Inhibition Of HMG-CoA Reductase Activity Research Articles

Bioactive Pigments of Monascus purpureus Attributed to Antioxidant, HMG-CoA Reductase Inhibition and Anti-atherogenic Functions

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.

Anti-hyperlipidemic potential of natural product based labdane-pyrroles via inhibition of cholesterol and triglycerides synthesis

Hyperlipidemia is the clinical condition where blood has an increased level of lipids, such as cholesterol and triglycerides. Therefore controlling hyperlipidemia is considered to be a protective strategy to treat many associated diseases. Thus, a novel natural product derived pyrrole, and pyrazole-(E)-Labda-8(17),12-diene-15,16-dial conjugates with cholesterol and triglycerides synthesis inhibition potential was designed through scaffold hopping approach and synthesized via one-pot selective cycloaddition. Amongst the tested hybrids, 3i exhibited excellent activity against triglyceride and cholesterol synthesis with the percentage inhibition of 71.73 ± 0.78 and 68.61 ± 1.19, which is comparable to the positive controls fenofibrate and atorvastatin, respectively. Compounds 3j and 3k also exhibited the considerable potential of promising leads. The HMG CoA reductase inhibitory activity of the compounds was consistent with that of inhibitory activity of cholesterol synthesis. Compound 3i showed the highest inhibitory potential (78.61 ± 2.80) percentage of suppression, which was comparable to that of the positive control pravastatin (78.05 ± 5.4). Favourably, none of the compounds showed cytotoxicity (HepG2) in the concentration ranging from 0.5 to 100 μM.

A-family anti-inflammatory cyclopentenone prostaglandins: A novel class of non-statin inhibitors of HMG-CoA reductase

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 (IC50 for PGA2 = 0.17 μM). PGA2 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, PGA2 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 PGA2 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 PGA2 should be exploited in atherosclerosis therapeutics.

Bunium persicum: A Review of Ethnopharmacology, Phytochemistry, and Biological Activities

Bunium persicum (Boiss) B. Fedtsh (Apiaceae, Persian name: Zireh Kermani) has been used to treat various diseases in traditional and folkloric medicine including gastrointestinal, respiratory, nasopharyngeal, cardiac, ocular, neurological, rheumatological and urinary tract diseases. Its essential oil contains different monoterpenes, sesquiterpenes and phenyl propenes. Other chemical constituents identified in B. persicum are phenolic compounds, fatty acids, carboxylic acids, and carbohydrates. Wide range of biological and pharmacological activities including antioxidant, analgesic, anti-inflammatory, acetylcholinesterase inhibitory, anticonvulsant, HMG-CoA reductase inhibitory, anti-pancreatic lipase, anticancer, antidiabetic, antihistamine, antidiarrheal, antispasmodic, antihematoxic, antityrosinase and antimicrobial activities have been reported from this plant in modern medicine. This article summarizes comprehensive information attributing traditional uses, phytochemistry, and pharmacological activities of Zireh Kermani.

Anti-hypercholesterolemic potential of diet supplemented with Anchomanes difformis and Pleurotus tuberregium tubers in high cholesterol fed rats.

One significant ethnomedicinal motivation behind Pleurotus tuberregium (PTT) and Anchomanes difformis (ADT) tubers is cardiovascular-related conditions treatment. This investigation is in this way planned for deciding the impact of PTT and ADT enhanced eating routine on key enzymes linked with hypercholesterolemia in elevated cholesterol fed rodents. Rats were isolated into control group, hypercholesterolemic-prompted untreated group, hypercholesterolemic-treated groups with dietary routine containing PTT (5% and 10%), ADT (5% and 10%), 5% PTT and 5% ADT conbination and traditional medication, atorvastatin for 28 days. Ten rodents were utilized for every one of the groups. Feeding with PTT and ADT comprehensive eating regimen and their combination significantly (P < 0.05) diminished the AChE, HMG-CoA, ALT, AST, ALP, LDH and CK activities and levels of mevalonate, triglyceride (TG), total cholesterol (TC), low density lipoprotein (LDLch), atherogenic indices, MDA and ROS yet significantly increased the SOD, CAT, GPx activities, and level of HDL, GSH when contrasted with HC-initiated untreated rodents. Likewise, histopathological of liver and heart demonstrated no obsessive changes in all the treated groups when contrasted with healthy control group. HPLC fingerprinting of the PTT and ADT aqueous concentrates uncovered the nearness of ferulic acid, vanillic acid, catechin, quercetin, chlorogenic acid, ellagic acid and gallic acid. Notwithstanding, aqueous concentrate of ADT contained plentiful convergences of the polyphenolics when contrasted with PTT concentrate. The tubers HMG-CoA reductase inhibitory activity could additionally support their antihypercholesterolemic use in folk medication. Accordingly, the tubers may in this way be valuable as restorative nourishment for helpful treatment of clinical conditions related hypercholesterolemia with the ADT diet holding more guarantee.

Investigation of HMG-CoA reductase inhibitory and antioxidant effects of various hydroxycoumarin derivatives.

Cardiovascular diseases are one of the primary causes of deaths worldwide, and the development of atherosclerosis is closely related to hypercholesterolemia. As the reduction of the low-density lipoprotein cholesterol level is critical for treating these diseases, the inhibition of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase, which is essentially responsible for cholesterol biosynthesis, stands out as a key solution to lower plasma cholesterol levels. In this study, we synthesized several dihydroxycoumarins and investigated their antioxidant and in vitro HMG-CoA reductase inhibitory effects. Furthermore, we carried out in silico studies and examined the quantum-chemical properties of the coumarin derivatives. We also performed molecular docking experiments and analyzed the binding strength of each coumarin derivative. Our results revealed that compound IV displayed the highest HMG-CoA reductase inhibitory activity (IC50 = 42.0 µM) in vitro. Cupric-reducing antioxidant capacity and ferric-reducing antioxidant power assays demonstrated that coumarin derivatives exhibit potent antioxidant activities. Additionally, a close relationship was found between the lowest unoccupied molecular orbital energy levels and the antioxidant activities.

Inhibitory effects of tangeretin and trans-ethyl caffeate on the HMG-CoA reductase activity: Potential agents for reducing cholesterol levels.

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.

Evaluation of lipid and cholesterol-lowering effect of bioflavonoids from bergamot extract

Several natural products have been reported to be involved in the suppression of adipogenesis. In this study, we reveal that a bergamot extract (BE) decreased the accumulation of intracellular lipids in murine pre-adipocytes 3T3-L1 cells during adipogenic differentiation. Both the inhibition of HMG-CoA reductase activity and the differentiation and proliferation of adipocytes could be used as a strategy for the treatment and prevention of obesity. The results of this study show a reduction of HMG-CoA activity and of lipid droplet accumulation in the presence of the BE, suggesting the potential of BE as an anti-adipogenic agent to lower the content of cholesterol and body fat and prevent a gain in body weight. Moreover, BE as the result of high percentages of flavonoid compounds such as neoriocitrin, naringin and neohesperidin, the main flavonoids contained in BE, led to significant inhibition of DPPH free radical, demonstrating a strong radical scavenging activity.

Aloe-emodin exerts cholesterol-lowering effects by inhibiting proprotein convertase subtilisin/kexin type 9 in hyperlipidemic rats

Hyperlipidemia (HPL) characterized by metabolic disorder of lipids and cholesterol is one of the important risk factors for cardiovascular diseases. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a potent circulating regulator of LDL through its ability to induce degradation of the low-density lipoprotein cholesterol receptor (LDLR) in the lysosome of hepatocytes. Aloe-emodin (AE) is one of potentially bioactive components of Chinese traditional medicine Daming capsule. In this study we evaluated the HPL-lowering efficacy of AE in both in vivo and in vitro HPL models. High-fat diet-induced rats were treated with AE (100 mg/kg per day, ig) for 6 weeks. We found that AE administration significantly decreased the levels of total cholesterol (TC) and LDL in the serum and liver tissues. Moreover, AE administration ameliorated HPL-induced hepatic lipid aggregation. But AE administration did not significantly inhibit HMG-CoA reductase activity in the liver of HPL rats. A cellular model of HPL was established in human hepatoma (HepG2) cells treated with cholesterol (20 μg/mL) and 25-hydroxycholesterol (2 μg/mL), which exhibited markedly elevated cholesterol levels. The increased cholesterol levels could be reversed by subsequent treatment with AE (30 μM). In both the in vivo and in vitro HPL models, we revealed that AE selectively suppressed the sterol-regulatory element-binding protein-2 (SREBP-2) and hepatocyte nuclear factor (HNF)1α-mediated PCSK9 signaling, which in turn upregulated LDL receptor (LDLR) and promoted LDL uptake. This study demonstrates that AE reduces cholesterol content in HPL rats by inhibiting the hepatic PCSK9/LDLR pathway.

Bipolaricins A-I, Ophiobolin-Type Tetracyclic Sesterterpenes from a Phytopathogenic Bipolaris sp. Fungus.

A preliminary phytochemical investigation on the EtOAc extracts of the fungus Bipolaris sp. TJ403-B1 resulted in the identification of 12 ophiobolin-type phytotoxins (1-12), including nine new ones, termed bipolaricins A-I (1-9). The structures of 1-9 were elucidated via spectroscopic data (including HRESIMS and 1D and 2D NMR) and single-crystal X-ray diffraction (Cu Kα) analyses. All of the isolated compounds were tested in terms of HMG-CoA reductase inhibitory, anti-inflammatory, and cytotoxic activities. Compound 10 showed HMG-CoA reductase inhibitory activity (IC50 = 8.4 ± 0.4 μM), and 2, 3, and 10-12 showed significant inhibitory potency against lipopolysaccharide (LPS)-induced nitric oxide production, with IC50 values in the range of 5.1 ± 0.3 to 20 ± 1 μM. Further experiments showed that 10 could significantly inhibit the production of IL-1β, RANTES, MIP-1β, and TNF-α as well as enhance the release of IL-13 in macrophages through the inhibition of HO-1 induction as well as the NF-κB pathway. These findings provide a scientific rationale for an anti-inflammatory therapeutic and a template for a new HMG-CoA reductase inhibitor to produce a potential anti-hyperlipidemia agent.

Simultaneous analysis of the total plasma concentration of atorvastatin and its five metabolites and the unbound plasma concentration of atorvastatin: Application in a clinical pharmacokinetic study of single oral dose

Atorvastatin (ATV) and its two active metabolites, o-hydroxy atorvastatin acid (o-OH-ATV) and p-hydroxy atorvastatin acid (p-OH-ATV) are responsible for its HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme-A) reductase inhibitory activity, while its corresponding inactive lactone forms (LAC) are related to the manifestation of myopathy. The present study reports the development and validation of a method for the simultaneous analysis of ATV and its five metabolites (o-OH-ATV, p-OH-ATV, ATV-LAC, o-OH-ATV-LAC, p-OH-ATV-LAC) as total plasma concentration and ATV as unbound plasma concentration using UPLC-MS/MS. The method was applied in a pharmacokinetic study following administration of a single oral 20, 40 or 80 mg ATV dose in healthy volunteers (n = 15). ATV and its five metabolites were separated on a C18 column using as mobile phase a mixture of 0.2% formic acid and acetonitrile (55:45, v/v) at a flow of 0.4 mL/min. The method showed linearity from 25 pg/mL to 200 ng/mL plasma as total concentration and from 6.25 pg to 25 ng/mL plasma ultrafiltrate as ATV unbound concentration. The coefficients of variation and the relative standard errors of the accuracy and precision analyses were <15%. The method allowed quantification of plasma concentrations of ATV and its five metabolites up to 36 h after 20, 40 or 80 mg ATV administration. The pharmacokinetic parameters dose normalized to 20 mg are presented as follow (n = 15, mean): unbound fraction 9.38%, maximum plasma concentration 9.52 ng/mL, time to reach maximum plasma concentration 0.98 h, apparent total clearance 742.90 L/h, apparent distribution volume 9005 L, and AUC metabolite/ATV ratios 0.06 for p-OH-ATV, 0.94 for o-OH-ATV, 1.43 for ATV-LAC, 0.25 for p-OH-ATV-LAC and 1.75 for o-OH-ATV-LAC. In conclusion, the methods for simultaneous analysis of ATV and its five metabolites as total plasma concentration and ATV as the unbound plasma concentration showed sensitivity, linearity, precision and accuracy compatible with application in pharmacokinetic studies of single oral dose of 20, 40 or 80 mg ATV.

Bipolarolides A-G: Ophiobolin-Derived Sesterterpenes with Three New Carbon Skeletons from Bipolaris sp. TJ403-B1.

Bipolarolides A-G (1-7), seven novel ophiobolin-derived sesterterpenes with three new types of skeletons, were characterized from fungus Bipolaris sp. TJ403-B1. Their structures were determined via spectroscopic analyses, X-ray crystallography, and quantum chemical 13 C NMR and electronic circular dichroism (ECD) calculations. Compounds 1 and 2 were uniquely defined by a multicyclic caged oxapentacyclo[9.3.0.01,6 .05,9 .18,12 ]pentadecane-bridged system. Compounds 3 and 4 featured an unprecedented 5-5-5-5-fused core skeleton, while 3 also contained an unexpected C-3-C-14 oxygen bridge to construct the caged architecture. Compounds 5-7 form a new class of highly modified pentacyclic oxaspiro[4.4]nonane-containing sesterterpene-alkaloid hybrids. Their biosynthetic pathways and potential HMG-CoA reductase inhibitory and antimicrobial activities are also discussed.

Influence of extraction methods of bay leaves (Syzygium polyanthum) on antioxidant and HMG-CoA Reductase inhibitory activity

ObjectiveBay leaf, one of the plants in Indonesia that has been shown to have activities to reduce cholesterol in the blood. HMG-CoA Reductase inhibition is one of many mechanisms in lowering the level of cholesterol in the blood. Here, we reported the inhibitory activity of HMG-CoA Reductase of bay leaves ethanol extracts that we suspected to be the mechanism of action of bay leaves in reducing cholesterol in the blood. In this research we also investigated the correlation between the inhibitory activities, the total phenol content and antioxidant activities of bay leaves (Syzygium polianthum) ethanol extracts. MethodsThe inhibitory activity of HMG-CoA Reductase was determined kinetically at 340 nm using simvastatin as positive control. In vitro scavenging assays of 2,2-diphenyl-1-picrylhydrazyl (DPPH), ferric ion reducing antioxidant power (FRAP), and beta-carotene method were used to determine the antioxidant activities. The total phenolic content was determined by Folin-Ciocalteu's method. ResultsThe IC50 of bay leaves ethanolic extract obtained by percolation and soxhlet extraction method towards HMG-CoA Reductase enzyme activity were 49.50 ± 0.700 μg/mL and 15.50 ± 0.707 μg/mL, respectively, while the IC50 of simvastatin was 0.00238 ± 0.00004 μg/mL. The antioxidant activity and total phenolic content of bay leaves ethanolic extract obtained by Soxhlet extraction method was higher compared to the percolation method (DPPH and beta-carotene assay results). The 3D linear analysis showed that there was a high correlation between the inhibition activities of HMG-CoA Reductase pattern of both extract types and the total phenol pattern and also the antioxidant pattern of these extracts. ConclusionThe result showed that the bay leaves ethanolic extract have a potent activity to reduce the cholesterol serum level by inhibition of HMG-CoA Reductase activity. The activity was due to the phenolic compounds in the extracts as well as the antioxidant activity of the extracts.

Nrf2-inducing and HMG-CoA reductase inhibitory activities of a polyphenol-rich fraction of Guazuma ulmifolia leaves

Objective: To fractionate and identify polyphenols from Guazuma ulmifolia Lam. leaves, and to explore their antioxidant, 5-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitory, and Nrf2 modulatory activities. Methods: The 1,1-diphenyl-2-picrylhydrazyl assay was used to evaluate the antioxidant activity of a polyphenolic fraction of the extract of Guazuma ulmifolia Lam. leaves. THP-1 gene reporter cell lines constructed with a transcriptional response element specific for Nrf2 and a minimal promoter for the firefly luciferase–green fluorescent protein transgene were used to determine the effect of the polyphenolic fraction on the Nrf2 signaling pathway. Furthermore, an assay of HMG-CoA reductase inhibitory activity was performed by using a commercial enzyme kit. Polyphenolic compounds were identified by liquid chromatography-tandem mass spectrometry. Results: The polyphenolic fraction showed fairly strong antioxidant activity [IC50 = (14.90 ± 4.70) μg/mL] and inhibited HMG-CoA reductase activity by 69.10%, which was slightly lower than that by pravastatin (84.37%) and quercetin (84.25%). Additionally, the polyphenolic fraction activated the Nrf2 antioxidant signaling pathway at 500 μg/mL. Eleven subfractions resulting from the column chromatography separation of the polyphenolic fraction also showed relatively strong antioxidant activities (IC50: 17.46μ217.14 μg/mL). The subfraction (F6) stimulated the Nrf2 signaling pathway and had HMG-CoA reductase inhibitory activity (65.43%). Moreover, the subfraction contained two main flavonoids: quercetin and quercimeritrin. Conclusions: The polyphenolic fraction of Guazuma ulmifolia could induce antioxidant genes via the Nrf2/antioxidant regulatory elements pathway, and is a promising candidate for an inhibitor of HMG-CoA reductase.

Siamese neem flower extract suppresses cholesterol absorption by interfering NPC1L1 and micellar property in vitro and in intestinal Caco-2 cells.

Siamese neem (Azadirachta indica A. Juss var. siamensis Valeton) (A. indica) leaf extract, a traditional ayurvedic medicine, has been reported to exhibit antipyretic, antibacterial, antidyslipidemic, and antihyperglycemia effects. This study investigated the mechanism of hypocholesterolemic effect of methanolic extract of Siamese neem flowers in in vitro studies and in Caco-2 cells. Pancreatic cholesterol esterase and 3-hydroxy 3-methylglutaryl-CoA (HMG-CoA) reductase activities were assessed. Cholesterol micelle formation was prepared for in vitro cholesterol physicochemical property analyses, micelle size and solubility, and transport of cholesterol into the Caco-2 cells. The expression of niemann-pick C1 like 1 (NPC1L1), and its major regulator, peroxisome proliferator-activated receptor δ (PPARδ), were determined by western blot and real time polymerase chain reaction, respectively. A. indica flower extract inhibited pancreatic cholesterol esterase activity and increased cholesterol micelles size. Uptake of cholesterol into Caco-2 cells was inhibited by A. indica flower extract in a dose-dependent manner. In addition, A. indica extract inhibited HMG-CoA reductase activity, resulting in low level of intracellular cholesterol accumulation, together with increased cytosolic NPC1L1 protein expression and decreased PPARδ gene expression. In conclusion, A. indica flower extract has cholesterol-lowering effects by inhibiting intestinal cholesterol absorption, interfering micellar cholesterol formation, and attenuating cholesterol synthesis. As such, A. indica flower extract has potential for developing into nutraceutical product for prevention of hypocholesterolemia.

A transcriptomic analysis of black cohosh: Actein alters cholesterol biosynthesis pathways and synergizes with simvastatin

Previous studies indicate that the herb black cohosh (Actaea racemosa L.) and the triterpene glycoside actein inhibit the growth of human breast cancer cells and activate stress-associated responses. This study assessed the transcriptomic effects of black cohosh and actein on rat liver tissue, using Ingenuity and ToxFX analyses. Sprague-Dawley rats were treated with an extract of black cohosh enriched in triterpene glycosides (27%) for 24 h or actein for 6 and 24 h, at 35.7 mg/kg, and liver tissue collected for gene expression analysis. Ingenuity analysis indicates the top canonical pathways are, for black cohosh, RAR Activation, and, for actein, Superpathway of Cholesterol Biosynthesis, at 24 h. Actein alters the expression of cholesterol biosynthetic genes, but does not inhibit HMG-CoA reductase activity. Black cohosh and actein inhibited the growth of human breast and colon cancer cells and synergized with the statin simvastatin. Combinations of black cohosh with certain classes of statins could enhance their activity, as well as toxic, such as inflammatory liver, side effects. Transcriptomic analysis indicates black cohosh and actein warrant further study to prevent and treat cancer and lipid disorders. This study lays the basis for an approach to characterize the mode of action and toxicity of herbal medicines.

Structural Modification of Natural Product Ganomycin I Leading to Discovery of a α-Glucosidase and HMG-CoA Reductase Dual Inhibitor Improving Obesity and Metabolic Dysfunction in Vivo.

It is a great challenge to develop drugs for treatment of metabolic syndrome. With ganomycin I as a leading compound, 14 meroterpene derivatives were synthesized and screened for their α-glucosidase and HMG-CoA reductase inhibitory activities. As a result, a α-glucosidase and HMG-CoA reductase dual inhibitor (( R, E)-5-(4-( tert-butyl)phenyl)-3-(4,8-dimethylnona-3,7-dien-1-yl)furan-2(5 H)-one, 7d) with improved chemical stability and long-term safety was obtained. Compound 7d showed multiple and strong in vivo efficacies in reducing weight gain, lowering HbAlc level, and improving insulin resistance and lipid dysfunction in both ob/ob and diet-induced obesity (DIO) mice models. Compound 7d was also found to reduce hepatic steatosis in ob/ob model. 16S rRNA gene sequencing, SCFA, and intestinal mucosal barrier function analysis indicated that gut microbiota plays a central and causative role in mediating the multiple efficacies of 7d. Our results demonstrate that 7d is a promising drug candidate for metabolic syndrome.

In vitro and in silico studies of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitory activity of the cowpea Gln-Asp-Phe peptide

Previous studies have shown that cowpea protein positively interferes with cholesterol metabolism. In this study, we evaluated the ability of the fraction containing peptides of <3 kDa, as well as that of the Gln-Asp-Phe (QDF) peptide, derived from cowpea β-vignin protein, to inhibit HMG-CoA reductase activity. We established isolation and chromatography procedures to effectively obtain the protein with a purity above 95%. In silico predictions were performed to identify peptide sequences capable of interacting with HMG-CoA reductase. In vitro experiments showed that the fraction containing peptides of <3 kDa displayed inhibition of HMG-CoA reductase activity. The tripeptide QDF inhibits HMG-CoA reductase (IC50 = 12.8 μM) in a dose-dependent manner. Furthermore, in silico studies revealed the binding profile of the QDF peptide and hinted at the molecular interactions that are responsible for its activity. Therefore, this study shows, for the first time, a peptide from cowpea β-vignin protein that inhibits HMG-CoA reductase and the chemical modifications that should be investigated to evaluate its binding profile.

TO EVALUATE THE ANTI-ATHEROSCLEROTIC POTENTIAL OF QUERCETIN IN ALLOXANINDUCED DIABETIC RATS FED WITH HIGH-FAT DIET

Objective: The main aim of the present study is concerned with the evaluation of anti-atherosclerotic potential of quercetin in alloxan-induced diabetic rats fed with high-fat diet (HFD).Methods: Atherosclerosis (AS) is the major cause for many of the cardiovascular disease, and it is accelerated in the presence of diabetes mellitus and causes profound alterations in the lipid profile. The method used for the induction of AS was using HFD for 60 days. In this study, rats were divided into four groups (n=6). Group I served as normal control, Group II alloxan (120 mg/kg b.w i.p)-treated diabetic rats, Group III received quercetin (50 mg/ kg b.w p.o), and Group IV received atorvastatin (10 mg/kg b.w p.o) along with alloxan (120 mg/kg b.w i.p) on the 1st day of the days of the study period. AS was induced in Group II, Group III, and Group IV rats by feeding them with HFD from the 1st day to 60th day. The body weight, feed intake was measured daily. The blood was withdrawn from retro-orbital plexus, and the serum was used for the estimation of lipid profile (total cholesterol [TC], triglycerides [TGs], low-density lipoprotein cholesterol [LDL-C], very LDL-C [VLDL-C], and high-density lipoprotein cholesterol [HDL-C]). After scarification under overdose of ketamine, the histopathological study of aorta was carried out.Results: The results showed that the quercetin-treated rats showed a decrease in body weight gain, decreased levels of TC, TGs, LDL-C, and VLDL-C, and increased levels of HDL-C were observed in Group III rats when compared to alloxan-induced diabetic rats fed with HFD (Group III). The histopathological study of aorta showed no development of plaques and of foam cells.Conclusion: From this study, it can be calculated that quercetin has anti-atherosclerotic activity as it significantly altered overall lipid profile in diabetic rats fed with HFD. This activity may be attributed to its antioxidant, inhibition of HMG-CoA reductase activity of quercetin.

HMG-CoA Reductase Inhibitory Activity of Gnetum gnemon Seed Extract and Identification of Potential Inhibitors for Lowering Cholesterol Level

Objectives: Melinjo (Gnetum gnemon) seeds have been known to have some biological properties. One of them is ant hypercholesterolemia. The present study investigated in vitro and in silico methods to predict potential antihypercholesterolemic of the Melinjo seed extracts of through HMG-CoA reductase inhibitory activity. Methods: Melinjo seed powders were successively extracted by reflux method using five solvents with gradient polarity including: n-hexane, dichloromethane, ethyl acetate and methanol. All extracts were evaluated in vitro using HMG-CoA Reductase assay kit, to analyze the inhibitory activity. Molecular docking of the phytochemical content of the seeds were carried out using Auto Dock Vina, and also Ligand Scout to analyses interaction between ligand and receptor. Results: Dichloromethane extract demonstrated the highest inhibitory activity against HMG-CoA reductase with IC50 value is 0.40 μg/mL, followed by that of ethyl acetate extract. UPLC-MS analyses showed that dichloromethane extract contained trans-resveratrol, piceid, gnetin C, gnetol, isorhapontigenin, ɛ-viniferin, gnemonol L, and gnemonol M. Molecular docking studies demonstrated that dimer of resveratrol such as gnemonol L, gnemosida, and ɛ-viniferin have better free binding energy than that of monomer. piceid, gnetin C, gnemonol L, and gnemonol M could be considered as HMG-CoA reductase inhibitor. Conclusion: Gnetum gnemon seed extract showed strong HMG-CoA reductase activity. Resveratrol dimer promises as a potential lead compound to design/synthesize anti-cholesterol. Key words: Gnetum gnemon, Melinjo, HMG-CoA Reductase, Resveratrol, Stilbene, Molecular Docking.