lipid metabolism and ERS in CAD.

Methods: Lipid metabolism-related genes (LRGs), ERS-related genes (ER-RGs), and the bulk RNA-seq dataset were collected related to CAD. Machine learning algorithms and receiver operating characteristic (ROC) analysis were then integrated to identify key genes. Subsequent analyses included gene set enrichment analysis (GSEA), immune cell infiltration profiling, regulatory network construction, and drug prediction. The causal relationship between key genes and CAD was analyzed by Mendelian randomization. Finally, the mRNA expression levels of key genes in clinical samples were verified with the help of qPCR experiments.

Results: 12 candidate genes were identified by integrating LASSO, SVM-RFE, and Boruta algorithms. The ROC analysis prioritized three high-confidence diagnostic key genes (NFKB1, LPIN1, and SEC24B). Furthermore, these key genes exhibited significant associations with the CAD immune microenvironment; notably, NFKB1 demonstrated a strong positive correlation with memory-activated CD4+ T cells. Furthermore, MR analysis showed SEC24B polymorphisms conferred reduced CAD risk (OR = 0.85), consistent with its protective expression pattern. The qPCR results show significant downregulation of both LPIN1 and NFKB1 in CAD patients.

Discussion: Our findings suggest that NFKB1, LPIN1, and SEC24B play pivotal roles in CAD by linking lipid metabolism with endoplasmic reticulum stress and modulating immune responses. The downregulation of NFKB1 and LPIN1 in CAD patients, together with the protective effect of SEC24B polymorphisms, highlights a complex interplay between metabolic and inflammatory pathways. These insights not only improve our understanding of CAD pathogenesis, but also point to potential molecular targets for precise therapeutic interventions.

Conclusion: This study elucidates the pathogenic mechanisms of L-ER RGs in CAD development, identifying NFKB1, LPIN1, and SEC24B as key molecular mediators. It not only reveals their roles in immune regulation and metabolic pathways but also provides actionable targets for precision therapeutics in CAD management.

Introduction: Monoclonal gammopathy, or paraproteinemia, involves monoclonal immunoglobulins in the blood and ranges from benign monoclonal gammopathy of undetermined significance (MGUS) to malignant multiple myeloma. Hemostatic abnormalities affect 15-30% of cases but are often under-recognized. This study presents three cases of Immunoglobulin A (IgA) monoclonal gammopathy with hemostatic dysfunction to enhance understanding of its pathophysiology and clinical impact.

Case presentation: This report presents a retrospective review of three patients with IgA monoclonal gammopathy at Changhua Christian Hospital, including two with lymphoplasmacytic lymphoma and one with plasma cell myeloma, each exhibiting hemostatic dysfunction. Despite the same underlying IgA monoclonal gammopathy, the etiologies, clinical presentations, and laboratory findings varied significantly among the patients. Two patients experienced clinically significant bleeding episodes associated with acquired von Willebrand syndrome (AvWS) and platelet dysfunction. Conversely, one patient exhibited multiple coagulation factor deficiencies and platelet dysfunction but did not have clinically significant bleeding episodes.

Conclusion: This case series highlights the diverse hemostatic manifestations of IgA monoclonal gammopathy, including AvWS, platelet dysfunction, and multiple clotting factor deficiencies. Despite having the same class of monoclonal protein, patients exhibited distinct clinical and laboratory findings, suggesting heterogeneous mechanisms of coagulation impairment. Awareness of these presentations in hematologic and immunologic practice is crucial for diagnosis and individualized management. Further research is needed to elucidate the molecular mechanisms underlying these hemostatic defects and develop targeted management strategies.