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1
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Liu Z, Chu A, Bai Z, Yang C. Daphnetin alleviates inflammation and promotes autophagy via the AMPK/mTOR pathway in gouty arthritis. J Cell Commun Signal 2025; 19:e70011. [PMID: 40304008 PMCID: PMC12037417 DOI: 10.1002/ccs3.70011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 03/05/2025] [Accepted: 03/07/2025] [Indexed: 05/02/2025] Open
Abstract
Gouty arthritis (GA) is an inflammatory disease resulting from monosodium urate (MSU) crystal deposition in joints and surrounding tissues. Daphnetin (DAP) is a coumarin derivative with potent anti-inflammatory activity. Nonetheless, whether DAP can protect against MSU-induced acute GA remains unclarified. In this study, C57BL/6 mice were injected intra-articularly with MSU crystal suspension to induce acute GA. THP-1 cells were stimulated with MSU to mimic the microenvironment of GA in vitro. Hematoxylin-eosin staining was conducted to observe the pathological changes in mouse synovial tissues. ELISA and RT-qPCR were employed for inflammatory cytokine level determination. Immunofluorescence staining was performed to estimate LC3 expression in THP-1 cells. Western blotting was used for protein expression analysis. The results showed that DAP pretreatment mitigated MSU-elicited ankle joint swelling and synovial damage in mice. Moreover, DAP hindered proinflammatory factor expression and promoted autophagy in MSU-stimulated GA mice and THP-1 cells. Mechanistically, DAP induced AMPK activation and mTOR inactivation. Blocking AMPK signaling counteracted DAP-mediated effects on inflammation and autophagy in MSU-stimulated THP-1 cells. In conclusion, DAP prevents MSU-elicited GA by alleviating inflammation and enhancing autophagy via AMPK/mTOR signaling transduction.
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Affiliation(s)
- Zhiyong Liu
- Department of Rheumatology and ImmunologyRenmin HospitalWuhan UniversityWuhanHubeiChina
| | - Aichun Chu
- Department of Rheumatology and ImmunologyRenmin HospitalWuhan UniversityWuhanHubeiChina
| | - Zhiqian Bai
- Department of Rheumatology and ImmunologyRenmin HospitalWuhan UniversityWuhanHubeiChina
| | - Chao Yang
- Department of OrthopedicsMaternal and Child Health Hospital of Hubei ProvinceWuhanChina
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2
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Gong B, Liu Y, Yan W, Cheng C, Yang H, Huang J, Liu Q, Liu Y, Guo J, Deng X, Zhou B, Zheng D, Liu X, Liu Z, Fang W. NAP1L1 degradation by FBXW7 reduces the deubiquitination of HDGF-p62 signaling to stimulate autophagy and induce primary cisplatin chemosensitivity in nasopharyngeal carcinoma. Mol Cancer 2025; 24:152. [PMID: 40414865 DOI: 10.1186/s12943-025-02349-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 05/05/2025] [Indexed: 05/27/2025] Open
Abstract
Nucleosome assembly protein 1-like 1 (NAP1L1) has been implicated in promoting tumor cell proliferation. However, its role in regulating autophagy in tumors, including nasopharyngeal carcinoma (NPC), remains unclear. In this study, we observed that autophagy-inducing agents reduced NAP1L1 protein levels without affecting its mRNA expression. Reduced NAP1L1 enhanced autophagosome formation and maturation, thereby promoting cisplatin (DDP) chemosensitivity in both in vitro and in vivo NPC models. Mechanistically, reduced NAP1L1 impaired the recruitment of ubiquitin-specific protease 14 (USP14), limiting the deubiquitination of heparin-binding growth factor (HDGF) and decreasing HDGF protein levels. In turn, reduced HDGF suppressed USP14-mediated p62 deubiquitination, leading to further declines in p62 protein levels. Notably, the F-box and WD repeat domain-containing protein 7 (FBXW7), an inhibitory E3 ubiquitin ligase, directly interacted with and ubiquitinated NAP1L1, promoting its degradation. This degradation triggered NPC autophagy and enhanced DDP chemosensitivity by disrupting NAP1L1-induced HDGF/p62 signaling. Clinically, NAP1L1 protein expression was inversely correlated with FBXW7 levels in NPC tissue samples. Patients exhibiting high NAP1L1 and low FBXW7 levels had the poorest DDP chemosensitivity and survival outcomes. Our findings demonstrate that FBXW7-mediated NAP1L1 degradation suppresses HDGF-p62 signaling, thereby inducing autophagy and enhancing DDP chemosensitivity. These results underscore the potential of NAP1L1 and FBXW7 as therapeutic targets for NPC treatment.
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Affiliation(s)
- Bin Gong
- Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Yahui Liu
- Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Weiwei Yan
- Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Chao Cheng
- Department of Otolaryngology, Shenzhen Longgang Otolaryngology Hospital, Shenzhen, Guangdong, China
| | - Huiling Yang
- School of Pharmacy, Guangdong Medical University, Dongguan, China
| | - Jiyu Huang
- Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Qing Liu
- Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Yuyan Liu
- Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Jiankang Guo
- Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Xiaojie Deng
- Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Beixian Zhou
- Center of Stem Cell and Regenerative Medicine, The People's Hospital of Gaozhou, Gaozhou, China.
| | - Dayong Zheng
- Department of Oncology, Shunde Hospital of Southern Medical Universtiy, Foshan, China.
| | - Xiong Liu
- Department of Otolaryngology-Head and Neck Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| | - Zhen Liu
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University Guangzhou, Guangdong, China.
- Central Laboratory, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.
| | - Weiyi Fang
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
- Central Laboratory, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.
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3
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Tu Y, Ren J, Fang W, Zhou C, Zhao B, Hua T, Chen Y, Chen Z, Feng Y, Jin H, Wang X. Daphnetin-mediated mitophagy alleviates intervertebral disc degeneration via the Nrf2/PINK1 pathway. Acta Biochim Biophys Sin (Shanghai) 2025. [PMID: 39838851 DOI: 10.3724/abbs.2025002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2025] Open
Abstract
Intervertebral disc degeneration (IDD) is a major cause of low back pain (LBP), and effective therapies are still lacking. Reactive oxygen species (ROS) stress induces NLRP3 inflammasome activation, and this, along with extracellular matrix metabolism (ECM) degradation in nucleus pulposus cells (NPCs), plays a crucial role in the progression of IDD. Daphnetin (DAP) is a biologically active phytochemical extracted from plants of the Genus Daphne, which possesses various bioactivities, including antioxidant properties. In the present study, we demonstrate that DAP significantly attenuates tert-butyl hydroperoxide (TBHP)-induced ECM degradation, oxidative stress and NLRP3 inflammasome activation in NPCs. Furthermore, DAP could facilitate mitophagy to increase the removal of damaged mitochondria, consequently reducing mitochondrial ROS accumulation and alleviating NLRP3 inflammasome activation. Mechanistically, we unveil that DAP activates mitophagy by stimulating the Nrf2/PINK1 signaling pathway in TBHP-induced NPCs. In vivo experiments further corroborate the protective effect of DAP against IDD progression in a rat model induced by disc puncture. Accordingly, our findings reveal that DAP could be a promising therapeutic candidate for the treatment of IDD.
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Affiliation(s)
- Yiting Tu
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China
- Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou 325000, China
- The Second School of Medicine, Wenzhou Medical University, Wenzhou 325000, China
| | - Jiaping Ren
- The First School of Medicine, Wenzhou Medical University, Wenzhou 325000, China
| | - Weiyuan Fang
- The Second School of Medicine, Wenzhou Medical University, Wenzhou 325000, China
| | - Chencheng Zhou
- The Second School of Medicine, Wenzhou Medical University, Wenzhou 325000, China
| | - Binli Zhao
- The Second School of Medicine, Wenzhou Medical University, Wenzhou 325000, China
| | - Tianyong Hua
- The Second School of Medicine, Wenzhou Medical University, Wenzhou 325000, China
| | - Yiqi Chen
- The Second School of Medicine, Wenzhou Medical University, Wenzhou 325000, China
| | - Zhenya Chen
- The Second School of Medicine, Wenzhou Medical University, Wenzhou 325000, China
| | - Yongzeng Feng
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China
- Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou 325000, China
- The Second School of Medicine, Wenzhou Medical University, Wenzhou 325000, China
| | - Haiming Jin
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China
- Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou 325000, China
- The Second School of Medicine, Wenzhou Medical University, Wenzhou 325000, China
| | - Xiangyang Wang
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China
- Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou 325000, China
- The Second School of Medicine, Wenzhou Medical University, Wenzhou 325000, China
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4
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Chiaramonte R, Sauro G, Giannandrea D, Limonta P, Casati L. Molecular Insights in the Anticancer Activity of Natural Tocotrienols: Targeting Mitochondrial Metabolism and Cellular Redox Homeostasis. Antioxidants (Basel) 2025; 14:115. [PMID: 39857449 PMCID: PMC11760857 DOI: 10.3390/antiox14010115] [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: 11/27/2024] [Revised: 01/14/2025] [Accepted: 01/16/2025] [Indexed: 01/27/2025] Open
Abstract
The role of mitochondria as the electric engine of cells is well established. Over the past two decades, accumulating evidence has pointed out that, despite the presence of a highly active glycolytic pathway (Warburg effect), a functional and even upregulated mitochondrial respiration occurs in cancer cells to meet the need of high energy and the biosynthetic demand to sustain their anabolic growth. Mitochondria are also the primary source of intracellular ROS. Cancer cells maintain moderate levels of ROS to promote tumorigenesis, metastasis, and drug resistance; indeed, once the cytotoxicity threshold is exceeded, ROS trigger oxidative damage, ultimately leading to cell death. Based on this, mitochondrial metabolic functions and ROS generation are considered attractive targets of synthetic and natural anticancer compounds. Tocotrienols (TTs), specifically the δ- and γ-TT isoforms, are vitamin E-derived biomolecules widely shown to possess striking anticancer properties since they regulate several intracellular molecular pathways. Herein, we provide for the first time an overview of the mitochondrial metabolic reprogramming and redox homeostasis perturbation occurring in cancer cells, highlighting their involvement in the anticancer properties of TTs. This evidence sheds light on the use of these natural compounds as a promising preventive or therapeutic approach for novel anticancer strategies.
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Affiliation(s)
- Raffaella Chiaramonte
- Department of Health Sciences, Università degli Studi di Milano, 20142 Milan, Italy; (R.C.); (G.S.); (D.G.)
| | - Giulia Sauro
- Department of Health Sciences, Università degli Studi di Milano, 20142 Milan, Italy; (R.C.); (G.S.); (D.G.)
| | - Domenica Giannandrea
- Department of Health Sciences, Università degli Studi di Milano, 20142 Milan, Italy; (R.C.); (G.S.); (D.G.)
| | - Patrizia Limonta
- Department of Pharmacological and Biomolecular Sciences “R. Paoletti”, Università degli Studi di Milano, 20133 Milan, Italy;
| | - Lavinia Casati
- Department of Health Sciences, Università degli Studi di Milano, 20142 Milan, Italy; (R.C.); (G.S.); (D.G.)
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5
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Zhao X, Shang L, Shen C. Daphnetin ameliorates diabetic cardiomyopathy by regulating inflammation and endoplasmic reticulum stress-induced apoptosis. Exp Anim 2025; 74:49-57. [PMID: 39111852 PMCID: PMC11742473 DOI: 10.1538/expanim.24-0027] [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: 03/27/2024] [Accepted: 07/31/2024] [Indexed: 01/15/2025] Open
Abstract
Daphnetin has been demonstrated to exert beneficial effects on diabetes mellitus and renal complications. However, the role and molecular mechanism of daphnetin in diabetic cardiomyopathy (DCM) remain unclear. In this study, rats were injected with streptozotocin (STZ) to induce diabetes. The diabetic rats were then administered daphnetin (1 and 4 mg/kg) or dimethyl sulfoxide (DMSO) daily for 12 weeks. The results demonstrated that the diabetic rats exhibited elevated blood glucose levels, which were dose-dependently ameliorated by daphnetin. At 13 weeks following STZ injection, the rats exhibited typical diabetic signs, cardiac dysfunction, and evident pathological alterations in myocardial tissues. The administration of daphnetin to diabetic rats resulted in improvement in cardiac function, reductions in myocardial injury biomarkers, and the inhibition of myocardial fibrosis. Furthermore, daphnetin treatment suppressed inflammation and endoplasmic reticulum stress-induced apoptosis in a dose-dependent manner. Additionally, daphnetin exhibited partial blockade of the activation of mitogen-activated protein kinase pathways induced by diabetes. These findings indicate that daphnetin may be a promising therapeutic agent for the treatment of DCM.
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Affiliation(s)
- Xiaolong Zhao
- Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, P.R. China
| | - Longqi Shang
- Department of Nursing, The Second Affiliated Hospital of Shenyang Medical College, No. 20 Beijiu Road, Shenyang, Liaoning Province 110000, P.R. China
| | - Chunjian Shen
- Department of Cardiothoracic Surgery, The Fourth People's Hospital of Shenyang, 20 Huanghe South Street,, Shenyang, Liaoning Province 110000, P.R. China
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Chen S, Huang Y, Lei L, Yang C, Ran D, Zhou E, Wang H, Ning X. Daphnetin ameliorates intervertebral disc degeneration via the Keap1/Nrf2/NF-κB axis in vitro and in vivo. Int Immunopharmacol 2025; 145:113785. [PMID: 39672027 DOI: 10.1016/j.intimp.2024.113785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 12/01/2024] [Accepted: 12/02/2024] [Indexed: 12/15/2024]
Abstract
Intervertebral disc degeneration (IVDD) is the primary cause of low back pain (LBP). Enhanced inflammation and reactive oxygen species (ROS) levels can cause apoptosis, which is one of the initial factors of IVDD. Our previous study showed that daphnetin (DAP) alleviates IVDD; however, the underlying mechanisms remain unknown. An IVDD mouse model was established by lumbar disc puncture to investigate the mechanisms of DAP regulation, and DAP was injected intraperitoneally. Moreover, nucleus pulposus cells (NPCs) were challenged with tumor necrosis factor-alpha (TNF-α)/H2O2 to mimic IVDD. Additionally, NPC apoptosis, ROS, and the expression of proinflammatory cytokines were comprehensively assessed. We found that DAP can reverse H2O2-induced ROS and play an anti-inflammatory role by inhibiting Nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. Moreover, we found that DAP inhibits the apoptosis of NPCs induced by H2O2/TNF-α. DAP may regulate ROS production and apoptosis via the Kelch-like ECH-associated protein 1/NF-E2-related factor 2/heme oxygenase-1 (Keap1/Nrf2/HO-1) pathway. These findings were confirmed by in vivo results. The comprehensive nature of our research provides a strong foundation for the potential use of DAP as a therapeutic agent to alleviate IVDD.
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Affiliation(s)
- Shunlun Chen
- Department of Orthopaedics, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, PR China
| | - Yuming Huang
- Department of Spinal Surgery, First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, PR China
| | - Linchuan Lei
- Department of Spine Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, PR China
| | - Cheng Yang
- Beijing Jishuitan Hospital Guizhou Hospital
| | - Dongcheng Ran
- School of Clinical Medicine, Guizhou Medical University, Guiyang 550004, PR China
| | - Enyu Zhou
- School of Clinical Medicine, Guizhou Medical University, Guiyang 550004, PR China
| | - Hua Wang
- Department of Spine Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, PR China.
| | - Xu Ning
- Department of Orthopaedics, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, PR China.
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Wang Z, Gao P, Gao J, Liang B, Ma Q, Sun Q, Hu Y, Wang Y, Peng Y, Liu H, Wu Y, Yi T, Liu J, Qu LN, Guo H, Shi L, Long J. Daphnetin ameliorates hepatic steatosis by suppressing peroxisome proliferator-activated receptor gamma (PPARG) in ob/ob mice. Biochem Pharmacol 2024; 230:116610. [PMID: 39510197 DOI: 10.1016/j.bcp.2024.116610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 09/29/2024] [Accepted: 11/04/2024] [Indexed: 11/15/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the predominant metabolic liver disorder and currently lacks effective and safe pharmaceutical interventions. Daphnetin (DA), a natural coumarin derivative with anti-inflammatory and antioxidant activities, is a promising agent for NAFLD treatment. In this study, we evaluated the effects and mechanisms of DA on hepatic lipid metabolism in ob/ob mice. Our results showed that DA effectively ameliorates glucose metabolism and hepatic lipid accumulation in ob/ob mice. Metabolomics and RNA sequencing (RNA-seq), combined with GEO data analysis, suggest that DA primarily modulates the peroxisome proliferator-activated receptor gamma (PPARG) pathway, as validated in vivo in ob/ob mice. Mechanistically, DA selectively targets PPARG in hepatic cells by inhibiting PPARG promoter activity and downregulating its expression, resulting in decreased transcription of downstream lipid metabolism-related genes, including fatty acid binding protein 4 (Fabp4), cluster of differentiation 36 (Cd36), and fatty acid synthase (Fasn). This effect was abolished in PPARG-deficient HepG2 cells subjected to palmitic acid (PA) insult. Our findings provide evidence that DA acts as a selective suppressor of hepatic PPARG, suggesting an attractive strategy by targeting PPARG for the prevention of hepatic steatosis.
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Affiliation(s)
- Zhen Wang
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science, Xi'an Jiaotong University, Xi'an 710049, PR China
| | - Peipei Gao
- Department of Health Education and Management and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710000, PR China
| | - Jing Gao
- College of Sports and Health Science, Xi'an Physical Education University, Xi'an 710068, PR China
| | - Bing Liang
- First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121001, PR China
| | - Qingqing Ma
- Guizhou Aerospace Hospital, Zunyi 563099, PR China
| | - Qiong Sun
- Yulin Hospital, First Affiliated Hospital of Xi'an Jiao Tong University, Yulin 718000, PR China
| | - Yachong Hu
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science, Xi'an Jiaotong University, Xi'an 710049, PR China
| | - Yan Wang
- Department of Stem Cell and Regenerative Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, PR China
| | - Yunhua Peng
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science, Xi'an Jiaotong University, Xi'an 710049, PR China
| | - Huadong Liu
- School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao 266071, PR China
| | - Yuan Wu
- Department of Endocrinology, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710000, PR China
| | - Tao Yi
- Faculty of Health Sciences and Sports, Macao Polytechnic University, Macau 999078, PR China
| | - Jiankang Liu
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science, Xi'an Jiaotong University, Xi'an 710049, PR China; School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao 266071, PR China
| | - Li-Na Qu
- Department of Cellular and Molecular Biology, State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing 100094, PR China
| | - Hui Guo
- Department of Endocrinology, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710000, PR China.
| | - Le Shi
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science, Xi'an Jiaotong University, Xi'an 710049, PR China.
| | - Jiangang Long
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science, Xi'an Jiaotong University, Xi'an 710049, PR China.
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Lv Z, Du Y, Zhang H, Fang H, Guo Y, Zeng L, Chen Y, Li D, Li R. Inhibition of JNK/STAT3/NF-KB pathway-mediated migration and clonal formation of lung adenocarcinoma A549 cells by daphnetin. Cell Adh Migr 2024; 18:27-37. [PMID: 39469948 PMCID: PMC11540088 DOI: 10.1080/19336918.2024.2418049] [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: 04/27/2024] [Revised: 06/28/2024] [Accepted: 10/11/2024] [Indexed: 10/30/2024] Open
Abstract
Daphnetin, a coumarin derivative isolated from Daphne odorifera, has anti-tumor effects. The MAPK, STAT3, and NF-κB signaling pathways are closely related to the pathogenesis of lung cancer. To investigate the effect of daphnetin on anti-lung adenocarcinoma A549 cells and its mechanism. The anti-tumor effects of daphnetin on the proliferation, clone formation, migration, and invasion of A549 lung adenocarcinoma cells were investigated. The results showed that daphnetin inhibited the proliferation, colony formation, migration, and invasion of A549 cells through the MAPK/STAT3/NF-KB pathway, and mainly inhibited the clonal formation and migration of A549 cells through the JNK pathway. These results provide a new research direction and theoretical basis for the use of daphnetin in the inhibition of lung adenocarcinoma.
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Affiliation(s)
- Zhe Lv
- Department of Clinical Laboratory, Jiangxi Provincial People’s Hospital & The first Affiliated Hospital of Nanchang Medical College, Nanchang, China
| | - Yuna Du
- Department of Clinical Laboratory, Jiangxi Provincial People’s Hospital & The first Affiliated Hospital of Nanchang Medical College, Nanchang, China
| | - Huiqing Zhang
- Department of Clinical Laboratory, Jiangxi Provincial People’s Hospital & The first Affiliated Hospital of Nanchang Medical College, Nanchang, China
| | - Hui Fang
- Department of Clinical Laboratory, Jiangxi Provincial People’s Hospital & The first Affiliated Hospital of Nanchang Medical College, Nanchang, China
| | - Yujie Guo
- Department of Clinical Laboratory, Jiangxi Provincial People’s Hospital & The first Affiliated Hospital of Nanchang Medical College, Nanchang, China
| | - Lifeng Zeng
- Department of Clinical Laboratory, Jiangxi Provincial People’s Hospital & The first Affiliated Hospital of Nanchang Medical College, Nanchang, China
| | - Yiguo Chen
- Department of Clinical Laboratory, Jiangxi Provincial People’s Hospital & The first Affiliated Hospital of Nanchang Medical College, Nanchang, China
| | - Dan Li
- Department of Clinical Laboratory, Jiangxi Provincial People’s Hospital & The first Affiliated Hospital of Nanchang Medical College, Nanchang, China
| | - Rong Li
- Department of Clinical Laboratory, Jiangxi Provincial People’s Hospital & The first Affiliated Hospital of Nanchang Medical College, Nanchang, China
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Şeker Karatoprak G, Dumlupınar B, Celep E, Kurt Celep I, Küpeli Akkol E, Sobarzo-Sánchez E. A comprehensive review on the potential of coumarin and related derivatives as multi-target therapeutic agents in the management of gynecological cancers. Front Pharmacol 2024; 15:1423480. [PMID: 39364049 PMCID: PMC11447453 DOI: 10.3389/fphar.2024.1423480] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Accepted: 08/16/2024] [Indexed: 10/05/2024] Open
Abstract
Current treatments for gynecological cancers include surgery, radiotherapy, and chemotherapy. However, these treatments often have significant side effects. Phytochemicals, natural compounds derived from plants, offer promising anticancer properties. Coumarins, a class of benzopyrone compounds found in various plants like tonka beans, exhibit notable antitumor effects. These compounds induce cell apoptosis, target PI3K/Akt/mTOR signaling pathways, inhibit carbonic anhydrase, and disrupt microtubules. Additionally, they inhibit tumor multidrug resistance and angiogenesis and regulate reactive oxygen species. Specific coumarin derivatives, such as auraptene, praeruptorin, osthole, and scopoletin, show anti-invasive, anti-migratory, and antiproliferative activities by arresting the cell cycle and inducing apoptosis. They also inhibit metalloproteinases-2 and -9, reducing tumor cell migration, invasion, and metastasis. These compounds can sensitize tumor cells to radiotherapy and chemotherapy. Synthetic coumarin derivatives also demonstrate potent antitumor and anticancer activities with minimal side effects. Given their diverse mechanisms of action and minimal side effects, coumarin-class phytochemicals hold significant potential as therapeutic agents in gynecological cancers, potentially improving treatment outcomes and reducing side effects. This review will aid in the synthesis and development of novel coumarin-based drugs for these cancers.
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Affiliation(s)
| | - Berrak Dumlupınar
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Istanbul Okan University, İstanbul, Türkiye
| | - Engin Celep
- Department of Pharmacognosy, Faculty of Pharmacy, Acıbadem Mehmet Ali Aydinlar University, Atasehir, Istanbul, Türkiye
| | - Inci Kurt Celep
- Department of Biotechnology, Faculty of Pharmacy, Istanbul Okan University, Istanbul, Türkiye
| | - Esra Küpeli Akkol
- Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, Ankara, Türkiye
| | - Eduardo Sobarzo-Sánchez
- Instituto de Investigación y Postgrado Facultad de Ciencias de la Salud Universidad Central de Chile, Santiago, Chile
- Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, Santiago de Compostela, Spain
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10
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Ma N, Zhang M, Hu J, Wei Z, Zhang S. Daphnetin induces ferroptosis in ovarian cancer by inhibiting NAD(P)H:Quinone oxidoreductase 1 (NQO1). PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 132:155876. [PMID: 39032284 DOI: 10.1016/j.phymed.2024.155876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Revised: 06/05/2024] [Accepted: 07/11/2024] [Indexed: 07/23/2024]
Abstract
BACKGROUND Ferroptosis, an emerging nonapoptotic, modulated cell death process characterized by iron accumulation and subsequent lipid peroxidation, has been intimately implicated in the development and progression of ovarian cancer (OC). Daphnetin (Daph), a natural product isolated from Daphne Korean Nakai, exhibits anticancer efficacy against various solid tumors. However, the specific role and potential mechanism underlying Daph-mediated modulation of ferroptosis in OC cells remain elusive. PURPOSE This study aims to analyze the proferroptotic impacts of Daph on OC cells and to further explore the underlying mechanisms involved. STUDY DESIGN AND METHODS We used CCK-8, wound healing and Transwell assays to assess whether Daph can inhibit the proliferation and migration of OC cells. Additionally, transmission electron microscopy (TEM), iron measurement, reactive oxygen species (ROS) analysis, lipid peroxidation assays, qRT-PCR and western blotting were utilized to evaluate the impact of Daph on ferroptosis and elucidate the potential underlying mechanism. Furthermore, RNA sequencing analysis, molecular docking analysis, cellular thermal shift assays (CETSAs) and NQO1 activity assays were used to predict and validate the binding and mechanistic interactions between Daph and NQO1. Subcutaneous tumorigenesis models were utilized to examine the effectiveness of Daph (and/or cisplatin) in vivo. RESULTS Daph exerted antitumor effects by inducing the death and suppressing the migration of A2780 and SKOV3 cells. Further, Daph induced ferroptosis in OC cells, as evidenced by the accumulation of intracellular ferrous iron (Fe2+), ROS and lipid peroxides, as well as the decreases in the glutathione/oxidized glutathione disulfide (GSH/GSSG) ratio and the expression of ferroptosis indicators (SLC7A11 and GPX4). RNA sequencing and molecular docking analyses revealed that the direct interaction between NQO1 and Daph reduced both the activity and expression of NQO1. Importantly, NQO1 overexpression effectively alleviated the effects of Daph on proliferation, migration, and ferroptosis in vitro and in vivo. Interestingly, we also found that combination treatment with Daph, a negative regulator of NQO1, and cisplatin synergistically induced cytotoxicity in OC cells. CONCLUSION Our findings are the firstly demonstrated that Daph acts as a novel ferroptosis inducer in OC cells by specifically targeting NQO1 and is thus a promising candidate agent for OC treatment.
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Affiliation(s)
- Ning Ma
- Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, China; Jilin Provincial Key Laboratory of Women's Reproductive Health, Changchun, China
| | - Mengwen Zhang
- Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, China; Jilin Provincial Key Laboratory of Women's Reproductive Health, Changchun, China
| | - Jianqiang Hu
- Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, China
| | - Zhentong Wei
- Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, China; Jilin Provincial Key Laboratory of Women's Reproductive Health, Changchun, China.
| | - Songling Zhang
- Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, China; Jilin Provincial Key Laboratory of Women's Reproductive Health, Changchun, China.
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11
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An X, Yu W, Liu J, Tang D, Yang L, Chen X. Oxidative cell death in cancer: mechanisms and therapeutic opportunities. Cell Death Dis 2024; 15:556. [PMID: 39090114 PMCID: PMC11294602 DOI: 10.1038/s41419-024-06939-5] [Citation(s) in RCA: 69] [Impact Index Per Article: 69.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 07/19/2024] [Accepted: 07/22/2024] [Indexed: 08/04/2024]
Abstract
Reactive oxygen species (ROS) are highly reactive oxygen-containing molecules generated as natural byproducts during cellular processes, including metabolism. Under normal conditions, ROS play crucial roles in diverse cellular functions, including cell signaling and immune responses. However, a disturbance in the balance between ROS production and cellular antioxidant defenses can lead to an excessive ROS buildup, causing oxidative stress. This stress damages essential cellular components, including lipids, proteins, and DNA, potentially culminating in oxidative cell death. This form of cell death can take various forms, such as ferroptosis, apoptosis, necroptosis, pyroptosis, paraptosis, parthanatos, and oxeiptosis, each displaying distinct genetic, biochemical, and signaling characteristics. The investigation of oxidative cell death holds promise for the development of pharmacological agents that are used to prevent tumorigenesis or treat established cancer. Specifically, targeting key antioxidant proteins, such as SLC7A11, GCLC, GPX4, TXN, and TXNRD, represents an emerging approach for inducing oxidative cell death in cancer cells. This review provides a comprehensive summary of recent progress, opportunities, and challenges in targeting oxidative cell death for cancer therapy.
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Affiliation(s)
- Xiaoqin An
- Department of Physiology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, PR China
- Provincial Key Laboratory of Medical Molecular Biology, Guizhou Medical University, Guiyang, Guizhou, PR China
- Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, PR China
| | - Wenfeng Yu
- Provincial Key Laboratory of Medical Molecular Biology, Guizhou Medical University, Guiyang, Guizhou, PR China
| | - Jinbao Liu
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, PR China
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.
| | - Li Yang
- Department of Physiology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, PR China.
| | - Xin Chen
- Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, PR China.
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, PR China.
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12
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Gou F, Cai F, Li X, Lin Q, Zhu J, Yu M, Chen S, Lu J, Hu C. Mitochondria-associated endoplasmic reticulum membranes involve in oxidative stress-induced intestinal barrier injury and mitochondrial dysfunction under diquat exposing. ENVIRONMENTAL TOXICOLOGY 2024; 39:3906-3919. [PMID: 38567716 DOI: 10.1002/tox.24232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 01/04/2024] [Accepted: 02/18/2024] [Indexed: 06/12/2024]
Abstract
Many factors induced by environmental toxicants have made oxidative stress a risk factor for the intestinal barrier injury and growth restriction, which is serious health threat for human and livestock and induces significant economic loss. It is well-known that diquat-induced oxidative stress is implicated in the intestinal barrier injury. Although some studies have shown that mitochondria are the primary target organelle of diquat, the underlying mechanism remains incompletely understood. Recently, mitochondria-associated endoplasmic reticulum membranes (MAMs) have aroused increasing concerns among scholars, which participate in mitochondrial dynamics and signal transduction. In this study, we investigated whether MAMs involved in intestinal barrier injury and mitochondrial dysfunction induced by diquat-induced oxidative stress in piglets and porcine intestinal epithelial cells (IPEC-J2 cells). The results showed that diquat induced growth restriction and impaired intestinal barrier. The mitochondrial reactive oxygen species (ROS) was increased and mitochondrial membrane potential was decreased following diquat exposure. The ultrastructure of mitochondria and MAMs was also disturbed. Meanwhile, diquat upregulated endoplasmic reticulum stress marker protein and activated PERK pathway. Furthermore, loosening MAMs alleviated intestinal barrier injury, decrease of antioxidant enzyme activity and mitochondrial dysfunction induced by diquat in IPEC-J2 cells, while tightening MAMs exacerbated diquat-induced mitochondrial dysfunction. These results suggested that MAMs may be associated with the intestinal barrier injury and mitochondrial dysfunction induced by diquat in the jejunum of piglets.
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Affiliation(s)
- Feiyang Gou
- College of Animal Sciences, Zhejiang University, Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou, China
| | - Fengzhou Cai
- College of Animal Sciences, Zhejiang University, Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou, China
| | - Xin Li
- College of Animal Sciences, Zhejiang University, Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou, China
| | - Qian Lin
- College of Animal Sciences, Zhejiang University, Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou, China
| | - Jiang Zhu
- College of Animal Sciences, Zhejiang University, Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou, China
| | - Minjie Yu
- College of Animal Sciences, Zhejiang University, Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou, China
| | - Shaokui Chen
- School of Animal Science and Nutritional Engineering, Wuhan Polytechnic University, Wuhan, China
| | - Jianjun Lu
- College of Animal Sciences, Zhejiang University, Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou, China
| | - Caihong Hu
- College of Animal Sciences, Zhejiang University, Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou, China
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Wei Z, Wei N, Su L, Gao S. The molecular effects underlying the pharmacological activities of daphnetin. Front Pharmacol 2024; 15:1407010. [PMID: 39011506 PMCID: PMC11246999 DOI: 10.3389/fphar.2024.1407010] [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: 03/26/2024] [Accepted: 06/13/2024] [Indexed: 07/17/2024] Open
Abstract
As an increasingly well-known derivative of coumarin, daphnetin (7,8-dithydroxycoumarin) has demonstrated various pharmacological activities, including anti-inflammation, anti-cancer, anti-autoimmune diseases, antibacterial, organ protection, and neuroprotection properties. Various studies have been conducted to explore the action mechanisms and synthetic methods of daphnetin, given its therapeutic potential in clinical. Despite these initial insights, the precise mechanisms underlying the pharmacological activities of daphnetin remain largely unknown. In order to address this knowledge gap, we explore the molecular effects from the perspectives of signaling pathways, NOD-like receptor protein 3 (NLRP3) inflammasome and inflammatory factors; and try to find out how these mechanisms can be utilized to inform new combined therapeutic strategies.
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Affiliation(s)
- Zhifeng Wei
- Department of Hematology, The First Hospital of Jilin University, Changchun, China
| | - Na Wei
- Department of Obstetrics, The Affiliated Taian City Central Hospital of Qingdao University, Taian, China
| | - Long Su
- Department of Hematology, The First Hospital of Jilin University, Changchun, China
| | - Sujun Gao
- Department of Hematology, The First Hospital of Jilin University, Changchun, China
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14
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Rahmani R, Eivazi N, Emamgholipour S, Aminian M, Jalilian A, Paknejad M. The obeticholic acid can positively regulate the cancerous behavior of MCF7 breast cancer cell line. Mol Biol Rep 2024; 51:250. [PMID: 38302816 DOI: 10.1007/s11033-023-09106-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Accepted: 12/05/2023] [Indexed: 02/03/2024]
Abstract
BACKGROUND The diagnosis and treatment processes of cancer are among the main challenges of medical science in recent decades. The use of different therapeutic agents is one of the most common methods frequently utilized for cancer treatment. Accumulating evidence points to a potential effect of Obeticholic acid (OCA), a specific ligand for farnesoid X receptor, on the regulation of cancer-associated pathways. In spite of tremendous efforts to introduce OCA into the clinical setting, there is a great deal of uncertainty about its impact on breast cancer treatment. This study was performed to evaluate the effects of OCA on breast cancer. METHODS AND RESULTS In this experiment, the MCF-7 (Michigan Cancer Foundation-7) cell line was treated with 0.1 µM OCA, and cancerous characteristics of the MCF-7 cell line was evaluated by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2 H-tetrazolium bromide) assay, gelatin zymography, western blot, Real-time PCR, flow cytometry, and ELISA techniques. The results indicated that OCA increased the rate of apoptosis and the expression levels of PPARα (Peroxisome proliferator-activated receptor alpha) and TIMP-1 (tissue inhibitor of metalloproteinase-1) genes in this cell line, while it reduced the mRNA levels of MMP7 (matrix metalloproteinase 7) and Bcl-2 (B-cell lymphoma 2) genes, as well as the protein levels of the active form of AKT (protein kinase B), Erk1/2 (extracellular signal-regulated kinase 1/2) and STAT3 (Signal transducers and activators of transcription-3). Also, OCA decreased the activity of MMP9, while it increased the secretion of VEGF-A (vascular endothelial growth factor-A). CONCLUSIONS It seems that OCA can exert anti-cancer effects on the MCF-7 cells by reducing growth, proliferation, migration, invasion, and regulation of the expression of genes involved in cancer-associated pathways. However, it should be noted that further studies are warranted to establish this concept, especially the increase of VEGF-A can be considered a challenge for the results of this study.
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Affiliation(s)
- Reza Rahmani
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of medical sciences, Tehran, Iran
| | - Neda Eivazi
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of medical sciences, Tehran, Iran
| | - Solaleh Emamgholipour
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of medical sciences, Tehran, Iran
- Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahdi Aminian
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of medical sciences, Tehran, Iran
| | - Ali Jalilian
- Department of plant secondary metabolites, Agricultural Biotechnology Research Institute of Iran-Isfahan Branch, Agricultural Research, Education and Extension Organization (AREEO), Isfahan, Iran
| | - Maliheh Paknejad
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of medical sciences, Tehran, Iran.
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Zhang H, Liu Y, Liu J, Chen J, Wang J, Hua H, Jiang Y. cAMP-PKA/EPAC signaling and cancer: the interplay in tumor microenvironment. J Hematol Oncol 2024; 17:5. [PMID: 38233872 PMCID: PMC10792844 DOI: 10.1186/s13045-024-01524-x] [Citation(s) in RCA: 34] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 01/02/2024] [Indexed: 01/19/2024] Open
Abstract
Cancer is a complex disease resulting from abnormal cell growth that is induced by a number of genetic and environmental factors. The tumor microenvironment (TME), which involves extracellular matrix, cancer-associated fibroblasts (CAF), tumor-infiltrating immune cells and angiogenesis, plays a critical role in tumor progression. Cyclic adenosine monophosphate (cAMP) is a second messenger that has pleiotropic effects on the TME. The downstream effectors of cAMP include cAMP-dependent protein kinase (PKA), exchange protein activated by cAMP (EPAC) and ion channels. While cAMP can activate PKA or EPAC and promote cancer cell growth, it can also inhibit cell proliferation and survival in context- and cancer type-dependent manner. Tumor-associated stromal cells, such as CAF and immune cells, can release cytokines and growth factors that either stimulate or inhibit cAMP production within the TME. Recent studies have shown that targeting cAMP signaling in the TME has therapeutic benefits in cancer. Small-molecule agents that inhibit adenylate cyclase and PKA have been shown to inhibit tumor growth. In addition, cAMP-elevating agents, such as forskolin, can not only induce cancer cell death, but also directly inhibit cell proliferation in some cancer types. In this review, we summarize current understanding of cAMP signaling in cancer biology and immunology and discuss the basis for its context-dependent dual role in oncogenesis. Understanding the precise mechanisms by which cAMP and the TME interact in cancer will be critical for the development of effective therapies. Future studies aimed at investigating the cAMP-cancer axis and its regulation in the TME may provide new insights into the underlying mechanisms of tumorigenesis and lead to the development of novel therapeutic strategies.
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Affiliation(s)
- Hongying Zhang
- Cancer Center, Laboratory of Oncogene, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yongliang Liu
- Cancer Center, Laboratory of Oncogene, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jieya Liu
- Cancer Center, Laboratory of Oncogene, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jinzhu Chen
- Cancer Center, Laboratory of Oncogene, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jiao Wang
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Hui Hua
- Laboratory of Stem Cell Biology, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Yangfu Jiang
- Cancer Center, Laboratory of Oncogene, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Hu X, Huang S, Ye S, Jiang J. The Natural Product Oridonin as an Anticancer Agent: Current Achievements and Problems. Curr Pharm Biotechnol 2024; 25:655-664. [PMID: 37605407 DOI: 10.2174/1389201024666230821110116] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 07/09/2023] [Accepted: 07/24/2023] [Indexed: 08/23/2023]
Abstract
Oridonin, an active diterpenoid isolated from traditional Chinese herbal medicine, has received a rising attention for its remarkable roles in cancer therapy. In recent years, increasing evidences have revealed that oridonin inhibits the occurrence and development of tumor cells through multiple mechanisms, including induction of apoptosis and autophagy, cell cycle arrest, and inhibition of angiogenesis as well as migration and invasion. In addition, several molecular signal targets have been identified, including ROS, EGFR, NF-κB, PI3K/Akt, and MAPK. In this paper, we review considerable knowledge about the molecular mechanisms and signal targets of oridonin, which has been studied in recent years. It is expected that oridonin may be developed as a novel anti-tumor herbal medicine in human cancer treatment.
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Affiliation(s)
- Xiangyan Hu
- Institute of Pharmacy and Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, P.R. China
| | - Sisi Huang
- Institute of Pharmacy and Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, P.R. China
- NHC Key Lab of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), Pharmacy School of Fudan University, Shanghai, 200032, P.R. China
| | - Shiying Ye
- Institute of Pharmacy and Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, P.R. China
| | - Jinhuan Jiang
- Institute of Pharmacy and Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, P.R. China
- Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, P.R. China
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Yuan W, Fang W, Zhang R, Lyu H, Xiao S, Guo D, Ali DW, Michalak M, Chen XZ, Zhou C, Tang J. Therapeutic strategies targeting AMPK-dependent autophagy in cancer cells. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2023; 1870:119537. [PMID: 37463638 DOI: 10.1016/j.bbamcr.2023.119537] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Revised: 07/04/2023] [Accepted: 07/07/2023] [Indexed: 07/20/2023]
Abstract
Macroautophagy is a health-modifying process of engulfing misfolded or aggregated proteins or damaged organelles, coating these proteins or organelles into vesicles, fusion of vesicles with lysosomes to form autophagic lysosomes, and degradation of the encapsulated contents. It is also a self-rescue strategy in response to harsh environments and plays an essential role in cancer cells. AMP-activated protein kinase (AMPK) is the central pathway that regulates autophagy initiation and autophagosome formation by phosphorylating targets such as mTORC1 and unc-51 like activating kinase 1 (ULK1). AMPK is an evolutionarily conserved serine/threonine protein kinase that acts as an energy sensor in cells and regulates various metabolic processes, including those involved in cancer. The regulatory network of AMPK is complicated and can be regulated by multiple upstream factors, such as LKB1, AKT, PPAR, SIRT1, or noncoding RNAs. Currently, AMPK is being investigated as a novel target for anticancer therapies based on its role in macroautophagy regulation. Herein, we review the effects of AMPK-dependent autophagy on tumor cell survival and treatment strategies targeting AMPK.
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Affiliation(s)
- Wenbin Yuan
- Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei Key Laboratory of Industrial Microbiology, National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan, China
| | - Wanyi Fang
- Membrane Protein Disease Research Group, Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Rui Zhang
- Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei Key Laboratory of Industrial Microbiology, National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan, China
| | - Hao Lyu
- Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei Key Laboratory of Industrial Microbiology, National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan, China
| | - Shuai Xiao
- Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei Key Laboratory of Industrial Microbiology, National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan, China
| | - Dong Guo
- Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei Key Laboratory of Industrial Microbiology, National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan, China
| | - Declan William Ali
- Department of Biological Sciences, University of Alberta, Edmonton, Alberta, Canada
| | - Marek Michalak
- Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
| | - Xing-Zhen Chen
- Membrane Protein Disease Research Group, Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Cefan Zhou
- Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei Key Laboratory of Industrial Microbiology, National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan, China.
| | - Jingfeng Tang
- Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei Key Laboratory of Industrial Microbiology, National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan, China.
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Wang H, Liu Y, Wang Y, Xu T, Xia G, Huang X. Umbelliprenin induces autophagy and apoptosis while inhibits cancer cell stemness in pancreatic cancer cells. Cancer Med 2023; 12:15277-15288. [PMID: 37409635 PMCID: PMC10417289 DOI: 10.1002/cam4.6170] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 05/12/2023] [Accepted: 05/19/2023] [Indexed: 07/07/2023] Open
Abstract
BACKGROUND Umbelliprenin is a sesquiterpene coumarin isolated from Artemisia absinthium L. and shows antitumor effects in various cancers by inducing apoptosis. However, the antitumor effect of umbelliprenin in human pancreatic cancer has not been clarified. METHODS The antitumor effects were determined by MTT and AnnexinV/PI double staining assay in vitro and xenograft mice in vivo. Autophagy was determined via immunofluorescence analysis. Apoptotic or autophagic related proteins were measured by immunoblotting. The pancreatic cancer cell stemness were determined by mammosphere formation and ALDEFLUOR assay. RESULTS It revealed that umbelliprenin inhibited pancreatic cancer cell proliferation in vitro and pancreatic cancer tumor growth in vivo. Moreover, umbelliprenin induced pancreatic cancer cell BxPC3 apoptosis and autophagy as evidenced by upregulated apoptosis and autophagy- related protein expression (p < 0.01). Blocking autophagy by 3-MA or Atg7 knockout enhanced umbelliprenin-induced apoptosis (p < 0.05). Umbelliprenin also reduced pancreatic cancer cell stemness by reducing Oct4, Nanog, and Sox2 mRNA levels (p < 0.01). Mechanistically, umbelliprenin greatly inhibited Akt/mTOR and Notch1 signal pathway. CONCLUSION Umbelliprenin may be a novel therapeutic approach for pancreatic cancer treatment.
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Affiliation(s)
- Hongcheng Wang
- Department of Hepatobiliary and Pancreatic SurgerySixth People's Hospital Affiliated Shanghai Jiao Tong UniversityShanghaiChina
- Department of General SurgeryThe Second People’ Hospital of Kashgar, 1SKashgarXinjiangChina
| | - Yongzhi Liu
- Affiliated Xiaoshan Hospital Hangzhou Normal UniversityZhejiangChina
| | - Yiwei Wang
- Department of Hepatobiliary and Pancreatic SurgerySixth People's Hospital Affiliated Shanghai Jiao Tong UniversityShanghaiChina
| | - Ting Xu
- Department of Hepatobiliary and Pancreatic SurgerySixth People's Hospital Affiliated Shanghai Jiao Tong UniversityShanghaiChina
| | - Guanggai Xia
- Department of Hepatobiliary and Pancreatic SurgerySixth People's Hospital Affiliated Shanghai Jiao Tong UniversityShanghaiChina
| | - Xinyu Huang
- Department of Hepatobiliary and Pancreatic SurgerySixth People's Hospital Affiliated Shanghai Jiao Tong UniversityShanghaiChina
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Wróblewska-Łuczka P, Góralczyk A, Łuszczki JJ. Daphnetin, a Coumarin with Anticancer Potential against Human Melanoma: In Vitro Study of Its Effective Combination with Selected Cytostatic Drugs. Cells 2023; 12:1593. [PMID: 37371063 DOI: 10.3390/cells12121593] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 05/30/2023] [Accepted: 06/07/2023] [Indexed: 06/29/2023] Open
Abstract
(1) The treatment of metastatic or drug-resistant melanoma is still a significant therapeutic problem. The aim of this study was to evaluate the anticancer potential of daphnetin (7,8-dihydroxycoumarin) and its combinations with five different cytostatic drugs (mitoxantrone, docetaxel, vemurafenib, epirubicin and cisplatin). (2) The viability, proliferation and cytotoxicity of daphnetin against four human malignant melanoma cell lines were evaluated. The interactions were assessed using isobolographic analysis for the combinations of daphnetin with each of the five cytostatic drugs. (3) Daphnetin showed anticancer activity against malignant melanoma, with IC50 values ranging from 40.48 ± 10.90 µM to 183.97 ± 18.82 µM, depending on the cell line. The combination of daphnetin with either vemurafenib or epirubicin showed an antagonistic interaction. Moreover, additive interactions were observed for the combinations of daphnetin with cisplatin and docetaxel. The most desirable synergistic interactions for human melanoma metastatic cell lines were observed for the combination of daphnetin with mitoxantrone. (4) The obtained results suggest that daphnetin should not be combined with vemurafenib or epirubicin in the treatment of malignant melanoma due to the abolition of their anticancer effects. The combination of daphnetin with mitoxantrone is beneficial in the treatment of metastatic melanoma due to their synergistic interaction.
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Affiliation(s)
- Paula Wróblewska-Łuczka
- Department of Occupational Medicine, Medical University of Lublin, ul. Jaczewskiego 8b, 20-090 Lublin, Poland
| | - Agnieszka Góralczyk
- Department of Occupational Medicine, Medical University of Lublin, ul. Jaczewskiego 8b, 20-090 Lublin, Poland
| | - Jarogniew J Łuszczki
- Department of Occupational Medicine, Medical University of Lublin, ul. Jaczewskiego 8b, 20-090 Lublin, Poland
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20
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Zhu Y, Wang S, Niu P, Chen H, Zhou J, Jiang L, Li D, Shi D. Raptor couples mTORC1 and ERK1/2 inhibition by cardamonin with oxidative stress induction in ovarian cancer cells. PeerJ 2023; 11:e15498. [PMID: 37304865 PMCID: PMC10257395 DOI: 10.7717/peerj.15498] [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: 02/02/2023] [Accepted: 05/12/2023] [Indexed: 06/13/2023] Open
Abstract
Background A balance on nutrient supply and redox homeostasis is required for cell survival, and increased antioxidant capacity of cancer cells may lead to chemotherapy failure. Objective To investigate the mechanism of anti-proliferation of cardamonin by inducing oxidative stress in ovarian cancer cells. Methods After 24 h of drug treatment, CCK8 kit and wound healing test were used to detect cell viability and migration ability, respectively, and the ROS levels were detected by flow cytometry. The differential protein expression after cardamonin administration was analyzed by proteomics, and the protein level was detected by Western blotting. Results Cardamonin inhibited the cell growth, which was related to ROS accumulation. Proteomic analysis suggested that MAPK pathway might be involved in cardamonin-induced oxidative stress. Western blotting showed that cardamonin decreased Raptor expression and the activity of mTORC1 and ERK1/2. Same results were observed in Raptor KO cells. Notably, in Raptor KO cells, the effect of cardamonin was weakened. Conclusion Raptor mediated the function of cardamonin on cellular redox homeostasis and cell proliferation through mTORC1 and ERK1/2 pathways.
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Abstract
Autophagy is a self-digestion process by which misfolded proteins and damaged organelles in eukaryotic cells are degraded to maintain cellular homeostasis. This process is involved in the tumorigenesis, metastasis, and chemoresistance of various tumors such as ovarian cancer (OC). Noncoding RNAs (ncRNAs), mainly including microRNAs, long noncoding RNAs, and circular RNAs, have been extensively investigated in cancer research for their roles in the regulation of autophagy. Recent studies have shown that in OC cells, ncRNAs can modulate the formation of autophagosomes, which affect tumor progression and chemoresistance. An understanding of the role of autophagy in OC progression, treatment, and prognosis is important, and the identification of the regulatory roles of ncRNAs in autophagy leads to intervention strategies for OC therapy. This review summarizes the role of autophagy in OC and discusses the role of ncRNA-mediated autophagy in OC, as an understanding of these roles may contribute to the development of potential therapeutic strategies for this disease.
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Affiliation(s)
- Cong Feng
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin 150040, P.R. China
- Heilongjiang University of Chinese Medicine, Harbin 150040, P.R. China
| | - Xingxing Yuan
- Heilongjiang University of Chinese Medicine, Harbin 150040, P.R. China
- Department of Gastroenterology, Heilongjiang Academy of Traditional Chinese Medicine, Harbin 150001, P.R. China
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22
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Shao W, Wang X, Liu Z, Song X, Wang F, Liu X, Yu Z. Cyperotundone combined with adriamycin induces apoptosis in MCF-7 and MCF-7/ADR cancer cells by ROS generation and NRF2/ARE signaling pathway. Sci Rep 2023; 13:1384. [PMID: 36697441 PMCID: PMC9877033 DOI: 10.1038/s41598-022-26767-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 12/20/2022] [Indexed: 01/26/2023] Open
Abstract
Breast cancer has become the most prevalent cancer, globally. Adriamycin is a first-line chemotherapeutic agent, however, cancer cells acquire resistance to it, which is one of the most common causes of treatment failure. ROS and NRF2 are essential oxidative stress factors that play a key role in the oxidative stress process and are associated with cancer. Our goal is to create novel therapeutic drugs or chemical sensitizers that will improve chemotherapy sensitivity. The optimal concentration and duration for MCF-7 and MCF-7/ADR cells in ADR and CYT were determined using the CCK-8 assay. We found that ADR + CYT inhibited the activity of MCF-7 and MCF-7/ADR cells in breast cancer, as well as causing apoptosis in MCF-7 and MCF-7/ADR cells and blocking the cell cycle in the G0/G1 phase. ADR + CYT induces apoptosis in MCF-7 and MCF-7/ADR cells through ROS generation and the P62/NRF2/HO-1 signaling pathway. In breast cancer-bearing nude mice, ADR + CYT effectively suppressed tumor development in vivo. Overall, our findings showed that CYT in combination with ADR has potent anti-breast cancer cell activity both in vivo and in vitro, suggesting CYT as the main drug used to improve chemosensitivity.
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Affiliation(s)
- Wenna Shao
- First Clinical College, Shandong University of Traditional Chinese Medicine, Jinan, 250014, Shandong, People's Republic of China.,Breast Cancer CenterShandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Shandong First Medical University, Jinan, 250117, Shandong, People's Republic of China
| | - Xinzhao Wang
- Breast Cancer CenterShandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Shandong First Medical University, Jinan, 250117, Shandong, People's Republic of China.,RemeGen, Ltd, 58 Middle Beijing Road, Yantai Economic & Technological Development Area, Yantai, 264006, Shandong, People's Republic of China
| | - Zhaoyun Liu
- Breast Cancer CenterShandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Shandong First Medical University, Jinan, 250117, Shandong, People's Republic of China
| | - Xiang Song
- First Clinical College, Shandong University of Traditional Chinese Medicine, Jinan, 250014, Shandong, People's Republic of China.,Breast Cancer CenterShandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Shandong First Medical University, Jinan, 250117, Shandong, People's Republic of China
| | - Fukai Wang
- Breast Cancer CenterShandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Shandong First Medical University, Jinan, 250117, Shandong, People's Republic of China
| | - Xiaoyu Liu
- First Clinical College, Shandong University of Traditional Chinese Medicine, Jinan, 250014, Shandong, People's Republic of China.,Breast Cancer CenterShandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Shandong First Medical University, Jinan, 250117, Shandong, People's Republic of China
| | - Zhiyong Yu
- First Clinical College, Shandong University of Traditional Chinese Medicine, Jinan, 250014, Shandong, People's Republic of China. .,Breast Cancer CenterShandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Shandong First Medical University, Jinan, 250117, Shandong, People's Republic of China.
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23
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Dong L, He J, Luo L, Wang K. Targeting the Interplay of Autophagy and ROS for Cancer Therapy: An Updated Overview on Phytochemicals. Pharmaceuticals (Basel) 2023; 16:ph16010092. [PMID: 36678588 PMCID: PMC9865312 DOI: 10.3390/ph16010092] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/21/2022] [Accepted: 01/04/2023] [Indexed: 01/11/2023] Open
Abstract
Autophagy is an evolutionarily conserved self-degradation system that recycles cellular components and damaged organelles, which is critical for the maintenance of cellular homeostasis. Intracellular reactive oxygen species (ROS) are short-lived molecules containing unpaired electrons that are formed by the partial reduction of molecular oxygen. It is widely known that autophagy and ROS can regulate each other to influence the progression of cancer. Recently, due to the wide potent anti-cancer effects with minimal side effects, phytochemicals, especially those that can modulate ROS and autophagy, have attracted great interest of researchers. In this review, we afford an overview of the complex regulatory relationship between autophagy and ROS in cancer, with an emphasis on phytochemicals that regulate ROS and autophagy for cancer therapy. We also discuss the effects of ROS/autophagy inhibitors on the anti-cancer effects of phytochemicals, and the challenges associated with harnessing the regulation potential on ROS and autophagy of phytochemicals for cancer therapy.
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Affiliation(s)
- Lixia Dong
- West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu 610041, China
| | - Jingqiu He
- West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu 610041, China
| | - Li Luo
- Center for Reproductive Medicine, Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu 610041, China
- Correspondence: (L.L.); (K.W.)
| | - Kui Wang
- West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu 610041, China
- Correspondence: (L.L.); (K.W.)
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24
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Pharmacological Activities of Ginkgolic Acids in Relation to Autophagy. Pharmaceuticals (Basel) 2022; 15:ph15121469. [PMID: 36558920 PMCID: PMC9785683 DOI: 10.3390/ph15121469] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/14/2022] [Accepted: 11/23/2022] [Indexed: 11/29/2022] Open
Abstract
Plant-derived natural compounds are widely used as alternative medicine in healthcare throughout the world. Ginkgolic acids, the phenolic compounds isolated from the leaves and seeds of Ginkgo biloba, are among the chemicals that have been explored the most. Ginkgolic acids exhibit cytotoxic activity against a vast number of human cancers in various preclinical models in vitro and in vivo. Additionally, the pharmacological activities of ginkgolic acids are also involved in antidiabetic, anti-bacteria, anti-virus, anti-fibrosis, and reno/neuroprotection. Autophagy as a highly conserved self-cleaning process that plays a crucial role in maintaining cellular and tissue homeostasis and has been proven to serve as a protective mechanism in the pathogenesis of many diseases, including neurodegenerative diseases, cancer, and infectious diseases. In this review, we surveyed the pharmacological activities of the major three forms of ginkgolic acids (C13:0, C15:1, and C17:1) that are linked to autophagic activity and the mechanisms to which these compounds may participate. A growing body of studies in last decade suggests that ginkgolic acids may represent promising chemical compounds in future drug development and an alternative remedy in humans.
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25
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Qin YY, Feng S, Zhang XD, Peng B. Screening of traditional Chinese medicine monomers as ribonucleotide reductase M2 inhibitors for tumor treatment. World J Clin Cases 2022; 10:11299-11312. [PMID: 36387821 PMCID: PMC9649558 DOI: 10.12998/wjcc.v10.i31.11299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 09/14/2022] [Accepted: 09/29/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Ribonucleotide reductase (RR) is a key enzyme in tumor proliferation, especially its subunit-RRM2. Although there are multiple therapeutics for tumors, they all have certain limitations. Given their advantages, traditional Chinese medicine (TCM) monomers have become an important source of anti-tumor drugs. Therefore, screening and analysis of TCM monomers with RRM2 inhibition can provide a reference for further anti-tumor drug development.
AIM To screen and analyze potential anti-tumor TCM monomers with a good binding capacity to RRM2.
METHODS The Gene Expression Profiling Interactive Analysis database was used to analyze the level of RRM2 gene expression in normal and tumor tissues as well as RRM2's effect on the overall survival rate of tumor patients. TCM monomers that potentially act on RRM2 were screened via literature mining. Using AutoDock software, the screened monomers were docked with the RRM2 protein.
RESULTS The expression of RRM2 mRNA in multiple tumor tissues was significantly higher than that in normal tissues, and it was negatively correlated with the overall survival rate of patients with the majority of tumor types. Through literature mining, we discovered that berberine, ursolic acid, gambogic acid, cinobufagin, quercetin, daphnetin, and osalmide have inhibitory effects on RRM2. The results of molecular docking identified that the above TCM monomers have a strong binding capacity with RRM2 protein, which mainly interacted through hydrogen bonds and hydrophobic force. The main binding sites were Arg330, Tyr323, Ser263, and Met350.
CONCLUSION RRM2 is an important tumor therapeutic target. The TCM monomers screened have a good binding capacity with the RRM2 protein.
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Affiliation(s)
- Ya-Ya Qin
- Department of Neurology, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Song Feng
- School of Basic Medicine, North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Xiao-Dong Zhang
- Department of Neurology, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Bin Peng
- School of Basic Medicine, North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
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26
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Javed M, Saleem A, Xaveria A, Akhtar MF. Daphnetin: A bioactive natural coumarin with diverse therapeutic potentials. Front Pharmacol 2022; 13:993562. [PMID: 36249766 PMCID: PMC9556945 DOI: 10.3389/fphar.2022.993562] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Accepted: 09/09/2022] [Indexed: 11/24/2022] Open
Abstract
Daphnetin (DAP), a coumarin derivative extracted from Daphne species, is biologically active phytochemical with copious bioactivities including anti-inflammatory, anti-oxidant, neuroprotective, analgesic, anti-pyretic, anti-malarial, anti-bacterial, anti-arthritic, neuroprotective, hepatoprotective, nephroprotective, and anti-cancer activities. A wide range of studies have been conducted exploring the significance and therapeutic potential of DAP. This study reviewed various databases such as NCBI, PubMed, Web of Science, Scopus and Google Scholar for published research articles regarding the sources, synthesis, and various bioactivities of DAP using different key words, including but not limited to "pharmacological activities," "sources," "neuroprotective effect," "synthesis," "cancer," "anti-inflammatory effect" of "daphnetin." Furthermore, this review encompasses both in-vivo and in-vitro studies on DAP for treating various diseases. A comprehensive review of the literature revealed that the DAP had a promising pharmacological and safety profile, and could be employed as a pharmaceutical moiety to treat a variety of illnesses including microbial infections, cancer, arthritis, hepatic damage, inflammation and neurological anomalies. The current review intends to provide an in-depth focus on all pharmacological activities and therapeutic approaches for the pharmaceutical and biomedical researchers.
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Affiliation(s)
- Maira Javed
- Department of Pharmacology, Faculty of Pharmaceutical Sciences, Government College University Faisalabad, Faisalabad, Pakistan
| | - Ammara Saleem
- Department of Pharmacology, Faculty of Pharmaceutical Sciences, Government College University Faisalabad, Faisalabad, Pakistan
| | - Anne Xaveria
- Department of Pharmacology, Faculty of Pharmaceutical Sciences, Government College University Faisalabad, Faisalabad, Pakistan
| | - Muhammad Furqan Akhtar
- Riphah Institute of Pharmaceutical Sciences, Riphah International University, Lahore Campus, Lahore, Pakistan
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27
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Vitto VAM, Bianchin S, Zolondick AA, Pellielo G, Rimessi A, Chianese D, Yang H, Carbone M, Pinton P, Giorgi C, Patergnani S. Molecular Mechanisms of Autophagy in Cancer Development, Progression, and Therapy. Biomedicines 2022; 10:1596. [PMID: 35884904 PMCID: PMC9313210 DOI: 10.3390/biomedicines10071596] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 06/25/2022] [Accepted: 06/30/2022] [Indexed: 01/18/2023] Open
Abstract
Autophagy is an evolutionarily conserved and tightly regulated process that plays an important role in maintaining cellular homeostasis. It involves regulation of various genes that function to degrade unnecessary or dysfunctional cellular components, and to recycle metabolic substrates. Autophagy is modulated by many factors, such as nutritional status, energy level, hypoxic conditions, endoplasmic reticulum stress, hormonal stimulation and drugs, and these factors can regulate autophagy both upstream and downstream of the pathway. In cancer, autophagy acts as a double-edged sword depending on the tissue type and stage of tumorigenesis. On the one hand, autophagy promotes tumor progression in advanced stages by stimulating tumor growth. On the other hand, autophagy inhibits tumor development in the early stages by enhancing its tumor suppressor activity. Moreover, autophagy drives resistance to anticancer therapy, even though in some tumor types, its activation induces lethal effects on cancer cells. In this review, we summarize the biological mechanisms of autophagy and its dual role in cancer. In addition, we report the current understanding of autophagy in some cancer types with markedly high incidence and/or lethality, and the existing therapeutic strategies targeting autophagy for the treatment of cancer.
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Affiliation(s)
- Veronica Angela Maria Vitto
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy; (V.A.M.V.); (S.B.); (G.P.); (A.R.); (D.C.); (P.P.)
| | - Silvia Bianchin
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy; (V.A.M.V.); (S.B.); (G.P.); (A.R.); (D.C.); (P.P.)
| | - Alicia Ann Zolondick
- Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI 96816, USA; (A.A.Z.); (H.Y.); (M.C.)
- Department of Molecular Biosciences and Bioengineering, University of Hawai’i at Manoa, Honolulu, HI 96816, USA
| | - Giulia Pellielo
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy; (V.A.M.V.); (S.B.); (G.P.); (A.R.); (D.C.); (P.P.)
| | - Alessandro Rimessi
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy; (V.A.M.V.); (S.B.); (G.P.); (A.R.); (D.C.); (P.P.)
| | - Diego Chianese
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy; (V.A.M.V.); (S.B.); (G.P.); (A.R.); (D.C.); (P.P.)
| | - Haining Yang
- Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI 96816, USA; (A.A.Z.); (H.Y.); (M.C.)
| | - Michele Carbone
- Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI 96816, USA; (A.A.Z.); (H.Y.); (M.C.)
| | - Paolo Pinton
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy; (V.A.M.V.); (S.B.); (G.P.); (A.R.); (D.C.); (P.P.)
| | - Carlotta Giorgi
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy; (V.A.M.V.); (S.B.); (G.P.); (A.R.); (D.C.); (P.P.)
| | - Simone Patergnani
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy; (V.A.M.V.); (S.B.); (G.P.); (A.R.); (D.C.); (P.P.)
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Liu Y, Liu X, Wang H, Ding P, Wang C. Agrimonolide inhibits cancer progression and induces ferroptosis and apoptosis by targeting SCD1 in ovarian cancer cells. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 101:154102. [PMID: 35526323 DOI: 10.1016/j.phymed.2022.154102] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 03/17/2022] [Accepted: 04/14/2022] [Indexed: 06/14/2023]
Abstract
BACKGROUND Ovarian cancer is a gynaecological tumour has high incidence and mortality rates. Agrimonolide, isolated from Agrimonia pilosa Ledeb, has multiple biomedical activities, including anticancer activity. PURPOSE Here, we aimed to reveal the function of agrimonolide on ovarian cancer progression. METHODS MTT assay, colony-formation assay, flow cytometry, transwell assay, scratch test, western immunoblotting, reactive oxygen species (ROS) detection, and ferroptosis analysis were performed to reveal the role and underlying mechanisms of agrimonolide in ovarian cancer cell lines (A2780 and SKOV-3). The effects of agrimonolide on the SKOV-3 xenograft model were also studied. RESULTS Agrimonolide dose-dependently inhibited proliferation, migration, and invasion and promoted apoptosis in A2780 and SKOV-3 cells. Agrimonolide induced ferroptosis in tumour cells, evidenced by the increased levels of ROS, total iron, and Fe2+ and downregulation of ferroptosis indicators (SLC7A11 and GPX4). The SwissTargetPrediction and Comparative Toxicogenomics Database predicted SCD1 as a target protein for agrimonolide. Molecular Operating Environment software docked agrimonolide in the SCD1 protein, and the binding energy of interaction was -8.21 kcal/mol. The effects of agrimonolide on proliferation, invasion, and induction of apoptosis and ferroptosis were attenuated by SCD1 overexpression in A2780 and SKOV-3 cells. Additionally, agrimonolide attenuated the tumour growth of ovarian cancer in the SKOV-3 xenograft model and significantly downregulated SCD1 in tumour tissues. CONCLUSION Our study is the first to suggest that agrimonolide acts as a novel apoptosis- and ferroptosis-inducing agent in ovarian cancer cells by targeting SCD1. Agrimonolide may be a novel therapeutic agent for treating ovarian cancer.
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Affiliation(s)
- Ying Liu
- Department of Obstetrics and Gynecology, Yantai Zhifu Hospital, Yantai, Shandong, 266000, P.R. China
| | - Xiaobei Liu
- Department of Reproductive Genetics, Taian City Central Hospital, Taian, Shandong, 271000, P.R. China
| | - Hui Wang
- Department of Obstetrics, Taian City Central Hospital, Taian, Shandong, 271000, P.R. China
| | - Pingping Ding
- Department of Gynecology, Affiliated Hospital of Shandong University of traditional Chinese Medicine, Jinan, Shandong, 250011, P.R. China
| | - Changlin Wang
- Department of Gynecology, Taian City Central Hospital, Taian, Shandong, 271000, P.R. China.
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Chen J, Wei Z, Fu K, Duan Y, Zhang M, Li K, Guo T, Yin R. Non-apoptotic cell death in ovarian cancer: Treatment, resistance and prognosis. Biomed Pharmacother 2022; 150:112929. [PMID: 35429741 DOI: 10.1016/j.biopha.2022.112929] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 04/02/2022] [Accepted: 04/05/2022] [Indexed: 11/19/2022] Open
Abstract
Ovarian cancer is mostly diagnosed at an advanced stage due to the absence of effective screening methods and specific symptoms. Repeated chemotherapy resistance and recurrence before PARPi are used as maintenance therapies, lead to low survival rates and poor prognosis. Apoptotic cell death plays a crucial role in ovarian cancer, which is proved by current researches. With the ongoing development of targeted therapy, non-apoptotic cell death has shown substantial potential in tumor prevention and treatment, including autophagy, ferroptosis, necroptosis, immunogenic cell death, pyroptosis, alkaliptosis, and other modes of cell death. We systematically reviewed the research progress on the role of non-apoptotic cell death in the onset, development, and outcome of ovarian cancer. This review provides a more theoretical basis for exploring therapeutic targets, reversing drug resistance in refractory ovarian cancer, and establishing risk prediction models that help realize the clinical transformation of vital drugs.
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Affiliation(s)
- Jinghong Chen
- Department of Obstetrics and Gynaecology, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Zhichen Wei
- The Second Clinical Medical College, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Kaiyu Fu
- Department of Obstetrics and Gynaecology, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yuanqiong Duan
- Department of Obstetrics and Gynaecology, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Mengpei Zhang
- Department of Obstetrics and Gynaecology, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Kemin Li
- Department of Obstetrics and Gynaecology, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Tao Guo
- Department of Obstetrics and Gynaecology, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Rutie Yin
- Department of Obstetrics and Gynaecology, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China.
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Syed AM, Kundu S, Ram C, Kulhari U, Kumar A, Mugale MN, Mohapatra P, Murty US, Sahu BD. Up-regulation of Nrf2/HO-1 and inhibition of TGF-β1/Smad2/3 signaling axis by daphnetin alleviates transverse aortic constriction-induced cardiac remodeling in mice. Free Radic Biol Med 2022; 186:17-30. [PMID: 35513128 DOI: 10.1016/j.freeradbiomed.2022.04.019] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 04/20/2022] [Accepted: 04/28/2022] [Indexed: 12/12/2022]
Abstract
Oxidative damage and accumulation of extracellular matrix (ECM) components play a crucial role in the adverse outcome of cardiac hypertrophy. Evidence suggests that nuclear factor erythroid-derived factor 2 related factor 2 (Nrf2) can modulate oxidative damage and adverse myocardial remodeling. Daphnetin (Daph) is a coumarin obtained from the plant genus Daphne species that exerts anti-oxidative and anti-inflammatory properties. Herein, we investigated the roles of Daph in transverse aortic constriction (TAC)-induced cardiac hypertrophy and fibrosis in mice. TAC-induced alterations in cardiac hypertrophy markers, histopathological changes, and cardiac function were markedly ameliorated by oral administration of Daph in mice. We found that Daph significantly reduced the reactive oxygen species (ROS) generation, increased the nuclear translocation of Nrf2, and consequently, reinstated the protein levels of NAD(P)H quinone dehydrogenase1 (NQO1), heme oxygenase-1 (HO-1), and other antioxidants in the heart. Besides, Daph significantly inhibited the TAC-induced accumulation of ECM components, including α-smooth muscle actin (α-SMA), collagen I, collagen III, and fibronectin, and interfered with the TGF-β1/Smad2/3 signaling axis. Further studies revealed that TAC-induced terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive nuclei and the protein levels of Bax/Bcl2 ratio and cleaved caspase 3 were substantially decreased by Daph treatment. We further characterized the effect of Daph on angiotensin II (Ang-II)-stimulated H9c2 cardiomyoblast cells and observed that Daph markedly decreased the Ang-II induced increase in cell size, production of ROS, and proteins associated with apoptosis and fibrosis. Mechanistically, Daph alone treatment enhanced the protein levels of Nrf2, NQO1, and HO-1 in H9c2 cells. The inhibition of this axis by Si-Nrf2 transfection abolished the protective effect of Daph in H9c2 cells. Taken together, Daph effectively counteracted the TAC-induced cardiac hypertrophy and fibrosis by improving the Nrf2/HO-1 axis and inhibiting the TGF-β1/Smad2/3 signaling axis.
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Affiliation(s)
- Abu Mohammad Syed
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, Changsari, 781101, Assam, India
| | - Sourav Kundu
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, Changsari, 781101, Assam, India
| | - Chetan Ram
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, Changsari, 781101, Assam, India
| | - Uttam Kulhari
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, Changsari, 781101, Assam, India
| | - Akhilesh Kumar
- Toxicology & Experimental Medicine, CSIR- Central Drug Research Institute (CDRI), Lucknow, 226 031, India
| | - Madhav Nilakanth Mugale
- Toxicology & Experimental Medicine, CSIR- Central Drug Research Institute (CDRI), Lucknow, 226 031, India
| | - Purusottam Mohapatra
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, Changsari, 781101, Assam, India
| | - Upadhyayula Suryanarayana Murty
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, Changsari, 781101, Assam, India
| | - Bidya Dhar Sahu
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, Changsari, 781101, Assam, India.
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Sun Q, Zhen P, Li D, Liu X, Ding X, Liu H. Amentoflavone promotes ferroptosis by regulating reactive oxygen species (ROS) /5’AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) to inhibit the malignant progression of endometrial carcinoma cells. Bioengineered 2022; 13:13269-13279. [PMID: 35635082 PMCID: PMC9275900 DOI: 10.1080/21655979.2022.2079256] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
It was reported that amentoflavone (AF) had anti-tumor ability. Therefore, this study aimed to investigate the role of AF in endometrial cancer as well as to discuss its underlying mechanism. The viability, proliferation, and apoptosis of endometrial carcinoma cells (KLE) with AF administration were detected by methyl tetrazolium (MTT) assay, clone formation, and terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL) assays. Thiobarbituric acid reactive substance (TBARS) production and Fe2+ level in AF-treated KLE cells were detected by TBARS assay and Iron assay. The expressions of proliferation- apoptosis-, ferroptosis-, and 5'AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling-related proteins in AF-treated KLE cells were detected by western blot analysis. Reactive oxygen species (ROS) expression in AF-treated KLE cells was determined by ROS assay kit. N-acetyl cysteine (NAC), which is an inhibitor of ROS, was used to confirm whether AF exerted its effects on KLE cells through ROS/AMPK/mTOR signaling. As a result, AF inhibited the viability and proliferation of KLE cells but promoted apoptosis and ferroptosis. The expressions of ROS and AMPK were increased, while mTOR expression was decreased in AF-treated KLE cells. NAC reversed the effects of AF on biological behaviors of KLE cells by inactivating ROS/AMPK/mTOR signaling. In conclusion, AF promoted ferroptosis by activating ROS/AMPK/mTOR to inhibit the viability and proliferation and promoted the apoptosis and ferroptosis of KLE cells.
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Affiliation(s)
- Qi Sun
- Traditional Chinese Medicine (Mongolian Medicine) College, Chifeng University, Chifeng, Inner Mongolia, China
| | - Peng Zhen
- Department of Radiation Oncology, Chifeng Cancer Hospital, Chifeng, Inner Mongolia, China
| | - Dandan Li
- Rehabilitation Department, Chifeng Cancer Hospital, Chifeng, Inner Mongolia, China
| | - Xiaochen Liu
- Rehabilitation Department, Chifeng Cancer Hospital, Chifeng, Inner Mongolia, China
| | - Xinling Ding
- Department of Human Anatomy, Basic Medical College, Chifeng University, Chifeng, Inner Mongolia, China
| | - Huihui Liu
- Cancer Rehabilitation Department, Chifeng Cancer Hospital, Chifeng, Inner Mongolia, China
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Li L, Yu J, Cheng S, Peng Z, Ben-David Y, Luo H. Transcription factor Fli-1 as a new target for antitumor drug development. Int J Biol Macromol 2022; 209:1155-1168. [PMID: 35447268 DOI: 10.1016/j.ijbiomac.2022.04.076] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 04/01/2022] [Accepted: 04/11/2022] [Indexed: 02/07/2023]
Abstract
The transcription factor Friend leukemia virus integration 1 (Fli-1) belonging to the E26 Transformation-Specific (ETS) transcription factor family is not only expressed in normal cells such as hematopoietic stem cells and vascular endothelial cells, but also abnormally expressed in various malignant tumors including Ewing sarcoma, Merkel cell sarcoma, small cell lung carcinoma, benign or malignant hemangioma, squamous cell carcinoma, adenocarcinoma, bladder cancer, leukemia, and lymphoma. Fli-1 binds to the promoter or enhancer of the target genes and participates in a variety of physiological and pathological processes of tumor cells, including cell growth, proliferation, differentiation, and apoptosis. The expression of Fli-1 gene is related to the specific biological functions and characteristics of the tissue in which it is located. In tumor research, Fli-1 gene is used as a specific marker for the occurrence, metastasis, efficacy, and prognosis of tumors, thus, a potential new target for tumor diagnosis and treatment. These studies indicated that Fli-1 may be a specific candidate for antitumor drug development. Recent studies identified small molecules regulating Fli-1 thanks to our screened strategy of natural products and their derivatives. Therefore, in this review, the advanced research on Fli-1 as a target for antitumor drug development is analyzed in different cancers. The inhibitors and agonists of Fli-1 that regulate its expression are introduced and their clinical applications in the treatment of cancer, thus providing new therapeutic strategies.
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Affiliation(s)
- Lanlan Li
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, P.R. China; College of Pharmacy, Guizhou Medical University, Guiyang 550025, P.R. China
| | - Jia Yu
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, P.R. China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Science, Guiyang 550014, P.R. China
| | - Sha Cheng
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, P.R. China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Science, Guiyang 550014, P.R. China
| | - Zhilin Peng
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, P.R. China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Science, Guiyang 550014, P.R. China
| | - Yaacov Ben-David
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, P.R. China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Science, Guiyang 550014, P.R. China
| | - Heng Luo
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, P.R. China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Science, Guiyang 550014, P.R. China.
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Torquato HFV, Junior MTR, Lima CS, Júnior RTDA, Talhati F, Dias DA, Justo GZ, Ferreira AT, Pilli RA, Paredes-Gamero EJ. A canthin-6-one derivative induces cell death by apoptosis/necroptosis-like with DNA damage in acute myeloid cells. Biomed Pharmacother 2022; 145:112439. [PMID: 34808555 DOI: 10.1016/j.biopha.2021.112439] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 11/10/2021] [Accepted: 11/12/2021] [Indexed: 02/07/2023] Open
Abstract
Natural products have long been considered a relevant source of new antitumor agents. Despite advances in the treatment of younger patients with acute myeloid leukemia (AML), the prognosis of elderly patients remains poor, with a high frequency of relapse. The cytotoxicity of canthin-6-one alkaloids has been extensively studied in different cell types, including leukemic strains. Among the canthin-6-one analogs tested, 10-methoxycanthin-6-one (Mtx-C) showed the highest cytotoxicity in the malignant AML cells Kasumi-1 and KG-1. Thus, we evaluated the cytotoxicity and cell death mechanisms related to Mtx-C using the EC50 (80 µM for Kasumi-1 and 36 µM for KG-1) treatment for 24 h. Our results identify reactive oxygen species production, mitochondrial depolarization, annexin V-FITC/7-AAD double staining, caspase cleave and upregulation of mitochondria-dependent apoptosis proteins (Bax, Bim, Bik, Puma and phosphorylation of p53) for both cell lineages. However, downregulation of Bcl-2 and the simultaneous execution of the apoptotic and necroptotic programs associated with the phosphorylation of the proteins receptor-interacting serine/threonine-protein kinase 3 and mixed lineage kinase domain-like pseudokinase occurred only in Kasumi-1 cells. About the lasted events, Kasumi-1 cell death was inhibited by pharmacological agents such as Zvad-FMK and necrostatin-1. The underlying molecular mechanisms of Mtx-C still include participation in the DNA damage and stress-signaling pathways involving p38 and c-Jun N-terminal mitogen-activated protein kinases and interaction with DNA. Thus, Mtx-C represents a promising tool for the development of new antileukemic molecules.
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Affiliation(s)
- Heron F V Torquato
- Departamento de Bioquímica, Universidade Federal de São Paulo, R. Três de Maio 100, 04044-020 São Paulo, SP, Brazil; Faculdade de Farmácia, Centro Universitário Braz Cubas, 08773-380 Mogi das Cruzes, SP, Brazil; Faculdade de Ciências Farmacêuticas, Alimentos e Nutrição, Universidade Federal de Mato Grosso do Sul, 79070-900 Campo Grande, MS, Brazil
| | | | - Cauê Santos Lima
- Departamento de Bioquímica, Universidade Federal de São Paulo, R. Três de Maio 100, 04044-020 São Paulo, SP, Brazil
| | - Roberto Theodoro de Araujo Júnior
- Departamento de Bioquímica, Universidade Federal de São Paulo, R. Três de Maio 100, 04044-020 São Paulo, SP, Brazil; Faculdade de Farmácia, Centro Universitário Braz Cubas, 08773-380 Mogi das Cruzes, SP, Brazil
| | - Fernanda Talhati
- Faculdade de Farmácia, Centro Universitário Braz Cubas, 08773-380 Mogi das Cruzes, SP, Brazil
| | - Dhebora Albuquerque Dias
- Faculdade de Ciências Farmacêuticas, Alimentos e Nutrição, Universidade Federal de Mato Grosso do Sul, 79070-900 Campo Grande, MS, Brazil
| | - Giselle Zenker Justo
- Departamento de Bioquímica, Universidade Federal de São Paulo, R. Três de Maio 100, 04044-020 São Paulo, SP, Brazil
| | - Alice Teixeira Ferreira
- Departamento de Biofísica, Universidade Federal de São Paulo, R. Três de Maio 100, 04044-020 São Paulo, SP, Brazil
| | - Ronaldo Aloise Pilli
- Instituto de Química, Universidade Estadual de Campinas, 13084-971 Campinas, SP, Brazil
| | - Edgar J Paredes-Gamero
- Departamento de Bioquímica, Universidade Federal de São Paulo, R. Três de Maio 100, 04044-020 São Paulo, SP, Brazil; Faculdade de Ciências Farmacêuticas, Alimentos e Nutrição, Universidade Federal de Mato Grosso do Sul, 79070-900 Campo Grande, MS, Brazil.
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Yao B, Yang Q, Yang Y, Li Y, Peng H, Wu S, Wang L, Zhang S, Huang M, Wang E, Xiong P, Luo T, Li L, Jia S, Deng Y, Deng Y. Screening for Active Compounds Targeting Human Natural Killer Cell Activation Identifying Daphnetin as an Enhancer for IFN-γ Production and Direct Cytotoxicity. Front Immunol 2021; 12:680611. [PMID: 34956168 PMCID: PMC8693168 DOI: 10.3389/fimmu.2021.680611] [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] [Received: 03/15/2021] [Accepted: 11/02/2021] [Indexed: 12/02/2022] Open
Abstract
Natural killer (NK) cells are a potent weapon against tumor and viral infection. Finding active compounds with the capacity of enhancing NK cell effector functions will be effective to develop new anti-cancer drugs. In this study, we initially screened 287 commercially available active compounds by co-culturing with peripheral blood mononuclear cells (PBMCs). We found that five compounds, namely, Daphnetin, MK-8617, LW6, JIB-04, and IOX1, increased the IFN-γ+ NK cell ratio in the presence of IL-12. Further studies using purified human primary NK cells revealed that Daphnetin directly promoted NK cell IFN-γ production in the presence of IL-12 but not IL-15, while the other four compounds acted on NK cells indirectly. Daphnetin also improved the direct cytotoxicity of NK cells against tumor cells in the presence of IL-12. Through RNA-sequencing, we found that PI3K-Akt-mTOR signaling acted as a central pathway in Daphnetin-mediated NK cell activation in the presence of IL-12. This was further confirmed by the finding that both inhibitors of PI3K-Akt and its main downstream signaling mTOR, LY294002, and rapamycin, respectively, can reverse the increase of IFN-γ production and cytotoxicity in NK cells promoted by Daphnetin. Collectively, we identify a natural product, Daphnetin, with the capacity of promoting human NK cell activation via PI3K-Akt-mTOR signaling in the presence of IL-12. Our current study opens up a new potential application for Daphnetin as a complementary immunomodulator for cancer treatments.
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Affiliation(s)
- Baige Yao
- Hunan Children's Research Institute (HCRI), Hunan Children's Hospital, Changsha, China.,Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Qinglan Yang
- Hunan Children's Research Institute (HCRI), Hunan Children's Hospital, Changsha, China.,Hunan Provincial Key Laboratory of Children's Emergency Medicine, Hunan Children's Hospital, Changsha, China
| | - Yao Yang
- Institute of Materia Medica, College of Pharmacy, Army Medical University (Third Military Medical University), Chongqing, China
| | - Yana Li
- Hunan Children's Research Institute (HCRI), Hunan Children's Hospital, Changsha, China.,Hunan Provincial Key Laboratory of Children's Emergency Medicine, Hunan Children's Hospital, Changsha, China
| | - Hongyan Peng
- Hunan Children's Research Institute (HCRI), Hunan Children's Hospital, Changsha, China.,Hunan Provincial Key Laboratory of Children's Emergency Medicine, Hunan Children's Hospital, Changsha, China
| | - Shuting Wu
- Hunan Children's Research Institute (HCRI), Hunan Children's Hospital, Changsha, China.,Hunan Provincial Key Laboratory of Children's Emergency Medicine, Hunan Children's Hospital, Changsha, China
| | - Lili Wang
- Hunan Children's Research Institute (HCRI), Hunan Children's Hospital, Changsha, China.,Hunan Provincial Key Laboratory of Children's Emergency Medicine, Hunan Children's Hospital, Changsha, China
| | - Shuju Zhang
- Hunan Children's Research Institute (HCRI), Hunan Children's Hospital, Changsha, China.,Hunan Provincial Key Laboratory of Children's Emergency Medicine, Hunan Children's Hospital, Changsha, China
| | - Minghui Huang
- Hunan Children's Research Institute (HCRI), Hunan Children's Hospital, Changsha, China.,Hunan Provincial Key Laboratory of Children's Emergency Medicine, Hunan Children's Hospital, Changsha, China
| | - Erqiang Wang
- Hunan Children's Research Institute (HCRI), Hunan Children's Hospital, Changsha, China.,Hunan Provincial Key Laboratory of Children's Emergency Medicine, Hunan Children's Hospital, Changsha, China
| | - Peiwen Xiong
- Hunan Children's Research Institute (HCRI), Hunan Children's Hospital, Changsha, China.,Hunan Provincial Key Laboratory of Children's Emergency Medicine, Hunan Children's Hospital, Changsha, China
| | - Ting Luo
- Hunan Children's Research Institute (HCRI), Hunan Children's Hospital, Changsha, China.,Hunan Provincial Key Laboratory of Children's Emergency Medicine, Hunan Children's Hospital, Changsha, China
| | - Liping Li
- Hunan Children's Research Institute (HCRI), Hunan Children's Hospital, Changsha, China.,Hunan Provincial Key Laboratory of Children's Emergency Medicine, Hunan Children's Hospital, Changsha, China
| | - Sujie Jia
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Yafei Deng
- Hunan Children's Research Institute (HCRI), Hunan Children's Hospital, Changsha, China.,Hunan Provincial Key Laboratory of Children's Emergency Medicine, Hunan Children's Hospital, Changsha, China
| | - Youcai Deng
- Institute of Materia Medica, College of Pharmacy, Army Medical University (Third Military Medical University), Chongqing, China
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Kim KY, Yun UJ, Yeom SH, Kim SC, Lee HJ, Ahn SC, Park KI, Kim YW. Inhibition of Autophagy Promotes Hemistepsin A-Induced Apoptosis via Reactive Oxygen Species-Mediated AMPK-Dependent Signaling in Human Prostate Cancer Cells. Biomolecules 2021; 11:biom11121806. [PMID: 34944451 PMCID: PMC8699411 DOI: 10.3390/biom11121806] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 11/29/2021] [Accepted: 11/29/2021] [Indexed: 12/09/2022] Open
Abstract
Chemotherapy is an essential strategy for cancer treatment. On the other hand, consistent exposure to chemotherapeutic drugs induces chemo-resistance in cancer cells through a variety of mechanisms. Therefore, it is important to develop a new drug inhibiting chemo-resistance. Although hemistepsin A (HsA) is known to have anti-tumor effects, the molecular mechanisms of HsA-mediated cell death are unclear. Accordingly, this study examined whether HsA could induce apoptosis in aggressive prostate cancer cells, along with its underlying mechanism. Using HsA on two prostate cancer cell lines, PC-3 and LNCaP cells, the cell analysis and in vivo xenograft model were assayed. In this study, HsA induced apoptosis and autophagy in PC-3 cells. HsA-mediated ROS production attenuated HsA-induced apoptosis and autophagy after treatment with N-acetyl-L-cysteine (NAC), a ROS scavenger. Moreover, autophagy inhibition by 3-MA or CQ is involved in accelerating the apoptosis induced by HsA. Furthermore, we showed the anti-tumor effects of HsA in mice, as assessed by the reduced growth of the xenografted tumors. In conclusion, HsA induced apoptosis and ROS generation, which were blocked by protective autophagy signaling.
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Affiliation(s)
- Kwang-Youn Kim
- Korean Medicine (KM) Application Center, Korea Institute of Oriental Medicine, 70 Cheomdan-ro, Dong-gu, Daegu 41062, Korea;
| | - Un-Jung Yun
- School of Korean Medicine, Dongguk University, Gyeongju 38066, Korea; (U.-J.Y.); (S.-H.Y.)
| | - Seung-Hee Yeom
- School of Korean Medicine, Dongguk University, Gyeongju 38066, Korea; (U.-J.Y.); (S.-H.Y.)
- Medical Research Center, College of Oriental Medicine, Daegu Haany University, Gyeongsan 38610, Korea;
| | - Sang-Chan Kim
- Medical Research Center, College of Oriental Medicine, Daegu Haany University, Gyeongsan 38610, Korea;
| | - Hu-Jang Lee
- College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Korea;
| | - Soon-Cheol Ahn
- Department of Microbiology & Immunology, Pusan National University School of Medicine, Yangsan 50612, Korea
- Correspondence: (S.-C.A.); (K.-I.P.); (Y.-W.K.)
| | - Kwang-Il Park
- College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Korea;
- Correspondence: (S.-C.A.); (K.-I.P.); (Y.-W.K.)
| | - Young-Woo Kim
- School of Korean Medicine, Dongguk University, Gyeongju 38066, Korea; (U.-J.Y.); (S.-H.Y.)
- Correspondence: (S.-C.A.); (K.-I.P.); (Y.-W.K.)
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Cannabidiol modulation of oxidative stress and signalling. Neuronal Signal 2021; 5:NS20200080. [PMID: 34497718 PMCID: PMC8385185 DOI: 10.1042/ns20200080] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 07/27/2021] [Accepted: 07/30/2021] [Indexed: 12/18/2022] Open
Abstract
Cannabidiol (CBD), one of the primary non-euphoric components in the Cannabis sativa L. plant, has undergone clinical development over the last number of years as a therapeutic for patients with Lennox-Gastaut syndrome and Dravet syndromes. This phytocannabinoid demonstrates functional and pharmacological diversity, and research data indicate that CBD is a comparable antioxidant to common antioxidants. This review gathers the latest knowledge regarding the impact of CBD on oxidative signalling, with focus on the proclivity of CBD to regulate antioxidants and control the production of reactive oxygen species. CBD is considered an attractive therapeutic agent for neuroimmune disorders, and a body of literature indicates that CBD can regulate redox function at multiple levels, with a range of downstream effects on cells and tissues. However, pro-oxidant capacity of CBD has also been reported, and hence caution must be applied when considering CBD from a therapeutic standpoint. Such pro- and antioxidant functions of CBD may be cell- and model-dependent and may also be influenced by CBD dose, the duration of CBD treatment and the underlying pathology.
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