Drug and Alcohol Rehabilitation: Polymorphisms in the CYP2E1 and GSTM1 Genes as Possible Protection Factors for Leprosy Patients.

Polymorphisms in the CYP2E1 and GSTM1 Genes as Possible Protection Factors for Leprosy Patients.

Filed under: Drug and Alcohol Rehabilitation

PLoS One. 2012; 7(10): e47498
Pinto P, Salgado CG, Santos N, Alencar DO, Santos S, Hutz MH, Ribeiro-Dos-Santos A

The CYP2E1 and GSTM1 genes encode metabolic enzymes that have key functions in drug modification and elimination.We investigated the possible effects of CYP2E1 and GSTM1 polymorphisms in 71 leprosy patients and in 110 individuals from the general population. The GSTM1*0 null allele and INDEL CYP2E1*1D mutant genotypes were analyzed by conventional PCR, while CYP2E1 SNPs (1053C>T, 1293G>C and 7632T>A) were determined by RT-PCR. In leprosy patients, the GSTM1*0 and CYP2E1*5 alleles and the combined alleles GSTM1*0/CYP2E1*6 and GSTM1*0/CYP2E1*5 were significantly related to a baciloscopic index (BI) (BI<3), while the CYP2E1*6 allele was related to a better clinical evolution in the leprosy spectrum.Therefore, GSTM1*0, CYP2E1*5 and CYP2E1*6 may be possible protection factors for leprosy patients. HubMed – drug


Bindarit inhibits human coronary artery smooth muscle cell proliferation, migration and phenotypic switching.

Filed under: Drug and Alcohol Rehabilitation

PLoS One. 2012; 7(10): e47464
Maddaluno M, Grassia G, Di Lauro MV, Parisi A, Maione F, Cicala C, De Filippis D, Iuvone T, Guglielmotti A, Maffia P, Mascolo N, Ialenti A

Bindarit, a selective inhibitor of monocyte chemotactic proteins (MCPs) synthesis, reduces neointimal formation in animal models of vascular injury and recently has been shown to inhibit in-stent late loss in a placebo-controlled phase II clinical trial. However, the mechanisms underlying the efficacy of bindarit in controlling neointimal formation/restenosis have not been fully elucidated. Therefore, we investigated the effect of bindarit on human coronary smooth muscle cells activation, drawing attention to the phenotypic modulation process, focusing on contractile proteins expression as well as proliferation and migration. The expression of contractile proteins was evaluated by western blot analysis on cultured human coronary smooth muscle cells stimulated with TNF-? (30 ng/mL) or fetal bovine serum (5%). Bindarit (100-300 µM) reduced the embryonic form of smooth muscle myosin heavy chain while increased smooth muscle ?-actin and calponin in both TNF-?- and fetal bovine serum-stimulated cells. These effects were associated with the inhibition of human coronary smooth muscle cell proliferation/migration and both MCP-1 and MCP-3 production. The effect of bindarit on smooth muscle cells phenotypic switching was confirmed in vivo in the rat balloon angioplasty model. Bindarit (200 mg/Kg/day) significantly reduced the expression of the embryonic form of smooth muscle myosin heavy chain, and increased smooth muscle ?-actin and calponin in the rat carodid arteries subjected to endothelial denudation. Our results demonstrate that bindarit induces the differentiated state of human coronary smooth muscle cells, suggesting a novel underlying mechanisms by which this drug inhibits neointimal formation.
HubMed – drug


A screen for selective killing of cells with chromosomal instability induced by a spindle checkpoint defect.

Filed under: Drug and Alcohol Rehabilitation

PLoS One. 2012; 7(10): e47447
Shaukat Z, Wong HW, Nicolson S, Saint RB, Gregory SL

The spindle assembly checkpoint is crucial for the maintenance of a stable chromosome number. Defects in the checkpoint lead to Chromosomal INstability (CIN), which is linked to the progression of tumors with poor clinical outcomes such as drug resistance and metastasis. As CIN is not found in normal cells, it offers a cancer-specific target for therapy, which may be particularly valuable because CIN is common in advanced tumours that are resistant to conventional therapy.Here we identify genes that are required for the viability of cells with a CIN phenotype. We have used RNAi knockdown of the spindle assembly checkpoint to induce CIN in Drosophila and then screened the set of kinase and phosphatase genes by RNAi knockdown to identify those that induce apoptosis only in the CIN cells. Genes identified include those involved in JNK signaling pathways and mitotic cytoskeletal regulation.The screen demonstrates that it is feasible to selectively kill cells with CIN induced by spindle checkpoint defects. It has identified candidates that are currently being pursued as cancer therapy targets (e.g. Nek2: NIMA related kinase 2), confirming that the screen is able to identify promising drug targets of clinical significance. In addition, several other candidates were identified that have no previous connection with mitosis or apoptosis. Further screening and detailed characterization of the candidates could potentially lead to the therapies that specifically target advanced cancers that exhibit CIN.
HubMed – drug


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