• Klíčová slova
• HOSPITALS *, NATIONAL HEALTH PROGRAMS *,
• MeSH
• akademie a ústavy * MeSH
• lidé MeSH
• nemocnice * MeSH
• programy národního zdraví * MeSH
• veřejné zdravotnictví * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

• Klíčová slova
• PUBLIC HEALTH *,
• MeSH
• lidé MeSH
• práce * MeSH
• veřejné zdravotnictví * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

The specialties of allergy and clinical immunology have entered the era of precision medicine with the stratification of diseases into distinct disease subsets, specific diagnoses, and targeted treatment options, including biologicals and small molecules. This article reviews recent developments in research and patient care and future trends in the discipline. The section on basic mechanisms of allergic diseases summarizes the current status and defines research needs in structural biology, type 2 inflammation, immune tolerance, neuroimmune mechanisms, role of the microbiome and diet, environmental factors, and respiratory viral infections. In the section on diagnostic challenges, clinical trials, precision medicine and immune monitoring of allergic diseases, asthma, allergic and nonallergic rhinitis, and new approaches to the diagnosis and treatment of drug hypersensitivity reactions are discussed in further detail. In the third section, unmet needs and future research areas for the treatment of allergic diseases are highlighted with topics on food allergy, biologics, small molecules, and novel therapeutic concepts in allergen-specific immunotherapy for airway disease. Unknowns and future research needs are discussed at the end of each subsection.

• Klíčová slova
• allergy, exposome, microbiome, neuroimmune, respiratory viral infections,
• MeSH
• alergeny imunologie   MeSH
• alergie diagnóza   epidemiologie   etiologie   terapie   MeSH
• imunologická tolerance MeSH
• imunomodulace MeSH
• individualizovaná medicína MeSH
• interakce hostitele a patogenu MeSH
• lidé MeSH
• náchylnost k nemoci * MeSH
• neuroimunomodulace MeSH
• péče o pacienta * normy   MeSH
• vystavení vlivu životního prostředí MeSH
• výzkum trendy   MeSH
• zánět komplikace   MeSH
• zdravotnické služby - potřeby a požadavky MeSH
• životní prostředí MeSH
• zlepšení kvality * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• alergeny MeSH

Polycyclic aromatic hydrocarbons (PAH) are ubiquitous environmental pollutants, distinguished by genotoxic, hepatotoxic, nephrotoxic and immunotoxic effects. Especially secondary toxicity after bioactivation by microsomal monooxygenases (dependent on cytochromes P450) is characteristic of them. The immunotoxic effect is the result of very global impact on immunological reactivity of an organism and immunosuppression by induction of apoptosis of pre-B lymphocytes represents one of its particular forms. It has been proved that the effect of PAH is caused mostly by the following mechanisms: enzymatic induction by the way of activation of AhR (Aromatic hydrocarbon Receptor); alteration of cellular DNA; development of oxidative stress; increase in the concentration of intercellular calcium and decline of activity of NF-kappaB (Nuclear Factor-kappa B). Most sensitive to these changes are particularly B-lymphocytic precursors and pre-B lymphocytes. Intensity of entire manifestations is also considerably dependent on the presence and intensity of mechanisms of active or passive resistance of cells.

• MeSH
• apoptóza účinky léků   MeSH
• B-lymfocyty účinky léků   imunologie   fyziologie   MeSH
• hematopoetické kmenové buňky účinky léků   imunologie   MeSH
• imunologická tolerance účinky léků   MeSH
• imunosupresiva toxicita   MeSH
• kostní dřeň účinky léků   fyziologie   MeSH
• látky znečišťující životní prostředí toxicita   MeSH
• lidé MeSH
• polycyklické aromatické uhlovodíky toxicita   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• imunosupresiva MeSH
• látky znečišťující životní prostředí MeSH
• polycyklické aromatické uhlovodíky MeSH

The role of biomembranes in the chronic toxicity of environmentally occurring chromium acetate hydroxide was investigated by using primary human fibroblasts. Transport of chromium acetate hydroxide across the plasma membrane of the cell, and the effects of chromium (III) ions on the plasma membrane as well as other intracellular membranes, were determined during six weeks of continuous exposure by using atomic absorption spectrometry, observation of cell morphology, membrane integrity assays (for lactate dehydrogenase leakage and lysosomal membrane disruption), and mitochondrial assays (for mitochondrial dehydrogenase activity and mitochondrial transmembrane potential analysis). The type of cell death induced by long-term exposure was determined in terms of phosphatidylserine externalisation, caspase-3 activation, and chromatin fragmentation. Chromium acetate hydroxide, at a concentration of 100 micromol/l, accumulated in exposed cells, inflicting plasma membrane damage and suppressing mitochondrial function. Antioxidant co-enzyme Q, at a concentration of 10 micromol/l, partially prevented plasma membrane damage and mitochondrial dysfunction. Exposure to chromium acetate hydroxide produced apoptosis, necrosis and an intermediate type of cell death in primary human fibroblasts. These results show that the plasma membrane and mitochondrial membrane are important targets for chronic chromium acetate hydroxide toxicity, and that this in vitro system holds promise for studying the toxicity resulting from long-term exposure to metal ions.

• MeSH
• apoptóza účinky léků   MeSH
• fibroblasty účinky léků   metabolismus   patologie   MeSH
• intracelulární membrány účinky léků   enzymologie   MeSH
• kultivované buňky MeSH
• kůže účinky léků   metabolismus   patologie   MeSH
• L-laktátdehydrogenasa metabolismus   MeSH
• látky znečišťující životní prostředí toxicita   MeSH
• lidé MeSH
• lyzozomy účinky léků   MeSH
• mitochondrie účinky léků   enzymologie   MeSH
• nekróza MeSH
• organokovové sloučeniny toxicita   MeSH
• sloučeniny chromu toxicita   MeSH
• ubichinon farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• L-laktátdehydrogenasa MeSH
• látky znečišťující životní prostředí MeSH
• organokovové sloučeniny MeSH
• sloučeniny chromu MeSH
• ubichinon MeSH

The circadian clock is an endogenous timekeeper system that controls the daily rhythms of a variety of physiological processes. Accumulating evidence indicates that genetic changes or unhealthy lifestyle can lead to a disruption of circadian homeostasis, which is a risk factor for severe dysfunctions and pathologies including cancer. Cell cycle, proliferation, and cell death are closely intertwined with the circadian clock, and thus disruption of circadian rhythms appears to be linked to cancer development and progression. At the molecular level, the cell cycle machinery and the circadian clocks are controlled by similar mechanisms, including feedback loops of genes and protein products that display periodic activation and repression. Here, we review the circadian rhythmicity of genes associated with the cell cycle, proliferation, and apoptosis, and we highlight the potential connection between these processes, the circadian clock, and neoplastic transformations. Understanding these interconnections might have potential implications for the prevention and therapy of malignant diseases.

• Klíčová slova
• Apoptosis, MAPK cascade, Wnt signaling, cancer, cell cycle, circadian clock, proliferation,
• MeSH
• apoptóza genetika   fyziologie   MeSH
• buněčný cyklus genetika   fyziologie   MeSH
• cirkadiánní hodiny genetika   fyziologie   MeSH
• cirkadiánní rytmus fyziologie   MeSH
• homeostáza MeSH
• lidé MeSH
• nádorová transformace buněk genetika   MeSH
• nádory etiologie   genetika   patologie   MeSH
• proliferace buněk genetika   fyziologie   MeSH
• rizikové faktory MeSH
• životní styl MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Exposure to polycyclic aromatic hydrocarbons (PAHs) has been positively associated with prostate cancer, but knowledge of the formation of PAH-DNA adducts and related genotoxic events in prostatic cells is limited. In the present study, benzo[a]pyrene (BaP), a potent mutagenic PAH, formed significant levels of DNA adducts in cell lines derived from human prostate carcinoma. When analyzing the effect of BaP on the induction of CYP1 enzymes participating in the metabolic activation of PAHs in LNCaP cells, we found that BaP induced expression of CYP1A1 and CYP1A2, but not CYP1B1 enzyme. Despite a significant amount of DNA adducts being formed by BaP and, to a lesser extent also by another strong genotoxin, dibenzo[a,l]pyrene, neither apoptosis nor cell-cycle arrest were induced in LNCaP cells. LNCaP cells were not sensitized to the induction of apoptosis by PAHs even through inhibition of the phosphoinositide-3-kinase/Akt pro-survival pathway. The lack of apoptosis was not due a disruption of expression of pro-apoptotic and pro-survival members of the Bcl-2 family of apoptosis regulators. In contrast to other genotoxic stimuli, genotoxic PAHs failed to induce DNA double-strand breaks, as illustrated by the lack of phosphorylation of histone H2AX or checkpoint kinase-2. BaP did not activate p53, as evidenced by the lack of p53 accumulation, phosphorylation at Ser15, or induction of p53 transcriptional targets. Taken together, although genotoxic PAHs produced significant levels of DNA adducts in a model of human prostate carcinoma cells, they did not activate the mechanisms leading to elimination of cells with significant damage to DNA, presumably due to their failure to activate the p53-dependent DNA damage response.

• MeSH
• apoptóza účinky léků   MeSH
• karcinom metabolismus   MeSH
• látky znečišťující životní prostředí toxicita   MeSH
• nádorové buněčné linie MeSH
• nádorový supresorový protein p53 metabolismus   MeSH
• nádory prostaty metabolismus   MeSH
• polycyklické aromatické uhlovodíky toxicita   MeSH
• poškození DNA účinky léků   MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• látky znečišťující životní prostředí MeSH
• nádorový supresorový protein p53 MeSH
• polycyklické aromatické uhlovodíky MeSH

The study investigated the effects of postnatal exposure to polycyclic aromatic hydrocarbons (PAHs) on the development of the rat ovary. Neonates were injected on each postnatal day 1-14 with benzo(a)pyrene (BaP), benz(a)anthracene (BaA) and benzo(k)fluoranthene (BkF) (0.1, 1.0, 5.0 or 10.0 mg kg(-1)), ethynylestradiol (EE; 1.0 µg kg(-1)) or a vehicle (control group). The rats were killed on day 23. Postnatal exposure to BaP increased the total number of antral follicles in ovaries (P < 0.05) and the number of nonatretic follicles (P < 0.01) as a result of a lower degree of apoptosis of granulosa cells, and the thickness of theca cell layers (P < 0.01). Similar histological findings were observed after BaA administration. Conversely, BkF exposure caused a decrease in the number of antral follicles, but did not alter the other investigated parameters. Degeneration of primordial oocytes after exposure to PAHs was observed only after exposure to BaP. Treatment with BaP at doses of 1.0 and 10.0 mg kg(-1) impaired 28.1 and 60.3% of the primordial follicles, respectively. Substantial alterations in ovarian ERβ expression were detected in the rats; their intensity differed with the type of PAH. Response of the ovaries to EE (three injections of 1.0 µg kg(-1) on postnatal days 20-22) in rats exposed to PAHs was suppressed in contrast to the controls. The study showed that postnatal exposure to BaP, BaA and BkF altered ovarian ERβ expression, disturbed morphological development of the ovaries and caused ovarian dysfunction in immature rats.

• MeSH
• apoptóza účinky léků   MeSH
• endokrinní disruptory toxicita   MeSH
• krysa rodu Rattus MeSH
• nemoci ovaria chemicky indukované   patologie   MeSH
• novorozená zvířata MeSH
• ovarium účinky léků   růst a vývoj   patologie   MeSH
• polycyklické aromatické uhlovodíky toxicita   MeSH
• potkani Wistar MeSH
• stárnutí patologie   MeSH
• vystavení vlivu životního prostředí škodlivé účinky   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• endokrinní disruptory MeSH
• polycyklické aromatické uhlovodíky MeSH

In mammals, germ cell differentiation is initiated in the Primordial Germ Cells (PGCs) during fetal development. Prenatal exposure to environmental toxicants such as endocrine disruptors may alter PGC differentiation, development of the male germline and induce transgenerational epigenetic disorders. The anti-androgenic compound vinclozolin represents a paradigmatic example of molecule causing transgenerational effects on germ cells. We performed prenatal exposure to vinclozolin in mice and analyzed the phenotypic and molecular changes in three successive generations. A reduction in the number of embryonic PGCs and increased rate of apoptotic cells along with decrease of fertility rate in adult males were observed in F1 to F3 generations. Blimp1 is a crucial regulator of PGC differentiation. We show that prenatal exposure to vinclozolin deregulates specific microRNAs in PGCs, such as miR-23b and miR-21, inducing disequilibrium in the Lin28/let-7/Blimp1 pathway in three successive generations of males. As determined by global maps of cytosine methylation, we found no evidence for prominent changes in DNA methylation in PGCs or mature sperm. Our data suggest that embryonic exposure to environmental endocrine disruptors induces transgenerational epigenetic deregulation of expression of microRNAs affecting key regulatory pathways of germ cells differentiation.

• MeSH
• apoptóza MeSH
• buněčná diferenciace MeSH
• endokrinní disruptory toxicita   MeSH
• epigeneze genetická účinky léků   MeSH
• látky znečišťující životní prostředí toxicita   MeSH
• metylace DNA MeSH
• mikro RNA genetika   metabolismus   MeSH
• myši MeSH
• oxazoly toxicita   MeSH
• protein PRDI-BF1 MeSH
• těhotenství MeSH
• testis účinky léků   patologie   MeSH
• transkripční faktory genetika   metabolismus   MeSH
• zárodečné buňky účinky léků   fyziologie   MeSH
• zpožděný efekt prenatální expozice chemicky indukované   genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• endokrinní disruptory MeSH
• látky znečišťující životní prostředí MeSH
• mikro RNA MeSH
• oxazoly MeSH
• Prdm1 protein, mouse MeSH Prohlížeč
• protein PRDI-BF1 MeSH
• transkripční faktory MeSH
• vinclozolin MeSH Prohlížeč

T-2 toxin is the most toxic trichothecene mycotoxin, and it exerts potent toxic effects, including immunotoxicity, neurotoxicity, and reproductive toxicity. Recently, several novel metabolites, including 3',4'-dihydroxy-T-2 toxin and 4',4'-dihydroxy-T-2 toxin, have been uncovered. The enzymes CYP3A4 and carboxylesterase contribute to T-2 toxin metabolism, with 3'-hydroxy-T-2 toxin and HT-2 toxin as the corresponding primary products. Modified forms of T-2 toxin, including T-2-3-glucoside, exert their immunotoxic effects by signaling through JAK/STAT but not MAPK. T-2-3-glucoside results from hydrolyzation of the corresponding parent mycotoxin and other metabolites by the intestinal microbiota, which leads to enhanced toxicity. Increasing evidence has shown that autophagy, hypoxia-inducible factors, and exosomes are involved in T-2 toxin-induced immunotoxicity. Autophagy promotes the immunosuppression induced by T-2 toxin, and a complex crosstalk between apoptosis and autophagy exists. Very recently, "immune evasion" activity was reported to be associated with this toxin; this activity is initiated inside cells and allows pathogens to escape the host immune response. Moreover, T-2 toxin has the potential to trigger hypoxia in cells, which is related to activation of hypoxia-inducible factor and the release of exosomes, leading to immunotoxicity. Based on the data from a series of human exposure studies, free T-2 toxin, HT-2 toxin, and HT-2-4-glucuronide should be considered human T-2 toxin biomarkers in the urine. The present review focuses on novel findings related to the metabolism, immunotoxicity, and human exposure assessment of T-2 toxin and its modified forms. In particular, the immunotoxicity mechanisms of T-2 toxin and the toxicity mechanism of its modified form, as well as human T-2 toxin biomarkers, are discussed. This work will contribute to an improved understanding of the immunotoxicity mechanism of T-2 toxin and its modified forms.

• Klíčová slova
• Biomarkers, Human exposure assessments, Immunotoxicity, Metabolism, Modified T-2 toxin, T-2 toxin,
• MeSH
• apoptóza MeSH
• autofagie MeSH
• biologické markery MeSH
• hypoxie buňky MeSH
• lidé MeSH
• signální transdukce MeSH
• T-2 toxin analogy a deriváty   metabolismus   toxicita   MeSH
• vystavení vlivu životního prostředí analýza   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• 3'-hydroxy-T-2 toxin MeSH Prohlížeč
• biologické markery MeSH
• HT-2 toxin MeSH Prohlížeč
• T-2 toxin MeSH