Hepatoprotective effects of diosmin and/or sildenafil against cholestatic liver cirrhosis: The role of Keap-1/Nrf-2 and P38-MAPK/NF-κB/iNOS signaling pathway

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

doi:10.1016/j.fct.2018.07.027

Cited by 52 publications

(23 citation statements)

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“…On the other hand, Ali et al reported data on efficacy of diosmin alone or in combination with sildenafil (erectile dysfunction approved drug with antioxidant and anti-inflammatory properties [21,22]) on the same model. Interestingly, diosmin alone was able to restore redox homeostasis by regulation of antioxidant enzymes GSR and SOD, a putative mechanism proposed for this molecule [23].…”

Section: Resultsmentioning

confidence: 99%

“…In order to compare parameters of the liver function and metabolic status on BDL-treated animals, we show tables of percentage change of each parameter vs. untreated cholestatic rats (Table 2 and Table 3). It should be noticed that only one study reported mortality as valid endpoint for evaluation of experimental efficacy [23]. Additionally, ductal enzymes AP and GGT were missing on several studies despite these biomarkers are pivotal for cholestasis diagnostic [24].…”

Section: Resultsmentioning

confidence: 99%

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Analysis of Flavonoids Bioactivity for Cholestatic Liver Disease: Systematic Literature Search and Experimental Approaches

et al. 2019

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Flavonoids are naturally occurring compounds that show health benefits on the liver. However, there is little investigation about identification and evaluation of new flavonoid-containing drugs for cholestatic liver disease, one of the most common liver illnesses. We aimed to a systematic search regarding efficacy of flavonoids for treatment of cholestatic liver disease, and then evaluate naringenin (NG) as representative flavonoid in an obstructive cholestasis model. We searched for information of experimental and clinical studies in four major databases without time and language limits. Intervention was defined as any flavonoid derivate compared with other flavonoid, placebo, or without comparator. In addition, we evaluated NG on a bile duct-ligated model in order to contribute evidence of its actions. Eleven experimental reports that support the efficacy of flavonoids in cholestatic liver disease were identified. However, there was no homogeneity in efficacy endpoints evaluated and methodology. On the other hand, NG showed beneficial effects by improving specific metabolic (cholesterol and lipoproteins) and liver damage (bilirubin and alkaline phosphatase) biomarkers. The review lacks homogeneous evidence about efficacy of flavonoids in experimental settings, and is susceptible to risk for bias. NG only showed improvements in specific disease biomarkers. More investigation is still needed to determine its potential for drug development.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Analysis of Flavonoids Bioactivity for Cholestatic Liver Disease: Systematic Literature Search and Experimental Approaches

et al. 2019

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“…In addition, diosmin mediated the upregulation of NF‐κB‐p65, P38‐mitogen‐activated protein kinases, Kelch‐like ECH‐associated protein 1 (Keap‐1), and inducible nitric oxide synthases and downregulation of nuclear factor erythroid 2‐related factor 2 (Nrf‐2), cytoglobin, and endothelial nitric oxide synthases levels. Therefore, diosmin demonstrated anticholestatic and hepatoprotective effects via multiple signalling pathways involving Keap‐1/Nrf‐2 and P38‐mitogen‐activated protein kinases/NF‐κB/inducible nitric oxide synthases (Ali, Azouz, Bakr, Abo‐Youssef, & Hemeida, ). Similar findings confirmed that diosmin combined with pentoxifylline ameliorated liver dysfunction.…”

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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“…Another interesting group of compounds that has recently shown promising anti-fibrogenic properties is that of phosphodiesterase 5 inhibitors (PDE5i) [45,46]. PDE5i are already approved for the treatment of erectile dysfunction [47], lower urinary tract disorders, and pulmonary arterial hypertension [48].…”

Section: Introductionmentioning

confidence: 99%

“…Cancers 2020, 12 4 of 28 targeting specific HDACs with higher selectivity and a better understanding of the role of each isozyme could lead the generation more effective and less toxic therapeutic agents for this condition. Another interesting group of compounds that has recently shown promising anti-fibrogenic properties is that of phosphodiesterase 5 inhibitors (PDE5i) [45,46]. PDE5i are already approved for the treatment of erectile dysfunction [47], lower urinary tract disorders, and pulmonary arterial hypertension [48].…”

Section: Introductionmentioning

confidence: 99%

Dual Pharmacological Targeting of HDACs and PDE5 Inhibits Liver Disease Progression in a Mouse Model of Biliary Inflammation and Fibrosis

Clavería-Cabello

Colyn

Uriarte

et al. 2020

Cancers

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Liver fibrosis, a common hallmark of chronic liver disease (CLD), is characterized by the accumulation of extracellular matrix secreted by activated hepatic fibroblasts and stellate cells (HSC). Fibrogenesis involves multiple cellular and molecular processes and is intimately linked to chronic hepatic inflammation. Importantly, it has been shown to promote the loss of liver function and liver carcinogenesis. No effective therapies for liver fibrosis are currently available. We examined the anti-fibrogenic potential of a new drug (CM414) that simultaneously inhibits histone deacetylases (HDACs), more precisely HDAC1, 2, and 3 (Class I) and HDAC6 (Class II) and stimulates the cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) pathway activity through phosphodiesterase 5 (PDE5) inhibition, two mechanisms independently involved in liver fibrosis. To this end, we treated Mdr2-KO mice, a clinically relevant model of liver inflammation and fibrosis, with our dual HDAC/PDE5 inhibitor CM414. We observed a decrease in the expression of fibrogenic markers and collagen deposition, together with a marked reduction in inflammation. No signs of hepatic or systemic toxicity were recorded. Mechanistic studies in cultured human HSC and cholangiocytes (LX2 and H69 cell lines, respectively) demonstrated that CM414 inhibited pro-fibrogenic and inflammatory responses, including those triggered by transforming growth factor β (TGFβ). Our study supports the notion that simultaneous targeting of pro-inflammatory and fibrogenic mechanisms controlled by HDACs and PDE5 with a single molecule, such as CM414, can be a new disease-modifying strategy.

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Hepatoprotective effects of diosmin and/or sildenafil against cholestatic liver cirrhosis: The role of Keap-1/Nrf-2 and P38-MAPK/NF-κB/iNOS signaling pathway

Cited by 52 publications

References 50 publications

Analysis of Flavonoids Bioactivity for Cholestatic Liver Disease: Systematic Literature Search and Experimental Approaches

Analysis of Flavonoids Bioactivity for Cholestatic Liver Disease: Systematic Literature Search and Experimental Approaches

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

Dual Pharmacological Targeting of HDACs and PDE5 Inhibits Liver Disease Progression in a Mouse Model of Biliary Inflammation and Fibrosis

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