Scielo RSS <![CDATA[Brazilian Journal of Medical and Biological Research]]> vol. 50 num. 11 lang. en <![CDATA[SciELO Logo]]> <![CDATA[Metabolomics as a promising tool for early osteoarthritis diagnosis]]> Osteoarthritis (OA) is the main cause of disability worldwide, due to progressive articular cartilage loss and degeneration. According to recent research, OA is more than just a degenerative disease due to some metabolic components associated to its pathogenesis. However, no biomarker has been identified to detect this disease at early stages or to track its development. Metabolomics is an emerging field and has the potential to detect many metabolites in a single spectrum using high resolution nuclear magnetic resonance (NMR) techniques or mass spectrometry (MS). NMR is a reproducible and reliable non-destructive analytical method. On the other hand, MS has a lower detection limit and is more destructive, but it is more sensitive. NMR and MS are useful for biological fluids, such as urine, blood plasma, serum, or synovial fluid, and have been used for metabolic profiling in dogs, mice, sheep, and humans. Thus, many metabolites have been listed as possibly associated to OA pathogenesis. The goal of this review is to provide an overview of the studies in animal models and humans, regarding the use of metabolomics as a tool for early osteoarthritis diagnosis. The concept of osteoarthritis as a metabolic disease and the importance of detecting a biomarker for its early diagnosis are highlighted. Then, some studies in plasma and synovial tissues are shown, and finally the application of metabolomics in the evaluation of synovial fluid is described. <![CDATA[Association between polymorphisms in the <em>APOB</em> gene and hyperlipidemia in the Chinese Yugur population]]> We investigated the influence of apolipoprotein B gene (APOB) variants on the risk of hyperlipidemia (HL) in 631 middle-aged and elderly members of the Chinese Yugur population (HL, n=336; normolipidemia, n=295). APOB polymorphisms were identified using mass spectrometry, and five single nucleotide polymorphisms (rs1042034, rs2163204, rs512535, rs676210, and rs679899) and serum lipids were further analyzed. rs1042034 and rs676210 were significantly associated with HL (P&lt;0.05). Compared with the GG or AA genotype, individuals with AG and AG+AA in rs1042034 and with AG and AG+GG in rs676210 had a 1.67-fold (95%CI=1.20–2.33),1.63-fold (95%CI=1.19–2.24), 1.72-fold (95%CI=1.24–2.40), and 1.67-fold (95%CI=1.21–2.291) increased risk of high HL, respectively. rs2163204 was in strong linkage disequilibrium with rs1042034, rs676210, and rs679899, and strong disequilibrium was observed between rs1042034 and rs676210 (D′&gt;0.9). Compared with the GTGAA haplotype, haplotypes ATGGA and ATAGG were more strongly associated with HL [odds ratio (OR)=1.46, 95%CI=0.02–2.11; OR=1.63, 95%CI=1.03–2.60, respectively]. The risk factors age (P=0.008), body mass index (P&lt;0.0001), GA+GG genotype in rs676210 (P=0.009), and alcohol consumption (P=0.056) contributed strongly to HL development. The A allele of rs1042034 and the G allele of rs676210 may thus predispose middle-aged and elderly members of the Chinese Yugur population to HL in combination with other genetic or nutritional factors, and could be used as new genetic markers for HL screening. <![CDATA[Molecular analysis of <em>CIB</em>4 gene and protein in Kermani sheep]]> The human calcium- and integrin-binding protein (CIB) family is composed of CIB1, CIB2, CIB3, and CIB4 proteins and the CIB4 gene affects fertility. Kermani sheep is one of the most important breeds of Iranian sheep breeds. The aim of this study was to analyze for the first time molecular characteristics of the CIB4 gene and protein in Kermani sheep. Different tissues were collected from the Kermani sheep and real time PCR was performed. The PCR products were sequenced, comparative analyses of the nucleotide sequences were performed, a phylogenetic tree was constructed, and different characteristics of CIB4 proteins were predicted. Real time PCR results showed that the CIB4 gene is expressed only in testis of Kermani sheep. The cDNA nucleotide sequence was identical with small tail Han sheep, cattle, goat, camel, horse, dog, mouse and human, respectively 100, 99, 99, 98, 98, 96, 96, and 96%. Hence, it can be suggested that the CIB4 gene plays a role in male fertility. Based on the phylogenetic analysis, sheep CIB4 gene has a close relationship with goat and cattle first, and then with camel and whale. Although we demonstrated that CIB4 is a testis-specific gene, expressed only in the testis and it interacts with other proteins, the mechanisms by which CIB4 expression is regulated need to be elucidated. <![CDATA[Synthesis and evaluation of coumarin derivatives against human lung cancer cell lines]]> Series of novel coumarin derivatives [I (a–d) and II (a–d)] were successfully synthesized and their structures were determined based on infrared 1H-nuclear magnetic resonance (NMR), HRMS, and single crystal X-ray crystallography. Additionally, the new synthesized compounds were evaluated to identify the molecular characteristics that contribute to their cytotoxicity, which was tested against SK-LU-1, SPC-A-1 and 95D human lung cancer cell lines, using the MTT assay. The results of this study showed that compounds Ic, Id, IIc, and IId exhibited an efficient percentage of inhibition of cell proliferation. <![CDATA[Tyrosine phosphorylation of Kv1.5 is upregulated in intrauterine growth retardation rats with exaggerated pulmonary hypertension]]> Intrauterine growth retardation (IUGR) is associated with the development of adult-onset diseases, including pulmonary hypertension. However, the underlying mechanism of the early nutritional insult that results in pulmonary vascular dysfunction later in life is not fully understood. Here, we investigated the role of tyrosine phosphorylation of voltage-gated potassium channel 1.5 (Kv1.5) in this prenatal event that results in exaggerated adult vascular dysfunction. A rat model of chronic hypoxia (2 weeks of hypoxia at 12 weeks old) following IUGR was used to investigate the physiological and structural effect of intrauterine malnutrition on the pulmonary artery by evaluating pulmonary artery systolic pressure and vascular diameter in male rats. Kv1.5 expression and tyrosine phosphorylation in pulmonary artery smooth muscle cells (PASMCs) were determined. We found that IUGR increased mean pulmonary artery pressure and resulted in thicker pulmonary artery smooth muscle layer in 14-week-old rats after 2 weeks of hypoxia, while no difference was observed in normoxia groups. In the PASMCs of IUGR-hypoxia rats, Kv1.5 mRNA and protein expression decreased while that of tyrosine-phosphorylated Kv1.5 significantly increased. These results demonstrate that IUGR leads to exaggerated chronic hypoxia pulmonary arterial hypertension (CH-PAH) in association with decreased Kv1.5 expression in PASMCs. This phenomenon may be mediated by increased tyrosine phosphorylation of Kv1.5 in PASMCs and it provides new insight into the prevention and treatment of IUGR-related CH-PAH. <![CDATA[Down-regulation of single-stranded DNA-binding protein 1 expression induced by HCMV infection promotes lipid accumulation in cells]]> The objective of this study was to observe the infection of human cytomegalovirus (HCMV) to human umbilical vein endothelial cells, and its effect on the expression of single-stranded DNA-binding protein (SSBP1) and on lipid metabolism in endothelial cells. We screened the differential expression of mRNAs after HCMV infection by suppression subtractive hybridization and the expression levels of SSBP1 mRNA and protein after HCMV infection by real-time PCR and western blot. After verification of successful infection by indirect immunofluorescent staining and RT-PCR, we found a differential expression of lipid metabolism-related genes including LDLR, SCARB, CETP, HMGCR, ApoB and LPL induced by HCMV infection. The expression levels of SSBP1 mRNA and protein after HCMV infection were significantly down-regulated. Furthermore, we found that upregulation of SSBP1 inhibited the expression of atherosclerosis-associated LDLR, SCARB, HMGCR, CETP as well as the accumulation of lipids in the cells. The results showed that the inhibition of SSBP1 by HCMV infection promotes lipid accumulation in the cells. <![CDATA[Women with recurrent spontaneous abortion have decreased 25(OH) vitamin D and VDR at the fetal-maternal interface]]> Immunological mechanisms have been proposed to underlie the pathogenesis of recurrent spontaneous abortion (RSA). Vitamin D has a potent immunomodulatory effect, which may affect pregnancy outcome. The objective of this study was to investigate 25-hydroxyvitamin D [25(OH) D] concentration and vitamin D receptor (VDR) expression in the decidual tissues of RSA patients. Thirty women with RSA (RSA group) and thirty women undergoing elective abortion (control group) were recruited during 2016 from gynecology outpatient clinics. We measured 25(OH) D, interleukin (IL)-17, IL-23, transforming growth factor β (TGF-β), VDR and 1-α-hydroxylase (CYP27B1) in decidual tissues collected during the abortion procedure. In the RSA group, 25(OH) D and TGF-β were significantly decreased while IL-17 and IL-23 were significantly increased compared with the control group. VDR expression was significantly decreased in the RSA group compared with the control group. Logistic regression analysis showed a significant negative correlation between 25(OH) D in decidual tissues and RSA. These results indicated that vitamin D concentrations in the decidua are associated with inflammatory cytokine production, suggesting that vitamin D and VDR may play a role in the etiology of RSA. <![CDATA[Bradykinin, insulin, and glycemia responses to exercise performed above and below lactate threshold in individuals with type 2 diabetes]]> The aim of this study was to analyze the acute responses of bradykinin, insulin, and glycemia to exercise performed above and below lactate threshold (LT) in individuals with type 2 diabetes mellitus (T2D). Eleven participants with a diagnosis of T2D randomly underwent three experimental sessions 72 h apart: 1) 20 min of exercise performed at 120% of LT (120%LT), 2) 20 min of exercise performed at 80% of LT (80%LT), and 3) 20 min of control session. Blood glucose was analyzed before, during, and at 45 min post-exercise. Bradykinin and insulin were analyzed before and at 45 min post-exercise. Both exercise sessions elicited a parallel decrease in glucose level during exercise (P≤0.002), with a greater decrease being observed for 120%LT (P=0.005). Glucose decreased 22.7 mg/dL (95%CI=10.3 to 35, P=0.001) at the 45 min post-exercise recovery period for 80%LT and decreased 31.2 mg/dL (95%CI=18.1 to 44.4, P&lt;0.001) for 120%LT (P=0.004). Insulin decreased at post-exercise for 80%LT (P=0.001) and control (P≤0.035). Bradykinin increased at 45 min post-exercise only for 80%LT (P=0.013), but was unrelated to the decrease in glucose (r=-0.16, P=0.642). In conclusion, exercise performed above and below LT reduced glycemia independently of insulin, but exercise above LT was more effective in individuals with T2D. However, these changes were unrelated to the increase in circulating bradykinin. <![CDATA[Effects of herbal medicine Sijunzi decoction on rabbits after relieving intestinal obstruction]]> Intestinal obstruction leads to blockage of the movement of intestinal contents. After relieving the obstruction, patients might still suffer with compromised immune function and nutritional deficiency. This study aimed to evaluate the effects of Sijunzi decoction on restoring the immune function and nutritional status after relieving the obstruction. Experimental rabbits (2.5±0.2 kg) were randomly divided into normal control group, 2-day intestinal obstruction group, 2-day natural recovery group, 4-day natural recovery group, 2-day treated group, and 4-day treated group. Sijunzi decoction was given twice a day to the treated groups. The concentration of markers was analyzed to evaluate the immune function and nutritional status. The concentration of interleukin-2, immunoglobulins and complement components of the treated groups were significantly higher than the natural recovery group (P&lt;0.05). The levels of CD4+ and CD4+/CD8+ increased then decreased in the treated groups. The levels of tumor necrosis factor-α and CD8+ were significantly lower than the natural recovery group. The level of total protein in the treated groups also increased then decreased after relieving the obstruction. The levels of albumin, prealbumin and insulin-like growth factor-1 were significantly higher in the treated groups than in the natural recovery group (P&lt;0.05). Transferrin level in the treated groups was significantly higher than the obstruction group (P&lt;0.05). Sijunzi decoction can lessen the inflammatory response and improve the nutrition absorption after relieving the obstruction. <![CDATA[Collaborative care model improves self-care ability, quality of life and cardiac function of patients with chronic heart failure]]> Chronic heart failure (CHF) is a common chronic disease that requires much care. This study aimed to explore the effects of collaborative care model (CCM) on patients with CHF. A total of 114 CHF patients were enrolled in this study, and were randomly and equally divided into two groups: control and experimental. Patients in the two groups received either usual care or CCM for 3 continuous months. The impacts of CCM on the self-care ability and quality of life were assessed using self-care of heart failure index and short form health survey 12, respectively. Further, cardiac function was assessed by measuring left ventricular ejection fraction (LVEF) and the level of N-terminal pro-B-type natriuretic peptide (NT-proBNP), and by the 6-min walking test. Clinical and demographic characteristics of patients in the control and CCM groups were statistically equivalent. Compared with usual care, CCM significantly enhanced self-care abilities of patients with CHF, including self-care maintenance, self-care management and self-care confidence (all P&lt;0.05). The physical and mental quality of life was also significantly improved by CCM (P&lt;0.01 or P&lt;0.05). Compared with usual care, CCM significantly increased the LVEF (P&lt;0.01), decreased the NT-proBNP level (P&lt;0.01), and enhanced exercise capacity (P&lt;0.001). In conclusion, CCM improved the self-care, quality of life and cardiac function of patients with CHF compared with usual care. <![CDATA[The regulatory role of IL-6R in hepatitis B-associated fibrosis and cirrhosis]]> This study investigated the expression and regulation of IL-6R in hepatitis B-associated moderate hepatic fibrosis and cirrhosis. Liver tissues, peripheral blood monocytes (PBMs) and serum were collected from 26 hepatitis B patients with liver fibrosis and 35 hepatitis B patients with liver cirrhosis. The levels of Il-6r mRNA expression in these samples were examined by quantitative real-time PCR and IL-6R protein levels were analyzed by western blot and ELISA. MiRNAs that regulate IL-6R expression were predicted by bioinformatics analysis, and validated by dual luciferase reporter assay. Compared with the hepatic fibrosis group, IL-6R was significantly upregulated at both mRNA and protein levels in liver tissues, PBMs and serum samples from the hepatic cirrhosis group (P&lt;0.05). The 3′UTR of Il-6r mRNA was predicted to contain a miR-30b binding site and IL-6R was identified as a possible target of miR-30b. MiR-30b expression was significantly downregulated in samples from hepatic cirrhosis patients compared with hepatic fibrosis patients (P&lt;0.05). In conclusion, IL-6R was upregulated while miR-30b was decreased in patients with liver cirrhosis. The miR-30 can directly regulate the expression of IL-6R. <![CDATA[Candesartan, rather than losartan, improves motor dysfunction in thioacetamide-induced chronic liver failure in rats]]> Minimal hepatic encephalopathy is more common than the acute syndrome. Losartan, the first angiotensin-II receptor blocker (ARB), and candesartan, another widely-used ARB, have protected against developing fibrogenesis, but there is no clear data about their curative antifibrotic effects. The current study was designed to examine their effects in an already-established model of hepatic fibrosis and also their effects on the associated motor dysfunction. Low-grade chronic liver failure (CLF) was induced in 3-month old Sprague-Dawley male rats using thioacetamide (TAA, 50 mg·kg−1·day−1) intraperitoneally for 2 weeks. The TAA-CLF rats were randomly divided into five groups (n=8) treated orally for 14 days (mg·kg−1·day−1) as follows: TAA (distilled water), losartan (5 and 10 mg/kg), and candesartan (0.1 and 0.3 mg/kg). Rats were tested for rotarod and open-field tests. Serum and hepatic biochemical markers, and hepatic histopathological changes were evaluated by H&amp;E and Masson's staining. The TAA-CLF rats showed significant increases of hepatic malondialdehyde, hepatic expression of tumor necrosis factor-α (TNF-α), and serum ammonia, alanine aminotransferase, γ-glutamyl transferase, TNF-α, and malondialdehyde levels as well as significant decreases of hepatic and serum glutathione levels. All treatments significantly reversed these changes. The histopathological changes were moderate in losartan-5 and candesartan-0.1 groups and mild in losartan-10 and candesartan-0.3 groups. Only candesartan significantly improved TAA-induced motor dysfunction. In conclusion, therapeutic antifibrotic effects of losartan and candesartan in thioacetamide-induced hepatic fibrosis in rats are possibly through angiotensin-II receptor blocking, antioxidant, and anti-inflammatory activities. Improved motor dysfunction by candesartan could be attributed to better brain penetration and slower “off-rate” from angiotensin-II receptors. Clinical trials are recommended. <![CDATA[Absorption mechanism of three curcumin constituents through <em>in situ</em> intestinal perfusion method]]> This study aimed to investigate the absorption mechanism of three curcumin constituents in rat small intestines. Self-emulsification was used to solubilize the three curcumin constituents, and the rat in situ intestinal perfusion method was used to study factors on drug absorption, including drug mass concentration, absorption site, and the different types and concentrations of absorption inhibitors. Within the scope of experimental concentrations, three curcumin constituents were absorbed in rat small intestines through the active transport mechanism. <![CDATA[Relationship between aerobic capacity and pelvic floor muscles function: a cross-sectional study]]> The objective of this study was to evaluate the relationship between aerobic capacity and pelvic floor muscles (PFM) function in adult women. Women aged 18 or over and without urinary dysfunction or other chronic diseases were eligible to participate. They completed the habitual physical activity (HPA) questionnaire, underwent a PFM functional evaluation by palpation and perineometry, and performed a submaximal (between 75 and 85% of maximum heart rate) cardiopulmonary exercise (CPX) test to determine the ventilatory anaerobic threshold (VAT). Forty-one women were included (35±16 years, 75% physically active, 17% very active, and 8% sedentary and 17% presented grade 1 PFM contraction, 31.8% grade 2, 26.8% grade 3, and 24.4% grade 4, according to the modified Oxford Scale). The average PFM contraction pressure obtained by perineometer was 53±26 cmH2O and the average oxygen consumption at VAT (VO2VAT) obtained from CPX was 14±2 mL·kg-1·min-1. Significant correlations were found between PFM contraction pressure and VO2VAT (r=0.55; P&lt;0.001); between PFM contraction pressure and HPA score (r=0.38; P=0.02); between age and VO2VAT (r=-0.25; P=0.049); and between VO2VAT and HPA score (r=0.36; P=0.02). An age-adjusted multiple linear regression equation (R2=0.32) was derived to estimate VO2VAT from the contraction value obtained by perineometer, so that the PFM contraction pressure was able to predict VO2VAT. The equation was validated using data from another group of 20 healthy women (33±12 years; PFM contraction: 49±23 cmH2O) and no significant difference was found between actual VO2VAT and predicted VO2VAT (13.1±1.9 vs 13.8±2.0 mL·kg-1·min-1). In conclusion, PFM function is associated with aerobic capacity in healthy women and PFM contraction pressure may be used to estimate VO2VAT in this population.