scholarly journals Aloperine attenuates high glucose-induced oxidative injury in Schwann cells via activation of NRF2/HO-1 pathway

2020 ◽  
Vol 19 (6) ◽  
pp. 1147-1152
Author(s):  
Yiran Chen ◽  
Tieming Ma ◽  
Zhimin Wang ◽  
Lianqun Jia ◽  
Xiaoqing Zhang ◽  
...  
Keyword(s):  
Cell Viability ◽  
Schwann Cells ◽  
High Glucose ◽  
Cell Injury ◽  
Annexin V ◽  
Oxidative Injury ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Oxygen Species ◽  
Potent Drug

Purpose: To determine the involvement of nuclear factor erythroid 2-related factor 2 (NRF2) and heme oxygenase-1 (HO-1) in the action of aloperine on Schwann cell injury caused by high glucose (HG).Methods: Cell viability was determined using MTT assay while the release of lactate dehydrogenase (LDH) was determined by biochemical assay. Apoptosis was assessed using flow cytometry, while the levels of malondialdehyde (MDA) were determined by Annexin V-FIT staining. Glutathione Stransferase (GST), glutathione peroxidase (GPX), and reactive oxygen species (ROS) were determined using enzyme-linked immunosorbent assay.Results: Treatment with HG suppressed RSC96 cell viability and increased LDH release, while aloperine reversed these results (p < 0.05). Apoptosis of RSC96 cells was induced by HG stimulation, but was abolished by aloperine. The levels of ROS, MDA, and GST were enhanced in cells followingtreatment with HG, but was reversed by aloperine (p < 0.05). The decreased level of GPX caused by HG in RSC96 cells was elevated by aloperine. Moreover, aloperine upregulated NRF2 and HO-1 in RSC96 cells treated with HG (p < 0.05).Conclusion: Aloperine attenuates HG-induced oxidative injury in Schwann cells via activation of NRF2/HO-1 pathway, suggesting its potential as a potent drug for the management of diabetic peripheral neuropathy. Keywords: Aloperine, Schwann cells, High glucose, Oxidative stress, NRF2, HO-1

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.

Trilobatin Protects Cardiomyocytes from Hypoxia/ Reperfusion Injury by Regulating the Nuclear Factor Erythroid 2-Related Factor 2/Heme Oxygenase-1 Pathway

2020 ◽  
Vol 19 (2) ◽  
pp. 133-138
Author(s):  
Wenyu Chen ◽  
Hui He
Keyword(s):  
Heme Oxygenase ◽  
Molecular Mechanisms ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Cellular Injury ◽  
Nuclear Factor ◽  
Oxygen Species ◽  
H9c2 Cells ◽  
Natural Plant ◽  
Induced Changes

Trilobatin is a natural plant-derived glycosylated flavonoid that has been shown to exhibit multiple beneficial pharmacologic activities including protection of heart against H/R-induced cardiomyocyte injury. However, the molecular mechanisms underlying protection from H/R-induced cardiomyocyte injury remain unknown. Using H9C2 cells as a model, we examined the effect of trilobatin on H/R-induced cellular injury, apoptosis, and generation of reactive oxygen species. The results showed that trilobatin protected H9C2 cells not only from cell death and apoptosis, but also counteracted H/R-induced changes in malondialdehyde, superoxide dismutase, glutathione, and glutathione peroxidase. The evaluation of the mechanism underlying the effect of trilobatin on protection from H/R-induced cellular injury suggested changes in the regulation of nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway.

scholarly journals Protective Effect of Heme Oxygenase-1 on High Glucose-Induced Pancreatic β-Cell Injury

2011 ◽  
Vol 35 (5) ◽  
pp. 469 ◽  
Author(s):  
Eun-Mi Lee ◽  
Young-Eun Lee ◽  
Esder Lee ◽  
Gyeong Ryul Ryu ◽  
Seung-Hyun Ko ◽  
...  
Keyword(s):  
Protective Effect ◽  
Heme Oxygenase ◽  
High Glucose ◽  
Cell Injury ◽  
Heme Oxygenase 1 ◽  
Pancreatic Β Cell ◽  
Β Cell

scholarly journals Metformin Protects H9C2 Cardiomyocytes from High-Glucose and Hypoxia/Reoxygenation Injury via Inhibition of Reactive Oxygen Species Generation and Inflammatory Responses: Role of AMPK and JNK

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Mingyan Hu ◽  
Ping Ye ◽  
Hua Liao ◽  
Manhua Chen ◽  
Feiyan Yang
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Viability ◽  
High Glucose ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion ◽  
Reactive Oxygen Species Generation ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Compound C ◽  
Hypoxia Reoxygenation

Metformin is a first-line drug for the management of type 2 diabetes. Recent studies suggested cardioprotective effects of metformin against ischemia/reperfusion injury. However, it remains elusive whether metformin provides direct protection against hypoxia/reoxygenation (H/R) injury in cardiomyocytes under normal or hyperglycemic conditions. This study in H9C2 rat cardiomyoblasts was designed to determine cell viability under H/R and high-glucose (HG, 33 mM) conditions and the effects of cotreatment with various concentrations of metformin (0, 1, 5, and 10 mM). We further elucidated molecular mechanisms underlying metformin-induced cytoprotection, especially the possible involvement of AMP-activated protein kinase (AMPK) and Jun NH(2)-terminal kinase (JNK). Results indicated that 5 mM metformin improved cell viability, mitochondrial integrity, and respiratory chain activity under HG and/or H/R (P<0.05). The beneficial effects were associated with reduced levels of reactive oxygen species generation and proinflammatory cytokines (TNF-α, IL-1α, and IL-6) (P<0.05). Metformin enhanced phosphorylation level of AMPK and suppressed HG + H/R induced JNK activation. Inhibitor of AMPK (compound C) or activator of JNK (anisomycin) abolished the cytoprotective effects of metformin. In conclusion, our study demonstrated for the first time that metformin possessed direct cytoprotective effects against HG and H/R injury in cardiac cells via signaling mechanisms involving activation of AMPK and concomitant inhibition of JNK.

scholarly journals Ethyl Rosmarinate Protects High Glucose-Induced Injury in Human Endothelial Cells

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3372 ◽  
Author(s):  
Yan-Hui Shen ◽  
Li-Ying Wang ◽  
Bao-Bao Zhang ◽  
Qi-Ming Hu ◽  
Pu Wang ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Endothelial Cells ◽  
Protective Effect ◽  
High Glucose ◽  
Reactive Oxygen ◽  
Annexin V ◽  
Ros Generation ◽  
Dependent Manner ◽  
Oxygen Species ◽  
Jnk Pathway

Ethyl rosmarinate (RAE) is one of the active constituents from Clinopodium chinense (Benth.) O. Kuntze, which is used for diabetic treatment in Chinese folk medicine. In this study, we investigated the protective effect of RAE on high glucose-induced injury in endothelial cells and explored its underlying mechanisms. Our results showed that both RAE and rosmarinic acid (RA) increased cell viability, decreased the production of reactive oxygen species (ROS), and attenuated high glucose-induced endothelial cells apoptosis in a dose-dependent manner, as evidenced by Hochest staining, Annexin V–FITC/PI double staining, and caspase-3 activity. RAE and RA both elevated Bcl-2 expression and reduced Bax expression, according to Western blot. We also found that LY294002 (phosphatidylinositol 3-kinase, or PI3K inhibitor) weakened the protective effect of RAE. In addition, PDTC (nuclear factor-κB, or NF-κB inhibitor) and SP600125 (c-Jun N-terminal kinase, or JNK inhibitor) could inhibit the apoptosis in endothelial cells caused by high glucose. Further, we demonstrated that RAE activated Akt, and the molecular docking analysis predicted that RAE showed more affinity with Akt than RA. Moreover, we found that RAE inhibited the activation of NF-κB and JNK. These results suggested that RAE protected endothelial cells from high glucose-induced apoptosis by alleviating reactive oxygen species (ROS) generation, and regulating the PI3K/Akt/Bcl-2 pathway, the NF-κB pathway, and the JNK pathway. In general, RAE showed greater potency than RA equivalent.

scholarly journals Fenofibrate Protects Cardiomyocytes from Hypoxia/Reperfusion- and High Glucose-Induced Detrimental Effects

PPAR Research ◽  
2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Fabiola Cortes-Lopez ◽  
Alicia Sanchez-Mendoza ◽  
David Centurion ◽  
Luz G. Cervantes-Perez ◽  
Vicente Castrejon-Tellez ◽  
...  
Keyword(s):  
Cell Viability ◽  
High Glucose ◽  
Cardiac Injury ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Peroxisome Proliferator ◽  
Related Factor ◽  
Irreversible Damage ◽  
Peroxisome Proliferator Activated Receptor ◽  
Subunit Expression ◽  
Endothelial Nitric Oxide

Lesions caused by high glucose (HG), hypoxia/reperfusion (H/R), and the coexistence of both conditions in cardiomyocytes are linked to an overproduction of reactive oxygen species (ROS), causing irreversible damage to macromolecules in the cardiomyocyte as well as its ultrastructure. Fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, promotes beneficial activities counteracting cardiac injury. Therefore, the objective of this work was to determine the potential protective effect of fenofibrate in cardiomyocytes exposed to HG, H/R, and HG+H/R. Cardiomyocyte cultures were divided into four main groups: (1) control (CT), (2) HG (25 mM), (3) H/R, and (4) HG+H/R. Our results indicate that cell viability decreases in cardiomyocytes undergoing HG, H/R, and both conditions, while fenofibrate improves cell viability in every case. Fenofibrate also decreases ROS production as well as nicotinamide adenine dinucleotide phosphate oxidase (NADPH) subunit expression. Regarding the antioxidant defense, superoxide dismutase (SOD Cu2+/Zn2+ and SOD Mn2+), catalase, and the antioxidant capacity were decreased in HG, H/R, and HG+H/R-exposed cardiomyocytes, while fenofibrate increased those parameters. The expression of nuclear factor erythroid 2-related factor 2 (Nrf2) increased significantly in treated cells, while pathologies increased the expression of its inhibitor Keap1. Oxidative stress-induced mitochondrial damage was lower in fenofibrate-exposed cardiomyocytes. Endothelial nitric oxide synthase was also favored in cardiomyocytes treated with fenofibrate. Our results suggest that fenofibrate preserves the antioxidant status and the ultrastructure in cardiomyocytes undergoing HG, H/R, and HG+H/R preventing damage to essential macromolecules involved in the proper functioning of the cardiomyocyte.

ALK7 Inhibition Protects Osteoblast Cells Against High Glucose-induced ROS Production via Nrf2/HO-1 Signaling Pathway

2021 ◽  
Vol 21 ◽  
Author(s):  
Zhen Zhao ◽  
Yu Lu ◽  
Huan Wang ◽  
Xiang Gu ◽  
Luting Zhu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Viability ◽  
Signaling Pathway ◽  
High Glucose ◽  
Collagen I ◽  
Cell Counting ◽  
Enzyme Linked Immunosorbent Assay ◽  
Heme Oxygenase 1 ◽  
Ros Production ◽  
Alizarin Red

Background: Some studies demonstrated that under high-glucose (HG) condition, osteoblasts develop oxidative stress, which will impair their normal functions. The effects of activin receptor-like kinase 7 (ALK7) silencing on HG-induced osteoblasts remained unclear. Objective: The aim of this study was to explore the effect of ALK7 on HG-induced osteoblasts. Methods: MC3T3-E1 cells were treated with different concentrations of HG (0, 50, 100, 200 and 300mg/dL), and the cell viability was detected using cell counting kit-8 (CCK-8). HG-treated MC3T3-E1 cells were transfected with siALK7 or ALK7 overexpression plasmid or siNrf2, and then the viability and apoptosis were detected by CCK-8 and flow cytometry. The levels of reactive oxygen species (ROS), collagen I and calcification nodule were determined by oxidative stress kits, Enzyme-linked immunosorbent assay and Alizarin red staining. The expressions of NF-E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and osteoblast-associated genes were determined by quantitative real-time PCR (qRT-PCR) and Western blot. Results: Cell viability was reduced with HG treatment. Silencing ALK7 inhibited the effect of HG on increasing cell apoptosis and ROS production, reduced cell viability, mineralized nodules, and downregulated collagen I and osteoblast-associated genes expression in MC3T3-E1 cells. ALK7 silencing activated the Nrf2/HO-1 signaling pathway by affecting expressions of HO-1 and Nrf2. ALK7 overexpression had the opposite effects. In addition, siNrf2 partially reversed the effects of ALK7 silencing on HG-induced MC3T3-E1 cells. Conclusion: ALK7 silencing protected osteoblasts under HG condition possibly through activating the Nrf2/HO-1 pathway.

The Diterpenoid Lactone Andrographolide Induces Reactive Oxygen Species (ROS) Dependent Apoptosis in ATRA Sensitive and Resistant APL Cell Lines.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2446-2446
Author(s):  
Shuo Yang ◽  
Jessica K. Altman ◽  
Sheila Prachand ◽  
Austin Tom ◽  
Bo Ding ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Viability ◽  
Cell Lines ◽  
Mitochondrial Membrane ◽  
Reactive Oxygen ◽  
Annexin V ◽  
Resistant Cell ◽  
Oxygen Species ◽  
Resistant Lines ◽  
Sensitive Line

Abstract Abstract 2446 Andrographolide is a crystalline diterpenoid lactone. It consists of an α-alkylidene- g-butyrolactone moiety and three hydroxyls at C-3, C-14 and C-19, which are responsible for its biological activities. It is the major bioactive ingredient of the medicinal plant Andrographis paniculata and it has been used in Asia for a variety of non-malignant conditions. We previously reported that Andrographolide results in mitochondrial-mediated apoptosis in lymphoma cell lines and fresh malignant cells from patients with lymphoma (Yang et al. Clin Cancer Res 2010:16:4755). Based on the mechanism of action in lymphoma and a prior report in APL (Manikam et al. J Pharm Pharmacol 2009:61:9), we hypothesized that andrographolide may have biological activity in acute promyelocytic leukemia (APL) an that this may be related to reactive oxygen species (ROS). We therefore investigated the effects of andrographolide on cell viability, apoptosis induction, mitochondrial membrane poential and signaling pathways in 3 APL cell lines, the ATRA sensitive line NB4 and the ATRA-resistant lines NB4–007/6 and NB4–306 and 3 samples from patients with APL. Methods: NB4 (ATRA sensitive cell line), NB4–007/6 and NB4–306 (ATRA resistant cell lines) were cultured in RPMI-1640 under standard conditions. Cell viability was measured using the trypan blue or propidium iodide exclusion method. Fresh leukemic cells were obtained from 3 patients after informed consent according to an NU IRB approved protocol. One had ATRA-resistant APL and 2 had de-novo untreated APL. We measured apoptosis by Annexin V-FITC by FACS. We measured mitochondrial membrane potential and cell differentiation by standard techniques. Results: Incubation with increasing concentrations of andrographolide demonstrates loss of cell viability as measured by MTT assay. The IC50 at 48 hours was 6uM for NB4–306, 6.5uM for NB4–007/6 and 9uM for NB4. Apoptosis by Annexin V/FACS demonstrated that at 48 hours there was increasing apoptosis in all 3 cell lines and that the ATRA-resistant cell lines NB4–007/6 and NB4–306 were significantly more sensitive to andrographolide than the ATRA sensitive cell line NB4 (p< 0.025). This was accompanied by PARP and caspase 3-cleavage. There was evidence of decrease in mitochondrial membrane potential, but no effect on differentiation as measured by CD11b expression by flow. We next interrogated signaling pathways and found that in the ATRA resistant line NB4–007/6 there was an increase in phosphorylation of the Forkhead box O transcription factors p-FOXO1 at Thr24 and up-regulation of FasL (which peaked at 6 hours) and p27Kip1. We also demonstrated that andrographolide caused N-acetyl L- cysteine (NAC) reversible down regulation of c-MYC (in the ATRA resistant lines) and p-AKT (T308) (in the ATRA sensitive line) expression. In fresh patient specimens (n=3) there was dose dependent increase in apoptosis at 48 hours (>70% at 10uM, 85% at 20uM). From prior reports and our own data we suspected that the effects of andrographolide were dependent on reactive oxygen species (ROS), and indeed apoptosis was completely inhibited by NAC. Conclusion: Taken together, these data suggest that andrographolide, a novel natural diterpenoid lactone with significant biological activity in cancer, may have activity in patients with ATRA-resistant APL by a mechanism of action that is distinct from ATRA. We believe that these data provide a compelling rationale to add this natural diterpenoid lactone to the clinical trial agenda in APL. Disclosures: No relevant conflicts of interest to declare.

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