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1.
Medicine (Baltimore) ; 100(35): e26201, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34477113

RESUMO

ABSTRACT: This retrospective study appraised the preventive effect of statin after carotid artery stenting (CAS).Records were extracted for 100 patients with CAS surgery indicator, aged between 20 and 75 years old, and treated for statin. The cohort study included treatment group (statin and routine treatment) and control group (routine treatment), each group 50 patients. Outcomes consisted of degree of nerve defect (as measured by National Institute of Health Stroke Scale), lipid profiles (mg/dL), and CAS complications within 30 days after surgery.After treatment, there were no significant differences in National Institute of Health Stroke Scale, lipid profiles, and mortality rate between 2 groups. However, significant differences in total cholesterol (mg/dL, P = .03), low-density lipoprotein (mg/dL, P = .01), transient ischemic attack (P = .03), ischemic stroke (P = .04), and cardiac complications (P = .03) were identified within 30 days after CAS between 2 groups.The results of this study showed that prior statin treatment may be effective for the prevention of CAS complications.


Assuntos
Artérias Carótidas/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/normas , Stents/normas , Idoso , Artérias Carótidas/fisiopatologia , China/epidemiologia , Estudos de Coortes , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Estatísticas não Paramétricas , Stents/estatística & dados numéricos , Resultado do Tratamento
2.
Graefes Arch Clin Exp Ophthalmol ; 259(9): 2707-2716, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34328550

RESUMO

BACKGROUND: Excessive angiogenesis of the retina is a key component of irreversible causes of blindness in many ocular diseases. Pitavastatin is a cholesterol-lowering drug used to reduce the risk of cardiovascular diseases. Various studies have shown the effects of pitavastatin on angiogenesis but the conclusions are contradictory. The effects of pitavastatin on retinal angiogenesis have not been revealed. This study investigated the effects of pitavastatin at clinically relevant concentrations on retinal angiogenesis and its underlying mechanisms using retinal microvascular endothelial cells (RMECs). METHODS: The effects of pitavastatin on retinal angiogenesis were determined using in vitro model of retinal angiogenesis, endothelial cell migration, adhesion, proliferation, and apoptosis assays. The mechanism studies were conducted using immunoblotting and stress fiber staining. RESULTS: Pitavastatin stimulated capillary network formation of RMECs in a similar manner as vascular endothelial growth factor (VEGF) and lipopolysaccharide (LPS). Pitavastatin also increased RMEC migration, adhesion to Matrigel, growth, and survival. The combination of pitavastatin with VEGF or LPS was more effective than VEGF or LPS alone in stimulating biological activities of RMECs, suggesting that pitavastatin can enhance the stimulatory effects of VEGF and LPS on retinal angiogenesis. Pitavastatin acted on RMECs in a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase-independent manner. In contrast, pitavastatin activated pro-angiogenic microenvironment via promoting the secretion of VEGF and stimulated retinal angiogenesis via multiple mechanisms including activation of RhoA-mediated pathways, induction of focal adhesion complex formation, and activation of ERK pathway. CONCLUSION: Our work provides a preclinical evidence on the pro-angiogenic effect of pitavastatin in retina via multiple mechanisms that are irrelevant to mevalonate pathway.


Assuntos
Células Endoteliais , Inibidores de Hidroximetilglutaril-CoA Redutases , Células Cultivadas , Coenzima A , Adesões Focais , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Oxirredutases , Quinolinas , Retina , Fator A de Crescimento do Endotélio Vascular
3.
Neurosci Biobehav Rev ; 128: 693-708, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34265321

RESUMO

Statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) treat dyslipidaemia and cardiovascular disease by inhibiting cholesterol biosynthesis. They also have immunomodulatory and anti-inflammatory properties. Beyond cardiovascular disease, cholesterol and inflammation appear to be components of the pathogenesis and pathophysiology of neuropsychiatric disorders. Statins may therefore afford some therapeutic benefit in mood disorders. In this paper, we review the pathophysiology of mood disorders with a focus on pharmacologically relevant pathways, using major depressive disorder and bipolar disorder as exemplars. Statins are discussed in the context of these disorders, with particular focus on the putative mechanisms involved in their anti-inflammatory and immunomodulatory effects. Recent clinical data suggest that statins may have antidepressant properties, however given their interactions with many known biological pathways, it has not been fully elucidated which of these are the major determinants of clinical outcomes in mood disorders. Moreover, it remains unclear what the appropriate dose, or appropriate patient phenotype for adjunctive treatment may be. High quality randomised control trials in concert with complementary biological investigations are needed if the potential clinical effects of statins on mood disorders, as well as their biological correlates, are to be better understood.


Assuntos
Transtorno Bipolar , Transtorno Depressivo Maior , Inibidores de Hidroximetilglutaril-CoA Redutases , Antidepressivos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Transtorno Depressivo Maior/tratamento farmacológico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Transtornos do Humor/tratamento farmacológico
4.
Int J Mol Sci ; 22(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208774

RESUMO

Bile acids (BA) play a significant role in the pathophysiology of nonalcoholic steatohepatitis (NASH). The present study evaluates the modulation of bile acid metabolomics by atorvastatin, a cholesterol-lowering agent commonly used to treat cardiovascular complications accompanying NASH. NASH was induced in mice by 24 weeks of consuming a high-saturated fat, high-fructose, and high-cholesterol diet (F), with atorvastatin administered orally (20 mg/kg/day) during the last three weeks. Biochemical and histological analyses confirmed the effectiveness of the F diet in inducing NASH. Untreated NASH animals had significantly reduced biliary secretion of BA and increased fecal excretion of BA via decreased apical sodium-dependent bile salt transporter (Asbt)-mediated reabsorption. Atorvastatin decreased liver steatosis and inflammation in NASH animals consistently with a reduction in crucial lipogenic enzyme stearoyl-coenzyme A (CoA) desaturase-1 and nuclear factor kappa light chain enhancer of activated B-cell pro-inflammatory signaling, respectively. In this group, atorvastatin also uniformly enhanced plasma concentration, biliary secretion and fecal excretion of the secondary BA, deoxycholic acid (DCA). However, in the chow diet-fed animals, atorvastatin decreased plasma concentrations of BA, and reduced BA biliary secretions. These changes stemmed primarily from the increased fecal excretion of BA resulting from the reduced Asbt-mediated BA reabsorption in the ileum and suppression of synthesis in the liver. In conclusion, our results reveal that atorvastatin significantly modulates BA metabolomics by altering their intestinal processing and liver synthesis in control and NASH mice.


Assuntos
Atorvastatina/farmacologia , Ácidos e Sais Biliares/metabolismo , Homeostase , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Biomarcadores , Dieta Hiperlipídica , Modelos Animais de Doenças , Fígado/metabolismo , Camundongos , Modelos Biológicos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/patologia , Triglicerídeos/biossíntese
5.
Molecules ; 26(12)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207840

RESUMO

Statins have been widely used for the treatment of hypercholesterolemia due to their ability to inhibit HMG-CoA reductase, the rate-limiting enzyme of de novo cholesterol synthesis, via the so-called mevalonate pathway. However, their inhibitory action also causes depletion of downstream intermediates of the pathway, resulting in the pleiotropic effects of statins, including the beneficial impact in the treatment of cancer. In our study, we compared the effect of all eight existing statins on the expression of genes, the products of which are implicated in cancer inhibition and suggested the molecular mechanisms of their action in epigenetic and posttranslational regulation, and in cell-cycle arrest, death, migration, or invasion of the cancer cells.


Assuntos
Antineoplásicos/farmacologia , Biologia Computacional/métodos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Ácido Mevalônico/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Transcriptoma/efeitos dos fármacos , Morte Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Epigênese Genética , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia
6.
Life Sci ; 283: 119846, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34324915

RESUMO

Hydroxycinnamic acid derivatives are an important class of polyphenols found in fruits, vegetables, and medicinal plants and widely consumed in human diet. In the present work, alterations of HepG2 cells biochemical profile under the effect of four hydroxycinnamic acid derivatives (caffeic acid, m-coumaric acid, chlorogenic acid and rosmarinic acid) relatively to the effect of pravastatin, a drug often prescribed to inhibit HMG-CoA reductase enzyme, the regulator enzyme in the cholesterol biosynthesis pathway, were reported. The application of FTIR spectroscopy in combination with multivariate analysis by PCA showed a similarity between pravastatin and the four hydroxycinnamic acid derivatives in metabolite profile modification expressed by various changes in proteins region, the phosphate region which mainly corresponds to nucleic acids as well as in lipids regions. FTIR structural analysis in the amide I region, using resolution enhancement methods, such as second derivative and amide I deconvolution method, revealed significant decrease in α-helix/random coil and intermolecular ß-sheet decreased while intramolecular ß-sheet in treated cells showed an increase. It was also noticed that the intracellular cholesterol as well as esterified ingredients such as cholesterol esters in the cell membrane decreased. Moreover, principal component analysis (PCA) of the spectral data showed that the compounds and pravastatin were well separated from untreated cells showing a different mode of action on HepG2 treated cells for each compound.


Assuntos
Membrana Celular/metabolismo , Ésteres do Colesterol/metabolismo , Ácidos Cumáricos/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Pravastatina/farmacologia , Transferência Ressonante de Energia de Fluorescência , Células Hep G2 , Humanos
7.
J Steroid Biochem Mol Biol ; 212: 105940, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34119628

RESUMO

Due to the biochemical importance of cholesterol homeostasis in cardiovascular disease (CVD), this study was aimed to identify metabolic signatures of serum sterols according to atherosclerotic CVD severity. Biogically active free cholesterol and its 11 analogues in serum samples obtained from subjects who underwent cardiovascular intervention were quantitatively evaluated by gas chromatography-mass spectrometry (GCMS). Study groups were divided by 29 patients with stable angina (SA), 35 patients with acute coronary syndrome (ACS), and 41 controls. In all subjects, serum levels of cholesterol and its upstream precursors of 7-dehydrocholesterol, lathosterol, and lanosterol were closely associated with CVD risk factors, such as total cholesterol, low-density lipoprotein cholesterol (LDL-C), and LDL-C/high-density lipoprotein cholesterol (HDL-C) ratio (r = 0.407 ∼ 0.684, P < 0.03 for all). Metabolic ratios of lathosterol/cholesterol (control = 55.75 ± 34.34, SA = 51.04 ± 34.93, ACS = 36.52 ± 22.00; P < 0.03) and lanosterol/cholesterol (control = 12.27 ± 7.43, SA = 10.97 ± 9.13, ACS = 8.01 ± 5.82; P < 0.03), were remarkably decreased. Both metabolic ratios and individual concentrations of lathosterol and lanosterol were also decreased in subjects with statin treatment than those in the control group without statin treatment (P < 0.05 for all), whereas three metabolic ratios of dietary sterols (sitosterol, campesterol, and stigmasterol) to free cholesterol were increased after statin therapy (P < 0.05 for all) in both SA and ACS groups. The present metabolic signatures suggest that both lathosterol/cholesterol and lanosterol/cholesterol ratios corresponding to cholesterol biosynthesis may reflect statin response. Individual dietary sterols to cholesterol ratios resulted in higher intestinal cholesterol absorption after statin therapy.


Assuntos
Doença da Artéria Coronariana/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Esteróis/biossíntese , Absorção Fisiológica , Adulto , Idoso , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/cirurgia , Dislipidemias/sangue , Dislipidemias/tratamento farmacológico , Dislipidemias/metabolismo , Dislipidemias/cirurgia , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Metabolismo dos Lipídeos , Masculino , Pessoa de Meia-Idade , Esteróis/sangue
8.
Int J Mol Sci ; 22(11)2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34073503

RESUMO

Drug-induced myopathies are classified as acquired myopathies caused by exogenous factors. These pathological conditions develop in patients without muscle disease and are triggered by a variety of medicaments, including lipid-lowering drugs (LLDs) such as statins, fibrates, and ezetimibe. Here we summarise the current knowledge gained via studies conducted using various models, such as cell lines and mammalian models, and compare them with the results obtained in zebrafish (Danio rerio) studies. Zebrafish have proven to be an excellent research tool for studying dyslipidaemias as a model of these pathological conditions. This system enables in-vivo characterization of drug and gene candidates to further the understanding of disease aetiology and develop new therapeutic strategies. Our review also considers important environmental issues arising from the indiscriminate use of LLDs worldwide. The widespread use and importance of drugs such as statins and fibrates justify the need for the meticulous study of their mechanism of action and the side effects they cause.


Assuntos
Ácidos Fíbricos/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Doenças Musculares , Peixe-Zebra/metabolismo , Animais , Modelos Animais de Doenças , Ácidos Fíbricos/farmacologia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Doenças Musculares/induzido quimicamente , Doenças Musculares/metabolismo , Doenças Musculares/patologia
9.
Molecules ; 26(10)2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-34064670

RESUMO

Statins are among the most widely used drug classes in the world. Apart from their basic mechanism of action, which is lowering cholesterol levels, many pleiotropic effects have been described so far, such as anti-inflammatory and antiatherosclerotic effects. A growing number of scientific reports have proven that these drugs have a beneficial effect on the functioning of the nervous system. The first reports proving that lipid-lowering therapy can influence the development of neurological and psychiatric diseases appeared in the 1990s. Despite numerous studies about the mechanisms by which statins may affect the functioning of the central nervous system (CNS), there are still no clear data explaining this effect. Most studies have focused on the metabolic effects of this group of drugs, however authors have also described the pleiotropic effects of statins, pointing to their probable impact on the neurotransmitter system and neuroprotective effects. The aim of this paper was to review the literature describing the impacts of statins on dopamine, serotonin, acetylcholine, and glutamate neurotransmission, as well as their neuroprotective role. This paper focuses on the mechanisms by which statins affect neurotransmission, as well as on their impacts on neurological and psychiatric diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), vascular dementia (VD), stroke, and depression. The pleiotropic effects of statin usage could potentially open floodgates for research in these treatment domains, catching the attention of researchers and clinicians across the globe.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/fisiopatologia , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/fisiopatologia , Fármacos Neuroprotetores/uso terapêutico , Transmissão Sináptica , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Fármacos Neuroprotetores/farmacologia , Neurotransmissores/metabolismo , Transmissão Sináptica/efeitos dos fármacos
12.
Radiol Oncol ; 55(3): 305-316, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33939900

RESUMO

BACKGROUND: Statins, small molecular 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, are widely used to lower cholesterol levels in lipid-metabolism disorders. Recent preclinical and clinical studies have shown that statins exert beneficial effects in the management of breast cancer by increasing recurrence free survival. Unfortunately, the underlying mechanisms remain elusive. MATERIALS AND METHODS: Simvastatin, one of the most widely prescribed lipophilic statins was utilized to investigate potential radiosensitizing effects and an impact on cell survival and migration in radioresistant breast cancer cell lines. RESULTS: Compared to parental cell counterparts, radioresistant MDA-MB-231-RR, T47D-RR andAu565-RR cells were characterized by upregulation of 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMGCR) expression accompanied by epithelial-to-mesenchymal transition (EMT) activation. Radioresistant breast cancer cells can be killed by simvastatin via mobilizing of a variety of pathways involved in apoptosis and autophagy. In the presence of simvastatin migratory abilities and vimentin expression is diminished while E-cadherin expression is increased. CONCLUSIONS: The present study suggests that simvastatin may effectively eradicate radioresistant breast carcinoma cells and diminish their mesenchymal phenotypes.


Assuntos
Neoplasias da Mama/patologia , Sobrevivência Celular/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Radiossensibilizantes/farmacologia , Sinvastatina/farmacologia , Morte Celular Autofágica/efeitos dos fármacos , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Transição Epitelial-Mesenquimal , Feminino , Humanos , Hidroximetilglutaril-CoA Redutases/metabolismo , Regulação para Cima
13.
J Gastrointest Cancer ; 52(2): 819-821, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33931828

RESUMO

PURPOSE: To asseess whether the mevalonate pathway can be targeted in managing patients with esophageal cancer. METHODS: This a narrative review of peer-revieweed publications indexed in MedLine PubMed. The search was conducted by using "Esophageal cancer", "Mevalonate pahtway", "Statins", and "Translational research." RESULTS: The mevalonate pathway is an important metabolic pathway that is involved in various cellular functions. Its downstream products are essential for cell-signaling, cell membrane integrity, protein synthesis, and cellular respiration. Statins, a class of medications that are best known as lipid-lowering drugs, inhibit the rate-limiting enzyme of this pathway. Many studies have shown that a variety of cancerous cells have a dysregulated mevalonate pathway. Esophageal cancer is a malignancy that has a poor prognosis, which is mainly due to patients presenting once the cancer is in the advances stages. Chemotherapy has been the mainstay for treating esophageal cancer. However, these agents are not consistently effective and fail to differentiate between the different subtypes of esophageal cancers. Identifying other classes of drugs which could possess anti esophageal cancer properties is appealing. CONCLUSION: There is a growing body of literature that has shown the anti-cancer properties of statins in the setting of various malignancies. Herein, we summarize the current literature as it pertains to how the mevalonate pathway can be targeted by statins for potentially treating esophageal cancer.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Esofágicas/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Ácido Mevalônico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Neoplasias Esofágicas/patologia , Humanos , Hidroximetilglutaril-CoA Redutases/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico
14.
Am J Med ; 134(9): 1091-1095, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34019857

RESUMO

In 2018, cardiovascular society cholesterol guidelines recommended the use of coronary artery calcium to guide statin therapy in patients 40-79 years of age who are at intermediate risk by multiple risk factor equations (ie, estimated 10-year risk for atherosclerotic disease of 7.5%-19.9% but in whom statin benefit is uncertain). Many such patients have no coronary calcium and remain at <5% risk over the next decade; hence, statin therapy can be delayed until a repeat calcium scan is conducted. Exceptions include patients with severe hypercholesterolemia, diabetes, and a strong family history of atherosclerotic disease. If coronary calcium equals 1-99 Agatston units, the 10-year risk is borderline (5% to <7.5%) and statin therapy is optional pending a repeat scan. If coronary calcium equals 100-299 Agatston units, the patient is clearly statin eligible (7.5% to <20% 10-year risk). And finally, if coronary calcium is ≥300 Agatston units, a patient is at high risk and is a candidate for high-intensity statins. Risk factor analysis combined judiciously with coronary calcium scanning offers the strongest evidence-based approach to use of statins in primary prevention.


Assuntos
Doença da Artéria Coronariana , Vasos Coronários/patologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Calcificação Vascular , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/prevenção & controle , Prática Clínica Baseada em Evidências , Humanos , Seleção de Pacientes , Prevenção Primária/métodos , Calcificação Vascular/diagnóstico por imagem , Calcificação Vascular/prevenção & controle
15.
Chem Biol Interact ; 345: 109528, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34022192

RESUMO

Statins are the low-density lipoproteins (LDL)-cholesterol-lowering drugs of first choice and are used to prevent the increased risk of cardiovascular and cerebrovascular diseases. Although some of their effects are well known, little is known about their ability to regulate other lipid-related proteins which control apoptotic mechanisms. The aim of this study was to explore whether statins can bind to cell death-inducing DNA fragmentation factor-like effector A (CIDEA), which might be a possible pleiotropic mechanism of action of these drugs on the modulation of apoptosis and lipid metabolism. The structures of statins were subjected to molecular docking and dynamics with the human CIDEA protein to investigate the interaction pattern and identify which residues are important. The docking results indicated that atorvastatin and rosuvastatin showed the best interaction energy (-8.51 and -8.04 kcal/mol, respectively) followed by fluvastatin (-7.39), pitavastatin (-6.5), lovastatin (-6.23), pravastatin (-6.04) and simvastatin (-5.29). Atorvastatin and rosuvastatin were further subjected to molecular dynamics at 50 ns with CIDEA and the results suggested that rosuvastatin-CIDEA complex had lower root-mean square deviation and root-mean square fluctuation when compared with atorvastatin-CIDEA. Since two arginine residues -ARG19 and ARG22-were identified to be common for the interaction with CIDEA, a single-point mutation was induced in these residues to determine whether they are important for binding interaction. Mutation of these two residues seemed to affect mostly the interaction of atorvastatin with CIDEA, suggesting that they are important for the binding and therefore indicate another possible metabolic mechanism of the pleiotropic effects of this statin.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Morte Celular/efeitos dos fármacos , Simulação por Computador , Inibidores de Hidroximetilglutaril-CoA Redutases/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Proteínas Reguladoras de Apoptose/química , Proteínas Reguladoras de Apoptose/genética , Humanos , Simulação de Acoplamento Molecular , Mutação Puntual , Ligação Proteica , Conformação Proteica
16.
Biochem Pharmacol ; 188: 114580, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33930349

RESUMO

Statins are 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors that lower atherogenic LDL-cholesterol levels. Statins exert clinically relevant anti-inflammatory effects; however, the underlying molecular mechanism remains unclear. Studies have shown that endogenous and exogenous pathogenic crystals, such as cholesterol and monosodium urate (MSU), and needle-like nanomaterials, such as multi-wall carbon nanotubes (MWCNT), induce the production of IL-1ß and play a critical role in the development of crystal-associated sterile inflammatory pathologies. In this study, we evaluated the effect of statins on crystal-induced IL-1ß production in macrophages. We found that various statins, including pitavastatin, atorvastatin, fluvastatin, and lovastatin, but not squalene synthase inhibitor, repressed IL-1ß release upon MWCNT stimulation. In addition, IL-1ß production induced by cholesterol crystals and MSU crystals, but not by ATP or nigericin, was diminished. MWCNT-stimulated IL-1ß release was dependent on the expression of NLRP3, but not AIM2, NLRC4, or MEFV. Statin-induced repression was accompanied by reduced levels of mature caspase-1 and decreased uptake of MWCNT into cells. Supplementation of mevalonate, geranylgeranyl pyrophosphate, or farnesyl pyrophosphate prevented the reduction in IL-1ß release, suggesting a crucial role of protein prenylation, but not cholesterol synthesis. The statin-induced repression of MWCNT-elicited IL-1ß release was observed in THP-1-derived and mouse peritoneal macrophages, but not in bone marrow-derived macrophages where statins act in synergy with lipopolysaccharide to enhance the expression of IL-1ß precursor protein. In summary, we describe a novel anti-inflammatory mechanism through which statins repress mature IL-1ß release induced by pathogenic crystals and nanoneedles by inhibiting the internalization of crystals by macrophages.


Assuntos
Colesterol/toxicidade , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Interleucina-1beta/antagonistas & inibidores , Macrófagos/efeitos dos fármacos , Nanotubos de Carbono/toxicidade , Animais , Cristalização/métodos , Feminino , Humanos , Interleucina-1beta/metabolismo , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Células THP-1
17.
Int J Mol Sci ; 22(5)2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33800828

RESUMO

Hypercholesterolemia is one of the major causes of cardiovascular disease, the risk of which is further increased if other forms of dyslipidemia occur. Current therapeutic strategies include changes in lifestyle coupled with drug administration. Statins represent the most common therapeutic approach, but they may be insufficient due to the onset of resistance mechanisms and side effects. Consequently, patients with mild hypercholesterolemia prefer the use of food supplements since these are perceived to be safer. Here, we investigate the phytochemical profile and cholesterol-lowering potential of Protium heptaphyllum gum resin extract (PHE). Chemical characterization via HPLC-APCI-HRMS2 and GC-FID/MS identified 13 compounds mainly belonging to ursane, oleanane, and tirucallane groups. Studies on human hepatocytes have revealed how PHE is able to reduce cholesterol production and regulate the expression of proteins involved in its metabolism. (HMGCR, PCSK9, LDLR, FXR, IDOL, and PPAR). Moreover, measuring the inhibitory activity of PHE against HMGR, moderate inhibition was recorded. Finally, molecular docking studies identified acidic tetra- and pentacyclic triterpenoids as the main compounds responsible for this action. In conclusion, our study demonstrates how PHE may be a useful alternative to contrast hypercholesterolemia, highlighting its potential as a sustainable multitarget natural extract for the nutraceutical industry that is rapidly gaining acceptance as a source of health-promoting compounds.


Assuntos
Anticolesterolemiantes/farmacologia , Hidrogênio/química , Gomas Vegetais/química , Resinas Vegetais/química , Triterpenos/farmacologia , Anticolesterolemiantes/isolamento & purificação , Domínio Catalítico/efeitos dos fármacos , Colesterol/metabolismo , Cromatografia Líquida de Alta Pressão , Suplementos Nutricionais , Avaliação Pré-Clínica de Medicamentos , Ionização de Chama , Cromatografia Gasosa-Espectrometria de Massas , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Lovastatina/farmacologia , Modelos Moleculares , Simulação de Acoplamento Molecular , Conformação Proteica , Triterpenos/isolamento & purificação
18.
Blood Coagul Fibrinolysis ; 32(3): 167-171, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33827111

RESUMO

Coronavirus disease 2019 infection produce a prothrombotic state. This is initiated through multiple pathways and is finally aggravated by cross talks with cytokine storm and neutrophil, platelet, complement activation. All these combine towards the second week of illness to produce thrombosis in the lung capillaries surrounding the alveolus producing characteristic pulmonary dysfunction (PaO2/FiO2 > 300, normal or minimally increased lung compliance and very high d-dimer levels) and a high rate of peripheral venous thrombosis. International and many national guidelines have approached this state in different ways but all emphasized the need for management and prevention of widespread thrombosis. It is felt more aggressive and graded thrombosis prevention and management should be initiated early in the treatment. d-Dimer, neutrophil count, SaO2, fibrinogen levels should be used to control the hypercoagulability. Drugs like statins which have anti-inflammatory action as well as ability to reduce fibrinogen and other clotting factors should be used in the beginning along with antiplatelet drugs and progressively complement activation and neutrophil extracellular traps inhibitors, oral mucopolysaccharides, full-scale anticoagulation along with judicial use of fibrinolysis supporting drugs should be added. In the present review, we have evaluated the various studies and argued the rationality that the anticoagulation in this condition should be initiated early during the infection and should be increased in a graded manner depending on clinical and laboratory progression of the condition until a strong specific antiviral drug for coronavirus disease 2019 infection is available.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , COVID-19/tratamento farmacológico , COVID-19/fisiopatologia , Trombofilia/tratamento farmacológico , Trombose/tratamento farmacológico , Anticoagulantes/uso terapêutico , Antivirais/uso terapêutico , Plaquetas/efeitos dos fármacos , Armadilhas Extracelulares/efeitos dos fármacos , Fibrinolíticos/uso terapêutico , Glicosaminoglicanos/farmacologia , Glicosaminoglicanos/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inflamação/tratamento farmacológico , Pulmão/efeitos dos fármacos , Pulmão/fisiopatologia , Pulmão/virologia , Inibidores da Agregação Plaquetária/uso terapêutico
19.
Int J Nanomedicine ; 16: 2933-2947, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33907400

RESUMO

Background: Intracerebral hemorrhage (ICH), a devastating subtype of stroke, has a poor prognosis. However, there is no effective therapy currently available due to its complex pathological progression, in which neuroinflammation plays a pivotal role in secondary brain injury. In this work, the use of statin-loaded nanomicelles to target the neuroinflammation and improve the efficacy was studied in a mouse model of ICH. Methods: Rosuvastatin-loaded nanomicelles were prepared by a co-solvent evaporation method using polyethylene glycol-poly(ε-caprolactone) (PEG-PCL) copolymer as a carrier. The prepared nanomicelles were characterized by transmission electron microscopy (TEM) and dynamic light scattering (DLS), and then in vitro and in vivo studies were performed. Results: TEM shows that the nanomicelles are spherical with a diameter of about 19.41 nm, and DLS shows that the size, zeta potential, and polymer dispersity index of the nanomicelles were 23.37 nm, -19.2 mV, and 0.221, respectively. The drug loading content is 8.28%. The in vivo study showed that the nanomicelles significantly reduced neuron degeneration, inhibited the inflammatory cell infiltration, reduced the brain edema, and improved neurological deficit. Furthermore, it was observed that the nanomicelles promoted the polarization of microglia/macrophages to M2 phenotype, and also the expression of the proinflammatory cytokines, such as IL-1ß and TNF-α, was significantly down-regulated, while the expression of the anti-inflammatory cytokine IL-10 was significantly up-regulated. The related mechanism was proposed and discussed. Conclusion: The nanomicelles treatment suppressed the neuroinflammation that might contribute to the promoted nerve functional recovery of the ICH mouse, making it potential to be applied in clinic.


Assuntos
Hemorragia Cerebral/tratamento farmacológico , Portadores de Fármacos/administração & dosagem , Inflamação/tratamento farmacológico , Nanoestruturas/química , Rosuvastatina Cálcica/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Edema Encefálico/tratamento farmacológico , Edema Encefálico/patologia , Hemorragia Cerebral/patologia , Modelos Animais de Doenças , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inflamação/patologia , Camundongos , Micelas , Microglia/efeitos dos fármacos , Microglia/patologia , Nanoestruturas/administração & dosagem , Poliésteres/química , Polietilenoglicóis/química , Células RAW 264.7 , Rosuvastatina Cálcica/administração & dosagem
20.
Biomolecules ; 11(4)2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33920915

RESUMO

Matrix metalloproteinases (MMPs) cleave extracellular matrix proteins, growth factors, cytokines, and receptors to influence organ development, architecture, function, and the systemic and cell-specific responses to diseases and pharmacological drugs. Conversely, many diseases (such as atherosclerosis, arthritis, bacterial infections (tuberculosis), viral infections (COVID-19), and cancer), cholesterol-lowering drugs (such as statins), and tetracycline-class antibiotics (such as doxycycline) alter MMP activity through transcriptional, translational, and post-translational mechanisms. In this review, we summarize evidence that the aforementioned diseases and drugs exert significant epigenetic pressure on genes encoding MMPs, tissue inhibitors of MMPs, and factors that transcriptionally regulate the expression of MMPs. Our understanding of human pathologies associated with alterations in the proteolytic activity of MMPs must consider that these pathologies and their medicinal treatments may impose epigenetic pressure on the expression of MMP genes. Whether the epigenetic mechanisms affecting the activity of MMPs can be therapeutically targeted warrants further research.


Assuntos
Antibacterianos/farmacologia , Descoberta de Drogas , Epigênese Genética/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Metaloproteinases da Matriz/genética , Tetraciclinas/farmacologia , Animais , Antibacterianos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/genética , Doenças Ósseas/tratamento farmacológico , Doenças Ósseas/genética , COVID-19/tratamento farmacológico , COVID-19/genética , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/genética , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/genética , Tetraciclinas/uso terapêutico , Viroses/tratamento farmacológico , Viroses/genética
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