MH_dev_319

DB00158 MEN and thiamine transporters mediated by facilitative carriers ( P41440 REA - 3 and Q96NT5 ) and folate receptors . The reduced folate carrier ( P41440 REA , P41440 REA ) , thiamine transporter - 1 ( O60779 REA , O60779 REA ) and thiamine transporter - 2 ( Q9BZV2 , Q9BZV2 ) evolved from the same family of solute carriers . P41440 REA transports folates but not thiamine . O60779 REA and Q9BZV2 transport thiamine but not folates . P41440 REA and O60779 REA deliver their substrates to systemic tissues ; Q9BZV2 mediates intestinal thiamine absorption . The proton-coupled folate transporter ( Q96NT5 , Q96NT5 ) is the mechanism by which folates are absorbed across the apical-brush-border membrane of the proximal small intestine . Two folate receptors ( P15328 REA and P14207 REA ) mediate folate transport across epithelia by an endocytic process . DB00158 MEN transporters are routes of delivery of drugs for the treatment of cancer and inflammatory diseases . There are autosomal recessive disorders associated with mutations in genes encoded for Q96NT5 ( hereditary folate malabsorption ) , P15328 REA ( cerebral folate deficiency ) , O60779 REA ( thiamine-responsive megaloblastic anemia ) , and Q9BZV2 ( biotin-responsive basal ganglia disease ) .

P15121 REA inhibition counteracts oxidative-nitrosative stress and poly ( ADP-ribose ) polymerase activation in tissue sites for diabetes complications . This study evaluated the effects of aldose reductase inhibition on diabetes-induced oxidative-nitrosative stress and poly ( ADP-ribose ) polymerase ( PARP ) activation . In animal experiments , control and streptozotocin-induced diabetic rats were treated with or without the aldose reductase inhibitor ( Q9Y4X5 REA ) fidarestat ( 16 mg . kg ( - 1 ) . day ( - 1 ) ) for 6 weeks starting from induction of diabetes . DB09391 pathway intermediate , but not glucose , accumulation in sciatic nerve and retina was completely prevented in diabetic rats treated with fidarestat . Sciatic motor nerve conduction velocity , hindlimb digital sensory nerve conduction velocity , and sciatic nerve concentrations of two major nonenzymatic antioxidants , glutathione and ascorbate , were reduced in diabetic versus control rats , and these changes were prevented in diabetic rats treated with fidarestat . DB02021 MEN prevented the diabetes-induced increase in nitrotyrosine ( a marker of peroxynitrite-induced injury ) and poly ( ADP-ribose ) immunoreactivities in sciatic nerve and retina . DB02021 MEN counteracted increased superoxide formation in aorta and epineurial vessels and in in vitro studies using hyperglycemia-exposed endothelial cells , and the DCF test / flow cytometry confirmed the endothelial origin of this phenomenon . DB02021 MEN did not cause direct inhibition of PARP activity in a cell-free system containing PARP and NAD ( + ) but did counteract high-glucose-induced PARP activation in Schwann cells . In conclusion , aldose reductase inhibition counteracts diabetes-induced nitrosative stress and PARP activation in sciatic nerve and retina . These findings reveal the new beneficial properties of fidarestat , thus further justifying the ongoing clinical trials of this specific , potent , and low-toxic Q9Y4X5 REA .

P29323 REA signalling pathway is not involved in PSA - P13591 REA - dependent alterations of hippocampal plasticity evoked by P21554 REA receptor activation . The present study investigated the potential role of the extracellular signal-regulated kinase ( P29323 REA ) pathway in the alternation of polysialylated neural cell adhesion molecule ( PSA - P13591 REA ) expression and proliferation rates in the dentate gyrus ( DG ) evoked by activation of the P21554 REA receptor . When given at a dose of 0.1 mg / kg , the P21554 REA receptor agonist , 3 - ( 1,1- dimethylheptyl ) - 11 - hydroxy-Delta (8 ) - tetrahydrocannabinol ( HU - 210 ) , increased the levels of the phosphorylated forms of P29323 REA ( pERK 1 and pERK 2 ) in the hippocampus when measured 30 min after injection . This HU - 210 - induced effect was inhibited by alpha - { amino [ ( 4 - aminophenyl ) thio ] methylene } - 2 - ( trifluoromethyl ) benzeneacetonitrile ( SL327 , 30 mg / kg ) - an inhibitor of mitogen-activated protein kinase kinase ( Q02750 REA / 2 ) , the upstream kinase of P29323 REA - given 1 h before HU - 210 administration . Additionally , SL327 alone significantly attenuated the basal level of both pERK 1 and pERK 2 . HU - 210 ( 0.1 mg / kg ) decreased the number of PSA - P13591 REA - immunoreactive ( IR ) cells but did not affect the rate of proliferation , which was analyzed as the number of Ki - 67 - IR cells measured in the DG 2 days after HU - 210 administration . The data indicated that SL327 ( 30 mg / kg ) alone decreased the number of PSA - P13591 REA - IR cells 2 days after treatment . Joint administration of SL327 and HU - 210 decreased the number of PSA - P13591 REA cells more robustly than did the administration of either alone . In addition , SL327 did not decrease the number of Ki - 67 - IR cells , while pretreatment with SL327 1 h before HU - 210 administration did . These results suggest that stimulation of the P29323 REA cascade caused by P21554 REA receptor activation is not involved in hippocampal plasticity governed by PSA - P13591 REA expression .

Structure-activity relationship studies of CNS agents - - XVII . Spiro [ piperidine - 4 ' , 1 - ( 1,2 , 3,4- tetrahydro-beta-carboline ) ] as a probe defining the extended topographic model of P08908 REA receptors . Spiro [ piperidine - 4 ' , 1 - ( 1,2 , 3,4- tetrahydro-beta-carboline ) ] ( 10 ) , its derivatives 11-15 and its analogs 16 and 17 were examined as ligands of serotonin P08908 REA receptors . It was shown that compounds 12 and 14 had essentially the same P08908 REA affinity as 1 - phenylpiperazine and its rigid analog 7 , whereas there were substantial differences in the steric arrangement of their crucial pharmacophores , i . e . aromatic and protonation centers . On the basis of the existing models and using the DB04829 MEN structure as a template , a new , extended three-point topographic model of P08908 REA receptors has been proposed .

Carbon-ion beam irradiation kills X-ray-resistant p53 - null cancer cells by inducing mitotic catastrophe . BACKGROUND AND PURPOSE : To understand the mechanisms involved in the strong killing effect of carbon-ion beam irradiation on cancer cells with P04637 REA tumor suppressor gene deficiencies . MATERIALS AND METHODS : DNA damage responses after carbon-ion beam or X-ray irradiation in isogenic HCT 116 colorectal cancer cell lines with and without P04637 REA ( p53 + / + and p53 - / - , respectively ) were analyzed as follows : cell survival by clonogenic assay , cell death modes by morphologic observation of DAPI-stained nuclei , DNA double-strand breaks ( DSBs ) by immunostaining of phosphorylated P16104 REA ( γ P16104 REA ) , and cell cycle by flow cytometry and immunostaining of Ser 10 - phosphorylated histone H3 . RESULTS : The p53 - / - cells were more resistant than the p53 + / + cells to X-ray irradiation , while the sensitivities of the p53 + / + and p53 - / - cells to carbon-ion beam irradiation were comparable . X-ray and carbon-ion beam irradiations predominantly induced apoptosis of the p53 + / + cells but not the p53 - / - cells . In the p53 - / - cells , carbon-ion beam irradiation , but not X-ray irradiation , markedly induced mitotic catastrophe that was associated with premature mitotic entry with harboring long-retained DSBs at 24 h post-irradiation . CONCLUSIONS : Efficient induction of mitotic catastrophe in apoptosis-resistant p53 - deficient cells implies a strong cancer cell-killing effect of carbon-ion beam irradiation that is independent of the p53 status , suggesting its biological advantage over X-ray treatment .

Chemoproteomics-based kinome profiling and target deconvolution of clinical multi-kinase inhibitors in primary chronic lymphocytic leukemia cells . The pharmacological induction of apoptosis in neoplastic B cells presents a promising therapeutic avenue for the treatment of chronic lymphocytic leukemia ( CLL ) . We profiled a panel of clinical multi-kinase inhibitors for their ability to induce apoptosis in primary CLL cells . Whereas inhibitors targeting a large number of receptor and intracellular tyrosine kinases including c - P10721 REA , P36888 REA , Q06187 REA and P43405 REA were comparatively inactive , the CDK inhibitors BMS - 387032 and flavopiridol showed marked efficacy similar to staurosporine . Using the kinobeads proteomics method , kinase expression profiles and binding profiles of the inhibitors to target protein complexes were quantitatively monitored in CLL cells . The targets most potently affected were P50750 REA , cyclin T1 , P51826 / 4 and Q03111 REA , which may represent four subunits of a deregulated positive transcriptional elongation factor ( p-TEFb ) complex . Albeit with lower potency , both drugs also bound the basal transcription factor BTF 2 / TFIIH containing P50613 REA . DB02010 and geldanamycin do not affect these targets and thus seem to exhibit a different mechanism of action . The data support a critical role of p-TEFb inhibitors in CLL that supports their future clinical development .

DB05812 MEN in prostate cancer : a new angle to an old problem . DB05812 MEN acetate is an orally administered potent inhibitor of cytochrome P450 , family 17 , subfamily A , polypeptide 1 ( P05093 REA ) , which is essential for synthesis of testosterone from cholesterol . Although decreasing serum testosterone through inhibition of testicular function is the first line of treatment for men with metastatic prostate cancer , residual androgens may still be detected in patients treated with luteinizing hormone-releasing hormone agonists or antagonists . Treatment with abiraterone results in rapid , and complete , inhibition of androgen synthesis in the adrenal glands and potentially within the tumor itself . An overall survival benefit of maximal androgen suppression was recently shown in a randomized placebo-controlled phase III clinical trial of abiraterone with prednisone versus prednisone in men with metastatic castrate-resistant prostate cancer previously treated with docetaxel chemotherapy . DB05812 MEN ' s efficacy shows the importance of androgen signaling in patients with castrate-resistant metastatic disease , with additional confirmation from recent studies of other novel agents such as MDV 3100 , an androgen receptor signaling inhibitor . These promising results now pose a new angle to an old problem about hormonal therapy and raise new questions about how resistance develops , how to best sequence therapy , and how to optimize combinations with other emerging novel agents .

Kinetics of homeostatic proliferation and thymopoiesis after DB00098 MEN induction therapy in kidney transplant patients . BACKGROUND : Lymphocyte-depleting therapy is associated with long-lasting effects on repopulated T cells and subsequent increased rates of infections and malignancies . The mechanisms of T-cell repopulation and their posttransplantation kinetics are not fully understood . METHODS : We studied thymopoiesis by CD31 ( + ) naïve T cells ( recent thymic emigrants ) and homeostatic proliferation by Ki - 67 ( + ) T cells in rabbit antithymocyte globulin ( DB00098 MEN ) - treated patients the first 6 months after transplantation . Patients receiving basiliximab or no induction therapy served as controls . RESULTS : At 6 months after transplantation , T-cell numbers were lower than before transplantation in DB00098 MEN - treated patients , whereas T-cell numbers remained stable in both control groups . In this time period , thymopoiesis was similar between the three treatment groups ; CD8 ( + ) T cells showed the highest percentage of recent thymic emigrants . At month 1 , percentages of Ki - 67 ( + ) naïve and memory P01730 REA ( + ) and CD8 ( + ) T cells were the highest in DB00098 MEN - treated patients , but these percentages declined in the months thereafter . When CD31 was used to distinguish between cytokine - and antigen-driven proliferation in naïve T cells , we found evidence for cytokine-dependent proliferation . Cytokine-dependent proliferation was also shown by in vivo increased percentages of phosphorylated P42229 REA and high expression levels of the interleukin - 7 receptor-α and interleukin - 15 receptor-α by T cells . CONCLUSION : These findings demonstrate that , in the first month after DB00098 MEN therapy , cytokine-induced homeostatic proliferation is involved in T-cell repopulation of both naïve and memory T cells . At later time points , the contribution of homeostatic proliferation diminished , which explains the observed incomplete T-cell recovery .

[ DB09053 SUB : A new drug of B-cell malignancies ] . DB09053 SUB ( Imbruvica ® ) is a first-in-class , orally administered once-daily , that inhibits B-cell antigen receptor signaling downstream of Bruton ' s tyrosine kinase ( Q06187 REA ) . DB09053 SUB has been approved in USA in February 2014 and in France in October 2014 for the treatment of patients with relapsed / refractory mantle cell lymphoma ( Q8WXI8 ) or chronic lymphocytic leukaemia ( CLL ) and for the treatment of patients with CLL and a chromosome 17 deletion ( del 17p ) or P04637 REA mutation . In clinical studies , ibrutinib induced an impressive overall response rate ( 68 % ) in patients with relapsed / refractory Q8WXI8 ( phase II study ) . In CLL , ibrutinib has shown to significantly improve progression-free survival , response rate and overall survival in patients with relapsed / refractory CLL , including in those with del 17p . DB09053 SUB had an acceptable tolerability profile . Less than 10 % of patients discontinued their treatment because of adverse events . Results are pending in other B-cell lymphomas subtypes such as in diffuse large B-cell lymphoma and in follicular lymphoma . An approval extension has already been enregistered for Waldenström disease in USA in January 2015 . Given its efficacy and tolerability , ibrutinib is an emerging treatment option for patients with B-cell malignancies .

[ DB05812 MEN acetate : a novel therapeutic option in hormone-refractory prostate cancer ] . Until recently , only therapy with docetaxel and prednisone has been shown to prolong survival in men with hormonorefractory metastatic prostate cancer . With approvals of sipuleucel-T , cabazitaxel , and abiraterone acetate , all based on improvement in overall survival , the scenary for management of men with metastatic prostate cancer has dramatically changed . DB05812 MEN acetate was developed to specifically inhibit cytochrome P450 ( CYP ) 17A1 , which is an essential enzyme in the biosynthesis of testosterone . In the phase III , the trial treatment with abiraterone acetate plus prednisone prolongs overall survival relative to prednisone alone in patients with metastatic castration-resistant prostate cancer who have disease progression after treatment with docetaxel and associated with an acceptable tolerability profile , which was generally similar to that of the placebo plus prednisone group . However , adverse events resulting from elevated mineralocorticoid levels because of P05093 REA inhibition , fluid retention and oedema , hypokalaemia , hypertension occurred in significantly more in abiraterone acetate plus prednisone than in placebo plus prednisone .

DB00158 MEN transport in mouse cumulus-oocyte complexes and preimplantation embryos . Endogenous folate stores are required in preimplantation embryos of several species , but how folates are accumulated and whether they can be replenished has not been determined . Folates are generally taken up into cells by specific transporters , mainly the reduced folate carrier RFC 1 ( P41440 REA protein ) and the high-affinity folate receptors P15328 REA and P14207 REA . Quantitative RT-PCR showed that Slc 19a1 mRNA was expressed in mouse cumulus-oocyte complexes ( COCs ) and oocytes , whereas Folr 1 showed expression only in preimplantation embryos , increasing from the 2 - cell stage onward . The mRNAs encoding Folr 2 and the intestinal folate transporter Slc 46a1 were not detected . DB00563 ( MTX ) , an antifolate often used as a model substrate for folate transport , exhibited saturable transport in COCs and in preimplantation embryos starting at the 2 - cell stage . However , folate transport characteristics differed between COCs and embryos . In COCs , transport of MTX and the reduced folate leucovorin was inhibited by the anion transport inhibitor SITS that blocks RFC 1 but was insensitive to dynasore , a specific dynamin inhibitor that instead inhibits folate receptor-receptor mediated endocytosis , whereas the opposite was found in 2 - cell embryos and blastocysts . The inhibitor profile and transport properties of MTX and leucovorin in COCs correspond to established transport characteristics of RFC 1 ( P41440 REA ) , whereas those in 2 - cell embryos and blastocysts correspond with those of P15328 REA , consistent with the mRNA expression patterns . Considerable folate was accumulated in COCs via RFC 1 , but the presence of cumulus cells did not enhance folate accumulation in the enclosed oocyte , indicating a lack of transfer from cumulus to oocyte .

LiCABEDS II . Modeling of ligand selectivity for G-protein-coupled cannabinoid receptors . The cannabinoid receptor subtype 2 ( CB2 ) is a promising therapeutic target for blood cancer , pain relief , osteoporosis , and immune system disease . The recent withdrawal of DB06155 MEN , which targets another closely related cannabinoid receptor ( P21554 REA ) , accentuates the importance of selectivity for the development of CB2 ligands in order to minimize their effects on the P21554 REA receptor . In our previous study , LiCABEDS ( Ligand Classifier of Adaptively Boosting Ensemble Decision Stumps ) was reported as a generic ligand classification algorithm for the prediction of categorical molecular properties . Here , we report extension of the application of LiCABEDS to the modeling of cannabinoid ligand selectivity with molecular fingerprints as descriptors . The performance of LiCABEDS was systematically compared with another popular classification algorithm , support vector machine ( SVM ) , according to prediction precision and recall rate . In addition , the examination of LiCABEDS models revealed the difference in structure diversity of P21554 REA and CB2 selective ligands . The structure determination from data mining could be useful for the design of novel cannabinoid lead compounds . More importantly , the potential of LiCABEDS was demonstrated through successful identification of newly synthesized CB2 selective compounds .

Acute treatment with cannabinoid receptor agonist WIN 55212.2 improves prepulse inhibition in psychosocially stressed mice . Cannabis , similar to psychosocial stress , is well known to exacerbate psychotic experiences and can precipitate psychotic episodes in vulnerable individuals . Cannabinoid receptors 1 ( P21554 REA ) are widely expressed in the brain and are particularly important to mediate the effects of cannabis . Chronic cannabis use in patients and chronic cannabinoids treatment in animals is known to cause reduced prepulse inhibition ( PPI ) . Similarly , chronic psychosocial stress in mice impairs PPI . In the present study , we investigated the synergistic effects of substances modulating the P21554 REA - receptors and chronic psychosocial stress on PPI . For this purpose , adult C57Bl / 6J mice were exposed to chronic psychosocial stress using the resident-intruder paradigm . The cannabinoid receptor agonist WIN 55212.2 served as a surrogate marker for the effects of cannabis in the brain . After exposure to stress mice were acutely injected with WIN 55212.2 ( 3 mg / kg ) with or without pre-treatment with DB06155 MEN ( 3 mg / kg ) , a specific P21554 REA - receptor antagonist , and subjected to behavioral testing . Stressed mice displayed a higher vulnerability to WIN 55212.2 in the PPI test than control animals . The effects of WIN 55212.2 on PPI were antagonized by DB06155 MEN suggesting an involvement of P21554 REA - receptors in sensorimotor gating . Interestingly , WIN 55212.2 increased PPI in psychosocially stressed mice although previous studies in rats showed the opposite effects . It may thus be possible , that depending on the doses of cannabinoids / P21554 REA - receptor agonists applied and environmental conditions ( psychosocial stress ) , opposite effects can be evoked in different experimental animals . Taken together , our data imply that P21554 REA - receptors might play a crucial role in the synergistic effects of psychosocial stress and cannabinoids in brain .

The receptor tyrosine kinase inhibitor amuvatinib ( DB05216 MEN ) sensitizes tumor cells to radio - and chemo-therapies in part by inhibiting homologous recombination . BACKGROUND AND PURPOSE : Q06609 REA is a key protein involved in homologous recombination ( HR ) and a potential target for radiation - and chemotherapies . Amuvatinib ( formerly known as DB05216 MEN ) is a novel receptor tyrosine kinase inhibitor that targets c - P10721 REA and PDGFRα and can sensitize tumor cells to ionizing radiation ( IR ) . Here , we studied amuvatinib mechanism on Q06609 REA and functional HR . MATERIALS AND METHODS : Protein and RNA analyses , direct repeat green fluorescent protein ( DR-GFP ) assay and polysomal fractioning were used to measure HR efficiency and global translation in amuvatinib-treated H1299 lung carcinoma cells . Synergy of amuvatinib with IR or mitomycin c ( DB00305 ) was assessed by clonogenic survival assay . RESULTS : Amuvaninib inhibited Q06609 REA protein expression and HR . This was associated with reduced ribosomal protein S6 phosphorylation and inhibition of global translation . Amuvatinib sensitized cells to IR and DB00305 , agents that are selectively toxic to HR-deficient cells . CONCLUSIONS : Amuvatinib is a promising agent that may be used to decrease tumor cell resistance . Our work suggests that this is associated with decreased Q06609 REA expression and function and supports the further study of amuvatinib in combination with chemotherapy and radiotherapy .

DB09053 SUB inhibits P11274 REA and NF-κB signaling and reduces tumor proliferation in tissue-resident cells of patients with CLL . Chronic lymphocytic leukemia ( CLL ) cells depend on microenvironmental factors for proliferation and survival . In particular , tissue-resident CLL cells show prominent activation of both B-cell receptor ( P11274 REA ) and NF-κB pathways . We evaluated the in vivo effects of ibrutinib , a Q06187 REA ( Q06187 REA ) inhibitor on tumor cell activation and proliferation in the blood , lymph node , and bone marrow of patients with CLL . Applying validated pathway-specific gene signatures , we detected a rapid and sustained downregulation of P11274 REA and NF-κB signaling in CLL cells from both the peripheral blood and tissue compartments during ibrutinib treatment . DB09053 SUB reduced phosphorylation of PLCγ 2 and P29323 REA and decreased nuclear protein expression of NF-κB p50 . DB09053 SUB significantly decreased tumor proliferation and expression of surface activation markers Q07108 and P42081 REA , independent of prognostic factors such as IGHV mutational status , chromosome 17p deletion , or prior treatment history . Interestingly , stronger inhibition of P11274 REA signaling in lymph node resident CLL cells after one dose of ibrutinib was associated with a higher rate of nodal response at the end of cycle 2 . Together , these data validate on-target effects of Q06187 REA inhibition in the tissue compartments and demonstrate that ibrutinib effectively inhibits pathways that promote tumor cell activation and proliferation in vivo . This study is registered at www.clinicaltrials.gov as # NCT 01500733 .

DB00098 MEN - associated Cd4 + T-cell depletion and infection risk in HIV-infected renal transplant recipients . HIV-infected patients are increasingly referred for kidney transplantation , and may be at an increased risk for rejection . Treatment for rejection frequently includes thymoglobulin . We studied thymoglobulin ' s effect on P01730 REA + T-cell count , risk of infection and rejection reversal in 20 consecutive HIV-infected kidney recipients . All patients used antiretroviral therapy and opportunistic infection prophylaxis . Maintenance immunosuppression consisted of prednisone , mycophenolate mofetil and cyclosporine . Eleven patients received thymoglobulin ( 7 for rejection and 4 for delayed / slow graft function ) while 9 did not . These two groups were similar in age , gender , race , donor characteristics and immunosuppression . Mean P01730 REA + T-cell counts remained stable in patients who did not receive thymoglobulin , but became profoundly suppressed in those who did , decreasing from 475 + / - 192 to 9 + / - 10 cells / microL ( p < 0.001 ) . Recovery time ranged from 3 weeks to 2 years despite effective HIV suppression . Although opportunistic infections were successfully suppressed , low P01730 REA + T-cell count was associated with increased risk of serious infections requiring hospitalization . Rejection reversed in 6 of 7 patients receiving thymoglobulin . We conclude that thymoglobulin reverses acute rejection in HIV-infected kidney recipients , but produces profound and long-lasting suppression of the P01730 REA + T-cell count associated with increased risk of infections requiring hospitalization .

Integrated STS / YAC physical , genetic , and transcript map of human Xq21 . 3 to q23 / q24 ( DXS 1203 - DXS 1059 ) . A map has been assembled that extends from the XY homology region in Xq21 . 3 to proximal Xq24 , approximately 20 Mb , formatted with 200 STSs that include 25 dinucleotide repeat polymorphic markers and more than 80 expressed sequences including 30 genes . New genes HTRP 5 , Q9Y6Q1 REA , STPK , 14-3- 3PKR , and P62158 and previously known genes including Q06187 REA , O60220 REA , GLA , PLP , P29400 REA , Q14031 REA , O75914 REA , and O43602 REA are localized ; candidate loci for other disorders for which genes have not yet been identified , including DFN - 2 , POF , megalocornea , and syndromic and nonsyndromic mental retardation , are also mapped in the region . The telomeric end of the contig overlaps a yeast artificial chromosome ( YAC ) contig from Xq24 - q26 and with other previously published contigs provides complete sequence-tagged site ( STS ) / YAC-based coverage of the long arm of the X chromosome . The order of published landmark loci in genetic and radiation hybrid maps is in general agreement . Combined with high-density STS landmarks , the multiple YAC clone coverage and integrated genetic , radiation hybrid , and transcript map provide resources to further disease gene searches and sequencing .

Inhibitors of P11274 REA signalling interrupt the survival signal mediated by the micro-environment in mantle cell lymphoma . Several studies provide evidences for mantle cell lymphoma ( Q8WXI8 ) cell survival relying on B-cell receptor ( P11274 REA ) - mediated signalling pathways , whereas the nature of this activation is unknown . Significant progress in Q8WXI8 treatment is achieved through therapies targeting P11274 REA - associated kinases , i . e . , DB09053 SUB and Fostamatinib , inhibitors of Q06187 REA and P43405 REA , respectively . Our study addresses survival signals emanating from the P11274 REA or the tumour environment and how inhibiting P11274 REA signalling effectors might impact these survival signals . We found that Q06187 REA was constitutively activated and that P43405 REA phosphorylation was highly increased and sustained upon P11274 REA activation of primary Q8WXI8 cells . Moreover , Q8WXI8 cells from leukaemic patients secreted high amount of IL - 1β , P05231 REA , P10145 REA and P13501 REA . Activation of the P11274 REA induced ( i ) cell survival , ( ii ) P40763 REA activation and ( iii ) increased autocrine secretion of IL - 1β , P05231 REA , P10145 REA , P13501 REA , P22301 REA , TNFα and P15692 REA . Specific inhibition of Q06187 REA by DB09053 SUB or P43405 REA by Fostamatinib ( R406 ) reversed these protective effects and decreased both basal and P11274 REA - induced autocrine cytokine secretions associated with P40763 REA phosphorylation . Interestingly , targeting Q06187 REA and P43405 REA prevented and inhibited P11274 REA - induced Q8WXI8 cell adhesion to human bone marrow stromal cells ( HMSCs ) in short - and long-term co-culture . We demonstrated that P11274 REA - induced survival relies on autocrine secretion of IL - 1β , TNFα and P13501 REA that might facilitate adhesion of Q8WXI8 cells to HMSC . Treatment with DB09053 SUB or Fostamatinib blocked the chemotactic signal thus increasing apoptosis .

The c - DB00134 receptor tyrosine kinase inhibitor DB05216 MEN radiosensitizes glioblastoma cells . PURPOSE : Glioblastoma multiforme ( GBM ) is resistant to current cytotoxic therapies , in part because of enhanced DNA repair . Activation of the receptor tyrosine kinase c - DB00134 has been shown to protect cancer cells from DNA damage . We hypothesized that inhibiting c - DB00134 would decrease this protection and thus sensitize resistant tumor cells to the effects of radiation therapy . MATERIALS AND METHODS : Eight human GBM cell lines were screened for radiosensitivity to the small-molecule c - DB00134 inhibitor DB05216 MEN with colony-count assays . Double-strand ( ds ) DNA breaks was quantified by using antibodies to gamma P16104 REA . Western blotting demonstrate expression of Q06609 REA , glycogen synthase kinase ( GSK ) - 3beta , and other proteins . A murine xenograft tumor flank model was used for in vivo radiosensitization studies . RESULTS : DB05216 MEN reduced c - DB00134 phosphorylation and enhanced radiation-induced cell kill by 0.4 logs in SF767 cells . Cells pretreated with DB05216 MEN had more ds DNA damage than cells treated with radiation alone . Mechanistically , DB05216 MEN was shown to inhibit dsDNA break repair and increase apoptosis . DB05216 MEN influences various survival and DNA repair related proteins such as pAKT , Q06609 REA and GSK 3beta . In vivo , the addition of DB05216 MEN to radiation resulted in a tumor-growth-delay enhancement ratio of 2.9 over radiation alone and extended survival time . CONCLUSIONS : GBM is a disease site where radiation is often used to address both macroscopic and microscopic disease . Despite attempts at dose escalation outcomes remain poor . DB05216 MEN , a potent small-molecule tyrosine kinase inhibitor of c - DB00134 , radiosensitized several GBM cell lines both in vitro and in vivo , and may help to improve outcomes for patients with GBM .

Xaliproden ( SR57746A ) induces P08908 REA receptor-mediated Q96HU1 kinase activation in PC12 cells . Neurotrophic growth factors are involved in cell survival . However , natural growth factors have a very limited therapeutic use because of their short half-life . In the present study , we investigated the mechanism of action of a non-peptidic neurotrophic drug , Xaliproden , a potential molecule for the treatment of motoneuron diseases , since the transduction pathways of this synthetic P08908 REA agonist are very poorly understood . Xaliproden does not activate the Trk receptor but causes a rapid increase in the activities of the P27361 REA and P28482 REA isoforms of Q96HU1 kinase , which then rapidly decrease to the basal level . We demonstrate that isoforms of the P29353 REA adapter protein are phosphorylated independently of each other and are probably not the source of the Xaliproden-induced Q96HU1 kinases activation . The inhibitor of Ras farnesylation , FPT - 1 , and the protein kinase C inhibitors , GF 109203X and chelerythrine , inhibited the Xaliproden-induced Q96HU1 kinase activation , suggesting p21Ras and PKC involvement . Moreover , the observations that the P08908 REA antagonist , pindobind , and pertussis toxin abolished the Xaliproden-induced P29323 REA stimulation suggested that Xaliproden activates the Q96HU1 kinase pathways by stimulating the G protein-coupled receptor , P08908 REA . These results demonstrate clearly that the non-peptidic compound , Xaliproden , exerts its neurotrophic effects through a mechanism of action differing from that of neurotrophins . These findings suggest that this compound does not involve MAPK activation by TrkA receptor stimulation but acts by Q96HU1 kinase pathway by a pertussis toxin-sensitive mechanism involving P08908 REA receptors , P38936 REA Ras and MEK - 1 and by PKC and Akt pathways .

P15121 REA inhibitor fidarestat attenuates leukocyte-endothelial interactions in experimental diabetic rat retina in vivo . PURPOSE : Dysregulation of the polyol pathway has been implicated as a major cause of diabetic retinopathy . The aldose reductase inhibitor fidarestat was recently reported to prevent retinal oxidative stress and overexpression of vascular endothelial growth factor ( P15692 REA ) protein in diabetic rats . In this study , we investigated the effect of fidarestat on leukocyte-endothelial cell interactions in an in vivo experimental model for diabetic retina . MATERIALS AND METHODS : Diabetes was induced in six-week-old male Long-Evans rats by intraperitoneal injection of streptozotocin ( Q11206 REA ) ( 75 mg / kg ) . The rats were divided into four experimental groups : non-diabetic control rats , untreated diabetic rats , and diabetic rats treated with a low ( 4 mg / kg / day ) or high ( 16 mg / kg / day ) oral dose of fidarestat . After four weeks of treatment , accumulated leukocytes in the retina were counted in vivo by acridine orange digital fluorography . Intercellular adhesion molecule - 1 ( P05362 REA ) and P15692 REA - 164 mRNA levels in the retina were analyzed using the quantitative reverse transcription-polymerase chain reaction . P05362 REA protein expression in the retina was investigated by immunohistochemistry . RESULTS : DB02021 MEN treatment significantly decreased concentrations of sorbitol and fructose in the retinas of Q11206 REA - induced diabetic rats . Leukocyte accumulation in the retinas of fidarestat-treated rats was significantly less than in the untreated diabetic group ( P < 0.01 ) . DB02021 MEN treatment significantly reduced the expression P05362 REA mRNA , but not P15692 REA - 164 mRNA , in the retina of diabetic rats . Immunohistochemical study also revealed the suppressive effect of fidarestat on expression of P05362 REA . CONCLUSIONS : Oral administration of fidarestat attenuated leukocyte accumulation in the retina of Q11206 REA induced-diabetic rats , suggesting that fidarestat may have a therapeutic role in preventing the progression of diabetic retinopathy .

P27361 REA / 2 activation modulates pyocyanin-induced toxicity in A549 respiratory epithelial cells . Pyocyanin ( Q15149 REA ) , a virulence factor produced by Pseudomonas aeruginosa , has many damaging effects on mammalian cells . Several lines of evidence suggest that this damage is primarily mediated by its ability to generate oxidative stress . However mechanisms underlying Q15149 REA - induced oxidative injury remain unclear . Although oxidative stress and subsequent MAPK signaling has been shown to modulate cell death in other models , its role in Q15149 REA - induced cytotoxicity remains unknown . Therefore the aim of this study was to investigate the role of redox-sensitive MAPK in Q15149 REA - induced toxicity in A549 cells . Here we show that Q15149 REA ( 50μM ) rapidly increased P27361 REA / 2 phosphorylation after 5min . Pre-treatment of A549 cells with the Q02750 REA / 2 inhibitor U0126 ( 10μM ) decreased Q15149 REA - induced P27361 REA / 2 phosphorylation and protected cells against apoptosis and cell injury suggesting a role for P29323 REA signalling . In contrast , JNK and p38 MAPK phosphorylation remained unchanged following exposure to Q15149 REA and pretreatment with either the JNK or p38 MAPK inhibitors ( 10μM SP600125 and 10μM SB203580 , respectively ) did not afford protection against Q15149 REA toxicity . This would suggest that Q15149 REA - induced cytotoxicity appears to occur independently of JNK and p38 MAPK signaling pathways . Finally , although we confirm that oxidative stress contributes to Q15149 REA - induced toxicity , our data suggest the contribution of oxidative stress is independent of P27361 REA / 2 signaling . These findings may provide insight for novel targeted therapies to reduce Q15149 REA - mediated lung injury in patients with chronic P . aeruginosa respiratory infections .

Attenuation of fever at near term : is interleukin - 6 - P40763 REA signalling altered ? Pregnant rats in late gestation show a reduced fever response after stimulation with lipopolysaccharide ( LPS ) . This can result from either an increased action of endogenous antipyretics or a reduction in the production or action of endogenous pyrogens . Nonpregnant rats given LPS release interleukin ( IL ) - 6 , which causes nuclear translocation of the signal transducer and activator of transcription 3 ( P40763 REA ) in the vascular organ of the lamina terminalis ( OVLT ) , followed by a significant increase in core body temperature . The present study investigated whether the reduced fever response in near-term pregnant rats is associated with a reduced nuclear P40763 REA response . Rats at gestation day 15 ( Q99943 REA ) , gestation day 21 ( Q96NT5 , near term ) and at lactation day 5 ( Q15004 REA ) were injected with LPS ( 50 microg / kg , i . p . ) or vehicle . Only near-term pregnant rats responded with an attenuated body temperature during the fever response . Immunohistological analysis indicated no significant difference in nuclear P40763 REA in the OVLT of the different animal groups 2 h after LPS . Measurement of total and phosphorylated P40763 REA protein in the OVLT with semiquantitative western blot revealed no significant differences of this protein among these immune challenged animal groups . P05231 REA concentrations were also similar at Q99943 REA , Q96NT5 and Q15004 REA 2 h after injection of LPS . These results lead to the conclusion that the attenuation of the fever response at near-term pregnancy is not associated with a reduced amount of nuclear P40763 REA in the OVLT , indicating a maintained P05231 REA - P40763 REA signalling pathway in the OVLT .

Induction of cytokine gene expression in human thyroid epithelial cells irradiated with HZE particles ( iron ions ) . Gene expression profiles were examined using cDNA microarray technology in human thyroid epithelial ( Htori - 3 ) cells exposed to a low , non-toxic dose ( 10 cGy ) of radiation from HZE particles in the form of iron ions in the absence or presence of selenomethionine ( SeM ) . A total of 215 genes were differentially regulated 2 h after exposure to a 10 - cGy dose of iron-ion radiation . In the microarray analysis , SeM had profound effects on the radiation-induced expression of several specific genes , which includes P00749 REA , P17936 REA , P15328 REA , P15291 REA and P02452 REA . Of particular interest to us was a gene cluster , " secreted proteins " , that was up-regulated after radiation exposure . Seven up-regulated genes of this gene cluster fall within the chemokine / cytokine gene cluster , namely , P09341 REA , P19875 REA , P05231 REA , P20809 REA , P10145 REA , Q13007 REA and TGFbeta 2 . In microarray studies , the radiation-induced up-regulated expression of some these genes encoding cytokine / chemokine proteins was significantly decreased by SeM treatment . For P10145 REA , TGFbeta 2 , P09341 REA and P19875 REA , these observations were validated by qPCR techniques . It is concluded that SeM can regulate ionizing radiation-induced gene expression and may serve as an effective countermeasure for some of the acute inflammatory / immune responses induced by low-dose HZE-particle radiation .

Possible difference in frequencies of genetic polymorphisms of estrogen receptor alpha , estrogen metabolism and P04637 REA genes between estrogen receptor-positive and - negative breast cancers . OBJECTIVE : Genetic polymorphisms associated with breast cancer risk are likely to differ among ethnic and molecular subtypes . The ability to identify genetic polymorphisms affecting the risk of estrogen receptor ( ER ) - positive breast cancer may lead to the more efficient selection of candidates for chemoprevention with endocrine agents . We focused on identifying common genotypes for ER-positive breast cancer in premenopausal Japanese women . METHODS : We compared genetic polymorphisms of ERalpha , estrogen metabolism genes ( P05093 REA , P11511 REA , P14061 REA Q13057 REA , Q16678 REA and P21964 REA ) , and p53 between ER-positive and - negative female Japanese breast cancer patients , and analyzed whether these polymorphisms affected the frequency of ER-positive breast cancer . RESULTS : Carriers of the G allele of ERalpha ( rs6905370 ) were more frequent in ER-positive breast cancer than in ER-negative breast cancer especially in those under 50 - year old . Pairwise analysis showed that combinations of the ERalpha G allele with the homozygous DB00150 genotype of P11511 REA codon 39 ( rs2236722 ) , the methionine ( DB00134 ) allele of P21964 REA codon 158 ( rs4680 ) or Pro allele of p53 codon 72 ( rs1042522 ) were more frequent in ER-positive than ER-negative breast cancer , especially in patients less than 50 - year old . The frequencies of these combinations were even higher in patients with strongly ER-positive tumors ( Allred ' s scores of 7 or 8 ) . CONCLUSION : Our study demonstrated genetic polymorphisms of ERalpha , P11511 REA , P21964 REA and p53 genes frequently occur in ER-positive breast cancer in premenopausal Japanese women .

Inhibitors of Q06187 REA and Q08881 REA : state of the new drugs for cancer , autoimmunity and inflammatory diseases . Q06187 REA and Q08881 REA are cytoplasmic tyrosine kinases of crucial importance for B and T cell development , with loss-of-function mutations causing X-linked agammaglobulinemia and susceptibility to severe , frequently lethal , Epstein-Barr virus infection , respectively . Over the last few years , considerable efforts have been made in order to develop small-molecule inhibitors for these kinases to treat lymphocyte malignancies , autoimmunity or allergy / hypersensitivity . The rationale is that even if complete lack of Q06187 REA or Q08881 REA during development causes severe immunodeficiency , inactivation after birth may result in a less severe phenotype . Moreover , therapy can be transient or only partially block the activity of Q06187 REA or Q08881 REA . Furthermore , a drug-induced B cell deficiency is treatable by gamma globulin substitution therapy . The newly developed Q06187 REA inhibitor P05154 REA - 32765 , recently renamed DB09053 SUB , has already entered several clinical trials for various forms of non-Hodgkin lymphoma as well as for multiple myeloma . Experimental animal studies have demonstrated highly promising treatment effects also in autoimmunity . Q08881 REA inhibitors are still under the early developmental phase , but it can be expected that such drugs will also become very useful . In this study , we present Q06187 REA and Q08881 REA with their signalling pathways and review the development of the corresponding inhibitors .

Rabbit anti-rat thymocyte immunoglobulin preserves renal function during ischemia / reperfusion injury in rat kidney transplantation . Ischemia / reperfusion ( I / R ) injury is an important cause of renal graft dysfunction in humans . Increases in cold and warm ischemia times lead to a higher risk of early post-transplant complications including delayed graft function and acute rejection . Moreover , prolonged cold ischemia is a predictor of long-term kidney graft loss . The protective effect of rabbit anti-rat thymocyte immunoglobulin ( DB00098 MEN ) was evaluated in a rat model of I / R injury following syngeneic kidney transplantation . Serum creatinine concentration was evaluated at 16 h and 24 h post-transplant . Animals were sacrificed 24 h post-transplant for evaluation of histology , infiltrating leukocytes , nitrotyrosine staining , and apoptosis . DB00098 MEN was effective in preventing renal function impairment , tissue damage and tubular apoptosis associated with I / R only when was given 2 h before transplantation but not at the time of reperfusion . Pretransplant DB00098 MEN treatment of recipient animals effectively reduced the amount of macrophages , P01730 REA ( + ) , CD8 ( + ) T cells and LFA - 1 ( + ) cells infiltrating renal graft subjected to cold ischemia as well as granzyme-B expression within ischemic kidney . On the other hand , granulocyte infiltration and oxidative stress were not modified by DB00098 MEN . If these results will be translated into the clinical setting , pretransplant administration of Thymoglobuline ( ® ) could offer the additional advantage over peri-transplant administration of limiting I / R-mediated kidney graft damage .

Rare allelic variants determine folate status in an unsupplemented European population . The role of folates as coenzymes in 1 - carbon metabolism and the clinical consequences of disturbed folate metabolism are widely known . DB00158 MEN status is a complex trait determined by both exogenous and endogenous factors . This study analyzed the association between 12 genetic variants and folate status in a Czech population with no folate fortification program . These 12 genetic variants were selected from 56 variant alleles found by resequencing the coding sequences and adjacent intronic regions of 6 candidate genes involved in folate metabolism or transport ( P15328 REA , P14207 REA , P41439 REA , P42898 REA , Q96NT5 , and P41440 REA ) from 29 individuals with low plasma and erythrocyte folate concentrations . Regression analyses of a cohort of 511 Czech controls not taking folate supplements revealed that only 2 variants in the P42898 REA gene were associated with altered folate concentrations in plasma and / or erythrocytes . In our previous study , we observed that the common variant P42898 REA c . 665C > T ( known as c . 677C > T ; p . A222V ) was associated with decreased plasma folate concentrations . In the present study , we show in addition that the rare variant P42898 REA c . 1958C > T ( p . T653M ) is associated with significantly increased erythrocyte folate concentrations ( P = 0.02 ) . Multivariate regression analysis revealed that this uncommon variant , which is present in 2 % of Czech control chromosomes , explains 0.9 % of the total variability of erythrocyte folate concentrations ; the magnitude of this effect size was comparable with that of the common P42898 REA c . 665C > T variant . This result indicates that the rare genetic variants may determine folate status to a similar extent as the common allelic variant .

The CHOICE trial : adalimumab demonstrates safety , fistula healing , improved quality of life and increased work productivity in patients with Crohn ' s disease who failed prior infliximab therapy . BACKGROUND : DB00051 MEN induces and maintains remission in adults with Crohn ' s disease . AIM : To evaluate safety , fistula healing , quality of life and work productivity in adalimumab-treated patients who failed infliximab , including primary nonresponders . METHODS : After a ≥ 8 - week infliximab washout , patients with moderate-to-severe Crohn ' s disease received open-label adalimumab as induction ( 160/80 mg at weeks 0/2 ) and maintenance ( 40 mg every other week ) therapies . At / after 8 weeks , patients with flare / nonresponse could receive weekly therapy . Minimum study duration was 8 weeks , continuing until the commercial availability of adalimumab for Crohn ' s disease . RESULTS : Of 673 patients enrolled , 17 % were infliximab primary nonresponders and 83 % were initial responders . Three percent of patients had serious infections ( mainly abscesses ) . Complete fistula healing was achieved by 34/88 ( 39 % ) patients with baseline fistulas . Improvements in quality of life and work productivity were sustained from week 4 to week 24 for all patients , as well as the subgroup of primary nonresponders . CONCLUSIONS : Blinded clinical trials have shown adalimumab to be both an effective first-line therapy for anti - P01375 REA - naïve patients and an important treatment option for infliximab-refractory or - intolerant patients . This trial presents open-label experience to support further the safety and effectiveness of adalimumab in patients who failed infliximab therapy , including primary nonresponders ( NCT 00338650 ) .

DB00051 MEN in ulcerative colitis : hypes and hopes . IMPORTANCE OF THE FIELD : The advent of anti - P01375 REA - α monoclonal antibodies has dramatically changed the management of inflammatory bowel diseases ( Q9UKU7 ) . Unlike Crohn ' s disease ( CD ) , only one anti - P01375 REA - α agent , infliximab , is currently approved for active moderate-to-severe ulcerative colitis ( UC ) . DB00051 MEN is a fully human anti - P01375 REA - α antibody that is effective and safe for the treatment of luminal and fistulising CD . AREAS COVERED IN THIS REVIEW : This review of the literature summarizes available data on of efficacy and safety profile adalimumab in patients with UC . WHAT THE READER WILL GAIN : DB00051 MEN may be effective in inducing and maintaining clinical remission in patients with moderate-to-severe UC . It may also induce mucosal healing and reduce the need for colectomy in patients with severe disease . The safety profile of the drug in UC is consistent with previous experience with this drug in CD . TAKE HOME MESSAGE : DB00051 MEN may be effective and well tolerated in UC . Its efficacy in maintaining clinical remission needs to be confirmed in a randomized controlled trial .

Toll-like receptor signaling is impaired in dendritic cells from patients with X-linked agammaglobulinemia . Bruton ' s tyrosine kinase ( Q06187 REA ) , which is defective in patients with X-linked agammaglobulinemia ( XLA ) , is expressed not only in B cells but also in monocytes and dendritic cells ( DCs ) . DCs play a crucial role in the innate immune response against infections by sensing pathogens through Toll-like receptors ( TLRs ) . However , it is not known whether Q06187 REA deficiency in XLA might impair TLR-mediated signaling in DCs , which are susceptible to various infections . The phenotypic maturation and cytokine production mediated by TLRs were examined in monocyte-derived DC from XLA patients and normal controls . The TLR expression in DCs was analyzed by flow cytometry . TLR-mediated signaling in DCs was evaluated for the phenotypic maturation based on Q01151 expression and production of cytokines , such as P01375 REA , P05231 REA and IL - 12p70 . TLR levels in DCs were similar between XLA and controls . O60603 REA , O00206 REA and Q9NYK1 /8 ligands elicited less phenotypic maturation of DCs from XLA patients than normal controls based on Q01151 expression . Stimulation with O60603 REA , O00206 REA and Q9NYK1 /8 ligands , as well as O15455 REA ligand , resulted in significantly lower production of P01375 REA , but neither P05231 REA nor IL - 12p70 , by DCs from XLA patients in comparison to normal controls . These findings suggest that Q06187 REA may thus be required for TLR signaling in DCs . The impaired TLR signaling in DCs may therefore be partly responsible for the occurrence of severe infections with bacteria and some viruses in XLA patients .

1 - Aryl - 5 - ( 1H - pyrrol - 1 - yl ) - 1H - pyrazole - 3 - carboxamide : an effective scaffold for the design of either P21554 REA or CB2 receptor ligands . New 1 - aryl - 5 - ( 1H - pyrrol - 1 - yl ) - 1H - pyrazole - 3 - carboxamides were synthesized as cannabinoid ( CB ) receptor ligands . Compound 11 ( CB ( 1 ) K ( i ) = 2.3 nM , CB ( 1 ) SI = 163.6 ) showed CB ( 1 ) receptor affinity and selectivity superior to DB06155 MEN and AM251 . Acute administration of 2mg / kg 11 reduced sucrose , but not regular food , intake in rats . On the other hand , compound 23 ( CB ( 2 ) K ( i ) = 0.51 nM , CB ( 2 ) SI = 30.0 ) showed significant affinity and selectivity for the CB ( 2 ) receptor . The results presented here show that the 1 - aryl - 5 - ( 1H - pyrrol - 1 - yl ) - 1H - pyrazole - 3 - carboxamide may serve as an effective scaffold for the design of either CB ( 1 ) or CB ( 2 ) receptor ligands .

DB00640 A2A receptor : a target for regulating renal interstitial fibrosis in obstructive nephropathy . Renal interstitial fibrosis ( Q9HBH0 ) is the common pathological process of chronic kidney diseases leading inevitably to renal function deterioration . Q9HBH0 and its preceding epithelial-mesenchymal transition ( EMT ) are commonly triggered by an early occurring renal inflammation . However , an effective approach to prevent EMT and Q9HBH0 is still lacking and of urgent need . Recently , the adenosine A2A receptor ( A2AR ) emerges as a novel inflammation regulator , therefore manipulation of A2AR may suppress the EMT process and as such protect against Q9HBH0 . To test this hypothesis we applied a unilateral ureteral obstruction ( UUO ) model of Q9HBH0 on A2AR knockout mice and their wild-type littermates , combined with the intervention of a selective A2AR agonist , CGS 21680 . On days 3 , 7 and 14 post-UUO we evaluated the effects of A2AR manipulation on the molecular pathological progresses of Q9HBH0 , including the cellular component of interstitial infiltration , expression of profibrotic factors , cellular biomarkers of EMT , and collagen deposition of extracellular matrix . Our data demonstrated that activation of A2AR significantly suppressed the deposition of collagen types I and III , reduced the infiltration of P01730 REA + T lymphocytes , and attenuated the expression of TGF-β 1 and Q13464 REA , which in turn inhibited and postponed the EMT progress . Conversely , genetic inactivation of A2AR exacerbated the aforementioned pathological processes of UUO-induced Q9HBH0 . Together , activation of A2AR effectively alleviated EMT and Q9HBH0 in mice , suggesting A2AR as a potential therapeutic target for the treatment of Q9HBH0 .

Attenuation of anti-tuberculosis therapy induced hepatotoxicity by Spirulina fusiformis , a candidate food supplement . Therapy using Isoniazid ( DB00951 ) and DB01045 MEN ( Q9HBH0 ) leads to induction of hepatotoxicity in some individuals undergoing anti-tuberculosis treatment . In this study , we assessed the effect of Spirulina fusiformis on DB00951 and Q9HBH0 induced hepatotoxicity in rats compared with hepatoprotective drug Silymarin . Induction of hepatotoxicity was measured by changes in the liver marker enzymes ( aspartate transaminase , alanine transaminase , and alkaline phosphatase ) . The antioxidant status was also analyzed in liver tissue homogenate and plasma by measurement of superoxide dismutase , catalase , glutathione-S-transferase , glutathione reductase , and lipid peroxidation levels . We also aimed to study the binding and interactions of the transcription factors Pregnane X Receptor ( O75469 REA ) and Farnesoid X Receptor ( Q96RI1 ) with DB00951 , Q9HBH0 , and representative active compounds of Spirulina fusiformis by in silico methods . The administration of DB00951 and Q9HBH0 resulted in significant ( p < 0.05 ) decrease in the antioxidant levels and total protein levels . There was also a significant ( p < 0.05 ) increase in the levels of liver marker enzymes . Spirulina fusiformis was seen to protect the parameters from significant changes upon challenge with DB00951 and Q9HBH0 in a dose-dependent manner . This was corroborated by histological examination of the liver . The results of the in silico analyses further support the wet lab results .

P15121 REA regulates TGF-beta 1 - induced production of fibronectin and type IV collagen in cultured rat mesangial cells . AIM : To study the effects of aldose reductase ( AR ) on production of fibronectin and type IV collagen in rat mesangial cells ( MsC ) . METHODS : The vector , pcDNA 3 - AR , was constructed based on pET - 15b - AR . Lipofect AMINE was used for stable transfection and G418 was used for selecting positive clones . DB02712 and zopolrestat were added for suppressing the activity of AR , respectively . The production of fibronectin and type IV collagen and the activation of Smads and MAPK signal transduction pathway were analysed by western blot and AP - 1 activity was analysed by electrophoretic mobility shift assays ( EMSA ) . RESULTS : The normal MsC showed increased expression of fibronectin and type IV collagen with stimulation of TGF-beta 1 . Compared with the normal MsC , the MsC pre-incubated with Q9Y4X5 REA showed reduced expression ( P < 0.05 ) and the AR-transfected MsC showed increased expression ( P < 0.05 ) . The normal MsC showed activation of P29323 REA , JNK and p38 with stimulation of TGF-beta 1 , while the activation of JNK and p38 was inhibited in the MsC pre-incubated with Q9Y4X5 REA and only the activation of JNK was enhanced in the AR-transfected MsC . The normal MsC showed enhanced AP - 1 activity with the stimulation of TGF-beta 1 , and similarly the activity was inhibited in the MsC pre-incubated with Q9Y4X5 REA and was more enhanced in the AR transfected MsC . CONCLUSION : AR can regulate the expression of fibronectin and type IV collagen with the stimulation of TGF-beta 1 in MsC , which may have relations with the activation of JNK-MAPK and p38 - MAPK signalling pathways and AP - 1 .

DB05812 MEN acetate , a first-in-class P05093 REA inhibitor , establishes a new treatment paradigm in castration-resistant prostate cancer .

The combined effects of single-nucleotide polymorphisms , tobacco products , and ethanol on normal resting blood mononuclear cells . INTRODUCTION : Tobacco and ethanol consumption are crucial factors in the development of various diseases including cancer . In this investigation , we evaluated the combined effects of a number of single nucleotide polymorphisms ( SNPs ) , with ethanol and tobacco products on healthy individuals . METHODS : Pure nicotine , cigarette smoke extract , and Swedish snuff ( snus ) extract were used . The effects were examined by means of in vitro cell cycle progression and cell death of peripheral blood mononuclear cells ( PBMCs ) obtained from healthy donors . RESULTS : After 3 days , in vitro , resting PBMCs entered the S and G2 stage in the presence of 100 µM nicotine . The PBMCs only proceeded to S stage , in the presence of 0.2 % ethanol . The nicotine - and ethanol-induced normal cell cycle progression correlated to a number of SNPs in the Q99665 REA , Rad 52 , O43543 REA , P04637 REA , P30281 REA , and O95477 REA genes . Certain SNPs in Caspases 8 , Q99665 REA , Rad 52 , P08253 REA , and Q00987 REA genes appeared to significantly influence the effects of EtOH - , snus - , and snus + EtOH-induced cell death . Importantly , the highest degree of cell death was observed in the presence of smoke + EtOH . The amount of cell death under this treatment condition also correlated to specific SNPs , located in the Q00987 REA , O95477 REA , or Q9H3R0 REA genes . CONCLUSIONS : Cigarette smoke in combination with ethanol strongly induced massive cell death . Long-term exposure to smoke and ethanol could provoke chronic inflammation , and this could be the initiation of disease including the development of cancer at various sites .

Effect of prototypical inducing agents on P-glycoprotein and CYP 3A expression in mouse tissues . P-glycoprotein ( P-gp ) and CYP 3A have considerable overlap in inducers in vitro . Characterizing P-gp induction in vivo and potential coregulation with CYP 3A are important goals for predicting drug interactions . This study examined P-gp expression in mouse tissues and potential coinduction with CYP 3A following oral treatment with 1 of 7 prototypical inducing agents for 5 days . P-gp expression in brain or liver was not induced by any treatment as determined by Western blot , whereas dexamethasone , pregnenolone - 16alpha - carbonitrile ( Q15149 REA ) , St . John ' s wort ( SJW ) , and rifampin induced hepatic CYP 3A expression . In intestine , rifampin and SJW induced P-gp expression 3.7- and 1.6- fold and CYP 3A 3.5- and 2.4- fold , respectively , whereas dexamethasone and Q15149 REA induced CYP 3A only . These observations suggest that P-gp in mouse small intestine is inducible by some , but not all , CYP 3A inducers , whereas P-gp expression in liver or brain is not readily induced . Intriguingly , rifampin and SJW , both activators of the human pregnane X receptor ( O75469 REA ) , induced CYP 3A in both liver and intestine but induced P-gp only in intestine , whereas Q15149 REA , an activator of murine O75469 REA , did not induce P-gp in any tissue . DB01045 MEN disposition was evaluated , and hepatic exposure to rifampin was comparable to intestine ; in contrast , brain concentrations were low . Overall , these observations demonstrate that P-gp induction in vivo is tissue-specific ; furthermore , there is a disconnect between P-gp induction and CYP 3A induction that is tissue - and inducer-dependent , suggesting that O75469 REA activation alone is insufficient for P-gp induction in vivo . Tissue-specific factors and inducer pharmacokinetic / pharmacodynamic properties may underlie these observations .

DB09053 SUB treatment ameliorates murine chronic graft-versus-host disease . Chronic graft-versus-host disease ( cGVHD ) is a life-threatening impediment to allogeneic hematopoietic stem cell transplantation , and current therapies do not completely prevent and / or treat cGVHD . P01730 REA + T cells and B cells mediate cGVHD ; therefore , targeting these populations may inhibit cGVHD pathogenesis . DB09053 SUB is an FDA-approved irreversible inhibitor of Bruton ' s tyrosine kinase ( Q06187 REA ) and P60568 REA inducible T cell kinase ( Q08881 REA ) that targets Th2 cells and B cells and produces durable remissions in B cell malignancies with minimal toxicity . Here , we evaluated whether ibrutinib could reverse established cGVHD in 2 complementary murine models , a model interrogating T cell-driven sclerodermatous cGVHD and an alloantibody-driven multiorgan system cGVHD model that induces bronchiolar obliterans ( BO ) . In the T cell-mediated sclerodermatous cGVHD model , ibrutinib treatment delayed progression , improved survival , and ameliorated clinical and pathological manifestations . In the alloantibody-driven cGVHD model , ibrutinib treatment restored pulmonary function and reduced germinal center reactions and tissue immunoglobulin deposition . Animals lacking Q06187 REA and Q08881 REA did not develop cGVHD , indicating that these molecules are critical to cGVHD development . Furthermore , ibrutinib treatment reduced activation of T and B cells from patients with active cGVHD . Our data demonstrate that B cells and T cells drive cGVHD and suggest that ibrutinib has potential as a therapeutic agent , warranting consideration for cGVHD clinical trials .

DB00051 MEN as second line anti-tumour necrosis factor alpha therapy for Crohn ' s disease : A single centre experience . BACKGROUND AND AIMS : Non-response , loss of response , or intolerance to anti-tumour necrosis factor alpha ( anti - P01375 REA α ) therapy is well recognised in Crohn ' s disease ( CD ) patients . Data concerning outcomes following the use of a second anti - P01375 REA α therapy , particularly in patients who do not respond to a first anti - P01375 REA α agent , are still emerging . The aim of this study was to assess response and tolerability to adalimumab following infliximab failure in a single centre cohort of CD patients . METHODS : Data were collected prospectively on 44 patients who received adalimumab therapy following infliximab failure . Initial response to adalimumab therapy at 6weeks following induction was defined using a two point decrease in the Harvey-Bradshaw Index , with remission at this point defined using a Harvey Bradshaw index ≤ 4 . Sustained clinical benefit at the last point of follow up was determined using a physician ' s global assessment . Corticosteroid-free sustained clinical benefit was also assessed at this point . RESULTS : Thirty-four ( 77 % ) patients had initial response to adalimumab therapy , with 28 ( 64 % ) having sustained clinical benefit . Corticosteroid-free sustained clinical benefit was achieved in nine ( 53 % ) of 17 patients requiring steroids at commencement of adalimumab . Four ( 44 % ) of the 9 patients who were primary non-responders to infliximab responded to adalimumab . The majority of CD patients who failed adalimumab therapy required surgery . CONCLUSIONS : Second-line anti - P01375 REA α therapy with adalimumab is effective at both inducing remission and maintaining response in CD patients who have failed infliximab , regardless of the reason for infliximab failure .

O75469 REA induces Q02318 REA and regulates cholesterol metabolism in the intestine . Mitochondrial sterol 27 - hydroxylase ( Q02318 REA ) catalyzes oxidative cleavage of the sterol side chain in the bile acid biosynthetic pathway in the liver and 27 - hydroxylation of cholesterol in most tissues . Recent studies suggest that 27 - hydroxycholesterol ( 27 - HOC ) activates liver orphan receptor alpha ( LXRalpha ) and induces the cholesterol efflux transporters O95477 REA and P45844 REA in macrophages . The steroid - and bile acid-activated pregnane X receptor ( O75469 REA ) plays critical roles in the detoxification of bile acids , cholesterol metabolites , and xenobiotics . The role of Q02318 REA in the intestine is not known . This study investigated O75469 REA and Q02318 REA regulation of cholesterol metabolism in the human intestinal cell lines Caco 2 and Ls174T . A human O75469 REA ligand , rifampicin , induced Q02318 REA mRNA expression in intestine cells but not in liver cells . DB01045 MEN induced Q02318 REA gene transcription , increased intracellular 27 - HOC levels , and induced O95477 REA and P45844 REA mRNA expression only in intestine cells . A functional O75469 REA binding site was identified in the human Q02318 REA gene . Chromatin immunoprecipitation assays revealed that rifampicin induced the O75469 REA recruitment of steroid receptor coactivator 1 to Q02318 REA chromatin . DB04540 loading markedly increased intracellular 27 - HOC levels in intestine cells . DB01045 MENMAX DB01045 MEN , 27 - HOC , and a potent LXRalpha agonist , T0901317 , induced O95477 REA and P45844 REA protein expression and stimulated cholesterol efflux from intestine cells to apolipoprotein A-I and HDL . This study suggests an intestine-specific O75469 REA / Q02318 REA / LXRalpha pathway that regulates intestine cholesterol efflux and HDL assembly .

P15121 REA inhibition suppresses azoxymethane-induced colonic premalignant lesions in C57BL / KsJ-db / db mice . Type - 2 diabetes and obesity-related metabolic abnormalities are major risk factors for the development of colon cancer . In the present study , we examined the effects of polyol pathway enzyme aldose reductase ( AR ) inhibitor , fidarestat , on the development of azoxymethane ( AOM ) - induced colonic premalignant lesions in C57BL / KsJ-db / db obese mice . Our results indicate that fidarestat given in the drinking water caused a significant reduction in the total number of colonic premalignant lesions in the AOM treated obese mice . Further , the expression levels of PKC-β 2 , AKT , P35354 REA and P35228 REA in the colonic mucosa of AOM-treated mice were significantly decreased by fidarestat . The serum levels of IL - 1α , P02778 REA , Q07325 REA , P01375 REA - α and P15692 REA are significantly suppressed in AOM + fidarestat treated obese mice . DB02021 MEN also decreased the expression of P35354 REA , P35228 REA , P98170 REA , survivin , β-catenin and NF-κB in high glucose-treated HT29 colon cancer cells . In conclusion , our results indicate that fidarestat inhibits the development of colonic premalignant lesions in an obesity-related colon cancer and is chemopreventive to colorectal carcinogenesis in obese individuals .

LSD and DOB : interaction with 5 - Q13049 REA receptors to inhibit DB01221 receptor-mediated transmission in the rat prefrontal cortex . Both the phenethylamine hallucinogen ( - ) -1-2 , 5 - dimethoxy - 4 - bromophenyl - 2 - aminopropane ( DOB ) , a selective serotonin 5 - Q13049 REA , 2C receptor agonist , and the indoleamine hallucinogen DB04829 MEN ( LSD , which binds to P08908 REA , 1B , 1D , 1E , 1F , 2A , 2C , 5 , 6 , 7 , dopamine D1 and D2 , and alpha 1 and alpha 2 adrenergic receptors ) , but not their non-hallucinogenic congeners , inhibited N-methyl-D-aspartate ( DB01221 ) - induced inward current and DB01221 receptor-mediated synaptic responses evoked by electrical stimulation of the forceps minor in pyramidal cells of the prefrontal cortical slices . The inhibitory effect of hallucinogens was mimicked by 5 - HT in the presence of selective P08908 REA and 5 - Q9H205 REA receptor antagonists . The inhibitory action of DOB , LSD and 5 - HT on the DB01221 transmission was blocked by the 5 - Q13049 REA receptor antagonists R - ( + ) - alpha - ( 2 , 3 - dimethoxyphenil ) - 1 - [ 4 - fluorophenylethyl ] - 4 - piperidineme thanol ( M100907 ) and ketanserin . However , at low concentrations , when both LSD and DOB by themselves only partially depressed the DB01221 response , they blocked the inhibitory effect of 5 - HT , suggesting a partial agonist action . Whereas N - ( 4 - aminobutyl ) - 5 - chloro - 2 - naphthalenesulphonamide ( W - 7 , a calmodulin antagonist ) and N - [ 2 - [ [ [ 3 - ( 4 ' - chlorophenyl ) - 2 - propenyl ] methylamino ] methyl ] phenyl ] - N - ( 2 - hydroxyethyl ) - 4 ' - methoxy-b enzenesulphonamide phosphate ( KN - 93 , a Ca2 + / P62158 - KII inhibitor ) , but not the negative control 2 - [ N - 4 ' methoxybenzenesulphonyl ] amino-N - ( 4 ' - chlorophenyl ) - 2 - propeny l-N - methylbenzylamine phosphate ( KN - 92 ) , blocked the inhibitory action of LSD and DOB , the selective protein kinase C inhibitor chelerythrine was without any effect . We conclude that phenethylamine and indoleamine hallucinogens may exert their hallucinogenic effect by interacting with 5 - Q13049 REA receptors via a Ca2 + / P62158 - KII-dependent signal transduction pathway as partial agonists and modulating the DB01221 receptors-mediated sensory , perceptual , affective and cognitive processes .

Structure-activity relationship studies of CNS agents . Part 9 : P08908 REA and 5 - HT2 receptor affinity of some 2 - and 3 - substituted 1,2 , 3,4- tetrahydro-beta-carbolines . The P08908 REA and 5 - HT2 receptor affinity of 2 - and 3 - substituted 1,2 , 3,4- tetrahydro-beta-carbolines 1-8 , 10 and 12-15 has been determined . It has been found that the specific P08908 REA affinity of the protonated form ( KiAH + ) 2 - n-hexyl derivatives 4 , 8 , 14 and DB04829 MEN is of the same order . It has been shown by means of molecular modelling methods that pharmacophores of all the active compounds can adopt a common position at the P08908 REA receptor model . The model also offers an explanation for the observed stereoselectivity chiral compounds .

A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors . P10721 REA or alpha-platelet-derived growth factor receptor ( alpha - P09619 REA ) activating mutations are the pathogenic mechanisms that characterize gastrointestinal stromal tumors ( GIST ) . Despite excellent responses to imatinib mesylate ( IM ) , patients are relapsing . We developed an IM-resistant GIST cell line ( GIST-R ) from the IM-sensitive GIST 882 cell line ( GIST-S ) by growing these cells in IM . Gene expression profiling ( GEP ) of GIST-S , GIST-R cells and two IM resistant GIST patients demonstrated that P10721 REA is downregulated implying a major role in IM resistance . Instead , GIST-R cells have acquired IM resistance by overexpressing the oncogenic receptor tyrosine kinase - P30530 REA - in a ' kinase switch ' . Further , the two IM resistant GIST patients express P30530 REA and not c-Kit , seen by immunohistochemistry ( IHC ) . Real time reverse transcriptase-polymerase chain reaction and Western blotting of the GIST-S and GIST-R cells confirmed the switch from Kit to P30530 REA . In GIST-R , P30530 REA is tyrosine phosphorylated and its ligand growth-arrest-specific gene 6 is overexpressed implying autocrine activation . The kinase switch is associated with a morphological change from spindle to epithelioid . Molecular modeling of the kinase domain of mutant c-Kit ( V654A ) and P30530 REA showed no binding to IM but efficient binding to DB05216 MEN , a novel c-Kit / P30530 REA kinase inhibitor . DB05216 MEN synergizes with docetaxel ( taxotere ) and is cytotoxic to GIST cells .