Polyphenol-rich extract from loquat fruit peel prevents hyperlipidemia and hepato-nephrotoxicity in mice: in vivo study and in silico prediction of possible mechanisms involving identified polyphenols and/or their circulating metabolites.

Hyperlipidemia is the most well-known cause of metabolic complications and tissue toxicity such as liver steatosis, atherosclerosis and obesity. This study aims to evaluate the preventive effect of loquat fruit peel extract (PE) against tyloxapol-induced hyperlipidemia and related tissue lipotoxicity in mice. The in vivo study was conducted on mice injected daily with tyloxapol at 100 mg per kg B.W. and treated simultaneously with the PE at concentrations of 100 and 200 mg kg-1 or fenofibrate for 28 days. Plasma and tissue lipid biochemical analyses were undertaken using enzymatic methods. The antioxidative stress was revealed by measuring the malondialdehyde content and activities of superoxide dismutase and catalase as well as the scavenging activity against lipoperoxyl radicals. The PE significantly prevented oxidative stress and restored lipid metabolism, plasma glucose, body weight, organ relative mass and biomarkers of hepato-nephrotoxicity as well as the histological structure of the liver and kidneys. It contains five major polyphenols, namely, ferulic acid, caffeic acid, neochlorogenic acid, chlorogenic acid and quercetin. According to molecular docking analysis, these compounds and their circulating metabolites could interact with major proteins implicated in lipid metabolism and oxidative stress. Overall, the study suggests that PE could prevent hyperlipidemia and related toxic tissue complications.

Loquat fruit peel extract regulates lipid metabolism and liver oxidative stress in mice: In vivo and in silico approaches.

ETHNOPHARMACOLOGICAL RELEVANCE: In Moroccan traditional medicine, fresh or dried loquat (Eriobotrya japonica (Thunb.) Lindl.) fruit peels infused in water and taken for 45 days are used as natural remedies against hypercholesterolemia, hyperglycemia and cardiovascular diseases. This is the first experimental study approving the folk medicinal use of loquat fruit peels originated from eastern Morocco. AIM OF THE STUDY: The study aims to investigate the effect of loquat fruit peel extract on lipid metabolism and liver oxidative status in mice as well as to predict the possible mechanisms. MATERIALS AND METHODS: The study was carried out using high fat/fructose diet-induced hyperlipidemic mice model treated with the loquat peel extract for 45 days at two doses (100 and 200 mg/kg/day) in comparison to fenofibrate drug. The plasma, tissue, fecal and biliary lipids and blood glucose were analyzed using enzymatic methods. The liver oxidative status was evaluated and the polyphenol profiling was conducted using the HPLC-DAD method. Possible mechanisms involved in the observed pharmacological effects were predicted by in silico method. RESULTS: The extract at a dose of 200 mg/kg possessed higher effect than at 100 mg/kg. It significantly reduced plasma total cholesterol (TC), triglycerides (TG), LDL-cholesterol, atherogenic index, LDL-C/HDL-C ratio and plasma glucose (-36%, -45%, -45%, -82%, -87%, 58%, respectively), while the HDL-cholesterol was increased (+172%). Moreover, the extract reduced TC and TG in the liver and adipose tissue by increasing their excretion in bile and fecal matter. It prevented the liver oxidative stress and decreased body weight and organ relative mass. The extract appears to be nontoxic (LD50 > 5000 mg/kg) and contains five polyphenols including ferulic acid (32.74 ± 0.71 mg/g), caffeic acid (21.48 ± 0.32 mg/g), 5-O-Caffeoylquinic acid (112.15 ± 1.86 mg/g), chlorogenic acid (42.05 ± 0.92 mg/g) and quercetin (32.69 ± 0.68 mg/g). These phenolics and/or their circulating metabolites presented differential interaction capacities with the potential enzymes and transcription factors implicated in lipid homeostasis such as HMG-CoA reductase, lipoprotein lipase, fatty acid synthase, Cyp7a1, ABCG, PPARs, RXR, FXR and RAR. CONCLUSION: Our findings justify the traditional use of loquat fruit peels and suggest that their aqueous extract could be used as substrate to produce phytotherapeutic drugs or dietary supplements to prevent hyperlipidemia, hyperglycemia and related cardiovascular diseases.

Thymus atlanticus polyphenol-rich extract regulates cholesterol metabolism by inhibiting its biosynthesis without affecting its excretion in hamsters fed a high-fat diet.

CONTEXT: Thymus atlanticus has been reported to have significant hypolipidaemic effect in animal models. However, the mechanism of this hypolipidaemic action still unknown. OBJECTIVE: To determinate the possible mechanism(s) of hypolipidaemic action of a Thymus atlanticus polyphenol-rich extract (PRE). MATERIALS AND METHODS: Plasma, faecal, and liver cholesterol, bile acid content in the faeces, and gene expression level of HMG-CoA reductase, CYP7A1, ABCG5 and ABCG8 were analysed after 9 weeks in hamsters feeding normal diet, high-fat diet (HFD) or HFD supplemented with 400 mg/kg body weight/day of PRE. RESULTS: PRE significantly decreased total cholesterol content (p < .05) and HMG-CoA reductase expression (p < .05), but did not affect the faecal cholesterol, bile acid contents and CYP7A1 and ABCG5/G8 expression (p > .05). CONCLUSION: We can conclude that the T. atlanticus extract is efficient in the alleviation of chronic hyperlipidaemia by acting as cholesterol biosynthesis inhibitor.

Systematic analysis of nutrigenomic effects of polyphenols related to cardiometabolic health in humans - Evidence from untargeted mRNA and miRNA studies.

Cardiovascular and metabolic disorders present major causes of mortality in the ageing population. Polyphenols present in human diets possess cardiometabolic protective properties, however their underlying molecular mechanisms in humans are still not well identified. Even though preclinical and in vitro studies advocate that these bioactives can modulate gene expression, most studies were performed using targeted approaches. With the objective to decipher the molecular mechanisms underlying polyphenols cardiometabolic preventive properties in humans, we performed integrative multi-omic bioinformatic analyses of published studies which reported improvements of cardiometabolic risk factors following polyphenol intake, together with genomic analyses performed using untargeted approach. We identified 5 studies within our criteria and nearly 5000 differentially expressed genes, both mRNAs and miRNAs, in peripheral blood cells. Integrative bioinformatic analyses (e.g. pathway and gene network analyses, identification of transcription factors, correlation of gene expression profiles with those associated with diseases and drug intake) revealed that these genes are involved in the processes such as cell adhesion and mobility, immune system, metabolism, or cell signaling. We also identified 27 miRNAs known to regulate processes such as cell cytoskeleton, chemotaxis, cell signaling, or cell metabolism. Gene expression profiles negatively correlated with expression profiles of cardiovascular disease patients, while a positive correlation was observed with gene expression profiles following intake of drugs against cardiometabolic disorders. These analyses further advocate for health protective effects of these bioactives against age-associated diseases. In conclusion, polyphenols can exert multi-genomic modifications in humans and use of untargeted methods coupled with bioinformatic analyses represent the best approach to decipher molecular mechanisms underlying healthy-ageing effects of these bioactives.

Phenolic-Rich Extract from Almond (Prunus dulcis) Hulls Improves Lipid Metabolism in Triton WR-1339 and High-Fat Diet-Induced Hyperlipidemic Mice and Prevents Lipoprotein Oxidation: A Comparison with Fenofibrate and Butylated Hydroxyanisole.

Hyperlipidemia and oxidative stress are risk factors for atherosclerosis. In this study, we investigated the hypolipidemic and anti-lipoprotein oxidation activities of polyphenol-rich extracts from almond hulls using Triton WR-1339 and high-fat diet-induced hyperlipemic mice as experimental models. We demonstrated that the almond hull extract significantly reduced total cholesterol, triglycerides and low-density lipoprotein-related plasma cholesterol (LDL-C) in the two experimental models of hyperlipidemia, but significantly increased high-density lipoprotein-related plasma cholesterol (HDL-C). Another beneficial effect of the extract was its ability to reduce the atherogenic index and LDL-C/HDL-C ratio. However, the extract exhibited effective antiradical activity against 2,2-diphenyl-1-picrylhydrazyl and significantly protected lipoprotein-rich plasma from mice against oxidation induced by copper ion. The extract contains 342.63±3.44 mg/g total phenolics, 144.67±6.83 mg/g tannins, and 20.66±0.92 mg/g flavonoids. These finding indicate that almond hulls contain polar products able to lower plasma lipid concentrations and which might be beneficial for the treatment of hyperlipidemia and prevention of atherosclerosis.

Effect of Phoenix dactylifera seeds (dates) extract in triton WR-1339 and high fat diet induced hyperlipidaemia in rats: A comparison with simvastatin.

ETHNOPHARMACOLOGICAL RELEVANCE: Date seeds are widely used in Moroccan traditional medicine for treating obesity and related diseases. AIM OF THE STUDY: Two date seed varieties (Jihel and Majhoul) were assessed for their phenolic profile and lipid-lowering activity. MATERIALS AND METHODS: The polyphenolic profile was determined using HPLC-DAD. Triton-WR-1339 and high-fat diet (HFD)-induced hyperlipidaemic rats were used to evaluate the hypolipidaemic effect of date seeds extracts. Serum lipid profile was measured using automatic biochemical analyser. RESULTS: Rutin, quercetin, p-coumaric and caffeic acids were the most prevalent chemical among the analysed phenolic compounds. Serum lipids: Total cholesterol, triglycerides, low-density lipoprotein-cholesterol were lowered and high-density lipoprotein-cholesterol were increased by date seed methanolic extract (at 200 mg/kg) in triton WR1339 -induced hyperlipidaemia in experimental rats. Chronic feeding of these extracts (at 200 mg/kg), to animals concurrently fed with high fat diet (HFD) for three weeks, caused a significant (p < 0.05) decrease in serum total cholesterol, triglycerides, low-density lipoprotein-cholesterol levels and atherogenic index, while it increased serum HDL-C. Furthermore, the supplementation of date seed extract was effective in preventing body weight gain. CONCLUSIONS: These findings are suggestive of hypolipidaemic and atherosclerosis prevention roles of Jihel and Majhoul date seeds.

Effect of Aqueous Extract and Polyphenol Fraction Derived from Thymus atlanticus Leaves on Acute Hyperlipidemia in the Syrian Golden Hamsters.

Thymus atlanticus, an endemic plant of Morocco, is traditionally used as a liniment or a drink to treat various diseases. However, there are few available scientific data regarding its biological effects. In this connection, the present study aimed to investigate the hypolipidemic and antioxidant effects of aqueous extract and polyphenol fraction of Thymus atlanticus in Syrian golden hamsters treated with Triton WR-1339 (triton, 20 mg/100 g body weight). The hamsters orally received the extracts (400 mg/kg), and blood samples were collected after 24 h of treatment to determine plasma lipid, insulin, and fasting blood glucose levels. Plasma malondialdehyde level and plasma total antioxidant (TAS) were also evaluated. The T. atlanticus extracts significantly decreased triglycerides, total cholesterol, VLDL-C, and LDL-C and increased HDL-C when compared with the hyperlipidemic group. Both extracts suppressed the effect of the triton injection on TAS and reduced the level of plasma malondialdehyde. The extracts produced no significant change in the blood glucose level but effectively prevented the mild hyperinsulinemia induced by triton. These findings suggest that T. atlanticus may be a useful alternative treatment for the control of hyperlipidemia and its related diseases.

Anti-inflammatory and anticoagulant effects of polyphenol-rich extracts from Thymus atlanticus: An in vitro and in vivo study.

ETHNOPHARMACOLOGICAL EVIDENCE: Thymus atlanticus (TA) is used in traditional medicine in Morocco to treat chronic inflammatory diseases, after local and oral treatment. AIM OF STUDY: This study aimed to investigate the in vitro and in vivo anti-inflammatory and anticoagulant activities of an aqueous extract (AE) and polyphenol fraction (PF) derived from TA. MATERIALS AND METHODS: The effect of AE and PF on monocyte chemoattractant protein-1 (MCP-1) production by naïve and LPS-stimulated peritoneal macrophages isolated from C57Bl/6 mice was assessed by ELISA assay. The effect of chronic administration of the extracts at three different doses by oral rout for 2 weeks on blood coagulation and inflammation induced by carrageenan in Wistar rats was evaluated. In addition, the in vitro anticoagulant effect was tested on blood plasma collected from healthy rats using the activated partial thromboplastin time (APTT), prothrombin time (PT) and thrombin time (TT) tests. The acute toxicity of AE was investigated. Phytochemical analysis was carried out by HPLC. RESULTS: Analysis by HPLC indicated rosmarinic acid as the main phenolic acid in TA extracts. Compared to control macrophages, MCP-1 level was lower in medium supplemented with AE at 50 and 500 µg/mL and PF at 500 µg/mL, but higher in medium with PF at 50 µg/mL. Rosmarinic and chicoric acids, served as controls, significantly decreased MCP-1 production. Chronic oral administration of TA extracts prevented inflammation induced by carrageenan and induced a significant prolongation of blood coagulation time, in a dose dependant manner, in Wistar rats. The results of the in vitro assay showed that the coagulation time was significantly prolonged in plasma incubated with extracts in APTT, PT and TT tests. Lethal dose 50 of AE in mice was 27.90 ± 1.19 g/kg. CONCLUSION: This study indicated TA as an herb with anti-inflammatory and anticoagulant proprieties and supports the traditional use of this plant for the treatment of inflammatory diseases.

Olive Mill Waste Extracts: Polyphenols Content, Antioxidant, and Antimicrobial Activities.

Natural polyphenols extracts have been usually associated with great bioactive properties. In this work, we investigated in vitro antioxidant and antimicrobial potential of the phenolic olive mill wastewater extracts (OWWE) and the olive cake extracts (OCE). Using the Folin Ciocalteux method, OWWE contained higher total phenol content compared to OCE (8.90 ± 0.728 g/L versus 0.95 ± 0.017 mg/g). The phenolic compounds identification was carried out with a performance liquid chromatograph coupled to tandem mass spectrometry equipment (HPLC-ESI-MS). With this method, a list of polyphenols from OWWE and OCE was obtained. The antioxidant activity was measured in aqueous (DPPH) and emulsion (BCBT) systems. Using the DPPH assay, the results show that OWWE was more active than OCE and interestingly the extracts originating from mountainous areas were more active than those produced from plain areas (EC50 = 12.1 ± 5.6 µg/mL; EC50 = 157.7 ± 34.9 µg/mL, resp.). However, when the antioxidant activity was reversed in the BCBT, OCE produced from plain area was more potent than mountainous OCE. Testing by the gel diffusion assay, all the tested extracts have showed significant spectrum antibacterial activity against Staphylococcus aureus, whereas the biophenols extracts showed more limited activity against Escherichia coli and Streptococcus faecalis.

Ocimum basilicum ethanolic extract decreases cholesterol synthesis and lipid accumulation in human macrophages.

Macrophage lipid accumulation induced by low density lipoproteins (LDL) plays a pivotal role in atherosclerotic plaque development. Previous work showed that Ocimum basilicum extract, used as hypocholesterolemic agent by traditional medicine in Morocco, has hypolipidemic activity in rat acute hyperlipimidemia. This study investigated the effects of ethanolic extract of O. basilicum on lipid accumulation in human macrophages. As modification of LDL increase atherogenicity of the particles we evaluated the effects of the extract on LDL oxidation. The extract caused a dose-related increase of LDL-resistance to Cu(2+)-induced oxidation. Furthermore, at the dose of 60 microg/ml, significantly decreases the accumulation of macrophage lipid droplets induced by modified LDL evaluated as by red-oil staining. Cholesterol esterification and triacylglycerol synthesis in the cells were not affected. Macrophage treatment with 60 microg/ml, but not 20 microg/ml, of the extract reduced newly synthesized unesterified cholesterol by about 60% and decreased scavenger receptors activity by about 20-30%, evaluated by the internalization of cholesterol carried by [(3)H]CE-aggregated-LDL. The results suggest that O. basilicum ethanolic extract has the capability to reduce foam cell formation through the reduction of cholesterol synthesis and the modulation of the activity of surface scavenger receptors.

The hypolipidaemic activity of aqueous Erica multiflora flowers extract in Triton WR-1339 induced hyperlipidaemic rats: a comparison with fenofibrate.

In the present study, an aqueous extract from Erica multiflora L. (Ericaceae) flowers was evaluated for its hypocholesterolaemic and hypotriglyceridaemic activities using Triton WR-1339 induced hyperlipemic rats as experimental model. Hyperlipideamia was developed by intraperitonial injection of Triton (200mg/kg body weight). The animals were divided into control (CG), hyperlipidaemic (HG), hyperlipidaemic plus herb extract (HG+EmE) and hyperlipidaemic plus fenofibrate (HG+FF) treated groups. Intragastric administration of Erica multiflora extract (0.25 g/100g body weight) to the rats caused a significant decrease on their plasma lipid levels (quantified using enzymatic kits). At 7h after treatment, plasma total cholesterol, triglycerides and LDL-cholesterol were decreased by 47%, 95% and 67%, respectively, but the change of HDL-cholesterol level was not significant. However, the hypolipidaemic effect of fenofibrate was limited to triglycerides and LDL-cholesterol, which were lowered by about 92% and 41%, respectively. At 24h after treatment, Erica multiflora extract reduced plasma total cholesterol by 68.5% and triglycerides by 91%. HDL-cholesterol was not significantly increased and LDL-cholesterol was lowered by 80.5%. In fenofibrate treated rats, only plasma triglyceride concentrations were lowered by 82%, while the other lipid parameters were not significantly changed indicating that this aqueous herb extract may contain products that lower plasma lipid concentrations and might be beneficial in treatment of hyperlipideamia.