Peter Kruzliak

Probiotics in prevention and treatment of obesity: a critical view.

The worldwide prevalence of obesity more than doubled between 1980 and 2014. The obesity pandemic is tightly linked to an increase in energy availability, sedentariness and greater control of ambient temperature that have paralleled the socioeconomic development of the past decades. The most frequent cause which leads to the obesity development is a dysbalance between energy intake and energy expenditure. The gut microbiota as an environmental factor which influence whole-body metabolism by affecting energy balance but also inflammation and gut barrier function, integrate peripheral and central food intake regulatory signals and thereby increase body weight. Probiotics have physiologic functions that contribute to the health of gut microbiota, can affect food intake and appetite, body weight and composition and metabolic functions through gastrointestinal pathways and modulation of the gut bacterial community.

Predictive role of circulating endothelial-derived microparticles in cardiovascular diseases

Endothelial-derived microparticles (EMPs) are a novel biological marker of endothelium injury and vasomotion disorders that are involved in pathogenesis of cardiovascular, metabolic, and inflammatory diseases. Circulating levels of EMPs are thought to reflect a balance between cell stimulation, proliferation, apoptosis, and cell death. Increased EMPs may be defined in several cardiovascular diseases, such as stable and unstable coronary artery disease, acute and chronic heart failure, hypertension, arrhythmias, thromboembolism, asymptomatic atherosclerosis as well as renal failure, metabolic disorders (including type two diabetes mellitus, abdominal obesity, metabolic syndrome, insulin resistance) and dyslipidemia. This review highlights the controversial opinions regarding impact of circulating EMPs in major cardiovascular and metabolic diseases and summarizes the perspective implementation of the EMPs in risk stratification models.

Therapeutic potential of nitric oxide donors in the prevention and treatment of angiogenesis-inhibitor-induced hypertension

Angiogenesis is critical to tumor growth as well as to metastases. This process is tightly regulated by pro- and anti-angiogenic growth factors and their receptors. Some of these factors are highly specific for the endothelium—e.g., vascular endothelial growth factor (VEGF). A variety of drugs that target VEGF or its receptors have been developed for the treatment of different tumor types and a number of new agents is expected to be introduced within the coming years. However, clinical experience has revealed that inhibition of VEGF induces several side effects including hypertension and renal and cardiac toxicity. Angiogenesis-inhibitor-induced hypertension represents “crux medicorum” as it is often pharmacoresistant to antihypertensive therapy. We consider two most important pathomechanisms in the development of hypertension induced by angiogenesis inhibitors. The first represents direct inhibition of NO production leading to reduced vasodilatation and the second consists in increased proliferation of vascular medial cells mediated by NO deficiency and is resulting in fixation of hypertension. Based on the results of experimental and clinical studies as well as on our clinical experience, we assume that NO donors could be successfully used not only for the treatment of developed angiogenesis-inhibitor-induced hypertension but also for preventive effects. We thoroughly documented three clinical cases of cancer patients with resistant hypertension who on receiving NO donor treatment achieved target blood pressure level and a good clinical status.

Unilateral absence of pulmonary artery: pathophysiology, symptoms, diagnosis and current treatment.

Unilateral absence of pulmonary artery (UAPA) is a rare malformation that can present as an isolated lesion or may be associated with other congenital heart defects. UAPA is often associated with other congenital cardiovascular anomalies, such as tetralogy of Fallot, atrial septal defect, coarctation of aorta, right aortic arch, truncus arteriosus and pulmonary atresia. Diagnosis of UAPA is very difficult and is based on taking a complete medical history, physical examination and imaging examinations. Clinical symptoms include exercise intolerance, haemoptysis and recurrent respiratory infections. Adult patients with UAPA are often asymptomatic. There is no consensus regarding the treatment for UAPA. The therapeutic approach should be based on symptoms of the patient, pulmonary artery anatomy and associated aortopulmonary collaterals. Treatment options for these patients include partial or total pneumonectomy, closure of selected collateral arteries not solely responsible for pulmonary blood flow or a primary versus staged pulmonary artery anastomosis. This review summarizes pathophysiology, symptomatology and current diagnosis and treatment of this disease.

Effects of serum bilirubin on atherosclerotic processes.

Abstract This review highlights the protective roles of bilirubin against the atherosclerotic process. Bilirubin belongs to the superfamily of tetrapyrrolic compounds formed during heme catabolism. Although for decades bilirubin was considered to be a harmful waste product, recent epidemiologic studies have shown that serum bilirubin levels have consistently been inversely associated with cardiovascular disease (CVD), as well as cardiovascular risk factors such as metabolic syndrome and diabetes. These clinical studies are supported by in vitro and in vivo experimental data and have demonstrated that bilirubin not only has an ability to scavenge overproduced reactive oxygen species and inhibit vascular smooth muscle cell proliferation but, additionally, has anti-inflammatory effects. In this review, we will discuss the inverse association of serum bilirubin and CVD and cardiovascular risk factors established in various clinical studies. We also review detailed experimental studies about the effect of bilirubin on atherosclerotic processes. In vitro, animal and human studies have proved that bilirubin inhibits oxidation of cholesterol which is an important step of atherosclerosis. Bilirubin attenuates chemotactic activity of monocytes and strongly inhibits adhesion of leukocytes to venule and production of pro-inflammatory cytokines. Bilirubin has inhibited serum-driven smooth muscle cell cycle progression at the G1 phase. Lastly, we will discuss briefly the influence of bilirubin on lipoprotein composition and endothelial dysfunction.

Nitric oxide and oxidative stress is associated with severity of diabetic retinopathy and retinal structural alterations

The aim of the study was to determine plasma nitric oxide (NO) and lipid peroxide (LPO) levels in diabetic retinopathy and its association with severity of disease.

Forced aggregation and defined factors allow highly uniform-sized embryoid bodies and functional cardiomyocytes from human embryonic and induced pluripotent stem cells.

In vitro human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) can differentiate into functional cardiomyocytes (CMs). Protocols for cardiac differentiation of hESCs and hiPSCs include formation of the three-dimensional cell aggregates called embryoid bodies (EBs). The traditional suspension method for EB formation from clumps of cells results in an EB population heterogeneous in size and shape. In this study we show that forced aggregation of a defined number of single cells on AggreWell plates gives a high number of homogeneous EBs that can be efficiently differentiated into functional CMs by application of defined growth factors in the media. For cardiac differentiation, we used three hESC lines and one hiPSC line. Our contracting EBs and the resulting CMs express cardiac markers, namely myosin heavy chain α and β, cardiac ryanodine receptor/calcium release channel, and cardiac troponin T, shown by real-time polymerase chain reaction and immunocytochemistry. Using Ca2+ imaging and atomic force microscopy, we demonstrate the functionality of RyR2 to release Ca2+ from the sarcoplasmic reticulum as well as reliability in contractile and beating properties of hESC-EBs and hiPSC-EBs upon the stimulation or inhibition of the β-adrenergic pathway.

Caffeine and cardiovascular diseases: critical review of current research

Abstract Caffeine is a most widely consumed physiological stimulant worldwide, which is consumed via natural sources, such as coffee and tea, and now marketed sources such as energy drinks and other dietary supplements. This wide use has led to concerns regarding the safety of caffeine and its proposed beneficial role in alertness, performance and energy expenditure and side effects in the cardiovascular system. The question remains “Which dose is safe?”, as the population does not appear to adhere to the strict guidelines listed on caffeine consumption. Studies in humans and animal models yield controversial results, which can be explained by population, type and dose of caffeine and low statistical power. This review will focus on comprehensive and critical review of the current literature and provide an avenue for further study.

Ex vivo immunosuppressive effects of mesenchymal stem cells on Crohn’s disease mucosal T cells are largely dependent on indoleamine 2,3-dioxygenase activity and cell-cell contact

IntroductionCrohn’s disease (CD) is a disabling chronic enteropathy sustained by a harmful T-cell response toward antigens of the gut microbiota in genetically susceptible subjects. Growing evidence highlights the safety and possible efficacy of mesenchymal stem cells (MSCs) as a new therapeutic tool for this condition. Therefore, we aimed to investigate the effects of bone marrow-derived MSCs on pathogenic T cells with a view to clinical application.MethodsT-cell lines from both inflamed and non-inflamed colonic mucosal specimens of CD patients and from healthy mucosa of control subjects were grown with the antigen muramyl-dipeptide in the absence or presence of donors’ MSCs. The MSC effects were evaluated in terms of T-cell viability, apoptotic rate, proliferative response, immunophenotype, and cytokine profile. The role of the indoleamine 2,3-dioxygenase (IDO) was established by adding a specific inhibitor, the 1-methyl-DL-tryptophan, and by using MSCs transfected with the small interfering RNA (siRNA) targeting IDO. The relevance of cell-cell contact was evaluated by applying transwell membranes.ResultsA significant reduction in both cell viability and proliferative response to muramyl-dipeptide, with simultaneous increase in the apoptotic rate, was found in T cells from both inflamed and non-inflamed CD mucosa when co-cultured with MSCs and was reverted by inhibiting IDO activity and expression. A reduction of the activated CD4+CD25+ subset and increase of the CD3+CD69+ population were also observed when T-cell lines from CD mucosa were co-cultured with MSCs. In parallel, an inhibitory effect was evident on the expression of the pro-inflammatory cytokines tumor necrosis factor-α, interferon-γ, interleukin-17A and -21, whereas that of the transforming growth factor-β and interleukin-6 were increased, and production of the tolerogenic molecule soluble HLA-G was high. These latter effects were almost completely eliminated by blocking the IDO, whose activity was upregulated in MSCs co-cultured with CD T cells. The use of a semipermeable membrane partially inhibited the MSC immunosuppressive effects. Finally, hardly any effects of MSCs were observed when T cells obtained from control subjects were used.ConclusionMSCs exert potent immunomodulant effects on antigen-specific T cells in CD through a complex paracrine and cell-cell contact-mediated action, which may be exploited for widespread therapeutic use.

Effect of Equal Daily Doses Achieved by Different Power Densities of Low-Level Laser Therapy at 635 nm on Open Skin Wound Healing in Normal and Diabetic Rats

Background and Objective. Despite the fact that the molecular mechanism of low-level laser therapy (LLLT) is not yet known, the exploitation of phototherapy in clinical medicine and surgery is of great interest. The present study investigates the effects of LLLT on open skin wound healing in normal and diabetic rats. Materials and Methods. Four round full-thickness skin wounds on dorsum were performed in male adult nondiabetic (n = 24) and diabetic (n = 24) Sprague–Dawley rats. AlGaInP (635 nm, wavelength; 5 J/cm2, daily dose) was used to deliver power densities of 1, 5, and 15 mW/cm2 three times daily until euthanasia. Results. PMNL infiltration was lower in the irradiated groups (15 mW/cm2). The synthesis and organisation of collagen fibres were consecutively enhanced in the 5 mW/cm2 and 15 mW/cm2 groups compared to the others in nondiabetic rats. In the diabetic group the only significant difference was recorded in the ratio PMNL/Ma at 15 mW/cm2. A significant difference in the number of newly formed capillaries in the irradiated group (5, 15 mW/cm2) was recorded on day six after injury compared to the control group. Conclusion. LLLT confers a protective effect against excessive inflammatory tissue response; it stimulates neovascularization and the early formation of collagen fibres.