Oxyberberine, a novel HO-1 agonist, effectively ameliorates oxidative stress and inflammatory response in LPS/D-GalN induced acute liver injury mice via coactivating erythrocyte metabolism and Nrf2 signaling pathway

Article

作者: Su, Ziren ; Xian, Yanfang ; Ai, Gaoxiang ; Wu, Xiaoyan ; Zhong, Linjiang ; Lin, Zhixiu ; Li, Yucui ; Chen, Jiannan ; Dou, Yaoxing ; Huang, Ronglei ; Qu, Chang ; Liu, Yuhong

Oxyberberine (OBB), a main gut-mediated metabolite of Phellodendron chinense Cortex (PC), exhibits prominent protective property against acute liver injury (ALI). Heme oxygenase-1 (HO-1) is a vital molecule in attenuating acute and chronic liver injury for its prominent anti-oxidative injury and anti-inflammation properties. The present study was performed to investigate the hepatoprotective role of OBB through HO-1 signaling pathway in lipopolysaccharide/D-galactosamine (LPS/D-GalN) induced ALI. Our results indicated that PC treatment improved survival rate and its metabolite OBB evidently improved histopathological deteriorations and liver function. Additionally, OBB dramatically ameliorated hepatic oxidative stress and inflammation. Besides, OBB exerted remarkable HO-1 agonistic activity, even be comparable to hemin (a HO-1 inducer), as evidenced by increased HO-1 level, carbon monoxide and bilirubin activities, which are the markers of erythrocyte metabolism. Moreover, OBB modulated the parameters of inflammation and oxidative stress through HO-1 dependent pathway. Beyond this, OBB also notably suppressed the translocation of p65, enhanced antioxidation defense genes expressions, promoted the degradation of Kelch-like ECH-associated protein 1 (Keap1) and the nuclear translocation of nuclear factor-erythroid-2-related factor 2 (Nrf2). In conclusion, OBB could be the principle active metabolite substance of PC and exert excellent hepatoprotective effects via inducing HO-1 through coactivation of erythrocyte metabolism and Nrf2/HO-1 pathway.

2022-07-01·Phytomedicine2区 · 医学

In vitro and in vivo hypoglycemia effect of oxyberberine, a novel HO-1 agonist: A renewed evidence linking HO-1 to diabetes mellitus

2区 · 医学

Article

作者: Huang, Ronglei ; Chen, Jiannan ; Su, Ziren ; Ai, Gaoxiang ; Dou, Yaoxing ; Huang, Ziwei ; Li, Yucui ; Liu, Yuhong ; Xie, Jianhui

BACKGROUNDOxyberberine (OBB), an important in vivo metabolite of berberine, exerts superior hypoglycemia effect. However, the underlying mechanism remains obscure. Heme oxygenase-1 (HO-1) holds a crucial status in the pathogenesis of diabetes. Previous research has indicated that OBB can specifically bind to hemoglobin and significantly up-regulated the HO-1 expression in diabetic rat. Based on cellular protection features of HO-1, this work aimed to probe the anti-diabetic effect of OBB and the association with the potential induction of HO-1 expression.METHODSA type 2 diabetic mellitus rat model was established. Glucolipid metabolism and insulin sensitivity were analyzed. Immunohistochemistry, Western blotting and in silico simulations were also performed.RESULTSAdministration of OBB or HO-1 inducer hemin significantly reduced fasting blood glucose level, blood fat, and inflammatory cytokine levels, while increased antioxidant capacity of pancreas. Meanwhile, OBB treatment remarkably stimulated liver glycogenesis and inhibited gluconeogenesis. Besides, OBB improved the glucose utilizing of muscle. Noteworthily, OBB inhibited the islet cell apoptosis and improved pancreatic function. In addition, OBB effectively improved the consumption of glucose in insulin-resistant HepG2 cells. Moreover, OBB also reduced oxidative stress, promoted glucose-elicited insulin secretion and enhanced expression of β-cell function proteins in INS-1 cells. Nevertheless, these effects were significantly reversed by treatment with Zincprotoporphrin (ZnPP). Additionally, in silico simulations indicated that OBB exhibited superior affinity with HO-1.CONCLUSIONOBB effectively ameliorated hyperglycemia, dyslipidemia, and insulin resistance, improved oral glucose tolerance, and maintained glucose metabolism homeostasis, at least in part, by promoting HO-1-mediated activation of phosphoinositide 3-kinase / protein kinase B (PI3K/Akt) and AMP-activated protein kinase (AMPK) pathways. These data eloquently suggest that OBB, as a novel HO-1 agonist, has good potential to be a promising candidate drug for the management of diabetes, and support a therapeutic role of HO-1 induction in diabetes that potentially paves the way to translational research.

2021-01-01·Renal Failure4区 · 医学

ATF4-dependent heme-oxygenase-1 attenuates diabetic nephropathy by inducing autophagy and inhibiting apoptosis in podocyte

4区 · 医学

ArticleOA

作者: Liang, Mingzhu ; Jin, Juan ; He, Wenfang ; He, Qiang ; Liang, Xudong ; Yuan, Shizhu

AIMPodocyte injury plays an important role in diabetic nephropathy (DN), yet the underlying molecular mechanisms of podocyte injury in DN is not clear. Here, we investigated the role of activating transcription factor 4 (ATF4) and HO-1 in DN-induced podocyte injury.METHODSProtein expression was measured by western blotting (WB) and immunofluorescence. Cellular apoptosis was quantified by flow cytometry. ATF4 siRNA knockdown and HO-1 overexpression in podocyte were employed to evaluate the role of ER stress in DN-induced apoptosis and autophagy response. Urinary protein levels, nephrin expression, serum creatinine and BUN were evaluated and glomerulosclerosis was quantified by Periodic Acid-Schiff staining.RESULTSExpression of ATF4 was increased in podocytes exposed to serum from DN mice. ATF4 knockdown enhanced DN-induced podocyte apoptosis. HO-1 overexpression reduced the decline of DN-induced podocyte autophagy and inhibited apoptosis and the beneficial effects of HO-1 overexpression in DN were blocked by ATF4 knockdown. The diabetic mice were significantly ameliorated by HO-1 agonist hemin treatment.CONCLUSIONSATF4 induces autophagy by enhancing the expression of HO-1, and inhibits podocyte apoptosis in DN. Treatment with the HO-1 agonist reduced proteinuria, apoptosis, and enhanced autophagy response, and thus improved renal function in DN mice.

100 项与 Oral GLP-1 agonist(Poolbeg) 相关的药物交易

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