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1.
Rev Med Liege ; 77(12): 745-751, 2022 Dec.
Artigo em Francês | MEDLINE | ID: mdl-36484754

RESUMO

PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9) inhibition has proven its interest to potentiate the cholesterol-lowering effects of statins. Indeed, this protein contributes to the intracellular degradation of LDL cholesterol receptors and thereby reduces their recycling and expression at the hepatocyte membrane. PCSK9 inhibition allows a major and sustained reduction of LDL cholesterol (LDL-c) in patients with familial hypercholesterolaemia or with established cardiovascular disease. Two monoclonal antibodies that inhibit the effect of PCSK9 are currently commercialized, alirocumab and evolocumab. Another approach consists in the inhibition of PCSK9 synthesis. Inclisiran is a novel small interfering RNA-based therapy (anti-sense). By binding to the messenger RNA (mRNA) precursor of PCSK9, inclisiran inhibits the PCSK9 gene expression, resulting in increased hepatocyte recycling and membrane expression of LDL receptors and decreased levels of LDL-c. This article summarizes the mode of action, pharmacokinetics, efficacy, safety profile, indications and reimbursement conditions of inclisiran. This novel cholesterol-lowering drug is indicated as add-on therapy in adults with atherosclerotic cardiovascular disease or with heterozygous familial hypercholesterolaemia in whom LDL-c level is ? 100 mg/dl and does not reach target LDL-c levels despite statin and ezetimibe or without statin or ezetimibe in case of intolerance or contra-indication for one of these medications.


L'inhibition de la protéine PCSK9 («Proprotéine Convertase Subtilisine/Kexine type 9¼) a démontré son intérêt hypocholestérolémiant pour potentialiser les effets des statines. En effet, cette protéine dégrade les récepteurs au LDL au niveau intra-cellulaire et empêche leur recyclage et leur expression à la surface membranaire des hépatocytes. L'inhibition de la PCSK9 permet de réduire de façon majeure les concentrations plasmatiques de cholestérol LDL (LDL-c) chez les patients avec hypercholestérolémie familiale ou avec maladie cardiovasculaire avérée. Deux anticorps monoclonaux bloquant l'action de la PCSK9 sont actuellement commercialisés, l'alirocumab et l'évolocumab. Une autre voie d'approche consiste à bloquer la synthèse de PCSK9. L'inclisiran est un petit ARN interférent (anti-sens) qui interfère avec les ARN messagers impliqués dans la synthèse de la PCSK9. Cet article résume le mode d'action, la pharmacocinétique, l'efficacité, le profil de sécurité, les indications et les conditions de remboursement de l'inclisiran. Ce nouvel agent hypocholestérolémiant est indiqué comme traitement d'appoint chez les adultes atteints d'une maladie cardiovasculaire athéroscléreuse documentée ou d'une hypercholestérolémie familiale hétérozygote, dont le taux de LDL-c est égal ou supérieur à 100 mg/dl et qui n'atteignent pas les valeurs cibles de LDL-c malgré la prise d'une statine et d'ézétimibe ou sans ces médicaments en cas d'intolérance ou de contre-indication pour l'un d'entre eux.


Assuntos
Anticolesterolemiantes , Doenças Cardiovasculares , Inibidores de Hidroximetilglutaril-CoA Redutases , Hiperlipoproteinemia Tipo II , Adulto , Humanos , Pró-Proteína Convertase 9/genética , LDL-Colesterol/metabolismo , LDL-Colesterol/uso terapêutico , Inibidores de PCSK9 , Anticolesterolemiantes/farmacologia , Anticolesterolemiantes/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/genética , RNA Interferente Pequeno/farmacologia , RNA Interferente Pequeno/uso terapêutico , Terapias em Estudo
2.
Biomed Pharmacother ; 156: 113957, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36411665

RESUMO

annually in Europe, 4 million people die from cardiovascular diseases, the main cause of which is atherosclerosis. In order to slow down the development of atherosclerotic plaques, the main therapeutic goal is to lower LDL cholesterol (LDL-C) level. Undoubtedly, statins are the basis of lipid-lowering therapy for many years. However, a European study shows that only 43% of statin-taking patients achieved their LDL-C targets. PCSK9 inhibitors are a new group of lipid-lowering drugs whose main point of action is the protein discovered in 2003 - the PCSK9 (proprotein convertase subtilisin/kexin 9). This protein is responsible for reducing the density of LDL receptors on the surface of hepatocytes, which increases the value of LDL-C. The discovery of this protein was soon after the basis for the start of research, thanks to which three monoclonal antibodies against PCSK9 were developed - evolocumab, alirocumab, bococizumab - and inclisiran, an inhibitor of PCSK9 synthesis in the liver. In addition to the mechanism of action of PCSK9 inhibitors, resulting in lowering LDL-C level, a number of pleiotropic mechanisms have also been identified, including effects on metabolic processes and inflammation. Until the registration and introduction of above-mentioned drugs into everyday clinical practice, many studies were carried out, in which, in addition to assessing the effectiveness of treatment, the safety and tolerability of the drug were also examined. The purpose of this review is to summarize information on the safety profile of PCSK9 inhibitors, which may help in making therapeutic decision.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Inibidores de PCSK9 , Humanos , Pró-Proteína Convertase 9 , LDL-Colesterol/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico
3.
Food Funct ; 13(23): 12194-12207, 2022 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-36331041

RESUMO

Polysaccharides from Enteromorpha prolifera (EP) possess multiple biological activities, while the role of EP in hypercholesterolemia and its relationship with the gut microbiota have not been elucidated. To address this issue, fifty male C57BL/6J mice were randomly subjected to a basal diet and a high-fat and high-cholesterol diet, and 3 treatment groups were fed an HFHC diet supplemented with different dosages of EP (100, 200 and 300 mg kg-1 day-1) for 12 weeks. Here we show that EP intervention lowered serum concentrations of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) and inhibited hepatic cholesterol deposition. EP intervention also upregulated the gene expression related to the hepatic cholesterol uptake and bile acid synthetic pathway. Apart from that, EP altered the gut microbiota, pre-dominantly increasing microbes associated with bile acid metabolism, such as norank_f_ Muribaculaceae. Moreover, bile acid profile analysis revealed that EP could alter the fecal bile acid profile and reduce fecal conjugated bile acids. Further correlation analysis indicated the negative correlation of Bacteroides, norank_f_ Muribaculaceae and Ileibacterium abundance with the levels of fecal conjugated bile acids and serum TC and LDL-C, while the abundance of Proteobacteria and Lachnoclosteridium showed a positive association with conjugated bile acids and serum TC. To sum up, the above findings revealed that EP may alleviate hypercholesterolemia and regulate cholesterol metabolism in ways that promote a favorable fecal microbiota composition and modulate bile acid metabolism.


Assuntos
Microbioma Gastrointestinal , Hipercolesterolemia , Masculino , Camundongos , Animais , Microbioma Gastrointestinal/fisiologia , LDL-Colesterol/metabolismo , Colesterol/metabolismo , Dieta Hiperlipídica/efeitos adversos , Camundongos Endogâmicos C57BL , Metabolismo dos Lipídeos , Ácidos e Sais Biliares/metabolismo , Polissacarídeos , Fígado/metabolismo
4.
Int J Mol Sci ; 23(21)2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-36361733

RESUMO

The association between APOE genotypes and cardiovascular disease (CVD) is partially mediated by LDL-cholesterol concentration but persists after adjusting for lipid levels and other cardiovascular risk factors. Data from the Aragon Workers Health Study (AWHS) (n = 4159) and the Lipid Unit at the Hospital Universitario Miguel Servet (HUMS) (n = 3705) were used to investigate the relationship between C-reactive protein (CRP) levels and APOE genotype. Lipoprotein particle and GlycA concentrations were analyzed in a subsample from AWHS. APOE genotyping was carried out by the Sanger method in both cohorts. APOE4 carriers had significantly lower levels of CRP than APOE3 carriers. Furthermore, APOE4 carriers had cholesterol-enriched LDL particles compared to APOE2 carriers. APOE4 carriers also had higher concentrations of small, medium, and large LDL particles. CRP levels were not associated with lipoprotein particle number, size, or composition. GlycA levels were not associated with APOE genotypes. However, GlycA levels were significantly associated with the size and the amount of cholesterol contained in HDL, VLDL, and LDL particles. APOE genotype influences CRP concentration regardless of lipid profile. APOE2 carriers showed the highest CRP levels, followed by APOE3 and APOE4. A more atherogenic lipid profile, but not inflammatory markers could partly explain the higher CVD risk observed in APOE4 carriers.


Assuntos
Apolipoproteína E4 , Doenças Cardiovasculares , Humanos , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Metabolismo dos Lipídeos/genética , Apolipoproteína E2/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Genótipo , LDL-Colesterol/metabolismo , Colesterol , Inflamação/genética , Doenças Cardiovasculares/genética
5.
Nutrients ; 14(19)2022 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-36235706

RESUMO

BACKGROUND: Fermented milk is beneficial for metabolic disorders, while the underlying mechanisms of action remain unclear. This study explored the benefits and underlying mechanisms of Bifidobacterium longum 070103 fermented milk (BLFM) in thirteen-week high-fat and high-sugar (HFHS) fed mice using omics techniques. METHODS AND RESULTS: BLFM with activated glucokinase (GK) was screened by a double-enzyme coupling method. After supplementing BLFM with 10 mL/kg BW per day, fasting blood glucose, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and leptin were significantly reduced compared with the HFHS group. Among them, the final body weight (BW), epididymal fat, perirenal fat, and brown fat in BLFM group had better change trends than Lacticaseibacillus rhamnosus GG fermented milk (LGGFM) group. The amplicon and metabolomic data analysis identified Bifibacterium as a key gut microbiota at regulating glycolipid metabolism. BLFM reverses HFHS-induced reduction in bifidobacteria abundance. Further studies showed that BLFM significantly reduces the content of 3-indoxyl sulofphate associated with intestinal barrier damage. In addition, mice treated with BLFM improved BW, glucose tolerance, insulin resistance, and hepatic steatosis. CONCLUSION: BLFM consumption attenuates obesity and related symptoms in HFHS-fed mice probably via the modulation of gut microbes and metabolites.


Assuntos
Bifidobacterium longum , Microbioma Gastrointestinal , Transtornos do Metabolismo dos Lipídeos , Animais , Bifidobacterium longum/metabolismo , Glicemia , LDL-Colesterol/metabolismo , Dieta Hiperlipídica/efeitos adversos , Glucoquinase/metabolismo , Glucose/metabolismo , Glicolipídeos , Leptina/metabolismo , Metabolismo dos Lipídeos , Camundongos , Camundongos Endogâmicos C57BL , Leite/metabolismo
6.
Int J Mol Sci ; 23(19)2022 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-36232746

RESUMO

The imbalance between reactive oxygen species (ROS) synthesis and their scavenging by anti-oxidant defences is the common soil of many disorders, including hypercholesterolemia. Platelets, the smallest blood cells, are deeply involved in the pathophysiology of occlusive arterial thrombi associated with myocardial infarction and stroke. A great deal of evidence shows that both increased intraplatelet ROS synthesis and impaired ROS neutralization are implicated in the thrombotic process. Hypercholesterolemia is recognized as cause of atherosclerosis, cerebro- and cardiovascular disease, and, closely related to this, is the widespread acceptance that it strongly contributes to platelet hyperreactivity via direct oxidized LDL (oxLDL)-platelet membrane interaction via scavenger receptors such as CD36 and signaling pathways including Src family kinases (SFK), mitogen-activated protein kinases (MAPK), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. In turn, activated platelets contribute to oxLDL generation, which ends up propagating platelet activation and thrombus formation through a mechanism mediated by oxidative stress. When evaluating the effect of lipid-lowering therapies on thrombogenesis, a large body of evidence shows that the effects of statins and proprotein convertase subtilisin/kexin type 9 inhibitors are not limited to the reduction of LDL-C but also to the down-regulation of platelet reactivity mainly by mechanisms sensitive to intracellular redox balance. In this review, we will focus on the role of oxidative stress-related mechanisms as a cause of platelet hyperreactivity and the pathophysiological link of the pleiotropism of lipid-lowering agents to the beneficial effects on platelet function.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Hipercolesterolemia , Hiperlipidemias , Trombose , Antioxidantes/metabolismo , Antígenos CD36/metabolismo , LDL-Colesterol/metabolismo , Humanos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NADP/metabolismo , NADPH Oxidases/metabolismo , Oxirredução , Pró-Proteína Convertases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Solo , Subtilisinas/metabolismo , Quinases da Família src/metabolismo
7.
Int Immunopharmacol ; 113(Pt A): 109318, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36257258

RESUMO

A variety of mechanisms contribute to the occurrence and development of inflammatory atherosclerosis (IA), resulting in cardiovascular disease. PCSK9 (proprotein convertase subtilisin/ kexin type 9) has now been recognized as a key player in the pathophysiology of atherosclerosis. Following PCSK9 activation, LDL receptors (LDLR) are degraded and as a result, LDL cholesterol (LDLC) levels are increased. Increasing evidence reports that the PCSK9 axis mediates IA through different pathways, such as LDLR, LOX1, NF-kB, and TLR4. In recent years, PCSK9 pathway dysregulation has been identified as one of the fundamental mechanisms involved in IA. Recently, the importance of epigenetic factors, in particular, in non-coding RNAs, including miRNAs and long ncRNAs (lncRNAs) as well as circular RNAs (circRNAs) in the regulation of physiological and pathological events has received great attention. In this regard, an expanding body of research has revealed that different ncRNAs play important roles in the progression of inflammatory atherosclerosis through targeting genes related to the PCSK9 pathway at the post-transcriptional level. Of importance, the current study aimed to review the relationship between the various ncRNAs and PCSK9 pathway to identify the molecular mechanisms underlying IA pathogenesis as well as to introduce the novel PCSK9 pathway-related therapeutic interventions in combating IA.


Assuntos
Aterosclerose , Pró-Proteína Convertase 9 , Humanos , Aterosclerose/terapia , Aterosclerose/tratamento farmacológico , LDL-Colesterol/metabolismo , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/metabolismo , Receptores de LDL/genética , Receptores de LDL/metabolismo , MicroRNAs , RNA Longo não Codificante , RNA Circular
8.
Adv Clin Chem ; 110: 145-169, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36210074

RESUMO

Sitosterolemia is an inherited metabolic disorder characterized by increased levels of plant sterols, such as sitosterol. This disease is caused by loss-of-function genetic mutations in the ATP-binding cassette (ABC) subfamily G member 5 or member 8 (ABCG5 or ABCG8, respectively), both of which play important roles in the selective excretion of plant sterols from the liver and intestine, leading to a failure to excrete plant sterols. Sitosterolemia, which is currently considered a rare genetic disorder, has been described as a phenocopy of homozygous familial hypercholesterolemia (FH). Typical phenotypes of sitosterolemia, including elevated low-density lipoprotein (LDL) cholesterol, tendon xanthomas, and premature coronary artery disease, overlap those of homozygous FH; however, there are substantial differences between these two diseases in terms of treatments and prognoses. Moreover, it is of note that sitosterolemia appears to be quite underdiagnosed, although accurate diagnosis and appropriate interventions will likely to lead to better prognoses compared with homozygous FH. Unlike cases of homozygous FH, dietary counseling is quite effective in reducing the LDL cholesterol as well as sitosterol of patients with sitosterolemia. In this chapter, we summarize the current understandings of this disease and provide useful tips for the diagnosis as well as better treatment of patients with sitosterolemia.


Assuntos
Fitosteróis , Sitosteroides , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Trifosfato de Adenosina , Colesterol/metabolismo , LDL-Colesterol/metabolismo , Humanos , Hipercolesterolemia , Enteropatias , Erros Inatos do Metabolismo Lipídico , Lipoproteínas/genética , Fitosteróis/efeitos adversos , Fitosteróis/genética , Sitosteroides/química
9.
Cells ; 11(19)2022 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-36230934

RESUMO

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secretory serine protease synthesized primarily by the liver. It mainly promotes the degradation of low-density lipoprotein receptor (LDL-R) by binding LDL-R, reducing low-density lipoprotein cholesterol (LDL-C) clearance. In addition to regulating LDL-R, PCSK9 inhibitors can also bind Toll-like receptors (TLRs), scavenger receptor B (SR-B/CD36), low-density lipoprotein receptor-related protein 1 (LRP1), apolipoprotein E receptor-2 (ApoER2) and very-low-density lipoprotein receptor (VLDL-R) reducing the lipoprotein concentration and slowing thrombosis. In addition to cardiovascular diseases, PCSK9 is also used in pancreatic cancer, sepsis, and Parkinson's disease. Currently marketed PCSK9 inhibitors include alirocumab, evolocumab, and inclisiran, as well as small molecules, nucleic acid drugs, and vaccines under development. This review systematically summarized the application, preclinical studies, safety, mechanism of action, and latest research progress of PCSK9 inhibitors, aiming to provide ideas for the drug research and development and the clinical application of PCSK9 in cardiovascular diseases and expand its application in other diseases.


Assuntos
Doenças Cardiovasculares , Ácidos Nucleicos , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol/metabolismo , Humanos , Lipoproteínas VLDL , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Pró-Proteína Convertase 9/metabolismo , Subtilisinas
10.
Cells ; 11(19)2022 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-36231033

RESUMO

Chronic low-grade inflammation induced by obesity is a central risk factor for the development of metabolic syndrome. High low-density lipoprotein cholesterol (LDL-c) induces inflammation, which is a common denominator in metabolic syndrome. IL-23 plays a significant role in the pathogenesis of meta-inflammatory diseases; however, its relationship with LDL-c remains elusive. In this cross-sectional study, we determined whether the adipose tissue IL-23 expression was associated with other inflammatory mediators in people with increased plasma LDL-c concentrations. Subcutaneous adipose tissue biopsies were collected from 60 people, sub-divided into two groups based on their plasma LDL-c concentrations (<2.9 and ≥2.9 mmol/L). Adipose expression of IL-23 and inflammatory markers were determined using real-time qRT-PCR; plasma concentrations of total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-c) and LDL-c were determined using the standard method; and adiponectin levels were measured by enzyme-linked immunosorbent assay (ELISA). Adipose IL-23 transcripts were found to be increased in people with high LDL-c, compared to low LDL-c group (H-LDL-c: 1.63 ± 0.10-Fold; L-LDL-c: 1.27 ± 0.09-Fold; p < 0.01); IL-23 correlated positively with LDL-c (r = 0.471, p < 0.0001). Immunochemistry analysis showed that AT IL-23 protein expression was also elevated in the people with H-LDL-c. IL-23 expression in the high LDL-c group was associated with multiple adipose inflammatory biomarkers (p ≤ 0.05), including macrophage markers (CD11c, CD68, CD86, CD127), TLRs (TLR8, TLR10), IRF3, pro-inflammatory cytokines (TNF-α, IL-12, IL-18), and chemokines (CXCL8, CCL3, CCL5, CCL15, CCL20). Notably, in this cohort, IL-23 expression correlated inversely with plasma adiponectin. In conclusion, adipose IL-23 may be an inflammatory biomarker for disease progression in people with high LDL-c.


Assuntos
Hiperlipidemias , Subunidade p19 da Interleucina-23/metabolismo , Síndrome Metabólica , Adiponectina/metabolismo , Tecido Adiposo/metabolismo , Biomarcadores/metabolismo , Quimiocinas/metabolismo , Colesterol/metabolismo , HDL-Colesterol , LDL-Colesterol/metabolismo , Estudos Transversais , Citocinas/metabolismo , Humanos , Hiperlipidemias/metabolismo , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Interleucina-12/metabolismo , Interleucina-18/metabolismo , Interleucina-23/metabolismo , Síndrome Metabólica/metabolismo , Receptor 8 Toll-Like/metabolismo , Triglicerídeos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
11.
BMC Womens Health ; 22(1): 398, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-36182923

RESUMO

OBJECTIVE: microRNAs (miRNAs) play pivotal roles in polycystic ovary syndrome (PCOS), an endocrine and metabolic disorder that commonly occurs in women of childbearing age. This paper aimed to measure miR-222-3p expression in sera of PCOS patients and to explore its clinical value on PCOS diagnosis and prediction of diabetic and cardiovascular complications. METHODS: Totally 111 PCOS patients and 94 healthy people were recruited and assigned to the overweight (ow) group and non-overweight (non-ow) group, followed by determination of serum miR-222-3p expression. The diagnostic efficiency of miR-222-3p on PCOS ow and non-ow patients was analyzed. Correlations between miR-222-3p and glycolipid metabolic indicators and diabetic and cardiovascular complications in PCOS were analyzed. The downstream target of miR-222-3p was predicted and their binding relationship was verified. The correlation between PGC-1α and miR-222-3p was analyzed. RESULTS: miR-222-3p was highly-expressed in PCOS patients (p < 0.001), in especially PCOS ow patients. The area under the curve (AUC) of miR-222-3p diagnosing PCOS non-ow patients was 0.9474 and cut-off value was 1.290 (89.06% sensitivity, 98.11% specificity), indicating that non-ow people with serum miR-222-3p > 1.290 could basically be diagnosed with PCOS. AUC of miR-222-3p diagnosing PCOS ow patients was 0.9647 and cut-off value was 2.425 (85.11% sensitivity, 100% specificity), suggesting that ow people with serum miR-222-3p > 2.425 could basically be diagnosed with PCOS. miR-222-3p was positively-correlated with fasting plasma glucose (FPG), fasting insulin (FINS), homeostatic model assessment-insulin resistance (HOMA-IR), and low-density lipoprotein cholesterol (LDL-C) and negatively-correlated with high-density lipoprotein cholesterol (HDL-C). miR-222-3p was independently-correlated with diabetic and cardiovascular complications in PCOS (p < 0.05). High expression of miR-222-3p predicted high risks of diabetic and cardiovascular complications in PCOS. miR-222-3p targeted PGC-1α and was negatively-correlated with PGC-1α (r = - 0.2851, p = 0.0224; r = - 0.3151, p = 0.0310). CONCLUSION: High expression of miR-222-3p assisted PCOS diagnosis and predicted increased risks of diabetic and cardiovascular complications. miR-222-3p targeted PGC-1α and was negatively-correlated with PGC-1α.


Assuntos
Resistência à Insulina , MicroRNAs , Síndrome do Ovário Policístico , Glicemia , HDL-Colesterol , LDL-Colesterol/metabolismo , Correlação de Dados , Feminino , Glucose , Glicolipídeos , Humanos , Insulina/metabolismo , Metabolismo dos Lipídeos , Obesidade/complicações , Sobrepeso/complicações , Síndrome do Ovário Policístico/complicações
12.
Nutr Res ; 106: 101-118, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36183668

RESUMO

Previously, our group found that the dietary trace mineral element selenium and vitamin B6 (VitB6) alone was involved in lipid metabolism. However, the effects of selenium combined with VitB6 on hyperlipidemia and lipid metabolism have not been reported until now. We hypothesized that selenium and VitB6 cosupplementation would alleviate the hyperlipidemic and hepatic dysfunction and with minimum side effects in a Sprague-Dawley rat model of hyperlipidemia induced by a high-fat diet. Our results showed that selenium combined with VitB6 could improve dyslipidemia and displayed better in vivo hypocholesterolemic abilities at early intervention. Moreover, cosupplementation reduced atherogenic indexes (atherogenic index and atherogenic index of plasm) and the ratio of ApoB/ApoA1. The liver function index aspartate aminotransferase in serum was reduced, as was and total cholesterol, triacylglycerol, and low-density lipoprotein cholesterol in liver. The intervention also increased the levels of ApoA1 in serum and high-density lipoprotein cholesterol of liver. In addition, the combination of selenium and VitB6 decreased liver lipid deposition and alleviated steatosis, reduced adipocyte size of white adipose tissue, increased the activities of hepatic lipase and total lipase and the hepatic 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMGR) level, decreased the hepatic mRNA transcription of lipogenic and regulatory genes including Srebf1 and downstream fat synthesis-related enzymes (Acc and Fasn) and cholesterol synthesis speed limiting enzyme Hmgr, increased the mRNA abundance of Lcat and Cyp7a1, increased the protein expression of SIRT1 and PPARα, and up-regulated the protein expression of sterol regulatory element-binding protein 1c in the livers of hyperlipidemia rats. We first demonstrated that oral selenium and VitB6 cosupplementation exerted synergism in lowering blood and liver lipid profiles and antiatherosclerotic effects in hyperlipidemic rats by reducing endogenous cholesterol and lipid synthesis, enhancing the transport of cholesterol to hepatocytes and promoting fatty acid beta oxidation.


Assuntos
Fígado Gorduroso , Hiperlipidemias , Selênio , Oligoelementos , Animais , Apolipoproteínas B , Aspartato Aminotransferases/metabolismo , Colesterol/metabolismo , HDL-Colesterol , LDL-Colesterol/metabolismo , Coenzima A/metabolismo , Coenzima A/farmacologia , Coenzima A/uso terapêutico , Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos/metabolismo , Fígado Gorduroso/metabolismo , Hiperlipidemias/tratamento farmacológico , Lipase/metabolismo , Lipase/farmacologia , Lipase/uso terapêutico , Metabolismo dos Lipídeos , Fígado/metabolismo , Oxirredutases/metabolismo , Oxirredutases/farmacologia , Oxirredutases/uso terapêutico , PPAR alfa/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Selênio/farmacologia , Selênio/uso terapêutico , Sirtuína 1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Oligoelementos/farmacologia , Oligoelementos/uso terapêutico , Triglicerídeos/metabolismo , Vitamina B 6 , Vitaminas/farmacologia
13.
Gene ; 851(146979)Oct. 2022.
Artigo em Inglês | Sec. Est. Saúde SP, CONASS, SESSP-IDPCPROD, Sec. Est. Saúde SP | ID: biblio-1400683

RESUMO

ABSTRACT: PCSK9 gain-of-function (GOF) variants increase degradation of low-density lipoprotein receptor (LDLR) and are potentially associated with Familial Hypercholesterolemia (FH). This study aimed to explore the effects of PCSK9 missense variants on protein structure and interactions with LDLR using molecular modeling analyses and in vitro functional studies. Variants in FH-related genes were identified in a Brazilian FH cohort using an exon-target gene sequencing strategy. Eight PCSK9 missense variants in pro- [p.(E32K) and p.(E57K)], catalytic [p.(R237W), p.(P279T) and p.(A443T)], and C-terminal histidine-cysteine rich (CHR) [p.(R469W), p.(Q619P) and p.(R680Q)] domains were identified. Molecular dynamics analyses revealed that GOF variants p.(E32K) and p.(R469W) increased extreme motions in PCSK9 amino acid backbone fluctuations and affected Hbond and water bridge interactions between the pro-domain and CM1 region of the CHR domain. HEK293FT cells transfected with plasmids carrying p.(E32K) and p.(R469W) variants reduced LDLR expression (8.7 % and 14.8 %, respectively) compared to wild type (p < 0.05) but these GOF variants did not affect PCSK9 expression and secretion. The missense variants p.(P279T) and p.(Q619P) also reduced protein stability and altered Hbond interactions. In conclusion, PCSK9 p.(E32K), p.(R469W), p.(P279T) and p.(Q619P) variants disrupt intramolecular interactions that are essential for PCSK9 structural conformation and biological activity and may have a potential role in FH pathogenesis.


Assuntos
Humanos , Mutação de Sentido Incorreto , Hiperlipoproteinemia Tipo II , Conformação Molecular , Pró-Proteína Convertase 9 , LDL-Colesterol/genética , LDL-Colesterol/metabolismo
14.
Biomed Res Int ; 2022: 7659765, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36132078

RESUMO

Background: The present study aimed to evaluate the effect of nanocurcumin and curcumin on liver transaminases, lipid profile, oxidant and antioxidant system, and pathophysiological changes in aluminium phosphide (ALP) induced hepatoxicity. Material and Methods. In this experimental study, thirty-six male Wistar rats were randomly divided into six groups curcumin (Cur), nanocurcumin (Nanocur), ALP, ALP+Cur, and ALP+Nanocur. All treatments were performed by oral gavage for seven days. After treatment, animals were sacrificed, and liver and blood samples were taken. Serum levels of aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (AP), total bilirubin, cholesterol, triglyceride, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and very-low-density lipoprotein (VLDL) were measured by photometric methods. Total antioxidant capacity (TAC) and malondialdehyde (MDA) as parameters of oxidative stress and mRNA expression of the nonenzyme protein including Sirtuin 1 (STR1), Forkhead box protein O1 (FOXO1) and protein O3 (FOXO3), catalase (CAT), and glutathione peroxidase (GPX) as the enzyme protein in homogenized tissues have been investigated. A histologist analyzed liver tissue sections after staining with hematoxylin-eosin. Results: In the aluminium phosphide group, there was a significant increase in MDA, ALT, AST, and AP and total bilirubin, cholesterol, triglyceride, LDL, and VLDL; AST, ALT, total bilirubin, LDL, VLDL, cholesterol, and MDA were significantly decreased; and HDL and TAC were significantly increased compared to ALP (P < 0.05). In the ALP+Nanocur group, ALT, AST, ALP, total bilirubin, cholesterol, LDL, VLDL, triglyceride, and MDA were significantly decreased and HDL and TAC were increased significantly (P < 0.05). The effect of nanocurcumin on controlling serum levels of LDL, VLDL, triglyceride, and MDA in ALP-poisoned rats was significantly more than curcumin (P < 0.05). The ALP group had significant changes in genes SIRT1, FOXO1a, FOXO3a, CAT, and GPX compared to healthy controls (P < 0.05). Nanocurcumin mice expressed more SIRT1, FOXO1a, CAT, and GPX genes than controls, and curcumin-treated mice expressed more SIRT1 and FOXO1a genes (P < 0.05). Histopathological findings also indicated a more significant protective effect of nanocurcumin relative to curcumin against ALP-induced hepatotoxicity. Conclusion: Nanocurcumin significantly protects the liver against aluminum phosphide toxicity. It is suggested that nanocurcumin-based drugs be developed to reduce the toxic effects of ALP in poisoned patients.


Assuntos
Antioxidantes , Curcumina , Alanina Transaminase/metabolismo , Fosfatase Alcalina/metabolismo , Compostos de Alumínio , Animais , Antioxidantes/farmacologia , Aspartato Aminotransferases , Bilirrubina/metabolismo , Catalase/metabolismo , LDL-Colesterol/metabolismo , Curcumina/metabolismo , Curcumina/farmacologia , Amarelo de Eosina-(YS)/metabolismo , Proteína Forkhead Box O1/metabolismo , Glutationa Peroxidase/metabolismo , Hematoxilina/metabolismo , Lipoproteínas HDL , Lipoproteínas VLDL/metabolismo , Lipoproteínas VLDL/farmacologia , Fígado/patologia , Masculino , Malondialdeído/metabolismo , Camundongos , Oxidantes/metabolismo , Estresse Oxidativo , Fosfinas , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Sirtuína 1/metabolismo , Triglicerídeos/metabolismo
15.
Chin J Nat Med ; 20(9): 669-678, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36162952

RESUMO

Diabetes-associated liver injury becomes a dominant hepatopathy, leading to hepatic failure worldwide. The current study was designed to evaluate the ameliorative effects of ginsenoside Rh1 (G-Rh1) on liver injury induced by T2DM. A T2DM model was established using C57BL/6 mice through feeding with HFD followed by injection with streptozotocin at 100 mg·kg-1.. Then the mice were continuously administered with G-Rh1 (5 and 10 mg·kg-1), to explore the protective effects of G-Rh1 against liver injury. Results showed that G-Rh1 exerted significant effects on maintaining the levels of FBG and insulin, and ameliorated the increased levels of TG, TC and LDL-C induced by T2DM. Moreover, apoptosis in liver tissue was relieved by G-Rh1, according to histological analysis. Particularly, in diabetic mice, it was observed that not only the increased secretion of G6Pase and PEPCK in the gluconeogenesis pathway, but also inflammatory factors including NF-κB and NLRP3 were suppressed by G-Rh1 treatment. Furthermore, the underlying mechanisms by which G-Rh1 exhibited ameliorative effects was associated with its capacity to inhibit the activation of the Akt/FoxO1 signaling pathway induced by T2DM. Taken together, our preliminary study demonstrated the potential mechnism of G-Rh1 in protecting the liver against T2DM-induced damage.


Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Animais , LDL-Colesterol/metabolismo , LDL-Colesterol/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Proteína Forkhead Box O1/farmacologia , Ginsenosídeos , Insulina/metabolismo , Fígado , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Estreptozocina
16.
Int J Mol Sci ; 23(18)2022 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-36142135

RESUMO

Acute ischemic stroke (AIS) represents an important cause of disability and death. Since only a minor percentage of patients with AIS are eligible for acute therapy, the management of risk factors is mandatory. An important risk factor of AIS is hyperlipemia. The current guidelines recommend a strict correction of it. Statins are recommended as the first-line treatment, while proprotein convertase subtilin/kexin type 9 (PCSK-9) inhibitors are administered as a second or even third option when the goal for a low-density lipoprotein cholesterol (LDL-C) level is not achieved. PCSK-9 inhibitors effectively decrease the LDL-C levels through the inhibition of PCSK-9-LDL-receptor complex formation. The in-depth understanding of the PCSK-9 protein mechanism in the metabolism of LDL-C led to the development of effective targeted approaches. Furthermore, a better understanding of the LDL-C metabolic pathway led to the development of newer approaches, which increased the therapeutic options. This article aims to offer an overview of the PCSK-9 inhibitors and their mechanism in reducing the LDL-C levels. Moreover, we will present the main indications of the current guidelines for patients with hyperlipemia and for those who have suffered an acute ischemic stroke, as well as the importance of LDL-C reduction in decreasing the rate of a recurrence.


Assuntos
Anticolesterolemiantes , Inibidores de Hidroximetilglutaril-CoA Redutases , Hiperlipidemias , AVC Isquêmico , Acidente Vascular Cerebral , Anticolesterolemiantes/efeitos adversos , Bacteriocinas , LDL-Colesterol/metabolismo , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipidemias/tratamento farmacológico , AVC Isquêmico/tratamento farmacológico , Pró-Proteína Convertases , Acidente Vascular Cerebral/induzido quimicamente , Acidente Vascular Cerebral/tratamento farmacológico
17.
Nutr Metab Cardiovasc Dis ; 32(11): 2638-2646, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36064689

RESUMO

BACKGROUND AND AIMS: ODYSSEY APPRISE trial evaluated efficacy and safety of alirocumab in 994 patients with hypercholesterolemia and high CV risk in a real-life setting. The aim of the present report is to detail on the Italian cohort enrolled and treated in the trial. METHODS AND RESULTS: The methodology of the of the multinational, single-arm, Phase 3b open-label ODYSSEY APPRISE (Clinicaltrials.gov: NCT02476006) has been previously reported. 255 Italian patients were enrolled and treated according to the trial protocol. Overall mean exposure to alirocumab was 83.3 ± 27.7 weeks. At week 12, LDL-C decreased by 51.3 ± 23.1% and this reduction was overall maintained for the duration of the study. A similar reduction was observed in patients with and without heterozygous familial hypercholesterolemia (HeFH 50.7% ± 23.9 vs. non-FH, 53.6% ± 19.6). LDL-C was reduced below 1.8 mmol/L and/or by ≥ 50% reduction from baseline in 62% of patients overall (61% in HeFH and 67% in non-FH). Alirocumab was similarly well tolerated in the Italian cohort as in the entire study population and the more common treatment emergent adverse events (TEAEs) were influenza, myalgia and nasopharyngitis. The incidence LDL-C levels <25 mg/dl and <15 mg/dl, was 8.2% and 2.9% respectively. CONCLUSION: The efficacy and safety of alirocumab in a real-life setting, in the Italian subgroup of patients are consistent with findings in the entire study population and confirm that alirocumab is a beneficial approach to further reduce LDL-C levels in patients at high CV risk on maximally tolerated conventional lipid lowering treatment. GOV IDENTIFIER: NCT02476006.


Assuntos
Anticorpos Monoclonais Humanizados , Hiperlipoproteinemia Tipo II , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticolesterolemiantes/efeitos adversos , LDL-Colesterol/metabolismo , Humanos , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Resultado do Tratamento
18.
Food Funct ; 13(20): 10665-10679, 2022 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-36172720

RESUMO

The improvement of lipid metabolism by capsaicin (CAP) has been extensively studied, mostly with respect to the vanilloid type 1 (TRPV1) ion channel and intestinal flora. In this study, a model was established in germ-free mice by using resiniferatoxin (RTX) to ablate TRPV1 ion channels. Bile acid composition, blood parameters, and colonic transcriptome analyses revealed that CAP could improve dyslipidemia caused by high-fat diet even in the absence of TRPV1 ion channels and intestinal flora. CAP fed to germ mice decreased the concentrations of low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), fasting blood glucose and fasting insulin, increased the concentration of high-density lipoprotein (HDL-C), and decreased the levels of plasma endotoxin and pro-inflammatory factor interleukin 6 (IL-6). Furthermore, CAP could affect both classical and alternative pathways of cholesterol conversion by changing the composition of bile acids, reducing the concentrations of glycocholic acid (GCA), ursodeoxycholic acid (UDCA) and glycochenodeoxycholic acid (GCDCA). First, changing the composition of bile acids inhibited the expression of colon Fgf15. CAP promoted the expression of Cyp7a1 (Cytochrome p450, family 7, subfamily a, and polypeptide 1) in the liver, and thus reduced TC and TG levels. In addition, it could change the composition of bile acids and increase the expression of Cyp7b1 (Cytochrome p450, family 7, subfamily b, and polypeptide 1) in the colon, increase Cyp7b1 protein in the liver and thus inhibit fat accumulation. In conclusion, CAP could alter the composition of bile acids and promote the conversion of cholesterol to bile acids, thereby improving lipid metabolism abnormalities caused by a high-fat diet.


Assuntos
Dislipidemias , Insulinas , Animais , Ácidos e Sais Biliares/metabolismo , Glicemia/metabolismo , Capsaicina , Colesterol/metabolismo , Colesterol 7-alfa-Hidroxilase/genética , Colesterol 7-alfa-Hidroxilase/metabolismo , LDL-Colesterol/metabolismo , Dieta Hiperlipídica/efeitos adversos , Dislipidemias/tratamento farmacológico , Dislipidemias/genética , Dislipidemias/metabolismo , Endotoxinas , Ácido Glicoquenodesoxicólico/metabolismo , Insulinas/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Lipoproteínas HDL , Fígado/metabolismo , Camundongos , Triglicerídeos/metabolismo , Ácido Ursodesoxicólico/metabolismo
19.
Mol Med ; 28(1): 120, 2022 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-36180828

RESUMO

BACKGROUND: The miR-351 gene is significantly upregulated in diabetic mice with atherosclerosis. However, the mechanism by which its presence is important for the overall disease has not been elucidated. Therefore, this study will investigate the mechanism of miR-351 in the process of diabetes mellitus with atherosclerosis through miR-351 gene knockout mice. METHODS: In this study, miR-351-/- C57BL/6 mice were first induced to form a type 2 diabetes mellitus model with atherosclerosis by STZ injection and a high-fat diet. Pathological tests (oil red O, HE, and Masson staining) combined with biochemical indices (TC, TG, LDL-C, HDL-C, TNF-α, hs-CRP, NO, SOD, MDA, CAT, and GSH-Px) were performed to evaluate the pathological degree of atherosclerosis in each group. Mouse aortic endothelial cells were treated with oxidized low-density lipoprotein (ox-LDL) and 30 mM glucose to establish a diabetic atherosclerosis cell model. Combined with cell oil red O staining and flow cytometry, the effects of silencing miR-351 on lipid accumulation and cell apoptosis in the diabetic atherosclerosis cell model were determined. Fluorescence in situ hybridization was used to detect the localization and transcription levels of miR-351 in cells. The target genes of miR-351 were predicted by bioinformatics and verified by dual-luciferase activity reporting. Western blotting was used to detect the expression levels of phosphorylated inosine 3-kinase regulatory subunit 1 (PIK3R1)/serine/threonine kinase 1 (Akt) and apoptosis-related proteins after transfection with integrin subunit ß3 (ITGB3) small interfering ribonucleic acid (siRNA). RESULTS: The expression of the miR-351 gene was significantly increased in the high-fat wild-type (HWT) group, and its expression was significantly decreased in the knockout mice. Silencing miR-351 effectively alleviated atherosclerosis in mice. The levels of miR-351 expression, apoptosis, lipid accumulation, and oxidative stress in ox-LDL + high glucose-induced endothelial cells were significantly increased. These phenomena were effectively inhibited in lentivirus-infected miR-351-silenced cell lines. Bioinformatics predicted that miR-351-5p could directly target the ITGB3 gene. Transfection of ITGB3 siRNA reversed the downregulation of apoptosis, decreased oil accumulation, and decreased oxidative stress levels induced by miR-351 silencing. In addition, it inhibited the activation of the PIK3R1/Akt pathway. CONCLUSION: Silencing miR-351 upregulates ITGB3 and activates the PIK3R1/Akt pathway, thereby exerting anti-apoptosis and protective effects on endothelial cells.


Assuntos
Aterosclerose , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , MicroRNAs , Animais , Aterosclerose/metabolismo , Compostos Azo , Proteína C-Reativa/metabolismo , LDL-Colesterol/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Células Endoteliais/metabolismo , Glucose/metabolismo , Hibridização in Situ Fluorescente , Inosina/metabolismo , Inosina/farmacologia , Integrinas/genética , Lipoproteínas LDL/metabolismo , Luciferases/genética , Luciferases/metabolismo , Luciferases/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno , Serina/genética , Serina/metabolismo , Serina/farmacologia , Transdução de Sinais , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
20.
Ecotoxicol Environ Saf ; 245: 114105, 2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-36155338

RESUMO

Microplastics (MPs) pollution becomes an increasing concern and researchers keep exploring the health effects caused by MPs exposure. The ageing process in the environment significantly alters the physicochemical characteristics of MPs and subsequently affects their toxicities. The health effects of aged MPs exposure and the mechanism underlying are worthy of exploration. Polystyrene microplastics (PS-MPs) (with size less than 50 µm) were obtained by grinding and screening polystyrene materials. PS-MPs continued to be aged by ozone treatment (0.4 mg/min, 9 h). Both male and female C57BL/6 mice were orally exposed to 0 or 2 mg/kg/d aged PS-MPs for 28 days. Results showed that PS-MPs were found in liver, ovary and spleen of females and liver, testis and spleen of males in the aged PS-MPs group. Exposure to aged PS-MPs significantly decreased abdominal fat/body coefficient, the adipocyte size and the serum LDL-C level in females. Compared to the control, serum estradiol (E2) level, the mRNA expression levels of genes regulating E2 production (17ß-hsd, 3ß-hsd and Star) in ovary and the protein expression levels of E2 receptors (ERα, ERß), AMPKα and p-AMPKα1 in liver increased significantly, and the mRNA expression levels of AMP-activated protein kinase (AMPK) downstream genes (Srebp-1c, Fas and Scd1) in liver decreased significantly in the female aged PS-MPs group. Liver metabolomic profiling showed that differential metabolites between female aged PS-MPs group and female control group were enriched in biotin metabolism and the level of biotin increased significantly in the female aged PS-MPs group. However, no significant changes were detected in males. These results indicated that aged PS-MPs exposure increased ovarian E2 production and activated the AMPK pathway in the liver which might inhibit liver lipid synthesis only in females. Our findings provide new insights into the potential sex-specific health effects of environmental MPs pollution.


Assuntos
Microplásticos , Ozônio , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Biotina , LDL-Colesterol/metabolismo , Estradiol/metabolismo , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Feminino , Metabolismo dos Lipídeos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microplásticos/toxicidade , Ozônio/metabolismo , Plásticos/metabolismo , Poliestirenos/metabolismo , Poliestirenos/toxicidade , RNA Mensageiro/metabolismo , Fatores Sexuais , Proteína de Ligação a Elemento Regulador de Esterol 1
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