Resumo em Inglês:

Currently, the potential for cardiovascular (CV) stress-induced risk is primarily based on the theoretical (obvious) side effects of stress on the CV system. Salivary cortisol and α-amylase, produced respectively by the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic-adrenomedullary (SAM) system during stress response, are still not included in the routine evaluation of CV risk and require additional and definitive validation. Therefore, this article overviews studies published between 2010 and 2015, in which salivary cortisol and α-amylase were measured as stress biomarkers to examine their associations with CV/CMR (cardiometabolic risk) clinical and subclinical indicators. A comprehensive search of PubMed, Web of Science and Scopus electronic databases was performed, and 54 key articles related to the use of salivary cortisol and α-amylase as subclinical indicators of stress and CV/CMR factors, including studies that emphasized methodological biases that could influence the accuracy of study outcomes, were ultimately identified. Overall, the biological impact of stress measured by salivary cortisol and α-amylase was associated with CV/CMR factors. Results supported the use of salivary cortisol and α-amylase as potential diagnostic tools for detecting stress-induced cardiac diseases and especially to describe the mechanisms by which stress potentially contributes to the pathogenesis and outcomes of CV diseases.

Resumo em Inglês:

Cardiomyocyte apoptosis plays key roles in the pathogenesis of heart diseases such as myocardial infarction. MicroRNAs are important regulators of gene expression, which are also involved in the regulation of cardiomyocyte apoptosis. However, cardiomyocyte apoptosis regulated by microRNA (miR)-122 is largely unexplored. The aim of this study focused on the role of miR-122 in cardiomyocyte apoptosis. Cardiomyocytes were isolated from neonatal mice and primarily cultured. MiR-122 mimic and inhibitor were transfected to cardiomyocytes and verified by qRT-PCR. Cell viability and apoptosis post-transfection were assessed by MTT assay and flow cytometry, respectively. Changes in expression of caspase-8 were quantified by qRT-PCR and western blot. Results showed that miR-122 mimic and inhibitor successfully induced changes in miR-122 levels in cultured cardiomyocytes (P<0.01). MiR-122 overexpression suppressed viability and promoted apoptosis of cardiomyocytes (P<0.05), and miR-122 knockdown promoted cell viability and inhibited apoptosis (P<0.05). The mRNA and protein levels of caspase-8 were elevated by miR-122 overexpression (P<0.01) and reduced by miR-122 knockdown (P<0.001). These results suggest an inductive role of miR-122 in cardiomyocyte apoptosis, which may be related to its regulation on caspase-8.

Resumo em Inglês:

Levels of hydrogen sulfide (H2S), a gaseous signaling molecule, are reduced in the serum of individuals who smoke. We hypothesized that tobacco smoke influenced smooth muscle relaxation by decreasing H2S levels and this effect could also influence expression of cystathionine γ-lyase (CSE) and sulfonylurea receptor-2 (SUR-2). The aim of this study was to explore the effect of tobacco smoke on H2S-mediated rat thoracic aorta relaxation and its possible mechanism. Thirty-two Sprague-Dawley rats were divided into four groups: control (C) group, short-term smoker (SS) group, mid-term smoker (MS) group, and long-term smoker (LS) group. H2S concentrations in serum, action of H2S on rat aortic vascular relaxation, and expression of CSE and SUR-2 in thoracic aortic smooth muscle were measured. Although there was no significant difference in H2S between the C and the SS groups, concentration of H2S was significantly reduced in both the LS and MS groups compared to control (P<0.01). Furthermore, H2S was significantly lower in the LS than in the MS group (P<0.05). Rat aortic vascular relaxation was lower in all three treatment groups compared to the control, with the most significant decrease observed in the LS group (P<0.05 compared to the MS group). Expression of CSE and SUR-2 was reduced in the LS and MS groups compared to control (P<0.05), with the lowest levels observed in the LS group (P<0.05). Therefore, tobacco smoke reduced expression of CSE and SUR-2 in rat thoracic aorta, which may inhibit H2S production and vascular dilation.

Resumo em Inglês:

We aimed to study the effect of fentanyl (Fen) preconditioning on cardiomyocyte apoptosis induced by ischemia-reperfusion (I/R) in rats. A total of 120 Sprague Dawley male rats (age: 3 months) were randomly divided into: sham operation group (S group), I/R group, normal saline I/R group (NS group), and fentanyl low, middle, and high dose groups (Fen1: 2 μg/kg; Fen2: 4 μg/kg; Fen3: 6 μg/kg). Heart rate (HR), mean arterial pressure (MAP), left ventricular developed pressure (LVDP), ±dp/dtmax, malondialdehyde (MDA), superoxide dismutase (SOD) activity, creatine phosphokinase-MB (CK-MB), and cardiac troponin-I (cTnI) were measured. Myocardial ischemic (MI) area, total apoptotic myocardial cells, and protein and mRNA expressions of B-cell lymphoma 2 (Bcl-2) and Bax were detected. HR and MAP were higher, while LVDP and ±dp/dtmax were close to the base value in the Fen groups compared to those in the I/R group. Decreased MDA concentration and CK-MB value and increased SOD activity were found in the Fen groups compared to the I/R group, while cTnI concentration was significantly lower in the Fen1 and Fen2 groups (all P<0.05). Myocardial damage was less in the Fen groups compared to the I/R group and the MI areas and apoptotic indexes were significantly lower in the Fen1 and Fen2 groups (all P<0.05). Furthermore, significantly increased protein and mRNA expressions of Bcl-2, and decreased protein and mRNA expressions of Bax were found in the Fen groups compared to the I/R group (all P<0.05). Fentanyl preconditioning may suppress cardiomyocyte apoptosis induced by I/R in rats by regulating Bcl-2 and Bax.

Resumo em Inglês:

This study aimed to explore the effects of continuous blood purification (CBP) treatment in pigs affected with acute respiratory distress syndrome (ARDS). A total of 12 healthy male pigs, weighing 12±1.8 kg, were randomly and equally assigned to the control and experimental groups. The ARDS pig model was prepared by intravenous injections of endotoxin (20 µg/kg). The control group was given conventional supportive therapy, while the experimental group was given continuous veno-venous hemofiltration therapy. During the treatment process, the variations in dynamic lung compliance, oxygenation index, hemodynamics, and urine volume per hour at different times (Baseline, 0, 2, 4, and 6 h) were recorded. The levels of tumor necrosis factor (TNF-α), interleukin 6 (IL-6), and IL-10 in serum and bronchoalveolar lavage fluid (BALF) were measured using the enzyme-linked immunosorbent assay. The histomorphological changes of the lung, heart, and kidney were visualized using a light microscope. The nuclear factor κB p65 protein content of the heart, lung, and kidney tissues was also detected using western blot. The experimental group outperformed the control group in both respiratory and hemodynamic events. CBP treatment cleared TNF-α, IL-6, and IL-10 partially from serum and BALF. The pathological examination of the heart, lung, and kidney tissues revealed that the injury was less severe in the experimental group. CBP treatment can improve the organ functions of pigs affected with endotoxin-induced ARDS and protect these organs to some extent.

Resumo em Inglês:

We determined the effect of N-acetylcysteine (NAC) on the expression of the phosphorylated p38 (p-p38) protein and superoxide anion generation (SAG), two important players in the processing of neuropathic pain, in the lumbosacral spinal cord of rats with chronic constriction injury (CCI)-induced neuropathic pain. The sciatic functional index (SFI) was also measured to assess the functional recovery post-nerve lesion. Thirty-six male Wistar rats were divided equally into the following groups: Naive (rats did not undergo surgical manipulation); Sham (rats in which all surgical procedures involved in CCI were used except the ligature), and CCI (rats in which four ligatures were tied loosely around the right common sciatic nerve), which received 2, 4, or 8 intraperitoneal injections of NAC (150 mg·kg-1·day-1) or saline beginning 4 h after CCI. Rats were sacrificed 1, 3, and 7 days after CCI. The SFI was measured on these days and the lumbosacral spinal cord was used for analysis of p-p38 expression and SAG. CCI induced a decrease in SFI as well as an increase in p-p38 expression and SAG in the spinal cord. The SFI showed a partial recovery at day 7 in saline-treated CCI rats, but recovery was improved in NAC-treated CCI rats. NAC induced a downregulation in p-p38 expression at all time-points evaluated, but did not reverse the increased SAG induced by CCI. Since p-p38 is a mediator in neuropathic pain and/or nerve regeneration, modulation of this protein may play a role in NAC-induced effects in CCI rats.

Resumo em Inglês:

Osteosarcoma (OS) is the most common primary bone malignancy, but current therapies are far from effective for all patients. A better understanding of the pathological mechanism of OS may help to achieve new treatments for this tumor. Hence, the objective of this study was to investigate ego modules and pathways in OS utilizing EgoNet algorithm and pathway-related analysis, and reveal pathological mechanisms underlying OS. The EgoNet algorithm comprises four steps: constructing background protein-protein interaction (PPI) network (PPIN) based on gene expression data and PPI data; extracting differential expression network (DEN) from the background PPIN; identifying ego genes according to topological features of genes in reweighted DEN; and collecting ego modules using module search by ego gene expansion. Consequently, we obtained 5 ego modules (Modules 2, 3, 4, 5, and 6) in total. After applying the permutation test, all presented statistical significance between OS and normal controls. Finally, pathway enrichment analysis combined with Reactome pathway database was performed to investigate pathways, and Fisher's exact test was conducted to capture ego pathways for OS. The ego pathway for Module 2 was CLEC7A/inflammasome pathway, while for Module 3 a tetrasaccharide linker sequence was required for glycosaminoglycan (GAG) synthesis, and for Module 6 was the Rho GTPase cycle. Interestingly, genes in Modules 4 and 5 were enriched in the same pathway, the 2-LTR circle formation. In conclusion, the ego modules and pathways might be potential biomarkers for OS therapeutic index, and give great insight of the molecular mechanism underlying this tumor.

Resumo em Inglês:

We evaluated serum total bilirubin levels as a predictor for metabolic syndrome (MetS) and investigated the relationship between serum total bilirubin levels and MetS prevalence. This cross-sectional study included 1728 participants over 65 years of age from Eastern China. Anthropometric data, lifestyle information, and previous medical history were collected. We then measured serum levels of fasting blood-glucose, total cholesterol, triglycerides, and total bilirubin, as well as alanine aminotransferase activity. The prevalence of MetS and each of its individual component were calculated per quartile of total bilirubin level. Logistic regression was used to assess the correlation between serum total bilirubin levels and MetS. Total bilirubin level in the women who did not have MetS was significantly higher than in those who had MetS (P<0.001). Serum total bilirubin quartiles were linearly and negatively correlated with MetS prevalence and hypertriglyceridemia (HTG) in females (P<0.005). Logistic regression showed that serum total bilirubin was an independent predictor of MetS for females (OR: 0.910, 95%CI: 0.863–0.960; P=0.001). The present study suggests that physiological levels of serum total bilirubin might be an independent risk factor for aged Chinese women, and the prevalence of MetS and HTG are negatively correlated to serum total bilirubin levels.

Resumo em Inglês:

The purpose of this study was to retrospectively review the pathologic complete response (pCR) rate from patients (n=86) with stage II and III HER2-positive breast cancer treated with neoadjuvant chemotherapy at our institution from 2008 to 2013 and to determine possible predictive and prognostic factors. Immunohistochemistry for hormone receptors and Ki-67 was carried out. Clinical and pathological features were analyzed as predictive factors of response to therapy. For survival analysis, we used Kaplan-Meier curves to estimate 5-year survival rates and the log-rank test to compare the curves. The addition of trastuzumab to neoadjuvant chemotherapy significantly improved pCR rate from 4.8 to 46.8%, regardless of the number of preoperative trastuzumab cycles (P=0.0012). Stage II patients achieved a higher response rate compared to stage III (P=0.03). The disease-free and overall survivals were not significantly different between the group of patients that received trastuzumab in the neoadjuvant setting (56.3 and 70% at 5 years, respectively) and the group that initiated it post-operatively (75.8 and 88.7% at 5 years, respectively). Axillary pCR post neoadjuvant chemotherapy with trastuzumab was associated with reduced risk of recurrence (HR=0.34; P=0.03) and death (HR=0.21; P=0.02). In conclusion, we confirmed that trastuzumab improves pCR rates and verified that this improvement occurs even with less than four cycles of the drug. Hormone receptors and Ki-67 expressions were not predictive of response in this subset of patients. Axillary pCR clearly denotes prognosis after neoadjuvant target therapy and should be considered to be a marker of resistance, providing an opportunity to investigate new strategies for HER2-positive treatment.

Resumo em Inglês:

The aim of this research was to explore whether IL-18 can be a serological marker for the diagnosis of systemic-onset juvenile idiopathic arthritis (sJIA). A total of 23 sJIA patients (13 males, median age 8.2), 20 acute lymphoblastic leukemia (ALL) patients, 18 patients with severe infections (SIF), 26 Kawasaki disease (KD) patients, 18 juvenile idiopathic arthritis (JIA) patients, and 25 healthy control patients were selected for this study. Enzyme-linked immunosorbent assays (ELISAs) were used to determine the serum concentrations of the S100A8, S100A9, and IL-6 proteins. The serum IL-18 levels were detected by a cytometric bead array (CBA). The serum IL-6 concentrations in various disease groups were significantly higher than that in the healthy control group. The IL-6 concentrations exhibited no significant difference between disease groups. The S100A8 level in the sJIA group was significantly higher than those of the ALL, JIA, and healthy control groups but showed no significant difference compared to the SIF and KD groups. The S100A9 serum concentration in the sJIA group was significantly higher than those in the ALL and healthy control groups and exhibited no significant difference from the SIF, KD, and JIA groups. The IL-18 level of the sJIA group was significantly higher than that of the other febrile disease groups. The IL-18 serum concentration may be used as a biological serum marker to distinguish sJIA from other febrile diseases.

Resumo em Inglês:

Immune thrombocytopenia (ITP) is a disease characterized by isolated thrombocytopenia. Abnormal effector T cell activation is an important mechanism in the pathogenesis of ITP. Regulatory T cells (Treg) have a strong immunosuppressive function for T cell activation and their importance in the pathophysiology and clinical treatment of ITP has been confirmed. Myeloid-derived suppressor cells (MDSCs) are other immunosuppressive cells, which can also suppress T cell activation by secreting arginase, iNOS and ROS, and are essential for Treg cells’ differentiation and maturation. Therefore, we speculate that MDSCs might also be involved in the immune-dysregulation mechanism of ITP. In this study, we tested MDSCs and Treg cells in peripheral blood samples of twenty-five ITP patients and ten healthy donors. We found that MDSCs and Treg cells decreased simultaneously in active ITP patients. Relapsed ITP patients showed lower MDSCs levels compared with new patients. All patients received immunosuppressive treatment including dexamethasone alone or in combination with intravenous immune globulin. We found that MDSCs’ level after treatment correlated with platelet recovery. Our study is the first that focused on MDSCs’ role in ITP. Based on our results, we concluded that circulating MDSCs could predict disease activity and treatment response in ITP patients. This preliminary conclusion indicates a substantial significance of MDSCs in the pathophysiology and clinical treatment of ITP, which deserves further investigation.

Resumo em Inglês:

Acute graft-versus-host disease (aGVHD) and cytomegalovirus reactivation are important complications after allogeneic stem cell transplantation (alloHSCT). Here, we evaluated the impact of treatment with alemtuzumab on the occurrence of aGVHD, cytomegalovirus reactivation and survival after alloHSCT. This was a prospective cohort study conducted at the allo-HSCT unit of Hospital das Clínicas, Universidade Federal de Minas Gerais, Brazil, from January 2009 to December 2011. Fifty-seven patients who underwent alloHSCT were included. Forty-five (79%) patients had a malignant disease. Alemtuzumab was administered before the conditioning regimen at a dose of 1 mg/kg in children and 30 mg/day for 2 days in adults or children weighing more than 40 kg (a total dose of 60 mg) with a non-malignant disease or patients with a malignant disease and high-risk for GVHD mortality. Alemtuzumab was used in 23 (40%) patients, of whom 17 received a reduced-intensity conditioning. Eleven patients presented aGVHD (grade 2–4) and only 1 of them received alemtuzumab. Cumulative incidence of aGVHD (grade 2–4) at day 100 after transplantation (D+100) was 4 for patients receiving alemtuzumab and 29% for patients not receiving alemtuzumab. Cumulative incidence of cytomegalovirus reactivation for patients receiving or not alemtuzumab was 62 and 38%, respectively. Sixteen patients died in the first 100 days after alloHSCT, most of them due to bacterial sepsis. Only 2 patients died of aGVHD until D+100. Overall survival was 50% without any impact of alemtuzumab. Alemtuzumab effectively controlled aGVHD but increased the risk of cytomegalovirus reactivation without improving survival.