Endocrine, metabolic & immune disorders drug targets最新文献

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 and aim: In the context of gastrointestinal diseases, the role of monoacylglycerol lipase (MAGL) is significant. Therefore, the objective of this study was to examine the protective effects of

Methods: In this study, a rat model of SAP was established, and the rats were divided into three groups for treatment: the Control group (CON), the SAP group (SAP), and the SAP group treated with JZL184 (JZL184). The serum levels of amylase (AMS), alanine aminotransferase (ALT), creatinine (Cr), nitric oxide (NO), cyclic guanosine monophosphate (cGMP), and phosphodiesterase (PDE) were measured using enzyme-linked immunosorbent detection kits. The ascites volume was determined using the cotton ball weighing method. The levels of reactive oxygen species (ROS) were detected using the ROS Kit. Additionally, histological tissue changes were assessed through hematoxylin and eosin staining.

Results: The SAP group showed increased levels of AMS, ALT, Cr, ROS, and ascites volume compared to the CON group. Additionally, the SAP group exhibited congested and edematous lung and pancreatic tissues with inflammation. However, the JZL184 group, when compared to the SAP group, showed decreased levels of AMS, ALT, Cr, and ROS, reduced ascites volume, and significantly reduced lung tissue and pancreatic histopathology scores. In the NO/cGMP/PDE system, compared with the CON group, the levels of NO and PDE in the SAP group were higher and the levels of cGMP were lower. Compared with the SAP group, the JZL184 group decreased NO and PDE levels and increased cGMP levels.

Conclusions: Indeed, the inhibition of MAGL with JZL184 has been found to have a protective effect on rats with SAP. Specifically, it has shown significant improvement in the pathological damage of lung and pancreatic tissues. Furthermore, JZL184 has also exhibited protective effects on the liver and kidney. The mechanism may be related to the effect of JZL184 on the NO/cGMP/ PDE signaling pathway.

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.

Sjögren's syndrome (SS) is an autoimmune disease and its management is palliative.There is no specific dietary protocol for SS patients. A gluten-free diet has been tested in SS patients with celiac disease (CD) and indicated modest improvements. Whether gluten-free diets persè could alleviate autoimmune inflammatory processes in the salivary glands of SS patients withassociated CD or even in SS patients without CD is an interesting hypothesis and warrants clinicalstudies. Hypokalemia in SS patients is among the most frequent sequelae of renal tubular acidosis.Supplementation with potassium (K)-rich diets can reduce inflammation and oxidative stress. Klevel in CD patients is highly abnormal at diagnosis and gluten-free diets help to normalize itsserum level in CD patients. Furthermore, treatment of severe cases of SS requires concomitant glucocorticoid therapy and K supplementation. Results of two separate clinical trials in (i) patientswith rheumatoid arthritis (RA) –a disease with similar pathology to SS- indicated that the enhanced serum cortisol followed K supplementation, and in (ii) celiac patients, serum K levelswere normalized after the administration of a gluten-free diet. We reviewed the literature extensively on this topic to propose a hypothesis to address this problem and suggest a novel potentialfor K-rich, gluten-free diets in SS patients. Based on causal associations, we propose that higher Kabsorption and cortisol secretion following gluten-free diets accompanied by K-rich diets in SS patients with low serum potassium levels, may confer a higher therapeutic potential. Clinical trialsare needed to test this hypothesis.

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.

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.

Background: The potential benefits of the ketogenic diet (KD) on ageing are currentlyreceiving increasing attention. Although there are various studies on this subject in the existing literature, there is a lack of systematic review and bibliometric analysis.

Aims: This study aimed to present a bibliometric overview and visualization analysis of the existing studies examining the relationship between KD and ageing, identify trends in this field, andprovide a basis for future research and sustainable development goals.

Materials and methods: This study involved a systematic review of the literature. In this study,Scopus (Elsevier) and Web of Science Core Collection (WoSCC) databases were used for bibliometric analysis. In the study, all articles, reviews, and other types of publications on KD and ageing published between 1995 and 2024 were analysed. Studies covering the years 1995-2025 and including the keywords ‘ketogenic diet OR ketogenic diets OR ketone diet AND aging AND PUBYEAR > 1995 AND PUBYEAR < 2025' in the title were included. The VOSviewer software(VOSviewer v.1.6.10) was utilized to visualize the data. The data obtained were evaluated by bibliometric methods, such as keyword analysis and cluster analysis.

Results: A significant increase in the number of studies on KD and ageing was observed. In thestudy, when the data obtained from WoSCC and Scopus databases and VOSviewer analysis results were evaluated together, a total of 10,170 scientific documents in the Scopus database and atotal of 168 scientific documents were identified in the Web of Science database between1995-2025 worldwide. The author publishing the most on the subject was found to be Cunnane,S.C. The country contributing the most to the field was found to be the United States of America(USA). The institution that produced the most documents was Harvard Medical School. In a totalof 10,170 records, the most preferred type of publication was articles. Nutrients journal was thejournal with the highest number of publications. According to the results of keyword analysis, thewords “ketogenic diet” and “aging” were the most frequently used and most strongly relatedwords.

Conclusion: The results of this study showed a significant increase in the number of studies investigating the effects of KD on ageing. More high-quality, randomised controlled clinical trialsare needed in this field. In particular, there is a lack of studies examining the effects of KD onage-related diseases at the molecular level.

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.