1
|
Wang F, Shen C. Impact of liquid-liquid phase separation- and immune-related gene signatures on multiple myeloma prognosis: focus on DDX21 and EZH2. Hematology 2025; 30:2445403. [PMID: 39713879 DOI: 10.1080/16078454.2024.2445403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 12/13/2024] [Indexed: 12/24/2024] Open
Abstract
OBJECTIVE Liquid-liquid phase separation (LLPS) may affect the therapeutic sensitivity of multiple myeloma (MM). This study aimed to identify LLPS-related genes with MM prognostic values and to confirm their effects on tumor progression. METHODS Based on public transcriptomic data, this study screened LLPS- and immune-related genes for MM-derived plasma cells. Subtypes were identified using consensus clustering, followed by comparisons using t-test and survival analysis. Least absolute shrinkage and selection operator was implemented to screen prognostic signatures, and Kaplan-Meier and receiver operator characteristic curves were plotted to assess their prognostic values. After transfected with sh-DDX21, CCK8, flow cytometry, and Transwells were used to observe MM cell proliferation, apoptosis, migration, and invasion. RESULTS By overlapping LLPS- and immune-related genes, 103 genes were obtained to cluster MM samples into three subtypes, which had significant differences in survival and immune landscape. Cox regression analysis screened out EZH2 and DDX21 that significantly overexpressed in MM to construct a prognostic model, with superior performance in predicting MM prognostic risks. Notably, subtype2 with more adverse prognosis showed significantly elevated risk scores and was more distributed in groups with high prognostic risk. In vitro experiments confirmed that cell proliferation, invasion, and migration were significantly inhibited in MM.1S cells transfected with sh-DDX21. CONCLUSION LLPS-related EZH2 and DDX21 were novel markers to predict prognostic risk of MM. Among them, DDX21 was experimentally confirmed to promote MM cell proliferation, migration and invasion. These potential prognostic markers could be targeted in future personalized therapeutic strategies for MM, potentially improving patient outcomes.
Collapse
Affiliation(s)
- Fengming Wang
- Department of Hematology, Shaoxing Shangyu people's Hospital, Shaoxing, People's Republic of China
| | - Chuyun Shen
- Department of Hematology, Shaoxing Shangyu people's Hospital, Shaoxing, People's Republic of China
| |
Collapse
|
2
|
Peng Y, Tao H, Liu D, Tang D, Wen C, Wu M, Xu T, Wang G, Zheng X, Dai Y. Comprehensive analysis of eccDNA characteristics and associated genes expression in peripheral blood of ASLE and ISLE patients. Epigenetics 2025; 20:2477903. [PMID: 40108975 PMCID: PMC11926905 DOI: 10.1080/15592294.2025.2477903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 11/09/2024] [Accepted: 03/06/2025] [Indexed: 03/22/2025] Open
Abstract
To explore SLE staging markers, we analyzed eccDNA in plasma using circular sequencing, comparing healthy controls (HC), active SLE (ASLE), and inactive SLE (ISLE) patients. We found higher eccDNA levels and lower GC content in ASLE and ISLE compared to healthy controls, with a negative correlation between GC content and anti-daDNA, C3, and C4 levels in SLE and HC samples. Differential expression of exon-derived eccGenes in ASLE and ISLE suggests their role in SLE development, with KEGG analysis showing enrichment in SLE-related pathways for these differentially expressed genes. By protein-protein interactions network analysis we found 9 exon-derived eccGenes that were significantly differentially expressed and scored high in both ISLE-HC and ASLE-ISLE as diagnostic criteria for differentiating different disease stages of SLE. In conclusion, the present study reveals that eccDNA length GC content as well as chromosomal distribution in ASLE, ISLE and HC suggests that with eccDNA is associated with the creation of SLE, suggesting GC count of eccDNA as a diagnostic marker for systemic lupus erythematosus. Significant changes in the abundance of eccDNA-related genes from exons such as SOS1, GAD2, BCL11B, PPT1, and GCNT3 were observed in ISLE as compared to ASLE and HC groups and were significantly correlated with SLEDAI-2K. This suggests that these exon-derived eccGenes may play a role in the development and progression of the disease. Consequently, the abundance levels of these exon-derived eccGenes could potentially assist in distinguishing different stages of SLE, beyond a confirmed diagnosis, thus serving as possible biomarkers for the condition.
Collapse
Affiliation(s)
- Yali Peng
- School of Medicine, Anhui University of Science & Technology, Huainan, China
| | - Huihui Tao
- School of Medicine, Anhui University of Science & Technology, Huainan, China
- Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety of Anhui Higher Education Institutes, Anhui University of Science & Technology, Huainan, China
- Anhui Province Engineering Laboratory of Occupational Health and Safety, Anhui University of Science & Technology, Huainan, China
| | - Dongzhou Liu
- Guangdong Provincial Autoimmune Disease Precision Medicine Engineering Research Center, Shenzhen Autoimmune Disease Engineering Research Center, Shenzhen Geriatrics Clinical Research Center, Shenzhen People ‘s Hospital, Second Clinical Medical College of Jinan University, Shenzhen People’s Hospital, Shenzhen, China
| | - Donger Tang
- Guangdong Provincial Autoimmune Disease Precision Medicine Engineering Research Center, Shenzhen Autoimmune Disease Engineering Research Center, Shenzhen Geriatrics Clinical Research Center, Shenzhen People ‘s Hospital, Second Clinical Medical College of Jinan University, Shenzhen People’s Hospital, Shenzhen, China
| | - Chunmei Wen
- School of Medicine, Anhui University of Science & Technology, Huainan, China
| | - Mengyao Wu
- School of Medicine, Anhui University of Science & Technology, Huainan, China
| | - Tiantian Xu
- School of Medicine, Anhui University of Science & Technology, Huainan, China
| | - Guoying Wang
- School of Medicine, Anhui University of Science & Technology, Huainan, China
| | - Xuejia Zheng
- The First Hospital of Anhui University of Science and Technology, Huainan, China
| | - Yong Dai
- School of Medicine, Anhui University of Science & Technology, Huainan, China
- Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety of Anhui Higher Education Institutes, Anhui University of Science & Technology, Huainan, China
- Anhui Province Engineering Laboratory of Occupational Health and Safety, Anhui University of Science & Technology, Huainan, China
- Guangdong Provincial Autoimmune Disease Precision Medicine Engineering Research Center, Shenzhen Autoimmune Disease Engineering Research Center, Shenzhen Geriatrics Clinical Research Center, Shenzhen People ‘s Hospital, Second Clinical Medical College of Jinan University, Shenzhen People’s Hospital, Shenzhen, China
- The First Hospital of Anhui University of Science and Technology, Huainan, China
| |
Collapse
|
3
|
Huang J, Wang L, Zhou J, Dai T, Zhu W, Wang T, Wang H, Zhang Y. Unveiling the ageing-related genes in diagnosing osteoarthritis with metabolic syndrome by integrated bioinformatics analysis and machine learning. ARTIFICIAL CELLS, NANOMEDICINE, AND BIOTECHNOLOGY 2025; 53:57-68. [PMID: 40022676 DOI: 10.1080/21691401.2025.2471762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 12/16/2024] [Accepted: 02/16/2025] [Indexed: 03/03/2025]
Abstract
Ageing significantly contributes to osteoarthritis (OA) and metabolic syndrome (MetS) pathogenesis, yet the underlying mechanisms remain unknown. This study aimed to identify ageing-related biomarkers in OA patients with MetS. OA and MetS datasets and ageing-related genes (ARGs) were retrieved from public databases. The limma package was used to identify differentially expressed genes (DEGs), and weighted gene coexpression network analysis (WGCNA) screened gene modules, and machine learning algorithms, such as random forest (RF), support vector machine (SVM), generalised linear model (GLM), and extreme gradient boosting (XGB), were employed. The nomogram and receiver operating characteristic (ROC) curve assess the diagnostic value, and CIBERSORT analysed immune cell infiltration. We identified 20 intersecting genes among DEGs of OA, key module genes of MetS, and ARGs. By comparing the accuracy of the four machine learning models for disease prediction, the SVM model, which includes CEBPB, PTEN, ARPC1B, PIK3R1, and CDC42, was selected. These hub ARGs not only demonstrated strong diagnostic values based on nomogram data but also exhibited a significant correlation with immune cell infiltration. Building on these findings, we have identified five hub ARGs that are associated with immune cell infiltration and have constructed a nomogram aimed at early diagnosing OA patients with MetS.
Collapse
Affiliation(s)
- Jian Huang
- Department of Orthopedics, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Lu Wang
- Department of Neurology, The Central Hospital of Xiaogan, Xiaogan, China
| | - Jiangfei Zhou
- Department of Orthopedics, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China
| | - Tianming Dai
- Guangzhou Institute of Traumatic Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China
| | - Weicong Zhu
- Guangzhou Institute of Traumatic Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China
| | - Tianrui Wang
- Department of Orthopedics, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Hongde Wang
- Department of Sports Medicine, Peking University Third Hospital, Institute of Sports Medicine of Peking University, Beijing, China
- Beijing Key Laboratory of Sports Injuries, Beijing, China
- Engineering Research Center of Sports Trauma Treatment Technology and Devices, Ministry of Education, Beijing, China
| | - Yingze Zhang
- Department of Orthopedics, The Affiliated Hospital of Qingdao University, Qingdao, China
| |
Collapse
|
4
|
Hu K, Zhu Q, Zou J, Li X, Ye M, Yang J, Chen S, Li F, Ding B, Yang S, Song C, Liang M. Proteomic analysis for busulfan-induced spermatogenesis disorder. Ann Med 2025; 57:2442534. [PMID: 39697060 DOI: 10.1080/07853890.2024.2442534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 11/05/2024] [Accepted: 11/08/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND Busulfan is the most commonly used drug for the treatment of chronic myelogenous leukemia and pretreatment for hematopoietic stem cell transplantation, which can damage the reproductive and immune system. However, little is known about the protein expression profiling in busulfan treated testis. METHODS This research studies the proteomics for busulfan-induced spermatogenesis disorder. The model of busulfan-induced mouse spermatogenesis disorder was subjected to label-free quantification proteomics analysis. Clustering heatmap, gene ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and protein interaction analyses were performed and validated by molecular experiments. RESULTS The busulfan-treated mouse model showed abnormal testis morphology and reduced sperm number and testis weight. Testicular and sperm damage was most severe at 30 days after busulfan treatment. The busulfan-treated mouse testes were subjected to label-free quantification proteomics, which revealed 190 significantly downregulated proteins including lactate dehydrogenase A like 6B (LDHAL6B) and ubiquitin-specific protease 7 (USP7). In addition, the testis and spermatozoa in the epididymis progressively improved from 70 to 80 days after busulfan treatment, and that the testis weight and spermatozoa number gradually increased from 40 to 80 days after busulfan treatment. Western blotting revealed that LDHAL6B protein significantly increased at 10 days, decreased from 20 to 60 days, and then gradually elevated from 70 to 80 days after busulfan treatment. CONCLUSION We revealed 190 significantly downregulated proteins in busulfan-treated mouse testes at 30 days and indicated that 70 days is the cut-off point of spermatogenic recovery for busulfan-treated mouse testis, increasing our understanding of this reproductive disorder model. An increased understanding of busulfan's toxic effect will help to prevent and treat reproductive diseases.
Collapse
Affiliation(s)
- Ke Hu
- School of Life Science, Bengbu Medical University, Bengbu, China
| | - Qinran Zhu
- School of Life Science, Bengbu Medical University, Bengbu, China
| | - Jiaqi Zou
- School of Life Science, Bengbu Medical University, Bengbu, China
| | - Xin Li
- School of Life Science, Bengbu Medical University, Bengbu, China
| | - Min Ye
- School of Life Science, Bengbu Medical University, Bengbu, China
| | - Jing Yang
- School of Life Science, Bengbu Medical University, Bengbu, China
| | - Sixieyang Chen
- School of Life Science, Bengbu Medical University, Bengbu, China
| | - Fan Li
- School of Laboratory Medicine, Bengbu Medical University, Bengbu, China
| | - Biao Ding
- First Affiliated Hospital, Bengbu Medical University, Bengbu, China
| | - Shuai Yang
- First Affiliated Hospital, Bengbu Medical University, Bengbu, China
| | - Chuanwang Song
- School of Laboratory Medicine, Bengbu Medical University, Bengbu, China
| | - Meng Liang
- School of Life Science, Bengbu Medical University, Bengbu, China
| |
Collapse
|
5
|
Zhang Y, Zhang Z, Liu R, He Y, Ning S, Yu J, Liu Y, Xia Y, Pang X, Lv W, Sun Q, Li Y, Wang Z, Liu L, Feng B. Identification of S100A9 as a target for diagnosis and treatment of Crohn's Disease after Vedolizumab treatment failure. Immunol Lett 2025; 275:107027. [PMID: 40280281 DOI: 10.1016/j.imlet.2025.107027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 04/11/2025] [Accepted: 04/22/2025] [Indexed: 04/29/2025]
Abstract
The vedolizumab medication is the treatment that precisely targets the gut for Crohn's Disease (CD). It can inhibit the migration of lymphocytes to the intestinal site despite the fact that a significant portion of the population continues to be ineffectively treated. In this study, peripheral blood leukocytes sampled from the CD patients who are nonresponsive or responsive to vedolizumab treatment were used for transcriptome sequencing. Intersected differentially expressed mRNA obtained from transcriptome sequencing and GSE191328 were utilized to predict key therapeutic targets. Bioinformatics analyses were used to explore potential biological mechanisms and to screen pivotal genes. Inhibitor of S100A9 increased the body weight and colon length of mice with colitis, and decreased the DAI score. Our study also demonstrated that the combination of anti-α4β7 integrin antibody with inhibitor of S100A9 further alleviates colitis. Through flow cytometry, changes in the composition of immune cell populations in colon tissues were found after intragastric administration of paquinimod, an inhibitor of S100A9. It is important that blocking S100A9 inhibited the recruitment of neutrophils in the mice's colon. Our findings lay a foundation for the further exploration of the new targets for non-responders to vedolizumab in CD patients.
Collapse
Affiliation(s)
- Yanru Zhang
- Department of Gastroenterology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou 450014, China
| | - Zhe Zhang
- Department of Gastroenterology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou 450014, China.
| | - Ruixian Liu
- Department of Gastroenterology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou 450014, China
| | - Yijia He
- Department of Gastroenterology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou 450014, China
| | - Shiyang Ning
- Department of Gastroenterology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou 450014, China
| | - Junzhi Yu
- Department of Gastroenterology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou 450014, China
| | - Yan Liu
- Department of Gastroenterology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou 450014, China
| | - Yimeng Xia
- Department of Gastroenterology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou 450014, China
| | - Xinji Pang
- Department of Gastroenterology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou 450014, China
| | - Wen Lv
- Department of Gastroenterology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou 450014, China
| | - Qiankun Sun
- Department of Gastroenterology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou 450014, China
| | - Yilong Li
- Department of Gastroenterology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou 450014, China
| | - Zhihong Wang
- Department of Gastroenterology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou 450014, China
| | - Lu Liu
- Department of Gastroenterology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou 450014, China
| | - Baisui Feng
- Department of Gastroenterology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou 450014, China.
| |
Collapse
|
6
|
Chen B, Wang C, Li W. Comprehensive genetic analysis based on multi - omics reveals novel therapeutic targets for mitral valve prolapse and drug molecular dynamics simulation. Int J Cardiol 2025; 433:133325. [PMID: 40311696 DOI: 10.1016/j.ijcard.2025.133325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 03/19/2025] [Accepted: 04/24/2025] [Indexed: 05/03/2025]
Abstract
OBJECTIVE Mitral valve prolapse (MVP), the most prevalent primary valvular disease, serves as a direct risk factor for multiple cardiovascular disorders and exhibits a high prevalence in the general population. As no specific pharmacological therapies currently exist for MVP, the identification of precise therapeutic targets is imperative. METHOD We conducted comprehensive causal genetic inference by integrating genetic data from expression quantitative trait loci (eQTL) and genome-wide association studies (GWAS). Analytical approaches included Mendelian Randomization (MR), colocalization analysis, Summary-data-based Mendelian Randomization (SMR), Linkage Disequilibrium Score Regression (LDSC), and High-Definition Likelihood (HDL) analysis. Protein quantitative trait loci (pQTL) were utilized to validate gene expression. Replication analyses were performed using additional exposure datasets. Methylation quantitative trait loci (mQTL) were employed to elucidate regulatory roles of methylation sites on genes and disease pathogenesis. Phenome-Wide Association Study (PheWAS) was conducted to predict potential adverse effects of gene-targeted therapies. Drug candidates targeting identified genes were predicted via the Drug Signature Database (DSigDB) and validated through molecular docking. Core targets were identified using the STRING database, followed by molecular dynamics simulations. RESULT Two-sample MR analysis showed that genetically predicted 266 genes had positive or negative causal relationships with MVP. Colocalization analysis indicated that 9 genes had a posterior probability greater than 0.75. Subsequent SMR analysis excluded the gene GAPVD1. HDL analysis showed that except for the gene PTPN1, the remaining 7 genes were all significantly genetically associated with MVP, and LDSC analysis further showed that only NMB was associated with MVP. Validation using pQTL data confirmed that increased NMB protein expression reduced the risk of MVP. Replication analysis further verified this conclusion. In addition, SMR analysis of methylation sites for 8 genes indicated that multiple methylation sites played a key role in gene regulation of mitral valve prolapse. PheWAS results showed that targeted therapy for 8 genes did not detect other causal associations at the genome-wide significance level. Molecular docking showed that quercetin had good binding ability with 8 target genes. The STRING database identified 3 core target proteins, and molecular dynamics simulations further verified the binding ability of quercetin with core target proteins. CONCLUSION This study successfully predicted the potential of multiple druggable genes as effective therapeutic targets for MVP through genetic methods, validated the potential of quercetin as a drug, and provided new ideas for drug treatment strategies for MVP.
Collapse
Affiliation(s)
- Bohang Chen
- Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning 110847, China
| | - Chuqiao Wang
- Liaoning Health Industry Group Fukuang General Hospital, Fushun, Liaoning 113008, China.
| | - Wenjie Li
- Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning 110032, China
| |
Collapse
|
7
|
Shaw P, Dey Bhowmik A, Gopinatha Pillai MS, Robbins N, Dwivedi SKD, Rao G. Anoikis resistance in Cancer: Mechanisms, therapeutic strategies, potential targets, and models for enhanced understanding. Cancer Lett 2025; 624:217750. [PMID: 40294841 DOI: 10.1016/j.canlet.2025.217750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 04/01/2025] [Accepted: 04/26/2025] [Indexed: 04/30/2025]
Abstract
Anoikis, defined as programmed cell death triggered by the loss of cell-extracellular matrix (ECM) and cell-cell interactions, is crucial for maintaining tissue homeostasis and preventing aberrant cell migration. Cancer cells, however, display anoikis resistance (AR) which in turn enables cancer metastasis. AR results from alterations in apoptotic signaling, metabolic reprogramming, autophagy modulation, and epigenetic changes, allowing cancer cells to survive in detached conditions. In this review we describe the mechanisms underlying both anoikis and AR, focusing on intrinsic and extrinsic pathways, disrupted cell-ECM interactions, and autophagy in cancer. Recent findings (i.e., between 2014 and 2024) on epigenetic regulation of AR and its role in metastasis are discussed. Therapeutic strategies targeting AR, including chemical inhibitors, are highlighted alongside a network analysis of 122 proteins reported to be associated with AR which identifies 53 hub proteins as potential targets. We also evaluate in vitro and in vivo models for studying AR, emphasizing their role in advancing metastasis research. Our overall goal is to guide future studies and therapeutic developments to counter cancer metastasis.
Collapse
Affiliation(s)
- Pallab Shaw
- Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences, Oklahoma City, 73104, Oklahoma, USA; Department of Pathology, The University of Oklahoma Health Sciences, Oklahoma City, 73104, Oklahoma, USA
| | - Arpan Dey Bhowmik
- Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences, Oklahoma City, 73104, Oklahoma, USA; Department of Obstetrics and Gynecology, The University of Oklahoma Health Sciences, Oklahoma City, 73104, Oklahoma, USA
| | - Mohan Shankar Gopinatha Pillai
- Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences, Oklahoma City, 73104, Oklahoma, USA; Department of Obstetrics and Gynecology, The University of Oklahoma Health Sciences, Oklahoma City, 73104, Oklahoma, USA
| | - Nathan Robbins
- James E. Hurley School of Science and Mathematics, Oklahoma Baptist University, Shawnee, OK, USA
| | - Shailendra Kumar Dhar Dwivedi
- Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences, Oklahoma City, 73104, Oklahoma, USA; Department of Obstetrics and Gynecology, The University of Oklahoma Health Sciences, Oklahoma City, 73104, Oklahoma, USA
| | - Geeta Rao
- Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences, Oklahoma City, 73104, Oklahoma, USA; Department of Pathology, The University of Oklahoma Health Sciences, Oklahoma City, 73104, Oklahoma, USA.
| |
Collapse
|
8
|
Irrou E, Elmachkouri YA, Haddad SE, Chagaleti BK, Mague JT, MK K, Alotaibi SH, Gomha SM, Oubella A, Hassan O, Sebbar NK, Taha ML. Synthesis of novel N4-substituted and C2-disubstituted 1,4-benzothiazine-1,1-dioxide derivatives: Integrative computational strategies for breast cancer therapy. J Mol Struct 2025; 1338:142310. [DOI: 10.1016/j.molstruc.2025.142310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/14/2025]
|
9
|
Yin L, Xu Y, Mu J, Leng Y, Ma L, Zheng Y, Li R, Wang Y, Li P, Zhu H, Wang D, Li J. CNKSR2 interactome analysis indicates its association with the centrosome/microtubule system. Neural Regen Res 2025; 20:2420-2432. [PMID: 39359098 PMCID: PMC11759008 DOI: 10.4103/nrr.nrr-d-23-01725] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 01/27/2024] [Accepted: 03/04/2024] [Indexed: 10/04/2024] Open
Abstract
JOURNAL/nrgr/04.03/01300535-202508000-00031/figure1/v/2024-09-30T120553Z/r/image-tiff The protein connector enhancer of kinase suppressor of Ras 2 (CNKSR2), present in both the postsynaptic density and cytoplasm of neurons, is a scaffolding protein with several protein-binding domains. Variants of the CNKSR2 gene have been implicated in neurodevelopmental disorders, particularly intellectual disability, although the precise mechanism involved has not yet been fully understood. Research has demonstrated that CNKSR2 plays a role in facilitating the localization of postsynaptic density protein complexes to the membrane, thereby influencing synaptic signaling and the morphogenesis of dendritic spines. However, the function of CNKSR2 in the cytoplasm remains to be elucidated. In this study, we used immunoprecipitation and high-resolution liquid chromatography-mass spectrometry to identify the interactors of CNKSR2. Through a combination of bioinformatic analysis and cytological experiments, we found that the CNKSR2 interactors were significantly enriched in the proteome of the centrosome. We also showed that CNKSR2 interacted with the microtubule protein DYNC1H1 and with the centrosome marker CEP290. Subsequent colocalization analysis confirmed the centrosomal localization of CNKSR2. When we downregulated CNKSR2 expression in mouse neuroblastoma cells (Neuro 2A), we observed significant changes in the expression of numerous centrosomal genes. This manipulation also affected centrosome-related functions, including cell size and shape, cell proliferation, and motility. Furthermore, we found that CNKSR2 interactors were highly enriched in de novo variants associated with intellectual disability and autism spectrum disorder. Our findings establish a connection between CNKSR2 and the centrosome, and offer new insights into the underlying mechanisms of neurodevelopmental disorders.
Collapse
Affiliation(s)
- Lin Yin
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Medical College, Qingdao University, Qingdao, Shandong Province, China
- School of Basic Medicine, Qingdao University, Qingdao, Shandong Province, China
| | - Yalan Xu
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Medical College, Qingdao University, Qingdao, Shandong Province, China
- School of Basic Medicine, Qingdao University, Qingdao, Shandong Province, China
| | - Jie Mu
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Medical College, Qingdao University, Qingdao, Shandong Province, China
- College of Life Sciences, and School of Pharmacy, Medical College, Qingdao University, Qingdao, Shandong Province, China
| | - Yu Leng
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Medical College, Qingdao University, Qingdao, Shandong Province, China
- School of Basic Medicine, Qingdao University, Qingdao, Shandong Province, China
| | - Lei Ma
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Medical College, Qingdao University, Qingdao, Shandong Province, China
- School of Basic Medicine, Qingdao University, Qingdao, Shandong Province, China
| | - Yu Zheng
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Medical College, Qingdao University, Qingdao, Shandong Province, China
- School of Basic Medicine, Qingdao University, Qingdao, Shandong Province, China
- Department of Urology, Qingdao Municipal Hospital Affiliated to Qingdao University, Qingdao, Shandong Province, China
| | - Ruizhi Li
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Medical College, Qingdao University, Qingdao, Shandong Province, China
- School of Basic Medicine, Qingdao University, Qingdao, Shandong Province, China
| | - Yin Wang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Medical College, Qingdao University, Qingdao, Shandong Province, China
| | - Peifeng Li
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Medical College, Qingdao University, Qingdao, Shandong Province, China
| | - Hai Zhu
- Department of Urology, Qingdao Municipal Hospital Affiliated to Qingdao University, Qingdao, Shandong Province, China
| | - Dong Wang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Medical College, Qingdao University, Qingdao, Shandong Province, China
| | - Jing Li
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Medical College, Qingdao University, Qingdao, Shandong Province, China
| |
Collapse
|
10
|
Lei X, Wang F, Zhang X, Huang J, Huang Y. The potential mechanisms by which Xiaoyao Powder may exert therapeutic effects on thyroid cancer were examined at various levels. Comput Biol Chem 2025; 117:108412. [PMID: 40056710 DOI: 10.1016/j.compbiolchem.2025.108412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 02/13/2025] [Accepted: 02/24/2025] [Indexed: 03/10/2025]
Abstract
BACKGROUND Thyroid cancer (TC) is the most prevalent endocrine malignancy, with a rising incidence necessitating safer treatment strategies to reduce overtreatment and its side effects. Xiaoyao Powder (XYP), a widely used herbal formula, shows promise in treating TC. This study aims to investigate the mechanisms by which XYP may affect TC. METHODS The components of XYP were identified through database retrieval, and targets related to TC were collected to construct a target network for key screening. GEO dataset samples analyzed immune cells and identified significantly differentially expressed core genes (SDECGs). Based on SDECG expression and clustering, samples were classified for comparison. WGCNA was employed to identify gene modules linked to clinical characteristics. ML models screened characteristic genes and constructed a nomogram validated using another GEO dataset. MR methods explored causal relationships between genes and TC. RESULTS The top ten active components of XYP were identified, along with 27 SDECGs that exhibited significant differences in immune cell infiltration between TC patients and normal controls. The nomogram effectively predicted TC risk, validated through ROC curves. Key characteristic genes included SMIM1, PPP1R16A, KIAA1462, DNAJC22, and EFNA5. CONCLUSION XYP may treat TC by regulating SMIM1, PPP1R16A, KIAA1462, DNAJC22, EFNA5, and associated immune pathways; this provides theoretical support for its potential mechanisms.
Collapse
Affiliation(s)
- Xiaoli Lei
- The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Feifei Wang
- Department of Quality Control, Liaocheng Traditional Chinese Medicine Hospital, Liaocheng, China
| | - Xinying Zhang
- Department of Endocrinology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Jiaxi Huang
- Department of Pharmacy, Huoqiu County First People's Hospital, Liuan, China
| | - Yanqin Huang
- Department of Endocrinology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China.
| |
Collapse
|
11
|
Zhang M, Yuan L, Yang X, Zhao X, Xie J, Liu X, Wang F. TRAF1 promotes the progression of Helicobacter pylori-associated gastric cancer through EGFR/STAT/OAS signalling. Life Sci 2025; 373:123656. [PMID: 40287055 DOI: 10.1016/j.lfs.2025.123656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Revised: 04/11/2025] [Accepted: 04/21/2025] [Indexed: 04/29/2025]
Abstract
AIMS Helicobacter pylori (H. pylori) is associated with various gastric diseases and is one of the pathogenic factors of gastric cancer (GC). We found that H. pylori induce the expression of TRAF1, but its mechanism of action is still unclear. Therefore, we wanted to determine whether TRAF1 is involved in the mechanism of H. pylori-related GC progression. MATERIALS AND METHODS In this study, we analysed TRAF1 expression and its prognostic significance using clinical specimens, performed functional studies involving TRAF1 overexpression or knockdown in cellular models, identified downstream signalling pathways regulated via RNA-seq, validated these mechanisms through pathway blockade and rescue experiments, and further confirmed the findings in an H. pylori-infected gastritis mouse model. KEY FINDINGS TRAF1 expression was significantly elevated in GC tissues and served as a poor prognostic biomarker. TRAF1 promoted GC cell proliferation, migration and invasion. RNA-seq analysis revealed that TRAF1 activated the EGFR/STAT/OAS signalling axis, upregulated STAT3 expression and increased the transcription of the OAS gene family. Pharmacological inhibition with ruxolitinib and AG490 effectively blocked EGFR/STAT/OAS signalling. In H. pylori-treated cell models, H. pylori infection activated the EGFR/STAT/OAS signalling axis. In vivo, we established an H. pylori-induced gastritis mouse model to validate the activation of this signalling pathway during the gastritis-carcinoma transition. SIGNIFICANCE TRAF1 may promote the proliferation, migration and invasion of H. pylori-associated GC by activating the EGFR/STAT/OAS signalling axis, suggesting that TRAF1 is a promising novel prognostic biomarker and therapeutic target for this malignancy.
Collapse
Affiliation(s)
- Minglin Zhang
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, 138 Tongzipo Road, Changsha, Hunan 410013, China
| | - Lingzhi Yuan
- Department of Digestive Nutrition, Hunan Children's Hospital, Central South University Affiliated Children's Hospital, Changsha, China
| | - Xueer Yang
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, 138 Tongzipo Road, Changsha, Hunan 410013, China
| | - Xuelin Zhao
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, 138 Tongzipo Road, Changsha, Hunan 410013, China
| | - Jie Xie
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, 138 Tongzipo Road, Changsha, Hunan 410013, China
| | - Xiaoming Liu
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, 138 Tongzipo Road, Changsha, Hunan 410013, China.
| | - Fen Wang
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, 138 Tongzipo Road, Changsha, Hunan 410013, China.
| |
Collapse
|
12
|
Tang Q, Chu J, Peng P, Zou Y, Wu Y, Wang Y. Probing the antibacterial mechanism of Aloe vera based on network pharmacology and computational analysis. J Mol Graph Model 2025; 138:109034. [PMID: 40157275 DOI: 10.1016/j.jmgm.2025.109034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 03/15/2025] [Accepted: 03/23/2025] [Indexed: 04/01/2025]
Abstract
Bacterial resistance has emerged as a major clinical challenge globally. Natural products, such as Aloe vera, offer promising antimicrobial potential due to their diverse active components. However, the explicit molecular mechanisms remain unknown. In this study, we employed a multidisciplinary approach integrating network pharmacology, molecular docking, and molecular dynamics simulation to explore the antibacterial mechanism of Aloe vera. We screened the eight major active components of Aloe vera and their targets using multi-source bioinformatics platforms, identifying 55 targets closely associated with the antibacterial effects of Aloe vera. Protein-protein interaction network analysis, revealed potential crucial targets, including cysteine-aspartic acid protease-3 (CASP3) and matrix metalloproteinase-9 (MMP-9). Gene ontology functional enrichment analysis revealed that these targets play critical roles in several essential biological processes, such as "response to xenobiotic stimulus", "positive regulation of gene expression", and "collagen catabolism". The Kyoto Encyclopedia of Genes and Genomes signal pathway analysis indicated that these targets are primarily involved in pathways associated with cancer, lipid metabolism, atherosclerosis, and the AGE/RAGE signaling pathway in diabetes. This finding suggests that Aloe vera may exert its antibacterial effects by regulating the host's immune response and metabolism. Molecular docking and molecular dynamics simulations demonstrated that active ingredients of Aloe vera, such as quercetin and aloe-emodin, can form stable complexes with CASP3 and MMP-9, exhibiting vigorous binding affinity to the active sites of the target. Further antibacterial activity assays and reverse transcription quantitative polymerase chain reaction (RT-qPCR) analysis demonstrated that aloe-emodin exerts antibacterial effects against gram-positive bacteria and inhibits the expression of the MMP-9 gene. This study provided insight into the antibacterial mechanisms of Aloe vera, highlighting MMP-9 as a key target. These findings lay a foundation for further studies on natural antibacterial agents.
Collapse
Affiliation(s)
- Qian Tang
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, 400054, China.
| | - Jingle Chu
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, 400054, China
| | - Peiqi Peng
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, 400054, China
| | - Yinjie Zou
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, 400054, China
| | - Yaguang Wu
- Department of Dermatology, The First Affiliated Hospital of Army Medical University, Chongqing, 400038, China.
| | - Yuanqiang Wang
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, 400054, China.
| |
Collapse
|
13
|
Naveed M, Choudary MAA, Aziz T, Makhdoom SI, Cheema SR, Zahra N, Mohamed RAEH, Al-Asmari F, Al-Joufi FA, Alwethaynani MS, Fallatah D. Using novel approaches to conjugate peptides of Macrotermes bellicosus and Curcuma longa for targeted intervention of irritable bowl diseases caused by tumor necrosis factor superfamily member 15 (TNFSF15). Mol Immunol 2025; 183:286-295. [PMID: 40424787 DOI: 10.1016/j.molimm.2025.05.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2025] [Revised: 05/15/2025] [Accepted: 05/20/2025] [Indexed: 05/29/2025]
Abstract
This study presents an in-silico approach to develop targeted therapies for Irritable Bowel Disease (IBD) by focusing on TNFSF15. Peptides derived from Macrotermes bellicosus and Curcuma longa were selected, conjugated with the 50S ribosomal protein L7/L12 adjuvant, and analyzed for immunogenic potential. Gene expression analysis showed differential TNFSF15 expression in gastrointestinal tissues. Functional enrichment revealed its role in immune regulation and cytokine signaling. Of the 20 peptides identified, 8 showed high antigenicity and 4 were allergenic. Structural modeling and docking predicted stable interactions with TNFSF15 (binding energy: -9.4 kJ/mol), supported by molecular dynamics. Immune simulations indicated robust IgM and IgG responses. These findings suggest that plant and insect derived peptides may offer promising therapeutic candidates for TNFSF15-associated IBD.
Collapse
Affiliation(s)
- Muhammad Naveed
- Department of Biotechnology, Faculty of Science and Technology, University of Central Punjab, Lahore 54590, Pakistan.
| | - Muhammad Azan Ali Choudary
- Department of Biotechnology, Faculty of Science and Technology, University of Central Punjab, Lahore 54590, Pakistan
| | - Tariq Aziz
- Laboratory of Animal Health, Food Hygiene and Quality, University of Ioannina, Arta, Greece; Institute of Molecular Biology and Biotechnology, The University of Lahore, Punjab, Pakistan.
| | - Syeda Izma Makhdoom
- Department of Biotechnology, Faculty of Science and Technology, University of Central Punjab, Lahore 54590, Pakistan
| | - Sana Rehman Cheema
- Department of Biotechnology, Faculty of Science and Technology, University of Central Punjab, Lahore 54590, Pakistan
| | - Nureen Zahra
- Institute of Molecular Biology and Biotechnology, The University of Lahore, Punjab, Pakistan
| | - Rania Ali El Hadi Mohamed
- Department of Biology, College of Science, Princess Nourah bint Abdulrahman university, P.O.Box 84428, Riyadh 11671, Saudi Arabia
| | - Fahad Al-Asmari
- Department of Food and Nutrition Sciences, College of Agricultural and Food Sciences, King Faisal University, Al Ahsa, Saudi Arabia
| | - Fakhria A Al-Joufi
- Department of Pharmacology, College of Pharmacy, Jouf University, Aljouf 72341, Saudi Arabia
| | - Maher S Alwethaynani
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Shaqra University, Alquwayiyah, Riyadh, Saudi Arabia
| | - Deema Fallatah
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| |
Collapse
|
14
|
An J, Song W, Wang Q, Tan B, Fei X, Wang R, Li S, Lu X, Li Y, Xie N. Role of the SPI1/CDKN2A/p53 signaling pathway in cuproptosis of lung adenocarcinoma cells. Oncol Lett 2025; 30:353. [PMID: 40438868 PMCID: PMC12117360 DOI: 10.3892/ol.2025.15099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Accepted: 04/01/2025] [Indexed: 06/01/2025] Open
Abstract
Lung adenocarcinoma (LUAD) is among the most prevalent malignancies worldwide. Cuproptosis, a copper-induced form of cell death, has been identified as a key process in LUAD progression; however, the molecular mechanisms underlying cuproptosis in LUAD and potential therapeutic targets remain unclear. The present study utilized The Cancer Genome Atlas database to retrieve mRNA expression profiles and clinical information of LUAD, identifying 10 candidate genes from differentially expressed genes associated with cuproptosis. Protein-protein interaction analysis indicated that CDK inhibitor 2A (CDKN2A), an upregulated gene in LUAD, may function as a hub gene. Furthermore, multiple online databases were used to analyze Spi-1 proto-oncogene (SPI1), a transcription factor upstream of CDKN2A, which was downregulated in LUAD cuproptosis. The LinkedOmics database identified the p53-mediated cuproptosis-related pathway regulated by CDKN2A. Gene expression patterns were examined through Gene Expression Profiling Interactive Analysis, the Human Protein Atlas and reverse transcription-quantitative polymerase chain reaction. Prognostic significance was assessed using the UALCAN and Kaplan-Meier plotter databases. In vitro experiments demonstrated that CDKN2A knockdown and SPI1 overexpression inhibited the proliferation and migration of the H1975 cell line. After copper-induced cuproptosis in H1975 cells, SPI1 expression was upregulated, whereas CDKN2A expression was downregulated. When H1975 cells were pretreated with tetrathiomolybdate, the upregulation of SPI1 was inhibited and the downregulation of CDKN2A was also suppressed. Cell Counting Kit-8 assays indicated that SPI1 overexpression and CDKN2A knockdown facilitated elesclomol-CuCl2-induced cuproptosis. Western blot analysis revealed an inverse association between SPI1 overexpression and CDKN2A/p53 levels. In conclusion, the present study demonstrated the role of the SPI1/CDKN2A/p53 axis in LUAD cuproptosis, providing insights into potential therapeutic targets and contributing to clinical research on treatment strategies.
Collapse
Affiliation(s)
- Jiayue An
- Department of Clinical Laboratory, The Second Medical College of Binzhou Medical University, Yantai, Shandong 264100, P.R. China
- Department of Biochemistry and Molecular Biology, Binzhou Medical University, Yantai, Shandong 264003, P.R. China
- Department of Thoracic Surgery, Yantaishan Hospital Affiliated to Binzhou Medical University, Yantai, Shandong 264003, P.R. China
| | - Wei Song
- Department of Biochemistry and Molecular Biology, Binzhou Medical University, Yantai, Shandong 264003, P.R. China
| | - Qin Wang
- Department of Biochemistry and Molecular Biology, Binzhou Medical University, Yantai, Shandong 264003, P.R. China
| | - Boyu Tan
- Department of Biochemistry and Molecular Biology, Binzhou Medical University, Yantai, Shandong 264003, P.R. China
| | - Xuan Fei
- Department of Biochemistry and Molecular Biology, Binzhou Medical University, Yantai, Shandong 264003, P.R. China
| | - Ruoxi Wang
- Department of Biochemistry and Molecular Biology, Binzhou Medical University, Yantai, Shandong 264003, P.R. China
| | - Siyan Li
- Department of Biochemistry and Molecular Biology, Binzhou Medical University, Yantai, Shandong 264003, P.R. China
| | - Xiyu Lu
- Department of Biochemistry and Molecular Biology, Binzhou Medical University, Yantai, Shandong 264003, P.R. China
| | - Youjie Li
- Department of Biochemistry and Molecular Biology, Binzhou Medical University, Yantai, Shandong 264003, P.R. China
| | - Ning Xie
- Department of Thoracic Surgery, Yantaishan Hospital Affiliated to Binzhou Medical University, Yantai, Shandong 264003, P.R. China
| |
Collapse
|
15
|
Yang G, Tan W, Yan L, Lao Q, Zheng W, Ding H, Yu J, Liu Y, Zou L, Guo M, Yu L, Zhou X, Li W, Yang L. Phillyrin for sepsis-related acute lung injury: A potential strategy suppressing GSK-3β. Mol Immunol 2025; 183:115-136. [PMID: 40359720 DOI: 10.1016/j.molimm.2025.04.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Revised: 04/18/2025] [Accepted: 04/27/2025] [Indexed: 05/15/2025]
Abstract
The efficacy of clinical drugs for acute lung injury/acute respiratory distress syndrome (ALI/ARDS) remains suboptimal. Phillyrin (PHN), a compound derived from Forsythia, is believed to alleviate sepsis-related ALI/ARDS; however, its mechanisms are not fully elucidated. In this study, we screened 8331 target genes associated with ALI/ARDS from public databases and identified six hub genes relevant to PHN treatment: AKT1, GSK-3β, PPP2CA, PPP2CB, PPP2R1A, and AR. Receiver operating characteristic analysis and single-cell sequencing analysis revealed the expression of AKT1, GSK-3β, PPP2CA, PPP2CB, and PPP2R1A were markedly elevated. Molecular docking and dynamics simulations indicated that PHN forms a structurally stable complex with glycogen synthase kinase-3β (GSK-3β). Mendelian randomization analyses suggested that PHN, as a potent GSK-3β inhibitor, may promote M2 macrophage polarization and reduce neutrophil recruitment. We validated these findings through in vivo and in vitro experiments, demonstrating that PHN lowers iNOS levels and raises MMR levels by downregulating GSK-3β mRNA expression and protein activity during lipopolysaccharide (LPS)-induced macrophage inflammation. Additionally, PHN inhibited GSK-3β mRNA expression and protein activity, reducing NF-κB-p65 nuclear translocation in LPS-induced zebrafish inflammation and mice ALI. This inhibition decreased levels of TNF-α and IL-6, increased IL-10 levels, promoted M2 macrophage polarization, suppressed neutrophil recruitment, and ultimately ameliorated ALI/ARDS. In conclusion, our results indicate that PHN effectively alleviates LPS-induced ALI/ARDS by suppressing GSK-3β signaling.
Collapse
Affiliation(s)
- Guangli Yang
- Department of Central Laboratory, Binhaiwan Central Hospital of Dongguan, Dongguan 523900, China
| | - Weifu Tan
- Dongguan Municipal Key Laboratory for Precise Prevention and Treatment of Neonatal Severe Illnesses, Binhaiwan Central Hospital of Dongguan, Dongguan 523900, China
| | - Lijun Yan
- Third Level Research Laboratory of State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Qiaocong Lao
- Central Laboratory, The Tenth Affiliated Hospital, Southern Medical University, Dongguan People's Hospital, Dongguan 523059, China
| | - Wujuan Zheng
- Department of Pharmacy, Binhaiwan Central Hospital of Dongguan, Dongguan 523900, China
| | - Hongyan Ding
- Omega-3 Research and Conversion Center, Dongguan Innovation Research Institute, Guangdong Medical University, Dongguan 523900, China
| | - Jingtao Yu
- Third Level Research Laboratory of State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Yong Liu
- Guangdong Provincial Key Laboratory of Natural Drugs Research and Development, School of Pharmacy, Guangdong Medical University, Dongguan 523808, China
| | - Liyi Zou
- Guangdong Provincial Key Laboratory of Natural Drugs Research and Development, School of Pharmacy, Guangdong Medical University, Dongguan 523808, China
| | - Maorun Guo
- Pingyi Health Center of Pingyi County, Linyi 273300, China
| | - Linzhong Yu
- Third Level Research Laboratory of State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Xiangjun Zhou
- Guangdong Provincial Key Laboratory of Natural Drugs Research and Development, School of Pharmacy, Guangdong Medical University, Dongguan 523808, China.
| | - Wei Li
- Dongguan Municipal Key Laboratory for Precise Prevention and Treatment of Neonatal Severe Illnesses, Binhaiwan Central Hospital of Dongguan, Dongguan 523900, China.
| | - Liling Yang
- Dongguan Municipal Key Laboratory for Precise Prevention and Treatment of Neonatal Severe Illnesses, Binhaiwan Central Hospital of Dongguan, Dongguan 523900, China; Third Level Research Laboratory of State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China; Department of Pharmacy, Binhaiwan Central Hospital of Dongguan, Dongguan 523900, China.
| |
Collapse
|
16
|
Liang H, Liu Y, Zhang C, Qin Y. Potential Shared Mitochondrial-Related Gene Signatures and Molecular Mechanisms Between Polycystic Ovary Syndrome (PCOS) and Major Depressive Disorder (MDD): Evidence from Transcriptome Data and Machine Learning. Mol Biotechnol 2025; 67:2628-2643. [PMID: 39048886 DOI: 10.1007/s12033-024-01225-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 06/24/2024] [Indexed: 07/27/2024]
Abstract
Polycystic ovary syndrome (PCOS) is strongly associated with major depressive disorder (MDD), but the shared pathophysiological mechanisms between them are ambiguous, and the aim of this study was to explore the shared genetic features and associated pathways between these two disorders. MDD-related genes and mitochondrial function genes were downloaded from the GeneCards database. Weighted gene co-expression network analysis of Merge Cohort (GSE80432 and GSE34526) was performed to identify PCOS-related genes. Overlaps between PCOS-related genes, MDD-related genes, and mitochondrial function genes were defined as mitochondrial function-related shared genes. Functional enrichment analysis and protein-protein interaction (PPI) network analysis were performed on the shared genes. Functional genes were then identified using Last Absolute Shrinkage and Selection Operator Regression (LASSO), and a support vector machine (SVM-RFE) was constructed to measure the accuracy of the calculations. Finally, the results were tested using the whole blood datasets GSE54250 (for PCOS) and GSE98793 (for MDD) as external validation sets. A total of 498 PCOS-related genes, 5909 MDD-related genes, and 7232 mitochondrial function genes were acquired, and totally, 40 shared genes were obtained from the overlap of the above three. The shared mitochondrial function genes were enriched for biological processes mainly involving cholesterol biosynthetic process, lipid metabolic process, triglyceride biosynthetic process, response to drug phosphatidic acid biosynthetic process, and endoplasmic reticulum membrane. Based on LASSO regression and SVM-RFE model, NPAS2 and NTS were identified as characteristic genes shared by two disorders. According to two external validation sets for PCOS and MDD, NPAS2 was finally identified as a key shared gene. Our analysis identified a mitochondrial functional gene-NPAS2-as the most critical candidate for linking PCOS and MDD. The present findings may provide new insights into the diagnosis and treatment of PCOS and MDD comorbidities.
Collapse
Affiliation(s)
- Huan Liang
- Department of Obstetrics and Gynecology, The Central Hospital of Enshi Tujia and Miao Autonomous Prefectrue, Enshi, Hubei, China.
| | - Yi Liu
- Department of Obstetrics and Gynecology, The Central Hospital of Enshi Tujia and Miao Autonomous Prefectrue, Enshi, Hubei, China.
| | - Chunhua Zhang
- Department of Obstetrics and Gynecology, The Central Hospital of Enshi Tujia and Miao Autonomous Prefectrue, Enshi, Hubei, China
| | - Yaoqin Qin
- Reproductive Medicine Centre, The Central Hospital of Enshi Tujia and Miao Autonomous Prefectrue, Enshi, Hubei, China
| |
Collapse
|
17
|
Kong Q, Liu S, He S, Luo Z, Lei R, Wang R, Liu X, Wu J. Celastrol enhanced CD8+T cell immunity in melanoma by targeting SHP2 and upregulating MHC-I. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 142:156731. [PMID: 40286748 DOI: 10.1016/j.phymed.2025.156731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 03/30/2025] [Accepted: 04/02/2025] [Indexed: 04/29/2025]
Abstract
BACKGROUND Celastrol (CEL) has demonstrated promising anti-cancer properties, yet its specific mechanisms against melanoma remain insufficient. This study investigated the CEL's anti-tumor effects and determined its potential mechanisms in the regulation of MHC-I expression in melanoma. In addition, we also tested its efficacy in sensitizing immune checkpoint inhibitors (ICIs) to melanoma. METHODS CEL's anti-tumor activity was evaluated in B16F10 melanoma-bearing C57BL/6 mice across five groups (control, CEL 0.5 mg/kg, CEL 1 mg/kg, CEL 2 mg/kg, and ICIs), the tumor volume, histopathology, and body weight were assessed. Mechanistic insights were obtained through network pharmacology and RNA sequencing in B16F10 cells. Differential gene and pathway analysis were validated using qRT-PCR, Western blotting, and flow cytometry. CD8+T cell activation and cytotoxicity were analyzed in co-culture with CEL-pretreated B16F10 cells using flow cytometry and ELISA. CEL's interaction with potential targets was determined by molecular docking, surface plasmon resonance (SPR), and siRNA. The synergistic effect of CEL combined with ICIs was confirmed in B16F10-bearing C57BL/6 mice, and tumor-infiltrating T cells were assessed by flow cytometry across four groups (control, CEL, ICIs, CEL+ICIs). RESULTS CEL exhibited a significant anti-tumor effect in B16F10 melanoma-bearing mice. Mechanistically, CEL-pretreated B16F10 cells notably enhanced CD8+T cell activation and promoted IFNγ and TNFα secretion, leading to B16F10 cell death. CEL upregulated MHC-I expression through activation of the JAK/STAT1 pathway in B16F10 cells. The binding assay revealed that CEL interacted with SHP2, with an affinity of 37.93 μM. When SHP2 was silenced in B16F10 cells by siRNA, CEL failed to induce MHC-I upregulation. Moreover, CEL combined with ICIs produced superior antitumor efficacy compared to ICIs alone, which was accompanied by increased CD8+T cell infiltration in melanoma. CONCLUSION CEL enhanced CD8+T cell immunity by upregulating MHC-I expression in melanoma cells, these effects were at least partially through targeting SHP2 and activating JAK/STAT1 pathway. CEL might be a novel sensitizer for ICIs in melanoma.
Collapse
Affiliation(s)
- Qing Kong
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Suqing Liu
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Shan He
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Zhuyu Luo
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Rui Lei
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Ruilong Wang
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Xiao Liu
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.
| | - Jinfeng Wu
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China; The Second Affiliated Hospital, Yunnan University of Chinese Medicine, Yunan, China.
| |
Collapse
|
18
|
Qian Y, Jia Y. Identification of Key Efferocytosis-Related Genes and Mechanisms in Diabetic Retinopathy. Mol Biotechnol 2025; 67:2785-2797. [PMID: 39085562 DOI: 10.1007/s12033-024-01239-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 07/09/2024] [Indexed: 08/02/2024]
Abstract
This study aimed to explore the key efferocytosis-related genes in diabetic retinopathy (DR) and their regulatory mechanisms. Public DR-related gene expression datasets, GSE160306 (training) and GSE60436 (validation), were downloaded. Differentially expressed efferocytosis-related genes (DEERGs) were analyzed using differential expression analysis and weighted gene co-expression network analysis. Functional enrichment analysis was conducted. Moreover, efferocytosis-related signature genes were identified using machine learning analysis, and their expression levels and diagnostic value were analyzed. Furthermore, nomograms were constructed; immune cell infiltration was analyzed; and gene set enrichment analysis, transcriptional regulation analysis, and small-molecule drug (SMD) prediction of efferocytosis-related signature genes were performed. In total, 36 DEERGs were identified in DR, and were markedly enriched in multiple functions, such as visual system development. Through further machine learning analysis, two efferocytosis-related signature genes, Ferritin Light Chain (FTL) and Fc Gamma Binding Protein (FCGBP), were identified, and were found to be upregulated in DR samples and showed high diagnostic performance for DR. A nomogram constructed using FTL and FCGBP accurately predicted the risk of DR. Moreover, the level of infiltration of immature B cells was positively correlated with FTL and FCGBP expression levels. Multiple transcription factors (TFs), such as CCCTC-Binding Factor (CTCF) and KLF Transcription Factor 9 (KLF9), were found to interact with both FTL and FCGBP. In addition, FTL can be targeted by miRNAs, such as miR-22-3p, and FCGBP can be targeted by miR-7973. In addition, both FTL and FCGBP can be targeted by SMDs, such as bisphenol A. Key efferocytosis-related genes, such as FTL and FCGBP, may promote DR development. Detecting or targeting FTL and FCGBP may aid in the prevention, diagnosis, and treatment of DR.
Collapse
Affiliation(s)
- Yu Qian
- Department of Ophthalmology, The First People's Hospital of Zhaoqing, 9 Donggang East Road, Zhaoqing, 526060, Guangdong, China.
| | - Yanwen Jia
- Department of Ophthalmology, Changzhou Second People's Hospital Affiliated Nanjing Medical University, Changzhou, 213004, Jiangsu, China
| |
Collapse
|
19
|
Maxwell CB, Stylianou P, Marshall H, Hall AJ, Quinn PA, Ng LL, Jones DJ, Bradding P, Roach KM. TGFβ1 generates a pro-fibrotic proteome in human lung parenchyma that is sensitive to pharmacological intervention. Eur J Pharmacol 2025; 997:177461. [PMID: 40049575 DOI: 10.1016/j.ejphar.2025.177461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 03/03/2025] [Accepted: 03/04/2025] [Indexed: 05/02/2025]
Abstract
INTRODUCTION Novel treatments for idiopathic pulmonary fibrosis (IPF) are needed urgently. A better understanding of the molecular pathways activated by TGFβ1 in human lung tissue may facilitate the development of more effective anti-fibrotic medications. This study utilized proteomic analysis to test the hypothesis that TGFβ1 induces pro-fibrotic effects on human lung parenchyma proteome, and to evaluate the viability of this model for testing novel therapeutic targets. METHODS Non-fibrotic human lung parenchymal tissue from 11 patients was cultured for 7 days in serum-free (SF) media supplemented with TGFβ1 (10 ng/mL) or vehicle control, and the putative antifibrotic KCa3.1 ion channel blocker senicapoc or vehicle control. The tissue was homogenised, digested for bottom-up proteomics, and analysed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Principal component analysis, differential expression analysis, pathway analysis, and drug repurposing analysis were performed. RESULTS TGFβ1 stimulation for 7 days induced a strong fibrotic protein response relevant to IPF pathology. A total of 2391 proteins were quantified, 306 upregulated and 285 downregulated (FDR-adjusted p-value<0.05). Of these, 118 were upregulated and 28 downregulated at log2(FC) > 0.58. These changes were attenuated by senicapoc (100 nM). Drug repurposing analysis identified 265 drugs predicted to inhibit the effects of TGFβ1 in this model. These included clotrimazole, a KCa3.1 blocker, and nintedanib, a drug licenced for the treatment of IPF, providing validation of this approach. CONCLUSION A pro-fibrotic proteome is induced in human lung parenchyma exposed to TGFβ1, sensitive to pharmacological intervention. This approach has the potential to enhance therapeutic drug screening for IPF treatment.
Collapse
Affiliation(s)
- Colleen B Maxwell
- Department of Cardiovascular Sciences and NIHR Leicester Cardiovascular BRC, Glenfield Hospital, University of Leicester, Leicester, UK; Leicester van Geest MultiOMICS Facility, Hodgkin Building, University of Leicester, Leicester, UK.
| | - Panayiota Stylianou
- Department of Respiratory Sciences, Leicester Respiratory NIHR BRC, Glenfield Hospital, University of Leicester, Leicester, UK
| | - Hilary Marshall
- Department of Respiratory Sciences, Leicester Respiratory NIHR BRC, Glenfield Hospital, University of Leicester, Leicester, UK
| | - Alfie J Hall
- Department of Respiratory Sciences, Leicester Respiratory NIHR BRC, Glenfield Hospital, University of Leicester, Leicester, UK
| | - Paulene A Quinn
- Department of Cardiovascular Sciences and NIHR Leicester Cardiovascular BRC, Glenfield Hospital, University of Leicester, Leicester, UK; Leicester van Geest MultiOMICS Facility, Hodgkin Building, University of Leicester, Leicester, UK
| | - Leong L Ng
- Department of Cardiovascular Sciences and NIHR Leicester Cardiovascular BRC, Glenfield Hospital, University of Leicester, Leicester, UK; Leicester van Geest MultiOMICS Facility, Hodgkin Building, University of Leicester, Leicester, UK
| | - Donald Jl Jones
- Leicester van Geest MultiOMICS Facility, Hodgkin Building, University of Leicester, Leicester, UK; Leicester Cancer Research Centre, University of Leicester, Leicester, UK
| | - Peter Bradding
- Department of Respiratory Sciences, Leicester Respiratory NIHR BRC, Glenfield Hospital, University of Leicester, Leicester, UK
| | - Katy M Roach
- Department of Respiratory Sciences, Leicester Respiratory NIHR BRC, Glenfield Hospital, University of Leicester, Leicester, UK
| |
Collapse
|
20
|
Yue Y, Li Q, Chen C, Yang J, Song W, Zhou C, Cui Y, Wei Z, He Q, Wang C, Lin H, Li J, Li J, Xi J, Song X, Yang W, Zhang Z, Shu W, Guo L, Wang S. Purine nucleoside phosphorylase dominates Influenza A virus replication and host hyperinflammation through purine salvage. Signal Transduct Target Ther 2025; 10:191. [PMID: 40517177 DOI: 10.1038/s41392-025-02272-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Revised: 04/21/2025] [Accepted: 05/18/2025] [Indexed: 06/16/2025] Open
Abstract
Influenza A virus (IAV) poses a significant threat to human health. The outcome of IAV results from the viral-host interaction, with the underlying molecular mechanisms largely unknown. By integrating the plasma proteomics data of the IAV-infected patients into the viral-inflammation protein-protein interaction (VI-PPI) network created in this study, purine nucleoside phosphorylase (PNP), the critical enzyme in purine salvage, was identified as a potential hub gene that connected the different stages of IAV infection. Extended survival rates and reduced pulmonary inflammatory lesions were observed in alveolar epithelial cell (AEC)-specific PNP conditional knockout mice upon H1N1 infection. Mechanistically, PB1-F2 of IAV was revealed as a novel viral transcriptional factor to bind to the TATA box of PNP promoter, leading to enhanced purine salvage in H1N1-challenged AECs. The activation of PNP-mediated purine salvage was verified in IAV-infected patients and A549 cells. PNP knockdown elicited a purine metabolic shift from augmented salvage pathway to de novo synthesis, constraining both viral infection and pro-inflammatory signaling through APRT-AICAR-AMPK activation. Moreover, durdihydroartemisinin (DHA), predicted by VI-PPI as a novel PNP inhibitor, exerted beneficial effects on the survival and weight gain of H1N1-challenged mice via its direct binding to PNP. To reveal for the first time, we found that PNP, activated by IAV, plays a hub role within H1N1-host interaction, simultaneously modulating viral replication and hyperinflammation through purine salvage. Our study sheds new light on a "two-for-one" strategy by targeting purine salvage in combating IAV-related pathology, suggesting PNP as a potential novel anti-influenza host target.
Collapse
Affiliation(s)
- Yang Yue
- Bioinformatics Center of AMMS, Beijing, China
| | - Qingyu Li
- Bioinformatics Center of AMMS, Beijing, China
| | - Changguo Chen
- The Sixth Medical Center of Chinese, PLA General Hospital, Beijing, China
| | - Juntao Yang
- State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Weian Song
- The Sixth Medical Center of Chinese, PLA General Hospital, Beijing, China
| | | | - Yuke Cui
- Bioinformatics Center of AMMS, Beijing, China
| | | | - Qi He
- Bioinformatics Center of AMMS, Beijing, China
| | | | - Hongjun Lin
- Bioinformatics Center of AMMS, Beijing, China
| | - Jiangbo Li
- Bioinformatics Center of AMMS, Beijing, China
| | - Jian Li
- Bioinformatics Center of AMMS, Beijing, China
| | - Ji Xi
- Bioinformatics Center of AMMS, Beijing, China
| | - Xiang Song
- Bioinformatics Center of AMMS, Beijing, China
| | - Wen Yang
- Bioinformatics Center of AMMS, Beijing, China
| | - Ze Zhang
- The Sixth Medical Center of Chinese, PLA General Hospital, Beijing, China
| | - Wenjie Shu
- Bioinformatics Center of AMMS, Beijing, China.
| | - Liang Guo
- Bioinformatics Center of AMMS, Beijing, China.
| | | |
Collapse
|
21
|
Luo W, JunxiaWang, Wang H, Liu F, Yang T, Wu Z, Guo W. Single cell analysis and bioinformatics reveal pyroptosis mechanisms in hepatocellular carcinoma. Discov Oncol 2025; 16:1096. [PMID: 40516009 DOI: 10.1007/s12672-025-02907-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Accepted: 06/04/2025] [Indexed: 06/16/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the third leading cause of cancer related death, and its molecular mechanisms have not been fully elucidated. This study aims to elucidate the molecular mechanisms linking pyroptosis and immune microenvironment changes in HCC, with a focus on macrophage polarization and inflammatory responses. METHODS Selected gene expression profiles from the Gene Expression Omnibus database, established protein-protein interaction (PPI) networks, and performed functional enrichment analysis using databases such as the Kyoto Encyclopedia of Genes and Genomes (KEGG). The expression of relevant hub genes was verified by immunohistochemistry, real-time quantitative PCR, and Western Blot based on clinical tissues. Single-cell identification of HCC cell types and malignant cells, trajectory analysis, and intercellular signal communication further analyzed the molecular mechanisms between immune cells and liver cells. Bioinformatics combined with single-cell analysis to elucidate the immune pyroptosis molecular mechanism that underlay the development of HCC. RESULTS Molecular biology has identified six pyroptosis hub genes in HCC. The key hub genes of immune pyroptosis were validated through immunohistochemistry and in vitro experiments. Enrichment analysis shows that intersecting genes are enriched in immune responses, chemokine mediated signaling pathways, and inflammatory responses. InferCNV and copyKAT accurately predict that malignant cells distribute in HCC tissues, and their main malignant cells may be hepatocytes, endothelium and epithelial cells. Cell trajectory analysis found that monocyte, macrophage polarization could play a first role in HCC. The cellular clustering of single cells revealed the infiltration of immune cells, especially the polarization of macrophages, which plays an important role. Immunohistochemistry suggests that hub genes such as HMGB1, CYCS, GSDMD, IL-1β, NLRP3, and IL18 are the link between macrophage polarization and pyroptosis during HCC development. CONCLUSIONS In summary, the main molecular mechanisms underlying the pathogenesis of HCC are related to immune cell infiltration, particularly macrophage infiltration polarization that promotes the secretion of inflammatory factors leading to hepatocyte pyroptosis. These findings provide novel insights into the macrophage-driven pyroptosis pathways in HCC, potentially paving the way for new immunotherapeutic strategies.
Collapse
Affiliation(s)
- Wei Luo
- Department of General Surgery, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China
| | - JunxiaWang
- Department of Pediatrics, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China
| | - Hongfei Wang
- Department of Pathology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China
| | - Fei Liu
- Department of General Surgery, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China
| | - Taiwei Yang
- Department of General Surgery, Xuyong County Second Name Hospital, Luzhou, China
| | - Zhongjun Wu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
| | - Wubin Guo
- Department of General Surgery, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China.
| |
Collapse
|
22
|
Yuan M, Wang K, Pang B, Lu H, Jiang S, Song K, He Z, Deng J, Yang J, Wang L. Preliminary investigation of the epigenetic regulation of KMT2D via H3K4me1/H3K27ac in oral squamous cell carcinoma. Cell Mol Life Sci 2025; 82:237. [PMID: 40515851 DOI: 10.1007/s00018-025-05765-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Revised: 01/07/2025] [Accepted: 05/06/2025] [Indexed: 06/16/2025]
Affiliation(s)
- Mujie Yuan
- Department of Oral & Maxillofacial Surgery, the Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266000, Shandong Province, China
- School of Stomatology, Qingdao University, Qingdao, 266000, Shandong Province, China
| | - Kexin Wang
- Department of Oral & Maxillofacial Surgery, the Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266000, Shandong Province, China
- School of Stomatology, Qingdao University, Qingdao, 266000, Shandong Province, China
| | - Baoxing Pang
- Department of Oral & Maxillofacial Surgery, the Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266000, Shandong Province, China
- School of Stomatology, Qingdao University, Qingdao, 266000, Shandong Province, China
| | - Haijun Lu
- Department of Radiation Oncology, the Affiliated Hospital of Qingdao University, Qingdao, Qingdao, 266000, Shandong Province, China
| | - Shuai Jiang
- Department of Oral & Maxillofacial Surgery, the Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266000, Shandong Province, China
| | - Kai Song
- Department of Oral & Maxillofacial Surgery, the Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266000, Shandong Province, China
- School of Stomatology, Qingdao University, Qingdao, 266000, Shandong Province, China
| | - Zongxuan He
- Department of Oral & Maxillofacial Surgery, the Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266000, Shandong Province, China
- School of Stomatology, Qingdao University, Qingdao, 266000, Shandong Province, China
| | - Jing Deng
- School of Stomatology, Qingdao University, Qingdao, 266000, Shandong Province, China.
| | - Jianjun Yang
- Department of Oral & Maxillofacial Surgery, the Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266000, Shandong Province, China.
- School of Stomatology, Qingdao University, Qingdao, 266000, Shandong Province, China.
| | - Lin Wang
- Department of Oral & Maxillofacial Surgery, the Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266000, Shandong Province, China.
- School of Stomatology, Qingdao University, Qingdao, 266000, Shandong Province, China.
| |
Collapse
|
23
|
Baluapuri A, Zhao NC, Marina RJ, Huang KL, Kuzkina A, Amodeo ME, Stein CB, Ahn LY, Farr JS, Schaffer AE, Khurana V, Wagner EJ, Adelman K. Integrator loss leads to dsRNA formation that triggers the integrated stress response. Cell 2025; 188:3184-3201.e21. [PMID: 40233738 DOI: 10.1016/j.cell.2025.03.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 12/16/2024] [Accepted: 03/13/2025] [Indexed: 04/17/2025]
Abstract
Integrator (INT) is a metazoan-specific complex that targets promoter-proximally paused RNA polymerase II (RNAPII) for termination, preventing immature RNAPII from entering gene bodies and functionally attenuating transcription of stress-responsive genes. Mutations in INT subunits are associated with many human diseases, including cancer, ciliopathies, and neurodevelopmental disorders, but how reduced INT activity contributes to disease is unknown. Here, we demonstrate that the loss of INT-mediated termination in human cells triggers the integrated stress response (ISR). INT depletion causes upregulation of short genes such as the ISR transcription factor activating transcription factor 3 (ATF3). Further, immature RNAPII that escapes into genes upon INT depletion is prone to premature termination, generating incomplete pre-mRNAs with retained introns. Retroelements within retained introns form double-stranded RNA (dsRNA) that is recognized by protein kinase R (PKR), which drives ATF4 activation and prolonged ISR. Critically, patient cells with INT mutations exhibit dsRNA accumulation and ISR activation, thereby implicating chronic ISR in diseases caused by INT deficiency.
Collapse
Affiliation(s)
- Apoorva Baluapuri
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; The Eli and Edythe L. Broad Institute, Cambridge, MA 02142, USA
| | - Nicole ChenCheng Zhao
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
| | - Ryan J Marina
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center at Harvard, Boston, MA 02115, USA
| | - Kai-Lieh Huang
- Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
| | - Anastasia Kuzkina
- APDA Center for Advanced Research, Division of Motor Disorders and Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Maria E Amodeo
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
| | - Chad B Stein
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
| | - Lucie Y Ahn
- Department of Genetics and Genome Sciences and Center for RNA Science and Therapeutics, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Jordan S Farr
- Department of Genetics and Genome Sciences and Center for RNA Science and Therapeutics, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Ashleigh E Schaffer
- Department of Genetics and Genome Sciences and Center for RNA Science and Therapeutics, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Vikram Khurana
- The Eli and Edythe L. Broad Institute, Cambridge, MA 02142, USA; APDA Center for Advanced Research, Division of Motor Disorders and Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Eric J Wagner
- Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
| | - Karen Adelman
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; The Eli and Edythe L. Broad Institute, Cambridge, MA 02142, USA; Ludwig Center at Harvard, Boston, MA 02115, USA.
| |
Collapse
|
24
|
Chen Y, Deng Q, Wang C, Liang C, Shi Y, Liu X, Deng C, Li J, Zhang H, Hua Q. Investigation of cognitive enhancements and mechanisms of kinsenoside in APP/PS1 mice through network pharmacology, in vivo experiments, and machine learning. Life Sci 2025; 378:123810. [PMID: 40513940 DOI: 10.1016/j.lfs.2025.123810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 06/10/2025] [Accepted: 06/10/2025] [Indexed: 06/16/2025]
Abstract
AIMS To investigate the therapeutic effects of kinsenoside on cognitive dysfunction in APP/PS1 transgenic mice and to explore its potential targets. MATERIALS AND METHODS Network pharmacology was employed to identify targets of kinsenoside in Alzheimer's disease (AD). The Morris water maze test was conducted to assess the therapeutic effects of kinsenoside on cognitive dysfunction in APP/PS1 transgenic mice, and immunofluorescence was used to evaluate the impact of kinsenoside on amyloid-beta (Aβ) pathology and brain lymphatic structure and function. The Raybiotech GSM-CAA-4000 protein chip was used to detect changes in inflammatory factors. Graph convolutional network (GCN) analysis was applied to analyze and identify core targets from the protein chip results, which were then intersected with the network pharmacology findings, followed by molecular docking and molecular dynamics simulations. RESULTS Network pharmacology analysis indicated that kinsenoside inhibits inflammation and oxidative stress signaling pathways involved in AD. The maximum neighborhood connectivity (MNC) algorithm identified HSP90AA1, HSP90AB1, PIK3CA, STAT3, IL6, and IFNγ as potential targets. In vivo mouse experiments demonstrated that kinsenoside has the ability to reduce Aβ plaque deposition and expand meningeal lymphatic vessels(mLVs), improving the glymphatic system drainage, which ultimately leads to improved cognitive function. This beneficial effect may be related to the inhibition of IFNγ by kinsenoside. CONCLUSION Based on preclinical data, kinsenoside shows promising potential in the treatment of AD.
Collapse
Affiliation(s)
- Yufeng Chen
- School of Life Sciences & School of Traditional Chinese Medicine & School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese medicine, Beijing 100029, China
| | - Qiqi Deng
- School of Life Sciences & School of Traditional Chinese Medicine & School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese medicine, Beijing 100029, China
| | - Chunxiang Wang
- School of Life Sciences & School of Traditional Chinese Medicine & School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese medicine, Beijing 100029, China
| | - Chengbang Liang
- School of Life Sciences & School of Traditional Chinese Medicine & School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese medicine, Beijing 100029, China
| | - Yu Shi
- School of Life Sciences & School of Traditional Chinese Medicine & School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese medicine, Beijing 100029, China
| | - Xiaoge Liu
- School of Life Sciences & School of Traditional Chinese Medicine & School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese medicine, Beijing 100029, China; School of Acupuncture-Moxibustion and Tuina, Changchun University of Chinese Medicine, Changchun 130117, China
| | - Chengeng Deng
- School of Life Sciences & School of Traditional Chinese Medicine & School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese medicine, Beijing 100029, China
| | - Jianyu Li
- Medical school, Wuhan University of Science and Technology, Wuhan 430000, China.
| | - Hao Zhang
- Medical school, Wuhan University of Science and Technology, Wuhan 430000, China.
| | - Qian Hua
- School of Life Sciences & School of Traditional Chinese Medicine & School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese medicine, Beijing 100029, China.
| |
Collapse
|
25
|
Wu K, Yang N, Ren J, Liu S, Wang K, Dai S, Lu Y, An Y, Tian F, Gao Z, Yang Z, Zhang Y, Yu W, Li N. Cytosolic WPRa4 and Plastoskeletal PMI4 Proteins Mediate Touch Response in a Model Organism Arabidopsis. Mol Cell Proteomics 2025:101015. [PMID: 40513778 DOI: 10.1016/j.mcpro.2025.101015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 06/08/2025] [Accepted: 06/10/2025] [Indexed: 06/16/2025] Open
Abstract
To elucidate the early signaling components involved in thigmomorphogenesis in Arabidopsis thaliana, we combined microscopy and proximity-labeling (PL)-based quantitative biotinylproteomics to characterize the touch-responsive putative cytoskeleton-interacting protein WPRa4. Our findings revealed that WPRa4 localizes near plastids and interacts with cytosolic Plastid Movement-Impaired (PMI) proteins and a plastidic translocon component, suggesting a cytoskeleton-plastid network in mechanosensing. Bioinformatic analysis of PL and cross-linking mass spectrometry (XL-MS) data identified PMI4 as a key mediator, with pmi4 mutants lacking touch-induced bolting delay, rosette size reduction, and Ca2+ oscillations. Transcriptomics further showed that PMI4 regulates touch-responsive and jasmonic acid (JA)-associated genes, such as LOX2. We propose a molecular model where interconnected Cytoskeleton-Plastoskeleton Continuum (CPC) proteins act as early mechanosensors, integrating the touch responses of plant aerial organs with calcium signaling and transcriptional reprogramming in Arabidopsis.
Collapse
Affiliation(s)
- Kebin Wu
- Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong SAR, China
| | - Nan Yang
- Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong SAR, China
| | - Jia Ren
- Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong SAR, China
| | - Shichang Liu
- Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong SAR, China
| | - Kai Wang
- Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong SAR, China
| | - Shuaijian Dai
- Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong SAR, China
| | - Yinglin Lu
- Institute of Nanfan and Seed Industry, Guangdong Academy of Sciences, Guangzhou, Guangdong, 510316, China
| | - Yuxing An
- Institute of Nanfan and Seed Industry, Guangdong Academy of Sciences, Guangzhou, Guangdong, 510316, China
| | - Fuyun Tian
- Zhongshan Institute of Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Science, Zhongshan, Guangdong 528437, China
| | - Zhaobing Gao
- Zhongshan Institute of Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Science, Zhongshan, Guangdong 528437, China
| | - Zhu Yang
- State Key Laboratory of Environmental and Biological Analysis, Department of Biology, Hong Kong Baptist University, Hong Kong, China
| | - Yage Zhang
- School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, 51805, China
| | - Weichuan Yu
- Department of Electric and Computer Engineering, The Hong Kong University of Science and Technology, Hong Kong SAR, China
| | - Ning Li
- Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong SAR, China; Guoke-Ningbo Life Science and Health Industry Research Institute, Zhejiang Province, China.
| |
Collapse
|
26
|
Basso MF, Iovieno P, Capuana M, Contaldi F, Ieri F, Menicucci F, Celso FL, Barone G, Martinelli F. Identification and expression of the AREB/ABF/ABI5 subfamily genes in chickpea and lentil reveal major players involved in ABA-mediated defense response to drought stress. PLANTA 2025; 262:22. [PMID: 40493071 DOI: 10.1007/s00425-025-04740-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Accepted: 05/29/2025] [Indexed: 06/12/2025]
Abstract
MAIN CONCLUSION This study identified and evaluated the expression of the AREB/ABF/ABI5 subfamily genes in chickpea and lentil, and revealed the major players involved in defense response to PEG-induced drought stress. Abscisic acid (ABA)-responsive element-binding protein/ABRE-binding factor/ABA-INSENSITIVE 5 (AREB/ABF/ABI5) subfamily proteins are major players in the ABA-mediated signaling pathway triggered by multiple stresses. AREB/ABF/ABI5 subfamily proteins belong to the basic-leucine zipper transcription factors that regulate the expression of several downstream defense genes to abiotic and biotic stresses. This protein set is highly targeted when trying to understand plant defense against abiotic stress or to improve plant tolerance to drought, cold, and salinity stresses. However, there is still very little information available about the genes of the AREB/ABF/ABI5 subfamily in chickpea and lentil. Herein, 8 chickpea and 9 lentil genes of the AREB/ABF/ABI5 subfamily were identified based on sequence analysis, and their expression levels were tested in a polyethylene glycol-induced drought experiment (20% PEG in Hoagland solution) using real-time RT-PCR and metadata analysis. Sequence analysis showed that members of this subfamily are highly conserved among themselves and with their orthologous genes in other closely related plant species. Overall, sequence data suggested that these genes may possess close or overlapping biological roles in regulating the transcription of abiotic stress-related defense genes. The meta-analysis from RNA-Seq datasets of unstressed plants showed that some members of this gene subfamily have a tissue-specific expression in both chickpea and lentil. Drought-contrasting chickpea and lentil cultivars showed that most AREB/ABF/ABI5 genes are modulated by PEG-induced drought. Furthermore, AREB/ABF/ABI5 genes had also a tendency for higher expression as cultivar tolerance increases. Therefore, this study identified the AREB/ABF/ABI5 subfamily genes in chickpea and lentil, and provides a comprehensive characterization of these members to support further focused research.
Collapse
Affiliation(s)
- Marcos Fernando Basso
- Department of Biology, University of Florence, Sesto Fiorentino, Via Madonna del Piano, 50019, Florence, Sesto Fiorentino, Italy
| | - Paolo Iovieno
- Institute of Biosciences and BioResources (IBBR), National Research Council of Italy (CNR), Via Madonna del Piano 10, 50019, Florence, Sesto Fiorentino, Italy
| | - Maurizio Capuana
- Institute of Biosciences and BioResources (IBBR), National Research Council of Italy (CNR), Via Madonna del Piano 10, 50019, Florence, Sesto Fiorentino, Italy
| | - Felice Contaldi
- Department of Biology, University of Florence, Sesto Fiorentino, Via Madonna del Piano, 50019, Florence, Sesto Fiorentino, Italy
| | - Francesca Ieri
- Institute of Biosciences and BioResources (IBBR), National Research Council of Italy (CNR), Via Madonna del Piano 10, 50019, Florence, Sesto Fiorentino, Italy
| | - Felicia Menicucci
- Institute for Sustainable Plant Protection (IPSP), National Research Council of Italy (CNR), Via Madonna del Piano 10, 50019, Florence, Sesto Fiorentino, Italy
| | - Fabrizio Lo Celso
- Department of Physics and Chemical, University of Palermo, Viale Delle Scienze, Edificio 17, 90128, Palermo, Italy
| | - Giampaolo Barone
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Viale Delle Scienze, Edificio 17, 90128, Palermo, Italy
| | - Federico Martinelli
- Department of Biology, University of Florence, Sesto Fiorentino, Via Madonna del Piano, 50019, Florence, Sesto Fiorentino, Italy.
| |
Collapse
|
27
|
Wang XR, Chen AJ, Hou CC, Wang YY, Guo J, Li MY. Unveiling the immunopharmacological mechanisms of Danggui Yinzi (DGYZ) in treating chronic urticaria: insights from network pharmacology and experimental validation. Chin Med 2025; 20:81. [PMID: 40490797 DOI: 10.1186/s13020-025-01137-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2025] [Accepted: 05/20/2025] [Indexed: 06/11/2025] Open
Abstract
BACKGROUND Chronic urticaria (CU), a prevalent and often debilitating allergic skin disorder, is primarily triggered by mast cell degranulation. Danggui Yinzi (DGYZ), a traditional Chinese medicine formula, has been employed to treat pruritic conditions. However, the molecular mechanisms underlying its effects in CU remain unclear. This study aimed to investigate the immunopharmacological mechanisms of DGYZ in CU, hypothesizing that it modulates immune responses through its bioactive components, which is critical for the development of novel therapeutic agents. METHODS Ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS) was used to identify the active compounds in DGYZ. In vivo, BALB/c mouse models of DNP-IgE/DNFB-induced CU were established and grouped into Normal Control (NC), Model, various-dose DGYZ, and Loratadine groups. Post-treatment, immunopharmacological parameters were assessed, and skin tissue was collected for histopathological analysis, mast cell quantification, and immunohistochemistry to evaluate the impact on immune cells and molecules. Serum levels of inflammatory cytokines (TNF-α, IL-6) were quantified using ELISA kits. In vitro, the human mast cell line LAD2 was pretreated with key active components of DGYZ (Quercetin and Paeoniflorin) at different concentrations before mast cell degranulation was induced. Degranulation markers (β-HEX, HIS) and the expression of proteins in immune-related signaling pathways (PI3K-Akt, TLR4) were then measured. RESULTS A total of 38 active components were identified in DGYZ. In vivo, DGYZ inhibited mast cell degranulation, blue spot reactions, and skin damage in mice. It also decreased the levels of inflammatory cytokines (TNF-α, IL-6) and suppressed the activation of associated signaling pathways. In vitro, both Quercetin and Paeoniflorin reduced mast cell degranulation and the activation of TLR4 and PI3K-Akt pathways. CONCLUSION This study, employing UPLC-Q-TOF-MS and both in vivo and in vitro experiments, provides a comprehensive analysis of the mechanism of DGYZ in CU. The findings indicate that DGYZ exerts therapeutic effects in CU by modulating immune responses. This research lays the foundation for a deeper understanding of its immunopharmacological mechanisms, potentially aiding the development of novel drugs and therapeutic strategies for CU management.
Collapse
Affiliation(s)
- Xu-Rui Wang
- Department of Chinese Medicine Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - An-Jing Chen
- Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Chang-Cheng Hou
- Jiangsu Province Hospital of Traditional Chinese Medicine Chongqing Hospital, Chongqing, China
| | - Yue-Yue Wang
- Jiangsu Province Hospital of Traditional Chinese Medicine Chongqing Hospital, Chongqing, China
| | - Jing Guo
- Dermatological Department, Hospital of Chengdu University of Traditional Chinese Medicine, No.39, 12 Qiao Road, Jinniu District, Chengdu, Sichuan, China.
| | - Ming-Yue Li
- Special Needs Outpatient Department, Hospital of Chengdu University of Traditional Chinese Medicine, No.39, 12 Qiao Road, Jinniu District, Chengdu, Sichuan, China.
| |
Collapse
|
28
|
Wang Y, Wei M, Naz S, Zheng X, Wu X. Genome-wide analysis reveals the evolutionary history of TAG intracellular lipases and their roles in different molting stages of Decapods. COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY. PART D, GENOMICS & PROTEOMICS 2025; 54:101444. [PMID: 39985982 DOI: 10.1016/j.cbd.2025.101444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 01/28/2025] [Accepted: 02/10/2025] [Indexed: 02/24/2025]
Abstract
Intracellular lipases can be broadly divided into two categories: neutral lipases and acid lipases. Adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), and monoacylglycerol lipase (MAGL) are three key neutral lipases responsible for the hydrolysis of triacylglycerol (TAG) in lipid droplets (LDs). Although these three TAG intracellular lipase genes have been identified and characterized in multiple model species, their evolutionary history remains largely unknown. For the TAG intracellular lipase genes in Decapoda, there is also a large knowledge gap. Thus, in this study, we performed a genome-wide identification and investigation of TAG intracellular lipase genes in Decapoda and outgroups, analyzing their phylogenetics, structural features, conserved motifs, and expression patterns. In total, 22 ATGL genes, 23 HSL genes and 21 MAGL genes were identified in 17 selected species. HSL is the oldest and most conserved gene to exist in any species. Furthermore, RNA-seq analysis was conducted on two representative Decapod species, Chinese mitten crab (Eriocheir sinensis) and swimming crab (Portunus trituberculatus), which represent freshwater and marine environments, respectively. The analysis revealed a positive correlation between the expression levels of TAG intracellular lipase genes and the energy demand during different molting stages. Overall, the results of this study provide valuable insights into the evolutionary history of TAG intracellular lipase genes, which could enhance our understanding for the role of these genes during key physiological processes of Decapods.
Collapse
Affiliation(s)
- Yufan Wang
- Centre for Research on Environmental Ecology and Fish Nutrition of the Ministry of Agriculture and Rural Affairs, Shanghai Ocean University, Shanghai 201306, China
| | - Maolei Wei
- Centre for Research on Environmental Ecology and Fish Nutrition of the Ministry of Agriculture and Rural Affairs, Shanghai Ocean University, Shanghai 201306, China
| | - Saira Naz
- Centre for Research on Environmental Ecology and Fish Nutrition of the Ministry of Agriculture and Rural Affairs, Shanghai Ocean University, Shanghai 201306, China
| | - Xirui Zheng
- Centre for Research on Environmental Ecology and Fish Nutrition of the Ministry of Agriculture and Rural Affairs, Shanghai Ocean University, Shanghai 201306, China
| | - Xugan Wu
- Centre for Research on Environmental Ecology and Fish Nutrition of the Ministry of Agriculture and Rural Affairs, Shanghai Ocean University, Shanghai 201306, China; Key Laboratory of Freshwater Aquatic Genetic Resources Certified by the Ministry of Agriculture and Rural Affairs of China, Shanghai Ocean University, Shanghai 201306, China; Shanghai Collaborative Innovation Center for Cultivating Elite Breeds and Green-culture of Aquaculture animals, Shanghai 201306, China.
| |
Collapse
|
29
|
Shen Y, Fan J, Li C, Wu F, Wu X, Tao L, Yang Q, Shen X. Restorative mechanisms of Shugan Yiyang capsule on male infertility through 'pharmaco-metabo-net' tripartite correlation analysis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 141:156706. [PMID: 40220430 DOI: 10.1016/j.phymed.2025.156706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Revised: 03/21/2025] [Accepted: 03/28/2025] [Indexed: 04/14/2025]
Abstract
BACKGROUND Shugan Yiyang capsule (SGYY), a commonly used traditional Chinese medicine formulation, is primarily indicated for the treatment of erectile dysfunction, yet existing studies on the therapeutic effects on male infertility (MI) are insufficient and the specific mechanisms remain poorly understood. Given the close relationship between MI, sperm quality, and erectile function, this study aims to investigate the role of SGYY in the restoration of MI and explore the underlying mechanisms. METHODS The efficacy of SGYY is comprehensively evaluated through pharmacodynamic, metabolomic, and network pharmacology. Sperm parameters, reproductive hormones, sexual behavior, neural enzymes, oxidative stress markers, pro-inflammatory cytokines, and testicular histopathology are measured to reveal the restorative effects of MI. Furthermore, urine and serum metabolomics, along with network pharmacology and surface plasmon resonance, are employed to explore the molecular mechanisms and predict core targets. RESULTS SGYY significantly improved overall health parameters, including body weight, water intake, urine output, food consumption, and spontaneous activity. Specifically, SGYY prominently recovered sexual behavior, ameliorated sperm quality, increased mitochondrial membrane potential, normalized reproductive hormones, upregulated endothelial nitric oxide synthase, attenuated oxidative stress markers, and pro-inflammatory cytokines, and repaired testicular pathological damage. Metabolomic analysis identified 47 candidate biomarkers, among which SGYY significantly modulated 39 potential biomarkers, encompassing 8 main metabolic pathways such as histidine metabolism, cysteine and methionine metabolism, propanoate metabolism, and taurine and hypotaurine metabolism. Additionally, network pharmacology predicted 8 core targets, comprising HSP90AA1, ESR1, MAPK1, CASP3, IL6, TNF, BCL2, and MAPK8. CONCLUSION SGYY improves sperm quality and erectile function by regulating oxidative stress, energy metabolism, and neurological function, thereby exerting a restorative effect on MI, as evidenced by the modulation of 8 main metabolic pathways, 39 potential biomarkers, and 8 core targets. Pharmacodynamic provides foundational validation, metabolomic uncovers intrinsic metabolic changes, and network pharmacology predicts therapeutic targets, with findings from the 'Pharmaco-Metabo-Net' tripartite correlation analysis providing a solid theoretical strategy and scientific evidence to support the clinical application of SGYY in restoring MI.
Collapse
Affiliation(s)
- Ying Shen
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Guizhou Medical University, Guiyang 561113, China; High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 561113, China; National Engineering Research Center of Miao's Medicines, Guizhou Yibai Pharmaceutical Co., Ltd., Guiyang 550008, China
| | - Jian Fan
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Guizhou Medical University, Guiyang 561113, China; Natural Products Research Center of Guizhou Province, Guiyang 550014, China
| | - Chunmei Li
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Guizhou Medical University, Guiyang 561113, China; High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 561113, China
| | - Fuli Wu
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Guizhou Medical University, Guiyang 561113, China; High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 561113, China
| | - Xiangli Wu
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Guizhou Medical University, Guiyang 561113, China; High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 561113, China
| | - Ling Tao
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Guizhou Medical University, Guiyang 561113, China; High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 561113, China.
| | - Qingbo Yang
- High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 561113, China; National Engineering Research Center of Miao's Medicines, Guizhou Yibai Pharmaceutical Co., Ltd., Guiyang 550008, China.
| | - Xiangchun Shen
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Guizhou Medical University, Guiyang 561113, China; High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 561113, China.
| |
Collapse
|
30
|
Lyu Z, Yang J, Xu Z, Wang W, Cheng W, Tsui KL, Zhang Q. Predicting the risk of ischemic stroke in patients with atrial fibrillation using heterogeneous drug-protein-disease network-based deep learning. APL Bioeng 2025; 9:026104. [PMID: 40191603 PMCID: PMC11970939 DOI: 10.1063/5.0242570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Accepted: 02/11/2025] [Indexed: 04/09/2025] Open
Abstract
Current risk assessment models for predicting ischemic stroke (IS) in patients with atrial fibrillation (AF) often fail to account for the effects of medications and the complex interactions between drugs, proteins, and diseases. We developed an interpretable deep learning model, the AF-Biological-IS-Path (ABioSPath), to predict one-year IS risk in AF patients by integrating drug-protein-disease pathways with real-world clinical data. Using a heterogeneous multilayer network, ABioSPath identifies mechanisms of drug actions and the propagation of comorbid diseases. By combining mechanistic pathways with patient-specific characteristics, the model provides individualized IS risk assessments and identifies potential molecular pathways involved. We utilized the electronic health record data from 7859 AF patients, collected between January 2008 and December 2009 across 43 hospitals in Hong Kong. ABioSPath outperformed baseline models in all evaluation metrics, achieving an AUROC of 0.7815 (95% CI: 0.7346-0.8283), a positive predictive value of 0.430, a negative predictive value of 0.870, a sensitivity of 0.500, a specificity of 0.885, an average precision of 0.409, and a Brier score of 0.195. Cohort-level analysis identified key proteins, such as CRP, REN, and PTGS2, within the most common pathways. Individual-level analysis further highlighted the importance of PIK3/Akt and cytokine and chemokine signaling pathways and identified IS risks associated with less-studied drugs like prochlorperazine maleate. ABioSPath offers a robust, data-driven approach for IS risk prediction, requiring only routinely collected clinical data without the need for costly biomarkers. Beyond IS, the model has potential applications in screening risks for other diseases, enhancing patient care, and providing insights for drug development.
Collapse
Affiliation(s)
| | - Jiannan Yang
- Musketeers Foundation Institute of Data Science, The University of Hong Kong, Hong Kong SAR, China
| | - Zhongzhi Xu
- School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Weilan Wang
- Centre for Healthy Longevity, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | | | - Kwok-Leung Tsui
- Department of Manufacturing, Systems, and Industrial Engineering, University of Texas, Arlington, Texas 76019, USA
| | | |
Collapse
|
31
|
Li YL, He R, Tang M, Lan JY, Liu GY, Jiang LH. Bioinformatics identification of shared signaling pathways and core targets linking Benzo[a]pyrene exposure to HCC progression. Toxicology 2025; 514:154129. [PMID: 40174762 DOI: 10.1016/j.tox.2025.154129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2025] [Revised: 03/18/2025] [Accepted: 03/29/2025] [Indexed: 04/04/2025]
Abstract
With the increasing prevalence of environmental pollutants, there is growing concern about the potential effects of these substances in major diseases such as liver cancer. Previous studies have suggested that various chemicals, such as benzo[a]pyrene(BaP), produced by burning carbon containing fuels, may negatively affect liver health, but the exact mechanisms remain unclear. This study aimed to explore the potential molecular mechanisms of BaP in the progression of liver cancer. Through an exhaustive study of databases such as ChEMBL, SwissTargetPrediction, STITCH and TCGA, we identified 169 potential targets that are closely related to BaP and liver cancer. Next, we conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses using the clusterProfiler package to study the biological functions and important pathways of potential targets induced by BaP, which showed that these targets were associated with mitochondrial function, cellular energy metabolism and REDOX reactions. The protein interaction (PPI) network was constructed using the STRING database and Cytoscape software to identify the core targets UBA52, NDUFS8, CYP1A2, NDUFS1 and CYP3A4. The interaction between BaP and these core proteins was further analyzed via molecular docking using the CB-Dock2 database, demonstrating high binding stability, which suggests their critical role in BaP-induced hepatocellular carcinoma (HCC) toxicity. Subsequently, we found significant differences in the expression of five core genes (UBA52, NDUFS8, CYP1A2, NDUFS1, CYP3A4) in HCC, and significant correlation between UBA52, NDUFS8 and CYP3A4 and survival of HCC patients. Single-cell sequencing analysis showed that the expression of UBA52 gene was particularly pronounced in the three immune cells.
Collapse
Affiliation(s)
- Yong-Le Li
- School of Basic Medicine, Youjiang Medical College for Nationalities, Baise 533000, China
| | - Rong He
- School of Basic Medicine, Youjiang Medical College for Nationalities, Baise 533000, China
| | - Meng Tang
- School of Basic Medicine, Youjiang Medical College for Nationalities, Baise 533000, China
| | - Jing-Yi Lan
- School of Basic Medicine, Youjiang Medical College for Nationalities, Baise 533000, China
| | - Guo-Yang Liu
- School of Basic Medicine, Youjiang Medical College for Nationalities, Baise 533000, China
| | - Li-He Jiang
- School of Basic Medicine, Youjiang Medical College for Nationalities, Baise 533000, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institute, Hefei 230032, China; Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, Guilin Medical University, Guilin 541001, China.
| |
Collapse
|
32
|
Yang J, Zhang S, Li X, Chen Z, Xu J, Chen J, Tan Y, Li G, Yu B, Gu X, Xu L. Convergent and divergent transcriptional reprogramming of motor and sensory neurons underlying response to peripheral nerve injury. J Adv Res 2025; 72:135-150. [PMID: 39002719 DOI: 10.1016/j.jare.2024.07.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Revised: 07/10/2024] [Accepted: 07/10/2024] [Indexed: 07/15/2024] Open
Abstract
INTRODUCTION Motor neurons differ from sensory neurons in aspects including origins and surrounding environment. Understanding the similarities and differences in molecular response to peripheral nerve injury (PNI) and regeneration between sensory and motor neurons is crucial for developing effective drug targets for CNS regeneration. However, genome-wide comparisons of molecular changes between sensory and motor neurons following PNI remains limited. OBJECTIVES This study aims to investigate genome-wide convergence and divergence of injury response between sensory and motor neurons to identify novel drug targets for neural repair. METHODS We analyzed two large-scale RNA-seq datasets of in situ captured sensory neurons (SNs) and motoneurons (MNs) upon PNI, retinal ganglion cells and spinal cord upon CNS injury. Additionally, we integrated these with other related single-cell level datasets. Bootstrap DESeq2 and WGCNA were used to detect and explore co-expression modules of differentially expressed genes (DEGs). RESULTS We found that SNs and MNs exhibited similar injury states, but with a delayed response in MNs. We identified a conserved regeneration-associated module (cRAM) with 274 shared DEGs. Of which, 47% of DEGs could be changed in injured neurons supported by single-cell resolution datasets. We also identified some less-studied candidates in cRAM, including genes associated with transcription, ubiquitination (Rnf122), and neuron-immune cells cross-talk. Further in vitro experiments confirmed a novel role of Rnf122 in axon growth. Analysis of the top 10% of DEGs with a large divergence suggested that both extrinsic (e.g., immune microenvironment) and intrinsic factors (e.g., development) contributed to expression divergence between SNs and MNs following injury. CONCLUSIONS This comprehensive analysis revealed convergent and divergent injury response genes in SNs and MNs, providing new insights into transcriptional reprogramming of sensory and motor neurons responding to axonal injury and subsequent regeneration. It also identified some novel regeneration-associated candidates that may facilitate the development of strategies for axon regeneration.
Collapse
Affiliation(s)
- Jian Yang
- Department of Neurosurgery, People's Hospital of Deyang City, Sichuan Clinical Research Center for Neurological Diseases, Deyang 618000, China; Co-innovation Center of Neuroregeneration, Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong 226000, China.
| | - Shuqiang Zhang
- Co-innovation Center of Neuroregeneration, Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong 226000, China
| | - Xiaodi Li
- Chinese Medicine Modernization and Big Data Research Center, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210000, China
| | - Zhifeng Chen
- Co-innovation Center of Neuroregeneration, Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong 226000, China
| | - Jie Xu
- Co-innovation Center of Neuroregeneration, Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong 226000, China
| | - Jing Chen
- Co-innovation Center of Neuroregeneration, Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong 226000, China
| | - Ya Tan
- Co-innovation Center of Neuroregeneration, Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong 226000, China
| | - Guicai Li
- Co-innovation Center of Neuroregeneration, Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong 226000, China
| | - Bin Yu
- Co-innovation Center of Neuroregeneration, Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong 226000, China
| | - Xiaosong Gu
- Co-innovation Center of Neuroregeneration, Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong 226000, China.
| | - Lian Xu
- Co-innovation Center of Neuroregeneration, Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong 226000, China; Institute for Translational Neuroscience, the Second Affiliated Hospital of Nantong University, Nantong University, Nantong, Jiangsu 226000, China.
| |
Collapse
|
33
|
Wang P, Zhang C, Wu P, Zhao Z, Sun N, Xue Q, Gao S, He J. Cell Death and Senescence-Based Molecular Classification and an Individualized Prediction Model for Lung Adenocarcinoma. MedComm (Beijing) 2025; 6:e70237. [PMID: 40443719 PMCID: PMC12122187 DOI: 10.1002/mco2.70237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 03/31/2025] [Accepted: 04/10/2025] [Indexed: 06/02/2025] Open
Abstract
The exploration of cell death and cellular senescence (CDS) in cancer has been an area of interest, yet a systematic evaluation of CDS features and their interactions in lung adenocarcinoma (LUAD) to understand tumor heterogeneity, tumor microenvironment (TME) characteristics, and patient clinical outcomes is previously uncharted. Our study characterized the activities and interconnections of 21 CDS features in 1788 LUAD cases across 15 cohorts, employing unsupervised clustering to categorize patients into three CDS subtypes with distinct TME profiles. The CDS index (CDSI), derived from principal component analysis, was developed to assess individual tumor CDS regulation patterns. Twelve CDSI core genes, enriched in proliferating T cells within the TME as per single-cell analysis, were identified and their functional roles and prognostic significance were validated. High CDSI correlated with improved overall survival in discovery cohort, four independent validation cohorts, and subgroup analysis. CDSI-low patients exhibited a favorable clinical response to immunotherapy and potential sensitivity to mitosis pathway drugs, while CDSI-high patients might benefit from drugs targeting ERK/MAPK and MDM2-p53 pathways. The clinical utility of CDSI was further validated using 9185 pan-cancer samples, demonstrating the broad relevance of our prediction model across various cancer types and its potential clinical implications for cancer management.
Collapse
Affiliation(s)
- Pan Wang
- Department of Thoracic SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Chaoqi Zhang
- Department of Thoracic SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Peng Wu
- Department of Thoracic SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Zhihong Zhao
- Department of Thoracic SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Nan Sun
- Department of Thoracic SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Qi Xue
- Department of Thoracic SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Shugeng Gao
- Department of Thoracic SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Jie He
- Department of Thoracic SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| |
Collapse
|
34
|
Suresh M, Sai KV, Mitra K, Ravindran R, Doble M. A network pharmacology-based approach to understand the mechanism of action of anti-mycobacterial activity of Acacia nilotica: a modelling and experimental study. Mol Divers 2025; 29:2227-2242. [PMID: 39292406 DOI: 10.1007/s11030-024-10985-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 08/29/2024] [Indexed: 09/19/2024]
Abstract
The rapid rise in drug-resistant tuberculosis poses a serious threat to public health and demands the discovery of new anti-mycobacterial agents. Medicinal plants are a proven potential source of bioactive compounds; however, identifying those responsible for the putative anti-mycobacterial action still remains a challenging task. In this study, we undertook a systematic network pharmacology approach to identify and evaluate anti-mycobacterial compounds from a traditional plant, Acacia nilotica, as a model system. The protein-protein interaction network revealed 17 key pathways in M. tuberculosis encompassing 40 unique druggable targets that are necessary for its growth and survival. The phytochemicals of A. nilotica were preferentially found to interfere with the cell division and cell wall biogenesis proteins, especially FtsZ and Mur. Notably, the compounds epigallocatechin, ellagic acid, chlorogenic acid, and D-pinitol were found to exhibit a potential polypharmacological effect against multiple proteins. Further, in vitro studies confirmed that the selected candidates, chlorogenic acid, and ellagic acid exhibited potent anti-mycobacterial activity (against M. smegmatis) with specific inhibition of purified M.tb FtsZ enzyme. Taken together, the present study demonstrates that network pharmacology combined with molecular docking can be utilized as an efficient approach to identify potential bioactive phytochemicals from natural products along with their mechanism of action. Hence, the compounds identified in this study can be potential lead candidates for developing novel anti-mycobacterial drugs, while the key proteins identified here can be potential drug targets.
Collapse
Affiliation(s)
- Madhumitha Suresh
- Bioengineering and Drug Design Lab, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, 600036, India
| | - Kadambari Vijay Sai
- Bioengineering and Drug Design Lab, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, 600036, India
| | - Kartik Mitra
- Bioengineering and Drug Design Lab, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, 600036, India.
| | - Radhika Ravindran
- Bioengineering and Drug Design Lab, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, 600036, India
| | - Mukesh Doble
- Department of Biotechnology, Theevanam Additives Nutraceuts Pvt Ltd, IITM Bioincubator, IIT Madras, Chennai, 600036, India
- Saveetha Dental College and Hospitals, SIMATS, Chennai, 600077, India
| |
Collapse
|
35
|
Mathur P, Kaur A, Agarwal KK, Agarwal LK, Mathur A, Choudhary D. Unlocking the genetic blueprint of duchenne muscular dystrophy: A personalized approach with MLPA and WES. Glob Med Genet 2025; 12:100038. [PMID: 40027239 PMCID: PMC11871439 DOI: 10.1016/j.gmg.2025.100038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Revised: 01/24/2025] [Accepted: 01/25/2025] [Indexed: 03/05/2025] Open
Abstract
Background Duchenne muscular dystrophy (DMD) is a progressive X-linked disorder causing muscle degeneration and multisystem involvement, requiring precise genetic diagnosis for timely intervention and treatment. Objective To investigate the genetic landscape of DMD using a two-tiered diagnostic approach combining MLPA and WES, and to correlate genetic findings with clinical outcomes for improved management. Materials and methods A cross-sectional study of 80 male DMD patients was conducted using a sequential genetic approach, combining MLPA and WES, with bioinformatics and statistical analyses to explore genotype-phenotype correlations. Results Pathogenic variants were identified in 65 cases (81.2 %), with deletions (67.5 %) being the most common, followed by duplications (6.3 %), splice-site (3.8 %), and nonsense variants (3.8 %). WES identified additional pathogenic variants in MLPA-negative cases, including novel mutations, expanding the known genetic spectrum of DMD. The combined MLPA-WES approach significantly improved diagnostic yield (χ² = 12.90, p < 0.001). Functional analysis revealed disruptions in glycogen metabolism (46 %), calcium transport (24 %), and mitochondrial function (12 %), with dystrophin-associated proteins (DAG1, SGCD) critically involved in muscle stability. Out-of-frame deletions were significantly associated with early disease onset (χ² = 49.03, p < 0.001) and severe phenotypes (χ² = 47.04, p < 0.001), supporting exon-skipping therapy. In-frame deletions correlated with milder progression, while nonsense variants posed a 2.5-fold increased risk of early cardiomyopathy (p = 0.002), emphasizing the need for early intervention. Conclusion Combining MLPA and WES enhances DMD diagnostic accuracy, enabling timely clinical interventions. Integrating functional analysis with genotype-phenotype correlations supports personalized therapeutic strategies, improving patient outcomes.
Collapse
Affiliation(s)
- Priyanshu Mathur
- Department of Pediatric Medicine, SMS Medical College, Jaipur, India
| | - Ashmeet Kaur
- Department of Pathology, SMS Medical College, Jaipur, India
| | | | | | - Avisha Mathur
- Department of Ophthalmology, SMS Medical College, Jaipur, India
| | - Deepti Choudhary
- LifeCell International Pvt Ltd, Vijayaraghava Road, I Lane, T. Nagar, Chennai 600017, India
| |
Collapse
|
36
|
Lin F, Hu S, Chen J, Li H, Li M, Li R, Xu M, Luo M. MiR-125b suppresses bladder Cancer cell growth and triggers apoptosis by regulating IL-6/IL-6R/STAT3 axis in vitro and in vivo. Cytokine 2025; 190:156926. [PMID: 40120148 DOI: 10.1016/j.cyto.2025.156926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 03/02/2025] [Accepted: 03/18/2025] [Indexed: 03/25/2025]
Abstract
Bladder cancer (BLCA) is an aggressive malignancy characterized by limited therapeutic options and a poor prognosis. Research has indicated that abnormally expressed miRNAs play a significant role in the pathogenesis of BLCA, although the specific mechanisms remain unclear. MiR-125b plays a tumor suppressor role in a variety of cancers and affects the biological processes of cancer cells such as proliferation, invasion, migration and apoptosis by regulating different signaling pathways. Elucidation of the molecular mechanisms underlying miR-125b may provide clinical therapeutic strategies for bladder cancer. Here, miR-125b was downregulated whereas its targets IL-6R and STAT3 were upregulated in BLCA, as evidenced by bioinformatics analysis. Kaplan-Meier analysis confirmed that miR-125b serves as an independent prognostic factor linked to overall survival (OS) in patients with bladder cancer. Furthermore, overexpression of miR-125b significantly inhibited BLCA cell proliferation, migration, and invasion, while promoting apoptosis, as evidenced by an increased Bax/Bcl-2 ratio and activated cleaved caspase-3. Further investigations demonstrated that miR-125b directly targets and downregulates both IL-6R and STAT3. In a xenograft model, miR-125b overexpression effectively inhibited tumor growth in bladder cancer by blocking IL-6/IL-6R and STAT3 signaling pathways. Collectively, these findings broaden our understanding of the mechanism by which miR-125b acting as a BLCA suppressor in apoptotic regulation by targeting the IL-6/IL-6R/STAT3 signaling pathway, providing novel insights regarding the design of novel miRNA based therapeutic strategies against BLCA.
Collapse
Affiliation(s)
- Fang Lin
- Basic Medicine Research Innovation Center for cardiometabolic diseases, Ministry of Education; Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China; Municipal Key Laboratory of Thrombosis and Vascular Biology, Luzhou, Sichuan, China; Department of Pharmacy, The Second People's Hospital of Yibin, Yibin, Sichuan, China
| | - Shaorun Hu
- Basic Medicine Research Innovation Center for cardiometabolic diseases, Ministry of Education; Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China; Municipal Key Laboratory of Thrombosis and Vascular Biology, Luzhou, Sichuan, China; Department of Pharmacy, The Second People's Hospital of Yibin, Yibin, Sichuan, China
| | - Jinxiang Chen
- Basic Medicine Research Innovation Center for cardiometabolic diseases, Ministry of Education; Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China; Municipal Key Laboratory of Thrombosis and Vascular Biology, Luzhou, Sichuan, China; Department of Pharmacy, The Second People's Hospital of Yibin, Yibin, Sichuan, China
| | - Haiyang Li
- Basic Medicine Research Innovation Center for cardiometabolic diseases, Ministry of Education; Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China; Municipal Key Laboratory of Thrombosis and Vascular Biology, Luzhou, Sichuan, China; Department of Pharmacy, The Second People's Hospital of Yibin, Yibin, Sichuan, China
| | - Mengting Li
- Basic Medicine Research Innovation Center for cardiometabolic diseases, Ministry of Education; Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China; Municipal Key Laboratory of Thrombosis and Vascular Biology, Luzhou, Sichuan, China; Department of Pharmacy, The Second People's Hospital of Yibin, Yibin, Sichuan, China
| | - Rong Li
- Basic Medicine Research Innovation Center for cardiometabolic diseases, Ministry of Education; Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China; Department of Pharmacy, The Second People's Hospital of Yibin, Yibin, Sichuan, China
| | - Min Xu
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu, China.
| | - Mao Luo
- Basic Medicine Research Innovation Center for cardiometabolic diseases, Ministry of Education; Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China; Municipal Key Laboratory of Thrombosis and Vascular Biology, Luzhou, Sichuan, China; Department of Pharmacy, The Second People's Hospital of Yibin, Yibin, Sichuan, China..
| |
Collapse
|
37
|
Friedlová N, Bortlíková L, Dosedělová L, Uhrík L, Hupp TR, Hernychová L, Vojtěšek B, Nekulová M. IFITM1 as a modulator of surfaceome dynamics and aggressive phenotype in cervical cancer cells. Oncol Rep 2025; 53:71. [PMID: 40314078 PMCID: PMC12059461 DOI: 10.3892/or.2025.8904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Accepted: 03/27/2025] [Indexed: 05/03/2025] Open
Abstract
Interferon‑induced transmembrane proteins (IFITMs) are frequently overexpressed in cancer cells, including cervical carcinoma cells, and play a role in the progression of various cancer types. However, their mechanisms of action remain incompletely understood. In the present study, by employing a combination of surface membrane protein isolation and quantitative mass spectrometry, it was comprehensively described how the IFITM1 protein influences the composition of the cervical cancer cell surfaceome. Additionally, the effects of interferon‑γ on protein expression and cell surface exposure were evaluated in the presence and absence of IFITM1. The IFITM1‑regulated membrane and membrane‑associated proteins identified are involved mainly in processes such as endocytosis and lysosomal transport, cell‑cell and cell‑extracellular matrix adhesion, antigen presentation and the immune response. To complement the proteomic data, gene expression was analyzed using reverse transcription‑quantitative PCR to distinguish whether the observed changes in protein levels were attributable to transcriptional regulation or differential protein dynamics. Furthermore, the proteomic and gene expression data are supported by functional studies demonstrating the impact of the IFITM1 and IFITM3 proteins on the adhesive, migratory and invasive capabilities of cervical cancer cells, as well as their interactions with immune cells.
Collapse
Affiliation(s)
- Nela Friedlová
- Research Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic
- Department of Experimental Biology, Faculty of Science, Masaryk University, 625 00 Brno, Czech Republic
| | - Lucie Bortlíková
- Research Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic
| | - Lenka Dosedělová
- Research Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic
| | - Lukáš Uhrík
- Research Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic
| | - Ted R. Hupp
- Research Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic
- University of Edinburgh, Institute of Genetics and Molecular Medicine, EH4 2XU Edinburgh, United Kingdom
| | - Lenka Hernychová
- Research Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic
| | - Bořivoj Vojtěšek
- Research Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic
| | - Marta Nekulová
- Research Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic
| |
Collapse
|
38
|
Vastrad SJ, Saraswathy GR, Dasari JB, Nair G, Madarakhandi A, Augustine D, Sowmya S. A comprehensive transcriptome based meta-analysis to unveil the aggression nexus of oral squamous cell carcinoma. Biochem Biophys Rep 2025; 42:102001. [PMID: 40271514 PMCID: PMC12016861 DOI: 10.1016/j.bbrep.2025.102001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Revised: 03/21/2025] [Accepted: 03/31/2025] [Indexed: 04/25/2025] Open
Abstract
Lymph node metastasis in oral cancer (OC) complicates management due to its aggressive nature and high risk of recurrence, underscoring the need for biomarkers for early detection and targeted therapies. However, the drivers of this aggressive phenotype remain unclear due to the variability in gene expression patterns. To address this, an integrative meta-analysis of six publicly available transcriptomic profiles, categorized by lymph nodal status, is conducted. Key determinants of disease progression are identified through functional characterization and the TopConfects ranking approach of nodal associated differentially expressed genes (DEGs). To explore the critical nexus between lymph node metastasis and OC recurrence, significant metastatic genes were cross-analysed with literature-derived genes exhibiting aberrant methylation patterns in OC recurrence. Their clinical relevance and expression patterns were then validated in an external dataset from the TCGA head and neck cancer cohort. The analysis identified elevated expression of genes involved in extracellular matrix remodelling and immune response, while the expression of genes related to cellular differentiation and barrier functions was reduced, driving the transition to nodal positivity. The highest-ranked gene, MMP1, showed a log-fold change (LFC) of 4.946 (95 % CI: 3.71, 6.18) in nodal-negative samples, which increased to 5.899 (95 % CI: 4.80, 6.99) in nodal-positive samples, indicating consistent elevation across disease stages. In contrast, TMPRSS11B was significantly downregulated, with an LFC of -5.512 (95 % CI: -6.63, -4.38) in nodal-negative samples and -5.898 (95 % CI: -7.15, -4.64) in nodal-positive samples. Furthermore, MEIS1, down-regulated in nodal-positive status, was found to exhibit hypermethylation at CpG sites associated with OC recurrence. This study represents the first transcriptomic meta-analysis to explore the intersection of lymph node metastasis and OC recurrence, identifying MEIS1 as a potential key contributor. These comprehensive insights into disease trajectories offer potential biomarkers and therapeutic targets for future treatment strategies.
Collapse
Affiliation(s)
- Soujanya J. Vastrad
- Department of Pharmacy Practice, Faculty of Pharmacy, M.S. Ramaiah University of Applied Sciences, New BEL Road, M.S.R. Nagar, Bengaluru, India
| | - Ganesan Rajalekshmi Saraswathy
- Department of Pharmacy Practice, Faculty of Pharmacy, M.S. Ramaiah University of Applied Sciences, New BEL Road, M.S.R. Nagar, Bengaluru, India
| | | | - Gouri Nair
- Department of Pharmacology, Faculty of Pharmacy, M. S. Ramaiah University of Applied Sciences, Bangalore, Karnataka, India
| | - Ashok Madarakhandi
- Department of Pharmaceutical Chemistry, KLE College of Pharmacy, (A Constituent Unit of KAHER-Belagavi), 2nd Block, Rajajinagar, Bangalore, India
| | - Dominic Augustine
- Department of Oral Pathology and Microbiology, Faculty of Dental Sciences, M.S. Ramaiah University of Applied Sciences, New BEL Road, M.S.R. Nagar, Bengaluru, India
| | - S.V. Sowmya
- Department of Oral Pathology and Microbiology, Faculty of Dental Sciences, M.S. Ramaiah University of Applied Sciences, New BEL Road, M.S.R. Nagar, Bengaluru, India
| |
Collapse
|
39
|
Cervera-Juanes RP, Zimmerman KD, Wilhelm LJ, Lowe CC, Gonzales SW, Carlson T, Hitzemann R, Ferguson BM, Grant KA. Pre-existing DNA methylation signatures in the prefrontal cortex of alcohol-naïve nonhuman primates define neural vulnerability for future risky ethanol consumption. Neurobiol Dis 2025; 209:106886. [PMID: 40139280 PMCID: PMC12044430 DOI: 10.1016/j.nbd.2025.106886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 03/13/2025] [Accepted: 03/23/2025] [Indexed: 03/29/2025] Open
Abstract
Alcohol use disorder (AUD) is a highly prevalent, complex, multifactorial and heterogeneous disorder, with 11 % and 30 % of adults meeting criteria for past-year and lifetime AUD, respectively. Identification of the molecular mechanisms underlying risk for AUD would facilitate effective deployment of personalized interventions. Studies using rhesus monkeys and rats, have demonstrated that individuals with low cognitive flexibility and a predisposition towards habitual behaviors show an increased risk for future heavy drinking. Further, low cognitive flexibility is associated with reduced dorsolateral prefrontal cortex (dlPFC) function in rhesus monkeys. To explore the underlying unique molecular signatures that increase risk for chronic heavy drinking, a genome-wide DNA methylation (DNAm) analysis of the alcohol-naïve dlPFC-A46 biopsy prior to chronic alcohol self-administration was conducted. The DNAm profile provides a molecular snapshot of the alcohol-naïve dlPFC, with mapped genes and associated signaling pathways that vary across individuals. The analysis identified 1,463 differentially methylated regions (DMRs) related to unique genes that were strongly associated with average ethanol intake consumed over 6 months of voluntary self-administration. These findings translate behavioral phenotypes into neural markers of risk for AUD, and hold promise for parallel discoveries in risk for other disorders involving impaired cognitive flexibility. SIGNIFICANCE: Alcohol use disorder (AUD) is a highly prevalent and heterogeneous disorder. Prevention strategies to accurately identify individuals with a high risk for AUD, would help reduce the prevalence, and severity of AUD. Our novel epigenomic analysis of the alcohol-naïve nonhuman primate cortex provides a molecular snapshot of the vulnerable brain, pointing to circuitry and molecular mechanisms associated with cortical development, synaptic functions, glutamatergic signaling and coordinated signaling pathways. With a complex disorder like AUD, having the ability to identify the molecular mechanisms underlying AUD risk is critical for better development of personalized effective treatments.
Collapse
Affiliation(s)
- Rita P Cervera-Juanes
- Department of Translational Neuroscience, School of Medicine, Wake Forest University, Winston-Salem, NC 27157, United States of America; Center for Precision Medicine, School of Medicine, Wake Forest University, Winston-Salem, NC 27157, United States of America.
| | - Kip D Zimmerman
- Center for Precision Medicine, School of Medicine, Wake Forest University, Winston-Salem, NC 27157, United States of America; Department of Internal Medicine, Atrium Health Wake Forest Baptist, Winston-Salem, NC 27157, United States of America
| | - Larry J Wilhelm
- Department of Translational Neuroscience, School of Medicine, Wake Forest University, Winston-Salem, NC 27157, United States of America
| | - Clara Christine Lowe
- Department of Translational Neuroscience, School of Medicine, Wake Forest University, Winston-Salem, NC 27157, United States of America
| | - Steven W Gonzales
- Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006, United States of America
| | - Tim Carlson
- Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006, United States of America
| | - Robert Hitzemann
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, United States of America; Portland Alcohol Research Center, Oregon Health & Science University, Portland, OR 97239, United States of America
| | - Betsy M Ferguson
- Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006, United States of America; Division of Genetics, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006, United States of America
| | - Kathleen A Grant
- Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006, United States of America; Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, United States of America; Portland Alcohol Research Center, Oregon Health & Science University, Portland, OR 97239, United States of America
| |
Collapse
|
40
|
Blasco-Roset A, Quesada-López T, Mestres-Arenas A, Villarroya J, Godoy-Nieto FJ, Cereijo R, Rupérez C, Neess D, Færgeman NJ, Giralt M, Planavila A, Villarroya F. Acyl CoA-binding protein in brown adipose tissue acts as a negative regulator of adaptive thermogenesis. Mol Metab 2025; 96:102153. [PMID: 40220929 PMCID: PMC12050000 DOI: 10.1016/j.molmet.2025.102153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2025] [Revised: 04/04/2025] [Accepted: 04/08/2025] [Indexed: 04/14/2025] Open
Abstract
OBJECTIVE Defective activity of brown adipose tissue (BAT) is linked to obesity and cardiometabolic diseases. While much is known regarding the biological signals that trigger BAT thermogenesis, relatively little is known about the repressors that may impair BAT function in physiological and pathological settings. Acyl CoA-binding protein (ACBP; also known as diazepam binding inhibitor, DBI) has intracellular functions related to lipid metabolism and can be secreted to act as a circulating regulatory factor that affects multiple organs. Our objective was to determine the role of ACBP in BAT function. METHODS Experimental models based on the targeted inactivation of the Acbp gene in brown adipocytes, both in vitro and in vivo, as well as brown adipocytes treated with recombinant ACBP, were developed and analyzed for transcriptomic and metabolic changes. RESULTS ACBP expression and release in BAT are suppressed by noradrenergic cAMP-dependent signals that stimulate thermogenesis. This regulation occurs through gene expression modulation and autophagy-related processes. Mice with targeted ablation of Acbp in brown adipocytes exhibit enhanced BAT thermogenic activity and protection against high-fat diet-induced obesity and glucose intolerance; this is associated with BAT transcriptome changes, including upregulation of BAT thermogenesis-related genes. Treatment of brown adipocytes with exogenous ACBP suppresses oxidative activity, lipolysis, and thermogenesis-related gene expression. ACBP treatment inhibits the noradrenergic-induced phosphorylation of p38 MAP-kinase and CREB, which are major intracellular mediators of brown adipocyte thermogenesis. CONCLUSIONS The ACBP system acts as a crucial auto regulatory repressor of BAT thermogenesis that responds reciprocally to the noradrenergic induction of BAT activity.
Collapse
Affiliation(s)
- Albert Blasco-Roset
- Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain; Institut de Recerca de Sant Joan de Déu, 08028 Barcelona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición, 28029 Madrid, Spain
| | - Tania Quesada-López
- Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain; Institut de Recerca de Sant Joan de Déu, 08028 Barcelona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición, 28029 Madrid, Spain; Institut d'Investigació Biomèdica Sant Pau (IIB-SANT PAU), Barcelona, Spain; Department of Infectious Diseases, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain
| | - Alberto Mestres-Arenas
- Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain; Institut de Recerca de Sant Joan de Déu, 08028 Barcelona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición, 28029 Madrid, Spain
| | - Joan Villarroya
- Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain; Institut de Recerca de Sant Joan de Déu, 08028 Barcelona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición, 28029 Madrid, Spain
| | - Francisco J Godoy-Nieto
- Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain; Institut de Recerca de Sant Joan de Déu, 08028 Barcelona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición, 28029 Madrid, Spain
| | - Rubén Cereijo
- Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain; Institut de Recerca de Sant Joan de Déu, 08028 Barcelona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición, 28029 Madrid, Spain
| | - Celia Rupérez
- Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain; Institut de Recerca de Sant Joan de Déu, 08028 Barcelona, Spain
| | - Ditte Neess
- Department of Biochemistry and Molecular Biology, University of South Denmark, DK-5230, Odense, Denmark
| | - Nils J Færgeman
- Department of Biochemistry and Molecular Biology, University of South Denmark, DK-5230, Odense, Denmark
| | - Marta Giralt
- Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain; Institut de Recerca de Sant Joan de Déu, 08028 Barcelona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición, 28029 Madrid, Spain
| | - Anna Planavila
- Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain; Institut de Recerca de Sant Joan de Déu, 08028 Barcelona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición, 28029 Madrid, Spain
| | - Francesc Villarroya
- Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain; Institut de Recerca de Sant Joan de Déu, 08028 Barcelona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición, 28029 Madrid, Spain.
| |
Collapse
|
41
|
Wu D, Hong L, Xu S, Zhong Z, Gong Q, Wang Q, Yan L. Integrating network pharmacology and experimental validation via PPAR signaling to ameliorate rheumatoid arthritis: Insights from Corydalis Decumbentis Rhizoma (Xiatianwu). Fitoterapia 2025; 183:106541. [PMID: 40239773 DOI: 10.1016/j.fitote.2025.106541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 04/11/2025] [Accepted: 04/11/2025] [Indexed: 04/18/2025]
Abstract
Corydalis Decumbentis Rhizoma (Xiatianwu, XTW) exhibits a positive effect in treating rheumatoid arthritis (RA). However, the precise molecular mechanisms underlying its effects remain unclear. In this study, TNF-α was used to induce inflammation and establish and in vitro RA model. Network pharmacology was employed to identify the important active components and targets in the treatment of XTW on RA. CCK-8 was used to investigate the cell viability. GW9662 (a PPARG antagonist) was applied to validate the network pharmacology prediction. ELISA was used to measure pro-inflammatory cytokines (IL-6, IL-1β, and INF-γ) and oxidative stress markers (MMP-2, MDA, and ROS). HPLC-MS was conducted to validate the four important active ingredients (bicuculline, ferulic acid, berberine, and jatrorrhizine) in XTW. Western blotting was carried out to detect the protein levels of PPAR-γ. In vitro experiments demonstrated that XTW exerted dose-dependent anti-RA effects by downregulating pro-inflammatory cytokines and oxidative stress markers. Through Network pharmacology, three targets (RXRA, PPARG, and PPARA) and four active ingredients (bicuculline, ferulic acid, berberine, and jatrorrhizine) were demonstrated important in the treatment of XTW on RA. Besides, PPAR signaling pathway may be a therapeutic target for XTW treating RA. Further experiments confirmed that XTW administration significantly inhibited inflammation and oxidative stress by upregulating the PPAR signaling pathway. In conclusion, XTW modulates RXRA, PPARG, and PPARA through the PPAR signaling pathway, thereby mitigating inflammation and oxidative stress in RA.
Collapse
Affiliation(s)
- Dongjiao Wu
- Department of Rheumatology, Ningbo Municipal Hospital of Traditional Chinese Medicine (TCM), Affiliated Hospital of Zhejiang Chinese Medical University, No.819 Liyuan North Road, Haishu District, Ningbo 315010, China
| | - Lu Hong
- Department of Rheumatology, Ningbo Municipal Hospital of Traditional Chinese Medicine (TCM), Affiliated Hospital of Zhejiang Chinese Medical University, No.819 Liyuan North Road, Haishu District, Ningbo 315010, China.
| | - Shuyi Xu
- The Third School of Clinical Medicine (School of Rehabilitation Medicine), Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Zhao Zhong
- Department of Rheumatology, Ningbo Municipal Hospital of Traditional Chinese Medicine (TCM), Affiliated Hospital of Zhejiang Chinese Medical University, No.819 Liyuan North Road, Haishu District, Ningbo 315010, China
| | - Qiongyao Gong
- Department of Rheumatology, Ningbo Municipal Hospital of Traditional Chinese Medicine (TCM), Affiliated Hospital of Zhejiang Chinese Medical University, No.819 Liyuan North Road, Haishu District, Ningbo 315010, China
| | - Qi Wang
- Department of Rheumatology, Ningbo Municipal Hospital of Traditional Chinese Medicine (TCM), Affiliated Hospital of Zhejiang Chinese Medical University, No.819 Liyuan North Road, Haishu District, Ningbo 315010, China
| | - Linjun Yan
- Department of Rheumatology, Ningbo Municipal Hospital of Traditional Chinese Medicine (TCM), Affiliated Hospital of Zhejiang Chinese Medical University, No.819 Liyuan North Road, Haishu District, Ningbo 315010, China
| |
Collapse
|
42
|
Shu F, Wang Y, Li L, Shi L, Zhang F, Ma Z, Mao D. Multi-omics integration and machine learning identify and validate neutrophil extracellular trap-associated gene signatures in chronic rhinosinusitis with nasal polyps. Clin Immunol 2025; 275:110473. [PMID: 40089249 DOI: 10.1016/j.clim.2025.110473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 03/05/2025] [Accepted: 03/07/2025] [Indexed: 03/17/2025]
Abstract
This study aimed to explore the molecular characteristics of neutrophil extracellular traps (NETs) in chronic rhinosinusitis with nasal polyps (CRSwNP). Differentially expressed gene analysis, weighted gene co-expression network analysis, and machine learning algorithms identified three core NETs-associated genes: CXCR4, CYBB, and PTAFR, which were significantly upregulated in CRSwNP patients. The diagnostic performance of these genes was evaluated using receiver operating characteristic (ROC) curves, and their clinical relevance was validated using multicenter data. Immune infiltration analysis showed strong correlations between these genes and neutrophil and immune cell infiltration. Single-cell RNA sequencing demonstrated that these genes were predominantly expressed in myeloid and immune cells and exhibited dynamic changes during disease progression. These genes may contribute to CRSwNP pathogenesis through IL-17 signaling and metabolism-related pathways. This study identifies novel biomarkers and therapeutic targets for precise diagnosis and personalized treatment of CRSwNP.
Collapse
Affiliation(s)
- Fu Shu
- College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400000, People's Republic of China
| | - Yaping Wang
- Department of Otorhinolaryngology, Yongchuan Chinese Medicine Hospital Affiliated to Chongqing Medical University, Chongqing 400000, People's Republic of China
| | - Linglong Li
- Department of Otorhinolaryngology, Yongchuan Chinese Medicine Hospital Affiliated to Chongqing Medical University, Chongqing 400000, People's Republic of China
| | - Lei Shi
- Department of Otorhinolaryngology, The Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang 110847, People's Republic of China
| | - Feng Zhang
- Department of Otorhinolaryngology, Yongchuan Chinese Medicine Hospital Affiliated to Chongqing Medical University, Chongqing 400000, People's Republic of China
| | - Zhixuan Ma
- Department of Otorhinolaryngology, The Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang 110847, People's Republic of China
| | - Dehong Mao
- Department of Otorhinolaryngology, Yongchuan Chinese Medicine Hospital Affiliated to Chongqing Medical University, Chongqing 400000, People's Republic of China.
| |
Collapse
|
43
|
Huynh DTN, Nguyen HT, Hsieh CM. Taiwan Chingguan Yihau may improve post-COVID-19 respiratory complications through PI3K/AKT, HIF-1, and TNF signaling pathways revealed by network pharmacology analysis. Mol Divers 2025; 29:2305-2321. [PMID: 39382736 DOI: 10.1007/s11030-024-10993-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Accepted: 09/14/2024] [Indexed: 10/10/2024]
Abstract
The emergence of new SARS-CoV-2 variants with a higher contagious capability and faster transmissible speed has imposed an incessant menace on global health and the economy. The SARS-CoV-2 infection might reoccur and last much longer than expected. Thence, there is a high possibility that COVID-19 can cause long-term health problems. This condition needs to be investigated thoroughly, especially the post-COVID-19 complications. Respiratory tract disorders are common and typical complications after recovery. Until now, there has been a lack of data on specialized therapeutic medicine for post-COVID-19 complications. The clinical efficacy of NRICM101 has been demonstrated in hospitalized COVID-19 patients. This herbal medicine may also be a promising therapy for post-COVID-19 complications, thanks to its phytochemical constituents. The potential pharmacological mechanisms of NRICM101 in treating post-COVID-19 respiratory complications were investigated using network pharmacology combined with molecular docking, and the results revealed that NRICM101 may exert a beneficial effect through the three primary pathways: PI3K/AKT, HIF-1, and TNF signaling pathways. Flavonoids (especially quercetin) have a predominant role and synergize with other active compounds to produce therapeutic effectiveness. Most of the main active compounds exist in three chief herbal ingredients, including Liquorice root (Glycyrrhiza glabra), Scutellaria root (Scutellaria baicalensis), and Mulberry leaf (Morus alba). To our knowledge, this is the first study of the NRICM101 effect on post-COVID-19 respiratory complications. Our findings may provide a better understanding of the potential mechanisms of NRICM101 in treating SARS-CoV-2 infection and regulating the immunoinflammatory response to improve post-COVID-19 respiratory complications.
Collapse
Affiliation(s)
- Dung Tam Nguyen Huynh
- College of Pharmacy, Taipei Medical University, Taipei, 11031, Taiwan
- Can Tho University of Medicine and Pharmacy, Can Tho City, 94117, Vietnam
| | - Hien Thi Nguyen
- Department of Nutrition and Food Safety, Faculty of Public Health, Can Tho University of Medicine and Pharmacy, Can Tho City, 94117, Vietnam
| | - Chien-Ming Hsieh
- College of Pharmacy, Taipei Medical University, Taipei, 11031, Taiwan.
| |
Collapse
|
44
|
Ninni A, Zaccaria F, Verteramo L, Sciarretta F, Silveira LS, Rosa-Neto JC, Carotti S, Nevi L, Grumati P, Patel S, Carrera G, Sgambato A, Lucchetti D, Colella F, Severi I, Senzacqua M, Giordano A, Bernardini S, Di Biagio C, Tortolici F, Rizzo G, Cochain C, Chiurchiù V, Ivanov S, Zhou B, Williams JW, Savage DB, Aquilano K, Lettieri-Barbato D. MACanalyzeR scRNAseq analysis tool reveals PPARγ HIGH/GDF15 HIGH lipid-associated macrophages facilitate thermogenic expansion in BAT. Nat Commun 2025; 16:5063. [PMID: 40450001 DOI: 10.1038/s41467-025-60295-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 05/13/2025] [Indexed: 06/03/2025] Open
Abstract
Macrophages are key regulators of adipose tissue plasticity. Obesity impairs brown adipose tissue (BAT) function in humans, yet macrophage-mediated mechanisms remain elusive. Here, we introduce MACanalyzeR, a single-cell RNA sequencing (scRNAseq) tool designed for comprehensive monocyte/macrophage metabolic profiling. Applying MACanalyzeR to BAT from obese male murine models (db/db and HFD-fed mice), we identify lipid-associated macrophages (LAMs) with foamy characteristics. Unlike db/db BAT LAMs, those in HFD BAT correlate with thermogenic gene expression and PPAR signaling activation. A distinct PpargHIGH LAM subcluster progressively accumulates in thermogenically active BAT. Macrophage-specific Pparg depletion disrupts BAT thermogenesis, inducing a white-like phenotype and metabolic dysfunctions. Mechanistically, PpargHIGH LAMs secrete GDF15, a key regulator of BAT identity and lipid metabolism under high-energy demand. Our study establishes MACanalyzeR as a powerful tool for immunometabolic interrogation and identifies PpargHIGH LAMs as critical mediators of BAT homeostasis.
Collapse
Affiliation(s)
- Andrea Ninni
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
- PhD Program in Evolutionary Biology and Ecology, Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Fabio Zaccaria
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
- PhD Program in Evolutionary Biology and Ecology, Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Luca Verteramo
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
- PhD Program in Evolutionary Biology and Ecology, Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | | | - Loreana Sanches Silveira
- Immunometabolism Research Group, Department of Cell Biology and Development, Institute of Biomedical Sciences, University of São Paulo (ICB1-USP), São Paulo, Brazil
| | - José Cesar Rosa-Neto
- Immunometabolism Research Group, Department of Cell Biology and Development, Institute of Biomedical Sciences, University of São Paulo (ICB1-USP), São Paulo, Brazil
| | - Simone Carotti
- Microscopic and Ultrastructural Anatomy Research Unit, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy
| | - Lorenzo Nevi
- Microscopic and Ultrastructural Anatomy Research Unit, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy
| | - Paolo Grumati
- Telethon Institute of Genetics and Medicine, Pozzuoli, Italy
- Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy
| | - Satish Patel
- Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - Giulia Carrera
- Laboratory of Resolution of Neuroinflammation, IRCCS Santa Lucia Foundation, Rome, Italy
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Alessandro Sgambato
- Multiplex Spatial Profiling Facility, Fondazione Policlinico Universitario 'Agostino Gemelli' IRCCS, Rome, Italy
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Donatella Lucchetti
- Multiplex Spatial Profiling Facility, Fondazione Policlinico Universitario 'Agostino Gemelli' IRCCS, Rome, Italy
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Filomena Colella
- Multiplex Spatial Profiling Facility, Fondazione Policlinico Universitario 'Agostino Gemelli' IRCCS, Rome, Italy
| | - Ilenia Severi
- Department of Experimental and Clinical Medicine, Marche Polytechnic University, Ancona, Italy
| | - Martina Senzacqua
- Department of Experimental and Clinical Medicine, Marche Polytechnic University, Ancona, Italy
| | - Antonio Giordano
- Department of Experimental and Clinical Medicine, Marche Polytechnic University, Ancona, Italy
- IRCSS INRCA, Ancona, Italy
- Center of Obesity, Marche Polytechnic University-United Hospitals, Ancona, Italy
| | | | | | - Flavia Tortolici
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Giuseppe Rizzo
- Institute of Experimental Biomedicine, University Hospital Würzburg, D16, Würzburg, Germany
| | - Clement Cochain
- Institute of Experimental Biomedicine, University Hospital Würzburg, D16, Würzburg, Germany
- Paris Cardiovascular Research Center, Université Paris Cité, INSERM U970, Paris, France
| | - Valerio Chiurchiù
- Laboratory of Resolution of Neuroinflammation, IRCCS Santa Lucia Foundation, Rome, Italy
- Institute of Translational Pharmacology, National Research Council, Rome, Italy
| | | | - Beiyan Zhou
- Department of Immunology, School of Medicine, University of Connecticut, Farmington, CT, USA
| | - Jesse W Williams
- Center for Immunology, University of Minnesota, Minneapolis, USA
- Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, USA
| | - David B Savage
- Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - Katia Aquilano
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | | |
Collapse
|
45
|
Sin YC, Abernathy B, Yuan ZF, Heier JL, Gonzalez JE, Parker LL, Mashek DG, Chen Y. Sorbate induces lysine sorbylation through noncanonical activities of class I HDACs to regulate the expression of inflammation genes. SCIENCE ADVANCES 2025; 11:eadv1071. [PMID: 40446041 PMCID: PMC12124360 DOI: 10.1126/sciadv.adv1071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Accepted: 04/25/2025] [Indexed: 06/02/2025]
Abstract
Environmental factors may affect gene expression through epigenetic modifications of histones and transcription factors. Here, we report that cellular uptake of sorbate, a common food preservative, induces lysine sorbylation (Ksor) in mammalian cells and tissue mediated by the noncanonical activities of class I histone deacetylases (HDAC1-3). We demonstrated that HDAC1-3 catalyze sorbylation upon sorbate uptake and desorbylation in the absence of sorbate both in vitro and in cells. Sorbate uptake in mice livers significantly induced histone Ksor, correlating with decreased expressions of inflammation-response genes. Accordingly, sorbate treatment in macrophage RAW264.7 cells upon lipopolysaccharide (LPS) stimulation dose-dependently down-regulated proinflammatory gene expressions and nitric oxide production. Proteomic profiling identified RelA, a component of the NF-κB complex, and its interacting proteins as bona fide Ksor targets and sorbate treatment significantly decreased NF-κB transcriptional activities in response to LPS stimulation in RAW264.7 cells. Together, our study demonstrated a noncanonical mechanism of sorbate uptake in regulating epigenetic histone modifications and inflammatory gene expression.
Collapse
Affiliation(s)
- Yi-Cheng Sin
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota Twin Cities, Minneapolis, MN, USA
- Bioinformatics and Computational Biology Program, University of Minnesota Twin Cities, Minneapolis, MN, USA
| | - Breann Abernathy
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota Twin Cities, Minneapolis, MN, USA
| | - Zuo-fei Yuan
- Center for Proteomics and Metabolomics, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Jason L. Heier
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota Twin Cities, Minneapolis, MN, USA
| | - Justin E. Gonzalez
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota Twin Cities, Minneapolis, MN, USA
| | - Laurie L. Parker
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota Twin Cities, Minneapolis, MN, USA
| | - Douglas G. Mashek
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota Twin Cities, Minneapolis, MN, USA
- Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, University of Minnesota Twin Cities, Minneapolis, MN, USA
- Institute for the Biology of Aging and Metabolism, University of Minnesota Twin Cities, Minneapolis, MN, USA
| | - Yue Chen
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota Twin Cities, Minneapolis, MN, USA
| |
Collapse
|
46
|
Cui H, Zhao Y, Li W, Cui H, Han J, Cai E. Design, Synthesis, Anti-Tumor Activity and Molecular Docking Studies of Novel Triphenylphosphine-Containing Formononetin Derivatives. Int J Mol Sci 2025; 26:5280. [PMID: 40508093 PMCID: PMC12154443 DOI: 10.3390/ijms26115280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2025] [Revised: 05/29/2025] [Accepted: 05/29/2025] [Indexed: 06/16/2025] Open
Abstract
Formononetin is widely used in anti-tumor research, but its poor water solubility leads to low absorption and poor utilization efficiency in vivo, limiting further development. The triphenylphosphine cation was partially attached to the 7-position hydroxyl group of formononetin to specifically target it into the mitochondria of tumor cells to enhance the anti-tumor effect. Detailed structural characterization via 1H-NMR and 13C-NMR analysis confirmed the physical properties and chemical structures of 21 newly synthesized derivatives. The effects of these derivatives on tumor cells were assessed by in vitro and computational methods. MTT results from four tumor cell lines showed that formononetin derivatives containing triphenylphosphine had stronger anti-tumor activity than formononetin and exhibited more cytotoxic effects in cancer cells than in normal cells. In particular, the final product 2c (IC50 = 12.19 ± 1.52 μM) showed more potent anti-tumor activity against A549 cells. It was also superior to formononetin and 5-FU. To identify the potential biological targets, the core-expressed gene SHMT2 in lung cancer mitochondria was screened using network pharmacology technology, and molecular docking analysis confirmed the stable binding of the end products to the amino acid residues of the core genes through the formation of hydrogen bonds and via other interactions. In addition, molecular docking simulations further confirmed that the end product exhibited excellent stability when bound to SHMT2. These results suggest that triphenylphosphine-containing formononetin derivatives are worthy of further exploration in the search for novel drug candidates for the treatment of cancer.
Collapse
Affiliation(s)
| | | | | | | | - Jiahong Han
- College of Chinese Medicinal Material, Jilin Agricultural University, 2888 Xincheng Street, Changchun 130118, China; (H.C.); (Y.Z.); (W.L.); (H.C.)
| | - Enbo Cai
- College of Chinese Medicinal Material, Jilin Agricultural University, 2888 Xincheng Street, Changchun 130118, China; (H.C.); (Y.Z.); (W.L.); (H.C.)
| |
Collapse
|
47
|
Sakuludomkan C, Khowsathit J, Thippraphan P, Koonrungsesomboon N, Takuathung MN, Taychaworaditsakul W. Network Pharmacology and Molecular Docking-Based Approach to Explore Potential Bioactive Compounds from Kaempferia parviflora on Chemokine Signaling Pathways in the Treatment of Psoriasis Disease. Int J Mol Sci 2025; 26:5243. [PMID: 40508056 PMCID: PMC12154073 DOI: 10.3390/ijms26115243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2025] [Revised: 05/23/2025] [Accepted: 05/28/2025] [Indexed: 06/16/2025] Open
Abstract
Psoriasis is a chronic inflammatory skin disorder characterized by keratinocyte hyperproliferation and dysregulated chemokine signaling. Kaempferia parviflora (KP) has long been valued for its medicinal properties; however, its specific role in psoriasis treatment remains unclear. This study investigates the anti-psoriatic potential of methoxyflavones derived from KP through an integrated approach combining network pharmacology, molecular docking, and experimental validation. A total of 232 target genes were identified as being associated with KP bioactive compounds, of which 64 overlapped with psoriasis-related genes implicated in chemokine signaling pathways. Molecular docking analyses revealed that key methoxyflavones interact with pivotal proteins such as protein kinase B (AKT1 or AKT), proto-oncogene tyrosine-protein kinase (SRC), and phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1), suggesting their potential involvement in modulating inflammation. Experimental results confirmed that 5,7,4'-trimethoxyflavone and 3,5,7-trimethoxyflavone significantly inhibited keratinocyte proliferation, migration, and macrophage activation, key processes in psoriasis progression. Additionally, both compounds reduced nitric oxide production, supporting their anti-inflammatory effects. Western blot analysis further demonstrated that these compounds tended to decrease the phosphorylation levels of AKT and SRC, supporting their role in influencing inflammatory signaling pathways. These findings suggest that methoxyflavones from KP act through multi-target mechanisms, offering potential as natural therapeutic agents for psoriasis. Further, in vivo studies are needed to validate their efficacy and explore their clinical applications.
Collapse
Affiliation(s)
- Chotiwit Sakuludomkan
- Clinical Research Center for Food and Herbal Product Trials and Development (CR-FAH), Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (C.S.); (N.K.); (M.N.T.)
- Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Jittasak Khowsathit
- Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (J.K.); (P.T.)
| | - Pilaiporn Thippraphan
- Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (J.K.); (P.T.)
| | - Nut Koonrungsesomboon
- Clinical Research Center for Food and Herbal Product Trials and Development (CR-FAH), Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (C.S.); (N.K.); (M.N.T.)
- Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Mingkwan Na Takuathung
- Clinical Research Center for Food and Herbal Product Trials and Development (CR-FAH), Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (C.S.); (N.K.); (M.N.T.)
- Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Weerakit Taychaworaditsakul
- Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (J.K.); (P.T.)
| |
Collapse
|
48
|
Cai H, Lan Y, Liu H, Hao Q. The impact of aging on achilles tendon ossification in mice. BMC Musculoskelet Disord 2025; 26:527. [PMID: 40437419 PMCID: PMC12117786 DOI: 10.1186/s12891-025-08788-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 05/21/2025] [Indexed: 06/01/2025] Open
Abstract
BACKGROUND Heterotopic ossification is a frequent complication of soft tissue injuries, particularly in tendons. Although ossification in tendon tissue has been reported in a range of aging and disease models, the underlying biomarkers and mechanisms remain unknown. And the characterisation and sensitivity of previous diagnostic biomarkers for tendon ectopic ossification do not meet the demands of clinical use. The aim of this study was to characterise the effects of aging on ossification in the mouse Achilles tendon and to identify characteristic genes and therapeutic targets for tendon ossification in mice by using a machine learning approach. METHODS We retrieved the transcriptome profile of GSE126118 from the Gene Expression Omnibus (GEO) database. Following background correction and normalization using the transcripts per million (TPM) method, differentially expressed genes (DEGs) were identified with the limma R package (p < 0.05, |log2FC| > 1). Subsequently, 468 senescence genes were downloaded from the Aging Atlas database, and senescence-associated DEGs (HO senescence genes) were identified. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and protein-protein interaction (PPI) network analyses were conducted on the identified DEGs. To further refine the HO aging signature, support vector machine (SVM) regression was employed. Additionally, we predicted transcription factors, miRNAs, and small molecule drugs potentially associated with the characterized genes. RESULTS Three characterised genes were identified as biomarkers associated with ectopic ossification and aging in the mouse Achilles tendon, Atp5o, Mmp2 and Mmp13. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses revealed significant enrichment in processes related to cartilage endochondral ossification, metalloendopeptidase activity, and mitochondrial proton transport ATP synthase complex. Additionally, HIF-1 and GnRH signaling pathways were prominently represented among the differentially expressed genes. CONCLUSION Atp5o, Mmp2 and Mmp13 were identified as relevant signature genes for the effects of aging on Achilles tendon ossification in mice. Atp5o, Mmp2, and Mmp13 may influence tendon ossification by affecting mitochondrial function as well as extracellular matrix degradation to regulate senescence. This finding suggests a potential link between these processes, opening new avenues for research into diagnostic markers and therapeutic targets. These genes hold promise for the development of novel treatments for tendon ossification, a debilitating condition currently lacking effective therapeutic options.
Collapse
Affiliation(s)
- Hanhua Cai
- Department of Orthopedics, Affiliated Hospital of Putian University, Putian, 351100, Fujian, China
| | - Yujian Lan
- Department of Orthopaedics, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, 646000, Sichuan, China
- Collage of Integrated Traditional Chinese and Western Medicine, Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Huan Liu
- Department of Orthopaedics, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Qi Hao
- Department of Orthopaedics, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, 646000, Sichuan, China.
- The Third People's Hospital of Longmatan District, Luzhou, 646000, Sichuan, China.
| |
Collapse
|
49
|
Zeng F, Li Y, Xu Y, Yu C, Li S, Wei N, Lin L, Yang W, Yang H, Li F, Shang J, Guo M, Yang F, Ji Z, Li K, Liu F, Zhai H. Exploring the optimal timing of HanChuan Zupa Granule for asthma treatment using a comprehensive research approach of "Disease circadian rhythm-drug target prediction-drug efficacy validation". JOURNAL OF ETHNOPHARMACOLOGY 2025; 348:119836. [PMID: 40254112 DOI: 10.1016/j.jep.2025.119836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/07/2024] [Revised: 02/09/2025] [Accepted: 04/17/2025] [Indexed: 04/22/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Hanchuan Zupa Granule(HCZP) is a classic Uygur medicine compound with a long history and proven efficacy. They have been included in the National Essential Medicines List of China and are commonly used in the treatment of asthma. It is of significant importance to elucidate its mechanisms through modern pharmacological research. AIM OF THE STUDY This study proposes a comprehensive research approach combining "disease circadian rhythm-drug target prediction-drug efficacy validation" to explore the optimal timing and mechanism of asthma treatment by examining the relationship between disease, medication, and time, supplemented by experimental investigations. MATERIALS AND METHODS ①Network pharmacology predicted the targets and mechanisms of HCZP's immune modulation in asthma. ②Preliminary research on antiasthmatic medication times from ancient and modern sources identified the most frequent time, which was used for grouping in this study. An ovalbumin-induced asthma model and the lung pathology, pulmonary function, and bronchial obstruction were used to detect the lung condition of asthmatic mice. Serum and lung tissue were analyzed for immunoglobulins and Th2 cytokines. MUC5AC mRNA and protein levels, along with mucus staining, were measured to evaluate airway mucus secretion. RESULTS ①Network pharmacological analyses showed that among the immune response-related pathways, the IL-17 signalling pathway had the highest aggregation and was associated with Th2 cells in asthma pathogenesis. ②In biological effect experiments, HCZP of all time subgroups could delay the progression of asthma pathology to a certain extent, increased FVC, FEV75, PEF, MMEF, IC to different degrees, and down-regulated IgE and Th2 characteristic cytokine expression. In terms of reducing mucus expression, the expression of MUC5AC was inhibited to varying degrees. In the treatment of asthma, the reasonable time to take the medicine is "evening (before going to bed)" CONCLUSION: This study, grounded in the disease circadian rhythm, applies an integrated approach combining drug target prediction and drug efficacy validation to explore the optimal timing for asthma treatment. This method is anticipated to introduce a novel strategy for clinical therapy.
Collapse
Affiliation(s)
- Fengping Zeng
- Standardization Research Center of Traditional Chinese Medicine Dispensing, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Yixuan Li
- Standardization Research Center of Traditional Chinese Medicine Dispensing, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Yan Xu
- Standardization Research Center of Traditional Chinese Medicine Dispensing, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Chenqian Yu
- Standardization Research Center of Traditional Chinese Medicine Dispensing, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Siyu Li
- Standardization Research Center of Traditional Chinese Medicine Dispensing, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Namin Wei
- Standardization Research Center of Traditional Chinese Medicine Dispensing, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Li Lin
- Standardization Research Center of Traditional Chinese Medicine Dispensing, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Wanjun Yang
- Standardization Research Center of Traditional Chinese Medicine Dispensing, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Huanfei Yang
- Standardization Research Center of Traditional Chinese Medicine Dispensing, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Feiyu Li
- Standardization Research Center of Traditional Chinese Medicine Dispensing, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Jing Shang
- Standardization Research Center of Traditional Chinese Medicine Dispensing, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Mengrui Guo
- Standardization Research Center of Traditional Chinese Medicine Dispensing, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Fanlin Yang
- Standardization Research Center of Traditional Chinese Medicine Dispensing, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Zhihong Ji
- New Cicon Pharmaceutical Co. LTD., Urumchi, 830001, China
| | - Keao Li
- New Cicon Pharmaceutical Co. LTD., Urumchi, 830001, China
| | - Fangyao Liu
- Southwest Minzu University, Chengdu, 610041, China.
| | - Huaqiang Zhai
- Standardization Research Center of Traditional Chinese Medicine Dispensing, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China.
| |
Collapse
|
50
|
Liu Q, Parrish RL, Tang S, Tasaki S, Bennett DA, Seyfried NT, De Jager PL, Menon V, Buchman AS, Yang J. Cell-type-specific Transcriptomic-wide Association Studies Detected 91 Independent Risk Genes for Alzheimer's Disease Dementia. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.05.27.25328452. [PMID: 40492066 PMCID: PMC12148273 DOI: 10.1101/2025.05.27.25328452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2025]
Abstract
Existing TWASs of AD dementia typically use a single statistical method to identify cell-type-specific risk genes. Here we sought to improve on existing approaches and utilized an omnibus xWAS pipeline to integrate snRNA-seq dataset (n=415) of dorsolateral prefrontal cortex (DLPFC) and the latest GWAS data of AD dementia to detect cell-type-specific risk genes. We identified 223 cell-type-specific TWAS risk genes across six major brain cell types, including 91 independent associations of which 11 are novel. Integrating proteomics data (n=716) of DLPFC and GWAS data, we identified 21 significant PWAS risk genes including 13 independent associations, overlapping with 32% independent cell-type-specific TWAS associations. Protein-protein interaction network analyses showed that our TWAS findings are functionally linked to established AD risk genes such as APOE, BIN1 , and MAPT . These results underscore the value of leveraging large-scale snRNA-seq and proteomics data to uncover novel cell-type-specific mechanisms underlying AD dementia.
Collapse
|