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Wheatley C. Complete Immunophenotypic Reversal of Chronic Lymphocytic Leukaemia With High Dose Parenteral Methylcobalamin: A Case Report and Brief Review of Cobalamin in Cancer. Cancer Rep (Hoboken) 2025; 8:e70106. [PMID: 40347057 PMCID: PMC12062518 DOI: 10.1002/cnr2.70106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 11/04/2024] [Accepted: 12/17/2024] [Indexed: 05/12/2025] Open
Abstract
BACKGROUND Supposed 'spontaneous' remissions in chronic lymphocytic leukaemia (CLL) are extremely rare. By the most stringent immunophenotypic criteria, there are only seven cases to date of unexplained, immune system effected cures. A historic review of this phenomenon is presented as context for this eighth case of CLL immunophenotypic reversal. CASE A 59-year-old, molecular biologist, stage I CLL, whose diagnosis and recovery were both thoroughly documented, not content to watch and wait, chose to treat himself, after individual tumour susceptibility testing, with evidence based, biological response modifiers, which initially seemed to keep his CLL stable. This included 1 mg of hydroxocobalamin injected i.m. daily. However, after some years his lymphocytosis began slowly to drift upwards. At that point, he was persuaded to change his injection protocol to methylcobalamin, at 50 mg i.m. a day, a dose whose clinical safety is sufficiently well-established, and a form of cobalamin that the research literature shows has anticancer actions. CONCLUSION This change in cobalamin form and dose proved a critical turning point. Complete disappearance of the lymphocytosis also coincided with a severe infection and an even further temporary increase of the parenteral methylcobalamin dose, both catalytic factors. In the 4th and 5th years following this, the patient's repeated immunophenotyping showed no clonal disease present. A brief review of the field of cobalamin in cancer research and treatment is given, with discussion of the various mechanisms by which cobalamins may impact on cancer/CLL. Historic analysis reveals that cyanocobalamin is generally cancer promotional, whereas hydroxocobalamin, methylcobalamin and adenosylcobalamin are cancer protective and cytotoxic. It is hypothesised that the actions of cobalamin in cancer aetiology and oncogenesis/progression are intertwined with those of nitric oxide, which tumours regulate to dupe the immune system to their presence, by causing a functional cobalamin deficiency in the host.
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Affiliation(s)
- Carmen Wheatley
- Orthomolecular Oncology and Medicine, UK Reg. Charity 1078066, Oxford, UK
- St Catherine's College, University of OxfordOxfordUK
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Liu Y, Yang C, Zhang J, Ihsan A, Ares I, Martínez M, Lopez-Torres B, Martínez-Larrañaga MR, Wang X, Anadón A, Martínez MA. Recent progress in adverse events of carboxylic acid non-steroidal anti-inflammatory drugs (CBA-NSAIDs) and their association with the metabolism: the consequences on mitochondrial dysfunction and oxidative stress, and prevention with natural plant extracts. Expert Opin Drug Metab Toxicol 2024:1-21. [PMID: 38980754 DOI: 10.1080/17425255.2024.2378885] [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: 02/09/2024] [Accepted: 07/08/2024] [Indexed: 07/11/2024]
Abstract
INTRODUCTION Carboxylic acid non-steroidal anti-inflammatory drugs (CBA-NSAIDs) are extensively used worldwide due to their antipyretic, analgesic, and anti-inflammatory effects. CBA-NSAIDs have reasonable margin of safety at therapeutic doses, and in the current climate, do not possess addiction potential like opioid drugs. Studies have revealed that various adverse events of CBA-NSAIDs are related mitochondrial dysfunction and oxidative stress. AREAS COVERED This review article summarizes adverse events induced by CBA-NSAIDs, mechanisms of mitochondrial damage, oxidative stress, and metabolic interactions. Meanwhile, this review discusses the treatment and prevention of CBA-NSAIDs damage by natural plant extracts based on antioxidant effects. EXPERT OPINION CBA-NSAIDs can induce reactive oxygen species (ROS) production, mediate DNA, protein and lipid damage, lead to imbalance of cell antioxidant status, change of mitochondrial membrane potential, activate oxidative stress signal pathway, thus leading to oxidative stress and cell damage. Adverse events caused by CBA-NSAIDs often exhibit dose and time dependence. In order to avoid adverse events caused by CBA-NSAIDs, it is necessary to provide detailed patient consultation and eliminate influencing factors. Moreover, constructive research studies on the organ-specific toxicity and mechanism of natural plant extracts in preventing and treating metabolic abnormalities of CBA-NSAIDs, will provide important value for warning and guidance for use of CBA-NSAIDs.
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Affiliation(s)
- Yanan Liu
- National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, Hubei, China
| | - Chao Yang
- National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, Hubei, China
| | - Jieying Zhang
- MAO Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei, China
| | - Awais Ihsan
- Department of Biosciences, COMSATS University Islamabad, Sahiwal Campus, Islamabad, Pakistan
| | - Irma Ares
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid (UCM), and Research Institute Hospital 12 de Octubre (i+12), Madrid, Spain
| | - Marta Martínez
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid (UCM), and Research Institute Hospital 12 de Octubre (i+12), Madrid, Spain
| | - Bernardo Lopez-Torres
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid (UCM), and Research Institute Hospital 12 de Octubre (i+12), Madrid, Spain
| | - María-Rosa Martínez-Larrañaga
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid (UCM), and Research Institute Hospital 12 de Octubre (i+12), Madrid, Spain
| | - Xu Wang
- National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, Hubei, China
| | - Arturo Anadón
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid (UCM), and Research Institute Hospital 12 de Octubre (i+12), Madrid, Spain
| | - María-Aránzazu Martínez
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid (UCM), and Research Institute Hospital 12 de Octubre (i+12), Madrid, Spain
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Baek KI, Ryu K. Role of Flow-Sensitive Endothelial Genes in Atherosclerosis and Antiatherogenic Therapeutics Development. J Cardiovasc Transl Res 2024; 17:609-623. [PMID: 38010480 DOI: 10.1007/s12265-023-10463-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 11/14/2023] [Indexed: 11/29/2023]
Abstract
Atherosclerosis is a chronic inflammatory disease that is the underlying cause of cardiovascular disease which initiates from endothelial dysfunction from genetic and environmental risk factors, including biomechanical forces: blood flow. Endothelial cells (ECs) lining the inner arterial wall regions exposed to disturbed flow are prone to atherosclerosis development, whereas the straight regions exposed to stable flow are spared from the disease. These flow patterns induce genome- and epigenome-wide changes in gene expression in ECs. Through the sweeping changes in gene expression, disturbed flow reprograms ECs from athero-protected cell types under the stable flow condition to pro-atherogenic cell conditions. The pro-atherogenic changes induced by disturbed flow, in combination with additional risk factors such as hypercholesterolemia, lead to the progression of atherosclerosis. The flow-sensitive genes and proteins are critical in understanding the mechanisms and serve as novel targets for antiatherogenic therapeutics.
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Affiliation(s)
- Kyung In Baek
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
| | - Kitae Ryu
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.
- Department of Biotechnology, The University of Suwon, 17, Wauan-Gil, Bongdam-Eup, Hwaseong-Si, Gyeonggi-Do, 18323, Republic of Korea.
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Shen W, Yuan Y, Liu X, Jiang J, Yu S, Zhou H, Zhu Q. A fluorogenic nitric oxide donor induced by yellow LED light for cells proliferation inhibition and imaging. Nitric Oxide 2024; 145:1-7. [PMID: 38309328 DOI: 10.1016/j.niox.2024.01.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 01/18/2024] [Accepted: 01/24/2024] [Indexed: 02/05/2024]
Abstract
Nitric oxide (NO), as a vital cellular signalling molecule in physiological processes, has been found to play an important role in various biological functions. In this study, we rationally designed three NO donors by tethering nitrobenzene derivatives to three fluorescent chromophores. NX-NO was found to release NO and exhibit a high fluorescence turn-on signal ratio upon exposure to LED yellow light. Additionally, it had excellent photo-stability and good inhibitory activity against cancer cell proliferation, and was successfully applied to cell imaging. Moreover, we detected the release of NO and fluorescence response in the blood of a mouse, suggesting its potential therapeutic application in living organisms.
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Affiliation(s)
- Wei Shen
- Department of Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, 321000, China
| | - Yuqing Yuan
- Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, China
| | - Xia Liu
- Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, China
| | - Jianze Jiang
- Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, China
| | - Shian Yu
- Department of Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, 321000, China
| | - Haihua Zhou
- Department of Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, 321000, China
| | - Qing Zhu
- Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, China.
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5
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A new look at the role of nitric oxide in preeclampsia: protein S-nitrosylation. Pregnancy Hypertens 2022; 29:14-20. [DOI: 10.1016/j.preghy.2022.05.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 05/20/2022] [Accepted: 05/23/2022] [Indexed: 11/19/2022]
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Caballano-Infantes E, Cahuana GM, Bedoya FJ, Salguero-Aranda C, Tejedo JR. The Role of Nitric Oxide in Stem Cell Biology. Antioxidants (Basel) 2022; 11:497. [PMID: 35326146 PMCID: PMC8944807 DOI: 10.3390/antiox11030497] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 02/24/2022] [Accepted: 02/25/2022] [Indexed: 02/07/2023] Open
Abstract
Nitric oxide (NO) is a gaseous biomolecule endogenously synthesized with an essential role in embryonic development and several physiological functions, such as regulating mitochondrial respiration and modulation of the immune response. The dual role of NO in embryonic stem cells (ESCs) has been previously reported, preserving pluripotency and cell survival or inducing differentiation with a dose-dependent pattern. In this line, high doses of NO have been used in vitro cultures to induce focused differentiation toward different cell lineages being a key molecule in the regenerative medicine field. Moreover, optimal conditions to promote pluripotency in vitro are essential for their use in advanced therapies. In this sense, the molecular mechanisms underlying stemness regulation by NO have been studied intensively over the current years. Recently, we have reported the role of low NO as a hypoxia-like inducer in pluripotent stem cells (PSCs), which supports using this molecule to maintain pluripotency under normoxic conditions. In this review, we stress the role of NO levels on stem cells (SCs) fate as a new approach for potential cell therapy strategies. Furthermore, we highlight the recent uses of NO in regenerative medicine due to their properties regulating SCs biology.
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Affiliation(s)
- Estefanía Caballano-Infantes
- Department of Molecular Biology and Biochemical Engineering, Universidad Pablo de Olavide, 41013 Seville, Spain; (G.M.C.); (F.J.B.)
- Department of Regeneration and Cell Therapy, Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), University of Pablo de Olavide-University of Seville-CSIC, 41092 Seville, Spain
| | - Gladys Margot Cahuana
- Department of Molecular Biology and Biochemical Engineering, Universidad Pablo de Olavide, 41013 Seville, Spain; (G.M.C.); (F.J.B.)
- Biomedical Research Network for Diabetes and Related Metabolic Diseases-CIBERDEM, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Francisco Javier Bedoya
- Department of Molecular Biology and Biochemical Engineering, Universidad Pablo de Olavide, 41013 Seville, Spain; (G.M.C.); (F.J.B.)
- Biomedical Research Network for Diabetes and Related Metabolic Diseases-CIBERDEM, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Carmen Salguero-Aranda
- Department of Pathology, Institute of Biomedicine of Seville (IBiS), Virgen del Rocio University Hospital, CSIC-University of Seville, 41013 Seville, Spain;
- Spanish Biomedical Research Network Centre in Oncology-CIBERONC, Instituto de Salud Carlos III, 28029 Madrid, Spain
- Department of Normal and Pathological Cytology and Histology, School of Medicine, University of Seville, 41004 Seville, Spain
| | - Juan R. Tejedo
- Department of Molecular Biology and Biochemical Engineering, Universidad Pablo de Olavide, 41013 Seville, Spain; (G.M.C.); (F.J.B.)
- Biomedical Research Network for Diabetes and Related Metabolic Diseases-CIBERDEM, Instituto de Salud Carlos III, 28029 Madrid, Spain
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Wu J, Tian S, Luo K, Zhang Y, Pan H, Zhang W, Mai K. Dietary recombinant human lysozyme improves the growth, intestinal health, immunity and disease resistance of Pacific white shrimp Litopenaeus vannamei. FISH & SHELLFISH IMMUNOLOGY 2022; 121:39-52. [PMID: 34983003 DOI: 10.1016/j.fsi.2021.12.052] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 12/21/2021] [Accepted: 12/29/2021] [Indexed: 06/14/2023]
Abstract
The present study was conducted to investigate the effects of dietary recombinant human lysozyme (RHL) on the growth, immune response, anti-oxidative activity, intestinal morphology, intestinal microflora and disease resistance of shrimp Litopenaeus vannamei. Shrimps with an initial body weight of 2.36 ± 0.02 g were fed diets supplemented with 0 (control group, R0), 0.0025% (R1), 0.005% (R2), 0.01% (R3), 0.02% (R4) and 0.04% (R5) of RHL, respectively. After a 10-week feeding trial, the final body weight, survival rate, weight gain ratio and protein efficiency rate of the shrimps in dietary RHL supplemented groups were significantly higher than that in the control group, while feed conversion ratio was significantly lower (P < 0.05). The total haemocyte count, total anti-oxidative capacity, respiratory burst, activities of phagocytosis, nitric oxide synthase, phenol oxidase and lysozyme in serum were significantly higher in dietary RHL supplemented groups than those in the control group (P < 0.05). Meanwhile, the intestinal pile height and wall thickness were significantly higher in dietary RHL supplemented groups than those in the control group (P < 0.05). Dietary RHL significantly improved the expressions of immune-related genes in gill, such as lipopolysaccharide-β-glucan binding protein, Toll, immune deficiency, heat shock protein 70 and Crustin (P < 0.05). The abundance of proteobacteria and bacteroidetes in intestine was higher, while the abundance of firmicutes and cyanobacteria was lower than those in the control group at the phylum level. In addition, dietary RHL supplementation significantly improved the protective ability of shrimp against V. parahaemolyticus infection (P < 0.05). Based on the broken-line model analysis for weight gain ratio after the feeding trial, the optimal level of dietary RHL supplementation for shrimp was estimated to be 0.006375%.
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Affiliation(s)
- Jing Wu
- The Key Laboratory of Aquaculture Nutrition and Feeds, Ministry of Agriculture and Rural Affairs, China; The Key Laboratory of Mariculture, Ministry of Education, China; Ocean University of China, Qingdao, 266003, China
| | - Shuangjie Tian
- The Key Laboratory of Aquaculture Nutrition and Feeds, Ministry of Agriculture and Rural Affairs, China; The Key Laboratory of Mariculture, Ministry of Education, China; Ocean University of China, Qingdao, 266003, China
| | - Kai Luo
- The Key Laboratory of Aquaculture Nutrition and Feeds, Ministry of Agriculture and Rural Affairs, China; The Key Laboratory of Mariculture, Ministry of Education, China; Ocean University of China, Qingdao, 266003, China
| | - Yanjiao Zhang
- The Key Laboratory of Aquaculture Nutrition and Feeds, Ministry of Agriculture and Rural Affairs, China; The Key Laboratory of Mariculture, Ministry of Education, China; Ocean University of China, Qingdao, 266003, China
| | - Hongtao Pan
- Zhejiang Aegis Biotech Co., Ltd., Jinghua, 322200, China
| | - Wenbing Zhang
- The Key Laboratory of Aquaculture Nutrition and Feeds, Ministry of Agriculture and Rural Affairs, China; The Key Laboratory of Mariculture, Ministry of Education, China; Ocean University of China, Qingdao, 266003, China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Wen Hai Road, Qingdao, 266237, China.
| | - Kangsen Mai
- The Key Laboratory of Aquaculture Nutrition and Feeds, Ministry of Agriculture and Rural Affairs, China; The Key Laboratory of Mariculture, Ministry of Education, China; Ocean University of China, Qingdao, 266003, China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Wen Hai Road, Qingdao, 266237, China
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Heck T, Ludwig M, Frizzo M, Rasia-Filho A, Homem de Bittencourt PI. Suppressed anti-inflammatory heat shock response in high-risk COVID-19 patients: lessons from basic research (inclusive bats), light on conceivable therapies. Clin Sci (Lond) 2020; 134:1991-2017. [PMID: 32749472 PMCID: PMC7403894 DOI: 10.1042/cs20200596] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 07/05/2020] [Accepted: 07/24/2020] [Indexed: 12/12/2022]
Abstract
The major risk factors to fatal outcome in COVID-19 patients, i.e., elderliness and pre-existing metabolic and cardiovascular diseases (CVD), share in common the characteristic of being chronic degenerative diseases of inflammatory nature associated with defective heat shock response (HSR). The molecular components of the HSR, the principal metabolic pathway leading to the physiological resolution of inflammation, is an anti-inflammatory biochemical pathway that involves molecular chaperones of the heat shock protein (HSP) family during homeostasis-threatening stressful situations (e.g., thermal, oxidative and metabolic stresses). The entry of SARS coronaviruses in target cells, on the other hand, aggravates the already-jeopardized HSR of this specific group of patients. In addition, cellular counterattack against virus involves interferon (IFN)-mediated inflammatory responses. Therefore, individuals with impaired HSR cannot resolve virus-induced inflammatory burst physiologically, being susceptible to exacerbated forms of inflammation, which leads to a fatal "cytokine storm". Interestingly, some species of bats that are natural reservoirs of zoonotic viruses, including SARS-CoV-2, possess an IFN-based antiviral inflammatory response perpetually activated but do not show any sign of disease or cytokine storm. This is possible because bats present a constitutive HSR that is by far (hundreds of times) more intense and rapid than that of human, being associated with a high core temperature. Similarly in humans, fever is a physiological inducer of HSR while antipyretics, which block the initial phase of inflammation, impair the resolution phase of inflammation through the HSR. These findings offer a rationale for the reevaluation of patient care and fever reduction in SARS, including COVID-19.
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Affiliation(s)
- Thiago Gomes Heck
- Research Group in Physiology, Department of Life Sciences, Regional University of Northwestern Rio Grande do Sul State (UNIJUI), Ijuí, RS, 98700-000 Brazil
- Postgraduate Program in Integral Attention to Health (PPGAIS), Regional University of Northwestern Rio Grande do Sul State (UNIJUI), Ijuí, RS, 98700-000 Brazil
| | - Mirna Stela Ludwig
- Research Group in Physiology, Department of Life Sciences, Regional University of Northwestern Rio Grande do Sul State (UNIJUI), Ijuí, RS, 98700-000 Brazil
- Postgraduate Program in Integral Attention to Health (PPGAIS), Regional University of Northwestern Rio Grande do Sul State (UNIJUI), Ijuí, RS, 98700-000 Brazil
| | - Matias Nunes Frizzo
- Research Group in Physiology, Department of Life Sciences, Regional University of Northwestern Rio Grande do Sul State (UNIJUI), Ijuí, RS, 98700-000 Brazil
- Postgraduate Program in Integral Attention to Health (PPGAIS), Regional University of Northwestern Rio Grande do Sul State (UNIJUI), Ijuí, RS, 98700-000 Brazil
| | - Alberto Antonio Rasia-Filho
- Federal University of Health Sciences of Porto Alegre (UFCSPA), Graduate Program in Biosciences, Porto Alegre, RS, 90050-170 Brazil
| | - Paulo Ivo Homem de Bittencourt
- Laboratory of Cellular Physiology, Department of Physiology, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, RS, 90050-170 Brazil
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Mazzei L, Sanz R, Manucha W. Alterations on a key nephrogenic/cardiogenic gene expression linked to hypertension development. CLINICA E INVESTIGACION EN ARTERIOSCLEROSIS 2019; 32:70-78. [PMID: 31472952 DOI: 10.1016/j.arteri.2019.06.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Accepted: 06/11/2019] [Indexed: 10/26/2022]
Abstract
The elevation of blood pressure produces specific organic lesions, including kidney and cardiac damage. On the other hand, cardiovascular disease usually leads to the development of hypertension. Thus, hypertension could be both a cause and a consequence of cardiovascular disease. Previous studies linked the lack of nitric oxide to cardiovascular abnormalities, including hypertension, arteriosclerosis, myocardial infarction, cardiac hypertrophy, diastolic heart failure, and reduced endothelium-derived hyperpolarizing factor responses, with shorter survival. The lack of this gas also leads to renal/cardiac abnormalities. It is widely known that nephrogenic deficiency is a risk factor for kidney disease. Besides, recent evidence suggests that alterations in WT-1, a key nephrogenic factor, could contribute to the development of hypertension. Moreover, some genes involved in the development of hypertension depend on WT-1. This knowledge makes it essential to investigate and understand the mechanisms regulating the expression of these genes during renal/cardiac development, and hypertension. As a consequence, the most in-depth knowledge of the complex aetiopathogenic mechanism responsible for the hypertensive disease will allow us to propose novel therapeutic tools.
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Affiliation(s)
- Luciana Mazzei
- Instituto de Medicina y Biología Experimental de Cuyo, Consejo Nacional de Investigación Científica y Tecnológica (IMBECU-CONICET), Mendoza, Argentina; Laboratorio de Farmacología Experimental Básica y Traslacional, Área de Farmacología, Departamento de Patología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Centro Universitario, CP 5500 Mendoza, Argentina
| | - Raúl Sanz
- Laboratorio de Farmacología Experimental Básica y Traslacional, Área de Farmacología, Departamento de Patología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Centro Universitario, CP 5500 Mendoza, Argentina
| | - Walter Manucha
- Instituto de Medicina y Biología Experimental de Cuyo, Consejo Nacional de Investigación Científica y Tecnológica (IMBECU-CONICET), Mendoza, Argentina; Laboratorio de Farmacología Experimental Básica y Traslacional, Área de Farmacología, Departamento de Patología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Centro Universitario, CP 5500 Mendoza, Argentina.
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Singh SK, Tiwari VK, Chadha NK, Munilkumar S, Prakash C, Pawar NA. Effect of dietary synbiotic supplementation on growth, immune and physiological status of Labeo rohita juveniles exposed to low pH stress. FISH & SHELLFISH IMMUNOLOGY 2019; 91:358-368. [PMID: 31085327 DOI: 10.1016/j.fsi.2019.05.023] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 05/04/2019] [Accepted: 05/10/2019] [Indexed: 06/09/2023]
Abstract
In this study, we investigated the effect of dietary Bacillus circulans PB7 (BCPB7) and fructoligosaccharide (FOS), used singly or in combination for evaluation of growth, immune and physiological status of Labeo rohita (rohu) juveniles reared under low pH and normal pH for 60 days. Experimental fishes were distributed in two sets such as one set continuously exposed to low pH (5.5) and other reared under normal pH (7.0), and fed with four iso-nitrogenous diets viz. basal (control), Bacillus circulans PB7 (BCPB7, 106 cfug-1), 1% fructooligosaccharide (FOS) and their combination. The effect of such pre, pro and synbiotics dietary treatments on growth performance (weight gain, specific growth rate, feed conversion ratio and protein efficiency ratio), immune response (hematological indices, serum biochemistry, lysozyme, NBT activity), antioxidative status in the form of antioxidant enzyme (catalase, superoxide dismutase, glutathione-S-transferase), acetylcholine esterase (AChE), Na+ K+ ATPase and stress bio-markers (cortisol, glucose and HSP-70) were examined. The group treated with low pH and fed with control diet (without supplementation) was found to be inhibited (p < 0.05) in growth and immuno-physiological function. However, supplementation of BCPB7 and FOS was non-significant (p < 0.05) on growth performance and physiological process but their concurrent feeding remarkably improved (p < 0.05) growth and immune-physiological function when exposed to low pH. Overall results indicate that dietary combination of BCPB7 and FOS can be considered an effective synbiotic formula against low pH stress in culture practices of L. rohita juveniles.
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Affiliation(s)
- Soibam Khogen Singh
- Aquaculture Division, ICAR-Central Institute of Fisheries Education, Mumbai-400061, Maharashtra, India; Department of Aquaculture, College of Fisheries, Central Agricultural University (Imphal), Lembucherra, Tripura West-799210, India.
| | - V K Tiwari
- Aquaculture Division, ICAR-Central Institute of Fisheries Education, Mumbai-400061, Maharashtra, India
| | - N K Chadha
- Aquaculture Division, ICAR-Central Institute of Fisheries Education, Mumbai-400061, Maharashtra, India
| | - Sukham Munilkumar
- ICAR-Central Institute of Fisheries Education, Kolkata Centre, Salt Lake, Kolkata, 70091, West Bengal, India
| | - Chandra Prakash
- Aquaculture Division, ICAR-Central Institute of Fisheries Education, Mumbai-400061, Maharashtra, India
| | - Nilesh A Pawar
- Aquaculture Division, ICAR-Central Institute of Fisheries Education, Mumbai-400061, Maharashtra, India
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Goettems-Fiorin PB, Costa-Beber LC, Dos Santos JB, Friske PT, Sulzbacher LM, Frizzo MN, Ludwig MS, Rhoden CR, Heck TG. Ovariectomy predisposes female rats to fine particulate matter exposure's effects by altering metabolic, oxidative, pro-inflammatory, and heat-shock protein levels. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2019; 26:20581-20594. [PMID: 31104233 DOI: 10.1007/s11356-019-05383-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/26/2018] [Accepted: 05/03/2019] [Indexed: 06/09/2023]
Abstract
The reduction of estrogen levels, as a result of menopause, is associated with the development of metabolic diseases caused by alterations in oxidative stress (OS), inflammatory biomarkers, and 70-kDa heat-shock protein (HSP70) expression. Additionally, exposure to fine particulate matter air pollution modifies liver OS levels and predisposes organisms to metabolic diseases, such as type 2 diabetes (T2DM). We investigated whether ovariectomy affects hepatic tissue and alters glucose metabolism in female rats exposed to particulate air pollution. First, 24 female Wistar rats received an intranasal instillation of saline or particles suspended in saline 5 times per week for 12 weeks. The animals then received either bilateral ovariectomy (OVX) or false surgery (sham) and continued to receive saline or particles for 12 additional weeks, comprising four groups: CTRL, Polluted, OVX, and Polluted+OVX. Ovariectomy increased body weight and adiposity and promoted edema in hepatic tissue, hypercholesterolemia, glucose intolerance, and a pro-inflammatory profile (reduced IL-10 levels and increased IL-6/IL-10 ratio levels), independent of particle exposure. The Polluted+OVX group showed an increase in neutrophils and neutrophil/lymphocyte ratios, decreased antioxidant defense (SOD activity), and increased liver iHSP70 levels. In conclusion, alterations in the reproductive system predispose female organisms to particulate matter air pollution effects by affecting metabolic, oxidative, pro-inflammatory, and heat-shock protein expression.
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Affiliation(s)
- Pauline Brendler Goettems-Fiorin
- Research Group in Physiology, Department of Life Sciences, Regional University of Northwestern Rio Grande do Sul State (UNIJUÍ), Rua do Comércio, 3000 - Bairro Universitário, Ijuí, RS, 98700-000, Brazil.
- Atmospheric Pollution Laboratory, Postgraduate Program in Health Sciences, Federal University of Health Sciences of Porto Alegre (UFCSPA), Rua Sarmento Leite, 245, Porto Alegre, RS, Brazil.
| | - Lilian Corrêa Costa-Beber
- Research Group in Physiology, Department of Life Sciences, Regional University of Northwestern Rio Grande do Sul State (UNIJUÍ), Rua do Comércio, 3000 - Bairro Universitário, Ijuí, RS, 98700-000, Brazil
- Postgraduate Program in Integral Attention to Health (PPGAIS-UNIJUÍ/UNICRUZ), Ijuí, RS, Brazil
| | - Jaíne Borges Dos Santos
- Research Group in Physiology, Department of Life Sciences, Regional University of Northwestern Rio Grande do Sul State (UNIJUÍ), Rua do Comércio, 3000 - Bairro Universitário, Ijuí, RS, 98700-000, Brazil
| | - Paula Taís Friske
- Research Group in Physiology, Department of Life Sciences, Regional University of Northwestern Rio Grande do Sul State (UNIJUÍ), Rua do Comércio, 3000 - Bairro Universitário, Ijuí, RS, 98700-000, Brazil
| | - Lucas Machado Sulzbacher
- Research Group in Physiology, Department of Life Sciences, Regional University of Northwestern Rio Grande do Sul State (UNIJUÍ), Rua do Comércio, 3000 - Bairro Universitário, Ijuí, RS, 98700-000, Brazil
| | - Matias Nunes Frizzo
- Research Group in Physiology, Department of Life Sciences, Regional University of Northwestern Rio Grande do Sul State (UNIJUÍ), Rua do Comércio, 3000 - Bairro Universitário, Ijuí, RS, 98700-000, Brazil
- Postgraduate Program in Integral Attention to Health (PPGAIS-UNIJUÍ/UNICRUZ), Ijuí, RS, Brazil
| | - Mirna Stela Ludwig
- Research Group in Physiology, Department of Life Sciences, Regional University of Northwestern Rio Grande do Sul State (UNIJUÍ), Rua do Comércio, 3000 - Bairro Universitário, Ijuí, RS, 98700-000, Brazil
- Postgraduate Program in Integral Attention to Health (PPGAIS-UNIJUÍ/UNICRUZ), Ijuí, RS, Brazil
| | - Cláudia Ramos Rhoden
- Atmospheric Pollution Laboratory, Postgraduate Program in Health Sciences, Federal University of Health Sciences of Porto Alegre (UFCSPA), Rua Sarmento Leite, 245, Porto Alegre, RS, Brazil
| | - Thiago Gomes Heck
- Research Group in Physiology, Department of Life Sciences, Regional University of Northwestern Rio Grande do Sul State (UNIJUÍ), Rua do Comércio, 3000 - Bairro Universitário, Ijuí, RS, 98700-000, Brazil.
- Postgraduate Program in Integral Attention to Health (PPGAIS-UNIJUÍ/UNICRUZ), Ijuí, RS, Brazil.
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12
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Zhao YQ, Zhang L, Tao J, Chi CF, Wang B. Eight antihypertensive peptides from the protein hydrolysate of Antarctic krill (Euphausia superba): Isolation, identification, and activity evaluation on human umbilical vein endothelial cells (HUVECs). Food Res Int 2019; 121:197-204. [DOI: 10.1016/j.foodres.2019.03.035] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Revised: 03/12/2019] [Accepted: 03/14/2019] [Indexed: 12/11/2022]
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13
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Liu S, Tan J, Hu Y, Jia X, Kogut MH, Yuan J, Zhang H. Dietary l-arginine supplementation influences growth performance and B-cell secretion of immunoglobulin in broiler chickens. J Anim Physiol Anim Nutr (Berl) 2019; 103:1125-1134. [PMID: 31155767 DOI: 10.1111/jpn.13110] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2018] [Revised: 03/25/2019] [Accepted: 04/12/2019] [Indexed: 11/29/2022]
Abstract
Our previous study has shown that high levels of l-arginine (ARG) have reduced serum and mucosal antibody concentrations. In order to provide a better understanding in the application of ARG supplementation in the poultry industry, the study was conducted to investigate the effect of high levels of ARG on performance and B-cell secretion of immunoglobulin M (IgM) and IgG development in broiler chickens. A total of 192 1-day-old male Arbor Acres Plus broilers were randomly allocated into 4 groups (8 replicates per group, 6 birds per replicate) fed diets containing one of four ARG concentrations (analysed): 9.8, 14.7, 19.1 and 23.4 g/kg respectively. Growth performance was measured based on body weight gain (BWG), feed intake (FI) and feed conversion ratio (FCR). Increasing ARG quadratically increased (p < 0.05) BWG and FI with reaching plateau at 14.7 g/kg, while linearly decreased (p < 0.05) FCR, indicating that maximal performance required ARG no more than 14.7 g/kg in diets. Serum IgG and IgM concentrations were linearly reduced (p < 0.05) with increasing ARG. Chickens fed 19.1 g/kg or 23.4 g/kg ARG had lower (p < 0.05) serum IgG or IgM than chickens fed 9.8 g/kg ARG. As for the mRNA expression of bursal IgG and IgM, they were significantly downregulated with increasing ARG (p < 0.05). Chickens on ARG (>19.1 g/kg) had a lower (p < 0.05) IgG and IgM mRNA expression than chickens fed 9.8 g/kg. Activator of transcription 3 (STAT3) mRNA expression was linearly reduced with increasing ARG (p < 0.05), the transcriptional repressor B-cell lymphoma 6 (BCL6) mRNA expression was quadratically (p < 0.05) responded, and these cytokines had the lowest expression at 19.1 g/kg. ARG supplementation (>14.7 g/kg) did not significantly improve the growth performance, while it may have a potential negative regulatory effect on B-cell-mediated humoral immunity in chickens associated with suppression of the STAT3 expression associated with the JAK/STAT3 pathway.
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Affiliation(s)
- Shasha Liu
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
| | - JianZhuang Tan
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China.,Tech-bank Food Co., Ltd, Zhejiang, China
| | - Yadi Hu
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Xianbo Jia
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Michael H Kogut
- Southern Plains Agricultural Research Center, USDA-Agricultural Research Service, College Station, Texas
| | - Jianmin Yuan
- State Key Lab of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Hongfu Zhang
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
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Qiao Y, Zhang X, Zhao G, Liu Z, Yu M, Fang Z, Li X. Hepatocellular iNOS protects liver from ischemia/reperfusion injury through HSF1-dependent activation of HSP70. Biochem Biophys Res Commun 2019; 512:882-888. [PMID: 30929917 DOI: 10.1016/j.bbrc.2019.03.133] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Accepted: 03/20/2019] [Indexed: 12/01/2022]
Abstract
Although the role of inducible nitric oxide synthase (iNOS) in hepatic ischemia/reperfusion (I/R) injury remains controversial and confusing, with both harmful and beneficial effects in animal studies, the mechanism of these incongruous actions remains unclear. In the current study, we generated bone marrow chimeric mice with hepatocyte-restricted expression of iNOS. Chimeric mice and primary hepatocytes were subjected to I/R or anoxia/reoxygenation stimulation, respectively. The role of iNOS in liver I/R injury and the underlying molecular mechanisms were investigated. Hepatocyte-derived iNOS resulted in hepatoprotection from I/R injury, as well as in vitro experiments. Mechanistically, iNOS upregulates Heat shock protein (HSP) 70 by augmenting heat shock factor 1 (HSF1) binding to the HSP70 gene promoter. Importantly, inhibition of HSP70 partly reversed the iNOS overexpression-mediated hepatoprotection. The present findings demonstrate that hepatocellular iNOS protects from hepatic I/R injury through the HSF1-dependent activation of the HSP70. The upregulation of hepatocellular iNOS may offer a promising strategy for protecting against I/R injury.
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Affiliation(s)
- Yingli Qiao
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, 317000, China; Department of Hepatobiliary Surgery, Liaocheng People's Hospital, Liaocheng, Shandong, 252000, China
| | - Xueli Zhang
- Department of Hepatobiliary Surgery, Liaocheng People's Hospital, Liaocheng, Shandong, 252000, China
| | - Guimei Zhao
- Department of Hepatobiliary Surgery, Liaocheng People's Hospital, Liaocheng, Shandong, 252000, China
| | - Zhiheng Liu
- Department of Hepatobiliary Surgery, Liaocheng People's Hospital, Liaocheng, Shandong, 252000, China
| | - Mingyong Yu
- Department of Organ Transplantation, Liaocheng People's Hospital, Liaocheng, Shandong, 252000, China
| | - Zheping Fang
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, 317000, China.
| | - Xuehua Li
- Department of Hepatobiliary Surgery, Liaocheng People's Hospital, Liaocheng, Shandong, 252000, China.
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15
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Natarajan K, Abraham P, Kota R, Isaac B. NF-κB-iNOS-COX2-TNF α inflammatory signaling pathway plays an important role in methotrexate induced small intestinal injury in rats. Food Chem Toxicol 2018; 118:766-783. [DOI: 10.1016/j.fct.2018.06.040] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2018] [Revised: 06/16/2018] [Accepted: 06/19/2018] [Indexed: 12/21/2022]
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16
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Elaboration of curcumin-loaded rice bran albumin nanoparticles formulation with increased in vitro bioactivity and in vivo bioavailability. Food Hydrocoll 2018. [DOI: 10.1016/j.foodhyd.2017.11.027] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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17
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Miragem AA, Homem de Bittencourt PI. Nitric oxide-heat shock protein axis in menopausal hot flushes: neglected metabolic issues of chronic inflammatory diseases associated with deranged heat shock response. Hum Reprod Update 2018; 23:600-628. [PMID: 28903474 DOI: 10.1093/humupd/dmx020] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Accepted: 06/28/2017] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Although some unequivocal underlying mechanisms of menopausal hot flushes have been demonstrated in animal models, the paucity of similar approaches in humans impedes further mechanistic outcomes. Human studies might show some as yet unexpected physiological mechanisms of metabolic adaptation that permeate the phase of decreased oestrogen levels in both symptomatic and asymptomatic women. This is particularly relevant because both the severity and time span of hot flushes are associated with increased risk of chronic inflammatory disease. On the other hand, oestrogen induces the expression of heat shock proteins of the 70 kDa family (HSP70), which are anti-inflammatory and cytoprotective protein chaperones, whose expression is modulated by different types of physiologically stressful situations, including heat stress and exercise. Therefore, lower HSP70 expression secondary to oestrogen deficiency increases cardiovascular risk and predisposes the patient to senescence-associated secretory phenotype (SASP) that culminates in chronic inflammatory diseases, such as obesities, type 2 diabetes, neuromuscular and neurodegenerative diseases. OBJECTIVE AND RATIONALE This review focuses on HSP70 and its accompanying heat shock response (HSR), which is an anti-inflammatory and antisenescent pathway whose intracellular triggering is also oestrogen-dependent via nitric oxide (NO) production. The main goal of the manuscript was to show that the vasomotor symptoms that accompany hot flushes may be a disguised clue for important neuroendocrine alterations linking oestrogen deficiency to the anti-inflammatory HSR. SEARCH METHODS Results from our own group and recent evidence on hypothalamic control of central temperature guided a search on PubMed and Google Scholar websites. OUTCOMES Oestrogen elicits rapid production of the vasodilatory gas NO, a powerful activator of HSP70 expression. Whence, part of the protective effects of oestrogen over cardiovascular and neuroendocrine systems is tied to its capacity of inducing the NO-elicited HSR. The hypothalamic areas involved in thermoregulation (infundibular nucleus in humans and arcuate nucleus in other mammals) and whose neurons are known to have their function altered after long-term oestrogen ablation, particularly kisspeptin-neurokinin B-dynorphin neurons, (KNDy) are the same that drive neuroprotective expression of HSP70 and, in many cases, this response is via NO even in the absence of oestrogen. From thence, it is not illogical that hot flushes might be related to an evolutionary adaptation to re-equip the NO-HSP70 axis during the downfall of circulating oestrogen. WIDER IMPLICATIONS Understanding of HSR could shed light on yet uncovered mechanisms of menopause-associated diseases as well as on possible manipulation of HSR in menopausal women through physiological, pharmacological, nutraceutical and prebiotic interventions. Moreover, decreased HSR indices (that can be clinically determined with ease) in perimenopause could be of prognostic value in predicting the moment and appropriateness of starting a HRT.
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Affiliation(s)
- Antônio Azambuja Miragem
- Laboratory of Cellular Physiology, Department of Physiology, Federal University of Rio Grande do Sul, Rua Sarmento Leite 500, ICBS, 2nd Floor, Suite 350, Porto Alegre, RS 90050-170, Brazil.,Federal Institute of Education, Science and Technology 'Farroupilha', Rua Uruguai 1675, Santa Rosa, RS 98900-000, Brazil
| | - Paulo Ivo Homem de Bittencourt
- Laboratory of Cellular Physiology, Department of Physiology, Federal University of Rio Grande do Sul, Rua Sarmento Leite 500, ICBS, 2nd Floor, Suite 350, Porto Alegre, RS 90050-170, Brazil
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18
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Kattaia AAAA, Abd El-Baset SA, Mohamed EM. Heat Shock Proteins in Oxidative and Nitrosative Stress. HEAT SHOCK PROTEINS AND STRESS 2018. [DOI: 10.1007/978-3-319-90725-3_7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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19
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The Role of Nitric Oxide from Neurological Disease to Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 1007:71-88. [PMID: 28840553 DOI: 10.1007/978-3-319-60733-7_5] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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20
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Mazzei L, Cuello-Carrión FD, Docherty N, Manucha W. Heat shock protein 70/nitric oxide effect on stretched tubular epithelial cells linked to WT-1 cytoprotection during neonatal obstructive nephropathy. Int Urol Nephrol 2017; 49:1875-1892. [PMID: 28711961 DOI: 10.1007/s11255-017-1658-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Accepted: 07/10/2017] [Indexed: 11/29/2022]
Abstract
BACKGROUND Mechanical stress is a key pathogenic driver of apoptosis in the tubular epithelium in obstructive nephropathy. Heat shock protein 70 (Hsp70) and Wilms' tumor (WT-1) have been proposed to represent linked downstream effectors of the cytoprotective properties of NO. In the present study, we sought to evaluate whether the cytoprotective effects of L-arginine in neonatal obstructive nephropathy may be associated with NO-dependent increases in WT-1 and Hsp70 expression. METHODS Neonatal Wistar-Kyoto rats were submitted to complete unilateral ureteral obstruction (UUO) and treated thereafter with vehicle, L-NAME or L-arginine by daily gavage for 14 days to block or augment NO levels, respectively. Normal rat kidney epithelial cells by NRK-52E were exposed to mechanical stress in vitro in the presence or absence of L-NAME, L-arginine, sodium nitroprusside (SNP), L-arginine + SNP or L-arginine/L-NAME. Induction of apoptosis and the mRNA expression of WT-1 and Hsp70 genes were assessed. RESULTS WT-1 and Hsp70 genes expression decreased in the presence of L-NAME and following UUO coincident with increased tubular apoptosis. L-arginine treatment increased NO levels, reduced apoptosis and restored expression levels of WT-1 and Hsp70 to control levels. L-arginine treatment in vitro reduced basal apoptotic rates and prevented apoptosis in response to mechanical strain, an effect enhanced by SNP co-incubation. L-NAME increased apoptosis and prevented the anti-apoptotic action of L-arginine. CONCLUSIONS L-arginine treatment in experimental neonatal UUO reduces apoptosis coincident with restoration of WT-1 and Hsp70 expression levels and directly inhibits mechanical strain-induced apoptosis in an NO-dependent manner in vitro. This potentially implicates an NO-Hsp70-WT-1 axis in the cytoprotective effects of L-arginine.
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Affiliation(s)
- Luciana Mazzei
- Laboratorio de Farmacología Experimental Básica y Traslacional. IMBECU-CONICET (National Council of Scientific and Technical Research of Argentina), Buenos Aires, Argentina.,Área de Farmacología, Departamento de Patología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina
| | - Fernando Darío Cuello-Carrión
- Laboratorio de Farmacología Experimental Básica y Traslacional. IMBECU-CONICET (National Council of Scientific and Technical Research of Argentina), Buenos Aires, Argentina
| | - Neil Docherty
- Conway Institute of Biomolecular and Biomedical Research, School of Medicine, University College Dublin, Dublin, Ireland
| | - Walter Manucha
- Laboratorio de Farmacología Experimental Básica y Traslacional. IMBECU-CONICET (National Council of Scientific and Technical Research of Argentina), Buenos Aires, Argentina. .,Área de Farmacología, Departamento de Patología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina. .,Pharmacology Area, Pathology Department, Medical Sciences College, National University of Cuyo, Mendoza, CP5500, Argentina.
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21
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Choi YK, Kim JH, Lee DK, Lee KS, Won MH, Jeoung D, Lee H, Ha KS, Kwon YG, Kim YM. Carbon Monoxide Potentiation of L-Type Ca 2+ Channel Activity Increases HIF-1α-Independent VEGF Expression via an AMPKα/SIRT1-Mediated PGC-1α/ERRα Axis. Antioxid Redox Signal 2017; 27:21-36. [PMID: 27554679 DOI: 10.1089/ars.2016.6684] [Citation(s) in RCA: 50] [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] [Indexed: 12/12/2022]
Abstract
AIMS The heme oxygenase-1 (HO-1)/carbon monoxide (CO) pathway induced in astrocytes after ischemic brain injury promotes vascular endothelial growth factor (VEGF) expression to maintain and repair neurovascular function. Although HO-1-derived CO has been shown to induce hypoxia-inducible factor-1α (HIF-1α)-dependent VEGF expression, the underlying mechanism independent of HIF-1α remains to be elucidated. RESULTS HO-1 and VEGF were coexpressed in astrocytes of ischemic mouse brain tissues. Experiments with specific siRNAs and pharmacological activators/inhibitors of various target genes demonstrated that astrocytes pre-exposed to the CO-releasing compound, CORM-2, or transfected with HO-1 increased HIF-1α-independent VEGF expression via sequential activation of the following signal cascades; Ca2+/calmodulin-dependent protein kinase kinase β-mediated AMP-activated protein kinase (AMPK)α activation, AMPKα-induced increases in nicotinamide phosphoribosyltransferase (NAMPT) expression and cellular NAD+ level, sirtuin 1 (SIRT1)-dependent peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) stabilization and activation, and PGC-1α/estrogen-related receptor (ERR)α-mediated VEGF expression. All of these sequential events were blocked by an L-type voltage-gated Ca2+ channel inhibitor and Ca2+ chelators, but not by other Ca2+ channel inhibitors. INNOVATION HO-1-derived CO elicits Ca2+ influx by activating L-type Ca2+ channels, which is a key player in HIF-1α-independent VEGF expression by activating the AMPKα-NAMPT-SIRT1-PGC-1α/ERRα pathway. CONCLUSION Our results provide new mechanistic insight into the possible role for L-type Ca2+ channels in HO-1/CO-induced angiogenesis. Antioxid. Redox Signal. 27, 21-36.
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Affiliation(s)
- Yoon Kyung Choi
- 1 Department of Molecular and Cellular Biochemistry, Kangwon National University , Chuncheon, Republic of Korea
- 2 Department of Bioscience and Biotechnology, Konkuk University , Seoul, Republic of Korea
| | - Ji-Hee Kim
- 1 Department of Molecular and Cellular Biochemistry, Kangwon National University , Chuncheon, Republic of Korea
| | - Dong-Keun Lee
- 1 Department of Molecular and Cellular Biochemistry, Kangwon National University , Chuncheon, Republic of Korea
| | - Kwang-Soon Lee
- 1 Department of Molecular and Cellular Biochemistry, Kangwon National University , Chuncheon, Republic of Korea
| | - Moo-Ho Won
- 3 Department of Neurobiology, School of Medicine, Kangwon National University , Chuncheon, Republic of Korea
| | - Dooil Jeoung
- 4 Department of Biochemistry, Kangwon National University , Chuncheon, Republic of Korea
| | - Hansoo Lee
- 5 Department of Life Sciences, College of Natural Sciences, Kangwon National University , Chuncheon, Republic of Korea
| | - Kwon-Soo Ha
- 1 Department of Molecular and Cellular Biochemistry, Kangwon National University , Chuncheon, Republic of Korea
| | - Young-Guen Kwon
- 6 Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University , Seoul, Republic of Korea
| | - Young-Myeong Kim
- 1 Department of Molecular and Cellular Biochemistry, Kangwon National University , Chuncheon, Republic of Korea
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Sikalias N, Karatzas T, Alexiou K, Mountzalia L, Demonakou M, Kostakis ID, Zacharioudaki A, Papalois A, Kouraklis G. Intermittent Ischemic Preconditioning Protects Against Hepatic Ischemia-Reperfusion Injury and Extensive Hepatectomy in Steatotic Rat Liver. J INVEST SURG 2017. [PMID: 28644700 DOI: 10.1080/08941939.2017.1334844] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Hepatic steatosis causes severe liver damage and has deleterious effects when associated with ischemia-reperfusion mechanisms. Ischemic preconditioning (IPC) protects lean liver against prolonged ischemia by improving micro-circulation and reducing lipid peroxidation. We investigated the effect of intermittent IPC on liver ischemia-reperfusion injury (IRI) and extensive hepatectomy in severe hepatic steatosis. METHODS Severe hepatic steatosis was performed by 12-14 weeks of choline-free diet in 108 Wistar rats. We induced 30-minute ischemia-reperfusion manipulations and extensive hepatectomy with or without prior IPC in steatotic livers and after 6 and 24 hours of reperfusion blood transaminases, and IL6, TNFα, NO and Lactate in blood and liver tissue were measured. RESULTS Steatotic rats subjected to hepatic ischemia-reperfusion alone after extensive hepatectomy, showed severe liver damage with significantly increased values of AST, ALT, TNFα and Lactate and significantly reduced IL6 and NO, while no one rat survived for more than 29 hours. On the contrary, steatotic rats subjected to intermittent IPC, 24 hours before ischemia-reperfusion, presented increased 30-day survival (67%), lower values of AST, ALT, TNFα and Lactate, and increased IL6 and NO levels. Simple and intermittent IPC manipulations, 1 hour before the IRI and extended hepatectomy, did not prolong survival more than 57 and 98 hours, respectively. Simple IPC, 24 hours before IRI and extended hepatectomy had the lowest possible survival (16.7%). CONCLUSIONS Hepatic steatosis and IRI after major liver surgery largely affect morbidity and mortality. Intermittent IPC, 24 hours before IRI and extensive hepatectomy, presents higher 30-day survival and improved liver function parameters.
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Affiliation(s)
- Nikolaos Sikalias
- a Department of Surgery , Sismanogleion General Hospital , Athens , Greece
| | - Theodore Karatzas
- b Second Department of Propedeutic Surgery , National and Kapodistrian University of Athens, School of Medicine , Athens , Greece
| | | | | | - Maria Demonakou
- c Department of Pathology , Sismanogleion General Hospital , Athens , Greece
| | - Ioannis D Kostakis
- b Second Department of Propedeutic Surgery , National and Kapodistrian University of Athens, School of Medicine , Athens , Greece
| | | | | | - Gregory Kouraklis
- b Second Department of Propedeutic Surgery , National and Kapodistrian University of Athens, School of Medicine , Athens , Greece
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Loughran P, Xu L, Billiar T. Nitric Oxide and the Liver. LIVER PATHOPHYSIOLOGY 2017:799-816. [DOI: 10.1016/b978-0-12-804274-8.00058-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Fukazawa K, Lang JD. Role of nitric oxide in liver transplantation: Should it be routinely used? World J Hepatol 2016; 8:1489-1496. [PMID: 28008339 PMCID: PMC5143429 DOI: 10.4254/wjh.v8.i34.1489] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Revised: 08/06/2016] [Accepted: 10/18/2016] [Indexed: 02/06/2023] Open
Abstract
Ischemia-reperfusion injury (IRI) continues to be a major contributor to graft dysfunction, thus supporting the need for therapeutic strategies focused on minimizing organ damage especially with growing numbers of extended criteria grafts being utilized which are more vulnerable to cold and warm ischemia. Nitric oxide (NO·) is highly reactive gaseous molecule found in air and regarded as a pollutant. Not surprising, it is extremely bioactive, and has been demonstrated to play major roles in vascular homeostasis, neurotransmission, and host defense inflammatory reactions. Under conditions of ischemia, NO· has consistently been demonstrated to enhance microcirculatory vasorelaxation and mitigate pro-inflammatory responses, making it an excellent strategy for patients undergoing organ transplantation. Clinical studies designed to test this hypothesis have yielded very promising results that includes reduced hepatocellular injury and enhanced graft recovery without any identifiable complications. By what means NO· facilitates extra-pulmonary actions is up for debate and speculation. The general premise is that they are NO· containing intermediates in the circulation, that ultimately mediate either direct or indirect effects. A plethora of data exists explaining how NO·-containing intermediate molecules form in the plasma as S-nitrosothiols (e.g., S-nitrosoalbumin), whereas other compelling data suggest nitrite to be a protective mediator. In this article, we discuss the use of inhaled NO· as a way to protect the donor liver graft against IRI in patients undergoing liver transplantation.
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Manukhina EB, Downey HF, Mallet RT. Role of Nitric Oxide in Cardiovascular Adaptation to Intermittent Hypoxia. Exp Biol Med (Maywood) 2016; 231:343-65. [PMID: 16565431 DOI: 10.1177/153537020623100401] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Hypoxia is one of the most frequently encountered stresses in health and disease. The duration, frequency, and severity of hypoxic episodes are critical factors determining whether hypoxia is beneficial or harmful. Adaptation to intermittent hypoxia has been demonstrated to confer cardiovascular protection against more severe and sustained hypoxia, and, moreover, to protect against other stresses, including ischemia. Thus, the direct and cross protective effects of adaptation to intermittent hypoxia have been used for treatment and prevention of a variety of diseases and to increase efficiency of exercise training. Evidence is mounting that nitric oxide (NO) plays a central role in these adaptive mechanisms. NO-dependent protective mechanisms activated by intermittent hypoxia include stimulation of NO synthesis as well as restriction of NO overproduction. In addition, alternative, nonenzymic sources of NO and negative feedback of NO synthesis are important factors in optimizing NO concentrations. The adaptive enhancement of NO synthesis and/or availability activates or increases expression of other protective factors, including heat shock proteins, antioxidants and prostaglandins, making the protection more robust and sustained. Understanding the role of NO in mechanisms of adaptation to hypoxia will support development of therapies to prevent and treat hypoxic or ischemic damage to organs and cells and to increase adaptive capabilities of the organism.
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Leite JSM, Cruzat VF, Krause M, Homem de Bittencourt PI. Physiological regulation of the heat shock response by glutamine: implications for chronic low-grade inflammatory diseases in age-related conditions. ACTA ACUST UNITED AC 2016. [DOI: 10.1186/s41110-016-0021-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Mangipudy RS, Rao PS, Andrews A, Bucci TJ, Witzmann FA, Mehendale HM. Dose-Dependent Modulation of Cell Death: Apoptosis Versus Necrosis in Thioacetamide Hepatotoxicity. Int J Toxicol 2016. [DOI: 10.1080/109158198226701] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Apoptosis is programmed cell death, morphologically and biochemically distinct from necrosis. The objective of the present study was to examine thioacetamide-induced apoptosis over an early time course of 0 to 8 h after administration of a 12-fold dose range (50, 150, 300, and 600 mg/kg, ip) of thioacetamide (TA). Male Sprague-Daw ley rats (200-225 g) were used for the study. The incidence of apoptosis was determined by in situ end labeling, transmission electron microscopy, and charge modification of heat shock protein 70 (Hsp 70). Light microscopic examination of liver sections revealed apoptotic bodies (ABs)as early as 2 h after TA administration. A dose-dependent increase in the incidence of ABs was seen with all doses until 4 h. Thereafter, the incidence of ABs continued to increase in a temporal manner with 50 and 150 mg/kg, while it decreased in the rats treated with 300 and 600 mg/kg. Between 4 and 8 h, while necrosis as assessed by serum alanine aminotransferase (ALT) and histopathology declined in the sixfold dose range (50, 150, and 300 mg TA/kg), it increased in a temporal manner with 600 mg TA/kg. Preliminary studies indicate an inverse relation between Hsp 70 abundance and the incidence of apoptosis. Hsp 70 expression was significantly higher in the 600 mg TA/kg group compared to the lower doses. Lowest abundance was recorded in the groups receiving 50 and 150 mg TA/kg, where maximum apoptosis was noted. These findings collectively suggest that although the processes of apoptosis and necrosis are initiated simultaneously, the proportion of cells dying via either mechanism seems to be regulated by the dose of TA. Lower doses seem to favor cell death via apoptosis, while higher doses favor cell death via necrosis. Additionally, the inverse relation between Hsp 70 and apoptosis at lower doses suggests a regulatory role for Hsp 70.
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Affiliation(s)
- Raja S. Mangipudy
- Division of Toxicology, College of Pharmacy and Health Sciences, Northeast Louisiana University, Monroe, Louisiana, USA
| | - Prathibha S. Rao
- Division of Toxicology, College of Pharmacy and Health Sciences, Northeast Louisiana University, Monroe, Louisiana, USA
| | - Annette Andrews
- Pathology Associates, Inc., National Center for Toxicology Research, Jefferson, Arkansas, USA
| | - Thomas J. Bucci
- Pathology Associates, Inc., National Center for Toxicology Research, Jefferson, Arkansas, USA
| | - Frank A. Witzmann
- Division of Molecular Anatomy, Indiana University—Purdue University at Indianapolis, Columbus, Indiana, USA
| | - Harihara M. Mehendale
- Division of Toxicology, College of Pharmacy and Health Sciences, Northeast Louisiana University, Monroe, Louisiana, USA
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Latour I, Buc-Calderon P. Survival and Metabolic Function of Freshly Isolated Rat Hepatocytes Exposed First to a Heat Shock and Then to an Oxidative Stress. Int J Toxicol 2016. [DOI: 10.1080/109158199225387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
The formation of heat shock proteins (hsp) leading to thermotolerance has been extensively reported in many cell types. In freshly isolated rat hepatocytes, hsp were synthesized after 60 minutes of incubation at 42°C. Cell survival was not modified by such a treatment, but protein synthesis, secretion of triglycerides as lipoproteins, and the maintenance of both ATP and glycogen levels were significantly impaired. When exposed to an oxidative stress, heat-shocked hepatocytes were not more resistant than cells always kept at 37°C. Conversely, the addition of tert-butyl hydroperoxide (tBOOH) resulted, in general, in an increased lactate dehydrogenase leakage. The metabolism of tBOOH, as estimated by the reduced glutathione (GSH) content and GSH peroxidase activity, was similar in both control and heat-shocked hepatocytes. Despite the synthesis of hsp in rat hepatocytes, the lack of resistance to a subsequent oxidant injury may be due to the metabolic impairment caused by the heat shock.
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Affiliation(s)
- Isabelle Latour
- Unité de Pharmacocinétique, Métabolisme, Nutrition et Toxicologie, Département des Sciences Pharmac eutiques, Université Catholique de Louvain, Bruxelles, Belgium
| | - Pedro Buc-Calderon
- Unité de Pharmacocinétique, Métabolisme, Nutrition et Toxicologie, Département des Sciences Pharmac eutiques, Université Catholique de Louvain, Bruxelles, Belgium
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Zhang L, Xiang W, Wang G, Yan Z, Zhu Z, Guo Z, Sengupta R, Chen AF, Loughran PA, Lu B, Wang Q, Billiar TR. Interferon β (IFN-β) Production during the Double-stranded RNA (dsRNA) Response in Hepatocytes Involves Coordinated and Feedforward Signaling through Toll-like Receptor 3 (TLR3), RNA-dependent Protein Kinase (PKR), Inducible Nitric Oxide Synthase (iNOS), and Src Protein. J Biol Chem 2016; 291:15093-107. [PMID: 27226571 DOI: 10.1074/jbc.m116.717942] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Indexed: 12/19/2022] Open
Abstract
The sensing of double-stranded RNA (dsRNA) in the liver is important for antiviral defenses but can also contribute to sterile inflammation during liver injury. Hepatocytes are often the target of viral infection and are easily injured by inflammatory insults. Here we sought to establish the pathways involved in the production of type I interferons (IFN-I) in response to extracellular poly(I:C), a dsRNA mimetic, in hepatocytes. This was of interest because hepatocytes are long-lived and, unlike most immune cells that readily die after activation with dsRNA, are not viewed as cells with robust antimicrobial capacity. We found that poly(I:C) leads to rapid up-regulation of inducible nitric oxide synthase (iNOS), double-stranded RNA-dependent protein kinase (PKR), and Src. The production of IFN-β was dependent on iNOS, PKR, and Src and partially dependent on TLR3/Trif. iNOS and Src up-regulation was partially dependent on TLR3/Trif but entirely dependent on PKR. The phosphorylation of TLR3 on tyrosine 759 was shown to increase in parallel to IFN-β production in an iNOS- and Src-dependent manner, and Src was found to directly interact with TLR3 in the endosomal compartment of poly(I:C)-treated cells. Furthermore, we identified a robust NO/cGMP/PKG-dependent feedforward pathway for the amplification of iNOS expression. These data identify iNOS/NO as an integral component of IFN-β production in response to dsRNA in hepatocytes in a pathway that involves the coordinated activities of TLR3/Trif and PKR.
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Affiliation(s)
- Liyong Zhang
- From the Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213
| | - Wenpei Xiang
- From the Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, the Family Planning Research Institute, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guoliang Wang
- From the Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213
| | - Zhengzheng Yan
- From the Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213
| | - Zhaowei Zhu
- From the Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213
| | - Zhong Guo
- From the Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213
| | - Rajib Sengupta
- From the Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213
| | - Alex F Chen
- From the Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213
| | - Patricia A Loughran
- From the Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, the Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, and
| | - Ben Lu
- the Xiangya Third Hospital and Central South University School of Medicine, Changsha, China
| | - Qingde Wang
- From the Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213
| | - Timothy R Billiar
- From the Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213,
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Mazzei L, Docherty NG, Manucha W. Mediators and mechanisms of heat shock protein 70 based cytoprotection in obstructive nephropathy. Cell Stress Chaperones 2015; 20:893-906. [PMID: 26228633 PMCID: PMC4595437 DOI: 10.1007/s12192-015-0622-z] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2015] [Revised: 06/24/2015] [Accepted: 07/09/2015] [Indexed: 12/19/2022] Open
Abstract
Urinary heat shock protein 70 (Hsp70) is rapidly increased in patients with clinical acute kidney injury, indicating that it constitutes a component of the endogenous stress response to renal injury. Moreover, experimental models have demonstrated that Hsp70 activation is associated with the cytoprotective actions of several drugs following obstruction, including nitric oxide (NO) donors, geranylgeranylacetone, vitamin D, and rosuvastatin. Discrete and synergistic effects of the biological activities of Hsp70 may explain its cytoprotective role in obstructive nephropathy. Basic studies point to a combination of effects including inhibition of apoptosis and inflammation, repair of damaged proteins, prevention of unfolded protein aggregation, targeting of damaged protein for degradation, and cytoskeletal stabilization as primary effectors of Hsp70 action. This review summarizes our understanding of how the biological actions of Hsp70 may affect renal cytoprotection in the context of obstructive injury. The potential of Hsp70 to be of central importance to the mechanism of action of various drugs that modify the genesis of experimental obstructive nephropathy is considered.
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Affiliation(s)
- Luciana Mazzei
- Área de Farmacología, Departamento de Patología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina.
- IMBECU-CONICET (National Council of Scientific and Technical Research of Argentina), Buenos Aires, Argentina.
| | - Neil G Docherty
- Conway Institute of Biomolecular and Biomedical Research, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland
| | - Walter Manucha
- Área de Farmacología, Departamento de Patología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina
- IMBECU-CONICET (National Council of Scientific and Technical Research of Argentina), Buenos Aires, Argentina
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Beltran-Povea A, Caballano-Infantes E, Salguero-Aranda C, Martín F, Soria B, Bedoya FJ, Tejedo JR, Cahuana GM. Role of nitric oxide in the maintenance of pluripotency and regulation of the hypoxia response in stem cells. World J Stem Cells 2015; 7:605-617. [PMID: 25914767 PMCID: PMC4404395 DOI: 10.4252/wjsc.v7.i3.605] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Revised: 11/13/2014] [Accepted: 12/17/2014] [Indexed: 02/06/2023] Open
Abstract
Stem cell pluripotency and differentiation are global processes regulated by several pathways that have been studied intensively over recent years. Nitric oxide (NO) is an important molecule that affects gene expression at the level of transcription and translation and regulates cell survival and proliferation in diverse cell types. In embryonic stem cells NO has a dual role, controlling differentiation and survival, but the molecular mechanisms by which it modulates these functions are not completely defined. NO is a physiological regulator of cell respiration through the inhibition of cytochrome c oxidase. Many researchers have been examining the role that NO plays in other aspects of metabolism such as the cellular bioenergetics state, the hypoxia response and the relationship of these areas to stem cell stemness.
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Kruzliak P, Pechanova O, Kara T. New perspectives of nitric oxide donors in cardiac arrest and cardiopulmonary resuscitation treatment. Heart Fail Rev 2015; 19:383-90. [PMID: 23712508 PMCID: PMC3976759 DOI: 10.1007/s10741-013-9397-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Nitric oxide (NO) is often used to treat heart failure accompanied with pulmonary edema. According to present knowledge, however, NO donors are contraindicated when systolic blood pressure is less than 90 mmHg. Based on recent findings and our own clinical experience, we formulated a hypothesis about the new breakthrough complex lifesaving effects of NO donors in patients with cardiac arrest and cardiopulmonary resuscitation therapy. It includes a direct hemodynamic effect of NO donors mediated through vasodilation of coronary arteries in cooperation with improvement of cardiac function and cardiac output through reversible inhibition of mitochondrial complex I and mitochondrial NO synthase, followed by reduction in reactive oxygen species and correction of myocardial stunning. Simultaneously, an increase in vascular sensitivity to sympathetic stimulation could lead to an increase in diastolic blood pressure. Confirmation of this hypothesis in clinical practice would mean a milestone in the treatment for cardiac arrest and cardiopulmonary resuscitation.
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Affiliation(s)
- Peter Kruzliak
- Institute of Normal and Pathological Physiology and Centre of Excellence for Regulatory Role of Nitric Oxide in Civilization Diseases, Slovak Academy of Sciences, Bratislava, Slovak Republic,
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33
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Girotti AW. Tumor-generated nitric oxide as an antagonist of photodynamic therapy. Photochem Photobiol Sci 2015; 14:1425-32. [PMID: 25706541 DOI: 10.1039/c4pp00470a] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Nitric oxide (NO) is a multifunctional free radical molecule produced naturally by nitric oxide synthase (NOS) enzymes. Many tumors exploit NO for survival and growth signaling, and also to thwart the effects of therapeutic treatments, including PDT. The anti-PDT effects of NO were discovered using animal tumor models, but the mechanisms involved are still not fully understood. Recent in vitro studies on breast and prostate cancer cells have shown that inducible NOS (iNOS) along with NO is dramatically upregulated after an ALA-PDT-like challenge. Cells were more resistant to apoptosis after a photochallenge and survivors grew, migrated, and invaded more rapidly, iNOS/NO playing a key role in all these effects. This perspective briefly reviews what is currently known about NO's negative effects on PDT and some of the signaling mechanisms involved. It also provides insights into how these effects may be attenuated by pharmacologic use of iNOS inhibitors.
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Affiliation(s)
- Albert W Girotti
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
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34
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Deng M, Loughran PA, Zhang L, Scott MJ, Billiar TR. Shedding of the tumor necrosis factor (TNF) receptor from the surface of hepatocytes during sepsis limits inflammation through cGMP signaling. Sci Signal 2015; 8:ra11. [PMID: 25628461 DOI: 10.1126/scisignal.2005548] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Proteolytic cleavage of the tumor necrosis factor (TNF) receptor (TNFR) from the cell surface contributes to anti-inflammatory responses and may be beneficial in reducing the excessive inflammation associated with multiple organ failure and mortality during sepsis. Using a clinically relevant mouse model of polymicrobial abdominal sepsis, we found that the production of inducible nitric oxide synthase (iNOS) in hepatocytes led to the cyclic guanosine monophosphate (cGMP)-dependent activation of the protease TACE (TNF-converting enzyme) and the shedding of TNFR. Furthermore, treating mice with a cGMP analog after the induction of sepsis increased TNFR shedding and decreased systemic inflammation. Similarly, increasing the abundance of cGMP with a clinically approved phosphodiesterase 5 inhibitor (sildenafil) also decreased markers of systemic inflammation, protected against organ injury, and increased circulating amounts of TNFR1 in mice with sepsis. We further confirmed that a similar iNOS-cGMP-TACE pathway was required for TNFR1 shedding by human hepatocytes in response to the bacterial product lipopolysaccharide. Our data suggest that increasing the bioavailability of cGMP might be beneficial in ameliorating the inflammation associated with sepsis.
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Affiliation(s)
- Meihong Deng
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Patricia A Loughran
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA. Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Liyong Zhang
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Melanie J Scott
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Timothy R Billiar
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
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Choi SY, Choi JY, Lee JM, Lee S, Cho EJ. Tartary buckwheat on nitric oxide-induced inflammation in RAW264.7 macrophage cells. Food Funct 2015; 6:2664-70. [DOI: 10.1039/c5fo00639b] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
We investigated the effects of tartary buckwheat (TB, Fagopyrum tataricum) on the production of pro-inflammatory mediators in lipopolysaccharide (LPS)- and interferon (IFN)-γ-stimulated RAW264.7 cells.
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Affiliation(s)
- Soo Yeon Choi
- Department of Food Science and Nutrition
- Pusan National University
- Busan 609-735
- Republic of Korea
| | - Ji Yeon Choi
- Department of Food Science and Nutrition
- Pusan National University
- Busan 609-735
- Republic of Korea
| | - Jeong Min Lee
- Department of Integrative Plant Science
- Chung-Ang University
- Anseong 456-756
- Republic of Korea
| | - Sanghyun Lee
- Department of Integrative Plant Science
- Chung-Ang University
- Anseong 456-756
- Republic of Korea
| | - Eun Ju Cho
- Department of Food Science and Nutrition
- Pusan National University
- Busan 609-735
- Republic of Korea
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36
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Song AS, Najjar AM, Diller KR. Thermally induced apoptosis, necrosis, and heat shock protein expression in 3D culture. J Biomech Eng 2014; 136:1852724. [PMID: 24658653 DOI: 10.1115/1.4027272] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2014] [Accepted: 03/24/2014] [Indexed: 12/14/2022]
Abstract
This study was conducted to compare the heat shock responses of cells grown in 2D and 3D culture environments as indicated by the level of heat shock protein 70 expression and the incidence of apoptosis and necrosis of prostate cancer cell lines in response to graded hyperthermia. PC3 cells were stably transduced with a dual reporter system composed of two tandem expression cassettes-a conditional heat shock protein promoter driving the expression of green fluorescent protein (HSPp-GFP) and a cytomegalovirus (CMV) promoter controlling the constitutive expression of a "beacon" red fluorescent protein (CMVp-RFP). Two-dimensional and three-dimensional cultures of PC3 prostate cancer cells were grown in 96-well plates for evaluation of their time-dependent response to supraphysiological temperature. To induce controlled hyperthermia, culture plates were placed on a flat copper surface of a circulating water manifold that maintained the specimens within ±0.1°C of a target temperature. Hyperthermia protocols included various combinations of temperature, ranging from 37°C to 57°C, and exposure times of up to 2 h. The majority of protocols were focused on temperature and time permutations, where the response gradient was greatest. Post-treatment analysis by flow cytometry analysis was used to measure the incidences of apoptosis (annexin V-FITC stain), necrosis (propidium iodide (PI) stain), and HSP70 transcription (GFP expression). Cells grown in 3D compared with 2D culture showed reduced incidence of apoptosis and necrosis and a higher level of HSP70 expression in response to heat shock at the temperatures tested. Cells responded differently to hyperthermia when grown in 2D and 3D cultures. Three-dimensional culture appears to enhance survival plausibly by activating protective processes related to enhanced-HSP70 expression. These differences highlight the importance of selecting physiologically relevant 3D models in assessing cellular responses to hyperthermia in experimental settings.
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Wu C, Wang J, Xu W, Zhang W, Mai K. Dietary ascorbic acid modulates the expression profile of stress protein genes in hepatopancreas of adult Pacific abalone Haliotis discus hannai Ino. FISH & SHELLFISH IMMUNOLOGY 2014; 41:120-125. [PMID: 25193867 DOI: 10.1016/j.fsi.2014.08.026] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/14/2011] [Revised: 08/19/2014] [Accepted: 08/25/2014] [Indexed: 06/03/2023]
Abstract
This study was conducted to investigate the effects of dietary ascorbic acid (AA) on transcriptional expression patterns of antioxidant proteins, heat shock proteins (HSP) and nuclear factor kappa B (NF-κB) in the hepatopancreas of Pacific abalone Haliotis discus hannai Ino (initial average length: 84.36 ± 0.24 mm) using real-time quantitative PCR assays. L-ascorbyl-2-molyphosphate (LAMP) was added to the basal diet to formulate four experimental diets containing 0.0, 70.3, 829.8 and 4967.5 mg AA equivalent kg(-1) diets, respectively. Each diet was fed to triplicate groups of adult abalone in acrylic tanks (200 L) in a flow-through seawater system. Each tank was stocked with 15 abalone. Animals were fed once daily (17:00) to apparent satiation for 24 weeks. The results showed that the dietary AA (70.3 mg kg(-1)) could significantly up-regulate the expression levels of Cu/Zn superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferase (GST), feritin (FT) and heat shock protein 26 (HSP26) in the hepatopancreas of abalone in this treatment compared to the controls. However, the expression levels of Mn-SOD, glutathione peroxidase (GPX), thioredoxin peroxidase (TPx), selenium-binding protein (SEBP), HSP70 and HSP90 were significantly down-regulated. Compared with those in the group with 70.3 mg kg(-1) dietary AA, the expression levels of CAT, GST and HSP26 were decreased in abalone fed with very high dietary AA (4967.5 mg kg(-1)). In addition, significant up-regulations of expression levels of Mn-SOD, GPX, TPx, SEBP, FT, HSP70, HSP90 and NF-κB were observed in abalone fed with apparently excessive dietary AA (829.8 and 4967.5 mg kg(-1)) as compared to those fed 70.3 mg kg(-1) dietary AA. These findings showed that dietary AA influenced the expression levels of antioxidant proteins, heat shock proteins and NF-κB in the hepatopancreas of abalone at transcriptional level. Levels of dietary AA that appeared adequate (70.3 mg kg(-1)) reduced the oxidative stress by influencing gene expression of antioxidant proteins, but excessive dietary AA (829.8 and 4967.5 mg kg(-1)) induced oxidative stress in Pacific abalone H. discus hannai.
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Affiliation(s)
- Chenglong Wu
- The Key Laboratory of Mariculture (Education Ministry of China), Ocean University of China, 5 Yushan Road, Qingdao, Shandong 266003, PR China; Zhejiang Provincial Key Laboratory of Aquatic Resources Conservation and Development, Huzhou University, 1 Xueshi Road, Huzhou 313000, PR China
| | - Jia Wang
- The Key Laboratory of Mariculture (Education Ministry of China), Ocean University of China, 5 Yushan Road, Qingdao, Shandong 266003, PR China
| | - Wei Xu
- The Key Laboratory of Mariculture (Education Ministry of China), Ocean University of China, 5 Yushan Road, Qingdao, Shandong 266003, PR China
| | - Wenbing Zhang
- The Key Laboratory of Mariculture (Education Ministry of China), Ocean University of China, 5 Yushan Road, Qingdao, Shandong 266003, PR China.
| | - Kangsen Mai
- The Key Laboratory of Mariculture (Education Ministry of China), Ocean University of China, 5 Yushan Road, Qingdao, Shandong 266003, PR China
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Lakshmanan J, Zhang B, Nweze IC, Du Y, Harbrecht BG. Glycogen Synthase Kinase 3 Regulates IL-1β Mediated iNOS Expression in Hepatocytes by Down-Regulating c-Jun. J Cell Biochem 2014; 116:133-41. [DOI: 10.1002/jcb.24951] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2013] [Accepted: 08/22/2014] [Indexed: 11/10/2022]
Affiliation(s)
- Jaganathan Lakshmanan
- Hiram C. Polk Jr., MD; Department of Surgery and Price Institute of Surgical Research; School of Medicine; University of Louisville; Louisville 40202 Kentucky
| | - Baochun Zhang
- Hiram C. Polk Jr., MD; Department of Surgery and Price Institute of Surgical Research; School of Medicine; University of Louisville; Louisville 40202 Kentucky
| | - Ikenna C. Nweze
- Hiram C. Polk Jr., MD; Department of Surgery and Price Institute of Surgical Research; School of Medicine; University of Louisville; Louisville 40202 Kentucky
| | - Yibo Du
- Hiram C. Polk Jr., MD; Department of Surgery and Price Institute of Surgical Research; School of Medicine; University of Louisville; Louisville 40202 Kentucky
| | - Brian G. Harbrecht
- Hiram C. Polk Jr., MD; Department of Surgery and Price Institute of Surgical Research; School of Medicine; University of Louisville; Louisville 40202 Kentucky
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Jain K, Suryakumar G, Ganju L, Singh SB. Differential hypoxic tolerance is mediated by activation of heat shock response and nitric oxide pathway. Cell Stress Chaperones 2014; 19:801-12. [PMID: 24590457 PMCID: PMC4389840 DOI: 10.1007/s12192-014-0504-9] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2013] [Revised: 02/11/2014] [Accepted: 02/12/2014] [Indexed: 12/16/2022] Open
Abstract
The fall in ambient oxygen pressure in high-altitude milieu elicits a wide range of physiological responses in the myocardium, which may differ from individual to individual. This condition, known as hypobaric hypoxia, invokes the cardioprotective heat shock response. The present study focuses on the role played by this ubiquitous response in mediating a differential tolerance to acute hypoxic stress. Sprague Dawley rats were exposed to simulated hypoxia equivalent to 223 mmHg pressure, screened on the basis of time taken for onset of a characteristic hyperventilatory response, and categorized as susceptible (<10 min), normal (10-25 min), or tolerant (>25 min). The tolerant animals displayed a significant upregulation of heat shock protein (Hsp)70/HSPA, evident through immunohistochemical staining of the cardiac tissue. The increased expression of transcription factor heat shock factor-1 led to the downstream activation of other chaperones, including Hsp90/HSPC, Hsp60/HSPD1, and Hsp27/HSPB1. The higher induction of HSPs in tolerant animals contributed to higher nitric oxide synthesis mediated by both endothelial nitric oxide synthase and inducible nitric oxide synthase activation. Conversely, susceptible animals showed significantly higher expression of the proinflammatory markers tumor necrosis factor alpha and nuclear factor kappa-light-chain enhancer of activated B cells in the myocardium. Evaluation of circulatory stress markers identified increased levels of reactive oxygen species, corticosterone and endothelin-1 in the susceptible animals highlighting their vulnerability to hypoxic stress. The heat shock response, through the action of chaperones and enhanced NO generation thus contributes substantially to the ability to sustain survival under acute sub lethal hypoxia.
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Affiliation(s)
- Kanika Jain
- Cellular Biochemistry Division, Defence Institute of Physiology and Allied Sciences, Lucknow Road, Timarpur, Delhi 110054 India
| | - Geetha Suryakumar
- Cellular Biochemistry Division, Defence Institute of Physiology and Allied Sciences, Lucknow Road, Timarpur, Delhi 110054 India
| | - Lilly Ganju
- Cellular Biochemistry Division, Defence Institute of Physiology and Allied Sciences, Lucknow Road, Timarpur, Delhi 110054 India
| | - Shashi Bala Singh
- Cellular Biochemistry Division, Defence Institute of Physiology and Allied Sciences, Lucknow Road, Timarpur, Delhi 110054 India
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Nitric oxide plays a dual role in the oxidative injury of cultured rat microglia but not astroglia. Neuroscience 2014; 281:164-77. [PMID: 25280787 DOI: 10.1016/j.neuroscience.2014.09.048] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2014] [Revised: 09/14/2014] [Accepted: 09/23/2014] [Indexed: 01/28/2023]
Abstract
Nitric oxide (NO) and oxidative stress caused by reactive oxygen species (ROS) accumulation are two important factors that lead to the progression of human neurological diseases. NO can be detrimental or protective to neurons under oxidative toxicity; however, in the case of brain exposure to oxidative stress, in addition to neurons, the existence of glia may also be disturbed by toxic ROS. The influence NO will have on ROS-mediated glial injury remains unclear. Here, we examined the effects of NO on cell viability under oxidative stress induced by hydrogen peroxide (H2O2) in rat primary mixed glia cultures, as well as pure astroglia and microglia cultures. We found that in mixed glia cultures, both H2O2 and NO donor S-nitroso-N-acetyl-d,l-penicillamine (SNAP) elicited cell death in a concentration-dependent manner. Combinations of H2O2 and SNAP at sublytic concentrations were sufficient to damage mixed glia, and sublytic concentrations of SNAP could reduce the insults that resulted from toxic H2O2. Furthermore, in microglia or astroglia, sublytic concentrations of H2O2 were toxic when combined with SNAP, and the potency was increased with an increased SNAP concentration. In microglia but not astroglia, a toxic H2O2-induced apoptotic injury was attenuated by a sublytic level of SNAP. H2O2 at toxic levels activated p38 mitogen-activated protein kinases (MAPK) and p53 pathways and increased DNA double strand breaks (DSBs) in microglia, whereas the rescue exerted by sublytic SNAP against toxic H2O2 occurred via the activation of both Akt and extracellular-signal-regulated kinase (ERK) cascades and decreased DNA DSBs. Moreover, a sublytic concentration of SNAP induced both heat shock protein 70 and heme oxygenase-1, which may be involved in decreasing the susceptibility of microglia to H2O2 toxicity. These results suggest that NO exhibits a concentration-dependent dual action of weakening or enhancing oxidative injury in mixed glia, particularly microglia.
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Park MY, Jeong YJ, Kang GC, Kim MH, Kim SH, Chung HJ, Jung JY, Kim WJ. Nitric oxide-induced apoptosis of human dental pulp cells is mediated by the mitochondria-dependent pathway. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2014; 18:25-32. [PMID: 24634593 PMCID: PMC3951820 DOI: 10.4196/kjpp.2014.18.1.25] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/11/2013] [Revised: 12/13/2013] [Accepted: 01/08/2014] [Indexed: 01/06/2023]
Abstract
Nitric oxide (NO) is recognized as a mediator and regulator of inflammatory responses. NO is produced by nitric oxide synthase (NOS), and NOS is abundantly expressed in the human dental pulp cells (HDPCs). NO produced by NOS can be cytotoxic at higher concentrations to HDPCs. However, the mechanism by which this cytotoxic pathway is activated in cells exposed to NO is not known. The purpose of this study was to elucidate the NO-induced cytotoxic mechanism in HDPCs. Sodium nitroprusside (SNP), a NO donor, reduced the viability of HDPCs in a dose- and time-dependent manner. We investigated the in vitro effects of nitric oxide on apoptosis of cultured HDPCs. Cells showed typical apoptotic morphology after exposure to SNP. Besides, the number of Annexin V positive cells was increased among the SNP-treated HDPCs. SNP enhanced the production of reactive oxygen species (ROS), and N-acetylcysteine (NAC) ameliorated the decrement of cell viability induced by SNP. However, a soluble guanylate cyclase inhibitor (ODQ) did not inhibited the decrement of cell viability induced by SNP. SNP increased cytochrome c release from the mitochondria to the cytosol and the ratio of Bax/Bcl-2 expression levels. Moreover, SNP-treated HDPCs elevated activities of caspase-3 and caspase-9. While pretreatment with inhibitors of caspase (z-VAD-fmk, z-DEVD-fmk) reversed the NO-induced apoptosis of HDPCs. From these results, it can be suggested that NO induces apoptosis of HDPCs through the mitochondria-dependent pathway mediated by ROS and Bcl-2 family, but not by the cyclic GMP pathway.
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Affiliation(s)
- Min Young Park
- Dental Science Research Institute and Medical Research Center for Biomineralization Disorders, Department of Oral Physiology, School of Dentistry, Chonnam National University, Gwangju 500-757, Korea
| | - Yeon Jin Jeong
- Dental Science Research Institute and Medical Research Center for Biomineralization Disorders, Department of Oral Physiology, School of Dentistry, Chonnam National University, Gwangju 500-757, Korea
| | - Gi Chang Kang
- Dental Science Research Institute and Medical Research Center for Biomineralization Disorders, Department of Oral Physiology, School of Dentistry, Chonnam National University, Gwangju 500-757, Korea
| | - Mi-Hwa Kim
- Dental Science Research Institute and Medical Research Center for Biomineralization Disorders, Department of Oral Physiology, School of Dentistry, Chonnam National University, Gwangju 500-757, Korea
| | - Sun Hun Kim
- Dental Science Research Institute and Medical Research Center for Biomineralization Disorders, Department of Oral Anatomy, School of Dentistry, Chonnam National University, Gwangju 500-757, Korea
| | - Hyun-Ju Chung
- Dental Science Research Institute and Medical Research Center for Biomineralization Disorders, Department of Periodontology, School of Dentistry, Chonnam National University, Gwangju 500-757, Korea
| | - Ji Yeon Jung
- Dental Science Research Institute and Medical Research Center for Biomineralization Disorders, Department of Oral Physiology, School of Dentistry, Chonnam National University, Gwangju 500-757, Korea
| | - Won Jae Kim
- Dental Science Research Institute and Medical Research Center for Biomineralization Disorders, Department of Oral Physiology, School of Dentistry, Chonnam National University, Gwangju 500-757, Korea
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Stitt BC, Burness G, Burgomaster KA, Currie S, McDermid JL, Wilson CC. Intraspecific Variation in Thermal Tolerance and Acclimation Capacity in Brook Trout (Salvelinus fontinalis): Physiological Implications for Climate Change. Physiol Biochem Zool 2014; 87:15-29. [DOI: 10.1086/675259] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
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Vince AR, Hayes MA, Jefferson BJ, Stalker MJ. Hepatic Injury Correlates With Apoptosis, Regeneration, and Nitric Oxide Synthase Expression in Canine Chronic Liver Disease. Vet Pathol 2013; 51:932-45. [DOI: 10.1177/0300985813513041] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Assessment of the clinical severity, pathogenesis, and prognosis of canine chronic liver disease poses significant challenges to clinicians and pathologists, relating in part to a lack of standardized terminology and assessment methods and also to a lack of understanding of the pathogenesis of chronic liver disease in the dog. This study graded the severity of necroinflammatory activity in chronic liver disease in dogs using a modification of Ishak’s grading scheme for human chronic liver disease and examined the association of grade score with hepatocellular apoptosis, regeneration, nitric oxide synthase isoform expression, copper and iron accumulation, and indicators of oxidative stress. Formalin-fixed, paraffin-embedded hematoxylin and eosin (HE)–stained liver biopsies from 45 dogs with chronic liver disease and 55 healthy control dogs were graded for various morphologic components of liver injury and response. The cumulative score for grade of necroinflammatory activity was strongly and significantly correlated with immunoreactive labels for hepatocellular proliferation (Ki-67); apoptosis (cleaved caspase-3); inducible nitric oxide synthase (iNOS) in lobular, portal, and septal stromal cells; endothelial nitric oxide synthase (eNOS) in hepatocytes and lobular, portal, and septal stromal cells; and total stainable hepatic iron. A weaker significant correlation was found between grade and accumulation of hepatocellular copper. No significant correlation was found between grade and immunoreactivity for malondialdehyde-protein adducts. These results document a method for grading of the severity of necroinflammatory disease in canine liver biopsies and show an association with increased iNOS and eNOS expression.
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Affiliation(s)
- A. R. Vince
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada
| | - M. A. Hayes
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada
| | - B. J. Jefferson
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada
| | - M. J. Stalker
- Animal Health Laboratory, Laboratory Services Division, University of Guelph, Guelph, Ontario, Canada
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Fouad AA, Al-Mulhim AS, Gomaa W. Protective effect of cannabidiol against cadmium hepatotoxicity in rats. J Trace Elem Med Biol 2013; 27:355-363. [PMID: 23993482 DOI: 10.1016/j.jtemb.2013.07.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2013] [Revised: 06/17/2013] [Accepted: 07/01/2013] [Indexed: 11/24/2022]
Abstract
The protective effect of cannabidiol, the non-psychoactive component of Cannabis sativa, against liver toxicity induced by a single dose of cadmium chloride (6.5 mgkg(-1) i.p.) was investigated in rats. Cannabidiol treatment (5 mgkg(-1)/day, i.p.) was applied for five days starting three days before cadmium administration. Cannabidiol significantly reduced serum alanine aminotransferase, and suppressed hepatic lipid peroxidation, prevented the depletion of reduced glutathione and nitric oxide, and catalase activity, and attenuated the elevation of cadmium level in the liver tissue resulted from cadmium administration. Histopathological examination showed that cadmium-induced liver tissue injury was ameliorated by cannabidiol treatment. Immunohistochemical analysis revealed that cannabidiol significantly decreased the cadmium-induced expression of tumor necrosis factor-α, cyclooxygenase-2, nuclear factor-κB, caspase-3, and caspase-9, and increased the expression of endothelial nitric oxide synthase in liver tissue. It was concluded that cannabidiol may represent a potential option to protect the liver tissue from the detrimental effects of cadmium toxicity.
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Affiliation(s)
- Amr A Fouad
- Department of Biomedical Sciences, Pharmacology Division, College of Medicine, King Faisal University, Al-Ahsa, Saudi Arabia.
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Piterková J, Luhová L, Mieslerová B, Lebeda A, Petřivalský M. Nitric oxide and reactive oxygen species regulate the accumulation of heat shock proteins in tomato leaves in response to heat shock and pathogen infection. PLANT SCIENCE : AN INTERNATIONAL JOURNAL OF EXPERIMENTAL PLANT BIOLOGY 2013; 207:57-65. [PMID: 23602099 DOI: 10.1016/j.plantsci.2013.02.010] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/10/2012] [Revised: 02/08/2013] [Accepted: 02/16/2013] [Indexed: 05/02/2023]
Abstract
Heat shock proteins (HSP) are produced in response to various stress stimuli to prevent cell damage. We evaluated the involvement of nitric oxide (NO) and reactive oxygen species (ROS) in the accumulation of Hsp70 proteins in tomato leaves induced by abiotic and biotic stress stimuli. A model system of leaf discs was used with two tomato genotypes, Solanum lycopersicum cv. Amateur and Solanum chmielewskii, differing in their resistance to fungal pathogen Oidium neolycopersici. Leaf discs were exposed to stress factors as heat shock and pathogen infection alone or in a combination, and treated with substances modulating endogenous NO and ROS levels. Two proteins of Hsp70 family were detected in stressed tomato leaf discs: a heat-inducible 72 kDa protein and a constitutive 75 kDa protein. The pathogenesis and mechanical stress influenced Hsp75 accumulation, whereas heat stress induced mainly Hsp72 production. Treatment with NO donor and NO scavenger significantly modulated the level of Hsp70 in variable manner related to the genotype resistance. Hsp70 accumulation correlated with endogenous NO level in S. lycopersicum and ROS levels in S. chmielewskii. We conclude NO and ROS are involved in the regulation of Hsp70 production and accumulation under abiotic and biotic stresses in dependence on plant ability to trigger its defence mechanisms.
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Affiliation(s)
- Jana Piterková
- Department of Biochemistry, Faculty of Science, Palacký University in Olomouc, Šlechtitelů 11, 78371 Olomouc, Czech Republic
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Seo OW, Kim JH, Lee KS, Lee KS, Kim JH, Won MH, Ha KS, Kwon YG, Kim YM. Kurarinone promotes TRAIL-induced apoptosis by inhibiting NF-κB-dependent cFLIP expression in HeLa cells. Exp Mol Med 2013; 44:653-64. [PMID: 22932446 PMCID: PMC3509182 DOI: 10.3858/emm.2012.44.11.074] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
This study was designed to investigate the effects of the prenylated flavonoid kurarinone on TNF-related apoptosis inducing ligand (TRAIL)-induced apoptosis and its underlying mechanism. A low dose of kurarinone had no significant effect on apoptosis, but this compound markedly promoted tumor cell death through elevation of Bid cleavage, cytochrome c release and caspase activation in HeLa cells treated with TRAIL. Caspase inhibitors inhibited kurarinone-mediated cell death, which indicates that the cytotoxic effect of this compound is mediated by caspase-dependent apoptosis. The cytotoxic effect of kurarinone was not associated with expression levels of Bcl-2 and IAP family proteins, such as Bcl-2, Bcl-xL, Bid, Bad, Bax, XIAP, cIAP-1 and cIAP-2. In addition, this compound did not regulate the death-inducing receptors DR4 and DR5. On the other hand, kurarinone significantly inhibited TRAIL-induced IKK activation, IκB degradation and nuclear translocation of NF-κB, as well as effectively suppressed cellular FLICE-inhibitory protein long form (cFLIPL) expression. The synergistic effects of kurarinone on TRAIL-induced apoptosis were mimicked when kurarinone was replaced by the NF-κB inhibitor withaferin A or following siRNA-mediated knockdown of cFLIPL. Moreover, cFLIP overexpression effectively antagonized kurarinone-mediated TRAIL sensitization. These data suggest that kurarinone sensitizes TRAIL-induced tumor cell apoptosis via suppression of NF-κB-dependent cFLIP expression, indicating that this compound can be used as an anti-tumor agent in combination with TRAIL.
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Affiliation(s)
- Ok Won Seo
- Vascular Homeostasis Laboratory, Departments of Molecular and Cellular Biochemistry and Institute of Medical Sciences School of Medicine Kangwon National University
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LI LH, WANG JS, KONG LY. Protective effects of Shengmai San and its three fractions on cerebral ischemia-reperfusion injury. Chin J Nat Med 2013; 11:222-30. [DOI: 10.1016/s1875-5364(13)60020-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2012] [Indexed: 11/26/2022]
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Bhowmick R, Girotti AW. Cytoprotective signaling associated with nitric oxide upregulation in tumor cells subjected to photodynamic therapy-like oxidative stress. Free Radic Biol Med 2013; 57:39-48. [PMID: 23261943 PMCID: PMC3594367 DOI: 10.1016/j.freeradbiomed.2012.12.005] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2012] [Revised: 12/04/2012] [Accepted: 12/07/2012] [Indexed: 12/12/2022]
Abstract
Photodynamic therapy (PDT) employs photoexcitation of a sensitizer to generate tumor-eradicating reactive oxygen species. We recently showed that irradiating breast cancer COH-BR1 cells after treating with 5-aminolevulinic acid (ALA, a pro-sensitizer) resulted in rapid upregulation of inducible nitric oxide (NO) synthase (iNOS). Apoptotic cell killing was strongly enhanced by an iNOS inhibitor (1400W), iNOS knockdown (kd), or a NO scavenger, suggesting that NO was acting cytoprotectively. Stress signaling associated with these effects was examined in this study. ALA/light-stressed COH-BR1 cells, and also breast adenocarcinoma MDA-MB-231 cells, mounted an iNOS/NO-dependent resistance to apoptosis that proved to be cGMP-independent. Immunocytochemistry and subcellular Western analysis of photostressed COH-BR1 cells revealed a cytosol-to-nucleus translocation of NF-κB which was negated by the NF-κB activation inhibitor Bay11. Bay11 also enhanced apoptosis and prevented iNOS induction, consistent with NF-κB involvement in the latter. JNK and p38 MAP kinase inhibitors suppressed apoptosis, implicating these kinases in death signaling. Post-irradiation extent and duration of JNK and p38 phosphorylation were dramatically elevated by 1400 W or iNOS-kd, suggesting that these activations were suppressed by NO. Regarding pro-survival stress signaling, rapid activation of Akt was unaffected by 1400 W, but prevented by Wortmannin, which also enhanced apoptosis. Thus, a link between upstream Akt activation and iNOS induction was apparent. Furthermore, p53 protein expression under photostress was elevated by iNOS-kd, whereas robust Survivin induction was abolished, consistent with p53 and Survivin being negatively and positively regulated by NO, respectively. Collectively, these findings enhance our understanding of cytoprotective signaling associated with photostress-induced NO and suggest iNOS inhibitor-based approaches for improving PDT efficacy.
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Affiliation(s)
- Reshma Bhowmick
- To whom correspondence may be addressed: Reshma Bhowmick, Ph.D. Department of Biochemistry Medical College of Wisconsin Milwaukee, WI, 53226 Tel: 414-955-8445
| | - Albert W. Girotti
- To whom correspondence may be addressed: Albert W. Girotti, Ph.D. Department of Biochemistry Medical College of Wisconsin Milwaukee, WI, 53226 Tel: 414-955-8432
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Comparative analysis of physicochemicals and antioxidative properties in new red rice (Oryza sativa L. cv. Gunganghongmi). ACTA ACUST UNITED AC 2013. [DOI: 10.1007/s12892-012-0057-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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Masoud MS, Anwar SS, Afzal MZ, Mehmood A, Khan SN, Riazuddin S. Pre-conditioned mesenchymal stem cells ameliorate renal ischemic injury in rats by augmented survival and engraftment. J Transl Med 2012; 10:243. [PMID: 23217165 PMCID: PMC3543338 DOI: 10.1186/1479-5876-10-243] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2012] [Accepted: 11/28/2012] [Indexed: 01/09/2023] Open
Abstract
Background Ischemia is the major cause of acute kidney injury (AKI), associated with high mortality and morbidity. Mesenchymal stem cells (MSCs) have multilineage differentiation potential and can be a potent therapeutic option for the cure of AKI. Methods MSCs were cultured in four groups SNAP (S-nitroso N-acetyl penicillamine), SNAP + Methylene Blue (MB), MB and a control for in vitro analysis. Cultured MSCs were pre-conditioned with either SNAP (100 μM) or MB (1 μM) or both for 6 hours. Renal ischemia was induced in four groups (as in in vitro study) of rats by clamping the left renal padicle for 45 minutes and then different pre-conditioned stem cells were transplanted. Results We report that pre-conditioning of MSCs with SNAP enhances their proliferation, survival and engraftment in ischemic kidney. Rat MSCs pre-conditioned with SNAP decreased cell apoptosis and increased proliferation and cytoprotective genes’ expression in vitro. Our in vivo data showed enhanced survival and engraftment, proliferation, reduction in fibrosis, significant improvement in renal function and higher expression of pro-survival and pro-angiogenic factors in ischemic renal tissue in SNAP pre-conditioned group of animals. Cytoprotective effects of SNAP pre-conditioning were abrogated by MB, an inhibitor of nitric oxide synthase (NOS) and guanylate cyclase. Conclusion The results of these studies demonstrate that SNAP pre-conditioning might be useful to enhance therapeutic potential of MSCs in attenuating renal ischemia reperfusion injury.
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Affiliation(s)
- Muhammad Shareef Masoud
- National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.
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