Antioxidative Stress
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Fang Chen ◽  
Qi Gao ◽  
Lijun Zhang ◽  
Yibing Ding ◽  
Hongwei Wang ◽  

Pulmonary fibrosis is a common cause of pulmonary hypertension and its development is associated with aberrant HDAC (histone deacetylase) activities and altered fibrogenic gene expressions; however, whether the epigenetic alterations causally affect pulmonary fibrosis remains poorly understood. Here, we report that HDAC3 aberration and the resultant inhibition of Nrf2 (nuclear factor erythroid-derived 2-related factor-2), a master transcription factor of antioxidative stress, contribute significantly to pulmonary fibrogenesis. HDAC3 is preferentially upregulated with concomitant Nrf2 suppression in fibrotic lungs of both idiopathic pulmonary fibrosis patients and bleomycin-treated mice. Genetic knockout of HDAC3 or Nrf2 inversely resisted or exacerbated the fibrotic pathologies, respectively, suggesting that they are crucial regulators of pulmonary fibrosis with opposite functions. Intriguingly, a HDAC3-selective inhibitor RGFP966 effectively reduced the Nrf2 suppression and normalized the fibrosis and adverse expressions of major fibrogenic proteins, Nrf2 downstream antioxidant enzymes and inflammatory cytokines. Nrf2 promoter contains a putative binding motif for FOXM1 (Forkhead box M1), a profibrotic transcriptional factor. HDAC3 and FOXM1 inducibly bound to Nrf2 promoter locus containing the motif in lung tissues of bleomycin mice, accompanied by reduced local histone3 acetylation, which were relieved by RGFP966. In cultured lung cells, RGFP966 blockage of the Nrf2 suppression was partially attenuated by a FOXM1 inhibitor or when the FOXM1 motif was mutated; while in Nrf2 knockout mice, the antifibrotic effects of RGFP966 were largely reduced. Thus, HDAC3 aberration and its suppression of Nrf2 plays important roles in pulmonary fibrogenesis and strategies targeting HDAC3/Nrf2 axis by HDAC3 inhibition might potentially benefit patients with idiopathic pulmonary fibrosis and the related pulmonary fibrotic disorders.

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0252906
Yangdi Chen ◽  
Fanggang Bi ◽  
Zixue Sun

Oligoasthenozoospermia is a complex disease caused by a variety of factors, and its incidence is increasing yearly worldwide. Yishen Tongluo formula (YSTLF), created by Professor Sun Zixue, has been used to treat oligoasthenozoospermia in clinical practice for several decades with a good therapeutic effect. However, the chemical and pharmacological profiles of YSTLF remain unclear and need to be elucidated. In this study, a network pharmacology approach was applied to explore the potential mechanisms of YSTLF in oligoasthenozoospermia treatment. All of the compounds in YSTLF were retrieved from the corresponding databases, and the bioactive ingredients were screened according to their oral bioavailability (OB) and drug-likeness (DL). The potential proteins of YSTLF were obtained from the traditional Chinese medicine systems pharmacology (TCMSP) database and the Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine (BATMAN-TCM) database, while the potential genes of oligoasthenozoospermia were obtained from the GeneCards database and the DisGeNET database. The STRING database was used to construct an interaction network according to the common targets identified by the online tool Venny for YSTLF and oligoasthenozoospermia. The topological characteristics of nodes were visualized and analyzed through Cytoscape. Biological functions and significant pathways were determined and analyzed using the Gene Ontology (GO) knowledgebase, the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Metascape. Finally, the disease-formula-compound-target-pathway network was constructed by Cytoscape. A total of 106 bioactive ingredients and 134 potential targets from YSTLF were associated with oligoasthenozoospermia or considered to be therapeutically relevant. Pathway analysis indicated that the PI3K/Akt, MAPK and apoptosis signaling pathways were significant pathways involved in oligoasthenozoospermia. In conclusion, the current study expounded the pharmacological actions and molecular mechanisms of YSTLF in treating oligoasthenozoospermia from a holistic viewpoint. The potential molecular mechanisms were closely related to antioxidative stress, antiapoptosis and anti-inflammation, with TNF, CCND1, ESR1, NFKBIA, NR3C1, MAPK8, and IL6 being possible targets. This network pharmacology prediction may offer a helpful tool to illustrate the molecular mechanisms of the Chinese herbal compound YSTLF in oligoasthenozoospermia treatment.

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 987
Ying Wang ◽  
Yanjun Pan ◽  
Yanan Liu ◽  
Dejene Disasa ◽  
Matsuura Akira ◽  

Two compounds that can prolong the replicative lifespan of yeast, geniposidic acid (Compound 1) and geniposide (Compound 2), were isolated from Gardenia jasminoides Ellis. Compared with Compound 1, Compound 2 was different at C11 and showed better bioactivity. On this basis, seven new geniposidic derivatives (3–9) were synthesized. Geniposidic 4-isoamyl ester (8, GENI), which remarkably prolonged the replicative and chronological lifespans of K6001 yeast at 1 µM, was used as the lead compound. Autophagy and antioxidative stress were examined to clarify the antiaging mechanism of GENI. GENI increased the enzymes activities and gene expression levels of superoxide dismutase (SOD) and reduced the contents of reactive oxygen species (ROS) and malondialdehyde (MDA) to improve the survival rate of yeast under oxidative stress. In addition, GENI did not extend the replicative lifespan of ∆sod1, ∆sod2, ∆uth1, ∆skn7, ∆cat, and ∆gpx mutants with K6001 background. The free green fluorescent protein (GFP) signal from the cleavage of GFP-Atg8 was increased by GENI. The protein level of free GFP showed a considerable increase and was time-dependent. Furthermore, GENI failed to extend the replicative lifespans of ∆atg32 and ∆atg2 yeast mutants. These results indicated that antioxidative stress and autophagy induction were involved in the antiaging effect of GENI.

2021 ◽  
Vol 2021 ◽  
pp. 1-23
Yadan Zhao ◽  
Zichen Zhang ◽  
Siru Qin ◽  
Wen Fan ◽  
Wei Li ◽  

Parkinson’s disease (PD) is a chronic and progressive neurodegenerative disease caused by degeneration of dopaminergic neurons in the substantia nigra. Existing pharmaceutical treatments offer alleviation of symptoms but cannot delay disease progression and are often associated with significant side effects. Clinical studies have demonstrated that acupuncture may be beneficial for PD treatment, particularly in terms of ameliorating PD symptoms when combined with anti-PD medication, reducing the required dose of medication and associated side effects. During early stages of PD, acupuncture may even be used to replace medication. It has also been found that acupuncture can protect dopaminergic neurons from degeneration via antioxidative stress, anti-inflammatory, and antiapoptotic pathways as well as modulating the neurotransmitter balance in the basal ganglia circuit. Here, we review current studies and reflect on the potential of acupuncture as a novel and effective treatment strategy for PD. We found that particularly during the early stages, acupuncture may reduce neurodegeneration of dopaminergic neurons and regulate the balance of the dopaminergic circuit, thus delaying the progression of the disease. The benefits of acupuncture will need to be further verified through basic and clinical studies.

2021 ◽  
Vol 8 ◽  
Lin Wang ◽  
Zheyi Wang ◽  
Zhihua Yang ◽  
Kang Yang ◽  
Hongtao Yang

We aimed to explore the active ingredients and molecular mechanism of Tripterygium wilfordii (TW) in the treatment of diabetic nephropathy (DN) through network pharmacology and molecular biology. First, the active ingredients and potential targets of TW were obtained through the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and related literature materials, and Cytoscape 3.7.2 software was used to construct the active ingredient-target network diagram of TW. Second, the target set of DN was obtained through the disease database, and the potential targets of TW in the treatment of DN were screened through a Venn diagram. A protein interaction network diagram (PPI) was constructed with the help of the String platform and Cytoscape 3.7.2. Third, the ClueGO plug-in tool was used to enrich the GO biological process and the KEGG metabolic pathway. Finally, molecular docking experiments and cell pathway analyses were performed. As a result, a total of 52 active ingredients of TW were screened, and 141 predicted targets and 49 target genes related to DN were identified. The biological process of GO is mediated mainly through the regulation of oxygen metabolism, endothelial cell proliferation, acute inflammation, apoptotic signal transduction pathway, fibroblast proliferation, positive regulation of cyclase activity, adipocyte differentiation and other biological processes. KEGG enrichment analysis showed that the main pathways involved were AGE-RAGE, vascular endothelial growth factor, HIF-1, IL-17, relaxin signalling pathway, TNF, Fc epsilon RI, insulin resistance and other signaling pathways. It can be concluded that TW may treat DN by reducing inflammation, reducing antioxidative stress, regulating immunity, improving vascular disease, reducing insulin resistance, delaying renal fibrosis, repairing podocytes, and reducing cell apoptosis, among others, with multicomponent, multitarget and multisystem characteristics.

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Liduo Yue ◽  
Yanbei Ren ◽  
Qingxi Yue ◽  
Zhou Ding ◽  
Kai Wang ◽  

As an antioxidant, α-lipoic acid (LA) has attracted much attention to cancer research. However, the exact mechanism of LA in cancer progression control and prevention remains to be unclear. In this study, we demonstrated that α-lipoic acid has inhibitory effects on the proliferation, migration, and proapoptotic effects of non-small-cell lung cancer (NSCLC) cell lines A549 and PC9. LA-induced NSCLC cell apoptosis was mediated by elevated mitochondrial reactive oxygen species (ROS). Further study confirmed that it is by downregulating the expression of PDK1 (the PDH kinase), resulted in less phospho-PDH phenotype which could interact with Keap1, the negative controller of NRF2, directly leading to NRF2 decrease. Thus, by downregulating the NRF2 antioxidant system, LA plays a role in promoting apoptosis through the ROS signaling pathway. Moreover, LA could enhance other PDK inhibitors with the proapoptosis effect. In summary, our study shows that LA promotes apoptosis and exerts its antitumor activity against lung cancer by regulating mitochondrial energy metabolism enzyme-related antioxidative stress system. Administration of LA to the tumor-bearing animal model further supported the antitumor effect of LA. These findings provided new ideas for the clinical application of LA in the field of cancer therapy.

2021 ◽  
Vol 2021 ◽  
pp. 1-21
Chunmei Zhang ◽  
Mengying Suo ◽  
Lingxin Liu ◽  
Yan Qi ◽  
Chen Zhang ◽  

Oxidative stress and apoptosis play a vital role in the pathogenesis of contrast-induced acute kidney injury (CI-AKI). The purpose of our study was to investigate the protective effects and mechanisms of melatonin against CI-AKI in a CI-AKI mouse model and NRK-52E cells. We established the CI-AKI model in mice, and the animals were pretreated with melatonin (20 mg/kg). Our results demonstrated that melatonin treatment exerted a renoprotective effect by decreasing the level of serum creatinine (SCr) and blood urea nitrogen (BUN), lessening the histological changes of renal tubular injuries, and reducing the expression of neutrophil gelatinase-associated lipid (NGAL), a marker of kidney injury. We also found that pretreatment with melatonin remarkably increased the expression of Sirt3 and decreased the ac-SOD2 K68 level. Consequently, melatonin treatment significantly decreased the oxidative stress by reducing the Nox4, ROS, and malondialdehyde (MDA) content and by increasing the superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity levels. The antiapoptotic effect of melatonin on CI-AKI was revealed by decreasing the ratio of Bax/Bcl2 and the cleaved caspase3 level and by reducing the number of apoptosis-positive tubular cells. In addition, melatonin treatment remarkably reduced the inflammatory cytokines of interleukin-1β (IL-1β), tumor necrosis factor α (TNFα), and transforming growth factor β (TGFβ) in vivo and in vitro. Sirt3 deletion and specific Sirt3 siRNA abolished the above renoprotective effects of melatonin in mice with iohexol-induced acute kidney injury and in NRK-52E cells. Thus, our results demonstrated that melatonin exhibited the renoprotective effects of antioxidative stress, antiapoptosis, and anti-inflammation by the activation of Sirt3 in the CI-AKI model in vivo and in vitro. Melatonin may be a potential drug to ameliorate CI-AKI in clinical practice.

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Dengjun Guo ◽  
Jie Zhou ◽  
Meng Zhang ◽  
Reyisha Taximaimaiti ◽  
Xiaoping Wang ◽  

Objective. To investigate the potential role of Momordica charantia polysaccharides (MCPs) in Parkinson’s disease (PD) and reveal the molecular mechanism of its function. Method. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium (1-methyl-4-phenylpyridinium, MPP+) were used to establish PD mice and cell models. The mice and cells were divided into 4 groups: Control group, Control+MCPs group, PD group, and PD+MCPs group. Pole climbing experiment and Rotarod experiment were used to observe the coordination ability of mice. High-performance liquid chromatography and enzyme-linked immunosorbent assay (ELISA) were used to determine neurotransmitters and metabolites, inflammatory factors TNF-α and IL-1β, oxidative stress-related markers SOD, MDA, and GSH in striatum tissues. Western blot was used to determine the protein levels of tyrosine hydroxylase (TH), oxidative stress-related protein Cytochrome C (Cytochrome C), and apoptosis-related proteins Bcl-2, Bax, and cleaved Caspase-3 in tissues and cells. Moreover, flow cytometry, PI staining, and fluorescence were used to observe cell apoptosis. Finally, the activation effect of MCPs on TLR4/MyD88/NF-κB signaling pathway was observed and verified. Results. Compared with the Control group, MPTP treatment can induce brain damage in mice (all P < 0.05 ), change the metabolic state of neurotransmitters (all P < 0.05 ), induce inflammation (all P < 0.05 ), and induce apoptosis and the occurrence of oxidation reaction (all P < 0.05 ); however, MCPs treatment can significantly reverse the above changes (all P < 0.05 ). In cell models, studies have found that MCPs can play a protective role by regulating the activation state of TLR4/MyD88/NF-κB pathway. Conclusion. This study found that the application of MCPs therapy can play anti-inflammatory, antioxidative stress, and antiapoptotic effects in PD by regulating the activation of the TLR4/MyD88/NF-κB pathway.

2021 ◽  
Vol 9 ◽  
Qinrui Li ◽  
Jingjing Liang ◽  
Na Fu ◽  
Ying Han ◽  
Jiong Qin

Autism spectrum disorder (ASD) is characterized by stereotyped behavior and deficits in communication and social interaction. There are no curative treatments for children with ASD. The ketogenic diet (KD) is a high-fat, appropriate-protein, and low-carbohydrate diet that mimics the fasting state of the body and is proven beneficial in drug-resistant epilepsy and some other brain diseases. An increasing number of studies demonstrated that a KD improved autistic behavior, but the underlying mechanisms are not known. We reviewed the neuroprotective role of a KD in ASD, which is likely mediated via improvements in energy metabolism, reductions in antioxidative stress levels, control of neurotransmitters, inhibition of the mammalian target of rapamycin (mTOR) signaling pathway, and modulation of the gut microbiota. A KD is likely a safe and effective treatment for ASD.

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