Discovery of an orally active VHL-recruiting PROTAC that achieves robust HMGCR degradation and potent hypolipidemic activity

HMG-CoA reductase (HMGCR) protein is usually upregulated after statin (HMGCR inhibitor) treatment, which inevitably diminishes its therapeutic efficacy, provoking the need for higher doses associated with adverse effects. The proteolysis targeting chimera (PROTAC) technology has recently emerged as a powerful approach for inducing protein degradation. Nonetheless, due to their bifunctional nature, developing orally bioavailable PROTACs remains a great challenge. Herein, we identified a powerful HMGCR-targeted PROTAC (

Functional Characteristics of Lactobacillus Strains Isolated from Camel's Milk.

This study aimed at isolation, identification and evaluation of probiotic potential of Lactobacillus isolates from camel's milk. Thirty four Lactobacillus isolates coded M 1 to M 34 were Gram positive, rods, catalase and oxidase negative and nonspore-forming bacteria. These isolates were identified by biochemical tests and API 50 CH kits. From these, 14 different Lactobacillus isolates (M 1, M 2, M 4, M 5, M 9, M 10, M 12, M 14, M 15, M 18, M 20, M 27, M 29 and M 31) which were tolerant to gastric and intestinal juices in a previous study were now tested for antipathogenic activity which varied according to the Lactobacillus species and the challenged pathogen. All 14 isolates demonstrated significant inhibitory effect against methicillin resistant Staphylococcus aureus (MRSA), Bacillus cereus and moderate to low activity against Salmonella typhimurium and Escherichia coli. When tested for bile tolerance at the concentration of 0.3 to 2.0%, the growth rate of 8 isolates M 2, M 5, M 9, M 10, M 12, M 14, M 18 and M 20 exceeded 60% in 0.3 and 0.5% bile. M 2 (L. fermentum) and M 12 (L. plantarum) and M 20 (L. paracasei ssp. paracasei) exhibited the highest growth rates of 82, 79.4 and 78.8% respectively. At higher levels of 1 and 2% bile, significant reduction (p < 0.05) was observed for all tested isolates except M 9 (L. plantarum) with growth rate of 66.5% at 2% bile. As for cholesterol reduction, M 10 (L. plantarum) and M 15 (L. paracasei ssp. paracasei) had the highest reduction rate of 58.0 and 53.2% respectively, which is comparable to the reference strain L. reuteri DSMZ 20056. Testing adhesion to intestinal epithelial cells and ileal tissues of BALB/c mouse; M 20 (L. paracasei ssp. paracasei) and M 2 (L. fermentum) exhibited highest attachment rate of more than 15 bacterial cells/epithelial cell. SEM images showed variable degrees of bacterial attachment to ileal tissues. These results suggest that camel milk is a rich source for potential probiotic lactobacilli which may be suitable for food and nutraceuticals industries; however, further in vivo investigations are needed.

Pharmacological activity of the hydroalcoholic extract from Hovenia dulcis thunberg fruit and the flavonoid dihydromyricetin during hypercholesterolemia induced in rats

Cerebrovascular accidents and coronary artery disease are the leading causes of cardiovascular mortalities in Brazil and high levels of LDL cholesterol are one of the main risk factors. In this context, several plant extracts and natural substances have shown promise as cholesterol-lowering. The objective of this study was to evaluate the potential of the hydroalcoholic extract of the fruit of H. dulcis and of dihydromyricetin in cholesterol reduction in hypercholesterolemic rats. Forty-two Wistar male rats were distributed into seven groups of six animals that received diets supplemented with 1% cholesterol and 0.3% cholic acid, with the exception of the control group, which received conventional diets. Animals were treated with oral suspensions containing: atorvastatin 1.0 mg/kg; H. dulcis extract at 50.0 and 100.0 mg/kg and dihydromyricetin at 25.0 and 50.0 mg/kg vehicle (control group). The following biochemical markers were evaluated; total cholesterol, HDL-C, LDL-C, triglycerides, AST, ALT, and alkaline phosphatase. The hypercholesterolemic diet was effective in inducing hypercholesterolemia, increasing total cholesterol by 112.7% relative to the control group. The treatments with two doses of the extract proved to be promising hypocholesterolemic agents, as they were able to substantially reduce total cholesterol and LDL-C, without significantly altering triglycerides, hepatic transaminases, and alkaline phosphatase, thereby encouraging the studies with the plant H. dulcis. The groups treated with the flavonoid dihydromyricetin, although they showed a significant reduction in total cholesterol and LDL-C, and found increases in triglycerides and hepatic transaminases, which is unwanted in the context of hypercholesterolaemia.

No Brasil, o acidente vascular cerebral e a doença arterial coronariana constituem as principais causas de mortalidade cardiovascular, sendo os altos níveis de colesterol LDL um dos principais fatores de risco. Nesse contexto, diversos extratos vegetais e substâncias naturais isoladas têm se mostrado promissoras como hipocolesterolemiantes. O objetivo do trabalho foi avaliar o potencial do extrato hidroalcoólico dos frutos de Hovenia dulcis e do flavonóide diidromiricetina na redução do colesterol em ratos hipercolesterolêmicos. Quarenta e dois ratos Wistar machos, foram distribuídos em 7 grupos de 6 animais, que receberam dieta suplementada com 1% de colesterol e 0,3% de ácido cólico, à exceção do grupo controle, que recebeu ração convencional. Posteriormente, os animais foram tratados com suspensões orais contendo: atorvastatina 1,0 mg/kg; extrato de H. dulcis de 50,0 e 100,0 mg/kg; diidromiricetina de 25,0 e 50,0 mg/kg e veículo (grupo controle). Avaliaram-se os parâmetros bioquímicos: colesterol total, HDL-C, LDL-C, triglicérides, AST, ALT e fosfatase alcalina. A dieta hipercolesterolêmica foi efetiva na indução da hipercolesterolemia, aumentando o colesterol total em 112,7% em relação ao controle. Os tratamentos com as duas doses do extrato mostraram-se promissores como agentes hipocolesterolemiantes, já que foram capazes de reduzir substancialmente o colesterol total e LDL-C, sem alterar significativamente triglicérides, as transaminases hepáticas e a fosfatase alcalina, incentivando, assim, a continuidade de estudos com a planta H. dulcis. Já os grupos tratados com o flavonóide diidromiricetina, apesar de apresentarem redução significativa do colesterol total e de LDL-C, apresentaram elevações nos triglicérides e nos parâmetros hepáticos, resultado indesejável no âmbito das hipercolesterolemias.