RESUMO
Alpha-1 antitrypsin (α1-AT) is the most abundant circulating protease inhibitor. The common severe Z allele of α1-AT (Glu342Lys) causes the protein to form ordered polymers that are retained within the endoplasmic reticulum of hepatocytes. These polymers form the periodic acid-Schiff positive inclusions that are associated with cirrhosis. The lack of circulating α1-AT predisposes the Z α1-AT homozygote to early onset emphysema. We review here the molecular basis of α1-AT deficiency and show how understanding the liver disease provides new insights in the pathobiology of the associated emphysema. The mechanism of α1-AT deficiency provides a paradigm for a wider group of conditions that we have termed the serpinopathies. We also examine the strategies that are being pursued to develop novel therapies for α1-AT deficiency. This review considers our understanding of the pathobiology of α1-AT deficiency and then illustrate the therapeutic possibilities that can ensue once we understand basic mechanisms of disease.
Assuntos
Deficiência de alfa 1-Antitripsina/genética , Animais , Humanos , Modelos Moleculares , Estrutura Terciária de Proteína , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/patologia , Doença Pulmonar Obstrutiva Crônica/terapia , alfa 1-Antitripsina/química , Deficiência de alfa 1-Antitripsina/patologia , Deficiência de alfa 1-Antitripsina/terapiaAssuntos
Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/terapia , Fatores de Necrose Tumoral/sangue , Idoso , Biomarcadores/sangue , Composição Corporal , Estudos de Casos e Controles , Ensaios Clínicos como Assunto , Estudos de Coortes , Citocina TWEAK , Exercício Físico , Feminino , Humanos , Inflamação , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/mortalidade , Músculo Quadríceps/patologiaAssuntos
Regulação Enzimológica da Expressão Gênica , Glutationa Transferase/genética , Isoenzimas/genética , Leucemia/enzimologia , Animais , Metilação de DNA , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Glutationa S-Transferase pi , Humanos , Leucemia/genética , Regiões Promotoras Genéticas/genética , Ratos , Fator de Transcrição AP-1/farmacologia , Transcrição GênicaRESUMO
Curcumin presents strong antioxidant and anticancer properties. However, molecular mechanisms leading to curcumin-induced cell death are poorly understood. The effect of curcumin was compared in two different leukemia cell lines: K562 and Jurkat. Cell death was induced in both cell lines, and apoptosis pathways were investigated by Western blot analysis. Decreases in pro-caspase 8 and 9 levels were observed. BH(3) interacting domain death agonist (Bid) was also cleaved. Jurkat cells appeared to be more sensitive to curcumin, and apoptosis takes place earlier.