The pathological potential of glial cells was recognized already by Rudolf Virchow, Santiago Ramon y Cajal and Pio Del Rio-Ortega. Many functions and roles performed by astroglia in the healthy brain determine their involvement in brain diseases; as indeed any kind of brain in sult does affect astrocytes, and their performance in pathological conditions, to a very large extent, determines the survival of the brain parenchyma, the degree of damage and neurological defect. Astrocytes being in general responsible for overall brain homeostasis are involved in virtually every form of brain pathology. Here we provide an overview of recent developments in identifying the role and mechanisms of the pathological potential of astroglia., A. Chvátal, M. Anděrová, H. Neprašová, I. Prajerová, L. Benešová, O. Butenko, A. Verkhratsky., and Obsahuje bibliografii a bibliografické odkazy
Nonalcoholic steatohepatitis (NASH) is a current health issue since the disease often leads to hepatocellular carcinoma; however, the pathogenesis of the disease has still not been fully elucidated. In this study, we investigated the pathophysiological changes observed in hepatic lesions in STAM mice, a novel NASH model. STAM mice, high fat-diet (HFD) fed mice, and streptozotocin (STZ) treated mice were prepared, and changes over time, such as biological parameters, mRNA expression, and histopathological findings, were evaluated once animal reached 5, 7, and 10 weeks of age. STZ mice presented with hyperglycemia and an increase in oxidative stress in immunohistochemical analyses of Hexanoyl-lysine: HEL from 5 weeks, with fibrosis in the liver also being observed from 5 weeks. HFD mice presented with hyperinsulinemia from 7 weeks and the slight hepatosteatosis was observed at 5 weeks, with changes significantly increasing until 10 weeks. STAM mice at 10 weeks showed significant hepatic changes, including hepatosteatosis, hypertrophic hepatocytes, and fibrosis, indicating pathological changes associated with NASH. These results suggested that the increase in oxidative stress with hyperglycemia triggered hepatic lesions in STAM mice, and insulin resistance promoted lesion formation with hepatic lipid accumulation. STAM mice may be a useful model for elucidating the pathogenesis of NASH with diabetes.
Diabetic nephropathy, included in diabetic kidney disease (DKD), is the primary disease leading to end-stage renal disease (ESRD) or dialysis treatment, accounting for more than 40 % of all patients with ESRD or receiving dialysis. Developing new therapeutics to prevent the transition to ESRD or dialysis treatment requires an understanding of the pathophysiology of DKD and an appropriate animal model for drug efficacy studies. In this study, we investigated the pathophysiology of diabetic kidney disease with type 2 diabetes in uninephrectomized db/db mice. In addition, the nephrectomized db/db mice from 10 weeks to 42 weeks were used to assess the efficacy of longterm administration of the angiotensin-II–receptor antagonist losartan. The blood and urinary biochemical parameters and the blood pressure which is a main pharmacological endpoint of the losartan therapy, were periodically measured. And at the end, histopathological analysis was performed. Uninephrectomized db/db mice clearly developed obesity and hyperglycemia from young age. Furthermore, they showed renal pathophysiological changes, such as increased urinary albumin-creatinine ratio (UACR) (the peak value 3104±986 in 40-week-old mice), glomerular hypertrophy and increased fibrotic areas in the tubulointerstitial tubules. The blood pressure in the losartan group was significantly low compared to the normotensive Vehicle group. However, as expected, Losartan suppressed the increase in UACR (829±500) indicating the medication was sufficient, but the histopathological abnormalities including tubular interstitial fibrosis did not improve. These results suggest that the uninephrectomized db/db mice are useful as an animal model of the severe DKD indicated by the comparison of the efficacy of losartan in this model with the efficacy of losartan in clinical practice.
a1_The modern concept of causality of diseases emphasizes the study of natural defense functions of the organism and possibilities of influencing them, which will lead to effective prevention of these diseases. A great deal of information has been obtained on the system growth hormone (GH)/insulin-like growth factor (IGF)-I, which is of quite fundamental importance for the integrity of the organism. A dysbalance of the system may be the cause of diseases of the neonatal period, as well as diseases associated with aging. In old age, the synthesis of the crucial peptide system, IGF-I, declines as well as the sensitivity of tissues to this hormone. At the same time the changes in the expression of IGF-binding proteins (IGFBP) occur. Systemic growth factors are present in measurable concentrations in the circulation, they are, however, taken up or synthesized by some tissues, where they act as local cellular regulators. IGF-I is produced by many tissues, including bones under the control of estrogens, growth hormone and the parathyroid hormone. A decline of bone IGF-I in the cortical portion of bones is one of the many mechanisms leading to the development of involutional osteoporosis. Correlation studies, which have provided evidence of a relationship between the IGF system and the building of peak bone mass and its subsequent loss contributed to the understanding of the pathogenesis of this disease. It may be foreseen that the results of intervention studies focused on the effects of the recombinant IGF-I will also influence therapeutic and preventive approaches. Modern antiresorption pharmacotherapy stabilizes or enhances bone density and reduces the risk of fractures. The addition of effective anabolics might increase the effectiveness of treatment by shifting the remodeling equilibrium in favor of formative processes., a2_Because both recombinant GH and IGF-I have certain therapeutic limitations, it is considered to utilize substances which either stimulate endogenous IGF-I production directly in the bone or modulate synthesis and distribution of binding proteins for the peptide. Further new findings related to physiology and pathophysiology of this peptide will contribute to designing new strategies in the prevention of osteoporosis and other serious diseases of old age, such as diabetes, neoplasias or cardiovascular diseases., I. Žofková., and Obsahuje bibliografii
Spontaneously Diabetic Torii (SDT) fatty rats, a new obese diabetic model, reportedly presented with features of non-alcoholic steatohepatitis (NASH) after 32 weeks of age. We tried to accelerate the onset of NASH in SDT fatty rats using dietary cholesterol loading and noticed changes in the blood choline level which is expected to be a NASH biomarker. Body weight and biochemical parameters were measured from 8 to 24 weeks of age. At 16, 20, 24 weeks, pathophysiological analysis of the livers were performed. Hepatic lipids, lipid peroxides, and the expression of mRNA related to triglyceride (TG) synthesis, inflammation, and fibrosis were evaluated at 24 weeks. Hepatic fibrosis was observed in SDT fatty rats fed cholesterol-enriched diets (SDT fatty-Cho) from 16 weeks. Furthermore, hepatic lipids and lipid peroxide were significantly higher in SDT fatty-Cho than SDT fatty rats fed normal diets at 24 weeks. Hepatic mRNA expression related to TG secretion decreased in SDT fatty-Cho, and the mRNA expression related to inflammation and fibrosis increased in SDT fatty-Cho at 24 weeks. Furthermore, SDT fatty-Cho presented with increased plasma choline, similar to human NASH. There were no significant changes in the effects of feeding a cholesterol-enriched diet in Sprague-Dawley rats. SDT fatty-Cho has the potential to become a valuable animal model for NASH associated with type 2 diabetes and obesity., Y. Toriniwa, M. Muramatsu, Y. Ishii, E. Riya, K. Miyajima, S. Ohshida, K. Kitatani, S. Takekoshi, T. Matsui, S. Kume, T. Yamada, T. Ohta., and Obsahuje bibliografii
Solid organ transplantation is an established treatment modality in patients with end-stage organ damage in cases where other therapeutic options fail. The long-term outcomes of solid organ transplant recipients have improved considerably since the introduction of the first calcineurin inhibitor (CNI) - cyclosporine. In 1984, the potent immunosuppressive properties of another CNI, tacrolimus, were discovered. The immunosuppressive effects of CNIs result from the inhibition of interleukin-2 synthesis and reduced proliferation of T cells due to calcineurin blockade. The considerable side effects that are associated with CNIs therapy include arterial hypertension and nephrotoxicity. The focus of this article was to review the available literature on the pathophysiological mechanisms of CNIs that induce chronic nephrotoxicity and arterial hypertension. CNIs lead to activation of the major vasoconstriction systems, such as the reninangiotensin and endothelin systems, and increase sympathetic nerve activity. On the other hand, CNIs are known to inhibit NO synthesis and NO-mediated vasodilation and to increase free radical formation. Altogether, these processes cause endothelial dysfunction and contribute to the impairment of organ function. A better insight into the mechanisms underlying CNI nephrotoxicity could assist in developing more targeted therapies of arterial hypertension or preventing CNI nephrotoxicity in organ transplant recipients, including heart transplantation., L. Hošková, I. Málek, L. Kopkan, J. Kautzner., and Obsahuje bibliografii
Hypertrophy of the left heart ventricle as a consequence of a haemodynamic overload is a process of ambiguous biological value. Although hypertrophy allows to increase the performance of the ventricle without substantial elevation in wall tension, it represents a risk factor of cardiac morbidity and mortality. The regression of hypertrophy seems to be a rational outcome of this ambivalent situation. Mot every reversal of hypertrophied muscle mass, however, can be unambiguously considered therapeutic success. The biological value of hypertrophy regression depends on the type of hypertrophy, on the level of deterioration of the heart by a long- lasting haemodynamic overload, as well as on the way in which the reversal of hypertrophy is achieved. Even in the case when functional characteristics are preserved or even improved compared to the hypertrophied heart, hypertrophy regression need not automatically mean a decrease of the cardiovascular risk induced by ventricular hypertrophy. Regression of hypertrophy may be even disadvantageous in those situations when reduction of hypertrophy and reduction of the haemodynamic overload proceed in a disproportional manner. Spontaneously developing regression of the hypertrophied left ventricle as demonstrated on the model of aortal insufficiency, is an explicitly pathological state, resulting in heart failure. Regression of myocardial hypertrophy should not be considered the primary therapeutic aim but rather a part of the management of haemodynamic overload of the heart. The main aim is to achieve optimal perfusion of the periphery, yet at the same time to provide such conditions which would prevent the working load of the heart to become a limiting factor of survival.
Extreme or unaccustomed eccentric exercise can cause exerciseinduced muscle damage, characterized by structural changes involving sarcomere, cytoskeletal, and membrane damage, with an increased permeability of sarcolemma for proteins. From a functional point of view, disrupted force transmission, altered calcium homeostasis, disruption of excitation-contraction coupling, as well as metabolic changes bring about loss of strength. Importantly, the trauma also invokes an inflammatory response and clinically presents itself by swelling, decreased range of motion, increased passive tension, soreness, and a transient decrease in insulin sensitivity. While being damaging and influencing heavily the ability to perform repeated bouts of exercise, changes produced by exercise-induced muscle damage seem to play a crucial role in myofibrillar adaptation. Additionally, eccentric exercise yields greater hypertrophy than isometric or concentric contractions and requires less in terms of metabolic energy and cardiovascular stress, making it especially suitable for the elderly and people with chronic diseases. This review focuses on our current knowledge of the mechanisms underlying exerciseinduced muscle damage, their dependence on genetic background, as well as their consequences at the structural, functional, metabolic, and clinical level. A comprehensive understanding of these is a prerequisite for proper inclusion of eccentric training in health promotion, rehabilitation, and performance enhancement., Andraž Stožer, Peter Vodopivc, Lidija Križančić Bombek., and Obsahuje bibliografii
Hypoxic-ischemic encephalopathy (HIE) is one of the leading pediatric neurological conditions causing long-term disabilities and socio-economical burdens. Nearly 20-50 % of asphyxiated newborns with HIE die within the newborn period and another third will develop severe health consequences and permanent handicaps. HIE is the result of severe systemic oxygen deprivation and reduced cerebral blood flow, commonly occurring in full-term infants. Hypoxic-ischemic changes trigger several molecular and cellular processes leading to cell death and
inflammation. Generated reactive oxygen species attack surrounding cellular components resulting in functional deficits and mitochondrial dysfunction. The aim of the present paper is to review present knowledge about the pathophysiology of perinatal hypoxic-ischemic encephalopathy, especially with respect to novel treatment strategies and biomarkers that might enhance early detection of this disorder and thus improve the general outcome of patients.