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Lotfy M, Khattab A, Shata M, Alhasbani A, Khalaf A, Alsaeedi S, Thaker M, Said H, Tumi H, Alzahmi H, Alblooshi O, Hamdan M, Hussein A, Kundu B, Adeghate EA. Melatonin increases AKT and SOD gene and protein expressions in diabetic rats. Heliyon 2024; 10:e28639. [PMID: 38586324 PMCID: PMC10998142 DOI: 10.1016/j.heliyon.2024.e28639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 03/19/2024] [Accepted: 03/21/2024] [Indexed: 04/09/2024] Open
Abstract
Diabetes mellitus (DM) is a chronic metabolic disease marked by hyperglycemia due to insulin deficiency or insulin resistance leading to many chronic complications. It is thus important to manage diabetes effectively in order to prevent and or delay these complications. Melatonin is produced by the pineal gland and regulates the wake-sleep circadian rhythm. Existing evidence suggests that melatonin may be effective in the management of DM. However, the evidence on the mechanism of the beneficial effect melatonin as a treatment for DM is limited. In this study, we investigated the effect of melatonin treatment on blood glucose, insulin (INS), AKT and superoxide dismutase (SOD) gene levels in diabetic rats. Non-diabetic and diabetic rats were treated orally for 4 weeks with either 25 mg or 50 mg/kg body weight of melatonin. At the end of the study, pancreatic and liver tissues morphology, glucose homeostasis, serum insulin and SOD levels, hepatic gene and protein expression of SOD as protecting antioxidant enzyme and AKT as central element involved in PI3K/AKT insulin signaling pathway were estimated. Melatonin treated diabetic rats showed reduced hyperglycemia, and increased serum insulin and SOD levels. In addition, melatonin induced an increased gene and protein expression of SOD and AKT. In conclusion, melatonin may play a role in treating diabetic rats via stimulation of insulin secretion, insulin signaling and reduction in oxidative stress.
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Affiliation(s)
- Mohamed Lotfy
- Biology Department, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Aalaa Khattab
- Faculty of Dentistry, The British University in Egypt, El Sherouk City, Cairo, Egypt
| | - Mohammed Shata
- Biology Department, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Ahmad Alhasbani
- Biology Department, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Abdallah Khalaf
- Biology Department, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Saeed Alsaeedi
- Biology Department, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Mahdi Thaker
- Biology Department, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Hazza Said
- Biology Department, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Harun Tumi
- Biology Department, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Hassan Alzahmi
- Biology Department, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Omar Alblooshi
- Biology Department, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Mohamad Hamdan
- Biology Department, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Amjad Hussein
- Biology Department, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Biduth Kundu
- Biology Department, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Ernest A. Adeghate
- Department of Anatomy, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
- Zayed Centre for Health Sciences, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
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Waddell H, Stevenson TJ, Mole DJ. The role of the circadian rhythms in critical illness with a focus on acute pancreatitis. Heliyon 2023; 9:e15335. [PMID: 37089281 PMCID: PMC10119767 DOI: 10.1016/j.heliyon.2023.e15335] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 01/20/2023] [Accepted: 04/03/2023] [Indexed: 04/25/2023] Open
Abstract
Circadian rhythms are responsible for governing various physiological processes, including hormone secretion, immune responses, metabolism, and the sleep/wake cycle. In critical illnesses such as acute pancreatitis (AP), circadian rhythms can become dysregulated due to disease. Evidence suggests that time of onset of disease, coupled with peripheral inflammation brought about by AP will impact on the circadian rhythms generated in the central pacemaker and peripheral tissues. Cells of the innate and adaptive immune system are governed by circadian rhythms and the diurnal pattern of expression can be disrupted during disease. Peak circadian immune cell release and gene expression can coincide with AP onset, that may increase pancreatic injury, tissue damage and the potential for systemic inflammation and multiple organ failure to develop. Here, we provide an overview of the role of circadian rhythms in AP and the underpinning inflammatory mechanisms to contextualise ongoing research into the chronobiology and chronotherapeutics of AP.
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Affiliation(s)
- Heather Waddell
- Medical Research Council Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, EH16 4TJ, UK
| | - Tyler J. Stevenson
- Institute of Biodiversity and Animal Health and Comparative Medicine, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, G61 1QH, UK
| | - Damian J. Mole
- Medical Research Council Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, EH16 4TJ, UK
- Clinical Surgery, School of Clinical Sciences and Community Health, The University of Edinburgh, Edinburgh, EH16 4SB, UK
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Cai Y, Cao Q, Li J, Liu T. Targeting and functional effects of biomaterials-based nanoagents for acute pancreatitis treatment. Front Bioeng Biotechnol 2023; 10:1122619. [PMID: 36704304 PMCID: PMC9871307 DOI: 10.3389/fbioe.2022.1122619] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 12/29/2022] [Indexed: 01/12/2023] Open
Abstract
Acute pancreatitis (AP) is a severe life-threatening inflammatory disease showing primary characteristics of excessive inflammatory response and oxidative stress. Based on the pathophysiology of AP, several anti-inflammatory and anti-oxidative stress agents have been studied. However, the low accumulated concentrations and scattered biodistributions limit the application of these agents. With the development of nanotechnology, functional nanomaterials can improve the bioavailability of drugs and extend their half-life by reducing immunogenicity to achieve targeted drug delivery. The biomaterial-based carriers can mediate the passive or active delivery of drugs to the target site for improved therapeutic effects, such as anti-oxidation and anti-inflammation for AP treatment. Other biomaterials-based nanomedicine may exhibit different functions with/without targeting effects. In this review, we have summarized the targeting and functional effects of biomaterials-based nanoagents specifically for AP treatment.
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Affiliation(s)
- Yujie Cai
- Department of Colorectal and Anal Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Qian Cao
- Department of Education, The Second Hospital of Jilin University, Changchun, China
| | - Jiannan Li
- Department of Colorectal and Anal Surgery, The Second Hospital of Jilin University, Changchun, China,*Correspondence: Jiannan Li, ; Tongjun Liu,
| | - Tongjun Liu
- Department of Colorectal and Anal Surgery, The Second Hospital of Jilin University, Changchun, China,*Correspondence: Jiannan Li, ; Tongjun Liu,
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Salivary Redox Homeostasis in Human Health and Disease. Int J Mol Sci 2022; 23:ijms231710076. [PMID: 36077473 PMCID: PMC9455999 DOI: 10.3390/ijms231710076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 08/25/2022] [Accepted: 08/31/2022] [Indexed: 11/16/2022] Open
Abstract
Homeostasis is a self-regulatory dynamic process that maintains a stable internal environment in the human body. These regulations are essential for the optimal functioning of enzymes necessary for human health. Homeostasis elucidates disrupted mechanisms leading to the development of various pathological conditions caused by oxidative stress. In our work, we discuss redox homeostasis and salivary antioxidant activity during healthy periods and in periods of disease: dental carries, oral cavity cancer, periodontal diseases, cardiovascular diseases, diabetes mellitus, systemic sclerosis, and pancreatitis. The composition of saliva reflects dynamic changes in the organism, which makes it an excellent tool for determining clinically valuable biomarkers. The oral cavity and saliva may form the first line of defense against oxidative stress. Analysis of salivary antioxidants may be helpful as a diagnostic, prognostic, and therapeutic marker of not only oral, but also systemic health.
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Apoptosis and (in) Pain—Potential Clinical Implications. Biomedicines 2022; 10:biomedicines10061255. [PMID: 35740277 PMCID: PMC9219669 DOI: 10.3390/biomedicines10061255] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 05/14/2022] [Accepted: 05/15/2022] [Indexed: 02/06/2023] Open
Abstract
The deregulation of apoptosis is involved in the development of several pathologies, and recent evidence suggests that apoptosis may be involved in chronic pain, namely in neuropathic pain. Neuropathic pain is a chronic pain state caused by primary damage or dysfunction of the nervous system; however, the details of the molecular mechanisms have not yet been fully elucidated. Recently, it was found that nerve endings contain transient receptor potential (TRP) channels that sense and detect signals released by injured tissues and respond to these damage signals. TRP channels are similar to the voltage-gated potassium channels or nucleotide-gated channels that participate in calcium and magnesium homeostasis. TRP channels allowing calcium to penetrate into nerve terminals can activate apoptosis, leading to nerve terminal destruction. Further, some TRPs are activated by acid and reactive oxygen species (ROS). ROS are mainly produced in the mitochondrial respiratory chain, and an increase in ROS production and/or a decrease in the antioxidant network may induce oxidative stress (OS). Depending on the OS levels, they can promote cellular proliferation and/or cell degeneration or death. Previous studies have indicated that proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), play an important role in the peripheral mediation of neuropathic pain. This article aims to perform a review of the involvement of apoptosis in pain, particularly the role of OS and neuroinflammation, and the clinical relevance of this knowledge. The potential discovery of new biomarkers and therapeutic targets can result in the development of more effective and targeted drugs to treat chronic pain, namely neuropathic pain. Highlights: Oxidative stress and neuroinflammation can activate cell signaling pathways that can lead to nerve terminal destruction by apoptosis. These could constitute potential new pain biomarkers and targets for therapy in neuropathic pain.
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Chen K, Zhu P, Chen W, Luo K, Shi XJ, Zhai W. Melatonin inhibits proliferation, migration, and invasion by inducing ROS-mediated apoptosis via suppression of the PI3K/Akt/mTOR signaling pathway in gallbladder cancer cells. Aging (Albany NY) 2021; 13:22502-22515. [PMID: 34580235 PMCID: PMC8507264 DOI: 10.18632/aging.203561] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 09/07/2021] [Indexed: 12/30/2022]
Abstract
BACKGROUND Melatonin is an indolic compound mainly secreted by the pineal gland and plays a vital role in the regulation of circadian rhythms and cancer therapy. However, the effects of melatonin in gallbladder cancer (GBC) and the related mechanism remain unknown. METHODS In this study, the antitumor activity of melatonin on gallbladder cancer was explored both in vitro and in vivo. After treatment with different concentrations of melatonin, the cell viability, migration, and invasion of gallbladder cancer cells (NOZ and GBC-SD cells) were evaluated by CCK-8 assay, wound healing, and Transwell assay. RESULTS The results showed that melatonin inhibited growth, migration, and invasion of gallbladder cancer cells. Subsequently, the assays suggested that melatonin significantly induced apoptosis in gallbladder cancer cells and altered the expression of the apoptotic proteins, including Bax, Bcl-2, cytochrome C, cleaved caspase-3, and PARP. Besides, the intracellular reactive oxygen species (ROS) was found to be upregulated after melatonin treatment in gallbladder cancer cells. Melatonin was found to suppress the PI3K/Akt/mTOR signaling pathway in a time-dependent manner by inhibiting the phosphorylation of PI3K, Akt, and mTOR. Treatment with N-acetyl-L-cysteine (NAC) or 740 Y-P remarkably attenuated the antitumor effects of melatonin in NOZ and GBC-SD cells. Finally, melatonin suppressed the growth of GBC-SD cells in an athymic nude mice xenograft model in vivo. CONCLUSIONS Our study revealed that melatonin could induce apoptosis by suppressing the PI3K/Akt/mTOR signaling pathway. Therefore, melatonin might serve as a potential therapeutic drug in the future treatment of gallbladder cancer.
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Affiliation(s)
- Kunlun Chen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province 450052, PR China
| | - Pengfei Zhu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province 450052, PR China
| | - Wenhui Chen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province 450052, PR China
| | - Kai Luo
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province 450052, PR China
| | - Xiao-Jing Shi
- Laboratory Animal Center, State Key Laboratory of Esophageal Cancer Prevention and Treatment, Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan Province 450052, PR China
| | - Wenlong Zhai
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province 450052, PR China
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Melatonin as a powerful antioxidant. ACTA PHARMACEUTICA (ZAGREB, CROATIA) 2021; 71:335-354. [PMID: 36654092 DOI: 10.2478/acph-2021-0027] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 09/18/2020] [Indexed: 01/20/2023]
Abstract
Melatonin is a hormone that has many body functions and, for several decades, its antioxidant potential has been increasingly talked about. There is a relationship between failure in melatonin production in the pineal gland, an insufficient supply of this hormone to the body, and the occurrence of free radical etiology diseases such as neurodegenerative diseases, cardiovascular diseases, diabetes, cancer and others. Despite the development of molecular biology, numerous in vitro and in vivo studies, the exact mechanism of melatonin antioxidant activity is still unknown. Nowadays, the use of melatonin supplementation is more and more common, not only to prevent insomnia, but also to slow down the aging process and provide protection against diseases. The aim of this study is to get acquainted with current reports on melatonin, antioxidative mechanisms and their importance in diseases of free radical etiology.
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Estaras M, Gonzalez-Portillo MR, Martinez R, Garcia A, Estevez M, Fernandez-Bermejo M, Mateos JM, Vara D, Blanco-Fernández G, Lopez-Guerra D, Roncero V, Salido GM, Gonzalez A. Melatonin Modulates the Antioxidant Defenses and the Expression of Proinflammatory Mediators in Pancreatic Stellate Cells Subjected to Hypoxia. Antioxidants (Basel) 2021; 10:577. [PMID: 33918063 PMCID: PMC8070371 DOI: 10.3390/antiox10040577] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 04/01/2021] [Accepted: 04/05/2021] [Indexed: 12/11/2022] Open
Abstract
Pancreatic stellate cells (PSC) play a major role in the formation of fibrotic tissue in pancreatic tumors. On its side, melatonin is a putative therapeutic agent for pancreatic cancer and inflammation. In this work, the actions of melatonin on PSC subjected to hypoxia were evaluated. Reactive oxygen species (ROS) generation reduced (GSH) and oxidized (GSSG) levels of glutathione, and protein and lipid oxidation were analyzed. The phosphorylation of nuclear factor erythroid 2-related factor (Nrf2), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), and the regulatory protein nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor-alpha (IκBα) was studied. The expression of Nrf2-regulated antioxidant enzymes, superoxide dismutase (SOD) enzymes, cyclooxygenase 2 (COX-2), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were also studied. Total antioxidant capacity (TAC) was assayed. Finally, cell viability was studied. Under hypoxia and in the presence of melatonin generation of ROS was observed. No increases in the oxidation of proteins or lipids were detected. The phosphorylation of Nrf2 and the expression of the antioxidant enzymes catalytic subunit of glutamate-cysteine ligase, catalase, NAD(P)H-quinone oxidoreductase 1, heme oxygenase-1, SOD1, and of SOD2 were augmented. The TAC was increased. Protein kinase C was involved in the effects of melatonin. Melatonin decreased the GSH/GSSG ratio at the highest concentration tested. Cell viability dropped in the presence of melatonin. Finally, melatonin diminished the phosphorylation of NF-kB and the expression of COX-2, IL-6, and TNF-α. Our results indicate that melatonin, at pharmacological concentrations, modulates the red-ox state, viability, and the expression of proinflammatory mediators in PSC subjected to hypoxia.
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Affiliation(s)
- Matias Estaras
- Institute of Molecular Pathology Biomarkers, University of Extremadura, 10003 Caceres, Spain; (M.E.); (M.R.G.-P.); (G.M.S.)
| | - Manuel R. Gonzalez-Portillo
- Institute of Molecular Pathology Biomarkers, University of Extremadura, 10003 Caceres, Spain; (M.E.); (M.R.G.-P.); (G.M.S.)
| | - Remigio Martinez
- Department of Animal Health, Veterinary Faculty, University of Extremadura, 10003 Caceres, Spain;
| | - Alfredo Garcia
- Department of Animal Production, CICYTEX-La Orden, 06187 Badajoz, Spain;
| | - Mario Estevez
- IPROCAR Research Institute, Food Technology, University of Extremadura, 10003 Cáceres, Spain;
| | - Miguel Fernandez-Bermejo
- Department of Gastroenterology, San Pedro de Alcantara Hospital, 10003 Caceres, Spain; (M.F.-B.); (J.M.M.); (D.V.)
| | - Jose M. Mateos
- Department of Gastroenterology, San Pedro de Alcantara Hospital, 10003 Caceres, Spain; (M.F.-B.); (J.M.M.); (D.V.)
| | - Daniel Vara
- Department of Gastroenterology, San Pedro de Alcantara Hospital, 10003 Caceres, Spain; (M.F.-B.); (J.M.M.); (D.V.)
| | - Gerardo Blanco-Fernández
- Hepatobiliary-Pancreatic Surgery and Liver Transplant Unit, Infanta Cristina Hospital, 06080 Badajoz, Spain; (G.B.-F.); (D.L.-G.)
| | - Diego Lopez-Guerra
- Hepatobiliary-Pancreatic Surgery and Liver Transplant Unit, Infanta Cristina Hospital, 06080 Badajoz, Spain; (G.B.-F.); (D.L.-G.)
| | - Vicente Roncero
- Unit of Histology and Pathological Anatomy, Veterinary Faculty, University of Extremadura, 10003 Caceres, Spain;
| | - Gines M. Salido
- Institute of Molecular Pathology Biomarkers, University of Extremadura, 10003 Caceres, Spain; (M.E.); (M.R.G.-P.); (G.M.S.)
| | - Antonio Gonzalez
- Institute of Molecular Pathology Biomarkers, University of Extremadura, 10003 Caceres, Spain; (M.E.); (M.R.G.-P.); (G.M.S.)
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Abdulwahab DA, El-Missiry MA, Shabana S, Othman AI, Amer ME. Melatonin protects the heart and pancreas by improving glucose homeostasis, oxidative stress, inflammation and apoptosis in T2DM-induced rats. Heliyon 2021; 7:e06474. [PMID: 33748504 PMCID: PMC7970364 DOI: 10.1016/j.heliyon.2021.e06474] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 12/11/2020] [Accepted: 03/05/2021] [Indexed: 02/08/2023] Open
Abstract
Cardiomyopathy and pancreatic injury are health issues associated with type 2 diabetes mellitus (T2DM) and are characterized by elevated oxidative stress, inflammation and apoptosis. Melatonin (MLT) is a hormone with multifunctional antioxidant activity. The protective effects of MLT on the heart and pancreas during the early development of diabetic cardiomyopathy and pancreatic injury were investigated in male Wistar rats with T2DM. MLT (10 mg/kg) was administered daily by gavage for 15 days after diabetic induction. Treatment of diabetic rats with MLT significantly normalized the levels of serum glucose, HbA1-c, and the lipid profile and improved the insulin levels and insulin resistance compared with diabetic rats, affirming its antidiabetic effect. MLT significantly prevented the development of oxidative stress and sustained the levels of glutathione and glutathione peroxidase activity in the heart and pancreas of diabetic animals, indicating its antioxidant capacity. Additionally, MLT prevented the increase in proinflammatory cytokines and expression of Bax, caspase-3 and P53. Furthermore, MLT enhanced the anti-inflammatory cytokine IL-10 and antiapoptotic protein Bcl-2. MLT controlled the levels of troponin T and creatine kinase-MB and lactate dehydrogenase activity, indicating its anti-inflammatory and antiapoptotic effects. Histological examinations confirmed the protective effects of MLT on T2DM-induced injury in the myocardium, pancreas and islets of Langerhans. In conclusion, the protective effects of melatonin on the heart and pancreas during the early development of T2DM are attributed to its antihyperglycemic, antilipidemic and antioxidant influences as well as its remarkable anti-inflammatory and antiapoptotic properties.
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Affiliation(s)
| | | | - Sameh Shabana
- Faculty of Science, Mansoura University, Mansoura, Egypt
| | - Azza I. Othman
- Faculty of Science, Mansoura University, Mansoura, Egypt
| | - Maggie E. Amer
- Faculty of Science, Mansoura University, Mansoura, Egypt
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Estaras M, Ameur FZ, Roncero V, Fernandez-Bermejo M, Blanco G, Lopez D, Mateos JM, Salido GM, Gonzalez A. The melatonin receptor antagonist luzindole induces Ca 2+ mobilization, reactive oxygen species generation and impairs trypsin secretion in mouse pancreatic acinar cells. Biochim Biophys Acta Gen Subj 2019; 1863:129407. [PMID: 31381958 DOI: 10.1016/j.bbagen.2019.07.016] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 07/23/2019] [Accepted: 07/31/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND In this work we studied the effects of the melatonin receptor-antagonist luzindole (1 μM-50 μM) on isolated mouse pancreatic acinar cells. METHODS Changes in intracellular free-Ca2+ concentration, reactive oxygen species production and trypsin secretion were analyzed. RESULTS Luzindole induced increases in [Ca2+]i that diminished CCK-8 induced Ca2+ mobilization, compared with that observed when CCK-8 was applied alone. Treatment of cells with thapsigargin (1 μM), in the absence of Ca2+ in the extracellular medium, evoked a transient increase in [Ca2+]i. The additional incubation of cells with luzindole (10 μM) failed to induce further mobilization of Ca2+. In the presence of luzindole a concentration-dependent increase in ROS generation was observed that decreased in the absence of Ca2+ or by pretreatment of cells with melatonin (100 μM). Incubation of pancreatic acinar cells with luzindole (10 μM) impaired CCK-8-induced trypsin secretion. Melatonin was unable to revert the effect of luzindole on CCK-8-induced trypsin secretion. CONCLUSION The melatonin receptor-inhibitor luzindole induces Ca2+-mediated pro-oxidative conditions and impairment of enzyme secretion, which creates a situation in pancreatic acinar cells that might compromise their function. GENERAL SIGNIFICANCE The effects of luzindole that we have observed, might be unspecific and could mislead the observations when it is used to study the actions of melatonin on the gland. Another possibility is that melatonin receptors exhibit a basal or agonist-independent activity in pancreatic acinar cells, which might be modulated by melatonin or luzindole.
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Affiliation(s)
- Matias Estaras
- Institute of Molecular Pathology Biomarkers, University of Extremadura, Caceres, Spain
| | - Fatma Z Ameur
- Laboratoire de Physiologie de la Nutrition et de Sécurité Alimentaire, Université d'Oran1, Ahmed BenBella, Algeria
| | - Vicente Roncero
- Unit of Histology and Pathological Anatomy, Veterinary Faculty, University of Extremadura, Caceres, Spain
| | | | - Gerardo Blanco
- Hepatobiliary-Pancreatic Surgery and Liver Transplant Unit, Infanta Cristina Hospital, Badajoz, Spain
| | - Diego Lopez
- Hepatobiliary-Pancreatic Surgery and Liver Transplant Unit, Infanta Cristina Hospital, Badajoz, Spain
| | - Jose M Mateos
- Department of Gastroenterology, San Pedro de Alcantara Hospital, Caceres, Spain
| | - Gines M Salido
- Institute of Molecular Pathology Biomarkers, University of Extremadura, Caceres, Spain
| | - Antonio Gonzalez
- Institute of Molecular Pathology Biomarkers, University of Extremadura, Caceres, Spain.
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11
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Lv C, Jin Q. Maresin-1 Inhibits Oxidative Stress and Inflammation and Promotes Apoptosis in a Mouse Model of Caerulein-Induced Acute Pancreatitis. Med Sci Monit 2019; 25:8181-8189. [PMID: 31671079 PMCID: PMC6844145 DOI: 10.12659/msm.917380] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Background This study aimed to investigate the effects of maresin-1 (MaR1) in a mouse model of caerulein-induced acute pancreatitis (AP). Material/Methods Fifty C57BL/6 mice with caerulein-induced AP were divided into the untreated control group (N=10), the untreated AP model group (N=10), the MaR1-treated (low-dose, 0.1 μg) AP model group (N=10), the MaR1-treated (middle-dose, 0.5 μg) AP model group (N=10), and the MaR1-treated (high-dose, 1 μg) AP model group (N=10). Enzyme-linked immunoassay (ELISA) measured serum levels of amylase, lipase, tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and IL-6 and mRNA was measured by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Malondialdehyde (MDA), protein carbonyls, superoxide dismutase (SOD), and the ratio of reduced glutathione/oxidized glutathione (GSH/GSSG) were measured. Histology of the pancreas included measurement of acinar cell apoptosis using the terminal-deoxynucleotidyl transferase-mediated nick end-labeling (TUNEL) assay. Western blot measured Toll-like receptor 4 (TLR4), MyD88, and phospho-NF-κB p65, and apoptosis-associated proteins Bcl-2, Bax, cleaved caspase-3, and cleaved caspase-9. Results Following treatment with MaR1, serum levels of amylase, lipase, TNF-α, IL-1β, and IL-6 decreased, MDA and protein carbonyl levels decreased, SOD and the GSH/GSSG ratio increased in a dose-dependent manner. In the MaR1-treated AP mice, inflammation of the pancreas and the expression of inflammatory cytokines, pancreatic acinar cell apoptosis, Bcl-2 expression, and expression of TLR4, MyD88, and p-NF-κB p65 were reduced, but Bax, cleaved caspase-3, and cleaved caspase-9 expression increased. Conclusions In a mouse model of caerulein-induced AP, treatment with MaR1 reduced oxidative stress and inflammation and reduced apoptosis.
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Affiliation(s)
- Chengjie Lv
- Department of Neonatal Surgery, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China (mainland)
| | - Qi Jin
- Department of Pharmacy, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China (mainland)
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12
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Antioxidant Defense, Oxidative Modification, and Salivary Gland Function in an Early Phase of Cerulein Pancreatitis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:8403578. [PMID: 30984340 PMCID: PMC6431492 DOI: 10.1155/2019/8403578] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/11/2018] [Revised: 12/10/2018] [Accepted: 12/20/2018] [Indexed: 12/22/2022]
Abstract
Acute pancreatitis (AP) is a multifactorial disease characterized by necroinflammatory changes of the pancreas. Our study is the first study which evaluated the relationship between the free radical production, enzymatic and nonenzymatic antioxidants, oxidative damage, and secretory function of the salivary glands of AP rats. Male Wistar rats were divided equally into 2 groups: control (n = 9) and AP (n = 9). AP was induced by intraperitoneal injection with cerulein and confirmed by higher serum amylase and lipase. We have demonstrated that the superoxide dismutase and glutathione reductase activities, as well as reduced glutathione concentration, were significantly decreased in both the parotid and submandibular glands of AP rats as compared to the control rats. The production of free radicals evidenced as dichlorodihydrofluorescein assay and the activity of NADPH oxidase and xanthine oxidase and IL-1β concentration were significantly higher in the parotid and submandibular glands of AP rats compared to the controls. In AP rats, we also showed a statistical increase in oxidation modification products (advanced glycation end products and advanced oxidation protein products), salivary amylase activity, and significant decrease in the total protein content. However, we did not show apoptosis and any morphological changes in the histological examination of the salivary glands of AP rats. To sum up, cerulein-induced AP intensifies production of oxygen free radicals, impairs the redox balance of the salivary glands, and is responsible for higher oxidative damage to these glands. Interestingly, oxidative modification of proteins and dysfunction of the antioxidant barrier are more pronounced in the submandibular glands of AP rats.
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Chen M, Zheng J, Liu G, Xu E, Wang J, Fuqua BK, Vulpe CD, Anderson GJ, Chen H. Ceruloplasmin and hephaestin jointly protect the exocrine pancreas against oxidative damage by facilitating iron efflux. Redox Biol 2018; 17:432-439. [PMID: 29883959 PMCID: PMC6007082 DOI: 10.1016/j.redox.2018.05.013] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2018] [Revised: 05/23/2018] [Accepted: 05/28/2018] [Indexed: 02/07/2023] Open
Abstract
Little is known about the iron efflux from the pancreas, but it is likely that multicopper ferroxidases (MCFs) are involved in this process. We thus used hephaestin (Heph) and ceruloplasmin (Cp) single-knockout mice and Heph/Cp double-knockout mice to investigate the roles of MCFs in pancreatic iron homeostasis. We found that both HEPH and CP were expressed in the mouse pancreas, and that ablation of either MCF had limited effect on the pancreatic iron levels. However, ablation of both MCFs together led to extensive pancreatic iron deposition and severe oxidative damage. Perls’ Prussian blue staining revealed that this iron deposition was predominantly in the exocrine pancreas, while the islets were spared. Consistent with these results, plasma lipase and trypsin were elevated in Heph/Cp knockout mice, indicating damage to the exocrine pancreas, while insulin secretion was not affected. These data indicate that HEPH and CP play mutually compensatory roles in facilitating iron efflux from the exocrine pancreas, and show that MCFs are able to protect the pancreas against iron-induced oxidative damage.
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Affiliation(s)
- Min Chen
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, China
| | - Jiashuo Zheng
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, China
| | - Guohao Liu
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, China
| | - En Xu
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, China
| | - Junzhuo Wang
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, China
| | - Brie K Fuqua
- Center for Environmental and Human Toxicology, Department of Physiological Sciences, University of Florida, Gainesville, FL, USA
| | - Chris D Vulpe
- Center for Environmental and Human Toxicology, Department of Physiological Sciences, University of Florida, Gainesville, FL, USA
| | - Gregory J Anderson
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Huijun Chen
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, China.
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Carrasco C, Naziroǧlu M, Rodríguez AB, Pariente JA. Neuropathic Pain: Delving into the Oxidative Origin and the Possible Implication of Transient Receptor Potential Channels. Front Physiol 2018; 9:95. [PMID: 29491840 PMCID: PMC5817076 DOI: 10.3389/fphys.2018.00095] [Citation(s) in RCA: 127] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2017] [Accepted: 01/29/2018] [Indexed: 12/25/2022] Open
Abstract
Currently, neuropathic pain is an underestimated socioeconomic health problem affecting millions of people worldwide, which incidence may increase in the next years due to chronification of several diseases, such as cancer and diabetes. Growing evidence links neuropathic pain present in several disorders [i.e., spinal cord injury (SCI), cancer, diabetes and alcoholism] to central sensitization, as a global result of mitochondrial dysfunction induced by oxidative and nitrosative stress. Additionally, inflammatory signals and the overload in intracellular calcium ion could be also implicated in this complex network that has not yet been elucidated. Recently, calcium channels namely transient receptor potential (TRP) superfamily, including members of the subfamilies A (TRAP1), M (TRPM2 and 7), and V (TRPV1 and 4), have demonstrated to play a role in the nociception mediated by sensory neurons. Therefore, as neuropathic pain could be a consequence of the imbalance between reactive oxygen species and endogen antioxidants, antioxidant supplementation may be a treatment option. This kind of therapy would exert its beneficial action through antioxidant and immunoregulatory functions, optimizing mitochondrial function and even increasing the biogenesis of this vital organelle; on balance, antioxidant supplementation would improve the patient's quality of life. This review seeks to deepen on current knowledge about neuropathic pain, summarizing clinical conditions and probable causes, the relationship existing between oxidative stress, mitochondrial dysfunction and TRP channels activation, and scientific evidence related to antioxidant supplementation.
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Affiliation(s)
- Cristina Carrasco
- Department of Physiology, Faculty of Sciences, University of Extremadura, Badajoz, Spain
| | - Mustafa Naziroǧlu
- Neuroscience Research Center, Suleyman Demirel University, Isparta, Turkey
| | - Ana B Rodríguez
- Department of Physiology, Faculty of Sciences, University of Extremadura, Badajoz, Spain
| | - José A Pariente
- Department of Physiology, Faculty of Sciences, University of Extremadura, Badajoz, Spain
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15
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Manchester LC, Coto-Montes A, Boga JA, Andersen LPH, Zhou Z, Galano A, Vriend J, Tan DX, Reiter RJ. Melatonin: an ancient molecule that makes oxygen metabolically tolerable. J Pineal Res 2015; 59:403-19. [PMID: 26272235 DOI: 10.1111/jpi.12267] [Citation(s) in RCA: 667] [Impact Index Per Article: 66.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Accepted: 08/10/2015] [Indexed: 12/11/2022]
Abstract
Melatonin is remarkably functionally diverse with actions as a free radical scavenger and antioxidant, circadian rhythm regulator, anti-inflammatory and immunoregulating molecule, and as an oncostatic agent. We hypothesize that the initial and primary function of melatonin in photosynthetic cyanobacteria, which appeared on Earth 3.5-3.2 billion years ago, was as an antioxidant. The evolution of melatonin as an antioxidant by this organism was necessary as photosynthesis is associated with the generation of toxic-free radicals. The other secondary functions of melatonin came about much later in evolution. We also surmise that mitochondria and chloroplasts may be primary sites of melatonin synthesis in all eukaryotic cells that possess these organelles. This prediction is made on the basis that mitochondria and chloroplasts of eukaryotes developed from purple nonsulfur bacteria (which also produce melatonin) and cyanobacteria when they were engulfed by early eukaryotes. Thus, we speculate that the melatonin-synthesizing actions of the engulfed bacteria were retained when these organelles became mitochondria and chloroplasts, respectively. That mitochondria are likely sites of melatonin formation is supported by the observation that this organelle contains high levels of melatonin that are not impacted by blood melatonin concentrations. Melatonin has a remarkable array of means by which it thwarts oxidative damage. It, as well as its metabolites, is differentially effective in scavenging a variety of reactive oxygen and reactive nitrogen species. Moreover, melatonin and its metabolites modulate a large number of antioxidative and pro-oxidative enzymes, leading to a reduction in oxidative damage. The actions of melatonin on radical metabolizing/producing enzymes may be mediated by the Keap1-Nrf2-ARE pathway. Beyond its direct free radical scavenging and indirect antioxidant effects, melatonin has a variety of physiological and metabolic advantages that may enhance its ability to limit oxidative stress.
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Affiliation(s)
- Lucien C Manchester
- Department of Cellular and Structural Biology, UT Health Science Center, San Antonio, TX, USA
| | - Ana Coto-Montes
- Department of Cellular and Structural Biology, UT Health Science Center, San Antonio, TX, USA
| | - Jose Antonio Boga
- Department of Cellular and Structural Biology, UT Health Science Center, San Antonio, TX, USA
| | - Lars Peter H Andersen
- Department of Cellular and Structural Biology, UT Health Science Center, San Antonio, TX, USA
| | - Zhou Zhou
- Department of Cellular and Structural Biology, UT Health Science Center, San Antonio, TX, USA
| | - Annia Galano
- Departamento de Quimica, Universidad Autonoma Metropolitana-Iztapalapa, Mexico DF, Mexico
| | - Jerry Vriend
- Department of Human Anatomy and Cell Biology, University of Manitoba, Winnipeg, MA, Canada
| | - Dun-Xian Tan
- Department of Cellular and Structural Biology, UT Health Science Center, San Antonio, TX, USA
| | - Russel J Reiter
- Department of Cellular and Structural Biology, UT Health Science Center, San Antonio, TX, USA
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16
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Santofimia-Castaño P, Clea Ruy D, Garcia-Sanchez L, Jimenez-Blasco D, Fernandez-Bermejo M, Bolaños JP, Salido GM, Gonzalez A. Melatonin induces the expression of Nrf2-regulated antioxidant enzymes via PKC and Ca2+ influx activation in mouse pancreatic acinar cells. Free Radic Biol Med 2015; 87:226-236. [PMID: 26163001 DOI: 10.1016/j.freeradbiomed.2015.06.033] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2015] [Revised: 05/24/2015] [Accepted: 06/23/2015] [Indexed: 12/12/2022]
Abstract
The goal of this study was to evaluate the potential activation of the nuclear factor erythroid 2-related factor and the antioxidant-responsive element (Nrf2-ARE) signaling pathway in response to melatonin in isolated mouse pancreatic acinar cells. Changes in intracellular free Ca(2+) concentration were followed by fluorimetric analysis of fura-2-loaded cells. The activations of PKC and JNK were measured by Western blot analysis. Quantitative reverse transcription-polymerase chain reaction was employed to detect the expression of Nrf2-regulated antioxidant enzymes. Immunocytochemistry was employed to determine nuclear location of phosphorylated Nrf2, and the cellular redox state was monitored following MitoSOX Red-derived fluorescence. Our results show that stimulation of fura-2-loaded cells with melatonin (1 µM to 1 mM), in the presence of Ca(2+) in the extracellular medium, induced a slow and progressive increase of [Ca(2+)](c) toward a stable level. Melatonin did not inhibit the typical Ca(2+) response induced by CCK-8 (1 nM). When the cells were challenged with indoleamine in the absence of Ca(2+) in the extracellular solution (medium containing 0.5 mM EGTA) or in the presence of 1 mM LaCl(3), to inhibit Ca(2+) entry, we could not detect any change in [Ca(2+)](c). Nevertheless, CCK-8 (1 nM) was able to induce the typical mobilization of Ca(2+). When the cells were incubated with the PKC activator PMA (1 µM) in the presence of Ca(2+) in the extracellular medium, we observed a response similar to that noted when the cells were challenged with melatonin 100 µM. However, in the presence of Ro31-8220 (3 µM), a PKC inhibitor, stimulation of cells with melatonin failed to evoke changes in [Ca(2+)]c. Immunoblots, using an antibody specific for phospho-PKC, revealed that melatonin induces PKCα activation, either in the presence or in the absence of external Ca(2+). Melatonin induced the phosphorylation and nuclear translocation of the transcription factor Nrf2, and evoked a concentration-dependent increase in the expression of the antioxidant enzymes NAD(P)H-quinone oxidoreductase 1, catalytic subunit of glutamate-cysteine ligase, and heme oxygenase-1. Incubation of MitoSOX Red-loaded pancreatic acinar cells in the presence of 1 nM CCK-8 induced a statistically significant increase in dye-derived fluorescence, reflecting an increase in oxidation, that was abolished by pretreatment of cells with melatonin (100 µM) or PMA (1 µM). On the contrary, pretreatment with Ro31-8220 (3 µM) blocked the effect of melatonin on CCK-8-induced increase in oxidation. Finally, phosphorylation of JNK in the presence of CCK-8 or melatonin was also observed. We conclude that melatonin, via modulation of PKC and Ca(2+) signaling, could potentially stimulate the Nrf2-mediated antioxidant response in mouse pancreatic acinar cells.
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Affiliation(s)
| | - Deborah Clea Ruy
- Facultade de Agronomia & Medicina Veterinaria, Universidade de Brasilia, 70900-100, Brasilia DF, Brazil
| | - Lourdes Garcia-Sanchez
- Cell Physiology Research Group (FICEL), Department of Physiology, University of Extremadura, Caceres, Spain
| | - Daniel Jimenez-Blasco
- Institute of Functional Biology and Genomics (IBFG), University of Salamanca-CSIC, Salamanca, Spain
| | - Miguel Fernandez-Bermejo
- Cell Physiology Research Group (FICEL), Department of Physiology, University of Extremadura, Caceres, Spain; Department of Gastroenterology, San Pedro de Alcantara Hospital, E-10003 Caceres, Spain
| | - Juan P Bolaños
- Institute of Functional Biology and Genomics (IBFG), University of Salamanca-CSIC, Salamanca, Spain
| | - Gines M Salido
- Cell Physiology Research Group (FICEL), Department of Physiology, University of Extremadura, Caceres, Spain
| | - Antonio Gonzalez
- Cell Physiology Research Group (FICEL), Department of Physiology, University of Extremadura, Caceres, Spain.
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17
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Bian ZX, Tsang SW. Therapeutic implications of antioxidant defense in acute pancreatitis. Hepatobiliary Pancreat Dis Int 2014; 13:346-7. [PMID: 25100117 DOI: 10.1016/s1499-3872(14)60266-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Affiliation(s)
- Zhao-Xiang Bian
- Clinical Division, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China.
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