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1.
Curr Atheroscler Rep ; 22(11): 64, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32870376

RESUMO

PURPOSE OF REVIEW: Statins are first-line therapy for lowering low-density lipoprotein (LDL) cholesterol in familial hypercholesterolemia (FH), particularly in heterozygous patients. We review advances and new questions on the use of statins in FH. RECENT FINDINGS: Cumulative evidence from registry data and sub-analyses of clinical trials mandates the value of statin therapy for prevention of atherosclerotic cardiovascular disease (ASCVD) in FH. Statins are safe in children and adolescents with FH, with longer term cardiovascular benefits. The potentially toxic effects of statins in pregnancy need to be considered, but no association has been reported in prospective cohort studies with birth defects. There is no rationale for discontinuation of statins in elderly FH unless indicated by adverse events. FH is undertreated, with > 80% of statin-treated FH patients failing to attain LDL cholesterol treatment targets. This may relate to adherence, tolerability, and genetic differences in statin responsiveness. Statin treatment from childhood may reduce the need for stringent cholesterol targets. Combination of statins with ezetimibe and PCSK9 inhibitors significantly improves the efficacy of treatment. Whether statin use could improve the clinical course of FH patients with COVID-19 and other respiratory infections remains an unsolved issue for future research. Statins are the mainstay for primary and secondary prevention of ASCVD in FH. Sustained long-term optimal statin treatment from an early age can effectively prevent ASCVD over decades of life. Despite their widespread use, statins merit further investigation in FH.


Assuntos
Infecções por Coronavirus/epidemiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hiperlipoproteinemia Tipo II , Conduta do Tratamento Medicamentoso , Pneumonia Viral/epidemiologia , Anticolesterolemiantes/classificação , Anticolesterolemiantes/farmacologia , Betacoronavirus , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Humanos , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/epidemiologia , Pandemias
2.
Vnitr Lek ; 66(5): 96-100, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32942879

RESUMO

PCSK9 inhibitors (inhibitors of proprotein convertase subtilisin/kexin type 9) offer a promising treatment strategy decreasing the concentrations of both atherogenic low density lipoprotein (LDL) and cholesterol contained within LDL. Alirocumab is one of two PCSK9 inhibitors that entered clinical practice so far. Alirocumab is a specific antibody against PCSK9, manufactured using recombinant technique. When the antibody binds to the PCSK9 isoenzyme, no complex encompassing PCSK9 and LDL receptor can be formed, thus enabling further recirculation of the LDL receptor. Increasing the amount of LDL receptors available on the cell membranes leads to higher internalization of LDL within cells and to lowering of LDL cholesterol concentration. It has been shown that alirocumab exerts favorable effect on atherogenic lipoproteins (i.e. decrease of concentrations of LDL cholesterol by more than 50%) both in monotherapy and in combination with statins or other hypolipidemics. Odyssey Outcomes study brought new information into light and changed the guidelines of treating the patients with cardivascular diseases. Alirokumab added to intensive statin therapy reduced significantly the risk of cardiovascular diseases and the post hoc analysis confirmed also the reduction of total death rate. The positive effect of alirocumab is higher in patients with higher initial LDL-C. The therapy with alirokumab is safe, with minimum adverse events.


Assuntos
Anticolesterolemiantes , Inibidores de Hidroximetilglutaril-CoA Redutases , Hipercolesterolemia , Anticorpos Monoclonais Humanizados , Anticolesterolemiantes/farmacologia , Anticolesterolemiantes/uso terapêutico , Humanos , Pró-Proteína Convertase 9
3.
Food Chem ; 332: 127372, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32615381

RESUMO

The physicochemical and physiological properties of soluble dietary fiber (SDF) and insoluble dietary fiber (IDF) from bamboo shoots were investigated in present study. IDF showed better adsorption capacity than the corresponding SDF from the same species. Microstructure observation results indicated that the surface of IDF was porous, whereas the SDF was relatively flat and compact. The cholesterol-adsorption capacities of IDF and SDF from Fargesia spathacea were relatively higher than the other species. Both SDF and IDF from F. spathacea showed potential prebiotic effects, although the Lactobacillus and Bifidobacterium promotion effects of SDF were relatively stronger than IDF. Compared with control, the concentration of total short chain fatty acids in IDF and SDF supplement groups were increased by 1.28 and 0.71 folds, respectively. These results suggested that F. spathacea dietary fibers with strong cholesterol-adsorption activity and prebiotic potential, could be used as a bioactive ingredient in functional foods production.


Assuntos
Anticolesterolemiantes/química , Anticolesterolemiantes/farmacologia , Fibras na Dieta/farmacologia , Caules de Planta/química , Poaceae/química , Prebióticos , Fenômenos Químicos , Suplementos Nutricionais , Alimento Funcional/análise
4.
Turk Kardiyol Dern Ars ; 48(4): 410-424, 2020 06.
Artigo em Inglês | MEDLINE | ID: covidwho-595169

RESUMO

OBJECTIVE: The aim of this study was to evaluate the effectiveness of plants used in the formulations of traditional Chinese medicine (TCM), which were also used in clinical trials to treat patients with the novel coronavirus COVID-19, and to assess their effects on the cardiovascular system. METHODS: A literature review of PubMed, ResearchGate, ScienceDirect, the Cochrane Library, and TCM monographs was conducted and the effects of the plants on the cardiovascular system and the mechanisms of action in COVID-19 treatment were evaluated. RESULTS: The mechanism of action, cardiovascular effects, and possible toxicity of 10 plants frequently found in TCM formulations that were used in the clinical treatment of COVID-19 were examined. CONCLUSION: TCM formulations that had been originally developed for earlier viral diseases have been used in COVID-19 treatment. Despite the effectiveness seen in laboratory and animal studies with the most commonly used plants in these formulations, the clinical studies are currently insufficient according to standard operating procedures. More clinical studies are needed to understand the safe clinical use of traditional plants.


Assuntos
Sistema Cardiovascular/efeitos dos fármacos , Infecções por Coronavirus/terapia , Medicamentos de Ervas Chinesas/uso terapêutico , Medicina Tradicional Chinesa , Pneumonia Viral/terapia , Animais , Antiarrítmicos/farmacologia , Antiarrítmicos/uso terapêutico , Antiarrítmicos/toxicidade , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/toxicidade , Anticolesterolemiantes/farmacologia , Anticolesterolemiantes/uso terapêutico , Anticolesterolemiantes/toxicidade , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Anti-Hipertensivos/toxicidade , Antivirais/farmacologia , Antivirais/uso terapêutico , Antivirais/toxicidade , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Bloqueadores dos Canais de Cálcio/toxicidade , Interações Medicamentosas , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/toxicidade , Humanos , Pandemias , Inibidores da Agregação de Plaquetas/farmacologia , Inibidores da Agregação de Plaquetas/uso terapêutico , Inibidores da Agregação de Plaquetas/toxicidade , Vasodilatadores/farmacologia , Vasodilatadores/uso terapêutico , Vasodilatadores/toxicidade
5.
Turk Kardiyol Dern Ars ; 48(4): 410-424, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32519978

RESUMO

OBJECTIVE: The aim of this study was to evaluate the effectiveness of plants used in the formulations of traditional Chinese medicine (TCM), which were also used in clinical trials to treat patients with the novel coronavirus COVID-19, and to assess their effects on the cardiovascular system. METHODS: A literature review of PubMed, ResearchGate, ScienceDirect, the Cochrane Library, and TCM monographs was conducted and the effects of the plants on the cardiovascular system and the mechanisms of action in COVID-19 treatment were evaluated. RESULTS: The mechanism of action, cardiovascular effects, and possible toxicity of 10 plants frequently found in TCM formulations that were used in the clinical treatment of COVID-19 were examined. CONCLUSION: TCM formulations that had been originally developed for earlier viral diseases have been used in COVID-19 treatment. Despite the effectiveness seen in laboratory and animal studies with the most commonly used plants in these formulations, the clinical studies are currently insufficient according to standard operating procedures. More clinical studies are needed to understand the safe clinical use of traditional plants.


Assuntos
Sistema Cardiovascular/efeitos dos fármacos , Infecções por Coronavirus/terapia , Medicamentos de Ervas Chinesas/uso terapêutico , Medicina Tradicional Chinesa , Pneumonia Viral/terapia , Animais , Antiarrítmicos/farmacologia , Antiarrítmicos/uso terapêutico , Antiarrítmicos/toxicidade , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/toxicidade , Anticolesterolemiantes/farmacologia , Anticolesterolemiantes/uso terapêutico , Anticolesterolemiantes/toxicidade , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Anti-Hipertensivos/toxicidade , Antivirais/farmacologia , Antivirais/uso terapêutico , Antivirais/toxicidade , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Bloqueadores dos Canais de Cálcio/toxicidade , Interações Medicamentosas , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/toxicidade , Humanos , Pandemias , Inibidores da Agregação de Plaquetas/farmacologia , Inibidores da Agregação de Plaquetas/uso terapêutico , Inibidores da Agregação de Plaquetas/toxicidade , Vasodilatadores/farmacologia , Vasodilatadores/uso terapêutico , Vasodilatadores/toxicidade
7.
Acta Cir Bras ; 35(1): e202000102, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32215463

RESUMO

PURPOSE: To evaluate the local effect of simvastatin (SVT) combined with deproteinized bovine bone (DBB) with hydroxyapatite/ß-tricalcium phosphate biphasic ceramics (HA/TCP) and with collagen sponge (CS) on bone repair in critical size defects (CSDs) in rat calvaria. METHODS: Forty-two 5-mm diameter CSDs were made bilaterally in the calvaria of 18 rats. The animals were allocated according to the type of biomaterial and associations used to fill the CSD. After 8 weeks, the animals were euthanized, and their calvaria were evaluated for repaired tissue composition using histologic and histometric analyses. RESULTS: In the histometric analysis, the use of SVT showed to increase bone formation in the CSDs when combined with all the bone substitutes tested in this study (p<0.05). Greater bone formation was observed in the groups with SVT compared to the groups without SVT. CONCLUSIONS: The use of SVT without the need for a vehicle and combined with a commercially available biomaterial may be a cheaper way to potentiate the formation of bone tissue without the need to produce new biomaterials. Therefore, SVT combined with DBB induced significantly greater new bone formation than did the other treatments.


Assuntos
Materiais Biocompatíveis/farmacologia , Substitutos Ósseos/farmacologia , Colágeno/farmacologia , Osteogênese/efeitos dos fármacos , Sinvastatina/farmacologia , Crânio/efeitos dos fármacos , Animais , Anticolesterolemiantes/farmacologia , Regeneração Óssea/efeitos dos fármacos , Transplante Ósseo/métodos , Bovinos , Modelos Animais de Doenças , Feminino , Ratos , Ratos Wistar , Crânio/cirurgia
8.
Int J Nanomedicine ; 15: 1335-1347, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32184589

RESUMO

Background: Atorvastatin calcium (AT) is an ocular anti-inflammatory with limited bioavailability when taken orally due to its low solubility in low pH and extensive first-pass effect. To overcome these problems, AT was entrapped in polymeric nanoparticles (NPs) to improve surface properties and sustained release, in addition to achieving site-specific action. Methods: AT was entrapped in chitosan (CS)-coated polylactic-co-glycolic acid (PLGA) NPs to form AT-PLGA-CS-NPs (F1). F1 and free AT were embedded in thermosensitive Pluronic®127-hydroxypropyl methylcellulose (HPMC) to form thermosensitive gels (F2) and (F3) while F4 is AT suspension in water. F1 was assessed for size, surface charge, polydispersity index (PDI), and morphology. F2 and F3 were examined for gelation temperature, gel strength, pH, and viscosity. In vitro release of the four formulations was also investigated. The ocular irritancy and anti-inflammatory efficacy of formulations against prostaglandin E1-(PGE1) induced ocular inflammation in rabbits were investigated by counting the polymorphonuclear leukocytes (PMNs) and protein migrated in tears. Results: Oval F1 of 80.0-190.0±21.6 nm exhibited a PDI of 0.331 and zeta potential of 17.4±5.62 mV with a positive surface charge. F2 and F3 gelation temperatures were 35.17±0.22°C and 36.93±0.31°C, viscosity 12,243±0.64 and 9759±0.22 cP, gel strength 15.56±0.6 and 12.45±0.1 s, and pHs of 7.4±0.02 and 7.4±0.1, respectively. In vitro release of F1, F2, F3, and F4 were 48.21±0.31, 26.48±0.5, 84.76±0.11, and 100% after 24 hrs, respectively. All formulations were non-irritant. F2 significantly inhibited lid closure up to 3 h, PMN counts and proteins in tear fluids up to 5 h compared to other formulations. Conclusion: AT-PLGA-CS-NP thermosensitive gels proved to be successful ocular anti-inflammatory drug delivery systems.


Assuntos
Anti-Inflamatórios/farmacologia , Atorvastatina/farmacologia , Quitosana/química , Oftalmopatias/tratamento farmacológico , Inflamação/tratamento farmacológico , Nanopartículas/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Animais , Anti-Inflamatórios/administração & dosagem , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/farmacologia , Atorvastatina/administração & dosagem , Materiais Biocompatíveis/química , Disponibilidade Biológica , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Oftalmopatias/induzido quimicamente , Oftalmopatias/patologia , Géis/química , Inflamação/induzido quimicamente , Inflamação/patologia , Nanopartículas/química , Coelhos
9.
Clin Sci (Lond) ; 134(5): 439-458, 2020 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-32091078

RESUMO

Sphingolipids have been implicated in the etiology of atherosclerosis. The commonly used sphingolipid inhibitors, myriocin (a ceramide inhibitor) and d-PDMP (d-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol, a glycosphingolipid inhibitor), have shown therapeutic potential but their efficacy and their underlying mechanisms remain unclear. Here, apolipoprotein E-deficient (apoE-/-) mice were fed a high-fat diet (HFD) and treated with a control, myriocin, d-PDMP, or atorvastatin for 12 weeks. We analyzed the effects of these drugs on the size and detailed composition of atherosclerotic plaques. Molecular biological approaches were used to explore how the inhibitors affect lipid metabolism and foam-cell formation. Treatment with myriocin or d-PDMP led to smaller and less vulnerable atherosclerotic lesions and was almost as effective as atorvastatin. Sphingolipid inhibitors down-regulated the expression of monocyte chemotactic protein 1 (MCP-1) and its receptor chemoattractant cytokine receptor 2 (CCR2), which play a key role in monocyte recruitment. They also decreased pro-inflammatory Ly-6chigh monocytes and influenced the uptake of modified LDL by down-regulating the expression of cluster of differentiation 36 (CD36) and lectin-like oxidized LDL (ox-LDL) receptor-1 (LOX-1). The inhibitors exhibited the advantage of maintaining normal glucose homeostasis compared with atorvastatin. These findings reveal for the first time that the modulation of sphingolipid synthesis can effectively alleviate atherosclerosis progression by preventing lipid uptake and reducing inflammatory responses in the arterial walls.


Assuntos
Apolipoproteínas E/deficiência , Aterosclerose/prevenção & controle , Ácidos Graxos Monoinsaturados/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Morfolinas/farmacologia , Vasculite/prevenção & controle , Animais , Anticolesterolemiantes/farmacologia , Apolipoproteínas E/genética , Aterosclerose/metabolismo , Atorvastatina/farmacologia , Transporte Biológico/efeitos dos fármacos , Ceramidas/antagonistas & inibidores , Ceramidas/metabolismo , Glicoesfingolipídeos/antagonistas & inibidores , Glicoesfingolipídeos/metabolismo , Imunossupressores/farmacologia , Lipídeos/sangue , Lipídeos/farmacocinética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , Placa Aterosclerótica/prevenção & controle , Vasculite/metabolismo
10.
J Exp Clin Cancer Res ; 39(1): 24, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32000827

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is a common primary malignant tumor which usually progresses to an advanced stage because of late diagnosis. Sorafenib (Sora) is a first line medicine for advanced stage HCC; however, it has been faced with enormous resistance. Simvastatin (Sim) is a cholesterol-lowering drug and has been reported to inhibit tumor growth. The present study aims to determine whether Sora and Sim co-treatment can improve Sora resistance in HCC. METHODS: The HCC cell line LM3 and an established Sora-resistant LM3 cell line (LM3-SR) were used to study the relationship between Sora resistance and aerobic glycolysis. Cell proliferation, apoptosis and glycolysis levels were analyzed by western blotting, flow cytometry analysis and biomedical tests. A xenograft model was also used to examine the effect of Sim in vivo. Detailed mechanistic studies were also undertaken by the use of activators and inhibitors, and lentivirus transfections. RESULTS: Our results demonstrated that the resistance to Sora was associated with enhanced aerobic glycolysis levels. Furthermore, LM3-SR cells were more sensitive to Sim than LM3 cells, suggesting that combined treatment with both Sora and Sim could enhance the sensitivity of LM3-SR cells to Sora. This finding may be due to the suppression of the HIF-1α/PPAR-γ/PKM2 axis. CONCLUSIONS: Simvastatin can inhibit the HIF-1α/PPAR-γ/PKM2 axis, by suppressing PKM2-mediated glycolysis, resulting in decreased proliferation and increased apoptosis in HCC cells, and re-sensitizing HCC cells to Sora.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Proteínas de Transporte/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Neoplasias Hepáticas/tratamento farmacológico , Proteínas de Membrana/antagonistas & inibidores , PPAR gama/antagonistas & inibidores , Sinvastatina/farmacologia , Sorafenibe/farmacologia , Animais , Anticolesterolemiantes/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Glicólise/efeitos dos fármacos , Células Hep G2 , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Nus , PPAR gama/metabolismo , Hormônios Tireóideos/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Chem Biol Interact ; 318: 108970, 2020 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-32007421

RESUMO

Cardiovascular disorders constitute the principal cause of deaths worldwide and will continue as the major disease-burden by the year 2060. A significant proportion of heart failures occur because of use and misuse of drugs and most of the investigational agents fail to achieve any clinical relevance. Here, we investigated rosuvastatin and retinoic acid for their "pharmacological pleiotropy" against high dose ß-adrenergic agonist (isoproterenol)-induced acute myocardial insult. Rats were pretreated with rosuvastatin and/or retinoic acid for seven days and the myocardial injury was induced by administering isoproterenol on the seventh and eighth day. After induction, rats were anaesthetized for electrocardiography, then sacrificed and different samples were collected/stored for various downstream assays. Myocardial injury with isoproterenol resulted in increased cardiac mass, decreased R-wave amplitude, increased QRS and QT durations; elevated levels of cardiac markers like cTnI, CK-MB, ALT and AST; increased lipid peroxidation, protein carbonylation and tissue nitric oxide levels; decreased endogenous antioxidants like SOD, CAT, GR, GST, GPx and total antioxidant activity; increased inflammatory markers like TNF-α and IL-6; decreased the mRNA expression of Nrf2 and Bcl-2; increased the mRNA expression of Bax, eNOS and iNOS genes. Pretreatment with rosuvastatin and/or retinoic acid mitigated many of the above biochemical and pathological alterations. Our results demonstrate that rosuvastatin and retinoic acid exert cardioprotective effects and may act as potential agents in the prevention of ß-adrenergic agonist-induced acute myocardial injury in rats. Cardioprotective potential of rosuvastatin and retinoic acid could be attributed to their influence on the redox pathways, immunomodulation, membrane stability, Nrf2 preservation, iNOS and Bax expression levels. Thus, they may act directly or indirectly at various steps, the breakpoints, in the pathophysiological cascade responsible for cardiac injury. Our study gives insights about the pharmacological pleiotropism of rosuvastatin and retinoic acid.


Assuntos
Isoproterenol/toxicidade , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/prevenção & controle , Rosuvastatina Cálcica/farmacologia , Transdução de Sinais/efeitos dos fármacos , Tretinoína/farmacologia , Agonistas Adrenérgicos beta/toxicidade , Animais , Anticolesterolemiantes/farmacologia , Antineoplásicos/uso terapêutico , Peso Corporal/efeitos dos fármacos , Coração/anatomia & histologia , Coração/efeitos dos fármacos , Masculino , Tamanho do Órgão , Distribuição Aleatória , Ratos , Ratos Wistar
12.
Sci Rep ; 10(1): 2158, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32034223

RESUMO

Statin-related muscle side effects are a constant healthcare problem since patient compliance is dependent on side effects. Statins reduce plasma cholesterol levels and can prevent secondary cardiovascular diseases. Although statin-induced muscle damage has been studied, preventive or curative therapies are yet to be reported. We exposed primary human muscle cell populations (n = 22) to a lipophilic (simvastatin) and a hydrophilic (rosuvastatin) statin and analyzed their expressome. Data and pathway analyses included GOrilla, Reactome and DAVID. We measured mevalonate intracellularly and analyzed eicosanoid profiles secreted by human muscle cells. Functional assays included proliferation and differentiation quantification. More than 1800 transcripts and 900 proteins were differentially expressed after exposure to statins. Simvastatin had a stronger effect on the expressome than rosuvastatin, but both statins influenced cholesterol biosynthesis, fatty acid metabolism, eicosanoid synthesis, proliferation, and differentiation of human muscle cells. Cultured human muscle cells secreted ω-3 and ω-6 derived eicosanoids and prostaglandins. The ω-6 derived metabolites were found at higher levels secreted from simvastatin-treated primary human muscle cells. Eicosanoids rescued muscle cell differentiation. Our data suggest a new aspect on the role of skeletal muscle in cholesterol metabolism. For clinical practice, the addition of omega-n fatty acids might be suitable to prevent or treat statin-myopathy.


Assuntos
Anticolesterolemiantes/farmacologia , Dinoprosta/metabolismo , Fibras Musculares Esqueléticas/efeitos dos fármacos , Rosuvastatina Cálcica/farmacologia , Sinvastatina/farmacologia , Transcriptoma , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Dinoprosta/farmacologia , Humanos , Fibras Musculares Esqueléticas/citologia , Fibras Musculares Esqueléticas/metabolismo
13.
Acta Vet Scand ; 62(1): 2, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31907058

RESUMO

BACKGROUND: The ATP binding cassette (ABC) transporters participate in the cholesterol and phospholipid transport within and through cell membranes of many cells including spermatozoa. Cholesterol efflux is important for capacitation of spermatozoa. ABCA1 expression has been assessed in canine spermatozoa previously but its role in capacitation still has to be determined. The aim of the study was to test whether inhibition of ABCA1 (1) decreases capacitation in ejaculated and epididymal canine sperm samples and (2) decreases cholesterol efflux in the same samples. Twenty-one ejaculates and sperm from 22 epididymal tails were collected from healthy dogs. Motility was measured by CASA and viability assessed after staining with SYBR-14/PI. Samples from ejaculated sperm and sperm from epididymal tails were aliquoted. One part was incubated with the ABCA1 inhibitor probucol, the other served as a negative control. In all samples, capacitation was evaluated by chlortetracyclin (CTC) assay and cholesterol was measured by cholesterol efflux assay and colorimetric enzymatic assay. RESULTS: In ejaculated sperm, blockade of ABCA1 with 100 µM of probucol/mL of sample resulted in a significantly higher percentage of uncapacitated and acrosome reacted spermatozoa (P < 0.001 and P = 0.031), capacitation was significantly decreased (35% in probucol samples vs 54.2% in controls, P < 0.001). In probucol inhibited sperm samples from epididymal tails, the percentage of capacitated spermatozoa did not differ between groups but the percentage of acrosome reacted spermatozoa increased significantly (P = 0.014). The cholesterol measurement revealed significantly lower cholesterol concentration in the probucol group when compared to the controls (P = 0.035), however only in ejaculated sperm samples. CONCLUSIONS: CTC assay and cholesterol measurement revealed significant differences between groups; we conclude that inhibition of ABCA1 significantly decreased capacitation and cholesterol efflux in ejaculated canine spermatozoa. The inhibition was not complete but ABCA1 is supposed to contribute to capacitation in canine ejaculated spermatozoa. ABCA1 is probably not important for capacitation of epididymal spermatozoa but might exert other functions during spermatozoa ripening.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/antagonistas & inibidores , Colesterol/metabolismo , Probucol/farmacologia , Capacitação Espermática/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Animais , Anticolesterolemiantes/farmacologia , Cães , Masculino
14.
J Biotechnol ; 309: 85-91, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-31926180

RESUMO

Ascomycete fungi Cordyceps are widely used in traditional Chinese medicine, and numerous investigations have been carried out to uncover their biological activities. However, primary researches on the physiological effects of Cordyceps were committed using crude extracts. At present, there are only a few compounds which were comprehensively characterized from Cordyceps, partial owing to the low production. In order to scientifically take advantage of Cordyceps, we used the strategy of genome mining to discover bioactive compounds from Cordyceps militaris. We found the putative biosynthetic gene cluster of the acyl-CoA:cholesterol acyltransferase inhibitor beauveriolides in the genome of C. militaris, and produced the compounds by heterologous expression in Aspergillus nidulans. Production of beauveriolide I and III also was detected in both ferment mycelia and fruiting bodies of C. militaris. The possible biosynthetic pathway was proposed. Our studies unveil the active compounds of C. militaris against atherosclerosis and Alzheimer's disease and provide the enzyme resources for the biosynthesis of new cyclodepsipeptide molecules.


Assuntos
Anticolesterolemiantes/metabolismo , Cordyceps/genética , Cordyceps/metabolismo , Depsipeptídeos/biossíntese , Depsipeptídeos/genética , Esterol O-Aciltransferase/efeitos dos fármacos , Acil Coenzima A/metabolismo , Doença de Alzheimer , Anticolesterolemiantes/farmacologia , Aspergillus nidulans/genética , Aterosclerose , Vias Biossintéticas/genética , Clonagem Molecular , Depsipeptídeos/química , Depsipeptídeos/isolamento & purificação , Carpóforos/metabolismo , Regulação Fúngica da Expressão Gênica , Medicina Tradicional Chinesa , Família Multigênica
15.
Curr Atheroscler Rep ; 22(1): 3, 2020 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-31927694

RESUMO

PURPOSE OF THE REVIEW: This review highlights selected cardiovascular disease (CVD) prevention studies presented at the 2019 American Heart Association (AHA) Scientific Sessions. RECENT FINDINGS: Several important cardiovascular prevention studies were presented at the 2019 AHA Scientific Sessions. Results from the Colchicine Cardiovascular Outcomes Trial (COLCOT) showed that low-dose colchicine reduces the risk of recurrent CVD events among patients with recent myocardial infarction. A prospective analysis from the UK Biobank cohort demonstrated that the increased CVD risk associated with clonal hematopoiesis of indeterminate potential is mitigated by a common disruptive mutation in the IL6R gene that suppresses the pro-inflammatory IL-1ß/IL-6 pathway. The Treat Stroke to Target trial demonstrated that reducing low-density lipoprotein cholesterol to <70 mg/dL among patients with ischemic stroke or transient ischemic attack reduces the risk of recurrent CVD events as compared with a higher LDL-C target of 90-110 mg/dL. A secondary analysis focusing on American participants enrolled in the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) showed that these patients receive a similar benefit in terms of cardiovascular risk reduction with icosapent ethyl as compared with the entire trial population. A post hoc analysis of the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial demonstrated that a genetic risk score comprising 27 single-nucleotide polymorphisms is associated with cardiovascular risk among patients with established atherosclerotic CVD and patients with high genetic risk receive a relatively higher benefit from evolocumab use. Similar results were observed with alirocumab use in a post hoc analysis of the ODYSSEY OUTCOMES trial where a genome-wide polygenic risk score comprising 6.5 million DNA variants was used. These studies presented at 2019 AHA Scientific Sessions will help guide our approach to preventing CVD.


Assuntos
American Heart Association , Aterosclerose/prevenção & controle , Infarto do Miocárdio/prevenção & controle , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticolesterolemiantes/farmacologia , Anticolesterolemiantes/uso terapêutico , Aterosclerose/tratamento farmacológico , Aterosclerose/genética , Colchicina/uso terapêutico , Ácido Eicosapentaenoico/análogos & derivados , Ácido Eicosapentaenoico/uso terapêutico , Humanos , Interleucina-6/metabolismo , Mutação , Infarto do Miocárdio/tratamento farmacológico , Pró-Proteína Convertase 9/antagonistas & inibidores , Receptores de Interleucina-6/genética , Fatores de Risco , Estados Unidos
16.
Lipids Health Dis ; 19(1): 6, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31931807

RESUMO

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


Assuntos
Anticolesterolemiantes/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Placa Aterosclerótica/tratamento farmacológico , Prosopis/química , Animais , Anticolesterolemiantes/química , HDL-Colesterol/sangue , LDL-Colesterol/sangue , VLDL-Colesterol/sangue , Modelos Animais de Doenças , Hidroximetilglutaril-CoA Redutases/genética , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Hipercolesterolemia/tratamento farmacológico , Masculino , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Placa Aterosclerótica/sangue , Placa Aterosclerótica/patologia , Pravastatina/farmacologia , Coelhos , Triglicerídeos/sangue
17.
Pharmacol Rev ; 72(1): 152-190, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31831519

RESUMO

Atherosclerosis is a leading cause of cardiovascular disease worldwide, and hypercholesterolemia is a major risk factor. Preventive treatments mainly focus on the effective reduction of low-density lipoprotein cholesterol, but their therapeutic value is limited by the inability to completely normalize atherosclerotic risk, probably due to the disease complexity and multifactorial pathogenesis. Consequently, high-density lipoprotein cholesterol gained much interest, as it appeared to be cardioprotective due to its major role in reverse cholesterol transport (RCT). RCT facilitates removal of cholesterol from peripheral tissues, including atherosclerotic plaques, and its subsequent hepatic clearance into bile. Therefore, RCT is expected to limit plaque formation and progression. Cellular cholesterol efflux is initiated and propagated by the ATP-binding cassette (ABC) transporters ABCA1 and ABCG1. Their expression and function are expected to be rate-limiting for cholesterol efflux, which makes them interesting targets to stimulate RCT and lower atherosclerotic risk. This systematic review discusses the molecular mechanisms relevant for RCT and ABCA1 and ABCG1 function, followed by a critical overview of potential pharmacological strategies with small molecules to enhance cellular cholesterol efflux and RCT. These strategies include regulation of ABCA1 and ABCG1 expression, degradation, and mRNA stability. Various small molecules have been demonstrated to increase RCT, but the underlying mechanisms are often not completely understood and are rather unspecific, potentially causing adverse effects. Better understanding of these mechanisms could enable the development of safer drugs to increase RCT and provide more insight into its relation with atherosclerotic risk. SIGNIFICANCE STATEMENT: Hypercholesterolemia is an important risk factor of atherosclerosis, which is a leading pathological mechanism underlying cardiovascular disease. Cholesterol is removed from atherosclerotic plaques and subsequently cleared by the liver into bile. This transport is mediated by high-density lipoprotein particles, to which cholesterol is transferred via ATP-binding cassette transporters ABCA1 and ABCG1. Small-molecule pharmacological strategies stimulating these transporters may provide promising options for cardiovascular disease treatment.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Anticolesterolemiantes/farmacologia , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Colesterol/metabolismo , Animais , Anticolesterolemiantes/uso terapêutico , Aterosclerose/sangue , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Doenças Cardiovasculares/sangue , Colesterol/sangue , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/sangue , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/metabolismo , Lipoproteínas HDL/metabolismo , Terapia de Alvo Molecular , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/uso terapêutico
18.
Clín. investig. arterioscler. (Ed. impr.) ; 31(6): 271-277, nov.-dic. 2019. graf, tab
Artigo em Espanhol | IBECS | ID: ibc-185153

RESUMO

Se presenta la cuarta actualización de las tablas de planificación terapéutica. Esta tabla es una sencilla herramienta de sobremesa que permite determinar la terapia hipocolesterolemiante oral más apropiada para su paciente, bien con monoterapia, bien con terapia combinada (estatinas más ezetimiba), teniendo en cuenta su colesterol ligado a lipoproteínas de baja densidad (c-LDL) de partida y el objetivo terapéutico a alcanzar. Estas indicaciones terapéuticas se basan en 2 principios fundamentales: la causalidad del c-LDL y que el efecto de protección cardiovascular depende del descenso del c-LDL. Se han diseñado como un código de colores que señala los fármacos que tienen la potencia necesaria para llevar a su paciente a objetivos terapéuticos. Se establecen unas recomendaciones sobre la estrategia a seguir para implementar el tratamiento más eficaz. También se muestra hasta qué niveles podemos esperar un descenso de c-LDL al añadir un inhibidor de PCSK9


This is the fourth update of the therapeutic planning tables. These tables are a simple desktop tool, to help in determining the most appropriate oral cholesterol-lowering therapy for patient. This can either be with monotherapy or combination therapy (statins plus ezetimibe), taking into account the patient LDL cholesterol (LDL-C) and the therapeutic objective to be achieved. These therapeutic indications are based on 2 fundamental principles: the causality of LDL-C, and that the effect of cardiovascular protection depends on the decrease in LDL-C. It is based on a colour code that indicates the drugs that have the necessary power to meet the therapeutic objectives of the patient. We provide some recommendations on the strategy to follow to implement the most effective treatment. It is assessed up to what levels a decrease in LDL-C can be expected by adding a PCSK9 inhibitor


Assuntos
Humanos , Anticolesterolemiantes/administração & dosagem , Hipercolesterolemia/tratamento farmacológico , Equivalência Terapêutica , Padrões de Referência , Anticolesterolemiantes/metabolismo , Anticolesterolemiantes/farmacologia , Valores de Referência
19.
Cardiovasc Ther ; 2019: 8496409, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31772618

RESUMO

Background: Cuban sugarcane wax acids (SCWA) and policosanol (PCO) are mixtures of higher aliphatic acids and alcohols, respectively, purified from sugarcane wax with different chief components. Although it has been known that they have antioxidant and anti-inflammatory activities, physiological properties on molecular mechanism of SCWA have been less studied than PCO. Methods: In this study, we compared antiatherogenic activities of SCWA and PCO via encapsulation with reconstituted high-density lipoproteins (rHDL). Results: After reconstitution, SCWA-rHDL showed smaller particle size than PCO-rHDL with increase of content. PCO-rHDL or SCWA-rHDL showed distinct inhibition of glycation with similar extent in the presence of fructose. PCO-rHDL or SCWA-rHDL showed strong antioxidant activity against cupric ion-mediated oxidation of low-density lipoproteins (LDL), and inhibition of oxLDL uptake into macrophages. Although PCO-rHDL showed 1.2-fold stronger inhibition against cholesteryl ester transfer protein (CETP) activity than SCWA-rHDL, SCWA-rHDL enhanced 15% more brain cell (BV-2) growth and 23% more regeneration of tail fin in zebrafish. Conclusion: PCO and SCWA both enhance the beneficial functions of HDL to maximize its antioxidant, antiglycation, and antiatherosclerotic activities and the inhibition of CETP. These enhancements of HDL functionality by PCO and SCWA could exert antiaging and rejuvenation activity.


Assuntos
Ácidos/farmacologia , Anticolesterolemiantes/farmacologia , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Álcoois Graxos/farmacologia , Lipoproteínas HDL/metabolismo , Lipoproteínas LDL/metabolismo , Macrófagos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Saccharum/química , Ceras/química , Ácidos/isolamento & purificação , Nadadeiras de Animais/efeitos dos fármacos , Nadadeiras de Animais/crescimento & desenvolvimento , Animais , Anticolesterolemiantes/isolamento & purificação , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Álcoois Graxos/isolamento & purificação , Humanos , Macrófagos/metabolismo , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Oxirredução , Extratos Vegetais/isolamento & purificação , Regeneração , Células THP-1 , Adulto Jovem , Peixe-Zebra/crescimento & desenvolvimento
20.
Nutrients ; 11(11)2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31731675

RESUMO

Soybean germ phytosterols (SGP) largely exist in soybean germ oil. Our previous study demonstrated that soybean germ oil was effective in reducing plasma cholesterol. However, it remains unknown if its phytosterols are the active ingredients responsible for the plasma cholesterol-lowering activity. The present study aimed to test the effect of SGP on plasma cholesterol and to investigate its associated underlying mechanisms using hamsters as animal model. Male hamsters (n = 40) were randomly divided into five groups (n = 8/group) and fed one of the five diets: a non-cholesterol diet (NCD), a high cholesterol diet (HCD), a HCD diet containing 0.5% cholestyramine (PC), and two HCD diets containing 0.1% (LP) and 0.2% (HP) SGP, respectively, for six weeks. Results showed that SPG reduced plasma cholesterol level in a dose-dependent manner, whereas it dose-dependently increased the excretion of both fecal neutral and acidic sterols. SGP was also effective in displacing cholesterol from micelles. It was concluded that SGP possessed hypocholesterolemic activity, likely by inhibiting cholesterol absorption in the intestine and promoting fecal sterol excretion.


Assuntos
Anticolesterolemiantes/farmacologia , Colesterol na Dieta/farmacologia , Colesterol/sangue , Dieta/efeitos adversos , Fitosteróis/farmacologia , Óleo de Soja/química , Animais , Cricetinae , Dieta/métodos , Fezes/química , Intestinos/efeitos dos fármacos , Masculino , Esteróis/análise
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