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Palol VV, Waidha K, Moovarkumudalvan B, Valavath Baburajan N, Saravanan SK, Lakshmanan D, Subramanyam V, Chinnadurai RK. β-1,3-glucan from Euglena gracilis: a promising epidrug targeting epigenetic regulators PRMTs and SIRTs for therapeutic applications in ovarian cancer. J Biomol Struct Dyn 2024:1-16. [PMID: 39535161 DOI: 10.1080/07391102.2024.2425832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 04/23/2024] [Indexed: 11/16/2024]
Abstract
Natural products serve as a valuable resource in drug discovery and the identification of bioactive molecules in the field of epimedicine, which targets epigenetic regulator enzymes through epidrugs. In this study, β-1,3-glucan (BG), a natural storage polysaccharide in Euglena gracilis, a well-known immunostimulatory agent, is propounded as a promising epidrug. To elucidate the therapeutic efficacy of BG against ovarian cancer, the molecular interactions between BG and epigenetic regulators, Protein Arginine Methyltransferases (PRMTs) and Sirtuins (SIRTs) were investigated using computational methods followed by in vitro gene expression studies in SKOV-3 ovarian cancer cell line. The binding energies of PRMT5 and SIRT5 against BG were observed as -65.5 and -68.2 kcal/mol, respectively. The in vitro cytotoxic effects of BG against human ovarian cancer cell line, SKOV-3 showed an IC50 of 150 µg/mL at 48 h. Significant epigenetic modifications were observed to be influenced by BG which increased the gene expression of PRMT5, SIRT5 and Nrf2 to 0.3, 0.5, and 0.7 fold-change respectively, while the Nrf1/2 plasmid showed reduced reporter activity by 29%. Collectively, both in silico and in vitro studies provided valuable insights into the epigenetic regulation of PRMT5 and SIRT5 by BG via Nrf1/2. Nonetheless, further preclinical and clinical investigations are essential to validate the therapeutic properties of BG as an epidrug against ovarian cancer.
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Affiliation(s)
- Varsha Virendra Palol
- Mahatma Gandhi Medical Advanced Research Institute (MGMARI), Sri Balaji Vidyapeeth (Deemed-to-be University), Pillayarkuppam, Puducherry, India
| | - Kamran Waidha
- The Shraga Segal Department of Microbiology, Immunology & Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
| | - Balasubramanian Moovarkumudalvan
- Mahatma Gandhi Medical Advanced Research Institute (MGMARI), Sri Balaji Vidyapeeth (Deemed-to-be University), Pillayarkuppam, Puducherry, India
| | | | - Suresh Kumar Saravanan
- Mahatma Gandhi Medical Preclinical Research Centre (MGMPRC), Sri Balaji Vidyapeeth (Deemed-to-be University), Pillayarkuppam, Puducherry, India
| | - Divya Lakshmanan
- Mahatma Gandhi Medical Advanced Research Institute (MGMARI), Sri Balaji Vidyapeeth (Deemed-to-be University), Pillayarkuppam, Puducherry, India
| | - Veni Subramanyam
- Mahatma Gandhi Medical Advanced Research Institute (MGMARI), Sri Balaji Vidyapeeth (Deemed-to-be University), Pillayarkuppam, Puducherry, India
| | - Raj Kumar Chinnadurai
- Mahatma Gandhi Medical Advanced Research Institute (MGMARI), Sri Balaji Vidyapeeth (Deemed-to-be University), Pillayarkuppam, Puducherry, India
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2
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Shi X, He L, Wang Y, Wu Y, Lin D, Chen C, Yang M, Huang S. Mitochondrial dysfunction is a key link involved in the pathogenesis of sick sinus syndrome: a review. Front Cardiovasc Med 2024; 11:1488207. [PMID: 39534498 PMCID: PMC11554481 DOI: 10.3389/fcvm.2024.1488207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 10/15/2024] [Indexed: 11/16/2024] Open
Abstract
Sick sinus syndrome (SSS) is a grave medical condition that can precipitate sudden death. The pathogenesis of SSS remains incompletely understood. Existing research postulates that the fundamental mechanism involves increased fibrosis of the sinoatrial node and its surrounding tissues, as well as disturbances in the coupled-clock system, comprising the membrane clock and the Ca2+ clock. Mitochondrial dysfunction exacerbates regional tissue fibrosis and disrupts the functioning of both the membrane and calcium clocks. This plays a crucial role in the underlying pathophysiology of SSS, including mitochondrial energy metabolism disorders, mitochondrial oxidative stress damage, calcium overload, and mitochondrial quality control disorders. Elucidating the mitochondrial mechanisms involved in the pathophysiology of SSS and further investigating the disease's mechanisms is of great significance.
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Affiliation(s)
- Xinxin Shi
- Department of Cardiology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Liming He
- Department of Cardiology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yucheng Wang
- Department of Cardiology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yue Wu
- Department of Cardiology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Dongming Lin
- Department of Cardiology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
| | - Chao Chen
- Department of Cardiology, Hangzhou TCM Hospital of Zhejiang Chinese Medical University, Hangzhou Hospital of Traditional Chinese Medicine, Hangzhou, China
| | - Ming Yang
- Department of Cardiology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Shuwei Huang
- Department of Cardiology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
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3
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Ulfig A, Jakob U. Redox heterogeneity in mouse embryonic stem cells individualizes cell fate decisions. Dev Cell 2024; 59:2118-2133.e8. [PMID: 39106861 PMCID: PMC11338707 DOI: 10.1016/j.devcel.2024.07.008] [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: 12/22/2023] [Revised: 04/23/2024] [Accepted: 07/09/2024] [Indexed: 08/09/2024]
Abstract
Pluripotent embryonic stem cells (ESCs) can develop into any cell type in the body. Yet, the regulatory mechanisms that govern cell fate decisions during embryogenesis remain largely unknown. We now demonstrate that mouse ESCs (mESCs) display large natural variations in mitochondrial reactive oxygen species (mitoROS) levels that individualize their nuclear redox state, H3K4me3 landscape, and cell fate. While mESCs with high mitoROS levels (mitoROSHIGH) differentiate toward mesendoderm and form the primitive streak during gastrulation, mESCs, which generate less ROS, choose the alternative neuroectodermal fate. Temporal studies demonstrated that mesendodermal (ME) specification of mitoROSHIGH mESCs is mediated by a Nrf2-controlled switch in the nuclear redox state, triggered by the accumulation of redox-sensitive H3K4me3 marks, and executed by a hitherto unknown ROS-dependent activation process of the Wnt signaling pathway. In summary, our study explains how ESC heterogeneity is generated and used by individual cells to decide between distinct cellular fates.
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Affiliation(s)
- Agnes Ulfig
- Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
| | - Ursula Jakob
- Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA; Biological Chemistry Department, University of Michigan Medical School, Ann Arbor, MI, USA.
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Shahidi S, Komaki A, Salehi I, Soleimani Asl S, Habibi P, Ramezani-Aliakbari F. Vitamin D Protects Against Cardiac Hypertrophy Through the Regulation of Mitochondrial Function in Aging Rats. Rejuvenation Res 2024; 27:51-60. [PMID: 38308474 DOI: 10.1089/rej.2023.0061] [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] [Indexed: 02/04/2024] Open
Abstract
Cardiac aging is defined as mitochondrial dysfunction of the heart. Vitamin D (VitD) is an effective agent in ameliorating cardiovascular disorders. In this study, we indicated the protective effects of VitD against cardiac aging. Male Wistar rats were randomly divided into four groups: control (CONT), D-galactose (D-GAL): aged rats induced by D-GAL, D-GAL + Ethanol: aged rats treated with ethanol, and D-GAL + VitD aged rats treated with VitD. Aging was induced by D-GAL at 150 mg/kg via intraperitoneal injection for 8 weeks. Aged rats were treated with VitD (D-GAL + VitD) by gavage for 8 weeks. The serum samples were used to evaluate biochemical factors, and heart tissues were assessed to determine oxidative stress and gene expression. The D-GAL rats exhibited cardiac hypertrophy, which was associated with decreased antioxidant enzyme activity, enhanced oxidative marker, and changes in the expression of mitochondrial genes in comparison with the control rats. Co-treatment with VitD ameliorated all these changes. In conclusion, VitD could protect the heart against D-GAL-induced aging via enhancing antioxidant effects, and the expression of mitochondrial genes.
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Affiliation(s)
- Siamak Shahidi
- Department of Physiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
- Department of Neuroscience, Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
- Department of Neuroscience, School of Sciences and Advanced Technology in Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Alireza Komaki
- Department of Neuroscience, Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
- Department of Neuroscience, School of Sciences and Advanced Technology in Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Iraj Salehi
- Department of Neuroscience, Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
- Department of Neuroscience, School of Sciences and Advanced Technology in Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Sara Soleimani Asl
- Department of Anatomy, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Parisa Habibi
- Department of Physiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
- Department of Neuroscience, Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Fatemeh Ramezani-Aliakbari
- Department of Physiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
- Department of Neuroscience, Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
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Ferreira MJ, Dias DDS, Silva GDC, de Araujo AA, Dutra MRH, Bernardes N, Irigoyen MC, De Angelis K. Concurrent exercise training potentiates the effects of angiotensin-converting enzyme inhibitor on regulatory systems of blood pressure control in ovariectomized hypertensive rats. J Hypertens 2024; 42:650-661. [PMID: 38441185 DOI: 10.1097/hjh.0000000000003670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/07/2024]
Abstract
OBJECTIVE Enalapril has shown satisfactory potential in controlling increased and sustained blood pressure (BP). However, multiple dysregulated mechanisms that interact with each other and are involved in the pathophysiology of arterial hypertension may not be affected, contributing to the remaining cardiovascular risk. Using an exercise training protocol, we investigated whether adding both approaches to arterial hypertension management could promote higher modulation of regulatory mechanisms of BP in postmenopausal rats. METHODS Spontaneously hypertensive rats were allocated into sedentary (S) and ovariectomized groups: sedentary (OS), sedentary treated with enalapril maleate (OSE) and trained treated with enalapril maleate (OTE). Both the pharmacological and exercise training protocols lasted for 8 weeks. The BP was directly recorded. Inflammation and oxidative stress were evaluated in the cardiac tissue. RESULTS Although BP reduction was similar between OSE and OTE, trained group showed lower vasopressor systems outflow after sympathetic ganglion blocking by hexamethonium (mean BP) (OTE: -53.7 ± 9.86 vs. OS: -75.7 ± 19.2 mmHg). Bradycardic and tachycardic response were increased in OTE group (-1.4 ± 0.4 and -2.6 ± 0.4 vs. OS: -0.6 ± 0.3 and -1.3 ± 0.4 bpm/mmHg, respectively), as well as BP variability. In addition, the combination of approaches induced an increase in interleukin 10, antioxidant defense (catalase and glutathione peroxidase) and nitrite levels compared with the OS group. CONCLUSION Despite similar BP, the inclusion of exercise training in antihypertensive drug treatment exacerbates the positive adaptations induced by enalapril alone on autonomic, inflammatory and oxidative stress profiles, probably affecting end-organ damage and remaining risk.
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Affiliation(s)
- Maycon Junior Ferreira
- Exercise Physiology Laboratory, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil
| | - Danielle da Silva Dias
- Postgraduate Program in Physical Education, Universidade Federal do Maranhão (UFMA), São Luís, MA
- Translational Physiology Laboratory, Universidade Nove de Julho (UNINOVE)
| | - Gabriel do Carmo Silva
- Exercise Physiology Laboratory, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil
| | | | | | | | - Maria-Cláudia Irigoyen
- Hypertension Unit, Heart Institute (InCor), Universidade de São Paulo (USP), São Paulo, SP, Brazil
| | - Kátia De Angelis
- Exercise Physiology Laboratory, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil
- Translational Physiology Laboratory, Universidade Nove de Julho (UNINOVE)
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Louka P, Orriss IR, Pitsillides AA. Stable Sulforaphane Targets the Early Stages of Osteoclast Formation to Engender a Lasting Functional Blockade of Osteoclastogenesis. Cells 2024; 13:165. [PMID: 38247857 PMCID: PMC10814088 DOI: 10.3390/cells13020165] [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: 12/20/2023] [Revised: 01/05/2024] [Accepted: 01/09/2024] [Indexed: 01/23/2024] Open
Abstract
Sulforaphane, the native but unstable form of SFX-01, is an antioxidant that activates the NRF2 and inhibits the NF-KB pathways to achieve its actions. Resolving the mechanism(s) by which SFX-01 serves to control the various osteoclastogenic stages may expose pathways that could be explored for therapeutic use. Here we seek to identify the stage of osteoclastogenesis targeted by SFX-01 and explore whether, like SFN, it exerts its actions via the NRF2 and NF-KB pathways. Osteoclasts generated from the bone marrow (BM) of mice were cultured with SFX-01 at different timepoints to examine each phase of osteoclastogenesis separately. This showed that SFX-01 exerted actions throughout the process of osteoclastogenesis, but had its largest effects in the early osteoclast precursor differentiation stage. Thus, treatment with SFX-01 for the duration of culture, for the initial 3 days differentiation or for as little as the first 24 h was sufficient for effective inhibition. This aligned with data suggesting that SFX-01 reduced DC-STAMP levels, osteoclast nuclear number and modified cytoskeletal architecture. Pharmacological regulation of the NRF2 pathways, via selective inhibitors/activators, supported the anti-osteoclastogenic roles of an SFX-01-mediated by NRF2 activation, as well as the need for tight NF-KB pathway regulation in osteoclast formation/function.
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Affiliation(s)
| | | | - Andrew A. Pitsillides
- Skeletal Biology Group, Comparative Biomedical Sciences, Royal Veterinary College, London NW1 0TU, UK; (P.L.); (I.R.O.)
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7
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Maiorino E, De Marzio M, Xu Z, Yun JH, Chase RP, Hersh CP, Weiss ST, Silverman EK, Castaldi PJ, Glass K. Joint clinical and molecular subtyping of COPD with variational autoencoders. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2023.08.19.23294298. [PMID: 38260473 PMCID: PMC10802661 DOI: 10.1101/2023.08.19.23294298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2024]
Abstract
Chronic Obstructive Pulmonary Disease (COPD) is a complex, heterogeneous disease. Traditional subtyping methods generally focus on either the clinical manifestations or the molecular endotypes of the disease, resulting in classifications that do not fully capture the disease's complexity. Here, we bridge this gap by introducing a subtyping pipeline that integrates clinical and gene expression data with variational autoencoders. We apply this methodology to the COPDGene study, a large study of current and former smoking individuals with and without COPD. Our approach generates a set of vector embeddings, called Personalized Integrated Profiles (PIPs), that recapitulate the joint clinical and molecular state of the subjects in the study. Prediction experiments show that the PIPs have a predictive accuracy comparable to or better than other embedding approaches. Using trajectory learning approaches, we analyze the main trajectories of variation in the PIP space and identify five well-separated subtypes with distinct clinical phenotypes, expression signatures, and disease outcomes. Notably, these subtypes are more robust to data resampling compared to those identified using traditional clustering approaches. Overall, our findings provide new avenues to establish fine-grained associations between the clinical characteristics, molecular processes, and disease outcomes of COPD.
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Affiliation(s)
- Enrico Maiorino
- Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School
| | - Margherita De Marzio
- Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School
| | - Zhonghui Xu
- Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School
| | - Jeong H. Yun
- Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School
| | - Robert P. Chase
- Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School
| | - Craig P. Hersh
- Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School
| | - Scott T. Weiss
- Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School
| | - Edwin K. Silverman
- Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School
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Shen H, Lei Y, Xie W, Ma T, Bao L, Gao Q, Chen B, Dai B, Qin D. Bioactive peptides PDBSN improve mitochondrial function and suppression the oxidative stress in human adiposity cells. Adipocyte 2023:2278213. [PMID: 37942520 DOI: 10.1080/21623945.2023.2278213] [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] [Received: 04/13/2023] [Accepted: 10/27/2023] [Indexed: 11/10/2023] Open
Abstract
Introduction: Mitochondria are essential for generating cellular energy and are significant in the pathogenesis of obesity. Peptide PDBSN has been demonstrated to inhibit the adipogenic differentiation of adipocytes in vitro and improves metabolic homoeostasis in vivo. Therefore, in this study, we further investigated the effects of PDBSN on the morphology, synthesis, and function of adipocyte mitochondria. Methods: Human visceral and subcutaneous primary preadipocytes (HPA-v and HPA-s) were cultured into mature adipocytes. Intracellular triglyceride content was assessed using oil-red O staining and tissue triglyceride determination. Gene and protein levels associated with mitochondrial synthesis were detected using real-time quantitative polymerase chain reaction and western blotting. Mitochondrial membrane potentials and ROS were detected using fluorescent indicators. Morphological changes were observed by electron microscopy. Results: PDBSN significantly increased mitochondrial membrane potential (MMP), while decreasing intracellular triglyceride (TG) and intracellular reactive oxygen species (ROS) levels. On the other hand, the transcription and protein levels of genetic marker genes PGC1-α and MTFA were significantly up-regulated after PDBSN administration. Further studies showed that transcriptional and protein levels of mitochondrial fusion and fission genetic markers MFN1, MFN2, NRF1, and DRP1 increased. Conclusion: PDBSN significantly reduces intracellular TG and ROS levels and increases MMP. The maximum respiratory capacity in adults significantly increases after PDBSN administration, and ROS levels are significantly reduced. This suggests that PDBSN improves mitochondrial function to some extent, which not only provides an essential basis for the pathophysiology of obesity but also provides insights for the development of new drugs to treat obesity and metabolic diseases.
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Affiliation(s)
- Huiping Shen
- Department of Pediatrics, Yixing People's Hospital, China
| | - Yong Lei
- Department of Pediatrics, Yixing People's Hospital, China
| | - Wen Xie
- Department of Pediatrics, Yixing People's Hospital, China
| | - Tieliang Ma
- Department of Pediatrics, Yixing People's Hospital, China
| | - Li Bao
- Department of Pediatrics, Yixing People's Hospital, China
| | - Qin Gao
- Department of Pediatrics, Yixing People's Hospital, China
| | - Bingyu Chen
- Department of Pediatrics, Yixing People's Hospital, China
| | - Biao Dai
- Department of Pediatrics, Yixing People's Hospital, China
| | - Dani Qin
- Department of Pediatrics, Yixing People's Hospital, China
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Chen YH, Wu JX, Yang SF, Hsiao YH. Synergistic Combination of Luteolin and Asiatic Acid on Cervical Cancer In Vitro and In Vivo. Cancers (Basel) 2023; 15:cancers15020548. [PMID: 36672499 PMCID: PMC9857275 DOI: 10.3390/cancers15020548] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 01/11/2023] [Accepted: 01/13/2023] [Indexed: 01/18/2023] Open
Abstract
Cervical cancer is an important issue globally because it is the second most common gynecological malignant tumor and conventional treatment effects have been shown to be limited. Lut and AsA are plant-derived natural flavonoid and triterpenoid products that have exhibited anticancer activities and can modulate various signaling pathways. Thus, the aim of the present study was to evaluate whether Lut combined with AsA could enhance the anticancer effect to inhibit cervical cancer cell proliferation and examine the underlying molecular mechanisms in vitro and in vivo. The results of a CCK-8 assay showed that Lut combined with AsA more effectively inhibited the proliferation of CaSki and HeLa cells than Lut or AsA treatment alone. Lut combined with AsA caused apoptosis induction and sub-G1-phase arrest in CaSki and HeLa cells, as confirmed by flow cytometry, mitoROS analysis, antioxidant activity measurement and western blot assay. In addition, Lut combined with AsA significantly inhibited the cell migration ability of CaSki and HeLa cells in a wound-healing assay. Furthermore, Lut combined with AsA induced apoptosis and inhibited migration through downregulated PI3K/AKT (PI3K, AKT and p70S6K), JNK/p38 MAPK and FAK (integrin β1, paxillin and FAK) signaling and upregulated ERK signaling. In an in vivo study, Lut combined with AsA markedly inhibited cervical cancer cell-derived xenograft tumor growth. Collectively, the present study showed that Lut combined with AsA may be used as an anticancer agent to improve the prognosis of cervical cancer. Indeed, with additional research to develop standardized dosages, Lut and AsA combination therapy could also be applied in clinical medicine.
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Affiliation(s)
- Ya-Hui Chen
- Women’s Health Research Laboratory, Changhua Christian Hospital, Changhua 50006, Taiwan
- Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
| | - Jyun-Xue Wu
- Women’s Health Research Laboratory, Changhua Christian Hospital, Changhua 50006, Taiwan
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
| | - Yi-Hsuan Hsiao
- Women’s Health Research Laboratory, Changhua Christian Hospital, Changhua 50006, Taiwan
- Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
- Department of Obstetrics and Gynecology, Changhua Christian Hospital, Changhua 50006, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
- College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
- College of Medicine, National Chung Hsing University, Taichung 40227, Taiwan
- Correspondence:
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10
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Nyamweya B, Rukshala D, Fernando N, de Silva R, Premawansa S, Handunnetti S. Cardioprotective Effects of Vitex negundo: A Review of Bioactive Extracts and Compounds. J Evid Based Integr Med 2023; 28:2515690X231176622. [PMID: 37279951 DOI: 10.1177/2515690x231176622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/08/2023] Open
Abstract
There has been accumulating interest in the application of medicinal plants as alternative medicine to treat various diseases and/or to develop modern medicines. Vitex negundo is one of such medicinal plants that has been of interest to many researchers and has been of use in traditional medicine. V. negundo is found in Sri Lanka, Madagascar, Malaysia, India, China, The Philippines and East Africa. Therapeutic properties of V. negundo have previously been reviewed. Different parts, preparations and bioactive components of V. negundo possess potential protective and therapeutic effects against cardiovascular disease and related conditions as demonstrated in previous studies. We review the present state of scientific knowledge on the potential use of V. negundo and some of its bioactive components in protecting against cardiovascular diseases and related pathologies. Previous studies in animal and non-animal experimental models, although limited in number and vary in design, seem to support the cardioprotective effect of V. negundo and some of its active components. However, there is need for further preclinical and clinical studies to validate the use of V. negundo and its active constituents in protection and treatment of cardiovascular diseases. Additionally, since only a few V. negundo compounds have been evaluated, specific cardioprotective effects or mechanisms and possible side effects of other V. negundo compounds need to be extensively evaluated.
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Affiliation(s)
- Boniface Nyamweya
- Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo, Colombo 03, Sri Lanka
| | - Dilani Rukshala
- Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo, Colombo 03, Sri Lanka
| | - Narmada Fernando
- Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo, Colombo 03, Sri Lanka
| | - Rajiva de Silva
- Department of Immunology, Medical Research Institute, Colombo 08, Sri Lanka
| | - Sunil Premawansa
- Departments of Zoology and Environment Sciences, University of Colombo, Colombo 03, Sri Lanka
| | - Shiroma Handunnetti
- Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo, Colombo 03, Sri Lanka
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11
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Nrf2 Regulates Oxidative Stress and Its Role in Cerebral Ischemic Stroke. Antioxidants (Basel) 2022; 11:antiox11122377. [PMID: 36552584 PMCID: PMC9774301 DOI: 10.3390/antiox11122377] [Citation(s) in RCA: 124] [Impact Index Per Article: 41.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 11/23/2022] [Accepted: 11/27/2022] [Indexed: 12/05/2022] Open
Abstract
Cerebral ischemic stroke is characterized by acute ischemia in a certain part of the brain, which leads to brain cells necrosis, apoptosis, ferroptosis, pyroptosis, etc. At present, there are limited effective clinical treatments for cerebral ischemic stroke, and the recovery of cerebral blood circulation will lead to cerebral ischemia-reperfusion injury (CIRI). Cerebral ischemic stroke involves many pathological processes such as oxidative stress, inflammation, and mitochondrial dysfunction. Nuclear factor erythroid 2-related factor 2 (Nrf2), as one of the most critical antioxidant transcription factors in cells, can coordinate various cytoprotective factors to inhibit oxidative stress. Targeting Nrf2 is considered as a potential strategy to prevent and treat cerebral ischemia injury. During cerebral ischemia, Nrf2 participates in signaling pathways such as Keap1, PI3K/AKT, MAPK, NF-κB, and HO-1, and then alleviates cerebral ischemia injury or CIRI by inhibiting oxidative stress, anti-inflammation, maintaining mitochondrial homeostasis, protecting the blood-brain barrier, and inhibiting ferroptosis. In this review, we have discussed the structure of Nrf2, the mechanisms of Nrf2 in cerebral ischemic stroke, the related research on the treatment of cerebral ischemia through the Nrf2 signaling pathway in recent years, and expounded the important role and future potential of the Nrf2 pathway in cerebral ischemic stroke.
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12
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Bar-Peled L, Kory N. Principles and functions of metabolic compartmentalization. Nat Metab 2022; 4:1232-1244. [PMID: 36266543 PMCID: PMC10155461 DOI: 10.1038/s42255-022-00645-2] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 08/24/2022] [Indexed: 01/20/2023]
Abstract
Metabolism has historically been studied at the levels of whole cells, whole tissues and whole organisms. As a result, our understanding of how compartmentalization-the spatial and temporal separation of pathways and components-shapes organismal metabolism remains limited. At its essence, metabolic compartmentalization fulfils three important functions or 'pillars': establishing unique chemical environments, providing protection from reactive metabolites and enabling the regulation of metabolic pathways. However, how these pillars are established, regulated and maintained at both the cellular and systemic levels remains unclear. Here we discuss how the three pillars are established, maintained and regulated within the cell and discuss the consequences of dysregulation of metabolic compartmentalization in human disease. Organelles are increasingly emerging as 'command-and-control centres' and the increased understanding of metabolic compartmentalization is revealing new aspects of metabolic homeostasis, with this knowledge being translated into therapies for the treatment of cancer and certain neurodegenerative diseases.
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Affiliation(s)
- Liron Bar-Peled
- Center for Cancer Research, Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Boston, MA, USA.
| | - Nora Kory
- Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
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13
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Esteras N, Abramov AY. Nrf2 as a regulator of mitochondrial function: Energy metabolism and beyond. Free Radic Biol Med 2022; 189:136-153. [PMID: 35918014 DOI: 10.1016/j.freeradbiomed.2022.07.013] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 06/20/2022] [Accepted: 07/19/2022] [Indexed: 12/14/2022]
Abstract
Mitochondria are unique and essential organelles that mediate many vital cellular processes including energy metabolism and cell death. The transcription factor Nrf2 (NF-E2 p45-related factor 2) has emerged in the last few years as an important modulator of multiple aspects of mitochondrial function. Well-known for controlling cellular redox homeostasis, the cytoprotective effects of Nrf2 extend beyond its ability to regulate a diverse network of antioxidant and detoxification enzymes. Here, we review the role of Nrf2 in the regulation of mitochondrial function and structure. We focus on Nrf2 involvement in promoting mitochondrial quality control and regulation of basic aspects of mitochondrial function, including energy production, reactive oxygen species generation, calcium signalling, and cell death induction. Given the importance of mitochondria in the development of multiple diseases, these findings reinforce the pharmacological activation of Nrf2 as an attractive strategy to counteract mitochondrial dysfunction.
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Affiliation(s)
- Noemí Esteras
- Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square, London, UK.
| | - Andrey Y Abramov
- Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square, London, UK.
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14
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Burwaiss A, Ammar M, Alghazeer R, Eljamil A, Alarbie D, Elghmasi S, Al-Griw M, Alansari WS, Shamlan G, Eskandrani AA. Tissue levels of oxidative stress markers and antioxidants in colorectal cancer patients. MAIN GROUP CHEMISTRY 2021. [DOI: 10.3233/mgc-210142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
The role of reactive oxygen species in the development of cancer has become well recognized in recent years; however, evidence for a link between oxidative stress and cancer risk has not been fully explored. One of the major cancers whose number of cases has increased significantly in recent years is colon and rectal cancer, which has the second highest mortality rate in Libya. Forty subjects were divided into three groups (20 tumors from colorectal cancer patients, adjacent surrounding tumor tissues, and 20 adjacent normal tissues). Evaluation of oxidative stress indices in the samples was performed by analyzing enzymatic and non-enzymatic parameters including the activity of glutathione peroxidase and catalase as antioxidant enzymes, reduced glutathione as an antioxidant, malondialdehyde MDA levels as an oxidative damage product, nitritc oxide content NO as an inflammatory marker, and total thiols as a measure of redox status. MDA and NO levels were significantly higher in tumor tissues than in adjacent healthy tissue. Also, the surrounding tumor tissue exhibited higher MDA and NO levels compared with control tissues. The oxidant and antioxidant levels in the tumor was significantly lower than those in the surrounding tumor tissue and control healthy tissue. The results suggest that oxidant and antioxidant parameters can be used as indicators of an imbalance in humans, and as this imbalance increases, the human body may be vulnerable to developing cancer.
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Affiliation(s)
- Abdullah Burwaiss
- Gastroenterology and Hepatology Department at Tripoli University Hospital (TUH), Tripoli, Libya
- Medicine Department, Faculty of Human Medicine, University of Tripoli, Tripoli, Libya
| | - Manal Ammar
- Chemistry Department, Faculty of Science, University of Tripoli, Tripoli, Libya
| | - Rabia Alghazeer
- Chemistry Department, Faculty of Science, University of Tripoli, Tripoli, Libya
| | - Ashour Eljamil
- Biochemistry Department, Faculty of Human Medicine, University of Tripoli, Tripoli, Libya
| | - Dalal Alarbie
- Gastroenterology and Hepatology Department at Tripoli University Hospital (TUH), Tripoli, Libya
| | - Sana Elghmasi
- Biochemistry Department, Faculty of Human Medicine, University of Tripoli, Tripoli, Libya
| | - Mohamed Al-Griw
- Histology & Genetics Department, Faculty of Medicine, University of Tripoli, Tripoli, Libya
| | - Wafa S. Alansari
- Biochemistry Department, Faculty of Science, University of Jeddah, Jeddah, Saudi Arabia
| | - Ghalia Shamlan
- Department of Food Science and Nutrition, College of Food and agriculture Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Areej A. Eskandrani
- Chemistry Department, Faculty of Science, Taibah University, Medina, Saudi Arabia
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15
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Mani S, Swargiary G, Ralph SJ. Targeting the redox imbalance in mitochondria: A novel mode for cancer therapy. Mitochondrion 2021; 62:50-73. [PMID: 34758363 DOI: 10.1016/j.mito.2021.11.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 10/14/2021] [Accepted: 11/01/2021] [Indexed: 12/19/2022]
Abstract
Changes in reactive oxygen species (ROS) levels affect many aspects of cell behavior. During carcinogenesis, moderate ROS production modifies gene expression to alter cell function, elevating metabolic activity and ROS. To avoid extreme ROS-activated death, cancer cells increase antioxidative capacity, regulating sustained ROS levels that promote growth. Anticancer therapies are exploring inducing supranormal, cytotoxic oxidative stress levels either inhibiting antioxidative capacity or promoting excess ROS to selectively destroy cancer cells, triggering mechanisms such as apoptosis, autophagy, necrosis, or ferroptosis. This review exemplifies pro-oxidants (natural/synthetic/repurposed drugs) and their clinical significance as cancer therapies providing revolutionary approaches.
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Affiliation(s)
- Shalini Mani
- Centre for Emerging Diseases, Department of Biotechnology, Jaypee Institute of Information Technology, Noida, India.
| | - Geeta Swargiary
- Centre for Emerging Diseases, Department of Biotechnology, Jaypee Institute of Information Technology, Noida, India
| | - Stephen J Ralph
- School of Medical Science, Griffith University, Southport, Australia.
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16
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Li L, Liu S, Zhou Y, Zhao M, Wang Y, Wang C, Lou P, Huang R, Ma L, Lu Y, Fu P, Liu J. Indispensable role of mitochondria in maintaining the therapeutic potential of curcumin in acute kidney injury. J Cell Mol Med 2021; 25:9863-9877. [PMID: 34532973 PMCID: PMC8505835 DOI: 10.1111/jcmm.16934] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 08/25/2021] [Accepted: 09/01/2021] [Indexed: 02/05/2023] Open
Abstract
Acute kidney injury (AKI) is a serious disease for which effective therapeutic agents are required. The capacity of curcumin (CUR) to resolve renal inflammation/oxidative stress and mitochondrial damage has been reported, but crosstalk between these effects and the consequence of this crosstalk remain elusive. In this study, a hypoxia/reoxygenation (H/R)-induced renal tubular epithelial cell (TEC) injury model and an ischaemia/reperfusion (I/R)-induced mouse AKI model were treated with CUR with or without mitochondrial inhibitors (rotenone and FCCP) or siRNA targeting mitochondrial transcription factor A (TFAM). Changes in mitochondrial function, inflammation, the antioxidant system and related pathways were analysed. In vitro, CUR suppressed NFκB activation and cytokine production and induced NRF2/HO-1 signalling in TECs under H/R conditions. CUR treatment also reduced mitochondrial ROS (mtROS) and mitochondrial fragmentation and enhanced mitochondrial biogenesis, TCA cycle activity and ATP synthesis in damaged TECs. However, the anti-inflammatory and antioxidant effects of CUR in damaged TECs were markedly abolished upon mitochondrial disruption. In vivo, CUR treatment improved renal function and antioxidant protein (NRF2 and SOD2) expression and reduced oxidative stress (8-OHdG), tubular apoptosis/death, cytokine release/macrophage infiltration and mitochondrial damage in the kidneys of AKI mice. In vitro, the anti-inflammatory and antioxidant effects of CUR in damaged kidneys were impaired when mitochondrial function was disrupted. These results suggest mitochondrial damage is a driving factor of renal inflammation and redox imbalance. The therapeutic capacity of CUR in kidneys with AKI is primarily dependent on mitochondrial mechanisms; thus, CUR is a potential therapy for various diseases characterized by mitochondrial damage.
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Affiliation(s)
- Ling Li
- Key Laboratory of Transplant Engineering and Immunology, National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu, China.,Division of Nephrology and National Clinical Research Center for Geriatrics, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu, China
| | - Shuyun Liu
- Key Laboratory of Transplant Engineering and Immunology, National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu, China
| | - Yijie Zhou
- Key Laboratory of Transplant Engineering and Immunology, National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu, China
| | - Meng Zhao
- Key Laboratory of Transplant Engineering and Immunology, National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu, China
| | - Yizhuo Wang
- Key Laboratory of Transplant Engineering and Immunology, National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu, China
| | - Chengshi Wang
- Key Laboratory of Transplant Engineering and Immunology, National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu, China
| | - Peng Lou
- Key Laboratory of Transplant Engineering and Immunology, National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu, China
| | - Rongshuang Huang
- Division of Nephrology and National Clinical Research Center for Geriatrics, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu, China
| | - Liang Ma
- Division of Nephrology and National Clinical Research Center for Geriatrics, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu, China
| | - Yanrong Lu
- Key Laboratory of Transplant Engineering and Immunology, National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu, China
| | - Ping Fu
- Division of Nephrology and National Clinical Research Center for Geriatrics, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu, China
| | - Jingping Liu
- Key Laboratory of Transplant Engineering and Immunology, National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu, China
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17
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Metformin Potentiates the Anticancer Effect of Everolimus on Cervical Cancer In Vitro and In Vivo. Cancers (Basel) 2021; 13:cancers13184612. [PMID: 34572837 PMCID: PMC8468269 DOI: 10.3390/cancers13184612] [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: 08/24/2021] [Revised: 09/07/2021] [Accepted: 09/10/2021] [Indexed: 01/14/2023] Open
Abstract
Simple Summary Recent studies have shown that metformin combined with clinical chemotherapeutic drugs could cause decreased cell toxicity and attenuate tumor resistance in various types of cancer. The aim of the present study was to elucidate whether combined treatment with metformin and everolimus has a synergistic anticancer effect in human cervical cancer in vitro and in vivo. The results showed that this combined treatment synergistically inhibited the growth of human cervical cancer cell lines and xenografts in nude mice, and induced caspase-dependent apoptosis, promoting sub-G1- and G0/G1-phase arrest and enhancing mtROS production. Combined treatment also synergistically inactivated PI3K/AKT signaling and activated MAPKs signaling in cervical cancer. Our data suggested that metformin potentiates the anticancer effect of everolimus on cervical cancer, and combined treatment provides a novel therapeutic strategy for patients with cervical cancer. Abstract Cervical cancer is globally the fourth most common cancer in women. Metformin is a widely used drug for the treatment of type II diabetes and has been shown to possess important anticancer properties in cervical cancer. Everolimus is an mTOR inhibitor and is widely used to treat NETs, RCC, TSC, and breast cancers. The present study investigated the anticancer effects of metformin and everolimus in cervical cancer, when used alone or in combination. CaSki and C33A human cervical cancer cells were treated with different concentrations of everolimus alone or in combination with metformin. Cell viability was assessed using a CCK-8 assay. Cell apoptosis, cell-cycle, and mtROS analyses were conducted using flow cytometry. Target protein levels were analyzed by Western blotting. Related mechanisms were confirmed using appropriate inhibitors (z-VAD-fmk and BIRB796). The in vitro results were further confirmed in a xenograft tumor study. Both metformin and everolimus, when used alone, were moderately effective in inhibiting cell proliferation and inducing cell apoptosis of CaSki and C33A cells. When used in combination, these two drugs synergistically inhibited the growth of human cervical cancer cells and xenografts in nude mice, promoted sub-G1- and G0/G1-phase cell-cycle arrest, and enhanced mtROS production. The protein expressions of PI3K (p110α) and p-AKT were significantly downregulated, while P27, P21, p-p38, p-ERK, and p-JNK were upregulated following combined treatment. These results revealed that metformin potentiates the anticancer effect of everolimus on cervical cancer, and combination treatment with metformin and everolimus provides a novel therapeutic strategy for patients with cervical cancer.
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18
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Sharma P, Kaushik P, Jain S, Sharma BM, Awasthi R, Kulkarni GT, Sharma B. Efficacy of Ulinastatin and Sulforaphane Alone or in Combination in Rat Model of Streptozotocin Diabetes Induced Vascular Dementia. CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE 2021; 19:470-489. [PMID: 34294616 PMCID: PMC8316668 DOI: 10.9758/cpn.2021.19.3.470] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 09/25/2020] [Accepted: 12/11/2020] [Indexed: 11/22/2022]
Abstract
Objective Vascular Dementia (VaD), is associated with metabolic conditions. Diabetes is a major risk factor for the development of VaD. This study investigates the efficacy of ulinastatin (UTI) and sulforaphane (SUL) in streptozotocin (STZ)-diabetes induced vascular endothelium dysfunction and related dementia. Methods Single dose STZ (50 mg/kg i.p.) was administered to Albino Wistar rats (male, 200−250 g). Morris water maze and attentional set shifting tests were used to assess the spatial learning, memory, reversal learning, and executive functioning in animals. Body weight, serum glucose, serum nitrite/nitrate, vascular endothelial function, aortic superoxide anion, brains’ oxidative markers (thiobarbituric acid reactive species-TBARS, reduced glutathione-GSH, superoxide dismutase-SOD, and catalase-CAT), inflammatory markers (IL-6, IL-10, TNF-a, and myeloperoxidase-MPO), acetylcholinesterase activity-AChE, blood brain barrier (BBB) permeability and histopathological changes were also assessed. UTI (10,000 U/kg) and SUL (25 mg/kg) were used alone as well as in combination, as the treatment drugs. Donepezil (0.5 mg/kg) was used as a positive control. Results STZ-administered rats showed reduction in body weight, learning, memory, reversal learning, executive functioning, impairment in endothelial function, BBB permeability, increase in serum glucose, brains’ oxidative stress, inflammation, AChE-activity, BBB permeability and histopathological changes. Administration of UTI and SUL alone as well as in combination, significantly and dose dependently attenuated the STZ-diabetes-induced impairments in the behavioral, endothelial, and biochemical parameters. Conclusion STZ administration caused diabetes and VaD which was attenuated by the administration of UTI and SUL. Therefore, these agents may be studied further for the assessment of their full potential in diabetes induced VaD.
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Affiliation(s)
- Poonam Sharma
- Department of Pharmacology, Amity Institute of Pharmacy, Amity University Uttar Pradesh, Noida, India
| | - Prachi Kaushik
- Department of Pharmacology, Amity Institute of Pharmacy, Amity University Uttar Pradesh, Noida, India
| | - Swati Jain
- Department of Pharmacology, School of Pharmacy, BIT, Meerut, India
| | | | - Rajendra Awasthi
- Amity Institute of Pharmacy, Amity University Uttar Pradesh, Noida, India
| | | | - Bhupesh Sharma
- Department of Pharmacology, Amity Institute of Pharmacy, Amity University Uttar Pradesh, Noida, India.,CNS and CVS Pharmacology, Conscience Research, Delhi, India
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19
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Hartwick Bjorkman S, Oliveira Pereira R. The Interplay Between Mitochondrial Reactive Oxygen Species, Endoplasmic Reticulum Stress, and Nrf2 Signaling in Cardiometabolic Health. Antioxid Redox Signal 2021; 35:252-269. [PMID: 33599550 PMCID: PMC8262388 DOI: 10.1089/ars.2020.8220] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Significance: Mitochondria-derived reactive oxygen species (mtROS) are by-products of normal physiology that may disrupt cellular redox homeostasis on a regular basis. Nonetheless, failure to resolve sustained mitochondrial stress to mitigate high levels of mtROS might contribute to the etiology of numerous pathological conditions, such as obesity, insulin resistance, and cardiovascular disease (CVD). Recent Advances: Notably, recent studies have demonstrated that moderate mitochondrial stress might result in the induction of different stress response pathways that ultimately improve the organism's ability to deal with subsequent stress, a process termed mitohormesis. mtROS have been shown to play a key role in regulating this adaptation. Critical Issue: mtROS regulate the convergence of different signaling pathways that, when disturbed, might impair cardiometabolic health. Conversely, mtROS seem to be required to mediate activation of prosurvival pathways, contributing to improved cardiometabolic fitness. In the present review, we will primarily focus on the role of mtROS in the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant pathway and examine the role of endoplasmic reticulum (ER) stress in coordinating the convergence of ER stress and oxidative stress signaling through activation of Nrf2 and activating transcription factor 4 (ATF4). Future Directions: The mechanisms underlying cardiometabolic protection in response to mitochondrial stress have only started to be investigated. Integrated understanding of how mtROS and ER stress cooperatively promote activation of prosurvival pathways might shed mechanistic insight into the role of mitohormesis in mediating cardiometabolic protection and might inform future therapeutic avenues for the treatment of metabolic diseases contributing to CVD. Antioxid. Redox Signal. 35, 252-269.
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Affiliation(s)
- Sarah Hartwick Bjorkman
- Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.,Department of Obstetrics and Gynecology, Reproductive Endocrinology and Infertility, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA
| | - Renata Oliveira Pereira
- Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
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20
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Xiang C, Zhang F, Gao J, Guo F, Zhang M, Zhou R, Wei J, Wang P, Zhang Y, Zhang J, Yang H. Yixin-Shu Capsules Ameliorated Ischemia-Induced Heart Failure by Restoring Trx2 and Inhibiting JNK/p38 Activation. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:8049079. [PMID: 33643519 PMCID: PMC7902134 DOI: 10.1155/2021/8049079] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 12/31/2020] [Accepted: 01/20/2021] [Indexed: 12/16/2022]
Abstract
Traditional Chinese medicine has shown great safety and efficacy in the treatment of heart failure (HF), whereas the mechanism remains unclear. In this study, the protective effect of Yixin-shu (YXS) capsules, a conventional medicine for various cardiovascular diseases, against myocardial ischemia-induced HF in rats was systematically investigated by RNA-seq technology. HF rats treated with YXS (0.8 or 1.6 g/kg/d, ig) for 6 weeks had significantly decreased brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) and collagen III and attenuated cardiac structure rupture and collagen deposition. Additionally, YXS treatment decreased the levels of interleukin-1β (IL-1β), interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), and lactate dehydrogenase (LDH) and TUNEL-positive rate and the nitrotyrosine staining, but increased levels of glutathione (GSH), total antioxidant capacity (T-AOC) activity, and mitochondrial membrane potential. Further experiments demonstrated that YXS restored Trx2 and inhibited the phosphorylation of JNK and p38, thereby improving cardiac function in the rats with HF. Silencing Trx2 decreased the protection of YXS in the response to H2O2 as evidenced by the increase of caspase-3 activity and decrease of GSH level. Thus, YXS enhanced heart function and decreased myocardial damage through restoring Trx2 and inhibiting JNK and p38 activation in ischemia-induced HF.
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Affiliation(s)
- Changpei Xiang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Fangbo Zhang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Jinhuan Gao
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Feifei Guo
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Mao Zhang
- Institute of Molecular Medicine, Peking University, Beijing 100871, China
| | - Rui Zhou
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Junying Wei
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Ping Wang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Yi Zhang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Jingjing Zhang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Hongjun Yang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
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21
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Saccà SC, Izzotti A, Vernazza S, Tirendi S, Scarfì S, Gandolfi S, Bassi AM. Can Polyphenols in Eye Drops Be Useful for Trabecular Protection from Oxidative Damage? J Clin Med 2020; 9:3584. [PMID: 33172106 PMCID: PMC7694784 DOI: 10.3390/jcm9113584] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 11/03/2020] [Accepted: 11/04/2020] [Indexed: 12/24/2022] Open
Abstract
Polyphenols, with anti-oxidant properties, counteract oxidative stress effects. Increasing evidence has found oxidative stressto be the main risk factor for trabecular meshwork (TM) damage, leading to high-tension glaucoma. Topical anti-oxidants could represent a new target for glaucoma treatment. Our aim is to investigate the protective mechanisms on a human TM culture of a patented polyphenol and fatty acid (iTRAB®)formulation in response to oxidative stress using an advanced invitromodel consisting of 3D-human TM cells, embedded in a natural hydrogel, and a milli-scaled multi-organ device model for constantdynamic conditions. The 3D-human TM cells(3D-HTMCs) were treated daily with 500 µM H2O2or 500 µM H2O2and 0.15% iTRAB®(m/v) for 72 h, and molecular differences in the intracellular reactive oxygen species (iROS), state of the cells, activation of the apoptosis pathway and NF-kB and the expression ofinflammatory and fibrotic markers wereanalyzed at different time-points.Concomitant exposure significantly reduced iROS and restored TM viability, iTRAB® having a significant inhibitory effect on the apoptotic pathway, activation of NF-κB, induction of pro-inflammatory (IL-1α, IL-1ß and TNFα) and pro-fibrotic (TGFβ) cytokines and the matrix metalloproteinase expressions. It is clear that this specific anti-oxidant provides a valid TM protection, suggesting iTRAB® could be an adjuvant therapy in primary open-angle glaucoma (POAG).
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Affiliation(s)
| | - Alberto Izzotti
- Department of Experimental Medicine (DIMES), University of Genoa, 16132 Genoa, Italy; (A.I.); (S.T.); (A.M.B.)
| | | | - Sara Tirendi
- Department of Experimental Medicine (DIMES), University of Genoa, 16132 Genoa, Italy; (A.I.); (S.T.); (A.M.B.)
- Inter-University Center for the Promotion of the 3Rs Principles in Teaching & Research (Centro 3R), Italy;
| | - Sonia Scarfì
- Inter-University Center for the Promotion of the 3Rs Principles in Teaching & Research (Centro 3R), Italy;
- Department of Earth, Environmental and Life Sciences (DISTAV), University of Genoa, 16132 Genoa, Italy
| | - Stefano Gandolfi
- Ophthalmology Unit, Department of Biological, Biotechnological and Translational Sciences, University of Parma, 43121 Parma, Italy;
| | - Anna Maria Bassi
- Department of Experimental Medicine (DIMES), University of Genoa, 16132 Genoa, Italy; (A.I.); (S.T.); (A.M.B.)
- Inter-University Center for the Promotion of the 3Rs Principles in Teaching & Research (Centro 3R), Italy;
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22
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Amara I, Salah A, Timoumi R, Annabi E, Scuto M, Trovato A, Neffati F, Calabrese V, Abid-Essefi S. Effect of di(2-ethylhexyl) phthalate on Nrf2-regulated glutathione homeostasis in mouse kidney. Cell Stress Chaperones 2020; 25:919-928. [PMID: 32500380 PMCID: PMC7591664 DOI: 10.1007/s12192-020-01127-8] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 05/21/2020] [Accepted: 05/25/2020] [Indexed: 12/22/2022] Open
Abstract
Environmental toxicants such as phthalate have been involved in multiple health disorders including renal diseases. Oxidative damage is implicated in many alterations caused by phthalate especially the di(2-ethylhexyl) phthalate (DEHP), which is the most useful phthalate. However, information regarding its mechanism of renal damage is lacking. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulates gene expression implicated in free radical scavenging and cytoprotection including the antioxidant glutathione (GSH) pathway. The aim of this study was to assess whether DEHP affects the Nrf2 pathway and the GSH concentration. Mice were divided into four groups: a control group and three groups treated with DEHP at different concentrations (5, 50, and 200 mg/kg body weight) for 30 days. Our results showed that DEHP altered the normal levels of serum biochemical parameters creatinine (CREA), urea, and lactate dehydrogenase (LDH). This phthalate caused oxidative damage through the induction of lipid peroxidation and protein oxidation as marked by increase of protein carbonyl (PC) and loss of protein-bound sulfhydryls (PSH). Simultaneously, DEHP treatment decreased the protein level of Nrf-2, HO-1, and GCLC (responsible of GSH synthesis) and decreased the GSH level. Inhibition of the Nrf2 pathway is related to the activation of the mitochondrial pathway of apoptosis. This apoptotic process is evidenced by an upregulation of p53 and Bax protein levels in addition to a downregulation of Bcl-2. Collectively, our data demonstrated that depletion of Nrf2 and GSH was associated with the elevation of oxidative stress and the activation of intrinsic apoptosis in mouse kidney treated with DEHP.
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Affiliation(s)
- Ines Amara
- Faculty of Dental Medicine, Laboratory for Research on Biologically Compatible Compounds, University of Monastir, LR01SE1, Rue Avicenne, 5000, Monastir, Tunisia
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
| | - Amal Salah
- Faculty of Dental Medicine, Laboratory for Research on Biologically Compatible Compounds, University of Monastir, LR01SE1, Rue Avicenne, 5000, Monastir, Tunisia
| | - Rim Timoumi
- Faculty of Dental Medicine, Laboratory for Research on Biologically Compatible Compounds, University of Monastir, LR01SE1, Rue Avicenne, 5000, Monastir, Tunisia
| | - Emna Annabi
- Faculty of Dental Medicine, Laboratory for Research on Biologically Compatible Compounds, University of Monastir, LR01SE1, Rue Avicenne, 5000, Monastir, Tunisia
| | - Maria Scuto
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
| | - Angela Trovato
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
| | - Fadwa Neffati
- Monastir University Hospital, Laboratory of Biochemistry-Toxicology, University of Monastir, Monastir, Tunisia
| | - Vittorio Calabrese
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
| | - Salwa Abid-Essefi
- Faculty of Dental Medicine, Laboratory for Research on Biologically Compatible Compounds, University of Monastir, LR01SE1, Rue Avicenne, 5000, Monastir, Tunisia.
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Kasai S, Shimizu S, Tatara Y, Mimura J, Itoh K. Regulation of Nrf2 by Mitochondrial Reactive Oxygen Species in Physiology and Pathology. Biomolecules 2020; 10:biom10020320. [PMID: 32079324 PMCID: PMC7072240 DOI: 10.3390/biom10020320] [Citation(s) in RCA: 330] [Impact Index Per Article: 66.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 02/13/2020] [Accepted: 02/13/2020] [Indexed: 02/06/2023] Open
Abstract
Reactive oxygen species (ROS) are byproducts of aerobic respiration and signaling molecules that control various cellular functions. Nrf2 governs the gene expression of endogenous antioxidant synthesis and ROS-eliminating enzymes in response to various electrophilic compounds that inactivate the negative regulator Keap1. Accumulating evidence has shown that mitochondrial ROS (mtROS) activate Nrf2, often mediated by certain protein kinases, and induce the expression of antioxidant genes and genes involved in mitochondrial quality/quantity control. Mild physiological stress, such as caloric restriction and exercise, elicits beneficial effects through a process known as “mitohormesis”. Exercise induces NOX4 expression in the heart, which activates Nrf2 and increases endurance capacity. Mice transiently depleted of SOD2 or overexpressing skeletal muscle-specific UCP1 exhibit Nrf2-mediated antioxidant gene expression and PGC1α-mediated mitochondrial biogenesis. ATF4 activation may induce a transcriptional program that enhances NADPH synthesis in the mitochondria and might cooperate with the Nrf2 antioxidant system. In response to severe oxidative stress, Nrf2 induces Klf9 expression, which represses mtROS-eliminating enzymes to enhance cell death. Nrf2 is inactivated in certain pathological conditions, such as diabetes, but Keap1 down-regulation or mtROS elimination rescues Nrf2 expression and improves the pathology. These reports aid us in understanding the roles of Nrf2 in pathophysiological alterations involving mtROS.
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Affiliation(s)
- Shuya Kasai
- Department of Stress Response Science, Center for Advanced Medical Research, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan; (S.K.); (S.S.); (J.M.)
| | - Sunao Shimizu
- Department of Stress Response Science, Center for Advanced Medical Research, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan; (S.K.); (S.S.); (J.M.)
- Department of Nature & Wellness Research, Innovation Division, Kagome Co., Ltd. Nasushiobara, Tochigi 329-2762, Japan
| | - Yota Tatara
- Department of Glycotechnology, Center for Advanced Medical Research, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan;
| | - Junsei Mimura
- Department of Stress Response Science, Center for Advanced Medical Research, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan; (S.K.); (S.S.); (J.M.)
| | - Ken Itoh
- Department of Stress Response Science, Center for Advanced Medical Research, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan; (S.K.); (S.S.); (J.M.)
- Correspondence: ; Tel.: +81-172-39-5158
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24
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Payen VL, Zampieri LX, Porporato PE, Sonveaux P. Pro- and antitumor effects of mitochondrial reactive oxygen species. Cancer Metastasis Rev 2020; 38:189-203. [PMID: 30820778 DOI: 10.1007/s10555-019-09789-2] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
In cancer, mitochondrial functions are commonly altered. Directly involved in metabolic reprogramming, mitochondrial plasticity confers to cancer cells a high degree of adaptability to a wide range of stresses and to the harsh tumor microenvironment. Lack of nutrients or oxygen caused by altered perfusion, metabolic needs of proliferating cells, co-option of the microenvironment, control of the immune system, cell migration and metastasis, and evasion of exogenous stress (e.g., chemotherapy) are all, at least in part, influenced by mitochondria. Mitochondria are undoubtedly one of the key contributors to cancer development and progression. Understanding their protumoral (dys)functions may pave the way to therapeutic strategies capable of turning them into innocent entities. Here, we will focus on the production and detoxification of mitochondrial reactive oxygen species (mtROS), on their impact on tumorigenesis (genetic, prosurvival, and microenvironmental effects and their involvement in autophagy), and on tumor metastasis. We will also summarize the latest therapeutic approaches involving mtROS.
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Affiliation(s)
- Valéry L Payen
- Pole of Pharmacology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCLouvain), Avenue Hippocrate 57 box B1.57.04, 1200, Brussels, Belgium.,Pole of Pediatrics, Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Brussels, Belgium.,Louvain Drug Research Institute, UCLouvain, Brussels, Belgium
| | - Luca X Zampieri
- Pole of Pharmacology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCLouvain), Avenue Hippocrate 57 box B1.57.04, 1200, Brussels, Belgium
| | - Paolo E Porporato
- Department of Molecular Biotechnology and Health Science, Molecular Biotechnology Centre, University of Torino, Torino, Italy
| | - Pierre Sonveaux
- Pole of Pharmacology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCLouvain), Avenue Hippocrate 57 box B1.57.04, 1200, Brussels, Belgium.
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25
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Causer AJ, Shute JK, Cummings MH, Shepherd AI, Gruet M, Costello JT, Bailey S, Lindley M, Pearson C, Connett G, Allenby MI, Carroll MP, Daniels T, Saynor ZL. Circulating biomarkers of antioxidant status and oxidative stress in people with cystic fibrosis: A systematic review and meta-analysis. Redox Biol 2020; 32:101436. [PMID: 32044291 PMCID: PMC7264436 DOI: 10.1016/j.redox.2020.101436] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Revised: 01/14/2020] [Accepted: 01/16/2020] [Indexed: 02/03/2023] Open
Abstract
Introduction Oxidative stress may play an important role in the pathophysiology of cystic fibrosis (CF). This review aimed to quantify CF-related redox imbalances. Methods Systematic searches of the Medline, CINAHL, CENTRAL and PsycINFO databases were conducted. Mean content of blood biomarkers from people with clinically-stable CF and non-CF controls were used to calculate the standardized mean difference (SMD) and 95% confidence intervals (95% CI). Results Forty-nine studies were eligible for this review including a total of 1792 people with CF and 1675 controls. Meta-analysis revealed that protein carbonyls (SMD: 1.13, 95% CI: 0.48 to 1.77), total F2-isoprostane 8-iso-prostaglandin F2α (SMD: 0.64, 95% CI: 0.23 to 1.05) and malondialdehyde (SMD: 1.34, 95% CI: 0.30 to 2.39) were significantly higher, and vitamins A (SMD: −0.66, 95% CI -1.14 to −0.17) and E (SMD: −0.74, 95% CI: −1.28 to −0.20), β-carotene (SMD: −1.80, 95% CI: −2.92 to −0.67), lutein (SMD: −1.52, 95% CI: −1.83 to −1.20) and albumin (SMD: −0.98, 95% CI: −1.68 to −0.27) were significantly lower in the plasma or serum of people with CF versus controls. Conclusions This systematic review and meta-analysis found good evidence for reduced antioxidant capacity and elevated oxidative stress in people with clinically-stable CF.
Blood biomarkers of oxidative stress were elevated in stable CF vs non-CF controls. Lipid peroxidation was positively correlated with age and immune cell count in CF. Antioxidants vitamins A & E, β-carotene, lutein and albumin were lower in stable CF. Antioxidants were positively correlated with body mass index and lung function in CF.
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Affiliation(s)
- Adam J Causer
- School of Sport, Health and Exercise Science, Faculty of Science and Health, University of Portsmouth, Portsmouth, UK; Cystic Fibrosis Unit, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Janis K Shute
- School of Pharmacy and Biomedical Sciences, Faculty of Science and Health, University of Portsmouth, Portsmouth, UK
| | - Michael H Cummings
- Department of Diabetes and Endocrinology, Queen Alexandra Hospital, Portsmouth, UK
| | - Anthony I Shepherd
- School of Sport, Health and Exercise Science, Faculty of Science and Health, University of Portsmouth, Portsmouth, UK
| | - Mathieu Gruet
- Laboratory of Impact of Physical Activity on Health (IAPS), UR n°201723207F, University of Toulon, France
| | - Joseph T Costello
- School of Sport, Health and Exercise Science, Faculty of Science and Health, University of Portsmouth, Portsmouth, UK
| | - Stephen Bailey
- School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK
| | - Martin Lindley
- School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK
| | - Clare Pearson
- Cystic Fibrosis Unit, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Gary Connett
- National Institute for Health Research, Southampton Biomedical Research Centre, Southampton Children's Hospital, Southampton, UK
| | - Mark I Allenby
- Cystic Fibrosis Unit, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Mary P Carroll
- Cystic Fibrosis Unit, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Thomas Daniels
- Cystic Fibrosis Unit, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Zoe L Saynor
- School of Sport, Health and Exercise Science, Faculty of Science and Health, University of Portsmouth, Portsmouth, UK; Cystic Fibrosis Unit, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
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26
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Paredes LC, Olsen Saraiva Camara N, Braga TT. Understanding the Metabolic Profile of Macrophages During the Regenerative Process in Zebrafish. Front Physiol 2019; 10:617. [PMID: 31178754 PMCID: PMC6543010 DOI: 10.3389/fphys.2019.00617] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 05/01/2019] [Indexed: 12/14/2022] Open
Abstract
In contrast to mammals, lower vertebrates, including zebrafish (Danio rerio), have the ability to regenerate damaged or lost tissues, such as the caudal fin, which makes them an ideal model for tissue and organ regeneration studies. Since several diseases involve the process of transition between fibrosis and tissue regeneration, it is necessary to attain a better understanding of these processes. It is known that the cells of the immune system, especially macrophages, play essential roles in regeneration by participating in the removal of cellular debris, release of pro- and anti-inflammatory factors, remodeling of components of the extracellular matrix and alteration of oxidative patterns during proliferation and angiogenesis. Immune cells undergo phenotypical and functional alterations throughout the healing process due to growth factors and cytokines that are produced in the tissue microenvironment. However, some aspects of the molecular mechanisms through which macrophages orchestrate the formation and regeneration of the blastema remain unclear. In the present review, we outline how macrophages orchestrate the regenerative process in zebrafish and give special attention to the redox balance in the context of tail regeneration.
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Affiliation(s)
| | - Niels Olsen Saraiva Camara
- Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo, São Paulo, Brazil.,Nephrology Division, Federal University of São Paulo, São Paulo, Brazil.,Renal Pathophysiology Laboratory, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
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27
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Paik JY, Lee HG, Piao JY, Kim SJ, Kim DH, Na HK, Surh YJ. Helicobacter pylori infection promotes autophagy through Nrf2-mediated heme oxygenase upregulation in human gastric cancer cells. Biochem Pharmacol 2019; 162:89-97. [DOI: 10.1016/j.bcp.2019.02.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Accepted: 02/01/2019] [Indexed: 10/27/2022]
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28
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Zhang Y, Ahmad KA, Khan FU, Yan S, Ihsan AU, Ding Q. Chitosan oligosaccharides prevent doxorubicin-induced oxidative stress and cardiac apoptosis through activating p38 and JNK MAPK mediated Nrf2/ARE pathway. Chem Biol Interact 2019; 305:54-65. [PMID: 30928397 DOI: 10.1016/j.cbi.2019.03.027] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2019] [Revised: 03/14/2019] [Accepted: 03/26/2019] [Indexed: 11/19/2022]
Abstract
Doxorubicin (DOX) is one of the most effective chemotherapeutic drugs; however, the incidence of cardiotoxicity compromises its therapeutic index. Oxidative stress and apoptosis are believed to be involved in DOX-induced cardiotoxicity. Chitosan oligosaccharides (COS), the enzymatic hydrolysates of chitosan, have been reported to possess diverse biological activities including antioxidant and anti-apoptotic properties. The objective of the present study was to investigate the potential role of COS against DOX-induced cardiotoxicity, and the effects of COS on apoptosis and oxidative stress in rats and H9C2 cells. Furthermore, we also shed light on the involved pathways during the whole process. For this purpose, first, we demonstrated that COS exhibited a significant protective effect on cardiac tissue by not only inducing a decrease in body and heart growth but also ameliorated oxidative damage and ECG alterations in DOX-treated rats. Second, we found that COS reversed the decrease of cell viability induced by DOX, reduced the intracellular reactive oxygen species (ROS), increased the mitochondrial membrane potential (MMP) and Bcl-2/Bax ratio. COS treatment also results in reduced caspase-3 and caspase-9 expressions, and an increase in the phosphorylation of MAPKs (mitogen-activated protein kinases) in DOX-exposed H9C2 cells. Additionally, cellular homeostasis was re-established via stabilization of MAPK mediated nuclear factor erythroid 2-related factor 2/antioxidant-response element (Nrf2/ARE) signaling and transcription of downstream cytoprotective genes. In summary, these findings suggest that COS could be a potential candidate for the prevention and treatment of DOX-induced cardiotoxicity.
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Affiliation(s)
- Yongtian Zhang
- Experimental and Teaching Center of Medical Basis for Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Khalil Ali Ahmad
- Experimental and Teaching Center of Medical Basis for Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China; Shanghai Jiao Tong University, School of Pharmacy, 800 Dongchuan Road, Shanghai, 200240, China
| | - Farhan Ullah Khan
- Shanghai Jiao Tong University, School of Pharmacy, 800 Dongchuan Road, Shanghai, 200240, China; Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu Province, 211198, China
| | - Simin Yan
- Experimental and Teaching Center of Medical Basis for Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Awais Ullah Ihsan
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu Province, 211198, China
| | - Qilong Ding
- Experimental and Teaching Center of Medical Basis for Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China.
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Allawzi A, Elajaili H, Redente EF, Nozik-Grayck E. Oxidative Toxicology of Bleomycin: Role of the Extracellular Redox Environment. CURRENT OPINION IN TOXICOLOGY 2019; 13:68-73. [PMID: 31289762 PMCID: PMC6615752 DOI: 10.1016/j.cotox.2018.08.001] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Bleomycin is a commonly used cancer therapeutic that is associated with oxidative stress leading to pulmonary toxicity. Bleomycin has been used in animal studies to model pulmonary fibrosis, acute respiratory distress syndrome, and pulmonary hypertension secondary to interstitial lung disease. The toxicity with bleomycin is initiated by direct oxidative damage, which then leads to subsequent inflammation and fibrosis mediated by generation of both extracellular ROS and intracellular ROS. While most studies focus on the intracellular ROS implicated in TGFβ signaling and fibrosis, the changes in the extracellular redox environment, particularly with the initiation of early inflammation, is also critical to the pathogenesis of bleomycin induced injury and fibrosis. In this review, we focus on the role of extracellular redox environment in bleomycin toxicity, with attention to the generation of extracellular ROS, alterations in the redox state of extracellular thiols, and the central role of the extracellular isoform of superoxide dismutase in the development of bleomycin induced injury and fibrosis.
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Affiliation(s)
- Ayed Allawzi
- Developmental Lung Biology and Cardiovascular Pulmonary Research Laboratories, Departments of Pediatrics and Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO
| | - Hanan Elajaili
- Developmental Lung Biology and Cardiovascular Pulmonary Research Laboratories, Departments of Pediatrics and Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO
| | - Elizabeth F. Redente
- Program in Cell Biology, Department of Pediatrics, National Jewish Health, Denver, CO
- Department of Research, Veterans Affairs Eastern Colorado Health Care System, Denver, CO
- Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO
| | - Eva Nozik-Grayck
- Developmental Lung Biology and Cardiovascular Pulmonary Research Laboratories, Departments of Pediatrics and Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO
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30
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Saccà SC, Corazza P, Gandolfi S, Ferrari D, Sukkar S, Iorio EL, Traverso CE. Substances of Interest That Support Glaucoma Therapy. Nutrients 2019; 11:E239. [PMID: 30678262 PMCID: PMC6412416 DOI: 10.3390/nu11020239] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 01/11/2019] [Accepted: 01/15/2019] [Indexed: 12/14/2022] Open
Abstract
Glaucoma is a multifactorial disease in which pro-apoptotic signals are directed to retinal ganglion cells. During this disease the conventional outflow pathway becomes malfunctioning. Aqueous humour builds up in the anterior chamber, leading to increased intraocular pressure. Both of these events are related to functional impairment. The knowledge of molecular mechanisms allows us to better understand the usefulness of substances that can support anti-glaucoma therapy. The goal of glaucoma therapy is not simply to lower intraocular pressure; it should also be to facilitate the survival of retinal ganglion cells, as these constitute the real target tissue in this disease, in which the visual pathway is progressively compromised. Indeed, an endothelial dysfunction syndrome affecting the endothelial cells of the trabecular meshwork occurs in both normal-tension glaucoma and high-tension glaucoma. Some substances, such as polyunsaturated fatty acids, can counteract the damage due to the molecular mechanisms - whether ischemic, oxidative, inflammatory or other - that underlie the pathogenesis of glaucoma. In this review, we consider some molecules, such as polyphenols, that can contribute, not only theoretically, to neuroprotection but which are also able to counteract the metabolic pathways that lead to glaucomatous damage. Ginkgo biloba extract, for instance, improves the blood supply to peripheral districts, including the optic nerve and retina and exerts a neuro-protective action by inhibiting apoptosis. Polyunsaturated fatty acids can protect the endothelium and polyphenols exert an anti-inflammatory action through the down-regulation of cytokines such as TNF-α and IL-6. All these substances can aid anti-glaucoma therapy by providing metabolic support for the cells involved in glaucomatous injury. Indeed, it is known that the food we eat is able to change our gene expression.
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Affiliation(s)
- Sergio Claudio Saccà
- Ophthalmology Unit, Department of Head/Neck Pathologies, Policlinico San Martino Hospital, IRCCS Hospital-University San Martino, Viale Benedetto XV, 16132 Genoa, Italy.
| | - Paolo Corazza
- Eye Clinic, Department of Neuroscience and Sensory Organs, University of Genoa, Policlinico San Martino Hospital IRCCS Hospital-University San Martino, Viale Benedetto XV, 16132 Genoa, Italy.
| | - Stefano Gandolfi
- Ophthalmology Unit, Department of Biological, Biotechnological and Translational Sciences, University of Parma, 43121 Parma, Italy.
| | - Daniele Ferrari
- Ophthalmology Unit, Department of Head/Neck Pathologies, Policlinico San Martino Hospital, IRCCS Hospital-University San Martino, Viale Benedetto XV, 16132 Genoa, Italy.
| | - Samir Sukkar
- U.O. di Dietetica e Nutrizione Clinica, Policlinico San Martino Hospital IRCCS Hospital-University San Martino, 35122 Genoa, Italy.
| | - Eugenio Luigi Iorio
- International Observatory of Oxidative Stress, Via Paolo Grisignano 21, 84127 Salerno, Italy.
| | - Carlo Enrico Traverso
- Eye Clinic, Department of Neuroscience and Sensory Organs, University of Genoa, Policlinico San Martino Hospital IRCCS Hospital-University San Martino, Viale Benedetto XV, 16132 Genoa, Italy.
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31
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Chaiswing L, St. Clair WH, St. Clair DK. Redox Paradox: A Novel Approach to Therapeutics-Resistant Cancer. Antioxid Redox Signal 2018; 29:1237-1272. [PMID: 29325444 PMCID: PMC6157438 DOI: 10.1089/ars.2017.7485] [Citation(s) in RCA: 89] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2017] [Accepted: 01/05/2018] [Indexed: 02/06/2023]
Abstract
SIGNIFICANCE Cancer cells that are resistant to radiation and chemotherapy are a major problem limiting the success of cancer therapy. Aggressive cancer cells depend on elevated intracellular levels of reactive oxygen species (ROS) to proliferate, self-renew, and metastasize. As a result, these aggressive cancers maintain high basal levels of ROS compared with normal cells. The prominence of the redox state in cancer cells led us to consider whether increasing the redox state to the condition of oxidative stress could be used as a successful adjuvant therapy for aggressive cancers. Recent Advances: Past attempts using antioxidant compounds to inhibit ROS levels in cancers as redox-based therapy have met with very limited success. However, recent clinical trials using pro-oxidant compounds reveal noteworthy results, which could have a significant impact on the development of strategies for redox-based therapies. CRITICAL ISSUES The major objective of this review is to discuss the role of the redox state in aggressive cancers and how to utilize the shift in redox state to improve cancer therapy. We also discuss the paradox of redox state parameters; that is, hydrogen peroxide (H2O2) as the driver molecule for cancer progression as well as a target for cancer treatment. FUTURE DIRECTIONS Based on the biological significance of the redox state, we postulate that this system could potentially be used to create a new avenue for targeted therapy, including the potential to incorporate personalized redox therapy for cancer treatment.
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Affiliation(s)
- Luksana Chaiswing
- Department of Toxicology and Cancer Biology, University of Kentucky-Lexington, Lexington, Kentucky
| | - William H. St. Clair
- Department of Radiation Medicine, University of Kentucky-Lexington, Lexington, Kentucky
| | - Daret K. St. Clair
- Department of Toxicology and Cancer Biology, University of Kentucky-Lexington, Lexington, Kentucky
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32
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Abstract
SIGNIFICANCE Oxidative stress increases in the brain with aging and neurodegenerative diseases. Previous work emphasized irreversible oxidative damage in relation to cognitive impairment. This research has evolved to consider a continuum of alterations, from redox signaling to oxidative damage, which provides a basis for understanding the onset and progression of cognitive impairment. This review provides an update on research linking redox signaling to altered function of neural circuits involved in information processing and memory. Recent Advances: Starting in middle age, redox signaling triggers changes in nervous system physiology described as senescent physiology. Hippocampal senescent physiology involves decreased cell excitability, altered synaptic plasticity, and decreased synaptic transmission. Recent studies indicate N-methyl-d-aspartate and ryanodine receptors and Ca2+ signaling molecules as molecular substrates of redox-mediated senescent physiology. CRITICAL ISSUES We review redox homeostasis mechanisms and consider the chemical character of reactive oxygen and nitrogen species and their role in regulating different transmitter systems. In this regard, senescent physiology may represent the co-opting of pathways normally responsible for feedback regulation of synaptic transmission. Furthermore, differences across transmitter systems may underlie differential vulnerability of brain regions and neuronal circuits to aging and disease. FUTURE DIRECTIONS It will be important to identify the intrinsic mechanisms for the shift in oxidative/reductive processes. Intrinsic mechanism will depend on the transmitter system, oxidative stressors, and expression/activity of antioxidant enzymes. In addition, it will be important to identify how intrinsic processes interact with other aging factors, including changes in inflammatory or hormonal signals. Antioxid. Redox Signal. 28, 1724-1745.
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Affiliation(s)
- Ashok Kumar
- 1 Department of Neuroscience, McKnight Brain Institute, University of Florida , Gainesville, Florida
| | - Brittney Yegla
- 1 Department of Neuroscience, McKnight Brain Institute, University of Florida , Gainesville, Florida
| | - Thomas C Foster
- 1 Department of Neuroscience, McKnight Brain Institute, University of Florida , Gainesville, Florida.,2 Genetics and Genomics Program, Genetics Institute, University of Florida , Gainesville, Florida
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Zheng Y, Ritzenthaler JD, Burke TJ, Otero J, Roman J, Watson WH. Age-dependent oxidation of extracellular cysteine/cystine redox state (E h(Cys/CySS)) in mouse lung fibroblasts is mediated by a decline in Slc7a11 expression. Free Radic Biol Med 2018; 118:13-22. [PMID: 29458149 PMCID: PMC5884717 DOI: 10.1016/j.freeradbiomed.2018.02.026] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Revised: 01/23/2018] [Accepted: 02/15/2018] [Indexed: 12/26/2022]
Abstract
Aging is associated with progressive oxidation of the extracellular environment. The redox state of human plasma, defined by the concentrations of cysteine (Cys) and cystine (CySS), becomes more oxidized as we age. Recently, we showed that fibroblasts isolated from the lungs of young and old mice retain this differential phenotype; old cells produce and maintain a more oxidizing extracellular redox potential (Eh(Cys/CySS)) than young cells. Microarray analysis identified down-regulation of Slc7a11, the light subunit of the CySS/glutamate transporter, as a potential mediator of age-related oxidation in these cells. The purpose of the present study was to investigate the mechanistic link between Slc7a11 expression and extracellular Eh(Cys/CySS). Sulforaphane treatment or overexpression of Slc7a11 was used to increase Slc7a11 in lung fibroblasts from old mice, and sulfasalazine treatment or siRNA-mediated knock down was used to decrease Slc7a11 in young fibroblasts. Slc7a11 mRNA levels were measured by real-time PCR, Slc7a11 activity was determined by measuring the rate of glutamate release, Cys, CySS, glutathione (GSH) and its disulfide (GSSG) were measured by HPLC, and Eh(Cys/CySS) was calculated from the Nernst equation. The results showed that both Eh(Cys/CySS) and Eh(GSH/GSSG) were more oxidized in the conditioned media of old cells than in young cells. Up-regulation of Slc7a11 via overexpression or sulforaphane treatment restored extracellular Eh(Cys/CySS) in cultures of old cells, whereas down-regulation reproduced the oxidizing Eh(Cys/CySS) in young cells. Only sulforaphane treatment was able to increase total GSH and restore Eh(GSH/GSSG), whereas overexpression, knock down and sulfasalazine had no effect on these parameters. In addition, inhibition of GSH synthesis with buthionine sulfoximine had no effect on the ability of cells to restore their extracellular redox potential in response to an oxidative challenge. In conclusion, our study reveals Slc7a11 is the key regulator of age-dependent changes in extracellular Eh(Cys/CySS) in primary mouse lung fibroblasts, and its effects are not dependent on GSH synthesis.
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Affiliation(s)
- Yuxuan Zheng
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, 505 South Hancock Street, Louisville, KY 40202, United States.
| | - Jeffrey D Ritzenthaler
- Department of Medicine, Divisions of Gastroenterology, Hepatology and Nutrition, and Pulmonary, Critical Care, & Sleep Medicine, University of Louisville School of Medicine, 550 South Jackson Street, Louisville, KY 40202, United States.
| | - Tom J Burke
- Department of Medicine, Divisions of Gastroenterology, Hepatology and Nutrition, and Pulmonary, Critical Care, & Sleep Medicine, University of Louisville School of Medicine, 550 South Jackson Street, Louisville, KY 40202, United States.
| | - Javier Otero
- Department of Medicine, Divisions of Gastroenterology, Hepatology and Nutrition, and Pulmonary, Critical Care, & Sleep Medicine, University of Louisville School of Medicine, 550 South Jackson Street, Louisville, KY 40202, United States.
| | - Jesse Roman
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, 505 South Hancock Street, Louisville, KY 40202, United States; Department of Medicine, Divisions of Gastroenterology, Hepatology and Nutrition, and Pulmonary, Critical Care, & Sleep Medicine, University of Louisville School of Medicine, 550 South Jackson Street, Louisville, KY 40202, United States; Robley Rex Veterans Affairs Medical Center, 800 Zorn Avenue, Louisville, KY 40206, United States.
| | - Walter H Watson
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, 505 South Hancock Street, Louisville, KY 40202, United States; Department of Medicine, Divisions of Gastroenterology, Hepatology and Nutrition, and Pulmonary, Critical Care, & Sleep Medicine, University of Louisville School of Medicine, 550 South Jackson Street, Louisville, KY 40202, United States.
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Tubbs E, Axelsson AS, Vial G, Wollheim CB, Rieusset J, Rosengren AH. Sulforaphane improves disrupted ER-mitochondria interactions and suppresses exaggerated hepatic glucose production. Mol Cell Endocrinol 2018; 461:205-214. [PMID: 28923347 DOI: 10.1016/j.mce.2017.09.016] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Revised: 08/10/2017] [Accepted: 09/13/2017] [Indexed: 02/07/2023]
Abstract
AIMS Exaggerated hepatic glucose production is one of the hallmarks of type 2 diabetes. Sulforaphane (SFN) has been suggested as a new potential anti-diabetic compound. However, the effects of SFN in hepatocytes are yet unclear. Accumulating evidence points to the close structural contacts between the ER and mitochondria, known as mitochondria-associated ER membranes (MAMs), as important hubs for hepatic metabolism. We wanted to investigate whether SFN could affect hepatic glucose production and MAMs. MATERIALS AND METHODS We used proximity ligation assays, analysis of ER stress markers and glucose production assays in hepatoma cell lines, primary mouse hepatocytes and diabetic animal models. RESULTS SFN counteracted the increase of glucose production in palmitate-treated mouse hepatocytes. SFN also counteracted palmitate-induced MAM disruptions. Moreover, SFN decreased the ER stress markers CHOP and Grp78. In ob/ob mice, SFN improved glucose tolerance and reduced exaggerated glucose production. In livers of these mice, SFN increased MAM protein content, restored impaired VDAC1-IP3R1 interactions and reduced ER stress markers. In mice on HFHSD, SFN improved glucose tolerance, MAM protein content and ER-mitochondria interactions to a similar extent to that of metformin. CONCLUSIONS The present findings show that MAMs are severely reduced in animal models of glucose intolerance, which reinforces the role of MAMs as a hub for insulin signaling in the liver. We also show that SFN restores MAMs and improves glucose tolerance by a similar magnitude to that of metformin. These data highlight SFN as a new potential anti-diabetic compound.
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Affiliation(s)
- Emily Tubbs
- Lund University Diabetes Centre, Jan Waldenströms Gata 35, SE-20502 Malmö, Sweden
| | - Annika S Axelsson
- Lund University Diabetes Centre, Jan Waldenströms Gata 35, SE-20502 Malmö, Sweden
| | - Guillaume Vial
- INSERM UMR-1060 CarMeN Laboratory, Lyon 1 University, INRA U1235, INSA of Lyon, Charles Merieux Lyon-Sud Medical Universities, Lyon, France
| | - Claes B Wollheim
- Lund University Diabetes Centre, Jan Waldenströms Gata 35, SE-20502 Malmö, Sweden; Department of Cell Physiology and Metabolism, University Medical Center, 1211 Geneva, Switzerland
| | - Jennifer Rieusset
- INSERM UMR-1060 CarMeN Laboratory, Lyon 1 University, INRA U1235, INSA of Lyon, Charles Merieux Lyon-Sud Medical Universities, Lyon, France
| | - Anders H Rosengren
- Lund University Diabetes Centre, Jan Waldenströms Gata 35, SE-20502 Malmö, Sweden; Department of Neuroscience and Physiology, University of Gothenburg, Medicinaregatan 11, SE-41390 Göteborg, Sweden.
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Cavalcante PAM, Gregnani MF, Henrique JS, Ornellas FH, Araújo RC. Aerobic but not Resistance Exercise Can Induce Inflammatory Pathways via Toll-Like 2 and 4: a Systematic Review. SPORTS MEDICINE - OPEN 2017; 3:42. [PMID: 29185059 PMCID: PMC5705532 DOI: 10.1186/s40798-017-0111-2] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Accepted: 11/15/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND Only a few studies have addressed the relationship between toll-like receptors 2 and 4 (TLR2 and TLR4) and the production of local and systemic cytokines in response to physical exercise, and they have produced conflicting results. We aimed to determine whether acute and chronic exercise outcomes are associated with changes in TLR2 and TLR4 expression and signaling and if so, the mechanisms that connect them. METHODS PubMed database were consulted. This systematic review selected 39 articles, 26 involving humans and 13 based on rodents. RESULTS In acute resistance exercise studies, 75% reported a decrease in TLR4 or TLR2 expression and 25% did not find differences. For chronic resistance exercise studies, 67% reported a reduction of expression and 33% did not find differences. Studies of both types reported reductions in pro-inflammatory cytokines. In acute aerobic exercise studies, 40% revealed a decline in the expression of the receptors, 7% reported no significant difference, 40% showed an increase, and 13% did not evaluate their expression. Fifty-eight percent of studies of chronic aerobic exercise revealed a reduction in expression, 17% did not find a difference, and 25% reported increases; they also suggested that the expression of the receptors might be correlated with that of inflammatory cytokines. In studies on combined exercise, 50% reported a decline in receptors expression and 50% did not find a difference. CONCLUSIONS The majority of the articles (54%) link different types of exercise to a decline in TLR4 and TLR2 expression. However, aerobic exercise may induce inflammations through its influence on these receptor pathways. Higher levels of inflammation were seen in acute sessions (40%) than regular sessions (25%).
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Affiliation(s)
- Paula Andréa Malveira Cavalcante
- Medicine (Nephrology) Program, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil.
- Laboratory of Exercise Genetics and Metabolism, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil.
- Department of Biophysics, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil.
- , Rua Pedro de Toledo, 669/9and., 04039-032, São Paulo, SP, Brazil.
| | - Marcos Fernandes Gregnani
- Molecular Biology Program, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil
- Laboratory of Exercise Genetics and Metabolism, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil
- Department of Biophysics, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil
| | - Jessica Salles Henrique
- Neurology/Neuroscience Program, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil
- Exercise Neurophysiology Laboratory, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil
| | - Fábio Henrique Ornellas
- Medicine (Nephrology) Program, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil
- Laboratory of Exercise Genetics and Metabolism, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil
- Department of Biophysics, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil
| | - Ronaldo Carvalho Araújo
- Medicine (Nephrology) Program, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil
- Molecular Biology Program, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil
- Laboratory of Exercise Genetics and Metabolism, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil
- Department of Biophysics, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil
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Uchida H, Nakajima Y, Ohtake K, Ito J, Morita M, Kamimura A, Kobayashi J. Protective effects of oral glutathione on fasting-induced intestinal atrophy through oxidative stress. World J Gastroenterol 2017; 23:6650-6664. [PMID: 29085210 PMCID: PMC5643286 DOI: 10.3748/wjg.v23.i36.6650] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Revised: 07/14/2017] [Accepted: 07/24/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To determine whether oral glutathione (GSH) administration can alleviate the effects of fasting-induced intestinal atrophy in the small intestinal mucosa.
METHODS Rats were divided into eight groups. One group was fed ad libitum, another was fed ad libitum and received oral GSH, and six groups were administrated saline (SA) or GSH orally during fasting. Mucosal height, apoptosis, and cell proliferation in the jejunum were histologically evaluated. iNOS protein expression (by immunohistochemistry), nitrite levels (by high performance liquid chromatography, as a measure of NO production), 8-hydroxydeoxyguanosine formation (by ELISA, indicating ROS levels), glutathione/oxidized glutathione (GSH/GSSG) ratio (by enzymatic colorimetric detection), and γ-glutamyl transpeptidase (Ggt1) mRNA levels in the jejunum (by semi-quantitative RT-PCR) were also estimated.
RESULTS Oral GSH administration was demonstrated to drastically reduce fasting-induced intestinal atrophy in the jejunum. In particular, jejunal mucosal height was enhanced in GSH-treated animals compared to SA-treated animals [527.2 ± 6.9 for 50 mg/kg GSH, 567.6 ± 5.4 for 500 mg/kg GSH vs 483.1 ± 4.9 (μm), P < 0.01 at 72 h]. This effect was consistent with decreasing changes in GSH-treated animals compared to SA-treated animals for iNOS protein staining [0.337 ± 0.016 for 50 mg/kg GSH, 0.317 ± 0.017 for 500 mg/kg GSH vs 0.430 ± 0.023 (area of staining part/area of tissue), P < 0.01 at 72 h] and NO [2.99 ± 0.29 for 50 mg/kg GSH, 2.88 ± 0.19 for 500 mg/kg GSH vs 5.34 ± 0.35 (nmol/g tissue), P < 0.01 at 72 h] and ROS [3.92 ± 0.46 for 50 mg/kg GSH, 4.58 ± 0.29 for 500 mg/kg GSH vs 6.42 ± 0.52 (8-OHdG pg/μg DNA), P < 0.01, P < 0.05 at 72 h, respectively] levels as apoptosis mediators in the jejunum. Furthermore, oral GSH administration attenuated cell proliferation decreases in the fasting jejunum [182.5 ± 1.9 for 500 mg/kg GSH vs 155.8 ± 3.4 (5-BrdU positive cells/10 crypts), P < 0.01 at 72 h]. Notably, both GSH concentration and Ggt1 mRNA expression in the jejunum were also attenuated in rats following oral administration of GSH during fasting as compared with fasting alone [0.45 ± 0.12 vs 0.97 ± 0.06 (nmol/mg tissue), P < 0.01; 1.01 ± 0.11 vs 2.79 ± 0.39 (Ggt1 mRNA/Gapdh mRNA), P < 0.01 for 500 mg/kg GSH at 48 h, respectively].
CONCLUSION Oral GSH administration during fasting enhances jejunal regenerative potential to minimize intestinal mucosal atrophy by diminishing fasting-mediated ROS generation and enterocyte apoptosis and enhancing cell proliferation.
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Affiliation(s)
- Hiroyuki Uchida
- Division of Pathophysiology, Department of Clinical Dietetics and Human Nutrition, Faculty of Pharmaceutical Science, Josai University, Sakado, Saitama 350-0295, Japan
| | - Yukari Nakajima
- Division of Pathophysiology, Department of Clinical Dietetics and Human Nutrition, Faculty of Pharmaceutical Science, Josai University, Sakado, Saitama 350-0295, Japan
| | - Kazuo Ohtake
- Division of Pathophysiology, Department of Clinical Dietetics and Human Nutrition, Faculty of Pharmaceutical Science, Josai University, Sakado, Saitama 350-0295, Japan
| | - Junta Ito
- Division of Pathophysiology, Department of Clinical Dietetics and Human Nutrition, Faculty of Pharmaceutical Science, Josai University, Sakado, Saitama 350-0295, Japan
| | - Masahiko Morita
- Kyowa Hakko Bio Co., Ltd. Healthcare Products Development Center, Tsukuba-shi, Ibaraki 305-0841, Japan
| | - Ayako Kamimura
- Kyowa Hakko Bio Co., Ltd. Healthcare Products Development Center, Tsukuba-shi, Ibaraki 305-0841, Japan
| | - Jun Kobayashi
- Division of Pathophysiology, Department of Clinical Dietetics and Human Nutrition, Faculty of Pharmaceutical Science, Josai University, Sakado, Saitama 350-0295, Japan
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Axelsson AS, Tubbs E, Mecham B, Chacko S, Nenonen HA, Tang Y, Fahey JW, Derry JMJ, Wollheim CB, Wierup N, Haymond MW, Friend SH, Mulder H, Rosengren AH. Sulforaphane reduces hepatic glucose production and improves glucose control in patients with type 2 diabetes. Sci Transl Med 2017; 9:9/394/eaah4477. [DOI: 10.1126/scitranslmed.aah4477] [Citation(s) in RCA: 179] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Revised: 02/23/2017] [Accepted: 05/05/2017] [Indexed: 12/13/2022]
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Lesnefsky EJ, Chen Q, Hoppel CL. Mitochondrial Metabolism in Aging Heart. Circ Res 2017; 118:1593-611. [PMID: 27174952 DOI: 10.1161/circresaha.116.307505] [Citation(s) in RCA: 233] [Impact Index Per Article: 29.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Accepted: 04/05/2016] [Indexed: 02/07/2023]
Abstract
Altered mitochondrial metabolism is the underlying basis for the increased sensitivity in the aged heart to stress. The aged heart exhibits impaired metabolic flexibility, with a decreased capacity to oxidize fatty acids and enhanced dependence on glucose metabolism. Aging impairs mitochondrial oxidative phosphorylation, with a greater role played by the mitochondria located between the myofibrils, the interfibrillar mitochondria. With aging, there is a decrease in activity of complexes III and IV, which account for the decrease in respiration. Furthermore, aging decreases mitochondrial content among the myofibrils. The end result is that in the interfibrillar area, there is ≈50% decrease in mitochondrial function, affecting all substrates. The defective mitochondria persist in the aged heart, leading to enhanced oxidant production and oxidative injury and the activation of oxidant signaling for cell death. Aging defects in mitochondria represent new therapeutic targets, whether by manipulation of the mitochondrial proteome, modulation of electron transport, activation of biogenesis or mitophagy, or the regulation of mitochondrial fission and fusion. These mechanisms provide new ways to attenuate cardiac disease in elders by preemptive treatment of age-related defects, in contrast to the treatment of disease-induced dysfunction.
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Affiliation(s)
- Edward J Lesnefsky
- From the Division of Cardiology, Department of Medicine, Pauley Heart Center (E.J.L, Q.C.), Departments of Biochemistry and Molecular Biology and Physiology and Biophsyics (E.J.L.), Virginia Commonwealth University, Richmond, VA (E.J.L., Q.C.); Medical Service, McGuire Veterans Affairs Medical Center, Richmond, VA (E.J.L.); and Departments of Pharmacology (C.L.H.) and Medicine (E.J.L., C.L.H.), Center for Mitochondrial Disease (C.L.H.), Case Western Reserve University, School of Medicine, Cleveland, OH
| | - Qun Chen
- From the Division of Cardiology, Department of Medicine, Pauley Heart Center (E.J.L, Q.C.), Departments of Biochemistry and Molecular Biology and Physiology and Biophsyics (E.J.L.), Virginia Commonwealth University, Richmond, VA (E.J.L., Q.C.); Medical Service, McGuire Veterans Affairs Medical Center, Richmond, VA (E.J.L.); and Departments of Pharmacology (C.L.H.) and Medicine (E.J.L., C.L.H.), Center for Mitochondrial Disease (C.L.H.), Case Western Reserve University, School of Medicine, Cleveland, OH
| | - Charles L Hoppel
- From the Division of Cardiology, Department of Medicine, Pauley Heart Center (E.J.L, Q.C.), Departments of Biochemistry and Molecular Biology and Physiology and Biophsyics (E.J.L.), Virginia Commonwealth University, Richmond, VA (E.J.L., Q.C.); Medical Service, McGuire Veterans Affairs Medical Center, Richmond, VA (E.J.L.); and Departments of Pharmacology (C.L.H.) and Medicine (E.J.L., C.L.H.), Center for Mitochondrial Disease (C.L.H.), Case Western Reserve University, School of Medicine, Cleveland, OH.
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O'Mealey GB, Berry WL, Plafker SM. Sulforaphane is a Nrf2-independent inhibitor of mitochondrial fission. Redox Biol 2016; 11:103-110. [PMID: 27889639 PMCID: PMC5126150 DOI: 10.1016/j.redox.2016.11.007] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Revised: 11/03/2016] [Accepted: 11/04/2016] [Indexed: 01/14/2023] Open
Abstract
The KEAP1-Nrf2-ARE antioxidant system is a principal means by which cells respond to oxidative and xenobiotic stresses. Sulforaphane (SFN), an electrophilic isothiocyanate derived from cruciferous vegetables, activates the KEAP1-Nrf2-ARE pathway and has become a molecule-of-interest in the treatment of diseases in which chronic oxidative stress plays a major etiological role. We demonstrate here that the mitochondria of cultured, human retinal pigment epithelial (RPE-1) cells treated with SFN undergo hyperfusion that is independent of both Nrf2 and its cytoplasmic inhibitor KEAP1. Mitochondrial fusion has been reported to be cytoprotective by inhibiting pore formation in mitochondria during apoptosis, and consistent with this, we show Nrf2-independent, cytoprotection of SFN-treated cells exposed to the apoptosis-inducer, staurosporine. Mechanistically, SFN mitigates the recruitment and/or retention of the soluble fission factor Drp1 to mitochondria and to peroxisomes but does not affect overall Drp1 abundance. These data demonstrate that the beneficial properties of SFN extend beyond activation of the KEAP1-Nrf2-ARE system and warrant further interrogation given the current use of this agent in multiple clinical trials.
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Affiliation(s)
- Gary B O'Mealey
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States
| | - William L Berry
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
| | - Scott M Plafker
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States.
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Jones IV AR, Meshulam T, Oliveira MF, Burritt N, Corkey BE. Extracellular Redox Regulation of Intracellular Reactive Oxygen Generation, Mitochondrial Function and Lipid Turnover in Cultured Human Adipocytes. PLoS One 2016; 11:e0164011. [PMID: 27741233 PMCID: PMC5065187 DOI: 10.1371/journal.pone.0164011] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Accepted: 09/19/2016] [Indexed: 12/04/2022] Open
Abstract
Background Many tissues play an important role in metabolic homeostasis and the development of diabetes and obesity. We hypothesized that the circulating redox metabolome is a master metabolic regulatory system that impacts all organs and modulates reactive oxygen species (ROS) production, lipid peroxidation, energy production and changes in lipid turnover in many cells including adipocytes. Methods Differentiated human preadipocytes were exposed to the redox couples, lactate (L) and pyruvate (P), β–hydroxybutyrate (βOHB) and acetoacetate (Acoc), and the thiol-disulfides cysteine/ cystine (Cys/CySS) and GSH/GSSG for 1.5–4 hours. ROS measurements were done with CM-H2DCFDA. Lipid peroxidation (LPO) was assessed by a modification of the thiobarbituric acid method. Lipolysis was measured as glycerol release. Lipid synthesis was measured as 14C-glucose incorporated into lipid. Respiration was assessed using the SeaHorse XF24 analyzer and the proton leak was determined from the difference in respiration with oligomycin and antimycin A. Results Metabolites with increasing oxidation potentials (GSSG, CySS, Acoc) increased adipocyte ROS. In contrast, P caused a decrease in ROS compared with L. Acoc also induced a significant increase in both LPO and lipid synthesis. L and Acoc increased lipolysis. βOHB increased respiration, mainly due to an increased proton leak. GSSG, when present throughout 14 days of differentiation significantly increased fat accumulation, but not when added later. Conclusions We demonstrated that in human adipocytes changes in the external redox state impacted ROS production, LPO, energy efficiency, lipid handling, and differentiation. A more oxidized state generally led to increased ROS, LPO and lipid turnover and more reduction led to increased respiration and a proton leak. However, not all of the redox couples were the same suggesting compartmentalization. These data are consistent with the concept of the circulating redox metabolome as a master metabolic regulatory system.
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Affiliation(s)
- Albert R. Jones IV
- Obesity Research Center, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Tova Meshulam
- Obesity Research Center, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Marcus F. Oliveira
- Obesity Research Center, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America
- Laboratório de Bioquímica de Resposta ao Estresse, Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro, Brazil
| | - Nathan Burritt
- Obesity Research Center, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Barbara E. Corkey
- Obesity Research Center, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America
- * E-mail:
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Porporato PE, Payen VL, Baselet B, Sonveaux P. Metabolic changes associated with tumor metastasis, part 2: Mitochondria, lipid and amino acid metabolism. Cell Mol Life Sci 2016; 73:1349-63. [PMID: 26646069 PMCID: PMC11108268 DOI: 10.1007/s00018-015-2100-2] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Revised: 11/16/2015] [Accepted: 11/23/2015] [Indexed: 12/13/2022]
Abstract
Metabolic alterations are a hallmark of cancer controlling tumor progression and metastasis. Among the various metabolic phenotypes encountered in tumors, this review focuses on the contributions of mitochondria, lipid and amino acid metabolism to the metastatic process. Tumor cells require functional mitochondria to grow, proliferate and metastasize, but shifts in mitochondrial activities confer pro-metastatic traits encompassing increased production of mitochondrial reactive oxygen species (mtROS), enhanced resistance to apoptosis and the increased or de novo production of metabolic intermediates of the TCA cycle behaving as oncometabolites, including succinate, fumarate, and D-2-hydroxyglutarate that control energy production, biosynthesis and the redox state. Lipid metabolism and the metabolism of amino acids, such as glutamine, glutamate and proline are also currently emerging as focal control points of cancer metastasis.
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Affiliation(s)
- Paolo E Porporato
- Pole of Pharmacology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), Avenue Emmanuel Mounier 52, box B1.53.09, 1200, Brussels, Belgium
| | - Valéry L Payen
- Pole of Pharmacology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), Avenue Emmanuel Mounier 52, box B1.53.09, 1200, Brussels, Belgium
| | - Bjorn Baselet
- Pole of Pharmacology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), Avenue Emmanuel Mounier 52, box B1.53.09, 1200, Brussels, Belgium
- Radiobiology Unit, Belgian Nuclear Research Centre, SCK·CEN, 2400 Mol, Belgium
| | - Pierre Sonveaux
- Pole of Pharmacology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), Avenue Emmanuel Mounier 52, box B1.53.09, 1200, Brussels, Belgium.
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An ERp57-mediated disulphide exchange promotes the interaction between Burkholderia cenocepacia and epithelial respiratory cells. Sci Rep 2016; 6:21140. [PMID: 26879174 PMCID: PMC4754759 DOI: 10.1038/srep21140] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Accepted: 01/19/2016] [Indexed: 01/29/2023] Open
Abstract
Previous studies have demonstrated that extracellular glutathione reduces the ability of the Cystic Fibrosis pathogen Burkholderia cenocepacia to infect primary or immortalized epithelial respiratory cells. We report here that the adhesion and invasion ability of B. cenocepacia is limited also by thiol-oxidizing and disulphide-reducing agents and by protein disulfide isomerase (PDI) inhibitors. PDI inhibitors also reduce the proinflammatory response elicited by cells in response to Burkholderia. These findings indicate that a membrane-associated PDI catalyzes thiol/disulphide exchange reactions which favor bacterial infection. The combined use of selective PDI inhibitors, RNA silencing and specific antibodies identified ERp57 as a major PDI involved in the interaction between B. cenocepacia and epithelial cells. This study contributes to the elucidation of the Burkholderia pathogenic mechanisms by showing that this microorganism exploits a membrane-associated host protein to infect epithelial cells and identifies ERp57 as a putative pharmacological target for the treatment of Burkholderia lung infections.
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Yin F, Sancheti H, Liu Z, Cadenas E. Mitochondrial function in ageing: coordination with signalling and transcriptional pathways. J Physiol 2015; 594:2025-42. [PMID: 26293414 DOI: 10.1113/jp270541] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2015] [Accepted: 08/13/2015] [Indexed: 12/14/2022] Open
Abstract
Mitochondrial dysfunction entailing decreased energy-transducing capacity and perturbed redox homeostasis is an early and sometimes initiating event in ageing and age-related disorders involving tissues with high metabolic rate such as brain, liver and heart. In the central nervous system (CNS), recent findings from our and other groups suggest that the mitochondrion-centred hypometabolism is a key feature of ageing brains and Alzheimer's disease. This hypometabolic state is manifested by lowered neuronal glucose uptake, metabolic shift in the astrocytes, and alternations in mitochondrial tricarboxylic acid cycle function. Similarly, in liver and adipose tissue, mitochondrial capacity around glucose and fatty acid metabolism and thermogenesis is found to decline with age and is implicated in age-related metabolic disorders such as obesity and type 2 diabetes mellitus. These mitochondrion-related disorders in peripheral tissues can impact on brain functions through metabolic, hormonal and inflammatory signals. At the cellular level, studies in CNS and non-CNS tissues support the notion that instead of being viewed as autonomous organelles, mitochondria are part of a dynamic network with close interactions with other cellular components through energy- or redox-sensitive cytosolic kinase signalling and transcriptional pathways. Hence, it would be critical to further understand the molecular mechanisms involved in the communication between mitochondria and the rest of the cell. Therapeutic strategies that effectively preserves or improve mitochondrial function by targeting key component of these signalling cascades could represent a novel direction for numerous mitochondrion-implicated, age-related disorders.
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Affiliation(s)
- Fei Yin
- Pharmacology & Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90089-9121, USA
| | - Harsh Sancheti
- Pharmacology & Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90089-9121, USA
| | - Zhigang Liu
- Pharmacology & Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90089-9121, USA
| | - Enrique Cadenas
- Pharmacology & Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90089-9121, USA
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Böhmert L, Niemann B, Lichtenstein D, Juling S, Lampen A. Molecular mechanism of silver nanoparticles in human intestinal cells. Nanotoxicology 2015; 9:852-60. [PMID: 25997095 DOI: 10.3109/17435390.2014.980760] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Silver nanoparticles are used in consumer products like food contact materials, drinking water technologies and supplements, due to their antimicrobial properties. This leads to an oral uptake and exposure of intestinal cells. In contrast to other studies we found no apoptosis induction by surfactant-coated silver nanoparticles in the intestinal cell model Caco-2 in a previous study, although the particles induced oxidative stress, morphological changes and cell death. Therefore, this study aimed to analyze the molecular mechanism of silver nanoparticles in Caco-2 cells. We used global gene expression profiling in differentiated Caco-2 cells, supported by verification of the microarray data by quantitative real-time RT-PCR and microscopic analysis, impedance measurements and assays for apoptosis and oxidative stress. Our results revealed that surfactant-coated silver nanoparticles probably affect the cells by outside-in signaling. They induce oxidative stress and have an influence on canonical pathways related to FAK, ILK, ERK, MAPK, integrins and adherence and tight junctions, thereby inducing transcription factors like AP1, NFkB and NRF2, which mediate cellular reactions in response to oxidative stress and metal ions and induce changes in the cytoskeleton and cell-cell and cell-matrix contacts. The present data confirm the absence of apoptotic cell death. Non-apoptotic, necrotic cell death, especially in the intestine, can cause inflammation and influence the mucosal immune response.
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Affiliation(s)
- Linda Böhmert
- a Department Food Safety , Federal Institute for Risk Assessment , Berlin , Germany
| | - Birgit Niemann
- a Department Food Safety , Federal Institute for Risk Assessment , Berlin , Germany
| | - Dajana Lichtenstein
- a Department Food Safety , Federal Institute for Risk Assessment , Berlin , Germany
| | - Sabine Juling
- a Department Food Safety , Federal Institute for Risk Assessment , Berlin , Germany
| | - Alfonso Lampen
- a Department Food Safety , Federal Institute for Risk Assessment , Berlin , Germany
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45
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Ghosh D, Brewer GJ. External cys/cySS redox state modification controls the intracellular redox state and neurodegeneration via Akt in aging and Alzheimer's disease mouse model neurons. J Alzheimers Dis 2015; 42:313-24. [PMID: 24844688 DOI: 10.3233/jad-132756] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The extracellular redox environment of cells is mainly set by the redox couple cysteine/cystine (cys/cySS) while intracellular redox is buffered by reduced/oxidized glutathione (GSH/GSSG), but controlled by NAD(P)H/NAD(P). With aging, the extracellular redox environment shifts in the oxidized direction beyond middle-age. Since aging is the primary risk factor in Alzheimer's disease (AD), here our aim was to determine if a reduced extracellular cys/cySS redox potential of cultured primary mouse neurons changes the intracellular redox environment, affects pAkt levels, and protects against neuron loss. A reductive shift in cys/cySS in the extracellular medium of neuron cultures from young (4 month) and old (21 month) neurons from non-transgenic) and triple transgenic AD-like mice (3xTg-AD) caused an increase in intracellular NAD(P)H and GSH levels along with lower reactive oxygen species levels. Importantly, the imposed reductive shift decreased neuron death markedly in the 21 month neurons of both genotypes. Moreover, a reduced cys/cySS redox state increased the pAkt/Akt ratio in 21 month aging and AD-like neurons that positively correlated with a decreased neuron loss. Our findings demonstrate that manipulating the extracellular redox environment toward a more reduced redox potential is neuroprotective in both aging and AD-like neurons and may be a powerful and pragmatic therapeutic tool in aging and age-related diseases like AD.
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Affiliation(s)
- Debolina Ghosh
- Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, USA
| | - Gregory J Brewer
- Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, USA Department of Neurology, University School of Medicine, Springfield, IL, USA Department of Biomedical Engineering, MIND Institute, University of California, Irvine, CA, USA
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46
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Nocito L, Kleckner AS, Yoo EJ, Jones IV AR, Liesa M, Corkey BE. The extracellular redox state modulates mitochondrial function, gluconeogenesis, and glycogen synthesis in murine hepatocytes. PLoS One 2015; 10:e0122818. [PMID: 25816337 PMCID: PMC4376787 DOI: 10.1371/journal.pone.0122818] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2014] [Accepted: 02/24/2015] [Indexed: 01/13/2023] Open
Abstract
Circulating redox state changes, determined by the ratio of reduced/oxidized pairs of different metabolites, have been associated with metabolic diseases. However, the pathogenic contribution of these changes and whether they modulate normal tissue function is unclear. As alterations in hepatic gluconeogenesis and glycogen metabolism are hallmarks that characterize insulin resistance and type 2 diabetes, we tested whether imposed changes in the extracellular redox state could modulate these processes. Thus, primary hepatocytes were treated with different ratios of the following physiological extracellular redox couples: β-hydroxybutyrate (βOHB)/acetoacetate (Acoc), reduced glutathione (GSH)/oxidized glutathione (GSSG), and cysteine/cystine. Exposure to a more oxidized ratio via extracellular βOHB/Acoc, GSH/GSSG, and cysteine/cystine in hepatocytes from fed mice increased intracellular hydrogen peroxide without causing oxidative damage. On the other hand, addition of more reduced ratios of extracellular βOHB/Acoc led to increased NAD(P)H and maximal mitochondrial respiratory capacity in hepatocytes. Greater βOHB/Acoc ratios were also associated with decreased β-oxidation, as expected with enhanced lipogenesis. In hepatocytes from fasted mice, a more extracellular reduced state of βOHB/Acoc led to increased alanine-stimulated gluconeogenesis and enhanced glycogen synthesis capacity from added glucose. Thus, we demonstrated for the first time that the extracellular redox state regulates the major metabolic functions of the liver and involves changes in intracellular NADH, hydrogen peroxide, and mitochondrial respiration. Because redox state in the blood can be communicated to all metabolically sensitive tissues, this work confirms the hypothesis that circulating redox state may be an important regulator of whole body metabolism and contribute to alterations associated with metabolic diseases.
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Affiliation(s)
- Laura Nocito
- Department of Medicine, Boston University, Boston, Massachusetts, United States of America
| | - Amber S. Kleckner
- Department of Medicine, Boston University, Boston, Massachusetts, United States of America
| | - Elsia J. Yoo
- Department of Medicine, Boston University, Boston, Massachusetts, United States of America
| | - Albert R. Jones IV
- Department of Medicine, Boston University, Boston, Massachusetts, United States of America
| | - Marc Liesa
- Department of Medicine, Boston University, Boston, Massachusetts, United States of America
| | - Barbara E. Corkey
- Department of Medicine, Boston University, Boston, Massachusetts, United States of America
- * E-mail:
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47
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Xie Z, Xia S, Qiao Y, Shi Y, Le G. Effect of GABA on oxidative stress in the skeletal muscles and plasma free amino acids in mice fed high-fat diet. J Anim Physiol Anim Nutr (Berl) 2014; 99:492-500. [DOI: 10.1111/jpn.12254] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2013] [Accepted: 08/18/2014] [Indexed: 12/15/2022]
Affiliation(s)
- Z.X. Xie
- The State Key Laboratory of Food Science and Technology; School of Food Science and Technology; Jiangnan University; Wuxi China
| | - S.F. Xia
- The State Key Laboratory of Food Science and Technology; School of Food Science and Technology; Jiangnan University; Wuxi China
| | - Y. Qiao
- The State Key Laboratory of Food Science and Technology; School of Food Science and Technology; Jiangnan University; Wuxi China
| | - Y.H. Shi
- The State Key Laboratory of Food Science and Technology; School of Food Science and Technology; Jiangnan University; Wuxi China
| | - G.W. Le
- The State Key Laboratory of Food Science and Technology; School of Food Science and Technology; Jiangnan University; Wuxi China
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48
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Kaludercic N, Deshwal S, Di Lisa F. Reactive oxygen species and redox compartmentalization. Front Physiol 2014; 5:285. [PMID: 25161621 PMCID: PMC4130307 DOI: 10.3389/fphys.2014.00285] [Citation(s) in RCA: 131] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2014] [Accepted: 07/11/2014] [Indexed: 01/01/2023] Open
Abstract
Reactive oxygen species (ROS) formation and signaling are of major importance and regulate a number of processes in physiological conditions. A disruption in redox status regulation, however, has been associated with numerous pathological conditions. In recent years it has become increasingly clear that oxidative and reductive modifications are confined in a spatio-temporal manner. This makes ROS signaling similar to that of Ca(2+) or other second messengers. Some subcellular compartments are more oxidizing (such as lysosomes or peroxisomes) whereas others are more reducing (mitochondria, nuclei). Moreover, although more reducing, mitochondria are especially susceptible to oxidation, most likely due to the high number of exposed thiols present in that compartment. Recent advances in the development of redox probes allow specific measurement of defined ROS in different cellular compartments in intact living cells or organisms. The availability of these tools now allows simultaneous spatio-temporal measurements and correlation between ROS generation and organelle and/or cellular function. The study of ROS compartmentalization and microdomains will help elucidate their role in physiology and disease. Here we will examine redox probes currently available and how ROS generation may vary between subcellular compartments. Furthermore, we will discuss ROS compartmentalization in physiological and pathological conditions focusing our attention on mitochondria, since their vulnerability to oxidative stress is likely at the basis of several diseases.
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Affiliation(s)
- Nina Kaludercic
- Neuroscience Institute, National Research Council of Italy (CNR) Padova, Italy
| | - Soni Deshwal
- Department of Biomedical Sciences, University of Padova Padova, Italy
| | - Fabio Di Lisa
- Neuroscience Institute, National Research Council of Italy (CNR) Padova, Italy ; Department of Biomedical Sciences, University of Padova Padova, Italy
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49
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Ziady AG, Hansen J. Redox balance in cystic fibrosis. Int J Biochem Cell Biol 2014; 52:113-23. [PMID: 24657650 DOI: 10.1016/j.biocel.2014.03.006] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2014] [Revised: 02/28/2014] [Accepted: 03/11/2014] [Indexed: 11/30/2022]
Abstract
The homeostatic balance between oxidants and antioxidants in biological systems is known as redox balance, and is regulated by complex processes. Redox balance regulates many of the known cellular pathways and disease processes. The dysregulation of redox balance can lead to acute or long-term oxidative or reductive stresses that are associated with many of the abnormalities observed in cystic fibrosis (CF). Over the past 5 decades researchers have examined contributors to redox dysregulation, their molecular products, and their impact on ion transport, cell proliferation, inflammation, bacterial killing, and the metabolism of nucleic acids, proteins, and lipids in CF. CF patients exhibit elevated markers of oxidative stress when compared to non-CF healthy controls; however, whether the reported redox imbalance is sufficient to produce pathology has been controversial. In addition, comparisons between CF and non-CF disease controls have been lacking. To better understand the mechanisms which mediate the generation of oxidants and antioxidants in CF and the importance of their balance in effecting oxidative or reductive stress, we will review the determinants of redox balance in the blood, lumen, and cellular compartments. From the perspective of methodological application, we will focus on the approaches most often used to study oxidant and antioxidants in CF, including biochemical, proteomic, metabolomic, and lipidomic studies, with a discussion of the few transcriptomic analyses that predict changes in the expression of regulators of redox. Finally, we will discuss the utility of oxidants and antioxidants as biomarkers of disease and the use of antioxidant therapy in CF.
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Affiliation(s)
- Assem G Ziady
- Department of Pediatrics, Emory University, Atlanta, GA 30322, USA; Children's Healthcare of Atlanta, Atlanta, GA, USA.
| | - Jason Hansen
- Department of Pediatrics, Emory University, Atlanta, GA 30322, USA
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50
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Li Z, Dong X, Zhang J, Zeng G, Zhao H, Liu Y, Qiu R, Mo L, Ye Y. Formononetin protects TBI rats against neurological lesions and the underlying mechanism. J Neurol Sci 2014; 338:112-7. [PMID: 24411660 DOI: 10.1016/j.jns.2013.12.027] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2013] [Revised: 12/07/2013] [Accepted: 12/17/2013] [Indexed: 01/01/2023]
Abstract
Traumatic brain injury (TBI) is a major cause of disability or death worldwide, especially in the young. Thus, effective medication with few side effects needs to be developed. This work aimed to explore the potential benefits of formononetin (FN) on TBI rodent model and to discuss the regarding mechanism. These findings showed that FN effectively increased the activities of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) in brain tissue of TBI rats (P<0.01), while it reduced intracephalic malonaldehyde (MDA), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) concentrations (P<0.01). Meanwhile, the hydrocephalus in the TBI rat was alleviated, and the injured nerve cell of the lesioned brain was reduced as showed in hematoxylin-eosin (HE) staining assay. In addition, the endogenous mRNA level of cyclooxygenase-2 (COX-2) in the brain of the TBI rat was significantly down-regulated (P<0.01). Furthermore, the protein expression of nuclear factor E2-related factor 2 (Nrf2) was effectively up-regulated (P<0.01). Taken together, we conclude that formononetin mediates the promising anti-TBI effects against neurocyte damage, which the underlying mechanisms are associated with inhibiting intracephalic inflammatory response and oxidative stress for neuroprotection.
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Affiliation(s)
- Zhengzhao Li
- Emergency Department, Western Hospital, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530007, PR China
| | - Xianhong Dong
- Department of Physiology and Neurobiology, Xinxiang Medical University, Xinxiang 453003, PR China
| | - Jianfeng Zhang
- Emergency Department, Western Hospital, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530007, PR China
| | - Guang Zeng
- Emergency Department, Western Hospital, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530007, PR China
| | - Huimin Zhao
- Emergency Department, Western Hospital, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530007, PR China
| | - Yun Liu
- Spine and Osteopathy Surgery Division, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, PR China
| | - Rubiao Qiu
- Guangxi Matemal and Child Health Hospital, Nanning, Guangxi Zhuang Autonomous Region 530003, PR China
| | - Linjian Mo
- Institute of Urology and Nephrology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, PR China
| | - Yu Ye
- Emergency Department, Western Hospital, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530007, PR China.
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