Effects of Ibuprofen and Diclofenac Pre-Treatment on Viability and Apoptosis Processes in Human Dental Pulp Stem Cells.

Background and Objectives: Stem cell-based regeneration strategies have shown therapeutic efficacy in various fields of regenerative medicine. These include bone healing after bone augmentation, often complicated by pain, which is managed by using nonsteroidal anti-inflammatory drugs (NSAIDs). However, information is limited about how NSAIDs affect the therapeutic potential of stem cells. Materials and Methods: We investigated the effects of ibuprofen and diclofenac on the characteristics, morphology, and immunophenotype of human mesenchymal stromal cells isolated from the dental pulp (DPSCs) and cultured in vitro, as well as their effects on the expression of angiogenic growth factors (VEGFA and HGF) and selected genes in apoptosis signalling pathways (BAX, BAK, CASP3, CASP9, and BCL2). Results: Ibuprofen and diclofenac significantly reduced the viability of DPSCs, while the expression of mesenchymal stem cell surface markers was unaffected. Both ibuprofen and diclofenac treatment significantly upregulated the expression of HGF, while the expression of VEGFA remained unchanged. Ibuprofen significantly altered the expression of several apoptosis-related genes, including the upregulation of CASP9 and BCL2, with decreased CASP3 expression. BAK, CASP3, CASP9, and BCL2 expressions were significantly increased in the diclofenac-treated DPSCs, while no difference was demonstrated in BAX expression. Conclusions: Our results suggest that concomitant use of the NSAIDs ibuprofen or diclofenac with stem cell therapy may negatively impact cell viability and alter the expression of apoptosis-related genes, affecting the efficacy of stem cell therapy.

Effect of Atorvastatin on Angiogenesis-Related Genes VEGF-A, HGF and IGF-1 and the Modulation of PI3K/AKT/mTOR Transcripts in Bone-Marrow-Derived Mesenchymal Stem Cells.

Stem cell transplantation represents a unique therapeutic tool in tissue engineering and regenerative medicine. However, it was shown that the post-injection survival of stem cells is poor, warranting a more comprehensive understanding of activated regenerative pathways. Numerous studies indicate that statins improve the therapeutic efficacy of stem cells in regenerative medicine. In the present study, we investigated the effect of the most widely prescribed statin, atorvastatin, on the characteristics and properties of bone-marrow-derived mesenchymal stem cells (BM-MSCs) cultured in vitro. We found that atorvastatin did not decrease the viability of BM-MSCs, nor did it change the expression of MSC cell surface markers. Atorvastatin upregulated the mRNA expression levels of VEGF-A and HGF, whereas the mRNA expression level of IGF-1 was decreased. In addition, the PI3K/AKT signaling pathway was modulated by atorvastatin as indicated by the high mRNA expression levels of PI3K and AKT. Moreover, our data revealed the upregulation of mTOR mRNA levels; however, no change was observed in the BAX and BCL-2 transcripts. We propose that atorvastatin benefits BM-MSC treatment due to its ability to upregulate angiogenesis-related genes expression and transcripts of the PI3K/AKT/mTOR pathway.

Physical properties and biological effects of ceramic materials emitting infrared radiation for pain, muscular activity, and musculoskeletal conditions.

BACKGROUND: Up to 33% of the general population worldwide suffer musculoskeletal conditions, with low back pain being the single leading cause of disability globally. Multimodal therapeutic options are available to relieve the pain associated with muscular disorders, including physical, complementary, and pharmacological therapies. However, existing interventions are not disease modifying and have several limitations. METHOD: Literature review. RESULTS: In this context, the use of nonthermal infrared light delivered via patches, fabrics, and garments containing infrared-emitting bioceramic minerals have been investigated. Positive effects on muscular cells, muscular recovery, and reduced inflammation and pain have been reported both in preclinical and clinical studies. There are several hypotheses on how infrared may contribute to musculoskeletal pain relief, however, the full mechanism of action remains unclear. This article provides an overview of the physical characteristics of infrared radiation and its biological effects, focusing on those that could potentially explain the mechanism of action responsible for the relief of musculoskeletal pain. CONCLUSIONS: Based on the current evidence, the following pathways have been considered: upregulation of endothelial nitric oxide synthase, increase in nitric oxide bioavailability, anti-inflammatory effects, and reduction in oxidative stress.

Multivessel Coronary Disease and Severe Atherosclerotic Aorta: Real-World Experience.

Background and Objectives: Surgical revascularisation of patients with atherosclerosis of the ascending aorta remains a challenge. Different surgical strategies have been described in coronary surgical patients to offer alternative revascularisation strategies other than the conventional surgical revascularisation in patients unsuitable for it. The aim of this study is to compare the real-world outcomes between two groups of patients who underwent off-pump surgery (left internal mammary artery graft to the left anterior descending artery) or a hybrid with a percutaneous revascularisation procedure at a later stage. Materials and Methods: This is a single-centre retrospective observational study. Between the years 2010 and 2021, 91/6863 patients (1.33%) were diagnosed with severe atherosclerosis of the ascending aorta. All the patients were treated with off-pump revascularisation (91 patients), and the cardiologist would decide at a later stage whether the rest of the vessels would be treated with percutaneous revascularisation (25 patients). Results: There was no statistical difference in the various preoperative characteristics, except for coronary artery left main disease (30.30% vs. 64%; p = 0.0043). The two groups had no statistical differences in the perioperative characteristics and postoperative complications. The 1-, 5-, and 10-year mortality rates in the two groups were 6.1% vs. 0%, 59% vs. 80%, and 93.9% vs. 100%, respectively (off-pump vs. hybrid with percutaneous revascularisation procedure, p = 0.1958). Conclusions: Both strategies have high long-term comparable mortality. The off-pump surgery and the HCR procedure at a later stage may be solutions for these high-risk patients, but the target treatment should be complete HCR revascularisation during the index hospitalization.

Selective inhibitors of cyclooxygenase 2 - their past, present and future.

Pain is a serious subjective experience, which, although it has a protective nature, it physically and mentally exhausts the patient. The pharmacological field of development and research in the treatment and relief of pain has been dynamic and interesting ever since the isolation of salicylic acid. After discovering the molecular nature of cyclooxygenase and its inhibition, research focused on selective COX-2 inhibitors, but they were a big disappointment. Today, the possibility of contributing to safe and effective analgesic-antiphlogistic treatment for the patient with a combination of drugs is emerging again.

New trends in advanced parkinson disease stage therapy.

The aim of the study was to point out the contribution of new invasive therapeutic procedures in the treatment of advanced stages of Parkinson's disease (PD) in comparison with classical oral pharmacotherapy. Data originated from a group of 43 patients with PD, 39% (17) with classic treatment, 23% (10) with intestinal gel of methyl ester levodopa (Duodopa), 19% (8) of patients were using subcutaneous delivery of apomorphine (APO) and the same quantity of patients had undergone deep brain stimulation (DBS). Majority of patients had advanced stages of PD, stage 4, by standards of Hoehn and Yahr scale (Hoehn and Yahr, 1967). Research observed improvement in majority of patients with novel treatments. A positive effect was also noted in the reduced need for oral therapy, where there was a significant decrease in all new therapies. Benefits were observed in the amount of antiparkinsonic drugs taken per os, where we observed reduction in all new therapies. A positive effect of the new therapeutic approaches in reducing "off" periods in patients has also been noted. In the case of Duodopa and DBS, the "off" period was shortened up to 50% and in the apomorphine pump up to 40%. Patients also reported reduction of some symptoms like rigidity, tremor and bradykinesis while dyskinesis still remains suba challenge. On the basis of the obtained results, it can be concluded that new therapeutic procedures for PCh will make it possible to manage symptoms typical of advanced stages of the disease, which without these procedures would lead to disability, which is the main reason for their indication. However, in early stages, well responding patients or in slow progressing disease oral antiparkinsonics are remaining as golden standard of treatment. This is not just due to good response but also because these classic drug formulations are significantly less expensive. In Slovakia, novel treatments are accessible through healthcare insurance only after secondary revision by insurance company doctors.

Normalization strategy for selection of reference genes for RT-qPCR analysis in left ventricles of failing human hearts.

BACKGROUND: Quantitative RT-PCR is a valuable tool for assessing the gene expression in different human tissues, particularly due to its exceptional sensitivity, accuracy and reliability. However, the choice of adequate control for normalization is a crucial step, greatly affecting the results of all subsequent analyses. So far, only a few studies were focused on the selection of optimal reference genes in left ventricles of failing human hearts, leading to several disparities in experimental results focused on differential gene expression in this area. Therefore, the main objective of this study was to identify a set of suitable reference genes in normal and failing left ventricle tissues, which could increase the reliability of RT-qPCR-based studies in the future. METHODS: We analyzed the expression of 15 commonly used housekeeping genes (ACTB, B2M, GAPDH, GUSB, HMBS, HPRT1, IPO8, PGK1, POLR2A, PPIA, RPLP0, TBP, TFRC, UBC and YWHAZ) in left ventricles of normal and failed hearts with two-step approach. In the first step, we excluded genes which are variantly expressed using ANOVA-based statistical method. Afterwards, the remaining genes were analyzed using geNorm, NormFinder and BestKeeper algorithms, together with delta Cq method. Finally, the geometric mean of gene rankings across all methods was calculated. RESULTS: Our analysis identified IPO8 and POLR2A as the most stably expressed genes, whereas ACTB and B2M were found to be expressed variantly, suggesting a potential role of these genes in the pathophysiological processes in failing human hearts. DISCUSSION/CONCLUSION: Using our two-step approach, we identified and validated two reference genes expressed invariantly in left ventricles of both healthy and failing human hearts, as well as provided a guideline for the selection of reference genes in studies comparing gene expression in these types of tissues.

First report of nosocomial outbreak of vancomycin-resistant Enterococcus faecium infection among COVID-19 patients hospitalized in a non-intensive care unit ward in Slovakia.

BACKGROUND: Enterococcus species account for most of the human enterococcal HAI and multidrug-resistant infections and have become a major threat to modern public health. We examine the rise in the number of vancomycin resistant E. faecium blood stream and urinary tract infections in a COVID-19 department during an epidemiologic outbreak investigation to detect and eliminate nosocomial clusters of the bacteria. METHODS:  Strain identification was performed by classical isolation and biochemical and cultivation methods. Antibiotic testing results were interpreted according to European committee on antimicrobial susceptibility testing (EUCAST) guidelines. Six isolated samples underwent the whole genome sequencing (WGS) during the outbreak investigation. Isolate relatedness was determined using the core genome multi-locus sequence typing. RESULTS:  WGS revealed two genotypically distinct VRE clusters, one of which had genetically closely related patients and environmental isolates. The cluster was terminated by enhanced infection control strategies. CONCLUSIONS:  This study provides the first description of an outbreak caused by vanB-ST117 and vanA-ST17 E. faecium strains among COVID-19 patients in Slovakia. This study can help to raise the awareness about the need for strict adherence to infection control measures and the implementation of rational antimicrobial stewardship as a routine part of COVID-19 management (Tab. 3, Fig. 3, Ref. 27). Text in PDF www.elis.sk Keywords: vancomycin-resistant Enterococcus faecium, antibiotic resistant, COVID-19, SARS-CoV-2, bacterial outbreak, healthcare-associated infection.

Ibrutinib treatment of mantle cell lymphoma complicated by progressive multifocal leukoencephalopathy
.

OBJECTIVE: Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease of the central nervous system, caused by reactivation of John Cunningham polyomavirus, affecting mainly patients in an immunocompromised state. Recently, drug-associated PML is gaining attention as more cases of PML in connection with the use of various immunomodulatory drugs emerge. Over the last couple of years, sporadic reports have occurred about a possible association between PML and the use of a new immunomodulatory drug, ibrutinib (Imbruvica), primarily indicated for the treatment of various B-cell malignancies. CASE REPORT: Herein, we report a case of a 62-year-old female patient with bilateral mantle cell lymphoma of conjunctiva diagnosed at IVA clinical stage (according to the Ann Arbor staging of lymphomas) of the disease. As a first line of treatment, the patient was given 6 cycles of rituximab-based chemotherapy followed by a complete remission. Seven years later, the patient relapsed, at which point the treatment with ibrutinib was initiated. Three weeks after the initial dosage, the patient started to show signs of progressive neurological symptomatology and died 4 months thereafter due to bilateral bronchopneumonia. Due to unspecific MRI signs and negative PCR results, the diagnosis of PML was confirmed only postmortem. CONCLUSION: This case report demonstrates a possible severe adverse effect of the immunomodulatory drug ibrutinib and the importance of a multidisciplinary approach in its diagnosis. Since PML is a rare but highly fatal disease, it is of utmost importance to be aware of the possible connection with the use of this drug to prevent missed or delayed diagnosis, considering that timely therapeutic intervention is crucial for improved prognosis.

TRP Channels Expression Profile in Human End-Stage Heart Failure.

Objectives: Many studies indicate the involvement of transient receptor potential (TRP) channels in the development of heart hypertrophy. However, the data is often conflicted and has originated in animal models. Here, we provide systematic analysis of TRP channels expression in human failing myocardium. Methods and results: Left-ventricular tissue samples were isolated from explanted hearts of NYHA III-IV patients undergoing heart transplants (n = 43). Quantitative real-time PCR was performed to assess the mRNA levels of TRPC, TRPM and TRPV channels. Analysis of functional, clinical and biochemical data was used to confirm an end-stage heart failure diagnosis. Compared to myocardium samples from healthy donor hearts (n = 5), we detected a distinct increase in the expression of TRPC1, TRPC5, TRPM4 and TRPM7, and decreased expression of TRPC4 and TRPV2. These changes were not dependent on gender, clinical or biochemical parameters, nor functional parameters of the heart. We detected, however, a significant correlation of TRPC1 and MEF2c expression. Conclusions: The end-stage heart failure displays distinct expressional changes of TRP channels. Our findings provide a systematic description of TRP channel expression in human heart failure. The results highlight the complex interplay between TRP channels and the need for deeper analysis of early stages of hypertrophy and heart failure development.

Recently Discovered Interstitial Cell Population of Telocytes: Distinguishing Facts from Fiction Regarding Their Role in the Pathogenesis of Diverse Diseases Called "Telocytopathies".

In recent years, the interstitial cells telocytes, formerly known as interstitial Cajal-like cells, have been described in almost all organs of the human body. Although telocytes were previously thought to be localized predominantly in the organs of the digestive system, as of 2018 they have also been described in the lymphoid tissue, skin, respiratory system, urinary system, meninges and the organs of the male and female genital tracts. Since the time of eminent German pathologist Rudolf Virchow, we have known that many pathological processes originate directly from cellular changes. Even though telocytes are not widely accepted by all scientists as an individual and morphologically and functionally distinct cell population, several articles regarding telocytes have already been published in such prestigious journals as Nature and Annals of the New York Academy of Sciences. The telocyte diversity extends beyond their morphology and functions, as they have a potential role in the etiopathogenesis of different diseases. The most commonly described telocyte-associated diseases (which may be best termed "telocytopathies" in the future) are summarized in this critical review. It is difficult to imagine that a single cell population could be involved in the pathogenesis of such a wide spectrum of pathological conditions as extragastrointestinal stromal tumors ("telocytomas"), liver fibrosis, preeclampsia during pregnancy, tubal infertility, heart failure and psoriasis. In any case, future functional studies of telocytes in vivo will help to understand the mechanism by which telocytes contribute to tissue homeostasis in health and disease.

Positioning Europe for the EPITRANSCRIPTOMICS challenge.

The genetic alphabet consists of the four letters: C, A, G, and T in DNA and C,A,G, and U in RNA. Triplets of these four letters jointly encode 20 different amino acids out of which proteins of all organisms are built. This system is universal and is found in all kingdoms of life. However, bases in DNA and RNA can be chemically modified. In DNA, around 10 different modifications are known, and those have been studied intensively over the past 20 years. Scientific studies on DNA modifications and proteins that recognize them gave rise to the large field of epigenetic and epigenomic research. The outcome of this intense research field is the discovery that development, ageing, and stem-cell dependent regeneration but also several diseases including cancer are largely controlled by the epigenetic state of cells. Consequently, this research has already led to the first FDA approved drugs that exploit the gained knowledge to combat disease. In recent years, the ~150 modifications found in RNA have come to the focus of intense research. Here we provide a perspective on necessary and expected developments in the fast expanding area of RNA modifications, termed epitranscriptomics.

The prognostic value of high sensitive cardiac troponin I in patients receiving cardiac resynchronisation therapy.

BACKGROUND: Cardiac troponin I (cTnI) is a valuable prognostic biomarker in patients with chronic heart failure (CHF). However, the prognostic importance of cTnI in patients who received cardiac resynchronisation therapy (CRT) remains unknown. The aim of this prospective study was to determine the prognostic value of high-sensitive cTnI (hs-cTnI) in CHF patients receiving CRT. METHODS: We performed measurements of baseline hs-cTnI levels in CRT patients with ischaemic as well as nonischaemic aetiology of CHF, and we investigated their possible association with response to CRT and survival of patients. RESULTS: Ninety consecutive CRT patients (mean age 64 ± 9 years, 71 men) were included. According to the best cut-off value of hs-cTnI level to predict CRT response and all cause mortality, patients were divided into group 1 (hs-cTnI level ≥6.5 ng/l, n = 46) and group 2 (hs-cTnI level <6.5 ng/l, n = 44). During the follow-up period (1155 ± 406 days), 47% of patients were CRT responders (30% in group 1 and 64% in group 2, p = .002) and 31% of patients died from any cause (48% in group 1 and 14% in group 2, p = .001). Regression analysis showed that hs-cTnI level <6.5 ng/l was an independent predictor of CRT response (OR 3.49, p = .019) and that hs-cTnI level ≥6.5 ng/l was an independent predictor of all cause mortality (HR 3.01, p = .021). CONCLUSION: The hs-cTnI can be an useful biomarker with prognostic value in patients receiving CRT.

Analysis of necroptotic proteins in failing human hearts.

BACKGROUND: Cell loss and subsequent deterioration of contractile function are hallmarks of chronic heart failure (HF). While apoptosis has been investigated as a participant in the progression of HF, it is unlikely that it accounts for the total amount of non-functional tissue. In addition, there is evidence for the presence of necrotic cardiomyocytes in HF. Therefore, the objective of this study was to investigate the necroptotic proteins regulating necroptosis, a form of programmed necrosis, and thereby assess its potential role in human end-stage HF. METHODS: Left ventricular samples of healthy controls (C) and patients with end-stage HF due to myocardial infarction (CAD) or dilated cardiomyopathy (DCM) were studied. Immunoblotting for necroptotic and apoptotic markers was performed. Triton X-114 fractionated samples were analyzed to study differences in subcellular localization. RESULTS: Elevated expression of RIP1 (receptor-interacting protein), pSer227-RIP3 and its total levels were observed in HF groups compared to controls. On the other hand, caspase-8 expression, a proapoptotic protease negatively regulating necroptosis, was downregulated suggesting activation of necroptosis signaling. Total mixed-lineage kinase domain-like protein (MLKL) expression did not differ among the groups; however, active cytotoxic forms of MLKL were present in all HF samples while they were expressed at almost undetectable levels in controls. Interestingly, pThr357-MLKL unlike pSer358-MLKL, was higher in DCM than CAD. In HF, the subcellular localization of both RIP3 and pThr357-MLKL was consistent with activation of necroptosis signaling. Expression of main apoptotic markers has not indicated importance of apoptosis. CONCLUSIONS: This is the first evidence showing that human HF of CAD or DCM etiology is positive for markers of necroptosis which may be involved in the development of HF.

Distribution pattern of dorsal root ganglion neurons synthesizing nitric oxide synthase in different animal species.

The main aim of the present review is to provide at first a short survey of the basic anatomical description of sensory ganglion neurons in relation to cell size, conduction velocity, thickness of myelin sheath, and functional classification of their processes. In addition, we have focused on discussing current knowledge about the distribution pattern of neuronal nitric oxide synthase containing sensory neurons especially in the dorsal root ganglia in different animal species; hence, there is a large controversy in relation to interpretation of the results dealing with this interesting field of research.

Cardiac Fibrosis: The Beneficial Effects of Exercise in Cardiac Fibrosis.

Numerous scientific findings have concluded that individuals who are active tend to develop less cardiovascular disease than those who enjoy more sedentary lifestyles. Animal models have further demonstrated that the beneficial effects of training on the heart effects of training are related to the signaling pathways of myocardial hypertrophy and fibrosis. As such, fibroblasts represent a very important population of cells within the myocardium as they play a crucial role in both cardiac development and response to injury. Fibroblasts establish and maintain the biochemical, electrical and mechanical environment of the heart through their complex interactions with cardiomyocytes. Cardiac injury disrupts the balance between fibroblasts and cardiomyocytes and creates a state favouring inflammation and fibrosis. Although this adaptive response initially serves to increase wound healing, it may eventually lead to increased cardiac damage and cardiac failure if homeostasis is not restored. Myofibroblasts are mediators of both the adaptive and maladaptive components of this reaction. This review focuses on the beneficial effects of exercise in cardiac fibrosis as demonstrated in basic research studies. Attention will be given to the characterisation of the relationship between exercise and cardiac remodelling, including the cellular and molecular adaptations of the heart in response to exercise as well as benefits of exercise in preventing or reversing the pathological remodelling of the fibrotic heart. By furthering our understanding of the beneficial and deleterious roles of cardiac fibroblasts and myofibroblasts and how these roles are related to each other in cardiac development and in heart disease, we may be able to design interventions to prevent the progression of cardiac fibrosis.

The Non-cardiomyocyte Cells of the Heart. Their Possible Roles in Exercise-Induced Cardiac Regeneration and Remodeling.

The non-cardiomyocyte cellular microenvironment of the heart includes diverse types of cells of mesenchymal origin. During development, the majority of these cells derive from the epicardium, while a subset derives from the endothelium/endocardium and neural crest derived mesenchyme. This subset includes cardiac fibroblasts and telocytes, the latter of which are a controversial type of "connecting cell" that support resident cardiac progenitors in the postnatal heart. Smooth muscle cells, pericytes, and endothelial cells are also present, in addition to adipocytes, which accumulate as epicardial adipose connective tissue. Furthermore, the heart harbors many cells of hematopoietic origin, such as mast cells, macrophages, and other immune cell populations. Most of these control immune reactions and inflammation. All of the above-mentioned non-cardiomyocyte cells of the heart contribute to this organ's well-orchestrated physiology. These cells also contribute to regeneration as a result of injury or age, in addition to tissue remodeling triggered by chronic disease or increased physical activity (exercise-induced cardiac growth). These processes in the heart, the most important vital organ in the human body, are not only fascinating from a scientific standpoint, but they are also clinically important. It is well-known that regular exercise can help prevent many cardiovascular diseases. However, the precise mechanisms underpinning myocardial remodeling triggered by physical activity are still unknown. Surprisingly, exercise-induced adaptation mechanisms are often identical or very similar to tissue remodeling caused by pathological conditions, such as hypertension, cardiac hypertrophy, and cardiac fibrosis. This review provides a summary of our current knowledge regarding the cardiac cellular microenvironment, focusing on the clinical applications this information to the study of heart remodeling during regular physical exercise.

The functional morphology and role of cardiac telocytes in myocardium regeneration.

Key morphological discoveries in recent years have included the discovery of new cell populations inside the heart called cardiac telocytes. These newly described cells of the connective tissue have extremely long cytoplasmic processes through which they form functionally connected three-dimensional networks that connect cells of the immune system, nerve fibers, cardiac stem cells, and cardiac muscle cells. Based on their functions, telocytes are also referred to as "connecting cells" or "nurse cells" for cardiac progenitor stem cells. In this critical review, we provide a summary of the latest research on cardiac telocytes localized in all layers of the heart - from the historical background of their discovery, through ultrastructural, immunohistochemical, and functional characterizations, to the application of this knowledge to the fields of cardiology, stem cell research, and regenerative medicine.

Circulating MicroRNAs as Potential Biomarkers of Exercise Response.

Systematic physical activity increases physical fitness and exercise capacity that lead to the improvement of health status and athletic performance. Considerable effort is devoted to identifying new biomarkers capable of evaluating exercise performance capacity and progress in training, early detection of overtraining, and monitoring health-related adaptation changes. Recent advances in OMICS technologies have opened new opportunities in the detection of genetic, epigenetic and transcriptomic biomarkers. Very promising are mainly small non-coding microRNAs (miRNAs). miRNAs post-transcriptionally regulate gene expression by binding to mRNA and causing its degradation or inhibiting translation. A growing body of evidence suggests that miRNAs affect many processes and play a crucial role not only in cell differentiation, proliferation and apoptosis, but also affect extracellular matrix composition and maintaining processes of homeostasis. A number of studies have shown changes in distribution profiles of circulating miRNAs (c-miRNAs) associated with various diseases and disorders as well as in samples taken under physiological conditions such as pregnancy or physical exercise. This overview aims to summarize the current knowledge related to the response of blood c-miRNAs profiles to different modes of exercise and to highlight their potential application as a novel class of biomarkers of physical performance capacity and training adaptation.

Upregulation of SERCA2a following short-term ACE inhibition (by enalaprilat) alters contractile performance and arrhythmogenicity of healthy myocardium in rat.

Chronic angiotensin-converting enzyme inhibitor (ACEIs) treatment can suppress arrhythmogenesis. To examine whether the effect is more immediate and independent of suppression of pathological remodelling, we tested the antiarrhythmic effect of short-term ACE inhibition in healthy normotensive rats. Wistar rats were administered with enalaprilat (ENA, i.p., 5 mg/kg every 12 h) or vehicle (CON) for 2 weeks. Intraarterial blood pressure in situ was measured in A. carotis. Cellular shortening was measured in isolated, electrically paced cardiomyocytes. Standard 12-lead electrocardiography was performed, and hearts of anaesthetized open-chest rats were subjected to 6-min ischemia followed by 10-min reperfusion to examine susceptibility to ventricular arrhythmias. Expressions of calcium-regulating proteins (SERCA2a, cardiac sarco/endoplasmic reticulum Ca(2+)-ATPase; CSQ, calsequestrin; TRD, triadin; PLB, phospholamban; Thr(17)-PLB-phosphorylated PLB at threonine-17, FKBP12.6, FK506-binding protein, Cav1.2-voltage-dependent L-type calcium channel alpha 1C subunit) were measured by Western blot; mRNA levels of L-type calcium channel (Cacna1c), ryanodine receptor (Ryr2) and potassium channels Kcnh2 and Kcnq1 were measured by qRT-PCR. ENA decreased intraarterial systolic as well as diastolic blood pressure (by 20%, and by 31%, respectively, for both P < 0.05) but enhanced shortening of cardiomyocytes at basal conditions (by 34%, P < 0.05) and under beta-adrenergic stimulation (by 73%, P < 0.05). Enalaprilat shortened QTc interval duration (CON 78 ± 1 ms vs. ENA 72 ± 2 ms; P < 0.05) and significantly decreased the total duration of ventricular fibrillations (VF) and the number of VF episodes (P < 0.05). Reduction in arrhythmogenesis was associated with a pronounced upregulation of SERCA2a (CON 100 ± 20 vs. ENA 304 ± 13; P < 0.05) and complete absence of basal Ca(2+)/calmodulin-dependent phosphorylation of PLB at Thr(17). Short-term ACEI treatment can provide protection against I/R injury-induced ventricular arrhythmias in healthy myocardium, and this effect is associated with increased SERCA2a expression.