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1
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Peng B, Wang Y, Zhang H. Mitonuclear Communication in Stem Cell Function. Cell Prolif 2025; 58:e13796. [PMID: 39726221 PMCID: PMC12099226 DOI: 10.1111/cpr.13796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 11/25/2024] [Accepted: 12/14/2024] [Indexed: 12/28/2024] Open
Abstract
Mitochondria perform multiple functions within the cell, including the production of ATP and a great deal of metabolic intermediates, while also contributing to the cellular stress response. The majority of mitochondrial proteins are encoded by nuclear genomes, highlighting the importance of mitonuclear communication for sustaining mitochondrial homeostasis and functional. As a crucial part of the intracellular signalling network, mitochondria can impact stem cell fate determinations. Considering the essential function of stem cells in tissue maintenance, regeneration and aging, it is important to understand how mitochondria influence stem cell fate. This review explores the significant roles of mitonuclear communication and mitochondrial proteostasis, highlighting their influence on stem cells. We also examine how mitonuclear interactions contribute to cellular homeostasis, stem cell therapies, and the potential for extending lifespan.
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Affiliation(s)
- Baozhou Peng
- Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
- The Department of Histology and Embryology, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
| | - Yaning Wang
- Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
- The Department of Histology and Embryology, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
| | - Hongbo Zhang
- Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
- The Department of Histology and Embryology, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
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2
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Yamasaki H, Itoh RD, Mizumoto KB, Yoshida YS, Otaki JM, Cohen MF. Spatiotemporal Characteristics Determining the Multifaceted Nature of Reactive Oxygen, Nitrogen, and Sulfur Species in Relation to Proton Homeostasis. Antioxid Redox Signal 2025; 42:421-441. [PMID: 38407968 DOI: 10.1089/ars.2023.0544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/28/2024]
Abstract
Significance: Reactive oxygen species (ROS), reactive nitrogen species (RNS), and reactive sulfur species (RSS) act as signaling molecules, regulating gene expression, enzyme activity, and physiological responses. However, excessive amounts of these molecular species can lead to deleterious effects, causing cellular damage and death. This dual nature of ROS, RNS, and RSS presents an intriguing conundrum that calls for a new paradigm. Recent Advances: Recent advancements in the study of photosynthesis have offered significant insights at the molecular level and with high temporal resolution into how the photosystem II oxygen-evolving complex manages to prevent harmful ROS production during the water-splitting process. These findings suggest that a dynamic spatiotemporal arrangement of redox reactions, coupled with strict regulation of proton transfer, is crucial for minimizing unnecessary ROS formation. Critical Issues: To better understand the multifaceted nature of these reactive molecular species in biology, it is worth considering a more holistic view that combines ecological and evolutionary perspectives on ROS, RNS, and RSS. By integrating spatiotemporal perspectives into global, cellular, and biochemical events, we discuss local pH or proton availability as a critical determinant associated with the generation and action of ROS, RNS, and RSS in biological systems. Future Directions: The concept of localized proton availability will not only help explain the multifaceted nature of these ubiquitous simple molecules in diverse systems but also provide a basis for new therapeutic strategies to manage and manipulate these reactive species in neural disorders, pathogenic diseases, and antiaging efforts.
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Affiliation(s)
- Hideo Yamasaki
- Faculty of Science, University of the Ryukyus, Okinawa, Japan
| | - Ryuuichi D Itoh
- Faculty of Science, University of the Ryukyus, Okinawa, Japan
| | | | - Yuki S Yoshida
- Faculty of Science, University of the Ryukyus, Okinawa, Japan
| | - Joji M Otaki
- Faculty of Science, University of the Ryukyus, Okinawa, Japan
| | - Michael F Cohen
- University of California Cooperative Extension, Santa Clara County, San Jose, California, USA
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3
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Liu S, Liang W, Wu J, Bao E, Tang S. Alleviation of lipopolysaccharide-induced heart inflammation in poultry treated with carnosic acid via the NF-κB and MAPK pathways. J Anim Sci 2025; 103:skae373. [PMID: 39657120 PMCID: PMC11781199 DOI: 10.1093/jas/skae373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 12/05/2024] [Indexed: 12/17/2024] Open
Abstract
In intensive poultry farming, environmental stress, pathogen infections, and noise can negatively impact growth or cause sudden death, leading to economic losses. The prevalent use of antibiotics as feed additives to prevent diseases in broilers has raised concerns about antibiotic resistance and highlighted the need for safer and more effective alternatives. Carnosic acid (CA), a bioactive compound derived from rosemary, exhibits notable pharmacological properties, including anti-inflammatory and antioxidant effects. This study investigates CA's efficacy in mitigating lipopolysaccharide (LPS)-induced heart inflammation in broilers. Broilers were pretreated with CA at varying doses (20, 40, and 80 mg/kg) for 7 days then exposed to LPS (200 mg/kg) for 24h to induce an inflammatory response. LPS treatment increased the levels of the cardiac damage markers creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) and inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), and inducible nitric oxide synthase (iNOS), but these effects were markedly decreased in CA-pretreated poultry. Histopathological analysis indicated that CA mitigated myocardial fiber rupture and inflammatory cell infiltration. Immunohistochemistry showed that CA sustained high expression levels of the protective protein crystallin alpha B (CRYAB), the expression of which was reduced by LPS. Mechanistic studies demonstrated that CA regulates key inflammatory signaling pathways via inhibiting LPS-induced activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) by reducing the phosphorylation of p65 and inhibitor of nuclear factor kappa-B alpha (IκBα). Additionally, CA attenuated mitogen-activated protein kinase (MAPK) pathway activation, as evidenced by decreased phosphorylation of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38 in the CA-treated groups compared to the LPS-only groups. These findings suggest that CA exerts a protective effect against LPS-induced cardiac inflammation by enhancing CRYAB expression and modulating the NF-κB and MAPK pathways. Importantly, the findings emphasize CA's potential as a natural feed additive to enhance cardiac health in poultry and present a promising alternative to conventional antibiotics in livestock management. Further research is needed to investigate its broader applications in animal health and other inflammatory conditions.
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Affiliation(s)
- Sirui Liu
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Wanqing Liang
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Jiaxin Wu
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Endong Bao
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Shu Tang
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
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4
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Wang K, Liu Y, Li S, Zhao N, Qin F, Tao Y, Song Z. Unveiling the therapeutic potential and mechanisms of stanniocalcin-1 in retinal degeneration. Surv Ophthalmol 2025; 70:106-120. [PMID: 39270826 DOI: 10.1016/j.survophthal.2024.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 07/30/2024] [Accepted: 08/16/2024] [Indexed: 09/15/2024]
Abstract
Retinal degeneration (RD) is a group of ocular diseases characterized by progressive photoreceptor apoptosis and visual impairment. Mitochondrial malfunction, excessive oxidative stress, and chronic activation of neuroglia collectively contribute to the development of RD. Currently, there is a lack of efficacious therapeutic interventions for RD. Stanniocalcin-1 (STC-1) is a promising candidate molecule to decelerate photoreceptor cell death. STC-1 is a secreted calcium/phosphorus regulatory protein that exerts diverse protective effects. Accumulating evidence suggests that STC-1 protects retinal cells from ischemic injury, oxidative stress, and excessive apoptosis through enhancing the expression of uncoupling protein-2 (UCP-2). Furthermore, STC-1 exerts its antiinflammatory effects by inhibiting the activation of microglia and macrophages, as well as the synthesis and secretion of proinflammatory cytokines, such as TNF-α, IL-1, and IL-6. By employing these mechanisms, STC-1 effectively shields the retinal photoreceptors and optic nerve, thereby slowing down the progression of RD. We summarize the STC-1-mediated therapeutic effects on the degenerating retina, with a particular focus on its underlying mechanisms. These findings highlight that STC-1 may act as a versatile molecule to treat degenerative retinopathy. Further research on STC-1 is imperative to establish optimal protocols for its clinical use.
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Affiliation(s)
- Kexin Wang
- Department of Ophthalmology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Henan Eye Institute, Henan Eye Hospital, Zhengzhou 450003, China
| | - Yashuang Liu
- Department of Ophthalmology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Henan Eye Institute, Henan Eye Hospital, Zhengzhou 450003, China
| | - Siyu Li
- College of Medicine, Zhengzhou University, Zhengzhou 450001, China
| | - Na Zhao
- College of Medicine, Zhengzhou University, Zhengzhou 450001, China
| | - Fangyuan Qin
- Department of Ophthalmology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Henan Eye Institute, Henan Eye Hospital, Zhengzhou 450003, China
| | - Ye Tao
- Department of Ophthalmology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Henan Eye Institute, Henan Eye Hospital, Zhengzhou 450003, China.
| | - Zongming Song
- Department of Ophthalmology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Henan Eye Institute, Henan Eye Hospital, Zhengzhou 450003, China.
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Sakamoto I, Shibuya S, Nojiri H, Takeno K, Nishimune H, Yaku K, Nakagawa T, Ishijima M, Shimizu T. Mitochondrial Redox Status Regulates Glycogen Metabolism via Glycogen Phosphorylase Activity. Antioxidants (Basel) 2024; 13:1421. [PMID: 39594562 PMCID: PMC11590902 DOI: 10.3390/antiox13111421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 11/11/2024] [Accepted: 11/15/2024] [Indexed: 11/28/2024] Open
Abstract
Mitochondria and glycogen are co-distributed in skeletal muscles to regulate the metabolic status. Mitochondria are also redox centers that regulate the muscle function during exercise. However, the pathophysiological relationship between the mitochondrial redox status and glycogen metabolism in the muscle remains unclear. In the present study, we examined the pathological effects of mitochondrial dysfunction induced by mitochondrial superoxide dismutase (SOD2) depletion on glycogen metabolism. We found that muscle glycogen was significantly accumulated in association with motor dysfunction in mice with a muscle-specific SOD2 deficiency. Muscle glycogen phosphorylase (GP-M) activity, which is a key enzyme for glycogen degradation at times when energy is needed (e.g., during exercise), was significantly decreased in the mutant muscle. Moreover, the GP-M activity on normal muscle sections decreased after treatment with paraquat, a superoxide generator. In contrast, treatment with antioxidants reversed the GP-M activity and motor disturbance of the mutant mice, indicating that GP-M activity was reversibly regulated by the redox balance. These results demonstrate that the maintenance of the mitochondrial redox balance regulates glycogen metabolism via GP-M activity.
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Affiliation(s)
- Ikko Sakamoto
- Department of Medicine for Orthopaedics and Motor Organ, Juntendo University Graduate School of Medicine, Tokyo 113-0034, Japan; (I.S.); (H.N.); (M.I.)
| | - Shuichi Shibuya
- Aging Stress Response Research Project Team, National Center for Geriatrics and Gerontology, Aichi 474-8511, Japan;
- Department of Regenerative Medicine, Faculty of Pharmacy, Sanyo-Onoda City University, Yamaguchi 756-0884, Japan
| | - Hidetoshi Nojiri
- Department of Medicine for Orthopaedics and Motor Organ, Juntendo University Graduate School of Medicine, Tokyo 113-0034, Japan; (I.S.); (H.N.); (M.I.)
| | - Kotaro Takeno
- Laboratory of Neurobiology of Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo 173-0015, Japan; (K.T.); (H.N.)
| | - Hiroshi Nishimune
- Laboratory of Neurobiology of Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo 173-0015, Japan; (K.T.); (H.N.)
- Department of Applied Biological Science, Tokyo University of Agriculture and Technology, Tokyo 183-8538, Japan
| | - Keisuke Yaku
- Department of Molecular and Medical Pharmacology, Faculty of Medicine, University of Toyama, Toyama 930-8555, Japan; (K.Y.); (T.N.)
| | - Takashi Nakagawa
- Department of Molecular and Medical Pharmacology, Faculty of Medicine, University of Toyama, Toyama 930-8555, Japan; (K.Y.); (T.N.)
| | - Muneaki Ishijima
- Department of Medicine for Orthopaedics and Motor Organ, Juntendo University Graduate School of Medicine, Tokyo 113-0034, Japan; (I.S.); (H.N.); (M.I.)
| | - Takahiko Shimizu
- Aging Stress Response Research Project Team, National Center for Geriatrics and Gerontology, Aichi 474-8511, Japan;
- Department of Food and Reproductive Function Advanced Research, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
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Masenga SK, Desta S, Hatcher M, Kirabo A, Lee DL. How PPAR-alpha mediated inflammation may affect the pathophysiology of chronic kidney disease. Curr Res Physiol 2024; 8:100133. [PMID: 39665027 PMCID: PMC11629568 DOI: 10.1016/j.crphys.2024.100133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 10/03/2024] [Accepted: 11/12/2024] [Indexed: 12/13/2024] Open
Abstract
Chronic kidney disease (CKD) is a major risk factor for death in adults. Inflammation plays a role in the pathogenesis of CKD, but the mechanisms are poorly understood. Peroxisome proliferator-activated receptor alpha (PPAR-α) is a nuclear receptor and one of the three members (PPARα, PPARβ/δ, and PPARγ) of the PPARs that plays an important role in ameliorating pathological processes that accelerate acute and chronic kidney disease. Although other PPARs members are well studied, the role of PPAR-α is not well described and its role in inflammation-mediated chronic disease is not clear. Herein, we review the role of PPAR-α in chronic kidney disease with implications for the immune system.
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Affiliation(s)
- Sepiso K. Masenga
- HAND Research Group, School of Medicine and Health Sciences, Mulungushi University, Livingstone Campus, Zambia
- Vanderbilt Institute for Global Health, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Selam Desta
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Physiology and Biophysics, College of Medicine, Howard University, Washington, DC, USA
| | - Mark Hatcher
- Department of Physiology and Biophysics, College of Medicine, Howard University, Washington, DC, USA
| | - Annet Kirabo
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Institute for Global Health, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Dexter L. Lee
- Department of Physiology and Biophysics, College of Medicine, Howard University, Washington, DC, USA
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7
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Skv M, Abraham SM, Eshwari O, Golla K, Jhelum P, Maity S, Komal P. Tremendous Fidelity of Vitamin D3 in Age-related Neurological Disorders. Mol Neurobiol 2024; 61:7211-7238. [PMID: 38372958 DOI: 10.1007/s12035-024-03989-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Accepted: 01/23/2024] [Indexed: 02/20/2024]
Abstract
Vitamin D3 (VD) is a secosteroid hormone and shows a pleiotropic effect in brain-related disorders where it regulates redox imbalance, inflammation, apoptosis, energy production, and growth factor synthesis. Vitamin D3's active metabolic form, 1,25-dihydroxy Vitamin D3 (1,25(OH)2D3 or calcitriol), is a known regulator of several genes involved in neuroplasticity, neuroprotection, neurotropism, and neuroinflammation. Multiple studies suggest that VD deficiency can be proposed as a risk factor for the development of several age-related neurological disorders. The evidence for low serum levels of 25-hydroxy Vitamin D3 (25(OH)D3 or calcidiol), the major circulating form of VD, is associated with an increased risk of Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), dementia, and cognitive impairment. Despite decades of evidence on low VD association with neurological disorders, the precise molecular mechanism behind its beneficial effect remains controversial. Here, we will be delving into the neurobiological importance of VD and discuss its benefits in different neuropsychiatric disorders. The focus will be on AD, PD, and HD as they share some common clinical, pathological, and epidemiological features. The central focus will be on the different attributes of VD in the aspect of its anti-oxidative, anti-inflammatory, anti-apoptotic, anti-cholinesterase activity, and psychotropic effect in different neurodegenerative diseases.
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Affiliation(s)
- Manjari Skv
- Department of Biological Sciences, Birla Institute of Technology and Science-Pilani (BITS-Pilani) Hyderabad campus, Shameerpet-Mandal, Hyderabad, Telangana, India
| | - Sharon Mariam Abraham
- Department of Biological Sciences, Birla Institute of Technology and Science-Pilani (BITS-Pilani) Hyderabad campus, Shameerpet-Mandal, Hyderabad, Telangana, India
| | - Omalur Eshwari
- Department of Biological Sciences, Birla Institute of Technology and Science-Pilani (BITS-Pilani) Hyderabad campus, Shameerpet-Mandal, Hyderabad, Telangana, India
| | - Kishore Golla
- Department of Biological Sciences, Birla Institute of Technology and Science-Pilani (BITS-Pilani) Hyderabad campus, Shameerpet-Mandal, Hyderabad, Telangana, India
| | - Priya Jhelum
- Centre for Research in Neuroscience and Brain Program, The Research Instituteof the, McGill University Health Centre , Montreal, QC, Canada
| | - Shuvadeep Maity
- Department of Biological Sciences, Birla Institute of Technology and Science-Pilani (BITS-Pilani) Hyderabad campus, Shameerpet-Mandal, Hyderabad, Telangana, India
| | - Pragya Komal
- Department of Biological Sciences, Birla Institute of Technology and Science-Pilani (BITS-Pilani) Hyderabad campus, Shameerpet-Mandal, Hyderabad, Telangana, India.
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8
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Waldeck-Weiermair M, Das AA, Covington TA, Yadav S, Kaynert J, Guo R, Balendran P, Thulabandu VR, Pandey AK, Spyropoulos F, Thomas DC, Michel T. An essential role for EROS in redox-dependent endothelial signal transduction. Redox Biol 2024; 73:103214. [PMID: 38805973 PMCID: PMC11153901 DOI: 10.1016/j.redox.2024.103214] [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: 04/29/2024] [Revised: 05/22/2024] [Accepted: 05/24/2024] [Indexed: 05/30/2024] Open
Abstract
The chaperone protein EROS ("Essential for Reactive Oxygen Species") was recently discovered in phagocytes. EROS was shown to regulate the abundance of the ROS-producing enzyme NADPH oxidase isoform 2 (NOX2) and to control ROS-mediated cell killing. Reactive oxygen species are important not only in immune surveillance, but also modulate physiological signaling responses in multiple tissues. The roles of EROS have not been previously explored in the context of oxidant-modulated cell signaling. Here we show that EROS plays a key role in ROS-dependent signal transduction in vascular endothelial cells. We used siRNA-mediated knockdown and developed CRISPR/Cas9 knockout of EROS in human umbilical vein endothelial cells (HUVEC), both of which cause a significant decrease in the abundance of NOX2 protein, associated with a marked decrease in RAC1, a small G protein that activates NOX2. Loss of EROS also attenuates receptor-mediated hydrogen peroxide (H2O2) and Ca2+ signaling, disrupts cytoskeleton organization, decreases cell migration, and promotes cellular senescence. EROS knockdown blocks agonist-modulated eNOS phosphorylation and nitric oxide (NO●) generation. These effects of EROS knockdown are strikingly similar to the alterations in endothelial cell responses that we previously observed following RAC1 knockdown. Proteomic analyses following EROS or RAC1 knockdown in endothelial cells showed that reduced abundance of these two distinct proteins led to largely overlapping effects on endothelial biological processes, including oxidoreductase, protein phosphorylation, and endothelial nitric oxide synthase (eNOS) pathways. These studies demonstrate that EROS plays a central role in oxidant-modulated endothelial cell signaling by modulating NOX2 and RAC1.
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Affiliation(s)
- Markus Waldeck-Weiermair
- Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA; Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstraße 6/6, 8010, Graz, Austria.
| | - Apabrita A Das
- Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA
| | - Taylor A Covington
- Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA
| | - Shambhu Yadav
- Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA
| | - Jonas Kaynert
- Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA
| | - Ruby Guo
- Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA
| | - Priyanga Balendran
- Cambridge Institute of Therapeutic Immunology & Infectious Disease, University of Cambridge, Puddicombe Way, Cambridge, CB2 0AW, UK
| | - Venkata Revanth Thulabandu
- Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA
| | - Arvind K Pandey
- Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA
| | - Fotios Spyropoulos
- Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA; Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA
| | - David C Thomas
- Cambridge Institute of Therapeutic Immunology & Infectious Disease, University of Cambridge, Puddicombe Way, Cambridge, CB2 0AW, UK.
| | - Thomas Michel
- Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA.
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9
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Valdivia A, Duran C, Lee M, Williams HC, Lee MY, San Martin A. Nox1-based NADPH oxidase regulates the Par protein complex activity to control cell polarization. Front Cell Dev Biol 2023; 11:1231489. [PMID: 37635877 PMCID: PMC10457011 DOI: 10.3389/fcell.2023.1231489] [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: 05/30/2023] [Accepted: 07/25/2023] [Indexed: 08/29/2023] Open
Abstract
Cell migration is essential for many biological and pathological processes. Establishing cell polarity with a trailing edge and forming a single lamellipodium at the leading edge of the cell is crucial for efficient directional cell migration and is a hallmark of mesenchymal cell motility. Lamellipodia formation is regulated by spatial-temporal activation of the small GTPases Rac and Cdc42 at the front edge, and RhoA at the rear end. At a molecular level, partitioning-defective (Par) protein complex comprising Par3, Par6, and atypical Protein Kinase (aPKC isoforms ζ and λ/ι) regulates front-rear axis polarization. At the front edge, integrin clustering activates Cdc42, prompting the formation of Par3/Par6/aPKC complexes to modulate MTOC positioning and microtubule stabilization. Consequently, the Par3/Par6/aPKC complex recruits Rac1-GEF Tiam to activate Rac1, leading to lamellipodium formation. At the rear end, RhoA-ROCK phosphorylates Par3 disrupting its interaction with Tiam and inactivating Rac1. RhoA activity at the rear end allows the formation of focal adhesions and stress fibers necessary to generate the traction forces that allow cell movement. Nox1-based NADPH oxidase is necessary for PDGF-induced migration in vitro and in vivo for many cell types, including fibroblasts and smooth muscle cells. Here, we report that Nox1-deficient cells failed to acquire a normal front-to-rear polarity, polarize MTOC, and form a single lamellipodium. Instead, these cells form multiple protrusions that accumulate Par3 and active Tiam. The exogenous addition of H2O2 rescues this phenotype and is associated with the hyperactivation of Par3, Tiam, and Rac1. Mechanistically, Nox1 deficiency induces the inactivation of PP2A phosphatase, leading to increased activation of aPKC. These results were validated in Nox1y/- primary mouse aortic smooth muscle cells (MASMCs), which also showed PP2A inactivation after PDGF-BB stimulation consistent with exacerbated activation of aPKC. Moreover, we evaluated the physiological relevance of this signaling pathway using a femoral artery wire injury model to generate neointimal hyperplasia. Nox1y/- mice showed increased staining for the inactive form of PP2A and increased signal for active aPKC, suggesting that PP2A and aPKC activities might contribute to reducing neointima formation observed in the arteries of Nox1y/- mice.
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Affiliation(s)
- Alejandra Valdivia
- Division of Cardiology, Department of Medicine, School of Medicine, Emory University, Atlanta, GA, United States
| | - Charity Duran
- Division of Cardiology, Department of Medicine, School of Medicine, Emory University, Atlanta, GA, United States
| | - Mingyoung Lee
- Division of Cardiology, Department of Medicine, School of Medicine, Emory University, Atlanta, GA, United States
| | - Holly C. Williams
- Division of Cardiology, Department of Medicine, School of Medicine, Emory University, Atlanta, GA, United States
| | - Moo-Yeol Lee
- Division of Cardiology, Department of Medicine, School of Medicine, Emory University, Atlanta, GA, United States
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University, Goyang, Republic of Korea
| | - Alejandra San Martin
- Division of Cardiology, Department of Medicine, School of Medicine, Emory University, Atlanta, GA, United States
- Institute of Biomedical Sciences, Faculty of Medicine and Faculty of Life Science, Universidad Andres Bello, Santiago, Chile
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10
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Ali F, Wang D, Cheng Y, Wu M, Saleem MZ, Wei L, Xie Y, Yan M, Chu J, Yang Y, Shen A, Peng J. Quercetin attenuates angiotensin II-induced proliferation of vascular smooth muscle cells and p53 pathway activation in vitro and in vivo. Biofactors 2023; 49:956-970. [PMID: 37296538 DOI: 10.1002/biof.1959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 04/23/2023] [Indexed: 06/12/2023]
Abstract
Quercetin is an essential flavonoid mostly found in herbal plants, fruits, and vegetables, which exhibits anti-hypertension properties. However, its pharmacological impact on angiotensin II (Ang II) induced the increase of blood pressure along with in-depth mechanism needs further exploration. The present study pointed out the anti-hypertensive role of quercetin and its comprehensive fundamental mechanisms. Our data showed that quercetin treatment substantially reduced the increase in blood pressure, pulse wave velocity, and aortic thickness of abdominal aorta in Ang II-infused C57BL/6 mice. RNA sequencing revealed that quercetin treatment reversed 464 differentially expressed transcripts in the abdominal aorta of Ang II-infused mice. Moreover, overlapping KEGG-enriched signaling pathways identified multiple common pathways between the comparison of Ang II versus control and Ang II + quercetin versus Ang II. Likewise, these pathways included cell cycle as well as p53 pathways. Transcriptome was further validated by immunohistochemistry, indicating that quercetin treatment significantly decreased the Ang II-induced expression of proliferating cell nuclear antigen (PCNA), cyclin-dependent kinase-4 (CDK4), and cyclin D1, while increased protein expression of p53, and p21 in abdominal aortic tissues of mice. In vitro, quercetin treatment meaningfully decreased the cell viability, arrested cell cycle at G0/G1 phase, and up-regulated the p53 and p21 proteins expression, as well as down-regulated the protein expression of cell cycle-related markers, for example, CDK4, cyclin D1 in Ang II stimulated vascular smooth muscle cells (VSMCs). This study addresses pharmacologic and mechanistic perspectives of quercetin against Ang-II-induced vascular injury and the increase of blood pressure.
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Affiliation(s)
- Farman Ali
- Clinical Research Institute, the Second Affiliated Hospital and Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
- Fujian Collaborative Innovation Center for Integrative Medicine in Prevention and Treatment of Major Chronic Cardiovascular Diseases, Fuzhou, Fujian, China
| | - Di Wang
- Clinical Research Institute, the Second Affiliated Hospital and Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
- Fujian Collaborative Innovation Center for Integrative Medicine in Prevention and Treatment of Major Chronic Cardiovascular Diseases, Fuzhou, Fujian, China
| | - Ying Cheng
- Clinical Research Institute, the Second Affiliated Hospital and Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
- Fujian Collaborative Innovation Center for Integrative Medicine in Prevention and Treatment of Major Chronic Cardiovascular Diseases, Fuzhou, Fujian, China
| | - Meizhu Wu
- Clinical Research Institute, the Second Affiliated Hospital and Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
- Fujian Collaborative Innovation Center for Integrative Medicine in Prevention and Treatment of Major Chronic Cardiovascular Diseases, Fuzhou, Fujian, China
| | - Muhammad Zubair Saleem
- Fujian Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University, Fuzhou, Fujian, China
| | - Lihui Wei
- Clinical Research Institute, the Second Affiliated Hospital and Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
- Fujian Collaborative Innovation Center for Integrative Medicine in Prevention and Treatment of Major Chronic Cardiovascular Diseases, Fuzhou, Fujian, China
- Center for Innovation and Transformation of Science and Technology, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
| | - Yi Xie
- Clinical Research Institute, the Second Affiliated Hospital and Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
- Fujian Collaborative Innovation Center for Integrative Medicine in Prevention and Treatment of Major Chronic Cardiovascular Diseases, Fuzhou, Fujian, China
| | - Mengchao Yan
- Clinical Research Institute, the Second Affiliated Hospital and Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
- Fujian Collaborative Innovation Center for Integrative Medicine in Prevention and Treatment of Major Chronic Cardiovascular Diseases, Fuzhou, Fujian, China
| | - Jiangfeng Chu
- Clinical Research Institute, the Second Affiliated Hospital and Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
- Fujian Collaborative Innovation Center for Integrative Medicine in Prevention and Treatment of Major Chronic Cardiovascular Diseases, Fuzhou, Fujian, China
| | - Yanyan Yang
- Clinical Research Institute, the Second Affiliated Hospital and Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
- Fujian Collaborative Innovation Center for Integrative Medicine in Prevention and Treatment of Major Chronic Cardiovascular Diseases, Fuzhou, Fujian, China
- Center for Innovation and Transformation of Science and Technology, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
| | - Aling Shen
- Clinical Research Institute, the Second Affiliated Hospital and Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
- Fujian Collaborative Innovation Center for Integrative Medicine in Prevention and Treatment of Major Chronic Cardiovascular Diseases, Fuzhou, Fujian, China
- Center for Innovation and Transformation of Science and Technology, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
| | - Jun Peng
- Clinical Research Institute, the Second Affiliated Hospital and Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
- Fujian Collaborative Innovation Center for Integrative Medicine in Prevention and Treatment of Major Chronic Cardiovascular Diseases, Fuzhou, Fujian, China
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11
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Wang C, Zhao R, Wang Z, Xu T, Huang P. Synthetic ditempolphosphatidylcholine liposome-like nanoparticles for anti-oxidative therapy of atherosclerosis. RSC Adv 2023; 13:16211-16221. [PMID: 37266511 PMCID: PMC10230271 DOI: 10.1039/d3ra01822a] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Accepted: 05/16/2023] [Indexed: 06/03/2023] Open
Abstract
Atherosclerosis (AS), a chronic inflammatory disease, is the leading cause of death worldwide. Anti-oxidative therapy has been developed for AS therapy in light of the critical role of ROS in pathogenesis of AS, but current anti-oxidants have exhibited limited outcomes in the clinic. Herein, new ROS-eliminating liposome-like NPs (Tempol-Lips) were assembled from synthetic lipids that covalently conjugated two Tempol molecules with phosphatidylcholine by esterification reaction. The obtained Tempol-Lips can be efficiently internalized into inflammatory macrophages and attenuated inflammation via scavenging overproduced intracellular ROS. After i.v. administration, Tempol-Lips with nanoscale character accumulated in the plaques of ApoE-/- mice through passive targeting and significantly inhibited the pathogenesis of AS, compared with those treated with control drugs. The therapeutic benefits of Tempol-Lips primarily are ascribed to the reduced local and systematic oxidative stress and inflammation. Preliminary studies in vivo further demonstrated Tempol-Lips were safe and biocompatible after long-term i.v. injection. Conclusively, Tempol-Lips can be developed as a novel anti-AS nanotherapy with potential translation in the clinic.
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Affiliation(s)
- Chunxiao Wang
- Department of Cardiology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University Yantai 264000 China
| | - Ruifu Zhao
- Department of Cardiology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University Yantai 264000 China
| | - Zhen Wang
- Department of Cardiology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University Yantai 264000 China
| | - Tingting Xu
- Department of Cardiology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University Yantai 264000 China
| | - Peng Huang
- Department of Cardiology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University Yantai 264000 China
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12
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Lu W, Lin Y, Haider N, Moly P, Wang L, Zhou W. Ginsenoside Rb1 protects human vascular smooth muscle cells against resistin-induced oxidative stress and dysfunction. Front Cardiovasc Med 2023; 10:1164547. [PMID: 37304947 PMCID: PMC10248054 DOI: 10.3389/fcvm.2023.1164547] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 05/05/2023] [Indexed: 06/13/2023] Open
Abstract
Resistin has been shown to play a key role in inducing vascular smooth muscle cells (VSMCs) malfunction in the atherosclerosis progression. Ginsenoside Rb1 is the main component of ginseng, which has been used for thousands of years and has been reported to have a powerful vascular protective effect. The aim of this study was to explore the protective effect of Rb1 on VSMCs dysfunction induced by resistin. In the presence or absence of Rb1, human coronary artery smooth muscle cells (HCASMC) were treated at different time points with or without 40 ng/ml resistin and acetylated low-density lipoprotein (acetylated LDL). Cell migration and proliferation were analyzed using wound healing test and CellTiter Aqueous Cell Proliferation Assay (MTS) test, respectively. Intracellular reactive oxygen species (ROS) (H2DCFDA as a dye probe) and superoxide dismutase (SOD) activities were measured by a microplate reader and the differences between groups were compared. Rb1 significantly reduced resistin-induced HCASMC proliferation. Resistin increased HCASMC migration time-dependently. At 20 µM, Rb1 could significantly reduce HCASMC migration. Resistin and Act-LDL increased ROS production to a similar level in HCASMCs, while Rb1 pretreated group reversed the effects of resistin and acetyl-LDL. Besides, the mitochondrial SOD activity was significantly reduced by resistin but was restored when pretreated with Rb1. We confirmed the protection of Rb1 on HCASMC and suggested that the mechanisms involved might be related to the reduction of ROS generation and increased activity of SOD. Our study clarified the potential clinical applications of Rb1 in the control of resistin-related vascular injury and in the treatment of cardiovascular disease.
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Affiliation(s)
- Weifeng Lu
- Department of Vascular Surgery, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China
| | - Yue Lin
- Department of Vascular Surgery, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China
| | - Nezam Haider
- Division of Vascular Surgery, Department of Surgery, University of Arizona, Tucson, AZ, United States
| | - Pricila Moly
- Division of Vascular Surgery, Department of Surgery, University of Arizona, Tucson, AZ, United States
| | - Lixin Wang
- Department of Vascular Surgery, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China
- Department of Vascular Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wei Zhou
- Division of Vascular Surgery, Department of Surgery, University of Arizona, Tucson, AZ, United States
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13
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Pérez-Sala D, Pajares MA. Appraising the Role of Astrocytes as Suppliers of Neuronal Glutathione Precursors. Int J Mol Sci 2023; 24:ijms24098059. [PMID: 37175763 PMCID: PMC10179008 DOI: 10.3390/ijms24098059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 04/25/2023] [Accepted: 04/25/2023] [Indexed: 05/15/2023] Open
Abstract
The metabolism and intercellular transfer of glutathione or its precursors may play an important role in cellular defense against oxidative stress, a common hallmark of neurodegeneration. In the 1990s, several studies in the Neurobiology field led to the widely accepted notion that astrocytes produce large amounts of glutathione that serve to feed neurons with precursors for glutathione synthesis. This assumption has important implications for health and disease since a reduction in this supply from astrocytes could compromise the capacity of neurons to cope with oxidative stress. However, at first glance, this shuttling would imply a large energy expenditure to get to the same point in a nearby cell. Thus, are there additional underlying reasons for this expensive mechanism? Are neurons unable to import and/or synthesize the three non-essential amino acids that are the glutathione building blocks? The rather oxidizing extracellular environment favors the presence of cysteine (Cys) as cystine (Cis), less favorable for neuronal import. Therefore, it has also been proposed that astrocytic GSH efflux could induce a change in the redox status of the extracellular space nearby the neurons, locally lowering the Cis/Cys ratio. This astrocytic glutathione release would also increase their demand for precursors, stimulating Cis uptake, which these cells can import, further impacting the local decline of the Cis/Cys ratio, in turn, contributing to a more reduced extracellular environment and subsequently favoring neuronal Cys import. Here, we revisit the experimental evidence that led to the accepted hypothesis of astrocytes acting as suppliers of neuronal glutathione precursors, considering recent data from the Human Protein Atlas. In addition, we highlight some potential drawbacks of this hypothesis, mainly supported by heterogeneous cellular models. Finally, we outline additional and more cost-efficient possibilities by which astrocytes could support neuronal glutathione levels, including its shuttling in extracellular vesicles.
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Affiliation(s)
- Dolores Pérez-Sala
- Department of Structural and Chemical Biology, Centro de Investigaciones Biológicas Margarita Salas (CSIC), Ramiro de Maeztu 9, 28040 Madrid, Spain
| | - María A Pajares
- Department of Structural and Chemical Biology, Centro de Investigaciones Biológicas Margarita Salas (CSIC), Ramiro de Maeztu 9, 28040 Madrid, Spain
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14
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The Dual Role of Oxidants in Male (In)fertility: Every ROSe Has a Thorn. Int J Mol Sci 2023; 24:ijms24054994. [PMID: 36902424 PMCID: PMC10002566 DOI: 10.3390/ijms24054994] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 02/22/2023] [Accepted: 03/01/2023] [Indexed: 03/08/2023] Open
Abstract
The role of oxidative stress (OS) in male infertility as a primary etiology and/or concomitant cause in other situations, such as inflammation, varicocele and gonadotoxin effects, is well documented. While reactive oxygen species (ROS) are implicated in many important roles, from spermatogenesis to fertilization, epigenetic mechanisms which are transmissible to offspring have also recently been described. The present review is focused on the dual aspects of ROS, which are regulated by a delicate equilibrium with antioxidants due to the special frailty of spermatozoa, in continuum from physiological condition to OS. When the ROS production is excessive, OS ensues and is amplified by a chain of events leading to damage of lipids, proteins and DNA, ultimately causing infertility and/or precocious pregnancy termination. After a description of positive ROS actions and of vulnerability of spermatozoa due to specific maturative and structural characteristics, we linger on the total antioxidant capacity (TAC) of seminal plasma, which is a measure of non-enzymatic non-proteic antioxidants, due to its importance as a biomarker of the redox status of semen; the therapeutic implications of these mechanism play a key role in the personalized approach to male infertility.
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Abstract
Oxidative stress is the result of an imbalance between the formation of reactive oxygen species (ROS) and the levels of enzymatic and non-enzymatic antioxidants. The assessment of biological redox status is performed by the use of oxidative stress biomarkers. An oxidative stress biomarker is defined as any physical structure or process or chemical compound that can be assessed in a living being (in vivo) or in solid or fluid parts thereof (in vitro), the determination of which is a reproducible and reliable indicator of oxidative stress. The use of oxidative stress biomarkers allows early identification of the risk of developing diseases associated with this process and also opens up possibilities for new treatments. At the end of the last century, interest in oxidative stress biomarkers began to grow, due to evidence of the association between the generation of free radicals and various pathologies. Up to now, a significant number of studies have been carried out to identify and apply different oxidative stress biomarkers in clinical practice. Among the most important oxidative stress biomarkers, it can be mentioned the products of oxidative modifications of lipids, proteins, nucleic acids, and uric acid as well as the measurement of the total antioxidant capacity of fluids in the human body. In this review, we aim to present recent advances and current knowledge on the main biomarkers of oxidative stress, including the discovery of new biomarkers, with emphasis on the various reproductive complications associated with variations in oxidative stress levels.
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16
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Zhang Z, Zhao L, Zhou X, Meng X, Zhou X. Role of inflammation, immunity, and oxidative stress in hypertension: New insights and potential therapeutic targets. Front Immunol 2023; 13:1098725. [PMID: 36703963 PMCID: PMC9871625 DOI: 10.3389/fimmu.2022.1098725] [Citation(s) in RCA: 128] [Impact Index Per Article: 64.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 12/21/2022] [Indexed: 01/12/2023] Open
Abstract
Hypertension is regarded as the most prominent risk factor for cardiovascular diseases, which have become a primary cause of death, and recent research has demonstrated that chronic inflammation is involved in the pathogenesis of hypertension. Both innate and adaptive immunity are now known to promote the elevation of blood pressure by triggering vascular inflammation and microvascular remodeling. For example, as an important part of innate immune system, classically activated macrophages (M1), neutrophils, and dendritic cells contribute to hypertension by secreting inflammatory cy3tokines. In particular, interferon-gamma (IFN-γ) and interleukin-17 (IL-17) produced by activated T lymphocytes contribute to hypertension by inducing oxidative stress injury and endothelial dysfunction. However, the regulatory T cells and alternatively activated macrophages (M2) may have a protective role in hypertension. Although inflammation is related to hypertension, the exact mechanisms are complex and unclear. The present review aims to reveal the roles of inflammation, immunity, and oxidative stress in the initiation and evolution of hypertension. We envisage that the review will strengthen public understanding of the pathophysiological mechanisms of hypertension and may provide new insights and potential therapeutic strategies for hypertension.
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Affiliation(s)
| | | | | | - Xu Meng
- *Correspondence: Xianliang Zhou, ; Xu Meng,
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Simantiris S, Papastamos C, Antonopoulos AS, Theofilis P, Sagris M, Bounta M, Konisti G, Galiatsatos N, Xanthaki A, Tsioufis K, Tousoulis D. Oxidative Stress Biomarkers in Coronary Artery Disease. Curr Top Med Chem 2023; 23:2158-2171. [PMID: 37138428 DOI: 10.2174/1568026623666230502140614] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 03/01/2023] [Accepted: 03/09/2023] [Indexed: 05/05/2023]
Abstract
Oxidative stress plays a central role in atherogenesis, implicated in endothelial dysfunction, coronary plaque formation, and destabilization. Therefore, identifying oxidative stress in the vascular wall by reliable biomarkers could aid in early diagnosis and better coronary artery disease (CAD) prognostication. Because of the short half-life of reactive oxygen species, the current approach is to measure stable products generated by the oxidation of macromolecules in plasma or urine. Most popular oxidative stress biomarkers are oxidized low-density lipoprotein, myeloperoxidase and lipid peroxidation biomarkers, such as malondialdehyde and F2-isoprostanes. Oxidative protein modification biomarkers and oxidized phospholipids have also been studied and discussed in the present review. Most of these biomarkers are associated with the presence and extent of CAD, are elevated in patients with acute coronary syndromes, and may predict outcomes independent of traditional CAD risk factors. However, further standardization of measurement methods and assessment in large randomized clinical trials are required to integrate these biomarkers into clinical practice. In addition, evidence that these biomarkers detect oxidative stress in the vascular wall lacks and more specific biomarkers should be developed to identify vascular oxidative stress. Consequently, several oxidative stress biomarkers have been developed, most of which can be associated with the presence and extent of CAD and event prognosis. However, they still have significant limitations that hinder their integration into clinical practice.
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Affiliation(s)
- Spyridon Simantiris
- 1st Cardiology Department, Hippokration Hospital, National and Kapodistrian University of Athens, Greece
| | - Charalampos Papastamos
- 1st Cardiology Department, Hippokration Hospital, National and Kapodistrian University of Athens, Greece
| | - Alexios S Antonopoulos
- 1st Cardiology Department, Hippokration Hospital, National and Kapodistrian University of Athens, Greece
| | - Panagiotis Theofilis
- 1st Cardiology Department, Hippokration Hospital, National and Kapodistrian University of Athens, Greece
| | - Marios Sagris
- 1st Cardiology Department, Hippokration Hospital, National and Kapodistrian University of Athens, Greece
| | - Martha Bounta
- Microbiology Department, Hippokration Hospital, National and Kapodistrian University of Athens, Greece
| | - Georgia Konisti
- Biochemistry Department, Hippokration Hospital, National and Kapodistrian University of Athens, Greece
| | - Nikolaos Galiatsatos
- Biochemistry Department, Hippokration Hospital, National and Kapodistrian University of Athens, Greece
| | - Anna Xanthaki
- Microbiology Department, Hippokration Hospital, National and Kapodistrian University of Athens, Greece
| | - Konstantinos Tsioufis
- 1st Cardiology Department, Hippokration Hospital, National and Kapodistrian University of Athens, Greece
| | - Dimitris Tousoulis
- 1st Cardiology Department, Hippokration Hospital, National and Kapodistrian University of Athens, Greece
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18
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de Oliveira GV, Alvares TS. Effect of curcumin on endothelial function in humans and their proposed physiological mechanism: Insights in formulating curcumin products supplementation. PHARMANUTRITION 2022. [DOI: 10.1016/j.phanu.2022.100313] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
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Higashi Y. Roles of Oxidative Stress and Inflammation in Vascular Endothelial Dysfunction-Related Disease. Antioxidants (Basel) 2022; 11:antiox11101958. [PMID: 36290681 PMCID: PMC9598825 DOI: 10.3390/antiox11101958] [Citation(s) in RCA: 89] [Impact Index Per Article: 29.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 09/27/2022] [Accepted: 09/27/2022] [Indexed: 11/30/2022] Open
Abstract
Oxidative stress and chronic inflammation play an important role in the pathogenesis of atherosclerosis. Atherosclerosis develops as the first step of vascular endothelial dysfunction induced by complex molecular mechanisms. Vascular endothelial dysfunction leads to oxidative stress and inflammation of vessel walls, which in turn enhances vascular endothelial dysfunction. Vascular endothelial dysfunction and vascular wall oxidative stress and chronic inflammation make a vicious cycle that leads to the development of atherosclerosis. Simultaneously capturing and accurately evaluating the association of vascular endothelial function with oxidative stress and inflammation would be useful for elucidating the pathophysiology of atherosclerosis, determining treatment efficacy, and predicting future cardiovascular complications. Intervention in both areas is expected to inhibit the progression of atherosclerosis and prevent cardiovascular complications.
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Affiliation(s)
- Yukihito Higashi
- Department of Regenerative Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 743-8551, Japan; ; Tel.: +81-82-257-5831
- Division of Regeneration and Medicine, Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima 734-8553, Japan
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Azimzadeh O, Moertl S, Ramadan R, Baselet B, Laiakis EC, Sebastian S, Beaton D, Hartikainen JM, Kaiser JC, Beheshti A, Salomaa S, Chauhan V, Hamada N. Application of radiation omics in the development of adverse outcome pathway networks: an example of radiation-induced cardiovascular disease. Int J Radiat Biol 2022; 98:1722-1751. [PMID: 35976069 DOI: 10.1080/09553002.2022.2110325] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Epidemiological studies have indicated that exposure of the heart to doses of ionizing radiation as low as 0.5 Gy increases the risk of cardiac morbidity and mortality with a latency period of decades. The damaging effects of radiation to myocardial and endothelial structures and functions have been confirmed radiobiologically at high dose, but much less is known at low dose. Integration of radiation biology and epidemiology data is a recommended approach to improve the radiation risk assessment process. The adverse outcome pathway (AOP) framework offers a comprehensive tool to compile and translate mechanistic information into pathological endpoints which may be relevant for risk assessment at the different levels of a biological system. Omics technologies enable the generation of large volumes of biological data at various levels of complexity, from molecular pathways to functional organisms. Given the quality and quantity of available data across levels of biology, omics data can be attractive sources of information for use within the AOP framework. It is anticipated that radiation omics studies could improve our understanding of the molecular mechanisms behind the adverse effects of radiation on the cardiovascular system. In this review, we explored the available omics studies on radiation-induced cardiovascular disease (CVD) and their applicability to the proposed AOP for CVD. RESULTS The results of 80 omics studies published on radiation-induced CVD over the past 20 years have been discussed in the context of the AOP of CVD proposed by Chauhan et al. Most of the available omics data on radiation-induced CVD are from proteomics, transcriptomics, and metabolomics, whereas few datasets were available from epigenomics and multi-omics. The omics data presented here show great promise in providing information for several key events of the proposed AOP of CVD, particularly oxidative stress, alterations of energy metabolism, extracellular matrix and vascular remodeling. CONCLUSIONS The omics data presented here shows promise to inform the various levels of the proposed AOP of CVD. However, the data highlight the urgent need of designing omics studies to address the knowledge gap concerning different radiation scenarios, time after exposure and experimental models. This review presents the evidence to build a qualitative omics-informed AOP and provides views on the potential benefits and challenges in using omics data to assess risk-related outcomes.
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Affiliation(s)
- Omid Azimzadeh
- Federal Office for Radiation Protection (BfS), Section Radiation Biology, 85764 Neuherberg, Germany
| | - Simone Moertl
- Federal Office for Radiation Protection (BfS), Section Radiation Biology, 85764 Neuherberg, Germany
| | - Raghda Ramadan
- Institute for Environment, Health and Safety, Radiobiology Unit, Belgian Nuclear Research Centre (SCK CEN), Mol, Belgium
| | - Bjorn Baselet
- Institute for Environment, Health and Safety, Radiobiology Unit, Belgian Nuclear Research Centre (SCK CEN), Mol, Belgium
| | - Evagelia C Laiakis
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA.,Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, DC 20057, USA
| | | | | | - Jaana M Hartikainen
- School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, and Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland
| | - Jan Christian Kaiser
- Helmholtz Zentrum München, Institute of Radiation Medicine (HMGU-IRM), 85764 Neuherberg, Germany
| | - Afshin Beheshti
- KBR, Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA, 94035, USA.,Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | - Sisko Salomaa
- Department of Environmental and Biological Sciences, University of Eastern Finland, Kuopio, Finland
| | - Vinita Chauhan
- Environmental Health Science Research Bureau, Health Canada, Ottawa, Ontario, Canada
| | - Nobuyuki Hamada
- Biology and Environmental Chemistry Division, Sustainable System Research Laboratory, Central Research Institute of Electric Power Industry (CRIEPI), Komae, Tokyo 201-8511, Japan
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Liu Y, Gong X, Wang J, Wang Y, Zhang Y, Li T, Yan J, Zhou M, Zhang B. Investigation of nickel sulfate-induced cytotoxicity and underlying toxicological mechanisms in human umbilical vein endothelial cells through oxidative stress, inflammation, apoptosis, and MAPK signaling pathways. ENVIRONMENTAL TOXICOLOGY 2022; 37:2058-2071. [PMID: 35499276 DOI: 10.1002/tox.23550] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 04/11/2022] [Accepted: 04/16/2022] [Indexed: 06/14/2023]
Abstract
Growing evidence indicates that nickle and its compounds have adverse effects on the cardiovascular system. In this study, the cytotoxic insults caused by nickel sulfate (NiSO4 ) in human umbilical vein endothelial cells (HUVECs) were explored by examining cell viability, oxidative stress, inflammation, apoptosis, and MAPK signaling pathway activity. Cultured HUVECs were treated with varying concentrations of NiSO4 (0, 62.5, 250, and 1000 μM) for 24 h. Subsequently, markers of oxidative stress, inflammation, apoptosis, and MAPK signaling pathways were analyzed using biochemical assays, real-time quantitative polymerase chain reaction, and western blot. Rates of apoptosis were evaluated using flow cytometry. The results showed that NiSO4 exerted dose- and time-dependent inhibitory effects on cell growth. It induced oxidative stress and lipid peroxidation by increasing the generation of reactive oxygen species, the oxidized glutathione to reduced glutathione ratio (GSSG/GSH ratio), and malondialdehyde levels. Further, it inhibited superoxide dismutase activity in HUVECs. Flow cytometry analysis results revealed that NiSO4 (62.5-1000 μM) could induce apoptosis in HUVECs. The protein and gene expressions of cleaved Caspase 3 and Bax were elevated, and those of Bcl-2 and Bcl-XL were reduced after NiSO4 treatment. Additionally, NiSO4 triggered inflammation in HUVECs, increasing the protein and mRNA levels of IL-6 and TNF-α and reducing those of TGF-β. Furthermore, western blot findings revealed that NiSO4 could activate MAPK signaling pathways, upregulating p38, JNK, and ERK1/2 in HUVECs by increasing the levels of p-P38，p-JNK, and p-ERK1/2 in a dose-dependent manner. MAPK pathway inhibitors (10 μM SB203580 and 10 μM SP600125) could attenuate the NiSO4 -induced increase in apoptosis and inflammation in HUVECs. They could also attenuate the dysregulation of inflammatory factors and related proteins caused by high-dose NiSO4 exposure. Interestingly, while the MEK inhibitor U0126 (10 μM) enhanced NiSO4 -induced apoptosis in HUVECs, it reduced cell inflammation. Taken together, these experimental results suggest that NiSO4 can inhibit cell growth, induce oxidative stress, and trigger subsequent inflammatory responses and apoptosis in HUVECs. These effects may be mediated by the P38 and JNK MAPK stress response pathways.
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Affiliation(s)
- Yanli Liu
- Department of Occupational and Environmental Health, School of Public Health, Lanzhou University, Lanzhou, China
| | - Xia Gong
- Department of Geratology, The First Hospital of Lanzhou University, Lanzhou, China
| | - Juan Wang
- Department of Cardiology, Gansu Provincial Hospital, Lanzhou, China
| | - Yongxiang Wang
- Department of Geratology, The First Hospital of Lanzhou University, Lanzhou, China
| | - Yong Zhang
- Department of Occupational and Environmental Health, School of Public Health, Lanzhou University, Lanzhou, China
| | - Tao Li
- Department of Geratology, The First Hospital of Lanzhou University, Lanzhou, China
| | - Juan Yan
- Department of Occupational and Environmental Health, School of Public Health, Lanzhou University, Lanzhou, China
| | - Min Zhou
- Department of Occupational and Environmental Health, School of Public Health, Lanzhou University, Lanzhou, China
| | - Benzhong Zhang
- Department of Occupational and Environmental Health, School of Public Health, Lanzhou University, Lanzhou, China
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22
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Prasuhn J, Kunert L, Brüggemann N. Neuroimaging Methods to Map In Vivo Changes of OXPHOS and Oxidative Stress in Neurodegenerative Disorders. Int J Mol Sci 2022; 23:ijms23137263. [PMID: 35806267 PMCID: PMC9266616 DOI: 10.3390/ijms23137263] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 06/24/2022] [Accepted: 06/25/2022] [Indexed: 12/11/2022] Open
Abstract
Mitochondrial dysfunction is a pathophysiological hallmark of most neurodegenerative diseases. Several clinical trials targeting mitochondrial dysfunction have been performed with conflicting results. Reliable biomarkers of mitochondrial dysfunction in vivo are thus needed to optimize future clinical trial designs. This narrative review highlights various neuroimaging methods to probe mitochondrial dysfunction. We provide a general overview of the current biological understanding of mitochondrial dysfunction in degenerative brain disorders and how distinct neuroimaging methods can be employed to map disease-related changes. The reviewed methodological spectrum includes positron emission tomography, magnetic resonance, magnetic resonance spectroscopy, and near-infrared spectroscopy imaging, and how these methods can be applied to study alterations in oxidative phosphorylation and oxidative stress. We highlight the advantages and shortcomings of the different neuroimaging methods and discuss the necessary steps to use these for future research. This review stresses the importance of neuroimaging methods to gain deepened insights into mitochondrial dysfunction in vivo, its role as a critical disease mechanism in neurodegenerative diseases, the applicability for patient stratification in interventional trials, and the quantification of individual treatment responses. The in vivo assessment of mitochondrial dysfunction is a crucial prerequisite for providing individualized treatments for neurodegenerative disorders.
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Affiliation(s)
- Jannik Prasuhn
- Institute of Neurogenetics, University of Lübeck, 23538 Lübeck, Germany; (J.P.); (L.K.)
- Department of Neurology, University Medical Center Schleswig Holstein, Campus Lübeck, 23538 Lübeck, Germany
- Center for Brain, Behavior and Metabolism, University of Lübeck, 23562 Lübeck, Germany
| | - Liesa Kunert
- Institute of Neurogenetics, University of Lübeck, 23538 Lübeck, Germany; (J.P.); (L.K.)
- Department of Neurology, University Medical Center Schleswig Holstein, Campus Lübeck, 23538 Lübeck, Germany
- Center for Brain, Behavior and Metabolism, University of Lübeck, 23562 Lübeck, Germany
| | - Norbert Brüggemann
- Institute of Neurogenetics, University of Lübeck, 23538 Lübeck, Germany; (J.P.); (L.K.)
- Department of Neurology, University Medical Center Schleswig Holstein, Campus Lübeck, 23538 Lübeck, Germany
- Center for Brain, Behavior and Metabolism, University of Lübeck, 23562 Lübeck, Germany
- Correspondence: ; Tel.: +49-451-500-43420; Fax: +49-451-500-43424
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23
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Chatterjee S, Sil PC. ROS-Influenced Regulatory Cross-Talk With Wnt Signaling Pathway During Perinatal Development. Front Mol Biosci 2022; 9:889719. [PMID: 35517861 PMCID: PMC9061994 DOI: 10.3389/fmolb.2022.889719] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 04/04/2022] [Indexed: 11/25/2022] Open
Abstract
Over a century ago, it was found that a rapid burst of oxygen is needed and produced by the sea urchin oocyte to activate fertilization and block polyspermy. Since then, scientific research has taken strides to establish that Reactive Oxygen Species (ROS), besides being toxic effectors of cellular damage and death, also act as molecular messengers in important developmental signaling cascades, thereby modulating them. Wnt signaling pathway is one such developmental pathway, which has significant effects on growth, proliferation, and differentiation of cells at the earliest embryonic stages of an organism, apart from being significant role-players in the instances of cellular transformation and cancer when this tightly-regulated system encounters aberrations. In this review, we discuss more about the Wnt and ROS signaling pathways, how they function, what roles they play overall in animals, and mostly about how these two major signaling systems cross paths and interplay in mediating major cellular signals and executing the predestined changes during the perinatal condition, in a systematic manner.
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Affiliation(s)
| | - Parames C. Sil
- Division of Molecular Medicine, Bose Institute, Kolkata, India
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24
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Najjar RS, Mu S, Feresin RG. Blueberry Polyphenols Increase Nitric Oxide and Attenuate Angiotensin II-Induced Oxidative Stress and Inflammatory Signaling in Human Aortic Endothelial Cells. Antioxidants (Basel) 2022; 11:antiox11040616. [PMID: 35453301 PMCID: PMC9026874 DOI: 10.3390/antiox11040616] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 03/16/2022] [Accepted: 03/21/2022] [Indexed: 02/07/2023] Open
Abstract
Accumulating evidence indicate that blueberries have anti-hypertensive properties, which may be mainly due to its rich polyphenol content and their high antioxidant capacity. Thus, we aimed to investigate the mechanisms by which blueberry polyphenols exert these effects. Human aortic endothelial cells (HAECs) were incubated with 200 µg/mL blueberry polyphenol extract (BPE) for 1 h prior to a 12 h treatment with angiotensin (Ang) II, a potent vasoconstrictor. Our results indicate that Ang II increased levels of superoxide anions and decreased NO levels in HAECs. These effects were attenuated by pre-treatment with BPE. Ang II increased the expression of the pro-oxidant enzyme NOX1, which was not attenuated by BPE. Pre-treatment with BPE attenuated the Ang II-induced increase in the phosphorylation of the redox-sensitive MAPK kinases, SAPK/JNK and p38. BPE increased the expression of the redox-transcription factor NRF2 as well as detoxifying and antioxidant enzymes it transcribes including HO-1, NQO1, and SOD1. We also show that BPE attenuates the Ang II-induced phosphorylation of the NF-κB p65 subunit. Further, we show that inhibition of NRF2 leads to a decrease in the expression of HO-1 and increased phosphorylation of the NF-κB p65 subunit in HAECs treated with BPE and Ang II. These findings indicate that BPE acts through a NRF2-dependent mechanism to reduce oxidative stress and increase NO levels in Ang II-treated HAECs.
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Affiliation(s)
- Rami S. Najjar
- Department of Nutrition, Georgia State University, Atlanta, GA 30302, USA;
| | - Shengyu Mu
- Department of Pharmacology & Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA;
| | - Rafaela G. Feresin
- Department of Nutrition, Georgia State University, Atlanta, GA 30302, USA;
- Department of Nutrition & Dietetics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
- Correspondence: ; Tel.: +1-404-413-1233
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25
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Shabanian S, Khazaie M, Ferns GA, Arjmand MH. Local renin-angiotensin system molecular mechanisms in intrauterine adhesions formation following gynecological operations, new strategy for novel treatment. J OBSTET GYNAECOL 2022; 42:1613-1618. [PMID: 35260037 DOI: 10.1080/01443615.2022.2036972] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
It has recently been proposed that local tissue renin-angiotensin system activation has a role in post-surgical adhesion. Intrauterine adhesions are scar tissues that form in the endometrial cavity causing the walls of the uterine to adhere together. Women, undergoing major gynecological surgery, are exposed to a high risk of adhesion formation. Post-operative uterine adhesion is associated with chronic pain and infertility that are important problems following post-operation uterine adhesion. A local renin-angiotensin system has been found in the organs of the female reproductive system, for example in the endometrium. Data about the physiological roles of local RAS in the gynecological tract are largely unknown, but dysfunctional local RAS in the endometrium may contribute to this pathological condition. Local AngII/AT1R may be over-activated after surgical injury or hypoxia leading to an up-regulation of the molecular mechanisms that may lead to a chronic immune response, oxidative stress, and increase the expression of fibrotic molecules like TGF-β to induce the risk of connective fibrotic tissues. Based on AngII/AT1R pathological potential to induce pelvic and uterine adhesions, using angiotensin receptor blockers could be a therapeutic strategy for the prevention and treatment of post-surgical adhesions.IMPACT STATEMENTWhat is already known on this subject? Intrauterine adhesions are described as fibrotic scar tissues following gynecological surgeries. It's reported that 55-100% of women are at risk of intrauterine adhesion after gynecological surgeries. Injury to tissues and hypoxia during the surgery, promote molecular mechanisms to contribute post-surgical adhesion. Recently evidence supports the existence of renin-angiotensin system components in the gynecological tract. Abnormal expression of local angiotensin II and AT1R in uterus tissue following gynecological surgeries up-regulate molecular mechanisms to induce post-operative adhesions.What do the results of this study add? Recently there has been an increased focus on the role of the local renin-angiotensin system in organ fibrosis. The results of this Mini-review article refer to the pathological roles of the local renin-angiotensin system in fibrotic bands formation after gynecological operations. Over-activation of local renin-angiotensin systems up-regulate molecular mechanisms such as inflammation and the TGF-β1 signalling pathway. TGF-β as a profibrotic molecule strongly induces the expression of some fibrotic molecules such as PAI and TIMP to increase the risk of intrauterine adhesions.What are the implications of these findings for clinical practice and/or further research? According to the biological roles of local renin-angiotensin system and AT1R following injuries to develop post-operative adhesion, the administration of ARBs may be considered as a new therapeutic strategy for the prevention of IUA.
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Affiliation(s)
- Sheida Shabanian
- Department of Obstetrics and Gynecology, Faculty of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Majid Khazaie
- Department of Medical Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Division of Medical Education, Brighton and Sussex Medical School, Brighton, UK
| | - Mohammad-Hassan Arjmand
- Clinical Biochemistry Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.,Cancer Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran
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26
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Basak S, Khare HA, Kempen PJ, Kamaly N, Almdal K. Nanoconfined anti-oxidizing RAFT nitroxide radical polymer for reduction of low-density lipoprotein oxidation and foam cell formation. NANOSCALE ADVANCES 2022; 4:742-753. [PMID: 36131819 PMCID: PMC9418007 DOI: 10.1039/d1na00631b] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 12/22/2021] [Indexed: 06/15/2023]
Abstract
Atherosclerosis is a leading cause of death worldwide. Antioxidant therapy has been considered a promising treatment modality for atherosclerosis, since reactive oxygen species (ROS) play a major role in the pathogenesis of atherosclerosis. We developed ROS-scavenging antioxidant nanoparticles (NPs) that can serve as an effective therapy for atherosclerosis. The newly developed novel antioxidant ROS-eliminating NPs were synthesized via reversible addition-fragmentation chain-transfer (RAFT) polymerization and act as a superoxide dismutase (SOD) mimetic agent. SOD is an anti-ROS enzyme which is difficult to use for passive delivery due to its low half-life and stability. Copolymers were synthesized using different feed ratios of 2,2,6,6-tetramethyl-4-piperidyl methacrylate (PMA) and glycidyl methacrylate (GMA) monomers and an anti-ROS nitroxyl radical polymer was prepared via oxidation. The copolymer was further conjugated with a 6-aminofluorescein via a oxirane ring opening reaction for intracellular delivery in RAW 264.7 cells. The synthesized copolymers were blended to create NPs (∼150 nm size) in aqueous medium and highly stable up to three weeks. The NPs were shown to be taken up by macrophages and to be cytocompatible even at high dose levels (500 μg mL-1). Finally, the nitroxide NPs has been shown to inhibit foam cell formation in macrophages by decreasing internalization of oxidized low-density lipoproteins.
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Affiliation(s)
- Suman Basak
- Department of Health Technology, DTU Health Tech, Technical University of Denmark Kgs. Lyngby 2800 Denmark
- Department of Chemistry, Technical University of Denmark Kgs. Lyngby 2800 Denmark
| | - Harshvardhan Ajay Khare
- Department of Health Technology, DTU Health Tech, Technical University of Denmark Kgs. Lyngby 2800 Denmark
- Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet and University of Copenhagen Copenhagen 2200 Denmark
| | - Paul J Kempen
- Department of Health Technology, DTU Health Tech, Technical University of Denmark Kgs. Lyngby 2800 Denmark
- National Centre for Nano Fabrication and Characterization, DTU Nanolab, Technical University of Denmark Kgs. Lyngby 2800 Denmark
| | - Nazila Kamaly
- Department of Chemistry, Molecular Sciences Research Hub, Imperial College London London W12 0BZ UK
| | - Kristoffer Almdal
- Department of Chemistry, Technical University of Denmark Kgs. Lyngby 2800 Denmark
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27
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Artyukhov VG, Basharina OV. Modern Ideas about the Mechanisms of Action of Ultraviolet Radiation on Cells and Subcellular Systems. BIOL BULL+ 2022. [DOI: 10.1134/s1062359021120025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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28
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Wang CY, Yang CC, Hsiao LD, Yang CM. Involvement of FoxO1, Sp1, and Nrf2 in Upregulation of Negative Regulator of ROS by 15d-PGJ 2 Attenuates H 2O 2-Induced IL-6 Expression in Rat Brain Astrocytes. Neurotox Res 2022; 40:154-172. [PMID: 34997457 PMCID: PMC8784370 DOI: 10.1007/s12640-020-00318-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 11/23/2020] [Accepted: 11/25/2020] [Indexed: 02/08/2023]
Abstract
Excessive production of reactive oxygen species (ROS) by NADPH oxidase (Nox) resulted in inflammation. The negative regulator of ROS (NRROS) dampens ROS generation during inflammatory responses. 15-Deoxy-∆12,14-prostaglandin J2 (15d-PGJ2) exhibits neuroprotective effects on central nervous system (CNS). However, whether 15d-PGJ2-induced NRROS expression was unknown in rat brain astrocytes (RBA-1). NRROS expression was determined by Western blot, RT/real-time PCR, and promoter activity assays. The signaling components were investigated using pharmacological inhibitors or specific siRNAs. The interaction between transcription factors and the NRROS promoter was investigated by chromatin immunoprecipitation assay. Upregulation of NRROS on the hydrogen peroxide (H2O2)-mediated ROS generation and interleukin 6 (IL-6) secretion was measured. 15d-PGJ2-induced NRROS expression was mediated through PI3K/Akt-dependent activation of Sp1 and FoxO1 and established the essential promoter regions. We demonstrated that 15d-PGJ2 activated PI3K/Akt and following by cooperation between phosphorylated nuclear FoxO1 and Sp1 to initiate the NRROS transcription. In addition, Nrf2 played a key role in NRROS expression induced by 15d-PGJ2 which was mediated through its phosphorylation. Finally, the NRROS stable clones attenuated the H2O2-induced ROS generation and expression of IL-6 through suppressing the Nox-2 activity. These results suggested that 15d-PGJ2-induced NRROS expression is mediated through a PI3K/Akt-dependent FoxO1 and Sp1 phosphorylation, and Nrf2 cascade, which suppresses ROS generation through attenuating the p47phox phosphorylation and gp91phox formation and IL-6 expression in RBA-1 cells. These results confirmed the mechanisms underlying 15d-PGJ2-induced NRROS expression which might be a potential strategy for prevention and management of brain inflammatory and neurodegenerative diseases.
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Affiliation(s)
- Chen-Yu Wang
- Department of Pharmacology, College of Medicine, China Medical University, Taichung, 40402, Taiwan
| | - Chien-Chung Yang
- Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital At Tao-Yuan, Kwei-San, Tao-Yuan, 33302, Taiwan.,School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan, 33302, Taiwan
| | - Li-Der Hsiao
- Department of Pharmacology, College of Medicine, China Medical University, Taichung, 40402, Taiwan
| | - Chuen-Mao Yang
- Department of Pharmacology, College of Medicine, China Medical University, Taichung, 40402, Taiwan. .,Ph.D. Program for Biotch Pharmaceutical Industry, China Medical University, Taichung, 40402, Taiwan. .,Department of Post-Baccalaureate Veterinary Medicine, College of Medical and Health Science, Asia University, Wufeng, Taichung, 41354, Taiwan.
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29
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Tian Z, Li Z, Guo T, Li H, Mu Y. Atorvastatin suppresses lipopolysaccharide-induced inflammation in human coronary artery endothelial cells. BRAZ J PHARM SCI 2022. [DOI: 10.1590/s2175-979020200001181092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Affiliation(s)
- Zhen Tian
- Northeast Agricultural University, China; Harbin Medical University, China
| | | | - Tian Guo
- Harbin Medical University, China
| | - He Li
- Harbin Medical University, China
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30
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Hassoun R, Budde H, Zhazykbayeva S, Herwig M, Sieme M, Delalat S, Mostafi N, Gömöri K, Tangos M, Jarkas M, Pabel S, Bruckmüller S, Skrygan M, Lódi M, Jaquet K, Sequeira V, Gambichler T, Remedios CD, Kovács Á, Mannherz HG, Mügge A, Sossalla S, Hamdani N. Stress activated signalling impaired protein quality control pathways in human hypertrophic cardiomyopathy. Int J Cardiol 2021; 344:160-169. [PMID: 34517018 DOI: 10.1016/j.ijcard.2021.09.009] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Revised: 08/30/2021] [Accepted: 09/06/2021] [Indexed: 01/09/2023]
Abstract
Hypertrophic cardiomyopathy (HCM) is a complex myocardial disorder with no well-established disease-modifying therapy so far. Our study aimed to investigate how autophagy, oxidative stress, inflammation, stress signalling pathways, and apoptosis are hallmark of HCM and their contribution to the cardiac dysfunction. Demembranated cardiomyocytes from patients with HCM display increased titin-based stiffness (Fpassive), which was corrected upon antioxidant treatment. Titin as a main determinant of Fpassive was S-glutathionylated and highly ubiquitinated in HCM patients. This was associated with a shift in the balance of reduced and oxidized forms of glutathione (GSH and GSSG, respectively). Both heat shock proteins (HSP27 and α-ß crystalline) were upregulated and S-glutathionylated in HCM. Administration of HSPs in vitro significantly reduced HCM cardiomyocyte stiffness. High levels of the phosphorylated monomeric superoxide anion-generating endothelial nitric oxide synthase (eNOS), decreased nitric oxide (NO) bioavailability, decreased soluble guanylyl cyclase (sGC) activity, and high levels of 3-nitrotyrosine were observed in HCM. Many regulators of signal transduction pathways that are involved in autophagy, apoptosis, cardiac contractility, and growth including the mitogen-activated protein kinase (MAPK), protein kinase B (AKT), glycogen synthase kinase 3ß (GSK-3ß), mammalian target of rapamycin (mTOR), forkhead box O transcription factor (FOXO), c-Jun N-terminal protein kinase (JNK), and extracellular-signal-regulated kinase (ERK1/2) were modified in HCM. The apoptotic factors cathepsin, procaspase 3, procaspase 9 and caspase 12, but not caspase 9, were elevated in HCM hearts and associated with increased proinflammatory cytokines (Interleukin 6 (IL-6), interleukin 18 (IL-18), intercellular cell adhesion molecule-1 (ICAM1), vascular cell adhesion molecule-1 (VCAM1), the Toll-like receptors 2 (TLR2) and the Toll-like receptors 4 (TLR4)) and oxidative stress (3-nitrotyrosine and hydrogen peroxide (H2O2)). Here we reveal stress signalling and impaired PQS as potential mechanisms underlying the HCM phenotype. Our data suggest that reducing oxidative stress can be a viable therapeutic approach to attenuating the severity of cardiac dysfunction in heart failure and potentially in HCM and prevent its progression.
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Affiliation(s)
- Roua Hassoun
- Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany; Department of Cardiology, St. Josef-Hospital and Bergmannsheil, Ruhr University Bochum, Bochum, Germany.
| | - Heidi Budde
- Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany; Department of Cardiology, St. Josef-Hospital and Bergmannsheil, Ruhr University Bochum, Bochum, Germany.
| | - Saltanat Zhazykbayeva
- Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany; Department of Cardiology, St. Josef-Hospital and Bergmannsheil, Ruhr University Bochum, Bochum, Germany.
| | - Melissa Herwig
- Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany; Department of Cardiology, St. Josef-Hospital and Bergmannsheil, Ruhr University Bochum, Bochum, Germany.
| | - Marcel Sieme
- Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany; Department of Cardiology, St. Josef-Hospital and Bergmannsheil, Ruhr University Bochum, Bochum, Germany.
| | - Simin Delalat
- Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany; Department of Cardiology, St. Josef-Hospital and Bergmannsheil, Ruhr University Bochum, Bochum, Germany.
| | - Nusratul Mostafi
- Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany; Department of Cardiology, St. Josef-Hospital and Bergmannsheil, Ruhr University Bochum, Bochum, Germany.
| | - Kamilla Gömöri
- Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany; Department of Cardiology, St. Josef-Hospital and Bergmannsheil, Ruhr University Bochum, Bochum, Germany.
| | - Melina Tangos
- Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany; Department of Cardiology, St. Josef-Hospital and Bergmannsheil, Ruhr University Bochum, Bochum, Germany.
| | - Muhammad Jarkas
- Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany; Department of Cardiology, St. Josef-Hospital and Bergmannsheil, Ruhr University Bochum, Bochum, Germany.
| | - Steffen Pabel
- Department of Internal Medicine II, University Medical Center Regensburg, Regensburg, Germany.
| | - Stefanie Bruckmüller
- Department of Dermatology, Skin Cancer Center, Ruhr University Bochum, Bochum, Germany.
| | - Marina Skrygan
- Department of Dermatology, Skin Cancer Center, Ruhr University Bochum, Bochum, Germany.
| | - Mária Lódi
- Department of Neuroanatomy and Molecular Brain Research, Ruhr University Bochum, Medical Faculty, Bochum, Germany.
| | - Kornelia Jaquet
- Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany; Department of Cardiology, St. Josef-Hospital and Bergmannsheil, Ruhr University Bochum, Bochum, Germany.
| | - Vasco Sequeira
- Comprehensive Heart Failure Center (CHFC), University Clinic Würzburg, Germany.
| | - Thilo Gambichler
- Department of Dermatology, Skin Cancer Center, Ruhr University Bochum, Bochum, Germany.
| | - Cris Dos Remedios
- Molecular Biophysics, Victor Chang Cardiac Research Institute, Faculty of Medicine and Health, Darlinghurst, Australia.
| | - Árpád Kovács
- Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany; Department of Cardiology, St. Josef-Hospital and Bergmannsheil, Ruhr University Bochum, Bochum, Germany.
| | - Hans Georg Mannherz
- Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany; Department of Anatomy and Molecular Embryology, Ruhr University, Bochum, Germany.
| | - Andreas Mügge
- Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany; Department of Cardiology, St. Josef-Hospital and Bergmannsheil, Ruhr University Bochum, Bochum, Germany.
| | - Samuel Sossalla
- Department of Internal Medicine II, University Medical Center Regensburg, Regensburg, Germany; Clinic for Cardiology & Pneumology, Georg-August University Goettingen, and DZHK (German Centre for Cardiovascular Research), partner site Goettingen, Germany.
| | - Nazha Hamdani
- Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany; Department of Cardiology, St. Josef-Hospital and Bergmannsheil, Ruhr University Bochum, Bochum, Germany.
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Li Q, Qiu Z, Wang Y, Guo C, Cai X, Zhang Y, Liu L, Xue H, Tang J. Tea polyphenols alleviate hydrogen peroxide-induced oxidative stress damage through the Mst/Nrf2 axis and the Keap1/Nrf2/HO-1 pathway in murine RAW264.7 cells. Exp Ther Med 2021; 22:1473. [PMID: 34737813 PMCID: PMC8561765 DOI: 10.3892/etm.2021.10908] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 10/05/2021] [Indexed: 12/22/2022] Open
Abstract
Tea polyphenols (TPs) are the major bioactive extract from green tea that have been extensively reported to prevent and treat oxidative stress damage. In previous studies, TPs have been demonstrated to protect cells against oxidative injury induced by hydrogen peroxide (H2O2). However, the underlying mechanism remains unclear. The aim of the current study was to investigate whether the protective and regulatory effects of TPs on oxidative stress damage were dependent on the mammalian STE20-like protein kinase (Mst)/nuclear factor (erythroid-derived 2)-like 2 (Nrf2) axis and the Kelch-like ECH-associated protein 1 (Keap1)/Nrf2/heme oxygenase 1 (HO-1) pathway in RAW264.7 cells, a murine macrophage cell line. Maintaining a certain range of intracellular reactive oxygen species (ROS) levels is critical to basic cellular activities, while excessive ROS generation can override the antioxidant capacity of the cell and result in oxidative stress damage. The inhibition of ROS generation offers an effective target for preventing oxidative damage. The results of the present study revealed that pretreatment with TPs inhibited the production of intracellular ROS and protected RAW264.7 cells from H2O2-induced oxidative damage. TPs was also demonstrated to attenuate the production of nitric oxide and malondialdehyde and increase the levels of antioxidant enzymes (superoxide dismutase, catalase and glutathione peroxidase). In addition, following TPs treatment, alterations in Mst1/2 at the mRNA and protein level inhibited the production of ROS and promoted the self-regulation of antioxidation. TPs-induced Keap1 gene downregulation also increased the expression of Nrf2 and HO-1. Collectively, the results of the present study demonstrated that TPs provided protection against H2O2-induced oxidative injury in RAW264.7 cells.
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Affiliation(s)
- Qian Li
- Key Laboratory of Particle and Radiation Imaging, Ministry of Education, Department of Engineering Physics, Tsinghua University, Beijing 100084, P.R. China
| | - Zhaoyan Qiu
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Yan Wang
- State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, Shanghai 200437, P.R. China
| | - Chunyan Guo
- Department of Pharmacy, Hebei North University, Zhangjiakou, Hebei 075000, P.R. China
| | - Xu Cai
- Key Laboratory of Particle and Radiation Imaging, Ministry of Education, Department of Engineering Physics, Tsinghua University, Beijing 100084, P.R. China
| | - Yandong Zhang
- Key Laboratory of Particle and Radiation Imaging, Ministry of Education, Department of Engineering Physics, Tsinghua University, Beijing 100084, P.R. China
| | - Li Liu
- State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, Shanghai 200437, P.R. China
| | - Hongkun Xue
- Key Laboratory of Particle and Radiation Imaging, Ministry of Education, Department of Engineering Physics, Tsinghua University, Beijing 100084, P.R. China
| | - Jintian Tang
- Key Laboratory of Particle and Radiation Imaging, Ministry of Education, Department of Engineering Physics, Tsinghua University, Beijing 100084, P.R. China
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Liu H, Cheng Y, Chu J, Wu M, Yan M, Wang D, Xie Q, Ali F, Fang Y, Wei L, Yang Y, Shen A, Peng J. Baicalin attenuates angiotensin II-induced blood pressure elevation and modulates MLCK/p-MLC signaling pathway. Biomed Pharmacother 2021; 143:112124. [PMID: 34492423 DOI: 10.1016/j.biopha.2021.112124] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 08/18/2021] [Accepted: 08/24/2021] [Indexed: 01/05/2023] Open
Abstract
Scutellaria baicalensis Georgi is an extensively used medicinal herb for the treatment of hypertension in traditional Chinese medicine. Baicalin, is an important flavonoid in Scutellaria baicalensis Georgi extracts, which exhibits therapeutic effects on anti-hypertension, but its underlying mechanisms remain to be further explored. Therefore, we investigated the effects and molecular mechanisms of Baicalin on anti-hypertension. In vivo studies revealed that Baicalin treatment significantly attenuated the elevation in blood pressure, the pulse propagation and thickening of the abdominal aortic wall in C57BL/6 mice infused with Angiotensin II (Ang II). Moreover, RNA-sequencing and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses identified 537 differentially expressed transcripts and multiple enriched signaling pathways (including vascular smooth muscle contraction and calcium signaling pathway). Consistently, we found that Baicalin pretreatment significantly alleviated the Ang II induced constriction of abdominal aortic ring, while promoted NE pre-contracted vasodilation of abdominal aortic ring at least partly dependent on L-type calcium channel. In addition, Ang II stimulation significantly increased cell viability and PCNA expression, while were attenuated after Baicalin treatment. Moreover, Baicalin pretreatment attenuated Ang II-induced intracellular Ca2+ release, Angiotensin II type 1 receptor (AT1R) expression and activation of MLCK/p-MLC pathway in vascular smooth muscle cells (VSMCs). The present work further addressed the pharmacological and mechanistic insights on anti-hypertension of Baicalin, which may help better understand the therapeutic effect of Scutellaria baicalensis Georgi on anti-hypertension.
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MESH Headings
- Angiotensin II
- Animals
- Aorta, Abdominal/drug effects
- Aorta, Abdominal/enzymology
- Aorta, Abdominal/physiopathology
- Blood Pressure/drug effects
- Calcium Signaling/drug effects
- Cell Proliferation/drug effects
- Cells, Cultured
- Disease Models, Animal
- Flavonoids/pharmacology
- Hypertension/chemically induced
- Hypertension/enzymology
- Hypertension/physiopathology
- Hypertension/prevention & control
- Hypoglycemic Agents/pharmacology
- Male
- Mice, Inbred C57BL
- Muscle, Smooth, Vascular/drug effects
- Muscle, Smooth, Vascular/enzymology
- Muscle, Smooth, Vascular/physiopathology
- Myocytes, Smooth Muscle/drug effects
- Myocytes, Smooth Muscle/enzymology
- Myosin Light Chains/metabolism
- Myosin-Light-Chain Kinase/metabolism
- Phosphorylation
- Rats, Wistar
- Mice
- Rats
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Affiliation(s)
- Huixin Liu
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Chen Keji Academic Thought Inheritance Studio, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China
| | - Ying Cheng
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China
| | - Jianfeng Chu
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Chen Keji Academic Thought Inheritance Studio, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China
| | - Meizhu Wu
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Chen Keji Academic Thought Inheritance Studio, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China
| | - Mengchao Yan
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Chen Keji Academic Thought Inheritance Studio, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China
| | - Di Wang
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Chen Keji Academic Thought Inheritance Studio, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China
| | - Qiurong Xie
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Chen Keji Academic Thought Inheritance Studio, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China
| | - Farman Ali
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Chen Keji Academic Thought Inheritance Studio, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China
| | - Yi Fang
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Chen Keji Academic Thought Inheritance Studio, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China
| | - Lihui Wei
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Chen Keji Academic Thought Inheritance Studio, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China
| | - Yanyan Yang
- Laboratory Animal Center, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China
| | - Aling Shen
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Chen Keji Academic Thought Inheritance Studio, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China.
| | - Jun Peng
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China; Chen Keji Academic Thought Inheritance Studio, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China.
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Regulation of Heme Oxygenase and Its Cross-Talks with Apoptosis and Autophagy under Different Conditions in Drosophila. Antioxidants (Basel) 2021; 10:antiox10111716. [PMID: 34829587 PMCID: PMC8614956 DOI: 10.3390/antiox10111716] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 10/24/2021] [Accepted: 10/25/2021] [Indexed: 01/09/2023] Open
Abstract
Heme oxygenase (HO) is one of the cytoprotective enzymes that can mitigate the effects of oxidative stress. Here, we found that the ho mRNA level oscillates in the brain of Drosophila melanogaster with two minima at the beginning of the day and night. This rhythm was partly masked by light as its pattern changed in constant darkness (DD). It followed a similar trend in the clock mutant per01 under light/dark regime (LD12:12); however, differences between time points were not statistically significant. In older flies (20 days old), the rhythm was vanished; however, 15 days of curcumin feeding restored this rhythm with an elevated ho mRNA level at all time points studied. In addition, flies exposed to paraquat had higher ho expression in the brain, but only at a specific time of the day which can be a protective response of the brain against stress. These findings suggest that the expression of ho in the fly’s brain is regulated by the circadian clock, light, age, exposure to stress, and the presence of exogenous antioxidants. We also found that HO cross-talks with apoptosis and autophagy under different conditions. Induction of neuronal ho was accompanied by increased transcription of apoptosis and autophagy-related genes. However, this trend changed after exposure to curcumin and paraquat. Our results suggest that HO is involved in the control of apoptotic and autophagic key processes protecting the brain against oxidative damage.
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Szafranska K, Kruse LD, Holte CF, McCourt P, Zapotoczny B. The wHole Story About Fenestrations in LSEC. Front Physiol 2021; 12:735573. [PMID: 34588998 PMCID: PMC8473804 DOI: 10.3389/fphys.2021.735573] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 08/16/2021] [Indexed: 02/06/2023] Open
Abstract
The porosity of liver sinusoidal endothelial cells (LSEC) ensures bidirectional passive transport of lipoproteins, drugs and solutes between the liver capillaries and the liver parenchyma. This porosity is realized via fenestrations - transcellular pores with diameters in the range of 50-300 nm - typically grouped together in sieve plates. Aging and several liver disorders severely reduce LSEC porosity, decreasing their filtration properties. Over the years, a variety of drugs, stimulants, and toxins have been investigated in the context of altered diameter or frequency of fenestrations. In fact, any change in the porosity, connected with the change in number and/or size of fenestrations is reflected in the overall liver-vascular system crosstalk. Recently, several commonly used medicines have been proposed to have a beneficial effect on LSEC re-fenestration in aging. These findings may be important for the aging populations of the world. In this review we collate the literature on medicines, recreational drugs, hormones and laboratory tools (including toxins) where the effect LSEC morphology was quantitatively analyzed. Moreover, different experimental models of liver pathology are discussed in the context of fenestrations. The second part of this review covers the cellular mechanisms of action to enable physicians and researchers to predict the effect of newly developed drugs on LSEC porosity. To achieve this, we discuss four existing hypotheses of regulation of fenestrations. Finally, we provide a summary of the cellular mechanisms which are demonstrated to tune the porosity of LSEC.
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Affiliation(s)
- Karolina Szafranska
- Vascular Biology Research Group, Department of Medical Biology, University of Tromsø - The Arctic University of Norway, Tromsø, Norway
| | - Larissa D Kruse
- Vascular Biology Research Group, Department of Medical Biology, University of Tromsø - The Arctic University of Norway, Tromsø, Norway
| | - Christopher Florian Holte
- Vascular Biology Research Group, Department of Medical Biology, University of Tromsø - The Arctic University of Norway, Tromsø, Norway
| | - Peter McCourt
- Vascular Biology Research Group, Department of Medical Biology, University of Tromsø - The Arctic University of Norway, Tromsø, Norway
| | - Bartlomiej Zapotoczny
- Vascular Biology Research Group, Department of Medical Biology, University of Tromsø - The Arctic University of Norway, Tromsø, Norway.,Department of Biophysical Microstructures, Institute of Nuclear Physics, Polish Academy of Sciences, Kraków, Poland
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35
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LaClair HJ, Khosrodad N, Sule AA, Koehler T, Krishnamoorthy G. Effect of ACE inhibitors and angiotensin receptor blockers on in-hospital mortality and length of stay in hospitalized COVID-19 patients. Vascul Pharmacol 2021; 141:106902. [PMID: 34363963 PMCID: PMC8339444 DOI: 10.1016/j.vph.2021.106902] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 08/02/2021] [Indexed: 11/28/2022]
Affiliation(s)
- Heather J LaClair
- Mercy Health Muskegon GME, 1675 Leahy street, Ste. 315A, Muskegon, MI 49442, USA.
| | - Nadia Khosrodad
- St. Joseph Mercy Oakland, 44405 Woodward avenue, Pontiac, MI 48341, USA; University of Michigan, GME, 4260 Plymouth Road, B1-313, Ann Arbor, MI 48109, USA.
| | - Anupam A Sule
- St. Joseph Mercy Oakland, 44405 Woodward avenue, Pontiac, MI 48341, USA.
| | - Tracy Koehler
- Mercy Health Muskegon GME, 1675 Leahy street, Ste. 315A, Muskegon, MI 49442, USA.
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36
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The Interplay between S-Glutathionylation and Phosphorylation of Cardiac Troponin I and Myosin Binding Protein C in End-Stage Human Failing Hearts. Antioxidants (Basel) 2021; 10:antiox10071134. [PMID: 34356367 PMCID: PMC8301081 DOI: 10.3390/antiox10071134] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 07/08/2021] [Accepted: 07/13/2021] [Indexed: 12/24/2022] Open
Abstract
Oxidative stress is defined as an imbalance between the antioxidant defense system and the production of reactive oxygen species (ROS). At low levels, ROS are involved in the regulation of redox signaling for cell protection. However, upon chronical increase in oxidative stress, cell damage occurs, due to protein, DNA and lipid oxidation. Here, we investigated the oxidative modifications of myofilament proteins, and their role in modulating cardiomyocyte function in end-stage human failing hearts. We found altered maximum Ca2+-activated tension and Ca2+ sensitivity of force production of skinned single cardiomyocytes in end-stage human failing hearts compared to non-failing hearts, which was corrected upon treatment with reduced glutathione enzyme. This was accompanied by the increased oxidation of troponin I and myosin binding protein C, and decreased levels of protein kinases A (PKA)- and C (PKC)-mediated phosphorylation of both proteins. The Ca2+ sensitivity and maximal tension correlated strongly with the myofilament oxidation levels, hypo-phosphorylation, and oxidative stress parameters that were measured in all the samples. Furthermore, we detected elevated titin-based myocardial stiffness in HF myocytes, which was reversed by PKA and reduced glutathione enzyme treatment. Finally, many oxidative stress and inflammation parameters were significantly elevated in failing hearts compared to non-failing hearts, and corrected upon treatment with the anti-oxidant GSH enzyme. Here, we provide evidence that the altered mechanical properties of failing human cardiomyocytes are partially due to phosphorylation, S-glutathionylation, and the interplay between the two post-translational modifications, which contribute to the development of heart failure.
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Smolyarova DD, Podgorny OV, Bilan DS, Belousov VV. A guide to genetically encoded tools for the study of H 2 O 2. FEBS J 2021; 289:5382-5395. [PMID: 34173331 DOI: 10.1111/febs.16088] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 04/23/2021] [Accepted: 06/24/2021] [Indexed: 01/09/2023]
Abstract
Cell metabolism heavily relies on the redox reactions that inevitably generate reactive oxygen species (ROS). It is now well established that ROS fluctuations near basal levels coordinate numerous physiological processes in living organisms, thus exhibiting regulatory functions. Hydrogen peroxide, the most long-lived ROS, is a key contributor to ROS-dependent signal transduction in the cell. H2 O2 is known to impact various targets in the cell; therefore, the question of how H2 O2 modulates physiological processes in a highly specific manner is central in redox biology. To resolve this question, novel genetic tools have recently been created for detecting H2 O2 and emulating its generation in living organisms with unmatched spatiotemporal resolution. Here, we review H2 O2 -sensitive genetically encoded fluorescent sensors and opto- and chemogenetic tools for controlled H2 O2 generation.
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Affiliation(s)
- Daria D Smolyarova
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia.,Faculty of Biology, Lomonosov Moscow State University, Russia
| | - Oleg V Podgorny
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia.,Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, Moscow, Russia.,Laboratory of Experimental Oncology, Pirogov Russian National Research Medical University, Moscow, Russia
| | - Dmitry S Bilan
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia.,Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, Moscow, Russia.,Laboratory of Experimental Oncology, Pirogov Russian National Research Medical University, Moscow, Russia
| | - Vsevolod V Belousov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia.,Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, Moscow, Russia.,Laboratory of Experimental Oncology, Pirogov Russian National Research Medical University, Moscow, Russia.,Federal Center of Brain Research and Neurotechnologies of the Federal Medical Biological Agency, Moscow, Russia.,Institute for Cardiovascular Physiology, Georg August University Göttingen, Germany
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38
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Cárdenas-Rodríguez N, Bandala C, Vanoye-Carlo A, Ignacio-Mejía I, Gómez-Manzo S, Hernández-Cruz EY, Pedraza-Chaverri J, Carmona-Aparicio L, Hernández-Ochoa B. Use of Antioxidants for the Neuro-Therapeutic Management of COVID-19. Antioxidants (Basel) 2021; 10:971. [PMID: 34204362 PMCID: PMC8235474 DOI: 10.3390/antiox10060971] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 06/07/2021] [Accepted: 06/15/2021] [Indexed: 02/07/2023] Open
Abstract
Coronavirus Disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is an emergent infectious disease that has caused millions of deaths throughout the world. COVID-19 infection's main symptoms are fever, cough, fatigue, and neurological manifestations such as headache, myalgias, anosmia, ageusia, impaired consciousness, seizures, and even neuromuscular junctions' disorders. In addition, it is known that this disease causes a series of systemic complications such as adverse respiratory distress syndrome, cardiac injury, acute kidney injury, and liver dysfunction. Due to the neurological symptoms associated with COVID-19, damage in the central nervous system has been suggested as well as the neuroinvasive potential of SARS-CoV-2. It is known that CoV infections are associated with an inflammation process related to the imbalance of the antioxidant system; cellular changes caused by oxidative stress contribute to brain tissue damage. Although anti-COVID-19 vaccines are under development, there is no specific treatment for COVID-19 and its clinical manifestations and complications; only supportive treatments with immunomodulators, anti-vascular endothelial growth factors, modulating drugs, statins, or nutritional supplements have been used. In the present work, we analyzed the potential of antioxidants as adjuvants for the treatment of COVID-19 and specifically their possible role in preventing or decreasing the neurological manifestations and neurological complications present in the disease.
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Affiliation(s)
- Noemí Cárdenas-Rodríguez
- Laboratorio de Neurociencias, Instituto Nacional de Pediatría, Secreatría de Salud, Ciudad de México 04530, Mexico; (A.V.-C.); (L.C.-A.)
| | - Cindy Bandala
- Division de Neurociencias, Instituto Nacional de Rehabilitación, Secretaría de Salud, Ciudad de México 14389, Mexico;
- Escuela Superior de Medicina, Instituto Politécnico Nacional, Ciudad de México 11340, Mexico
| | - América Vanoye-Carlo
- Laboratorio de Neurociencias, Instituto Nacional de Pediatría, Secreatría de Salud, Ciudad de México 04530, Mexico; (A.V.-C.); (L.C.-A.)
| | - Iván Ignacio-Mejía
- Laboratorio de Medicina Traslacional, Escuela Militar de Graduados de Sanidad, SEDENA, Ciudad de México 11200, Mexico;
| | - Saúl Gómez-Manzo
- Laboratorio de Bioquímica Genética, Instituto Nacional de Pediatría, Secretaría de Salud, Ciudad de México 04530, Mexico;
| | | | - José Pedraza-Chaverri
- Departamento de Biología, Facultad de Química, UNAM, Ciudad de México 04150, Mexico; (E.Y.H.-C.); (J.P.-C.)
| | - Liliana Carmona-Aparicio
- Laboratorio de Neurociencias, Instituto Nacional de Pediatría, Secreatría de Salud, Ciudad de México 04530, Mexico; (A.V.-C.); (L.C.-A.)
| | - Beatriz Hernández-Ochoa
- Laboratorio de Inmunoquímica, Hospital Infantil de México Federico Gómez, Secretaría de Salud, Ciudad de México 06720, Mexico;
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Ezrokhi M, Zhang Y, Luo S, Cincotta AH. Time-of-Day-Dependent Effects of Bromocriptine to Ameliorate Vascular Pathology and Metabolic Syndrome in SHR Rats Held on High Fat Diet. Int J Mol Sci 2021; 22:ijms22116142. [PMID: 34200262 PMCID: PMC8201259 DOI: 10.3390/ijms22116142] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 05/28/2021] [Accepted: 06/04/2021] [Indexed: 12/31/2022] Open
Abstract
The treatment of type 2 diabetes patients with bromocriptine-QR, a unique, quick release micronized formulation of bromocriptine, improves glycemic control and reduces adverse cardiovascular events. While the improvement of glycemic control is largely the result of improved postprandial hepatic glucose metabolism and insulin action, the mechanisms underlying the drug's cardioprotective effects are less well defined. Bromocriptine is a sympatholytic dopamine agonist and reduces the elevated sympathetic tone, characteristic of metabolic syndrome and type 2 diabetes, which potentiates elevations of vascular oxidative/nitrosative stress, known to precipitate cardiovascular disease. Therefore, this study investigated the impact of bromocriptine treatment upon biomarkers of vascular oxidative/nitrosative stress (including the pro-oxidative/nitrosative stress enzymes of NADPH oxidase 4, inducible nitric oxide (iNOS), uncoupled endothelial nitric oxide synthase (eNOS), the pro-inflammatory/pro-oxidative marker GTP cyclohydrolase 1 (GTPCH 1), and the pro-vascular health enzyme, soluble guanylate cyclase (sGC) as well as the plasma level of thiobarbituric acid reactive substances (TBARS), a circulating marker of systemic oxidative stress), in hypertensive SHR rats held on a high fat diet to induce metabolic syndrome. Inasmuch as the central nervous system (CNS) dopaminergic activities both regulate and are regulated by CNS circadian pacemaker circuitry, this study also investigated the time-of-day-dependent effects of bromocriptine treatment (10 mg/kg/day at either 13 or 19 h after the onset of light (at the natural waking time or late during the activity period, respectively) among animals held on 14 h daily photoperiods for 16 days upon such vascular biomarkers of vascular redox state, several metabolic syndrome parameters, and mediobasal hypothalamic (MBH) mRNA expression levels of neuropeptides neuropeptide Y (NPY) and agouti-related protein (AgRP) which regulate the peripheral fuel metabolism and of mRNA expression of other MBH glial and neuronal cell genes that support such metabolism regulating neurons in this model system. Such bromocriptine treatment at ZT 13 improved (reduced) biomarkers of vascular oxidative/nitrosative stress including plasma TBARS level, aortic NADPH oxidase 4, iNOS and GTPCH 1 levels, and improved other markers of coupled eNOS function, including increased sGC protein level, relative to controls. However, bromocriptine treatment at ZT 19 produced no improvement in either coupled eNOS function or sGC protein level. Moreover, such ZT 13 bromocriptine treatment reduced several metabolic syndrome parameters including fasting insulin and leptin levels, as well as elevated systolic and diastolic blood pressure, insulin resistance, body fat store levels and liver fat content, however, such effects of ZT 19 bromocriptine treatment were largely absent versus control. Finally, ZT 13 bromocriptine treatment reduced MBH NPY and AgRP mRNA levels and mRNA levels of several MBH glial cell/neuronal genes that code for neuronal support/plasticity proteins (suggesting a shift in neuronal structure/function to a new metabolic control state) while ZT 19 treatment reduced only AgRP, not NPY, and was with very little effect on such MBH glial cell genes expression. These findings indicate that circadian-timed bromocriptine administration at the natural circadian peak of CNS dopaminergic activity (that is diminished in insulin resistant states), but not outside this daily time window when such CNS dopaminergic activity is naturally low, produces widespread improvements in biomarkers of vascular oxidative stress that are associated with the amelioration of metabolic syndrome and reductions in MBH neuropeptides and gene expressions known to facilitate metabolic syndrome. These results of such circadian-timed bromocriptine treatment upon vascular pathology provide potential mechanisms for the observed marked reductions in adverse cardiovascular events with circadian-timed bromocriptine-QR therapy (similarly timed to the onset of daily waking as in this study) of type 2 diabetes subjects and warrant further investigations into related mechanisms and the potential application of such intervention to prediabetes and metabolic syndrome patients as well.
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Machado MMF, Banin RM, Thomaz FM, de Andrade IS, Boldarine VT, de Souza Figueiredo J, Hirata BKS, Oyama LM, Lago JHG, Ribeiro EB, Telles MM. Ginkgo biloba Extract (GbE) Restores Serotonin and Leptin Receptor Levels and Plays an Antioxidative Role in the Hippocampus of Ovariectomized Rats. Mol Neurobiol 2021; 58:2692-2703. [PMID: 33492645 DOI: 10.1007/s12035-021-02281-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 01/05/2021] [Indexed: 01/09/2023]
Abstract
Since Ginkgo biloba extract (GbE) was reported to improve the hypothalamic serotonergic system of ovariectomized (OVX) rats, the present study aimed to verify the GbE effects on hippocampal oxidative stress, inflammation, and levels of the serotonin transporter (5-HTT), and both the serotonin (5-HT1A, 5-HT1B) and leptin receptors of OVX rats. Two-month-old female Wistar rats had their ovaries surgically removed (OVX) or not (SHAM). After 60 days, OVX rats were gavaged daily with GbE 500 mg kg-1 (OVX+GbE), while SHAM and OVX groups received saline 0.9% (vehicle) for 14 days. Rats were then euthanized, and hippocampi were collected. Both 5-HT1A and 5-HT1B levels were significantly reduced in OVX rats compared to SHAM rats, while 5-HT1A was higher in OVX+GbE rats in comparison to OVX rats. Similarly, LepR levels were increased in OVX+GbE rats compared to OVX rats, reaching similar levels to SHAM rats. Superoxide dismutase activity increased in OVX rats in relation to SHAM rats, which was restored to SHAM levels by GbE treatment. Additionally, GbE significantly increased the glutathione peroxidase activity in comparison to the SHAM group. No differences were observed either in catalase activity or in the levels of 5-HTT, PKCα, TLR-4, NF-κBp50, ERK, and CREB. In summary, our results show a potential effect of GbE on hippocampal pathways involved in feeding behavior, and thus, they suggest that GbE activity might improve menopausal-related hippocampal disorders, offering an alternative therapeutic tool particularly for women to whom hormone replacement therapy may be contraindicated.
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Affiliation(s)
- Meira Maria Forcelini Machado
- Post-graduate Program in Chemical Biology, Institute of Environmental Sciences, Chemical and Pharmaceutical, Universidade Federal de São Paulo, Diadema, SP, Brazil
| | - Renata Mancini Banin
- Post-graduate Program in Chemical Biology, Institute of Environmental Sciences, Chemical and Pharmaceutical, Universidade Federal de São Paulo, Diadema, SP, Brazil
| | - Fernanda Malanconi Thomaz
- Post-graduate Program in Chemical Biology, Institute of Environmental Sciences, Chemical and Pharmaceutical, Universidade Federal de São Paulo, Diadema, SP, Brazil
| | - Iracema Senna de Andrade
- Discipline of Nutrition Physiology, Department of Physiology, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Valter Tadeu Boldarine
- Discipline of Nutrition Physiology, Department of Physiology, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Jéssica de Souza Figueiredo
- Post-graduate Program in Chemical Biology, Institute of Environmental Sciences, Chemical and Pharmaceutical, Universidade Federal de São Paulo, Diadema, SP, Brazil
| | - Bruna Kelly Sousa Hirata
- Post-graduate Program in Chemical Biology, Institute of Environmental Sciences, Chemical and Pharmaceutical, Universidade Federal de São Paulo, Diadema, SP, Brazil
| | - Lila Missae Oyama
- Discipline of Nutrition Physiology, Department of Physiology, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - João Henrique Ghilardi Lago
- Post-graduate Program in Chemical Biology, Institute of Environmental Sciences, Chemical and Pharmaceutical, Universidade Federal de São Paulo, Diadema, SP, Brazil
- Center of Natural and Human Sciences, Universidade Federal do ABC, Santo André, SP, Brazil
| | - Eliane Beraldi Ribeiro
- Discipline of Nutrition Physiology, Department of Physiology, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Mônica Marques Telles
- Post-graduate Program in Chemical Biology, Institute of Environmental Sciences, Chemical and Pharmaceutical, Universidade Federal de São Paulo, Diadema, SP, Brazil.
- Discipline of Nutrition Physiology, Department of Physiology, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
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Oliveira G, Volino-Souza M, Conte-Júnior CA, Alvares TS. Food-derived polyphenol compounds and cardiovascular health: A nano-technological perspective. FOOD BIOSCI 2021. [DOI: 10.1016/j.fbio.2021.101033] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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Elshony HS, Idris A, Al-Ghamdi A, Muddassir R. Intracerebral Hemorrhage in Patients with Neuromyelitis Optica: Case Report with Literature Review for Possible Pathological Association. Case Rep Neurol 2021; 13:157-165. [PMID: 33790774 PMCID: PMC7989829 DOI: 10.1159/000513644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 11/14/2020] [Indexed: 11/19/2022] Open
Abstract
Neuromyelitis optica (NMO) is an autoimmune demyelinating disorder of the central nervous system which is characterized by attacks of optic neuritis and transverse myelitis. An association between NMO and intracerebral hemorrhage (ICH) has been rarely recognized, having been reported only 3 times before. Here we report on a patient with NMO who eventually developed subarachnoid hemorrhage, in order to emphasize that the association between NMO and ICH is mostly not incidental and that the pathological basis for this association should be investigated thoroughly.
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Affiliation(s)
- Hosna Saad Elshony
- Department of Neurology/Internal Medicine, Security Forces Hospital, Makkah, Saudi Arabia
| | - Abdelrahman Idris
- Department of Neurology/Internal Medicine, Security Forces Hospital, Makkah, Saudi Arabia
| | - Abdulaziz Al-Ghamdi
- Department of Neurology/Internal Medicine, Security Forces Hospital, Makkah, Saudi Arabia
| | - Rabia Muddassir
- Department of Neurology/Internal Medicine, Security Forces Hospital, Makkah, Saudi Arabia
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Tavakkoli M, Aali S, Khaledifar B, Ferns GA, Khazaei M, Fekri K, Arjmand MH. The Potential Association between the Risk of Post-Surgical Adhesion and the Activated Local Angiotensin II Type 1 Receptors: Need for Novel Treatment Strategies. Gastrointest Tumors 2021; 8:107-114. [PMID: 34307308 DOI: 10.1159/000514614] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 01/17/2021] [Indexed: 12/22/2022] Open
Abstract
Background Post-surgical adhesion bands (PSABs) are a common complication after abdominal or pelvic surgeries for different reasons like cancer treatment. Despite improvements in surgical techniques and the administration of drugs or the use of physical barriers, there has only been limited improvement in the frequency of postoperative adhesions. Complications of PSAB are pain, infertility, intestinal obstruction, and increased mortality. The most important molecular mechanisms for the development of PSAB are inflammatory response, oxidative stress, and overexpression of pro-fibrotic molecules such as transforming growth factor β. However, questions remain about the pathogenesis of this problem, for example, the causes for individual differences or why certain tissue sites are more prone to post-surgical adhesions. Summary Addressing the pathological causes of PSAB, the potential role of local angiotensin II/angiotensin II type 1 receptors (AngII/AT1R), may help to prevent this problem. Key Message The objective of this article was to explore the role of the AngII/AT1R axis potential to induce PSAB and the therapeutic potential of angiotensin receptor blockers in the prevention and treatment of PSAB.
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Affiliation(s)
- Mahmood Tavakkoli
- Kidney Transplantation Complications Research Center, Department of Internal Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Saeed Aali
- Department of Urology, Kashani Academic Hospital, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Borzoo Khaledifar
- Department of Surgery, Faculty of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Gordon A Ferns
- Brighton & Sussex Medical School, Division of Medical Education, Brighton, United Kingdom
| | - Majid Khazaei
- Department of Medical Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Kiavash Fekri
- Cancer Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran
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Zalewski DP, Ruszel KP, Stępniewski A, Gałkowski D, Bogucki J, Kołodziej P, Szymańska J, Płachno BJ, Zubilewicz T, Feldo M, Kocki J, Bogucka-Kocka A. Identification of Transcriptomic Differences between Lower Extremities Arterial Disease, Abdominal Aortic Aneurysm and Chronic Venous Disease in Peripheral Blood Mononuclear Cells Specimens. Int J Mol Sci 2021; 22:3200. [PMID: 33801150 PMCID: PMC8004090 DOI: 10.3390/ijms22063200] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 03/14/2021] [Accepted: 03/18/2021] [Indexed: 01/10/2023] Open
Abstract
Several human tissues are investigated in studies of molecular biomarkers associated with diseases development. Special attention is focused on the blood and its components due to combining abundant information about systemic responses to pathological processes as well as high accessibility. In the current study, transcriptome profiles of peripheral blood mononuclear cells (PBMCs) were used to compare differentially expressed genes between patients with lower extremities arterial disease (LEAD), abdominal aortic aneurysm (AAA) and chronic venous disease (CVD). Gene expression patterns were generated using the Ion S5XL next-generation sequencing platform and were analyzed using DESeq2 and UVE-PLS methods implemented in R programming software. In direct pairwise analysis, 21, 58 and 10 differentially expressed genes were selected from the comparison of LEAD vs. AAA, LEAD vs. CVD and AAA vs. CVD patient groups, respectively. Relationships between expression of dysregulated genes and age, body mass index, creatinine levels, hypertension and medication were identified using Spearman rank correlation test and two-sided Mann-Whitney U test. The functional analysis, performed using DAVID website tool, provides potential implications of selected genes in pathological processes underlying diseases studied. Presented research provides new insight into differences of pathogenesis in LEAD, AAA and CVD, and selected genes could be considered as potential candidates for biomarkers useful in diagnosis and differentiation of studied diseases.
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Affiliation(s)
- Daniel P. Zalewski
- Chair and Department of Biology and Genetics, Medical University of Lublin, 4a Chodźki St., 20-093 Lublin, Poland;
| | - Karol P. Ruszel
- Chair of Medical Genetics, Department of Clinical Genetics, Medical University of Lublin, 11 Radziwiłłowska St., 20-080 Lublin, Poland; (K.P.R.); (J.K.)
| | - Andrzej Stępniewski
- Ecotech Complex Analytical and Programme Centre for Advanced Environmentally Friendly Technologies, University of Marie Curie-Skłodowska, 39 Głęboka St., 20-612 Lublin, Poland;
| | - Dariusz Gałkowski
- Department of Pathology and Laboratory Medicine, Rutgers-Robert Wood Johnson Medical School, One Robert Wood Johnson Place, New Brunswick, NJ 08903-0019, USA;
| | - Jacek Bogucki
- Chair and Department of Organic Chemistry, Medical University of Lublin, 4a Chodźki St., 20-093 Lublin, Poland;
| | - Przemysław Kołodziej
- Laboratory of Diagnostic Parasitology, Chair and Department of Biology and Genetics, Medical University of Lublin, 4a Chodźki St., 20-093 Lublin, Poland;
| | - Jolanta Szymańska
- Department of Integrated Paediatric Dentistry, Chair of Integrated Dentistry, Medical University of Lublin, 6 Chodźki St., 20-093 Lublin, Poland;
| | - Bartosz J. Płachno
- Department of Plant Cytology and Embryology, Institute of Botany, Faculty of Biology, Jagiellonian University in Kraków, 9 Gronostajowa St., 30-387 Cracow, Poland;
| | - Tomasz Zubilewicz
- Chair and Department of Vascular Surgery and Angiology, Medical University of Lublin, 11 Staszica St., 20-081 Lublin, Poland; (T.Z.); (M.F.)
| | - Marcin Feldo
- Chair and Department of Vascular Surgery and Angiology, Medical University of Lublin, 11 Staszica St., 20-081 Lublin, Poland; (T.Z.); (M.F.)
| | - Janusz Kocki
- Chair of Medical Genetics, Department of Clinical Genetics, Medical University of Lublin, 11 Radziwiłłowska St., 20-080 Lublin, Poland; (K.P.R.); (J.K.)
| | - Anna Bogucka-Kocka
- Chair and Department of Biology and Genetics, Medical University of Lublin, 4a Chodźki St., 20-093 Lublin, Poland;
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Ishii S, Ashino T, Fujimori H, Numazawa S. Reactive sulfur species inhibit the migration of PDGF-treated vascular smooth muscle cells by blocking the reactive oxygen species-regulated Akt signaling pathway. Free Radic Res 2021; 55:186-197. [PMID: 33641584 DOI: 10.1080/10715762.2021.1887485] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Vascular smooth muscle cell (VSMC) migration contributes to vascular remodeling after injury, whereas oxidative stress generated through dysfunctional redox homeostasis induces hypermigration, leading to arteriosclerosis. Platelet-derived growth factor (PDGF)-induced reactive oxygen species (ROS) serve as intracellular signaling molecules in VSMCs. Reactive sulfur species (RSS) may serve as a biological defense system because of the antioxidative properties of highly nucleophilic sulfane sulfur. However, insufficient information is available on its function in PDGF-induced VSMC migration. Here we show that PDGF significantly increased the levels of intracellular sulfane sulfur and that intracellular sulfane sulfur donors, donor 5a and Na2S4, inhibited the increase in ROS levels in PDGF-treated VSMCs and inhibited their migration. Consistent with the migration results, sulfane sulfur donors inhibited Akt phosphorylation, a downstream signaling molecule in the PDGF cascade, without affecting the autophosphorylation of PDGF receptor-β. Further, sulfane sulfur donors inhibited vinculin and paxillin recruitment to the leading edge of VSMCs in response to PDGF to decrease focal adhesion formation. These findings suggest that RSS are required for PDGF-stimulated VSMC migration through the regulation of the ROS-regulated Akt pathway, which may contribute to focal adhesion formation. Our findings provide insight into RSS as novel regulators of vascular redox homeostasis.
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Affiliation(s)
- Shunichi Ishii
- Division of Toxicology, Department of Pharmacology, Toxicology, and Therapeutics, Showa University School of Pharmacy, Tokyo, Japan.,Pharmacological Research Center, Showa University, Tokyo, Japan
| | - Takashi Ashino
- Division of Toxicology, Department of Pharmacology, Toxicology, and Therapeutics, Showa University School of Pharmacy, Tokyo, Japan.,Pharmacological Research Center, Showa University, Tokyo, Japan
| | - Hiroki Fujimori
- Division of Toxicology, Department of Pharmacology, Toxicology, and Therapeutics, Showa University School of Pharmacy, Tokyo, Japan.,Pharmacological Research Center, Showa University, Tokyo, Japan
| | - Satoshi Numazawa
- Division of Toxicology, Department of Pharmacology, Toxicology, and Therapeutics, Showa University School of Pharmacy, Tokyo, Japan.,Pharmacological Research Center, Showa University, Tokyo, Japan
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Akhigbe R, Ajayi A. The impact of reactive oxygen species in the development of cardiometabolic disorders: a review. Lipids Health Dis 2021; 20:23. [PMID: 33639960 PMCID: PMC7916299 DOI: 10.1186/s12944-021-01435-7] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 01/26/2021] [Indexed: 02/07/2023] Open
Abstract
Oxidative stress, an alteration in the balance between reactive oxygen species (ROS) generation and antioxidant buffering capacity, has been implicated in the pathogenesis of cardiometabolic disorders (CMD). At physiological levels, ROS functions as signalling mediators, regulates various physiological functions such as the growth, proliferation, and migration endothelial cells (EC) and smooth muscle cells (SMC); formation and development of new blood vessels; EC and SMC regulated death; vascular tone; host defence; and genomic stability. However, at excessive levels, it causes a deviation in the redox state, mediates the development of CMD. Multiple mechanisms account for the rise in the production of free radicals in the heart. These include mitochondrial dysfunction and uncoupling, increased fatty acid oxidation, exaggerated activity of nicotinamide adenine dinucleotide phosphate oxidase (NOX), reduced antioxidant capacity, and cardiac metabolic memory. The purpose of this study is to discuss the link between oxidative stress and the aetiopathogenesis of CMD and highlight associated mechanisms. Oxidative stress plays a vital role in the development of obesity and dyslipidaemia, insulin resistance and diabetes, hypertension via various mechanisms associated with ROS-led inflammatory response and endothelial dysfunction.
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Affiliation(s)
- Roland Akhigbe
- Department of Physiology, College of Medicine, Ladoke Akintola University of Technology, Ogbomoso, Oyo State Nigeria
- Reproductive Biology and Toxicology Research Laboratories, Oasis of Grace Hospital, Osogbo, Osun State Nigeria
- Department of Chemical Sciences, Kings University, Odeomu, Osun Nigeria
| | - Ayodeji Ajayi
- Department of Physiology, College of Medicine, Ladoke Akintola University of Technology, Ogbomoso, Oyo State Nigeria
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47
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Cross-over Loop Cysteine C152 Acts as an Antioxidant to Maintain the Folding Stability and Deubiquitinase Activity of UCH-L1 Under Oxidative Stress. J Mol Biol 2021; 433:166879. [PMID: 33617897 DOI: 10.1016/j.jmb.2021.166879] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 01/07/2021] [Accepted: 02/12/2021] [Indexed: 11/20/2022]
Abstract
Redox-dependent inactivation of deubiquitinases (DUBs) is a critical factor for attenuating their DUB activity in response to cellular oxidative stress. Ubiquitin C-terminal hydrolase isoform (UCH-L1) is an important DUB that is highly expressed in human neuronal cells and is implicated in a myriad of human diseases such as neurodegenerative diseases and cancer. Increasing evidence suggests an important role of UCH-L1 in redox regulation and the protection of neuronal cells from oxidative stress. In this study, we examined the molecular basis of how UCH-L1 responds to oxidation in a reversible manner. Using H2O2 as a model oxidant, we showed by mass spectrometry that a subset of methionine and cysteine residues, namely (M1, M6, M12, C90, and C152) were more susceptible to oxidation. Spectroscopic analysis showed that oxidation of C90 can lead to profound structural changes in addition to the loss of function. Importantly, we further demonstrated that C152, which is located at the substrate recognition cross-over loop, serves as a reactive oxygen species (ROS) scavenger to protect catalytic C90 from oxidation under moderate oxidative conditions. Hydrogen-deuterium exchange mass spectrometry analysis provided detailed structural mapping of the destabilizing effect of H2O2-mediated oxidation, which resulted in global destabilization far beyond the oxidation sites. These perturbations may be responsible for irreversible aggregation when subject to prolonged oxidative stress.
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Houshmand G, Naghizadeh B, Ghorbanzadeh B, Ghafouri Z, Goudarzi M, Mansouri MT. Celecoxib inhibits acute edema and inflammatory biomarkers through peroxisome proliferator-activated receptor-γ in rats. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2021; 23:1544-1550. [PMID: 33489027 PMCID: PMC7811815 DOI: 10.22038/ijbms.2020.43995.10315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Objective(s): Celecoxib (CLX), a selective cyclooxygenase-II (COX-2) inhibitor, has been used for management of several inflammatory disorders. The present study aimed to explore the role of peroxisome proliferator-activated receptor-gamma (PPARγ) in CLX induced anti-inflammatory response in rats. Materials and Methods: Carrageenan-induced paw edema was used as an acute inflammation model. Rats were treated with various intra-peritoneal (IP) doses of CLX (0.3–30 mg/kg) and pioglitazone (PGL; PPARγ agonist, 1–20 mg/kg) alone or in combination. Amounts of PPARγ, COX-2, and prostaglandin E2 (PGE2) in paw tissue, and extents of TNF-α and IL-10 in serum were measured. Moreover, levels of oxidative stress parameters as malondialdehyde (MDA), glutathione (GSH), glutathione peroxidase (GPx) activity in the cortex, hippocampus, and paw tissues were also determined. Results: CLX and PGL dose-dependent administration (IP), alone or in combination reduced carrageenan-induced paw edema. Further, both agents, alone or in combination, reduced either the amounts of COX-2, PGE2, and MDA in the inflamed paw, and the levels of TNF-α in serum which were elevated by carrageenan. Both drugs also increased both levels of PPARγ, GSH, GPx activity in paws, and serum levels of IL-10 that were decreased by carrageenan. Intraplantar injection of GW-9662 (IPL), a selective PPARγ antagonist, inhibited all biochemical modifications caused by both single and combined drug treatments. Conclusion: CLX produced its anti-inflammatory effects probably through PPARγ receptor activation. Besides, increased anti-inflammatory effects of CLX with PGL suggest that their combination might be applied for the clinical management of inflammation especially in patients suffering from diabetes.
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Affiliation(s)
- Gholamreza Houshmand
- Department of Pharmacology, School of Medicine, Mazandaran University of Medical Sciences (MAZUMS), Sari, Iran
| | - Bahareh Naghizadeh
- Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Behnam Ghorbanzadeh
- Department of Pharmacology, School of Medicine, Dezful University of Medical Sciences, Dezful, Iran
| | - Zahra Ghafouri
- Department of Biochemistry Biophysics and Genetics, School of Medicine, Mazandaran University of Medical Sciences (MAZUMS), Sari, Iran
| | - Mehdi Goudarzi
- Medicinal Plant Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.,Toxicology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mohammad Taghi Mansouri
- Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.,Toxicology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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49
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Prevel R, Roubaud-Baudron C, Tellier E, Le Besnerais M, Kaplanski G, Veyradier A, Benhamou Y, Coppo P. [Endothelial dysfunction in thrombotic thrombocytopenic purpura: therapeutic perspectives]. Rev Med Interne 2021; 42:202-209. [PMID: 33455838 DOI: 10.1016/j.revmed.2020.12.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 11/19/2020] [Accepted: 12/26/2020] [Indexed: 01/05/2023]
Abstract
Immune Thrombotic Thrombocytopenic Purpura (iTTP) is a rare but severe disease with a mortality rate of almost 100 % in the absence of adequate treatment. iTTP is caused by a severe deficiency in ADAMTS13 activity due to the production of inhibitory antibodies. Age has been shown to be a major prognostic factor. iTTP patients in the elderly (60yo and over) have more frequent organ involvement, especially heart and kidney failures compared with younger patients. They also have non-specific neurologic symptoms leading to a delayed diagnosis. Factors influencing this impaired survival among older patients remain unknown so far. Alteration of the functional capacity of involved organs could be part of the explanation as could be the consequences of vascular aging. In fact, severe ADAMTS13 deficiency is necessary but likely not sufficient for iTTP physiopathology. A second hit leading to endothelial activation is thought to play a central role in iTTP. Interestingly, the mechanisms involved in endothelial activation may share common features with those involved in vascular aging, potentially leading to endothelial dysfunction. It could thus be interesting to better investigate the causes of mid- and long-term mortality among older iTTP patients to confirm whether inflammation and endothelial activation really impact vascular aging and long-term mortality in those patients, in addition to their presumed role at iTTP acute phase. If so, further insights into the mechanisms involved could lead to new therapeutic targets.
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Affiliation(s)
- R Prevel
- CHU Bordeaux, Pôle de Gérontologie Clinique, 33000 Bordeaux, France; CHU Bordeaux, FHU Acronim 33000 Bordeaux, France; University Bordeaux, INSERM 1045 CRCTB 33000 Bordeaux, France
| | - C Roubaud-Baudron
- CHU Bordeaux, Pôle de Gérontologie Clinique, 33000 Bordeaux, France; University Bordeaux, INSERM UMR 1053 Bariton 33000 Bordeaux, France
| | - E Tellier
- Vascular Research Center of Marseille, Inserm, UMRS_1076, Aix-Marseille Université, Marseille, France
| | - M Le Besnerais
- Service de Médecine Interne, CHU Charles Nicolle, Rouen, France; INSERM U1096, UFR médecine pharmacie Rouen, Rouen, France
| | - G Kaplanski
- Vascular Research Center of Marseille, Inserm, UMRS_1076, Aix-Marseille Université, Marseille, France; Aix-Marseille université, 13284, Service de médecine interne, hôpital de la Conception, AP-HM, 147, boulevard Baille, 13385 Marseille cedex 05, France; Centre de Référence des Microangiopathies Thrombotiques (CNR-MAT, www.cnr-mat.fr), Paris, France
| | - A Veyradier
- Centre de Référence des Microangiopathies Thrombotiques (CNR-MAT, www.cnr-mat.fr), Paris, France; Hématologie biologique, Hôpital Lariboisière, AP-HP, Université Paris Diderot, Paris, France
| | - Y Benhamou
- Service de Médecine Interne, CHU Charles Nicolle, Rouen, France; INSERM U1096, UFR médecine pharmacie Rouen, Rouen, France; Centre de Référence des Microangiopathies Thrombotiques (CNR-MAT, www.cnr-mat.fr), Paris, France
| | - P Coppo
- Centre de Référence des Microangiopathies Thrombotiques (CNR-MAT, www.cnr-mat.fr), Paris, France; Service d'Hématologie, Centre de Référence des Microangiopathies Thrombotiques (CNR-MAT, www.cnr-mat.fr), AP-HP.6, Paris, France.
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