Identification of Candidate Biomarkers for Transplant Rejection from Transcriptome Data: A Systematic Review.

BACKGROUND: Traditional methods for rejection control in transplanted patients are considered invasive, risky, and prone to sampling errors. Using molecular biomarkers as an alternative protocol to biopsies, for monitoring rejection may help to mitigate some of these problems, increasing the survival rates and well-being of patients. Recent advances in omics technologies provide an opportunity for screening new molecular biomarkers to identify those with clinical utility. OBJECTIVE: This systematic literature review (SLR) aimed to summarize existing evidence derived from large-scale expression profiling regarding differentially expressed mRNA and miRNA in graft rejection, highlighting potential molecular biomarkers in transplantation. METHODS: The study was conducted following PRISMA methodology and the BiSLR guide for performing SLR in bioinformatics. PubMed, ScienceDirect, and EMBASE were searched for publications from January 2001 to January 2018, and studies (i) aiming at the identification of transplant rejection biomarkers, (ii) including human subjects, and (iii) applying methodologies for differential expression analysis from large-scale expression profiling were considered eligible. Differential expression patterns reported for genes and miRNAs in rejection were summarized from both cross-organ and organ-specific perspectives, and pathways enrichment analysis was performed for candidate biomarkers to interrogate their functional role in transplant rejection. RESULTS: A total of 821 references were collected, resulting in 604 studies after removal of duplicates. After application of inclusion and exclusion criteria, 33 studies were included in our analysis. Among the 1517 genes and 174 miRNAs identifed, CXCL9, CXCL10, STAT1, hsa-miR-142-3p, and hsa-miR-155 appeared to be particularly promising as biomarkers in transplantation, with an increased expression associated with transplant rejection in multiple organs. In addition, hsa-miR-28-5p was consistently decreased in samples taken from rejected organs. CONCLUSION: Despite the need for further research to fill existing knowledge gaps, transcriptomic technologies have a relevant role in the discovery of accurate biomarkers for transplant rejection diagnostics. Studies have reported consistent evidence of differential expression associated with transplant rejection, although issues such as experimental heterogeneity hinder a more systematic characterization of observed molecular changes. Special attention has been giving to large-scale mRNA expression profiling in rejection, whereas there is still room for improvements in the characterization of miRnome in this condition. PROSPERO REGISTRATION NUMBER: CRD42018083321.

Cardiac hypertrophy in mice submitted to a swimming protocol: influence of training volume and intensity on myocardial renin-angiotensin system.

Exercise promotes physiological cardiac hypertrophy and activates the renin-angiotensin system (RAS), which plays an important role in cardiac physiology, both through the classical axis [angiotensin II type 1 receptor (AT1R) activated by angiotensin II (ANG II)] and the alternative axis [proto-oncogene Mas receptor (MASR) activated by angiotensin-(1-7)]. However, very intense exercise could have deleterious effects on the cardiovascular system. We aimed to analyze the cardiac hypertrophy phenotype and the classical and alternative RAS axes in the myocardium of mice submitted to swimming exercises of varying volume and intensity for the development of cardiac hypertrophy. Male Balb/c mice were divided into three groups, sedentary, swimming twice a day without overload (T2), and swimming three times a day with a 2% body weight overload (T3), totaling 6 wk of training. Both training groups developed similar cardiac hypertrophy, but only T3 mice improved their oxidative capacity. We observed that T2 had increased levels of MASR, which was followed by the activation of its main downstream protein AKT; meanwhile, AT1R and its main downstream protein ERK remained unchanged. Furthermore, no change was observed regarding the levels of angiotensin peptides, in either group. In addition, we observed no change in the ratio of expression of the myosin heavy chain ß-isoform to that of the α-isoform. Fibrosis was not observed in any of the groups. In conclusion, our results suggest that increasing exercise volume and intensity did not induce a pathological hypertrophy phenotype, but instead improved the oxidative capacity, and this process might have the participation of the RAS alternative axis.

Aerobic exercise training induces metabolic benefits in rats with metabolic syndrome independent of dietary changes.

OBJECTIVES: We evaluated the effects of aerobic exercise training without dietary changes on cardiovascular and metabolic variables and on the expression of glucose transporter Type 4 in rats with metabolic syndrome. METHODS: Twenty male spontaneously hypertensive rats received monosodium glutamate during the neonatal period. The animals were allocated to the following groups: MS (sedentary metabolic syndrome), MS-T (trained on a treadmill for 1 hour/day, 5 days/week for 10 weeks), H (sedentary spontaneously hypertensive rats) and H-T (trained spontaneously hypertensive rats). The Lee index, blood pressure (tail-cuff system), insulin sensitivity (insulin tolerance test) and functional capacity were evaluated before and after 10 weeks of training. Glucose transporter Type 4 expression was analyzed using Western blotting. The data were compared using analysis of variance (ANOVA) (p<0.05). RESULTS: At baseline, the MS rats exhibited lower insulin sensitivity and increased Lee index compared with the H rats. Training decreased the body weight and Lee index of the MS rats (MS-T vs. MS), but not of the H rats (H-T vs. H). There were no differences in food intake between the groups. At the end of the experiments, the systolic blood pressure was lower in the two trained groups than in their sedentary controls. Whole-body insulin sensitivity increased in the trained groups. Glucose transporter Type 4 content increased in the heart, white adipose tissue and gastrocnemius muscle of the trained groups relative to their respective untrained groups. CONCLUSION: In conclusion, the present study shows that an isolated aerobic exercise training intervention is an efficient means of improving several components of metabolic syndrome, that is, training reduces obesity and hypertension and increases insulin sensitivity.

Aerobic exercise training induces metabolic benefits in rats with metabolic syndrome independent of dietary changes

OBJECTIVES: We evaluated the effects of aerobic exercise training without dietary changes on cardiovascular and metabolic variables and on the expression of glucose transporter Type 4 in rats with metabolic syndrome. METHODS: Twenty male spontaneously hypertensive rats received monosodium glutamate during the neonatal period. The animals were allocated to the following groups: MS (sedentary metabolic syndrome), MS-T (trained on a treadmill for 1 hour/day, 5 days/week for 10 weeks), H (sedentary spontaneously hypertensive rats) and H-T (trained spontaneously hypertensive rats). The Lee index, blood pressure (tail-cuff system), insulin sensitivity (insulin tolerance test) and functional capacity were evaluated before and after 10 weeks of training. Glucose transporter Type 4 expression was analyzed using Western blotting. The data were compared using analysis of variance (ANOVA) (p<0.05). RESULTS: At baseline, the MS rats exhibited lower insulin sensitivity and increased Lee index compared with the H rats. Training decreased the body weight and Lee index of the MS rats (MS-T vs. MS), but not of the H rats (H-T vs. H). There were no differences in food intake between the groups. At the end of the experiments, the systolic blood pressure was lower in the two trained groups than in their sedentary controls. Whole-body insulin sensitivity increased in the trained groups. Glucose transporter Type 4 content increased in the heart, white adipose tissue and gastrocnemius muscle of the trained groups relative to their respective untrained groups. CONCLUSION: In conclusion, the present study shows that an isolated aerobic exercise training intervention is an efficient means of improving several components of metabolic syndrome, that is, training reduces obesity and hypertension and increases insulin sensitivity. .