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Hai B, Zhang Y, Huang J, Mprah R, Wang M. Exploring the key ingredients and mechanisms of Banxia Xiexin decoction for the treatment of polycystic ovary syndrome based on network pharmacology and experimental validation. Ann Med 2025; 57:2503921. [PMID: 40375680 PMCID: PMC12086915 DOI: 10.1080/07853890.2025.2503921] [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: 01/09/2024] [Revised: 04/29/2024] [Accepted: 05/11/2024] [Indexed: 05/18/2025] Open
Abstract
PURPOSE This study aimed to investigate the key bioactive constituents and polypharmacological mechanisms of Banxia Xiexin Decoction (BXD) against polycystic ovary syndrome (PCOS) through integrated network pharmacology and experimental validation. METHODS Network pharmacology was used to determine the key ingredients, potential targets and signaling pathways. 3-week-old female mice were injected subcutaneously with DHEA (6mg/100g body weight) daily to construct a PCOS model and administered different doses BXD and its key ingredients for intervention. Ovarian pathology, vaginal smears, oxidative stress-related indicators, and hub genes were tested to evaluate its therapeutic effects. RESULTS We identified 3 key ingredients and 99 potential targets for BXD treatment of PCOS. Biological functions of these targets were mainly enriched in oxidative stress, hormone response and apoptosis. KEGG analysis showed they were mainly involved in signaling pathways such as PI3K-AKT, MAPK, HIF-1 and IL17. By PPI and algorithmic analysis, we identified 8 hub genes, 5 of which (JUN, MAPK1, MAPK3, FOS, TP53) were related to oxidative stress. Further analysis indicated that quercetin, glycyrrhetinic acid A and naringenin are the three key ingredients of BXD, and they have superior binding effects on the hub genes. Animal experiments demonstrated that BXD and its three key ingredients significantly ameliorated the PCOS symptoms, oxidative stress-related indicators and the expression of hub genes. CONCLUSIONS Five oxidative stress-related hub targets of BXD for PCOS were identified, including FOS, JUN, MAPK3, TP53 and HSP90AA1, while three key ingredients of BXD, quercetin, glycyrrhetinic acid A and naringenin, were uncovered.
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Affiliation(s)
- Bai Hai
- Institute of Applied Biotechnology, College of Agronomy and Life Science, Shanxi Datong University, Datong, P.R. China
| | - Yingying Zhang
- Department of Medical Informatics Engineering, Xuzhou Medical University, Xuzhou, P.R. China
| | - Jing Huang
- Department of Medical Informatics Engineering, Xuzhou Medical University, Xuzhou, P.R. China
| | - Richard Mprah
- Department of Physiology, Basic Medical College, Xuzhou Medical University, Xuzhou, P.R. China
| | - Mingming Wang
- Department of Physiology, Basic Medical College, Xuzhou Medical University, Xuzhou, P.R. China
- National Experimental Teaching Demonstration Center for Basic Medicine, Xuzhou Medical University, Xuzhou, P.R. China
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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.
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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
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Huang L, Li H, Han Y. Exploring the mechanism of Epimedium in treating diabetic nephropathy based on network pharmacology and experimental validation study. Cytotechnology 2025; 77:82. [PMID: 40151768 PMCID: PMC11937453 DOI: 10.1007/s10616-025-00748-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Accepted: 03/21/2025] [Indexed: 03/29/2025] Open
Abstract
Diabetic nephropathy (DN) is a severe complication of diabetes, characterized by chronic inflammation, metabolic disturbances, and progressive renal damage. Natural perennial herb, such as Epimedium, has shown potential therapeutic effects on DN, but its underlying mechanisms remain unclear. This study aimed to explore the pharmacological mechanisms of Epimedium in the treatment of DN through network pharmacology, molecular docking, and experimental validation. Active components of Epimedium were identified using TCMSP and SwissTargetPrediction databases, while DN-related targets were retrieved from GeneCards, DisGeNET, OMIM, and TTD databases. Overlapping targets were analyzed via PPI network and Cytoscape's cytoHubba plugin to identify hub genes. GO and KEGG enrichment analyses were conducted to explore functional pathways. Molecular docking validated the binding affinity between key targets and active components. Finally, high-glucose-induced HK-2 cell injury models were used to verify the protective effects of Epimedium through RT-qPCR, western blotting, and mitochondrial function assays. A total of 224 overlapping targets were identified, with AKT1, TNF, HSP90AA1, and SRC serving as key hub genes. GO and KEGG analyses revealed significant enrichment in pathways such as the PI3K-Akt signaling pathway and lipid metabolism. Molecular docking demonstrated strong interactions between Epimedium components and hub targets. Experimental validation showed that Epimedium restored nephrin and WT1 protein levels, mitigated mitochondrial dysfunction, and reversed high-glucose-induced overexpression of key targets. Epimedium exerts therapeutic effects on DN through multi-target interactions, primarily via the PI3K-Akt pathway, highlighting its potential as a novel treatment for DN. Supplementary Information The online version contains supplementary material available at 10.1007/s10616-025-00748-0.
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Affiliation(s)
- Leyu Huang
- Department of Pharmacy, Shenzhen Bao’an Shiyan People’s Hospital, Shenzhen, Guangdong China
- Bao’an Clinical Institute of Shantou University Medical College, Shantou, Guangdong China
| | - Hui Li
- Department of Pharmacy, Huazhong University of Science and Technology Union Shenzhen Hospital (Former Nanshan District People’s Hospital), Shenzhen, Guangdong China
| | - Ying Han
- Department of Pharmacy, Huazhou Hospital of Traditional Chinese Medicine, Maoming, Guangdong China
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Bieganowski P, Dalidowska I, Gazi O, Guzowska M, Przybylski M. Study of Hsp90α and Hsp90β role in virus replication using cell lines with Hsp90 gene knockouts. Virus Genes 2025; 61:277-283. [PMID: 39948206 DOI: 10.1007/s11262-025-02141-7] [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: 09/18/2024] [Accepted: 02/04/2025] [Indexed: 05/06/2025]
Abstract
Replication of the human Enterovirus 71 (EV71) and herpes simplex virus 1 (HSV-1) requires Hsp90 chaperone activity. Vertebrate cells express two cytosolic Hsp90 proteins, Hsp90α and Hsp90β. Earlier reports suggested that EV71 replication might depend solely on the Hsp90β, whereas HSV-1 replication depended on Hsp90α. Here, we describe construction of the cell line knockouts missing Hsp90α or Hsp90β protein. Using these cells, we found that HSV-1 and, another enterovirus, Coxsackievirus B5 (CVB5) replicate in both Hsp90α and Hsp90β knockout cells with equal efficiency. The presented results demonstrate that cell lines with a mutation inactivating the specific HSP90 gene might be an easy-to-use and robust system to study specific cellular functions of Hsp90α and Hsp90β.
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Affiliation(s)
- Pawel Bieganowski
- Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland
| | - Iga Dalidowska
- Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland
| | - Olga Gazi
- Chair and Depatment of Medical Microbiology, Medical University of Warsaw, Warsaw, Poland
| | - Magdalena Guzowska
- Division of Biochemistry and Dietetics, Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Poland
| | - Maciej Przybylski
- Chair and Depatment of Medical Microbiology, Medical University of Warsaw, Warsaw, Poland.
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Feng Y, Li Z, Sun H, Hu Y, Sun J, Peng Y, Xie K, Sui J, Li Y, Zou J, Xu M. Discovery of antiepileptic Q-Markers for Bombyx batryticatus: Integrating serum pharmacochemistry, network pharmacology and temporal-efficacy validation. JOURNAL OF ETHNOPHARMACOLOGY 2025; 350:119992. [PMID: 40403898 DOI: 10.1016/j.jep.2025.119992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/26/2025] [Revised: 05/13/2025] [Accepted: 05/17/2025] [Indexed: 05/24/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Bombyx batryticatus (BB) is a well-known animal-derived traditional Chinese medicine (TCM) commonly used for the treatment of epilepsy, convulsions, headaches, and other disorders. However, quality evaluation and control of BB remains incomplete, necessitating robust quality control paradigms. AIM OF THE STUDY To identify the Quality markers (Q-markers) of BB for the treatment of epilepsy by integrating serum pharmacochemistry, network pharmacology, HPLC-UV quantification, and temporal-efficacy validation, all in accordance with the core principles of Q-markers. MATERIALS AND METHODS Initially, Q-markers candidates were screened through serum pharmacochemistry-based tracing to achieve "traceability". Additionally, network pharmacology predictions and relevant literature were consulted to confirm potential bioactivity. Next, fingerprint and their contents in BB were determined by HPLC-UV, which provided the dosage basis for the efficacy validation experiment and ensured of "measurability". Finally, their antiepileptic effects were investigated through a temporal pharmacodynamic study using acute pentylenetetrazole (PTZ)-induced mouse epilepsy model to ensure "pharmacological effectiveness". RESULTS HPLC-Q-TOF/MS analysis identified 65 compounds in the BB extract, of which 31 were found in mouse serum, including 9 amino acids, 4 nucleosides, 8 peptides, 5 fatty acids, 3 organic acids and 2 other components. Only 8 cyclic peptides were screened for network pharmacology analysis, and 4 potential bioactive components were selected for HPLC-UV quantification. The average contents of the final selected candidates across 15 batches of BB were as follows: beauvericin at 192.3 μg/g, bassianolide at 325.6 μg/g, and ammonium oxalate at 66515 μg/g. The PTZ model experiment showed that BB powder suspension (0.86 g/kg, i.g.) significantly prolonged seizure latency from 1 to 8 h (P < 0.05) with fluctuating efficacy (the maximum effect Emax1 at 3 h and Emax2 at 8 h). Ammonium oxalate (50 mg/kg, i.g.) demonstrated rapid-onset protection (Emax at 1-2 h), significantly increasing seizure latency at 1-4 h (P < 0.01) and achieving 90 % survival rate at 2 h (vs. 30 % model, P < 0.05), suggesting its role as an active ingredient in the early stage of BB's anticonvulsant effects. Beauvericin and bassianolide showed delayed efficacy (both Emax at 6 h), significantly extending seizure latency at 4-8 h and 2-8 h (P < 0.05), respectively, indicating their potential as active ingredients in the later stage. CONCLUSION Beauvericin, bassianolide and ammonium oxalate could be used as the Q-markers of BB, and the strategy applied in this study could effectively aid in identifying Q-markers for other TCMs.
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Affiliation(s)
- Yunhua Feng
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing, 210029, Jiangsu, China
| | - Zhenyang Li
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing, 210029, Jiangsu, China
| | - Huijie Sun
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing, 210029, Jiangsu, China
| | - Yu Hu
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing, 210029, Jiangsu, China
| | - Jianguo Sun
- China Pharmaceutical University, Nanjing, 210009, Jiangsu, China
| | - Ying Peng
- China Pharmaceutical University, Nanjing, 210009, Jiangsu, China
| | - Kaicheng Xie
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing, 210029, Jiangsu, China
| | - Jinyi Sui
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing, 210029, Jiangsu, China
| | - Yang Li
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing, 210029, Jiangsu, China
| | - Jiandong Zou
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing, 210029, Jiangsu, China.
| | - Meijuan Xu
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing, 210029, Jiangsu, China.
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Liu J, Su Y, Zhang C, Dong H, Yu R, Yang X, Tian Y, Feng Y, Zhang J, Shi M, Wang C, Li W, Liu J, He L, Yang X, Liu H. NCOA3 impairs the efficacy of anti-PD-L1 therapy via HSP90α/EZH2/CXCL9 axis in colon cancer. Int Immunopharmacol 2025; 155:114579. [PMID: 40215778 DOI: 10.1016/j.intimp.2025.114579] [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: 12/05/2024] [Revised: 03/19/2025] [Accepted: 03/27/2025] [Indexed: 04/29/2025]
Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized colon cancer treatment, but their efficacy is largely restricted by the limited presence of CD8+ cytotoxic T lymphocytes (CTLs). However, the specific genetic alterations that impact the CD8+ CTL infiltration in colon cancer remain poorly understood. Here, we analyzed clinical and multi-omics data from the Memorial Sloan-Kettering Cancer Center (MSKCC) ICIs-treated and The Cancer Genome Atlas (TCGA) colon adenocarcinoma (COAD) cohorts to screen the key mutations that may influence the efficacy of immunotherapy. We found that patients with NCOA3 mutations exhibit better response to immunotherapy and higher CD8+ CTL infiltration. In vitro and in vivo experiments revealed that mutant NCOA3 increases the efficacy of anti-PD-L1 and CD8+ CTL recruitment by upregulating C-X-C motif chemokine ligand 9 (CXCL9), which is dependent on its impaired intrinsic histone acetyltransferase activity. Mechanistically, wild-type NCOA3 as histone acetyltransferase upregulates Heat shock protein 90 alpha (HSP90α) by enhancing histone H3 lysine 27 acetylation (H3K27ac) at its promoter region. Increased HSP90α stabilizes Enhancer of zeste homolog 2 (EZH2), which then increase the histone H3 lysine 27 trimethylation (H3K27me3) at the CXCL9 promoter region, thereby suppressing the expression of CXCL9. Targeted inhibition of NCOA3 by small molecular inhibitor SI-2 improves the efficacy of PD-L1 blockade therapy. NCOA3 could serve as a novel biomarker and potential target to improve the efficacy of immunotherapy.
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Affiliation(s)
- Jiaqi Liu
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Yixi Su
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Chi Zhang
- Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Haiyan Dong
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Runfeng Yu
- Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Xin Yang
- Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Yu Tian
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Yanchun Feng
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Jingdan Zhang
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Mengchen Shi
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Chen Wang
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Weiqian Li
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Jun Liu
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Lingyuan He
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Xiangling Yang
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China.
| | - Huanliang Liu
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China.
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Sun X, Wei Z, Su Y, Fang R, Fan Y, Zeng D, Ding Q, Miao Y, Liu J, Sun Q. Structural characteristics and anti-tumor activities of a novel polysaccharide from Klebsiella sp. SXW12. Carbohydr Polym 2025; 356:123368. [PMID: 40049944 DOI: 10.1016/j.carbpol.2025.123368] [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: 09/24/2024] [Revised: 01/27/2025] [Accepted: 02/08/2025] [Indexed: 05/13/2025]
Abstract
The purpose of this study is to elucidate the structure and biological properties of an extracellular polysaccharide (EPS), named EPS12, produced by Klebsiella sp. SXW12, a strain isolated from pond sludge. The maximum EPS12 yield of 15 g/L was obtained after optimizing the fermentation conditions by single-factor effects. EPS12 was an acidic homogeneous polysaccharide, and the molecular weight was measured to be 9.39 × 104 Da. Monosaccharide composition, methylation analysis, and NMR showed that EPS12 backbone was →3)-β-D-Glcp-(1 → 4)-β-D-GlcpA-(1 → 4) -α-L-Fucp-(1→, and terminal-β-D-Glcp was connected to the O-4 of →3)-β-D-Glcp-(1→. Network pharmacology analysis suggested that EPS12 may have anti-cancer effects. The anti-tumor effect of EPS12 on LLC-LUC tumor mice was studied. The results indicated that EPS12 exhibited excellent anti-tumor activity in mice at low doses (1, 2, and 4 mg/kg body weight). In vivo, EPS12 increased spleen index, promoted lymphocyte proliferation, and reduced spleen cell apoptosis through the Bcl-2-Bax/Bak-Caspase-3 apoptotic signaling pathway, and exhibited good biosafety. In addition, EPS12 could partially regulate the metabolic profiles of splenocytes. These properties make EPS12 a potential efficient and cost-effective anti-tumor agent or health product.
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Affiliation(s)
- Xiaqing Sun
- Anhui Key Laboratory of Infection and Immunity, Bengbu Medical University, Bengbu 233030, China; Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical University, Bengbu 233030, China
| | - Zhenxuan Wei
- Anhui Key Laboratory of Infection and Immunity, Bengbu Medical University, Bengbu 233030, China
| | - Yawen Su
- Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical University, Bengbu 233030, China; Key Laboratory of Basic and Clinical Cardiovascular Diseases, Bengbu Medical University, Bengbu 233030, China
| | - Rui Fang
- Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical University, Bengbu 233030, China
| | - Yizhuo Fan
- Anhui Key Laboratory of Infection and Immunity, Bengbu Medical University, Bengbu 233030, China
| | - Dejie Zeng
- Department of Physiology, Bengbu Medical University, Bengbu 233030, China
| | - Qiankun Ding
- Department of Physiology, Bengbu Medical University, Bengbu 233030, China
| | - Yaqiong Miao
- Anhui Key Laboratory of Infection and Immunity, Bengbu Medical University, Bengbu 233030, China; Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical University, Bengbu 233030, China
| | - Junhao Liu
- Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical University, Bengbu 233030, China; Key Laboratory of Basic and Clinical Cardiovascular Diseases, Bengbu Medical University, Bengbu 233030, China.
| | - Qi Sun
- Department of Physiology, Bengbu Medical University, Bengbu 233030, China; Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical University, Bengbu 233030, China; Key Laboratory of Basic and Clinical Cardiovascular Diseases, Bengbu Medical University, Bengbu 233030, China.
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Chen J, Zhang H, Qiu M, Hu J, Lin L, Mai L, Huang G, Chen X, Li X, Qin X, Zhao H. Honokiol in the treatment of triple-negative breast cancer: a network pharmacology approach and experimental validation. Biochem Biophys Res Commun 2025; 771:152008. [PMID: 40398092 DOI: 10.1016/j.bbrc.2025.152008] [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: 05/12/2025] [Accepted: 05/12/2025] [Indexed: 05/23/2025]
Abstract
Triple-negative breast cancer (TNBC) is a rare and highly metastatic form of cancer. Honokiol (HNK), a biphenolic compound, has been utilized in TNBC treatment, though its specific targets remain unclear. This study aimed to elucidate the effects of HNK on TNBC by combining network pharmacology predictions and experimental validation to uncover its mechanisms. MDA-MB 231 and MDA-MB 468 cells were pre-treated with varying doses of HNK for 24 h. Cell viability, proliferation, and apoptosis were assessed using CCK8 and FACS assays, whereas a wound healing assay was used to evaluate cell migration. A tubule formation assay was used to assess blood vessel formation in HUVECs. Additionally, in vivo activity was confirmed using a zebrafish xenograft model. Network pharmacology and molecular docking predicted active ingredients, key targets, and potential mechanisms of HNK against TNBC. Results indicated that HNK induces apoptosis in MDA-MB 231 and MDA-MB 468 cells and inhibits their migration and proliferation. Furthermore, HNK suppressed blood vessel formation. Zebrafish xenograft experiments validated HNK's inhibitory effect on TNBC cells in vivo. Network pharmacology identified 36 potential HNK targets against TNBC, including HSP90AA1, AKT1, EGFR, ERBB2, HSP90AB1, PGR, MDM2, HDAC1, NR3C1, and MAPK14. Key signaling pathways such as PI3K-Akt, MAPK, Rap1, Ras, and FoxO were implicated in HNK's anti-TNBC mechanism. Molecular docking demonstrated spontaneous interactions between HNK and the targeted proteins. In conclusion, HNK may reduce angiogenesis by blocking the EGFR and HSP90AB1 pathways thereby decreasing proliferation and increasing apoptosis in TNBC cells.
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Affiliation(s)
- Jing Chen
- Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, PR China; Medical Research Institute, Guangdong Provincial Key Laboratory of South China Structural Heart Disease, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, PR China
| | - Haipeng Zhang
- Department of Blood Transfusion, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, PR China
| | - Min Qiu
- Department of Cardiovascular Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, PR China
| | - Jiemei Hu
- Department of Gynecology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, PR China
| | - Lu Lin
- Department of Pharmacy, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, PR China
| | - Liping Mai
- Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, PR China
| | - Guiping Huang
- Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, PR China
| | - Xiuyun Chen
- Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, PR China
| | - Xiaohong Li
- Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, PR China
| | - Xianyu Qin
- Department of Thoracic Surgery, Thoracic Cancer Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, PR China.
| | - Haishan Zhao
- Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, PR China.
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9
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Nido GS, Castelli M, Mostafavi S, Rubiolo A, Shadad O, Alves G, Tysnes OB, Flønes IH, Dölle C, Tzoulis C. Single-nucleus transcriptomics reveals disease- and pathology-specific signatures in α-synucleinopathies. Brain 2025; 148:1588-1603. [PMID: 39546628 PMCID: PMC12073976 DOI: 10.1093/brain/awae355] [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] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 10/05/2024] [Accepted: 10/14/2024] [Indexed: 11/17/2024] Open
Abstract
α-Synucleinopathies are progressive neurodegenerative disorders characterized by intracellular aggregation of α-synuclein, but their molecular pathogenesis remains unknown. Here, we explore cell-specific changes in gene expression across different α-synucleinopathies. We perform single-nucleus RNA sequencing on nearly 300 000 nuclei from the prefrontal cortex of individuals with idiopathic Parkinson's disease (PD, n = 20), Parkinson's disease caused by LRRK2 mutations (LRRK2-PD, n = 7), multiple system atrophy (n = 6) and healthy controls (n = 13). Idiopathic PD and LRRK2-PD exhibit a largely overlapping cell type-specific signature, which is distinct from that of multiple system atrophy and includes an overall decrease of the transcriptional output in neurons. Notably, most of the differential expression signal in idiopathic PD and LRRK2-PD is concentrated in a specific deep cortical neuronal subtype expressing adrenoceptor alpha 2A. Although most differentially expressed genes are highly cell type and disease specific, PDE10A is found to be downregulated consistently in most cortical neurons and across all three diseases. Finally, exploiting the variable presence and/or severity of α-synuclein pathology in LRRK2-PD and idiopathic PD, we identify cell type-specific signatures associated with α-synuclein pathology, including a neuronal upregulation of SNCA itself, encoding α-synuclein. Our findings provide new insights into the cell-specific transcriptional landscape of the α-synucleinopathy spectrum.
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Affiliation(s)
- Gonzalo S Nido
- Neuro-SysMed, Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway
- Department of Clinical Medicine, University of Bergen, 5020 Bergen, Norway
- K.G. Jebsen Center for Translational Research in Parkinson’s disease, University of Bergen, 5020 Bergen, Norway
| | - Martina Castelli
- Neuro-SysMed, Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway
| | - Sepideh Mostafavi
- Neuro-SysMed, Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway
| | - Anna Rubiolo
- Neuro-SysMed, Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway
- Department of Clinical Medicine, University of Bergen, 5020 Bergen, Norway
- K.G. Jebsen Center for Translational Research in Parkinson’s disease, University of Bergen, 5020 Bergen, Norway
| | - Omnia Shadad
- Neuro-SysMed, Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway
- Department of Clinical Medicine, University of Bergen, 5020 Bergen, Norway
| | - Guido Alves
- The Norwegian Centre for Movement Disorders and Department of Neurology, Stavanger University Hospital, 4068 Stavanger, Norway
- Department of Mathematics and Natural Sciences, University of Stavanger, 4062 Stavanger, Norway
| | - Ole-Bjørn Tysnes
- Neuro-SysMed, Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway
- Department of Clinical Medicine, University of Bergen, 5020 Bergen, Norway
| | - Irene H Flønes
- Neuro-SysMed, Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway
- Department of Clinical Medicine, University of Bergen, 5020 Bergen, Norway
- K.G. Jebsen Center for Translational Research in Parkinson’s disease, University of Bergen, 5020 Bergen, Norway
| | - Christian Dölle
- Neuro-SysMed, Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway
- Department of Clinical Medicine, University of Bergen, 5020 Bergen, Norway
- K.G. Jebsen Center for Translational Research in Parkinson’s disease, University of Bergen, 5020 Bergen, Norway
| | - Charalampos Tzoulis
- Neuro-SysMed, Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway
- Department of Clinical Medicine, University of Bergen, 5020 Bergen, Norway
- K.G. Jebsen Center for Translational Research in Parkinson’s disease, University of Bergen, 5020 Bergen, Norway
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10
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Li Y, Zhang H, Zeng W, Miao Y, Sun S, Zhang Y, Xiong B. Intermediate Filament Protein BFSP1 Maintains Oocyte Asymmetric Division by Modulating Spindle Length. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2504066. [PMID: 40349178 DOI: 10.1002/advs.202504066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/04/2025] [Revised: 04/15/2025] [Indexed: 05/14/2025]
Abstract
The cytoskeleton is composed of microtubules, microfilaments, and intermediate filaments in cells. While the functions of microtubules and microfilaments have been well elucidated, the roles of intermediate filaments and associated proteins remain largely unknown, especially in meiosis. BFSP1 is an intermediate filament protein mainly expressed in the eye lens to play important roles in the development of congenital cataract. Here, we document that BFSP1 functions as a spindle regulator to drive the oocyte asymmetric division. Specifically, we found that BFSP1 distributed on the spindle apparatus during oocyte meiotic maturation. Depletion of BFSP1 resulted in symmetric division of oocytes, accompanied by the formation of elongated spindles at metaphase I and anaphase/telophase I stages. In addition, immunoprecipitation combined with mass spectrometry analysis identified MAP1B, a microtubule-associated protein, as an interacting partner of BFSP1. Depletion or mutation of MAP1B phenocopied the meiotic defects observed in BFSP1-depleted oocytes, and expression of exogenous MAP1B-EGFP in BFSP1-depleted oocytes recovered the spindle length and asymmetric division. We further determined that BFSP1 recruited molecular chaperone HSP90α on the spindle to stabilize MAP1B, thereby controlling the spindle length. To sum up, our findings reveal a unique meiotic role for BFSP1 in the regulation of spindle dynamics and oocyte asymmetric division.
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Affiliation(s)
- Yu Li
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China
| | - Hanwen Zhang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China
| | - Wenjun Zeng
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China
| | - Yilong Miao
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China
| | - Shaochen Sun
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China
| | - Yu Zhang
- College of Animal Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Bo Xiong
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China
- College of Animal Sciences, Zhejiang University, Hangzhou, 310058, China
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11
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Gao K, Hua K, Wang S, Chen X, Zhu T. Exploring the reproductive exposure risks of phthalates and organophosphates in atmospheric particulate matter based on quantitative structure-activity relationships and network toxicology models. JOURNAL OF HAZARDOUS MATERIALS 2025; 488:137395. [PMID: 39874773 DOI: 10.1016/j.jhazmat.2025.137395] [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: 11/17/2024] [Revised: 01/24/2025] [Accepted: 01/24/2025] [Indexed: 01/30/2025]
Abstract
Minimal study focused on the association between mixed pollutants in atmospheric particulate matter (PM2.5) and their reproductive health risks. Utilizing a novel quantitative structure-activity relationship (QSAR) integrated machine learning algorithms, we evaluated the mixed reproductive health risks associated with phthalates (PAEs) and organophosphates (OPEs) exposure by assessing the affinities of these compounds binding to estrogen receptors (ER) and androgen receptors (AR). The mixed toxicity equivalent factor (TEFmix) and mixed toxicity equivalent quantity (TEQmix) by the QSAR model were all smaller than the sum TEF and TEQ of individual PAEs and OPEs, which may be due to the antagonistic effect of PAEs and OPEs monomers on reproductive toxicity. Based on network toxicology approach, a total of 590 potential targets associated with PAEs and OPEs affecting sex hormones were initially identified, with an additional 50 core targets, including AR and ER. Di-2-ethylhexyl phthalate (DEHP), triphenyl phosphate (TPHP) and mono-(2-ethylhexyl) phthalate (MEHP) were key components to disrupt AR and ER signaling pathway, and was confirmed by molecular docking analysis. In addition to ER and AR, serine/threonine kinase 1 (AKT1) and heat shock protein 90α family A member 1 (HSP90AA1) might be key targets for reproductive toxicity, which have hardly mentioned before. Our study provided precious information on the mixed reproductive exposure risk of PAEs and OPEs in PM2.5, and innovatively explored the potential mechanisms of PAEs and OPEs affecting human reproductive health using network toxicology.
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Affiliation(s)
- Ke Gao
- Key Laboratory of Beijing on Regional Air Pollution Control, Department of Environmental Science, Beijing University of Technology, Beijing, China; SKL-ESPC and BIC-ESAT, College of Environmental Sciences and Engineering, Peking University, Beijing, China.
| | - Kai Hua
- Key Laboratory of Beijing on Regional Air Pollution Control, Department of Environmental Science, Beijing University of Technology, Beijing, China
| | - Shiyuan Wang
- Key Laboratory of Beijing on Regional Air Pollution Control, Department of Environmental Science, Beijing University of Technology, Beijing, China
| | - Xi Chen
- SKL-ESPC and BIC-ESAT, College of Environmental Sciences and Engineering, Peking University, Beijing, China; Hebei Technology Innovation Center of Human Settlement in Green Building, Shenzhen Institute of Building Research Co., Ltd., Xiong'an, China
| | - Tong Zhu
- SKL-ESPC and BIC-ESAT, College of Environmental Sciences and Engineering, Peking University, Beijing, China.
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12
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Chaudhury S, D'Amico T, Blagg BSJ. The Hsp90β Isoform: An Attractive Target for Drug Development. Med Res Rev 2025. [PMID: 40293270 DOI: 10.1002/med.22114] [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: 07/30/2024] [Revised: 02/12/2025] [Accepted: 04/09/2025] [Indexed: 04/30/2025]
Abstract
The beta isoform of 90 kDa heat shock protein (Hsp90β) plays a critical role in maintaining cellular proteostasis by assisting in the folding and refolding of proteins, which is essential for both normal cellular function and stress response. It is constitutively expressed in mammalian cells, differentiating it from the inducible Hsp90α isoform. Hsp90β's involvement in diverse cellular processes, such as signal transduction, cell cycle control, and apoptosis, underscores its significant role in various diseases, including cancer and neurodegenerative disorders. The isoform-specific functions of Hsp90β and its interaction with unique client proteins make it a promising target for therapeutic intervention, particularly in the development of selective inhibitors that avoid the adverse effects observed with pan-Hsp90 inhibitors. This review delves into the structural and functional intricacies of Hsp90β, its role in disease, and the potential for selective drug development.
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Affiliation(s)
- Subhabrata Chaudhury
- Department of Chemistry and Biochemistry, Warren Family Research Center for Drug Discovery and Development, University of Notre Dame, Notre Dame, Indiana, USA
| | - Terin D'Amico
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA
| | - Brian S J Blagg
- Department of Chemistry and Biochemistry, Warren Family Research Center for Drug Discovery and Development, University of Notre Dame, Notre Dame, Indiana, USA
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13
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Wang YM, Wang WC, Pan Y, Zeng L, Wu J, Wang ZB, Zhuang XL, Li ML, Cooper DN, Wang S, Shao Y, Wang LM, Fan YY, He Y, Hu XT, Wu DD. Regional and aging-specific cellular architecture of non-human primate brains. Genome Med 2025; 17:41. [PMID: 40296047 PMCID: PMC12038948 DOI: 10.1186/s13073-025-01469-x] [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: 01/19/2024] [Accepted: 04/08/2025] [Indexed: 04/30/2025] Open
Abstract
BACKGROUND Deciphering the functionality and dynamics of brain networks across different regions and age groups in non-human primates (NHPs) is crucial for understanding the evolution of human cognition as well as the processes underlying brain pathogenesis. However, systemic delineation of the cellular composition and molecular connections among multiple brain regions and their alterations induced by aging in NHPs remain largely unresolved. METHODS In this study, we performed single-nucleus RNA sequencing on 39 samples collected from 10 brain regions of two young and two aged rhesus macaques using the DNBelab C4 system. Validation of protein expression of signatures specific to particular cell types, brain regions, and aging was conducted through a series of immunofluorescence and immunohistochemistry staining experiments. Loss-of-function experiments mediated by short hairpin RNA (shRNA) targeting two age-related genes (i.e., VSNL1 and HPCAL4) were performed in U251 glioma cells to verify their aging effects. Senescence-associated beta-galactosidase (SA-β-gal) staining and quantitative PCR (qPCR) of senescence marker genes were employed to assess cellular senescence in U251 cells. RESULTS We have established a large-scale cell atlas encompassing over 330,000 cells for the rhesus macaque brain. Our analysis identified numerous gene expression signatures that were specific to particular cell types, subtypes, brain regions, and aging. These datasets greatly expand our knowledge of primate brain organization and highlight the potential involvement of specific molecular and cellular components in both the regionalization and functional integrity of the brain. Our analysis also disclosed extensive transcriptional alterations and cell-cell connections across brain regions in the aging macaques. Finally, by examining the heritability enrichment of human complex traits and diseases, we determined that neurological traits were significantly enriched in neuronal cells and multiple regions with aging-relevant gene expression signatures, while immune-related traits exhibited pronounced enrichment in microglia. CONCLUSIONS Taken together, our study presents a valuable resource for investigating the cellular and molecular architecture of the primate nervous system, thereby expanding our understanding of the mechanisms underlying brain function, aging, and disease.
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Affiliation(s)
- Yun-Mei Wang
- State Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China
- Yunnan Key Laboratory of Biodiversity Information, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Wen-Chao Wang
- State Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, Yunnan, China
- National Resource Center for Non-Human Primates, Kunming Primate Research Center, and National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650107, Yunnan, China
- KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, Yunnan, China
| | - Yongzhang Pan
- State Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China
- Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Lin Zeng
- State Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China
- Yunnan Key Laboratory of Biodiversity Information, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Jing Wu
- State Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, Yunnan, China
- National Resource Center for Non-Human Primates, Kunming Primate Research Center, and National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650107, Yunnan, China
- KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, Yunnan, China
| | - Zheng-Bo Wang
- State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Yunnan Key Laboratory of Primate Biomedical Research, Kunming, 650107, China
| | - Xiao-Lin Zhuang
- State Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China
| | - Ming-Li Li
- State Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China
| | - David N Cooper
- Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK
| | - Sheng Wang
- State Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China
- Yunnan Key Laboratory of Biodiversity Information, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Yong Shao
- State Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China
| | - Li-Min Wang
- State Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, Yunnan, China
- National Resource Center for Non-Human Primates, Kunming Primate Research Center, and National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650107, Yunnan, China
- KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, Yunnan, China
| | - Ying-Yin Fan
- State Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, Yunnan, China
- National Resource Center for Non-Human Primates, Kunming Primate Research Center, and National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650107, Yunnan, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, Yunnan, China
| | - Yonghan He
- State Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China.
- Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Xin-Tian Hu
- State Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China.
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, Yunnan, China.
- National Resource Center for Non-Human Primates, Kunming Primate Research Center, and National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650107, Yunnan, China.
- KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, Yunnan, China.
| | - Dong-Dong Wu
- State Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China.
- National Resource Center for Non-Human Primates, Kunming Primate Research Center, and National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650107, Yunnan, China.
- Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, 650201, Yunnan, China.
- KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, Yunnan, China.
- Kunming Natural History Museum of Zoology, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, Yunnan, China.
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14
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Li W, Dasgupta A, Yang K, Wang S, Hemandhar-Kumar N, Chepyala SR, Yarbro JM, Hu Z, Salovska B, Fornasiero EF, Peng J, Liu Y. Turnover atlas of proteome and phosphoproteome across mouse tissues and brain regions. Cell 2025; 188:2267-2287.e21. [PMID: 40118046 PMCID: PMC12033170 DOI: 10.1016/j.cell.2025.02.021] [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: 09/23/2024] [Revised: 01/27/2025] [Accepted: 02/21/2025] [Indexed: 03/23/2025]
Abstract
Understanding how proteins in different mammalian tissues are regulated is central to biology. Protein abundance, turnover, and post-translational modifications such as phosphorylation are key factors that determine tissue-specific proteome properties. However, these properties are challenging to study across tissues and remain poorly understood. Here, we present Turnover-PPT, a comprehensive resource mapping the abundance and lifetime of 11,000 proteins and 40,000 phosphosites in eight mouse tissues and various brain regions using advanced proteomics and stable isotope labeling. We reveal tissue-specific short- and long-lived proteins, strong correlations between interacting protein lifetimes, and distinct impacts of phosphorylation on protein turnover. Notably, we discover a remarkable pattern of turnover changes for peroxisome proteins in specific tissues and that phosphorylation regulates the stability of neurodegeneration-related proteins, such as Tau and α-synuclein. Thus, Turnover-PPT provides fundamental insights into protein stability, tissue dynamic proteotypes, and functional protein phosphorylation and is accessible via an interactive web-based portal at https://yslproteomics.shinyapps.io/tissuePPT.
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Affiliation(s)
- Wenxue Li
- Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA; Cancer Biology Institute, Yale University School of Medicine, West Haven, CT 06516, USA
| | - Abhijit Dasgupta
- Departments of Structural Biology and Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Ka Yang
- Departments of Structural Biology and Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Shisheng Wang
- Department of General Surgery and Liver Transplant Center, Proteomics-Metabolomics Analysis Platform, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Nisha Hemandhar-Kumar
- Department of Neuro- and Sensory Physiology, University Medical Center Göttingen, 37073 Göttingen, Germany
| | - Surendhar R Chepyala
- Departments of Structural Biology and Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Jay M Yarbro
- Departments of Structural Biology and Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Zhenyi Hu
- Cancer Biology Institute, Yale University School of Medicine, West Haven, CT 06516, USA
| | - Barbora Salovska
- Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA; Cancer Biology Institute, Yale University School of Medicine, West Haven, CT 06516, USA
| | - Eugenio F Fornasiero
- Department of Neuro- and Sensory Physiology, University Medical Center Göttingen, 37073 Göttingen, Germany; Department of Life Sciences, University of Trieste, 34127 Trieste, Italy.
| | - Junmin Peng
- Departments of Structural Biology and Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
| | - Yansheng Liu
- Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA; Cancer Biology Institute, Yale University School of Medicine, West Haven, CT 06516, USA; Department of Biomedical Informatics & Data Science, Yale University School of Medicine, New Haven, CT 06510, USA.
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15
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Gao K, Liu R, Zheng C, Wang S, Hua K, Lu L, Guo Z. Differentiated distribution between albumen, yolk and eggshell of parents and metabolites neonicotinoids and their reproductive exposure risk. JOURNAL OF HAZARDOUS MATERIALS 2025; 487:137138. [PMID: 39793386 DOI: 10.1016/j.jhazmat.2025.137138] [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: 09/23/2024] [Revised: 12/15/2024] [Accepted: 01/04/2025] [Indexed: 01/13/2025]
Abstract
Differential distribution of neonicotinoids (NEOs) in albumen, yolk, and eggshell is a critical factor influencing their bio-accumulative behavior and the subsequent human health risks. However, there is currently no relevant research available. We collected 62 egg samples from 31 sampling sites across China and analyzed the concentrations and characteristics of 12 parents NEOs (p-NEOs) and 8 metabolites NEOs (m-NEOs) in albumen, yolk, and eggshell. NEOs were frequently detected in differentiated egg matrices, with the highest concentrations observed in Northeast China. The concentrations of m-NEOs were generally higher than those of p-NEOs. A positive correlation was found between the distribution of m-NEOs in albumen and their logKow (p < 0.05). Dietary intake exposure posed a higher risk of NEOs to children and females. The toxicity equivalence (TEQ) of 5-hydroxy-imidacloprid and thiacloprid-amide, in interaction with androgen and estrogen receptors, was higher compared to other NEOs. Network toxicology and molecular docking indicated that AKT1 may serve as the core target for reproductive toxicity induced by dinotefuran, cycloxaprid, and nitenpyram exposure. This study provided valuable data on the occurrence, differential distribution, and reproductive exposure risk of NEOs in eggs for the first time. These findings are instrumental for future management policies concerning the environmental behavior and health effects of NEOs.
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Affiliation(s)
- Ke Gao
- Key Laboratory of Beijing on Regional Air Pollution Control, Department of Environmental Science, Beijing University of Technology, Beijing 100124, PR China.
| | - Ruyun Liu
- Key Laboratory of Beijing on Regional Air Pollution Control, Department of Environmental Science, Beijing University of Technology, Beijing 100124, PR China
| | - Congyi Zheng
- Key Laboratory of Beijing on Regional Air Pollution Control, Department of Environmental Science, Beijing University of Technology, Beijing 100124, PR China
| | - Shiyuan Wang
- Key Laboratory of Beijing on Regional Air Pollution Control, Department of Environmental Science, Beijing University of Technology, Beijing 100124, PR China
| | - Kai Hua
- Key Laboratory of Beijing on Regional Air Pollution Control, Department of Environmental Science, Beijing University of Technology, Beijing 100124, PR China
| | - Liping Lu
- Key Laboratory of Beijing on Regional Air Pollution Control, Department of Environmental Science, Beijing University of Technology, Beijing 100124, PR China
| | - Zhiyong Guo
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products, PR China.
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Zhang N, Tian X, Liu F, Jin X, Zhang J, Hao L, Jiang S, Liu Q. Reversal of sorafenib resistance in hepatocellular carcinoma by curcumol: insights from network pharmacology, molecular docking, and experimental validation. Front Pharmacol 2025; 16:1514997. [PMID: 40242448 PMCID: PMC12000033 DOI: 10.3389/fphar.2025.1514997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Accepted: 03/24/2025] [Indexed: 04/18/2025] Open
Abstract
Background Curcumol, a bioactive sesquiterpenoid extracted from traditional Chinese medicine (TCM), has demonstrated potential in overcoming tumor drug resistance. However, its mechanisms in reversing drug resistance, particularly in hepatocellular carcinoma (HCC) resistant to sorafenib, are not yet fully elucidated. This study aims to explore the molecular mechanisms by which curcumol reverses sorafenib resistance in HCC using a combination of network pharmacology, molecular docking, and in vivo and in vitro experiments. Methods We identified curcumol targets and genes associated with sorafenib-resistant HCC, resulting in a set of overlapping targets. These intersection targets underwent enrichment analysis using DAVID, and a protein-protein interaction (PPI) network was constructed via the STRING database and Cytoscape. Molecular docking confirmed the binding of curcumol to core targets. In vitro assays, including CCK-8, colony formation assay, apoptosis detection, wound healing, and Transwell assays, evaluated curcumol's effects on sorafenib-resistant HCC cells. Western blotting assessed the impact on PI3K/AKT and JAK/STAT3 signaling pathways. Additionally, a sorafenib-resistant HCC xenograft mouse model was established to observe the in vivo efficacy of curcumol combined with sorafenib. Results We identified 117 potential targets for curcumol in reversing sorafenib resistance in HCC. Among them, five core targets-ALB, STAT3, HSP90AA1, HSP90AB1, and SRC-showed strong binding affinity with curcumol. KEGG pathway analysis of the intersecting genes highlighted significant involvement of the PI3K/AKT, JAK/STAT3, Ras, Rap1, HIF-1, FoxO, and mTOR signaling pathways. In vitro experiments revealed that curcumol significantly enhanced the sensitivity of sorafenib-resistant HCC cells to sorafenib, inhibiting cell proliferation, invasion, and migration while promoting apoptosis. In vivo studies further confirmed that curcumol combined with sorafenib effectively inhibited tumor growth in sorafenib-resistant HCC models. Conclusion This study provides compelling evidence that curcumol can reverse sorafenib resistance in HCC by modulating multiple signaling pathways, including PI3K/AKT and JAK/STAT3 pathways. Our findings suggest that curcumol holds promise as a novel therapeutic agent for overcoming drug resistance in HCC, offering a new avenue for clinical intervention.
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Affiliation(s)
- Ni Zhang
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Xinchen Tian
- Clinical Medical Laboratory Center, Jining First People’s Hospital, Jining Medical University, Jining, Shandong, China
| | - Fen Liu
- Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Xiaohan Jin
- Jining No. 1 People’s Hospital, Shandong First Medical University, Jining, China
- Center for Post-Doctoral Studies, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Jiaqi Zhang
- Clinical Medical Laboratory Center, Jining First People’s Hospital, Jining Medical University, Jining, Shandong, China
| | - Lingli Hao
- Clinical Medical Laboratory Center, Jining First People’s Hospital, Jining Medical University, Jining, Shandong, China
| | - Shulong Jiang
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
- Clinical Medical Laboratory Center, Jining First People’s Hospital, Jining Medical University, Jining, Shandong, China
| | - Qingbin Liu
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
- Clinical Medical Laboratory Center, Jining First People’s Hospital, Jining Medical University, Jining, Shandong, China
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Tian XM, Wang S, Li TJ, Yang XX, Bao YR, Meng XS. Exploring the transformation of chemical components and the discovery of anti-tumor active components in the fruit of Sinopodophyllum hexandrum. Front Nutr 2025; 12:1555318. [PMID: 40230723 PMCID: PMC11994434 DOI: 10.3389/fnut.2025.1555318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2025] [Accepted: 03/12/2025] [Indexed: 04/16/2025] Open
Abstract
Introduction The fruit of Sinopodophyllum hexandrum (FSH) is derived from Sinopodophyllum hexandrum (Royle) Ying, a plant belonging to the family Berberidaceae of the order Ranunculaceae. It is mainly distributed in the Himalayan alpine region, and born in the understory of forests, and wetlands at the edge of forests, thickets or grasses. FSH grows at an altitude of 2,200-4,300 meters above sea level. Its main pharmacological activities include anti-tumor, anti-inflammation, analgesia, heat clearing and detoxification. In the current experiment, ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) was adopted for investigating the chemical components contained in FSH, their transformation patterns in vivo and the potential anti-tumor components, so as to provide an experimental basis for the utilization and development of the resources of FSH. Methods The chemical components of FSH and their transformation patterns in vivo were investigated by UPLC-Q-TOF-MS, and the potential anti-tumor active components were predicted from the in vivo transformed components of FSH by using a network pharmacology approach. Results Totally 85 chemical components were identified in FSH, among which, 61 were flavonoids and 24 were lignans. The above components were transformed in vivo, including 36 prototype components and 13 transformed products. As revealed by the results of network pharmacology on the prediction of anti-tumor components of FSH, 17 compounds such as Kaempferol, Uralenol, and 8-Prenylquercetin in FSH were used as the potential anti-tumor components. Conclusion In this study, the chemical composition, in vivo transformed components of FSH and their metabolites are investigated, and the in vivo transformed components are predicted to have potential anti-tumor pharmacological activities. This study provides the experimental bases for the utilization and development of the resources of FSH.
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Affiliation(s)
- Xiang-mu Tian
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, China
| | - Shuai Wang
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, China
- Liaoning Multi-Dimensional Analysis of Traditional Chinese Medicine Technical Innovation Center, Dalian, China
- Liaoning Province Modern Chinese Medicine Research Engineering Laboratory, Dalian, China
- Shenyang Key Laboratory for Causes and Drug Discovery of Chronic Diseases, Shenyang, China
| | - Tian-jiao Li
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, China
- Liaoning Multi-Dimensional Analysis of Traditional Chinese Medicine Technical Innovation Center, Dalian, China
- Liaoning Province Modern Chinese Medicine Research Engineering Laboratory, Dalian, China
| | - Xin-xin Yang
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, China
- Liaoning Multi-Dimensional Analysis of Traditional Chinese Medicine Technical Innovation Center, Dalian, China
- Liaoning Province Modern Chinese Medicine Research Engineering Laboratory, Dalian, China
- Shenyang Key Laboratory for Causes and Drug Discovery of Chronic Diseases, Shenyang, China
| | - Yong-rui Bao
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, China
- Liaoning Multi-Dimensional Analysis of Traditional Chinese Medicine Technical Innovation Center, Dalian, China
- Liaoning Province Modern Chinese Medicine Research Engineering Laboratory, Dalian, China
- Shenyang Key Laboratory for Causes and Drug Discovery of Chronic Diseases, Shenyang, China
| | - Xian-sheng Meng
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, China
- Liaoning Multi-Dimensional Analysis of Traditional Chinese Medicine Technical Innovation Center, Dalian, China
- Liaoning Province Modern Chinese Medicine Research Engineering Laboratory, Dalian, China
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Liu K, Xu Y, Ying M, Chen M. Impact of a Nanoscale Iron-Chlorobenzene Mixture on Pulmonary Injury in Rat Pups: Extending Exposure Knowledge Using Network Technology. TOXICS 2025; 13:221. [PMID: 40137548 PMCID: PMC11946418 DOI: 10.3390/toxics13030221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/24/2025] [Revised: 03/05/2025] [Accepted: 03/13/2025] [Indexed: 03/29/2025]
Abstract
Particulate matter coexists with persistent organic pollutants (POPs) in the atmosphere, which can enter the human body by accompanying inhalable particles in the respiratory tract. Photochemical conversion further alters the chemical composition of the precursor particles and secondary products. This study investigated the effects of nanoscale iron-chlorobenzene mixtures and their photochemical conversion products on early lung development in rat pups. Using network toxicology and animal experiments, we constructed a compound toxicity-target network and developed air exposure models. This study revealed that both pollutants, before and after photochemical conversion, bound to the aryl hydrocarbon receptor (AhR), increased oxidative stress, altered lung tissue morphology, and reduce inflammatory factor expression. Rat pups were highly sensitive to pollutants during critical stages of lung development. However, no significant differences in oxidative stress or inflammation were observed between the pollutants, likely because of immature lung tissues. Once tissue damage reached a threshold, the response to increasing pollutant concentrations diminished. This study provides insights into atmospheric pollutant toxicity and scientific evidence for the risk assessment of dioxin-like nanoscale mixtures.
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Affiliation(s)
- Kezhou Liu
- School of Automation (Artificial Intelligence), Hangzhou Dianzi University, Hangzhou 310018, China; (Y.X.); (M.Y.)
| | - Ying Xu
- School of Automation (Artificial Intelligence), Hangzhou Dianzi University, Hangzhou 310018, China; (Y.X.); (M.Y.)
| | - Mengjie Ying
- School of Automation (Artificial Intelligence), Hangzhou Dianzi University, Hangzhou 310018, China; (Y.X.); (M.Y.)
| | - Meiling Chen
- School of Environment and Resources, Zhejiang University, Hangzhou 310058, China;
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Li J, Guo Y, Yang Y, Xue Q, Cao H, Yang G, Jia L, Yu H. Preconditioning with acteoside ameliorates myocardial ischemia‑reperfusion injury by targeting HSP90AA1 and the PI3K/Akt signaling pathway. Mol Med Rep 2025; 31:77. [PMID: 39886969 PMCID: PMC11795246 DOI: 10.3892/mmr.2025.13442] [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: 09/25/2024] [Accepted: 12/18/2024] [Indexed: 02/01/2025] Open
Abstract
The present study aimed to investigate the cardioprotective effects of acteoside (AC) on myocardial ischemia‑reperfusion injury (MIRI). To meet this aim, a network pharmacological analysis was conducted to search for key genes and signaling pathways associated with AC and MIRI. The infarct size of the rat heart was evaluated using 2,3,5‑triphenyltetrazolium chloride staining, and the serum levels of creatine kinase MB isoenzyme, cardiac troponin I, malondialdehyde and superoxide dismutase were subsequently detected in an in vivo experiment. The inhibitory effect of AC on oxidative stress was further confirmed by assessing the intracellular accumulation of reactive oxygen species (ROS). Hematoxylin and eosin staining was subsequently carried out to observe cardiac histopathological damage. The anti‑apoptotic effects of AC were determined using terminal deoxynucleotidyl‑transferase‑mediated dUTP nick end labeling assay and Hoechst 33342 staining, and the expression levels of apoptosis‑associated proteins in the myocardial tissue were assessed using immunohistochemical analysis. In addition, cell viability was determined using a Cell Counting Kit‑8 assay, and the expression levels of key target proteins associated with AC and MIRI were detected by western blot analysis. The results suggested that pretreatment with AC could mitigate MIRI‑induced myocardial damage, oxidative stress and apoptosis. The anti‑apoptotic effects of AC were associated with elevated Bcl‑2 levels, and reduced caspase‑3 and Bax expression levels in myocardial tissue. In vitro, AC pretreatment both led to an increased rate of cell survival and alleviated oxidative stress, as demonstrated by a decreased level of intracellular ROS accumulation. Moreover, guided by the network pharmacological analysis, heat‑shock protein 90AA1 (HSP90AA1) and the phosphoinositide 3‑kinase (PI3K)/serine‑threonine protein kinase (Akt) signaling pathway emerged as key targets for the action of AC against MIRI. Furthermore, the western blot analysis results showed that pretreatment with AC led to a significant increase in the activity of the PI3K/Akt signaling pathway, in addition to increased expression levels of glycogen synthase kinase‑3β and HSP90AA1. Taken together, the findings of the present study revealed that AC may exert cardioprotective effects on MIRI through suppressing apoptosis and oxidative stress by regulating the expression and activity of key proteins.
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Affiliation(s)
- Jing Li
- Department of Physiology, Basic Medical College, Jiamusi University, Jiamusi, Heilongjiang 154000, P.R. China
| | - Yuxin Guo
- Department of Physiology, Basic Medical College, Jiamusi University, Jiamusi, Heilongjiang 154000, P.R. China
| | - Yang Yang
- Department of Physiology, Basic Medical College, Jiamusi University, Jiamusi, Heilongjiang 154000, P.R. China
| | - Qing Xue
- Department of Cardiology, The First Affiliated Hospital to Jiamusi University, Jiamusi, Heilongjiang 154000, P.R. China
| | - Hong Cao
- Department of Cardiology, The First Affiliated Hospital to Jiamusi University, Jiamusi, Heilongjiang 154000, P.R. China
| | - Guangyuan Yang
- Department of Cardiology, The First Affiliated Hospital to Jiamusi University, Jiamusi, Heilongjiang 154000, P.R. China
| | - Linlin Jia
- Department of Physiology, Basic Medical College, Jiamusi University, Jiamusi, Heilongjiang 154000, P.R. China
- Department of Medical Nursing, Nursing College, Zhangzhou Health Vocational College, Zhangzhou, Fujian 363000, P.R. China
| | - Haibo Yu
- Department of Cardiology, The First Affiliated Hospital to Jiamusi University, Jiamusi, Heilongjiang 154000, P.R. China
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20
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Qu F, Wang Y, Zhang Y, Chen F, Ai Y, Wen W, Liao J, Li H, Pei H, Lu M, Yang L, Wang N, Cui H. Alisol B 23-Acetate Down-Regulated GRP94 to Restore Endoplasmic Reticulum Homeostasis on Non-Alcoholic Steatohepatitis. Food Sci Nutr 2025; 13:e70086. [PMID: 40051602 PMCID: PMC11883119 DOI: 10.1002/fsn3.70086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 02/18/2025] [Accepted: 02/20/2025] [Indexed: 03/09/2025] Open
Abstract
Non-alcoholic steatohepatitis (NASH) poses a serious threat to human health. Alisol B 23-Acetate (AB23A) has shown beneficial effects on NASH, but its mechanism of action remains unclear. We conducted in vitro experiments by inducing L02 cell damage with free fatty acids (FFA) and administering various concentrations of AB23A. We found that AB23A intervention reduced triglyceride (TG) levels in FFA-induced L02 cells and improved cellular steatosis. Transcriptomic analysis revealed that AB23A intervention significantly downregulated glucose-regulated protein 94 (Grp94), indicating that AB23A primarily regulates the protein processing pathway in the endoplasmic reticulum. Within this pathway, AB23A intervention also significantly downregulated endoplasmic reticulum stress (ERS)-related genes (PERK, eIF2α, ATF4) and ER-associated degradation (ERAD)-related genes (FBXO2, DERL, HSP90AA1). When we silenced GRP94, the regulatory effects of AB23A on TG levels, cellular steatosis, ERS-related proteins (p-PERK/PERK, p-eIF2α/eIF2α, ATF4), and ERAD-related proteins (FBXO2, DERL, HSP90α) disappeared. In vivo, AB23A intervention promoted recovery of the liver index in NASH mice, reduced hepatic inflammatory infiltration and lipid deposition, improved serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, and reduced liver TG levels. RT-qPCR and Western blot results demonstrated that AB23A intervention dose-dependently downregulated the gene and protein expression of GRP94 and ERS- and ERAD-related factors. There was no significant difference between the effects of high-dose AB23A intervention and PPC intervention. This study demonstrated, through both in vitro and in vivo experiments, that AB23A improves hepatic steatosis. This effect may be related to the downregulation of GRP94, which suppresses ERS and ERAD, thereby restoring ER homeostasis.
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Affiliation(s)
- Fei Qu
- Jiaxing Hospital of Traditional Chinese MedicineJiaxingChina
| | - Yuming Wang
- Tianjin University of Traditional Chinese MedicineTianjinChina
| | - Yanping Zhang
- Jiaxing Hospital of Traditional Chinese MedicineJiaxingChina
| | - Feng Chen
- Jiaxing Hospital of Traditional Chinese MedicineJiaxingChina
| | - Yuanliang Ai
- Kunming Municipal Hospital of Traditional Chinese MedicineKunmingChina
| | - Weibo Wen
- Yunnan University of Chinese MedicineKunmingChina
| | - Jiabao Liao
- Yunnan University of Chinese MedicineKunmingChina
| | - Hanzhou Li
- Tianjin University of Traditional Chinese MedicineTianjinChina
| | - Huan Pei
- Yunnan University of Chinese MedicineKunmingChina
| | - Mingxi Lu
- Qingdao Agricultural UniversityQingdaoChina
| | - Ling Yang
- Yunnan University of Chinese MedicineKunmingChina
| | - Ning Wang
- Yunnan University of Chinese MedicineKunmingChina
| | - Huantian Cui
- Yunnan University of Chinese MedicineKunmingChina
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Su M, Zhu J, Bai L, Cao Y, Wang S. Exploring manzamine a: a promising anti-lung cancer agent from marine sponge Haliclona sp. Front Pharmacol 2025; 16:1525210. [PMID: 40070571 PMCID: PMC11893592 DOI: 10.3389/fphar.2025.1525210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Accepted: 02/11/2025] [Indexed: 03/14/2025] Open
Abstract
Manzamine A (MA), a bioactive compound derived from the marine sponge Haliclona sp., shows considerable therapeutic potential, particularly in the treatment of various cancer types. Extracted with acetone and purified through chromatography, MA exhibits a bioavailability of 20.6% when administered orally in rats, underscoring its feasibility for therapeutic use. This compound disrupts key cellular mechanisms essential for cancer progression, including microtubule dynamics and DNA replication enzymes, demonstrating strong anti-proliferative effects against multiple cancer cell lines while sparing normal cells. Additionally, network pharmacology and molecular docking studies reveal MA's interactions with important targets related to lung cancer progression, such as EGFR and SRC, bolstering its potential as a novel anti-lung cancer agent. Pathway analyses further indicate that MA influences critical signaling pathways involved in tumor growth and metastasis. Given the urgent need for effective treatments against drug-resistant cancers and the limited toxicity profile of MA, further exploration of its pharmacological benefits and mechanism could pave the way for new therapeutic strategies in lung cancer.
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Affiliation(s)
- Min Su
- School of Pharmacy, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Jie Zhu
- Department of Scientific Research Management and Foreign Affairs, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Luyuan Bai
- School of Basic Medicine, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Yu Cao
- Clinical Trials Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Shaohui Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Tabuchi Y, Kuroda K, Furusawa Y, Hirano T, Nagaoka R, Omura M, Hasegawa H, Hirayama J, Suzuki N. Genes involved in osteogenic differentiation induced by low‑intensity pulsed ultrasound in goldfish scales. Biomed Rep 2025; 22:18. [PMID: 39651404 PMCID: PMC11621920 DOI: 10.3892/br.2024.1896] [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: 04/02/2024] [Accepted: 07/09/2024] [Indexed: 12/11/2024] Open
Abstract
The teleost scale is a unique calcified tissue that contains osteoclasts, osteoblasts, osteocytes and the bone matrix, similar to mammalian bone. Here, the effects of low-intensity pulsed ultrasound (LIPUS) on osteoblasts and osteoclasts in goldfish scales were investigated. Scales were treated with LIPUS, which is equivalent to use under clinical conditions (30 mW/cm2 for 20 min), then cultured at 15˚C. Alkaline phosphatase activity, a marker of osteoblasts, or tartrate-resistant acid phosphatase (TRAP) activity, a marker of osteoclasts was measured. The gene expression profile was examined using RNA-sequencing. Gene network and biological function analyses were performed using the Ingenuity® Pathways Knowledge Base. A single exposure of LIPUS significantly increased ALP activity but did not affect TRAP activity. These data indicated that LIPUS induced osteoblastic activation in goldfish scales. Using RNA-sequencing, numerous genes that were significantly and differentially expressed 3, 6, and 24 h after LIPUS exposure were observed. Ingenuity® pathway analysis demonstrated that three gene networks, GN-3h, GN-6h, and GN-24h, were obtained from upregulated genes at 3, 6 and 24 h culture, respectively, and included several genes associated with osteoblast differentiation, such as protein kinase D1, prostaglandin-endoperoxide synthase 2, TNFRSF11B (tumor necrosis factor receptor superfamily, member 11b) and WNT3A (Wnt family member 3A). A significant upregulation of expression levels of these genes in scales treated with LIPUS was confirmed by reverse transcription-quantitative polymerase chain reaction. These results contribute to elucidating the molecular mechanisms of osteoblast activation induced by LIPUS.
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Affiliation(s)
- Yoshiaki Tabuchi
- Division of Molecular Genetics Research, Life Science Research Center, University of Toyama, Toyama 930-0194, Japan
| | - Kouhei Kuroda
- Noto Marine Laboratory, Institute of Nature and Environmental Technology, Kanazawa University, Ishikawa 927-0553, Japan
| | - Yukihiro Furusawa
- Department of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, Toyama 939-0398, Japan
| | - Tetsushi Hirano
- Division of Molecular Genetics Research, Life Science Research Center, University of Toyama, Toyama 930-0194, Japan
| | - Ryo Nagaoka
- Laboratory of Medical Information Sensing, Faculty of Engineering, University of Toyama, Toyama 930-8555, Japan
| | - Masaaki Omura
- Laboratory of Medical Information Sensing, Faculty of Engineering, University of Toyama, Toyama 930-8555, Japan
| | - Hideyuki Hasegawa
- Laboratory of Medical Information Sensing, Faculty of Engineering, University of Toyama, Toyama 930-8555, Japan
| | - Jun Hirayama
- Department of Clinical Engineering, Faculty of Health Sciences, Komatsu University, Ishikawa 923-0961, Japan
| | - Nobuo Suzuki
- Noto Marine Laboratory, Institute of Nature and Environmental Technology, Kanazawa University, Ishikawa 927-0553, Japan
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Reynolds TS, Mishra SJ, Blagg BSJ. Assessment of Hsp90β-selective inhibitor safety and on-target effects. Sci Rep 2025; 15:3692. [PMID: 39880847 PMCID: PMC11779861 DOI: 10.1038/s41598-025-86647-y] [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: 10/11/2024] [Accepted: 01/13/2025] [Indexed: 01/31/2025] Open
Abstract
The heat shock protein 90 (Hsp90) family of molecular chaperones mediates the folding and activation of ~ 400 client proteins, many of which contribute to oncogenesis. As a result, Hsp90 pan-inhibitors, which inhibit all four Hsp90 isoforms, have been investigated in the clinic for the treatment of cancer. Unfortunately, detrimental side effects were observed and hindered the clinical development of pan-Hsp90 inhibitors. The two most common on-target toxicities, cardio-toxicity and ocular-toxicity, have been attributed to inhibition of the Hsp90α isoform. As an alternative strategy, Hsp90β-selective inhibitors have been developed, which have shown promising anti-cancer activity in vitro and in vivo in combination with immune-checkpoint blockade therapy. This study aims to assess the potential risks of cardio-toxicity and ocular-toxicity exhibited by Hsp90β-selective inhibitors in vitro. In summary, the Hsp90β-selective NDNB1182 was found to avoid the cardio- and ocular-toxicity typical of Hsp90 pan-inhibitors (e.g. 17-AAG), providing a promising path toward the generation of isoform-selective Hsp90 inhibitors.
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Affiliation(s)
- Tyelor S Reynolds
- Department of Chemistry and Biochemistry, The University of Notre Dame, 305 McCourtney Hall, Notre Dame, IN, 46556, USA
| | - Sanket J Mishra
- Department of Chemistry and Biochemistry, The University of Notre Dame, 305 McCourtney Hall, Notre Dame, IN, 46556, USA
- Grannus Therapeutics Inc., 1400 E Angela Blvd, South Bend, IN, 46617, USA
| | - Brian S J Blagg
- Department of Chemistry and Biochemistry, The University of Notre Dame, 305 McCourtney Hall, Notre Dame, IN, 46556, USA.
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Meng Y, Wang Y, Li S, Cai Z, Zhuang G, Yang Y. Design, Synthesis, and Antitumor Activity of Novel Eupatilin Derivatives Based on the Mannich Reaction. Chem Pharm Bull (Tokyo) 2025; 73:112-120. [PMID: 40010724 DOI: 10.1248/cpb.c24-00599] [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] [Indexed: 02/28/2025]
Abstract
Eupatilin, a natural bioactive flavone, is the active ingredient in traditional Chinese medicine Artemisia argyi Levl. et Vant. To enhance the antitumor effect of eupatilin, we designed a series of novel eupatilin-Mannich derivatives and investigated antitumor activity against several human cancer cell lines, including gastric cancer cells (AGS), esophageal cancer cells (Eca-109), and breast cancer cells (MDA-MB-231). Among all derivatives, the majority demonstrated superior antitumor activity compared to eupatilin, with compound 3d exhibiting the most effective antitumor activity against AGS cells. Furthermore, compound 3d effectively inhibited colony formation and migration of AGS cells. Network pharmacology combined with molecular docking studies indicated that compound 3d exerts antitumor activity by targeting the Hsp90AA1 and multiple signaling pathways. In addition, the Western blot experiment results showed that compound 3d reduced the expression of Hsp90AA1 in AGS cells, indicating that Hsp90AA1 may be the potential target of compound 3d. In summary, several novel eupatilin derivatives were prepared via the Mannich reaction, representing the first structure modification study of eupatilin. The mechanism of action of compound 3d was estimated through cell experiments, network pharmacology, molecular docking, and Western blot experiments, to provide lead compounds for the discovery of natural product-based antitumor candidates.
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Affiliation(s)
- Yaqi Meng
- Center of Scientific Research (Institute of Nanyang Geoherbs), Nanyang Medical College, Nanyang 473061, China
- Key Laboratory of Research on Effective Substances and Quality Control of Traditional Chinese Medicine, Nanyang Medical College, Nanyang 473061, China
| | - Yuqing Wang
- Center of Scientific Research (Institute of Nanyang Geoherbs), Nanyang Medical College, Nanyang 473061, China
- Key Laboratory of Research on Effective Substances and Quality Control of Traditional Chinese Medicine, Nanyang Medical College, Nanyang 473061, China
| | - Shujiao Li
- Center of Scientific Research (Institute of Nanyang Geoherbs), Nanyang Medical College, Nanyang 473061, China
- Key Laboratory of Research on Effective Substances and Quality Control of Traditional Chinese Medicine, Nanyang Medical College, Nanyang 473061, China
| | - Zhiyan Cai
- Center of Scientific Research (Institute of Nanyang Geoherbs), Nanyang Medical College, Nanyang 473061, China
- Key Laboratory of Research on Effective Substances and Quality Control of Traditional Chinese Medicine, Nanyang Medical College, Nanyang 473061, China
| | - Guo Zhuang
- Center of Scientific Research (Institute of Nanyang Geoherbs), Nanyang Medical College, Nanyang 473061, China
- Key Laboratory of Research on Effective Substances and Quality Control of Traditional Chinese Medicine, Nanyang Medical College, Nanyang 473061, China
| | - Yanli Yang
- Center of Scientific Research (Institute of Nanyang Geoherbs), Nanyang Medical College, Nanyang 473061, China
- Key Laboratory of Research on Effective Substances and Quality Control of Traditional Chinese Medicine, Nanyang Medical College, Nanyang 473061, China
- School of Pharmacy, Henan University, Kaifeng 475001, China
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Cui Y, Luo S, Wu B, Li Q, Han F, Wang Z. Immunomodulatory Effects of SPHK1 and Its Interaction with TFAP2A in Yellow Drum ( Nibea albiflora). Int J Mol Sci 2024; 25:13641. [PMID: 39769404 PMCID: PMC11728317 DOI: 10.3390/ijms252413641] [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: 11/05/2024] [Revised: 12/18/2024] [Accepted: 12/19/2024] [Indexed: 01/16/2025] Open
Abstract
Sphingosine kinases (SPHKs) are essential enzymes that catalyze the phosphorylation of sphingosine to produce sphingosine-1-phosphate (S1P), which plays pivotal roles in inflammation and immune regulation. In this study, genome-wide association analysis (GWAS) identified the Ydsphk1 gene as closely associated with the resistance of yellow drum (Nibea albiflora) to Vibrio harveyi. Structural prediction showed that YDSPHK1 contains a typical diacylglycerol kinase catalytic (DAGKc) domain (154-291 aa). By constructing and transfecting Ydsphk1 expression plasmids into yellow drum kidney cells, we found that YDSPHK1 is localized in the cytoplasm. Subsequent RNA-Seq analysis of an overexpression plasmid identified 25 differentially expressed genes (DEGs), including 13 upregulated and 12 downregulated. Notably, nsun5 and hsp90aa1 were significantly upregulated, while Nfkbia and hmox1 were downregulated. Promoter analysis indicated that the core regulatory regions of Ydsphk1 are located between -1931~-1679 bp and -419~+92 bp, with two predicted TFAP2A binding sites in the -419~+92 bp region. Further studies demonstrated that varying concentrations of TFAP2A significantly reduced Ydsphk1 promoter activity. These findings underscore the pivotal role of Ydsphk1 in regulating immune responses in yellow drum, particularly through its impact on key immune-related genes and pathways such as NF-κB signaling and ferroptosis. The identification of Ydsphk1 as a mediator of immune regulation provides valuable insights into the molecular mechanisms of immune defense and highlights its potential as a target for enhancing pathogen resistance in aquaculture practices. This study lays a strong foundation for future research aimed at developing innovative strategies for disease management in aquaculture species.
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Affiliation(s)
- Yu Cui
- State Key Laboratory of Mariculture Breeding, Key Laboratory of Healthy Mariculture for the East China Sea, Fisheries College, Jimei University, Xiamen 361021, China; (Y.C.); (S.L.); (B.W.); (Q.L.)
| | - Shuai Luo
- State Key Laboratory of Mariculture Breeding, Key Laboratory of Healthy Mariculture for the East China Sea, Fisheries College, Jimei University, Xiamen 361021, China; (Y.C.); (S.L.); (B.W.); (Q.L.)
| | - Baolan Wu
- State Key Laboratory of Mariculture Breeding, Key Laboratory of Healthy Mariculture for the East China Sea, Fisheries College, Jimei University, Xiamen 361021, China; (Y.C.); (S.L.); (B.W.); (Q.L.)
| | - Qiaoying Li
- State Key Laboratory of Mariculture Breeding, Key Laboratory of Healthy Mariculture for the East China Sea, Fisheries College, Jimei University, Xiamen 361021, China; (Y.C.); (S.L.); (B.W.); (Q.L.)
| | - Fang Han
- State Key Laboratory of Mariculture Breeding, Key Laboratory of Healthy Mariculture for the East China Sea, Fisheries College, Jimei University, Xiamen 361021, China; (Y.C.); (S.L.); (B.W.); (Q.L.)
| | - Zhiyong Wang
- State Key Laboratory of Mariculture Breeding, Key Laboratory of Healthy Mariculture for the East China Sea, Fisheries College, Jimei University, Xiamen 361021, China; (Y.C.); (S.L.); (B.W.); (Q.L.)
- Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, China
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Kobzeva K, Ivenkov M, Gromov R, Bushueva O. HSP90 Family Members, Their Regulators and Ischemic Stroke Risk: A Comprehensive Molecular-Genetics and Bioinformatics Analysis. Front Biosci (Schol Ed) 2024; 16:19. [PMID: 39736019 DOI: 10.31083/j.fbs1604019] [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: 10/09/2024] [Revised: 11/15/2024] [Accepted: 11/21/2024] [Indexed: 12/31/2024]
Abstract
BACKGROUND Disruptions in proteostasis are recognized as key drivers in cerebro- and cardiovascular disease progression. Heat shock proteins (HSPs), essential for maintaining protein stability and cellular homeostasis, are pivotal in neuroperotection. Consequently, deepening the understanding the role of HSPs in ischemic stroke (IS) risk is crucial for identifying novel therapeutic targets and advancing neuroprotective strategies. AIM Our objective was to examine the potential correlation between single nucleotide polymorphisms (SNPs) in genes that encode members of the Heat shock protein 90 (HSP90), small heat shock proteins (HSPB), and heat shock factors (HSF) families, and the risk and clinical characteristics of IS. METHODS 953 IS patients and 1265 controls from Central Russia were genotyped for nine SNPs in genes encoding HSP90AA1, HSFs, and HSPBs using the MassArray-4 system and probe-based polymerase chain reaction (PCR). RESULTS In smokers, SNP rs1133026 HSPB8 increased the risk of IS (risk allele A, odds ratio (OR) = 1.43, 95% Confidence Interval (CI) 1.02-2.02, p = 0.035), and rs556439 HSF2 increased the brain infarct size (risk allele A, p = 0.02). In non-smokers, SNPs rs4279640 HSF1 (protective allele T, OR = 0.58, 95% CI 0.37-0.92, p = 0.02) and rs4264324 HSP90AA1 (protective allele C, OR = 0.11, 95% CI 0.01-0.78, p = 0.001) lowered the risk of recurrent stroke; SNP rs7303637 HSPB8 increased the age of onset of IS (protective allele T, p = 0.04). In patients with body mass index (BMI) ≥25, SNPs rs556439 HSF2 (risk allele A, OR = 1.33, 95% CI 1.04-1.69, p = 0.02) and rs549302 HSF2 (risk allele G, OR = 1.34, 95% CI 1.02-1.75, p = 0.03) were linked to a higher risk of IS. CONCLUSIONS The primary molecular mechanisms through which the studied SNPs contribute to IS pathogenesis were found to be the regulation of cell death, inflammatory and oxidative stress responses.
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Affiliation(s)
- Ksenia Kobzeva
- Laboratory of Genomic Research, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 305041 Kursk, Russia
| | - Maxim Ivenkov
- Laboratory of Genomic Research, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 305041 Kursk, Russia
| | - Rostislav Gromov
- Laboratory of Genomic Research, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 305041 Kursk, Russia
| | - Olga Bushueva
- Laboratory of Genomic Research, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 305041 Kursk, Russia
- Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, 305041 Kursk, Russia
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Wang X, Mao J. Systematic pharmacology-based strategy to investigate the mechanism of beta-sitosterol for the treatment of rheumarthritis. Front Genet 2024; 15:1507606. [PMID: 39698463 PMCID: PMC11652534 DOI: 10.3389/fgene.2024.1507606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 11/11/2024] [Indexed: 12/20/2024] Open
Abstract
Objective: β-Sitosterol, which is derived from Vladimiriae Radix (VR), is used for the treatment of rheumatoid arthritis (RA), but the pharmacological mechanisms through which β-sitosterol affects RA have not been fully elucidated. Methods: Through the Traditional Chinese Medicine Systems Pharmacology and Analysis (TCMSP), PubChem, SwissTargetPrediction, GeneCards, DisGeNET, and OMIM databases, "β-sitosterol-RA"-related genes were obtained, and a target protein interaction network (protein-protein interaction [PPI]) was constructed. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were carried out for the intersecting genes. Discovery Studio 2019 software was used to perform molecular docking on MMP9, CASP3, HSP90AA1, SRC, EGFR, and ALB genes. β-Sitosterol was co-cultured with MH7A cells in three experimental groups: control group (DMSO), positive drug group (methotrexate, 80 μmol/L), and drug intervention group (10, 20, 40, 80, and 160 μmol/L β-sitosterol). The CCK8 method was used to investigate the inhibitory effect of β-sitosterol on the proliferation of MH7A cells. RT-PCR was used to analyze the mRNA expression of the abovementioned core targets. Results: A total of 41 genes associated with β-sitosterol and RA were obtained, mainly involving the FoxO signaling pathway and PI3K/AKT signaling pathway. The molecular docking results suggested that β-sitosterol could bind effectively to six core targets. The experimental results showed that β-sitosterol could significantly inhibit the excessive proliferation of MH7A cells (p< 0.05). The RT-PCR results showed that the expression of MMP9, HSP90AA1, SRC, EGFR, and ALB core genes in the control group was significantly upregulated, while the CASP3 gene was downregulated. Compared to the control group, the mRNA expression of MMP9, HSP90AA1, SRC, EGFR, and ALB decreased (p< 0.01), while the apoptosis-related gene CASP3 increased in both the drug intervention (80 μmol/L β-sitosterol) and positive drug groups (80 μmol/L methotrexate). Conclusion: Hence, β-sitosterol could contribute to the inhibition of RA by modulating cell proliferation and regulating the aforementioned six core proteins, potentially through the regulation of the FoxO and PI3K/AKT signaling pathways.
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Affiliation(s)
- Xiaodong Wang
- Department of Medical Technology, Chongqing Medical and Pharmaceutical College, Chongqing, China
| | - Jingxin Mao
- Department of Medical Technology, Chongqing Medical and Pharmaceutical College, Chongqing, China
- College of Pharmaceutical Sciences, Southwest University, Chongqing, China
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Feng Z, Wang Y, Liang Y, Gu X, Yang Y, Zhang Y, Peng Q. Development and validation of a prognostic risk score model for hepatocellular carcinoma in the Asian population based on immunogenic cell death-related genes. Discov Oncol 2024; 15:744. [PMID: 39630208 PMCID: PMC11618282 DOI: 10.1007/s12672-024-01630-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 11/25/2024] [Indexed: 12/08/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC), the predominant form of liver cancer, is marked by limited therapeutic success and unfavorable prognoses. Its etiology varies regionally, with hepatitis B virus (HBV) being the predominant cause in most of Asia. Immunogenic cell death (ICD), a specific type of cell death, has been extensively linked to HCC treatment in numerous studies. This research aims to explore the significance of ICD-related genes in the Asian HCC cohort, potentially offering novel approaches for HCC management. METHODS We initially obtained transcriptomic and clinical data pertinent to Asian HCC from the TCGA database. Subsequently, we classified the samples into distinct subgroups according to ICD gene expression levels and conducted analyses of the tumor microenvironment and enrichment. Furthermore, we randomly allocated the samples into training and testing cohorts, thereafter developing and validating an ICD gene-based prognostic model tailored for the Asian HCC population. RESULTS The Asian HCC samples were categorized into two subgroups: high and low ICD expression. In the low ICD expression group, we observed diminished infiltration of immune and stromal cells, increased tumor purity, and improved prognosis. Moreover, we devised a 5-gene risk-score prognostic model comprising BAX, CASP8, HMGB1, HSP90AA1, and IL6, demonstrating efficacy in prognostic predictions for the Asian HCC cohort. CONCLUSION Our investigation unveils new perspectives on the influence of ICDs within Asian HCC populations. The derived 5-gene risk-score prognostic model, based on ICDs, not only serves as a tool for assessing prognosis in Asian HCC cases but also suggests potential therapeutic targets for HCC treatment.
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Affiliation(s)
- Zhengyang Feng
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China
- State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, China
| | - Yanjie Wang
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Yong Liang
- Department of Oncology, The Fifth People's Hospital of Huai'an, Huai'an, China
| | - Xuhao Gu
- Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Yinyin Yang
- Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Yusong Zhang
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China.
| | - Qiliang Peng
- Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China.
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Kizir D, Karaman M, Demir Y, Ceylan H. Effect of tannic acid on doxorubicin-induced cellular stress: Expression levels of heat shock genes in rat spleen. Biotechnol Appl Biochem 2024; 71:1339-1345. [PMID: 38945802 DOI: 10.1002/bab.2633] [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: 05/14/2024] [Accepted: 06/16/2024] [Indexed: 07/02/2024]
Abstract
Doxorubicin (DOX), an anthracycline group antibiotic, has been extensively employed as a potent chemotherapeutic agent for treating solid and hematopoietic tumors in humans. Amid exposure to diverse stress conditions, living organisms swiftly initiate the synthesis of heat shock proteins (HSPs), a set of highly conserved proteins. Tannic acid (TA) has garnered increasing study attention due to its special chemical properties, health benefits, and wide availability. This study's primary aim is to elucidate the impact of DOX and TA on the expression levels of Hsp90aa1, Hspa1a, Hspa4, and Hspa5 in the spleen tissues of rats. Sprague Dawley rats (Rattus norvegicus, male, 9-10 weeks old, 180 ± 20 g) were randomly divided into 4 groups: control, DOX (30 mg/kg cumulative), TA (50 mg/kg), and DOX + TA (5 mg/kg and 50 mg/kg, respectively). Subsequently, spleen tissues were collected from rats, and complementary DNA libraries were generated after the application process. The quantitative real-time PCR method was used to detect and quantify the mRNA expression changes of the Hsp90aa1, Hspa1a, Hspa4, and Hspa5 genes our results showed that the mRNA expressions of the targeted genes were up-regulated in rat spleen tissues exposed to DOX. However, this increase was remarkably suppressed by TA treatment. These findings suggest that TA may serve as a protective agent, mitigating the toxic effects of DOX in the rat spleen.
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Affiliation(s)
- Duygu Kizir
- Department of Molecular Biology and Genetics, Faculty of Science, Atatürk University, Erzurum, Turkey
| | - Melike Karaman
- Department of Molecular Biology and Genetics, Faculty of Science, Atatürk University, Erzurum, Turkey
| | - Yeliz Demir
- Nihat Delibalta Göle Vocational High School, Department of Pharmacy Services, Ardahan University, Ardahan, Turkey
| | - Hamid Ceylan
- Department of Molecular Biology and Genetics, Faculty of Science, Atatürk University, Erzurum, Turkey
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Zheng J, Wang L, Liu A, Shen H, Wang B, Jiang Y, Jing P, Guan D, Yu L, Zhang X. Predicting the therapeutic role and potential mechanisms of Indole-3-acetic acid in diminished ovarian reserve based on network pharmacology and molecular docking. Hereditas 2024; 161:47. [PMID: 39568012 PMCID: PMC11580193 DOI: 10.1186/s41065-024-00348-6] [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: 09/09/2024] [Accepted: 11/10/2024] [Indexed: 11/22/2024] Open
Abstract
BACKGROUND Indole-3-acetic acid (IAA), an indole analog produced by intestinal microorganisms metabolizing tryptophan, has anti-inflammatory and antioxidant properties and thus has potential applications in ovarian protection, although the exact mechanism is unknown. The present study preliminarily investigated the pharmacological mechanism of IAA in alleviating diminished ovarian reserve (DOR) by network pharmacology and molecular docking. METHODS Relevant target proteins of IAA were searched in SwissTargetPrediction, PharmMapper, TargetNet, BATMAN-TCM, and SuperPred databases. The potential targets of DOR were obtained from GeneCards, DisGenet, OMIM, and Drugbank databases. Both common targets were then imported into the String website to construct a PPI network, and these targets were analyzed for GO and KEGG enrichment. Finally, we utilized molecular docking to validate the possible binding conformations between IAA and the candidate targets. We used in vitro experiments to preliminarily investigate the effects of IAA on DOR. RESULTS We obtained 88 potential targets for IAA and DOR interaction. We received 16 pivotal targets by constructed protein interaction screening. KEGG enrichment analysis mainly included the AGE-RAGE signaling pathway, IL-17 signaling pathway, Chemical carcinogenesis-reactive oxygen species in diabetic complications, etc. GO functional analysis showed that IAA treatment of DOR may involve biological processes such as response to external stimuli, hypoxia, gene expression, and regulation of enzyme activity. Molecular docking and in vitro experiments further revealed the potential effects of IAA on MMP2, TNF-α, AKT1, HSP90AA1, and NF-κ B. CONCLUSION We preliminarily revealed the potential protective effects of IAA against DOR through multiple targets and pathways, which provides a new research strategy for the molecular mechanism of IAA to alleviate DOR in the future. However, further studies need to demonstrate whether IAA can be used as a compound to prevent and treat DOR.
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Affiliation(s)
- Jianxiu Zheng
- Lanzhou University, Chengguan District, No. 222 Tian Shui South Road, Lanzhou, Gansu, 730000, People's Republic of China
- The First School of Clinical Medicine, Lanzhou University, Chengguan District, No. 1, Dong Gang Xi Road, Lanzhou, Gansu, 730000, People's Republic of China
| | - Liyan Wang
- The First Hospital of Lanzhou University, Chengguan District, No. 1 Dong Gang Xi Road, Lanzhou, Gansu, 730000, People's Republic of China
- Key Laboratory for Reproductive Medicine and Embryo, Gansu Province, Lanzhou, People's Republic of China
| | - Ahui Liu
- Lanzhou University, Chengguan District, No. 222 Tian Shui South Road, Lanzhou, Gansu, 730000, People's Republic of China
- The First School of Clinical Medicine, Lanzhou University, Chengguan District, No. 1, Dong Gang Xi Road, Lanzhou, Gansu, 730000, People's Republic of China
| | - Haofei Shen
- The First Hospital of Lanzhou University, Chengguan District, No. 1 Dong Gang Xi Road, Lanzhou, Gansu, 730000, People's Republic of China
| | - Bin Wang
- The First Hospital of Lanzhou University, Chengguan District, No. 1 Dong Gang Xi Road, Lanzhou, Gansu, 730000, People's Republic of China
| | - Yanbiao Jiang
- Lanzhou University, Chengguan District, No. 222 Tian Shui South Road, Lanzhou, Gansu, 730000, People's Republic of China
- The First School of Clinical Medicine, Lanzhou University, Chengguan District, No. 1, Dong Gang Xi Road, Lanzhou, Gansu, 730000, People's Republic of China
| | - Panpan Jing
- The First Hospital of Lanzhou University, Chengguan District, No. 1 Dong Gang Xi Road, Lanzhou, Gansu, 730000, People's Republic of China
| | - Defeng Guan
- The First Hospital of Lanzhou University, Chengguan District, No. 1 Dong Gang Xi Road, Lanzhou, Gansu, 730000, People's Republic of China
| | - Liulin Yu
- The First Hospital of Lanzhou University, Chengguan District, No. 1 Dong Gang Xi Road, Lanzhou, Gansu, 730000, People's Republic of China
| | - Xuehong Zhang
- The First Hospital of Lanzhou University, Chengguan District, No. 1 Dong Gang Xi Road, Lanzhou, Gansu, 730000, People's Republic of China.
- Key Laboratory for Reproductive Medicine and Embryo, Gansu Province, Lanzhou, People's Republic of China.
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Park JH, Wandless TJ. p53 engagement is a hallmark of an unfolded protein response in the nucleus of mammalian cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.08.622663. [PMID: 39574672 PMCID: PMC11581032 DOI: 10.1101/2024.11.08.622663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/02/2024]
Abstract
Exposure to exogenous and endogenous stress is associated with the intracellular accumulation of aberrant unfolded and misfolded proteins. In eukaryotic cells, protein homeostasis within membrane-bound organelles is regulated by specialized signaling pathways, with the unfolded protein response in the endoplasmic reticulum serving as a foundational example. Yet, it is unclear if a similar surveillance mechanism exists in the nucleus. Here we leveraged engineered proteins called destabilizing domains to acutely expose mammalian cells to nuclear- or cytosolic- localized unfolded protein. We show that the appearance of unfolded protein in either compartment engages a common transcriptional response associated with the transcription factors Nrf1 and Nrf2. Uniquely, only in the nucleus does unfolded protein activate a robust p53-driven transcriptional response and a transient p53-independent cell cycle delay. These studies highlight the distinct effects of localized protein folding stress and the unique protein quality control environment of the nucleus.
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Ruan C, Wang C, Gu J, Zhu Z. Isoscopoletin inhibits hepatocellular carcinoma cell proliferation via regulating glycolysis-related proteins. PLoS One 2024; 19:e0310530. [PMID: 39509399 PMCID: PMC11542786 DOI: 10.1371/journal.pone.0310530] [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: 04/07/2024] [Accepted: 08/28/2024] [Indexed: 11/15/2024] Open
Abstract
OBJECTIVE Isoscopoletin is one of the primary metabolites of natural product scoparone, which was reported to against tumor proliferation. The aim of this study was to explore the mechanism of isoscopoletin against hepatocellular carcinoma (HCC). METHODS Transcriptomics was used to reveal the possible pathways of isoscopoletin against HCC in vitro. The potential targets of isoscopoletin against HCC through affecting glycolysis were analyzed by network pharmacology, then the potential binding abilities of isoscopoletin to glycolysis-related proteins were initially verified by high throughput virtual molecular docking. The affinities of isoscopoletin for glycolysis-related proteins were assayed using microscale thermophoresis (MST), which was reverse-validated by inhibiting the binding ability of isoscopoletin to GPD2. Glucose consumption and lactate production were examined to evaluate the effects of isoscopoletin on intracellular glycolysis, and the regulation of glycolysis-related targets by isoscopoletin was detected using RT-qPCR and ELISA kits. RESULTS The results of transcriptomics showed that the differentially expressed genes (DEGs) were mainly enriched in glycolysis and other metabolic-related pathways. Network pharmacology and molecular docking revealed that GPD2, GPI, HSP90AA1 and PGK2 were the core targets in the glycolysis process of isoscopoletin against HCC. MST results showed that there was a strong affinity between isoscopoletin and GPD2, GPI, Hsp90α and PGK2. In vitro results showed that isoscopoletin inhibited glucose consumption and lactate production, while regulating the levels of glycolysis-related proteins. CONCLUSION This study suggests that isoscopoletin may exist an anti-tumor effect by regulating the glycolysis-related proteins GPD2, GPI, Hsp90α and PGK2, inhibiting the glycolysis process in HCC cells, then blocking the energy supply of tumor cells.
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Affiliation(s)
- Chenyao Ruan
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Chen Wang
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China
| | - Jiawen Gu
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Zhihui Zhu
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
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Reynolds TS, Blagg BSJ. Extracellular heat shock protein 90 alpha (eHsp90α)'s role in cancer progression and the development of therapeutic strategies. Eur J Med Chem 2024; 277:116736. [PMID: 39126794 PMCID: PMC11374465 DOI: 10.1016/j.ejmech.2024.116736] [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: 06/04/2024] [Revised: 07/30/2024] [Accepted: 08/01/2024] [Indexed: 08/12/2024]
Abstract
Heat shock protein 90 alpha (Hsp90α) is an abundantly expressed and evolutionarily conserved molecular chaperone. Hsp90α is the inducible Hsp90 isoform, and its expression and secretion extracellularly (eHsp90α) can be triggered in response to a variety of cellular stresses to protect/activate client proteins and to facilitate cellular adjustment to the stress. As a result, cancers often have high expression levels of intracellular and extracellular (plasma) Hsp90α, allowing them to support their oncogenesis and progression. In fact, (e)Hsp90α has been implicated in regulating processes such as cell signaling transduction, DNA repair, promotion of the Epithelial-to-Mesenchymal Transition (EMT), promotion of angiogenesis, immune response, and cell migration. Hsp90α levels have been correlated with cancer progression and severity in several cancers, indicating that it may be a useful biomarker or drug-target for cancer. To date, the development of intracellular Hsp90α-targeted therapies include standard N-terminal ATP-competitive inhibitors and allosteric regulators that bind to Hsp90α's middle or C-terminal domain. On-target toxicities and dosing complications as a result of Hsp90α inhibition has driven the development of eHsp90α-targeted therapies. Examples include anti-Hsp90α monoclonal antibodies and cell-impermeable Hsp90α small molecule inhibitors. This review aims to discuss the many roles Hsp90α plays in cancer progression with a focus on the current development of Hsp90α-targeted therapies.
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Affiliation(s)
- Tyelor S Reynolds
- Department of Chemistry and Biochemistry, The University of Notre Dame, 305 McCourtney Hall, Notre Dame, IN, 46556, USA
| | - Brian S J Blagg
- Department of Chemistry and Biochemistry, The University of Notre Dame, 305 McCourtney Hall, Notre Dame, IN, 46556, USA.
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Yu W, Jiang H. Paeoniflorin alleviates high glucose-induced endothelial cell apoptosis in diabetes mellitus by inhibiting HRAS-activated RAS pathway. Endocr J 2024; 71:1045-1053. [PMID: 39085078 PMCID: PMC11778359 DOI: 10.1507/endocrj.ej24-0122] [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: 03/12/2024] [Accepted: 06/18/2024] [Indexed: 08/02/2024] Open
Abstract
Paeoniflorin (Pae) can improve diabetes mellitus (DM), especially endothelial dysfunction induced by high glucose (HG). Molecularly, the mechanism pertinent to Pae and DM lacks further in-depth research. Hence, this study determined the molecular mechanism of Pae in treating DM through network pharmacology. The target of Pae was analyzed by TCMSP database, and DM-related genes were dissected by Genecards database and Omim database. PPI network was constructed for cross targets through Cytoscape 3.9.1 and STRING platform. GO and KEGG analyses were carried out on the cross targets. Protein molecular docking verification was completed by AutoDockTools and Pymol programs. Human umbilical vein endothelial cells (HUVECs) were separately treated with HG, Pae (5, 10, 20 μM) and/or HRAS overexpression plasmids (oe-HRAS). The cell viability, apoptosis and the protein expressions of HRAS and Ras-GTP were evaluated. There were 50 cross targets between Pae and DM, and VEGFA, EGFR, HRAS, SRC and HSP90AA1 were the key genes identified by PPI network analysis. GO and KEGG analyses revealed signal paths such as Rap1 and Ras. Molecular docking results confirmed that Pae had a good binding ability with key genes. In HG-treated HUVECs, Pae dose-dependently facilitated cell viability, attenuated cell apoptosis, and dwindled the expressions of HRAS and Ras-GTP, but these effects of Pae were reversed by oe-HRAS. In conclusion, Pae regulates the viability and apoptosis of HG-treated HUVECs by inhibiting the expression of HRAS.
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Affiliation(s)
- Wenting Yu
- Department of Infection Control, Red Flag Hospital Affiliated to Mudanjiang Medical College, Heilongjiang 157011, China
| | - Hongchun Jiang
- The Third Department of Ophthalmology, Mudanjiang Medical College Affiliated Hongqi Hospital First Branch, Heilongjiang 157099, China
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Chen Y, Tu Y, Cao J, Wang Y, Ren Y. Rhein Alleviates Doxorubicin-Induced Myocardial Injury by Inhibiting the p38 MAPK/HSP90/c-Jun/c-Fos Pathway-Mediated Apoptosis. Cardiovasc Toxicol 2024; 24:1139-1150. [PMID: 39240427 DOI: 10.1007/s12012-024-09917-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Accepted: 08/30/2024] [Indexed: 09/07/2024]
Abstract
Doxorubicin (Dox) has been limited in clinical application due to its cardiac toxicity that varies with the dose. This study aimed to explore how Rhein modulates Dox-induced myocardial toxicity. The general condition and echocardiographic changes of mice were observed to evaluate cardiac function and structure, with myocardial cell injury and apoptosis checked by TUNEL and HE staining. The ELISA assessed markers of myocardial damage and inflammation. The TCMSP and SwissTargetPrediction databases were used to retrieve Rhein's targets while GeneCards was used to find genes related to Dox-induced myocardial injury. Intersection genes were analyzed by Protein-Protein Interaction Networks. The core network genes underwent GO and KEGG enrichment analysis using R software. Western blot was used to detect protein expression. Compared to the Dox group, there was no remarkable difference in heart mass /body mass ratio in the Rhein+Dox group. However, heart mass/tibia length increased. Mice in the Rhein+Dox group had significantly increased LVEF, LVPWs, and LVFS compared to those in the Dox group. Myocardial cell damage, inflammation, and apoptosis significantly reduced in the Rhein+Dox group compared to the model group. Eleven core network genes were selected. Further, Rhein+Dox group showed significantly downregulated expression of p38/p-p38, HSP90AA1, c-Jun/p-c-Jun, c-Fos/p-c-Fos, Bax, and cleaved-caspase-3/caspase-3 while Bcl-2 expression significantly upregulated compared to the Dox group. The study suggests that Rhein mediates cardioprotection against Dox-induced myocardial injury, at least partly, by influencing multiple core genes in the MAPK signaling pathway to inhibit myocardial cell apoptosis.
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Affiliation(s)
- Yong Chen
- Chongqing Hospital of Traditional Chinese Medicine, No.6, Panxi 7th Road, Jiangbei District, Chongqing, 400021, China
| | - Yadan Tu
- Chongqing Hospital of Traditional Chinese Medicine, No.6, Panxi 7th Road, Jiangbei District, Chongqing, 400021, China
| | - Jin Cao
- Chongqing Hospital of Traditional Chinese Medicine, No.6, Panxi 7th Road, Jiangbei District, Chongqing, 400021, China
| | - Yigang Wang
- Chongqing Hospital of Traditional Chinese Medicine, No.6, Panxi 7th Road, Jiangbei District, Chongqing, 400021, China
| | - Yi Ren
- Chongqing Hospital of Traditional Chinese Medicine, No.6, Panxi 7th Road, Jiangbei District, Chongqing, 400021, China.
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Wang Y, Lao Y, Li R, You C, Qing L, Xiao X, Liu S, Wang W, Zhao Y, Dong Z. Network pharmacological analysis and experimental study of melatonin in chronic prostatitis/chronic pelvic pain syndrome. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:8691-8706. [PMID: 38822120 DOI: 10.1007/s00210-024-03183-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Accepted: 05/22/2024] [Indexed: 06/02/2024]
Abstract
This study is aimed at exploring the potential mechanisms of melatonin (MT) in treating chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) using network pharmacology and experimental study. The target genes of MT were acquired from the Swiss Target Prediction, SuperPred, SEA, and PharmMapper databases, and the CP/CPPS targets were collected based on OMIM, DisGeNET, and GeneCards databases. The intersection of MT and CP/CPPS target genes was analyzed. A PPI network was constructed using Cytoscape to identify core targets. The shared targets underwent GO and KEGG enrichment analyses by Using R software. Molecular docking of MT with core targets was performed using AutoDock and PyMOL. GROMACS software was used for molecular dynamics simulation. And using cell experiments to verify the potential effect of MT in CP/CPPS. Network pharmacology analysis reveals 284 shared targets between MT and CP/CPPS, with AKT1, SRC, HSP90AA1, PTGS2, BCL2L1, ALB, CASP3, NFKB1, HIF1A, and ESR1 identified as key targets. Enrichment analysis indicates that MT affects CP/CPPS through various biological processes, and pathway analysis emphasizes the significance of PI3K-Akt, MAPK, Ras, FoxO, HIF-1, EGFR, and apoptosis pathways. Molecular docking confirms strong binding between MT and core targets. It is worth noting that the molecular dynamics simulation showed that the average binding free energy of AKT1, PTGS2, ALB, HSP90AA1 proteins, and MT was - 26.15, - 29.48, - 18.59, and - 20.09 kcal/mol, respectively. These results indicated that AKT1, PTGS2, ALB, and HSP90AA1 proteins were strongly bound to MT. Cell experiments demonstrate that MT can inhibit the secretion of IL-1β, IL-6, and TNF-α in LPS-induced RWPE-1 cells, alleviate inflammation, and suppress cell apoptosis and oxidative stress. Network pharmacology, molecular docking, molecular dynamics simulation, and cell experiments showed that MT could play a role in CP/CPPS by regulating multiple targets and pathways. These findings provide an important scientific basis for further exploration of the molecular mechanism and clinical application of MT in CP/CPPS treatment and are expected to provide new ideas and directions for the development of novel therapeutic strategies.
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Affiliation(s)
- Yanan Wang
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, 730000, Gansu, China
- Institute of Urology, The Second Hospital of Lanzhou University, Lanzhou, 730030, Gansu, China
- Gansu Province Key Laboratory of Urological Diseases, Lanzhou, 730030, Gansu, China
| | - Yongfeng Lao
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, 730000, Gansu, China
- Institute of Urology, The Second Hospital of Lanzhou University, Lanzhou, 730030, Gansu, China
- Gansu Province Key Laboratory of Urological Diseases, Lanzhou, 730030, Gansu, China
| | - Rongxin Li
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, 730000, Gansu, China
- Institute of Urology, The Second Hospital of Lanzhou University, Lanzhou, 730030, Gansu, China
- Gansu Province Key Laboratory of Urological Diseases, Lanzhou, 730030, Gansu, China
| | - Chengyu You
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, 730000, Gansu, China
- Institute of Urology, The Second Hospital of Lanzhou University, Lanzhou, 730030, Gansu, China
- Gansu Province Key Laboratory of Urological Diseases, Lanzhou, 730030, Gansu, China
| | - Liangliang Qing
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, 730000, Gansu, China
- Institute of Urology, The Second Hospital of Lanzhou University, Lanzhou, 730030, Gansu, China
- Gansu Province Key Laboratory of Urological Diseases, Lanzhou, 730030, Gansu, China
| | - Xi Xiao
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, 730000, Gansu, China
- Institute of Urology, The Second Hospital of Lanzhou University, Lanzhou, 730030, Gansu, China
- Gansu Province Key Laboratory of Urological Diseases, Lanzhou, 730030, Gansu, China
| | - Shuai Liu
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, 730000, Gansu, China
- Institute of Urology, The Second Hospital of Lanzhou University, Lanzhou, 730030, Gansu, China
- Gansu Province Key Laboratory of Urological Diseases, Lanzhou, 730030, Gansu, China
| | - Wenyun Wang
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, 730000, Gansu, China
- Institute of Urology, The Second Hospital of Lanzhou University, Lanzhou, 730030, Gansu, China
- Gansu Province Key Laboratory of Urological Diseases, Lanzhou, 730030, Gansu, China
| | - Yu Zhao
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, 730000, Gansu, China
- Institute of Urology, The Second Hospital of Lanzhou University, Lanzhou, 730030, Gansu, China
- Gansu Province Key Laboratory of Urological Diseases, Lanzhou, 730030, Gansu, China
| | - Zhilong Dong
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, 730000, Gansu, China.
- Institute of Urology, The Second Hospital of Lanzhou University, Lanzhou, 730030, Gansu, China.
- Gansu Province Key Laboratory of Urological Diseases, Lanzhou, 730030, Gansu, China.
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Li W, Dasgupta A, Yang K, Wang S, Hemandhar-Kumar N, Yarbro JM, Hu Z, Salovska B, Fornasiero EF, Peng J, Liu Y. An Extensive Atlas of Proteome and Phosphoproteome Turnover Across Mouse Tissues and Brain Regions. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.15.618303. [PMID: 39464138 PMCID: PMC11507808 DOI: 10.1101/2024.10.15.618303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 10/29/2024]
Abstract
Understanding how proteins in different mammalian tissues are regulated is central to biology. Protein abundance, turnover, and post-translational modifications like phosphorylation, are key factors that determine tissue-specific proteome properties. However, these properties are challenging to study across tissues and remain poorly understood. Here, we present Turnover-PPT, a comprehensive resource mapping the abundance and lifetime of 11,000 proteins and 40,000 phosphosites across eight mouse tissues and various brain regions, using advanced proteomics and stable isotope labeling. We revealed tissue-specific short- and long-lived proteins, strong correlations between interacting protein lifetimes, and distinct impacts of phosphorylation on protein turnover. Notably, we discovered that peroxisomes are regulated by protein turnover across tissues, and that phosphorylation regulates the stability of neurodegeneration-related proteins, such as Tau and α-synuclein. Thus, Turnover-PPT provides new fundamental insights into protein stability, tissue dynamic proteotypes, and the role of protein phosphorylation, and is accessible via an interactive web-based portal at https://yslproteomics.shinyapps.io/tissuePPT.
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Affiliation(s)
- Wenxue Li
- Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA
- Cancer Biology Institute, Yale University School of Medicine, West Haven, CT 06516, USA
| | - Abhijit Dasgupta
- Departments of Structural Biology and Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
- Current address: Department of Computer Science and Engineering, SRM University AP, Neerukonda, Guntur, Andhra Pradesh 522240, India
| | - Ka Yang
- Departments of Structural Biology and Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
- Current address: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
| | - Shisheng Wang
- Department of Pulmonary and Critical Care Medicine, and Proteomics-Metabolomics Analysis Platform, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Nisha Hemandhar-Kumar
- Department of Neuro- and Sensory Physiology, University Medical Center Göttingen, 37073 Göttingen, Germany
| | - Jay M. Yarbro
- Departments of Structural Biology and Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Zhenyi Hu
- Cancer Biology Institute, Yale University School of Medicine, West Haven, CT 06516, USA
- Current address: Interdisciplinary Research center on Biology and chemistry, Shanghai institute of Organic chemistry, Chinese Academy of Sciences, Shanghai 201210, China
| | - Barbora Salovska
- Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA
- Cancer Biology Institute, Yale University School of Medicine, West Haven, CT 06516, USA
| | - Eugenio F. Fornasiero
- Department of Neuro- and Sensory Physiology, University Medical Center Göttingen, 37073 Göttingen, Germany
- Department of Life Sciences, University of Trieste, 34127 Trieste, Italy
| | - Junmin Peng
- Departments of Structural Biology and Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Yansheng Liu
- Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA
- Cancer Biology Institute, Yale University School of Medicine, West Haven, CT 06516, USA
- Department of Biomedical Informatics & Data Science, Yale University School of Medicine, New Haven, CT 06510, USA
- Lead Contact
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Ying M, Yang Y, Huo Q, Sun J, Hong X, Yang F, Fang Y, Lu L, Mao T, Xiao P, Tao G. Nrf-2/HO-1 activation protects against oxidative stress and inflammation induced by metal welding fume UFPs in 16HBE cells. Sci Rep 2024; 14:24057. [PMID: 39402078 PMCID: PMC11473639 DOI: 10.1038/s41598-024-74599-8] [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: 06/04/2024] [Accepted: 09/27/2024] [Indexed: 10/17/2024] Open
Abstract
As one of the main occupational hazards, welding fumes can cause oxidative damage and induce series of diseases, such as COPD or asthma. To clarify the effects of the metal fume ultrafine particulates (MF-UFPs) of welding fumes on oxidative damage, UFPs were collected by melt inert gas (MIG) and manual metal arc (MMA) welding, and the composition was confirmed. Human bronchial epithelial 16HBE cells were treated with 0-1000 µg/cm2 MF-UFPs to analyse the cytotoxicity, oxidative stress and cytokines. The protein and mRNA expression of Keap1-Nrf-2/antioxidant response elements (AREs) signalling pathway components were also analysed. After 4 h of treatment, the cell viability decreased 25% after 33.85 and 32.81 µg/cm2 MIG/MMA-UFPs treated. The intracellular ATP concentrations were also decreased significantly, while LDH leakage was increased. The decreased mitochondrial membrane potential and increased ROS suggested the occurrence of oxidative damage, and the results of proteome profiling arrays also showed a significant increase in IL-6 and IL-8. The expression of AREs which related to antioxidant and anti-inflammatory were also increased. These results indicate that the MF-UFPs can cause oxidative stress in 16HBE cells and activate the Nrf-2/ARE signalling pathway to against oxidative damage.
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Affiliation(s)
- Mengchao Ying
- Shanghai Municipal Center for Disease Control & Prevention, Shanghai, 200336, China
- State Environmental Protection Key Laboratory of Environmental Health Impact Assessment of Emerging Contaminants, Shanghai, 200233, China
| | - Yun Yang
- Shanghai Municipal Center for Disease Control & Prevention, Shanghai, 200336, China
- State Environmental Protection Key Laboratory of Environmental Health Impact Assessment of Emerging Contaminants, Shanghai, 200233, China
| | - Qian Huo
- Shanghai Municipal Center for Disease Control & Prevention, Shanghai, 200336, China
- State Environmental Protection Key Laboratory of Environmental Health Impact Assessment of Emerging Contaminants, Shanghai, 200233, China
| | - Jingqiu Sun
- Shanghai Municipal Center for Disease Control & Prevention, Shanghai, 200336, China
- State Environmental Protection Key Laboratory of Environmental Health Impact Assessment of Emerging Contaminants, Shanghai, 200233, China
| | - Xinyu Hong
- Shanghai Municipal Center for Disease Control & Prevention, Shanghai, 200336, China
- State Environmental Protection Key Laboratory of Environmental Health Impact Assessment of Emerging Contaminants, Shanghai, 200233, China
| | - Feng Yang
- Shanghai Municipal Center for Disease Control & Prevention, Shanghai, 200336, China
| | - Yamin Fang
- Shanghai Municipal Center for Disease Control & Prevention, Shanghai, 200336, China
- State Environmental Protection Key Laboratory of Environmental Health Impact Assessment of Emerging Contaminants, Shanghai, 200233, China
| | - Lingyi Lu
- Xuhui District Center for Disease Control and Prevention, Shanghai, 200237, China
| | - Tingfeng Mao
- Xuhui District Center for Disease Control and Prevention, Shanghai, 200237, China
| | - Ping Xiao
- Shanghai Municipal Center for Disease Control & Prevention, Shanghai, 200336, China.
- State Environmental Protection Key Laboratory of Environmental Health Impact Assessment of Emerging Contaminants, Shanghai, 200233, China.
| | - Gonghua Tao
- Shanghai Municipal Center for Disease Control & Prevention, Shanghai, 200336, China.
- State Environmental Protection Key Laboratory of Environmental Health Impact Assessment of Emerging Contaminants, Shanghai, 200233, China.
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Bahmei A, Karimi F, Mahini SM, Irandoost H, Tandel P, Niknam H, Tamaddon G. Targeting telomerase with MST-312 leads to downregulation of CCND1, MDM2, MYC, and HSP90AA1 and induce apoptosis in Jurkat cell line. Med Oncol 2024; 41:267. [PMID: 39400638 DOI: 10.1007/s12032-024-02412-7] [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: 12/04/2023] [Accepted: 05/23/2024] [Indexed: 10/15/2024]
Abstract
Acute lymphoblastic leukemia is a challenging disease to treat, especially in older adults who are most commonly diagnosed and have a high risk of relapse, even with current treatment options. MST-312, targets the RNA component of telomerase, inhibiting its activity and leading to growth arrest and telomere shortening in cancer cells. This study aimed to investigate the effects of MST-312 on apoptosis rates and the expression of telomerase target genes, CCND1, MDM2, MYC, and HSP90AA1, in Jurkat cell line. Jurkat cell line was cultured and treated with various concentrations of MST-312(0 µM, 0.5 µM, 1 µM, 2 µM, and 4 µM). The optimal concentration of MST-312 was determined using MTT assay. Flow cytometry was employed to evaluate the apoptosis induced by MST-312 treatment. The expression levels of the target genes were measured using real-time polymerase chain reaction before and after the treatment with MST-312. P-value < 0.05 was considered statistically significant. The percentages of apoptotic cells after 48 h, as determined by flow cytometry analysis, were 30.32%, 52.35%, 57.60%, and 68.82%, respectively, compared to the control group which was 4.6%. The expression levels of all genes, including CCND1, MDM2, MYC, and HSP90AA1, were decreased compared to the control group. The results showed that MST-312 induced dose- and time-dependent apoptosis and downregulated the expression of CCND1, MDM2, MYC, and HSP90AA1in Jurkat cell line.
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Affiliation(s)
- Atefeh Bahmei
- Division of Hematology and Blood Bank, Department of Medical Laboratory Sciences, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Fatemeh Karimi
- Shiraz Molecular Pathology Research Center, Daneshbod Path Lab, Shiraz, Iran
| | - Seyed Moein Mahini
- Division of Hematology and Blood Bank, Department of Medical Laboratory Sciences, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hamed Irandoost
- Division of Hematology and Blood Bank, Department of Medical Laboratory Sciences, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Parisa Tandel
- Division of Hematology and Blood Bank, Department of Medical Laboratory Sciences, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Homa Niknam
- Division of Hematology and Blood Bank, Department of Medical Laboratory Sciences, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Gholmhossein Tamaddon
- Diagnostic Laboratory Sciences and Technology Research Center, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran.
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Xu Z, Rasteh AM, Dong A, Wang P, Liu H. Identification of molecular targets of Hypericum perforatum in blood for major depressive disorder: a machine-learning pharmacological study. Chin Med 2024; 19:141. [PMID: 39385284 PMCID: PMC11465934 DOI: 10.1186/s13020-024-01018-5] [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: 06/05/2024] [Accepted: 10/01/2024] [Indexed: 10/12/2024] Open
Abstract
BACKGROUND Major depressive disorder (MDD) is one of the most common psychiatric disorders worldwide. Hypericum perforatum (HP) is a traditional herb that has been shown to have antidepressant effects, but its mechanism is unclear. This study aims to identify the molecular targets of HP for the treatment of MDD. METHODS We performed differential analysis and weighted gene co-expression network analysis (WGCNA) with blood mRNA expression cohort of MDD and healthy control to identify DEGs and significant module genes (gene list 1). Three databases, CTD, DisGeNET, and GeneCards, were used to retrieve MDD-related gene intersections to obtain MDD-predicted targets (gene list 2). The validated targets were retrieved from the TCMSP database (gene list 3). Based on these three gene lists, 13 key pathways were identified. The PPI network was constructed by extracting the intersection of genes and HP-validated targets on all key pathways. Key therapeutic targets were obtained using MCODE and machine learning (LASSO, SVM-RFE). Clinical diagnostic assessments (Nomogram, Correlation, Intergroup expression), and gene set enrichment analysis (GSEA) were performed for the key targets. In addition, immune cell analysis was performed on the blood mRNA expression cohort of MDD to explore the association between the key targets and immune cells. Finally, molecular docking prediction was performed for the targets of HP active ingredients on MDD. RESULTS Differential expression analysis and WGCNA module analysis yielded 933 potential targets for MDD. Three disease databases were intersected with 982 MDD-predicted targets. The TCMSP retrieved 275 valid targets for HP. Separate enrichment analysis intersected 13 key pathways. Five key targets (AKT1, MAPK1, MYC, EGF, HSP90AA1) were finally screened based on all enriched genes and HP valid targets. Combined with the signaling pathway and immune cell analysis suggested the effect of peripheral immunity on MDD and the important role of neutrophils in immune inflammation. Finally, the binding of HP active ingredients (quercetin, kaempferol, and luteolin) and all 5 key targets were predicted based on molecular docking. CONCLUSIONS The active constituents of Hypericum perforatum can act on MDD and key targets and pathways of this action were identified.
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Affiliation(s)
- Zewen Xu
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | | | | | - Panpan Wang
- The First Affiliated Hospital of Jinan University, Guangzhou, China.
| | - Hengrui Liu
- Cancer Research Institute, Jinan University, Guangzhou, China.
- Tianjin Yinuo Biomedical Co., Ltd, Tianjin, China.
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Hu S, Tang Y, Li X, Li W, Zeng Y, Jiang M, Chen R, Zheng P, Yang L, Song Z, Xie D, Chen Y, Yuan Y. Hsp90aa1/JUN/Ccl2 regulatory axis mediates migration and differentiation of NSPCs, promoting the onset and progression of early post-ischemic stroke epilepsy. Neurobiol Dis 2024; 200:106635. [PMID: 39128813 DOI: 10.1016/j.nbd.2024.106635] [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: 01/27/2024] [Revised: 08/07/2024] [Accepted: 08/08/2024] [Indexed: 08/13/2024] Open
Abstract
Early-onset epilepsy following ischemic stroke is a severe neurological condition, the pathogenesis of which remains incompletely understood. Recent studies suggest that Neural stem/progenitor cells (NSPCs) play a crucial role in the disease process, yet the precise molecular mechanisms regulating NSPCs have not been thoroughly investigated. This study utilized single-cell transcriptome sequencing and bioinformatics analysis to identify disease-related genes, which were subsequently validated in both in vitro and in vivo experiments. The findings revealed that Hsp90aa1 (heat shock protein 90 kDa alpha, class A member 1), Jun proto-oncogene (JUN), and CC Motif Ligation 2 (Ccl2) constitute an important regulatory axis influencing the migration and differentiation of NSPCs, potentially impacting the onset and progression of early-onset epilepsy post-ischemic stroke. Additionally, the expression of Hsp90aa1 was found to influence the likelihood of seizure occurrence and the severity of brain ischemia.
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Affiliation(s)
- Shuntong Hu
- Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Yongzhong Tang
- Department of Anesthesiology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Xiaobo Li
- Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Wenjun Li
- Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Yini Zeng
- Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Mi Jiang
- Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China; Department of Neurology, University of Michigan, Ann Arbor, MI, USA
| | - Ru Chen
- Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Ping Zheng
- Department of Neurosurgery, Shanghai Pudong New Area People's Hospital, Shanghai, China
| | - Liang Yang
- Department of Neurosurgery, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Zhi Song
- Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Dujie Xie
- Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China.
| | - Yiwei Chen
- Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China.
| | - Yi Yuan
- Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China.
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42
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Wang Y, Li S, Ren T, Zhang Y, Li B, Geng X. Mechanism of emodin in treating hepatitis B virus-associated hepatocellular carcinoma: network pharmacology and cell experiments. Front Cell Infect Microbiol 2024; 14:1458913. [PMID: 39346898 PMCID: PMC11427391 DOI: 10.3389/fcimb.2024.1458913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Accepted: 08/27/2024] [Indexed: 10/01/2024] Open
Abstract
Introduction Hepatocellular carcinoma (HCC) is a pressing global issue, with Hepatitis B virus (HBV) infection remaining the primary. Emodin, an anthraquinone compound extracted from the natural plant's. This study investigates the molecular targets and possible mechanisms of emodin in treating HBV-related HCC based on network pharmacology and molecular docking and validates the screened molecular targets through in vitro experiments. Methods Potential targets related to emodin were obtained through PubChem, CTD, PharmMapper, SuperPred, and TargetNet databases. Potential disease targets for HBV and HCC were identified using the DisGeNET, GeneCards, OMIM, and TTD databases. A Venn diagram was used to determine overlapping genes between the drug and the diseases. Enrichment analysis of these genes was performed using GO and KEGG via bioinformatics websites. The overlapping genes were imported into STRING to construct a protein-protein interaction network. Cytoscape 3.9.1 software was used for visualizing and analyzing the core targets. Molecular docking analysis of the drug and core targets was performed using Schrodinger. The regulatory effects of emodin on these core targets were validate through in vitro experiments. Results A total of 43 overlapping genes were identified. GO analysis recognized 926 entries, and KEGG analysis identified 135 entries. The main pathways involved in the KEGG analysis included cancer, human cytomegalovirus infection and prostate cancer. The binding energies of emodin with HSP90AA1, PTGS2, GSTP1, SOD2, MAPK3, and PCNA were all less than -5 kcal/mol. Compared to normal liver tissue, the mRNA levels of XRCC1, MAPK3, and PCNA were significantly elevated in liver cancer tissue. The expression levels of XRCC1, HIF1A, MAPK3, and PCNA genes were closely related to HCC progression. High expressions of HSP90AA1, TGFB1, HIF1A, MAPK3, and PCNA were all closely associated with poor prognosis in HCC. In vitro experiments demonstrated that emodin significantly downregulated the expression of HSP90AA1, MAPK3, XRCC1, PCNA, and SOD2, while significantly upregulating the expression of PTGS2 and GSTP1. Conclusion This study, based on network pharmacology and molecular docking validation, suggests that emodin may exert therapeutic effects on HBV-related HCC by downregulating the expression of XRCC1, MAPK3, PCNA, HSP90AA1, and SOD2, and upregulating the expression of PTGS2 and GSTP1.
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Affiliation(s)
- Yupeng Wang
- National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, Beijing, China
| | - Shuangxing Li
- National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, Beijing, China
| | - Tianqi Ren
- National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, Beijing, China
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yikun Zhang
- National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, Beijing, China
| | - Bo Li
- National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, Beijing, China
| | - Xingchao Geng
- National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, Beijing, China
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Nithyasree V, Magdalene P, Praveen Kumar PK, Preethi J, Gromiha MM. Role of HSP90 in Type 2 Diabetes Mellitus and Its Association with Liver Diseases. Mol Biotechnol 2024:10.1007/s12033-024-01251-1. [PMID: 39162909 DOI: 10.1007/s12033-024-01251-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Accepted: 07/31/2024] [Indexed: 08/21/2024]
Abstract
Non-alcoholic fatty acid liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) are the fatal liver diseases which encompass a spectrum of disease severity associated with increased risk of type 2 diabetes mellitus (T2DM), a metabolic disorder. Heat shock proteins serve as markers in early prognosis and diagnosis of early stages of liver diseases associated with metabolic disorder. This review aims to comprehensively investigate the significance of HSP90 isoforms in T2DM and liver diseases. Additionally, we explore the collective knowledge on plant-based drug compounds that regulate HSP90 isoform targets, highlighting their potential in treating T2DM-associated liver diseases. Furthermore, this review focuses on the computational systems' biology and next-generation sequencing technology approaches that are used to unravel the potential medicine for the treatment of pleiotropy of these 2 diseases and to further elucidate the mechanism.
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Affiliation(s)
- V Nithyasree
- Department of Biotechnology, Sri Venkateswara College of Engineering, Sriperumbudur Tk, Pennalur, Tamil Nadu, 602117, India
| | - P Magdalene
- Department of Biotechnology, Sri Venkateswara College of Engineering, Sriperumbudur Tk, Pennalur, Tamil Nadu, 602117, India
| | - P K Praveen Kumar
- Department of Biotechnology, Sri Venkateswara College of Engineering, Sriperumbudur Tk, Pennalur, Tamil Nadu, 602117, India.
- Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, 600036, India.
| | - J Preethi
- Department of Biotechnology, Sri Venkateswara College of Engineering, Sriperumbudur Tk, Pennalur, Tamil Nadu, 602117, India
| | - M Michael Gromiha
- Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, 600036, India
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Huang H, Lu X, Guo J, Chen Y, Yi M, Jia K. Protective efficacy and immune responses of largemouth bass (Micropterus salmoides) immunized with an inactivated vaccine against the viral hemorrhagic septicemia virus genotype IVa. FISH & SHELLFISH IMMUNOLOGY 2024; 151:109691. [PMID: 38871138 DOI: 10.1016/j.fsi.2024.109691] [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: 04/08/2024] [Revised: 06/09/2024] [Accepted: 06/10/2024] [Indexed: 06/15/2024]
Abstract
Viral hemorrhagic septicemia virus (VHSV) poses a significant threat to the aquaculture industry, prompting the need for effective preventive measures. Here, we developed an inactivated VHSV and revealed the molecular mechanisms underlying the host's protective response against VHSV. The vaccine was created by treating VHSV with 0.05 % formalin at 16 °C for 48 h, which was determined to be the most effective inactivation method. Compared with nonvaccinated fish, vaccinated fish exhibited a remarkable increase in survival rate (99 %) and elevated levels of serum neutralizing antibodies, indicating strong immunization. To investigate the gene changes induced by vaccination, RNA sequencing was performed on spleen samples from control and vaccinated fish 14 days after vaccination. The analysis revealed 893 differentially expressed genes (DEGs), with notable up-regulation of immune-related genes such as annexin A1a, coxsackievirus and adenovirus receptor homolog, V-set domain-containing T-cell activation inhibitor 1-like, and heat shock protein 90 alpha class A member 1 tandem duplicate 2, indicating a vigorous innate immune response. Furthermore, KEGG enrichment analysis highlighted significant enrichment of DEGs in processes related to antigen processing and presentation, necroptosis, and viral carcinogenesis. GO enrichment analysis further revealed enrichment of DEGs related to the regulation of type I interferon (IFN) production, type I IFN production, and negative regulation of viral processes. Moreover, protein-protein interaction network analysis identified central hub genes, including IRF3 and HSP90AA1.2, suggesting their crucial roles in coordinating the immune response elicited by the vaccine. These findings not only confirm the effectiveness of our vaccine formulation but also offer valuable insights into the underlying immunological mechanisms, which can be valuable for future vaccine development and disease management in the aquaculture industry.
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Affiliation(s)
- Hao Huang
- School of Marine Sciences, Sun Yat-sen University, Guangzhou, 510000, China.
| | - Xiaobing Lu
- School of Marine Sciences, Sun Yat-sen University, Guangzhou, 510000, China; Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai, 519000, China; Guangdong Provincial Key Laboratory of Marine Resources and Coastal Engineering, Guangzhou, 510000, China.
| | - Jiasen Guo
- School of Marine Sciences, Sun Yat-sen University, Guangzhou, 510000, China.
| | - Yihong Chen
- Institute of Modern Aquaculture Science and Engineering (IMASE)/Guangzhou Key Laboratory of Subtropical Biodiversity and Biomonitoring, Guangdong Provincial Key Laboratory for Healthy and Safe Aquaculture, College of Life Science, South China Normal University, Guangzhou, 510631, China.
| | - Meisheng Yi
- School of Marine Sciences, Sun Yat-sen University, Guangzhou, 510000, China; Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai, 519000, China; Guangdong Provincial Key Laboratory of Marine Resources and Coastal Engineering, Guangzhou, 510000, China.
| | - Kuntong Jia
- School of Marine Sciences, Sun Yat-sen University, Guangzhou, 510000, China; Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai, 519000, China; Guangdong Provincial Key Laboratory of Marine Resources and Coastal Engineering, Guangzhou, 510000, China.
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Kim H, Chen J, Prescott B, Walker ME, Grams ME, Yu B, Vasan RS, Floyd JS, Sotoodehnia N, Smith NL, Arking DE, Coresh J, Rebholz CM. Plasma proteins associated with plant-based diets: Results from the Atherosclerosis Risk in Communities (ARIC) study and Framingham Heart Study (FHS). Clin Nutr 2024; 43:1929-1940. [PMID: 39018652 PMCID: PMC11342917 DOI: 10.1016/j.clnu.2024.07.005] [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: 05/13/2024] [Revised: 06/25/2024] [Accepted: 07/09/2024] [Indexed: 07/19/2024]
Abstract
BACKGROUND & AIMS Plant-based diets are associated with a lower risk of chronic diseases. Large-scale proteomics can identify objective biomarkers of plant-based diets, and improve our understanding of the pathways that link plant-based diets to health outcomes. This study investigated the plasma proteome of four different plant-based diets [overall plant-based diet (PDI), provegetarian diet, healthful plant-based diet (hPDI), and unhealthful plant-based diet (uPDI)] in the Atherosclerosis Risk in Communities (ARIC) Study and replicated the findings in the Framingham Heart Study (FHS) Offspring cohort. METHODS ARIC Study participants at visit 3 (1993-1995) with completed food frequency questionnaire (FFQ) data and proteomics data were divided into internal discovery (n = 7690) and replication (n = 2543) data sets. Multivariable linear regression was used to examine associations between plant-based diet indices (PDIs) and 4955 individual proteins in the discovery sample. Then, proteins that were internally replicated in the ARIC Study were tested for external replication in FHS (n = 1358). Pathway overrepresentation analysis was conducted for diet-related proteins. C-statistics were used to predict if the proteins improved prediction of plant-based diet indices beyond participant characteristics. RESULTS In ARIC discovery, a total of 837 diet-protein associations (PDI = 233; provegetarian = 182; hPDI = 406; uPDI = 16) were observed at false discovery rate (FDR) < 0.05. Of these, 453 diet-protein associations (PDI = 132; provegetarian = 104; hPDI = 208; uPDI = 9) were internally replicated. In FHS, 167/453 diet-protein associations were available for external replication, of which 8 proteins (PDI = 1; provegetarian = 0; hPDI = 8; uPDI = 0) replicated. Complement and coagulation cascades, cell adhesion molecules, and retinol metabolism were over-represented. C-C motif chemokine 25 for PDI and 8 proteins for hPDI modestly but significantly improved the prediction of these indices individually and collectively (P value for difference in C-statistics<0.05 for all tests). CONCLUSIONS Using large-scale proteomics, we identified potential candidate biomarkers of plant-based diets, and pathways that may partially explain the associations between plant-based diets and chronic conditions.
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Affiliation(s)
- Hyunju Kim
- Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA; Cardiovascular Health Research Unit, Department of Medicine, University of Washington School of Public Health, Seattle, WA, USA.
| | - Jingsha Chen
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Brenton Prescott
- Section of Preventive Medicine and Epidemiology, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston University, Boston, MA, USA
| | - Maura E Walker
- Section of Preventive Medicine and Epidemiology, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston University, Boston, MA, USA; Department of Health Sciences, Sargent College of Health and Rehabilitation Sciences, Boston University, Boston, MA, USA
| | - Morgan E Grams
- Division of Precision Medicine, New York University Grossman School of Medicine, New York, NY, USA
| | - Bing Yu
- Department of Epidemiology, Human Genetics & Environmental Sciences, University of Texas Health Sciences Center at Houston School of Public Health, Houston, TX, USA
| | - Ramachandran S Vasan
- University of Texas School of Public Health in San Antonio, San Antonio, TX, USA
| | - James S Floyd
- Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA; Cardiovascular Health Research Unit, Department of Medicine, University of Washington School of Public Health, Seattle, WA, USA
| | - Nona Sotoodehnia
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington School of Public Health, Seattle, WA, USA; Division of Cardiology, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Nicholas L Smith
- Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA; Cardiovascular Health Research Unit, Department of Medicine, University of Washington School of Public Health, Seattle, WA, USA
| | - Dan E Arking
- Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Josef Coresh
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Optimal Aging Institute and Division of Epidemiology, Department of Population Health, New York University Grossman School of Medicine, New York, NY, USA
| | - Casey M Rebholz
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, MD, USA; Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA
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Deng ZH, Chen YX, Xue-Gao, Yang JY, Wei XY, Zhang GX, Qian JX. Mesenchymal stem cell-derived exosomes ameliorate hypoxic pulmonary hypertension by inhibiting the Hsp90aa1/ERK/pERK pathway. Biochem Pharmacol 2024; 226:116382. [PMID: 38909785 DOI: 10.1016/j.bcp.2024.116382] [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: 11/12/2023] [Revised: 06/19/2024] [Accepted: 06/20/2024] [Indexed: 06/25/2024]
Abstract
Hypoxic pulmonary hypertension (HPH) is a serious and life-threatening chronic cardiopulmonary disease characterized by progressive elevation of pulmonary artery pressure and pulmonary vascular remodeling. Mesenchymal stem cell- derived exosomes (MSC-Exos) can relieve HPH by reversing pulmonary vascular remodeling. The HPH model was established in healthy male Sprague-Dawley (SD) rats aged 6 to 8 weeks. The rats were placed in a room with oxygen concentration of (10 ± 1) % for 8 hours a day over 28 days, were then injected intravenously with MSC-Exos (100 ug protein/kg) or equal-volume phosphate buffer saline (PBS) once a day over 1 week. Right ventricular systolic pressure (RVSP), right ventricular hypertrophy index (RVHI) and pulmonary vascular remodeling were observed after anesthesia. In addition, platelet-derived growth factor BB (PDGF-BB) was used to stimulate rat pulmonary artery smooth muscle cells (PASMCs) to construct HPH pathological cell models. The results showed that MSC-Exos could not only reduce the elevation of RVSP, right ventricular hypertrophy and the degree of pulmonary vascular remodeling in HPH rats, but also reduce the proliferation, migration and apoptosis resistance of PASMCs. Finally, GSE53408 and GSE113439 datasets were analyzed and showed that the expression of Hsp90aa1 and pERK/ERK were significantly increased in HPH, also could be inhibited by MSC-Exos. Meanwhile, inhibition of Hsp90aa1 also reduced PASMCs migration and pERK/ERK protein level. In conclusion, MSC-Exos alleviated HPH by suppressing PASMCs proliferation, migration and apoptosis resistance through inhibiting the Hsp90aa1/ERK/pERK pathway.
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Affiliation(s)
- Zhi-Hua Deng
- Department of Respiratory and Critical Care Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou 215000, China
| | - Yao-Xin Chen
- Department of Respiratory and Critical Care Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou 215000, China
| | - Xue-Gao
- Department of Respiratory and Critical Care Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou 215000, China
| | - Jing-Yu Yang
- Department of Endocrinology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou 215000, China
| | - Xia-Ying Wei
- Department of Respiratory and Critical Care Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou 215000, China
| | - Guo-Xing Zhang
- Department of Physiology and Neurosciences, Medical College of Soochow University, Suzhou 215000, China
| | - Jin-Xian Qian
- Department of Respiratory and Critical Care Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou 215000, China.
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Zhao H, Xiong M, Yang X, Yao L, Li Z, Zhang J, Lv J. Isolation and target identification of antihepatoma polyprenylphenols from the edible mushroom Suillus granulatus. Food Funct 2024; 15:7430-7440. [PMID: 38904163 DOI: 10.1039/d4fo01500b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/22/2024]
Abstract
Eight polyprenylphenol derivatives were isolated from the wild edible mushroom Suillus granulatus, including seven novel compounds, named suillin F-L (2-8), and one previously identified compound (1). The structures of the new compounds were elucidated using HR-ESI-MS and 1D and 2D NMR data. The absolute configuration of compound 8 was assigned based on the comparison of the experimental and calculated ECD data. All isolated compounds were evaluated for their cytotoxicity against HepG2 cancer cell lines. Compounds 1 and 3-6 demonstrated significant antitumor activity compared to the positive control (cisplatin), with IC50 values ranging from 8.19 to 13.97 μM. Furthermore, DARTS assay and LC-MS/MS analysis were used to identify HSP90AA1 as the direct target of compound 5, and the interaction between compound 5 and HSP90AA1 was verified by molecular docking.
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Affiliation(s)
- Hanyu Zhao
- College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei 050024, China.
| | - Miaomiao Xiong
- College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei 050024, China.
| | - Xiaomin Yang
- College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei 050024, China.
| | - Lan Yao
- Institute of Biology, Hebei Academy of Science, Shijiazhuang, Hebei 050081, China
| | - Zhuang Li
- College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei 050024, China.
| | - Jinxiu Zhang
- College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei 050024, China.
| | - Jianhua Lv
- College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei 050024, China.
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Gao Y, Wu Y, Tie F, Wang H. Stilbenoids from fenugreek seeds alleviate insulin resistance by regulating the PI3K/AKT/mTOR signaling pathway in a type 2 diabetes zebrafish model. Heliyon 2024; 10:e32007. [PMID: 39040253 PMCID: PMC11260975 DOI: 10.1016/j.heliyon.2024.e32007] [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: 02/25/2024] [Revised: 05/25/2024] [Accepted: 05/27/2024] [Indexed: 07/24/2024] Open
Abstract
Insulin resistance (IR) is the main cause of type 2 diabetes mellitus (T2DM). The specific targets and underlying mechanisms responsible for the ameliorative effects of the stilbenoid compounds found in fenugreek seeds for ameliorating IR require further study. Here, we were predicted by using the network pharmacology prediction, molecular docking and molecular dynamics simulation approach the targets in common and the potential mechanismsof three stilbenoid compounds (rhaponticin, desoxyrhaponticin, and rhapontigenin) in relation to T2DM and IR. The results showed that the compounds may improve IR through the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway. Molecular docking studies revealed that they exhibit high binding affinity with the structural domains of peroxisome proliferator-activated receptor gamma (PPARG), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), PI3K, and AKT. These results suggest that PPARG and GAPDH may be the potential targets for these three compounds in the treatment of T2DM.Subsequently, experiments using the zebrafish T2DM model showed that the stilbenoid compounds had varying degrees of efficacy in improving IR through the PI3K/AKT/mTOR signaling pathway, and rhaponticin had the most promising effects. The findings implicate a potential mechanism of action for the three stilbenoid compounds in enhancing insulin resistance (IR) through modulation of the PI3K/AKT/mTOR pathway.
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Affiliation(s)
- Yidan Gao
- Key Laboratory of Tibetan Medicine Research, Qinghai Provincial Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Chinese Academy of Science, Xining, 810008, PR China
| | - Yun Wu
- Key Laboratory of Tibetan Medicine Research, Qinghai Provincial Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Chinese Academy of Science, Xining, 810008, PR China
| | - Fangfang Tie
- Key Laboratory of Tibetan Medicine Research, Qinghai Provincial Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Chinese Academy of Science, Xining, 810008, PR China
| | - Honglun Wang
- Key Laboratory of Tibetan Medicine Research, Qinghai Provincial Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Chinese Academy of Science, Xining, 810008, PR China
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Ding Y, Li H, Cao S, Yu Y. Effects of catechin on the malignant biological behavior of gastric cancer cells through the PI3K/Akt signaling pathway. Toxicol Appl Pharmacol 2024; 490:117036. [PMID: 39009138 DOI: 10.1016/j.taap.2024.117036] [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: 05/14/2024] [Revised: 07/11/2024] [Accepted: 07/11/2024] [Indexed: 07/17/2024]
Abstract
Catechin is a kind of flavonoids, mainly derived from the plant Camellia sinensis. It has a strong antioxidant effect, and it also has significant therapeutic effects on anti-cancer, anti-diabetes, and anti-infection. This study was intended to look at how catechin affected the malignant biological activity of gastric cancer cells. We used databases to predict the targets of catechin and the pathogenic targets of gastric cancer. Venn diagram was used to find the intersection genes, the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses were performed on intersection genes. Using the STRING database, the Protein-Protein Interaction (PPI) network was built. The top 8 genes were screened by Cytoscape 3.9.1, then their binding was verified by molecular docking. The proliferation ability, cell cycle, apoptosis and migration of gastric cancer cells were detected, as well as the protein expression levels of PI3K, p-AKT, and AKT and the mRNA expression levels of AKT1, VEGFA, EGFR, HRAS, and HSP90AA1 in gastric cancer cells. Our research revealed that different concentrations of catechin could effectively inhibit the proliferation and migration of gastric cancer cells, regulate the cell cycle, and promote the death of these cells, and it's possible that the PI3K/Akt pathway was crucial in mediating this impact. Moreover, adding the PI3K/Akt pathway agonist significantly reduced the promoting effect of catechin on the apoptosis of gastric cancer cells. This study suggested that catechin was a potential drug for the treatment of gastric cancer.
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Affiliation(s)
- Ye Ding
- Henan Key Laboratory of Helicobacter Pylori & Microbiota and Gastrointestinal Cancer, Marshall Medical Research Center, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China; Department of Gastroenterology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Hao Li
- Henan Key Laboratory of Helicobacter Pylori & Microbiota and Gastrointestinal Cancer, Marshall Medical Research Center, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China; Department of Gastroenterology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Saisai Cao
- Henan Key Laboratory of Helicobacter Pylori & Microbiota and Gastrointestinal Cancer, Marshall Medical Research Center, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China; Department of Gastroenterology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Yong Yu
- Henan Key Laboratory of Helicobacter Pylori & Microbiota and Gastrointestinal Cancer, Marshall Medical Research Center, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China; Department of Gastroenterology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China.
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Liu P, Li Z, Zhang H, Wang Y, Liao Y, Guo Y, Wang C, Zou Y, Zou R, Niu L. Mild heat stress promotes the differentiation of odontoblast-like MDPC-23 cells via yes-associated protein. Int J Hyperthermia 2024; 41:2369749. [PMID: 38925872 DOI: 10.1080/02656736.2024.2369749] [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: 12/21/2023] [Revised: 06/06/2024] [Accepted: 06/13/2024] [Indexed: 06/28/2024] Open
Abstract
PURPOSE Dentin hypersensitivity (DH) is a prevalent condition, but long-term effective treatments are scarce. Differentiation of odontoblast-like cells is promising for inducing tertiary dentinogenesis and ensuring sustained therapeutic efficacy against DH. This study examined the effects and mechanism of action of mild heat stress (MHS) on the differentiation of odontoblast-like MDPC-23 cells. METHODS We used a heating device to accurately control the temperature and duration, mimicking the thermal microenvironment of odontoblast-like cells. Using this device, the effects of MHS on cell viability and differentiation were examined. Cell viability was assessed using the MTT assay. The expression and nucleoplasmic ratio of the yes-associated protein (YAP) were examined by western blotting and immunofluorescence. The gene expression levels of heat shock proteins (HSPs) and dentin matrix protein-1 (DMP1) were measured using qPCR. Dentin sialophosphoprotein (DSPP) expression was evaluated using immunofluorescence and immunoblotting. Verteporfin was used to inhibit YAP activity. RESULTS Mild heat stress (MHS) enhanced the odontoblast differentiation of MDPC-23 cells while maintaining cell viability. MHS also increased YAP activity, as well as the levels of HSP25 mRNA, HSP70 mRNA, HSP90α mRNA, DMP1 mRNA, and DSPP protein. However, after YAP inhibition, both cell viability and the levels of HSP90α mRNA, DMP1 mRNA, and DSPP protein were reduced. CONCLUSION YAP plays a crucial role in maintaining cell viability and promoting odontoblast differentiation of MDPC-23 cells under MHS. Consequently, MHS is a potential therapeutic strategy for DH, and boosting YAP activity could be beneficial for maintaining cell viability and promoting odontoblast differentiation.
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Affiliation(s)
- Peiqi Liu
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, China
- Clinical Research Center of Shaanxi Province for Dental and Maxillofacial Diseases, College of Stomatology, Xi'an Jiaotong University, Xi'an, China
- College of Stomatology, Xi'an Jiaotong University, Xi'an, China
| | - Zhen Li
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, China
- Clinical Research Center of Shaanxi Province for Dental and Maxillofacial Diseases, College of Stomatology, Xi'an Jiaotong University, Xi'an, China
- College of Stomatology, Xi'an Jiaotong University, Xi'an, China
| | - Hui Zhang
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, China
- Clinical Research Center of Shaanxi Province for Dental and Maxillofacial Diseases, College of Stomatology, Xi'an Jiaotong University, Xi'an, China
- College of Stomatology, Xi'an Jiaotong University, Xi'an, China
- Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, China
| | - Yijie Wang
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, China
- Clinical Research Center of Shaanxi Province for Dental and Maxillofacial Diseases, College of Stomatology, Xi'an Jiaotong University, Xi'an, China
- College of Stomatology, Xi'an Jiaotong University, Xi'an, China
| | - Yuxin Liao
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, China
- Clinical Research Center of Shaanxi Province for Dental and Maxillofacial Diseases, College of Stomatology, Xi'an Jiaotong University, Xi'an, China
- College of Stomatology, Xi'an Jiaotong University, Xi'an, China
| | - Yi Guo
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, China
- Clinical Research Center of Shaanxi Province for Dental and Maxillofacial Diseases, College of Stomatology, Xi'an Jiaotong University, Xi'an, China
- College of Stomatology, Xi'an Jiaotong University, Xi'an, China
| | - Chenxu Wang
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, China
- Clinical Research Center of Shaanxi Province for Dental and Maxillofacial Diseases, College of Stomatology, Xi'an Jiaotong University, Xi'an, China
- College of Stomatology, Xi'an Jiaotong University, Xi'an, China
| | - Yuanwu Zou
- Department of Epidemiology and Biostatistics, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Rui Zou
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, China
- Clinical Research Center of Shaanxi Province for Dental and Maxillofacial Diseases, College of Stomatology, Xi'an Jiaotong University, Xi'an, China
- College of Stomatology, Xi'an Jiaotong University, Xi'an, China
| | - Lin Niu
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, China
- Clinical Research Center of Shaanxi Province for Dental and Maxillofacial Diseases, College of Stomatology, Xi'an Jiaotong University, Xi'an, China
- College of Stomatology, Xi'an Jiaotong University, Xi'an, China
- Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, China
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