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1.
Vitamin D changes expression of DNA repair genes in the patients with multiple sclerosis.
Amirinejad, R, Shirvani-Farsani, Z, Naghavi Gargari, B, Sahraian, MA, Mohammad Soltani, B, Behmanesh, M
Gene. 2021;:145488
Abstract
Oxidative stress (OS) plays an essential role in demyelination and tissue injury related to pathogenesis of multiple sclerosis (MS). On the other hand, vitamin D (VD) as an antioxidant reduces oxidative stress and has been used as adjuvant therapy in autoimmune diseases. Although VD supplementation is suggested as a protective and immunomodulation factor for MS patients, the molecular mechanisms remain unclear. Given that VD may modulate the immune system of MS patients through the DNA repair pathway, we aimed to evaluate the effects of VD supplementation in DNA repair genes expression including OGG1, MYH, MTH1, and ITPA. Transcript levels were measured using the RT-qPCR method in peripheral blood mononuclear cells (PBMCs) of relapsing-remitting multiple sclerosis (RRMS) patients before and after two months of VD supplementation. Furthermore, in silico analysis and correlation gene expression analysis was performed to find the biological binding sites and the effect of NRF2 on the regulation of DNA repair genes. Our data revealed that in MS patients, 2-month VD treatment significantly altered the expression of MYH, OGG1, MTH1, and NRF2 genes. A significant correlation was observed between DNA repair genes and NRF2 expression, which was confirmed by the presence of antioxidant response element (ARE) binding sites in the promoter of OGG1, MYH, and MTH1 genes. This study demonstrated that the impact of VD on MS patients may be mediated through the improvement of DNA repair system efficiency. This finding brought some new evidence for the involvement of DNA repair genes in the physiopathology of MS patients.
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2.
Exercise training impacts skeletal muscle gene expression related to the kynurenine pathway.
Allison, DJ, Nederveen, JP, Snijders, T, Bell, KE, Kumbhare, D, Phillips, SM, Parise, G, Heisz, JJ
American journal of physiology. Cell physiology. 2019;(3):C444-C448
Abstract
Exercise positively impacts mood and symptoms of depression; however, the mechanisms underlying these effects are not fully understood. Recent evidence highlights a potential role for skeletal muscle-derived transcription factors to influence tryptophan metabolism, along the kynurenine pathway, which has important implications in depression. This has important consequences for older adults, whose age-related muscle deterioration may influence this pathway and may increase their risk for depression. Although exercise training has been shown to improve skeletal muscle mass in older adults, whether this also translates into improvements in transcription factors and metabolites related to the kynurenine pathway has yet to be examined. The aim of the present study was to examine the influence of a 12-wk exercise program on skeletal muscle gene expression of transcription factors, kynurenine aminotransferase (KAT) gene expression, and plasma concentrations of tryptophan metabolites (kynurenines) in healthy older men over 65 yr of age. Exercise training significantly increased skeletal muscle gene expression of transcription factors (peroxisome proliferator-activated receptor-γ coactivator 1α, peroxisome proliferator-activated receptor-α, and peroxisome proliferator-activated receptor-δ: 1.77, 1.99, 2.18-fold increases, respectively, P < 0.01] and KAT isoforms 1-4 (6.5, 2.1, 2.2, and 2.6-fold increases, respectively, P ≤ 0.01). Concentrations of plasma kynurenines were not altered. These results demonstrate that 12 wk of exercise training significantly altered skeletal muscle gene expression of transcription factors and gene expression related to the kynurenine pathway, but not circulating kynurenine metabolites in older men. These findings warrant future research to determine whether distinct exercise modalities or varying intensities could induce a shift in the kynurenine pathway in depressed older adults.
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Ribociclib plus letrozole in early breast cancer: A presurgical, window-of-opportunity study.
Curigliano, G, Gómez Pardo, P, Meric-Bernstam, F, Conte, P, Lolkema, MP, Beck, JT, Bardia, A, Martínez García, M, Penault-Llorca, F, Dhuria, S, et al
Breast (Edinburgh, Scotland). 2016;:191-8
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Abstract
OBJECTIVES Cyclin D-cyclin-dependent kinase (CDK) 4/6-inhibitor of CDK4/6-retinoblastoma (Rb) pathway hyperactivation is associated with hormone receptor-positive (HR+) breast cancer (BC). This study assessed the biological activity of ribociclib (LEE011; CDK4/6 inhibitor) plus letrozole compared with single-agent letrozole in the presurgical setting. MATERIALS AND METHODS Postmenopausal women (N = 14) with resectable, HR+, human epidermal growth factor receptor 2-negative (HER2-) early BC were randomized 1:1:1 to receive 2.5 mg/day letrozole alone (Arm 1), or with 400 or 600 mg/day ribociclib (Arm 2 or 3). Circulating tumor DNA and tumor biopsies were collected at baseline and, following 14 days of treatment, prior to or during surgery. The primary objective was to assess antiproliferative response per Ki67 levels in Arms 2 and 3 compared with Arm 1. Additional assessments included safety, pharmacokinetics, and genetic profiling. RESULTS Mean decreases in the Ki67-positive cell fraction from baseline were: Arm 1 69% (range 38-100%; n = 2), Arm 2 96% (range 78-100%; n = 6), Arm 3 92% (range 75-100%; n = 3). Decreased phosphorylated Rb levels and CDK4, CDK6, CCND2, CCND3, and CCNE1 gene expression were observed following ribociclib treatment. Ribociclib and letrozole pharmacokinetic parameters were consistent with single-agent data. The ribociclib plus letrozole combination was well tolerated, with no Grade 3/4 adverse events over the treatment. CONCLUSION The results suggest absence of a drug-drug interaction between ribociclib and letrozole and indicate ribociclib plus letrozole may reduce Ki67 expression in HR+, HER2- BC (NCT01919229).
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Phenylbutyrate increases SMN gene expression in spinal muscular atrophy patients.
Brahe, C, Vitali, T, Tiziano, FD, Angelozzi, C, Pinto, AM, Borgo, F, Moscato, U, Bertini, E, Mercuri, E, Neri, G
European journal of human genetics : EJHG. 2005;(2):256-9
Abstract
Spinal muscular atrophy (SMA) is caused by insufficient levels of survival motor neuron (SMN) protein. Recently, we found that sodium 4-phenylbutyrate (PB), a well-tolerated FDA approved drug, enhances SMN gene expression in vitro. We provide here the first evidence that oral administration of PB (triButyrate significantly increases SMN expression in leukocytes of SMA patients. This finding provides a strong rationale to further investigate the effects of PB as also supported by preliminary clinical data.
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Single and combination drug therapy for fetal hemoglobin augmentation in hemoglobin E-beta 0-thalassemia: Considerations for treatment.
Singer, ST, Kuypers, FA, Olivieri, NF, Weatherall, DJ, Mignacca, R, Coates, TD, Davies, S, Sweeters, N, Vichinsky, EP
Annals of the New York Academy of Sciences. 2005;:250-6
Abstract
Patients with hemoglobin E (Hb E)-beta 0-thalassemia, one of the most common hemoglobinopathies worldwide, could benefit from drugs that increase fetal and total hemoglobin levels and thereby decrease the need for transfusions. The long-term clinical outcome of such therapy, its hematologic effects, and which patients are likely to benefit from treatment are unknown. Consequently, the use of such drugs for Hb E-beta 0-thalassemia is limited, and countries where resources for safe and regular transfusion are scarce cannot benefit from them. In a multicenter trial of 42 patients treated with hydroxyurea for two years, almost half the patients demonstrated a significant increase in steady-state hemoglobin level. Drug toxicity was minimal. Combined treatment of hydroxyurea with erythropoietin benefited selected patients, but the addition of sodium phenyl butyrate was ineffective. After 5 years of follow-up, a subset of patients remained off transfusions. Hydroxyurea should be considered for a subset of Hb E-beta 0-thalassemia patients.
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Modulation of COX-2 expression in peripheral blood cells by increased intake of fruit and vegetables?
Almendingen, K, Brevik, A, Nymoen, DA, Hilmarsen, HT, Andresen, PA, Andersen, LF, Vatn, M
European journal of clinical nutrition. 2005;(4):597-602
Abstract
BACKGROUND Enhanced cyclooxygenase-2 (COX-2) expression is associated with carcinogenesis, ischemia, angiogenesis, inflammation, and neurodegeneration. The preventing effect of aspirin and nonsteroidal anti-inflammatory drugs is partly due to inhibition of the COX-2 enzyme. Fruit and vegetables (FVs) contain numerous compounds that may decrease disease risk by several different mechanisms, for example through the inhibition of COX-2 activity. OBJECTIVE We tested the hypothesis that an increased intake of FVs would modulate the COX-2 expression in peripheral blood cells. DESIGN A strictly controlled dietary crossover study (n = 39). After 1 week run-in period with no FVs in the diet, one group was given two portions of FVs (2 FV), while another group was given five portions (5 FV) daily for 14 days. Following a 2 weeks washout period and 1 week run-in, the regimens were switched between the groups. Gene expression analysis of COX-2 mRNA in blood samples was performed by quantitative real-time-PCR. RESULTS No significant treatment effect of diet intervention was found in the crossover analyses (P = 0.74). However, the individual variation in response may seem large. CONCLUSIONS These data does not contradict the recommendations for an increased intake of FVs. Further studies on expression directly and indirectly, through analysis of factors regulating and being regulated by COX-2, should be carried out. A first step would be to evaluate the correspondence between COX-2 mRNA expression and products of the COX pathway, like prostaglandins. Naturally occurring polymorphisms of COX-2 promoters and coding regions might contribute to functional variations and response to different diets. SPONSORSHIP Norwegian Research Council, National Nutrition Council, Throne Holst Foundation for Nutrition Research, Freia Chokoladefabriks Medisinske Fond and the Norwegian Cancer Society.
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Effects of Lactobacillus GG on genes expression pattern in small bowel mucosa.
Di Caro, S, Tao, H, Grillo, A, Elia, C, Gasbarrini, G, Sepulveda, AR, Gasbarrini, A
Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2005;(5):320-9
Abstract
BACKGROUND AND AIMS Probiotics have been used for cure and prevention of several clinical conditions. However, further insights into the mechanism of action are needed to understand the rationale of their use. The aim of this study was to investigate the influence of Lactobacillus GG on the genetic expression patterns in the small bowel mucosa. METHODS Six male patients (38+/-5 years) with endoscopically proven oesophagitis were enrolled. All patients were treated for 1 month with esomeprazole and randomised to receive Lactobacillus GG or placebo. After 1 month of treatment, upper endoscopy was repeated. Biopsies of the duodenal mucosa were taken prior to and after the treatment, and the genes expression patterns were assessed using GeneChip Human U133A array. Genes with significant expression changes were selected and analysed to identify specific cellular pathways modified by Lactobacillus GG. To support the array data, 10 target genes were studied using Syber-Green PCR. RESULTS Microarray analysis showed that Lactobacillus GG administration determined the up- and down-regulation of 334 and 92 genes, respectively. Real-time PCR confirmed the reliability of the analysis. Lactobacillus GG mainly affected the expression of genes involved in immune response and inflammation (TGF-beta and TNF family members, cytokines, nitric oxide synthase 1, defensin alpha 1), apoptosis, cell growth and cell differentiation (cyclins and caspases, oncogenes), cell-cell signalling (ICAMs and integrins), cell adhesion (cadherins), signal transcription and transduction. CONCLUSIONS These data indicate that administration of Lactobacillus GG is associated with a complex genetic response of the duodenal mucosa, reflected by the up- and down-regulation of several genes involved in specific cellular pathways.
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Improved net protein balance, lean mass, and gene expression changes with oxandrolone treatment in the severely burned.
Wolf, SE, Thomas, SJ, Dasu, MR, Ferrando, AA, Chinkes, DL, Wolfe, RR, Herndon, DN
Annals of surgery. 2003;(6):801-10; discussion 810-1
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Abstract
OBJECTIVE To determine the effects of the anabolic agent oxandrolone on muscle protein and gene expression in severely burned children. SUMMARY BACKGROUND DATA The authors previously showed that oxandrolone increased net muscle protein synthesis in emaciated burned patients receiving delayed treatment for severe burns. They hypothesized that similar effects would be seen in those treated early after burn. METHODS Thirty-two severely burned children were enrolled in a prospective randomized trial. Subjects underwent studies to assess leg protein net balance 5 days after the first excision and grafting procedure. Immediately after these studies, treatment with placebo (n = 18) or 0.1 mg/kg oxandrolone (n = 14) twice a day was started. One week after this, another net balance study was performed in each subject. Body weights and total body potassium counting were used to determine body compositional changes. Muscle biopsies were taken 1 week after treatment in oxandrolone subjects to examine gene expression changes with gene array (12,600 genes). RESULTS Protein net balance did not change in the placebo group, while oxandrolone-treated subjects had a significant improvement. Body weights and fat free mass significantly decreased in the placebo group, while no changes were found in the oxandrolone-treated subjects. Expression changes were seen in 14 genes in the oxandrolone group compared to placebo. Some of these included myosin light chain (+2.7-fold change), tubulin (+2.3), calmodulin (-2.3), and protein phosphatase I inhibitor (-2.8). CONCLUSIONS Oxandrolone improves protein net balance and lean mass in the severely burned. These changes are associated with increased gene expression for functional muscle proteins.
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Myocardial gene expression in dilated cardiomyopathy treated with beta-blocking agents.
Lowes, BD, Gilbert, EM, Abraham, WT, Minobe, WA, Larrabee, P, Ferguson, D, Wolfel, EE, Lindenfeld, J, Tsvetkova, T, Robertson, AD, et al
The New England journal of medicine. 2002;(18):1357-65
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Abstract
BACKGROUND Beta-blocker therapy may improve cardiac function in patients with idiopathic dilated cardiomyopathy. We tested the hypothesis that beta-blocker therapy produces favorable functional effects in dilated cardiomyopathy by altering the expression of myocardial genes that regulate contractility and pathologic hypertrophy. METHODS We randomly assigned 53 patients with idiopathic dilated cardiomyopathy to treatment with a beta-adrenergic-receptor blocking agent (metoprolol or carvedilol) or placebo. The amount of messenger RNA (mRNA) for contractility-regulating genes (those encoding beta1- and beta2-adrenergic receptors, calcium ATPase in the sarcoplasmic reticulum, and alpha- and beta-myosin heavy-chain isoforms) and of genes associated with pathologic hypertrophy (beta-myosin heavy chain and atrial natriuretic peptide) was measured with a quantitative reverse-transcription polymerase chain reaction in total RNA extracted from biopsy specimens of the right ventricular septal endomyocardium. Myocardial levels of beta-adrenergic receptors were also measured. Measurements were conducted at base line and after six months of treatment, and changes in gene expression were compared with changes in the left ventricular ejection fraction as measured by radionuclide ventriculography. RESULTS Twenty-six of 32 beta-blocker-treated patients (those with complete mRNA measurements) had an improvement in left ventricular ejection fraction of at least 5 ejection-fraction (EF) units (mean [+/-SE] increase, 18.8+/-1.8). As compared with the six beta-blocker-treated patients who did not have a response (mean change, a decrease of 2.5+/-1.8 EF units), those who did have a response had an increase in sarcoplasmic-reticulum calcium ATPase mRNA and alpha-myosin heavy chain mRNA and a decrease in beta-myosin heavy chain mRNA. The change in sarcoplasmic-reticulum calcium ATPase was not present in the patients in the placebo group who had a spontaneous response. There were no differences between those who had a response and those who did not in terms of the change in mRNA or protein expression of beta-adrenergic receptors. CONCLUSIONS In idiopathic dilated cardiomyopathy, functional improvement related to treatment with beta-blockers is associated with changes in myocardial gene expression.