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Eddin LB, Meeran MFN, Subramanya SB, Jha NK, Ojha S. Therapeutic potential of agents targeting cannabinoid type 2 receptors in organ fibrosis. Pharmacol Res Perspect 2024; 12:e1219. [PMID: 39425446 PMCID: PMC11489134 DOI: 10.1002/prp2.1219] [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: 01/11/2024] [Revised: 04/08/2024] [Accepted: 04/24/2024] [Indexed: 10/21/2024] Open
Abstract
The endocannabinoid system has garnered attention as a potential therapeutic target in a range of pathological disorders. Cannabinoid receptors type 2 (CB2) are a class of G protein-coupled receptors responsible for transmitting intracellular signals triggered by both endogenous and exogenous cannabinoids, including those derived from plants (phytocannabinoids) or manufactured synthetically (synthetic cannabinoids). Recent recognition of the role of CB2 receptors in fibrosis has fueled interest in therapeutic targeting of CB2 receptors in fibrosis. Fibrosis is characterized by the alteration of the typical cellular composition within the tissue parenchyma, resulting from exposure to diverse etiological factors. The pivotal function of CB2 agonists has been widely recognized in the regulation of inflammation, fibrogenesis, and various other biological pathologies. The modulation of CB2 receptors, whether by enhancing their expression or activating their function, has the potential to provide benefits in numerous conditions, particularly by avoiding any associated adverse effects on the central nervous system. The sufficient activation of CB2 receptors resulted in the complete suppression of gene expression related to transforming growth factor β1 and its subsequent fibrogenic response. Multiple reports have also indicated the diverse functions that CB2 agonists possess in mitigating chronic inflammation and subsequent fibrosis development in various types of tissues. While currently in the preclinical stage, the advancement of CB2 compounds has garnered significant attention within the realm of drug discovery. This review presents a comprehensive synthesis of various independent experimental studies elucidating the pivotal role of identified natural and synthetic CB2 agonists in the pathophysiology of organ fibrosis, specifically in the cardiac, hepatic, and renal systems.
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Affiliation(s)
- Lujain Bader Eddin
- Department of Pharmacology and Therapeutics, College of Medicine and Health SciencesUnited Arab Emirates UniversityAl AinUAE
| | - M. F. Nagoor Meeran
- Department of Pharmacology and Therapeutics, College of Medicine and Health SciencesUnited Arab Emirates UniversityAl AinUAE
| | - Sandeep B. Subramanya
- Department of Physiology, College of Medicine and Health SciencesUnited Arab Emirates UniversityAl AinUAE
| | - Niraj Kumar Jha
- Centre for Global Health Research, Saveetha Medical CollegeSaveetha Institute of Medical and Technical Sciences, Saveetha UniversityChennaiIndia
- School of Bioengineering & BiosciencesLovely Professional UniversityPhagwaraIndia
- Department of Biotechnology, School of Applied & Life Sciences (SALS)Uttaranchal UniversityDehradunIndia
| | - Shreesh Ojha
- Department of Pharmacology and Therapeutics, College of Medicine and Health SciencesUnited Arab Emirates UniversityAl AinUAE
- Zayed Bin Sultan Center for Health SciencesUnited Arab Emirates UniversityAl AinUAE
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Yousof SM, Shehata SA, Ismail EA, Abd El-moneam SM, Mansour BS, Farag MA, Elshamy AI, El-Nasser G. El Gendy A, Serag A, Abd El-Fadeal NM, Abdel-Karim RI, Mostafa MM, El-Sheikh DH, Zayed MA. Acacia saligna extract alleviates quetiapine-induced sexual toxicity in male albino rats: Insights from UPLC-MS/MS metabolite profiling, structural and PI3K/NF-κB pathway assessments. Heliyon 2024; 10:e33993. [PMID: 39071580 PMCID: PMC11280294 DOI: 10.1016/j.heliyon.2024.e33993] [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: 03/02/2024] [Revised: 06/28/2024] [Accepted: 07/02/2024] [Indexed: 07/30/2024] Open
Abstract
Background Quetiapine (QET) abuse has increased due to its anxiolytic and hedonic effects, necessitating protective adjunct treatments. Acacia saligna (A. saligna) flowers, used in traditional medicine, have potential health benefits. Aim To investigate the protective role of A. saligna flower extract against QET-induced sexual toxicity, and to elucidate the possible underlying mechanisms through metabolomic and physiological studies. Methods A. saligna extract was subjected to metabolite profiling via High-Resolution Ultra-Performance Liquid Chromatography-Mass Spectrometry (UPLC-ESI-qTOF-MS). Forty-eight adult male albino rats were assigned into six groups for 30 days. The intracavernosal pressure (ICP), semen, biochemical, hormonal, histological, genetic and Western blot (WB) analyses were determined. Results A. saligna extract is rich in phenolic compounds, flavonoids, tannins, and unsaturated fatty acids. QET significantly decreased ICP and negatively affected semen parameters. A. saligna mitigated decreased sperm motility and ameliorated overexpressed proinflammatory genes in QET-55 group. A. saligna ameliorated the reduction of the antioxidant biomarkers, testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH), concurrent with downregulation of the nuclear factor kappa B (NF-κB) protein. A. saligna counteracted the disrupted testicular and prostatic structures revealed by histological examination. Conclusion The extract from A. saligna, which contains a high concentration of antioxidants and anti-inflammatory chemicals, effectively mitigates sexual toxicity caused by QET. This study provided the first known explanation of the hypothesized processes behind the protective properties of A. saligna through biological, biochemical, and histological parameters. The results emphasize the potential of A. saligna as a safeguarding agent against drug-induced sexual toxicity.
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Affiliation(s)
- Shimaa Mohammad Yousof
- Medical Physiology Department, Faculty of Medicine, King Abdulaziz University, Rabigh Branch, 21589, Saudi Arabia
- Medical Physiology Department, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt
- Neuroscience and Geroscience Unit, King Fahad Research Centre, King Abdulaziz University, KSA
| | - Shaimaa A. Shehata
- Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine- Suez Canal University, Ismailia, 41522, Egypt
| | - Ezzat A. Ismail
- Urology Department, Faculty of Medicine, Suez Canal University, Ismailia, 41522, Egypt
| | - Samar M. Abd El-moneam
- Human Anatomy and Embryology, Faculty of Medicine, Suez Canal University, Ismailia, 41522, Egypt
| | - Basma S.A. Mansour
- Human Anatomy and Embryology, Faculty of Medicine, Suez Canal University, Ismailia, 41522, Egypt
| | - Mohamed A. Farag
- Pharmacognosy Department, College of Pharmacy, Cairo University, Kasr el Aini, Giza 12613, Egypt
| | - Abdelsamed I. Elshamy
- Department of Natural Compounds Chemistry, National Research Center, Dokki, Giza 12622, Egypt
| | - Abd El-Nasser G. El Gendy
- Medicinal and Aromatic Plants Research Department, National Research Centre, 33 El Bohouth St., Dokki, Giza, 12622, Egypt
| | - Ahmed Serag
- Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Cairo, 11751, Egypt
| | - Noha M. Abd El-Fadeal
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Suez Canal University, Ismailia, 41522, Egypt
- Biochemistry Department, Ibn Sina National College for Medical Studies, Jeddah, 22421, Saudi Arabia
| | - Rehab Ibrahim Abdel-Karim
- Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine- Suez Canal University, Ismailia, 41522, Egypt
| | - Mostafa M. Mostafa
- Clinical Biochemistry Department, Faculty of Medicine, King Abdulaziz University, Rabigh Branch, 21589, Saudi Arabia
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Kasr Al Ainy, Cairo, 11562, Egypt
| | - Dina H. El-Sheikh
- Medical Physiology Department, Faculty of Medicine, Prince Sattam Bin Abdulaziz University, Al Kharj Branch, 16273, Saudi Arabia
- Medical Physiology Department, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt
- Pharmacognosy Department, College of Pharmacy, Cairo University, Kasr el Aini, Giza 12613, Egypt
| | - Mohamed A. Zayed
- Medical Physiology Department, Faculty of Medicine, King Abdulaziz University, Rabigh Branch, 21589, Saudi Arabia
- Medical Physiology Department, Faculty of Medicine, Menoufia University, Menoufia, 13829, Egypt
- Neuroscience and Geroscience Unit, King Fahad Research Centre, King Abdulaziz University, KSA
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3
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Bo Y, Zhao X, Li L. Cardiotoxic effects of common and emerging drugs: role of cannabinoid receptors. Clin Sci (Lond) 2024; 138:413-434. [PMID: 38505994 DOI: 10.1042/cs20231156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 02/23/2024] [Accepted: 03/12/2024] [Indexed: 03/21/2024]
Abstract
Drug-induced cardiotoxicity has become one of the most common and detrimental health concerns, which causes significant loss to public health and drug resources. Cannabinoid receptors (CBRs) have recently achieved great attention for their vital roles in the regulation of heart health and disease, with mounting evidence linking CBRs with the pathogenesis and progression of drug-induced cardiotoxicity. This review aims to summarize fundamental characteristics of two well-documented CBRs (CB1R and CB2R) from aspects of molecular structure, signaling and their functions in cardiovascular physiology and pathophysiology. Moreover, we describe the roles of CB1R and CB2R in the occurrence of cardiotoxicity induced by common drugs such as antipsychotics, anti-cancer drugs, marijuana, and some emerging synthetic cannabinoids. We highlight the 'yin-yang' relationship between CB1R and CB2R in drug-induced cardiotoxicity and propose future perspectives for CBR-based translational medicine toward cardiotoxicity curation and clinical monitoring.
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Affiliation(s)
- Yiming Bo
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Xin Zhao
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Liliang Li
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
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More SA, Deore RS, Pawar HD, Sharma C, Nakhate KT, Rathod SS, Ojha S, Goyal SN. CB2 Cannabinoid Receptor as a Potential Target in Myocardial Infarction: Exploration of Molecular Pathogenesis and Therapeutic Strategies. Int J Mol Sci 2024; 25:1683. [PMID: 38338960 PMCID: PMC10855244 DOI: 10.3390/ijms25031683] [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: 12/31/2023] [Revised: 01/22/2024] [Accepted: 01/25/2024] [Indexed: 02/12/2024] Open
Abstract
The lipid endocannabinoid system has recently emerged as a novel therapeutic target for several inflammatory and tissue-damaging diseases, including those affecting the cardiovascular system. The primary targets of cannabinoids are cannabinoid type 1 (CB1) and 2 (CB2) receptors. The CB2 receptor is expressed in the cardiomyocytes. While the pathological changes in the myocardium upregulate the CB2 receptor, genetic deletion of the receptor aggravates the changes. The CB2 receptor plays a crucial role in attenuating the advancement of myocardial infarction (MI)-associated pathological changes in the myocardium. Activation of CB2 receptors exerts cardioprotection in MI via numerous molecular pathways. For instance, delta-9-tetrahydrocannabinol attenuated the progression of MI via modulation of the CB2 receptor-dependent anti-inflammatory mechanisms, including suppression of pro-inflammatory cytokines like IL-6, TNF-α, and IL-1β. Through similar mechanisms, natural and synthetic CB2 receptor ligands repair myocardial tissue damage. This review aims to offer an in-depth discussion on the ameliorative potential of CB2 receptors in myocardial injuries induced by a variety of pathogenic mechanisms. Further, the modulation of autophagy, TGF-β/Smad3 signaling, MPTP opening, and ROS production are discussed. The molecular correlation of CB2 receptors with cardiac injury markers, such as troponin I, LDH1, and CK-MB, is explored. Special attention has been paid to novel insights into the potential therapeutic implications of CB2 receptor activation in MI.
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Affiliation(s)
- Sagar A. More
- Department of Pharmacology, Shri Vile Parle Kelavani Mandal’s Institute of Pharmacy, Dhule 424001, Maharashtra, India; (S.A.M.); (R.S.D.); (H.D.P.); (K.T.N.); (S.S.R.)
| | - Rucha S. Deore
- Department of Pharmacology, Shri Vile Parle Kelavani Mandal’s Institute of Pharmacy, Dhule 424001, Maharashtra, India; (S.A.M.); (R.S.D.); (H.D.P.); (K.T.N.); (S.S.R.)
| | - Harshal D. Pawar
- Department of Pharmacology, Shri Vile Parle Kelavani Mandal’s Institute of Pharmacy, Dhule 424001, Maharashtra, India; (S.A.M.); (R.S.D.); (H.D.P.); (K.T.N.); (S.S.R.)
| | - Charu Sharma
- Department of Internal Medicine, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates;
| | - Kartik T. Nakhate
- Department of Pharmacology, Shri Vile Parle Kelavani Mandal’s Institute of Pharmacy, Dhule 424001, Maharashtra, India; (S.A.M.); (R.S.D.); (H.D.P.); (K.T.N.); (S.S.R.)
| | - Sumit S. Rathod
- Department of Pharmacology, Shri Vile Parle Kelavani Mandal’s Institute of Pharmacy, Dhule 424001, Maharashtra, India; (S.A.M.); (R.S.D.); (H.D.P.); (K.T.N.); (S.S.R.)
| | - Shreesh Ojha
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Sameer N. Goyal
- Department of Pharmacology, Shri Vile Parle Kelavani Mandal’s Institute of Pharmacy, Dhule 424001, Maharashtra, India; (S.A.M.); (R.S.D.); (H.D.P.); (K.T.N.); (S.S.R.)
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Ren Z, Liu Y, Cai A, Yu Y, Wang X, Lan L, Guo X, Yan H, Gao X, Li H, Tian Y, Ji H, Chen H, Ding F, Ma W, Wang N, Cai B, Yang B. Cannabidiol represses miR-143 to promote cardiomyocyte proliferation and heart regeneration after myocardial infarction. Eur J Pharmacol 2024; 963:176245. [PMID: 38052413 DOI: 10.1016/j.ejphar.2023.176245] [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: 08/09/2023] [Revised: 11/29/2023] [Accepted: 11/29/2023] [Indexed: 12/07/2023]
Abstract
Mammalian heart is capable to regenerate almost completely early after birth through endogenous cardiomyocyte proliferation. However, this regenerative capacity diminishes gradually with growth and is nearly lost in adulthood. Cannabidiol (CBD) is a major component of cannabis and has various biological activities to regulate oxidative stress, fibrosis, inflammation, and cell death. The present study was conducted to investigate the pharmacological effects of CBD on heart regeneration in post-MI mice. MI models in adult mice were constructed via coronary artery ligation, which were administrated with or without CBD. Our results demonstrate that systemic administration (10 mg/kg) of CBD markedly increased cardiac regenerative ability, reduced infarct size, and restored cardiac function in MI mice. Consistently, in vitro study also showed that CBD was able to promote the proliferation of neonatal cardiomyocytes. Mechanistically, the expression of miR-143-3p related to cardiomyocyte proliferation was significantly down-regulated in CBD-treated cardiomyocytes, while the overexpression of miR-143-3p inhibited cardiomyocyte mitosis and eliminated CBD-induced cardiomyocyte proliferation. Moreover, CBD enhanced the expression of Yap and Ctnnd1, which were demonstrated as the target genes of miR-143-3p. Silencing of Yap and Ctnnd1 hindered the proliferative effects of CBD. We further revealed that inhibition of the cannabinoid receptor 2 impeded the regulatory effect of CBD on miR-143-3p and its downstream target Yap/Ctnnd1, which ultimately eliminated the pro-proliferative effect of CBD on neonatal and adult cardiomyocytes. Taken together, CBD promotes cardiomyocyte proliferation and heart regeneration after MI via miR-143-3p/Yap/Ctnnd1 signaling pathway, which provides a new strategy for cardiac repair in adult myocardium.
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Affiliation(s)
- Zhongyu Ren
- Department of Pharmacy, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, China; Department of Pharmacology (National Key Laboratory of Frigid Zone Cardiovascular Diseases, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Yining Liu
- Department of Pharmacy, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Ao Cai
- Department of Pharmacy, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, China; Department of Pharmacology (National Key Laboratory of Frigid Zone Cardiovascular Diseases, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Yang Yu
- Department of Pharmacy, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Xiuxiu Wang
- Department of Pharmacy, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Lan Lan
- Department of Pharmacology (National Key Laboratory of Frigid Zone Cardiovascular Diseases, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Xiaofei Guo
- Department of Pharmacology (National Key Laboratory of Frigid Zone Cardiovascular Diseases, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Hong Yan
- Department of Pharmacy, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, China; Department of Pharmacology (National Key Laboratory of Frigid Zone Cardiovascular Diseases, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Xinlu Gao
- Department of Pharmacy, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, China; Department of Pharmacology (National Key Laboratory of Frigid Zone Cardiovascular Diseases, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Hanjing Li
- Department of Pharmacy, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, China; Department of Pharmacology (National Key Laboratory of Frigid Zone Cardiovascular Diseases, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Yanan Tian
- Department of Pharmacy, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, China; Department of Pharmacology (National Key Laboratory of Frigid Zone Cardiovascular Diseases, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Haoyu Ji
- Department of Pharmacy, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Hongyang Chen
- Department of Pharmacy, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, China; Department of Pharmacology (National Key Laboratory of Frigid Zone Cardiovascular Diseases, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Fengzhi Ding
- Department of Physiology, Wannan Medical College, Wuhu, 241000, China
| | - Wenya Ma
- Department of Pharmacy, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Ning Wang
- Department of Pharmacy, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, China; Department of Pharmacology (National Key Laboratory of Frigid Zone Cardiovascular Diseases, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China.
| | - Benzhi Cai
- Department of Pharmacy, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, China; Department of Pharmacology (National Key Laboratory of Frigid Zone Cardiovascular Diseases, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China; NHC Key Laboratory of Cell Transplantation, The First Affiliated Hospital Harbin Medical University, Harbin, 150001, China.
| | - Baofeng Yang
- Department of Pharmacology (National Key Laboratory of Frigid Zone Cardiovascular Diseases, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China.
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De Simone G, Mazza B, Vellucci L, Barone A, Ciccarelli M, de Bartolomeis A. Schizophrenia Synaptic Pathology and Antipsychotic Treatment in the Framework of Oxidative and Mitochondrial Dysfunction: Translational Highlights for the Clinics and Treatment. Antioxidants (Basel) 2023; 12:antiox12040975. [PMID: 37107350 PMCID: PMC10135787 DOI: 10.3390/antiox12040975] [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: 03/10/2023] [Revised: 04/05/2023] [Accepted: 04/13/2023] [Indexed: 04/29/2023] Open
Abstract
Schizophrenia is a worldwide mental illness characterized by alterations at dopaminergic and glutamatergic synapses resulting in global dysconnectivity within and between brain networks. Impairments in inflammatory processes, mitochondrial functions, energy expenditure, and oxidative stress have been extensively associated with schizophrenia pathophysiology. Antipsychotics, the mainstay of schizophrenia pharmacological treatment and all sharing the common feature of dopamine D2 receptor occupancy, may affect antioxidant pathways as well as mitochondrial protein levels and gene expression. Here, we systematically reviewed the available evidence on antioxidants' mechanisms in antipsychotic action and the impact of first- and second-generation compounds on mitochondrial functions and oxidative stress. We further focused on clinical trials addressing the efficacy and tolerability of antioxidants as an augmentation strategy of antipsychotic treatment. EMBASE, Scopus, and Medline/PubMed databases were interrogated. The selection process was conducted in respect of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. Several mitochondrial proteins involved in cell viability, energy metabolism, and regulation of oxidative systems were reported to be significantly modified by antipsychotic treatment with differences between first- and second-generation drugs. Finally, antioxidants may affect cognitive and psychotic symptoms in patients with schizophrenia, and although the evidence is only preliminary, the results indicate that further studies are warranted.
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Affiliation(s)
- Giuseppe De Simone
- Section of Psychiatry, Laboratory of Translational and Molecular Psychiatry and Unit of Treatment-Resistant Psychosis, Department of Neuroscience, Reproductive Sciences, and Dentistry, University Medical School of Naples "Federico II", Via Pansini 5, 80131 Naples, Italy
| | - Benedetta Mazza
- Section of Psychiatry, Laboratory of Translational and Molecular Psychiatry and Unit of Treatment-Resistant Psychosis, Department of Neuroscience, Reproductive Sciences, and Dentistry, University Medical School of Naples "Federico II", Via Pansini 5, 80131 Naples, Italy
| | - Licia Vellucci
- Section of Psychiatry, Laboratory of Translational and Molecular Psychiatry and Unit of Treatment-Resistant Psychosis, Department of Neuroscience, Reproductive Sciences, and Dentistry, University Medical School of Naples "Federico II", Via Pansini 5, 80131 Naples, Italy
| | - Annarita Barone
- Section of Psychiatry, Laboratory of Translational and Molecular Psychiatry and Unit of Treatment-Resistant Psychosis, Department of Neuroscience, Reproductive Sciences, and Dentistry, University Medical School of Naples "Federico II", Via Pansini 5, 80131 Naples, Italy
| | - Mariateresa Ciccarelli
- Section of Psychiatry, Laboratory of Translational and Molecular Psychiatry and Unit of Treatment-Resistant Psychosis, Department of Neuroscience, Reproductive Sciences, and Dentistry, University Medical School of Naples "Federico II", Via Pansini 5, 80131 Naples, Italy
| | - Andrea de Bartolomeis
- Section of Psychiatry, Laboratory of Translational and Molecular Psychiatry and Unit of Treatment-Resistant Psychosis, Department of Neuroscience, Reproductive Sciences, and Dentistry, University Medical School of Naples "Federico II", Via Pansini 5, 80131 Naples, Italy
- UNESCO Chair on Health Education and Sustainable Development, University of Naples "Federico II", 80131 Naples, Italy
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Gao P, Cao M, Jiang X, Wang X, Zhang G, Tang X, Yang C, Komuro I, Ge J, Li L, Zou Y. Cannabinoid Receptor 2-Centric Molecular Feedback Loop Drives Necroptosis in Diabetic Heart Injuries. Circulation 2023; 147:158-174. [PMID: 36448459 DOI: 10.1161/circulationaha.122.059304] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 10/03/2022] [Indexed: 12/02/2022]
Abstract
BACKGROUND Diabetic heart dysfunction is a common complication of diabetes. Cell death is a core event that leads to diabetic heart dysfunction. However, the time sequence of cell death pathways and the precise time to intervene of particular cell death type remain largely unknown in the diabetic heart. This study aims to identify the particular cell death type that is responsible for diabetic heart dysfunction and to propose a promising therapeutic strategy by intervening in the cell death pathway. METHODS Type 2 diabetes models were established using db/db leptin receptor-deficient mice and high-fat diet/streptozotocin-induced mice. The type 1 diabetes model was established in streptozotocin-induced mice. Apoptosis and programmed cell necrosis (necroptosis) were detected in diabetic mouse hearts at different ages. G protein-coupled receptor-targeted drug library was searched to identify potential receptors regulating the key cell death pathway. Pharmacological and genetic approaches that modulate the expression of targets were used. Stable cell lines and a homemade phosphorylation antibody were prepared to conduct mechanistic studies. RESULTS Necroptosis was activated after apoptosis at later stages of diabetes and was functionally responsible for cardiac dysfunction. Cannabinoid receptor 2 (CB2R) was a key regulator of necroptosis. Mechanically, during normal glucose levels, CB2R inhibited S6 kinase-mediated phosphorylation of BACH2 at serine 520, thereby leading to BACH2 translocation to the nucleus, where BACH2 transcriptionally repressed the necroptosis genes Rip1, Rip3, and Mlkl. Under hyperglycemic conditions, high glucose induced CB2R internalization in a β-arrestin 2-dependent manner; thereafter, MLKL (mixed lineage kinase domain-like), but not receptor-interacting protein kinase 1 or 3, phosphorylated CB2R at serine 352 and promoted CB2R degradation by ubiquitin modification. Cardiac re-expression of CB2R rescued diabetes-induced cardiomyocyte necroptosis and heart dysfunction, whereas cardiac knockout of Bach2 diminished CB2R-mediated beneficial effects. In human diabetic hearts, both CB2R and BACH2 were negatively associated with diabetes-induced myocardial injuries. CONCLUSIONS CB2R transcriptionally repressed necroptosis through interaction with BACH2; in turn, MLKL formed a negative feedback to phosphorylate CB2R. Our study provides the integrative view of a novel molecular mechanism loop for regulation of necroptosis centered by CB2R, which represents a promising alternative strategy for controlling diabetic heart dysfunction.
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Affiliation(s)
- Pan Gao
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, China (P.G., M.C., X.J., X.W., G.Z., C.Y., J.G., Y.Z.)
| | - Mengying Cao
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, China (P.G., M.C., X.J., X.W., G.Z., C.Y., J.G., Y.Z.)
| | - Xueli Jiang
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, China (P.G., M.C., X.J., X.W., G.Z., C.Y., J.G., Y.Z.)
| | - Xiaolin Wang
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, China (P.G., M.C., X.J., X.W., G.Z., C.Y., J.G., Y.Z.)
| | - Guoping Zhang
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, China (P.G., M.C., X.J., X.W., G.Z., C.Y., J.G., Y.Z.)
| | - Xinru Tang
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China (X.T., L.L.)
| | - Chunjie Yang
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, China (P.G., M.C., X.J., X.W., G.Z., C.Y., J.G., Y.Z.)
| | - Issei Komuro
- Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Japan (I.K.)
| | - Junbo Ge
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, China (P.G., M.C., X.J., X.W., G.Z., C.Y., J.G., Y.Z.)
| | - Liliang Li
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China (X.T., L.L.)
| | - Yunzeng Zou
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, China (P.G., M.C., X.J., X.W., G.Z., C.Y., J.G., Y.Z.)
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8
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Wang S, He M, Andersen J, Lin Y, Zhang M, Liu Z, Li L. Sudden unexplained death in schizophrenia patients: An autopsy-based comparative study from China. Asian J Psychiatr 2023; 79:103314. [PMID: 36399950 DOI: 10.1016/j.ajp.2022.103314] [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: 07/04/2022] [Revised: 09/06/2022] [Accepted: 09/13/2022] [Indexed: 11/06/2022]
Abstract
Explainable sudden deaths in schizophrenia patients due to both cardiac (SCD) and non-cardiac causes (SNCD) have been extensively documented. However, sudden unexplained death (SUD) in this cohort remains to be elucidated. This study retrospectively analyzed 18 SUD cases that underwent systematic autopsy at our institutes during the period 2010-2022. The etiological, demographic, and autopsy features of the SUD cases were then compared with 37 year-matched sudden explainable deaths (23 SCD cases and 14 SNCD cases). Our results showed that the average age of the SUD was 39.0 ( ± 8.4) years, with the disease duration of 11.8 ( ± 8.1) years and a male/female ratio of 11:7. Most cases occurred during daytime (72.2%) and outside of hospital (77.8%). A large proportion of the SUD cases (77.8%) had persistent psychiatric episodes before death. Clozapine was found to be the most commonly used antipsychotic (33.3%), followed by Olanzapine (27.8%), Risperidone (27.8%) and Chlorpromazine (27.8%) in the SUD cases. When compared among groups, the SUD cases showed significantly younger ages (p = 0.035), lower heart weight (p = 0.004) and lower proportion of Clozapine use (p = 0.045). The presence of persistent psychiatric episodes was significantly higher in the SUD group than in any explainable deaths (p = 0.018) and was an independent risk factor for SUD (OR = 4.205, p = 0.040). This is the first autopsy-based study of SUD cases from China. We conclude that a stable mental state maintained by antipsychotics (i.e., Clozapine) is vital to schizophrenia patients.
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Affiliation(s)
- Shouyu Wang
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
| | - Meng He
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
| | - John Andersen
- Department of Gynecologic Pathology, Johns Hopkins Hospital, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
| | - Yezhe Lin
- Department of Psychiatry and Behavioral Science, Virginia Tech Carilion School of Medicine, Roanoke, VA 24016, USA; Clinical Research Center for Mental Disorders, Chinese-German Institute of Mental Health, Shanghai Pudong New Area Mental Health Center, School of Medicine, Tongji University, Shanghai 200124, China.
| | - Molin Zhang
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
| | - Zheng Liu
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
| | - Liliang Li
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
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9
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Xu D, Xu C, Xue X, Xu Y, Zhao J, Huang T, Wang Z, Zhao Q, Zhou Z, Huang Y, Yu L, Wang H. Activation of cannabinoid receptor 2 attenuates Angiotensin II-induced atrial fibrillation via a potential NOX/CaMKII mechanism. Front Cardiovasc Med 2022; 9:968014. [PMID: 36312282 PMCID: PMC9616165 DOI: 10.3389/fcvm.2022.968014] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 09/29/2022] [Indexed: 11/13/2022] Open
Abstract
Background Atrial fibrillation (AF) is the most frequent arrythmia managed in clinical practice. Several mechanisms have been proposed to contribute to the occurrence and persistence of AF, in which oxidative stress plays a non-negligible role. The endocannabinoid system (ECS) is involved in a variety physiological and pathological processes. Cannabinoid receptor 1 (CB1R) and cannabinoid receptor 2 (CB2R) are expressed in the heart, and studies have shown that activating CB2R has a protective effect on the myocardium. However, the role of CB2R in AF is unknown. Materials and methods Angiotensin II (Ang II)-infused mice were treated with the CB2R agonist AM1241 intraperitoneally for 21 days. Atrial structural remodeling, AF inducibility, electrical transmission, oxidative stress and fibrosis were measured in mice. Results The susceptibility to AF and the level of oxidative stress were increased significantly in Ang II-infused mice. In addition, nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2), NOX4, and oxidized Ca2+/calmodulin-dependent protein kinase II (ox-CaMKII) were highly expressed. More importantly, treatment with AM1241 activated CB2R, resulting in a protective effect. Conclusion The present study demonstrates that pharmacological activation of CB2R exerts a protective effect against AF via a potential NOX/CaMKII mechanism. CB2R is a potential therapeutic target for AF.
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Affiliation(s)
- Dengyue Xu
- Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, Shenyang, Liaoning, China,Postgraduate College, China Medical University, Shenyang, Liaoning, China
| | - Chennian Xu
- Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, Shenyang, Liaoning, China
| | - Xiaodong Xue
- Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, Shenyang, Liaoning, China
| | - Yinli Xu
- Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, Shenyang, Liaoning, China
| | - Jikai Zhao
- Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, Shenyang, Liaoning, China
| | - Tao Huang
- Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, Shenyang, Liaoning, China
| | - Zhishang Wang
- Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, Shenyang, Liaoning, China
| | - Qiusheng Zhao
- Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, Shenyang, Liaoning, China
| | - Zijun Zhou
- Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, Shenyang, Liaoning, China
| | - Yuting Huang
- Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, Shenyang, Liaoning, China
| | - Liming Yu
- Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, Shenyang, Liaoning, China,Liming Yu,
| | - Huishan Wang
- Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, Shenyang, Liaoning, China,*Correspondence: Huishan Wang,
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10
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Liu Z, Zhang ML, Tang XR, Li XQ, Wang J, Li LL. Cardiotoxicity of current antipsychotics: Newer antipsychotics or adjunct therapy? World J Psychiatry 2022; 12:1108-1111. [PMID: 36158311 PMCID: PMC9476838 DOI: 10.5498/wjp.v12.i8.1108] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 04/19/2022] [Accepted: 07/06/2022] [Indexed: 02/05/2023] Open
Abstract
Use of newer antipsychotics for substitution of current antipsychotics might be one way awaiting to be clinically verified to address antipsychotic cardiotoxic effects. Alternatively, the combination of existing antipsychotics with cardioprotective agents is also beneficial for patients with mental disorders for avoiding cardiotoxicity to the maximum.
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Affiliation(s)
- Zheng Liu
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Mo-Lin Zhang
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Xin-Ru Tang
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Xiao-Qing Li
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Jing Wang
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Li-Liang Li
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
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11
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Li L, Gao P, Tang X, Liu Z, Cao M, Luo R, Li X, Wang J, Lin X, Peng C, Li Z, Zhang J, Zhang X, Cao Z, Zou Y, Jin L. CB1R-stabilized NLRP3 inflammasome drives antipsychotics cardiotoxicity. Signal Transduct Target Ther 2022; 7:190. [PMID: 35739093 PMCID: PMC9225989 DOI: 10.1038/s41392-022-01018-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 04/25/2022] [Accepted: 05/06/2022] [Indexed: 12/21/2022] Open
Abstract
Long-term use of antipsychotics is a common cause of myocardial injury and even sudden cardiac deaths that often lead to drug withdrawn or discontinuation. Mechanisms underlying antipsychotics cardiotoxicity remain largely unknown. Herein we performed RNA sequencing and found that NLRP3 inflammasome-mediated pyroptosis contributed predominantly to multiple antipsychotics cardiotoxicity. Pyroptosis-based small-molecule compound screen identified cannabinoid receptor 1 (CB1R) as an upstream regulator of the NLRP3 inflammasome. Mechanistically, antipsychotics competitively bond to the CB1R and led to CB1R translocation to the cytoplasm, where CB1R directly interacted with NLRP3 inflammasome via amino acid residues 177-209, rendering stabilization of the inflammasome. Knockout of Cb1r significantly alleviated antipsychotic-induced cardiomyocyte pyroptosis and cardiotoxicity. Multi-organ-based investigation revealed no additional toxicity of newer CB1R antagonists. In authentic human cases, the expression of CB1R and NLRP3 inflammasome positively correlated with antipsychotics-induced cardiotoxicity. These results suggest that CB1R is a potent regulator of the NLRP3 inflammsome-mediated pyroptosis and small-molecule inhibitors targeting the CB1R/NLRP3 signaling represent attractive approaches to rescue cardiac side effects of antipsychotics.
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Affiliation(s)
- Liliang Li
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences & Human Phenome Institute, Fudan University, Shanghai, 200438, China.
| | - Pan Gao
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Xinru Tang
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Zheng Liu
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Mengying Cao
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Ruoyu Luo
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences & Human Phenome Institute, Fudan University, Shanghai, 200438, China
| | - Xiaoqing Li
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Jing Wang
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Xinyi Lin
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Chao Peng
- National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Science, Shanghai, 201210, China
| | - Zhihong Li
- National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Science, Shanghai, 201210, China
| | - Jianhua Zhang
- Academy of Forensic Science, Ministry of Justice, and Shanghai Key Laboratory of Forensic Medicine, Shanghai, 200063, China
| | - Xian Zhang
- Department of Cardiology, Kunshan Hospital of Integrated Traditional Chinese and Western Medicine, Kunshan, Jiangsu, 215301, China
| | - Zhonglian Cao
- School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Yunzeng Zou
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
| | - Li Jin
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences & Human Phenome Institute, Fudan University, Shanghai, 200438, China.
- Shanghai Medical College, Fudan University, Shanghai, 200032, China.
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12
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Li XQ, Tang XR, Li LL. Antipsychotics cardiotoxicity: What's known and what's next. World J Psychiatry 2021; 11:736-753. [PMID: 34733639 PMCID: PMC8546771 DOI: 10.5498/wjp.v11.i10.736] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 07/08/2021] [Accepted: 09/02/2021] [Indexed: 02/06/2023] Open
Abstract
Chronic use of antipsychotic medications entails a dilemma between the benefit of alleviating psychotic symptoms and the risk of troubling, sometimes life-shortening adverse effects. Antipsychotic-induced cardiotoxicity is one of the most life-threatening adverse effects that raises widespread concerns. These cardiotoxic effects range from arrhythmia to heart failure in the clinic, with myocarditis/cardiomyopathy, ischemic injuries, and unexplained cardiac lesions as the pathological bases. Multiple mechanisms have been proposed to underlie antipsychotic cardiotoxicity. This review aims to summarize the clinical signs and pathological changes of antipsychotic cardiotoxicity and introduce recent progress in understanding the underlying mechanisms at both the subcellular organelle level and the molecular level. We also provide an up-to-date perspective on future clinical monitoring and therapeutic strategies for antipsychotic cardiotoxicity. We propose that third-generation antipsychotics or drug adjuvant therapy, such as cannabinoid receptor modulators that confer dual benefits - i.e., alleviating cardiotoxicity and improving metabolic disorders - deserve further clinical evaluation and marketing.
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Affiliation(s)
- Xiao-Qing Li
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Xin-Ru Tang
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Li-Liang Li
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
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13
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Cannabinoid Type-2 Receptor Agonist, JWH133 May Be a Possible Candidate for Targeting Infection, Inflammation, and Immunity in COVID-19. IMMUNO 2021. [DOI: 10.3390/immuno1030020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
The COVID-19 pandemic, caused by SARS-CoV-2, is a deadly disease affecting millions due to the non-availability of drugs and vaccines. The majority of COVID-19 drugs have been repurposed based on antiviral, immunomodulatory, and antibiotic potential. The pathogenesis and advanced complications with infection involve the immune-inflammatory cascade. Therefore, a therapeutic strategy could reduce infectivity, inflammation, and immune modulation. In recent years, modulating the endocannabinoid system, particularly activation of the cannabinoid type 2 (CB2) receptor is a promising therapeutic target for modulation of immune-inflammatory responses. JWH133, a selective, full functional agonist of the CB2 receptor, has been extensively studied for its potent anti-inflammatory, antiviral, and immunomodulatory properties. JWH133 modulates numerous signaling pathways and inhibits inflammatory mediators, including cytokines, chemokines, adhesion molecules, prostanoids, and eicosanoids. In this study, we propose that JWH133 could be a promising candidate for targeting infection, immunity, and inflammation in COVID-19, due to its pharmacological and molecular mechanisms in numerous preclinical efficacy and safety studies, along with its immunomodulatory, anti-inflammatory, organoprotective, and antiviral properties. Thus, JWH133 should be investigated in preclinical and clinical studies for its potential as an agent or adjuvant with other agents for its effect on viremia, infectivity, immune modulation, resolution of inflammation, reduction in severity, and progression of complications in COVID-19. JWH133 is devoid of psychotropic effects due to CB2 receptor selectivity, has negligible toxicity, good bioavailability and druggable properties, including pharmacokinetic and physicochemical effects. We believe that JWH133 could be a promising drug and may inspire further studies for an evidence-based approach against COVID-19.
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14
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D’Errico S, Russa RL, Maiese A, Santurro A, Scopetti M, Romano S, Zanon M, Frati P, Fineschi V. Atypical antipsychotics and oxidative cardiotoxicity: review of literature and future perspectives to prevent sudden cardiac death. J Geriatr Cardiol 2021; 18:663-685. [PMID: 34527032 PMCID: PMC8390928 DOI: 10.11909/j.issn.1671-5411.2021.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Oxidative stress is considered the principal mediator of myocardial injury under pathological conditions. It is well known that reactive oxygen (ROS) or nitrogen species (RNS) are involved in myocardial injury and repair at the same time and that cellular damage is generally due to an unbalance between generation and elimination of the free radicals due to an inadequate mechanism of antioxidant defense or to an increase in ROS and RNS. Major adverse cardiovascular events are often associated with drugs with associated findings such as fibrosis or inflammation of the myocardium. Despite efforts in the preclinical phase of the development of drugs, cardiotoxicity still remains a great concern. Cardiac toxicity due to second-generation antipsychotics (clozapine, olanzapine, quetiapine) has been observed in preclinical studies and described in patients affected with mental disorders. A role of oxidative stress has been hypothesized but more evidence is needed to confirm a causal relationship. A better knowledge of cardiotoxicity mechanisms should address in the future to establish the right dose and length of treatment without impacting the physical health of the patients.
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Affiliation(s)
- Stefano D’Errico
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Raffaele La Russa
- Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy
- IRCSS Neuromed Mediterranean Neurological Institute, Pozzilli, Italy
| | - Aniello Maiese
- IRCSS Neuromed Mediterranean Neurological Institute, Pozzilli, Italy
- Department of Surgical Pathology, Medical, Molecular and Critical Area, University of Pisa, Pisa, Italy
| | - Alessandro Santurro
- Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Matteo Scopetti
- Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Silvia Romano
- Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Martina Zanon
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Paola Frati
- IRCSS Neuromed Mediterranean Neurological Institute, Pozzilli, Italy
- Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Vittorio Fineschi
- IRCSS Neuromed Mediterranean Neurological Institute, Pozzilli, Italy
- Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Rome, Italy
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15
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Wang J, Li X, Liu Z, Lin X, Zhong F, Li S, Tang X, Zhang Y, Li L. Second-generation antipsychotics induce cardiotoxicity by disrupting spliceosome signaling: Implications from proteomic and transcriptomic analyses. Pharmacol Res 2021; 170:105714. [PMID: 34098070 DOI: 10.1016/j.phrs.2021.105714] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 05/18/2021] [Accepted: 06/02/2021] [Indexed: 02/07/2023]
Abstract
Second-generation antipsychotics (SGAs) are first-line drugs that are prescribed for mental disorders in clinic. Severe cardiotoxicity has been widely reported and thus limits their clinical application. This study aimed to identify the common mechanism underlying SGAs-induced cardiotoxicity using dual-omics analyses. Balb/C mice were intraperitoneally injected with two representative SGAs, olanzapine (2.5 mg/kg) and clozapine (25 mg/kg), at clinically comparable doses for 0, 7, 14 and 21 days. Our results showed that both SGAs induced cardiomyocyte degeneration, inflammation infiltration, and cardiac fibrosis, all of which worsened with time. Proteomic analysis revelaed that 22 differentially expressed (DE) proteins overlapped in olanzapine and clozapine-treated hearts. These proteins were significantly enriched in muscle contraction, amino acid metabolism and spliceosomal assembly by GO term analysis and spliceosome signaling was among the top enriched pathways by KEGG analysis. Among the 22 DE proteins, three spliceosome signal proteins were validated in a dynamic detection, and their expression significantly correlated with the extent of SGAs-induced cardiac fibrosis. Following the spliceosome signaling dysregulation, RNA sequencing revealed that alternative splicing events in the mouse hearts were markedly enhanced by SGAs treatments, and the production of vast transcript variants resulted in dysregulation of multiple pathways that are critical for cardiomyocytes adaptation and cardiac remodeling. Pladienolide B, a specific inhibitor of mRNA splicing, successfully corrected SGAs-induced alternative splicing and significantly attenuated the secretion of pro-inflammatory factors and cell deaths induced by SGAs exposure. Our study concluded that the spliceosome signaling was a common pathway driving SGAs cardiotoxicity. Pharmacological inhibition of the spliceosome signaling represents a novel therapeutic strategy against SGAs cardiotoxicity.
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Affiliation(s)
- Jing Wang
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
| | - Xiaoqing Li
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
| | - Zheng Liu
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
| | - Xinyi Lin
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
| | - Fan Zhong
- Department of Systems Biology for Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
| | - Shuhao Li
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
| | - Xinru Tang
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
| | - Yang Zhang
- Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
| | - Liliang Li
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
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16
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Hashiesh HM, Sharma C, Goyal SN, Jha NK, Ojha S. Pharmacological Properties, Therapeutic Potential and Molecular Mechanisms of JWH133, a CB2 Receptor-Selective Agonist. Front Pharmacol 2021; 12:702675. [PMID: 34393784 PMCID: PMC8363263 DOI: 10.3389/fphar.2021.702675] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 07/02/2021] [Indexed: 12/15/2022] Open
Abstract
The endocannabinoid system has attracted attention as a pharmacological target for several pathological conditions. Cannabinoid (CB2)-selective agonists have been the focus of pharmacological studies because modulation of the CB2 receptor (CB2R) can be useful in the treatment of pain, inflammation, arthritis, addiction, and cancer among other possible therapeutic applications while circumventing CNS-related adverse effects. Increasing number of evidences from different independent preclinical studies have suggested new perspectives on the involvement of CB2R signaling in inflammation, infection and immunity, thus play important role in cancer, cardiovascular, renal, hepatic and metabolic diseases. JWH133 is a synthetic agonist with high CB2R selectivity and showed to exert CB2R mediated antioxidant, anti-inflammatory, anticancer, cardioprotective, hepatoprotective, gastroprotective, nephroprotective, and immunomodulatory activities. Cumulative evidences suggest that JWH133 protects against hepatic injury, renal injury, cardiotoxicity, fibrosis, rheumatoid arthritis, and cancer as well as against oxidative damage and inflammation, inhibits fibrosis and apoptosis, and acts as an immunosuppressant. This review provides a comprehensive overview of the polypharmacological properties and therapeutic potential of JWH133. This review also presents molecular mechanism and signaling pathways of JWH133 under various pathological conditions except neurological diseases. Based on the available data, this review proposes the possibilities of developing JWH133 as a promising therapeutic agent; however, further safety and toxicity studies in preclinical studies and clinical trials in humans are warranted.
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Affiliation(s)
- Hebaallah Mamdouh Hashiesh
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Charu Sharma
- Department of Internal Medicine, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Sameer N Goyal
- Shri Vile Parle Kelavani Mandal's Institute of Pharmacy, Dhule, India
| | - Niraj Kumar Jha
- Department of Biotechnology, School of Engineering and Technology (SET), Sharda University, Greater Noida, India
| | - Shreesh Ojha
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.,Zayed Bin Sultan Center for Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
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17
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Tang X, Liu Z, Li X, Wang J, Li L. Cannabinoid Receptors in Myocardial Injury: A Brother Born to Rival. Int J Mol Sci 2021; 22:6886. [PMID: 34206926 PMCID: PMC8268439 DOI: 10.3390/ijms22136886] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 06/22/2021] [Accepted: 06/24/2021] [Indexed: 12/12/2022] Open
Abstract
Cannabinoid receptors typically include type 1 (CB1) and type 2 (CB2), and they have attracted extensive attention in the central nervous system (CNS) and immune system. Due to more in-depth studies in recent years, it has been found that the typical CB1 and CB2 receptors confer functional importance far beyond the CNS and immune system. In particular, many works have reported the critical involvement of the CB1 and CB2 receptors in myocardial injuries. Both pharmacological and genetic approaches have been used for studying CB1 and CB2 functions in these studies, revealing that the brother receptors have many basic differences and sometimes antagonistic functions in a variety of myocardial injuries, despite some sequence or location identity they share. Herein, we introduce the general differences of CB1 and CB2 cannabinoid receptors, and summarize the functional rivalries between the two brother receptors in the setting of myocardial injuries. We point out the importance of individual receptor-based modulation, instead of dual receptor modulators, when treating myocardial injuries.
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Affiliation(s)
| | | | | | | | - Liliang Li
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; (X.T.); (Z.L.); (X.L.); (J.W.)
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18
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Ye L, Li S, Liu X, Zhang D, Li L, Jiang Y. CB1R Promotes Chronic Alcohol-Induced Neuronal Necroptosis in Mice Prefrontal Cortex. Alcohol Alcohol 2021; 56:230-239. [PMID: 33382401 DOI: 10.1093/alcalc/agaa135] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 11/10/2020] [Accepted: 11/18/2020] [Indexed: 12/30/2022] Open
Abstract
AIMS Alcohol abuse induces multiple neuropathology and causes global burden to human health. Prefrontal cortex (PFC) is one of the most susceptible regions to alcohol-induced neuropathology. However, precise mechanisms underlying these effects on PFC remain to be elucidated. Herein, we investigated whether RIP1/RIP3/MLKL-mediated necroptosis was involved in the alcohol-induced PFC injury, and explored the effect that cannabinoid receptors (CBRs) exerted on the neurotoxicity of alcohol. METHODS In this study, dynamic development of neuronal necroptosis in the PFC region was monitored after 95% (v/v) alcohol vapor administration for 15 and 30 days, respectively. Selective CBRs agonists or inverse agonists were pretreated according to the experimental design. All the PFC tissues were isolated and further examined by biochemical and histopathological analyses. RESULTS It was found that chronic alcohol exposure increased the protein level of MLKL and also the phosphorylated levels of RIP1, RIP3 and MLKL in a time-dependent manner, all of which indicated the activation of necroptosis signaling. Particularly, compared to astrocytes, neurons from the PFC showed more prototypical necrotic morphology in response to alcohol insults. In parallel, an increased protein level of CB1R was also found after 15 and 30 days alcohol exposure. Administration of specific inverse agonists of CB1R (AM251 and AM281), but not its agonists or CB2R modulators, significantly alleviated the RIP1/RIP3/MLKL-mediated neuronal necroptosis. CONCLUSION We reported the involvement of RIP1/RIP3/MLKL-mediated necroptosis in alcohol-induced PFC neurotoxicity, and identified CB1R as a critical regulator of neuronal necroptosis that enhanced our understanding of alcohol-induced neuropathology in the PFC.
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Affiliation(s)
- Lin Ye
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, 131 Dongan Road, Xuhui District, Shanghai 200032, China
| | - Shuhao Li
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, 131 Dongan Road, Xuhui District, Shanghai 200032, China
| | - Xiaochen Liu
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, 131 Dongan Road, Xuhui District, Shanghai 200032, China
| | - Dingang Zhang
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, 131 Dongan Road, Xuhui District, Shanghai 200032, China
| | - Liliang Li
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, 131 Dongan Road, Xuhui District, Shanghai 200032, China
| | - Yan Jiang
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, 131 Dongan Road, Xuhui District, Shanghai 200032, China
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Liu X, Zhang D, Dong X, Zhu R, Ye Y, Li L, Jiang Y. Pharmacological activation of CB2 receptor protects against ethanol-induced myocardial injury related to RIP1/RIP3/MLKL-mediated necroptosis. Mol Cell Biochem 2020; 474:1-14. [PMID: 32681290 DOI: 10.1007/s11010-020-03828-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 07/07/2020] [Indexed: 12/16/2022]
Abstract
Chronic ethanol abuse can lead to harmful consequences for the heart, resulting in systolic dysfunction, variability in the heart rate, arrhythmia, and cardiac remodelling. However, the precise molecular mechanism responsible for ethanol-induced cardiomyopathy is poorly understood. In this regard, the present study aimed to describe the RIP1/RIP3/MLKL-mediated necroptotic cell death that may be involved in ethanol-induced cardiomyopathy and characterize CBR-mediated effects on the signalling pathway and myocardial injury. We performed an ethanol vapour administration experiment to analyse the effects of ethanol on cardiac structure and function in male C57BL/6J mice. Ethanol induced a significant decline in the cardiac structure and function, as evidenced by a decline in ejection fraction and fractional shortening, and an increase in serum Creatine Kinase levels, myocardial collagen content, and inflammatory reaction. Furthermore, ethanol also upregulated the expression levels of necroptosis-related markers such as p-RIP1, p-RIP3, and p-MLKL in the myocardium. Nec-1 treatment exerted significant cardioprotective effects by salvaging the heart tissue, improving the cardiac function, and mitigating inflammation and necroptosis. In addition, ethanol abuse caused an imbalance in the endocannabinoid system and regulated two cannabinoid receptors (CB1R and CB2R) in the myocardium. Treatment with selective CB2R agonists, JWH-133 or AM1241, markedly improved the cardiac dysfunction and reduced the ethanol-induced necroptosis in the myocardium. Altogether, our data provide evidence that ethanol abuse-induced cardiotoxicity can possibly be attributed to the RIP1/RIP3/MLKL-mediated necroptosis. Moreover, pharmacological activation of CB2R may represent a new cardioprotective strategy against ethanol-induced cardiotoxicity.
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Affiliation(s)
- Xiaochen Liu
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, 131 Dongan Road, Xuhui District, Shanghai, 200032, China
| | - Dingang Zhang
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, 131 Dongan Road, Xuhui District, Shanghai, 200032, China
| | - Xiaoru Dong
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, 131 Dongan Road, Xuhui District, Shanghai, 200032, China
| | - Rongzhe Zhu
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, 131 Dongan Road, Xuhui District, Shanghai, 200032, China
| | - Yonghong Ye
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, 131 Dongan Road, Xuhui District, Shanghai, 200032, China
| | - Liliang Li
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, 131 Dongan Road, Xuhui District, Shanghai, 200032, China
| | - Yan Jiang
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, 131 Dongan Road, Xuhui District, Shanghai, 200032, China.
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Turra BO, Barbisan F, Azzolin VF, Teixeira CF, Flores T, Braun LE, de Oliveira Nerys DA, Rissi VB, de Oliveira Alves A, Assmann CE, da Cruz Jung IE, Marques LPS, da Cruz IBM. Unmetabolized quetiapine exerts an in vitro effect on innate immune cells by modulating inflammatory response and neutrophil extracellular trap formation. Biomed Pharmacother 2020; 131:110497. [PMID: 33152899 DOI: 10.1016/j.biopha.2020.110497] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 06/30/2020] [Accepted: 07/02/2020] [Indexed: 12/31/2022] Open
Abstract
Quetiapine is an antipsychotic drug that is used to treat psychiatric and neurological disorders. Despite its efficiency and low-toxicity, quetiapine administration has been associated with undesirable side effects such as the development of low-grade inflammatory disorders and neutropenia states. As the liver rapidly metabolizes quetiapine to metabolites, the non-metabolized part of this molecule might play a role in immune alterations. In an in vitro study, this hypothesis was tested by exposing activated and inactivated RAW-264.7 macrophages and human neutrophils to unmetabolized quetiapine (u-QUE). Based on our findings, u-QUE was not cytotoxic to these cells. u-QUE differentially modulates macrophages according to their activation states. In inactivated macrophages, u-QUE induced a proinflammatory state as observed by an increase in cellular proliferation; increased levels of oxidative molecules (nitric oxide and superoxide), protein levels, and gene overexpression of proinflammatory cytokines (IL-1β, IL-6, and TNF-α); and decreased levels of IL-10, an anti-inflammatory cytokine. Conversely, on phytohemagglutinin (PHA)-activated macrophages, u-QUE exerted an anti-inflammatory effect. u-QUE induced neutrophil extracellular trap (NET) formation and increased the sensitivity of the neutrophils previously activated by exposure to dead yeast cells for NET formation. These results confirm the effect of quetiapine on macrophage and neutrophil function, which may be associated with the side effects of this psychopharmaceutical agent.
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Affiliation(s)
- Bárbara Osmarin Turra
- Graduate Program of Pharmacology, Universidade Federal Santa Maria, Santa Maria, RS, Brazil
| | - Fernanda Barbisan
- Graduate Program in Gerontology, Universidade Federal Santa Maria, Santa Maria, RS, Brazil
| | | | | | - Thamara Flores
- Graduate Program of Pharmacology, Universidade Federal Santa Maria, Santa Maria, RS, Brazil
| | | | | | - Vitor Braga Rissi
- Biotechnology and Animal Reproduction Laboratory, Universidade Federal Santa Maria, Santa Maria, RS, Brazil
| | | | - Charles Elias Assmann
- Graduate Program of Biological Sciences, Universidade Federal Santa Maria, Santa Maria, RS, Brazil
| | | | | | - Ivana Beatrice Mânica da Cruz
- Graduate Program of Pharmacology, Universidade Federal Santa Maria, Santa Maria, RS, Brazil; Graduate Program in Gerontology, Universidade Federal Santa Maria, Santa Maria, RS, Brazil.
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Audebrand A, Désaubry L, Nebigil CG. Targeting GPCRs Against Cardiotoxicity Induced by Anticancer Treatments. Front Cardiovasc Med 2020; 6:194. [PMID: 32039239 PMCID: PMC6993588 DOI: 10.3389/fcvm.2019.00194] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Accepted: 12/23/2019] [Indexed: 01/01/2023] Open
Abstract
Novel anticancer medicines, including targeted therapies and immune checkpoint inhibitors, have greatly improved the management of cancers. However, both conventional and new anticancer treatments induce cardiac adverse effects, which remain a critical issue in clinic. Cardiotoxicity induced by anti-cancer treatments compromise vasospastic and thromboembolic ischemia, dysrhythmia, hypertension, myocarditis, and cardiac dysfunction that can result in heart failure. Importantly, none of the strategies to prevent cardiotoxicity from anticancer therapies is completely safe and satisfactory. Certain clinically used cardioprotective drugs can even contribute to cancer induction. Since G protein coupled receptors (GPCRs) are target of forty percent of clinically used drugs, here we discuss the newly identified cardioprotective agents that bind GPCRs of adrenalin, adenosine, melatonin, ghrelin, galanin, apelin, prokineticin and cannabidiol. We hope to provoke further drug development studies considering these GPCRs as potential targets to be translated to treatment of human heart failure induced by anticancer drugs.
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Affiliation(s)
| | | | - Canan G. Nebigil
- Laboratory of CardioOncology and Therapeutic Innovation, CNRS, Illkirch, France
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