BACKGROUND: Renal cell carcinoma (RCC) is a disease typified by anomalies in cell metabolism. The function of mitochondria, including subunits of mitochondrial respiratory complex II (CII), in particular SDHB, are often affected. Here we investigated the state and function of CII in RCC patients. METHODS: We evaluated tumour tissue as well as the adjacent healthy kidney tissue of 78 patients with RCC of different histotypes, focusing on their mitochondrial function. As clear cell RCC (ccRCC) is by far the most frequent histotype of RCC, we focused on these patients, which were grouped based on the pathological WHO/ISUP grading system to low- and high-grade patients, indicative of prognosis. We also evaluated mitochondrial function in organoids derived from tumour tissue of 7 patients. RESULTS: ccRCC tumours were characterized by mutated von Hippel-Lindau gene and high expression of carbonic anhydrase IX. We found low levels of mitochondrial DNA, protein and function, together with CII function in ccRCC tumour tissue, but not in other RCC types and non-tumour tissues. Mitochondrial content increased in high-grade tumours, while the function of CII remained low. Tumour organoids from ccRCC patients recapitulated molecular characteristics of RCC tissue. CONCLUSIONS: Our findings suggest that the state of CII, epitomized by its assembly and SDHB levels, deteriorates with the progressive severity of ccRCC. These observations hold the potential for stratification of patients with worse prognosis and may guide the exploration of targeted therapeutic interventions.
- MeSH
- antigeny nádorové MeSH
- dospělí MeSH
- karboanhydrasa IX metabolismus genetika MeSH
- karcinom z renálních buněk * patologie metabolismus genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- mitochondriální DNA genetika metabolismus MeSH
- mitochondrie * metabolismus patologie genetika MeSH
- mutace MeSH
- nádorový supresorový protein VHL genetika metabolismus MeSH
- nádory ledvin * patologie metabolismus genetika MeSH
- respirační komplex II * metabolismus genetika MeSH
- senioři MeSH
- sukcinátdehydrogenasa genetika metabolismus MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Nitric oxide (NO)-stimulated cyclic guanosine monophosphate (cGMP) is a key regulator of cardiovascular health, as NO-cGMP signalling is impaired in diseases like pulmonary hypertension, heart failure and chronic kidney disease. The development of NO-independent sGC stimulators and activators provide a novel therapeutic option to restore altered NO signalling. sGC stimulators have been already approved for the treatment of pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), and chronic heart failure (HFrEF), while sGC activators are currently in phase-2 clinical trials for CKD. The best characterized effect of increased cGMP via the NO-sGC-cGMP pathway is vasodilation. However, to date, none of the sGC agonists are in development for hypertension (HTN). According to WHO, the global prevalence of uncontrolled HTN continues to rise, contributing significantly to cardiovascular mortality. While there are effective antihypertensive treatments, many patients require multiple drugs, and some remain resistant to all therapies. Thus, in addition to improved diagnosis and lifestyle changes, new pharmacological strategies remain in high demand. In this review we explore the potential of sGC stimulators and activators as novel antihypertensive agents, starting with the overview of NO-sGC-cGMP signalling, followed by potential mechanisms by which the increase in cGMP may regulate vascular tone and BP. These effects may encompass not only acute vasodilation, but also mid-term and chronic effects, such as the regulation of salt and water balance, as well as mitigation of vascular ageing and remodelling. The main section summarizes the preclinical and clinical evidence supporting the BP-lowering efficacy of sGC agonists.
- MeSH
- agonisté guanylátcyklázy terapeutické užití farmakologie MeSH
- aktivátory enzymů terapeutické užití farmakologie MeSH
- antihypertenziva * terapeutické užití farmakologie MeSH
- guanosinmonofosfát cyklický * metabolismus MeSH
- hypertenze * farmakoterapie patofyziologie MeSH
- lidé MeSH
- oxid dusnatý metabolismus MeSH
- rozpustná guanylátcyklasa * metabolismus MeSH
- signální transdukce účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC) is a rare subtype of renal neoplasm predominantly affecting younger individuals. It is characterized by germline mutations in SDHx genes, particularly type B. Histologically, SDH-deficient RCC features eosinophilic cytoplasmic cells forming solid nests or microcysts, sometimes entrapping normal tubules. We present three SDH-deficient RCC cases with overlapping morphological features with fumarate hydratase-deficient RCC and TFEB-rearranged RCC, an appearance that has not been previously described. All tumors lacked SDHB expression and harbored pathogenic SDHB mutations, with the germline nature confirmed in two cases. Metastasis developed in two patients. Our case set highlights the diagnostic challenges of molecularly defined renal tumors and expands the morphological spectrum of SDH-deficient RCC with unusual histological features. Clinically, these tumors appear to be aggressive.
- MeSH
- dediferenciace buněk MeSH
- dospělí MeSH
- fumarasa nedostatek genetika MeSH
- karcinom z renálních buněk * genetika patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádorové biomarkery genetika analýza MeSH
- nádory ledvin * patologie genetika MeSH
- sukcinátdehydrogenasa * nedostatek genetika MeSH
- transkripční faktory BHLH-Zip genetika MeSH
- zárodečné mutace MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
Hyponatremie je stanovena jako koncentrace sodíku nižší než 135 mmol/l. Jedná se o celosvětově nejčastější poruchu elektrolytů. Nejčastějšími projevy hyponatremie jsou gastrointestinální a neurologické obtíže. Příležitostně může vést hyponatremie k poruchám srdečního rytmu. V námi prezentované kazuistice vedla těžká hyponatremie k sinusové bradykardii s alternujícím stupněm atrioventrikulární blokády a srdeční zástavě. Obnovení sinusového rytmu bylo dosaženo až po úpravě koncentrace sodíku. Těžká hyponatremie a protrahovaná zástava oběhu však u pacienta vedly k malignímu otoku mozku. Tento jedinečný případ zdůrazňuje kritickou roli sodíku v srdeční elektrofyziologii a ukazuje důležitost monitorace koncentrace sodíku u pacientů se zástavou oběhu.
Hyponatremia, characterized by sodium levels below 135 mmol/l, is the most prevalent electrolyte disorder worldwide. It presents with a wide range of clinical symptoms, particularly in the neurological and gastrointestinal domains, occasionally leading to cardiac arrhythmias. In our specific case, severe hyponatremia resulting from potomania resulted in sinus bradycardia with alternating atrioventricular block and subsequent cardiac arrest. Restoration of sinus rhythm was achieved following correction of the sodium levels. However severe hyponatremia and long-lasting CPR resulted in brain oedema, which ultimately led to brain death. Per national regulations, the patient was enrolled in an organ donor program, resulting in successful organ transplants. This unique case underscores the critical role of sodium levels in cardiac electrophysiology and highlights the necessity of monitoring electrolyte levels in patients experiencing cardiac arrest.
- MeSH
- edém mozku etiologie MeSH
- elektrokardiografie MeSH
- fosfopyruváthydratasa analýza MeSH
- hypertrofie pravé komory srdeční komplikace MeSH
- hyponatremie * komplikace MeSH
- kardiopulmonální resuscitace MeSH
- lidé středního věku MeSH
- lidé MeSH
- mozková smrt MeSH
- pití alkoholu škodlivé účinky MeSH
- pitva MeSH
- recidiva MeSH
- srdeční zástava * etiologie komplikace patologie terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
The cerebral biomarkers, neurofilament light chain (NfL), amyloid-β, tau, and neuron specific enolase (NSE) reflect a wide spectrum of neurological damage in the brain and spinal cord. With this study, we aimed to assess whether these biomarkers hold any potential diagnostic value for the three most common canine neurological diseases. Canines suffering from meningoencephalitis of unknown origin (MUO), brain tumors, and selected non-infectious myelopathies were included. For each diagnosis, we analyzed these biomarkers in the cerebrospinal fluid collected via cranial puncture from the cisterna magna. Elevated levels of CSF tau, NfL, and NSE were observed in MUO, with all three biomarkers being intercorrelated. Tau and NSE were increased while amyloid-β was decreased in dogs suffering from tumors. In contrast, no biomarker changes were observed in dogs with myelopathies. Covariates such as age, sex, or castration had minimal impact. CSF biomarkers may reflect molecular changes related to MUO and tumors, but not to non-infectious myelopathies. The combination of NfL, tau, and NSE may represent useful biomarkers for MUO as they reflect the same pathology and are not influenced by age.
- MeSH
- amyloidní beta-protein mozkomíšní mok MeSH
- biologické markery * mozkomíšní mok MeSH
- fosfopyruváthydratasa mozkomíšní mok MeSH
- meningoencefalitida mozkomíšní mok veterinární diagnóza MeSH
- nádory mozku mozkomíšní mok veterinární MeSH
- nemoci nervového systému mozkomíšní mok veterinární diagnóza MeSH
- nemoci psů * mozkomíšní mok diagnóza MeSH
- neurofilamentové proteiny * mozkomíšní mok MeSH
- proteiny tau * mozkomíšní mok MeSH
- psi MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- psi MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Injekční aplikace výplňového materiálu zejména do oblasti obličeje jsou populární estetickou procedurou, která se využívá k obnovení objemu, zlepšení kontur a vyhlazení vrásek. Za nejbezpečnější je považována kyselina hyaluronová, ale i ta nese riziko vzniku vaskulárních komplikací. Tyto komplikace mohou být závažné a vést k ischemii, nekróze tkání nebo dokonce slepotě či centrální mozkové příhodě. Tento článek se zaměřuje na identifikaci rizik spojených s vaskulárními komplikacemi při aplikaci dermálních výplní a na strategie pro jejich prevenci a řešení.
The application of filler material, particularly in the facial area, is a popular aesthetic procedure used to restore volume, improve contours and smooth wrinkles. Hyaluronic acid is considered the safest option, but it too carries the risk of vascular complications. These complications can be severe and lead to ischemia, tissue necrosis, or even blindness or stroke. This article focuses on identifying the risks associated with vascular complications associated with dermal filler application and strategies for prevention and management.
- MeSH
- arteria centralis retinae patologie MeSH
- dermální výplně škodlivé účinky MeSH
- hyaluronoglukosaminidasa * farmakologie škodlivé účinky MeSH
- injekce subkutánní škodlivé účinky MeSH
- kyselina hyaluronová škodlivé účinky MeSH
- lidé MeSH
- nemoci cév * chemicky indukované patologie prevence a kontrola terapie MeSH
- nežádoucí účinky léčiv patologie prevence a kontrola terapie MeSH
- oční symptomy MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Bordetella pertussis infects the upper airways of humans and disarms host defense by the potent immuno-subversive activities of its pertussis (PT) and adenylate cyclase (CyaA) toxins. CyaA action near-instantly ablates the bactericidal activities of sentinel CR3-expressing myeloid phagocytes by hijacking cellular signaling pathways through the unregulated production of cAMP. Moreover, CyaA-elicited cAMP signaling also inhibits the macrophage colony-stimulating factor (M-CSF)-induced differentiation of incoming inflammatory monocytes into bactericidal macrophages. We show that CyaA/cAMP signaling via protein kinase A (PKA) downregulates the M-CSF-elicited expression of monocyte receptors for transferrin (CD71) and hemoglobin-haptoglobin (CD163), as well as the expression of heme oxygenase-1 (HO-1) involved in iron liberation from internalized heme. The impact of CyaA action on CD71 and CD163 levels in differentiating monocytes is largely alleviated by the histone deacetylase inhibitor trichostatin A (TSA), indicating that CyaA/cAMP signaling triggers epigenetic silencing of genes for micronutrient acquisition receptors. These results suggest a new mechanism by which B. pertussis evades host sentinel phagocytes to achieve proliferation on airway mucosa.IMPORTANCETo establish a productive infection of the nasopharyngeal mucosa and proliferate to sufficiently high numbers that trigger rhinitis and aerosol-mediated transmission, the pertussis agent Bordetella pertussis deploys several immunosuppressive protein toxins that compromise the sentinel functions of mucosa patrolling phagocytes. We show that cAMP signaling elicited by very low concentrations (22 pM) of Bordetella adenylate cyclase toxin downregulates the iron acquisition systems of CD14+ monocytes. The resulting iron deprivation of iron, a key micronutrient, then represents an additional aspect of CyaA toxin action involved in the inhibition of differentiation of monocytes into the enlarged bactericidal macrophage cells. This corroborates the newly discovered paradigm of host defense evasion mechanisms employed by bacterial pathogens, where manipulation of cellular cAMP levels blocks monocyte to macrophage transition and replenishment of exhausted phagocytes, thereby contributing to the formation of a safe niche for pathogen proliferation and dissemination.
- MeSH
- adenylátcyklasový toxin * metabolismus genetika MeSH
- AMP cyklický * metabolismus MeSH
- antigeny CD14 * metabolismus MeSH
- antigeny diferenciační myelomonocytární MeSH
- Bordetella pertussis * MeSH
- buněčná diferenciace * MeSH
- CD antigeny metabolismus genetika MeSH
- lidé MeSH
- monocyty * metabolismus imunologie mikrobiologie MeSH
- proteinkinasy závislé na cyklickém AMP metabolismus MeSH
- receptory buněčného povrchu metabolismus genetika MeSH
- signální transdukce * MeSH
- upregulace MeSH
- železo metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Endothelial glycocalyx (EG) plays a crucial role in maintaining the plasma proteins within the intravascular space. OBJECTIVE: We studied whether exogenous albumin protects the EG in an experimental model of EG enzymatic damage in rats. METHODS: Rats were divided into three groups of 10 animals that received (1) Evans blue (2) Evans blue + hyaluronidase, or (3) Evans blue + hyaluronidase + 20% human albumin via the tail vein. Spectrophotometric analysis was performed 2 h later to quantify the leakage of Evans blue-labeled albumin into the heart, lungs, brain, kidneys, liver, small intestine, spleen, and skeletal muscle. RESULTS: Administration of hyaluronidase numerically increased the capillary leakage of Evans blue in all examined tissues. Co-administration of albumin decreased the leakage of albumin in all tissues except the heart. In the lungs, the ratio between the absorbance and dry organ weight decreased from 5.3 ± 2.4 to 1.7 ± 0.5 (mean ± SD) (P < 0.002), and in the liver, the absorbance decreased from 2.2 ± 0.7 to 1.5 ± 0.4 (P < 0.011). CONCLUSION: Exogenous albumin decreased the capillary leakage of albumin which was interpreted as a sign of maintained EG integrity.
- MeSH
- albuminy * metabolismus MeSH
- cévní endotel účinky léků metabolismus MeSH
- Evansova modř MeSH
- glykokalyx * metabolismus účinky léků MeSH
- hyaluronoglukosaminidasa farmakologie MeSH
- kapilární permeabilita * účinky léků MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- potkani Wistar MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Klíčová slova
- aplikace intralymfatická, studie DIAGNODE-2,
- MeSH
- beta-buňky účinky léků MeSH
- C-peptid fyziologie MeSH
- diabetes mellitus 1. typu * imunologie MeSH
- glutamát dekarboxyláza * terapeutické užití MeSH
- lidé MeSH
- randomizované kontrolované studie jako téma metody MeSH
- vitamin D MeSH
- Check Tag
- lidé MeSH
This review summarises progress in the research of homocystinuria (HCU) in the past three decades. HCU due to cystathionine β-synthase (CBS) was discovered in 1962, and Prof. Jan Peter Kraus summarised developments in the field in the first-ever Komrower lecture in 1993. In the past three decades, significant advancements have been achieved in the biology of CBS, including gene organisation, tissue expression, 3D structures, and regulatory mechanisms. Renewed interest in CBS arose in the late 1990s when this enzyme was implicated in biogenesis of H2S. Advancements in genetic and biochemical techniques enabled the identification of several hundreds of pathogenic CBS variants and the misfolding of missense mutations as a common mechanism. Several cellular, invertebrate and murine HCU models allowed us to gain insights into functional and metabolic pathophysiology of the disease. Establishing the E-HOD consortium and patient networks, HCU Network Australia and HCU Network America, offered new possibilities for acquiring clinical data in registries and data on patients' quality of life. A recent analysis of data from the E-HOD registry showed that the clinical variability of HCU is broad, extending from severe childhood disease to milder (late) adulthood forms, which typically respond to pyridoxine. Pyridoxine responsiveness appears to be the key factor determining the clinical course of HCU. Increased awareness about HCU played a role in developing novel therapies, such as gene therapy, correction of misfolding by chaperones, removal of methionine from the gut and enzyme therapies that decrease homocysteine or methionine in the circulation.
