MH_dev_155

Kinin-B 2 receptor exerted neuroprotection after diisopropylfluorophosphate-induced neuronal damage . The kinin-B 2 receptor ( B2BKR ) activated by its endogenous ligand bradykinin participates in various metabolic processes including the control of arterial pressure and inflammation . Recently , functions for this receptor in brain development and protection against glutamate-provoked excitotoxicity have been proposed . Here , we report neuroprotective properties for bradykinin against organophosphate poisoning using acute hippocampal slices as an in vitro model . Following slice perfusion for 10min with diisopropylfluorophosphate ( DB00677 MEN ) to initiate the noxious stimulus , responses of pyramidal neurons upon an electric impulse were reduced to less than 30 % of control amplitudes . Effects on synaptic-elicited population spikes were reverted when preparations had been exposed to bradykinin 30min after challenging with DB00677 MEN . Accordingly , bradykinin-induced population spike recovery was abolished by HOE - 140 , a B2BKR antagonist . However , the kinin-B 1 receptor ( B1BKR ) agonist Lys-des - DB00125 ( 9 ) - bradykinin , inducing the phosphorylation of mitogen-activated protein kinase ( MEK / MAPK ) and cell death , abolished bradykinin-mediated neuroprotection , an effect , which was reverted by the P29323 REA inhibitor PD98059 . In agreement with pivotal B1BKR functions in this process , antagonism of endogenous B1BKR activity alone was enough for restoring population spike activity . On the other hand pralidoxime , an oxime , reactivating acetylcholinesterase ( P22303 REA ) after organophosphate poisoning , induced population spike recovery after DB00677 MEN exposure in the presence of bradykinin and Lys-des - DB00125 ( 9 ) - bradykinin . Lys-des - DB00125 ( 9 ) - bradykinin did not revert protection exerted by pralidoxime , however when instead bradykinin and Ly-des - DB00125 ( 9 ) - bradykinin were superfused together , recovery of population spikes diminished . These findings again confirm the neuroprotective feature of bradykinin , which is , diminished by its endogenous metabolites , stimulating the B1BKR , providing a novel understanding of the physiological roles of these receptors .

Inhibitory interactions between phosphorylation sites in the C terminus of α-Amino - 3 - hydroxy - 5 - methyl - 4 - isoxazolepropionic acid-type glutamate receptor P42261 REA subunits . The C terminus of AMPA-type glutamate receptor ( AMPAR ) P42261 REA subunits contains several phosphorylation sites that regulate AMPAR activity and trafficking at excitatory synapses . Although many of these sites have been extensively studied , little is known about the signaling mechanisms regulating P42261 REA phosphorylation at DB00156 - 840 . Here , we report that neuronal depolarization in hippocampal slices induces a calcium and protein phosphatase 1/2 A-dependent dephosphorylation of P42261 REA at DB00156 - 840 and a nearby site at DB00133 - 845 . Despite these similarities , inhibitors of DB01221 - type glutamate receptors and protein phosphatase 2B prevented depolarization-induced DB00133 - 845 dephosphorylation but had no effect on DB00156 - 840 dephosphorylation . Instead , depolarization-induced DB00156 - 840 dephosphorylation was prevented by blocking voltage-gated calcium channels , indicating that distinct Ca ( 2 + ) sources converge to regulate P42261 REA dephosphorylation at DB00156 - 840 and DB00133 - 845 in separable ways . Results from immunoprecipitation / depletion assays indicate that DB00156 - 840 phosphorylation inhibits protein kinase A ( PKA ) - mediated increases in DB00133 - 845 phosphorylation . Consistent with this , PKA-mediated increases in AMPAR currents , which are dependent on DB00133 - 845 phosphorylation , were inhibited in P29320 REA - 293 cells expressing a DB00156 - 840 phosphomimetic version of P42261 REA . Conversely , mimicking DB00133 - 845 phosphorylation inhibited protein kinase C phosphorylation of DB00156 - 840 in vitro , and PKA activation inhibited DB00156 - 840 phosphorylation in hippocampal slices . Together , the regulation of DB00156 - 840 and DB00133 - 845 phosphorylation by distinct sources of Ca ( 2 + ) influx and the presence of inhibitory interactions between these sites highlight a novel mechanism for conditional regulation of AMPAR phosphorylation and function .

mTORC 1 - dependent protein synthesis underlying rapid antidepressant effect requires GABABR signaling . Administration of N-methyl-D-aspartate receptors ( NMDAR ) antagonists initiates a rapid anti-depressant response requiring mammalian Target of DB00877 MEN Complex 1 ( mTORC 1 ) kinase ; however the molecular mechanism is unknown . We have determined that upon NMDAR blockade , dendritic γ-amino-butyric acid B receptors ( GABABR ) facilitate dendritic calcium entry . The GABABR-mediated increase in calcium signal requires the availability of dendritic L-type calcium channels . Moreover , GABABR can activate P42345 REA and increase P42345 REA dependent expression of P23560 REA under the same NMDAR blocked conditions . In vivo , blocking GABABR prevents the fast-acting , anti-depressant effect of the Q13224 REA antagonist , Ro -25-6891 , decreases active mTORC 1 kinase , and reduces expression of P23560 REA and the AMPA receptor subunit P42261 REA . These findings propose a novel role for GABABRs in the antidepressant action of Q13224 REA antagonists and as an initiator / regulator of mTORC 1 - mediated translation .

Divergence in signaling pathways involved in promotion of cell viability mediated by P09038 REA , P01138 REA , and P01133 REA in PC12 cells . We employed a series of inhibitors of intracellular cascade to disclose the precise molecular mechanisms by which basic fibroblast growth factor ( P09038 REA ) promotes viability of PC12 cells and compared with nerve growth factor ( P01138 REA ) and epidermal growth factor ( P01133 REA ) . The Q02750 REA and 2 inhibitors , U0126 and PD98059 , significantly suppressed cell viability mediated by P09038 REA in a dose-dependent manner , and to a greater extent compared with P01133 REA and P01138 REA . The degree of MEK dependency for growth factor-mediated cell viability was estimated to be in the order of P09038 REA , P01133 REA , and P01138 REA . DB00877 MEN strongly inhibited the effect of P01138 REA on cell viability , compared with P09038 REA and P01133 REA . The mechanisms of action of P01138 REA - mediated cell viability may depend largely on P08133 REA S6 kinase-related signal transduction pathways comparing to P09038 REA and P01133 REA . The present findings suggest that different signal transduction systems may be involved in the molecular mechanisms by which P09038 REA , P01138 REA , and P01133 REA mediate cell viability .

Therapy with a synthetic retinoid - - ( Ro 10-1670 ) etretin - - increases the cellular retinoic acid-binding protein in nonlesional psoriatic skin . Cellular retinol ( P09455 REA ) - and retinoic acid ( CRABP ) - binding proteins were determined in samples of lesional and nonlesional skin of psoriatic patients , before and during oral administration of a synthetic retinoid , DB00459 MEN ( Ro 10-1670 ) . A 200 % increase in CRABP levels , measured by the ability of the protein to bind retinoic acid , was observed in the normal skin during treatment . The P09455 REA levels were not altered during therapy . The results show that P09455 REA and CRABP are independently regulated in human skin and suggest that synthetic retinoids may exert their pharmacologic effects by interfering with the regulation of natural retinoic acid receptors .

Activation status of receptor tyrosine kinase downstream pathways in primary lung adenocarcinoma with reference of P01116 REA and P00533 REA mutations . The activation status of signal transduction pathways involving receptor tyrosine kinases and its association with P00533 REA or P01116 REA mutations have been widely studied using cancer cell lines , although it is still uncertain in primary tumors . To study the activation status of main components of growth factor-induced pathways , phosphorylated Akt ( pAkt ) , extracellular signal-regulated kinases 1 and 2 ( pERK ) and other downstream proteins were immunohistochemically examined using surgical samples of 193 primary lung adenocarcinomas . Also , thyroid transcription factor - 1 ( Q15669 REA - 1 ) expression and mutation status of P00533 REA and P01116 REA were examined . Advanced tumor stages ( p < 0.001 ) , negative Q15669 REA - 1 expression ( p < 0.001 ) and Akt activation ( p= 0.015 ) were independent and significant poor prognostic markers . Akt activation related to advanced stage ( p= 0.021 ) , invasiveness ( p= 0.004 ) , and not to mutations . Q15669 REA - 1 expression associated with never-smoker ( p= 0.013 ) , pre - or minimally invasiveness ( p < 0.001 ) and P00533 REA mutations ( p= 0.017 ) as well as with pERK ( p= 0.039 ) expression . P00533 REA mutations did not correlated with pAkt and pERK expression , which was different from the results based on cultured cells , while P01116 REA mutations were solely and significantly linked to P29323 REA activation ( p= 0.009 ) . In lung adenocarcinoma , tumors with Q15669 REA - 1 expression have distinct characteristics regarding mutations , signal protein activation and clinical issues . Moreover , this property was revealed to be important in outcome estimation at any tumor stage , whereas Akt activation is abnormally affected according to the tumor stage regardless of their cell origin . The signal proteins were differently related to mutation status from cultured cells .

Exposure to an organophosphate ( DB00677 MEN ) during a defined period in neonatal life induces permanent changes in brain muscarinic receptors and behaviour in adult mice . The organophosphate DB00677 MEN ( DB00677 MEN ) is a well-known inhibitor of cholinesterases . We have recently observed that neonatal exposure to a single subsymptomal dose of DB00677 MEN induces permanent alterations in muscarinic cholinergic receptors ( MAChRs ) and in spontaneous behaviour , in the mice as adults . In order to determine if there is a critical period for these effects , neonatal mice were given a single oral dose of 1.5 mg / kg DB00677 MEN b.wt . on postnatal day 3 , 10 or 19 , causing equal inhibition of P22303 REA . At the adult age of 4 months the mice were tested for spontaneous motor behaviour , and were subsequently sacrificed for measurement of density of MAChRs and subpopulations of MAChRs in the cerebral cortex by using the antagonist quinuclidinyl benzilate ( [ 3H ] QNB ) , and agonist carbachol , respectively . At adult age , mice exposed to DB00677 MEN on postnatal day ( P01160 REA ) 3 or 10 showed significant ( P < or = 0.01 ) alterations in spontaneous motor behaviour and a significant ( P < or = 0.01 ) decrease in muscarinic receptor density . There were no alterations mice exposed on P01160 REA 19 . The proportions and affinity-constants of high - and low-affinity MAChR binding sites were not affected in mice showing altered MAChR density . The lack of effect on mice exposed on P01160 REA 19 was not due to differences in P22303 REA activity .

The combination of rapamycin and MAPK inhibitors enhances the growth inhibitory effect on Nara-H cells . The inhibition of the mammalian target of rapamycin ( P42345 REA ) signaling pathway promotes the initiation of autophagy , and the mitogen-activated protein kinase ( MAPK ) / extracellular signal-regulated protein kinase ( P29323 REA ) is well known to induce autophagy . Autophagy is a self-defense mechanism of cancer cells that are subjected to antitumor agents , and blocking autophagy can trigger apoptosis . In the present study , we demonstrate that an P42345 REA inhibitor , rapamycin , induces autophagy in the Nara-H malignant fibrous histiocytoma ( Q9H334 REA ) cell line through the activation of P27361 REA / 2 . DB00877 MEN - induced apoptosis was enhanced following the inhibition of the MEK / P29323 REA pathway . In the Nara-H cells , we examined the effects of rapamycin treatment on cell proliferation and on the phosphorylation of the P42345 REA pathway components and autophagy by western blot analysis . Furthermore , we examined the effects of rapamycin with or without the MEK inhibitor , U0126 , on the induction of apoptosis by using fluorescence microscopy . DB00877 MEN inhibited Nara-H cell proliferation and decreased the phosphorylation of the P42345 REA pathway in the Nara-H cells . DB00877 MEN induced the apoptosis of Nara-H cells , and this apoptosis was enhanced by U0126 . Simultaneously , phospho - P27361 REA / 2 was activated by rapamycin . The present study demonstrates that rapamycin induces autophagy in Nara-H cells by activating the MEK / P29323 REA signaling pathway , and the rapamycin-induced apoptosis can be enhanced by the MEK inhibitor , U0126 . These results suggest that self ‑ protective mechanisms involving P42345 REA inhibitors in Nara-H cells are prevented by the inhibition of the MEK / P29323 REA pathway . The combination of an P42345 REA inhibitor ( e . g . , rapamycin ) and an MEK inhibitor ( e . g . , U0126 ) may offer effective treatment for Q9H334 REA , as this combination effectively activates apoptotic pathways .

Expression of cytosolic retinoid-binding protein genes in human skin biopsies and cultured keratinocytes and fibroblasts . Using reverse transcription coupled to polymerase chain reaction we have studied the mRNA expression of serum retinol-binding protein and cytosolic receptors for retinol and retinoic acid in skin biopsies , and in cultured epidermal keratinocytes and dermal fibroblasts . Transcripts for cellular retinol-binding protein ( P09455 REA ) I and cellular retinoic-acid-binding protein ( CRABP ) I were found in normal skin , keratinocytes , and fibroblasts . CRABP II transcripts were detected in skin and keratinocytes . A decreased mRNA expression of CRABP I and an increased mRNA expression of CRABP II were found in lesional psoriatic skin compared with uninvolved skin . mRNA transcripts for serum retinol-binding protein ( s - P02753 REA ) were detected in all tissues and cells . The biological importance of s - P02753 REA expression in keratinocytes and fibroblasts is not known , but hypothetically this protein may be involved in the intracellular shuttling of retinol and retinoic acid , or in the retransportation of cellular retinoids into the extracellular space .

Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation . Matrix metalloproteinases ( MMPs ) are essential for proper extracellular matrix remodeling , a process that takes place during obesity-mediated adipose tissue formation . Here , we examine expression profiles and the potential role of MMPs and their tissue inhibitors ( TIMPs ) in adipose tissue remodeling during obesity . Expression patterns are studied by Northern blot and real-time PCR in two genetic models of obesity ( ob / ob and db / db mice ) and in a diet-induced model of obesity ( AKR mice ) . Of the MMPs and TIMPs studied , mRNA levels for P08253 REA , P08254 REA , P39900 REA , P50281 REA , Q99542 REA , and P01033 REA are strongly induced in obese adipose tissues compared with lean tissues . In contrast , P09237 REA and P35625 REA mRNAs are markedly decreased in obesity . Interestingly , enzymatic activities of P39900 REA and of a new identified adipocyte-derived 30 - kDa metalloproteinase are enhanced in obese adipose tissue fractions , demonstrating that MMP / P01033 REA balance is shifted toward increased matrix degradation in obesity . Finally , we analyze the modulation of P08253 REA , Q99542 REA , and P01033 REA during 3T3 - Q9NUQ9 preadipocyte differentiation , and we explore the effect of inhibition of MMP activity on in vitro adipogenesis . We find that the synthetic MMP inhibitor BB - 94 ( DB03880 MEN ) decreases adipose conversion of 3T3 - Q9NUQ9 and primary rat preadipocytes . BB - 94 represses differentiation without affecting mitotic clonal expansion but prevents the early expression of P17676 REA , a transcription factor that is thought to play a major role in the adipogenic program . Such findings support a role for the MMP / P01033 REA system in the control of proteolytic events and adipogenesis during obesity-mediated fat mass development .

Inhibition of the striatum-enriched phosphodiesterase Q9Y233 REA : a novel approach to the treatment of psychosis . Phosphodiesterase 10A ( Q9Y233 REA ) is a recently identified cyclic nucleotide phosphodiesterase expressed primarily in dopaminoreceptive medium spiny neurons of the striatum . We report that papaverine is a potent , specific inhibitor of Q9Y233 REA and use this compound to explore the role of Q9Y233 REA in regulating striatal function . DB01113 SUB administration produces an increase in striatal tissue levels of cGMP and an increase in extracellular DB02527 measured by microdialysis . These cyclic nucleotide changes are accompanied by increases in the phosphorylation of CREB and P29323 REA , downstream markers of neuronal activation . In rats , papaverine potentiates haloperidol-induced catalepsy , consistent with the hypothesis that inhibition of Q9Y233 REA can increase striatal output and prompting a further evaluation of papaverine in models predictive of antipsychotic activity . DB01113 SUB is found to inhibit conditioned avoidance responding in rats and mice and to inhibit PCP - and amphetamine-stimulated locomotor activity in rats . The effects of papaverine on striatal cGMP and CREB and P29323 REA phosphorylation , as well as on conditioned avoidance responding , were absent in Q9Y233 REA knockout mice , indicating that the effects of the compound are the result of Q9Y233 REA inhibition . These results indicate that Q9Y233 REA regulates the activation of striatal medium spiny neurons through effects on DB02527 - and cGMP-dependent signaling cascades . Furthermore , the present results demonstrate that papaverine has efficacy in behavioral models predictive of antipsychotic activity . Thus , inhibition of Q9Y233 REA may represent a novel approach to the treatment of psychosis .

Bradykinin-induced P05231 REA expression through bradykinin B2 receptor , phospholipase C , protein kinase Cdelta and NF-kappaB pathway in human synovial fibroblasts . Bradykinin ( BK ) is an inflammatory mediator , and shows elevated levels in regions of severe injury and inflammatory diseases . It has been shown to induce interleukin - 6 ( P05231 REA ) expression in inflammatory responses in rheumatoid arthritis . We investigated the signaling pathway involved in P05231 REA production caused by BK in synovial fibroblasts . BK caused concentration - and time-dependent increases in P05231 REA production . By using pharmacological inhibitors or genetic inhibition of the BK receptor , siRNA revealed that B2 but not B1 BK receptors are involved in BK-mediated up-regulation of P05231 REA . BK-mediated P05231 REA production was attenuated by phospholipase C inhibitor ( U73122 ) , protein kinase Cdelta inhibitor ( rottlerin ) , NF-kappaB inhibitor ( PDTC ) , IkappaB protease inhibitor ( TPCK ) and NF-kappaB inhibitor peptide . Stimulation of synovial fibroblasts with BK activated O15111 REA alpha / beta ( IKK alpha / beta ) , P25963 REA phosphorylation , P25963 REA degradation , p65 phosphorylation at DB00133 ( 276 ) , p65 and p50 translocation from the cytosol to the nucleus and kappaB-luciferase activity . BK mediated an increase of IKK alpha / beta and P25963 REA phosphorylation , kappaB-luciferase activity and p65 and p50 binding to the NF-kappaB element was inhibited by B2 BK receptor antagonist ( HOE 140 ) , U73122 and rottlerin . Our results suggest that BK increased P05231 REA production in synovial fibroblasts via the B2 BK receptor / PI - P98160 REA / PKCdelta / and NF-kappaB signaling pathway .

Cortical neurons from intrauterine growth retardation rats exhibit lower response to neurotrophin P23560 REA . Intrauterine growth retardation ( IUGR ) is putatively involved in the pathophysiology of schizophrenia . The animal model of IUGR induced by synthetic thromboxane A2 ( TXA 2 ) is useful to clarify the effect of IUGR on pups ' brains , however , analysis at the cellular level is still needed . P23560 REA ( P23560 REA ) , which plays a role in neuronal survival and synaptic plasticity in the central nervous system ( CNS ) , may also be associated with schizophrenia . However , the possible relationship between IUGR and P23560 REA function remains unclear . Here , we examined how IUGR by TXA 2 impacts P23560 REA function by using dissociated cortical neurons . We found that , although P23560 REA levels in cultured neurons from the cerebral cortex of low birth weight pups with IUGR were unchanged , TrkB ( P23560 REA receptor ) was decreased compared with control-rats . P23560 REA - stimulated MAPK / P27361 REA / 2 and PI3K / Akt pathways , which are downstream intracellular signaling pathways of TrkB , were repressed in IUGR-rat cultures . Expression of glutamate receptors such as P42261 REA and Q12879 REA was also suppressed in IUGR-rat cultures . Furthermore , in IUGR-rat cultures , anti-apoptotic protein Bcl 2 was decreased and P23560 REA failed to prevent neurons from cell death caused by serum-deprivation . Taken together , IUGR resulted in reductions in cell viability and in synaptic function following TrkB down-regulation , which may play a role in schizophrenia-like behaviors .

Metalloproteinases control brain inflammation induced by pertussis toxin in mice overexpressing the chemokine P13500 REA in the central nervous system . Inflammatory leukocytes infiltrate the CNS parenchyma in neuroinflammation . This involves cellular migration across various structures associated with the blood-brain barrier : the vascular endothelium , the glia limitans , and the perivascular space between them . Leukocytes accumulate spontaneously in the perivascular space in brains of transgenic ( Tg ) mice that overexpress P13500 REA under control of a CNS-specific promoter . The Tg mice show no clinical symptoms , even though leukocytes have crossed the endothelial basement membrane . Pertussis toxin ( PTx ) given i . p . induced encephalopathy and weight loss in Tg mice . We used flow cytometry , ultra-small superparamagnetic iron oxide-enhanced magnetic resonance imaging , and immunofluorescent staining to show that encephalopathy involved leukocyte migration across the glia limitans into the brain parenchyma , identifying this as the critical step in inducing clinical symptoms . Metalloproteinase ( MPs ) enzymes are implicated in leukocyte infiltration in neuroinflammation . Unmanipulated Tg mice had elevated expression of tissue inhibitor of metalloproteinase - 1 , matrix metalloproteinase ( MMP ) - 10 , and - 12 mRNA in the brain . PTx further induced expression of tissue inhibitor of metalloproteinase - 1 , metalloproteinase disintegrins - 12 , P22894 REA , and - 10 in brains of Tg mice . Levels of the microglial-associated MP P51511 REA were not affected in control or PTx-treated Tg mice . PTx also up-regulated expression of proinflammatory cytokines IL - 1beta and P01375 REA mRNA in Tg CNS . Weight loss and parenchymal infiltration , but not perivascular accumulation , were significantly inhibited by the broad-spectrum MP inhibitor BB - 94 / DB03880 MEN . Our finding that MPs mediate PTx-induced parenchymal infiltration to the chemokine-overexpressing CNS has relevance for the pathogenesis of human diseases involving CNS inflammation , such as multiple sclerosis .

Membrane type 1 matrix metalloproteinase regulates collagen-dependent mitogen-activated protein / extracellular signal-related kinase activation and cell migration . Mitogen-activated protein kinase-extracellular signal-related kinase ( P29323 REA ) kinase 1 ( Q02750 REA ) / P29323 REA signaling has been implicated in the regulation of tumor cell invasion and metastasis . Migration of HT1080 cells on type I collagen was suppressed by the matrix metalloproteinase ( MMP ) inhibitors BB94 and tissue inhibitor of metalloproteinase ( P01033 REA ) - 2 but not by P01033 REA . P16035 REA - specific inhibition suggests that membrane type 1 MMP ( P50281 REA ) is likely involved in this process . Activation of P29323 REA was induced in HT1080 cells adhered on dishes coated with type I collagen , and this was inhibited by BB94 . P08253 REA processing in HT1080 cells , which also was stimulated by cultivation on type I collagen , was inhibited by MEK inhibitor PD98059 . Expression of a constitutively active form of Q02750 REA promoted P08253 REA processing concomitant with the increase of P50281 REA levels , suggesting that P50281 REA is regulated by MEK / P29323 REA signaling . In addition , expression of the hemopexin-like domain of P50281 REA in HT1080 cells interfered with P08253 REA processing , P29323 REA activation , and cell migration , implying that the enzymatic activity of P50281 REA is involved in collagen-induced P29323 REA activation , which results in enhanced cell migration . Thus , adhesion of HT1080 cells to type I collagen induces P50281 REA - dependent P29323 REA activation , which in turn causes an increase in P50281 REA levels and subsequent cell migration .

Genetic analysis of expression profile involved in retinoid metabolism in non-alcoholic fatty liver disease . AIM : The patients with non-alcoholic fatty liver disease ( NAFLD ) have been reported to be at greater risk for progression to chronic liver disease including liver cirrhosis ( LC ) . To examine the mechanisms for the progression of NAFLD , a genetic analysis of hepatic expression profile in retinoid metabolism in NAFLD was performed since the loss of retinoid signaling is associated with the progression of liver disease via reactive oxygen species ( ROS ) generation . METHODS : Fifty-one genes , which are associated with retinoid metabolism and action , were examined in thirty six subjects including 17 patients with simple steatosis , 11 with non-alcoholic steatohepatitis ( NASH ) and eight controls were examined by real-time reverse transcriptase polymerase chain reaction . Immunohistochemical study was also done by 3 kinds of antibodies . RESULTS : Higher expression of P09455 REA O95237 REA , DGT 1/2 and CES 1 in NAFLD suggests that mutual conversion between retinyl ester and retinal occurs actively . Expression of P07327 REA / 2/3 , Q92781 REA / 10/11 , O75911 REA and RALDH 1/3 was increased in NAFLD , suggesting that oxidation process from retinol to all-trans retinoic acid ( DB00755 ) was enhanced . Importantly , greater expression of O43174 REA indicated that degradation of DB00755 was enhanced in NAFLD . Further , expression of P00441 REA / 2 , catalase , thioredoxin and uncoupling protein 2 was also enhanced . CONCLUSION : Hyperdynamic state of retinoid metabolism is present in the liver tissues with NAFLD , which may be a putative mechanism by which NAFLD progresses to chronic liver disease including LC .

Genetic deletion of P01375 REA receptor suppresses excitatory synaptic transmission via reducing AMPA receptor synaptic localization in cortical neurons . The distribution of postsynaptic glutamate receptors has been shown to be regulated by proimmunocytokine tumor necrosis factor α ( P01375 REA - α ) signaling . The role of P01375 REA - α receptor subtypes in mediating glutamate receptor expression , trafficking , and function still remains unclear . Here , we report that P01375 REA receptor subtypes ( P19438 REA and P20333 REA ) differentially modulate α-amino - 3 - hydroxy - 5 - methyl - 4 - isoxazole propionic acid receptor ( AMPAR ) clustering and function in cultured cortical neurons . We find that genetic deletion of P19438 REA decreases surface expression and synaptic localization of the AMPAR P42261 REA subunit , reduces the frequency of miniature excitatory postsynaptic current ( mEPSC ) , and reduces AMPA-induced maximal whole-cell current . In addition , these results are not observed in P20333 REA - deleted neurons . The decreased AMPAR expression and function in P19438 REA - deleted cells are not significantly restored by short ( 2 h ) or long ( 24 h ) term exposure to P01375 REA - α . In P20333 REA - deleted cells , P01375 REA - α promotes AMPAR trafficking to the synapse and increases mEPSC frequency . In the present study , we find no significant change in the Q05586 REA subunit of NMDAR clusters , location , and mEPSC . This includes applying or withholding the P01375 REA - α treatment in both P19438 REA - and P20333 REA - deleted neurons . Our results indicate that P01375 REA receptor subtype 1 but not 2 plays a critical role in modulating AMPAR clustering , suggesting that targeting P19438 REA gene might be a novel approach to preventing neuronal AMPAR-mediated excitotoxicity .

P05231 REA , P01579 REA and P01375 REA production by liver-associated T cells and acute liver injury in rats administered concanavalin A . The relationship between the development of acute hepatitis and the production of P01375 REA P01579 REA and P05231 REA by liver-associated T lymphocytes following intravenous injection of concanavalin A ( Con A ) was studied in rats . Following a single injection of Con A , there was a dose and time-dependent correlation in the serum levels of serum alanine aminotransferase ( ALT ) , P05231 REA , P01579 REA and P01375 REA . These increases correlated with an increase in the numbers of P01730 REA + , CD8 + and CD25 + T cells in blood and P01730 REA + and CD25 + T cells in the liver perfusate , but not with CD8 + T cells in liver perfusate . Increased levels of P05231 REA , P01579 REA and P01375 REA were constitutively produced by liver-associated P01730 REA + T cells when cultured . In Con A-stimulated cultures , liver-associated P01730 REA + T cells secreted increasing levels of P01375 REA in a time-dependent manner following Con A injection , but P01375 REA production by peripheral blood lymphocytes was transient with peak levels detected at 1 h which then declined over 24 h . Histological examination of the liver revealed fatty change , hepatocyte degeneration and necrosis , with an associated cell infiltrate of neutrophils and P01730 REA + T cells both in the portal areas and around the central veins . These results support the hypothesis that Con A-induced liver damage is mediated by P01730 REA + T cells acting within the liver , at least in part through the secretion of P01375 REA , P01579 REA and P05231 REA .

Combined immunohistochemistry for the differential diagnosis of cystic jaw lesions : its practical use in surgical pathology . AIMS : Histopathological distinction of cystic jaw lesions , including odontogenic tumours , is challenging because their lining epithelia , which are basically stratified squamous epithelia , resemble each other , especially when they become hyperplastic from inflammatory reaction . The aim of this study was to seek practical measures to differentiate such lesions . METHODS AND RESULTS : Nineteen surgical specimens from unicystic ameloblastomas ( UAs ) , 17 from keratocystic odontogenic tumours ( KCOTs ) , 13 from dentigerous cysts ( DCs ) , 10 from lateral periodontal cysts ( LPCs ) and 20 from radicular cysts ( RCs ) , all of which contained both typical flat and rete-peg-shaped lining epithelia , were examined for their immunohistochemical profiles . Among them , keratin ( K ) 10 , Q04695 REA , perlecan , proliferating cell nuclear antigen ( P12004 REA ) and UEA-I lectin binding ( UEA ) were selected as useful immunohistochemical markers for their differential diagnosis . P13645 REA was positive ( + ) in KCOT and DC . Q04695 REA was not present in RC . P98160 REA was found in UA , KCOT and Q16549 . P12004 REA + cells were found frequently in UA and KCOT . These localization patterns were constant even when linings were not flat . CONCLUSIONS : Using a combination of six kinds of immunohistochemical pattern , it is now possible to discriminate reliably and objectively these five cystic jaw lesions in routine practice .

The P08908 REA receptor agonist Bay x 3702 inhibits apoptosis induced by serum deprivation in cultured neurons . We examined whether the highly selective P08908 REA receptor agonist ( - ) - ( R ) - 2 - [ 4 - [ [ ( 3,4- dihydro - 2H - 1 - benzopyran - 2 - yl ) methyl ] - amino ] butyl ] - 11 , 2 - benz-isothiazol - 3 ( 2H ) - one 1,1- dioxide monohydrochloride ( Bay x 3702 ) could inhibit neuronal apoptosis induced by serum deprivation . In primary cultures of chick embryonic neurons and in mixed neuronal / glial cultures from neonatal rat hippocampus , Bay x 3702 ( 1 microM ) rescued serum-deprived neurons from apoptosis . The antiapoptotic effect of Bay x 3702 ( 1 microM ) was blocked in chick neurons by the selective P08908 REA receptor antagonists 4 - iodo-N - [ 2 - [ 4 - ( methoxyphenyl ) - 1 - piperazin ] ethyl ] - N - 2 - pyridinyl-be nzamide hydrochloride ( p-MPPI , 10 microM ) and 4 - [ 3 - benzotriazol - 1 - propyl ] - 1 - ( 2 - methoxyphenyl ) - piperazine ( BPMP , 10 microM ) as well as by anti-nerve growth factor ( anti - P01138 REA ) antibodies and in rat neurons by N - [ 2-4- ( 2 - methoxy ) - 1 - piperazinyl ] ethyl ] - N - ( 2 - pyridinyl ) cyclohexane-carbo xamide trihydrochloride ( WAY 100635 , 10 microM ) . We found only under control conditions ( medium with serum ) , but not in serum-deprived cultures , that P01138 REA secretion was 6 - fold increased by Bay x 3702 ( 1 microM ) compared to untreated cultures . Additionally , Bay x 3702 ( 4 microg / kg i . v . ) , infused within a period of 4 h , significantly increased the P01138 REA content of the rat hippocampus , but not of the striatum . In summary , our data suggest that Bay x 3702 inhibited growth factor withdrawal-induced apoptosis by the stimulation of P08908 REA receptors and that the P01138 REA signalling pathway is involved in the mechanism of action .

Tandospirone activates neuroendocrine and P29323 REA ( Q96HU1 kinase ) signaling pathways specifically through P08908 REA receptor mechanisms in vivo . Tandospirone , an azapirone , is a selective serotonin ( 1A ) ( 5 - HT ( 1A ) ) receptor agonist . The effects of tandospirone on plasma hormones and on mitogen-activated protein ( Q96HU1 ) kinase activity in the brain of male rats were studied . Tandospirone produced a time - and dose-dependent increase in plasma levels of oxytocin , adrenocorticotropin ( DB01285 ) , corticosterone , and prolactin . The minimal dose of tandospirone that led to a significant elevation of plasma oxytocin , DB01285 , and prolactin levels was 1.0 mg / kg ( s . c . ) , while the minimal dose for corticosterone release was 3.0 mg / kg ( s . c . ) . The ED ( 50 ) of tandospirone was 1.3 mg / kg for oxytocin , 1.2 mg / kg for DB01285 , 3.0 mg / kg for corticosterone , and 0.24 mg / kg for prolactin . Pretreatment with the specific 5 - HT ( 1A ) receptor antagonist WAY 100,635 ( 0.3 mg / kg , s . c . ) completely blocked the effects of tandospirone on plasma levels of oxytocin , DB01285 , and corticosterone but shifted the dose-response curve for prolactin to the right . Tandospirone injection ( 10 mg / kg , s . c . ) stimulated the Q96HU1 kinase signaling cascade , specifically the phosphorylation of Q8NFH3 / 44 extracellular signal-regulated kinase ( P29323 REA ) . Western blot analysis revealed a significant increase in phosphorylated P29323 REA ( p - P29323 REA ) levels in the hypothalamic paraventricular nucleus ( PVN ) as well as the dorsal raphe nucleus 5 min following tandospirone injection . These increases were blocked by pretreatment with WAY 100,635 ( 0.3 mg / kg ) . The results are the first evidence that systemic 5 - HT ( 1A ) receptor agonist administration produces a rapid increase in p - P29323 REA levels in vivo , providing further insight into the signaling mechanisms of the 5 - HT ( 1A ) receptor .

Sympathetic neurons express and secrete P08253 REA and P50281 REA to control nerve sprouting via pro - P01138 REA conversion . Recently , we have shown that high frequency electrical field stimulation ( HFES ) of sympathetic neurons ( SN ) induces nerve sprouting by up-regulation of nerve growth factor ( P01138 REA ) which targets the tyrosine kinase A receptor ( TrkA ) in an autocrine / paracrine manner . There is increasing evidence that matrix metalloproteinase - 2 ( P08253 REA ) is not only involved in extracellular matrix ( Q13201 REA ) turnover but may also exert beneficial effects during neuronal growth . Therefore , this study aimed to investigate the regulation and function of P08253 REA and its major activator membrane type 1 - matrix metalloproteinase ( P50281 REA ) as well its inhibitor P01033 REA in SN under conditions of HFES . Moreover , we analyzed molecular mechanisms of the beneficial effect of losartan , an angiotensin II type I receptor ( O00400 REA ) blocker on HFES-induced nerve sprouting . Cell cultures of SN from the superior cervical ganglia ( SCG ) of neonatal rats were electrically stimulated for 48 h with a frequency of 5 or 50 Hz . HFES increased P08253 REA and P50281 REA mRNA and protein expression , whereas P01033 REA expression remained unchanged . Under conditions of HFES , we observed a shift from pro - to active - P08253 REA indicating an increase in P08253 REA enzyme activity . Specific pharmacological P08253 REA inhibition contributed to an increase in pro - P01138 REA amount in the cell culture supernatant and significantly reduced HFES-induced neurite outgrowth . Losartan abolished HFES-induced nerve sprouting in a significant manner by preventing HFES-induced P01138 REA , P08253 REA , and P50281 REA up-regulation . In summary , specific P08253 REA blockade prevents sympathetic nerve sprouting ( SNS ) by inhibition of pro - P01138 REA conversion while losartan abolishes HFES-induced SNS by reducing total P01138 REA , P08253 REA and P50281 REA expression .

Effects of retinol binding protein - 4 on vascular endothelial cells . The study was designed to investigate the effect of retinol binding protein ( P02753 REA ) - 4 on the phosphatidylinositol 3 - kinase ( PI3K ) and mitogen-activated protein kinase ( MAPK ) pathways , which mediate the effects of insulin in vascular endothelial cells . The effects of P02753 REA on nitric oxide ( NO ) and insulin-stimulated endothelin - 1 ( ET - 1 ) secretion and on phosphorylation ( p ) of Akt , endothelial NO synthetase ( P29474 REA ) , and extracellular signal-regulated kinase ( P29323 REA ) 1/2 were investigated in bovine vascular aortic endothelial cells ( BAECs ) . P02753 REA showed an acute vasodilatatory effect on aortic rings of rats within a few minutes . In BAECs , P02753 REA - treatment for 5min significantly increased NO production , but inhibited insulin-stimulated ET - 1 secretion . P02753 REA - induced NO production was not inhibited by tetraacetoxymethylester ( BAPTA-AM ) , an intracellular calcium chelator , but was completely abolished by wortmannin , a PI3K inhibitor . P02753 REA significantly increased p-Akt and p - P29474 REA production , and significantly inhibited p - P27361 REA / 2 production . Triciribine , an Akt inhibitor , and wortmannin significantly inhibited P02753 REA - induced p-Akt and p - P29474 REA production . Inhibition of Akt 1 by small interfering RNA decreased p - P29474 REA production enhanced by P02753 REA in human umbilical vein endothelial cells . In conclusion , P02753 REA has a robust acute effect of enhancement of NO production via stimulation of part of the PI3K / Akt / P29474 REA pathway and inhibition of P27361 REA / 2 phosphorylation and insulin-induced ET - 1 secretion , probably in the MAPK pathway , which results in vasodilatation .

Pharmacogenetics studies in STAR * D : strengths , limitations , and results . Several lines of evidence support an important genetic contribution to the wide individual variation in therapeutic response to antidepressant medications . The Sequenced Treatment Alternatives to Relieve Depression ( STAR * D ) study provided the largest cohort assembled to date of DNA from patients with nonpsychotic major depressive disorder , uniformly treated with citalopram and followed prospectively for up to 12 weeks . This pivotal study changed the face of pharmacogenetics research by increasing the sample size by an order of magnitude as well as by providing detailed prospective information about antidepressant response and tolerability . Several groups have identified markers in genes and tested the replication of previous findings of genes associated with outcome and side effects of antidepressant treatment . Variants in P28223 REA , Q16099 REA , and KCNK 2 were associated with citalopram treatment outcome . Replication was achieved in markers in the Q13451 REA gene . Other findings in Q9HCR9 and P23560 REA were not successfully replicated , and reports of potential confounders in previous associations with serotonin transporter variation ( P31645 REA ) were identified . Polymorphisms in pharmacokinetic genes involved in metabolism and transmembrane transport were also not associated with antidepressant response . Adverse events were also tested . Treatment-emergent suicidal ideation was associated with GRIK 2 , P42263 REA , O95428 , Q8IU57 , and P16220 REA . Sexual dysfunction was linked with variation in Q8TCU5 , P42261 REA P42263 REA , and GRIK 2 . Reported and future findings of pharmacogenetics studies in STAR * D could help elucidate pathways involved in major depression and those pertinent to antidepressant outcome and side effects . Replication of these findings in independent samples could lead to the development of new treatments and to optimization of available treatments .

Neonatal exposure to anti-nerve growth factor antibodies affects exploratory behavior of developing mice in the hole board . The aim of this study was to assess in developing mice whether the neutralization of endogenous P01138 REA following ICV administration of anti - P01138 REA antibodies ( 50 micrograms / 2 microliters ) on postnatal days 3 , 6 , 9 , and 12 affected locomotor activity , exploratory behavior , and response to the cholinergic blocker scopolamine . In Experiments 1 and 2 activity and age-typical scopolamine effects were evaluated on P01160 REA 13 or 17 in an automated apparatus . No significant main effect of anti - P01138 REA treatment was found at either age . On day 13 scopolamine ( 0.2 , 1 , or 2 mg / kg ) decreased locomotion in both anti - P01138 REA and control animals . In Experiment 3 , locomotion and exploratory behavior were analyzed in an open field arena or in a hole board apparatus on P01160 REA 16 . No significant effects of anti - P01138 REA treatment on general motor activity and investigation of a novel object in the open field was found , though anti - P01138 REA animals tended to be less active than controls . In the hole board anti - P01138 REA pups showed a different pattern of head dipping behavior from controls , exploring mainly the holes located in the periphery of the apparatus .

Bacterial superantigens bypass Lck-dependent T cell receptor signaling by activating a Galpha 11 - dependent , P98160 REA - beta-mediated pathway . The paradigm to explain antigen-dependent T cell receptor ( TCR ) signaling is based on the activation of the P01730 REA or CD8 coreceptor-associated kinase Lck . It is widely assumed that this paradigm is also applicable to signaling by bacterial superantigens . However , these bacterial toxins can activate human T cells lacking Lck , suggesting the existence of an additional pathway of TCR signaling . Here we showed that this alternative pathway operates in the absence of Lck-dependent tyrosine-phosphorylation events and was initiated by the TCR-dependent activation of raft-enriched heterotrimeric Galpha 11 proteins . This event , in turn , activated a phospholipase C-beta and protein kinase C-mediated cascade that turned on the mitogen-activated protein kinases P27361 REA and P28482 REA , triggered Ca ( 2 + ) influx , and translocated the transcription factors NF-AT and NF-kappaB to the nucleus , ultimately inducing the production of interleukin - 2 in Lck-deficient T cells . The triggering of this alternative pathway by superantigens suggests that these toxins use a G protein-coupled receptor as a coreceptor on T cells .

Caspase-mediated degradation of AMPA receptor subunits : a mechanism for preventing excitotoxic necrosis and ensuring apoptosis . Activation of ionotropic glutamate receptors of the AMPA and DB01221 subtypes likely contributes to neuronal injury and death in various neurodegenerative disorders . Excitotoxicity can manifest as either apoptosis or necrosis , but the mechanisms that determine the mode of cell death are not known . We now report that levels of AMPA receptor subunits P42261 REA and P48058 REA are rapidly decreased in cultured rat hippocampal neurons undergoing apoptosis in response to withdrawal of trophic support ( WTS ) , whereas levels of DB01221 receptor subunits Q9UHB4 , Q12879 REA , and Q13224 REA are unchanged . Exposure of isolated synaptosomal membranes to " apoptotic " cytosolic extracts resulted in rapid degradation of AMPA receptor subunits . Treatment of cells and synaptosomal membranes with the caspase inhibitors prevented degradation of AMPA receptor subunits , demonstrating a requirement for caspases in the process . DB01373 responses to AMPA receptor activation were reduced after withdrawal of trophic support and enhanced after treatment with caspase inhibitors . Vulnerability of neurons to excitotoxic necrosis was decreased after withdrawal of trophic support and potentiated by treatment with caspase inhibitors . Our data indicate that caspase-mediated degradation of AMPA receptor subunits occurs during early periods of cell stress and may serve to ensure apoptosis by preventing excitotoxic necrosis .

Dissection of the phenotypic and genotypic associations with nicotinic dependence . INTRODUCTION : Strong evidence demonstrates that nicotine dependence is associated with 4 genetic variants rs16969968 , rs6474412 , rs3733829 , and rs1329650 in large-scale Genome-Wide Association Studies . We examined how these identified genetic variants relate to nicotine dependence defined by different categorical and dimensional measures . METHODS : Four genetic variants were analyzed in 2,047 subjects of European descent ( 1,062 cases and 985 controls ) . DB00184 MEN dependence was assessed with multiple smoking measures , including the Fagerström Test for DB00184 MEN Dependence , the Diagnostic and Statistical Manual for Mental Disorders-IV ( DSM-IV ) nicotine dependence , the DB00184 MEN Dependence Syndrome Scale , and the Wisconsin Inventory of Smoking Dependence Motives . Single-item measures of cigarettes per day ( O75976 REA ) and time to first cigarette ( Q15669 REA ) in the morning were also examined . RESULTS : Among the variants , association effect sizes were largest for rs16969968 , with measures of craving and heavy smoking , especially cigarettes smoked per day , showing the largest effects . Significant but weaker associations were found for rs6474412 and rs3733729 but not for rs1329650 . None of the more comprehensive measures of smoking behaviors yielded stronger genetic associations with these variants than did O75976 REA . CONCLUSIONS : O75976 REA is an important simple measure that captures in part the genetic associations of P30532 REA and nicotine dependence , even when other more comprehensive measures of smoking behaviors are examined . The P30532 REA gene is associated with heavy compulsive smoking and craving ; this should inform the mission to improve the diagnostic validity of DSM-V .

Adulthood nicotine treatment alleviates behavioural impairments in rats neonatally treated with quinpirole : possible roles of acetylcholine function and neurotrophic factor expression . Increases in dopamine D ( 2 ) receptor sensitivity are known to be common in drug abuse and neurological disorders . Past data from this laboratory have shown that long-term increases in D ( 2 ) sensitivity can be produced by quinpirole treatment ( a D ( 2 ) / D ( 3 ) agonist ) during early development . The present investigation was designed to test the hypothesis that nicotine administration in adulthood would reduce both cognitive and skilled reaching impairments produced by increases in D ( 2 ) sensitivity . Female Sprague-Dawley rats were treated with quinpirole ( 1 mg / kg ) or saline from postnatal day 1 ( PD 1 ) to PD 21 . Beginning in adulthood ( PD 61 ) , rats were treated with nicotine ( 0.3 mg / kg free base ) or saline twice daily for 14 consecutive days before behavioural testing commenced . Animals neonatally treated with quinpirole demonstrated performance deficits on the Morris water task and a skilled reaching task compared to controls . Deficits on both tasks were completely alleviated by adulthood nicotine treatment . Animals neonatally treated with quinpirole demonstrated a significant 36 % decrease of P28329 REA in the hippocampus compared to saline controls that was partially eliminated by nicotine . Additionally , neonatal quinpirole produced a significant decrease in hippocampal P01138 REA content compared to controls , however , nicotine failed to alleviate this decrease in P01138 REA . The results of this investigation demonstrate that long-term increases in dopamine D ( 2 ) receptor sensitivity produce significant decreases in hippocampal cholinergic and P01138 REA expression that may result in cognitive impairment . DB00184 MEN alleviates both cognitive and skilled reaching impairments caused by increases in D ( 2 ) sensitivity , but the mechanism through which nicotine is acting is currently unknown .

Suppression of NF-kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta . BACKGROUND & AIMS : Activation of NF-kappaB / Rel has been implicated in the pathogenesis of inflammatory bowel disease ( Q9UKU7 ) . Various drugs used in the treatment of Q9UKU7 , such as glucocorticoids , DB00244 , and sulfasalazine , interfere with NF-kappaB / Rel signaling . The aim of this study was to define the molecular mechanism by which sulfasalazine inhibits NF-kappaB activation . METHODS : The effects of sulfasalazine and its moieties on NF-kappaB signaling were evaluated using electromobility shift , transfection , and immune complex kinase assays . The direct effect of sulfasalazine on O15111 REA ( IKK ) activity was investigated using purified recombinant O15111 REA and - beta proteins . RESULTS : NF-kappaB / Rel activity induced by tumor necrosis factor alpha , 12 - O-tetradecanoylphorbol - 13 - acetate , or overexpression of NF-kappaB-inducing kinase , O15111 REA , O14920 REA , or constitutively active O15111 REA and O14920 REA mutants was inhibited dose dependently by sulfasalazine . Sulfasalazine inhibited tumor necrosis factor alpha-induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells , as well as the catalytic activity of purified O15111 REA and O14920 REA in vitro . In contrast , the moieties of sulfasalazine , DB00244 , and sulfapyridine or DB00233 MEN had no effect . Activation of extracellular signal-related kinase ( P29323 REA ) 1 and 2 , c-Jun-N-terminal kinase ( JNK ) 1 , and p38 was unaffected by sulfasalazine . The decrease in substrate phosphorylation by O15111 REA and - beta is associated with a decrease in autophosphorylation of IKKs and can be antagonized by excess adenosine triphosphate . CONCLUSIONS : These data identify sulfasalazine as a direct inhibitor of O15111 REA and - beta by antagonizing adenosine triphosphate binding . The suppression of NF-kappaB activation by inhibition of the IKKs contributes to the well-known anti-inflammatory and immunosuppressive effects of sulfasalazine .

Differential effects of interleukin - 2 and interleukin - 15 versus interleukin - 21 on P01730 REA + cutaneous T-cell lymphoma cells . In this study , we compared the effects of interleukin - 2 ( P60568 REA ) , P40933 REA , and Q9HBE4 on gene expression , activation of cell signaling pathways , and functional properties of cells derived from P01730 REA + cutaneous T-cell lymphoma ( CTCL ) . Whereas both P60568 REA and P40933 REA modulated , in a CTCL cell line , the expression of > 1,000 gene transcripts by at least 2 - fold , Q9HBE4 up-regulated < 40 genes . All three cytokines induced tyrosine phosphorylation of Jak 1 and Jak 3 in CTCL cell lines and native leukemic ( Sezary ) cells . However , only P60568 REA and P40933 REA strongly activated signal transducers and activators of transcription 5 , phosphoinositide 3 - kinase / Akt , and mitogen-activated protein / extracellular signal-regulated kinase ( P29323 REA ) kinase / P29323 REA signaling pathways in the cell lines and mitogen-primed native cells . In contrast , Q9HBE4 selectively activated signal transducers and activators of transcription 3 . Whereas all three cytokines protected CTCL cells from apoptosis , only P60568 REA and P40933 REA promoted their proliferation . The effects of the cytokine stimulation were Jak 3 kinase - and Jak 1 kinase - dependent . These findings document the vastly different effect of P60568 REA and P40933 REA versus Q9HBE4 on CTCL cells . They also suggest two novel therapeutic approaches to CTCL and , possibly , other P01730 REA + T-cell lymphomas : inhibition of the Jak 1 / Jak 3 kinase complex and , given the known strong immunostimulatory properties of Q9HBE4 on CD8 + T , natural killer , and B cells , application of this cytokine to boost an immune response against malignant P01730 REA + T cells .

Potentiation of P01138 REA - induced neurite outgrowth in PC12 cells by papaverine : role played by P98160 REA - γ , IP3 receptors . DB01113 SUB , an inhibitor of phosphodiesterase ( PDE ) 10A , is gaining attention for its potential in the treatment of neuropsychiatric diseases such as schizophrenia . However , the precise mechanisms underlying the putative neuroprotective / neurotrophic actions of papaverine remain unclear . Thus , we investigated the effects of papaverine on nerve growth factor ( P01138 REA ) - induced neurite outgrowth in PC12 cells . DB01113 SUB potentiated P01138 REA - induced neurite outgrowth in PC12 cells in a concentration-dependent manner . In contrast , the selective Q9Y233 REA inhibitor MP - 10 had no effect on P01138 REA - induced neurite outgrowth . The potentiation of P01138 REA - induced neurite outgrowth by papaverine was blocked by the P98160 REA - γ inhibitor U73122 . Furthermore , papaverine ' s potentiation of P01138 REA - induced neurite outgrowth was also blocked by the co-administration of inositol 1,4 , 5 - trisphosphate ( IP ( 3 ) ) receptor antagonists ( xestospongin C and 2 - aminoethoxydiphenyl borate ( 2 - Q9H4A4 ) ) and by reduced expression of IP ( 3 ) receptor gene ( i . e . , itpr 1 and itpr 3 ) by siRNA . Our findings suggest that papaverine could potentiate P01138 REA - induced neurite outgrowth , and that activation of P98160 REA - γ and IP ( 3 ) receptors might be involved in the mechanism underlying papaverine ' s potentiation of neurite outgrowth in PC12 cells .

MEK - P29323 REA signaling dictates DNA-repair gene P16455 REA expression and temozolomide resistance of stem-like glioblastoma cells via the Q00987 REA - p53 axis . Overcoming the resistance of glioblastoma cells against temozolomide , the first-line chemotherapeutic agent of choice for newly diagnosed glioblastoma , is a major therapeutic challenge in the management of this deadly brain tumor . The gene encoding O ( 6 ) - methylguanine DNA methyltransferase ( P16455 REA ) , which removes the methyl group attached by temozolomide , is often silenced by promoter methylation in glioblastoma but is nevertheless expressed in a significant fraction of cases and is therefore regarded as one of the most clinically relevant mechanisms of resistance against temozolomide . However , to date , signaling pathways regulating P16455 REA in P16455 REA - expressing glioblastoma cells have been poorly delineated . Here in this study , we provide lines of evidence that the mitogen-activated protein / extracellular signal-regulated kinase kinase ( MEK ) - extracellular signal-regulated kinase ( P29323 REA ) - murine double minute 2 ( Q00987 REA ) - p53 pathway plays a critical role in the regulation of P16455 REA expression , using stem-like glioblastoma cells directly derived from patient tumor samples and maintained in the absence of serum , which not only possess stem-like properties but are also known to phenocopy the characteristics of the original tumors from which they are derived . We show that , in stem-like glioblastoma cells , MEK inhibition reduced Q00987 REA expression and that inhibition of either MEK or Q00987 REA resulted in p53 activation accompanied by p53 - dependent downregulation of P16455 REA expression . MEK inhibition rendered otherwise resistant stem-like glioblastoma cells sensitive to temozolomide , and combination of MEK inhibitor and temozolomide treatments effectively deprived stem-like glioblastoma cells of their tumorigenic potential . Our findings suggest that targeting of the MEK - P29323 REA - Q00987 REA - p53 pathway in combination with temozolomide could be a novel and promising therapeutic strategy in the treatment of glioblastoma .

P04818 REA genotype-directed chemotherapy for patients with gastric and gastroesophageal junction cancers . BACKGROUND : Retrospective studies indicate associations between TSER ( thymidylate synthase enhancer region ) genotypes and clinical outcomes in patients receiving DB00544 MEN based chemotherapy , but well-controlled prospective validation has been lacking . METHODS : In this phase II study ( NCT 00515216 registered through ClinicalTrials.gov , http://clinicaltrials.gov/show/NCT00515216 ) , patients with " good risk " TSER genotypes ( at least one TSER * 2 allele ) were treated with FOLFOX chemotherapy to determine whether prospective patient selection can improve overall response rates ( ORR ) in patients with gastric and gastroesophageal junction ( GEJ ) cancers , compared with historical outcomes in unselected patients ( estimated 43 % ) . RESULTS : The ORR in genotype-selected patients was Q04695 REA % ( 9 partial responses out of 23 evaluable patients , 95 % CI , 22.2 to 59.2 ) , not achieving the primary objective of improving ORR . An encouraging disease control rate ( DCR , consisting of partial responses and stable diseases ) of 95.7 % was noted and patients with homozygous TSER * 2 genotype showed better tumor response . CONCLUSIONS : In this first prospective , multi-institutional study in patients with gastric or GEJ cancers , selecting patients with at least one TSER * 2 allele did not improve the ORR but led to an encouraging DCR . Further studies are needed to investigate the utility of selecting patients homozygous for the TSER * 2 allele and additional genomic markers in improving clinical outcomes for patients with gastric and GEJ cancers . TRIAL REGISTRATION : ClinicalTrials.gov NCT 00515216 .

Human motor neuron progenitor transplantation leads to endogenous neuronal sparing in 3 models of motor neuron loss . Motor neuron loss is characteristic of many neurodegenerative disorders and results in rapid loss of muscle control , paralysis , and eventual death in severe cases . In order to investigate the neurotrophic effects of a motor neuron lineage graft , we transplanted human embryonic stem cell-derived motor neuron progenitors ( hMNPs ) and examined their histopathological effect in three animal models of motor neuron loss . Specifically , we transplanted hMNPs into rodent models of SMA ( Δ7SMN ) , P35858 REA ( P00441 REA G93A ) , and spinal cord injury ( SCI ) . The transplanted cells survived and differentiated in all models . In addition , we have also found that hMNPs secrete physiologically active growth factors in vivo , including P01138 REA and P20783 REA , which significantly enhanced the number of spared endogenous neurons in all three animal models . The ability to maintain dying motor neurons by delivering motor neuron-specific neurotrophic support represents a powerful treatment strategy for diseases characterized by motor neuron loss .

Expression of P20839 REA and P12268 REA after transplantation and initiation of immunosuppression . BACKGROUND : DB01024 MEN ( DB00603 ) mediates immunosuppressive effects by inhibiting inosine monophosphate dehydrogenase ( IMPDH ) . Induction of IMPDH activity has been observed in whole blood and erythrocyte samples during immunosuppressive therapy . Information concerning the mechanisms for increased IMPDH activity is limited and the potential implications of induction have been debated . METHODS : Whole blood , P01730 REA + cell , and reticulocyte samples were collected from 30 renal transplant patients pre - and posttransplantation . The expressions of two IMPDH isoforms , type 1 and 2 , were analyzed by real-time reverse-transcription polymerase chain reaction and quantified using a housekeeping gene index . The IMPDH activity was determined by ultraviolet high-performance liquid chromatography . RESULTS : Transplantation and the initiation of immunosuppressive therapy was associated with increased P20839 REA ( 50-88 % , P < 0.0005 ) and decreased P12268 REA ( 42-56 % , P < 0.0005 ) expression . In P01730 REA + cells , however , P12268 REA increased ( 15 % , P= 0.009 ) . These changes are probably related to glucocorticoid effects . Two weeks posttransplant , DB00603 - treated patients displayed elevated P20839 REA and 2 in reticulocytes , suggesting enzyme induction in these cells during prolonged DB00603 therapy . Patients with acute rejection during follow-up demonstrated higher P12268 REA expression in P01730 REA + cells pretransplant than nonrejecting patients ( median expression 1.26 vs . 0.87 respectively , P= 0.017 ) . CONCLUSIONS : Knowledge of changes in P20839 REA and 2 expression after transplantation and initiation of immunosuppression is important considering the action of DB00603 on IMPDH and the potential for pharmacodynamic monitoring of DB00603 by measuring IMPDH activity . The expression of P12268 REA in P01730 REA + cells pretransplant may be an indicator of immune activation .

Incorporating age at onset of smoking into genetic models for nicotine dependence : evidence for interaction with multiple genes . DB00184 MEN dependence is moderately heritable , but identified genetic associations explain only modest portions of this heritability . We analyzed 3369 SNPs from 349 candidate genes and investigated whether incorporation of SNP-by-environment interaction into association analyses might bolster gene discovery efforts and prediction of nicotine dependence . Specifically , we incorporated the interaction between allele count and age at onset of regular smoking ( AOS ) into association analyses of nicotine dependence . Subjects were from the Collaborative Genetic Study of DB00184 MEN Dependence and included 797 cases ascertained for Fagerström nicotine dependence and 811 non-nicotine-dependent smokers as controls , all of European descent . Compared with main effect models , SNP x AOS interaction models resulted in higher numbers of nominally significant tests , increased predictive utility at individual SNPs and higher predictive utility in a multi-locus model . Some SNPs previously documented in main effect analyses exhibited improved fits in the joint analysis , including rs16969968 from P30532 REA and rs2314379 from Q9Y6R4 . P30532 REA exhibited larger effects in later-onset smokers , in contrast with a previous report that suggested the opposite interaction ( Weiss et al . 2008 ) . However , a number of SNPs that did not emerge in main effect analyses were among the strongest findings in the interaction analyses . These include SNPs located in Q13224 REA ( P = 1.5 x 10 ( - 5 ) ) , which encodes a subunit of the N-methyl-D-aspartate receptor channel , a key molecule in mediating age-dependent synaptic plasticity . Incorporation of logically chosen interaction parameters , such as AOS , into genetic models of substance use disorders may increase the degree of explained phenotypic variation and constitutes a promising avenue for gene discovery .

Concise prediction models of anticancer efficacy of 8 drugs using expression data from 12 selected genes . We developed concise , accurate prediction models of the in vitro activity for 8 anticancer drugs ( DB00544 MEN , DB00515 , DB00305 , DOX , CPT - 11 , SN - 38 , TXL and TXT ) , along with individual clinical responses to DB00544 MEN using expression data of 12 genes . We first performed cDNA microarray analysis and MTT assay of 19 human cancer cell lines to sort out genes which were correlative in expression levels with cytotoxicities of the 8 drugs ; we selected 13 genes with proven functional significance to drug sensitivity from a huge number of potent prediction marker genes . The correlation significance of each was confirmed using expression data quantified by real-time RT-PCR , and finally 12 genes ( P08183 REA , Q9UNQ0 , P10632 REA , P08684 REA , Q12882 REA , P09211 REA , P16455 REA , P15559 REA , P16435 REA , P11388 REA , P07437 REA and P04818 REA ) were selected as more reliable predictors of drug response . Using multiple regression analysis , we fixed 8 prediction formulae which embraced the variable expressions of the 12 genes and arranged them in order , to predict the efficacy of the drugs by referring to the value of Akaike ' s information criterion for each sample . These formulae appeared to accurately predict the in vitro efficacy of the drugs . For the first clinical application model , we fixed prediction formulae for individual clinical response to DB00544 MEN in the same way using 41 clinical samples obtained from 30 gastric cancer patients and found to be of predictive value in terms of survival , time to treatment failure and tumor growth . None of the 12 selected genes alone could predict such clinical responses .

Augmentation by citalopram of risperidone-induced monoamine release in rat prefrontal cortex . RATIONALE : A typical antipsychotics ( APDs ) , e . g . olanzapine and risperidone , have been reported to be effective adjunctive treatment for depression if selective serotonin ( 5 - HT ) reuptake inhibitors ( SSRIs ) alone are ineffective . OBJECTIVES AND METHODS : We utilized microdialysis in awake , freely moving rats to study the effect of risperidone in combination with citalopram , an SSRI , on extracellular 5 - HT , dopamine ( DA ) , and norepinephrine ( NE ) efflux in rat medial prefrontal cortex ( mPFC ) . RESULTS : DB00734 MENMAX DB00734 MEN ( 1.0 mg / kg , s . c . ) , given alone , significantly increased 5 - HT , DA , and NE concentrations in the mPFC . DB00215 ( 10 mg / kg , s . c . ) , by itself , produced a significant increase in 5 - HT levels only . The combination of risperidone and citalopram produced significantly greater increases in efflux of both DA and NE than risperidone alone . However , the effect of this combination on extracellular 5 - HT concentrations was not significantly different than that of citalopram alone . The augmentation of DA and NE efflux induced by risperidone plus citalopram could be partially blocked by the selective P08908 REA antagonist , WAY 100635 ( 0.2 mg / kg , s . c . ) . CONCLUSIONS : The results suggest that the ability of atypical APDs to augment the therapeutic efficacy of SSRIs in major depression and treatment-resistant depression may be due , at least in part , to potentiation of SSRI-induced increases in cortical DA and NE . The contributions of P08908 REA receptor stimulation and 5 - Q13049 REA and alpha 2 adrenergic receptor antagonism to this augmentation are discussed .

Developmental changes of glutamate receptors in the rat cerebral cortex and hippocampus . We studied the immunohistochemical localization of the glutamate receptors ( P42261 REA , - 2 , and - 3 , ) in the developing rat cerebral cortex and hippocampus using antibodies to GluR 1 and to an epitope common to GluR 2 and GluR 3 ( GluR 2/3 ) subunits . In the cerebral cortex , GluR 1 immunoreactivity appeared in the neurons from postnatal day ( P01160 REA ) 0 , increased with maturation , was highest at P01160 REA 10 , decreased until P01160 REA 30 , and thereafter remained at the same level as on P01160 REA 0 . GluR 2/3 immunoreactivity appeared earlier in scattered neurons on embryonal day ( ED ) 18 , increased with maturation and reached a peak between P01160 REA 10 and P01160 REA 15 , after which the immunoreactivity gradually decreased and reached a plateau at P01160 REA 30 . For both GluR 1 and GluR 2/3 , some of the pyramidal neurons showed intense staining . In the pyramidal layers of the hippocampus , GluR 1 and GluR 2/3 immunoreactivity was found in all the pyramidal neurons of the P00915 REA - 4 area from ED 20 . In the dentate gyrus of the hippocampus , GluR 1 and GluR 2/3 immunoreactivity was found in the neurons of the granule cells after P01160 REA 0 . Immunoreactivity in the neurons of the subiculum was found after P01160 REA 5 and that of the polymorphic cell layers was found after P01160 REA 15-20 . Our results indicate that the development of glutamate receptor subunits in the rat cerebral cortex and hippocampus is expressed in different spatial patterns and distinct temporal patterns throughout development and is scheduled during the early postnatal period , when synaptic plasticity or synaptic connection occurs in these regions .

PDE 10 inhibition increases P42261 REA and CREB phosphorylation and improves spatial and recognition memories in a Huntington ' s disease mouse model . Huntington ' s disease ( HD ) causes motor disturbances , preceded by cognitive impairment , in patients and mouse models . We showed that increased hippocampal DB02527 - dependent protein kinase ( PKA ) signaling disrupts recognition and spatial memories in R6 HD mouse models . However , unchanged levels of hippocampal phosphorylated ( p ) DB02527 - responsive element-binding protein ( CREB ) suggested unaltered nuclear PKA activity in R6 mice . Here , we extend this finding by showing that nuclear pPKA catalytic subunit ( Thr 197 ) and pPKA substrate levels were unaltered in the hippocampus of R6 / 1 mice . Phosphodiesterases ( PDEs ) play an important role in the regulation of PKA activity . Q9Y233 REA , a DB02527 / cGMP dual-substrate PDE , was reported to be restricted to the nuclear region in nonstriatal neurons . Using cell fractionation we confirmed that Q9Y233 REA was enriched in nuclear fractions , both in wild-type and R6 / 1 mice hippocampus , without differences in its levels or intracellular distribution between genotypes . We next investigated whether inhibition of PDE 10 with papaverine could improve cognitive function in HD mice . DB01113 SUB treatment improved spatial and object recognition memories in R6 / 1 mice , and significantly increased pGluA 1 and pCREB levels in R6 / 1 mice hippocampus . DB01113 SUB likely acted through the activation of the PKA pathway as the phosphorylation level of distinct cGMP-dependent kinase ( cGK ) substrates was not modified in either genotype . Moreover , hippocampal DB02527 , but not cGMP , levels were increased after acute papaverine injection . Our results show that inhibition of PDE 10 improves cognition in R6 mice , at least in part through increased P42261 REA and CREB phosphorylation . Thus , PDE 10 might be a good therapeutic target to improve cognitive impairment in HD .

Expression pattern and biochemical characteristics of a major epidermal retinol dehydrogenase . The biological functions of vitamin A in the epidermis are mediated by all-trans retinoic acid , which is biosynthesized from retinol in two oxidative reactions . The first step involves enzymatic conversion of retinol to retinaldehyde . The physiological significance and relative contributions of the various retinol dehydrogenases to the oxidation of retinol in epidermal cells remain unclear . We report the characterization of a retinol dehydrogenase / reductase of the SDR superfamily , hRoDH-E 2 , which is abundantly expressed in the epidermis , epidermal appendages and in cultured epidermal keratinocytes . Both in live keratinocytes and in isolated keratinocyte microsomes , where the enzyme normally localizes , hRoDH-E 2 functions as a bona fide retinol dehydrogenase . In the prevailing oxidative reaction it recognizes both free - and P09455 REA - bound retinol , and shows preference toward NADP as a co-substrate . In comparison , hRoDH-E 2 retinol dehydrogenase activity in the simple epithelial P29320 REA 293 cells is much lower and in CHO cells is non-existent . hRoDH-E 2 transcripts are distributed throughout the epidermal layers but are more abundant in the basal cells . In contrast , the protein is detected predominantly in the basal and the most differentiated living layers . Its synthesis is negatively regulated by retinoic acid . The biochemical properties and the differential expression of hRoDH-E 2 in the strata where retinoic acid signaling is critical for epidermal homeostasis support a conclusion that hRoDH-E 2 bears the characteristics of the major microsomal retinol dehydrogenase activity in the epidermal keratinocytes in physiological circumstances .

IκB kinase / nuclear factor κB-dependent insulin-like growth factor 2 ( Igf 2 ) expression regulates synapse formation and spine maturation via Igf 2 receptor signaling . Alterations of learning and memory in mice with deregulated neuron-specific nuclear factor κB ( NF-κB ) activity support the idea that plastic changes of synaptic contacts may depend at least in part on IκB kinase ( IKK ) / NF-κB-related synapse-to-nucleus signaling . There is , however , little information on the molecular requirements and mechanisms regulating this IKK / NF-κB-dependent synapse development and remodeling . Here , we report that the NF-κB inducing IKK kinase complex is localized at the postsynaptic density ( A5PKW4 ) and activated under basal conditions in the adult mouse brain . Using different models of conditional genetic inactivation of O14920 REA function in mouse principal neurons , we show that IKK / NF-κB signaling is critically involved in synapse formation and spine maturation in the adult brain . IKK / NF-κB blockade in the forebrain of mutant animals is associated with reduced levels of mature spines and postsynaptic proteins P78352 REA , Q12959 REA , P42261 REA , AMPAR-mediated basal synaptic transmission and a spatial learning impairment . Synaptic deficits can be restored in adult animals within 1 week by IKK / NF-κB reactivation , indicating a highly dynamic IKK / NF-κB-dependent regulation process . We further identified the insulin-like growth factor 2 gene ( Igf 2 ) as a novel IKK / NF-κB target . Exogenous Igf 2 was able to restore synapse density and promoted spine maturation in IKK / NF-κB signaling-deficient neurons within 24 h . This process depends on Igf 2 / Igf 2R - mediated MEK / P29323 REA activation . Our findings illustrate a fundamental role of IKK / NF-κB-Igf 2 - Igf 2R signaling in synapse formation and maturation in adult mice , thus providing an intriguing link between the molecular actions of IKK / NF-κB in neurons and the memory enhancement factor Igf 2 .

Novel MEK inhibitor trametinib and other retinoblastoma gene ( RB ) - reactivating agents enhance efficacy of 5 - fluorouracil on human colon cancer cells . Chemotherapy for colorectal cancer has become more complicated and diversified with the appearance of molecular-targeting agents . DB00544 MEN ( DB00544 MEN ) has been a mainstay of chemotherapy for colorectal cancer , but it is still unknown whether the combining of DB00544 MEN with novel molecular-targeting agents is effective . P04818 REA ( TS ) is a direct target of DB00544 MEN , and the low TS level has been generally supposed to sensitize DB00544 MEN ' s efficacy . We therefore hypothesized that RB-reactivating agents could enhance the efficacy of DB00544 MEN , because the RB-reactivating agents could suppress the function of transcription factor E2F of TS gene promoter . We used three RB-reactivating agents , trametinib / GSK 1120212 ( MEK inhibitor ) , fenofibrate ( Q07869 REA α agonist ) , and LY294002 ( PI3K inhibitor ) , with DB00544 MEN against human colon cancer HT - 29 and HCT 15 cells . DB08911 induced p15 and p27 expression and reduced cyclin D1 levels in HT - 29 cells . Fenofibrate also dephosphorlated P27361 REA / 2 and reduced cyclin D1 levels in HT - 29 cells . LY294002 induced p27 expression in HCT 15 cells . All three agents caused dephosphorylation of RB protein and P55008 - phase arrest with a reduction of TS expression . As a consequence , the combination of DB00544 MEN with each of the agents resulted in a significant decrease of colony numbers in HT - 29 or HCT 15 cells . These results suggest " RB-reactivation therapy " using molecular-targeting agents to be a new strategy for DB00544 MEN - based chemotherapy . In particular , we strongly expect trametinib , which was discovered in Japan and was recently submitted to FDA for approval , to be used together with established regimens for colorectal cancer .

Effect of P14416 REA , 5 - Q13049 REA , and P21964 REA genes on antipsychotic response to risperidone . DB00734 MEN is a widely used atypical antipsychotic with certain advantages over typical antipsychotics . Although variations in the efficacy of treatment with risperidone have been observed , no specific predictable marker has been identified as of yet . In all , 73 Japanese patients with schizophrenia were given risperidone for 8 weeks , and clinical symptoms were evaluated using the Positive and Negative Syndrome Scale ( PANSS ) . Six candidate polymorphisms ( P28223 REA - 1438G > A , 102T > C , H452Y ; P14416 REA - 141delC , Taq I A ; P21964 REA V158M ) were genotyped . The diplotype configuration for each individual was estimated by the maximum-likelihood method . Multiple linear regressions were used to analyze the effects of these haplotypes / genotype and other prognostic factors on PANSS scale performance . After adjustment for the effects of patient-related variables , P28223 REA diplotype and P21964 REA genotype , as well as other potential prognostic factors , did not significantly influence the clinical performance . A P14416 REA haplotype tended to correlate with better clinical performance . Compared with patients who had Ins-A 2 / Ins-A 2 diplotype ( n = 25 ) , PANSS total scores of patients with Ins-A 2 / Del-A 1 diplotype ( n = 10 ) showed 40 % greater improvement ( P= 0.03 ) . The PANSS total scores of patients with P28223 REA A-T / A-T diplotype ( n = 22 ) tended to show 15 % worse improvement compared with A-T / G-C diplotype ( n = 33 ) ( P= 0.06 ) . These results should be treated with caution because of limitations due to small sample size , heterogeneity of patients with respect to past antipsychotic use history , and no correction for multiple corrections . However , the present findings generate important hypotheses in a sample of Japanese schizophrenia patients that may lay the foundation for future pharmacogenomics investigations in other populations .