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1
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Reimers A, Odin P, Ljung H. Drug-Induced Cognitive Impairment. Drug Saf 2025; 48:339-361. [PMID: 39718691 PMCID: PMC11903592 DOI: 10.1007/s40264-024-01506-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/04/2024] [Indexed: 12/25/2024]
Abstract
Drug-induced cognitive impairment (DICI) is a well-established, yet under-recognised, complication of many types of pharmacological treatment. While there is a large body of scientific literature on DICI, most papers are about drug-induced dementia in the elderly and one specific drug class. However, DICI also comprises subclinical symptoms, domain-specific forms of cognitive impairment as well as mild cognitive impairment (MCI), and delirium. Even mild forms of DICI, if not recognised as such, can have deleterious and life-long consequences. In addition, DICI also occurs in younger adults and in children, and has been reported with many different drug classes. The aim of this review is to raise awareness of DICI by providing an overview on the type(s) and symptoms of observed DICI and the suspected underlying mechanism(s) for various drug classes: antiseizure medications, antidepressants, antiparkinsonian drugs, antipsychotics, lithium, benzodiazepines/Z-drugs, opioids, first-generation antihistamines, drugs for urinary incontinence, proton pump inhibitors, glucocorticoids, NSAIDs, statins, antihypertensives, and chemotherapeutic agents.
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Affiliation(s)
- Arne Reimers
- Department of Clinical Chemistry and Pharmacology, Department of Laboratory Medicine, Lund University, Box 117, 22100, Lund, Sweden.
- Department of Clinical Chemistry and Pharmacology, Skåne University Hospital, 22185, Lund, Sweden.
| | - Per Odin
- Division of Neurology, Department of Clinical Sciences Lund, Lund University, Box 117, 22100, Lund, Sweden
- Department of Neurology, Rehabilitation Medicine, Memory and Geriatrics, Skåne University Hospital, 22185, Lund, Sweden
| | - Hanna Ljung
- Division of Neurology, Department of Clinical Sciences Lund, Lund University, Box 117, 22100, Lund, Sweden
- Department of Neurology, Rehabilitation Medicine, Memory and Geriatrics, Skåne University Hospital, 22185, Lund, Sweden
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2
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Millichap L, Turton N, Alomosh R, Heaton RA, Bateman A, Al-Shanti N, Lightfoot AP, Damiani E, Marcheggiani F, Orlando P, Silvestri S, Tiano L, Hargreaves IP. The effect of simvastatin induced neurotoxicity on mitochondrial function in human neuronal cells. Toxicol Mech Methods 2025:1-12. [PMID: 40028788 DOI: 10.1080/15376516.2025.2471807] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 02/17/2025] [Accepted: 02/20/2025] [Indexed: 03/05/2025]
Abstract
3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGR) inhibitors, commonly known as statins, are drugs frequently used in the treatment of hypercholesterolemia and hyperlipidemia. However, the current study has demonstrated that simvastatin induces neurotoxicity and is associated with cellular coenzyme Q10 (CoQ10) depletion. CoQ10 has a significant role in the mitochondrial electron transport chain (ETC), in addition to being a fundamental lipid-soluble antioxidant. Depletion of CoQ10 is frequently associated with impaired mitochondrial function and increased oxidative stress. The aim of this study was to investigate the potential mechanisms of simvastatin-induced neurotoxicity assessing mitochondrial function and evidence of oxidative stress in an in vitro SH-SY5Y human neuronal cell line. Fluorescence studies assessed via flow cytometry determined significant increases in intracellular and mitochondrial reactive oxygen species production following SH-SY5Y treatment with simvastatin compared to control cells. Additionally, spectrophotometric enzyme studies determined a significant (p < 0.0001) inhibition of ETC complex I and II-III activities which accompanied a significant decrease in neuronal CoQ10 content (p < 0.005) and cell viability (p < 0.0001). The results of the present study have indicated evidence of mitochondrial dysfunction and increased oxidative stress, resulting in increased loss of neuronal viability following simvastatin treatment. Thus, these results demonstrate evidence of neurotoxicity associated with statin therapy.
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Affiliation(s)
- Lauren Millichap
- Department of Life and Environmental Sciences, Polytechnic University of Marche, Ancona, Italy
| | - Nadia Turton
- School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK
| | - Razan Alomosh
- Department of Life Sciences, Manchester Metropolitan University, Manchester, UK
| | - Robert A Heaton
- Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK
| | - Amy Bateman
- Department of Life Sciences, Manchester Metropolitan University, Manchester, UK
| | - Nasser Al-Shanti
- Department of Life Sciences, Manchester Metropolitan University, Manchester, UK
| | - Adam P Lightfoot
- Department of Life Sciences, Manchester Metropolitan University, Manchester, UK
| | - Elisabetta Damiani
- Department of Life and Environmental Sciences, Polytechnic University of Marche, Ancona, Italy
| | - Fabio Marcheggiani
- Department of Life and Environmental Sciences, Polytechnic University of Marche, Ancona, Italy
| | - Patrick Orlando
- Department of Life and Environmental Sciences, Polytechnic University of Marche, Ancona, Italy
| | - Sonia Silvestri
- Department of Life and Environmental Sciences, Polytechnic University of Marche, Ancona, Italy
| | - Luca Tiano
- Department of Life and Environmental Sciences, Polytechnic University of Marche, Ancona, Italy
| | - Iain P Hargreaves
- School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK
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de Mello TF, Goedert AB, de Souza JSS, da Cruz JVR, da Silva AS, Knorst JK, Muller YMR, Silva FRMB, Leite GAA. Prolonged exposure to rosuvastatin from pre-puberty to adulthood impairs sperm quality in mice and leads to paternally mediated developmental toxicity. Reprod Toxicol 2024; 130:108717. [PMID: 39276807 DOI: 10.1016/j.reprotox.2024.108717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 08/19/2024] [Accepted: 09/10/2024] [Indexed: 09/17/2024]
Abstract
Nowadays, changes in human lifestyle have increased dyslipidemia, reinforcing the necessity of using lipid-lowering drugs, such as statins, to control the lipid profile. Among the statins, rosuvastatin has shown greater efficacy in controlling dyslipidemia. Previous studies have shown adverse effects in adult men and pre-pubertal rodents after exposure to statins, such as reduced testosterone levels and delayed puberty. This study aimed to evaluate the reproductive parameters and fertility of male mice exposed to rosuvastatin from pre-puberty to sexual maturity by simulating human chronic exposure to rosuvastatin from pre-puberty to adulthood. This is the first study to evaluate male reproduction and developmental outcomes after prolonged rosuvastatin exposure since pre-puberty, mimicking the human exposure to relevant doses of the drug. Then, we hypothesize that prolonged exposure to rosuvastatin since pre-puberty may impair reproductive parameters in males and generate paternally mediated developmental toxicity. Male mice were divided into three experimental groups that received a 0.9 % saline solution, 1.5 or 5.5 mg/kg/day of rosuvastatin, by intragastric oral gavage, from postnatal day (PND) 23 to PND 80. Puberty onset was delayed and sperm quality was reduced in both rosuvastatin-treated groups. Furthermore, testicular interstitial tissue showed increased vascularization in a dose-dependent manner. After mating with non-treated females, the post-implantation loss rate increased in both rosuvastatin-exposed groups. There was an increase in the percentage of fetuses with opened eyelids in the offspring of males exposed to 1.5 mg/kg/day of the statin and a decrease in the craniocaudal distance of male offspring from males exposed to the higher dose. In summary, our hypothesis that rosuvastatin exposure would cause male reproductive toxicity and developmental impairment in the offspring of male mice was confirmed. This study raises concerns about the reproductive health of men who take this medication from infancy until adulthood in prolonged treatment.
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Affiliation(s)
- Tainara Fernandes de Mello
- Laboratório de Reprodução e Toxicologia (Laretox), Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil; Programa de Pós-graduação em Biologia Celular e do Desenvolvimento, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
| | - Ana Beatriz Goedert
- Laboratório de Reprodução e Toxicologia (Laretox), Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
| | - Julia Schubert Sengl de Souza
- Laboratório de Reprodução e Toxicologia (Laretox), Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
| | - João Victor Ramos da Cruz
- Laboratório de Reprodução e Toxicologia (Laretox), Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
| | - Alice Santos da Silva
- Laboratório de Reprodução e Toxicologia (Laretox), Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil; Programa de Pós-graduação em Biologia Celular e do Desenvolvimento, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
| | - Jennyfer Karen Knorst
- Laboratório de Reprodução e Toxicologia (Laretox), Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
| | - Yara Maria Rauh Muller
- Programa de Pós-graduação em Biologia Celular e do Desenvolvimento, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
| | | | - Gabriel Adan Araújo Leite
- Laboratório de Reprodução e Toxicologia (Laretox), Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil; Departamento de Biologia Celular, Embriologia e Genética, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
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Zhao Y, Zheng G, Yang S, Liu S, Wu Y, Miao Y, Liang Z, Hua Y, Zhang J, Shi J, Li D, Cheng Y, Zhang Y, Chen Y, Fan G, Ma C. The plant extract PNS mitigates atherosclerosis via promoting Nrf2-mediated inhibition of ferroptosis through reducing USP2-mediated Keap1 deubiquitination. Br J Pharmacol 2024; 181:4822-4844. [PMID: 39228119 DOI: 10.1111/bph.17311] [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: 12/14/2023] [Revised: 06/04/2024] [Accepted: 06/23/2024] [Indexed: 09/05/2024] Open
Abstract
BACKGROUND AND PURPOSE Atherosclerosis is the basis of cardiovascular disease. Ferroptosis is a form of programmed cell death characterized by lipid peroxidation, which contributes to atherogenesis. The plant extract PNS (Panax notoginseng saponins), containing the main active ingredients of Panax notoginseng, exhibits anti-atherogenic properties. Herein, we determined whether PNS and its major components could attenuate atherosclerosis by suppressing ferroptosis and revealed the underlying mechanism(s). EXPERIMENTAL APPROACH The anti-atherogenic effects of PNS and their association with inhibition of ferroptosis was determined in apoE-/- mice. In vitro, the anti-ferroptotic effect and mechanism(s) of PNS components were demonstrated in the presence of ferroptosis inducers. Expression of ferroptosis markers and the ubiquitination of Keap1 were evaluated in USP2-/- macrophages. Finally, the anti-atherogenic effect of USP2 knockout was determined by using USP2-/- mice treated with high-fat diet (HFD) and AAV-PCSK9. KEY RESULTS PNS inhibited ferroptosis and atherosclerosis in vivo. PNS suppressed ferroptosis and ferroptosis-aggravated foam cell formation and inflammation in vitro. Mechanistically, PNS and its components activated Nrf2 by antagonizing Keap1, which was attributed to the inhibition of USP2 expression. USP2 knockout antagonized ferroptosis and ferroptosis-aggravated foam cell formation and inflammation, thus mitigating atherosclerosis. USP2 knockout abolished inhibitory effects of PNS on foam cell formation and inflammation in vitro. CONCLUSION AND IMPLICATIONS PNS reduced USP2-mediated Keap1 de-ubiquitination and promoted Keap1 degradation, thereby activating Nrf2, improving iron metabolism and reducing lipid peroxidation, thus contributing to an anti-atherosclerotic outcome. Our study revealed the mechanism(s) underlying inhibition of ferroptosis and atherosclerosis by PNS.
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Affiliation(s)
- Yun Zhao
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Guobin Zheng
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Shu Yang
- Department of Geriatrics, The First Affiliated Hospital of Southern University of Science and Technology (Shenzhen People's Hospital), Shenzhen, China
| | - Shangjing Liu
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Yifan Wu
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Yaodong Miao
- Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Zhen Liang
- Department of Geriatrics, The First Affiliated Hospital of Southern University of Science and Technology (Shenzhen People's Hospital), Shenzhen, China
| | - Yunqing Hua
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Jing Zhang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Jia Shi
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Dan Li
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Yanfei Cheng
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Yunsha Zhang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Yuanli Chen
- Anhui Provincial International Science and Technology Cooperation Base for Major Metabolic Diseases and Nutritional Interventions, Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, School of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Guanwei Fan
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Chuanrui Ma
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
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Oshitari T. Translational Research and Therapies for Neuroprotection and Regeneration of the Optic Nerve and Retina: A Narrative Review. Int J Mol Sci 2024; 25:10485. [PMID: 39408817 PMCID: PMC11476551 DOI: 10.3390/ijms251910485] [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: 08/23/2024] [Revised: 09/23/2024] [Accepted: 09/27/2024] [Indexed: 10/20/2024] Open
Abstract
Most retinal and optic nerve diseases pose significant threats to vision, primarily due to irreversible retinal neuronal cell death, a permanent change, which is a critical factor in their pathogenesis. Conditions such as glaucoma, retinitis pigmentosa, diabetic retinopathy, and age-related macular degeneration are the top four leading causes of blindness among the elderly in Japan. While standard treatments-including reduction in intraocular pressure, anti-vascular endothelial growth factor therapies, and retinal photocoagulation-can partially delay disease progression, their therapeutic effects remain limited. To address these shortcomings, a range of neuroprotective and regenerative therapies, aimed at preventing retinal neuronal cell loss, have been extensively studied and increasingly integrated into clinical practice over the last two decades. Several of these neuroprotective therapies have achieved on-label usage worldwide. This narrative review introduces several neuroprotective and regenerative therapies for retinal and optic nerve diseases that have been successfully translated into clinical practice, providing foundational knowledge and success stories that serve as valuable references for researchers in the field.
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Affiliation(s)
- Toshiyuki Oshitari
- Department of Ophthalmology and Visual Science, Chiba University Graduate School of Medicine, Inohana 1-8-1, Chuo-ku, Chiba 260-8670, Japan; ; Tel.: +81-43-226-2124; Fax: +81-43-224-4162
- Department of Ophthalmology, International University of Health and Welfare School of Medicine, 4-3 Kozunomori, Narita 286-8686, Japan
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Bell G, Thoma A, Hargreaves IP, Lightfoot AP. The Role of Mitochondria in Statin-Induced Myopathy. Drug Saf 2024; 47:643-653. [PMID: 38492173 DOI: 10.1007/s40264-024-01413-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/22/2024] [Indexed: 03/18/2024]
Abstract
Statins represent the primary therapy for combatting hypercholesterolemia and reducing mortality from cardiovascular events. Despite their pleiotropic effects in lowering cholesterol synthesis, circulating cholesterol, as well as reducing the risk of other systemic diseases, statins have adverse events in a small, but significant, population of treated patients. The most prominent of these adverse effects is statin-induced myopathy, which lacks precise definition but is characterised by elevations in the muscle enzyme creatine kinase alongside musculoskeletal complaints, including pain, weakness and fatigue. The exact aetiology of statin-induced myopathy remains to be elucidated, although impaired mitochondrial function is thought to be an important underlying cause. This may result from or be the consequence of several factors including statin-induced inhibition of coenzyme Q10 (CoQ10) biosynthesis, impaired Ca2+ signalling and modified reactive oxygen species (ROS) generation. The purpose of this review article is to provide an update on the information available linking statin therapy with mitochondrial dysfunction and to outline any mechanistic insights, which may be beneficial in the future treatment of myopathic adverse events.
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Affiliation(s)
- Gavin Bell
- School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK
| | - Anastasia Thoma
- Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus
| | - Iain P Hargreaves
- School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK.
| | - Adam P Lightfoot
- Department of Life Sciences, Manchester Metropolitan University, Manchester, UK.
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7
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Freire de Carvalho J, Skare T. Coenzyme Q10 supplementation in rheumatic diseases: A systematic review. Clin Nutr ESPEN 2024; 59:63-69. [PMID: 38220408 DOI: 10.1016/j.clnesp.2023.11.016] [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: 05/02/2023] [Revised: 11/13/2023] [Accepted: 11/18/2023] [Indexed: 01/16/2024]
Abstract
Coenzyme Q10 (CoQ10) is a potent antioxidant and anti-inflammatory substance used to treat some rheumatic diseases. Our objective was to review the use of CoQ10 in rheumatic diseases. PubMed/Medline, Embase, Scopus, and Web of Science databases were searched for articles on CoQ10 and rheumatic diseases between 1966 and April 2023. Twenty articles were found, including 483 patients. The investigated conditions were Fibromyalgia (FM) with 15 studies, Rheumatoid Arthritis (RA) with 3 studies, and Antiphospholipid Syndrome (APS) with 2 studies. After CoQ10 supplementation, RA patients observed improvements in disease activity index, inflammatory biomarkers (erythrocyte sedimentation rate), cytokine levels, and a decrease in malondialdehyde. In APS, CoQ10 improved endothelial function and decreased prothrombotic and proinflammatory mediators. Regarding FM, in most of the studies, the patients observed improvements in pain, fatigue, sleep, tender points count, mood disorders, and scores on the Fibromyalgia Impact Questionnaire (FIQ). The drug was well tolerated, with reports of minor side effects in two studies. CoQ10 supplementation seems to be efficacious as a complementary treatment for RA and FM. Upcoming studies with larger samples and including other rheumatic diseases are welcome.
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Affiliation(s)
- Jozélio Freire de Carvalho
- Núcleo de Pesquisa em Doenças Crônicas não Transmissíveis (NUPEN), School of Nutrition from the Federal University of Bahia, Salvador, Bahia, Brazil.
| | - Thelma Skare
- Unit of Rheumatology, Hospital Evangélico Mackenzie, Curitiba, PR, Brazil
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8
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Ramesh R, Hariharan S, Sundar L. Stroke-Like Episodes and Epilepsy in a Patient with COQ8A-Related Coenzyme Q10 Deficiency. Ann Indian Acad Neurol 2023; 26:980-982. [PMID: 38229639 PMCID: PMC10789413 DOI: 10.4103/aian.aian_511_23] [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: 06/09/2023] [Revised: 08/13/2023] [Accepted: 08/14/2023] [Indexed: 01/18/2024] Open
Abstract
Coenzyme q10 (CoQ10) deficiency is an extremely uncommon disease that has very rarely been reported in adulthood. This case describes an elderly male with ataxia since adolescence, and visual disturbance since 40, presenting with recurrent episodes of seizures. Imaging revealed stroke-like episodes, with other immune and infective evaluations being negative. He was eventually diagnosed to have Primary CoQ10 deficiency secondary to CoQ8A mutation. This account highlights the challenges in diagnosing and managing primary Coenzyme Q10 deficiency, especially when it presents later in life with atypical features such as stroke-like episodes.
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Affiliation(s)
- Rithvik Ramesh
- Department of Neurology, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, Tamil Nadu, India
- Consultant Neurologist, Hariharan Diabetes and Heart Care Hospitals, Chennai, Tamil Nadu, India
| | - Sundar Hariharan
- Department of Cardiology, Hariharan Diabetes and Heart Care Hospitals, Chennai, Tamil Nadu, India
| | - Latha Sundar
- Department of Anasthesiology, Hariharan Diabetes and Heart Care Hospitals, Chennai, Tamil Nadu, India
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da Silva RHS, de Moura M, de Paula L, Arantes KC, da Silva M, de Amorim J, Miguel MP, Martins DB, de Melo e Silva D, Melo MM, Botelho AFM. Effects of coenzyme Q10 and N-acetylcysteine on experimental poisoning by paracetamol in Wistar rats. PLoS One 2023; 18:e0290268. [PMID: 37607187 PMCID: PMC10443853 DOI: 10.1371/journal.pone.0290268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 08/05/2023] [Indexed: 08/24/2023] Open
Abstract
Paracetamol (PAR) is a drug widely used in human and veterinary medicine as an analgesic and antipyretic, often involved in cases of intoxication. The most common clinical signs result from damage to red blood cells and hepatocytes, and this intoxication is considered a model for the induction of acute liver failure. In the present study, the hepatoprotective effects of coenzyme Q10 (CoQ10) and N-acetylcysteine (NAC) against experimental paracetamol (PAR) poisoning were analysed. Thirty-five adult Wistar rats (Rattus novergicus albinus) were randomly assigned to five groups, and thirty-one of these survived the treatments. Negative control group (CON-) received 1mL of 0.9% NaCl orally (PO). Other groups received 1.2g/kg of PAR (PO). Positive control group (CON+) received only PAR. NAC group received 800 mg/kg intraperitoneally (IP) of NAC 1h after the administration of PAR and at 12 h received 1mL of 0.9% NaCl, IP. The fourth group (CoQ10) received 1h and 12 h after intoxication, CoQ10 (10mg/kg IP). And the fifth group (NAC+CoQ10) received NAC (800mg/kg, IP) and CoQ10 (10mg/kg, IP). After 12 hours, the rats were euthanized and necropsied to collect liver and kidney tissues for histopathological evaluation and electronic microscopy. A single dose of PAR caused severe acute hepatitis. NAC couldn't reverse the liver and kidney damages. The group that received CoQ10 and NAC had moderate liver damage, while the group that received only CoQ10 had lower values of liver enzymes and mild liver and kidney damage. Animals that received treatment with CoQ10 or NAC+CoQ10 presented normal hepatocyte mitochondria and nuclei. Although CoQ10 couldn't reverse PAR organ damage, results indicate promising hepatoprotection in Wistar rats.
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Affiliation(s)
- Rayanne Henrique Santana da Silva
- Veterinary Toxicology Laboratory, Veterinary Hospital, Veterinary and Animal Science School, Federal University of Goiás, Goiânia, Goiás, Brazil
| | - Mariana de Moura
- Department of Genetics, Laboratory of Mutagenesis, Federal University of Goiás, Goiânia, Goiás, Brazil
| | - Larissa de Paula
- Pathology Sector, Instituto de Patologia Tropical e Saúde Pública, Federal University of Goiás, Goiânia, Goiás, Brazil
| | - Kelly Carolina Arantes
- Veterinary Toxicology Laboratory, Veterinary Hospital, Veterinary and Animal Science School, Federal University of Goiás, Goiânia, Goiás, Brazil
| | - Marina da Silva
- Veterinary Clinical Pathology Laboratory, Veterinary Hospital, Veterinary and Animal Science School, Federal University of Goiás, Goiânia, Goiás, Brazil
| | - Jaqueline de Amorim
- Veterinary Clinical Pathology Laboratory, Veterinary Hospital, Veterinary and Animal Science School, Federal University of Goiás, Goiânia, Goiás, Brazil
| | - Marina Pacheco Miguel
- Pathology Sector, Instituto de Patologia Tropical e Saúde Pública, Federal University of Goiás, Goiânia, Goiás, Brazil
| | - Danieli Brolo Martins
- Veterinary Clinical Pathology Laboratory, Veterinary Hospital, Veterinary and Animal Science School, Federal University of Goiás, Goiânia, Goiás, Brazil
| | - Daniela de Melo e Silva
- Department of Genetics, Laboratory of Mutagenesis, Federal University of Goiás, Goiânia, Goiás, Brazil
| | - Marília Martins Melo
- Veterinary Toxicology Laboratory, Veterinary Hospital, Veterinary and Animal Science School, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Ana Flávia Machado Botelho
- Veterinary Toxicology Laboratory, Veterinary Hospital, Veterinary and Animal Science School, Federal University of Goiás, Goiânia, Goiás, Brazil
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10
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Golomb BA, Han JH, Langsjoen PH, Dinkeloo E, Zemljic-Harpf AE. Statin Use in Relation to COVID-19 and Other Respiratory Infections: Muscle and Other Considerations. J Clin Med 2023; 12:4659. [PMID: 37510774 PMCID: PMC10380486 DOI: 10.3390/jcm12144659] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 07/04/2023] [Accepted: 07/11/2023] [Indexed: 07/30/2023] Open
Abstract
Statins have been widely advocated for use in COVID-19 based on large favorable observational associations buttressed by theoretical expected benefits. However, past favorable associations of statins to pre-COVID-19 infection outcomes (also buttressed by theoretical benefits) were unsupported in meta-analysis of RCTs, RR = 1.00. Initial RCTs in COVID-19 appear to follow this trajectory. Healthy-user/tolerator effects and indication bias may explain these disparities. Moreover, cholesterol drops in proportion to infection severity, so less severely affected individuals may be selected for statin use, contributing to apparent favorable statin associations to outcomes. Cholesterol transports fat-soluble antioxidants and immune-protective vitamins. Statins impair mitochondrial function in those most reliant on coenzyme Q10 (a mevalonate pathway product also transported on cholesterol)-i.e., those with existing mitochondrial compromise, whom data suggest bear increased risks from both COVID-19 and from statins. Thus, statin risks of adverse outcomes are amplified in those patients at risk of poor COVID-19 outcomes-i.e., those in whom adjunctive statin therapy may most likely be given. High reported rates of rhabdomyolysis in hospitalized COVID-19 patients underscore the notion that statin-related risks as well as benefits must be considered. Advocacy for statins in COVID-19 should be suspended pending clear evidence of RCT benefits, with careful attention to risk modifiers.
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Affiliation(s)
- Beatrice A. Golomb
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA;
| | - Jun Hee Han
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA;
| | | | - Eero Dinkeloo
- Navy and Marine Corps Public Health Center, Portsmouth, VA 23704, USA;
| | - Alice E. Zemljic-Harpf
- Department of Anesthesiology, University of California, San Diego, La Jolla, CA 92093, USA
- Veterans Affairs San Diego Healthcare System, San Diego, CA 92093, USA
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11
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Galper J, Kim WS, Dzamko N. LRRK2 and Lipid Pathways: Implications for Parkinson's Disease. Biomolecules 2022; 12:1597. [PMID: 36358947 PMCID: PMC9687231 DOI: 10.3390/biom12111597] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 10/28/2022] [Accepted: 10/28/2022] [Indexed: 04/10/2024] Open
Abstract
Genetic alterations in the LRRK2 gene, encoding leucine-rich repeat kinase 2, are a common risk factor for Parkinson's disease. How LRRK2 alterations lead to cell pathology is an area of ongoing investigation, however, multiple lines of evidence suggest a role for LRRK2 in lipid pathways. It is increasingly recognized that in addition to being energy reservoirs and structural entities, some lipids, including neural lipids, participate in signaling cascades. Early investigations revealed that LRRK2 localized to membranous and vesicular structures, suggesting an interaction of LRRK2 and lipids or lipid-associated proteins. LRRK2 substrates from the Rab GTPase family play a critical role in vesicle trafficking, lipid metabolism and lipid storage, all processes which rely on lipid dynamics. In addition, LRRK2 is associated with the phosphorylation and activity of enzymes that catabolize plasma membrane and lysosomal lipids. Furthermore, LRRK2 knockout studies have revealed that blood, brain and urine exhibit lipid level changes, including alterations to sterols, sphingolipids and phospholipids, respectively. In human LRRK2 mutation carriers, changes to sterols, sphingolipids, phospholipids, fatty acyls and glycerolipids are reported in multiple tissues. This review summarizes the evidence regarding associations between LRRK2 and lipids, and the functional consequences of LRRK2-associated lipid changes are discussed.
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Affiliation(s)
- Jasmin Galper
- Charles Perkins Centre and Faculty of Medicine and Health, School of Medical Sciences, University of Sydney, Camperdown, NSW 2050, Australia
| | - Woojin S Kim
- Brain and Mind Centre and Faculty of Medicine and Health, School of Medical Sciences, University of Sydney, Camperdown, NSW 2050, Australia
| | - Nicolas Dzamko
- Charles Perkins Centre and Faculty of Medicine and Health, School of Medical Sciences, University of Sydney, Camperdown, NSW 2050, Australia
- Brain and Mind Centre and Faculty of Medicine and Health, School of Medical Sciences, University of Sydney, Camperdown, NSW 2050, Australia
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12
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Gasmi A, Bjørklund G, Mujawdiya PK, Semenova Y, Piscopo S, Peana M. Coenzyme Q 10 in aging and disease. Crit Rev Food Sci Nutr 2022; 64:3907-3919. [PMID: 36300654 DOI: 10.1080/10408398.2022.2137724] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Coenzyme Q10 (CoQ10) is an essential component of the electron transport chain. It also acts as an antioxidant in cellular membranes. It can be endogenously produced in all cells by a specialized mitochondrial pathway. CoQ10 deficiency, which can result from aging or insufficient enzyme function, has been considered to increase oxidative stress. Some drugs, including statins and bisphosphonates, often used by older individuals, can interfere with enzymes responsible for endogenous CoQ10 synthesis. Oral supplementation with high doses of CoQ10 can increase both its circulating and intracellular levels and several clinical trials observed that its administration provided beneficial effects on different disorders such as cardiovascular disease and inflammation which have been associated with low CoQ10 levels and high oxidative stress. Moreover, CoQ10 has been suggested as a promising therapeutic agent to prevent and slow the progression of other diseases including metabolic syndrome and type 2 diabetes, neurodegenerative and male infertility. However, there is still a need for further studies and well-designed clinical trials involving a large number of participants undergoing longer treatments to assess the benefits of CoQ10 for these disorders.
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Affiliation(s)
- Amin Gasmi
- Société Francophone de Nutrithérapie et de Nutrigénétique Appliquée, Villeurbanne, France
| | - Geir Bjørklund
- Council for Nutritional and Environmental Medicine (CONEM), Mo i Rana, Norway
| | | | - Yuliya Semenova
- Nazarbayev University School of Medicine, Astana, Kazakhstan
| | - Salva Piscopo
- Société Francophone de Nutrithérapie et de Nutrigénétique Appliquée, Villeurbanne, France
| | - Massimiliano Peana
- Department of Chemical, Physical, Mathematical and Natural Sciences, University of Sassari, Sassari, Italy
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13
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Tippairote T, Bjørklund G, Gasmi A, Semenova Y, Peana M, Chirumbolo S, Hangan T. Combined Supplementation of Coenzyme Q 10 and Other Nutrients in Specific Medical Conditions. Nutrients 2022; 14:4383. [PMID: 36297067 PMCID: PMC9609170 DOI: 10.3390/nu14204383] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 10/07/2022] [Accepted: 10/15/2022] [Indexed: 07/23/2023] Open
Abstract
Coenzyme Q10 (CoQ10) is a compound with a crucial role in mitochondrial bioenergetics and membrane antioxidant protection. Despite the ubiquitous endogenous biosynthesis, specific medical conditions are associated with low circulating CoQ10 levels. However, previous studies of oral CoQ10 supplementation yielded inconsistent outcomes. In this article, we reviewed previous CoQ10 trials, either single or in combination with other nutrients, and stratified the study participants according to their metabolic statuses and medical conditions. The CoQ10 supplementation trials in elders reported many favorable outcomes. However, the single intervention was less promising when the host metabolic statuses were worsening with the likelihood of multiple nutrient insufficiencies, as in patients with an established diagnosis of metabolic or immune-related disorders. On the contrary, the mixed CoQ10 supplementation with other interacting nutrients created more promising impacts in hosts with compromised nutrient reserves. Furthermore, the results of either single or combined intervention will be less promising in far-advanced conditions with established damage, such as neurodegenerative disorders or cancers. With the limited high-level evidence studies on each host metabolic category, we could only conclude that the considerations of whether to take supplementation varied by the individuals' metabolic status and their nutrient reserves. Further studies are warranted.
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Affiliation(s)
- Torsak Tippairote
- Department of Nutritional and Environmental Medicine, HP Medical Center, Bangkok 10540, Thailand
| | - Geir Bjørklund
- Council for Nutritional and Environmental Medicine, Toften 24, 8610 Mo i Rana, Norway
| | - Amin Gasmi
- Société Francophone de Nutrithérapie et de Nutrigénétique Appliquée, 69100 Villeurbanne, France
| | - Yuliya Semenova
- School of Medicine, Nazarbayev University, Astana 020000, Kazakhstan
| | - Massimiliano Peana
- Department of Chemical, Physical, Mathematical and Natural Sciences, University of Sassari, via Vienna 2, 07100 Sassari, Italy
| | - Salvatore Chirumbolo
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37134 Verona, Italy
- CONEM Scientific Secretary, Strada Le Grazie 9, 37134 Verona, Italy
| | - Tony Hangan
- Faculty of Medicine, Ovidius University of Constanta, 900470 Constanta, Romania
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14
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Liang D, Minikes AM, Jiang X. Ferroptosis at the intersection of lipid metabolism and cellular signaling. Mol Cell 2022; 82:2215-2227. [PMID: 35390277 DOI: 10.1016/j.molcel.2022.03.022] [Citation(s) in RCA: 595] [Impact Index Per Article: 198.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 03/11/2022] [Accepted: 03/14/2022] [Indexed: 12/12/2022]
Abstract
Ferroptosis, a newly emerged form of regulated necrotic cell death, has been demonstrated to play an important role in multiple diseases including cancer, neurodegeneration, and ischemic organ injury. Mounting evidence also suggests its potential physiological function in tumor suppression and immunity. The execution of ferroptosis is driven by iron-dependent phospholipid peroxidation. As such, the metabolism of biological lipids regulates ferroptosis via controlling phospholipid peroxidation, as well as various other cellular processes relevant to phospholipid peroxidation. In this review, we provide a comprehensive analysis by focusing on how lipid metabolism impacts the initiation, propagation, and termination of phospholipid peroxidation; how multiple signal transduction pathways communicate with ferroptosis via modulating lipid metabolism; and how such intimate cross talk of ferroptosis with lipid metabolism and related signaling pathways can be exploited for the development of rational therapeutic strategies.
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Affiliation(s)
- Deguang Liang
- Cell Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065, USA
| | - Alexander M Minikes
- Cell Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065, USA; BCMB Allied Program, Weill Cornell Graduate School of Medical Sciences, 1300 York Ave., New York, NY 10065, USA
| | - Xuejun Jiang
- Cell Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065, USA.
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15
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Retinitis Pigmentosa (RP): The Role of Oxidative Stress in the Degenerative Process Progression. Biomedicines 2022; 10:biomedicines10030582. [PMID: 35327384 PMCID: PMC8945005 DOI: 10.3390/biomedicines10030582] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 02/20/2022] [Accepted: 02/23/2022] [Indexed: 02/05/2023] Open
Abstract
Purpose: Retinitis Pigmentosa is a term that includes a group of inherited bilateral and progressive retinal degenerations, with the involvement of rod photoreceptors, which frequently leads to blindness; oxidative stress may be involved in the degeneration progression as proposed by several recent studies. The goal of this study is to evaluate whether circulating free radicals taken from capillary blood are related to one of the most important features of Retinitis pigmentosa that can affect frequently patients: cystoid macular oedema (CME). Materials: A total of 186 patients with Retinitis Pigmentosa (range: 25−69 years) were enrolled; all patients completed an ophthalmologic examination and SD-OCT at baseline and were divided into three subgroups according to the SD-OCT features. ROS blood levels were determined using FORT with monitoring of free oxygen radicals. Results: Test levels of free oxygen radicals were significantly increased, almost twice, in RP patients showing cystoid macular oedema and significantly increased compared to the control group. (p < 0.001). Discussion: Our findings suggest that oxidative stress may speed cone photoreceptors’ morphological damage (CMT); because long lasting oxidative stress in the RP may cause oxidative damage, with animal models of RP suggesting this is a micromolecular mechanism of photoreceptors’ (cone) death, it can be similar to cone damage in human RP eyes. The limitations of this paper are the relatively small sample, the horizontal design of the study, and the lack of data about the levels of ROS in the vitreous body.
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16
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Tong HF, Lee HCH, Tong TYT, Lam SF, Sheng B, Chan KW, Li JKY, Tam HKV, Ching CK. Neurological manifestations in m.3243A>G-related disease triggered by metformin. J Diabetes Complications 2022; 36:108111. [PMID: 35123869 DOI: 10.1016/j.jdiacomp.2021.108111] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Revised: 12/06/2021] [Accepted: 12/18/2021] [Indexed: 12/26/2022]
Abstract
INTRODUCTION m.3243A>G-related disease has multi-systemic manifestations including diabetes mellitus. It is uncertain whether metformin would trigger neurological manifestations of this disease. This study aims to review the diagnosis and management of m.3243A>G-related diabetes genetically confirmed by our laboratory and to evaluate the risk of metformin use triggering neurological manifestations. METHODS Cases with m.3243A>G detected between 2009 and 2020 were reviewed. Cases with diabetes mellitus were included. Cases with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) before diabetes onset were excluded. Odds ratio was calculated for association between metformin use and newly developed neurological manifestations. RESULTS Sixteen patients were identified. Odds ratio for metformin use was 3.50 [0.37-33.0; p = 0.3287]. One illustrative case with clear causal relationship between metformin use and neurological manifestations was described in detail. CONCLUSION m.3243A>G-related diabetes mellitus is underdiagnosed. Red flags including positive family history, short stature, low body weight and hearing loss are often overlooked. Early diagnosis allows regular systemic assessment. In the era of precision medicine and novel therapies, it is prudent to avoid metformin as it could trigger neurological manifestations in this condition. Coenzyme Q10, DPP-IV inhibitors, SGLT2 inhibitors and GLP-1 receptor agonists may be considered.
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Affiliation(s)
- Hok-Fung Tong
- Kowloon West Cluster Laboratory Genetic Service, Department of Pathology, Princess Margaret Hospital, Hong Kong
| | - Han-Chih Hencher Lee
- Kowloon West Cluster Laboratory Genetic Service, Department of Pathology, Princess Margaret Hospital, Hong Kong
| | - Tsz-Yan Tammy Tong
- Kowloon West Cluster Laboratory Genetic Service, Department of Pathology, Princess Margaret Hospital, Hong Kong
| | - Siu-Fung Lam
- Department of Medicine and Geriatrics, Princess Margaret Hospital, Hong Kong; Health Sense Diabetes & Endocrine Centre, Hong Kong
| | - Bun Sheng
- Department of Medicine and Geriatrics, Princess Margaret Hospital, Hong Kong
| | - Kin-Wah Chan
- Department of Medicine and Geriatrics, Princess Margaret Hospital, Hong Kong
| | | | - Ho-Kee Vicki Tam
- Department of Medicine and Geriatrics, Caritas Medical Centre, Hong Kong
| | - Chor-Kwan Ching
- Kowloon West Cluster Laboratory Genetic Service, Department of Pathology, Princess Margaret Hospital, Hong Kong.
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17
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Aaseth J, Alexander J, Alehagen U. Coenzyme Q 10 supplementation - In ageing and disease. Mech Ageing Dev 2021; 197:111521. [PMID: 34129891 DOI: 10.1016/j.mad.2021.111521] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 06/01/2021] [Accepted: 06/09/2021] [Indexed: 12/21/2022]
Abstract
Coenzyme Q10 (CoQ10) is an essential component of the mitochondrial electron transport chain. It is also an antioxidant in cellular membranes and lipoproteins. All cells produce CoQ10 by a specialized cytoplasmatic-mitochondrial pathway. CoQ10 deficiency can result from genetic failure or ageing. Some drugs including statins, widely used by inter alia elderly, may inhibit endogenous CoQ10 synthesis. There are also chronic diseases with lower levels of CoQ10 in tissues and organs. High doses of CoQ10 may increase both circulating and intracellular levels, but there are conflicting results regarding bioavailability. Here, we review the current knowledge of CoQ10 biosynthesis and primary and acquired CoQ10 deficiency, and results from clinical trials based on CoQ10 supplementation. There are indications that supplementation positively affects mitochondrial deficiency syndrome and some of the symptoms of ageing. Cardiovascular disease and inflammation appear to be alleviated by the antioxidant effect of CoQ10. There is a need for further studies and well-designed clinical trials, with CoQ10 in a formulation of proven bioavailability, involving a greater number of participants undergoing longer treatments in order to assess the benefits of CoQ10 treatment in neurodegenerative disorders, as well as in metabolic syndrome and its complications.
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Affiliation(s)
- Jan Aaseth
- Research Department, Innlandet Hospital Trust, PO Box 104, N-2381, Brumunddal, Norway
| | - Jan Alexander
- Norwegian Institute of Public Health, PO Box 222 Skøyen, N-0213, Oslo, Norway.
| | - Urban Alehagen
- Division of Cardiovascular Medicine, Department of Medical and Health Sciences, Linköping University, Se-581 85, Linköping, Sweden
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18
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López-Pedrera C, Villalba JM, Patiño-Trives AM, Luque-Tévar M, Barbarroja N, Aguirre MÁ, Escudero-Contreras A, Pérez-Sánchez C. Therapeutic Potential and Immunomodulatory Role of Coenzyme Q 10 and Its Analogues in Systemic Autoimmune Diseases. Antioxidants (Basel) 2021; 10:antiox10040600. [PMID: 33924642 PMCID: PMC8069673 DOI: 10.3390/antiox10040600] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Revised: 04/06/2021] [Accepted: 04/09/2021] [Indexed: 12/14/2022] Open
Abstract
Coenzyme Q10 (CoQ10) is a mitochondrial electron carrier and a powerful lipophilic antioxidant located in membranes and plasma lipoproteins. CoQ10 is endogenously synthesized and obtained from the diet, which has raised interest in its therapeutic potential against pathologies related to mitochondrial dysfunction and enhanced oxidative stress. Novel formulations of solubilized CoQ10 and the stabilization of reduced CoQ10 (ubiquinol) have improved its bioavailability and efficacy. Synthetic analogues with increased solubility, such as idebenone, or accumulated selectively in mitochondria, such as MitoQ, have also demonstrated promising properties. CoQ10 has shown beneficial effects in autoimmune diseases. Leukocytes from antiphospholipid syndrome (APS) patients exhibit an oxidative perturbation closely related to the prothrombotic status. In vivo ubiquinol supplementation in APS modulated the overexpression of inflammatory and thrombotic risk-markers. Mitochondrial abnormalities also contribute to immune dysregulation and organ damage in systemic lupus erythematosus (SLE). Idebenone and MitoQ improved clinical and immunological features of lupus-like disease in mice. Clinical trials and experimental models have further demonstrated a therapeutic role for CoQ10 in Rheumatoid Arthritis, multiple sclerosis and type 1 diabetes. This review summarizes the effects of CoQ10 and its analogs in modulating processes involved in autoimmune disorders, highlighting the potential of these therapeutic approaches for patients with immune-mediated diseases.
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Affiliation(s)
- Chary López-Pedrera
- Rheumatology Service, Reina Sofia Hospital/Maimonides Institute for Research in Biomedicine of Córdoba (IMIBIC), University of Córdoba, 14004 Córdoba, Spain; (A.M.P.-T.); (M.L.-T.); (N.B.); (M.Á.A.); (A.E.-C.)
- Correspondence: ; Tel.: +34-957-213795
| | - José Manuel Villalba
- Department of Cell Biology, Immunology and Physiology, Agrifood Campus of International Excellence, University of Córdoba, ceiA3, 14014 Córdoba, Spain; (J.M.V.); (C.P.-S.)
| | - Alejandra Mª Patiño-Trives
- Rheumatology Service, Reina Sofia Hospital/Maimonides Institute for Research in Biomedicine of Córdoba (IMIBIC), University of Córdoba, 14004 Córdoba, Spain; (A.M.P.-T.); (M.L.-T.); (N.B.); (M.Á.A.); (A.E.-C.)
| | - Maria Luque-Tévar
- Rheumatology Service, Reina Sofia Hospital/Maimonides Institute for Research in Biomedicine of Córdoba (IMIBIC), University of Córdoba, 14004 Córdoba, Spain; (A.M.P.-T.); (M.L.-T.); (N.B.); (M.Á.A.); (A.E.-C.)
| | - Nuria Barbarroja
- Rheumatology Service, Reina Sofia Hospital/Maimonides Institute for Research in Biomedicine of Córdoba (IMIBIC), University of Córdoba, 14004 Córdoba, Spain; (A.M.P.-T.); (M.L.-T.); (N.B.); (M.Á.A.); (A.E.-C.)
| | - Mª Ángeles Aguirre
- Rheumatology Service, Reina Sofia Hospital/Maimonides Institute for Research in Biomedicine of Córdoba (IMIBIC), University of Córdoba, 14004 Córdoba, Spain; (A.M.P.-T.); (M.L.-T.); (N.B.); (M.Á.A.); (A.E.-C.)
| | - Alejandro Escudero-Contreras
- Rheumatology Service, Reina Sofia Hospital/Maimonides Institute for Research in Biomedicine of Córdoba (IMIBIC), University of Córdoba, 14004 Córdoba, Spain; (A.M.P.-T.); (M.L.-T.); (N.B.); (M.Á.A.); (A.E.-C.)
| | - Carlos Pérez-Sánchez
- Department of Cell Biology, Immunology and Physiology, Agrifood Campus of International Excellence, University of Córdoba, ceiA3, 14014 Córdoba, Spain; (J.M.V.); (C.P.-S.)
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19
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Marcheggiani F, Kordes S, Cirilli I, Orlando P, Silvestri S, Vogelsang A, Möller N, Blatt T, Weise JM, Damiani E, Tiano L. Anti-ageing effects of ubiquinone and ubiquinol in a senescence model of human dermal fibroblasts. Free Radic Biol Med 2021; 165:282-288. [PMID: 33482334 DOI: 10.1016/j.freeradbiomed.2021.01.032] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 12/22/2020] [Accepted: 01/14/2021] [Indexed: 12/18/2022]
Abstract
Coenzyme Q10 (CoQ10) is an endogenous lipophilic quinone found in equilibrium between its oxidised (ubiquinone) and reduced (ubiquinol) form, ubiquitous in biological membranes and endowed with antioxidant and bioenergetic properties, both crucial to the ageing process. CoQ10 biosynthesis decreases with age in different tissues including skin and its biosynthesis can be modulated by 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors such as statins. Statin-induced CoQ10 deprivation has previously been shown to be associated with the development of a senescence phenotype in cultured human dermal fibroblasts (HDF), hence this model was used to further investigate the role of CoQ10 in skin ageing. The present study aimed to compare the bioavailability of exogenously added CoQ10, in the form of ubiquinone or ubiquinol, to CoQ10-deprived HDF, and to determine their efficacy in rescuing the senescent phenotype induced by CoQ10 deprivation. First, additional senescence markers were implemented to further support the pro-ageing effect of statin-induced CoQ10 deprivation in HDF. Indeed, numerous senescence-associated secretory phenotype (SASP) markers such as p21, IL-8, CXCL1, and MMP-1 were upregulated, whereas components of the extracellular matrix were downregulated (elastin, collagen type 1). Next, we showed that CoQ10 supplementation to statin-treated HDF was able to counteract CoQ10 deprivation and rescued the development of selected senescence/ageing markers in HDF. Ubiquinol resulted more bioavailable than ubiquinone at the same concentration (15 μg/mL) and it significantly improved the cellular oxidative status even within isolated mitochondria highlighting an effective subcellular delivery. Ubiquinol was also more efficient compared to ubiquinone in reverting the expression of the senescent phenotype, quantified in terms of β-galactosidase positivity, p21, collagen type 1, and elastin at the gene and protein expression levels. In conclusion, our results highlight the pivotal role of CoQ10 for skin vitality and strongly support the use of both forms as a beneficial and effective anti-ageing skin care treatment.
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Affiliation(s)
- Fabio Marcheggiani
- Department of Life and Environmental Sciences, Polytechnic University of Marche, Via Brecce Bianche, Ancona, I-60131, Italy.
| | - Sebastian Kordes
- Research and Development, Beiersdorf AG, Unnastrasse 48, Hamburg, 20245, Germany.
| | - Ilenia Cirilli
- Department of Life and Environmental Sciences, Polytechnic University of Marche, Via Brecce Bianche, Ancona, I-60131, Italy; School of Pharmacy, University of Camerino, Via Gentile III da Varano, Camerino, 62032, Italy.
| | - Patrick Orlando
- Department of Life and Environmental Sciences, Polytechnic University of Marche, Via Brecce Bianche, Ancona, I-60131, Italy.
| | - Sonia Silvestri
- Department of Life and Environmental Sciences, Polytechnic University of Marche, Via Brecce Bianche, Ancona, I-60131, Italy.
| | - Alexandra Vogelsang
- Research and Development, Beiersdorf AG, Unnastrasse 48, Hamburg, 20245, Germany.
| | - Nadine Möller
- Research and Development, Beiersdorf AG, Unnastrasse 48, Hamburg, 20245, Germany.
| | - Thomas Blatt
- Research and Development, Beiersdorf AG, Unnastrasse 48, Hamburg, 20245, Germany.
| | - Julia M Weise
- Research and Development, Beiersdorf AG, Unnastrasse 48, Hamburg, 20245, Germany.
| | - Elisabetta Damiani
- Department of Life and Environmental Sciences, Polytechnic University of Marche, Via Brecce Bianche, Ancona, I-60131, Italy.
| | - Luca Tiano
- Department of Life and Environmental Sciences, Polytechnic University of Marche, Via Brecce Bianche, Ancona, I-60131, Italy.
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20
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Zhang Q, Dong J, Yu Z. Pleiotropic use of Statins as non-lipid-lowering drugs. Int J Biol Sci 2020; 16:2704-2711. [PMID: 33110390 PMCID: PMC7586431 DOI: 10.7150/ijbs.42965] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 08/01/2020] [Indexed: 12/14/2022] Open
Abstract
Statins, known as HMG-CoA reductase (HMGCR) inhibitors, have primarily been utilized for metabolic and angiographic medical applications because of their cholesterol-lowering effects. Similar to other drugs, statins may also induce a series of potential side effects. Statins inhibit the HMGCR (rate-limiting enzyme) activity in early stages of mevalonate pathway and then indirectly affect a number of intermediate products, including non-sterol isoprenoids (coenzyme Q10, dolichol etc.), which can result in impaired functions of body organs. Recently, scores of studies have uncovered additional functional mechanisms of statins in other diseases, such as diabetes mellitus, nervous system diseases, coronary heart disease, inflammation and cancers. This review aims to summarize the positive and adverse mechanisms of statin therapy. Statin care should be taken in the treatment of many diseases including cancers. Since the underlying mechanisms are not fully elucidated, future studies should spend more time and efforts on basic research to explore the mechanisms of statins.
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Affiliation(s)
- Qijia Zhang
- Digestive internal medicine and Department of infectious diseases, Zhuhai Hospital of Integrated Traditional Chinese and Western Medicine, Zhuhai, China
| | - Jianlong Dong
- College of Life Science, Northeast Agricultural University, Harbin, China
| | - Ze Yu
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou, China
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21
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Fernández-Del-Río L, Kelly ME, Contreras J, Bradley MC, James AM, Murphy MP, Payne GS, Clarke CF. Genes and lipids that impact uptake and assimilation of exogenous coenzyme Q in Saccharomyces cerevisiae. Free Radic Biol Med 2020; 154:105-118. [PMID: 32387128 PMCID: PMC7611304 DOI: 10.1016/j.freeradbiomed.2020.04.029] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 04/18/2020] [Accepted: 04/28/2020] [Indexed: 12/13/2022]
Abstract
Coenzyme Q (CoQ) is an essential player in the respiratory electron transport chain and is the only lipid-soluble antioxidant synthesized endogenously in mammalian and yeast cells. In humans, genetic mutations, pathologies, certain medical treatments, and aging, result in CoQ deficiencies, which are linked to mitochondrial, cardiovascular, and neurodegenerative diseases. The only strategy available for these patients is CoQ supplementation. CoQ supplements benefit a small subset of patients, but the poor solubility of CoQ greatly limits treatment efficacy. Consequently, the efficient delivery of CoQ to the mitochondria and restoration of respiratory function remains a major challenge. A better understanding of CoQ uptake and mitochondrial delivery is crucial to make this molecule a more efficient and effective therapeutic tool. In this study, we investigated the mechanism of CoQ uptake and distribution using the yeast Saccharomyces cerevisiae as a model organism. The addition of exogenous CoQ was tested for the ability to restore growth on non-fermentable medium in several strains that lack CoQ synthesis (coq mutants). Surprisingly, we discovered that the presence of CoQ biosynthetic intermediates impairs assimilation of CoQ into a functional respiratory chain in yeast cells. Moreover, a screen of 40 gene deletions considered to be candidates to prevent exogenous CoQ from rescuing growth of the CoQ-less coq2Δ mutant, identified six novel genes (CDC10, RTS1, RVS161, RVS167, VPS1, and NAT3) as necessary for efficient trafficking of CoQ to mitochondria. The proteins encoded by these genes represent essential steps in the pathways responsible for transport of exogenously supplied CoQ to its functional sites in the cell, and definitively associate CoQ distribution with endocytosis and intracellular vesicular trafficking pathways conserved from yeast to human cells.
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Affiliation(s)
- Lucía Fernández-Del-Río
- Department of Chemistry and Biochemistry and the Molecular Biology Institute, University of California, Los Angeles, USA
| | - Miranda E Kelly
- Department of Chemistry and Biochemistry and the Molecular Biology Institute, University of California, Los Angeles, USA
| | - Jaime Contreras
- Department of Chemistry and Biochemistry and the Molecular Biology Institute, University of California, Los Angeles, USA
| | - Michelle C Bradley
- Department of Chemistry and Biochemistry and the Molecular Biology Institute, University of California, Los Angeles, USA
| | - Andrew M James
- MRC Mitochondrial Biology Unit, University of Cambridge, UK
| | - Michael P Murphy
- MRC Mitochondrial Biology Unit, University of Cambridge, UK; Department of Medicine, University of Cambridge, UK
| | - Gregory S Payne
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, USA
| | - Catherine F Clarke
- Department of Chemistry and Biochemistry and the Molecular Biology Institute, University of California, Los Angeles, USA.
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Ibrahim Fouad G. Synergistic anti-atherosclerotic role of combined treatment of omega-3 and co-enzyme Q10 in hypercholesterolemia-induced obese rats. Heliyon 2020; 6:e03659. [PMID: 32258512 PMCID: PMC7118318 DOI: 10.1016/j.heliyon.2020.e03659] [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: 10/10/2019] [Revised: 12/16/2019] [Accepted: 03/20/2020] [Indexed: 01/13/2023] Open
Abstract
Hypercholesterolemia is a metabolic disorder associated with atherosclerosis. This study aimed to investigate the effects of omega-3 and/or coenzyme Q10 (CoQ10) on hypercholesterolemia-induced atherosclerosis. Rats were divided into five groups; (1): served as the negative control, (2): served as hypercholesterolemic (HC) control, (3): HC-rats administrated omega-3 orally, (4): HC-rats administrated CoQ10 orally, and (5): HC-rats administered the combination treatment of both omega-3 and CoQ10. Lipid profile was assayed and cardiovascular risk indices were calculated. Serum levels of Adiponectin (APN) and creatine kinase (CK-MB) were determined using ELISA. Besides, oxidative stress markers, malondialdehyde (MDA), nitric oxide (NO) and glutathione (GSH) were assayed in the heart homogenate. Histopathological investigation of the aortae and heart tissues were investigated. The results revealed that atherogenic HC-rats demonstrated a significant elevation in lipid profiles, except for HDL-C, along with decreased levels of APN, but increased CK-MB activities. Hypercholesterolemia increased lipid peroxidation, reduced NO production, and decreased GSH content in the cardiac tissue. Treatment of atherogenic HC-rats with omega-3 and/or CoQ10 improved dyslipidemia and ameliorated most of the HC-induced biochemical and histopathological changes. The histological observations of aortae and cardiac tissues validated our biochemical results. We concluded that the combined treatment of nutraceuticals such as omega-3 and CoQ10 demonstrated the best outcome, demonstrating their anti-hyperlipidemic, cardioprotective, and atheroprotective potentials. Together, this study supports a beneficial role of dietary co-administration of omega-3 and CoQ10 in obese patients who are prone to develop cardiovascular disorders.
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Affiliation(s)
- Ghadha Ibrahim Fouad
- Department of Therapeutic Chemistry, National Research Centre, 33 El-Bohouth Street, Dokki, Cairo, 12622, Egypt
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23
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Bahrami A, Bo S, Jamialahmadi T, Sahebkar A. Effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on ageing: Molecular mechanisms. Ageing Res Rev 2020; 58:101024. [PMID: 32006687 DOI: 10.1016/j.arr.2020.101024] [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: 05/20/2019] [Revised: 12/11/2019] [Accepted: 01/27/2020] [Indexed: 12/15/2022]
Abstract
Human ageing is determined by degenerative alterations and processes with different manifestations such as gradual organ dysfunction, tissue function loss, increased population of aged (senescent) cells, incapability of maintaining homeostasis and reduced repair capacity, which collectively lead to an increased risk of diseases and death. The inhibitors of HMG-CoA reductase (statins) are the most widely used lipid-lowering agents, which can reduce cardiovascular morbidity and mortality. Accumulating evidence has documented several pleiotropic effects of statins in addition to their lipid-lowering properties. Recently, several studies have highlighted that statins may have the potential to delay the ageing process and inhibit the onset of senescence. In this review, we focused on the anti-ageing mechanisms of statin drugs and their effects on cardiovascular and non-cardiovascular diseases.
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Barros S, Coimbra AM, Alves N, Pinheiro M, Quintana JB, Santos MM, Neuparth T. Chronic exposure to environmentally relevant levels of simvastatin disrupts zebrafish brain gene signaling involved in energy metabolism. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART A 2020; 83:113-125. [PMID: 32116137 DOI: 10.1080/15287394.2020.1733722] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Simvastatin (SIM), a hypocholesterolaemic drug belonging to the statins group, is a widely prescribed pharmaceutical for prevention of cardiovascular diseases. Several studies showed that lipophilic statins, as SIM, cross the blood-brain barrier and interfere with the energy metabolism of the central nervous system in humans and mammalian models. In fish and other aquatic organisms, the effects of SIM on the brain energy metabolism are unknown, particularly following exposure to low environmentally relevant concentrations. Therefore, the present study aimed at investigating the influence of SIM on gene signaling pathways involved in brain energy metabolism of adult zebrafish (Danio rerio) following chronic exposure (90 days) to environmentally relevant SIM concentrations ranging from 8 ng/L to 1000 ng/L. Real-time PCR was used to determine the transcript levels of several genes involved in different pathways of the brain energy metabolism (glut1b, gapdh, acadm, accα, fasn, idh3a, cox4i1, and cox5aa). The findings here reported integrated well with ecological and biochemical responses obtained in a parallel study. Data demonstrated that SIM modulates transcription of key genes involved in the mitochondrial electron transport chain, in glucose transport and metabolism, in fatty acid synthesis and β-oxidation. Further, SIM exposure led to a sex-dependent transcription profile for some of the studied genes. Overall, the present study demonstrated, for the first time, that SIM modulates gene regulation of key pathways involved in the energy metabolism in fish brain at environmentally relevant concentrations.
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Affiliation(s)
- Susana Barros
- CIMAR/CIIMAR-Interdisciplinary Centre of Marine and Environmental Research, Endocrine Disruptors and Emerging Contaminants Group, University of Porto, Matosinhos, Portugal
- Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal
| | - Ana M Coimbra
- Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal
| | - Nélson Alves
- CIMAR/CIIMAR-Interdisciplinary Centre of Marine and Environmental Research, Endocrine Disruptors and Emerging Contaminants Group, University of Porto, Matosinhos, Portugal
| | - Marlene Pinheiro
- CIMAR/CIIMAR-Interdisciplinary Centre of Marine and Environmental Research, Endocrine Disruptors and Emerging Contaminants Group, University of Porto, Matosinhos, Portugal
| | - José Benito Quintana
- Department of Analytical Chemistry, Nutrition and Food Sciences, IAQBUS - Institute of Research on Chemical and Biological Analysis, Universidade De Santiago De Compostela, Santiago De Compostela, Spain
| | - Miguel M Santos
- CIMAR/CIIMAR-Interdisciplinary Centre of Marine and Environmental Research, Endocrine Disruptors and Emerging Contaminants Group, University of Porto, Matosinhos, Portugal
- FCUP, Department of Biology, Faculty of Sciences, University of Porto (U. Porto), Porto, Portugal
| | - Teresa Neuparth
- CIMAR/CIIMAR-Interdisciplinary Centre of Marine and Environmental Research, Endocrine Disruptors and Emerging Contaminants Group, University of Porto, Matosinhos, Portugal
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25
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Kukes VG, Parfenova OK, Romanov BK, Prokofiev AB, Parfenova EV, Sidorov NG, Gazdanova AA, Pavlova LI, Zozina VI, Andreev AD, Aleksandrova TV, Chernova SV, Ramenskaya GV. The Mechanism of Action of Ethoxidol on Oxidative Stress Indices in Heart Failure and Hypotension. Sovrem Tekhnologii Med 2020; 12:67-72. [PMID: 34513055 PMCID: PMC8353682 DOI: 10.17691/stm2020.12.2.08] [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: 10/22/2019] [Indexed: 11/14/2022] Open
Abstract
The aim of the investigation was to study the effect of 2-ethyl-6-methyl-3-hydroxypyridine malate (Ethoxidol) on the concentration of oxidative stress metabolites in patients with chronic heart failure (CHF) and hypertension. Materials and Methods 126 patients with FC I-III CHF have been examined. In addition to their individual therapy these patients received intravenous infusions of Ethoxidol. Blood content of 2,3-diphosphoglycerate (2,3-DPG), oxygen tension (рО2), pH, concentration of total peroxides, lactate, and aldosterone were identified. 2,3-DPG levels (g/L erythrocytes) in whole blood samples were determined by an enzyme assay using the reagent kit (Rosh, Germany), values of рО2, рСО2, рН, lactate in the venous blood were measured using gas analyzer Stat Profil pHOx Ultra (Nova Biomedical, USA). Indices of oxidative stress, i.e. the concentration of plasma total peroxides, were investigated by ELISA using OxyStat kit (Biomedica, Austria). Peripheral venous blood samples were collected from all patients before and 6 days after the daily intravenous Ethoxidol infusion. Results In patients with FC I, II, III CHF, on day 7 after intravenous Ethoxidol infusion at a dose of 100 mg/day, statistically significant growth (p=0.0002) of PaO2 level by 15.7, 17.4, and 22.8%, respectively, was noted. In patients with FC I, II, III CHF in the group receiving standard therapy, statistically significant (p=0.002) reduction of 2,3-DPG level by 2.7, 2.4, and 4.0%, respectively, was registered. On day 7 after the infusion of Ethoxidol at a dose of 100 mg/day, its decrease by 5.7, 10.5, and 26.2%, respectively (p<0.0001), was also observed. Conclusion The increased concentrations of active oxygen forms have been established to negatively affect various bodily functions and adversely influence the pathophysiology of numerous diseases. Application of antioxidants, including Ethoxidol presented by us in this article, may become a clue to the development of preventive measures for many serious diseases.
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Affiliation(s)
- V G Kukes
- Academician of the Russian Academy of Sciences, Professor, Department of Clinical Pharmacology and Propedeutics of Internal Diseases, I.M. Sechenov First Moscow State Medical University (Sechenov University), 8/2 Malaya Trubetskaya St., Moscow, 119991, Russia; Head of the Scientific Direction "Pharmacology", Scientific Centre for Expert Evaluation of Medicinal Products of the Ministry of Health of the Russian Federation, 8, Bld. 2, Petrovsky Boulevard, Moscow, 127051, Russia
| | - O K Parfenova
- Student, A.P. Nelyubin Institute of Pharmacy, I.M. Sechenov First Moscow State Medical University (Sechenov University), 8/2 Malaya Trubetskaya St., Moscow, 119991, Russia
| | - B K Romanov
- Deputy Director General on Scientific Work, Scientific Centre for Expert Evaluation of Medicinal Products of the Ministry of Health of the Russian Federation, 8, Bld. 2, Petrovsky Boulevard, Moscow, 127051, Russia
| | - A B Prokofiev
- Professor, Department of Clinical Pharmacology and Propedeutics of Internal Diseases, I.M. Sechenov First Moscow State Medical University (Sechenov University), 8/2 Malaya Trubetskaya St., Moscow, 119991, Russia; Director of the Clinical Pharmacology Center, Scientific Centre for Expert Evaluation of Medicinal Products of the Ministry of Health of the Russian Federation, 8, Bld. 2, Petrovsky Boulevard, Moscow, 127051, Russia
| | - E V Parfenova
- Professor, Corresponding Member of the Russian Academy of Sciences, Deputy Director General, National Medical Research Center of Cardiology of the Ministry of Health of the Russian Federation, 15A 3 Cherepkovskaya St., Moscow, 121552, Russia; Director of the Institute of Experimental Cardiology, National Medical Research Center of Cardiology of the Ministry of Health of the Russian Federation, 15A 3 Cherepkovskaya St., Moscow, 121552, Russia
| | - N G Sidorov
- Student, A.P. Nelyubin Institute of Pharmacy, I.M. Sechenov First Moscow State Medical University (Sechenov University), 8/2 Malaya Trubetskaya St., Moscow, 119991, Russia
| | - A A Gazdanova
- Associate Professor, Department of Clinical Pharmacology and Propedeutics of Internal Diseases, I.M. Sechenov First Moscow State Medical University (Sechenov University), 8/2 Malaya Trubetskaya St., Moscow, 119991, Russia
| | - L I Pavlova
- Associate Professor, Department of Clinical Pharmacology and Propedeutics of Internal Diseases, I.M. Sechenov First Moscow State Medical University (Sechenov University), 8/2 Malaya Trubetskaya St., Moscow, 119991, Russia
| | - V I Zozina
- PhD Student, Department of Clinical Pharmacology and Propedeutics of Internal Diseases, I.M. Sechenov First Moscow State Medical University (Sechenov University), 8/2 Malaya Trubetskaya St., Moscow, 119991, Russia
| | - A D Andreev
- Student, Medical Faculty, I.M. Sechenov First Moscow State Medical University (Sechenov University), 8/2 Malaya Trubetskaya St., Moscow, 119991, Russia
| | - T V Aleksandrova
- Senior Analyst, Scientific Centre for Expert Evaluation of Medicinal Products of the Ministry of Health of the Russian Federation, 8, Bld. 2, Petrovsky Boulevard, Moscow, 127051, Russia
| | - S V Chernova
- Associate Professor, Department of Pharmaceutical and Toxicological Chemistry named after A.P. Arzamastsev, I.M. Sechenov First Moscow State Medical University (Sechenov University), 8/2 Malaya Trubetskaya St., Moscow, 119991, Russia
| | - G V Ramenskaya
- Director, A.P. Nelyubin Institute of Pharmacy, I.M. Sechenov First Moscow State Medical University (Sechenov University), 8/2 Malaya Trubetskaya St., Moscow, 119991, Russia; Head of the Department of Pharmaceutical and Toxicological Chemistry named after A.P. Arzamastsev, I.M. Sechenov First Moscow State Medical University (Sechenov University), 8/2 Malaya Trubetskaya St., Moscow, 119991, Russia
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Tabatabaei-Malazy O, Ardeshirlarijani E, Namazi N, Nikfar S, Jalili RB, Larijani B. Dietary antioxidative supplements and diabetic retinopathy; a systematic review. J Diabetes Metab Disord 2019; 18:705-716. [PMID: 31890694 PMCID: PMC6915253 DOI: 10.1007/s40200-019-00434-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Accepted: 08/20/2019] [Indexed: 12/11/2022]
Abstract
PURPOSE There is controversial data regarding the effects of dietary antioxidative supplements on diabetic retinopathy (DR). We conducted a systematic review of both observational and randomized controlled clinical trials (RCTs) to clarify whether they are effective or not. METHODS All observational and RCTs conducted by antioxidative supplements on DR published up to 1 January 2018 in PubMed, Web of Sciences, Scopus and Cochrane Library databases were included. Exclusion criteria were animal studies, and studies conducted in Type 1 diabetes mellitus (T1DM), children or pregnant women. Main outcome measures were reporting the incidence or progression of DR in T2DM by assessment of visual fields, and measurements of oxidative and antioxidative biomarkers. The quality of reporting of included articles and risk of bias were assessed. RESULTS Finally, we reached 14 observational studies and 7 RCTs that conducted on 256,259 subjects. Due to severe methodological heterogeneity, only qualitative synthesis was carried. All studies were reported a significantly lower level of antioxidants and higher level of oxidative stress biomarkers in DR compared with others. There was an inverse significant correlation between vitamin C and malondialdehyde (MDA) (r = -0.81) or DNA damage (r = -0.41). These figures were statistically significant between vitamin E and MDA (r = 0.77) or superoxide dismutase (r = 0.44). Coefficient of correlation between MDA and zinc (-0.82), coenzyme Q10 (0.56), and magnesium (-0.73) was significant. Multi-oxidants trials were shown non-significant beneficial effects on DR. CONCLUSIONS Although our study supports the positive effects of antioxidative supplements on DR, more high quality studies are needed to confirm.
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Affiliation(s)
- Ozra Tabatabaei-Malazy
- Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Nazli Namazi
- Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Shekoufeh Nikfar
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Personalized Medicine Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Evidence-based Evaluation of Cost-Effectiveness and Clinical Outcomes Group, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran
- Department of Pharmacoeconomics and Pharmaceutical Administration, Faculty of Pharmacy and Pharmaceutical Policy Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Baradar Jalili
- Department of Surgery, University of British Columbia, Vancouver, British Columbia Canada
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
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27
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Orlando P, Chellan N, Louw J, Tiano L, Cirilli I, Dludla P, Joubert E, Muller CJF. Aspalathin-Rich Green Rooibos Extract Lowers LDL-Cholesterol and Oxidative Status in High-Fat Diet-Induced Diabetic Vervet Monkeys. Molecules 2019; 24:molecules24091713. [PMID: 31052590 PMCID: PMC6539440 DOI: 10.3390/molecules24091713] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 04/29/2019] [Accepted: 05/01/2019] [Indexed: 12/17/2022] Open
Abstract
Type 2 diabetic patients possess a two to four-fold-increased risk for cardiovascular diseases (CVD). Hyperglycemia, oxidative stress associated with endothelial dysfunction and dyslipidemia are regarded as pro-atherogenic mechanisms of CVD. In this study, high-fat diet-induced diabetic and non-diabetic vervet monkeys were treated with 90 mg/kg of aspalathin-rich green rooibos extract (Afriplex GRT) for 28 days, followed by a 1-month wash-out period. Supplementation showed improvements in both the intravenous glucose tolerance test (IVGTT) glycemic area under curve (AUC) and total cholesterol (due to a decrease of the low-density lipoprotein [LDL]) values in diabetics, while non-diabetic monkeys benefited from an increase in high-density lipoprotein (HDL) levels. No variation of plasma coenzyme Q10 (CoQ10) were found, suggesting that the LDL-lowering effect of Afriplex GRT could be related to its ability to modulate the mevalonate pathway differently from statins. Concerning the plasma oxidative status, a decrease in percentage of oxidized CoQ10 and circulating oxidized LDL (ox-LDL) levels after supplementation was observed in diabetics. Finally, the direct correlation between the amount of oxidized LDL and total LDL concentration, and the inverse correlation between ox-LDL and plasma CoQ10 levels, detected in the diabetic monkeys highlighted the potential cardiovascular protective role of green rooibos extract. Taken together, these findings suggest that Afriplex GRT could counteract hyperglycemia, oxidative stress and dyslipidemia, thereby lowering fundamental cardiovascular risk factors associated with diabetes.
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Affiliation(s)
- Patrick Orlando
- Department of Life and Environmental Sciences, DiSVA-Biochemistry, Polytechnic University of Marche, 60131 Ancona, Italy.
| | - Nireshni Chellan
- Biomedical Research and Innovation Platform (BRIP), South African Medical Research Council, Tygerberg 7505, South Africa.
- Division of Medical Physiology, Faculty of Health Sciences, Stellenbosch University, Tygerberg 7505, South Africa.
| | - Johan Louw
- Biomedical Research and Innovation Platform (BRIP), South African Medical Research Council, Tygerberg 7505, South Africa.
- Division of Medical Physiology, Faculty of Health Sciences, Stellenbosch University, Tygerberg 7505, South Africa.
- Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa 3886, South Africa.
| | - Luca Tiano
- Department of Life and Environmental Sciences, DiSVA-Biochemistry, Polytechnic University of Marche, 60131 Ancona, Italy.
| | - Ilenia Cirilli
- Department of Clinical Dental Sciences, Polytechnic University of Marche, 60131 Ancona, Italy.
| | - Phiwayinkosi Dludla
- Biomedical Research and Innovation Platform (BRIP), South African Medical Research Council, Tygerberg 7505, South Africa.
| | - Elizabeth Joubert
- Plant Bioactives Group, Post-Harvest and Agro-Processing Technologies, Agricultural Research Council (ARC), Infruitec-Nietvoorbij, Private Bag X5026, Stellenbosch 7599, South Africa.
- Department of Food Science, Stellenbosch University, Private Bag X1, Matieland 7602, South Africa.
| | - Christo J F Muller
- Biomedical Research and Innovation Platform (BRIP), South African Medical Research Council, Tygerberg 7505, South Africa.
- Division of Medical Physiology, Faculty of Health Sciences, Stellenbosch University, Tygerberg 7505, South Africa.
- Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa 3886, South Africa.
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28
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Veloso CD, Belew GD, Ferreira LL, Grilo LF, Jones JG, Portincasa P, Sardão VA, Oliveira PJ. A Mitochondrial Approach to Cardiovascular Risk and Disease. Curr Pharm Des 2019; 25:3175-3194. [PMID: 31470786 DOI: 10.2174/1389203720666190830163735] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 08/24/2019] [Indexed: 12/16/2022]
Abstract
BACKGROUND Cardiovascular diseases (CVDs) are a leading risk factor for mortality worldwide and the number of CVDs victims is predicted to rise through 2030. While several external parameters (genetic, behavioral, environmental and physiological) contribute to cardiovascular morbidity and mortality; intrinsic metabolic and functional determinants such as insulin resistance, hyperglycemia, inflammation, high blood pressure and dyslipidemia are considered to be dominant factors. METHODS Pubmed searches were performed using different keywords related with mitochondria and cardiovascular disease and risk. In vitro, animal and human results were extracted from the hits obtained. RESULTS High cardiac energy demand is sustained by mitochondrial ATP production, and abnormal mitochondrial function has been associated with several lifestyle- and aging-related pathologies in the developed world such as diabetes, non-alcoholic fatty liver disease (NAFLD) and kidney diseases, that in turn can lead to cardiac injury. In order to delay cardiac mitochondrial dysfunction in the context of cardiovascular risk, regular physical activity has been shown to improve mitochondrial parameters and myocardial tolerance to ischemia-reperfusion (IR). Furthermore, pharmacological interventions can prevent the risk of CVDs. Therapeutic agents that can target mitochondria, decreasing ROS production and improve its function have been intensively researched. One example is the mitochondria-targeted antioxidant MitoQ10, which already showed beneficial effects in hypertensive rat models. Carvedilol or antidiabetic drugs also showed protective effects by preventing cardiac mitochondrial oxidative damage. CONCLUSION This review highlights the role of mitochondrial dysfunction in CVDs, also show-casing several approaches that act by improving mitochondrial function in the heart, contributing to decrease some of the risk factors associated with CVDs.
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Affiliation(s)
- Caroline D Veloso
- CNC-Center for Neuroscience and Cell Biology, UC-Biotech, University of Coimbra, Biocant Park, Cantanhede, Portugal
| | - Getachew D Belew
- CNC-Center for Neuroscience and Cell Biology, UC-Biotech, University of Coimbra, Biocant Park, Cantanhede, Portugal
| | - Luciana L Ferreira
- CNC-Center for Neuroscience and Cell Biology, UC-Biotech, University of Coimbra, Biocant Park, Cantanhede, Portugal
| | - Luís F Grilo
- CNC-Center for Neuroscience and Cell Biology, UC-Biotech, University of Coimbra, Biocant Park, Cantanhede, Portugal
| | - John G Jones
- CNC-Center for Neuroscience and Cell Biology, UC-Biotech, University of Coimbra, Biocant Park, Cantanhede, Portugal
| | - Piero Portincasa
- Clinica Medica "A. Murri", Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro" Medical School, Bari, Italy
| | - Vilma A Sardão
- CNC-Center for Neuroscience and Cell Biology, UC-Biotech, University of Coimbra, Biocant Park, Cantanhede, Portugal
| | - Paulo J Oliveira
- CNC-Center for Neuroscience and Cell Biology, UC-Biotech, University of Coimbra, Biocant Park, Cantanhede, Portugal
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29
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Gröber U, Schmidt J, Kisters K. Important drug-micronutrient interactions: A selection for clinical practice. Crit Rev Food Sci Nutr 2018; 60:257-275. [PMID: 30580552 DOI: 10.1080/10408398.2018.1522613] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Interactions between drugs and micronutrients have received only little or no attention in the medical and pharmaceutical world in the past. Since more and more pharmaceutics are used for the treatment of patients, this topic is increasingly relevant. As such interactions - depending on the duration of treatment and the status of micronutrients - impact the health of the patient and the action of the drugs, physicians and pharmacists should pay more attention to such interactions in the future. This review aims to sensitize physicians and pharmacists on drug micronutrient interactions with selected examples of widely pescribed drugs that can precipitate micronutrient deficiencies. In this context, the pharmacist, as a drug expert, assumes a particular role. Like no other professional in the health care sector, he is particularly predestined and called up to respond to this task. The following article intends to point out the relevance of mutual interactions between micronutrients and various examples of widely used drugs, without claiming to be exhaustive.
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Affiliation(s)
- Uwe Gröber
- Academy of Micronutrient Medicine, Essen, Germany
| | | | - Klaus Kisters
- Academy of Micronutrient Medicine, Essen, Germany.,Medizinische Klinik I, St. Anna Hospital, Herne, Germany
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30
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Zhang X, Liu H, Hao Y, Xu L, Zhang T, Liu Y, Guo L, Zhu L, Pei Z. Coenzyme Q10 protects against hyperlipidemia-induced cardiac damage in apolipoprotein E-deficient mice. Lipids Health Dis 2018; 17:279. [PMID: 30526612 PMCID: PMC6286539 DOI: 10.1186/s12944-018-0928-9] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Accepted: 11/26/2018] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Hyperlipidemia is a well-established risk factor for cardiac damage, which can lead to cardiovascular diseases. Many studies have shown that Coenzyme Q10(CoQ10) protects against cardiac damage in vivo. The aim of this study was to investigate the possible protective effects of CoQ10 against cardiac damage in apolipoprotein E-deficient (ApoE-/-) mice. METHODS Eight-week-old male C57BL/6 and ApoE-/- mice were randomly divided into four groups: C57BL/6 mice fed a normal diet (C57BL/6 group); C57BL/6 mice fed a normal diet + CoQ10 (C57BL/6 + CoQ10 group); ApoE-/- mice fed a high-fat diet (ApoE-/- HD group), and ApoE-/- mice fed a high-fat diet + CoQ10 (ApoE-/- HD + CoQ10 group). All groups were fed the different diets for 16 weeks. Blood samples were obtained from the inferior vena cava and collected in serum tubes. The samples were then stored at - 80 °C until used. Coronal sections of heart tissues were fixed in 10% formalin and then embedded in paraffin for histological evaluation. The remainder of the heart tissues was snap-frozen in liquid nitrogen for mRNA or immunohistochemical analysis. RESULTS The metabolic parameters such as total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-c), and triglycerides (TG) levels were lower in ApoE-/-HD + CoQ10 mice than in ApoE-/- HD mice. There were significant pathophysiological changes (H&E, PAS, Masson and CD68 staining) in ApoE-/- mice in the HD group compared with those in the HD + CoQ10 group. CoQ10 reduced HD-induced cardiac tissue damage via autophagy (p62 and LC3), as evidenced by immunoblotting, immunohistochemistry, and RT-qPCR. CoQ10 also inhibited inflammation (IL-6 and TNF-α) gene expression in ApoE-/- mice. CONCLUSIONS These results indicate that CoQ10 is a potential therapeutic target for cardiac damage caused by hyperlipidemia.
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Affiliation(s)
- Xiaoqing Zhang
- Department of Infection, Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Dalian, China
| | - Hongyang Liu
- Department of Heart Intensive Care Unit, the First Affiliated Hospital of Dalian Medical University, No.193 Lianhe Road, Dalian, China
| | - Yuhua Hao
- Department of Infection, Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Dalian, China
| | - Lulu Xu
- Department of Infection, Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Dalian, China
| | - Tiemei Zhang
- Department of Infection, Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Dalian, China
| | - Yingshu Liu
- Department of Endocrinology, Dalian Municipal Central Hospital, 42 Xuegong Road, Dalian, China
| | - Lipeng Guo
- Department of Cardiology, Dalian Third People' Hospital Affiliated to Dalian Medical University, No.40 Qianshan Road, Dalian, China
| | - Liyue Zhu
- Rehabilitation Center, Zhejiang Hospital, 12 Lingyin Road, Hangzhou, Zhejiang, China
| | - Zuowei Pei
- Department of Cardiology, Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Dalian, China.
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Lorza‐Gil E, de Souza JC, García‐Arévalo M, Vettorazzi JF, Marques AC, Salerno AG, Trigo JR, Oliveira HCF. Coenzyme Q
10
protects against β‐cell toxicity induced by pravastatin treatment of hypercholesterolemia. J Cell Physiol 2018; 234:11047-11059. [DOI: 10.1002/jcp.27932] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Accepted: 10/25/2018] [Indexed: 12/28/2022]
Affiliation(s)
- Estela Lorza‐Gil
- Department of Structural and Functional Biology Biology Institute, State University of Campinas Campinas SP Brazil
| | - Jane C. de Souza
- Department of Structural and Functional Biology Biology Institute, State University of Campinas Campinas SP Brazil
| | - Marta García‐Arévalo
- Department of Structural and Functional Biology Biology Institute, State University of Campinas Campinas SP Brazil
| | - Jean F. Vettorazzi
- Department of Structural and Functional Biology Biology Institute, State University of Campinas Campinas SP Brazil
| | - Ana Carolina Marques
- Department of Structural and Functional Biology Biology Institute, State University of Campinas Campinas SP Brazil
| | - Alessandro G. Salerno
- Department of Structural and Functional Biology Biology Institute, State University of Campinas Campinas SP Brazil
| | - Jose Roberto Trigo
- Department of Animal Biology Biology Institute, State University of Campinas Campinas SP Brazil
| | - Helena C. F. Oliveira
- Department of Structural and Functional Biology Biology Institute, State University of Campinas Campinas SP Brazil
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Abstract
BACKGROUND Ageing can be classified in two different ways, chronological ageing and biological ageing. While chronological age is a measure of the time that has passed since birth, biological (also known as transcriptomic) ageing is defined by how time and the environment affect an individual in comparison to other individuals of the same chronological age. Recent research studies have shown that transcriptomic age is associated with certain genes, and that each of those genes has an effect size. Using these effect sizes we can calculate the transcriptomic age of an individual from their age-associated gene expression levels. The limitation of this approach is that it does not consider how these changes in gene expression affect the metabolism of individuals and hence their observable cellular phenotype. RESULTS We propose a method based on poly-omic constraint-based models and machine learning in order to further the understanding of transcriptomic ageing. We use normalised CD4 T-cell gene expression data from peripheral blood mononuclear cells in 499 healthy individuals to create individual metabolic models. These models are then combined with a transcriptomic age predictor and chronological age to provide new insights into the differences between transcriptomic and chronological ageing. As a result, we propose a novel metabolic age predictor. CONCLUSIONS We show that our poly-omic predictors provide a more detailed analysis of transcriptomic ageing compared to gene-based approaches, and represent a basis for furthering our knowledge of the ageing mechanisms in human cells.
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Affiliation(s)
- Elisabeth Yaneske
- Department of Computer Science and Information Systems, Teesside University, Borough Road, Middlesbrough, UK
| | - Claudio Angione
- Department of Computer Science and Information Systems, Teesside University, Borough Road, Middlesbrough, UK
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A. El-Laithy N, M.E. Mahdy E, R. Youness E, Shafee N, S.S. Mowafy M, M. Mabrouk M. Effect of Co Enzyme Q10 Alone or in Combination with Vitamin C on Lipopolysaccharide-Induced Brain Injury in Rats. ACTA ACUST UNITED AC 2018. [DOI: 10.13005/bpj/1483] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Our was to determine the impact of CoenzymeQ10 (Co Q10) and vitamin C alone or in combination on oxidative stress in brain tissue of rats during endotoxemia induced by single intraperitoneal dose of Lipopolysaccharide (LPS), 500µg/kg. Both CoQ10&vitamin C were given orally to rats with doses (200&100 mg/kg) respectively for 7successive days prior induction of endotoxemia .LPS injected, with Co Q10 with doses (100 &200 mg/kg) &vit. C (50&100 mg/kg).In addition CoQ10 and vitamin C together in doses (100&50 mg/kg) & (200&100 mg/kg) respectively were added to LPS-treated rats. Then euthanized 4 hours later. Histopathological assessment of brain tissue was done. Results: LPS injection induced oxidative stress in brain tissue, resulting in marked increase in malondiadehyde (MDA), nitrite (NO) and Amyloid beta (Aβ), while decreasing reduced glutathione (GSH), paraoxonase-1 (PON1) and brain derived neurotrophic factor (BDNF).CoQ10 and vit.C administration with doses(200&100 mg/ kg) before endotoxemia result in reduction of brain MDA, NO and Aβ, while increasing levels of GSH, PON1 and BDNF compared to controls. The addition of both Co Q10 &vit.C to LPS- treated rats lead to decrease of brain NO, MDA and Aβ, also increase of GSH, PON1 and BDNF. This effect was more obviouswith high doses, this due to the ameliorating effect of both CoQ10 and vit.C on oxidative stress of brain tissue during endotoxemia.This consisted with the histopathological results. Conclusion: this work focuses on the possible role of CoQ10 &vit.C as antioxidants in protecting brain tissue.
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Affiliation(s)
| | - Elsayed M.E. Mahdy
- Department of Chemistry , Faculty of Science, Helwan University, Helwan, Egypt
| | - Eman R. Youness
- Department of Medical Biochemistry, National Research Centre, Cairo, Egypt
| | - Nermeen Shafee
- Department of Pathology, National Research Centre, Cairo, Egypt
| | | | - Mahmoud M. Mabrouk
- Department of Medical Biochemistry, National Research Centre, Cairo, Egypt
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Ascorbic acid co-administered with rosuvastatin reduces reproductive impairment in the male offspring from male rats exposed to the statin at pre-puberty. Food Chem Toxicol 2018; 118:416-429. [DOI: 10.1016/j.fct.2018.05.043] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Revised: 05/14/2018] [Accepted: 05/17/2018] [Indexed: 12/24/2022]
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35
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Siasos G, Tsigkou V, Kosmopoulos M, Theodosiadis D, Simantiris S, Tagkou NM, Tsimpiktsioglou A, Stampouloglou PK, Oikonomou E, Mourouzis K, Philippou A, Vavuranakis M, Stefanadis C, Tousoulis D, Papavassiliou AG. Mitochondria and cardiovascular diseases-from pathophysiology to treatment. ANNALS OF TRANSLATIONAL MEDICINE 2018; 6:256. [PMID: 30069458 DOI: 10.21037/atm.2018.06.21] [Citation(s) in RCA: 181] [Impact Index Per Article: 25.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Mitochondria are the source of cellular energy production and are present in different types of cells. However, their function is especially important for the heart due to the high demands in energy which is achieved through oxidative phosphorylation. Mitochondria form large networks which regulate metabolism and the optimal function is achieved through the balance between mitochondrial fusion and mitochondrial fission. Moreover, mitochondrial function is upon quality control via the process of mitophagy which removes the damaged organelles. Mitochondrial dysfunction is associated with the development of numerous cardiac diseases such as atherosclerosis, ischemia-reperfusion (I/R) injury, hypertension, diabetes, cardiac hypertrophy and heart failure (HF), due to the uncontrolled production of reactive oxygen species (ROS). Therefore, early control of mitochondrial dysfunction is a crucial step in the therapy of cardiac diseases. A number of anti-oxidant molecules and medications have been used but the results are inconsistent among the studies. Eventually, the aim of future research is to design molecules which selectively target mitochondrial dysfunction and restore the capacity of cellular anti-oxidant enzymes.
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Affiliation(s)
- Gerasimos Siasos
- Department of Cardiology, "Hippokration" General Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece.,Division of Cardiovascular, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Vasiliki Tsigkou
- Department of Cardiology, "Hippokration" General Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Marinos Kosmopoulos
- Department of Cardiology, "Hippokration" General Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Dimosthenis Theodosiadis
- Department of Cardiology, "Hippokration" General Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Spyridon Simantiris
- Department of Cardiology, "Hippokration" General Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Nikoletta Maria Tagkou
- Department of Cardiology, "Hippokration" General Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Athina Tsimpiktsioglou
- Department of Cardiology, "Hippokration" General Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Panagiota K Stampouloglou
- Department of Cardiology, "Hippokration" General Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Evangelos Oikonomou
- Department of Cardiology, "Hippokration" General Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Konstantinos Mourouzis
- Department of Cardiology, "Hippokration" General Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Anastasios Philippou
- Department of Experimental Physiology, Medical School, National and Kapodistrian University of Athens, Greece
| | - Manolis Vavuranakis
- Department of Cardiology, "Hippokration" General Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | | | - Dimitris Tousoulis
- Department of Cardiology, "Hippokration" General Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Athanasios G Papavassiliou
- Department of Biological Chemistry, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
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36
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Oxidative stress as a possible mechanism of statin-induced myopathy. Inflammopharmacology 2018; 26:667-674. [PMID: 29574631 DOI: 10.1007/s10787-018-0469-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Accepted: 03/15/2018] [Indexed: 01/05/2023]
Abstract
Statins, inhibitors of hydroxy methyl glutaryl coenzyme-A (HMG-CoA) reductase, are the most widely used drugs for treating hypercholesterolemia. However, statins can cause disabling myopathy as their main adverse effect. Several molecular mechanisms underlie the statin-induced myopathy including the decrease in the levels of essential mevalonate and cholesterol derivatives. This review discusses a further mechanism involving the loss of other anti-oxidant defenses besides ubiquinone (Co-Q) in skeletal muscles which produce a significant amount of reactive oxygen species (ROS). Therefore, to maintain their function, skeletal muscles need a high level of anti-oxidants.
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37
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Huyut Z, Bakan N, Yıldırım S, Alp HH. Effects of the Phosphodiesterase-5 (PDE-5) Inhibitors, Avanafil and Zaprinast, on Bone Remodeling and Oxidative Damage in a Rat Model of Glucocorticoid-Induced Osteoporosis. Med Sci Monit Basic Res 2018; 24:47-58. [PMID: 29557941 PMCID: PMC5865409 DOI: 10.12659/msmbr.908504] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Accepted: 02/08/2018] [Indexed: 01/06/2023] Open
Abstract
Background The aim of this study was to evaluate the effects of the phosphodiesterase-5 (PDE-5) inhibitors, zaprinast and avanafil, on NO signalling pathway, bone mineral density (BMD), epiphyseal bone width, bone marrow angiogenesis, and parameters of oxidative stress in a rat model of glucocorticoid-induced osteoporosis (GIOP). Material/Methods Twenty-four 8-month-old male rats in four groups were given a single daily treatment during a 30-day period: an (untreated) control group (n=6): a dexamethasone-treated group (120 μ/kg) (n=6); a group treated with dexamethasone (120 μ/kg) and zaprinast (10 mg/kg) (n=6): and a group treated with dexamethasone (120 μ/kg) and avanafil (10 mg/kg) (n=6). Rat whole body bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DEXA), and bone histology was performed. Also, selected oxidative stress parameters by HPLC method and the other biochemical parameters by ELISA method were measured. Results The GIOP model rats treated with zaprinast and avanafil showed a significant increase in NO, cyclic guanosine monophosphate (cGMP), and protein kinase G (PKG) (NO/cGMP/PKG) signaling-pathway components, and in C-terminal telopeptide of type I collagen (CTX-1), bone marrow angiogenesis, BMD, and epiphyseal bone width, compared with the (untreated) control rats (p<0.05). Levels of pyridinoline (PD) and deoxypyridinoline (DPD) were significantly reduced in the dexamethasone + zaprinast, and dexamethasone + avanafil treatment groups (p<0.05). Malondialdehyde (MDA), ubiquinone-10 (CoQ10), ubiquinol CoQ10 (CoQ10H), and 8-hydroxy-2′-deoxyguanosine (8-OHdG) were significantly increased in the dexamethasone-treated group, compared with the (untreated) controls (p<0.05). Conclusions In the GIOP rat model, markers of oxidative stress and bone atrophy were significantly reduced by treatment with the PDE-5 inhibitors, zaprinast and avanafil.
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Affiliation(s)
- Zübeyir Huyut
- Department of Biochemistry, Medical Faculty, Yuzuncu Yıl University, Van, Turkey
| | - Nuri Bakan
- Department of Biochemistry, Medical Faculty, Ataturk University, Erzurum, Turkey
| | - Serkan Yıldırım
- Department of Pathology, Faculty of Veterinary, Atatürk University, Erzurum, Turkey
| | - Hamit Hakan Alp
- Department of Biochemistry, Medical Faculty, Yuzuncu Yıl University, Van, Turkey
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38
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Hernández-Camacho JD, Bernier M, López-Lluch G, Navas P. Coenzyme Q 10 Supplementation in Aging and Disease. Front Physiol 2018; 9:44. [PMID: 29459830 PMCID: PMC5807419 DOI: 10.3389/fphys.2018.00044] [Citation(s) in RCA: 234] [Impact Index Per Article: 33.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Accepted: 01/12/2018] [Indexed: 12/21/2022] Open
Abstract
Coenzyme Q (CoQ) is an essential component of the mitochondrial electron transport chain and an antioxidant in plasma membranes and lipoproteins. It is endogenously produced in all cells by a highly regulated pathway that involves a mitochondrial multiprotein complex. Defects in either the structural and/or regulatory components of CoQ complex or in non-CoQ biosynthetic mitochondrial proteins can result in a decrease in CoQ concentration and/or an increase in oxidative stress. Besides CoQ10 deficiency syndrome and aging, there are chronic diseases in which lower levels of CoQ10 are detected in tissues and organs providing the hypothesis that CoQ10 supplementation could alleviate aging symptoms and/or retard the onset of these diseases. Here, we review the current knowledge of CoQ10 biosynthesis and primary CoQ10 deficiency syndrome, and have collected published results from clinical trials based on CoQ10 supplementation. There is evidence that supplementation positively affects mitochondrial deficiency syndrome and the symptoms of aging based mainly on improvements in bioenergetics. Cardiovascular disease and inflammation are alleviated by the antioxidant effect of CoQ10. There is a need for further studies and clinical trials involving a greater number of participants undergoing longer treatments in order to assess the benefits of CoQ10 treatment in metabolic syndrome and diabetes, neurodegenerative disorders, kidney diseases, and human fertility.
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Affiliation(s)
- Juan D Hernández-Camacho
- Centro Andaluz de Biología del Desarrollo and CIBERER, Instituto de Salud Carlos III, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain
| | - Michel Bernier
- Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States
| | - Guillermo López-Lluch
- Centro Andaluz de Biología del Desarrollo and CIBERER, Instituto de Salud Carlos III, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain
| | - Plácido Navas
- Centro Andaluz de Biología del Desarrollo and CIBERER, Instituto de Salud Carlos III, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain
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39
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Significance of Ubiad1 for Epidermal Keratinocytes Involves More Than CoQ10 Synthesis: Implications for Skin Aging. COSMETICS 2018. [DOI: 10.3390/cosmetics5010009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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40
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van Diemen MP, Berends CL, Akram N, Wezel J, Teeuwisse WM, Mik BG, Kan HE, Webb A, Beenakker JWM, Groeneveld GJ. Validation of a pharmacological model for mitochondrial dysfunction in healthy subjects using simvastatin: A randomized placebo-controlled proof-of-pharmacology study. Eur J Pharmacol 2017; 815:290-297. [DOI: 10.1016/j.ejphar.2017.09.031] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Revised: 09/16/2017] [Accepted: 09/20/2017] [Indexed: 10/18/2022]
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The Combination of Physical Exercise with Muscle-Directed Antioxidants to Counteract Sarcopenia: A Biomedical Rationale for Pleiotropic Treatment with Creatine and Coenzyme Q10. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:7083049. [PMID: 29123615 PMCID: PMC5632475 DOI: 10.1155/2017/7083049] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Revised: 08/13/2017] [Accepted: 08/23/2017] [Indexed: 12/21/2022]
Abstract
Sarcopenia represents an increasing public health risk due to the rapid aging of the world's population. It is characterized by both low muscle mass and function and is associated with mobility disorders, increased risk of falls and fractures, loss of independence, disabilities, and increased risk of death. Despite the urgency of the problem, the development of treatments for sarcopenia has lagged. Increased reactive oxygen species (ROS) production and decreased antioxidant (AO) defences seem to be important factors contributing to muscle impairment. Studies have been conducted to verify whether physical exercise and/or AOs could prevent and/or delay sarcopenia through a normalization of the etiologically relevant ROS imbalance. Despite the strong rationale, the results obtained were contradictory, particularly with regard to the effects of the tested AOs. A possible explanation might be that not all the agents included in the general heading of "AOs" could fulfill the requisites to counteract the complex series of events causing/accelerating sarcopenia: the combination of the muscle-directed antioxidants creatine and coenzyme Q10 with physical exercise as a biomedical rationale for pleiotropic prevention and/or treatment of sarcopenia is discussed.
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Atorvastatin but Not Pravastatin Impairs Mitochondrial Function in Human Pancreatic Islets and Rat β-Cells. Direct Effect of Oxidative Stress. Sci Rep 2017; 7:11863. [PMID: 28928397 PMCID: PMC5605712 DOI: 10.1038/s41598-017-11070-x] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Accepted: 08/14/2017] [Indexed: 12/14/2022] Open
Abstract
Statins are a class of drugs widely prescribed as frontline therapy for lowering plasma LDL-cholesterol in cardiovascular risk prevention. Several clinical reports have recently suggested an increased risk of type 2 diabetes associated with chronic use of these drugs. The pathophysiology of this effect remains to be fully elucidated but impaired β-cell function constitutes a potential mechanism. The aim of this study was to explore the effect of a chronic treatment with lipophilic and hydrophilic statins on β-cell function, using human pancreatic islets and rat insulin-secreting INS-1 cells; we particularly focused on the role of mitochondria and oxidative stress. The present study demonstrates, for the first time, that atorvastatin (lipophilic) but not pravastatin (hydrophilic) affected insulin release and mitochondrial metabolism due to the suppression of antioxidant defense system and induction of ROS production in pancreatic β-cell models. Mevalonate addition and treatment with a specific antioxidant (N-AcetylCysteine) effectively reversed the observed defects. These data demonstrate that mitochondrial oxidative stress is a key element in the pathogenesis of statin-related diabetes and may have clinical relevance to design strategies for prevention or reduction of statin induced β-cell dysfunction and diabetes in patients treated with lipophilic statins.
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Saeedi Saravi SS, Saeedi Saravi SS, Arefidoust A, Dehpour AR. The beneficial effects of HMG-CoA reductase inhibitors in the processes of neurodegeneration. Metab Brain Dis 2017; 32:949-965. [PMID: 28578514 DOI: 10.1007/s11011-017-0021-5] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Accepted: 04/28/2017] [Indexed: 12/13/2022]
Abstract
Statins, cholesterol lowering drugs, have been demonstrated to exert beneficial effects in other conditions such as primary and progressing neurodegenerative diseases beyond their original role. Observation that statins ameliorate the neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS) and cerebral ischemic stroke, the neuroprotective effects of these drugs are thought to be linked to their anti-inflammatory, anti-oxidative, and anti-excitotoxic properties. Despite the voluminous literature on the clinical advantages of 3-hydroxy-3-methylglutaryl Co-enzyme A reductase (HMGCR) inhibitors (statins) in cardiovascular system, the neuroprotective effects and the underlying mechanisms are little understood. Hence, the present review tries to provide a critical overview on the statin-induced neuroprotection, which are presumed to be associated with the ability to reduce cholesterol, Amyloid-β and apolipoprotein E (ApoE) levels, decrease reactive oxygen and nitrogen species (ROS and RNS) formation, inhibit excitotoxicity, modulate matrix metalloproteinases (MMPs), stimulate endothelial nitric oxide synthase (eNOS), and increase cerebral blood perfusion. This review is also aimed to illustrate that statins protect neurons against the neuro-inflammatory processes through balancing pro-inflammatory/anti-inflammatory cytokines. Ultimately, the beneficial role of statins in ameliorating the development of PD, AD, MS and cerebral ischemic stroke has been separately reviewed.
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Affiliation(s)
- Seyed Soheil Saeedi Saravi
- Department of Toxicology-Pharmacology, Faculty of Pharmacy, Guilan University of Medical Sciences, Rasht, Iran
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Experimental Medicine Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Sobhan Saeedi Saravi
- Department of Toxicology-Pharmacology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
| | - Alireza Arefidoust
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Experimental Medicine Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ahmad Reza Dehpour
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
- Experimental Medicine Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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Ramachandran R, Wierzbicki AS. Statins, Muscle Disease and Mitochondria. J Clin Med 2017; 6:jcm6080075. [PMID: 28757597 PMCID: PMC5575577 DOI: 10.3390/jcm6080075] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2017] [Revised: 06/28/2017] [Accepted: 07/12/2017] [Indexed: 12/25/2022] Open
Abstract
Cardiovascular disease (CVD) accounts for >17 million deaths globally every year, and this figure is predicted to rise to >23 million by 2030. Numerous studies have explored the relationship between cholesterol and CVD and there is now consensus that dyslipidaemia is a causal factor in the pathogenesis of atherosclerosis. Statins have become the cornerstone of the management of dyslipidaemia. Statins have proved to have a very good safety profile. The risk of adverse events is small compared to the benefits. Nevertheless, the potential risk of an adverse event occurring must be considered when prescribing and monitoring statin therapy to individual patients. Statin-associated muscle disease (SAMS) is by far the most studied and the most common reason for discontinuation of therapy. The reported incidence varies greatly, ranging between 5% and 29%. Milder disease is common and the more serious form, rhabdomyolysis is far rarer with an incidence of approximately 1 in 10,000. The pathophysiology of, and mechanisms leading to SAMS, are yet to be fully understood. Literature points towards statin-induced mitochondrial dysfunction as the most likely cause of SAMS. However, the exact processes leading to mitochondrial dysfunction are not yet fully understood. This paper details some of the different aetiological hypotheses put forward, focussing particularly on those related to mitochondrial dysfunction.
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Affiliation(s)
- Radha Ramachandran
- Departments of Chemical Pathology/Metabolic Medicine, Guys and St Thomas' Hospitals NHS Foundation Trust, London SE1 7EH, UK.
- Adult Inherited Metabolic Diseases, Centre for Inherited Metabolic Diseases, Evelina, Guys and St Thomas' Hospitals NHS Foundation Trust, Lambeth Palace Road, London SE1 7EH, UK.
| | - Anthony S Wierzbicki
- Departments of Chemical Pathology/Metabolic Medicine, Guys and St Thomas' Hospitals NHS Foundation Trust, London SE1 7EH, UK.
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Powers JM, Murphy G, Ralph N, O'Gorman SM, Murphy JEJ. Polypharmacy and sun exposure: Implications for mitochondrial DNA deletions in skin. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY 2017. [PMID: 28649007 DOI: 10.1016/j.jphotobiol.2017.06.020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Most somatic cells contain many copies of mitochondrial DNA (mtDNA). Because of both the high copy number and the lack of repair mechanisms available to mtDNA, damage to it largely goes unrepaired, and can accumulate over time. Large scale deletions are a recognised type of damage sustained by mtDNA as a consequence of exposure to the ultraviolet light in sunlight. A group of patients were identified as having abnormally high levels of either a 4977 base pair deletion (mtDNA4977) or 3895 base pair deletion (mtDNA3895), in mtDNA from sun exposed skin or skin suspected to be a non-melanoma skin cancer, but not in their non-sun exposed skin biopsies. In three of the four cases, skin cancer was ruled out due to histological testing. Additional factors from these patients' medical histories were studied, and it was noted that they shared diagnoses for multiple pathologies common to an older population, and that they were being treated with the same or related pharmaceuticals, including some that had been known to cause dermal side effects. Investigation into the biochemistry underlying the symptoms, the effects of sun exposure and side effects of the prescribed pharmaceuticals revealed a possible synergistic relationship leading to the localised high levels of mtDNA deletions.
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Affiliation(s)
- Julia Montelin Powers
- Mitochondrial Biology & Radiation Research Centre, Dept Life Sciences, IT Sligo, Sligo, Ireland.
| | | | - Nikki Ralph
- Dept of Dermatology, Beaumont Hospital, Dublin, Ireland
| | | | - James E J Murphy
- Mitochondrial Biology & Radiation Research Centre, Dept Life Sciences, IT Sligo, Sligo, Ireland
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Rumyantsev NA, Kukes VG, Kazakov RE, Rumyantsev AA, Sychev DA. [Use of pharmacogenetic testing to prevent adverse drug reactions during statin therapy]. TERAPEVT ARKH 2017; 89:82-87. [PMID: 28252633 DOI: 10.17116/terarkh201789182-87] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The number of patients receiving statins increases every year and due to the fact that they should take statins during their lives, the problem of their safety use comes to the forefront. The paper analyzes the safety of using the medications of this group and discusses the diagnosis of myopathies induced by statins and the occurrence of immune-mediated statin myopathies. It considers a personalized approach to prescribing statins, analyzes Russian and foreign experience in using pharmacogenetics to reduce the risk of myopathies, publishes the results of the authors' experience in clinically introducing pharmacogenetic testing at hospitals, and analyzes the long-term results of determining the polymorphism of the SLCO1B1 gene for the prediction of the risk of adverse events when using statins and estimating patient compliance to prescribed treatment.
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Affiliation(s)
- N A Rumyantsev
- I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow, Russia; Research Center for Examination of Medical Products, Ministry of Health of Russia, Moscow, Russia
| | - V G Kukes
- I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow, Russia; Research Center for Examination of Medical Products, Ministry of Health of Russia, Moscow, Russia
| | - R E Kazakov
- Research Center for Examination of Medical Products, Ministry of Health of Russia, Moscow, Russia
| | - A A Rumyantsev
- N.N. Blokhin Russian Cancer Research Center, Moscow, Russia
| | - D A Sychev
- Russian Medical Academy of Postgraduate Education, Ministry of Health of Russia, Moscow, Russia
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Saeedi Saravi SS, Saeedi Saravi SS, Khoshbin K, Dehpour AR. Current insights into pathogenesis of Parkinson's disease: Approach to mevalonate pathway and protective role of statins. Biomed Pharmacother 2017; 90:724-730. [PMID: 28419968 DOI: 10.1016/j.biopha.2017.04.038] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Revised: 04/07/2017] [Accepted: 04/10/2017] [Indexed: 10/19/2022] Open
Abstract
Although Parkinson's disease (PD) is considered as the second most common life threatening age-related neurodegenerative disorder, but the underlying mechanisms for pathogenesis of PD are remained to be fully found. However, a complex relationship between genetic and environmental predisposing factors are involved in progression of PD. Dopaminergic neuronal cell death caused by mutations and accumulation of α-synuclein in Lewy bodies and neurites was suggested as the main strategy for PD, but current studies have paid attention to the role of mevalonate pathway in incidence of neurodegenerative diseases including PD. The discovery may change the therapeutic protocols from symptomatic treatment by dopamine precursors and agonists to neurodegenerative process halting drugs. Moreover, the downstream metabolites of mevalonate pathway may be used as diagnostic biomarkers for early diagnosis of PD. Statins, as cholesterol lowering drugs, may ameliorate the enzyme complex dysfunction, a key step in the progression of the neurodegenerative disorders, oxidative stress-induced damage and neuro-inflammation. Statins exert the neuroprotective effects on striatal dopaminergic neurons through blocking the mevalonate pathway. In the present review, we have focused on the new approaches to pathogenesis of PD regarding to mevalonate pathway, in addition to the previous understood mechanisms for the disease. It tries to elucidate the novel findings about PD for the development of future diagnostic and therapeutic strategies. Moreover, we explain the controversial role of statins in improvement or progression of PD and the position of these drugs in neuroprotection in PD patients.
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Affiliation(s)
- Seyed Soheil Saeedi Saravi
- Department of Toxicology-Pharmacology, Faculty of Pharmacy, Guilan University of Medical Sciences, Rasht, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Sobhan Saeedi Saravi
- Department of Toxicology-Pharmacology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
| | - Katayoun Khoshbin
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ahmad Reza Dehpour
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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Žmitek K, Pogačnik T, Mervic L, Žmitek J, Pravst I. The effect of dietary intake of coenzyme Q10 on skin parameters and condition: Results of a randomised, placebo-controlled, double-blind study. Biofactors 2017; 43:132-140. [PMID: 27548886 DOI: 10.1002/biof.1316] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Revised: 07/01/2016] [Accepted: 07/20/2016] [Indexed: 11/10/2022]
Abstract
Coenzyme Q10 (CoQ10) is a natural constituent of foods and is also often used in both functional foods and supplements. In addition, it is a common ingredient of cosmetics where it is believed to reduce the signs of skin ageing. However, the existing data about the effect of dietary intake of CoQ10 on skin parameters and condition are scarce. To gain an insight into this issue, we conducted a double-blind, placebo-controlled experiment with 33 healthy subjects. Our objective was to investigate the effects of 12 weeks of daily supplementation with 50 and 150 mg of CoQ10 on skin parameters and condition. Study was conducted with a water-soluble form of CoQ10 with superior bioavailability (Q10Vital® ). While the results of some previous in vitro studies showed possible protection in UVB response, we did not observe significant changes in the minimal erythema dose (MED). On the other hand, the intake of CoQ10 limited seasonal deterioration of viscoelasticity and reduced some visible signs of ageing. We determined significantly reduced wrinkles and microrelief lines, and improved skin smoothness. Supplementation with CoQ10 did not significantly affect skin hydration and dermis thickness. © 2016 BioFactors, 43(1):132-140, 2017.
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Affiliation(s)
- Katja Žmitek
- VIST-Higher School of Applied Sciences, Institute of Cosmetics, Ljubljana, Slovenia
- Nutrition Institute, Ljubljana, Slovenia
| | - Tina Pogačnik
- VIST-Higher School of Applied Sciences, Institute of Cosmetics, Ljubljana, Slovenia
| | - Liljana Mervic
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Janko Žmitek
- VIST-Higher School of Applied Sciences, Institute of Cosmetics, Ljubljana, Slovenia
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Domanico D, Fragiotta S, Cutini A, Carnevale C, Zompatori L, Vingolo EM. Circulating levels of reactive oxygen species in patients with nonproliferative diabetic retinopathy and the influence of antioxidant supplementation: 6-month follow-up. Indian J Ophthalmol 2016; 63:9-14. [PMID: 25686055 PMCID: PMC4363979 DOI: 10.4103/0301-4738.151455] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Aims: The aim was to evaluate circulating levels of reactive oxygen species (ROS) and changes in central macular thickness (CMT) in patients with nonproliferative diabetic retinopathy (NPDR) after antioxidant supplementation. Materials and Methods: A total of 68 patients (68 eyes) with NPDR were enrolled. Patients were randomly divided into two groups: Treated with antioxidant supplement (Group A) and untreated control group (Group B). Each tablet, for oral administration, containing pycnogenol 50 mg, Vitamin E 30 mg and coenzyme Q10 20 mg. CMT and free oxygen radical test (FORT) were analyzed at baseline (T0), 3 (T1) and 6 (T2) months in both groups. Results: In Group A, FORT levels and CMT were significantly reduced over time (P < 0.001 for both). In Group B, FORT levels were increased (P < 0.001) and CMT did not vary significantly (P = 0.81) over 3 time points. Conclusions: This is the first study showing the reduction of ROS levels in patients with NPDR thanks to antioxidant therapy. Moreover, our findings have suggested also an influence on retinal thickness.
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Affiliation(s)
| | | | | | - Carmela Carnevale
- Department of Sense Organs UOC B, Policlinico Umberto I Hospital, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
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