scholarly journals Shikonin Attenuates Acetaminophen-Induced Hepatotoxicity by Upregulation of Nrf2 through Akt/GSK3β Signaling

Molecules ◽  
2018 ◽  
Vol 24 (1) ◽  
pp. 110 ◽  
Author(s):  
Huachao Li ◽  
Yueming Chen ◽  
Jiahao Zhang ◽  
Xiangcui Chen ◽  
Zheng Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Liver Toxicity ◽  
Mrna Level ◽  
Normal Liver ◽  
Close Correlation ◽  
In Vivo Studies ◽  
Gsk 3Β ◽  
Nrf2 Expression ◽  
Apap Hepatotoxicity

Acetaminophen (APAP) overdose-induced acute liver damage is mostly due to overwhelmingly increased oxidative stress. Nuclear factor-erythroid 2-related factor2 (Nrf2) plays an important role in alleviating APAP hepatic toxicity. Shikonin (SHK) enhances Nrf2 in multiple lines of normal cells. Nevertheless, whether SHK protects against APAP-induced liver toxicity remains undefined. This study found SHK defended APAP-induced liver toxicity, as well as reversed the levels of serum alanine/aspartate aminotransferases (ALT/AST), liver myeloperoxidase (MPO) activity, and reactive oxygen species (ROS), while it enhanced the liver glutathione (GSH) level in APAP-treated mice. SHK rescued the cell viability and GSH depletion, but neutralized oxidative stress in APAP-treated human normal liver L-02 cells. Mechanically, SHK increased Nrf2 expression in the exposure of APAP at the protein level but not at the mRNA level. Inhibition of Nrf2 blocked the SHK effect in APAP-treated hepatocytes. Furthermore, SHK improved Nrf2 stability through stimulating PI3K/Akt pathway, thus inhibiting GSK-3β. In vivo studies confirmed the close correlation of liver protection of SHK against APAP and Akt/GSK-3β/Nrf2 pathway. In conclusion, this study reveals that SHK prevents APAP hepatotoxicity by upregulation of Nrf2 via PI3K/Akt/GSK-3β pathway. Therefore, SHK may be a promising candidate against APAP-induced liver injury.

scholarly journals Fighting Liver Fibrosis with Naturally Occurring Antioxidants

Planta Medica ◽  
2018 ◽  
Vol 84 (18) ◽  
pp. 1318-1333 ◽  
Author(s):  
Ligen Lin ◽  
Fayang Zhou ◽  
Shengnan Shen ◽  
Tian Zhang
Keyword(s):  
Oxidative Stress ◽  
Liver Fibrosis ◽  
Normal Liver ◽  
Natural Antioxidants ◽  
In Vivo Studies ◽  
Lead Compounds ◽  
Naturally Occurring ◽  
Wound Healing Response

AbstractLiver fibrosis is a wound-healing response characterized by the accumulation of extracellular matrix following various liver injuries, which results in the deformation of the normal liver architecture and the development of liver cirrhosis and even hepatocellular carcinoma. Numerous in vitro and in vivo studies indicated that oxidative stress mediates the initiation and progression of liver fibrosis. Overaccumulation of reactive oxygen species disrupts macromolecules, induces necrosis and apoptosis of hepatocytes, stimulates the production of pro-fibrogenic mediators, and directly activates hepatic stellate cells, thereby resulting in liver damage and initiating liver fibrosis. Ameliorating oxidative stress is a potential therapeutic strategy for the treatment of liver fibrosis. Natural antioxidants have attracted increasing attention in treating liver fibrosis due to their safety and efficacy. In this review, the pathogenesis of liver fibrosis and the role of oxidative stress in liver fibrosis were discussed. Naturally occurring antioxidants that can treat and prevent liver fibrosis were summarized. Advances in clinical trials were also presented. The main purpose of this review is to provide a comprehensive and up-to-date knowledge from the biological importance of oxidative stress in liver fibrosis to representative antioxidants for treating liver fibrosis. Naturally occurring antioxidants show a potential for further investigations as lead compounds in fighting liver fibrosis.

scholarly journals Alcohol-and-HIV-Induced Lysosomal Dysfunction Regulates Extracellular Vesicles Secretion in Vitro and in Liver-Humanized Mice

Biology ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 29
Author(s):  
Raghubendra Singh Dagur ◽  
Moses New-Aaron ◽  
Murali Ganesan ◽  
Weimin Wang ◽  
Svetlana Romanova ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Extracellular Vesicles ◽  
Treated Group ◽  
Human Hepatocytes ◽  
In Vivo Studies ◽  
People Living With Hiv ◽  
Humanized Mouse Model ◽  
And Function

Background: Alcohol abuse is common in people living with HIV-1 and dramaticallyenhances the severity of HIV-induced liver damage by inducing oxidative stress and lysosomaldysfunction in the liver cells. We hypothesize that the increased release of extracellular vesicles(EVs) in hepatocytes and liver humanized mouse model is linked to lysosome dysfunction. Methods:The study was performed on primary human hepatocytes and human hepatoma RLWXP-GFP (Huh7.5 cells stably transfected with CYP2E1 and XPack-GFP) cells and validated on ethanol-fed liverhumanizedfumarylacetoacetate hydrolase (Fah)-/-, Rag2-/-, common cytokine receptor gamma chainknockout (FRG-KO) mice. Cells and mice were infected with HIV-1ADA virus. Results: We observedan increase in the secretion of EVs associated with a decrease in lysosomal activity and expressionof lysosomal-associated membrane protein 1. Next-generation RNA sequencing of primary humanhepatocytes revealed 63 differentially expressed genes, with 13 downregulated and 50 upregulatedgenes in the alcohol–HIV-treated group. Upstream regulator analysis of differentially expressedgenes through Ingenuity Pathway Analysis identified transcriptional regulators affecting downstreamgenes associated with increased oxidative stress, lysosomal associated disease, and function andEVs biogenesis. Our in vitro findings were corroborated by in vivo studies on human hepatocytetransplantedhumanized mice, indicating that intensive EVs’ generation by human hepatocytes andtheir secretion to serum was associated with increased oxidative stress and reduction in lysosomalactivities triggered by HIV infection and ethanol diet. Conclusion: HIV-and-ethanol-metabolisminducedEVs release is tightly controlled by lysosome status in hepatocytes and participates in thedevelopment of double-insult-induced liver injury.

Protective effect of GSK-3β/Nrf2 mediated by dimethyl fumarate in middle cerebral artery embolization reperfusion rat model

2021 ◽  
Vol 18 ◽  
Author(s):  
Yuan Li ◽  
Lan Chu ◽  
Chunfeng Liu ◽  
Zongyi Zha ◽  
Yuanlu Shu
Keyword(s):  
Oxidative Stress ◽  
Protective Effect ◽  
Sham Group ◽  
Infarct Volume ◽  
Dimethyl Fumarate ◽  
Control Group ◽  
Related Factor ◽  
Nissl Staining ◽  
Gsk 3Β ◽  
Nrf2 Expression

Aim: This study investigated the protective effect of dimethyl fumarate (DMF) in rats by mediating GSK3-β/Nrf2 using the middle cerebral artery embolization reperfusion (MCAO/R) rat model. Background: After an acute ischemic stroke (AIS), oxidative stress occurs. Dimethyl fumarate (DMF), a nuclear factor-E2-related factor 2 (Nrf2) activator, approved by the US Food and Drug Administration (FDA), was observed to regulate the Nrf2 pathway by acting as an anti-oxidative stress agent; however, whether this agent is involved in inhibiting GSK-3β remains to be established. Methods: DMF model was used to explore the effects of GSK-3β on Nrf2 expression level, Nrf2-ARE binding activity and Nrf2/ARE downstream expression level of anti-oxidant stress protein in Cerebral ischemia-reperfusion injury (CIRI). 60 rats were randomly divided into Sham group, MCAO/R group, solvent control group (DMSO group) and DMF treatment group, with 15 rats in each group. The MCAO/R, DMSO and DMF groups were considered in the MCAO/R model using the modified thread embolization method. In contrast, the Sham group was only anaesthetized and disinfected, and tissue muscle was dissected without inserting suture emboli. DMF group was gavaged with 45mg/kg per day of DMF, DMSO control group was gavaged with DMSO of equal volume, while MCAO/R group was only modeled without any intragastric treatment. The rats were treated seven days after the operation, and a neurological function Longa score was estimated. The rats were sacrificed seven days later, and the infarct volume was assessed by TTC staining. Hematoxylin-eosin (HE) staining was used to observe the pathological changes in rat brain tissue. Nissl staining was used to observe the expression of neurons in the infarcted cortex. Western blotting (WB) was used to observe the protein expression levels of glycogen synthase kinase 3β(GSK-3β), nuclear factor E2-related factor 2 (Nrf2), downstream heme oxygenase 1 (HO1) and NADPH quinone oxidoreductase 1 (NQO1) in four groups. The expression levels of GSK-3β and Nrf2 in the four groups were observed by immunohistochemistry and immunofluorescence. Results: (1) The Longa score of the MCAO/R, DMSO and DMF groups was found to be higher compared to the Sham group, indicating successful operation. The Longa score of the DMF group was lower than that of the other three groups 4-7 days after surgery (P<0.05). (2) HE and Nissl staining showed that the DMF group had lower neuron necrosis and higher gliosis compared to the control groups. (3) TTC staining results showed that the infarct volume of the DMF group was significantly smaller than the MCAO/R and DMSO groups. (4) Protein results showed that the GSK-3β expression in the DMF group was lower than that in all groups, while the expression of Nrf2, HO1 and NQO1 was higher compared to other groups. Conclusion: DMF can reduce neurological deficits and infarct size in the MCAO/R model. The protective effect may be related to decreased GSK-3β expression and increased Nrf2 expression, which may play a role in anti-oxidative stress.

scholarly journals Long non-coding RNA LINC00641 promotes the growth and invasiveness of hepatocellular carcinoma by antagonizing miR-501-3p

2021 ◽  
Author(s):  
Haitao Xie ◽  
Hui Zhou ◽  
Yan Jiang ◽  
Wenqian Xu ◽  
Leping Zeng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Normal Liver ◽  
In Vivo Studies ◽  
Luciferase Reporter ◽  
Normal Tissues ◽  
Non Coding Rna ◽  
Long Non Coding Rna ◽  
Proliferation And Invasion ◽  
Hcc Cells

IntroductionLong non-coding RNA LINC00641 has been reported to regulate tumor progression in several cancers. However, the expression and function of LINC00641 in hepatocellular carcinoma (HCC) is still unclear.Material and methodsIn this study, we measured the expression of LINC00641 in 79 pairs of HCC and adjacent normal liver tissues. The clinical significance of LINC00641 in HCC was explored. We also investigated the function of LINC00641 in HCC proliferation and invasion.ResultsWe observed that LINC00641 expression was significantly increased in HCC relative to normal tissues (P < 0.0001). High expression of LINC00641 was significantly associated with vascular invasion, advanced TNM stage, and reduced overall survival in HCC patients. Knockdown of LINC00641 inhibited the proliferation, colony formation, and invasion of HCC cells. In contrast, overexpression of LINC00641 promoted HCC cell growth and invasiveness. In vivo studies confirmed that knockdown of LINC00641 restrained tumorigenesis of HCC cells. Mechanistic studies revealed that LINC00641 inhibited the expression of miR-501-3p, which has been previously reported to act as a tumor suppressor in HCC. Furthermore, luciferase reporter assays validated that LINC00641 harbored a target site for miR-501-3p. Rescue experiments demonstrated that LINC00641-induced proliferation and invasion of HCC cells was reversed by co-expression of miR-501-3p.ConclusionsTaken together, LINC00641 contributes to aggressive phenotype of HCC cells by sponging miR-501-3p and represents a promising therapeutic target for this disease.

scholarly journals Autophagy and Ubiquitin-Mediated Proteolytic Degradation of PML/Rarα Fusion Protein in Matrine-Induced Differentiation Sensitivity Recovery of ATRA-Resistant APL (NB4-LR1) Cells: in Vitro and in Vivo Studies

2018 ◽  
Vol 48 (6) ◽  
pp. 2286-2301 ◽  
Author(s):  
Dijiong  Wu ◽  
Keding Shao ◽  
Qihao Zhou ◽  
Jie Sun ◽  
Ziqi Wang ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Fusion Protein ◽  
Cell Lines ◽  
Mrna Level ◽  
In Vivo Studies ◽  
Proteolytic Degradation ◽  
Induced Differentiation ◽  
Fluorescent Substrate

Background/Aims: Although the cure rate of acute promyelocytic leukemia (APL) has exceeded 90%, the relapse/refractory APL that resistant to all-trans retinoic acid (ATRA) or ATO was still serious concern. Matrine (MAT) could improve the differentiation ability of ATRA-resistant APL cells. This study aimed to explore how the APL-specific fusion protein was degraded in ATRA-resistant APL with the application of MAT and ATRA. Methods: ATRA-sensitive (NB4) and ATRA-resistant (NB4-LR1) cell lines were used. Nitroblue tetrazolium reduction assay and flow cytometry were used to detect the differentiation ability. The activity of ubiquitin-proteasome and autophagy-mediated pathways in both cells treated with ATRA with or without MAT were compared in protein and mRNA level (Western blot analysis, qRT-PCR), the Fluorescent substrate Suc-LLVY-AMC detection was used to detect the activity of proteasome, and electron microscope for observing autophagosome. MG 132(proteasome inhibitor), rapamycin (autophagy activator), hydroxychloroquine (lysosomal inhibitor) and STI571 [retinoic acid receptor alpha (RARα) ubiquitin stabilizer] were used as positive controls. The effect of MAT was observed in vivo using xenografts. Results: MAT improved the sensitivity of NB4-LR1cells to ATRA treatment, which was consistent with the expression of PML-RARα fusion protein. MAT promoted the ubiquitylation level in NB4-LR1. MG 132 induced the decrease in RARα in both cell lines, and hampered the differentiation of NB4 cells. MAT also promoted the autophagy in NB4-LR1 cells, with an increase in microtubule-associated protein 1 light chain3 (LC3)-II and LC3-II/LC3-I ratio and exhaustion of P62. The expression of LC3II increased significantly in the MAT and ATRA + MAT groups in combination with lysosomal inhibitors. A similar phenomenon was observed in mouse xenografts. MAT induced apoptosis and differentiation. Conclusions: Autophagy and ubiquitin-mediated proteolytic degradation of PML/RARα fusion protein are crucial in MAT-induced differentiation sensitivity recovery of NB4-LR1 cells.

Preclinical studies conducted on nanozyme antioxidants: shortcomings and challenges based on US FDA regulations

Nanomedicine ◽  
2021 ◽  
Author(s):  
Milad Ghorbani ◽  
Zhila Izadi ◽  
Samira Jafari ◽  
Eudald Casals ◽  
Foroogh Rezaei ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Clinical Trials ◽  
Clinical Studies ◽  
In Vivo Studies ◽  
Preclinical Studies ◽  
Future Studies ◽  
Clinical Stages ◽  
Us Fda ◽  
Considerable Body

The wide prevalence of oxidative stress-induced diseases has led to a growing demand for antioxidant therapeutics worldwide. Nanozyme antioxidants are drawing enormous attention as practical alternatives for conventional antioxidants. The considerable body of research over the last decade and the promising results achieved signify the potential of nanozyme antioxidants to secure a place in the expanding market of antioxidant therapeutics. Nonetheless, there is no report on clinical trials for their further evaluation. Through analyzing in-depth selected papers which have conducted in vivo studies on nanozyme antioxidants, this review aims to pinpoint and discuss possible reasons impeding development of research toward clinical studies and to offer some practical solutions for future studies to bridge the gap between preclinical and clinical stages.

scholarly journals Design and Synthesis of New Benzo[d]oxazole-Based Derivatives and Their Neuroprotective Effects on β-Amyloid-Induced PC12 Cells

Molecules ◽  
2020 ◽  
Vol 25 (22) ◽  
pp. 5391
Author(s):  
Zheng Liu ◽  
Ming Bian ◽  
Qian-Qian Ma ◽  
Zhuo Zhang ◽  
Huan-Huan Du ◽  
...  
Keyword(s):  
Pc12 Cells ◽  
Glycogen Synthase ◽  
B Cell Lymphoma ◽  
Nuclear Factor Κb ◽  
In Vivo Studies ◽  
Neuroprotective Effects ◽  
Β Amyloid ◽  
Gsk 3Β

A series of novel synthetic substituted benzo[d]oxazole-based derivatives (5a–5v) exerted neuroprotective effects on β-amyloid (Aβ)-induced PC12 cells as a potential approach for the treatment of Alzheimer’s disease (AD). In vitro studies show that most of the synthesized compounds were potent in reducing the neurotoxicity of Aβ25-35-induced PC12 cells at 5 μg/mL. We found that compound 5c was non-neurotoxic at 30 μg/mL and significantly increased the viability of Aβ25-35-induced PC12 cells at 1.25, 2.5 and 5 μg/mL. Western blot analysis showed that compound 5c promoted the phosphorylation of Akt and glycogen synthase kinase (GSK-3β) and decreased the expression of nuclear factor-κB (NF-κB) in Aβ25-35-induced PC12 cells. In addition, our findings demonstrated that compound 5c protected PC12 cells from Aβ25-35-induced apoptosis and reduced the hyperphosphorylation of tau protein, and decreased the expression of receptor for AGE (RAGE), β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1), inducible nitric oxide synthase (iNOS) and Bcl-2-associated X protein/B-cell lymphoma 2 (Bax/Bcl-2) via Akt/GSK-3β/NF-κB signaling pathway. In vivo studies suggest that compound 5c shows less toxicity than donepezil in the heart and nervous system of zebrafish.

scholarly journals Hyperoxia, reactive oxygen species, and hyperventilation: oxygen sensitivity of brain stem neurons

2004 ◽  
Vol 96 (2) ◽  
pp. 784-791 ◽  
Author(s):  
Jay B. Dean ◽  
Daniel K. Mulkey ◽  
Richard A. Henderson ◽  
Stephanie J. Potter ◽  
Robert W. Putnam
Keyword(s):  
Oxidative Stress ◽  
Brain Stem ◽  
Brain Slices ◽  
Respiratory Control ◽  
In Vivo Studies ◽  
Future Research ◽  
Direct Effects ◽  
Underlying Assumption

Hyperoxia is a popular model of oxidative stress. However, hyperoxic gas mixtures are routinely used for chemical denervation of peripheral O2 receptors in in vivo studies of respiratory control. The underlying assumption whenever using hyperoxia is that there are no direct effects of molecular O2 and reactive O2 species (ROS) on brain stem function. In addition, control superfusates used routinely for in vitro studies of neurons in brain slices are, in fact, hyperoxic. Again, the assumption is that there are no direct effects of O2 and ROS on neuronal activity. Research contradicts this assumption by demonstrating that O2 has central effects on the brain stem respiratory centers and several effects on neurons in respiratory control areas; these need to be considered whenever hyperoxia is used. This mini-review summarizes the long-recognized, but seldom acknowledged, paradox of respiratory control known as hyperoxic hyperventilation. Several proposed mechanisms are discussed, including the recent hypothesis that hyperoxic hyperventilation is initiated by increased production of ROS during hyperoxia, which directly stimulates central CO2 chemoreceptors in the solitary complex. Hyperoxic hyperventilation may provide clues into the fundamental role of redox signaling and ROS in central control of breathing; moreover, oxidative stress may play a role in respiratory control dysfunction. The practical implications of brain stem O2 and ROS sensitivity are also considered relative to the present uses of hyperoxia in respiratory control research in humans, animals, and brain stem tissues. Recommendations for future research are also proposed.

scholarly journals Neuroprotective Effects of Lindleyin on Hydrogen Peroxide-Induced Cell Injury and MPTP-Induced Parkinson’s Disease in C57BL/6 Mice

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Jin-Jie Zhang ◽  
Xiao-Rong Shi ◽  
Wen-Wen Lv ◽  
Xiao-Long Zhou ◽  
Ying-Dong Sun ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Hydrogen Peroxide ◽  
Parkinson's Disease ◽  
Cell Injury ◽  
In Vivo Studies ◽  
Antioxidant Enzyme Activities ◽  
Apoptotic Pathway ◽  
Neuroprotective Effects

Oxidative stress (OS) is a crucial factor influencing the development of Parkinson’s disease (PD). Here we first reported that Lindleyin (Lin), one of the major components of rhubarb, possessed neuroprotective effects against H2O2-induced SH-SY5Y cell injury and MPTP-induced PD of C57BL/6 mice. The results showed that Lin can decrease cell death and apoptotic rate induced by H2O2 through inhibiting mitochondrial apoptotic pathway and increasing the activities of SOD, GSH-Px, and CAT as well as decreasing the level of MDA. In addition, in vivo studies showed that oral administration of Lin (5 or 20 mg/kg) showed significant change in motor function deficits, antioxidant enzyme activities, apoptotic pathway, and tyrosine hydroxylase expression. Our results reveal that Lin might be a promising anti-PD agent by reducing OS and apoptosis.

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