ABSTRACT
Despite the well-established association of gene expression deregulation with low muscle mass (LMM), the associated biological mechanisms remain unclear. Transcriptomic studies are capable to identify key mediators in complex diseases. We aimed to identify relevant mediators and biological mechanisms associated with age-related LMM. LMM-associated genes were detected by logistic regression using microarray data of 20 elderly women with LMM and 20 age and race-matched controls extracted from our SPAH Study (GSE152073). We performed weighted gene co-expression analysis (WGCNA) that correlated the identified gene modules with laboratorial characteristics. Gene enrichment analysis was performed and an LMM predictive model was constructed using Support Vector Machine (SVM). Overall, 821 discriminating transcripts clusters were identified (|beta coefficient| >1; p-value <0.01). From this list, 45 predictors of LMM were detected by SVM and validated with 0.7 of accuracy. Our results revealed that the well-described association of inflammation, immunity and metabolic alterations is also relevant at transcriptomic level. WGCNA highlighted a correlation of genes modules involved in immunity pathways with vitamin D level (R = 0.63, p = 0.004) and the Agatston score (R = 0.51, p = 0.02). Our study generated a predicted regulatory network and revealed significant metabolic pathways related to aging processes, showing key mediators that warrant further investigation.
Subject(s)
Aging , Gene Regulatory Networks , Immune System , Inflammation , Muscle, Skeletal , Sarcopenia/metabolism , Transcriptome , Aged , Aged, 80 and over , Female , Gene Expression Profiling , Humans , Inflammation/genetics , Inflammation/metabolism , Logistic Models , Metabolic Networks and Pathways , Sarcopenia/genetics , Support Vector Machine , Vitamin D/bloodABSTRACT
OBJECTIVE: To evaluate the prevalence of 25-hydroxyvitamin D insufficiency (25OHD<20 ng/mL) and to develop a predictive model for this status. METHODS: This is a cross-sectional study including 908 community-dwelling older subjects, 18% (158) of which were randomly selected to be a "test" sample, with the remaining (750) composing a "development" sample. A radioimmunoassay technique was used to measure 25OHD levels. Anthropometrical data, information about lifestyle habits and co-morbidities were obtained. Multiple logistic regression models were created. An Index Risk of Vitamin D Insufficiency (IRVDI) was designed and subsequently validated. The performance of this tool was assessed through ROC analysis. RESULTS: The prevalence of 25OHD<20 ng/mL was of 58.0% (CI 95% 51.6-64.6). The clinical independent factors for 25OHD<20 ng/mL were female gender (OR=2.16; 95%CI 1.13-4.13; p=0.020), diabetes (OR=1.84; 95%CI 1.23-2.74; p=0.003) and season (winter/spring) (OR=3.63, 95%CI 2.62-4.88; p<0.001). After statistical adjustments, the IRVDI was able to identify older people at risk for vitamin D insufficiency with a sensitivity of 55.9%, specificity 72.3% and ROC area of 0.685 (p<0.001). CONCLUSIONS: Our results suggest that vitamin D insufficiency is common among Brazilian community-dwelling elderly. Female gender, diabetes and the season (winter/spring) were the important parameters that predicted this status. The clinical use of these parameters can be help to design and target appropriate public health interventions. The IRVDI is a convenient tool for the selection of older people at risk for vitamin D insufficiency.
Subject(s)
Geriatric Assessment , Vitamin D Deficiency/epidemiology , Vitamin D/analogs & derivatives , Vitamins/blood , Aged , Brazil/epidemiology , Cross-Sectional Studies , Diabetes Mellitus/blood , Female , Humans , Life Style , Logistic Models , Male , Models, Biological , Odds Ratio , Prevalence , ROC Curve , Residence Characteristics , Risk Assessment , Seasons , Sex Factors , Vitamin D/blood , Vitamin D Deficiency/blood , Vitamin D Deficiency/etiologyABSTRACT
Phosphodiesterase type-5 (PDE5) specifically cleaves cyclic guanosine monophosphate (cGMP), a key intracellular secondary messenger. The PDE5 inhibitor sildenafil is a well-known vasodilator that also has gastrointestinal myorelaxant properties. In the present study, we further investigated sildenafil-induced myorelaxation in rat isolated duodenum, assessing its interaction with nitric oxide (NO) synthase and K(+) channel opening. The spontaneous contractions of duodenal strips were reversibly inhibited by sildenafil (0.1-300 microM) in a concentration-dependent manner [mean (95% confidence interval); EC(50) = 6.8 (2.7-17.3) microM]. The sildenafil-induced myorelaxation was significantly decreased by the NO synthase inhibitor N-nitro-L-arginine methyl ester [increasing the EC(50) value to 41.9 (26.1-67.3) microM]. Sodium nitroprusside or forskolin pretreatments enhanced the sildenafil-induced myorelaxation. In isolated strips pretreated with BaCl(2) (0.2 mM), 4-aminopyridine (4-AP, 3 mM), or glybenclamide (1 microM), the sildenafil-induced EC(50) value was significantly increased to 32.8 (19.1-56.4), 27.1 (15.2-48.3) and 20.1 (16.4-24.7) microM, respectively. Minoxidil (50 microM) or diazoxide (100 microM) also significantly attenuated the sildenafil-induced potency. In conclusion, the NO synthase/cyclic nucleotide pathway activation is involved in sildenafil-induced inhibition of spontaneous duodenal contractions. Its pharmacological action seems to be influenced by K(+) channel opening, especially the voltage-sensitive ones, being inhibited by 4-AP and K(ATP) channels, sensitive to glybenclamide.
