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Zhan XZ, Wei TH, Huang C, Yu H, Chen XL, Kong XT, Shang ZH, Sun SL, Lu MY, Ni HW. Modulating JAK2/STAT3 signaling by quercetin in Qiling Baitouweng Tang: a potential therapeutic approach for diffuse large B-cell lymphoma. Mol Divers 2025; 29:2407-2431. [PMID: 39369170 DOI: 10.1007/s11030-024-10999-2] [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: 06/26/2024] [Accepted: 09/24/2024] [Indexed: 10/07/2024]
Abstract
Qiling Baitouweng Tang (QLBTWT) is a traditional clinical formula for treating diffuse large B-cell lymphoma (DLBCL), but its molecular action is not fully understood. This research is utilized in silico analysis and liquid chromatography tandem mass spectrometry (LC‒MS/MS) to identify the active constituents of QLBTWT with anti-DLBCL properties and their targets. The study identified 14 compounds, including quercetin, naringenin, and astilbin, as potentially effective against DLBCL. Molecular modeling highlighted the favorable interaction of quercetin with the JAK2 protein. In vitro studies confirmed the ability of quercetin to inhibit DLBCL cell growth and migration while inducing apoptosis and causing G2/M phase cell cycle arrest. Molecular dynamics simulations revealed that quercetin binds to JAK2 as a type II inhibitor. In vivo studies in U2932 xenograft models demonstrated that QLBTWT inhibited tumor growth in a dose-dependent manner, which was associated with the JAK2/STAT3 signaling pathway. Overall, this study elucidates the therapeutic effect of QLBTWT on DLBCL through quercetin-mediated suppression of the JAK2/STAT3 pathway, offering novel therapeutic insights for DLBCL.
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Affiliation(s)
- Xin-Zhuo Zhan
- Department of Hematology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Tian-Hua Wei
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Chen Huang
- Department of Hematology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Hui Yu
- Department of Hematology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Xiao-Li Chen
- Department of Hematology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Xiang-Tu Kong
- Department of Hematology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Zhi-Hao Shang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Shan-Liang Sun
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China.
| | - Meng-Yi Lu
- Department of Biostatistics, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, China.
| | - Hai-Wen Ni
- Department of Hematology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China.
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Xue Y, Chen T, Ma Z, Pu X, Xu J, Zhai S, Du X, Ji Y, Simon MC, Zhai W, Xue W. Osalmid sensitizes clear cell renal cell carcinoma to navitoclax through a STAT3/BCL-XL pathway. Cancer Lett 2025; 613:217514. [PMID: 39894195 DOI: 10.1016/j.canlet.2025.217514] [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: 08/22/2024] [Revised: 01/28/2025] [Accepted: 01/30/2025] [Indexed: 02/04/2025]
Abstract
Clear cell renal cell carcinoma (ccRCC) is a common and lethal urinary malignancy characterized by its resistance to apoptosis. Despite the emerging treatment options available for ccRCC, only a small proportion of patients achieve long-term survival benefits. Previous studies have demonstrated that inducing tumor cell senescence, followed by treatment using senolytics, represents a potential strategy for triggering tumor cell apoptosis. However, it remains unclear whether this strategy is suitable for the treatment of ccRCC. Using the whole-genome CRISPR screening database Dependency Map portal (DepMap), we identified ribonucleotide reductase family member 2 (RRM2), which catalyzes the conversion of ribonucleotides to deoxyribonucleotides (dNTPs), as an essential targetable gene for ccRCC. Herein, we report that the combination of the choleretic drug osalmid targeting RRM2 and the senolytic compound navitoclax targeting BCL-XL represents a novel therapeutic approach for ccRCC. Furthermore, we have validated this approach across a panel of human ccRCC cells with different genetic backgrounds and multiple preclinical models, including cell line-derived xenografts (CDX), patient-derived xenografts (PDX), and patient-derived organoids (PDO). Mechanistically, osalmid-mediated inhibition of dNTPs generation induces cellular senescence in ccRCC, concomitant with STAT3 activation and upregulation of BCL-XL, thus rendering these cells vulnerable to navitoclax, which targets the BCL-2 protein family.
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Affiliation(s)
- Yizheng Xue
- Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200120, China; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Tianyi Chen
- Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200120, China
| | - Zehua Ma
- Department of Urology, Guizhou Provincial People's Hospital, Guiyang, 550001, China
| | - Xinyuan Pu
- Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200120, China
| | - Junyao Xu
- Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200120, China
| | - Shuanfeng Zhai
- Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200120, China
| | - Xinxing Du
- Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200120, China
| | - Yiyi Ji
- Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, IL, 60637, USA, Howard Hughes Medical Institute
| | - M Celeste Simon
- Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Wei Zhai
- Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200120, China; Shanghai Immune Therapy Institute State, Key Laboratory of Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Wei Xue
- Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200120, China.
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Zhan XZ, Bo YW, Zhang Y, Zhang HD, Shang ZH, Yu H, Chen XL, Kong XT, Zhao WZ, Teimonen T, Liu T, Lu MY, Yang Y, Sun SL, Ni HW. Luteolin inhibits diffuse large B-cell lymphoma cell growth through the JAK2/STAT3 signaling pathway. Front Pharmacol 2025; 16:1545779. [PMID: 40051568 PMCID: PMC11882856 DOI: 10.3389/fphar.2025.1545779] [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: 12/15/2024] [Accepted: 01/31/2025] [Indexed: 03/09/2025] Open
Abstract
Luteolin, a flavonoid present in botanical drugs, plants, and dietary sources, has demonstrated anticancer properties against various tumors, yet its role in diffuse large B-cell lymphoma (DLBCL) remains unclear. This study aimed to uncover the molecular mechanism of luteolin in DLBCL treatment using a combination of in vitro and in vivo experiments and computational analysis. Human DLBCL cell lines U2932 and OCI-LY10 were utilized to assess luteolin's impact on cell growth, apoptosis, cell cycle progression, and the modulation of JAK2/STAT3 pathway proteins. In vivo, a U2932 tumor-bearing nude mice model was employed to evaluate luteolin's antitumor efficacy and its effects on JAK2/STAT3 pathway protein expression. Additionally, molecular dynamics simulations were conducted to explore the interaction between luteolin and JAK2. The findings revealed that luteolin significantly suppressed cell proliferation, induced apoptosis, and arrested the cell cycle at the G2/M phase in both cell lines. In the mouse model, luteolin effectively inhibited tumor growth and downregulated the expression of phosphorylated JAK2 and STAT3 without altering the total protein levels of JAK2 and STAT3. Computational analysis indicated stable binding of luteolin to JAK2. Collectively, these results suggest that luteolin's anti-DLBCL activity may be mediated through the regulation of the JAK2/STAT3 signaling pathway, positioning it as a potential therapeutic agent for DLBCL.
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Affiliation(s)
- Xin-Zhuo Zhan
- Department of Hematology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Yi-Wen Bo
- School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yu Zhang
- School of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Hai-Dong Zhang
- Department of Hematology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Zhi-Hao Shang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Hui Yu
- Department of Hematology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Xiao-Li Chen
- Department of Hematology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Xiang-Tu Kong
- Department of Hematology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Wan-Zhou Zhao
- The Nanjing Han & Zaenker Cancer Institute (NHZCI), OG Pharmaceuticals, Nanjing, Jiangsu, China
| | | | - Tao Liu
- School of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Meng-Yi Lu
- Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Ye Yang
- School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Shan-Liang Sun
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing, China
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Hai-Wen Ni
- Department of Hematology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
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Xu H, Li T, Wang Q, Lv Y, Sun C, Yan R, Wu X, Jin Y, Wang Z. Small Molecular Oligopeptides Adorned with Tryptophan Residues as Potent Antitumor Agents: Design, Synthesis, Bioactivity Assay, Computational Prediction, and Experimental Validation. J Chem Inf Model 2025; 65:1514-1536. [PMID: 39817413 DOI: 10.1021/acs.jcim.4c01759] [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: 01/18/2025]
Abstract
Tryptophan participates in important life activities and is involved in various metabolic processes. The indole and aromatic binuclear ring structure in tryptophan can engage in diverse interactions, including π-π, π-alkyl, hydrogen bonding, cation-π, and CH-π interactions with other side chains and protein targets. These interactions offer extensive opportunities for drug development. In this letter, we have designed and synthesized a series of linear oligopeptides adorned with tryptophan residues and identified their potential targets through artificial intelligence-assisted technology and experimental verification. In vitro bioactivity assays revealed that the oligopeptides containing Gly-Pro-Trp residues exhibited promising antitumor activity by inducing autophagy and apoptosis. The PharmMapper pharmacophore mapping approach, molecular docking, and molecular dynamics simulations together identified poly(ADP-ribose) polymerase 1 (PARP1), an enzyme associated with chromatin regulation, as the potential target for the designed compounds. Experimental biolayer interferometry (BLI) and enzyme-linked immunosorbent assay (ELISA) have verified that the oligopeptides could bind with PARP1 and influence PARP1 expression levels. A quantitative structure-activity relationship has been established between the chemical structures of the prepared compounds and their IC50 values. In summary, the research presents a feasible approach for exploring oligopeptide-based antitumor agents.
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Affiliation(s)
- Hongyu Xu
- Key Laboratory for Photonic and Electronic Bandgap Materials, Ministry of Education, College of Chemistry and Chemical Engineering, Harbin Normal University, Harbin 150025, China
| | - Tong Li
- Key Laboratory for Photonic and Electronic Bandgap Materials, Ministry of Education, College of Chemistry and Chemical Engineering, Harbin Normal University, Harbin 150025, China
| | - Qi Wang
- Key Laboratory for Photonic and Electronic Bandgap Materials, Ministry of Education, College of Chemistry and Chemical Engineering, Harbin Normal University, Harbin 150025, China
| | - Yang Lv
- Key Laboratory for Photonic and Electronic Bandgap Materials, Ministry of Education, College of Chemistry and Chemical Engineering, Harbin Normal University, Harbin 150025, China
| | - Changhong Sun
- Key Laboratory for Photonic and Electronic Bandgap Materials, Ministry of Education, College of Chemistry and Chemical Engineering, Harbin Normal University, Harbin 150025, China
| | - Rui Yan
- Key Laboratory for Photonic and Electronic Bandgap Materials, Ministry of Education, College of Chemistry and Chemical Engineering, Harbin Normal University, Harbin 150025, China
| | - Xiaodan Wu
- Key Laboratory for Photonic and Electronic Bandgap Materials, Ministry of Education, College of Chemistry and Chemical Engineering, Harbin Normal University, Harbin 150025, China
| | - Yingxue Jin
- Key Laboratory for Photonic and Electronic Bandgap Materials, Ministry of Education, College of Chemistry and Chemical Engineering, Harbin Normal University, Harbin 150025, China
| | - Zhiqiang Wang
- Key Laboratory for Photonic and Electronic Bandgap Materials, Ministry of Education, College of Chemistry and Chemical Engineering, Harbin Normal University, Harbin 150025, China
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Luo Q, Zhou L, Luo D, Yu L. Clonal hematopoiesis of indeterminate potential (CHIP): A potential contributor to lymphoma. Crit Rev Oncol Hematol 2025; 206:104589. [PMID: 39667716 DOI: 10.1016/j.critrevonc.2024.104589] [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: 08/13/2024] [Revised: 11/27/2024] [Accepted: 12/04/2024] [Indexed: 12/14/2024] Open
Abstract
Clonal hematopoiesis (CH) typically refers to the clonal expansion of hematopoietic stem cells (HSCs) due to genetic mutations, serving as the pathogenic basis for various diseases. Clonal hematopoiesis of indeterminate potential (CHIP) is a subtype of CH, emerging as a significant risk factor for myeloid malignancies and cardiovascular diseases, which has attracted increasing attention. However, recent research has unveiled previously overlooked links between CHIP and lymphoma. This paper reviews the relationship between CHIP and lymphoma, focusing on the role and mechanism of TET2 and DNMT3A-mediated CHIP in lymphoma from the perspective of laboratory research and clinical observation. Additionally, we explore the therapeutic implications of targeting CHIP genes and inflammatory pathways in lymphoma. Our findings underscore the multifaceted influence of CHIP on lymphoma development and provide a promising avenue for therapeutic interventions in CHIP mediated lymphoma.
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Affiliation(s)
- QingQing Luo
- Department of Hematology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi Provincial Key Laboratory of Hematological Diseases (2024SSY06052), Nanchang, Jiangxi, China
| | - LiLi Zhou
- Department of Hematology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi Provincial Key Laboratory of Hematological Diseases (2024SSY06052), Nanchang, Jiangxi, China
| | - DaYa Luo
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.
| | - Li Yu
- Department of Hematology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi Provincial Key Laboratory of Hematological Diseases (2024SSY06052), Nanchang, Jiangxi, China.
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Li Y, Qin M, Liu N, Zhang C. Organoid development and applications in gynecological cancers: the new stage of tumor treatment. J Nanobiotechnology 2025; 23:20. [PMID: 39819668 PMCID: PMC11740664 DOI: 10.1186/s12951-024-03086-z] [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: 08/16/2024] [Accepted: 12/29/2024] [Indexed: 01/19/2025] Open
Abstract
Gynecologic cancers (GCs), including cervical cancer (CC), ovarian cancer (OC), endometrial cancer (EC), as well as vulvar and vaginal cancers, represent major health threats to women, with increasing incidence rates observed globally. Conventional treatments, such as surgery, radiation therapy, and chemotherapy, are often hindered by challenges such as drug resistance and recurrence, contributing to high mortality rates. Organoid technology has emerged as a transformative tool in cancer research, offering in vitro models that closely replicate the tumor cell architecture and heterogeneity of primary cancers. Tumor-derived organoids preserve the histological and molecular characteristics of the original tumors, making them invaluable for studying tumor biology, molecular pathways, and the tumor immune microenvironment. Furthermore, organoids play a crucial role in biomarker discovery, drug screening, and the development of personalized therapeutic strategies. In contrast to traditional cell lines and patient-derived xenograft (PDX) models, gynecologic cancer organoids accurately mirror the genetic mutations and specific gene expression profiles of primary tumors. This review provides an overview of recent advancements in the development of gynecologic cancer organoid models, highlighting their contributions to understanding disease mechanisms, facilitating drug discovery, and advancing precision medicine. It also addresses the potential and challenges of organoid technology, with a focus on its role in advancing personalized treatment approaches for GCs.
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Affiliation(s)
- Yang Li
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China
| | - Meiying Qin
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China
| | - Ning Liu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China.
| | - Chunmei Zhang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China.
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Lu S, Yang DJ. Sanguinarine Inhibits Cell Growth in EBV-Positive Diffuse Large B-Cell Lymphoma. Arch Immunol Ther Exp (Warsz) 2025; 73:aite-2025-0009. [PMID: 40198977 DOI: 10.2478/aite-2025-0009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Accepted: 01/14/2025] [Indexed: 04/10/2025]
Abstract
To investigate the effects of Sanguinarine (SAG) on the progression of diffuse large B-cell lymphoma (DLBCL) and to explore its underlying mechanism, this study utilized Epstein-Barr virus (EBV)-positive DLBCL cell lines, FARAGE, and GM12878S. Cell counting kit-8 and bromodeoxyuridine assays were used to assess the effects of SAG on the cell proliferation. Flow cytometry and immunoblotting were employed to analyze cell cycle arrest and apoptosis. Additionally, the molecular mechanism was explored through further immunoblotting analysis of the mechanism. SAG suppressed the growth of EBV-positive DLBCL cells. Furthermore, SAG induced cell cycle arrest and promoted apoptosis in these cells. Mechanistically, SAG suppressed the Wnt/β-catenin pathway, thereby suppressing DLBCL progression in vitro. SAG effectively inhibits cell growth and induces apoptosis in EBV-positive DLBCL via Wnt/β-catenin pathway, offering potential therapeutic insights for this lymphoma subtype.
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Affiliation(s)
- Suli Lu
- Department of Medicine, Hunan Polytechnic of Environment and Biology, Hengyang, Hunan 421005, China
| | - Dae-Jung Yang
- Department of Physical Therapy, Graduate School of Sehan University, Sehan University, Mokpo, Republic of Korea
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Liu X, Yang L, Guan K, Chen Z, Yang H. CSE1L Silencing Enhances Cytarabine-mediated Cytotoxicity in Acute Myeloid Leukemia. Indian J Hematol Blood Transfus 2024; 40:629-637. [PMID: 39469152 PMCID: PMC11512944 DOI: 10.1007/s12288-024-01773-3] [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: 10/18/2023] [Accepted: 04/08/2024] [Indexed: 10/30/2024] Open
Abstract
Purpose This study aims to investigate the increased toxicity of Cytarabine (Ara-c) by knockdown of chromosome segregation 1-like (CSE1L) in acute myeloid leukemia(AML) cells(Kasumi-1, U937, and THP-1 cells) and to explore its possible mechanisms. Methods Target gene silencing was achieved using the shRNA-mediated lentivirus method. Apoptosis was identified using the Annexin V PE/7-AAD double-staining assay. Cell viability was assessed with the Cell Counting Kit-8 (CCK-8) assay. Protein expression was detected by Western blotting. Results In vitro, knocking down CSE1L promoted caspase-3 and caspase-9 proteins expression and induced apoptosis in AML cells. Knockdown of CSE1L enhanced AML cells' sensitivity to Ara-c. knockdown of CSE1L reduced the expression levels of p-JKA2 and p-STAT3 proteins, while no significant difference was observed in the expression levels of total JAK2 and STAT3 proteins. Furthermore, JAK2 overexpression reversed the increase in Ara-c toxicity to AML cells caused by CSE1L knockdown. Conclusion In conclusion, our study reveals that CSE1L is a potential therapeutic target for overcoming Ara-c resistance in AML cells. Thus, we have gained new insights into the oncogenic process of CSE1L in AML cells and raised the prospect of knockdown of CSE1L in AML in combination with cytarabine-targeted therapy.
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Affiliation(s)
- Xiaoyu Liu
- Department of Laboratory Medicine, Suining Municipal Hospital of TCM, Suining, China
| | - Lin Yang
- Department of Laboratory Medicine, Suining Municipal Hospital of TCM, Suining, China
| | - Kunping Guan
- Department of Laboratory Medicine, Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Zhen Chen
- Department of Laboratory Medicine, Suining Municipal Hospital of TCM, Suining, China
| | - Hua Yang
- Department of Laboratory Medicine, Suining Municipal Hospital of TCM, Suining, China
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Feng H, Zhang X, Kang J. Analyzing the involvement of diverse cell death-related genes in diffuse large B-cell lymphoma using bioinformatics techniques. Heliyon 2024; 10:e30831. [PMID: 38779021 PMCID: PMC11108851 DOI: 10.1016/j.heliyon.2024.e30831] [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: 12/28/2023] [Revised: 04/26/2024] [Accepted: 05/06/2024] [Indexed: 05/25/2024] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL) stands as the most prevalent subtype of non-Hodgkin's lymphoma and exhibits significant heterogeneity. Various forms of programmed cell death (PCD) have been established to have close associations with tumor onset and progression. To this end, this study has compiled 16 PCD-related genes. The investigation delved into genes linked with prognosis, constructing risk models through consecutive application of univariate Cox regression analysis and Lasso-Cox regression analysis. Furthermore, we employed RT-qPCR to validate the mRNA expression levels of certain diagnosis-related genes. Subsequently, the models underwent validation through KM survival curves and ROC curves, respectively. Additionally, nomogram models were formulated employing prognosis-related genes and risk scores. Lastly, disparities in immune cell infiltration abundance and the expression of immune checkpoint-associated genes between high- and low-risk groups, as classified by risk models, were explored. These findings contribute to a more comprehensive understanding of the role played by the 16 PCD-associated genes in DLBCL, shedding light on potential novel therapeutic strategies for the condition.
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Affiliation(s)
- Heyuan Feng
- Flow Cytometry Room, Beijing Gaobo Boren Hospital, Beijing, China
| | - Xiyuan Zhang
- Department of Blood Transfusion, No.970 Hospital of PLA Joint Logistics Support Force, Shandong, China
| | - Jian Kang
- Flow Cytometry Room, Beijing Gaobo Boren Hospital, Beijing, China
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Dai Y, Shi S, Liu H, Zhou H, Ding W, Liu C, Jin L, Xie W, Kong H, Zhang Q. Protein tyrosine phosphatase PTPRO represses lung adenocarcinoma progression by inducing mitochondria-dependent apoptosis and restraining tumor metastasis. Cell Death Dis 2024; 15:11. [PMID: 38182570 PMCID: PMC10770368 DOI: 10.1038/s41419-023-06375-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: 01/12/2023] [Revised: 11/30/2023] [Accepted: 12/05/2023] [Indexed: 01/07/2024]
Abstract
Emerging evidence indicates that protein activities regulated by receptor protein tyrosine phosphatases (RPTPs) are crucial for a variety of cellular processes, such as proliferation, apoptosis, and immunological response. Protein tyrosine phosphatase receptor type O (PTPRO), an RPTP, has been revealed as a putative suppressor in the development of particular tumors. However, the function and the underlying mechanisms of PTPRO in regulating of lung adenocarcinoma (LUAD) are not well understood. In this view, the present work investigated the role of PTPRO in LUAD. Analysis of 90 pairs of clinical LUAD specimens revealed significantly lower PTPRO levels in LUAD compared with adjacent non-tumor tissue, as well as a negative correlation of PTPRO expression with tumor size and TNM stage. Survival analyses demonstrated that PTPRO level can help stratify the prognosis of LUAD patients. Furthermore, PTPRO overexpression was found to suppress the progression of LUAD both in vitro and in vivo by inducing cell death via mitochondria-dependent apoptosis, downregulating protein expression of molecules (Bcl-2, Bax, caspase 3, cleaved-caspase 3/9, cleaved-PARP and Bid) essential in cell survival. Additionally, PTPRO decreased LUAD migration and invasion by regulating proteins involved in the epithelial-to-mesenchymal transition (E-cadherin, N-cadherin, and Snail). Moreover, PTPRO was shown to restrain JAK2/STAT3 signaling pathways. Expression of PTPRO was negatively correlated with p-JAK2, p-STAT3, Bcl-2, and Snail levels in LUAD tumor samples. Furthermore, the anti-tumor effect of PTPRO in LUAD was significant but compromised in STAT3-deficient cells. These data support the remarkable suppressive role of PTPRO in LUAD, which may represent a viable therapeutic target for LUAD patients.
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Affiliation(s)
- Yuan Dai
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
- Department of Respiratory Medicine, Jiangsu Province Official Hospital, Nanjing, China
| | - Shuangshuang Shi
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Hongda Liu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Hong Zhou
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Wenqiu Ding
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Chenyang Liu
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Linling Jin
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Weiping Xie
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China.
| | - Hui Kong
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China.
| | - Qun Zhang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China.
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Upregulation of Actin-Related Protein 2 (ACTR2) Exacerbated the Malignancy of Diffuse Large B-Cell Lymphoma through Activating Wnt Signaling. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:9351921. [PMID: 36570337 PMCID: PMC9771665 DOI: 10.1155/2022/9351921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 10/29/2022] [Accepted: 11/16/2022] [Indexed: 12/15/2022]
Abstract
This investigation mainly explores the roles of actin-related protein 2 (ACTR2) in diffuse large B-cell lymphoma (DLBCL). We first assessed the level of ACTR2 and its association with the overall survival (OS) of DLBCL. The results indicated that ACTR2 was upregulated in DLBCL and was associated with unfavorable prognosis of DLBCL. Next, the effect of ACTR2 knockdown or overexpression on DLBCL was evaluated in vitro. Our investigation revealed that ACTR2 depletion inhibited the malignant behaviors of DLBCL cells; whereas, ACTR2 abundance promoted those behaviors. Besides, ACTR2 activated the Wnt signaling in DLBCL and exerted its oncogenic influence on DLBCL through Wnt signaling in vitro and in vivo. To summarize, our study implicated that ACTR2 was a promising therapeutic target for DLBCL, which might become a novel direction to improve our understanding on DLBCL.
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12
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Qin YY, Feng S, Zhang XD, Peng B. Screening of traditional Chinese medicine monomers as ribonucleotide reductase M2 inhibitors for tumor treatment. World J Clin Cases 2022; 10:11299-11312. [PMID: 36387821 PMCID: PMC9649558 DOI: 10.12998/wjcc.v10.i31.11299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 09/14/2022] [Accepted: 09/29/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Ribonucleotide reductase (RR) is a key enzyme in tumor proliferation, especially its subunit-RRM2. Although there are multiple therapeutics for tumors, they all have certain limitations. Given their advantages, traditional Chinese medicine (TCM) monomers have become an important source of anti-tumor drugs. Therefore, screening and analysis of TCM monomers with RRM2 inhibition can provide a reference for further anti-tumor drug development.
AIM To screen and analyze potential anti-tumor TCM monomers with a good binding capacity to RRM2.
METHODS The Gene Expression Profiling Interactive Analysis database was used to analyze the level of RRM2 gene expression in normal and tumor tissues as well as RRM2's effect on the overall survival rate of tumor patients. TCM monomers that potentially act on RRM2 were screened via literature mining. Using AutoDock software, the screened monomers were docked with the RRM2 protein.
RESULTS The expression of RRM2 mRNA in multiple tumor tissues was significantly higher than that in normal tissues, and it was negatively correlated with the overall survival rate of patients with the majority of tumor types. Through literature mining, we discovered that berberine, ursolic acid, gambogic acid, cinobufagin, quercetin, daphnetin, and osalmide have inhibitory effects on RRM2. The results of molecular docking identified that the above TCM monomers have a strong binding capacity with RRM2 protein, which mainly interacted through hydrogen bonds and hydrophobic force. The main binding sites were Arg330, Tyr323, Ser263, and Met350.
CONCLUSION RRM2 is an important tumor therapeutic target. The TCM monomers screened have a good binding capacity with the RRM2 protein.
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Affiliation(s)
- Ya-Ya Qin
- Department of Neurology, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Song Feng
- School of Basic Medicine, North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Xiao-Dong Zhang
- Department of Neurology, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Bin Peng
- School of Basic Medicine, North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
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13
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Liu W, Jin W, Zhu S, Chen Y, Liu B. Targeting regulated cell death (RCD) with small-molecule compounds in cancer therapy: A revisited review of apoptosis, autophagy-dependent cell death and necroptosis. Drug Discov Today 2021; 27:612-625. [PMID: 34718209 DOI: 10.1016/j.drudis.2021.10.011] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 07/10/2021] [Accepted: 10/21/2021] [Indexed: 02/05/2023]
Abstract
Evasion of regulated cell death (RCD), mainly referring to apoptosis, autophagy-dependent cell death, necroptosis, and other subroutines, is one of the well-established hallmarks of cancer cells. Accumulating evidence has revealed several small-molecule compounds that target different subroutines of RCD in cancer therapy. In this review, we summarize key pathways of apoptosis, autophagy-dependent cell death and necroptosis in cancer, and describe small-molecule compounds that target these pathways and have potential as therapeutics. These inspiring findings light the way towards the discovery of more 'magic bullets' that could work individually or cooperatively to target precisely the three RCD subroutines and so improve cancer treatment.
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Affiliation(s)
- Wei Liu
- State Key Laboratory of Biotherapy and Cancer Center and Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Wenke Jin
- State Key Laboratory of Biotherapy and Cancer Center and Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Shiou Zhu
- State Key Laboratory of Biotherapy and Cancer Center and Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yi Chen
- State Key Laboratory of Biotherapy and Cancer Center and Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu 610041, China.
| | - Bo Liu
- State Key Laboratory of Biotherapy and Cancer Center and Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu 610041, China.
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14
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Li B, Wan Q, Li Z, Chng WJ. Janus Kinase Signaling: Oncogenic Criminal of Lymphoid Cancers. Cancers (Basel) 2021; 13:cancers13205147. [PMID: 34680295 PMCID: PMC8533975 DOI: 10.3390/cancers13205147] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Revised: 10/08/2021] [Accepted: 10/11/2021] [Indexed: 12/24/2022] Open
Abstract
Simple Summary Janus kinases (JAKs) are transmembrane receptors that pass signals from extracellular ligands to downstream. Increasing evidence has suggested that JAK family aberrations promote lymphoid cancer pathogenesis and progression through mediating gene expression via the JAK/STAT pathway or noncanonical JAK signaling. We are here to review how canonical JAK/STAT and noncanonical JAK signalings are represented and deregulated in lymphoid malignancies and how to target JAK for therapeutic purposes. Abstract The Janus kinase (JAK) family are known to respond to extracellular cytokine stimuli and to phosphorylate and activate signal transducers and activators of transcription (STAT), thereby modulating gene expression profiles. Recent studies have highlighted JAK abnormality in inducing over-activation of the JAK/STAT pathway, and that the cytoplasmic JAK tyrosine kinases may also have a nuclear role. A couple of anti-JAK therapeutics have been developed, which effectively harness lymphoid cancer cells. Here we discuss mutations and fusions leading to JAK deregulations, how upstream nodes drive JAK expression, how classical JAK/STAT pathways are represented in lymphoid malignancies and the noncanonical and nuclear role of JAKs. We also summarize JAK inhibition therapeutics applied alone or synergized with other drugs in treating lymphoid malignancies.
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Affiliation(s)
- Boheng Li
- College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China; or (Q.W.)
| | - Qin Wan
- College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China; or (Q.W.)
| | - Zhubo Li
- College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China; or (Q.W.)
- Correspondence: or (Z.L.); (W.-J.C.)
| | - Wee-Joo Chng
- Department of Haematology-Oncology, National University Cancer Institute of Singapore, Singapore 119074, Singapore
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
- Correspondence: or (Z.L.); (W.-J.C.)
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15
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Zhang H, Chi F, Qin K, Mu X, Wang L, Yang B, Wang Y, Bai M, Li Z, Su L, Yu B. Chidamide induces apoptosis in DLBCL cells by suppressing the HDACs/STAT3/Bcl‑2 pathway. Mol Med Rep 2021; 23:308. [PMID: 33649847 PMCID: PMC7974270 DOI: 10.3892/mmr.2021.11947] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 02/11/2021] [Indexed: 12/16/2022] Open
Abstract
Diffuse large B‑cell lymphoma (DLBCL) is a highly heterogeneous malignant tumor type, and epigenetic modifications such as acetylation or deacetylation serve vital roles in its development. Chidamide, a novel histone deacetylase inhibitor, exerts an anticancer effect against various types of cancer. The present study aimed to evaluate the cellular effect of chidamide on a number of DLBCL cell lines and to investigate its underlying mechanism. The results demonstrated that chidamide induced the death of these cells in a concentration‑(0‑30 µmol/l) and time‑dependent (24‑72 h) manner, as determined using the Cell Counting Kit‑8 cell viability assay. Moreover, chidamide promoted cellular apoptosis, which was identified via flow cytometry and western blot analysis, with an increase in cleaved caspase‑3 expression and a decrease in Bcl‑2 expression. Chidamide treatment also decreased the expression level of STAT3 and its phosphorylation, which was accompanied by the downregulation of a class‑I histone deacetylase (HDAC) inhibitor, chidamide. Collectively, these data suggested that chidamide can be a potent therapeutic agent to treat DLBCL by inducing the apoptotic death of DLBCL cells by inhibiting the HDACs/STAT3/Bcl‑2 pathway.
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Affiliation(s)
- Hongwei Zhang
- Department of Hematology, Cancer Hospital of Shanxi Province, Taiyuan, Shanxi 030013, P.R. China
| | - Fenqing Chi
- Department of Biochemistry and Molecular Biology, Key Laboratory of Cellular Physiology of Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Keru Qin
- Department of Biochemistry and Molecular Biology, Key Laboratory of Cellular Physiology of Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Xiuli Mu
- Department of Biochemistry and Molecular Biology, Key Laboratory of Cellular Physiology of Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Lieyang Wang
- Department of Hematology, Cancer Hospital of Shanxi Province, Taiyuan, Shanxi 030013, P.R. China
| | - Bin Yang
- Department of Hematology, Cancer Hospital of Shanxi Province, Taiyuan, Shanxi 030013, P.R. China
| | - Yanli Wang
- Department of Hematology, Cancer Hospital of Shanxi Province, Taiyuan, Shanxi 030013, P.R. China
| | - Min Bai
- Department of Hematology, Cancer Hospital of Shanxi Province, Taiyuan, Shanxi 030013, P.R. China
| | - Zhenhua Li
- Department of Hematology, Cancer Hospital of Shanxi Province, Taiyuan, Shanxi 030013, P.R. China
| | - Liping Su
- Department of Hematology, Cancer Hospital of Shanxi Province, Taiyuan, Shanxi 030013, P.R. China
| | - Baofeng Yu
- Department of Biochemistry and Molecular Biology, Key Laboratory of Cellular Physiology of Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
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16
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Cheng Y, Fu Y, Wang Y, Wang J. The m6A Methyltransferase METTL3 Is Functionally Implicated in DLBCL Development by Regulating m6A Modification in PEDF. Front Genet 2020; 11:955. [PMID: 33061938 PMCID: PMC7481464 DOI: 10.3389/fgene.2020.00955] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 07/30/2020] [Indexed: 12/22/2022] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of lymphoma, whose treatment still has a major challenge of achieving a satisfactory curative effect. The underlying mechanisms also have not been fully illustrated. N6-Methyladenosine (m6A) has been identified as the most prevalent internal modification of mRNAs present in eukaryotes, which is involved in the pathogenesis of cancers. It remains unclear how m6A mRNA methylation is functionally linked to the pathogenesis of DLBCL. In this study, we sought to explore the roles of METTL3 on DLBCL development. The results showed that m6A level for RNA methylation and the expression level of METTL3 were upregulated in DLBCL tissues and cell lines. Functionally, downregulated METTL3 expression in DLBCL cells inhibited the cell proliferation ability. Further mechanism analysis indicated that METTL3 knockdown abates the m6A methylation and total mRNA level of pigment epithelium-derived factor (PEDF). However, Wnt/β-catenin signaling was not thus activated. Overexpressed PEDF abrogates the inhibition of cell proliferation in DLBCL cells that is caused by METTL3 silence. In summary, the above-mentioned results demonstrated that the METTL3 promotes DLBCL progression by regulating the m6A level of PEDF.
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Affiliation(s)
- Yingying Cheng
- Department of Hematology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Yuanyuan Fu
- Department of Hematology, Changzhou Traditional Chinese Medicine Hospital, Changzhou, China
| | - Ying Wang
- Department of Hematology, Changzhou Traditional Chinese Medicine Hospital, Changzhou, China
| | - Jinbi Wang
- Department of Hematology, Changzhou Traditional Chinese Medicine Hospital, Changzhou, China
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17
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Song HT, Cui Y, Zhang LL, Cao G, Li L, Li G, Jia XJ. Ruxolitinib attenuates intimal hyperplasia via inhibiting JAK2/STAT3 signaling pathway activation induced by PDGF-BB in vascular smooth muscle cells. Microvasc Res 2020; 132:104060. [PMID: 32818511 DOI: 10.1016/j.mvr.2020.104060] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 08/14/2020] [Accepted: 08/14/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Cardiovascular diseases are associated with proliferation and phenotypic switch. Platelet-derived growth factor-BB (PDGF-BB) is a major initiating factor for proliferative vascular diseases, such as neointimal lesion formation, restenosis after angioplasty, and atherosclerosis. Ruxolitinib, a potent Janus kinase (JAK) 1 and 2 inhibitor, has been reported to significantly block the proliferation-related signaling pathway of JAK2/signal transducers and activators of transcription 3 (STAT3) and harbor a broad spectrum of anti-cancer activities, including proliferation inhibition, apoptosis induction, and anti-inflammation. However, the role of ruxolitinib in regulating PDGF-BB-induced VSMC proliferation remains to be elucidated. Thus, this study investigates the role of ruxolitinib in regulating PDGF-BB-induced VSMC proliferation and its underlying mechanisms. METHODS In vivo, the medial thickness of the carotid artery was evaluated using a mouse carotid ligation model, ruxolitinib was administered orally to the mice every other day, and the mice were euthanized on day 28 to evaluate the therapeutic effects of ruxolitinib. Cell proliferation markers were measured using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blotting. In vitro, VSMCs were treated with ruxolitinib with or without PDGF-BB at an indicated time and concentration. Cell proliferation and apoptosis were measured using Cell Counting Kit-8 assay, MTS assays and flow cytometry. The JAK2/STAT3 signaling pathway involved in the effects of ruxolitinib on VSMCs was detected by western blotting with the specific pathway inhibitor AG490. RESULTS In vivo, ruxolitinib significantly decreased the ratio-of-intima ratio (I/M ratio) by inhibiting the expression of PCNA and cyclinD1 (p <0.05). In vitro, ruxolitinib inhibited PDGF-BB-induced VSMC proliferation compared with the PDGF-BB treatment group (p <0.05). In addition, ruxolitinib inhibited the PDGF-BB-induced activation of the JAK2/STAT3 signaling pathway and decreased the expression of proliferation related-proteins cyclinD1 and PCNA in VSMCs (p <0.05). CONCLUSION Our findings suggest that ruxolitinib inhibits VSMC proliferation in vivo and in vitro by suppressing the activation of the JAK2/STAT3 signaling pathway. Therefore, ruxolitinib has a therapeutic potential for proliferative vascular diseases.
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Affiliation(s)
- Hong-Tao Song
- Department of Vascular Surgery, The Second Hospital of Shijiazhuang, Shijiazhuang, China
| | - Yuan Cui
- Department of Internal Medicine, Affiliated Hospital of Hebei Academy of Chinese Medicine, Shijiazhuang, China
| | - Li-Li Zhang
- Department of Endocrine, The Second Hospital of Shijiazhuang, Shijiazhuang, China
| | - Guang Cao
- Department of Orthopedic Surgery, The Second Hospital of Shijiazhuang, Shijiazhuang, China
| | - Lin Li
- Department of Administrative Office, District Center for Disease Control and Prevention of Jizhou, Tianjin, China
| | - Gang Li
- Department of Vascular Surgery, The Second Hospital of Shijiazhuang, Shijiazhuang, China
| | - Xin-Ju Jia
- Department of Endocrine, The First Hospital of Hebei Medical University, Shijiazhuang, China.
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18
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Pecyna P, Wargula J, Murias M, Kucinska M. More Than Resveratrol: New Insights into Stilbene-Based Compounds. Biomolecules 2020; 10:E1111. [PMID: 32726968 PMCID: PMC7465418 DOI: 10.3390/biom10081111] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 07/20/2020] [Accepted: 07/22/2020] [Indexed: 02/07/2023] Open
Abstract
The concept of a scaffold concerns many aspects at different steps on the drug development path. In medicinal chemistry, the choice of relevant "drug-likeness" scaffold is a starting point for the design of the structure dedicated to specific molecular targets. For many years, the chemical uniqueness of the stilbene structure has inspired scientists from different fields such as chemistry, biology, pharmacy, and medicine. In this review, we present the outstanding potential of the stilbene-based derivatives. Naturally occurring stilbenes, together with powerful synthetic chemistry possibilities, may offer an excellent approach for discovering new structures and identifying their therapeutic targets. With the development of scientific tools, sophisticated equipment, and a better understanding of the disease pathogenesis at the molecular level, the stilbene scaffold has moved innovation in science. This paper mainly focuses on the stilbene-based compounds beyond resveratrol, which are particularly attractive due to their biological activity. Given the "fresh outlook" about different stilbene-based compounds starting from stilbenoids with particular regard to isorhapontigenin and methoxy- and hydroxyl- analogues, the update about the combretastatins, and the very often overlooked and underestimated benzanilide analogues, we present a new story about this remarkable structure.
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Affiliation(s)
- Paulina Pecyna
- Department of Genetics and Pharmaceutical Microbiology, University of Medical Sciences, Swiecickiego 4 Street, 60-781 Poznan, Poland;
| | - Joanna Wargula
- Department of Organic Chemistry, University of Medical Sciences, Grunwaldzka 6 Street, 60-780 Poznan, Poland;
| | - Marek Murias
- Department of Toxicology, University of Medical Sciences, Dojazd 30 Street, 60-631 Poznan, Poland;
| | - Malgorzata Kucinska
- Department of Toxicology, University of Medical Sciences, Dojazd 30 Street, 60-631 Poznan, Poland;
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19
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Abstract
The concept of a scaffold concerns many aspects at different steps on the drug development path. In medicinal chemistry, the choice of relevant "drug-likeness" scaffold is a starting point for the design of the structure dedicated to specific molecular targets. For many years, the chemical uniqueness of the stilbene structure has inspired scientists from different fields such as chemistry, biology, pharmacy, and medicine. In this review, we present the outstanding potential of the stilbene-based derivatives. Naturally occurring stilbenes, together with powerful synthetic chemistry possibilities, may offer an excellent approach for discovering new structures and identifying their therapeutic targets. With the development of scientific tools, sophisticated equipment, and a better understanding of the disease pathogenesis at the molecular level, the stilbene scaffold has moved innovation in science. This paper mainly focuses on the stilbene-based compounds beyond resveratrol, which are particularly attractive due to their biological activity. Given the "fresh outlook" about different stilbene-based compounds starting from stilbenoids with particular regard to isorhapontigenin and methoxy- and hydroxyl- analogues, the update about the combretastatins, and the very often overlooked and underestimated benzanilide analogues, we present a new story about this remarkable structure.
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