RESUMO
BACKGROUND: Given the sparse data on the renin-angiotensin system (RAS) and its biological effector molecules ACE1 and ACE2 in pediatric COVID-19 cases, we investigated whether the ACE1 insertion/deletion (I/D) polymorphism could be a genetic marker for susceptibility to COVID-19 in Egyptian children and adolescents. METHODS: This was a case-control study included four hundred sixty patients diagnosed with COVID-19, and 460 well-matched healthy control children and adolescents. The I/D polymorphism (rs1799752) in the ACE1 gene was genotyped by polymerase chain reaction (PCR), meanwhile the ACE serum concentrations were assessed by ELISA. RESULTS: The ACE1 D/D genotype and Deletion allele were significantly more represented in patients with COVID-19 compared to the control group (55% vs. 28%; OR = 2.4; [95% CI: 1.46-3.95]; for the DD genotype; P = 0.002) and (68% vs. 52.5%; OR: 1.93; [95% CI: 1.49-2.5] for the D allele; P = 0.032). The presence of ACE1 D/D genotype was an independent risk factor for severe COVID-19 among studied patients (adjusted OR: 2.6; [95% CI: 1.6-9.7]; P < 0.001. CONCLUSIONS: The ACE1 insertion/deletion polymorphism may confer susceptibility to SARS-CoV-2 infection in Egyptian children and adolescents. IMPACT: Recent studies suggested a crucial role of renin-angiotensin system and its biological effector molecules ACE1 and ACE2 in the pathogenesis and progression of COVID-19. To our knowledge, ours is the first study to investigate the association of ACE1 I/D polymorphism and susceptibility to COVID-19 in Caucasian children and adolescents. The presence of the ACE1 D/D genotype or ACE1 Deletion allele may confer susceptibility to SARS-CoV-2 infection and being associated with higher ACE serum levels; may constitute independent risk factors for severe COVID-19. The ACE1 I/D genotyping help design further clinical trials reconsidering RAS-pathway antagonists to achieve more efficient targeted therapies.
RESUMO
This study aimed to investigate the potential anti-fibrotic activity of vinpocetine in an experimental model of pulmonary fibrosis by bleomycin and in the MRC-5 cell line. Pulmonary fibrosis was induced in BALB/c mice by oropharyngeal aspiration of a single dose of bleomycin (5 mg/kg). The remaining induced animals received a daily dose of pirfenidone (as a standard anti-fibrotic drug) (300 mg/kg/PO) and vinpocetine (20 mg/kg/PO) on day 7 of the induction till the end of the experiment (day 21). The results of the experiment revealed that vinpocetine managed to alleviate the fibrotic endpoints by statistically improving (P ≤ 0.05) the weight index, histopathological score, reduced expression of fibrotic-related proteins in immune-stained lung sections, as well as fibrotic markers measured in serum samples. It also alleviated tissue levels of oxidative stress and inflammatory and pro-fibrotic mediators significantly elevated in bleomycin-only induced animals (P ≤ 0.05). Vinpocetine managed to express a remarkable attenuating effect in pulmonary fibrosis both in vivo and in vitro either directly by interfering with the classical TGF-ß1/Smad2/3 signaling pathway or indirectly by upregulating the expression of Nrf2 enhancing the antioxidant system, activating PPAR-γ and downregulating the NLRP3/NF-κB pathway making it a candidate for further clinical investigation in cases of pulmonary fibrosis.
Assuntos
Células Epiteliais Alveolares , Fibrose Pulmonar , Transdução de Sinais , Alcaloides de Vinca , Animais , Humanos , Masculino , Camundongos , Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Bleomicina/efeitos adversos , Linhagem Celular , Modelos Animais de Doenças , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/metabolismo , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/patologia , Fibrose Pulmonar/induzido quimicamente , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Alcaloides de Vinca/farmacologiaRESUMO
BACKGROUND: Ischaemic hepatitis is centrilobular necrosis which is usually associated with an acute cardiovascular event and in a general hospital setting has been considered to be a rare condition. It is though thought to be frequently unrecognized, which is important as it has implications for both investigations and drug therapy. Previous reports have not focused on the elderly. OBJECTIVES: (1) To determine the incidence of ischaemic hepatitis in elderly patients admitted to a Department of Geriatric Medicine and (2) to assess both the clinical and biochemical features of the condition. METHODS: 1,905 elderly patients (1,270 F, 635 M) admitted consecutively to our department over a 2-year period were assessed prospectively. All were aged > or =65 years (mean 78, range 65-98). Ischaemic hepatitis was diagnosed by a rapid development of abnormal liver function tests of hepatocellular type in acutely ill patients in whom a fall in blood pressure occurred and other causes of liver dysfunction were excluded. The admission, lowest and subsequent blood pressures were recorded. Daily renal and liver function tests, including prothrombin times, were measured during the acute illness. RESULTS: Nineteen patients (1%) developed ischaemic hepatitis. The clinical picture was dominated by the causal condition, the commonest being left ventricular failure (12 patients). The mean fall in systolic, diastolic and mean blood pressures were 61, 44 and 48 mm Hg, respectively. Within 3 days the alanine aminotransferase increased to more than 5 times normal and there were marked elevations of the lactic dehydrogenase. In those who survived, the liver enzymes returned to normal within 7-22 days (mean 13). The prothrombin time was prolonged to >20 s in 6 patients (32%). Six patients died, 5 from left ventricular failure; the mean creatinine in 5 of those who died was 244 micromol/l (range 174-355) and in each the urea was >25 micromol/l. CONCLUSION: Ischaemic hepatitis is an uncommon but not rare condition in elderly patients admitted acutely to a Department of Geriatric Medicine. There was a dramatic rise in liver enzymes which in survivors returned to normal within 3 weeks. Clinical features were dominated by the causal condition and a third of the patients died.