scholarly journals Bioactive nano-selenium antagonizes cobalt nanoparticle-mediated oxidative stress via the Keap1-Nrf2-ARE signaling pathway

2022 ◽  
Vol 24 (1) ◽  
Author(s):  
Siqi Wang ◽  
Chen Wang ◽  
Weinan Zhang ◽  
Wentao Fan ◽  
Fan Liu ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Cell Activity ◽  
Inflammatory Factors ◽  
Ros Generation ◽  
Ros Production ◽  
Metal On Metal ◽  
Human Participant ◽  
Artificial Joint Replacement ◽  
Cobalt Nanoparticle

AbstractAt present, no effective treatment exists for the clinical toxicity of cobalt nanoparticles (CoNPs, 30 nm) after metal-on-metal (MOM) artificial joint replacement. As such, a better understanding of the CoNPs-toxicity mechanism is necessary and urgent for the development of effective and safe detoxification drugs. Our purpose was to explore the role of bioactive nano-selenium (BNS, > 97%) in antagonizing the toxicity of CoNPs and its mechanism through the Keap1-Nrf2-ARE signaling pathway. To examine BNS detoxification, we exposed HUVEC cells to CoNPs and BNS for 24 h, before measuring cell activity, reactive oxygen species (ROS), the GSH level, inflammatory factors, and KNA signaling pathway-related transcript and protein expression. CoNPs stimulate intracellular inflammation and ROS production to bring about significant downregulation of cellular activity and the GSH level. Conversely, BNS reduces ROS generation and suppresses inflammatory factors within cells to reduce CoNPs-mediated cytotoxicity, possibly via the KNA signaling pathway. Based on our results, BNS antagonizes CoNPs toxic effects by suppressing ROS production through the KNA pathway. Our research provides new insight into the clinical treatment of CoNPs toxicity and explores the potential of BNS in detoxification therapy. Trial registration: no human participant.

scholarly journals Bioactive nano-selenium antagonizes cobalt nanoparticle- mediated oxidative stress via the Keap1-Nrf2-ARE signaling pathway

2021 ◽  
Author(s):  
Siqi Wang ◽  
Chen Wang ◽  
Weinan Zhang ◽  
Wentao Fan ◽  
Fan Liu ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Cell Activity ◽  
Inflammatory Factors ◽  
Ros Generation ◽  
Ros Production ◽  
Metal On Metal ◽  
Artificial Joint Replacement ◽  
Huvec Cells ◽  
Cobalt Nanoparticle

Abstract BackgroundAt present, no effective treatment exists for the clinical toxicity of cobalt nanoparticles (CoNPs) after metal-on-metal (MOM) artificial joint replacement. As such, a better understanding of the CoNPs-toxicity mechanism is necessary and urgent for the development of effective and safe detoxification drugs. Our purpose was to explore the role of bioactive nano-selenium (BNS) in antagonizing the toxicity of CoNPs and its mechanism through the Keap1-Nrf2-ARE signaling pathway. MethodsTo examine BNS detoxification, we exposed HUVEC cells to CoNPs (400μmol/l) and BNS (50μg/ml) for 24h, before measuring cell activity, reactive oxygen species (ROS), inflammatory factors, and KNA signaling pathway related transcript and protein expression. ResultsCoNPs stimulate intracellular inflammation and ROS production to bring about significant downregulation of cellular activity. Conversely, BNS reduces ROS generation and suppresses inflammatory factors within cells to reduce CoNPs-mediated cytotoxicity, possibly via the KNA signaling pathway. ConclusionsBased on our results, BNS antagonizes CoNPs toxic effects by suppressing ROS production through the KNA pathway. Our research provides new insight into the clinical treatment of CoNPs toxicity and explores the potential of BNS in detoxification therapy.

Abstract 96: Melatonin Prevents Atherosclerosis via Regulating NLRP3 Inflammasome: The Role of Sirt3 Signaling

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Sai Ma ◽  
Jiangwei Chen ◽  
Zhenli Luo ◽  
Yabin Wang ◽  
Feng Cao
Keyword(s):  
Protective Effect ◽  
Signaling Pathway ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Factors ◽  
Ros Generation ◽  
Inflammasome Activation ◽  
Mitochondrial Ros ◽  
Nlrp3 Inflammasome Activation

Introduction: NLRP3 inflammasome mediated inflammatory factors secretion is critically involved in atherosclerosis (AS). Melatonin has anti-inflammatory properties. However, it is unknown whether melatonin is beneficial in AS. Hypothesis: Melatonin plays a beneficial role in AS by decreasing NLRP3 inflammasome activation in macrophages. Methods: AS model was induced with high fat diet in apoE -/- mice. Plaque stability was examined with historical staining. In vitro study was performed in ox-LDL treated RAW264.7 cells. NLRP3 inflammasome activation, inflammatory factors secretion, mitochondrial ROS generation, autophagy, mitophagy indexes and potential signaling pathways were investigated. Results: Historical staining results showed that melatonin treatment markedly alleviated AS plaque progression. Despite of unchanged protein expression, Sirt 3 activity was elevated in plaque tissue in melatonin treated mice. Melatonin attenuated NLRP3 inflammasome activation and inflammatory factors secretion in ox-LDL treated macrophages, while this protective effect was abolished by Sirt3-siRNA. Mitochondrial ROS (mitoROS), which was an inducer for NLRP3 inflammasome, was reduced by melatonin through the elimination of damaged mitochondria (mitophagy). Similar with Sirt3-siRNA, autophagy inhibitor 3-MA also abolished the effects of melatonin on mitoROS clearance, indicating the crucial role of autophagy and mitophagy in melatonin caused NLRP3 inactivation. Furthermore, melatonin protected against AS via Sirt3/FoxO3/Parkin signaling pathway. Conclusions: Melatonin prevented atherosclerotic progression. Melatonin reduced mitochondrial ROS through the activation of autophagy and mitophagy, thereby attenuating NLRP3 inflammasome activation in macrophages. Moreover, the protective effect of melatonin was mediated by Sirt3/FoxO3/Parkin signaling pathway. Our study provides insight into a new therapeutic target for AS.

scholarly journals The Roles of ROS Generation in RANKL-Induced Osteoclastogenesis: Suppressive Effects of Febuxostat

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 929
Author(s):  
Mohannad Ashtar ◽  
Hirofumi Tenshin ◽  
Jumpei Teramachi ◽  
Ariunzaya Bat-Erdene ◽  
Masahiro Hiasa ◽  
...  
Keyword(s):  
Bone Marrow Cells ◽  
Tumor Lysis Syndrome ◽  
Oxidase Inhibitor ◽  
Ros Generation ◽  
Ros Production ◽  
Xanthine Oxidase Inhibitor ◽  
Ovariectomized Mice ◽  
Bone Damage ◽  
Anticancer Treatment

Receptor activator of NF-κB ligand (RANKL), a critical mediator of osteoclastogenesis, is upregulated in multiple myeloma (MM). The xanthine oxidase inhibitor febuxostat, clinically used for prevention of tumor lysis syndrome, has been demonstrated to effectively inhibit not only the generation of uric acid but also the formation of reactive oxygen species (ROS). ROS has been demonstrated to mediate RANKL-mediated osteoclastogenesis. In the present study, we therefore explored the role of cancer-treatment-induced ROS in RANKL-mediated osteoclastogenesis and the suppressive effects of febuxostat on ROS generation and osteoclastogenesis. RANKL dose-dependently induced ROS production in RAW264.7 preosteoclastic cells; however, febuxostat inhibited the RANKL-induced ROS production and osteoclast (OC) formation. Interestingly, doxorubicin (Dox) further enhanced RANKL-induced osteoclastogenesis through upregulation of ROS production, which was mostly abolished by addition of febuxostat. Febuxostat also inhibited osteoclastogenesis enhanced in cocultures of bone marrow cells with MM cells. Importantly, febuxostat rather suppressed MM cell viability and did not compromise Dox’s anti-MM activity. In addition, febuxostat was able to alleviate pathological osteoclastic activity and bone loss in ovariectomized mice. Collectively, these results suggest that excessive ROS production by aberrant RANKL overexpression and/or anticancer treatment disadvantageously impacts bone, and that febuxostat can prevent the ROS-mediated osteoclastic bone damage.

scholarly journals Monoclonal Antibody to CD14, TLR4, or CD11b: Impact of Epitope and Isotype Specificity on ROS Generation by Human Granulocytes and Monocytes

2020 ◽  
Vol 2020 ◽  
pp. 1-20
Author(s):  
Dmitry S. Kabanov ◽  
Sergey V. Grachev ◽  
Isabella R. Prokhorenko
Keyword(s):  
Cellular Response ◽  
Adaptive Immune System ◽  
Interferon Γ ◽  
Ros Generation ◽  
Ros Production ◽  
Therapeutic Approaches ◽  
Igg Antibody ◽  
Therapeutic Efficiency ◽  
Molecular Patterns

Lipopolysaccharides (LPSs or endotoxins) from Gram-negative bacteria represent pathogen-associated molecular patterns (PAMPs) that are recognized by CD14 and Toll-like receptor 4 (TLR4). Lipopolysaccharides prime polymorphonuclear leukocytes (PMNs) for substantial production of reactive oxygen species (ROS) during its response to secondary stimuli such as chemoattractants or pathogens. The excessive ROS production can damage surrounding host tissues, thereby amplifying the inflammatory reaction caused by pathogens. Today, specific antibodies against CD14, TLR4, and CD11b are being used as the essential tools to elucidate the role of these receptors in acute inflammation and some of these antibodies have advised as therapeutic agents for clinical use. Because each antibody has two antigen-binding arms [F(ab ′ )2] and one Fc arm, its effect on cellular response is much more complicated rather than simple blockage of target receptor. In fact, IgG antibody, once bound to target receptor, engages Fc receptors γ (FcγRs) and thereby is able to activate the adaptive immune system. The consequences of antibody-dependent binary heterotypic association of CD14, TLR4, or CD11b with FcγRs as well as homotypic one on ROS production are not well elucidated. Moreover, the consequences of antigenic recognition of CD14, TLR4, or CD11b by specific F(ab ′ )2 fragments are not always investigated. In this review, we will discuss known mechanisms underlying the therapeutic efficiency of CD14, TLR4, and CD11b/CD18 antibodies with a focus on LPS-dependent ROS or cytokine production by PMNs or monocytes. The impacts of F(ab ′ )2 as well as antibody IgG subclasses (isotypes) in therapeutic efficiency or agonistic potency of known antibodies against abovementioned receptors are presented. We also pay attention to how the efficiency of different IgG antibody subclasses is modulated during LPS-induced inflammation and by production of priming agents such as interferon γ (IFN-γ). Our review reinforces the molecular targets and therapeutic approaches to amelioration of harmful consequences of excessive activation of human pattern recognition receptors.

scholarly journals Immunoregulatory Role of MicroRNA-21 in Macrophages in Response to Bacillus Calmette-Guerin Infection Involves Modulation of the TLR4/MyD88 Signaling Pathway

2017 ◽  
Vol 42 (1) ◽  
pp. 91-102 ◽  
Author(s):  
Xin Xue ◽  
Yi Qiu ◽  
Hong-Li Yang
Keyword(s):  
Cell Viability ◽  
Signaling Pathway ◽  
Cell Apoptosis ◽  
Inflammatory Factors ◽  
Enzyme Linked Immunosorbent Assay ◽  
Control Group ◽  
Bacillus Calmette Guerin ◽  
Myd88 Signaling ◽  
Apoptosis And Necrosis

Background/Aims: The purpose of this study is to explore the immunoregulatory role of microRNA-21 (miR-21) targeting of the TLR4/MyD88 signaling pathway in macrophages in response to Bacillus Calmette-Guerin (BCG) infection. Methods: After infection with BCG, mouse RAW246.7 cells were assigned into control, BCG, miR-21 mimic + BCG, mimic-negative control (NC) + BCG, miR-21 inhibitor + BCG, inhibitor-NC + BCG, BCG + TAK242 (an inhibitor of the TLR4 signaling pathway), and miR-21 inhibitor + TAK242 + BCG groups. Western blotting and qRT-PCR were used to detect the expression of miR-21, TLR4 and MyD88. The levels of TNF-a, IL-6 and IL-10 were detected by enzyme-linked immunosorbent assay (ELISA). Cell viability was measured using an MTT assay. Cell apoptosis and necrosis rates were detected using flow cytometry. Results: Compared with the control group, miR-21 expression and levels of TNF-a, IL-6 and IL-10, as well as cell apoptosis and necrosis rates, were elevated, while expression of TLR4 and MyD88, as well as cell viability, were reduced in BCG infection groups. Compared with the BCG group, miR-21 expression was increased in the miR-21 mimic + BCG group but decreased in the miR-21 inhibitor + BCG and miR-21 inhibitor + TAK242 + BCG groups. The expression of TLR4 and MyD88, as well as the cell viability, were decreased, while levels of TNF-a, IL-6 and IL-10, as well as cell apoptosis and necrosis rates, were increased in the miR-21 mimic + BCG and TAK242 + BCG groups. The opposite trends were found in the miR-21 inhibitor + BCG group. Compared with the TAK242 + BCG group, the miR-21 inhibitor + TAK242 + BCG group had higher expression of TLR4 and MyD88 as well as higher cell viability and lower levels of TNF-a, IL-6, IL-10, cell apoptosis and necrosis rates. However, the miR-21 inhibitor + TAK242 + BCG group exhibited the opposite trends when compared with the miR-21 inhibitor + BCG group. Conclusion: Our results suggest that miR-21 can negatively modulate the TLR4/MyD88 signaling pathway, resulting in decreased cell viability, increased cell apoptosis and increased levels of inflammatory factors following BCG infection in macrophages.

scholarly journals Klotho protects chondrocyte viability via FOXO1/3 in osteoarthritis

2021 ◽  
Vol 20 (9) ◽  
pp. 1961-1968
Author(s):  
Wei Wei ◽  
Liefeng Ji ◽  
Wanli Duan ◽  
Jiang Zhu
Keyword(s):  
Oxidative Stress ◽  
Survival Rate ◽  
Protective Effect ◽  
Collagen I ◽  
Inflammatory Factors ◽  
Ros Production ◽  
Chondrocyte Viability ◽  
Tnf Α ◽  
Collagen Ii

Purpose: To investigate the effect of Klotho and FOXO1/3 on the CH viability in OA.Methods: The survival rate of CHs, Klotho and FOXO1/3 protein expression, and ROS production were measured in the OA cartilages of different degenerative phases. H2O2 was also used to injure CHs, and the cell viability, Klotho and FOXO1/3 expressions, as well as ROS levels were investigated to clarify the effect of exogenic Klotho on the injured CHs. Additionally, in order to verify the role of FOXO1/3 in Klotho-treated CHs, SOD2, GPX1, inflammatory factors, collagen I/II, SOX9, and Runx-2 levels were analyzed by silencing FOXO1 and FOXO3 expression via siRNA transfection.Results: Klotho and FOXO1/3 expressions significantly decreased, and ROS production increased in severely human OA cartilage (p <0.05). Besides, H2O2 affected CHs viability with the suppression of Klotho and FOXO1/3 expression but ROS production was elevated. Exogenic Klotho application partly reversed the injury caused by H2O2. Furthermore, Klotho treatment of the injured CHs contributed to SOD2 and GPX1 expressions, and suppressed IL-1β, IL-6, TNF-α and MMP-13 production, resulting in  the upregulation of collagen II and SOX9 as well as downregulation of collagen I and Runx-2. However, the protective effect of Klotho was weakened by FOXO1 and FOXO3 gene silencing.Conclusion: Klotho protects CHs viability by suppressing oxidative stress and inflammation, which is associated with the mediation of FOXO1 and FOXO3. These findings provide new insights into the treatment of OA.

scholarly journals The Role of Smoothened in Cancer

2020 ◽  
Vol 21 (18) ◽  
pp. 6863 ◽  
Author(s):  
Kuo-Shyang Jeng ◽  
I-Shyan Sheen ◽  
Chuen-Miin Leu ◽  
Ping-Hui Tseng ◽  
Chiung-Fang Chang
Keyword(s):  
Stem Cells ◽  
Signaling Pathway ◽  
Cell Activity ◽  
Therapeutic Approaches ◽  
Colon Cancers ◽  
Stem Cell Activity ◽  
Different Types ◽  
Hh Signaling ◽  
Novel Therapeutic

Smoothened (SMO) belongs to the Hedgehog (HH) signaling pathway, which regulates cell growth, migration, invasion and stem cells in cancer. The HH signaling pathway includes both canonical and noncanonical pathways. The canonical HH pathway functions through major HH molecules such as HH ligands, PTCH, SMO and GLI, whereas the noncanonical HH pathway involves the activation of SMO or GLI through other pathways. The role of SMO has been discussed in different types of cancer, including breast, liver, pancreatic and colon cancers. SMO expression correlates with tumor size, invasiveness, metastasis and recurrence. In addition, SMO inhibitors can suppress cancer formation, reduce the proliferation of cancer cells, trigger apoptosis and suppress cancer stem cell activity. A better understanding of the role of SMO in cancer could contribute to the development of novel therapeutic approaches.

scholarly journals Rottlerin ameliorates DSS-induced colitis by improving intestinal barrier function via activation of the Epac-2/Rap-1 signaling pathway

2020 ◽  
Author(s):  
Xue Song ◽  
Lugen Zuo ◽  
Luyao Wang ◽  
Zihan Zhu ◽  
Jing Tao ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Barrier Function ◽  
Intestinal Barrier ◽  
Inflammatory Factors ◽  
Intestinal Barrier Function ◽  
Control Group ◽  
Treatment Groups ◽  
Normal Feeding ◽  
Anti Inflammatory

ABSTRACTOBJECTIVESRottlerin, a pan PDE inhibitor, has a variety of pharmacological activities, including enhancing barrier function and mediating anti-inflammatory activity by changing the distribution of occludin and ZO-1. Nevertheless, the function of rottlerin on Crohn disease (CD) keep unknown. Our aim of the study is to investigate the role of rottlerin on CD-like colitis and its mechanism.METHODSWild-type mice which were 8-10 weeks old were randomly divided into three treatment groups: (i) the normal feeding, no administration (control) group, (ii) the group administered 3% dextran sodium sulfate (DSS) alone, and (iii) the group administered rottlerin (100 mg/kg) and 3% DSS. In this study, the effect of rottlerin on the function and structure of the intestinal barrier was investigated, and the possible mechanism was discussed. We performed signaling pathway analysis and flow cytometry to identify the detailed mechanisms by which rottlerin (10 μg/mL) treatment inhibits cell growth arrest and the attenuation of TJ proteins in LPS-treated FHs 74 int cells.RESULTSRottlerin treatment significantly ameliorated colitis induced by DSS in WT mice, which was manifested by a decrease in inflammation score, the attenuation of inflammatory factors and the inhibition of destruction on intestinal barrier structure. Rottlerin enhanced the levels of occludin and ZO-1, and improved the function of intestinal barrier, which may have been why rottlerin ameliorated colitis in WT mice. The anti-inflammatory effect of rottlerin may be partly due to the activation of Epac-2/Rap-1 signaling.CONCLUSIONSRottlerin may treat CD in humans via enhancing TJ proteins expression and improving the function of intestinal barrier.

scholarly journals The Role of LncRNA H19 in MAPK Signaling Pathway Implicated in the Progression of Bronchopulmonary Dysplasia

2020 ◽  
Vol 29 ◽  
pp. 096368972091829 ◽  
Author(s):  
Wenhui Mo ◽  
Yi Li ◽  
Weijie Chang ◽  
Yaoming Luo ◽  
Bingbin Mai ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Bronchopulmonary Dysplasia ◽  
Respiratory Illness ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Inflammatory Factors ◽  
Normal Lung ◽  
Mouse Lung

Bronchopulmonary dysplasia (BPD), also known as neonatal chronic lung disease, is an important cause of respiratory illness in preterm newborns that results in significant morbidity and mortality. Long noncoding RNAs (lncRNAs) have been discovered with many biological functions. However, the role of lncRNAs in the pathogenesis of BPD remains poorly understood. Here, we established a mouse lung injury model that mimicked human BPD. Subsequently, we found the lncRNA H19 expression level was significantly increased in BPD compared with normal lung tissues using quantitative real-time polymerase chain reaction. Next, we observed that overexpression of lncRNA H19 enhanced mitogen-activated protein kinase (MAPK) signaling pathway. In addition, we also found that dysfunction of lncRNA H19 altered the expression of inflammatory factors. Thus, our study validates that lncRNA H19 contributes to the progression of BPD by regulating MAPK signaling pathway, which could be used as a potential target for treating BPD.

Abstract 113: Glucose Metabolic Disorders in Aging-Associated Microglial NADPH Oxidase 2 Activation and Oxidative Damage of Cerebral Microvasculature and Neurons

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Li Geng ◽  
Jian-Mei Li
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Blood Pressure ◽  
Nadph Oxidase ◽  
Metabolic Disorders ◽  
Aging Brain ◽  
Ros Generation ◽  
Ros Production ◽  
The Brain

Aging has been recognised to be a major risk factor for the development of cardiovascular and neurodegenerative diseases and growing evidence suggests a role for oxidative stress. A Nox2-containing NADPH oxidase has been reported to be a major source of reactive oxygen species (ROS) generation in the vascular system and in the brain. However, the role of Nox2 enzyme in aging-related metabolic disorders and vascular neurodegeneration remains unclear. In this study, we used age-matched wild-type (WT) and Nox2-deficient (Nox2 -/- ) mice on a C57BL/6 background at young (3-4 month) and aging (20-24 month) to investigate the role of Nox2 in aging-related oxidative stress, metabolic disorders and cerebral vascular dysfunction. There was an aging-related increase in blood pressure in WT mice (126 mmHg for young and 148 mmHg for aging) (P<0.05); however the blood pressure was well maintained without significant change in Nox2 -/- aging mice. Compared to young WT mice, WT aging mice had significantly high levels of fasting serum insulin and this was accompanied with delayed clearance of glucose (P<0.05) indicating insulin resistance. In contrast, there was no indication of insulin resistance for Nox2 -/- aging mice. We then examined aging-related brain oxidative stress. Compared to WT young mice, there were significant increases (2.7±0.7 folds) in the levels of ROS production by WT aging brain tissue homogenates as detected by lucigenin-chemiluminescence and DHE fluorescence. Increased ROS production in WT aging brain was accompanied by a significant increase (1.8±0.3 folds) in the Nox2 expression detected mainly in the microglial cells (labelled by Iba-1) and decreases in brain capillaries (labelled by CD31) (2.4±0.8 folds) and neurons (labelled by Neu-N) (2.9±0.5 folds) (all P<0.05). Knockout of Nox2 abolished aging-associated increases in brain ROS production and significantly reduced the aging-related pathophysiological changes in the brain. In conclusion, aging-associated metabolic disorders play a crucial role in aging-associated Nox2 activation and vascular neurodegeneration. Nox2-containing NADPH oxidase represents a valuable therapeutic target for oxidative stress-related brain microvascular damage and neurodegeneration.

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