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Wang H, Zhang H, Miao L, Wang C, Teng H, Li X, Zhang X, Yang G, Wang S, Zeng X. α-amanitin induces hepatotoxicity via PPAR-γ inhibition and NLRP3 inflammasome activation. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2025; 290:117749. [PMID: 39862693 DOI: 10.1016/j.ecoenv.2025.117749] [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: 11/07/2024] [Revised: 01/07/2025] [Accepted: 01/14/2025] [Indexed: 01/27/2025]
Abstract
Mushroom poisoning, predominantly caused by α-amanitin, is a critical food safety concern in worldwide, with severe cases leading to hepatotoxicity and fatalities. This study delves into the hepatotoxic effects of α-amanitin, focusing on the NLRP3 inflammasome and PPAR-γ's regulatory role in inflammation. In vitro studies with L-02 cells showed that α-amanitin reduces cell viability and triggers NLRP3 inflammasome activation, increasing NF-κB phosphorylation and pro-inflammatory cytokines IL-18 and IL-1β. The NLRP3 inhibitor MCC950 mitigated these effects without impacting NF-κB. Conversely, PPAR-γ knockdown intensified the inflammatory response. In vivo, α-amanitin induced dose-dependent liver injury in mice, evident by elevated serum ALT and AST, and histological liver damage. MCC950 pretreatment offered protection against hepatotoxicity, while PPAR-γ inhibition with GW9662 worsened the condition. The study highlights the interplay between α-amanitin, NLRP3, and PPAR-γ in hepatotoxicity, proposing potential therapeutic targets for mushroom poisoning-induced liver diseases.
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Affiliation(s)
- Haowei Wang
- Department of Forensic Medicine, School of Forensic Medicine, Kunming Medical University, Kunming, China
| | - Huijie Zhang
- Department of Forensic Medicine, School of Forensic Medicine, Kunming Medical University, Kunming, China
| | - Lin Miao
- Department of Forensic Medicine, School of Forensic Medicine, Kunming Medical University, Kunming, China
| | - Chan Wang
- Department of Forensic Medicine, School of Forensic Medicine, Kunming Medical University, Kunming, China
| | - Hanxin Teng
- Department of Pathogen Biology and Immunology, School of Basic Medical Science, Kunming Medical University, Kunming, China
| | - Xiaodong Li
- Department of Forensic Medicine, School of Forensic Medicine, Kunming Medical University, Kunming, China
| | - Xiaoxing Zhang
- Department of Forensic Medicine, School of Forensic Medicine, Kunming Medical University, Kunming, China
| | - Genmeng Yang
- Department of Forensic Medicine, School of Forensic Medicine, Kunming Medical University, Kunming, China.
| | - Shangwen Wang
- Department of Forensic Medicine, School of Forensic Medicine, Kunming Medical University, Kunming, China.
| | - Xiaofeng Zeng
- Department of Forensic Medicine, School of Forensic Medicine, Kunming Medical University, Kunming, China.
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Stöckert P, Rusch S, Schlosser-Hupf S, Mehrl A, Zimmermann K, Pavel V, Mester P, Brosig AM, Schilling T, Müller M, Schmid S. Increasing incidence of mycotoxicosis in South-Eastern Germany: a comprehensive analysis of mushroom poisonings at a University Medical Center. BMC Gastroenterol 2024; 24:450. [PMID: 39690424 DOI: 10.1186/s12876-024-03550-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Accepted: 12/03/2024] [Indexed: 12/19/2024] Open
Abstract
BACKGROUND Mushrooms, an integral component of human diets, range from esteemed delicacies to potentially lethal toxins. The risk of severe poisoning from misidentified species, poses a significant challenge. For clinicians, recognizing mushroom poisoning amidst nonspecific symptoms and determining the specific mushroom ingested are critical yet complex tasks. Additionally, climate change affects the distribution and proliferation of mushroom species, potentially heightening the risk of exposure to toxic varieties. The identification of mushroom intoxication is critical for appropriate treatment. Poisoning with highly toxic species, such as Amanita phalloides (death cap), can result in acute liver and kidney failure. Considering the limited therapeutic options currently available for acute liver failure, we investigated the application of plasmapheresis, a procedure involving the replacement of the patient's plasma with donor plasma, as a potential intervention to improve clinical outcomes in severe cases of mushroom poisoning. METHODS This study aimed to assess the trends and treatment outcomes of mushroom poisoning cases from 2005 to 2022, with a particular focus on the number of incidents and the potential impacts of climate change. We undertook a retrospective monocentric cohort study, evaluating 43 patients with mushroom poisoning. The study focused on identifying the variety of mushrooms involved, including psychotropic, spoiled, inedible, or toxic species, and closely examined patients with elevated transaminases indicative for liver damage. To assess clinical outcomes, we evaluated several aspects, including hepatic encephalopathy and other symptoms. Additionally, we monitored blood analysis results through serial measurements, including transaminases, bilirubin, INR, and creatinine levels. Furthermore, we explored the impact of climate changes on the incidence of mushroom poisoning. RESULTS While the incidence of mushroom poisonings remained relatively stable during the first eight years of the study period, it nearly doubled over the past nine years. Nine distinct mushroom types were documented. The study showed no change in season patterns of mushroom poisonings. In cases of severe liver damage accompanied by coagulopathy, plasmapheresis was utilized to replace deficient clotting factors and mitigate the inflammatory response. This intervention proved effective in stabilizing coagulation parameters, such as the international normalized ratio (INR) Plasmapheresis was performed until the INR reached stable levels, preventing the occurrence of severe bleeding complications. In instances where liver failure was deemed irreversible, plasmapheresis functioned as a bridging therapy to manage bleeding risks and to stabilize the patient while awaiting liver transplantation. CONCLUSION The findings underscore the need for heightened awareness among healthcare professionals regarding mushroom poisoning and emphasize the importance of considering climate change as a factor that may alter mushroom distribution and toxicity. Additionally, this study highlights the potential of plasmapheresis in managing severe cases.
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Affiliation(s)
- Petra Stöckert
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany
| | - Sophia Rusch
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany
| | - Sophie Schlosser-Hupf
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany
| | - Alexander Mehrl
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany
| | - Katharina Zimmermann
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany
| | - Vlad Pavel
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany
| | - Patricia Mester
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany
| | - Andreas M Brosig
- Institute of Clinical Chemistry and Laboratory Medicine, Transfusion Medicine, University Hospital Regensburg, Regensburg, Germany
| | - Tobias Schilling
- Department of Interdisciplinary Acute, Emergency and Intensive Care Medicine (DIANI), Klinikum Stuttgart, Stuttgart, Germany
| | - Martina Müller
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany
| | - Stephan Schmid
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany.
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Gezer A, Üstündağ H, Karadağ Sarı E, Bedir G, Gür C, Mendil AS, Duysak L. β-carotene protects against α-amanitin nephrotoxicity via modulation of oxidative, autophagic, nitric oxide signaling, and polyol pathways in rat kidneys. Food Chem Toxicol 2024; 193:115040. [PMID: 39389447 DOI: 10.1016/j.fct.2024.115040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 09/26/2024] [Accepted: 10/06/2024] [Indexed: 10/12/2024]
Abstract
Alpha-amanitin (α-AMA), a toxic component of Amanita phalloides, causes severe hepato- and nephrotoxicity. This study investigated the protective effects of βeta-carotene (βC) against α-AMA-induced kidney damage in rats. Thirty-two male Sprague-Dawley rats were divided into four groups: Control, βC (50 mg/kg/day), α-AMA (3 mg/kg), and βC+α-AMA. βC was administered orally for 7 days before α-AMA injection. Renal function, oxidative stress markers, histopathological changes, and enzyme activities were evaluated 48 h post-α-AMA administration. α-AMA significantly increased serum creatinine and urea levels, decreased glutathione and catalase activity, and increased malondialdehyde levels (P < 0.001). βC pretreatment attenuated these changes (P < 0.05). Histopathological examination revealed reduced tubular degeneration in the βC+α-AMA group (P < 0.001). Immunohistochemical analysis showed increased LC3B and Beclin-1 expression in α-AMA-treated rats, indicating enhanced autophagy, partially reversed by βC. Additionally, α-AMA reduced nitric oxide synthase (NOS) activity and increased aldose reductase (AR) activity, both normalized by βC pretreatment (P < 0.01). βC demonstrates protective effects against α-AMA-induced nephrotoxicity through antioxidant action, modulation of autophagy, and regulation of NOS and AR pathways, suggesting its potential as a therapeutic agent in α-AMA poisoning.
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Affiliation(s)
- Arzu Gezer
- Atatürk University, Pharmaceutical Research and Development, Graduate School of Natural and Applied Sciences, Erzurum, Turkiye; Atatürk University, Vocational School of Health Services, Erzurum, Turkiye.
| | - Hilal Üstündağ
- Erzincan Binali Yıldırım University, Faculty of Medicine, Department of Physiology, Erzincan, Turkiye.
| | - Ebru Karadağ Sarı
- Kafkas University, Faculty of Veterinary Medicine, Department of Histology and Embryology, Kars, Turkiye
| | - Gürsel Bedir
- Atatürk University, School of Medicine, Department of Histology and Embryology, Erzurum, Turkiye
| | - Cihan Gür
- Atatürk University, Vocational School of Health Services, Erzurum, Turkiye
| | - Ali Sefa Mendil
- Erciyes University, Faculty of Veterinary Medicine, Department of Pathology, Kayseri, Turkiye
| | - Lale Duysak
- Atatürk University, Faculty of Pharmacy, Department of Biochemistry, Erzurum, Turkiye
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Zhang S, Fan M, Zhang Y, Li S, Lu C, Zhou J, Zou L. Establishment and validation of a nomogram model for prediction of clinical outcomes in patients with amanita phalloides poisoning. Heliyon 2024; 10:e37320. [PMID: 39295998 PMCID: PMC11409095 DOI: 10.1016/j.heliyon.2024.e37320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 07/30/2024] [Accepted: 09/01/2024] [Indexed: 09/21/2024] Open
Abstract
Amanita phalloides poisoning, renowned for its high mortality rates, is one of the most serious food safety issue in certain regions worldwide. Assessment of prognosis and development of more efficacious therapeutic strategies are critical importance for amanita phalloides poisoning patients. The aim of the study is to establish a nomogram to predict the clinical outcome of amanita phalloides poisoning patients based on the independent risk factor for prognosis. Herein, between January 2013 and September 2023, a cohort of 149 patients diagnosed with amanita phalloides poisoning was enrolled and randomly allocated into training and validation cohorts, comprising 102 and 47 patients, respectively. Multivariate logistic regression analysis was performed to identify the independent risk factors for morality of amanita phalloides poisoning patients in training cohort. Subsequently, a nomogram model was constructed to visually display the risk prediction model. The predictive accuracy of nomogram was verified by the validation cohort. The C index, the area under the receiver operating characteristic curve (AUC), and calibration plots were used to assessed the performance of nomogram. The clinical utility was evaluated by decision curve analysis (DCA). In the present study, the results showed that hepatic encephalopathy (HE), upper gastrointestinal bleeding (UGB), AST, and PT were the independent risk factors associated with the mortality of amantia phalloides poisoning patients. We constructed a new nomogram to evaluate the probability of death induced by amantia phalloides poisoning. The AUC for the prediction accuracy of the nomogram was 0.936 for the training cohort and 0.929 for the validation cohort. The calibration curves showed that the predicted probability matched the actual likelihood. The results of the DCA suggested that the nomogram has a good potential for clinical application. In summary, we developed a new nomogram to assess the probability of mortality for amanita phalloides poisoning patients. This nomogram might facilitate clinicians in making more efficacious treatment strategies for patients with amanita phalloides poisoning.
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Affiliation(s)
- Sicheng Zhang
- The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha, Hunan, 410005, PR China
| | - Maiying Fan
- Department of Emergency Medicine, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan, 410005, PR China
- Clinical Research Center for Emergency and Critical Care in Hunan Province, Changsha, Hunan, 410005, PR China
| | - Yiyuan Zhang
- Department of Emergency Medicine, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan, 410005, PR China
| | - Shumei Li
- The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha, Hunan, 410005, PR China
- Department of Emergency Medicine, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan, 410005, PR China
| | - Congyu Lu
- Department of Emergency Medicine, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan, 410005, PR China
| | - Junhua Zhou
- The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha, Hunan, 410005, PR China
| | - Lianhong Zou
- Department of Emergency Medicine, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan, 410005, PR China
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Zhao Z, Yi S, E H, Jiang L, Zhou C, Zhao X, Yang L. α-amanitin induce inflammatory response by activating ROS/NF-κB-NLRP3 signaling pathway in human hepatoma HepG2 cells. CHEMOSPHERE 2024; 364:143157. [PMID: 39178962 DOI: 10.1016/j.chemosphere.2024.143157] [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: 05/14/2024] [Revised: 08/19/2024] [Accepted: 08/20/2024] [Indexed: 08/26/2024]
Abstract
α-amanitin (AMA) is a hepatotoxic mushroom toxin responsible for over 90% of mushroom poisoning fatalities worldwide, seriously endangering human life and health. Few evidences have indicated that AMA leads to inflammatory responses and inflammatory infiltration in vitro and in vivo. However, the molecular mechanism remains unknown. In this study, human hepatocellular carcinomas cells (HepG2) were exposed to AMA at various concentrations for short period of times. Results revealed that AMA increased ROS production and elevated the releases of malondialdehyde (MDA) and lactate dehydrogenase (LDH), resulting in oxidative damage in HepG2 cells. Also, AMA exposure significantly increased the secreted levels of inflammatory cytokines and activated the NLRP3 inflammasome. The inflammatory responses were reversed by NLRP3 inhibitor MCC950 and NF-κB inhibitor Bay11-7082. Additionally, N-acetylcysteine (NAC) blocked the upregulation of the NF-κB/NLRP3 signaling pathway and remarkably alleviated the inflammatory response. These results demonstrated that AMA could induce inflammation through activating the NLRP3 inflammasome triggered by ROS/NF-κB signaling pathway. Our research provides new insights into the molecular mechanism of AMA-induced inflammation damage and may contribute to establish new prevention strategies for AMA hepatotoxicity.
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Affiliation(s)
- Zhiyong Zhao
- Institute for Agro-food Standards and Testing Technology, Laboratory of Quality & Safety Risk Assessment for Agro-products (Shanghai), Ministry of Agriculture and Rural Affairs, Shanghai Academy of Agricultural Sciences, No.1000 Jinqi Road, Shanghai, 201403, PR China; Shanghai Guosen Biotechnology Co., Ltd., Shanghai, 201400, PR China.
| | - Siliang Yi
- Institute for Agro-food Standards and Testing Technology, Laboratory of Quality & Safety Risk Assessment for Agro-products (Shanghai), Ministry of Agriculture and Rural Affairs, Shanghai Academy of Agricultural Sciences, No.1000 Jinqi Road, Shanghai, 201403, PR China; College of Veterinary Medicine, Hunan Agricultural University, No.1 Nongda Road, Changsha, 410128, PR China
| | - Hengchao E
- Institute for Agro-food Standards and Testing Technology, Laboratory of Quality & Safety Risk Assessment for Agro-products (Shanghai), Ministry of Agriculture and Rural Affairs, Shanghai Academy of Agricultural Sciences, No.1000 Jinqi Road, Shanghai, 201403, PR China
| | - Lihuang Jiang
- Institute for Agro-food Standards and Testing Technology, Laboratory of Quality & Safety Risk Assessment for Agro-products (Shanghai), Ministry of Agriculture and Rural Affairs, Shanghai Academy of Agricultural Sciences, No.1000 Jinqi Road, Shanghai, 201403, PR China; College of Veterinary Medicine, Hunan Agricultural University, No.1 Nongda Road, Changsha, 410128, PR China
| | - Changyan Zhou
- Institute for Agro-food Standards and Testing Technology, Laboratory of Quality & Safety Risk Assessment for Agro-products (Shanghai), Ministry of Agriculture and Rural Affairs, Shanghai Academy of Agricultural Sciences, No.1000 Jinqi Road, Shanghai, 201403, PR China
| | - Xiaoyan Zhao
- Institute for Agro-food Standards and Testing Technology, Laboratory of Quality & Safety Risk Assessment for Agro-products (Shanghai), Ministry of Agriculture and Rural Affairs, Shanghai Academy of Agricultural Sciences, No.1000 Jinqi Road, Shanghai, 201403, PR China.
| | - Lingchen Yang
- College of Veterinary Medicine, Hunan Agricultural University, No.1 Nongda Road, Changsha, 410128, PR China.
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Sezer F, Elmazoğlu Z, Esendağlı G, İlhan SÖ, Karasu Ç. Protection against α-Amanitin-induced liver toxicity: Efficacy of pomegranate seed oil and black cumin oil. Toxicon 2024; 247:107854. [PMID: 38977085 DOI: 10.1016/j.toxicon.2024.107854] [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: 04/15/2024] [Revised: 07/05/2024] [Accepted: 07/05/2024] [Indexed: 07/10/2024]
Abstract
The consumption of mushrooms containing α-Amanitin (α-A) can lead to severe liver damage. In this study, toxicological experiments were conducted to confirm the protective effects of pomegranate seed oil (PSO) and black cumin oil (BCO) against α-A-induced hepatotoxicity. Rats exposed once to α-A (3 mg/kg bw, i.p.) or saline alone (0.1 ml, i.p.) were either left untreated or treated with PSO or BCO at a dose of 2 ml/kg bw/day by oral gavage on the same day, and the treatment was continued for 7 days. Serum aminotransferases (ALT and AST), alkaline phosphatase (ALP) and total protein levels were measured and the active caspase 3 (cl-caspase 3) was evaluated by western blotting in the liver. Serum ALT, AST and ALP levels tended to decrease in the α-A exposed group, but no statistically significant difference was found compared to the saline group (p > 0.05). PSO and BCO did not affect serum liver function tests in rats exposed to saline or α-A. α-A toxicity was demonstrated by a significant decrease in serum total protein level (p < 0.05), a significant increase in liver cl-caspase 3 expression (p < 0.05), and structural liver damage mainly characterized by mononuclear inflammation and steatosis. When α-A exposed rats were treated with BCO, the increase in cl-caspase 3 was not inhibited, on the contrary BCO increased cl-caspase 3 in healthy rats (p < 0.05). PSO significantly ameliorated α-A-induced cl-caspase 3 increase and inflammatory histopathology in the liver. Both PSO and BCO completely prevented α-A-induced protein degradation. The findings indicate that PSO and BCO may protect liver functions against α-A-induced hepatotoxicity, encouraging future comprehensive studies to test them at different doses and frequency.
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Affiliation(s)
- Fatih Sezer
- Department of Medical Pharmacology, Faculty of Medicine, Gazi University, Ankara, Turkey.
| | | | - Güldal Esendağlı
- Department of Pathology, Faculty of Medicine, Gazi University, Ankara, Turkey.
| | - Sevil Özger İlhan
- Department of Medical Pharmacology, Faculty of Medicine, Gazi University, Ankara, Turkey.
| | - Çimen Karasu
- Department of Medical Pharmacology, Faculty of Medicine, Gazi University, Ankara, Turkey.
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Gezer A, Ustundag H, Mendil AS, Bedir G, Duysak L. Hepatoprotective effects of resveratrol on α-amanitin-induced liver toxicity in rats. Toxicon 2024; 247:107855. [PMID: 38996975 DOI: 10.1016/j.toxicon.2024.107855] [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: 06/12/2024] [Revised: 07/07/2024] [Accepted: 07/08/2024] [Indexed: 07/14/2024]
Abstract
OBJECTIVE The hepatoprotective effects of resveratrol against α-Amanitin (α-AMA)-induced liver toxicity were investigated in an experimental rat model, focusing on oxidative stress, inflammation, apoptosis, and liver function. METHODS Thirty-two male Sprague-Dawley rats were divided into four groups (n = 8 per group): Control, resveratrol, α-AMA, and resveratrol+α-AMA. The resveratrol group received 20 mg/kg resveratrol orally for 7 days. The α-AMA group received 3 mg/kg α-AMA intraperitoneally on the 8th day. The resveratrol+α-AMA group received 20 mg/kg resveratrol orally (7 days) followed by 3 mg/kg α-AMA intraperitoneally on the 8th day. Liver tissues and blood samples were collected 48 h after α-amanitin administration for histopathological, immunohistochemical (NFkB, LC3B), and biochemical analyses (GSH, MDA, CAT, GPx, MPO, NOS, AST, ALT). RESULTS α-AMA significantly increased AST and ALT levels, oxidative stress marker (MDA), and inflammatory marker (MPO), while reducing antioxidant levels (GSH, CAT, GPx) and NOS concentration (P < 0.001 for all parameters). Histopathological analysis showed severe liver damage with increased NFkB and LC3B expression. resveratrol treatment significantly reduced AST and ALT levels (P < 0.01 for both parameters), decreased MDA and MPO levels, and increased NOS concentration, GSH, CAT, and GPx levels (P < 0.05 for all parameters). Reduced NFkB and LC3B expression in the resveratrol+α-AMA group and showed histopathological improvements. CONCLUSION Resveratrol demonstrated substantial hepatoprotective effects against α-AMA induced liver toxicity by reducing oxidative stress, inflammation, and apoptosis, and improving liver function. These findings suggest that resveratrol could be a potential therapeutic agent for treating liver damage caused by potent hepatotoxins like α-AMA.
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Affiliation(s)
- Arzu Gezer
- Vocational School of Health Services, Atatürk University, Erzurum, Türkiye; Pharmaceutical Research and Development, Graduate School of Natural and Applied Sciences, Atatürk University, Erzurum, Türkiye.
| | - Hilal Ustundag
- Erzincan Binali Yıldırım University, Faculty of Medicine, Department of Physiology, Erzincan, Türkiye.
| | - Ali Sefa Mendil
- Erciyes University, Faculty of Veterinary Medicine, Department of Pathology, Kayseri, Türkiye
| | - Gursel Bedir
- Atatürk University, School of Medicine, Department of Histology and Embryology, Erzurum, Türkiye
| | - Lale Duysak
- Atatürk University, Faculty of Pharmacy, Department of Biochemistry, Erzurum, Türkiye
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Caré W, Bruneau C, Rapior S, Langrand J, Le Roux G, Vodovar D. [Amatoxin-containing mushroom poisoning: An update]. Rev Med Interne 2024; 45:423-430. [PMID: 37949692 DOI: 10.1016/j.revmed.2023.10.459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Accepted: 10/19/2023] [Indexed: 11/12/2023]
Abstract
Amatoxin-containing mushroom poisoning occurs after consumption of certain mushroom species, of the genera Amanita, Lepiota and Galerina. Amanita phalloides is the most implicated species, responsible for over more than 90% of mushroom-related deaths. The α-amanitin is responsible for most of the observed effects. Symptoms are characterized by severe delayed gastrointestinal disorders (more than six hours after ingestion). The liver being the main target organ, outcome is marked by an often severe hepatitis which can evolve towards terminal liver failure, justifying orthotopic liver transplantation. Acute renal failure is common. Diagnosis of amatoxin-containing mushroom poisoning is based primarily on clinical data; it can be biologically confirmed using detection of amatoxins, especially from urine samples. In the absence of an antidote, early hospital management is essential. It is based on supportive care (early compensation of hydroelectrolytic losses), gastrointestinal digestive decontamination, elimination enhancement, amatoxin uptake inhibitors and antioxidant therapy. Combined therapy associating silibinin and N-acetylcysteine is recommended. Prognosis of this severe poisoning has greatly benefited from improved resuscitation techniques. Mortality is currently less than 10%. In the event of a suspected or confirmed case, referral to a Poison Control Center is warranted in order to establish the diagnosis and guide the medical management of patients in an early and appropriate way.
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Affiliation(s)
- W Caré
- Centre antipoison de Paris, fédération de toxicologie (FeTox), hôpital Fernand-Widal, AP-HP, 200, rue du Faubourg-Saint-Denis, 75010 Paris, France; Service de médecine interne, hôpital d'instruction des armées Bégin, 69, avenue de Paris, 91460 Saint-Mandé, France; Université Paris-Cité, Inserm UMR-S 1144, optimisation thérapeutique en neuropsychopharmacologie, 4, avenue de l'Observatoire, 75006 Paris, France.
| | - C Bruneau
- Centre antipoison d'Angers, centre hospitalier universitaire d'Angers, 4, rue Larrey, 49000 Angers, France
| | - S Rapior
- CEFE, CNRS, université de Montpellier, EPHE, IRD, laboratoire de botanique, phytochimie et mycologie, UFR des sciences pharmaceutiques et biologiques, 15, avenue Charles-Flahault, CS 14491, 34093 Montpellier cedex 5, France
| | - J Langrand
- Centre antipoison de Paris, fédération de toxicologie (FeTox), hôpital Fernand-Widal, AP-HP, 200, rue du Faubourg-Saint-Denis, 75010 Paris, France; Université Paris-Cité, Inserm UMR-S 1144, optimisation thérapeutique en neuropsychopharmacologie, 4, avenue de l'Observatoire, 75006 Paris, France
| | - G Le Roux
- Centre antipoison d'Angers, centre hospitalier universitaire d'Angers, 4, rue Larrey, 49000 Angers, France; Institut de recherche en santé, environnement et travail (IRSET), Inserm UMR 1085, équipe 10 ESTER, université d'Angers, 49000 Angers, France
| | - D Vodovar
- Centre antipoison de Paris, fédération de toxicologie (FeTox), hôpital Fernand-Widal, AP-HP, 200, rue du Faubourg-Saint-Denis, 75010 Paris, France; Université Paris-Cité, Inserm UMR-S 1144, optimisation thérapeutique en neuropsychopharmacologie, 4, avenue de l'Observatoire, 75006 Paris, France; UFR de médecine, université de Paris, 75006 Paris, France
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Zhou Y, Wang J, Zhao Y, Zhao Y, Yang J, Wang K, Liu X, Qu W, Zhang L, Gu X. Salidroside Inhibits α-Amanitin-Induced AML-12 Cell Apoptosis via the Regulation of PINK1/Parkin-Mediated Mitophagy and Mitochondrial Function. Chem Res Toxicol 2024; 37:1053-1061. [PMID: 38847154 DOI: 10.1021/acs.chemrestox.4c00139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/18/2024]
Abstract
Poisoning caused by the mushroom Amanita phalloides, due to the toxin α-amanitin, accounts for approximately 90% of food poisoning deaths in China with no specific antidotes. To investigate the role of salidroside (Sal) in α-amanitin (α-AMA)-induced mitophagy, mouse liver cells AML-12 were exposed to α-AMA in the presence of Sal or not. Intracellular reactive oxygen species (ROS) levels were measured using a ROS detection kit, mitochondrial activity was evaluated using a mitochondrial red fluorescent probe kit or JC-1 dye, and protein expression levels of PINK1, Parkin, LC3 II, P62, Bax, Bcl-2, Caspase 3, Cleaved-Caspase 3, PARP I, and Cleaved-PARP I were detected through Western blot. Results demonstrated that α-AMA led to increased intracellular ROS levels, cell apoptosis, and decreased mitochondrial membrane potential. Notably, expression levels of mitophagy-related proteins PINK1, Parkin, and LC3 increased significantly while the P62 protein expression decreased remarkably. Furthermore, Sal reversed the α-AMA-induced decrease in cell viability and mitochondrial membrane potential and increase in intracellular ROS level. In addition, Sal promoted expression levels of PINK1, Parkin, and LC3 II while suppressing the Bax/Bcl-2 ratio, Cleaved-Caspase 3, and Cleaved-PARP I as well as P62. The results above proved that salidroside alleviates α-AMA-induced mouse liver cells damage via promoting PINK1/Parkin-mediated mitophagy and reducing cell apoptosis.
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Affiliation(s)
- Yaxiong Zhou
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Yunnan Agricultural University, Jin Hei Road No. 95, Panlong District, Kunming 650051, P. R. China
| | - Juyu Wang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Yunnan Agricultural University, Jin Hei Road No. 95, Panlong District, Kunming 650051, P. R. China
| | - Yu Zhao
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Yunnan Agricultural University, Jin Hei Road No. 95, Panlong District, Kunming 650051, P. R. China
| | - Yang Zhao
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Yunnan Agricultural University, Jin Hei Road No. 95, Panlong District, Kunming 650051, P. R. China
| | - Jieyan Yang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Yunnan Agricultural University, Jin Hei Road No. 95, Panlong District, Kunming 650051, P. R. China
| | - Kuan Wang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Yunnan Agricultural University, Jin Hei Road No. 95, Panlong District, Kunming 650051, P. R. China
| | - Xiang Liu
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Yunnan Agricultural University, Jin Hei Road No. 95, Panlong District, Kunming 650051, P. R. China
| | - Weijie Qu
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Yunnan Agricultural University, Jin Hei Road No. 95, Panlong District, Kunming 650051, P. R. China
| | - Limei Zhang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Yunnan Agricultural University, Jin Hei Road No. 95, Panlong District, Kunming 650051, P. R. China
| | - Xiaolong Gu
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Yunnan Agricultural University, Jin Hei Road No. 95, Panlong District, Kunming 650051, P. R. China
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10
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Gong M, Li Z, Xu H, Ma B, Gao P, Wang L, Li J, Wu Q, Wu J, Xie J. Amanitin-induced variable cytotoxicity in various cell lines is mediated by the different expression levels of OATP1B3. Food Chem Toxicol 2024; 188:114665. [PMID: 38641045 DOI: 10.1016/j.fct.2024.114665] [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: 02/02/2024] [Revised: 03/02/2024] [Accepted: 04/11/2024] [Indexed: 04/21/2024]
Abstract
Amanita phalloides is one of the deadliest mushrooms worldwide, causing most fatal cases of mushroom poisoning. Among the poisonous substances of Amanita phalloides, amanitins are the most lethal toxins to humans. Currently, there are no specific antidotes available for managing amanitin poisoning and treatments are lack of efficacy. Amanitin mainly causes severe injuries to specific organs, such as the liver, stomach, and kidney, whereas the lung, heart, and brain are hardly affected. However, the molecular mechanism of this phenomenon remains not understood. To explore the possible mechanism of organ specificity of amanitin-induced toxicity, eight human cell lines derived from different organs were exposed to α, β, and γ-amanitin at concentrations ranging from 0.3 to 100 μM. We found that the cytotoxicity of amanitin differs greatly in various cell lines, among which liver-derived HepG2, stomach-derived BGC-823, and kidney-derived HEK-293 cells are most sensitive. Further mechanistic study revealed that the variable cytotoxicity is mainly dependent on the different expression levels of the organic anion transporting polypeptide 1B3 (OATP1B3), which facilitates the internalization of amanitin into cells. Besides, knockdown of OATP1B3 in HepG2 cells prevented α-amanitin-induced cytotoxicity. These results indicated that OATP1B3 may be a crucial therapeutic target against amanitin-induced organ failure.
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Affiliation(s)
- Mengqiang Gong
- School of Agriculture, Yangtze University, Jingzhou, 434025, China; Laboratory of Toxicant Analysis, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing, 100850, China
| | - Zhi Li
- Laboratory of Toxicant Analysis, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing, 100850, China
| | - Hua Xu
- Laboratory of Toxicant Analysis, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing, 100850, China
| | - Bo Ma
- Laboratory of Toxicant Analysis, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing, 100850, China
| | - Pengxia Gao
- Laboratory of Toxicant Analysis, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing, 100850, China
| | - Lili Wang
- Laboratory of Toxicant Analysis, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing, 100850, China
| | - Junkai Li
- School of Agriculture, Yangtze University, Jingzhou, 434025, China
| | - Qinglai Wu
- School of Agriculture, Yangtze University, Jingzhou, 434025, China.
| | - Jianfeng Wu
- Laboratory of Toxicant Analysis, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing, 100850, China.
| | - Jianwei Xie
- Laboratory of Toxicant Analysis, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing, 100850, China.
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11
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Ning D, Xue J, Lou X, Shao R, Liu Y, Chen G. Transforming toxins into treatments: the revolutionary role of α-amanitin in cancer therapy. Arch Toxicol 2024; 98:1705-1716. [PMID: 38555326 DOI: 10.1007/s00204-024-03727-0] [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: 01/17/2024] [Accepted: 03/07/2024] [Indexed: 04/02/2024]
Abstract
Amanita phalloides is the primary species responsible for fatal mushroom poisoning, as its main toxin, α-amanitin, irreversibly and potently inhibits eukaryotic RNA polymerase II (RNAP II), leading to cell death. There is no specific antidote for α-amanitin, which hinders its clinical application. However, with the advancement of precision medicine in oncology, including the development of antibody-drug conjugates (ADCs), the potential value of various toxic small molecules has been explored. These ADCs ingeniously combine the targeting precision of antibodies with the cytotoxicity of small-molecule payloads to precisely kill tumor cells. We searched PubMed for studies in this area using these MeSH terms "Amanitins, Alpha-Amanitin, Therapeutic use, Immunotherapy, Immunoconjugates, Antibodies" and did not limit the time interval. Recent studies have conducted preclinical experiments on ADCs based on α-amanitin, showing promising therapeutic effects and good tolerance in primates. The current challenges include the not fully understood toxicological mechanism of α-amanitin and the lack of clinical studies to evaluate the therapeutic efficacy of ADCs developed based on α-amanitin. In this article, we will discuss the role and therapeutic efficacy of α-amanitin as an effective payload in ADCs for the treatment of various cancers, providing background information for the research and application strategies of current and future drugs.
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Affiliation(s)
- Deyuan Ning
- Medical School, Kunming University of Science and Technology, Kunming, China
| | - Jinfang Xue
- Medical School, Kunming University of Science and Technology, Kunming, China
| | - Xiran Lou
- Medical School, Kunming University of Science and Technology, Kunming, China
| | - Ruifei Shao
- Medical School, Kunming University of Science and Technology, Kunming, China
| | - Yu Liu
- Medical School, Kunming University of Science and Technology, Kunming, China
| | - Guobing Chen
- Department of Emergency Medicine, The First People's Hospital of Yunnan Province, No 157 Jinbi Road, Xishan District, Kunming, 650032, China.
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12
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Gouvinhas I, Silva J, Alves MJ, Garcia J. The most dreadful mushroom toxins: a review of their toxicological mechanisms, chemical structural characteristics, and treatment. EXCLI JOURNAL 2024; 23:833-859. [PMID: 39165585 PMCID: PMC11333700 DOI: 10.17179/excli2024-7257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 04/26/2024] [Indexed: 08/22/2024]
Abstract
Mushroom consumption is a worldwide custom that continues to grow in popularity. On the other hand, foraging for wild mushrooms can lead to serious disease and even death if deadly mushrooms are accidentally consumed. Mushroom poisoning is difficult to diagnose and treat since the symptoms are similar to those of other disorders. In terms of chemistry, mushroom poisoning is associated with extraordinarily strong toxins, meaning that isolating and identifying toxins has substantial scientific relevance, especially in understanding the lethal components of toxic mushrooms. Most of these toxins exhibit exceptional physiological features that might help enhance chemistry, biochemistry, physiology, and pharmacology research. Despite the discovery of more than 100 poisons, several dangerous mushrooms remain unexplored. This review covers the chemistry (including chemical structures, complete synthesis, and biosynthesis), as well as the toxicology, namely the toxicokinetics, mechanisms of toxicology, and clinical toxicology of these poisons, in addition to the discussion of the development of their most effective diagnostic and therapeutic strategies with the hopes of spurring additional studies, focusing on individual classes of toxins found in poisonous mushrooms such as amatoxins, gyromitrin, orellanine, and phallatoxins. See also the graphical abstract(Fig. 1).
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Affiliation(s)
- Irene Gouvinhas
- CITAB - Centre for the Research and Technology of Agro-Environment and Biological Sciences/ Inov4Agro - Institute for Innovation, Capacity Building and Sustainability of Agri-Food Production, University of Trás-os-Montes e Alto Douro, 5001- 801 Vila Real, Portugal
| | - Jani Silva
- AquaValor - Centro de Valorização e Transferência de Tecnologia da Água - Associação, Rua Dr. Júlio Martins n.º 1, 5400-342 Chaves, Portugal
| | - Maria José Alves
- AquaValor - Centro de Valorização e Transferência de Tecnologia da Água - Associação, Rua Dr. Júlio Martins n.º 1, 5400-342 Chaves, Portugal
| | - Juliana Garcia
- CITAB - Centre for the Research and Technology of Agro-Environment and Biological Sciences/ Inov4Agro - Institute for Innovation, Capacity Building and Sustainability of Agri-Food Production, University of Trás-os-Montes e Alto Douro, 5001- 801 Vila Real, Portugal
- AquaValor - Centro de Valorização e Transferência de Tecnologia da Água - Associação, Rua Dr. Júlio Martins n.º 1, 5400-342 Chaves, Portugal
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13
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Wu Z, Li H, Zhao W, Zheng M, Cheng J, Cao Z, Sun C. Kidney toxicity and transcriptome analyses of male ICR mice acutely exposed to the mushroom toxin α-amanitin. Food Chem Toxicol 2024; 187:114622. [PMID: 38531469 DOI: 10.1016/j.fct.2024.114622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 03/20/2024] [Accepted: 03/22/2024] [Indexed: 03/28/2024]
Abstract
Amatoxins are responsible for most fatal mushroom poisoning cases, as it causes both hepatotoxicity and nephrotoxicity. However, studies on amatoxin nephrotoxicity are limited. Here, we investigated nephrotoxicity over 4 days and nephrotoxicity/hepatotoxicity over 14 days in mice. The organ weight ratio, serological indices, and tissue histology results indicated that a nephrotoxicity mouse model was established with two stages: (1) no apparent effects within 24 h; and (2) the appearance of adverse effects, with gradual worsening within 2-14 days. For each stage, the kidney transcriptome revealed patterns of differential mRNA expression and significant pathway changes, and Western blot analysis verified the expression of key proteins. Amanitin-induced nephrotoxicity was directly related to RNA polymerase II because mRNA levels decreased, RNA polymerase II-related pathways were significantly enriched at the transcription level, and RNA polymerase II protein was degraded in the early poisoning stage. In the late stage, nephrotoxicity was more severe than hepatotoxicity. This is likely associated with inflammation because inflammation-related pathways were significantly enriched and NF-κB activation was increased in the kidney.
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Affiliation(s)
- Zhijun Wu
- National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, 100050, China.
| | - Haijiao Li
- National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, 100050, China
| | - Wenjin Zhao
- National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, 100050, China
| | - Min Zheng
- National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, 100050, China
| | - Juan Cheng
- National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, 100050, China
| | - Zhengjie Cao
- National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, 100050, China
| | - Chengye Sun
- National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, 100050, China.
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Kaci H, Bakos É, Needs PW, Kroon PA, Valentová K, Poór M, Özvegy-Laczka C. The 2-aminoethyl diphenylborinate-based fluorescent method identifies quercetin and luteolin metabolites as substrates of Organic anion transporting polypeptides, OATP1B1 and OATP2B1. Eur J Pharm Sci 2024; 196:106740. [PMID: 38437885 DOI: 10.1016/j.ejps.2024.106740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 01/28/2024] [Accepted: 03/01/2024] [Indexed: 03/06/2024]
Abstract
Organic anion transporting polypeptides (OATPs), OATP1B1 and OATP2B1 are membrane proteins mediating the cellular uptake of chemically diverse organic compounds. OATP1B1 is exclusively expressed in hepatocytes and plays a key role in hepatic detoxification. The ubiquitously expressed OATP2B1 promotes the intestinal absorption of orally administered drugs. Flavonoids are widely found in foods and beverages, and many of them can inhibit OATP function, resulting in food-drug interactions. In our previous work, we have shown that not only luteolin (LUT) and quercetin (Q), but also some of their metabolites can inhibit OATP1B1 and OATP2B1 activity. However, data about the potential direct transport of these flavonoids by OATPs have been incomplete. Hence, in the current study, we developed a simple, fluorescence-based method for the measurement of intracellular flavonoid levels. The method applies a cell-permeable small molecule (2-aminoethyl diphenylborinate, 2-APB), that, upon forming a complex with flavonoids, results in their fluorescence enhancement. This way the direct uptake of LUT and Q, and also their metabolites' could be investigated both by confocal microscopy and in a fluorescence plate reader in living cells. With this approach we identified quercetin-3'-O-sulfate, luteolin-3'-O-glucuronide, luteolin-7-O-glucuronide and luteolin-3'-O-sulfate as substrates of both OATP1B1 and OATP2B1. Our results highlight that OATP1B1 and OATP2B1 can be key participants in the transmembrane movement of LUT and Q conjugates with otherwise low cell permeability. In addition, the novel method developed in this study can be a good completion to existing fluorescence-based assays to investigate OATP function.
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Affiliation(s)
- Hana Kaci
- Institute of Molecular Life Sciences, RCNS, HUN-REN, H-1117 Budapest, Magyar tudósok krt. 2., Hungary; Doctoral School of Biology, Institute of Biology, ELTE Eötvös Loránd University, 1117 Budapest Pázmány Péter sétány 1/C, Hungary
| | - Éva Bakos
- Institute of Molecular Life Sciences, RCNS, HUN-REN, H-1117 Budapest, Magyar tudósok krt. 2., Hungary
| | - Paul W Needs
- Food, Microbiome & Health Programme, Quadram Institute Bioscience, Norwich Research Park, Norwich, Norfolk NR4 7UQ, UK
| | - Paul A Kroon
- Food, Microbiome & Health Programme, Quadram Institute Bioscience, Norwich Research Park, Norwich, Norfolk NR4 7UQ, UK
| | - Kateřina Valentová
- Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, Prague CZ-142 00, Czech Republic
| | - Miklós Poór
- Molecular Medicine Research Group, János Szentágothai Research Centre, University of Pécs, Ifjúság útja 20, Pécs H-7624, Hungary; Department of Pharmacology, Faculty of Pharmacy, University of Pécs, Rókus u. 2, Pécs H-7624, Hungary; Department of Laboratory Medicine, Medical School, University of Pécs, Ifjúság útja 13, Pécs H-7624, Hungary
| | - Csilla Özvegy-Laczka
- Institute of Molecular Life Sciences, RCNS, HUN-REN, H-1117 Budapest, Magyar tudósok krt. 2., Hungary.
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15
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Durkan K, Ichedef C, Baris E, Arici MA. Biodistribution of radiolabeled alpha-amanitin in mice: An Investigation. Toxicon 2024; 241:107661. [PMID: 38408526 DOI: 10.1016/j.toxicon.2024.107661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 02/22/2024] [Accepted: 02/23/2024] [Indexed: 02/28/2024]
Abstract
Mushroom poisonings caused by Amanita phalloides are the leading cause of mushroom-related deaths worldwide. Alpha-Amanitin (α-AMA), a toxic substance present in these mushrooms, is responsible for the resulting hepatotoxicity and nephrotoxicity. The objective of our study was to determine the distribution of α-AMA in Balb/c mice by labeling with Iodine-131. Mice were injected with a toxic dose (1.4 mg/kg) of α-AMA labeled with Iodine-131. The mice were sacrificed at the 1st, 2nd, 4th, 8th, 24th, and 48th hours under anesthesia. The organs of the mice were removed, and their biodistribution was assessed in all experiments. The percent injected dose per gram (ID/g %) value for kidney, liver, lung, and heart tissues at 1st hour were 1.59 ± 0.07, 1.25 ± 0.33, 3.67 ± 0.80 and 1.07 ± 0.01 respectively. This study provides insights into the potential long-term effects of α-AMA accumulation in specific organs. Additionally, this study has generated essential data that can be used to demonstrate the impact of antidotes on the biological distribution of α-AMA in future toxicity models.
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Affiliation(s)
- Kubra Durkan
- Department of Nuclear Applications, Institute of Nuclear Sciences, Ege University, 35100, Bornova, Izmir, Turkey.
| | - Cigdem Ichedef
- Department of Nuclear Applications, Institute of Nuclear Sciences, Ege University, 35100, Bornova, Izmir, Turkey
| | - Elif Baris
- Department of Pharmacology, Faculty of Medicine, Izmir University of Economics, Izmir, Turkey
| | - M Aylin Arici
- Department of Medical Pharmacology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey
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Zhong J, Xu P, Li H, Sun C, Tong Y, Yao Q, Yu C. Acute hepatic and kidney injury after ingestion of Lepiota brunneoincarnata: Report of 2 cases. Toxicon 2024; 239:107605. [PMID: 38184282 DOI: 10.1016/j.toxicon.2024.107605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 12/11/2023] [Accepted: 01/03/2024] [Indexed: 01/08/2024]
Abstract
Lepiota brunneoincarnata is a highly toxic mushroom species known to cause acute liver failure. However, there are limited reports investigating L. brunneoincarnata causing acute hepatic and renal damage. The present article reports 2 cases of L. brunneoincarnata poisoning in a mother and son from Chuxiong City, Yunnan Province, China. Both patients presented with gastrointestinal symptoms approximately 8-9 h after ingesting the suspect mushrooms and sought medical attention 27-28 h post-ingestion, both exhibiting acute hepatic and kidney injuries. Morphological and molecular biology studies confirmed the species of the mushrooms as L. brunneoincarnata. Liquid chromatography-tandem mass spectrometry analysis revealed mean fresh-weight concentrations of 123.5 μg/g α-amanitin and 45.7 μg/g β-amanitin in the mushrooms. The patients underwent standard treatments, including multiple-dose activated charcoal, oral silibinin capsules, N-acetylcysteine, penicillin G, hemoperfusion, and plasma exchange. One patient recovered completely and was discharged after 16 days of hospitalization. The other patient exhibited gradual improvement in liver and renal function; however, renal function deteriorated 9 days after ingestion, and the patient declined renal replacement therapy and returned home 14 days post-ingestion. The patient was then re-hospitalized due to oliguria and edema in both lower extremities. Renal biopsy revealed acute tubular necrosis, inflammatory cell infiltration, minor glomerular capsular fibrosis, loss of microvilli in the renal tubular epithelial cells, and interstitial edema. The patient underwent 2 rounds of continuous renal replacement therapy, which eventually resulted in improvement, and was discharged 31 days after mushroom consumption. It is noteworthy that this patient had already progressed to chronic kidney insufficiency 11 months after intoxication.
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Affiliation(s)
- JiaJu Zhong
- Department of Emergency Medicine, The People's Hospital of Chuxiong Yi Autonomous Prefecture, Chuxiong, Yunnan, China; National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Pin Xu
- Department of Emergency Medicine, The People's Hospital of Chuxiong Yi Autonomous Prefecture, Chuxiong, Yunnan, China
| | - HaiJiao Li
- National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, China
| | - ChengYe Sun
- National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Yun Tong
- Department of Emergency Medicine, The People's Hospital of Chuxiong Yi Autonomous Prefecture, Chuxiong, Yunnan, China
| | - QunMei Yao
- Department of Emergency Medicine, The People's Hospital of Chuxiong Yi Autonomous Prefecture, Chuxiong, Yunnan, China.
| | - ChengMin Yu
- Department of Emergency Medicine, The People's Hospital of Chuxiong Yi Autonomous Prefecture, Chuxiong, Yunnan, China.
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Visser M, Hof WFJ, Broek AM, van Hoek A, de Jong JJ, Touw DJ, Dekkers BGJ. Unexpected Amanita phalloides-Induced Hematotoxicity-Results from a Retrospective Study. Toxins (Basel) 2024; 16:67. [PMID: 38393145 PMCID: PMC10891511 DOI: 10.3390/toxins16020067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 01/17/2024] [Accepted: 01/23/2024] [Indexed: 02/25/2024] Open
Abstract
INTRODUCTION Amanita phalloides poisoning is a serious health problem with a mortality rate of 10-40%. Poisonings are characterized by severe liver and kidney toxicity. The effect of Amanita phalloides poisonings on hematological parameters has not been systematically evaluated thus far. METHODS Patients with suspected Amanita phalloides poisonings were retrospectively selected from the hospital database of the University Medical Center Groningen (UMCG). Medical data-including demographics; liver, kidney, and blood parameters; treatment; and outcomes-were collected. The severity of the poisoning was scored using the poison severity score. RESULTS Twenty-eight patients were identified who were admitted to the UMCG with suspected Amanita phalloides poisoning between 1994 and 2022. A time-dependent decrease was observed for hemoglobin and hematocrit concentrations, leukocytes, and platelets. Six out of twenty-eight patients developed acute liver failure (ALF). Patients with ALF showed a higher increase in liver enzymes, international normalized ratios, and PSS compared to patients without ALF. Conversely, hemoglobin and platelet numbers were decreased even further in these patients. Three out of six patients with ALF died and one patient received a liver transplant. CONCLUSION Our study shows that Amanita phalloides poisonings may be associated with hematotoxicity in patients. The quantification of hematological parameters is of relevance in intoxicated patients, especially in those with ALF.
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Affiliation(s)
- Miranda Visser
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen (UMCG), 9713 GZ Groningen, The Netherlands; (M.V.); (W.F.J.H.); (A.M.B.); (A.v.H.); (J.J.d.J.); (D.J.T.)
| | - Willemien F. J. Hof
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen (UMCG), 9713 GZ Groningen, The Netherlands; (M.V.); (W.F.J.H.); (A.M.B.); (A.v.H.); (J.J.d.J.); (D.J.T.)
| | - Astrid M. Broek
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen (UMCG), 9713 GZ Groningen, The Netherlands; (M.V.); (W.F.J.H.); (A.M.B.); (A.v.H.); (J.J.d.J.); (D.J.T.)
| | - Amanda van Hoek
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen (UMCG), 9713 GZ Groningen, The Netherlands; (M.V.); (W.F.J.H.); (A.M.B.); (A.v.H.); (J.J.d.J.); (D.J.T.)
| | - Joyce J. de Jong
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen (UMCG), 9713 GZ Groningen, The Netherlands; (M.V.); (W.F.J.H.); (A.M.B.); (A.v.H.); (J.J.d.J.); (D.J.T.)
| | - Daan J. Touw
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen (UMCG), 9713 GZ Groningen, The Netherlands; (M.V.); (W.F.J.H.); (A.M.B.); (A.v.H.); (J.J.d.J.); (D.J.T.)
- Department of Pharmaceutical Analysis, Groningen Research Institute of Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands
| | - Bart G. J. Dekkers
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen (UMCG), 9713 GZ Groningen, The Netherlands; (M.V.); (W.F.J.H.); (A.M.B.); (A.v.H.); (J.J.d.J.); (D.J.T.)
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18
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Hof WFJ, Visser M, de Jong JJ, Rajasekar MN, Schuringa JJ, de Graaf IAM, Touw DJ, Dekkers BGJ. Unraveling Hematotoxicity of α-Amanitin in Cultured Hematopoietic Cells. Toxins (Basel) 2024; 16:61. [PMID: 38276537 PMCID: PMC10820516 DOI: 10.3390/toxins16010061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 01/13/2024] [Accepted: 01/19/2024] [Indexed: 01/27/2024] Open
Abstract
Amanita phalloides poisonings account for the majority of fatal mushroom poisonings. Recently, we identified hematotoxicity as a relevant aspect of Amanita poisonings. In this study, we investigated the effects of the main toxins of Amanita phalloides, α- and β-amanitin, on hematopoietic cell viability in vitro. Hematopoietic cell lines were exposed to α-amanitin or β-amanitin for up to 72 h with or without the pan-caspase inhibitor Z-VAD(OH)-FMK, antidotes N-acetylcysteine, silibinin, and benzylpenicillin, and organic anion-transporting polypeptide 1B3 (OATP1B3) inhibitors rifampicin and cyclosporin. Cell viability was established by trypan blue exclusion, annexin V staining, and a MTS assay. Caspase-3/7 activity was determined with Caspase-Glo assay, and cleaved caspase-3 was quantified by Western analysis. Cell number and colony-forming units were quantified after exposure to α-amanitin in primary CD34+ hematopoietic stem cells. In all cell lines, α-amanitin concentration-dependently decreased viability and mitochondrial activity. β-Amanitin was less toxic, but still significantly reduced viability. α-Amanitin increased caspase-3/7 activity by 2.8-fold and cleaved caspase-3 by 2.3-fold. Z-VAD(OH)-FMK significantly reduced α-amanitin-induced toxicity. In CD34+ stem cells, α-amanitin decreased the number of colonies and cells. The antidotes and OATP1B3 inhibitors did not reverse α-amanitin-induced toxicity. In conclusion, α-amanitin induces apoptosis in hematopoietic cells via a caspase-dependent mechanism.
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Affiliation(s)
- Willemien F. J. Hof
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen (UMCG), 9713 GZ Groningen, The Netherlands; (W.F.J.H.)
| | - Miranda Visser
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen (UMCG), 9713 GZ Groningen, The Netherlands; (W.F.J.H.)
| | - Joyce J. de Jong
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen (UMCG), 9713 GZ Groningen, The Netherlands; (W.F.J.H.)
| | - Marian N. Rajasekar
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen (UMCG), 9713 GZ Groningen, The Netherlands; (W.F.J.H.)
| | - Jan Jacob Schuringa
- Department of Experimental Hematology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands
| | - Inge A. M. de Graaf
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen (UMCG), 9713 GZ Groningen, The Netherlands; (W.F.J.H.)
| | - Daan J. Touw
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen (UMCG), 9713 GZ Groningen, The Netherlands; (W.F.J.H.)
| | - Bart G. J. Dekkers
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen (UMCG), 9713 GZ Groningen, The Netherlands; (W.F.J.H.)
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Liu Y, Li S, Feng Y, Zhang Y, Ouyang J, Li S, Wang J, Tan L, Zou L. Serum metabolomic analyses reveal the potential metabolic biomarkers for prediction of amatoxin poisoning. Toxicon 2023; 230:107153. [PMID: 37178797 DOI: 10.1016/j.toxicon.2023.107153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 05/04/2023] [Accepted: 05/05/2023] [Indexed: 05/15/2023]
Abstract
Amatoxin poisoning leads to over 90% of deaths in mushroom poisoning. The objective of present study was to identify the potential metabolic biomarkers for early diagnosis of amatoxin poisoning. Serum samples were collected from 61 patients with amatoxin poisoning and 61 healthy controls. An untargeted metabolomics analysis was performed using the ultra-high-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UPLC-QTOF-MS/MS). Multivariate statistical analysis revealed that the patients with amatoxin poisoning could be clearly separated from healthy controls on the basis of their metabolic fingerprints. There were 33 differential metabolites including 15 metabolites up-regulated metabolites and 18 down-regulated metabolites in patients with amatoxin poisoning compared to healthy controls. These metabolites mainly enriched in the lipid metabolism and amino acid metabolism pathways, such as Glycerophospholipid metabolism, Sphingolipid metabolism, Phenylalanine tyrosine and typtophan biosynthesis, Tyrosine metabolism, Arginine and proline metabolism, which may serve important roles in the amatoxin poisoning. Among the differential metabolites, a total of 8 significant metabolic markers were identified for discriminating patients with amatoxin poisoning from healthy controls, including Glycochenodeoxycholate-3-sulfate (GCDCA-S), 11-Oxo-androsterone glucuronide, Neomenthol-glucuronide, Dehydroisoandrosterone 3-glucuronide, Glucose 6-phosphate (G6P), Lanthionine ketimine, Glycerophosphocholine (GPC) and Nicotinamide ribotide, which achieved satisfactory diagnostic accuracy (AUC>0.8) in both discovery and validation cohorts. Strikingly, the Pearson's correlation analysis indicated that 11-Oxo-androsterone glucuronide, G6P and GCDCA-S were positively correlated with the liver injury induced by amatoxin poisoning. The findings of the current study may provide insight into the pathological mechanism of amatoxin poisoning and screened out the reliable metabolic biomarkers to contribute the clinical early diagnosis of amatoxin poisoning.
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Affiliation(s)
- Yarong Liu
- The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha, Hunan, 410013, PR China; Institute of Clinical Translational Medicine, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha, Hunan, 410005, PR China; Key Laboratory of Molecular Epidemiology of Hunan Province, Hunan Normal University, No. 371 Tongzipo Road, Changsha, Hunan, 410013, PR China
| | - Shumei Li
- The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha, Hunan, 410013, PR China; Institute of Clinical Translational Medicine, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha, Hunan, 410005, PR China; Key Laboratory of Molecular Epidemiology of Hunan Province, Hunan Normal University, No. 371 Tongzipo Road, Changsha, Hunan, 410013, PR China
| | - Yang Feng
- The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha, Hunan, 410013, PR China; Institute of Clinical Translational Medicine, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha, Hunan, 410005, PR China; Key Laboratory of Molecular Epidemiology of Hunan Province, Hunan Normal University, No. 371 Tongzipo Road, Changsha, Hunan, 410013, PR China
| | - Yiyuan Zhang
- Institute of Clinical Translational Medicine, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha, Hunan, 410005, PR China
| | - Jielin Ouyang
- The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha, Hunan, 410013, PR China; Institute of Clinical Translational Medicine, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha, Hunan, 410005, PR China; Key Laboratory of Molecular Epidemiology of Hunan Province, Hunan Normal University, No. 371 Tongzipo Road, Changsha, Hunan, 410013, PR China
| | - Shutong Li
- The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha, Hunan, 410013, PR China; Institute of Clinical Translational Medicine, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha, Hunan, 410005, PR China; Key Laboratory of Molecular Epidemiology of Hunan Province, Hunan Normal University, No. 371 Tongzipo Road, Changsha, Hunan, 410013, PR China
| | - Jia Wang
- Institute of Clinical Translational Medicine, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha, Hunan, 410005, PR China.
| | - Lihong Tan
- Institute of Clinical Translational Medicine, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha, Hunan, 410005, PR China.
| | - Lianhong Zou
- Institute of Clinical Translational Medicine, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha, Hunan, 410005, PR China; Key Laboratory of Molecular Epidemiology of Hunan Province, Hunan Normal University, No. 371 Tongzipo Road, Changsha, Hunan, 410013, PR China.
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20
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Takumi S, Hashimoto K, Tomioka M, Sato M, He W, Komatsu Y, Aoki S, Ikeda R, Shiozaki K, Furukawa T, Komatsu M. Acteoside from Conandron ramondioides Reduces Microcystin-LR Cytotoxicity by Inhibiting Intracellular Uptake Mediated by OATP1B3. PLANTA MEDICA 2023; 89:616-623. [PMID: 36626925 DOI: 10.1055/a-1978-8768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/26/2023]
Abstract
The hepatotoxin microcystin-LR is a strong inhibitor of serine/threonine protein phosphatase (PP) 1 and PP2A. The onset of its cytotoxicity depends on its selective uptake via the hepatocyte uptake transporters, organic anion transporting polypeptide (OATP) 1B1 and OATP1B3. Understanding and preventing the cytotoxicity of microcystin-LR is crucial to maintain human health. This chemoprevention study demonstrates that the herbal plant extract of iwajisha (20 µg/mL) reduced microcystin-LR cytotoxicity in OATP1B3-expressing cells by approximately six times. In addition, 20 µM acteoside, which is one of the major compounds in iwajisha, reduced microcystin-LR cytotoxicity by approximately 7.4 times. Acteoside could also reduce the cytotoxicity of other compounds, such as okadaic acid and nodularin, which are both substrates of OATP1B3 and inhibitors of PP1/PP2A. To investigate the mechanism by which the cytotoxicity of microcystin-LR is attenuated by acteosides, microcystin-LR and microcystin-LR-binding proteins in cells were examined after microcystin-LR and acteosides were co-exposed. Thus, acteoside noncompetitively inhibited microcystin-LR uptake by OATP1B3-expressing cells. Furthermore, acteoside inhibited the intracellular interaction of microcystin-LR with its binding protein(s), including the 22 kDa protein. Furthermore, using immunoblot analysis, acteoside induced the phosphorylation of extracellular signal-regulated kinase (ERK), which is one of the survival signaling molecules. These results suggest that acteoside reduces microcystin-LR cytotoxicity through several mechanisms, including the inhibition of microcystin-LR uptake via OATP1B3, and decreased interaction between microcystin-LR and its binding protein(s), and that ERK signaling activation contributes to the attenuation effect of acteoside against microcystin-LR cytotoxicity.
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Affiliation(s)
- Shota Takumi
- Division of Food and Chemical Biology, Faculty of Fisheries, Kagoshima University, Kagoshima, Japan
- The United Graduate School of Agricultural Sciences, Kagoshima University, Kagoshima, Japan
| | - Kairi Hashimoto
- Division of Food and Chemical Biology, Faculty of Fisheries, Kagoshima University, Kagoshima, Japan
| | - Masaru Tomioka
- Division of Food and Chemical Biology, Faculty of Fisheries, Kagoshima University, Kagoshima, Japan
| | - Mina Sato
- Division of Food and Chemical Biology, Faculty of Fisheries, Kagoshima University, Kagoshima, Japan
| | - Weijie He
- Division of Food and Chemical Biology, Faculty of Fisheries, Kagoshima University, Kagoshima, Japan
| | - Yumiko Komatsu
- Department of Domestic Science, Kagoshima Women's College, Kagoshima, Japan
| | - Shunji Aoki
- Department of Pharmacy, School of Pharmacy, Hyogo Medical University, Kobe, Japan
| | - Ryuji Ikeda
- Department of Pharmacy, University of Miyazaki Hospital, Miyazaki, Japan
| | - Kazuhiro Shiozaki
- Division of Food and Chemical Biology, Faculty of Fisheries, Kagoshima University, Kagoshima, Japan
- The United Graduate School of Agricultural Sciences, Kagoshima University, Kagoshima, Japan
| | - Tatsuhiko Furukawa
- Department of Pathology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Masaharu Komatsu
- Division of Food and Chemical Biology, Faculty of Fisheries, Kagoshima University, Kagoshima, Japan
- The United Graduate School of Agricultural Sciences, Kagoshima University, Kagoshima, Japan
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21
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Barbosa I, Domingues C, Ramos F, Barbosa RM. Analytical methods for amatoxins: A comprehensive review. J Pharm Biomed Anal 2023; 232:115421. [PMID: 37146495 DOI: 10.1016/j.jpba.2023.115421] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 04/22/2023] [Accepted: 04/24/2023] [Indexed: 05/07/2023]
Abstract
Amatoxins are toxic bicyclic octapeptides found in certain wild mushroom species, particularly Amanita phalloides. These mushrooms contain predominantly α- and β-amanitin, which can lead to severe health risks for humans and animals if ingested. Rapid and accurate identification of these toxins in mushroom and biological samples is crucial for diagnosing and treating mushroom poisoning. Analytical methods for the determination of amatoxins are critical to ensure food safety and prompt medical treatment. This review provides a comprehensive overview of the research literature on the determination of amatoxins in clinical specimens, biological and mushroom samples. We discuss the physicochemical properties of toxins, highlighting their influence on the choice of the analytical method and the importance of sample preparation, particularly solid-phase extraction with cartridges. Chromatographic methods are emphasised with a focus on liquid chromatography coupled to mass spectrometry as one of the most relevant analytical method for the determination of amatoxins in complex matrices. Furthermore, current trends and future perspectives in amatoxin detection are also suggested.
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Affiliation(s)
- Isabel Barbosa
- University of Coimbra, Faculty of Pharmacy, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal.
| | - Cátia Domingues
- University of Coimbra, Faculty of Pharmacy, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal; REQUIMTE/LAQV, R. D. Manuel II, Apartado, Oporto 55142, Portugal; University of Coimbra, Faculty of Medicine, Institute for Clinical and Biomedical Research (iCBR) area of Environment Genetics and Oncobiology (CIMAGO), 3000-548 Coimbra, Portugal
| | - Fernando Ramos
- University of Coimbra, Faculty of Pharmacy, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal; REQUIMTE/LAQV, R. D. Manuel II, Apartado, Oporto 55142, Portugal
| | - Rui M Barbosa
- University of Coimbra, Faculty of Pharmacy, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal; University of Coimbra, Center for Neuroscience and Cell Biology, Rua Larga, 3004-504 Coimbra, Portugal
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22
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Klein I, Isensee J, Wiesen MHJ, Imhof T, Wassermann MK, Müller C, Hucho T, Koch M, Lehmann HC. Glycyrrhizic Acid Prevents Paclitaxel-Induced Neuropathy via Inhibition of OATP-Mediated Neuronal Uptake. Cells 2023; 12:cells12091249. [PMID: 37174648 PMCID: PMC10177491 DOI: 10.3390/cells12091249] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 04/11/2023] [Accepted: 04/21/2023] [Indexed: 05/15/2023] Open
Abstract
Peripheral neuropathy is a common side effect of cancer treatment with paclitaxel. The mechanisms by which paclitaxel is transported into neurons, which are essential for preventing neuropathy, are not well understood. We studied the uptake mechanisms of paclitaxel into neurons using inhibitors for endocytosis, autophagy, organic anion-transporting polypeptide (OATP) drug transporters, and derivatives of paclitaxel. RT-qPCR was used to investigate the expression levels of OATPs in different neuronal tissues and cell lines. OATP transporters were pharmacologically inhibited or modulated by overexpression and CRISPR/Cas9-knock-out to investigate paclitaxel transport in neurons. Through these experiments, we identified OATP1A1 and OATP1B2 as the primary neuronal transporters for paclitaxel. In vitro inhibition of OATP1A1 and OAT1B2 by glycyrrhizic acid attenuated neurotoxicity, while paclitaxel's antineoplastic effects were sustained in cancer cell lines. In vivo, glycyrrhizic acid prevented paclitaxel-induced toxicity and improved behavioral and electrophysiological measures. This study indicates that a set of OATPs are involved in paclitaxel transport into neurons. The inhibition of OATP1A1 and OATP1B2 holds a promising strategy to prevent paclitaxel-induced peripheral neuropathy.
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Affiliation(s)
- Ines Klein
- Department of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany
| | - Jörg Isensee
- Translational Pain Research, Department of Anaesthesiology and Intensive Care Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany
| | - Martin H J Wiesen
- Pharmacology at the Laboratory Diagnostics Center, Therapeutic Drug Monitoring, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany
| | - Thomas Imhof
- Center for Biochemistry, Institute for Dental Research and Oral Musculoskeletal Research, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany
| | - Meike K Wassermann
- Department of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany
| | - Carsten Müller
- Pharmacology at the Laboratory Diagnostics Center, Therapeutic Drug Monitoring, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany
| | - Tim Hucho
- Translational Pain Research, Department of Anaesthesiology and Intensive Care Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany
| | - Manuel Koch
- Center for Biochemistry, Institute for Dental Research and Oral Musculoskeletal Research, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany
| | - Helmar C Lehmann
- Department of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany
- Department of Neurology, Hospital Leverkusen, 51375 Leverkusen, Germany
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23
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Determination of protein-bound α-amanitin in mouse plasma: A potential new indicator of poisoning with the mushroom toxin α-amanitin. Toxicon 2023; 226:107067. [PMID: 36871921 DOI: 10.1016/j.toxicon.2023.107067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 02/22/2023] [Accepted: 02/24/2023] [Indexed: 03/06/2023]
Abstract
Approximately 70%∼90% of mushroom poisoning deaths are caused by the class of mushroom toxins known as amatoxins. However, the rapid elimination of amatoxins from plasma within 48 h after mushroom ingestion limits the practical value of plasma amatoxin analysis as a diagnostic indicator of Amanita mushroom poisoning. To increase the positive detection rate and extend the detection window of amatoxin poisoning, we developed a new method to detect protein-bound α-amanitin based on the hypothesis that RNAP II-bound α-amanitin released from the tissue into the plasma could be degraded by trypsin hydrolysis and then detected by conventional liquid chromatography-mass spectrometry (LC‒MS). Toxicokinetic studies on mice intraperitoneally injected with 0.33 mg/kg α-amanitin were conducted to obtain and compare the concentration trends, detection rates, and detection windows of both free α-amanitin and protein-bound α-amanitin. By comparing detection results with and without trypsin hydrolysis in the liver and plasma of α-amanitin-poisoned mice, we verified the credibility of this method and the existence of protein-bound α-amanitin in plasma. Under the optimized trypsin hydrolysis conditions, we obtained a time-dependent trend of protein-bound α-amanitin in mouse plasma at 1-12 days postexposure. In contrast to the short detection window (0-4 h) of free α-amanitin in mouse plasma, the detection window of protein-bound α-amanitin was extended to 10 days postexposure, with a total detection rate of 53.33%, ranging from the limit of detection to 23.94 μg/L. In conclusion, protein-bound α-amanitin had a higher positive detection rate and a longer detection window than free α-amanitin in mice.
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24
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Payload diversification: a key step in the development of antibody-drug conjugates. J Hematol Oncol 2023; 16:3. [PMID: 36650546 PMCID: PMC9847035 DOI: 10.1186/s13045-022-01397-y] [Citation(s) in RCA: 86] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 12/30/2022] [Indexed: 01/18/2023] Open
Abstract
Antibody-drug conjugates (ADCs) is a fast moving class of targeted biotherapeutics that currently combines the selectivity of monoclonal antibodies with the potency of a payload consisting of cytotoxic agents. For many years microtubule targeting and DNA-intercalating agents were at the forefront of ADC development. The recent approval and clinical success of trastuzumab deruxtecan (Enhertu®) and sacituzumab govitecan (Trodelvy®), two topoisomerase 1 inhibitor-based ADCs, has shown the potential of conjugating unconventional payloads with differentiated mechanisms of action. Among future developments in the ADC field, payload diversification is expected to play a key role as illustrated by a growing number of preclinical and clinical stage unconventional payload-conjugated ADCs. This review presents a comprehensive overview of validated, forgotten and newly developed payloads with different mechanisms of action.
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25
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Xue J, Lou X, Ning D, Shao R, Chen G. Mechanism and treatment of α-amanitin poisoning. Arch Toxicol 2023; 97:121-131. [PMID: 36271256 DOI: 10.1007/s00204-022-03396-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 10/10/2022] [Indexed: 12/31/2024]
Abstract
Amanita poisoning has a high mortality rate. The α-amanitin toxin in Amanita is the main lethal toxin. There is no specific detoxification drug for α-amanitin, and the clinical treatment mainly focuses on symptomatic and supportive therapy. The pathogenesis of α-amanitin mainly includes: α-amanitin can inhibit the activity of RNA polymeraseII in the nucleus, including the inhibition of the largest subunit of RNA polymeraseII, RNApb1, bridge helix, and trigger loop. In addition, α-amanitin acts in vivo through the enterohepatic circulation and transport system. α-Amanitin can cause the cell death. The existing mechanisms of cell damage mainly focus on apoptosis, oxidative stress, and autophagy. In addition to the pathogenic mechanism, α-amanitin also has a role in cancer treatment, which is the focus of current research. The mechanism of action of α-amanitin on the body is still being explored.
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Affiliation(s)
- Jinfang Xue
- Medical School, Kunming University of Science and Technology, Kunming, People's Republic of China
| | - Xiran Lou
- Medical School, Kunming University of Science and Technology, Kunming, People's Republic of China
| | - Deyuan Ning
- Medical School, Kunming University of Science and Technology, Kunming, People's Republic of China
| | - Ruifei Shao
- Medical School, Kunming University of Science and Technology, Kunming, People's Republic of China
| | - Guobing Chen
- Department of Emergency Medicine, The First People's Hospital of Yunnan Province, No. 157 Jinbi Road, Xishan District, Kunming, 650032, People's Republic of China.
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26
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Kaci H, Bodnárová S, Fliszár-Nyúl E, Lemli B, Pelantová H, Valentová K, Bakos É, Özvegy-Laczka C, Poór M. Interaction of luteolin, naringenin, and their sulfate and glucuronide conjugates with human serum albumin, cytochrome P450 (CYP2C9, CYP2C19, and CYP3A4) enzymes and organic anion transporting polypeptide (OATP1B1 and OATP2B1) transporters. Biomed Pharmacother 2023; 157:114078. [PMID: 36481402 DOI: 10.1016/j.biopha.2022.114078] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 11/28/2022] [Accepted: 12/02/2022] [Indexed: 12/12/2022] Open
Abstract
Luteolin and naringenin are flavonoids found in various foods/beverages and present in certain dietary supplements. After a high intake of these flavonoids, their sulfate and glucuronide conjugates reach micromolar concentrations in the bloodstream. Some pharmacokinetic interactions of luteolin and naringenin have been investigated in previous studies; however, only limited data are available in regard to their metabolites. In this study, we aimed to investigate the interactions of the sulfate and glucuronic acid conjugates of luteolin and naringenin with human serum albumin, cytochrome P450 (CYP2C9, 2C19, and 3A4) enzymes, and organic anion transporting polypeptide (OATP1B1 and OATP2B1) transporters. Our main findings are as follows: (1) Sulfate conjugates formed more stable complexes with albumin than the parent flavonoids. (2) Luteolin and naringenin conjugates showed no or only weak inhibitory action on the CYP enzymes examined. (3) Certain conjugates of luteolin and naringenin are potent inhibitors of OATP1B1 and/or OATP2B1 enzymes. (4) Conjugated metabolites of luteolin and naringenin may play an important role in the pharmacokinetic interactions of these flavonoids.
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Affiliation(s)
- Hana Kaci
- Drug Resistance Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Eötvös Loránd Research Network, Magyar tudósok krt. 2., H-1117 Budapest, Hungary; Doctoral School of Biology, Institute of Biology, Eötvös Loránd University, Pázmány P. stny. 1/C, H-1117 Budapest, Hungary
| | - Slávka Bodnárová
- Department of Pharmacology, Faculty of Pharmacy, University of Pécs, Rókus u. 2, H-7624 Pécs, Hungary
| | - Eszter Fliszár-Nyúl
- Department of Pharmacology, Faculty of Pharmacy, University of Pécs, Rókus u. 2, H-7624 Pécs, Hungary; Food Biotechnology Research Group, János Szentágothai Research Centre, University of Pécs, Ifjúság útja 20, H-7624 Pécs, Hungary
| | - Beáta Lemli
- Department of Pharmacology, Faculty of Pharmacy, University of Pécs, Rókus u. 2, H-7624 Pécs, Hungary; Green Chemistry Research Group, János Szentágothai Research Center, University of Pécs, Ifjúság útja 20, H-7624 Pécs, Hungary
| | - Helena Pelantová
- Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, CZ-142 20 Prague, Czech Republic
| | - Kateřina Valentová
- Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, CZ-142 20 Prague, Czech Republic
| | - Éva Bakos
- Drug Resistance Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Eötvös Loránd Research Network, Magyar tudósok krt. 2., H-1117 Budapest, Hungary
| | - Csilla Özvegy-Laczka
- Drug Resistance Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Eötvös Loránd Research Network, Magyar tudósok krt. 2., H-1117 Budapest, Hungary
| | - Miklós Poór
- Department of Pharmacology, Faculty of Pharmacy, University of Pécs, Rókus u. 2, H-7624 Pécs, Hungary; Food Biotechnology Research Group, János Szentágothai Research Centre, University of Pécs, Ifjúság útja 20, H-7624 Pécs, Hungary.
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27
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Najjar MK, Manore SG, Regua AT, Lo HW. Antibody-Drug Conjugates for the Treatment of HER2-Positive Breast Cancer. Genes (Basel) 2022; 13:2065. [PMID: 36360302 PMCID: PMC9691220 DOI: 10.3390/genes13112065] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 11/03/2022] [Accepted: 11/04/2022] [Indexed: 11/09/2022] Open
Abstract
Human epidermal growth factor receptor 2 (HER2) receptor tyrosine kinase is overexpressed in 20-30% of breast cancers and is associated with poor prognosis and worse overall patient survival. Most women with HER2-positive breast cancer receive neoadjuvant chemotherapy plus HER2-targeted therapies. The development of HER2-directed therapeutics is an important advancement in targeting invasive breast cancer. Despite the efficacy of anti-HER2 monoclonal antibodies, they are still being combined with adjuvant chemotherapy to improve overall patient outcomes. Recently, significant progress has been made towards the development of a class of therapeutics known as antibody-drug conjugates (ADCs), which leverage the high specificity of HER2-targeted monoclonal antibodies with the potent cytotoxic effects of various small molecules, such as tubulin inhibitors and topoisomerase inhibitors. To date, two HER2-targeting ADCs have been approved by the FDA for the treatment of HER2-positive breast cancer: Ado-trastuzumab emtansine (T-DM1; Kadcyla®) and fam-trastuzumab deruxtecan-nxki (T-Dxd; Enhertu®). Kadcyla and Enhertu are approved for use as a second-line treatment after trastuzumab-taxane-based therapy in patients with HER2-positive breast cancer. The success of ADCs in the treatment of HER2-positive breast cancer provides novel therapeutic advancements in the management of the disease. In this review, we discuss the basic biology of HER2, its downstream signaling pathways, currently available anti-HER2 therapeutic modalities and their mechanisms of action, and the latest clinical and safety characteristics of ADCs used for the treatment of HER2-positive breast cancer.
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Affiliation(s)
- Mariana K. Najjar
- Wake Forest Graduate School of Biomedical Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
| | - Sara G. Manore
- Wake Forest Graduate School of Biomedical Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
| | - Angelina T. Regua
- Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, MSE R162, 6431 Fannin Street, Houston, TX 77030, USA
| | - Hui-Wen Lo
- Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, MSE R162, 6431 Fannin Street, Houston, TX 77030, USA
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
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Tan JL, Stam J, van den Berg AP, van Rheenen PF, Dekkers BGJ, Touw DJ. Amanitin intoxication: effects of therapies on clinical outcomes - a review of 40 years of reported cases. Clin Toxicol (Phila) 2022; 60:1251-1265. [PMID: 36129244 DOI: 10.1080/15563650.2022.2098139] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
BACKGROUND AND AIMS Amanita phalloides poisoning causes severe liver damage which may be potentially fatal. Several treatments are available, but their effectiveness has not been systematically evaluated. We performed a systematic review to investigate the effect of the most commonly used therapies: N-acetylcysteine (NAC), benzylpenicillin (PEN), and silibinin (SIL) on patient outcomes. In addition, other factors contributing to patient outcomes are identified. METHODS We searched MEDLINE and Embase for case series and case reports that described patient outcomes after poisoning with amanitin-containing Amanita mushrooms. We extracted clinical characteristics, treatment details, and outcomes. We used the liver item from the Poisoning Severity Score (PSS) to categorize intoxication severity. RESULTS We included 131 publications describing a total of 877 unique cases. The overall survival rate of all patients was 84%. Patients receiving only supportive care had a survival rate of 59%. The use of SIL or PEN was associated with a 90% (OR 6.40 [3.14-13.04]) and 89% (OR 5.24 [2.87-9.56]) survival rate, respectively. NAC/SIL combination therapy was associated with 85% survival rate (OR 3.85 [2.04, 7.25]). NAC/PEN/SIL treatment group had a survival rate of 76% (OR 2.11 [1.25, 3.57]). Due to the limited number of cases, the use of NAC alone could not be evaluated. Additional analyses in 'proven cases' (amanitin detected), 'probable cases' (mushroom identified by mycologist), and 'possible cases' (neither amanitin detected nor mushroom identified) showed comparable results, but the results did not reach statistical significance. Transplantation-free survivors had significantly lower peak values of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total serum bilirubin (TSB), and international normalized ratio (INR) compared to liver transplantation survivors and patients with fatal outcomes. Higher peak PSS was associated with increased mortality. CONCLUSION Based on data available, no statistical differences could be observed for the effects of NAC, PEN or SIL in proven poisonings with amanitin-containing mushrooms. However, monotherapy with SIL or PEN and combination therapy with NAC/SIL appear to be associated with higher survival rates compared to supportive care alone. AST, ALT, TSB, and INR values are possible predictors of potentially fatal outcomes.
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Affiliation(s)
- Jia Lin Tan
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Janine Stam
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Department of Analytical Biochemistry, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands
| | - Aad P van den Berg
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Patrick F van Rheenen
- Department of Paediatric Gastroenterology, Hepatology and Nutrition, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Bart G J Dekkers
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Daan J Touw
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Department of Pharmaceutical Analysis, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands
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Horowitz BZ. Silibinin: a toxicologist's herbal medicine? Clin Toxicol (Phila) 2022; 60:1194-1197. [PMID: 36222816 DOI: 10.1080/15563650.2022.2128815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Silymarin is an herbal remedy, commonly called milk thistle, or St. Mary's Thistle, and has been used for over 2000 years. It has been available as a capsule of the plant extract in Europe since 1974 to treat hepatic disorders. To date toxicologists have relied on animal studies, human case series, or retrospective reviews to decide on its use. In the U.S. the ability to use IV silibinin, its pharmacologically active purified flavonolignan, is hindered by its lack of availability as a Food and Drug Administration approved pharmaceutical preparation. This commentary reviews the in vitro studies, animal studies, and human retrospective analyses which form the basis for its clinical use. Despite the numerous publications, summarized in this issue in a systematic review, the mortality rate from Amanita mushroom ingestion remains stubbornly the same over four decades of use, and hovers around 10%. Although in the retrospective systematic review the use of silibinin, or penicillin, compared to routine care is statistically significantly superior when the primary outcome is fatality. Despite this there is no quality randomized trial to definitively demonstrate its utility. While, intravenous silibinin has a low toxicity, unanswered is whether it is useful in protecting the liver in cases of amanitin-containing mushrooms toxicity, and whether earlier administration would likely improve outcomes.
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Affiliation(s)
- B Z Horowitz
- Oregon-Alaska Poison Center, Oregon Health Sciences University, Portland, OR, USA
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30
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Toxicology Case Presentations. Vet Clin North Am Small Anim Pract 2022; 53:175-190. [DOI: 10.1016/j.cvsm.2022.07.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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31
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Nies AT, Schaeffeler E, Schwab M. Hepatic solute carrier transporters and drug therapy: Regulation of expression and impact of genetic variation. Pharmacol Ther 2022; 238:108268. [DOI: 10.1016/j.pharmthera.2022.108268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 07/25/2022] [Accepted: 08/15/2022] [Indexed: 11/30/2022]
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Li C, Jia WW, Yang JL, Cheng C, Olaleye OE. Multi-compound and drug-combination pharmacokinetic research on Chinese herbal medicines. Acta Pharmacol Sin 2022; 43:3080-3095. [PMID: 36114271 PMCID: PMC9483253 DOI: 10.1038/s41401-022-00983-7] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 08/12/2022] [Indexed: 12/02/2022]
Abstract
Traditional medicine has provided a basis for health care and disease treatment to Chinese people for millennia, and herbal medicines are regulated as drug products in China. Chinese herbal medicines have two features. They normally possess very complex chemical composition. This makes the identification of the constituents that are together responsible for the therapeutic action of an herbal medicine challenging, because how to select compounds from an herbal medicine for pharmacodynamic study has been a big hurdle in such identification efforts. To this end, a multi-compound pharmacokinetic approach was established to identify potentially important compounds (bioavailable at the action loci with significant exposure levels after dosing an herbal medicine) and to characterize their pharmacokinetics and disposition. Another feature of Chinese herbal medicines is their typical use as or in combination therapies. Coadministration of complex natural products and conventional synthetic drugs is prevalent worldwide, even though it remains very controversial. Natural product–drug interactions have raised wide concerns about reduced drug efficacy or safety. However, growing evidence shows that incorporating Chinese herbal medicines into synthetic drug-based therapies delivers benefits in the treatment of many multifactorial diseases. To address this issue, a drug-combination pharmacokinetic approach was established to assess drug–drug interaction potential of herbal medicines and degree of pharmacokinetic compatibility for multi-herb combination and herbal medicine–synthetic drug combination therapies. In this review we describe the methodology, techniques, requirements, and applications of multi-compound and drug-combination pharmacokinetic research on Chinese herbal medicines and to discuss further development for these two types of pharmacokinetic research.
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Mun SJ, Cho E, Kim JS, Yang CS. Pathogen-derived peptides in drug targeting and its therapeutic approach. J Control Release 2022; 350:716-733. [PMID: 36030988 DOI: 10.1016/j.jconrel.2022.08.041] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/18/2022] [Accepted: 08/21/2022] [Indexed: 02/06/2023]
Abstract
Peptides, short stretches of amino acids or small proteins that occupy a strategic position between proteins and amino acids, are readily accessible by chemical and biological methods. With ideal properties for forming high-affinity and specific interactions with host target proteins, they have established an important niche in the drug development spectrum complementing small molecule and biological therapeutics. Among the most successful biomedicines in use today, peptide-based drugs show great promise. This, coupled with recent advances in synthetic and nanochemical biology, has led to the creation of tailor-made peptide therapeutics for improved biocompatibility. This review presents an overview of the latest research on pathogen-derived, host-cell-interacting peptides. It also highlights strategies for using peptide-based therapeutics that address cellular transport challenges through the introduction of nanoparticles that serve as platforms to facilitate the delivery of peptide biologics and therapeutics for treating various inflammatory diseases. Finally, this paper describes future perspectives, specific pathogen-based peptides that can enhance specificity, efficiency, and capacity in functional peptide-based therapeutics, which are in the spotlight as new treatment alternatives for various diseases, and also presents verified sequences and targets that can increase chemical and pharmacological value.
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Affiliation(s)
- Seok-Jun Mun
- Department of Bionano Technology, Hanyang University, Seoul 04673, Republic of Korea; Center for Bionano Intelligence Education and Research, Ansan 15588, Republic of Korea
| | - Euni Cho
- Department of Bionano Technology, Hanyang University, Seoul 04673, Republic of Korea; Center for Bionano Intelligence Education and Research, Ansan 15588, Republic of Korea
| | - Jae-Sung Kim
- Department of Bionano Technology, Hanyang University, Seoul 04673, Republic of Korea; Institute of Natural Science & Technology, Hanyang University, Ansan 15588, Republic of Korea
| | - Chul-Su Yang
- Center for Bionano Intelligence Education and Research, Ansan 15588, Republic of Korea; Department of Molecular and Life Science, Hanyang University, Ansan 15588, Republic of Korea.
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34
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Hau RK, Tash JS, Georg GI, Wright SH, Cherrington NJ. Physiological Characterization of the Transporter-Mediated Uptake of the Reversible Male Contraceptive H2-Gamendazole Across the Blood-Testis Barrier. J Pharmacol Exp Ther 2022; 382:299-312. [PMID: 35779861 PMCID: PMC9426764 DOI: 10.1124/jpet.122.001195] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 06/14/2022] [Indexed: 11/22/2022] Open
Abstract
The blood-testis barrier (BTB) is formed by a tight network of Sertoli cells (SCs) to limit the movement of reproductive toxicants from the blood into the male genital tract. Transporters expressed at the basal membranes of SCs also influence the disposition of drugs across the BTB. The reversible, nonhormonal contraceptive, H2-gamendazole (H2-GMZ), is an indazole carboxylic acid analog that accumulates over 10 times more in the testes compared with other organs. However, the mechanism(s) by which H2-GMZ circumvents the BTB are unknown. This study describes the physiologic characteristics of the carrier-mediated process(es) that permit H2-GMZ and other analogs to penetrate SCs. Uptake studies were performed using an immortalized human SC line (hT-SerC) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Uptake of H2-GMZ and four analogs followed Michaelis-Menten transport kinetics (one analog exhibited poor penetration). H2-GMZ uptake was strongly inhibited by indomethacin, diclofenac, MK-571, and several analogs. Moreover, H2-GMZ uptake was stimulated by an acidic extracellular pH, reduced at basic pHs, and independent of extracellular Na+, K+, or Cl- levels, which are intrinsic characteristics of OATP-mediated transport. Therefore, the characteristics of H2-GMZ transport suggest that one or more OATPs may be involved. However, endogenous transporter expression in wild-type Chinese hamster ovary (CHO), Madin-Darby canine kidney (MDCK), and human embryonic kidney-293 (HEK-293) cells limited the utility of heterologous transporter expression to identify a specific OATP transporter. Altogether, characterization of the transporters involved in the flux of H2-GMZ provides insight into the selectivity of drug disposition across the human BTB to understand and overcome the pharmacokinetic and pharmacodynamic difficulties presented by this barrier. SIGNIFICANCE STATEMENT: Despite major advancements in female contraceptives, male alternatives, including vasectomy, condom usage, and physical withdrawal, are antiquated and the widespread availability of nonhormonal, reversible chemical contraceptives is nonexistent. Indazole carboxylic acid analogs such as H2-GMZ are promising new reversible, antispermatogenic drugs that are highly effective in rodents. This study characterizes the carrier-mediated processes that permit H2-GMZ and other drugs to enter Sertoli cells and the observations made here will guide the development of drugs that effectively circumvent the BTB.
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Affiliation(s)
- Raymond K Hau
- Department of Pharmacology and Toxicology, College of Pharmacy (R.K.H., N.J.C.), and Department of Physiology, College of Medicine (S.H.W.), The University of Arizona, Tucson, Arizona; Department of Molecular and Integrative Physiology, KU School of Medicine, The University of Kansas Medical Center, Kansas City, Kansas (J.S.T.); Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, College of Pharmacy, The University of Minnesota, Minneapolis, Minnesota (G.I.G.)
| | - Joseph S Tash
- Department of Pharmacology and Toxicology, College of Pharmacy (R.K.H., N.J.C.), and Department of Physiology, College of Medicine (S.H.W.), The University of Arizona, Tucson, Arizona; Department of Molecular and Integrative Physiology, KU School of Medicine, The University of Kansas Medical Center, Kansas City, Kansas (J.S.T.); Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, College of Pharmacy, The University of Minnesota, Minneapolis, Minnesota (G.I.G.)
| | - Gunda I Georg
- Department of Pharmacology and Toxicology, College of Pharmacy (R.K.H., N.J.C.), and Department of Physiology, College of Medicine (S.H.W.), The University of Arizona, Tucson, Arizona; Department of Molecular and Integrative Physiology, KU School of Medicine, The University of Kansas Medical Center, Kansas City, Kansas (J.S.T.); Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, College of Pharmacy, The University of Minnesota, Minneapolis, Minnesota (G.I.G.)
| | - Stephen H Wright
- Department of Pharmacology and Toxicology, College of Pharmacy (R.K.H., N.J.C.), and Department of Physiology, College of Medicine (S.H.W.), The University of Arizona, Tucson, Arizona; Department of Molecular and Integrative Physiology, KU School of Medicine, The University of Kansas Medical Center, Kansas City, Kansas (J.S.T.); Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, College of Pharmacy, The University of Minnesota, Minneapolis, Minnesota (G.I.G.)
| | - Nathan J Cherrington
- Department of Pharmacology and Toxicology, College of Pharmacy (R.K.H., N.J.C.), and Department of Physiology, College of Medicine (S.H.W.), The University of Arizona, Tucson, Arizona; Department of Molecular and Integrative Physiology, KU School of Medicine, The University of Kansas Medical Center, Kansas City, Kansas (J.S.T.); Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, College of Pharmacy, The University of Minnesota, Minneapolis, Minnesota (G.I.G.)
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Bajraktari-Sylejmani G, von Linde T, Burhenne J, Haefeli WE, Sauter M, Weiss J. Evaluation of PepT1 (SLC15A1) Substrate Characteristics of Therapeutic Cyclic Peptides. Pharmaceutics 2022; 14:pharmaceutics14081610. [PMID: 36015235 PMCID: PMC9415731 DOI: 10.3390/pharmaceutics14081610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 07/22/2022] [Accepted: 07/29/2022] [Indexed: 11/27/2022] Open
Abstract
The human peptide transporter hPepT1 (SLC15A1), physiologically transporting dipeptides and tripeptides generated during food digestion, also plays a role in the uptake of small bioactive peptides and peptide-like drugs. Moreover, it might be addressed in prodrug strategies of poorly absorbed drugs. We hypothesised that the cyclic drug peptides octreotide and pasireotide could be substrates of this transporter because their diameter can resemble the size of dipeptides or tripeptides due to their strong structural curvature and because they reach the systemic circulation in Beagle dogs. For investigating possible hPepT1 substrate characteristics, we generated and characterised a CHO-K1 cell line overexpressing SLC15A1 by transfection and selection via magnetic beads. Possible inhibition of the uptake of the prototypical substrate Gly-Sar by octreotide and pasireotide was screened, followed by quantifying the uptake of the cyclic peptides in cells overexpressing SLC15A1 compared with the parental cell line. Although inhibition of Gly-Sar uptake was observed, uptake of octreotide and pasireotide was not increased in SLC15A1 overexpressing cells, indicating a lack of transport by hPepT1. Our data clearly indicate that octreotide and pasireotide are nonsubstrate inhibitors of hPepT1 and that their oral bioavailability cannot be explained by absorption via hPepT1.
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36
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Patra A, Mukherjee AK. Mushroom mycetism – A neglected and challenging medical emergency in the Indian subcontinent: A road map for its prevention and treatment. Toxicon 2022; 217:56-77. [DOI: 10.1016/j.toxicon.2022.07.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 07/22/2022] [Accepted: 07/25/2022] [Indexed: 11/27/2022]
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Kaae JA, Bever CS, Poppenga RH. Early diagnosis of amanitin exposure (amatoxicosis) in a dog with a point‐of‐care diagnostic test. J Vet Emerg Crit Care (San Antonio) 2022; 32:824-829. [DOI: 10.1111/vec.13235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 06/15/2021] [Accepted: 07/17/2021] [Indexed: 11/27/2022]
Affiliation(s)
- Jennifer A. Kaae
- Pet Emergency and Specialty Center of Marin San Rafael California USA
| | - Candace S. Bever
- Foodborne Toxin Detection and Prevention Research Unit, Agricultural Research Service (ARS) United States Department of Agriculture (USDA) Albany California USA
| | - Robert H. Poppenga
- Toxicology Section of the California Animal Health and Food Safety Laboratory System School of Veterinary Medicine University of California, Davis Davis California USA
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Huang QJ, Liao GC, Zhuang XR, Yang ML, Yao JJ, Deng JH, Zhang YM, Wang Y, Qi XX, Pan DF, Guan Y, Huang ZY, Zhang FX, Liu ZQ, Lu LL. Ras inhibitor farnesylthiosalicylic acid conjugated with IR783 dye exhibits improved tumor-targeting and altered anti-breast cancer mechanisms in mice. Acta Pharmacol Sin 2022; 43:1843-1856. [PMID: 34845369 PMCID: PMC9253319 DOI: 10.1038/s41401-021-00775-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 09/05/2021] [Indexed: 11/09/2022]
Abstract
Ras has long been viewed as a promising target for cancer therapy. Farnesylthiosalicylic acid (FTS), as the only Ras inhibitor has ever entered phase II clinical trials, has yielded disappointing results due to its strong hydrophobicity, poor tumor-targeting capacity, and low therapeutic efficiency. Thus, enhancing hydrophilicity and tumor-targeting capacity of FTS for improving its therapeutic efficacy is of great significance. In this study we conjugated FTS with a cancer-targeting small molecule dye IR783 and characterized the anticancer properties of the conjugate FTS-IR783. We showed that IR783 conjugation greatly improved the hydrophilicity, tumor-targeting and therapeutic potential of FTS. After a single oral administration in Balb/c mice, the relative bioavailability of FTS-IR783 was increased by 90.7% compared with FTS. We demonstrated that organic anion transporting polypeptide (OATP) and endocytosis synergistically drove the uptake of the FTS-IR783 conjugate in breast cancer MDA-MB-231 cells, resulting in superior tumor-targeting ability of the conjugate both in vitro and in vivo. We further revealed that FTS-IR783 conjugate could bind with and directly activate AMPK rather than affecting Ras, and subsequently regulate the TSC2/mTOR signaling pathway, thus achieving 2-10-fold increased anti-cancer therapeutic efficacy against 6 human breast cancer cell lines compared to FTS both in vivo and in vitro. Overall, our data highlights a promising approach for the modification of the anti-tumor drug FTS using IR783 and makes it possible to return FTS back to the clinic with a better efficacy.
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Affiliation(s)
- Qiu-ju Huang
- grid.411866.c0000 0000 8848 7685Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People’s Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006 China ,grid.411866.c0000 0000 8848 7685School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006 China
| | - Guo-chao Liao
- grid.411866.c0000 0000 8848 7685Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People’s Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006 China
| | - Xue-rong Zhuang
- grid.411866.c0000 0000 8848 7685Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People’s Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006 China
| | - Meng-lan Yang
- grid.411866.c0000 0000 8848 7685Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People’s Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006 China
| | - Jing-jing Yao
- grid.411866.c0000 0000 8848 7685Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People’s Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006 China
| | - Jian-hua Deng
- grid.411866.c0000 0000 8848 7685Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People’s Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006 China
| | - Yan-min Zhang
- grid.411866.c0000 0000 8848 7685Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People’s Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006 China
| | - Ying Wang
- grid.411866.c0000 0000 8848 7685Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People’s Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006 China
| | - Xiao-xiao Qi
- grid.411866.c0000 0000 8848 7685Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People’s Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006 China
| | - Dong-feng Pan
- grid.27755.320000 0000 9136 933XDepartment of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA 22903 USA
| | - Yang Guan
- grid.411866.c0000 0000 8848 7685Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People’s Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006 China
| | - Zhi-ying Huang
- grid.411866.c0000 0000 8848 7685Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People’s Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006 China
| | - Feng-xue Zhang
- grid.411866.c0000 0000 8848 7685School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006 China
| | - Zhong-qiu Liu
- grid.411866.c0000 0000 8848 7685Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People’s Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006 China ,grid.259384.10000 0000 8945 4455State Key Laboratory of Quality Research in Chinese Medicine/ Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macao, SAR China
| | - Lin-lin Lu
- grid.411866.c0000 0000 8848 7685Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People’s Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006 China ,grid.259384.10000 0000 8945 4455State Key Laboratory of Quality Research in Chinese Medicine/ Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macao, SAR China
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Mitchell ST. Letter to the Editor: Regarding the Toxicology Letters publication: "The enterohepatic circulation of amanitin: Kinetics and therapeutical implications (Thiel et al 2011).". Toxicol Lett 2022; 367:1-2. [PMID: 35781014 DOI: 10.1016/j.toxlet.2022.06.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 04/15/2022] [Accepted: 06/29/2022] [Indexed: 11/30/2022]
Affiliation(s)
- S T Mitchell
- Department of Family Medicine, Dominican Hospital, Santa Cruz, CA 95076, USA.
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40
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Garcia J, Carvalho A, das Neves RP, Malheiro R, Rodrigues DF, Figueiredo PR, Bovolini A, Duarte JA, Costa VM, Carvalho F. Antidotal effect of cyclosporine A against α-amanitin toxicity in CD-1 mice, at clinical relevant doses. Food Chem Toxicol 2022; 166:113198. [PMID: 35671903 DOI: 10.1016/j.fct.2022.113198] [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: 11/21/2021] [Revised: 05/25/2022] [Accepted: 05/30/2022] [Indexed: 12/12/2022]
Abstract
Amanita phalloides is one of the most toxic mushrooms worldwide, being responsible for the majority of human fatal cases of mushroom intoxications. α-Amanitin, the most deleterious toxin of A. phalloides, inhibits RNA polymerase II (RNAP II), causing hepatic and renal failure. Herein, we used cyclosporine A after it showed potential to displace RNAP II α-amanitin in silico. That potential was not confirmed either by the incorporation of ethynyl-UTP or by the monitoring of fluorescent RNAP II levels. Nevertheless, concomitant incubation of cyclosporine A with α-amanitin, for a short period, provided significant protection against its toxicity in differentiated HepaRG cells. In mice, the concomitant administration of α-amanitin [0.45 mg/kg intraperitoneal (i.p.)] with cyclosporine A (10 mg/kg i.p. plus 2 × 10 mg/kg cyclosporine A i.p. at 8 and 12 h post α-amanitin) resulted in the full survival of α-amanitin-intoxicated mice, up to 30 days after the toxin's administration. Since α-amanitin is a substrate of the organic-anion-transporting polypeptide 1B3 and cyclosporine A inhibits this transporter and is a potent anti-inflammatory agent, we hypothesize that these mechanisms are responsible for the protection observed. These results indicate a potential antidotal effect of cyclosporine A, and its safety profile advocates for its use at an early stage of α-amanitin intoxications.
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Affiliation(s)
- Juliana Garcia
- UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal; Laboratório Associado i4HB - Instituto para a Saúde e a Bioeconomia, Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, 4050-313, Porto, Portugal
| | - Alexandra Carvalho
- CNC - Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-517, Coimbra, Portugal; IIIUC-Institute of Interdisciplinary Research, University of Coimbra, 3030-789, Coimbra, Portugal
| | - Ricardo Pires das Neves
- CNC - Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-517, Coimbra, Portugal
| | - Rui Malheiro
- UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal; Laboratório Associado i4HB - Instituto para a Saúde e a Bioeconomia, Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, 4050-313, Porto, Portugal
| | - Daniela F Rodrigues
- UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal; Laboratório Associado i4HB - Instituto para a Saúde e a Bioeconomia, Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, 4050-313, Porto, Portugal
| | - Pedro R Figueiredo
- CNC - Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-517, Coimbra, Portugal
| | | | - José Alberto Duarte
- CIAFEL, Faculty of Sport, University of Porto, Porto, Portugal; TOXRUN - Toxicology Research Unit, University Institute of Health Sciences, CESPU, CRL, 4585-116, Gandra, Portugal
| | - Vera Marisa Costa
- UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal; Laboratório Associado i4HB - Instituto para a Saúde e a Bioeconomia, Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, 4050-313, Porto, Portugal.
| | - Félix Carvalho
- UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal; Laboratório Associado i4HB - Instituto para a Saúde e a Bioeconomia, Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, 4050-313, Porto, Portugal.
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41
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Lin LY, Tong YL, Lu YQ. The characteristics of liver injury induced by Amanita and clinical value of α-amanitin detection. Hepatobiliary Pancreat Dis Int 2022; 21:257-266. [PMID: 35168873 DOI: 10.1016/j.hbpd.2022.01.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 12/17/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND Amanita poisoning as a foodborne disease has raised concerning mortality issues. Reducing the interval between mushroom ingestion and medical intervention could greatly influence the outcomes of Amanita poisoning patients, while treatment is highly dependent on a confirmed diagnosis. To this end, we developed an early detection-guided intervention strategy by optimizing diagnostic process with performing α-amanitin detection, and further explored whether this strategy influenced the progression of Amanita poisoning. METHODS This study was a retrospective analysis of 25 Amanita poisoning patients. Thirteen patients in the detection group were diagnosed mainly based on α-amanitin detection, and 12 patients were diagnosed essentially on the basis of mushroom consumption history, typical clinical patterns and mushroom identification (conventional group). Amanita poisoning patients received uniform therapy, in which plasmapheresis was executed once confirming the diagnosis of Amanita poisoning. We compared the demographic baseline, clinical and laboratory data, treatment and outcomes between the two groups, and further explored the predictive value of α-amanitin concentration in serum. RESULTS Liver injury induced by Amanita appeared worst at the fourth day and alanine aminotransferase (ALT) rose higher than aspartate aminotransferase (AST). The mortality rate was 7.7% (1/13) in the detection group and 50.0% (6/12) in the conventional group (P = 0.030), since patients in the detection group arrived hospital much earlier and received plasmapheresis at the early stage of disease. The early detection-guided intervention helped alleviate liver impairment caused by Amanita and decreased the peak AST as well as ALT. However, the predictive value of α-amanitin concentration in serum was still considered limited. CONCLUSIONS In the management of mushroom poisoning, consideration should be given to the rapid detection of α-amanitin in suspected Amanita poisoning patients and the immediate initiation of medical treatment upon a positive toxin screening result.
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Affiliation(s)
- Li-Ying Lin
- Department of Emergency Medicine, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Ya-Ling Tong
- Department of Emergency Medicine, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Yuan-Qiang Lu
- Department of Emergency Medicine, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; The Key Laboratory for Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases of Zhejiang Province, Hangzhou 310003, China.
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42
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Wu Z, Li H, Zhang Y, Ding C, Zhao W, Dai J, Yu C, Yao Q, Zheng F, Fan J, Sun C. Liver transcriptome analyses of acute poisoning and recovery of male ICR mice exposed to the mushroom toxin α-amanitin. Arch Toxicol 2022; 96:1751-1766. [PMID: 35384471 DOI: 10.1007/s00204-022-03278-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 03/14/2022] [Indexed: 11/02/2022]
Abstract
Approximately 70-90% of mushroom poisoning deaths are caused by α-amanitin-induced liver injury resulting from RNA polymerase II (RNAP II) inhibition. Liver regeneration ability may contribute greatly to individual survival after α-amanitin poisoning. However, it is unclear what cellular pathways are activated to stimulate regeneration. We conducted dose-effect and time-effect studies in mice that were intraperitoneally injected with 0.33-0.66 mg/kg α-amanitin to establish a poisoning model. The liver/body weight ratio, serological indices, and pathology were evaluated to characterize the liver injury. In the time-effect study, the liver transcriptome was analyzed to explore the mRNA changes resulting from RNAP II inhibition and the underlying pathways associated with recovery. Based on the two animal studies, we established a poisoning model with three sequential liver states: early injury, regulation, and recovery. The mRNA changes reflected by the differentially expressed genes (DEGs) in the transcriptome could be used to illustrate the inhibition of RNAP II by α-amanitin. DEGs at four key time points were well matched with the three liver states, including 8-h downregulated genes in the early injury state, 16-h and 72-h upregulated genes in the regulation state, and 96-h upregulated/downregulated genes in the recovery state. By clustering analysis, the mTOR signaling pathway was screened out as the most promising potential pathway promoting recovery. The results of our investigations of the pathways and events downstream of the mTOR pathway indicated that the activation of mTOR probably contributes crucially to liver regeneration, which could be a promising basis for drug development.
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Affiliation(s)
- Zhijun Wu
- Chinese Center for Disease Control and Prevention, National Institute for Occupational Health and Poison Control, Beijing, 100050, China
| | - Haijiao Li
- Chinese Center for Disease Control and Prevention, National Institute for Occupational Health and Poison Control, Beijing, 100050, China
| | - Yizhe Zhang
- Chinese Center for Disease Control and Prevention, National Institute for Occupational Health and Poison Control, Beijing, 100050, China
| | - Chunguang Ding
- National Center for Occupational Safety and Health, Beijing, 202300, China
| | - Wenjin Zhao
- Chinese Center for Disease Control and Prevention, National Institute for Occupational Health and Poison Control, Beijing, 100050, China
| | - Jing Dai
- National Center for Occupational Safety and Health, Beijing, 202300, China
| | - Chengmin Yu
- The People's Hospital of Chuxiong Yi Autonomous Prefecture, Chuxiong, 675000, Yunnan, China
| | - Qunmei Yao
- The People's Hospital of Chuxiong Yi Autonomous Prefecture, Chuxiong, 675000, Yunnan, China
| | - Fenshuang Zheng
- The Emergency Department of the Affiliated Hospital of Yunnan University, Kunming, 650021, Yunnan, China
| | - Jingguang Fan
- National Center for Occupational Safety and Health, Beijing, 202300, China.
| | - Chengye Sun
- Chinese Center for Disease Control and Prevention, National Institute for Occupational Health and Poison Control, Beijing, 100050, China.
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43
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Toxicokinetics of β-Amanitin in Mice and In Vitro Drug-Drug Interaction Potential. Pharmaceutics 2022; 14:pharmaceutics14040774. [PMID: 35456608 PMCID: PMC9030691 DOI: 10.3390/pharmaceutics14040774] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 03/21/2022] [Accepted: 03/29/2022] [Indexed: 01/01/2023] Open
Abstract
The toxicokinetics of β-amanitin, a toxic bicyclic octapeptide present abundantly in Amanitaceae mushrooms, was evaluated in mice after intravenous (iv) and oral administration. The area under plasma concentration curves (AUC) following iv injection increased in proportion to doses of 0.2, 0.4, and 0.8 mg/kg. β-amanitin disappeared rapidly from plasma with a half-life of 18.3−33.6 min, and 52.3% of the iv dose was recovered as a parent form. After oral administration, the AUC again increased in proportion with doses of 2, 5, and 10 mg/kg. Absolute bioavailability was 7.3−9.4%, which resulted in 72.4% of fecal recovery from orally administered β-amanitin. Tissue-to-plasma AUC ratios of orally administered β-amanitin were the highest in the intestine and stomach. It also readily distributed to kidney > spleen > lung > liver ≈ heart. Distribution to intestines, kidneys, and the liver is in agreement with previously reported target organs after acute amatoxin poisoning. In addition, β-amanitin weakly or negligibly inhibited major cytochrome P450 and 5′-diphospho-glucuronosyltransferase activities in human liver microsomes and suppressed drug transport functions in mammalian cells that overexpress transporters, suggesting the remote drug interaction potentials caused by β-amanitin exposure.
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44
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Gu X, Zhang L, Sun W, Liu K, Xu H, Wu P, Gui M, Qu W. Autophagy Promotes α-Amanitin-Induced Apoptosis of Hepa1-6 Liver Cells. Chem Res Toxicol 2022; 35:392-401. [PMID: 35175747 DOI: 10.1021/acs.chemrestox.1c00297] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
It is estimated that 90% of deaths from food poisoning in China can be attributed to Amanita poisoning, whose main toxin is α-amanitin. Studies showed that apoptosis plays a critical role in liver injuries induced by α-amanitin. Although the relationship between autophagy and apoptosis in different liver models has been addressed many times, whether autophagy plays a pro or con effect on α-amanitin-induced apoptosis has not been clarified. Therefore, this study was conducted to explore the effect of autophagy in α-amanitin-induced apoptosis in Hepa1-6 liver cells. A 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay was applied to determine cell viability, a 2',7'-dichlorofluorescin diacetate probe was used to monitor reactive oxygen species (ROS) levels, a flow cytometer and dansylcadaverine (MDC) staining were used to observe α-amanitin-induced apoptosis and autophagy, respectively, and apoptosis and autophagy proteins were assessed by western blotting. The results showed that α-amanitin suppressed cell viability in a time- and concentration-dependent manner. Moreover, the release of ROS was increased with increasing α-amanitin amount. Cell apoptosis and autophagy were noticed and characterized by the increased apoptosis rate and autophagic vesicles under a fluorescence microscope as well as upregulation of Bax/Bcl-2, cleaved caspase-3, and LC3-II/I and downregulation of p62. Further, the autophagy activator rapamycin (Rap) and the inhibitor 3-methylademine (3-MA) were introduced, which showed that the apoptosis rate and the ratio of Bax/Bcl-2 as well as the protein expression level of cleaved caspase-3 increased significantly with the pretreatment of Rap and decreased remarkably with the pretreatment of 3-MA. Moreover, cell viability was found to decrease further with the promotion of autophagy. Notably, the ROS level was attenuated after autophagy was elevated. In conclusion, autophagy could promote α-amanitin-induced Hepa1-6 cell apoptosis, and the process is unassociated with ROS levels. This research provides a theoretical basis for the study of the toxicological mechanism of α-amanitin-induced liver injuries.
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Affiliation(s)
- Xiaolong Gu
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Yunnan Agricultural University, No. 65, Jin Hei Road, Panlong District, Kunming 650051, P. R. China
| | - Limei Zhang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Yunnan Agricultural University, No. 65, Jin Hei Road, Panlong District, Kunming 650051, P. R. China
| | - Weixing Sun
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Yunnan Agricultural University, No. 65, Jin Hei Road, Panlong District, Kunming 650051, P. R. China
| | - Kai Liu
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Yunnan Agricultural University, No. 65, Jin Hei Road, Panlong District, Kunming 650051, P. R. China
| | - Hui Xu
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Yunnan Agricultural University, No. 65, Jin Hei Road, Panlong District, Kunming 650051, P. R. China
| | - Peng Wu
- Yunnan Plateau Characteristic Agricultural Industry Research Institute, Yunnan Agricultural University, Kunming 650201, Yunnan, P. R. China
| | - Mingying Gui
- Yunnan Plateau Characteristic Agricultural Industry Research Institute, Yunnan Agricultural University, Kunming 650201, Yunnan, P. R. China
| | - Weijie Qu
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Yunnan Agricultural University, No. 65, Jin Hei Road, Panlong District, Kunming 650051, P. R. China
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Pryyma A, Matinkhoo K, Bu YJ, Merkens H, Zhang Z, Bénard F, Perrin DM. Synthesis and preliminary evaluation of octreotate conjugates of bioactive synthetic amatoxins for targeting somatostatin receptor (sstr2) expressing cells. RSC Chem Biol 2022; 3:69-78. [PMID: 35128410 PMCID: PMC8729174 DOI: 10.1039/d1cb00036e] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 09/27/2021] [Indexed: 11/28/2022] Open
Abstract
Targeted cancer therapy represents a paradigm-shifting approach that aims to deliver a toxic payload selectively to target-expressing cells thereby sparing normal tissues the off-target effects associated with traditional chemotherapeutics. Since most targeted constructs rely on standard microtubule inhibitors or DNA-reactive molecules as payloads, new toxins that inhibit other intracellular targets are needed to realize the full potential of targeted therapy. Among these new payloads, α-amanitin has gained attraction as a payload in targeted therapy. Here, we conjugate two synthetic amanitins at different sites to demonstrate their utility as payloads in peptide drug conjugates (PDCs). As an exemplary targeting agent, we chose octreotate, a well-studied somatostatin receptor (sstr2) peptide agonist for the conjugation to synthetic amatoxins via three tailor-built linkers. The linker chemistry permitted the evaluation of one non-cleavable and two cleavable self-immolative conjugates. The immolating linkers were chosen to take advantage of either the reducing potential of the intracellular environment or the high levels of lysosomal proteases in tumor cells to trigger toxin release. Cell-based assays on target-positive Ar42J cells revealed target-specific reduction in viability with up to 1000-fold enhancement in bioactivity compared to the untargeted amatoxins. Altogether, this preliminary study enabled the development of a highly modular synthetic platform for the construction of amanitin-based conjugates that can be readily extended to various targeting moieties.
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Affiliation(s)
- Alla Pryyma
- Department of Chemistry, University of British Columbia 2036 Main Mall Vancouver BC V6T 1Z1 Canada
| | - Kaveh Matinkhoo
- Department of Chemistry, University of British Columbia 2036 Main Mall Vancouver BC V6T 1Z1 Canada
| | - Yong Jia Bu
- Department of Chemistry, University of British Columbia 2036 Main Mall Vancouver BC V6T 1Z1 Canada
| | - Helen Merkens
- Department of Molecular Oncology, BC Cancer Vancouver BC V5Z 1L3 Canada
| | - Zhengxing Zhang
- Department of Molecular Oncology, BC Cancer Vancouver BC V5Z 1L3 Canada
| | - Francois Bénard
- Department of Molecular Oncology, BC Cancer Vancouver BC V5Z 1L3 Canada
| | - David M Perrin
- Department of Chemistry, University of British Columbia 2036 Main Mall Vancouver BC V6T 1Z1 Canada
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Mackenzie CA, Austin E, Thompson M, Tirona RG. Cyclosporine as a novel treatment for amatoxin-containing mushroom poisoning: a case series. TOXICOLOGY COMMUNICATIONS 2022. [DOI: 10.1080/24734306.2021.2006957] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Affiliation(s)
- Constance A. Mackenzie
- Ontario Poison Centre, Hospital for Sick Children, Division of Clinical Pharmacology and Toxicology, Toronto, Ontario, Canada
- Divisions of Clinical Pharmacology and Toxicology/Respirology, Western University, London, Ontario, Canada
| | - Emily Austin
- Ontario Poison Centre, Hospital for Sick Children, Division of Clinical Pharmacology and Toxicology, Toronto, Ontario, Canada
- St. Michael’s Hospital, Division of Emergency Medicine, Toronto, Ontario, Canada
| | - Margaret Thompson
- Ontario Poison Centre, Hospital for Sick Children, Division of Clinical Pharmacology and Toxicology, Toronto, Ontario, Canada
- St. Michael’s Hospital, Division of Emergency Medicine, Toronto, Ontario, Canada
| | - Rommel G. Tirona
- Departments of Physiology & Pharmacology and Medicine, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada
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47
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Abstract
Pharmacogenetic testing in patients with cancer requiring cytotoxic chemotherapy offers the potential to predict, prevent, and mitigate chemotherapy-related toxicities. While multiple drug-gene pairs have been identified and studied, few drug-gene pairs are currently used routinely in the clinical status. Here we review what is known, theorized, and unknown regarding the use of pharmacogenetic testing in cancer.
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Affiliation(s)
- Zahra Talebi
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Alex Sparreboom
- Division of Pharmaceutics and Pharmacology, College of Pharmacy & Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Susan I Colace
- Division of Hematology, Oncology, and Blood & Marrow Transplant, Nationwide Children's Hospital, Columbus, OH, USA.
- The Ohio State University, Columbus, OH, USA.
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48
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Zhang Z, Li H, Deng Y, Schuck K, Raulefs S, Maeritz N, Yu Y, Hechler T, Pahl A, Fernández-Sáiz V, Wan Y, Wang G, Engleitner T, Öllinger R, Rad R, Reichert M, Diakopoulos KN, Weber V, Li J, Shen S, Zou X, Kleeff J, Mihaljevic A, Michalski CW, Algül H, Friess H, Kong B. AGR2-Dependent Nuclear Import of RNA Polymerase II Constitutes a Specific Target of Pancreatic Ductal Adenocarcinoma in the Context of Wild-Type p53. Gastroenterology 2021; 161:1601-1614.e23. [PMID: 34303658 DOI: 10.1053/j.gastro.2021.07.030] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 06/25/2021] [Accepted: 07/17/2021] [Indexed: 12/02/2022]
Abstract
BACKGROUND & AIMS Promoted by pancreatitis, oncogenic KrasG12D triggers acinar cells' neoplastic transformation through acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia. Anterior gradient 2 (Agr2), a known inhibitor of p53, is detected at early stage of pancreatic ductal adenocarcinoma (PDAC) development. RNA polymerase II (RNAPII) is a key nuclear enzyme; regulation of its nuclear localization in mammalian cells represents a potential therapeutic target. METHODS A mouse model of inflammation-accelerated KrasG12D-driven ADM and pancreatic intraepithelial neoplasia development was used. Pancreas-specific Agr2 ablation was performed to access its role in pancreatic carcinogenesis. Hydrophobic hexapeptides loaded in liposomes were developed to disrupt Agr2-RNAPII complex. RESULTS We found that Agr2 is up-regulated in ADM-to-pancreatic intraepithelial neoplasia transition in inflammation and KrasG12D-driven early pancreatic carcinogenesis. Genetic ablation of Agr2 specifically blocks this metaplastic-to-neoplastic process. Mechanistically, Agr2 directs the nuclear import of RNAPII via its C-terminal nuclear localization signal, undermining the ATR-dependent p53 activation in ADM lesions. Because Agr2 binds to the largest subunit of RNAPII in a peptide motif-dependent manner, we developed a hexapeptide to interfere with the nuclear import of RNAPII by competitively disrupting the Agr2-RNAPII complex. This novel hexapeptide leads to dysfunction of RNAPII with concomitant activation of DNA damage response in early neoplastic lesions; hence, it dramatically compromises PDAC initiation in vivo. Moreover, the hexapeptide sensitizes PDAC cells and patient-derived organoids harboring wild-type p53 to RNAPII inhibitors and first-line chemotherapeutic agents in vivo. Of note, this therapeutic effect is efficient across various cancer types. CONCLUSIONS Agr2 is identified as a novel adaptor protein for nuclear import of RNAPII in mammalian cells. Also, we provide genetic evidence defining Agr2-dependent nuclear import of RNAPII as a pharmaceutically accessible target for prevention and treatment in PDAC in the context of wild-type p53.
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MESH Headings
- Active Transport, Cell Nucleus
- Animals
- Antineoplastic Agents/pharmacology
- Carcinoma in Situ/drug therapy
- Carcinoma in Situ/enzymology
- Carcinoma in Situ/genetics
- Carcinoma in Situ/pathology
- Carcinoma, Pancreatic Ductal/drug therapy
- Carcinoma, Pancreatic Ductal/enzymology
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/pathology
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/pathology
- Gene Expression Regulation, Neoplastic
- Metaplasia
- Mice, Inbred C57BL
- Mice, Inbred NOD
- Mice, Knockout
- Mice, SCID
- Mucoproteins/genetics
- Mucoproteins/metabolism
- Mutation
- Oligopeptides/pharmacology
- Oncogene Proteins/genetics
- Oncogene Proteins/metabolism
- Pancreatic Neoplasms/drug therapy
- Pancreatic Neoplasms/enzymology
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/pathology
- Proto-Oncogene Proteins p21(ras)/genetics
- RNA Polymerase II/genetics
- RNA Polymerase II/metabolism
- Tumor Suppressor Protein p53/genetics
- Tumor Suppressor Protein p53/metabolism
- Mice
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Affiliation(s)
- Zhiheng Zhang
- Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Hongzhen Li
- Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, China; Department of Surgery, Ulm University Hospital, Ulm University, Ulm, Germany
| | - Yibin Deng
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, and College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Kathleen Schuck
- Department of Surgery, Ulm University Hospital, Ulm University, Ulm, Germany
| | - Susanne Raulefs
- Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Nadja Maeritz
- Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Yuanyuan Yu
- Department of Surgery, Ulm University Hospital, Ulm University, Ulm, Germany
| | | | - Andreas Pahl
- Heidelberg Pharma Research GmbH, Ladenburg, Germany
| | - Vanesa Fernández-Sáiz
- Department of Medicine III, Klinikum rechts der Isar, Technische Universität München, Munich, Germany; Center for Translational Cancer Research, Technische Universität München, Munich, Germany
| | - Yuan Wan
- The Pq Laboratory of Micro/Nano BiomeDx, Department of Biomedical Engineering, Binghamton University, State University of New York, Binghamton, New York
| | - Guosheng Wang
- The Pq Laboratory of Micro/Nano BiomeDx, Department of Biomedical Engineering, Binghamton University, State University of New York, Binghamton, New York
| | - Thomas Engleitner
- Center for Translational Cancer Research, Technische Universität München, Munich, Germany; Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany; Comprehensive Cancer Center Munich, Technical University of Munich, Munich, Germany
| | - Rupert Öllinger
- Center for Translational Cancer Research, Technische Universität München, Munich, Germany; Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany; German Cancer Consortium at the partner site Munich, Munich, Germany
| | - Roland Rad
- Center for Translational Cancer Research, Technische Universität München, Munich, Germany; Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany; German Cancer Consortium at the partner site Munich, Munich, Germany
| | - Maximilian Reichert
- Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | | | - Verena Weber
- Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Jingjing Li
- Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, China
| | - Shanshan Shen
- Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, China
| | - Xiaoping Zou
- Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, China
| | - Jörg Kleeff
- Department of Visceral, Vascular and Endocrine Surgery, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Andre Mihaljevic
- Department of Surgery, Ulm University Hospital, Ulm University, Ulm, Germany
| | | | - Hana Algül
- Comprehensive Cancer Center Munich, Technical University of Munich, Munich, Germany
| | - Helmut Friess
- Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Bo Kong
- Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, China; Department of Surgery, Ulm University Hospital, Ulm University, Ulm, Germany.
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49
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Park R, Choi WG, Lee MS, Cho YY, Lee JY, Kang HC, Sohn CH, Song IS, Lee HS. Pharmacokinetics of α-amanitin in mice using liquid chromatography-high resolution mass spectrometry and in vitro drug-drug interaction potentials. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART A 2021; 84:821-835. [PMID: 34187333 DOI: 10.1080/15287394.2021.1944942] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
The aim of this study was to determine pharmacokinetics of α-amanitin, a toxic bicyclic octapeptide isolated from the poisonous mushrooms, following intravenous (iv) or oral (po) administration in mice using a newly developed and validated liquid chromatography-high resolution mass spectrometry. The iv injected α-amanitin disappeared rapidly from the plasma with high a clearance rate (26.9-30.4 ml/min/kg) at 0.1, 0.2, or 0.4 mg/kg doses, which was consistent with a rapid and a major excretion of α-amanitin via the renal route (32.6%). After the po administration of α-amanitin at doses of 2, 5, or 10 mg/kg to mice, the absolute bioavailability of α-amanitin was 3.5-4.8%. Due to this low bioavailability, 72.5% of the po administered α-amanitin was recovered from the feces. When α-amanitin is administered po, the tissue to plasma area under the curve ratio was higher in stomach > large intestine > small intestine > lung ~ kidneys > liver but not detected in brain, heart, and spleen. The high distribution of α-amanitin to intestine, kidneys, and liver is in agreement with the previously reported major intoxicated organs following acute α-amanitin exposure. In addition, α-amanitin weakly or negligibly inhibited cytochrome P450 and 5'-diphospho-glucuronosyltransferase enzymes activity in human liver microsomes as well as major drug transport functions in mammalian cells overexpressing transporters. Data suggested remote drug interaction potential may be associated with α-amanitin exposure.
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Affiliation(s)
- Ria Park
- College of Pharmacy and BK21 Four-sponsored Advanced Program for SmartPharma Leaders, The Catholic University of Korea, Bucheon, Republic of Korea
| | - Won-Gu Choi
- College of Pharmacy and BK21 Four-sponsored Advanced Program for SmartPharma Leaders, The Catholic University of Korea, Bucheon, Republic of Korea
| | - Min Seo Lee
- College of Pharmacy and BK21 Four-sponsored Advanced Program for SmartPharma Leaders, The Catholic University of Korea, Bucheon, Republic of Korea
| | - Yong-Yeon Cho
- College of Pharmacy and BK21 Four-sponsored Advanced Program for SmartPharma Leaders, The Catholic University of Korea, Bucheon, Republic of Korea
| | - Joo Young Lee
- College of Pharmacy and BK21 Four-sponsored Advanced Program for SmartPharma Leaders, The Catholic University of Korea, Bucheon, Republic of Korea
| | - Han Chang Kang
- College of Pharmacy and BK21 Four-sponsored Advanced Program for SmartPharma Leaders, The Catholic University of Korea, Bucheon, Republic of Korea
| | - Chang Hwan Sohn
- Department of Emergency Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea
| | - Im-Sook Song
- Kyungpook National University, Daegu, Republic of Korea
| | - Hye Suk Lee
- College of Pharmacy and BK21 Four-sponsored Advanced Program for SmartPharma Leaders, The Catholic University of Korea, Bucheon, Republic of Korea
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50
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Yao G, Knittel CH, Kosol S, Wenz MT, Keller BG, Gruß H, Braun AC, Lutz C, Hechler T, Pahl A, Süssmuth RD. Iodine-Mediated Tryptathionine Formation Facilitates the Synthesis of Amanitins. J Am Chem Soc 2021; 143:14322-14331. [PMID: 34459587 DOI: 10.1021/jacs.1c06565] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Synthetic methods on the macrocyclization of peptides are of high interest since they facilitate the synthesis of various types of potentially bioactive compounds, e.g. addressing targets like protein-protein-interactions. Herein, we report on an efficient method to construct tryptathionine-cross-links in peptides between the amino acids Trp and Cys. This reaction not only is the basis for the total synthesis of the death cap toxin α-amanitin but also provides rapid access to various new amanitin analogues. This study for the first time presents a systematic compilation of structure-activity relations (SAR) of amatoxins with regard to RNA polymerase II inhibition and cytotoxicity with one amanitin derivative of superior RNAP II inhibition. The present approach paves the way for the synthesis of structurally diverse amatoxins as future payloads for antibody-toxin conjugates in cancer therapy.
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Affiliation(s)
- Guiyang Yao
- Institut für Chemie, Technische Universität Berlin, Strasse des 17. Juni 124, 10623 Berlin, Germany
| | - Caroline H Knittel
- Institut für Chemie, Technische Universität Berlin, Strasse des 17. Juni 124, 10623 Berlin, Germany
| | - Simone Kosol
- Institut für Chemie, Technische Universität Berlin, Strasse des 17. Juni 124, 10623 Berlin, Germany
| | - Marius T Wenz
- Department of Biology, Chemistry, Pharmacy, Freie Universität Berlin, Takustrasse 3, 14195 Berlin, Germany
| | - Bettina G Keller
- Department of Biology, Chemistry, Pharmacy, Freie Universität Berlin, Takustrasse 3, 14195 Berlin, Germany
| | - Hendrik Gruß
- Heidelberg Pharma Research GmbH, Gregor-Mendel-Straße 22, 68526 Ladenburg, Germany
| | - Alexandra C Braun
- Heidelberg Pharma Research GmbH, Gregor-Mendel-Straße 22, 68526 Ladenburg, Germany
| | - Christian Lutz
- Heidelberg Pharma Research GmbH, Gregor-Mendel-Straße 22, 68526 Ladenburg, Germany
| | - Torsten Hechler
- Heidelberg Pharma Research GmbH, Gregor-Mendel-Straße 22, 68526 Ladenburg, Germany
| | - Andreas Pahl
- Heidelberg Pharma Research GmbH, Gregor-Mendel-Straße 22, 68526 Ladenburg, Germany
| | - Roderich D Süssmuth
- Institut für Chemie, Technische Universität Berlin, Strasse des 17. Juni 124, 10623 Berlin, Germany
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