|
1
|
Engeli BE, Lachenmeier DW, Diel P, Guth S, Villar Fernandez MA, Roth A, Lampen A, Cartus AT, Wätjen W, Hengstler JG, Mally A. Cannabidiol in Foods and Food Supplements: Evaluation of Health Risks and Health Claims. Nutrients 2025; 17:489. [PMID: 39940347 PMCID: PMC11820564 DOI: 10.3390/nu17030489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 01/20/2025] [Accepted: 01/22/2025] [Indexed: 02/16/2025] Open
Abstract
BACKGROUND Cannabidiol (CBD) is a cannabinoid present in the hemp plant (Cannabis sativa L.). Non-medicinal CBD oils with typically 5-40% CBD are advertised for various alleged positive health effects. While such foodstuffs containing cannabinoids are covered by the Novel Food Regulation in the European Union (EU), none of these products have yet been authorized. Nevertheless, they continue to be available on the European market. METHODS The Permanent Senate Commission on Food Safety (SKLM) of the German Research Foundation (DFG) reviewed the currently available data on adverse and potential beneficial effects of CBD in the dose range relevant for foods. RESULTS Increased liver enzyme activities were observed in healthy volunteers following administration of 4.3 mg CBD/kg bw/day and higher for 3-4 weeks. As lower doses were not tested, a no observed adverse effect level (NOAEL) could not be derived, and the dose of 4.3 mg/kg bw/day was identified as the lowest observed adverse effect level (LOAEL). Based on the CBD content and dose recommendations of CBD products on the market, the SKLM considered several exposure scenarios and concluded that the LOAEL for liver toxicity may be easily reached, e.g., via consumption of 30 drops of an oil containing 20% CBD, or even exceeded. A critical evaluation of the available data on potential beneficial health effects of CBD in the dose range at or below the LOAEL of 4.3 mg/kg bw/day revealed no scientific evidence that would substantiate health claims, e.g., in relation to physical performance, the cardiovascular, immune, and nervous system, anxiety, relaxation, stress, sleep, pain, or menstrual health. CONCLUSIONS The SKLM concluded that consumption of CBD-containing foods/food supplements may not provide substantiated health benefits and may even pose a health risk to consumers.
Collapse
Affiliation(s)
- Barbara E. Engeli
- Federal Food Safety and Veterinary Office (FSVO), Division Knowledge Foundation, Section Risk Assessment, Schwarzenburgstr 155, 3003 Bern, Switzerland;
| | - Dirk W. Lachenmeier
- Chemisches und Veterinäruntersuchungsamt (CVUA) Karlsruhe, Weißenburger Str. 3, 76187 Karlsruhe, Germany;
| | - Patrick Diel
- Department of Molecular and Cellular Sports Medicine, Institute of Cardiovascular Research and Sports Medicine, German Sport University Cologne, Am Sportpark Müngersdorf 6, 50933 Cologne, Germany;
| | - Sabine Guth
- Leibniz Research Centre for Working Environment and Human Factors (IfADo), Ardeystr. 67, 44139 Dortmund, Germany; (S.G.); (M.A.V.F.); (A.R.); (J.G.H.)
| | - Maria A. Villar Fernandez
- Leibniz Research Centre for Working Environment and Human Factors (IfADo), Ardeystr. 67, 44139 Dortmund, Germany; (S.G.); (M.A.V.F.); (A.R.); (J.G.H.)
| | - Angelika Roth
- Leibniz Research Centre for Working Environment and Human Factors (IfADo), Ardeystr. 67, 44139 Dortmund, Germany; (S.G.); (M.A.V.F.); (A.R.); (J.G.H.)
| | - Alfonso Lampen
- Risk Assessment Strategies, Bundesinstitut für Risikobewertung (BfR), Max-Dohrn-Str. 8–10, 10589 Berlin, Germany;
| | | | - Wim Wätjen
- Institut für Agrar-und Ernährungswissenschaften, Martin-Luther-Universität Halle-Wittenberg, Weinbergweg 22, 06120 Halle (Saale), Germany;
| | - Jan G. Hengstler
- Leibniz Research Centre for Working Environment and Human Factors (IfADo), Ardeystr. 67, 44139 Dortmund, Germany; (S.G.); (M.A.V.F.); (A.R.); (J.G.H.)
| | - Angela Mally
- Department of Toxicology, University of Würzburg, Versbacher Str. 9, 97078 Würzburg, Germany
| |
Collapse
|
|
2
|
Bauer L, Alkotub B, Ballmann M, Hasanzadeh Kafshgari M, Rammes G, Multhoff G. Cannabidiol (CBD) Protects Lung Endothelial Cells from Irradiation-Induced Oxidative Stress and Inflammation In Vitro and In Vivo. Cancers (Basel) 2024; 16:3589. [PMID: 39518030 PMCID: PMC11544820 DOI: 10.3390/cancers16213589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 10/14/2024] [Accepted: 10/21/2024] [Indexed: 11/16/2024] Open
Abstract
Objective: Radiotherapy, which is commonly used for the local control of thoracic cancers, also induces chronic inflammatory responses in the microvasculature of surrounding normal tissues such as the lung and heart that contribute to fatal radiation-induced lung diseases (RILDs) such as pneumonitis and fibrosis. In this study, we investigated the potential of cannabidiol (CBD) to attenuate the irradiation damage to the vasculature. Methods: We investigated the ability of CBD to protect a murine endothelial cell (EC) line (H5V) and primary lung ECs isolated from C57BL/6 mice from irradiation-induced damage in vitro and lung ECs (luECs) in vivo, by measuring the induction of oxidative stress, DNA damage, apoptosis (in vitro), and induction of inflammatory and pro-angiogenic markers (in vivo). Results: We demonstrated that a non-lethal dose of CBD reduces the irradiation-induced oxidative stress and early apoptosis of lung ECs by upregulating the expression of the cytoprotective mediator heme-oxygenase-1 (HO-1). The radiation-induced increased expression of inflammatory (ICAM-2, MCAM) and pro-angiogenic (VE-cadherin, Endoglin) markers was significantly reduced by a continuous daily treatment of C57BL/6 mice with CBD (i.p. 20 mg/kg body weight), 2 weeks before and 2 weeks after a partial irradiation of the lung (less than 20% of the lung volume) with 16 Gy. Conclusions: CBD has the potential to improve the clinical outcome of radiotherapy by reducing toxic side effects on the microvasculature of the lung.
Collapse
Affiliation(s)
- Lisa Bauer
- Department of Radiation Oncology, TUM School of Medicine and Health, University Hospital of the Technical University of Munich (TUM), 81675 Munich, Germany;
- Radiation Immuno-Oncology Group, Central Institute for Translational Cancer Research (TranslaTUM), TUM School of Medicine and Health, University Hospital of the Technical University of Munich (TUM), 81675 Munich, Germany;
| | - Bayan Alkotub
- Institute of Biological and Medical Imaging (IBMI), Helmholtz Zentrum München (HMGU), 85764 Neuherberg, Germany;
- Chair of Biological Imaging at the Central Institute for Translational Cancer Research (TranslaTUM), School of Medicine and Health, University Hospital of the Technical University of Munich (TUM), 81675 Munich, Germany
| | - Markus Ballmann
- Department of Anesthesiology and Intensive Care Medicine, TUM School of Medicine and Health, University Hospital of the Technical University of Munich (TUM), 81675 Munich, Germany; (M.B.); (G.R.)
| | - Morteza Hasanzadeh Kafshgari
- Radiation Immuno-Oncology Group, Central Institute for Translational Cancer Research (TranslaTUM), TUM School of Medicine and Health, University Hospital of the Technical University of Munich (TUM), 81675 Munich, Germany;
| | - Gerhard Rammes
- Department of Anesthesiology and Intensive Care Medicine, TUM School of Medicine and Health, University Hospital of the Technical University of Munich (TUM), 81675 Munich, Germany; (M.B.); (G.R.)
| | - Gabriele Multhoff
- Department of Radiation Oncology, TUM School of Medicine and Health, University Hospital of the Technical University of Munich (TUM), 81675 Munich, Germany;
- Radiation Immuno-Oncology Group, Central Institute for Translational Cancer Research (TranslaTUM), TUM School of Medicine and Health, University Hospital of the Technical University of Munich (TUM), 81675 Munich, Germany;
| |
Collapse
|
|
3
|
Pagano S, Valenti C, Negri P, Billi M, Di Michele A, Bruscoli S, Febo M, Coniglio M, Marinucci L. Acute and chronic cannabidiol treatment: In vitro toxicological aspects on human oral cells. Food Chem Toxicol 2024; 185:114513. [PMID: 38342230 DOI: 10.1016/j.fct.2024.114513] [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: 11/06/2023] [Revised: 02/06/2024] [Accepted: 02/08/2024] [Indexed: 02/13/2024]
Abstract
Cannabidiol is gaining increasing interest for its potential anti-inflammatory, immunomodulatory, and antineoplastic effects. The purpose of this study is to investigate the biological effects of acute and chronic CBD administration on gingival fibroblasts and oral keratinocytes. Viability, morphology, migration, apoptosis and cell cycle, and expression of related genes (p53, BCL2, p21, and BAX) and of endocannabinoid system receptors (CB1, CB2 and GPR55) with real-time PCR and DNA damage with phospho-γ-H2AX immunofluorescence detection were analyzed. Concentrations between 100 μM and 0.001 μM were used: 50 μM (toxic dose), 25 μM (viability promoter), and 1 μM (nontoxic), were selected for subsequent chronic analysis. Acute treatment reveals significant effects than chronic, in particular in fibroblasts: concentrations ≥50 μM are highly cytotoxic, with increased apoptosis and reduced migration. Cell death correlates with increased p53 and BAX, followed by arrest in G0/G1 phase, with elevated p21 levels, suggesting a time- and dose-dependent damage. An increase in H2AX phosphorylation was observed with 25 μM and 50 μM, while 1 μM was biocompatible. Keratinocytes showed less cytotoxic effect than fibroblasts. Induced cell damage was dose- and time-related, with less damage after chronic treatment. Further investigations are needed with longer time frames to evaluate CBD dose- and time-dependent effects to identify an effective therapeutic dose.
Collapse
Affiliation(s)
- Stefano Pagano
- Department of Medicine and Surgery, Faculty of Dentistry, University of Perugia, S. Andrea delle Fratte, 06156, Perugia, Italy.
| | - Chiara Valenti
- Department of Medicine and Surgery, Faculty of Dentistry, University of Perugia, S. Andrea delle Fratte, 06156, Perugia, Italy; CISAS "Giuseppe Colombo", University of Padua, Via Venezia, 15, 35131, Padua, Italy.
| | - Paolo Negri
- Department of Medicine and Surgery, Faculty of Dentistry, University of Perugia, S. Andrea delle Fratte, 06156, Perugia, Italy.
| | - Monia Billi
- Department of Medicine and Surgery, Section of General Pathology, University of Perugia, S. Andrea delle Fratte, 06156, Perugia, Italy.
| | - Alessandro Di Michele
- Department of Physics and Geology, University of Perugia, Via Pascoli, 06123, Perugia, Italy.
| | - Stefano Bruscoli
- Department of Medicine and Surgery, Section of Pharmacology, University of Perugia, S. Andrea delle Fratte, 06156, Perugia, Italy.
| | - Marta Febo
- Department of Medicine and Surgery, Section of Pharmacology, University of Perugia, S. Andrea delle Fratte, 06156, Perugia, Italy.
| | - Maddalena Coniglio
- Department of Medicine and Surgery, Faculty of Dentistry, University of Perugia, S. Andrea delle Fratte, 06156, Perugia, Italy.
| | - Lorella Marinucci
- Department of Medicine and Surgery, Section of Biosciences and Medical Embryology, University of Perugia, S. Andrea delle Fratte, 06156, Perugia, Italy.
| |
Collapse
|
|
4
|
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.
Collapse
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.
| |
Collapse
|
|
5
|
Hassan FU, Liu C, Mehboob M, Bilal RM, Arain MA, Siddique F, Chen F, Li Y, Zhang J, Shi P, Lv B, Lin Q. Potential of dietary hemp and cannabinoids to modulate immune response to enhance health and performance in animals: opportunities and challenges. Front Immunol 2023; 14:1285052. [PMID: 38111585 PMCID: PMC10726122 DOI: 10.3389/fimmu.2023.1285052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 11/17/2023] [Indexed: 12/20/2023] Open
Abstract
Cannabinoids are a group of bioactive compounds abundantly present in Cannabis sativa plant. The active components of cannabis with therapeutic potential are known as cannabinoids. Cannabinoids are divided into three groups: plant-derived cannabinoids (phytocannabinoids), endogenous cannabinoids (endocannabinoids), and synthetic cannabinoids. These compounds play a crucial role in the regulation various physiological processes including the immune modulation by interacting with the endocannabinoid system (A complex cell-signaling system). Cannabinoid receptor type 1 (CB1) stimulates the binding of orexigenic peptides and inhibits the attachment of anorexigenic proteins to hypothalamic neurons in mammals, increasing food intake. Digestibility is unaffected by the presence of any cannabinoids in hemp stubble. Endogenous cannabinoids are also important for the peripheral control of lipid processing in adipose tissue, in addition to their role in the hypothalamus regulation of food intake. Regardless of the kind of synaptic connection or the length of the transmission, endocannabinoids play a crucial role in inhibiting synaptic transmission through a number of mechanisms. Cannabidiol (CBD) mainly influences redox equilibrium through intrinsic mechanisms. Useful effects of cannabinoids in animals have been mentioned e.g., for disorders of the cardiovascular system, pain treatment, disorders of the respiratory system or metabolic disorders. Dietary supplementation of cannabinoids has shown positive effects on health, growth and production performance of small and large animals. Animal fed diet supplemented with hemp seeds (180 g/day) or hemp seed cake (143 g/kg DM) had achieved batter performance without any detrimental effects. But the higher level of hemp or cannabinoid supplementation suppress immune functions and reduce productive performance. With an emphasis on the poultry and ruminants, this review aims to highlight the properties of cannabinoids and their derivatives as well as their significance as a potential feed additive in their diets to improve the immune status and health performance of animals.
Collapse
Affiliation(s)
- Faiz-ul Hassan
- Institute of Bast Fiber Crops, Chinese Academy of Agricultural Sciences, Changsha, China
- Faculty of Animal Production and Technology, Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan
| | - Chunjie Liu
- Institute of Bast Fiber Crops, Chinese Academy of Agricultural Sciences, Changsha, China
| | - Maryam Mehboob
- Department of Zoology, Wildlife and Fisheries, University of Agriculture, Faisalabad, Pakistan
| | - Rana Muhammad Bilal
- Faculty of Animal Production and Technology, Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan
| | - Muhammad Asif Arain
- Faculty of Veterinary and Animal Sciences, Lasbela University of Agriculture, Water and Marine Sciences, Uthal, Balochistan, Pakistan
| | - Faisal Siddique
- Faculty of Animal Production and Technology, Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan
| | - Fengming Chen
- Hunan Provincial Key Laboratory of the TCM Agricultural Biogenomics, Changsha Medical University, Changsha, China
| | - Yuying Li
- Institute of Bast Fiber Crops, Chinese Academy of Agricultural Sciences, Changsha, China
| | - Jingmeng Zhang
- Institute of Bast Fiber Crops, Chinese Academy of Agricultural Sciences, Changsha, China
| | - Pengjun Shi
- Institute of Bast Fiber Crops, Chinese Academy of Agricultural Sciences, Changsha, China
| | - Biguang Lv
- Institute of Bast Fiber Crops, Chinese Academy of Agricultural Sciences, Changsha, China
| | - Qian Lin
- Institute of Bast Fiber Crops, Chinese Academy of Agricultural Sciences, Changsha, China
| |
Collapse
|
|
6
|
Montreekachon P, Chaichana N, Makeudom A, Kerdvongbundit V, Krisanaprakornkit W, Krisanaprakornkit S. Proliferative effect of cannabidiol in human gingival fibroblasts via the mitogen-activated extracellular signal-regulated kinase (MEK) 1/2. J Periodontal Res 2023; 58:1223-1234. [PMID: 37641169 DOI: 10.1111/jre.13178] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 08/12/2023] [Accepted: 08/17/2023] [Indexed: 08/31/2023]
Abstract
BACKGROUND AND OBJECTIVES Cannabidiol exerts its anti-inflammatory and anti-oxidant activities in various human cells. However, its proliferative effect has not been extrapolated to human gingival fibroblasts (HGFs). This study aimed to determine the proliferative and promigratory effects of cannabidiol in HGFs and to elucidate the signaling mechanism(s). MATERIALS AND METHODS HGFs, characterized by their CD73, CD90, and CD105 expressions by flow cytometry, were treated with cannabidiol at 0.01-30 μM. The cytotoxicity was determined by the MTT assay, while the proliferative effect was examined by the BrdU assay, immunoblot and immunofluorescence for cyclin D1 and Ki-67 expressions, respectively, and cell cycle analysis. The promigratory effect of cannabidiol was investigated by a wound healing assay. Phosphorylation of the p38 MAPK, JNK, and ERK upon treatment with cannabidiol was explored, and their involvement in cell proliferation and cyclin D1 and Ki-67 expressions was studied using pharmacological inhibitors. RESULTS No toxicity was found in HGFs treated with any doses of cannabidiol up to 30 μM. The mean percentage of cell proliferation was significantly enhanced by treatment with cannabidiol at 3 or 10 μM (p < .001), consistent with upregulated expressions of cyclin D1 and Ki-67 and increased percentages of HGFs in the S and G2/M phases. Moreover, treatment with cannabidiol significantly induced cell migration (p < .05). The p38 MAPK and ERK1/2 were significantly activated by cannabidiol (p < .05), but only pretreatment with UO126, a MEK1/2 inhibitor, significantly inhibited cell proliferation and cyclin D1 and Ki-67 expressions (p < .05). CONCLUSION Treatment with cannabidiol at non-toxic doses promotes HGFs' proliferation and migration.
Collapse
Affiliation(s)
- Pattanin Montreekachon
- Department of Restorative Dentistry and Periodontology, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand
| | - Nopphanai Chaichana
- Department of Restorative Dentistry and Periodontology, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand
| | - Anupong Makeudom
- School of Dentistry, Mae Fah Luang University, Chiang Rai, Thailand
| | | | | | - Suttichai Krisanaprakornkit
- Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand
- Center of Excellence in Oral and Maxillofacial Biology, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand
| |
Collapse
|
|
7
|
Wendt F, Wittig F, Rupprecht A, Ramer R, Langer P, Emmert S, Frank M, Hinz B. A Thia-Analogous Indirubin N-Glycoside Disrupts Mitochondrial Function and Causes the Death of Human Melanoma and Cutaneous Squamous Cell Carcinoma Cells. Cells 2023; 12:2409. [PMID: 37830623 PMCID: PMC10572502 DOI: 10.3390/cells12192409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 09/08/2023] [Accepted: 09/20/2023] [Indexed: 10/14/2023] Open
Abstract
Skin cancer is the most common malignant disease worldwide and, therefore, also poses a challenge from a pharmacotherapeutic perspective. Derivatives of indirubin are an interesting option in this context. In the present study, the effects of 3-[3'-oxo-benzo[b]thiophen-2'-(Z)-ylidene]-1-(β-d-glucopyranosyl)-oxindole (KD87), a thia-analogous indirubin N-glycoside, on the viability and mitochondrial properties of melanoma (A375) and squamous cell carcinoma cells (A431) of the skin were investigated. In both cell lines, KD87 caused decreased viability, the activation of caspases-3 and -7, and the inhibition of colony formation. At the mitochondrial level, a concentration-dependent decrease in both the basal and ATP-linked oxygen consumption rate and in the reserve capacity of oxidative respiration were registered in the presence of KD87. These changes were accompanied by morphological alterations in the mitochondria, a release of mitochondrial cytochrome c into the cytosol and significant reductions in succinate dehydrogenase complex subunit B (SDHB, subunit of complex II) in A375 and A431 cells and NADH:ubiquinone oxidoreductase subunit B8 (NDUFB8, subunit of complex I) in A375 cells. The effect of KD87 was accompanied by a significant upregulation of the enzyme heme oxygenase-1, whose inhibition led to a partial but significant reduction in the metabolic-activity-reducing effect of KD87. In summary, our data show a mitochondria-targeting effect of KD87 as part of the cytotoxic effect of this compound on skin cancer cells, which should be considered in future studies with this class of compounds.
Collapse
Affiliation(s)
- Franziska Wendt
- Institute of Pharmacology and Toxicology, Rostock University Medical Centre, 18057 Rostock, Germany; (F.W.); (F.W.); (A.R.); (R.R.)
| | - Felix Wittig
- Institute of Pharmacology and Toxicology, Rostock University Medical Centre, 18057 Rostock, Germany; (F.W.); (F.W.); (A.R.); (R.R.)
| | - Anne Rupprecht
- Institute of Pharmacology and Toxicology, Rostock University Medical Centre, 18057 Rostock, Germany; (F.W.); (F.W.); (A.R.); (R.R.)
| | - Robert Ramer
- Institute of Pharmacology and Toxicology, Rostock University Medical Centre, 18057 Rostock, Germany; (F.W.); (F.W.); (A.R.); (R.R.)
| | - Peter Langer
- Institute of Organic Chemistry, University of Rostock, 18059 Rostock, Germany;
| | - Steffen Emmert
- Clinic and Policlinic for Dermatology, Rostock University Medical Centre, 18057 Rostock, Germany;
| | - Marcus Frank
- Electron Microscopy Centre, Rostock University Medical Centre, 18057 Rostock, Germany;
- Department Life, Light and Matter, University of Rostock, 18059 Rostock, Germany
| | - Burkhard Hinz
- Institute of Pharmacology and Toxicology, Rostock University Medical Centre, 18057 Rostock, Germany; (F.W.); (F.W.); (A.R.); (R.R.)
| |
Collapse
|
|
8
|
Teichmann E, Blessing E, Hinz B. Non-Psychoactive Phytocannabinoids Inhibit Inflammation-Related Changes of Human Coronary Artery Smooth Muscle and Endothelial Cells. Cells 2023; 12:2389. [PMID: 37830604 PMCID: PMC10571842 DOI: 10.3390/cells12192389] [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: 08/18/2023] [Revised: 09/08/2023] [Accepted: 09/12/2023] [Indexed: 10/14/2023] Open
Abstract
Atherosclerosis is associated with vascular smooth muscle cell proliferation, chronic vascular inflammation, and leukocyte adhesion. In view of the cardioprotective effects of cannabinoids described in recent years, the present study investigated the impact of the non-psychoactive phytocannabinoids cannabidiol (CBD) and tetrahydrocannabivarin (THCV) on proliferation and migration of human coronary artery smooth muscle cells (HCASMC) and on inflammatory markers in human coronary artery endothelial cells (HCAEC). In HCASMC, CBD and THCV at nontoxic concentrations exhibited inhibitory effects on platelet-derived growth factor-triggered proliferation (CBD) and migration (CBD, THCV). When interleukin (IL)-1β- and lipopolysaccharide (LPS)-stimulated HCAEC were examined, both cannabinoids showed a concentration-dependent decrease in the expression of vascular cell adhesion molecule-1 (VCAM-1), which was mediated independently of classical cannabinoid receptors and was not accompanied by a comparable inhibition of intercellular adhesion molecule-1. Further inhibitor experiments demonstrated that reactive oxygen species, p38 mitogen-activated protein kinase activation, histone deacetylase, and nuclear factor κB (NF-κB) underlie IL-1β- and LPS-induced expression of VCAM-1. In this context, CBD and THCV were shown to inhibit phosphorylation of NF-κB regulators in LPS- but not IL-1β-stimulated HCAEC. Stimulation of HCAEC with IL-1β and LPS was associated with increased adhesion of monocytes, which, however, could not be significantly abolished by CBD and THCV. In summary, the results highlight the potential of the non-psychoactive cannabinoids CBD and THCV to regulate inflammation-related changes in HCASMC and HCAEC. Considering their effect on both cell types studied, further preclinical studies could address the use of CBD and THCV in drug-eluting stents for coronary interventions.
Collapse
Affiliation(s)
| | | | - Burkhard Hinz
- Institute of Pharmacology and Toxicology, Rostock University Medical Center, Schillingallee 70, 18057 Rostock, Germany; (E.T.); (E.B.)
| |
Collapse
|
|
9
|
Kuret T, Kreft ME, Romih R, Veranič P. Cannabidiol as a Promising Therapeutic Option in IC/BPS: In Vitro Evaluation of Its Protective Effects against Inflammation and Oxidative Stress. Int J Mol Sci 2023; 24:ijms24055055. [PMID: 36902479 PMCID: PMC10003465 DOI: 10.3390/ijms24055055] [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: 01/24/2023] [Revised: 02/25/2023] [Accepted: 03/03/2023] [Indexed: 03/09/2023] Open
Abstract
Several animal studies have described the potential effect of cannabidiol (CBD) in alleviating the symptoms of interstitial cystitis/bladder pain syndrome (IC/BPS), a chronic inflammatory disease of the urinary bladder. However, the effects of CBD, its mechanism of action, and modulation of downstream signaling pathways in urothelial cells, the main effector cells in IC/BPS, have not been fully elucidated yet. Here, we investigated the effect of CBD against inflammation and oxidative stress in an in vitro model of IC/BPS comprised of TNFα-stimulated human urothelial cells SV-HUC1. Our results show that CBD treatment of urothelial cells significantly decreased TNFα-upregulated mRNA and protein expression of IL1α, IL8, CXCL1, and CXCL10, as well as attenuated NFκB phosphorylation. In addition, CBD treatment also diminished TNFα-driven cellular reactive oxygen species generation (ROS), by increasing the expression of the redox-sensitive transcription factor Nrf2, the antioxidant enzymes superoxide dismutase 1 and 2, and hem oxygenase 1. CBD-mediated effects in urothelial cells may occur by the activation of the PPARγ receptor since inhibition of PPARγ resulted in significantly diminished anti-inflammatory and antioxidant effects of CBD. Our observations provide new insights into the therapeutic potential of CBD through modulation of PPARγ/Nrf2/NFκB signaling pathways, which could be further exploited in the treatment of IC/BPS.
Collapse
|
|
10
|
Dziemitko S, Harasim-Symbor E, Chabowski A. How do phytocannabinoids affect cardiovascular health? An update on the most common cardiovascular diseases. Ther Adv Chronic Dis 2023; 14:20406223221143239. [PMID: 36636553 PMCID: PMC9830002 DOI: 10.1177/20406223221143239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 11/17/2022] [Indexed: 01/09/2023] Open
Abstract
Cardiovascular disease (CVD) causes millions of deaths worldwide each year. Despite the great progress in therapies available for patients with CVD, some limitations, including drug complications, still exist. Hence, the endocannabinoid system (ECS) was proposed as a new avenue for CVDs treatment. The ECS components are widely distributed through the body, including the heart and blood vessels, thus the action of its endogenous and exogenous ligands, in particular, phytocannabinoids play a key role in various pathological states. The cardiovascular action of cannabinoids is complex as they affect vasculature and myocardium directly via specific receptors and exert indirect effects through the central and peripheral nervous system. The growing interest in phytocannabinoid studies, however, has extended the knowledge about their molecular targets as well as therapeutical properties; nonetheless, some areas of their actions are not yet fully recognized. Researchers have reported various cannabinoids, especially cannabidiol, as a promising approach to CVDs; hence, the purpose of this review is to summarize and update the cardiovascular actions of the most potent phytocannabinoids and the potential therapeutic role of ECS in CVDs, including ischemic reperfusion injury, arrhythmia, heart failure as well as hypertension.
Collapse
Affiliation(s)
- Sylwia Dziemitko
- Department of Physiology, Medical University of
Bialystok, Bialystok 15-222, Poland
| | - Ewa Harasim-Symbor
- Department of Physiology, Medical University of
Bialystok, Bialystok, Poland
| | - Adrian Chabowski
- Department of Physiology, Medical University of
Bialystok, Bialystok, Poland
| |
Collapse
|
|
11
|
Goenka S. Comparative Study of Δ9-Tetrahydrocannabinol and Cannabidiol on Melanogenesis in Human Epidermal Melanocytes from Different Pigmentation Phototypes: A Pilot Study. J Xenobiot 2022; 12:131-144. [PMID: 35736025 PMCID: PMC9224588 DOI: 10.3390/jox12020012] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 05/21/2022] [Accepted: 06/06/2022] [Indexed: 11/26/2022] Open
Abstract
Δ9-tetrahydrocannabinol (THC) is one of the primary ingredients of cannabis plants and is responsible for the psychoactive properties of cannabis. While cannabidiol (CBD), the non-psychoactive compound from cannabis, has been shown to stimulate human epidermal melanogenesis, the effects of THC have not been addressed in human epidermal melanocytes. Moreover, to date, no study has tested the effects of these compounds on melanocytes differing in pigmentation, representative of different skin phototypes, which would be significant as different ethnicities are known to differentially metabolize these xenobiotics. Herein, the effects of THC were studied and compared alongside CBD in human epidermal melanocytes derived from lightly-pigmented (HEMn-LP; Caucasian) and darkly-pigmented (HEMn-DP; African-American) cells over a chronic exposure of 6 d. Results demonstrated that both compounds displayed cytotoxicity at 4 µM but stimulated melanin synthesis and tyrosinase activity in a similar manner in LP and DP cells at nontoxic concentrations of 1-2 µM. However, THC and CBD showed a differential effect on dendricity in both cells; THC and CBD reversibly increased dendricity in LP cells while there was no significant change in DP cells. THC and CBD induced higher levels of reactive oxygen species (ROS) in LP cells while there was no change in the ROS levels in DP cells. In summary, although THC was relatively less cytotoxic as compared to CBD to both LP and DP cells, it exhibited a similar capacity as CBD to stimulate melanin synthesis and export in LP cells which was accompanied by a significant oxidative stress. DP cells were relatively resistant to the effects of both THC and CBD which might implicate the protective effects conferred by melanin in dark-skinned individuals.
Collapse
Affiliation(s)
- Shilpi Goenka
- Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY 11794-5281, USA;
- Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794-5281, USA
| |
Collapse
|
|
12
|
El-Azab MF, Wakiel AE, Nafea YK, Youssef ME. Role of cannabinoids and the endocannabinoid system in modulation of diabetic cardiomyopathy. World J Diabetes 2022; 13:387-407. [PMID: 35664549 PMCID: PMC9134026 DOI: 10.4239/wjd.v13.i5.387] [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: 05/31/2021] [Revised: 07/18/2021] [Accepted: 04/28/2022] [Indexed: 02/06/2023] Open
Abstract
Diabetic complications, chiefly seen in long-term situations, are persistently deleterious to a large extent, requiring multi-factorial risk reduction strategies beyond glycemic control. Diabetic cardiomyopathy is one of the most common deleterious diabetic complications, being the leading cause of mortality among diabetic patients. The mechanisms of diabetic cardiomyopathy are multi-factorial, involving increased oxidative stress, accumulation of advanced glycation end products (AGEs), activation of various pro-inflammatory and cell death signaling pathways, and changes in the composition of extracellular matrix with enhanced cardiac fibrosis. The novel lipid signaling system, the endocannabinoid system, has been implicated in the pathogenesis of diabetes and its complications through its two main receptors: Cannabinoid receptor type 1 and cannabinoid receptor type 2, alongside other components. However, the role of the endocannabinoid system in diabetic cardiomyopathy has not been fully investigated. This review aims to elucidate the possible mechanisms through which cannabinoids and the endocannabinoid system could interact with the pathogenesis and the development of diabetic cardiomyopathy. These mechanisms include oxidative/ nitrative stress, inflammation, accumulation of AGEs, cardiac remodeling, and autophagy. A better understanding of the role of cannabinoids and the endocannabinoid system in diabetic cardiomyopathy may provide novel strategies to manipulate such a serious diabetic complication.
Collapse
Affiliation(s)
- Mona F El-Azab
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Ahmed E Wakiel
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Yossef K Nafea
- Program of Biochemistry, McMaster University, Hamilton L8S 4L8, Ontario, Canada
| | - Mahmoud E Youssef
- Department of Pharmacology and Biochemistry, Delta University for Science and Technology, Mansoura 35511, New Cairo, Egypt
| |
Collapse
|
|
13
|
Wang T, Chen Y, Li Y, Wang Z, Qiu C, Yang D, Chen K. TRPV1 Protect against Hyperglycemia and Hyperlipidemia Induced Liver Injury via OPA1 in Diabetes. TOHOKU J EXP MED 2022; 256:131-139. [PMID: 35197406 DOI: 10.1620/tjem.256.131] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Type 2 diabetes mellitus (T2DM)-associated mitochondrial impairment may a key factor leading to liver injury. Transient receptor potential receptor vanilloid 1 (TRPV1) regulates the energy expenditure and cholesterol metabolism in hepatocytes and protects against oxidative toxicity. Optic atrophy 1 (OPA1) is involved in the protection of TRPV1 on cardiac microvascular and lung injury. The aim of this study is to identify the role of TRPV1 in redox signals and liver protection via OPA1. TRPV1 knockout (TRPV1-/-) mice were used. And T2DM associated liver injury was induced by high glucose and high fatty acid (HG/HF) treatment. Mechanisms were studied by TUNEL staining, transmission electron microscope (TEM) analysis, reverse transcription polymerase chain reaction (RT-PCR) and Western blotting in vivo and in vitro. We determined that HG/HF treatment increased TRPV1 expression in liver tissues and AML12 cells. The knockout of TRPV1 increased the apoptotic hepatocytes rate. The inhibition of TRPV1 by 5'-iRTX in HG/HF group elevated the reactive oxygen species (ROS) levels, whereas TRPV1 agonist capsaicin reduced ROS. Our studies also showed that the OPA1 expression was lower in livers from HG/HF treated mice than the control, and genetic ablation of TRPV1 decreased OPA1 expression to a greater extent than the HG/HF mice. The protective effects of TRPV1 on mitochondrial were blocked by OPA1 siRNA. In conclusion, our study showed that the identified regulation of TRPV1 to OPA1 has important implication to the pathogenesis of T2DM-associated liver injury. Targeting the action of TRPV1 and OPA1 presents a potential therapeutic intervention.
Collapse
Affiliation(s)
- Ting Wang
- Department of Cardiology, The General Hospital of Western Theater Command
| | - Yingmei Chen
- Department of Cardiology, The General Hospital of Western Theater Command
| | - Yong Li
- Department of Cardiology, The People's Hospital of Chaotian District in Guangyuan
| | - Zhen Wang
- Department of Cardiology, The General Hospital of Western Theater Command
| | - Chenming Qiu
- Department of Cardiology, The General Hospital of Western Theater Command
| | - Dachun Yang
- Department of Cardiology, The General Hospital of Western Theater Command
| | - Ken Chen
- Department of Cardiology, Chongqing Renji Hospital, University of Chinese Academy of Sciences.,Department of Cardiology, The Fifth People's Hospital of Chongqing
| |
Collapse
|
|
14
|
Vasoprotective Endothelial Effects of Chronic Cannabidiol Treatment and Its Influence on the Endocannabinoid System in Rats with Primary and Secondary Hypertension. Pharmaceuticals (Basel) 2021; 14:ph14111120. [PMID: 34832902 PMCID: PMC8624681 DOI: 10.3390/ph14111120] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 10/30/2021] [Accepted: 10/31/2021] [Indexed: 11/20/2022] Open
Abstract
Our study aimed to examine the endothelium (vascular)-protecting effects of chronic cannabidiol (CBD) administration (10 mg/kg once daily for 2 weeks) in aortas and small mesenteric (G3) arteries isolated from deoxycorticosterone-induced hypertensive (DOCA-salt) rats and spontaneously hypertensive rats (SHR). CBD reduced hypertrophy and improved the endothelium-dependent vasodilation in response to acetylcholine in the aortas and G3 of DOCA-salt rats and SHR. The enhancement of vasorelaxation was prevented by the inhibition of nitric oxide (NO) with L-NAME and/or the inhibition of cyclooxygenase (COX) with indomethacin in the aortas and G3 of DOCA-salt and SHR, respectively. The mechanism of the CBD-mediated improvement of endothelial function in hypertensive vessels depends on the vessel diameter and may be associated with its NO-, the intermediate-conductance calcium-activated potassium channel- or NO-, COX-, the intermediate and the small-conductance calcium-activated potassium channels-dependent effect in aortas and G3, respectively. CBD increased the vascular expression of the cannabinoid CB1 and CB2 receptors and aortic levels of endocannabinoids with vasorelaxant properties e.g., anandamide, 2-arachidonoylglycerol and palmitoyl ethanolamide in aortas of DOCA-salt and/or SHR. In conclusion, CBD treatment has vasoprotective effects in hypertensive rats, in a vessel-size- and hypertension-model-independent manner, at least partly via inducing local vascular changes in the endocannabinoid system.
Collapse
|
|
15
|
Cannabidiol modulation of oxidative stress and signalling. Neuronal Signal 2021; 5:NS20200080. [PMID: 34497718 PMCID: PMC8385185 DOI: 10.1042/ns20200080] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 07/27/2021] [Accepted: 07/30/2021] [Indexed: 12/18/2022] Open
Abstract
Cannabidiol (CBD), one of the primary non-euphoric components in the Cannabis sativa L. plant, has undergone clinical development over the last number of years as a therapeutic for patients with Lennox-Gastaut syndrome and Dravet syndromes. This phytocannabinoid demonstrates functional and pharmacological diversity, and research data indicate that CBD is a comparable antioxidant to common antioxidants. This review gathers the latest knowledge regarding the impact of CBD on oxidative signalling, with focus on the proclivity of CBD to regulate antioxidants and control the production of reactive oxygen species. CBD is considered an attractive therapeutic agent for neuroimmune disorders, and a body of literature indicates that CBD can regulate redox function at multiple levels, with a range of downstream effects on cells and tissues. However, pro-oxidant capacity of CBD has also been reported, and hence caution must be applied when considering CBD from a therapeutic standpoint. Such pro- and antioxidant functions of CBD may be cell- and model-dependent and may also be influenced by CBD dose, the duration of CBD treatment and the underlying pathology.
Collapse
|
|
16
|
A brief history of carbon monoxide and its therapeutic origins. Nitric Oxide 2021; 111-112:45-63. [PMID: 33838343 DOI: 10.1016/j.niox.2021.04.001] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 02/03/2021] [Accepted: 04/01/2021] [Indexed: 02/06/2023]
Abstract
It is estimated that 10% of carbon throughout the cosmos is in the form of carbon monoxide (CO). Earth's earliest prebiotic atmosphere included the trinity of gasotransmitters CO, nitric oxide (NO), and hydrogen sulfide (H2S), for which all of life has co-evolved with. The history of CO can be loosely traced to mythological and prehistoric origins with rudimentary understanding emerging in the middle ages. Ancient literature is focused on CO's deadly toxicity which is understandable in the context of our primitive relationship with coal and fire. Scientific inquiry into CO appears to have emerged throughout the 1700s followed by chemical and toxicological profiling throughout the 1800s. Despite CO's ghastly reputation, several of the 18th and 19th century scientists suggested a therapeutic application of CO. Since 2000, the fundamental understanding of CO as a deadly nuisance has undergone a paradigm shift such that CO is now recognized as a neurotransmitter and viable pharmaceutical candidate. This review is intended to provide a brief history on the trace origins pertaining to endogenous formation and therapeutic application of CO.
Collapse
|
|
17
|
Therapeutic Applications of Cannabinoids in Cardiomyopathy and Heart Failure. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:4587024. [PMID: 33194003 PMCID: PMC7641267 DOI: 10.1155/2020/4587024] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Revised: 09/21/2020] [Accepted: 09/23/2020] [Indexed: 02/06/2023]
Abstract
A large number of cannabinoids have been discovered that could play a role in mitigating cardiac affections. However, none of them has been as widely studied as cannabidiol (CBD), most likely because, individually, the others offer only partial effects or can activate potential harmful pathways. In this regard, CBD has proven to be of great value as a cardioprotective agent since it is a potent antioxidant and anti-inflammatory molecule. Thus, we conducted a review to condensate the currently available knowledge on CBD as a therapy for different experimental models of cardiomyopathies and heart failure to detect the molecular pathways involved in cardiac protection. CBD therapy can greatly limit the production of oxygen/nitrogen reactive species, thereby limiting cellular damage, protecting mitochondria, avoiding caspase activation, and regulating ionic homeostasis. Hence, it can affect myocardial contraction by restricting the activation of inflammatory pathways and cytokine secretion, lowering tissular infiltration by immune cells, and reducing the area of infarct and fibrosis formation. These effects are mediated by the activation or inhibition of different receptors and target molecules of the endocannabinoid system. In the final part of this review, we explore the current state of CBD in clinical trials as a treatment for cardiovascular diseases and provide evidence of its potential benefits in humans.
Collapse
|
|
18
|
Navarrete C, Garcia-Martin A, DeMesa J, Muñoz E. Cannabinoids in Metabolic Syndrome and Cardiac Fibrosis. Curr Hypertens Rep 2020; 22:98. [PMID: 33089434 DOI: 10.1007/s11906-020-01112-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/28/2020] [Indexed: 12/21/2022]
Abstract
PURPOSE OF REVIEW This article provides a concise overview of how cannabinoids and the endocannabinoid system (ECS) have significant implications for the prevention and treatment of metabolic syndrome (MetS) and for the treatment of cardiovascular disorders, including cardiac fibrosis. RECENT FINDINGS Over the past few years, the ECS has emerged as a pivotal component of the homeostatic mechanisms for the regulation of many bodily functions, including inflammation, digestion, and energy metabolism. Therefore, the pharmacological modulation of the ECS by cannabinoids represents a novel strategy for the management of many diseases. Specifically, increasing evidence from preclinical research studies has opened new avenues for the development of cannabinoid-based therapies for the management and potential treatment of MetS and cardiovascular diseases. Current information indicates that modulation of the ECS can help maintain overall health and well-being due to its homeostatic function. From a therapeutic perspective, cannabinoids and the ECS have also been shown to play a key role in modulating pathophysiological states such as inflammatory, neurodegenerative, gastrointestinal, metabolic, and cardiovascular diseases, as well as cancer and pain. Thus, targeting and modulating the ECS with cannabinoids or cannabinoid derivatives may represent a major disease-modifying medical advancement to achieve successful treatment for MetS and certain cardiovascular diseases.
Collapse
Affiliation(s)
| | | | - Jim DeMesa
- Emerald Health Pharmaceuticals, San Diego, CA, USA
| | - Eduardo Muñoz
- Instituto Maimónides de Investigación Biomédica de Córdoba, University of Córdoba, Avda. Menéndez Pidal s/n, 14004, Córdoba, Spain.
- Departamento de Biologia Celular, Fisiologia e Inmunologia, Universidad de Córdoba, Córdoba, Spain.
- Hospital Universitario Reina Sofia, Córdoba, Spain.
| |
Collapse
|
|
19
|
Bublitz K, Böckmann S, Peters K, Hinz B. Cannabinoid-Induced Autophagy and Heme Oxygenase-1 Determine the Fate of Adipose Tissue-Derived Mesenchymal Stem Cells under Stressful Conditions. Cells 2020; 9:cells9102298. [PMID: 33076330 PMCID: PMC7602569 DOI: 10.3390/cells9102298] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 10/02/2020] [Accepted: 10/05/2020] [Indexed: 01/17/2023] Open
Abstract
The administration of adipose tissue-derived mesenchymal stem cells (ADMSCs) represents a promising therapeutic option after myocardial ischemia or myocardial infarction. However, their potential is reduced due to the high post-transplant cell mortality probably caused by oxidative stress and mitogen-deficient microenvironments. To identify protection strategies for ADMSCs, this study investigated the influence of the non-psychoactive phytocannabinoid cannabidiol (CBD) and the endocannabinoid analogue R(+)-methanandamide (MA) on the induction of heme oxygenase-1 (HO-1) and autophagy under serum-free conditions. At a concentration of 3 µM, CBD induced an upregulation of HO-1 mRNA and protein within 6 h, whereas for MA only a late and comparatively lower increase in the HO-1 protein could be detected after 48 h. In addition, both cannabinoids induced time- and concentration-dependent increases in LC3A/B-II protein, a marker of autophagy, and in metabolic activity. A participation of several cannabinoid-binding receptors in the effect on metabolic activity and HO-1 was excluded. Similarly, knockdown of HO-1 by siRNA or inhibition of HO-1 activity by tin protoporphyrin IX (SnPPIX) had no effect on CBD-induced autophagy and metabolic activity. On the other hand, the inhibition of autophagy by bafilomycin A1 led to a significant decrease in cannabinoid-induced metabolic activity and to an increase in apoptosis. Under these circumstances, a significant induction of HO-1 expression after 24 h could also be demonstrated for MA. Remarkably, inhibition of HO-1 by SnPPIX under conditions of autophagy deficit led to a significant reversal of apoptosis in cannabinoid-treated cells. In conclusion, the investigated cannabinoids increase metabolic viability of ADMSCs under serum-free conditions by inducing HO-1-independent autophagy but contribute to apoptosis under conditions of additional autophagy deficit via an HO-1-dependent pathway.
Collapse
Affiliation(s)
- Katharina Bublitz
- Institute of Pharmacology and Toxicology, Rostock University Medical Center, Schillingallee 70, D-18057 Rostock, Germany; (K.B.); (S.B.)
| | - Sabine Böckmann
- Institute of Pharmacology and Toxicology, Rostock University Medical Center, Schillingallee 70, D-18057 Rostock, Germany; (K.B.); (S.B.)
| | - Kirsten Peters
- Department of Cell Biology, Rostock University Medical Center, Schillingallee 69, D-18057 Rostock, Germany;
| | - Burkhard Hinz
- Institute of Pharmacology and Toxicology, Rostock University Medical Center, Schillingallee 70, D-18057 Rostock, Germany; (K.B.); (S.B.)
- Correspondence: ; Tel.: +49-381-494-5770
| |
Collapse
|
|
20
|
Pagano S, Coniglio M, Valenti C, Federici MI, Lombardo G, Cianetti S, Marinucci L. Biological effects of Cannabidiol on normal human healthy cell populations: Systematic review of the literature. Biomed Pharmacother 2020; 132:110728. [PMID: 33038581 DOI: 10.1016/j.biopha.2020.110728] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 08/29/2020] [Accepted: 09/02/2020] [Indexed: 12/13/2022] Open
Abstract
A systematic review was performed to evaluate the biological effects of Cannabidiol (CBD), one of the major components of Cannabis Sativa, on normal human healthy cell populations in terms of cell viability, proliferation, migration, apoptosis and inflammation. Inclusion criteria were: studies on cell lines and primary cell culture from healthy donors, CBD exposure as variable, no CBD exposure as control and published in English language. Quality assessment was based on ToxR tool, with a score of reliability ranging from 15 to 18.Following the PRISMA statement, three independent reviewers performed both a manual and an electronic search using MEDLINE via PubMed, Scopus, Web of Science and Cochrane. From a total of 9437eligible articles, 29 studies have been selected. The average quality assessment score was 16.48.Theresults showed heterogeneous CBD concentration exposure (0.01-50 μM or 0.1 nmol/mL-15 mg/mL). The definition of a threshold limit would allow the identification of specific effects on expected outcomes. From the data obtained CBD resulted to inhibit cell viability in a dose-dependent manner above 2 μM, while in oral cell populations the inhibitory concentration is higher than 10 μM. Moreover, it was observed a significantly inhibition of cell migration and proliferation. On the contrary, it was highlighted a stimulation of apoptosis only at high doses (from 10 μM).Finally, CBD produced an anti-inflammatory effect, with a reduction of the pro-inflammatory cytokine gene expression and secretion. CBD down-regulated ROS production, although at high concentrations (16 μM) increased ROS-related genes expression. The diffusion of CBD for therapeutic and recreational uses require a precise definition of its potential biological effects. A thorough knowledge of these aspects would allow a safe use of this substance without any possible side effects.
Collapse
Affiliation(s)
- Stefano Pagano
- Department of Biomedical and Surgical Sciences, Odontostomatological University Centre: Chair Prof. Stefano Cianetti, University of Perugia, Perugia, Italy.
| | - Maddalena Coniglio
- Department of Biomedical and Surgical Sciences, Odontostomatological University Centre: Chair Prof. Stefano Cianetti, University of Perugia, Perugia, Italy.
| | - Chiara Valenti
- Department of Biomedical and Surgical Sciences, Odontostomatological University Centre: Chair Prof. Stefano Cianetti, University of Perugia, Perugia, Italy.
| | - Maria Isabella Federici
- Department of Biomedical and Surgical Sciences, Odontostomatological University Centre: Chair Prof. Stefano Cianetti, University of Perugia, Perugia, Italy.
| | - Guido Lombardo
- Department of Biomedical and Surgical Sciences, Odontostomatological University Centre: Chair Prof. Stefano Cianetti, University of Perugia, Perugia, Italy.
| | - Stefano Cianetti
- Department of Biomedical and Surgical Sciences, Odontostomatological University Centre: Chair Prof. Stefano Cianetti, University of Perugia, Perugia, Italy.
| | - Lorella Marinucci
- Department of Experimental Medicine, Section of Biosciences and Medical Embryology, University of Perugia, Perugia, Italy.
| |
Collapse
|
|
21
|
Sadowska O, Baranowska-Kuczko M, Gromotowicz-Popławska A, Biernacki M, Kicman A, Malinowska B, Kasacka I, Krzyżewska A, Kozłowska H. Cannabidiol Ameliorates Monocrotaline-Induced Pulmonary Hypertension in Rats. Int J Mol Sci 2020; 21:ijms21197077. [PMID: 32992900 PMCID: PMC7582795 DOI: 10.3390/ijms21197077] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 09/11/2020] [Accepted: 09/22/2020] [Indexed: 12/15/2022] Open
Abstract
Cannabidiol (CBD) is known for its vasorelaxant (including in the human pulmonary artery), anti-proliferative and anti-inflammatory properties. The aim of our study was to examine the potential preventive effect of chronic CBD administration (10 mg/kg/day for three weeks) on monocrotaline (MCT)-induced pulmonary hypertension (PH) rats. PH was connected with elevation of right ventricular systolic pressure; right ventricle hypertrophy; lung edema; pulmonary artery remodeling; enhancement of the vasoconstrictor and decreasing vasodilatory responses; increases in plasma concentrations of tissue plasminogen activator, plasminogen activator inhibitor type 1 and leukocyte count; and a decrease in blood oxygen saturation. CBD improved all abovementioned changes induced by PH except right ventricle hypertrophy and lung edema. In addition, CBD increased lung levels of some endocannabinoids (anandamide, N-arachidonoyl glycine, linolenoyl ethanolamide, palmitoleoyl ethanolamide and eicosapentaenoyl ethanolamide but not 2-arachidonoylglycerol). CBD did not affect the cardiopulmonary system of control rats or other parameters of blood morphology in PH. Our data suggest that CBD ameliorates MCT-induced PH in rats by improving endothelial efficiency and function, normalization of hemostatic alterations and reduction of enhanced leukocyte count determined in PH. In conclusion, CBD may be a safe, promising therapeutic or adjuvant therapy agent for the treatment of human pulmonary artery hypertension.
Collapse
Affiliation(s)
- Olga Sadowska
- Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, 15-222 Białystok, Poland; (O.S.); (M.B.-K.); (A.K.); (B.M.); (A.K.)
| | - Marta Baranowska-Kuczko
- Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, 15-222 Białystok, Poland; (O.S.); (M.B.-K.); (A.K.); (B.M.); (A.K.)
- Department of Clinical Pharmacy, Medical University of Białystok, 15-222 Białystok, Poland
| | | | - Michał Biernacki
- Department of Analytical Chemistry, Medical University of Białystok, 15-222 Białystok, Poland;
| | - Aleksandra Kicman
- Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, 15-222 Białystok, Poland; (O.S.); (M.B.-K.); (A.K.); (B.M.); (A.K.)
| | - Barbara Malinowska
- Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, 15-222 Białystok, Poland; (O.S.); (M.B.-K.); (A.K.); (B.M.); (A.K.)
| | - Irena Kasacka
- Department of Histology and Cytophysiology, Medical University of Bialystok, 15-222 Bialystok, Poland;
| | - Anna Krzyżewska
- Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, 15-222 Białystok, Poland; (O.S.); (M.B.-K.); (A.K.); (B.M.); (A.K.)
| | - Hanna Kozłowska
- Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, 15-222 Białystok, Poland; (O.S.); (M.B.-K.); (A.K.); (B.M.); (A.K.)
- Correspondence: ; Tel.: +48-85-748-5699
| |
Collapse
|
|
22
|
The Effects of Cannabidiol, a Non-Intoxicating Compound of Cannabis, on the Cardiovascular System in Health and Disease. Int J Mol Sci 2020; 21:ijms21186740. [PMID: 32937917 PMCID: PMC7554803 DOI: 10.3390/ijms21186740] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 09/09/2020] [Accepted: 09/10/2020] [Indexed: 12/12/2022] Open
Abstract
Cannabidiol (CBD) is a non-intoxicating and generally well-tolerated constituent of cannabis which exhibits potential beneficial properties in a wide range of diseases, including cardiovascular disorders. Due to its complex mechanism of action, CBD may affect the cardiovascular system in different ways. Thus, we reviewed the influence of CBD on this system in health and disease to determine the potential risk of cardiovascular side effects during CBD use for medical and wellness purposes and to elucidate its therapeutic potential in cardiovascular diseases. Administration of CBD to healthy volunteers or animals usually does not markedly affect hemodynamic parameters. Although CBD has been found to exhibit vasodilatory and antioxidant properties in hypertension, it has not affected blood pressure in hypertensive animals. Hypotensive action of CBD has been mainly revealed under stress conditions. Many positive effects of CBD have been observed in experimental models of heart diseases (myocardial infarction, cardiomyopathy, myocarditis), stroke, neonatal hypoxic ischemic encephalopathy, sepsis-related encephalitis, cardiovascular complications of diabetes, and ischemia/reperfusion injures of liver and kidneys. In these pathological conditions CBD decreased organ damage and dysfunction, oxidative and nitrative stress, inflammatory processes and apoptosis, among others. Nevertheless, further clinical research is needed to recommend the use of CBD in the treatment of cardiovascular diseases.
Collapse
|
|
23
|
Targeting Heme Oxygenase-1 in the Arterial Response to Injury and Disease. Antioxidants (Basel) 2020; 9:antiox9090829. [PMID: 32899732 PMCID: PMC7554957 DOI: 10.3390/antiox9090829] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 08/31/2020] [Accepted: 09/03/2020] [Indexed: 02/06/2023] Open
Abstract
Heme oxygenase-1 (HO-1) catalyzes the degradation of heme into carbon monoxide (CO), iron, and biliverdin, which is rapidly metabolized to bilirubin. The activation of vascular smooth muscle cells (SMCs) plays a critical role in mediating the aberrant arterial response to injury and a number of vascular diseases. Pharmacological induction or gene transfer of HO-1 improves arterial remodeling in animal models of post-angioplasty restenosis, vascular access failure, atherosclerosis, transplant arteriosclerosis, vein grafting, and pulmonary arterial hypertension, whereas genetic loss of HO-1 exacerbates the remodeling response. The vasoprotection evoked by HO-1 is largely ascribed to the generation of CO and/or the bile pigments, biliverdin and bilirubin, which exert potent antioxidant and anti-inflammatory effects. In addition, these molecules inhibit vascular SMC proliferation, migration, apoptosis, and phenotypic switching. Several therapeutic strategies are currently being pursued that may allow for the targeting of HO-1 in arterial remodeling in various pathologies, including the use of gene delivery approaches, the development of novel inducers of the enzyme, and the administration of unique formulations of CO and bilirubin.
Collapse
|
|
24
|
Karimian Azari E, Kerrigan A, O’Connor A. Naturally Occurring Cannabinoids and their Role in Modulation of Cardiovascular Health. J Diet Suppl 2020; 17:625-650. [DOI: 10.1080/19390211.2020.1790708] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
| | - Aileen Kerrigan
- Research and Development department, University College Dublin, Dublin, Ireland
| | | |
Collapse
|
|
25
|
Cannabidiol Promotes Endothelial Cell Survival by Heme Oxygenase-1-Mediated Autophagy. Cells 2020; 9:cells9071703. [PMID: 32708634 PMCID: PMC7407143 DOI: 10.3390/cells9071703] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 07/06/2020] [Accepted: 07/10/2020] [Indexed: 12/17/2022] Open
Abstract
Cannabidiol (CBD), a non-psychoactive cannabinoid, has been reported to mediate antioxidant, anti-inflammatory, and anti-angiogenic effects in endothelial cells. This study investigated the influence of CBD on the expression of heme oxygenase-1 (HO-1) and its functional role in regulating metabolic, autophagic, and apoptotic processes of human umbilical vein endothelial cells (HUVEC). Concentrations up to 10 µM CBD showed a concentration-dependent increase of HO-1 mRNA and protein and an increase of the HO-1-regulating transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). CBD-induced HO-1 expression was not decreased by antagonists of cannabinoid-activated receptors (CB1, CB2, transient receptor potential vanilloid 1), but by the reactive oxygen species (ROS) scavenger N-acetyl-L-cysteine (NAC). The incubation of HUVEC with 6 µM CBD resulted in increased metabolic activity, while 10 µM CBD caused decreased metabolic activity and an induction of apoptosis, as demonstrated by enhanced caspase-3 cleavage. In addition, CBD triggered a concentration-dependent increase of the autophagy marker LC3A/B-II. Both CBD-induced LC3A/B-II levels and caspase-3 cleavage were reduced by NAC. The inhibition of autophagy by bafilomycin A1 led to apoptosis induction by 6 µM CBD and a further increase of the proapoptotic effect of 10 µM CBD. On the other hand, the inhibition of HO-1 activity with tin protoporphyrin IX (SnPPIX) or knockdown of HO-1 expression by Nrf2 siRNA was associated with a decrease in CBD-mediated autophagy and apoptosis. In summary, our data show for the first time ROS-mediated HO-1 expression in endothelial cells as a mechanism by which CBD mediates protective autophagy, which at higher CBD concentrations, however, can no longer prevent cell death inducing apoptosis.
Collapse
|
|
26
|
Zhang H, Xue S, Feng Y, Shen J, Zhao J. MicroRNA-24-3p inhibition prevents cell growth of vascular smooth muscle cells by targeting Bcl-2-like protein 11. Exp Ther Med 2020; 19:2467-2474. [PMID: 32256723 PMCID: PMC7086294 DOI: 10.3892/etm.2020.8517] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Accepted: 11/29/2019] [Indexed: 12/15/2022] Open
Abstract
Numerous reports have shown that dysfunction of vascular smooth muscle cells (VSMCs) serves a critical function in the development of cardiovascular disease, including coronary heart disease (CHD). microRNAs (miRNAs/miRs) have been reported to play important roles in regulating the function of VSMCs. The present study aimed to determine the role of miR-24-3p in VSMCs and to uncover the underlying mechanism. The expression of miR-24-3p in the peripheral blood samples of CHD patients was measured by reverse transcription-quantitative (RT-q)PCR. It was found that the level of miR-24-3p in the peripheral blood of patients with CHD was significantly upregulated compared with that in healthy controls. A dual luciferase reporter assay was performed to determine whether Bcl-2-like protein 11 (Bcl-2L11) was a target gene of miR-24-3p, and it was identified that Bcl-2L11 was a direct target of miR-24-3p. The mRNA level and protein expression of Bcl-2L11 in the peripheral blood of patients with CHD were measured by RT-qPCR and western blotting, respectively. The findings suggested that Bcl-2L11 was downregulated in the peripheral blood of patients with CHD. In addition, it was found that downregulation of miR-24-3p suppressed VSMC proliferation and promoted VSMC apoptosis, while the effects of the miR-24-3p inhibitor on cell viability and apoptosis were reversed by Bcl-2L11-small interfering (si)RNA. Additionally, downregulation of miR-24-3p increased the levels of Bcl-2L11, caspase-3 and Bax, and decreased Bcl-2 expression in VSMCs; these changes were abolished by Bcl-2L11-siRNA. In conclusion, the aforementioned results indicated that miR-24-3p was an important regulator in VSMC proliferation and apoptosis by targeting Bcl-2L11, which suggested that miR-24-3p might be a potential therapeutic target for the treatment of CHD.
Collapse
Affiliation(s)
- Huanxin Zhang
- Department of Cardiology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Shizhen Xue
- Department of Cardiology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Yi Feng
- Department of Cardiology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Jun Shen
- Department of Cardiology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Jixian Zhao
- Department of Cardiology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| |
Collapse
|
|
27
|
Cannabidiol Protects Dopaminergic Neurons in Mesencephalic Cultures against the Complex I Inhibitor Rotenone Via Modulation of Heme Oxygenase Activity and Bilirubin. Antioxidants (Basel) 2020; 9:antiox9020135. [PMID: 32033040 PMCID: PMC7070382 DOI: 10.3390/antiox9020135] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 01/25/2020] [Accepted: 01/30/2020] [Indexed: 12/13/2022] Open
Abstract
Phytocannabinoids protect neurons against stressful conditions, possibly via the heme oxygenase (HO) system. In cultures of primary mesencephalic neurons and neuroblastoma cells, we determined the capability of cannabidiol (CBD) and tetrahydrocannabinol (THC) to counteract effects elicited by complex I-inhibitor rotenone by analyzing neuron viability, morphology, gene expression of IL6, CHOP, XBP1, HO-1 (stress response), and HO-2, and in vitro HO activity. Incubation with rotenone led to a moderate stress response but massive degeneration of dopaminergic neurons (DN) in primary mesencephalic cultures. Both phytocannabinoids inhibited in-vitro HO activity, with CBD being more potent. Inhibition of the enzyme reaction was not restricted to neuronal cells and occurred in a non-competitive manner. Although CBD itself decreased viability of the DNs (from 100% to 78%), in combination with rotenone, it moderately increased survival from 28.6% to 42.4%. When the heme degradation product bilirubin (BR) was added together with CBD, rotenone-mediated degeneration of DN was completely abolished, resulting in approximately the number of DN determined with CBD alone (77.5%). Using N18TG2 neuroblastoma cells, we explored the neuroprotective mechanism underlying the combined action of CBD and BR. CBD triggered the expression of HO-1 and other cell stress markers. Co-treatment with rotenone resulted in the super-induction of HO-1 and an increased in-vitro HO-activity. Co-application of BR completely mitigated the rotenone-induced stress response. Our findings indicate that CBD induces HO-1 and increases the cellular capacity to convert heme when stressful conditions are met. Our data further suggest that CBD via HO may confer full protection against (oxidative) stress when endogenous levels of BR are sufficiently high.
Collapse
|
|
28
|
Lu J, Shan J, Liu N, Ding Y, Wang P. Tanshinone IIA Can Inhibit Angiotensin II-Induced Proliferation and Autophagy of Vascular Smooth Muscle Cells via Regulating the MAPK Signaling Pathway. Biol Pharm Bull 2019; 42:1783-1788. [PMID: 31391347 DOI: 10.1248/bpb.b19-00053] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
To examine the effect of tanshinone IIA on Angiotensin II (Ang II)-induced proliferation and autophagy in vascular smooth muscle cells (VSMCs) and the related mechanism. VSMCs were treated with Ang II with or without tanshinone IIA (1, 5 and 10 µg/mL), and the proliferation, apoptosis in cells with different treatment were examined by methylthiazolyl tetrazolium (MTT) and flow cytometry methods. Moreover, the expression of autophagy related proteins and mitogen-activated protein kinase (MAPK) signaling molecules were examined by RT-quantitative (q)PCR and Western blot methods. Ang II induced significantly increase in the proliferation and autophagy of VSMCs, and the MAPK signaling was activated. Tanshinone IIA can attenuate Ang II-induced effects via down-regulating the MAPK signaling pathway. Tanshinone IIA can inhibit Ang II-induced proliferation and autophagy of VSMCs via regulating the MAPK signaling pathway.
Collapse
Affiliation(s)
- Jingping Lu
- Department of Cardiology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine
| | - Jinjun Shan
- Jiangsu Key Laboratory of Pediatric Respiratory Disease, Institute of Pediatics, Affiliated Hospital of Nanjing University of Chinese Medicine
| | - Ning Liu
- Department of Cardiology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine
| | - Yao Ding
- Department of Cardiology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine
| | - Pei Wang
- Department of Cardiology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine
| |
Collapse
|