BACKGROUND: The pathophysiology of sepsis-induced acute kidney injury remains elusive. Although mitochondrial dysfunction is often perceived as the main culprit, data from preclinical models yielded conflicting results so far. The aim of this study was to assess the immune-metabolic background of sepsis-associated renal dysfunction using sequential biopsy approach with mitochondria function evaluation in a large clinically relevant porcine models mimicking two different paces and severity of sepsis and couple this approach with traditional parameters of renal physiology. METHODS: In this randomized, open-label study, 15 anaesthetized, mechanically ventilated and instrumented (renal artery flow probe and renal vein catheter) pigs were randomized in two disease severity groups-low severity (LS) sepsis (0.5 g/kg of autologous faeces intraperitoneally) and high severity (HS) sepsis (1 g/kg of autologous faeces intraperitoneally). Sequential cortical biopsies of the left kidney were performed and a pyramid-shaped kidney specimen with cortex, medulla and renal papilla was resected and processed at the end of the experiment. Oxygraphic data and western blot analysis of proteins involved in mitochondrial biogenesis and degradation were obtained. RESULTS: In contrast to increased mitochondrial activity observed in LS sepsis, a significant decrease in the oxidative phosphorylation capacity together with an increase in the respiratory system uncoupling was observed during the first 24 h after sepsis induction in the HS group. Those changes preceded alterations of renal haemodynamics. Furthermore, serum creatinine rose significantly during the first 24 h, indicating that renal dysfunction is not primarily driven by haemodynamic changes. Compared to cortex, renal medulla had significantly lower oxidative phosphorylation capacity and electron-transport system activity. PGC-1-alfa, a marker of mitochondrial biogenesis, was significantly decreased in HS group. CONCLUSIONS: In this experimental model, unique sequential tissue data show that the nature and dynamics of renal mitochondrial responses to sepsis are profoundly determined by the severity of infectious challenge and resulting magnitude of inflammatory insult. High disease severity is associated with early and stepwise progression of mitochondria dysfunction and acute kidney injury, both occurring independently from later renal macro-haemodynamic alterations. Our data may help explain the conflicting results of preclinical studies and suggest that sepsis encompasses a very broad spectrum of sepsis-induced acute kidney injury endotypes.
- Publikační typ
- časopisecké články MeSH
Alzheimerova choroba (AD) je nejčastější příčinou demence a významně se podílí na celkové morbiditě a mortalitě v populaci, zejména u seniorů. AD rozdělujeme na geneticky podmíněnou a sporadickou, které se liší etiopatogenezí, četností výskytu i průběhem. Sporadická forma AD představuje 99 % případů onemocnění. Její etiologie je komplexní a do velké míry zůstává neobjasněna; pravděpodobně se jedná o souhru mnoha endogenních a exogenních faktorů. V práci je podán základní přehled hypotéz vysvětlujících vznik a progresi AD s důrazem na nejrozšířenější amyloidovou hypotézu, která za klíčový faktor považuje nepřiměřenou tvorbu nebo nedostatečné odstraňování toxických forem amyloidových peptidů z amyloidového prekurzorového proteinu. Další teorie vzniku AD se přiklánějí k primární- mu působení jiných činitelů, např. tau proteinu, nepřiměřeného působení některých mediátorů, metabolických, neurovaskulárních, zánětlivých, infekčních a jiných faktorů. Práce také shrnuje některé kontroverzní závěry o patofyziologii choroby, které patrně pramení z obecné aplikace poznatků získaných výzkumem rozdílných forem choroby a přímé translace výsledků výzkumu na experimentálních modelech AD na lidské onemocnění. Navzdory obrovskému pokroku ve výzkumu AD nebyla dosud nalezena kauzální léčba.
Alzheimer's disease (AD) is the most common cause of dementia and contributes significantly to overall morbidity and mortality in the population. Despite the global and social importance of AD and dementia, despite extensive research, the etiopathogenetic mechanisms associated with AD have not yet been fully elucidated. The disease can be divided into early onset or familial AD and sporadic or late onset AD, which differ in etiopathogenesis, prevalence, course, and genetic predisposition. The sporadic form of AD represents 99% of cases of the disease. Its etiology is complex and largely unclear; it probably results from an interplay of many endogenous and exogenous factors. The present article provides a basic overview of hypotheses explaining the origin and progress of AD with emphasis on the most common amyloid hypothesis regarding excessive synthesis or insufficient clearance of toxic forms of amyloid peptides as the key factor of AD pathophysiology. Other theories tend to explain AD development by the primary impact of other factors, such as tau protein, the inappropriate effects of some neurotransmitters, metabolic, neurovascular, inflammatory, infectious, and other factors. The article also summarizes some controversial conclusions on the pathophysiology of the disease, which probably stem from the general application of knowledge gained in the research on different forms of the disease and direct translation of research results on experimental models of AD to human disease. Despite enormous advances in AD research, causal treatment of this devastating disease has not yet been found.
- Klíčová slova
- hypotézy vzniku nemoci, amyloidová hypotéza, mitochondriální hypotéza,
- MeSH
- Alzheimerova nemoc * dějiny etiologie patofyziologie MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Kuncová J. Intravezikální, radiofrekvencí indukovaná chemohypertermie v léčbě svalovinu neinfiltrujících nádorů močového měchýře. Intravezikální, radiofrekvencí indukovaná chemohypertermie Synergo® RITE patří mezi metody tzv. přístrojově asistované instilace vyvinuté ke zvýšení efektivity intravezikání chemoterapie v léčbě svalovinu neinfiltrujících nádorů močového měchýře. Léčba touto metodou je v současné době v České republice schválená jako standardní v přesně definovaných indikacích. V přehledovém článku jsou zmíněny mechanismy účinku termoterapie a radiofrekvenčního záření na nádorové tkáně. V textu jsou uvedeny základní informace o Synergo® RITE systému, o indikacích a protokolech léčby a nežádoucí účincích terapie a uvedena jsou i data z klinických studií.
Kuncová J. Intravesical, radiofrequency-induced chemohyperthermia in the treatment of non-muscle invasive bladder cancer. Intravesical, radiofrequency-induced chemohyperthermia Synergo® RITE is one of the so-called device-assisted instillation methods developed to increase the effectiveness of intravesical chemotherapy in the treatment of non-muscle invasive bladder tumors. Treatment with this method is currently approved as standard in precisely defined indications in the Czech Republic. The mechanisms of the effect of thermotherapy and radiofrequency treatment on tumor tissues are discussed in this review article. The text provides basic information on the Synergo® RITE system, treatment indications, protocols and side effects of therapy, and also data from clinical trials.
- Klíčová slova
- radiofrekvencí indukovaná chemohypertermie,
- MeSH
- indukovaná hypertermie * metody MeSH
- lidé MeSH
- nádory močového měchýře * terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Five-sixths nephrectomy is a widely used experimental model of chronic kidney disease (CKD) that is associated with severe mitochondrial dysfunction of the remnant tissue. In this study, we assessed the effect of CKD on mitochondrial respiration separately in the rat kidney cortex and medulla 10 weeks after induction of CKD by subtotal 5/6 nephrectomy (SNX). Mitochondrial oxygen consumption was evaluated on mechanically permeabilized samples of kidney cortex and medulla using high-resolution respirometry and expressed per mg of tissue wet weight or IU citrate synthase (CS) activity. Mitochondrial respiration in the renal cortex of SNX rats was significantly reduced in all measured respiratory states if expressed per unit wet weight and remained lower if recalculated per IU citrate synthase activity, i.e. per mitochondrial mass. In contrast, the profound decrease in the activity of CS in SNX medulla resulted in significantly elevated respiratory states expressing the OXPHOS capacity when Complexes I and II or II only are provided with electrons, LEAK respiration after oligomycin injection, and Complex IV-linked oxygen consumption per unit CS activity suggesting compensatory hypermetabolic state in remaining functional mitochondria that is not sufficient to fully compensate for respiratory deficit expressed per tissue mass. The results document that CKD induced by 5/6 nephrectomy in the rat is likely to cause not only mitochondrial respiratory dysfunction (in the kidney cortex), but also adaptive changes in the medulla that tend to at least partially compensate for mitochondria loss.
- MeSH
- chronická renální insuficience * MeSH
- citrátsynthasa MeSH
- krysa rodu rattus MeSH
- kůra ledviny MeSH
- ledviny * metabolismus MeSH
- mitochondrie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Mitochondria are considered central regulator of the aging process; however, majority of studies dealing with the impact of age on mitochondrial oxygen consumption focused on skeletal muscle concluding (although not uniformly) a general declining trend with advancing age. In addition, gender related differences in mitochondrial respiration have not been satisfactorily described yet. The aim of the present study was to evaluate mitochondrial oxygen consumption in various organs of aging male and female Fischer 344 rats at the ages of 6, 12 and 24 months. Mitochondrial respiration of homogenized (skeletal muscle, left and right heart ventricle, hippocampus, cerebellum, kidney cortex), gently mechanically permeabilized (liver) tissue or intact cells (platelets) was determined using high-resolution respirometry (oxygraphs O2k, Oroboros, Austria). The pattern of age-related changes differed in each tissue: in the skeletal muscle and kidney cortex of both sexes and in female heart, parameters of mitochondrial respiration significantly declined with age. Resting respiration of intact platelets displayed an increasing trend and it did not correlate with skeletal muscle respiratory states. In the heart of male rats and brain tissues of both sexes, respiratory states remained relatively stable over analyzed age categories with few exceptions of lower mitochondrial oxygen consumption at the age of 24 months. In the liver, OXPHOS capacity was higher in females than in males with either no difference between the ages of 6 and 24 months or even significant increase at the age of 24 months in the male rats. In conclusion, the results of our study indicate that the concept of general pattern of age-dependent decline in mitochondrial oxygen consumption across different organs and tissues could be misleading. Also, the statement of higher mitochondrial respiration in females seems to be conflicting, since the gender-related differences may vary with the tissue studied, combination of substrates used and might be better detectable at younger ages than in old animals.
- MeSH
- anestezie MeSH
- buněčné dýchání MeSH
- dýchání MeSH
- kosterní svaly metabolismus MeSH
- krysa rodu rattus MeSH
- mitochondrie * MeSH
- spotřeba kyslíku fyziologie MeSH
- stárnutí MeSH
- svalové mitochondrie * metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Diabetic foot ulcer (DFU) is a serious complication of diabetes and hyperbaric oxygen therapy (HBOT) is also considered in comprehensive treatment. The evidence supporting the use of HBOT in DFU treatment is controversial. The aim of this work was to introduce a DFU model in ZDF rat by creating a wound on the back of an animal and to investigate the effect of HBOT on the defect by macroscopic evaluation, quantitative histological evaluation of collagen (types I and III), evaluation of angiogenesis and determination of interleukin 6 (IL6) levels in the plasma. The study included 10 rats in the control group (CONT) and 10 in the HBOT group, who underwent HBOT in standard clinical regimen. Histological evaluation was performed on the 18th day after induction of defect. The results show that HBOT did not affect the macroscopic size of the defect nor IL6 plasma levels. A volume fraction of type I collagen was slightly increased by HBOT without reaching statistical significance (1.35+/-0.49 and 1.94+/-0.67 %, CONT and HBOT, respectively). In contrast, the collagen type III volume fraction was ~120 % higher in HBOT wounds (1.41+/-0.81 %) than in CONT ones (0.63+/-0.37 %; p=0.046). In addition, the ratio of the volume fraction of both collagens in the wound ((I+III)w) to the volume fraction of both collagens in the adjacent healthy skin ((I+III)h) was ~65 % higher in rats subjected to HBOT (8.9+/-3.07 vs. 5.38+/-1.86 %, HBOT and CONT, respectively; p=0.028). Vessels density (number per 1 mm2) was found to be higher in CONT vs. HBOT (206.5+/-41.8 and 124+/-28.2, respectively, p<0.001). Our study suggests that HBOT promotes collagen III formation and decreases the number of newly formed vessels at the early phases of healing.
The contribution of environmental pollutants to the obesity pandemic is still not yet fully recognized. Elucidating possible cellular and molecular mechanisms of their effects is of high importance. Our study aimed to evaluate the effect of chronic, 21-day-long, 2,2-bis (4-chlorophenyl)-1,1-dichlorethylenedichlorodiphenyldichloroethylene (p,p'-DDE) exposure of human adipose-derived mesenchymal stem cells committed to adipogenesis on mitochondrial oxygen consumption on days 4, 10, and 21. In addition, the mitochondrial membrane potential (MMP), the quality of the mitochondrial network, and lipid accumulation in maturing cells were evaluated. Compared to control differentiating adipocytes, exposure to p,p'-DDE at 1 μM concentration significantly increased basal (routine) mitochondrial respiration, ATP-linked oxygen consumption and MMP of intact cells on day 21 of adipogenesis. In contrast, higher pollutant concentration seemed to slow down the gradual increase in ATP-linked oxygen consumption typical for normal adipogenesis. Organochlorine p,p'-DDE did not alter citrate synthase activity. In conclusion, in vitro 1 μM p,p'-DDE corresponding to human exposure is able to increase the mitochondrial respiration per individual mitochondrion at the end of adipocyte maturation. Our data reveal that long-lasting exposure to p,p'-DDE could interfere with the metabolic programming of mature adipocytes.
- MeSH
- adipogeneze účinky léků MeSH
- buněčná diferenciace účinky léků MeSH
- dichlordifenyldichlorethylen toxicita MeSH
- kultivované buňky MeSH
- látky znečišťující životní prostředí toxicita MeSH
- lidé MeSH
- membránový potenciál mitochondrií MeSH
- mezenchymální kmenové buňky cytologie účinky léků MeSH
- mitochondrie účinky léků MeSH
- obezita metabolismus MeSH
- tukové buňky cytologie účinky léků MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Metabolic syndrome is associated with hypercholesterolemia, cardiac remodeling, and increased susceptibility to ventricular arrhythmias. Effects of diet-induced hypercholesterolemia on susceptibility to torsades de pointes arrhythmias (TdP) together with potential indicators of arrhythmic risk were investigated in three experimental groups of Carlsson's rabbit model: (1) young rabbits (YC, young control, age 12-16 weeks), older rabbits (AC, adult control, age 20-24 weeks), and older age-matched cholesterol-fed rabbits (CH, cholesterol, age 20-24 weeks). TdP was induced by α-adrenergic stimulation by methoxamine and IKr block in 83% of YC rabbits, 18% of AC rabbits, and 21% of CH rabbits. High incidence of TdP was associated with high incidence of single (SEB) and multiple ectopic beats (MEB), but the QTc prolongation and short-term variability (STV) were similar in all three groups. In TdP-susceptible rabbits, STV was significantly higher compared with arrhythmia-free rabbits but not with rabbits with other than TdP arrhythmias (SEB, MEB). Amplitude-aware permutation entropy analysis of baseline ECG could identify arrhythmia-resistant animals with high sensitivity and specificity. The data indicate that the TdP susceptibility in methoxamine-sensitized rabbits is affected by the age of rabbits but probably not by hypercholesterolemia. Entropy analysis could potentially stratify the arrhythmic risk and identify the low-risk individuals.
- Publikační typ
- časopisecké články MeSH
Sarcomas are a heterogeneous group of mesenchymal tumours, with a great variability in their clinical behaviour. While our knowledge of sarcoma initiation has advanced rapidly in recent years, relatively little is known about mechanisms of sarcoma progression. JUN-murine fibrosarcoma progression series consists of four sarcoma cell lines, JUN-1, JUN-2, JUN-2fos-3, and JUN-3. JUN-1 and -2 were established from a single tumour initiated in a H2K/v-jun transgenic mouse, JUN-3 originates from a different tumour in the same animal, and JUN-2fos-3 results from a targeted in vitro transformation of the JUN-2 cell line. The JUN-1, -2, and -3 cell lines represent a linear progression from the least transformed JUN-2 to the most transformed JUN-3, with regard to all the transformation characteristics studied, while the JUN-2fos-3 cell line exhibits a unique transformation mode, with little deregulation of cell growth and proliferation, but pronounced motility and invasiveness. The invasive sarcoma sublines JUN-2fos-3 and JUN-3 show complex metabolic profiles, with activation of both mitochondrial oxidative phosphorylation and glycolysis and a significant increase in spared respiratory capacity. The specific transcriptomic profile of invasive sublines features very complex biological relationships across the identified genes and proteins, with accentuated autocrine control of motility and angiogenesis. Pharmacologic inhibition of one of the autocrine motility factors identified, Ccl8, significantly diminished both motility and invasiveness of the highly transformed fibrosarcoma cell. This progression series could be greatly valuable for deciphering crucial aspects of sarcoma progression and defining new prognostic markers and potential therapeutic targets.
- Publikační typ
- časopisecké články MeSH
