Effect of resveratrol on experimental non-alcoholic steatohepatitis

Heebøll, Sara; Thomsen, Karen Louise; Clouston, Andrew D.; Sundelin, Elias; Radko, Yulia; Christensen, Lars Porskjær; Ramezani-Moghadam, Mehdi; Kreutzfeldt, Martin; Pedersen, Steen B.; Jessen, Niels; Hebbard, Lionel; George, Jacob; Grønbæk, Henning

doi:10.1016/j.phrs.2015.03.005

Cited by 41 publications

(24 citation statements)

References 42 publications

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“…Several natural (resveratrol, /-lipoic acid) and synthetic (BML-278, which is 1000-fold more potent SIRT-1 activator than resveratrol, and SRT1720 [47]) SIRT-1 activators are being evaluated: they improved experimental NAFLD [48,49] and CKD [50,51], and ameliorated steatosis and inflammatory markers in NAFLD patients [52].…”

Section: Role Of Energy and Nutrient Sensors 5 0 -Amp-activated Protmentioning

confidence: 99%

Emerging Liver–Kidney Interactions in Nonalcoholic Fatty Liver Disease

Musso

Cassader

Cohney

et al. 2015

Trends in Molecular Medicine

109

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Section: Role Of Energy and Nutrient Sensors 5 0 -Amp-activated Protmentioning

confidence: 99%

Emerging Liver–Kidney Interactions in Nonalcoholic Fatty Liver Disease

Musso

Cassader

Cohney

et al. 2015

Trends in Molecular Medicine

109

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“…Despite the previous mentioned positive effects of RES in human health, its low-water solubility, mode of action, targets, route and dose of administration, as well as its low bioavailability, preclude its regular use as a therapeutic approach [10][11][12][13]. In order to overcome the poor watersolubility of RES, and to be able to observe measurable effects, some groups, using elevated RES doses (1000 to 1500 mg/person/day), did not get the positive effects observed in humans at low concentrations (150 mg/day) as reported by others [14,15] but, rather observed adverse effects [16,17]. For more than10 years, such a phenomenon has been assigned to hormetic effect of RES [18][19][20][21][22][23].…”

mentioning

confidence: 99%

Resveratrol formulated with a natural deep eutectic solvent inhibits active matrix metalloprotease‐9 in hormetic conditions

Shamseddin

Crauste

Durand

et al. 2017

Euro J Lipid Sci & Tech

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Despite the promising anti-oxidant and anti-inflammatory effects of resveratrol (RES) on human health, pre-clinical and clinical studies are frequently disappointing, probably due to its low water-solubility and poor bioavailability. Even though a hormetic mode of action was clearly established for RES, the high doses commonly used to mitigate these issues, lead to adverse effects. Common hallmarks of multiple pathologies results from pathological-enhanced endothelial permeability due to both enhanced inflammation and matrix metalloprotease-9 (aMMP-9) activities. The main aim of this work was to optimize the RES capacity to inhibit aMMP-9 by using a new class of solvents, natural deep eutectic solvents (NADES) for a new RES formulation as compared with dimethyl-sulfoxide (DMSO). To obtain the appropriate NADES, 18 compounds combinations were prepared to select those exhibiting the optimized capacity to dissolve RES. The RES-NADES 1,2-propanediol:choline-chloride:water (PCW, 1:1:1 molar ratio) and compared with RES-DMSO for their aMMP-9-inhibitory capacities. Low concentrations of RES-NADES/PCW formulation exhibited both a biocompatible solubility and a strong increased aMMP-9-inhibitory activity, at least 10-fold, higher than RES-DMSO, reaching its hormetic mode of action. Following in vivo validations, some particular NADES could potentially be considered as the new generation of formulation for druggable compounds. Practical applications: Formulation of resveratrol in Natural Deep Eutectic solvents (NADES) optimizes its capacity to inhibit active matrix metalloprotease-9. The Resveratrol-NADES 1,2-propanediol:choline-was the most efficient and low concentrations exhibited both a biocompatible solubility and an increased aMMP-9-inhibitory activity, at least 10-fold, higher than RES-DMSO. Consequently, the NADES/PCW formulation allowed resveratrol to reach its hormetic mode of action. Following in vivo validations, some particular NADES could potentially be considered as the new generation of formulation for druggable compounds. The effect of resveratrol (RES) dissolved in either NADES/PCW or DMSO was assessed on the TNFa-activated human monocytes (THP-1). NADES/PCW was able to confer a significant increase of the MMP-9 inhibitory activity of RES, at low doses (at least 10-fold higher) than DMSO, Thus, these data on RES-NADES/PCW formulation support the hormetic effect of resveratrol in preserving the endothelial monolayer integrity by decreasing the exacerbated vascular permeability induced by the overproduction of active MMP-9, during inflammation resulting from infections, cancer, or other pathologies. (Résumé d'auteur

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“…Thereafter, they were fed with an MCD diet for 6 weeks or an HFD diet for 12 weeks to induce NASH. At the end of the 6th or 12th week, the mice were randomly divided into four groups that received treatments with RSV (100 mg/kg) (Heebøll et al, 2015), OCA (10 mg/kg) (Rodrigues et al, 2017), RLA8 (100 mg/kg), and saturated NaHCO 3 solution (0.1 ml/10 g), respectively. All drugs were administered through gavage once a day for 3 weeks for the MCD model and 4 weeks for the HFD model.…”

Section: Methodsmentioning

confidence: 99%

RLA8—A New and Highly Effective Quadruple PPAR-α/γ/δand GPR40 Agonist to Reverse Nonalcoholic Steatohepatitis and Fibrosis

Chen

Wang

et al. 2019

J Pharmacol Exp Ther

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Nonalcoholic fatty liver disease (NAFLD) is a very common chronic hepatic disease, with nonalcoholic steatohepatitis (NASH) as a major and severe subcategory that can lead to cirrhosis and hepatocellular carcinoma, and thereby to a high mortality rate. Currently, there has been no approved drug to treat NAFLD or NASH. The current study has presented RLA8, a novel and balanced quadruple agonist for hepatic lipid metabolism and inflammation-related peroxisome proliferator-activated receptors (PPARs)-a/g/d and G protein-coupled receptor 40 (GPR40), as a NASH drug candidate. The efficacy of RLA8 to treat NASH was evaluated in vivo using two mouse models induced by methionine/choline-deficient diet or by high-fat diet, respectively. RLA8 was shown to improve serum alanine aminotransferase and high-density lipoprotein cholesterol levels, reduce hepatic free fatty acid and triglyceride levels, and alleviate insulin resistance. Cytokine and lipoperoxide analysis revealed that RLA8 could reduce oxidative stress and inflammation. Histochemical and morphologic examination of mouse livers showed that RLA8 could improve pathologic changes such as steatosis, ballooning, collagen fiber, and inflammation. Polymerase chain reaction and Western blot analyses proved that RLA8 could result in PPARs and GPR40 activation, accompanied by upregulation of the 59AMP-activated protein kinase-acetyl-CoA carboxylase pathway and inhibition of the expression of lipogenic genes and proteins, which provided more insights into its action mechanisms. In summary, RLA8 has significantly better efficacy to improve NASH-induced liver damage such as steatosis, inflammation, and fibrosis, and, consequently, it represents a new and highly promising NASH drug candidate that is worthy of further investigation and development.

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Effect of resveratrol on experimental non-alcoholic steatohepatitis

Cited by 41 publications

References 42 publications

Emerging Liver–Kidney Interactions in Nonalcoholic Fatty Liver Disease

Emerging Liver–Kidney Interactions in Nonalcoholic Fatty Liver Disease

Resveratrol formulated with a natural deep eutectic solvent inhibits active matrix metalloprotease‐9 in hormetic conditions

RLA8—A New and Highly Effective Quadruple PPAR-α/γ/δand GPR40 Agonist to Reverse Nonalcoholic Steatohepatitis and Fibrosis

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