BACKGROUND: Impaired kidney concentration capacity is present in half of the patients with autosomal dominant polycystic kidney disease (ADPKD). The kidney concentrating capacity was further impaired within the animal model of autosomal recessive polycystic kidney disease (ARPKD). To date, only one small study has investigated it in children having ARPKD. Therefore, we aimed to study the kidney concentrating ability in a larger cohort of children with ARPKD. METHODS: Eighteen children (median age 8.5 years, range 1.3-16.8) were retrospectively investigated. A standardized kidney concentrating capacity test was performed after the application of a nasal drop of desmopressin (urine osmolality > 900 mOsmol/kg). The glomerular filtration rate was estimated using the Schwartz formula (eGFR) and blood pressure (BP) was measured as office BP. RESULTS: Kidney concentrating capacity was decreased (urine osmolality < 900 mOsmol/kg) in 100% of children with ARPKD. The median urine osmolality after desmopressin application was 389 (range 235-601) mOsmol/kg. Sixteen patients (89%) were defined as hypertensive based on their actual BP level or their use of antihypertensive drugs. The maximum amounts of urinary concentration correlated significantly with eGFR (r = 0.72, p < 0.0001) and hypertensive scores (r = 0.50, p < 0.05), but not with kidney size. Twelve patients (67%) were defined as having CKD stages 2-4. The median concentrating capacity was significantly lower in children within this group, when compared to children with CKD stage 1 possessing a normal eGFR (544 mOsmol/kg, range 413-600 mOsmol/kg vs. 327 mOsmol/kg, range 235-417 mOsmol/l, p < 0.001). CONCLUSIONS: Impaired kidney concentrating capacity is present in most children with ARPKD and is associated with decreased eGFR and hypertension. A higher resolution version of the Graphical abstract is available as Supplementary information.
- MeSH
- chronická renální insuficience * komplikace MeSH
- desmopresin MeSH
- dítě MeSH
- hodnoty glomerulární filtrace MeSH
- hypertenze * MeSH
- ledviny MeSH
- lidé MeSH
- polycystické ledviny autozomálně dominantní * MeSH
- polycystické ledviny autozomálně recesivní * komplikace MeSH
- retrospektivní studie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Carotenoids are the most abundant lipid-soluble phytochemicals and are used as dietary supplements to protect against diseases caused by oxidative stress. Astaxanthin, a xanthophyll carotenoid, is a very potent antioxidant with numerous beneficial effects on cellular functions and signaling pathways. In this study, using spleen cells from healthy Balb/c mice, we report the bio-functional effects of an astaxanthin-rich extract (EXT) prepared from the microalga Haematococcus pluvialis and its astaxanthin monoesters-rich fraction (ME) and astaxanthin diesters-rich fraction (DE) obtained by fractionation of EXT using countercurrent chromatography (CCC). After incubation under standard culture conditions (humidity, 37 °C, 5% CO2, atmospheric oxygen), the viability of untreated splenocytes, as determined by the trypan blue exclusion assay, the MTT assay, and the neutral red assay, decreases to approximately 75% after 24 h compared with naïve splenocytes. This effect correlated with the decrease in mitochondrial membrane potential and the transition of ~59% of cells to the early stage of apoptosis, as well as with the decreased ROS production, indicating that hyperoxia in cell-culture deteriorates cell functions. They are restored or stimulated by co-cultivation with EXT, ME, and DE up to 10 μg/mL in the order EXT > DE > ME, suggesting that esterification increases bioavailability to cells in vitro. ROS and H2O2 concentrations reflect mRNA transcriptional activity of Nrf2, superoxide dismutase 1 (SOD1), catalase, and glutathione peroxidase 1, as well as SOD-mediated ROS conversion, whereas they inversely correlate with iNOS-mediated NO production. The highest-tested concentration of EXT, ME, and DE (40 μg/mL) is detrimental to cells, probably because of the overwhelming scavenging activity of astaxanthin and its esters for the reactive oxygen/nitrogen species required for cellular functions and signal transduction at low physiological concentrations. In this study, we demonstrate that differential activities of ME and DE contribute to the final antioxidant and cytoprotective effects of astaxanthin extract, which is beneficial in preventing a wide range of ROS-induced adverse effects, with DE being more effective. In addition, the selection of physioxia-like conditions for pharmacological research is highlighted.
- Publikační typ
- časopisecké články MeSH
Prvé zmienky o zriedkavých chorobách (ZCH) siahajú až do stredoveku. V tom čase boli ZCH vnímané ako nezvyčajné fenotypy, spravidla somatické alebo neskôr biochemické. Až 19. storočie otvorilo otázky dedičnosti pri "zvláštnych" klinických obrazoch, ktoré boli pozorované opakovane. Dnes poznáme viac ako 6 000 rôznych ZCH, a hoci jednotlivo sa vyskytujú u malého počtu pacientov, spoločne postihujú 3,5-5,9 % celosvetovej populácie. Väčšina z nich je geneticky podmienená a rýchly vývoj metód molekulovej diagnostiky akceleroval identifikáciu patogénnych, s chorobou asociovaných variantov. Výskum sa pohol vpred aj smerom k personalizovanej liečbe ZCH. Komplexným zdrojom informácií na poli ZCH pre odborníkov i pacientov je voľne dostupný referenčný internetový portál Orphanet (www.orpha.net). Už 23 rokov prináša aktuálne vedomosti o ZCH. Navyše združuje vo forme databázy diagnostické a výskumné laboratóriá, medicínske expertné centrá, výskumné projekty, pacientske organizácie, registre, biobanky a lieky na ZCH.
The history of rare diseases (RDs) dates back to the Middle Ages. At that time, RDs were rather described as "uncommon" phenotypes, somatic or biochemical. "Strange" clinical pictures that were observed repeatedly were thought to have a hereditary component firstly in the 19th century. To date, approximately 6 000 different RDs are known, and although they occur individually in a small number of patients, they affect together 3.5-5.9 % population worldwide. Most of them are genetically determined and the rapid development of molecular diagnostic methods has accelerated the identification of pathogenic, disease-causing variants. Research has also moved towards personalized treatment of RDs. Orphanet is the most comprehensive information portal on RDs for professionals and patients, as well (www.orpha.net). It offers its updated content about RDs for 23 years. Additionally, it is a database of diagnostic and research laboratories, medical expert centers, research projects, patient organizations, registries, biobanks and orphan drugs.
- Klíčová slova
- Orphanet,
- MeSH
- databáze faktografické MeSH
- informační služby MeSH
- internet MeSH
- lidé MeSH
- šíření informací MeSH
- vzácné nemoci * MeSH
- zdravotnické informační systémy MeSH
- Check Tag
- lidé MeSH
The aim of this study was to investigate the use of a standardized animal model subjected to antibiotic treatment, and the effects of this treatment on the course of dextran sodium sulphate (DSS)-induced colitis in mice. By decontamination with selective antibiotics and observation of pathogenesis of ulcerative colitis (UC) induced chemically by exposure of mice to various concentrations of DSS, we obtained an optimum animal PGF model of acute UC manifested by mucin depletion, epithelial degeneration and necrosis, leading to the disappearance of epithelial cells, infiltration of lamina propria and submucosa with neutrophils, cryptitis, and accompanied by decreased viability of intestinal microbiota, loss of body weight, dehydration, moderate rectal bleeding, and a decrease in the selected markers of cellular proliferation and apoptosis. The obtained PGF model did not exhibit changes that could contribute to inflammation by means of alteration of the metabolic status and the induced dysbiosis did not serve as a bearer of pathogenic microorganisms participating in development of ulcerative colitis. The inflammatory process was induced particularly by exposure to DSS and its toxic action on compactness and integrity of mucosal barrier in the large intestine. This offers new possibilities of the use of this animal model in studies with or without participation of pathogenic microbiota in IBD pathogenesis.
- MeSH
- antibakteriální látky farmakologie MeSH
- apoptóza fyziologie MeSH
- epitelové buňky patologie MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední BALB C MeSH
- myši MeSH
- proliferace buněk fyziologie MeSH
- síran dextranu farmakologie MeSH
- střevní mikroflóra účinky léků fyziologie MeSH
- střevní sliznice mikrobiologie patologie MeSH
- ulcerózní kolitida chemicky indukované farmakoterapie patologie MeSH
- zánět farmakoterapie patologie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Silymarin (SIL) represents a natural mixture of polyphenols showing an array of health benefits. The present study, carried out on a model cestode infection induced by Mesocestoides vogae tetrathyridia in the ICR strain of mice, was aimed at investigating the impact of SIL as adjunct therapy on the activity of praziquantel (PZQ) in relation to parasite burden, immunity and liver fibrosis within 20 days post-therapy. In comparison with PZQ alone, co-administration of SIL and PZQ stimulated production of total IgG antibodies to somatic and excretory-secretory antigens of metacestodes and modified the expression patterns of immunogenic molecules in both antigenic preparations. The combined therapy resulted in the elevation of IFN-γ and a decline of TNF-α and TGF-β1 in serum as compared to untreated group; however, SIL attenuated significantly the effect of PZQ on IL-4 and stimulated PZQ-suppressed phagocytosis of peritoneal macrophages. In the liver, SIL boosted the effect of PZQ on gene expression of the same cytokines in a similar way as was found in serum, except for down-regulation of PZQ-stimulated TNF-α. Compared to PZQ therapy, the infiltration of mast cells into liver after SIL co-administration was nearly abolished and correlated with suppressed activities of genes for collagen I, collagen III and α-SMA. In conclusion, co-administration of SIL modified the effects of PZQ therapy on antigenic stimulation of the immune system and modulated Th1/Th2/Tregs cytokines. In liver this was accompanied by reduced fibrosis, which correlated with significantly higher reduction of total numbers of tetrathyridia after combined therapy as compared with PZQ treatment.
- MeSH
- antioxidancia aplikace a dávkování MeSH
- cestodózy farmakoterapie MeSH
- cytokiny účinky léků MeSH
- down regulace účinky léků MeSH
- Mesocestoides účinky léků MeSH
- myši inbrední ICR MeSH
- myši MeSH
- praziquantel aplikace a dávkování MeSH
- silymarin aplikace a dávkování MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Závažné formy polycystických obličiek so skorým nástupom v detskom veku predstavujú rozsiahlu skupinu ochorení s prekrývajúcim sa klinickým prejavom. Charakteristickým znakom sú zväčšené obličky so zníženou funkciou, ktoré môžu byť v prenatálnom období výsledkom Potterovej sekvencie. Etiológia tohto prejavu je však geneticky veľmi heterogénna a môže byť spôsobená poruchou širokej skupiny génov. Najčastejšou príčinou sú mutácie v géne PKHD1, ktoré vedú k vzniku autozómovo recesívnej formy polycystických obličiek (ARPKD). Takmer v rovnakom počte prípadov je klinický obraz prudkej formy polycystických obličiek s nástupom v detskom veku výsledkom porúch génov PKD1 alebo PKD2 asociovaných so vznikom autozómovo dominantnej formy ochorenia (ADPKD). Tieto mutácie často vznikajú de novo alebo môžu ovplyvniť obe alely a viesť k recesívnemu modelu dedičnosti. Poruchy génu DZIP1L sú pomerne novou príčinou tzv. ARPKD-like fenotypu. Včasnú a jednoznačnú diagnostiku týchto ochorení potvrdí genetické vyšetrenie. Súčasné možnosti sekvenovania novej generácie umožňujú simultánnu analýzu celej skupiny génov a predstavujú kľúčovú úlohu v rýchlej diagnostike týchto ochorení. Identifikácia kauzálneho génu je esenciálnym nástrojom na určenie správnej diagnózy a rodičovské poradenstvo.
Severe forms of early-onset polycystic kidneys in children represent a large group of diseases with overlapping clinical manifestations. A characteristic feature is enlarged kidneys with reduced function, which may be the result in Potter´s sequence in the prenatal period. However, the etiology of this manifestation is genetically very heterogeneous and can be caused by a disorder of a wide range of genes. The most common are PKHD1 mutations that lead to an autosomal recessive form of polycystic kidney (ARPKD). In almost the same number of cases the clinical manifestation of a severe form of polycystic kidney with onset in childhood is the result of PKD1 or PKD2 mutations associated with an autosomal dominant disease form (ADPKD). These mutations often arise de novo or can affect both alleles and lead to a recessive model of inheritance. Mutations in DZIP1L are a relatively new cause of the so-called ARPKD-like phenotype. Early and unambiguous diagnosis of these diseases will be confirmed by genetic testing. The current possibilities of next-generation sequencing allow simultaneous analysis of whole group of genes and represent a key role in the rapid diagnosis of these diseases. Causal gene identification is an essential tool for determining the correct diagnosis and parental counseling.
- MeSH
- chronické selhání ledvin MeSH
- genetická predispozice k nemoci MeSH
- genetické testování MeSH
- lidé MeSH
- mutace MeSH
- nefrotický syndrom diagnóza MeSH
- polycystická choroba ledvin * diagnóza patologie terapie MeSH
- polycystické ledviny autozomálně recesivní diagnóza patologie terapie MeSH
- renální insuficience MeSH
- tuberózní skleróza diagnóza komplikace MeSH
- Check Tag
- lidé MeSH
Mesocestoides vogae larvae represent a suitable model for evaluating the larvicidal potential of various compounds. In this study we investigated the in vitro effects of three natural flavonolignans-silybin (SB), 2,3-dehydrosilybin (DHSB) and silychristin (SCH)-on M. vogae larvae at concentrations of 5 and 50 μM under aerobic and hypoxic conditions for 72 h. With both kinds of treatment, the viability and motility of larvae remained unchanged, metabolic activity, neutral red uptake and concentrations of neutral lipids were reduced, in contrast with a significantly elevated glucose content. Incubation conditions modified the effects of individual FLs depending on their concentration. Under both sets of conditions, SB and SCH suppressed metabolic activity, the concentration of glucose, lipids and partially motility more at 50 μM, but neutral red uptake was elevated. DHSB exerted larvicidal activity and affected motility and neutral lipid concentrations differently depending on the cultivation conditions, whereas it decreased glucose concentration. DHSB at the 50 μM concentration caused irreversible morphological alterations along with damage to the microvillus surface of larvae, which was accompanied by unregulated neutral red uptake. In conclusion, SB and SCH suppressed mitochondrial functions and energy stores, inducing a physiological misbalance, whereas DHSB exhibited a direct larvicidal effect due to damage to the tegument and complete disruption of larval physiology and metabolism.
- MeSH
- antioxidancia farmakologie MeSH
- hypoxie * MeSH
- larva účinky léků fyziologie MeSH
- Mesocestoides účinky léků fyziologie MeSH
- ochranné látky farmakologie MeSH
- silibinin farmakologie MeSH
- silymarin farmakologie MeSH
- techniky in vitro MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
