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Kim JY, Lee J, Lee SH, Jung EM, Lee KH. Modulatory effects of cinnamomi cortex and its components epicatechin and linalool on skin circadian rhythms. Sci Rep 2025; 15:4480. [PMID: 39915616 PMCID: PMC11803083 DOI: 10.1038/s41598-025-88325-5] [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: 10/04/2024] [Accepted: 01/28/2025] [Indexed: 02/09/2025] Open
Abstract
Circadian rhythms, intrinsic 24-h cycles regulating physiological processes, are crucial for skin homeostasis. Disruptions in these rhythms are linked to various skin disorders and impaired barrier function. Circadian rhythms can be modulated by botanical compounds, which hold therapeutic potential. However, the effect of cinnamomi cortex (CC), an anti-inflammatory, antioxidant, and antimicrobial agent, on the circadian rhythm of keratinocytes remains unclear. This study aimed to examine the effects of CC extract and its 18 individual components on the circadian rhythm of HaCaT, an immortalized human keratinocyte line. CC extract and its bioactive components epicatechin (EC) and linalool (LO) significantly enhanced the circadian amplitude without altering the period. Gene expression analysis revealed that CC extract, EC, and LO altered the mRNA and protein levels of clock genes in a time-dependent manner. During molecular docking simulations, both EC and LO exhibited strong binding affinities for RORA, a key nuclear receptor involved in circadian regulation. Enhanced BMAL1 promoter activity following EC and LO treatments corroborated these findings. Furthermore, EC and LO demonstrated significant antioxidant activities, as evidenced by reduced reactive oxygen species levels and increased expression of antioxidant enzymes. EC and LO also upregulated skin barrier-related and ceramide synthesis genes and modulated the expression of cellular longevity-promoting genes. In conclusion, CC extract, particularly the components EC and LO, modulated circadian rhythms, reduced oxidative stress, and enhanced skin barrier function in keratinocytes. These findings highlight the potential of CC extract and its components as novel dermatological treatments to improve skin health and combat aging.
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Affiliation(s)
- Ji-Young Kim
- Department of Molecular Biology, Pusan National University, Busan, 46241, Republic of Korea
| | - Juyeon Lee
- Department of Molecular Biology, Pusan National University, Busan, 46241, Republic of Korea
| | - Soo-Hyeon Lee
- Department of Molecular Biology, Pusan National University, Busan, 46241, Republic of Korea
| | - Eui-Man Jung
- Department of Molecular Biology, Pusan National University, Busan, 46241, Republic of Korea
| | - Kyung-Ha Lee
- Department of Molecular Biology, Pusan National University, Busan, 46241, Republic of Korea.
- Institute of Systems Biology, Pusan National University, Busan, 46241, Republic of Korea.
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2
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Egg M, Kietzmann T. Little strokes fell big oaks: The use of weak magnetic fields and reactive oxygen species to fight cancer. Redox Biol 2025; 79:103483. [PMID: 39729909 PMCID: PMC11733197 DOI: 10.1016/j.redox.2024.103483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 12/18/2024] [Accepted: 12/23/2024] [Indexed: 12/29/2024] Open
Abstract
The increase in early-stage cancers, particularly gastrointestinal, breast and kidney cancers, has been linked to lifestyle changes such as consumption of processed foods and physical inactivity, which contribute to obesity and diabetes - major cancer risk factors. Conventional treatments such as chemotherapy and radiation often lead to severe long-term side effects, including secondary cancers and tissue damage, highlighting the need for new, safer and more effective therapies, especially for young patients. Weak electromagnetic fields (WEMF) offer a promising non-invasive approach to cancer treatment. While WEMF have been used therapeutically for musculoskeletal disorders for decades, their role in oncology is still emerging. WEMFs affect multiple cellular processes through mechanisms such as the radical pair mechanism (RPM), which alters reactive oxygen species (ROS) levels, mitochondrial function, and glycolysis, among others. This review explores the potential of WEMF in conjunction with reactive oxygen species as a cancer therapy, highlighting WEMFs selective targeting of cancer cells and its non-ionizing nature, which could reduce collateral damage compared to conventional treatments. In addition, synchronization of WEMF with circadian rhythms may further enhance its therapeutic efficacy, as has been demonstrated in other cancer therapies.
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Affiliation(s)
- Margit Egg
- Institute of Zoology, University Innsbruck, Technikerstraße 25, 6020, Innsbruck, Tyrol, A-6020, Austria.
| | - Thomas Kietzmann
- Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, P.O. Box 3000, 90014, Oulu, Finland
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3
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Castro-Pascual IC, Ferramola ML, Altamirano FG, Cargnelutti E, Devia CM, Delgado SM, Lacoste MG, Anzulovich AC. Circadian organization of clock factors, antioxidant defenses, and cognitive genes expression, is lost in the cerebellum of aged rats. Possible targets of therapeutic strategies for the treatment of age-related cerebellar disorders. Brain Res 2024; 1845:149195. [PMID: 39182901 DOI: 10.1016/j.brainres.2024.149195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 08/10/2024] [Accepted: 08/21/2024] [Indexed: 08/27/2024]
Abstract
Aging is a major risk factor for cognitive deficits, impaired locomotion, and gait disorders. Although oxidative stress and circadian disruption are involved in both normal aging and the pathogenesis of age-associated diseases, just a very few studies explore the consequences of aging on circadian rhythms in the cerebellum. Here, we investigated age-dependent changes in the circadian organization of the molecular clock, antioxidant defenses and synaptic plasticity-related factors, in the rat cerebellum, and discussed the impact of that altered temporal organization on the cognitive function of this brain area. Particularly, we examined the circadian patterns of Brain and muscle ARNT-like 1 (BMAL1) protein levels, Glutathione peroxidase 4 (GPx4) gene expression, GPx and Catalase (CAT) enzymes activity, reduced glutathione (GSH) levels, and the Brain-derived neurotrophic factor (Bdnf) and its Tyrosine kinase receptor B (TrkB) circadian expression. Endogenously-driven circadian rhythms of BMAL1, GPx4, CAT, GSH, and Bdnf/TrkB factors, were observed in the young rat cerebellum. The rhythms' acrophases show a circadian organization that might be crucial for the daily cerebellar-dependent cognitive functions. Notably, aging disrupted circadian rhythms and the temporal organization of BMAL1, antioxidant defenses, and cognitive Bdnf/TrkB gene expression. Increased oxidative stress and disruption of clock-controlled rhythms during aging, might precede and cause the loss of circadian organization in the aged cerebellum. We expect our results highlight circadian rhythms of the studied factors as new targets for the treatment of age-dependent cerebellar disorders.
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Affiliation(s)
| | - Mariana L Ferramola
- Department of Biochemistry, Faculty of Chemistry, Biochemistry and Pharmacy, National University of San Luis (UNSL), San Luis, Argentina; Laboratory of Chronobiology, IMIBIO-SL (CONICET-UNSL), Argentina.
| | | | - Ethelina Cargnelutti
- Department of Biochemistry, Faculty of Chemistry, Biochemistry and Pharmacy, National University of San Luis (UNSL), San Luis, Argentina; Laboratory of Chronobiology, IMIBIO-SL (CONICET-UNSL), Argentina
| | - Cristina M Devia
- Department of Biochemistry, Faculty of Chemistry, Biochemistry and Pharmacy, National University of San Luis (UNSL), San Luis, Argentina
| | - Silvia M Delgado
- Department of Biochemistry, Faculty of Chemistry, Biochemistry and Pharmacy, National University of San Luis (UNSL), San Luis, Argentina; Laboratory of Chronobiology, IMIBIO-SL (CONICET-UNSL), Argentina
| | - María G Lacoste
- Department of Biochemistry, Faculty of Chemistry, Biochemistry and Pharmacy, National University of San Luis (UNSL), San Luis, Argentina; Laboratory of Chronobiology, IMIBIO-SL (CONICET-UNSL), Argentina
| | - Ana C Anzulovich
- Department of Biochemistry, Faculty of Chemistry, Biochemistry and Pharmacy, National University of San Luis (UNSL), San Luis, Argentina; Laboratory of Chronobiology, IMIBIO-SL (CONICET-UNSL), Argentina.
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4
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Ansarin A, Mahdavi AM, Javadivala Z, Shanehbandi D, Zarredar H, Ansarin K. The cross-talk between leptin and circadian rhythm signaling proteins in physiological processes: a systematic review. Mol Biol Rep 2023; 50:10427-10443. [PMID: 37874505 DOI: 10.1007/s11033-023-08887-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 10/04/2023] [Indexed: 10/25/2023]
Abstract
BACKGROUND Today, modern lifestyles and disrupted sleep patterns cause circadian clock rhythm impairments that are associated with altered leptin levels, which subsequently affect a wide range of physiological processes and have significant health burdens on societies. Nevertheless, there has been no systematic review of circadian clock genes and proteins, leptin, and related signaling pathways. METHODS Accordingly, we systematically reviewed circadian clock proteins, leptin, and molecular mechanisms between them by searching Pubmed, Scopus, ProQuest, Web of Sciences, and Google Scholar until September 2022. After considering the inclusion and exclusion criteria, 20 animal studies were selected. The risk of bias was assessed in each study. RESULTS The results clarified the reciprocal interconnected relationship between circadian clock genes and leptin. Circadian clock genes regulate leptin expression and signaling via different mechanisms, such as CLOCK-BMAL1 heterodimers, which increase the expression of PPARs. PPARs induce the expression of C/EBPα, a key factor in upregulating leptin expression. CLOCK-BMAL1 also induces the expression of Per1 and Rev-erb genes. PER1 activates mTORC1 and mTORC1 enhances the expression of C/EBPα. In addition, REV-ERBs activate the leptin signaling pathway. Also, leptin controls the expression of circadian clock genes by triggering the AMPK and ERK/MAPK signaling pathways, which regulate the activity of PPARs. Moreover, the roles of these molecular mechanisms are elucidated in different physiological processes and organs. CONCLUSIONS Crosstalk between circadian clock genes and leptin and their affecting elements should be considered in the selection of new therapeutic targets for related disorders, especially obesity and metabolic impairments.
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Affiliation(s)
- Atefeh Ansarin
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Pashmineh Research Complex, Daneshgah Street, P.O. Box: 5448151429, Tabriz, Iran
| | - Aida Malek Mahdavi
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Pashmineh Research Complex, Daneshgah Street, P.O. Box: 5448151429, Tabriz, Iran
- Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zeinab Javadivala
- Department of Health Education & Promotion, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Dariush Shanehbandi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Habib Zarredar
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Pashmineh Research Complex, Daneshgah Street, P.O. Box: 5448151429, Tabriz, Iran
| | - Khalil Ansarin
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Pashmineh Research Complex, Daneshgah Street, P.O. Box: 5448151429, Tabriz, Iran.
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5
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Cortés-Espinar AJ, Ibarz-Blanch N, Soliz-Rueda JR, Bonafos B, Feillet-Coudray C, Casas F, Bravo FI, Calvo E, Ávila-Román J, Mulero M. Rhythm and ROS: Hepatic Chronotherapeutic Features of Grape Seed Proanthocyanidin Extract Treatment in Cafeteria Diet-Fed Rats. Antioxidants (Basel) 2023; 12:1606. [PMID: 37627601 PMCID: PMC10452039 DOI: 10.3390/antiox12081606] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 08/02/2023] [Accepted: 08/09/2023] [Indexed: 08/27/2023] Open
Abstract
Polyphenols play a key role in the modulation of circadian rhythms, while the cafeteria diet (CAF) is able to perturb the hepatic biological rhythm and induce important ROS production. Consequently, we aimed to elucidate whether grape seed proanthocyanidin extract (GSPE) administration recovers the CAF-induced hepatic antioxidant (AOX) misalignment and characterize the chronotherapeutic properties of GSPE. For this purpose, Fischer 344 rats were fed a standard diet (STD) or a CAF and concomitantly treated with GSPE at two time-points (ZT0 vs. ZT12). Animals were euthanized every 6 h and the diurnal rhythms of hepatic ROS-related biomarkers, hepatic metabolites, and AOX gene expression were examined. Interestingly, GSPE treatment was able to recover the diurnal rhythm lost due to the CAF. Moreover, GSPE treatment also increased the acrophase of Sod1, as well as bringing the peak closer to that of the STD group. GSPE also corrected some hepatic metabolites altered by the CAF. Importantly, the differences observed at ZT0 vs. ZT12 due to the time of GSPE administration highlight a chronotherapeutic profile on the proanthocyanin effect. Finally, GSPE could also reduce diet-induced hepatic oxidative stress not only by its ROS-scavenging properties but also by retraining the circadian rhythm of AOX enzymes.
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Affiliation(s)
- Antonio J. Cortés-Espinar
- Nutrigenomics Research Group, Department of Biochemistry and Biotechnology, Universitat Rovira i Virgili, 43007 Tarragona, Spain; (A.J.C.-E.); (N.I.-B.); (J.R.S.-R.); (F.I.B.); (E.C.)
- Nutrigenomics Research Group, Institut d’Investigació Sanitària Pere Virgili, 43007 Tarragona, Spain
- DMEM, EMN, UMR 866, INRAe, Université de Montpellier, 34090 Montpellier, France; (B.B.); (C.F.-C.); (F.C.)
| | - Néstor Ibarz-Blanch
- Nutrigenomics Research Group, Department of Biochemistry and Biotechnology, Universitat Rovira i Virgili, 43007 Tarragona, Spain; (A.J.C.-E.); (N.I.-B.); (J.R.S.-R.); (F.I.B.); (E.C.)
- Nutrigenomics Research Group, Institut d’Investigació Sanitària Pere Virgili, 43007 Tarragona, Spain
| | - Jorge R. Soliz-Rueda
- Nutrigenomics Research Group, Department of Biochemistry and Biotechnology, Universitat Rovira i Virgili, 43007 Tarragona, Spain; (A.J.C.-E.); (N.I.-B.); (J.R.S.-R.); (F.I.B.); (E.C.)
- Nutrigenomics Research Group, Institut d’Investigació Sanitària Pere Virgili, 43007 Tarragona, Spain
| | - Béatrice Bonafos
- DMEM, EMN, UMR 866, INRAe, Université de Montpellier, 34090 Montpellier, France; (B.B.); (C.F.-C.); (F.C.)
| | - Christine Feillet-Coudray
- DMEM, EMN, UMR 866, INRAe, Université de Montpellier, 34090 Montpellier, France; (B.B.); (C.F.-C.); (F.C.)
| | - François Casas
- DMEM, EMN, UMR 866, INRAe, Université de Montpellier, 34090 Montpellier, France; (B.B.); (C.F.-C.); (F.C.)
| | - Francisca Isabel Bravo
- Nutrigenomics Research Group, Department of Biochemistry and Biotechnology, Universitat Rovira i Virgili, 43007 Tarragona, Spain; (A.J.C.-E.); (N.I.-B.); (J.R.S.-R.); (F.I.B.); (E.C.)
- Nutrigenomics Research Group, Institut d’Investigació Sanitària Pere Virgili, 43007 Tarragona, Spain
| | - Enrique Calvo
- Nutrigenomics Research Group, Department of Biochemistry and Biotechnology, Universitat Rovira i Virgili, 43007 Tarragona, Spain; (A.J.C.-E.); (N.I.-B.); (J.R.S.-R.); (F.I.B.); (E.C.)
- Nutrigenomics Research Group, Institut d’Investigació Sanitària Pere Virgili, 43007 Tarragona, Spain
| | - Javier Ávila-Román
- Molecular and Applied Pharmacology Group (FARMOLAP), Department of Pharmacology, Universidad de Sevilla, 41012 Sevilla, Spain
| | - Miquel Mulero
- Nutrigenomics Research Group, Department of Biochemistry and Biotechnology, Universitat Rovira i Virgili, 43007 Tarragona, Spain; (A.J.C.-E.); (N.I.-B.); (J.R.S.-R.); (F.I.B.); (E.C.)
- Nutrigenomics Research Group, Institut d’Investigació Sanitària Pere Virgili, 43007 Tarragona, Spain
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6
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Zhang Z, Cheng J, Yang L, Li X, Hua R, Xu D, Jiang Z, Li Q. The role of ferroptosis mediated by Bmal1/Nrf2 in nicotine -induce injury of BTB integrity. Free Radic Biol Med 2023; 200:26-35. [PMID: 36893944 DOI: 10.1016/j.freeradbiomed.2023.02.024] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 02/20/2023] [Accepted: 02/27/2023] [Indexed: 03/09/2023]
Abstract
Nicotine has shown the toxic effects on male reproductive system, and testicular damage is associated with ferroptosis, which is a non-apoptotic regulated cell death driven by iron-dependent lipid peroxidation. However, the role of nicotine on ferroptosis of testicular cells is largely elusive. In the present study, we showed that nicotine destroyed blood-testis barrier (BTB) by interfering with the circadian rhythm of BTB-related factors (ZO-1, N-Cad, Occludin and CX-43) and induced ferroptosis, as reflected via increased clock-control levels of lipid peroxide and decreased ferritin and GPX4, which involved in the circadian. Inhibition of ferroptosis with Fer-1 alleviated nicotine-induced injury of BTB and impaired sperm in vivo. Mechanically, we uncover that the core molecular clock protein, Bmal1, regulates the expression of Nrf2 via direct E-box binding to its promoter to regulate its activity, and nicotine decreases the transcription of Nrf2 through Bmal1 and inactivates Nrf2 pathway and its downstream antioxidant gene, which leads to the imbalance of redox state and ROS accumulation. Intriguingly, nicotine induced lipid peroxidation and subsequent ferroptosis by Bmal1-mediated Nrf2. In conclusion, our study reveals a clear role for the molecular clock in controlling Nrf2 in testis to mediate the ferroptosis induced by nicotine. These findings provide a potential mechanism to prevent smoking and/or cigarette smoke-induced male reproductive injury.
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Affiliation(s)
- Zelin Zhang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, PR China
| | - Jianyong Cheng
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, PR China
| | - Li Yang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, PR China
| | - Xiaoya Li
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, PR China
| | - Rongmao Hua
- College of Pharmacy, Shenzhen Technology University, Shenzhen, 518118, PR China
| | - Dejun Xu
- College of Animal Science and Technology, Southwest University, Beibei, Chongqin, 400715, PR China
| | - Zhongliang Jiang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, PR China.
| | - Qingwang Li
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, PR China.
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7
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Nibbe P, Schleusener J, Siebert S, Borgart R, Brandt D, Westphalen R, Schüler N, Berger B, Peters EMJ, Meinke MC, Lohan SB. Oxidative stress coping capacity (OSC) value: Development and validation of an in vitro measurement method for blood plasma using electron paramagnetic resonance spectroscopy (EPR) and vitamin C. Free Radic Biol Med 2023; 194:230-244. [PMID: 36442587 DOI: 10.1016/j.freeradbiomed.2022.11.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 11/18/2022] [Accepted: 11/22/2022] [Indexed: 11/27/2022]
Abstract
Oxidative stress as a driver of disease is reinforcing the trend towards supplementation with antioxidants. While antioxidants positively influence the redox status when applied at physiological doses, higher concentrations may have pro-oxidative effects. Precise assessment methods for testing the supply of antioxidants are lacking. Using in-situ-irradiation as stressor and electron paramagnetic resonance (EPR) spectroscopy as readout system for formed radicals, a stress response assessment method was developed, using protein solutions and plasma samples from transfusion medicine. The method was validated in a double-blind placebo-controlled in vivo cross-over pilot study in blood plasma samples of individuals before and after vitamin C supplementation. Reference measurements were performed for the exogenous antioxidants β-carotene and vitamin C, and glutathione as an endogenous representative. Malondialdehyde was studied for oxidative stress indication. Protein solutions without antioxidants showed a linear increase in radical concentration during irradiation. The in-vitro-addition of vitamin C or plasma samples from subjects displayed two slopes (m1, m2) for radical production, whereby m1 represented the amount of antioxidants and proteins, m2 only the protein content. These two slopes in combination with the intervening transition area (T) were used to calculate the oxidative stress coping capacity (OSC), which correlated positively with vitamin C concentration in blood plasma, while oxidative stress biomarkers showed only fluctuations within their reference ranges. Furthermore, a selective radical quenching mechanism for vitamin C was observed: the proportion of reactive oxygen species (ROS) in the plasma samples was degraded in dependence to the vitamin C concentration ingested. The proportion of lipid oxygen species (LOS) remained stable while the ascorbyl radical increased with higher vitamin C intake. OSC may represent a sensitive method to detect treatment effects on the redox status in vivo in future validation and treatment studies, and potentially in clinical routine.
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Affiliation(s)
- Pauline Nibbe
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Dermatology, Venereology and Allergology, Center of Experimental and Applied Cutaneous Physiology, Charitéplatz 1, 10117, Berlin, Germany
| | - Johannes Schleusener
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Dermatology, Venereology and Allergology, Center of Experimental and Applied Cutaneous Physiology, Charitéplatz 1, 10117, Berlin, Germany
| | - Silas Siebert
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Dermatology, Venereology and Allergology, Center of Experimental and Applied Cutaneous Physiology, Charitéplatz 1, 10117, Berlin, Germany
| | - Richard Borgart
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Dermatology, Venereology and Allergology, Center of Experimental and Applied Cutaneous Physiology, Charitéplatz 1, 10117, Berlin, Germany
| | - Doreen Brandt
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Dermatology, Venereology and Allergology, Center of Experimental and Applied Cutaneous Physiology, Charitéplatz 1, 10117, Berlin, Germany
| | - Ronja Westphalen
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Dermatology, Venereology and Allergology, Center of Experimental and Applied Cutaneous Physiology, Charitéplatz 1, 10117, Berlin, Germany
| | - Nadine Schüler
- Freiberg Instruments GmbH, Delfter Str. 6, 09599, Freiberg, Germany
| | - Bastian Berger
- Freiberg Instruments GmbH, Delfter Str. 6, 09599, Freiberg, Germany
| | - Eva M J Peters
- Justus-Liebig-Universität Giessen, Department of Psychosomatic Medicine and Psychotherapy, Psychoneuroimmunology Laboratory, Aulweg 123, 35390, Gießen, Germany; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charité Center 12 (CC12) for Internal Medicine and Dermatology, Charitéplatz 1, 10117, Berlin, Germany
| | - Martina C Meinke
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Dermatology, Venereology and Allergology, Center of Experimental and Applied Cutaneous Physiology, Charitéplatz 1, 10117, Berlin, Germany
| | - Silke B Lohan
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Dermatology, Venereology and Allergology, Center of Experimental and Applied Cutaneous Physiology, Charitéplatz 1, 10117, Berlin, Germany.
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8
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Mezhnina V, Ebeigbe OP, Poe A, Kondratov RV. Circadian Control of Mitochondria in Reactive Oxygen Species Homeostasis. Antioxid Redox Signal 2022; 37:647-663. [PMID: 35072523 PMCID: PMC9587791 DOI: 10.1089/ars.2021.0274] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 01/06/2022] [Indexed: 12/11/2022]
Abstract
Significance: Mitochondria produce most of the cellular ATP through the process of oxidative phosphorylation. Energy metabolism in the mitochondria is associated with the production of reactive oxygen species (ROS). Excessive ROS production leads to oxidative stress and compromises cellular physiology. Energy metabolism in the mitochondria depends on nutrient flux and cellular metabolic needs, which are in turn connected with the feeding/fasting cycle. In animals, the feeding/fasting cycle is controlled by the circadian clock that generates 24-h rhythms in behavior, metabolism, and signaling. Recent Advances: Here, we discuss the role of the circadian clock and rhythms in mitochondria on ROS homeostasis. The circadian clock is involved in mitochondrial ROS production and detoxification through the control of nutrient flux and oxidation, uncoupling, antioxidant defense, and mitochondrial dynamics. Critical Issues: Little is known on the molecular mechanisms of circadian control of mitochondrial functions. The circadian clock regulates the expression and activity of mitochondrial metabolic and antioxidant enzymes. The regulation involves a direct transcriptional control by Circadian Locomotor Output Cycles Kaput/brain and muscle ARNT-like 1(CLOCK/BMAL1), nuclear factor erythroid-2-related factor 2 (NRF2) transcriptional network, and sirtuin-dependent posttranslational protein modifications. Future Perspectives: We hypothesize that the circadian clock orchestrates mitochondrial physiology to synchronize it with the feeding/fasting cycle. Circadian coordination of mitochondrial function couples energy metabolism with diets and contributes to antioxidant defense to prevent metabolic diseases and delay aging. Antioxid. Redox Signal. 37, 647-663.
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Affiliation(s)
- Volha Mezhnina
- Department of Biological, Geological, and Environmental Sciences and Center for Gene Regulation in Health and Disease, Cleveland State University, Cleveland, Ohio, USA
| | - Oghogho P. Ebeigbe
- Department of Biological, Geological, and Environmental Sciences and Center for Gene Regulation in Health and Disease, Cleveland State University, Cleveland, Ohio, USA
| | - Allan Poe
- Department of Biological, Geological, and Environmental Sciences and Center for Gene Regulation in Health and Disease, Cleveland State University, Cleveland, Ohio, USA
| | - Roman V. Kondratov
- Department of Biological, Geological, and Environmental Sciences and Center for Gene Regulation in Health and Disease, Cleveland State University, Cleveland, Ohio, USA
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Chhunchha B, Kubo E, Singh DP. Obligatory Role of AMPK Activation and Antioxidant Defense Pathway in the Regulatory Effects of Metformin on Cellular Protection and Prevention of Lens Opacity. Cells 2022; 11:3021. [PMID: 36230981 PMCID: PMC9563310 DOI: 10.3390/cells11193021] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 09/15/2022] [Accepted: 09/21/2022] [Indexed: 11/18/2022] Open
Abstract
Increasing levels of oxidative-stress due to deterioration of the Nrf2 (NFE2-related factor)/ARE (antioxidant response element) pathway is found to be a primary cause of aging pathobiology. Metformin having anti-aging effects can delay/halt aging-related diseases. Herein, using lens epithelial cell lines (LECs) of human (h) or mouse (m) and aging h/m primary LECs along with lenses as model systems, we demonstrated that Metformin could correct deteriorated Bmal1/Nrf2/ARE pathway by reviving AMPK-activation, and transcriptional activities of Bmal1/Nrf2, resulting in increased antioxidants enzymatic activity and expression of Phase II enzymes. This ensued reactive oxygen species (ROS) mitigation with cytoprotection and prevention of lens opacity in response to aging/oxidative stress. It was intriguing to observe that Metformin internalized lens/LECs and upregulated OCTs (Organic Cation Transporters). Mechanistically, we found that Metformin evoked AMPK activation-dependent increase of Bmal1, Nrf2, and antioxidants transcription by promoting direct E-Box and ARE binding of Bmal1 and Nrf2 to the promoters. Loss-of-function and disruption of E-Box/ARE identified that Metformin acted by increasing Bmal1/Nrf2-mediated antioxidant expression. Data showed that AMPK-activation was a requisite for Bmal1/Nrf2-antioxidants-mediated defense, as pharmacologically inactivating AMPK impeded the Metformin's effect. Collectively, the results for the first-time shed light on the hitherto incompletely uncovered crosstalk between the AMPK and Bmal1/Nrf2/antioxidants mediated by Metformin for blunting oxidative/aging-linked pathobiology.
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Affiliation(s)
- Bhavana Chhunchha
- Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Eri Kubo
- Department of Ophthalmology, Kanazawa Medical University, Ishikawa 9200293, Japan
| | - Dhirendra P. Singh
- Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA
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10
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Baba K, Suen TC, Goyal V, Stowie A, Davidson A, DeBruyne J, Tosini G. The circadian clock mediates the response to oxidative stress in a cone photoreceptor‒like (661W) cell line via regulation of glutathione peroxidase activity. F1000Res 2022; 11:1072. [PMID: 36405557 PMCID: PMC9639596 DOI: 10.12688/f1000research.125133.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/05/2022] [Indexed: 06/26/2024] Open
Abstract
Background: The mammalian retina contains an autonomous circadian clock that controls many physiological functions within this tissue. Our previous studies have indicated that disruption of this circadian clock by removing Bmal1 from the retina affects the visual function, retinal circuitry, and cone photoreceptor viability during aging. In the present study, we employed a mouse-derived cone photoreceptor‒like cell, 661W, to investigate which molecular mechanisms of the circadian clock may modulate cone photoreceptor viability during aging. Methods: Bmal1 knockout (BKO) cells were generated from 661W cells using the CRISPR/Cas9 gene editing tool. Deletion of Bmal1 from 661W was verified by western blot and monitoring Per2-luc bioluminescence circadian rhythms. To investigate the effect of Bmal1 removal on an oxidative stress challenge, cells were treated with hydrogen peroxide (H 2O 2,1 mM) for two hours and then cell viability was assessed. Cells were also cultured and harvested for gene expression analysis and antioxidant assay. Results: Our data indicated that 661W cells contain a functional circadian clock that mediates the response to an oxidative stress challenge in vitro and that such a response is no longer present in the BKO cell. We also hypothesized that the effect was due to the circadian regulation of the intracellular antioxidant defense mechanism. Our results indicated that in 661W cells, the antioxidant defense mechanism is under circadian control, whereas in BKO cells, there is an overall reduction in this antioxidant defense mechanism, and it is no longer under circadian control. Conclusions: Our work supported the notion that the presence of a functional circadian clock and its ability to modulate the response to an oxidative stress is the underlying mechanism that may protect cones during aging.
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Affiliation(s)
- Kenkichi Baba
- Department of Pharmacology and Toxicology, Morehouse School of Medicine, Atlanta, Georgia, 30310, USA
- Neuroscience Institute, Morehouse School of Medicine, Atlanta, Georgia, 30310, USA
| | - Ting-Chung Suen
- Department of Pharmacology and Toxicology, Morehouse School of Medicine, Atlanta, Georgia, 30310, USA
- Neuroscience Institute, Morehouse School of Medicine, Atlanta, Georgia, 30310, USA
| | - Varunika Goyal
- Department of Pharmacology and Toxicology, Morehouse School of Medicine, Atlanta, Georgia, 30310, USA
- Neuroscience Institute, Morehouse School of Medicine, Atlanta, Georgia, 30310, USA
| | - Adam Stowie
- Neuroscience Institute, Morehouse School of Medicine, Atlanta, Georgia, 30310, USA
- Department of Neurobiology, Morehouse School of Medicine, Atlanta, Georgia, 30310, USA
| | - Alec Davidson
- Neuroscience Institute, Morehouse School of Medicine, Atlanta, Georgia, 30310, USA
- Department of Neurobiology, Morehouse School of Medicine, Atlanta, Georgia, 30310, USA
| | - Jason DeBruyne
- Department of Pharmacology and Toxicology, Morehouse School of Medicine, Atlanta, Georgia, 30310, USA
- Neuroscience Institute, Morehouse School of Medicine, Atlanta, Georgia, 30310, USA
| | - Gianluca Tosini
- Department of Pharmacology and Toxicology, Morehouse School of Medicine, Atlanta, Georgia, 30310, USA
- Neuroscience Institute, Morehouse School of Medicine, Atlanta, Georgia, 30310, USA
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11
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Baba K, Suen TC, Goyal V, Stowie A, Davidson A, DeBruyne J, Tosini G. The circadian clock mediates the response to oxidative stress in a cone photoreceptor‒like (661W) cell line via regulation of glutathione peroxidase activity. F1000Res 2022; 11:1072. [PMID: 36405557 PMCID: PMC9639596 DOI: 10.12688/f1000research.125133.2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/16/2022] [Indexed: 11/23/2022] Open
Abstract
Background: The mammalian retina contains an autonomous circadian clock that controls many physiological functions within this tissue. Our previous studies have indicated that disruption of this circadian clock by removing Bmal1 from the retina affects the visual function, retinal circuitry, and cone photoreceptor viability during aging. In the present study, we employed a mouse-derived cone photoreceptor‒like cell, 661W, to investigate which molecular mechanisms of the circadian clock may modulate cone photoreceptor viability during aging. Methods: Bmal1 knockout (BKO) cells were generated from 661W cells using the CRISPR/Cas9 gene editing tool. Deletion of Bmal1 from 661W was verified by western blot and monitoring Per2-luc bioluminescence circadian rhythms. To investigate the effect of Bmal1 removal on an oxidative stress challenge, cells were treated with hydrogen peroxide (H 2O 2,1 mM) for two hours and then cell viability was assessed. Cells were also cultured and harvested for gene expression analysis and antioxidant assay. Results: Our data indicated that 661W cells contain a functional circadian clock that mediates the response to an oxidative stress challenge in vitro and that such a response is no longer present in the BKO cell. We also hypothesized that the effect was due to the circadian regulation of the intracellular antioxidant defense mechanism. Our results revealed that in 661W cells, the antioxidant defense mechanism showed time dependent variation , whereas in BKO cells, there was an overall reduction in this antioxidant defense mechanism, and it no longer showed time dependent variation. Conclusions: Our work supported the notion that the presence of a functional circadian clock and its ability to modulate the response to an oxidative stress is the underlying mechanism that may protect cones during aging.
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Affiliation(s)
- Kenkichi Baba
- Department of Pharmacology and Toxicology, Morehouse School of Medicine, Atlanta, Georgia, 30310, USA
- Neuroscience Institute, Morehouse School of Medicine, Atlanta, Georgia, 30310, USA
| | - Ting-Chung Suen
- Department of Pharmacology and Toxicology, Morehouse School of Medicine, Atlanta, Georgia, 30310, USA
- Neuroscience Institute, Morehouse School of Medicine, Atlanta, Georgia, 30310, USA
| | - Varunika Goyal
- Department of Pharmacology and Toxicology, Morehouse School of Medicine, Atlanta, Georgia, 30310, USA
- Neuroscience Institute, Morehouse School of Medicine, Atlanta, Georgia, 30310, USA
| | - Adam Stowie
- Neuroscience Institute, Morehouse School of Medicine, Atlanta, Georgia, 30310, USA
- Department of Neurobiology, Morehouse School of Medicine, Atlanta, Georgia, 30310, USA
| | - Alec Davidson
- Neuroscience Institute, Morehouse School of Medicine, Atlanta, Georgia, 30310, USA
- Department of Neurobiology, Morehouse School of Medicine, Atlanta, Georgia, 30310, USA
| | - Jason DeBruyne
- Department of Pharmacology and Toxicology, Morehouse School of Medicine, Atlanta, Georgia, 30310, USA
- Neuroscience Institute, Morehouse School of Medicine, Atlanta, Georgia, 30310, USA
| | - Gianluca Tosini
- Department of Pharmacology and Toxicology, Morehouse School of Medicine, Atlanta, Georgia, 30310, USA
- Neuroscience Institute, Morehouse School of Medicine, Atlanta, Georgia, 30310, USA
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12
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de Jesus DS, Bargi-Souza P, Cruzat V, Yechoor V, Carpinelli AR, Peliciari-Garcia RA. BMAL1 modulates ROS generation and insulin secretion in pancreatic β-cells: An effect possibly mediated via NOX2. Mol Cell Endocrinol 2022; 555:111725. [PMID: 35868425 DOI: 10.1016/j.mce.2022.111725] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 07/11/2022] [Accepted: 07/12/2022] [Indexed: 12/15/2022]
Abstract
The pancreatic β cells circadian clock plays a relevant role in glucose metabolism. NADPH oxidase (NOX) family is responsible for producing reactive oxygen species (ROS), such as superoxide anion and hydrogen peroxide, using NADPH as an electron donor. In pancreatic β-cells, NOX-derived ROS inhibits basal and glucose-stimulated insulin secretion. Thus, we hypothesized that the absence of BMAL1, a core circadian clock component, could trigger an increase of NOX2-derived ROS in pancreatic β cells, inhibiting insulin secretion under basal and stimulated glucose conditions. To test such hypothesis, Bmal1 knockdown (KD) was performed in cultured clonal β-cell line (INS-1E) and knocked out in isolated pancreatic islets, using a tissue-specific β-cells Bmal1 knockout (KO) mice. The insulin secretion was assessed in the presence of NOX inhibitors. The Bmal1 KD within INS-1E cells elicited a rise of intracellular ROS content under both glucose stimuli (2.8 mM and 16.7 mM), associated with an increase in Nox2 expression. Additionally, alterations of glutathione levels, CuZnSOD and catalase activities, reduction of ATP/ADP ratio, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and aconitase activities, followed by glucokinase and Slc2a2 (Glut2) expression were also observed in INS-1E β-cells, reflecting in a diminished insulin secretion pattern. The isolated islets from β-cell Bmal1-/- mice have shown a similar cellular response, where an increased NOX2-derived ROS content and a reduced basal- and glucose-stimulated insulin secretion were observed. Therefore, together with NOX inhibition (Apocynin), polyethene-glycol linked to superoxide dismutase (PEG-SOD), phorbol myristate acetate (PMA), and diethyldithiocarbamate (DDC) data, our findings suggest a possible BMAL1-mediated NOX2-derived ROS generation in pancreatic β cells, leading to the modulation of both basal- and glucose-stimulated insulin secretion.
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Affiliation(s)
- Daniel Simoes de Jesus
- Department of Physiology and Biophysics, Institute of Biomedical Science, University of São Paulo, São Paulo (USP), SP, Brazil; Centre for Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London, UK
| | - Paula Bargi-Souza
- Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
| | - Vinicius Cruzat
- Faculty of Health, Torrens University, Melbourne, Victoria, Australia
| | - Vijay Yechoor
- Diabetes and Beta Cell Biology Center, Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, USA
| | - Angelo Rafael Carpinelli
- Department of Physiology and Biophysics, Institute of Biomedical Science, University of São Paulo, São Paulo (USP), SP, Brazil
| | - Rodrigo Antonio Peliciari-Garcia
- Department of Biological Sciences, Morphophysiology and Pathology Sector, Federal University of São Paulo (UNIFESP), Diadema, SP, Brazil.
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13
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Couchie D, Medali T, Diderot V, Raymondjean M, Friguet B, Rouis M. Circadian rhythmicity of the thioredoxin system in cultured murine peritoneal macrophages. Biochimie 2022; 198:76-85. [PMID: 35341928 DOI: 10.1016/j.biochi.2022.03.006] [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: 01/25/2022] [Revised: 03/15/2022] [Accepted: 03/22/2022] [Indexed: 11/16/2022]
Abstract
Macrophages play a pivotal role in atherosclerosis through a variety of events related to cellular oxidative stress. This process is mainly due to an excessive production of reactive oxygen species whose elimination occurs through antioxidant systems including the thioredoxin (Trx) system. In this paper, we investigated whether the Trx system would exhibit circadian rhythmicity in dexamethasone synchronized cultured macrophages and monitored the impact of the rhythmicity of Trx-1 on markers of atherosclerosis. We found that the clock-related genes BMAL-1, PER-2, CRY-1 and REV ERB α exhibited a robust circadian expression. However, the Trx genes family (Trx-1, Trx-2, TrxR1 and TXNIP) did not exhibit a circadian expression at the mRNA level in spite of the presence of E-box elements within the promoter regions of TrxR1 and TXNIP genes. Nevertheless, both Trx-1 and TXNIP exhibited a circadian expression at the protein level and proteasome inhibition abolished the rhythmicity of Trx-1. Moreover, we found a link between low Trx-1 level and elevated atherogenic markers such as 4-HNE, TNF-α and cholesterol accumulation in macrophages. Our results indicate that the Trx gene family does not exhibit the same circadian regulation and that the presence of E-box elements in the TXNIP promoter is not sufficient to ensure a circadian rhythmicity at the transcriptional level. In addition, since a link was found between a low level of Trx-1 protein during circadian rhythm and high levels of atherogenic markers, administration of Trx-1 at certain time points could be an interesting approach to protect against atherosclerosis development.
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Affiliation(s)
- D Couchie
- Sorbonne Université, CNRS, INSERM, Institut de Biologie Paris Seine, Biological Adaptation and Ageing (B2A-IBPS), F-75005, Paris, France
| | - T Medali
- Sorbonne Université, CNRS, INSERM, Institut de Biologie Paris Seine, Biological Adaptation and Ageing (B2A-IBPS), F-75005, Paris, France
| | - V Diderot
- Sorbonne Université, CNRS, INSERM, Institut de Biologie Paris Seine, Biological Adaptation and Ageing (B2A-IBPS), F-75005, Paris, France
| | - M Raymondjean
- Sorbonne Université, CNRS, INSERM, Institut de Biologie Paris Seine, Biological Adaptation and Ageing (B2A-IBPS), F-75005, Paris, France
| | - B Friguet
- Sorbonne Université, CNRS, INSERM, Institut de Biologie Paris Seine, Biological Adaptation and Ageing (B2A-IBPS), F-75005, Paris, France
| | - M Rouis
- Sorbonne Université, CNRS, INSERM, Institut de Biologie Paris Seine, Biological Adaptation and Ageing (B2A-IBPS), F-75005, Paris, France.
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14
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McClean C, Davison GW. Circadian Clocks, Redox Homeostasis, and Exercise: Time to Connect the Dots? Antioxidants (Basel) 2022; 11:antiox11020256. [PMID: 35204138 PMCID: PMC8868136 DOI: 10.3390/antiox11020256] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 01/11/2022] [Accepted: 01/18/2022] [Indexed: 12/14/2022] Open
Abstract
Compelling research has documented how the circadian system is essential for the maintenance of several key biological processes including homeostasis, cardiovascular control, and glucose metabolism. Circadian clock disruptions, or losses of rhythmicity, have been implicated in the development of several diseases, premature ageing, and are regarded as health risks. Redox reactions involving reactive oxygen and nitrogen species (RONS) regulate several physiological functions such as cell signalling and the immune response. However, oxidative stress is associated with the pathological effects of RONS, resulting in a loss of cell signalling and damaging modifications to important molecules such as DNA. Direct connections have been established between circadian rhythms and oxidative stress on the basis that disruptions to circadian rhythms can affect redox biology, and vice versa, in a bi-directional relationship. For instance, the expression and activity of several key antioxidant enzymes (SOD, GPx, and CAT) appear to follow circadian patterns. Consequently, the ability to unravel these interactions has opened an exciting area of redox biology. Exercise exerts numerous benefits to health and, as a potent environmental cue, has the capacity to adjust disrupted circadian systems. In fact, the response to a given exercise stimulus may also exhibit circadian variation. At the same time, the relationship between exercise, RONS, and oxidative stress has also been scrutinised, whereby it is clear that exercise-induced RONS can elicit both helpful and potentially harmful health effects that are dependent on the type, intensity, and duration of exercise. To date, it appears that the emerging interface between circadian rhythmicity and oxidative stress/redox metabolism has not been explored in relation to exercise. This review aims to summarise the evidence supporting the conceptual link between the circadian clock, oxidative stress/redox homeostasis, and exercise stimuli. We believe carefully designed investigations of this nexus are required, which could be harnessed to tackle theories concerned with, for example, the existence of an optimal time to exercise to accrue physiological benefits.
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Bevinakoppamath S, Ramachandra SC, Yadav AK, Basavaraj V, Vishwanath P, Prashant A. Understanding the Emerging Link Between Circadian Rhythm, Nrf2 Pathway, and Breast Cancer to Overcome Drug Resistance. Front Pharmacol 2022; 12:719631. [PMID: 35126099 PMCID: PMC8807567 DOI: 10.3389/fphar.2021.719631] [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: 06/02/2021] [Accepted: 12/27/2021] [Indexed: 12/12/2022] Open
Abstract
The levels of different molecules in the cell are rhythmically cycled by the molecular clock present at the cellular level. The circadian rhythm is closely linked to the metabolic processes in the cells by an underlying mechanism whose intricacies need to be thoroughly investigated. Nevertheless, Nrf2 has been identified as an essential bridge between the circadian clock and cellular metabolism and is activated by the by-product of cellular metabolism like hydrogen peroxide. Once activated it binds to the specific DNA segments and increases the transcription of several genes that play a crucial role in the normal functioning of the cell. The central clock located in the suprachiasmatic nucleus of the anterior hypothalamus synchronizes the timekeeping in the peripheral tissues by integrating the light-dark input from the environment. Several studies have demonstrated the role of circadian rhythm as an effective tumor suppressor. Tumor development is triggered by the stimulation or disruption of signaling pathways at the cellular level as a result of the interaction between cells and environmental stimuli. Oxidative stress is one such external stimulus that disturbs the prooxidant/antioxidant equilibrium due to the loss of control over signaling pathways which destroy the bio-molecules. Altered Nrf2 expression and impaired redox balance are associated with various cancers suggesting that Nrf2 targeting may be used as a novel therapeutic approach for treating cancers. On the other hand, Nrf2 has also been shown to enhance the resistance of cancer cells to chemotherapeutic agents. We believe that maximum efficacy with minimum side effects for any particular therapy can be achieved if the treatment strategy regulates the circadian rhythm. In this review, we discuss the various molecular mechanisms interlinking the circadian rhythm with the Nrf2 pathway and contributing to breast cancer pathogenesis, we also talk about how these two pathways work in close association with the cell cycle which is another oscillatory system, and whether this interplay can be exploited to overcome drug resistance during chemotherapy.
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Affiliation(s)
- Supriya Bevinakoppamath
- Center of Excellence in Molecular Biology and Regenerative Medicine, Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education and Research, Mysore, India
| | - Shobha Chikkavaddaragudi Ramachandra
- Center of Excellence in Molecular Biology and Regenerative Medicine, Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education and Research, Mysore, India
| | - Anshu Kumar Yadav
- Center of Excellence in Molecular Biology and Regenerative Medicine, Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education and Research, Mysore, India
| | - Vijaya Basavaraj
- Department of Pathology, JSS Medical College, JSS Academy of Higher Education and Research, Mysore, India
| | - Prashant Vishwanath
- Center of Excellence in Molecular Biology and Regenerative Medicine, Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education and Research, Mysore, India
| | - Akila Prashant
- Center of Excellence in Molecular Biology and Regenerative Medicine, Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education and Research, Mysore, India
- Special Interest Group-Human Genomics and Rare Disorders, JSS Academy of Higher Education and Research, Mysore, India
- *Correspondence: Akila Prashant,
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16
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Chen WH, Huang QY, Wang ZY, Zhuang XX, Lin S, Shi QY. Therapeutic potential of exosomes/miRNAs in polycystic ovary syndrome induced by the alteration of circadian rhythms. Front Endocrinol (Lausanne) 2022; 13:918805. [PMID: 36465652 PMCID: PMC9709483 DOI: 10.3389/fendo.2022.918805] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 10/19/2022] [Indexed: 11/17/2022] Open
Abstract
Polycystic ovary syndrome (PCOS) is a reproductive dysfunction associated with endocrine disorders and is most common in women of reproductive age. Clinical and/or biochemical manifestations include hyperandrogenism, persistent anovulation, polycystic ovary, insulin resistance, and obesity. Presently, the aetiology and pathogenesis of PCOS remain unclear. In recent years, the role of circadian rhythm changes in PCOS has garnered considerable attention. Changes in circadian rhythm can trigger PCOS through mechanisms such as oxidative stress and inflammation; however, the specific mechanisms are unclear. Exosomes are vesicles with sizes ranging from 30-120nm that mediate intercellular communication by transporting microRNAs (miRNAs), proteins, mRNAs, DNA, or lipids to target cells and are widely involved in the regulation of various physiological and pathological processes. Circadian rhythm can alter circulating exosomes, leading to a series of related changes and physiological dysfunctions. Therefore, we speculate that circadian rhythm-induced changes in circulating exosomes may be involved in PCOS pathogenesis. In this review, we summarize the possible roles of exosomes and their derived microRNAs in the occurrence and development of PCOS and discuss their possible mechanisms, providing insights into the potential role of exosomes for PCOS treatment.
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Affiliation(s)
- Wei-hong Chen
- Department of Gynaecology and Obstetrics, the Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Qiao-yi Huang
- Department of Gynaecology and Obstetrics, the Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Zhi-yi Wang
- Department of Gynaecology and Obstetrics, the Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Xuan-xuan Zhuang
- Department of Gynaecology and Obstetrics, the Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Shu Lin
- Centre of Neurological and Metabolic Research, the Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
- Group of Neuroendocrinology, Garvan Institute of Medical Research, Sydney, NSW, Australia
- *Correspondence: Qi-yang Shi, ; Shu Lin,
| | - Qi-yang Shi
- Department of Gynaecology and Obstetrics, the Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
- *Correspondence: Qi-yang Shi, ; Shu Lin,
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17
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Aging disrupts the temporal organization of antioxidant defenses in the heart of male rats and phase shifts circadian rhythms of systolic blood pressure. Biogerontology 2021; 22:603-621. [PMID: 34554336 DOI: 10.1007/s10522-021-09938-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 09/14/2021] [Indexed: 12/26/2022]
Abstract
Aging is one of the main risk factors for cardiovascular diseases, and oxidative stress is a key element responsible for the development of age-related pathologies. In addition, the alteration of circadian rhythms also contributes to cardiovascular pathology, but the underlying mechanisms are not well defined. We investigated the aging consequences on the temporal patterns of antioxidant defenses, the molecular clock machinery, and the blood pressure, in the heart of male rats maintained under constant darkness (free running) conditions. Male Holtzman rats from young adult (3-month-old) and older (22-month-old) groups were maintained under constant darkness (12-h dark:12-h dark, DD) condition during fifteen days before the experiment. After the DD period, heart ventricle samples were isolated every 4-h throughout a 24-h period. We observed circadian rhythms of catalase (CAT) and glutathione peroxidase (GPx) mRNA expression, as well as ultradian rhythms of Nrf2 mRNA levels, in the heart of young adult rats. We also found circadian oscillations of CAT and GPx enzymatic activities, reduced glutathione (GSH) and BMAL1 protein in the same group. Interestingly, aging abolished the rhythms of CAT and GPx enzymatic activities, phase-shifted the rhythm's acrophases of GSH and BMAL1 protein levels and turned circadian the ultradian oscillation of Nrf2 expression. Moreover, aging phase-shifted the circadian pattern of systolic blood pressure. In conclusion, aging modifies the temporal organization of antioxidant defenses and blood pressure, probably, as a consequence of a disruption in the circadian rhythm of the clock's transcriptional regulator, BMAL1, in heart.
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Shilovsky GA, Putyatina TS, Morgunova GV, Seliverstov AV, Ashapkin VV, Sorokina EV, Markov AV, Skulachev VP. A Crosstalk between the Biorhythms and Gatekeepers of Longevity: Dual Role of Glycogen Synthase Kinase-3. BIOCHEMISTRY (MOSCOW) 2021; 86:433-448. [PMID: 33941065 PMCID: PMC8033555 DOI: 10.1134/s0006297921040052] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
This review discusses genetic and molecular pathways that link circadian timing with metabolism, resulting in the emergence of positive and negative regulatory feedback loops. The Nrf2 pathway is believed to be a component of the anti-aging program responsible for the healthspan and longevity. Nrf2 enables stress adaptation by activating cell antioxidant defense and other metabolic processes via control of expression of over 200 target genes in response to various types of stress. The GSK3 system represents a “regulating valve” that controls fine oscillations in the Nrf2 level, unlike Keap1, which prevents significant changes in the Nrf2 content in the absence of oxidative stress and which is inactivated by the oxidative stress. Furthermore, GSK3 modifies core circadian clock proteins (Bmal1, Clock, Per, Cry, and Rev-erbα). Phosphorylation by GSK3 leads to the inactivation and degradation of circadian rhythm-activating proteins (Bmal1 and Clock) and vice versa to the activation and nuclear translocation of proteins suppressing circadian rhythms (Per and Rev-erbα) with the exception of Cry protein, which is likely to be implicated in the fine tuning of biological clock. Functionally, GSK3 appears to be one of the hubs in the cross-regulation of circadian rhythms and antioxidant defense. Here, we present the data on the crosstalk between the most powerful cell antioxidant mechanism, the Nrf2 system, and the biorhythm-regulating system in mammals, including the impact of GSK3 overexpression and knockout on the Nrf2 signaling. Understanding the interactions between the regulatory cascades linking homeostasis maintenance and cell response to oxidative stress will help in elucidating molecular mechanisms that underlie aging and longevity.
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Affiliation(s)
- Gregory A Shilovsky
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119991, Russia. .,Faculty of Biology, Lomonosov Moscow State University, Moscow, 119234, Russia.,Institute for Information Transmission Problems, Russian Academy of Sciences, Moscow, 127051, Russia
| | - Tatyana S Putyatina
- Faculty of Biology, Lomonosov Moscow State University, Moscow, 119234, Russia
| | - Galina V Morgunova
- Faculty of Biology, Lomonosov Moscow State University, Moscow, 119234, Russia
| | - Alexander V Seliverstov
- Institute for Information Transmission Problems, Russian Academy of Sciences, Moscow, 127051, Russia
| | - Vasily V Ashapkin
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119991, Russia
| | - Elena V Sorokina
- Faculty of Biology, Lomonosov Moscow State University, Moscow, 119234, Russia
| | - Alexander V Markov
- Faculty of Biology, Lomonosov Moscow State University, Moscow, 119234, Russia
| | - Vladimir P Skulachev
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119991, Russia
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Oxidative Dysregulation in Early Life Stress and Posttraumatic Stress Disorder: A Comprehensive Review. Brain Sci 2021; 11:brainsci11060723. [PMID: 34072322 PMCID: PMC8228973 DOI: 10.3390/brainsci11060723] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 05/24/2021] [Accepted: 05/26/2021] [Indexed: 12/30/2022] Open
Abstract
Traumatic stress may chronically affect master homeostatic systems at the crossroads of peripheral and central susceptibility pathways and lead to the biological embedment of trauma-related allostatic trajectories through neurobiological alterations even decades later. Lately, there has been an exponential knowledge growth concerning the effect of traumatic stress on oxidative components and redox-state homeostasis. This extensive review encompasses a detailed description of the oxidative cascade components along with their physiological and pathophysiological functions and a systematic presentation of both preclinical and clinical, genetic and epigenetic human findings on trauma-related oxidative stress (OXS), followed by a substantial synthesis of the involved oxidative cascades into specific and functional, trauma-related pathways. The bulk of the evidence suggests an imbalance of pro-/anti-oxidative mechanisms under conditions of traumatic stress, respectively leading to a systemic oxidative dysregulation accompanied by toxic oxidation byproducts. Yet, there is substantial heterogeneity in findings probably relative to confounding, trauma-related parameters, as well as to the equivocal directionality of not only the involved oxidative mechanisms but other homeostatic ones. Accordingly, we also discuss the trauma-related OXS findings within the broader spectrum of systemic interactions with other major influencing systems, such as inflammation, the hypothalamic-pituitary-adrenal axis, and the circadian system. We intend to demonstrate the inherent complexity of all the systems involved, but also put forth associated caveats in the implementation and interpretation of OXS findings in trauma-related research and promote their comprehension within a broader context.
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20
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de Assis LVM, Oster H. The circadian clock and metabolic homeostasis: entangled networks. Cell Mol Life Sci 2021; 78:4563-4587. [PMID: 33683376 PMCID: PMC8195959 DOI: 10.1007/s00018-021-03800-2] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/28/2021] [Accepted: 02/23/2021] [Indexed: 12/12/2022]
Abstract
The circadian clock exerts an important role in systemic homeostasis as it acts a keeper of time for the organism. The synchrony between the daily challenges imposed by the environment needs to be aligned with biological processes and with the internal circadian clock. In this review, it is provided an in-depth view of the molecular functioning of the circadian molecular clock, how this system is organized, and how central and peripheral clocks communicate with each other. In this sense, we provide an overview of the neuro-hormonal factors controlled by the central clock and how they affect peripheral tissues. We also evaluate signals released by peripheral organs and their effects in the central clock and other brain areas. Additionally, we evaluate a possible communication between peripheral tissues as a novel layer of circadian organization by reviewing recent studies in the literature. In the last section, we analyze how the circadian clock can modulate intracellular and tissue-dependent processes of metabolic organs. Taken altogether, the goal of this review is to provide a systemic and integrative view of the molecular clock function and organization with an emphasis in metabolic tissues.
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Affiliation(s)
| | - Henrik Oster
- Center of Brain, Behavior and Metabolism, University of Lübeck, Institute of Neurobiology, Marie Curie Street, 23562, Lübeck, Germany.
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21
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Patel SA, Kondratov RV. Clock at the Core of Cancer Development. BIOLOGY 2021; 10:150. [PMID: 33672910 PMCID: PMC7918730 DOI: 10.3390/biology10020150] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 02/08/2021] [Accepted: 02/11/2021] [Indexed: 12/29/2022]
Abstract
To synchronize various biological processes with the day and night cycle, most organisms have developed circadian clocks. This evolutionarily conserved system is important in the temporal regulation of behavior, physiology and metabolism. Multiple pathological changes associated with circadian disruption support the importance of the clocks in mammals. Emerging links have revealed interplay between circadian clocks and signaling networks in cancer. Understanding the cross-talk between the circadian clock and tumorigenesis is imperative for its prevention, management and development of effective treatment options. In this review, we summarize the role of the circadian clock in regulation of one important metabolic pathway, insulin/IGF1/PI3K/mTOR signaling, and how dysregulation of this metabolic pathway could lead to uncontrolled cancer cell proliferation and growth. Targeting the circadian clock and rhythms either with recently discovered pharmaceutical agents or through environmental cues is a new direction in cancer chronotherapy. Combining the circadian approach with traditional methods, such as radiation, chemotherapy or the recently developed, immunotherapy, may improve tumor response, while simultaneously minimizing the adverse effects commonly associated with cancer therapies.
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Affiliation(s)
- Sonal A. Patel
- Fusion Pharmaceuticals Inc., Hamilton, ON L8P 0A6, Canada;
- Department of Biological, Geological and Environmental Sciences, Cleveland State University, Cleveland, OH 44115, USA
| | - Roman V. Kondratov
- Department of Biological, Geological and Environmental Sciences, Cleveland State University, Cleveland, OH 44115, USA
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22
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Circadian Deregulation as Possible New Player in Pollution-Induced Tissue Damage. ATMOSPHERE 2021. [DOI: 10.3390/atmos12010116] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Circadian rhythms are 24-h oscillations driven by a hypothalamic master oscillator that entrains peripheral clocks in almost all cells, tissues and organs. Circadian misalignment, triggered by industrialization and modern lifestyles, has been linked to several pathological conditions, with possible impairment of the quality or even the very existence of life. Living organisms are continuously exposed to air pollutants, and among them, ozone or particulate matters (PMs) are considered to be among the most toxic to human health. In particular, exposure to environmental stressors may result not only in pulmonary and cardiovascular diseases, but, as it has been demonstrated in the last two decades, the skin can also be affected by pollution. In this context, we hypothesize that chronodistruption can exacerbate cell vulnerability to exogenous damaging agents, and we suggest a possible common mechanism of action in deregulation of the homeostasis of the pulmonary, cardiovascular and cutaneous tissues and in its involvement in the development of pathological conditions.
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23
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Clement S, Campbell JM, Deng W, Guller A, Nisar S, Liu G, Wilson BC, Goldys EM. Mechanisms for Tuning Engineered Nanomaterials to Enhance Radiation Therapy of Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2020; 7:2003584. [PMID: 33344143 PMCID: PMC7740107 DOI: 10.1002/advs.202003584] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Indexed: 05/12/2023]
Abstract
Engineered nanomaterials that produce reactive oxygen species on exposure to X- and gamma-rays used in radiation therapy offer promise of novel cancer treatment strategies. Similar to photodynamic therapy but suitable for large and deep tumors, this new approach where nanomaterials acting as sensitizing agents are combined with clinical radiation can be effective at well-tolerated low radiation doses. Suitably engineered nanomaterials can enhance cancer radiotherapy by increasing the tumor selectivity and decreasing side effects. Additionally, the nanomaterial platform offers therapeutically valuable functionalities, including molecular targeting, drug/gene delivery, and adaptive responses to trigger drug release. The potential of such nanomaterials to be combined with radiotherapy is widely recognized. In order for further breakthroughs to be made, and to facilitate clinical translation, the applicable principles and fundamentals should be articulated. This review focuses on mechanisms underpinning rational nanomaterial design to enhance radiation therapy, the understanding of which will enable novel ways to optimize its therapeutic efficacy. A roadmap for designing nanomaterials with optimized anticancer performance is also shown and the potential clinical significance and future translation are discussed.
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Affiliation(s)
- Sandhya Clement
- ARC Centre of Excellence for Nanoscale BiophotonicsThe Graduate School of Biomedical EngineeringUniversity of New South WalesHigh StreetKensingtonNew South Wales2052Australia
| | - Jared M. Campbell
- ARC Centre of Excellence for Nanoscale BiophotonicsThe Graduate School of Biomedical EngineeringUniversity of New South WalesHigh StreetKensingtonNew South Wales2052Australia
| | - Wei Deng
- ARC Centre of Excellence for Nanoscale BiophotonicsThe Graduate School of Biomedical EngineeringUniversity of New South WalesHigh StreetKensingtonNew South Wales2052Australia
| | - Anna Guller
- ARC Centre of Excellence for Nanoscale BiophotonicsThe Graduate School of Biomedical EngineeringUniversity of New South WalesHigh StreetKensingtonNew South Wales2052Australia
- Institute for Regenerative MedicineSechenov First Moscow State Medical University (Sechenov University)Trubetskaya StreetMoscow119991Russia
| | - Saadia Nisar
- ARC Centre of Excellence for Nanoscale BiophotonicsThe Graduate School of Biomedical EngineeringUniversity of New South WalesHigh StreetKensingtonNew South Wales2052Australia
| | - Guozhen Liu
- ARC Centre of Excellence for Nanoscale BiophotonicsThe Graduate School of Biomedical EngineeringUniversity of New South WalesHigh StreetKensingtonNew South Wales2052Australia
| | - Brian C. Wilson
- Department of Medical BiophysicsUniversity of Toronto/Princess Margaret Cancer CentreUniversity Health NetworkColledge StreetTorontoOntarioON M5G 2C1Canada
| | - Ewa M. Goldys
- ARC Centre of Excellence for Nanoscale BiophotonicsThe Graduate School of Biomedical EngineeringUniversity of New South WalesHigh StreetKensingtonNew South Wales2052Australia
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24
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Peroxisome Proliferator-Activated Receptors as Molecular Links between Caloric Restriction and Circadian Rhythm. Nutrients 2020; 12:nu12113476. [PMID: 33198317 PMCID: PMC7696073 DOI: 10.3390/nu12113476] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Revised: 11/04/2020] [Accepted: 11/09/2020] [Indexed: 02/06/2023] Open
Abstract
The circadian rhythm plays a chief role in the adaptation of all bodily processes to internal and environmental changes on the daily basis. Next to light/dark phases, feeding patterns constitute the most essential element entraining daily oscillations, and therefore, timely and appropriate restrictive diets have a great capacity to restore the circadian rhythm. One of the restrictive nutritional approaches, caloric restriction (CR) achieves stunning results in extending health span and life span via coordinated changes in multiple biological functions from the molecular, cellular, to the whole-body levels. The main molecular pathways affected by CR include mTOR, insulin signaling, AMPK, and sirtuins. Members of the family of nuclear receptors, the three peroxisome proliferator-activated receptors (PPARs), PPARα, PPARβ/δ, and PPARγ take part in the modulation of these pathways. In this non-systematic review, we describe the molecular interconnection between circadian rhythm, CR-associated pathways, and PPARs. Further, we identify a link between circadian rhythm and the outcomes of CR on the whole-body level including oxidative stress, inflammation, and aging. Since PPARs contribute to many changes triggered by CR, we discuss the potential involvement of PPARs in bridging CR and circadian rhythm.
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25
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Vahidi Ferdowsi P, Ng R, Adulcikas J, Sohal SS, Myers S. Zinc Modulates Several Transcription-Factor Regulated Pathways in Mouse Skeletal Muscle Cells. Molecules 2020; 25:E5098. [PMID: 33153045 PMCID: PMC7663025 DOI: 10.3390/molecules25215098] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 10/28/2020] [Indexed: 02/07/2023] Open
Abstract
Zinc is an essential metal ion involved in many biological processes. Studies have shown that zinc can activate several molecules in the insulin signalling pathway and the concomitant uptake of glucose in skeletal muscle cells. However, there is limited information on other potential pathways that zinc can activate in skeletal muscle. Accordingly, this study aimed to identify other zinc-activating pathways in skeletal muscle cells to further delineate the role of this metal ion in cellular processes. Mouse C2C12 skeletal muscle cells were treated with insulin (10 nM), zinc (20 µM), and the zinc chelator TPEN (various concentrations) over 60 min. Western blots were performed for the zinc-activation of pAkt, pErk, and pCreb. A Cignal 45-Reporter Array that targets 45 signalling pathways was utilised to test the ability of zinc to activate pathways that have not yet been described. Zinc and insulin activated pAkt over 60 min as expected. Moreover, the treatment of C2C12 skeletal muscle cells with TPEN reduced the ability of zinc to activate pAkt and pErk. Zinc also activated several associated novel transcription factor pathways including Nrf1/Nrf2, ATF6, CREB, EGR1, STAT1, AP-1, PPAR, and TCF/LEF, and pCREB protein over 120 min of zinc treatment. These studies have shown that zinc's activity extends beyond that of insulin signalling and plays a role in modulating novel transcription factor activated pathways. Further studies to determine the exact role of zinc in the activation of transcription factor pathways will provide novel insights into this metal ion actions.
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Affiliation(s)
| | | | | | | | - Stephen Myers
- College of Health and Medicine, School of Health Sciences, University of Tasmania, Newnham Campus, Launceston 7250, Australia; (P.V.F.); (R.N.); (J.A.); (S.S.S.)
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26
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Yang CH, Hwang CF, Chuang JH, Lian WS, Wang FS, Huang EI, Yang MY. Constant Light Dysregulates Cochlear Circadian Clock and Exacerbates Noise-Induced Hearing Loss. Int J Mol Sci 2020; 21:E7535. [PMID: 33066038 PMCID: PMC7589695 DOI: 10.3390/ijms21207535] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 09/30/2020] [Accepted: 10/09/2020] [Indexed: 02/08/2023] Open
Abstract
Noise-induced hearing loss is one of the major causes of acquired sensorineural hearing loss in modern society. While people with excessive exposure to noise are frequently the population with a lifestyle of irregular circadian rhythms, the effects of circadian dysregulation on the auditory system are still little known. Here, we disturbed the circadian clock in the cochlea of male CBA/CaJ mice by constant light (LL) or constant dark. LL significantly repressed circadian rhythmicity of circadian clock genes Per1, Per2, Rev-erbα, Bmal1, and Clock in the cochlea, whereas the auditory brainstem response thresholds were unaffected. After exposure to low-intensity (92 dB) noise, mice under LL condition initially showed similar temporary threshold shifts to mice under normal light-dark cycle, and mice under both conditions returned to normal thresholds after 3 weeks. However, LL augmented high-intensity (106 dB) noise-induced permanent threshold shifts, particularly at 32 kHz. The loss of outer hair cells (OHCs) and the reduction of synaptic ribbons were also higher in mice under LL after noise exposure. Additionally, LL enhanced high-intensity noise-induced 4-hydroxynonenal in the OHCs. Our findings convey new insight into the deleterious effect of an irregular biological clock on the auditory system.
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Affiliation(s)
- Chao-Hui Yang
- Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan;
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Tao-Yuan 33302, Taiwan; (J.-H.C.); (F.-S.W.)
| | - Chung-Feng Hwang
- Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan;
| | - Jiin-Haur Chuang
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Tao-Yuan 33302, Taiwan; (J.-H.C.); (F.-S.W.)
- Division of Pediatric Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
| | - Wei-Shiung Lian
- Core Laboratory for Phenomics & Diagnostics, Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan;
| | - Feng-Sheng Wang
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Tao-Yuan 33302, Taiwan; (J.-H.C.); (F.-S.W.)
- Core Laboratory for Phenomics & Diagnostics, Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan;
| | - Ethan I. Huang
- Department of Otolaryngology, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan;
| | - Ming-Yu Yang
- Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan;
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Tao-Yuan 33302, Taiwan; (J.-H.C.); (F.-S.W.)
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27
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Huang H, Li Z, Ruan Y, Feng W, Chen J, Li X, Ouyang L, Huang H. Circadian rhythm disorder: a potential inducer of vascular calcification? J Physiol Biochem 2020; 76:513-524. [PMID: 32945991 DOI: 10.1007/s13105-020-00767-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 09/14/2020] [Indexed: 12/24/2022]
Abstract
Over the past decades, circadian rhythm has drawn a great attention in cardiovascular diseases. The expressions of rhythm genes fluctuate in accordance with the diurnal changes of vascular physiology, which highlights the pivotal effect of vascular clock. Recent researches show that the circadian clock can directly regulate the synthetic and secretory function of endothelial cells and phenotypic switch of vascular smooth muscle cells to adjust vascular relaxation and contraction. Importantly, dysfunction of vascular cells is involved in vascular calcification. Secretion of osteogenic cytokines and calcified vesicles in the vessel, osteogenic phenotype switch of vascular smooth muscle cells are all implicated in the calcification process. Moreover, circadian rhythm disorder can lead to abnormal hormone secretion, oxidative stress, inflammatory reaction, and autophagy, all of which should not be ignored in vascular calcification. Vascular senescence is another pathogenetic mechanism in vascular calcification. Accelerated vascular senescence may act as an important intermediate factor to promote vascular calcification in circadian rhythm disorders. In this review, we elaborate the potential effect of circadian rhythm disorder in vascular calcification and try to provide a new direction in the prevention of vascular calcification.
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Affiliation(s)
- Haoran Huang
- Department of Cardiology, The Eighth Affiliated Hospital, Sun Yat-sen University, No. 3025, Shennan Middle Road, Futian District, Shenzhen, 518000, China
- Department of Pediatric Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhaohuai Li
- Department of Cardiology, The Eighth Affiliated Hospital, Sun Yat-sen University, No. 3025, Shennan Middle Road, Futian District, Shenzhen, 518000, China
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Yuyi Ruan
- Department of Cardiology, The Eighth Affiliated Hospital, Sun Yat-sen University, No. 3025, Shennan Middle Road, Futian District, Shenzhen, 518000, China
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Weijing Feng
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Department of Cardiology, Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jie Chen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaoxue Li
- Department of Cardiology, The Eighth Affiliated Hospital, Sun Yat-sen University, No. 3025, Shennan Middle Road, Futian District, Shenzhen, 518000, China
| | - Liu Ouyang
- Department of Cardiology, The Eighth Affiliated Hospital, Sun Yat-sen University, No. 3025, Shennan Middle Road, Futian District, Shenzhen, 518000, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Hui Huang
- Department of Cardiology, The Eighth Affiliated Hospital, Sun Yat-sen University, No. 3025, Shennan Middle Road, Futian District, Shenzhen, 518000, China.
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28
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Chhunchha B, Kubo E, Singh DP. Clock Protein Bmal1 and Nrf2 Cooperatively Control Aging or Oxidative Response and Redox Homeostasis by Regulating Rhythmic Expression of Prdx6. Cells 2020; 9:E1861. [PMID: 32784474 PMCID: PMC7463585 DOI: 10.3390/cells9081861] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 08/06/2020] [Accepted: 08/06/2020] [Indexed: 02/06/2023] Open
Abstract
Many disorders of aging, including blinding-diseases, are associated with deficiency of brain and muscle arnt-like protein 1 (Bmal1) and, thereby, dysregulation of antioxidant-defense pathway. However, knowledge is limited regarding the role of Bmal1 regulation of antioxidant-pathway in the eye lens/lens epithelial cells (LECs) at the molecular level. We found that, in aging human (h)LECs, a progressive decline of nuclear factor erythroid 2-related factor 2 (Nrf2)/ARE (antioxidant response element)-mediated antioxidant genes was connected to Bmal1-deficiency, leading to accumulation of reactive oxygen species (ROS) and cell-death. Bmal1-depletion disrupted Nrf2 and expression of its target antioxidant genes, like Peroxiredoxin 6 (Prdx6). DNA binding and transcription assays showed that Bmal1 controlled expression by direct binding to E-Box in Prdx6 promoter to regulate its transcription. Mutation at E-Box or ARE reduced promoter activity, while disruption of both sites diminished the activity, suggesting that both sites were required for peak Prdx6-transcription. As in aging hLECs, ROS accumulation was increased in Bmal1-deficient cells and the cells were vulnerable to death. Intriguingly, Bmal1/Nrf2/Prdx6 and PhaseII antioxidants showed rhythmic expression in mouse lenses in vivo and were reciprocally linked to ROS levels. We propose that Bmal1 is pivotal for regulating oxidative responses. Findings also reveal a circadian control of antioxidant-pathway, which is important in combating lens/LECs damage induced by aging or oxidative stress.
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Affiliation(s)
- Bhavana Chhunchha
- Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA;
| | - Eri Kubo
- Department of Ophthalmology, Kanazawa Medical University, Ishikawa 9200293, Japan;
| | - Dhirendra P. Singh
- Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA;
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29
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Liu WW, Wei SZ, Huang GD, Liu LB, Gu C, Shen Y, Wang XH, Xia ST, Xie AM, Hu LF, Wang F, Liu CF. BMAL1 regulation of microglia-mediated neuroinflammation in MPTP-induced Parkinson's disease mouse model. FASEB J 2020; 34:6570-6581. [PMID: 32246801 DOI: 10.1096/fj.201901565rr] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 12/21/2019] [Accepted: 03/06/2020] [Indexed: 12/14/2022]
Abstract
Dysfunction of the circadian rhythm is one of most common nonmotor symptoms in Parkinson's disease (PD), but the molecular role of the circadian rhythm in PD is unclear. We here showed that inactivation of brain and muscle ARNT-like 1 (BMAL1) in 1-methyl-4-phenyl-1,2,4,5-tetrahydropyridine (MPTP)-treated mice resulted in obvious motor functional deficit, loss of dopaminergic neurons (DANs) in the substantia nigra pars compacta (SNpc), decrease of dopamine (DA) transmitter, and increased activation of microglia and astrocytes in the striatum. Time on the rotarod or calorie consumption, and food and water intake were reduced in the Bmal1-/- mice after MPTP treatment, suggesting that absence of Bmal1 may exacerbate circadian and PD motor function. We observed a significant reduction of DANs (~35%) in the SNpc, the tyrosine hydroxylase protein level in the striatum (~60%), the DA (~22%), and 3,4-dihydroxyphenylacetic acid content (~29%), respectively, in MPTP-treated Bmal1-/- mice. Loss of Bmal1 aggravated the inflammatory reaction both in vivo and in vitro. These findings suggest that BMAL1 may play an essential role in the survival of DANs and maintain normal function of the DA signaling pathway via regulating microglia-mediated neuroinflammation in the brain.
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Affiliation(s)
- Wen-Wen Liu
- Department of Neurology and Suzhou Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, China
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, China
| | - Shi-Zhuang Wei
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, China
| | - Guo-Dong Huang
- Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, USA
| | - Lu-Bing Liu
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, China
| | - Chao Gu
- Department of Neurology and Suzhou Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, China
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, China
| | - Yun Shen
- Department of Neurology and Suzhou Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Xian-Hui Wang
- Department of Neurology and Suzhou Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, China
- Department of Neurology, Taicang Affiliated Hospital of Soochow University, The First People's Hospital of Taicang, Taicang, China
| | - Shu-Ting Xia
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, China
| | - An-Mu Xie
- Department of Neurology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Li-Fang Hu
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, China
| | - Fen Wang
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, China
| | - Chun-Feng Liu
- Department of Neurology and Suzhou Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, China
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, China
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30
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Kukkemane K, Jagota A. Therapeutic effects of hydro-alcoholic leaf extract of Withania somnifera on age-induced changes in daily rhythms of Sirt1, Nrf2 and Rev-erbα in the SCN of male Wistar rats. Biogerontology 2020; 21:593-607. [PMID: 32249404 DOI: 10.1007/s10522-020-09875-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Accepted: 03/30/2020] [Indexed: 12/23/2022]
Abstract
The temporal expression pattern of the circadian clock genes are known to be altered/attenuated with advance in age. Withania somnifera (WS) essentially consists of numerous active constituents including withanolides is known to have antioxidant, anti-inflammatory and adaptogenic properties. We have earlier demonstrated therapeutic effects of hydro-alcoholic leaf extract of WS on the age-induced alterations in the levels and daily rhythms of various clock genes such as rBmal1, rPer1, rPer2 and rCry1. We have now studied effects of hydro-alcoholic leaf extract of WS on the age-induced alterations in the levels and daily rhythms of expression of SIRT1 (an NAD+ dependent histone deacetylase and a modulator of clock) and NRF2 (a clock controlled gene and a master transcription factor regulating various endogenous antioxidant enzymes) in addition to rRev-erbα in SCN of adult [3 months (m)], middle-aged (12 m) and old-aged (24 m) male Wistar rats. The daily rhythms of rNrf2 expression showed 6 h phase delay in middle age and 12 h phase advance in old age. WS restored rSirt1 daily rhythms and phase in old age whereas it restored the phase of rNrf2 in the SCN of both middle and old aged animals. At protein level, SIRT1 expression showed phase advances in 12 m and 24 m whereas NRF2 daily rhythms were abolished in both the age groups. WS restored the phase and daily rhythms of SIRT1 as well as NRF2 in 12 m old rats. However, rRev-erbα expression was found insensitive to WS treatment in all the age groups studied. Pairwise correlation analysis demonstrated significant stoichiometric interactions among rSirt1, rNrf2 and rRev-erbα in 3 m which altered with aging significantly. WS treatment resulted in differential restorations of such interactions.
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Affiliation(s)
- Kowshik Kukkemane
- Neurobiology and Molecular Chronobiology Laboratory, Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, 500046, India
| | - Anita Jagota
- Neurobiology and Molecular Chronobiology Laboratory, Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, 500046, India.
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De Nobrega AK, Luz KV, Lyons LC. Resetting the Aging Clock: Implications for Managing Age-Related Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1260:193-265. [PMID: 32304036 DOI: 10.1007/978-3-030-42667-5_9] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Worldwide, individuals are living longer due to medical and scientific advances, increased availability of medical care and changes in public health policies. Consequently, increasing attention has been focused on managing chronic conditions and age-related diseases to ensure healthy aging. The endogenous circadian system regulates molecular, physiological and behavioral rhythms orchestrating functional coordination and processes across tissues and organs. Circadian disruption or desynchronization of circadian oscillators increases disease risk and appears to accelerate aging. Reciprocally, aging weakens circadian function aggravating age-related diseases and pathologies. In this review, we summarize the molecular composition and structural organization of the circadian system in mammals and humans, and evaluate the technological and societal factors contributing to the increasing incidence of circadian disorders. Furthermore, we discuss the adverse effects of circadian dysfunction on aging and longevity and the bidirectional interactions through which aging affects circadian function using examples from mammalian research models and humans. Additionally, we review promising methods for managing healthy aging through behavioral and pharmacological reinforcement of the circadian system. Understanding age-related changes in the circadian clock and minimizing circadian dysfunction may be crucial components to promote healthy aging.
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Affiliation(s)
- Aliza K De Nobrega
- Department of Biological Science, Program in Neuroscience, Florida State University, Tallahassee, FL, USA
| | - Kristine V Luz
- Department of Biological Science, Program in Neuroscience, Florida State University, Tallahassee, FL, USA
| | - Lisa C Lyons
- Department of Biological Science, Program in Neuroscience, Florida State University, Tallahassee, FL, USA.
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Maiese K. Nicotinamide: Oversight of Metabolic Dysfunction Through SIRT1, mTOR, and Clock Genes. Curr Neurovasc Res 2020; 17:765-783. [PMID: 33183203 PMCID: PMC7914159 DOI: 10.2174/1567202617999201111195232] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 10/24/2020] [Accepted: 10/27/2020] [Indexed: 12/13/2022]
Abstract
Metabolic disorders that include diabetes mellitus present significant challenges for maintaining the welfare of the global population. Metabolic diseases impact all systems of the body and despite current therapies that offer some protection through tight serum glucose control, ultimately such treatments cannot block the progression of disability and death realized with metabolic disorders. As a result, novel therapeutic avenues are critical for further development to address these concerns. An innovative strategy involves the vitamin nicotinamide and the pathways associated with the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), the mechanistic target of rapamycin (mTOR), mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), AMP activated protein kinase (AMPK), and clock genes. Nicotinamide maintains an intimate relationship with these pathways to oversee metabolic disease and improve glucose utilization, limit mitochondrial dysfunction, block oxidative stress, potentially function as antiviral therapy, and foster cellular survival through mechanisms involving autophagy. However, the pathways of nicotinamide, SIRT1, mTOR, AMPK, and clock genes are complex and involve feedback pathways as well as trophic factors such as erythropoietin that require a careful balance to ensure metabolic homeostasis. Future work is warranted to gain additional insight into these vital pathways that can oversee both normal metabolic physiology and metabolic disease.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, New York, New York 10022
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Maiese K. Cognitive impairment with diabetes mellitus and metabolic disease: innovative insights with the mechanistic target of rapamycin and circadian clock gene pathways. Expert Rev Clin Pharmacol 2020; 13:23-34. [PMID: 31794280 PMCID: PMC6959472 DOI: 10.1080/17512433.2020.1698288] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 11/25/2019] [Indexed: 12/18/2022]
Abstract
Introduction: Dementia is the 7th leading cause of death that imposes a significant financial and service burden on the global population. Presently, only symptomatic care exists for cognitive loss, such as Alzheimer's disease.Areas covered: Given the advancing age of the global population, it becomes imperative to develop innovative therapeutic strategies for cognitive loss. New studies provide insight to the association of cognitive loss with metabolic disorders, such as diabetes mellitus.Expert opinion: Diabetes mellitus is increasing in incidence throughout the world and affects 350 million individuals. Treatment strategies identifying novel pathways that oversee metabolic and neurodegenerative disorders offer exciting prospects to treat dementia. The mechanistic target of rapamycin (mTOR) and circadian clock gene pathways that include AMP activated protein kinase (AMPK), Wnt1 inducible signaling pathway protein 1 (WISP1), erythropoietin (EPO), and silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) provide novel strategies to treat cognitive loss that has its basis in metabolic cellular dysfunction. However, these pathways are complex and require precise regulation to maximize treatment efficacy and minimize any potential clinical disability. Further investigations hold great promise to treat both the onset and progression of cognitive loss that is associated with metabolic disease.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, New York, New York 10022
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Ji G, Lv K, Chen H, Wang Y, Zhang Y, Li Y, Qu L. Hydrogen peroxide modulates clock gene expression via PRX2-STAT3-REV-ERBα/β pathway. Free Radic Biol Med 2019; 145:312-320. [PMID: 31585206 DOI: 10.1016/j.freeradbiomed.2019.09.036] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 09/26/2019] [Accepted: 09/28/2019] [Indexed: 12/12/2022]
Abstract
The circadian rhythm is a widespread physiological phenomenon present in almost all forms of life and is constituted by a system of interlocked transcriptional/translational feedback loops (TTFLs). External zeitgebers regulate biological rhythms through the direct or indirect regulation of circadian genes. Oxidative stress is involved in many diseases and injuries, such as ageing, diabetes, Alzheimer's disease, and cancer. Despite an increasing number of studies on circadian rhythm disorders caused by oxidative stress, little is known about the effects of oxidants on clock gene expression and the underlying mechanism. In this study, we found that the protein expression of circadian genes Clock, Bmal1, Per1/2, and Cry1/2 in NIH3T3 cells was upregulated by hydrogen peroxide (H2O2), an important mediator of oxidative stress. In addition, H2O2 modulated the circadian rhythm of Bmal1-luciferase via RORα, REV-ERBα (NR1D1), and REV-ERBβ (NR1D2). Further studies showed that H2O2 regulated biological rhythm by PRX2-STAT3-REV-ERBα/β pathway. These findings provide an accessory loop-related mechanism by which non-transcriptional oscillation interplays with TTFLs.
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Affiliation(s)
- Guohua Ji
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, 26 Beiqing Road, Beijing, 100094, PR China
| | - Ke Lv
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, 26 Beiqing Road, Beijing, 100094, PR China
| | - Hailong Chen
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, 26 Beiqing Road, Beijing, 100094, PR China
| | - Yanli Wang
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, 26 Beiqing Road, Beijing, 100094, PR China
| | - Yongliang Zhang
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, 26 Beiqing Road, Beijing, 100094, PR China
| | - Yinghui Li
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, 26 Beiqing Road, Beijing, 100094, PR China
| | - Lina Qu
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, 26 Beiqing Road, Beijing, 100094, PR China.
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Emerging role of circadian rhythm in bone remodeling. J Mol Med (Berl) 2018; 97:19-24. [PMID: 30446776 DOI: 10.1007/s00109-018-1723-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 11/07/2018] [Accepted: 11/09/2018] [Indexed: 12/31/2022]
Abstract
The 24-h rhythm of behavioral and physiological processes is a typical biological phenomenon regulated by a group of circadian rhythm genes. Dysfunction of the circadian rhythm can cause a wide range of problems, such as cancer and metabolic diseases. In recent decades, increased understanding of the roles of circadian rhythm genes in the bone remodeling process have been documented, including osteoblastic bone formation, osteoclastic bone resorption, and osteoblast/osteoclast communication. A timely review of the current findings may help to facilitate the new field of circadian rhythmic bone remodeling research. Targeted pharmacological modulation of circadian rhythm genes is a possible therapeutic approach through which to overcome bone remodeling problems in the future.
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Xu Y, Wang X, Jiang S, Men C, Xu D, Guo Y, Wu J. Microcystin-LR regulates circadian clock and antioxidant gene expression in cultured rat cardiomyocytes. Cell Mol Biol Lett 2018; 23:50. [PMID: 30337942 PMCID: PMC6180438 DOI: 10.1186/s11658-018-0115-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Accepted: 09/28/2018] [Indexed: 12/25/2022] Open
Abstract
Background Microcystins are waterborne environmental toxins that induce oxidative stress and cause injuries in the heart. On the other hand, many physiological processes, including antioxidant defense, are under precise control by the mammalian circadian clock. Results In the present study, we evaluated the effect of microcystin-LR (MC-LR) on the rhythmic expression patterns of circadian and antioxidant genes in rat cardiomyocytes using the serum shock technique. We found that a non-toxic dose (10 μm) of MC-LR decreased the amplitudes of rhythmic patterns of clock genes, while it increased the expression levels of antioxidant genes. Conclusions Our results indicate an influence of MC-LR on the circadian clock system and clock-controlled antioxidant genes, which will shed some light on the explanation of heart toxicity induced by MC-LR from the viewpoint of chronobiology.
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Affiliation(s)
- Yonghua Xu
- 1Department of General Surgery, The Fourth Affiliated Hospital of Nantong University, Yancheng, 224006 China
| | - Xiangmin Wang
- 2Department of Geriatric Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Rd, Nanjing, 210029 China
| | - Surong Jiang
- 2Department of Geriatric Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Rd, Nanjing, 210029 China
| | - Chen Men
- 2Department of Geriatric Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Rd, Nanjing, 210029 China
| | - Di Xu
- 2Department of Geriatric Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Rd, Nanjing, 210029 China
| | - Yan Guo
- 2Department of Geriatric Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Rd, Nanjing, 210029 China
| | - Jun Wu
- 2Department of Geriatric Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Rd, Nanjing, 210029 China
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Doria HB, Ferreira MB, Rodrigues SD, Lo SM, Domingues CE, Nakao LS, de Campos SX, Ribeiro CADO, Randi MAF. Time does matter! Acute copper exposure abolishes rhythmicity of clock gene in Danio rerio. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2018; 155:26-36. [PMID: 29499429 DOI: 10.1016/j.ecoenv.2018.02.068] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2017] [Revised: 02/14/2018] [Accepted: 02/22/2018] [Indexed: 06/08/2023]
Abstract
The circadian clock is a key cellular timing system that coordinates physiology and behavior. Light is a key regulator of the clock mechanism via its activation of Per and Cry clock gene expression. Evidence points to a key role of reactive oxygen species (ROS) in resetting this process. In this context, the aim of the present study was to explore copper as a ROS generator, using an innovative approach investigating its effects on circadian timing. Liver and brain from Danio rerio specimens exposed to 0, 5, 25 and 45 μg/L copper concentrations were obtained. Daily oscillations of superoxide dismutase (SOD) and catalase (CAT) enzymatic activity and their correlations both with clock genes (per1, per2, and cry1a) and with organism energy cost were determined. CAT expression correlates with per2 and cry1a and, thus, provides data to support the hypothesis of hydrogen peroxide production by a phototransducing flavin-containing oxidase. Higher SOD activity is correlated with higher intracellular ATP levels. Copper disturbed the daily oscillation of antioxidant enzymes and clock genes, with disturbed per1 rhythmicity in both the brain and liver, while cry1a rhythmicity was abolished in the liver at 25 μg/L copper. Coordination between the SOD and the CAT enzymes was lost when copper concentrations exceeded the limits established by international laws. These results indicate that organism synchronization with the environment may be impaired due to acute copper exposure.
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Affiliation(s)
- Halina Binde Doria
- Federal University of Paraná (UFPR), Department of Cellular Biology, School of Biological Sciences, Caixa Postal 19.031, Postal Code: 81531-990, Curitiba, Paraná, Brazil.
| | - Marianna Boia Ferreira
- Federal University of Paraná (UFPR), Department of Cellular Biology, School of Biological Sciences, Caixa Postal 19.031, Postal Code: 81531-990, Curitiba, Paraná, Brazil
| | - Silvia Daniele Rodrigues
- Federal University of Paraná (UFPR), Department of Basic Pathology, School of Biological Sciences, Caixa Postal 19.031, Postal Code: 81531-990, Curitiba, Paraná, Brazil
| | - Sze Mei Lo
- Federal University of Paraná (UFPR), Department of Basic Pathology, School of Biological Sciences, Caixa Postal 19.031, Postal Code: 81531-990, Curitiba, Paraná, Brazil
| | - Cinthia Eloise Domingues
- Ponta Grossa State University (UEPG), Research Group on Environmental and Sanitary Analytical Chemistry (QAAS), Caixa Postal 992, Postal Code: 84030-900, Ponta Grossa, Paraná, Brazil
| | - Lia Sumie Nakao
- Federal University of Paraná (UFPR), Department of Basic Pathology, School of Biological Sciences, Caixa Postal 19.031, Postal Code: 81531-990, Curitiba, Paraná, Brazil
| | - Sandro Xavier de Campos
- Ponta Grossa State University (UEPG), Research Group on Environmental and Sanitary Analytical Chemistry (QAAS), Caixa Postal 992, Postal Code: 84030-900, Ponta Grossa, Paraná, Brazil
| | - Ciro Alberto de Oliveira Ribeiro
- Federal University of Paraná (UFPR), Department of Cellular Biology, School of Biological Sciences, Caixa Postal 19.031, Postal Code: 81531-990, Curitiba, Paraná, Brazil
| | - Marco Antonio Ferreira Randi
- Federal University of Paraná (UFPR), Department of Cellular Biology, School of Biological Sciences, Caixa Postal 19.031, Postal Code: 81531-990, Curitiba, Paraná, Brazil
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Haberzettl P. Circadian toxicity of environmental pollution. Inhalation of polluted air to give a precedent. CURRENT OPINION IN PHYSIOLOGY 2018; 5:16-24. [PMID: 30931418 DOI: 10.1016/j.cophys.2018.05.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Exposures to environmental stressors that derive from pollution (e.g. air, light) or lifestyle choices (e.g. diet, activity, 24-hour-×-7-day) are associated with adverse human health outcomes. For instance, there is evidence that air pollution exposure and changes in sleep/wake pattern increase the risk for vascular and cardiometabolic disorders. Interestingly, air pollution exposure affects pulmonary and cardiovascular functions that follow circadian rhythmicity and increases the risk for pulmonary and cardiovascular events that occur in diurnal patterns suggesting a link between air pollution induced cardiovascular and pulmonary injury and changes in circadian rhythm. Indeed, recent research identified circadian rhythm as an air pollution target and circadian rhythm as factor that increases air pollution sensitivity. Using air pollution exposure as precedent, this review highlights research on how environmental pollution affect circadian rhythm and how circadian rhythm affects the toxicity of environmental stressors.
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Affiliation(s)
- Petra Haberzettl
- Diabetes and Obesity Center, Institute of Molecular Cardiology, School of Medicine, University of Louisville, Louisville, KY 40202, USA
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Maiese K. Moving to the Rhythm with Clock (Circadian) Genes, Autophagy, mTOR, and SIRT1 in Degenerative Disease and Cancer. Curr Neurovasc Res 2018; 14:299-304. [PMID: 28721811 DOI: 10.2174/1567202614666170718092010] [Citation(s) in RCA: 84] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Revised: 06/22/2017] [Accepted: 07/06/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND The mammalian circadian clock and its associated clock genes are increasingly been recognized as critical components for a number of physiological and disease processes that extend beyond hormone release, thermal regulation, and sleep-wake cycles. New evidence suggests that clinical behavior disruptions that involve prolonged shift work and even space travel may negatively impact circadian rhythm and lead to multi-system disease. METHODS In light of the significant role circadian rhythm can hold over the body's normal physiology as well as disease processes, we examined and discussed the impact circadian rhythm and clock genes hold over lifespan, neurodegenerative disorders, and tumorigenesis. RESULTS In experimental models, lifespan is significantly reduced with the introduction of arrhythmic mutants and leads to an increase in oxidative stress exposure. Interestingly, patients with Alzheimer's disease and Parkinson's disease may suffer disease onset or progression as a result of alterations in the DNA methylation of clock genes as well as prolonged pharmacological treatment for these disorders that may lead to impairment of circadian rhythm function. Tumorigenesis also can occur with the loss of a maintained circadian rhythm and lead to an increased risk for nasopharyngeal carcinoma, breast cancer, and metastatic colorectal cancer. Interestingly, the circadian clock system relies upon the regulation of the critical pathways of autophagy, the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), and silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) as well as proliferative mechanisms that involve the wingless pathway of Wnt/β-catenin pathway to foster cell survival during injury and block tumor cell growth. CONCLUSION Future targeting of the pathways of autophagy, mTOR, SIRT1, and Wnt that control mammalian circadian rhythm may hold the key for the development of novel and effective therapies against aging- related disorders, neurodegenerative disease, and tumorigenesis.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, Newark, NY. United States
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40
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Rodrigo GC, Herbert KE. Regulation of vascular function and blood pressure by circadian variation in redox signalling. Free Radic Biol Med 2018; 119:115-120. [PMID: 29106991 DOI: 10.1016/j.freeradbiomed.2017.10.381] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Revised: 10/24/2017] [Accepted: 10/25/2017] [Indexed: 12/21/2022]
Abstract
There is accumulating evidence that makes the link between the circadian variation in blood pressure and circadian variations in vascular contraction. The importance of vascular endothelium-derived redox-active and redox-derived species in the signalling pathways involved in controlling vascular smooth muscle contraction are well known, and when linked to the circadian variations in the processes involved in generating these species, suggests a cellular mechanism for the circadian variations in blood pressure that links directly to the peripheral circadian clock. Relaxation of vascular smooth muscle cells involves endothelial-derived relaxing factor (EDRF) which is nitric oxide (NO) produced by endothelial NO synthase (eNOS), and endothelial-derived hyperpolarising factor (EDHF) which includes hydrogen peroxide (H2O2) produced by NADPH oxidase (Nox). Both of these enzymes appear to be under the direct control of the circadian clock mechanism in the endothelial cells, and disruption to the clock results in endothelial and vascular dysfunction. In this review, we focus on EDRF and EDHF and summarise the recent findings on the influence of the peripheral circadian clock mechanism on processes involved in generating the redox species involved and how this influences vascular contractility, which may account for some of the circadian variations in blood pressure and peripheral resistance. Moreover, the direct link between the peripheral circadian clock and redox-signalling pathways in the vasculature, has a bearing on vascular endothelial dysfunction in disease and aging, which are both known to lead to dysfunction of the circadian clock.
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Affiliation(s)
- Glenn C Rodrigo
- Department of Cardiovascular Sciences, University of Leicester, Glenfield General Hospital, Leicester, United Kingdom.
| | - Karl E Herbert
- Department of Cardiovascular Sciences, University of Leicester, Glenfield General Hospital, Leicester, United Kingdom
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Moldogazieva NT, Mokhosoev IM, Feldman NB, Lutsenko SV. ROS and RNS signalling: adaptive redox switches through oxidative/nitrosative protein modifications. Free Radic Res 2018; 52:507-543. [PMID: 29589770 DOI: 10.1080/10715762.2018.1457217] [Citation(s) in RCA: 199] [Impact Index Per Article: 28.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Over the last decade, a dual character of cell response to oxidative stress, eustress versus distress, has become increasingly recognized. A growing body of evidence indicates that under physiological conditions, low concentrations of reactive oxygen and nitrogen species (RONS) maintained by the activity of endogenous antioxidant system (AOS) allow reversible oxidative/nitrosative modifications of key redox-sensitive residues in regulatory proteins. The reversibility of redox modifications such as Cys S-sulphenylation/S-glutathionylation/S-nitrosylation/S-persulphidation and disulphide bond formation, or Tyr nitration, which occur through electrophilic attack of RONS to nucleophilic groups in amino acid residues provides redox switches in the activities of signalling proteins. Key requirement for the involvement of the redox modifications in RONS signalling including ROS-MAPK, ROS-PI3K/Akt, and RNS-TNF-α/NF-kB signalling is their specificity provided by a residue microenvironment and reaction kinetics. Glutathione, glutathione peroxidases, peroxiredoxins, thioredoxin, glutathione reductases, and glutaredoxins modulate RONS level and cell signalling, while some of the modulators (glutathione, glutathione peroxidases and peroxiredoxins) are themselves targets for redox modifications. Additionally, gene expression, activities of transcription factors, and epigenetic pathways are also under redox regulation. The present review focuses on RONS sources (NADPH-oxidases, mitochondrial electron-transportation chain (ETC), nitric oxide synthase (NOS), etc.), and their cross-talks, which influence reversible redox modifications of proteins as physiological phenomenon attained by living cells during the evolution to control cell signalling in the oxygen-enriched environment. We discussed recent advances in investigation of mechanisms of protein redox modifications and adaptive redox switches such as MAPK/PI3K/PTEN, Nrf2/Keap1, and NF-κB/IκB, powerful regulators of numerous physiological processes, also implicated in various diseases.
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Affiliation(s)
- N T Moldogazieva
- a Department of Biotechnology, I.M. Sechenov First Moscow State Medical University (Sechenov University) , Moscow , Russia
| | - I M Mokhosoev
- a Department of Biotechnology, I.M. Sechenov First Moscow State Medical University (Sechenov University) , Moscow , Russia
| | - N B Feldman
- a Department of Biotechnology, I.M. Sechenov First Moscow State Medical University (Sechenov University) , Moscow , Russia
| | - S V Lutsenko
- a Department of Biotechnology, I.M. Sechenov First Moscow State Medical University (Sechenov University) , Moscow , Russia
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Maiese K. Novel Treatment Strategies for the Nervous System: Circadian Clock Genes, Non-coding RNAs, and Forkhead Transcription Factors. Curr Neurovasc Res 2018; 15:81-91. [PMID: 29557749 PMCID: PMC6021214 DOI: 10.2174/1567202615666180319151244] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2017] [Revised: 01/23/2018] [Accepted: 02/07/2018] [Indexed: 12/16/2022]
Abstract
BACKGROUND With the global increase in lifespan expectancy, neurodegenerative disorders continue to affect an ever-increasing number of individuals throughout the world. New treatment strategies for neurodegenerative diseases are desperately required given the lack of current treatment modalities. METHODS Here, we examine novel strategies for neurodegenerative disorders that include circadian clock genes, non-coding Ribonucleic Acids (RNAs), and the mammalian forkhead transcription factors of the O class (FoxOs). RESULTS Circadian clock genes, non-coding RNAs, and FoxOs offer exciting prospects to potentially limit or remove the significant disability and death associated with neurodegenerative disorders. Each of these pathways has an intimate relationship with the programmed death pathways of autophagy and apoptosis and share a common link to the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) and the mechanistic target of rapamycin (mTOR). Circadian clock genes are necessary to modulate autophagy, limit cognitive loss, and prevent neuronal injury. Non-coding RNAs can control neuronal stem cell development and neuronal differentiation and offer protection against vascular disease such as atherosclerosis. FoxOs provide exciting prospects to block neuronal apoptotic death and to activate pathways of autophagy to remove toxic accumulations in neurons that can lead to neurodegenerative disorders. CONCLUSION Continued work with circadian clock genes, non-coding RNAs, and FoxOs can offer new prospects and hope for the development of vital strategies for the treatment of neurodegenerative diseases. These innovative investigative avenues have the potential to significantly limit disability and death from these devastating disorders.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, Newark, New Jersey 07101
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Aryl hydrocarbon receptor (AHR): "pioneer member" of the basic-helix/loop/helix per-Arnt-sim (bHLH/PAS) family of "sensors" of foreign and endogenous signals. Prog Lipid Res 2017; 67:38-57. [PMID: 28606467 DOI: 10.1016/j.plipres.2017.06.001] [Citation(s) in RCA: 200] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Revised: 05/05/2017] [Accepted: 06/05/2017] [Indexed: 12/21/2022]
Abstract
The basic-helix/loop/helix per-Arnt-sim (bHLH/PAS) family comprises many transcription factors, found throughout all three kingdoms of life; bHLH/PAS members "sense" innumerable intracellular and extracellular "signals" - including endogenous compounds, foreign chemicals, gas molecules, redox potential, photons (light), gravity, heat, and osmotic pressure. These signals then initiate downstream signaling pathways involved in responding to that signal. The term "PAS", abbreviation for "per-Arnt-sim" was first coined in 1991. Although the mouse Arnt gene was not identified until 1991, evidence of its co-transcriptional binding partner, aryl hydrocarbon receptor (AHR), was first reported in 1974 as a "sensor" of foreign chemicals, up-regulating cytochrome P450 family 1 (CYP1) and other enzyme activities that usually metabolize the signaling chemical. Within a few years, AHR was proposed also to participate in inflammation. The mouse [Ah] locus was shown (1973-1989) to be relevant to chemical carcinogenesis, mutagenesis, toxicity and teratogenesis, the mouse Ahr gene was cloned in 1992, and the first Ahr(-/-) knockout mouse line was reported in 1995. After thousands of studies from the early 1970s to present day, we now realize that AHR participates in dozens of signaling pathways involved in critical-life processes, affecting virtually every organ and cell-type in the animal, including many invertebrates.
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Forssell-Aronsson E, Quinlan RA. THE IMPACT OF CIRCADIAN RHYTHMS ON MEDICAL IMAGING AND RADIOTHERAPY REGIMES FOR THE PAEDIATRIC PATIENT. RADIATION PROTECTION DOSIMETRY 2017; 173:16-20. [PMID: 27885090 DOI: 10.1093/rpd/ncw328] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
Daily rhythmic changes are found in cellular events in cell cycle, DNA repair, apoptosis and angiogenesis in both normal and tumour tissue, as well as in enzymatic activity and drug metabolism. In this paper, we hypothesize that circadian rhythms need to be considered in radiation protection and optimization in personalized medicine, especially for paediatric care. The sensitivity of the eye lens to ionizing radiation makes the case for limiting damage to the lens epithelium by planning medical radio-imaging procedures for the afternoon, rather than the morning. Equally, the tumour and normal tissue response to radiotherapy is also subject to diurnal variation enabling optimization of time of treatment.
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Affiliation(s)
- E Forssell-Aronsson
- Department of Radiation Physics, Institute of Clinical Sciences, Sahlgrenska Cancer Center,Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, SE 413 45 Gothenburg, Sweden
| | - R A Quinlan
- Department of Biosciences, University of Durham, Mountjoy Science Site, Durham DH1 3LE, UK
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Abstract
Diets and feeding regimens affect many physiological systems in the organism and may contribute to the development or prevention of various pathologies including cardiovascular diseases or metabolic syndromes. Some of the dietary paradigms, such as calorie restriction, have many well-documented positive metabolic effects as well as the potential to extend longevity in different organisms. Recently, the circadian clocks were put forward as integral components of the calorie restriction mechanisms. The circadian clocks generate the circadian rhythms in behavior, physiology, and metabolism; circadian disruption is associated with reduced fitness and decreased longevity. Here we focus on recent advances in the interplay between the circadian clocks and dietary paradigms. We discuss how the regulation of the circadian clocks by feeding/nutrients and regulation of nutrient signaling pathways by the clocks may contribute to the beneficial effects of calorie restriction on metabolism and longevity, and whether the circadian system can be engaged for future medical applications.
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Affiliation(s)
- Amol Chaudhari
- Department of Biological, Geological, and Environmental Sciences and Center for Gene Regulation in Health and Diseases, Cleveland State University, Cleveland, OH, USA
| | - Richa Gupta
- Department of Biological, Geological, and Environmental Sciences and Center for Gene Regulation in Health and Diseases, Cleveland State University, Cleveland, OH, USA
| | - Kuldeep Makwana
- Department of Biological, Geological, and Environmental Sciences and Center for Gene Regulation in Health and Diseases, Cleveland State University, Cleveland, OH, USA
| | - Roman Kondratov
- Department of Biological, Geological, and Environmental Sciences and Center for Gene Regulation in Health and Diseases, Cleveland State University, Cleveland, OH, USA
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Höytö A, Herrala M, Luukkonen J, Juutilainen J, Naarala J. Cellular detection of 50 Hz magnetic fields and weak blue light: effects on superoxide levels and genotoxicity. Int J Radiat Biol 2017; 93:646-652. [PMID: 28264623 DOI: 10.1080/09553002.2017.1294275] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
PURPOSE We tested the hypothesis that the effects of 50 Hz magnetic fields (MFs) on superoxide levels and genotoxicity depend on the presence of blue light. MATERIALS AND METHODS Human SH-SY5Y neuroblastoma cells were exposed to a 50 Hz, 100 μT MF with or without non-phototoxic level of blue light for 24 h. We also studied whether these treatments alter responses to menadione, an agent that induces mitochondrial superoxide (O2• -) production and DNA damage. Micronuclei, proliferation, viability, cytosolic and mitochondrial O2• - levels were assessed. RESULTS MF (without blue light) increased cytosolic O2• - production and blue light suppressed this effect. Mitochondrial O2• - production was reduced by both MF and blue light, but these effects were not additive. Micronucleus frequency was not affected by blue light or MF alone, but blue light (significantly when combined with MF) enhanced menadione-induced micronuclei. CONCLUSIONS The original simple hypothesis (blue light is needed for MF effects) was not supported, but interaction of MF and blue light was nevertheless observed. The results are consistent with MF effects on light-independent radical reactions.
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Affiliation(s)
- Anne Höytö
- a Department of Environmental and Biological Sciences , University of Eastern Finland , Kuopio , Finland
| | - Mikko Herrala
- a Department of Environmental and Biological Sciences , University of Eastern Finland , Kuopio , Finland
| | - Jukka Luukkonen
- a Department of Environmental and Biological Sciences , University of Eastern Finland , Kuopio , Finland
| | - Jukka Juutilainen
- a Department of Environmental and Biological Sciences , University of Eastern Finland , Kuopio , Finland
| | - Jonne Naarala
- a Department of Environmental and Biological Sciences , University of Eastern Finland , Kuopio , Finland
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Chow ES, Long DM, Giebultowicz JM. Circadian rhythm in mRNA expression of the glutathione synthesis gene Gclc is controlled by peripheral glial clocks in Drosophila melanogaster. PHYSIOLOGICAL ENTOMOLOGY 2016; 41:369-377. [PMID: 28503020 PMCID: PMC5423673 DOI: 10.1111/phen.12164] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
Abstract
Circadian coordination of metabolism, physiology, and behaviour is found in all living kingdoms. Clock genes are transcriptional regulators, and their rhythmic activities generate daily rhythms in clock-controlled genes which result in cellular and organismal rhythms. Insects provide numerous examples of rhythms in behaviour and reproduction, but less is known about control of metabolic processes by circadian clocks in insects. Recent data suggest that several pathways involved in protecting cells from oxidative stress may be modulated by the circadian system, including genes involved in glutathione (GSH) biosynthesis. Specifically, rhythmic expression of the gene encoding the catalytic subunit (Gclc) of the rate-limiting GSH biosynthetic enzyme was detected in Drosophila melanogaster heads. The aim of this study was to determine which clocks in the fly multi-oscillatory circadian system are responsible for Gclc rhythms. Genetic disruption of tissue-specific clocks in D. melanogaster revealed that transcriptional rhythms in Gclc mRNA levels occur independently of the central pacemaker neurons, because these rhythms persisted in heads of behaviourally arrhythmic flies with a disabled central clock but intact peripheral clocks. Disrupting the clock specifically in glial cells abolished rhythmic expression of Gclc, suggesting that glia play an important role in Gclc transcriptional regulation, which may contribute to maintaining homeostasis in the fly nervous system.
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Affiliation(s)
- Eileen S Chow
- Department of Integrative Biology, Oregon State University, Corvallis, Oregon, U.S.A
| | - Dani M Long
- Department of Integrative Biology, Oregon State University, Corvallis, Oregon, U.S.A
- IGERT in Aging Sciences, Center for Healthy Aging Research, Oregon State University, Corvallis, Oregon, U.S.A
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48
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Xu J, Li Y, Wang Y, Xu Y, Zhou C. Loss of Bmal1 decreases oocyte fertilization, early embryo development and implantation potential in female mice. ZYGOTE 2016; 24:760-7. [PMID: 27140828 DOI: 10.1017/s0967199416000083] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Biological clock genes expressed in reproductive tissues play important roles in maintaining the normal functions of reproductive system. However, disruption of female circadian rhythm on oocyte fertilization, preimplantation embryo development and blastocyst implantation potential is still unclear. In this study, ovulation, in vivo and in vitro oocyte fertilization, embryo development, implantation and intracellular reactive oxygen species (ROS) levels in ovary and oviduct were studied in female Bmal1+/+ and Bmal1-/- mice. The number of naturally ovulated oocyte in Bmal1-/- mice decreased (5.2 ± 0.8 vs 7.8 ± 0.8, P < 0.001), with an increasing abnormal oocyte ratio (20.4 ± 3.5 vs 11.7 ± 2.0%, P = 0.001) after superovulation. Significantly lower fertilization rate and obtained blastocyst number were observed in Bmal1-/- female mice either mated with wild-type in vivo or fertilized by sperm from wild-type male mice in vitro (all P < 0.05). Interestingly, in vitro fertilization rate of oocytes derived from Bmal1-/- increased significantly compared with in vivo study (P < 0.01). After transferring blastocysts derived from Bmal1+/+ and Bmal1-/- female mice to pseudopregnant mice, the implantation sites of the latter decreased 5 days later (8.0 ± 0.8 vs 5.3 ± 1.0, P = 0.005). The intracellular ROS levels in the ovary on proestrus day and in the oviduct on metestrus day increased significantly in Bmal1-/- mice compared with that of Bmal1+/+ mice. Deletion of the core biological clock gene Bmal1 significantly decreases oocyte fertilization rate, early embryo development and implantation potential in female mice, and these may be possibly caused by excess ROS levels generated in ovary and oviduct.
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Affiliation(s)
- Jian Xu
- Reproductive Medicine Center,Guangzhou Women and Children's Medical Center,Guangzhou,Guangzhou Medical University,China
| | - Yan Li
- Reproductive Medicine Center,Henan Provincial People's Hospital,Zhengzhou,Henan,China
| | - Yizi Wang
- Reproductive Medicine Center,First Affiliated Hospital of Sun Yat-sen University,Guangzhou,China;Guangdong Provincial Key Laboratory of Reproductive Medicine,Guangdong,China
| | - Yanwen Xu
- Reproductive Medicine Center,First Affiliated Hospital of Sun Yat-sen University,58 Zhongshan Road II,Guangzhou,China
| | - Canquan Zhou
- Reproductive Medicine Center,First Affiliated Hospital of Sun Yat-sen University,58 Zhongshan Road II,Guangzhou,China
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Tamaru T, Ikeda M. Circadian adaptation to cell injury stresses: a crucial interplay of BMAL1 and HSF1. J Physiol Sci 2016; 66:303-6. [PMID: 26910317 PMCID: PMC10717996 DOI: 10.1007/s12576-016-0436-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2015] [Accepted: 02/02/2016] [Indexed: 10/22/2022]
Abstract
The circadian clock system confers daily anticipatory physiological processes with the ability to be reset by environmental cues. This "circadian adaptation system" (CAS), driven by cell-autonomous molecular clocks, orchestrates various rhythmic physiological processes in the entire body. Hence, the dysfunction of these clocks exacerbates various diseases, which may partially be due to the impairment of protective pathways. If this is the case, how does the CAS respond to cell injury stresses that are critical in maintaining health and life by evoking protective pathways? To address this question, here we review and discuss recent evidence revealing life-protective (pro-survival) molecular networks between clock (e.g., BMAL1, CLOCK, and PER2) and adaptation (e.g., HSF1, Nrf2, NF-κB, and p53) pathways, which are evoked by various cell injury stresses (e.g., heat, reactive oxygen species, and UV). The CK2 protein kinase-integrated interplay of the BMAL1 (clock) and HSF1 (heat-shock response) pathways is one of the crucial events in CAS.
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Affiliation(s)
- Teruya Tamaru
- Department of Physiology and Advanced Research Center for Medical Science, Toho University School of Medicine, 5-21-16 Ohmori-nishi Ohta-ku, Tokyo, 143-8540, Japan.
| | - Masaaki Ikeda
- Department of Physiology, Faculty of Medicine, Saitama Medical University, 38 Morohongo Moroyama-machi, Iruma-gun, Saitama, 350-0495, Japan
- Molecular Clock Project, Project Research Division, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama, 350-1241, Japan
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50
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Becattini B, Zani F, Breasson L, Sardi C, D'Agostino VG, Choo MK, Provenzani A, Park JM, Solinas G. JNK1 ablation in mice confers long-term metabolic protection from diet-induced obesity at the cost of moderate skin oxidative damage. FASEB J 2016; 30:3124-32. [PMID: 27230858 DOI: 10.1096/fj.201600393r] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Accepted: 05/19/2016] [Indexed: 12/22/2022]
Abstract
Obesity and insulin resistance are associated with oxidative stress, which may be implicated in the progression of obesity-related diseases. The kinase JNK1 has emerged as a promising drug target for the treatment of obesity and type 2 diabetes. JNK1 is also a key mediator of the oxidative stress response, which can promote cell death or survival, depending on the magnitude and context of its activation. In this article, we describe a study in which the long-term effects of JNK1 inactivation on glucose homeostasis and oxidative stress in obese mice were investigated for the first time. Mice lacking JNK1 (JNK1(-/-)) were fed an obesogenic high-fat diet (HFD) for a long period. JNK1(-/-) mice fed an HFD for the long term had reduced expression of antioxidant genes in their skin, more skin oxidative damage, and increased epidermal thickness and inflammation compared with the effects in control wild-type mice. However, we also observed that the protection from obesity, adipose tissue inflammation, steatosis, and insulin resistance, conferred by JNK1 ablation, was sustained over a long period and was paralleled by decreased oxidative damage in fat and liver. We conclude that compounds targeting JNK1 activity in brain and adipose tissue, which do not accumulate in the skin, may be safer and most effective.-Becattini, B., Zani, F., Breasson, L., Sardi, C., D'Agostino, V. G., Choo, M.-K., Provenzani, A., Park, J. M., Solinas, G. JNK1 ablation in mice confers long-term metabolic protection from diet-induced obesity at the cost of moderate skin oxidative damage.
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Affiliation(s)
- Barbara Becattini
- Laboratory of Metabolic Stress Biology, Department of Medicine, University of Fribourg, Fribourg, Switzerland
| | - Fabio Zani
- Laboratory of Metabolic Stress Biology, Department of Medicine, University of Fribourg, Fribourg, Switzerland
| | - Ludovic Breasson
- Laboratory of Metabolic Stress Biology, Department of Medicine, University of Fribourg, Fribourg, Switzerland
| | - Claudia Sardi
- Laboratory of Metabolic Stress Biology, Department of Medicine, University of Fribourg, Fribourg, Switzerland
| | | | - Min-Kyung Choo
- Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA
| | | | - Jin Mo Park
- Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA
| | - Giovanni Solinas
- Laboratory of Metabolic Stress Biology, Department of Medicine, University of Fribourg, Fribourg, Switzerland;
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