Current molecular medicine最新文献

{"title":"Effect of hucMSC-derived Exosomes on the Pressure Ulcers in Mice.","authors":"Fei Yan, Junzheng Yang, Meihua Gong, Guangheng Li, Li Yu","doi":"10.2174/0115665240450312260206114749","DOIUrl":"https://doi.org/10.2174/0115665240450312260206114749","url":null,"abstract":"<p><strong>Introduction: </strong>Pressure ulcers (PUs) are a result of sustained compression of the local skin, leading to impaired blood circulation and subsequent nutritional deficiencies in the skin and subcutaneous tissues. Exosomes are one type of extracellular vesicle with a size range of 40 to 160 nm. Currently, the effects of Human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-exos) on the PUs and the underlying mechanisms remain largely unexplored.</p><p><strong>Methods: </strong>In this study, a PUs model was constructed using BALB/c mice, and the effect of hucMSC-exos on the PUs mice was evaluated by using histopathological examination, quantitative real-time polymerase chain reaction (qRT-PCR), and western blotting.</p><p><strong>Results: </strong>The results of HE staining and Masson staining demonstrated that the treatment of hucMSC-exos could alleviate the histopathological changes of mice. Furthermore, the results of qPCR demonstrated that hucMSC-exos decreased the levels of collagen I, collagen III, and α-SMA in PUs mice; and the results of western blotting demonstrated that the expressions of HMGB1 and α-SMA could be decreased by the administration of hucMSC-exos.</p><p><strong>Discussion: </strong>The data in the manuscript suggest that hucMSC-exos are both safe and effective in the treatment of PUs. It is recommended that large-scale animal experiments and long-term administration time of hucMSC-exos should be conducted to further verify the effect of hucMSC-exos in PUs.</p><p><strong>Conclusion: </strong>The findings of this study demonstrated that hucMSC-exos alleviated the symptoms of PU mice by regulating HGMB1 and α-SMA, thus demonstrating the therapeutic potential of hucMSC-exos in PUs.</p>","PeriodicalId":10873,"journal":{"name":"Current molecular medicine","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147765168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sulfur Dioxide Inhibits TNF-α-induced Photoreceptor Cell Apoptosis Through Sulfenylation of Caspase-3 at Cysteine 163.","authors":"Jiantong Du, Yaqian Huang, Kun Li, Xiaoqi Yu, Boyang Lv","doi":"10.2174/0115665240478494260327203818","DOIUrl":"https://doi.org/10.2174/0115665240478494260327203818","url":null,"abstract":"<p><strong>Introduction/objective: </strong>Photoreceptor cell apoptosis contributes significantly to vision loss in retinal degenerative diseases. Gasotransmitter sulfur dioxide (SO2) has been implicated in the regulation of apoptotic processes. This study investigated changes in the endogenous SO2/aspartate aminotransferase (AAT) system during tumor necrosis factor-α (TNF-α)-induced photoreceptor cell apoptosis.</p><p><strong>Methods: </strong>We examined the effect of endogenous SO2 on the TNF-α-stimulated apoptosis in 661 W photoreceptor cells and investigated the underlying molecular mechanisms. TNF-α-stimulated 661 W photoreceptor cells served as a cellular model to assess apoptosis via a TdT-mediated dUTP nick-end labeling (TUNEL) assay. We evaluated caspase-3 activation using western blotting and quantified its activity using a colorimetric assay. Site-directed mutagenesis and biotin-switch assays were performed to detect the effects of caspase-3 sulfenylation.</p><p><strong>Results: </strong>During TNF-α-induced apoptosis in photoreceptor cells, the endogenous SO₂ system was markedly upregulated, which correlated with the effective inhibition of apoptosis. SO2 directly suppresses caspase-3 activity in retinal photoreceptor cells and recombinant proteins. Importantly, site-directed mutagenesis revealed that the C163S mutation in caspase-3 abolished SO2-mediated sulfenylation, thereby reducing its anti-apoptotic effects. These findings indicate that endogenous SO2 exerts its protective effects by sulfenylating caspase-3 at cysteine 163.</p><p><strong>Discussion: </strong>Our study demonstrates that upregulation of the endogenous SO2 system directly inhibits caspase-3 activation through sulfenylating cysteine 163 in caspase-3, effectively reducing TNF-α-induced apoptosis in 661 W cells. These findings highlight the precise regulatory role of SO2 in apoptosis.</p><p><strong>Conclusion: </strong>This study provides novel insights into potential therapeutic targets for retinal degenerative diseases.</p>","PeriodicalId":10873,"journal":{"name":"Current molecular medicine","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147671019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Network-based Transcriptomic Profiling of Fetal Astrocyte Differentiation Reveals Therapeutic Targets for Neurodegenerative Disease.","authors":"Arya Moftakhar-Bazkiaei, Maryam Farzaneh","doi":"10.2174/0115665240412373260224061022","DOIUrl":"https://doi.org/10.2174/0115665240412373260224061022","url":null,"abstract":"<p><strong>Introduction: </strong>Neurodegenerative disorders, including Alzheimer's Disease (AD), Parkinson's Disease (PD), and Age-related Macular Degeneration (AMD), are marked by the progressive loss of specific neuronal populations. Astrocytes, the glial cells surrounding neurons, play a critical role in maintaining neuronal health by providing neurotrophic support, producing antioxidants, and clearing waste. Dysfunctional astrocytes contribute to disease progression, yet their developmental trajectory and molecular regulation remain incompletely understood.</p><p><strong>Method: </strong>This study aims to computationally characterize transcriptional differences between fetal astrocytes and neural stem cell lines to identify key regulatory genes, pathways, and therapeutic targets relevant to astrocyte-linked neurodegeneration. Using microarray data and bioinformatics pipelines, 359 Differentially Expressed Genes (DEGs) were identified, including 249 upregulated and 110 downregulated transcripts.</p><p><strong>Results: </strong>Protein-Protein Interaction (PPI) network analysis revealed ten hub genes- COL1A1, TIMP1, LOX, COL6A1, COL6A3, COL5A1, CD44, LTBP2, ACTA2, and PLAU-central to extracellular matrix remodeling and cell adhesion. Drug-gene interaction analysis linked these genes to compounds such as Estradiol valerate, Retinoic acid, and Calcitriol, suggesting therapeutic relevance.</p><p><strong>Discussion: </strong>Enrichment analysis highlighted transcriptional regulation, apoptosis, and ECM-receptor interaction as dominant biological themes. Key miRNA-mRNA interactions, including hsa-miR-877-5p and hsa-miR-767-5p targeting LOX and COL6A3 were also identified.</p><p><strong>Conclusion: </strong>Overall, this study integrates transcriptomic profiling, network modeling, and drug-gene interaction analysis to uncover astrocyte-specific molecular targets, offering a computational framework for therapeutic exploration in neurodegenerative disease.</p>","PeriodicalId":10873,"journal":{"name":"Current molecular medicine","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147618535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Overexpression of Membrane Metalloendopeptidase Attenuates Oxidative Stress and Inflammation in Diabetic Neuropathy via the Nrf2/HO-1 Pathway.","authors":"Zenghui Liu, Jianlin Ge, Jiafeng Sun, Xuefeng Yang, Qian Su, Xin Sun, Boxiang Du","doi":"10.2174/0115665240406476260220084033","DOIUrl":"https://doi.org/10.2174/0115665240406476260220084033","url":null,"abstract":"<p><strong>Objective: </strong>To investigate the role of Membrane Metalloendopeptidase (MME) in oxidative stress and inflammation in painful diabetic neuropathy, and to explore the underlying mechanism.</p><p><strong>Methods: </strong>A diabetic mouse model was established with streptozocin (STZ) injections. Neuropathic pain was assessed using paw withdrawal latency (PWL). Target genes related to painful diabetic neuropathy were identified using the Comparative Toxicogenomic Database (CTD), DisGeNET, and GeneCards. Protein-protein interactions between MME and the Nrf2/HO-1 signaling pathway were analyzed using the String database. The effects of MME overexpression, with or without the Nrf2 inhibitor ML385, on neuropathy were examined. Blood glucose, insulin levels, oxidative stress indicators, and inflammatory cytokines were measured. Gene expression was quantified by qRT-PCR, and protein levels were assessed by Western blot and immunohistochemistry.</p><p><strong>Results: </strong>Diabetic mice showed elevated blood glucose, MDA, ROS, TNF-α, IL-1β, IL-6, and decreased serum insulin, PWL, SOD activity, and MME levels. MME interacted with Nrf2 and HO-1, which were reduced in diabetic mice. Overexpression of MME led to improved serum insulin, PWL, SOD activity, and increased Nrf2 and HO-1 levels, while reducing MDA, ROS, TNF-α, IL-1β, and IL-6. These effects were partially reversed by ML385.</p><p><strong>Conclusion: </strong>Overexpression of MME mitigates oxidative stress and inflammation in painful diabetic neuropathy by activating the Nrf2/HO-1 signaling pathway.</p>","PeriodicalId":10873,"journal":{"name":"Current molecular medicine","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147607830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut Microbiota and Metabolic Profiles Reveal the Mechanism of Weight Loss in Patients with Obesity Stimulated By Acupuncture.","authors":"Yan Huo, Jianfang Gao, Ying Lv, Bingwei Ai","doi":"10.2174/0115665240391524251201102455","DOIUrl":"https://doi.org/10.2174/0115665240391524251201102455","url":null,"abstract":"<p><strong>Introduction: </strong>This study aims to elucidate the mechanisms underlying the efficacy of Quantitative Lifting And Inserting Acupuncture (QLIA) in treating simple obesity through integrated metabolomic and gut microbiota analyses.</p><p><strong>Methods: </strong>Thirty patients with obesity were randomized into treatment (QLIA), control (standard needle lifting), and healthy groups (standard needle lifting) (n=10 each). Acupuncture was administered three times per week for 8 weeks. 16S rRNA sequencing was performed on fecal samples, and serum samples were analyzed using ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLCMS/ MS) metabolomics.</p><p><strong>Results and discussion: </strong>QLIA significantly altered gut microbiota α-diversity and β- diversity. The Firmicutes/Bacteroidetes ratio was significantly increased in the QLIAtreated group. The treatment group showed increased abundance of beneficial bacteria such as Bifidobacterium and Dialister, and decreased abundance of potentially harmful bacteria such as Escherichia-Shigella. KEGG pathway analysis revealed upregulation of amino acid biosynthesis and carbohydrate metabolism pathways and downregulation of nucleotide biosynthesis pathways in the gut microbiota. Metabolomic analysis showed significantly elevated levels of acetyl-Lcarnitine and decreased levels of N-acetylneuraminic acid in the treatment group after acupuncture. PICRUSt analysis primarily implicated amino acid metabolic pathways. Serum metabolite analysis identified lipid, carbohydrate, and amino acid metabolism pathways as key targets of acupuncture intervention. Comparative analysis of metabolic pathways revealed amino acid metabolism as a shared target in both gut microbiota and serum metabolite profiles. These findings suggest that QLIA exerts its weight-loss effects by reshaping the gut microbiota structure and modulating host metabolic profiles, thereby highlighting a synergistic mechanism involving the gut-host metabolic axis.</p><p><strong>Conclusion: </strong>QLIA significantly promoted weight loss in simple obesity by modulating key metabolic pathways and altering gut microbiota composition. The study provides insight into the mechanisms underlying acupuncture-induced weight loss and supports its potential as a therapeutic option for obesity.</p>","PeriodicalId":10873,"journal":{"name":"Current molecular medicine","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147607871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Role of MicroRNA-200 Family in Gastrointestinal Cancers.","authors":"Jun Li, Jinling Pan, Jinjun Wen, Chuan Wang","doi":"10.2174/0115665240440515260204045401","DOIUrl":"https://doi.org/10.2174/0115665240440515260204045401","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;Gastrointestinal cancers, including esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, and colorectal cancer, are a major health burden worldwide, characterized by high incidence and mortality rates. Traditional diagnostic methods are not satisfactory. The compliance of patients with endoscopic examinations is poor, and the sensitivity and specificity of conventional tumor markers are also not high. Liquid biopsy, especially the detection of exosomal microRNAs (miRNAs), as a promising alternative method, has emerged, among which the miR-200 family has been identified as a key regulatory factor in the pathogenesis of gastrointestinal cancers.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;A literature search was conducted from 2002 to 2025, and the keywords used included \"gastrointestinal cancer\", \"miR-200 family\", and \"exosomal miRNA\". The studies involved included those on the role of miR-200 in gastrointestinal cancers, as well as research on exosomal miR-200 as a biomarker or therapeutic target. Inclusion criteria include: original studies published in English and peer-reviewed, which explored the biological, diagnostic, prognostic, or therapeutic effects of the miR-200 family in gastrointestinal cancers, and provided the complete papers that are accessible. If the research is a review, a conference summary, an editorial, a duplicate dataset, or lacks sufficient experimental or clinical data related to miR-200, it will be excluded. This literature search was conducted in the PubMed database. After screening, a total of 248 articles were obtained, and finally, 133 studies were included in the analysis. This review adhered to the guidelines of SANRA and employed a narrative research method. The key findings were qualitatively synthesized to summarize the mechanism of miR-200 and its clinical relevance.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;MicroRNA-200 regulates the occurrence and development of gastrointestinal cancers by modulating epithelial-mesenchymal transition (EMT), angiogenesis, cancer stem cell properties, and chemotherapy resistance. Its expression in tumor tissues is closely related to clinical pathological features, prognosis, and treatment response. Furthermore, the miR-200 present in exosomes exhibits extremely high stability in circulation and specificity towards cancer.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Discussion: &lt;/strong&gt;Studies have shown that miR-200 family regulates the occurrence and development of gastrointestinal cancer by targeting epithelial-mesenchymal transition, angiogenesis, and other characteristics, and its expression is related to clinicopathological characteristics and prognosis. Exosomal miR-200 family has shown good diagnostic performance in gastrointestinal malignancies. In an independent validation cohort, the AUC of combined miR-200a-3p and miR200b-3p expression in pancreatic ductal adenocarcinoma (PDAC) was 0.97, with a sensitivity of 100% and a specificity of 88%. Notably, combining this miRNA","PeriodicalId":10873,"journal":{"name":"Current molecular medicine","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147493675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of Integrated Turbidity Spectrophotometric Biosensor System with Osmotic Fragility/DichlorophenolIndophenol Precipitation Assays for Thalassemia Red Blood Cell Screening.","authors":"Preeya Pramool, Surakiate Wanram, Kanathip Butchai, Purinut Charoenrat, Somkid Pencharee, Surasak Wanram","doi":"10.2174/0115665240429789260211021243","DOIUrl":"https://doi.org/10.2174/0115665240429789260211021243","url":null,"abstract":"<p><strong>Introduction: </strong>Thalassemia remains a major public health burden, particularly in low-resource regions where access to advanced laboratory diagnostics is limited. Although high-performance liquid chromatography (HPLC) and capillary electrophoresis (CE) provide reliable hemoglobin characterization, their cost, infrastructure requirements, and turnaround time restrict large-scale screening. From a practical screening perspective, there is a clear need for a rapid, portable, and objective point-of-care (POC) approach that supports early identification and appropriate referral.</p><p><strong>Methods: </strong>We developed an integrated turbidity spectrophotometric biosensor that quantitatively combines the osmotic fragility (OF) test and the dichlorophenolindophenol precipitation (DCIP) clear assay. The system employs a portable LEDbased spectrophotometric reader controlled by an ESP32 microcontroller, integrated with real-time web-based visualization and automated interpretation. Ninety-nine EDTA blood specimens were analyzed. Red blood cell fragility and hemoglobin stability were assessed using time-resolved absorbance slope measurements at 540 and 600 nm for OF and DCIP, respectively. Analytical reproducibility, diagnostic performance, and agreement with reference methods were evaluated.</p><p><strong>Results: </strong>The biosensor demonstrated high analytical reproducibility, with mean coefficients of variation of 2.8% for OF slopes and 3.5% for DCIP slopes. Diagnostic performance was robust, yielding AUC values of 0.94 for OF and 0.90 for DCIP. An integrated decision algorithm achieved an overall concordance of 90.2% with goldstandard methods and provided preliminary interpretation within 3 minutes through a secure web-based dashboard.</p><p><strong>Discussion: </strong>Quantitative integration of OF and DCIP assays within a single platform improves screening objectivity while maintaining rapid turnaround, supporting decentralized and point-of-care testing.</p><p><strong>Conclusion: </strong>This integrated turbidity biosensor offers a rapid and scalable POC solution for preliminary thalassemia screening in underserved settings. Future development will focus on mobile integration, secure linkage with public health systems, and incorporation of additional hematologic or molecular parameters to further enhance diagnostic confidence.</p>","PeriodicalId":10873,"journal":{"name":"Current molecular medicine","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147493762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microbiota-driven Immunopathogenesis in Systemic Lupus Erythematosus: Cross-site Mechanisms and Intervention Strategies.","authors":"Shuqing Feng, Qin Huang","doi":"10.2174/0115665240433654260209063544","DOIUrl":"https://doi.org/10.2174/0115665240433654260209063544","url":null,"abstract":"<p><p>Systemic lupus erythematosus (SLE) is a complex autoimmune disease whose pathogenesis involves intricate interactions with the human microbiota. Accumulating evidence reveals significant compositional and functional dysbiosis in the gut, oral, skin, and vaginal microbiota of SLE patients compared to healthy individuals. These dysbioses actively contribute to disease development and progression through a multitude of mechanisms. These include impaired epithelial barrier integrity, exemplified by the \"leaky gut\" phenomenon, which facilitates the translocation of microbial antigens. Molecular mimicry, where microbial antigens share structural similarities with host self-antigens, triggers the production of cross-reactive autoantibodies. Furthermore, dysregulated production of microbial metabolites, such as short-chain fatty acids, tryptophan derivatives like tryptamine, and histamine, directly modulates host immune cell function, promotes inflammatory responses, and influences epigenetic regulation. The causal role of specific microbiota in SLE is substantiated by experimental models, including fecal microbiota transplantation studies where transfer of SLE-associated microbiota can recapitulate autoimmune features in recipient germ-free mice, and mono-colonization with pathobionts like Ruminococcus gnavus or Staphylococcus aureus can drive specific aspects of the disease. This growing understanding has paved the way for novel microbiota-targeting interventions. Strategies such as dietary modifications, probiotic and prebiotic supplementation, and fecal microbiota transplantation show considerable promise in preclinical and early clinical studies for restoring microbial homeostasis, rebalancing dysregulated immune responses, and alleviating disease activity. However, challenges in patient-specific variability, understanding precise mechanisms, and ensuring longterm safety remain. Future research must focus on delineating detailed causal pathways, validating efficacy in large-scale trials, and ultimately developing personalized microbiota-targeting interventions to improve SLE management and patient outcomes.</p>","PeriodicalId":10873,"journal":{"name":"Current molecular medicine","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147493664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Systematic Review and Meta-Analysis of Immune Signatures Involved in the Prevalence of Exhaustion in Humans, Mice, and Bovine Species.","authors":"Khushbu Sharma, Shalini Sharma, Shweta Dhanda, Saurabh Gupta, Shivalingappa Yamanappa Mukartal, Sarvesh Rustagi, Kundan Kumar Chaubey, Sanjay Kumar","doi":"10.2174/0115665240414612260116235015","DOIUrl":"https://doi.org/10.2174/0115665240414612260116235015","url":null,"abstract":"<p><strong>Introduction: </strong>Immune exhaustion is known to occur in chronic infections as well as cancer, and is characterized by constant antigenic stimulation and gradual loss of T cell function and upregulation of immune exhaustion markers. This systematic review aims to explore conserved and divergent exhaustion signatures across humans, mice, and bovines to advance our understanding for better translational outcomes.</p><p><strong>Methods: </strong>Following PRISMA 2020 guidelines, studies from 2011-2023 were analyzed using a random-effects model (metaprop, logit transformation). Subgroup analyses (species, disease type), sensitivity and heterogeneity (I²) analyses were performed. Publication bias was performed to evaluate biomarker variability.</p><p><strong>Results: </strong>Meta-analysis identified an almost consistent role of IL-6 (48%), IL-2 (51%), TNF-α (46%), IFN-γ (41%), and IL-10 (48%) in immune exhaustion throughout various chronic disease conditions. Co-inhibitory receptors such as PD-1 (51%), TIM-3 (54%), LAG-3 (59%), and CTLA-4 (64%) were highly upregulated. Extreme heterogeneity (I² >95%) pointed towards considerable variation mainly due to species differences, disease category, and methodological factors, with fewer murine and bovine studies compared to human literature.</p><p><strong>Discussion: </strong>The confluence of pro-inflammatory cytokines with elevated checkpoint receptor expression highlights the fact that immune exhaustion is conserved across mammals. However, the limitation in extrapolation attributed to high heterogeneity and species imbalance exists in the study. Furthermore, the variations in disease models and technical differences in detection methods point towards a need for standardization and integrated comparative analyses to boost biomarker interpretation.</p><p><strong>Conclusion: </strong>Co-inhibitory receptors and various cytokines appear to be the conserved contributors to immune exhaustion across species. Further, enriching cross-species data sets and accounting for methodological variability will improve the translational importance and support in developing more precise therapeutic interventions.</p>","PeriodicalId":10873,"journal":{"name":"Current molecular medicine","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147621695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Synergistic Effect of Nutlin-3a and a Wip1 Inhibitor in Inducing p53 Activity.","authors":"Ali Hikmat Alburghaif, Hany Akeel Al-Hussaniy, Ali Mahmoud Al-Samydai, Zainab Malik Saleem, Alhasan Ali Jabbar","doi":"10.2174/0115665240437546260121175241","DOIUrl":"https://doi.org/10.2174/0115665240437546260121175241","url":null,"abstract":"<p><strong>Introduction: </strong>The p53 protein plays a major role in maintaining genome stability as well as the response of cells to stress. One of the principal things that regulates p53 is MDM2, and the way it interacts with p53 is of great significance in the degradation of p53. This dephosphorylation of p53 by Wip1 increases its affinity to MDM2, which causes p53 degradation. Wip1 is used to increase the growth of tumors by undermining the p53 pathway. However, the active form of p53 can be retained with the help of preventing Wip1, and this fact makes it useful as a target of cancer treatment. An ever-increasing body of preclinical evidence suggests the possibility that Wip1 inhibitors would be used alongside potent MDM2 inhibitors to enhance p53 activity and enhance treatment outcomes. The purpose of the review was to examine studies pertaining to the action of a Wip1 inhibitor and Nutlin-3a in order to induce p53 functionality.</p><p><strong>Method: </strong>We searched Google Scholar, PubMed, and other search engines using such terms as MDM2 inhibitors, Wip1 inhibitors, and Nutlin. Newer articles published after 2020 were chosen to ensure that the recent findings are included.</p><p><strong>Results: </strong>Wip1, an attractive antineoplastic target to control the p53 pathway, is a dephosphorylator of p53 at serine-15. Nutlin-3a with a Wip1 inhibitor appears to act synergistically to push p53 half-maximal inhibitory concentrations (IC50) into the low micromolar range. This combination greatly stimulates downstream p53-dependent response, which leads to a strong reduction of cell proliferation.</p><p><strong>Discussion: </strong>We find that MDM2 inhibitors in combination with Wip1 inhibitors are synergistic in stimulating p53 activity. The results emphasize the need to use a combination of p53 induction and the inactivation of its suppressors in the treatment of cancer.</p><p><strong>Conclusion: </strong>As p53 is the most commonly mutated gene across a broad range of tumors, enhancing p53 activity is a prerequisite for achieving potent therapeutic effects. We envision that combination therapies involving Nutlin-3a, Wip1 inhibitors, and other effective cancer treatments may synergistically improve p53 activity and enhance therapeutic outcomes.</p>","PeriodicalId":10873,"journal":{"name":"Current molecular medicine","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147621705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}