Rationale: Loss of histone macroH2A1 induces appearance of cancer stem cells (CSCs)-like cells in hepatocellular carcinoma (HCC). How CSCs interact with the tumor microenvironment and the adaptive immune system is unclear. Methods: We screened aggressive human HCC for macroH2A1 and CD44 CSC marker expression. We also knocked down (KD) macroH2A1 in HCC cells, and performed integrated transcriptomic and secretomic analyses. Results: Human HCC showed low macroH2A1 and high CD44 expression compared to control tissues. MacroH2A1 KD CSC-like cells transferred paracrinally their chemoresistant properties to parental HCC cells. MacroH2A1 KD conditioned media transcriptionally reprogrammed parental HCC cells activated regulatory CD4+/CD25+/FoxP3+ T cells (Tregs). Conclusions: Loss of macroH2A1 in HCC cells drives cancer stem-cell propagation and evasion from immune surveillance.

• MeSH
• antigeny CD44 metabolismus   MeSH
• chemorezistence * MeSH
• forkhead transkripční faktory metabolismus   MeSH
• genový knockdown MeSH
• glykolýza MeSH
• hepatocelulární karcinom farmakoterapie   imunologie   metabolismus   patologie   MeSH
• histony metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metabolomika metody   MeSH
• nádorové buněčné linie MeSH
• nádorové kmenové buňky účinky léků   imunologie   patologie   MeSH
• nádorové mikroprostředí imunologie   MeSH
• nádory jater farmakoterapie   imunologie   metabolismus   patologie   MeSH
• parakrinní signalizace * MeSH
• receptor interleukinu-2 - alfa-podjednotka metabolismus   MeSH
• regulace genové exprese u nádorů MeSH
• regulační T-lymfocyty imunologie   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Many cancers arise at sites of infection and inflammation. Cellular senescence, a permanent state of cell cycle arrest that provides a barrier against tumorigenesis, is accompanied by elevated proinflammatory cytokines such as IL1, IL6, IL8 and TNFα. Here we demonstrate that media conditioned by cells undergoing any of the three main forms of senescence, i.e. replicative, oncogene- and drug-induced, contain high levels of IL1, IL6, and TGFb capable of inducing reactive oxygen species (ROS)-mediated DNA damage response (DDR). Persistent cytokine signaling and activated DDR evoke senescence in normal bystander cells, accompanied by activation of the JAK/STAT, TGFβ/SMAD and IL1/NFκB signaling pathways. Whereas inhibition of IL6/STAT signaling had no effect on DDR induction in bystander cells, inhibition of either TGFβ/SMAD or IL1/NFκB pathway resulted in decreased ROS production and reduced DDR in bystander cells. Simultaneous inhibition of both TGFβ/SMAD and IL1/NFκB pathways completely suppressed DDR indicating that IL1 and TGFβ cooperate to induce and/or maintain bystander senescence. Furthermore, the observed IL1- and TGFβ-induced expression of NAPDH oxidase Nox4 indicates a mechanistic link between the senescence-associated secretory phenotype (SASP) and DNA damage signaling as a feature shared by development of all major forms of paracrine bystander senescence.

• MeSH
• buněčné linie MeSH
• bystander efekt účinky léků   MeSH
• etoposid farmakologie   MeSH
• geny ras * MeSH
• interleukin-1 metabolismus   MeSH
• interleukin-6 metabolismus   MeSH
• Janus kinasy metabolismus   MeSH
• kultivační média speciální metabolismus   MeSH
• lidé MeSH
• NADPH-oxidasy metabolismus   MeSH
• NF-kappa B metabolismus   MeSH
• oxidační stres účinky léků   MeSH
• parakrinní signalizace účinky léků   MeSH
• poškození DNA * MeSH
• proliferace buněk * MeSH
• proteiny Smad metabolismus   MeSH
• RNA interference MeSH
• signální transdukce účinky léků   MeSH
• stárnutí buněk účinky léků   MeSH
• transfekce MeSH
• transformující růstový faktor beta metabolismus   MeSH
• transkripční faktory STAT metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Growth stimuli in cancer growth resemble those exhibited in wound healing. However, the process of nemosis is absent in cancer-associated fibroblasts (CAFs), which remain constitutively active. CAFs are present in almost all solid tumors but are most abundant in breast, prostate and pancreatic cancers. TGF-β1, TGF-β2, PDGF, IL-6, bFGF, reactive oxide species and protein kinase C are considered the key players in tumor-induced transdifferentiation of surrounding fibroblasts. Full-extent transdifferentiation was obtained only when the medium contained TGF-β1 or TGF-β2 (with or without other factors), whereas PDGF, bFGF or IL-6 (each alone) induced only partial transdifferentiation. Recent evidence suggests that the fibroblasts associated with primary cancers differ from those associated with metastases. The metastases-associated fibroblasts are converted by a metastasis-specific spectrum of factors. A large portion of paracrine tumor signaling is mediated by cancer cell-derived vesicles termed exosomes and microvesicles. The cancer cell-derived exosomes contain abundant and diverse proteomes and a number of signaling factors (TGF-ß1, TGF-ß2, IL-6, MMP2 and MMP9), particularly under hypoxic conditions. In contrast to the traditional view, the clonal expansion and selection of neoplastic cells should not be viewed outside the host body context. It is vital for a neoplastic cell to achieve the ability to re-program host body cells into CAFs and by this influence to modulate its microenvironment and receive positive feedback for growth and drug resistance. Neoplastic cells, which fail to develop such capacity, do not pass critical barriers in tumorigenesis and remain dormant and benign.

• MeSH
• fibroblasty cytologie   MeSH
• lidé MeSH
• nádorové mikroprostředí fyziologie   MeSH
• nádory patologie   MeSH
• signální transdukce fyziologie   MeSH
• transdiferenciace buněk fyziologie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

OBJECTIVE: Progranulin (PGRN) is implicated in the pathogenesis of rheumatoid arthritis (RA). The aim of this study was to assess the relationship between PGRN and disease activity in RA. METHODS: PGRN levels were evaluated in patients with RA (n = 47) and OA (n = 42) and healthy controls (n = 41). Immunohistochemical analysis of PGRN in synovial tissues was performed. The association between PGRN and C-reactive protein (CRP), disease activity score (DAS28-CRP), and health assessment questionnaire (HAQ) was studied. RESULTS: Circulating PGRN was elevated in patients with RA and OA compared to healthy controls (227.1 ± 100.2 and 221.5 ± 102.5 versus 128.1 ± 34.7 ng/mL; P < 0.001). Synovial fluid levels of PGRN were higher in patients with RA compared to OA (384.5 ± 275.3 versus 241.4 ± 165.2 ng/mL; P = 0.002). PGRN expression was significantly upregulated in the synovial tissue of RA patients particularly in the inflammatory infiltrates. Serum PGRN levels correlated with DAS28 (r = 0.327, P = 0.049) and HAQ score (r = 0.323, P = 0.032), while synovial fluid PGRN correlated only with HAQ (r = 0.310, P = 0.043) in patients with RA. PGRN levels were not associated with CRP or autoantibodies. CONCLUSIONS: This study demonstrates increased PGRN expression at local sites of inflammation and association between PGRN levels, disease activity, and functional impairment in patients with RA.

• MeSH
• C-reaktivní protein metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mezibuněčné signální peptidy a proteiny metabolismus   MeSH
• revmatoidní artritida metabolismus   patologie   MeSH
• senioři MeSH
• synoviální membrána metabolismus   MeSH
• synoviální tekutina metabolismus   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Stem cell treatment provides a promising therapy for patients with spinal cord injury (SCI). However, the applied stem cells exert their effects in different manners that are dependent on the route used for administration. METHODS: In the present study, we administered neural precursors derived from induced pluripotent stem cells (iPS-NPs) either intraspinally into the lesion center or intrathecally into the subarachnoid space of rats with a balloon-induced spinal cord compression lesion. Functional locomotor performance, cell survival, astrogliosis, axonal sprouting and the expression of endogenous neurotrophic growth factors were evaluated using behavioral tests (BBB, flat beam test, rotarod, plantar test), morphometric analysis, immunohistochemistry and qPCR. RESULTS: Both treatments facilitated the functional locomotor recovery of rats with SCI. iPS-NPs injected intraspinally survived well for 2 months and were positive for MAP2, while cells grafted intrathecally were undetectable at the site of administration or in the spinal cord tissue. Intraspinal implantation increased gray and white matter sparing and axonal sprouting and reduced astrogliosis, while intrathecal application resulted only in an improvement of white matter sparing and an increase in axonal sprouting, in parallel with no positive effect on the expression of endogenous neurotrophic growth factor genes or glial scar reduction. CONCLUSIONS: Intrathecally grafted iPS-NPs had a moderate therapeutic benefit on SCI through a paracrine mechanism that does not require the cells to be present in the tissue; however, the extended survival of i.s. grafted cells in the spinal cord may promote long-term spinal cord tissue regeneration.

• MeSH
• buněčná diferenciace MeSH
• indukované pluripotentní kmenové buňky cytologie   transplantace   MeSH
• krysa rodu rattus MeSH
• lokomoce MeSH
• nervové kmenové buňky cytologie   transplantace   MeSH
• parakrinní signalizace MeSH
• poranění míchy patologie   patofyziologie   terapie   MeSH
• potkani Wistar MeSH
• proteiny nervové tkáně genetika   metabolismus   MeSH
• regenerace nervu MeSH
• spinální injekce metody   MeSH
• viabilita buněk MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH

Procathepsin D (pCD) is a major secreted protein in estrogen receptor-positive (ER+) breast cancer cell lines. Several independent studies have documented pronounced mitogenic effect of secreted pCD on cancer tissue-derived cell lines, including those from breast, lung, and prostate cancer. It has also been shown that the proliferative effect of pCD involves both autocrine and paracrine modes of action. Recent studies have suggested that pCD could act as a key paracrine communicator between cancer and stromal cells. We have shown earlier that the proliferative activity of pCD depends on the activation peptide sequence of pCD. The present study casts light on the mechanism by which pCD influences the proliferation of cancer cells expressing the ER. Results described in the current paper clearly show that pCD initiates secretion of cytokines interleukin-4 (IL-4), IL-8, IL-10, IL-13, macrophage inflammatory protein-1beta and (MIP-1beta) from such tumor cells. Secreted cytokines take part in the proliferation of the cancer cells, as proven by selective inhibition using antibodies. In addition, expression of cytokine receptors on tested cell lines corresponded to the effects of individual cytokines. An analogous pattern was also observed for fibroblasts, which, under physiologic conditions, are the cells in closest contact with the tumor tissue and play a role in tumor growth and invasion. Our observations were further supported by coculture experiments that are in agreement. Although very similar in response to addition of pCD, the invasive ER- cells do not secrete cytokines. Together with previous in vivo results, these data point to pCD as one of key molecules for therapeutic attack in breast cancer.

• MeSH
• autokrinní signalizace MeSH
• cytokiny sekrece   MeSH
• financování organizované MeSH
• kathepsin D sekrece   terapeutické užití   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory prsu farmakoterapie   patologie   sekrece   MeSH
• parakrinní signalizace MeSH
• prekurzory enzymů sekrece   terapeutické užití   MeSH
• proliferace buněk MeSH
• receptory pro estrogeny MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• zvířata MeSH

Vzestup výskytu obezity z ní činí celosvětově neinfekční epidemiologickou hrozbu pro zdraví populace. Vnější aspekty (životní styl, energetický příjem, pohyb) hrají pro obezitu klíčovou roli, ale nikoli jedinou. Genetický podíl není zatím vysvětlen. Na rozsáhlé populační studii budeme sledovat geny pro perilipin a FOXC2 a jejich roli v genetické determinaci obezity.; The increase of the obesity abundance makes it a worldwide non-infectious epidemiological danger for the population health. External aspects (life style, energy intake, locomotor activity) play a key role, genetic effects being yet unexplained. In an extensive population study, we will follow genes for perilipin and FOXC2 and their roles in the genetic determination of the obesity.

• MeSH
• genotyp MeSH
• mezibuněčné signální peptidy a proteiny analýza   MeSH
• nadváha genetika   MeSH
• obezita genetika   MeSH
• polymorfismus genetický MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• vnitřní lékařství
• genetika, lékařská genetika
• NLK Publikační typ
• závěrečné zprávy o řešení grantu IGA MZ ČR

The thymus plays a critical role in establishing and maintaining the peripheral T-cell pool. It does so by providing a microenvironment within which T-cell precursors differentiate and undergo selection processes to create a functional population of major histocompatibility complex-restricted, self-tolerant T cells. These cells are central to adaptive immunity. Thymic T-cell development is influenced by locally produced soluble factors and cell-to-cell interactions, as well as by sympathetic noradrenergic and endocrine system signalling. Thymic lymphoid and non-lymphoid cells have been shown not only to express beta- and alpha(1)- adrenoceptors (ARs), but also to synthesize catecholamines (CAs). Thus, it is suggested that CAs influence T-cell development via both neurocrine/endocrine and autocrine/paracrine action, and that they serve as immunotransmitters between thymocytes and nerves. CAs acting at multiple sites along the thymocyte developmental route affect T-cell generation not only numerically, but also qualitatively. Thymic CA level and synthesis, as well as AR expression exhibit sex steroid-mediated sexual dimorphism. Moreover, the influence of CAs on T-cell development exhibits glucocorticoid-dependent plasticity. This review summarizes recent findings in this field and our current understanding of complex and multifaceted neuroendocrine-immune communications at thymic level.

• MeSH
• adrenergní receptory fyziologie   imunologie   MeSH
• experimenty na zvířatech MeSH
• financování organizované MeSH
• glukokortikoidy fyziologie   imunologie   MeSH
• homeostáza fyziologie   imunologie   MeSH
• katecholaminy fyziologie   imunologie   MeSH
• krysa rodu rattus MeSH
• metaanalýza jako téma MeSH
• pohlavní dimorfismus MeSH
• statistika jako téma MeSH
• T-lymfocyty cytologie   fyziologie   imunologie   MeSH
• thymové hormony fyziologie   izolace a purifikace   metabolismus   MeSH
• thymus anatomie a histologie   enzymologie   fyziologie   MeSH
• Check Tag
• krysa rodu rattus MeSH
• Publikační typ
• přehledy MeSH

Insulin-like Growth Factor-2 (IGF2) is important for the regulation of human embryonic growth and development, and for adults' physiology. Incorrect processing of the IGF2 precursor, pro-IGF2(156), leads to the formation of two IGF2 proforms, big-IGF2(87) and big-IGF2(104). Unprocessed and mainly non-glycosylated IGF2 proforms are found at abnormally high levels in certain diseases, but their mode of action is still unclear. Here, we found that pro-IGF2(156) has the lowest ability to form its inactivating complexes with IGF-Binding Proteins and has higher proliferative properties in cells than IGF2 and other IGF prohormones. We also showed that big-IGF2(104) has a seven-fold higher binding affinity for the IGF2 receptor than IGF2, and that pro-IGF2(87) binds and activates specific receptors and stimulates cell growth similarly to the mature IGF2. The properties of these pro-IGF2 forms, especially of pro-IGF2(156) and big-IGF2(104), indicate them as hormones that may be associated with human diseases related to the accumulation of IGF-2 proforms in the circulation.

• MeSH
• buněčný cyklus MeSH
• dospělí MeSH
• insulinu podobný růstový faktor II * MeSH
• lidé MeSH
• mezibuněčné signální peptidy a proteiny * MeSH
• mitogeny MeSH
• proliferace buněk MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• biologické faktory MeSH
• cílená genová oprava MeSH
• mezibuněčné signální peptidy a proteiny MeSH
• peptidy MeSH
• proteinové inženýrství MeSH
• transformace genetická MeSH
• Publikační typ
• abstrakty MeSH
• sborníky MeSH

• Konspekt
• Biochemie. Molekulární biologie. Biofyzika
• NLK Obory
• biochemie
• biologie