Endocrine, metabolic & immune disorders drug targets最新文献

Background: 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.

Aims: 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.

Objective: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Aims: There is a close relationship between obesity and hyperuricemia. Relative Fat Mass (RFM) is considered a new indicator for evaluating obesity. We aim to explore the relationship between RFM and the risk of hyperuricemia in adults.

Methods: This cross-sectional study included adult participants from the 2007-2018 National Health and Nutrition Examination Survey (NHANES). The RFM was calculated as: RFM =64 - (20 × height/waist circumference) + (12 × sex), where sex is defined as 0 for men and 1 for women. Hyperuricemia was confirmed by using serum uric acid (SUA) levels ≥ 7 mg/dL in men and ≥ 6 mg/dL in women. The relationship between RFM and the risk of hyperuricemia was thoroughly investigated.

Results: A total of 29369 participants were enrolled in this study. The RFM levels in the hyperuricemia group were higher than those in the non-hyperuricemia group (P < 0.01). Logistic and linear regression indicated that RFM levels were positively associated with the risk of hyperuricemia (OR=1.08, 95% CI: 1.05-1.11, P < 0.001) and SUA levels (β=0.04, 95% CI: 0.03-0.05, P < 0.001). The relationship remained consistent across subgroups. Smooth curve fitting showed a nonlinear relationship, with an inflection point at 34.22. Above this threshold, the link between RFM levels and hyperuricemia was found to be more remarkable.

Conclusion: Higher RFM is associated with an increased risk of hyperuricemia. RFM could act as a cost-efficient and straightforward measure for hyperuricemia risk assessment.

SGLT2 inhibitors are a family of drugs that were developed to treat diabetes mellitus. In randomized controlled trials, SGLT2 inhibitors seem to prevent kidney deterioration in patients with nephropathies, both diabetic and non-diabetic. However, in contrast to biochemical/physiological results (proteinuria and serum creatinine levels) that improve in all studies, the clinical results (all-cause mortality, cardiovascular death, need for dialysis, or renal transplant) do not consistently improve. In this article, the author would like to suggest that SGLT2 inhibitors do not, in fact, prevent the progression of renal diseases but rather alter laboratory results. This study will present a theory that gives an alternative explanation for the findings in the studies that would explain the above discrepancy between biochemical/physiological and clinical results. In general, the author claims that SGLT2 inhibitors change the kinetics of renal creatinine and microalbumin excretion but do not prevent parenchymal adverse changes in kidneys. This causes a dissociation between renal function markers (such as serum creatinine level and urinary protein) and the real kidney function. Thus, the clinical renal prognosis does not improve despite seemingly better laboratory results.

Background: 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.

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

Methods: 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.

Results: 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.

Conclusion: 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.

Introduction: 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.

Methods: 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.

Results: 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.

Discussion: 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.

Conclusion: 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.

Background: 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.

Objective: 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.

Methods: 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.

Results: 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 drugbased therapies.

Conclusion: 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.

Introduction: 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 HNinduced kidney injury through the miR-223/NLRP3/Caspase-1 pathway.

Materials and methods: 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.

Results: 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.

Discussion: 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.

Conclusion: 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.

Background: Disulfidptosis is a new type of regulatory cell death (RCD), but the pathophysiological functions and mechanisms of DRGs in CESC remain to be examined.

Aims: This study explored the mutation status of disulfidptosis-related genes (DRGs) in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC).

Objective: 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.

Methods: 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.

Results: 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.

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