scholarly journals Nitrosative Stress and Human Disease: Therapeutic Potential of Denitrosylation

2021 ◽  
Vol 22 (18) ◽  
pp. 9794
Author(s):  
Somy Yoon ◽  
Gwang-Hyeon Eom ◽  
Gaeun Kang
Keyword(s):  
Posttranslational Modification ◽  
Nitrosative Stress ◽  
Therapeutic Potential ◽  
Disulfide Bridge ◽  
Side Chain ◽  
No Production ◽  
Cumulative Stress ◽  
Functional Relevance ◽  
Physiologic Regulation ◽  
Oxidative Insult

Proteins dynamically contribute towards maintaining cellular homeostasis. Posttranslational modification regulates the function of target proteins through their immediate activation, sudden inhibition, or permanent degradation. Among numerous protein modifications, protein nitrosation and its functional relevance have emerged. Nitrosation generally initiates nitric oxide (NO) production in association with NO synthase. NO is conjugated to free thiol in the cysteine side chain (S-nitrosylation) and is propagated via the transnitrosylation mechanism. S-nitrosylation is a signaling pathway frequently involved in physiologic regulation. NO forms peroxynitrite in excessive oxidation conditions and induces tyrosine nitration, which is quite stable and is considered irreversible. Two main reducing systems are attributed to denitrosylation: glutathione and thioredoxin (TRX). Glutathione captures NO from S-nitrosylated protein and forms S-nitrosoglutathione (GSNO). The intracellular reducing system catalyzes GSNO into GSH again. TRX can remove NO-like glutathione and break down the disulfide bridge. Although NO is usually beneficial in the basal context, cumulative stress from chronic inflammation or oxidative insult produces a large amount of NO, which induces atypical protein nitrosation. Herein, we (1) provide a brief introduction to the nitrosation and denitrosylation processes, (2) discuss nitrosation-associated human diseases, and (3) discuss a possible denitrosylation strategy and its therapeutic applications.

Replacement of the interchain disulfide bridge-forming amino acids A7 and B7 by glutamate impairs the structure and activity of insulin

2004 ◽  
Vol 385 (12) ◽  
pp. 1171-1175 ◽  
Author(s):  
Zhan-Yun Guo ◽  
Xiao-Yuan Jia ◽  
You-Min Feng
Keyword(s):  
Biological Activity ◽  
Disulfide Bonds ◽  
Negative Charge ◽  
Disulfide Bridge ◽  
Site Directed Mutagenesis ◽  
Side Chain ◽  
Insulin Analogs ◽  
High Biological Activity ◽  
Chemical Groups ◽  
Structure And Activity

Abstract Insulin contains three disulfide bonds, one intrachain bond, A6–A11, and two interchain bonds, A7–B7 and A20–B19. Site-directed mutagenesis results (the two cysteine residues of disulfide A7–B7 were replaced by serine) showed that disulfide A7–B7 is crucial to both the structure and activity of insulin. However, chemical modification results showed that the insulin analogs still retained relatively high biological activity when A7Cys and B7Cys were modified by chemical groups with a negative charge. Did the negative charge of the modification groups restore the loss of activity and/or the disturbance of structure of these insulin analogs caused by deletion of disulfide A7–B7? To answer this question, an insulin analog with both A7Cys and B7Cys replaced by Glu, which has a long side-chain and a negative charge, was prepared by protein engineering, and its structure and activity were analyzed. Both the structure and activity of the present analog are very similar to that of the mutant with disulfide A7–B7 replaced by Ser, but significantly different from that of wild-type insulin. The present results suggest that removal of disulfide A7–B7 will result in serious loss of biological activity and the native conformation of insulin, even if the disulfide is replaced by residues with a negative charge.

scholarly journals Treatment of Stress Urinary Incontinence by Cinnamaldehyde, the Major Constituent of the Chinese Medicinal HerbRamulus Cinnamomi

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Yung-Hsiang Chen ◽  
Yu-Ning Lin ◽  
Wen-Chi Chen ◽  
Wen-Tsong Hsieh ◽  
Huey-Yi Chen
Keyword(s):  
Nitric Oxide ◽  
Urinary Incontinence ◽  
Stress Urinary Incontinence ◽  
Therapeutic Potential ◽  
Contractile Force ◽  
Survival Motor Neuron ◽  
Raw 264.7 Cells ◽  
Major Constituent ◽  
No Production ◽  
Organ Bath

Stress urinary incontinence (SUI) is a common disorder in middle-aged women and the elderly population. Although surgical treatment of SUI has progressed, pharmacological therapies remain unelucidated. We screened potential herbal medicines against SUI with anex vivoorgan bath assay.Ramulus Cinnamomiand its major constituent cinnamaldehyde cause a high contractile force of the urethra and a low contractile force of blood vessels. Cinnamaldehyde dose-dependently reduced lipopolysaccharide-induced nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) expression in RAW 264.7 cells. In the vaginal distension- (VD-) induced SUI model in mice, cinnamaldehyde significantly reversed the VD-induced SUI physical signs and reduced blood pressure. Cinnamaldehyde may offer therapeutic potential against SUI without the possible side effect of hypertension. The modulation of several SUI-related proteins including myosin, iNOS, survival motor neuron (SMN) protein, and superoxide dismutase 3 (SOD3) may play some crucial roles in the therapeutic approach against SUI. This information may offer clues to the pathogenesis of SUI and open additional avenues for potential therapy strategies.

scholarly journals Structure-Dependent Effects of Bisphosphonates on Inflammatory Responses in Cultured Neonatal Mouse Calvaria

Antioxidants ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 503
Author(s):  
Keiko Suzuki ◽  
Sadaaki Takeyama ◽  
Shinobu Murakami ◽  
Masahiro Nagaoka ◽  
Mirei Chiba ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Inflammatory Responses ◽  
Bone Diseases ◽  
Neonatal Mouse ◽  
Side Chain ◽  
Inos Mrna ◽  
No Production ◽  
Tyrosine Nitration ◽  
Mouse Calvaria ◽  
Neonatal Mouse Calvaria

Bisphosphonates (BPs) are classified into two groups, according to their side chain structures, as nitrogen-containing BPs (NBPs) and non-nitrogen-containing BPs (non-NBPs). In this study, we examined the effects of NBPs and non-NBPs on inflammatory responses, by quantifying the inflammatory mediators, prostaglandin E2 (PGE2) and nitric oxide (NO), in cultured neonatal mouse calvaria. All examined NBPs (pamidronate, alendronate, incadronate, risedronate, zoledronate) stimulated lipopolysaccharide (LPS)-induced PGE2 and NO production by upregulating COX-2 and iNOS mRNA expression, whereas non-NBPs (etidronate, clodronate, tiludronate) suppressed PGE2 and NO production, by downregulating gene expression. Additionally, [4-(methylthio) phenylthio] methane bisphosphonate (MPMBP), a novel non-NBP with an antioxidant methylthio phenylthio group in its side chain, exhibited the most potent anti-inflammatory activity among non-NBPs. Furthermore, results of immunohistochemistry showed that the nuclear translocation of NF-κB/p65 and tyrosine nitration of cytoplasmic protein were stimulated by zoledronate, while MPMBP inhibited these phenomena, by acting as a superoxide anion (O2−) scavenger. These findings indicate that MPMBP can act as an efficacious agent that causes fewer adverse effects in patients with inflammatory bone diseases, including periodontitis and rheumatoid arthritis.

scholarly journals Anthocyanins and Their Metabolites as Therapeutic Agents for Neurodegenerative Disease

Antioxidants ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 333 ◽  
Author(s):  
Aimee N. Winter ◽  
Paula C. Bickford
Keyword(s):  
Neurodegenerative Diseases ◽  
Nitrosative Stress ◽  
Therapeutic Potential ◽  
Stress Protein ◽  
Motor Impairments ◽  
Oxidative And Nitrosative Stress ◽  
Beneficial Effects ◽  
Neuronal Populations ◽  
Neurodegenerative Process ◽  
Lateral Sclerosis

Neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS), are characterized by the death of neurons within specific regions of the brain or spinal cord. While the etiology of many neurodegenerative diseases remains elusive, several factors are thought to contribute to the neurodegenerative process, such as oxidative and nitrosative stress, excitotoxicity, endoplasmic reticulum stress, protein aggregation, and neuroinflammation. These processes culminate in the death of vulnerable neuronal populations, which manifests symptomatically as cognitive and/or motor impairments. Until recently, most treatments for these disorders have targeted single aspects of disease pathology; however, this strategy has proved largely ineffective, and focus has now turned towards therapeutics which target multiple aspects underlying neurodegeneration. Anthocyanins are unique flavonoid compounds that have been shown to modulate several of the factors contributing to neuronal death, and interest in their use as therapeutics for neurodegeneration has grown in recent years. Additionally, due to observations that the bioavailability of anthocyanins is low relative to that of their metabolites, it has been proposed that anthocyanin metabolites may play a significant part in mediating the beneficial effects of an anthocyanin-rich diet. Thus, in this review, we will explore the evidence evaluating the neuroprotective and therapeutic potential of anthocyanins and their common metabolites for treating neurodegenerative diseases.

scholarly journals (−)-Epicatechin induces calcium and translocation independent eNOS activation in arterial endothelial cells

2011 ◽  
Vol 300 (4) ◽  
pp. C880-C887 ◽  
Author(s):  
Israel Ramirez-Sanchez ◽  
Lisandro Maya ◽  
Guillermo Ceballos ◽  
Francisco Villarreal
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Cardiovascular Effects ◽  
Mesenteric Arteries ◽  
No Production ◽  
Human Coronary Artery ◽  
Calmodulin Binding ◽  
Pathway Activation ◽  
Functional Relevance ◽  
Endothelial Nitric Oxide

The consumption of cacao-derived (i.e., cocoa) products provides beneficial cardiovascular effects in healthy subjects as well as individuals with endothelial dysfunction such as smokers, diabetics, and postmenopausal women. The vascular actions of cocoa are related to enhanced nitric oxide (NO) production. These actions can be reproduced by the administration of the cacao flavanol (−)-epicatechin (EPI). To further understand the mechanisms behind the vascular action of EPI, we investigated the effects of Ca2+ depletion on endothelial nitric oxide (NO) synthase (eNOS) activation/phosphorylation and translocation. Human coronary artery endothelial cells were treated with EPI or with bradykinin (BK), a well-known Ca2+-dependent eNOS activator. Results demonstrate that both EPI and BK induce increases in intracellular calcium and NO levels. However, under Ca2+-free conditions, EPI (but not BK) is still capable of inducing NO production through eNOS phosphorylation at serine 615, 633, and 1177. Interestingly, EPI-induced translocation of eNOS from the plasmalemma was abolished upon Ca2+ depletion. Thus, under Ca2+-free conditions, EPI can stimulate NO synthesis independent of calmodulin binding to eNOS and of its translocation into the cytoplasm. We also examined the effect of EPI on the NO/cGMP/vasodilator-stimulated phosphoprotein (VASP) pathway activation in isolated Ca2+-deprived canine mesenteric arteries. Results demonstrate that under these conditions, EPI induces the activation of this vasorelaxation-related pathway and that this effect is inhibited by pretreatment with nitro-l-arginine methyl ester, suggesting a functional relevance for this phenomenon.

scholarly journals S-nitrosylation drives cell senescence and aging in mammals by controlling mitochondrial dynamics and mitophagy

2018 ◽  
Vol 115 (15) ◽  
pp. E3388-E3397 ◽  
Author(s):  
Salvatore Rizza ◽  
Simone Cardaci ◽  
Costanza Montagna ◽  
Giuseppina Di Giacomo ◽  
Daniela De Zio ◽  
...  
Keyword(s):  
Quality Control ◽  
Life Span ◽  
Immune Function ◽  
Posttranslational Modification ◽  
Nitrosative Stress ◽  
Mitochondrial Dynamics ◽  
Cell Senescence ◽  
Primary Cells ◽  
Cellular Homeostasis ◽  
Therapeutic Implications

S-nitrosylation, a prototypic redox-based posttranslational modification, is frequently dysregulated in disease. S-nitrosoglutathione reductase (GSNOR) regulates protein S-nitrosylation by functioning as a protein denitrosylase. Deficiency of GSNOR results in tumorigenesis and disrupts cellular homeostasis broadly, including metabolic, cardiovascular, and immune function. Here, we demonstrate that GSNOR expression decreases in primary cells undergoing senescence, as well as in mice and humans during their life span. In stark contrast, exceptionally long-lived individuals maintain GSNOR levels. We also show that GSNOR deficiency promotes mitochondrial nitrosative stress, including excessive S-nitrosylation of Drp1 and Parkin, thereby impairing mitochondrial dynamics and mitophagy. Our findings implicate GSNOR in mammalian longevity, suggest a molecular link between protein S-nitrosylation and mitochondria quality control in aging, and provide a redox-based perspective on aging with direct therapeutic implications.

scholarly journals Cepharanthine: a review of the antiviral potential of a Japanese-approved alopecia drug in COVID-19

2020 ◽  
Vol 72 (6) ◽  
pp. 1509-1516 ◽  
Author(s):  
Moshe Rogosnitzky ◽  
Paul Okediji ◽  
Igor Koman
Keyword(s):  
Viral Entry ◽  
Cytokine Production ◽  
Therapeutic Potential ◽  
Antiviral Agent ◽  
Drug Repurposing ◽  
Preclinical Model ◽  
No Production ◽  
Drug Of Choice ◽  
Naturally Occurring

AbstractCepharanthine (CEP) is a naturally occurring alkaloid derived from Stephania cepharantha Hayata and demonstrated to have unique anti-inflammatory, antioxidative, immunomodulating, antiparasitic, and antiviral properties. Its therapeutic potential as an antiviral agent has never been more important than in combating COVID-19 caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) virus. Cepharanthine suppresses nuclear factor-kappa B (NF-κB) activation, lipid peroxidation, nitric oxide (NO) production, cytokine production, and expression of cyclooxygenase; all of which are crucial to viral replication and inflammatory response. Against SARS-CoV-2 and homologous viruses, CEP predominantly inhibits viral entry and replication at low doses; and was recently identified as the most potent coronavirus inhibitor among 2406 clinically approved drug repurposing candidates in a preclinical model. This review critically analyzes and consolidates available evidence establishing CEP’s potential therapeutic importance as a drug of choice in managing COVID-19 cases.

scholarly journals Salvia ceratophylla L. from South of Jordan: new insights on chemical composition and biological activities

2020 ◽  
Vol 10 (5) ◽  
pp. 307-316
Author(s):  
Mohammad Sanad Abu-Darwish ◽  
Célia Cabral ◽  
Zulfigar Ali ◽  
Mei Wang ◽  
Shabana I. Khan ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Gas Chromatography ◽  
Therapeutic Potential ◽  
Biological Activities ◽  
Vero Cells ◽  
Gas Chromatography Mass Spectrometry ◽  
No Production ◽  
Main Constituent ◽  
Microbial Infections

Abstract In Jordan, Salvia ceratophylla L. is traditionally used in the treatment of cancer, microbial infections, and urinary disorders. This study aimed: (1) to chemically characterize S. ceratophylla essential oil (EO) from South Jordan, by gas chromatography (GC) and gas chromatography-mass spectrometry (GC–MS); and (2) to evaluate in vitro the cytotoxic, anti-inflammatory, and antiprotozoal activities of the EO, it’s predominant components, and the hexane (A), ethyl acetate (B), methanol (C) and crude-methanol extracts (D). The analysis revealed that the EO has 71 compounds, with linalool (54.8%) as main constituent. Only the hexane extract (A) showed some cytotoxic activity against SK-MEL, KB, BT-549, SK-OV-3, LLC-PK1 and VERO cells lines with IC50 between 60 and > 100 µg/mL. The EO inhibited NO production (IC50 90 µg/mL) and NF-κB activity (IC50 38 µg/mL). The extracts A, B, and D inhibited NO production and NF- κB activity with IC50 between 32 and 150 µg/mL. Linalool considerably inhibited NO production (IC50 18 µg/mL). The extracts tested did not exhibit antileishmanial activity. Regarding antitrypanosomal activity, the EO exhibited significant results with IC50 2.65 µg/mL. In conclusion, Jordan S. ceratophylla EO represents a rich source of linalool and bears a promising therapeutic potential for further antitrypanosomal drug development.

New evidence for vascular interactions between aldosterone, angiotensin II and antioxidants in isolated smooth muscle cells of rats

Open Medicine ◽  
2012 ◽  
Vol 7 (6) ◽  
pp. 704-712
Author(s):  
Raducu Popescu ◽  
Walther Bild ◽  
Alin Ciobica ◽  
Veronica Bild
Keyword(s):  
Oxidative Stress ◽  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Smooth Muscle Cells ◽  
Nitrosative Stress ◽  
Reactive Oxygen ◽  
Muscle Cells ◽  
No Production ◽  
Nitrogen Species ◽  
First Case

AbstractAccumulating evidence suggests that the nongenomic cardiovascular actions of aldosterone are produced by varied cellular pathways and mediated by a multitude of messenger systems including the reactive oxygen and nitrogen species. Considering the involvement of the oxidative and nitrosative stress in the pathways leading to the activation of the angiotensin — aldosterone system, in the current study we tried to evaluate the functional interactions between aldosterone, angiotensin II and antioxidants in isolated vascular smooth muscle of aortic rings from rats. Our data provide additional arguments that the nongenomic actions of aldosterone on aortic smooth muscle cells of rats are a question of cross-talk and balance between its rapid vasoconstrictor and vasodilator effects, as result of the activation of reactive oxygen species in the first case and of nitrogen species in the second. In this way, it seems that at low ambient oxidative stress, aldosterone promotes nitric oxide (NO) production and vasodilatation, while in situations with increased oxidative stress the endothelial dysfunction and detrimental effects induced by vasoconstriction will prevail. Thus, aldosterone could be considered both “friend and foe”. This could be relevant for the ways in which aldosterone damages cardiovascular functions and could lead to significant therapeutic improvements.

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