Gene polymorphisms in VEGFA and COL2A1 are associated with response to inhaled corticosteroids in children with asthma.

Aim: The purpose of this study was to investigate the involvement of single-nucleotide polymorphisms in VEGFA, TBX21 and COL2A1 in the response to inhaled corticosteroids in asthmatic children. Subjects & methods: Children with mild-to-moderate asthma were enrolled in the study. The SEQUENOM MassARRAY method was used to sequence 27 SNP genotypes. By ranking the data from smallest to largest, we could infer whether the change in distribution of forced expiratory volume in one second/forced vital capcacity (FEV1/FVC) and fractional exhaled nitric oxide differed between genotype groups. Results:VEGFA rs3025039 T allele carriers had a smaller change in FEV1 than CC carriers (p = 0.040), and in COL2A1 rs3809324, the frequency of T allele carriers was lower than that of GG carriers (p = 0.048). rs3025039 was also associated with changes in FEV1/FVC (p = 0.016). Conclusion:VEGFA and COL2A1 polymorphisms are significantly associated with the response to inhaled corticosteroids in asthmatic children.

ß­blockers inhibit the viability of breast cancer cells by regulating the ERK/COX­2 signaling pathway and the drug response is affected by ADRB2 single­nucleotide polymorphisms.

The ß2­adrenergic receptor (ß2­AR, encoded by the ADRB2 gene) is a member of the G­protein­coupled receptor superfamily that can be stimulated by catecholamines. Studies in vivo and in vitro have confirmed that ß­blockers (ß­AR antagonists) exert antitumor effects on various tumors. Furthermore, ADRB2 single­nucleotide polymorphisms (SNPs) have been identified to alter the expression and conformation of ß2­AR, which may alter the ß­blocker drug response. The aim of the present study was to investigate the effect of ß­blockers on triple­negative breast cancer cells and determine whether ADRB2 SNPs affect the response to ß­blocker drugs. Propranolol and ICI 118,551 significantly inhibited the viability of MDA­MB­231 cells, arrested cell cycle progression at G0/G1 and S phase and induced cell apoptosis. Western blot analysis indicated that the phosphorylation levels of extracellular­signal­regulated kinase (ERK)1/2 and the expression levels of cyclo­oxygenase 2 (COX­2) were significantly decreased following ß­blocker treatment. Four haplotypes, which comprised ADRB2 SNPs rs1042713 and rs1042714, were transfected into 293 cells. After 24 and 48 h of transfection, ADRB2 mRNA expression was significantly decreased in mutant groups compared with the wild­type group. The ADRB2 SNPs exerted no effect on cell viability, but did affect the drug response of ICI 118,551. Furthermore, ADRB2 SNPs also affected the regulatory function of ICI 118,551 on the ERK/COX­2 signaling pathway. Collectively, propranolol and ICI 118,551 inhibited the viability of MDA­MB­231 cells by downregulating the ERK/COX­2 signaling pathway and inducing apoptosis. The results of the present study indicated that SNPs rs1042713 and rs1042714 of ADRB2 affected the response to ICI 118,551, and the underlying molecular mechanism was elucidated.

NR3C1 gene polymorphisms are associated with steroid resistance in patients with primary nephrotic syndrome.

AIM: The aim of this study was to investigate the role of SNPs of genes involved in the glucocorticoid pathway in the development of steroid resistance in patients with primary nephrotic syndrome. METHODS: Sequenom MassARRAY method was used to sequence 25 SNP genotypes in 154 patients. The frequency distribution of the genotypes was compared between patients with steroid-sensitive nephrotic syndrome and those with steroid-resistant nephrotic syndrome. RESULTS: NR3C1 rs6196 G allele carriers had a decreased risk of steroid resistance compared with that of the A allele carriers. The presence of rs10052957 and rs258751 A alleles could reduce the incidence of steroid resistance compared with that with G allele. Haplotype analysis showed AAG and GGA haplotypes that contain NR3C1 rs10052957, rs258751 and rs6196 were associated with steroid resistance. CONCLUSION: NR3C1 gene polymorphisms are significantly associated with the response to glucocorticoids in patients with primary nephrotic syndrome.

Resveratrol, an activator of SIRT1, restores erectile function in streptozotocin-induced diabetic rats.

The high incidence of erectile dysfunction (ED) in diabetes highlights a need for effective treatment strategies. Resveratrol, an activator of silent information regulator 2-related enzymes 1 (sirtuin1, SIRT1), has received attention for its valuable effects in cancer, neurodegenerative diseases, longevity and cardiovascular disease. To explore the effects of resveratrol in diabetes-induced ED, resveratrol was administered to rats with streptozocin (65 mg kg(-1))-induced diabetes. Erectile function, cavernous structure, tissue protein expression of silent information regulator 2-related enzymes 1 (sirtuin1, SIRT1), p53 and forkhead transcription factor O 3a (FOXO3a), superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels in the corpora cavernosa were studied. We found that SIRT1 was expressed in cavernosal tissue, and it was downregulated in the corpora of diabetic rats. The administration of resveratrol upregulated the expression of SIRT1 and restored erectile function. In contrast, resveratrol downregulated the expression of p53 and FOXO3a, which regulate apoptosis and oxidative stress. Furthermore, the resveratrol-treated group showed an improvement in smooth muscle content, SOD activity and MDA levels when compared with the diabetic group. Therefore, the ability of resveratrol to improve diabetes-induced ED is likely related to its activation of SIRT1 expression, thus causing the suppression of apoptosis and resistance towards oxidative stress.

[Deacetylase SIRT1 and vascular endothelial function].

Silent information regulator factor 2-related enzyme 1 (Sirtuins 1, SIRT1) is a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, which can deacetylate histone and non-histone proteins and other transcription factors, and is involved in the regulation of many physiological functions, including gene transcription, energy metabolism, cell senescence and oxidative stress. Recent studies show that through adjusting the activity of endothelial nitric oxide syntheses (eNOS), p53, forkhead box class O (FOXO) and nuclear factor kappa B (NF-kappaB), SIRT1 can protect the functions of vascular endothelia and nerves in a variety of pathological conditions. Therefore, SIRT1 may be used as a potential therapeutic target of these diseases, particularly erectile dysfunction, which are associated with endothelial dysfunction.

[Effects of hydroxycamptothecin on TGFb1, a-SMA and collagen I expression in rat hepatic satellite cells].

To investigate the molecular mechanism of hydroxycamptothecin (HCPT)-mediated anti-hepatic fibrosis by evaluting its effects on expression of tumor growth factor-beta 1 (TGFb1), alpha-smooth muscle actin (a-SMA) and collagen I (Col I) in hepatic satellite cells (HSCs). Cultured HSCs were treated with different concentrations of HCPT: low-dose group, 0.25 mg/L; middle-dose group, 0.5 mg/L; high-dose group, 0.75 mg/L; and control group, 0 mg/L. Cell proliferation was assessed by the MTT assay. The mRNA expressions of TGFb1, a-SMA and Col I were determined by reverse transcription-polymerase chain reaction. The protein expressions of TGFb1 and a-SMA were detected by Western blot. The content of Col I in the cultured HSCs' supernatant was measured by enzyme-linked immunosorbent assay. The MTT absorbance values of the low-dose group (0.631+/-0.074), middle-dose group (0.469+/- 0.012) and high-dose group (0.204+/- 0.001) were significantly lower than that of the control group (0.793+/-0.098; F = 82.86, P less than 0.01). Compared with the control group, the HCPT-treated groups showed significantly down-regulated gene expressions of TGFb1 (control: 0.716+/-0.064 vs. low: 0.611+/-0.040, middle: 0.510+/-0.014, high: 0.403+/-0.026), a-SMA (control: 0.696+/-0.075 vs. low: 0.579+/-0.037, middle: 0.470+/-0.024, high: 0.299+/-0.017), and Col I (control: 1.019+/-0.056 vs. low: 0.835+/-0.022, middle: 0.696+/-0.055, high: 0.322+/-0.104) (all, P less than 0.01). Meanwhile, HCPT-treated HSCs showed significantly reduced protein expressions of TGFb1 (control: 0.872+/-0.053 vs. low: 0.654+/-0.047, middle: 0.545+/-0.042, high: 0.436+/-0.039) and a-SMA (control: 0.858+/-0.050 vs. low: 0.620+/-0.045, middle: 0.525+/-0.042, high: 0.434+/-0.052) (all, P less than 0.01). The Col I levels secreted by HSCs were significantly lower in the HCPT-treated groups (low: 168.367+/-16.453 ng/ml; middle: 141.284+/-11.731 ng/ml; high: 132.910+/-10.048 ng/ml) than in the control group (188.733 +/-18.299 ng/ml) (all, P less than 0.01). The mechanism of HCPT-mediated anti-hepatic fibrosis may involve down-regulation of TGFb1 expression to inhibit HSC proliferation and activation, as well as reduction of Col I synthesis and secretion.