Reviews
DOI: 10.1556/2060.2020.00021
Abstract: Pulmonary arterial hypertension (PAH) is a rare and progressive disease, characterized by increased vascular resistance leading to right ventricle (RV) failure. The extent of right ventricular dysfunction crucially influences disease prognosis; however, currently no therapies have specific cardioprotective effects. Besides discussing the pathophysiology of right ventricular adaptation in PAH, this review focuses on the roles of growth factors (GFs) in disease pathomechanism. We also summarize the involvement of GFs in the preservation of cardiomyocyte function, to evaluate their potential as cardioprotective biomarkers and novel therapeutic targets in PAH.
Keywords: pulmonary hypertension, heart failure, cardiac remodeling, predictive marker, cardioprotection, growth hormones
DOI: 10.1556/2060.2020.00019
Abstract: A considerable number of patients arriving in dental offices are being treated with ongoing medication for a variety of chronic diseases. As a result, dentists must be familiar with the potential side effects these therapeutic agents may have on the tissues of the oral cavity, and in particular on the salivary gland. Salivary gland function may be altered by a wide range of medications, leading to effects such as xerostomia, hyposalivation, hypersalivation or even swelling of the glands. These disorders can cause a variety of other health complications. This review will focus on the most common groups of drugs responsible for salivary gland dysfunction, including psychoactive drugs, antidepressants, antipsychotics, antihypertensives, and antihistamines.
Keywords: salivary glands dysfunction, medication side effects, xerostomia, hyposalivation, hypersalivation
Original papers - Animal experiments
DOI: 10.1556/2060.2020.00022
Abstract: Introduction: Exposure to noise stress during early life may permanently affect the structure and function of the central nervous system. The aim of this study was to evaluate the effects of prenatal exposure to urban traffic noise on the spatial learning and memory of the rats’ offspring and the expression of glucocorticoid receptors (GRs) in their hippocampi. Methods: Three g\roups of pregnant rats were exposed to recorded urban traffic noise for 1, 2 or 4 h/day during the last week of pregnancy. At the age of 45 days, their male offspring were introduced to the Morris water maze (MWM) for assessment of spatial learning and memory. The corticosterone levels were measured in the offspring’s sera by radioimmunoassay, and the relative expression of glucocorticoid and mineralocorticoid receptors (MRs) in their hippocampi was evaluated via RT-PCR. Results: Facing urban traffic noise for 2 and 4 h/day during the third trimester of pregnancy caused the offspring to spend more time and to travel a larger distance than the controls to find the target platform. Analogously, these two groups were inferior to their control counterparts in the probe test. Also, prenatal noise stress elevated the corticosterone concentration in the sera of the rats’ offspring and dose-dependently decreased the relative expression of the mRNA of both GRs and MRs in their hippocampi. Conclusions: Urban traffic noise exposure during the last trimester of pregnancy impairs spatial learning and memory of rat offspring and reduces GRs and MRs gene expression in the hippocampus.
Keywords: noise, stress, prenatal period, glucocorticoid receptor, spatial learning and memory, hippocampus
DOI: 10.1556/2060.2020.00020
Abstract: Objective: It has been shown that high-intensity interval training (HIIT) leads to skeletal muscle hypertrophy; however, its mechanisms of cellular and molecular regulation are still unclear. The purpose of this study was to investigate the effect of HIIT on muscle hypertrophy and major signal transduction pathways. Design: 12 male rats were randomly divided into two groups: control and HIIT. The exercise group performed 30-min HIIT in each session (5 3 4-min intervals running at 85–95% VO2max separated by 2-min active rest at 55–60% VO2max), 3 days/week for 8 weeks. Muscle fiber cross-sectional area (CSA) and the expression of signal transduction pathway proteins were determined in the gastrocnemius muscle. Results: In the HIIT group, the expression of IGF-I, IGF-IR Akt, p-Akt, AMPKa, p-AMPKa and follistatin increased significantly, whereas a significant decrease was observed in the expression of FoxO1, p-FoxO1, myostatin, ActRIIB, Smad2/3 and p-Smad2/3 (P < 0.05). In addition, CSA and gastrocnemius muscle weight increased significantly in the HIIT group (P < 0.05). Conclusions: HIIT induced muscle hypertrophy by improving IGF-I/Akt/FoxO and myostatin/Smad signal transduction pathways.
Keywords: insulin-like growth factor I, follistatin, myostatin, cross-sectional area, muscle growth
DOI: 10.1556/2060.2020.00024
Abstract: Purpose: Knee osteoarthritis (OA) is a common type of degenerative joint disease which decreases the quality of life. Sex-determining region Y box 9 (SOX9) and hypoxia-inducible factor-1 (HIF1) are considered as the key regulators of OA. We investigated the effect of combined therapies with mesenchymal stem cells (MSCs), ozone (O3) and exercise training on SOX9 and HIF1 expression in the cartilage of rats with knee OA. Methods: Knee OA was induced by surgical method. OA rats were divided into model, MSCs, ozone, exercise, MSCs þ ozone, MSCs þ exercise, ozone þ exercise and MSCs þ ozone þ exercise groups. Rats in the MSCs group received intraarticular injection of 1 3 106 cells/kg. Rats in the ozone group received O3 at the concentration of 20 mg/mL, once weekly for 3 weeks. Rats in the exercise group were trained on rodent treadmill three times per week. 48 hours after the programs, cartilage tissues were isolated and the expression of SOX9 and HIF1 was determined using Real-Time PCR. Results: Significant differences were found in the expression of SOX9 and HIF1 between groups (P < 0.0001). Although combined therapies with exercise, MSCs and O3 significantly increased the expression of SOX9 and HIF1 in the cartilage tissue of rats with knee OA, combination of exercise with O3 was significantly more effective compared to the other combined therapies (P < 0.001). Conclusions: Combined therapy with exercise, MSCs and O3 significantly increased the expression of SOX9 and HIF1 genes in the cartilage of rats with knee OA; however, exercise þ O3 was significantly more effective.
Keywords: knee osteoarthritis, O3 therapy, MSCs therapy, exercise training, SOX9, HIF1
DOI: 10.1556/2060.2020.00025
Abstract: In order to investigate the role of the vagus nerve in the possible gastroprotective effect of obestatin on the indomethacin-induced acute oxidative gastric injury, Sprague-Dawley rats of both sexes were injected subcutaneously with indomethacin (25 mg/kg, 5% NaHCO3) followed by obestatin (10, 30 or 100 mg/kg). In other sets of rats, surgical vagotomy (Vx) or selective degeneration of vagal afferent fibers by perivagal capsaicin was performed before the injections of indomethacin or indomethacin þ obestatin (30 mg/kg). Gastric serosal blood flow was measured, and 4 h after ulcer induction gastric tissue samples were taken for histological and biochemical assays. Obestatin reduced the severity of indomethacin-induced acute ulcer via the reversal of reactive hyperemia, by inhibiting ulcer-induced neutrophil infiltration and lipid peroxidation along with the replenishment of glutathione (GSH) stores, whereas Vx abolished the inhibitory effect of obestatin on blood flow and lipid peroxidation, and worsened the severity of ulcer. On the other hand, serosal blood flow was even amplified by the selective denervation of the capsaicin-sensitive vagal afferent fibers, but obestatin-induced reduction in ulcer severity was not altered. In conclusion, the gastroprotective effect of obestatin on indomethacin-induced ulcer appears to involve the activation of the vagovagal pathway.
Keywords: NSAID, obestatin, vagus, neutrophil, capsaicin, hyperemia, indomethacin
Human studies
DOI: 10.1556/2060.2020.00026
Abstract: Objective: In this observational study we addressed accelerated arteriosclerosis (AS) in patients with chronic renal failure (CRF) on hemodialysis (HD) by measuring vascular stiffness (VS) parameters and attempted to relate them to pro-inflammatory and protective factors. Patients: 96 consecutive patients receiving regular HD were included. 20 adult patients without major renal, cardiovascular or metabolic morbidities served as controls. Methods: AS parameters (carotid-femoral pulse wave velocity – PWV, aortic augmentation index – Aix) were measured by using applanation tonometry (SphygmoCor, AtCor Medical, Sidney). In addition to routine laboratory tests 25(OH) vitamin D3 (vitamin D3) and high-sensitivity Creactive protein (hsCRP) were quantified by immunometric assay; whereas fetuin-A, a-Klotho, tumor necrosis factor-a (TNF-a) and transforming growth factor-b1 (TGF-b1) were determined by ELISA. Results: Pro-inflammatory biomarkers (hsCRP, TNF-a and TGF-b1) were markedly elevated (P < 0.01), while anti-inflammatory factors (fetuin-A: P < 0.05, a-Klotho: P < 0.01, vitamin D3: P < 0.01) significantly depressed in HD patients when compared to controls. PWV was significantly affected only by total cholesterol, fetuin-A and dialysis time. Multiple linear regression analyses revealed that several clinical and laboratory parameters were associated with pro- and anti-inflammatory biomarkers rather than VS. The impact of baseline clinical and biochemical variables on outcome measures were also analyzed after threeyear follow-up, and it was demonstrated that low levels of vitamin D, a-Klotho protein and fetuin-A were related to adverse cardiovascular outcomes, whereas all-cause mortality was associated with elevated hsCRP and depressed vitamin D. Conclusions: Our results provide additional information on the pathomechanism of accelerated AS in patients with CRF, and documented direct influence of pro- and anti-inflammatory biomarkers on major outcome measures.
Keywords: chronic renal failure, hemodialysis, arterial stiffness, inflammation, follow-up
DOI: 10.1556/2060.2020.00028
Abstract: Aim: To investigate the ratio of cerebral tissue oxygenation index (cTOI) to peripheral muscle tissue oxygenation index (pTOI) measured by near-infrared spectroscopy (NIRS) in cardio-circulatory stable preterm neonates without signs of inflammation/infection on the first day after birth. Methods: Observational study analysing secondary outcome parameters of the ‘Avoiding Hypotension in Preterm Neonates (AHIP)’ trial (ClinicalTrials.gov identifier: NCT01910467). Preterm neonates, who had cTOI and pTOI measurements during 24 h after birth, were included. In each neonate the mean of the cTOI/ pTOI-ratio, cTOI, pTOI and routine monitoring parameters were calculated for each hour and for the 24-h measuring period. Courses of all measured parameters were analysed. Results: Eighty-seven stable preterm neonates (33.1 [32.1–34.1] weeks of gestation) were included. The mean value over the 24-h measuring period for the cTOI/pTOI-ratio was 0.96 ± 0.02, for cTOI 70.1 ± 1.4 and for pTOI 73.4 ± 0.9. Routine monitoring parameters were in the normal ranges over 24 h. The courses of the cTOI/pTOIratio and cTOI showed significantly lower values from hour 5 to 15 compared to the first hours after birth. Heart rate decreased significantly over time, whereas mean arterial blood pressure increased significantly. pTOI, arterial oxygen saturation and body temperature showed no significant change over time. Conclusion: We are the first to report on cTOI/pTOI-ratios for cardio-circulatory stable preterm neonates over a 24-h period after birth, showing significantly lower values from hour 5 to 15 compared to the first hours after birth.
Keywords: cerebral oxygenation, near-infrared spectroscopy, peripheral muscle oxygenation, preterm neonates, haemodynamic changes
DOI: 10.1556/2060.2020.00023
Abstract: Introduction: Atherosclerosis is an inflammatory disease causing a vast array of cardiovascular diseases. Adipophilin has been reported to be highly expressed in atherosclerotic lesions. This study investigated the possible existence of auto-reactive T cells against an HLA-A02-restricted adipophilin-derived peptide as well as peptides from Epstein-barr virus (EBV), Cytomegalovirus (CMV) and influenza (Flu) virus in patients with atherosclerosis. Methods: HLA-A02 expression on peripheral blood mononuclear cells (PBMCs) was examined by flow cytometry. PBMCs from HLA-A02 individuals were stimulated with adipophilin, CMV, EBV, and Flu peptides at a concentration of 10 mM. Interferon (IFN)-g production was evaluated in the culture supernatant using a commercial ELISA test. Results: The levels of IFN-g production against an HLA-A02-restricted adipophilin peptide and peptides from CMV, EBV, and Flu revealed no statistically significant differences between patients and healthy controls. However, we found a positive correlation between IFN-g production against adipophilin and Body mass index (BMI) of patients (R = 0.8, P = 0.003), whereas no significant correlation was found in healthy controls (R = - 0.267, P = 0.378). No correlation between BMI and IFN-g production against CMV, EBV, or Flu peptides was found. Discussion: Atherosclerotic patients with higher BMIs might have greater numbers of T cells against adipophilin that is highly expressed in atherosclerotic plaques. Therefore, autoimmune reactions may have a greater role in the development of atherosclerosis in individuals with higher BMI.
Keywords: atherosclerosis, adipophilin, HLA-A02, BMI
DOI: 10.1556/2060.2020.00029
Abstract: Although the use of aspirin has substantially reduced the risks of cardiovascular events and death, its potential mechanisms have not been fully elucidated. In a previous study, we found that aspirin triggers cellular autophagy. In the present study, we aimed to determine the protective effects of aspirin on human coronary artery endothelial cells (HCAECs) and explore its underlying mechanisms. HCAECs were treated with oxidized low-density lipoprotein (ox-LDL), angiotensin II (Ang-II), or high glucose (HG) with or without aspirin stimulation. The expression levels of endothelial nitric oxide (NO) synthase (eNOS), p-eNOS, LC3, p62, phosphor-nuclear factor kappa B (p-NF-kB), p-p38 mitogen-activated protein kinase (p-p38 MAPK), and Beclin-1 were detected via immunoblotting analysis. Concentrations of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) were measured via ELISA. NO levels were determined using the Griess reagent. Autophagic flux was tracked by tandem mRFP-GFP-tagged LC3. Results showed that aspirin increased eNOS level and reduced injury to the endothelial cells (ECs) caused by ox-LDL, Ang-II, and HG treatment in a dose-dependent manner. Aspirin also increased the LC3II/LC3I ratio, decreased p62 expression, and enhanced autophagic flux (autophagosome and autolysosome puncta) in the HCAECs. p-NF-kB and p-p38 mitogen-activated protein kinase inhibition, sVCAM-1 and sICAM-1 secretion, and eNOS activity promotion by aspirin treatment were found to be dependent on Beclin-1. These results suggested that aspirin can protect ECs from ox-LDL-, Ang-II-, and HG-induced injury by activating autophagy in a Beclin-1-dependent manner.
Keywords: aspirin, endothelial cells, autophagy, Beclin-1, protection
DOI: 10.1556/2060.2020.00018
Abstract: Sodium induced volume loading may alter pressor responses to physical stress, an early symptom of cardiovascular disease. Purpose: Study 1: Determine the time point where total blood volume and serum sodium were elevated following saline consumption. Study 2: Examine the BP response to isometric handgrip (HG) and the cold pressor test (CPT) following saline consumption. Methods: Study 1: Eight participants drank 423 mL of normal saline (sodium 154 mmol/L) and had blood draws every 30 min for 3 h. Study 2: Sixteen participants underwent two randomized data collection visits; a control and experimental visit 90 min following saline consumption. Participants underwent 2 min of isometric HG, post exercise ischemia (PEI), and CPT. Results: Study 1: Total blood volume (3.8 ± 3.0 Δ%) and serum sodium (3.5 ± 3.6 Δ%) were elevated (P < 0.05) by the 90 min time point. Study 2: There were no differences in mean arterial pressure (MAP) during HG (EXP: 17.4 ± 8.2 ΔmmHg; CON: 19.1 ± 6.0 ΔmmHg), PEI (EXP: 16.9 ± 11.7 ΔmmHg; CON: 16.9 ± 7.8 ΔmmHg), or the CPT (EXP: 20.3 ± 10.8 ΔmmHg; CON: 20.9 ± 11.7 ΔmmHg) between conditions (P > 0.05). MAP recovery from the CPT was slower following saline consumption (1 min recovery: EXP; 15.7 ± 7.9 ΔmmHg, CON; 12.3 ± 8.9 ΔmmHg, P < 0.05). Conclusion: Data showed no difference in cardiovascular responses during HG or the CPT between conditions. BP recovery was delayed by saline consumption following the CPT.
Keywords: exercise pressor reflex, sodium, salt, blood pressure, cold pressor test, handgrip
DOI: 10.1556/2060.2020.00027
Abstract: Aim: We investigated the effect of age on post-cardiac arrest treatment outcomes in an elderly population, based on a local database and a systemic review of the literature. Methods: Data were collected retrospectively from medical charts and reports. Sixty-one comatose patients, cooled to 32–34 8C for 24 h, were categorized into three groups: younger group (≤65 years), older group (66–75 years), and very old group (>75 years). Circumstances of cardiopulmonary resuscitation (CPR), patients’ characteristics, post-resuscitation treatment, hemodynamic monitoring, neurologic outcome and survival were compared across age groups. Kruskal-Wallis test, Chi-square test and binary logistic regression (BLR) were applied. In addition, a literature search of PubMed/Medline database was performed to provide a background. Results: Age was significantly associated with having a cardiac arrest on a monitor and a history of hypertension. No association was found between age and survival or neurologic outcome. Age did not affect hemodynamic parameter changes during target temperature management (TTM), except mean arterial pressure (MAP). Need of catecholamine administration was the highest among very old patients. During the literature review, seven papers were identified. Most studies had a retrospective design and investigated interventions and outcome, but lacked unified age categorization. All studies reported worse survival in the elderly, although old survivors showed a favorable neurologic outcome in most of the cases. Conclusion: There is no evidence to support the limitation of post-cardiac arrest therapy in the aging population. Furthermore, additional prospective studies are needed to investigate the characteristics and outcome of post-cardiac arrest therapy in this patient group.
Keywords: elderly, cardiopulmonary resuscitation, post-resuscitation therapy, target temperature management, hemodynamic monitoring
DOI: 10.1556/2060.2020.00017
Abstract: No previous studies have evaluated the potential combined effects of acute exercise and acute hypoxia exposure on memory function, which was the purpose of this study. Twenty-five participants (Mage 5 21.2 years) completed two laboratory visits in a counterbalanced order, involving 1) acute exercise (a 20-min bout of moderate-intensity exercise) and then 30 min of exposure to hypoxia (FIO2 5 0.12), and 2) exposure to hypoxia alone (FIO2 5 0.12) for 30 min. Following this, participants completed a cued-recall and memory interference task (AB/AC paradigm), assessing cued-recall memory (recall 1 and recall 2) and memory interference (proactive and retroactive interference). For cued-recall memory, we observed a significant main effect for condition, with Exercise þ Hypoxia condition having significantly greater cuedrecall performance than Hypoxia alone. Memory interference did not differ as a function of the experimental condition. This experiment demonstrates that engaging in an acute bout of exercise prior to acute hypoxia exposure had an additive effect in enhancing cued-recall memory performance.
Keywords: cognition, cognitive function, synaptic plasticity
DOI: 10.1556/2060.2020.00016
Abstract: Breast cancer is characterized by oncobiosis, the abnormal composition of the microbiome in neoplastic diseases. The biosynthetic capacity of the oncobiotic flora in breast cancer is suppressed, as suggested by metagenomic studies. The microbiome synthesizes a set of cytostatic and antimetastatic metabolites that are downregulated in breast cancer, including cadaverine, a microbiome metabolite with cytostatic properties. We set out to assess how the protein expression of constitutive lysine decarboxylase (LdcC), a key enzyme for cadaverine production, changes in the feces of human breast cancer patients (n 5 35). We found that the fecal expression of Escherichia coli LdcC is downregulated in lobular cases as compared to invasive carcinoma of no special type (NST) cases. Lobular breast carcinoma is characterized by low or absent expression of E-cadherin. Fecal E. coli LdcC protein expression is downregulated in E-cadherin negative breast cancer cases as compared to positive ones. Receiver operating characteristic (ROC) analysis of LdcC expression in lobular and NST cases revealed that fecal E. coli LdcC protein expression might have predictive values. These data suggest that the oncobiotic transformation of the microbiome indeed leads to the downregulation of the production of cytostatic and antimetastatic metabolites. In E-cadherin negative lobular carcinoma that has a higher potential for metastasis formation, the protein levels of enzymes producing antimetastatic metabolites are downregulated. This finding represents a new route that renders lobular cases permissive for metastasis formation. Furthermore, our findings underline the role of oncobiosis in regulating metastasis formation in breast cancer.
Keywords: breast cancer, microbiome, Escherichia coli, LdcC, cadaverine