Dataset Information

Aggregation of M3 (E376D) variant of alpha1- antitrypsin.

ABSTRACT: Alpha1-antitrypsin (?1AT) is an abundant serine-protease inhibitor in circulation. It has an important role in neutralizing the neutrophil elastase activity. Different pathogenic point mutations like Z^(E342K)-?1AT have been implicated in the development of liver cirrhosis and Chronic Obstructive Pulmonary Disease (COPD), the latter being a cluster of progressive lung diseases including chronic bronchitis and emphysema. M3-?1AT (376Glu?>?Asp) is another variant of ?1AT which so far is largely being considered as normal though increased frequency of the variant has been reported in many human diseases including COPD. We also observed increased frequency of M3-?1AT in COPD cases in Kashmiri population. The frequency of heterozygous (AC) genotype in cases and controls was 58.57% and 27.61% (odds-ratio 6.53 (2.27-15.21); p?

SUBMITTER: Bashir A

PROVIDER: S-EPMC7237413 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Aggregation of M3 (E376D) variant of alpha1- antitrypsin.

Bashir Arif A Hazari Younis Y Pal Debnath D Maity Dibyajyoti D Bashir Samirul S Singh Laishram Rajendrakumar LR Shah Naveed Nazir NN Fazili Khalid Majid KM

Scientific reports 20200519 1

Alpha1-antitrypsin (α1AT) is an abundant serine-protease inhibitor in circulation. It has an important role in neutralizing the neutrophil elastase activity. Different pathogenic point mutations like Z<sup>(E342K)</sup>-α1AT have been implicated in the development of liver cirrhosis and Chronic Obstructive Pulmonary Disease (COPD), the latter being a cluster of progressive lung diseases including chronic bronchitis and emphysema. M3-α1AT (376Glu > Asp) is another variant of α1AT which so far is ...[more]

PMID: 32427833

Similar Datasets

Project description:ObjectivePancreatic ?-cell failure is central to the development and progression of type 2 diabetes (T2D). The aggregation of human islet amyloid polypeptide (hIAPP) has been associated with pancreatic islet inflammation and dysfunction in T2D. Alpha1-antitrypsin (AAT) is a circulating protease inhibitor with anti-inflammatory properties. Here, we sought to investigate the potential therapeutic effect of AAT treatment in a mouse model characterized by hIAPP overexpression in pancreatic ?-cells.MethodsMice overexpressing hIAPP (hIAPP-Tg) in pancreatic ?-cells were used as a model of amyloid-induced ?-cell dysfunction. Glucose homeostasis was evaluated by glucose tolerance tests and insulin secretion assays. Apoptosis and amyloid formation was assessed in hIAPP-Tg mouse islets cultured at high glucose levels. Dissociated islet cells were cocultured with macrophages obtained from the peritoneal cavity.ResultsNontreated hIAPP-Tg mice were glucose intolerant and exhibited impaired insulin secretion. Interestingly, AAT treatment improved glucose tolerance and restored the insulin secretory response to glucose in hIAPP-Tg mice. Moreover, AAT administration normalized the expression of the essential ?-cell genes MafA and Pdx1, which were downregulated in pancreatic islets from hIAPP-Tg mice. AAT prevented the formation of amyloid deposits and apoptosis in hIAPP-Tg islets cultured at high glucose concentrations. Since islet macrophages mediate hIAPP-induced ?-cell dysfunction, we investigated the effect of AAT in cocultures of macrophages and islet cells. AAT prevented hIAPP-induced ?-cell apoptosis in these cocultures without reducing the hIAPP-induced secretion of IL-1? by macrophages. Remarkably, AAT protected ?-cells against the cytotoxic effects of conditioned medium from hIAPP-treated macrophages. Similarly, AAT also abrogated the cytotoxic effects of exogenous proinflammatory cytokines on pancreatic ?-cells.ConclusionsThese results demonstrate that treatment with AAT improves glucose homeostasis in mice overexpressing hIAPP and protects pancreatic ?-cells from the cytotoxic actions of hIAPP mediated by macrophages. These results support the use of AAT-based therapies to recover pancreatic ?-cell function for the treatment of T2D.

Dataset Information

Aggregation of M3 (E376D) variant of alpha1- antitrypsin.

Publications

Aggregation of M3 (E376D) variant of alpha1- antitrypsin.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets