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Huang W, Zheng J, Wang M, Du LY, Bai L, Tang H. The potential therapeutic role of melatonin in organ fibrosis: a comprehensive review. Front Med (Lausanne) 2024; 11:1502368. [PMID: 39735699 PMCID: PMC11681627 DOI: 10.3389/fmed.2024.1502368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Accepted: 11/30/2024] [Indexed: 12/31/2024] Open
Abstract
Organ fibrosis is a pathological process characterized by the inability of normal tissue cells to regenerate sufficiently to meet the dynamic repair demands of chronic injury, resulting in excessive extracellular matrix deposition and ultimately leading to organ dysfunction. Despite the increasing depth of research in the field of organ fibrosis and a more comprehensive understanding of its pathogenesis, effective treatments for fibrosis-related diseases are still lacking. Melatonin, a neuroendocrine hormone synthesized by the pineal gland, plays a crucial role in regulating biological rhythms, sleep, and antioxidant defenses. Recent studies have shown that melatonin may have potential in inhibiting organ fibrosis, possibly due to its functions in anti-oxidative stress, anti-inflammation, remodeling the extracellular matrix (ECM), inhibiting epithelial-mesenchymal transition (EMT), and regulating apoptosis, thereby alleviating fibrosis. This review aims to explore the therapeutic potential of melatonin in fibrosis-related human diseases using findings from various in vivo and in vitro studies. These discoveries should provide important insights for the further development of new drugs to treat fibrosis.
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Affiliation(s)
- Wei Huang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
- Laboratory of Infectious and Liver Diseases, Institute of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Juan Zheng
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Ming Wang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
- Laboratory of Infectious and Liver Diseases, Institute of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Ling-Yao Du
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
- Laboratory of Infectious and Liver Diseases, Institute of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Lang Bai
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
- Laboratory of Infectious and Liver Diseases, Institute of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
- Laboratory of Infectious and Liver Diseases, Institute of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
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Reiter RJ, De Almeida Chuffa LG, Simão VA, Martín Giménez VM, De Las Heras N, Spandidos DA, Manucha W. Melatonin and vitamin D as potential synergistic adjuvants for cancer therapy (Review). Int J Oncol 2024; 65:114. [PMID: 39450562 PMCID: PMC11575929 DOI: 10.3892/ijo.2024.5702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 10/08/2024] [Indexed: 10/26/2024] Open
Abstract
Significant advancements have been made in cancer therapy; however, limitations remain with some conventional approaches. Adjuvants are agents used alongside primary treatments to enhance their efficacy and the treatment outcomes of patients. Modern lifestyles contribute to deficiencies in melatonin and vitamin D. Limited sun exposure affects vitamin D synthesis, and artificial light at night suppresses melatonin production. Both melatonin and vitamin D possess anti‑inflammatory, immune‑boosting and anticancer properties, rendering them potential adjuvants of interest. Studies suggest melatonin and vitamin D supplementation may address antioxidant imbalances in lip, oral and pharyngeal cancers. Moreover, promising results from breast, head and neck, brain, and osteosarcoma research indicate potential for tumor growth inhibition, improved survival, and a better quality of life of patients with cancer. The radioprotective properties of melatonin and vitamin D are another exciting area of exploration, potentially enhancing radiotherapy effectiveness while reducing side effects. For its part, the sleep‑promoting effects of melatonin may indirectly benefit patients with cancer by influencing the immune system. Thus, the prevalence of vitamin D and melatonin deficiencies highlights the importance of supplementation, as lower levels can worsen side‑effects from cancer treatments. The present review explores the potential of combining melatonin and vitamin D as synergistic adjuvants for cancer therapy. These agents have shown promise individually in cancer prevention and treatment, and their combined effects warrant investigation. Therefore, large‑scale controlled trials are crucial to definitively determine the optimal dosage, safety and efficacy of this combination in improving the lives of patients with cancer.
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Affiliation(s)
- Russel J Reiter
- Department of Cellular and Structural Biology, UT Health, San Antonio, TX 78229, USA
| | - Luiz Gustavo De Almeida Chuffa
- Department of Structural and Functional Biology, UNESP, São Paulo State University, Institute of Bio‑sciences, Botucatu, São Paulo, CEP 18618‑689, Brazil
| | - Vinícius Augusto Simão
- Department of Structural and Functional Biology, UNESP, São Paulo State University, Institute of Bio‑sciences, Botucatu, São Paulo, CEP 18618‑689, Brazil
| | - Virna Margarita Martín Giménez
- Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, 15706 Santiago de Compostela, Spain
| | - Natalia De Las Heras
- Department of Physiology, Faculty of Medicine, Complutense University, 28040 Madrid, Spain
| | - Demetrios A Spandidos
- Laboratory of Clinical Virology, School of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Walter Manucha
- Pharmacology Area, Department of Pathology, Faculty of Medical Sciences, National University of Cuyo, 5500 Mendoza, Argentina
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Megha KB, Arathi A, Shikha S, Alka R, Ramya P, Mohanan PV. Significance of Melatonin in the Regulation of Circadian Rhythms and Disease Management. Mol Neurobiol 2024; 61:5541-5571. [PMID: 38206471 DOI: 10.1007/s12035-024-03915-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Accepted: 12/30/2023] [Indexed: 01/12/2024]
Abstract
Melatonin, the 'hormone of darkness' is a neuronal hormone secreted by the pineal gland and other extra pineal sites. Responsible for the circadian rhythm and seasonal behaviour of vertebrates and mammals, melatonin is responsible for regulating various physiological conditions and the maintenance of sleep, body weight and the neuronal activities of the ocular sites. With its unique amphiphilic structure, melatonin can cross the cellular barriers and elucidate its activities in the subcellular components, including mitochondria. Melatonin is a potential scavenger of oxygen and nitrogen-reactive species and can directly obliterate the ROS and RNS by a receptor-independent mechanism. It can also regulate the pro- and anti-inflammatory cytokines in various pathological conditions and exhibit therapeutic activities against neurodegenerative, psychiatric disorders and cancer. Melatonin is also found to show its effects on major organs, particularly the brain, liver and heart, and also imparts a role in the modulation of the immune system. Thus, melatonin is a multifaceted candidate with immense therapeutic potential and is still considered an effective supplement on various therapies. This is primarily due to rectification of aberrant circadian rhythm by improvement of sleep quality associated with risk development of neurodegenerative, cognitive, cardiovascular and other metabolic disorders, thereby enhancing the quality of life.
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Affiliation(s)
- K B Megha
- Toxicology Division, Biomedical Technology Wing, Sree Chitra Tirunal Institute for Medical Sciences and Technology (Govt. of India), Poojapura, Trivandrum, 695 012, Kerala, India
| | - A Arathi
- Toxicology Division, Biomedical Technology Wing, Sree Chitra Tirunal Institute for Medical Sciences and Technology (Govt. of India), Poojapura, Trivandrum, 695 012, Kerala, India
| | - Saini Shikha
- CSIR-Institute of Microbial Technology, Sector 39-A, Chandigarh, 160036, India
| | - Rao Alka
- CSIR-Institute of Microbial Technology, Sector 39-A, Chandigarh, 160036, India
- Academy of Scientific and Innovation Research (AcSIR), Ghaziabad, 201002, India
| | - Prabhu Ramya
- P.G. Department of Biotechnology, Government Arts College, Trivandrum, 695 014, India
| | - P V Mohanan
- Toxicology Division, Biomedical Technology Wing, Sree Chitra Tirunal Institute for Medical Sciences and Technology (Govt. of India), Poojapura, Trivandrum, 695 012, Kerala, India.
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Cinar D, Altinoz E, Elbe H, Bicer Y, Cetinavci D, Ozturk I, Colak T. Therapeutic Effect of Melatonin on CCl 4-Induced Fibrotic Liver Model by Modulating Oxidative Stress, Inflammation, and TGF-β1 Signaling Pathway in Pinealectomized Rats. Inflammation 2024:10.1007/s10753-024-02101-7. [PMID: 39007940 DOI: 10.1007/s10753-024-02101-7] [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: 05/23/2024] [Revised: 07/05/2024] [Accepted: 07/08/2024] [Indexed: 07/16/2024]
Abstract
The study aimed to determine the CCl4-induced liver fibrosis model in pinealectomized rats and biochemically, immunohistochemically, and histopathologically investigate the therapeutic effect of melatonin on liver fibrosis. The surgical procedure for pinealectomy was performed at the beginning of the study, and the sham and pinealectomized rats were administered CCl4 dissolved in corn oil (1:1) alone every other day to induce liver fibrosis or together with melatonin (10 mg/kg) therapy for 15 days. Melatonin is an essential therapeutic agent and offers an alternative therapeutic strategy in CCl4-induced liver fibrosis by suppressing inflammation, oxidative stress, and the TGF-β1 signaling pathway. Treatment with melatonin ameliorated CCl4-induced liver fibrosis by restoring hepatocellular damage and reducing plasma AST, ALT, and ALP values. Melatonin increases the activity of SOD and CAT, which are important enzymes for antioxidant defence, and raises GSH levels, which further enhances antioxidant function. Also, melatonin reduced hepatic inflammation (IL-6 and IL-1β) and oxidative stress indices. Moreover, histopathological changes and immunohistochemical expression of TGF-β1 were restored following melatonin supplementation in the CCl4-induced liver fibrosis model in pinealectomized rats. Our study shows that melatonin supplementation has a beneficial effect in protecting the liver fibrosis induced by CCl4 in pinealectomized rats.
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Affiliation(s)
- Derya Cinar
- Department of Anatomy, School of Health Science, Karabuk University, Karabuk, Turkey
| | - Eyup Altinoz
- Department of Medical Biochemistry, Faculty of Medicine, Karabuk University, Karabuk, Turkey
| | - Hulya Elbe
- Department of Histology and Embryology, Faculty of Medicine, Mugla Sıtkı Kocman University, Mugla, Turkey
| | - Yasemin Bicer
- Department of Medical Biochemistry, Faculty of Medicine, Karabuk University, Karabuk, Turkey
| | - Dilan Cetinavci
- Department of Histology and Embryology, Mugla Training and Research Hospital, Mugla, Turkey
| | - Ipek Ozturk
- Department of Medical Biochemistry, Faculty of Medicine, Karabuk University, Karabuk, Turkey
| | - Tuncay Colak
- Department of Anatomy, Faculty of Medicine, Kocaeli University, Kocaeli, Turkey.
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Hosseinzadeh A, Pourhanifeh MH, Amiri S, Sheibani M, Irilouzadian R, Reiter RJ, Mehrzadi S. Therapeutic potential of melatonin in targeting molecular pathways of organ fibrosis. Pharmacol Rep 2024; 76:25-50. [PMID: 37995089 DOI: 10.1007/s43440-023-00554-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Revised: 10/29/2023] [Accepted: 10/31/2023] [Indexed: 11/24/2023]
Abstract
Fibrosis, the excessive deposition of fibrous connective tissue in an organ in response to injury, is a pathological condition affecting many individuals worldwide. Fibrosis causes the failure of tissue function and is largely irreversible as the disease progresses. Pharmacologic treatment options for organ fibrosis are limited, but studies suggest that antioxidants, particularly melatonin, can aid in preventing and controlling fibrotic damage to the organs. Melatonin, an indole nocturnally released from the pineal gland, is commonly used to regulate circadian and seasonal biological rhythms and is indicated for treating sleep disorders. While it is often effective in treating sleep disorders, melatonin's anti-inflammatory and antioxidant properties also make it a promising molecule for treating other disorders such as organ fibrosis. Melatonin ameliorates the necrotic and apoptotic changes that lead to fibrosis in various organs including the heart, liver, lung, and kidney. Moreover, melatonin reduces the infiltration of inflammatory cells during fibrosis development. This article outlines the protective effects of melatonin against fibrosis, including its safety and potential therapeutic effects. The goal of this article is to provide a summary of data accumulated to date and to encourage further experimentation with melatonin and increase its use as an anti-fibrotic agent in clinical settings.
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Affiliation(s)
- Azam Hosseinzadeh
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hossein Pourhanifeh
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Shiva Amiri
- Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Mohammad Sheibani
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Rana Irilouzadian
- Clinical Research Development Unit of Shohada-e Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Russel J Reiter
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, USA
| | - Saeed Mehrzadi
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran.
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Tokuyama-Toda R, Umeki H, Okubo M, Terada-Ito C, Yudo T, Ide S, Tadokoro S, Shimozuma M, Satomura K. The Preventive Effect of Melatonin on Radiation-Induced Oral Mucositis. Cells 2023; 12:2178. [PMID: 37681910 PMCID: PMC10487273 DOI: 10.3390/cells12172178] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 08/23/2023] [Accepted: 08/29/2023] [Indexed: 09/09/2023] Open
Abstract
Melatonin exerts various physiological effects through melatonin receptors and their ability to scavenge free radicals. Radiotherapy is a common treatment for head and neck tumors, but stomatitis, a side effect affecting irradiated oral mucosa, can impact treatment outcomes. This study investigated the preventive effect of melatonin, a potent free radical scavenger, on radiation-induced oral mucositis. Mice were irradiated with 15 Gy of X-ray radiation to the head and neck, and the oral mucosa was histologically compared between a melatonin-administered group and a control group. The results showed that radiation-induced oral mucositis was suppressed in mice administered melatonin before and after irradiation. It was suggested that the mechanism involved the inhibition of apoptosis and the inhibition of DNA damage. From these findings, we confirmed that melatonin has a protective effect against radiation-induced oral mucositis.
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Affiliation(s)
- Reiko Tokuyama-Toda
- Department of Oral Medicine and Stomatology, School of Dental Medicine, Tsurumi University, 2-1-3, Tsurumi, Tsurumi-ku, Yokohama City 230-8501, Japan; (H.U.); (M.O.); (C.T.-I.); (T.Y.); (S.I.); (S.T.); (M.S.); (K.S.)
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7
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Klymenko A, Lutz D. Melatonin signalling in Schwann cells during neuroregeneration. Front Cell Dev Biol 2022; 10:999322. [PMID: 36299487 PMCID: PMC9589221 DOI: 10.3389/fcell.2022.999322] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 09/23/2022] [Indexed: 11/13/2022] Open
Abstract
It has widely been thought that in the process of nerve regeneration Schwann cells populate the injury site with myelinating, non–myelinating, phagocytic, repair, and mesenchyme–like phenotypes. It is now clear that the Schwann cells modify their shape and basal lamina as to accommodate re–growing axons, at the same time clear myelin debris generated upon injury, and regulate expression of extracellular matrix proteins at and around the lesion site. Such a remarkable plasticity may follow an intrinsic functional rhythm or a systemic circadian clock matching the demands of accurate timing and precision of signalling cascades in the regenerating nervous system. Schwann cells react to changes in the external circadian clock clues and to the Zeitgeber hormone melatonin by altering their plasticity. This raises the question of whether melatonin regulates Schwann cell activity during neurorepair and if circadian control and rhythmicity of Schwann cell functions are vital aspects of neuroregeneration. Here, we have focused on different schools of thought and emerging concepts of melatonin–mediated signalling in Schwann cells underlying peripheral nerve regeneration and discuss circadian rhythmicity as a possible component of neurorepair.
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Colares JR, Hartmann RM, Schemitt EG, Fonseca SRB, Brasil MS, Picada JN, Dias AS, Bueno AF, Marroni CA, Marroni NP. Melatonin prevents oxidative stress, inflammatory activity, and DNA damage in cirrhotic rats. World J Gastroenterol 2022; 28:348-364. [PMID: 35110954 PMCID: PMC8771613 DOI: 10.3748/wjg.v28.i3.348] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 06/24/2021] [Accepted: 01/10/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Cirrhosis is an important health problem characterized by a significant change in liver parenchyma. In animals, this can be reproduced by an experimental model of bile duct ligation (BDL). Melatonin (MLT) is a physiological hormone synthesized from serotonin that has been studied for its beneficial properties, including its antioxidant potential.
AIM To evaluate MLT’s effects on oxidative stress, the inflammatory process, and DNA damage in an experimental model of secondary biliary cirrhosis.
METHODS Male Wistar rats were divided into 4 groups: Control (CO), CO + MLT, BDL, and BDL + MLT. MLT was administered (20 mg/kg) daily beginning on day 15 after biliary obstruction. On day 29 the animals were killed. Blood samples, liver tissue, and bone marrow were collected for further analysis.
RESULTS BDL caused changes in biochemical and histological parameters and markers of inflammatory process. Thiobarbituric acid (0.46 ± 0.01) reactive substance levels, superoxide dismutase activity (2.30 ± 0.07) and nitric oxide levels (2.48 ± 0.36) were significantly lower (P < 0.001) n the groups that received MLT. DNA damage was also lower (P < 0.001) in MLT-treated groups (171.6 ± 32.9) than the BDL-only group (295.5 ± 34.8). Tissue damage and the expression of nuclear factor kappa B, interleukin-1β, Nrf2, NQO1 and Hsp70 were significantly lower in animals treated with MLT (P < 0.001).
CONCLUSION When administered to rats with BDL-induced secondary biliary cirrhosis, MLT effectively restored the evaluated parameters.
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Affiliation(s)
- Josieli R Colares
- Medical Sciences Program, Universidade Federal do Rio Grande do Sul, Porto Alegre 90050-170, Brazil
| | - Renata M Hartmann
- Medical Sciences Program, Universidade Federal do Rio Grande do Sul, Porto Alegre 90050-170, Brazil
| | - Elizângela G Schemitt
- Medical Sciences Program, Universidade Federal do Rio Grande do Sul, Porto Alegre 90050-170, Brazil
| | - Sandielly R B Fonseca
- Medical Sciences Program, Universidade Federal do Rio Grande do Sul, Porto Alegre 90050-170, Brazil
| | - Marilda S Brasil
- Biological Sciences Program, Universidade Federal do Rio Grande do Sul, Porto Alegre 90050-170, Brazil
| | - Jaqueline N Picada
- Cellular and Molecular Biology Program, Lutheran University of Brazil (ULBRA), Canoas 92425-900, Brazil
| | - Alexandre S Dias
- Pneumological Sciences Program, Universidade Federal do Rio Grande do Sul, Porto Alegre 90050-170, Brazil
| | - Aline F Bueno
- Pneumological Sciences Program, Universidade Federal do Rio Grande do Sul, Porto Alegre 90050-170, Brazil
| | - Cláudio A Marroni
- Posgraduate Program in Hepatology, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre 90050-170, Brazil
| | - Norma P Marroni
- Medical Sciences Program, Universidade Federal do Rio Grande do Sul, Porto Alegre 90050-170, Brazil
- Biological Sciences Program, Universidade Federal do Rio Grande do Sul, Porto Alegre 90050-170, Brazil
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Amygdalin isolated from Amygdalus mongolica protects against hepatic fibrosis in rats. ACTA PHARMACEUTICA (ZAGREB, CROATIA) 2021; 71:459-471. [PMID: 36654093 DOI: 10.2478/acph-2021-0022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 07/21/2020] [Indexed: 01/20/2023]
Abstract
The aim of this research was to investigate the effect of amygdalin on hepatic fibrosis in rats. Amygdalin was purified and identified from the seeds of Amygdalus mongo lica. Sprague Dawley rats in the control and model groups were administered water. Sprague Dawley rats were divided into the low-, middle-, and high-dose amygdalin groups that received 20, 40, and 80 mg kg-1 amygdalin, respectively. whereas the silymarin group was treated with 50 mg kg-1 silymarin. The control and model groups were administered water. Liver tissue analysis revealed significantly lower activities of ALT, AST, ALP, SOD, and MDA in the drug-treated groups compared to the model group. Serum analysis revealed significantly lower HYC and C-IV in the middle-dose amygdalin-treated group compared to the model group. The histopathological changes were less severe in the drug-treated groups as observed by the formation of pseudolobuli and decreased collagen fiber deposition. Hepatic fibrosis-related genes were expressed at significantly lower levels in the amygdalin-treated groups than in the model group. Amygdalin from A. mongolica represents a therapeutic candidate for hepatic fibrosis prevention and treatment.
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KARAKAYA B, KULOĞLU T, ÖNALAN E, KAYA TEKTEMUR N, DÖNDER E. Investigation of benfotiamine’s protective effects on liver tissue in experimental carbon tetrachloride induced liver injury. CUKUROVA MEDICAL JOURNAL 2020; 45:680-687. [DOI: 10.17826/cumj.676060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023] Open
Abstract
Purpose: In this study, we aimed to investigate the protective effects of benfotiamine on experimental liver injury caused by carbon tetrachloride (CCl4).Materials and Methods: In this study, 30 male Wistar albino rats were used. Rats were equally divided into 5 groups. No application was made to control group. The CCl4 group was injected i.p with1ml/kg CCl4:olive oil (1:2) mixture on the 1st and 8th days, and the CCl4+benfotiamine group was treated i.p with 1 ml/kg CCl4: olive oil (1:2) mixture twice on the 1st and 8th days and orally with 70 mg/kg/day benfotiamine. To the benfotiamine group, 70 mg/kg/day benfotiamine was given orally for 14 days. To the olive oil group, 2 ml/kg olive oil was given i.p. on 1st and 8th days. Finally, rats were decapitated. Liver tissues were removed and paraffin blocks were prepared. Tissues were stored at –80 oC for malonaldeyhde (MDA) assay.Results: There were no significant differences between the control, benfotiamine and olive oil groups. Compared with the control group, there was a significant increase in MDA, apoptosis and bax immunoreactivity in CCl4 group. Compared with the CCl4 group, there was a significant decrease in MDA, apoptosis and bax immunoreactivity in the CCl4+benfotiamine group.Conclusion: CCl4 increases MDA, apoptosis and bax immunoreactivity, and benfotiamine, given as treatment, reduces these parameters.
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Affiliation(s)
| | | | | | | | - Emir DÖNDER
- Fırat Üniversitesi Tıp Fakültesi İç Hastalıkları
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11
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Hu C, Zhao L, Tao J, Li L. Protective role of melatonin in early-stage and end-stage liver cirrhosis. J Cell Mol Med 2019; 23:7151-7162. [PMID: 31475778 PMCID: PMC6815834 DOI: 10.1111/jcmm.14634] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Revised: 06/13/2019] [Accepted: 07/28/2019] [Indexed: 02/06/2023] Open
Abstract
The liver is composed of hepatocytes, cholangiocytes, Kupffer cells, sinusoidal endothelial cells, hepatic stellate cells (HSCs) and dendritic cells; all these functional and interstitial cells contribute to the synthesis and secretion functions of liver tissue. However, various hepatotoxic factors including infection, chemicals, high‐fat diet consumption, surgical procedures and genetic mutations, as well as biliary tract diseases such as sclerosing cholangitis and bile duct ligation, ultimately progress into liver cirrhosis after activation of fibrogenesis. Melatonin (MT), a special hormone isolated from the pineal gland, participates in regulating multiple physiological functions including sleep promotion, circadian rhythms and neuroendocrine processes. Current evidence shows that MT protects against liver injury by inhibiting oxidation, inflammation, HSC proliferation and hepatocyte apoptosis, thereby inhibiting the progression of liver cirrhosis. In this review, we summarize the circadian rhythm of liver cirrhosis and its potential mechanisms as well as the therapeutic effects of MT on liver cirrhosis and earlier‐stage liver diseases including liver steatosis, nonalcoholic fatty liver disease and liver fibrosis. Given that MT is an antioxidative and anti‐inflammatory agent that is effective in eliminating liver injury, it is a potential agent with which to reverse liver cirrhosis in its early stage.
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Affiliation(s)
- Chenxia Hu
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, School of Medicine, First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
| | - Lingfei Zhao
- Kidney Disease Center, College of Medicine, First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, Zhejiang, China.,Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jingjing Tao
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, School of Medicine, First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
| | - Lanjuan Li
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, School of Medicine, First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
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12
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Luo C, Yang Q, Liu Y, Zhou S, Jiang J, Reiter RJ, Bhattacharya P, Cui Y, Yang H, Ma H, Yao J, Lawler SE, Zhang X, Fu J, Rozental R, Aly H, Johnson MD, Chiocca EA, Wang X. The multiple protective roles and molecular mechanisms of melatonin and its precursor N-acetylserotonin in targeting brain injury and liver damage and in maintaining bone health. Free Radic Biol Med 2019; 130:215-233. [PMID: 30315933 DOI: 10.1016/j.freeradbiomed.2018.10.402] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 09/01/2018] [Accepted: 10/02/2018] [Indexed: 12/20/2022]
Abstract
Melatonin is a neurohormone associated with sleep and wakefulness and is mainly produced by the pineal gland. Numerous physiological functions of melatonin have been demonstrated including anti-inflammation, suppressing neoplastic growth, circadian and endocrine rhythm regulation, and its potent antioxidant activity as well as its role in regeneration of various tissues including the nervous system, liver, bone, kidney, bladder, skin, and muscle, among others. In this review, we summarize the recent advances related to the multiple protective roles of melatonin receptor agonists, melatonin and N-acetylserotonin (NAS), in brain injury, liver damage, and bone health. Brain injury, including traumatic brain injury, ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, and newborn perinatal hypoxia-ischemia encephalopathy, is a major cause of mortality and disability. Liver disease causes serious public health problems and various factors including alcohol, chemical pollutants, and drugs induce hepatic damage. Osteoporosis is the most common bone disease in humans. Due in part to an aging population, both the cost of care of fracture patients and the annual fracture rate have increased steadily. Despite the discrepancy in the pathophysiological processes of these disorders, time frames and severity, they may share several common molecular mechanisms. Oxidative stress is considered to be a critical factor in these pathogeneses. We update the current state of knowledge related to the molecular processes, mainly including anti-oxidative stress, anti-apoptosis, autophagy dysfunction, and anti-inflammation as well as other properties of melatonin and NAS. Particularly, the abilities of melatonin and NAS to directly scavenge oxygen-centered radicals and toxic reactive oxygen species, and indirectly act through antioxidant enzymes are disscussed. In this review, we summarize the similarities and differences in the protection provided by melatonin and/or NAS in brain, liver and bone damage. We analyze the involvement of melatonin receptor 1A (MT1), melatonin receptor 1B (MT2), and melatonin receptor 1C (MT3) in the protection of melatonin and/or NAS. Additionally, we evaluate their potential clinical applications. The multiple mechanisms of action and multiple organ-targeted properties of melatonin and NAS may contribute to development of promising therapies for clinical trials.
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Affiliation(s)
- Chengliang Luo
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Qiang Yang
- Hubei Provincial Key Lab for Quality and Safety of Traditional Chinese Medicine Health Food, Jing Brand Research Institute, Daye, Hubei, China
| | - Yuancai Liu
- Hubei Provincial Key Lab for Quality and Safety of Traditional Chinese Medicine Health Food, Jing Brand Research Institute, Daye, Hubei, China
| | - Shuanhu Zhou
- Department of Orthopedic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Jiying Jiang
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Histology and Embryology, Weifang Medical University, Weifang, Shandong, China
| | - Russel J Reiter
- Department of Cellular and Structural Biology, University Texas Health Science Center, San Antonio, TX, USA
| | - Pallab Bhattacharya
- National Institute of Pharmaceutical Education and Research, Ahmedabad, India
| | - Yongchun Cui
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Hongwei Yang
- Department of Neurosurgery, University of Massachusetts Medical School, Worcester, MA, USA
| | - He Ma
- Third Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, China
| | - Jiemin Yao
- Third Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, China
| | - Sean E Lawler
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Xinmu Zhang
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Jianfang Fu
- Department of Endocrinology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Renato Rozental
- Lab Neuroproteção & Estratégias Regenerativas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Hany Aly
- Department of Neonatology, Cleveland Clinic Children's Hospital, Cleveland, OH, USA
| | - Mark D Johnson
- Department of Neurosurgery, University of Massachusetts Medical School, Worcester, MA, USA
| | - E Antonio Chiocca
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Xin Wang
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
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Fahmy MA, Diab KA, Abdel-Samie NS, Omara EA, Hassan ZM. Carbon tetrachloride induced hepato/renal toxicity in experimental mice: antioxidant potential of Egyptian Salvia officinalis L essential oil. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2018; 25:27858-27876. [PMID: 30056541 DOI: 10.1007/s11356-018-2820-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Accepted: 07/20/2018] [Indexed: 06/08/2023]
Abstract
The present research designed to assess the protective role of Salvia officinalis essential oil (SO) against carbon tetrachloride (CCl4)-induced liver and kidney damage in mice. This is evidenced by estimation of antiradical scavenging activity of SO using DPPH assay, biochemical markers, histological investigation of liver and kidney sections, and comet assay. Mice were given CCl4 (1.2 mL/kg for 24 h or 0.8 mL/kg for 2 weeks, 3 times/week) and with or without SO (0.1, 0.2, and 0.4 mL/kg, for 2 week, 5 times/week). The findings demonstrated that both acute and subacute treatment with CCl4 alone had adverse side effects on liver and kidney of mice. These effects were evidenced by a significant increase in serum hepatic enzymes (ALT, AST, ALP, LDH, and G-GT), bilirubin, and renal function markers (blood urea, creatinine). Toxic effect of CCl4 was accompanied by a decline in the serum total protein, albumin, globulin, and prothrombin (%). CCl4 induced oxidative stress as evidenced by increasing serum lipid peroxidation (LPO) along with decreasing serum total glutathione S transferase (GST). A remarkable increase in hepatic DNA strand breakages and histopathological distortion in liver and kidney specimens were observed in CCl4-intoxicated groups. Ultrastructurally, hepatocytes exhibited irregular nuclei, vacuolated cytoplasm, and distorted microorganelles. Essential oil form S. officinalis possessed antiradical scavenging (EC50 = 4602 μg/mL) lower than ascorbic acid (EC50 = 5.9 μg/mL). This oil was effectively exhibited hepato-nephroprotective activity especially at its higher concentrations in co-treated groups (SO plus CCl4). The activity of SO was associated with lowering the liver enzymes, bilirubin, urea, and creatinine, along with increasing total protein, albumin, globulin, and prothrombin. The increase in GST content and the decrease in LPO and DNA breakage levels, alongside repairing the histo-architectural distortions further confirmed the protective activity of SO. SO is a potential candidate for counteracting hepato/renal injury associating CCl4. This effect may occur via antioxidant defense mechanism which in part related to the complexity of its chemical constituents.
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Affiliation(s)
- Maha A Fahmy
- Genetics and Cytology Department, National Research Centre (NRC), 33 El-Bohouth St., Dokki, Cairo, Egypt
| | - Kawthar A Diab
- Genetics and Cytology Department, National Research Centre (NRC), 33 El-Bohouth St., Dokki, Cairo, Egypt.
| | - Negm S Abdel-Samie
- Genetics and Cytology Department, National Research Centre (NRC), 33 El-Bohouth St., Dokki, Cairo, Egypt
| | - Enayat A Omara
- Pathology Department, National Research Centre (NRC), 33 El-Bohouth St., Dokki, Cairo, Egypt
| | - Zeinab M Hassan
- Natural Compounds Department, National Research Centre (NRC), 33 El-Bohouth St., Dokki, Cairo, Egypt
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14
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Wang YR, Hong RT, Xie YY, Xu JM. Melatonin Ameliorates Liver Fibrosis Induced by Carbon Tetrachloride in Rats via Inhibiting TGF-β1/Smad Signaling Pathway. Curr Med Sci 2018; 38:236-244. [DOI: 10.1007/s11596-018-1871-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Revised: 12/28/2017] [Indexed: 12/18/2022]
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Saad RA, EL-Bab MF, Shalaby AA. Attenuation of acute and chronic liver injury by melatonin in rats. JOURNAL OF TAIBAH UNIVERSITY FOR SCIENCE 2018. [DOI: 10.1016/j.jtusci.2013.04.008] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Ramadan A. Saad
- Department of Physiology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Mohamed Fath EL-Bab
- Department of Physiology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
- Department of Physiology, College of Medicine, Taibah University, Al-Madinah Al-Munawarah, Saudi Arabia
| | - Abir A. Shalaby
- Department of Biochemistry, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, Egypt
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16
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Mortezaee K, Khanlarkhani N. Melatonin application in targeting oxidative‐induced liver injuries: A review. J Cell Physiol 2017; 233:4015-4032. [DOI: 10.1002/jcp.26209] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Accepted: 10/04/2017] [Indexed: 01/03/2023]
Affiliation(s)
- Keywan Mortezaee
- Department of AnatomySchool of MedicineKurdistan University of Medical SciencesSanandajIran
| | - Neda Khanlarkhani
- Department of Anatomy, School of MedicineTehran University of Medical SciencesTehranIran
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Lebda MA, Sadek KM, Abouzed TK, Tohamy HG, El-Sayed YS. Melatonin mitigates thioacetamide-induced hepatic fibrosis via antioxidant activity and modulation of proinflammatory cytokines and fibrogenic genes. Life Sci 2017; 192:136-143. [PMID: 29180002 DOI: 10.1016/j.lfs.2017.11.036] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2017] [Revised: 11/18/2017] [Accepted: 11/23/2017] [Indexed: 12/11/2022]
Abstract
AIMS The potential antifibrotic effects of melatonin against induced hepatic fibrosis were explored. MAIN METHODS Rats were allocated into four groups: placebo; thioacetamide (TAA) (200mg/kg bwt, i.p twice weekly for two months); melatonin (5mg/kgbwt, i.p daily for a week before TAA and continued for an additional two months); and melatonin plus TAA. Hepatic fibrotic changes were evaluated biochemically and histopathologically. Hepatic oxidative/antioxidative indices were assessed. The expression of hepatic proinflammatory cytokines (tumor necrosis factor-α, and interleukin-1β), fibrogenic-related genes (transforming growth factor-1β, collagen I, collagen, III, laminin, and autotaxin) and an antioxidant-related gene (thioredoxin-1) were detected by qRT-PCR. KEY FINDINGS In fibrotic rats, melatonin lowered serum aspartate aminotransferase, alanine aminotransferase, and autotaxin activities, bilirubin, hepatic hydroxyproline and plasma ammonia levels. Melatonin displayed hepatoprotective and antifibrotic potential as indicated by mild hydropic degeneration of some hepatocytes and mild fibroplasia. In addition, TAA induced the depletion of glutathione, glutathione s-transferase, glutathione peroxidase, superoxide dismutase, catalase, and paraoxonase-1 (PON-1), while inducing the accumulation of malondialdehyde, protein carbonyl (C=O) and nitric oxide (NO), and DNA fragmentation. These effects were restored by melatonin pretreatment. Furthermore, melatonin markedly attenuated the expression of proinflammatory cytokines and fibrogenic genes via the upregulation of thioredoxin-1 mRNA transcripts. SIGNIFICANCE Melatonin exhibits potent anti-inflammatory, antioxidant and fibrosuppressive activities against TAA-induced hepatic fibrogenesis via the suppression of oxidative stress, DNA damage, proinflammatory cytokines and fibrogenic gene transcripts. In addition, we demonstrate that the antifibrotic activity of melatonin is mediated by the induction of thioredoxin-1 with attenuation of autotaxin expressions.
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Affiliation(s)
- Mohamed A Lebda
- Department of Biochemistry, Faculty of Veterinary Medicine, Alexandria University, Egypt.
| | - Kadry M Sadek
- Department of Biochemistry, Faculty of Veterinary Medicine, Damanhur University, Egypt
| | - Tarek K Abouzed
- Department of Biochemistry, Faculty of Veterinary Medicine, Kafr Elsheikh University, Egypt
| | - Hossam G Tohamy
- Department of Pathology, Faculty of Veterinary Medicine, Alexandria University, Egypt
| | - Yasser S El-Sayed
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Damanhur University, Egypt.
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18
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Özerkan D, Özsoy N, Akbulut KG, Güney Ş, Öztürk G. The protective effect of vitamin D against carbon tetrachloride damage to the rat liver. Biotech Histochem 2017; 92:513-523. [PMID: 28910170 DOI: 10.1080/10520295.2017.1361549] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
We investigated the protective effect of vitamin D against liver damage caused by carbon tetrachloride (CCl4). Twenty-four male rats were divided into four equal groups: G1, untreated controls; G2, administered CCl4; G3, administered both CCl4 and vitamin D for 10 weeks; G4, administered CCl4 for 10 weeks and vitamin D for 12 weeks. At the end of experiment, intracardiac blood samples were taken and liver samples were removed. Hepatic damage due to CCl4 was assessed using biochemistry and histopathology. Glutathione (GSH) levels decreased, while malondialdehyde (MDA) levels increased in liver tissues of G2. Alanine transaminase (ALT), alkaline phosphatase (ALP), and gamma-glutamyl-transaminase (GGT) levels increased, while albumin (ALB) levels decreased. Hepatocyte degeneration, lobular disorder, sinusoid dilation, focal necrotic areas, hyperemia, and glycogen loss were observed. Hepatic fibrosis was observed around portal areas and central veins. Bridging fibrous septa were formed between portal veins. By immunohistochemistry, both matrix metalloproteinase-9 (MMP-9) and desmin reactivity were increased. All aspects of liver damage were at least partially prevented in rats treated with vitamin D. Vitamin D appears to act as an antioxidant and anti-fibrotic to protect the rat liver against damage.
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Affiliation(s)
- D Özerkan
- a Department of Genetics and Bioengineering, Faculty of Engineering and Architecture , Kastamonu University , Kastamonu
| | - N Özsoy
- b Department of Biology, Faculty of Science , Ankara University , Ankara
| | - K G Akbulut
- c Department of Physiology, Faculty of Medicine , Gazi University , Ankara
| | - Ş Güney
- c Department of Physiology, Faculty of Medicine , Gazi University , Ankara
| | - G Öztürk
- d Department of Physiology, Faculty of Medicine , Istanbul Medeniyet University , Istanbul , Turkey
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19
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Adikwu E, Bokolo B. Melatonin and N- Acetylcysteine as Remedies for Tramadol-Induced Hepatotoxicity in Albino Rats. Adv Pharm Bull 2017; 7:367-374. [PMID: 29071218 PMCID: PMC5651057 DOI: 10.15171/apb.2017.044] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2017] [Revised: 07/17/2017] [Accepted: 07/19/2017] [Indexed: 12/21/2022] Open
Abstract
Purpose: The therapeutic benefit derived from the clinical use of tramadol (TD) has been characterized by hepatotoxicity due to misuse and abuse. The implications of drug-induced hepatotoxicity include socio-economic burden which makes the search for remedy highly imperative. The present study investigated the protective effects of melatonin (MT) and n-acetylcysteine (NAC) on TD-induced hepatotoxicity in albino rats. Methods: Forty five adult rats used for this study were divided into nine groups of five rats each. The rats were pretreated with 10mg/kg/day of NAC, 10mg/kg/day of MT and combined doses of NAC and MT prior to the administration of 15 mg/kg/day of TD intraperitoneally for 7 days respectively. At the termination of drug administration, rats were weighed, sacrificed, and serum was extracted and evaluated for liver function parameters. The liver was harvested, weighed and evaluated for oxidative stress indices and liver enzymes. Results: Alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, total bilirubin, conjugated bilirubin, and malondialdehyde levels were significantly (P<0.05) increased in rats administered with TD when compared to control. Furthermore, glutathione, superoxide dismutase and catalase levels were decreased significantly (P<0.05) in rats administered with TD when compared to control. The Liver of TD-treated rats showed necrosis of hepatocytes. However, the observed biochemical and liver histological alterations in TD-treated rats were attenuated in NAC and MT pretreated rats. Interestingly, pretreatment with combined doses of NAC and MT produced significant (P<0.05) effects on all evaluated parameters in comparison to their individual doses. Conclusion: Based on the findings in this study, melatonin and n- acetylcysteine could be used clinically as remedies for tramadol associated hepatotoxity.
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Affiliation(s)
- Elias Adikwu
- Department of Pharmacology, Faculty of Basic Medical Sciences, University of Port Harcourt, Choba, Rivers State, Nigeria
| | - Bonsome Bokolo
- Department of Pharmacology, Faculty of Basic Medical Sciences, Niger Delta University Wilberforce Island, Bayelsa State, Nigeria
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20
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Zhang JJ, Meng X, Li Y, Zhou Y, Xu DP, Li S, Li HB. Effects of Melatonin on Liver Injuries and Diseases. Int J Mol Sci 2017; 18:ijms18040673. [PMID: 28333073 PMCID: PMC5412268 DOI: 10.3390/ijms18040673] [Citation(s) in RCA: 82] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Revised: 03/15/2017] [Accepted: 03/17/2017] [Indexed: 02/07/2023] Open
Abstract
Liver injuries and diseases are serious health problems worldwide. Various factors, such as chemical pollutants, drugs, and alcohol, could induce liver injuries. Liver diseases involve a wide range of liver pathologies, including hepatic steatosis, fatty liver, hepatitis, fibrosis, cirrhosis, and hepatocarcinoma. Despite all the studies performed up to now, therapy choices for liver injuries and diseases are very few. Therefore, the search for a new treatment that could safely and effectively block or reverse liver injuries and diseases remains a priority. Melatonin is a well-known natural antioxidant, and has many bioactivities. There are numerous studies investigating the effects of melatonin on liver injuries and diseases, and melatonin could regulate various molecular pathways, such as inflammation, proliferation, apoptosis, metastasis, and autophagy in different pathophysiological situations. Melatonin could be used for preventing and treating liver injuries and diseases. Herein, we conduct a review summarizing the potential roles of melatonin in liver injuries and diseases, paying special attention to the mechanisms of action.
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Affiliation(s)
- Jiao-Jiao Zhang
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.
| | - Xiao Meng
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.
| | - Ya Li
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.
| | - Yue Zhou
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.
| | - Dong-Ping Xu
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.
| | - Sha Li
- School of Chinese Medicine, The University of Hong Kong, Hong Kong 999077, China.
| | - Hua-Bin Li
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.
- South China Sea Bioresource Exploitation and Utilization Collaborative Innovation Center, Sun Yat-sen University, Guangzhou 510006, China.
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21
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Yu N, Sun YT, Su XM, He M, Dai B, Kang J. Melatonin attenuates TGFβ1-induced epithelial-mesenchymal transition in lung alveolar epithelial cells. Mol Med Rep 2016; 14:5567-5572. [PMID: 27878256 DOI: 10.3892/mmr.2016.5950] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Accepted: 07/01/2016] [Indexed: 11/06/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is the most common interstitial lung disease. However, the pathogenesis remains to be fully elucidated. Melatonin is secreted by the pineal gland, it has a strong antioxidant effect, and exerts an anti-fibrosis effect. Whether melatonin attenuates pulm -onary fibrosis by inhibiting epithelial‑mesenchymal transition (EMT) requires further research. The present study aimed to investigate whether melatonin prevents transforming growth factor‑β1 (TGF‑β1)‑induced EMT and underlying signaling pathways using reverse transcription‑quantitative polymerase chain reaction, western blot analysis and immunofluorescence. The results demonstrated that melatonin inhibits EMT in A549 cells, and the Wnt/β‑catenin and Smad2/3 signaling pathways are involved in the EMT of the A549 cell line as they were suppressed by melatonin. The present study indicates that melatonin inhibited TGFβ1‑induced epithelial‑mesenchymal transition in the A549 cell line and may potentially be useful in the treatment of IPF.
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Affiliation(s)
- Na Yu
- Department of Respiratory Medicine, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Yi-Tian Sun
- Department of Respiratory Medicine, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, P.R. China
| | - Xin-Ming Su
- Department of Respiratory Medicine, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Miao He
- Environment and Non‑Communicable Disease Research Center, School of Public Health, China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Bing Dai
- Department of Respiratory Medicine, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Jian Kang
- Department of Respiratory Medicine, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
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Opie LH, Lecour S. Melatonin has multiorgan effects. EUROPEAN HEART JOURNAL. CARDIOVASCULAR PHARMACOTHERAPY 2016; 2:258-65. [DOI: 10.1093/ehjcvp/pvv037] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/13/2015] [Accepted: 09/15/2015] [Indexed: 01/04/2023]
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Hu W, Ma Z, Jiang S, Fan C, Deng C, Yan X, Di S, Lv J, Reiter RJ, Yang Y. Melatonin: the dawning of a treatment for fibrosis? J Pineal Res 2016; 60:121-31. [PMID: 26680689 DOI: 10.1111/jpi.12302] [Citation(s) in RCA: 85] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Accepted: 12/11/2015] [Indexed: 12/28/2022]
Abstract
Fibrosis is a common occurrence following organ injury and failure. To date, there is no effective treatment for this condition. Melatonin targets numerous molecular pathways, a consequence of its antioxidant and anti-inflammatory actions that reduce excessive fibrosis. Herein, we review the multiple protective effects of melatonin against fibrosis. There exist four major phases of the fibrogenic response including primary injury to the organ, activation of effector cells, the elaboration of extracellular matrix (ECM) and dynamic deposition. Melatonin regulates each of these phases. Additionally, melatonin reduces fibrosis levels in numerous organs. Melatonin exhibits its anti-fibrosis effects in heart, liver, lung, kidney, and other organs. In addition, adhesions which occur following surgical procedures are also inhibited by melatonin. The information reviewed here should be significant to understanding the protective role of melatonin against fibrosis, contribute to the design of further experimental studies related to melatonin and the fibrotic response and shed light on a potential treatment for fibrosis.
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Affiliation(s)
- Wei Hu
- Department of Biomedical Engineering, The Fourth Military Medical University, Xi'an, China
- Department of General Surgery, Beidaihe Sanatorium, Beijing Military Area Command, Qinhuangdao, China
| | - Zhiqiang Ma
- Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China
| | - Shuai Jiang
- Department of Aerospace Medicine, The Fourth Military Medical University, Xi'an, China
| | - Chongxi Fan
- Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China
| | - Chao Deng
- Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Xiaolong Yan
- Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China
| | - Shouyin Di
- Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China
| | - Jianjun Lv
- Department of Biomedical Engineering, The Fourth Military Medical University, Xi'an, China
| | - Russel J Reiter
- Department of Cellular and Structural Biology, UT Health Science Center, San Antonio, TX, USA
| | - Yang Yang
- Department of Biomedical Engineering, The Fourth Military Medical University, Xi'an, China
- Department of General Surgery, Beidaihe Sanatorium, Beijing Military Area Command, Qinhuangdao, China
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Esteban-Zubero E, Alatorre-Jiménez MA, López-Pingarrón L, Reyes-Gonzales MC, Almeida-Souza P, Cantín-Golet A, Ruiz-Ruiz FJ, Tan DX, García JJ, Reiter RJ. Melatonin's role in preventing toxin-related and sepsis-mediated hepatic damage: A review. Pharmacol Res 2016; 105:108-120. [PMID: 26808084 DOI: 10.1016/j.phrs.2016.01.018] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2015] [Revised: 01/13/2016] [Accepted: 01/15/2016] [Indexed: 02/07/2023]
Abstract
The liver is a central organ in detoxifying molecules and would otherwise cause molecular damage throughout the organism. Numerous toxic agents including aflatoxin, heavy metals, nicotine, carbon tetrachloride, thioacetamide, and toxins derived during septic processes, generate reactive oxygen species followed by molecular damage to lipids, proteins and DNA, which culminates in hepatic cell death. As a result, the identification of protective agents capable of ameliorating the damage at the cellular level is an urgent need. Melatonin is a powerful endogenous antioxidant produced by the pineal gland and a variety of other organs and many studies confirm its benefits against oxidative stress including lipid peroxidation, protein mutilation and molecular degeneration in various organs, including the liver. Recent studies confirm the benefits of melatonin in reducing the cellular damage generated as a result of the metabolism of toxic agents. These protective effects are apparent when melatonin is given as a sole therapy or in conjunction with other potentially protective agents. This review summarizes the published reports that document melatonin's ability to protect hepatocytes from molecular damage due to a wide variety of substances (aflatoxin, heavy metals, nicotine, carbon tetrachloride, chemotherapeutics, and endotoxins involved in the septic process), and explains the potential mechanisms by which melatonin provides these benefits. Melatonin is an endogenously-produced molecule which has a very high safety profile that should find utility as a protective molecule against a host of agents that are known to cause molecular mutilation at the level of the liver.
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Affiliation(s)
- Eduardo Esteban-Zubero
- Department of Pharmacology and Physiology, University of Zaragoza, Calle Domingo Miral s/n, 50009, Zaragoza, Spain.
| | - Moisés Alejandro Alatorre-Jiménez
- Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA
| | - Laura López-Pingarrón
- Department of Medicine, Psychiatry and Dermatology, University of Zaragoza, Calle Domingo Miral s/n, 50009. Zaragoza, Spain
| | - Marcos César Reyes-Gonzales
- Department of Pharmacology and Physiology, University of Zaragoza, Calle Domingo Miral s/n, 50009, Zaragoza, Spain
| | - Priscilla Almeida-Souza
- Department of Pharmacology and Physiology, University of Zaragoza, Calle Domingo Miral s/n, 50009, Zaragoza, Spain
| | - Amparo Cantín-Golet
- Department of Medicine, Psychiatry and Dermatology, University of Zaragoza, Calle Domingo Miral s/n, 50009. Zaragoza, Spain
| | - Francisco José Ruiz-Ruiz
- Department of Medicine, Psychiatry and Dermatology, University of Zaragoza, Calle Domingo Miral s/n, 50009. Zaragoza, Spain
| | - Dun-Xian Tan
- Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA
| | - José Joaquín García
- Department of Pharmacology and Physiology, University of Zaragoza, Calle Domingo Miral s/n, 50009, Zaragoza, Spain
| | - Russel J Reiter
- Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
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Mortezaee K, Sabbaghziarani F, Omidi A, Dehpour AR, Omidi N, Ghasemi S, Pasbakhsh P, Ragerdi Kashani I. Therapeutic value of melatonin post-treatment on CCl 4-induced fibrotic rat liver. Can J Physiol Pharmacol 2016; 94:119-130. [DOI: 10.1139/cjpp-2015-0266] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Melatonin is known for being beneficial in targeting liver diseases. This study aimed to investigate whether melatonin post-treatment is capable of rat carbon tetrachloride (CCl4)-induced liver fibrosis reduction. Thirty-two male Sprague-Dawley rats were divided into 4 groups: normal; fibrosis with CCl4 injection (1 mL/kg) twice weekly for 8 weeks; phosphate-buffered saline (PBS); and melatonin (20 mg/kg) for a further 4 weeks on cessation of CCl4. At the beginning of week 13, liver tissue samples were used for hematoxylin-eosin (H&E), periodic acid-Schiff (PAS), Masson’s trichrome (MT), and Oil Red O staining, quantitative real-time PCR (qRT-PCR) analysis of the matrix metalloproteinase-9 (MMP-9), MMP-13, transforming growth factor-β1 (TGF-β1), Bcl-2, and Bax genes as well as immunofluorescence (IF) of the first 3, and sera for measurement of aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, and hydroxyproline. Chronic administration of CCl4 followed by considerable increase in tissue disruption, macro- and micro-vesicles, collagen, lipid droplets (LDs), AST, ALT, hydroxyproline, TGF-β1, and Bax, and decrease in glycogen depository, albumin, Bcl-2, MMP-9, and MMP-13; however, the pattern was reverse when it comes to melatonin treatment (for all p < 0.05). Our results reveal the beneficial aspects of melatonin in treatment of liver fibrosis probably via inhibition of TGF-β1expression.
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Affiliation(s)
- Keywan Mortezaee
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Poursina Street, Tehran, Iran, 1417613151
| | - Fatemeh Sabbaghziarani
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Poursina Street, Tehran, Iran, 1417613151
| | - Ameneh Omidi
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Poursina Street, Tehran, Iran, 1417613151
| | - Ahmad Reza Dehpour
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Negar Omidi
- Department of Surgery, Ziaian Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Soudabeh Ghasemi
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Poursina Street, Tehran, Iran, 1417613151
| | - Parichehr Pasbakhsh
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Poursina Street, Tehran, Iran, 1417613151
| | - Iraj Ragerdi Kashani
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Poursina Street, Tehran, Iran, 1417613151
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26
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San-Miguel B, Crespo I, Sánchez DI, González-Fernández B, Ortiz de Urbina JJ, Tuñón MJ, González-Gallego J. Melatonin inhibits autophagy and endoplasmic reticulum stress in mice with carbon tetrachloride-induced fibrosis. J Pineal Res 2015; 59:151-62. [PMID: 25958928 DOI: 10.1111/jpi.12247] [Citation(s) in RCA: 85] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2015] [Accepted: 05/05/2015] [Indexed: 01/05/2023]
Abstract
This study aimed to investigate whether inhibition of autophagy and endoplasmic reticulum (ER stress) associates with the antifibrogenic effect of melatonin in mice treated with carbon tetrachloride (CCl4 ). Mice received CCl4 5 μL/g body wt i.p. twice a week for 4 wk or 6 wk. Melatonin was given at 5 or 10 mg/kg/day i.p, beginning 2 wk after the start of CCl4 administration. Treatment with CCl4 resulted in fibrosis evidenced by the staining of α-smooth muscle actin (α-SMA)-positive cells. CCl4 induced an autophagic response measured as the presence of autophagic vesicles, protein 1 light chain 3 (LC3) staining, conversion of LC3-I to autophagosome-associated LC3-II, changes in expression of beclin-1, UV radiation resistance-associated gene (UVRAG), ubiquitin-like autophagy-related (Atg5), Atg12, Atg16L1, sequestosome 1 (p62/SQSTM1), and lysosome-associated membrane protein (LAMP)-2, and increased phosphorylation of the mammalian target of rapamycin (mTOR). There was an increase in the expression of the ER stress chaperones CCAAT/enhancer-binding protein homologous protein (CHOP), immunoglobulin-heavy-chain-binding protein (BiP/GRP78), and 94-kDa glucose-regulated protein (GRP94), and in the mRNA levels of pancreatic ER kinase (PERK), activating transcription factor 6 (ATF6), ATF4, inositol-requiring enzyme 1 (IRE1), and spliced X-box-binding protein-1 (XBP1). Phospho-IRE1, ATF6, and phospho-PERK protein concentration also increased significantly. Immunohistochemical staining of α-SMA indicated an abrogation of hepatic stellate cells activation by melatonin. Furthermore, treatment with the indole resulted in significant inhibition of the autophagic flux and the unfolded protein response. Findings from this study give new insight into molecular pathways accounting for the protective effect of melatonin in fibrogenesis.
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Affiliation(s)
| | - Irene Crespo
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain
| | - Diana I Sánchez
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
| | | | | | - María J Tuñón
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain
| | - Javier González-Gallego
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain
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27
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Melatonin limits the expression of profibrogenic genes and ameliorates the progression of hepatic fibrosis in mice. Transl Res 2015; 165:346-57. [PMID: 25445210 DOI: 10.1016/j.trsl.2014.10.003] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2014] [Revised: 10/02/2014] [Accepted: 10/02/2014] [Indexed: 02/07/2023]
Abstract
We investigated whether melatonin ameliorates fibrosis and limits the expression of fibrogenic genes in mice treated with carbon tetrachloride (CCl4). Mice in treatment groups received CCl4 5 μL/g body weight intraperitoneally twice a week for 4 or 6 weeks. Melatonin was given at 5 or 10 mg/kg/d intraperitoneally, beginning 2 weeks after the start of CCl4 administration. Treatment with CCl4 resulted in fibrosis evidenced by the staining of Van Gieson and α-smooth muscle actin (α-SMA) positive cells in the liver. At both 4 and 6 weeks, CCl4 induced an increase in the messenger RNA levels of collagens I and III, transforming growth factor (TGF)-β, platelet-derived growth factor (PDGF), connective tissue growth factor (CTGF), amphiregulin, matrix metalloproteinase (MMP)-9, and tissue inhibitor of metalloproteinase (TIMP)-1. Protein concentrations of CTGF, amphiregulin, MMP-9, TIMP-1, and phospho-Smad3 were also significantly augmented in fibrotic mice. Melatonin successfully attenuated liver injury, as shown by histopathology and decreased levels of serum transaminases. Immunohistochemical staining of α-SMA indicated an abrogation of hepatic stellate cell activation by the indol. Furthermore, melatonin treatment resulted in significant inhibition of the expression of collagens I and III, TGF-β, PDGF, CTGF, amphiregulin, and phospho-Smad3. The MMP-9 activity decreased and the expression of nuclear factor erythroid-2-related factor 2 (Nrf2) increased in mice receiving melatonin. Data obtained suggest that attenuation of multiple profibrogenic gene pathways contributes to the beneficial effects of melatonin in mice with CCl4-induced liver fibrosis.
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Han Y, Onori P, Meng F, DeMorrow S, Venter J, Francis H, Franchitto A, Ray D, Kennedy L, Greene J, Renzi A, Mancinelli R, Gaudio E, Glaser S, Alpini G. Prolonged exposure of cholestatic rats to complete dark inhibits biliary hyperplasia and liver fibrosis. Am J Physiol Gastrointest Liver Physiol 2014; 307:G894-904. [PMID: 25214401 PMCID: PMC4216989 DOI: 10.1152/ajpgi.00288.2014] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Biliary hyperplasia and liver fibrosis are common features in cholestatic liver disease. Melatonin is synthesized by the pineal gland as well as the liver. Melatonin inhibits biliary hyperplasia of bile duct-ligated (BDL) rats. Since melatonin synthesis (by the enzyme serotonin N-acetyltransferase, AANAT) from the pineal gland increases after dark exposure, we hypothesized that biliary hyperplasia and liver fibrosis are diminished by continuous darkness via increased melatonin synthesis from the pineal gland. Normal or BDL rats (immediately after surgery) were housed with light-dark cycles or complete dark for 1 wk before evaluation of 1) the expression of AANAT in the pineal gland and melatonin levels in pineal gland tissue supernatants and serum; 2) biliary proliferation and intrahepatic bile duct mass, liver histology, and serum chemistry; 3) secretin-stimulated ductal secretion (functional index of biliary growth); 4) collagen deposition, liver fibrosis markers in liver sections, total liver, and cholangiocytes; and 5) expression of clock genes in cholangiocytes. In BDL rats exposed to dark there was 1) enhanced AANAT expression/melatonin secretion in pineal gland and melatonin serum levels; 2) improved liver morphology, serum chemistry and decreased biliary proliferation and secretin-stimulated choleresis; and 4) decreased fibrosis and expression of fibrosis markers in liver sections, total liver and cholangiocytes and reduced biliary expression of the clock genes PER1, BMAL1, CLOCK, and Cry1. Thus prolonged dark exposure may be a beneficial noninvasive therapeutic approach for the management of biliary disorders.
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Affiliation(s)
- Yuyan Han
- 4Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center, Temple, Texas;
| | - Paolo Onori
- 7Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, La Sapienza, Rome, Italy
| | - Fanyin Meng
- 1Research, Central Texas Veterans Health Care System, Temple, Texas; ,2Baylor Scott & White Digestive Disease Research Center, Scott & White, Temple, Texas; ,3Operational Funds, Baylor Scott & White, Temple, Texas; ,4Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center, Temple, Texas;
| | - Sharon DeMorrow
- 2Baylor Scott & White Digestive Disease Research Center, Scott & White, Temple, Texas; ,4Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center, Temple, Texas;
| | - Julie Venter
- 4Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center, Temple, Texas;
| | - Heather Francis
- 1Research, Central Texas Veterans Health Care System, Temple, Texas; ,2Baylor Scott & White Digestive Disease Research Center, Scott & White, Temple, Texas; ,3Operational Funds, Baylor Scott & White, Temple, Texas; ,4Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center, Temple, Texas;
| | - Antonio Franchitto
- 5Eleonora Lorillard Spencer Cenci Foundation, Rome, Italy; ,7Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, La Sapienza, Rome, Italy
| | - Debolina Ray
- 4Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center, Temple, Texas;
| | - Lindsey Kennedy
- 1Research, Central Texas Veterans Health Care System, Temple, Texas;
| | - John Greene
- 6Pathology, Baylor Scott & White, Temple, Texas; and
| | - Anastasia Renzi
- 7Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, La Sapienza, Rome, Italy
| | - Romina Mancinelli
- 7Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, La Sapienza, Rome, Italy
| | - Eugenio Gaudio
- 7Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, La Sapienza, Rome, Italy
| | - Shannon Glaser
- 1Research, Central Texas Veterans Health Care System, Temple, Texas; ,2Baylor Scott & White Digestive Disease Research Center, Scott & White, Temple, Texas; ,4Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center, Temple, Texas;
| | - Gianfranco Alpini
- Research, Central Texas Veterans Health Care System, Temple, Texas; Baylor Scott & White Digestive Disease Research Center, Scott & White, Temple, Texas; Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center, Temple, Texas;
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Yang JJ, Tao H, Hu W, Liu LP, Shi KH, Deng ZY, Li J. MicroRNA-200a controls Nrf2 activation by target Keap1 in hepatic stellate cell proliferation and fibrosis. Cell Signal 2014; 26:2381-9. [PMID: 25049078 DOI: 10.1016/j.cellsig.2014.07.016] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2014] [Accepted: 07/09/2014] [Indexed: 01/19/2023]
Abstract
Hepatic fibrosis is a common final pathological process in the progression of liver disease, which is primarily due to oxidative stress. Nrf2 is known to coordinate induction of genes that encode antioxidant enzymes. Moreover, Nrf2 expression is largely regulated through the association of Nrf2 with Keap1, which results in cytoplasmic Nrf2 degradation. Conversely, little is known concerning the regulation of Keap1 expression. Although the function of miRNA-200a controls Keap1 gene expression has been discussed in many cancers and fibrotic diseases, its role in hepatic fibrosis is still poorly understood. By using miRNA mimic, we observed miRNA-200a silencing in activated hepatic stellate cell and demonstrated that upon re-expression, miRNA-200a targets the Keap1, and leading to Keap1 mRNA degradation. We find that treatment with miRNA-200a mimics, restored miRNA-200a expression and reduced Keap1 levels. This reduction in Keap1 levels corresponded with Nrf2 nuclear translocation and activation of Nrf2-dependent NQO1 gene transcription. Moreover, we found that Nrf2 activation inhibited the TGF-β1-independent growth of hepatic stellate cell. Finally, our study demonstrates that miRNA-200a regulates the Keap1/Nrf2 pathway in hepatic stellate cell and fibrosis, and we find that epigenetic therapy can restore miRNA-200a regulation of Keap1 expression, therefore reactivating the Nrf2-dependent antioxidant pathway in liver fibrosis.
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Affiliation(s)
- Jing-Jing Yang
- Department of Pharmacology, The Second Hospital of Anhui Medical University, Hefei 230601, China
| | - Hui Tao
- Department of Cardiothoracic Surgery, The Second Hospital of Anhui Medical University, Hefei 230601, China
| | - Wei Hu
- Department of Pharmacology, The Second Hospital of Anhui Medical University, Hefei 230601, China
| | - Li-Ping Liu
- Department of Pharmacology, The Second Hospital of Anhui Medical University, Hefei 230601, China
| | - Kai-Hu Shi
- Department of Cardiothoracic Surgery, The Second Hospital of Anhui Medical University, Hefei 230601, China
| | - Zi-Yu Deng
- Department of Scientific and Educational, The Second Hospital of Anhui Medical University, China
| | - Jun Li
- School of Pharmacy, Anhui Medical University, Hefei 230032, China.
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Özerkan D, Özsoy N, Yılmaz E. Vitamin D and melatonin protect the cell's viability and ameliorate the CCl4 induced cytotoxicity in HepG2 and Hep3B hepatoma cell lines. Cytotechnology 2014; 67:995-1002. [PMID: 24997582 DOI: 10.1007/s10616-014-9738-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2014] [Accepted: 05/02/2014] [Indexed: 12/16/2022] Open
Abstract
Carbon tetrachloride (CCl4) is widely used to induce liver toxicity in in vitro/in vivo models. Lipid peroxidation (LPO) begins with toxicity and affects cell viability. Recently, the beneficial effects of melatonin and Vitamin D on cell proliferation in human normal and cancer cells were found. This study was planned to evaluate antioxidant and cytoprotective activity of melatonin and Vitamin D in CCl4 induced cytotoxicity in HepG2 and Hep3B hepatoma cell lines. Based on the cytotoxicity assay, melatonin and Vitamin D were evaluated for cytotoprotective potential against CCl4 induced toxicity in HepG2 and Hep3B liver cell lines by monitoring cell viability, LPO and glutathione (GSH) level. Different dosages of CCl4 (0.1, 0.2, 0.3 and 0.4 % v/v) were applied to HepG2 and Hep3B cells in order to determine the most toxic dosage of it in a time dependent manner. The same experiments were repeated with exogenously applied melatonin (MEL) and Vitamin D to groups treated with/without CCL4. Cell viability was determined with MTT measurements at the 2nd, 24th and 48th h. GSH content and Malondialdehyde levels were measured from the cell lysates. As a result, both melatonin and Vitamin D administration during CCl4 exposure protected liver cells from CCl4 induced cell damage. Increase in LPO and decrease in GSH were found in the CCl4 groups of both cells. Contrary to these results administration of MEL and Vitamin D on cells exhibited results similar to the control groups. Therefore, melatonin and Vitamin D might be a promising therapeutic agent in several toxic hepatic diseases.
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Affiliation(s)
- Dilşad Özerkan
- Department of Biology, Faculty of Arts and Sciences, Kastamonu University, 37100, Kastamonu, Turkey.
| | - Nesrin Özsoy
- Department of Biology, Faculty of Science, Ankara University, Tandogan, 06100, Ankara, Turkey.
| | - Erkan Yılmaz
- Institute of Biotechnology, Ankara University, Tandogan, 06100, Ankara, Turkey.
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31
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Zhou WC, Zhang QB, Qiao L. Pathogenesis of liver cirrhosis. World J Gastroenterol 2014; 20:7312-7324. [PMID: 24966602 PMCID: PMC4064077 DOI: 10.3748/wjg.v20.i23.7312] [Citation(s) in RCA: 380] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2013] [Revised: 03/16/2014] [Accepted: 04/29/2014] [Indexed: 02/06/2023] Open
Abstract
Liver cirrhosis is the final pathological result of various chronic liver diseases, and fibrosis is the precursor of cirrhosis. Many types of cells, cytokines and miRNAs are involved in the initiation and progression of liver fibrosis and cirrhosis. Activation of hepatic stellate cells (HSCs) is a pivotal event in fibrosis. Defenestration and capillarization of liver sinusoidal endothelial cells are major contributing factors to hepatic dysfunction in liver cirrhosis. Activated Kupffer cells destroy hepatocytes and stimulate the activation of HSCs. Repeated cycles of apoptosis and regeneration of hepatocytes contribute to pathogenesis of cirrhosis. At the molecular level, many cytokines are involved in mediation of signaling pathways that regulate activation of HSCs and fibrogenesis. Recently, miRNAs as a post-transcriptional regulator have been found to play a key role in fibrosis and cirrhosis. Robust animal models of liver fibrosis and cirrhosis, as well as the recently identified critical cellular and molecular factors involved in the development of liver fibrosis and cirrhosis will facilitate the development of more effective therapeutic approaches for these conditions.
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32
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Glaser S, Han Y, Francis H, Alpini G. Melatonin regulation of biliary functions. Hepatobiliary Surg Nutr 2014; 3:35-43. [PMID: 24696836 PMCID: PMC3954997 DOI: 10.3978/j.issn.2304-3881.2013.10.04] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2013] [Accepted: 10/20/2013] [Indexed: 12/19/2022]
Abstract
The intrahepatic biliary epithelium is a three-dimensional tubular system lined by cholangiocytes, epithelial cells that in addition to modify ductal bile are also the targets of vanishing bile duct syndromes (i.e., cholangiopathies) such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) that are characterized by the damage/proliferation of cholangiocytes. Cholangiocyte proliferation is critical for the maintenance of the biliary mass and secretory function during the pathogenesis of cholangiopathies. Proliferating cholangiocytes serve as a neuroendocrine compartment during the progression of cholangiopathies, and as such secrete and respond to hormones, neurotransmitters and neuropeptides contributing to the autocrine and paracrine pathways that regulate biliary homeostasis. The focus of this review is to summarize the recent findings related to the role of melatonin in the modulation of biliary functions and liver damage in response to a number of insults. We first provide a general background on the general function of cholangiocytes including their anatomic characteristics, their innervation and vascularization as well the role of these cells on secretory and proliferation events. After a background on the synthesis and regulation of melatonin and its role on the maintenance of circadian rhythm, we will describe the specific effects of melatonin on biliary functions and liver damage. After a summary of the topics discussed, we provide a paragraph on the future perspectives related to melatonin and liver functions.
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Seo KW, Sohn SY, Bhang DH, Nam MJ, Lee HW, Youn HY. Therapeutic effects of hepatocyte growth factor-overexpressing human umbilical cord blood-derived mesenchymal stem cells on liver fibrosis in rats. Cell Biol Int 2013; 38:106-16. [PMID: 24115681 DOI: 10.1002/cbin.10186] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2013] [Accepted: 08/26/2013] [Indexed: 01/18/2023]
Abstract
Fibrosis is a common end stage for a variety of liver diseases, including most chronic liver diseases, and results from an imbalance between collagen deposition and degradation. Mesenchymal stem cells (MSCs) have the ability to migrate into fibrotic livers and differentiate into hepatocytes. Hepatocyte growth factor (HGF) has potent anti-apoptotic and mitogenic effects on hepatocytes during liver injury and plays an essential role in the development and regeneration of the liver. In this study, human HGF-overexpressing human umbilical cord blood-derived MSCs (hHGF-HUCB-MSCs) were prepared using the pMEX Expression System, and the upregulation of hHGF expression was confirmed by RT-PCR and ELISA. HGF expressed by hHGF-HUCB-MSCs exerted a stimulatory effect on hepatocyte proliferation in vitro. hHGF-HUCB-MSCs were transplanted to investigate the therapeutic effects of these cells on carbon tetrachloride (CCL4)-induced liver fibrosis in a rat model. After 4 weeks of cell treatment once per week with 2 × 10(6) cells, biochemical analysis of the serum and histopathological analysis of the liver tissue were performed. The results of the biochemical analysis of the serum show that the hHGF-HUCB-MSC-treated group had higher levels of alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase, indicating the improvement of liver function. Histopathology showed that the hHGF-HUCB-MSC-treated group had reduction in the density of collagen fibres. Thus hHGF-HUCB-MSCs can enhance liver regeneration and could be useful for the treatment of patients with liver fibrosis or cirrhosis.
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Affiliation(s)
- Kyoung-Won Seo
- Department of Veterinary Internal Medicine, College of Veterinary Medicine, Chungnam National University, 99 Daehakro, Yuseoung gu, Daejon, 305-764, Republic of Korea
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Rudra DS, Pal U, Maiti NC, Reiter RJ, Swarnakar S. Melatonin inhibits matrix metalloproteinase-9 activity by binding to its active site. J Pineal Res 2013; 54:398-405. [PMID: 23330737 DOI: 10.1111/jpi.12034] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2012] [Accepted: 12/03/2012] [Indexed: 12/21/2022]
Abstract
The zinc-dependent matrix metalloproteinases (MMPs) are key enzymes associated with extracellular matrix (ECM) remodeling; they play critical roles under both physiological and pathological conditions. MMP-9 activity is linked to many pathological processes, including rheumatoid arthritis, atherosclerosis, gastric ulcer, tumor growth, and cancer metastasis. Specific inhibition of MMP-9 activity may be a promising target for therapy for diseases characterized by dysregulated ECM turnover. Potent MMP-9 inhibitors including an indole scaffold were recently reported in an X-ray crystallographic study. Herein, we addressed whether melatonin, a secretory product of pineal gland, has an inhibitory effect on MMP-9 function. Gelatin zymographic analysis showed a significant reduction in pro- and active MMP-9 activity in vitro in a dose- and time-dependent manner. In addition, a human gastric adenocarcinoma cell line (AGS) exhibited a reduced (~50%) MMP-9 expression when incubated with melatonin, supporting an inhibitory effect of melatonin on MMP-9. Atomic-level interaction between melatonin and MMP-9 was probed with computational chemistry tools. Melatonin docked into the active site cleft of MMP-9 and interacted with key catalytic site residues including the three histidines that form the coordination complex with the catalytic zinc as well as proline 421 and alanine 191. We hypothesize that under physiological conditions, tight binding of melatonin in the active site might be involved in reducing the catalytic activity of MMP-9. This finding could provide a novel approach to physical docking of biomolecules to the catalytic site of MMPs, which inhibits this protease, to arrest MMP-9-mediated inflammatory signals.
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Affiliation(s)
- Deep Sankar Rudra
- Drug Development Diagnostics and Biotechnology Division, Department of Physiology, Indian Institute of Chemical Biology, Kolkata, India
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35
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Efficacy evaluation of the protein isolated from Peganum harmala seeds as an antioxidant in liver of rats. ASIAN PAC J TROP MED 2013; 6:285-95. [DOI: 10.1016/s1995-7645(13)60058-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2012] [Revised: 05/30/2012] [Accepted: 12/15/2012] [Indexed: 11/18/2022] Open
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Chojnacki C, Wachowska-Kelly P, Błasiak J, Reiter RJ, Chojnacki J. Melatonin secretion and metabolism in patients with hepatic encephalopathy. J Gastroenterol Hepatol 2013. [PMID: 23190028 DOI: 10.1111/jgh.12055] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM The rhythm of melatonin secretion and its blood level changes in cirrhotic patients, but the causes of these alterations have not been sufficiently appreciated. The aim of study was to estimate the dependence between melatonin secretion and metabolism and the severity of hepatic encephalopathy. METHODS The study included 75 alcoholic cirrhotic patients (A, B, C) with hepatic insufficiency and 25 healthy subjects (group K). Three groups of patients were identified, 25 patients each, with grade 1, 2, and 3 hepatic encephalopathy according to West-Haven Scale. Immunoenzymatic method was used to measure serum melatonin (at 02:00 h and 09:00 h) level and 6-sulfatoxymelatonin (6-HMS) excretion in the urine (during night and day). RESULTS Nocturnal serum melatonin levels (pg/mL) in groups were: K-57.1 ± 11.4, A-38.5 ± 11.2, B-53.4 ± 17.9, C-79.5 ± 27.9 (P < 0.01); whereas diurnal levels were: K-10.9 ± 3.5, A-33.5 ± 12.0, B-53.8 ± 23.1, C-98.5 ± 34.6 (P < 0.01). Similar differences were found in the evaluation of 6-HMS excretion (μg/9 h) in urine at night: group K-23.4 ± 14.4, A-16.6 ± 5.4, B-14.3 ± 6.2 (P < 0.01), C-3.3 ± 1.5 (P < 0.001). Diurnal 6-HMS excretion (μg/15 h) was lower only in group C and it was respectively: K-6.9 ± 3.4, A-7.1 ± 1.7, B-7.6 ± 1.7, C-4.3 ± 2.2 (P < 0.001). Serum ammonia concentrations (μg/dL) were: group K-30.4 ± 8.9, A-51.8 ± 25.4 (P < 0.05), B-73.0 ± 29.8 (P < 0.001), C-107.5 ± 34.8 (P < 0.001). No correlation between melatonin and ammonia levels in all groups was found. CONCLUSIONS The elevated melatonin blood levels both at night and day may account for some of the clinical manifestations of hepatic encephalopathy (daytime sleepiness, fatigue).
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Affiliation(s)
- Cezary Chojnacki
- Department of Gastroenterology, Medical University of Lodz, Lodz, Poland
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Melatonin levels in serum and ascitic fluid of patients with hepatic encephalopathy. Gastroenterol Res Pract 2012; 2012:510764. [PMID: 23346104 PMCID: PMC3546494 DOI: 10.1155/2012/510764] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2012] [Accepted: 12/04/2012] [Indexed: 01/24/2023] Open
Abstract
Cirrhotic patients exhibit disturbed melatonin homeostasis, which may lead to sleep disturbances, but an influence on the hepatic encephalopathy has not been elucidated. Aim. In the present study, the association of melatonin levels in serum and ascitic fluid and ammonia concentration related to the intensity of hepatic encephalopathy (HE) was investigated.
Material and Methods. The study included 90 alcoholic patients with hepatic encephalopathy and 30 healthy volunteers (C). Patients were divided in three groups according to 0–4 West-Haven Score: HE1 (n = 28), HE2 (n = 30), and HE3 (n = 32). Melatonin was measured by radioimmune assay. Results. In fasting patients with hepatic encephalopathy we noted higher melatonin serum levels [pg/mL] than in healthy subjects groups: C—11.3 ± 3.9, HE1 – 34.3 ± 12.2 (P < 0.01), HE2—54.8 ± 23.9, and HE3—119.8 ± 96.4 (P < 0.001). No correlation between melatonin and ammonia levels was found. Melatonin was detected in ascetic fluid in 24 patients of group HE2 and 27 patients of group HE2 of hepatic encephalopathy. Conclusions. Our results suggest that high blood levels of melatonin in cirrhotic liver patients may account for some of the clinical manifestations of hepatic encephalopathy, for example, daytime sleepiness, fatigue.
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El Denshary ES, Al-Gahazali MA, Mannaa FA, Salem HA, Hassan NS, Abdel-Wahhab MA. Dietary honey and ginseng protect against carbon tetrachloride-induced hepatonephrotoxicity in rats. EXPERIMENTAL AND TOXICOLOGIC PATHOLOGY : OFFICIAL JOURNAL OF THE GESELLSCHAFT FUR TOXIKOLOGISCHE PATHOLOGIE 2012; 64:753-760. [PMID: 21330121 DOI: 10.1016/j.etp.2011.01.012] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/10/2010] [Revised: 11/06/2010] [Accepted: 01/18/2011] [Indexed: 02/07/2023]
Abstract
Liver diseases are amongst the most serious health problems in the world today and hepatocellular carcinoma is one of the world's deadliest cancers. The aim of the current study was to evaluate the protective effect of sider honey and/or Korean ginseng extract (KGE) against carbon tetrachloride (CCl(4))-induced hepato-nephrotoxicity in rat. Eighty male Sprague-Dawley (SD) rats were allocated into different groups and over a 4-week period, they orally received honey and/or KGE or were treated either with CCl(4) alone (100 mg/kg b.w) or with CCl(4) after a pretreatment period with honey, KGE or a combination of both. Clinical, clinico-pathological and histopathological evaluations were done and CCl(4)-treated groups were compared with rats receiving no treatment and with rats given honey, KGE or a combination of these substances. The results indicated that oral administration of CCl(4) induced severe hepatic and kidney injury associated with oxidative stress. The combined treatment with CCl(4) plus honey and/or KGE resulted in a significant improvement in all evaluated parameters. This improvement was prominent in the group receiving CCl(4) after combined pretreatment with honey and KGE. Animals receiving honey and/or KGE (without CCl(4)-treatment) were comparable to the control untreated group. It could be concluded that honey and KGE protect SD rats against the severe CCl(4)-induced hepatic and renal toxic effects. Our results suggest that the protective activity of honey and KGE may have been related to their antioxidant properties.
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Aktas C, Kanter M, Erboga M, Mete R, Oran M. Melatonin attenuates oxidative stress, liver damage and hepatocyte apoptosis after bile-duct ligation in rats. Toxicol Ind Health 2012; 30:835-44. [PMID: 23095487 DOI: 10.1177/0748233712464811] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The goal of this study was to evaluate the possible protective effects of melatonin against cholestatic oxidative stress, liver damage and hepatocyte apoptosis in the common rats with bile duct ligation (BDL). A total of 24 male Wistar albino rats were divided into three groups: control, BDL and BDL + received melatonin; each group contains eight animals. Melatonin-treated BDL rats received daily melatonin 100 mg/kg/day via intraperitoneal injection. The application of BDL clearly increased the malondialdehyde (MDA) levels and decreased the superoxide dismutase (SOD) and glutathione (GSH) activities. Melatonin treatment significantly decreased the elevated tissue MDA levels and increased the reduced SOD and GSH enzyme levels in the tissues. The changes demonstrate that the bile duct proliferation and fibrosis in expanded portal tracts include the extension of proliferated bile ducts into lobules, mononuclear cells and neutrophil infiltration into the widened portal areas as observed in the BDL group. The data indicate that melatonin attenuates BDL-induced cholestatic liver injury, bile duct proliferation and fibrosis. The α-smooth muscle actin (α-SMA) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells in the BDL were observed to be reduced with the melatonin treatment. These results suggest that administration of melatonin is a potentially beneficial agent to reduce liver damage in BDL by decreasing oxidative stress.
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Affiliation(s)
- Cevat Aktas
- Department of Histology and Embryology, Faculty of Medicine, Namik Kemal University, Tekirdag, Turkey
| | - Mehmet Kanter
- Department of Histology and Embryology, Faculty of Medicine, Medeniyet University, Istanbul, Turkey
| | - Mustafa Erboga
- Department of Histology and Embryology, Faculty of Medicine, University of Trakya, Edirne, Turkey
| | - Rafet Mete
- Department of Gastroenterology, Faculty of Medicine, Namik Kemal University, Tekirdag, Turkey
| | - Mustafa Oran
- Department of Internal Diseases, Faculty of Medicine, Namik Kemal University, Tekirdag, Turkey
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Ligustrazine attenuates oxidative stress-induced activation of hepatic stellate cells by interrupting platelet-derived growth factor-β receptor-mediated ERK and p38 pathways. Toxicol Appl Pharmacol 2012; 265:51-60. [PMID: 23022513 DOI: 10.1016/j.taap.2012.09.016] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2012] [Revised: 09/14/2012] [Accepted: 09/18/2012] [Indexed: 12/13/2022]
Abstract
Hepatic fibrosis represents a frequent event following chronic insult to trigger wound healing reactions with accumulation of extracellular matrix (ECM) in the liver. Activation of hepatic stellate cells (HSCs) is the pivotal event during liver fibrogenesis. Compelling evidence indicates that oxidative stress is concomitant with liver fibrosis irrespective of the underlying etiology. Natural antioxidant ligustrazine exhibits potent antifibrotic activities, but the mechanisms are poorly understood. Our studies were to investigate the ligustrazine effects on HSC activation stimulated by hydrogen peroxide (H(2)O(2)), an in vitro model mimicking the oxidative stress in liver fibrogenesis, and to elucidate the possible mechanisms. Our results demonstrated that H(2)O(2) at 5μM significantly stimulated HSC proliferation and expression of marker genes of HSC activation; whereas ligustrazine dose-dependently suppressed proliferation and induced apoptosis in H(2)O(2)-activated HSCs, and attenuated expression of fibrotic marker genes. Mechanistic investigations revealed that ligustrazine reduced platelet-derived growth factor-β receptor (PDGF-βR) expression and blocked the phosphorylation of extracellular regulated protein kinase (ERK) and p38 kinase, two downstream effectors of PDGF-βR. Further molecular evidence suggested that ligustrazine interruption of ERK and p38 pathways was dependent on the blockade of PDGF-βR and might be involved in ligustrazine reduction of fibrotic marker gene expression under H(2)O(2) stimulation. Furthermore, ligustrazine modulated some proteins critical for HSC activation and ECM homeostasis in H(2)O(2)-stimulated HSCs. These data collectively indicated that ligustrazine could attenuate HSC activation caused by oxidative stress, providing novel insights into ligustrazine as a therapeutic option for hepatic fibrosis.
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Tzeng JI, Chen MF, Chung HH, Cheng JT. Silymarin decreases connective tissue growth factor to improve liver fibrosis in rats treated with carbon tetrachloride. Phytother Res 2012; 27:1023-8. [PMID: 22933420 DOI: 10.1002/ptr.4829] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2012] [Revised: 07/29/2012] [Accepted: 08/01/2012] [Indexed: 12/21/2022]
Abstract
Silymarin is an herbal product showing potential as protection against hepatic disorders. In an attempt to develop the agent for the treatment of hepatic fibrosis, we screened the effects of silymarin on a rat model of hepatic fibrosis induced by carbon tetrachloride (CCl₄). Intraperitoneal administration of CCl₄ to rats for 8 weeks not only increased the plasma levels of glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) but also induced a marked increase in the formation of hepatic fibrosis. Moreover, the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) were also reduced in the liver of rats treated with CCl₄. Oral administration of silymarin (200 mg/kg, three times daily), in parallel, decreased the plasma levels of GOT and GPT. Furthermore, in addition to the improvement of hepatic fibrosis, the hepatic levels of hydroxyproline and connective tissue growth factor (CTGF) were both markedly decreased by silymarin. Silymarin also elevated the activities of SOD and GPx in liver isolated from CCl₄-treated rats. The results suggest that oral administration of silymarin protects against CCl₄-induced hepatic fibrosis in rats, likely due to the decrease in fibrotic parameters such as CTGF.
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Affiliation(s)
- Jann-Inn Tzeng
- Department of Food Sciences and Technology, Chia Nan University of Pharmacy and Sciences, Jen-Te, Tainan City, Taiwan 71701
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Bravo E, D'Amore E, Ciaffoni F, Mammola CL. Evaluation of the spontaneous reversibility of carbon tetrachloride-induced liver cirrhosis in rabbits. Lab Anim 2012; 46:122-8. [PMID: 22522417 DOI: 10.1258/la.2012.011035] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
There is a general consensus that liver fibrosis in humans is potentially reversible, while scepticism prevails on the concept that cirrhosis can be truly reversed. The availability of suitable experimental models is fundamental for disease research. The experimental murine model of liver cirrhosis induced by carbon tetrachloride (CCl(4)) reproduces both the histological picture of the postnecrotic cirrhosis and its biochemical and clinical parameters. Normal hepatic structure is modified by formation of regeneration nodules. Fibrosis represents a morphological element of disease and an effect of hepatocyte necrosis. However, the relevance for research of this well-established model of liver cirrhosis is hampered by some spontaneous cirrhosis regression reported in mice and rats. It has been reported that CCl(4) also induces experimental liver cirrhosis in rabbits, but it is not known whether the process is reversible in this species. The aim of our study was to investigate this question. Male New Zealand White rabbits were treated intragastrically with CCl(4) or the vehicle only for 19 weeks and groups were sacrificed three and five months after treatment interruption. Cirrhotic and control livers were processed for routine light microscopy and for morphometric study of fibrosis by semiquantitative evaluation. The degree of fibrosis was based on the Knodell's scoring system.
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Affiliation(s)
- E Bravo
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome, Italy.
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Zheng B, Tan L, Mo X, Yu W, Wang Y, Tucker-Kellogg L, Welsch RE, So PTC, Yu H. Predicting in vivo anti-hepatofibrotic drug efficacy based on in vitro high-content analysis. PLoS One 2011; 6:e26230. [PMID: 22073152 PMCID: PMC3206809 DOI: 10.1371/journal.pone.0026230] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2011] [Accepted: 09/22/2011] [Indexed: 01/11/2023] Open
Abstract
Background/Aims Many anti-fibrotic drugs with high in vitro efficacies fail to produce significant effects in vivo. The aim of this work is to use a statistical approach to design a numerical predictor that correlates better with in vivo outcomes. Methods High-content analysis (HCA) was performed with 49 drugs on hepatic stellate cells (HSCs) LX-2 stained with 10 fibrotic markers. ∼0.3 billion feature values from all cells in >150,000 images were quantified to reflect the drug effects. A systematic literature search on the in vivo effects of all 49 drugs on hepatofibrotic rats yields 28 papers with histological scores. The in vivo and in vitro datasets were used to compute a single efficacy predictor (Epredict). Results We used in vivo data from one context (CCl4 rats with drug treatments) to optimize the computation of Epredict. This optimized relationship was independently validated using in vivo data from two different contexts (treatment of DMN rats and prevention of CCl4 induction). A linear in vitro-in vivo correlation was consistently observed in all the three contexts. We used Epredict values to cluster drugs according to efficacy; and found that high-efficacy drugs tended to target proliferation, apoptosis and contractility of HSCs. Conclusions The Epredict statistic, based on a prioritized combination of in vitro features, provides a better correlation between in vitro and in vivo drug response than any of the traditional in vitro markers considered.
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Affiliation(s)
- Baixue Zheng
- Computation and Systems Biology Program, Singapore-MIT Alliance, National University of Singapore, Singapore, Singapore
- Institute of Bioengineering and Nanotechnology, A*STAR, Singapore, Singapore
- Mechanobiology Institute, National University of Singapore, Singapore, Singapore
| | - Looling Tan
- Institute of Bioengineering and Nanotechnology, A*STAR, Singapore, Singapore
| | - Xuejun Mo
- Institute of Bioengineering and Nanotechnology, A*STAR, Singapore, Singapore
- Department of Chemistry, Faculty of Science, National University of Singapore, Singapore, Singapore
| | - Weimiao Yu
- Imaging Informatics Division, Bioinformatics Institute, A*STAR, Singapore, Singapore
- Central Imaging Facility, Institute of Molecular and Cell Biology, A*STAR, Singapore, Singapore
| | - Yan Wang
- Institute of Bioengineering and Nanotechnology, A*STAR, Singapore, Singapore
- Department of Hepatobiliary Surgery, Southern Medical University Affiliated Zhujiang Hospital, Guangzhou, China
| | - Lisa Tucker-Kellogg
- Computation and Systems Biology Program, Singapore-MIT Alliance, National University of Singapore, Singapore, Singapore
- Mechanobiology Institute, National University of Singapore, Singapore, Singapore
| | - Roy E. Welsch
- Computation and Systems Biology Program, Singapore-MIT Alliance, National University of Singapore, Singapore, Singapore
- Engineering Systems Division, Sloan School of Management, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America
| | - Peter T. C. So
- Computation and Systems Biology Program, Singapore-MIT Alliance, National University of Singapore, Singapore, Singapore
- Singapore-MIT Alliance for Research and Technology, BioSyM, Singapore, Singapore
- Department of Mechanical Engineering and Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America
| | - Hanry Yu
- Computation and Systems Biology Program, Singapore-MIT Alliance, National University of Singapore, Singapore, Singapore
- Institute of Bioengineering and Nanotechnology, A*STAR, Singapore, Singapore
- Mechanobiology Institute, National University of Singapore, Singapore, Singapore
- Singapore-MIT Alliance for Research and Technology, BioSyM, Singapore, Singapore
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Graduate School for Integrative Sciences, National University of Singapore, Singapore, Singapore
- NUS Tissue-Engineering Programme, National University of Singapore, Singapore, Singapore
- Department of Mechanical Engineering and Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America
- * E-mail:
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Renzi A, Glaser S, DeMorrow S, Mancinelli R, Meng F, Franchitto A, Venter J, White M, Francis H, Han Y, Alvaro D, Gaudio E, Carpino G, Ueno Y, Onori P, Alpini G. Melatonin inhibits cholangiocyte hyperplasia in cholestatic rats by interaction with MT1 but not MT2 melatonin receptors. Am J Physiol Gastrointest Liver Physiol 2011; 301:G634-43. [PMID: 21757639 PMCID: PMC3191552 DOI: 10.1152/ajpgi.00206.2011] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
In bile duct-ligated (BDL) rats, large cholangiocytes proliferate by activation of cAMP-dependent signaling. Melatonin, which is secreted from pineal gland as well as extrapineal tissues, regulates cell mitosis by interacting with melatonin receptors (MT1 and MT2) modulating cAMP and clock genes. In the liver, melatonin suppresses oxidative damage and ameliorates fibrosis. No information exists regarding the role of melatonin in the regulation of biliary hyperplasia. We evaluated the mechanisms of action by which melatonin regulates the growth of cholangiocytes. In normal and BDL rats, we determined the hepatic distribution of MT1, MT2, and the clock genes, CLOCK, BMAL1, CRY1, and PER1. Normal and BDL (immediately after BDL) rats were treated in vivo with melatonin before evaluating 1) serum levels of melatonin, bilirubin, and transaminases; 2) intrahepatic bile duct mass (IBDM) in liver sections; and 3) the expression of MT1 and MT2, clock genes, and PKA phosphorylation. In vitro, large cholangiocytes were stimulated with melatonin in the absence/presence of luzindole (MT1/MT2 antagonist) and 4-phenyl-2-propionamidotetralin (MT2 antagonist) before evaluating cell proliferation, cAMP levels, and PKA phosphorylation. Cholangiocytes express MT1 and MT2, CLOCK, BMAL1, CRY1, and PER1 that were all upregulated following BDL. Administration of melatonin to BDL rats decreased IBDM, serum bilirubin and transaminases levels, the expression of all clock genes, cAMP levels, and PKA phosphorylation in cholangiocytes. In vitro, melatonin decreased the proliferation, cAMP levels, and PKA phosphorylation, decreases that were blocked by luzindole. Melatonin may be important in the management of biliary hyperplasia in human cholangiopathies.
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Affiliation(s)
| | - Shannon Glaser
- 2Department of Medicine, ,3Scott & White Digestive Disease Research Center,
| | - Sharon DeMorrow
- 2Department of Medicine, ,3Scott & White Digestive Disease Research Center,
| | - Romina Mancinelli
- Departments of 5Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, and
| | - Fanyin Meng
- 2Department of Medicine, ,3Scott & White Digestive Disease Research Center, ,4Division of Research and Education, Scott & White and Texas A&M Health Science Center College of Medicine, Temple, Texas;
| | - Antonio Franchitto
- Departments of 5Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, and
| | | | | | - Heather Francis
- 2Department of Medicine, ,3Scott & White Digestive Disease Research Center, ,4Division of Research and Education, Scott & White and Texas A&M Health Science Center College of Medicine, Temple, Texas;
| | | | - Domenico Alvaro
- 6Science and Medical-Surgical Biotechnology, Fondazione Eleonora Lorillard Spencer Cenci, Polo Pontino, University of Rome “Sapienza”, Rome;
| | - Eugenio Gaudio
- Departments of 5Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, and
| | - Guido Carpino
- 7Department of Health Science, University of Rome “Foro Italico”, Rome;
| | - Yoshiyuki Ueno
- 8Rohoku University Graduate School of Medicine Sendai, Japan;
| | - Paolo Onori
- 9Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy
| | - Gianfranco Alpini
- 1Division of Research, Central Texas Veterans Health Care System, ,2Department of Medicine, ,3Scott & White Digestive Disease Research Center,
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Bera TK, Chatterjee K, De D, Ali KM, Jana K, Maiti S, Ghosh D. Hepatoprotective activity of Livshis, a polyherbal formulation in CCl4-induced hepatotoxic male Wistar rats: A toxicity screening approach. ACTA ACUST UNITED AC 2011. [DOI: 10.1016/j.gmbhs.2012.03.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
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Pentoxifylline and melatonin in combination with pioglitazone ameliorate experimental non-alcoholic fatty liver disease. Eur J Pharmacol 2011; 662:70-7. [DOI: 10.1016/j.ejphar.2011.04.049] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2010] [Revised: 02/28/2011] [Accepted: 04/18/2011] [Indexed: 01/21/2023]
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Su J, Tang GD, Yang HY, Qin MB, Liang ZH. Role of ghrelin and NF-κB in the pathogenesis of acute necrotizing pancreatitis-associated liver injury. Shijie Huaren Xiaohua Zazhi 2011; 19:568-574. [DOI: 10.11569/wcjd.v19.i6.568] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the expression of ghrelin in the liver of rats with acute necrotizing pancreatitis (ANP) with liver injury and to explore the role of ghrelin and NF-κB in the pathogenesis of ANP-associated liver injury and the mechanism underlying the therapeutic effects of melatonin against ANP.
METHODS: Seventy-two male Sprague-Dawley rats were randomly and equally divided into control group, ANP group, and melatonin intervention group. Rats of the ANP group and melatonin intervention group were injected with 6% L-Arg (1.5 g/kg) intraperitoneally three times to induce ANP. Rats of the control group were injected with same volume of normal saline. The melatonin intervention group was given 1% melatonin (50 μg/kg) intraperitoneally 0.5 h before the first injection of L-Arg. Rats were sacrificed at 6, 12, and 24 h after the injection of melatonin. Pathological changes in the pancreatic and hepatic tissue were observed and graded under a microscope. The expression of ghrelin and NF-κB mRNAs was evaluated by RT-PCR, while the protein expression of NF-κB was detected by Western blot.
RESULTS: Pancreatic and hepatic pathological scores, serum amylase, and expression of NF-κB mRNA (6 h: 0.74 ± 0.04 vs 0.40 ± 0.05; 12 h: 0.77 ± 0.03 vs 0.40 ± 0.02; 24 h: 0.82 ± 0.04 vs 0.40 ± 0.03, all P = 0.001) and protein in the liver at all time points were significantly higher (24 h: 0.48 ± 0.07 vs 0.6 ± 0.04, P < 0.05), and ghrelin mRNA expression was significantly lower in the ANP group than in the control group (6 h: 0.39 ± 0.04 vs 0.66 ± 0.03; 12 h: 0.14 ± 0.37 vs 0.30 ± 0.05; 24 h: 0.22 ± 0.02 vs 0.59 ± 0.05, all P < 0.05). Pancreatic pathological scores, hepatic pathological scores, serum amylase, and expression of NF-κB mRNA(6 h: 0.50 ± 0.05 vs 0.74 ± 0.04, 12 h: 0.54 ± 0.04 vs 0.77 ± 0.03, 24 h: 0.57 ± 0.03 vs 0.82 ± 0.04, all P < 0.05) and protein were decreased (24 h: 0.32 ± 0.04 vs 0.48 ± 0.07, P < 0.05), and ghrelin mRNA expression was elevated (6 h: 0.54 ± 0.03 vs 0.39 ± 0.04, 12 h: 0.40 ± 0.09 vs 0.30 ± 0.05, 24 h: 0.39 ± 0.04 vs 0.22 ± 0.02, all P < 0.05) in the melatonin intervention group compared with in the ANP group.
CONCLUSION: The expression of ghrelin may be related to the severity of ANP with liver injury. NF-κB may also be involved in the pathogenesis of ANP with liver injury. Exogenous melatonin can reduce ANP possibly by up-regulating ghrelin expression and down-regulating NF-κB expression.
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Downregulation of matrix metalloproteinase-9 by melatonin during prevention of alcohol-induced liver injury in mice. Biochimie 2011; 93:854-66. [PMID: 21354255 DOI: 10.1016/j.biochi.2011.02.007] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2010] [Accepted: 02/14/2011] [Indexed: 01/18/2023]
Abstract
Matrix metalloproteinases (MMPs) have been implicated in inflammatory and degradative processes in several diseases. The study aims to explore the mechanism of MMP-9 regulation in alcohol-induced acute liver injury and its protection by melatonin in mice. Alcohol-induced acute liver injury was induced in female Balb/C mice by ethanol administration and protection studies were carried out with a well-known antioxidant molecule, melatonin. Degree of liver injury was monitored by histological and biochemical analysis of liver tissues. Oral administration of ethanol in mouse caused significant increase in alanine amino transferase (ALT) activity in serum. Depletion of glutathione and enhancement of lipid peroxidation as well as protein oxidation was observed in liver tissues following ethanol treatment. However, melatonin exhibited potent hepatoprotective activity by inhibiting ALT activity and oxidative stress. Additionally, MMP-9 expression was increased by ethanol in a dose and time dependent manner in liver tissue and serum. Increased secretion of proMMP-9 was strongly correlated with the expression of proinflammatory cytokines e.g., tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL6. Melatonin showed hepatoprotective role by downregulation of MMP-9 and upregulation of tissue inhibitor of metalloproteases (TIMP-1) expression in liver tissue. Nuclear factor (NF)-κB, plays an important role in inducing inflammatory genes during oxidative stress, thus the role of NF-κB in ethanol-induced liver injury was investigated. Ethanol induced nuclear translocation of NF-κB and increased degradation of inhibitor of NF-κB (IκBα) in liver tissues. Moreover, ethanol-induced NF-κB translocation into nucleus was inhibited significantly by melatonin. This is the first study to elucidate the induction of MMP-9 expression by NF-κB-dependent pathway in ethanol-induced acute liver injury in mice. This study also identifies the novel role of melatonin in hepatoprotection via MMP-9 down regulation.
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Abstract
Matrix metalloproteinases (MMPs) are part of a superfamily of metal-requiring proteases that play important roles in tissue remodeling by breaking down proteins in the extracellular matrix that provides structural support for cells. The intricate balance in protease/anti-protease stoichiometry is a contributing factor in a number of diseases. Melatonin possesses multifunctional bioactivities including antioxidative, anti-inflammatory, endocrinologic and behavioral effects. As melatonin affects the redox status of tissues, the association of reactive oxygen species (ROS) with tissue injury under different circumstances may be mitigated by melatonin. Redox signaling is expanding into all areas of basic and clinical sciences, and this timely review focuses on the topic of regulation of MMP activities by melatonin. This is a rapidly growing field. Accumulating evidence indicates that oxidative stress plays an important role in regulating the activities of MMPs that are involved in various cellular processes such as cellular proliferation, angiogenesis, apoptosis, invasion and metastasis. This review offers sections on MMPs, melatonin, major physiological and pathophysiological conditions in the context to MMPs, followed by redox signaling mechanisms that are known to influence the cellular processes. Finally, we discuss the emerging molecular mechanisms relevant to regulatory actions of melatonin on the activities of MMPs. The possibility that melatonin might have therapeutic significance via regulation of MMPs may be a novel approach in the treatment of some diseases.
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Affiliation(s)
- Snehasikta Swarnakar
- Department of Physiology, Drug Development Diagnostic and Biotechnology Division, Indian Institute of Chemical Biology, Jadavpur, Kolkata, India.
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Abstract
Melatonin, the hormone of darkness and messenger of the photoperiod, is also well known to exhibit strong direct and indirect antioxidant properties. Melatonin has previously been demonstrated to be a powerful organ protective substance in numerous models of injury; these beneficial effects have been attributed to the hormone’s intense radical scavenging capacity. The present report reviews the hepatoprotective potential of the pineal hormone in various models of oxidative stress in vivo, and summarizes the extensive literature showing that melatonin may be a suitable experimental substance to reduce liver damage after sepsis, hemorrhagic shock, ischemia/reperfusion, and in numerous models of toxic liver injury. Melatonin’s influence on hepatic antioxidant enzymes and other potentially relevant pathways, such as nitric oxide signaling, hepatic cytokine and heat shock protein expression, are evaluated. Based on recent literature demonstrating the functional relevance of melatonin receptor activation for hepatic organ protection, this article finally suggests that melatonin receptors could mediate the hepatoprotective actions of melatonin therapy.
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