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Xiang Z, Ma B, Pei X, Wang W, Gong W. Mechanism of action of genistein on breast cancer and differential effects of different age stages. PHARMACEUTICAL BIOLOGY 2025; 63:141-155. [PMID: 39996512 PMCID: PMC11864014 DOI: 10.1080/13880209.2025.2469607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 02/12/2025] [Accepted: 02/14/2025] [Indexed: 02/26/2025]
Abstract
CONTEXT Genistein, a soy-derived isoflavone, exhibits structural similarities with 17β-estradiol and demonstrates antioxidant, anti-inflammatory, and estrogenic properties. Despite its low bioavailability limiting its clinical application, it shows potential for breast cancer prevention and treatment. OBJECTIVE This review aims to summarize the pharmacological effects and molecular mechanisms of genistein in breast cancer, focusing on its therapeutic potential, strategies to overcome bioavailability limitations, and its role in personalized medicine. Differential impacts among population subgroups are also discussed. METHODS A systematic review was conducted using PubMed, ScienceDirect, and Google Scholar databases. Studies were selected based on their focus on genistein's mechanisms of action, strategies to enhance its bioavailability, and interactions with other therapies. RESULTS Genistein exerted anticancer effects by modulating estrogen receptor β (ERβ), inhibiting angiogenesis, arresting the cell cycle, and inducing apoptosis. Its antioxidant properties help mitigate tumor-associated oxidative stress. Bioavailability enhancement strategies, such as nanoparticle and lipid-based formulations, show promise. Age-dependent effects were evident, with distinct responses observed in prepubertal, menopausal, and postmenopausal populations, underscoring its potential for personalized therapies. Furthermore, genistein influences epigenetic modifications, including DNA methylation and miRNA expression, bolstering its anticancer efficacy. CONCLUSION Genistein is a promising candidate for breast cancer therapy, particularly for personalized treatment. Strategies to enhance bioavailability and further clinical research are essential to optimize its therapeutic potential and evaluate its efficacy in combination therapies.
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Affiliation(s)
- Zhebin Xiang
- Zhejiang Chinese Medical University, Hangzhou, China
| | - Bo Ma
- Zhejiang Hospital, Hangzhou, China
| | - Xiujun Pei
- Shandong Provincial Hospital, Shandong, China
| | - Wenjie Wang
- Zhejiang Chinese Medical University, Hangzhou, China
| | - Weilun Gong
- Zhejiang Chinese Medical University, Hangzhou, China
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Hou YX, Ren W, He QQ, Huang LY, Gao TH, Li H. Tetramethylpyrazine induces reactive oxygen species-based mitochondria-mediated apoptosis in colon cancer cells. World J Gastrointest Oncol 2025; 17:104922. [PMID: 40235896 PMCID: PMC11995317 DOI: 10.4251/wjgo.v17.i4.104922] [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: 01/08/2025] [Revised: 01/26/2025] [Accepted: 02/21/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Colon cancer is one of the most common malignancies worldwide, and chemotherapy is a widely used strategy in colon cancer clinical therapy. Chemotherapy resistance is the main cause of recurrence and progression in colon cancer. Thus, novel drugs for treatment are urgently needed. Tetramethylpyrazine (TMP), a component of the traditional Chinese medicine Chuanxiong Hort, has been proven to exhibit a beneficial effect in tumors. AIM To investigate the potential anticancer activity of TMP in colon cancer and the underlying mechanisms. METHODS Colon cancer cells were incubated with different concentrations of TMP. Cell viability was evaluated by crystal violet staining assay, and cell apoptosis was assessed by flow cytometry. Apoptosis-associated protein expression was measured using Western blot analysis. Intracellular reactive oxygen species (ROS) levels were assessed by flow cytometry using DCF fluorescence intensity. Xenografts were established by the subcutaneous injection of colon cancer cells into nude mice; tumor growth was monitored and intracellular ROS was detected in tumors by malondialdehyde assay. RESULTS TMP induced apoptosis of colon cancer cells via the activation of the mitochondrial pathway. TMP increased the generation of intracellular ROS and triggered mitochondria-mediated apoptosis in a caspase-dependent manner. CONCLUSION Our study demonstrates that TMP induces the apoptosis of colon cancer cells and increases the generation of intracellular ROS. TMP triggers mitochondria-mediated apoptosis in a caspase-dependent manner. The accumulation of intracellular ROS is involved in TMP-induced apoptosis. Our findings suggest that TMP may be a potential therapeutic drug for the treatment of colon cancer.
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Affiliation(s)
- Yan-Xu Hou
- The Second Department of Gastrointestinal Oncology Surgery, Xingtai People’s Hospital of Hebei Medical University, Xingtai 054001, Hebei Province, China
| | - Wei Ren
- The Second Department of Gastrointestinal Oncology Surgery, Xingtai People’s Hospital of Hebei Medical University, Xingtai 054001, Hebei Province, China
| | - Qing-Qiang He
- The Second Department of Gastrointestinal Oncology Surgery, Xingtai People’s Hospital of Hebei Medical University, Xingtai 054001, Hebei Province, China
| | - Li-Yan Huang
- The Second Department of Gastrointestinal Oncology Surgery, Xingtai People’s Hospital of Hebei Medical University, Xingtai 054001, Hebei Province, China
| | - Tian-Hua Gao
- The Second Department of Gastrointestinal Oncology Surgery, Xingtai People’s Hospital of Hebei Medical University, Xingtai 054001, Hebei Province, China
| | - Hua Li
- The Second Department of Gastrointestinal Oncology Surgery, Xingtai People’s Hospital of Hebei Medical University, Xingtai 054001, Hebei Province, China
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Ding JM, Zhong HM, Huang K, Zeng W, Chen L. Apoptosis and long non-coding RNAs: Focus on their roles in ischemic stroke. Brain Res 2025; 1849:149346. [PMID: 39581527 DOI: 10.1016/j.brainres.2024.149346] [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: 08/08/2024] [Revised: 11/04/2024] [Accepted: 11/18/2024] [Indexed: 11/26/2024]
Abstract
Ischemic stroke (IS) is a severe and sudden cerebrovascular event, associated with notably high rates of mortality and morbidity. The process of apoptosis, a genetically orchestrated form of programmed cell death, is divided into two pathways: intrinsic and extrinsic. The intricate involvement of long non-coding RNA (lncRNA) in the pathobiology of IS, particularly in modulating neuronal apoptosis, is a burgeoning area of research. This review synthesizes the current understanding of the regulatory mechanisms of lncRNA on neuronal apoptosis in the context of ischemic stroke. Specifically, we highlight the roles of lncRNA such as ANRIL, C2dat1/2, H19, TUG1, MEG3, SNHG, and GAS5, which have been implicated in the facilitation of neuronal apoptosis. Conversely, the lncRNA N1LR has been shown to exert an inhibitory effect on this process. The role of MALAT1 in neuronal apoptosis remains a subject of ongoing debate, as its function oscillates between pro-apoptotic and anti-apoptotic roles, thus highlighting the need for further elucidation.
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Affiliation(s)
- Jia Min Ding
- The First Clinical Medical College of Gannan Medical University, Ganzhou, China
| | - Hui Min Zhong
- The First Clinical Medical College of Gannan Medical University, Ganzhou, China
| | - Kuan Huang
- Anesthesia Surgical Center The First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Wen Zeng
- Department of Anesthesiology, The 2nd Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Li Chen
- Anesthesia Surgical Center The First Affiliated Hospital of Gannan Medical University, Ganzhou, China; Anesthesia Key Laboratory of Gannan Medical University, Ganzhou, China; Prevention and Treatment of Cardiovascular and Cerebrovascular Disease, Ministry of Education, Gannan Medical University, Ganzhou 34100, China.
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Chueh FS, Hsu SY, Lai KC, Liu YC, Lyu PC, Kuo YH, Huang YP, Hsieh WT. Physalin A induces apoptosis through conjugating with Fas-FADD cell death receptor in human oral squamous carcinoma cells and suppresses HSC-3 cell xenograft tumors in NOD/SCID mice. Hum Exp Toxicol 2025; 44:9603271251335220. [PMID: 40239116 DOI: 10.1177/09603271251335220] [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: 04/18/2025]
Abstract
IntroductionOral carcinoma cancer exhibits high global incidence and mortality. Physalin A (PA) was reported to induce programmed cell death in cancer cells. No study has yet investigated the influence of PA in oral squamous cell carcinoma. Herein, this study aims to explore PA-induced anti-cancer effects in human oral carcinoma.MethodsThis study used DNA gel electrophoresis and Annexin V/PI staining to detect DNA fragmentation and cell apoptosis. Western blotting and immunofluorescence analyzed protein expression. Flow cytometry measured Ca2+ release and mitochondrial membrane potential (∆Ψm). Moreover, molecular docking models predicted the molecular binding affinity.ResultsDNA gel electrophoresis and annexin V/PI staining confirmed PA-induced DNA fragmentation and apoptosis. Flow cytometry showed PA increased Ca2+ release and reduced ∆Ψm levels. PA activated cleaved caspase-3, -8, and -9, upregulated Bax and Bid, and downregulated Bcl-2. PA dose-dependently increased Fas (CD95/APO-1), apoptosis-inducing factor (AIF), and cytochrome c release in western blotting analysis. Confocal microscopy confirmed increased Bax, AIF, cleaved caspase-3, and Fas, with decreased Bcl-2. Molecular docking showed strong PA binding via hydrophobic interactions with the Fas-associated death domain (FADD). Compared with cisplatin, PA inhibited HSC-3 cell xenograft tumor growth in NOD/SCID mice.DiscussionWe reveal that PA binds to the Fas-FADD complex, inducing caspase-8 activation and triggering extrinsic and intrinsic mitochondria-dependent apoptosis in HSC-3 cells. It also suppresses HSC-3 cell xenograft tumors in NOD/SCID mice. These findings suggest PA as a potential anti-oral cancer agent in the future.
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Affiliation(s)
- Fu-Shin Chueh
- Department of Food Nutrition and Health Biotechnology, Asia University, Taichung, Taiwan
| | - Sheng-Yao Hsu
- Department of Ophthalmology, Kaohsiung Show Chwan Memorial Hospital, Taiwan
- Department of Optometry, Chung Hwa University of Medical Technology, Tainan, Taiwan
| | - Kuang-Chi Lai
- Department of Surgery, China Medical University Beigang Hospital, Yunlin, Taiwan
| | - Yi-Chung Liu
- Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan
| | - Ping-Chiang Lyu
- Institute of Bioinformatics and Structural Biology, National Tsing-Hua University, Hsinchu, Taiwan
| | - Yueh-Hsiung Kuo
- Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung, Taiwan
- Chinese Medicine Research Center, China Medical University, Taichung, Taiwan
- Department of Biotechnology, Asia University, Taichung, Taiwan
| | - Yi-Ping Huang
- Department of Physiology, School of Medicine, China Medical University, Taichung, Taiwan
| | - Wen-Tsong Hsieh
- Chinese Medicine Research Center, China Medical University, Taichung, Taiwan
- Department of Pharmacology, China Medical University, Taichung, Taiwan
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Qiao Y, Kou J, Tian Y, Ma W, Yu Y, Pang J, Pei Y, Zhang Y, Ye B, Xie Z, Liu J, Wang Z, Wang L, Gao X, Ma N, Zhang Y. Subcellular localization and function analysis of PINK1 mitron in PD progression: Mitron modulates mitochondrial morphology to regulate neuronal death. J Biol Chem 2024; 300:107773. [PMID: 39276929 PMCID: PMC11497375 DOI: 10.1016/j.jbc.2024.107773] [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: 12/11/2023] [Revised: 08/30/2024] [Accepted: 09/02/2024] [Indexed: 09/17/2024] Open
Abstract
Parkinson's disease (PD) is a multifactorial neurodegenerative disorder. Loss or degeneration of the dopaminergic neurons in the substantia nigra and development of Lewy bodies in dopaminergic neurons were the defining pathologic changes. MiRNAs fine-tune the protein levels by posttranscriptional gene regulation. MiR-7019-3p is encoded within the fifth intron of PD-associated protein PINK1. In present study, we firstly demonstrated miR-7019-3p expression is significantly upregulated in PD mice model and neuron cell models, miR-7019-3p mainly existed in mitochondria, miR-7019-3p could regulate the structure, and function of mitochondria in neuronal cells. We predicted and verified that mitochondria-associated protein optic atrophy 1 and 12s rRNA, 16s rRNA, and polycistronic RNA are target genes of miR-7019-3p. Finally, we proved that SP1 protein could independently regulate the expression of miR-7019-3p at the upstream. The evidences in the study suggest the role miR-7019-3p in the regulation of mitochondrial structure and function, and this kind of regulation could be implemented or promoted through the pathway of SP1-miR-7019-3p-optic atrophy 1/12s rRNA, 16s rRNA, and polycistronic RNA. Our results have suggested a promising and potential therapeutic target for reversing mitochondria dysregulation in neuronal cells during PD process.
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Affiliation(s)
- Yu Qiao
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China; Key Laboratory of Cardiovascular Medicine Research (Harbin Medical University), Ministry of Education, Harbin, China; Translational Medicine Center of Northern China, Harbin Medical University, Harbin, China; Medical Science Institute of Hei Longjiang Province, Harbin, China
| | - Jiayuan Kou
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China; Key Laboratory of Cardiovascular Medicine Research (Harbin Medical University), Ministry of Education, Harbin, China; Translational Medicine Center of Northern China, Harbin Medical University, Harbin, China; Medical Science Institute of Hei Longjiang Province, Harbin, China
| | - Ye Tian
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China; Key Laboratory of Cardiovascular Medicine Research (Harbin Medical University), Ministry of Education, Harbin, China; Translational Medicine Center of Northern China, Harbin Medical University, Harbin, China; Medical Science Institute of Hei Longjiang Province, Harbin, China
| | - Wenkai Ma
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China; Key Laboratory of Cardiovascular Medicine Research (Harbin Medical University), Ministry of Education, Harbin, China; Translational Medicine Center of Northern China, Harbin Medical University, Harbin, China; Medical Science Institute of Hei Longjiang Province, Harbin, China
| | - Yang Yu
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China; Key Laboratory of Cardiovascular Medicine Research (Harbin Medical University), Ministry of Education, Harbin, China; Translational Medicine Center of Northern China, Harbin Medical University, Harbin, China; Medical Science Institute of Hei Longjiang Province, Harbin, China
| | - Jingjing Pang
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China; Key Laboratory of Cardiovascular Medicine Research (Harbin Medical University), Ministry of Education, Harbin, China; Translational Medicine Center of Northern China, Harbin Medical University, Harbin, China; Medical Science Institute of Hei Longjiang Province, Harbin, China
| | - Yingting Pei
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China; Key Laboratory of Cardiovascular Medicine Research (Harbin Medical University), Ministry of Education, Harbin, China; Translational Medicine Center of Northern China, Harbin Medical University, Harbin, China; Medical Science Institute of Hei Longjiang Province, Harbin, China
| | - Yu Zhang
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China; Key Laboratory of Cardiovascular Medicine Research (Harbin Medical University), Ministry of Education, Harbin, China; Translational Medicine Center of Northern China, Harbin Medical University, Harbin, China; Medical Science Institute of Hei Longjiang Province, Harbin, China
| | - Bin Ye
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China; Key Laboratory of Cardiovascular Medicine Research (Harbin Medical University), Ministry of Education, Harbin, China; Translational Medicine Center of Northern China, Harbin Medical University, Harbin, China; Medical Science Institute of Hei Longjiang Province, Harbin, China
| | - Ziying Xie
- Department of Laboratory Diagnosis, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jinying Liu
- Department of Laboratory Diagnosis, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhihui Wang
- Department of Laboratory Diagnosis, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Lujing Wang
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China; Key Laboratory of Cardiovascular Medicine Research (Harbin Medical University), Ministry of Education, Harbin, China; Translational Medicine Center of Northern China, Harbin Medical University, Harbin, China; Medical Science Institute of Hei Longjiang Province, Harbin, China
| | - Xu Gao
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China; Key Laboratory of Cardiovascular Medicine Research (Harbin Medical University), Ministry of Education, Harbin, China; Translational Medicine Center of Northern China, Harbin Medical University, Harbin, China; Medical Science Institute of Hei Longjiang Province, Harbin, China.
| | - Ning Ma
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China; Key Laboratory of Cardiovascular Medicine Research (Harbin Medical University), Ministry of Education, Harbin, China; Translational Medicine Center of Northern China, Harbin Medical University, Harbin, China; Medical Science Institute of Hei Longjiang Province, Harbin, China.
| | - Yanfen Zhang
- Department of Laboratory Diagnosis, Second Affiliated Hospital of Harbin Medical University, Harbin, China.
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Hink F, Aduriz-Arrizabalaga J, Lopez X, Suga H, De Sancho D, Rogers JM. Mixed Stereochemistry Macrocycle Acts as a Helix-Stabilizing Peptide N-Cap. J Am Chem Soc 2024; 146:24348-24357. [PMID: 39182188 DOI: 10.1021/jacs.4c05378] [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: 08/27/2024]
Abstract
Interactions between proteins and α-helical peptides have been the focus of drug discovery campaigns. However, the large interfaces formed between multiple turns of an α-helix and a binding protein represent a significant challenge to inhibitor discovery. Modified peptides featuring helix-stabilizing macrocycles have shown promise as inhibitors of these interactions. Here, we tested the ability of N-terminal to side-chain thioether-cyclized peptides to inhibit the α-helix binding protein Mcl-1, by screening a trillion-scale library. The enriched peptides were lariats featuring a small, four-amino-acid N-terminal macrocycle followed by a short linear sequence that resembled the natural α-helical Mcl-1 ligands. These "Heliats" (helical lariats) bound Mcl-1 with tens of nM affinity, and inhibited the interaction between Mcl-1 and a natural peptide ligand. Macrocyclization was found to stabilize α-helical structures and significantly contribute to affinity and potency. Yet, the 2nd and 3rd positions within the macrocycle were permissible to sequence variation, so that a minimal macrocyclic motif, of an N-acetylated d-phenylalanine at the 1st position thioether connected to a cysteine at the 4th, could be grafted into a range of peptides and stabilize helical conformations. We found that d-stereochemistry is more helix-stabilizing than l- at the 1st position in the motif, as the d-amino acid can utilize polyproline II torsional angles that allow for more optimal intrachain hydrogen bonding. This mixed stereochemistry macrocyclic N-cap is synthetically accessible, requiring only minor modifications to standard solid-phase peptide synthesis, and its compatibility with peptide screening can provide ready access to helix-focused peptide libraries for de novo inhibitor discovery.
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Affiliation(s)
- Fabian Hink
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen 2100, Denmark
| | - Julen Aduriz-Arrizabalaga
- Polimero eta Material Aurreratuak: Fisika, Kimika eta Teknologia, Kimika Fakultatea, UPV/EHU & Donostia International Physics Center (DIPC), PK 1072, Donostia-San Sebastian, Euskadi 20018, Spain
| | - Xabier Lopez
- Polimero eta Material Aurreratuak: Fisika, Kimika eta Teknologia, Kimika Fakultatea, UPV/EHU & Donostia International Physics Center (DIPC), PK 1072, Donostia-San Sebastian, Euskadi 20018, Spain
| | - Hiroaki Suga
- Department of Chemistry, Graduate School of Science, The University of Tokyo, Tokyo, Bunkyo-ku 113-0033, Japan
| | - David De Sancho
- Polimero eta Material Aurreratuak: Fisika, Kimika eta Teknologia, Kimika Fakultatea, UPV/EHU & Donostia International Physics Center (DIPC), PK 1072, Donostia-San Sebastian, Euskadi 20018, Spain
| | - Joseph M Rogers
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen 2100, Denmark
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Gao W, Liu YF, Zhang YX, Wang Y, Jin YQ, Yuan H, Liang XY, Ji XY, Jiang QY, Wu DD. The potential role of hydrogen sulfide in cancer cell apoptosis. Cell Death Discov 2024; 10:114. [PMID: 38448410 PMCID: PMC10917771 DOI: 10.1038/s41420-024-01868-w] [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: 07/12/2023] [Revised: 02/05/2024] [Accepted: 02/14/2024] [Indexed: 03/08/2024] Open
Abstract
For a long time, hydrogen sulfide (H2S) has been considered a toxic compound, but recent studies have found that H2S is the third gaseous signaling molecule which plays a vital role in physiological and pathological conditions. Currently, a large number of studies have shown that H2S mediates apoptosis through multiple signaling pathways to participate in cancer occurrence and development, for example, PI3K/Akt/mTOR and MAPK signaling pathways. Therefore, the regulation of the production and metabolism of H2S to mediate the apoptotic process of cancer cells may improve the effectiveness of cancer treatment. In this review, the role and mechanism of H2S in cancer cell apoptosis in mammals are summarized.
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Affiliation(s)
- Wei Gao
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Ya-Fang Liu
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Yan-Xia Zhang
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Yan Wang
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Yu-Qing Jin
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Hang Yuan
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Xiao-Yi Liang
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Xin-Ying Ji
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China.
- Faculty of Basic Medical Subjects, Shu-Qing Medical College of Zhengzhou, Zhengzhou, Henan, 450064, China.
| | - Qi-Ying Jiang
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China.
| | - Dong-Dong Wu
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475004, China.
- School of Stomatology, Henan University, Kaifeng, Henan, 475004, China.
- Department of Stomatology, Huaihe Hospital of Henan University, Kaifeng, Henan, 475000, China.
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Ma T, Huang YB, Chen J, Zhang L, Liu YH, Lu CH. MRPL21 promotes HCC proliferation through TP53 mutation-induced apoptotic resistance. Tissue Cell 2024; 86:102298. [PMID: 38181584 DOI: 10.1016/j.tice.2023.102298] [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: 08/28/2023] [Revised: 12/29/2023] [Accepted: 12/30/2023] [Indexed: 01/07/2024]
Abstract
BACKGROUND AND AIMS The specific mechanisms underlying the inhibition of hepatocellular carcinoma (HCC) proliferation and metastasis by mitochondrial apoptosis are not yet fully understood. However, it plays a vital role in suppressing HCC's ability to proliferate and spread. The involvement of MRPL21, a member within the family of mitochondrial ribosomal proteins (MRPs), is well-documented in both cellular apoptosis and energy metabolism. This study aims to explore and unravel the underlying mechanisms through which MRPL21 contributes to mitochondrial apoptosis and resistance against apoptosis in HCC. METHODS To evaluate the level of MRPL21 expression at the gene and protein expression levels, analysis was performed on human liver samples and blood using techniques for quantification. A knockdown plasmid targeting MRPL21 was constructed to investigate its impact on the growth and apoptosis of hepatocellular carcinoma (HCC). To evaluate the impact of MRPL21 knockdown on hepatocellular carcinoma (HCC) cell proliferation and apoptosis, various assays were performed including CCK-8 assays, flow cytometry analysis, detection of reactive oxygen species (ROS), and assessment of mitochondrial membrane potential (MMP). Furthermore, the role of MRPL21 in TP53 mutation was examined using Nutlin-3. RESULTS In HCC tissues and blood samples, an upregulation of MRPL21 expression was observed when compared to samples obtained from healthy individuals, and it is correlated with a poor prognosis for HCC. Silencing MRPL21 can effectively suppress Hep3B and HCCLM3 cells proliferation by modulating the mitochondrial membrane potential, it triggers the generation of reactive oxygen species (ROS), thereby leading to G0/G1 cell cycle arrest and initiation of early apoptosis. Furthermore, by inhibiting P53 activity, Nutlin-3 treatment can enhance MRPL21-deficiency-mediated apoptosis in Hep3B and HCCLM3 cells. CONCLUSION Through its influence on TP53 mutation, MRPL21 promotes HCC proliferation and progression while conferring resistance to apoptosis. These findings suggest that MRPL21 holds promise as a valuable biomarker for the treatment of HCC.
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Affiliation(s)
- Tao Ma
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China; Research Center of Clinical Medicine, Nantong University, Affiliated Hospital of Nantong University, Nantong, China
| | - Ya-Bin Huang
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Jing Chen
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China; Research Center of Clinical Medicine, Nantong University, Affiliated Hospital of Nantong University, Nantong, China
| | - Lu Zhang
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China; Research Center of Clinical Medicine, Nantong University, Affiliated Hospital of Nantong University, Nantong, China
| | - Yan-Hua Liu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China.
| | - Cui-Hua Lu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China.
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Lin S, Chen Z, Li S, Chen B, Wu Y, Zheng Y, Huang J, Chen Y, Lin X, Yao H. Anti-tumor effect and mechanism of the total biflavonoid extract from S doederleinii on human cervical cancer cells in vitro and in vivo. Heliyon 2024; 10:e24778. [PMID: 38304845 PMCID: PMC10830543 DOI: 10.1016/j.heliyon.2024.e24778] [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: 08/31/2023] [Revised: 01/11/2024] [Accepted: 01/15/2024] [Indexed: 02/03/2024] Open
Abstract
In this study, the therapeutic effect and possible mechanism of the total biflavonoid extract of Selaginella doederleinii Hieron (SDTBE) against cervical cancer were originally investigated in vitro and in vivo. First, the inhibition of SDTBE on proliferation of cervical cancer HeLa cells was evaluated, followed by morphological observation with AO/EB staining, Annexin V/PI assay, and autophagic flux monitoring to evaluate the possible effect of SDTBE on cell apoptosis and autophagy. Cell cycle, as well as mitochondrial membrane potential (ΔѰm), was detected with flow cytometry. Further, the apoptosis related protein expression and the autophagy related gene LC3 mRNA transcription level were analyzed by Western blot (WB) and real-time quantitative polymerase chain reaction (RT-qPCR), respectively. Finally, the anti-cervical cancer effect of the SDTBE was also validated in vivo in HeLa cells grafts mice. As results, SDTBE inhibited HeLa cells proliferation with the IC50 values of 49.05 ± 6.76 and 44.14 ± 4.75 μg/mL for 48 and 72 h treatment, respectively. The extract caused mitochondrial ΔѰ loss, induced cell apoptosis by upregulating Bax, downregulating Bcl-2, activating Caspase-9 and Caspase-3, promoting cell autophagy and blocking the cell cycle in G0/G1 phase. Furthermore, 100, 200, and 300 mg/kg SDTBE suppressed the growth of HeLa cells xenografts in mice with the mean inhibition rates, 25.3 %, 57.5 % and 62.9 %, respectively, and the change of apoptosis related proteins and microvascular density was confirmed in xenografts by immunohistochemistry analysis. The results show that SDTBE possesses anti-cervical cancer effect, and the mechanism involves in activating Caspase-dependent mitochondrial apoptosis pathway.
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Affiliation(s)
- Shilan Lin
- Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Zhijie Chen
- Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Shaoguang Li
- Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Bing Chen
- Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Youjia Wu
- Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Yanjie Zheng
- Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Jianyong Huang
- Department of Pharmacy, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Yan Chen
- Department of Medical Chemistry, School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Xinhua Lin
- Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Hong Yao
- Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, China
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10
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Ahmed H, Ijaz MU, Jahan S, Riaz M, Samir H, Swelum AA. Coenzyme Q10 improves the quality and in vitro fertility of post-thawed buffalo (Bubalus bubalis) semen via its antioxidative effect. Reprod Domest Anim 2024; 59:e14515. [PMID: 38268218 DOI: 10.1111/rda.14515] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 11/24/2023] [Accepted: 12/08/2023] [Indexed: 01/26/2024]
Abstract
This study aimed to determine the effects of Coenzyme Q10 (CoQ10) in the freezing medium on functional and oxidative stress parameters and in vitro fertilization (IVF) rate of buffalo sperm. Collected samples were relocated to the laboratory for initial evaluation, gentle dilution in extenders, cooling (4°C, 2 h), equilibration (4°C, 4 h), packaging (straws, 0.5 mL), programmable freezing, and thawing (37°C, 30 s). Statistical analysis depicted that adding CoQ10 (100 μM) in a freezing medium caused a significant augmentation in total motility (%), average path, and straight-line velocities (μm/sec) of buffalo sperm than control. Adding CoQ10 (100 μM) improved sperm progressive motility, rapid velocity, and functional parameters (%) compared to the control and 10 μM of CoQ10. Moreover, CoQ10 in a freezing medium caused a significant augmentation in seminal plasma catalase (U/mL) and glutathione reductase (GSH; nmol/109 ) at 100 μM than control and other treatments. CoQ10 inclusion (100 μM) ameliorates seminal plasma superoxide dismutase (U/mL), glutathione-S-transferase (GST; nmol/mL/min) fructose (μg/mL), and ATP (nmol/million) than control. Furthermore, CoQ10 at 100 μM improved seminal plasma glutathione peroxidase (μM) levels than control, 10 μM, and 20 μM. Lastly, hydrogen peroxide (H2 O2; nM) production was significantly lower at 100 μM than at control and 10 μM. CoQ10 (100 μM) caused a significant augmentation in the un-capacitated pattern followed by a reduction in the capacitated pattern, and apoptosis-like changes (%) than control, and other treatments, whereas viability was increased than control and other treatments. CoQ10 (100 μM) significantly improved the IVF rate in comparison with control, CoQ10 at 10 μM, and 20 μM groups. In conclusion, the addition of CoQ10 (100 μM) in the freezing medium can improve the quality and in vitro fertility of post-thawed buffalo semen via its antioxidative effect. Further studies are needed to evaluate the effect of CoQ10 on the in vivo fertility of buffalo bull semen.
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Affiliation(s)
- Hussain Ahmed
- Department of Zoology, University of Buner, Khyber Pakhtunkhwa, KP, Pakistan
- Department of Animal Sciences, Reproductive Physiology Laboratory, Quaid-i-Azam University, Campus, Islamabad, Pakistan
| | - Muhammad Umar Ijaz
- Department of Zoology, Wildlife and Fisheries, University of Agriculture, Faisalabad, Pakistan
| | - Sarwat Jahan
- Department of Animal Sciences, Reproductive Physiology Laboratory, Quaid-i-Azam University, Campus, Islamabad, Pakistan
| | - Mehreen Riaz
- Department of Zoology, Women University Swabi, Swabi, KP, Pakistan
| | - Haney Samir
- Department of Veterinary Medicine, Tokyo University of Agriculture and Technology, Fuchu, Japan
- Department of Theriogenology, Faculty of Veterinary Medicine, Cairo University, Cairo, Egypt
| | - Ayman A Swelum
- Department of Animal Production, College of Food and Agriculture Science, King Saud University, Riyadh, Saudi Arabia
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11
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Liu C, Ding Z, Zhang Z, Zhao L, Zhang C, Huang F. Morphological changes of mitochondria-related to apoptosis during postmortem aging of beef muscles. Food Chem X 2023; 19:100806. [PMID: 37780314 PMCID: PMC10534185 DOI: 10.1016/j.fochx.2023.100806] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 07/08/2023] [Accepted: 07/20/2023] [Indexed: 10/03/2023] Open
Abstract
This study aimed to investigate how postmortem muscle cells' mitochondria changed in morphology from three aspects: the outer membrane, cristae, and fission/fusion. Atomic force microscopy (AFM) results showed that mitochondria underwent a morphology transformation from normal to swelling and collapse. Meanwhile, the cleavage of OPA1, upregulation of OMA1, downregulation of Mic60 and transmission electron microscope micrographs revealed that mitochondrial cristae ruptured with an aging time extended. Additionally, the increased expressions of Fis1 and Drp1, and the AFM topographic images mutually confirmed mitochondrial fission. These results further proved from the perspective of mitochondrial morphology that the degree of mitochondrial damage increased with the postmortem aging time extended, which was consistent with the results of the release of cytochrome c caused by the increase of mitochondrial permeability transition pore opening and the decrease of mitochondrial membrane permeability, and further induced the apoptosis of postmortem muscle cells.
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Affiliation(s)
- Chunmei Liu
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences/Key Laboratory of Agro-Products Processing, Ministry of Agriculture and Rural Affairs, Beijing 100193, China
| | - Zhenjiang Ding
- Beijing Key Laboratory of the Innovative Development of Functional Staple and Nutritional Intervention for Chronic Diseases, China National Research Institute of Food and Fermentation Industries, Beijing 100015, China
| | - Zihan Zhang
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences/Key Laboratory of Agro-Products Processing, Ministry of Agriculture and Rural Affairs, Beijing 100193, China
| | - Laiyu Zhao
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences/Key Laboratory of Agro-Products Processing, Ministry of Agriculture and Rural Affairs, Beijing 100193, China
| | - Chunhui Zhang
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences/Key Laboratory of Agro-Products Processing, Ministry of Agriculture and Rural Affairs, Beijing 100193, China
| | - Feng Huang
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences/Key Laboratory of Agro-Products Processing, Ministry of Agriculture and Rural Affairs, Beijing 100193, China
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12
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Xiao J, Ma J, Khan MZ, Alugongo GM, Chen T, Liu S, Li S, Cao Z. Unlocking the potential of milk whey protein components in colorectal cancer prevention and therapy. Crit Rev Food Sci Nutr 2023; 64:12961-12998. [PMID: 37846905 DOI: 10.1080/10408398.2023.2258970] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2023]
Abstract
Extensive research from large prospective cohort studies and meta-analytical investigations over recent decades have consistently indicated that dairy foods have protective effects, reducing the risk of colorectal cancer. Most of the literature has explored the potential role of milk minerals and vitamins in managing colorectal cancer. Yet, there is a paucity of a comprehensive summary of the anticancer attributes of milk protein components and their underlying mechanisms of action. Recent advancements have spotlighted the potential of whey proteins, including β-lactoglobulin, α-lactalbumin, serum albumin, and lactoferrin, as promising candidates for both the prevention and treatment of colorectal cancer. Notably, whey proteins have demonstrated a more pronounced capacity for suppressing carcinogen-induced tumors when compared to casein. Their strong binding affinity enables them to serve as effective carriers for small molecules or drugs targeting colon cancer therapy. Furthermore, numerous studies have underscored the anti-inflammatory and antioxidant prowess of whey proteins in cancer prevention. Additionally, whey proteins have been shown to trigger apoptosis, hinder tumor cell proliferation, and impede metastasis. This comprehensive review, therefore, not only substantiates the significance of incorporating whey protein components into a balanced daily diet but also underscores their potential in safeguarding against the onset and progression of colorectal cancer.
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Affiliation(s)
- Jianxin Xiao
- State Key Laboratory of Animal Nutrition and Feeding, Beijing Engineering Technology Research Center of Raw Milk Quality and Safety Control, College of Animal Science and Technology, China Agricultural University, Beijing, China
- Key Laboratory of Low Carbon Culture and Safety Production in Cattle in Sichuan, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Jiaying Ma
- State Key Laboratory of Animal Nutrition and Feeding, Beijing Engineering Technology Research Center of Raw Milk Quality and Safety Control, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Muhammad Zahoor Khan
- Faculty of Veterinary and Animal Sciences, University of Agriculture Dera Ismail Khan, Khyber Pakhtunkhwa, Pakistan
| | - Gibson Maswayi Alugongo
- State Key Laboratory of Animal Nutrition and Feeding, Beijing Engineering Technology Research Center of Raw Milk Quality and Safety Control, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Tianyu Chen
- State Key Laboratory of Animal Nutrition and Feeding, Beijing Engineering Technology Research Center of Raw Milk Quality and Safety Control, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Shuai Liu
- State Key Laboratory of Animal Nutrition and Feeding, Beijing Engineering Technology Research Center of Raw Milk Quality and Safety Control, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Shengli Li
- State Key Laboratory of Animal Nutrition and Feeding, Beijing Engineering Technology Research Center of Raw Milk Quality and Safety Control, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Zhijun Cao
- State Key Laboratory of Animal Nutrition and Feeding, Beijing Engineering Technology Research Center of Raw Milk Quality and Safety Control, College of Animal Science and Technology, China Agricultural University, Beijing, China
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13
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Xu J, Sun Y, Fu W, Fu S. MYCT1 in cancer development: Gene structure, regulation, and biological implications for diagnosis and treatment. Biomed Pharmacother 2023; 165:115208. [PMID: 37499454 DOI: 10.1016/j.biopha.2023.115208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 07/10/2023] [Accepted: 07/19/2023] [Indexed: 07/29/2023] Open
Abstract
Myc target 1 (MYCT1), located at 6q25.2, is a crucial player in cancer development. While widely distributed in cells, its subcellular localization varies across different cancer types. As a novel c-Myc target gene, MYCT1 is subject to regulation by multiple transcription factors. Studies have revealed aberrant expression of MYCT1 in various cancers, impacting pivotal biological processes such as proliferation, apoptosis, migration, genomic instability, and differentiation in cancer cells. Additionally, MYCT1 plays a critical role in modulating tumor angiogenesis and remodeling tumor immune responses within the tumor microenvironment. Despite certain debated functions, MYCT1 undeniably holds significance in cancer development. In this review, we comprehensively examine the relationship between MYCT1 and cancer, encompassing gene structure, regulation of gene expression, gene mutation, and biological function, with the aim of providing valuable insights for cancer diagnosis and treatment.
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Affiliation(s)
- Jianan Xu
- Department of Medical genetics, China Medical University, Shenyang 110022, PR China
| | - Yuanyuan Sun
- Department of Medical genetics, China Medical University, Shenyang 110022, PR China
| | - Weineng Fu
- Department of Medical genetics, China Medical University, Shenyang 110022, PR China
| | - Shuang Fu
- Department of Hematology Laboratory, Shengjing Hospital of China Medical University, Shenyang 110022, PR China; Department of Medical genetics, China Medical University, Shenyang 110022, PR China.
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14
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Nosalova N, Keselakova A, Kello M, Martinkova M, Fabianova D, Pilatova MB. Involvement of Both Extrinsic and Intrinsic Apoptotic Pathways in Tridecylpyrrolidine-Diol Derivative-Induced Apoptosis In Vitro. Int J Mol Sci 2023; 24:11696. [PMID: 37511455 PMCID: PMC10380684 DOI: 10.3390/ijms241411696] [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: 06/16/2023] [Revised: 07/17/2023] [Accepted: 07/18/2023] [Indexed: 07/30/2023] Open
Abstract
Despite the decreasing trend in mortality from colorectal cancer, this disease still remains the third most common cause of death from cancer. In the present study, we investigated the antiproliferative and pro-apoptotic effects of (2S,3S,4R)-2-tridecylpyrrolidine-3,4-diol hydrochloride on colon cancer cells (Caco-2 and HCT116). The antiproliferative effect and IC50 values were determined by the MTT and BrdU assays. Flow cytometry, qRT-PCR and Western blot were used to study the cellular and molecular mechanisms involved in the induction of apoptotic pathways. Colon cancer cell migration was monitored by the scratch assay. Concentration-dependent cytotoxic and antiproliferative effects on both cell lines, with IC50 values of 3.2 ± 0.1 μmol/L (MTT) vs. 6.46 ± 2.84 μmol/L (BrdU) for HCT116 and 2.17 ± 1.5 μmol/L (MTT) vs. 1.59 ± 0.72 μmol/L (BrdU), for Caco-2 were observed. The results showed that tridecylpyrrolidine-induced apoptosis was associated with the externalization of phosphatidylserine, reduced mitochondrial membrane potential (MMP) accompanied by the activation of casp-3/7, the cleavage of PARP and casp-8, the overexpression of TNF-α and FasL and the dysregulation of Bcl-2 family proteins. Inhibition of the migration of treated cells across the wound area was detected. Taken together, our data show that the anticancer effects of tridecylpyrrolidine analogues in colon cancer cells are mediated by antiproliferative activity, the induction of both extrinsic and intrinsic apoptotic pathways and the inhibition of cell migration.
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Affiliation(s)
- Natalia Nosalova
- Department of Pharmacology, Faculty of Medicine, P.J. Šafárik University, 040 01 Košice, Slovakia
| | - Alexandra Keselakova
- Department of Pharmacology, Faculty of Medicine, P.J. Šafárik University, 040 01 Košice, Slovakia
| | - Martin Kello
- Department of Pharmacology, Faculty of Medicine, P.J. Šafárik University, 040 01 Košice, Slovakia
| | - Miroslava Martinkova
- Department of Organic Chemistry, Faculty of Science, Institute of Chemical Sciences, P.J. Šafárik University, 040 01 Košice, Slovakia
| | - Dominika Fabianova
- Department of Organic Chemistry, Faculty of Science, Institute of Chemical Sciences, P.J. Šafárik University, 040 01 Košice, Slovakia
| | - Martina Bago Pilatova
- Department of Pharmacology, Faculty of Medicine, P.J. Šafárik University, 040 01 Košice, Slovakia
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15
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Cao X, Yao F, Zhang B, Sun X. Mitochondrial dysfunction in heart diseases: Potential therapeutic effects of Panax ginseng. Front Pharmacol 2023; 14:1218803. [PMID: 37547332 PMCID: PMC10399631 DOI: 10.3389/fphar.2023.1218803] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 07/12/2023] [Indexed: 08/08/2023] Open
Abstract
Heart diseases have a high incidence and mortality rate, and seriously affect people's quality of life. Mitochondria provide energy for the heart to function properly. The process of various heart diseases is closely related to mitochondrial dysfunction. Panax ginseng (P. ginseng), as a traditional Chinese medicine, is widely used to treat various cardiovascular diseases. Many studies have confirmed that P. ginseng and ginsenosides can regulate and improve mitochondrial dysfunction. Therefore, the role of mitochondria in various heart diseases and the protective effect of P. ginseng on heart diseases by regulating mitochondrial function were reviewed in this paper, aiming to gain new understanding of the mechanisms, and promote the clinical application of P. ginseng.
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Affiliation(s)
- Xinxin Cao
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China
- Key Laboratory of Efficacy Evaluation of Chinese Medicine Against Glyeolipid Metabolism Disorder Disease, State Administration of Traditional Chinese Medicine, Beijing, China
| | - Fan Yao
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China
- Key Laboratory of Efficacy Evaluation of Chinese Medicine Against Glyeolipid Metabolism Disorder Disease, State Administration of Traditional Chinese Medicine, Beijing, China
| | - Bin Zhang
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China
- Key Laboratory of Efficacy Evaluation of Chinese Medicine Against Glyeolipid Metabolism Disorder Disease, State Administration of Traditional Chinese Medicine, Beijing, China
| | - Xiaobo Sun
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China
- Key Laboratory of Efficacy Evaluation of Chinese Medicine Against Glyeolipid Metabolism Disorder Disease, State Administration of Traditional Chinese Medicine, Beijing, China
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16
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Park JW, Tyl MD, Cristea IM. Orchestration of Mitochondrial Function and Remodeling by Post-Translational Modifications Provide Insight into Mechanisms of Viral Infection. Biomolecules 2023; 13:biom13050869. [PMID: 37238738 DOI: 10.3390/biom13050869] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 05/17/2023] [Accepted: 05/18/2023] [Indexed: 05/28/2023] Open
Abstract
The regulation of mitochondria structure and function is at the core of numerous viral infections. Acting in support of the host or of virus replication, mitochondria regulation facilitates control of energy metabolism, apoptosis, and immune signaling. Accumulating studies have pointed to post-translational modification (PTM) of mitochondrial proteins as a critical component of such regulatory mechanisms. Mitochondrial PTMs have been implicated in the pathology of several diseases and emerging evidence is starting to highlight essential roles in the context of viral infections. Here, we provide an overview of the growing arsenal of PTMs decorating mitochondrial proteins and their possible contribution to the infection-induced modulation of bioenergetics, apoptosis, and immune responses. We further consider links between PTM changes and mitochondrial structure remodeling, as well as the enzymatic and non-enzymatic mechanisms underlying mitochondrial PTM regulation. Finally, we highlight some of the methods, including mass spectrometry-based analyses, available for the identification, prioritization, and mechanistic interrogation of PTMs.
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Affiliation(s)
- Ji Woo Park
- Lewis Thomas Laboratory, Department of Molecular Biology, Princeton University, Washington Road, Princeton, NJ 08544, USA
| | - Matthew D Tyl
- Lewis Thomas Laboratory, Department of Molecular Biology, Princeton University, Washington Road, Princeton, NJ 08544, USA
| | - Ileana M Cristea
- Lewis Thomas Laboratory, Department of Molecular Biology, Princeton University, Washington Road, Princeton, NJ 08544, USA
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17
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Lee WY, Lee R, Park HJ. Tebuconazole Induces ER-Stress-Mediated Cell Death in Bovine Mammary Epithelial Cell Lines. TOXICS 2023; 11:397. [PMID: 37112622 PMCID: PMC10144106 DOI: 10.3390/toxics11040397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 04/16/2023] [Accepted: 04/20/2023] [Indexed: 06/19/2023]
Abstract
Tebuconazole (TEB) is a triazole fungicide used to increase crop production by controlling fungi, insects, and weeds. Despite their extensive use, people are concerned about the health risks associated with pesticides and fungicides. Numerous studies have defined the cellular toxicity of triazole groups in pesticides, but the mechanisms of TEB toxicity in bovine mammary gland epithelial cells (MAC-T cells) have not yet been studied. Damage to the mammary glands of dairy cows directly affects milk production. This study investigated the toxicological effects of TEB on MAC-T cells. We found that TEB decreases both cell viability and proliferation and activates apoptotic cell death via the upregulation of pro-apoptotic proteins, such as cleaved caspases 3 and 8 and BAX. TEB also induced endoplasmic reticulum (ER) stress via the upregulation of Bip/GRP78; PDI; ATF4; CHOP; and ERO1-Lα. We found that TEB induced mitochondria-mediated apoptotic MAC-T cell death by activating ER stress. This cell damage eventually led to a dramatic reduction in the expression levels of the milk-protein-synthesis-related genes LGB; LALA; CSN1S1; CSN1S2; and CSNK in MAC-T cells. Our data suggest that the exposure of dairy cows to TEB may negatively affect milk production by damaging the mammary glands.
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Affiliation(s)
- Won-Young Lee
- Department of Livestock, Korea National University of Agriculure and Fisheries, Jeonju-si 54874, Republic of Korea
| | - Ran Lee
- Department of Livestock, Korea National University of Agriculure and Fisheries, Jeonju-si 54874, Republic of Korea
- Department of Animal Biotechnology, College of Life Science, Sangji University, Wonju-si 26339, Republic of Korea
| | - Hyun-Jung Park
- Department of Animal Biotechnology, College of Life Science, Sangji University, Wonju-si 26339, Republic of Korea
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18
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Kouroumalis E, Tsomidis I, Voumvouraki A. Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy. Biomedicines 2023; 11:1166. [PMID: 37189787 PMCID: PMC10135776 DOI: 10.3390/biomedicines11041166] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 04/09/2023] [Accepted: 04/12/2023] [Indexed: 05/17/2023] Open
Abstract
The pathogenesis of hepatocellular carcinoma (HCC) is a multifactorial process that has not yet been fully investigated. Autophagy and apoptosis are two important cellular pathways that are critical for cell survival or death. The balance between apoptosis and autophagy regulates liver cell turnover and maintains intracellular homeostasis. However, the balance is often dysregulated in many cancers, including HCC. Autophagy and apoptosis pathways may be either independent or parallel or one may influence the other. Autophagy may either inhibit or promote apoptosis, thus regulating the fate of the liver cancer cells. In this review, a concise overview of the pathogenesis of HCC is presented, with emphasis on new developments, including the role of endoplasmic reticulum stress, the implication of microRNAs and the role of gut microbiota. The characteristics of HCC associated with a specific liver disease are also described and a brief description of autophagy and apoptosis is provided. The role of autophagy and apoptosis in the initiation, progress and metastatic potential is reviewed and the experimental evidence indicating an interplay between the two is extensively analyzed. The role of ferroptosis, a recently described specific pathway of regulated cell death, is presented. Finally, the potential therapeutic implications of autophagy and apoptosis in drug resistance are examined.
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Affiliation(s)
- Elias Kouroumalis
- Department of Gastroenterology, PAGNI University Hospital, University of Crete School of Medicine, 71500 Heraklion, Crete, Greece
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Crete, Greece
| | - Ioannis Tsomidis
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Crete, Greece
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Central Macedonia, Greece
| | - Argyro Voumvouraki
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Central Macedonia, Greece
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19
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Hassan AK, El-Kalaawy AM, Abd El-Twab SM, Alblihed MA, Ahmed OM. Hesperetin and Capecitabine Abate 1,2 Dimethylhydrazine-Induced Colon Carcinogenesis in Wistar Rats via Suppressing Oxidative Stress and Enhancing Antioxidant, Anti-Inflammatory and Apoptotic Actions. Life (Basel) 2023; 13:984. [PMID: 37109513 PMCID: PMC10146346 DOI: 10.3390/life13040984] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 04/07/2023] [Accepted: 04/08/2023] [Indexed: 04/29/2023] Open
Abstract
Colon cancer is a major cause of cancer-related death, with significantly increasing rates of incidence worldwide. The current study was designed to evaluate the anti-carcinogenic effects of hesperetin (HES) alone and in combination with capecitabine (CAP) on 1,2 dimethylhydrazine (DMH)-induced colon carcinogenesis in Wistar rats. The rats were given DMH at 20 mg/kg body weight (b.w.)/week for 12 weeks and were orally treated with HES (25 mg/kg b.w.) and/or CAP (200 mg/kg b.w.) every other day for 8 weeks. The DMH-administered rats exhibited colon-mucosal hyperplastic polyps, the formation of new glandular units and cancerous epithelial cells. These histological changes were associated with the significant upregulation of colon Ki67 expression and the elevation of the tumor marker, carcinoembryonic antigen (CEA), in the sera. The treatment of the DMH-administered rats with HES and/or CAP prevented these histological cancerous changes concomitantly with the decrease in colon-Ki67 expression and serum-CEA levels. The results also indicated that the treatments with HES and/or CAP showed a significant reduction in the serum levels of lipid peroxides, an elevation in the serum levels of reduced glutathione, and the enhancement of the activities of colon-tissue superoxide dismutase, glutathione reductase and glutathione-S-transferase. Additionally, the results showed an increase in the mRNA expressions of the anti-inflammatory cytokine, IL-4, as well as the proapoptotic protein, p53, in the colon tissues of the DMH-administered rats treated with HES and/or CAP. The TGF-β1 decreased significantly in the DMH-administered rats and this effect was counteracted by the treatments with HES and/or CAP. Based on these findings, it can be suggested that both HES and CAP, singly or in combination, have the potential to exert chemopreventive effects against DMH-induced colon carcinogenesis via the suppression of oxidative stress, the stimulation of the antioxidant defense system, the attenuation of inflammatory effects, the reduction in cell proliferation and the enhancement of apoptosis.
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Affiliation(s)
- Asmaa K. Hassan
- Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef 62521, Egypt
| | - Asmaa M. El-Kalaawy
- Pharmacology Department, Faculty of Medicine, Beni-Suef University, Beni-Suef 62521, Egypt
| | - Sanaa M. Abd El-Twab
- Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef 62521, Egypt
| | - Mohamed A. Alblihed
- Department of Microbiology, College of Medicine, Taif University, Taif 21944, Saudi Arabia
| | - Osama M. Ahmed
- Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef 62521, Egypt
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20
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Govindaraj S, Ganesan K, Dharmasivam M, Raman L, Kuppusamy KM, Pandiappan V, Alam MM, Mohammed A. Discovery of Novel Dimeric Pyridinium Bromide Analogues Inhibits Cancer Cell Growth by Activating Caspases and Downregulating Bcl-2 Protein. ACS OMEGA 2023; 8:13243-13251. [PMID: 37065022 PMCID: PMC10099142 DOI: 10.1021/acsomega.3c00526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 03/16/2023] [Indexed: 06/19/2023]
Abstract
Flexible dimeric substituted pyridinium bromides with primary and tertiary amines are prepared by conventional and solvent-free methods. The formation of compounds 2 and 4 is much easier than that of compounds 1 and 3 because of the benzyl carbon which is more electropositive than the primary alkyl carbon. The newly synthesized dimeric pyridinium compounds are optimized using DFT and B3LYP 6-31 g(d,p). The in vitro antiproliferative activity is studied in lung (A549) and breast cancer cell lines (MDA-MB 231). Among the four compounds, 1,1'-(1,3-phenylene bis(methylene)bis 2-aminopyridinium bromide 4 showed potent anticancer activity when compared to the standard drug 5-fluorouracil. 1,1'-(1,3-Phenylene bis(methylene)bis 2-aminopyridinium bromide 4 is not toxic to normal cell lines 3T3-L1 and MRC-5 cell lines. Also, 1,1'-(1,3-phenylene bis(methylene)bis 2-aminopyridinium bromide 4-induced apoptosis in cancer cell lines is examined using AO/EB and Hoechst staining, which is further supported by cell cycle analysis. Western blot analysis showed that 1,1'-(1,3-phenylene bis(methylene)bis 2-aminopyridinium bromide 4 induces apoptosis through the extrinsic apoptotic pathway by upregulating caspase 3 and caspase 9. This compound also downregulates intrinsic apoptotic proteins, including Bcl-2, Bcl-x, and Bad. From the present study results, it is confirmed that 1,1'-(1,3-phenylene bis(methylene)bis 2-aminopyridinium bromide 4 has potent anticancer activity when compared to other compounds.
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Affiliation(s)
| | - Kilivelu Ganesan
- PG
and Research Department of Chemistry, Presidency
College, Chennai 600005, India
| | - Mahendiran Dharmasivam
- Centre
for Cancer Cell Biology and Drug Discovery, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland 4111, Australia
| | - Lakshmisundaram Raman
- Sri
Ramachandra Faculty of Pharmacy, Sri Ramachandra
Institute of Higher Educational and Research (DU), Porur, Chennai 600116, India
| | - Kalaivani M. Kuppusamy
- Research
Centre for Cellular Genomics and Cancer Research, Sree Balaji Medical College and Hospital, Chennai 600044, India
| | - Viswanathan Pandiappan
- Department
of Uyivedhiyal, JSA Medical College for
Siddha and Research Centre, Ulundurpet, Kallakkurichi 606 104, India
| | - Mohammed Mujahid Alam
- Department
of Chemistry, College of Science, King Khalid
University, PO Box 9004, Abha 61413, Kingdom of Saudi Arabia
| | - Amanullah Mohammed
- Department
of Clinical Biochemistry, College of Medicine, King Khalid University, Abha 61413, Kingdom
of Saudi Arabia
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21
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Ibrahim SS, Ragy NI, Nagy NA, El-Kammar H, Elbakry AM, Ezzatt OM. Evaluation of muco-adhesive tacrolimus patch on caspase-3 induced apoptosis in oral lichen planus: a randomized clinical trial. BMC Oral Health 2023; 23:99. [PMID: 36788511 PMCID: PMC9930326 DOI: 10.1186/s12903-023-02803-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 02/09/2023] [Indexed: 02/16/2023] Open
Abstract
BACKGROUND The study compared the clinical effectiveness of topical Tacrolimus (TAC) in patches or gel with Triamcinolone acetonide (TRI) gel for erosive/atrophic oral lichen planus (OLP) and investigated the influence of these therapies on Caspase-3 expression as a marker of apoptosis. METHODS Thirty patients were randomly assigned into three equal groups to receive either topical TAC 0.1% patch twice daily, topical TAC 0.1% gel, or topical TRI 0.1% gel four times daily for 8 weeks. Each patient's clinical score (CS), visual analogue scale (VAS), and total atrophic area (TAA) of the marker lesion were measured at baseline, 2, 4, and 8 weeks of treatment, as well as after 4 weeks of treatment free period. Caspase-3 expression and lymphocytic counts (LC) were assessed in pre- and post-treatment biopsied stained sections. RESULTS TAC patch resulted in a higher reduction in CS [- 14.00 (15.54%)] and VAS [- 70.21 (15.82%)] followed by TAC gel then TRI gel within the first two weeks. The reduction in VAS and TAA were significantly higher in TAC groups compared to TRI gel, although the difference between TAC treatment was not significant and this was observed throughout the treatment and follow-up periods. Caspase-3 expression increased in connective tissue in all groups. It decreased significantly within the epithelium in both TAC groups but increased in TRI gel. (LC) were significantly lowered with the TAC patch compared to other groups. The percentage change in Caspase-3 epithelial expression was significantly correlated to the CS, TAA, and LC. CONCLUSION Both TAC patch and gel significantly decreased pain and lesion size than TRI gel, with a significant reduction in Caspase-3 expression within the epithelium in comparison to the increase seen with TRI gel. The study protocol was registered at www. CLINICALTRIALS gov (NCT05139667) on 01/12/2021.
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Affiliation(s)
- Suzan S Ibrahim
- Department of Oral Medicine, Periodontology and Oral Diagnosis, Faculty of Dentistry, Ain Shams University, Cairo, Egypt
- Department of Oral Medicine, Periodontology Oral Diagnosis and Radiology, Faculty of Dental Medicine, Nahda University, Beni Suef, Egypt
| | - Nivine I Ragy
- Department of Oral Medicine, Periodontology, and Oral Diagnosis, Faculty of Oral and Dental Medicine, Future University in Egypt, St. South 90Th, New Cairo 1, Cairo, 11835, Egypt
| | - Noha A Nagy
- Department of Oral Medicine, Periodontology, and Oral Diagnosis, Faculty of Oral and Dental Medicine, Future University in Egypt, St. South 90Th, New Cairo 1, Cairo, 11835, Egypt.
| | - Hala El-Kammar
- Department of Oral Pathology, Faculty of Oral and Dental Medicine, Future University in Egypt, Cairo, Egypt
| | - Asmaa M Elbakry
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Heliopolis University, Cairo, Egypt
| | - Ola M Ezzatt
- Department of Oral Medicine, Periodontology and Oral Diagnosis, Faculty of Dentistry, Ain Shams University, Cairo, Egypt.
- Department of Oral Medicine, Periodontology and Oral Diagnosis, Faculty of Dentistry, Ain Shams University, 20 Organization of African Union St., Cairo, 1156, Egypt.
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22
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Deng Y, Meng X, Ling C, Lu T, Chang H, Li L, Yang Y, Song G, Ding Y. Nanosized Titanium Dioxide Induced Apoptosis and Abnormal Expression of Blood-Testis Barrier Junction Proteins Through JNK Signaling Pathway in TM4 Cells. Biol Trace Elem Res 2022; 200:5172-5187. [PMID: 35013891 DOI: 10.1007/s12011-022-03099-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Accepted: 01/02/2022] [Indexed: 12/13/2022]
Abstract
Nanosized titanium dioxide (nano-TiO2) has been widely used in consumer products. It can cross the blood-testis barrier (BTB), and it has adverse effects on the male reproductive system. However, the specific mechanism has not been fully elucidated. The purpose of this study was to understand the role of the JNK signaling pathway in the apoptosis and abnormal expression of BTB junction proteins induced by nano-TiO2 in TM4 cells. After different concentration of nano-TiO2 treatments, the cell viability, apoptosis, mitochondrial membrane potential (Δψm), BTB junction proteins (Claudin-11, ZO-1, β-catenin), apoptosis-related proteins (Bax, Bcl-2, cleaved caspase-9, cleaved caspase-3), and phosphorylated (p)-JNK protein were examined. The results showed that cell viability, apoptosis rates, Δψm, and apoptosis-related protein levels changed in a concentration-dependent manner. Cell viability decreased significantly from 100 μg/mL nano-TiO2 group. Apoptosis rates increased significantly from 150 μg/mL nano-TiO2 group, and Δψm decreased significantly from 150 μg/mL nano-TiO2 group. The protein levels of Bax, cleaved caspase-9, and cleaved caspase-3 increased significantly from 150 μg/mL nano-TiO2 group, and the protein level of Bcl-2 decreased significantly from 100 μg/mL nano-TiO2 group. The protein level of p-JNK increased significantly from 100 μg/mL nano-TiO2 group. Abnormal expression of ZO-1 and β-catenin started from 150 μg/mL nano-TiO2 group, and abnormal expression of Claudin-11 started from 100 μg/mL nano-TiO2 group. Cells were treated with JNK inhibitor SP100625 to determine whether the changes of the above indicators in the concentration of 150 μg/mL nano-TiO2 group can be reversed. We found that SP100625 at 20 μM significantly reversed these effects. These results highlighted that nano-TiO2 could activate the JNK signaling pathway to induce mitochondria-mediated apoptosis and abnormal expression of BTB junction proteins in TM4 cells.
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Affiliation(s)
- Yaxin Deng
- Department of Preventive Medicine/the Key Laboratories for Xinjiang Endemic and Ethnic Diseases, School of Medicine, Shihezi University, Shihezi, 832002, Xinjiang, China
| | - Xiaojia Meng
- Department of Preventive Medicine/the Key Laboratories for Xinjiang Endemic and Ethnic Diseases, School of Medicine, Shihezi University, Shihezi, 832002, Xinjiang, China
| | - Chunmei Ling
- The Third People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, 830091, Xinjiang, China
| | - Tianjiao Lu
- Department of Preventive Medicine/the Key Laboratories for Xinjiang Endemic and Ethnic Diseases, School of Medicine, Shihezi University, Shihezi, 832002, Xinjiang, China
| | - Hongmei Chang
- Department of Preventive Medicine/the Key Laboratories for Xinjiang Endemic and Ethnic Diseases, School of Medicine, Shihezi University, Shihezi, 832002, Xinjiang, China
| | - Li Li
- Department of Preventive Medicine/the Key Laboratories for Xinjiang Endemic and Ethnic Diseases, School of Medicine, Shihezi University, Shihezi, 832002, Xinjiang, China
| | - Yaqian Yang
- Department of Preventive Medicine/the Key Laboratories for Xinjiang Endemic and Ethnic Diseases, School of Medicine, Shihezi University, Shihezi, 832002, Xinjiang, China
| | - Guanling Song
- Department of Preventive Medicine/the Key Laboratories for Xinjiang Endemic and Ethnic Diseases, School of Medicine, Shihezi University, Shihezi, 832002, Xinjiang, China.
- Department of Public Health, School of Medicine, Shihezi University, Shihezi, 832002, Xinjiang, China.
| | - Yusong Ding
- Department of Preventive Medicine/the Key Laboratories for Xinjiang Endemic and Ethnic Diseases, School of Medicine, Shihezi University, Shihezi, 832002, Xinjiang, China.
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23
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Jin J, Shan Y, Zhang L, Wu Z, Wu S, Sun M, Bao W. Pterostilbene Ameliorates Fumonisin B1-Induced Cytotoxic Effect by Interfering in the Activation of JAK/STAT Pathway. Antioxidants (Basel) 2022; 11:antiox11122360. [PMID: 36552567 PMCID: PMC9774891 DOI: 10.3390/antiox11122360] [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: 10/24/2022] [Revised: 11/23/2022] [Accepted: 11/24/2022] [Indexed: 11/29/2022] Open
Abstract
Fumonisin B1 (FB1) is a mycotoxin that poses a great threat to agricultural production and the health of humans and animals. Pterostilbene (PTE) is a natural plant polyphenolic compound with good anti-inflammatory, antioxidant and cell regeneration effects, yet its effectiveness in treating FB1-induced cytotoxicity remains to be explored. In this study, we used porcine alveolar macrophages (3D4/21) as a model to characterize the cytotoxicity induced by FB1, and to investigate the potential alleviating effect of PTE on FB1-induced cytotoxicity. We demonstrate that FB1 induces cytotoxicity, apoptosis, pro-inflammatory cytokine production and mitochondrial damage, which can be largely recovered by PTE treatment, suggesting the promising application of PTE to treat FB1-induced damage. Mechanistically, FB1 activates the JAK/STAT signaling pathway, while PTE attenuates FB1-induced cytotoxicity through the inhibition of key JAK/STAT genes such as JAK2 and STAT3. Overall, our study characterized the molecular mechanism for FB1-induced cytotoxicity and found PTE to be a promising component which can alleviate FB1-induced cytotoxicity by interfering in the activation of JAK/STAT pathway.
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Affiliation(s)
- Jian Jin
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
- Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
| | - Yiyi Shan
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Liangliang Zhang
- Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
| | - Zhengchang Wu
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Shenglong Wu
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Mingan Sun
- Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
- Correspondence: (M.S.); (W.B.)
| | - Wenbin Bao
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
- Correspondence: (M.S.); (W.B.)
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24
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Abdulmalek S, Mostafa N, Gomaa M, El‑Kersh M, Elkady AI, Balbaa M. Bee venom-loaded EGFR-targeting peptide-coupled chitosan nanoparticles for effective therapy of hepatocellular carcinoma by inhibiting EGFR-mediated MEK/ERK pathway. PLoS One 2022; 17:e0272776. [PMID: 35947632 PMCID: PMC9365195 DOI: 10.1371/journal.pone.0272776] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Accepted: 07/27/2022] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the world's most risky diseases due to the lack of clear and cost-effective therapeutic targets. Currently, the toxicity of conventional chemotherapeutic medications and the development of multidrug resistance is driving research into targeted therapies. The nano-biomedical field's potential for developing an effective therapeutic nano-sized drug delivery system is viewed as a significant pharmaceutical trend for the encapsulation and release of numerous anticancer therapies. In this regard, current research is centered on the creation of biodegradable chitosan nanoparticles (CSNPs) for the selective and sustained release of bee venom into liver cancer cells. Furthermore, surface modification with polyethylene glycol (PEG) and GE11 peptide-conjugated bee venom-CSNPs allows for the targeting of EGFR-overexpressed liver cancer cells. A series of in vitro and in vivo cellular analyses were used to investigate the antitumor effects and mechanisms of targeted bee venom-CSNPs. Targeted bee venom-CSNPs, in particular, were found to have higher cytotoxicity against HepG2 cells than SMMC-7721 cells, as well as stronger cellular uptake and a substantial reduction in cell migration, leading to improved cancer suppression. It also promotes cancer cell death in EGFR overexpressed HepG2 cells by boosting reactive oxygen species, activating mitochondria-dependent pathways, inhibiting EGFR-stimulated MEK/ERK pathway, and elevating p38-MAPK in comparison to native bee venom. In hepatocellular carcinoma (HCC)-induced mice, it has anti-cancer properties against tumor tissue. It also improved liver function and architecture without causing any noticeable toxic side effects, as well as inhibiting tumor growth by activating the apoptotic pathway. The design of this cancer-targeted nanoparticle establishes GE11-bee venom-CSNPs as a potential chemotherapeutic treatment for EGFR over-expressed malignancies. Finally, our work elucidates the molecular mechanism underlying the anticancer selectivity of targeted bee venom-CSNPs and outlines therapeutic strategies to target liver cancer.
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Affiliation(s)
- Shaymaa Abdulmalek
- Department of Biochemistry, Faculty of Science, Alexandria University, Alexandria, Egypt
| | - Nouf Mostafa
- Department of Biochemistry, Faculty of Science, Alexandria University, Alexandria, Egypt
- Plant Protection Research Institute, Agriculture Research Center, Giza, Egypt
| | - Marwa Gomaa
- Plant Protection Research Institute, Agriculture Research Center, Giza, Egypt
| | - Mohamed El‑Kersh
- Department of Biochemistry, Faculty of Science, Alexandria University, Alexandria, Egypt
| | - Ayman I. Elkady
- Zoology Department, Faculty of Science, Alexandria University, Alexandria, Egypt
| | - Mahmoud Balbaa
- Department of Biochemistry, Faculty of Science, Alexandria University, Alexandria, Egypt
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25
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Brahme A. Quantifying Cellular Repair, Misrepair and Apoptosis Induced by Boron Ions, Gamma Rays and PRIMA-1 Using the RHR Formulation. Radiat Res 2022; 198:271-296. [PMID: 35834822 DOI: 10.1667/rade-22-00011.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Accepted: 06/14/2022] [Indexed: 11/03/2022]
Abstract
The recent interaction cross-section-based formulation for radiation-induced direct cellular inactivation, mild and severe sublethal damage, DNA-repair and cell survival have been developed to accurately describe cellular repair, misrepair and apoptosis in TP53 wild-type and mutant cells. The principal idea of this new non-homologous repairable-homologous repairable (RHR) damage formulation is to separately describe the mild damage that can be rapidly handled by the most basic repair processes including the non-homologous end joining (NHEJ), and more complex damage requiring longer repair times and high-fidelity homologous recombination (HR) repair. Taking the interaction between these two key mammalian DNA repair processes more accurately into account has significantly improved the method as indicated in the original publication. Based on the principal mechanisms of 7 repair and 8 misrepair processes presently derived, it has been possible to quite accurately describe the probability that some of these repair processes when unsuccessful can induce cellular apoptosis with increasing doses of γrays, boron ions and PRIMA-1. Interestingly, for all LETs studied (≈0.3-160 eV/nm) the increase in apoptosis saturates when the cell survival reaches about 10% and the fraction of un-hit cells is well below the 1% level. It is shown that most of the early cell kill for low-to-medium LETs are due to apoptosis since the cell survival as well as the non-apoptotic cells agree very well at low doses and other death processes dominate beyond D > 1 Gy. The low-dose apoptosis is due to the fact that the full activation of the checkpoint kinases ATM and Chk2 requires >8 and >18 DSBs per cell to phosphorylate p53 at serine 15 and 20. Therefore, DNA repair is not fully activated until well after 1/2 Gy, and the cellular response may be apoptotic by default before the low-dose hyper sensitivity (LDHS) is replaced by an increased radiation tolerance as the DNA repair processes get maximal efficiency. In effect, simultaneously explaining the LDHS and inverse dose rate phenomena. The partial contributions by the eight newly derived misrepair processes was determined so they together accurately described the experimental apoptosis induction data for γ rays and boron ions. Through these partial misrepair contributions it was possible to predict the apoptotic response based solely on carefully analyzed cell survival data, demonstrating the usefulness of an accurate DNA repair-based cell survival approach. The peak relative biological effectiveness (RBE) of the boron ions was 3.5 at 160 eV/nm whereas the analogous peak relative apoptotic effectiveness (RAE) was 3.4 but at 40 eV/nm indicating the clinical value of the lower LET light ion (15 \le {\rm{LET}} \le 55{\rm{\ eV}}/{\rm{nm}},{\rm{\ }}2 \le Z \le 5) in therapeutic applications to maximize tumor apoptosis and senescence. The new survival expressions were also applied on mouse embryonic fibroblasts with key knocked-out repair genes, showing a good agreement between the principal non-homologous and homologous repair terms and also a reasonable prediction of the associated apoptotic induction. Finally, the formulation was used to estimate the increase in DNA repair and apoptotic response in combination with the mutant p53 reactivating compound PRIMA-1 and γ rays, indicating a 10-2 times increase in apoptosis with 5 μM of the compound reaching apoptosis levels not far from peak apoptosis boron ions in a TP53 mutant cell line. To utilize PRIMA-1 induced apoptosis and cellular sensitization for reactive oxygen species (ROS), concomitant biologically optimized radiation therapy is proposed to maximize the complication free tumor cure for the multitude of TP53 mutant tumors seen in the clinic. The experimental data also indicated the clinically very important high-absorbed dose ROS effect of PRIMA-1.
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Affiliation(s)
- Anders Brahme
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
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26
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Al Faruque H, Choi ES, Kim JH, Kim E. Enhanced effect of autologous EVs delivering paclitaxel in pancreatic cancer. J Control Release 2022; 347:330-346. [PMID: 35561870 DOI: 10.1016/j.jconrel.2022.05.012] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 05/02/2022] [Accepted: 05/05/2022] [Indexed: 10/18/2022]
Abstract
We engineered human pancreatic cancer cell (PANC-1)-derived extracellular vesicles (EVs) by conjugating the functional ligand RGD and magnetic nanoparticles (MNPs) onto EV surfaces (rmExo), for pancreatic cancer therapy. Paclitaxel (PTX) loaded into rmExo (rmExo-PTX) was intravenously injected into xenograft mice prepared using PANC-1 cells, which showed a significant reduction in tumor size compared to the free PTX-treated and control groups. The enhanced therapeutic effect was attributed to the modification of the surface of EVs using RGD, which has affinity for αvβ3 that is highly expressed in pancreatic cancer cells. Moreover, autologous EVs seemed to have more benefits in delivering PTX due to an unknown homing property to parent tumor cells, as exemplified by the reduced therapeutic effect of RGD-modified PANC-1 EVs on HT29 xenograft mice and RGD-modified U937 EVs on PANC-1 xenograft mice. The RGD-modified autologous EV vehicles were effective at penetrating and internalizing tumor cells, and eventually regressing the tumors, by mediating spontaneous removal of α-smooth muscle actin and collagen type 1 in the extracellular matrix of xenografts. Our results also identified an important molecule involved in the home-driving properties of PANC-1 EVs, integrin β3, which was expressed both on PANC-1 cells and the EVs derived from them. Additional therapeutic effect by permanent magnet near tumor xenograft was not observed in this study.
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Affiliation(s)
- Hasan Al Faruque
- Division of Bio-Fusion Research, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Techno-jungangdaero 333, Daegue 42988, Republic of Korea.
| | - Eun-Sook Choi
- Division of Electronic Information System Research, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Techno-jungangdaero 333, Daegue 42988, Republic of Korea.
| | - Jung-Hee Kim
- Division of Electronic Information System Research, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Techno-jungangdaero 333, Daegue 42988, Republic of Korea.
| | - Eunjoo Kim
- Division of Electronic Information System Research, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Techno-jungangdaero 333, Daegue 42988, Republic of Korea.
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27
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Lee JH, Yoo ES, Han SH, Jung GH, Han EJ, Choi EY, Jeon SJ, Jung SH, Kim B, Cho SD, Nam JS, Choi C, Che JH, Jung JY. Chrysin Induces Apoptosis and Autophagy in Human Melanoma Cells via the mTOR/S6K Pathway. Biomedicines 2022; 10:biomedicines10071467. [PMID: 35884773 PMCID: PMC9312811 DOI: 10.3390/biomedicines10071467] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 06/14/2022] [Accepted: 06/17/2022] [Indexed: 11/18/2022] Open
Abstract
Chrysin is known to exert anti-inflammatory, antioxidant, and anticancer effects. The aim of this study was to investigate the anticancer effects of chrysin in the human melanoma cells A375SM and A375P. The results obtained demonstrated successful inhibition of the viability of these cells by inducing apoptosis and autophagy. This was confirmed by the level of apoptosis-related proteins: Bax and cleaved poly (ADP-ribose) polymerase both increased, and Bcl-2 decreased. Moreover, levels of LC3 and Beclin 1, both autophagy-related proteins, increased in chrysin-treated cells. Autophagic vacuoles and acidic vesicular organelles were observed in both cell lines treated with chrysin. Both cell lines showed different tendencies during chrysin-induced autophagy inhibition, indicating that autophagy has different effects depending on the cell type. In A375SM, the early autophagy inhibitor 3-methyladenine (3-MA) was unaffected; however, cell viability decreased when treated with the late autophagy inhibitor hydroxychloroquine (HCQ). In contrast, HCQ was unaffected in A375P; however, cell viability increased when treated with 3-MA. Chrysin also decreased the phosphorylation of mTOR/S6K pathway proteins, indicating that this pathway is involved in chrysin-induced apoptosis and autophagy for A375SM and A375P. However, studies to elucidate the mechanisms of autophagy and the action of chrysin in vivo are still needed.
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Affiliation(s)
- Jae-Han Lee
- Department of Companion, Laboratory Animal Science, Kongju National University, Yesan 32439, Korea; (J.-H.L.); (E.-S.Y.); (S.-H.H.); (G.-H.J.); (E.-J.H.); (E.-Y.C.); (S.-j.J.); (S.-H.J.)
| | - Eun-Seon Yoo
- Department of Companion, Laboratory Animal Science, Kongju National University, Yesan 32439, Korea; (J.-H.L.); (E.-S.Y.); (S.-H.H.); (G.-H.J.); (E.-J.H.); (E.-Y.C.); (S.-j.J.); (S.-H.J.)
| | - So-Hee Han
- Department of Companion, Laboratory Animal Science, Kongju National University, Yesan 32439, Korea; (J.-H.L.); (E.-S.Y.); (S.-H.H.); (G.-H.J.); (E.-J.H.); (E.-Y.C.); (S.-j.J.); (S.-H.J.)
| | - Gi-Hwan Jung
- Department of Companion, Laboratory Animal Science, Kongju National University, Yesan 32439, Korea; (J.-H.L.); (E.-S.Y.); (S.-H.H.); (G.-H.J.); (E.-J.H.); (E.-Y.C.); (S.-j.J.); (S.-H.J.)
| | - Eun-Ji Han
- Department of Companion, Laboratory Animal Science, Kongju National University, Yesan 32439, Korea; (J.-H.L.); (E.-S.Y.); (S.-H.H.); (G.-H.J.); (E.-J.H.); (E.-Y.C.); (S.-j.J.); (S.-H.J.)
| | - Eun-Young Choi
- Department of Companion, Laboratory Animal Science, Kongju National University, Yesan 32439, Korea; (J.-H.L.); (E.-S.Y.); (S.-H.H.); (G.-H.J.); (E.-J.H.); (E.-Y.C.); (S.-j.J.); (S.-H.J.)
| | - Su-ji Jeon
- Department of Companion, Laboratory Animal Science, Kongju National University, Yesan 32439, Korea; (J.-H.L.); (E.-S.Y.); (S.-H.H.); (G.-H.J.); (E.-J.H.); (E.-Y.C.); (S.-j.J.); (S.-H.J.)
| | - Soo-Hyun Jung
- Department of Companion, Laboratory Animal Science, Kongju National University, Yesan 32439, Korea; (J.-H.L.); (E.-S.Y.); (S.-H.H.); (G.-H.J.); (E.-J.H.); (E.-Y.C.); (S.-j.J.); (S.-H.J.)
| | - Bumseok Kim
- College of Veterinary Medicine, Bio-Safety Research Institute, Jeonbuk National University, Iksan 54896, Korea;
| | - Sung-Dae Cho
- Department of Oral Pathology, School of Dentistry, Dental Research Institute, Seoul National University, Seoul 03080, Korea;
| | - Jeong-Seok Nam
- Gwangju Institute of Science and Technology, School of Life Sciences, Gwangju 61005, Korea;
| | - Changsun Choi
- School of Food Science and Technology, Chung-ang University, Ansung 17456, Korea;
| | - Jeong-Hwan Che
- Biomedical Center for Animal Resource Development, Seoul National University College of Medicine, Seoul 03080, Korea;
- Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Korea
| | - Ji-Youn Jung
- Department of Companion, Laboratory Animal Science, Kongju National University, Yesan 32439, Korea; (J.-H.L.); (E.-S.Y.); (S.-H.H.); (G.-H.J.); (E.-J.H.); (E.-Y.C.); (S.-j.J.); (S.-H.J.)
- Correspondence:
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28
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Evaluation of Apoptosis and Autophagy Activities in the Brain of Dogs Naturally Infected with Canine Distemper Virus Based on Changes in Apoptotic and Autophagic Markers. ACTA VET-BEOGRAD 2022. [DOI: 10.2478/acve-2022-0016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
This study investig ated the activation of apoptosis and autophagy in CDV infected brain tissues of dogs with acute neurological signs, by determining Cas-3, Cas-8, Cas-9, Bax, Bcl-2, LC3B, and Beclin-1 expression with real-time PCR. The expression levels of Beclin-1 and LC3B, autophagy markers, were significantly up-regulated in comparison with the control group (p < 0.001). The expression levels of apoptotic markers Cas-3, Cas-8, Cas-9 and Bax were slightly up-regulated, but Bcl-2 was slightly down-regulated in contrast to the control group (p < 0.05). Therefore, the autophagy markers were more activated than apoptotic markers in dogs with acute neurological signs. In conclusion, autophagy takes part in the pathogenesis of demyelination in canine distemper. Knowing this may be helpful to create new therapeutic strategies, such as new effective antiviral medicines.
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Rao Q, Xie K, Varier KM, Huang L, Song J, Yang J, Qiu J, Huang Y, Li Y, Gajendran B, Li Y, Liu S. Design, Synthesis, and Antileukemic Evaluation of a Novel Mikanolide Derivative Through the Ras/Raf/MEK/ERK Pathway. Front Pharmacol 2022; 13:809551. [PMID: 35721186 PMCID: PMC9205396 DOI: 10.3389/fphar.2022.809551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 04/06/2022] [Indexed: 11/13/2022] Open
Abstract
Chronic myeloid leukemia (CML) accounts for a major cause of death in adult leukemia patients due to mutations or other reasons for dysfunction in the ABL proto-oncogene. The ubiquitous BCR–ABL expression stimulates CML by activating CDK1 and cyclin B1, promoting pro-apoptotic, and inhibiting antiapoptotic marker expression along with regulations in RAS pathway activation. Thus, inhibitors of cyclins and the RAS pathway by ERK are of great interest in antileukemic treatments. Mikanolide is a sesquiterpene dilactone isolated from several Asteraceae family Mikania sp. plants. Sesquiterpene dilactone is a traditional medicine for treating ailments, such as flu, cardiovascular diseases, bacterial infections, and other blood disorders. It is used as a cytotoxic agent as well. The need of the hour is potent chemotherapeutic agents with cytotoxic effects inhibition of proliferation and activation of apoptotic machinery. Recently, ERK inhibitors are used in clinics as anticancer agents. Thus, in this study, we synthesized 22-mikanolide derivatives that elucidated to be potent antileukemic agents in vitro. However, a bioactive mikanolide derivative, 3g, was found with potent antileukemic activity, through the Ras/Raf/MEK/ERK pathway. It can arrest the cell cycle by inhibiting phosphorylation of CDC25C, triggering apoptosis, and promoting DNA and mitochondrial damage, thus suggesting it as a potential chemotherapeutic agent for leukemia patients.
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Affiliation(s)
- Qing Rao
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, China
- The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, China
| | - Kaiqiang Xie
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, China
- The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, China
| | - Krishnapriya M. Varier
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, China
- The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, China
- School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang, China
| | - Lei Huang
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, China
- The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, China
| | - Jingrui Song
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, China
- The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, China
| | - Jue Yang
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, China
- The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, China
| | - Jianfei Qiu
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, China
- The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, China
| | - Yubing Huang
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, China
- The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, China
| | - Yan Li
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, China
- The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, China
- *Correspondence: Yan Li, ; Babu Gajendran, ; Yanmei Li, ; Sheng Liu,
| | - Babu Gajendran
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, China
- The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, China
- School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang, China
- *Correspondence: Yan Li, ; Babu Gajendran, ; Yanmei Li, ; Sheng Liu,
| | - Yanmei Li
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, China
- The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, China
- *Correspondence: Yan Li, ; Babu Gajendran, ; Yanmei Li, ; Sheng Liu,
| | - Sheng Liu
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, China
- The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, China
- *Correspondence: Yan Li, ; Babu Gajendran, ; Yanmei Li, ; Sheng Liu,
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Cinnamaldehyde induces autophagy-mediated cell death through ER stress and epigenetic modification in gastric cancer cells. Acta Pharmacol Sin 2022; 43:712-723. [PMID: 33980998 PMCID: PMC8888591 DOI: 10.1038/s41401-021-00672-x] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 03/28/2021] [Indexed: 02/06/2023]
Abstract
Previous reports suggested that cinnamaldehyde (CA), the bioactive ingredient in Cinnamomum cassia, can suppress tumor growth, migratory, and invasive abilities. However, the role and molecular mechanisms of CA in GC are not completely understood. In the present study, we found that CA-induced ER stress and cell death via the PERK-CHOP axis and Ca2+ release in GC cells. Inhibition of ER stress using specific-siRNA blocked CA-induced cell death. Interestingly, CA treatment resulted in autophagic cell death by inducing Beclin-1, ATG5, and LC3B expression and by inhibiting p62 expression whereas autophagy inhibition suppressed CA-induced cell death. We showed that CA induces the inhibition of G9a and the activation of LC3B. Moreover, CA inhibited G9a binding on Beclin-1 and LC3B promoter. Overall, these results suggested that CA regulates the PERK-CHOP signaling, and G9a inhibition activates autophagic cell death via ER stress in GC cells.
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Naito Y, Kato H, Zhou L, Sugita S, He H, Zheng J, Hao Q, Sawa T, Lee JW. Therapeutic Effects of Hyaluronic Acid Against Cytotoxic Extracellular Vesicles Released During Pseudomonas Aeruginosa Pneumonia. Shock 2022; 57:408-416. [PMID: 34387224 PMCID: PMC8840981 DOI: 10.1097/shk.0000000000001846] [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] [Indexed: 11/26/2022]
Abstract
ABSTRACT Extracellular vesicles (EVs) have now been recognized as important mediators of cellular communication during injury and repair. We previously found that plasma EVs isolated from ex vivo perfused human lungs injured with Escherichia coli bacterial pneumonia were inflammatory, and exogenous administration of high molecular weight (HMW) hyaluronic acid (HA) as therapy bound to these EVs, decreasing inflammation and injury. In the current study, we studied the role of EVs released during severe Pseudomonas aeruginosa (PA) pneumonia in mice and determined whether intravenous administration of exogenous HMW HA would have therapeutic effects against the bacterial pneumonia. EVs were collected from the bronchoalveolar lavage fluid (BALF) of mice infected with PA103 by ultracentrifugation and analyzed by NanoSight and flow cytometry. In a cytotoxicity assay, administration of EVs released from infected mice (I-EVs) decreased the viability of A549 cells compared to EV isolated from sham control mice (C-EVs). Either exogenous HMW HA or an anti-CD44 antibody, when co-incubated with I-EVs, significantly improved the viability of the A549 cells. In mice with PA103 pneumonia, administration of HMW HA improved pulmonary edema and bacterial count in the lungs and decreased TNF-α and caspase-3 levels in the supernatant of lung homogenates. In conclusion, EVs isolated from BALF of mice with P. aeruginosa pneumonia were cytotoxic and inflammatory, and intravenous HMW HA administration was protective against P. aeruginosa pneumonia.
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Affiliation(s)
- Yoshifumi Naito
- Department of Anesthesiology, Kyoto Prefectural University of Medicine, Japan
| | - Hideya Kato
- Department of Anesthesiology, Kyoto Prefectural University of Medicine, Japan
| | - Li Zhou
- Department of Anesthesiology, University of California San Francisco, San Francisco, California
| | - Shinji Sugita
- Department of Anesthesiology, University of California San Francisco, San Francisco, California
| | - Hongli He
- Department of Anesthesiology, University of California San Francisco, San Francisco, California
| | - Justin Zheng
- Department of Anesthesiology, University of California San Francisco, San Francisco, California
| | - Qi Hao
- Department of Anesthesiology, University of California San Francisco, San Francisco, California
| | - Teiji Sawa
- Department of Anesthesiology, Kyoto Prefectural University of Medicine, Japan
| | - Jae-Woo Lee
- Department of Anesthesiology, University of California San Francisco, San Francisco, California
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Chainumnim S, Saenkham A, Dolsophon K, Chainok K, Suksamrarn S, Tanechpongtamb W. Stem Extract from Momordica cochinchinensis Induces Apoptosis in Chemoresistant Human Prostate Cancer Cells (PC-3). MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27041313. [PMID: 35209099 PMCID: PMC8878451 DOI: 10.3390/molecules27041313] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 02/10/2022] [Indexed: 12/28/2022]
Abstract
Natural compounds have been recognized as valuable sources for anticancer drug development. In this work, different parts from Momordica cochinchinensis Spreng were selected to perform cytotoxic screening against human prostate cancer (PC-3) cells. Chromatographic separation and purification were performed for the main constituents of the most effective extract. The content of the fatty acids was determined by Gas Chromatography-Flame Ionization Detector (GC–FID). Chemical structural elucidation was performed by spectroscopic means. For the mechanism of the apoptotic induction of the most effective extract, the characteristics were evaluated by Hoechst 33342 staining, sub-G1 peak analysis, JC-1 staining, and Western blotting. As a result, extracts from different parts of M. cochinchinensis significantly inhibited cancer cell viability. The most effective stem extract induced apoptosis in PC-3 cells by causing nuclear fragmentation, increasing the sub-G1 peak, and changing the mitochondrial membrane potential. Additionally, the stem extract increased the pro-apoptotic (caspase-3 and Noxa) mediators while decreasing the anti-apoptotic (Bcl-xL and Mcl-1) mediators. The main constituents of the stem extract are α-spinasterol and ligballinol, as well as some fatty acids. Our results demonstrated that the stem extract of M. cochinchinensis has cytotoxic and apoptotic effects in PC-3 cells. These results provide basic knowledge for developing antiproliferative agents for prostate cancer in the future.
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Affiliation(s)
- Seksom Chainumnim
- Department of Biochemistry, Faculty of Medicine, Srinakharinwirot University, Bangkok 10110, Thailand;
| | - Audchara Saenkham
- Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Srinakharinwirot University, Bangkok 10110, Thailand; (A.S.); (K.D.)
| | - Kulvadee Dolsophon
- Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Srinakharinwirot University, Bangkok 10110, Thailand; (A.S.); (K.D.)
| | - Kittipong Chainok
- Thammasat University Research Unit in Multifunctional Crystalline Materials and Applications (TU-MCMA), Faculty of Science and Technology, Thammasat University, Khlong Luang, Pathum Thani 12121, Thailand;
| | - Sunit Suksamrarn
- Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Srinakharinwirot University, Bangkok 10110, Thailand; (A.S.); (K.D.)
- Correspondence: (S.S.); (W.T.); Tel.: +66-813446669 (W.T.)
| | - Wanlaya Tanechpongtamb
- Department of Biochemistry, Faculty of Medicine, Srinakharinwirot University, Bangkok 10110, Thailand;
- Correspondence: (S.S.); (W.T.); Tel.: +66-813446669 (W.T.)
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Chen Y, He Y, Wei X, Jiang DS. Targeting regulated cell death in aortic aneurysm and dissection therapy. Pharmacol Res 2022; 176:106048. [PMID: 34968685 DOI: 10.1016/j.phrs.2021.106048] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 12/11/2021] [Accepted: 12/23/2021] [Indexed: 02/08/2023]
Abstract
Regulated cell death (RCD) is a basic biological phenomenon associated with cell and tissue homeostasis. Recent studies have enriched our understanding of RCD, and many novel cell death types, such as ferroptosis and pyroptosis, have been discovered and defined. Aortic aneurysm and dissection (AAD) is a life-threatening condition, but the pathogenesis remains largely unclear. A series of studies have indicated that the death of smooth muscle cells, endothelial cells and inflammatory cells participates in the development of AAD and that corresponding interventions could alleviate disease progression. Many treatments against cell death have been used to impede the process of AAD in vitro and in vivo, which provides strategies to protect against this condition. In this review, we focus on various types of regulated cell death and provide a framework of their roles in AAD, and the information contributes to further exploration of the molecular mechanisms of AAD.
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Affiliation(s)
- Yue Chen
- Division of Cardiothoracic and Vascular Surgery, Sino-Swiss Heart-Lung Transplantation Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yi He
- Division of Cardiothoracic and Vascular Surgery, Sino-Swiss Heart-Lung Transplantation Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiang Wei
- Division of Cardiothoracic and Vascular Surgery, Sino-Swiss Heart-Lung Transplantation Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei, China.
| | - Ding-Sheng Jiang
- Division of Cardiothoracic and Vascular Surgery, Sino-Swiss Heart-Lung Transplantation Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei, China.
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Wan R, Fan J, Song H, Sun W, Yin Y. Oxygen-Glucose Deprivation/Reperfusion-Induced Sirt3 Reduction Facilitated Neuronal Injuries in an Apoptosis-Dependent Manner During Prolonged Reperfusion. Neurochem Res 2022; 47:1012-1024. [PMID: 35091982 DOI: 10.1007/s11064-021-03502-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Revised: 11/10/2021] [Accepted: 12/03/2021] [Indexed: 12/21/2022]
Abstract
Cerebral ischemia is a major cause of morbidity and permanent disability. To date, no treatments for cerebral ischemia/reperfusion injury can be effectively administered beyond 4-6 h after the ischemic insult. Our study aimed to clarify the significance of Sirt3 during acute cerebral ischemia and explore Sirt3-targeted therapy for ischemic injuries. Upon establishing the oxygen-glucose deprivation/reperfusion (OGD/R) cell model, changes of Sirt3 protein levels and the effects of Sirt3 overexpression on primary hippocampal neurons were detected at indicated time points. Moreover, mitochondrial damage was observed in neurons upon OGD/R injury. The results showed that compared with the normoxia group, Sirt3 protein was significantly decreased in hippocampal neurons exposed to 1 h of OGD followed by 12 h of reperfusion. In addition, the reduction of Sirt3 protein levels contributed to OGD/R-induced neuronal injuries, a higher ratio of neuronal apoptosis, and extensive production of reactive oxygen species (ROS). However, all neuronal injuries were partly rescued by Sirt3 overexpression induced by lentivirus transfection. Mitochondrial morphologies were significantly impaired after OGD/R, but partly salvaged by Sirt3 overexpression. We further explored whether pharmacologically activating Sirt3 is protective for neurons, and found that treatment with honokiol (a Sirt3 agonist) after OGD exposure activated Sirt3 during reperfusion and significantly alleviated OGD/R-induced neuronal injuries. Because mitochondrial functions are essential for neuronal survival, the current results indicate that Sirt3 may be an efficient target to suppress ischemic injuries via maintenance of mitochondrial homeostasis. Our current findings shed light on a novel therapeutic strategy against subacute ischemic injuries.
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Affiliation(s)
- Rongqi Wan
- Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, People's Republic of China
| | - Jiahui Fan
- Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, People's Republic of China
| | - Huimeng Song
- Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, People's Republic of China
| | - Wei Sun
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.
| | - Yanling Yin
- Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, People's Republic of China.
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Gil HS, Lee JH, Farag AK, Hassan AHE, Chung KS, Choi JH, Roh EJ, Lee KT. AKF-D52, a Synthetic Phenoxypyrimidine-Urea Derivative, Triggers Extrinsic/Intrinsic Apoptosis and Cytoprotective Autophagy in Human Non-Small Cell Lung Cancer Cells. Cancers (Basel) 2021; 13:cancers13225849. [PMID: 34831003 PMCID: PMC8616202 DOI: 10.3390/cancers13225849] [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: 10/13/2021] [Revised: 11/17/2021] [Accepted: 11/19/2021] [Indexed: 01/24/2023] Open
Abstract
Simple Summary We previously reported the antiproliferative effects of a phenoxypyridine urea derivative. In this study, we aimed to investigate the antiproliferative effects of 1-(3,5-dimethoxyphenyl)-3-(4-(3-methoxyphenoxy)-2-((4-morpholinophenyl)amino)pyrimidin-5-yl)urea (AKF-D52) in non-small cell lung cancer cells. We found that (i) AKF-D52 induces apoptosis in caspase-dependent and caspase-independent pathways; (ii) AKF-D52-induced apoptosis is caused by the clustering of a death-inducing signaling complex and mitochondrial-dependent signaling; (iii) AKF-D52 induces cytoprotective autophagy, and pre-treatment with an autophagy inhibitor enhances the apoptotic effect of AKF-D52; and (iv) AKF-D52-induced apoptosis and autophagy are attenuated by the reactive oxygen species (ROS) scavenger α-tocopherol. Furthermore, AKF-D52 suppressed tumor growth in a xenograft mouse model. Collectively, our findings regarding the efficacy and molecular mechanisms of AKF-D52 identify this compound as a potential therapeutic agent for the treatment of lung cancer. Abstract Previously, we discovered that 1-(3,5-dimethoxyphenyl)-3-(4-(3-methoxyphenoxy)-2-((4-morpholinophenyl)amino)pyrimidin-5-yl)urea (AKF-D52), a synthetic phenoxypyrimidine urea derivative, acts as a growth inhibitor of various cancer cell types. In this study, we elucidated the antiproliferative properties of AFK-D52 and underlying mechanisms in non-small cell lung cancer (NSCLC) cells and an A549 xenograft animal model. AKF-D52 was found to induce both caspase-dependent and -independent apoptotic cell death. Furthermore, the mitochondrial component of the AKF-D52-induced apoptosis mechanism involves a reduction in mitochondrial membrane potential and regulation in B cell lymphoma-2 family protein expression. Moreover, AKF-D52 activates the extrinsic pathway through up-regulated expression of death receptor 3 and Fas and then the formation of a death-inducing signaling complex. AKF-D52 also induced autophagy by increasing acidic vesicular organelle formation and microtubule-associated protein 1A/1B-light chain 3-II levels and reducing p62 levels. Notably, pretreatment with autophagy inhibitors enhanced AKF-D52-induced cell death, indicating that the induced autophagy is cytoprotective. AKF-D52 treatment also triggered reactive oxygen species (ROS) production in NSCLC cells, whereas the antioxidant α-tocopherol abolished AKF-D52-induced cell death. In a xenograft lung cancer mouse model, AKF-D52 administration attenuated tumor growth by inducing apoptosis and autophagy in tumor tissues. Collectively, our data indicate that AKF-D52-induced ROS production plays a role in mediating apoptosis and cytoprotective autophagy in NSCLC.
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Affiliation(s)
- Hyo-Sun Gil
- Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, 26, Kyungheedae-ro, Seoul 02447, Korea; (H.-S.G.); (J.-H.L.); (K.-S.C.)
- Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, 26, Kyungheedae-ro, Seoul 02447, Korea;
| | - Jeong-Hun Lee
- Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, 26, Kyungheedae-ro, Seoul 02447, Korea; (H.-S.G.); (J.-H.L.); (K.-S.C.)
- Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, 26, Kyungheedae-ro, Seoul 02447, Korea;
| | - Ahmed K. Farag
- Manufacturing Department, Curachem, Inc., Cheongju-si 28161, Chungcheongbuk-do, Korea;
| | - Ahmed H. E. Hassan
- Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt;
| | - Kyung-Sook Chung
- Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, 26, Kyungheedae-ro, Seoul 02447, Korea; (H.-S.G.); (J.-H.L.); (K.-S.C.)
| | - Jung-Hye Choi
- Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, 26, Kyungheedae-ro, Seoul 02447, Korea;
- Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, 26, Kyungheedae-ro, Seoul 02447, Korea
- Department of Biomedical and Pharmaceutical Sciences, Graduate School, Kyung Hee University, 26, Kyungheedae-ro, Seoul 02447, Korea
| | - Eun-Joo Roh
- Division of Bio-Medical Science &Technology, KIST School, University of Science and Technology, Seoul 02792, Korea;
| | - Kyung-Tae Lee
- Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, 26, Kyungheedae-ro, Seoul 02447, Korea; (H.-S.G.); (J.-H.L.); (K.-S.C.)
- Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, 26, Kyungheedae-ro, Seoul 02447, Korea;
- Department of Biomedical and Pharmaceutical Sciences, Graduate School, Kyung Hee University, 26, Kyungheedae-ro, Seoul 02447, Korea
- Correspondence: ; Tel.: +82-2-9610860; Fax: +82-2-9619580
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Hu C, Zhao L, Zhang F, Li L. Regulation of autophagy protects against liver injury in liver surgery-induced ischaemia/reperfusion. J Cell Mol Med 2021; 25:9905-9917. [PMID: 34626066 PMCID: PMC8572770 DOI: 10.1111/jcmm.16943] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 08/10/2021] [Accepted: 09/08/2021] [Indexed: 12/16/2022] Open
Abstract
Transient ischaemia and reperfusion in liver tissue induce hepatic ischaemia/reperfusion (I/R) tissue injury and a profound inflammatory response in vivo. Hepatic I/R can be classified into warm I/R and cold I/R and is characterized by three main types of cell death, apoptosis, necrosis and autophagy, in rodents or patients following I/R. Warm I/R is observed in patients or animal models undergoing liver resection, haemorrhagic shock, trauma, cardiac arrest or hepatic sinusoidal obstruction syndrome when vascular occlusion inhibits normal blood perfusion in liver tissue. Cold I/R is a condition that affects only patients who have undergone liver transplantation (LT) and is caused by donated liver graft preservation in a hypothermic environment prior to entering a warm reperfusion phase. Under stress conditions, autophagy plays a critical role in promoting cell survival and maintaining liver homeostasis by generating new adenosine triphosphate (ATP) and organelle components after the degradation of macromolecules and organelles in liver tissue. This role of autophagy may contribute to the protection of hepatic I/R‐induced liver injury; however, a considerable amount of evidence has shown that autophagy inhibition also protects against hepatic I/R injury by inhibiting autophagic cell death under specific circumstances. In this review, we comprehensively discuss current strategies and underlying mechanisms of autophagy regulation that alleviates I/R injury after liver resection and LT. Directed autophagy regulation can maintain liver homeostasis and improve liver function in individuals undergoing warm or cold I/R. In this way, autophagy regulation can contribute to improving the prognosis of patients undergoing liver resection or LT.
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Affiliation(s)
- Chenxia Hu
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lingfei Zhao
- Key Laboratory of Kidney Disease Prevention and Control Technology, Kidney Disease Center, Institute of Nephrology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Fen Zhang
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lanjuan Li
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Qin Z, Tong H, Li T, Cao H, Zhu J, Yin S, He W. SPHK1 contributes to cisplatin resistance in bladder cancer cells via the NONO/STAT3 axis. Int J Mol Med 2021; 48:204. [PMID: 34549307 PMCID: PMC8480383 DOI: 10.3892/ijmm.2021.5037] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 08/13/2021] [Indexed: 12/12/2022] Open
Abstract
Sphingosine-1-phosphate (S1P) serves an important role in various physiological and pathophysiological processes, including the regulation of cell apoptosis, proliferation and survival. Sphingosine kinase 1 (SPHK1) is a lipid kinase that phosphorylates sphingosine to generate S1P. S1P has been proven to be positively correlated with chemotherapy resistance in breast cancer, colorectal carcinoma and non-small cell lung cancer. However, whether SPHK1 is involved in the development of cisplatin resistance remains to be elucidated. The present study aimed to identify the association between SPHK1 and chemoresistance in bladder cancer cells and to explore the therapeutic implications in patients with bladder cancer. Bladder cancer cell proliferation and apoptosis were determined using Cell Counting Kit-8 assays and flow cytometry, respectively. Apoptosis-related proteins were detected via western blotting. The results revealed that SPHK1 was positively correlated with cisplatin resistance in bladder cancer cells, exhibiting an antiapoptotic effect that was reflected by the downregulation of apoptosis-related proteins (Bax and cleaved caspase-3) and the upregulation of an antiapoptotic protein (Bcl-2) in SPHK1-overexpression cell lines. Suppression of SPHK1 by small interfering RNA or FTY-720 significantly reversed the antiapoptotic effect. A potential mechanism underlying SPHK1-induced cisplatin resistance and apoptosis inhibition may be activation of STAT3 via binding non-POU domain containing octamer binding. In conclusion, the present study suggested that SPHK1 displayed significant antiapoptotic effects in cisplatin-based treatment, thus may serve as a potential novel therapeutic target for the treatment for bladder cancer.
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Affiliation(s)
- Zijia Qin
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Hang Tong
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Tinghao Li
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Honghao Cao
- Department of Urology, Rongchang Traditional Chinese Medicine Hospital, Chongqing 402460, P.R. China
| | - Junlong Zhu
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Siwen Yin
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Weiyang He
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
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38
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Kunimi H, Lee D, Ibuki M, Katada Y, Negishi K, Tsubota K, Kurihara T. Inhibition of the HIF-1α/BNIP3 pathway has a retinal neuroprotective effect. FASEB J 2021; 35:e21829. [PMID: 34314069 DOI: 10.1096/fj.202100572r] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 07/01/2021] [Accepted: 07/16/2021] [Indexed: 12/15/2022]
Abstract
Retinal ischemia is a leading cause of irreversible blindness worldwide. Inner retinal dysfunction including loss of retinal ganglion cells is encountered in a number of retinal ischemic disorders. We previously reported administration of two different hypoxia-inducible factor (HIF) inhibitors exerted neuroprotective effects in a murine model of retinal ischemia/reperfusion (I/R) which mimics these disorders, as inner retinal degeneration could be involved in pathological HIF induction. However, this notion needs further investigation. Therefore, in this study, we attempted to use retina-specific Hif-1α conditional knockout (cKO) mice to uncover this notion more clearly under the same condition. Hif-1α cKO mice showed inner retinal neurodegeneration to a lesser extent than control mice. Hif-1α depletion in a murine 661W retinal cell line reduced cell death under pseudohypoxic and hypoxic conditions. Among hypoxia-related genes, the expression of BCL2 19 kDa protein-interacting protein 3 (Bnip3) was substantially upregulated in the inner retinal layer after retinal I/R. In this regard, we further examined Bnip3 depletion in retinal neurons in vitro and in vivo and found the similar neuroprotective effects. Our results support the notion that the HIF-1α/BNIP3 pathway may have a critical role in inner retinal neurodegeneration, which can be linked with the development of new promising therapeutics for inner retinal ischemic disorders.
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Affiliation(s)
- Hiromitsu Kunimi
- Laboratory of Photobiology, Keio University School of Medicine, Shinanomachi, Japan.,Department of Ophthalmology, Keio University School of Medicine, Shinanomachi, Japan
| | - Deokho Lee
- Laboratory of Photobiology, Keio University School of Medicine, Shinanomachi, Japan.,Department of Ophthalmology, Keio University School of Medicine, Shinanomachi, Japan
| | - Mari Ibuki
- Laboratory of Photobiology, Keio University School of Medicine, Shinanomachi, Japan.,Department of Ophthalmology, Keio University School of Medicine, Shinanomachi, Japan
| | - Yusaku Katada
- Laboratory of Photobiology, Keio University School of Medicine, Shinanomachi, Japan.,Department of Ophthalmology, Keio University School of Medicine, Shinanomachi, Japan
| | - Kazuno Negishi
- Department of Ophthalmology, Keio University School of Medicine, Shinanomachi, Japan
| | - Kazuo Tsubota
- Department of Ophthalmology, Keio University School of Medicine, Shinanomachi, Japan.,Tsubota Laboratory, Inc., Tokyo, Japan
| | - Toshihide Kurihara
- Laboratory of Photobiology, Keio University School of Medicine, Shinanomachi, Japan.,Department of Ophthalmology, Keio University School of Medicine, Shinanomachi, Japan
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Asadi A, Ghahremani R, Abdolmaleki A, Rajaei F. Role of sperm apoptosis and oxidative stress in male infertility: A narrative review. Int J Reprod Biomed 2021; 19:493-504. [PMID: 34401644 PMCID: PMC8350854 DOI: 10.18502/ijrm.v19i6.9371] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 06/22/2020] [Accepted: 12/05/2020] [Indexed: 01/02/2023] Open
Abstract
Activation of caspase, externalization of phosphatidyl serine, change in the mitochondrial membrane potential, and DNA fragmentation are apoptosis markers found in human ejaculated spermatozoa. Also, reactive oxygen species (ROS) play a vital role in the different types of male infertility. In this review, data sources including Google Scholar, Scopus, PubMed, and Science Direct were searched for publications with no particular time restriction to get a holistic and comprehensive view of the research. Apoptosis regulates the male germ cells, correct function and development from the early embryonic stages of gonadal differentiation to fertilization. In addition to maintaining a reasonable ratio between the Sertoli and germ cells, apoptosis is one of the well-known quality control mechanisms in the testis. Also, high ROS levels cause a heightened and dysregulated apoptotic response. Apoptosis is one of the well-known mechanisms of quality control in the testis. Nevertheless, increased apoptosis may have adverse effects on sperm production. Recent studies have shown that ROS and the consequent oxidative stress play a crucial role in apoptosis. This review aims to assimilate and summarize recent findings on the apoptosis in male reproduction and fertility. Also, this review discusses the update on the role of ROS in normal sperm function to guide future research in this area.
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Affiliation(s)
- Asadollah Asadi
- Department of Biology, Faculty of Science, University of Mohaghegh Ardabili, Ardabil, Iran
| | - Rozita Ghahremani
- Department of Biology, Faculty of Science, University of Mohaghegh Ardabili, Ardabil, Iran
| | - Arash Abdolmaleki
- Department of Engineering Sciences, Faculty of Advanced Technologies, University of Mohaghegh Ardabili, Namin, Iran.,BioScience and Biotechnology Research Center (BBRC), Sabalan University of Advanced Technologies (SUAT), Namin, Iran
| | - Farzad Rajaei
- Cellular and Molecular Research Center, Qazvin University of Medical Sciences, Qazvin, Iran
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40
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Chen C, Zhang H, Yu Y, Huang Q, Wang W, Niu J, Lou J, Ren T, Huang Y, Guo W. Chloroquine suppresses proliferation and invasion and induces apoptosis of osteosarcoma cells associated with inhibition of phosphorylation of STAT3. Aging (Albany NY) 2021; 13:17901-17913. [PMID: 34170850 PMCID: PMC8312460 DOI: 10.18632/aging.203196] [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: 11/28/2020] [Accepted: 05/31/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND Osteosarcoma (OS) is characterized by a high rate of metastasis. It has been found that tumor cells can bypass apoptosis which leads to an uncontrolled proliferation, but chloroquine (CQ) can have an effect on the tumors by inducing apoptosis. We aimed to explore the effects and the hypothetical mechanism of CQ effects on OS. METHODS We first estimated the CQ effects on proliferation, apoptosis, migration, invasion, and lamellipodia formation of OS cells. Mice bearing xenograft model were used to test the anti-tumor growth and lung metastasis effects of CQ in OS. Western blot and immunohistochemistry were used to explore the mechanism of CQ effects and the association between p-STAT3 expression and lung metastasis of OS patients. RESULTS CQ induces the apoptosis and suppressed the viability, proliferation, migration, invasion, and lamellipodia formation of OS cells in vitro. In vivo experiments demonstrated that CQ inhibited tumor growth and lung metastasis. CQ induced apoptosis was dependent on the lysosomal inhibition and inhibition of protein turnover. The lung metastasis was associated with the p-STAT3 expression in OS patients. CONCLUSION CQ inhibited progression of OS cells in vitro, and suppressed tumor growth and lung metastasis in vivo. p-STAT3 can be a predictive biomarker for lung metastasis in osteosarcoma patients.
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Affiliation(s)
- Chenglong Chen
- Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing, People's Republic of China.,Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, People's Republic of China
| | - Hongliang Zhang
- Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing, People's Republic of China.,Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, People's Republic of China
| | - Yiyang Yu
- Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing, People's Republic of China.,Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, People's Republic of China
| | - Qingshan Huang
- Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing, People's Republic of China.,Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, People's Republic of China
| | - Wei Wang
- Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing, People's Republic of China.,Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, People's Republic of China
| | - Jianfang Niu
- Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing, People's Republic of China.,Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, People's Republic of China
| | - Jingbing Lou
- Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing, People's Republic of China.,Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, People's Republic of China
| | - Tingting Ren
- Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing, People's Republic of China.,Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, People's Republic of China
| | - Yi Huang
- Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing, People's Republic of China.,Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, People's Republic of China
| | - Wei Guo
- Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing, People's Republic of China.,Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, People's Republic of China
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Jin C, Xue W, Liu Q, Han J, Luo R, Feng J, Liu J, Guo T, Peng X, Hu T. LKB1/AMPKα signaling pathway and mitochondrial fission/fusion dynamics regulate apoptosis induced by 3-chlorpropane-1,2-diol in HEK293 cells. Food Chem Toxicol 2021; 154:112350. [PMID: 34139305 DOI: 10.1016/j.fct.2021.112350] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 06/11/2021] [Accepted: 06/13/2021] [Indexed: 12/12/2022]
Abstract
Mitochondrial dynamics and bioenergetics are considered play pivotal roles in the maintenance of mitochondrial function and cell viability. During the widely distributed food contaminant 3-chlorpropane-1,2-diol (3-MCPD) induced nephrotoxicity, mitochondrial morphology and function were impaired, but the specific mechanism responsible for the process has not been fully elucidated. In the present study, using an in vitro human embryonic kidney 293 (HEK293) cell culture model, the role of LKB1/AMPK pathway and mitochondrial fission and fusion dynamics in 3-MCPD-induced cell apoptosis was investigated by using the AMPK inhibitor dorsomorphin and mitochondrial division inhibitor 1 (Mdivi-1), respectively. The results revealed that 3-MCPD significantly decreased the ATP levels, activated the energy-sensing regulator AMPKα and its upstream protein kinase LKB1, disrupted mitochondrial dynamics equilibrium characterized by promoting division and inhibiting fusion, thus inducing cell apoptosis. Notably, suppression of AMPK by dorsomorphin mitigated 3-MCPD-induced cytotoxicity through improvement of the function and dynamics of mitochondria and alleviated apoptosis via the mitochondria-dependent pathway. Moreover, inhibition of mitochondrial fission by Mdivi-1 protected against apoptosis induced by 3-MCPD. Taken together, these results suggest that 3-MCPD triggers apoptosis through activation of LKB1/AMPKα signaling pathway and regulation of mitochondrial fission and fusion dynamics in HEK293 cells.
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Affiliation(s)
- Chengni Jin
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Wei Xue
- College of Grassland Agriculture, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Qi Liu
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Jiahui Han
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Ruilin Luo
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Jiayu Feng
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Jiayu Liu
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Tianmin Guo
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Xiaoli Peng
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China.
| | - Tianming Hu
- College of Grassland Agriculture, Northwest A&F University, Yangling, Shaanxi, 712100, China.
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42
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Kaur G, Iyer LM, Burroughs AM, Aravind L. Bacterial death and TRADD-N domains help define novel apoptosis and immunity mechanisms shared by prokaryotes and metazoans. eLife 2021; 10:70394. [PMID: 34061031 PMCID: PMC8195603 DOI: 10.7554/elife.70394] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Accepted: 05/23/2021] [Indexed: 12/12/2022] Open
Abstract
Several homologous domains are shared by eukaryotic immunity and programmed cell-death systems and poorly understood bacterial proteins. Recent studies show these to be components of a network of highly regulated systems connecting apoptotic processes to counter-invader immunity, in prokaryotes with a multicellular habit. However, the provenance of key adaptor domains, namely those of the Death-like and TRADD-N superfamilies, a quintessential feature of metazoan apoptotic systems, remained murky. Here, we use sensitive sequence analysis and comparative genomics methods to identify unambiguous bacterial homologs of the Death-like and TRADD-N superfamilies. We show the former to have arisen as part of a radiation of effector-associated α-helical adaptor domains that likely mediate homotypic interactions bringing together diverse effector and signaling domains in predicted bacterial apoptosis- and counter-invader systems. Similarly, we show that the TRADD-N domain defines a key, widespread signaling bridge that links effector deployment to invader-sensing in multicellular bacterial and metazoan counter-invader systems. TRADD-N domains are expanded in aggregating marine invertebrates and point to distinctive diversifying immune strategies probably directed both at RNA and retroviruses and cellular pathogens that might infect such communities. These TRADD-N and Death-like domains helped identify several new bacterial and metazoan counter-invader systems featuring underappreciated, common functional principles: the use of intracellular invader-sensing lectin-like (NPCBM and FGS), transcription elongation GreA/B-C, glycosyltransferase-4 family, inactive NTPase (serving as nucleic acid receptors), and invader-sensing GTPase switch domains. Finally, these findings point to the possibility of multicellular bacteria-stem metazoan symbiosis in the emergence of the immune/apoptotic systems of the latter.
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Affiliation(s)
- Gurmeet Kaur
- Computational Biology Branch, National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, United States
| | - Lakshminarayan M Iyer
- Computational Biology Branch, National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, United States
| | - A Maxwell Burroughs
- Computational Biology Branch, National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, United States
| | - L Aravind
- Computational Biology Branch, National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, United States
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New epigenetic players in stroke pathogenesis: From non-coding RNAs to exosomal non-coding RNAs. Biomed Pharmacother 2021; 140:111753. [PMID: 34044272 PMCID: PMC8222190 DOI: 10.1016/j.biopha.2021.111753] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 04/22/2021] [Accepted: 05/19/2021] [Indexed: 12/17/2022] Open
Abstract
Non-coding RNAs (ncRNAs) have critical role in the pathophysiology as well as recovery after ischemic stroke. ncRNAs, particularly microRNAs, and the long non-coding RNAs (lncRNAs) are critical for angiogenesis and neuroprotection, and they have been suggested to be therapeutic, diagnostic and prognostic tools in cerebrovascular diseases, including stroke. Moreover, exosomes have been considered as nanocarriers capable of transferring various cargos, such as lncRNAs and miRNAs to recipient cells, with prominent inter-cellular roles in the mediation of neuro-restorative events following strokes and neural injuries. In this review, we summarize the pathogenic role of ncRNAs and exosomal ncRNAs in the stroke.
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44
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Liu H, Chi Z, Jin H, Yang W. MicroRNA miR-188-5p as a mediator of long non-coding RNA MALAT1 regulates cell proliferation and apoptosis in multiple myeloma. Bioengineered 2021; 12:1611-1626. [PMID: 33944676 PMCID: PMC8806342 DOI: 10.1080/21655979.2021.1920325] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Multiple myeloma (MM), a malignancy of plasma cells mainly derived from the bone marrow, has remained incurable generally. LncRNA MALAT1 has been reported to be upregulated in the MM cells and knockdown of MALAT1 inhibited MM cell cycle progression and enhanced cell apoptosis. Online target prediction showed that two target sites for MALAT1 existed in miR-188-5p, which has been identified as a tumor suppressor in other types of cancers. However, the role of miR-188-5p in the MM and whether miR-188-5p mediates the MM tumor progression regulated by MALAT1 are still unknown. Herein, four main MM cell lines were adopted to investigate the effects of miR-188-5p on cell proliferation and apoptosis via transfection with miR-188-5p mimic/inhibitor and co-transfection with miR-188-5p inhibitor and MALAT1-shRNA plasmids. Xenograft tumor model was also established to study these effects in vivo. Overexpression of miR-188-5p inhibited cell viability, cell proliferation as well as tumor growth and arrested cell cycle at G1 to S transition, but miR-188-5p knockdown showed opposite effects on the MM cells in vitro and in vivo. Moreover, MALAT1 was shown to be inversely correlated with miR-188-5p expression through direct binding to miR-188-5p, and in turn, miR-188-5p could mediate the MM cell proliferation and apoptosis regulated by MALAT1. These findings indicate that miR-188-5p serves as a tumor suppressor in the progression of the MM and is directly involved in MM cell proliferation and apoptosis regulated by MALAT1, which may provide a potential therapeutic target or prognostic indictor for MM clinical treatment.
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Affiliation(s)
- Hui Liu
- Department of Hematology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Zuofei Chi
- Department of Pediatric Hematology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Hong Jin
- Department of Pathogenic Biology, College of Basic Medical Science, China Medical University, Shengyang, China
| | - Wei Yang
- Department of Hematology, Shengjing Hospital of China Medical University, Shenyang, China
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45
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Long Q, Xiao X, Yi P, Liu Y, Varier KM, Rao Q, Song J, Qiu J, Wang C, Liu W, Gajendran B, He Z, Liu S, Li Y. L20, a Calothrixin B analog, induces intrinsic apoptosis on HEL cells through ROS/γ-H2AX/p38 MAPK pathway. Biomed Pharmacother 2021; 137:111336. [DOI: 10.1016/j.biopha.2021.111336] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 01/25/2021] [Accepted: 01/27/2021] [Indexed: 12/20/2022] Open
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46
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Kang MJ, Kim JE, Park JW, Choi HJ, Bae SJ, Choi SI, Hong JT, Hwang DY. Effects of Gallotannin-Enriched Extract of Galla Rhois on the Activation of Apoptosis, Cell Cycle Arrest, and Inhibition of Migration Ability in LLC1 Cells and LLC1 Tumors. Pathol Oncol Res 2021; 27:588084. [PMID: 34257536 PMCID: PMC8262247 DOI: 10.3389/pore.2021.588084] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 03/16/2021] [Indexed: 12/19/2022]
Abstract
Gallotannin (GT) and GT-enriched extracts derived from various sources are reported to have anti-tumor activity in esophageal, colon and prostate tumors, although their anti-tumor effects have not been determined in lung carcinomas. To investigate the anti-tumor activity of GT-enriched extract of galla rhois (GEGR) against lung carcinomas, alterations in the cytotoxicity, apoptosis activation, cell cycle progression, migration ability, tumor growth, histopathological structure, and the regulation of signaling pathways were analyzed in Lewis lung carcinoma (LLC1) cells and LLC1 tumor bearing C57BL/6NKorl mice, after exposure to GEGR. A high concentration of GT (69%) and DPPH scavenging activity (IC50=7.922 µg/ml) was obtained in GEGR. GEGR treatment exerted strong cytotoxicity, cell cycle arrest at the G2/M phase and subsequent activation of apoptosis, as well as inhibitory effects on the MAPK pathway and PI3K/AKT mediated cell migration in LLC1 cells. In the in vivo syngeneic model, exposure to GEGR resulted in suppressed growth of the LLC1 tumors, as well as inhibition of NF-κB signaling and their inflammatory cytokines. Taken together, our results provide novel evidence that exposure to GEGR induces activation of apoptosis, cell cycle arrest, and inhibition of cell migration via suppression of the MAPK, NF-κB and PI3K/AKT signaling pathways in LLC1 cells and the LLC1 syngeneic model.
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Affiliation(s)
- Mi Ju Kang
- Department of Biomaterials Science (BK21 FOUR Program), College of Natural Resources and Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
| | - Ji Eun Kim
- Department of Biomaterials Science (BK21 FOUR Program), College of Natural Resources and Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
| | - Ji Won Park
- Department of Biomaterials Science (BK21 FOUR Program), College of Natural Resources and Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
| | - Hyun Jun Choi
- Department of Biomaterials Science (BK21 FOUR Program), College of Natural Resources and Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
| | - Su Ji Bae
- Department of Biomaterials Science (BK21 FOUR Program), College of Natural Resources and Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
| | - Sun Il Choi
- Division of Convergence Technology, Research Institute of National Cancer Center, Goyang, South Korea
| | - Jin Tae Hong
- College of Pharmacy, Chungbuk National University, Chungju, Korea
| | - Dae Youn Hwang
- Department of Biomaterials Science (BK21 FOUR Program), College of Natural Resources and Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
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Karges J, Tharaud M, Gasser G. Polymeric Encapsulation of a Ru(II)-Based Photosensitizer for Folate-Targeted Photodynamic Therapy of Drug Resistant Cancers. J Med Chem 2021; 64:4612-4622. [PMID: 33818111 DOI: 10.1021/acs.jmedchem.0c02006] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The currently used photodynamic therapy (PDT) photosensitizers (PSs) are generally associated with a poor cancer cell selectivity, which is responsible for some undesirable side effects. To overcome these problems, there is an urgent need for a selective drug delivery system for PDT PSs. Herein, the encapsulation of a promising Ru(II) polypyridine complex in a polymer with terminal folate groups to form nanoparticles is presented. While the Ru(II) complex itself has a cytotoxic effect in the dark, the encapsulation is able to overcome this drawback. Upon light exposure, the nanoparticles were found to be highly phototoxic in 2D monolayer cells as well as 3D multicellular tumor spheroids upon 480 or 595 nm irradiation. Importantly, the nanoparticles demonstrated a high selectivity for cancerous cells over noncancerous cells and were found to be active in drug resistant cancer cells lines, indicating that they are able to overcome drug resistances.
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Affiliation(s)
- Johannes Karges
- Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, 75005 Paris, France
| | - Mickaël Tharaud
- Université de Paris, Institut de Physique du Globe de Paris, CNRS, F-75005 Paris, France
| | - Gilles Gasser
- Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, 75005 Paris, France
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48
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GE11 Peptide Conjugated Liposomes for EGFR-Targeted and Chemophotothermal Combined Anticancer Therapy. Bioinorg Chem Appl 2021; 2021:5534870. [PMID: 33868396 PMCID: PMC8035035 DOI: 10.1155/2021/5534870] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 03/13/2021] [Accepted: 03/23/2021] [Indexed: 01/01/2023] Open
Abstract
How to actively target tumor sites manipulating the controllable release of the encapsulated anticancer drugs and photosensitizers for synergistic anticancer therapy remains a big challenge. In this study, a cancer cell-targeted, near-infrared (NIR) light-triggered and anticancer drug loaded liposome system (LPs) was developed for synergistic cancer therapy. Photosensitizer indocyanine green (ICG) and chemotherapy drug Curcumin (CUR) were coencapsulated into the liposomes, followed by the surface conjugation of GE11 peptide for epidermal growth factor receptor (EGFR) targeting on the cancer cell surface. Strictly controlled by NIR light, GE11 peptide modified and CUR/ICG-loaded LPs (GE11-CUR/ICG-LPs) could introduce hyperthermia in EGFR overexpressed A549 cancer cells for photothermal therapy, which could also trigger the increased release of CUR for enhanced cancer cell inhibition. GE11-CUR/ICG-LPs synergized photochemotherapy could induce reactive oxygen species (ROS) generation and cytoskeleton disruption to activate stronger apoptotic signaling events than the photothermal therapy or chemotherapy alone by regulating Bax/Bcl-2 and PI3K/AKT pathways. This EGFR-targeted drug-delivery nanosystem with NIR sensitivity may potentially serve in more effective anticancer therapeutics with reduced off-target effects.
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Pemafibrate Pretreatment Attenuates Apoptosis and Autophagy during Hepatic Ischemia-Reperfusion Injury by Modulating JAK2/STAT3 β/PPAR α Pathway. PPAR Res 2021; 2021:6632137. [PMID: 33777128 PMCID: PMC7972847 DOI: 10.1155/2021/6632137] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 03/01/2021] [Indexed: 11/18/2022] Open
Abstract
Hepatic ischemia-reperfusion injury (HIRI) is a common phenomenon in liver transplantation and liver surgery. This article is aimed at clarifying the role of pemafibrate in HIRI through JAK2/STAT3β/PPARα. In the experiment, we divided Balb/c into seven groups, namely, normal control (NC), Sham, PEM (1.0 mg/kg), IRI, IRI + PEM (0.1 mg/kg), IRI + PEM (0.5 mg/kg), and IRI + PEM (1.0 mg/kg). We used biochemical assay, histopathological evaluation, immunohistochemistry, RT-PCR and qRT-PCR, ELISA analysis, and other methods to determine the level of serum AST, ALT, IL-1β, and TNF-α in the liver at three time points (2 h, 8 h, and 24 h) after reperfusion of apoptosis factor, autophagy factor, and the JAK2/STAT3/PPARα content in tissues. Our experiment results showed that the pemafibrate can effectively reduce the level of hepatic IR injury. In addition, pemafibrate has anti-inflammatory, antiapoptotic, and antiautophagy effects, which are mediated by the JAK2/STAT3β/PPARα pathway.
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Lin X, Gajendran B, Varier KM, Liu W, Song J, Rao Q, Wang C, Qiu J, Ni W, Qin X, Wen M, Liu H, Li Y. Paris Saponin VII Induces Apoptosis and Cell Cycle Arrest in Erythroleukemia Cells by a Mitochondrial Membrane Signaling Pathway. Anticancer Agents Med Chem 2021; 21:498-507. [PMID: 32538736 DOI: 10.2174/1871520620666200615134039] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 04/19/2020] [Accepted: 05/10/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND AND PURPOSE Leukemia is considered a top-listed ailment, according to WHO, which contributes to the death of a major population of the world every year. Paris Saponin VII (PS), a saponin which was isolated from the roots of Trillium kamtschaticum, from our group, was reported to provide hemostatic, cytotoxic and antimicrobial activities. However, its molecular mechanism underlying the anti-proliferative effects remains unclear. Thus, this study hypothesized to assess that mechanism in PS treated HEL cells. METHODS The MTT assay was used to analyze the PS inhibited cell viability in the HEL cells. We further found that PS could induce S phase cell cycle arrest through flow cytometry as well as the western blot analysis of intrinsic and extrinsic apoptotic molecules. RESULTS The MTT assay showed the IC50 concentration of PS as 0.667μM. The study revealed that PS treatment inhibits cell proliferation dose-dependently. It further caused mitochondrial membrane potential changes by PS treatment. Mechanistic protein expression revealed a dose-dependent upsurge for Bid and Bim molecules, while Bcl2 and PARP expression levels were significantly (P<0.05) down-regulated in PS treated HEL cells resulting in caspase -3 release and increased the Bim levels upon 24h of incubation. CONCLUSION These findings indicate that PS possesses an excellent anti-leukemic activity via the regulation of the mitochondrial pathway, leading to S phase cell cycle arrest and caspase-dependent apoptosis, suggesting it as a potential alternative chemotherapeutic agent for leukemia patients.
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Affiliation(s)
- Xin Lin
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, Guizhou Province- 550014, China
| | - Babu Gajendran
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, Guizhou Province- 550014, China
| | - Krishnapriya M Varier
- Department of Medical Biochemistry, Dr. ALM PGIBMS, University of Madras, Taramani Campus, Chennai, Tamilnadu-600113, India
| | - Wuling Liu
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, Guizhou Province- 550014, China
| | - Jingrui Song
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, Guizhou Province- 550014, China
| | - Qing Rao
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, Guizhou Province- 550014, China
| | - Chunlin Wang
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, Guizhou Province- 550014, China
| | - Jianfei Qiu
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, Guizhou Province- 550014, China
| | - Wei Ni
- State Key Laboratory of Phytochemistry and Plant Resources in West China, and Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China
| | - XuJie Qin
- State Key Laboratory of Phytochemistry and Plant Resources in West China, and Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China
| | - Min Wen
- College of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou, China
| | - Haiyang Liu
- State Key Laboratory of Phytochemistry and Plant Resources in West China, and Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China
| | - Yanmei Li
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, Guizhou Province- 550014, China
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