Search

Aim: The preparation of a delivery system able to guarantee a delayed release of lovastatin from red yeast rice (RYR) is mandatory to counteract cholesterol biosynthesis effectively., Materials & Methods: Polymeric formulations were prepared mixing alginate and gelatin, in different ratios, with RYR. The effect of different composition on stiffness, viscosity, swelling behavior and mesostructure of matrices was analyzed., Results: Formulations obtained combining polymers in comparable amount (i.e., 60/40 and 50/50) guaranteed a delayed release of lovastatin from RYR, a prolonged inhibitory activity toward 3-hydroxy-3-methylglutaryl-coenzyme A reductase and a decreased cholesterol synthesis., Conclusion: The formulation obtained combining 60% gelatin and 40% of alginate showed physicochemical properties suitable to lead a lovastatin release profile compatible with cholesterol biosynthesis.

PCSK-9 inhibitors are a new, subcutaneously applied, highly efficient and well tolerated lipid lowering treatment, currently available with two active substances – evolocumab and alirocumab. The lipid lowering effect of both of them is very similar, in clinical trials they led to LDL-cholesterol reduction by 50–60%, not only in trials where PCSK-9 inhibitors were added to high-dose statin treatment (FOURIER, ODYSSEY OUTCOMES), but also in trials where patients with statin intolerance (GAUSS-2,3, ODYSSEY ALTERNATIVE) who either did not use statins at all, or only in small doses were included. The following article describes the case-reports of one high-risk patient in secondary prevention of cardiovascular disease suffering from partial statin intolerance, in who the addition of PCSK-9 inhibitors led to a significant LDL-cholesterol reduction, achieving the LDL-cholesterol target value and thereby lowering cardiovascular risk. [ABSTRACT FROM AUTHOR]

While therapy with HMG-CoA reductase inhibitors, or statins, has provided the principal pharmacological innovation in the treatment of hypercholesterolemia in recent years, extensive use of these agents has shown that not all patients respond to them and that still greater reductions in low-density lipoprotein (LDL) cholesterol can further protect patients from cardiovascular events. The strategy of increasing the doses of statins is effective but associated with an increase in adverse effects. The combination of statins with other agents has also, in some cases, increased efficacy, but has likewise been limited by toxicity. The administration of a new agent with a novel mechanism of action, ezetimibe, with a well-characterized and effective statin, simvastatin, in a single tablet now appears to provide enhanced treatment without compromising safety. Monotherapy with either ezetimibe or simvastatin has demonstrated the ability to significantly lower LDL cholesterol. Simultaneous administration of the two agents benefits from their two distinct mechanisms of action: inhibition of biliary and dietary cholesterol absorption by ezetimibe and inhibition of hepatic cholesterol synthesis by simvastatin. The two mechanisms have exhibited complementary activity in preclinical evaluation and have demonstrated an absence of pharmacokinetic interaction in humans. Large clinical trials have consistently shown that the addition of ezetimibe to simvastatin produces significantly greater reductions in LDL cholesterol than simvastatin alone, with tolerability similar to statin monotherapy. Ezetimibe/simvastatin has also been associated with other beneficial effects on lipids, and it achieves greater efficacy than monotherapy with the use of lower, safer doses of the statin. These findings indicate that use of the ezetimibe/simvastatin single tablet will allow more patients to meet increasingly stringent LDL cholesterol goals, thereby avoiding negative cardiovascular outcomes., (Copyright 2005 Prous Science. All rights reserved.)

We have studied the effect of simvastatin, an inhibitor of the rate-limiting enzyme in cholesterol biosynthesis, alone and in combination with cholestyramine in 48 patients. Simvastatin 40 mg decreased total serum cholesterol, LDL cholesterol and apolipoprotein B by 35%, 40% and 35%, respectively, while HDL cholesterol and apolipoprotein A-I increased by 10% (p less than 0.01) and 7% (p less than 0.05), respectively. The addition of 8 g cholestyramine caused a further decrease in total cholesterol and LDL cholesterol to a total of 42% and 49%, respectively. Eighteen of the 48 patients have now been under combined treatment for 2 years. The initial high decreases in total cholesterol and LDL cholesterol were stabilized for the whole period. Some patients developed gastrointestinal complaints, which made necessary a reduction of simvastatin in two cases. Biochemical side effects (e.g. increases in CK and transaminases) were not observed.

Hypercholesterolemia plays a crucial role in the formation of lipid plaques, particularly with elevated low-density lipoprotein (LDL-C) levels, which are linked to increased risks of cardiovascular disease, cerebrovascular disease, and peripheral arterial disease. Controlling blood cholesterol values, specifically reducing LDL-C, is widely recognized as a key modifiable risk factor for decreasing the morbidity and mortality associated with cardiovascular diseases. Historically, statins, by inhibiting the enzyme β-hydroxy β-methylglutaryl-coenzyme A (HMG)-CoA reductase, have been among the most effective drugs. However, newer non-statin agents have since been introduced into hypercholesterolemia therapy, providing a viable alternative with a favorable cost–benefit ratio. This paper aims to delve into the latest therapies, shedding light on their mechanisms of action and therapeutic benefits. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular diseases, with an estimated 18.6 million deaths per year, are the leading cause of death worldwide. One of the major risk factors is elevated blood low-density lipoprotein cholesterol (LDL-C) secondary to multiple environmental and genetic factors. Genes involved in LDL-C metabolism are the targets of the most common treatment options. Advanced molecular techniques could pave the way for identifying novel targets in dyslipidemia therapies. The LIM domain and actin-binding 1 (LIMA1) gene binds to the NPC1L1 protein and facilitates its more efficient recycling to the plasma membrane. Inhibition of LIMA1 could disrupt cellular cholesterol hemostasis with a probable decrease in blood LDL-C levels. Objectives: The present study was designed to knock out exon 2 of the LIMA1 gene using lentiviruses as an in vitro model for reducing cholesterol absorption. Methods: A CRISPR/Cas9 system with dual guide RNAs (gRNAs) was designed to completely excise exon 2 of LIMA1. Two gRNAs (gRNA1 and gRNA2) were cloned in the LentiCRISPR v2 vector. LentiCRISPR viruses were produced in the HEK293T cell line to encode the CRISPR/Cas9 complex structure. HepG2 cell lines were transduced with two different LentiCRISPR viruses simultaneously. Results: Exon 2 deletion was detected by PCR, gel electrophoresis, and subsequent Sanger sequencing of the PCR product. Exon 2 deletion caused a frameshift mutation, and the subsequent production of nonfunctional transcripts led to gene knockout. The dual gRNA CRISPR/Cas9 system could be used in gene editing setups. Conclusions: The in vitro knockout model of LIMA1 could be considered as preliminary work to study the role and mechanism of action of the LIMA1 protein, along with its potential as a target for hypercholesterolemia therapy. [ABSTRACT FROM AUTHOR]

Biotransformation is a process in which molecules are modified in the presence of a biocatalyst or enzymes, as well as the metabolic alterations that occur in organisms from exposure to the molecules. Microbial biotransformation is an important process in natural product drug discovery as novel compounds are biosynthesised. Additionally, biotransformation products offer compounds with improved efficacy, solubility, reduced cytotoxic and allows for the understanding of structure activity relationships. One of the driving forces for these impeccable findings are associated with the presence of cytochrome P450 monooxygenases that is present in all organisms such as mammals, bacteria, and fungi. Numerous fungal strains have been used and reported for their ability to biotransform different compounds. This review focused on studies using Alternaria species as biocatalysts in the biotransformation of natural product compounds. Alternaria species facilitates reactions that favour stereoselectivity, regioselectivity under mild conditions. Additionally, microbial biotransformation products, their application in food, pharmaceutical and agricultural sector is discussed in this review. [ABSTRACT FROM AUTHOR]

The aim of the work was to develop a «green» and extraction-free spectrophotometric procedure for the assay of rosuvastatin in tablets. The present work describes three new spectrophotometric procedures (A, B and C) that can be utilized for routine quality control of rosuvastatin in laboratories. Materials and methods. Analytical instrumentation: Shimadzu UV-1800 double beam UV-vis spectrophotometer (Japan) with attached UV-Probe ver. 2.62 software, RAD WAG AS 200/C precise analytical balance (Poland). Rosuvastatin calcium (purity≥98 % (HPLC)) was bought from Sigma-Aldrich Chemicals Co. (St. Louis, MO, USA). Rosuvastatin 10 mg tablets were acquired from a nearby drugstore. All solvents used in this study, including methanol, ethanol, chloroform, acetonitrile and ethyl acetate, were produced by Honeywell and had a purity of 99.9 %. BCG, BCP and BTB were acquired from Sigma-Aldrich Chemicals Co. (USA, St. Louis). All chemicals utilized in the experiment were of analytical purity. Results and discussion. New simple «green» and extraction-free spectrophotometric procedures for assay of rosuvastatin in tablets involve the formation of ion-pair complexes with sulphophtalein dyes (BCG (Method A), BCP (Method B), BTB (Method C)) have been developed. The absorbances of the coloured reaction products were registered at 405 nm (Method A) and 400 nm (Methods B, C). The concentration was linearly proportional to absorbance values in the range of 2.51-20.08 μg/mL (method A), 2.50-24.90 μg/mL (method B) and 2.51-12.56 μg/mL (method C). Estimation of LOD and LOQ parameters were obtained as 0.67 μg/mL and 2.23 μg/mL (method A), 0.39 μg/mL and 1.32 μg/mL (method B), 0.30 μg/mL and 1.01 μg/mL (method C). The stoichiometric ratio of the reactive components of rosuvastatin - BCG, BCP, and BTB corresponded 1: 1. The %RSD values of intra-day and inter-day were obtained less than <1.5 %, which showed excellent repeatability and RE % data was ≤3 %. The effect on the environment of the proposed spectrophotometric procedures and their compliance with the GAC principles were endorsed by the output of AGREE, GAPI, and AES metrics tools. The values of these three «green» metrics show that the proposed spectrophotometric procedures had a low environmental impact compared with the reported ones. Conclusions. The developed fast, simple and cost-effective methods A, B, and C can be used for routine analysis of rosuvastatin in tablets. [ABSTRACT FROM AUTHOR]

BGT-002, a new type of ATP-citrate lyase inhibitor, is a promising therapeutic for treatment of hypercholesterolemia. After an oral administration of BGT-002 to subjects, it underwent extensive metabolism and an acyl monoglucuronide (ZM326E-M2) on 1- carboxylic acid group was the major circulating metabolite. In this study, an LC-MS/MS method was developed and validated for the simultaneous determination of BGT-002 and ZM326E-M2 in plasma and the evaluation of their pharmacokinetic characteristics in humans. After extraction from the plasma by acetonitrile-induced protein precipitation, the analytes were separated on a Waters ACQUITY UPLC® BEH C 18 column using acetonitrile and 2 mM ammonium acetate containing 0.1% formic acid as the mobile phase for gradient elution. Negative electrospray ionization was performed using multiple reaction monitoring (MRM) of m/z 501.3→325.4 for ZM326E-M2 and m/z 507.3→331.2 for D 6 -ZM326E-M2, and pseudo-MRM of m/z 325.3→325.3 for BGT-002 and m/z 331.3→331.3 for D 6 -ZM326E, respectively. The method was validated with respect to accuracy, precision, linearity, stability, selectivity, matrix effect, and recovery. The analytical range in human plasma was linear over a concentration range of 0.0500–50.0 μg/mL for BGT-002 and 0.0100–10.0 μg/mL for ZM326E-M2. The pharmacokinetic results showed that after a single oral administration of 100 mg BGT-002, the parent drug was rapidly absorbed with a mean time to peak concentration (t max) of 1.13 h, compared with BGT-002, the t max (4.00 h) of ZM326E-M2 was significantly delayed. The peak concentration and plasma exposure of ZM326E-M2 were about 14.1% and 19.5% of the parent drug, suggesting that attention should be paid to the safety and efficacy of ZM326E-M2 in clinical research. • BGT-002 is a new type of ATP-citrate lyase inhibitor developed for hypercholesterolemia therapy • First LC-MS/MS method for the simultaneous quantification of BGT-002 and its acyl glucuronide metabolite in human plasma. • The developed method was successfully applied to a clinical pharmacokinetic study. [ABSTRACT FROM AUTHOR]

The degradation of low-density lipoprotein receptor (LDLR) is induced by proprotein convertase subtilisin/kexin type 9 (PCSK9), resulting in elevated plasma concentrations of LDL cholesterol. Therefore, inhibiting the interactions between PCSK9 and LDLR is a desirable therapeutic goal for managing hypercholesterolemia. Aptamers, which are RNA or single-stranded DNA sequences, can recognize their targets based on their secondary structure. Aptamers exhibit high selectivity and affinity for binding to target molecules. The systematic evolution of ligands by exponential enrichment (SELEX), a combination of biological approaches, is used to screen most aptamers in vitro. Due to their unique advantages, aptamers have garnered significant interest since their discovery and have found extensive applications in various fields. Aptamers have been increasingly utilized in the development of biosensors for sensitive detection of pathogens, analytes, toxins, drug residues, and malignant cells. Furthermore, similar to monoclonal antibodies, aptamers can serve as therapeutic tools. Unlike certain protein therapeutics, aptamers do not elicit antibody responses, and their modified sugars at the 2'-positions generally prevent toll-like receptor-mediated innate immune responses. The focus of this review is on aptamer-based targeting of PCSK9 and the application of aptamers both as biosensors and therapeutic agents. [ABSTRACT FROM AUTHOR]

Squalene monooxygenase catalyzes the epoxidation of C-C double bond of squalene to yield 2,3-oxidosqualene, the key step of sterol biosynthesis pathways in eukaryotes. Sterols are essential compounds of these organisms and squalene epoxidation is an important regulatory point in their synthesis. Squalene monooxygenase downregulation in vertebrates and fungi decreases synthesis of cholesterol and ergosterol, respectively, which makes squalene monooxygenase a potent and attractive target of hypercholesterolemia and antifungal therapies. Currently some fungal squalene monooxygenase inhibitors (terbinafine, naftifine, butenafine) are in clinical use, whereas mammalian enzymes' inhibitors are still under investigation. Research on new squalene monooxygenase inhibitors is important due to the prevalence of hypercholesterolemia and the lack of both sufficient and safe remedies. In this paper we (i) review data on activity and the structure of squalene monooxygenase, (ii) present its inhibitors, (iii) compare current strategies of lowering cholesterol level in blood with some of the most promising strategies, (iv) underline advantages of squalene monooxygenase as a target for hypercholesterolemia therapy, and (v) discuss safety concerns about hypercholesterolemia therapy based on inhibition of cellular cholesterol biosynthesis and potential usage of squalene monooxygenase inhibitors in clinical practice. After many years of use of statins there is some clinical evidence for their adverse effects and only partial effectiveness. Currently they are drugs of choice but are used with many restrictions, especially in case of children, elderly patients and women of childbearing potential. Certainly, for the next few years, statins will continue to be a suitable tool for cost-effective cardiovascular prevention; however research on new hypolipidemic drugs is highly desirable. We suggest that squalene monooxygenase inhibitors could become the hypocholesterolemic agents of the future. [ABSTRACT FROM AUTHOR]

Constitutive expression of short hairpin RNAs (shRNAs) may cause cellular toxicity in vivo and using microRNA (miRNA) scaffolds can circumvent this problem. Previously, we have shown that embedding small interfering RNA sequences targeting apolipoprotein B100 (ApoB) in shRNA (shApoB) or miRNA (miApoB) scaffolds resulted in differential processing and long-term efficacy in vivo. Here we show that adeno-associated virus (AAV)-shApoB- or AAV-miApoB-mediated ApoB knockdown induced differential liver morphology and transcriptome expression changes. Our analyses indicate that ApoB knockdown with both shApoB and miApoB resulted in alterations of genes involved in lipid metabolism. In addition, in AAV-shApoB-injected animals, genes involved in immune system activation or cell growth and death were affected, which was associated with increased hepatocyte proliferation. Subsequently, in AAV-miApoB-injected animals, changes of genes involved in oxidoreductase activity, oxidative phosphorylation and nucleic bases biosynthetic processes were observed. Our results demonstrate that long-term knockdown of ApoB in vivo by shApoB or miApoB induces several transcriptome changes in murine liver. The increased hepatocyte profileration by AAV-shRNA may have severe long-term effects indicating that AAV-mediated RNA interference therapy using artificial miRNA may be a safer approach for familial hypercholesterolemia therapy. [ABSTRACT FROM AUTHOR]

Lung cancer is the most common cause of cancer-related death. Nonetheless, a decrease in overall incidence and mortality has been observed in the last 30 years due to prevention strategies and improvements in the use of chemotherapeutic agents. In recent studies, Simvastatin (SIM) has demonstrated anti-tumor activity, as well as potent chemopreventive action. As an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA), SIM has been shown to stimulate apoptotic cell death. In this study, an MTT assay revealed the cytotoxic activity of SIM against human large cell lung cancer (Non-small cell lung cancer; NSCLC) cells (NCI-H460); however, induced apoptosis was not observed in NCI-H460 cells. Protein expression levels of cell cycle regulating proteins Cdk4, Cyclin D1, p16 and p27 were markedly altered by SIM. Collectively, our results indicate that SIM inhibits cell proliferation and arrests NCI-H460 cell cycle progression via inhibition of cyclin-dependent kinases and cyclins and the enhancement of CDK inhibitors p16 and p27. Our findings suggest that, in addition to the known effects on hypercholesterolemia therapy, SIM may also provide antitumor activity in established NSCLC. [ABSTRACT FROM AUTHOR]

Copyright of CyTA: Journal of Food is the property of Taylor & Francis Ltd 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.)