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1.
BMJ Open ; 10(9): e040644, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32928868

RESUMO

OBJECTIVE: To review evidence on routinely prescribed drugs in the UK that could upregulate or downregulate ACE2 and potentially affect COVID-19 disease. DESIGN: Systematic review. DATA SOURCE: MEDLINE, EMBASE, CINAHL, the Cochrane Library and Web of Science. STUDY SELECTION: Any design with animal or human models examining a currently prescribed UK drug compared with a control, placebo or sham group, and reporting an effect on ACE2 level, activity or gene expression. DATA EXTRACTION AND SYNTHESIS: MEDLINE, EMBASE, CINAHL, the Cochrane Library, Web of Science and OpenGrey from inception to 1 April 2020. Methodological quality was assessed using the SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) risk-of-bias tool for animal studies and Cochrane risk-of-bias tool for human studies. RESULTS: We screened 3360 titles and included 112 studies with 21 different drug classes identified as influencing ACE2 activity. Ten studies were in humans and one hundred and two were in animal models None examined ACE2 in human lungs. The most frequently examined drugs were angiotensin receptor blockers (ARBs) (n=55) and ACE inhibitors (ACE-I) (n=22). More studies reported upregulation than downregulation with ACE-I (n=22), ARBs (n=55), insulin (n=8), thiazolidinedione (n=7) aldosterone agonists (n=3), statins (n=5), oestrogens (n=5) calcium channel blockers (n=3) glucagon-like peptide 1 (GLP-1) agonists (n=2) and Non-steroidal anti-inflammatory drugs (NSAIDs) (n=2). CONCLUSIONS: There is an abundance of the academic literature and media reports on the potential of drugs that could attenuate or exacerbate COVID-19 disease. This is leading to trials of repurposed drugs and uncertainty among patients and clinicians concerning continuation or cessation of prescribed medications. Our review indicates that the impact of currently prescribed drugs on ACE2 has been poorly studied in vivo, particularly in human lungs where the SARS-CoV-2 virus appears to enact its pathogenic effects. We found no convincing evidence to justify starting or stopping currently prescribed drugs to influence outcomes of COVID-19 disease.


Assuntos
Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Infecções por Coronavirus , Estrogênios/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hipoglicemiantes/farmacologia , Pandemias , Peptidil Dipeptidase A/efeitos dos fármacos , Pneumonia Viral , Anti-Inflamatórios não Esteroides/farmacologia , Betacoronavirus/metabolismo , Regulação para Baixo , Peptídeo 1 Semelhante ao Glucagon/agonistas , Humanos , Insulina/farmacologia , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Peptidil Dipeptidase A/metabolismo , Tiazolidinedionas/farmacologia , Reino Unido , Regulação para Cima
2.
Curr Atheroscler Rep ; 22(11): 64, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32870376

RESUMO

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


Assuntos
Infecções por Coronavirus/epidemiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hiperlipoproteinemia Tipo II , Conduta do Tratamento Medicamentoso , Pneumonia Viral/epidemiologia , Anticolesterolemiantes/classificação , Anticolesterolemiantes/farmacologia , Betacoronavirus , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Humanos , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/epidemiologia , Pandemias
3.
J Med Microbiol ; 69(6): 838-843, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32427094

RESUMO

Introduction. Sporotrichosis, caused by species of the Sporothrix schenckii complex, is the most prevalent subcutaneous mycosis in many areas of Latin America. Statins are a class of drugs widely used for lowering high sterol levels through their action on 3-hydroxy-3-methylglutaryl-CoA reductase, a key enzyme in the synthesis of sterol.Aim. In this study, the antifungal activity of statins (simvastatin, atorvastatin, pravastatin) against planktonic cells and biofilms of S. schenckii complex species was evaluated, as well as the interaction of pravastatin with classical antifungals (amphotericin B, itraconazole, terbinafine).Methodology. Eighteen strains of Sporothrix species were used. The antifungal susceptibility assay was performed using the broth microdilution method. Mature biofilms were exposed to statins and metabolic activity was measured by the XTT reduction assay.Results. MICs of statins ranged from 8 to 512 µg ml-1 and from 8 to 256 µg ml-1 for filamentous and yeast forms, respectively. Regarding mature biofilms, MICs of 50 % inhibition (SMIC50) were 128 µg ml-1 for simvastatin and atorvastatin and >2048 µg ml-1 for pravastatin. MICs of 90 % inhibition (SMIC90) were 512 µg ml-1 for simvastatin and >2048 µg ml-1 for atorvastatin and pravastatin.Conclusion. These results highlight the antifungal and antibiofilm potential of statins against S. schenckii complex species.


Assuntos
Biofilmes/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Plâncton/efeitos dos fármacos , Sporothrix/efeitos dos fármacos , Antifúngicos/farmacologia , Testes de Sensibilidade Microbiana , Sporothrix/fisiologia
5.
Invest Ophthalmol Vis Sci ; 61(5): 29, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32421147

RESUMO

Purpose: Matrix metalloproteinases (MMPs) are involved in extracellular matrix (ECM) maintenance and remodeling. The present study aimed to determine whether transforming growth factor (TGF)-ß2 regulates MMP-2 and MMP-9 levels and activities in astrocytes derived from the optic nerve head (ONH) and the role of statins in such modulation. Methods: Primary astrocytes cultured from the lamina cribrosa of human donor ONHs were incubated with three types of statins (5 µg/mL) for 1 hour followed by recombinant TGF-ß2 (5 ng/mL) for various periods to test their effects. Levels and activities of MMP-2 and MMP-9 in astrocytes in vitro were determined by western blotting and zymography, respectively. Levels of phosphorylated myosin phosphatase target subunit 1 (MYPT1) in astrocyte lysates were determined by western blotting, and those of phosphorylated myosin light chain (MLC) were determined by western blotting and immunocytochemistry. Results: MMP-2 and MMP-9 levels were upregulated by TGF-ß2 in human ONH astrocytes. Prior incubation with simvastatin, lovastatin, and atorvastatin inhibited TGF-ß2-mediated MMP-2 and MMP-9 expression and activities. Prior incubation with statins downregulated the TGF-ß2-induced phosphorylation of MYPT1 and MLC, which are downstream substrates of RhoA and ROCKs. Conclusions: Statins inhibited the TGF-ß2-mediated regulation of MMP-2 and MMP-9 by inhibiting the RhoA/ROCK signaling pathway. Considering the role of MMP in ECM remodeling, the present findings support the notion that statins positively impact ECM remodeling within the ONH.


Assuntos
Astrócitos/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/fisiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Fator de Crescimento Transformador beta2/antagonistas & inibidores , Quinases Associadas a rho/antagonistas & inibidores , Proteína rhoA de Ligação ao GTP/antagonistas & inibidores , Adulto , Astrócitos/enzimologia , Atorvastatina/farmacologia , Western Blotting , Células Cultivadas , Feminino , Humanos , Imuno-Histoquímica , Lovastatina/farmacologia , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , Fosfatase de Miosina-de-Cadeia-Leve/metabolismo , Disco Óptico/citologia , Fosforilação , Transdução de Sinais/efeitos dos fármacos , Sinvastatina/farmacologia , Fator de Crescimento Transformador beta2/farmacologia
6.
Diabetes Res Clin Pract ; 164: 108197, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32389742

RESUMO

AIM: To provide information on the balance between the cardiovascular (CV) benefit and the diabetogenic harm of statin therapy in the current clinical practice. METHODS: All the 115,939 residents (older than 50 years) in the Italian Lombardy Region newly treated with statins between 2003 and 2005, were followed from the first statin prescription until 2012 to identify those experiencing a macrovascular complication and those with at least one sign suggestive of new onset diabetes. The proportion of days of follow-up covered by statin prescriptions measured adherence with statins. Hazard ratio, and relative 95% confidence interval (CI), for the two considered outcomes associated with statin adherence, were separately estimated (proportional hazard models). Number needed to treat (NNT) and number needed to harm (NNH), i.e., number of individuals who must be treated with statins in order to prevent a macrovascular complication, or to generate a new onset diabetes, respectively, were calculated to evaluate the balance between CV benefit and diabetogenic harm of statin therapy. RESULTS: Compared to those at very low adherence with statins, patients at high adherence showed a significant reduction of macrovascular risk (28%, 95% CI: 23%-33%) and a greater risk of developing diabetic condition (67%, 50%-86%). In the whole cohort, the NNT was 26, whereas the NNH 65. NNT was lower than NNH also in all considered strata of age, gender, clinical profile. CONCLUSIONS: This large cohort investigation provides real-world evidence that the balance between CV benefit and diabetogenic harm of statin therapy is largely favourable to treatment benefits.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus/induzido quimicamente , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Idoso , Doenças Cardiovasculares/tratamento farmacológico , Estudos de Coortes , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Itália , Masculino , Pessoa de Meia-Idade , Fatores de Risco
7.
Curr Atheroscler Rep ; 22(5): 19, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32458165

RESUMO

PURPOSE OF REVIEW: In this review, we discuss the evidence supporting the effects of statins on mast cells (MCs) in atherosclerosis and their molecular mechanism of action. RECENT FINDINGS: Statins or HMG-CoA reductase inhibitors are known for their lipid-lowering properties and are widely used in the prevention and treatment of cardiovascular diseases. There is growing evidence that statins have an inhibitory effect on MCs, which contributes to the pleiotropic effect of statins in various diseases. MCs are one of the crucial effectors of the immune system which play an essential role in the pathogenesis of multiple disorders. Recent studies have shown that MCs are involved in the development of atherosclerotic plaques. MCs secrete various inflammatory cytokines (IL-6, IL4, TNF-α, and IFNγ) and inflammatory mediators (histamine, tryptase, proteoglycans) after activation by various stimulants. This, in turn, will exacerbate atherosclerosis. Statins suppress the activation of MCs via IgE inhibition which leads to inhibition of inflammatory mediators and cytokines which are involved in the development and progression of atherosclerosis. In keeping with this evidence presented here, MCs can be considered as one of the therapeutic targets for statins in the treatment of atherosclerosis.


Assuntos
Aterosclerose/tratamento farmacológico , Aterosclerose/fisiopatologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Mastócitos/efeitos dos fármacos , Animais , Degranulação Celular/efeitos dos fármacos , Citocinas/metabolismo , Liberação de Histamina/efeitos dos fármacos , Humanos , Mastócitos/imunologia , Mastócitos/metabolismo , Inibidores de Metaloproteinases de Matriz/farmacologia , Inibidores de Metaloproteinases de Matriz/uso terapêutico , Inibidores de Fosfolipase A2/farmacologia , Inibidores de Fosfolipase A2/uso terapêutico , Placa Aterosclerótica/fisiopatologia , Receptores de LDL/agonistas , Receptores Toll-Like/antagonistas & inibidores , Receptores Toll-Like/metabolismo
8.
Nature ; 581(7808): 310-315, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32433607

RESUMO

Microbiome community typing analyses have recently identified the Bacteroides2 (Bact2) enterotype, an intestinal microbiota configuration that is associated with systemic inflammation and has a high prevalence in loose stools in humans1,2. Bact2 is characterized by a high proportion of Bacteroides, a low proportion of Faecalibacterium and low microbial cell densities1,2, and its prevalence varies from 13% in a general population cohort to as high as 78% in patients with inflammatory bowel disease2. Reported changes in stool consistency3 and inflammation status4 during the progression towards obesity and metabolic comorbidities led us to propose that these developments might similarly correlate with an increased prevalence of the potentially dysbiotic Bact2 enterotype. Here, by exploring obesity-associated microbiota alterations in the quantitative faecal metagenomes of the cross-sectional MetaCardis Body Mass Index Spectrum cohort (n = 888), we identify statin therapy as a key covariate of microbiome diversification. By focusing on a subcohort of participants that are not medicated with statins, we find that the prevalence of Bact2 correlates with body mass index, increasing from 3.90% in lean or overweight participants to 17.73% in obese participants. Systemic inflammation levels in Bact2-enterotyped individuals are higher than predicted on the basis of their obesity status, indicative of Bact2 as a dysbiotic microbiome constellation. We also observe that obesity-associated microbiota dysbiosis is negatively associated with statin treatment, resulting in a lower Bact2 prevalence of 5.88% in statin-medicated obese participants. This finding is validated in both the accompanying MetaCardis cardiovascular disease dataset (n = 282) and the independent Flemish Gut Flora Project population cohort (n = 2,345). The potential benefits of statins in this context will require further evaluation in a prospective clinical trial to ascertain whether the effect is reproducible in a randomized population and before considering their application as microbiota-modulating therapeutics.


Assuntos
Disbiose/epidemiologia , Disbiose/prevenção & controle , Microbioma Gastrointestinal/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Bacteroides/isolamento & purificação , Estudos de Coortes , Estudos Transversais , Faecalibacterium/isolamento & purificação , Fezes/microbiologia , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Doenças Inflamatórias Intestinais/microbiologia , Masculino , Obesidade/microbiologia , Prevalência
9.
Adv Exp Med Biol ; 1177: 133-148, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32246446

RESUMO

Coronary artery disease (CAD) is one of the leading causes of death worldwide. It is well known that dyslipidemia is a major pathogenic risk factor for atherosclerosis and CAD, which results in cardiac ischemic injury and myocardial infarction. Lipid-modifying drugs can effectively improve lipid abnormalities including reducing low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) or increasing high-density lipoprotein cholesterol (HDL-C), and eventually decrease the incidence of cardiovascular events. This chapter will review basic principles of lipid metabolism and focus on the therapeutic strategies of lipids modifying drugs (statins, proprotein convertase subtilisin/kexin type 9 inhibitors, ezetimibe, niacin, polyunsaturated fatty acids, and so on) in patients with arteriosclerotic cardiovascular disease. Meanwhile, the challenges and perspectives of the lipid-lowering agents currently in clinical practice as well as their limitations will be outlined.


Assuntos
Hipolipemiantes/farmacologia , Lipídeos/sangue , Aterosclerose/sangue , Aterosclerose/tratamento farmacológico , LDL-Colesterol/sangue , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/tratamento farmacológico , Dislipidemias/sangue , Dislipidemias/tratamento farmacológico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia
10.
Metabolism ; 107: 154226, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32277945

RESUMO

BACKGROUND: Aberrant endothelial function is a major contributing factor in cardiovascular disease. Dyslipidemia leads to decreased nitric oxide (NO) bioavailability, an early sign of endothelial failure. Low insulin gene enhancer protein (ISL1) levels decrease healthy NO bioavailability. We hypothesized that the microRNA miR-652-3p negatively regulates endothelial ISL1 expression and that dyslipidemia-induced miR-652-3p upregulation induces aberrant endothelial functioning via ISL1 downregulation. METHODS: Various in vitro experiments were conducted in human umbilical vein endothelial cells (HUVECs). Luciferase assays were performed in HEK293 cells. We constructed a high-fat diet (HFD) Apoe-/- murine model of dyslipidemia and a rat model of low-density lipoprotein (LDL)-induced dyslipidemia to conduct in vivo and ex vivo experiments. RESULTS: Luciferase assays confirmed miR-652-3p's targeting of the ISL1 3'-untranslated region (3'-UTR). Simvastatin blocked oxidized LDL (ox-LDL)-induced increases in miR-652-3p and ox-LDL-induced decreases in ISL1 protein expression, endothelial NO synthase (eNOS) activation, and NO production. Simvastatin's effects were abrogated by miR-652-3p overexpression and phenocopied by miR-652-3p inhibition. The dyslipidemic mouse model exhibited increased miR-652-3p and decreased ISL1 protein levels in the endothelium, effects opposed by simvastatin or miR-652-3p inhibition. The impact of simvastatin in vivo was abolished by overexpressing miR-652-3p or knocking-down ISL1. The rat model of dyslipidemia exhibited a similar pattern of miR-652-3p upregulation, attenuated ISL1 protein levels, decreased eNOS activation, and decreased NO production, effects mitigated by simvastatin. CONCLUSIONS: Dyslipidemia upregulates endothelial miR-652-3p, which decreases ISL1 protein levels, eNOS activation, and NO production. Simvastatin therapy lowers endothelial miR-652-3p expression to protect endothelial function under dyslipidemic conditions.


Assuntos
Dislipidemias/patologia , Dislipidemias/prevenção & controle , Endotélio/patologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Proteínas com Homeodomínio LIM/biossíntese , MicroRNAs/biossíntese , Fatores de Transcrição/biossíntese , Animais , Apolipoproteínas E/genética , Regulação para Baixo/efeitos dos fármacos , Dislipidemias/genética , Ativação Enzimática , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/efeitos dos fármacos , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos , Ratos Sprague-Dawley
11.
Drug Dev Res ; 81(5): 541-543, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32227357

RESUMO

Corona virus disease (COVID-19) has created pandemic in the world as declared by WHO on March 12, 2020. It is a viral disease caused by SARS-CoV 2 virus and has affected large populations in over 120 countries. There is no specific treatment available and management is empirical. Until such time that an effective vaccine is available for COVID-19 viral infection, one can repurpose known therapeutic drug molecules such as angiotensin receptor 2 blocker, a commonly used antihypertensive drug, to control COVID-19 virus from gaining entry into the host cell by blocking the angiotensin receptor. Clinical trials should also be undertaken to use statins, which are lipid-lowering drugs but have anti-inflammatory and immunomodulatory properties to prevent acute lung injury in COVID-19 infection.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos , Pneumonia Viral/tratamento farmacológico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia
12.
Diabetes Res Clin Pract ; 162: 108114, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32165164

RESUMO

AIMS: Sodium-glucose cotransporter-2 inhibitors (gliflozins) and statins are oral drugs that may have beneficial cardiovascular effects in patients with type 2 diabetes, especially in those with known cardiovascular disease. We planned a systematic review and meta-analysis of cardiovascular outcome trials (CVOTs) that evaluated the effect of gliflozins on MACE risk in patients with T2D stratified by age and by statin use. METHODS: The electronic search was carried out until 20 January 2020. RCTs were included if they were CVOTs performed in adults with T2D, compared add-on therapy with any gliflozin versus placebo, and had major cardiovascular events (MACE) as primary outcome. We limited the evaluation to MACE in order to minimize the statistical impact of post-hoc analyses. We used a random-effect model to calculate hazard ratio (HR) and 95% CI. RESULTS: The hazard ratio for MACE was 0.95 (95% CI, 0.86-1.05) in people <65 years and 0.83 (95% CI, 0.71-0.96) for people ≥65 years, with no subgroup differences (P-value = 0.15), suggesting that the effect was consistent across age categories. The hazard ratio for MACE was 0.87 (95% CI, 0.81-0.94) in people taking a statin and 0.88 (95% CI, 0.77-1.01) for people not taking statin, with no subgroup differences (P-value = 0.90). CONCLUSIONS: The results are reassuring, as they confirm that the efficacy profile of gliflozins is unchanged by age, and may further enhance the CV protection offered by statin.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Idoso , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Masculino , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
13.
Diabetes Res Clin Pract ; 162: 108034, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32004694

RESUMO

Three hundred and eighty-nine older patients with diabetes attending an ambulatory diabetes center were included to determine risk factors of severe hypoglycemia (SH). Thirty-three (8.5%) patients had at least one severe hypoglycemia. In multivariate analyze, statin was associated with lower risk and insulin was associated with higher risk of SH.


Assuntos
Diabetes Mellitus/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipoglicemia/tratamento farmacológico , Idoso , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Estudos Longitudinais , Masculino
14.
Proc Natl Acad Sci U S A ; 117(8): 4158-4168, 2020 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-32051246

RESUMO

Cancer cells display novel characteristics which can be exploited for therapeutic advantage. Isolated studies have shown that 1) the mevalonate pathway and 2) increased macropinocytosis are important in tumorigenesis, but a connection between these two observations has not been envisioned. A library screen for compounds that selectively killed Dictyostelium pten - cells identified pitavastatin. Pitavastatin also killed human breast epithelial MCF10A cells lacking PTEN or expressing K-RasG12V, as well as mouse tumor organoids. The selective killing of cells with oncogenic defects was traced to GGPP (geranylgeranyl diphosphate) depletion. Disruption of GGPP synthase in Dictyostelium revealed that GGPP is needed for pseudopod extension and macropinocytosis. Fluid-phase uptake through macropinocytosis is lower in PTEN-deleted cells and, as reported previously, higher in cells expressing activated Ras. Nevertheless, uptake was more sensitive to pitavastatin in cells with either of these oncogenic mutations than in wild-type cells. Loading the residual macropinosomes after pitavastatin with high concentrations of protein mitigated the cell death, indicating that defective macropinocytosis leads to amino acid starvation. Our studies suggest that the dependence of cancer cells on the mevalonate pathway is due to the role of GGPP in macropinocytosis and the reliance of these cells on macropinocytosis for nutrient uptake. Thus, inhibition of the networks mediating these processes is likely to be effective in cancer intervention.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Ácido Mevalônico/farmacologia , Pinocitose/efeitos dos fármacos , Quinolinas/farmacologia , Animais , Linhagem Celular , Dictyostelium/efeitos dos fármacos , Dictyostelium/fisiologia , Humanos , Camundongos , Oncogenes , Organoides
15.
Am J Respir Cell Mol Biol ; 62(4): 479-492, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31944822

RESUMO

Idiopathic pulmonary fibrosis is a lung disease with limited therapeutic options that is characterized by pathological fibroblast activation and aberrant lung remodeling with scar formation. YAP (Yes-associated protein) is a transcriptional coactivator that mediates mechanical and biochemical signals controlling fibroblast activation. In this study, we developed a high-throughput small-molecule screen for YAP inhibitors in primary human lung fibroblasts. Multiple HMG-CoA (hydroxymethylglutaryl-coenzyme A) reductase inhibitors (statins) were found to inhibit YAP nuclear localization via induction of YAP phosphorylation, cytoplasmic retention, and degradation. We further show that the mevalonate pathway regulates YAP activation, and that simvastatin treatment reduces fibrosis markers in activated human lung fibroblasts and in the bleomycin mouse model of pulmonary fibrosis. Finally, we show that simvastatin modulates YAP in vivo in mouse lung fibroblasts. Our results highlight the potential of small-molecule screens for YAP inhibitors and provide a mechanism for the antifibrotic activity of statins in idiopathic pulmonary fibrosis.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas de Ciclo Celular/antagonistas & inibidores , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Fibrose Pulmonar/tratamento farmacológico , Acil Coenzima A/metabolismo , Animais , Biomarcadores/metabolismo , Bleomicina/farmacologia , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Citoplasma/efeitos dos fármacos , Citoplasma/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Ácido Mevalônico/metabolismo , Camundongos , Fosfoproteínas/metabolismo , Fibrose Pulmonar/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sinvastatina/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia
16.
Am J Cardiol ; 125(7): 1026-1032, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31955829

RESUMO

The association between hypocholesterolemia and diabetes mellitus (DM) in patients with coronary artery disease (CAD) remains poorly investigated. We undertook this study to investigate whether there is an association between hypocholesterolemia and odds of DM in these patients. This observational study included 14,952 patients with CAD: 8,592 without statins (statin-naive group) and 6,360 with statins on admission (statin-treated group). Hypocholesterolemia was defined as a total cholesterol within the first quintile of the total cholesterol concentration (total cholesterol <157 mg/dl). The primary outcome measure of this study was presence of DM. Hypocholesterolemia was present in 2,926 patients (20%; 1,102 statin-naive patients and 1,824 statin-treated patients). DM was present in 1,029 patients with hypocholesterolemia and 2,793 patients without hypocholesterolemia (35% vs 23%; odds ratio [OR] 1.79, 95% confidence interval [CI] 1.64 to 1.96; p <0.001). After adjustment, hypocholesterolemia was independently associated with the odds of DM in all patients (adjusted OR 1.55 [1.38 to 1.74]; p <0.001), statin-naive patients (adjusted OR 1.51 [1.25 to 1.82]; p <0.001) and statin-treated patients (adjusted OR 1.64 [1.41 to 1.91]; p <0.001). For every 20 mg/dl lower total cholesterol, the odds of being with DM increased by 14% (adjusted OR 1.14 [1.11 to 1.16]; p <0.001) with no cholesterol-by-statin interaction (Pint = 0.803). The association between hypocholesterolemia and odds of DM was entirely driven by low-density lipoprotein-cholesterol. For every 20 mg/dl lower low-density lipoprotein-cholesterol, the odds of DM increased by 14 % (adjusted OR 1.14 [1.11 to 1.16]; p <0.001). In conclusion, in patients with CAD, hypocholesterolemia was independently associated with the odds of DM with a dose-response relation and no cholesterol-by-statin interaction.


Assuntos
LDL-Colesterol/sangue , Doença da Artéria Coronariana/sangue , Diabetes Mellitus/sangue , Dislipidemias/sangue , Idoso , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/terapia , Dislipidemias/complicações , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea , Prognóstico , Fatores de Risco
17.
Lipids Health Dis ; 19(1): 6, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31931807

RESUMO

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


Assuntos
Anticolesterolemiantes/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Placa Aterosclerótica/tratamento farmacológico , Prosopis/química , Animais , Anticolesterolemiantes/química , HDL-Colesterol/sangue , LDL-Colesterol/sangue , VLDL-Colesterol/sangue , Modelos Animais de Doenças , Hidroximetilglutaril-CoA Redutases/genética , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Hipercolesterolemia/tratamento farmacológico , Masculino , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Placa Aterosclerótica/sangue , Placa Aterosclerótica/patologia , Pravastatina/farmacologia , Coelhos , Triglicerídeos/sangue
18.
Clin Ther ; 42(2): e13-e31, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31955966

RESUMO

PURPOSE: Chronic inflammation increases the risks for cardiovascular disease, type 2 diabetes, and cancer. Recently, the antiinflammatory effects of statins, as cholesterol-lowering medications, have been considered. This study systematically reviewed and summarized earlier findings from randomized clinical trials about the effects of statins on serum concentrations of C-reactive protein (CRP) and interleukin (IL)-6 in patients with abnormal glucose homeostasis. METHODS: Relevant articles published through October 2019 were searched using suitable key words on the PubMed/MEDLINE, SCOPUS, EMBASE, and Google Scholar databases. RCTs were included if they compared the effects of statins on serum concentrations of CRP and IL-6 in adults with abnormal glucose homeostasis. The effect sizes were represented as weighted mean differences (WMDs) and 95% CI s using a random-effects model. Subgroup analysis was performed to find possible sources of heterogeneity. FINDINGS: Overall, 17 publications with 21 effect sizes and which enrolled 3766 subjects (1895 participants in intervention and 1871 in control groups) were included. Combining 13 effect sizes from 10 studies, a significant reduction in serum CRP concentration following the administration of atorvastatin was found (WMD, -0.35; 95% CI, -0.54 to -0.17; I2 = 90.6%). Based on 5 effect sizes from 4 studies, we found a statistically significant reduction in serum IL-6 concentration after atorvastatin therapy (WMD, -0.44; 95% CI, -0.65 to -0.22; I2 = 93.9%). Pooling 6 effect sizes from 5 studies revealed a significantly reduced serum concentration of CRP after simvastatin therapy (WMD, -0.66; 95% CI, -0.79 to -0.54; I2 = 97.6%). IMPLICATIONS: The administration of atorvastatin or simvastatin in patients with abnormal glucose hemostasis was associated with a reduced serum CRP concentration. Atorvastatin therapy might also help to decrease serum IL-6 concentration in these patients.


Assuntos
Atorvastatina/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Sinvastatina/farmacologia , Glicemia/efeitos dos fármacos , Proteína C-Reativa/análise , Citocinas/sangue , Glucose/metabolismo , Homeostase , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
19.
Cancer Res ; 80(6): 1293-1303, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31969375

RESUMO

Small-cell lung cancer (SCLC) is an aggressive form of lung cancer with dismal survival rates. While kinases often play key roles driving tumorigenesis, there are strikingly few kinases known to promote the development of SCLC. Here, we investigated the contribution of the MAPK module MEK5-ERK5 to SCLC growth. MEK5 and ERK5 were required for optimal survival and expansion of SCLC cell lines in vitro and in vivo. Transcriptomics analyses identified a role for the MEK5-ERK5 axis in the metabolism of SCLC cells, including lipid metabolism. In-depth lipidomics analyses showed that loss of MEK5/ERK5 perturbs several lipid metabolism pathways, including the mevalonate pathway that controls cholesterol synthesis. Notably, depletion of MEK5/ERK5 sensitized SCLC cells to pharmacologic inhibition of the mevalonate pathway by statins. These data identify a new MEK5-ERK5-lipid metabolism axis that promotes the growth of SCLC. SIGNIFICANCE: This study is the first to investigate MEK5 and ERK5 in SCLC, linking the activity of these two kinases to the control of cell survival and lipid metabolism.


Assuntos
Metabolismo dos Lipídeos/efeitos dos fármacos , Neoplasias Pulmonares/patologia , MAP Quinase Quinase 5/metabolismo , Proteína Quinase 7 Ativada por Mitógeno/metabolismo , Carcinoma de Pequenas Células do Pulmão/patologia , Animais , Atorvastatina/farmacologia , Atorvastatina/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Colesterol/biossíntese , Técnicas de Silenciamento de Genes , Humanos , Hidroximetilglutaril-CoA Redutases/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Lipidômica , Neoplasias Pulmonares/tratamento farmacológico , MAP Quinase Quinase 5/genética , Sistema de Sinalização das MAP Quinases/genética , Ácido Mevalônico/metabolismo , Camundongos , Proteína Quinase 7 Ativada por Mitógeno/genética , RNA-Seq , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Drugs Aging ; 37(3): 175-185, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31919804

RESUMO

PURPOSE: The use of statins in the primary prevention of cardiovascular disease (CVD) is increasing in older adults. Nonetheless, good clinical evidence for the safety and tolerability of statins in this population is limited. OBJECTIVE: We aimed to evaluate the safety and tolerability of statins in older adults without overt CVD, focusing on statin-related muscle symptoms. METHODS: Double-blinded randomised controlled trials (RCTs) of statins published before January 2012 were identified from a Cochrane review updated to 2012. Trials published between January 2012 and July 2018 were identified through the CENTRAL, MEDLINE and EMBASE databases. Eligible trials were limited to those including individuals aged ≥ 65 years without overt CVD, who were followed for at least 1 year. Trials had to have reported at least one of the outcomes of interest. Pooled relative risk (RR) estimates and 95% confidence intervals (CIs) were calculated using random-effects models. RESULTS: We identified 11 trials, including 18,192 participants (mean age 73.7 years; 43% females). Compared with placebo, statins neither increased the risks of muscle-related symptoms (RR 1.01; 95% CI 0.90-1.12), total adverse events (AEs) and serious AEs nor led to more total permanent treatment discontinuations and discontinuations due to AEs or specifically due to muscle-related symptoms. No evidence of heterogeneity was observed in any of these outcomes. CONCLUSIONS: This meta-analysis of RCTs found no excess incidence of muscle-related symptoms, total AEs, serious AEs and treatment discontinuations attributable to statin treatment compared with placebo among older adults without CVD.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Prevenção Primária/métodos , Segurança , Idoso , Doenças Cardiovasculares/prevenção & controle , Humanos
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