A novel chemically engineered multifunctional statin conjugate as self-assembled nanoparticles inhibiting bile acid transporters.

Statins are widely used to treat hyperlipidemia; however, their mechanism-inhibiting cholesterol production without promoting its utilization-causes problems, such as inducing diabetes. In our research, we develop, for the first time, a chemically engineered statin conjugate that not only inhibits cholesterol production but also enhances its consumption through its multifunctional properties. The novel rosuvastatin (RO) and ursodeoxycholic acid (UDCA) conjugate (ROUA) is designed to bind to and inhibit the core of the apical sodium-dependent bile acid transporter (ASBT), effectively blocking ASBT's function in the small intestine, maintaining the effect of rosuvastatin. Consequently, ROUA not only preserves the cholesterol-lowering function of statins but also prevents the reabsorption of bile acids, thereby increasing cholesterol consumption. Additionally, ROUA's ability to self-assemble into nanoparticles in saline-attributable to its multiple hydroxyl groups and hydrophobic nature-suggests its potential for a prolonged presence in the body. The oral administration of ROUA nanoparticles in animal models using a high-fat or high-fat/high-fructose diet shows remarkable therapeutic efficacy in fatty liver, with low systemic toxicity. This innovative self-assembling multifunctional molecule design approach, which boosts a variety of therapeutic effects while minimizing toxicity, offers a significant contribution to the advancement of drug development.

Pharmacophore Modeling and Binding Affinity of Secondary Metabolites from Angelica keiskei to HMG Co-A Reductase.

Statins are cholesterol-lowering drugs with a mechanism of inhibiting 3-hydroxy-3-methylglutaryl-CoA reductase, but long-term use can cause side effects. An example of a plant capable of reducing cholesterol levels is Angelica keiskei (ashitaba). Therefore, this study aimed to obtain suitable compounds with inhibitory activity against the HMG-CoA reductase enzyme from ashitaba through in silico tests. The experiment began with screening and pharmacophore modeling, followed by molecular docking on ashitaba's compounds, statins groups, and the native ligand was (3R,5R)-7-[4-(benzyl carbamoyl)-2-(4-fluorophenyl)-5-(1-methylethyl)-1H-imidazole-1-yl]-3,5-dihydroxyheptanoic acid (4HI). Based on the results of the molecular docking simulations, 15 hit compounds had a small binding energy (ΔG). Pitavastatin, as the comparator drug (ΔG = -8.24 kcal/mol; Ki = 2.11 µM), had a lower ΔG and inhibition constant (Ki) than the native ligand 4HI (ΔG = -7.84 kcal/mol; Ki = 7.96µM). From ashitaba's compounds, it was found that 4'-O-geranylnaringenin, luteolin, isobavachalcone, dorsmannin A, and 3'-carboxymethyl-4,2'-dihydroxy-4'-methoxychalcone have low ΔG of below -6 kcal/mol. The lowest ΔG value was found in 3'-carboxymethyl-4,2'-dihydroxy-4'-methoxy chalcone with a ΔG of -6.67 kcal/mol and Ki value of 16.66 µM, which was lower than the ΔG value of the other comparator drugs, atorvastatin (ΔG = -5.49 kcal/mol; Ki = 1148.17 µM) and simvastatin (ΔG = -6.50 kcal/mol; Ki = 22.34 µM). This compound also binds to the important amino acid residues, including ASN755D, ASP690C, GLU559D, LYS735D, LYS691C, and SER684C, through hydrogen bonds. Based on the results, the compound effectively binds to six important amino acids with good binding affinity and only requires a small concentration to reduce half of the enzyme activity.

Structural elucidation and complete NMR spectral assignments of Monascus monacolin analogues.

Three new monacolin analogues, 3,6-dihydroxy-monacolin P (1), 6-methoxy monacolin S (2), and 6-methoxy dehydromonacolin S (3), were isolated from a fraction that strongly inhibited 3-hydroxy-3-methylglutaryl-CoA reductase from the ethyl acetate portion of red yeast rice ethanol extract. Their structures were determined through a combination of 1D and 2D NMR experiments, mass spectrometry analysis, and known literature reports.

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.

Maternidade atrás das grades: em busca da cidadania e da saúde. Um estudo sobre a legislação brasileira / Motherhood behind bars: the struggle for citizens' rights and health for women inmates and their children in Brazil / La maternidad entre rejas: en búsqueda de la ciudadanía y de la salud. Un estudio sobre la legislación brasileña

Este estudo analisa as conexões entre saúde, direitos, legislação e políticas públicas a partir da pesquisa documental realizada no âmbito federal e nos estados do Rio Grande do Sul, Mato Grosso, Paraná e São Paulo, acerca das garantias legais das mulheres e seus filhos que vivem no cárcere. Busca instrumentalizar uma atuação garantista dos agentes públicos e dar visibilidade à problemática, diante das extremas vulnerabilidades e invisibilidade jurídica e administrativa da questão. Foram identificadas 33 normas legais, com pontos de tensão, como a possibilidade de prisão domiciliar e as disparidades quanto a prazos e condições de permanência das crianças no sistema penitenciário. A garantia legal constitucional do direito à amamentação é refletida nas regulamentações identificadas. Mas constatam-se ausências de outros aspectos relativos à maternidade na prisão, que se traduzem em dupla penalidade às mulheres, arbitrariamente estendida aos seus filhos. É necessária a ampliação e efetivação da regulamentação existente para prevenir e coibir as violações de direitos apontadas.

This study analyzes the links between health, rights, legislation, and public policies based on document research on legal safeguards for women and their children residing in prison. The research was conducted at the Federal level and in four States of Brazil: Rio Grande do Sul, Mato Grosso, Paraná, and São Paulo. The study aims to back measures by public agencies to guarantee such rights and to raise awareness of the problem, given the extreme vulnerability of women inmates and their children and the issue's legal and administrative invisibility. The authors identified 33 different legal provisions as points of tension, such as the possibility of house arrest and disparities in the terms and conditions for children to remain inside the prison system. Various provisions cite the Constitutional guarantee of women inmates' right to breastfeed in prison. Meanwhile, the study found gaps in other issues pertaining to motherhood in prison, expressed as dual incarceration (imprisonment arbitrarily extended to their children). It is necessary to expand and enforce the existing legislation to prevent such violations of rights.

Este estudio analiza las conexiones entre la salud, derechos humanos, legislación y políticas públicas, partiendo de una investigación documental, realizada a nivel federal y en los estados de Río Grande do Sul, Mato Grosso, Paraná y São Paulo, sobre las garantías jurídicas de las mujeres presas y sus hijos. El estudio pretende instrumentalizar una actuación garantista de los agentes públicos y dar visibilidad a esta problemática, frente a la extrema vulnerabilidad e invisibilidad jurídica y administrativa existente. Se identificaron 33 normas legales, con puntos de tensión, como la posibilidad de arresto domiciliario y disparidades en cuanto a los términos y condiciones de la estancia de los niños en el sistema penitenciario. La garantía constitucional del derecho a la lactancia materna se refleja en las regulaciones identificadas. No obstante, hay ausencias de otros aspectos de la maternidad en la cárcel, que se traduce en una doble pena para las mujeres, extendida arbitrariamente a sus hijos. Es necesaria la ampliación y ejecución efectiva de las regulación existente para prevenir y frenar las violaciones de los derechos.

Papel das estatinas na modulação da função endotelial vasomotora na hipertensão e doença coronariana / The role of statins in the modulation of endothelium vasomotor function in hypertension and coronary artery disease

o benefício em longo prazo do tratamento com estatinas naprevenção de eventos coronarianos primários e secundários éindiscutível. Embora uma parte deste benefício esteja ligadaao efeito sobre a redução da circulação de lipoproteínasaterogênicas, outros mecanismos, como a modulação datrombogênese, a redução da inflamação e melhora da funçãoendotelial, têm sido investigados. O efeito da estatina sobrea função endotelial está ligado à sua inibição da produçãode superóxido e sua regulação positiva da síntese do óxidonítrico (NOS) no endotélio. Na prática clínica, o benefíciona função do endotélio depois do tratamento com estatinatem sido observado em uma ampla variedade de condiçõesque incluem a hipertensão arterial sistêmica, doença arterialcrônica e síndrome coronariana aguda. Esta breve revisãoincidirá sobre as principais conclusões relacionadas à terapiacom estatina sobre o tônus arterial sistêmico e doença arterialcoronariana aguda e crônica...

The long-term benefit of statin treatment on the prevention of primary and secondary coronary events is undisputed. Although a proportion of this effect has been linked to its reduction of circulating atherogenic lipoproteins, other mechanisms have been studied such as modulation of thrombogenesis, reduction of inflammation, and improvement of endothelia! function. Its favorable effect on endothelial function is tied to its inhibition of superoxide production and its positive regulation of nitric oxide synthase (NOS) in the endothelium. In the clinica! setting, the gain in endothelia! function after statin treatment has been observed in a wide range of conditions that include systernic hypertension, chronic arterial disease, and acute coronary syndrome. This brief review will focus on the main findings related to statin therapy on the systernic arterial tone and both acute and chronic coronary artery disease...

Farmacocinética das estatinas / Pharmacokinetics of statins

As estatinas são agentes hipolipemiantes que exercem os seus efeitos através da inibição da HMG-CoA redutase, enzima fundamental na síntese do colesterol, levando a uma redução do colesterol tecidual e um conseqüente aumento na expressão dos receptores de LDL. Existem consideráveis diferenças entre as estatinas, no que tange às propriedades farmacocinéticas, bem como ao coeficiente de hidrofilicidade, via hepática de metabolização (especialmente, do citocromo P450 e isoenzimas), meia-vida plasmática e eficácia na redução lipídica. As estatinas também podem diferir na capacidade de interação com outras drogas que utilizam a mesma via de metabolização. Recentemente, muitos efeitos pleiotrópicos têm sido relatados com estas drogas, bem como propriedades antiinflamatórias, melhora na função endotelial e benefícios na hemostasia.