Search

Mezgebu Legesse Habte,1 Daniel Seifu Melka,2 Maria Degef,2 MKC Menon,2 Helen Yifter,3 Teka Obsa Feyisa1 1Department of Biochemistry, School of Medicine, College of Health and Medical Sciences, Harmaya University, Harar, Ethiopia; 2Department of Medical Biochemistry, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia; 3Department of Medical Endocrinology, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, EthiopiaCorrespondence: Mezgebu Legesse HabteDepartment of Biochemistry, School of Medicine, College of Health and Medical Sciences, Harmaya University, EthiopiaTel +251 934095576Email mezgebulegesse@gmail.comBackground: Diabetes mellitus (DM) is an epidemic disease affecting millions worldwide; the majority being type 2 diabetes mellitus (T2DM). Diabetes mellitus has been shown to be an important risk factor for the development of a variety of cardiovascular diseases, which are becoming common in Ethiopia. Consequently, risk-reducing statin therapy is recommended for nearly all patients with T2DM at 40 years of age or older regardless of cholesterol level. However, some controversies exist regarding its safety.Objective: The aim of this study was to assess and compare the levels of lipid profile, liver enzymes, creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) among T2DM patients on statin therapy.Methodology: A hospital-based cross-sectional study was conducted on a total of 100 T2DM patients. The study participants were divided into four groups consisting of equal numbers of participants (n = 25). Group I, II, and III were T2DM patients who were on statin therapy for 14 days– 6 months, 6– 18 months and ˃18 months, respectively. Group IV consisted of T2DM patients who were not on statin therapy. Convenient sampling technique was implemented till the required number had been achieved. Sociodemographic data was collected by using a standardized questionnaire. Fasting blood was collected and lipid profile, liver enzymes, CK-MB, LDH and fasting blood sugar were analyzed. Data was entered using epi-data and analyzed by one way ANOVA followed by Tukey post hoc multiple comparison tests using SPSS V. 20.00. A P-value < 0.05 was considered statistically significant.Results: The mean values of total cholesterol and TAG were significantly lower among group III as compared to group I (P-values = 0.019 & 0.01). Similarly, LDL-c was significantly lower among group III as compared to group I (P = 0.022) and group IV (P = 0.027). Serum liver enzymes, CK-MB and LDH were not significantly different among the study groups (P > 0.05). The mean values of alanine aminotransferase (ALT) and AST were found within normal range while mean ALP was higher in all study groups. Fasting blood glucose value was not significantly different among the study groups, but higher than normal cut-off value in all groups.Conclusion: Statin therapy taken for a longer time has an effect in lowering total cholesterol, LDL- c and TAG in T2DM patients. Statin therapy has not brought significant change on CK-MB, LDH, liver enzymes and other parameters among T2DM patients.Keywords: CK-MB, HMG-COA reductase, lipid profile, liver enzymes, statin, T2DM, LDH

Abstract Background The HMG-CoA reductase is key enzyme of cholesterol biosynthesis which potentially contributes in management of hypercholesterolemia. The present study was designed to assess the inhibitory effect of phytoconstituents of an ethanolic extract of Prosopis cineraria pods on HMG – CoA reductase and regression potential of atherosclerotic plaque. Methods Healthy, adult male, albino rabbits in which hypercholesterolemia was induced by supplying the high fat diet and a supplement of cholesterol powder with coconut oil (500 mg/5 ml/Day/kg body weight) for 15 days, were used as a disease model. Phytochemical analysis of an ethanolic extract Prosopis cineraria pods was conducted using LCMS, GCMS and FTIR analysis. Further, in-vitro, in-vivo and in-silico assessments were performed. Results The in-vitro assessment of HMG -CoA reductase activity indicated a 67.1 and 97.3% inhibition by the extract and a standard drug (Pravastatin), respectively. Additionally, an in-silico evaluation was made using appropriate docking software and results also indicated as significant interactions of the identified compounds with the target enzyme. Treatment of rabbits with the ethanolic extract of P. cineraria pod resulted in significant (P ≤ 0.001) reductions in total cholesterol, LDL cholesterol, VLDL cholesterol, and triglyceride. Accordingly, reductions were occurred in atherosclerotic plaque, intima and media of aortal wall along with lumen volume of the aorta significantly increased (P ≤ 0.001). Conclusion It can be illustrating that the ethanolic extract of Prosopis cineraria pod contains potent bioactive phytocompounds might be inhibit HMG – CoA reductase and have regression potential of atherosclerotic plaque.

Copyright of Journal of Food Safety & Quality is the property of Journal of Food Safety & Quality Editorial Department and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

This study presents a simple approach in design of tripeptides as a competitive inhibitor for 3-hydroxy-3-methylglutaryl CoA reductase (HMGR). HMGR is a major rate limiting enzyme in cholesterol biosynthesis and therefore constitutes the target enzyme of an extensive research to discover new compounds focused on its inhibition. In previous studies, the two hypocholesterolemic peptides (LPYP and IAVPGEVA) were isolated and identified from soy protein. Based on these peptide sequences, a number of peptides were designed previously by using the correlation between the conformational flexibility and bioactivity. The design method that was applied in previous studies was slightly modified for the purpose of the current research and 5 tripeptides were designed and synthesized. Among the designed tripeptides, YIE showed the highest ability to inhibit HMGR. A kinetic analysis revealed that this peptide is a competitive inhibitor of HMG-CoA with an equilibrium constant of inhibitor binding (Ki) of 0.23 ± 0.03 μM. This is an overall 700-fold increase in inhibitory activity compared to the first isolated LPYP peptide from soybeans. The obtained correlation between the observed and predicted inhibitory activities is good enough in spite of the fact that a different length of peptides was used in the presented design. Statistical analysis suggests that the proposed approach is acceptable in the design of tripeptides. [ABSTRACT FROM AUTHOR]

We recently provided evidence suggesting that mitochondrial aquaporin-8 (mtAQP8), a channel protein able to conduct H 2 O 2 , is involved in the modulation of hepatocyte cholesterogenesis. To expand that study, we cultured human hepatocyte-derived Huh-7 cells in medium with lipoprotein-deficient serum (LPDS) to induce the de novo synthesis of cholesterol and fatty acids. We found that LPDS induced mtAQP8 expression and that AQP8 gene silencing significantly down-regulated the LPDS-induced synthesis of cholesterol and fatty acids as well as the expression of the corresponding key biosynthetic enzymes, 3-hydroxy-3-methylglutaryl-CoA reductase and fatty acid synthase. Our data further support a regulatory role of mtAQP8 in hepatocyte lipid homeostasis. • Hepatocyte mtAQP8 expression and lipid synthesis are induced in LPDS culture medium. • mtAQP8 silencing downregulates LPDS-induced cholesterol and fatty acid synthesis. • mtAQP8 silencing downregulates LPDS-induced HMG-CoA reductase expression. • mtAQP8 silencing downregulates LPDS-induced fatty acid synthase expression. [ABSTRACT FROM AUTHOR]

Conyza blinii H.Lév. is a traditional medicine for the treatment of bronchitis cough. Triterpene saponins (conyzasaponins) are major pharmacological components in C. blinii. Here, two C. blinii genes coding for the important regulatory enzymes of the conyzasaponins biosynthetic pathway, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) and squalene synthase (SQS), were cloned and characterized. The open reading frames of CbHMGR and CbSQS were 1740 bp and 1257 bp in length, respectively. Gene structure display server analysis revealed that there were four introns in the gDNA of CbHMGR and no intron in the gDNA of CbSQS. The analyses of their deduced amino acid sequences showed that these two genes had the typical domains shown in homologous proteins. The phylogenetic relationship between the two genes and their homologous genes were consistent with their natural evolution. The GCMS results of enzymatic activity assays showed that CbHMGR catalysed the formation of mevalonate from HMG-CoA. CbSQS catalysed the synthesis of squalene with farnesyl diphosphate as a substrate. These findings will provide a sound base for further research on the conyzasaponins biosynthetic pathway and may have applications in the synthetic biology of conyzasaponins production. [ABSTRACT FROM AUTHOR]

Mono‐ and sesquiterpenoids are the main chemical constituents of essential oils. Essential oils and their constituents have received increasing attention for lipid‐lowering properties in both cell and animal models. Despite the chemical diversity of essential oil compounds, the effects of many of these compounds on cholesterol metabolism are highly similar. In this report, we review the literature regarding the effects of essential oils and their terpenoid constituents on cholesterol homeostasis, and explore likely mechanisms using protein–ligand docking. We identified 98 experimental and seven clinical studies on essential oils, isolated compounds, and blends; 100 of these described improvements either in blood cholesterol levels or in sterol metabolic pathways. Our review and docking analysis confirmed two likely mechanisms common to many essential oil compounds: (1) direct agonism of peroxisome‐proliferator‐activated receptors, and (2) direct interaction with sterol‐sensing domains, motifs found in key sterol regulatory proteins including sterol regulatory element binding protein cleavage activating protein and HMG‐CoA reductase. Notably, these direct interactions lead to decreased transcription and accelerated degradation of HMG‐CoA reductase. Our work suggests that terpene derivatives in essential oils have cholesterol‐lowering activity and could potentially work synergistically with statins, however, further high quality studies are needed to establish their clinical efficacy. [ABSTRACT FROM AUTHOR]

When a yeast cell runs out of fuel, it can increase the flux through a central metabolic pathway by simply changing the location of an enzyme.

Eukaryotes compartmentalize metabolic pathways into sub-cellular domains, but the role of inter-organelle contacts in organizing metabolic reactions remains poorly understood. Here, we show that in response to acute glucose restriction (AGR) yeast undergo metabolic remodeling of their mevalonate pathway that is spatially coordinated at nucleus-vacuole junctions (NVJs). The NVJ serves as a metabolic platform by selectively retaining HMG-CoA Reductases (HMGCRs), driving mevalonate pathway flux in an Upc2-dependent manner. Both spatial retention of HMGCRs and increased mevalonate pathway flux during AGR is dependent on NVJ tether Nvj1. Furthermore, we demonstrate that HMGCRs associate into high-molecular-weight assemblies during AGR in an Nvj1-dependent manner. Loss of Nvj1-mediated HMGCR partitioning can be bypassed by artificially multimerizing HMGCRs, indicating NVJ compartmentalization enhances mevalonate pathway flux by promoting the association of HMGCRs in high molecular weight assemblies. Loss of HMGCR compartmentalization perturbs yeast growth following glucose starvation, indicating it promotes adaptive metabolic remodeling. Collectively, we propose a non-canonical mechanism regulating mevalonate metabolism via the spatial compartmentalization of rate-limiting HMGCR enzymes at an inter-organelle contact site.

Hypercholesterolemia is a serious condition that may lead to coronary heart disease, heart attack and stroke raising the rate of morbidity and mortality in hypocholesterolemic patients. Statins are one of the largest selling drugs for hypercholesterolemia. They serve as potential competitive inhibitors of HMG-CoA reductase that catalyzes the rate-limiting step of cholesterol biosynthesis cascade. They can be broadly classified into fermentation-derived, semisynthetic and synthetic statins. For the current study, synthetic statins like fluvastatin, cerivastatin, rosuvastatin were subjected to in silico analysis for their competitive binding with HMG-CoA reductase through molecular docking. The molecular interaction between HMG-CoA reductase with statins and their ADMET properties were studied using Maestro suite of Schrödinger software. The results of molecular docking depicted that fluvastatin had the highest docking score while that of rosuvastatin was the least. The prediction of pharmacokinetics of drug performed by QikProp also pointed the efficacy of fluvastatin as a potent inhibitor for HMG-CoA reductase enabling it to be an effective drug to treat hypercholesterolemia among the three synthetic statins. [ABSTRACT FROM AUTHOR]

Monascus purpureus is known to produce pigment molecules. The pigments were extracted from M. purpureus fermented rice. In-vitro antioxidant effects of pigments were observed and presumed to alleviate oxidative stress related atherosclerosis effect in rats fed with high fat diet (HFD) for 14 weeks. The formation of lipid peroxide due to the oxidation of serum lipid was higher in rats fed with HFD. While, the feeding of fermented rice (groups III-V) significantly lowered the formation of lipid peroxide (27.1–51.7%) in serum of rats, indicated antioxidative effect of pigments. In addition, feeding of fermented rice lowered serum cholesterol and triacylglycerol by 44.82 and 45.30%, respectively. Whereas, LDL-cholesterol levels were decreased by 70.12% and HDL-cholesterol increased by 34.58%. The atherogenic indices (LDL/HDL and TC/HDL) were reduced by 77.80 and 61.05%, respectively, in rats fed with fermented rice. These data confirmed the anti-atherosclerotic effect of pigments. Further liver enzyme, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity was significantly inhibited up to 54%. The identification of statins, sterols and fatty acids in fermented rice revealed the HMG-CoA reductase inhibitory activity. This was confirmed by synthesis of lower levels of cholesterol and triacylglycerol in liver of rats fed with fermented rice. Accordingly antioxidant, inhibition of HMG-CoA reductase, anti-atherogenic functions of M. purpureus fermented rice is attributed to the collective effect of bioactive metabolites.

Statins, as the most important cholesterol-lowering agents, inhibit the production of blood cholesterol by blocking an enzyme called the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-COA) reductase. Statins have beneficial effects in some tissues during various injuries. Recent evidence suggests that unlike the beneficial effects of statins, administration of high doses of these drugs may increase renal impairment, although more research is needed in this regard. Therefore, this study aimed to evaluate the possible effect of different doses of statins on the morphology and function of the kidney tubular cells.

Recently, targeting metabolic reprogramming has emerged as a potential therapeutic approach for fighting cancer. Sterol regulatory element binding protein-2 (SREBP-2), a basic helix-loop-helix leucine zipper transcription factor, mainly regulates genes involved in cholesterol biosynthesis and homeostasis. SREBP-2 binds to the sterol regulatory elements (SREs) in the promoters of its target genes and activates the transcription of mevalonate pathway genes, such as HMG-CoA reductase (HMGCR), mevalonate kinase and other key enzymes. In this review, we first summarized the structure of SREBP-2 and its activation and regulation by multiple signaling pathways. We then found that SREBP-2 and its regulated enzymes, including HMGCR, FPPS, SQS, and DHCR4 from the mevalonate pathway, participate in the progression of various cancers, including prostate, breast, lung, and hepatocellular cancer, as potential targets. Importantly, preclinical and clinical research demonstrated that fatostatin, statins, and N-BPs targeting SREBP-2, HMGCR, and FPPS, respectively, alone or in combination with other drugs, have been used for the treatment of different cancers. This review summarizes new insights into the critical role of the SREBP-2-regulated mevalonate pathway for cancer and its potential for targeted cancer therapy.

Numerous and different types of cancers possess the dysregulation of the mevalonate pathway as a common feature. Statins, traditionally applied in cardiovascular diseases to reduce lipid levels, subsequently have been discovered to exhibit anti-cancer activities also. Indeed, statins influence proliferation, migration, and survival of cancer cells by regulating crucial signaling proteins, such as Rho, Ras, and Rac. Recently, several studies have demonstrated that simvastatin, fluvastatin, and lovastatin are implicated in different pathways that enhance the survival time of patients with cancer under treatment in combination with antineoplastic agents. In this minireview, we present an overview of the most important studies conducted regarding the use of statins in cancer therapy up to date.

The recent increase in azole-resistant Aspergillus fumigatus is a global concern. Identifying the mutations that confer azole resistance is essential for developing novel methods for prompt diagnosis and effective drug treatment. We screened A. fumigatus clinical isolates for novel mutations conferring azole resistance. We compared the genomic sequences of susceptible and resistant isolates without mutations in cyp51A (non-cyp51A) and found mutations in hmg1 and erg6 involved in ergosterol biosynthesis. We also found the novel mutations in these genes in azole-resistant isolates with different genetic backgrounds. The resistant isolates with mutations in hmg1 showed increased intracellular ergosterol levels compared with susceptible isolates. This finding supports the concept that the ergosterol level is a determinant for resistance to any class of azoles. Multiple isolates with increased resistance to azole possessed a mutation in hmg1, indicating that this mutation is widely present in non-cyp51A azole-resistant A. fumigatus.

Abstract Background For decades, various cardiovascular symptoms have been relieved by the use of Ya-Hom Navakot, which is a formulation comprising 54 herbal medicines. The Thailand Ministry of Public Health listed Ya-Hom Navakot’s nine active principle and nomenclative herbal ingredients and termed them ‘Phikud Navakot’ (PN). Several reports have confirmed that PN has cardiovascular benefits similar to Ya-Hom Navakot. However, whether PN facilitates lipid-lowering activity remains unclear. Methods The present study investigated an in vitro model for examining the gene expression levels of 3-hydroxyl-3-methylglutaryl-CoA reductase (HMGCR) and low-density lipoprotein receptor (LDL-R) in HepG2 cells using qRT-PCR. The ethanol and water extractions of Ya-Hom Navakot, PN and Ya-Hom Navakot without PN were compared. Results One mg/ml of both NYEF and NYWF were found to significantly lower cholesterol by either the up-regulation of LDL-R or down-regulation of HMGCR compared with negative controls and 1 mg/ml simvastatin (p

Cymbopogon citratus (DC) Stapf., commonly known as lemongrass, possesses strong antioxidant and cardiotonic properties. Lemongrass water extract contains several polyphenolic compounds including gallic acid, isoquercetin, quercetin, rutin, catechin and tannic acid. Rutin, isoquercetin catechin and quercetin are the flavonoids most abundantly found in the extract. The extract significantly decreased total cholesterol, low-density lipoprotein and atherogenic index in rats after treatment (p < 0.05). Expression of genes and protein of sterol regulatory element binding protein-1c (SREBP1c) and HMG-CoA reductase (HMGR) was also lowered significantly in treated groups (p < 0.05). Moreover, serum antioxidant capacity increased in treated rats in comparison with untreated ones (p < 0.05) and was associated with decreased serum lipid peroxidation.

Introduction: Zingiber officinale Roscoe, commonly known as ginger, is used as a cooking spice and therapeutically for its antioxidant and androgenic activities. We investigated the effects of Z. officinale hydro-alcoholic extract on HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase level in the testis of streptozotocin (STZ)-induced diabetic rats. Methods: The current experimental study was performed on four groups of male Wistar rats one of them was kept as a healthy control, while the others were rendered diabetic via a single intraperitoneal injection of STZ (60 mg kg-1). One group was considered as diabetic control; while the others were given orally hydro-alcoholic extract (200 and 400 mg kg-1) for 56 consecutive days. Body weight, blood glucose and insulin concentrations were evaluated using standard methods. The HMG-COA reductase level was determined by western blot analysis. Results: Treatment with the extract resulted in a significant reduction of serum glucose concentration and HMG-COA reductase level in the rat’s testis compared to diabetic controls (P < 0.01). A significant increase in body weight was observed in treated diabetic rats. Also, serum insulin was significantly increased in diabetic rats treated with 400 mg/kg of the extract compared to diabetic controls (P < 0.05). Conclusion: Ginger has a potential influence on the regulation of cholesterol homeostasis by modulating of HMG-COA reductase level. The results provide scientific evidence to confirm the traditional use of Z. officinale in the treatment of diabetes mellitus.

Disruption of the intracellular lipid balance leading to cholesterol accumulation is one of the features of cells that participate in the development of atherosclerotic lesions. Evidence form our laboratory indicates that anti-inflammatory cyclopentenone prostaglandins (cyPGs) of A- and J-family deviate lipid metabolism from the synthesis of cholesterol and cholesteryl esters to the synthesis of phospholipids in foam-cell macrophages. cyPGs possessing an α,β-unsaturated cyclopentane ring are highly electrophilic substances able to promptly react with reactive cysteines of intracellular molecules through Michael addition. On the other hand, HMG-CoA reductase (HMGCR), the enzyme responsible for the rate-limiting step in cholesterol biosynthesis, presents critically reactive cysteines at the entry of catalytic domain, particularly Cys561, that could be target of cyPG inhibition. In the present study, we showed that cyPGs (but not other non-α,β-unsaturated PGs) physically interact with HMGCR, in a dithiothreitol- and β-mercaptoethanol-sensitive way, and block the activity of the catalytic subunit of the enzyme (IC 50 for PGA 2 = 0.17 μM). PGA 2 inhibits HMGCR activity in cultured rat and human macrophages/macrophage-foam cells and leads to enhanced expression of HMGCR protein, as observed with statins. In cell culture models, PGA 2 effectively inhibits the reductase at non-toxic doses (e.g. , 1 μM) that block cell proliferation thus suggesting that part of the well-known antiproliferative effect of PGA 2 may be due to its ability of blocking HMGCR activity, as cells cannot proliferate without a robust cholesterogenesis. Therefore, besides the powerfully anti-inflammatory and antiproliferative effects, the anticholesterogenic effects of PGA 2 should be exploited in atherosclerosis therapeutics. Image 1 • Cyclopentenone prostaglandins (cyPGs) modulate lipid metabolism in atherosclerosis. • The cyPG PGA 2 physically interacts with HMG-CoA reductase blocking cholesterogenesis. • Part of PGA 2 antiproliferative effect could be due to its action on the reductase. • Anticholesterogenic effects of PGA 2 should be exploited in atherosclerosis therapy. [ABSTRACT FROM AUTHOR]

Sanghuangporus baumii (Pilát) (Zhou and Dai), a traditional Chinese medicinal fungus, has been confirmed to produce triterpenoids, which possess a good anti-cancer effect. However, the triterpenoids yield of S. baumii is low and its biosynthetic mechanism is not clearly understood. To investigate the triterpenoids biosynthetic mechanism, the whole cDNA sequence of the HMG-CoA reductase (HMGR) gene was obtained. The open reading frame of HMGR gene cDNA named SbHMGR, comprised 4170 bp, encoding a polypeptide of 1389 amino acids with a predicted protein molecular weight of 147.53 kDa. The HMGR gene includes four exons and three introns. Subsequently, the triterpenoids content was determined at different developmental stages of S. baumii. It showed a dynamic tendency—increased first, then decreased and peaked on 14th day in the mycelium stage. In addition, the changing trend of SbHMGR enzyme activity and transcript level of SbHMGR gene were measured. They were nearly consistent with the triterpenoids content, suggesting that SbHMGR gene may play a key regulatory role in triterpenoids biosynthetic pathway. Similarly, changes in the transcript level of downstream key genes (SbMVD, SbIDI, SbLSD) of SbHMGR gene were also positively correlated with the triterpenoids content, indicating those three genes were also involved in triterpenoids biosynthetic pathway. Moreover, SbHMGR gene had been observed to be expressed in prokaryote. The results will be valuable for elucidation of the biosynthetic pathway of triterpenoids in S. baumii, lay a foundation for genetic modifications to improve triterpenoids yield. [ABSTRACT FROM AUTHOR]

In this study, the physicochemical properties, pharmacokinetics properties, and drug-likeness of pigments from Monascus-fermented rice (Monascus pigments, MPs) were predicted in silico using SwissADME tool. In silico prediction of physicochemical properties showed that MPs had desirable lipophilic drug-like physicochemical properties including molecular weight (236 to 543), TPSA (44.76 to 179.77), lipophilicity (-0.81 to 4.14), and water solubility (-4.94 to -0.77). The pharmacokinetic properties of MPs (i.e., GIA, P-glycoprotein substrate, and CYP3A4 inhibitor) illustrated that most MPs had high intestinal absorption and bioavailability, but some MPs might cause pharmacokinetics-related drug--drug interactions. Following this, six main well-known MPs (monascin, ankaflavin, rubropunctatin, monascorubrin, rubropunctamine, monascorubramine) were selected for molecular docking with some enzyme receptors. The docking results were shown with the best molecular docking poses, and the interacting residues, number and distance of hydrogen bonds of the MPs and monacolin K (for docking with 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMG-CoA reductase)), or MPs and oleic acid (for docking with lipase). Dissociation constants showed that MPs had lower inhibitory potential for HMGR (compared with Monacolin K), and higher inhibitory potential for lipase. Individual pigments from Monascus-fermented rice, therefore, have the potential to be developed as drug candidates for controlling hyperlipidemia. [ABSTRACT FROM AUTHOR]

Sterol synthesis is a highly complex and integrated pathway in mammals. In the present review, we briefly summarize the main steps of this pathway, especially concerning its main rate-limiting enzymes, HMG-CoA reductase (HMGCR) and squalene epoxidase (SQLE), in relation with cancer. We focus on studies reporting key findings linking cholesterol with cancer. The inhibition of HMGCR and SQLE to prevent and inhibit cancer are reviewed. Finally, a pan-cancer review of publicly available data on genomic aberrations in the main enzymes involved in sterol biosynthesis and their transcription factors is reported, providing hitherto unexplored findings that may be the subject of future research in cancer metabolomics and tumor targeted treatment. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases (CVDs) are one of the most important causes for mortality worldwide. Elevated levels of total cholesterol, and particularly LDL‐cholesterol (LDL‐C) are the main risk factor for acute myocardial infarction (AMI) and ischemic heart disease. The risk of CVDs could be reduced by decreasing the elevated cholesterol levels. β‐hydroxy β‐methylglutaryl‐CoA reductase (HMGCoAR) is the primary and rate‐limiting enzyme in the cholesterol biosynthesis pathway. Recently, the crucial role of nutraceuticals in maintaining normal physiological function was established. Nutraceuticals play an important role in preventing several non‐communicable diseases such as obesity, CVDs, cancer, diabetes, and reducing hyperlipidemia. Although the effect of nutraceuticals and herbal medicine on CVDs and dyslipidemia was previously investigated thoroughly, the effect of these natural products on HMGCoAR as one of the important enzymes involved in CVDs etiopathogenesis has not yet been investigated. Therefore, the major aim of this paper was to review the effects of nutraceuticals and medicinal plants on HMGCoAR. Results indicate that different types of natural foods, isolated nutrients, herbal products, and dietary supplements as nutraceuticals decrease the expression and activity of HMGCoAR. This review shows that medicinal plants and nutraceuticals could be used to decrease HMGCoAR activity as accessible and convenient and economical natural compounds to prevent dyslipidemia and CVDs. [ABSTRACT FROM AUTHOR]

To investigate the effects of oral administration of probiotics consortium on lipid metabolism in aflatoxin B1 (AFB1) exposed rats, ninety female albino rats were first grouped into two: NC (control fed standard feed) and AF (fed AFB1-contaminated feed at 40 ppb). After eight weeks, baseline animals were sacrificed from both groups while the others further divided into four groups - NC treated with and without the probiotics consortium, aflatoxin treated with and without the probiotics consortium (NCT, NCC, AFT, and AFC respectively). Five animals from each group were sacrificed weekly for four weeks, with the collection of blood, liver, brain, and the small intestine. Administration of probiotics instigated significant (p < 0.05) reductions in the elevated plasma and organ lipids as well as HDL-TAG and VLDL + LDL CHO concentrations of animals exposed to AF. AF-induced hepatic lipogenesis and up-regulation of 3-hydroxy-3-methylglutaryl-CoA reductase activity were also significantly (p < 0.05) attenuated following treatment with probiotics in a time-dependent manner. Moreover, neither AF nor probiotics had any effect on glycerol-3-phosphate acyltransferase. Lipid peroxidation was significantly (p < 0.05) reduced in probiotics-treated AF groups, compared to the AF-control groups. This study indicates that the probiotic consortium used synergistically ameliorated the AFB1-induced disruptions in lipid metabolism. Image 1 • Perturbations in blood and organs lipid contents are hallmarks of aflatoxicosis. • These perturbations were mainly characterized by elevations in the lipid contents. • The four lactobacilli consortium synergistically reduced the lipid concentrations. • The probiotics also reduced the elevated activities of lipid-biosynthesizing enzymes. [ABSTRACT FROM AUTHOR]

Statins, as the most important cholesterol-lowering agents, inhibit the production of blood cholesterol by blocking an enzyme called the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-COA) reductase. Statins have beneficial effects in some tissues during various injuries. Recent evidence suggests that unlike the beneficial effects of statins, administration of high doses of these drugs may increase renal impairment, although more research is needed in this regard. Therefore, this study aimed to evaluate the possible effect of different doses of statins on the morphology and function of the kidney tubular cells. [ABSTRACT FROM AUTHOR]

Recently, targeting metabolic reprogramming has emerged as a potential therapeutic approach for fighting cancer. Sterol regulatory element binding protein-2 (SREBP-2), a basic helix-loop-helix leucine zipper transcription factor, mainly regulates genes involved in cholesterol biosynthesis and homeostasis. SREBP-2 binds to the sterol regulatory elements (SREs) in the promoters of its target genes and activates the transcription of mevalonate pathway genes, such as HMG-CoA reductase (HMGCR), mevalonate kinase and other key enzymes. In this review, we first summarized the structure of SREBP-2 and its activation and regulation by multiple signaling pathways. We then found that SREBP-2 and its regulated enzymes, including HMGCR, FPPS, SQS, and DHCR4 from the mevalonate pathway, participate in the progression of various cancers, including prostate, breast, lung, and hepatocellular cancer, as potential targets. Importantly, preclinical and clinical research demonstrated that fatostatin, statins, and N-BPs targeting SREBP-2, HMGCR, and FPPS, respectively, alone or in combination with other drugs, have been used for the treatment of different cancers. This review summarizes new insights into the critical role of the SREBP-2-regulated mevalonate pathway for cancer and its potential for targeted cancer therapy. [ABSTRACT FROM AUTHOR]

Cholesterol is an essential component of mammalian membranes, and its homeostasis is strictly regulated, with imbalances causing atherosclerosis, Niemann Pick disease, and familial hypercholesterolemia. Cellular cholesterol supply is mediated by LDL-cholesterol import and de novo cholesterol biosynthesis, and both pathways are adjusted to cellular demand by the cholesterol-sensitive SREBP2 transcription factor. Cholesterol homeostasis is modulated by a wide variety of metabolic pathways and the ubiquitination machinery, in particular E3 ubiquitin ligases. In this article, we review recent progress in understanding the role of E3 ubiquitin ligases in the metabolic control of cellular sterol homeostasis. [ABSTRACT FROM AUTHOR]

One of the pathways to reduce cholesterol production in the liver is through the inhibition of HMG-Coa reductase (HMGCR) by current drugs, statins. However, these have side effects if consumed in prolonged periods. Tangeretin and trans-ethyl caffeate as alternative drugs in reducing hypercholesterolemia and preventing atherosclerosis have never been reported. Their effects on inhibiting HMGCR activity were investigated through enzymatic method (in vitro and in vivo). The toxicity property was analyzed on the Serum Glutamate Oxalate Transaminase (SGOT)/Serum Glutamate Piruvate Transaminase (SGPT) levels and rat liver histology. The results showed that both compounds inhibited HMGCR activity significantly compare to the control simvastatin (p < 0.05). Tangeretin which showed very good activity in inhibiting HMGCR (83.8 of % inhibition, equal to simvastatin) was selected and used for anti-hypercholesterolemia in vivo assessment. Furthermore, tangeretin was shown to effectively reduced Total Cholesterol (TC) and Low Density Lipoprotein (LDL), and increased High Density Lipoprotein (HDL) levels significantly compared to the simvastatin group (p < 0.05). Tangeretin group was also proven to inhibit HMGCR rat liver activity significantly compare to the control simvastatin (p < 0.05). The toxicity study on the SGOT/SGPT levels and liver histology revealed that there were no side effects after administration by tangeretin. Results found that both tangeretin and trans-ethyl caffeate are potent candidates as anti-hypercholesterolemia agent in vitro. In addition, tangeretin was also shown to be safe and suitable as an alternative treatment for controlling hypercholesterolemia in vivo as well as have potency for preventing atherosclerosis. [ABSTRACT FROM AUTHOR]

Background: HMG-CoA reductase inhibitors, are large used lipid lowering medical that are effective in the functions of male reproductive. In addition, Metformin is affected on level of cholesterol that results in production of sperm. This study was designed to evaluate whether influence of simvastatin, metformin alone and combination in male rats. Methods: In this experiment 24 adult male rats were randomly divided into four groups (n=6) as following: control group (G1). 2nd group(G2)20 mg/kg simvastatin. 3rd group(G3) 150mg/kg of metformin. 4th group (G4) 150mg/kg metformin + 20m/kg simvastatin. The administration rout by oral gavage for 40 days. Results: There is a significant increase (P≤0.05) in blood parameters, HDL cholesterol, blood glucose, total protein and sperm abnormality in treated groups. Histopathological study of testes reveals degeneration, vacuolation of germinal epithelium, destruction the wall of some seminiferous tubules. Liver tissue shows dilated, congested sinusoid, vacuolation of hepatocytes and central vein congestion, on the other hands, kidney reveals a vacuolation of some epithelial lining of glomeruli and renal tubules, atrophy of some glomeruli and dilation of bowman's capsules. Conclusion: Simvastatin have a better effect on lipid profile. On the other hands, have more effects on testicular function. [ABSTRACT FROM AUTHOR]

In the present study, ergosteryl-ferulate (5), oryzanol analog was evaluated for its possibility as the inhibitor of HMG-CoA reductase (HMGR), through in silico and in vitro approach. Firstly, the study was conducted through molecular docking simulation using AutoDock Tools software to predict the interaction of 5 in complexes with HMGR. In addition, four major compounds of oryzanol (1-4) were employed as a comparison. Secondly, 5 was synthesized through esterification using thionyl chloride as an activator. Lastly, 5 was evaluated for its capacity to inhibit HMGR activity using HMGR assay kit. Molecular docking simulation results suggest that oryzanol (1-4) and 5 exhibited a binding affinity against HMGR. The activity of 5 was predicted to be the best among the oryzanol compounds (1-4), in which, the free binding energy and inhibition constant were -4.17 kcal/mol and 0.88mM. The in vitro assay showed that 5 had inhibitory activity against HMGR 1.93 times higher than oryzanol. In summary, 5 has more potential candidates for HMGR inhibitor than oryzanol. [ABSTRACT FROM AUTHOR]

In a multicenter study, we determined a prevalence rate of 4% for azole-resistant Aspergillus fumigatus in Taiwan. Resistance emerged mainly from the environment (TR34/L98H, TR34/L98H/S297T/F495I, and TR46/Y121F/T289A mutations) but occasionally during azole treatment. A high mortality rate observed for azole-resistant aspergillosis necessitates diagnostic stewardship in healthcare and antifungal stewardship in the environment. [ABSTRACT FROM AUTHOR]

In a multicenter study, we determined a prevalence rate of 4% for azole-resistant Aspergillus fumigatus in Taiwan. Resistance emerged mainly from the environment (TR34/L98H, TR34/L98H/S297T/F495I, and TR46/Y121F/T289A mutations) but occasionally during azole treatment. A high mortality rate observed for azole-resistant aspergillosis necessitates diagnostic stewardship in healthcare and antifungal stewardship in the environment. [ABSTRACT FROM AUTHOR]

The sterol biosynthesis pathway of Leishmania spp. is used as a pharmacological target; however, available information about the mechanisms of the regulation and remodeling of sterol-related genes is scarce. The present study investigated compensatory mechanisms of the sterol biosynthesis pathway using an inhibitor of HMG-CoA reductase (simvastatin) and by developing drug-resistant parasites to evaluate the impact on sterol remodeling, cross-resistance, and gene expression. Simvastatin-resistant L. amazonensis parasites (LaSimR) underwent reprogramming of sterol metabolism manifested as an increase in cholestane- and stigmastane-based sterols and a decrease in ergostane-based sterols. The levels of the transcripts of sterol 24-C-methyltransferase (SMT), sterol C14-α-demethylase (C14DM), and protease subtilisin (SUB) were increased in LaSimR. LaSimR was cross-resistance to ketoconazole (a C14DM inhibitor) and remained sensitive to terbinafine (an inhibitor of squalene monooxygenase). Sensitivity of the LaSimR mutant to other antileishmanial drugs unrelated to the sterol biosynthesis pathway, such as trivalent antimony and pentamidine, was similar to that of the wild-type strain; however, LaSimR was cross-resistant to miltefosine, general serine protease inhibitor N-p-tosyl-l-phenylalanine chloromethyl ketone (TPCK), subtilisin-specific inhibitor 4-[(diethylamino)methyl]-N-[2-(2-methoxyphenyl)ethyl]-N-(3R)-3-pyrrolidinyl-benzamide dihydrochloride (PF-429242), and tunicamycin. The findings on the regulation of the sterol pathway can support the development of drugs and protease inhibitors targeting this route in parasites.

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase is a key enzyme involved in cholesterol biosynthesis and one of the most important targets for the treatment of hypercholesterolemia. A limited number of studies on the HMG-CoA reductase inhibitory potential of natural products are available. Thus, in the current study, we aimed to test the HMG-CoA reductase inhibitory capacity of extracts from the roots and aerial parts of Salvia multicaulis Vahl., through activity-guided isolation. Our findings revealed that the root extract prepared with dichloromethane–acetone (1:1) showed the highest inhibition (71.97 ± 0.37%) at 100 µg/mL. The extract was then initially fractionated by column chromatography and the obtained fractions were monitored by thin layer chromatography. Fractions which were similar to each other were combined and a total of 15 fractions were obtained. Further conventional chromatographic studies were carried out on the active fractions. Based on these fractions, 10 known compounds, comprising 9 terpenes and 1 steroid derivative in total, were isolated and their structures were verified by a combination of IT-TOF-MS, and 1D and 2D NMR techniques. According to the enzyme inhibition data of the identified compounds, 7-acetoxyhorminone exerted the highest inhibition (84.15 ± 0.10%, IC50 = 63.6 ± 1.21 µg/mL). The molecular docking experiments on 7-acetoxyhorminone and horminone indicated that both compounds strongly bind to the active site of the enzyme.

HMG-CoA (3-hydroxy-3-methyl glutaryl coenzyme A) reductase inhibitors are associated with muscle injury. Chronic kidney disease (CKD) carries a high risk for the development of statin-induced myopathy. Statin therapy decreases the absolute risk of cardiovascular diseases in patients with CKD; however, rhabdomyolysis increases with deteriorating kidney function. [ABSTRACT FROM AUTHOR]

Aster glehni F. Schmidt (AG), is a natural product known to have anti-obesity effects, but the mechanism underlying these effects is not well documented. We hypothesized that AG may have inhibitory effects on enzymes related to lipid accumulation. Herein, AG fractions were tested against HMG-CoA reductase (HMGR) and fatty acid synthase (FAS), two important enzymes involved in cholesterol and fatty acid synthesis, respectively. We found that dicaffeoylquinic acid (DCQA) methyl esters present in AG are largely responsible for the inhibition of HMGR and FAS. Since free DCQA is a major form present in AG, we demonstrated that a simple methylation of the AG extract could increase the overall inhibitory effects against those enzymes. Through this simple process, we were able to increase the inhibitory effect by 150%. We believe that our processed AG effectively modulates the HMGR and FAS activities, providing promising therapeutic potential for cholesterol- and lipid-lowering effects.

Miglė Paškevičiūtė,1 Vilma Petrikaitė1,21Department of Drug Chemistry, Faculty of Pharmacy, Lithuanian University of Health Sciences, Kaunas, Lithuania; 2Department of Biothermodynamics and Drug Design, Vilnius University Institute of Biotechnology, Vilnius, LithuaniaPurpose: To evaluate the anticancer activity of lovastatin (LOVA), mevastatin (MEVA), pitavastatin (PITA), and simvastatin (SIMVA) in 2D and 3D models of three human pancreatic cancer cell lines (BxPC-3, MIA PaCa-2, and PANC-1).Methods: The effect of statins on cell viability was estimated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test. The activity of statins in 3D pancreatic cancer cell cultures was examined by measuring the size change of spheroids. The type of cell death was identified by cell staining with Hoechst 33342 and propidium iodide. The activity of statins on the clonogenicity of cancer cells was tested by evaluating the effect on the colony-forming ability of cells.Results: The rank order of the activity of tested statins on cell viability was as follows: PITA > SIMVA > LOVA > MEVA. Among the tested statins, PITA had the greatest effect on cell viability (half maximal effective concentration values after 72 h on BxPC-3, MIA PaCa-2, and PANC-1 cells were 1.4±0.4 µM, 1.0±0.2 µM, and 1.0±0.5 µM, respectively). PITA also showed the strongest effect on tumor spheroid growth. Statins suppressed the colony formation of cancer cells. PITA demonstrated the greatest reduction in colony size and number. Apoptosis and necrosis assay results showed that at lower concentrations statins mostly induced cell death through apoptosis, whereas higher concentrations of compounds activated also necrotic processes.Conclusion: Statins, especially PITA, demonstrate an anticancer activity against pancreatic cancer cell lines BxPC-3, MIA PaCa-2, and PANC-1 in both 2D and 3D models.Keywords: HMG-CoA reductase, cell viability, spheroid, apoptosis

In this study, we attempt to find out whether chronic low dose 3-Iodothyronamine (an endogenous metabolite of thyroid hormone) administration could modulate liver de novo cholesterol synthesis, the same as thyroid hormones. Eighteen male mice were divided randomly into treatment (n=10) and control (n=8) groups. The experimental procedure was applied for 7 days during which test group received T1AM whereas the control group received dimethyl sulfoxide and normal saline. The liver was analyzed for HMG-CoA reductase concentration and hepatic lipase activity whiles cholesterol, LDL and HDL concentrations were measured in the blood serum. There was non-significant decrease in HMG-CoA reductase concentration (224±21.2 versus 187±32.5) in test group compared to control. Interestingly LDL and cholesterol concentrations exhibited significant decrease in test group versus the control. There was non-significant decrease in hepatic lipase activity (771±316 versus 645±317) in test group versus the control. It appears that T1AM reduced serum LDL and cholesterol just like T3, in contrast, it decreased liver cholesterol biosynthesis contrary to THs.

Premna integrifolia Linn. is a medicinal plant used in “Dhasamula” drug preparation of Ayurvedic systems of medicine in the treatment of various ailments like bronchitis, dyspepsia, liver disorders, piles, constipation, hyperlipidemia and fever. The anti-atherosclerotic activity of hydroalcoholic extract (HAE) of root bark of P. integrifolia was evaluated in high fat diet induced atherosclerosis rats. Sixty Wistar rats were divided into six groups: the first group served as control, the second group was fed with high fat diet and the other three groups were fed with high fat diet along with various concentrations of HAE and the last group was treated with atorvastatin for 30 days. Lipid and lipoprotein profile, atherogenic index, and cardiac markers and histopathological evaluation of aorta were determined in high fat diet induced atherosclerosis rats. HAE of P. integrifolia produced a significant and dose-dependent anti-atherosclerotic activity in terms of reduction in lipids and lipoprotein profile, atherogenic index, HMG-CoA reductase activity, marker enzymes such as lactate dehydrogenase (LDH), creatine phosphokinase (CPK), aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP), alteration in collagen and calcium contents, mild mineralization and focal rupture of intima and media of aorta was noticed in treated groups as compared to the control. The results suggested that anti-atherosclerotic activity of HAE of P. integrifolia Linn. was due to its modulatory activity on metabolic pathway of lipid. The results contribute to the validation of the traditional use of Agnimantha in high fat diet induced atherosclerosis rats.

ABSTRACT Aspergillus fumigatus is the predominant pathogen of invasive aspergillosis, a disease state credited with over 200,000 life-threatening infections each year. The triazole class of antifungals are clinically essential to the treatment of invasive aspergillosis, both as frontline and as salvage therapy. Unfortunately, resistance to the triazoles among A. fumigatus isolates is now increasingly reported worldwide, and a large proportion of this resistance remains unexplained. In this work, we characterize the contributions of previously identified mechanisms of triazole resistance, including mutations in the sterol-demethylase-encoding gene cyp51A, overexpression of sterol-demethylase genes, and overexpression of the efflux pump-encoding gene abcC, among a large collection of highly triazole-resistant clinical A. fumigatus isolates. Upon revealing that these mechanisms alone cannot substantiate the majority of triazole resistance exhibited by this collection, we subsequently describe the identification and characterization of a novel genetic determinant of triazole resistance. Mutations in the 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase-encoding gene, hmg1, were identified in a majority of triazole-resistant clinical isolates in our collection. Introduction of three different hmg1 mutations, predicted to encode residue alterations in the conserved sterol sensing domain of Hmg1, resulted in significantly increased resistance to the triazole class of agents. Additionally, correction of a hmg1 mutation in a pan-triazole-resistant clinical isolate of A. fumigatus with a novel Cas9-ribonucleoprotein-mediated system was shown to restore clinical susceptibility to all triazole agents. Mutations in hmg1 were also shown to lead to the accumulation of ergosterol precursors, such as eburicol, by sterol profiling, while not altering the expression of sterol-demethylase genes. IMPORTANCE Aspergillus fumigatus is the predominant pathogen of invasive aspergillosis, a disease state credited with over 200,000 life-threatening infections annually. The triazole class of antifungals are clinically essential to the treatment of invasive aspergillosis. Unfortunately, resistance to the triazoles among A. fumigatus isolates is now increasingly reported worldwide. In this work, we challenge the current paradigm of clinical triazole resistance in A. fumigatus, by first demonstrating that previously characterized mechanisms of resistance have nominal impact on triazole susceptibility and subsequently identifying a novel mechanism of resistance with a profound impact on clinical triazole susceptibility. We demonstrate that mutations in the HMG-CoA reductase gene, hmg1, are common among resistant clinical isolates and that hmg1 mutations confer resistance to all clinically available triazole antifungals.

Statins inhibit the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase), which is the rate-limiting enzyme in cholesterol biosynthesis. Statin therapy reduces morbidity and mortality in those who are at high risk of cardiovascular disease. Monacolin J is a statin compound, which is an intermediate in the lovastatin biosynthesis pathway, in the fungus Aspergillus terreus. It is also found in red yeast rice, which is made by culturing rice with the yeast Monascus purpureus. Monacolin J has a hydroxyl substituent at position C’-8 of monacolin L. Here, a new statin derivative from monacolin J was made through the catalysis of CYP102A1 from Bacillus megaterium. A set of CYP102A1 mutants of monacolin J hydroxylation with high catalytic activity was screened. The major hydroxylated product was C-6′a-hydroxymethyl monacolin J, whose structure was confirmed using LC–MS and NMR analysis. The C-6′a-hydroxymethyl monacolin J has never been reported before. It showed a greater ability to inhibit HMG-CoA reductase than the monacolin J substrate itself. Human liver microsomes and human CYP3A4 also showed the ability to catalyze monacolin J in producing the same product of the CYP102A1-catalyzed reaction. This result motivates a new strategy for the development of a lead for the enzymatic and chemical processes to develop statin drug candidates.

Statin derivatives can inhibit the replication of a range of viruses, including hepatitis C virus (HCV, Hepacivirus), dengue virus (Flavivirus), African swine fever virus (Asfarviridae) and poliovirus (Picornaviridae). We assess the antiviral effect of fluvastatin in cells infected with orbiviruses (bluetongue virus (BTV) and Great Island virus (GIV)). The synthesis of orbivirus outer-capsid protein VP2 (detected by confocal immunofluorescence imaging) was used to assess levels of virus replication, showing a reduction in fluvastatin-treated cells. A reduction in virus titres of ~1.7 log (98%) in fluvastatin-treated cells was detected by a plaque assay. We have previously identified a fourth non-structural protein (NS4) of BTV and GIV, showing that it interacts with lipid droplets in infected cells. Fluvastatin, which inhibits 3-hydroxy 3-methyl glutaryl CoA reductase in the mevalonic acid pathway, disrupts these NS4 interactions. These findings highlight the role of the lipid pathways in orbivirus replication and suggest a greater role for the membrane-enveloped orbivirus particles than previously recognised. Chemical intermediates of the mevalonic acid pathway were used to assess their potential to rescue orbivirus replication. Pre-treatment of IFNAR(−/−) mice with fluvastatin promoted their survival upon challenge with live BTV, although only limited protection was observed.

A series of highly potent antihyperlipidemic agents constituted by a fibrate-based structure was recently reported by our group, whose synthesis started from isovanillin derivatives. In the interest of evaluating the bioisosteric effect of the vanillin-based isomers on their antihyperlipidemic activity, the present study focuses on the synthesis of 5-acyl-1-phenoxyacetic methyl esters 5a–c and their saturated side-chain 5-alkyl-1-phenoxyacetates 6a–c. Their strong in vivo effect was associated with the inhibition of HMG-CoA reductase. Since 1,2-dihydroquinolines inhibit this enzyme, a series of such heterocycles (9a–d) was prepared by our efficient regioselective, one-step, solvent-free method. Apart from showing hypolipidemic activity in vivo, some of the compounds displayed antifungal, antioxidant and cytotoxic activity in vitro. The binding mode of four compounds at the active site of HMGRh was examined with docking simulations, observing an interaction with most of the amino acids targeted by simvastatin. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the antihypercholesterolemic effect of chemical constituents of W. coagulans by determining inhibitory effect of the compounds against HMG-CoA reductase, using in-silico methods. Method: Docking simulations of twenty-one chemical constituents, found in the fruits of W. coagulans were performed against HMGCR(PDB ID: 2Q1L) using Molegro Virtual Docker software. The best docked poses were then selected, based on the docking score and amino acids involved in the interaction within the ligand and active site of protein. Results: Five compounds viz. Coagulin D (comp no. 11), Ergosta-5,25-diene-3ß,24e-diol (comp no. 13), Withacoagulin (comp no. 15), and Withaferin (comp no. 16), showed the highest MolDock scores. These compounds with highest docking score, also formed hydrogen bond interactions with His (752), Lys (692, 735), Asp (690), Glu (559) within the binding site of HMG-CoA reductase, thus, halting enzyme activity. Whereas, Withanolide D (comp no. 17) with high MolDock score did not show hydrogen bonding interactions. Conclusion: The high MolDock score and maximum binding with catalytic region of the enzyme indicate that compounds selected from the fruits of W. coagulans are potential blockers of HMG-CoA reductase. Thus, the compounds may be useful for the management of hypercholesterolemia, which untreated, often leads to coronary artery disease. [ABSTRACT FROM AUTHOR]

Background: The HMG-CoA reductase is key enzyme of cholesterol biosynthesis which potentially contributes in management of hypercholesterolemia. The present study was designed to assess the inhibitory effect of phytoconstituents of an ethanolic extract of Prosopis cineraria pods on HMG – CoA reductase and regression potential of atherosclerotic plaque. Methods: Healthy, adult male, albino rabbits in which hypercholesterolemia was induced by supplying the high fat diet and a supplement of cholesterol powder with coconut oil (500 mg/5 ml/Day/kg body weight) for 15 days, were used as a disease model. Phytochemical analysis of an ethanolic extract Prosopis cineraria pods was conducted using LCMS, GCMS and FTIR analysis. Further, in-vitro, in-vivo and in-silico assessments were performed. Results: The in-vitro assessment of HMG -CoA reductase activity indicated a 67.1 and 97.3% inhibition by the extract and a standard drug (Pravastatin), respectively. Additionally, an in-silico evaluation was made using appropriate docking software and results also indicated as significant interactions of the identified compounds with the target enzyme. Treatment of rabbits with the ethanolic extract of P. cineraria pod resulted in significant (P ≤ 0.001) reductions in total cholesterol, LDL cholesterol, VLDL cholesterol, and triglyceride. Accordingly, reductions were occurred in atherosclerotic plaque, intima and media of aortal wall along with lumen volume of the aorta significantly increased (P ≤ 0.001). Conclusion: It can be illustrating that the ethanolic extract of Prosopis cineraria pod contains potent bioactive phytocompounds might be inhibit HMG – CoA reductase and have regression potential of atherosclerotic plaque. [ABSTRACT FROM AUTHOR]