New Role of JAK2/STAT3 Signaling in Endothelial Cell Oxidative Stress Injury and Protective Effect of Melatonin

Duan, Weixun; Yang, Yang; Yi, Wei; Yan, Jing; Liang, Zhenxin; Wang, Ning; Li, Yue; Chen, Wensheng; Yu, Shuang; Jin, Zhenxiao

doi:10.1371/journal.pone.0057941

Cited by 70 publications

(48 citation statements)

References 51 publications

(56 reference statements)

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“…In addition, our study has proven that inhibition of the SOCS1-JAK2-STAT3 signaling pathway could reduce oxidative stress injury in the brains of rats subjected to ischemic stroke. One study found that the role of the JAK2/STAT3 signaling pathway could induce oxidative stress injury in response to hydrogen peroxide, which is similar to our results [33]. Additionally, previous evidence has illustrated that treatment with hrACE2 could prevent the activation of the JAK2/STAT3/SOCS3 pathway resulting in ACE2 protecting against oxidative stress [34].…”

Section: Discussionsupporting

confidence: 89%

Inhibition of the SOCS1-JAK2-STAT3 Signaling Pathway Confers Neuroprotection in Rats with Ischemic Stroke

Wang

Qiao

Liu

et al. 2017

Cell Physiol Biochem

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Background: The present study aims to investigate the protective effects of the SOCS1-JAK2-STAT3 signaling pathway on neurons in a rat model of ischemic stroke. Methods: Our study was conducted using an ischemic stroke rat model. After the microglia were extracted, 40 neonatal Sprague-Dawley (SD) rats were assigned into the blank, AG490, model and negative control (NC) groups. The neurological function of all the rats was evaluated. Histopathological changes were observed. qRT-PCR and western blotting were applied to measure the expression of genes and proteins in the SOCS1-JAK2-STAT3 signaling pathway and related to apoptosis. The TUNEL assay was conducted to calculate the cellular morphology and apoptosis of neuronal cells. Cell viability was detected using the MTT assay. In addition, immunoassays were used to measure the content of superoxide dismutase (SOD), glutathione (GSH) and malondialdehyde (MDA) as well as the levels of oxidative stress. Results: Compared with the blank group, the model and NC groups showed higher neurological function scores—the cytoplasm of the neurons were cavitated, the organelles were reduced with unclear margins, some of the neurons were necrotic, and apoptosis was increased. In addition, the NC and model groups exhibited decreased cell viability, lower mRNA and protein expression of SOCS1 SOCS3 and bcl-2 and reduced SOD and GSH levels but higher mRNA and protein expression levels of AK2, STAT3,Bax and caspase-3 as well as increased protein expression of P-JAK2, P-STAT3 and activated caspase-3 (c-caspase-3). Moreover, the MDA levels were up-regulated in the NC and model groups. In contrast, opposing trends were found in the AG490 group compared with the NC and model groups. Conclusion: These data demonstrate that inhibiting the SOCS1-JAK2-STAT3 signaling pathway can reduce the loss of nerve function and apoptosis of neuronal cells, which provides a new target for the clinical treatment of ischemic stroke.

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Section: Discussionsupporting

confidence: 89%

Inhibition of the SOCS1-JAK2-STAT3 Signaling Pathway Confers Neuroprotection in Rats with Ischemic Stroke

Wang

Qiao

Liu

et al. 2017

Cell Physiol Biochem

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“…Melatonin plays a dual role of an antioxidant and an anti‐inflammatory regulator by modulating the activity of the major pro‐inflammatory transcription factor, NF‐kB, along with regulating other signaling pathways, including the STAT3 pathway . In this study, we found that melatonin effectively inhibited the phosphorylation of JAK2 and STAT3 induced by visfatin, whereas in visfatin‐stimulated macrophages, melatonin did not inhibit the degradation of IκBα but rather repressed the translocation of NF‐κB p65 to the nucleus evoked by visfatin.…”

Section: Discussionmentioning

confidence: 55%

Melatonin inhibits visfatin‐induced inducible nitric oxide synthase expression and nitric oxide production in macrophages

Kang

Park

et al. 2013

Journal of Pineal Research

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Aberrant expression of inducible nitric oxide synthase (iNOS) in macrophages, which has been reported to be suppressed by melatonin, has an important contribution in the development of pathological inflammation. Visfatin, an adipokine, regulates the expression of various inflammatory factors, leading to inflammation; however, the influence of visfatin on iNOS-driven processes in macrophages is unclear. Here, we report the assessment of the role of visfatin in the regulation of iNOS gene expression in macrophages. Our data show that the levels of iNOS protein in peritoneal macrophages as well as nitric oxide (NO) in blood plasma were significantly lower after lipopolysaccharide treatment in visfatin(+/-) mice than those in the WT mice. In addition, visfatin increases iNOS mRNA and protein levels in RAW 264.7 cells, along with increasing production of NO. The enhancement of iNOS expression was prevented by treating the cells with inhibitors of the Janus kinase 2/signal transducers and activators of transcription 3 (JAK2/STAT3), nuclear factor (NF)-κB, extracellular signal-regulated kinase 1/2, and c-Jun N-terminal kinase pathways. Our results also show that visfatin-induced iNOS expression and NO production were significantly inhibited by melatonin, an effect that was closely associated with a reduction in phosphorylated JAK2/STAT3 levels and with the inhibition of p65 translocation into nucleus. In conclusion, our data show, for the first time, that melatonin suppresses visfatin-induced iNOS upregulation in macrophages by inhibiting the STAT3 and NF-κB pathways. Moreover, our data suggest that melatonin could be therapeutically useful for attenuating the development of visfatin-iNOS axis-associated diseases.

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“…For instance, apoa1, a component of HDL, can block T-cell signals from macrophages and lower the expression level of TNF-α and IL-1, which are the standard inflammatory markers. Furthermore, published studies previously have demonstrated that STAT3 is also referred to the inflammatory response through mediating various inflammatory factors including IL-6/STAT3 [23][24][25] . High-mobility group nucleosome-binding protein 1 (HMGN1) has been identified and characterized as one of the nuclear alarmins, which can definitely enter extracellular space as a result of cell death.…”

Section: Discussionmentioning

confidence: 99%

Integrative analysis of proteomic and metabonomics data for identification of pathways related to Rhizoma Paridis-induced hepatotoxicity

Zhao

Wang

Huang

et al. 2020

Sci Rep

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Clinical reports on hepatotoxicity that arise from Rhizoma Paridis have recently received widespread attention. Because the hepatotoxicity mechanism is little understood, this research strived to investigate the hepatotoxicity mechanism of Rhizoma Paridis extracts based on iTRAQ quantitative proteomics and metabonomics. The extraction solutions were administrated to rats for 7 days by gavage, and the hepatotoxicity was assessed through quantification of biochemical indexes and Oil red O staining. Additionally, the mechanism of hepatotoxicity was investigated by metabonomics based upon GC-MS and iTRAQ quantitative proteomics. The biochemical and histopathological analysis stood out that Rhizoma Paridis extract could induce liver injury, which was proved by the formation of fat droplets, the changes of mitochondrial structure, and biochemical parameters. The iTRAQ proteomics and metabonomics revealed that Rhizoma Paridis-induced hepatotoxicity was chiefly connected with the abnormal activity of mitochondrion function, which brought about oxidative stress injuries and inflammation, finally causing cell apoptosis. Collectively, we have provided previously uncharacterized hepatotoxic mechanism induced by Rhizoma Paridis and a reference to ensure its safe use in the future.Rhizoma Paridis, the roots of the Paris polyphylla Smith var. (Franch.), was first recorded in 'Shennong Herb' and Li Shizhen's 'Compendium of Materia' . The prepared Rhizoma Paridis has remarkable therapeutic effects on fractures, parotitis, hemostasis, snake bite, and abscess in the clinic for thousands of years. In addition, modern pharmacology indicated that Raw Rhizoma Paridis has beneficial impact on anti-tumor, immunity adjustment, analgesia, and anti-inflammation 1-3 . However, clinical researches regarding adverse reactions caused by Rhizoma Paridis and its preparations 4 , especially hepatotoxicity, have attracted significant attention in recent years 5 . The Chinese Pharmacopoeia clearly describes its hypotoxicity and reminds the patient and doctor to note the possible problems of orally ingesting Rhizoma Paridis and its drug preparations in high doses or over prolonged periods and when taken with other liver-damaging drugs. Despite these warnings, the mechanisms remained little known 6 .Recently, omic technologies are becoming important in vitro and in vivo tools for identifying potential hepatotoxicity mechanisms. The proteomics can identify the differentially expressed proteins that occur in a specific function, which may involve disease-or disorder-related changes in transcription, translation, transport, degradation, and covalent modification 7,8 . Metabolomics is another powerful technology for identifying a number of low-molecular-weight endogenous metabolites and assessing the dynamic variations in the biological samples 1

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New Role of JAK2/STAT3 Signaling in Endothelial Cell Oxidative Stress Injury and Protective Effect of Melatonin

Cited by 70 publications

References 51 publications

Inhibition of the SOCS1-JAK2-STAT3 Signaling Pathway Confers Neuroprotection in Rats with Ischemic Stroke

Inhibition of the SOCS1-JAK2-STAT3 Signaling Pathway Confers Neuroprotection in Rats with Ischemic Stroke

Melatonin inhibits visfatin‐induced inducible nitric oxide synthase expression and nitric oxide production in macrophages

Integrative analysis of proteomic and metabonomics data for identification of pathways related to Rhizoma Paridis-induced hepatotoxicity

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