Morbus Hailey-Hailey, benigní familiární pemfigus, je chronická autozomálně dominantní akantolytická genodermatóza charakterizovaná tvorbou plihých puchýřů a erozí v intertriginózních lokalizacích. V chronických lézích dochází ke tvorbě erytematózních plaků, vlhkých vegetací, bolestivých fisur a ložiska nepříjemně zapáchají. Průběh onemocnění je remitující, relabující, se zhoršením v letních měsících. Mezi provokační faktory vedoucí ke zhoršení onemocnění patří UV záření, mechanické dráždění, pocení, infekce, stres, hormonální změny. Postiženi jsou nejčastěji lidé ve věku 30-40 let, bez predilekce rasy a pohlaví. Pozitivní rodinná anamnéza je až u 70 % pacientů. Defekt v genu ATP2C1 na 3. chromozomu je zodpovědný za dysregulaci Ca2+ transportu v buňce s narušením keratinocytových vazeb s následnou akantolýzou v celé šíři epidermis s ojedinělým zachováním intaktních vazeb mezi keratinocyty, tvorbou suprabazálních štěrbin a s typickým histologickým obrazem podobajícím se rozpadající se cihlové zdi. V terapii využíváme lokální kortikosteroidy, antibiotika, antimykotika, kombinované preparáty, lokální imunomodulátory, celkově podáváme kortikosteroidy, antibiotika, antimykotika, antivirotika a tzv. DMARD ́s (disease-modifying antirheumatic drugs). Z fyzikálních metod doplňujeme terapii o laserové ošetření, aplikaci botulotoxinu, fototerapii, dermabrazi, chirurgické řešení. V následujícím kazuistickém sdělení jsou popsány 2 klinické případy pacientů léčených v naší ambulanci.

Morbus Hailey-Hailey, benign familiar pemfigus, is a chronic autosomal dominant acantholytic dermatosis, which is characterised by flaccid bullae in the intergtriginous areas that rupture easily. In chronic lesions appear erythematous plaques, moist vege­tations, painful fissures and lesions are malodorous. Disease has relapsing-remitting course, with worsening during the summer. Trigger factors are UV light, friction, sweating, infection, stress, hormonal changes. It affects mainly people in their 30 ́s-40 ́s, without sex or racial predominance. Positive family history is in 70 % of cases. Defect in ATP2C1 gene, localised at 3rd chromosome is responsible for dysregulation of Ca2+ transport in cells, which influences keratinocytic adhesion, followed by acantholysis throughout the whole epidermis with formation of suprabasal clefting and with a typical histological picture of dilapitated brick wall. For treatment we use topical corticosterids, antibiotics, antimycotics, combined topical treatment, local imunomodulators. Systemically we use corticosteroids, antibiotics, antimycotics, antivirotics and disease-modifying antirheumatic drugs. Patients can as well undergo laser therapy, phototherapy, botulotoxin A injections, dermabrasion and other surgical methods. In a following case report we present 2 cases of patients with Hailey-Hailey disease treated in our dermatological office.

• MeSH
• akantolýza MeSH
• benigní familiární pemfigus * diagnóza   farmakoterapie   MeSH
• diferenciální diagnóza MeSH
• dospělí MeSH
• genetická onemocnění kůže diagnóza   MeSH
• glukokortikoidy MeSH
• lidé MeSH
• prednison aplikace a dávkování   terapeutické užití   MeSH
• recidiva MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

Matrix Gla protein (MGP) je cirkulující protein s nízkou molekulární hmotností, který působí jako přirozený inhibitor kalcifikace. Řadíme ho do skupiny proteinů označených jako vitamin K dependentní proteiny. Jeho hlavní funkcí je prevence ukládání vápníku do měkkých tkání. Pro správné fungování musí být MGP dostatečně karboxylován a fosforylován, což je proces, který vyžaduje vitamin K2 jako kofaktor gamma-glutamylkarboxylasy. Nedostatek vitaminu K se projevuje kardiovaskulárním onemocněním, nedostatečnou mineralizací kostní tkáně a vznikem kalcifikujících deposit v měkkých tkáních. Cílem práce bylo navržení metod pro sledování hladiny MGP a defosforylovaného nedostatečně karboxylovaného MGP (dp-uc MGP) za využití imunochemické detekce a aplikovat je na analýzu reálných pacientských vzorků pro použití v klinických laboratořích, kde by tyto markery mohly sloužit jako potencionální markery závažnosti kloubních onemocnění, kardiovaskulárních onemocnění a také jako markery vypovídající o stavu vitaminu K v organismu.

Matrix Gla protein (MGP) is a circulating protein with a low molecular weight that acts as a natural inhibitor of calcification. It belongs to the group of vitamin K‐dependent proteins. For its proper function, MGP must undergo vitamin K-dependent carboxylation and phosphorylation. Its main function is the prevention of soft-tissue calcification. It requires vitamin K2 as a cofactor for gamma glutamyl carboxylase. Vitamin K insufficiency is manifested by cardiovascular diseases, insufficient mineralization of bone tissue and the formation of calcifying deposits in soft tissues. The aim of this study was to design methods for monitoring the levels of MGP and dp-uc MGP by using immunochemical detection and to apply them to the analysis of real samples for use in clinical laboratories. These markers could serve as potential markers of the severity of joint diseases, cardiovascular diseases and also as markers indicating the status of vitamin K in organism.

• MeSH
• ELISA MeSH
• fosfor analýza   MeSH
• kosti a kostní tkáň * metabolismus   MeSH
• lidé MeSH
• matrixový protein Gla * analýza   MeSH
• vápník analýza   MeSH
• vitamin K analýza   MeSH
• výzkum MeSH
• Check Tag
• lidé MeSH

The human Sec61 complex is a widely distributed and abundant molecular machine. It resides in the membrane of the endoplasmic reticulum to channel two types of cargo: protein substrates and calcium ions. The SEC61A1 gene encodes for the pore-forming Sec61α subunit of the Sec61 complex. Despite their ubiquitous expression, the idiopathic SEC61A1 missense mutations p.V67G and p.T185A trigger a localized disease pattern diagnosed as autosomal dominant tubulointerstitial kidney disease (ADTKD-SEC61A1). Using cellular disease models for ADTKD-SEC61A1, we identified an impaired protein transport of the renal secretory protein renin and a reduced abundance of regulatory calcium transporters, including SERCA2. Treatment with the molecular chaperone phenylbutyrate reversed the defective protein transport of renin and the imbalanced calcium homeostasis. Signal peptide substitution experiments pointed at targeting sequences as the cause for the substrate-specific impairment of protein transport in the presence of the V67G or T185A mutations. Similarly, dominant mutations in the signal peptide of renin also cause ADTKD and point to impaired transport of this renal hormone as important pathogenic feature for ADTKD-SEC61A1 patients as well.

• MeSH
• endoplazmatické retikulum metabolismus   MeSH
• fenylbutyráty metabolismus   farmakologie   MeSH
• HEK293 buňky MeSH
• lidé MeSH
• missense mutace MeSH
• molekulární chaperony metabolismus   MeSH
• nemoci ledvin patofyziologie   MeSH
• polycystická choroba ledvin MeSH
• renin genetika   metabolismus   MeSH
• sarkoplazmatická Ca2+-ATPáza metabolismus   MeSH
• translokační kanály SEC chemie   genetika   metabolismus   MeSH
• transport proteinů genetika   MeSH
• vápník metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

In tumor cells with defects in apoptosis, autophagy allows prolonged survival. Autophagy leads to an accumulation of damaged mitochondria by autophagosomes. An acidic environment is maintained in compartments of cells, such as autophagosomes, late endosomes, and lysosomes; these organelles belong to the "acid store" of the cells. Nicotinic acid adenine dinucleotide phosphate (NAADP) may affect the release of Ca2+ from these organelles and affect the activity of Ca2+ ATPases and other ion transport proteins. Recently, a growing amount of evidence has shown that the variations in the expression of calcium channels or pumps are associated with the occurrence, disease-presentation, and the prognosis of colorectal cancer. We hypothesized that activity of ATPases in cancer tissue is higher because of intensive energy metabolism of tumor cells. The aim of our study was to ascertain the effect of NAADP on ATPase activity on tissue samples of colorectal cancer patients' and healthy individuals. We tested the effect of NAADP on the activity of Na+/K+ ATPase; Ca2+ ATPase of endoplasmic reticulum (EPR) and plasma membrane (PM) and basal ATPase activity. Patients' colon mucus cancer samples were obtained during endoscopy from cancer and healthy areas (control) of colorectal mucosa of the same patients. Results. The mean activity of Na+/K+ pump in samples of colorectal cancer patients (n = 5) was 4.66 ± 1.20 μmol Pi/mg of protein per hour, while in control samples from healthy tissues of the same patient (n = 5) this value was 3.88 ± 2.03 μmol Pi/mg of protein per hour. The activity of Ca2+ ATPase PM in control samples was 6.42 ± 0.63 μmol Pi/mg of protein per hour and in cancer -8.50 ± 1.40 μmol Pi/mg of protein per hour (n = 5 pts). The mean activity of Ca2+ ATPase of EPR in control samples was 7.59 ± 1.21 μmol Pi/mg versus 7.76 ± 0.24 μmol Pi/mg in cancer (n = 5 pts). Basal ATPase activity was 3.19 ± 0.87 in control samples versus 4.79 ± 1.86 μmol Pi/mg in cancer (n = 5 pts). In cancer samples, NAADP reduced the activity of Na+/K+ ATPase by 9-times (p < 0.01) and the activity of Ca2+ ATPase EPR about 2-times (p < 0.05). NAADP caused a tendency to decrease the activity of Ca2+ ATPase of PM, but increased basal ATPase activity by 2-fold vs. the mean of this index in cancer samples without the addition of NAADP. In control samples NAADP caused only a tendency to decrease the activities of Na+/K+ ATPase and Ca2+ ATPase EPR, but statistically decreased the activity of Ca2+ ATPase of PM (p < 0.05). In addition, NAADP caused a strong increase in basal ATPase activity in control samples (p < 0.01). Conclusions: We found that the activity of Na+/K+ pump, Ca2+ ATPase of PM and basal ATPase activity in cancer tissues had a strong tendency to be higher than in the controls. NAADP caused a decrease in the activities of Na+/K+ ATPase and Ca2+ ATPase EPR in cancer samples and increased basal ATPase activity. In control samples, NAADP decreased Ca2+ ATPase of PM and increased basal ATPase activity. These data confirmed different roles of NAADP-sensitive "acidic store" (autophagosomes, late endosomes, and lysosomes) in control and cancer tissue, which hypothetically may be connected with autophagy role in cancer development. The effect of NAADP on decreasing the activity of Na+/K+ pump in cancer samples was the most pronounced, both numerically and statistically. Our data shows promising possibilities for the modulation of ion-transport through the membrane of cancer cells by influence on the "acidic store" (autophagosomes, late endosomes and lysosomes) as a new approach to the treatment of colorectal cancer.

• Publikační typ
• časopisecké články MeSH

Calreticulin (CALR) is an endoplasmic reticulum (ER)-resident protein involved in a spectrum of cellular processes. In healthy cells, CALR operates as a chaperone and Ca2+ buffer to assist correct protein folding within the ER. Besides favoring the maintenance of cellular proteostasis, these cell-intrinsic CALR functions support Ca2+-dependent processes, such as adhesion and integrin signaling, and ensure normal antigen presentation on MHC Class I molecules. Moreover, cancer cells succumbing to immunogenic cell death (ICD) expose CALR on their surface, which promotes the uptake of cell corpses by professional phagocytes and ultimately supports the initiation of anticancer immunity. Thus, loss-of-function CALR mutations promote oncogenesis not only as they impair cellular homeostasis in healthy cells, but also as they compromise natural and therapy-driven immunosurveillance. However, the prognostic impact of total or membrane-exposed CALR levels appears to vary considerably with cancer type. For instance, while genetic CALR defects promote pre-neoplastic myeloproliferation, patients with myeloproliferative neoplasms bearing CALR mutations often experience improved overall survival as compared to patients bearing wild-type CALR. Here, we discuss the context-dependent impact of CALR on malignant transformation, tumor progression and response to cancer therapy.

• MeSH
• kalretikulin genetika   metabolismus   MeSH
• lidé MeSH
• mutace MeSH
• myeloproliferativní poruchy metabolismus   patologie   MeSH
• nádory metabolismus   patologie   MeSH
• prezentace antigenu MeSH
• prognóza MeSH
• signální transdukce MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

Defects in DNA single-strand break repair (SSBR) are linked with neurological dysfunction but the underlying mechanisms remain poorly understood. Here, we show that hyperactivity of the DNA strand break sensor protein Parp1 in mice in which the central SSBR protein Xrcc1 is conditionally deleted (Xrcc1Nes-Cre ) results in lethal seizures and shortened lifespan. Using electrophysiological recording and synaptic imaging approaches, we demonstrate that aberrant Parp1 activation triggers seizure-like activity in Xrcc1-defective hippocampus ex vivo and deregulated presynaptic calcium signalling in isolated hippocampal neurons in vitro. Moreover, we show that these defects are prevented by Parp1 inhibition or deletion and, in the case of Parp1 deletion, that the lifespan of Xrcc1Nes-Cre mice is greatly extended. This is the first demonstration that lethal seizures can be triggered by aberrant Parp1 activity at unrepaired SSBs, highlighting PARP inhibition as a possible therapeutic approach in hereditary neurological disease.

• MeSH
• DNA vazebné proteiny * genetika   metabolismus   MeSH
• DNA MeSH
• myši MeSH
• neurony metabolismus   MeSH
• oprava DNA genetika   MeSH
• poly(ADP-ribosa)polymerasa 1 genetika   metabolismus   MeSH
• vápník * MeSH
• záchvaty genetika   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The most recent genome-editing system called CRISPR-Cas9 (clustered regularly interspaced short palindromic repeat system with associated protein 9-nuclease) was employed to delete four non-essential genes (i.e., Caeco1, Caidh1, Carom2, and Cataf10) individually to establish their gene functionality annotations in pathogen Candida albicans. The biological roles of these genes were investigated with respect to the cell wall integrity and biogenesis, calcium/calcineurin pathways, susceptibility of mutants towards temperature, drugs and salts. All the mutants showed increased vulnerability compared to the wild-type background strain towards the cell wall-perturbing agents, (antifungal) drugs and salts. All the mutants also exhibited repressed and defective hyphal growth and smaller colony size than control CA14. The cell cycle of all the mutants decreased enormously except for those with Carom2 deletion. The budding index and budding size also increased for all mutants with altered bud shape. The disposition of the mutants towards cell wall-perturbing enzymes disclosed lower survival and more rapid cell wall lysis events than in wild types. The pathogenicity and virulence of the mutants was checked by adhesion assay, and strains lacking rom2 and eco1 were found to possess the least adhesion capacity, which is synonymous to their decreased pathogenicity and virulence.

• MeSH
• acetyltransferasy nedostatek   genetika   fyziologie   MeSH
• antifungální látky farmakologie   MeSH
• buněčná adheze MeSH
• buněčná stěna účinky léků   MeSH
• buněčný cyklus MeSH
• Candida albicans účinky léků   genetika   patogenita   fyziologie   MeSH
• chitinasy farmakologie   MeSH
• CRISPR-Cas systémy MeSH
• delece genu MeSH
• endo-1,3-beta-glukanasa farmakologie   MeSH
• faktory asociované s proteinem vázajícím TATA box nedostatek   genetika   fyziologie   MeSH
• fungální proteiny genetika   fyziologie   MeSH
• geny hub * MeSH
• hyfy růst a vývoj   MeSH
• isocitrátdehydrogenasa nedostatek   genetika   fyziologie   MeSH
• kationty farmakologie   MeSH
• nepohlavní rozmnožování MeSH
• otevřené čtecí rámce MeSH
• poškození DNA MeSH
• vápník fyziologie   MeSH
• virulence genetika   MeSH
• Publikační typ
• časopisecké články MeSH

Hypocalcaemic cardiomyopathy is a rare form of dilated cardiomyopathy. The authors here present two cases in which symptomatic dilated cardiomyopathy was the result of severe hypocalcaemia. First, we report about a 26-year-old woman with primary hypoparathyroidism and then about a 74-year-old man with secondary hypoparathyroidism following a thyroidectomy. In both cases, the left ventricular systolic function improved after calcium supplementation. In the first case, a lack of compliance led to a repeated decrease of both serum calcium level and left ventricular systolic function. The authors also present a comprehensive summary of all cases of hypocalcaemic dilated cardiomyopathy that have been described in literature to date. The mean age of the affected patients was 48.3 years, of which 62% were female patients. The most common causes of hypocalcaemic cardiomyopathy are primary hypoparathyroidism (50%) and post-thyroidectomy hypoparathyroidism (26%). In the post-thyroidectomy subgroup, the median time for the development of hypocalcaemic cardiomyopathy is 10 years (range: 1.5 months to 36 years). Hypocalcaemic cardiomyopathy leads to heart failure with reduced ejection fraction in 87% of patients. Generally, the most common complications of hypoparathyroidism and/or hypocalcaemia are cerebral calcifications, cognitive deficit, and cataracts. Once calcium supplementation is administered, the disease has a good prognosis and, in most individuals, a significant improvement (21%) or even normalization (74%) of the left ventricular systolic function occurs.

• MeSH
• dilatační kardiomyopatie * diagnóza   etiologie   MeSH
• dospělí MeSH
• hypokalcemie * diagnóza   etiologie   MeSH
• hypoparatyreóza * komplikace   diagnóza   MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• tyreoidektomie MeSH
• vápník MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• přehledy MeSH

Ageing is associated with the accumulation of damage to all the macromolecules within and outside cells leading to progressively more cellular and tissue defects and resulting in age-related frailty, disability and disease. As a result of the aging process the bone deteriorates in composition, structure and function. Age-related musculoskeletal losses are a major public health burden because they can cause physical disability and increased mortality. We tried to find out on a small set of old women, without risk factors for osteoporosis, what caused them the loss of bone minerals. All 492 women had just only one risk factor - the old age. Laboratory findings have shown a decreased serum C telopeptide and low serum alkaline phosphatase circulating markers, used to quantify bone resorption and formation, and very low level of vitamin D. Very low level of vitamin D that disrupted calcium absorption through the intestine, and decreased calcemia increased parathyroid hormone levels with resulting bone effect. The manifestation of physiological aging is worsening eyesight, peripheral neuropathy, depression, worsening of physical condition, skin aging, sarcopenia and bone mineral loss. Senile osteoporosis, which is not caused by known risk factors for osteoporosis, does not appear to be a separate disease, but is part of the physiological process of aging. Treatment of senile osteoporosis should be focused on the control of secondary hyperparathyroidism by administration of vitamin D and calcium. The risk of fractures in the advanced age is determined by a large number of factors ranging from hazards in the home environment to frailty and poor balance.

• MeSH
• alkalická fosfatasa krev   MeSH
• kolagen typu I krev   MeSH
• kostní denzita MeSH
• lidé MeSH
• osteogeneze MeSH
• osteoporóza krev   MeSH
• parathormon krev   MeSH
• peptidy krev   MeSH
• stárnutí krev   patologie   MeSH
• vápník metabolismus   MeSH
• vitamin D krev   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

The inflammatory airway disease cystic fibrosis (CF) is characterized by airway obstruction due to mucus hypersecretion, airway plugging, and bronchoconstriction. The cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel is dysfunctional in CF, leading to defects in epithelial transport. Although CF pathogenesis is still disputed, activation of alternative Cl- channels is assumed to improve lung function in CF. Two suitable non-CFTR Cl- channels are present in the airway epithelium, the Ca2+ activated channel TMEM16A and SLC26A9. Activation of these channels is thought to be feasible to improve hydration of the airway mucus and to increase mucociliary clearance. Interestingly, both channels are upregulated during inflammatory lung disease. They are assumed to support fluid secretion, necessary to hydrate excess mucus and to maintain mucus clearance. During inflammation, however, TMEM16A is upregulated particularly in mucus producing cells, with only little expression in ciliated cells. Recently it was shown that knockout of TMEM16A in ciliated cells strongly compromises Cl- conductance and attenuated mucus secretion, but does not lead to a CF-like lung disease and airway plugging. Along this line, activation of TMEM16A by denufosol, a stable purinergic ligand, failed to demonstrate any benefit to CF patients in earlier studies. It rather induced adverse effects such as cough. A number of studies suggest that TMEM16A is essential for mucus secretion and possibly also for mucus production. Evidence is now provided for a crucial role of TMEM16A in fusion of mucus-filled granules with the apical plasma membrane and cellular exocytosis. This is probably due to local Ca2+ signals facilitated by TMEM16A. Taken together, TMEM16A supports fluid secretion by ciliated airway epithelial cells, but also maintains excessive mucus secretion during inflammatory airway disease. Because TMEM16A also supports airway smooth muscle contraction, inhibition rather than activation of TMEM16A might be the appropriate treatment for CF lung disease, asthma and COPD. As a number of FDA-approved and well-tolerated drugs have been shown to inhibit TMEM16A, evaluation in clinical trials appears timely.

• Publikační typ
• časopisecké články MeSH
• přehledy MeSH