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1.
J Pediatr Endocrinol Metab ; 35(3): 325-332, 2022 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-34905667

RESUMO

BACKGROUND: Classical homocystinuria (HCU) is an autosomal recessive inborn error of metabolism, which is caused by the cystathionine-ß-synthase (CBS: encoded by CBS) deficiency. Symptoms of untreated classical HCU patients include intellectual disability (ID), ectopia lentis and long limbs, along with elevated plasma methionine, and homocysteine. METHODS: A total of 429 ID patients (age range: 1.6-23 years) were sampled from Northern areas of Punjab, Pakistan. Biochemical and genetic analyses were performed to find classical HCU disease in ID patients. RESULTS: Biochemically, nine patients from seven unrelated families were identified with high levels of plasma methionine and homocysteine. Targeted exonic analysis of CBS confirmed seven causative homozygous mutations; of which three were novel missense mutations (c.451G>T; p.Gly151Trp, c.975G>C; p.Lys325Asn and c.1039 + 1G>T splicing), and four were recurrent variants (c.451 + 1G>A; IVS4 + 1 splicing, c.770C>T; p.Thr257Met, c.808_810del GAG; p.Glu270del and c.752T>C; p.Leu251Pro). Treatment of patients was initiated without further delay with pyridoxine, folic acid, cobalamin, and betaine as well as dietary protein restriction. The immediate impact was noticed in behavioral improvement, decreased irritability, improved black hair color, and socialization. Overall, health outcomes in this disorder depend on the age and symptomatology at the time of treatment initiation. CONCLUSIONS: With personalized treatment and care, such patients can reach their full potential of living as healthy a life as possible. This screening study is one of the pioneering initiatives in Pakistan which would help to minimize the burden of such treatable inborn errors of metabolism in the intellectually disabled patients.


Assuntos
Cistationina beta-Sintase , Homocistinúria , Adolescente , Adulto , Povo Asiático , Criança , Pré-Escolar , Cistationina beta-Sintase/genética , Cistationina beta-Sintase/metabolismo , Homocistinúria/diagnóstico , Homocistinúria/genética , Homocistinúria/terapia , Humanos , Lactente , Mutação , Paquistão/epidemiologia , Adulto Jovem
2.
Cardiovasc Res ; 118(5): 1359-1373, 2022 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-34320175

RESUMO

AIMS: NOX-derived reactive oxygen species (ROS) are mediators of signalling pathways implicated in vascular smooth muscle cell (VSMC) dysfunction in hypertension. Among the numerous redox-sensitive kinases important in VSMC regulation is c-Src. However, mechanisms linking NOX/ROS to c-Src are unclear, especially in the context of oxidative stress in hypertension. Here, we investigated the role of NOX-induced oxidative stress in VSMCs in human hypertension focusing on NOX5, and explored c-Src, as a putative intermediate connecting NOX5-ROS to downstream effector targets underlying VSMC dysfunction. METHODS AND RESULTS: VSMC from arteries from normotensive (NT) and hypertensive (HT) subjects were studied. NOX1,2,4,5 expression, ROS generation, oxidation/phosphorylation of signalling molecules, and actin polymerization and migration were assessed in the absence and presence of NOX5 (melittin) and Src (PP2) inhibitors. NOX5 and p22phox-dependent NOXs (NOX1-4) were down-regulated using NOX5 siRNA and p22phox-siRNA approaches. As proof of concept in intact vessels, vascular function was assessed by myography in transgenic mice expressing human NOX5 in a VSMC-specific manner. In HT VSMCs, NOX5 was up-regulated, with associated oxidative stress, hyperoxidation (c-Src, peroxiredoxin, DJ-1), and hyperphosphorylation (c-Src, PKC, ERK1/2, MLC20) of signalling molecules. NOX5 siRNA reduced ROS generation in NT and HT subjects. NOX5 siRNA, but not p22phox-siRNA, blunted c-Src phosphorylation in HT VSMCs. NOX5 siRNA reduced phosphorylation of MLC20 and FAK in NT and HT. In p22phox- silenced HT VSMCs, Ang II-induced phosphorylation of MLC20 was increased, effects blocked by melittin and PP2. NOX5 and c-Src inhibition attenuated actin polymerization and migration in HT VSMCs. In NOX5 transgenic mice, vascular hypercontractilty was decreased by melittin and PP2. CONCLUSION: We define NOX5/ROS/c-Src as a novel feedforward signalling network in human VSMCs. Amplification of this system in hypertension contributes to VSMC dysfunction. Dampening the NOX5/ROS/c-Src pathway may ameliorate hypertension-associated vascular injury.


Assuntos
Hipertensão , Músculo Liso Vascular , Actinas/metabolismo , Angiotensina II/metabolismo , Animais , Células Cultivadas , Humanos , Meliteno/metabolismo , Meliteno/farmacologia , Camundongos , Camundongos Transgênicos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , NADPH Oxidase 5/genética , NADPH Oxidase 5/metabolismo , NADPH Oxidase 5/farmacologia , Oxirredução , Proteínas Tirosina Quinases/metabolismo , RNA Interferente Pequeno/genética , Espécies Reativas de Oxigênio/metabolismo
3.
Arch Virol ; 154(9): 1523-7, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19669078

RESUMO

Hepatitis C virus (HCV) is normally present in the blood of infected patients; however, it can also be present in some other body fluids. Therefore, in this study, a concurrent presence of HCV-RNA was investigated in oral fluid and urine of 80 Pakistani chronic HCV patients. HCV-RNA was detected in 31 (38.8%) oral fluid and 10 (12.5%) urine samples using RT-PCR in all 80 of the patients whose sera tested positive for HCV-RNA. From this study, it is concluded that, in addition to the blood, HCV RNA can also be found in oral secretions as well as urine of chronic HCV patients.


Assuntos
Hepacivirus/isolamento & purificação , Hepatite C Crônica/virologia , RNA Viral/análise , Adolescente , Adulto , Feminino , Hepacivirus/genética , Hepatite C Crônica/sangue , Hepatite C Crônica/urina , Humanos , Masculino , Pessoa de Meia-Idade , Paquistão , RNA Viral/sangue , RNA Viral/urina , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Saliva/virologia , Urina/virologia
4.
Cell Metab ; 17(4): 534-48, 2013 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-23562077

RESUMO

The molecular mechanisms involved in the development of obesity and related complications remain unclear. Here, we report that obese mice and human subjects have increased activity of neutrophil elastase (NE) and decreased serum levels of the NE inhibitor α1-antitrypsin (A1AT, SerpinA1). NE null (Ela2(-/-)) mice and A1AT transgenic mice were resistant to high-fat diet (HFD)-induced body weight gain, insulin resistance, inflammation, and fatty liver. NE inhibitor GW311616A reversed insulin resistance and body weight gain in HFD-fed mice. Ela2(-/-) mice also augmented circulating high molecular weight (HMW) adiponectin levels, phosphorylation of AMP-activated protein kinase (AMPK), and fatty acid oxidation (FAO) in the liver and brown adipose tissue (BAT) and uncoupling protein (UCP1) levels in the BAT. These data suggest that the A1AT-NE system regulates AMPK signaling, FAO, and energy expenditure. The imbalance between A1AT and NE contributes to the development of obesity and related inflammation, insulin resistance, and liver steatosis.


Assuntos
Metabolismo Energético , Resistência à Insulina , Elastase de Leucócito/metabolismo , Obesidade/metabolismo , alfa 1-Antitripsina/sangue , Quinases Proteína-Quinases Ativadas por AMP , Adiponectina/sangue , Tecido Adiposo Marrom/metabolismo , Animais , Dieta Hiperlipídica , Ácidos Graxos/química , Ácidos Graxos/metabolismo , Fígado Gorduroso/complicações , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Células Hep G2 , Humanos , Inflamação , Canais Iônicos/metabolismo , Leptina/metabolismo , Elastase de Leucócito/antagonistas & inibidores , Elastase de Leucócito/sangue , Fígado/metabolismo , Metaboloma , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Camundongos Transgênicos , Proteínas Mitocondriais/metabolismo , Obesidade/complicações , Obesidade/patologia , Oxirredução , Fosforilação , Piperidinas/farmacologia , Proteínas Quinases/metabolismo , Proteína Desacopladora 1 , Aumento de Peso/efeitos dos fármacos , alfa 1-Antitripsina/genética , alfa 1-Antitripsina/metabolismo
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