A Molecular Docking Study against COVID-19 Protease with a Pomegranate Phyto-Constituents 'Urolithin' and Other Repurposing Drugs: From a Supplement to Ailment

Aim:We conducted an in silico study on Urolithin and different antimicrobial agents targeting virus protease and peptidase.Methodology: The dockingstudy was completed by using docking tools. Drug compounds and COVID-19 receptor molecules were prepared, docking was performed and interaction was visualized through Discovery Studio visualizer.Results: Urolithin A has interacted against peptidase (PDBID:2GTB) with binding energy -6.93kcal/mol and against protease (PDBID:6LU7) with the binding energy -5.46 kcal/mol,while Urolithin Bhasinteracted to peptidase (PDBID:2GTB) with binding energy -6.74kcal/moland with protease it interacted with a binding energy -4.67 kcal/mol. The antimicrobial agent Ofloxacin was found to interactagainst protease(PDBID:6LU7) with a binding energy -6.84 kcal/mol and against protease(PDB:6LU7) with a binding energy -8.00 kcal/mol. Conclusion: The most common interacting amino acids of target enzymes of the virus with studied drugs were His41, His164, Met165, Glu166, Gln189. From the docking studies, it is observed that Ofloxacin and Urolithin have the potential to inhibit the virus protease as well as peptidase significantly and these could prevent the entry of the virus to the inside of the host cell. Thus, further antiviral research on these antimicrobial agents and Urolithin could be helpful to control the COVID-19 disease

Urolithin A activates autophagy to improve liver insulin resistance in diabetic mice / 中草药

Objective: To investigate the effect of urolithin A (UA) on liver insulin signaling pathway in type 2 diabetes model mice and its relationship with autophagy. Methods: C57BL/6 mice were randomly divided into four groups according to body weight, namely control group, model group, UA (50 mg/kg) group, UA (50 mg/kg) combined with chloroquine (50 mg/kg) group. After 6 weeks of high-fat diet, a type 2 diabetes model was established by ip streptozotocin (STZ). The mice in each group were ig administrated for 7 weeks, and their body weight, water intake, blood lipids, fasting blood glucose (FBG), and fasting insulin (FINS) levels were measured; HE staining was used to observe pathological changes in mouse liver tissue; Western blotting was used to detect mouse phosphorylated protein kinase B (p-Akt), glucose transporter 2 (Glut2), phosphorylated glycogen synthase kinase-3β(p-GSK3β) and autophagy-related protein microtubule-related protein 1 light chain 3 II/I (LC3II/I) and selective autophagy linker protein (p62) expression levels. Results: Compared with the model group, UA significantly improved liver tissue steatosis and edema in diabetic model mice, significantly reduced plasma triacylglycerol, free fatty acids, low-density lipoprotein-cholesterol, FBG, FINS levels, and increased high-density lipoprotein-cholesterol level (P < 0.01); UA significantly reduced HOMA-IR and increased ISI (P < 0.01), up-regulated the protein expression of p-Akt, Glut2, p-GSK3β, and LC3II/I in liver tissues, and inhibited the expression of p62 protein (P < 0.01). Combined with chloroquine, FBG, FINS, and HOMA-IR in mice were increased, and ISI was decreased (P < 0.05); Liver tissue edema and steatosis were significantly aggravated; The expression levels of p-Akt, Glut2, LC3II/I protein in liver tissue were decreased, and p62 protein expression levels were increased (P < 0.05), indicating that the autophagy inhibitor chloroquine significantly weakened the effect of UA. Conclusion: UA may improve liver insulin resistance in diabetic mice by activating liver autophagy.

Mitochondrial Quality Control in the Heart: New Drug Targets for Cardiovascular Disease

Despite considerable efforts to prevent and treat cardiovascular disease (CVD), it has become the leading cause of death worldwide. Cardiac mitochondria are crucial cell organelles responsible for creating energy-rich ATP and mitochondrial dysfunction is the root cause for developing heart failure. Therefore, maintenance of mitochondrial quality control (MQC) is an essential process for cardiovascular homeostasis and cardiac health. In this review, we describe the major mechanisms of MQC system, such as mitochondrial unfolded protein response and mitophagy. Moreover, we describe the results of MQC failure in cardiac mitochondria. Furthermore, we discuss the prospects of 2 drug candidates, urolithin A and spermidine, for restoring mitochondrial homeostasis to treat CVD.

Study on Improvement Effect of Methylated Urolithin A on Oleic Acid-induced Lipid Accumulation in Huh- 7 Cells and Its Me- chanism / 中国药房

OBJECTIVE： To study the improvement effect and mechanism of methylated urolithin A on oleic acid-induced lipid accumulation in human liver cancer Huh-7 cells. METHODS： Oleic acid was adopted to induce lipid accumulation model cells. Huh-7 cells were divided into control group （culture medium）， model group （1 mmol/L oleic acid）， low-dose group （1 mmol/L oleic acid+10 μmol/L methylated urolithin A） and high-dose group （1 mmol/L oleic acid+20 μmol/L methylated urolithin A）. Oil red O staining was used to observe lipid accumulation in cells. Triglyceride（TG） enzyme assay was applied to determine the TG content in cells. PCR was employed to detect the mRNA expression of FASN， SREBP-1， PPAR-α and PPAR-γ in cells. Western blotting was used to determine the protein expression of FASN in cells. RESULTS： After induced by oleic acid， a large amount of lipid droplet accumulated around the cells； the intracellular lipid and TG content， mRNA expression levels of FASN， SREBP-1 and PPAR-γ， protein expression levels of FASN were increased significantly， while mRNA expression level of PPAR-α was decreased significantly （P＜0.01）. After intervened with methylated urolithin A， lipid droplet around the cells decreased significantly； the contents of lipid and TG in cells were decreased significantly， while the mRNA expression levels of FASN， SREBP-1 and PPARγ and protein expression level of FASN were decreased significantly （P＜0.05 or P＜0.01）. CONCLUSIONS： Methylated urolithin A can improve oleic acid-induced lipid accumulation in Huh-7 cells， the mechanism of which may be associated with inhibiting fat synthesis， promoting lipid metabolism and down-regulating the expression of metabolism-related factors as FASN， SREBP-1 and PPAR-γ.

Antiproliferative effect of urolithin A, the ellagic acid-derived colonic metabolite, on hepatocellular carcinoma HepG2. 2. 15 cells by targeting Lin28a/let-7a axis

An abnormality in the Lin28/let-7a axis is relevant to the progression of hepatitis B virus (HBV)-positive hepatocellular carcinoma (HCC), which could be a novel therapeutic target for this malignant tumor. The present study aimed to investigate the antiproliferative and anti-invasive effects of urolithin A in a stable full-length HBV gene integrated cell line HepG2.2.15 using CCK-8 and transwell assays. The RNA and protein expressions of targets were assessed by quantitative PCR and western blot, respectively. Results revealed that urolithin A induced cytotoxicity in HepG2.2.15 cells, which was accompanied by the cleavage of caspase-3 protein and down-regulation of Bcl-2/Bax ratio. Moreover, urolithin A suppressed the protein expressions of Sp-1, Lin28a, and Zcchc11, and elevated the expression of microRNA let-7a. Importantly, urolithin A also regulated the Lin28a/let-7a axis in transient HBx-transfected HCC HepG2 cells. Furthermore, urolithin A decelerated the HepG2.2.15 cell invasion, which was involved in suppressing the let-7a downstream factors HMGA2 and K-ras. These findings indicated that urolithin A exerted the antiproliferative effect by regulating the Lin28a/let-7a axis and may be a potential supplement for HBV-infected HCC therapy.