This current study seeks to examine the pre-protective function of Quercetin in Cadmium (Cd)-induced liver damage, along with its modulation of the PI3K/Akt/NF-kappaB signaling pathway. A total of 60 male C57BL/6J mice were randomly assigned to four groups: control (C), quercetin (Q, 100 mg/kg/day), Cd (Cd, 2.5 mg/kg/day), and quercetin and Cd (Q+Cd). Before receiving Cd treatment, quercetin was administered intragastrically for 4 weeks. In the present study, liver markers, oxidative stress parameters, pro-inflammatory cytokines, liver histopathology, apoptotic markers and PI3K/Akt/NF-kappaB signaling molecules were examined. We observed that the body weight of the Cd-treated mice dramatically rise after 4 weeks of quercetin pre-administration, and the Cd concentration was significantly decreased. Liver function markers like alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) were significantly reduced in quercetin treatment in Cd-induced mice. Additionally, we observed that quercetin reduced Cd-mediated liver injury in mice by assessing the level of malondialdehyde (MDA), and the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione (GSH) concentrations and the histological alterations. By monitoring tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1beta (IL-1beta), quercetin successfully reduced the inflammatory cytokines that the Cd metal caused in the liver. Additionally, in the liver tissues of Cd-mediated, quercetin could enhance the expression of Bcl-2 and decrease the expression of p-Akt, p-PI3K, Bax, Caspase-9, Caspase-3, NF-kappaB. In conclusion, quercetin protects against Cd induced liver injury via several pathways, including oxidative stress, inflammation and apoptosis, and its protective effect correlates with antioxidant activity.

• MeSH
• antioxidancia * farmakologie   MeSH
• fosfatidylinositol-3-kinasy * metabolismus   MeSH
• játra účinky léků   patologie   metabolismus   MeSH
• kadmium * toxicita   MeSH
• lékové postižení jater * prevence a kontrola   metabolismus   patologie   MeSH
• myši inbrední C57BL * MeSH
• myši MeSH
• NF-kappa B * metabolismus   MeSH
• oxidační stres účinky léků   MeSH
• protoonkogenní proteiny c-akt * metabolismus   MeSH
• quercetin * farmakologie   terapeutické užití   MeSH
• signální transdukce * účinky léků   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

T cells are pivotal in the adaptive immune defense, necessitating a delicate balance between robust response against infections and self-tolerance. Their activation involves intricate cross-talk among signaling pathways triggered by the T-cell antigen receptors (TCR) and co-stimulatory or inhibitory receptors. The molecular regulation of these complex signaling networks is still incompletely understood. Here, we identify the adaptor protein ABIN1 as a component of the signaling complexes of GITR and OX40 co-stimulation receptors. T cells lacking ABIN1 are hyper-responsive ex vivo, exhibit enhanced responses to cognate infections, and superior ability to induce experimental autoimmune diabetes in mice. ABIN1 negatively regulates p38 kinase activation and late NF-κB target genes. P38 is at least partially responsible for the upregulation of the key effector proteins IFNG and GZMB in ABIN1-deficient T cells after TCR stimulation. Our findings reveal the intricate role of ABIN1 in T-cell regulation.

• MeSH
• adaptorové proteiny signální transdukční * metabolismus   genetika   MeSH
• aktivace lymfocytů imunologie   genetika   MeSH
• cytotoxické T-lymfocyty * imunologie   metabolismus   MeSH
• diabetes mellitus 1. typu imunologie   genetika   metabolismus   MeSH
• glukokortikoidy indukovaný protein související s TNRF MeSH
• interferon gama metabolismus   MeSH
• lidé MeSH
• mitogenem aktivované proteinkinasy p38 metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• NF-kappa B metabolismus   MeSH
• receptory antigenů T-buněk metabolismus   MeSH
• receptory OX40 metabolismus   genetika   MeSH
• signální transdukce * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Naringin inhibits inflammation and oxidative stress, the P2 purinoreceptor X4 receptor (P2X4R) is associated with glial cell activation and inflammation, the purpose of this study is to investigate the effects of naringin on P2X4 receptor expression on satellite glial cells (SGCs) and its possible mechanisms. ATP promoted the SGC activation and upregulated P2X4R expression; naringin inhibited SGC activation, decreased expression of P2X4R, P38 MAPK/ERK, and NF-κB, and reduced levels of Ca2+, TNF-α, and IL-1β in SGCs in an ATP-containing environment. These findings suggest that naringin attenuates the ATP-induced SGC activation and reduces P2X4R expression via the Ca2+-P38 MAPK/ERK-NF-κB pathway.

• MeSH
• adenosintrifosfát metabolismus   farmakologie   MeSH
• krysa rodu rattus MeSH
• mitogenem aktivované proteinkinasy p38 metabolismus   farmakologie   MeSH
• neuroglie metabolismus   MeSH
• NF-kappa B * metabolismus   MeSH
• novorozená zvířata MeSH
• potkani Sprague-Dawley MeSH
• purinergní receptory P2X4 * genetika   metabolismus   MeSH
• spinální ganglia metabolismus   MeSH
• vápník metabolismus   farmakologie   MeSH
• zánět MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Chronic exposure to low dose of T-2 toxin causes growth retardation and reduced body weight, resulting in economic losses. Excessive inflammatory cytokines and GH deficiency are important mechanisms that contribute to growth inhibition induced by T-2 toxin. However, the regulation of the inflammatory cytokines expecially IL-6, IL-1β, and TNF-α induced by T-2 toxin still remained unclear. The new transcription factor AKNA, belonging to AT-hook protein family, is closely associated with inflammation. However, it was unclear how AKNA regulate the expression of inflammatory cytokines, and there was no report on the role of AKNA in T-2 toxin mediated toxicity. Here, we investigated the role of AKNA in T-2 toxin-mediated inflammatory response and GH deficiency and the signal transduction pathway of AKNA. We showed that AKNA regulated by PKA/CREB and NF-κB pathway is a novel downstream molecular target in T-2 toxin-mediated inflammation and GH deficiency. T-2 toxin activates the PKA/CREB and NF-κB/p65 pathways, thereby promoting the direct binding of phospho-CREB and phospho-p65 to the AKNA promoter, thus inhibiting AKNA expression. GH and inflammatory cytokines (TNF-α, IL-1β, and IL-6) expression were significantly downregulated after AKNA silencing. Furthermore, the expression of differential genes induced by T-2 toxin in the rat pituitary was further confirmed by acute toxicity tests in rats, which was consistent with the results in GH3 cells. By histopathological analysis, we confirmed the pituitary might be a novel direct target organ of T-2 toxin. These findings provided new insights into the significant role of AKNA in T-2 toxin-induced inflammatory response and growth inhibition.

• MeSH
• buněčné linie MeSH
• DNA vazebné proteiny genetika   metabolismus   MeSH
• down regulace MeSH
• fosforylace MeSH
• interleukin-1beta genetika   metabolismus   MeSH
• interleukin-6 genetika   metabolismus   MeSH
• jaderné proteiny genetika   metabolismus   MeSH
• krysa rodu rattus MeSH
• NF-kappa B metabolismus   MeSH
• promotorové oblasti (genetika) MeSH
• protein vázající cAMP responzivní element metabolismus   MeSH
• proteinkinasy závislé na cyklickém AMP metabolismus   MeSH
• T-2 toxin toxicita   MeSH
• TNF-alfa genetika   metabolismus   MeSH
• transkripční faktory genetika   metabolismus   MeSH
• umlčování genů MeSH
• zánět chemicky indukované   genetika   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• aktivace lymfocytů MeSH
• atopická dermatitida * genetika   imunologie   MeSH
• glutamin metabolismus   terapeutické užití   MeSH
• leucin metabolismus   terapeutické užití   MeSH
• lidé MeSH
• mTORC1 MeSH
• NF-kappa B metabolismus   MeSH
• signální adaptorové proteiny CARD * genetika   MeSH
• T-lymfocyty imunologie   metabolismus   MeSH
• zárodečné mutace * MeSH
• Check Tag
• lidé MeSH

Activated B-cell-like (ABC) and germinal center B-cell-like diffuse large B-cell lymphoma (DLBCL) represent the 2 major molecular DLBCL subtypes. They are characterized by differences in clinical course and by divergent addiction to oncogenic pathways. To determine activity of novel compounds in these 2 subtypes, we conducted an unbiased pharmacologic in vitro screen. The phosphatidylinositol-3-kinase (PI3K) α/δ (PI3Kα/δ) inhibitor AZD8835 showed marked potency in ABC DLBCL models, whereas the protein kinase B (AKT) inhibitor AZD5363 induced apoptosis in PTEN-deficient DLBCLs irrespective of their molecular subtype. These in vitro results were confirmed in various cell line xenograft and patient-derived xenograft mouse models in vivo. Treatment with AZD8835 induced inhibition of nuclear factor κB signaling, prompting us to combine AZD8835 with the Bruton's tyrosine kinase inhibitor ibrutinib. This combination was synergistic and effective both in vitro and in vivo. In contrast, the AKT inhibitor AZD5363 was effective in PTEN-deficient DLBCLs through downregulation of the oncogenic transcription factor MYC. Collectively, our data suggest that patients should be stratified according to their oncogenic dependencies when treated with PI3K and AKT inhibitors.

• MeSH
• apoptóza účinky léků   MeSH
• difúzní velkobuněčný B-lymfom klasifikace   farmakoterapie   genetika   patologie   MeSH
• fixní kombinace léků MeSH
• fosfatidylinositol-3-kinasy genetika   metabolismus   MeSH
• fosfohydroláza PTEN nedostatek   genetika   MeSH
• inhibitory fosfoinositid-3-kinasy MeSH
• inhibitory proteinkinas farmakologie   MeSH
• lidé MeSH
• myši MeSH
• NF-kappa B antagonisté a inhibitory   genetika   metabolismus   MeSH
• orgánová specificita MeSH
• oxadiazoly farmakologie   MeSH
• piperidiny farmakologie   MeSH
• protinádorové látky farmakologie   MeSH
• protoonkogenní proteiny c-akt antagonisté a inhibitory   genetika   metabolismus   MeSH
• protoonkogenní proteiny c-myc antagonisté a inhibitory   genetika   metabolismus   MeSH
• pyrazoly farmakologie   MeSH
• pyrimidiny farmakologie   MeSH
• pyrroly farmakologie   MeSH
• regulace genové exprese u nádorů * MeSH
• screeningové testy protinádorových léčiv MeSH
• signální transdukce MeSH
• synergismus léků MeSH
• tyrosinkinasy antagonisté a inhibitory   genetika   metabolismus   MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

We investigated the mutation spectrum of the TANK-Binding Kinase 1 (TBK1) gene and its associated phenotypic spectrum by exonic resequencing of TBK1 in a cohort of 2,538 patients with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), or FTD plus ALS, ascertained within the European Early-Onset Dementia Consortium. We assessed pathogenicity of predicted protein-truncating mutations by measuring loss of RNA expression. Functional effect of in-frame amino acid deletions and missense mutations was further explored in vivo on protein level and in vitro by an NFκB-induced luciferase reporter assay and measuring phosphorylated TBK1. The protein-truncating mutations led to the loss of transcript through nonsense-mediated mRNA decay. For the in-frame amino acid deletions, we demonstrated loss of TBK1 or phosphorylated TBK1 protein. An important fraction of the missense mutations compromised NFκB activation indicating that at least some functions of TBK1 are lost. Although missense mutations were also present in controls, over three times more mutations affecting TBK1 functioning were found in the mutation fraction observed in patients only, suggesting high-risk alleles (P = 0.03). Total mutation frequency for confirmed TBK1 LoF mutations in the European cohort was 0.7%, with frequencies in the clinical subgroups of 0.4% in FTD, 1.3% in ALS, and 3.6% in FTD-ALS.

• MeSH
• aktivace enzymů MeSH
• alely MeSH
• amyotrofická laterální skleróza diagnóza   epidemiologie   genetika   MeSH
• běloši genetika   MeSH
• fenotyp MeSH
• frontotemporální demence diagnóza   epidemiologie   genetika   MeSH
• genetické asociační studie MeSH
• heterozygot MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace MeSH
• NF-kappa B metabolismus   MeSH
• protein-serin-threoninkinasy genetika   metabolismus   MeSH
• sekvenční delece MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• substituce aminokyselin MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Tolerogenic dendritic cells (tDCs) may offer an intervention therapy in autoimmune diseases or transplantation. Stable immaturity and tolerogenic function of tDCs after encountering inflammatory environment are prerequisite for positive outcome of immunotherapy. However, the signaling pathways regulating their stable tolerogenic properties are largely unknown. In this study, we demonstrated that human monocyte-derived tDCs established by using paricalcitol (analogue of vitamin D2), dexamethasone and monophosphoryl lipid A exposed for 24h to LPS, cytokine cocktail, polyI:C or CD40L preserved reduced expression of co-stimulatory molecules, increased levels of inhibitory molecules ILT-3, PDL-1 and TIM-3, increased TLR-2, increased secretion of IL-10 and TGF-β, reduced IL-12 and TNF-α secretion and reduced T cell stimulatory capacity. tDCs further induced IL-10-producing T regulatory cells that suppressed the proliferation of responder T cells. In the inflammatory environment, tDCs maintained up-regulated indoleamine 2, 3 dioxygenase but abrogated IκB-α phosphorylation and reduced transcriptional activity of p65/RelA, RelB and c-Rel NF-κB subunits except p50. Mechanistically, p38 MAPK, ERK1/2, mTOR, STAT3 and mTOR-dependent glycolysis regulated expression of ILT-3, PDL-1 and CD86, secretion of IL-10 and T cell stimulatory capacity of tDCs in the inflammatory environment. Stability of tDCs in the inflammatory environment is thus regulated by multiple signaling pathways.

• MeSH
• buněčná diferenciace fyziologie   MeSH
• dendritické buňky účinky léků   metabolismus   MeSH
• dexamethason farmakologie   MeSH
• ergokalciferoly farmakologie   MeSH
• glykolýza účinky léků   MeSH
• kultivované buňky MeSH
• lidé MeSH
• mitogenem aktivované proteinkinasy metabolismus   MeSH
• NF-kappa B metabolismus   MeSH
• signální transdukce MeSH
• TOR serin-threoninkinasy metabolismus   MeSH
• transkripční faktor STAT3 metabolismus   MeSH
• zánět metabolismus   patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

NF-κB is constitutively activated in chronic lymphocytic leukemia (CLL); however, the implicated molecular mechanisms remain largely unknown. Thus, we performed targeted deep sequencing of 18 core complex genes within the NF-κB pathway in a discovery and validation CLL cohort totaling 315 cases. The most frequently mutated gene was NFKBIE (21/315 cases; 7%), which encodes IκBε, a negative regulator of NF-κB in normal B cells. Strikingly, 13 of these cases carried an identical 4-bp frameshift deletion, resulting in a truncated protein. Screening of an additional 377 CLL cases revealed that NFKBIE aberrations predominated in poor-prognostic patients and were associated with inferior outcome. Minor subclones and/or clonal evolution were also observed, thus potentially linking this recurrent event to disease progression. Compared with wild-type patients, NFKBIE-deleted cases showed reduced IκBε protein levels and decreased p65 inhibition, along with increased phosphorylation and nuclear translocation of p65. Considering the central role of B cell receptor (BcR) signaling in CLL pathobiology, it is notable that IκBε loss was enriched in aggressive cases with distinctive stereotyped BcR, likely contributing to their poor prognosis, and leading to an altered response to BcR inhibitors. Because NFKBIE deletions were observed in several other B cell lymphomas, our findings suggest a novel common mechanism of NF-κB deregulation during lymphomagenesis.

• MeSH
• B-buněčný lymfom metabolismus   MeSH
• buněčné jádro metabolismus   MeSH
• chromozomální aberace MeSH
• chronická lymfatická leukemie genetika   metabolismus   MeSH
• cytoplazma metabolismus   MeSH
• delece genu MeSH
• kinasa I-kappa B genetika   fyziologie   MeSH
• kohortové studie MeSH
• lidé MeSH
• lymfom z B-buněk marginální zóny metabolismus   MeSH
• lymfom z plášťových buněk metabolismus   MeSH
• mutační analýza DNA MeSH
• NF-kappa B metabolismus   MeSH
• posunová mutace MeSH
• receptory antigenů B-buněk metabolismus   MeSH
• regulace genové exprese u leukemie * MeSH
• sekvenční analýza hybridizací s uspořádaným souborem oligonukleotidů MeSH
• signální transdukce MeSH
• stanovení celkové genové exprese MeSH
• viabilita buněk MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Cancer is a major public health problem worldwide. In the United States alone, 1 in 4 deaths is due to cancer and for 2013 a total of 1,660,290 new cancer cases and 580,350 cancer-related deaths are projected. Comprehensive profiling of multiple cancer genomes has revealed a highly complex genetic landscape in which a large number of altered genes, varying from tumor to tumor, impact core biological pathways and processes. This has implications for therapeutic targeting of signaling networks in the development of treatments for specific cancers. The NFκB transcription factor is constitutively active in a number of hematologic and solid tumors, and many signaling pathways implicated in cancer are likely connected to NFκB activation. A critical mediator of NFκB activity is TGFβ-activated kinase 1 (TAK1). Here, we identify TAK1 as a novel interacting protein and target of fibroblast growth factor receptor 3 (FGFR3) tyrosine kinase activity. We further demonstrate that activating mutations in FGFR3 associated with both multiple myeloma and bladder cancer can modulate expression of genes that regulate NFκB signaling, and promote both NFκB transcriptional activity and cell adhesion in a manner dependent on TAK1 expression in both cancer cell types. Our findings suggest TAK1 as a potential therapeutic target for FGFR3-associated cancers, and other malignancies in which TAK1 contributes to constitutive NFκB activation.

• MeSH
• apoptóza MeSH
• buněčná adheze MeSH
• fosforylace MeSH
• imunoprecipitace MeSH
• kvantitativní polymerázová řetězová reakce MeSH
• lidé MeSH
• MAP kinasy kinas (kinas) genetika   metabolismus   MeSH
• messenger RNA genetika   MeSH
• mnohočetný myelom genetika   metabolismus   patologie   MeSH
• nádorové biomarkery genetika   metabolismus   MeSH
• nádorové buňky kultivované MeSH
• nádory močového měchýře genetika   metabolismus   patologie   MeSH
• NF-kappa B genetika   metabolismus   MeSH
• peptidové fragmenty MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• proliferace buněk MeSH
• receptor fibroblastových růstových faktorů, typ 3 genetika   metabolismus   MeSH
• sekvenční analýza hybridizací s uspořádaným souborem oligonukleotidů MeSH
• signální transdukce MeSH
• spektrometrie hmotnostní - ionizace laserem za účasti matrice MeSH
• stanovení celkové genové exprese MeSH
• techniky dvojhybridového systému MeSH
• transformující růstový faktor beta genetika   metabolismus   MeSH
• tyrosin metabolismus   MeSH
• western blotting MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH