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Feng Q, Li J, Xiao C, Wang Z, Li X, Xiong L, Peng C, Chen Z, Tian F, Chen J, Ji J, Zheng X, Xiao K. Study on the embryotoxic effects and potential mechanisms of Aconitum diterpenoid alkaloids in rat whole embryo culture through morphological and transcriptomic analysis. JOURNAL OF ETHNOPHARMACOLOGY 2025; 340:119198. [PMID: 39631717 DOI: 10.1016/j.jep.2024.119198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 11/28/2024] [Accepted: 12/01/2024] [Indexed: 12/07/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The lateral root of Aconitum carmichaelii Debeaux, or Fuzi, is recognized in Asia for its anti-inflammatory, analgesic, and cardiotonic effects. Its main active compounds are diester diterpenoid alkaloids (DDAs) such as aconitine (AC), mesoacitine (MA), and hypoaconitine (HA), which are also toxic and have a narrow therapeutic window, limiting their clinical use. Although Aconitum DDAs are known for cardiotoxic and neurotoxic effects, their impact on embryonic development remains unclear. AIM OF THE STUDY The embryotoxicity of three representative Aconitum DDAs (AC, MA, and HA) and their metabolites were systematically assessed, and the mechanisms underlying AC-induced embryotoxicity was explored. MATERIALS AND METHODS The embryotoxicity of these DDAs was assessed by indicators such as morphological scores in a whole embryo culture (WEC) system. Immunofluorescence analysis was conducted to detect DNA damage and apoptosis in embryos, and transcriptomic analysis and western blotting were performed to explore the underlying mechanisms. RESULTS DDAs, particularly AC, induced dose-dependent developmental retardation and malformation in rat embryos. Notably, the embryotoxicity of AC metabolites such as benzoyltrypine (BAC) and aconine, was significantly reduced. AC treatment caused substantial DNA damage and apoptosis in embryos. Transcriptomic analysis indicate that AC treatment may impair DNA replication and histone synthesis by activating the p53/p21/CDK2/NPAT pathway, ultimately affecting embryonic development. CONCLUSION Among these Aconitum DDAs, AC exhibited the strongest embryotoxicity, mainly through DNA damage and regulation of histone genes via the p53/p21/CDK2/NPAT pathway.
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Affiliation(s)
- Qiyi Feng
- Laboratory of Precision Therapeutics, Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jue Li
- Laboratory of Precision Therapeutics, Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Chunxiu Xiao
- Laboratory of Precision Therapeutics, Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Zhifan Wang
- Laboratory of Precision Therapeutics, Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xiaojie Li
- Laboratory of Precision Therapeutics, Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Liang Xiong
- Key Laboratory of Systematic Research of Distinctive Chinese Medicine Resources in Southwest China, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Cheng Peng
- Key Laboratory of Systematic Research of Distinctive Chinese Medicine Resources in Southwest China, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Zhaoyan Chen
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Fangyuan Tian
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jingyao Chen
- Laboratory of Precision Therapeutics, Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China; Tianfu Jincheng Laboratory (Frontier Medical Center), Chengdu, 610041, China.
| | - Jiecheng Ji
- Laboratory of Precision Therapeutics, Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China; Tianfu Jincheng Laboratory (Frontier Medical Center), Chengdu, 610041, China.
| | - Xiuli Zheng
- Laboratory of Precision Therapeutics, Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China; Tianfu Jincheng Laboratory (Frontier Medical Center), Chengdu, 610041, China.
| | - Kai Xiao
- Laboratory of Precision Therapeutics, Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China; Tianfu Jincheng Laboratory (Frontier Medical Center), Chengdu, 610041, China.
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Yang C, Fu J, Zheng F, Fu Y, Duan X, Zuo R, Zhu J. Aconitine promotes ROS-activated P38/MAPK/Nrf2 pathway to inhibit autophagy and promote myocardial injury. J Cardiothorac Surg 2024; 19:665. [PMID: 39707526 DOI: 10.1186/s13019-024-03149-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Accepted: 11/26/2024] [Indexed: 12/23/2024] Open
Abstract
BACKGROUND Aconitine has cardiotoxicity, but the mechanism of cardiotoxicity induced by aconitine is limited. The aim of this study was to investigate the mechanism of myocardial injury induced by aconitine. METHODS Using aconitine, ROS inhibitor N-acetylcysteine(NAC), the autophagy activitor Rapamycin (Rap) or the P38/MAPK pathway activitor Dehydrocorydaline treats H9C2 cells. CCK-8 assay was used to assay cell proliferation activity. Flow Cytometry was used to detect cell apoptosis. Dichloro-dihydrofluorescein diacetate was used to detect ROS levels. The expression of LC3 was detected by Immunofluorescence Staining. Western blotting detected the expression of related proteins. The mRNA levels of inflammatory factors were detected by RT-qPCR. RESULTS Aconitine inhibits cardiomyocyte proliferation, induces apoptosis and secretion of inflammatory factors. Aconitine activates the P38/MAPK/Nrf2 pathway, induces ROS increase, and promotes autophagy. NAC can inhibit proliferation inhibition, apoptosis, inflammation and P38/MAPK/Nrf2 pathway activation induced by aconitine. Rap and P38 activators can partially recover the effects of NAC on proliferation, apoptosis, inflammation and autophagy of cardiomyocytes. CONCLUSION Aconitine promotes ROS-activated P38/MAPK/Nrf2 pathway to inhibit autophagy and promote myocardial injury.
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Affiliation(s)
- Chunai Yang
- Department of Emergency, The Affiliated Hospital of Yunnan University, Kunming, 650021, China
| | - Jinxiao Fu
- Department of Geriatric Medicine, The Affiliated Hospital of Yunnan University, 176 Qingnian Road, Wuhua District, Kunming, 650021, Yunnan, China.
| | - Fenshuang Zheng
- Department of Emergency, The Affiliated Hospital of Yunnan University, Kunming, 650021, China
| | - Yangshan Fu
- Department of Emergency, The Affiliated Hospital of Yunnan University, Kunming, 650021, China
| | - Xueqiong Duan
- Department of Emergency, The Affiliated Hospital of Yunnan University, Kunming, 650021, China
| | - Ruiling Zuo
- Department of Emergency, The Affiliated Hospital of Yunnan University, Kunming, 650021, China
| | - Junbo Zhu
- Department of Emergency, The Affiliated Hospital of Yunnan University, Kunming, 650021, China
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Yang N, Guo J, Zhang J, Gao S, Xiang Q, Wen J, Huang Y, Rao C, Chen Y. A toxicological review of alkaloids. Drug Chem Toxicol 2024; 47:1267-1281. [PMID: 38465444 DOI: 10.1080/01480545.2024.2326051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 02/25/2024] [Accepted: 02/27/2024] [Indexed: 03/12/2024]
Abstract
Alkaloids are naturally occurring compounds with complex structures found in natural plants. To further improve the understanding of plant alkaloids, this review focuses on the classification, toxicity and mechanisms of action, providing insight into the occurrence of alkaloid-poisoning events and guiding the safe use of alkaloids in food, supplements and clinical applications. Based on their chemical structure, alkaloids can be divided into organic amines, diterpenoids, pyridines, isoquinolines, indoles, pyrrolidines, steroids, imidazoles and purines. The mechanisms of toxicity of alkaloids, including neurotoxicity, hepatoxicity, nephrotoxicity, cardiotoxicity and cytotoxicity, have also been reviewed. Some cases of alkaloid poisoning have been introduced when used as food or clinically, including accidental food poisoning, excessive consumption, and poisoning caused by the improper use of alkaloids in a clinical setting, and the importance of safety evaluation was illustrated. This review summarizes the toxicity and mechanism of action of alkaloids and provides evidence for the need for the safe use of alkaloids in food, supplements and clinical applications.
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Affiliation(s)
- Nannan Yang
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Jiafu Guo
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Jian Zhang
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Song Gao
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Qiwen Xiang
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Jiayu Wen
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Yan Huang
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Chaolong Rao
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- R&D Center for Efficiency, Safety and Application in Chinese Materia Medica with Medical and Edible Values, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Yan Chen
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
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Park M, Seo EH, Yi JM, Cha S. Discovery and Prediction Study of the Dominant Pharmacological Action Organ of Aconitum carmichaeli Debeaux Using Multiple Bioinformatic Analyses. Int J Mol Sci 2024; 25:10219. [PMID: 39337710 PMCID: PMC11432385 DOI: 10.3390/ijms251810219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 09/12/2024] [Accepted: 09/17/2024] [Indexed: 09/30/2024] Open
Abstract
Herbs, such as Aconitum carmichaeli Debeaux (ACD), have long been used as therapies, but it is difficult to identify which organs of the human body are affected by the various compounds. In this study, we predicted the organ where the drug predominantly acts using bioinformatics and verified it using transcriptomics. We constructed a computer-aided brain system network (BSN) and intestinal system network (ISN). We predicted the action points of ACD using network pharmacology (NP) analysis and predicted the dockable proteins acting in the BSN and ISN using statistical-based docking analysis. The predicted results were verified using ACD-induced transcriptome analysis. The predicted results showed that both the NP and docking analyses predominantly acted on the BSN and showed better hit rates in the hub nodes. In addition, we confirmed through verification experiments that the SW1783 cell line had more than 10 times more differentially expressed genes than the HT29 cell line and that the dominant acting organ is the brain, using network dimension spanning analysis. In conclusion, we found that ACD preferentially acts in the brain rather than in the intestine, and this multi-bioinformatics-based approach is expected to be used in future studies of drug efficacy and side effects.
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Affiliation(s)
- Musun Park
- Korean Medicine (KM) Data Division, Korea Institute of Oriental Medicine, Daejeon 34054, Republic of Korea; (E.-H.S.); (S.C.)
| | - Eun-Hye Seo
- Korean Medicine (KM) Data Division, Korea Institute of Oriental Medicine, Daejeon 34054, Republic of Korea; (E.-H.S.); (S.C.)
| | - Jin-Mu Yi
- KM Convergence Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Republic of Korea;
| | - Seongwon Cha
- Korean Medicine (KM) Data Division, Korea Institute of Oriental Medicine, Daejeon 34054, Republic of Korea; (E.-H.S.); (S.C.)
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Wu Z, Qian J, Feng C, Chen Z, Gao X, Liu Y, Gao Y. A review of Aconiti Lateralis Radix Praeparata (Fuzi) for kidney disease: phytochemistry, toxicology, herbal processing, and pharmacology. Front Pharmacol 2024; 15:1427333. [PMID: 39021829 PMCID: PMC11251978 DOI: 10.3389/fphar.2024.1427333] [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: 05/03/2024] [Accepted: 06/11/2024] [Indexed: 07/20/2024] Open
Abstract
Background Aconiti Lateralis Radix Praeparata, commonly known as Fuzi in. traditional Chinese medicine (TCM), is widely utilized in clinical practice despite its inherent toxicity. Since ancient times, TCM practitioners have explored various processing techniques to broaden its clinical applications and enhance its safety profile. This review aims to summarize the effects of processing on the chemical composition, toxicity, and pharmacological properties of Fuzi, as well as investigate potential underlying mechanisms. Methods Data on phytochemistry, toxicology, pharmacology, and processing methods of Fuzi were gathered from the literature of electronic databases, including Web of Science, PubMed, and CNKI. Results Fuzi contains over 100 kinds of chemical compounds, including alkaloids, flavonoids, and polysaccharides, among which alkaloids are the main active compounds. Diester-diterpenoid alkaloids are the main contributors to Fuzi's toxicity and have side effects on some organs, such as the heart, liver, kidneys, nervous system, and reproductive system. The chemical composition of aconite, particularly its alkaloid content, was changed by hydrolysis or substitution reaction during processing to enhance its efficacy and reduce its toxicity. Salted aconite could enhance the therapeutic efficacy of Fuzi in treating kidney diseases and influence its pharmacokinetics. Conclusion Processing plays an important role in increasing the efficiency and decreasing toxicity of aconite. Further studies are needed to elucidate the changes of aconite before and after processing and the underlying mechanisms of these changes, thereby providing evidence for the clinical safety of drug use.
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Affiliation(s)
- Ziyang Wu
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
| | - Jiawen Qian
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
| | - Chenhang Feng
- The Third Affiliated Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Zhouqi Chen
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
| | - Xiangfu Gao
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
| | - Yang Liu
- Shaanxi Academy of Traditional Chinese Medicine, Xi’an, China
| | - Yuancheng Gao
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
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Cao B, Kong H, Shen C, She G, Tian S, Liu H, Cui L, Zhang Y, He Q, Xia Q, Liu K. Dimethyl phthalate induced cardiovascular developmental toxicity in zebrafish embryos by regulating MAPK and calcium signaling pathways. THE SCIENCE OF THE TOTAL ENVIRONMENT 2024; 926:171902. [PMID: 38521262 DOI: 10.1016/j.scitotenv.2024.171902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Revised: 03/12/2024] [Accepted: 03/20/2024] [Indexed: 03/25/2024]
Abstract
Dimethyl phthalate (DMP), the lowest-molecular-weight phthalate ester (PAE), is one of the most commonly detected persistent organic pollutants in the environment, but its toxic effects, especially cardiovascular developmental toxicity, are largely unknown. In this study, zebrafish embryos were exposed to sublethal concentrations of DMP from 4 to 96 hpf. Our results showed that DMP treatment induced yolk retention, pericardial edema, and swim bladder deficiency, as well as increased SV-BA distance and decreased heart rate, stroke volume, ventricular axis shortening rate and ejection fraction. In addition, oxidative stress and apoptosis were found to be highly involved in this process. The results of transcriptome sequencing and mRNA expression of related genes indicated that MAPK and calcium signaling pathways were perturbed by DMP. These findings have the potential to provide new insights into the potential developmental toxicity and cardiovascular disease risk of DMP.
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Affiliation(s)
- Bianneng Cao
- Biology Institute, Qilu University of Technology, Shandong Academy of Sciences, Jinan 250103, China
| | - Haotian Kong
- Biology Institute, Qilu University of Technology, Shandong Academy of Sciences, Jinan 250103, China
| | - Chuanlin Shen
- Biology Institute, Qilu University of Technology, Shandong Academy of Sciences, Jinan 250103, China
| | - Gaimei She
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Shuimiao Tian
- Biology Institute, Qilu University of Technology, Shandong Academy of Sciences, Jinan 250103, China
| | - Haojie Liu
- Biology Institute, Qilu University of Technology, Shandong Academy of Sciences, Jinan 250103, China
| | - Lishuang Cui
- Biology Institute, Qilu University of Technology, Shandong Academy of Sciences, Jinan 250103, China
| | - Yun Zhang
- Biology Institute, Qilu University of Technology, Shandong Academy of Sciences, Jinan 250103, China
| | - Qiuxia He
- Biology Institute, Qilu University of Technology, Shandong Academy of Sciences, Jinan 250103, China
| | - Qing Xia
- Biology Institute, Qilu University of Technology, Shandong Academy of Sciences, Jinan 250103, China.
| | - Kechun Liu
- Biology Institute, Qilu University of Technology, Shandong Academy of Sciences, Jinan 250103, China.
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Gao J, Mang Q, Liu Y, Sun Y, Xu G. Integrated mRNA and miRNA analysis reveals the regulatory network of oxidative stress and inflammation in Coilia nasus brains during air exposure and salinity mitigation. BMC Genomics 2024; 25:446. [PMID: 38714962 PMCID: PMC11075292 DOI: 10.1186/s12864-024-10327-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Accepted: 04/19/2024] [Indexed: 05/12/2024] Open
Abstract
BACKGROUND Air exposure is an inevitable source of stress that leads to significant mortality in Coilia nasus. Our previous research demonstrated that adding 10‰ NaCl to aquatic water could enhance survival rates, albeit the molecular mechanisms involved in air exposure and salinity mitigation remained unclear. Conversely, salinity mitigation resulted in decreased plasma glucose levels and improved antioxidative activity. To shed light on this phenomenon, we characterized the transcriptomic changes in the C. nasus brain upon air exposure and salinity mitigation by integrated miRNA-mRNA analysis. RESULTS The plasma glucose level was elevated during air exposure, whereas it decreased during salinity mitigation. Antioxidant activity was suppressed during air exposure, but was enhanced during salinity mitigation. A total of 629 differentially expressed miRNAs (DEMs) and 791 differentially expressed genes (DEGs) were detected during air exposure, while 429 DEMs and 1016 DEGs were identified during salinity mitigation. GO analysis revealed that the target genes of DEMs and DEGs were enriched in biological process and cellular component during air exposure and salinity mitigation. KEGG analysis revealed that the target genes of DEMs and DEGs were enriched in metabolism. Integrated analysis showed that 24 and 36 predicted miRNA-mRNA regulatory pairs participating in regulating glucose metabolism, Ca2+ transport, inflammation, and oxidative stress. Interestingly, most of these miRNAs were novel miRNAs. CONCLUSION In this study, substantial miRNA-mRNA regulation pairs were predicted via integrated analysis of small RNA sequencing and RNA-Seq. Based on predicted miRNA-mRNA regulation and potential function of DEGs, miRNA-mRNA regulatory network involved in glucose metabolism and Ca2+ transport, inflammation, and oxidative stress in C. nasus brain during air exposure and salinity mitigation. They regulated the increased/decreased plasma glucose and inhibited/promoted antioxidant activity during air exposure and salinity mitigation. Our findings would propose novel insights to the mechanisms underlying fish responses to air exposure and salinity mitigation.
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Affiliation(s)
- Jun Gao
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Freshwater Fisheries Research Center, Ministry of Agriculture, Chinese Academy of Fishery Sciences, Wuxi, Jiangsu, 214081, China
| | - Qi Mang
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Freshwater Fisheries Research Center, Ministry of Agriculture, Chinese Academy of Fishery Sciences, Wuxi, Jiangsu, 214081, China
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, Jiangsu, 214081, China
| | - Yuqian Liu
- College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, 201306, China
| | - Yi Sun
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Freshwater Fisheries Research Center, Ministry of Agriculture, Chinese Academy of Fishery Sciences, Wuxi, Jiangsu, 214081, China
| | - Gangchun Xu
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Freshwater Fisheries Research Center, Ministry of Agriculture, Chinese Academy of Fishery Sciences, Wuxi, Jiangsu, 214081, China.
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, Jiangsu, 214081, China.
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Song L, Mi S, Zhao Y, Liu Z, Wang J, Wang H, Li W, Wang J, Zu W, Du H. Integrated virtual screening and in vitro studies for exploring the mechanism of triterpenoids in Chebulae Fructus alleviating mesaconitine-induced cardiotoxicity via TRPV1 channel. Front Pharmacol 2024; 15:1367682. [PMID: 38500766 PMCID: PMC10945000 DOI: 10.3389/fphar.2024.1367682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 02/19/2024] [Indexed: 03/20/2024] Open
Abstract
Background: In traditional Mongolian or Tibetan medicine in China, Chebulae Fructus (CF) is widely used to process or combine with aconitums to decrease the severe toxicity of aconitums. Researches in this area have predominantly focused on tannins, with few research on other major CF components for cardiotoxicity mitigation. The present study aimed to clarify whether triterpenoids can attenuate the cardiotoxicity caused by mesaconitine (MA) and investigate the mechanism of cardiotoxicity attenuation. Methods: Firstly, the pharmacophore model, molecular docking, and 3D-QSAR model were used to explore the mechanism of CF components in reducing the toxicity of MA mediated by the TRPV1 channel. Then three triterpenoids were selected to verify whether the triterpenoids had the effect of lowering the cardiotoxicity of MA using H9c2 cells combined with MTT, Hoechst 33258, and JC-1. Finally, Western blot, Fluo-3AM, and MTT assays combined with capsazepine were used to verify whether the triterpenoids reduced H9c2 cardiomyocyte toxicity induced by MA was related to the TRPV1 channel. Results: Seven triterpenoids in CF have the potential to activate the TRPV1 channel. And they exhibited greater affinity for TRPV1 compared to other compounds and MA. However, their activity was relatively lower than that of MA. Cell experiments revealed that MA significantly reduced H9c2 cell viability, resulting in diminished mitochondrial membrane potential and nuclear pyknosis and damage. In contrast, the triterpenoids could improve the survival rate significantly and counteract the damage of MA to the cells. We found that MA, arjungenin (AR), and maslinic acid (MSA) except corosolic acid (CRA) upregulated the expression of TRPV1 protein. MA induced a significant influx of calcium, whereas all three triterpenoids alleviated this trend. Blocking the TRPV1 channel with capsazepine only increased the cell viability that had been simultaneously treated with MA, and AR, or MSA. However, there was no significant difference in the CRA groups treated with or without capsazepine. Conclusion: The triterpenoids in CF can reduce the cardiotoxicity caused by MA. The MSA and AR function as TRPV1 agonists with comparatively reduced activity but a greater capacity to bind to TRPV1 receptors, thus antagonizing the excessive activation of TRPV1 by MA.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Hong Du
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
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Zhao P, Tian Y, Geng Y, Zeng C, Ma X, Kang J, Lu L, Zhang X, Tang B, Geng F. Aconitine and its derivatives: bioactivities, structure-activity relationships and preliminary molecular mechanisms. Front Chem 2024; 12:1339364. [PMID: 38318112 PMCID: PMC10839071 DOI: 10.3389/fchem.2024.1339364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 01/12/2024] [Indexed: 02/07/2024] Open
Abstract
Aconitine (AC), which is the primary bioactive diterpene alkaloid derived from Aconitum L plants, have attracted considerable interest due to its unique structural feature. Additionally, AC demonstrates a range of biological activities, such as its ability to enhance cardiac function, inhibit tumor growth, reduce inflammation, and provide analgesic effects. However, the structure-activity relationships of AC are remain unclear. A clear understanding of these relationships is indeed critical in developing effective biomedical applications with AC. In line with these challenges, this paper summarized the structural characteristics of AC and relevant functional and bioactive properties and the structure-activity relationships presented in biomedical applications. The primary temporal scope of this review was established as the period spanning from 2010 to 2023. Subsequently, the objective of this review was to provide a comprehensive understanding of the specific action mechanism of AC, while also exploring potential novel applications of AC derivatives in the biomedical field, drawing upon their structural characteristics. In conclusion, this review has provided a comprehensive analysis of the challenges and prospects associated with AC in the elucidation of structure-bioactivity relationships. Furthermore, the importance of exploring modern biotechnology approaches to enhance the potential biomedical applications of AC has been emphasized.
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Affiliation(s)
- Pengyu Zhao
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ye Tian
- Guizhou Yunfeng Pharmaceutical Co., Ltd., Qianxinan Buyi and Miao Autonomous Prefecture, China
| | - Yuefei Geng
- Sichuan Key Laboratory of Medical American Cockroach, Chengdu, China
| | - Chenjuan Zeng
- Guizhou Yunfeng Pharmaceutical Co., Ltd., Qianxinan Buyi and Miao Autonomous Prefecture, China
| | - Xiuying Ma
- Sichuan Key Laboratory of Medical American Cockroach, Chengdu, China
| | - Jie Kang
- Guizhou Yunfeng Pharmaceutical Co., Ltd., Qianxinan Buyi and Miao Autonomous Prefecture, China
| | - Lin Lu
- Sichuan Engineering Research Center for Medicinal Animals, Chengdu, China
| | - Xin Zhang
- Sichuan Good Doctor Pharmaceutical Group, Chengdu, China
| | - Bo Tang
- Sichuan Engineering Research Center for Medicinal Animals, Chengdu, China
| | - Funeng Geng
- Sichuan Key Laboratory of Medical American Cockroach, Chengdu, China
- Chengdu University of Traditional Chinese Medicine, Chengdu, China
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He G, Wang X, Liu W, Li Y, Shao Y, Liu W, Liang X, Bao X. Chemical constituents, pharmacological effects, toxicology, processing and compatibility of Fuzi (lateral root of Aconitum carmichaelii Debx): A review. JOURNAL OF ETHNOPHARMACOLOGY 2023; 307:116160. [PMID: 36773791 DOI: 10.1016/j.jep.2023.116160] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 12/23/2022] [Accepted: 01/08/2023] [Indexed: 06/18/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The lateral root of Aconitum carmichaelii Debx is known as Fuzi in Chinese. It is traditionally valued and used for dispelling cold, relieving pain effects, restoring 'Yang,' and treating shock despite its high toxicity. This review aims to provide comprehensive information on the chemical composition, pharmacological research, preparation, and compatibility of Fuzi to help reduce its toxicity and increase its efficiency, based on the scientific literature. In addition, this review will establish a new foundation for further studies on Fuzi. MATERIALS AND METHODS A systematic review of the literature on Fuzi was performed using several resources, namely classic books on Chinese herbal medicine and various scientific databases, such as PubMed, the Web of Science, and the China Knowledge Resource Integrated databases. RESULTS Fuzi extracts contain diester-type alkaloids, monoester-type alkaloids, other types of alkaloids, and non-alkaloids types, and have various pharmacological activities, such as strong heart effect, effect on blood vessels, and antidepressant, anti-diabetes, anti-inflammatory, pain-relieving, antitumor, immunomodulatory, and other therapeutic effects. However, these extracts can also lead to various toxicities such as cardiotoxicity, neurotoxicity, reproductive toxicity, hepatotoxicity, and embryonic toxicity. In vivo and in vitro experiments have demonstrated that different processing methods and suitable compatibility with other herbs can effectively reduce the toxicities and increase the efficiency of Fuzi. CONCLUSION The therapeutic potential of Fuzi has been demonstrated in conditions, such as heart failure, various pains, inflammation, and tumors, which is attributed to the diester-type alkaloids, monoester-type alkaloids, other types of alkaloids, and non-alkaloid types. In contrast, they are also toxic components. Proper processing and suitable compatibility can effectively reduce toxicity and increase the efficiency of Fuzi. Thus more pharmacological and toxicological mechanisms on main active compounds are necessary to be explored.
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Affiliation(s)
- Guannan He
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xiaoxin Wang
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Weiran Liu
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yuling Li
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yumeng Shao
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Weidong Liu
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xiaodong Liang
- Shandong University of Traditional Chinese Medicine, Jinan, China.
| | - Xia Bao
- Shandong University of Traditional Chinese Medicine, Jinan, China
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Zhang J, Sun L, Cui P, Zou L, Chen Y, Liang J, Ji S, Walayat N, Lyu F, Ding Y. Effects of combined treatment of electrolytic water and chitosan on the quality and proteome of large yellow croaker (Pseudosciaena crocea) during refrigerated storage. Food Chem 2023; 406:135062. [PMID: 36462361 DOI: 10.1016/j.foodchem.2022.135062] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 10/26/2022] [Accepted: 11/23/2022] [Indexed: 11/29/2022]
Abstract
The labeled quantitative proteomic method was used to study the changes in muscle proteins of large yellow croaker (Pseudosciaena crocea) treated with electrolytic water (EW) and chitosan (CHI) combined preservation during 12 days of refrigeration storage (4 °C). The analysis indicated that the freshness instructed by total viable count (TVC), total volatile basic nitrogen (TVB-N) and K value was significantly maintained after combined preservation during storage at 4 °C for 12 days (CS12). Furthermore, 46 differentially abundant proteins (DAPs) were detected in storage at 4 °C for 12 days (S12) compared to the freshness group (F), which bioinformatics confirmed were mainly skeletal proteins and enzymes. Correlation analysis showed that 19 highly correlated DAPs could be used as potential protein markers of freshness. Changes in the relation of freshness and protein were shown in further correlative analysis of F and CS12, which were caused by combined preservation. Therefore, combined preservation is promising in the quality and stability of large yellow croakers.
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Affiliation(s)
- Jianyou Zhang
- College of Food Science and Technology, Zhejiang University of Technology, Hangzhou 310014, China; Key Laboratory of Marine Fishery Resources Exploitment & Utilization of Zhejiang Province, Hangzhou 310014, China; National R&D Branch Center for Pelagic Aquatic Products Processing (Hangzhou), Hangzhou 310014, China; Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian 116034, China
| | - Lei Sun
- College of Food Science and Technology, Zhejiang University of Technology, Hangzhou 310014, China; Key Laboratory of Marine Fishery Resources Exploitment & Utilization of Zhejiang Province, Hangzhou 310014, China; National R&D Branch Center for Pelagic Aquatic Products Processing (Hangzhou), Hangzhou 310014, China
| | - Pengbo Cui
- College of Food Science and Technology, Zhejiang University of Technology, Hangzhou 310014, China; Key Laboratory of Marine Fishery Resources Exploitment & Utilization of Zhejiang Province, Hangzhou 310014, China; National R&D Branch Center for Pelagic Aquatic Products Processing (Hangzhou), Hangzhou 310014, China; Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian 116034, China
| | - Ligen Zou
- Hangzhou Academy of Agricultural Sciences, Hangzhou 310014, China
| | - Yutong Chen
- College of Food Science and Technology, Zhejiang University of Technology, Hangzhou 310014, China; Key Laboratory of Marine Fishery Resources Exploitment & Utilization of Zhejiang Province, Hangzhou 310014, China; National R&D Branch Center for Pelagic Aquatic Products Processing (Hangzhou), Hangzhou 310014, China
| | - Jianqin Liang
- College of Food Science and Technology, Zhejiang University of Technology, Hangzhou 310014, China; Key Laboratory of Marine Fishery Resources Exploitment & Utilization of Zhejiang Province, Hangzhou 310014, China; National R&D Branch Center for Pelagic Aquatic Products Processing (Hangzhou), Hangzhou 310014, China
| | - Shengqiang Ji
- College of Food Science and Technology, Zhejiang University of Technology, Hangzhou 310014, China; Key Laboratory of Marine Fishery Resources Exploitment & Utilization of Zhejiang Province, Hangzhou 310014, China; National R&D Branch Center for Pelagic Aquatic Products Processing (Hangzhou), Hangzhou 310014, China
| | - Noman Walayat
- College of Food Science and Technology, Zhejiang University of Technology, Hangzhou 310014, China
| | - Fei Lyu
- College of Food Science and Technology, Zhejiang University of Technology, Hangzhou 310014, China; Key Laboratory of Marine Fishery Resources Exploitment & Utilization of Zhejiang Province, Hangzhou 310014, China; National R&D Branch Center for Pelagic Aquatic Products Processing (Hangzhou), Hangzhou 310014, China; Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian 116034, China.
| | - Yuting Ding
- College of Food Science and Technology, Zhejiang University of Technology, Hangzhou 310014, China; Key Laboratory of Marine Fishery Resources Exploitment & Utilization of Zhejiang Province, Hangzhou 310014, China; National R&D Branch Center for Pelagic Aquatic Products Processing (Hangzhou), Hangzhou 310014, China; Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian 116034, China
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Wang M, Hu WJ, Zhou X, Yu K, Wang Y, Yang BY, Kuang HX. Ethnopharmacological use, pharmacology, toxicology, phytochemistry, and progress in Chinese crude drug processing of the lateral root of Aconitum carmichaelii Debeaux. (Fuzi): A review. JOURNAL OF ETHNOPHARMACOLOGY 2023; 301:115838. [PMID: 36257343 DOI: 10.1016/j.jep.2022.115838] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 10/01/2022] [Accepted: 10/11/2022] [Indexed: 06/16/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The lateral root of Aconitum carmichaelii Debeaux. (also known as Fuzi in Chinese) is a toxic Chinese medicine but widely used in clinical practice with remarkable effects. It is specifically used to treat cardiovascular diseases, rheumatoid arthritis, and other diseases, in Korea, Japan, and India. AIM OF THIS REVIEW This study aimed to summarize and discuss the effects of drug processing on toxicity, chemical composition, and pharmacology of the lateral root of Aconitum carmichaelii Debeaux. This review could provide feasible insights for further studies. MATERIALS AND METHODS Relevant information on phytochemistry, pharmacology, and toxicology of Fuzi was collected through published materials and electronic databases, including the Chinese Pharmacopoeia, Flora of China, Web of Science, PubMed, Baidu Scholar, Google Scholar, and CNKI. RESULTS More than 100 chemical compounds, including alkaloids, flavonoids, and polysaccharides were revealed. Modern pharmacological studies show that these chemical components have good effects on anti-inflammatory, anti-tumor, anti-aging, treatment of cardiovascular diseases, and improving immunity. Di-ester alkaloids are the main source of Fuzi toxicity. Increasing studies have shown that Fuzi can induce multiple organ damage, especially cardiotoxicity and neurotoxicity. At present, most of the Fuzi used in clinical practice are processed. The processing affects the chemical structure, pharmacology, and toxicology of Fuzi. Moreover, different processing methods have different effects on Fuzi. CONCLUSIONS This review analyzed the effects of Fuzi processing methods on its toxicity and efficiency. The lateral roots of aconite are the known medicinal part of Fuzi; however, the aerial parts of aconite are understudied and require further research to expand its medicinal potential. Processing and compatibility are the primary means to reduce Fuzi toxicity. Nevertheless, establishing a reasonable unified safe dose range requires further discussion.
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Affiliation(s)
- Meng Wang
- Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Heilongjiang University of Chinese Medicine, Harbin, 150000, China.
| | - Wen-Jing Hu
- Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Heilongjiang University of Chinese Medicine, Harbin, 150000, China
| | - Xiao Zhou
- Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Heilongjiang University of Chinese Medicine, Harbin, 150000, China
| | - Kuo Yu
- Beidahuang Industry Group General Hospital, Harbin, 150000, China
| | - Yan Wang
- Beidahuang Industry Group General Hospital, Harbin, 150000, China
| | - Bing-You Yang
- Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Heilongjiang University of Chinese Medicine, Harbin, 150000, China
| | - Hai-Xue Kuang
- Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Heilongjiang University of Chinese Medicine, Harbin, 150000, China.
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Chen W, Luo H, Zhong Z, Wei J, Wang Y. The safety of Chinese medicine: A systematic review of endogenous substances and exogenous residues. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 108:154534. [PMID: 36371955 DOI: 10.1016/j.phymed.2022.154534] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 10/24/2022] [Accepted: 11/01/2022] [Indexed: 06/16/2023]
Abstract
BACKGROUND Safety and toxicity have become major challenges in the internationalization of Chinese medicine. Inspite of its wide application, security problems of Chinese medicine still occur from time to time, raising widespread concerns about its safety. Most of the studies either only partially discussed the intrinsic toxicities or extrinsic harmful residues in Chinese medicine, or briefly described detoxification and attenuation methods. It is necessary to systematically discuss Chinese medicine's extrinsic and intrinsic toxic components and corresponding toxicity detoxification or detection methods as a whole. PURPOSE This review comprehensively summarizes various toxic components in Chinese medicine from intrinsic and extrinsic. Then the corresponding methods for detoxification or detection of toxicity are highlighted. It is expected to provide a reference for safeguards for developing and using Chinese medicine. METHODS A literature search was conducted in the databases, including PubMed, Web of Science,Wan-fang database, and the China National Knowledge Infrastructure (CNKI). Keywords used were safety, toxicity, intrinsic toxicities, extrinsic harmful residues, alkaloids, terpene and macrolides, saponins, toxic proteins, toxic crystals, minerals, heavy metals, pesticides, mycotoxins, sulfur dioxide, detoxification, detection, processing (Paozhi), compatibility (Peiwu), Chinese medicine, etc., and combinations of these keywords. All selected articles were from 2006 to 2022, and each was assessed critically for our exclusion criteria. Studies describe the classification of toxic components of Chinese medicine, the toxic effects and mechanisms of Chinese medicine, and the corresponding methods for detoxification or detection of toxicity. RESULTS The toxic components of Chinese medicines can be classified as intrinsic toxicities and extrinsic harmful residues. Firstly, we summarized the intrinsic toxicities of Chinese medicine, the adverse effects and toxicity mechanisms caused by these components. Next, we focused on the detoxification or attenuation methods for intrinsic toxicities of Chinese medicine. The other main part discussed the latest progress in analytical strategies for exogenous hazardous substances, including heavy metals, pesticides, and mycotoxins. Beyond reviewing mainstream instrumental methods, we also introduced the emerging biochip, biosensor and immuno-based techniques. CONCLUSION In this review, we provide an overall assessment of the recent progress in endogenous toxins and exogenous hazardous substances concerning Chinese medicine, which is expected to render deeper insights into the safety of Chinese medicine.
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Affiliation(s)
- Wenyue Chen
- Macao Centre for Research and Development in Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR 999078, China
| | - Hua Luo
- Macao Centre for Research and Development in Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR 999078, China; College of Pharmacy, Guangxi Medical University, Nanning 530021, China; Guangxi University of Chinese Medicine, Nanning 530001, China
| | - Zhangfeng Zhong
- Macao Centre for Research and Development in Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR 999078, China; College of Pharmacy, Guangxi Medical University, Nanning 530021, China; Guangxi University of Chinese Medicine, Nanning 530001, China
| | - Jinchao Wei
- Macao Centre for Research and Development in Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR 999078, China.
| | - Yitao Wang
- Macao Centre for Research and Development in Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR 999078, China.
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Xiang G, Xing N, Wang S, Zhang Y. Antitumor effects and potential mechanisms of aconitine based on preclinical studies: an updated systematic review and meta-analysis. Front Pharmacol 2023; 14:1172939. [PMID: 37180714 PMCID: PMC10174313 DOI: 10.3389/fphar.2023.1172939] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 04/17/2023] [Indexed: 05/16/2023] Open
Abstract
Background: Herbs originating from the Aconitum L. (Ranunculaceae), such as Aconitum carmichaelii Debeaux. (Wutou), Aconitum pendulum Busch. (Tiebangchui), and Aconitum kusnezoffii Reichb. (Caowu), etc. are highly valued for their medicinal properties. The roots and tubers of these herbs are commonly used to treat an array of ailments, including joint pain and tumors. The alkaloids present in them are the primary active components, with aconitine being the most notable. Aconitine has gained attention for its exceptional anti-inflammatory and analgesic properties, as well as its potential as an anti-tumor and cardiotonic agent. However, the exact process through which aconitine hinders the growth of cancerous cells and triggers their programmed cell death remains unclear. Therefore, we have undertaken a comprehensive systematic review and meta-analysis of the current research on the potential antitumor properties of aconitine. Methods: We conducted a thorough search of relevant preclinical studies in databases including PubMed, Web of Science, VIP, WanFang Data, CNKI, Embase, Cochrane Library, and National Center for Biotechnology Information (NCBI). The search was conducted up until 15 September 2022, and the data were statistically analyzed using RevMan 5.4 software. The number of tumor cell value-added, tumor cell apoptosis rate, thymus index (TI), and Bcl-2 gene expression level were the main indicators to be analyzed. Results: After applying the final inclusion criteria, a total of thirty-seven studies, comprising both in vivo and in vitro research were analyzed. The results showed that treatment with aconitine led to a significant reduction in tumor cell proliferation, a noteworthy increase in the rate of apoptosis among tumor cells, a decrease in the thymus index, and a reduction in the expression level of Bcl-2. These results suggested that aconitine could inhibit the proliferation, invasion, and migration abilities of tumor cells by regulating Bcl-2 etc., thereby enhancing the anti-tumor effects. Conclusion: In summary, our present study demonstrated that aconitine effectively reduced tumor size and volume, indicating a strong anti-tumor effect. Additionally, aconitine could increase the expression levels of caspase-3, Bax and other targets. Mechanistically, it may regulate the expression levels of Bax and Bcl-2 through the NF-κB signaling pathway, ultimately inhibiting tumor cell proliferation through autophagy.
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Affiliation(s)
- Gelin Xiang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- State Key Laboratory of Southwestern Chinese Medicine Resources, Research Center for Academic Inheritance and Innovation of Ethnomedicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Nan Xing
- State Key Laboratory of Southwestern Chinese Medicine Resources, Research Center for Academic Inheritance and Innovation of Ethnomedicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Shaohui Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- State Key Laboratory of Southwestern Chinese Medicine Resources, Research Center for Academic Inheritance and Innovation of Ethnomedicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Shaohui Wang, ; Yi Zhang,
| | - Yi Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- State Key Laboratory of Southwestern Chinese Medicine Resources, Research Center for Academic Inheritance and Innovation of Ethnomedicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Shaohui Wang, ; Yi Zhang,
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15
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Chen Y, Shi S, Dai Y. Research progress of therapeutic drugs for doxorubicin-induced cardiomyopathy. Biomed Pharmacother 2022; 156:113903. [PMID: 36279722 DOI: 10.1016/j.biopha.2022.113903] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 10/16/2022] [Accepted: 10/19/2022] [Indexed: 12/06/2022] Open
Abstract
Doxorubicin (DOX), as a kind of chemotherapy agent with remarkable therapeutic effect, can be used to treat diverse malignant tumors clinically. Dose-dependent cardiotoxicity is the most serious adverse reaction after DOX treatment, which eventually leads to cardiomyopathy and greatly limits the clinical application of DOX. DOX-induced cardiomyopathy is not a result of a single mechanistic action, and multiple mechanisms have been discovered and demonstrated experimentally, such as oxidative stress, inflammation, mitochondrial damage, calcium homeostasis disorder, ferroptosis, autophagy and apoptosis. Dexrazoxane (DEX) is the only protective agent approved by FDA for the treatment of DOX cardiomyopathy, but its clinical treatment still has some limitations. Therefore, we need to find other effective therapeutic drugs as soon as possible. In this paper, the drugs that effectively improve cardiomyopathy in recent years are mainly described from the aspects of natural drugs, endogenous substances, new dosage forms, herbal medicines, chemical modification and marketed drugs. The aim of the present study is to evaluate the effects of these drugs on DOX-induced anticancer and cardiomyopathy curative effects, so as to provide some reference value for clinical treatment of DOX-induced cardiomyopathy in the future.
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Affiliation(s)
- Ye Chen
- Department of pharmacy, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province 646000, China; School of pharmacy, Southwest Medical University, Luzhou, Sichuan Province 646000, China
| | - Saixian Shi
- Department of pharmacy, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province 646000, China; School of pharmacy, Southwest Medical University, Luzhou, Sichuan Province 646000, China
| | - Yan Dai
- Department of pharmacy, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province 646000, China.
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16
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Liao YP, Shen LH, Cai LH, Chen J, Shao HQ. Acute myocardial necrosis caused by aconitine poisoning: A case report. World J Clin Cases 2022; 10:12416-12421. [PMID: 36483800 PMCID: PMC9724530 DOI: 10.12998/wjcc.v10.i33.12416] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Revised: 10/13/2022] [Accepted: 10/24/2022] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Herbal medicine has a long history of use in the prevention and treatment of disease and is becoming increasingly popular globally. However, there are also widespread concerns about its safety. Among them, the cardiotoxicity of aconitine has been described.
CASE SUMMARY We report a case of a 61-year-old male with aconitine poisoning presenting with malignant arrhythmia and severe cardiogenic shock, which was successfully managed with aggressive advanced life support and heart transplantation.
CONCLUSION This is the first case wherein in vivo cardiac pathology was obtained, confirming that aconitine caused acute myocardial necrosis.
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Affiliation(s)
- Yu-Ping Liao
- Department of Critical Care Medicine, Dongguan People’s Hospital, Dongguan 523058, Guangdong Province, China
| | - Li-Han Shen
- Department of Critical Care Medicine, Dongguan People’s Hospital, Dongguan 523058, Guangdong Province, China
| | - Li-Hua Cai
- Department of Critical Care Medicine, Dongguan People’s Hospital, Dongguan 523058, Guangdong Province, China
| | - Jie Chen
- Department of Critical Care Medicine, Dongguan People’s Hospital, Dongguan 523058, Guangdong Province, China
| | - Han-Quan Shao
- Department of Critical Care Medicine, Dongguan People’s Hospital, Dongguan 523058, Guangdong Province, China
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Nie H, Pan M, Chen J, Yang Q, Hung TC, Xing D, Peng M, Peng X, Li G, Yan W. Titanium dioxide nanoparticles decreases bioconcentration of azoxystrobin in zebrafish larvae leading to the alleviation of cardiotoxicity. CHEMOSPHERE 2022; 307:135977. [PMID: 35948095 DOI: 10.1016/j.chemosphere.2022.135977] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 08/03/2022] [Accepted: 08/04/2022] [Indexed: 06/15/2023]
Abstract
Interactions between titanium dioxide nanoparticles (n-TiO2) and pollutants in the aquatic environment may alter the bioavailability of pollutants, and thus altering their toxicity and fate. In order to investigate the bioconcentration of azoxystrobin (AZ) and its mechanism of cardiotoxicity in the presence of n-TiO2, the experiment was divided into control, n-TiO2 (100 μg/L), AZ (40, 200 and 1000 μg/L) and AZ (40, 200, 1000 μg/L) + n-TiO2 groups, and the zebrafish embryos were exposed to the exposure solution until 72 h post-fertilization. Results suggested the presence of n-TiO2 notably reduced the accumulation of AZ in larvae compared with exposure to AZ alone, thereby significantly decreasing AZ-induced cardiotoxicity, including heart rate changes, pericardium edema, venous thrombosis, increased sinus venosus and bulbus arteriosus distance and changes in cardiac-related gene expression. Further studies showed that AZ + n-TiO2 together restrained total-ATPase and Ca2+-ATPase activities, while the activity of Na+K+-ATPase increased at first and then decreased. Furthermore, there were significant changes in the expressions of oxidative phosphorylation and calcium channel-related genes, suggesting mitochondrial dysfunction may be the potential mechanism of cardiotoxicity induced by AZ and n-TiO2. This study supplies a new perspective for the joint action of AZ and environmental coexisting pollutants and provides a basis for ecological risk management of pesticides.
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Affiliation(s)
- Hongyan Nie
- College of Fisheries, Huazhong Agricultural University, Wuhan, 430070, China
| | - Meiqi Pan
- College of Fisheries, Huazhong Agricultural University, Wuhan, 430070, China
| | - Juan Chen
- Changsha Xinjia Bio-Engineering Co., Ltd., Changsha, 410000, Hunan, China
| | - Qing Yang
- Key Laboratory of Ecological Impacts of Hydraulic Projects and Restoration of Aquatic Ecosystem of Ministry of Water Resources and Chinese Academy of Sciences, Wuhan, 430079, China
| | - Tien-Chieh Hung
- Department of Biological and Agricultural Engineering, University of California-Davis, Davis, CA, 95616, USA
| | - Dan Xing
- Dadu River Hydropower Development Co., Ltd., Chengdu, China
| | - Maomin Peng
- Institute of Quality Standard and Testing Technology for Agro-Products, Hubei Academy of Agricultural Sciences, Hubei Key Laboratory of Nutritional Quality and Safety of Agro-products, Wuhan, 430064, Hubei, China
| | - Xitian Peng
- Institute of Quality Standard and Testing Technology for Agro-Products, Hubei Academy of Agricultural Sciences, Hubei Key Laboratory of Nutritional Quality and Safety of Agro-products, Wuhan, 430064, Hubei, China
| | - Guangyu Li
- College of Fisheries, Huazhong Agricultural University, Wuhan, 430070, China; Hubei Provincial Engineering Laboratory for Pond Aquaculture, Wuhan, 430070, China.
| | - Wei Yan
- Institute of Quality Standard and Testing Technology for Agro-Products, Hubei Academy of Agricultural Sciences, Hubei Key Laboratory of Nutritional Quality and Safety of Agro-products, Wuhan, 430064, Hubei, China
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Zhang J, Li D, Zhong D, Zhou Q, Yin Y, Gao J, Peng C. Processed lateral root of Aconitum carmichaelii Debx.: A review of cardiotonic effects and cardiotoxicity on molecular mechanisms. Front Pharmacol 2022; 13:1026219. [PMID: 36324672 PMCID: PMC9618827 DOI: 10.3389/fphar.2022.1026219] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 10/03/2022] [Indexed: 11/13/2022] Open
Abstract
Fuzi, the lateral root of A. carmichaelii Debx., is a typical traditional herbal medicine with both poisonousness and effectiveness, and often used in the treatment of heart failure and other heart diseases. In this review, we searched domestic and foreign literature to sort out the molecular mechanisms of cardiotonic and cardiotoxicity of Fuzi, also including its components. The major bioactive components of Fuzi for cardiotonic are total alkaloids, polysaccharide and the water-soluble alkaloids, with specific mechanisms manifested in the inhibition of myocardial fibrosis, apoptosis and autophagy, and improvement of mitochondrial energy metabolism, which involves RAAS system, PI3K/AKT, JAK/STAT, AMPK/mTOR signaling pathway, etc. Diester-diterpenoid alkaloids in Fuzi can produce cardiotoxic effects by over-activating Na+ and Ca2+ ion channels, over-activating NLRP3/ASC/caspase-3 inflammatory pathway and mitochondria mediated apoptosis pathway. And three clinically used preparations containing Fuzi are also used as representatives to summarize their cardiac-strengthening molecular mechanisms. To sum up, Fuzi has shown valuable cardiotonic effects due to extensive basic and clinical studies, but its cardiotonic mechanisms have not been systematically sorted out. Therefore, it is a need for deeper investigation in the mechanisms of water-soluble alkaloids with low content but obvious therapeutic effect, as well as polysaccharide.
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Affiliation(s)
- Jing Zhang
- State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Dan Li
- State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Dan Zhong
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qinmei Zhou
- State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yanpeng Yin
- State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jihai Gao
- State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Jihai Gao, ; Cheng Peng,
| | - Cheng Peng
- State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Jihai Gao, ; Cheng Peng,
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Gong S, Yuan M, Liu Y, Zhu Y, Zeng C, Peng C, Guo L. Application of Stable Isotopes with Machine Learning Techniques for Identifying Aconiti Lateralis Radix Praeparata (Fuzi) Geographical Origins. Microchem J 2022. [DOI: 10.1016/j.microc.2022.108002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
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Synergistic and Attenuating Effect of Electroacupuncture on Aconitine in Improving Heart Failure and Its Calcium Regulation Mechanism. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:4940745. [PMID: 35873628 PMCID: PMC9303489 DOI: 10.1155/2022/4940745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 06/23/2022] [Indexed: 11/25/2022]
Abstract
Objective The objective is to observe the synergistic and attenuating effect of electroacupuncture (EA) on aconitine (ACO) in improving heart failure (HF) and to explore its underlying mechanism for calcium regulation. Methods Twenty-four male Sprague-Dawley rats were randomly divided into four groups: normal control (NC) (n = 6), HF(n = 6), ACO (n = 6), and ACO + EA (n = 6). The maximum rates of left ventricular pressure rising and declining (±dp/dtmax), arrhythmia, the left ventricular systolic pressure (LVSP), ejection fraction (LVEF), and fractional shortening (LVFS) were measured by physiological recorder and ultrasound, respectively. Protein expressions of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA2a), phospholamban (PLB), and Na+-Ca2+ exchange (NCX1) in the left ventricle tissue were detected by fluorescence immunoblotting. Results Compared with the NC group, LVSP, ±dp/dtmax, LVEF, and LVFS were decreased in the HF group; compared with the HF group, LVSP, ±dp/dtmax, LVEF, and LVFS were significantly increased in the ACO + EA group. Compared with the ACO group, the incidence and the degree of arrhythmia were significantly reduced in the ACO + EA group. Compared with the NC group, the activity of SERCA2a was decreased, and the expression of PLB and NCX1 was enhanced in the HF group; compared with the HF group and ACO group, the activity of SERCA2a was increased, and the expression of PLB and NCX1 was significantly attenuated in the ACO + EA group. Conclusions EA plays a synergistic and attenuated role in ACO improving HF, and the mechanism may be related to the enhancement of the SERCA2a activity and the decrease of the expression of PLB and NCX1 in cardiomyocytes.
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21
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An insight into current advances on pharmacology, pharmacokinetics, toxicity and detoxification of aconitine. Biomed Pharmacother 2022; 151:113115. [PMID: 35605296 DOI: 10.1016/j.biopha.2022.113115] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Revised: 05/05/2022] [Accepted: 05/10/2022] [Indexed: 11/20/2022] Open
Abstract
Aconitine is a diterpenoid alkaloid, which mainly exists in the plants of Aconitum. In the last decade, a plethora of studies on the pharmacological activities of aconitine has been conducted and demonstrated that aconitine possessed an extensive range of pharmacological activities such as anti-tumor, anti-inflammatory, analgesic, local anesthesia, and immunomodulatory effects. Pharmacokinetic studies indicated that aconitine may have the characteristics of poor bioavailability, wide distribution, and slow elimination. However, studies have also found that aconitine has toxic effects on the heart, nerves, embryos, etc. Therefore, we believe that aconitine may not be suitable for heart patients and pregnant women to treat related diseases. It is important to note that all of these pharmacological effects require further high-quality studies to determine the clinical efficacy of aconitine. This review aims to summarize the advances in pharmacological, pharmacokinetics, toxicity, and detoxification of aconitine in the last decade with an emphasis on its anti-tumor and anti-inflammatory activities, to provide researchers with the latest information and point out the limitations of relevant research at the current stage and the aspects that should be strengthened in future research.
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22
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Li CY, Zhou Z, Xu T, Wang NY, Tang C, Tan XY, Feng ZG, Zhang Y, Liu Y. Aconitum pendulum and Aconitum flavum: A narrative review on traditional uses, phytochemistry, bioactivities and processing methods. JOURNAL OF ETHNOPHARMACOLOGY 2022; 292:115216. [PMID: 35331875 DOI: 10.1016/j.jep.2022.115216] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 03/05/2022] [Accepted: 03/19/2022] [Indexed: 06/14/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Composed of dried Aconitum pendulum and Aconitum flavum roots, Tiebangchui, is an important Tibetan medicine and has been traditionally and widely used as a remedy for cold and pain for thousands of years because of its extraordinary pharmacological activities. The toxicity and efficacy of Tiebangchui as a typical toxic traditional Tibetan medicine, are interdependent, and thus to make sure its safe use in clinics is also noteworthy. AIM OF THE STUDY This review aims to document and summarize critical and comprehensive information about traditional uses, phytochemistry, pharmacology, toxicology and processing methods of Tiebangchui. Perspectives for possible future investigations have been discussed. MATERIALS AND METHODS Relevant information about Tiebangchui (A. pendulum and A. flavum) was collected from internationally recognized electronic scientific databases, such as Web of Science, PubMed, Science Direct, Springer Link, ACS, and CNKI. Then, classic Tibetan medical books, such as Four Medical Tantra, and Jing Zhu Materia Medica, and official drug standards were reviewed. RESULTS A total of 95 chemical constituents have been isolated and identified from Tiebangchui, and most of them were diterpenoid alkaloids. These phytochemicals showed a wide range of pharmacological properties, such as anti-inflammation, anti-rheumatoid arthritis, analgesic, local anesthetic, anti-cancer and anti-bacterial activities. Hence, Tiebangchui is broadly used in hundreds of preparations to treat fever, arthritis, rheumatic arthralgia, traumatic injury, furuncle and swelling. Cardiotoxicity, neurotoxicity and gastrointestinal toxicity are the main toxic effects caused by the Aconitum alkaloids of Tiebangchui. Various processing methods, including steaming, decocting and sand-frying, and traditional Tibetan medicine processing methods, such as processing with Hezi decoction, Qingke wine and Zanba, are effective in attenuating toxicity while retaining efficacy. CONCLUSIONS The present review provides primary information of Tiebangchui, particularly for its traditional uses, botanical characteristics, phytochemicals, outstanding bioactivities and processing methods. However, studies that explored the in vivo pharmacokinetics and mechanism of Tiebangchui, as well as its quality markers, qualitative and quantitative analysis are still insufficient. Processing methods that attenuate toxicities, evaluations of efficacy, in vivo processes and biological effects, the mechanisms of processed products should be further explored.
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Affiliation(s)
- Cong-Ying Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Zhen Zhou
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Tong Xu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Nai-Yu Wang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Ce Tang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Xiao-Yan Tan
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Zi-Ge Feng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Yi Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Yue Liu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
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Jiang H, Zhang Y, Zhang Y, Wang X, Meng X. An Updated Meta-Analysis Based on the Preclinical Evidence of Mechanism of Aconitine-Induced Cardiotoxicity. Front Pharmacol 2022; 13:900842. [PMID: 35754486 PMCID: PMC9213726 DOI: 10.3389/fphar.2022.900842] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 05/02/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Most Aconitum species in traditional Chinese medicine have the effect of dispelling wind, dehumidifying, warming the meridian, and relieving pain. Aconitine is the characteristic chemical component with the function of anti-inflammation, analgesic, and heart-strengthening effects. However, improper use will produce cardiotoxicity and neurotoxicity. Currently, the mechanisms of cardiotoxicity caused by aconitine are wheels within wheels without being fully disclosed. The systematic review and meta-analysis were therefore conducted to summarize the available evidence of myocardial toxicity caused by aconitine. Methods: We searched PubMed, Embase, Web of Science, National Knowledge Infrastructure, WANFANG, and VIP information database for relevant preclinical studies. All the data were analyzed by RevMan version 5.3. Results: Thirty-two studies met the final inclusion criteria, including both in vivo and in vitro study types. After aconitine treatment, the heart rate of animals was obviously abnormal, and the morphology and function of myocardial cells were significantly changed. Aconitine can induce changes in the electrophysiological activity of cardiac myocytes by regulating Na+, Ca2+, and K+ currents. Meanwhile, the mechanisms of cardiotoxicity of aconitine may be related to triggering mitochondrial dysfunction by inducing mitochondrial apoptosis and autophagy. It should not be ignored that the overactivation of NLRP3 inflammasome also exacerbates aconitine's cardiotoxicity. Conclusion: The altered ion channels and mitochondrial function, as well as the signaling pathways interacting with NLRP3, may deserve further study for aconitine-induced cardiotoxicity.
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Affiliation(s)
- Hong Jiang
- School of Pharmacy, and Research Institute of Integrated TCM and Western Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yating Zhang
- School of Pharmacy, and Research Institute of Integrated TCM and Western Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- State Key Laboratory of Southwestern Chinese Medicine Resources, Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yi Zhang
- Ethnic Medicine Academic Heritage Innovation Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaobo Wang
- School of Pharmacy, and Research Institute of Integrated TCM and Western Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- State Key Laboratory of Southwestern Chinese Medicine Resources, Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xianli Meng
- School of Pharmacy, and Research Institute of Integrated TCM and Western Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- State Key Laboratory of Southwestern Chinese Medicine Resources, Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Ethnic Medicine Academic Heritage Innovation Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Lu H, Mei L, Guo Z, Wu K, Zhang Y, Tang S, Zhu Y, Zhao B. Hematological and Histopathological Effects of Subacute Aconitine Poisoning in Mouse. Front Vet Sci 2022; 9:874660. [PMID: 35464374 PMCID: PMC9020262 DOI: 10.3389/fvets.2022.874660] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Accepted: 03/03/2022] [Indexed: 12/04/2022] Open
Abstract
Aconitine is the principal toxic ingredient of Aconitum, which can cause systemic poisoning involving multiple organs and systems after animal ingestion. The purpose of this study was to investigate the effects of aconitine on hematological indices and histological changes in mice. One hundred twenty mice were divided into a control group (normal saline), low-dose group (0.14 μmol/L), middle-dose group (0.28 μmol/L) and high-dose group (0.56 μmol/L), which were continuously lavaged for 30 days. The blood of 10 mice were collected randomly and analyzed by group at the 10th, 20th, and 30th days, and some tissues were collected and stained with hematoxylin-eosin to observe histological changes at the 30th day. Compared with the control group, the organ coefficient (%) of liver, spleen, lungs, and brain of the high-dose group were significantly increased (p < 0.05 or p < 0.01). WBC and Gran initially decreased and then increased in each poisoning group, with significant differences in the high-dose group (p < 0.05 or p < 0.01). RBC, HGB, HCT, and PLT decreased continuously in all groups except the low-dose group at the 20th and 30th days (p < 0.05 or p < 0.01). Moreover, BUN, ALT and AST increased in each poisoning group, in comparison with the control group, with significant differences except for the low-dose group (p < 0.05 or p < 0.01). CRE initially increased and then decreased, the TP and ALB decreased, with significant differences observed in the high-dose and middle-dose groups (p < 0.05). All the mice in the poison-treated groups showed varying degrees of histopathological changes such as degeneration and necrosis of tissues, especially heart and cerebellum. Our data suggest that different doses of aconitine have remarkable effects on hematological and histopathological changes in mice, in a significant time and dose-effect relationship.
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Affiliation(s)
- Hao Lu
- College of Veterinary Medicine, Northwest A&F University, Xianyang, China
| | - Li Mei
- College of Landscape and Architecture and Art, Northwest A&F University, Xianyang, China
| | - Ziyu Guo
- College of Veterinary Medicine, Northwest A&F University, Xianyang, China
| | - Kexin Wu
- College of Veterinary Medicine, Northwest A&F University, Xianyang, China
| | - Yunhao Zhang
- College of Veterinary Medicine, Northwest A&F University, Xianyang, China
| | - Shiyu Tang
- College of Veterinary Medicine, Northwest A&F University, Xianyang, China
| | - Yiru Zhu
- College of Veterinary Medicine, Northwest A&F University, Xianyang, China
| | - Baoyu Zhao
- College of Veterinary Medicine, Northwest A&F University, Xianyang, China
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Zhou J, Peng C, Li Q, Yan X, Yang L, Li M, Cao X, Xie X, Chen D, Rao C, Huang S, Peng F, Pan X. Dopamine Homeostasis Imbalance and Dopamine Receptors-Mediated AC/cAMP/PKA Pathway Activation are Involved in Aconitine-Induced Neurological Impairment in Zebrafish and SH-SY5Y Cells. Front Pharmacol 2022; 13:837810. [PMID: 35370746 PMCID: PMC8971779 DOI: 10.3389/fphar.2022.837810] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 02/25/2022] [Indexed: 11/25/2022] Open
Abstract
Aconitine is one of the main bioactive and toxic ingredients of Aconitum species. Increasingly, aconitine has been reported to induce neurotoxicity. However, whether aconitine has effects on the dopaminergic nervous system remains unclear. In this study, zebrafish embryos at 6-days postfertilization were exposed to aconitine at doses of 0.5, 1, and 2 μM for 24 h, and SH-SY5Y cells were treated with 50, 100, and 200 μM of aconitine for 24 h. Results demonstrated that aconitine treatment induced deformities and enhanced the swimming behavior of zebrafish larvaes. Aconitine exposure suppressed cell proliferation and increased the number of reactive oxygen species and apoptosis in zebrafish larvaes and SH-SY5Y cells. Aconitine altered the levels of dopamine and its metabolites by regulating the expression of genes and proteins related to dopamine synthesis, storage, degradation, and reuptake in vivo and in vitro. Moreover, aconitine activated the AC/cAMP/PKA pathway by activating the dopamine D1 receptor (D1R) and inhibiting the dopamine D2 receptor (D2R) to disturb intracellular calcium homeostasis, eventually leading to the damage of nerve cells. Furthermore, the D1R antagonist SCH23390 and D2R agonist sumanirole pretreatment effectively attenuated the excitatory state of larvaes. Sumanirole and PKA antagonist H-89 pretreatment effectively decreased intracellular Ca2+ accumulation induced by aconitine in vivo. SCH23390 and sumanirole also reduced aconitine-induced cytotoxicity by inhibiting the AC/cAMP/PKA pathway in vitro. These results suggested that dopamine homeostasis imbalance and dopamine receptors (DRs)-mediated AC/cAMP/PKA pathway activation might be vital mechanisms underlying aconitine-induced neurological injury.
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Affiliation(s)
- Jie Zhou
- Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy and School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Department of Pharmacy, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Cheng Peng
- Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy and School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qiuju Li
- Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy and School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaoyu Yan
- Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy and School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Liang Yang
- Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy and School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Mengting Li
- Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy and School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaoyu Cao
- Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy and School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaofang Xie
- Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy and School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Dayi Chen
- Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy and School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Chaolong Rao
- Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy and School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Sizhou Huang
- Development and Regeneration Key Laboratory of Sichuan Province, Department of Anatomy and Histology and Embryology, School of Basic Medicine, Chengdu Medical College, Chengdu, China
| | - Fu Peng
- West China School of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
- *Correspondence: Fu Peng, ; Xiaoqi Pan,
| | - Xiaoqi Pan
- Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy and School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Fu Peng, ; Xiaoqi Pan,
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Prakash V, Jain V, Chauhan SS, Parthasarathi R, Roy SK, Anbumani S. Developmental toxicity assessment of 4-MBC in Danio rerio embryo-larval stages. THE SCIENCE OF THE TOTAL ENVIRONMENT 2022; 804:149920. [PMID: 34509837 DOI: 10.1016/j.scitotenv.2021.149920] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 08/16/2021] [Accepted: 08/22/2021] [Indexed: 06/13/2023]
Abstract
Enormous production of cosmetic products and its indiscriminate use tends to discharge into the aquatic environment and might threaten non-target organisms inhabiting aquatic ecosystems. In the present study, developmental toxicity of 4-methylbenzylidene camphor (4-MBC), a widely used organic UV filter in personal care products has been evaluated using zebrafish embryo-larval stages. Waterborne exposure induced developmental toxicity and deduced 2.71 mg/L as 96 h LC50 whereas embryos exposed to sub-lethal concentrations (50 and 500 μg/L) caused a significant delay in hatching rate, heart rate, reduced larval length, and restricted hatchlings motility besides the axial curvature. Chronic exposure to 10 dpf resulted in significant decrease in SOD activity at 500 μg/L with no changes in CAT level besides a significant increase in GST enzyme at 5 μg/L concentration in 5 dpf sampled larvae. However, all the three enzymes were significantly elevated in 10 dpf larvae indicating differential oxidative stress during the stages of development. Similar trend is noticed for acetylcholine esterase enzyme activity. A concentration dependent increase in malondialdehyde content was noted in larvae sampled at 5 and 10 dpf. In addition, multixenobiotic resistance (MXR) activity inhibition, and elevated oxidative tissue damage were noticed at 5 dpf with no significant changes in 10 dpf larvae. Furthermore, immunoblot analysis confirms 4-MBC induced apoptosis in zebrafish larvae with promoted cleaved Caspase-3, Bax and inhibited Bcl-2 proteins expression. Subsequently, docking studies revealed the binding potential of 4-MBC to zebrafish Abcb4 and CYP450 8A1 proteins with the binding energy of -8.1 and -8.5 kcal/mol representing target proteins interaction and toxicity potentiation. Our results showed that 4-MBC exposure triggers oxidative stress at sub-lethal concentrations leading to apoptosis, deformities and locomotion perturbations in developing zebrafish.This is first of its kind in systematically demonstrating developmental toxicity of 4-MBC and the information shall be used for aquatic toxicity risk assessment.
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Affiliation(s)
- Ved Prakash
- Ecotoxicology Laboratory, Regulatory Toxicology Group, CSIR-Indian Institute of Toxicology Research, "Vishvigyan Bhawan", 31, Mahatma Gandhi Marg, P.O. Box No.80, Lucknow 226001, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Veena Jain
- Analytical Chemistry Laboratory, Regulatory Toxicology Group, CSIR-Indian Institute of Toxicology Research, "Vishvigyan Bhawan", 31, Mahatma Gandhi Marg, P.O. Box No.80, Lucknow 226001, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Shweta Singh Chauhan
- Computational Toxicology Facility, CSIR-Indian Institute of Toxicology Research, "Vishvigyan Bhawan", 31, Mahatma Gandhi Marg, P.O. Box No.80, Lucknow 226001, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Ramakrishnan Parthasarathi
- Computational Toxicology Facility, CSIR-Indian Institute of Toxicology Research, "Vishvigyan Bhawan", 31, Mahatma Gandhi Marg, P.O. Box No.80, Lucknow 226001, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Somendu K Roy
- Analytical Chemistry Laboratory, Regulatory Toxicology Group, CSIR-Indian Institute of Toxicology Research, "Vishvigyan Bhawan", 31, Mahatma Gandhi Marg, P.O. Box No.80, Lucknow 226001, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Sadasivam Anbumani
- Ecotoxicology Laboratory, Regulatory Toxicology Group, CSIR-Indian Institute of Toxicology Research, "Vishvigyan Bhawan", 31, Mahatma Gandhi Marg, P.O. Box No.80, Lucknow 226001, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
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Zhang Y, Xia Q, Wang J, Zhuang K, Jin H, Liu K. Progress in using zebrafish as a toxicological model for traditional Chinese medicine. JOURNAL OF ETHNOPHARMACOLOGY 2022; 282:114638. [PMID: 34530096 DOI: 10.1016/j.jep.2021.114638] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 08/25/2021] [Accepted: 09/11/2021] [Indexed: 06/13/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Traditional Chinese medicine (TCM) has been applied for more than 2000 years. However, modern basic research on the safety of TCMs is limited. Establishing safety evaluation technology in line with the characteristics of TCM and conducting large-scale basic toxicity research are keys to comprehensively understand the toxicity of TCMs. In recent years, zebrafish has been used as a model organism for toxicity assessment and is increasingly utilized for toxicity research of TCMs. Yet, a comprehensive review in using zebrafish as a toxicological model for TCMs is lacked. AIM OF THE STUDY We aim to summarize the progress and limitation in toxicity evaluation of TCMs using zebrafish and put forward the future research ideas. MATERIALS AND METHODS The scientific databases, including Springer, Science Direct, Wiley, Pubmed and China Knowledge Resource Integrated (CNKI) were searched using the key words of zebrafish, toxicology, traditional Chinese medicine, acute toxicity, liver injury, cardiotoxicity, kidney toxicity, developmental toxicity, neurotoxicity, gastrointestinal irritation, immunotoxicity, ototoxicity, and osteotoxicity. RESULTS Zebrafish assays are low experimental cost and short cycle, easily achieving high-throughput toxicity screening, and exemption from ethical legislation up to 5 dpf. It has been widely used to evaluate the acute toxicity, liver toxicity, cardiotoxicity, nephrotoxicity, developmental toxicity, neurotoxicity, gastrointestinal irritation, immunotoxicity, and ototoxicity caused by TCMs, although some physiological difference limited its application. CONCLUSIONS Zebrafish is a powerful model for TCMs toxicity evaluation, but it is not flawless. The toxicity testing criterion and high throughput assays are urgent to be established. This review provides references for future studies.
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Affiliation(s)
- Yun Zhang
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China; Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, Jinan, China
| | - Qing Xia
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China; Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, Jinan, China
| | - Jiabo Wang
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Kaiyan Zhuang
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China; Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, Jinan, China
| | - Hongtao Jin
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Kechun Liu
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China; Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, Jinan, China.
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Wang W, Jiang J, Huang Y, Peng F, Hu T, Wu J, Pan X, Rao C. Aconitine induces autophagy via activating oxidative DNA damage-mediated AMPK/ULK1 signaling pathway in H9c2 cells. JOURNAL OF ETHNOPHARMACOLOGY 2022; 282:114631. [PMID: 34520828 DOI: 10.1016/j.jep.2021.114631] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 09/07/2021] [Accepted: 09/09/2021] [Indexed: 06/13/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Aconitum species, with a medicinal history of 2000 years, was traditionally used in the treatment of rheumatism, arthritis, bruises, and pains. However, many studies have reported that Aconitum species can cause arrhythmia in experimental animals, resulting in myocardial fibrosis and cardiomyocyte damage. Cardiotoxicity is the main toxic effect of aconitine, but the detailed mechanism remains unclear. AIM OF THE STUDY This study aimed to explore the effects and underlying mechanism of autophagy in H9c2 cardiomyocytes induced by aconitine. MATERIALS AND METHODS H9c2 cells were incubated with different concentrations of aconitine for 24 h, and the intervention sections were pretreated with various inhibitors for 1 h. The effects of aconitine on the oxidative DNA damage, autophagy and viability of H9c2 cells were evaluated by flow cytometry, confocal microscopy, enzyme-linked immunosorbent assay and Western blot. RESULTS In H9c2 cells, the cell viability declined, LDH release rate, the number of autophagosomes, protein expression levels of LC3 and Beclin-1 increased significantly after 24 h of aconitine incubation. The pretreatment of autophagy inhibitor 3-MA decreased markedly autophagosomes and protein expression levels of LC3 and Beclin-1, which suggested that aconitine could induce cell autophagy. The significant increase of ROS and 8-OHdG showed that aconitine could cause oxidative DNA damage through ROS accumulation. Meanwhile, treatment of aconitine dramatically increased AMPKThr172 and ULK1Ser317 phosphorylation, and Compound C inhibited AMPKThr172 and ULK1Ser317 phosphorylation, which proved that aconitine induced autophagy via AMPK activation mediated ULK1 phosphorylation. Antioxidant NAC significantly reduced LDH, ROS and 8-OHdG, inhibited the phosphorylation of AMPKThr172 and ULK1Ser317, and down-regulated autophagosomes and proteins expression levels of LC3 and Beclin-1. Consequently, the inhibition of oxidative DNA damage and AMPK/ULK1 signaling pathway alleviated the aconitine-induced autophagic death of H9c2 cells. CONCLUSIONS These results showed that aconitine induces autophagy of H9c2 cardiomyocytes by activating AMPK/ULK1 signaling pathway mediated by oxidative DNA damage. The autophagy induced by aconitine in cardiomyocytes is dependent on the activation of the AMPK pathway, which may provide novel insights into the prevention of aconitine-related toxicity.
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Affiliation(s)
- Wenlin Wang
- School of Pharmacy and School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu City, Sichuan Province, 611137, China; R&D Center for Efficiency, Safety and Application in Chinese Materia Medica with Medical and Edible Values, Chengdu University of Traditional Chinese Medicine, Chengdu City, Sichuan Province, 611137, China.
| | - Jialuo Jiang
- School of Pharmacy and School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu City, Sichuan Province, 611137, China; R&D Center for Efficiency, Safety and Application in Chinese Materia Medica with Medical and Edible Values, Chengdu University of Traditional Chinese Medicine, Chengdu City, Sichuan Province, 611137, China.
| | - Yan Huang
- School of Pharmacy and School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu City, Sichuan Province, 611137, China; R&D Center for Efficiency, Safety and Application in Chinese Materia Medica with Medical and Edible Values, Chengdu University of Traditional Chinese Medicine, Chengdu City, Sichuan Province, 611137, China.
| | - Fu Peng
- West China School of Pharmacy, West China School of Public Health, Sichuan University, Chengdu City, Sichuan Province, 610041, China.
| | - Tingting Hu
- School of Pharmacy and School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu City, Sichuan Province, 611137, China; R&D Center for Efficiency, Safety and Application in Chinese Materia Medica with Medical and Edible Values, Chengdu University of Traditional Chinese Medicine, Chengdu City, Sichuan Province, 611137, China.
| | - Jiayang Wu
- West China School of Pharmacy, West China School of Public Health, Sichuan University, Chengdu City, Sichuan Province, 610041, China.
| | - Xiaoqi Pan
- School of Pharmacy and School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu City, Sichuan Province, 611137, China; R&D Center for Efficiency, Safety and Application in Chinese Materia Medica with Medical and Edible Values, Chengdu University of Traditional Chinese Medicine, Chengdu City, Sichuan Province, 611137, China.
| | - Chaolong Rao
- School of Pharmacy and School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu City, Sichuan Province, 611137, China; R&D Center for Efficiency, Safety and Application in Chinese Materia Medica with Medical and Edible Values, Chengdu University of Traditional Chinese Medicine, Chengdu City, Sichuan Province, 611137, China.
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Wang H, Liu Y, Guo Z, Wu K, Zhang Y, Tian Y, Zhao B, Lu H. Aconitine induces cell apoptosis via mitochondria and death receptor signaling pathways in hippocampus cell line. Res Vet Sci 2022; 143:124-133. [PMID: 35026629 DOI: 10.1016/j.rvsc.2022.01.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 12/20/2021] [Accepted: 01/03/2022] [Indexed: 01/10/2023]
Abstract
Aconitine is a plant toxin derived from aconitum genus and well known for its neurological and vascular toxicity. However, the mechanism of toxicity on the growth and apoptosis of the neurological cells has not been well investigated. In this study, we used HT22 cell lines derived from hippocampus to explore the mechanism. We began with examination of the viability and DA (dopamine) contents of cells treated with different dose of aconitine. In this study, we investigated the role of apoptosis in AC-induced HT22 cells. Our results showed that aconitine inhibited HT22 cells growth and increased DA contents in a dose dependent manner. Aconitine treatment induced apoptosis in HT22 cells and we found aconitine induced apoptosis by upregulating the expression of Bax, Cyto c, Apaf-1, Caspase9, Fas, Fas-L, Fadd, Caspase8, Caspase3 with concomitant decreasing of Bcl-2 and Bid expression. Collectively, results suggest that aconitine induce apoptosis through mitochondrial-mediated and death receptor signaling pathways in HT22 cells.
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Affiliation(s)
- Hui Wang
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Yanbing Liu
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Ziyu Guo
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Kexin Wu
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Yunhao Zhang
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Yanan Tian
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine, Texas A&M University, College Station, TX 77843, USA
| | - Baoyu Zhao
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Hao Lu
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, China.
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30
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Anaeigoudari A, Azdaki N, Khazdair MR. A comprehensive review of cardiotoxic effects of selected plants. TOXIN REV 2021. [DOI: 10.1080/15569543.2020.1766506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Affiliation(s)
- Akbar Anaeigoudari
- Department of Physiology, Jiroft University of Medical Sciences, Jirof, Iran
| | - Nahid Azdaki
- Department of Cardiology, School of Medicine Cardiovascular Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Mohammad Reza Khazdair
- Cardiovascular Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran
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31
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Zhao X, Ni S, Liang N, Huang Q, Pan Z, Zhang L, Song J, Fu Y. Clinical application of Aconitum carmichaelii Debx. (Fu Zi in Chinese) by traditional Chinese medicine physicians--A cross-sectional questionnaire survey in Beijing. JOURNAL OF TRADITIONAL CHINESE MEDICAL SCIENCES 2021. [DOI: 10.1016/j.jtcms.2021.10.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
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32
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Chan YT, Wang N, Feng Y. The toxicology and detoxification of Aconitum: traditional and modern views. Chin Med 2021; 16:61. [PMID: 34315520 PMCID: PMC8314510 DOI: 10.1186/s13020-021-00472-9] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 07/16/2021] [Indexed: 01/23/2023] Open
Abstract
Aconitum carmichaeli Debx.-derived herbal medicine has been used for anti-inflammation and anti-arrhythmia purpose for more than two thousand years. It is processed into Chuanwu (Radix Aconiti praeparata) and Fuzi (Radix Aconiti lateralis praeparata) in Traditional Chinese Medicine, which are two useful drugs but with toxic properties. There have been patients poisoned by accidental ingestion of Aconitum plants or misuse of the herbal drug, and this is of great concern to study in-depth. In this review, we provided the traditional and contemporary practice of using Aconitum herbs as medicine, from functions, processing methods to toxicity in ethnomedicine aspects to discuss the underlying connections of traditional and modern understanding on the toxicity of Aconitum plants. We summarized the functions and toxicology of the herbal drugs are analyzed from chemical and clinical aspects, with the help of traditional and modern knowledge of medicine. The medicinal doses and lethal doses determined by researches are summarized, and the usage and processing methods are updated and reviewed in the modern view. In addition, clinical management of poisoned cases using western medicine is discussed. This review provides insights and awareness of safety when using Aconitum-derived herbal medicine, and the application of modern scientific knowledge to optimize the detoxification processes. We suggest the possibility to renew the current standard processing method from the official Pharmacopoeia all over the world.
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Affiliation(s)
- Yau-Tuen Chan
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, China
| | - Ning Wang
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, China.
| | - Yibin Feng
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, China.
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33
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Li Y, Zhang Z, Li S, Yu T, Jia Z. Therapeutic Effects of Traditional Chinese Medicine on Cardiovascular Diseases: the Central Role of Calcium Signaling. Front Pharmacol 2021; 12:682273. [PMID: 34305595 PMCID: PMC8299363 DOI: 10.3389/fphar.2021.682273] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 06/01/2021] [Indexed: 12/18/2022] Open
Abstract
Calcium, as a second messenger, plays an important role in the pathogenesis of cardiovascular diseases (CVDs). The malfunction of calcium signaling in endothelial cells and vascular smooth muscle cells promotes hypertension. In cardiomyocytes, calcium overload induces apoptosis, leading to myocardial infarction and arrhythmias. Moreover, the calcium–calcineurin–nuclear factor of activated T cells (NFAT) pathway is essential for expressing the cardiac pro-hypertrophic gene. Heart failure is also characterized by reduced calcium transient amplitude and enhanced sarcoplasmic reticulum (SR) calcium leakage. Traditional Chinese medicine (TCM) has been used to treat CVDs for thousands of years in China. Because of its multicomponent and multitarget characteristics, TCM's unique advantages in CVD treatment are closely related to the modulation of multiple calcium handling proteins and calcium signaling pathways in different types of cells involved in distinct CVDs. Thus, we systematically review the diverse mechanisms of TCM in regulating calcium pathways to treat various types of CVDs, ranging from hypertrophic cardiomyopathy to diabetic heart disease.
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Affiliation(s)
- Yuxin Li
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Zhang Zhang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Sen Li
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Tingting Yu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Zhaoqi Jia
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
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34
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Mi L, Li YC, Sun MR, Zhang PL, Li Y, Yang H. A systematic review of pharmacological activities, toxicological mechanisms and pharmacokinetic studies on Aconitum alkaloids. Chin J Nat Med 2021; 19:505-520. [PMID: 34247774 DOI: 10.1016/s1875-5364(21)60050-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Indexed: 12/24/2022]
Abstract
The tubers and roots of Aconitum (Ranunculaceae) are widely used as heart medicine or analgesic agents for the treatment of coronary heart disease, chronic heart failure, rheumatoid arthritis and neuropathic pain since ancient times. As a type of natural products mainly extracted from Aconitum plants, Aconitum alkaloids have complex chemical structures and exert remarkable biological activity, which are mainly responsible for significant effects of Aconitum plants. The present review is to summarize the progress of the pharmacological, toxicological, and pharmacokinetic studies of Aconitum alkaloids, so as to provide evidence for better clinical application. Research data concerning pharmacological, toxicological and pharmacokinetic studies of Aconitum alkaloids were collected from different scientific databases (PubMed, CNKI, Google Scholar, Baidu Scholar, and Web of Science) using the phrase Aconitum alkaloids, as well as generic synonyms. Aconitum alkaloids are both bioactive compounds and toxic ingredients in Aconitum plants. They produce a wide range of pharmacological activities, including protecting the cardiovascular system, nervous system, and immune system and anti-cancer effects. Notably, Aconitum alkaloids also exert strong cardiac toxicity, neurotoxicity and liver toxicity, which are supported by clinical studies. Finally, pharmacokinetic studies indicated that cytochrome P450 proteins (CYPs) and efflux transporters (ETs) are closely related to the low bioavailability of Aconitum alkaloids and play an important role in their metabolism and detoxification in vivo.
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Affiliation(s)
- Li Mi
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Yu-Chen Li
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Meng-Ru Sun
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Pei-Lin Zhang
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Yi Li
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
| | - Hua Yang
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
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35
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Xia Q, Gao S, Rapael Gnanamuthu SR, Zhuang K, Song Z, Zhang Y, Wang X, Tu P, Li J, Liu K. Involvement of Nrf2-HO-1/JNK-Erk Signaling Pathways in Aconitine-Induced Developmental Toxicity, Oxidative Stress, and ROS-Mitochondrial Apoptosis in Zebrafish Embryos. Front Pharmacol 2021; 12:642480. [PMID: 33967776 PMCID: PMC8097150 DOI: 10.3389/fphar.2021.642480] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 02/22/2021] [Indexed: 12/13/2022] Open
Abstract
Aconitine (AC), one of the bioactive diterpenoid alkaloids extracted from Aconitum plants, is widely used in traditional herbal medicine to treat various diseases. Emerging evidence indicates that AC has attracted great interest for its wide cardiotoxicity and neurotoxicity. However, the toxic effects of AC on embryonic development and its underlying mechanisms remain unclear. Here, a developmental toxicity assay of AC was performed on zebrafish embryos from 4 to 96 h post fertilization (hpf), and its underlying mechanisms were discussed. AC exposure impaired the cardiac, liver, and neurodevelopment. Especially, a high dose of AC (7.27 and 8.23 μM) exposure resulted in malformations at 72 and 96 hpf, including reduced body length, curved body shape, pericardial edema, yolk retention, swim bladder and brain developmental deficiency, and degeneration of dopaminergic neurons. High-concentration AC exposure caused a deficient cardiovascular system with cardiac dysfunctions, increased heart rates at 72 and 96 hpf, and reduced locomotor behavior at 120 hpf. AC treatment significantly increased the ROS level and triggered cell apoptosis in the heart and brain regions of embryos at 96 hpf in 7.27 and 8.23 μM AC treatment zebrafish. Oxidative stress was confirmed by reduced levels of T-SOD activity associated with accumulation of lipid peroxidation in larvae. The expression levels of oxidative stress-related genes (Nrf2, HO-1, Cat, and Sod-1) Erk1/2 and Bcl-2 were significantly downregulated at 96 hpf. The expression pattern of JNK and mitochondrial apoptosis-related genes (Bad, Bax, Cyto C, Casp-9, and Casp-3) was significantly upregulated. Taken together, all these parameters collectively provide the first evidence of AC-induced developmental toxicity in zebrafish embryo/larvae through ROS-medicated mitochondrial apoptosis involving Nrf2/HO-1 and JNK/Erk pathways.
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Affiliation(s)
- Qing Xia
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China.,Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, Jinan, China.,Shandong Provincial Engineering Laboratory for Biological Testing Technology, Jinan, China
| | - Shuo Gao
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China.,School of Pharmacy, Hebei University, Baoding, China
| | - Samuel Rajendran Rapael Gnanamuthu
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China.,Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, Jinan, China.,Shandong Provincial Engineering Laboratory for Biological Testing Technology, Jinan, China
| | - Kaiyan Zhuang
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China.,Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, Jinan, China.,Shandong Provincial Engineering Laboratory for Biological Testing Technology, Jinan, China
| | - Zhenzhen Song
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China.,Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, Jinan, China.,School of Pharmacy, Hebei University, Baoding, China
| | - Yun Zhang
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China.,Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, Jinan, China.,Shandong Provincial Engineering Laboratory for Biological Testing Technology, Jinan, China
| | - Xue Wang
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China.,Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, Jinan, China.,Shandong Provincial Engineering Laboratory for Biological Testing Technology, Jinan, China
| | - Pengfei Tu
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China.,Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, Jinan, China.,State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Jianheng Li
- School of Pharmacy, Hebei University, Baoding, China
| | - Kechun Liu
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China.,Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, Jinan, China.,Shandong Provincial Engineering Laboratory for Biological Testing Technology, Jinan, China
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36
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Zhou J, Peng F, Cao X, Xie X, Chen D, Yang L, Rao C, Peng C, Pan X. Risk Compounds, Preclinical Toxicity Evaluation, and Potential Mechanisms of Chinese Materia Medica-Induced Cardiotoxicity. Front Pharmacol 2021; 12:578796. [PMID: 33867974 PMCID: PMC8044783 DOI: 10.3389/fphar.2021.578796] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 01/29/2021] [Indexed: 02/05/2023] Open
Abstract
Chinese materia medica (CMM) has been applied for the prevention and treatment of diseases for thousands of years. However, arrhythmia, myocardial ischemia, heart failure, and other cardiac adverse reactions during CMM application were gradually reported. CMM-induced cardiotoxicity has aroused widespread attention. Our review aimed to summarize the risk compounds, preclinical toxicity evaluation, and potential mechanisms of CMM-induced cardiotoxicity. All relevant articles published on the PubMed, Embase, and China National Knowledge Infrastructure (CNKI) databases for the latest twenty years were searched and manually extracted. The risk substances of CMM-induced cardiotoxicity are relatively complex. A single CMM usually contains various risk compounds, and the same risk substance may exist in various CMM. The active and risk substances in CMM may be transformed into each other under different conditions, such as drug dosage, medication methods, and body status. Generally, the risk compounds of CMM-induced cardiotoxicity can be classified into alkaloids, terpenoids, steroids, heavy metals, organic acids, toxic proteins, and peptides. Traditional evaluation methods of chemical drug-induced cardiotoxicity primarily include cardiac function monitoring, endomyocardial biopsy, myocardial zymogram, and biomarker determination. In the preclinical stage, CMM-induced cardiotoxicity should be systematically evaluated at the overall, tissue, cellular, and molecular levels, including cardiac function, histopathology, cytology, myocardial zymogram, and biomarkers. Thanks to the development of systematic biology, the higher specificity and sensitivity of biomarkers, such as genes, proteins, and metabolic small molecules, are gradually applied for evaluating CMM-induced cardiotoxicity. Previous studies on the mechanisms of CMM-induced cardiotoxicity focused on a single drug, monomer or components of CMM. The interaction among ion homeostasis (sodium, potassium, and calcium ions), oxidative damage, mitochondrial injury, apoptosis and autophagy, and metabolic disturbance is involved in CMM-induced cardiotoxicity. Clarification on the risk compounds, preclinical toxicity evaluation, and potential mechanisms of CMM-induced cardiotoxicity must be beneficial to guide new CMM development and post-marketed CMM reevaluation.
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Affiliation(s)
- Jie Zhou
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy and School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Department of Pharmacy, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Fu Peng
- West China School of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaoyu Cao
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy and School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaofang Xie
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy and School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Dayi Chen
- School of Pharmacy and School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Lian Yang
- School of Pharmacy and School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Chaolong Rao
- School of Pharmacy and School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy and School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaoqi Pan
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy and School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Li ES, Saha MS. Optimizing Calcium Detection Methods in Animal Systems: A Sandbox for Synthetic Biology. Biomolecules 2021; 11:343. [PMID: 33668387 PMCID: PMC7996158 DOI: 10.3390/biom11030343] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 02/19/2021] [Accepted: 02/21/2021] [Indexed: 12/16/2022] Open
Abstract
Since the 1970s, the emergence and expansion of novel methods for calcium ion (Ca2+) detection have found diverse applications in vitro and in vivo across a series of model animal systems. Matched with advances in fluorescence imaging techniques, the improvements in the functional range and stability of various calcium indicators have significantly enhanced more accurate study of intracellular Ca2+ dynamics and its effects on cell signaling, growth, differentiation, and regulation. Nonetheless, the current limitations broadly presented by organic calcium dyes, genetically encoded calcium indicators, and calcium-responsive nanoparticles suggest a potential path toward more rapid optimization by taking advantage of a synthetic biology approach. This engineering-oriented discipline applies principles of modularity and standardization to redesign and interrogate endogenous biological systems. This review will elucidate how novel synthetic biology technologies constructed for eukaryotic systems can offer a promising toolkit for interfacing with calcium signaling and overcoming barriers in order to accelerate the process of Ca2+ detection optimization.
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Affiliation(s)
| | - Margaret S. Saha
- Department of Biology, College of William and Mary, Williamsburg, VA 23185, USA;
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38
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Wang M, Shi Y, Yao L, Li Q, Wang Y, Fu D. Potential Molecular Mechanisms and Drugs for Aconitine-Induced Cardiotoxicity in Zebrafish through RNA Sequencing and Bioinformatics Analysis. Med Sci Monit 2020; 26:e924092. [PMID: 32598336 PMCID: PMC7341694 DOI: 10.12659/msm.924092] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Background Accumulating evidence suggests that cardiotoxicity is one of the main manifestations of aconitine (AC) poisoning. However, the molecular mechanism of AC-induced cardiotoxicity remains unclear, there is little direct evidence for therapeutic targets and drugs of AC-induced cardiotoxicity. Material/Methods Zebrafish were exposed to AC to evaluate cardiotoxicity by calculating the heart rates and observing the changes of cardiac and vascular structure. RNA-seq (RNA sequencing) and bioinformatics analysis were used to obtain differentially expressed genes (DEGs). The anti-AC cardiotoxicity compound was identified via connectivity map (CMAP) analysis and molecular docking. Results AC-induced cardiotoxicity in zebrafish predominantly included arrhythmias, extended sinus venous and bulbus arteriosus (SV-BA) distance, and larger pericardial edema aera. A total of 1380 DEGs were identified by RNA-seq and bioinformatics analysis. cyclin-dependent kinase-1 (CDK1) was screened as the hub gene and the most potential therapeutic target due to its significant downregulation in cardiotoxicity based on protein-protein interaction (PPI) and drug-gene interaction (DGIdb) network analysis. Cell cycle signal pathway was the most significant pathways identified in the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Furthermore, the expression of CDK1 was validated in the Gene Expression Omnibus (GEO) database GSE71906, GSE65705, and GSE95140. Finally, heptaminol was identified as a novel anti-AC cardiotoxicity compound via CMAP analysis and molecular docking. Conclusions Totally, hub genes and key pathways identified in this study can aid in the understanding of the molecular changes in AC-induced cardiotoxicity. Meanwhile, we provide a systematic method to explore drug toxicity prevention and treatment.
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Affiliation(s)
- Mingzhu Wang
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China (mainland)
| | - Yanan Shi
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China (mainland)
| | - Lei Yao
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China (mainland)
| | - Qiang Li
- Children's Hospital of Fudan University, Shanghai, China (mainland)
| | - Youhua Wang
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China (mainland)
| | - Deyu Fu
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China (mainland)
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