Therapeutic properties of Isoliquiritigenin with molecular modeling studies: Investigation of anti-pancreatic acinar cell tumor and as HMG-CoA reductase inhibitor for treatment of hypercholesterolemia

IntroductionIsoliquiritigenin, one of the components in the root of Glycyrrhiza glabra L., is a member of the flavonoids, which are known to have an anti-tumor activity in vitro and in vivo. HMG-CoA reductase inhibitors, called statins, are used to reduce the risk of heart disease by lowering blood cholesterol levels.Material and methodsHMG-CoA Reductase activity according to the method described by Takahashi S. et al. The structure of human HMG-COA reductase in the resolution of 2.22 Å with X-RAY diffraction method (PDB ID: 1HWK) was obtained from the PDB database.ResultsIn our study, inhibition result of Isoliquiritigenin on HMG-CoA reductase showed lower value IC50 = 193.77±14.85 µg / mL. For a better understanding of biological activities and interactions, the molecular docking study was accomplished. The results of molecular docking revealed that isoliquiritigenin with a docking score of -6.740 has a strong binding affinity to the HMG-COA reductase. Therefore, this compound could be considered as a potential inhibitor for the enzyme. Also, the properties of Isoliquiritigenin against common human pancreatic acinar cell tumor cell lines i.e. 266-6, TGP49, and TGP47 were evaluated.ConclusionsThe treated cells with Isoliquiritigenin were assessed by MTT assay for 48h about the cytotoxicity and anti-human pancreatic acinar cell tumor properties on normal (HUVEC) and human pancreatic acinar cell tumor cell lines i.e. 266-6, TGP49, and TGP47. The IC50 of Isoliquiritigenin were 262, 389, and 211 µg/mL against 266-6, TGP49, and TGP47 cell lines, respectively.

Type 1 polyisoprenoid diphosphate phosphatase modulates geranylgeranyl-mediated control of HMG CoA reductase and UBIAD1

UbiA prenyltransferase domain-containing protein-1 (UBIAD1) utilizes geranylgeranyl pyrophosphate (GGpp) to synthesize the vitamin K2 subtype menaquinone-4. The prenyltransferase has emerged as a key regulator of sterol-accelerated, endoplasmic reticulum (ER)-associated degradation (ERAD) of HMG CoA reductase, the rate-limiting enzyme in synthesis of cholesterol and nonsterol isoprenoids including GGpp. Sterols induce binding of UBIAD1 to reductase, inhibiting its ERAD. Geranylgeraniol (GGOH), the alcohol derivative of GGpp, disrupts this binding and thereby stimulates ERAD of reductase and translocation of UBIAD1 to Golgi. We now show that overexpression of Type 1 polyisoprenoid diphosphate phosphatase (PDP1), which dephosphorylates GGpp and other isoprenyl pyrophosphates to corresponding isoprenols, abolishes protein geranylgeranylation as well as GGOH-induced ERAD of reductase and Golgi transport of UBIAD1. Conversely, these reactions are enhanced in the absence of PDP1. Our findings indicate PDP1-mediated hydrolysis of GGpp significantly contributes to a feedback mechanism that maintains optimal intracellular levels of the nonsterol isoprenoid.

Wogonoside: Anti-human colon cancer activities and survey of HMG-CoA ‎reductase inhibition properties with molecular modeling

IntroductionThe biological activities and interactions of wogonoside in the presence of HMG-COA reductase were investigated using the molecular docking study as a versatile theoretical approach. Wogonoside showed a considerable binding affinity to the enzyme with a docking score of -7.582 kcal/mol.Material and methodsThe in vitro cytotoxic and anti- colon ‎ carcinoma effects of biologically synthesized Wogonoside ‎against GP5d, MDST8‎, HCA-46‎, HT115, LS174T, and COLO 320DM cancer cell lines were ‎assessed.ResultsThe results indicated that the compound makes hydrophobic contacts with essential residues of the catalytic domain of the enzyme. Therefore, wogonosid could be considered as a potential inhibitor for HMG-COA reductase. The IC50 of the Wogonoside were 105, 198, 173, 382, 71, and 183 µg/mL against GP5d, ‎MDST8‎, HCA-46‎, HT115, LS174T, and COLO 320DM cancer cell lines. The anti-colon‎ ‎carcinoma properties of the Wogonoside could significantly remove GP5d, MDST8‎, HCA-46‎, ‎HT115, LS174T, and COLO 320DM cancer cell lines in a time and concentration-dependent ‎manner by MTT assay. ‎ConclusionsIt appears that the anti-human colorectal carcinoma effect of recent nanoparticles is due to their antioxidant effects. We have obtained results for the HMG-CoA Reductase enzyme at the micromolar level. In our study, inhibition result of on HMG-CoA reductase showed lower values 28.70±4.73 micromolar.

A Possible Role for HMG-CoA Reductase Inhibitors and Its Association with HMGCR Genetic Variation in Parkinson’s Disease

Parkinson’s disease (PD) is the second most common neurodegenerative disease characterised by both motor- and non-motor symptoms, including cognitive impairment. The aetiopathogenesis of PD, as well as its protective and susceptibility factors, are still elusive. Neuroprotective effects of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors—statins—via both cholesterol-dependent and independent mechanisms have been shown in animal and cell culture models. However, the available data provide conflicting results on the role of statin treatment in PD patients. Moreover, cholesterol is a vital component for brain functions and may be considered as protective against PD. We present possible statin effects on PD under the hypothesis that they may depend on the HMG-CoA reductase gene (HMGCR) variability, such as haplotype 7, which was shown to affect cholesterol synthesis and statin treatment outcome, diminishing possible neuroprotection associated with HMG-CoA reductase inhibitors administration. Statins are among the most prescribed groups of drugs. Thus, it seems important to review the available data in the context of their possible neuroprotective effects in PD, and the HMG-CoA reductase gene’s genetic variability.

Abnormal Liver Function Test and Statins

Introduction: Statins or 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors are one of the foremost commonly endorsed medications in cardiac patients. A bit like any other lesson of drugs, they have the potential to cause liver harm over time indeed with reasonable utilize. This drug induced liver harm (DILI) can be either coordinate (hepatocellular) or peculiar. As with multiple other hepatic pathologies, DILI may be asymptomatic or clinically quiet. Subsequently, it is judicious to carry out liver work tests (LFTs) from time to time. LFTs are an inexpensive, noninvasive, and fast first-line examination to monitor liver status. Be that as it may, the design of liver damage with statin utilize isn't particular and a relationship over time may not be clear. Objectives: To assess the derangements in Liver function test with regard to statin utilization and decide if there is any correlation exists. Method: Retrospective Observational study conducted in Punjab Institute of Cardiology, Lahore, from 31st July 2020 to 30 June 2021. Data Collection Procedure: This study is conducted at Punjab Institute of cardiology, Lahore, a total of 100 patients admitted from 1st July 2020 to 30 June 2021 with ischemic heart diseases were considered for inclusion as this was retrospective observational cohort study. The patients already taken statin were included in this study. LFTs were noted before the start of statin in their records then during the use of statin at 3rd and 6th month with great care. The collected data was analyzed by using SPSS version 23. Results: A total number of 100 patients were included in this study after inclusion exclusion criteria. The ratio male to female is 3:2.Patients using two types of statin i.e. Atorvastatin 20mg and Rosuvastatin 10mg were included. LFTs elevation was seen in the study. Conclusion: The use of statins clinically proved insignificant elevation of LFTs and hence it is safe to prescribe. Keywords: (HMG-CoA) reductase, Liver finction tests, Statin, LFTs