|
1
|
Bhatia A, Thakur S, Kohal R, Brar S, Gupta GD, Verma SK. A comprehensive update on phytochemistry and medicinal developments of apocynin. Fitoterapia 2025; 183:106558. [PMID: 40280248 DOI: 10.1016/j.fitote.2025.106558] [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: 01/26/2025] [Revised: 04/11/2025] [Accepted: 04/18/2025] [Indexed: 04/29/2025]
Abstract
The natural phenolic compound apocynin, referred to as acetovanillone, generated significant attention due to its diverse pharmacological properties, especially as an NADPH oxidase inhibitor, and it was applicable orally and effectively even at small doses. During chronic inflammation, various pro-inflammatory-related factors such as nuclear factor kappa β (NF-kβ), nitrotyrosine, poly adenosine diphosphate ribose polymerase (PARP), inducible nitric oxide synthase (iNOS), cluster of differentiation 31 (CD31), intercellular adhesion molecule-1 (ICAM-1), glycoproteins granule membrane protein 140 (GMP140), tumor necrosis factor-alpha (TNFα), p38 mitogen-activated protein kinases (p38 MAPK), membrane cofactor protein (MCP), interleukin-6 (IL-6), all of which could be targeted by apocynin. Research suggests that apocynin significantly benefits conditions like diabetes, cardiovascular diseases, and neurological disorders due to its ability to mitigate inflammation and enhance endothelial function. Further investigations are essential to examine apocynin and its derivatives, mainly its long-term potency. Future research must focus on clinical trials to evaluate its safety, effectiveness, and optimal dosing in various applications. This review provides a recent update on apocynin, covering aspects such as its extraction and isolation, chemical framework, biosynthesis, synthetic derivatives, pharmacological activities, patent landscape, stability and specifications.
Collapse
Affiliation(s)
- Anchal Bhatia
- Department of Pharmacognosy, ISF College of Pharmacy, Moga 142 001, Punjab, India
| | - Shimple Thakur
- Department of Pharmacognosy, ISF College of Pharmacy, Moga 142 001, Punjab, India
| | - Rupali Kohal
- Department of Pharmacognosy, ISF College of Pharmacy, Moga 142 001, Punjab, India
| | - Seema Brar
- Department of Pharmacognosy, ISF College of Pharmacy, Moga 142 001, Punjab, India
| | - Ghanshyam Das Gupta
- Department of Pharmaceutics, ISF College of Pharmacy, Moga 142 001, Punjab, India
| | - Sant Kumar Verma
- Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga 142 001, Punjab, India.
| |
Collapse
|
|
2
|
Chen D, Guo Z, Yao L, Sun Y, Dian Y, Zhao D, Ke Y, Zeng F, Zhang C, Deng G, Li L. Targeting oxidative stress-mediated regulated cell death as a vulnerability in cancer. Redox Biol 2025; 84:103686. [PMID: 40424719 DOI: 10.1016/j.redox.2025.103686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2025] [Accepted: 05/17/2025] [Indexed: 05/29/2025] Open
Abstract
Reactive oxygen species (ROS), regulators of cellular behaviors ranging from signaling to cell death, have complex production and control mechanisms to maintain a dynamic redox balance under physiological conditions. Redox imbalance is frequently observed in tumor cells, where ROS within tolerable limits promote oncogenic transformation, while excessive ROS induce a range of regulated cell death (RCD). As such, targeting ROS-mediated regulated cell death as a vulnerability in cancer. However, the precise regulatory networks governing ROS-mediated cancer cell death and their therapeutic applications remain inadequately characterized. In this Review, we first provide a comprehensive overview of the mechanisms underlying ROS production and control within cells, highlighting their dynamic balance. Next, we discuss the paradoxical nature of the redox system in tumor cells, where ROS can promote tumor growth or suppress it, depending on the context. We also systematically explored the role of ROS in tumor signaling pathways and revealed the complex ROS-mediated cross-linking networks in cancer cells. Following this, we focus on the intricate regulation of ROS in RCD and its current applications in cancer therapy. We further summarize the potential of ROS-induced RCD-based therapies, particularly those mediated by drugs targeting specific redox balance mechanisms. Finally, we address the measurement of ROS and oxidative damage in research, discussing existing challenges and future prospects of targeting ROS-mediated RCD in cancer therapy. We hope this review will offer promise for the clinical application of targeting oxidative stress-mediated regulated cell death in cancer therapy.
Collapse
Affiliation(s)
- Danyao Chen
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, China; Furong Laboratory, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, China; Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ziyu Guo
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, China; Furong Laboratory, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, China
| | - Lei Yao
- Department of Liver Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yuming Sun
- Department of Plastic and Cosmetic Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan Province, China
| | - Yating Dian
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, China; Furong Laboratory, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, China
| | - Deze Zhao
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yizhe Ke
- The First Affliated Hospital of Shihezi University, China
| | - Furong Zeng
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
| | - Chunfang Zhang
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.
| | - Guangtong Deng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, China; Furong Laboratory, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, China.
| | - Linfeng Li
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.
| |
Collapse
|
|
3
|
Dempsey B, Pereira da Silva B, Cruz LC, Vileigas D, Silva ARM, Pereira da Silva R, Meotti FC. Unraveling the effects of uric acid on endothelial cells: A global proteomic study. Redox Biol 2025; 82:103625. [PMID: 40203480 PMCID: PMC12005352 DOI: 10.1016/j.redox.2025.103625] [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: 01/28/2025] [Revised: 03/27/2025] [Accepted: 03/29/2025] [Indexed: 04/11/2025] Open
Abstract
This work aims to understand how normouricemic levels of uric acid can induce endothelial dysfunction seeking global proteomic alterations in Human Umbilical Vein cells (HUVEC). It reveals significant alterations in redox-sensitive and antioxidant proteins, chaperones, and proteins associated with cell migration and adhesion in response to uric acid exposure. Monitoring cellular oxidation with the roGFP2-Grx1 probe proved increased oxidation levels induced by uric acid, which can be attenuated by peroxidasin (PXDN) inhibition, suggesting a regulatory role for PXDN in mitigating oxidative stress induced by uric acid. As a consequence of uric acid oxidation and the formation of reactive intermediate, we identified adducts in proteins (+140 kDa) in a novel post-translation modification named uratylation. Increased misfolded protein levels and p62 aggregation were also found, indicating disturbances in cellular proteostasis. Furthermore, uric acid promoted monocyte adhesion and upregulated ICAM and VCAM protein levels, implicating a pro-inflammatory response in endothelial cells. These findings provide critical insights into the molecular mechanisms underlying vascular damage associated with uric acid.
Collapse
Affiliation(s)
- Bianca Dempsey
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil
| | | | - Litiele Cezar Cruz
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil
| | - Danielle Vileigas
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil
| | - Amanda R M Silva
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil
| | | | - Flavia Carla Meotti
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil.
| |
Collapse
|
|
4
|
Skorupa A, Jakubczyk M, Michalkiewicz S. Electroanalysis of Apocynin Part 2: Investigations on a Boron-Doped Diamond Electrode in Aqueous Buffered Solutions. MATERIALS (BASEL, SWITZERLAND) 2025; 18:2044. [PMID: 40363547 PMCID: PMC12072782 DOI: 10.3390/ma18092044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/07/2025] [Revised: 04/25/2025] [Accepted: 04/28/2025] [Indexed: 05/15/2025]
Abstract
In this study, the voltammetric behavior of apocynin on a boron-doped diamond electrode in a phosphate buffer (pH 7.3) has been reported for the first time. The oxidation process is quasi-reversible, diffusion-controlled, and involves one electron and one proton. The product of the electrode reaction is an unstable radical that undergoes successive chemical transformations near the working electrode. The proposed mechanism of this process can be described as EqCi and served as the basis for the development of a new voltammetric method for determining apocynin in natural samples. The analytical signal was the anodic peak on DPV curves at a potential of 0.605 V vs. Ag/AgCl. A linear response was observed in the concentration range of 0.213-27.08 mg L-1. The estimated LOD and LOQ values were 0.071 and 0.213 mg L-1, respectively. The effectiveness of the method was demonstrated both in control determinations and in the analysis of the dietary supplement. This procedure is simple, fast, sensitive, selective, and requires no complicated sample preparation, which is limited only to a simple extraction with ethanol. The low consumption of non-toxic reagents makes it environmentally friendly. To the best of our knowledge, this is the first presentation of a voltammetric procedure to determine this analyte studied in a phosphate buffer solution on a boron-doped diamond electrode. It can also be easily adapted to determine other phenolic compounds with antioxidant properties in various matrices.
Collapse
Affiliation(s)
- Agata Skorupa
- Institute of Chemistry, Jan Kochanowski University, 7 Uniwersytecka St., PL-25406 Kielce, Poland; (M.J.); (S.M.)
| | | | | |
Collapse
|
|
5
|
Noce B, Marchese S, Massari M, Lambona C, Reis J, Fiorentino F, Raucci A, Fioravanti R, Castelôa M, Mormino A, Garofalo S, Limatola C, Basile L, Gottinger A, Binda C, Mattevi A, Mai A, Valente S. Design of Benzyl-triazolopyrimidine-Based NADPH Oxidase Inhibitors Leads to the Discovery of a Potent Dual Covalent NOX2/MAOB Inhibitor. J Med Chem 2025; 68:6292-6311. [PMID: 40042998 PMCID: PMC11956017 DOI: 10.1021/acs.jmedchem.4c02644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 02/17/2025] [Accepted: 02/21/2025] [Indexed: 03/28/2025]
Abstract
NADPH oxidases (NOXs) are enzymes dedicated to reactive oxygen species (ROS) production and are implicated in cancer, neuroinflammation, and neurodegenerative diseases. VAS2870 is a covalent inhibitor of mainly NOX2 and NOX5. It alkylates a conserved active-site cysteine, blocking productive substrate binding. To enhance potency and selectivity toward NOXs, we conducted some chemical modifications, leading to the discovery of compound 9a that preferentially inhibits NOX2 with an IC50 of 0.155 μM, and only upon its preactivation. We found that 9a, bearing a pargyline moiety, is also able to selectively inhibit MAOB over MAOA (465-fold) with an IC50 of 0.182 μM, being the first-in-class dual NOX2/MAOB covalent inhibitor. Tested in the BV2 microglia neuroinflammation model, 9a decreased ROS production and downregulated proinflammatory cytokines as iNOS, IL-1β, and IL-6 expression more efficiently than the single target inhibitors (rasagiline for MAOB and VAS2870 for NOXs) but also, more importantly, than their combination.
Collapse
Affiliation(s)
- Beatrice Noce
- Department
of Drug Chemistry and Technologies, Sapienza
University of Rome, P.le Aldo Moro 5, Rome 00185, Italy
| | - Sara Marchese
- Department
of Biology and Biotechnology Lazzaro Spallanzani, University of Pavia, Via Adolfo Ferrata 9A, Pavia 27100, Italy
| | - Marta Massari
- Department
of Biology and Biotechnology Lazzaro Spallanzani, University of Pavia, Via Adolfo Ferrata 9A, Pavia 27100, Italy
| | - Chiara Lambona
- Department
of Drug Chemistry and Technologies, Sapienza
University of Rome, P.le Aldo Moro 5, Rome 00185, Italy
| | - Joana Reis
- Department
of Biology and Biotechnology Lazzaro Spallanzani, University of Pavia, Via Adolfo Ferrata 9A, Pavia 27100, Italy
| | - Francesco Fiorentino
- Department
of Drug Chemistry and Technologies, Sapienza
University of Rome, P.le Aldo Moro 5, Rome 00185, Italy
| | - Alessia Raucci
- Department
of Drug Chemistry and Technologies, Sapienza
University of Rome, P.le Aldo Moro 5, Rome 00185, Italy
| | - Rossella Fioravanti
- Department
of Drug Chemistry and Technologies, Sapienza
University of Rome, P.le Aldo Moro 5, Rome 00185, Italy
| | - Mariana Castelôa
- CIQUP-IMS/Department
of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Rua do Campo Alegre s/n, Porto 4169-007, Portugal
| | - Alessandro Mormino
- Department
of Physiology and Pharmacology, Sapienza
University of Rome, P.le
Aldo Moro 5, Rome 00185, Italy
| | - Stefano Garofalo
- Department
of Physiology and Pharmacology, Sapienza
University of Rome, P.le
Aldo Moro 5, Rome 00185, Italy
| | - Cristina Limatola
- Department
of Physiology and Pharmacology, Sapienza
University of Rome, P.le
Aldo Moro 5, Rome 00185, Italy
| | - Lorenzo Basile
- Department
of Biology and Biotechnology Lazzaro Spallanzani, University of Pavia, Via Adolfo Ferrata 9A, Pavia 27100, Italy
| | - Andrea Gottinger
- Department
of Biology and Biotechnology Lazzaro Spallanzani, University of Pavia, Via Adolfo Ferrata 9A, Pavia 27100, Italy
| | - Claudia Binda
- Department
of Biology and Biotechnology Lazzaro Spallanzani, University of Pavia, Via Adolfo Ferrata 9A, Pavia 27100, Italy
| | - Andrea Mattevi
- Department
of Biology and Biotechnology Lazzaro Spallanzani, University of Pavia, Via Adolfo Ferrata 9A, Pavia 27100, Italy
| | - Antonello Mai
- Department
of Drug Chemistry and Technologies, Sapienza
University of Rome, P.le Aldo Moro 5, Rome 00185, Italy
| | - Sergio Valente
- Department
of Drug Chemistry and Technologies, Sapienza
University of Rome, P.le Aldo Moro 5, Rome 00185, Italy
| |
Collapse
|
|
6
|
Hraoui G, Grondin M, Breton S, Averill-Bates DA. Nrf2 mediates mitochondrial and NADPH oxidase-derived ROS during mild heat stress at 40 °C. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2025; 1872:119897. [PMID: 39800224 DOI: 10.1016/j.bbamcr.2025.119897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 12/29/2024] [Accepted: 01/02/2025] [Indexed: 01/15/2025]
Abstract
Hyperthermia is an adjuvant to chemotherapy and radiotherapy and sensitizes tumors to these treatments. However, repeated heat treatments result in acquisition of heat resistance (thermotolerance) in tumors. Thermotolerance is an adaptive survival response that appears to be mediated by upregulated cellular defenses. However, the mechanisms of activation remain unclear. When HeLa cells were exposed to mild heat shock at 40 °C for 3 h, levels of superoxide and peroxides increased. Cells were treated with mitochondrial antioxidant MitoQ and NADPH oxidase (NOX) inhibitor apocynin to characterize the contribution of these two sources to the total reactive oxygen species (ROS) pool. We found that both mitochondria and NOX are sources of ROS during mild heat shock at 40 °C. Heat-derived ROS are thought to activate the adaptive survival response at 40 °C. Nrf2, the master regulator of the cellular antioxidant response, is thought to play a pivotal role in establishing the adaptive survival response. Nrf2 was overexpressed or knocked down to assess its role. Moreover, Nrf2 levels correlate with the cellular redox state, and do so via scavenging of mitochondria- and NOX-derived ROS. Knockdown of Nrf2 markedly increased levels of ROS that were scavenged by either apocynin or MitoQ. Finally, critical defense proteins such as DJ-1 and PGAM5 seemed to require a two-key activation system mediated by Nrf2 and mitochondrial ROS. Our study characterized mitochondrial and NOX-derived ROS as being essential in activating cellular defenses alongside Nrf2 and underlines potential therapeutic targets that may contribute to the acquisition of thermotolerance.
Collapse
Affiliation(s)
- Georges Hraoui
- Département des sciences biologiques, Université du Québec à Montréal, C.P. 8888, succ. Centre-ville, Montréal, Québec H3C 3P8, Canada
| | - Mélanie Grondin
- Département des sciences biologiques, Université du Québec à Montréal, C.P. 8888, succ. Centre-ville, Montréal, Québec H3C 3P8, Canada
| | - Sophie Breton
- Département de sciences biologiques, Université de Montréal, Montréal, Québec H2V 0B3, Canada
| | - Diana A Averill-Bates
- Département des sciences biologiques, Université du Québec à Montréal, C.P. 8888, succ. Centre-ville, Montréal, Québec H3C 3P8, Canada.
| |
Collapse
|
|
7
|
Cammisotto V, Valeriani E, Pignatelli P, Violi F. Nicotinamide Adenine Dinucleotide Phosphate Oxidases and Metabolic Dysfunction-Associated Steatotic Liver Disease. Antioxidants (Basel) 2025; 14:83. [PMID: 39857417 PMCID: PMC11763266 DOI: 10.3390/antiox14010083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 01/01/2025] [Accepted: 01/11/2025] [Indexed: 01/27/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by lipid accumulation in the liver due to an excess in their supplies or an impairment in their management. While some patients remain stable for years, a proportion of them progress up to steatohepatitis (MASH). MASLD links with systemic pathways being associated with metabolic and non-metabolic diseases. Although liver lipid accumulation represents the first hit for MASLD, the pathophysiology of its development and progression to MASH remains not completely understood. Oxidative stress has received particular attention in recent years, as most of the oxidative process occurs in the liver, which is also the target of oxidative stress-induced damage. Growing evidence linked the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) to the increased liver production of reactive oxygen species up to liver damage and fibrosis. NOX acts both in hepatocytes and in non-parenchymal hepatic cells, contributing to hepatocyte lipotoxicity, impaired hepatic microcirculation, hepatic stellate, and mesenchymal stem cells activation and proliferation. This review aims to summarize the current knowledge on the involvement of oxidative stress in the MASLD-MASH transition, focusing on the role of NOX isoforms, and to suggest targeting NOX as a therapeutic approach in MASLD.
Collapse
Affiliation(s)
- Vittoria Cammisotto
- Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00185 Rome, Italy; (V.C.); (P.P.); (F.V.)
| | - Emanuele Valeriani
- Department of General Surgery and Surgical Specialty, Sapienza University of Rome, 00185 Rome, Italy
- Department of Infectious Disease, Azienda Ospedaliero-Universitaria Policlinico Umberto I, 00161 Rome, Italy
| | - Pasquale Pignatelli
- Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00185 Rome, Italy; (V.C.); (P.P.); (F.V.)
| | - Francesco Violi
- Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00185 Rome, Italy; (V.C.); (P.P.); (F.V.)
| |
Collapse
|
|
8
|
Sharma S, Sharma A, Chauhan RS. Computational dissection through network pharmacology and structure-based analysis unravels mechanistic actions of bioactive compounds in a hepatoprotective herb, Picrorhiza kurroa for the treatment of NAFLD and NASH. J Biomol Struct Dyn 2024:1-16. [PMID: 39644498 DOI: 10.1080/07391102.2024.2438358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 05/17/2024] [Indexed: 12/09/2024]
Abstract
Non-Alcoholic fatty liver disease has become a silent pandemic worldwide with no authorized medicine available. Picrorhiza kurroa is a traditional hepatoprotective herb wherein extracts provide therapeutic efficacy but not the individual compounds. Hence, the aim of the study is exploration of active molecules in P. kurroa extracts and identification of mechanistic actions to pinpoint potential leads towards drug development. We employed network pharmacology to identify the significance of combinatorial effect of compounds on multiple targets. The NAFLD/NASH associated genes encoding protein targets overlapped with the predicted protein targets of P. kurroa compounds. Then, overlapping targets were considered further to capture the interactive targets from Protein-Protein-Interaction network of NAFLD and NASH. The networks were generated to capture the role of proteins in different signaling pathways, diseases, and effective compounds as therapeutics. Furthermore, structural, and biophysical analysis was performed for significant complexes. We observed that the compounds like astragalin, Picroside-I, Vernicoside, Rutin, Quercetin, Kaempferol, Gallic acid, Ellagic acid in P. kurroa acted synergistically by enhancing the bioavailability of active compounds and affecting various morbidities of NAFLD through involvement in different signaling and disease pathways such as oxidative phosphorylation, FoxO signaling, inflammation, several cancerous and diabetic pathways. The network pharmacology revealed the interactive behavior of proteins involved in NAFLD treated by P. kurroa compounds. Furthermore, molecular docking and molecular dynamic simulation study showed potential candidates in therapeutics. Overall, the study suggested multi-target drug discovery for treating complex diseases by providing leads in herbal extracts as potential therapeutic botanicals.
Collapse
Affiliation(s)
- Shilpa Sharma
- Department of Biotechnology, School of Engineering & Applied Sciences, Bennett University, Greater Noida, Uttar Pradesh, India
| | - Ashish Sharma
- Department of Biotechnology, School of Engineering & Applied Sciences, Bennett University, Greater Noida, Uttar Pradesh, India
| | | |
Collapse
|
|
9
|
Malaviya P, Kumar J, Kowluru RA. Role of ferroptosis in mitochondrial damage in diabetic retinopathy. Free Radic Biol Med 2024; 225:821-832. [PMID: 39433112 PMCID: PMC11624098 DOI: 10.1016/j.freeradbiomed.2024.10.296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 10/17/2024] [Accepted: 10/18/2024] [Indexed: 10/23/2024]
Abstract
Diabetic retinopathy is driven by oxidative stress-mitochondrial damage. Activation of ROS producing cytosolic NADPH oxidase 2 (Nox2) in diabetes precedes retinal mitochondrial damage, initiating a vicious cycle of free radicals. Elevated ROS levels peroxidize membrane lipids increasing damaging lipid peroxides (LPOs). While glutathione peroxidase 4 (GPx4) neutralizes LPOs, an imbalance in its generation-neutralization leads to ferroptosis, which is characterized by increased LPOs, free iron and decreased GPx4 activity. Mitochondria are rich in polyunsaturated fatty acids and iron and have mitochondrial isoform of GPx4. Our aim was to investigate mitochondrial ferroptosis in diabetic retinopathy, focusing on Nox2 mediated ROS production. Using human retinal endothelial cells, incubated in 5 mM or 20 mM D-glucose for 12-96 h, with or without Nox2 inhibitors (100 μM apocynin, 5 μM EHop-016 or 5 μM Gp91 ds-tat), or ferroptosis inhibitors (1 μM ferrostatin-1, 50 μM deferoxamine) or activator (0.1 μM RSL3), cytosolic and mitochondrial ROS, LPOs, iron, GPx4 activity, mitochondrial integrity (membrane permeability, oxygen consumption rate, mtDNA copy numbers) and cell death were quantified. High glucose significantly increased ROS, LPOs and iron levels and inhibited GPx4 activity in cytosol, and while Nox2 and ferroptosis inhibitors prevented glucose-induced increase in ferroptosis markers, mitochondrial damage and cell death, RSL3, further worsened them. Furthermore, high glucose also increased ferroptosis markers in the mitochondria, which followed their increase in the cytosol, suggesting a role of cytosolic ROS in mitochondrial ferroptosis. Thus, targeting Nox2-ferroptosis should help break down the self-perpetuating vicious cycle of free radicals, initiated by the damaged mitochondria, and could provide novel therapeutics to prevent/retard the development of diabetic retinopathy.
Collapse
Affiliation(s)
- Pooja Malaviya
- Kresge Eye Institute, Wayne State University, Detroit, MI, USA
| | - Jay Kumar
- Kresge Eye Institute, Wayne State University, Detroit, MI, USA
| | - Renu A Kowluru
- Kresge Eye Institute, Wayne State University, Detroit, MI, USA.
| |
Collapse
|
|
10
|
Yadav P, Beura SK, Panigrahi AR, Kulkarni PP, Yadav MK, Munshi A, Singh SK. Lysophosphatidylcholine induces oxidative stress and calcium-mediated cell death in human blood platelets. Cell Biol Int 2024; 48:1266-1284. [PMID: 38837523 DOI: 10.1002/cbin.12192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 05/06/2024] [Accepted: 05/11/2024] [Indexed: 06/07/2024]
Abstract
Platelets are essential component of circulation that plays a major role in hemostasis and thrombosis. During activation and its demise, platelets release platelet-derived microvesicles, with lysophosphatidylcholine (LPC) being a prominent component in their lipid composition. LPC, an oxidized low-density lipoprotein, is involved in cellular metabolism, but its higher level is implicated in pathologies like atherosclerosis, diabetes, and inflammatory disorders. Despite this, its impact on platelet function remains relatively unexplored. To address this, we studied LPC's effects on washed human platelets. A multimode plate reader was employed to measure reactive oxygen species and intracellular calcium using H2DCF-DA and Fluo-4-AM, respectively. Flow cytometry was utilized to measure phosphatidylserine expression, mitochondrial membrane potential (ΔΨm), and mitochondrial permeability transition pore (mPTP) formation using FITC-Annexin V, JC-1, and CoCl2/calcein-AM, respectively. Additionally, platelet morphology and its ultrastructure were observed via phase contrast and electron microscopy. Sonoclot and light transmission aggregometry were employed to examine fibrin formation and platelet aggregation, respectively. The findings demonstrate that LPC induced oxidative stress and increased intracellular calcium in platelets, resulting in increased phosphatidylserine expression and reduced ΔΨm. LPC triggered caspase-independent platelet death and mPTP opening via cytosolic and mitochondrial calcium, along with microvesiculation and reduced platelet counts. LPC increased the platelet's size, adopting a balloon-shaped morphology, causing membrane fragmentation and releasing its cellular contents, while inducing a pro-coagulant phenotype with increased fibrin formation and reduced integrin αIIbβ3 activation. Conclusively, this study reveals LPC-induced oxidative stress and calcium-mediated platelet death, necrotic in nature with pro-coagulant properties, potentially impacting inflammation and repair mechanisms during vascular injury.
Collapse
Affiliation(s)
- Pooja Yadav
- Department of Zoology, School of Basic Sciences, Central University of Punjab, Ghudda, Bathinda, India
| | - Samir K Beura
- Department of Zoology, School of Basic Sciences, Central University of Punjab, Ghudda, Bathinda, India
| | - Abhishek R Panigrahi
- Department of Zoology, School of Basic Sciences, Central University of Punjab, Ghudda, Bathinda, India
| | - Paresh P Kulkarni
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Mithlesh K Yadav
- Department of Zoology, School of Basic Sciences, Central University of Punjab, Ghudda, Bathinda, India
| | - Anjana Munshi
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Ghudda, Bathinda, India
| | - Sunil K Singh
- Department of Zoology, School of Basic Sciences, Central University of Punjab, Ghudda, Bathinda, India
- Department of Biochemistry, School of Basic Sciences, Central University of Punjab, Ghudda, Bathinda, India
| |
Collapse
|
|
11
|
Ertik O, Sezen Us A, Gul IB, Us H, Coremen M, Karabulut Bulan O, Yanardag R. Reduction of oxidative damage in prostate tissue caused by radiation and/or chloroquine by apocynin. Free Radic Res 2024; 58:458-475. [PMID: 39148420 DOI: 10.1080/10715762.2024.2393147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 08/05/2024] [Accepted: 08/09/2024] [Indexed: 08/17/2024]
Abstract
Prostate damage can occur in men due to age and genetic factors, especially when exposed to external factors. Radiation (RAD) is a prominent factor leading to oxidative stress and potential prostate damage. Additionally, chloroquine (CQ), used in malaria treatment, can induce oxidative stress in a dose-dependent manner. Therefore, reducing and preventing oxidative damage in prostate tissue caused by external factors is crucial. Rats used in the study were divided into seven groups, CQ, apocynin (APO), RAD, CQ + APO, CQ + RAD, APO + RAD, CQ + APO + RAD. Subsequently, in vivo biochemical parameters of prostate tissues were examined, including reduced glutathione, lipid peroxidation, superoxide dismutase, glutathione reductase, glutathione peroxidase, glutathione-S-transferase activities, and total antioxidant status, total oxidant status, reactive oxygen species, oxidative stress index, advanced oxidation protein products and histologically. The in vivo results presented in our study showed that APO reduced oxidative stress and had a protective effect on prostate tissue in the CQ, RAD, and CQ + RAD groups as a results of biochemical and histological experiments. Additionally, in silico studies revealed a higher binding affinity of diapocynin to target proteins compared to APO. As a histological results, RAD and CQ alone or in combination did not induce damage in prostate tissues, whereas mild histopathological findings such as hyperemia and haemorrhage were observed in all APO-treated groups. The results suggest that the use of APO for the treatment of oxidative damage induced by CQ and RAD in rats.
Collapse
Affiliation(s)
- Onur Ertik
- Department of Chemistry, Faculty of Engineering, Istanbul University-Cerrahpaşa, Istanbul, Türkiye
- Department of Chemistry, Faculty of Engineering and Science, Bursa Technical University, Bursa, Türkiye
| | - Ayca Sezen Us
- Department of Biology, Faculty of Science, Istanbul University, Istanbul, Türkiye
| | - Ilknur Bugan Gul
- Department of Biology, Faculty of Science, Istanbul University, Istanbul, Türkiye
| | - Huseyin Us
- Department of Biology, Faculty of Science, Istanbul University, Istanbul, Türkiye
| | - Melis Coremen
- Department of Biology, Faculty of Science, Istanbul University, Istanbul, Türkiye
| | - Omur Karabulut Bulan
- Department of Biology, Faculty of Science, Istanbul University, Istanbul, Türkiye
| | - Refiye Yanardag
- Department of Chemistry, Faculty of Engineering, Istanbul University-Cerrahpaşa, Istanbul, Türkiye
| |
Collapse
|
|
12
|
Davis CK, Bathula S, Jeong S, Arruri V, Choi J, Subramanian S, Ostrom CM, Vemuganti R. An antioxidant and anti-ER stress combination therapy elevates phosphorylation of α-Syn at serine 129 and alleviates post-TBI PD-like pathology in a sex-specific manner in mice. Exp Neurol 2024; 377:114795. [PMID: 38657855 PMCID: PMC12017472 DOI: 10.1016/j.expneurol.2024.114795] [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: 02/22/2024] [Revised: 04/13/2024] [Accepted: 04/21/2024] [Indexed: 04/26/2024]
Abstract
Clinical studies have shown that traumatic brain injury (TBI) increases the onset of Parkinson's disease (PD) in later life by >50%. Oxidative stress, endoplasmic reticulum (ER) stress, and inflammation are the major drivers of both TBI and PD pathologies. We presently evaluated if curtailing oxidative stress and ER stress concomitantly using a combination of apocynin and tert-butylhydroquinone and salubrinal during the acute stage after TBI in mice reduces the severity of late-onset PD-like pathology. The effect of multiple low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on post-TBI neurodegeneration was also evaluated. The combo therapy elevated the level of phosphorylation at serine 129 (pS129) of α-Syn in the pericontusional cortex of male mice at 72 h post-TBI. Motor and cognitive deficits induced by TBI lasted at least 3 months and the combo therapy curtailed these deficits in both sexes. At 3 months post-TBI, male mice given combo therapy exhibited significantly lesser α-Syn aggregates in the SN and higher TH+ cells in the SNpc, compared to vehicle control. However, the aggregate number was not significantly different between groups of female mice. Moreover, TBI-induced loss of TH+ cells was negligible in female mice irrespective of treatment. The MPTP treatment aggravated PD-like pathology in male mice but had a negligible effect on the loss of TH+ cells in female mice. Thus, the present study indicates that mitigation of TBI-induced oxidative stress and ER stress at the acute stage could potentially reduce the risk of post-TBI PD-like pathology at least in male mice, plausibly by elevating pS129-α-Syn level.
Collapse
Affiliation(s)
- Charles K Davis
- Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA
| | | | - Soomin Jeong
- Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA; Neuroscience Training Program, University of Wisconsin, Madison, WI, USA
| | - Vijay Arruri
- Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA
| | - Jeongwoo Choi
- Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA
| | - Shruti Subramanian
- Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA
| | - Carlie M Ostrom
- Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA
| | - Raghu Vemuganti
- Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA; Neuroscience Training Program, University of Wisconsin, Madison, WI, USA; William S. Middleton Memorial Veterans Hospital, Madison, WI, USA.
| |
Collapse
|
|
13
|
Tan JJ, Dai YF, Wang F, Lv ZH, Huang LJ, Peng LY, Li XP. Pepsin-mediated inflammation in laryngopharyngeal reflux via the ROS/NLRP3/IL-1β signaling pathway. Cytokine 2024; 178:156568. [PMID: 38471420 DOI: 10.1016/j.cyto.2024.156568] [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: 09/29/2023] [Revised: 02/19/2024] [Accepted: 03/01/2024] [Indexed: 03/14/2024]
Abstract
BACKGROUND Laryngopharyngeal reflux (LPR) is one of the most common disorders in otorhinolaryngology, affecting up to 10% of outpatients visiting otolaryngology departments. In addition, 50% of hoarseness cases are related to LPR. Pepsin reflux-induced aseptic inflammation is a major trigger of LPR; however, the underlying mechanisms are unclear. The nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome has become an important bridge between stimulation and sterile inflammation and is activated by intracellular reactive oxygen species (ROS) in response to danger signals, leading to an inflammatory cascade. In this study, we aimed to determine whether pepsin causes LPR-associated inflammatory injury via mediating inflammasome activation and explore the potential mechanism. METHODS We evaluated NLRP3 inflammasome expression and ROS in the laryngeal mucosa using immunofluorescence and immunohistochemistry. Laryngeal epithelial cells were exposed to pepsin and analyzed using flow cytometry, western blotting, and real-time quantitative PCR to determine ROS, NLRP3, and pro-inflammatorycytokine levels. RESULTS Pepsin expression was positively correlated with ROS as well as caspase-1 and IL-1β levels in laryngeal tissues. Intracellular ROS levels were elevated by increased pepsin concentrations, which were attenuated by apocynin (APO)-a ROS inhibitor-in vitro. Furthermore, pepsin significantly induced the mRNA and protein expression of thioredoxin-interacting protein, NLRP3, caspase-1, and IL-1β in a dose-dependent manner. APO and the NLRP3 inhibitor, MCC950, inhibited NLRP3 inflammasome formation and suppressed laryngeal epithelial cell damage. CONCLUSION Our findings verified that pepsin could regulate the NLRP3/IL-1β signaling pathway through ROS activation and further induce inflammatory injury in LPR. Targeting the ROS/NLRP3 inflammasome signaling pathway may help treat patients with LPR disease.
Collapse
Affiliation(s)
- Jia-Jie Tan
- Department of Otolaryngology, Head and Neck Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yuan-Feng Dai
- Department of Otolaryngology, Head and Neck Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Fan Wang
- Department of Otolaryngology, Head and Neck Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Ze-Hong Lv
- Department of Otolaryngology, Head and Neck Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Li-Jun Huang
- Department of Otolaryngology, Head and Neck Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Ling-Yi Peng
- Department of Otolaryngology, Head and Neck Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Xiang-Ping Li
- Department of Otolaryngology, Head and Neck Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
| |
Collapse
|
|
14
|
Feng X, Liu X, Wang F, Zhang X, Zhu L, Shu H, Wang C, Duan L, Wang H, Ren Q, Dong F, Zhang Z, Man D, Qu M. Prenatal High-Sucrose Diet Induced Vascular Dysfunction of Renal Interlobar Arteries in the Offspring via PPARγ-RXRg-ROS/Akt Signaling. Mol Nutr Food Res 2024; 68:e2300871. [PMID: 38704749 DOI: 10.1002/mnfr.202300871] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 03/21/2024] [Indexed: 05/07/2024]
Abstract
SCOPE Prenatal nutrition imbalance correlates with developmental origin of cardiovascular diseases; however whether maternal high-sucrose diet (HS) during pregnancy causes vascular damage in renal interlobar arteries (RIA) from offspring still keeps unclear. METHODS AND RESULTS Pregnant rats are fed with normal drinking water or 20% high-sucrose solution during the whole gestational period. Swollen mitochondria and distributed myofilaments are observed in vascular smooth muscle cells of RIA exposed to prenatal HS. Maternal HS increases phenylephrine (PE)-induced vasoconstriction in the RIA from adult offspring. NG-Nitro-l-arginine (L-Name) causes obvious vascular tension in response to PE in offspring from control group, not in HS. RNA-Seq of RIA is performed to reveal that the gene retinoid X receptor g (RXRg) is significantly decreased in the HS group, which could affect vascular function via interacting with PPARγ pathway. By preincubation of RIA with apocynin (NADPH inhibitor) or capivasertib (Akt inhibitor), the results indicate that ROS and Akt are the vital important factors to affect the vascular function of RIA exposure to prenatal HS. CONCLUSION Maternal HS during the pregnancy increases PE-mediated vasoconstriction of RIA from adult offspring, which is mainly related to the enhanced Akt and ROS regulated by the weakened PPARγ-RXRg.
Collapse
Affiliation(s)
- Xueqin Feng
- Department of Obstetrics, Affiliated Hospital of Jining Medical University, Guhuai Road 89, Jining, 272001, China
| | - Xinying Liu
- Department of Obstetrics, Affiliated Hospital of Jining Medical University, Guhuai Road 89, Jining, 272001, China
- Department of Clinical Medicine, Jining Medical University, Jining, 272001, China
| | - Fuling Wang
- Department of Obstetrics, Affiliated Hospital of Jining Medical University, Guhuai Road 89, Jining, 272001, China
| | - Xiaoyun Zhang
- Department of Obstetrics, Affiliated Hospital of Jining Medical University, Guhuai Road 89, Jining, 272001, China
| | - Liangxi Zhu
- Department of Obstetrics, Affiliated Hospital of Jining Medical University, Guhuai Road 89, Jining, 272001, China
| | - Hua Shu
- Department of Obstetrics, Affiliated Hospital of Jining Medical University, Guhuai Road 89, Jining, 272001, China
| | - Chunxia Wang
- Department of Obstetrics, Affiliated Hospital of Jining Medical University, Guhuai Road 89, Jining, 272001, China
| | - Liting Duan
- Department of Obstetrics, Affiliated Hospital of Jining Medical University, Guhuai Road 89, Jining, 272001, China
| | - Haixia Wang
- Department of Obstetrics, Affiliated Hospital of Jining Medical University, Guhuai Road 89, Jining, 272001, China
| | - Qinggui Ren
- Department of Mammary gland Surgery, Affiliated Hospital of Jining Medical University, Jining, 272001, China
| | - Fangxiang Dong
- Department of Obstetrics, Affiliated Hospital of Jining Medical University, Guhuai Road 89, Jining, 272001, China
| | - Ziteng Zhang
- Departments of Thoracic Surgery, Qinghai Red Cross Hospital, Xining, 272001, China
| | - Dongmei Man
- Department of Obstetrics, Affiliated Hospital of Jining Medical University, Guhuai Road 89, Jining, 272001, China
| | - Miaomiao Qu
- Department of Obstetrics, Affiliated Hospital of Jining Medical University, Guhuai Road 89, Jining, 272001, China
| |
Collapse
|
|
15
|
Michalkiewicz S, Skorupa A, Jakubczyk M, Bębacz K. Application of a Carbon Fiber Microelectrode as a Sensor for Apocynin Electroanalysis. MATERIALS (BASEL, SWITZERLAND) 2024; 17:1593. [PMID: 38612107 PMCID: PMC11012570 DOI: 10.3390/ma17071593] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 03/26/2024] [Accepted: 03/28/2024] [Indexed: 04/14/2024]
Abstract
In this study, a carbon fiber microelectrode (CF) was applied for the investigation of the electrochemical behavior of the natural antioxidant, apocynin (APO). Given the limited solubility of APO in water, a mixture of anhydrous acetic acid (AcH) with 20%, v/v acetonitrile (AN) and 0.1 mol L-1 sodium acetate (AcNa) was used. The electrochemical properties of APO were examined through linear sweep voltammetry (LSV), differential pulse voltammetry (DPV), and cyclic voltammetry (CV). The anodic oxidation of APO, which is the basis of the method used, proved to be diffusion-controlled and proceeded with a two-electron and one proton exchange. Both radicals and radical cations, arising from the first and second step of electrode reactions, respectively, underwent subsequent chemical transformations to yield more stable final products (EqCiEiCi mechanism). Using optimized DPV conditions, the anodic peak current of APO at a potential of 0.925 V vs. Ag/AgCl showed a good linear response within the concentration range of 2.7 × 10-6-2.6 × 10-4 mol L-1. The detection and quantification limits were determined as 8.9 × 10-7 and 2.7 × 10-6 mol L-1, respectively. The developed DPV method enabled the successful determination of APO in herbal extracts and in dietary supplements. It should be noted that this is the first method to be used for voltammetric determination of APO.
Collapse
Affiliation(s)
- Slawomir Michalkiewicz
- Institute of Chemistry, Jan Kochanowski University, PL-25406 Kielce, Poland; (A.S.); (M.J.)
| | - Agata Skorupa
- Institute of Chemistry, Jan Kochanowski University, PL-25406 Kielce, Poland; (A.S.); (M.J.)
| | - Magdalena Jakubczyk
- Institute of Chemistry, Jan Kochanowski University, PL-25406 Kielce, Poland; (A.S.); (M.J.)
| | | |
Collapse
|
|
16
|
Abstract
The deterioration of the brain's microvasculature, particularly in the hippocampus, appears to be a very early event in the development of Alzheimer's disease (AD), preceding even the deposition of amyloid-β. A damaged microvasculature reduces the supply of oxygen and glucose to this region and limits the production of energy, ATP. The damage may be a function of the rise with age in the expression and activity of NADPH oxidase (NOX) in these microvessels. This rise renders these vessels vulnerable to the effects of oxidative stress and inflammation. The rise in NOX activity with age is even more marked in the AD brain where an inverse correlation has been demonstrated between NOX activity and cognitive ability. Apocynin, a putative NOX inhibitor, has been shown to block the damaging effects of NOX activation. Apocynin acts as a strong scavenger of H2O2, and as a weak scavenger of superoxide. Like apocynin, sodium oxybate (SO) has also been shown to block the toxic effects of NOX activation. The application of SO generates NADPH and ATP. SO inhibits oxidative stress and maintains normal cerebral ATP levels under hypoxic conditions. Moreover, it acts epigenetically to attenuate the expression of NOX. SO may delay the onset and slow the progress of AD by suppling energy and maintaining an antioxidative environment in the brain throughout the night. The slow wave activity produced by SO may also activate the glymphatic system and promote the clearance of amyloid-β from the brain.
Collapse
Affiliation(s)
- Mortimer Mamelak
- Department of Psychiatry, Baycrest Hospital, University of Toronto, Toronto, Ontario, Canada
| |
Collapse
|
|
17
|
Sepulchro Mulher LCC, Simões RP, Rossi KA, Schereider IRG, Silva Nascimento CLD, Ávila RA, Padilha AS. In vitro cadmium exposure induces structural damage and endothelial dysfunction in female rat aorta. Biometals 2023; 36:1405-1420. [PMID: 37651061 DOI: 10.1007/s10534-023-00526-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 07/31/2023] [Indexed: 09/01/2023]
Abstract
Cadmium is a heavy metal that is widespread in the environment and has been described as a metalloestrogen and a cardiovascular risk factor. Experimental studies conducted in male animals have shown that cadmium exposure induces vascular dysfunction, which could lead to vasculopathies caused by this metal. However, it is necessary to investigate the vascular effects of cadmium in female rats to understand its potential sex-dependent impact on the cardiovascular system. While its effects on male rats have been studied, cadmium may act differently in females due to its potential as a metalloestrogen. In vitro studies conducted in a controlled environment allow for a direct assessment of cadmium's impact on vascular function, and the use of female rats ensures that sex-dependent effects are evaluated. Therefore, the aim of this study was to investigate the in vitro effects of Cadmium Chloride (CdCl2, 5 µM) exposure on vascular reactivity in the isolated aorta of female Wistar rats. Exposure to CdCl2 damaged the architecture of the vascular endothelium. CdCl2 incubation increased the production and release of O2•-, reduced the participation of potassium (K+) channels, and increased the participation of the angiotensin II pathway in response to phenylephrine. Moreover, estrogen receptors alpha (Erα) modulated vascular reactivity to phenylephrine in the presence of cadmium, supporting the hypothesis that cadmium could act as a metalloestrogen. Our results demonstrated that in vitro cadmium exposure induces damage to endothelial architecture and an increase in oxidative stress in the isolated aorta of female rats, which could precipitate vasculopathies. Graphical Abstract. Own source from Canva and Servier Medical Art servers.
Collapse
Affiliation(s)
- Lorraine Christiny Costa Sepulchro Mulher
- Physiological Sciences Post-Graduation Program, CCS/UFES, Federal University of Espírito Santo, Av. Marechal Campos, 1468, 26 Maruípe, Vitoria, ES, 29043-900, Brazil
| | - Rakel Passos Simões
- Physiological Sciences Post-Graduation Program, CCS/UFES, Federal University of Espírito Santo, Av. Marechal Campos, 1468, 26 Maruípe, Vitoria, ES, 29043-900, Brazil
| | - Karoline Alves Rossi
- Physiological Sciences Post-Graduation Program, CCS/UFES, Federal University of Espírito Santo, Av. Marechal Campos, 1468, 26 Maruípe, Vitoria, ES, 29043-900, Brazil
| | - Ingridy Reinholz Grafites Schereider
- Physiological Sciences Post-Graduation Program, CCS/UFES, Federal University of Espírito Santo, Av. Marechal Campos, 1468, 26 Maruípe, Vitoria, ES, 29043-900, Brazil
| | - Camilla Lóren da Silva Nascimento
- Physiological Sciences Post-Graduation Program, CCS/UFES, Federal University of Espírito Santo, Av. Marechal Campos, 1468, 26 Maruípe, Vitoria, ES, 29043-900, Brazil
| | - Renata Andrade Ávila
- Physiological Sciences Post-Graduation Program, CCS/UFES, Federal University of Espírito Santo, Av. Marechal Campos, 1468, 26 Maruípe, Vitoria, ES, 29043-900, Brazil
| | - Alessandra Simão Padilha
- Physiological Sciences Post-Graduation Program, CCS/UFES, Federal University of Espírito Santo, Av. Marechal Campos, 1468, 26 Maruípe, Vitoria, ES, 29043-900, Brazil.
| |
Collapse
|
|
18
|
Higuera-Martínez G, Arciniega-Martínez IM, Jarillo-Luna RA, Cárdenas-Jaramillo LM, Levaro-Loquio D, Velásquez-Torres M, Abarca-Rojano E, Reséndiz-Albor AA, Pacheco-Yépez J. Apocynin, an NADPH Oxidase Enzyme Inhibitor, Prevents Amebic Liver Abscess in Hamster. Biomedicines 2023; 11:2322. [PMID: 37626818 PMCID: PMC10452916 DOI: 10.3390/biomedicines11082322] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 08/02/2023] [Accepted: 08/15/2023] [Indexed: 08/27/2023] Open
Abstract
Amebiasis is an intestinal infection caused by Entamoeba histolytica. Amebic liver abscess (ALA) is the most common extraintestinal complication of amebiasis. In animal models of ALA, neutrophils have been shown to be the first cells to come into contact with Entamoeba histolytica during the initial phase of ALA. One of the multiple mechanisms by which neutrophils exhibit amebicidal activity is through reactive oxygen species (ROS) and the enzyme NADPH oxidase (NOX2), which generates and transports electrons to subsequently reduce molecular oxygen into superoxide anion. Previous reports have shown that ROS release in the susceptible animal species (hamster) is mainly stimulated by the pathogen, in turn provoking such an exacerbated inflammatory reaction that it is unable to be controlled and results in the death of the animal model. Apocynin is a natural inhibitor of NADPH oxidase. No information is available on the role of NOX in the evolution of ALA in the hamster, a susceptible model. Our study showed that administration of a selective NADPH oxidase 2 (NOX2) enzyme inhibitor significantly decreases the percentage of ALA, the size of inflammatory foci, the number of neutrophils, and NOX activity indicated by the reduction in superoxide anion (O2-) production. Moreover, in vitro, the apocynin damages amoebae. Our results showed that apocynin administration induces a decrease in the activity of NOX that could favor a decrease in ALA progression.
Collapse
Affiliation(s)
- Germán Higuera-Martínez
- Sección de Estudios de Postgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City 11340, Mexico; (G.H.-M.); (I.M.A.-M.); (D.L.-L.); (M.V.-T.); (E.A.-R.); (A.A.R.-A.)
| | - Ivonne Maciel Arciniega-Martínez
- Sección de Estudios de Postgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City 11340, Mexico; (G.H.-M.); (I.M.A.-M.); (D.L.-L.); (M.V.-T.); (E.A.-R.); (A.A.R.-A.)
| | - Rosa Adriana Jarillo-Luna
- Coordinación de Ciencias Morfológicas, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City 11340, Mexico; (R.A.J.-L.); (L.M.C.-J.)
| | - Luz María Cárdenas-Jaramillo
- Coordinación de Ciencias Morfológicas, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City 11340, Mexico; (R.A.J.-L.); (L.M.C.-J.)
| | - David Levaro-Loquio
- Sección de Estudios de Postgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City 11340, Mexico; (G.H.-M.); (I.M.A.-M.); (D.L.-L.); (M.V.-T.); (E.A.-R.); (A.A.R.-A.)
| | - Maritza Velásquez-Torres
- Sección de Estudios de Postgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City 11340, Mexico; (G.H.-M.); (I.M.A.-M.); (D.L.-L.); (M.V.-T.); (E.A.-R.); (A.A.R.-A.)
| | - Edgar Abarca-Rojano
- Sección de Estudios de Postgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City 11340, Mexico; (G.H.-M.); (I.M.A.-M.); (D.L.-L.); (M.V.-T.); (E.A.-R.); (A.A.R.-A.)
| | - Aldo Arturo Reséndiz-Albor
- Sección de Estudios de Postgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City 11340, Mexico; (G.H.-M.); (I.M.A.-M.); (D.L.-L.); (M.V.-T.); (E.A.-R.); (A.A.R.-A.)
| | - Judith Pacheco-Yépez
- Sección de Estudios de Postgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City 11340, Mexico; (G.H.-M.); (I.M.A.-M.); (D.L.-L.); (M.V.-T.); (E.A.-R.); (A.A.R.-A.)
| |
Collapse
|
|
19
|
Chan SMH, Brassington K, Almerdasi SA, Dobric A, De Luca SN, Coward‐Smith M, Wang H, Mou K, Akhtar A, Alateeq RA, Wang W, Seow HJ, Selemidis S, Bozinovski S, Vlahos R. Inhibition of oxidative stress by apocynin attenuated chronic obstructive pulmonary disease progression and vascular injury by cigarette smoke exposure. Br J Pharmacol 2023; 180:2018-2034. [PMID: 36908040 PMCID: PMC10953324 DOI: 10.1111/bph.16068] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 02/07/2023] [Accepted: 03/07/2023] [Indexed: 03/14/2023] Open
Abstract
BACKGROUND AND PURPOSE Cardiovascular disease affects up to half of the patients with chronic obstructive pulmonary disease (COPD), exerting deleterious impact on health outcomes and survivability. Vascular endothelial dysfunction marks the onset of cardiovascular disease. The present study examined the effect of a potent NADPH Oxidase (NOX) inhibitor and free-radical scavenger, apocynin, on COPD-related cardiovascular disease. EXPERIMENTAL APPROACH Male BALB/c mice were exposed to either room air (Sham) or cigarette smoke (CS) generated from 9 cigarettes·day-1 , 5 days a week for up to 24 weeks with or without apocynin treatment (5 mg·kg-1 ·day-1 , intraperitoneal injection). KEY RESULTS Eight-weeks of apocynin treatment reduced airway neutrophil infiltration (by 42%) and completely preserved endothelial function and endothelial nitric oxide synthase (eNOS) availability against the oxidative insults of cigarette smoke exposure. These preservative effects were maintained up until the 24-week time point. 24-week of apocynin treatment markedly reduced airway inflammation (reduced infiltration of macrophage, neutrophil and lymphocyte), lung function decline (hyperinflation) and prevented airway collagen deposition by cigarette smoke exposure. CONCLUSION AND IMPLICATIONS Limiting NOX activity may slow COPD progression and lower cardiovascular disease risk, particularly when signs of oxidative stress become evident.
Collapse
Affiliation(s)
- Stanley M. H. Chan
- Centre for Respiratory Science and Health, School of Health and Biomedical SciencesRMIT UniversityBundooraVictoria3083Australia
| | - Kurt Brassington
- Centre for Respiratory Science and Health, School of Health and Biomedical SciencesRMIT UniversityBundooraVictoria3083Australia
| | - Suleman Abdullah Almerdasi
- Centre for Respiratory Science and Health, School of Health and Biomedical SciencesRMIT UniversityBundooraVictoria3083Australia
| | - Aleksandar Dobric
- Centre for Respiratory Science and Health, School of Health and Biomedical SciencesRMIT UniversityBundooraVictoria3083Australia
| | - Simone N. De Luca
- Centre for Respiratory Science and Health, School of Health and Biomedical SciencesRMIT UniversityBundooraVictoria3083Australia
| | - Madison Coward‐Smith
- Centre for Respiratory Science and Health, School of Health and Biomedical SciencesRMIT UniversityBundooraVictoria3083Australia
| | - Hao Wang
- Centre for Respiratory Science and Health, School of Health and Biomedical SciencesRMIT UniversityBundooraVictoria3083Australia
| | - Kevin Mou
- Centre for Respiratory Science and Health, School of Health and Biomedical SciencesRMIT UniversityBundooraVictoria3083Australia
| | - Alina Akhtar
- Centre for Respiratory Science and Health, School of Health and Biomedical SciencesRMIT UniversityBundooraVictoria3083Australia
| | - Rana Abdullah Alateeq
- Centre for Respiratory Science and Health, School of Health and Biomedical SciencesRMIT UniversityBundooraVictoria3083Australia
| | - Wei Wang
- Centre for Respiratory Science and Health, School of Health and Biomedical SciencesRMIT UniversityBundooraVictoria3083Australia
| | - Huei Jiunn Seow
- Centre for Respiratory Science and Health, School of Health and Biomedical SciencesRMIT UniversityBundooraVictoria3083Australia
| | - Stavros Selemidis
- Centre for Respiratory Science and Health, School of Health and Biomedical SciencesRMIT UniversityBundooraVictoria3083Australia
| | - Steven Bozinovski
- Centre for Respiratory Science and Health, School of Health and Biomedical SciencesRMIT UniversityBundooraVictoria3083Australia
| | - Ross Vlahos
- Centre for Respiratory Science and Health, School of Health and Biomedical SciencesRMIT UniversityBundooraVictoria3083Australia
| |
Collapse
|
|
20
|
Frara N, Giaddui D, Braverman AS, Jawawdeh K, Wu C, Ruggieri, Sr MR, Barbe MF. Mechanisms involved in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox)-derived reactive oxygen species (ROS) modulation of muscle function in human and dog bladders. PLoS One 2023; 18:e0287212. [PMID: 37352265 PMCID: PMC10289437 DOI: 10.1371/journal.pone.0287212] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 06/01/2023] [Indexed: 06/25/2023] Open
Abstract
Roles of redox signaling in bladder function is still under investigation. We explored the physiological role of reactive oxygen species (ROS) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) in regulating bladder function in humans and dogs. Mucosa-denuded bladder smooth muscle strips obtained from 7 human organ donors and 4 normal dogs were mounted in muscle baths, and trains of electrical field stimulation (EFS) applied for 20 minutes at 90-second intervals. Subsets of strips were incubated with hydrogen peroxide (H2O2), angiotensin II (Ang II; Nox activator), apocynin (inhibitor of Noxs and ROS scavenger), or ZD7155 (specific inhibitor of angiotensin type 1 (AT1) receptor) for 20 minutes in continued EFS trains. Subsets treated with inhibitors were then treated with H2O2 or Ang II. In human and dog bladders, the ROS, H2O2 (100μM), caused contractions and enhanced EFS-induced contractions. Apocynin (100μM) attenuated EFS-induced strip contractions in both species; subsequent treatment with H2O2 restored strip activity. In human bladders, Ang II (1μM) did not enhance EFS-induced contractions yet caused direct strip contractions. In dog bladders, Ang II enhanced both EFS-induced and direct contractions. Ang II also partially restored EFS-induced contractions attenuated by prior apocynin treatment. In both species, treatment with ZD7155 (10μM) inhibited EFS-induced activity; subsequent treatment with Ang II did not restore strip activity. Collectively, these data provide evidence that ROS can modulate bladder function without exogenous stimuli. Since inflammation is associated with oxidative damage, the effects of Ang II on bladder smooth muscle function may have pathologic implications.
Collapse
Affiliation(s)
- Nagat Frara
- Center for Translational Medicine at the Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, United States of America
| | - Dania Giaddui
- Center for Translational Medicine at the Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, United States of America
| | - Alan S. Braverman
- Center for Translational Medicine at the Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, United States of America
| | - Kais Jawawdeh
- Center for Translational Medicine at the Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, United States of America
| | - Changhao Wu
- Department of Biochemistry and Physiology, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom
| | - Michael R. Ruggieri, Sr
- Center for Translational Medicine at the Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, United States of America
- Department of Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts, United States of America
| | - Mary F. Barbe
- Center for Translational Medicine at the Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, United States of America
| |
Collapse
|
|
21
|
Mason H, Rai G, Kozyr A, De Jonge N, Gliniewicz E, Berg LJ, Wald G, Dorrier C, Henderson MJ, Zakharov A, Dyson T, Audley J, Pettinato AM, Padilha EC, Shah P, Xu X, Leto TL, Simeonov A, Zarember KA, McGavern DB, Gallin JI. Development of an improved and specific inhibitor of NADPH oxidase 2 to treat traumatic brain injury. Redox Biol 2023; 60:102611. [PMID: 36709665 PMCID: PMC9894920 DOI: 10.1016/j.redox.2023.102611] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 12/22/2022] [Accepted: 01/11/2023] [Indexed: 01/19/2023] Open
Abstract
NADPH oxidases (NOX's), and the reactive oxygen species (ROS) they produce, play an important role in host defense, thyroid hormone synthesis, apoptosis, gene regulation, angiogenesis and other processes. However, overproduction of ROS by these enzymes is associated with cardiovascular disease, fibrosis, traumatic brain injury (TBI) and other diseases. Structural similarities between NOX's have complicated development of specific inhibitors. Here, we report development of NCATS-SM7270, a small molecule optimized from GSK2795039, that inhibited NOX2 in primary human and mouse granulocytes. NCATS-SM7270 specifically inhibited NOX2 and had reduced inhibitory activity against xanthine oxidase in vitro. We also studied the role of several NOX isoforms during mild TBI (mTBI) and demonstrated that NOX2 and, to a lesser extent, NOX1 deficient mice are protected from mTBI pathology, whereas injury is exacerbated in NOX4 knockouts. Given the pathogenic role played by NOX2 in mTBI, we treated mice transcranially with NCATS-SM7270 after injury and revealed a dose-dependent reduction in mTBI induced cortical cell death. This inhibitor also partially reversed cortical damage observed in NOX4 deficient mice following mTBI. These data demonstrate that NCATS-SM7270 is an improved and specific inhibitor of NOX2 capable of protecting mice from NOX2-dependent cell death associated with mTBI.
Collapse
Affiliation(s)
- Hannah Mason
- Viral Immunology and Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892, USA.
| | - Ganesha Rai
- National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA
| | - Arina Kozyr
- Clinical Pathophysiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute for Allergy and Infectious Diseases, Bethesda, MD, 20892, USA
| | - Nathaniel De Jonge
- Clinical Pathophysiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute for Allergy and Infectious Diseases, Bethesda, MD, 20892, USA
| | - Emily Gliniewicz
- Clinical Pathophysiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute for Allergy and Infectious Diseases, Bethesda, MD, 20892, USA
| | - Lars J Berg
- Clinical Pathophysiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute for Allergy and Infectious Diseases, Bethesda, MD, 20892, USA
| | - Gal Wald
- Clinical Pathophysiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute for Allergy and Infectious Diseases, Bethesda, MD, 20892, USA
| | - Cayce Dorrier
- Viral Immunology and Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Mark J Henderson
- National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA
| | - Alexey Zakharov
- National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA
| | - Tristan Dyson
- Viral Immunology and Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892, USA
| | - John Audley
- Clinical Pathophysiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute for Allergy and Infectious Diseases, Bethesda, MD, 20892, USA
| | - Anthony M Pettinato
- Clinical Pathophysiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute for Allergy and Infectious Diseases, Bethesda, MD, 20892, USA
| | - Elias Carvalho Padilha
- National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA
| | - Pranav Shah
- National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA
| | - Xin Xu
- National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA
| | - Thomas L Leto
- Molecular Defenses Section, Laboratory of Clinical Immunology and Microbiology, National Institute for Allergy and Infectious Diseases, Bethesda, MD, 20892, USA
| | - Anton Simeonov
- National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA
| | - Kol A Zarember
- Clinical Pathophysiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute for Allergy and Infectious Diseases, Bethesda, MD, 20892, USA.
| | - Dorian B McGavern
- Viral Immunology and Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892, USA.
| | - John I Gallin
- Clinical Pathophysiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute for Allergy and Infectious Diseases, Bethesda, MD, 20892, USA.
| |
Collapse
|
|
22
|
Mohammad A, Babiker F, Al-Bader M. Effects of Apocynin, a NADPH Oxidase Inhibitor, in the Protection of the Heart from Ischemia/Reperfusion Injury. Pharmaceuticals (Basel) 2023; 16:492. [PMID: 37111249 PMCID: PMC10141704 DOI: 10.3390/ph16040492] [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: 02/17/2023] [Revised: 03/21/2023] [Accepted: 03/23/2023] [Indexed: 03/29/2023] Open
Abstract
Ischemia and perfusion (I/R) induce inflammation and oxidative stress, which play a notable role in tissue damage. The aim of this study was to investigate the role of an NADPH oxidase inhibitor (apocynin) in the protection of the heart from I/R injury. Hearts isolated from Wistar rats (n = 8 per group) were perfused with a modified Langendorff preparation. Left ventricular (LV) contractility and cardiovascular hemodynamics were evaluated by a data acquisition program, and infarct size was evaluated by 2,3,5-Triphenyl-2H-tetrazolium chloride (TTC) staining. Furthermore, the effect of apocynin on the pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) and anti-inflammatory cytokine (IL-10) was evaluated using an enzyme linked immunosorbent assay (ELISA). Hearts were subjected to 30 min of regional ischemia, produced by ligation of the left anterior descending (LAD) coronary artery, followed by 30 min of reperfusion. Hearts were infused with apocynin before ischemia, during ischemia or at reperfusion. To understand the potential pathways of apocynin protection of the heart, a nitric oxide donor (S-nitroso-N-acetylpenicillamine, SNAP), nitric oxide blocker (N (gamma)-nitro-L-arginine methyl ester, L-Name), nicotinic acid adenine dinucleotide phosphate (NAADP) inhibiter (Ned-K), cyclic adenosine diphosphate ribose (cADPR) agonist, or CD38 blocker (Thiazoloquin (az)olin (on)e compound, 78c) was infused with apocynin. Antioxidants were evaluated by measuring superoxide dismutase (SOD) and catalase (CAT) activity. Apocynin infusion before ischemia or at reperfusion protected the heart by normalizing cardiac hemodynamics and decreasing the infarct size. Apocynin treatment resulted in a significant (p < 0.05) decrease in pro-inflammatory cytokine levels and a significant increase (p < 0.05) in anti-inflammatory and antioxidant levels. Apocynin infusion protected the heart by improving LV hemodynamics and coronary vascular dynamics. This treatment decreased the infarct size and inflammatory cytokine levels and increased anti-inflammatory cytokine and antioxidant levels. This protection follows a pathway involving CD38, nitric oxide and acidic stores.
Collapse
Affiliation(s)
| | - Fawzi Babiker
- Department of Physiology, Faculty of Medicine, Kuwait University, P.O. Box 24923, Kuwait City 13110, Kuwait
| | | |
Collapse
|
|
23
|
De Luca SN, Chan SMH, Dobric A, Wang H, Seow HJ, Brassington K, Mou K, Alateeq R, Akhtar A, Bozinovski S, Vlahos R. Cigarette smoke-induced pulmonary impairment is associated with social recognition memory impairments and alterations in microglial profiles within the suprachiasmatic nucleus of the hypothalamus. Brain Behav Immun 2023; 109:292-307. [PMID: 36775074 DOI: 10.1016/j.bbi.2023.02.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 01/29/2023] [Accepted: 02/07/2023] [Indexed: 02/12/2023] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is a major, incurable respiratory condition that is primarily caused by cigarette smoking (CS). Neurocognitive disorders including cognitive dysfunction, anxiety and depression are highly prevalent in people with COPD. It is understood that increased lung inflammation and oxidative stress from CS exposure may 'spill over' into the systemic circulation to promote the onset of these extra-pulmonary comorbidities, and thus impacts the quality of life of people with COPD. The precise role of the 'spill-over' of inflammation and oxidative stress in the onset of COPD-related neurocognitive disorders are unclear. The present study investigated the impact of chronic CS exposure on anxiety-like behaviors and social recognition memory, with a particular focus on the role of the 'spill-over' of inflammation and oxidative stress from the lungs. Adult male BALB/c mice were exposed to either room air (sham) or CS (9 cigarettes per day, 5 days a week) for 24 weeks and were either daily co-administered with the NOX2 inhibitor, apocynin (5 mg/kg, in 0.01 % DMSO diluted in saline, i.p.) or vehicle (0.01 % DMSO in saline) one hour before the initial CS exposure of the day. After 23 weeks, mice underwent behavioral testing and physiological diurnal rhythms were assessed by monitoring diurnal regulation profiles. Lungs were collected and assessed for hallmark features of COPD. Consistent with its anti-inflammatory and oxidative stress properties, apocynin treatment partially lessened lung inflammation and lung function decline in CS mice. CS-exposed mice displayed marked anxiety-like behavior and impairments in social recognition memory compared to sham mice, which was prevented by apocynin treatment. Apocynin was unable to restore the decreased Bmal1-positive cells, key in cells in diurnal regulation, in the suprachiasmatic nucleus of the hypothalamus to that of sham levels. CS-exposed mice treated with apocynin was associated with a restoration of microglial area per cell and basal serum corticosterone. This data suggests that we were able to model the CS-induced social recognition memory impairments seen in humans with COPD. The preventative effects of apocynin on memory impairments may be via a microglial dependent mechanism.
Collapse
Affiliation(s)
- Simone N De Luca
- Centre for Respiratory Science and Health, School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
| | - Stanley M H Chan
- Centre for Respiratory Science and Health, School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
| | - Aleksandar Dobric
- Centre for Respiratory Science and Health, School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
| | - Hao Wang
- Centre for Respiratory Science and Health, School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
| | - Huei Jiunn Seow
- Centre for Respiratory Science and Health, School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
| | - Kurt Brassington
- Centre for Respiratory Science and Health, School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
| | - Kevin Mou
- Centre for Respiratory Science and Health, School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
| | - Rana Alateeq
- Centre for Respiratory Science and Health, School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
| | - Alina Akhtar
- Centre for Respiratory Science and Health, School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
| | - Steven Bozinovski
- Centre for Respiratory Science and Health, School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
| | - Ross Vlahos
- Centre for Respiratory Science and Health, School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia.
| |
Collapse
|
|
24
|
Jeske R, Chen X, Ma S, Zeng EZ, Driscoll T, Li Y. Bioreactor Expansion Reconfigures Metabolism and Extracellular Vesicle Biogenesis of Human Adipose-derived Stem Cells In Vitro. Biochem Eng J 2022; 188:108711. [PMID: 36540623 PMCID: PMC9762695 DOI: 10.1016/j.bej.2022.108711] [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] [Indexed: 11/05/2022]
Abstract
Human mesenchymal stem cells (hMSCs), including human adipose tissue-derived stem cells (hASCs), as well as the secreted extracellular vesicles (EVs), are promising therapeutics in treating inflammatory and neural degenerative diseases. However, prolonged expansion can lead to cellular senescence characterized by a gradual loss of self-renewal ability while altering secretome composition and EV generation. Additionally, hMSCs are highly sensitive to biophysical microenvironment in bioreactor systems utilized in scaling production. In this study, hASCs grown on Plastic Plus or Synthemax II microcarriers in a spinner flask bioreactor (SFB) system were compared to traditional 2D culture. The SFB microenvironment was found to increase the expression of genes associated with hASC stemness, nicotinamide adenine dinucleotide (NAD+) metabolism, glycolysis, and the pentose phosphate pathway as well as alter cytokine secretion (e.g., PGE2 and CXCL10). Elevated reactive oxidative species levels in hASCs of SFB culture were observed without increasing rates of cellular senescence. Expression levels of Sirtuins responsible for preventing cellular senescence through anti-oxidant and DNA repair mechanisms were also elevated in SFB cultures. In particular, the EV biogenesis genes were significantly upregulated (3-10 fold) and the EV production increased 40% per cell in SFB cultures of hASCs. This study provides advanced understanding of hASC sensitivity to the bioreactor microenvironment for EV production and bio-manufacturing towards the applications in treating inflammatory and neural degenerative diseases.
Collapse
Affiliation(s)
- Richard Jeske
- Department of Chemical and Biomedical Engineering, FAMU-FSU college of engineering, Florida state university, USA
| | - Xingchi Chen
- Department of Chemical and Biomedical Engineering, FAMU-FSU college of engineering, Florida state university, USA
| | - Shaoyang Ma
- Department of Chemical and Biomedical Engineering, FAMU-FSU college of engineering, Florida state university, USA
| | - Eric Z Zeng
- Department of Chemical and Biomedical Engineering, FAMU-FSU college of engineering, Florida state university, USA
| | - Tristan Driscoll
- Department of Chemical and Biomedical Engineering, FAMU-FSU college of engineering, Florida state university, USA
| | - Yan Li
- Department of Chemical and Biomedical Engineering, FAMU-FSU college of engineering, Florida state university, USA
| |
Collapse
|
|
25
|
Wound Healing and Anti-Inflammatory Effects of a Newly Developed Ointment Containing Jujube Leaves Extract. LIFE (BASEL, SWITZERLAND) 2022; 12:life12121947. [PMID: 36556312 PMCID: PMC9785415 DOI: 10.3390/life12121947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 11/15/2022] [Accepted: 11/19/2022] [Indexed: 11/24/2022]
Abstract
Ziziphus jujuba Mill. (jujube) is a well-known medicinal plant with pronounced wound healing properties. The present study aimed to establish the chemical composition of the lyophilized ethanolic extract from Romanian Ziziphus jujuba leaves and to evaluate the healing and anti-inflammatory properties of a newly developed lipophilic ointment containing 10% dried jujube leaves extract. The ultra-High-Performance Liquid Chromatography Electrospray Ionization Tandem Mass Spectrometry method was used, and 47 compounds were detected, among them the novel epicatechin and caffeic acid. The extract contains significant amounts of rutin (29.836 mg/g), quercetin (15.180 mg/g) and chlorogenic acid (350.96 µg/g). The lipophilic ointment has a slightly tolerable pH, between 5.41-5.42, and proved to be non-toxic in acute dermal irritation tests on New Zealand albino rabbits and after repeated administration on Wistar rats. The ointment also has a healing activity comparable to Cicatrizin (a pharmaceutical marketed product) on Wistar rats and a moderate anti-inflammatory action compared to the control group, but statistically insignificant compared to indomethacin in the rat-induced inflammation test by intraplantar administration of kaolin. The healing and anti-inflammatory properties of the tested ointment are due to phenolic acids and flavonoids content, less because of minor components as apocynin, scopoletin, and isofraxidin.
Collapse
|
|
26
|
Graton ME, Ferreira BHSH, Troiano JA, Potje SR, Vale GT, Nakamune ACMS, Tirapelli CR, Miller FJ, Ximenes VF, Antoniali C. Comparative study between apocynin and protocatechuic acid regarding antioxidant capacity and vascular effects. Front Physiol 2022; 13:1047916. [PMID: 36457305 PMCID: PMC9707364 DOI: 10.3389/fphys.2022.1047916] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 10/18/2022] [Indexed: 03/14/2024] Open
Abstract
Reactive oxygen species (ROS) derived from NOX enzymes activity play an important role in the development of cardiovascular diseases. Compounds able to decrease oxidative stress damage are potential candidates as drugs and/or supplements for hypertension treatment. Here, we aimed to compare in vitro ROS scavenging potency, effective NOX inhibition and effects on vascular reactivity of apocynin to another phenolic compound, protocatechuic acid, in vascular cells from spontaneously hypertensive rat (SHR), where redox signaling is altered and contributes to the development and/or maintenance of hypertension. We evaluated the in vitro antioxidant capacity and free radical scavenging capacity of both phenolic compounds. Moreover, we investigated the effect of both compounds on lipid peroxidation, lucigenin chemiluminescence, nitric oxide (NO•) levels and ROS concentration in vascular cells of SHR or human umbilical vein endothelial cell (HUVEC). Apocynin and protocatechuic acid presented antioxidant capacity and ability as free radical scavengers, decreased thiobarbituric acid reactive substances (TBARS) in aortic cells from SHR, and increased NO• concentration in isolated HUVEC. Both compounds were able to reduce lucigenin chemiluminescence and increased the potency of acetylcholine in aorta of SHR. However, in SHR aortas, only apocynin diminished the contraction induced by phenylephrine. In conclusion, these results strongly reinforce the potential application of substances such as apocynin and protocatechuic acid that combine abilities as scavenging and/or prevention of ROS generation, establishment of NO bioactivity and modulation of vascular reactivity. Due to its phytochemical origin and low toxicity, its potential therapeutic use in vascular diseases should be considered.
Collapse
Affiliation(s)
- Murilo E. Graton
- Programa de Pós-graduação Multicêntrico em Ciências Fisiológicas, SBFis, São Paulo State University (UNESP), Araçatuba, São Paulo, Brazil
- Department of Basic Sciences, School of Dentistry, São Paulo State University (UNESP), Araçatuba, São Paulo, Brazil
| | - Bruno H. S. H. Ferreira
- Department of Support, Production and Animal Health, School of Veterinary Medicine, São Paulo State University (UNESP), Araçatuba, São Paulo, Brazil
| | - Jéssica A. Troiano
- Programa de Pós-graduação Multicêntrico em Ciências Fisiológicas, SBFis, São Paulo State University (UNESP), Araçatuba, São Paulo, Brazil
- Department of Basic Sciences, School of Dentistry, São Paulo State University (UNESP), Araçatuba, São Paulo, Brazil
- Fundação Dracenense de Educação e Cultura (FUNDEC), Faculdades de Dracena (UNIFADRA), Dracena, São Paulo, Brazil
| | - Simone R. Potje
- Department of Biosciences, Minas Gerais State University (UEMG), Belo Horizonte, Minas Gerais, Brazil
| | - Gabriel T. Vale
- Department of Biosciences, Minas Gerais State University (UEMG), Belo Horizonte, Minas Gerais, Brazil
| | - Ana Cláudia M. S. Nakamune
- Programa de Pós-graduação Multicêntrico em Ciências Fisiológicas, SBFis, São Paulo State University (UNESP), Araçatuba, São Paulo, Brazil
- Department of Basic Sciences, School of Dentistry, São Paulo State University (UNESP), Araçatuba, São Paulo, Brazil
| | - Carlos R. Tirapelli
- Department of Psychiatry Nursing and Human Sciences, College of Nursing of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil
| | - Francis J. Miller
- Nashville VA Medical Center, Vanderbilt University, Nashville, TN, United States
| | - Valdecir F. Ximenes
- Department of Chemistry, Faculty of Sciences, São Paulo State University (UNESP), Bauru, São Paulo, Brazil
| | - Cristina Antoniali
- Programa de Pós-graduação Multicêntrico em Ciências Fisiológicas, SBFis, São Paulo State University (UNESP), Araçatuba, São Paulo, Brazil
- Department of Basic Sciences, School of Dentistry, São Paulo State University (UNESP), Araçatuba, São Paulo, Brazil
| |
Collapse
|
|
27
|
Paloschi MV, Boeno CN, Lopes JA, Rego CMA, Silva MDS, Santana HM, Serrath SN, Ikenohuchi YJ, Farias BJC, Felipin KP, Nery NM, Dos Reis VP, de Lima Lemos CT, Evangelista JR, da Silva Setúbal S, Soares AM, Zuliani JP. Reactive oxygen species-dependent-NLRP3 inflammasome activation in human neutrophils induced by l-amino acid oxidase derived from Calloselasma rhodostoma venom. Life Sci 2022; 308:120962. [PMID: 36113732 DOI: 10.1016/j.lfs.2022.120962] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 08/31/2022] [Accepted: 09/10/2022] [Indexed: 11/20/2022]
Abstract
l-Amino acid oxidase isolated from Calloselasma rhodostoma (Cr-LAAO) snake venom is a potent stimulus for neutrophil activation and production of inflammatory mediators, contributing to local inflammatory effects in victims of envenoming. Cr-LAAO triggered the activation of nicotinamide adenine dinucleotide phosphatase (NADPH) oxidase complex and protein kinase C (PKC)-α signaling protein for reactive oxygen species (ROS) production. This study aims to evaluate the ROS participation in the NLRP3 inflammasome complex activation in human neutrophil. Human neutrophils were isolated and stimulated for 1 or 2 h with RPMI (negative control), LPS (1 μg/mL, positive control) or Cr-LAAO (50 μg/mL). The neutrophil transcriptome was examined using the microarray technique, and RT-qPCR for confirmation of gene expression. Immunofluorescence assays for NLRP3, caspase-1, IL-1β and GSDMD proteins was performed by Western blot in the presence and/or absence of Apocynin, an inhibitor of NADPH oxidase. IL-1β release was also detected in the presence and/or absence of NLRP3, caspase-1 and NADPH oxidase inhibitors. Results showed that Cr-LAAO upregulated the expression of genes that participate in the NADPH oxidase complex formation and inflammasome assembly. NLRP3 was activated and accumulated in the cytosol forming punctas, indicating its activation. Gasdermin D was not cleaved but lactate dehydrogenase was released. Furthermore, ROS inhibition decreased the expression of NLRP3 inflammasome complex proteins, as observed by protein expression in the presence and/or absence of apocynin, an NADPH oxidase inhibitor. IL-1β was also released, and pharmacological inhibition of NLRP3, caspase-1, and ROS reduced the amount of released cytokine. This is the first report demonstrating the activation of the NLRP3 inflammasome complex via ROS generation by Cr-LAAO, which may lead to the development of local inflammatory effects observed in snakebite victims.
Collapse
Affiliation(s)
- Mauro Valentino Paloschi
- Laboratório de Imunologia Celular Aplicada à Saúde, Fundação Oswaldo Cruz, FIOCRUZ Rondônia, Porto Velho, RO, Brazil
| | - Charles Nunes Boeno
- Laboratório de Imunologia Celular Aplicada à Saúde, Fundação Oswaldo Cruz, FIOCRUZ Rondônia, Porto Velho, RO, Brazil
| | - Jéssica Amaral Lopes
- Laboratório de Imunologia Celular Aplicada à Saúde, Fundação Oswaldo Cruz, FIOCRUZ Rondônia, Porto Velho, RO, Brazil
| | - Cristina Matiele Alves Rego
- Laboratório de Imunologia Celular Aplicada à Saúde, Fundação Oswaldo Cruz, FIOCRUZ Rondônia, Porto Velho, RO, Brazil
| | - Milena Daniela Souza Silva
- Laboratório de Imunologia Celular Aplicada à Saúde, Fundação Oswaldo Cruz, FIOCRUZ Rondônia, Porto Velho, RO, Brazil
| | - Hallison Mota Santana
- Laboratório de Imunologia Celular Aplicada à Saúde, Fundação Oswaldo Cruz, FIOCRUZ Rondônia, Porto Velho, RO, Brazil
| | - Suzanne Nery Serrath
- Laboratório de Imunologia Celular Aplicada à Saúde, Fundação Oswaldo Cruz, FIOCRUZ Rondônia, Porto Velho, RO, Brazil
| | - Yoda Janaina Ikenohuchi
- Laboratório de Imunologia Celular Aplicada à Saúde, Fundação Oswaldo Cruz, FIOCRUZ Rondônia, Porto Velho, RO, Brazil
| | - Braz Junior Campos Farias
- Laboratório de Imunologia Celular Aplicada à Saúde, Fundação Oswaldo Cruz, FIOCRUZ Rondônia, Porto Velho, RO, Brazil
| | - Kátia Paula Felipin
- Laboratório de Imunologia Celular Aplicada à Saúde, Fundação Oswaldo Cruz, FIOCRUZ Rondônia, Porto Velho, RO, Brazil
| | - Neriane Monteiro Nery
- Laboratório de Imunologia Celular Aplicada à Saúde, Fundação Oswaldo Cruz, FIOCRUZ Rondônia, Porto Velho, RO, Brazil
| | - Valdison Pereira Dos Reis
- Laboratório de Imunologia Celular Aplicada à Saúde, Fundação Oswaldo Cruz, FIOCRUZ Rondônia, Porto Velho, RO, Brazil
| | - Caleb Torres de Lima Lemos
- Laboratório de Imunologia Celular Aplicada à Saúde, Fundação Oswaldo Cruz, FIOCRUZ Rondônia, Porto Velho, RO, Brazil
| | - Jaina Rodrigues Evangelista
- Laboratório de Imunologia Celular Aplicada à Saúde, Fundação Oswaldo Cruz, FIOCRUZ Rondônia, Porto Velho, RO, Brazil
| | - Sulamita da Silva Setúbal
- Laboratório de Imunologia Celular Aplicada à Saúde, Fundação Oswaldo Cruz, FIOCRUZ Rondônia, Porto Velho, RO, Brazil
| | - Andreimar Martins Soares
- Centro de Estudos de Biomoléculas Aplicadas à Saúde (CEBio), Fundação Oswaldo Cruz, FIOCRUZ Rondônia e Departamento de Medicina, Universidade Federal de Rondônia, UNIR, Porto Velho, RO, Brazil
| | - Juliana Pavan Zuliani
- Laboratório de Imunologia Celular Aplicada à Saúde, Fundação Oswaldo Cruz, FIOCRUZ Rondônia, Porto Velho, RO, Brazil; Centro de Estudos de Biomoléculas Aplicadas à Saúde (CEBio), Fundação Oswaldo Cruz, FIOCRUZ Rondônia e Departamento de Medicina, Universidade Federal de Rondônia, UNIR, Porto Velho, RO, Brazil.
| |
Collapse
|
|
28
|
Qiu J, Liu D, Li P, Zhou L, Zhou L, Liu X, Zhang Y, Yuan M, Tse G, Li G, Liu T. NADPH Oxidase Mediates Oxidative Stress and Ventricular Remodeling through SIRT3/FOXO3a Pathway in Diabetic Mice. Antioxidants (Basel) 2022; 11:1745. [PMID: 36139819 PMCID: PMC9495652 DOI: 10.3390/antiox11091745] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 08/29/2022] [Accepted: 08/30/2022] [Indexed: 12/03/2022] Open
Abstract
Oxidative stress and mitochondrial dysfunction are important mechanisms of ventricular remodeling, predisposed to the development of diabetic cardiomyopathy (DCM) in type 2 diabetes mellitus. In this study, we have successfully established a model of type 2 diabetes using a high-fat diet (HFD) in combination with streptozotocin (STZ). The mice were divided into three groups of six at random: control, diabetes, and diabetes with apocynin and the H9c2 cell line was used as an in vitro model for investigation. We examined the molecular mechanisms of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation on mitochondrial dysfunction and ventricular remodeling in the diabetic mouse model. Hyperglycemia-induced oxidative stress led to a reduced expression of sirtuin 3 (SIRT3), thereby promoting forkhead box class O 3a (FOXO3a) acetylation in ventricular tissue and H9c2 cells. Reactive oxygen species (ROS) overproduction promoted ventricular structural modeling and conduction defects. These alterations were mitigated by inhibiting NADPH oxidase with the pharmaceutical drug apocynin (APO). Apocynin improved SIRT3 and Mn-SOD expression in H9c2 cells transfected with SIRT3 siRNA. In our diabetic mouse model, apocynin improved myocardial mitochondrial function and ROS overproduction through the recovery of the SIRT3/FOXO3a pathway, thereby reducing ventricular remodeling and the incidence of DCM.
Collapse
Affiliation(s)
- Jiuchun Qiu
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Daiqi Liu
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Pengsha Li
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Lingling Zhou
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
- Department of Cardiology, Wenzhou People’s Hospital, No. 299 Guan Road, Wenzhou 325000, China
| | - Lu Zhou
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Xing Liu
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Yue Zhang
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Meng Yuan
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Gary Tse
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Guangping Li
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Tong Liu
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
| |
Collapse
|
|
29
|
Guo J, Yu X, Liu Y, Lu L, Zhu D, Zhang Y, Li L, Zhang P, Gao Q, Lu X, Sun M. Prenatal hypothyroidism diminished exogenous NO-mediated diastolic effects in fetal rat thoracic aorta smooth muscle via increased oxidative stress. Reprod Toxicol 2022; 113:52-61. [PMID: 35970333 DOI: 10.1016/j.reprotox.2022.08.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 08/05/2022] [Accepted: 08/10/2022] [Indexed: 10/15/2022]
Abstract
Maternal hypothyroidism is an important problem of modern healthcare and is reported to increase the risk of cardiovascular diseases in the offspring later in life. However, it is unclear whether hypothyroidism during pregnancy causes vascular damage in the fetal period. We established the prenatal hypothyroidism rat model and collected the fetuses at the 21th day of gestation (GD21). Thyroid hormone concentrations in maternal and offspring blood serum were assessed by enzyme-linked immunosorbent assay (ELISA). The thoracic aortas of the fetuses were isolated for microvessel functional testing and histochemical stainings. qPCR and Western blot were performed to access mRNA and protein expression. We found that the concentrations of thyroid hormones in the serum of pregnant rats and fetuses were significantly suppressed at GD21. The responses of the fetal thoracic aortas to SNP were significantly attenuated in the PTU group. However, no statistical difference was found between the two groups when treated with either inhibitor (ODQ) or activator (BAY58-2667) of sGC. The production of O2-• in the arterial wall was significantly increased in hypothyroid fetuses. Moreover, the level of NADPH oxidase (NOX) was increased, while superoxide dismutase 2 (SOD2) was down-regulated in the PTU group, ultimately contributing to the increased production of superoxide. Additionally, decreased SNP-mediated vasodilation found in fetal vessels was improved by either NOX inhibitor (Apocynin) or SOD mimic (Tempol). These results indicate that increased oxidative stress is probably the cause of the diminished diastolic effect of exogenous NO in the thoracic artery of prenatal hypothyroidism exposed fetuses.
Collapse
Affiliation(s)
- Jun Guo
- Institute for Fetology, the First Affiliated Hospital of Soochow University, Suzhou City, Jiangsu 215006, China
| | - Xi Yu
- Institute for Fetology, the First Affiliated Hospital of Soochow University, Suzhou City, Jiangsu 215006, China
| | - Yanping Liu
- Institute for Fetology, the First Affiliated Hospital of Soochow University, Suzhou City, Jiangsu 215006, China
| | - Likui Lu
- Institute for Fetology, the First Affiliated Hospital of Soochow University, Suzhou City, Jiangsu 215006, China
| | - Dan Zhu
- Institute for Fetology, the First Affiliated Hospital of Soochow University, Suzhou City, Jiangsu 215006, China
| | - Yingying Zhang
- Institute for Fetology, the First Affiliated Hospital of Soochow University, Suzhou City, Jiangsu 215006, China
| | - Lingjun Li
- Institute for Fetology, the First Affiliated Hospital of Soochow University, Suzhou City, Jiangsu 215006, China
| | - Pengjie Zhang
- Institute for Fetology, the First Affiliated Hospital of Soochow University, Suzhou City, Jiangsu 215006, China
| | - Qinqin Gao
- Institute for Fetology, the First Affiliated Hospital of Soochow University, Suzhou City, Jiangsu 215006, China
| | - Xiyuan Lu
- Institute for Fetology, the First Affiliated Hospital of Soochow University, Suzhou City, Jiangsu 215006, China.
| | - Miao Sun
- Institute for Fetology, the First Affiliated Hospital of Soochow University, Suzhou City, Jiangsu 215006, China.
| |
Collapse
|
|
30
|
Light Emitting Diode Photobiomodulation Enhances Oxidative Redox Capacity in Murine Macrophages Stimulated with Bothrops jararacussu Venom and Isolated PLA2s. BIOMED RESEARCH INTERNATIONAL 2022; 2022:5266211. [PMID: 35872869 PMCID: PMC9307370 DOI: 10.1155/2022/5266211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Accepted: 06/16/2022] [Indexed: 11/24/2022]
Abstract
Photobiomodulation therapy associated with conventional antivenom treatment has been shown to be effective in reducing the local effects caused by bothropic venoms in preclinical studies. In this study, we analyzed the influence of photobiomodulation using light emitting diode (LED) on the oxidative stress produced by murine macrophages stimulated with Bothrops jararacussu venom and it isolated toxins BthTX-I and BthTX-II. Under LED treatment, we evaluated the activity of the antioxidant enzymes catalase, superoxide dismutase, and peroxidase as well as the release of hydrogen peroxide and the enzyme lactate dehydrogenase. To investigate whether NADPH oxidase complex activation and mitochondrial pathways could contribute to hydrogen peroxide production by macrophages, we tested the effect of two selective inhibitors, apocynin and CCCP3, respectively. Our results showed that LED therapy was able to decrease the production of hydrogen peroxide and the liberation of lactate dehydrogenase, indicating less cell damage. In addition, the antioxidant enzymes catalase, superoxide dismutase, and peroxidase increased in response to LED treatment. The effect of LED treatment on macrophages was inhibited by CCCP3, but not by apocynin. These findings show that LED photobiomodulation treatment protects macrophages, at least in part, by reducing oxidative stress caused B. jararacussu venom and toxins.
Collapse
|
|
31
|
Begum R, Thota S, Abdulkadir A, Kaur G, Bagam P, Batra S. NADPH oxidase family proteins: signaling dynamics to disease management. Cell Mol Immunol 2022; 19:660-686. [PMID: 35585127 DOI: 10.1038/s41423-022-00858-1] [Citation(s) in RCA: 66] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 03/12/2022] [Indexed: 12/16/2022] Open
Abstract
Reactive oxygen species (ROS) are pervasive signaling molecules in biological systems. In humans, a lack of ROS causes chronic and extreme bacterial infections, while uncontrolled release of these factors causes pathologies due to excessive inflammation. Professional phagocytes such as neutrophils (PMNs), eosinophils, monocytes, and macrophages use superoxide-generating NADPH oxidase (NOX) as part of their arsenal of antimicrobial mechanisms to produce high levels of ROS. NOX is a multisubunit enzyme complex composed of five essential subunits, two of which are localized in the membrane, while three are localized in the cytosol. In resting phagocytes, the oxidase complex is unassembled and inactive; however, it becomes activated after cytosolic components translocate to the membrane and are assembled into a functional oxidase. The NOX isoforms play a variety of roles in cellular differentiation, development, proliferation, apoptosis, cytoskeletal control, migration, and contraction. Recent studies have identified NOX as a major contributor to disease pathologies, resulting in a shift in focus on inhibiting the formation of potentially harmful free radicals. Therefore, a better understanding of the molecular mechanisms and the transduction pathways involved in NOX-mediated signaling is essential for the development of new therapeutic agents that minimize the hyperproduction of ROS. The current review provides a thorough overview of the various NOX enzymes and their roles in disease pathophysiology, highlights pharmacological strategies, and discusses the importance of computational modeling for future NOX-related studies.
Collapse
Affiliation(s)
- Rizwana Begum
- Laboratory of Pulmonary Immunotoxicology, Department of Environmental Toxicology, Southern University and A&M College, Baton Rouge, LA, 70813, USA
| | - Shilpa Thota
- Laboratory of Pulmonary Immunotoxicology, Department of Environmental Toxicology, Southern University and A&M College, Baton Rouge, LA, 70813, USA
| | - Abubakar Abdulkadir
- Laboratory of Pulmonary Immunotoxicology, Department of Environmental Toxicology, Southern University and A&M College, Baton Rouge, LA, 70813, USA
| | - Gagandeep Kaur
- Laboratory of Pulmonary Immunotoxicology, Department of Environmental Toxicology, Southern University and A&M College, Baton Rouge, LA, 70813, USA.,Department of Environmental Medicine, University of Rochester, School of Medicine and Dentistry, Rochester, NY, 14642, USA
| | - Prathyusha Bagam
- Laboratory of Pulmonary Immunotoxicology, Department of Environmental Toxicology, Southern University and A&M College, Baton Rouge, LA, 70813, USA.,Division of Systems Biology, National Center for Toxicological Research, Jefferson, AR, 72079, USA
| | - Sanjay Batra
- Laboratory of Pulmonary Immunotoxicology, Department of Environmental Toxicology, Southern University and A&M College, Baton Rouge, LA, 70813, USA.
| |
Collapse
|
|
32
|
Abstract
We elaborated a convenient one-step approach for the synthesis of previously unknown 2-(5-acetyl-7-methoxy-2-(4-methoxyphenyl)benzofuran-3-yl)acetic acid. The suggested protocol includes the multicomponent reaction of acetovanillone, 4-methoxyphenylglyoxal and Meldrum’s acid. We have demonstrated that the considered reaction is a one-pot telescoped process including the preliminary condensation of the components in MeCN followed by acid-catalyzed cyclization. The structure of the synthesized product was confirmed by 1H, 13C-NMR spectroscopy and high-resolution mass-spectrometry.
Collapse
|
|
33
|
Kim JH, Jo S, Lee S, Yoo GM, Na HG, Choi YS, Bae CH, Song SY, Kim YD. Peroxiredoxin 2 Inhibits Lipopolysaccharide Induced Mucin Expression and Reactive Oxygen Species Production in Human Airway Epithelial Cells. KOREAN JOURNAL OF OTORHINOLARYNGOLOGY-HEAD AND NECK SURGERY 2021; 64:887-895. [DOI: 10.3342/kjorl-hns.2021.00171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 05/11/2021] [Indexed: 07/25/2023]
Abstract
Background and Objectives Peroxiredoxin (Prx) is an antioxidant enzyme involved in signaling pathway. Prx2 is the most abundant in mammalian gray matter neurons and has protective role under oxidative stress. MUC5AC and MUC5B are typical mucin genes in human airway epithelial cells. Even if free radicals play a key role in chronic respiratory inflammatory diseases, the effects of the Prx2 on mucin expression and oxidative stress are not clearly known. The purpose of this study is to investigate the effect of Prx2 on lipopolysaccharide (LPS)-induced MUC5AC/5B expression and reactive oxygen species (ROS) in human airway epithelial cells.Subjects and Method In NCI-H292 cells and human nasal epithelial cells, the effects of Prx2 on LPS-induced MUC5AC/5B expression and ROS production were investigated using reverse transcriptase-polymerase chain reaction, real-time polymerase chain reaction, enzyme linked immunosorbent assay (ELISA) and flow cytometry analysis.Results MUC5AC, MUC5B mRNA expression and protein production were increased by LPS. ROS production was also increased by LPS. Prx2 suppressed the LPS-induced MUC5AC mRNA expression and protein production as well as ROS production. However, Prx2 did not inhibit MUC5B mRNA expression and protein production. N-acetylcysteine, diphenyleneiodonium, and apocynin also inhibited LPS-induced ROS production.Conclusion These results may show that Prx2 suppresses LPS-induced MUC5AC expression via ROS in human airway epithelial cells.
Collapse
|
|
34
|
Dietary Polyphenols: Promising Adjuvants for Colorectal Cancer Therapies. Cancers (Basel) 2021; 13:cancers13184499. [PMID: 34572726 PMCID: PMC8465098 DOI: 10.3390/cancers13184499] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 08/29/2021] [Accepted: 09/03/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Colorectal cancer is a leading cause of death worldwide. Despite the development of novel surgical and therapeutic strategies, 50% of patients relapse after treatment. Therapy failure, due to low efficacy, adverse effects and drug resistance, is thus a major concern. The idea of combining standard therapy with non-toxic bioactive natural compounds is a recent topic in cancer research and aims to increase the efficacy of current antitumor therapies while reducing drug toxicity and adverse effects. In recent years, several studies have explored the capacity of polyphenols, dietary bioactive compounds enriched in fruit and vegetables, to act as adjuvants to improve colorectal cancer therapy. In the present review, we discuss these studies, highlighting the mechanisms underlying the adjuvant effect, and bring out the potential of this novel therapeutic approach as well as the critical issues related to clinical application. Abstract Colorectal cancer (CRC) is a major cancer type and a leading cause of death worldwide. Despite advances in therapeutic management, the current medical treatments are not sufficient to control metastatic disease. Treatment-related adverse effects and drug resistance strongly contribute to therapy failure and tumor recurrence. Combination therapy, involving cytotoxic treatments and non-toxic natural compounds, is arousing great interest as a promising more effective and safer alternative. Polyphenols, a heterogeneous group of bioactive dietary compounds mainly found in fruit and vegetables, have received great attention for their capacity to modulate various molecular pathways active in cancer cells and to affect host anticancer response. This review provides a summary of the most recent (i.e., since 2016) preclinical and clinical studies using polyphenols as adjuvants for CRC therapies. These studies highlight the beneficial effects of dietary polyphenols in combination with cytotoxic drugs or irradiation on both therapy outcome and drug resistance. Despite substantial preclinical evidence, data from a few pilot clinical trials are available to date with promising but still inconclusive results. Larger randomized controlled studies and polyphenol formulations with improved bioavailability are needed to translate the research progress into clinical applications and definitively prove the added value of these molecules in CRC management.
Collapse
|
|
35
|
Effective Accentuation of Voltage-Gated Sodium Current Caused by Apocynin (4'-Hydroxy-3'-methoxyacetophenone), a Known NADPH-Oxidase Inhibitor. Biomedicines 2021; 9:biomedicines9091146. [PMID: 34572332 PMCID: PMC8464932 DOI: 10.3390/biomedicines9091146] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 08/23/2021] [Accepted: 08/31/2021] [Indexed: 12/22/2022] Open
Abstract
Apocynin (aPO, 4'-Hydroxy-3'-methoxyacetophenone) is a cell-permeable, anti-inflammatory phenolic compound that acts as an inhibitor of NADPH-dependent oxidase (NOX). However, the mechanisms through which aPO can interact directly with plasmalemmal ionic channels to perturb the amplitude or gating of ionic currents in excitable cells remain incompletely understood. Herein, we aimed to investigate any modifications of aPO on ionic currents in pituitary GH3 cells or murine HL-1 cardiomyocytes. In whole-cell current recordings, GH3-cell exposure to aPO effectively stimulated the peak and late components of voltage-gated Na+ current (INa) with different potencies. The EC50 value of aPO required for its differential increase in peak or late INa in GH3 cells was estimated to be 13.2 or 2.8 μM, respectively, whereas the KD value required for its retardation in the slow component of current inactivation was 3.4 μM. The current-voltage relation of INa was shifted slightly to more negative potential during cell exposure to aPO (10 μM); however, the steady-state inactivation curve of the current was shifted in a rightward direction in its presence. Recovery of peak INa inactivation was increased in the presence of 10 μM aPO. In continued presence of aPO, further application of rufinamide or ranolazine attenuated aPO-stimulated INa. In methylglyoxal- or superoxide dismutase-treated cells, the stimulatory effect of aPO on peak INa remained effective. By using upright isosceles-triangular ramp pulse of varying duration, the amplitude of persistent INa measured at low or high threshold was enhanced by the aPO presence, along with increased hysteretic strength appearing at low or high threshold. The addition of aPO (10 μM) mildly inhibited the amplitude of erg-mediated K+ current. Likewise, in HL-1 murine cardiomyocytes, the aPO presence increased the peak amplitude of INa as well as decreased the inactivation or deactivation rate of the current, and further addition of ranolazine or esaxerenone attenuated aPO-accentuated INa. Altogether, this study provides a distinctive yet unidentified finding that, despite its effectiveness in suppressing NOX activity, aPO may directly and concertedly perturb the amplitude, gating and voltage-dependent hysteresis of INa in electrically excitable cells. The interaction of aPO with ionic currents may, at least in part, contribute to the underlying mechanisms through which it affects neuroendocrine, endocrine or cardiac function.
Collapse
|
|
36
|
Lee MTW, Mahy W, Rackham MD. The medicinal chemistry of mitochondrial dysfunction: a critical overview of efforts to modulate mitochondrial health. RSC Med Chem 2021; 12:1281-1311. [PMID: 34458736 PMCID: PMC8372206 DOI: 10.1039/d1md00113b] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 05/17/2021] [Indexed: 12/16/2022] Open
Abstract
Mitochondria are subcellular organelles that perform a variety of critical biological functions, including ATP production and acting as hubs of immune and apoptotic signalling. Mitochondrial dysfunction has been extensively linked to the pathology of multiple neurodegenerative disorders, resulting in significant investment from the drug discovery community. Despite extensive efforts, there remains no disease modifying therapies for neurodegenerative disorders. This manuscript aims to review the compounds historically used to modulate the mitochondrial network through the lens of modern medicinal chemistry, and to offer a perspective on the evidence that relevant exposure was achieved in a representative model and that exposure was likely to result in target binding and engagement of pharmacology. We hope this manuscript will aid the community in identifying those targets and mechanisms which have been convincingly (in)validated with high quality chemical matter, and those for which an opportunity exists to explore in greater depth.
Collapse
Affiliation(s)
| | - William Mahy
- MSD The Francis Crick Institute 1 Midland Road London NW1 1AT UK
| | | |
Collapse
|
|
37
|
Singh M, Agarwal S, Tiwari RK, Chanda S, Singh K, Agarwal P, Kashyap A, Pancham P, Mall S, R. R, Sharma S. Neuroprotective Ability of Apocynin Loaded Nanoparticles (APO-NPs) as NADPH Oxidase (NOX)-Mediated ROS Modulator for Hydrogen Peroxide-Induced Oxidative Neuronal Injuries. Molecules 2021; 26:5011. [PMID: 34443598 PMCID: PMC8400077 DOI: 10.3390/molecules26165011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 07/10/2021] [Accepted: 07/13/2021] [Indexed: 12/12/2022] Open
Abstract
Apocynin (APO) is a known multi-enzymatic complexed compound, employed as a viable NADPH oxidase (NOX) inhibitor, extensively used in both traditional and modern-day therapeutic strategies to combat neuronal disorders. However, its therapeutic efficacy is limited by lower solubility and lesser bioavailability; thus, a suitable nanocarrier system to overcome such limitations is needed. The present study is designed to fabricate APO-loaded polymeric nanoparticles (APO-NPs) to enhance its therapeutic efficacy and sustainability in the biological system. The optimized APO NPs in the study exhibited 103.6 ± 6.8 nm and -13.7 ± 0.43 mV of particle size and zeta potential, respectively, along with further confirmation by TEM. In addition, the antioxidant (AO) abilities quantified by DPPH and nitric oxide scavenging assays exhibited comparatively higher AO potential of APO-NPs than APO alone. An in-vitro release profile displayed a linear diffusion pattern of zero order kinetics for APO from the NPs, followed by its cytotoxicity evaluation on the PC12 cell line, which revealed minimal toxicity with higher cell viability, even after treatment with a stress inducer (H2O2). The stability of APO-NPs after six months showed minimal AO decline in comparison to APO only, indicating that the designed nano-formulation enhanced therapeutic efficacy for modulating NOX-mediated ROS generation.
Collapse
Affiliation(s)
- Manisha Singh
- Centre for Emerging Diseases (CFED), Department of Biotechnology, Jaypee Institute of Information Technology, Sector-62, Noida 201309, Uttar Pradesh, India; (S.A.); (P.P.); (R.R.)
| | - Shriya Agarwal
- Centre for Emerging Diseases (CFED), Department of Biotechnology, Jaypee Institute of Information Technology, Sector-62, Noida 201309, Uttar Pradesh, India; (S.A.); (P.P.); (R.R.)
| | - Raj Kumar Tiwari
- Pharmacognosy and Phytochemistry, School of Health Sciences, Pharmaceutical Sciences, UPES, Dehradun 248007, Uttarakhand, India;
| | - Silpi Chanda
- Pharmacognosy and Phytochemistry, IEC School of Pharmacy, IEC University, Solan 174103, Himachal Pradesh, India;
| | - Kuldeep Singh
- Department of Chemistry, Maharishi Markandeshwar (Deemed to Be University), Mullana 133207, Haryana, India;
| | - Prakhar Agarwal
- Department of Biosciences and Bioengineering, Indian Institute of Technology, Bombay 400076, Maharashtra, India;
| | - Aishwarya Kashyap
- Department of Biotechnology, Vellore Institute of Technology, School of Bio Sciences & Technology (SBST), Vellore 632014, Tamil Nadu, India;
| | - Pranav Pancham
- Centre for Emerging Diseases (CFED), Department of Biotechnology, Jaypee Institute of Information Technology, Sector-62, Noida 201309, Uttar Pradesh, India; (S.A.); (P.P.); (R.R.)
| | - Shweta Mall
- Department of Animal Genetics and Breeding, Southern Regional Station of Indian Council of Agriculture Research—Research Institute, Bangalore 560030, Karnataka, India;
| | - Rachana R.
- Centre for Emerging Diseases (CFED), Department of Biotechnology, Jaypee Institute of Information Technology, Sector-62, Noida 201309, Uttar Pradesh, India; (S.A.); (P.P.); (R.R.)
| | - Shalini Sharma
- Sunder Deep Pharmacy College, NH-9, Delhi-Meerut Expressway, Ghaziabad 201015, Uttar Pradesh, India;
| |
Collapse
|
|
38
|
Zhou L, Liu Y, Wang Z, Liu D, Xie B, Zhang Y, Yuan M, Tse G, Li G, Xu G, Liu T. Activation of NADPH oxidase mediates mitochondrial oxidative stress and atrial remodeling in diabetic rabbits. Life Sci 2021; 272:119240. [PMID: 33600862 DOI: 10.1016/j.lfs.2021.119240] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 02/05/2021] [Accepted: 02/13/2021] [Indexed: 01/05/2023]
Abstract
AIMS The mechanisms of atrial fibrillation (AF) in diabetes mellitus (DM) involve a complex interplay between increased oxidative stress, mitochondrial dysfunction and atrial remodeling. In this study, we examined the effects of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation on mitochondrial oxidative stress and atrial remodeling in a rabbit model of diabetes mellitus (DM). MAIN METHODS Healthy rabbits were selected and randomly divided into control, diabetic and apocynin administration group. Parameters of echocardiography, atrial electrophysiology, oxidative stress and mitochondrial function were compared between the different groups. KEY FINDINGS Compared to the control group, the DM group showed higher activity of NADPH oxidase, increased oxidative stress, larger left atrial diameter, a reduction in atrial mean conduction velocity. These findings were associated with increased interstitial fibrosis of the atria and higher atrial fibrillation (AF) inducibility. Moreover, atrial ultrastructure and mitochondrial function such as the mitochondrial respiratory control rate (RCR) were impaired. NADPH oxidase inhibition using the pharmacological agent apocynin improved these changes. SIGNIFICANCE NADPH oxidase activity plays an important role in mitochondrial oxidative stress, which is associated with AF inducibility by promoting adverse atrial remodeling. The NADPH oxidase inhibitor apocynin can prevent these pathological changes and may be a potential drug for AF treatment.
Collapse
Affiliation(s)
- Lingling Zhou
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, People's Republic of China
| | - Yang Liu
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, People's Republic of China; Department of Cardiology, Tianjin Fourth Central Hospital, The Fourth Central Hospital Affiliated to Nankai University, The Fourth Center Clinical College of Tianjin Medical University, Tianjin 300140, People's Republic of China
| | - Zhaojia Wang
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, People's Republic of China
| | - Daiqi Liu
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, People's Republic of China
| | - Bingxin Xie
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, People's Republic of China
| | - Yue Zhang
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, People's Republic of China
| | - Meng Yuan
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, People's Republic of China
| | - Gary Tse
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, People's Republic of China
| | - Guangping Li
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, People's Republic of China
| | - Gang Xu
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, People's Republic of China.
| | - Tong Liu
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, People's Republic of China.
| |
Collapse
|
|
39
|
Damal Villivalam S, Ebert SM, Lim HW, Kim J, You D, Jung BC, Palacios HH, Tcheau T, Adams CM, Kang S. A necessary role of DNMT3A in endurance exercise by suppressing ALDH1L1-mediated oxidative stress. EMBO J 2021; 40:e106491. [PMID: 33847380 DOI: 10.15252/embj.2020106491] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Revised: 12/25/2020] [Accepted: 01/13/2021] [Indexed: 02/06/2023] Open
Abstract
Exercise can alter the skeletal muscle DNA methylome, yet little is known about the role of the DNA methylation machinery in exercise capacity. Here, we show that DNMT3A expression in oxidative red muscle increases greatly following a bout of endurance exercise. Muscle-specific Dnmt3a knockout mice have reduced tolerance to endurance exercise, accompanied by reduction in oxidative capacity and mitochondrial respiration. Moreover, Dnmt3a-deficient muscle overproduces reactive oxygen species (ROS), the major contributors to muscle dysfunction. Mechanistically, we show that DNMT3A suppresses the Aldh1l1 transcription by binding to its promoter region, altering its epigenetic profile. Forced expression of ALDH1L1 elevates NADPH levels, which results in overproduction of ROS by the action of NADPH oxidase complex, ultimately resulting in mitochondrial defects in myotubes. Thus, inhibition of ALDH1L1 pathway can rescue oxidative stress and mitochondrial dysfunction from Dnmt3a deficiency in myotubes. Finally, we show that in vivo knockdown of Aldh1l1 largely rescues exercise intolerance in Dnmt3a-deficient mice. Together, we establish that DNMT3A in skeletal muscle plays a pivotal role in endurance exercise by controlling intracellular oxidative stress.
Collapse
Affiliation(s)
- Sneha Damal Villivalam
- Nutritional Sciences and Toxicology Department, University of California Berkeley, Berkeley, CA, USA
| | - Scott M Ebert
- Departments of Internal Medicine and Molecular Physiology and Biophysics and Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA, USA.,Emmyon, Inc., Coralville, IA, USA
| | - Hee Woong Lim
- Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Department of Pediatrics & Biomedical Informatics, University of Cincinnati, Cincinnati, OH, USA
| | - Jinse Kim
- Nutritional Sciences and Toxicology Department, University of California Berkeley, Berkeley, CA, USA
| | - Dongjoo You
- Nutritional Sciences and Toxicology Department, University of California Berkeley, Berkeley, CA, USA
| | - Byung Chul Jung
- Nutritional Sciences and Toxicology Department, University of California Berkeley, Berkeley, CA, USA
| | - Hector H Palacios
- Nutritional Sciences and Toxicology Department, University of California Berkeley, Berkeley, CA, USA
| | - Tabitha Tcheau
- Nutritional Sciences and Toxicology Department, University of California Berkeley, Berkeley, CA, USA
| | - Christopher M Adams
- Departments of Internal Medicine and Molecular Physiology and Biophysics and Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA, USA.,Emmyon, Inc., Coralville, IA, USA.,Iowa City Department of Veterans Affairs Medical Center, Iowa City, IA, USA
| | - Sona Kang
- Nutritional Sciences and Toxicology Department, University of California Berkeley, Berkeley, CA, USA
| |
Collapse
|
|
40
|
Najibi M, Honwad HH, Moreau JA, Becker SM, Irazoqui JE. A NOVEL NOX/PHOX-CD38-NAADP-TFEB AXIS IMPORTANT FOR MACROPHAGE ACTIVATION DURING BACTERIAL PHAGOCYTOSIS. Autophagy 2021; 18:124-141. [PMID: 33818279 PMCID: PMC8865266 DOI: 10.1080/15548627.2021.1911548] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Macrophage activation in the presence of bacterial cells and molecules entails complex programs of gene expression. How such triggers elicit specific gene expression programs is incompletely understood. We previously discovered that TFEB (transcription factor EB) is a key contributor to macrophage activation during bacterial phagocytosis. However, the mechanism linking phagocytosis of bacterial cells to TFEB activation and downstream pro-inflammatory cytokine induction remained unknown. We found that macrophages lacking both TFEB and TFE3 (transcription factor E3) were unable to mount a pro-inflammatory phenotype in response to bacterial infection. The NOX/PHOX (NADPH oxidase)-dependent oxidative burst was required for nuclear translocation of TFEB during phagocytosis of Gram-positive or -negative bacteria, and reactive oxygen species (ROS) were sufficient to trigger TFEB activation in a CD38- and NAADP (nicotinic acid adenine dinucleotide phosphate)-dependent manner. Consistent with the Ca2+-releasing activity of NAADP, intracellular Ca2+ chelation and PPP3/calcineurin inhibition prevented TFEB activation by phagocytosis and ROS (reactive oxygen species), impairing the induction of pro-inflammatory cytokines such as IL6 and TNF/TNFα. Therefore, here we describe a previously unknown pathway that links phagocytosis with macrophage pro-inflammatory polarization via TFEB and related transcription factor TFE3. These findings reveal that activation of TFEB and TFE3 is a key regulatory event for the activation of macrophages, and have important implications for infections, inflammation, cancer, obesity, and atherosclerosis.
Collapse
Affiliation(s)
- Mehran Najibi
- Department of Microbiology and Physiological Systems and Program in Innate Immunity, University of Massachusetts Medical School, Worcester, USA.,Present Address: Department of Pathology, The Warren Alpert Medical School of Brown University, Providence
| | - Havisha H Honwad
- Department of Microbiology and Physiological Systems and Program in Innate Immunity, University of Massachusetts Medical School, Worcester, USA
| | - Joseph A Moreau
- Department of Microbiology and Physiological Systems and Program in Innate Immunity, University of Massachusetts Medical School, Worcester, USA
| | - Stephanie M Becker
- Department of Microbiology and Physiological Systems and Program in Innate Immunity, University of Massachusetts Medical School, Worcester, USA
| | - Javier E Irazoqui
- Department of Microbiology and Physiological Systems and Program in Innate Immunity, University of Massachusetts Medical School, Worcester, USA
| |
Collapse
|
|
41
|
Abstract
Apocynin is a naturally occurring acetophenone, found in the roots of Apocynum cannabinum and Picrorhiza kurroa. Various chemical and pharmaceutical modifications have been carried out to enhance the absorption and duration of action of apocynin, like, formulation of chitosan-based apocynin-loaded solid lipid nanoparticles, chitosan-oligosaccharide based nanoparticles, and biodegradable polyanhydride nanoparticles. Apocynin has been subjected to a wide range of experimental screening and has proved to be useful for amelioration of a variety of disorders, like diabetic complications, neurodegeneration, cardiovascular disorders, lung cancer, hepatocellular cancer, pancreatic cancer, and pheochromocytoma. Apocynin has been primarily reported as an NADPH oxidase (NOX) inhibitor and prevents translocation of its p47phox subunit to the plasma membrane, observed in neurodegeneration and hypertension. However, recent studies highlight its off-target effects that it is able to function as a scavenger of non-radical oxidant species, which is relevant for its activity against NOX 4 mediated production of hydrogen peroxide. Additionally, apocynin has shown inhibition of eNOS-dependent superoxide production in diabetic cardiomyopathy, reduction of NLRP3 activation and TGFβ/Smad signaling in diabetic nephropathy, diminished VEGF expression and decreased retinal NF-κB activation in diabetic retinopathy, inhibition of P38/MAPK/Caspase3 pathway in pheochromocytoma, inhibition of AKT-GSK3β and ERK1/2 pathways in pancreatic cancer, and decreased FAK/PI3K/Akt signaling in hepatocellular cancer. This review aims to discuss the pharmacokinetics and mechanisms of the pharmacological actions of apocynin.
Collapse
Affiliation(s)
- Shreya R Savla
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS, Mumbai, India
| | - Ankit P Laddha
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS, Mumbai, India
| | - Yogesh A Kulkarni
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS, Mumbai, India
| |
Collapse
|
|
42
|
Santos WHD, Yoguim MI, Daré RG, da Silva-Filho LC, Lautenschlager SOS, Ximenes VF. Development of a caffeic acid–phthalimide hybrid compound for NADPH oxidase inhibition. RSC Adv 2021; 11:17880-17890. [PMID: 35480205 PMCID: PMC9033209 DOI: 10.1039/d1ra01066b] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 05/12/2021] [Indexed: 11/21/2022] Open
Abstract
NADPH oxidases are pharmacological targets for the treatment of inflammation-based diseases. This work presents the synthesis and study of a caffeic acid/phthalimide hybrid compound (C2) as a potential inhibitor of NADPH oxidases. Throughout the study, we have compared compound C2 with its precursor caffeic acid (C1). The redox properties were compared using three different antioxidant methodologies and showed that C2 was slightly less effective than C1, a well-established and robust antioxidant. However, C2 was three-fold more effective than albumin (used as a model protein). This chemical feature was decisive for the higher efficiency of C2 as an inhibitor of the release of superoxide anions by stimulated neutrophils and enzymatic activity of cell-free NADPH oxidase. Docking simulation studies were performed using the crystal structure of the recombinant dehydrogenase domain of the isoform NOX5 of C. stagnale, which retains the FAD cofactor (PDB: 5O0X). Considering that C2 could bind at the FAD redox site of NOX5, studies were conducted by comparing the interactions and binding energies of C1 and C2. The binding energies were −50.30 (C1) and −74.88 (C2) (kJ mol−1), which is in agreement with the higher efficacy of the latter as an NADPH oxidase inhibitor. In conclusion, incorporating the phthalimide moiety into caffeic acid was decisive for its effectiveness as an NADPH oxidase inhibitor. The incorporation of the phthalimide moiety into caffeic acid was decisive for its effectiveness as an NADPH oxidase inhibitor.![]()
Collapse
Affiliation(s)
| | - Maurício Ikeda Yoguim
- Department of Chemistry
- Faculty of Sciences
- UNESP – São Paulo State University
- Bauru
- Brazil
| | - Regina Gomes Daré
- Department of Pharmaceutical Sciences
- Maringa State University (UEM)
- Maringa
- Brazil
| | | | | | | |
Collapse
|
|
43
|
Peruru R, Dodoala S. Therapeutic potential of diosmin, a citrus flavonoid against arsenic-induced neurotoxicity via suppression of NOX 4 and its subunits. Indian J Pharmacol 2021; 53:132-142. [PMID: 34100397 PMCID: PMC8265410 DOI: 10.4103/ijp.ijp_837_19] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
OBJECTIVES: Water contaminated with arsenic affected millions of people worldwide and arsenic exposure is related to various neurological disorders. Hence, the current study was planned to investigate the neuroprotective activity of diosmin (DSN) against arsenic induced neurotoxicity as an attempt to identify therapeutic intervention to combat arsenicism. MATERIALS AND METHODS: Sodium arsenite an inducer of neurotoxicity was administered orally (13 mg/kg) and DSN treatment at two selected doses (50 and 100 mg/kg) was done for 21 days. Behavioral and biochemical variations were examined by various parameters. Furthermore, histopathological and immunohistochemistry studies were done with the brain sections. RESULTS: The behavioral studies evidenced that arsenic has suppressed the exploratory behavior and motor coordination in rats and DSN treatment has recovered the behavioral changes to normal. Arsenic administration has also found to induce oxidative stress and DSN co-treatment has ameliorated the oxidative stress markers. Interestingly, depleted levels of neurotransmitters were observed with the arsenic and it was restored back by the DSN treatment. Histopathological alterations like pyknosis of the neuronal cells were identified with arsenic exposure and subsided upon DSN co administration. Immunohistochemical studies have revealed the expression of NOX4 and its gp91phox and P47phox subunits and its suppression by DSN treatment may be the key therapeutic factor of it. CONCLUSIONS: Treatment with DSN showed a beneficial effect in protecting against arsenic-induced neurotoxicity by suppressing the toxicity changes and the antioxidant effect of DSN might be attributed to its ability of suppressing NOX4 and its subunits.
Collapse
Affiliation(s)
- Rupasree Peruru
- Department of Pharmacology, Institute of Pharmaceutical Technology, Sri Padmavati Mahila Visvavidyalayam (Women's University), Tirupati, Andhra Pradesh, India
| | - Sujatha Dodoala
- Department of Pharmacology, Institute of Pharmaceutical Technology, Sri Padmavati Mahila Visvavidyalayam (Women's University), Tirupati, Andhra Pradesh, India
| |
Collapse
|
|
44
|
Watanabe S, Fujii H, Kono K, Watanabe K, Goto S, Nishi S. Influence of oxidative stress on vascular calcification in the setting of coexisting chronic kidney disease and diabetes mellitus. Sci Rep 2020; 10:20708. [PMID: 33244056 PMCID: PMC7693179 DOI: 10.1038/s41598-020-76838-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Accepted: 10/26/2020] [Indexed: 12/20/2022] Open
Abstract
Vascular calcification (VC) is a common complication in patients with chronic kidney disease (CKD). Particularly, CKD patients with diabetes mellitus (DM) develop severe VC. Specific mechanisms of VC remain unclear; this study aimed to investigate them in the context of coexisting CKD and DM, mainly regarding oxidative stress. Sprague Dawley rats were randomly divided into six groups as follows: control rats (Control), 5/6 nephrectomized rats (CKD), streptozotocin-injected rats (DM), 5/6 nephrectomized and streptozotocin-injected rats (CKD + DM), CKD + DM rats treated with insulin (CKD + DM + INS), and CKD + DM rats treated with antioxidant apocynin (CKD + DM + APO). At 18 weeks old, the rats were sacrificed for analysis. Compared to the control, DM and CKD groups, calcification of aortas significantly increased in the CKD + DM group. Oxidative stress and osteoblast differentiation-related markers considerably increased in the CKD + DM group compared with the other groups. Moreover, apocynin considerably reduced oxidative stress, osteoblast differentiation-related markers, and aortic calcification despite high blood glucose levels. Our data indicate that coexisting CKD and DM hasten VC primarily through an increase in oxidative stress; anti-oxidative therapy may prevent the VC progression.
Collapse
Affiliation(s)
- Shuhei Watanabe
- Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Hideki Fujii
- Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan.
| | - Keiji Kono
- Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Kentaro Watanabe
- Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Shunsuke Goto
- Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Shinichi Nishi
- Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| |
Collapse
|
|
45
|
Micronutrients and bioactive compounds in the immunological pathways related to SARS-CoV-2 (adults and elderly). Eur J Nutr 2020; 60:559-579. [PMID: 33084959 PMCID: PMC7576552 DOI: 10.1007/s00394-020-02410-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 10/06/2020] [Indexed: 01/08/2023]
Abstract
The new coronavirus pandemic is affecting the entire world with more than 25 million confirmed cases in August 2020 according to the World Health Organization. It is known that the virus can affect several tissues and can progress to a respiratory failure in severe cases. To prevent the progression to this stage of the disease and minimize all the damage caused by coronavirus (SARS-CoV-2) the immune system must be in its integrity. A healthy nutritional status are fundamental to efficient immunological protection and consequently a good response to SARS-CoV-2. Micronutrients and bioactive compounds perform functions in immune cells that are extremely essential to stop SARS-CoV-2. Their adequate consumption is part of a non-pharmacological intervention to keep the immune system functioning. This review has as main objective to inform how micronutrients and bioactive compounds could act in the essential immunological pathways could stop SARS-CoV-2, focusing on the functions that have already established in the literature and transposing to this scenario.
Collapse
|
|
46
|
Gd-Complex of a Rosmarinic Acid Conjugate as an Anti-Inflammatory Theranostic Agent via Reactive Oxygen Species Scavenging. Antioxidants (Basel) 2020; 9:antiox9080744. [PMID: 32823673 PMCID: PMC7464237 DOI: 10.3390/antiox9080744] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 08/10/2020] [Accepted: 08/10/2020] [Indexed: 12/26/2022] Open
Abstract
Rosmarinic acid (RosA), an important polyphenol, is known for its antioxidant and anti-inflammatory activities. However, its application in theranostics has been rarely reported. Therefore, a new single-molecule anti-inflammatory theranostic compound containing RosA would be of great interest. A gadolinium (Gd) complex of 1,4,7,10-tetraazacyclododecane-1,4,7-trisacetic acid (DO3A) and RosA (Gd(DO3A-RosA)(H2O)) was synthesized and examined for use as a single-molecule theranostic agent. Its kinetic stability is comparable to that of clinically used macrocyclic magnetic resonance imaging contrast agents. In addition, its relaxivity is higher than that of structurally analogous Gd-BT-DO3A. This agent was evaluated for inflammatory targeting magnetic resonance contrast and showed strong and prolonged enhancement of imaging in inflamed tissues of mice. The theranostic agent also possesses antioxidant and anti-inflammatory activities, as evidenced by reactive oxygen species scavenging, superoxide dismutase activity, and inflammatory factors. The novel RosA-conjugated Gd complex is a promising theranostic agent for the imaging of inflamed tissues, as well as for the treatment of inflammation and oxidative stress.
Collapse
|
|
47
|
Abstract
Significance: The oxidative stress, resulting from an imbalance in the production and scavenging of reactive oxygen species (ROS), is known to be involved in the development and progression of several pathologies. The excess of ROS production is often due to an overactivation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) and for this reason these enzymes became promising therapeutic targets. However, even if NOX are now well characterized, the development of new therapies is limited by the lack of highly isoform-specific inhibitors. Recent Advances: In the past decade, several groups and laboratories have screened thousands of molecules to identify new specific inhibitors with low off-target effects. These works have led to the characterization of several new potent NOX inhibitors; however, their specificity varies a lot depending on the molecules. Critical Issues: Here, we are reviewing more than 25 known NOX inhibitors, focusing mainly on the newly identified ones such as APX-115, NOS31, Phox-I1 and 2, GLX7013114, and GSK2795039. To have a better overall view of these molecules, the inhibitors were classified according to their specificity, from pan-NOX inhibitors to highly isoform-specific ones. We are also presenting the use of these compounds both in vitro and in vivo. Future Directions: Several of these new molecules are potent and very specific inhibitors that could be good candidates for the development of new drugs. Even if the results are very promising, most of these compounds were only validated in vitro or in mice models and further investigations will be required before using them as potential therapies.
Collapse
Affiliation(s)
- Mathieu Chocry
- Aix-Marseille Université, Institut de Neurophysiopathologie (INP), CNRS, Marseille, France
| | - Ludovic Leloup
- Aix-Marseille Université, Institut de Neurophysiopathologie (INP), CNRS, Marseille, France
| |
Collapse
|
|
48
|
Liu F, Fan LM, Michael N, Li J. In vivo and in silico characterization of apocynin in reducing organ oxidative stress: A pharmacokinetic and pharmacodynamic study. Pharmacol Res Perspect 2020; 8:e00635. [PMID: 32761799 PMCID: PMC7406636 DOI: 10.1002/prp2.635] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 07/10/2020] [Accepted: 07/11/2020] [Indexed: 12/21/2022] Open
Abstract
Apocynin has been widely used in vivo as a Nox2-contaninig nicotinamide adenine dinucleotide phosphate oxidase inhibitor. However, its time-dependent tissue distribution and inhibition on organ reactive oxygen species (ROS) production remained unclear. In this study, we examined apocynin pharmacokinetics and pharmacodynamics (PKPD) after intravenous (iv) injection (bolus, 5 mg/kg) of mice (CD1, 12-week). Apocynin was detected using a HPLC coupled to a linear ion-trap tandem mass spectrometer. Apocynin peak concentrations were detected in plasma at 1 minute (5494 ± 400 ng/mL) (t1/2 = 0.05 hours, clearance = 7.76 L/h/kg), in urine at 15 minutes (14 942 ± 5977 ng/mL), in liver at 5 minutes (2853 ± 35 ng/g), in heart at 5 minutes (3161 ± 309 ng/g) and in brain at 1 minute (4603 ± 208 ng/g) after iv injection. These were accompanied with reduction of ROS production in the liver, heart and brain homogenates. Diapocynin was not detected in these samples. Therapeutic effect of apocynin was examined using a mouse model (C57BL/6J) of high-fat diet (HFD, 16 weeks)-induced obesity and accelerated aging. Apocynin (5 mmol/L) was supplied in drinking water during the HFD period and was detected at the end of treatment in the brain (5369 ± 1612 ng/g), liver (4818 ± 1340 ng/g) and heart (1795 ± 1487 ng/g) along with significant reductions of ROS production in these organs. In conclusion, apocynin PKPD is characterized by a short half-life, rapid clearance, good distribution and inhibition of ROS production in major organs. Diapocynin is not a metabolite of apocynin in vivo. Apocynin crosses easily the blood-brain barrier and reduces brain oxidative stress associated with metabolic disorders and aging.
Collapse
Affiliation(s)
- Fangfei Liu
- School of Biological SciencesUniversity of ReadingReadingUK
| | | | | | - Jian‐Mei Li
- School of Biological SciencesUniversity of ReadingReadingUK
| |
Collapse
|
|
49
|
Natural antioxidants' effects on endoplasmic reticulum stress-related diseases. Food Chem Toxicol 2020; 138:111229. [PMID: 32105807 DOI: 10.1016/j.fct.2020.111229] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 02/20/2020] [Accepted: 02/22/2020] [Indexed: 12/11/2022]
Abstract
Endoplasmic reticulum (ER) stress is a normal molecular process induced by the over-accumulation of misfolded or unfolded proteins. ER stress induces the unfolded protein response (UPR), which reduces global protein synthesis, increases ER capacity and protein degradation, to restart ER homeostasis, allowing cell survival. However, the over-induction of UPR can also trigger inflammatory processes, tissue damage and cell death. ER stress is involved in several pathologies, like endothelial dysfunction, diabetes and heart, liver, kidney or neurological diseases. Although the progression of these diseases is the result of several pathological mechanisms, oxidative stress has been widely related to these pathologies. Moreover, ER stress can establish a progressive pathological cycle with oxidative stress. Therefore, the use of natural antioxidants, able to modulate both oxidative and ER stress, can be a new strategy to mitigate these diseases. This review is focused on the effects of natural antioxidant compounds on ER stress in endothelial dysfunction, diabetes and heart, liver, kidney or neurological diseases.
Collapse
|
|
50
|
Wang M, Luo L. An Effective NADPH Oxidase 2 Inhibitor Provides Neuroprotection and Improves Functional Outcomes in Animal Model of Traumatic Brain Injury. Neurochem Res 2020; 45:1097-1106. [PMID: 32072445 DOI: 10.1007/s11064-020-02987-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 02/07/2020] [Accepted: 02/11/2020] [Indexed: 12/23/2022]
Abstract
Traumatic brain injury (TBI) has become a leading cause of death and disability all over the world. Pharmacological suppression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) can inhibit oxidative stress which is implicated in the pathology of TBI. GSK2795039 was reported to target NOX2 to inhibit [Formula: see text] and ROS production. The present study aimed to investigate the effect of GSK2795039 on NOX2 activity and neurological deficits in a TBI mouse model. TBI mouse model was established by a weight-drop to mouse skull. GSK2795039 at a dose of 100 mg/kg was administrated to mice 30 min before TBI. NOX2 expression and activity were detected by Western blot and biochemical method. Neurological damage and apoptosis were detected by behavioral test and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. GSK2795039 significantly inhibited NOX2 expression and activity in the TBI mouse model. It also attenuated TBI-induced neurological deficits, apoptosis, and neurological recovery. The results indicate that GSK2795039 can be used as a potential drug for TBI treatment.
Collapse
Affiliation(s)
- Mengwei Wang
- Department of Emergency, The Fourth Affiliated Hospital of China Medical University, No. 4 Chongshan East Road, Huanggu District, Shenyang, 110032, Liaoning, China.
| | - Le Luo
- Shanghai Zhuole Biotechnology Center, No. 2066 Wangyuan Road, Shanghai, 201499, China
| |
Collapse
|