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• Klíčová slova
• nucleophosmin 1, CEBPA,
• MeSH
• akutní myeloidní leukemie * diagnóza   etiologie   genetika   mortalita   patofyziologie   terapie   MeSH
• cytarabin terapeutické užití   MeSH
• cytostatické látky terapeutické užití   MeSH
• genetické markery MeSH
• homologní transplantace MeSH
• indukční chemoterapie MeSH
• jaderné proteiny genetika   MeSH
• konsolidační chemoterapie MeSH
• lidé MeSH
• mutace MeSH
• nádorové biomarkery MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• prognóza MeSH
• proteiny vázající zesilovač transkripce CCAAT genetika   MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   MeSH
• průtoková cytometrie MeSH
• recidiva MeSH
• reziduální nádor genetika   MeSH
• rizikové faktory MeSH
• transplantace kostní dřeně MeSH
• tyrosinkinasa 3 podobná fms genetika   MeSH
• věkové faktory MeSH
• Check Tag
• lidé MeSH

OBJECTIVES: Hyaluronan, a linear glycosaminoglycan, is an abundant component of extracellular matrix. In its native form, the high-molar-mass hyaluronan polymers have an array of structural and regulatory, mainly anti-inflammatory and anti-angiogenic, functions. In contradiction, the biological effects of fragmented low molecular weight hyaluronan are suggested to be pro-angiogenic and pro-inflammatory. METHODS: The effects of highly purified pharmacological grade hyaluronan of defined molecular weights 11, 52, 87, 250 and 970 kilodaltons were tested on mouse macrophage cell lines RAW 264.7 and MHS. The surface expression of CD44 and Toll-like receptor 2, surface receptors for hyaluronan, was determined by flow cytometry. Activation of macrophages was determined based on nitric oxide and tumour necrosis factor alpha production, inducible nitric oxide synthase expression, and the activation of the nuclear factor kappa B transcriptional factor. RESULTS: Both macrophage cell lines expressed CD44 and Toll-like receptor 2, which were significantly increased by the pre-treatment of macrophages with bacterial lipopolysaccharide. Hyaluronan of any molecular weight did not activate production of nitric oxide or tumour necrosis factor alpha in any mouse macrophage cell lines. Correspondingly, hyaluronan of any tested molecular weight did not stimulate nuclear factor kappa B activation. Similarly, hyaluronan of any molecular weight neither exerted stimulatory nor inhibitory effects on macrophages pre-treated by lipopolysaccharide. CONCLUSION: Interestingly, the data does not support the current view of low molecular weight hyaluronan as a pro-inflammatory mediator for macrophages. Further studies are necessary to clarify the effects of different molecular weight hyaluronan on phagocytes.

• MeSH
• aktivace makrofágů účinky léků   fyziologie   MeSH
• antigeny CD44 metabolismus   MeSH
• buněčné linie MeSH
• kyselina hyaluronová chemie   metabolismus   farmakologie   MeSH
• lipopolysacharidy toxicita   MeSH
• makrofágy chemie   účinky léků   fyziologie   MeSH
• molekulová hmotnost MeSH
• myši MeSH
• NF-kappa B metabolismus   MeSH
• oxid dusnatý metabolismus   MeSH
• průtoková cytometrie MeSH
• synthasa oxidu dusnatého, typ II metabolismus   MeSH
• TNF-alfa metabolismus   MeSH
• toll-like receptor 2 metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Doxorubicin is one of the most potent anti-tumor drugs with a broad spectrum of use. To reduce its toxic effect and improve its pharmacokinetics, we conjugated it to an HPMA copolymer carrier that enhances its passive accumulation within solid tumors via the EPR effect and decreases its cytotoxicity to normal, noncancer cells. In this study, we compared the antiproliferative, pro-survival, and death signals triggered in EL-4 cancer cells exposed to free doxorubicin and doxorubicin conjugated to a HPMA copolymer carrier via either enzymatically (PK1) or hydrolytically (HYD) degradable bonds. We have previously shown that the intracellular distribution of free doxorubicin, HYD, and PK1 is markedly different. Here, we demonstrated that these three agents greatly differ also in the antiproliferative effect and cell death signals they trigger. JNK phosphorylation sharply increased in cells treated with HYD, while treatment with free doxorubicin moderately decreased and treatment with PK1 even strongly decreased it. On the other hand, treatment with free doxorubicin greatly increased p38 phosphorylation, while PK1 and HYD increased it slightly. PK1 also significantly increased ERK phosphorylation, while both the free doxorubicin and HYD conjugate slightly decreased it. Long-term inhibition of JNK significantly increased both proliferation and viability of EL-4 cells treated with free doxorubicin, showing that the JNK signaling pathway could be critical for mediating cell death in EL-4 cells exposed to free doxorubicin. Both activation of caspase 3 and decreased binding activity of the p50 subunit of NFkappaB were observed in cells treated with free doxorubicin and HYD, while no such effects were seen in cells incubated with PK1. Analysis of the expression of genes involved in apoptosis and regulation of the cell cycle demonstrated that free doxorubicin and HYD have very similar mechanisms of action, while PK1 has very different characteristics.

• MeSH
• akrylamidy analýza   farmakologie   chemie   MeSH
• apoptóza genetika   MeSH
• CDC geny MeSH
• doxorubicin analýza   farmakologie   chemie   MeSH
• exprese genu účinky léků   MeSH
• financování organizované MeSH
• fosforylace MeSH
• inhibiční koncentrace 50 MeSH
• kaspasa 3 metabolismus   MeSH
• lymfom T-buněčný chemie   metabolismus   MeSH
• mitogenem aktivované proteinkinasy kinas antagonisté a inhibitory   metabolismus   MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• NF-kappa B metabolismus   MeSH
• proliferace buněk účinky léků   MeSH
• průtoková cytometrie MeSH
• viabilita buněk MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH

To elucidate the role of innate immune responses in celiac disease, we investigated the effect of gliadin on blood monocytes from patients with celiac disease. Gliadin induced substantial TNF-alpha and IL-8 production by monocytes from patients with active celiac disease, lower levels by monocytes from patients with inactive celiac disease, and even lower levels by monocytes from healthy donors. In healthy donor monocytes gliadin induced IL-8 from monocytes expressing HLA-DQ2 and increased monocyte expression of the costimulatory molecules CD80 and CD86, the dendritic cell marker CD83, and the activation marker CD40. Gliadin also increased DNA binding activity of NF-kappaB p50 and p65 subunits in monocytes from celiac patients, and NF-kappaB inhibitors reduced both DNA binding activity and cytokine production. Thus, gliadin activation of HLA-DQ2(+) monocytes leading to chemokine and proinflammatory cytokine production may contribute to the host innate immune response in celiac disease.

• MeSH
• aktivace makrofágů imunologie   MeSH
• antigeny CD40 metabolismus   MeSH
• antigeny CD80 metabolismus   MeSH
• antigeny CD86 metabolismus   MeSH
• CD antigeny metabolismus   MeSH
• celiakie imunologie   metabolismus   MeSH
• cytokiny biosyntéza   MeSH
• financování organizované MeSH
• gliadin metabolismus   MeSH
• HLA-DQ antigeny metabolismus   MeSH
• imunoglobuliny metabolismus   MeSH
• interleukin-8 biosyntéza   MeSH
• lidé MeSH
• membránové glykoproteiny metabolismus   MeSH
• monocyty metabolismus   MeSH
• NF-kappa B metabolismus   MeSH
• peptidové fragmenty MeSH
• průtoková cytometrie MeSH
• TNF-alfa biosyntéza   MeSH
• Check Tag
• lidé MeSH

This study investigated the effect of exercise training on the flow-mediated dilation (FMD) in gastrocnemius muscle arteries from spontaneously hypertensive rats (SHR). SHR and WKY rats were divided into sedentary and exercised groups. After swimming exercise for eight weeks, the isolated arteries were mounted on pressurized myograph and FMD responses examined. The role of nitric oxide (NO), prostaglandins (PGs) and endothelium derived hyperpolarizing factor (EDHF) on FMD were assessed by obtaining dilation responses in the presence and absence of pharmacological antagonists. N(omega)-nitro-L-arginine methyl ester (L-NAME), indomethacin (INDO) and tetraethylamonium (TEA) were used to inhibit nitric oxide synthase, cyclooxygenase and EDHF-mediated responses, respectively. The FMD response was significantly blunted in arteries of SHR compared with WKY rats, and, improved by exercise training in SHR (SHR-ET) group. In SHR arteries, L NAME and TEA did not affect dilation responses to flow, while INDO led to a significant enhancement in this response. Although dilation response was not altered by L-NAME in arteries obtained from trained SHR, TEA caused a significant attenuation and INDO led to significant increases. These results demonstrate that exercise training improves FMD in SHR, and, this enhancement induced by exercise training occurs through EDHF-mediated mechanism(s).

• MeSH
• hypertenze patofyziologie   terapie   MeSH
• kondiční příprava zvířat fyziologie   metody   MeSH
• kosterní svaly MeSH
• krysa rodu rattus MeSH
• potkani inbrední SHR MeSH
• potkani inbrední WKY MeSH
• rychlost toku krve fyziologie   MeSH
• vazodilatace fyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• srovnávací studie MeSH

The paper deals with modeling the liver perfusion intended to improve quantitative analysis of the tissue scans provided by the contrast-enhanced computed tomography (CT). For this purpose, we developed a model of dynamic transport of the contrast fluid through the hierarchies of the perfusion trees. Conceptually, computed time-space distributions of the so-called tissue density can be compared with the measured data obtained from CT; such a modeling feedback can be used for model parameter identification. The blood flow is characterized at several scales for which different models are used. Flows in upper hierarchies represented by larger branching vessels are described using simple 1D models based on the Bernoulli equation extended by correction terms to respect the local pressure losses. To describe flows in smaller vessels and in the tissue parenchyma, we propose a 3D continuum model of porous medium defined in terms of hierarchically matched compartments characterized by hydraulic permeabilities. The 1D models corresponding to the portal and hepatic veins are coupled with the 3D model through point sources, or sinks. The contrast fluid saturation is governed by transport equations adapted for the 1D and 3D flow models. The complex perfusion model has been implemented using the finite element and finite volume methods. We report numerical examples computed for anatomically relevant geometries of the liver organ and of the principal vascular trees. The simulated tissue density corresponding to the CT examination output reflects a pathology modeled as a localized permeability deficiency.

• MeSH
• analýza metodou konečných prvků MeSH
• biologické modely MeSH
• jaterní oběh * fyziologie   MeSH
• játra krevní zásobení   diagnostické zobrazování   MeSH
• kontrastní látky farmakokinetika   MeSH
• lidé MeSH
• matematické pojmy MeSH
• počítačová rentgenová tomografie statistika a číselné údaje   MeSH
• počítačová simulace MeSH
• poréznost MeSH
• vylepšení rentgenového snímku metody   MeSH
• zobrazování trojrozměrné statistika a číselné údaje   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Nowadays, most of the newly developed active pharmaceutical ingredients (APIs) consist of cohesive particles with a mean particle size of <100μm, a wide particle size distribution (PSD) and a tendency to agglomerate, therefore they are difficult to handle in continuous manufacturing (CM) lines. The current paper focuses on the impact of various glidants on the bulk properties of difficult-to-handle APIs. Three challenging powders were included: two extremely cohesive APIs (acetaminophen micronized (APAPμ) and metoprolol tartrate (MPT)) which previously have shown processing issues during different stages of the continuous direct compression (CDC)-line and a spray dried placebo (SD) powder containing hydroxypropylmethyl cellulose (HPMC), known for its sub-optimal flow with a high specific surface area (SSA) and low density. Four flow-enhancing excipients were used: a hydrophilic (Aerosil® 200) and hydrophobic (Aerosil® R972) fumed silica grade, a mesoporous silica grade (Syloid® 244FP), and a calcium phosphate excipient (TRI-CAFOS® 200-7). The APIs and binary API/glidant blends (varied between 0.5-2.75 w/w%) were characterized for their bulk properties relevant for CDC. The results indicated that optimizing different bulk parameters (e.g., density, flow, compressibility..) of an API required varying weight percentages of the glidant (e.g., different surface area coverage (SAC)) depending on the APIs. Moreover, even at similar SAC, the impact of the glidant on the bulk characteristic of the APIs depended on the glidant type properties. While nano-sized silicon dioxide were effective for improving the flowability of a powder, other glidants (mesoporous silica and tricalcium phosphate (TCP)) showed also promise as alternatives. Additionally, an excess of glidant, referred to as oversilication, negatively impacted some bulk parameters, but other characteristics were unaffected. Finally, to determine the appropriate concentration of the different classes of glidants, SAC calculations, an understanding of the glidant's working mechanism, and knowledge about the API's characteristics (i.e., morphology, compressibility, flowability, aeration, density, and wall friction) are required. This study confirmed the necessity of including various material characterization techniques to assess the impact of glidants on the bulk characteristics of APIs.

• MeSH
• deriváty hypromelózy * chemie   MeSH
• farmaceutická chemie metody   MeSH
• fosforečnany vápenaté * chemie   MeSH
• hydrofobní a hydrofilní interakce MeSH
• metoprolol * chemie   MeSH
• nerozplněné léky MeSH
• oxid křemičitý chemie   MeSH
• paracetamol * chemie   MeSH
• pomocné látky * chemie   MeSH
• prášky, zásypy, pudry * MeSH
• příprava léků metody   MeSH
• reologie * MeSH
• velikost částic * MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• cévy patofyziologie   MeSH
• dilatace patologická MeSH
• krevní tlak MeSH
• regionální krevní průtok MeSH

Cilostazol is a phosphodiesterase-3 inhibitor that functions as a platelet aggregation inhibitor and is used for treating peripheral artery diseases and ischemic stroke. Dendritic cells (DCs) play an active role in the immunological processes related to atherosclerosis. Cilostazol has anti-atherogenic and anti-inflammatory effects, but the effects of cilostazol on DC maturation remain unknown. The purpose of this study was to determine the effects of cilostazol on lipopolysaccharide (LPS)-induced maturation of DCs. DC2.4 cells were treated with cilostazol for 12 h and subsequently stimulated with LPS to induce maturation. Cilostazol reduced the expression of maturation-associated markers induced by LPS, such as CD40, CD86, and MHCII, improved the endocytotic function, and decreased production of the tumour necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) of these cells. To further elucidate the mechanisms responsible for the inhibition of DC2.4 maturation by cilostazol, we investigated the effect of cilostazol on LPS-stimulated nuclear factor-kappa B (NF-κB) activation. Our results indicated that cilostazol treatment decreased IκBα degradation and inhibited NF-κB p65 translocation, and the inhibitory effects of cilostazol were cAMP-independent. Therefore, inhibition of NF-κB by cilostazol might result in the suppression of DC maturation. In conclusion, cilostazol suppressed LPS-stimulated DC maturation, which might contribute to its anti-atherosclerosis effect.

• MeSH
• antigeny CD40 imunologie   MeSH
• antigeny CD86 imunologie   MeSH
• ateroskleróza imunologie   patofyziologie   MeSH
• buněčná imunita imunologie   účinky léků   MeSH
• dendritické buňky * chemie   imunologie   účinky léků   MeSH
• fibrinolytika MeSH
• inhibitory agregace trombocytů MeSH
• inhibitory fosfodiesterasy 3 MeSH
• interleukin-6 imunologie   MeSH
• lipopolysacharidy terapeutické užití   MeSH
• MHC antigeny II. třídy imunologie   MeSH
• NF-kappa B * genetika   imunologie   účinky léků   MeSH
• polymerázová řetězová reakce MeSH
• průtoková cytometrie MeSH
• techniky in vitro MeSH
• tetrazoly * farmakologie   imunologie   MeSH
• TNF-alfa imunologie   MeSH
• vazodilatancia MeSH
• western blotting MeSH
• Publikační typ
• práce podpořená grantem MeSH

• MeSH
• chirurgické laloky MeSH
• lidé MeSH
• mikrochirurgie MeSH
• mikrocirkulace MeSH
• rychlost toku krve MeSH
• Check Tag
• lidé MeSH