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Rai M, Rai A, Mori T, Nakabayashi R, Nakamura M, Kojoma M, Suzuki H, Saito K, Yamazaki M. Multi-omics analysis reveals tissue-specific biosynthesis and accumulation of diterpene alkaloids in Aconitum japonicum. J Nat Med 2025; 79:499-516. [PMID: 40111723 PMCID: PMC12058934 DOI: 10.1007/s11418-025-01881-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Accepted: 01/21/2025] [Indexed: 03/22/2025]
Abstract
Aconitum japonicum, native to the mountainous regions of Japan, is a toxic perennial plant widely recognized for its therapeutic potential. Despite its pharmacological importance, the complete biosynthetic pathway of diterpene alkaloids, bioactive compounds with significant pharmaceutical implications and derived from Aconitum species, remains elusive. In this study, leveraging high-throughput metabolome and transcriptome analyses, we conducted a comprehensive investigation using four tissues of A. japonicum, including leaf, mother root, daughter root, and rootlet. By integrating these multi-omics datasets, we achieved a holistic insight into the gene expression patterns and metabolite profiles intricately linked with diterpene alkaloid biosynthesis. Our findings unveil potential regulatory networks and pinpoint key candidate genes pivotal in diterpene alkaloid synthesis. Through comparative analyses across tissues, we delineate tissue-specific variations in gene expression and metabolite accumulation, shedding light on the spatial regulation of these biosynthetic pathways within the plant. Furthermore, this study contributes to a deeper understanding of the molecular mechanisms dictating the production of diterpene alkaloids in A. japonicum. Besides advancing our knowledge of plant secondary metabolism in A. japonicum, this study also provides a high-quality multi-omics resource for future studies aimed at functionally characterizing the target genes involved in different metabolic processes.
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Affiliation(s)
- Megha Rai
- Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
- Crop Sciences, University of Illinois Urbana Champaign, Illinois, USA
| | - Amit Rai
- Crop Sciences, University of Illinois Urbana Champaign, Illinois, USA
| | - Tetsuya Mori
- RIKEN Center for Sustainable Resource Science, Yokohama, Japan
| | - Ryo Nakabayashi
- RIKEN Center for Sustainable Resource Science, Yokohama, Japan
| | - Michimi Nakamura
- Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
| | - Marsheige Kojoma
- Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Hokkaido, Japan
| | | | - Kazuki Saito
- RIKEN Center for Sustainable Resource Science, Yokohama, Japan
- Plant Molecular Science Center, Chiba University, Chiba, Japan
| | - Mami Yamazaki
- Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
- Plant Molecular Science Center, Chiba University, Chiba, Japan.
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2
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Zhu KX, Wu M, Bian ZL, Han SL, Fang LM, Ge FF, Wang XZ, Xie SF. Growing attention on the toxicity of Chinese herbal medicine: a bibliometric analysis from 2013 to 2022. Front Pharmacol 2024; 15:1293468. [PMID: 38362153 PMCID: PMC10867220 DOI: 10.3389/fphar.2024.1293468] [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: 09/13/2023] [Accepted: 01/22/2024] [Indexed: 02/17/2024] Open
Abstract
Introduction: Despite the clinical value of Chinese herbal medicine (CHM), restricted comprehension of its toxicity limits the secure and efficacious application. Previous studies primarily focused on exploring specific toxicities within CHM, without providing an overview of CHM's toxicity. The absence of a quantitative assessment of focal points renders the future research trajectory ambiguous. Therefore, this study aimed to reveal research trends and areas of concern for the past decade. Methods: A cross-sectional study was conducted on publications related to CHM and toxicity over the past decade from Web of Science Core Collection database. The characteristics of the publication included publication year, journal, institution, funding, keywords, and citation counts were recorded. Co-occurrence analysis and trend topic analysis based on bibliometric analysis were conducted on keywords and citations. Results: A total of 3,225 publications were analyzed. Number of annal publications increased over the years, with the highest number observed in 2022 (n = 475). The Journal of Ethnopharmacology published the most publications (n = 425). The most frequently used toxicity classifications in keywords were hepatotoxicity (n = 119) or drug-induced liver injury (n = 48), and nephrotoxicity (n = 40). Co-occurrence analysis revealed relatively loose connections between CHM and toxicity, and their derivatives. Keywords emerging from trend topic analysis for the past 3 years (2019-2022) included ferroptosis, NLRP3 inflammasome, machine learning, network pharmacology, traditional uses, and pharmacology. Conclusion: Concerns about the toxicity of CHM have increased in the past decade. However, there remains insufficient studies that directly explore the intersection of CHM and toxicity. Hepatotoxicity and nephrotoxicity, as the most concerned toxicity classifications associated with CHM, warrant more in-depth investigations. Apoptosis was the most concerned toxicological mechanism. As a recent increase in attention, exploring the mechanisms of ferroptosis in nephrotoxicity and NLRP3 inflammasome in hepatotoxicity could provide valuable insights. Machine learning and network pharmacology are potential methods for future studies.
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Affiliation(s)
- Ke-Xin Zhu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China
| | - Min Wu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China
| | - Zhi-Lin Bian
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China
| | - Shi-Liang Han
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China
| | - Li-Ming Fang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China
| | - Feng-Feng Ge
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China
| | - Xue-Zhou Wang
- International Acupuncture and Moxibustion Innovation Institute, School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, China
| | - Sheng-Fang Xie
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China
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3
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Bjørklund G, Cruz-Martins N, Goh BH, Mykhailenko O, Lysiuk R, Shanaida M, Lenchyk L, Upyr T, Rusu ME, Pryshlyak A, Shanaida V, Chirumbolo S. Medicinal Plant-derived Phytochemicals in Detoxification. Curr Pharm Des 2024; 30:988-1015. [PMID: 37559241 DOI: 10.2174/1381612829666230809094242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Revised: 07/01/2023] [Accepted: 07/11/2023] [Indexed: 08/11/2023]
Abstract
The average worldwide human life expectancy is 70 years, with a significantly higher value in Western societies. Many modern diseases are not associated with premature mortality but with a decreased quality of life in aged patients and an excessive accumulation of various toxic compounds in the human body during life. Today, scientists are especially interested in finding compounds that can help increase a healthy lifespan by detoxifying the body. Phytotherapy with specific approaches is used in alternative medicine to remove toxins from the body. Worldwide, research is conducted to identify medicinal plant-derived molecules that, with few or no side effects, may protect the liver and other organs. This review provides updated information about the detoxification process, the traditional and modern use of the most effective medicinal plants, their active metabolites as detoxifying agents, and the mechanisms and pathways involved in the detoxification process. Among medicinal plants with substantial detoxifying properties, a major part belongs to the Asteraceae family (Silybum marianum, Cynara scolymus, Arctium lappa, Helichrysum species, Inula helenium, and Taraxacum officinale). The most widely used hepatoprotective phytocomponent is silymarin, a standardized extract from the Silybum marianum seeds containing a mixture of flavonolignans. Many polysaccharides, polyphenols, and terpenoids have a detoxifying effect. Overall, scientific data on medicinal plants used in phytotherapeutic practice worldwide provides an understanding and awareness of their efficacy in detoxification.
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Affiliation(s)
- Geir Bjørklund
- Department of Research, Council for Nutritional and Environmental Medicine (CONEM), Toften 24, Mo i Rana 8610, Norway
| | - Natália Cruz-Martins
- Faculty of Medicine, University of Porto, Alameda Prof. Hernani Monteiro, Porto, Portugal
- Institute for Research and Innovation in Health (i3S), University of Porto, Porto, Portugal
- Institute of Research and Advanced Training in Health Sciences and Technologies (CESPU), Rua Central de Gandra, 1317, 4585-116 Gandra PRD, Portugal
- TOXRUN-Toxicology Research Unit, University Institute of Health Sciences, CESPU, CRL, 4585-116 Gandra, Portugal
| | - Bey Hing Goh
- Biofunctional Molecule Exploratory (BMEX) Research Group, School of Pharmacy, Monash University Malaysia, Victoria, Malaysia
- Institute of Pharmaceutical Science, University of Veterinary and Animal Science, Lahore, Pakistan
- Center of Health Outcomes Research and Therapeutic Safety (Cohorts), School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand
| | - Olha Mykhailenko
- Department of Pharmaceutical Chemistry, National University of Pharmacy of Ministry of Health of Ukraine, Kharkiv, Ukraine
- CONEM Ukraine Bromatology and Medicinal Chemistry Group, National University of Pharmacy, Kharkiv, Ukraine
| | - Roman Lysiuk
- Department of Pharmacognosy and Botany, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine
- CONEM Ukraine Life Science Research Group, Department of Pharmacognosy and Botany, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine
| | - Mariia Shanaida
- Department of Pharmacognosy and Medical Botany, I. Horbachevsky Ternopil National Medical University, Ternopil, Ukraine
| | - Larysa Lenchyk
- CONEM Ukraine Pharmacognosy and Natural Product Chemistry Research Group, National University of Pharmacy, Kharkiv, Ukraine
- Department of Pharmaceutical Technologies and Quality of Medicines, Institute for Advanced Training of Pharmacy Specialists, National University of Pharmacy, Kharkiv, Ukraine
| | - Taras Upyr
- CONEM Ukraine Pharmacognosy and Natural Product Chemistry Research Group, National University of Pharmacy, Kharkiv, Ukraine
| | - Marius Emil Rusu
- Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Antonina Pryshlyak
- Department of Human Anatomy, I. Horbachevsky Ternopil National Medical University, Ternopil, Ukraine
| | - Volodymyr Shanaida
- Design of Machine Tools, Instruments and Machines Department, Ternopil Ivan Puluj National Technical University, Ternopil, Ukraine
| | - Salvatore Chirumbolo
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
- CONEM Scientific Secretary, Verona, Italy
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4
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Wanting H, Jian Z, Chaoxin X, Cheng Y, Chengjian Z, Lin Z, Dan C. Using a zebrafish xenograft tumor model to compare the efficacy and safety of VEGFR-TKIs. J Cancer Res Clin Oncol 2023:10.1007/s00432-022-04560-7. [PMID: 36609710 DOI: 10.1007/s00432-022-04560-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 12/24/2022] [Indexed: 01/09/2023]
Abstract
PURPOSE We constructed a zebrafish xenograft tumor model to compare and quantify the antiangiogenic efficacy and safety of nine vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs), axitinib, lenvatinib, pazopanib, apatinib, cabozantinib, sunitinib, semaxanib, sorafenib, and regorafenib, in parallel. METHODS CT26 and GL261 tumor cells were implanted into the perivitelline space of Tg (flk1: eGFP) zebrafish to construct a xenograft tumor model. VEGFR-TKIs' antiangiogenic efficacy was quantified using AngioTool software, and the median effective dose (ED50) was calculated. The toxicity was evaluated by calculating the median lethal dose (LD50) and gross morphological changes. Cardiac toxicity was further assessed by heart rate, heart rhythm, the distance between the sinus venosus (SV) and bulbus arteriosus (BA), and pericardial edema. RESULTS Using the zebrafish xenograft tumor model, we found that all nine VEGFR-TKIs exhibited antiangiogenic abilities, but the effectiveness of semaxanib was worse than that of other VEGFR-TKIs. Meanwhile, the zebrafish toxicity assay showed that all tested VEGFR-TKIs were associated with cardiac-related toxicity, especially apatinib and axitinib, which caused serious pericardial edema in zebrafish at relatively low concentrations. A narrow therapeutic window was found for most VEGFR-TKIs, and the simultaneous occurrence of toxic effects of semaxanib was recognized. CONCLUSION Our findings showed the potential of using a zebrafish xenograft tumor model to accelerate VEGFR-TKI screening and further the development of more efficient and less toxic VEGFR-TKIs.
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Affiliation(s)
- Hou Wanting
- Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, People's Republic of China
| | - Zhong Jian
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan Province, People's Republic of China
| | - Xiao Chaoxin
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan Province, People's Republic of China
| | - Yi Cheng
- Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, People's Republic of China
| | - Zhao Chengjian
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan Province, People's Republic of China
| | - Zhou Lin
- Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, People's Republic of China.
| | - Cao Dan
- Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, People's Republic of China.
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Chen ZY, Wei XY, Qiu ZD, Huang Y, Tan T, Feng YL, Guo J, Cui GH, Huang LQ, Lai CJS. Compatibility of Fuzi and Ginseng Significantly Increase the Exposure of Aconitines. Front Pharmacol 2022; 13:883898. [PMID: 35662724 PMCID: PMC9156935 DOI: 10.3389/fphar.2022.883898] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 04/05/2022] [Indexed: 11/13/2022] Open
Abstract
The herb-pair ginseng-Fuzi (the root of Aconitum carmichaelii) is the material basis of Shenfu prescriptions and is popular in traditional Chinese medicine for the treatment of heart failure, and even shock with severe-stage of COVID-19. A narrow therapeutic window of Fuzi may cause significant regional loss of property and life in clinics. Therefore, systemic elucidation of active components is crucial to improve the safety dose window of Shenfu oral prescriptions. A high performance liquid chromatography-mass spectrometry method was developed for quantification of 10 aconitines in SD rat plasma within 9 min. The limit of detection and the limit of quantification were below 0.032 ng/ml and 0.095 ng/ml, respectively. Furthermore, a systemic comparison with their pharmacokinetic characteristics after oral administration of a safe dosage of 2 g/kg of Fuzi and ginseng-Fuzi decoction for 24 h was conducted. Eight representative diester, monoester, and non-ester aconitines and two new active components (i.e., songorine and indaconitine) were all adopted to elucidating the differences of the pharmacokinetic parameters in vivo. The compatibility of Fuzi and ginseng could significantly increase the in vivo exposure of active components. The terminal elimination half-life and the area under the concentration-time curve of mesaconitine, benzoylaconitine, benzoylmesaconitine, benzoylhypaconitine, and songorine were all increased significantly. The hypaconitine, benzoylmesaconitine, and songorine were regarded as the main active components in vivo, which gave an effective clue for the development of new Shenfu oral prescriptions.
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Affiliation(s)
- Ze-Yan Chen
- State Key Laboratory Breeding Base of Dao-di Herbs, National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.,School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Xu-Ya Wei
- State Key Laboratory Breeding Base of Dao-di Herbs, National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.,Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Zi-Dong Qiu
- State Key Laboratory Breeding Base of Dao-di Herbs, National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yun Huang
- Pharmaceutical College, Hebei Medical University, Shijiazhuang, China
| | - Ting Tan
- Jiangxi University of Traditional Chinese Medicine, Nanchang, China.,The National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Yu-Lin Feng
- Jiangxi University of Traditional Chinese Medicine, Nanchang, China.,The National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Juan Guo
- State Key Laboratory Breeding Base of Dao-di Herbs, National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Guang-Hong Cui
- State Key Laboratory Breeding Base of Dao-di Herbs, National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Lu-Qi Huang
- State Key Laboratory Breeding Base of Dao-di Herbs, National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.,School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Chang-Jiang-Sheng Lai
- State Key Laboratory Breeding Base of Dao-di Herbs, National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
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6
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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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7
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Acute Developmental Toxicity of Panax notoginseng in Zebrafish Larvae. Chin J Integr Med 2022; 29:333-340. [PMID: 35089525 DOI: 10.1007/s11655-022-3302-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/25/2020] [Indexed: 11/03/2022]
Abstract
OBJECTIVE To evaluate toxicity of raw extract of Panax notoginseng (rPN) and decocted extract of PN (dPN) by a toxicological assay using zebrafish larvae, and explore the mechanism by RNA sequencing assay. METHODS Zebrafish larvae was used to evaluate acute toxicity of PN in two forms: rPN and dPN. Three doses (0.5, 1.5, and 5.0 µ g/mL) of dPN were used to treat zebrafishes for evaluating the developmental toxicity. Behavior abnormalities, body weight, body length and number of vertebral roots were used as specific phenotypic endpoints. RNA sequencing (RNA-seq) assay was applied to clarify the mechanism of acute toxicity, followed by real time PCR (qPCR) for verification. High performance liquid chromatography analysis was performed to determine the chemoprofile of this herb. RESULTS The acute toxicity result showed that rPN exerted higher acute toxicity than dPN in inducing death of larval zebrafishes (P<0.01). After daily oral intake for 21 days, dPN at doses of 0.5, 1.5 and 5.0 µ g/mL decreased the body weight, body length, and vertebral number of larval zebrafishes, indicating developmental toxicity of dPN. No other adverse outcome was observed during the experimental period. RNA-seq data revealed 38 genes differentially expressed in dPN-treated zebrafishes, of which carboxypeptidase A1 (cpa1) and opioid growth factor receptor-like 2 (ogfrl2) were identified as functional genes in regulating body development of zebrafishes. qPCR data showed that dPN significantly down-regulated the mRNA expressions of cpa1 and ogfrl2 (both P<0.01), verifying cpa1 and ogfrl2 as target genes for dPN. CONCLUSION This report uncovers the developmental toxicity of dPN, suggesting potential risk of its clinical application in children.
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Hu Q, He Y, Wang F, Wu J, Ci Z, Chen L, Xu R, Yang M, Lin J, Han L, Zhang D. Microwave technology: a novel approach to the transformation of natural metabolites. Chin Med 2021; 16:87. [PMID: 34530887 PMCID: PMC8444431 DOI: 10.1186/s13020-021-00500-8] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 09/04/2021] [Indexed: 12/13/2022] Open
Abstract
Microwave technology is used throughout the world to generate heat using energy from the microwave range of the electromagnetic spectrum. It is characterized by uniform energy transfer, low energy consumption, and rapid heating which preserves much of the nutritional value in food products. Microwave technology is widely used to process food such as drying, because food and medicinal plants are the same organisms. Microwave technology is also used to process and extract parts of plants for medicinal purposes; however, the special principle of microwave radiation provide energy to reaction for transforming chemical components, creating a variety of compounds through oxidation, hydrolysis, rearrangement, esterification, condensation and other reactions that transform original components into new ones. In this paper, the principles, influencing factors of microwave technology, and the transformation of natural metabolites using microwave technology are reviewed, with an aim to provide a theoretical basis for the further study of microwave technology in the processing of medicinal materials.
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Affiliation(s)
- Qi Hu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Yanan He
- State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Fang Wang
- State Key Laboratory of Innovation Medicine and High Efficiency and Energy Saving Pharmaceutical Equipment, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004, China
| | - Jing Wu
- Xinqi Microwave Co., Ltd., Guiyang, 550000, China
| | - Zhimin Ci
- State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Lumeng Chen
- State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Runchun Xu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Ming Yang
- State Key Laboratory of Innovation Medicine and High Efficiency and Energy Saving Pharmaceutical Equipment, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004, China
| | - Junzhi Lin
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China.
| | - Li Han
- State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Dingkun Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
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9
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Qiu LZ, Zhou W, Yue LX, Wang YH, Hao FR, Li PY, Gao Y. Repeated Aconitine Treatment Induced the Remodeling of Mitochondrial Function via AMPK-OPA1-ATP5A1 Pathway. Front Pharmacol 2021; 12:646121. [PMID: 34177570 PMCID: PMC8224173 DOI: 10.3389/fphar.2021.646121] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Accepted: 03/08/2021] [Indexed: 12/19/2022] Open
Abstract
Aconitine is attracting increasing attention for its unique positive inotropic effect on the cardiovascular system, but underlying molecular mechanisms are still not fully understood. The cardiotonic effect always requires abundant energy supplement, which is mainly related to mitochondrial function. And OPA1 has been documented to play a critical role in mitochondrial morphology and energy metabolism in cardiomyocytes. Hence, this study was designed to investigate the potential role of OPA1-mediated regulation of energy metabolism in the positive inotropic effect caused by repeated aconitine treatment and the possible mechanism involved. Our results showed that repeated treatment with low-doses (0-10 μM) of aconitine for 7 days did not induce detectable cytotoxicity and enhanced myocardial contraction in Neonatal Rat Ventricular Myocytes (NRVMs). Also, we first identified that no more than 5 μM of aconitine triggered an obvious perturbation of mitochondrial homeostasis in cardiomyocytes by accelerating mitochondrial fusion, biogenesis, and Parkin-mediated mitophagy, followed by the increase in mitochondrial function and the cellular ATP content, both of which were identified to be related to the upregulation of ATP synthase α-subunit (ATP5A1). Besides, with compound C (CC), an inhibitor of AMPK, could reverse aconitine-increased the content of phosphor-AMPK, OPA1, and ATP5A1, and the following mitochondrial function. In conclusion, this study first demonstrated that repeated aconitine treatment could cause the remodeling of mitochondrial function via the AMPK-OPA1-ATP5A1 pathway and provide a possible explanation for the energy metabolism associated with cardiotonic effect induced by medicinal plants containing aconitine.
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Affiliation(s)
- Li-Zhen Qiu
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.,Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, China
| | - Wei Zhou
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, China
| | - Lan-Xin Yue
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, China
| | - Yi-Hao Wang
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, China
| | - Fei-Ran Hao
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, China
| | - Peng-Yan Li
- The Fifth Medical Center, General Hospital of PLA, Beijing, China
| | - Yue Gao
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.,Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, China
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Toxicity Assessment of Herbal Medicine Using Zebrafish Embryos: A Systematic Review. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2019; 2019:7272808. [PMID: 31781278 PMCID: PMC6875295 DOI: 10.1155/2019/7272808] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Revised: 09/30/2019] [Accepted: 10/18/2019] [Indexed: 12/22/2022]
Abstract
Herbal remedies have been practiced by humans over centuries and therefore possess time-proven safety. However, it is imperative to evaluate the toxic effects of herbal medicine to confirm their safety, particularly when developing therapeutic leads. Use of laboratory animals such as rats, mice, and rabbits was considered as gold standard in herbal toxicity assessments. However, in the last few decades, the ethical consideration of using higher vertebrates for toxicity testing has become more contentious. Thus, possible alternative models entailing lower vertebrates such as zebrafish were introduced. The zebrafish embryotoxicity model is at the forefront of toxicology assessment due to the transparent nature of embryos, low cost, short cycle, higher fecundity, and genetic redundancy to the humans. Recently, its application has been extended to herbal toxicology. The present review intends to provide a comprehensive assembly of studies that applied the zebrafish embryo model for the assessment of herbal toxicity. A systematic literature survey was carried out in popular scientific databases. The literature search identified a total of 1014 articles in PubMed = 12, Scopus SciVerse® = 623, and Google Scholar = 1000. After screening, 25 articles were included in this review, and they were categorized into three groups in which the zebrafish embryotoxicity assay has been applied to investigate the toxicity of (1) polyherbal formulae/medical prescription (2 full texts), (2) crude extracts (12 full texts), and (3) phytocompounds/isolated constituents (11 full texts). These studies have investigated the toxicity of 6 polyherbal formulae, 16 crude extracts, and more than 30 phytocompounds/isolated constituents using the zebrafish embryotoxicity model. Moreover, this model has explicated the teratogenic effects and specific organ toxicities such as the kidney, heart, and liver. Furthermore, in some studies, the molecular mechanisms underlying the toxicity of herbal medicine have been elucidated. This comprehensive collection of scientific data solidifies the zebrafish embryo model as an effective model system for studying toxicological effects of a broad spectrum of herbal remedies. Henceforth, it provides a novel insight into the toxicity assessment of herbal medicine.
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