Nifuroxazide, a STAT3 inhibitor, mitigates inflammatory burden and protects against diabetes-induced nephropathy in rats

Said, Eman; Zaitone, Sawsan A.; El-Dosoky, Mohamed; Elsherbiny, Nehal M.

doi:10.1016/j.cbi.2017.12.030

Cited by 67 publications

(37 citation statements)

References 43 publications

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“…The selective compound targeting STAT3 (nifuroxazide) inhibited hyperglycemia-induced cell responses and ameliorated renal damage in experimental DN. 71 We also observed that blockade of IL-17A diminished STAT3 activation in the diabetic kidney. All these findings support the notion that the beneficial effects of IL-17A neutralization could be due to its antiinflammatory actions, blocking these important signaling pathways involved in the genesis of diabetic renal damage.…”

Section: Discussionsupporting

confidence: 54%

Interleukin-17A blockade reduces albuminuria and kidney injury in an accelerated model of diabetic nephropathy

Lavoz

Matus

Orejudo

et al. 2019

Kidney International

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Diabetic nephropathy (DN) is one of the most common complications of diabetes, and currently the first end-stage renal disease worldwide. New strategies to treat DN using agents that target inflammatory pathways have attracted special interest. Recent pieces of evidences suggest a promising effect of IL-17A, the Th17 effector cytokine. Among experimental DN models, mouse strain BTBR ob/ob (leptin deficiency mutation) develops histological features similar to human DN, which means an opportunity to study mechanisms and novel therapies aimed at DN regression. We found that BTBR ob/ob mice presented renal activation of the factors controlling Th17 differentiation. The presence of IL-17A-expressing cells, mainly CD4 D and gd lymphocytes, was associated with upregulation of proinflammatory factors, macrophage infiltration and the beginning of renal damage. To study IL-17A involvement in experimental DN pathogenesis, treatment with an IL-17A neutralizing antibody was carried out starting when the renal damage had already appeared. IL-17A blockade ameliorated renal dysfunction and disease progression in BTBR ob/ob mice. These beneficial effects correlated to podocyte number restoration and inhibition of NF-kB/ proinflammatory factors linked to a decrease in renal inflammatory-cell infiltration. These data demonstrate that IL-17A takes part in diabetes-mediated renal damage and could be a promising therapeutic target to improve DN.

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Section: Discussionsupporting

confidence: 54%

Interleukin-17A blockade reduces albuminuria and kidney injury in an accelerated model of diabetic nephropathy

Lavoz

Matus

Orejudo

et al. 2019

Kidney International

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“…The anti-inflammatory effect of verapamil also based on STAT3 inhibition in other models of neurotoxicity (Hashioka et al 2012). In addition, STAT3 inhibition has been proven to be beneficial in the diabetic (Said et al 2018) and non-diabetic lung injuries (Zhao et al 2016).…”

Section: Discussionmentioning

confidence: 99%

STAT3 and Nrf2 pathways modulate the protective effect of verapamil on lung injury of diabetic rats

Mohamed

Hafez

Mohamed

et al. 2018

Endocrine Regulations

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Objective. We aimed to assess the protective role of verapamil, L-type calcium channel blockers, against early lung damage in diabetic rats. Lung injury has recently been recognized as a consequent complication of diabetes mellitus. Hyperglycemia induces inflammatory changes in lung tissue early in the disease. Methods. Twenty four adult male rats were grouped into control, diabetic, diabetic treated with verapamil, and verapamil control. Streptozotocin (STZ) was used to induce diabetes. Oxidative parameters and antioxidative mechanisms were assessed in lung homogenate. Tumor necrosis factor alpha (TNFα) protein was measured as a pro-inflammatory mediator. Signal transducer and activator of transcription 3 (STAT3) gene expression and nuclear erythroid factor 2 (Nrf2) immunoexpression were screened. Results. The lung showed oxidative damage and inflammatory infiltration in STZ diabetic rats early at 2 weeks. The parameters significantly improved in lung tissue treated with verapamil. Histopathology of the lung tissue confirmed the results. Inhibition of STAT3/TNFα pathway was involved in the protection offered by verapamil. Activation of Nrf2 together with an increasing antioxidant capacity of diabetic lung significantly ameliorates the injury induced by diabetes. Conclusions. Verapamil afforded protection in diabetic lung injury. The protection was mediated by the anti-inflammatory and antioxidant effects of verapamil.

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“…Hyperglycemia induces the activation of JAK/STAT3 signaling in glomerular mesangial cells, resulting in cell proliferation and synthesis of extracellular matrix molecules (25). Giving STAT3 inhibitor dramatically decreased renal macrophage infiltration and attenuated inflammation and fibrosis in diabetic rats (44). Moreover, Lu's group constructed streptozocin-induced STAT3 knockdown diabetic mice and found that STAT3 deficiency dramatically reduced the expression of inflammation markers, like IL-6, MCP-1 (45).…”

Section: Discussionmentioning

confidence: 99%

Epac ameliorates tubulointerstitial inflammation in diabetic nephropathy via C/EBPβ/SOCS3/STAT3 pathway

Yang

Zhang

Wang

et al. 2020

Preprint

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Background: Tubulointerstitial inflammation plays a pivotal role in the progression of diabetic nephrology (DN), and tubular cells act as the driving force in the inflammation cascade. The aim of the study is to investigate whether activation of Epac alleviates tubulointerstitial inflammation through SOCS3/JAK/STAT3 pathway under DN. Methods: The kidney morphological changes and the level of oxidative stress were observed in db/db mice treated with Epac agonist (8-pCPT-2’-O-Me-cAMP). The expression of inflammatory cytokines, fibrosis markers, C/EBPβ, SOCS3 and p-STAT3 in renal tissues were assessed. In in vitro study, the changes of above genes and proteins were also detected in human proximal tubular cell line (HK-2) incubated with high glucose (HG) with and without Epac agonist. Overexpression of SOCS3 plasmid, SOCS3 siRNA and C/EBP-β siRNA were employed and the translocation of C/EBP-β and p-STAT3 were observed by immunofluorescence. Macrophage migration assay were detected in Transwell system. Results: In db/db mice, we observed that the expression of MCP-1 was up-regulated in renal tubular cells, which concurrent with increased influx of macrophages, cytokines production (MCP-1, TNF-α, and IL-6), and tubulointerstitial fibrosis. Moreover, we also found that these changes were accompanied by reduced C/EBP-β expression and increased SOCS3 and phosphorylated STAT3 (p-STAT3) expression. However, after treated db/db mice with 8-O-cAMP, an Epac activator, the expression of SOCS3 further up-regulated while other protein expression profile was partially reversed. In vitro , high glucose (30mM, HG) treatment down-regulated C/EBP-β expression while increased SOCS3, p-STAT3 and MCP-1 expression in HK-2 cells; Activation of Epac by 8-O-cAMP further increased the gene and protein expression of SOCS3 while reversed the changes of the other proteins. Mechanistically, under HG ambience, knockdown of C/EBP-β or SOCS3 in HK-2 cells partially blocked the inhibitory effect of Epac activation on MCP-1 expression. Furthermore, 8-O-cAMP treatment enhanced the nuclear-translocation of C/EBP-β and further increased the transcription of SOCS3 gene, which decreased MCP-1 expression through inhibiting the phosphorylation of STAT3 in HK-2 cells. Conclusions: These data indicate that Epac ameliorates tubulointerstitial inflammation in DN at least partially through C/EBPβ/SOCS3/STAT3 pathway. Therefore, Activation of Epac by 8-O-cAMP may be a novel therapeutic strategy for DN.

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Nifuroxazide, a STAT3 inhibitor, mitigates inflammatory burden and protects against diabetes-induced nephropathy in rats

Cited by 67 publications

References 43 publications

Interleukin-17A blockade reduces albuminuria and kidney injury in an accelerated model of diabetic nephropathy

Interleukin-17A blockade reduces albuminuria and kidney injury in an accelerated model of diabetic nephropathy

STAT3 and Nrf2 pathways modulate the protective effect of verapamil on lung injury of diabetic rats

Epac ameliorates tubulointerstitial inflammation in diabetic nephropathy via C/EBPβ/SOCS3/STAT3 pathway

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