Activation of c-Jun N-terminal kinase and p38 after cerebral ischemia upregulates cerebral sodium-glucose transporter type 1

Yamazaki, Yoji; Arita, Kyoko; Harada, Shinichi; Tokuyama, Shogo

doi:10.1016/j.jphs.2017.02.016

Cited by 15 publications

(10 citation statements)

References 46 publications

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“…TGF-β1 stimulation in CFs resulted in increased proliferation, increased collagen I and collagen III expression, and increased p38 and ERK1/2 phosphorylation ( Xu et al, 2017 ), whereas inhibition of the activation of p38 kinase and ERK1/2 could effectively attenuate cardiac fibrosis ( Tao et al, 2016 ). Activation of MAPKs participates in the upregulation of cerebral SGLT-1 expression ( Yamazaki et al, 2018 ). Moreover, the relationship between the SGLT1 and MAPK signaling pathways in the heart has also been reported in our previous study ( Lin et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

SGLT1 Knockdown Attenuates Cardiac Fibroblast Activation in Diabetic Cardiac Fibrosis

et al. 2021

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Background: Cardiac fibroblast (CF) activation is a hallmark feature of cardiac fibrosis in diabetic cardiomyopathy (DCM). Inhibition of the sodium-dependent glucose transporter 1 (SGLT1) attenuates cardiomyocyte apoptosis and delays the development of DCM. However, the role of SGLT1 in CF activation remains unclear.Methods: A rat model of DCM was established and treated with si‐SGLT1 to examine cardiac fibrosis. In addition, in vitro experiments were conducted to verify the regulatory role of SGLT1 in proliferation and collagen secretion in high-glucose– (HG–) treated CFs.Results: SGLT1 was found to be upregulated in diabetic cardiac tissues and HG-induced CFs. HG stimulation resulted in increased proliferation and migration, increased the expression of transforming growth factor-β1 and collagen I and collagen III, and increased phosphorylation of p38 mitogen-activated protein kinase and extracellular signal-regulated kinase (ERK) 1/2. These trends in HG-treated CFs were significantly reversed by si-SGLT1. Moreover, the overexpression of SGLT1 promoted CF proliferation and collagen synthesis and increased phosphorylation of p38 mitogen-activated protein kinase and ERK1/2. SGLT1 silencing significantly alleviated cardiac fibrosis, but had no effect on cardiac hypertrophy in diabetic hearts.Conclusion: These findings provide new information on the role of SGLT1 in CF activation, suggesting a novel therapeutic strategy for the treatment of DCM fibrosis.

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Section: Discussionmentioning

confidence: 99%

SGLT1 Knockdown Attenuates Cardiac Fibroblast Activation in Diabetic Cardiac Fibrosis

et al. 2021

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“…IL‐1β induced MCP‐1 in ARPE‐19 cells through p38MAPK signaling pathways 26 . Activation of p38MAPK after cerebral ischemia upregulated cerebral SGLT1 27 . We demonstrated that IL‐1β increased SGLT1 and MCP‐1 gene expressions in PC12HS cells, suggesting that IL‐1β increases SGLT1 gene expression through p38MAPK signaling pathways in PC12HS cells.…”

Section: Discussionmentioning

confidence: 66%

“… 26 Activation of p38MAPK after cerebral ischemia upregulated cerebral SGLT1. 27 We demonstrated that IL‐1β increased SGLT1 and MCP‐1 gene expressions in PC12HS cells, suggesting that IL‐1β increases SGLT1 gene expression through p38MAPK signaling pathways in PC12HS cells. Mizagliflozin did not reduce IL‐1β‐induced increases in SGLT1 and MCP‐1 gene expressions, whereas it ameliorated IL‐1β‐induced cell death in PC12HS cells.…”

Section: Discussionmentioning

confidence: 68%

Mizagliflozin, a selective SGLT1 inhibitor, improves vascular cognitive impairment in a mouse model of small vessel disease

Ishida

Saito

Sato

et al. 2021

Pharmacology Res & Perspec

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Previously, we showed that sodium/glucose cotransporter 1 (SGLT1) participates in vascular cognitive impairment in small vessel disease. We hypothesized that SGLT1 inhibitors can improve the small vessel disease induced‐vascular cognitive impairment. We examined the effects of mizagliflozin, a selective SGLT1 inhibitor, and phlorizin, a non‐selective SGLT inhibitor, on vascular cognitive impairment in a mouse model of small vessel disease. Small vessel disease was created using a mouse model of asymmetric common carotid artery surgery (ACAS). Two and/or 4 weeks after ACAS, all experiments were performed. Cerebral blood flow (CBF) was decreased in ACAS compared with sham‐operated mice. Phlorizin but not mizagliflozin reversed the decreased CBF of ACAS mice. Both mizagliflozin and phlorizin reversed the ACAS‐induced decrease in the latency to fall in a wire hang test of ACAS mice. Moreover, they reversed the ACAS‐induced longer escape latencies in the Morris water maze test of ACAS mice. ACAS increased SGLT1 and proinflammatory cytokine gene expressions in mouse brains and phlorizin but not mizagliflozin normalized all gene expressions in ACAS mice. Hematoxylin/eosin staining demonstrated that they inhibited pyknotic cell death in the ACAS mouse hippocampus. In PC12HS cells, IL‐1β increased SGLT1 expression and decreased survival rates of cells. Both mizagliflozin and phlorizin increased the survival rates of IL‐1β‐treated PC12HS cells. These results suggest that mizagliflozin and phlorizin can improve vascular cognitive impairment through the inhibition of neural SGLT1 and phlorizin also does so through the improvement of CBF in a mouse model of small vessel disease.

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“…Oxidative stress decreases neuronal cell death by associating it with activation of the intracellular JNK signaling pathway [ 76 ]. Stress from ischemia increases sodium-glucose transporter type 1 (SGLT-1) in the brain, and SP600125 (JNK inhibitor) ameliorated ischemic neuronal damage and significantly inhibited the increase in SGLT-1 12 hours after MCAO [ 77 ]. Edaravone was used to treat acute ischemic stroke as a potent antioxidant, which has been reported to inhibit oxidative stress and the JNK-c-Jun pathway and simultaneously inhibit overall MAPK activity in the aged rat brain, which can greatly reduce neuronal damage after I/R injury [ 78 ].…”

Section: Discussionmentioning

confidence: 99%

Exploration of the mechanism of luteolin against ischemic stroke based on network pharmacology, molecular docking and experimental verification

et al. 2021

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Stroke is a leading cause of morbidity and mortality worldwide. As the most common type of stroke cases, treatment effectiveness is still limited despite intensive research. Recently, traditional Chinese medicine has attracted attention because of potential benefits for stroke treatment. Among these, luteolin, a natural plant flavonoid compound, offers neuroprotection following against ischemic stroke, although the specific mechanisms are unknown. Here we used network pharmacology, molecular docking, and experimental verification to explore the mechanisms whereby luteolin can benefit stroke recovery. The pharmacological and molecular properties of luteolin were obtained from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. The potential targets of luteolin and ischemic stroke were collected from interrogating public databases. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed by Funrich and Database for Annotation, Visualization and Integrated Discovery respectively, a luteolin-target-pathway network constructed using Cytoscape, Autodock vina was used for molecular docking simulation with Discovery Studio was used to visualize and analyze the docked conformations. Lastly, we employed an in vitro model of stroke injury to evaluate the effects of luteolin on cell survival and expression of the putative targets. From 95 candidate luteolin target genes, our analysis identified six core targets . KEGG analysis of the candidate targets identified that luteolin provides therapeutic effects on stroke through TNF signaling and other pathways. Our experimental analyses confirmed the conclusions analyzed above. In summary, the molecular and pharmacological mechanisms of luteolin against stroke are indicated in our study from a systematic perspective.

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Activation of c-Jun N-terminal kinase and p38 after cerebral ischemia upregulates cerebral sodium-glucose transporter type 1

Cited by 15 publications

References 46 publications

SGLT1 Knockdown Attenuates Cardiac Fibroblast Activation in Diabetic Cardiac Fibrosis

SGLT1 Knockdown Attenuates Cardiac Fibroblast Activation in Diabetic Cardiac Fibrosis

Mizagliflozin, a selective SGLT1 inhibitor, improves vascular cognitive impairment in a mouse model of small vessel disease

Exploration of the mechanism of luteolin against ischemic stroke based on network pharmacology, molecular docking and experimental verification

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