Current Molecular Medicine - Volume 20, Issue 3, 2020

The peptide hormone relaxin was originally linked to reproductive physiology, where it is believed to mediate systemic and renal hemodynamic adjustments to pregnancy. Recently, its broad range of effects in the cardiovascular system has been the focus of intensive research regarding its implications under pathological conditions and potential therapeutic potential. An understanding of the multitude of cardioprotective actions prompted the study of serelaxin, recombinant human relaxin-2, for the treatment of acute heart failure. Despite early promising results from phase II studies, recently revealed RELAX-AHF-2 outcomes were rather disappointing and the treatment for acute heart failure remains an unmet medical need. This article reviews the physiologic actions of relaxin on the cardiovascular system and its relevance in the pathophysiology of cardiovascular disease. We summarize the most updated clinical data and discuss future directions of serelaxin for the treatment of acute heart failure. This should encourage additional work to determine how can relaxin's beneficial effects be exploited for the treatment of cardiovascular disease.

Background: A number of human inflammatory diseases and tumors have been shown to cause alterations in the glycosylation pattern of plasma proteins in a specific manner. These highly variable and versatile post-translational modifications finetune protein functions by influencing sorting, folding, enzyme activity and subcellular localization. However, relatively little is known about regulatory factors of this procedure and about the accurate causative connection between glycosylation and disease. Objective: The aim of the present study was to investigate whether certain single nucleotide polymorphisms (SNPs) in genes encoding glycosyltransferases and glycosidases could be associated with elevated risk for chronic obstructive pulmonary disease (COPD) and lung adenocarcinoma. Methods: A total of 32 SNPs localized in genes related to N-glycosylation were selected for the association analysis. Polymorphisms with putative biological functions (missense or regulatory variants) were recruited. SNPs were genotyped by a TaqMan OpenArray platform. A single base extension-based method in combination with capillary gel electrophoresis was used for verification. Results: The TaqMan OpenArray approach provided accurate and reliable genotype data (global call rate: 94.9%, accuracy: 99.6%). No significant discrepancy was detected between the obtained and expected genotype frequency values (Hardy–Weinberg equilibrium) in the healthy control sample group in case of any SNP confirming reliable sampling and genotyping. Allele frequencies of the rs3944508 polymorphism localized in the 3’ UTR of the MGAT5 gene significantly differed between the sample groups compared. Conclusion: Our results suggest that the rs34944508 SNP might modulate the risk for lung cancer by influencing the expression of MGAT5. This enzyme catalyzes the addition of N-acetylglucosamine (GlcNAc) in beta 1-6 linkage to the alpha-linked mannose of biantennary N-linked oligosaccharides, thus, increasing branching that is the characteristic of invasive malignancies.

Background: Thermotolerance is an acquired state of increased heat resistance that occurs following exposure to non-lethal proteotoxic stress. A large body of evidences implicates that molecular chaperon members belonging to the heat shock protein family could be acting as potential mediators of the thermotolerant state. Objective: Recent evidence has demonstrated heat shock proteins HSP90, HSP70 and HSP27 have inhibited heat-induced cell death by intervening at various steps in stressinduced apoptotic pathways. Previous studies have shown that HSP70 prevented heatinduced apoptosis by preventing the NOXA dependent decrease in MCL-1 levels leading to both BAX activation and cytochrome c release from mitochondria. We have also demonstrated that HSP70 expressing cells have enhanced levels of miR-23a prevent heat-induced increase in NOXA levels and suppress apoptosis. Methods: Stably transfected cell lines expressing either a control shRNA or a miR-23a targeting shRNA are quantified using both RT-PCR and semi-quantitative RT-PCR to determine the effect of different hyperthermic exposure treatment on miR-23a and Noxa mRNA expression levels. Results: This study shows that thermotolerant-induced pre-heat shock treatment is capable of increasing miR-23a levels. Furthermore, stable cell clones expressing a miR- 23a targeting shRNA having reduced miR-23a levels are incapable of developing a thermotolerance state, leading to apoptosis. Conclusion: These results demonstrate the novel finding that miR-23a is an important factor in the development of the thermotolerant state.

Background: Maternal natural killer cells (NK cells) are a prevailing leukocyte population in the uteroplacental bed. Current descriptions of the effect of cytokines from the placental microenvironment on the expression of receptors by trophoblast and NK cells are inadequate and contradictory. There is insufficient information about the ability of NK cells to migrate through trophoblast cells. Objective: To assess the impact of conditioned media obtained during culturing of placentas from the first and the third trimesters of healthy pregnancies on the phenotype of trophoblast and NK cells and impact on adhesion and transmigration of NK cells through trophoblast cell layer. Results: We established that conditioned media obtained from both first and third trimester placentas increased the intensity of CD106, CD49e, CD49a, CD31, CD51/61, and integrin β6 expression by trophoblast cells. Conditioned media obtained from first trimester placentas increased the intensity of CD11a, CD29, CD49d, CD58, CD29 expression by NK cells. The presence of conditioned media from third trimester placentas resulted in more intense CD29, CD49d, CD11a, CD29, CD49d, and CD58 expression by NK cells. Migration of NK cells through trophoblast cells in the presence of conditioned media from first trimester placentas was increased compared with the migration level in the presence of conditioned media from third trimester placentas. This may be associated with increased expression of CD18 by NK cells. Conclusion: First trimester placental secretory products increase adhesion receptor expression by both trophoblast and NK cells. Under these conditions, trophoblast is capable of ensuring NK cell adhesion and transmigration.

Background: Shuangshen Pingfei San (SPS) is the derivative from the classic formula Renshen Pingfei San in treating idiopathic pulmonary fibrosis (IPF). Methods: In this study, Chou’s 5-steps rule was performed to explore the potential active compound and mechanism of SPS on IPF. Compound–target network, target– pathway network, herb–target network and the core gene target interaction network were established and analyzed. A total of 296 compounds and 69 candidate therapeutic targets of SPS in treating IPF were obtained. Network analysis revealed that the main active compounds were flavonoids (such as apigenin, quercetin, naringenin, luteolin), other clusters (such as ginsenoside Rh2, diosgenin, tanshinone IIa), which might also play significant roles. SPS regulated multiple IPF relative genes, which affect fibrosis (PTGS2, KDR, FGFR1, TGFB, VEGFA, MMP2/9) and inflammation (PPARG, TNF, IL13, IL4, IL1B, etc.). Conclusion: In conclusion, anti-pulmonary fibrosis effect of SPS might be related to the regulation of inflammation and pro-fibrotic signaling pathways. These findings revealed that the potential active compounds and mechanisms of SPS on IPF were a benefit to further study.

Background: By including untreated obstructive sleep apnea-hypopnea syndrome (OSAHS) patients as the control group, this study explores the influence of minimally invasive surgical treatment and continuous positive airway pressure (CPAP) therapy on OSAHS patients, with the subjective and objective performance. The study also discusses their relationship, determines the effect factor, and provides a simple and practical method for evaluation of clinical efficacy. Methods: A total of 90 OSAHS patients, who were diagnosed in the Sleep Disorders Diagnosis and Treatment Center of Sichuan Province from May 2014 to May 2016, were selected for the present study. These patients were divided into three groups: surgery group, CPAP group, and untreated group. These patients were followed up at six months, one year, and two years, respectively. The physiological indicators, clinical symptoms, degree of daytime sleepiness and quality of life were compared among these three groups. The daytime sleepiness and the quality of life before and after minimally invasive surgery and CPAP treatment were evaluated, and the subjective and objective efficacy of surgery and CPAP treatment was explored. Results: Among these 90 patients, 11 (12.2%) patients had hypertension, while two (2.2%) patients had diabetes. The average AHI score was 50.53±23.39 per hour, and the mean minimum oxygen saturation and mean oxygen saturation was 71.25±14.16% and 90.13±5.90%, respectively. There were statistically significant differences in mouth breathing, morning sore throat and daytime sleepiness in the group having received surgery at 0.5 year and one year. In the CPAP group, there were statistically significant differences in mouth breathing, morning sore throat and daytime sleepiness at 0.5 year, one year and two years. Moreover, there were statistically significant differences in memory loss at one year and two years, and there were statistically significant differences in frequent nocturia at one year. The ESS value in the surgery group decreased at 0.5 year and one year, but increased at two years. The situation was the same in terms of the total points and in each dimension of the SF-36 paramter. The delta values of ESS among the three groups had statistical significance at 0.5 year, one year and two years, in which the CPAP group experienced the most changes, followed by the surgery group and the group received health education. Conclusion: For minimally invasive surgery, CPAP therapy and health education can improve daytime sleepiness and quality of life. CPAP therapy was found to be the most effective, followed by minimally invasive surgery and provision of health education. However, the treatment of OSAHS should be comprehensive.

Objective: This study aims to investigate the effect of morphine with naloxone on intestinal peristalsis and the number of interstitial cells of Cajal (ICC) in colon tissues of rabbits. Methods: Thirty rabbits were randomly divided into five groups (n=6, each group): saline control group (NS group), low concentration of morphine group (L group), medium concentration of morphine group (M group), high concentration of morphine group (H group), medium concentration of morphine and naloxone mixed with antagonist group (NM group). Rabbits in these five groups were administered with an epidural puncture tube and dorsal epidural analgesia pump, and were continuously infused for seven days. Fecal characteristics were observed, and the ink propulsion rate was calculated. The expression level of ICC C-kit protein in colon tissues was tested by western blot. Results: The stool characteristics in the L, M and H groups were more severe than those in the NS and NM groups. Furthermore, the intestinal propulsion rate in the L, M and H groups was lower than that in the NS and NM groups. The C-kit mRNA and protein expression in the colon of rabbits were significantly lower in the L, M and H groups, when compared to the NS and NM groups. Conclusion: Naloxone blocked the mRNA and protein expression of C-kit, and improved intestinal motor function.