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BMC Biotechnology (2)
International Journal of Clinical and Experimental Medicine (1)
Rasouli, Mina (3)
Ahmad, Zalinah (2)
Omar, Abdul Rahman (2)
Abbasi, Sakineh (1)
Allaudin, Zeenathul N (1)
Azman, Ahmad Zaid Fattah (1)
Kalbasi, Samira (1)
Nouri, Mehrnaz (1)
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Association of estrogen receptor-α A908G (K303R) mutation with breast cancer risk
International Journal of Clinical and Experimental Medicine
Genetic mutations in premalignant breast lesions may have a role in malignancy progression or influence the behavior of subsequent disease. A point mutation in estrogen receptor-α (ER-α) as A908G (Lys303→Arg) was originally involved to hypersensitive to estrogen breast hyperplasia. We detected this mutation among Iranian women with invasive breast cancer. A population-based case-control study was conducted in 150 newly diagnosed invasive breast cancer and 147 healthy control individuals controls to screen for presence of the ER-α A908G mutation by using single-strand conformation polymorphism (SSCP) analysis and 33Pcycle DNA sequencing. We detected the 10.7% ER-α A908G mutation in the form of heterozygote genotype only among cancer patients (χ2=22.752, P=0.00). The allelic frequency of mutant allele AGG in codon 303 was significantly (χ2=29.709, P=0.001) higher in patients with the family history of breast cancer (28.9%) than those without the family history of breast cancer (1.9%). Our data suggest that ER-α codon 303 mutation is correlated with various aspects of breast cancer in Iran. ER-α genotype might represent a surrogate marker for predicting breast cancer developing later in life.
Breast cancer; mutation; estrogen receptor; PCR-SSCP; lymph node metastasis
Evaluation of insulin expression and secretion in genetically engineered gut K and L-cells
Azman, Ahmad Zaid Fattah
Omar, Abdul Rahman
Gene therapy could provide an effective treatment of diabetes. Previous studies have investigated the potential for several cell and tissue types to produce mature and active insulin. Gut K and L-cells could be potential candidate hosts for gene therapy because of their special features.
In this study, we isolated gut K and L-cells to compare the potential of both cell types to produce insulin when exposed to similar conditions. The isolated pure K and L-cells were transfected with recombinant plasmids encoding insulin and with specific promoters for K or L-cells. Insulin expression was studied in response to glucose or meat hydrolysate. We found that glucose and meat hydrolysate efficiently induced insulin secretion from K and L-cells. However, the effects of meat hydrolysate on insulin secretion were more potent in both cells compared with glucose. Results of enzyme-linked immunosorbent assays showed that L-cells secreted more insulin compared with K-cells regardless of the stimulator, although this difference was not statistically significant.
The responses of K and L-cells to stimulation with glucose or meat hydrolysate were generally comparable. Therefore, both K and L-cells show similar potential to be used as surrogate cells for insulin gene expression in vitro. The potential use of these cells for diabetic gene therapy warrants further investigation.
Diabetes gene therapy; Insulin expression; K-cells; L-cells
Engineering an L-cell line that expresses insulin under the control of the glucagon-like peptide-1 promoter for diabetes treatment
Omar, Abdul Rahman
Allaudin, Zeenathul N
Diabetes mellitus is a complicated disease with a pathophysiology that includes hyperinsulinemia, hyperglycemia and other metabolic impairments leading to many clinical complications. It is necessary to develop appropriate treatments to manage the disease and reduce possible acute and chronic side effects. The advent of gene therapy has generated excitement in the medical world for the possible application of gene therapy in the treatment of diabetes. The glucagon-like peptide-1 (GLP-1) promoter, which is recognised by gut L-cells, is an appealing candidate for gene therapy purposes. The specific properties of L-cells suggest that L-cells and the GLP-1 promoter would be useful for diabetes therapy approaches.
In this study, L-cells were isolated from a primary intestinal cell line to create suitable target cells for insulin expression studies. The isolated cells displayed L-cell properties and were therefore used as an L-cell surrogate. Next, the isolated L-cells were transfected with the recombinant plasmid consisting of an insulin gene located downstream of the GLP-1 promoter. The secretion tests revealed that an increase in glucose concentration from 5 mM to 25 mM induced insulin gene expression in the L-cells by 2.7-fold. Furthermore, L-cells quickly responded to the glucose stimulation; the amount of insulin protein increased 2-fold in the first 30 minutes and then reached a plateau after 90 minutes.
Our data showed that L-cells efficiently produced the mature insulin protein. In addition, the insulin protein secretion was positively regulated with glucose induction. In conclusion, GLP-1 promoter and L-cell could be potential candidates for diabetes gene therapy agents.
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