Psoriasis is characterized by hyperproliferation and abnormal differentiation of keratinocytes, and inflammation. 1,25-Dihydroxyvitamin D3, which is used for the treatment of psoriasis, binds to vitamin D receptor (VDR) and modulates gene transcription. We analyzed VDR gene FokI, ApaI and TaqI polymorphisms in 51 Turkish familial psoriasis patients (psoriasis vulgaris and psoriatic arthritis) and 100 healthy subjects, and evaluated the correlation between VDR genotypes and calcipotriol response. We found that the TT genotype was significantly more frequent in the patients than in the controls (51 vs. 35%: P < or = 0.05). The frequency of the T allele in patients was also significantly higher than that in the controls (73.5 vs. 59.5%: P < or = 0.025). In psoriatic arthritis patients, T allele frequency was even higher (91.7%: P < or = 0.05). With regard to response to calcipotriol treatment, in nonresponsive patients TT genotype and T allele frequencies were higher than they were in the controls (63.6 vs. 35%: P < or = 0.025, 81.8 vs. 59.5%: P < or = 0.01, respectively). In conclusion, we show that VDR gene TaqI polymorphism is associated with familial psoriasis in the Turkish population. We also demonstrate that VDR gene polymorphisms may play a role in partial resistance to calcipotriol therapy.
Spinal muscular atrophy is an autosomal recessive motor neuron disease that is caused by mutation of the survival motor neuron gene (SMN1) but all patients retain a nearly identical copy, SMN2. The disease severity correlates inversely with increased SMN2 copy. Currently, the most promising therapeutic strategy for spinal muscular atrophy is induction of SMN2 gene expression by histone deacetylase inhibitors. Polyphenols are known for protection against oxidative stress and degenerative diseases. Among our candidate prodrug library, we found that (E )-resveratrol, which is one of the polyphenolic compounds, inhibited histone deacetylase activity in a concentration-dependent manner and half-maximum inhibition was observed at 650 microM. Molecular docking studies showed that (E )-resveratrol had more favorable free energy of binding (-9.09 kcal/mol) and inhibition constant values (0.219 microM) than known inhibitors. To evaluate the effect of (E )-resveratrol on SMN2 expression, spinal muscular atrophy type I fibroblast cell lines was treated with (E )-resveratrol. The level of full-length SMN2 mRNA and protein showed 1.2- to 1.3-fold increase after treatment with 100 microM (E )-resveratrol in only one cell line. These results indicate that response to (E )-resveratrol treatment is variable among cell lines. This data demonstrate a novel activity of (E )-resveratrol and that it could be a promising candidate for the treatment of spinal muscular atrophy.
IntroductionProximal spinal muscular atrophy (SMA) is a common autosomal recessively inherited neuromuscular disorder. It is caused by homozygous absence of the survival motor neuron 1 (SMN1) gene. SMN2, which modulates the severity of the disease, represents a major target for therapy. The aim of this study was to investigate whether SMN2 expression can be increased by caffeic acid, chlorogenic acid and curcumin, which are designed by modifications of the carboxylic acid class of histone deacetylase (HDAC) inhibitors.Material and methodsUsing quantitative real-time PCR, we analysed the levels of full-length SMN2 and Δ7SMN2 mRNA. We performed LDH cytotoxicity assay to analyse whether SMN2 activating concentrations of caffeic acid, chlorogenic acid and curcumin were cytotoxic to fibroblasts.ResultsWe found that caffeic acid and curcumin were more efficient than chlorogenic acid and increased full-length SMN2 mRNA levels 1.5 and 1.7-fold, respectively. Δ7SMN2 mRNA levels were measured to investigate alternative splicing of exon 7. We also found that cytotoxicity was not observed at SMN2 activating concentrations.ConclusionsOur data suggest that carboxylic acid derivatives including phenolic structure and symmetry could be a good candidate for SMA treatment.
Background/Objective:The relationship between vitamin D receptor gene polymorphisms and bone density, osteocalcin and growth was investigated. Subjects: Eighty eight adolescents aged between 8-15, with no history of illness influencing the level of bone parameters, were examined in our study. Methods: Areal BMD for lumbar spine (L1-4) was assessed by dual energy X-ray absorptiometry (DEXA). Height and weight were measured on the day of the DEXA scans. Serum osteocalcin level was determined by using ELISA method. DNA was extracted from white blood cells, amplified by the polymerase chain reaction (PCR) and the polymorphic sites were analyzed by using ApaI, TaqI and FokI restriction enzymes. Results: The most frequent genotypes were FF (% 54.6), Aa (% 53.4) and Tt (% 48.8). No significant relationship was found between VDR genotypes and areal BMD, osteocalcin level or growth in either sex. But there was a strong tendency for a higher BMD at the lumbar spine of TT and AA genotypes compared to tt and Aa genotypes. The children with TT genotype were taller and heavier than the children with tt genotype. Conclusion: Our results suggest that VDR gene TaqI polymorphism may be associated with
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