scholarly journals Anti-Interleukin-16 Neutralizing Antibody Treatment Alleviates Sepsis-Induced Cardiac Injury and Dysfunction via the Nuclear Factor Erythroid-2 Related Factor 2 Pathway in Mice

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Jianwei Zhang ◽  
Zicong Yang ◽  
Zhishan Liang ◽  
Mengjie Wang ◽  
Changxing Hu ◽  
...  
Keyword(s):  
Troponin T ◽  
Cardiac Injury ◽  
Cecal Ligation ◽  
Neutralizing Antibody ◽  
Serum Lactate ◽  
Serum Lactate Dehydrogenase ◽  
Related Factor ◽  
Nuclear Factor ◽  
Antibody Treatment ◽  
Nrf2 Pathway

Several interleukin (IL) members have been reported to participate in sepsis. In this study, the effects of IL-16 on sepsis-induced cardiac injury and dysfunction were examined, and the related mechanisms were detected. IL-16 expression in septic mice was first measured, and the results showed that both cardiac and serum IL-16 expression levels were increased in mice with sepsis induced by LPS or cecal ligation and puncture (CLP) compared with control mice. Then, IL-16 was neutralized, and the effects on lipopolysaccharide- (LPS-) induced cardiac injury were detected. The results showed that an anti-IL-16 neutralizing antibody (nAb) significantly reduced mortality and increased serum lactate dehydrogenase (LDH), creatine kinase myocardial bound (CK-MB), and cardiac troponin T (cTnT) levels while improving cardiac function in mice with LPS-induced sepsis. Neutralization of IL-16 also increased the activation of antioxidant pathways and the expression of antioxidant factors in septic mice while decreasing the activation of prooxidant pathways and the expression of prooxidants. Treatment with the anti-IL-16 nAb increased mitochondrial apoptosis-inducing factor (AIF) expression, decreased nuclear AIF and cleaved poly-ADP-ribose polymerase (PARP) expression, and decreased TUNEL-positive cell percentages in LPS-treated mice. Additionally, treatment with CPUY192018, the nuclear factor erythroid-2 related factor 2 (Nrf2) pathway, significantly increased mortality and reversed the above effects in mice treated with LPS and the anti-IL-16 nAb. Our results showed that the anti-IL-16 nAb regulates oxidative stress through the Nrf2 pathway and participates in the regulation of cardiac injury in septic mice. Neutralization of IL-16 may be a beneficial strategy for the prevention of cardiac injury and dysfunction in sepsis patients.

Uncoupling protein 2 facilitates insulin-elicited protection against lipopolysaccharide-induced myocardial dysfunction

2020 ◽  
Vol 10 (3) ◽  
pp. 337-349
Author(s):  
Yiting Chen ◽  
Guangdao Chen ◽  
Junliang Zhang ◽  
Tao Wang ◽  
Juxing Zhang ◽  
...  
Keyword(s):  
Troponin T ◽  
Uncoupling Protein ◽  
Myocardial Dysfunction ◽  
Magnetic Bead ◽  
Serum Lactate ◽  
Serum Lactate Dehydrogenase ◽  
H9c2 Cell ◽  
Uncoupling Protein 2 ◽  
Beneficial Effects ◽  
Lps Challenge

Sepsis-induced myocardial dysfunction is a critical cause of high mortality among patients with sepsis. Previously, insulin has been suggested to protect against lethal endotoxemia, while uncoupling protein 2 (UCP2) has been reported to exert beneficial effects against sepsis. Thus, this study aimed to investigate whether UCP2 is involved in insulin-elicited protection against myocardial dysfunction in lipopolysaccharide (LPS)-induced sepsis. Treatment of male SD rats with insulin for 30 min before LPS challenge improved the survival and cardiac function in endotoxemic rats, which was likely due to an insulin-dependent reduction of serum lactate dehydrogenase (LDH) activity and cardiac troponin T (cTn-T) levels, mitochondrial oxidative stress, and cardiomyocyte apoptosis. Insulin treatment also increased the Bcl-2/Bax ratio, prevented the release of cytochrome c into the cytosol, and reduced cleaved caspase-9 levels, which was determined by purifying the proteins using the His-tag Magnetic Bead Purification Kit (Fe3O4). Moreover, UCP2 was found to be upregulated in endotoxemic rats which were pretreated with insulin. To determine whether the apoptotic role of insulin is associated with UCP2 upregulation, we examined the effects of genipin, a UCP2 inhibitor, on insulin activity in LPS-treated H9c2 cells. Insulin strongly attenuated LPS-induced H9c2 cell apoptosis and stimulated UCP2 expression. However, genipin treatment eliminated the antiapoptotic effects of insulin. Thus, our results demonstrate that insulin-induced UCP2 upregulation plays a role in the protective effect of insulin against LPS-induced myocardial dysfunction.

scholarly journals Basic Concepts on the Role of Nuclear Factor Erythroid-Derived 2-Like 2 (Nrf2) in Age-Related Diseases

2019 ◽  
Vol 20 (13) ◽  
pp. 3208 ◽  
Author(s):  
Fabiane Valentini Francisqueti-Ferron ◽  
Artur Junio Togneri Ferron ◽  
Jéssica Leite Garcia ◽  
Carol Cristina Vágula de Almeida Silva ◽  
Mariane Róvero Costa ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Transcription Factor ◽  
Transcriptional Factor ◽  
Future Research ◽  
Related Factor ◽  
Nuclear Factor ◽  
Nrf2 Pathway ◽  
Age Related ◽  
Basic Concepts

The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) is one of the most important oxidative stress regulator in the human body. Once Nrf2 regulates the expression of a large number of cytoprotective genes, it plays a crucial role in the prevention of several diseases, including age-related disorders. However, the involvement of Nrf2 on these conditions is complex and needs to be clarified. Here, a brief compilation of the Nrf2 enrollment in the pathophysiology of the most common age-related diseases and bring insights for future research on the Nrf2 pathway is described. This review shows a controversial response of this transcriptional factor on the presented diseases. This reinforces the necessity of more studies to investigate modulation strategies for Nrf2, making it a possible therapeutic target in the treatment of age-related disorders.

Nuclear factor-κB inhibition by pyrrolidinedithiocarbamate attenuates gastric ischemia-reperfusion injury in rats

2005 ◽  
Vol 83 (6) ◽  
pp. 483-492 ◽  
Author(s):  
Eman El Eter ◽  
Hanan H Hagar ◽  
Ali Al-Tuwaijiri ◽  
Maha Arafa
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Thiobarbituric Acid ◽  
Nuclear Factor Κb ◽  
Serum Lactate ◽  
Serum Lactate Dehydrogenase ◽  
Nuclear Factor ◽  
P53 Expression ◽  
Apoptotic Protein ◽  
Gastric Ischemia

Pyrrolidinedithiocarbamate (PDTC) is a potent antioxidant and an inhibitor of nuclear factor-κB (NF-κB). The present study examined the impact of PDTC preconditioning on gastric protection in response to ischemia-reperfusion (I/R) injury to the rat stomach. Male Wistar rats were recruited and divided into 3 groups (n=7). One group was subjected to gastric ischemia for 30 min and reperfusion for 1 hour. The second group of rats was preconditioned with PDTC (200 mg/kg body mass i.v.) 15 min prior to ischemia and before reperfusion. The third group of rats was sham-operated and served as the control group. Gastric I/R injury increased serum lactate dehydrogenase level, vascular permeability of gastric mucosa (as indicated by Evans blue dye extravasation) and gastric content of inflammatory cytokine; tumor necrosis factor-α (TNF-α). Moreover, oxidative stress was increased as indicated by elevated lipid peroxides formation (measured as thiobarbituric acid reactive substances) and depleted reduced glutathione in gastric tissues. NF-κB translocation was also detected by electrophoretic mobility shift assay. Microscopically, gastric tissues subjected to I/R injury showed ulceration, hemorrhages, and neutrophil infiltration. Immunohistochemical studies of gastric sections revealed increased expression of p53 and Bcl-2 proteins. PDTC pretreatment reduced Evans blue extravasation, serum lactate dehydrogenase levels, gastric TNF-α levels, and thiobarbituric acid reactive substances content, and increased gastric glutathione content. Moreover, PDTC pretreatment abolished p53 expression and inhibited NF-κB translocation. Finally, histopathological changes were nearly restored by PDTC pretreatment. These results clearly demonstrate that NF-κB activation and pro-apoptotic protein p53 induction are involved in gastric I/R injury. PDTC protects against gastric I/R injury by an antioxidant, NF-κB inhibition, and by reduction of pro-apoptotic protein p53 expression, which seems to be downstream to NF-κB, thus promoting cell survival. Key words: pyrrolidinedithiocarbamate, ischemia–reperfusion injury, gastric mucosa, nuclear factor-κB, inflammatory cytokines, oxidative stress.

scholarly journals Natural Astaxanthin From Haematococcus Pluvialis Enhanced Antioxidant Capacity And Improved Semen Quality In Aging Layer Breeder Roosters Through The Mitogen-Activated Protein Kinase/Nuclear Factor-Erythroid 2-Related Factor 2 (MAPK/Nrf2) Pathway

2021 ◽  
Author(s):  
Shan Gao ◽  
Nuo Heng ◽  
Fang Liu ◽  
Yong Guo ◽  
Yu Chen ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Antioxidant Capacity ◽  
Hydroxyl Radicals ◽  
Semen Quality ◽  
Mitogen Activated Protein Kinase ◽  
Related Factor ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
Nrf2 Pathway ◽  
Mitogen Activated Protein

Abstract Background: Natural astaxanthin (ASTA) has strong antioxidant properties and has been widely used as a health product to improve human health. However, the effects of ASTA on the reproductive performance of aging roosters have been poorly studied. We aimed to investigate the effects of dietary ASTA on semen quality and antioxidant capacity in aging roosters and to explore the potential mechanism of semen quality change via anti-oxidation defense system.Methods: In the present study, 96 53-week-old Jinghong No. 1 layer breeder roosters were fed a corn-soybean meal basal diet containing ASTA at 0, 25, 50, or 100 mg/kg for 6 week. Results: Semen quality in the ASTA groups remarkably improved as compared to those in the control group and antioxidant activities, the abilities to scavenge hydroxyl radicals and superoxide anions increased gradually with ASTA addition (P < 0.05). In addition, the mRNA levels of antioxidant enzymes, the mRNA and protein levels of the mitogen-activated protein kinase (MAPK), nuclear factor-erythroid 2-related factor 2 (Nrf2) were markedly increased in the 50-100 mg/kg ASTA group (P < 0.05). Conclusions: Collectively, these results demonstrate that dietary ASTA may improve semen quality by increasing antioxidant enzyme activities, and the ability to scavenge hydroxyl radicals, which may be related to up-regulation of the MAPK/Nrf2 pathway.

scholarly journals N-acetylcysteine alleviates PCB52-induced hepatotoxicity by repressing oxidative stress and inflammatory responses

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9720
Author(s):  
Wen-Tao Zhou ◽  
Li-Bin Wang ◽  
Hao Yu ◽  
Kai-Kai Zhang ◽  
Li-Jian Chen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Viability ◽  
Inflammatory Responses ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Nuclear Factor ◽  
Oxygen Species ◽  
Nrf2 Pathway ◽  
Protein Levels ◽  
Saline Pretreatment

Polychlorinated biphenyls (PCBs), particularly low chlorinated congeners in our environment, can induce human hepatotoxicity. However, the mechanisms by which PCBs cause hepatotoxicity remain elusive. Moreover, there are no effective treatments for this condition. In this study, 40 μM PCB52 was administered to rat (Brl-3A) and human hepatocytes (L-02) for 48 h following the N-acetylcysteine (NAC)/saline pretreatment. A significant decrease in cell viability was observed in PCB52-treated cells relative to the control. Besides, PCB52 significantly increased reactive oxygen species (ROS) levels and malondialdehyde (MDA) contents, suggesting induction of oxidative stress. The expression of Traf6, MyD88, and Tnf in Brl-3A cells and that of MYD88, TNF, and IL1B in L-02 cells were significantly upregulated by PCB52. Consistently, overexpression of TLR4, MyD88, Traf6, and NF-κB p65 proteins was observed in PCB52-treated cells, indicating activation of inflammatory responses. Nevertheless, no changes in kelch-like ECH-associated protein 1 (keap1), nuclear factor-erythroid 2-related factor (nrf2), and heme oxygenase-1 proteins were observed in PCB52-treated cells, indicating non-activation of the keap1/nrf2 pathway. Pretreatment with NAC significantly ameliorated PCB52 effects on cell viability, ROS levels, MDA contents and expression of inflammatory elements at both RNA and protein levels. However, no changes in keap1, nrf2 and HO-1 protein levels were detected following NAC pretreatment. Taken together, with non-activated keap1/nrf2 pathway, PCB52-induced oxidative stress and inflammatory responses could be responsible for its hepatotoxicity. These effects were effectively attenuated by NAC pretreatment, which scavenges ROS and dampens inflammatory responses. This study might provide novel strategies for the treatment of the PCBs-associated hepatotoxic effects.

Protective effects of curcumin against mercury-induced hepatic injuries in rats, involvement of oxidative stress antagonism, and Nrf2-ARE pathway activation

2016 ◽  
Vol 36 (9) ◽  
pp. 949-966 ◽  
Author(s):  
W Liu ◽  
Z Xu ◽  
H Li ◽  
M Guo ◽  
T Yang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Radical Scavenging ◽  
Antioxidant Response ◽  
Serum Lactate ◽  
Serum Lactate Dehydrogenase ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Protective Effects ◽  
Glutamylcysteine Synthetase ◽  
Subunit Expression

Mercury (Hg) represents a ubiquitous environmental heavy metal that could lead to severe toxic effects in a variety of organs usually at a low level. The present study focused on the liver oxidative stress, one of the most important roles playing in Hg hepatotoxicity, by evaluation of different concentrations of mercuric chloride (HgCl2) administration. Moreover, the protective potential of curcumin against Hg hepatotoxic effects was also investigated. Eighty-four rats were randomly divided into six groups for a three-days experiment: control, dimethyl sulfoxide control, HgCl2 treatment (0.6, 1.2, and 2.4 mg kg−1 day−1), and curcumin pretreatment (100 mg kg−1 day−1) groups. Exposure of HgCl2 resulted in acute dose-dependent hepatotoxic effects. Administration of 2.4 mg kg−1 HgCl2 significantly elevated total Hg, nonprotein sulfhydryl, reactive oxygen species formation, malondialdehyde, apoptosis levels, serum lactate dehydrogenase, and alanine transaminase activities, with an impairment of superoxide dismutase and glutathione peroxidase in the liver. Moreover, HgCl2 treatment activated nuclear factor-E2-related factor 2-antioxidant response element (Nrf2-ARE) signaling pathway in further investigation, with a significant upregulation of Nrf2, heme oxygenase-1, and γ-glutamylcysteine synthetase heavy subunit expression, relative to control. Pretreatment with curcumin obviously prevented HgCl2-induced liver oxidative stress, which may be due to its free radical scavenging or Nrf2-ARE pathway-inducing properties. Taking together these data suggest that curcumin counteracts HgCl2 hepatotoxicity through antagonizing liver oxidative stress.

scholarly journals Propofol Inhibits Ischemia/Reperfusion-Induced Cardiotoxicity Through the Protein Kinase C/Nuclear Factor Erythroid 2-Related Factor Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Shengqiang Li ◽  
Zhen Lei ◽  
Meng Zhao ◽  
Yonghao Hou ◽  
Di Wang ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Ischemia Reperfusion ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Nuclear Factor ◽  
H9c2 Cells ◽  
Nrf2 Pathway ◽  
Kinase C ◽  
Creatine Kinase Mb

Both hydrogen peroxide (H2O2, H) and ischemia/reperfusion (I/R) can damage cardiomyocytes, which was inhibited by propofol (P). The present research was designed to examine whether propofol can reduce myocardial I/R injury by activating protein kinase C (PKC)/nuclear factor erythroid-2-related factor 2 (NRF2) pathway in H9C2 cells and rat Langendorff models. H9C2 cells were disposed of no reagents (C), H2O2 for 24 h (H), propofol for 1 h before H2O2 (H+P), and chelerythrine (CHE, PKC inhibitor) for 1 h before propofol and H2O2 (H+P+CHE). N = 3. The PKC gene of H9C2 was knocked down by siRNA and overexpressed by phorbol 12-myristate 13-acetate (PMA, PKC agonist). The cell viability and the expressions of PKC, NRF2, or heme oxygenase-1(HO-1) were evaluated. Propofol significantly reduced H9C2 cell mortality induced by H2O2, and significantly increased NRF2 nuclear location and HO-1 expression, which were restrained by siRNA knockout of PKC and promoted by PMA. Rat hearts were treated with KrebsHenseleit solution for 120 min (C), with (I/R+P) or without (I/R) propofol for 20 min before stopping perfusion for 30 min and reperfusion for 60 min, and CHE for 10 min before treated with propofol. N = 6. The levels of lactate dehydrogenase (LDH), superoxide dismutase (SOD), and creatine kinase-MB (CK-MB) in perfusion fluid and antioxidant enzymes in the myocardium were assessed. I/R, which increased LDH and CK-MB expression and reduced SOD expression, boosted the pathological damage and infarcts of the myocardium after reperfusion. However, propofol restrained all these effects, an activity that was antagonized by CHE. The results suggest that propofol pretreatment protects against I/R injury by activating of PKC/NRF2 pathway.

scholarly journals Anti-Interleukin-16-Neutralizing Antibody Attenuates Cardiac Inflammation and Protects against Cardiac Injury in Doxorubicin-Treated Mice

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Jianwei Zhang ◽  
Zicong Yang ◽  
Zhishan Liang ◽  
Mengjie Wang ◽  
Changxing Hu ◽  
...  
Keyword(s):  
Troponin T ◽  
Cardiac Injury ◽  
Neutralizing Antibody ◽  
Serum Levels ◽  
Cardiomyocyte Apoptosis ◽  
Macrophage Differentiation ◽  
Cardiac Inflammation ◽  
Pathway Activation ◽  
M1 Macrophage

Background. Interleukin-16 (IL-16) is an important inflammatory regulator and has been shown to have a powerful effect on the regulation of the inflammatory response. Cardiac inflammation has been reported to be closely related to doxorubicin- (DOX-) induced cardiac injury. In this study, the role of IL-16 in DOX-induced cardiac injury and the possible mechanisms were examined. Methods. Cardiac IL-16 levels were first measured in DOX- or saline-treated mice. Additionally, mice were pretreated with the anti-IL-16-neutralizing antibody (nAb) or isotype IgG for 1 day and further administered DOX or saline for 5 days. Then, cardiac injury, cardiac M1 macrophage levels, and cardiomyocyte apoptosis were analyzed. The effects of the anti-IL-16 nAb on macrophage differentiation and cardiomyocyte apoptosis were also investigated in vitro. Results. DOX administration increased IL-16 expression in cardiac macrophages compared with that of saline treatment. The anti-IL-16 nAb significantly decreased serum levels of lactate dehydrogenase (LDH), myocardial-bound creatine kinase (CK-MB), and cardiac troponin T (cTnT) and elevated cardiac function in DOX-induced mice. Treatment with the anti-IL-16 nAb also reduced p65 pathway activation, decreased M1 macrophage-related marker and cytokine expression, and protected against cardiomyocyte apoptosis in DOX-induced mice. In cell studies, the anti-IL-16 nAb also reduced DOX-induced M1 macrophage differentiation and alleviated apoptosis in cardiomyocytes cocultured with macrophages. Conclusions. The anti-IL-16 nAb protects against DOX-induced cardiac injury by reducing cardiac inflammation, and IL-16 may be a promising target to prevent DOX-related cardiac injury.

scholarly journals Molecules from American Ginseng Suppress Colitis through Nuclear Factor Erythroid-2-Related Factor 2

Nutrients ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1850
Author(s):  
Anusha Chaparala ◽  
Hossam Tashkandi ◽  
Alexander A. Chumanevich ◽  
Erin E. Witalison ◽  
Anthony Windust ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
American Ginseng ◽  
Chronic Inflammatory Bowel Disease ◽  
Related Factor ◽  
Nuclear Factor ◽  
Nrf2 Pathway ◽  
Nrf2 Knockout ◽  
Inflammatory Bowel

Ulcerative colitis (UC) is a chronic inflammatory bowel disease that affects millions of people worldwide and increases the risk of colorectal cancer (CRC) development. We have previously shown that American ginseng (AG) can treat colitis and prevent colon cancer in mice. We further fractionated AG and identified the most potent fraction, hexane fraction (HAG), and the most potent compound in this fraction, panaxynol (PA). Because (1) oxidative stress plays a significant role in the pathogenesis of colitis and associated CRC and (2) nuclear factor erythroid-2-related factor 2 (Nrf2) is the master regulator of antioxidant responses, we examined the role of Nrf2 as a mechanism by which AG suppresses colitis. Through a series of in vitro and in vivo Nrf2 knockout mouse experiments, we found that AG and its components activate the Nrf2 pathway and decrease the oxidative stress in macrophages (mΦ) and colon epithelial cells in vitro. Consistent with these in vitro results, the Nrf2 pathway is activated by AG and its components in vivo, and Nrf2-/- mice are resistant to the suppressive effects of AG, HAG and PA on colitis. Results from this study establish Nrf2 as a mediator of AG and its components in the treatment of colitis.

Dysregulation of the Keap1–Nrf2 pathway in cancer

2015 ◽  
Vol 43 (4) ◽  
pp. 645-649 ◽  
Author(s):  
Hanna M. Leinonen ◽  
Emilia Kansanen ◽  
Petri Pölönen ◽  
Merja Heinäniemi ◽  
Anna-Liisa Levonen
Keyword(s):  
Cancer Cells ◽  
Large Scale ◽  
Target Genes ◽  
Metabolic Reprogramming ◽  
Pivotal Role ◽  
Related Factor ◽  
Nuclear Factor ◽  
Nrf2 Pathway ◽  
Cancer Types ◽  
Constitutively Active

Accumulating evidence suggests that dysregulation of the Kelch-like ECH-associated protein 1 (Keap1)–nuclear factor E2-related factor 2 (Nrf2) pathway resulting in constitutively active Nrf2 and increased expression of cytoprotective Nrf2 target genes, has a pivotal role in cancer. Cancer cells are able to hijack the Keap1–Nrf2 system via multiple mechanisms leading to enhanced chemo- and radio-resistance and proliferation via metabolic reprogramming as well as inhibition of apoptosis. In this mini-review, we will describe the mechanisms leading to increased Nrf2 activity in cancer with a focus on the information achieved from large-scale multi-omics projects across various cancer types.

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