C188‐9 reduces TGF‐β1‐induced fibroblast activation and alleviates ISO‐induced cardiac fibrosis in mice

Liu, Jiao; Jin, Yuxuan; Wang, Bei; Zhang, Jinying; Zuo, Shengkai

doi:10.1002/2211-5463.13212

Cited by 4 publications

(3 citation statements)

References 32 publications

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“…However, the precise functions of miR-21 and miR-208b in cardiac fibrosis are still unclear. TGF-β is a key mediator implicated in cardiac fibrosis ( 8 ), and activated TGF-β binds to TGF-β receptors, resulting in subsequent activation of its downstream target Smad-3, which promotes myofibroblast proliferation and migration and ultimately leads to cardiac fibrosis ( 9 ). To elucidate the molecular mechanism of cardiac fibrosis after acute myocardial infarction (AMI) regarding miR-208b/miR-21 via the TGF-β1/Smad-3 signaling pathway, we detected the expression levels of miR-208b/miR-21 and TGF-β1/Smad-3 in cells and blood samples from AMI patients and analyzed their relationships.…”

Section: Introductionmentioning

confidence: 99%

MiR-208b/miR-21 Promotes the Progression of Cardiac Fibrosis Through the Activation of the TGF-β1/Smad-3 Signaling Pathway: An in vitro and in vivo Study

Zhang¹,

Yuan²,

Zhou³

et al. 2022

Front. Cardiovasc. Med.

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BackgroundRegulatory molecule microRNAs (miRNAs) have been implicated in myocardial fibrosis. However, the specific mechanism by which they lead to myocardial fibrosis remains unclear. This study aimed to explore the roles of miR-208b, miR-21 and transforming growth factor-β1 (TGF-β1)/Smad-3 signaling pathway components in cardiac fibrosis development.Materials and MethodsThirty-six consecutive acute myocardial infarction (AMI) patients were included in this study. Plasma was collected on admission and at 24 h, 48 h and 6 d. The levels of plasma miR-208b, miR-21, TGF-β1, and Smad-3 were measured using reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and cardiac calcium protein T (cTnT) and creatine kinase isoenzyme (CK-MB) were detected by electrochemiluminescence analysis. H9C2 cells were exposed to hypoxia and divided into 4 groups (hypoxia treatment for 6 h, 24 h, 48 h, and 72 h). These stimulated cells were then transfected with miRNA inhibitors and mimics for gene overexpression and inhibition. RT-qPCR was used to detect the expression of miR-208b, miR-21, TGF-β1, and Smad-3, and western blot analysis was used to detect TGF-β1 and Smad-3 protein expression.ResultsThe plasma analysis showed cTnT and CK-MB expression peaked at 24 h after symptom onset; miR-208b, miR-21, TGF-β1, and Smad-3 levels showed no peak and increased gradually with time. Cell experiments revealed that miR-208b and TGF-β1 were upregulated along with increased hypoxia exposure; miR-21 expression peaked at 24 h and 72 h, with the highest peak at 72 h, and Smad-3 expression peaked at 6 h and 72 h, with the highest peak at 72 h. miR-208b and miR-21 expressions were positively correlated with TGF-β/Smad-3 expression. TGF-β1/Smad-3 mRNA and protein levels were elevated in the miR-208b and miR-21 overexpression groups and reduced in the miR-208b and miR-21 inhibition groups.ConclusionMiR-208b and miR-21 promote cardiac fibrosis progression through TGF-β1/Smad-3 signaling pathway activation.

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Section: Introductionmentioning

confidence: 99%

MiR-208b/miR-21 Promotes the Progression of Cardiac Fibrosis Through the Activation of the TGF-β1/Smad-3 Signaling Pathway: An in vitro and in vivo Study

Zhang¹,

Yuan²,

Zhou³

et al. 2022

Front. Cardiovasc. Med.

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“…Ruxolitinib, a potent JAK1/JAK2 inhibitor, was used to inhibit the signaling pathway of JAK2 signal transducers and activators of STAT3 (19). Cells were pretreated by GZFL (50 mg/ml) for 1 h and then exposed to LPS (100 ng/ml) with or without 5 mM Ruxolitinib for 24 h. C188-9, a small molecular inhibitor, was used for suppressing STAT3 activation (20). Cells were administered to the indicated concentration of C188-9 (10 mM) and cultured for 12 h at 37°C.…”

Section: Primary Microglial Preparation and Drug Administrationmentioning

confidence: 99%

Guizhi Fuling capsule relieves memory deficits by inhibition of microglial neuroinflammation through blocking JAK2/STAT3 pathway in presenilin1/2 conditional double knockout mice

et al. 2023

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Chronic neuroinflammation has been regarded as an important part of the pathological initiation of Alzheimer’s disease (AD), which is associated with the regulation of microglial activation. Preventing microglial activation to inhibit neuroinflammation may become a potential target for the treatment of neurodegenerative diseases. Guizhi Fuling capsule (GZFL) has a strong repression on inflammatory responses. Here, the presenilin1/2 conditional double knockout (PS cDKO) mice, a well-established mouse model of AD, were divided into: WT mice (WT), WT mice+GZFL (WT+GZFL), PS cDKO mice (cDKO), and PS cDKO mice+GZFL (cDKO+GZFL). Mice in the WT+GZFL and cDKO+GZFL group were fed standard chow containing 2000 ppm GZFL for 90 days. After 60 days of GZFL treatment, mice were given to behavioral tests for 30 days in order to explore the effects of GZFL on cognitive and motor function. Then, mice were sacrificed for examining the effects of GZFL on inflammation. Furthermore, primary microglia were obtained from neonatal Sprague-Dawley rats and pretreated with or without GZFL (50 μg/ml) for 1 h in the absence or presence of lipopolysaccharide (LPS) (100 ng/ml) stimulation to speculate whether the underlying mechanism of GZFL’s anti-inflammatory potential was closely associated with Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. Our findings indicated that GZFL has the ability to alleviate memory deficits in PS cDKO mice, which attributes to the improvement of neuroinflammation by inhibiting microglial activation and the levels of pro-inflammatory mediators. In addition, GZFL could inverse the tau hyperphosphorylation and the lessened expression of synaptic proteins in hippocampus of PS cDKO mice. Furthermore, GZFL prevented LPS-induced neuroinflammatory responses in primary microglia by decreasing the levels of pro-inflammatory mediators. It is noteworthy that therapeutic effects of GZFL on memory impairment are depended on the inhibition of neuroinflammatory responses by the blockage of JAK2/STAT3 signaling pathway. Taken together, GZFL may be an effective compound Chinese medicine for the improvement and postponement of neurodegenerative progression in AD.

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“…Ruxolitinib, a potent JAK1/JAK2 inhibitor, was used to inhibit the signaling pathway of JAK2 signal transducers and activators of STAT3 [32]. Cells were pretreated by GZFL (50 μg/ml) for 1 h and then exposed to LPS (100 ng/ml) with or without 5 μM Ruxolitinib for 24 h. C188-9, a small molecular inhibitor, was used for suppressing STAT3 activation [33]. Cells were administered to the indicated concentration of C188-9 (10 μM) and cultured for 12 h at 37°C.…”

Section: Primary Microglial Preparation and Drug Administrationmentioning

confidence: 99%

Guizhi Fuling capsule relieves memory deficits by inhibition of microglial neuroinflammation through blocking JAK2/STAT3 pathway in presenilin1/2 conditional double knockout mice

Yang

Tong

Wang

et al. 2023

Preprint

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Background Chronic neuroinflammation has been regarded as an important part of the pathological initiation of Alzheimer’s disease (AD), which is associated with the regulation of microglial activation. Preventing of microglial activation to inhibit neuroinflammation may become a potential target for the treatment of neurodegenerative diseases. Guizhi Fuling capsule (GZFL) has a strong repression on inflammatory responses. The phenotypes of presenilin1/2 conditional double knockout (PS cDKO) mice, which could well simulate a series of pathological characteristics in AD patients aggravated with age, were subject to behavioral tests and molecular biological analyses to evaluate the latent neuroprotective effects of GZFL on neuroinflammation-mediated cognitive deficits. Primary microglia induced by lipopolysaccharide (LPS) were used to explore the possible mechanism of GZFL on the improvement of neuroinflammation via testing the production of pro-inflammatory mediators and activation of Janus kinase 2 (JAK2) / signal transducer and activator of transcription 3 (STAT3) signaling pathway. Materials and methods PS cDKO mice were divided into: WT mice (WT), WT mice+GZFL (WT+GZFL), PS cDKO mice (cDKO), and PS cDKO mice+GZFL (cDKO+GZFL). Mice in the WT+GZFL and cDKO+GZFL group were fed standard chow containing 2000 ppm GZFL for 90 days. After 60 days of GZFL treatment, mice were given to behavioral tests for 30 days in order to explore the effects of GZFL on cognitive and motor function. Then, mice were sacrificed for examining the effects of GZFL on inflammation. Furthermore, primary microglia were obtained from neonatal Sprague-Dawley rats and pretreated with or without GZFL (50 μg/ml) for 1 h in the absence or presence of LPS (100 ng/ml) stimulation to speculate whether the underlying mechanism of GZFL’s anti-inflammatory potential was closely associated with JAK2/STAT3 signaling pathway. Results Our findings indicated that GZFL has the ability to alleviate memory deficits in PS cDKO mice, which attributes to the improvement of neuroinflammation by inhibiting microglial activation and the levels of pro-inflammatory mediators. In addition, GZFL can inverse the tau hyperphosphorylation and the lessened expression of synaptic proteins in hippocampus of PS cDKO mice. Furthermore, GZFL plays a key role in preventing LPS-induced neuroinflammatory responses in primary microglia by decreasing the levels of pro-inflammatory mediators. It is noteworthy that therapeutic effects of GZFL on memory impairment are depended on the inhibition of neuroinflammatory responses by the blockage of JAK2/STAT3 signaling pathway. Conclusions GZFL may be an effective compound Chinese medicine for the improvement and postponement of neurodegenerative progression in AD.

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C188‐9 reduces TGF‐β1‐induced fibroblast activation and alleviates ISO‐induced cardiac fibrosis in mice

Cited by 4 publications

References 32 publications

MiR-208b/miR-21 Promotes the Progression of Cardiac Fibrosis Through the Activation of the TGF-β1/Smad-3 Signaling Pathway: An in vitro and in vivo Study

MiR-208b/miR-21 Promotes the Progression of Cardiac Fibrosis Through the Activation of the TGF-β1/Smad-3 Signaling Pathway: An in vitro and in vivo Study

Guizhi Fuling capsule relieves memory deficits by inhibition of microglial neuroinflammation through blocking JAK2/STAT3 pathway in presenilin1/2 conditional double knockout mice

Guizhi Fuling capsule relieves memory deficits by inhibition of microglial neuroinflammation through blocking JAK2/STAT3 pathway in presenilin1/2 conditional double knockout mice

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