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

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.