Targeting Keap-1/Nrf-2 pathway and cytoglobin as a potential protective mechanism of diosmin and pentoxifylline against cholestatic liver cirrhosis

Ali, Fares E.M.; Bakr, Adel G.; Abo-Youssef, Amira M.; Azouz, Amany A.; Hemeida, Ramadan A.M.

doi:10.1016/j.lfs.2018.05.048

Cited by 47 publications

(34 citation statements)

References 53 publications

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“…The procedure of Western blotting was performed as the previously described method. [ 43 ] Protein samples for each group were resolved in 10% sodium dodecyl sulfate‐polyacrylamide gel electrophoresis gel and transferred to polyvinylidene difluoride membrane using a semidry transfer technique. Primary antibodies for NRF2, cytoglobin, NF‐ k B‐p65, I k Bα (Santa Cruz Biotechnology), IKKβ, and β‐actin (Thermo Fisher Scientific) were diluted 1:1000 in 5% fetal bovine serum in Tris phosphate‐buffered saline Tween‐20 (TBST).…”

Section: Methodsmentioning

confidence: 99%

Nephroprotective effect of umbelliferone against cisplatin‐induced kidney damage is mediated by regulation of NRF2, cytoglobin, SIRT1/FOXO‐3, and NF‐kB‐p65 signaling pathways

Ali

Hassanein

El-Bahrawy

et al. 2021

J Biochem & Molecular Tox

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Cisplatin (Cis) is one of the most potent and effective broad‐spectrum antitumor drugs, but its use is limited due to nephrotoxicity. The current study investigated the renoprotective effect of umbelliferone (UMB) on Cis‐induced nephrotoxicity in rats. Renal injury was induced by a single injection of Cis (7 mg/kg, ip). Our results exhibited that the injection of Cis significantly disrupted renal function biomarkers as well as KIM‐1 expression. The expressions of TNF‐α, IL‐1β, NF‐kB‐p65, and IKKβ were elevated along with downregulation of IkBα expression. Also, Cis disrupted cellular oxidant/antioxidant balance through the reduction of glutathione (GSH), glutathione‐S‐transferase (GST), and superoxide dismutase (SOD) levels and elevation of malondialdehyde (MDA) content. On the contrary, the levels of renal function biomarkers, cytokines, NF‐kB‐p65, IkBα, IKKβ, and oxidant/antioxidant status have been improved after UMB treatment. Mechanistically, rats administered Cis only exhibited a significant decrease in NRF2 and cytoglobin expressions as well as the CREB, SIRT1, FOXO‐3, and PPAR‐γ genes. Treatment with UMB significantly upregulated NRF2 and cytoglobin proteins, as well as effectively increased the expression of CREB, SIRT1, FOXO‐3, PPAR‐γ, and NRF2 genes. Histopathological findings strongly supported our biochemical results, as evidenced by attenuation of renal hemorrhage, cast diffusion, and inflammatory cell infiltration. Interestingly, UMB significantly enhanced Cis cytotoxicity in both HL‐60 and HeLa cells in a dose‐dependent manner. Together, our results demonstrated that UMB can protect against Cis‐induced nephrotoxicity in normal rats along with the enhancement of its in vitro antitumor activity. These findings suggested that UMB could be used as a potential adjuvant therapy in Cis chemotherapeutic protocols.

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Section: Methodsmentioning

confidence: 99%

Nephroprotective effect of umbelliferone against cisplatin‐induced kidney damage is mediated by regulation of NRF2, cytoglobin, SIRT1/FOXO‐3, and NF‐kB‐p65 signaling pathways

Ali

Hassanein

El-Bahrawy

et al. 2021

J Biochem & Molecular Tox

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“…Cygb is significantly deregulated by its promoter hypermethylation in most malignancies, 26,28,29 thereby promoting tumorigenesis and progression. [16][17][18][19][20][21][30][31][32] In this study, we found that Cygb is significantly deregulated in human HCC tissues, as compared with these adjacent non-tumor tissues and hepatolithiasis tissues ( Figure 1A-C), Cygb decrease promotes HCC proliferation, whereas Cygb restoration inhibits cell proliferation (Figure 2A-D). We proposed that Cytoglobin functions as tumor suppressor, and its decrease is negatively associated with HCC progression.…”

Section: Discussionmentioning

confidence: 62%

“…[11][12][13][14] Emerging evidences indicated that Cygb is negatively associated with liver fibrosis and HCC tumorigenesis via regulating oxidative stress pathways. [15][16][17][18][19] Cygb absence accounts for a high incidence of multiple malignancies including liver, lung and colon cancer and lymphoma in aged Cygb −/− mice, compared with wide-type mice. 20,21 Its deficiency also contributes to tumor recurrence and poor prognosis in human gliomas.…”

Section: The Interaction Of Ons Withmentioning

confidence: 99%

“…It is a dynamic mediator in the maintenance of redox homeostasis and performs the activities of peroxidase and nitric oxide dioxygenase (NOD), which catalyzes nitric oxide (NO) or nitrite to nitrate in rat hepatocytes . Emerging evidences indicated that Cygb is negatively associated with liver fibrosis and HCC tumorigenesis via regulating oxidative stress pathways . Cygb absence accounts for a high incidence of multiple malignancies including liver, lung and colon cancer and lymphoma in aged Cygb −/− mice, compared with wide‐type mice .…”

Section: Introductionmentioning

confidence: 99%

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Cytoglobin ameliorates the stemness of hepatocellular carcinoma via coupling oxidative‐nitrosative stress signals

Zhang

Pei

Yang

et al. 2018

Molecular Carcinogenesis

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Cancer stem cells (CSCs) account for tumor self‐renewal and heterogeneity. Oxidative‐nitrosative stress (ONS) is an independent etiologic factor throughout tumorigenesis. Emerging evidences indicated that the interaction of ONS with CSCs contributes to tumor progression and resistance to chemoradiotherapy. Cytoglobin (Cygb) is a member of human hexacoordinate hemoglobin family and acts as a dynamic mediator of redox homeostasis. We observed that Cygb is significantly deregulated in human hepatocellular carcinoma (HCC) tissue and its decrease aggravates the growth of liver cancer stem cells (LCSCs) and increases the subpopulation of CD133(+) LCSCs. Cygb restoration inhibits HCC proliferation and LCSC growth, and decreases the subpopulation of CD133 (+) LCSCs in vitro. We found that Cygb absence promotes LCSC phenotypes and PI3 K/AKT activation, whereas Cygb restoration inhibits LCSC phenotypes and PI3 K/AKT activation. Furthermore, exogenous antioxidants can eliminate the inhibitory effect of Cygb to LCSC growth and phenotypes, as well as PI3 K/AKT activation. Collectively, this study demonstrated that cytoglobin functions as a tumor suppressor and targets CSCs at an ONS‐dependent manner. Thus, Cygb restoration could be a novel and promising therapeutic strategy against HCC with aberrant ROS/RNS accumulation.

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“…Similar findings confirmed that diosmin combined with pentoxifylline ameliorated liver dysfunction. The combined therapy might be due to regulating the Keap‐1/Nrf‐2/glutathione (GSH) and NF‐κB‐ p65/p38‐mitogen‐activated protein kinases signalling pathways (Ali, Bakr, Abo‐Youssef, Azouz, & Hemeida, ).…”

Section: Flavonoidsmentioning

confidence: 99%

Natural products for the prevention and treatment of cholestasis: A review

Jiang

Zhang

et al. 2020

Phytotherapy Research

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Cholestasis is a common manifestation of decreased bile flow in various liver diseases. It results in fibrosis and even cirrhosis without proper treatment. It is believed that a wide range of factors, including transporter dysfunction, oxidative stress, inflammatory damage, and immune disruption, can cause cholestasis. In recent years, natural products have drawn much attention for specific multiple-target activities in diseases. Many attempts have been made to investigate the anticholestatic effects of natural products with advanced technology. This review summarizes recent studies on the biological activities and mechanisms of recognized compounds for cholestasis treatment. Natural products, including various flavonoids, phenols, acids, quinones, saponins, alkaloids, glycosides, and so on, function as comprehensive regulators via ameliorating oxidative stress, inflammation, and apoptosis, restoring bile acid balance with hepatic transporters, and adjusting immune disruption. Moreover, in this progress, nuclear factor erythroid 2-related factor 2, reactive oxygen species production, heme oxygenase-1, NF-κB, cholesterol 7 alpha-hydroxylase, and farnesoid X receptors are thought as main targets for the activity of natural products. Therefore, this review presents the detailed mechanisms that include multiple targets and diverse signalling pathways. Natural products are the valuable when seeking novel therapeutic agents to treat cholestatic liver diseases.

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Targeting Keap-1/Nrf-2 pathway and cytoglobin as a potential protective mechanism of diosmin and pentoxifylline against cholestatic liver cirrhosis

Cited by 47 publications

References 53 publications

Nephroprotective effect of umbelliferone against cisplatin‐induced kidney damage is mediated by regulation of NRF2, cytoglobin, SIRT1/FOXO‐3, and NF‐kB‐p65 signaling pathways

Nephroprotective effect of umbelliferone against cisplatin‐induced kidney damage is mediated by regulation of NRF2, cytoglobin, SIRT1/FOXO‐3, and NF‐kB‐p65 signaling pathways

Cytoglobin ameliorates the stemness of hepatocellular carcinoma via coupling oxidative‐nitrosative stress signals

Natural products for the prevention and treatment of cholestasis: A review

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