|
1
|
Ng C, Kim M, Yanti, Kwak MK. Oxidative stress and NRF2 signaling in kidney injury. Toxicol Res 2025; 41:131-147. [PMID: 40013079 PMCID: PMC11850685 DOI: 10.1007/s43188-024-00272-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 11/24/2024] [Accepted: 11/30/2024] [Indexed: 02/28/2025] Open
Abstract
Oxidative stress plays a crucial role in the pathogenesis of acute kidney injury (AKI), chronic kidney disease (CKD), and the AKI-to-CKD transition. This review examines the intricate relationship between oxidative stress and kidney pathophysiology, emphasizing the potential therapeutic role of nuclear factor erythroid 2-related factor 2 (NRF2), a master regulator of cellular redox homeostasis. In diverse AKI and CKD models, diminished NRF2 activity exacerbates oxidative stress, whereas genetic and pharmacological NRF2 activation alleviates kidney damage induced by nephrotoxic agents, ischemia-reperfusion injury, fibrotic stimuli, and diabetic nephropathy. The renoprotective effects of NRF2 extend beyond antioxidant defense, encompassing its anti-inflammatory and anti-fibrotic properties. The significance of NRF2 in renal fibrosis is further underscored by its interaction with the transforming growth factor-β signaling cascade. Clinical trials using bardoxolone methyl, a potent NRF2 activator, have yielded both encouraging and challenging outcomes, illustrating the intricacy of modulating NRF2 in human subjects. In summary, this overview suggests the therapeutic potential of targeting NRF2 in kidney disorders and highlights the necessity for continued research to refine treatment approaches.
Collapse
Affiliation(s)
- Cherry Ng
- Department of Pharmacy and BK21FOUR Advanced Program for Smart Pharma Leaders, Graduate School of The Catholic University of Korea, Gyeonggi-do, 14662 Republic of Korea
| | - Maxine Kim
- Department of Pharmacy and BK21FOUR Advanced Program for Smart Pharma Leaders, Graduate School of The Catholic University of Korea, Gyeonggi-do, 14662 Republic of Korea
| | - Yanti
- Faculty of Biotechnology, Atma Jaya Catholic University of Indonesia, Jakarta, 12930 Indonesia
| | - Mi-Kyoung Kwak
- Department of Pharmacy and BK21FOUR Advanced Program for Smart Pharma Leaders, Graduate School of The Catholic University of Korea, Gyeonggi-do, 14662 Republic of Korea
- College of Pharmacy, The Catholic University of Korea, 43 Jibong-Ro, Bucheon, Gyeonggi-do 14662 Republic of Korea
| |
Collapse
|
|
2
|
Park SY, Kim KY, Gwak DS, Shin SY, Jun DY, Kim YH. L-Cysteine mitigates ROS-induced apoptosis and neurocognitive deficits by protecting against endoplasmic reticulum stress and mitochondrial dysfunction in mouse neuronal cells. Biomed Pharmacother 2024; 180:117538. [PMID: 39393330 DOI: 10.1016/j.biopha.2024.117538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 09/30/2024] [Accepted: 10/04/2024] [Indexed: 10/13/2024] Open
Abstract
Oxidative stress and mitochondrial dysfunction play critical roles in neurodegenerative diseases. Glutathione (GSH), a key brain antioxidant, helps to neutralize reactive oxygen species (ROS) and maintain redox balance. We investigated the effectiveness of L-cysteine (L-Cys) in preventing apoptosis induced by the ROS generator 2,3-dimethoxy-1,4-naphthoquinone (DMNQ) in mouse hippocampal neuronal HT22 cells, as well as alleviating memory and cognitive impairments caused by the GSH synthesis inhibitor L-buthionine sulfoximine (BSO) in mice. DMNQ-induced apoptotic events in HT22 cells, including elevated cytosolic and mitochondrial ROS levels, DNA fragmentation, endoplasmic reticulum stress, and mitochondrial damage-mediated apoptotic pathways were dose-dependently abrogated by L-Cys (0.5-2 mM). The reduced intracellular GSH level, caused by DMNQ treatment, was restored by L-Cys cotreatment. Although L-Cys did not significantly restore GSH in the presence of BSO, it prevented DMNQ-induced ROS elevation, mitochondrial damage, and apoptosis. Furthermore, compared to N-acetylcysteine and GSH, L-Cys had higher 2,2-diphenyl-1-picrylhydrazyl and 2,2-azino-bis-3-ethylbenzothiazoline-6-sulphonic acid radical-scavenging activity. L-Cys also restored mitochondrial respiration capacity in DMNQ-treated HT22 cells by reversing mitochondrial fission-fusion dynamic balance. BSO administration (500 mg/kg/day) in mice led to neuronal deficits, including memory and cognitive impairments, which were effectively mitigated by oral L-Cys (15 or 30 mg/kg/day). L-Cys also reduced BSO-induced ROS levels in the mice hippocampus and cortex. These findings suggest that even though it does not contribute to intracellular GSH synthesis, exogenous L-Cys protects neuronal cells against oxidative stress-induced mitochondrial damage and apoptosis, by acting as a ROS scavenger, which is beneficial in ameliorating neurocognitive deficits caused by oxidative stress.
Collapse
Affiliation(s)
- Shin Young Park
- Laboratory of Immunobiology, School of Life Science, College of Natural Sciences, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu 41566, Republic of Korea; AT-31 BIO Inc., Business Incubation Center, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu 41566, Republic of Korea
| | - Ki Yun Kim
- Laboratory of Immunobiology, School of Life Science, College of Natural Sciences, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu 41566, Republic of Korea; AT-31 BIO Inc., Business Incubation Center, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu 41566, Republic of Korea
| | - Dong Seol Gwak
- Laboratory of Immunobiology, School of Life Science, College of Natural Sciences, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu 41566, Republic of Korea
| | - Soon Young Shin
- Department of Biological Sciences, Sanghuh College of Life Sciences, Konkuk University, Seoul 05029, Republic of Korea
| | - Do Youn Jun
- AT-31 BIO Inc., Business Incubation Center, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu 41566, Republic of Korea
| | - Young Ho Kim
- Laboratory of Immunobiology, School of Life Science, College of Natural Sciences, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu 41566, Republic of Korea; AT-31 BIO Inc., Business Incubation Center, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu 41566, Republic of Korea.
| |
Collapse
|
|
3
|
Löser A, Schwarz M, Kipp AP. NRF2 and Thioredoxin Reductase 1 as Modulators of Interactions between Zinc and Selenium. Antioxidants (Basel) 2024; 13:1211. [PMID: 39456464 PMCID: PMC11505002 DOI: 10.3390/antiox13101211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 10/07/2024] [Accepted: 10/07/2024] [Indexed: 10/28/2024] Open
Abstract
BACKGROUND Selenium and zinc are essential trace elements known to regulate cellular processes including redox homeostasis. During inflammation, circulating selenium and zinc concentrations are reduced in parallel, but underlying mechanisms are unknown. Accordingly, we modulated the zinc and selenium supply of HepG2 cells to study their relationship. METHODS HepG2 cells were supplied with selenite in combination with a short- or long-term zinc treatment to investigate intracellular concentrations of selenium and zinc together with biomarkers describing their status. In addition, the activation of the redox-sensitive transcription factor NRF2 was analyzed. RESULTS Zinc not only increased the nuclear translocation of NRF2 after 2 to 6 h but also enhanced the intracellular selenium content after 72 h, when the cells were exposed to both trace elements. In parallel, the activity and expression of the selenoprotein thioredoxin reductase 1 (TXNRD1) increased, while the gene expression of other selenoproteins remained unaffected or was even downregulated. The zinc effects on the selenium concentration and TXNRD activity were reduced in cells with stable NRF2 knockdown in comparison to control cells. CONCLUSIONS This indicates a functional role of NRF2 in mediating the zinc/selenium crosstalk and provides an explanation for the observed unidirectional behavior of selenium and zinc.
Collapse
Affiliation(s)
- Alina Löser
- Department of Nutritional Physiology, Institute of Nutritional Sciences, Friedrich Schiller University Jena, 07743 Jena, Germany; (A.L.); (M.S.)
- TraceAge-DFG Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly, Potsdam-Berlin-Jena-Wuppertal, 14558 Nuthetal, Germany
| | - Maria Schwarz
- Department of Nutritional Physiology, Institute of Nutritional Sciences, Friedrich Schiller University Jena, 07743 Jena, Germany; (A.L.); (M.S.)
- TraceAge-DFG Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly, Potsdam-Berlin-Jena-Wuppertal, 14558 Nuthetal, Germany
| | - Anna Patricia Kipp
- Department of Nutritional Physiology, Institute of Nutritional Sciences, Friedrich Schiller University Jena, 07743 Jena, Germany; (A.L.); (M.S.)
- TraceAge-DFG Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly, Potsdam-Berlin-Jena-Wuppertal, 14558 Nuthetal, Germany
| |
Collapse
|
|
4
|
Jin X, Lou X, Qi H, Zheng C, Li B, Siwu X, Liu R, Lv Q, Zhao A, Ruan J, Jiang M. NRF2 signaling plays an essential role in cancer progression through the NRF2-GPX2-NOTCH3 axis in head and neck squamous cell carcinoma. Oncogenesis 2024; 13:35. [PMID: 39333079 PMCID: PMC11437035 DOI: 10.1038/s41389-024-00536-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 09/13/2024] [Accepted: 09/18/2024] [Indexed: 09/29/2024] Open
Abstract
The activation of nuclear factor erythroid 2-related factor 2 (NRF2) has been observed in various cancers. Yet its exact contribution to the development of head and neck squamous cell carcinoma (HNSCC) remains undetermined. We previously found that NRF2 signaling is critical for the differentiation of squamous basal progenitor cells, while disruption of NRF2 causes basal cell hyperplasia. In this study, we revealed a correlation between elevated NRF2 activity and poor outcomes in HNSCC patients. We demonstrated that NRF2 facilitates tumor proliferation, migration, and invasion, as evidenced by both in vitro and in vivo studies. Significantly, NRF2 augments the expression of the antioxidant enzyme GPX2, thereby enhancing the proliferative, migratory, and invasive properties of HNSCC cells. Activation of GPX2 is critical for sustaining cancer stem cells (CSCs) by up-regulating NOTCH3, a key driver of cancer progression. These results elucidate that NRF2 regulates HNSCC progression through the NRF2-GPX2-NOTCH3 axis. Our findings proposed that pharmacological targeting of the NRF2-GPX2-NOTCH3 axis could be a potential therapeutic approach against HNSCC.
Collapse
Affiliation(s)
- Xiaoye Jin
- Center for Genetic Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Institute of Genetics, Zhejiang University International School of Medicine, Zhejiang Provincial Key Laboratory of Genetic & Developmental Disorders, Hangzhou, China
| | - Xiayuan Lou
- Center for Genetic Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Institute of Genetics, Zhejiang University International School of Medicine, Zhejiang Provincial Key Laboratory of Genetic & Developmental Disorders, Hangzhou, China
| | - Haoxiang Qi
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China
| | - Chao Zheng
- Center for Genetic Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Institute of Genetics, Zhejiang University International School of Medicine, Zhejiang Provincial Key Laboratory of Genetic & Developmental Disorders, Hangzhou, China
| | - Bo Li
- Center for Genetic Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Institute of Genetics, Zhejiang University International School of Medicine, Zhejiang Provincial Key Laboratory of Genetic & Developmental Disorders, Hangzhou, China
| | - Xuerong Siwu
- Center for Genetic Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Institute of Genetics, Zhejiang University International School of Medicine, Zhejiang Provincial Key Laboratory of Genetic & Developmental Disorders, Hangzhou, China
| | - Ren Liu
- Center for Genetic Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Institute of Genetics, Zhejiang University International School of Medicine, Zhejiang Provincial Key Laboratory of Genetic & Developmental Disorders, Hangzhou, China
| | - Qiaoli Lv
- Institute of Cancer Research, Jiangxi Cancer Hospital, Nanchang, China
| | - An Zhao
- Institute of Cancer Research, Zhejiang Cancer Hospital, Hangzhou, China
| | - Jian Ruan
- Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University and Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Hangzhou, China
| | - Ming Jiang
- Center for Genetic Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
- Institute of Genetics, Zhejiang University International School of Medicine, Zhejiang Provincial Key Laboratory of Genetic & Developmental Disorders, Hangzhou, China.
| |
Collapse
|
|
5
|
Luchkova A, Mata A, Cadenas S. Nrf2 as a regulator of energy metabolism and mitochondrial function. FEBS Lett 2024; 598:2092-2105. [PMID: 39118293 DOI: 10.1002/1873-3468.14993] [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: 03/09/2024] [Revised: 06/13/2024] [Accepted: 06/27/2024] [Indexed: 08/10/2024]
Abstract
Nuclear factor erythroid-2-related factor 2 (Nrf2) is essential for the control of cellular redox homeostasis. When activated, Nrf2 elicits cytoprotective effects through the expression of several genes encoding antioxidant and detoxifying enzymes. Nrf2 can also improve antioxidant defense via the pentose phosphate pathway by increasing NADPH availability to regenerate glutathione. Microarray and genome-wide localization analyses have identified many Nrf2 target genes beyond those linked to its redox-regulatory capacity. Nrf2 regulates several intermediary metabolic pathways and is involved in cancer cell metabolic reprogramming, contributing to malignant phenotypes. Nrf2 also modulates substrate utilization for mitochondrial respiration. Here we review the experimental evidence supporting the essential role of Nrf2 in the regulation of energy metabolism and mitochondrial function.
Collapse
Affiliation(s)
- Alina Luchkova
- Centro de Biología Molecular Severo Ochoa (CSIC/UAM), Cantoblanco, Madrid, Spain
| | - Ana Mata
- Centro de Biología Molecular Severo Ochoa (CSIC/UAM), Cantoblanco, Madrid, Spain
| | - Susana Cadenas
- Centro de Biología Molecular Severo Ochoa (CSIC/UAM), Cantoblanco, Madrid, Spain
| |
Collapse
|
|
6
|
O’Connor C, Keele GR, Martin W, Stodola T, Gatti D, Hoffman BR, Korstanje R, Churchill GA, Reinholdt LG. Unraveling the genetics of arsenic toxicity with cellular morphology QTL. PLoS Genet 2024; 20:e1011248. [PMID: 38662777 PMCID: PMC11075906 DOI: 10.1371/journal.pgen.1011248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 05/07/2024] [Accepted: 04/03/2024] [Indexed: 05/08/2024] Open
Abstract
The health risks that arise from environmental exposures vary widely within and across human populations, and these differences are largely determined by genetic variation and gene-by-environment (gene-environment) interactions. However, risk assessment in laboratory mice typically involves isogenic strains and therefore, does not account for these known genetic effects. In this context, genetically heterogenous cell lines from laboratory mice are promising tools for population-based screening because they provide a way to introduce genetic variation in risk assessment without increasing animal use. Cell lines from genetic reference populations of laboratory mice offer genetic diversity, power for genetic mapping, and potentially, predictive value for in vivo experimentation in genetically matched individuals. To explore this further, we derived a panel of fibroblast lines from a genetic reference population of laboratory mice (the Diversity Outbred, DO). We then used high-content imaging to capture hundreds of cell morphology traits in cells exposed to the oxidative stress-inducing arsenic metabolite monomethylarsonous acid (MMAIII). We employed dose-response modeling to capture latent parameters of response and we then used these parameters to identify several hundred cell morphology quantitative trait loci (cmQTL). Response cmQTL encompass genes with established associations with cellular responses to arsenic exposure, including Abcc4 and Txnrd1, as well as novel gene candidates like Xrcc2. Moreover, baseline trait cmQTL highlight the influence of natural variation on fundamental aspects of nuclear morphology. We show that the natural variants influencing response include both coding and non-coding variation, and that cmQTL haplotypes can be used to predict response in orthogonal cell lines. Our study sheds light on the major molecular initiating events of oxidative stress that are under genetic regulation, including the NRF2-mediated antioxidant response, cellular detoxification pathways, DNA damage repair response, and cell death trajectories.
Collapse
Affiliation(s)
- Callan O’Connor
- The Jackson Laboratory, Bar Harbor, Maine, United States of America
- Graduate School of Biomedical Sciences, Tufts University, Boston, Massachusetts, United States of America
| | - Gregory R. Keele
- The Jackson Laboratory, Bar Harbor, Maine, United States of America
- RTI International, Research Triangle Park, Durham, North Carolina, United States of America
| | - Whitney Martin
- The Jackson Laboratory, Bar Harbor, Maine, United States of America
| | - Timothy Stodola
- The Jackson Laboratory, Bar Harbor, Maine, United States of America
| | - Daniel Gatti
- The Jackson Laboratory, Bar Harbor, Maine, United States of America
| | - Brian R. Hoffman
- The Jackson Laboratory, Bar Harbor, Maine, United States of America
| | - Ron Korstanje
- The Jackson Laboratory, Bar Harbor, Maine, United States of America
- Graduate School of Biomedical Sciences, Tufts University, Boston, Massachusetts, United States of America
| | - Gary A. Churchill
- The Jackson Laboratory, Bar Harbor, Maine, United States of America
- Graduate School of Biomedical Sciences, Tufts University, Boston, Massachusetts, United States of America
| | - Laura G. Reinholdt
- The Jackson Laboratory, Bar Harbor, Maine, United States of America
- Graduate School of Biomedical Sciences, Tufts University, Boston, Massachusetts, United States of America
| |
Collapse
|
|
7
|
Jiang Q, Galvão MC, Thanh LP, Aboragah AA, Mauck J, Gionbelli MP, Alhidary IA, McCann JC, Loor JJ. Short-term feed restriction induces inflammation and an antioxidant response via cystathionine-β-synthase and glutathione peroxidases in ruminal epithelium from Angus steers. J Anim Sci 2024; 102:skae257. [PMID: 39215655 PMCID: PMC11465371 DOI: 10.1093/jas/skae257] [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: 04/16/2024] [Accepted: 08/29/2024] [Indexed: 09/04/2024] Open
Abstract
Decreased intake is induced by stressors such as parturition, transportation, dietary transitions, and disease. An important function of one-carbon metabolism (OCM) is to produce the antioxidant glutathione to help reduce oxidative stress. Although various components of OCM are expressed in the bovine rumen and small intestine, the relationship between reduced feed intake, OCM, and antioxidant mechanisms in gut tissues is unknown. This study aimed to assess alterations in immune and antioxidant pathways in ruminal epithelium due to acute feed restriction (FR). Seven group-housed ruminally cannulated Angus steers (663 ± 73 kg body weight, 2 yr old) had ad libitum access to a finishing diet (dry-rolled corn, corn silage, modified wet distiller's grains) during 15 d of a pre-FR period (PRE). Subsequently, steers were moved to a metabolism barn with tie stalls and individually fed at 25% of estimated intake in PRE for 3 d (FR period, FRP). This was followed by 15 d of recovery (POST) during which steers had ad libitum access to the same diet as in PRE and FRP. Plasma and ruminal tissue biopsies were collected during each period. Plasma free fatty acid and IL1-β concentrations were higher (P ≤ 0.03) in FRP than PRE or POST. The mRNA abundance of the proinflammatory genes tumor necrosis factor, toll-like receptor 2 (TLR2), and TLR4 in the ruminal epithelium peaked (P < 0.05) at FRP and remained higher at POST. These responses agreed with the higher (P < 0.05) abundance of phosphorylated (p)-MAPK (an inflammation activator) and p-EEF2 (translational repressor) in FRP than PRE and POST. Although ruminal glutathione peroxidase (GPX) enzyme activity did not increase at FRP compared with PRE and POST, protein abundance of GPX1 and GPX3 along with the antioxidant response regulator NFE2L2 were highest (P < 0.01), and the activity of cystathionine-beta synthase tended (P = 0.06) to be highest during FR. Although FR had minimal negative effects on tissue integrity-related genes (only filamin A was downregulated), it led to a systemic inflammatory response and triggered inflammation and antioxidant mechanisms within the ruminal epithelium. Thus, deploying anti-inflammatory and antioxidant mechanisms via molecules that feed into OCM (e.g., dietary methyl donors such as methionine, choline, betaine, and folate) could potentially counteract the stressors associated with FR.
Collapse
Affiliation(s)
- Qianming Jiang
- Department of Animal Sciences, University of Illinois, Urbana, IL, USA
| | - Matheus C Galvão
- Department of Animal Sciences, University of Illinois, Urbana, IL, USA
- Department of Animal Science, Universidade Federal de Lavras, Lavras, Minas Gerais, Brazil
| | - Lam Phuoc Thanh
- Faculty of Animal Sciences, Can Tho University, Ninh Kieu, Can Tho, Vietnam
| | - Ahmad A Aboragah
- Department of Animal Production, College of Food and Agriculture Sciences, King Saud University, Riyadh, Saudi Arabia
| | - John Mauck
- Department of Animal Sciences, University of Illinois, Urbana, IL, USA
| | - Mateus Pies Gionbelli
- Department of Animal Science, Universidade Federal de Lavras, Lavras, Minas Gerais, Brazil
| | - Ibrahim A Alhidary
- Department of Animal Production, College of Food and Agriculture Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Joshua C McCann
- Department of Animal Sciences, University of Illinois, Urbana, IL, USA
| | - Juan J Loor
- Department of Animal Sciences, University of Illinois, Urbana, IL, USA
- Division of Nutritional Sciences, University of Illinois, Urbana, IL, USA
| |
Collapse
|
|
8
|
Dike C, Orish CN, Ezejiofor AN, Cirovic A, Cirovic A, Babatunde B, Sikoki F, Orisakwe OE. Selenium and zinc alleviate quaternary metal mixture -induced neurotoxicity in rats by inhibiting oxidative damage and modulating the expressions of NF-kB and Nrf2/Hmox-1 pathway. IBRO Neurosci Rep 2023; 15:57-67. [PMID: 37415728 PMCID: PMC10320409 DOI: 10.1016/j.ibneur.2023.06.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 06/12/2023] [Accepted: 06/13/2023] [Indexed: 07/08/2023] Open
Abstract
Background This study evaluated the potential protective effects of Zn and Se in the cerebellum and cerebral cortex, two fundamentally important brain regions, in albino rats that were exposed to heavy metals mixture (Al, Pb, Hg and Mn). Methods Animals were divided into five groups of seven animals per group with following patterns of exposure, controls group 1 were orally treated with deionized water for 60 days; group 2 was exposed to heavy metal mixture (HMM) with following concentrations (20 mg·kg-1 of Pb body weight; 0.40 mg·kg-1 of Hg; 0.56 mg·kg-1 of Mn; and 35 mg·kg-1; of Al), while groups 3,4 and 5 were exposed to HMM and orally co-treated with zinc chloride (ZnCl2; 0.80 mg/kg), sodium selenite (Na2SeO3;1.50 mg/kg) and zinc chloride plus sodium selenite (ZnCl0.2 + Na2SeO3) respectively. Results Exposure to HMM depressed cellular antioxidant apparatus, induced generation of lipid peroxidation markers (Malondialdehyde and NO), downregulated expression of transcription factors (Nrf2, and NF-kB) and upregulated Caspase 3 levels. HMM potentiated acetylcholinesterase activity and induced moderate histopathological alterations. Nevertheless, Zn, Se and in particular Zn + Se had recovering effects on all mentioned hazardous effects produced by HMM exposure in the cerebral cortex and cerebellum. Conclusions Selenium and zinc exert neuroprotection via Nrf2/NF-kB signaling pathways against quaternary heavy metal mixture-induced impairments in albino Sprague Dawley rats.
Collapse
Affiliation(s)
- Chinyere Dike
- African Centre of Excellence for Public Health and Toxicological Research (ACE-PUTOR), University of Port Harcourt, PMB, 5323 Port Harcourt, Choba, Nigeria
| | - Chinna N. Orish
- Department of Anatomy, Faculty of Basic Medical Sciences, College of Health Sciences, University of Port Harcourt, PMB, 5323 Port Harcourt, Choba, Nigeria
| | - Anthonet N. Ezejiofor
- African Centre of Excellence for Public Health and Toxicological Research (ACE-PUTOR), University of Port Harcourt, PMB, 5323 Port Harcourt, Choba, Nigeria
| | - Ana Cirovic
- University of Belgrade, Faculty of Medicine, Institute of Anatomy, Belgrade, Serbia
| | - Aleksandar Cirovic
- University of Belgrade, Faculty of Medicine, Institute of Anatomy, Belgrade, Serbia
| | - Bolaji Babatunde
- Department of Animal and Environmental Biology, Faculty of Science, University of Port Harcourt, PMB, 5323 Port Harcourt, Choba, Nigeria
| | - Francis Sikoki
- Department of Animal and Environmental Biology, Faculty of Science, University of Port Harcourt, PMB, 5323 Port Harcourt, Choba, Nigeria
| | - Orish E. Orisakwe
- African Centre of Excellence for Public Health and Toxicological Research (ACE-PUTOR), University of Port Harcourt, PMB, 5323 Port Harcourt, Choba, Nigeria
| |
Collapse
|
|
9
|
Feng Y, Chen X, Chen D, He J, Zheng P, Luo Y, Yu B, Huang Z. Dietary grape seed proanthocyanidin extract supplementation improves antioxidant capacity and lipid metabolism in finishing pigs. Anim Biotechnol 2023; 34:4021-4031. [PMID: 37647084 DOI: 10.1080/10495398.2023.2252012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/01/2023]
Abstract
Grape seed proanthocyanidin extract (GSPE) plays a significant role in body health, including improving antioxidant capacity and maintaining lipid metabolism stability. However, whether dietary GSPE supplementation can improve lipid metabolism in finishing pigs remains unclear. Here 18 castrated male Duroc × Landrace × Yorkshire finishing pigs were randomly divided into three groups with six replicates and one pig per replicate. Pigs were fed a basal diet (control), a basal diet supplemented with 100 mg/kg GSPE, or a basal diet supplemented with 200 mg/kg GSPE for 30 days. Antioxidant analysis showed that dietary 200 mg/kg GSPE supplementation increased glutathione, total antioxidant capacity and glutathione peroxidase levels, and reduced malondialdehyde levels in serum, muscle and liver. Dietary 200 mg/kg GSPE supplementation also upregulated the mRNA and protein levels of nuclear-related factor 2 (Nrf2). Lipid metabolism analysis showed that dietary GSPE supplementation increased serum high-density lipoprotein cholesterol levels and reduced serum triglyceride and total cholesterol levels. Besides, GPSE upregulated the mRNA expression of lipolysis- and fatty acid oxidation-related genes downregulated the mRNA expression of lipogenesis-related genes, and activated the AMPK signal in finishing pigs. Together, we provided evidence that dietary GSPE supplementation improved the antioxidant capacity and lipid metabolism in finishing pigs.
Collapse
Affiliation(s)
- Yadi Feng
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan, P. R. China
| | - Xiaoling Chen
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan, P. R. China
| | - Daiwen Chen
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan, P. R. China
| | - Jun He
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan, P. R. China
| | - Ping Zheng
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan, P. R. China
| | - Yuheng Luo
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan, P. R. China
| | - Bing Yu
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan, P. R. China
| | - Zhiqing Huang
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan, P. R. China
| |
Collapse
|
|
10
|
O'Connor C, Keele GR, Martin W, Stodola T, Gatti D, Hoffman BR, Korstanje R, Churchill GA, Reinholdt LG. Cell morphology QTL reveal gene by environment interactions in a genetically diverse cell population. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.11.18.567597. [PMID: 38014303 PMCID: PMC10680806 DOI: 10.1101/2023.11.18.567597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2023]
Abstract
Genetically heterogenous cell lines from laboratory mice are promising tools for population-based screening as they offer power for genetic mapping, and potentially, predictive value for in vivo experimentation in genetically matched individuals. To explore this further, we derived a panel of fibroblast lines from a genetic reference population of laboratory mice (the Diversity Outbred, DO). We then used high-content imaging to capture hundreds of cell morphology traits in cells exposed to the oxidative stress-inducing arsenic metabolite monomethylarsonous acid (MMAIII). We employed dose-response modeling to capture latent parameters of response and we then used these parameters to identify several hundred cell morphology quantitative trait loci (cmQTL). Response cmQTL encompass genes with established associations with cellular responses to arsenic exposure, including Abcc4 and Txnrd1, as well as novel gene candidates like Xrcc2. Moreover, baseline trait cmQTL highlight the influence of natural variation on fundamental aspects of nuclear morphology. We show that the natural variants influencing response include both coding and non-coding variation, and that cmQTL haplotypes can be used to predict response in orthogonal cell lines. Our study sheds light on the major molecular initiating events of oxidative stress that are under genetic regulation, including the NRF2-mediated antioxidant response, cellular detoxification pathways, DNA damage repair response, and cell death trajectories.
Collapse
Affiliation(s)
- Callan O'Connor
- The Jackson Laboratory, Bar Harbor, ME 04609, USA
- Graduate School of Biomedical Sciences, Tufts University, Boston, MA 02111, USA
| | - Gregory R Keele
- The Jackson Laboratory, Bar Harbor, ME 04609, USA
- RTI International, RTP, NC 27709, USA
| | | | | | - Daniel Gatti
- The Jackson Laboratory, Bar Harbor, ME 04609, USA
| | | | | | | | - Laura G Reinholdt
- The Jackson Laboratory, Bar Harbor, ME 04609, USA
- Graduate School of Biomedical Sciences, Tufts University, Boston, MA 02111, USA
| |
Collapse
|
|
11
|
Zhou Y, Zhang A, Fang C, Yuan L, Shao A, Xu Y, Zhou D. Oxidative stress in pituitary neuroendocrine tumors: Affecting the tumor microenvironment and becoming a new target for pituitary neuroendocrine tumor therapy. CNS Neurosci Ther 2023; 29:2744-2759. [PMID: 37341156 PMCID: PMC10493678 DOI: 10.1111/cns.14315] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 05/29/2023] [Accepted: 06/07/2023] [Indexed: 06/22/2023] Open
Abstract
Pituitary adenomas (PAs), or pituitary neuroendocrine tumors (PitNETs), are commonly found in the anterior pituitary gland. Although the majority of PitNETs are benign and stable, several tumors have malignant characteristics. The tumor microenvironment (TME) plays an important role in the process of tumorigenesis and is composed of several types of cells. Various cells in the TME are significantly affected by oxidative stress. It has been reported that immunotherapeutic strategies have good effects in several cancers. However, the clinical potential of immunotherapies in PitNETs has not yet been fully discussed. Oxidative stress can regulate PitNET cells and immune cells in the TME, thus affecting the immune status of the TME of PitNETs. Therefore, modulation of oxidative stress-regulated immune cells using a combination of several agents and the immune system to suppress PitNETs is a promising therapeutic direction. In this review, we systematically analyzed the oxidative stress process within PitNET cells and various immune cells to elucidate the potential value of immunotherapy.
Collapse
Affiliation(s)
- Yuhang Zhou
- The First Clinical Medical CollegeHeilongjiang University of Chinese MedicineHarbinChina
- Health Management CenterTongde Hospital of Zhejiang ProvinceHangzhouChina
| | - Anke Zhang
- Department of Neurosurgery, The Second Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
| | - Chaoyou Fang
- Department of Neurosurgery, Shanghai General Hospital, School of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Ling Yuan
- School of Public Health, School of MedicineShanghai Jiaotong UniversityShanghaiChina
| | - Anwen Shao
- Department of Neurosurgery, The Second Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
| | - Yuanzhi Xu
- Department of Neurosurgery, Huashan Hospital, School of MedicineFudan UniversityShanghaiChina
| | - Danyang Zhou
- Health Management CenterTongde Hospital of Zhejiang ProvinceHangzhouChina
| |
Collapse
|
|
12
|
Chaudière J. Biological and Catalytic Properties of Selenoproteins. Int J Mol Sci 2023; 24:10109. [PMID: 37373256 DOI: 10.3390/ijms241210109] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 06/06/2023] [Accepted: 06/08/2023] [Indexed: 06/29/2023] Open
Abstract
Selenocysteine is a catalytic residue at the active site of all selenoenzymes in bacteria and mammals, and it is incorporated into the polypeptide backbone by a co-translational process that relies on the recoding of a UGA termination codon into a serine/selenocysteine codon. The best-characterized selenoproteins from mammalian species and bacteria are discussed with emphasis on their biological function and catalytic mechanisms. A total of 25 genes coding for selenoproteins have been identified in the genome of mammals. Unlike the selenoenzymes of anaerobic bacteria, most mammalian selenoenzymes work as antioxidants and as redox regulators of cell metabolism and functions. Selenoprotein P contains several selenocysteine residues and serves as a selenocysteine reservoir for other selenoproteins in mammals. Although extensively studied, glutathione peroxidases are incompletely understood in terms of local and time-dependent distribution, and regulatory functions. Selenoenzymes take advantage of the nucleophilic reactivity of the selenolate form of selenocysteine. It is used with peroxides and their by-products such as disulfides and sulfoxides, but also with iodine in iodinated phenolic substrates. This results in the formation of Se-X bonds (X = O, S, N, or I) from which a selenenylsulfide intermediate is invariably produced. The initial selenolate group is then recycled by thiol addition. In bacterial glycine reductase and D-proline reductase, an unusual catalytic rupture of selenium-carbon bonds is observed. The exchange of selenium for sulfur in selenoproteins, and information obtained from model reactions, suggest that a generic advantage of selenium compared with sulfur relies on faster kinetics and better reversibility of its oxidation reactions.
Collapse
Affiliation(s)
- Jean Chaudière
- CBMN (CNRS, UMR 5248), University of Bordeaux, 33600 Pessac, France
| |
Collapse
|
|
13
|
Jiang Q, Sherlock DN, Zhang H, Guyader J, Pan YX, Loor JJ. One-carbon metabolism and related pathways in ruminal and small intestinal epithelium of lactating dairy cows. J Anim Sci 2023; 101:skad062. [PMID: 36852676 PMCID: PMC10103064 DOI: 10.1093/jas/skad062] [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: 11/12/2022] [Accepted: 02/23/2023] [Indexed: 03/01/2023] Open
Abstract
Physiological and environmental stresses such as the transition into lactation and heat load contribute to gastrointestinal tract (GIT) dysfunction. The nonruminant gastrointestinal tract has mechanisms to cope with pro-oxidant and pro-inflammatory stressors arising from the gut lumen or within intestinal cells. One-carbon metabolism (OCM) contributes to anti-oxidant capacity via the production of glutathione (GSH) and taurine, and the synthesis of phospholipid, creatine, and the osmolyte glycinebetaine among others. A multipronged approach was used to assess the biological relevance of OCM and closely-related pathways on GIT function in dairy cows. Ruminal papillae (Rum) and scrapings from duodenum (Duo), jejunum (Jej), and ileum (Ile) were collected at slaughter from eight multiparous Holstein cows averaging 128 ± 12 d in milk and producing 39 ± 5 kg/d. A MIXED model ANOVA with preplanned orthogonal contrasts was used for statistical analysis. Methionine adenosyl transferase 1 activity (MAT) was ~10-fold greater (P < 0.01) and cystathionine β-synthase activity doubled in Rum vs. small intestine. Total glutathione peroxidase (GPX) activity was greatest (P = 0.03) in Ile, but similar to Rum. Activity and mRNA abundance of betaine-homocysteine S-methyltransferase were undetectable. There was a 2.5-fold greater protein abundance of GPX1 (P < 0.01) and a ~2-fold greater abundance of GPX3 (P < 0.01) in Rum vs. small intestine. Among the various amino acids (AA) with roles in OCM or closely-related pathways (e.g. creatine synthesis), concentrations of arginine, aspartate, glutamine, methionine, and serine were lower (P < 0.01) in Rum vs. small intestine. Unlike AA, concentrations of OCM-related intermediates S-5'-adenosyl-homocysteine (SAH), glycinebetaine, carnitine, creatine (CRE), and cysteinesulfinic acid were greater (P < 0.01) while taurine was lower in Rum vs. small intestine. Intermediates of the folate cycle were undetectable. The fact that S-adenosylmethionine (SAM) was undetectable while MAT activity and SAH were greater in Rum suggested that availability of SAM (a methyl donor) is a key determinant of flux through the folate and methionine cycles in the GIT. Except for adenosine, concentrations of glutamate, glycine, α-ketoglutarate, hypotaurine, and GSH were lowest in Ile. Together, the data underscored unique differences in activity of one-carbon metabolism and related pathways across sections of the GIT.
Collapse
Affiliation(s)
- Qianming Jiang
- Department of Animal Sciences, University of Illinois, Urbana 61801, IL, USA
| | - Danielle N Sherlock
- Department of Animal Sciences, University of Illinois, Urbana 61801, IL, USA
| | - Huimin Zhang
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | | | - Yuan-Xiang Pan
- Department of Food Science and Human Nutrition, University of Illinois, Urbana 61801, IL, USA
- Division of Nutritional Sciences, University of Illinois, Urbana 61801, IL, USA
| | - Juan J Loor
- Department of Animal Sciences, University of Illinois, Urbana 61801, IL, USA
- Division of Nutritional Sciences, University of Illinois, Urbana 61801, IL, USA
| |
Collapse
|
|
14
|
Schwarz M, Löser A, Cheng Q, Wichmann-Costaganna M, Schädel P, Werz O, Arnér ESJ, Kipp AP. Side-by-side comparison of recombinant human glutathione peroxidases identifies overlapping substrate specificities for soluble hydroperoxides. Redox Biol 2023; 59:102593. [PMID: 36608588 PMCID: PMC9827380 DOI: 10.1016/j.redox.2022.102593] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 12/20/2022] [Accepted: 12/26/2022] [Indexed: 01/03/2023] Open
Abstract
Five out of eight human glutathione peroxidases (GPXs) are selenoproteins, representing proteins that contain selenium as part of the amino acid selenocysteine. The GPXs are important for reducing hydroperoxides in a glutathione-consuming manner and thus regulate cellular redox homeostasis. GPX1, GPX2, and GPX4 represent the three main cytosolic GPXs, but they differ in their expression patterns with GPX1 and GPX4 being expressed ubiquitously, whereas GPX2 is mainly expressed in epithelial cells. GPX1 and GPX2 have been described to reduce soluble hydroperoxides, while GPX4 reduces complex lipid hydroperoxides, thus protecting cells from lipid peroxidation and ferroptosis. But most of these data are derived from cells that are devoid of one of the isoforms and thus, compensation or other cellular effects might affect the conclusions. So far, the use of isolated recombinant human selenoprotein glutathione peroxidases in pure enzyme assays has not been employed to study their substrate specificities side by side. Using recombinant GPX1, GPX2, and GPX4 produced in E. coli we here assessed their GPX activities by a NADPH-consuming glutathione reductase-coupled assay with 17 different peroxides (all at 50 μM) as substrates. GPX4 was clearly the only isoform able to reduce phosphatidylcholine hydroperoxide. In contrast, small soluble hydroperoxides such as H2O2, cumene hydroperoxide, and tert-butyl hydroperoxide were reduced by all three isoforms, but with approximately 10-fold higher efficiency for GPX1 in comparison to GPX2 and GPX4. Also, several fatty acid-derived hydroperoxides were reduced by all three isoforms and again GPX1 had the highest activity. Interestingly, the stereoisomerism of the fatty acid-derived hydroperoxides clearly affected the activity of the GPX enzymes. Overall, distinct substrate specificity is obvious for GPX4, but not so when comparing GPX1 and GPX2. Clearly GPX1 was the most potent isoform of the three GPXs in terms of turnover in reduction of soluble and fatty-acid derived hydroperoxides.
Collapse
Affiliation(s)
- Maria Schwarz
- Department of Nutritional Physiology, Institute of Nutritional Sciences, Friedrich Schiller University Jena, Jena, 07743, Germany,TraceAge-DFG Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly, Potsdam-Berlin-Jena, Germany
| | - Alina Löser
- Department of Nutritional Physiology, Institute of Nutritional Sciences, Friedrich Schiller University Jena, Jena, 07743, Germany,TraceAge-DFG Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly, Potsdam-Berlin-Jena, Germany
| | - Qing Cheng
- Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77, Stockholm, Sweden
| | - Mareike Wichmann-Costaganna
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Germany
| | - Patrick Schädel
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Germany
| | - Oliver Werz
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Germany
| | - Elias SJ. Arnér
- Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77, Stockholm, Sweden,Department of Selenoprotein Research, National Institute of Oncology, 1122, Budapest, Hungary
| | - Anna P. Kipp
- Department of Nutritional Physiology, Institute of Nutritional Sciences, Friedrich Schiller University Jena, Jena, 07743, Germany,TraceAge-DFG Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly, Potsdam-Berlin-Jena, Germany,Corresponding author. Department of Nutritional Physiology, Institute of Nutritional Sciences, Friedrich Schiller University Jena, Dornburger Str. 24, 07743, Jena, Germany.
| |
Collapse
|
|
15
|
Dodson M, Shakya A, Chen J, Chen WT, McKee NW, Zhang DD. The NRF2-anti-ferroptosis Axis in Health and Disease. FERROPTOSIS IN HEALTH AND DISEASE 2023:213-239. [DOI: 10.1007/978-3-031-39171-2_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
16
|
Dodson M, Shakya A, Anandhan A, Chen J, Garcia JG, Zhang DD. NRF2 and Diabetes: The Good, the Bad, and the Complex. Diabetes 2022; 71:2463-2476. [PMID: 36409792 PMCID: PMC9750950 DOI: 10.2337/db22-0623] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Accepted: 09/06/2022] [Indexed: 11/22/2022]
Abstract
Despite decades of scientific effort, diabetes continues to represent an incredibly complex and difficult disease to treat. This is due in large part to the multifactorial nature of disease onset and progression and the multiple organ systems affected. An increasing body of scientific evidence indicates that a key mediator of diabetes progression is NRF2, a critical transcription factor that regulates redox, protein, and metabolic homeostasis. Importantly, while experimental studies have confirmed the critical nature of proper NRF2 function in preventing the onset of diabetic outcomes, we have only just begun to scratch the surface of understanding the mechanisms by which NRF2 modulates diabetes progression, particularly across different causative contexts. One reason for this is the contradictory nature of the current literature, which can often be accredited to model discrepancies, as well as whether NRF2 is activated in an acute or chronic manner. Furthermore, despite therapeutic promise, there are no current NRF2 activators in clinical trials for the treatment of patients with diabetes. In this review, we briefly introduce the transcriptional programs regulated by NRF2 as well as how NRF2 itself is regulated. We also review the current literature regarding NRF2 modulation of diabetic phenotypes across the different diabetes subtypes, including a brief discussion of contradictory results, as well as what is needed to progress the NRF2 diabetes field forward.
Collapse
Affiliation(s)
- Matthew Dodson
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ
| | - Aryatara Shakya
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ
| | - Annadurai Anandhan
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ
| | - Jinjing Chen
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ
| | - Joe G.N. Garcia
- Department of Medicine, University of Arizona Health Sciences, University of Arizona, Tucson, AZ
| | - Donna D. Zhang
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ
- Arizona Cancer Center, University of Arizona, Tucson, AZ
| |
Collapse
|
|
17
|
Deng L, Li Y, Wu Q, Zeng Q, He Y, Chen A. Investigating potential ferroptosis‐related differentially expressed genes of
UVB
‐induced skin photodamage. Int J Dermatol 2022; 62:79-87. [DOI: 10.1111/ijd.16472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 10/18/2022] [Accepted: 10/19/2022] [Indexed: 11/29/2022]
Affiliation(s)
- Li Deng
- Department of Dermatology, The First Affiliated Hospital Chongqing Medical University Chongqing China
- Department of Dermatology, The Affiliated Hospital Southwest Medical University Luzhou China
| | - Yi Li
- Department of Nuclear Medicine, The Affiliated Hospital Southwest Medical University Luzhou China
| | - Qian Wu
- Department of Dermatology, The First Affiliated Hospital Chongqing Medical University Chongqing China
- Department of Dermatology Qijiang Hospital of the First Affiliated Hospital of Chongqing Medical University Chongqing China
| | - QianWen Zeng
- Department of Dermatology, The First Affiliated Hospital Chongqing Medical University Chongqing China
| | - Yuanmin He
- Department of Dermatology, The Affiliated Hospital Southwest Medical University Luzhou China
| | - AiJun Chen
- Department of Dermatology, The First Affiliated Hospital Chongqing Medical University Chongqing China
| |
Collapse
|
|
18
|
Huang H, Dai Y, Duan Y, Yuan Z, Li Y, Zhang M, Zhu W, Yu H, Zhong W, Feng S. Effective prediction of potential ferroptosis critical genes in clinical colorectal cancer. Front Oncol 2022; 12:1033044. [PMID: 36324584 PMCID: PMC9619366 DOI: 10.3389/fonc.2022.1033044] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 09/27/2022] [Indexed: 08/30/2023] Open
Abstract
Background Colon cancer is common worldwide, with high morbidity and poor prognosis. Ferroptosis is a novel form of cell death driven by the accumulation of iron-dependent lipid peroxides, which differs from other programmed cell death mechanisms. Programmed cell death is a cancer hallmark, and ferroptosis is known to participate in various cancers, including colon cancer. Novel ferroptosis markers and targeted colon cancer therapies are urgently needed. To this end, we performed a preliminary exploration of ferroptosis-related genes in colon cancer to enable new treatment strategies. Methods Ferroptosis-related genes in colon cancer were obtained by data mining and screening for differentially expressed genes (DEGs) using bioinformatics analysis tools. We normalized the data across four independent datasets and a ferroptosis-specific database. Identified genes were validated by immunohistochemical analysis of pathological and healthy clinical samples. Results We identified DEGs in colon cancer that are involved in ferroptosis. Among these, five core genes were found: ELAVL1, GPX2, EPAS1, SLC7A5, and HMGB1. Bioinformatics analyses revealed that the expression of all five genes, except for EPAS1, was higher in tumor tissues than in healthy tissues. Conclusions The preliminary exploration of the five core genes revealed that they are differentially expressed in colon cancer, playing an essential role in ferroptosis. This study provides a foundation for subsequent research on ferroptosis in colon cancer.
Collapse
Affiliation(s)
- Hongliang Huang
- Department of Pharmacy, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangzhou, China
- School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Yuexiang Dai
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yingying Duan
- Department of Pharmacy, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangzhou, China
- School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Zhongwen Yuan
- Department of Pharmacy, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangzhou, China
- School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Yanxuan Li
- The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Maomao Zhang
- The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Wenting Zhu
- Department of Pharmacy, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangzhou, China
| | - Hang Yu
- Department of Pharmacy, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangzhou, China
| | - Wenfei Zhong
- Department of Pharmacy, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangzhou, China
| | - Senling Feng
- Department of Pharmacy, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangzhou, China
- School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, China
| |
Collapse
|
|
19
|
Ahmed KM, Veeramachaneni R, Deng D, Putluri N, Putluri V, Cardenas MF, Wheeler DA, Decker WK, Frederick AI, Kazi S, Sikora AG, Sandulache VC, Frederick MJ. Glutathione peroxidase 2 is a metabolic driver of the tumor immune microenvironment and immune checkpoint inhibitor response. J Immunother Cancer 2022; 10:jitc-2022-004752. [PMID: 36002187 PMCID: PMC9413193 DOI: 10.1136/jitc-2022-004752] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/13/2022] [Indexed: 11/03/2022] Open
Abstract
BACKGROUND The existence of immunologically 'cold tumors' frequently found across a wide spectrum of tumor types represents a significant challenge for cancer immunotherapy. Cold tumors have poor baseline pan-leukocyte infiltration, including a low prevalence of cytotoxic lymphocytes, and not surprisingly respond unfavorably to immune checkpoint (IC) inhibitors. We hypothesized that cold tumors harbor a mechanism of immune escape upstream and independent of ICs that may be driven by tumor biology rather than differences in mutational neoantigen burden. METHODS Using a bioinformatic approach to analyze TCGA (The Cancer Genome Atlas) RNA sequencing data we identified genes upregulated in cold versus hot tumors across four different smoking-related cancers, including squamous carcinomas from the oral cavity (OCSCC) and lung (LUSC), and adenocarcinomas of the bladder (BLCA) and lung (LUAD). Biological significance of the gene most robustly associated with a cold tumor phenotype across all four tumor types, glutathione peroxidase 2 (GPX2), was further evaluated using a combination of in silico analyses and functional genomic experiments performed both in vitro and in in vivo with preclinical models of oral cancer. RESULTS Elevated RNA expression of five metabolic enzymes including GPX2, aldo-keto reductase family 1 members AKR1C1, AKR1C3, and cytochrome monoxygenases (CP4F11 and CYP4F3) co-occurred in cold tumors across all four smoking-related cancers. These genes have all been linked to negative regulation of arachidonic acid metabolism-a well-established inflammatory pathway-and are also known downstream targets of the redox sensitive Nrf2 transcription factor pathway. In OCSCC, LUSC, and LUAD, GPX2 expression was highly correlated with Nrf2 activation signatures, also elevated in cold tumors. In BLCA, however, GPX2 correlated more strongly than Nrf2 signatures with decreased infiltration of multiple leukocyte subtypes. GPX2 inversely correlated with expression of multiple pro- inflammatory cytokines/chemokines and NF-kB activation in cell lines and knockdown of GPX2 led to increased secretion of prostaglandin E2 (PGE2) and interleukin-6. Conversely, GPX2 overexpression led to reduced PGE2 production in a murine OCSCC model (MOC1). GPX2 overexpressing MOC1 tumors had a more suppressive tumor immune microenvironment and responded less favorably to anti-cytotoxic T-lymphocytes-associated protein 4 IC therapy in mice. CONCLUSION GPX2 overexpression represents a novel potentially targetable effector of immune escape in cold tumors.
Collapse
Affiliation(s)
- Kazi Mokim Ahmed
- Bobby R. Alford Department of Otolaryngology - Head and Neck Surgery, Baylor College of Medicine, Houston, Texas, USA
| | - Ratna Veeramachaneni
- Department of Head and Neck Surgery, Division of Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Defeng Deng
- Bobby R. Alford Department of Otolaryngology - Head and Neck Surgery, Baylor College of Medicine, Houston, Texas, USA
| | - Nagireddy Putluri
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
| | - Vasanta Putluri
- Advanced Technology Core, Dan Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA
| | - Maria F Cardenas
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA
| | - David A Wheeler
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA
| | - William K Decker
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA
| | - Andy I Frederick
- Undergraduate School of Engineering, Cornell University, Ithaca, New York, USA
| | - Sawad Kazi
- The University of Texas at Austin School of Biological Sciences, Austin, Texas, USA
| | - Andrew G Sikora
- Department of Head and Neck Surgery, Division of Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Vlad C Sandulache
- Bobby R. Alford Department of Otolaryngology - Head and Neck Surgery, Baylor College of Medicine, Houston, Texas, USA
- ENT Section, Operative Care Line, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA
- Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA
| | - Mitchell J Frederick
- Bobby R. Alford Department of Otolaryngology - Head and Neck Surgery, Baylor College of Medicine, Houston, Texas, USA
| |
Collapse
|
|
20
|
Esworthy RS, Doroshow JH, Chu FF. The beginning of GPX2 and 30 years later. Free Radic Biol Med 2022; 188:419-433. [PMID: 35803440 PMCID: PMC9341242 DOI: 10.1016/j.freeradbiomed.2022.06.232] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 05/26/2022] [Accepted: 06/16/2022] [Indexed: 02/07/2023]
Abstract
We published the first paper to characterize GPX2 (aka GSHPx-GI) as a selenoenzyme with glutathione peroxidase activity in 1993. Among the four Se-GPX isozymes, GPX1-4, GPX1 and GPX2 are closely related in terms of structure, substrate specificities, and subcellular localization. What sets them apart are distinct patterns of gene regulation, tissue distribution and response to selenium. While we identified the digestive tract epithelium as the main site of GPX2 expression, later work has shown GPX2 is found more widely in epithelial tissues with concentration of expression in stem cell and proliferative compartments. GPX2 expression is regulated over a wide range of levels by many pathways, including NRF2, WNT, p53, RARE and this often results in attaching undue significance to GPX2 as GPX2 is only a part of a system of hydroperoxidase activities, including GPX1, peroxiredoxins and catalase. These other activities may play equal or greater roles, particularly in cell lines cultured without selenium supplementation and often with very low GPX2 levels. This could be assessed by examining levels of mRNA and protein among these various peroxidases at the outset of studies. As an example, it was found that GPX1 responds to the absence of GPX2 in mouse ileum and colon epithelium with higher expression. As such, both Gpx1 and Gpx2 had to be knocked out in mice to produce ileocolitis. However, we note that the actual role of GPX1 and GPX2 in relation to peroxiredoxin function is unclear. There may be an interdependence that requires only low amounts of GPX1 and/or GPX2 in a supporting role to maintain proper peroxiredoxin function. GPX2 levels may be prognostic for cancer progression in colon, breast, prostate and liver, however, there is no consistent trend for higher or lower levels to be favorable.
Collapse
Affiliation(s)
- R Steven Esworthy
- Department of Cancer Genetics & Epigenetics, Beckman Research Institute of City of Hope. Duarte, California, USA, 91010.
| | - James H Doroshow
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, MD, USA.
| | - Fong-Fong Chu
- Department of Cancer Genetics & Epigenetics, Beckman Research Institute of City of Hope. Duarte, California, USA, 91010.
| |
Collapse
|
|
21
|
Zhang Y, Wu Q, Liu J, Zhang Z, Ma X, Zhang Y, Zhu J, Thring RW, Wu M, Gao Y, Tong H. Sulforaphane alleviates high fat diet-induced insulin resistance via AMPK/Nrf2/GPx4 axis. Biomed Pharmacother 2022; 152:113273. [PMID: 35709656 DOI: 10.1016/j.biopha.2022.113273] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 05/31/2022] [Accepted: 06/08/2022] [Indexed: 02/07/2023] Open
Abstract
Insulin resistance is a characteristic feature of type 2 diabetes. Sulforaphane (SFN) is a natural antioxidant extracted from the cruciferous vegetables. Recent study reported that SFN exhibits excellent anti-diabetic effects, however, the underlying mechanism is still unclear. This study aimed to investigate the therapeutic effects of SFN on a high-fat diet (HFD)-induced insulin resistance and potential mechanism. SFN was found to effectively reduce body weight, fasting blood glucose and hyperlipidemia, and improve liver function in HFD-fed mice. Furthermore, SFN effectively increased glucose uptake and improved insulin signaling in palmitic acid (PA)-induced HepG2 cells. SFN also led to increased expression of antioxidant genes downstream of Nrf2 and decreased accumulation of lipid peroxides MDA and 4-HNE, both in vivo and in vitro. Further studies revealed that SFN significantly reduced glutathione peroxidase 4 (GPx4) inactivation-mediated oxidative stress by activating the AMPK and Nrf2 signaling pathways. In PA-induced HepG2 cells and flies, the alleviation of insulin resistance by SFN was diminished by GPx4 inhibitor. Taken together, SFN ameliorated HFD-induced insulin resistance by activating the AMPK-Nrf2-GPx4 pathway, providing new insights into SFN as a therapeutic compound for the alleviation of insulin resistance.
Collapse
Affiliation(s)
- Ya Zhang
- Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou 325035, China; Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou 325035, China
| | - Qifang Wu
- Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou 325035, China
| | - Jian Liu
- Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou 325035, China
| | - Zhongshan Zhang
- Zhejiang Province Key Laboratory of Vector Biology and Pathogen Control, Huzhou University, Huzhou Cent Hosp, Huzhou 313000, China
| | - Xiaojing Ma
- National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Yaoyue Zhang
- Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou 325035, China
| | - Jiawen Zhu
- Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou 325035, China
| | - Ronald W Thring
- Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou 325035, China
| | - Mingjiang Wu
- Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou 325035, China
| | - Yitian Gao
- Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou 325035, China.
| | - Haibin Tong
- Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou 325035, China.
| |
Collapse
|
|
22
|
Dihydromyricetin Enhances Intestinal Antioxidant Capacity of Growing-Finishing Pigs by Activating ERK/Nrf2/HO-1 Signaling Pathway. Antioxidants (Basel) 2022; 11:antiox11040704. [PMID: 35453388 PMCID: PMC9028153 DOI: 10.3390/antiox11040704] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 03/29/2022] [Accepted: 03/29/2022] [Indexed: 02/01/2023] Open
Abstract
Oxidative stress is one of the main factors affecting animal health and reducing performance. The small intestine is the primary site of free-radical attacks. Dihydromyricetin (DHM) is a flavonoid compound with antioxidant, anti-inflammatory, and other biological activities, which is mainly extracted from Rattan tea. However, the effects of DHM on the intestinal antioxidant function of growing-finishing pigs and related mechanisms remain unclear. The aim of this study was to investigate the effect of dietary DHM supplementation on the intestinal antioxidant capacity of growing-finishing pigs and its mechanism. Our results show that dietary 0.03% DHM increased the activities of the total antioxidant capacity (T-AOC), catalase (CAT), and glutathione peroxidase (GSH-Px), decreased malondialdehyde (MDA) level, and upregulated protein expressions of HO-1, NQO1, nuclear Nrf2, and phospho-ERK (p-ERK) in the jejunum of growing-finishing pigs. Again, we found that 20 μmol/mL and 40 μmol/mL DHM treatment significantly upregulated the protein expression of HO-1 and promoted the nuclear translocation of Nrf2 and ERK phosphorylation in IPCE-J2 cells. ERK inhibitor PD98059 eliminated the DHM-induced upregulation of p-ERK, nuclear Nrf2, and HO-1. Our findings provided the first evidence that DHM enhanced the intestinal antioxidant capacity of growing-finishing pigs by activating the ERK/Nrf2/HO-1 signaling pathway.
Collapse
|
|
23
|
Ungur RA, Borda IM, Codea RA, Ciortea VM, Năsui BA, Muste S, Sarpataky O, Filip M, Irsay L, Crăciun EC, Căinap S, Jivănescu DB, Pop AL, Singurean VE, Crișan M, Groza OB, Martiș (Petruț) GS. A Flavonoid-Rich Extract of Sambucus nigra L. Reduced Lipid Peroxidation in a Rat Experimental Model of Gentamicin Nephrotoxicity. MATERIALS (BASEL, SWITZERLAND) 2022; 15:772. [PMID: 35160718 PMCID: PMC8837157 DOI: 10.3390/ma15030772] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 01/03/2022] [Accepted: 01/12/2022] [Indexed: 12/04/2022]
Abstract
The use of gentamicin (GM) is limited due to its nephrotoxicity mediated by oxidative stress. This study aimed to evaluate the capacity of a flavonoid-rich extract of Sambucus nigra L. elderflower (SN) to inhibit lipoperoxidation in GM-induced nephrotoxicity. The HPLC analysis of the SN extract recorded high contents of rutin (463.2 ± 0.0 mg mL-1), epicatechin (9.0 ± 1.1 µg mL-1), and ferulic (1.5 ± 0.3 µg mL-1) and caffeic acid (3.6 ± 0.1 µg mL-1). Thirty-two Wistar male rats were randomized into four groups: a control group (C) (no treatment), GM group (100 mg kg-1 bw day-1 GM), GM+SN group (100 mg kg-1 bw day-1 GM and 1 mL SN extract day-1), and SN group (1 mL SN extract day-1). Lipid peroxidation, evaluated by malondialdehyde (MDA), and antioxidant enzymes activity-superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX)-were recorded in renal tissue after ten days of experimental treatment. The MDA level was significantly higher in the GM group compared to the control group (p < 0.0001), and was significantly reduced by SN in the GM+SN group compared to the GM group (p = 0.021). SN extract failed to improve SOD, CAT, and GPX activity in the GM+SN group compared to the GM group (p > 0.05), and its action was most probably due to the ability of flavonoids (rutin, epicatechin) and ferulic and caffeic acids to inhibit synthesis and neutralize reactive species, to reduce the redox-active iron pool, and to inhibit lipid peroxidation. In this study, we propose an innovative method for counteracting GM nephrotoxicity with a high efficiency and low cost, but with the disadvantage of the multifactorial environmental variability of the content of SN extracts.
Collapse
Affiliation(s)
- Rodica Ana Ungur
- Department of Medical Specialties, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 8 Victor Babeș Street, 400012 Cluj-Napoca, Romania; (R.A.U.); (V.M.C.); (L.I.)
| | - Ileana Monica Borda
- Department of Medical Specialties, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 8 Victor Babeș Street, 400012 Cluj-Napoca, Romania; (R.A.U.); (V.M.C.); (L.I.)
| | - Răzvan Andrei Codea
- Faculty of Veterinary Medicine, University of Agricultural Science and Veterinary Medicine, 3-5 Mănăștur Street, 400372 Cluj-Napoca, Romania;
| | - Viorela Mihaela Ciortea
- Department of Medical Specialties, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 8 Victor Babeș Street, 400012 Cluj-Napoca, Romania; (R.A.U.); (V.M.C.); (L.I.)
| | - Bogdana Adriana Năsui
- Department of Community Health, Faculty of Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 8 Victor Babeș Street, 400012 Cluj-Napoca, Romania;
| | - Sevastița Muste
- Food Engineering Department, University of Agricultural Sciences and Veterinary Medicine, 64 Calea Floresti, 400509 Cluj-Napoca, Romania; (S.M.); (G.S.M.)
| | - Orsolya Sarpataky
- Faculty of Veterinary Medicine, University of Agricultural Science and Veterinary Medicine, 3-5 Mănăștur Street, 400372 Cluj-Napoca, Romania;
| | - Miuța Filip
- Raluca Ripan Institute for Research in Chemistry, Babeş-Bolyai University, 30 Fântânele Street, 400294 Cluj-Napoca, Romania;
| | - Laszlo Irsay
- Department of Medical Specialties, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 8 Victor Babeș Street, 400012 Cluj-Napoca, Romania; (R.A.U.); (V.M.C.); (L.I.)
| | - Elena Cristina Crăciun
- Department of Pharmaceutical Biochemistry and Clinical Laboratory, Faculty of Pharmacy, “Iuliu Hatieganu” University of Medicine and Pharmacy, 6 Pasteur Street, 400349 Cluj-Napoca, Romania;
| | - Simona Căinap
- Department of Mother and Child, Faculty of Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 8 Victor Babeș Street, 400012 Cluj-Napoca, Romania;
| | - Delia Bunea Jivănescu
- Department of Internal Medicine, Faculty of Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 8 Victor Babeș Street, 400012 Cluj-Napoca, Romania;
| | - Anca Lucia Pop
- Department of Clinical Laboratory, Food Safety, Nutrition, “Carol Davila” University of Medicine and Pharmacy, 6 Traian Vuia Street, 020945 Bucharest, Romania;
| | - Victoria Emilia Singurean
- Department of Morphological Sciences, Faculty of Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 8 Victor Babeș Street, 400012 Cluj-Napoca, Romania; (V.E.S.); (M.C.); (O.B.G.)
| | - Maria Crișan
- Department of Morphological Sciences, Faculty of Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 8 Victor Babeș Street, 400012 Cluj-Napoca, Romania; (V.E.S.); (M.C.); (O.B.G.)
| | - Oana Bianca Groza
- Department of Morphological Sciences, Faculty of Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 8 Victor Babeș Street, 400012 Cluj-Napoca, Romania; (V.E.S.); (M.C.); (O.B.G.)
| | - Georgiana Smaranda Martiș (Petruț)
- Food Engineering Department, University of Agricultural Sciences and Veterinary Medicine, 64 Calea Floresti, 400509 Cluj-Napoca, Romania; (S.M.); (G.S.M.)
| |
Collapse
|
|
24
|
Horniblow RD, Pathak P, Balacco DL, Acharjee A, Lles E, Gkoutos G, Beggs AD, Tselepis C. IRON-MEDIATED EPIGENETIC ACTIVATION OF NRF2 TARGETS. J Nutr Biochem 2021; 101:108929. [PMID: 34954079 DOI: 10.1016/j.jnutbio.2021.108929] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 10/27/2021] [Accepted: 12/07/2021] [Indexed: 01/10/2023]
Abstract
The toxic effects of excess dietary iron within the colonic lumen are well documented, particularly in the context of Inflammatory Bowel Disease (IBD) and Colorectal Cancer (CRC). Proposed mechanisms that underpin iron-associated intestinal disease include: i) the pro-inflammatory and ROS-promoting nature of iron, ii) gene-expression alterations, and iii) intestinal microbial dysbiosis. However, to date no studies have examined the effect of iron on the colonic epigenome. Here we demonstrate that chronic iron exposure of colonocytes leads to significant hypomethylation of the epigenome. Bioinformatic analysis highlights a significant epigenetic effect on NRF2 (nuclear factor erythroid 2-related factor 2) pathway targets (including NAD(P)H Quinone Dehydrogenase 1 [NQO1] and Glutathione peroxidase 2 [GPX2]); this demethylating effect was validated and subsequent gene and protein expression quantified. These epigenetic modifications were not observed upon the diminishment of cellular lipid peroxidation with endogenous glutathione and the subsequent removal of iron. Additionally, the induction of TET1 expression was found post-iron treatment, highlighting the possibility of an oxidative-stress induction of TET1 and subsequent hypomethylation of NRF2 targets. In addition, a strong time dependence on the establishment of iron-orchestrated hypomethylation was found which was concurrent with the increase in the intracellular labile iron pool (LIP) and lipid peroxidation levels. These epigenetic changes were further validated in murine intestinal mucosa in models administered a chronic iron diet, providing evidence for the likelihood of dietary-iron mediated epigenetic alterations in vivo. Furthermore, significant correlations were found between NQO1 and GPX2 demethylation and human intestinal tissue iron-status, thus suggesting that these iron-mediated epigenetic modifications are likely in iron-replete enterocytes. Together, these data describe a novel mechanism by which excess dietary iron is able to alter the intestinal phenotype, which could have implications in iron-mediated intestinal disease and the regulation of ferroptosis.
Collapse
Affiliation(s)
- Richard D Horniblow
- School of Biomedical Science, Institute of Clinical Science, University of Birmingham, Edgbaston, Birmingham, UK.
| | - Prachi Pathak
- School of Biomedical Science, Institute of Clinical Science, University of Birmingham, Edgbaston, Birmingham, UK
| | - Dario L Balacco
- Birmingham Dental School, Institute of Clinical Science, University of Birmingham, Edgbaston, Birmingham, UK
| | - Animesh Acharjee
- Institute of Translational Medicine, University of Birmingham, Edgbaston, Birmingham, UK; Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham, UK; NIHR Surgical Reconstruction and Microbiology Research Centre, Birmingham, UK
| | - Eva Lles
- Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham, UK
| | - Georgios Gkoutos
- Institute of Translational Medicine, University of Birmingham, Edgbaston, Birmingham, UK; Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham, UK; NIHR Surgical Reconstruction and Microbiology Research Centre, Birmingham, UK; MRC Health Data Research UK (HDR), Midlands Site, UK
| | - Andrew D Beggs
- Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham, UK
| | - Chris Tselepis
- School of Biomedical Science, Institute of Clinical Science, University of Birmingham, Edgbaston, Birmingham, UK
| |
Collapse
|
|
25
|
Wang Y, Duan Y, Huang J, Wang J, Zhou C, Jiang S, Lin H, Zhang Z. Characterization and functional study of nuclear factor erythroid 2-related factor 2 (Nrf2) in black tiger shrimp (Penaeus monodon). FISH & SHELLFISH IMMUNOLOGY 2021; 119:289-299. [PMID: 34656756 DOI: 10.1016/j.fsi.2021.10.016] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 10/09/2021] [Accepted: 10/12/2021] [Indexed: 06/13/2023]
Abstract
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a member of the Cap'n'collar basic region leucine zipper (CNC-bZIP) transcription factor family, and is activated by diverse oxidants, pro-oxidants, antioxidants and chemopreventive agents. The full-length cDNA of Nrf2 from Penaeus monodon (PmNrf2; 2024 bp long with 729 bp coding region, GenBank accession no. MW390830) was cloned. The 242-amino-acid polypeptide encoded by this gene had a predicted molecular mass of 27.80 kDa. Sequence homology and phylogenetic analysis showed that PmNrf2 was similar to the insect Cap'n'Collar (CNC) transcription factor and mammalian Nrf2. Tissue expression profile analyzed by quantitative real-time RT-PCR (qRT-PCR) demonstrated that PmNrf2 was constitutively expressed in all examined tissues, with the highest expression observed in the intestines and the weakest expression observed in the hemocyte. PmNrf2 expression profiles were detected in the hepatopancreas of shrimp after bacterial challenge. The results suggested that PmNrf2 was involved in the responses to bacterial challenge, but the temporal expression pattern trend of PmNrf2 differed between the gram-negative and gram-positive bacterial challenges in the shrimp hepatopancreas. The recombinant PmNrf2 protein was expressed and purified through affinity chromatography. Furthermore, an anti-PmNrf2 polyclonal antibody was obtained, which was able to clearly detect PmNrf2 protein expression in the hepatopancreas of shrimp. Knockdown of PmNrf2 by RNA interference (RNAi) resulted in a reduction in the expression of PmGPx gene. Taken together, the results of our study indicated that PmNrf2 played a role in regulation the transcription of PmGPx antioxidant enzyme genes.
Collapse
Affiliation(s)
- Yun Wang
- Key Laboratory of Aquatic Product Processing, Ministry of Agriculture and Rural Affairs, South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, 510300, PR China; Guangdong Provincial Key Laboratory of Fishery Ecology and Environment, Guangzhou, 510300, PR China
| | - Yafei Duan
- Key Laboratory of Aquatic Product Processing, Ministry of Agriculture and Rural Affairs, South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, 510300, PR China
| | - Jianhua Huang
- Key Laboratory of Aquatic Product Processing, Ministry of Agriculture and Rural Affairs, South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, 510300, PR China; Shenzhen Base of South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Shenzhen, PR China
| | - Jun Wang
- Key Laboratory of Aquatic Product Processing, Ministry of Agriculture and Rural Affairs, South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, 510300, PR China
| | - Chuanpeng Zhou
- Key Laboratory of Aquatic Product Processing, Ministry of Agriculture and Rural Affairs, South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, 510300, PR China
| | - Shigui Jiang
- Key Laboratory of Aquatic Product Processing, Ministry of Agriculture and Rural Affairs, South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, 510300, PR China; Guangdong Provincial Key Laboratory of Fishery Ecology and Environment, Guangzhou, 510300, PR China
| | - Heizhao Lin
- Key Laboratory of Aquatic Product Processing, Ministry of Agriculture and Rural Affairs, South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, 510300, PR China; Shenzhen Base of South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Shenzhen, PR China
| | - Zhe Zhang
- Guangdong Provincial Key Laboratory of Fishery Ecology and Environment, Guangzhou, 510300, PR China.
| |
Collapse
|
|
26
|
Maiorino M. Redox Pioneer: Professor Regina Brigelius-Flohé. Antioxid Redox Signal 2021; 35:595-601. [PMID: 34036804 DOI: 10.1089/ars.2020.8202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Dr. Regina Brigelius-Flohé (PhD 1978) is recognized here as redox pioneer because she has published an article on redox biology, as first author, that has been cited >1000 times, plus four articles cited >500 times, and a total of 30 articles cited >100 times. She obtained her doctorate in biochemistry at the Institute of Biochemistry of the University of Münster, Germany. She held positions in both, academia (Münster, Munich, Düsseldorf, Hannover, and Potsdam, Germany) and industry (Aachen, Germany). Dr. Brigelius-Flohé is the pioneer who, as head of the department of biochemistry of micronutrients of the German Institute of Human Nutrition (DIfE; Potsdam-Rehbrücke, Germany), worked out the metabolism of tocopherols and tocotrienols ("Key Finding 1"). She was the first to sequence glutathione peroxidase 4 (GPx4) ("Key Finding 2"), and unraveled the role of selenium, in particular of GPxs, in inflammation and carcinogenesis ("Key Finding 3"). Her contributions, thus, focused on serious biomedical problems such as nutrition, inflammation, and carcinogenesis. She has been a member of the scientific advisory board of the German Society of Biochemistry and Molecular Biology for 6 years and was president of SFRR-Europe in 2005-2006. She edited several books and serves on the editorial board of journals in the fields of nutrition, free radicals, and redox regulation. Antioxid. Redox Signal. 35, 595-601.
Collapse
Affiliation(s)
- Matilde Maiorino
- Dipartimento di Medicina Molecolare, Università degli Studi di Padova, Padova, Italy
| |
Collapse
|
|
27
|
Chun KS, Raut PK, Kim DH, Surh YJ. Role of chemopreventive phytochemicals in NRF2-mediated redox homeostasis in humans. Free Radic Biol Med 2021; 172:699-715. [PMID: 34214633 DOI: 10.1016/j.freeradbiomed.2021.06.031] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 06/14/2021] [Accepted: 06/24/2021] [Indexed: 12/17/2022]
Abstract
While functioning as a second messenger in the intracellular signaling, ROS can cause oxidative stress when produced in excess or not neutralized/eliminated properly. Excessive ROS production is implicated in multi-stage carcinogenesis. Our body is equipped with a defense system to cope with constant oxidative stress caused by the external insults, including redox-cycling chemicals, radiation, and microbial infection as well as endogenously generated ROS. The transcription factor, nuclear transcription factor erythroid 2-related factor 2 (NRF2) is a master switch in the cellular antioxidant signaling and plays a vital role in adaptive survival response to ROS-induced oxidative stress. Although NRF2 is transiently activated when cellular redox balance is challenged, this can be overwhelmed by massive oxidative stress. Therefore, it is necessary to maintain the NRF2-mediated antioxidant defense capacity at an optimal level. This review summarizes the natural NRF2 inducers/activators, especially those present in the plant-based diet, in relation to their cancer chemopreventive potential in humans. The molecular mechanisms underlying their stabilization or activation of NRF2 are also discussed.
Collapse
Affiliation(s)
- Kyung-Soo Chun
- College of Pharmacy, Keimyung University, Daegu 42691, South Korea
| | - Pawan Kumar Raut
- College of Pharmacy, Keimyung University, Daegu 42691, South Korea
| | - Do-Hee Kim
- Department of Chemistry, College of Convergence and Integrated Science, Kyonggi University, Suwon, Gyeonggi-do 16227, South Korea
| | - Young-Joon Surh
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, South Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, South Korea; Cancer Research Institute, Seoul National University, Seoul 03080, South Korea.
| |
Collapse
|
|
28
|
Neonatal Vitamin C and Cysteine Deficiencies Program Adult Hepatic Glutathione and Specific Activities of Glucokinase, Phosphofructokinase, and Acetyl-CoA Carboxylase in Guinea Pigs' Livers. Antioxidants (Basel) 2021; 10:antiox10060953. [PMID: 34204849 PMCID: PMC8231532 DOI: 10.3390/antiox10060953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 06/07/2021] [Accepted: 06/09/2021] [Indexed: 11/17/2022] Open
Abstract
Premature neonates are submitted to an early-life oxidative stress from parenteral nutrition, which is vitamin C (VC) deficient and induces low endogenous levels of glutathione. The oxidative stress caused by these deficiencies may permanently affect liver glycolysis and lipogenesis. This study evaluates the short- and long-term effects of neonatal VC and cysteine deficient diets on redox and energy metabolism. Three-day-old Hartley guinea pigs from both sexes were given a regular or a deficient diet (VC, cysteine, or both) until week 1 of life. Half of the animals were sacrificed at this age, while the other half ate a complete diet until 12 weeks. Liver glutathione and the activity and protein levels of glucokinase, phosphofructokinase, and acetyl-CoA-carboxylase were measured. Statistics: factorial ANOVA (5% threshold). At 1 week, all deficient diets decreased glutathione and the protein levels of glucokinase and phosphofructokinase, while cysteine deficiency decreased acetyl-CoA-carboxylase levels. A similar enzyme level was observed in control animals at 12 weeks. At this age, VC deficiency decreased glutathione, while cysteine increased it. Acetyl-CoA-carboxylase protein levels were increased, which decreased its specific activity. Early-life VC and cysteine deficiencies induce neonatal oxidative stress and an adult-like metabolism, while predisposing to increased lipogenic rates during adulthood.
Collapse
|
|
29
|
Zhang J, Zhou H, Li H, Ying Z, Liu X. Research progress on separation of selenoproteins/Se-enriched peptides and their physiological activities. Food Funct 2021; 12:1390-1401. [PMID: 33464257 DOI: 10.1039/d0fo02236e] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Selenium (Se) is an essential nutrient associated with several physiological processes in humans and has raised interest because of its antioxidant and immune properties. Se deficiency is related to a variety of diseases and dysfunctions in humans. Due to its higher bioavailability and lower toxicity, organic Se is more recommendable than inorganic Se in the frame of a balanced diet. Se is present in 25 identified selenoproteins that commonly occur in human organisms. As part of selenocysteine (SeC), Se becomes co-translationally incorporated into the polypeptide chain and involved in the regulation of oxidative stress, redox mechanisms, and other crucial cellular processes responsible for innate and adaptive immune responses. This review presents the current information regarding the presence of selenoproteins in the human body, and the separation of selenoproteins and selenopeptides from various plants and their physiological roles in the immune and oxidation systems of humans. In general, the application of selenoproteins and Se-enriched peptides are practically important for the clinical arena, whereby it can be used for exploring new healthy foods.
Collapse
Affiliation(s)
- Jian Zhang
- National Soybean Processing Industry Technology Innovation Center, Beijing Advanced Innovation Center for Food Nutrition and Human Health, Beijing Engineering and Technology Research Center of Food Additives, Beijing Technology and Business University, Beijing 100048, Peoples' Republic of China.
| | - Haochun Zhou
- National Soybean Processing Industry Technology Innovation Center, Beijing Advanced Innovation Center for Food Nutrition and Human Health, Beijing Engineering and Technology Research Center of Food Additives, Beijing Technology and Business University, Beijing 100048, Peoples' Republic of China.
| | - He Li
- National Soybean Processing Industry Technology Innovation Center, Beijing Advanced Innovation Center for Food Nutrition and Human Health, Beijing Engineering and Technology Research Center of Food Additives, Beijing Technology and Business University, Beijing 100048, Peoples' Republic of China.
| | - Zhiwei Ying
- National Soybean Processing Industry Technology Innovation Center, Beijing Advanced Innovation Center for Food Nutrition and Human Health, Beijing Engineering and Technology Research Center of Food Additives, Beijing Technology and Business University, Beijing 100048, Peoples' Republic of China.
| | - Xinqi Liu
- National Soybean Processing Industry Technology Innovation Center, Beijing Advanced Innovation Center for Food Nutrition and Human Health, Beijing Engineering and Technology Research Center of Food Additives, Beijing Technology and Business University, Beijing 100048, Peoples' Republic of China.
| |
Collapse
|
|
30
|
Vaghari-Tabari M, Ferns GA, Qujeq D, Andevari AN, Sabahi Z, Moein S. Signaling, metabolism, and cancer: An important relationship for therapeutic intervention. J Cell Physiol 2021; 236:5512-5532. [PMID: 33580511 DOI: 10.1002/jcp.30276] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 12/28/2020] [Accepted: 12/30/2020] [Indexed: 11/05/2022]
Abstract
In cancerous cells, significant changes occur in the activity of signaling pathways affecting a wide range of cellular activities ranging from growth and proliferation to apoptosis, invasiveness, and metastasis. Extensive changes also happen with respect to the metabolism of a cancerous cell encompassing a wide range of functions that include: nutrient acquisition, biosynthesis of macromolecules, and energy generation. These changes are important and some therapeutic approaches for treating cancers have focused on targeting the metabolism of cancerous cells. Oncogenes and tumor suppressor genes have a significant effect on the metabolism of cells. There appears to be a close interaction between metabolism and the signaling pathways in a cancerous cell, in which the interaction provides the metabolic needs of a cancerous cell for uncontrolled proliferation, resistance to apoptosis, and metastasis. In this review, we have reviewed the latest findings in this regard and briefly review the most recent research findings regarding targeting the metabolism of cancer cells as a therapeutic approach for treatment of cancer.
Collapse
Affiliation(s)
- Mostafa Vaghari-Tabari
- Department of Clinical Biochemistry and Laboratory Medicine, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Gordon A Ferns
- Department of Medical Education, Brighton & Sussex Medical School, Falmer, Brighton, Sussex, UK
| | - Durdi Qujeq
- Cellular and Molecular Biology Research Center (CMBRC), Health Research Institute, Babol University of Medical Sciences, Babol, Iran.,Department of Clinical Biochemistry, Babol University of Medical Sciences, Babol, Iran
| | - Ali Nosrati Andevari
- Department of Biochemistry, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Zahra Sabahi
- Medicinal Plants Processing Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Soheila Moein
- Medicinal Plants Processing Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| |
Collapse
|
|
31
|
Nabil M, El Raey MA, Abdo W, Abdelfattah MAO, El-Shazly AM, Sobeh M, Mahmoud MF. Gastro-Protective Effects of Albizia anthelmintica Leaf Extract on Indomethacin-Induced Gastric Ulcer in Wistar Rats: In Silico and In Vivo Studies. Antioxidants (Basel) 2021; 10:176. [PMID: 33530540 PMCID: PMC7911069 DOI: 10.3390/antiox10020176] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 01/17/2021] [Accepted: 01/19/2021] [Indexed: 12/18/2022] Open
Abstract
We have previously reported that the leaf extract of Albizia anthelmintica exhibited substantial antioxidant, anti-inflammatory, analgesic, and antipyretic properties in vivo. We also comprehensively characterized the active phytoconstituents and found several flavonoids and galloyl glucosides derivatives. In the current work, we explored the gastroprotective effects of the leaf extract in an indomethacin-induced ulcer model and the mechanisms involved. The rats being pretreated with the tested extract (100 and 200 mg kg-1) significantly prevented gastric lesions by 87.4% and 92.3%, respectively, and they had no structural derangements in the gastric mucosa. The extract significantly reduced the elevated levels of IKκB, NF-κB, TNF-α, IL-6, iNOS, and lipid peroxidation; increased the reduced level of glutathione peroxidase (GPx) activity; and reduced glutathione (GSH) in the indomethacin-induced ulcer model. The protective activities of the extract were similar in most aspects to those exerted by the known anti-ulcer drug famotidine. These activities might be attributed to the anti-inflammatory and antioxidant activities, and the reduction of iNOS levels. In conclusion, Albizia anthelmintica is a potential candidate for management of gastric ulcers with antioxidant properties.
Collapse
Affiliation(s)
- Mohamed Nabil
- Pharmaceutical and Fermentation Industries Development Center (PFIDC), City of Scientific Research and Technological Applications (SRTA-City), New Borg El-Arab 21934, Egypt;
- Pharmacology Department, Faculty of Pharmacy, Deraya University, New Mina 61768, Egypt
| | - Mohamed A. El Raey
- Department of Phytochemistry and Plant Systematics, Pharmaceutical Division, National Research Centre, Dokki, Cairo 12622, Egypt;
| | - Walied Abdo
- Department of Pathology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafr El Sheikh 33516, Egypt;
| | | | - Assem M. El-Shazly
- Department of Pharmacognosy, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt;
| | - Mansour Sobeh
- AgroBioSciences Research Department, Mohammed VI Polytechnic University, Lot 660–Hay MoulayRachid, Ben-Guerir 43150, Morocco
| | - Mona F. Mahmoud
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt
| |
Collapse
|
|
32
|
Tauber S, Sieckmann MK, Erler K, Stahl W, Klotz LO, Steinbrenner H. Activation of Nrf2 by Electrophiles Is Largely Independent of the Selenium Status of HepG2 Cells. Antioxidants (Basel) 2021; 10:antiox10020167. [PMID: 33498683 PMCID: PMC7911449 DOI: 10.3390/antiox10020167] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 01/15/2021] [Accepted: 01/21/2021] [Indexed: 12/13/2022] Open
Abstract
Selenoenzymes, whose activity depends on adequate selenium (Se) supply, and phase II enzymes, encoded by target genes of nuclear factor erythroid 2-related factor 2 (Nrf2), take part in governing cellular redox homeostasis. Their interplay is still not entirely understood. Here, we exposed HepG2 hepatoma cells cultured under Se-deficient, Se-adequate, or Se-supranutritional conditions to the Nrf2 activators sulforaphane, cardamonin, or diethyl maleate. Nrf2 protein levels and intracellular localization were determined by immunoblotting, and mRNA levels of Nrf2 target genes and selenoproteins were assessed by qRT-PCR. Exposure to electrophiles resulted in rapid induction of Nrf2 and its enrichment in the nucleus, independent of the cellular Se status. All three electrophilic compounds caused an enhanced expression of Nrf2 target genes, although with differences regarding extent and time course of their induction. Whereas Se status did not significantly affect mRNA levels of the Nrf2 target genes, gene expression of selenoproteins with a low position in the cellular "selenoprotein hierarchy", such as glutathione peroxidase 1 (GPX1) or selenoprotein W (SELENOW), was elevated under Se-supplemented conditions, as compared to cells held in Se-deficient media. In conclusion, no major effect of Se status on Nrf2 signalling was observed in HepG2 cells.
Collapse
Affiliation(s)
- Sarah Tauber
- Institute of Nutritional Sciences, Nutrigenomics Section, Friedrich Schiller University Jena, D-07743 Jena, Germany; (S.T.); (M.K.S.); (K.E.); (L.-O.K.)
| | - Maria Katharina Sieckmann
- Institute of Nutritional Sciences, Nutrigenomics Section, Friedrich Schiller University Jena, D-07743 Jena, Germany; (S.T.); (M.K.S.); (K.E.); (L.-O.K.)
| | - Katrin Erler
- Institute of Nutritional Sciences, Nutrigenomics Section, Friedrich Schiller University Jena, D-07743 Jena, Germany; (S.T.); (M.K.S.); (K.E.); (L.-O.K.)
| | - Wilhelm Stahl
- Institute of Biochemistry and Molecular Biology I, Medical Faculty, Heinrich Heine University Düsseldorf, D-40001 Düsseldorf, Germany;
| | - Lars-Oliver Klotz
- Institute of Nutritional Sciences, Nutrigenomics Section, Friedrich Schiller University Jena, D-07743 Jena, Germany; (S.T.); (M.K.S.); (K.E.); (L.-O.K.)
| | - Holger Steinbrenner
- Institute of Nutritional Sciences, Nutrigenomics Section, Friedrich Schiller University Jena, D-07743 Jena, Germany; (S.T.); (M.K.S.); (K.E.); (L.-O.K.)
- Correspondence: ; Tel.: +49-3641-949757
| |
Collapse
|
|
33
|
Morris G, Walker AJ, Walder K, Berk M, Marx W, Carvalho AF, Maes M, Puri BK. Increasing Nrf2 Activity as a Treatment Approach in Neuropsychiatry. Mol Neurobiol 2021; 58:2158-2182. [PMID: 33411248 DOI: 10.1007/s12035-020-02212-w] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 11/16/2020] [Indexed: 02/07/2023]
Abstract
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor encoded by NFE2L2. Under oxidative stress, Nrf2 does not undergo its normal cytoplasmic degradation but instead travels to the nucleus, where it binds to a DNA promoter and initiates transcription of anti-oxidative genes. Nrf2 upregulation is associated with increased cellular levels of glutathione disulfide, glutathione peroxidase, glutathione transferases, thioredoxin and thioredoxin reductase. Given its key role in governing the cellular antioxidant response, upregulation of Nrf2 has been suggested as a common therapeutic target in neuropsychiatric illnesses such as major depressive disorder, bipolar disorder and schizophrenia, which are associated with chronic oxidative and nitrosative stress, characterised by elevated levels of reactive oxygen species, nitric oxide and peroxynitrite. These processes lead to extensive lipid peroxidation, protein oxidation and carbonylation, and oxidative damage to nuclear and mitochondrial DNA. Intake of N-acetylcysteine, coenzyme Q10 and melatonin is accompanied by increased Nrf2 activity. N-acetylcysteine intake is associated with improved cerebral mitochondrial function, decreased central oxidative and nitrosative stress, reduced neuroinflammation, alleviation of endoplasmic reticular stress and suppression of the unfolded protein response. Coenzyme Q10, which acts as a superoxide scavenger in neuroglial mitochondria, instigates mitohormesis, ameliorates lipid peroxidation in the inner mitochondrial membrane, activates uncoupling proteins, promotes mitochondrial biogenesis and has positive effects on the plasma membrane redox system. Melatonin, which scavenges mitochondrial free radicals, inhibits mitochondrial nitric oxide synthase, restores mitochondrial calcium homeostasis, deacetylates and activates mitochondrial SIRT3, ameliorates increased permeability of the blood-brain barrier and intestine and counters neuroinflammation and glutamate excitotoxicity.
Collapse
Affiliation(s)
- G Morris
- Institute for Mental and Physical Health and Clinical Translation (IMPACT), Barwon Health, School of Medicine, Deakin University, Geelong, VIC, Australia
| | - A J Walker
- Institute for Mental and Physical Health and Clinical Translation (IMPACT), Barwon Health, School of Medicine, Deakin University, Geelong, VIC, Australia
| | - K Walder
- Institute for Mental and Physical Health and Clinical Translation (IMPACT), Barwon Health, School of Medicine, Deakin University, Geelong, VIC, Australia
| | - M Berk
- Institute for Mental and Physical Health and Clinical Translation (IMPACT), Barwon Health, School of Medicine, Deakin University, Geelong, VIC, Australia.,CMMR Strategic Research Centre, School of Medicine, Deakin University, Geelong, VIC, Australia.,Orygen, The National Centre of Excellence in Youth Mental Health, The Department of Psychiatry and the Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - W Marx
- Institute for Mental and Physical Health and Clinical Translation (IMPACT), Barwon Health, School of Medicine, Deakin University, Geelong, VIC, Australia
| | - A F Carvalho
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada.,Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada
| | - M Maes
- Institute for Mental and Physical Health and Clinical Translation (IMPACT), Barwon Health, School of Medicine, Deakin University, Geelong, VIC, Australia.,Department of Psychiatry, Chulalongkorn University, Bangkok, Thailand
| | | |
Collapse
|
|
34
|
Wang Y, Chen X, Huang Z, Chen D, Yu B, Yu J, Chen H, He J, Luo Y, Zheng P. Dietary Ferulic Acid Supplementation Improves Antioxidant Capacity and Lipid Metabolism in Weaned Piglets. Nutrients 2020; 12:nu12123811. [PMID: 33322714 PMCID: PMC7763429 DOI: 10.3390/nu12123811] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 12/08/2020] [Accepted: 12/10/2020] [Indexed: 02/06/2023] Open
Abstract
Ferulic acid (FA) is a phenolic compound that has antioxidant, hepatoprotective, anticarcinogenic, anti-inflammatory, antiallergic, antimicrobial, antiviral, and vasodilatory effects. This study was conducted to explore the effects of dietary FA supplementation on antioxidant capacity and lipid metabolism in weaned piglets. Eighteen 21-day-old castrated male DLY (Duroc × Landrace × Yorkshire) weaned piglets were randomly divided into control, 0.05%, and 0.45% FA groups. The results showed that, in serum, CAT and T-SOD activities and content of HDL-C were increased, but the content of MDA and the activities of T-CHO and LDL-C were decreased, by FA supplementation. In liver, dietary FA supplementation increased CAT, T-SOD, and GSH-PX activities and upregulated the mRNA levels of SOD1, SOD2, CAT, GST, GPX1, GR, Nrf2, HSL, CPT1b, and PPARα but decreased the contents of MDA and TG. Furthermore, dietary FA supplementation increased the protein level of Nrf2, HO-1, and NQO-1. In longissimus dorsi muscle, dietary FA supplementation increased the activity of T-SOD and the mRNA abundance of SOD1, SOD2, CAT, GST, GPX1, GR, and Nrf2 but decreased the contents of MDA and T-CHO. Additionally, dietary FA supplementation increased the protein expressions of Nrf2, HO-1, and NQO1. Together, our data suggest that FA could improve antioxidant capacity and lipid metabolism in weaned piglets.
Collapse
Affiliation(s)
- Youxia Wang
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China; (Y.W.); (X.C.); (D.C.); (B.Y.); (J.Y.); (J.H.); (Y.L.); (P.Z.)
| | - Xiaoling Chen
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China; (Y.W.); (X.C.); (D.C.); (B.Y.); (J.Y.); (J.H.); (Y.L.); (P.Z.)
| | - Zhiqing Huang
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China; (Y.W.); (X.C.); (D.C.); (B.Y.); (J.Y.); (J.H.); (Y.L.); (P.Z.)
- Correspondence: ; Tel./Fax: +86-28-8629-0976
| | - Daiwen Chen
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China; (Y.W.); (X.C.); (D.C.); (B.Y.); (J.Y.); (J.H.); (Y.L.); (P.Z.)
| | - Bing Yu
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China; (Y.W.); (X.C.); (D.C.); (B.Y.); (J.Y.); (J.H.); (Y.L.); (P.Z.)
| | - Jie Yu
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China; (Y.W.); (X.C.); (D.C.); (B.Y.); (J.Y.); (J.H.); (Y.L.); (P.Z.)
| | - Hong Chen
- College of Food Science, Sichuan Agricultural University, Yaan 625014, China;
| | - Jun He
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China; (Y.W.); (X.C.); (D.C.); (B.Y.); (J.Y.); (J.H.); (Y.L.); (P.Z.)
| | - Yuheng Luo
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China; (Y.W.); (X.C.); (D.C.); (B.Y.); (J.Y.); (J.H.); (Y.L.); (P.Z.)
| | - Ping Zheng
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China; (Y.W.); (X.C.); (D.C.); (B.Y.); (J.Y.); (J.H.); (Y.L.); (P.Z.)
| |
Collapse
|
|
35
|
Schwarz M, Lossow K, Schirl K, Hackler J, Renko K, Kopp JF, Schwerdtle T, Schomburg L, Kipp AP. Copper interferes with selenoprotein synthesis and activity. Redox Biol 2020; 37:101746. [PMID: 33059313 PMCID: PMC7567034 DOI: 10.1016/j.redox.2020.101746] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 10/01/2020] [Accepted: 10/04/2020] [Indexed: 12/19/2022] Open
Abstract
Selenium and copper are essential trace elements for humans, needed for the biosynthesis of enzymes contributing to redox homeostasis and redox-dependent signaling pathways. Selenium is incorporated as selenocysteine into the active site of redox-relevant selenoproteins including glutathione peroxidases (GPX) and thioredoxin reductases (TXNRD). Copper-dependent enzymes mediate electron transfer and other redox reactions. As selenoprotein expression can be modulated e.g. by H2O2, we tested the hypothesis that copper status affects selenoprotein expression. To this end, hepatocarcinoma HepG2 cells and mice were exposed to a variable copper and selenium supply in a physiologically relevant concentration range, and transcript and protein expression as well as GPX and TXNRD activities were compared. Copper suppressed selenoprotein mRNA levels of GPX1 and SELENOW, downregulated GPX and TXNRD activities and decreased UGA recoding efficiency in reporter cells. The interfering effects were successfully suppressed by applying the copper chelators bathocuproinedisulfonic acid or tetrathiomolybdate. In mice, a decreased copper supply moderately decreased the copper status and negatively affected hepatic TXNRD activity. We conclude that there is a hitherto unknown interrelationship between copper and selenium status, and that copper negatively affects selenoprotein expression and activity most probably via limiting UGA recoding. This interference may be of physiological relevance during aging, where a particular shift in the selenium to copper ratio has been reported. An increased concentration of copper in face of a downregulated selenoprotein expression may synergize and negatively affect the cellular redox homeostasis contributing to disease processes.
Collapse
Affiliation(s)
- Maria Schwarz
- Department of Molecular Nutritional Physiology, Institute of Nutritional Sciences, Friedrich Schiller University Jena, Jena, 07743, Germany; TraceAge-DFG Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly, Potsdam-Berlin-Jena, Germany
| | - Kristina Lossow
- Department of Molecular Nutritional Physiology, Institute of Nutritional Sciences, Friedrich Schiller University Jena, Jena, 07743, Germany; TraceAge-DFG Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly, Potsdam-Berlin-Jena, Germany; German Institute of Human Nutrition, Nuthetal, 14558, Germany
| | - Katja Schirl
- Department of Molecular Nutritional Physiology, Institute of Nutritional Sciences, Friedrich Schiller University Jena, Jena, 07743, Germany
| | - Julian Hackler
- TraceAge-DFG Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly, Potsdam-Berlin-Jena, Germany; Institute for Experimental Endocrinology, Charité - University Medical School Berlin, Berlin, 13353, Germany
| | - Kostja Renko
- Institute for Experimental Endocrinology, Charité - University Medical School Berlin, Berlin, 13353, Germany; German Federal Institute for Risk Assessment (BfR), Berlin, Germany
| | - Johannes Florian Kopp
- TraceAge-DFG Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly, Potsdam-Berlin-Jena, Germany; Department of Food Chemistry, Institute of Nutritional Science, University of Potsdam, Nuthetal, 14558, Germany
| | - Tanja Schwerdtle
- TraceAge-DFG Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly, Potsdam-Berlin-Jena, Germany; German Federal Institute for Risk Assessment (BfR), Berlin, Germany; Department of Food Chemistry, Institute of Nutritional Science, University of Potsdam, Nuthetal, 14558, Germany
| | - Lutz Schomburg
- TraceAge-DFG Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly, Potsdam-Berlin-Jena, Germany; Institute for Experimental Endocrinology, Charité - University Medical School Berlin, Berlin, 13353, Germany
| | - Anna Patricia Kipp
- Department of Molecular Nutritional Physiology, Institute of Nutritional Sciences, Friedrich Schiller University Jena, Jena, 07743, Germany; TraceAge-DFG Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly, Potsdam-Berlin-Jena, Germany.
| |
Collapse
|
|
36
|
Madadi E, Mazloum-Ravasan S, Yu JS, Ha JW, Hamishehkar H, Kim KH. Therapeutic Application of Betalains: A Review. PLANTS 2020; 9:plants9091219. [PMID: 32957510 PMCID: PMC7569795 DOI: 10.3390/plants9091219] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 09/08/2020] [Accepted: 09/11/2020] [Indexed: 12/15/2022]
Abstract
Anthocyanins, betalains, riboflavin, carotenoids, chlorophylls and caramel are the basic natural food colorants used in modern food manufacture. Betalains, which are composed of red–violet betacyanin and yellow betaxanthins, are water-soluble pigments that color flowers and fruits. Betalains are pigments primarily produced by plants of the order Caryophyllales. Because of their anti-inflammatory, cognitive impairment, anticancer and anti-hepatitis properties, betalains are useful as pharmaceutical agents and dietary supplements. Betalains also exhibit antimicrobial and antimalarial effects, and as an example, betalain-rich Amaranthus spinosus displays prominent antimalarial activity. Studies also confirmed the antidiabetic effect of betalains, which reduced glycemia by 40% without causing weight loss or liver impairment. These findings show that betalain colorants may be a promising alternative to the synthetic dyes currently used as food additives.
Collapse
Affiliation(s)
- Elaheh Madadi
- Biotechnology Research Center and Student’s Research Committee, Tabriz University of Medical Sciences, Tabriz 51368, Iran;
| | - Sahand Mazloum-Ravasan
- Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz 51368, Iran;
| | - Jae Sik Yu
- School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea; (J.S.Y.); (J.W.H.)
| | - Ji Won Ha
- School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea; (J.S.Y.); (J.W.H.)
| | - Hamed Hamishehkar
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz 51368, Iran
- Correspondence: (H.H.); (K.H.K.); Tel.: +98-41-3336-3277 (H.H.); +82-31-290-7700 (K.H.K.)
| | - Ki Hyun Kim
- School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea; (J.S.Y.); (J.W.H.)
- Correspondence: (H.H.); (K.H.K.); Tel.: +98-41-3336-3277 (H.H.); +82-31-290-7700 (K.H.K.)
| |
Collapse
|
|
37
|
Nakano Y, Shimoda M, Okudomi S, Kawaraya S, Kawahara M, Tanaka KI. Seleno-l-methionine suppresses copper-enhanced zinc-induced neuronal cell death via induction of glutathione peroxidase. Metallomics 2020; 12:1693-1701. [PMID: 32926024 DOI: 10.1039/d0mt00136h] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Excessive zinc ion (Zn2+) release is induced in pathological situations and causes neuronal cell death. Previously, we have reported that copper ions (Cu2+) markedly exacerbated Zn2+-induced neuronal cell death by potentiating oxidative stress, the endoplasmic reticulum (ER) stress response, and the activation of the c-Jun amino-terminal kinase (JNK) signaling pathway. In contrast, selenium (Se), an essential trace element, and amino acids containing selenium (such as seleno-l-methionine) have been reported to inhibit stress-induced neuronal cell death and oxidative stress. Thus, we investigated the effect of seleno-l-methionine on Cu2+/Zn2+-induced neuronal cell death in GT1-7 cells. Seleno-l-methionine treatment clearly restored the Cu2+/Zn2+-induced decrease in the viable cell number and attenuated the Cu2+/Zn2+-induced cytotoxicity. Accordingly, the levels of ER stress-related factors (especially, CHOP and GADD34) and of phosphorylated JNK increased upon CuCl2 and ZnCl2 co-treatment, whereas pre-treatment with seleno-l-methionine significantly suppressed these upregulations. Analysis of reactive oxygen species (ROS) as upstream factors of these pathways revealed that Cu2+/Zn2+-induced ROS production was clearly suppressed by seleno-l-methionine treatment. Finally, we found that seleno-l-methionine induced the antioxidative protein, glutathione peroxidase. Taken together, our findings suggest that seleno-l-methionine suppresses Cu2+/Zn2+-induced neuronal cell death and oxidative stress via induction of glutathione peroxidase. Thus, we think that seleno-l-methionine may help prevent refractory neurological diseases.
Collapse
Affiliation(s)
- Yukari Nakano
- Department of Bio-Analytical Chemistry, Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo 202-8585, Japan.
| | | | | | | | | | | |
Collapse
|
|
38
|
Abstract
Significance: The selenium-containing Glutathione peroxidases (GPxs)1-4 protect against oxidative challenge, inhibit inflammation and oxidant-induced regulated cell death. Recent Advances: GPx1 and GPx4 dampen phosphorylation cascades predominantly via prevention of inactivation of phosphatases by H2O2 or lipid hydroperoxides. GPx2 regulates the balance between regeneration and apoptotic cell shedding in the intestine. It inhibits inflammation-induced carcinogenesis in the gut but promotes growth of established cancers. GPx3 deficiency facilitates platelet aggregation likely via disinhibition of thromboxane biosynthesis. It is also considered a tumor suppressor. GPx4 is expressed in three different forms. The cytosolic form proved to inhibit interleukin-1-driven nuclear factor κB activation and leukotriene biosynthesis. Moreover, it is a key regulator of ferroptosis, because it reduces hydroperoxy groups of complex lipids and silences lipoxygenases. By alternate substrate use, the nuclear form contributes to chromatin compaction. Mitochondrial GPx4 forms the mitochondrial sheath of spermatozoa and, thus, guarantees male fertility. Out of the less characterized GPxs, the cysteine-containing GPx7 and GPx8 are unique in contributing to oxidative protein folding in the endoplasmic reticulum by reacting with protein isomerase as an alternate substrate. A yeast 2-Cysteine glutathione peroxidase equipped with CP and CR was reported to sense H2O2 for inducing an adaptive response. Critical Issues: Most of the findings compiled are derived from tissue culture and/or animal studies only. Their impact on human physiology is sometimes questionable. Future Directions: The expression of individual GPxs and GPx-dependent regulatory phenomena are to be further investigated, in particular in respect to human health.
Collapse
Affiliation(s)
- Regina Brigelius-Flohé
- Department of Biochemistry of Micronutrients, German Institute of Human Nutrition-Potsdam-Rehbrücke (DIfE), Nuthetal, Germany
| | - Leopold Flohé
- Depatamento de Biochímica, Universidad de la República, Montevideo, Uruguay.,Dipartimento di Medicina Moleculare, Università degli Studi di Padova, Padova, Italy
| |
Collapse
|
|
39
|
Chang C, Worley BL, Phaëton R, Hempel N. Extracellular Glutathione Peroxidase GPx3 and Its Role in Cancer. Cancers (Basel) 2020; 12:cancers12082197. [PMID: 32781581 PMCID: PMC7464599 DOI: 10.3390/cancers12082197] [Citation(s) in RCA: 119] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 08/03/2020] [Accepted: 08/04/2020] [Indexed: 12/26/2022] Open
Abstract
Mammalian cells possess a multifaceted antioxidant enzyme system, which includes superoxide dismutases, catalase, the peroxiredoxin/thioredoxin and the glutathione peroxidase systems. The dichotomous role of reactive oxygen species and antioxidant enzymes in tumorigenesis and cancer progression complicates the use of small molecule antioxidants, pro-oxidants, and targeting of antioxidant enzymes as therapeutic approaches for cancer treatment. It also highlights the need for additional studies to investigate the role and regulation of these antioxidant enzymes in cancer. The focus of this review is on glutathione peroxidase 3 (GPx3), a selenoprotein, and the only extracellular GPx of a family of oxidoreductases that catalyze the detoxification of hydro- and soluble lipid hydroperoxides by reduced glutathione. In addition to summarizing the biochemical function, regulation, and disease associations of GPx3, we specifically discuss the role and regulation of systemic and tumor cell expressed GPx3 in cancer. From this it is evident that GPx3 has a dichotomous role in different tumor types, acting as both a tumor suppressor and pro-survival protein. Further studies are needed to examine how loss or gain of GPx3 specifically affects oxidant scavenging and redox signaling in the extracellular tumor microenvironment, and how GPx3 might be targeted for therapeutic intervention.
Collapse
Affiliation(s)
- Caroline Chang
- Department of Comparative Medicine, Penn State University College of Medicine, Hershey, PA 17033, USA;
| | - Beth L. Worley
- Department of Pharmacology, Penn State University College of Medicine, Hershey, PA 17033, USA;
| | - Rébécca Phaëton
- Department of Obstetrics & Gynecology & Department of Microbiology and Immunology, Penn State University College of Medicine, Hershey, PA 17033, USA;
| | - Nadine Hempel
- Department of Pharmacology, Penn State University College of Medicine, Hershey, PA 17033, USA;
- Correspondence: ; Tel.: +1-717-531-4037
| |
Collapse
|
|
40
|
Yang H, Kuhn C, Kolben T, Ma Z, Lin P, Mahner S, Jeschke U, von Schönfeldt V. Early Life Oxidative Stress and Long-Lasting Cardiovascular Effects on Offspring Conceived by Assisted Reproductive Technologies: A Review. Int J Mol Sci 2020; 21:ijms21155175. [PMID: 32707756 PMCID: PMC7432066 DOI: 10.3390/ijms21155175] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 07/18/2020] [Accepted: 07/20/2020] [Indexed: 02/06/2023] Open
Abstract
Assisted reproductive technology (ART) has rapidly developed and is now widely practised worldwide. Both the characteristics of ART (handling gametes/embryos in vitro) and the infertility backgrounds of ART parents (such as infertility diseases and unfavourable lifestyles or diets) could cause increased oxidative stress (OS) that may exert adverse influences on gametogenesis, fertilisation, and foetation, even causing a long-lasting influence on the offspring. For these reasons, the safety of ART needs to be closely examined. In this review, from an ART safety standpoint, the origins of OS are reviewed, and the long-lasting cardiovascular effects and potential mechanisms of OS on the offspring are discussed.
Collapse
Affiliation(s)
- Huixia Yang
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, 81377 Munich, Germany; (H.Y.); (C.K.); (T.K.); (Z.M.); (P.L.); (S.M.); (V.v.S.)
| | - Christina Kuhn
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, 81377 Munich, Germany; (H.Y.); (C.K.); (T.K.); (Z.M.); (P.L.); (S.M.); (V.v.S.)
- Department of Obstetrics and Gynecology, University Hospital Augsburg, 86156 Augsburg, Germany
| | - Thomas Kolben
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, 81377 Munich, Germany; (H.Y.); (C.K.); (T.K.); (Z.M.); (P.L.); (S.M.); (V.v.S.)
| | - Zhi Ma
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, 81377 Munich, Germany; (H.Y.); (C.K.); (T.K.); (Z.M.); (P.L.); (S.M.); (V.v.S.)
| | - Peng Lin
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, 81377 Munich, Germany; (H.Y.); (C.K.); (T.K.); (Z.M.); (P.L.); (S.M.); (V.v.S.)
| | - Sven Mahner
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, 81377 Munich, Germany; (H.Y.); (C.K.); (T.K.); (Z.M.); (P.L.); (S.M.); (V.v.S.)
| | - Udo Jeschke
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, 81377 Munich, Germany; (H.Y.); (C.K.); (T.K.); (Z.M.); (P.L.); (S.M.); (V.v.S.)
- Department of Obstetrics and Gynecology, University Hospital Augsburg, 86156 Augsburg, Germany
- Correspondence: ; Tel.: +49-(0)821-400-165505
| | - Viktoria von Schönfeldt
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, 81377 Munich, Germany; (H.Y.); (C.K.); (T.K.); (Z.M.); (P.L.); (S.M.); (V.v.S.)
| |
Collapse
|
|
41
|
Dabo AJ, Ezegbunam W, Wyman AE, Moon J, Railwah C, Lora A, Majka SM, Geraghty P, Foronjy RF. Targeting c-Src Reverses Accelerated GPX-1 mRNA Decay in Chronic Obstructive Pulmonary Disease Airway Epithelial Cells. Am J Respir Cell Mol Biol 2020; 62:598-607. [PMID: 31801023 DOI: 10.1165/rcmb.2019-0177oc] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Enhanced expression of the cellular antioxidant glutathione peroxidase (GPX)-1 prevents cigarette smoke-induced lung inflammation and tissue destruction. Subjects with chronic obstructive pulmonary disease (COPD), however, have decreased airway GPX-1 levels, rendering them more susceptible to disease onset and progression. The mechanisms that downregulate GPX-1 in the airway epithelium in COPD remain unknown. To ascertain these factors, analyses were conducted using human airway epithelial cells isolated from healthy subjects and human subjects with COPD and lung tissue from control and cigarette smoke-exposed A/J mice. Tyrosine phosphorylation modifies GPX-1 expression and cigarette smoke activates the tyrosine kinase c-Src. Therefore, studies were conducted to evaluate the role of c-Src on GPX-1 levels in COPD. These studies identified accelerated GPX-1 mRNA decay in COPD airway epithelial cells. Targeting the tyrosine kinase c-Src with siRNA inhibited GPX-1 mRNA degradation and restored GPX-1 protein levels in human airway epithelial cells. In contrast, silencing the tyrosine kinase c-Abl, or the transcriptional activator Nrf2, had no effect on GPX-1 mRNA stability. The chemical inhibitors for c-Src (saracatinib and dasanitib) restored GPX-1 mRNA levels and GPX-1 activity in COPD airway cells in vitro. Similarly, saracatinib prevented the loss of lung Gpx-1 expression in response to chronic smoke exposure in vivo. Thus, this study establishes that the decreased GPX-1 expression that occurs in COPD lungs is at least partially due to accelerated mRNA decay. Furthermore, these findings show that targeting c-Src represents a potential therapeutic approach to augment GPX-1 responses and counter smoke-induced lung disease.
Collapse
Affiliation(s)
- Abdoulaye J Dabo
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, and.,Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, New York; and
| | - Wendy Ezegbunam
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, and
| | - Anne E Wyman
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, and
| | - Jane Moon
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, and
| | - Christopher Railwah
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, and
| | - Alnardo Lora
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, and
| | - Susan M Majka
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, National Jewish Health, Denver, Colorado
| | - Patrick Geraghty
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, and.,Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, New York; and
| | - Robert F Foronjy
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, and.,Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, New York; and
| |
Collapse
|
|
42
|
Zhang H, Lu J, Wu S. Sp4 controls constitutive expression of neuronal serine racemase and NF-E2-related factor-2 mediates its induction by valproic acid. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2020; 1863:194597. [PMID: 32603878 DOI: 10.1016/j.bbagrm.2020.194597] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 06/12/2020] [Accepted: 06/21/2020] [Indexed: 01/10/2023]
Abstract
Serine racemase (SR) synthesizes l-type serine to its enantimor, d-serine which participates in physiological processes and in pathological conditions. In the central nervous system, SR is highly expressed in neurons and astrocytes but expressed at relatively lower amount in microglia. However, the mechanism by which SR is highly expessed in neurons is hitherto unknown. We report that the SR mRNA and protein levels in Neuro-2a were increased by valproic acid (VPA), a neuron differentiation stimulator as well as a histone deacetylase inhibitor. SR proximal promoter contained nine putative Sp-binding elements and in the exon 1, three putative anti-oxidant elements (AREs) were conservative among human, rat, and mouse genome. The promoter constructs including 5'-, 3'-fragment, and full length fragment from mouse were individually cloned into a luciferase reporter. Using dual-luciferase assay, the promoter harboring 3'-fragment contained much lower activity than the construct containing 5'-fragment which was though resistant to VPA induction, relative to 3'-fragment. Overexpression of Sp4 or Nrf2 increased whereas knockdown of either decreased Srr mRNA and SR protein. Using site-directed mutagenesis, mutation of Sp-binding elements or AREs in the constructs significantly decreased luciferase activity of the corresponding promoter construct. With chromatin immunoprecipitation, Sp4 was demonstrated to interact directly with the Sp-binding elements whereas Nrf2 bound AREs in Srr mRNA promoter. Altogether, our study highlights that Sp4 controls constitutive expression of SR in neuron and VPA mediates SR expression in N2A cells which is associated with its effect on neuron differentiation, that is, the effect is mediated via Nrf2.
Collapse
Affiliation(s)
- He Zhang
- School of Optometry and Ophthalmology and the Eye Hospital, Wenzhou Medical University, China; State Key Laboratory of Optometry, Ophthalmology, and Visual Science, 270 Xueyuan Road, Wenzhou, Zhejiang 325003, China
| | - Jinfang Lu
- School of Optometry and Ophthalmology and the Eye Hospital, Wenzhou Medical University, China; School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Shengzhou Wu
- School of Optometry and Ophthalmology and the Eye Hospital, Wenzhou Medical University, China; State Key Laboratory of Optometry, Ophthalmology, and Visual Science, 270 Xueyuan Road, Wenzhou, Zhejiang 325003, China.
| |
Collapse
|
|
43
|
The interplay between oxidative stress and bioenergetic failure in neuropsychiatric illnesses: can we explain it and can we treat it? Mol Biol Rep 2020; 47:5587-5620. [PMID: 32564227 DOI: 10.1007/s11033-020-05590-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 06/12/2020] [Indexed: 12/12/2022]
Abstract
Nitro-oxidative stress and lowered antioxidant defences play a key role in neuropsychiatric disorders such as major depression, bipolar disorder and schizophrenia. The first part of this paper details mitochondrial antioxidant mechanisms and their importance in reactive oxygen species (ROS) detoxification, including details of NO networks, the roles of H2O2 and the thioredoxin/peroxiredoxin system, and the relationship between mitochondrial respiration and NADPH production. The second part highlights and identifies the causes of the multiple pathological sequelae arising from self-amplifying increases in mitochondrial ROS production and bioenergetic failure. Particular attention is paid to NAD+ depletion as a core cause of pathology; detrimental effects of raised ROS and reactive nitrogen species on ATP and NADPH generation; detrimental effects of oxidative and nitrosative stress on the glutathione and thioredoxin systems; and the NAD+-induced signalling cascade, including the roles of SIRT1, SIRT3, PGC-1α, the FOXO family of transcription factors, Nrf1 and Nrf2. The third part discusses proposed therapeutic interventions aimed at mitigating such pathology, including the use of the NAD+ precursors nicotinamide mononucleotide and nicotinamide riboside, both of which rapidly elevate levels of NAD+ in the brain and periphery following oral administration; coenzyme Q10 which, when given with the aim of improving mitochondrial function and reducing nitro-oxidative stress in the brain, may be administered via the use of mitoquinone, which is in essence ubiquinone with an attached triphenylphosphonium cation; and N-acetylcysteine, which is associated with improved mitochondrial function in the brain and produces significant decreases in oxidative and nitrosative stress in a dose-dependent manner.
Collapse
|
|
44
|
Reszka E, Lesicka M, Wieczorek E, Jabłońska E, Janasik B, Stępnik M, Konecki T, Jabłonowski Z. Dysregulation of Redox Status in Urinary Bladder Cancer Patients. Cancers (Basel) 2020; 12:cancers12051296. [PMID: 32455559 PMCID: PMC7280975 DOI: 10.3390/cancers12051296] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 05/12/2020] [Accepted: 05/18/2020] [Indexed: 02/06/2023] Open
Abstract
The alteration of redox homeostasis constitutes an important etiological feature of common human malignancies. We investigated DNA damage, selenium (Se) levels and the expression of cytoprotective genes involved in (1) the KEAP1/NRF2/ARE pathway, (2) selenoprotein synthesis, and (3) DNA methylation and histone deacetylation as putative key players in redox status dysregulation in the blood of urinary bladder cancer (UBC) patients. The study involved 122 patients and 115 control individuals. The majority of patients presented Ta and T1 stages. UBC recurrence occurred within 0.13 to 29.02 months. DNA damage and oxidative DNA damage were significantly higher in the patients compared to the controls, while plasma Se levels were significantly reduced in the cases compared to the controls. Of the 25 investigated genes, elevated expression in the peripheral blood leukocytes in patients was observed for NRF2, GCLC, MMP9 and SEP15, while down-regulation was found for KEAP1, GSR, HMOX1, NQO1, OGG1, SEPW1, DNMT1, DNMT3A and SIRT1. After Bonferroni correction, an association was found with KEAP1, OGG1, SEPW1 and DNMT1. Early recurrence was associated with the down-regulation of PRDX1 and SRXN1 at the time of diagnosis. Peripheral redox status is significantly dysregulated in the blood of UBC patients. DNA strand breaks and PRDX1 and SRXN1 expression may provide significant predictors of UBC recurrence.
Collapse
Affiliation(s)
- Edyta Reszka
- Department of Molecular Genetics and Epigenetics, Nofer Institute of Occupational Medicine, 91-348 Lodz, Poland; (M.L.); (E.W.); (E.J.)
- Correspondence: ; Tel.: +48-42-631-46-27
| | - Monika Lesicka
- Department of Molecular Genetics and Epigenetics, Nofer Institute of Occupational Medicine, 91-348 Lodz, Poland; (M.L.); (E.W.); (E.J.)
| | - Edyta Wieczorek
- Department of Molecular Genetics and Epigenetics, Nofer Institute of Occupational Medicine, 91-348 Lodz, Poland; (M.L.); (E.W.); (E.J.)
| | - Ewa Jabłońska
- Department of Molecular Genetics and Epigenetics, Nofer Institute of Occupational Medicine, 91-348 Lodz, Poland; (M.L.); (E.W.); (E.J.)
| | - Beata Janasik
- Department of Biological Monitoring, Nofer Institute of Occupational Medicine, 91-348 Lodz, Poland;
| | - Maciej Stępnik
- Department of Toxicology and Carcinogenesis, Nofer Institute of Occupational Medicine, 91-348 Lodz, Poland;
| | - Tomasz Konecki
- Ist Urology Clinic, Medical University of Lodz, 90-549 Lodz, Poland; (T.K.); (Z.J.)
| | - Zbigniew Jabłonowski
- Ist Urology Clinic, Medical University of Lodz, 90-549 Lodz, Poland; (T.K.); (Z.J.)
| |
Collapse
|
|
45
|
Morris G, Puri BK, Carvalho A, Maes M, Berk M, Ruusunen A, Olive L. Induced Ketosis as a Treatment for Neuroprogressive Disorders: Food for Thought? Int J Neuropsychopharmacol 2020; 23:366-384. [PMID: 32034911 PMCID: PMC7311648 DOI: 10.1093/ijnp/pyaa008] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Revised: 01/05/2020] [Accepted: 02/06/2020] [Indexed: 12/12/2022] Open
Abstract
Induced ketosis (or ketone body ingestion) can ameliorate several changes associated with neuroprogressive disorders, including schizophrenia, bipolar disorder, and major depressive disorder. Thus, the effects of glucose hypometabolism can be bypassed through the entry of beta-hydroxybutyrate, providing an alternative source of energy to glucose. The weight of evidence suggests that induced ketosis reduces levels of oxidative stress, mitochondrial dysfunction, and inflammation-core features of the above disorders. There are also data to suggest that induced ketosis may be able to target other molecules and signaling pathways whose levels and/or activity are also known to be abnormal in at least some patients suffering from these illnesses such as peroxisome proliferator-activated receptors, increased activity of the Kelch-like ECH-associated protein/nuclear factor erythroid 2-related factor 2, Sirtuin-1 nuclear factor-κB p65, and nicotinamide adenine dinucleotide (NAD). This review explains the mechanisms by which induced ketosis might reduce mitochondrial dysfunction, inflammation, and oxidative stress in neuropsychiatric disorders and ameliorate abnormal levels of molecules and signaling pathways that also appear to contribute to the pathophysiology of these illnesses. This review also examines safety data relating to induced ketosis over the long term and discusses the design of future studies.
Collapse
Affiliation(s)
- Gerwyn Morris
- The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Australia
| | - Basant K Puri
- C.A.R., Cambridge, United Kingdom,Hammersmith Hospital, London, United Kingdom
| | - Andre Carvalho
- Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada,Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | - Michael Maes
- Department of Psychiatry and Medical Psychology, Medical Faculty, Medical University of Plovdiv, Plovdiv, Bulgaria,Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Michael Berk
- The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Australia,Orygen, The National Centre of Excellence in Youth Mental Health, the Department of Psychiatry, and the Florey Institute for Neuroscience and Mental Health, University of Melbourne, Australia,Correspondence: Michael Berk, PO Box 281 Geelong, Victoria 3220 Australia ()
| | - Anu Ruusunen
- The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Australia
| | - Lisa Olive
- The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Australia
| |
Collapse
|
|
46
|
Morris G, Puri BK, Walker AJ, Berk M, Walder K, Bortolasci CC, Marx W, Carvalho AF, Maes M. The compensatory antioxidant response system with a focus on neuroprogressive disorders. Prog Neuropsychopharmacol Biol Psychiatry 2019; 95:109708. [PMID: 31351160 DOI: 10.1016/j.pnpbp.2019.109708] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 07/16/2019] [Accepted: 07/22/2019] [Indexed: 02/07/2023]
Abstract
Major antioxidant responses to increased levels of inflammatory, oxidative and nitrosative stress (ONS) are detailed. In response to increasing levels of nitric oxide, S-nitrosylation of cysteine thiol groups leads to post-transcriptional modification of many cellular proteins and thereby regulates their activity and allows cellular adaptation to increased levels of ONS. S-nitrosylation inhibits the function of nuclear factor kappa-light-chain-enhancer of activated B cells, toll-like receptor-mediated signalling and the activity of several mitogen-activated protein kinases, while activating nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2 or NFE2L2); in turn, the redox-regulated activation of Nrf2 leads to increased levels and/or activity of key enzymes and transporter systems involved in the glutathione system. The Nrf2/Kelch-like ECH-associated protein-1 axis is associated with upregulation of NAD(P)H:quinone oxidoreductase 1, which in turn has anti-inflammatory effects. Increased Nrf2 transcriptional activity also leads to activation of haem oxygenase-1, which is associated with upregulation of bilirubin, biliverdin and biliverdin reductase as well as increased carbon monoxide signalling, anti-inflammatory and antioxidant activity. Associated transcriptional responses, which may be mediated by retrograde signalling owing to elevated hydrogen peroxide, include the unfolded protein response (UPR), mitohormesis and the mitochondrial UPR; the UPR also results from increasing levels of mitochondrial and cytosolic reactive oxygen species and reactive nitrogen species leading to nitrosylation, glutathionylation, oxidation and nitration of crucial cysteine and tyrosine causing protein misfolding and the development of endoplasmic reticulum stress. It is shown how these mechanisms co-operate in forming a co-ordinated rapid and prolonged compensatory antioxidant response system.
Collapse
Affiliation(s)
- Gerwyn Morris
- IMPACT Strategic Research Centre, Barwon Health, School of Medicine, Deakin University, Geelong, VIC, Australia
| | - Basant K Puri
- Department of Medicine, Hammersmith Hospital, Imperial College London, London, United Kingdom
| | - Adam J Walker
- IMPACT Strategic Research Centre, Barwon Health, School of Medicine, Deakin University, Geelong, VIC, Australia
| | - Michael Berk
- IMPACT Strategic Research Centre, Barwon Health, School of Medicine, Deakin University, Geelong, VIC, Australia; Orygen, The National Centre of Excellence in Youth Mental Health, The Department of Psychiatry, The Florey Institute for Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia
| | - Ken Walder
- CMMR Strategic Research Centre, School of Medicine, Deakin University, Geelong, VIC, Australia
| | - Chiara C Bortolasci
- CMMR Strategic Research Centre, School of Medicine, Deakin University, Geelong, VIC, Australia
| | - Wolfgang Marx
- IMPACT Strategic Research Centre, Barwon Health, School of Medicine, Deakin University, Geelong, VIC, Australia
| | - Andre F Carvalho
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada.
| | - Michael Maes
- IMPACT Strategic Research Centre, Barwon Health, School of Medicine, Deakin University, Geelong, VIC, Australia
| |
Collapse
|
|
47
|
Campo-Sabariz J, Moral-Anter D, Brufau MT, Briens M, Pinloche E, Ferrer R, Martín-Venegas R. 2-Hydroxy-(4-methylseleno)butanoic Acid Is Used by Intestinal Caco-2 Cells as a Source of Selenium and Protects against Oxidative Stress. J Nutr 2019; 149:2191-2198. [PMID: 31504719 DOI: 10.1093/jn/nxz190] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Revised: 06/13/2019] [Accepted: 07/23/2019] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Selenium (Se) participates in different functions in humans and other animals through its incorporation into selenoproteins as selenocysteine. Inadequate dietary Se is considered a risk factor for several chronic diseases associated with oxidative stress. OBJECTIVE The role of 2-hydroxy-(4-methylseleno)butanoic acid (HMSeBA), an organic form of Se used in animal nutrition, in supporting selenoprotein synthesis and protecting against oxidative stress was investigated in an in vitro model of intestinal Caco-2 cells. METHODS Glutathione peroxidase (GPX) and thioredoxin reductase (TXNRD) activities, selenoprotein P1 protein (SELENOP) and gene (SELENOP) expression, and GPX1 and GPX2 gene expression were studied in Se-deprived (FBS removal) and further HMSeBA-supplemented (0.1-625 μM, 72 h) cultures. The effect of HMSeBA supplementation (12.5 and 625 μM, 24 h) on oxidative stress induced by H2O2 (1 mM) was evaluated by the production of reactive oxygen species (ROS), 4-hydroxy-2-nonenal (4-HNE) adducts, and protein carbonyl residues compared with a sodium selenite control (SS, 5 μM). RESULTS Se deprivation induced a reduction (P < 0.05) in GPX activity (62%), GPX1 expression, and both SELENOP (33%) and SELENOP expression. In contrast, an increase (P < 0.05) in GPX2 expression and no effect in TXNRD activity (P = 0.09) were observed. HMSeBA supplementation increased (P < 0.05) GPX activity (12.5-625 μM, 1.68-1.82-fold) and SELENOP protein expression (250 and 625 μM, 1.87- and 2.04-fold). Moreover, HMSeBA supplementation increased (P < 0.05) GPX1 (12.5 and 625 μM), GPX2 (625 μM), and SELENOP (12.5 and 625 μM) expression. HMSeBA (625 μM) was capable of decreasing (P < 0.05) ROS (32%), 4-HNE adduct (49%), and protein carbonyl residue (75%) production after H2O2 treatment. CONCLUSION Caco-2 cells can use HMSeBA as an Se source for selenoprotein synthesis, resulting in protection against oxidative stress.
Collapse
Affiliation(s)
- Joan Campo-Sabariz
- Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain.,Nutrition and Food Safety Research Institute, University of Barcelona, Barcelona, Spain
| | - David Moral-Anter
- Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain.,Nutrition and Food Safety Research Institute, University of Barcelona, Barcelona, Spain
| | - M Teresa Brufau
- Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain.,Nutrition and Food Safety Research Institute, University of Barcelona, Barcelona, Spain
| | | | | | - Ruth Ferrer
- Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain.,Nutrition and Food Safety Research Institute, University of Barcelona, Barcelona, Spain
| | - Raquel Martín-Venegas
- Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain.,Nutrition and Food Safety Research Institute, University of Barcelona, Barcelona, Spain
| |
Collapse
|
|
48
|
Cheng Q, Jiang S, Huang L, Wang Y, Yang W, Yang Z, Ge J. Effects of zearalenone-induced oxidative stress and Keap1-Nrf2 signaling pathway-related gene expression in the ileum and mesenteric lymph nodes of post-weaning gilts. Toxicology 2019; 429:152337. [PMID: 31760079 DOI: 10.1016/j.tox.2019.152337] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 11/08/2019] [Accepted: 11/20/2019] [Indexed: 12/29/2022]
Abstract
Zearalenone (ZEA) contamination of feed affects animal husbandry and the human health. Currently, the molecular mechanism underlying small intestine-related diseases caused by ZEA-induced oxidative stress is not well understood. In this study, we aimed to identify the mechanisms involved in ZEA (0.5-1.5 mg/kg)-induced oxidative stress in the ileum and mesenteric lymph nodes (MLNs) and the role of the Kelch-like erythroid cell-derived protein with CNC homology-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway in post-weaning gilts. Forty post-weaning gilts (Landrace × Yorkshire × Duroc) with an average body weight of 14.01 ± 0.86 kg were randomly allocated to four groups and fed a corn-soybean meal basal diet supplemented with < 0.1, 0.5, 1.0, or 1.5 mg/kg ZEA. The results showed that the activity of total superoxide dismutase and glutathione peroxidase decreased (p < 0.05) linearly and quadratically and that the content of malondialdehyde increased (p < 0.05) quadratically in the ileum and MLNs with increasing ZEA in the diet. Immunohistochemical analysis showed that the expression of Nrf2 and glutathione peroxidase 1 (Gpx1) immunoreactive proteins in the ileum and MLNs were significantly enhanced with increasing ZEA. The relative mRNA and protein expression of Nrf2, Gpx1, quinone oxidoreductase 1 (Nqo1), hemeoxygenase 1 (Ho1), modifier subunit of glutamate-cysteine ligase (Gclm), and catalytic subunit of glutamate-cysteine ligase (Gclc) increased (p < 0.05) linearly and quadratically, and the relative mRNA and protein expression of Keap1 decreased (p < 0.05) linearly and quadratically in the ileum with increasing ZEA concentrations in the diet. Further, the relative mRNA and protein expression of Nrf2 and Gpx1 increased (p < 0.05) linearly and quadratically, and the relative mRNA and protein expression of Nqo1, Ho1, and Gclm decreased (p < 0.05) quadratically in the MLNs as ZEA concentrations increased in the diet. Our results provide valuable genetic information on ZEA-induced oxidative stress in the ileum and MLNs of post-weaning gilts and have elucidated the key regulatory genes involved in the Keap1-Nrf2 signaling pathway. Results indicated that the Keap1-Nrf2 signaling pathway might be a key target to further prevent and treat ZEA-induced injury to the ileum in post-weaning gilts.
Collapse
Affiliation(s)
- Qun Cheng
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Department of Animal Sciences and Technology, Shandong Agricultural University, Taian 271018, Shandong, China
| | - Shuzhen Jiang
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Department of Animal Sciences and Technology, Shandong Agricultural University, Taian 271018, Shandong, China
| | - Libo Huang
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Department of Animal Sciences and Technology, Shandong Agricultural University, Taian 271018, Shandong, China
| | - Yuxi Wang
- Agriculture and Agri-Food Canada, Lethbridge Research Centre, PO Box 3000, Lethbridge, Alberta, T1J 4B1, Canada
| | - Weiren Yang
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Department of Animal Sciences and Technology, Shandong Agricultural University, Taian 271018, Shandong, China.
| | - Zaibin Yang
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Department of Animal Sciences and Technology, Shandong Agricultural University, Taian 271018, Shandong, China
| | - Jinshan Ge
- Shandong Zhongcheng Feed Technology Co., Ltd, No. 226 Gongye 2 Road, Feicheng City, Shandong,271600, China
| |
Collapse
|
|
49
|
Distinct and overlapping functions of glutathione peroxidases 1 and 2 in limiting NF-κB-driven inflammation through redox-active mechanisms. Redox Biol 2019; 28:101388. [PMID: 31765890 PMCID: PMC6883322 DOI: 10.1016/j.redox.2019.101388] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 11/08/2019] [Accepted: 11/13/2019] [Indexed: 02/08/2023] Open
Abstract
Glutathione peroxidase 2 (GPx2) is one of the five selenoprotein GPxs having a selenocysteine in the active center. GPx2 is strongly expressed in the gastrointestinal epithelium, as is another isoform, GPx1, though with a different localization pattern. Both GPxs are redox-active enzymes that are important for the reduction of hydroperoxides. Studies on GPx2-deficient mice and human HT-29 cells with a stable knockdown (kd) of GPx2 revealed higher basal and IL-1β-induced expression of NF-κB target genes in vivo and in vitro. The activation of the IKK–IκBα–NF-κB pathway was increased in cultured GPx2 kd cells. Basal signaling was only restored by re-expressing active GPx2 in GPx2 kd cells but not by redox-inactive GPx2. As it is still not clear if the two isoforms GPx1 and GPx2 have different functions, kd cell lines for either GPx1 or GPx2 were studied in parallel. The inhibitory effect of GPx2 on NF-κB signaling and its target gene expression was stronger than that of GPx1, whereas cyclooxygenase (COX)- and lipoxygenase (LOX)-derived lipid mediator levels increased more strongly in GPx1 kd than in GPx2 kd cells. Under unstimulated conditions, the levels of the COX-derived prostaglandins PGE2 and PGD2 were enhanced in GPx2 as well as in GPx1 kd compared to control cells. Specifically, in GPx1 kd cells IL-1β stimulation led to a dramatic shift of the PGE2/PGD2 ratio towards pro-inflammatory PGE2. Taken together, GPx2 and GPx1 have overlapping functions in controlling inflammatory lipid mediator synthesis and, most probably, exert their anti-inflammatory effects by preventing excessive PGE2 production. In view of the high activity of COX and LOX pathways during inflammatory bowel disease our data therefore provide new insights into the mechanisms of the protective function of GPx1 and GPx2 during colitis as well as inflammation-driven carcinogenesis.
Loss of GPx2 results in higher basal and IL-1β-induced NF-κB activation. Suppressive effects of GPx2 on NF-κB are mediated in a redox-dependent manner. Both GPx isoforms modulate the lipid mediator profile in response to IL-1β. COX-derived prostaglandins increase more strongly in GPx1 than in GPx2 kd cells.
Collapse
|
|
50
|
Glutathione peroxidases in poultry biology: Part 1. Classification and mechanisms of action. WORLD POULTRY SCI J 2019. [DOI: 10.1017/s0043933918000284] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
|