Effect of icariin on ubiquitination of amyloid precur-sor protein in Alzheimer's disease mice / 中国药理学与毒理学杂志

OBJECTIVE To investigate the effect of icariin(ICA)on the ubiquitination modification of β-amy-loid precursor protein(APP)in Alzheimer's disease mice.METHODS In vitro,① HEK 293 cells stably overex-pressing human APP695(OE-hAPP)were treated with different concentrations of ICA(10-100 μmol·L-1)for 24 h and the cell viability was detected by MTT assay.②CHX(50 mg·L-1)was used to block protein synthesis and MG132(20 μmol·L-1)inhibits proteasome activity,then the level of APP in different time(0,0.5,1,2,3 and 4 h)and the ubiquitination were tested by Western blotting.③ E3 ubiquitin ligases HMG-CoA reductase degradation pro-tein 1(HRD1)protein expression in OE-hAPP was tested by Western blotting,as well as the level and ubiquitination of APP were tested under HRD1 silent condition by Co-IP and Western blotting.In vivo,① male APP/PS1 mice and wild type(WT)mice were randomly divided into 5 groups:WT,WT+ICA,APP/PS1,APP/PS1+ICA,and APP/PS1+donepezil(DPZ)groups.ICA(60 mg·kg-1·d-1)and DPZ(1 mg·kg-1·d-1)were treated for 3 months by gavage from 6 months of age,and WT mice were given equal volume of distilled water.②Morris water maze and Y-maze experiments were used to detect the alteration of spatial learning memory function.③ After then,the brain tissues were collected,total proteins were extracted,APP antibodies were subjected to Co-IP,and total ubiqui-tination(Ub),K48-linked polyubiquitination(UbK48)and K63-linked polyubiquitination of APP level,APP and HRD1 proteins were detected by Western blotting.RESULTS In vitro results showed that ICA significantly enhanced APP degradation(vs control,P＜0.01),up-reg-ulated HRD1 expression(vs control,P＜0.05;vs OE-hAPP,P＜0.05),elevated the level Ub and UbK48 of APP,as well as increased APP degradation.Moreover,silenced HRD1 gene abolished abovementioned effects of ICA(vs control-siRNA,P＜0.05;vs HRD1-siRNA,P＜0.05).In vivo results showed that ICA improved the spa-tial learning and memory function APP/PS1 mice by Mor-ris water maze and Y-maze tests,increased HRD1 expres-sion(vs APP/PS1 + vehicle,P＜0.05),enhanced APP ubiquitination and reduced APP protein level(vs APP/PS1 + vehicle,P＜0.01).CONCLUSION ICA promotes the ubiquitination and proteasome-dependent degrada-tion of APP by up-regulating HRD1,thereby improving the spatial learning and memory function of Alzheimer disease mice.

Effects of statin response on cardiovascular outcomes in patients with ST-segment elevation myocardial infarction

SUMMARY OBJECTIVE: This study aimed to evaluate the effects of statin response on cardiovascular outcomes in patients with ST-segment elevation myocardial infarction. METHODS: A total of 1029 ST-segment elevation myocardial infarction patients were enrolled in the study. The patients who failed to achieve >40% reduction in baseline low-density lipoprotein cholesterol levels within 30 days to 12 months after statin initiation were defined as suboptimal statin responders. The adjusted hazard ratios for cardiovascular outcomes for low-density lipoprotein cholesterol response to statins were estimated via the Cox proportional regression model. The relationship between the statin response and cardiovascular outcomes was also evaluated in a subgroup of on-treatment low-density lipoprotein cholesterol levels below 55 mg/dL. RESULTS: Among the study population, 573 (55.6%) patients demonstrated suboptimal low-density lipoprotein cholesterol response to statin therapy. These patients showed a significantly higher incidence of the composite of major adverse cardiovascular events, including cardiovascular death, reinfarction, recurrent myocardial infarction, and target vessel revascularization during the follow-up compared with optimal responders (adjusted hazard ratios 3.99; 95%CI 2.66-6.01; p<0.001). In a subgroup of patients with on-treatment low-density lipoprotein cholesterol levels below 55 mg/dL, suboptimal statin responders also showed unfavorable cardiovascular outcomes (adjusted hazard ratios 8.73; 95%CI 2.81-27.1; p<0.001). CONCLUSIONS: The present study showed that over half of the patients with ST-segment elevation myocardial infarction did not exhibit optimal low-density lipoprotein cholesterol response to statin. These patients have an increased risk of future major adverse cardiovascular events.

Design and Evaluation of Lovastatin Solid Dispersions Incorporated Trilayer Matrix Tablets

The current work is aimed to design, prepare and evaluate the trilayer matrix tablets incorporated with lovastatin solid dispersion (SD) for extend drug release. The lovastatin SD prepared by using solvent evaporation technique with varying amounts of polymers (GMS II, Soluplus, Kolliphor ELP, PEG 2000 and Urea) for enhancing the drug solubility. All the formulations examined for physicochemical parameters are within the permissible limits. The optimized SD formulation was incorporated into trilayer matrix tablets which were prepared using different polymers (HPMC 15M & K100M, Chitosan, xanthan gum) by direct compression method for sustaining the drug release. The drug dissolution of optimized lovastatin SD formulation SD15 (drug, soluplus and SLN) was 99.88±5.32% within 60 min which is higher than pure drug 47.33±2.25% and other formulations. The FT-IR, XRD and SEM data assure the compatibility of drug and excipients and amorphous nature of lovastatin. The solid dispersions were further incorporated in to trilayer matrix tablets with active layer and barrier layers. Eight formulations of lovastatin trilayer matrix tablets (AF9-HF9) designed and checked for pre compression parameters. Formulation GF9 demonstrated highest drug release of 99.41±5.28% for 24 hours sustainably over an extended period of time and excellent flow properties. The release order kinetics data indicate the zero order release with highest R2 of 0.9957 for GF9, superior than market extended release formulation (R2=0.9934). All the formulations showed best fit to Higuchi model and Korsmeyer-Peppa’s model indicating diffusion and non-Fickian diffusion process of drug release. GF90 was found to be stable for 180 days at accelerated conditions. Hence the solubility, dissolution rate of lovastatin was enhanced by SD technique further incorporated in to trilayer matrix tablets for sustainable extended drug release upto 24 h.

Statins & risk of Clostridium difficile infection: A meta-analysis

Background & objectives: Clostridium difficile infection is one of the most common healthcare-associated infections worldwide. Recent epidemiologic studies have suggested that statin users may have a lower risk of C. difficile infection, although the results are inconsistent. This meta-analysis was conducted with the aim of summarizing all available data to assess the risk of C. difficile infection among statin users versus non-users. Methods: A literature review was performed using the MEDLINE and EMBASE databases from inception to October 2017. Cohort, case-control and cross-sectional studies that compared the risk of C. difficile infection among statin users versus non-users were included. Pooled odds ratio (OR) and 95 per cent confidence interval (CI) were calculated using a random-effect, generic inverse variance method. Results: Six case-control studies and two cross-sectional studies met the eligibility criteria and were included in this meta-analysis. The risk of C. difficile infection among statin users was significantly lower than non-users with the pooled OR of 0.74 (95% CI, 0.61-0.89). The statistical heterogeneity of this study was high (I[2]=90%). Interpretation & conclusions: This meta-analysis demonstrated a decreased risk of C. difficile infection among statin users versus non-users. Further studies are required to clarify the role of statins for prevention of C. difficile infection in clinical practice.

The Modulating Effect Of Barley Β-Glucan Extract On High Fat Diet Induced Obesity-A Biochemical Study In Albino Wistar Rats

Objective: Diet-inducedhyperlipidemia and obesity are the major risk factors for type II diabetes mellitus, hypertension, musculoskeletal and cardiovascular disorders (CVD). The objective of the present study is to furnish scientific proof for the lipid-lowering effect of β-glucan, a lead compound present in barley with a defined mechanism of action. Methods: Obesity was induced in male albino Wistar rats by feeding ahigh-fat diet (HFD) for 14 w and were randomly divided into four groups of equal number (n=6). Group 1 and 2 served as control fed with normal diet (5% fat). Group 3 and 4 were fed HFD (23%fat) for 14 w. In addition, group 2 and 4 rats were administered orally with 200 mg/kg body weight of barley β glucan (BRBG) from the third week. After 14 w, the rats were sacrificed, and serum/plasma levels of total cholesterol (TC), phospholipids, triglycerides (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL) and adiponectin were determined. Results: Biochemical changes were observed in weight gain, body mass index (BMI),adiposity index (ADI), total fat pad mass (TFP), blood lipids, LDL, lipid peroxides (LPO) and antioxidant enzyme activity of HFD fed rats when compared with BRBG co-administered rats. In addition, serum adiponectin levels and 3-hydroxy-3methyl-glutaryl-coenzyme Areductase(HMG CoA reductase)activity were elevated in rats administered BRBG along with HFD. Histological examination in HFD induced rats revealed a profound change in cell size with increased hypertrophy in visceral adipose tissue. Conclusions: The results indicate that barley consumption could reverse most of these biochemical and histological changes in HFD fed rats owing to its hypolipidemic and antioxidant effect.

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

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: 17.46–217.14 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.

Zaluzania montagnifolia: essential oil composition and biological properties / Zaluzania montagnifolia: composición del aceite esencial y actividades biológicas

The chemical composition of the seasonal essential oils (2015-2016) from the leaves and flowers of Zaluzania montagnifolia is presented. The chemical content of those oils showed quantitative and qualitative differences. Germacrene D (19.9-29.8%), camphor (12.4- 19.4%) and ß-caryophyllene (13.7-18.5%) were the most abundant volatiles in the leaves. The essential oils from the flowers contained high amounts of camphor (32.7-37.2%) limonene (19.8-24.9%) and germacrene D (3.2-7.3%). All the seasonal essential oils showed a potent in vitro inhibition against HMG-CoA reductase. The essential oils from flowers (IC50, 40.5-55.1 µg mL-1) showed better inhibition properties than those of leaves (IC50, 84.4-123.5 µg mL-1). Camphor (IC50, 72.5 µg mL-1) and borneol (IC50, 84.4 µg mL-1) exerted a non-competitive inhibition on the enzyme. Additionally, the hydrodistillates exhibited antibacterial activity against the phytopathogenic Pseudomonas syringae pv. tabaci TBR2004 (MIC, 62.7-76.5 µg mL-1) P. syringae pv. tomato DC3000 (MIC, 45.4-50.4 µg mL-1) and P. syringae pv. phaseolicola NPS3121 (MIC, 26.7-31.9 µg mL-1). Germacrene D (MIC, 35.4-66.2 µg mL-1) and ß-caryophyllene (MIC, 36.5-54.2 µg mL-1) were the strongest anti-Pseudomonas syringae agents.

Se presenta la composición química de los aceites esenciales estacionales (2015-2016) provenientes de hojas y flores de Zaluzania montagnifolia. El contenido químico de los aceites esenciales mostró diferencias cualitativas y cuantitativas. El germacreno D (19.9-29.8%), alcanfor (12.4-19.4%) y ß-cariofileno (13.7-18.5%) fueron los volátiles más abundantes en las hojas. Los aceites esenciales de las flores contuvieron altas concentraciones de alcanfor (32.7-37.2%), limoneno (19.8-24.9%) y germacreno D (3.2-7.3%). Todos los aceites esenciales estacionales mostraron una potente inhibición in vitro contra la HMG-CoA reductasa. Los aceites esenciales de las flores (IC50, 40.5-55.1 µg mL-1) mostraron mejores propiedades inhibitorias que aquellos de las hojas (IC50, 84.4-123.5 µg mL-1). El alcanfor (IC50, 72.5 µg mL-1) y el borneol (IC50, 84.4 µg mL-1) ejercieron una inhibición no competitiva sobre la enzima. Adicionalmente, los hidrodestilados exhibieron una actividad antibacterial contra los fitopatógenos Pseudomonas syringae pv. tabaci TBR2004 (MIC, 62.7-76.5 µg mL-1) P. syringae pv. tomato DC3000 (MIC, 45.4-50.4 µg mL-1) y P. syringae pv. phaseolicola NPS3121 (MIC, 26.7-31.9 µg mL-1). El germacreno D (MIC, 35.4-66.2 µg mL-1) y ß-cariofileno (MIC, 36.5-54.2 µg mL-1) fueron los agentes más fuertes contra los patovares de Pseudomonas syringae.

Functional Implications of HMG-CoA Reductase Inhibition on Glucose Metabolism

HMG-CoA reductase inhibitors, i.e. statins, are effective in reducing cardiovascular disease events but also in cardiac-related and overall mortality. Statins are in general well-tolerated, but currently the concerns are raised if statins may increase the risk of new-onset diabetes mellitus (NOD). In this review, the possible effects of statins on organs/tissues being involved in glucose metabolism, i.e. liver, pancreas, adipose tissue, and muscles, had been discussed. The net outcome seems to be inconsistent and often contradictory, which may be largely affected by in vitro experimental settings or/and in vivo animal conditions. The majority of studies point out statin-induced changes of regulations of isoprenoid metabolites and cell-associated cholesterol contents as predisposing factors related to the statin-induced NOD. On the other hand, it should be considered that dysfunctions of isoprenoid pathway and mitochondrial ATP production and the cholesterol homeostasis are already developed under (pre)diabetic and hypercholesterolemic conditions. In order to connect the basic findings with the clinical manifestation more clearly, further research efforts are needed.

Effect of Huangqi San on AMPK/ACC/CPT1 pathway in hyperlipidemia rats / 中国中药杂志

To investigate the mechanism of the treatment of hyperlipidemia rats induced by Huangqi San. The 40 male SD rats were randomly divided into normal group, model group, Huangqi San low and high dose group (1, 2 g·kg⁻¹), and positive lipitor group (2 mg·kg⁻¹). The normal group feeds on base feed, and other groups feed on high-fat feed. After 8 weeks, the hyperlipidemia model was successful. After intervention by drugs for 13 weeks, fasting blood glucose, total cholesterol, triglycerides and LDL cholesterol content of all rats were measured. The pathological changes of liver and skeletal muscle of rats were observed in rats. Real-time PCR and Western blot were used to detect the mRNA and protein expression levels of AMPK signaling pathway in the liver and skeletal muscles (AMPK, ACC, CPT1A, SREBP2, HMGCR). The degree of FPG, TC, TG and LDL-C were the highest in the model group, and the liver and skeletal muscle pathology were the most obvious. After intervention by Huangqi San and lipitor, a significant reduction in the blood sugar blood fat, liver, and skeletal muscle injury has improved significantly, except SREBF2 and HMGCR mRNA and protein expression of this enzyme is reduced, other AMPK pathway related mRNA and protein expression increased significantly. Huangqi San effect is superior to lipitor. Huangqi San may improve hyperlipidemia by regulating the AMPK signaling pathway, increasing the oxidation of fatty acids and inhibiting cholesterol synthesis.

Anti-atherosclerotic activity of root bark of Premna integrifolia Linn. in high fat diet induced atherosclerosis model rats / 药物分析学报

Premna integrifolia Linn. is a medicinal plant used inDhasamuladrug 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.

Hypocholesterolemic Effect of Moringa oleifera Polyphenols in Rats Fed High Fat-Cholesterol Diet?

Introduction: One of the greatest risk factors for cardiovascular diseases is hypercholesterolemia. Moringa oleifera is a good source of phytochemicals and is well explored for its antioxidant properties. Methods: The main aim of the present study was to assess the potential cholesterol lowering effect of Moringa oleifera leaf polyphenols (MOP) in an animal model. Five groups of male Wister rats were fed for 45 days as follows: a standard diet (GI); high fat-cholesterol diet (GII); high fat-cholesterol with MOP (100 and 200mg/kg body wt GIII & GIV respectively); and high fat-cholesterol with statins (Atorvastatin) (G-V). Results: Administration of MOP rich extract (GII and GIV) significantly (p=0.05) lowered the serum cholesterol, triglycerides and low-density lipoprotein cholesterol. A significant (p=0.05) decrease in the activity of the HMG CoA reductase enzyme was observed in GIII, GIV and GV but not in GI & GII. Conclusion: The results demonstrate that the polyphenol extract of Moringa oleifera leaves has a significant cholesterol lowering effect through inhibiting HMG CoA reductase activity and faecal bile acid binding.

Effect of Rosuvastatin on Bovine Pericardial Aortic Tissue Valve Calcification in a Rat Subdermal Implantation Model

BACKGROUND AND OBJECTIVES: There are pathophysiologic similarities between calcification and atherosclerosis because both are the product of an active inflammatory process. The aim of this study was to examine the effects of statin treatment on calcification in bovine pericardial tissue valves. MATERIALS AND METHODS: Forty Sprague-Dawley rats were randomly divided into 4 groups according to hypercholesterolemia induction and statin intake (Group 1, n=10: normal diet without statin treatment, Group 2, n=10: normal diet with statin treatment, Group 3, n=10: high fat diet without statin treatment, Group 4, n=10: high fat diet with statin treatment). Serum lipid levels were measured just before the experiment and after 4 and 12 weeks. Bovine pericardial tissue valve cusps were surgically implanted in rat dorsal subcutis at 4 weeks. After the surgery, statin was administered daily to Groups 2 and 4. Serum interleukin-6 (IL-6) level was measured at 5 weeks. Cusps were explanted at 12 weeks and calcium levels were determined by atomic absorption spectroscopy. RESULTS: Mean IL-6 was significantly higher in Group 3 at 5 weeks (7.14, 2.03, 31.70, and 6.90 pg/dL for each group, respectively). Mean calcium level in Group 3 was significantly higher among groups but Group 4 was significantly lower compared to Group 3 and was similar to Group 1, 2 (1.86, 1.92, 2.55, and 1.80 mg/g for each group, respectively, p<0.01). CONCLUSION: Hypercholesterolemia may be a significant risk factor for bovine pericardial valve calcification. Statin treatment significantly attenuated calcification of bovine pericardial valve tissue in a rat subdermal implantation model and might prolong the durability of bioprostheses.

Inhibition of HMG-CoA reductase activity and cholesterol permeation through Caco-2 cells by caffeoylquinic acids from Vernonia condensata leaves

ABSTRACT The aim of this study was to provide scientific knowledge to support the use of Vernonia condensata Baker, Asteraceae, beverages for their alleged hypocholesterolemic properties by testing their action as HMG-CoA reductase inhibitors and their capacity to lower dietary cholesterol permeation. Chlorogenic acid, and other caffeoylquinic acids derivatives were identified as the main components of these beverages by LC–MS/MS. No changes in the composition were notice after the in vitro gastrointestinal digestion and no toxicity against Caco-2 and HepG2 cell lines was detected. Cholesterol permeation through Caco-2 monolayers was reduced in 37% in the presence of these herbal teas, and the caffeoylquinic acids permeated the monolayers in 30–40% of their initial amount in 6 h. HMG-CoA reductase activity was reduced with these beverages, showing an IC50 of 217 µg ml−1. It was concluded that caffeoylquinic acids, the major components, justified 98% of the enzyme inhibition measured.

Effect of hydroalcoholic fruit extract of Persea americana Mill. on high fat diet induced obesity: A dose response study in rats.

The fruits of Persea Americana Mill., commonly known as Avocado, are traditionally consumed for various health benefits including weight reduction. Here, we studied the effect of hydroalcoholic fruit extract of Persea americana (HAEPA) on high fat diet (HFD) induced obesity in rats. Obesity was induced in male Sprague Dawley rats by feeding HFD for 14 wk. The hypolipidemic effect was evaluated by co-administering 25, 50, 100 and 200 mg/kg body wt. of HAEPA. There was a significant increase in weight gain, body mass index (BMI), blood lipids, low density lipoproteins (LDL), lipid peroxides (LPO) and serum transaminases in HFD fed rats. HFD+HAEPA fed rats showed a significant decrease in blood lipids, LPO, liver lipids and increase in antioxidant status when compared to HFD control rats. The activity of lipid metabolic key enzymes such as fatty acid synthase and HMG CoA reductase in liver were also found to be decreased significantly in HAEPA co-administered rats. Lipoprotein lipase activity was found increased in HFD+HAEPA rats. Among the 4 doses studied, 100 mg of HAEPA/kg body wt. exhibited optimum hypolipidemic activity. Histopathological observations in liver and visceral adipose tissue added more evidence for the lipid lowering effect of HAEPA. It can be concluded that avocado fruit extract can act as hypolipidemic agent probably by modulating the activities of HMG CoA reductase and fatty acid synthase in liver.

Effect of Coenzyme Q10 Supplementation in Statin-Treated Obese Rats

Statins, HMG-CoA reductase inhibitors, are known to cause serious muscle injuries (e.g. myopathy, myositis and rhabdomyolysis), and these adverse effects can be rescued by co-administration of coenzyme Q10 (CoQ10) with statins. The goal of the current research is to assess the efficacy of combined treatment of CoQ10 with Atorvastatin for hyperlipidemia induced by high-fat diet in SD rats. 4-week-old Sprague-Dawley male rats were fed normal diet or high-fat diet for 6 weeks. Then, rats were treated with either Statin or Statin with various dosages of CoQ10 (30, 90 or 270 mg/kg/day, p.o.) for another 6 weeks. Compared to Statin only-treatment, CoQ10 supplementation significantly reduced creatine kinase and aspartate aminotransferase levels in serum which are markers for myopathy. Moreover, CoQ10 supplementation with Statin further reduced total fat, triglycerides, total cholesterol, and low-density lipoprotein-cholesterol. In contrast, the levels of high-density lipoprotein-cholesterol and CoQ10 were increased in the CoQ10 co-treated group. These results indicate that CoQ10 treatment not only reduces the side effects of Statin, but also has an anti-obesity effect. Therefore an intake of supplementary CoQ10 is helpful for solving problem of obese metabolism, so the multiple prescription of CoQ10 makes us think a possibility that can be solved in being contiguous to the obesity problem, a sort of disease of the obese metabolism.

Inhibition of HMG-CoA reductase by MFS, a purified extract from the fermentation of marine fungus Fusarium solani FG319, and optimization of MFS production using response surface methodology / 中国天然药物

The present study was designed to isolate and characterize a purified extract from Fusarium solani FG319, termed MFS (Metabolite of Fusarium solani FG319) that showed anti-atherosclerosis activity by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Response surface methodology (RSM) was employed to achieve an improved yield from the fermentation medium. The inhibiting effect of the isolate, MFS, on HMG-CoA reductase was greater than that of the positive control, lovastatin. The average recovery of MFS and the relative standard deviation (RSD) ranged between 99.75% to 101.18%, and 0.31% to 0.74%, respectively. The RSDs intra- and inter-assay of the three samples ranged from 0.288% to 2.438%, and from 0.934% to 2.383%, respectively. From the RSM, the concentration of inducer, cultivation time, and culture temperatures had significant effects on the MFS production, with the effect of inducer concentration being more pronounced that other factors. In conclusion, the optimal conditions for the MFS production were achieved using RSM and that MFS could be explored as an anti-atherosclerosis agent based on its ability to inhibit HMG-CoA reductase.

Optimization, validation and application of an assay for the activity of HMG-CoA reductase in vitro by LC-MS/MS / 药物分析学报

A stable HMG-CoA reductase (HMGR) reaction in vitro was developed by a sensitive, selective and precise liquid chromatography–tandem mass spectrometry (LC–MS/MS) method. The optimized enzyme reac-tion condition contained 1.5μg of HMGR, 20 nM of NADPH with 50 min of reaction time. The method was validated by several intra-and inter-day assays. The production transitions of m/z 147.0/59.1 and m/z 154.0/59.1 were used to detect and quantify mevalonolactone (MVAL) and MVAL-D7, respectively. The accuracy and precision of the method were evaluated over the concentration range of 0.005–1.000μg/mL for MVAL and 0.010–0.500μg/mL for lovastatin acid in three validation batch runs. The lower limit of quantitation was found to be 0.005μg/mL for MVAL and 0.010μg/mL for lovastatin acid. Intra-day and inter-day precision ranged from 0.95%to 2.39%and 2.26%to 3.38%for MVAL, 1.46%to 3.89%and 0.57% to 5.10% for lovastatin acid, respectively. The results showed that the active ingredients in Xuezhikang capsules were 12.2 and 14.5 mg/g, respectively. This assay method could be successfully applied to the quality control study of Xuezhikang capsule for the first time.

Myotonic Potentials in the Myopathy Induced by HMG-CoA Reductase Inhibitor

HMG-CoA reductase inhibitor is widely used for the treatment of dyslipidemia, and for the prevention of stroke and cardiovascular disease. However, it is necessary to consider the adverse effects associated with this drug. Myopathy is a well-known side effect of statin therapy, but myotonic potentials in cases with statin myopathy have thus far been reported only rarely. We report four cases of myopathy with myotonic potentials on electromyography after multidrug administration. All of the patients recovered shortly after statin withdrawal.

In silico analysis of phytochemical compounds for optimizing the inhibitors of HMG CoA reductase.

HMGCoA Reductase (HMGCR), a key enzyme in the cholesterol biosynthesis, catalyzes the conversion of 3- hydroxy-3-methylglutaryl coenzyme A (HMGCoA) into mevalonate. Thus this enzyme is the target of the cholesterol-lowering drugs known as the statins. Phytoformulation1 is a polyherbal formulation consists of the extracts of plant constituents. The present study was designed to examine the ability of the secondary metabolites of Phytoformulation 1 as an antagonist to HMGCoA reductase enzyme by in silico molecular docking. The docking analysis was carried out by Ligand Fit Accelry’s Discovery studio 2.1, which allows virtual screening of database of compounds and predict the strongest binders based on various scoring functions. Fifteen ligands were docked with HMG CoA reductase receptor, out of which four compounds Dichloroacetic acid 2, 2- dimethylpropyl ester, 1, 6, 10-Dodecatriene-3-ol, 3, 7, 11-trimethyl-[S-(Z)]-, Isopropyl acrylate and 3, 3- Dimethylacryloyl chloride were able to form hydrogen bonds with active site of target protein. Thus it may be concluded that the secondary metabolites of Phytoformulation 1 can be an inhibitor of the HMGCR receptor that could be used to treat hyperlipidemia and further in vivo studies may be carried out to prove the same.

Las estatinas: Actividad biologica y produccion biotecnologica / Statins: Biological activity and biotechnological production

Las estatinas de tipo I son metabolitos f¨²ngicos de gran inter¨¦s no s¨®lo por su efecto hipocolesterolemiante sino por el n¨²mero de efectos pleiotr¨®picos que presentan. El papel de las estatinas en la reducci¨®n de l¨ªpidos en la sangre est¨¢ ampliamente documentado. En la actualidad, los estudios cl¨ªnicos han puesto en evidencia que las estatinas impactan positivamente en varios ¨®rganos y en diferentes estados de algunas enfermedades, independientemente de la reducci¨®n en los niveles de colesterol. Exhiben efecto antiinflamatorio, antioxidante y acci¨®n inmunomoduladora, lo que les confiere potencial impacto terap¨¦utico en el tratamiento de varias enfermedades. Estudios recientes las posicionan como antirretrovirales, impidiendo la replicaci¨®n del virus de inmunodeficiencia adquirida (VIH). El hecho de que generan pro-apoptosis, inhibici¨®n en el crecimiento y respuesta a favor de la diferenciaci¨®n de las c¨¦lulas neopl¨¢sicas de diversos or¨ªgenes, las hace ¨²tiles en el tratamiento de leucemia, c¨¢ncer de mama, c¨¢ncer colo-rectal, de pulm¨®n, de pr¨®stata y de p¨¢ncreas. No se deben dejar de lado los efectos ben¨¦ficos sobre el metabolismo ¨®seo, gracias a su asociaci¨®n con el aumento en la densidad mineral ¨®sea y el efecto protector contra el Alzheimer y otros tipos de demencia, posiblemente debido a su participaci¨®n en la relaci¨®n entre el ¦Â-amiloide y los niveles de colesterol.

Statins of type I are fungic metabollites of great importance not only by its hypocholestorolemic but also by its number pleoitropic effects that they show. The role of statins in the reduction of lipids in the blood is broadly reported. Currently, clinic surveys have put into evidence that statins both impact in a positive manner on several organs and in different stages of some diseases, regardless of the cholesterol reduction levels. They show an anti-inflammatory effect, anti-oxidant, and immune modulator action, which give them a therapeutic potential in the treatment of several diseases. Recent studies place them as anti-retrovirus avoiding the replication of the human immunodeficiency virus (HIV). The fact that they generate pro-apoptosis, inhibition on growing, and an favorable effect of the neo-plastic cell differentiation of diverse origins make them useful in the leukemia treatment, breast-cancer, colorectal, lung cancer, prostate cancer, and pancreas cancer. The beneficial side effects on bone metabolism should not be left aside due to its association with the increase of bone mineral density, the protector effect against Alzheimer and other types of dementia, possibly due to its participation in the relationship between ¦¢-amyloid and the cholesterol levels.