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2.
Nutrients ; 13(8)2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34444660

RESUMO

Dietary protamine can ameliorate hyperlipidemia; however, the protamine-derived active peptide and its hypolipidemic mechanism of action are unclear. Here, we report the discovery of a novel anti-obesity and hypocholesterolemic peptide, RPR (Arg-Pro-Arg), derived from protamine in mice fed a high-fat diet for 50 days. Serum cholesterol levels were significantly lower in the protamine and RPR groups than in the control group. White adipose tissue weight was significantly decreased in the protamine and RPR groups. The fecal excretion of cholesterol and bile acid was significantly higher in the protamine and RPR groups than in the control group. We also observed a significant decrease in the expression of hepatic SCD1, SREBP1, and adipocyte FAS mRNA, and significantly increased expression of hepatic PPARα and adipocyte PPARγ1 mRNA in the protamine group. These findings demonstrate that the anti-obesity effects of protamine are linked to the upregulation of adipocyte PPARγ1 and hepatic PPARα and the downregulation of hepatic SCD1 via SREBP1 and adipocyte FAS. RPR derived from protamine has a crucial role in the anti-obesity action of protamine by evaluating the effective dose of adipose tissue weight loss.


Assuntos
Tecido Adiposo Branco/efeitos dos fármacos , Fármacos Antiobesidade/farmacologia , Anticolesterolemiantes/farmacologia , Colesterol/sangue , Obesidade/tratamento farmacológico , Oligopeptídeos/farmacologia , Protaminas/farmacologia , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/fisiopatologia , Adiposidade/efeitos dos fármacos , Animais , Biomarcadores/sangue , Dieta Hiperlipídica , Modelos Animais de Doenças , Ácido Graxo Sintase Tipo I/genética , Ácido Graxo Sintase Tipo I/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Obesidade/genética , Obesidade/metabolismo , Obesidade/fisiopatologia , PPAR alfa/genética , PPAR alfa/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Perda de Peso/efeitos dos fármacos
3.
Sci Rep ; 11(1): 15809, 2021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34349148

RESUMO

Statins are the cornerstone of therapy for individuals with hyperlipidemia. The aim of this study was to analyze the undesirable effects of mild, moderate and high doses of rosuvastatin in CD-1 male mice who received a cholesterol-rich diet, focusing on the morphological and functional changes on hepatocyte mitochondria. In a mouse model we studied the combined administration of a cholesterol-rich diet along with mild and moderate doses of rosuvastatin (1, 2.5 or 5 mg/kg/day) during several days. After the animals were sacrificed, liver mitochondria were isolated for microscopic studies and to analyze the respiratory function. The respiratory control (state-3/state-4) was evaluated in mice who received high doses of rosuvastatin. Rosuvastatin doses higher than 20 mg/kg/day induced premature death in mice with a hypercholesterolemic diet, but not in mice with a cholesterol-free diet. Doses from 2.5 to 5 mg/kg/day also induced morphological and functional alterations in mitochondria but these hypercholesterolemic animals survived longer. Giving 1 mg/kg/day, which is close to the maximal therapeutic dose for humans, did not affect mitochondrial architecture or respiratory function after two months of treatment. We analyzed the effect of rosuvastatin on hepatic tissue because it is where statins are mainly accumulated and it is the main site of endogenous cholesterol synthesis. Our results contribute to understand the side effects of rosuvastatin in hypercholesterolemic mice, effects that could also affect humans who are intolerant to statins.


Assuntos
Anticolesterolemiantes/farmacologia , Colesterol na Dieta/efeitos adversos , Hipercolesterolemia/tratamento farmacológico , Mitocôndrias Hepáticas/efeitos dos fármacos , Rosuvastatina Cálcica/farmacologia , Animais , Hipercolesterolemia/induzido quimicamente , Hipercolesterolemia/metabolismo , Hipercolesterolemia/patologia , Masculino , Camundongos , Mitocôndrias Hepáticas/metabolismo
4.
Sci Rep ; 11(1): 15288, 2021 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-34315963

RESUMO

Lactobacillus plantarum (renamed as Lactiplantibacillus plantarum) has been isolated from many sources but very rarely from rhizospheric soil. This is the first report on isolation and assessment of probiotic capabilities of L. plantarum strains isolated from rhizospheric soil. The isolates were confirmed by 16S rRNA gene sequencing and named as NS14, NS16 and NGG. All the isolates were evaluated for bile salt hydrolysis, hypocholestrolemic potential and probiotic attributes. Our results indicated that all the strains harboured bsh and showed in vitro cholesterol assimilation capabilities which increased when bile salts were also present in the culture medium. Also, all the strains remained viable at high temperatures and in the presence of NaCl, lysozyme, simulated gastric juice, bile salts and, exhibited auto- and co-aggregation capabilities. Additionally, L. plantarum strain NS14 survived in the presence of phenols, acidic environment (pH 2-3) and was resistant to many clinically relevant antibiotics. Since, L. plantarum NS14 exhibited most of the desirable and essential characteristics of a probiotic it should be further investigated as a potent probiotic with an additional benefit as a hypocholesterolemic biotherapeutic. Moreover, rhizosphere can be explored as a useful ecological niche for isolating microorganisms with biotechnological and probiotic potential.


Assuntos
Anticolesterolemiantes/farmacologia , Ácidos e Sais Biliares/metabolismo , Lactobacillus plantarum/metabolismo , Probióticos , Sequência de Aminoácidos , Hidrólise , Técnicas In Vitro , Lactobacillus plantarum/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Homologia de Sequência de Aminoácidos
5.
Int J Mol Sci ; 22(14)2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34299106

RESUMO

Atherosclerosis involves an ongoing inflammatory response of the vascular endothelium and vessel wall of the aorta and vein. The pleiotropic effects of statins have been well described in many in vitro and in vivo studies, but these effects are difficult to achieve in clinical practice due to the low bioavailability of statins and their first-pass metabolism in the liver. The aim of this study was to test a vessel wall local drug delivery system (DDS) using PLA microstructures loaded with simvastatin. Wistar rats were fed high cholesterol chow as a model. The rat vessels were chemically injured by repeated injections of perivascular paclitaxel and 5-fluorouracil. The vessels were then cultured and treated by the injection of several concentrations of poly(L,L-lactide) microparticles loaded with the high local HMG-CoA inhibitor simvastatin (0.58 mg/kg) concentration (SVPLA). Histopathological examinations of the harvested vessels and vital organs after 24 h, 7 days and 4 weeks were performed. Microcirculation in mice as an additional test was performed to demonstrate the safety of this approach. A single dose of SVPLA microspheres with an average diameter of 6.4 µm and a drug concentration equal to 8.1% of particles limited the inflammatory reaction of the endothelium and vessel wall and had no influence on microcirculation in vivo or in vitro. A potent pleiotropic (anti-inflammatory) effect of simvastatin after local SVPLA administration was observed. Moreover, significant concentrations of free simvastatin were observed in the vessel wall (compared to the maximum serum level). In addition, it appeared that simvastatin, once locally administered as SVPLA particles, exerted potent pleiotropic effects on chemically injured vessels and presented anti-inflammatory action. Presumably, this effect was due to the high local concentrations of simvastatin. No local or systemic side effects were observed. This approach could be useful for local simvastatin DDSs when high, local drug concentrations are difficult to obtain, or systemic side effects are present.


Assuntos
Anti-Inflamatórios/farmacologia , Anticolesterolemiantes/farmacologia , Dioxanos/química , Sistemas de Liberação de Medicamentos , Inflamação/tratamento farmacológico , Sinvastatina/farmacologia , Animais , Anti-Inflamatórios/química , Anticolesterolemiantes/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Microesferas , Ratos , Ratos Wistar , Sinvastatina/administração & dosagem
6.
Nutrients ; 13(6)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207558

RESUMO

Hypercholesterolemia can cause many diseases, but it can effectively regulated by Lactobacillus. This study aimed to evaluate the cholesterol-lowering mechanism of Enterococcus faecium strain 132 and Lactobacillusparacasei strain 201. These results showed that both the strains decreased serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), liver TC and TG and increased fecal TC, TG and total bile acid (TBA) levels. Additionally, both strains also reduced glutamic-pyruvic transaminase (ALT), glutamic oxaloacetic transaminase (AST) and levels of tissue inflammation levels to improve the lipid profile, and they reduced fat accumulation partially by alleviating inflammatory responses. Furthermore, both strains regulated the expression of the CYP8B1, CYP7A1, SREBP-1, SCD1 and LDL-R gene to promote cholesterol metabolism and reduce TG accumulation. Interventions with both strains also altered the gut microbiota, and decreasing the abundance of Veillonellaceae, Erysipelotrichaceae and Prevotella. Furthermore, fecal acetic acid and propionic acid were increased by this intervention. Overall, the results suggested that E. faecium strain 132 and L. paracasei strain 201 can alleviate hypercholesterolemia in rats and might be applied as a new type of hypercholesterolemia agent in functional foods.


Assuntos
Anticolesterolemiantes/farmacologia , Colesterol/metabolismo , Enterococcus faecium , Hipercolesterolemia/microbiologia , Lactobacillus paracasei , Probióticos/farmacologia , Ácido Acético/análise , Animais , Colesterol 7-alfa-Hidroxilase/metabolismo , LDL-Colesterol/metabolismo , Modelos Animais de Doenças , Fezes/química , Fezes/microbiologia , Alimento Funcional/microbiologia , Microbioma Gastrointestinal/fisiologia , Humanos , Hipercolesterolemia/metabolismo , Fígado/metabolismo , Fígado/microbiologia , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Masculino , Propionatos/análise , Ratos , Estearoil-CoA Dessaturase/metabolismo , Esteroide 12-alfa-Hidroxilase/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Triglicerídeos/metabolismo
7.
Molecules ; 26(13)2021 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-34279425

RESUMO

Blackcurrant extract (BCE) ameliorates dyslipidemia in menopausal model animals and in elderly women at a risk of dyslipidemia. However, it is unknown whether the daily intake of BCE can prevent lipid abnormalities in healthy individuals. Lipids are essential for the body, but they also cause arteriosclerosis. In this noncomparative pilot study, we examined the effects of BCE administered for 29 days on serum lipids in young healthy women. Blood samples were collected before and on days 4 and 29 after BCE intake, and 20 lipoprotein fractions in the serum were separated using a gel-permeation high-performance liquid chromatography method to measure the triacylglycerol and cholesterol levels in lipoproteins. There were no effects on lipids on day 4 of BCE intake, but the total cholesterol level decreased on day 29. Furthermore, the levels of total very-low-density lipoprotein (VLDL) cholesterol, small VLDL cholesterol, and large low-density lipoprotein cholesterol were significantly decreased. These results suggest that the daily intake of BCE has a hypocholesterolemic effect in healthy women, and that it is effective in preventing atherosclerosis.


Assuntos
Anticolesterolemiantes/farmacologia , Dislipidemias/tratamento farmacológico , Lipídeos/sangue , Lipoproteínas/sangue , Extratos Vegetais/farmacologia , Ribes/química , Adulto , Dislipidemias/sangue , Dislipidemias/patologia , Feminino , Humanos , Projetos Piloto , Adulto Jovem
8.
Biochem Pharmacol ; 190: 114649, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34111424

RESUMO

Statins reduce cardiovascular complications in patients with high LDL-cholesterol but are associated with myopathy. We compared the toxicity of simvastatin of C2C12 myoblasts and myotubes. Since myoblasts can proliferate and fuse to myotubes, myoblasts can be considered as satellite cells and myotubes as mature muscle fibers. Simvastatin increased plasma membrane permeability and decreased the cellular ATP content in both myoblasts and myotubes, but with a stronger effect on myoblasts. While insulin prevented cytotoxicity up to 8 h after addition of simvastatin to myotubes, prevention in myoblasts required simultaneous addition. Mevalonate and geranylgeraniol prevented simvastatin-associated cytotoxicity in both myoblasts and myotubes. Simvastatin impaired the phosphorylation of the insulin receptor (IR ß), Akt ser473 and S6rp, and increased phosphorylation of AMPK thr172 in both myotubes and myoblasts, which was prevented by insulin and mevalonate. Simvastatin impaired oxygen consumption and increased superoxide production by myoblasts and myotubes and induced apoptosis via cytochrome c release. In addition, simvastatin impaired proliferation and fusion of myoblasts to myotubes by inhibiting the expression of the nuclear transcription factor MyoD and of the metalloprotease ADAM-12. Decreased expression of the proliferation factor Ki-67 and of ADAM-12 were also observed in gastrocnemius of mice treated with simvastatin. In conclusion, myoblasts were more susceptible to the toxic effects of simvastatin and simvastatin impaired myoblast proliferation and myotube formation. Impaired muscle regeneration may represent a new mechanism of statin myotoxicity.


Assuntos
Proliferação de Células/efeitos dos fármacos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Sinvastatina/farmacologia , Animais , Anticolesterolemiantes/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Diterpenos/farmacologia , Masculino , Ácido Mevalônico/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória
9.
Anticancer Res ; 41(6): 2795-2804, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34083269

RESUMO

BACKGROUND/AIM: Neuroblastoma is the most common childhood extracranial solid malignancy. Although cancer cells need iron and lipids for active cell division, possible links between iron and lipid metabolism in neuroblastomas have not been studied. MATERIALS AND METHODS: We evaluated the levels and association between iron and cholesterol on in vitro neuroblastoma cancer models. RESULTS: We found that the levels of iron and cholesterol are diverse among neuroblastoma cell lines. There is a bi-directional association between iron and cholesterol in drug-resistant neuroblastoma SK-N-AS cells. In drug-resistant neuroblastoma cells, low concentration of an iron chelator did not have an impact on iron levels, but on cellular cholesterol levels. Furthermore, a cholesterol decreasing agent, simvastatin, influenced both iron and cholesterol levels in drug-resistant neuroblastoma cells. CONCLUSION: Cholesterol decreasing agents may be more effective than iron chelators for drug-resistant neuroblastoma treatment.


Assuntos
Colesterol/metabolismo , Ferro/metabolismo , Neuroblastoma/metabolismo , Anticolesterolemiantes/farmacologia , Linhagem Celular Tumoral , Humanos , Quelantes de Ferro/farmacologia , Neuroblastoma/patologia
10.
Int J Mol Sci ; 22(10)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34069880

RESUMO

This research focuses on the proteolytic capacity of sea bass byproduct (SB) and their hypocholesterolemic activity via the cholesterol micelle formation (CMF) inhibition. SB was fermented with seven mixed lactic acid bacteria for 5 h at 42 °C. The lactic fermented SB was hydrolyzed with Protease N for 6 h under HHP to obtain the SB hydrolysates (HHP-assisted Protease N hydrolysis after fermentation, F-HHP-PN6). The supernatant was separated from the SB hydrolysate and freeze-dried. As the hydrolysis time extended to 6 h, soluble protein content increased from 187.1 to 565.8 mg/g, and peptide content increased from 112.8 to 421.9 mg/g, while inhibition of CMF increased from 75.0% to 88.4%. Decreasing the CMF inhibitory activity from 88.4% to 42.1% by simulated gastrointestinal digestion (FHHP-PN6 was further hydrolyzed by gastrointestinal enzymes, F-HHP-PN6-PP) reduced the CMF inhibitory activity of F-HHP-PN6. Using gel filtration chromatography, the F-HHP-PN6-PP was fractioned into six fractions. The molecular weight of the fifth fraction from F-HHP-PN6-PP was between 340 and 290 Da, and the highest inhibitory efficiency ratio (IER) on CMF was 238.9%/mg/mL. Further purification and identification of new peptides with CMF inhibitory activity presented the peptide sequences in Ser-Ala-Gln, Pro-Trp, and Val-Gly-Gly-Thr; the IERs were 361.7, 3230.0, and 302.9%/mg/mL, respectively.


Assuntos
Bass/metabolismo , Colesterol/química , Hidrolisados de Proteína/farmacologia , Sequência de Aminoácidos , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Anticolesterolemiantes/farmacologia , Antioxidantes/farmacologia , Fermentação , Hidrólise , Pressão Hidrostática , Micelas , Peso Molecular , Oligopeptídeos , Peptídeo Hidrolases/metabolismo , Peptídeos/química , Peptídeos/metabolismo , Hidrolisados de Proteína/metabolismo , Proteínas/química , Proteínas/metabolismo , Proteólise
11.
Life Sci ; 279: 119697, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34102194

RESUMO

AIMS: Vitamin D and rosuvastatin are well-known drugs that mediate beneficial effects in treating type-2 diabetes (T2D) complications; however, their anti-neuropathic potential is debatable. Hence, our study investigates their neurotherapeutic potential and the possible underlying mechanisms using a T2D-associated neuropathy rat model. MAIN METHODS: Diabetic peripheral neuropathy (DPN) was induced with 8 weeks of administration of a high fat fructose diet followed by a single i.p. injection of streptozotocin (35 mg/kg). Six weeks later, DPN developed and rats were divided into five groups; viz., control, untreated DPN, DPN treated with vitamin D (cholecalciferol, 3500 IU/kg/week), DPN treated with rosuvastatin (10 mg/kg/day), or DPN treated with combination vitamin D and rosuvastatin. We determined their anti-neuropathic effects on small nerves (tail flick test); large nerves (electrophysiological and histological examination); neuronal inflammation (TNF-α and IL-18); apoptosis (caspase-3 activity and Bcl-2); mitochondrial function (NRF-1, TFAM, mtDNA, and ATP); and NICD1, Wnt-10α/ß-catenin, and TGF-ß/Smad-7 pathways. KEY FINDINGS: Two-month treatment with vitamin D and/or rosuvastatin regenerated neuronal function and architecture and abated neuronal inflammation and apoptosis. This was verified by the inhibition of the neuronal content of TNF-α, IL-18, and caspase-3 activity, while augmenting Bcl-2 content in the sciatic nerve. These treatments inhibited the protein expressions of NICD1, Wnt-10α, ß-catenin, and TGF-ß; increased the sciatic nerve content of Smad-7; and enhanced mitochondrial biogenesis and function. SIGNIFICANCE: Vitamin D and/or rosuvastatin alleviated diabetes-induced neuropathy by suppressing Notch1 and Wnt-10α/ß-catenin; modulating TGF-ß/Smad-7 signaling pathways; and enhancing mitochondrial function, which lessened neuronal degeneration, demyelination, and fibrosis.


Assuntos
Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 2/complicações , Neuropatias Diabéticas/prevenção & controle , Regulação da Expressão Gênica/efeitos dos fármacos , Rosuvastatina Cálcica/farmacologia , Vitamina D/administração & dosagem , Animais , Anticolesterolemiantes/farmacologia , Neuropatias Diabéticas/etiologia , Neuropatias Diabéticas/metabolismo , Neuropatias Diabéticas/patologia , Quimioterapia Combinada , Masculino , Fator 1 Relacionado a NF-E2/genética , Fator 1 Relacionado a NF-E2/metabolismo , Ratos , Ratos Wistar , Receptor Notch1/genética , Receptor Notch1/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Vitaminas/administração & dosagem , Proteínas Wnt/genética , Proteínas Wnt/metabolismo
12.
BMC Med ; 19(1): 151, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34187478

RESUMO

BACKGROUND: Beyond their success in cardiovascular disease prevention, statins are increasingly recognized to have sex-specific pleiotropic effects. To gain additional insight, we characterized associations of genetically mimicked statins across the phenotype sex-specifically. We also assessed whether any apparently non-lipid effects identified extended to genetically mimicking other widely used lipid modifiers (proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and ezetimibe) or were a consequence of low-density lipoprotein cholesterol (LDL-c). METHODS: We performed a sex-specific phenome-wide association study assessing the association of genetic variants in HMGCR, mimicking statins, with 1701 phenotypes. We used Mendelian randomization (MR) to assess if any non-lipid effects found were evident for genetically mimicked PCSK9 inhibitors and ezetimibe or for LDL-c. RESULTS: As expected, genetically mimicking statins was inversely associated with LDL-c, apolipoprotein B (ApoB), and total cholesterol (TC) and positively associated with glycated hemoglobin (HbA1c) and was related to body composition. Genetically mimicking statins was also inversely associated with serum calcium, sex hormone-binding globulin (SHBG), and platelet count and positively associated with basal metabolic rate (BMR) and mean platelet volume. Stronger associations with genetically mimicked statins were evident for women than men for lipid traits (LDL-c, ApoB, and TC), calcium, and SHBG, but not for platelet attributes, body composition, or BMR. Genetically mimicking PCSK9 inhibitors or ezetimibe was also associated with lower lipids, but was not related to calcium, SHBG, BMR, or body composition. Genetically higher LDL-c increased lipids and decreased BMR, but did not affect calcium, HbA1c, platelet attributes, or SHBG with minor effects on body composition. CONCLUSIONS: Similar inverse associations were found for genetically mimicking statins on lipid traits in men and women as for other lipid modifiers. Besides the positive associations with HbA1c, BMI (which may explain the higher BMR), and aspects of body composition in men and women, genetically mimicking statins was additionally associated with platelet attributes in both sexes and was inversely associated with serum calcium and SHBG in women. This genetic evidence suggests potential pathways that contribute to the effects of statins particularly in women. Further investigation is needed to confirm these findings and their implications for clinical practice.


Assuntos
Anticolesterolemiantes , Inibidores de Hidroximetilglutaril-CoA Redutases , Anticolesterolemiantes/farmacologia , LDL-Colesterol , Ezetimiba/farmacologia , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Masculino , Análise da Randomização Mendeliana , Pró-Proteína Convertase 9
13.
Clin Investig Arterioscler ; 33 Suppl 1: 10-17, 2021 May.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-33966807

RESUMO

Therapeutic intervention should be determined by the risk of developing atheromatous cardiovascular disease (CVD). The higher the risk, the more intense the action should be. This is the reason for the stratification of patient risk. In primary prevention, the two main guidelines used, the American Heart Association and the American College of Cardiology (ACC/AHA) use the Pooled cohort equations (PCE) and the guidelines of the European societies use the SCORE tables. The PCE calculates the risk of fatal and non-fatal CVD, and the SCORE calculates risk of fatal CVD only. In young people, it is useful to consider the lifetime risk calculation. The Spanish Society of Arteriosclerosis (SEA) recommends the SCORE system in Spain. SCORE and PCE calculate the risk for people up to 70 and 75 years of age. Prediction and potentials are available for 80 years of age and above, with the data available being much more scarce. Risk stratification in secondary prevention may be useful to identify the subgroup of patients who may benefit from more intensive treatment. Imaging tests, especially coronary calcium scans and vascular ultrasound, can help to better the profile risk. European guidelines identify LDL cholesterol as a therapeutic target. They recommend initiating treatment with statins, and increasing dose and potency until targets are achieved, and then to treatment with potent statins at a maximum tolerated dose, and ezetimibe if targets are not achieved. As a third step, PCSK9 inhibitors are indicated. They set very ambitious targets, as low as 40 mg/dL in those subjects with recurrences before two years of CVD despite high-intensity statin therapy, and below 55 mg/dL for all very high-risk subjects.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Guias de Prática Clínica como Assunto , Idoso , Idoso de 80 Anos ou mais , Anticolesterolemiantes/farmacologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , LDL-Colesterol/sangue , Fatores de Risco de Doenças Cardíacas , Humanos , Prevenção Primária/métodos , Prevenção Secundária/métodos
14.
Drug Des Devel Ther ; 15: 1955-1963, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34007155

RESUMO

Bempedoic acid is a first-in-class, oral, inhibitor of cholesterol biosynthesis that is approved for use in patients with atherosclerotic cardiovascular disease (ASCVD) and for primary prevention in individuals with heterozygous familial hypercholesterolemia (HeFH) by the United States Food and Drug Administration. Pooled data from the phase III clinical trials, CLEAR Harmony and CLEAR Wisdom, have demonstrated the safety and efficacy of bempedoic acid with regard to lowering of low-density lipoprotein cholesterol (LDL-C) in patients with HeFH as an adjunct or alternative to currently existing lipid-lowering therapies. CLEAR Outcomes is a cardiovascular outcomes trial that is currently underway that will provide additional insight as to where bempedoic acid will fit into treatment regimens among the non-statin lipid-lowering therapy options. Patients who might particularly benefit from bempedoic acid are those with HeFH and those unable to take adequate doses of statins or take any statin therapy altogether who need additional LDL-C lowering. In this review, we will discuss the profile of bempedoic acid from its design, development, and its place in therapy for the management of LDL-C for the purposes of ASCVD prevention.


Assuntos
Anticolesterolemiantes/uso terapêutico , Ácidos Dicarboxílicos/uso terapêutico , Ácidos Graxos/uso terapêutico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Animais , Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/farmacologia , Aterosclerose/tratamento farmacológico , LDL-Colesterol/sangue , Ácidos Dicarboxílicos/efeitos adversos , Ácidos Dicarboxílicos/farmacologia , Desenho de Fármacos , Desenvolvimento de Medicamentos , Ácidos Graxos/efeitos adversos , Ácidos Graxos/farmacologia , Humanos
15.
Drugs ; 81(9): 1101-1105, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34003472

RESUMO

The recombinant human monoclonal antibody evinacumab (evinacumab-dgnb, EVKEEZA™) is an angiopoietin-like protein three (ANGPTL3) inhibitor that has been developed by Regeneron Pharmaceuticals for the treatment of homozygous familial hypercholesterolaemia (HoFH), refractory hypercholesterolemia (both familial and non-familial) and severe hypertriglyceridaemia. Based on the results of the phase III ELIPSE HoFH trial, evinacumab was recently approved in the USA as an adjunct to other LDL-C lowering therapies for the treatment of adult and paediatric patients aged 12 years and older with HoFH, and has received a positive opinion in the EU. This article summarizes the milestones in the development of evinacumab leading to this first approval for HoFH.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Hipertrigliceridemia/tratamento farmacológico , Proteínas Semelhantes a Angiopoietina/antagonistas & inibidores , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/farmacologia , Método Duplo-Cego , Aprovação de Drogas , Humanos , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Estados Unidos
16.
Clin Investig Arterioscler ; 33 Suppl 1: 46-52, 2021 May.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-33966813

RESUMO

The use of low-density lipoprotein cholesterol (LDLc)-lowering medications has led to a significant reduction of cardiovascular risk in both primary and secondary prevention. Statins represent the cornerstone of lipid-lowering treatment and substantially decreases cardiovascular morbidity and mortality. However, there are still unmet clinical needs in the management of dyslipidaemia. Indeed, it is difficult to achieve LDLc targets in many patients, particularly in those at high/very high cardiovascular risk and in those with very high baseline LDLc concentrations. Moreover, a considerable proportion of patients are unable to tolerate maximum statin doses, mostly due to muscle-related adverse effects. In the present narrative review, a summary is presented on the current knowledge on the effects of the different cholesterol-lowering drugs, including those recently approved by European and American regulatory agencies, on lipid profile, and on cardiovascular risk. Since difficult-to-treat patients may benefit from new combination therapies as a result of the emergence of new drugs with clinical evidence, updates of the clinical guidelines would be recommended.


Assuntos
Anticolesterolemiantes/farmacologia , Doenças Cardiovasculares/prevenção & controle , Dislipidemias/tratamento farmacológico , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/efeitos adversos , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/mortalidade , LDL-Colesterol/sangue , Dislipidemias/complicações , Fatores de Risco de Doenças Cardíacas , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Pró-Proteína Convertase 9/antagonistas & inibidores
17.
Expert Rev Clin Pharmacol ; 14(7): 793-806, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33970743

RESUMO

Introduction: Reducing low-density lipoprotein cholesterol (LDL-C) with lipid-lowering therapies has been associated with a decrease in the frequency of cardiovascular events.Areas covered: A systematic search was conducted on PubMed (MEDLINE), using the MeSH terms [Rosuvastatin] + [Ezetimibe] + [Dyslipidemia] + [treatment]. Original data from clinical trials, prospective and retrospective studies and more useful reviews were selected.Expert opinion: While statins continue to be the cornerstone of dyslipidemia management, many patients do not attain LDL-C targets with high-intensity statins alone. Rosuvastatin is a high-intensity statin with a low risk of adverse effects and drug-drug interactions and proven benefits in the prevention of cardiovascular disease. Rosuvastatin and ezetimibe have complementary mechanisms of action that enhance their ability to reduce LDL-C levels. Various studies have shown that the combination of rosuvastatin 10-40 mg and ezetimibe 10 mg enables considerable reductions in LDL-C (up to 60-75%) with a good safety profile in a broad spectrum of patients with hypercholesterolemia, including those at high risk and those with atherosclerotic cardiovascular disease. In addition, a fixed-dose combination of rosuvastatin and ezetimibe may improve adherence to medication. In this review, the available evidence on the combination of rosuvastatin and ezetimibe is updated.


Assuntos
Ezetimiba/administração & dosagem , Hipercolesterolemia/tratamento farmacológico , Rosuvastatina Cálcica/administração & dosagem , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/farmacologia , LDL-Colesterol/sangue , Combinação de Medicamentos , Ezetimiba/efeitos adversos , Ezetimiba/farmacologia , Fatores de Risco de Doenças Cardíacas , Humanos , Adesão à Medicação , Rosuvastatina Cálcica/efeitos adversos , Rosuvastatina Cálcica/farmacologia
18.
Parasitology ; 148(9): 1107-1115, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34024307

RESUMO

Coccidia are obligate apicomplexan parasites that affect humans and animals. In fast replicating species, in vitro merogony takes only 24­48 h. In this context, successful parasite proliferation requires nutrients and other building blocks. Coccidian parasites are auxotrophic for cholesterol, so they need to obtain this molecule from host cells. In humans, ezetimibe has been applied successfully as hypolipidaemic compound, since it reduces intestinal cholesterol absorption via blockage of Niemann−Pick C-1 like-1 protein (NPC1L1), a transmembrane protein expressed in enterocytes. To date, few data are available on its potential anti-parasitic effects in primary host cells infected with apicomplexan parasites of human and veterinary importance, such as Toxoplasma gondii, Neospora caninum and Besnoitia besnoiti. Current inhibition experiments show that ezetimibe effectively blocks T. gondii, B. besnoiti and N. caninum tachyzoite infectivity and replication in primary bovine endothelial host cells. Thus, 20 µm ezetimibe blocked parasite proliferation by 73.1−99.2%, via marked reduction of the number of tachyzoites per meront, confirmed by 3D-holotomographic analyses. The effects were parasitostatic since withdrawal of the compound led to parasite recovery with resumed proliferation. Ezetimibe-glucuronide, the in vivo most effective metabolite, failed to affect parasite proliferation in vitro, thereby suggesting that ezetimibe effects might be NPC1L1-independent.


Assuntos
Anticolesterolemiantes/farmacologia , Coccidiostáticos/farmacologia , Ezetimiba/farmacologia , Neospora/efeitos dos fármacos , Sarcocystidae/efeitos dos fármacos , Toxoplasma/efeitos dos fármacos , Animais , Bovinos , Doenças dos Bovinos/parasitologia , Doenças dos Bovinos/prevenção & controle , Coccidiose/parasitologia , Coccidiose/prevenção & controle , Coccidiose/veterinária , Células Endoteliais , Toxoplasmose/parasitologia , Toxoplasmose/prevenção & controle , Toxoplasmose Animal/parasitologia , Toxoplasmose Animal/prevenção & controle
19.
Int J Mol Sci ; 22(7)2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33810299

RESUMO

Rosuvastatin (RST) is primarily used to treat high cholesterol levels. As it has potentially harmful but not well-documented effects on embryos, RST is contraindicated during pregnancy. To demonstrate whether RST could induce molecular epigenetic events in the brains of newborn rats, pregnant mothers were treated daily with oral RST from the 11th day of pregnancy for 10 days (or until delivery). On postnatal day 1, the brains of the control and RST-treated rats were removed for Western blot or immunohistochemical analyses. Several antibodies that recognize different methylation sites for H2A, H2B, H3, and H4 histones were quantified. Analyses of cell-type-specific markers in the newborn brains demonstrated that prenatal RST administration did not affect the composition and cell type ratios as compared to the controls. Prenatal RST administration did, however, induce a general, nonsignificant increase in H2AK118me1, H2BK5me1, H3, H3K9me3, H3K27me3, H3K36me2, H4, H4K20me2, and H4K20me3 levels, compared to the controls. Moreover, significant changes were detected in the number of H3K4me1 and H3K4me3 sites (134.3% ± 19.2% and 127.8% ± 8.5% of the controls, respectively), which are generally recognized as transcriptional activators. Fluorescent/confocal immunohistochemistry for cell-type-specific markers and histone methylation marks on tissue sections indicated that most of the increase at these sites belonged to neuronal cell nuclei. Thus, prenatal RST treatment induces epigenetic changes that could affect neuronal differentiation and development.


Assuntos
Anticolesterolemiantes/efeitos adversos , Encéfalo/efeitos dos fármacos , Embrião de Mamíferos/efeitos dos fármacos , Epigênese Genética , Código das Histonas , Rosuvastatina Cálcica/efeitos adversos , Animais , Anticolesterolemiantes/farmacologia , Encéfalo/embriologia , Encéfalo/metabolismo , Feminino , Histonas/efeitos dos fármacos , Histonas/metabolismo , Metilação , Ratos , Ratos Sprague-Dawley , Rosuvastatina Cálcica/farmacologia
20.
Int J Mol Sci ; 22(6)2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33808697

RESUMO

Proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors are a group of drugs whose main mechanism of action is binding to the PCSK-9 molecule, which reduces the degradation of the low-density lipoprotein receptor (LDL-R) and, hence, increases the uptake of low-density lipoprotein cholesterol (LDLc) from the bloodstream as well as reducing its concentration. The effectiveness of three monoclonal antibodies, namely, alirocumab (human IgG1/κ monoclonal antibody, genetically engineered in Chinese hamster ovary cells), evolocumab (the first fully human monoclonal antibody), and bococizumab (humanized mouse antibody), in inhibiting the action of PCSK-9 and reducing LDLc levels has been confirmed. The first two, after clinical trials, were approved by the Food and Drug Administration (FDA) and are used primarily in the treatment of autosomal familial hypercholesterolemia and in cases of statin intolerance. They are currently used both as monotherapy and in combination with statins and ezetimibe to intensify therapy and achieve therapeutic goals following the American Heart Association (AHA) and European Society of Cardiology (ESC) guidelines. However, the lipid-lowering effect is not the only effect of action described by researchers that PCSK-9 inhibitors have. This paper is a review of the literature describing the pleiotropic effects of PCSK-9 inhibitors, which belong to a group of drugs that are being increasingly used, especially when standard lipid-lowering therapy fails. The article focuses on activities other than lipid-lowering, such as the anti-atherosclerotic effect and stabilization of atherosclerotic plaque, the anti-aggregation effect, the anticoagulant effect, the antineoplastic effect, and the ability to influence the course of bacterial infections. In this publication, we try to systematically review the current scientific data, both from our own scientific work and knowledge from international publications.


Assuntos
Pró-Proteína Convertase 9/antagonistas & inibidores , Inibidores de Proteases/farmacologia , Animais , Antibacterianos/farmacologia , Anticolesterolemiantes/farmacologia , Anticolesterolemiantes/uso terapêutico , Anticoagulantes/farmacologia , Anticoagulantes/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Coagulação Sanguínea/efeitos dos fármacos , Humanos , Placa Aterosclerótica/tratamento farmacológico , Inibidores de Proteases/uso terapêutico , Agregação Patológica de Proteínas/tratamento farmacológico
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