ABSTRACT
Objective To investigate the effects of fluorofenidone(AKF-PD)on diabetic kidney disease in db/db mice and its possible mechanisms.Methods(1)Fifty-six mice aged 8 weeks(half male and half female),including 42 db/db mice and 14 wild-type mice were studied.Fortytwo db/db mice randomly were divided into model group(mock-treated diabetic db/db mice),AKF-PD(250 mg· kg-1· d-1)treatment group and losartan(20 mg· kg-1· d-1)treatment group.Wild-type mice and model mice were treated with vehicle(0.5％sodium carboxymethylcellulose),while the treatment groups received either AKF-PD or losartan.After 18 weeks,the blood glucose and urinary albumin were measured,the pathological changes of kidney were observed by PAS staining.The protein expressions of type Ⅳ collagen and fibronectin(FN)in kidney tissue were detected by immunohistochemistry.(2)Mouse glomerular mesangial cells(MES-13 cells)were divided into six groups:normal glucose group(5.5 mmol/L glucose),hypertonic group(5.5 mmol/L glucose+19.5 mmol/L mannitol),high glucose group(25.0 mmol/L glucose),AKF-PD group(25.0 mmol/L glucose+400 mg/L AKF-PD)and losartan group(25.0 mmol/L glucose+2 μmol/L losartan).After 72 h treatment,the expressions of type Ⅰ collagen,type Ⅳ collagen and transforming growth factor-β1(TGF-β1)mRNA were detected by realtime PCR,and the content of TGF-β1 protein in the culture supernatant was detected by ELISA.Results(1)Compared with the wild type mice,model mice had increased weight,blood glucose and glomerulosclerosis index(all P ＜ 0.01),accompanied with heavy albuminuria,glomerular hypertrophy,mesangial area expansion and deposition of collagen type Ⅳ and FN(all P ＜ 0.01).Compared with model mice,in AKF-PD and losartan groups 24 h urinary albumin and glomerulosclerosis index decreased(all P ＜ 0.01),glomerular hypertrophy and mesangial area expansion alleviated,and the protein expressions of collagen type Ⅳ and FN were inhibited(all P ＜ 0.01).(2)Compared with the normal glucose group,the mRNA expressions of type Ⅰ collagen and type Ⅳ collagen increased in high glucose group,meanwhile the mRNA and protein expressions of TGF-β1 increased(all P ＜ 0.01).In AKF-PD and losartan groups the expressions of type Ⅰ collagen,type Ⅳ collagen and TGF-β1 were inhibited as compared with high glucose group(all P ＜ 0.05).Conclusion Fluorofenidone may play an anti-fibrotic effect in db/db mice by reducing the expression of TGF-β1 and inhibiting collagen synthesis in glomerular mesangial cells.
ABSTRACT
JUSTIFICATIVA E OBJETIVOS: Pacientes com fibrilação atrial (FA) estão mais propensos à ocorrência de eventos vasculares, como acidente vascular encefálico (AVE) e fenômenos tromboembólicos, sendo necessária anticoagulação oral. A varfarina, o anticoagulante mais utilizado, tem uma série de limitações referentes ao seu uso. Nesse contexto, foram desenvolvidos novos anticoagulantes orais (NOACs): inibidores da trombina (dabigatrana) e do fator Xa (rivaroxabana e apixabana). Essa revisão sistemática procurou elencar os principais resultados de Ensaios Clínicos Randomizados (ECRs) abordando o tema NOACs em pacientes com fibrilação atrial para a prevenção de acidente vascular encefálico e/ou fenômenos tromboembólicos. CONTEÚDO: Foram pesquisados Ensaios Clínicos Randomizados, cegos ou abertos, em indivíduos adultos, nas bases PubMed, Scopus, Web of Science, SciELO, LILACS e Cochrane CENTRAL. A avaliação da qualidade dos estudos foi feita utilizando a escala Downs & Black. Foram selecionados cinco Ensaios Clínicos Randomizados e descritos os seus resultados. A rivaroxabana se mostrou não inferior a varfarina no que diz respeito ao desfecho combinado embolismo sistêmico e acidente vascular encefálico, enquanto que a apixabana e a dabigatrana 150mg mostraram-se superiores. Todos os três medicamentos estiveram associados a menor incidência de hemorragia intracraniana quando comparado a varfarina. A apixabana mostrou perfil mais favorável em relação à ocorrência de qualquer sangramento. CONCLUSÕES: os Ensaios Clínicos Randomizados selecionados demonstraram a eficácia dos NOACs na prevenção de acidente vascular encefálicos e/ou embolismo sistêmico em pacientes com fibrilçao atrial. Contudo, são necessários mais estudos para preencher as lacunas do conhecimento quanto à eficácia e segurança desta nova classe de anticoagulantes orais.
BACKGROUND AND OBJECTIVES: Patients with atrial fibrillation (AF) are more likely to the occurrence of vascular events including stroke and thromboembolism systemic. Thus anticoagulation is necessary to prevent these events. Warfarin is the current gold standard but has a number of limitations regarding your use. In this context, new oral anticoagulants (NOACs) were developed: thrombin inhibitors (dabigatran) and factor Xa inhibitors (rivaroxaban and apixaban). The aim of this systematic review was to analyze the results of the main randomized clinical trials (RCTs) envolving NOACs in patients with atrial fibrillation for the prevention of stroke and/or thromboembolic events. CONTENTS: Double blinded or open label randomized clinical trials envolving patients with FA testing these drugs were researched in PubMed, Scopus, Web of Science, SciELO, LILACS and Cochrane CENTRAL. The quality assessment of studies used the Downs & Black Scale Five randomized clinical trials were selected, envolving 57.457 patients. Dabigatran, apixaban and rivaroxaban were at least non inferior to the warfarin in the outcome of stroke and systemic embolism. Apixaban and dabigatran 150mg were also superior than warfarin in efficacy. All three drugs were associated with a lower incidence of intracranial hemorrhage. Apixaban was related to lower risk of total bleeding. CONCLUSIONS: NOACs have efficacy to prevent AVE and systemic thromboembolism in patients with FA. However further studies are needed to resolve the issues that remain open and to provide more security to the use of these drugs in clinical practice.