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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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Li W, Tan M, Wang H, Wang Z, Pang Y, Yang R, Zhong S, Pan X, Chen S, Wang Q, Li D, Xiao Y, Chen W, Chen L. METTL3-mediated m6A mRNA modification was involved in cadmium-induced liver injury. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2023; 331:121887. [PMID: 37236586 DOI: 10.1016/j.envpol.2023.121887] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 05/12/2023] [Accepted: 05/23/2023] [Indexed: 05/28/2023]
Abstract
Cadmium is an environmental pollutant that has extensive deleterious effects. However, the mechanisms underlying the hepatotoxicity induced by long-term exposure to cadmium remained undefined. In the present study, we explored the role of m6A methylation in the development of cadmium-induced liver disease. We showed a dynamic change of RNA methylation in liver tissue from mice administrated with cadmium chloride (CdCl2) for 3, 6 and 9 months, respectively. Particularly, the METTL3 expression was declined in a time-dependent manner, associated with the degree of liver injury, indicating the involvement of METTL3 in hepatotoxicity induced by CdCl2. Moreover, we established a mouse model with liver-specific over-expression of Mettl3 and administrated these mice with CdCl2 for 6 months. Notably, METTL3 highly expressed in hepatocytes attenuated CdCl2-induced steatosis and liver fibrosis in mice. In vitro assay also showed METTL3 overexpression ameliorated the CdCl2-induced cytotoxicity and activation of primary hepatic stellate cells. Furthermore, transcriptome analysis identified 268 differentially expressed genes both in mice liver tissue treated with CdCl2 for 3 months and 9 months. Among them, 115 genes were predicted to be regulated by METTL3 determined by m6A2Target database. Further analysis revealed the perturbation of metabolic pathway, glycerophospholipid metabolism, ErbB signaling pathway, Hippo signaling pathway, and choline metabolism in cancer, and circadian rhythm, led to hepatotoxicity induced by CdCl2. Collectively, our findings reveal new insight into the crucial role of epigenetic modifications in hepatic diseases caused by long-term exposure to cadmium.
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Affiliation(s)
- Wenxue Li
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China; Department of Toxicology, Guangzhou Center for Disease Control and Prevention, Guangzhou, 510440, China
| | - Mingxue Tan
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China
| | - Huiqi Wang
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China
| | - Ziwei Wang
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China
| | - Yaqin Pang
- Faculty of Toxicology, School of Public Health, Youjiang Medical College for Nationalities, Guangxi, 533000, China
| | - Rongfang Yang
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China
| | - Shiyuan Zhong
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China
| | - Xinhong Pan
- Department of Toxicology, Guangzhou Center for Disease Control and Prevention, Guangzhou, 510440, China
| | - Shen Chen
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China
| | - Qing Wang
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China
| | - Daochuan Li
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China
| | - Yongmei Xiao
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China
| | - Wen Chen
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China
| | - Liping Chen
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China.
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Deng G, Jiang Z, Lu H, Lu N, Zhu R, Zhu C, Zhou P, Tang X. A Study on the Amelioration of Circadian Rhythm Disorders in Fat Mice Using High-Protein Diets. Nutrients 2023; 15:3459. [PMID: 37571396 PMCID: PMC10421159 DOI: 10.3390/nu15153459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 08/02/2023] [Accepted: 08/03/2023] [Indexed: 08/13/2023] Open
Abstract
This innovative study investigates the effects of high-protein diets (milk protein) on the circadian rhythm of hepatic lipid metabolism. We aimed to understand how high-protein interventions regulate biological clock genes, maintain lipid metabolism balance, and affect the circadian rhythm of antioxidant levels in vivo. We divided 120 SPF-class C57BL/6J mice into the control, high-fat/low-protein (HF-LP), and high-fat/high-protein (HF-HP) groups. Mice were sacrificed during active (2 a.m. and 8 a.m.) and rest periods (2 p.m. and 8 p.m.). In the HF-LP group, hepatic lipid anabolic enzymes were consistently expressed at high levels, while key lipolytic enzymes slowly increased after feeding with no significant diurnal differences. This led to an abnormal elevation in blood lipid levels, a slow increase in and low levels of superoxide dismutase, and a rapid increase in malondialdehyde levels, deviating from the diurnal trend observed in the control group. However, high-protein interventions in the HF-HP group restored lipid synthase activity and the expression of key catabolic enzymes, exhibiting a precise circadian rhythm. It also improved the lipid-metabolism rhythm, which was disrupted by the high-fat diet. Overall, high-protein interventions restored the expression of key enzymes involved in lipid metabolism, improving the lipid-metabolism rhythm, which was disrupted by the high-fat diet.
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Affiliation(s)
- Guoliang Deng
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (G.D.); (Z.J.); (H.L.); (N.L.); (R.Z.); (C.Z.); (P.Z.)
| | - Zhiqing Jiang
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (G.D.); (Z.J.); (H.L.); (N.L.); (R.Z.); (C.Z.); (P.Z.)
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi 214122, China
| | - Hui Lu
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (G.D.); (Z.J.); (H.L.); (N.L.); (R.Z.); (C.Z.); (P.Z.)
| | - Naiyan Lu
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (G.D.); (Z.J.); (H.L.); (N.L.); (R.Z.); (C.Z.); (P.Z.)
- Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, Jiangnan University, Wuxi 214122, China
| | - Rongxiang Zhu
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (G.D.); (Z.J.); (H.L.); (N.L.); (R.Z.); (C.Z.); (P.Z.)
| | - Chengkai Zhu
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (G.D.); (Z.J.); (H.L.); (N.L.); (R.Z.); (C.Z.); (P.Z.)
| | - Peng Zhou
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (G.D.); (Z.J.); (H.L.); (N.L.); (R.Z.); (C.Z.); (P.Z.)
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China
| | - Xue Tang
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (G.D.); (Z.J.); (H.L.); (N.L.); (R.Z.); (C.Z.); (P.Z.)
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China
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Chen YT, Huang PY, Chai CY, Yu S, Hsieh YL, Chang HC, Kuo CW, Lee YC, Yu HS. Early detection of the initial stages of LED light-triggered non-alcoholic fatty liver disease by wax physisorption kinetics-Fourier transform infrared imaging. Analyst 2023; 148:643-653. [PMID: 36621928 DOI: 10.1039/d2an01546c] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Light-emitting diodes (LEDs), particularly in the blue waveform range, are regarded as a major source of circadian rhythm dysregulation. A circadian rhythm dysregulation induced by blue LEDs is associated with non-alcoholic fatty liver disease (NAFLD). Hepatocellular accumulation of lipids is a key event in the early stages of NAFLD. Kupffer cells (KCs) have been reported to be lost in the early onset of NAFLD followed by an inflammatory reaction that alters the liver response to lipid overload. This study focused on the detection of the initial stages (subpathological stages) of LED light-triggered NAFLD. Mice were exposed to either blue or white LED irradiation for 44 weeks. Synchrotron radiation-based Fourier-transform infrared microspectroscopy (SR-FTIRM) and wax physisorption kinetic-Fourier transform infrared (WPK-FTIR) imaging were used to evaluate the ratio of lipid to protein and the glycosylation of glycoprotein, respectively. Immunohistopathological studies on KCs and circadian-related proteins were performed. Although liver biopsy showed normal pathology, an SR-FTIRM study revealed a high hepatic lipid-to-protein ratio after receiving LED illumination. The results of WPK-FTIR demonstrated that a high inflammation index was found in the high irradiance of the blue LED illumnation group. These groups showed a decrease in KC number and an increase in Bmal1 and Reverbα circadian protein expression. These findings provide explanations for the reduction of KCs without subsequent inflammation. A significant reduction of Per2 and Cry1 expression is correlated with the findings of WPK-FTIR imaging. WPK-FTIR is a sensitive method for detecting initiative stages of NAFLD induced by long-term blue LED illumination.
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Affiliation(s)
- Yi-Ting Chen
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.,Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.,Department of Pathology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Pei-Yu Huang
- Life Science Group, National Synchrotron Radiation Research Center, Hsinchu 30076, Taiwan
| | - Chee-Yin Chai
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.,Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.,Department of Pathology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.,Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan
| | - Sebastian Yu
- Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. .,Department of Dermatology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Yu-Lin Hsieh
- Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.,School of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.,Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
| | - Hao-Chao Chang
- Taiwan Instrument Research Institute, National Applied Research Laboratories, Hsinchu 30205, Taiwan
| | - Chin-Wei Kuo
- Life Science Group, National Synchrotron Radiation Research Center, Hsinchu 30076, Taiwan
| | - Yao-Chang Lee
- Life Science Group, National Synchrotron Radiation Research Center, Hsinchu 30076, Taiwan.,Department of Optics and Photonics, National Central University, Taoyuan 320317, Taiwan.,Chemistry Department, National Tsing Hua University, Hsinchu 30013, Taiwan
| | - Hsin-Su Yu
- Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. .,National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli County 35053, Taiwan.,Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
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AMPK inhibits liver gluconeogenesis: fact or fiction? Biochem J 2023; 480:105-125. [PMID: 36637190 DOI: 10.1042/bcj20220582] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/21/2022] [Accepted: 01/04/2023] [Indexed: 01/14/2023]
Abstract
Is there a role for AMPK in the control of hepatic gluconeogenesis and could targeting AMPK in liver be a viable strategy for treating type 2 diabetes? These are frequently asked questions this review tries to answer. After describing properties of AMPK and different small-molecule AMPK activators, we briefly review the various mechanisms for controlling hepatic glucose production, mainly via gluconeogenesis. The different experimental and genetic models that have been used to draw conclusions about the role of AMPK in the control of liver gluconeogenesis are critically discussed. The effects of several anti-diabetic drugs, particularly metformin, on hepatic gluconeogenesis are also considered. We conclude that the main effect of AMPK activation pertinent to the control of hepatic gluconeogenesis is to antagonize glucagon signalling in the short-term and, in the long-term, to improve insulin sensitivity by reducing hepatic lipid content.
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Raza GS, Sodum N, Kaya Y, Herzig KH. Role of Circadian Transcription Factor Rev-Erb in Metabolism and Tissue Fibrosis. Int J Mol Sci 2022; 23:12954. [PMID: 36361737 PMCID: PMC9655416 DOI: 10.3390/ijms232112954] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 10/21/2022] [Accepted: 10/22/2022] [Indexed: 09/12/2023] Open
Abstract
Circadian rhythms significantly affect metabolism, and their disruption leads to cardiometabolic diseases and fibrosis. The clock repressor Rev-Erb is mainly expressed in the liver, heart, lung, adipose tissue, skeletal muscles, and brain, recognized as a master regulator of metabolism, mitochondrial biogenesis, inflammatory response, and fibrosis. Fibrosis is the response of the body to injuries and chronic inflammation with the accumulation of extracellular matrix in tissues. Activation of myofibroblasts is a key factor in the development of organ fibrosis, initiated by hormones, growth factors, inflammatory cytokines, and mechanical stress. This review summarizes the importance of Rev-Erb in ECM remodeling and tissue fibrosis. In the heart, Rev-Erb activation has been shown to alleviate hypertrophy and increase exercise capacity. In the lung, Rev-Erb agonist reduced pulmonary fibrosis by suppressing fibroblast differentiation. In the liver, Rev-Erb inhibited inflammation and fibrosis by diminishing NF-κB activity. In adipose tissue, Rev- Erb agonists reduced fat mass. In summary, the results of multiple studies in preclinical models demonstrate that Rev-Erb is an attractive target for positively influencing dysregulated metabolism, inflammation, and fibrosis, but more specific tools and studies would be needed to increase the information base for the therapeutic potential of these substances interfering with the molecular clock.
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Affiliation(s)
- Ghulam Shere Raza
- Research Unit of Biomedicine, Medical Research Center, Faculty of Medicine, University of Oulu, 90220 Oulu, Finland
| | - Nalini Sodum
- Research Unit of Biomedicine, Medical Research Center, Faculty of Medicine, University of Oulu, 90220 Oulu, Finland
| | - Yagmur Kaya
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Marmara University, 34854 Istanbul, Turkey
| | - Karl-Heinz Herzig
- Research Unit of Biomedicine, Medical Research Center, Faculty of Medicine, University of Oulu, 90220 Oulu, Finland
- Oulu University Hospital, University of Oulu, 90220 Oulu, Finland
- Pediatric Gastroenterology and Metabolic Diseases, Pediatric Institute, Poznan University of Medical Sciences, 60-572 Poznań, Poland
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Wang H, Zhang L, Xia Z, Cui JY. Effect of Chronic Cadmium Exposure on Brain and Liver Transporters and Drug-Metabolizing Enzymes in Male and Female Mice Genetically Predisposed to Alzheimer's Disease. Drug Metab Dispos 2022; 50:1414-1428. [PMID: 35878927 PMCID: PMC9513859 DOI: 10.1124/dmd.121.000453] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 06/27/2022] [Indexed: 11/22/2022] Open
Abstract
Cadmium (Cd) exposure is associated with increased Alzheimer's disease (AD) risks. The human Apolipoprotein E (ApoE) gene encodes a lipid-transporting protein that is critical for brain functions. Compared with ApoE2 and E3, ApoE4 is associated with increased AD risk. Xenobiotic biotransformation-related genes have been implicated in the pathogenesis of AD. However, little is known about the effects of Cd, ApoE, and sex on drug-processing genes. We investigated the Cd-ApoE interaction on the transcriptomic changes in the brains and livers of ApoE3/ApoE4 transgenic mice. Cd disrupts the transcriptomes of transporter and drug-processing genes in brain and liver in a sex- and ApoE-genotype-specific manner. Proinflammation related genes were enriched in livers of Cd-exposed ApoE4 males, whereas circadian rhythm and lipid metabolism related genes were enriched in livers of Cd-exposed ApoE3 females. In brains, Cd up-regulated the arachidonic acid-metabolizing Cyp2j isoforms only in the brains of ApoE3 mice, whereas the dysregulation of cation transporters was male-specific. In livers, several direct target genes of the major xenobiotic-sensing nuclear receptor pregnane X receptor were uniquely upregulated in Cd-exposed ApoE4 males. There was a female-specific hepatic upregulation of the steroid hormone-metabolizing Cyp2 isoforms and the bile acid synthetic enzyme Cyp7a1 by Cd exposure. The dysregulated liver transporters were mostly involved in intermediary metabolism, with the most significant response observed in ApoE3 females. In conclusion, Cd dysregulated the brain and liver drug-processing genes in a sex- and ApoE-genotype specific manner, and this may serve as a contributing factor for the variance in the susceptibility to Cd neurotoxicity. SIGNIFICANCE STATEMENT: Xenobiotic biotransformation plays an important role in modulating the toxicity of environmental pollutants. The human ApoE4 allele is the strongest genetic risk factor for AD, and cadmium (Cd) is increasingly recognized as an environmental factor of AD. Very little is known regarding the interactions between Cd exposure, sex, and the genes involved in xenobiotic biotransformation in brain and liver. The present study has addressed this critical knowledge gap.
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Affiliation(s)
- Hao Wang
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington
| | - Liang Zhang
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington
| | - Zhengui Xia
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington
| | - Julia Yue Cui
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington
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Skrlec I, Talapko J. Hepatitis B and circadian rhythm of the liver. World J Gastroenterol 2022; 28:3282-3296. [PMID: 36158265 PMCID: PMC9346465 DOI: 10.3748/wjg.v28.i27.3282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/15/2022] [Accepted: 06/13/2022] [Indexed: 02/06/2023] Open
Abstract
The circadian rhythm in humans is determined by the central clock located in the hypothalamus's suprachiasmatic nucleus, and it synchronizes the peripheral clocks in other tissues. Circadian clock genes and clock-controlled genes exist in almost all cell types. They have an essential role in many physiological processes, including lipid metabolism in the liver, regulation of the immune system, and the severity of infections. In addition, circadian rhythm genes can stimulate the immune response of host cells to virus infection. Hepatitis B virus (HBV) infection is the leading cause of liver disease and liver cancer globally. HBV infection depends on the host cell, and hepatocyte circadian rhythm genes are associated with HBV replication, survival, and spread. The core circadian rhythm proteins, REV-ERB and brain and muscle ARNTL-like protein 1, have a crucial role in HBV replication in hepatocytes. In addition to influencing the virus's life cycle, the circadian rhythm also affects the pharmacokinetics and efficacy of antiviral vaccines. Therefore, it is vital to apply antiviral therapy at the appropriate time of day to reduce toxicity and improve the effectiveness of antiviral treatment. For these reasons, understanding the role of the circadian rhythm in the regulation of HBV infection and host responses to the virus provides us with a new perspective of the interplay of the circadian rhythm and anti-HBV therapy. Therefore, this review emphasizes the importance of the circadian rhythm in HBV infection and the optimization of antiviral treatment based on the circadian rhythm-dependent immune response.
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Affiliation(s)
- Ivana Skrlec
- Department of Biophysics, Biology, and Chemistry, Faculty of Dental Medicine and Health, J. J. Strossmayer University of Osijek, Osijek 31000, Croatia
| | - Jasminka Talapko
- Department of Anatomy Histology, Embryology, Pathology Anatomy and Pathology Histology, Faculty of Dental Medicine and Health, Osijek 31000, Croatia
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PPAR-γ Agonist Pioglitazone Restored Mouse Liver mRNA Expression of Clock Genes and Inflammation-Related Genes Disrupted by Reversed Feeding. PPAR Res 2022; 2022:7537210. [PMID: 35663475 PMCID: PMC9162826 DOI: 10.1155/2022/7537210] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 04/27/2022] [Accepted: 05/03/2022] [Indexed: 11/17/2022] Open
Abstract
Introduction The master clock, which is located in the suprachiasmatic nucleus (SCN), harmonizes clock genes present in the liver to synchronize life rhythms and bioactivity with the surrounding environment. The reversed feeding disrupts the expression of clock genes in the liver. Recently, a novel role of PPAR-γ as a regulator in correlating circadian rhythm and metabolism was demonstrated. This study examined the influence of PPAR-γ agonist pioglitazone (PG) on the mRNA expression profile of principle clock genes and inflammation-related genes in the mouse liver disrupted by reverse feeding. Methods Mice were randomly assigned to daytime-feeding and nighttime-feeding groups. Mice in daytime-feeding groups received food from 7 AM to 7 PM, and mice in nighttime-feeding groups received food from 7 PM to 7 AM. PG was administered in the dose of 20 mg/kg per os as aqueous suspension 40 μl at 7 AM or 7 PM. Each group consisted of 12 animals. On day 8 of the feeding intervention, mice were sacrificed by cervical dislocation at noon (05 hours after light onset (HALO)) and midnight (HALO 17). Liver expressions of Bmal1, Clock, Rev-erb alpha, Cry1, Cry2, Per1, Per2, Cxcl5, Nrf2, and Ppar-γ were determined by quantitative reverse transcription PCR. Liver expression of PPAR-γ, pNF-κB, and IL-6 was determined by Western blotting. Glucose, ceruloplasmin, total cholesterol, triglyceride concentrations, and ALT and AST activities were measured in sera by photometric methods. The null hypothesis tested was that PG and the time of its administration have no influence on the clock gene expression impaired by reverse feeding. Results Administration of PG at 7 AM to nighttime-feeding mice did not reveal any influence on the expression of the clock or inflammation-related genes either at midnight or at noon. In the daytime-feeding group, PG intake at 7 PM led to an increase in Per2 and Rev-erb alpha mRNA at noon, an increase in Ppar-γ mRNA at midnight, and a decrease in Nfκb (p65) mRNA at noon. In general, PG administration at 7 PM slightly normalized the impaired expression of clock genes and increased anti-inflammatory potency impaired by reversed feeding. This pattern was supported by biochemical substrate levels—glucose, total cholesterol, ALT, and AST activities. The decrease in NF-κB led to the inhibition of serum ceruloplasmin levels as well as IL-6 in liver tissue. According to our data, PG intake at 7 PM exerts strong normalization of clock gene expression with a further increase in Nrf2 and, especially, Ppar-γ and PPAR-γ expression with inhibition of Nfκb and pNF-κB expression in daytime-feeding mice. These expression changes resulted in decreased hyperglycemia, hypercholesterolemia, ALT, and AST activities. Thus, PG had a potent chronopharmacological effect when administered at 7 PM to daytime-feeding mice. Conclusions Our study indicates that reversed feeding induced the disruption of mouse liver circadian expression pattern of clock genes accompanied by increasing Nfκb and pNF-κB and IL-6 expression and decreasing Nrf2 and PPAR-γ. Administration of PG restored the clock gene expression profile and decreased Nfκb, pNF-κB, and IL-6, as well as increased Nrf2, Ppar-γ, and PPAR-γ expression. PG intake at 7 PM was more effective than at 7 AM in reversed feeding mice.
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Luan J, Yang K, Ding Y, Zhang X, Wang Y, Cui H, Zhou D, Chen L, Ma Z, Wang W, Zhang W, Liu X. Valsartan-mediated chronotherapy in spontaneously hypertensive rats via targeting clock gene expression in vascular smooth muscle cells. Arch Physiol Biochem 2022; 128:490-500. [PMID: 31794282 DOI: 10.1080/13813455.2019.1695840] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE This study was to investigate the underlying mechanisms of valsartan chronotherapy in regulating blood pressure variability. METHODS RT-PCR was used to assay clock genes expression rhythm in the hypothalamus, aortic vessels, and target organs after valsartan chronotherapy. WB was used to measure Period 1 (Per1), Period 2 (Per2) protein expression in aortic vessels, as well as to measure phosphorylation of 20-kDa regulatory myosin light chain (MLC20) in VSMCs. RESULTS Specific clock genes in the hypothalamus, and Per1 and Per2 in aorta abdominalis, exhibited disordered circadian expression in vivo. Valsartan asleep time administration (VSA) restored circadian clock gene expression in a tissue- and gene-specific manner. In vitro, VSA was more efficient in blocking angiotensin II relative to VWA, which led to differential circadian rhythms of Per1 and Per2, ultimately corrected MLC20 phosphorylation. CONCLUSION VSA may be efficacious in regulating circadian clock genes rhythm, then concomitantly correct circadian blood pressure rhythms.
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Affiliation(s)
- Jiajie Luan
- Department of Pharmacy, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, P.R. China
- School of Pharmacy, Wannan Medical College, Wuhu, P.R. China
| | - Kui Yang
- Department of Pharmacy, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, P.R. China
- School of Pharmacy, Wannan Medical College, Wuhu, P.R. China
| | - Yanyun Ding
- Department of Pharmacy, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, P.R. China
- School of Pharmacy, Wannan Medical College, Wuhu, P.R. China
| | - Xiaotong Zhang
- Department of Pharmacy, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, P.R. China
- School of Pharmacy, Wannan Medical College, Wuhu, P.R. China
| | - Yaqin Wang
- Department of Pharmacy, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, P.R. China
- School of Pharmacy, Wannan Medical College, Wuhu, P.R. China
| | - Haiju Cui
- Department of Pharmacy, XuanCheng Vocational and Technical college, XuanCheng, Anhui, P.R. China
| | - Deixi Zhou
- Department of Pharmacy, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, P.R. China
| | - Lu Chen
- Department of Pharmacy, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, P.R. China
| | - Zhangqing Ma
- School of Pharmacy, Wannan Medical College, Wuhu, P.R. China
| | - Wusan Wang
- School of Pharmacy, Wannan Medical College, Wuhu, P.R. China
| | - Wen Zhang
- Department of Pharmacy, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, P.R. China
- School of Pharmacy, Wannan Medical College, Wuhu, P.R. China
| | - Xiaoyun Liu
- Department of Pharmacy, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, P.R. China
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11
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Time-of-Day Circadian Modulation of Grape-Seed Procyanidin Extract (GSPE) in Hepatic Mitochondrial Dynamics in Cafeteria-Diet-Induced Obese Rats. Nutrients 2022; 14:nu14040774. [PMID: 35215423 PMCID: PMC8876123 DOI: 10.3390/nu14040774] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 02/04/2022] [Accepted: 02/08/2022] [Indexed: 12/13/2022] Open
Abstract
Major susceptibility to alterations in liver function (e.g., hepatic steatosis) in a prone environment due to circadian misalignments represents a common consequence of recent sociobiological behavior (i.e., food excess and sleep deprivation). Natural compounds and, more concisely, polyphenols have been shown as an interesting tool for fighting against metabolic syndrome and related consequences. Furthermore, mitochondria have been identified as an important target for mediation of the health effects of these compounds. Additionally, mitochondrial function and dynamics are strongly regulated in a circadian way. Thus, we wondered whether some of the beneficial effects of grape-seed procyanidin extract (GSPE) on metabolic syndrome could be mediated by a circadian modulation of mitochondrial homeostasis. For this purpose, rats were subjected to “standard”, “cafeteria” and “cafeteria diet + GSPE” treatments (n = 4/group) for 9 weeks (the last 4 weeks, GSPE/vehicle) of treatment, administering the extract/vehicle at diurnal or nocturnal times (ZT0 or ZT12). For circadian assessment, one hour after turning the light on (ZT1), animals were sacrificed every 6 h (ZT1, ZT7, ZT13 and ZT19). Interestingly, GSPE was able to restore the rhythm on clock hepatic genes (Bmal1, Per2, Cry1, Rorα), as this correction was more evident in nocturnal treatment. Additionally, during nocturnal treatment, an increase in hepatic fusion genes and a decrease in fission genes were observed. Regarding mitochondrial complex activity, there was a strong effect of cafeteria diet at nearly all ZTs, and GSPE was able to restore activity at discrete ZTs, mainly in the diurnal treatment (ZT0). Furthermore, a differential behavior was observed in tricarboxylic acid (TCA) metabolites between GSPE diurnal and nocturnal administration times. Therefore, GSPE may serve as a nutritional preventive strategy in the recovery of hepatic-related metabolic disease by modulating mitochondrial dynamics, which is concomitant to the restoration of the hepatic circadian machinery.
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12
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Singh SP, Anirvan P, Khandelwal R, Satapathy SK. Nonalcoholic Fatty Liver Disease (NAFLD) Name Change: Requiem or Reveille? J Clin Transl Hepatol 2021; 9:931-938. [PMID: 34966656 PMCID: PMC8666378 DOI: 10.14218/jcth.2021.00174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 06/21/2021] [Accepted: 07/18/2021] [Indexed: 12/04/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) affects about a quarter of the world's population and poses a major health and economic burden globally. Recently, there have been hasty attempts to rename NAFLD to metabolic-associated fatty liver disease (MAFLD) despite the fact that there is no scientific rationale for this. Quest for a "positive criterion" to diagnose the disease and destigmatizing the disease have been the main reasons put forth for the name change. A close scrutiny of the pathogenesis of NAFLD would make it clear that NAFLD is a heterogeneous disorder, involving different pathogenic mechanisms of which metabolic dysfunction-driven hepatic steatosis is only one. Replacing NAFLD with MAFLD would neither enhance the legitimacy of clinical practice and clinical trials, nor improve clinical care or move NAFLD research forward. Rather than changing the nomenclature without a strong scientific backing to support such a change, efforts should be directed at understanding NAFLD pathogenesis across diverse populations and ethnicities which could potentially help develop newer therapeutic options.
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Affiliation(s)
- Shivaram P. Singh
- Department of Gastroenterology, Sriram Chandra Bhanj Medical College, Cuttack, Odisha, India
| | - Prajna Anirvan
- Department of Gastroenterology, Sriram Chandra Bhanj Medical College, Cuttack, Odisha, India
| | - Reshu Khandelwal
- Department of Gastroenterology, Sriram Chandra Bhanj Medical College, Cuttack, Odisha, India
| | - Sanjaya K. Satapathy
- Division of Hepatology, Sandra Atlas Bass Center for Liver Diseases and Transplantation, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, Manhasset, NY, USA
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13
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Hassan SA, Ali AAH, Sohn D, Flögel U, Jänicke RU, Korf H, von Gall C. Does timing matter in radiotherapy of hepatocellular carcinoma? An experimental study in mice. Cancer Med 2021; 10:7712-7725. [PMID: 34545699 PMCID: PMC8559477 DOI: 10.1002/cam4.4277] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 08/18/2021] [Accepted: 08/27/2021] [Indexed: 01/10/2023] Open
Abstract
This study investigates whether a chronotherapeutic treatment of hepatocellular carcinoma (HCC) may improve treatment efficacy and mitigate side effects on non-tumoral liver (NTL). HCC was induced in Per2::luc mice which were irradiated at four time points of the day. Proliferation and DNA-double strand breaks were analyzed in irradiated and nonirradiated animals by detection of Ki67 and γ-H2AX. Prior to whole animal experiments, organotypic slice cultures were investigated to determine the dosage to be used in whole animal experiments. Irradiation was most effective at the proliferation peaks in HCC at ZT02 (early inactivity phase) and ZT20 (late activity phase). Irradiation effects on NTL were minimal at ZT20. As compared with NTL, nonirradiated HCC revealed disruption in daily variation and downregulation of all investigated clock genes except Per1. Irradiation affected rhythmic clock gene expression in NTL and HCC at all ZTs except at ZT20 (late activity phase). Irradiation at ZT20 had no effect on total leukocyte numbers. Our results indicate ZT20 as the optimal time point for irradiation of HCC in mice at which the ratio between efficacy of tumor treatment and toxic side effects was maximal. Translational studies are now needed to evaluate whether the late activity phase is the optimal time point for irradiation of HCC in man.
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Affiliation(s)
- Soha A. Hassan
- Institute of Anatomy II, Medical FacultyHeinrich‐Heine‐UniversityDüsseldorfGermany
- Zoology DepartmentFaculty of ScienceSuez UniversitySuezEgypt
| | - Amira A. H. Ali
- Institute of Anatomy II, Medical FacultyHeinrich‐Heine‐UniversityDüsseldorfGermany
- Department of Anatomy and EmbryologyFaculty of MedicineMansoura UniversityMansouraEgypt
| | - Dennis Sohn
- Laboratory of Molecular Radiooncology, Clinic and Policlinic for Radiation Therapy and RadiooncologyMedical Faculty of Heinrich‐Heine‐UniversityDüsseldorfGermany
| | - Ulrich Flögel
- Department of Molecular CardiologyHeinrich‐Heine‐UniversityDüsseldorfGermany
| | - Reiner U. Jänicke
- Laboratory of Molecular Radiooncology, Clinic and Policlinic for Radiation Therapy and RadiooncologyMedical Faculty of Heinrich‐Heine‐UniversityDüsseldorfGermany
| | - Horst‐Werner Korf
- Institute of Anatomy IMedical FacultyHeinrich‐Heine‐UniversityDüsseldorfGermany
| | - Charlotte von Gall
- Institute of Anatomy II, Medical FacultyHeinrich‐Heine‐UniversityDüsseldorfGermany
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14
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Zanthoxylum zanthoxyloides Alkaloidal Extract Improves CCl 4-Induced Hepatocellular Carcinoma-Like Phenotypes in Rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:3804379. [PMID: 34367300 PMCID: PMC8337135 DOI: 10.1155/2021/3804379] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 07/02/2021] [Accepted: 07/13/2021] [Indexed: 02/07/2023]
Abstract
Background Despite the enrollment of new small molecules such as Sorafenib for the treatment of hepatocellular carcinoma (HCC), HCC still remains a significant contributor to cancer-related mortality and morbidity globally. Zanthoxylum zanthoxyloides is long suspected of possessing anticancer bioactive compounds that may hold the prospect of adjunctive therapy against inflammation-related cancers such as HCC. Objective This study assessed the effects of an alkaloidal extract of the leaves of Zanthoxylum zanthoxyloides on CCl4/olive oil (1 : 1 v/v)-induced HCC-like phenotypes in rats. Materials and Methods Zanthoxylum zanthoxyloides alkaloidal extract (ZZAE) was prepared using Soxhlet and liquid-liquid extraction methods. Subsequently, ZZAE was characterized phytochemically. In the curative method, experimental HCC was established in adult (8-10 weeks old) male Sprague-Dawley rats weighing 150-300 g by twice-daily administration of CCl4/olive oil (1 : 1 v/v) (2 mL/kg ip). After confirmation of experimental HCC in rats, the rats were randomly reassigned into seven (7) groups of seven (7) rats each and treated daily for 12 weeks as follows: control (normal saline, 5 ml/kg po), model (CCl4, 5 ml/kg, ip), ZZAE (50, 100, and 200 mg/kg po), carvedilol (6.25 mg/kg po), and 20% Tween20 (1 mL/rat, po). To assess whether ZZAE has a prophylactic (preventive) effect, rats were first treated with ZZAE and later exposed to CCl4 reconstituted in olive oil. Results ZZAE (100 and 200 mg/kg) and carvedilol decreased tumor incidence compared to that of control. Compared to control, ZZAE (100 and 200 mg/kg) significantly (P < 0.05) improved serum GGT. Compared to control, ZZAE improved hepatohistological distortions induced by CCl4/olive oil and also improved liver/body weight ratio. Compared to water, ZZAE arrested mitosis in the Allium cepa assay. Conclusion ZZAE ameliorated CCl4/olive oil-induced HCC-like phenotype in rats and demonstrated general hepatoprotective effects by improving liver and kidney function markers. This finding rationalizes the need for further studies on ZZAE as a potential source of bioactive anti-HCC compounds.
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15
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Pathway-level analysis of genome-wide circadian dynamics in diverse tissues in rat and mouse. J Pharmacokinet Pharmacodyn 2021; 48:361-374. [PMID: 33768484 DOI: 10.1007/s10928-021-09750-3] [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: 11/03/2020] [Accepted: 03/17/2021] [Indexed: 10/21/2022]
Abstract
A computational framework is developed to enable the characterization of genome-wide, multi-tissue circadian dynamics at the level of "functional groupings of genes" defined in the context of signaling, cellular/genetic processing and metabolic pathways in rat and mouse. Our aim is to identify how individual genes come together to generate orchestrated rhythmic patterns and how these may vary within and across tissues. We focus our analysis on four tissues (adipose, liver, lung, and muscle). A genome-wide pathway-centric analysis enables us to develop a comprehensive picture on how the observed circadian variation at the individual gene level, orchestrates functional responses at the pathway level. Such pathway-based "meta-data" analysis enables the rational integration and comparison across platforms and/or experimental designs evaluating emergent dynamics, as opposed to comparisons of individual elements. One of our key findings is that when considering the dynamics at the pathway level, a complex behavior emerges. Our work proposes that tissues tend to coordinate gene's circadian expression in a way that optimizes tissue-specific pathway activity, depending of each tissue's broader role in homeostasis.
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16
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Kelleci Çelik F, Charehsaz M, Aydin A. Toxicological evaluation of the interaction between circadian rhythm activator; KL001 and general anesthetic; isoflurane. BIOL RHYTHM RES 2019. [DOI: 10.1080/09291016.2019.1698808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Affiliation(s)
- Feyza Kelleci Çelik
- Department of Pharmaceutical Toxicology, Sağlık Bilimleri University Faculty of Pharmacy, İstanbul, Turkey
| | - Mohammad Charehsaz
- Department of Pharmaceutical Toxicology, Yeditepe University Faculty of Pharmacy, Istanbul, Turkey
| | - Ahmet Aydin
- Department of Pharmaceutical Toxicology, Yeditepe University Faculty of Pharmacy, Istanbul, Turkey
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17
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Wang Y, Lv K, Zhao M, Chen H, Ji G, Zhang Y, Wang T, Cao H, Li Y, Qu L. Analysis of miRNA expression profiles in the liver of Clock Δ19 mutant mice. PeerJ 2019; 7:e8119. [PMID: 31799078 PMCID: PMC6885354 DOI: 10.7717/peerj.8119] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Accepted: 10/29/2019] [Indexed: 12/31/2022] Open
Abstract
The circadian clock controls the physiological functions of many tissues including the liver via an autoregulatory transcriptional−translational feedback loop, of which CLOCK is a core positive component. In addition, many studies have indicated that microRNAs (miRNAs) regulate liver function. However, how CLOCK-regulated miRNAs are linked to liver function remains largely unknown. In this study, miRNAs expression profiles were performed in the liver of ClockΔ19 mutant mice. Compared to wild type mice, totals of 61 and 57 putative CLOCK-regulated miRNAs were differentially expressed (fold change absolute value ≥2) at zeitgeber time 2 and zeitgeber time 14, respectively. According to the pathway analyses, the target genes of differentially expressed miRNAs were mainly involved in pathways in cancer, the PI3K-Akt signaling pathway and the MAPK signaling pathway. Protein−protein interaction analyses revealed that the hub genes were primarily associated with pathway in cancer and circadian rhythms. Expression validation showed that while the expression levels of miR-195 and miR-340 were up-regulated, the rhythms of these two miRNAs were always maintained. The expression level of nr1d2 mRNA was down-regulated. We identified a number of prospective CLOCK-regulated miRNAs that play roles in the various physiological processes of the liver, providing a reference to better understanding the potential regulatory mechanisms in the liver.
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Affiliation(s)
- Yanli Wang
- School of Life Sciences, Northwestern Polytechnical University, Xian, Shaanxi, China
| | - Ke Lv
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Mei Zhao
- Institute of Psychology, Chinese Academy of Sciences, Beijing, China
| | - Hailong Chen
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Guohua Ji
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Yongliang Zhang
- School of Life Sciences, Northwestern Polytechnical University, Xian, Shaanxi, China
| | - Tingmei Wang
- School of Life Sciences, Northwestern Polytechnical University, Xian, Shaanxi, China
| | - Hongqing Cao
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Yinghui Li
- School of Life Sciences, Northwestern Polytechnical University, Xian, Shaanxi, China.,State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Lina Qu
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
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18
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Relationship between shift work and liver enzymes: a cross-sectional study based on the Korea National Health and Examination Survey (2007-2015). Ann Occup Environ Med 2019; 31:e15. [PMID: 31583106 PMCID: PMC6761479 DOI: 10.35371/aoem.2019.31.e15] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Accepted: 07/15/2019] [Indexed: 01/12/2023] Open
Abstract
Background Shift work has well-known adverse effects on health. However, few studies have investigated the relationship between shift work and hepatic disorders. This study aimed to evaluate the association between shift work and abnormal level of liver enzymes. Methods The aggregated data from the 2007–2009, 2010–2012, and 2013–2015 cycles of the Korea National Health and Nutrition Examination Survey was used for this study. The χ2 test and multiple logistic regression analysis were used to assess relationship between shift work and abnormal level of liver enzymes stratified by gender. Results The odds ratio (OR) of abnormal serum level of alanine aminotransferase (abnormal ALT) in female shift workers was higher with 1.31 (95% confidence interval: 1.00–1.71) compared with day workers after adjusting for covariates. After dividing into subgroups of the shift work pattern, the ORs of abnormal liver enzymes for each pattern compared with day work were not significantly higher. Conclusions This study provides limited support for the hypothesis that shift work is related to liver enzyme abnormalities, but offers some evidence in favor of the idea that shift work affects female workers more than males on abnormal ALT. Further studies are needed to define the relationship between shift work and abnormal liver enzymes to be carried out as well as the gender difference in the association.
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19
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Radlicz C, Mezitis NHE. Chrononutrition and the Diabetic Patient. THE JOURNAL OF THE AMERICAN OSTEOPATHIC ASSOCIATION 2019; 119:469. [PMID: 31233113 DOI: 10.7556/jaoa.2019.086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
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20
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Mezitis NHE, Bhatnagar V. Chrononutrition Applied to Diabetes Management: A Paradigm Shift Long Delayed. Diabetes Spectr 2018; 31:349-353. [PMID: 30510391 PMCID: PMC6243221 DOI: 10.2337/ds18-0014] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
| | - Vikrant Bhatnagar
- Ohio University Heritage College of Osteopathic Medicine, Athens, OH
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21
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Sánchez DI, González-Fernández B, Crespo I, San-Miguel B, Álvarez M, González-Gallego J, Tuñón MJ. Melatonin modulates dysregulated circadian clocks in mice with diethylnitrosamine-induced hepatocellular carcinoma. J Pineal Res 2018; 65:e12506. [PMID: 29770483 DOI: 10.1111/jpi.12506] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Accepted: 04/17/2018] [Indexed: 01/07/2023]
Abstract
Disruption of circadian rhythms, which are regulated by the circadian clock machinery, plays an important role in different long-term diseases including hepatocellular carcinoma (HCC). Melatonin has been reported to alleviate promotion and progression of HCC, but the potential contribution of circadian clock modulation is unknown. We investigated the effects of melatonin in mice which received diethylnitrosamine (DEN) (35 mg/kg body weight ip) once a week for 8 weeks. Melatonin was given at 5 or 10 mg kg-1 d-1 ip beginning 4 weeks after the onset of DEN administration and ending at the sacrifice time (10, 20, 30, or 40 weeks). Liver expression of Bmal1, Clock, Npas2, Rorα, and Sirt1 increased, whereas Cry1, Per1, Per2, Per3, CK1ε, Rev-erbα, and Rev-erbβ decreased following DEN administration. Melatonin treatment prevented changes in the expression of clock genes, and this effect was accompanied by an upregulation of the MT1 receptor and reduced levels of the hypoxia-inducible factors Hif-1α and Hif-2α. An increased expression of p21, p53, and PARP1/2, a higher Bax/Bcl-2 ratio, and a lower expression of Cyclin D1, CDK6, HSP70, HSP90, and GRP78 proteins were also observed in melatonin-treated mice. Melatonin significantly potentiated the suppression of proliferation and cell cycle arrest induced by the synthetic REV-ERB agonist SR9009 in human Hep3B cells, and BMAL1 knocking down attenuated the pro-apoptotic and antiproliferative effect of melatonin. Results support a contribution of changes in the circadian clock components to the beneficial effects of melatonin in HCC and highlight the usefulness of strategies modulating the circadian machinery in hepatocarcinogenesis.
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Affiliation(s)
- Diana I Sánchez
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
| | | | - 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
| | | | | | - 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
| | - María Jesús Tuñón
- 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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22
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González-Fernández B, Sánchez DI, Crespo I, San-Miguel B, de Urbina JO, González-Gallego J, Tuñón MJ. Melatonin Attenuates Dysregulation of the Circadian Clock Pathway in Mice With CCl 4-Induced Fibrosis and Human Hepatic Stellate Cells. Front Pharmacol 2018; 9:556. [PMID: 29892224 PMCID: PMC5985434 DOI: 10.3389/fphar.2018.00556] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Accepted: 05/09/2018] [Indexed: 12/14/2022] Open
Abstract
Dysregulation of the circadian clock machinery is a critical mechanism in the pathogenesis of fibrosis. This study aimed to investigate whether the antifibrotic effect of melatonin is associated with attenuation of circadian clock pathway disturbances in mice treated with carbon tetrachloride (CCl4) and in human hepatic stellate cells line LX2. Mice received CCl4 5 μL/g body weight i.p. twice a week for 4 or 6 weeks. Melatonin was given at 5 or 10 mg/kg/day i.p., beginning 2 weeks 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 and a significant decrease of peroxisome proliferator-activated receptor (PPARα) expression. CCl4 led to a lower expression of brain and muscle Arnt-like protein 1 (BMAL1), circadian locomotor output cycles kaput (CLOCK), period 1–3 (PER1, 2, and 3), cryptochrome 1 and 2 (CRY1 and 2) and the retinoic acid receptor-related orphan receptor (RORα). The expression of the nuclear receptor REV-ERBα showed a significant increase. Melatonin significantly prevented all these changes. We also found that melatonin (100 or 500 μM) potentiated the inhibitory effect of REV-ERB ligand SR9009 on α-SMA and collagen1 expression and increased the expression of PPARα in LX2 cells. Analysis of circadian clock machinery revealed that melatonin or SR9009 exposure upregulated BMAL1, CLOCK, PER2, CRY1, and RORα expression, with a higher effect of combined treatment. Findings from this study give new insight into molecular pathways accounting for the protective effect of melatonin in liver fibrosis.
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Affiliation(s)
| | - Diana I Sánchez
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
| | - 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
| | | | | | - 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
| | - 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
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Li T, Ni L, Zhao Z, Liu X, Lai Z, Di X, Xie Z, Song X, Wang X, Zhang R, Liu C. Melatonin attenuates smoking-induced hyperglycemia via preserving insulin secretion and hepatic glycogen synthesis in rats. J Pineal Res 2018; 64:e12475. [PMID: 29437243 PMCID: PMC5947659 DOI: 10.1111/jpi.12475] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Accepted: 02/02/2018] [Indexed: 12/11/2022]
Abstract
Epidemiology survey indicated that cigarette smoking is a risk factor of diabetes. However, the precise mechanisms remain to be clarified. In this study, we found that smoking caused metabolic malfunctions on pancreas and liver in experimental animal model. These were indicated by hyperglycemia, increased serum hemoglobin A1c level and decreased insulin secretion, inhibition of liver glycogen synthase (LGS), and hepatic glycogen synthesis. Mechanistic studies revealed that all these alterations were caused by the inflammatory reaction and reactive oxygen species (ROS) induced by the smoking. Melatonin treatment significantly preserved the functions of both pancreas and liver by reducing β cell apoptosis, CD68-cell infiltration, ROS production, and caspase-3 expression. The siRNA-knockdown model identified that the protective effects of melatonin were mediated by melatonin receptor-2 (MT2). This study uncovered potentially underlying mechanisms related to the association between smoking and diabetes. In addition, it is, for first time, to report that melatonin effectively protects against smoking-induced glucose metabolic alterations and the signal transduction pathway of melatonin is mainly mediated by its MT2 receptor. These observations provide solid evidence for the clinically use of melatonin to reduce smoking-related diabetes, and the therapeutic regimens are absent currently.
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Affiliation(s)
- Tianjia Li
- Department of Vascular SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Leng Ni
- Department of Vascular SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Zhewei Zhao
- Department of Vascular SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Xinnong Liu
- Department of Vascular SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Zhichao Lai
- Department of Vascular SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Xiao Di
- Department of Vascular SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Zhibo Xie
- Department of Vascular SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Xitao Song
- Department of Vascular SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Xuebin Wang
- Department of Vascular SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Rui Zhang
- Department of Vascular SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Changwei Liu
- Department of Vascular SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
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Forrestel AC, Miedlich SU, Yurcheshen M, Wittlin SD, Sellix MT. Chronomedicine and type 2 diabetes: shining some light on melatonin. Diabetologia 2017; 60:808-822. [PMID: 27981356 DOI: 10.1007/s00125-016-4175-1] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Accepted: 11/18/2016] [Indexed: 12/19/2022]
Abstract
In mammals, the circadian timing system drives rhythms of physiology and behaviour, including the daily rhythms of feeding and activity. The timing system coordinates temporal variation in the biochemical landscape with changes in nutrient intake in order to optimise energy balance and maintain metabolic homeostasis. Circadian disruption (e.g. as a result of shift work or jet lag) can disturb this continuity and increase the risk of cardiometabolic disease. Obesity and metabolic disease can also disturb the timing and amplitude of the clock in multiple organ systems, further exacerbating disease progression. As our understanding of the synergy between the timing system and metabolism has grown, an interest has emerged in the development of novel clock-targeting pharmaceuticals or nutraceuticals for the treatment of metabolic dysfunction. Recently, the pineal hormone melatonin has received some attention as a potential chronotherapeutic drug for metabolic disease. Melatonin is well known for its sleep-promoting effects and putative activity as a chronobiotic drug, stimulating coordination of biochemical oscillations through targeting the internal timing system. Melatonin affects the insulin secretory activity of the pancreatic beta cell, hepatic glucose metabolism and insulin sensitivity. Individuals with type 2 diabetes mellitus have lower night-time serum melatonin levels and increased risk of comorbid sleep disturbances compared with healthy individuals. Further, reduced melatonin levels, and mutations and/or genetic polymorphisms of the melatonin receptors are associated with an increased risk of developing type 2 diabetes. Herein we review our understanding of molecular clock control of glucose homeostasis, detail the influence of circadian disruption on glucose metabolism in critical peripheral tissues, explore the contribution of melatonin signalling to the aetiology of type 2 diabetes, and discuss the pros and cons of melatonin chronopharmacotherapy in disease management.
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Affiliation(s)
- Andrew C Forrestel
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 693, Rochester, NY, 14642, USA
| | - Susanne U Miedlich
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 693, Rochester, NY, 14642, USA
| | - Michael Yurcheshen
- UR Medicine Sleep Center, Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Steven D Wittlin
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 693, Rochester, NY, 14642, USA
| | - Michael T Sellix
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 693, Rochester, NY, 14642, USA.
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25
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Li T, Cao R, Xia R, Xia Z. Effects of 72 Hours Sleep Deprivation on Liver Circadian Clock Gene Expression and Oxidative Stress in Rats. ACTA ACUST UNITED AC 2017. [DOI: 10.4236/ym.2017.14020] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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26
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Li H, Lu YF, Chen H, Liu J. Dysregulation of metallothionein and circadian genes in human hepatocellular carcinoma. Chronobiol Int 2016; 34:192-202. [PMID: 27997226 DOI: 10.1080/07420528.2016.1256300] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2016] [Revised: 10/26/2016] [Accepted: 10/31/2016] [Indexed: 12/25/2022]
Abstract
Hepatocellular carcinoma (HCC) is the major threat to human health, and disruption of circadian clock genes is implicated in hepatocarcinogenesis. This study examined the dysregulation of metallothioneins and circadian genes in achieved human HCC (n = 24), peri-HCC tissues (n = 24) as compared with normal human livers (n = 36). Total RNA was extracted and reverse transcribed. Real-time RT-qPCR was performed to determine the expression of genes of interest. The results demonstrated the downregulation of metallothionein-1 (MT-1), MT-2, and metal transcription factor-1 (MFT-1) in human HCC as compared with Peri-HCC and normal tissues. MTs are a biomarker for HCC and have typical circadian rhythms; the expression of major circadian clock genes was also determined. HCC produced a dramatic decrease in the expression of core clock genes, circadian locomotor output cycles kaput (Clock) and brain and muscle Arnt-like protein 1 (Bmal1), and decreased the expression of the clock feedback control genes, Periods (Per1, Per2) and Cryptochromes (Cry1, Cry2). On the other hand, the expression of clock target genes nuclear orphan receptor factor protein (Nr1d1) and D-box-binding protein (Dbp) was upregulated as compared with Peri-HCC and normal livers. Peri-HCC also had mild alterations in these gene expressions. In summary, the present study clearly demonstrated the dysregulation of MTs and circadian clock genes in human HCC, which could provide the information of targeting MT and circadian clock in HCC management.
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Affiliation(s)
- Huan Li
- a Key Lab for Basic Pharmacology of Ministry of Education , Zunyi Medical College , Zunyi , China
| | - Yuan-Fu Lu
- a Key Lab for Basic Pharmacology of Ministry of Education , Zunyi Medical College , Zunyi , China
| | - Hong Chen
- b The Institute of Organ Transplantation , The General Hospital of Chinese People's Armed Police Forces , Beijing , China
| | - Jie Liu
- a Key Lab for Basic Pharmacology of Ministry of Education , Zunyi Medical College , Zunyi , China
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27
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Vinod C, Jagota A. Daily NO rhythms in peripheral clocks in aging male Wistar rats: protective effects of exogenous melatonin. Biogerontology 2016; 17:859-871. [PMID: 27614960 DOI: 10.1007/s10522-016-9656-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Accepted: 06/21/2016] [Indexed: 02/07/2023]
Abstract
In mammals suprachiasmatic nucleus (SCN), acts as a light entrainable master clock and by generation of temporal oscillations regulates the peripheral organs acting as autonomous clocks resulting in overt behavioral and physiological rhythms. SCN also controls synthesis and release of melatonin (hormonal message for darkness) from pineal. Nitric Oxide (NO) acts as an important neurotransmitter in generating the phase shifts of circadian rhythms and participates in sleep-wake processes, maintenance of vascular tone as well as signalling and regulating inflammatory processes. Aging is associated with disruption of circadian timing system and decline in endogenous melatonin leading to several physiological disorders. Here we report the effect of aging on NO daily rhythms in various peripheral clocks such as kidney, intestine, liver, heart, lungs and testis. NO levels were measured at zeitgeber time (ZT) 0, 6, 12 and 18 in these tissues using Griess assay in male Wistar rats. Aging resulted in alteration of NO levels as well as phase of NO in both 12 and 24 months groups. Correlation analysis demonstrated loss of stoichiometric interaction between the various peripheral clocks with aging. Age induced alterations in NO daily rhythms were found to be most significant in liver and, interestingly least in lungs. Neurohormone melatonin, an endogenous synchroniser and an antiaging agent decreases with aging. We report further differential restoration with exogenous melatonin administration of age induced alterations in NO daily rhythms and mean levels in kidney, intestine and liver and the stoichiometric interactions between the various peripheral clocks.
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Affiliation(s)
- Ch Vinod
- Neurobiology and Molecular Chronobiology Lab, Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, 500046, India
| | - Anita Jagota
- Neurobiology and Molecular Chronobiology Lab, Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, 500046, India.
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Cairns RA, Mak TW. Lung Cancer Resets the Liver's Metabolic Clock. Cell Metab 2016; 23:767-9. [PMID: 27166941 DOI: 10.1016/j.cmet.2016.04.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
The impact of a tumor on distant organs is not well characterized but may be important for understanding immune interactions and the process of metastasis. Masri and colleagues (2016) now identify an interesting effect of lung tumor development on circadian regulation of liver metabolism.
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Affiliation(s)
- Rob A Cairns
- The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, ON M5G 2C1, Canada; The Princess Margaret Cancer Centre and Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2C1, Canada
| | - Tak W Mak
- The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, ON M5G 2C1, Canada; The Princess Margaret Cancer Centre and Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2C1, Canada.
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