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.

Introduction: Type 2 diabetes mellitus is a chronic metabolic disorder often accompanied by alterations in serum magnesium levels. This study aimed to investigate the relationship between serum magnesium concentration and glycemic control, comorbidities, and medication use in patients with type 2 diabetes mellitus.

Methods: A retrospective cross-sectional analysis was conducted using data from 502 patients. Glycemic control was assessed based on HbA1c levels, and serum magnesium concentrations were evaluated concerning clinical and demographic variables. Statistical analyses included ttests, Mann-Whitney U tests, logistic regression, and ROC curve analysis.

Results: Patients with poor glycemic control had significantly lower serum magnesium levels. Magnesium levels were lower in females, particularly postmenopausal women. Magnesium levels were significantly associated with hypertension, gender, and the use of specific medications such as metformin and indapamide. Logistic regression revealed a significant inverse association between serum Magnesium levels and congestive heart failure (OR = 0.055), but not with other comorbidities. ROC analysis revealed limited predictive value of magnesium for glycemic control (AUC = 0.41).

Discussion: Although group-level differences in magnesium were evident, magnesium levels alone were not reliable predictors of glycemic control. However, the associations with CHF, HT, gender, and specific medications suggest that magnesium plays a multifaceted role in type 2 diabetes mellitus management.

Conclusion: Regular monitoring of serum magnesium may aid in identifying at-risk patients, especially those with hypertension, CHF, or on magnesium-depleting medications. Further prospective studies are needed to clarify the clinical utility of magnesium in diabetes care.

Aim: The purpose of this study was to identify molecular subtypes and hub genes in fibromyalgia [FM] based on immune-related genes [IRGs].

Background: FM is a chronic disease featuring widespread pain, and the immune system may be involved in the FM progression.

Objective: The objectives of this study are as follows: 1] To identify the molecular subtypes of FM based on IRGs. 2] To screen and validate the hub genes in FM. 3] To predict the transcription factor [TF] targeting hub genes and 4] To evaluate the correlation between immune cell infiltration, hallmark pathways, and hub genes.

Methods: Two FM datasets were acquired from the Gene Expression Omnibus [GEO] database. IRGs were collected from the ImmPort database. Molecular subtypes of FM were identified using the "ConsensusClusterPlus" package. IRGs score and differentially expressed genes [DEGs] between different FM subtypes and control samples were obtained using "GSVA" and "limma" packages. Key module genes related to FM subtypes were identified using the "WGCNA" package. Hub genes were screened and verified using "glmnet" and "pROC" packages. TF-hub gene regulatory network was constructed by Cytoscape software. The correlation between immune cells, hallmark pathways, and hub genes was analyzed by the Spearman method. Finally, the DSigDB database was used to obtain associations between characterized genes and drugs, and the expression of key genes was verified using qRT-PCR.

Results: FM samples were classified into two subtypes, and the IRGs score of the C2 subtype was lower than that of the C1 subtype. Then, 184 module genes were obtained and mainly enriched in immune-related pathways. Next, 11 hub genes [TSPAN16, RILPL2, RASSF5, PGAP2, PADI2, NACC1, LRRC25, ITGAD, HIPK1, ATP6V0D1, AP1M2] were screened with good diagnostic performance. Besides, 45 TFs targeting hub genes were predicted. Most hub genes were negatively associated with CD4/CD8 T cells while positively correlated with macrophages, mast cell, monocyte, and neutrophil, as well as inflammatory response, angiogenesis pathways, etc. Molecular docking suggests that chloroquine and L-citrulline may be potent agents for the treatment of NACC1 and PADI2. RILPL2 and ITGAD were significantly differentially expressed in control and FM group mouse models.

Conclusion: This study identified two subtypes and 11 hub genes of FM based on IRGs, providing a reference for the clinical diagnosis of FM.

Introduction: This study aims to investigate the relationship between steroid use, adrenal suppression, and frequent emergency department (ED) visits in patients with Chronic Obstructive Pulmonary Disease (COPD).Systemic glucocorticoids are commonly prescribed in the management of COPD exacerbations; however, prolonged or repeated steroid use may lead to adrenal suppression. Although the standard steroid regimen for COPD exacerbations is short-term, frequent ED visits may result in cumulative steroid exposure, raising concerns about adrenal insufficiency and its clinical consequences.This study investigates the potential association between steroid-induced adrenal suppression and frequent ED visits among COPD patients. It further examines the impact of steroid administration on cortisol and Adrenocorticotropic hormone (ACTH) levels.

Methods: This prospective, cross-sectional, observational study was conducted in a university- based ED. Patients with COPD, with dyspnea and who presented to the ED between 06:00-08:00 were included. Demographics, previous presentations to the ED, medications used, hormone levels, and other laboratory results were recorded.

Results: Fifty patients (82% were male) included. Sputum symptoms along with incidences of heart failure were higher in patients who received steroids in the ED. Ronchi was higher, crackles and pretibial edema were lower in the patients who received steroids in the ED. Among the patients with low cortisol levels, the frequency of patients who received steroids in the ED was higher than those who did not.

Conclusion: Primary healthcare clinicians should monitor COPD patients for potential adrenal insufficiency. Careful regulation of steroid dosages during exacerbation treatment and minimizing polypharmacy are essential to mitigate the long-term effects of prolonged steroid use.

Background: Observational studies suggest an association between the immune system and type 2 diabetes. The present study sought to ascertain the causal relationship between BDH1 and type 2 diabetes and investigate whether immunocytes mediate this relationship.

Methods: Appropriate single nucleotide polymorphisms (SNPs) were carefully selected from publicly available GWAS databases based on rigorous criteria to ensure the validity of the Mendelian randomization (MR) analysis. Inverse variance weighting (IVW) was employed as the primary approach for assessing effect sizes, supplemented by four sensitivity analysis techniques: weighted median, simple mode, weighted mode, and MR-Egger regression tests, all aimed at ensuring the robustness and reliability of the IVW results. Reverse MR was conducted to confirm the feasibility of the mediation analysis. Lastly, Cochran's Q test, MR Egger intercept regression, and MR-PRESSO analysis were utilized to examine heterogeneity and horizontal pleiotropy.

Results: The expression of BDH1 is inversely associated with the risk of type 2 diabetes, with an odds ratio of 0.97 (95% CI: 0.95-0.99). IgD+ CD38+ B cell absolute count (20.7%), HLA DR on dendritic cell (18.7%), BAFF-R on CD20- CD38- B cell (9.5%), CD25 on IgD+ CD24+ B cell (4.1%), and BAFF-R on IgD+ B cell (3.4%), all exhibit certain mediating effects, whereas IgD+ CD38+ B cell absolute count, activated and resting CD4 regulatory T cell %, CD4+ T cell, transitional B cell absolute count, CD28- CD8 dim T cell absolute count, CD45 on HLA DR+ CD8+ T cell, FSC-A on HLA DR+ natural killer, and SSC-A on plasmacytoid dendritic cell exert masking effects.

Conclusion: The findings indicate that immunocytes could serve as a crucial mediating mechanism through which BDH1 exerts its protective effect against type 2 diabetes, offering novel insights for the prevention and therapeutic management of the disease.

Background: Immune Checkpoint Inhibitor (ICPi) therapy has revolutionized cancer treatment but can lead to immune-related adverse events (irAE), including thyroid dysfunction. The impact of ICPi on patients with pre-existing autoimmune thyroid diseases (PATD), particularly the development of Graves' disease, remains poorly understood.

Case description: We provide the first complete case of Graves' disease with ICPi therapy in a patient who already had Hashimoto's thyroiditis.. The patient, a 52-year-old male, was diagnosed with lung adenocarcinoma and received Atezolizumab. Clinical evaluation revealed hyperthyroidism, confirmed by elevated thyroid hormones and autoantibodies (TRAb and TSAb). The patient was managed with methimazole and demonstrated a transient hyperthyroid phase followed by persistent hypothyroidism. Only 16 confirmed cases of Graves' disease induced by ICPi were reported. We conducted a review to investigate the clinical characteristics, risk factors, and prognosis trends associated with ICPi-induced Graves disease in PTAD patients. Additionally, changes in thyroid function and autoantibodies during and after ICPi treatment are examined.

Conclusion: This case underscores the importance of monitoring thyroid function and autoantibodies in patients with PATD undergoing ICPi therapy. The findings suggest distinct differences in the humoral immune response between ICPi-induced and spontaneous Graves' disease, necessitating further research into autoantibody dynamics and their relationship with cellular immunity in these patients.

Introduction: An increase in the intraorbital adipose tissue is the main pathological feature of thyroid-associated ophthalmopathy (TAO). IGF-1R activates PI3K/AKT signaling and accelerates adipogenesis. Pingmu decoction has been demonstrated to promote orbital adipocyte apoptosis; however, less is reported regarding the action mechanism of Danshenol A (DA), a single active ingredient of Salvia miltiorrhiza (Danshen). Accordingly, this study aimed to investigate the role and association of DA and IGF-1R in the proliferation and lipid accumulation of orbital adipocytes.

Methods: Primary human orbital preadipocytes were chosen and authenticated using immunofluorescence. Cells were treated with the IGF-1R agonist ginsenoside Rg5, IGF-1R overexpression plasmid, dexamethasone (Dex), and/or DA, after which cell proliferation and differentiation were assessed by cell counting kit-8 (CCK-8), oil red O staining, real-time quantitative polymerase chain reaction, and Western blot assays.

Results: Orbital preadipocytes showed positive expression of Pref-1. Treatment with IGF-1R agonist, as well as Dex, promoted orbital adipocyte viability and lipid accumulation, and increased the expression of adiponectin and leptin. It was observed that the overexpression of IGF-1R boosted PI3K/AKT activation and elevated PPARγ and C/EBPα expressions. Importantly, DA reversed the effects of IGF-1R on cell viability, lipid accumulation, and the PI3K/AKT signaling pathway.

Discussion: This study, for the first time, revealed the molecular mechanism by which DA regulates orbital fat metabolism through targeted inhibition of the IGF-1R/PI3K/AKT signaling axis. Notably, IGF-1R overexpression partially counteracted the inhibitory effect of DA, suggesting that this component has multi-target regulatory characteristics.

Conclusion: This study not only reveals a new mechanism by which DA treats TAO but also provides theoretical support for the treatment of adipose metabolism.

Introduction: This study investigated the association between AIM2 cg11003133 DNA methylation and Rheumatoid Arthritis (RA), evaluating its diagnostic potential for RA and subtypes.

Methods: MethylTarget™ sequencing targeted AIM2 cg11003133 (chr1:159076528-159076740) in RA, Ankylosing Spondylitis (AS), Psoriatic Arthritis (PsA), gout, Systemic Lupus Erythematosus (SLE), Dermatomyositis (DM), primary Sjögren's Syndrome (SS), and Healthy Controls (HC) patients. Logistic regression, random forest, and XGBoost models were applied, with Spearman's correlation used to assess associations.

Results: RA and RF/CCP-positive patients showed significantly higher methylation at cg11003133_79/91 compared to HC and AS (FDR < 0.05), but lower levels compared to DM. Methylation at cg11003133_139 was elevated in RA compared to AS/SS (FDR = 0.04/0.03). Anti- TNF-α non-responders had higher cg11003133_79/91 methylation levels compared to HC/AS non-responders (FDR < 0.05). RF-negative RA patients had higher cg11003133_91 methylation than AS patients who failed anti-TNF-α treatment (FDR < 0.05). Haplotype CCCC correlated positively with CRP (r = 0.14, P = 0.006); TTTT was significantly negatively correlated with erythrocyte sedimentation rate, CRP, and the presence of diabetes (r = -0.18, -0.15, and -0.14; P < 0.001, 0.003, and 0.008, respectively). XGBoost and RF models achieved AUCs of 0.9911 and 0.9975 for RA versus non-RA, and 1 for RF/CCP double-negative versus double-positive RA.

Discussion: AIM2 cg11003133 methylation is strongly linked to RA, aligning with its role in inflammasome activation. While promising for diagnostics, larger validation is needed.

Conclusions: AIM2 cg11003133 methylation may serve as a diagnostic biomarker for RA and subtypes.

Introduction: Acute Kidney Injury (AKI) is a clinical syndrome with rapid onset and poor prognosis, and existing diagnostic methods suffer from low sensitivity and delay. To achieve early identification and precise intervention, there is an urgent need to discover new precise biomarkers.

Methods: AKI samples were acquired from Gene Expression Omnibus (GEO) database. AKI-related module genes were identified using the "WGCNA" package. The "Limma" package was used to filter Differentially Expressed Genes (DEGs). Protein interaction networks were constructed by intersecting key modular genes with DEGs, and six algorithms (MCC, MNC, Degree, EPC, Closeness, and Radiality) in the cytoHubba plug-in were combined to screen candidate genes. Diagnostic biomarkers were cross-screened using LASSO regression with Support Vector Machine-Recursive Feature Elimination (SVM-RFE) machine learning algorithm, and their predictive performance was verified by Receiver Operating Characteristic (ROC) analysis. Transcription Factors (TFs) regulatory network was constructed applying Cytoscape 3.8.0. Finally, the prediction and molecular docking analysis of potential target drugs were performed using the DSigDB database and AutoDockTools.

Results: A total of 498 key modular genes significantly associated with AKI were screened, and 88 AKI- related DEGs and 18 candidate genes were further identified. Importantly, four biomarkers with high diagnostic value (DDX17, FUBP1, PABPN1, and SF3B1) were screened and validated using dual machine learning algorithms, including LASSO regression and SVM-RFE. The area under the ROC curve (AUC) values for these biomarkers were greater than 0.8, indicating good predictive performance. Moreover, 19 TFs and 17 miRNA of SF3B1, 10 TFs and 58 miRNA of PABPN1, 15 TFs and 60 miRNA of FUBP1, together with 13 TFs and 109 miRNA of DDX17, were screened. Drug prediction and molecular docking analysis revealed that Demecolcine and Testosterone Enanthate stably bind to certain markers.

Discussion: Four potential biomarkers closely related to AKI were identified, which may be involved in the occurrence and progression of AKI by regulating key processes such as transcription. The predicted Demecolcine and Testosterone Enanthate may also be involved in the repair of renal injury by regulating key target genes. Although further experimental validation is still needed, these may still provide new intervention strategies for the treatment of AKI.

Conclusion: To conclude, four AKI biomarkers with high diagnostic value were screened by integrating multiple computational methods, revealing a new perspective on the molecular mechanism of AKI. The results provided a new theoretical basis for achieving early precision diagnosis and individualized treatment of AKI.

Introduction: Jiangtang Decoction (JTD) demonstrates notable efficacy in managing Type 2 Diabetes Mellitus (T2DM) and Non-Alcoholic Fatty Liver Disease (NAFLD). This study aimed to elucidate JTD's causal targets and therapeutic mechanisms by integrating network pharmacology, Summary-data Mendelian Randomization (SMR), and molecular docking, complemented by in vitro validation.

Materials and methods: JTD's targets were cross-matched with genes associated with T2DM or NAFLD. SMR and co-localization analyses, utilizing eQTL and pQTL data, identified causal signals for each disease and their shared counterparts. GO/KEGG enrichment analyses were performed on these shared signals. Molecular docking assessed binding interactions. In vitro experiments, including ELISA (Enzyme-linked immunosorbent assay) and lipid staining, evaluated JTD's hypoglycemic/hypolipidemic effects, while PCR/immunofluorescence validated key molecular predictions in High-Glucose and High-Lipid (HGHL)-induced HepG2 cells.

Results: Initial network pharmacology identified 1107 JTD targets for T2DM and 1126 for NAFLD. SMR analyses revealed 78 eQTLs and 67 pQTLs for T2DM, and 40 eQTLs and 38 pQTLs for NAFLD. Eight shared causal genetic signals were identified: ADAMTS4, ALDH2, GLO1, CDH1, PDHB, PRKAB1, TCF4, and EP300. In vitro, JTD significantly attenuated hepatic gluconeogenesis and lipid deposition, downregulated IL-1β, and notably restored PRKAB1 expression in HepG2 cells treated with HGHL.

Discussion: Enrichment analysis revealed shared processes, including membrane microdomains, oxidoreductase activity, and responses to nutrient and oxygen levels. PRKAB1 exhibited a strong binding affinity with the JTD component Salsalate.

Conclusion: This study identified eight genes that are genetically predicted to be causal for the therapeutic effects of JTD on both T2DM and NAFLD, thereby establishing a genetic link between the conditions. These targets and associated pathways illuminate common underlying mechanisms, supporting JTD's potential for integrated treatment strategies and providing a basis for further investigation.