Endocrine, Metabolic & Immune Disorders-Drug Targets - Current Issue

Metabolic dysfunction-related fatty liver disease (MAFLD) has emerged as the predominant chronic liver disorder among children and adolescents. Like in adults, pediatric MAFLD encompasses a disease spectrum progressing from isolated steatosis to inflammatory changes, fibrotic development, and ultimately, cirrhosis. Despite increasing recognition of MAFLD as a major pediatric health issue, current literature lacks a systematic quantitative evaluation of research trends, leading to knowledge gaps in this field. To address this limitation, a comprehensive bibliometric analysis was performed to assess global research output on pediatric MAFLD by focusing specifically on the 2014-2023 period. This analysis avoids the confounding effects of the heterogeneity of earlier data while achieving sufficient temporal resolution to reveal emerging trends that might be obscured in long-term studies. This study synthesizes existing evidence, enhances understanding of this disciplinary field, and informs future research directions in pediatric MAFLD.

Articles concerning children with MAFLD published from 2014-2023 were identified from the Science Citation Index-Expanded of the Web of Science Core Collection. CiteSpace software, VOSviewer, and the Online Analysis Platform of Literature Metrology were used to analyze the current publication trends and hotspots.

The analysis identified 1,609 English-language articles on pediatric MAFLD published from 2014 to 2023. The United States emerged as the most active participant in international collaborations. The University of California San Diego (UCSD) demonstrated the highest research output among the analyzed institutions. Additionally, UCSD exhibited the most extensive collaborative network, engaging in frequent and substantive research partnerships with a diverse range of academic and scientific organizations. Valerio Nobili was found to be the most prolific author, with 67 articles. Keyword burst analysis revealed that cardiovascular risk factors were the most intense research hotspot.

Current research on pediatric MAFLD warrants greater attention, particularly regarding cardiovascular risk factors. This study provides valuable references for researchers, offering insights to guide future research directions and potential collaborations.

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.

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.

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.

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.

Disulfidptosis is a new type of regulatory cell death (RCD), but the pathophysiological functions and mechanisms of disulfidptosis-related genes (DRGs) in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) remain to be examined.

This study explored the mutation status of DRGs in CESC.

After analyzing the mutation profiles of DRGs in CESC, this study established a prognostic model for CESC and also explored the differences in immune infiltration (accumulation of immune system cells in tissues or organs), related enriched pathways, and drug sensitivity between high-risk and low-risk CESC groups.

The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) were accessed to source related data. The mutation profiles of DRGs in CESC were analyzed using Mutect2 software, and disulfidptosis scores were calculated by ssGSEA. WGCNA was performed to identify modular genes, which were further filtered and used to formulate a risk model by applying the survival and glmnet packages. Low- and high-risk groups of CESC patients were classified using the survminer package. GSEA was performed to conduct pathway analysis, and immune infiltration was assessed using the MCPcounter package, ESTIMATE, and TIMER algorithms. Finally, immunotherapy response and drug sensitivity were analyzed using the TIDE method and the pRRophetic package, respectively.

Except for NDUFA11, ARL6IP5, EPM2AIP1, GBE1, RBM38, ULK4, and ZBTB47 were found to be the DRGs significantly mutated in CESC. The six genes were integrated to develop a RiskScore model with a relatively high Area Under the Curve (AUC) value. Significant differences between the two risk groups were determined, indicating that the model was highly reliable. Notably, the low-risk group was enriched in energy metabolism-correlated pathways, while the high-risk group was primarily enriched in immune-correlated pathways. The high-risk group showed higher immune cell activity, higher TIDE score, and more B cells than the low-risk group. Drug sensitivity study revealed that the high-risk group was more sensitive to chemotherapy drugs.

This study provides novel insights into CESC prognosis, immunotherapy, and drug development, contributing to the clinical treatment for CESC.

The purpose of this study was to identify molecular subtypes and hub genes in fibromyalgia (FM) based on immune-related genes (IRGs).

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

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.

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.

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 binding to NACC1 and PADI2. RILPL2 and ITGAD were significantly differentially expressed in FM-modeled mice.

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

Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer, and myocardial infarction (MI) is an acute cardiovascular disease resulting from the disruption of coronary blood supply. Recent studies have suggested that these two diseases may share common molecular mechanisms.

The aim of this study was to discover common diagnostic genes for LUAD and MI and analyze their molecular functions and potential drug values by applying bioinformatics analysis.

The objective was to provide a theoretical basis for further research on the pathological mechanisms of LUAD and MI, contributing to the development of novel diagnostic and therapeutic strategies for the two diseases.

In this study, the datasets of LUAD and MI were obtained from TCGA and GEO databases, and differential expression analysis was performed to screen significantly differentially expressed genes (DEGs). Subsequently, disease-related genes were identified using WGCNA analysis, and the biological functions of these genes were explored by functional enrichment analysis. After screening key genes using the protein-protein interaction (PPI) network and the cytoHubba algorithm, biomarkers were determined by LASSO and SVM-RFE machine-learning methods. Finally, immune infiltration analysis and drug prediction were performed, and biomarker expression was verified by single-cell sequencing analysis.

A total of 158 differentially upregulated genes were identified between LUAD and MI. WGCNA analysis screened 86 genes that were significantly associated with both diseases and were enriched in an inflammatory response and immune regulation-related pathways, such as the IL-17 signaling pathway. Ten significant genes were identified by the PPI network and cytoHubba and then reduced to 4 using LASSO and SVM-RFE. Noticeably, MMP9 was significantly overexpressed in both diseases. Immune infiltration analysis showed that MMP9 was significantly related to multiple immune cell infiltration. Drug prediction and molecular docking analysis predicted Ilomastat and Osthole as the potential target drugs. Single-cell sequencing analysis revealed that MMP9 was high-expressed in the macrophages in LUAD tissues.

This study identified MMP9 as a common diagnostic gene and potential therapeutic target for both LUAD and MI and revealed its role in inflammation and immune regulation through comprehensive bioinformatics analysis. These findings provided a theoretical basis for further research on the pathological mechanisms of LUAD and MI, contributing to the development of novel diagnostic and therapeutic strategies.

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.

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.

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.

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.

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.

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.

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.

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

Bladder cancer is one of the major health threats worldwide, and aberrant regulation of nitrogen metabolism is closely related to its development. Understanding the role of nitrogen metabolism-related genes in BC is pivotal for the development of new therapeutic strategies and prognostic assessment.

This study aimed to explore the prognostic factors associated with nitrogen metabolism in bladder cancer (BC) and to construct a prognostic model.

Differential expression gene analysis was performed to identify genes associated with nitrogen metabolism by analyzing mRNA expression data from BC patients. The prognostic relationship between these genes and BC patients was analyzed using univariate Cox regression. One hundred one combinatorial machine learning methods were applied for feature selection, and key prognostic genes were identified based on the method with the highest combined score. Immunocyte infiltration analysis was carried out to assess the tumor microenvironmental characteristics of patients in different risk groups.

Twenty-five genes significantly associated with prognosis were identified from nitrogen metabolism-related genes. Twenty-three most prognostically predictive signature genes were screened under feature screening with multiple machine-learning models. Immune cell infiltration analysis showed that patients in the high-risk group had significantly different immune cell infiltration, suggesting that these genes may influence BC progression by regulating immune escape mechanisms. These results provide new biomarkers and potential therapeutic targets for precision treatment and prognostic assessment of BC.

The findings suggest that nitrogen metabolism-related genes play a key role in the prognosis of bladder cancer and may be involved in regulating the tumor immune microenvironment. Different immune environments were demonstrated in high and low Riskscore groups, implying that these genes may contribute to immune evasion and thus promote tumor progression. These observations are consistent with emerging evidence that emphasizes the interplay between metabolism and immunity during cancer development. By combining nitrogen metabolism with immune analysis, this study provides a new perspective for stratifying BC patients and identifying therapeutic targets.

The expression patterns of nitrogen metabolism-related genes identified can be used as effective biomarkers for bladder cancer prognosis, providing a scientific basis for personalized treatment. Future studies can further explore the specific biological functions and mechanisms of action of these genes to promote more effective clinical applications.

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

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.

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.

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

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

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.

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.

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.

This study provides strong evidence for thecausal 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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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 t-tests, Mann-Whitney U tests, logistic regression, and ROC curve analysis.

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).

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.

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.

The aim of this study is to investigate the expression patterns and regulatory functions of Copines family genes in different cellular subpopulations in testicular cancer based on single-cell data and to analyze the regulatory mechanism of Copines family genes in cancer.

Testicular cancer is a frequently diagnosed male tumor. Emerging evidence suggests that Copines family genes are implicated in a variety of cancer phenotypes and cancer progression. Analyzing the expression pattern of Copines family genes in testicular cancer may help improve the treatment efficacy of the cancer.

This study sought to characterize the expression profiles of Copines family genes in the cellular subpopulations of testicular cancer and to identify key signaling pathways through which they regulate cancer progression.

Based on single-cell transcriptomic data of testicular cancer, we classified testicular cancer cell subpopulations and analyzed the expressions of Copines family genes in each subpopulation. Cell subpopulations were grouped according to the expression levels of Copines family genes, and differentially expressed Copines family genes between the groups were screened by differential expression analysis. Functional enrichment analysis on the differentially expressed genes (DEGs) was performed with a clusterprofiler package. Functional pathways enriched by the Copines family genes were calculated by AUCell enrichment score. Copy number variation (CNV) analysis was performed using inferCNV to analyze gene mutation patterns across cellular subpopulations, and pseudotime analysis was conducted using Monocle to infer cellular differentiation pathways of cellular subpopulations.

Single-cell clustering identified four major cell subpopulations, namely, NK/T cells, tumor cells, B cells, and macrophages. Notably, the control samples had a relatively small proportion of tumor cells. Further clustering of the tumor cells identified six cell subpopulations, among which multiple Copines genes, especially CPNE1 and CPNE3, showed a high expression. The testicular cancer samples were grouped by the expression patterns of Copines genes, and the DEGs between groups included GNLY, MGP1, CFD2, CCL21, SPARCL13 as well as some other genes involved in the malignant progression of cancer. Pseudotime analysis showed that the upregulated genes were enriched in cell migration and PI3K-Akt pathway, while the downregulated genes were related to immunity. This indicated that the Copines genes regulated the cellular heterogeneity and malignant transformation in testicular cancer.

This study revealed the potential molecular mechanism through which Copines family genes drove the progression of testicular cancer through regulating PI3K-Akt signaling pathway and cell cycle, providing a new target for the development of precision treatment targeting Copines family genes and prognostic assessment of the cancer.

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.

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.

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.

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.

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).

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

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 LIR-ALI.

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.

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.

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.

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.

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.

Hepatic Ischemia-Reperfusion Injury (IRI) is a critical complication in liver transplantation and resection, driven by oxidative stress and sterile inflammation mediated by damage-associated molecular patterns (DAMPs). Current therapeutic challenges arise from interconnected cell death pathways and redundant inflammatory mechanisms.

This review synthesizes mechanistic insights into DAMP signaling and regulated cell death modalities in IRI, aiming to identify translational gaps and propose precision-targeted therapies.

A literature search in PubMed using keywords “IRI,” “DAMPs,” and cell death modes was conducted without date restrictions. Peer-reviewed studies on human/animal models were included, with qualitative synthesis of DAMP-cell death interactions.

During ischemia, mitochondrial dysfunction releases HMGB1, ATP, and mtDNA, activating Kupffer cell TLR4/RAGE and cGAS-STING pathways, triggering NLRP3 inflammasome- driven cytokine storms. Reperfusion amplifies ROS bursts, lipid peroxidation, and iron overload, creating a self-sustaining cycle of damage. Cell death modalities exhibit spatiotemporal specificity: hepatocyte ferroptosis dominates early injury, while macrophage pyroptosis and necroptosis predominate in steatotic livers during late phases. HMGB1 lactylation and mtDNA-cGAS signaling emerge as key regulators. Machine perfusion (e.g., hypothermic oxygenated perfusion) reduces biliary complications via mitochondrial resuscitation, outperforming conventional drug-based therapies.

Current single-pathway targeting shows limited efficacy due to IRI’s complexity. Future strategies should integrate temporal targeting (ferroptosis inhibitors pre-reperfusion; pyroptosis blockers post-reperfusion), DAMP-neutralizing agents (anti-HMGB1 antibodies), and precision preservation combining multi-omics biomarkers with ex vivo pharmacological preconditioning. Addressing metabolic vulnerabilities in fatty livers and refining cell death-specific interventions are critical for bridging translational gaps.

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.

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.

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.

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.

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.

Childhood acute lymphoblastic leukemia (cALL), the most common pediatric hematologic malignancy, arises primarily from B-cell origin and is strongly associated with immune dysfunction. This article integrated single-cell and bulk transcriptomic data to identify key B-cell subsets and cALL-related molecules as biomarkers.

Single-cell RNA sequencing (scRNA-seq) Data from 2 pre-B high hyperdiploid (HHD) ALL patients and 3 healthy pediatric bone marrow samples (GSE132509) were utilized for cell clustering using the Seurat package. Functional enrichment, pseudo-time trajectory, and cell-cell communication analyses were performed using clusterProfiler, Monocle2, and CellChat R packages, respectively. Bulk RNA-seq data of 511 cALL samples in the TARGET-ALL-P2 cohort were used to construct a prognostic model via Cox and LASSO regression. Immune infiltration differences between different risk groups were analyzed using ESTIMATE, MCP-counter, and CIBERSORT algorithms.

The scRNA-seq analysis identified five cell subpopulations, with B cells demonstrating significant enrichment in cALL samples. Notably, the C2 subset was associated with cell proliferation. Ligand-receptor analysis revealed key interactions involving B cell C2. Four marker genes (CENPF, IGLL1, ANP32E, and PSMA2) were identified to build a risk model. Low-risk patients showed better survival, while high-risk patients had higher ESTIMATE scores.

This study examined the key role of B cells in cALL, constructed a risk model with strong prognostic predictive ability applying multi-omics analysis, and primarily explored its potential mechanism in immune regulation.

This study revealed the critical role of B cells in cALL, and the prognostic model showed a high prediction accuracy, providing a potential target for individualized treatment of cALL.

Hyperuricemia Nephropathy (HN) is an emerging metabolic disorder that predisposes individuals to Chronic Kidney Disease (CKD), yet effective treatments remain limited. Inflammation plays a pivotal role in HN-induced kidney injury, with the NLRP3 inflammasome serving as a central mediator of this process. This study investigates the therapeutic effects of Yipishen Xiezhuo Jiedu Decoction (YPSXZJDD), a traditional Chinese medicine, on HN-induced kidney injury through the miR-223/NLRP3/Caspase-1 pathway.

The key active components of YPSXZJDD were screened using UHPLC-Q Exactive Orbitrap-MS, and a Protein-Protein Interaction (PPI) network diagram was constructed to explore potential mechanisms of action. The identified components were then utilized to intervene in both cellular and animal models of hyperuricemic nephropathy, evaluating their therapeutic effects and underlying mechanisms.

Catalpol and Tanshinone IIA were identified as the key active components of YPSXZJDD. These compounds significantly mitigated renal epithelial cell apoptosis and inflammation by upregulating miR-223, which in turn inhibited the NLRP3/Caspase-1 pathway. The upregulation of miR-223 led to a marked reduction in NLRP3 activity and inflammatory responses, thereby alleviating HN-induced kidney damage.

The findings of this study underscore the critical role of miR-223 in regulating the NLRP3 inflammasome and highlight its potential as a therapeutic target for HN. The inhibition of the NLRP3/Caspase-1 pathway by miR-223 significantly reduces inflammation and renal injury, demonstrating the therapeutic efficacy of YPSXZJDD. These results offer a novel perspective on the application of traditional Chinese medicine in treating HN, highlighting the importance of miR-223 in regulating inflammation.

This study demonstrates that YPSXZJDD alleviates HN-induced kidney injury by upregulating miR-223 and inhibiting the NLRP3/Caspase-1 pathway. The therapeutic potential of YPSXZJDD is supported by its ability to mitigate inflammation and renal damage, offering a promising approach for HN treatment. Further research into the broader role of miR-223 in kidney disease and related conditions is warranted to expand the understanding of its therapeutic applications.

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.

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.

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.

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.

The objective of this study was to evaluate the demographic, clinical, laboratory, and ultrasonographic characteristics of patients diagnosed with subclinical hypothyroidism, with a particular emphasis on the anti-thyroid peroxidase (anti-TPO) antibody and inflammatory biomarkers.

The study included 157 patients diagnosed with subclinical hypothyroidism, categorised into anti-TPO-positive and anti-TPO-negative groups. A retrospective comprehensive evaluation comprising demographic data, thyroid medication status, ultrasonographic characteristics, and laboratory parameters was conducted and statistically analysed between the groups.

Of 157 patients, 48.4% were anti-TPO positive. This group was significantly associated with increased levothyroxine (LT4) use and sonographic parenchymal heterogeneity. However, there were no significant differences in nodule presence, number, size, or structure. A positive correlation was found between anti-TPO and ferritin levels. In addition, a positive correlation was observed between the thyroid-stimulating hormone (TSH)/free T4 ratio and the solidity of nodules, as well as between TSH and the neutrophil-to-lymphocyte ratio (NLR). Surprisingly, a negative correlation was found between anti-TPO levels and the number of nodules, as well as the cystic characterisation of the nodules.

In our study, higher levels of anti-TPO and TSH were associated with inflammatory markers such as ferritin and NLR, suggesting a possible link with systemic inflammation. Furthermore, anti-TPO and the TSH/T4 ratio also showed associations with specific sonographic features of the thyroid gland.

TSH and anti-TPO levels might be associated with systemic inflammation and thyroid sonographic findings in patients with subclinical hypothyroidism. More studies on larger patient populations should confirm the same results to suggest their clinical significance.