interacts_with DB01166?
DB00741 is a suppressor of apoptosis in bovine corpus luteum . Glucocorticoid ( GC ) acts as a modulator of physiological functions in several organs . In the present study , we examined whether GC suppresses luteolysis in bovine corpus luteum ( CL ) . DB00741 ( an active GC ) reduced the mRNA expression of caspase 8 ( Q14790 ) and caspase 3 ( P42574 ) and reduced the enzymatic activity of P42574 and cell death induced by tumor necrosis factor ( P01375 ) and interferon gamma ( P01579 ) in cultured bovine luteal cells . mRNAs and proteins of GC receptor ( P04150 ) , 11beta-hydroxysteroid dehydrogenase type 1 ( P28845 ) , and P80365 were expressed in CL throughout the estrous cycle . Moreover , the protein expression and the enzymatic activity of P28845 were high at the early and the midluteal stages compared to the regressed luteal stage . These results suggest that cortisol suppresses P01375 - P01579 -induced apoptosis in vitro by reducing apoptosis signals via Q14790 and P42574 in bovine CL and that the local increase in cortisol production resulting from increased P28845 at the early and midluteal stages helps to maintain CL function by suppressing apoptosis of luteal cells . FTY720 induces apoptosis of chronic myelogenous leukemia cells via dual activation of O43521 and P55957 and overcomes various types of resistance to tyrosine kinase inhibitors . PP2A activator FTY720 has been shown to possess the anti-leukemic activity for chronic myelogenous leukemia ( CML ) , however , the cell killing mechanism underlying its anti-leukemic activity has remained to be verified . We investigated the precise mechanisms underlying the apoptosis induction by FTY720 , especially focusing on the roles of BH3-only proteins , and the therapeutic potency of FTY720 for CML . Enforced expression of either P10415 or the dominant-negative protein of Q13158 ( Q13158 .DN ) partly protected CML cells from apoptosis by FTY720 , indicating the involvement of both cell extrinsic and intrinsic apoptosis pathways . FTY720 activates pro-apoptotic BH3-only proteins : O43521 , which is essential for apoptosis by P11274 - P00519 tyrosine kinase inhibitors ( TKIs ) , and P55957 , which accelerates the extrinsic apoptosis pathway . Gene knockdown of either O43521 or P55957 partly protected K562 cells from apoptosis by FTY720 , but the extent of cell protection was not as much as that by overexpression of either P10415 or Q13158 .DN . Moreover , knockdown of both O43521 and P55957 did not provide additional protection compared with knockdown of only O43521 or P55957 , indicating that O43521 and P55957 complement each other in apoptosis by FTY720 , especially when either is functionally impaired . FTY720 can overcome TKI resistance caused by P00519 kinase domain mutations , dysfunction of O43521 resulting from gene deletion polymorphism , and galectin-3 overexpression . In addition , DB05764 , a BH3-mimetic , significantly augmented cell death induction by FTY720 both in TKI-sensitive and -resistant leukemic cells . These results provide the rationale that FTY720 , with its unique effects on O43521 and P55957 , could lead to new therapeutic strategies for CML . Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 ( P04275 ) release and morphological change in response to injury-associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 , plasminogen activator inhibitor type 1( P05121 ) , antithrombin III ( P01008 ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 ) ( 1 , 10 , 100 ng/ml ) for up to 48 hours to test the amount of P04275 secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 and P01008 difference between FAECs and FVECs. P09038 ( 10 ng/ml ) significantly increased P04275 secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease . aChE and BuChE inhibition by rivastigmin have no effect on peripheral insulin resistance in elderly patients with Alzheimer disease . BACKGROUND : P01308 resistance ( IR ) may play a role in most pathogenic processes that promote the development of Late Onset Alzheimer Disease ( LOAD ) . This study was designed to determine the interaction between inhibition of both butyrylcholinesterase ( BuChE ) and acetylcholinesterase ( P22303 ) with rivastigmine and peripheral insulin resistance ( IR ) in LOAD . METHODS : Seventy-Nine consecutive elderly patients , 31 late onset AD and 48 non-demented patients were evaluated . IR was calculated with HOMA . All of the patients were evaluated through comprehensive geriatric assessments at baseline and in the 6th and 12th months . RESULTS : End of the study , compared to the baseline values , there was a significant increase in the 6th month in both MMSE and IADL scores ( t =2.200 , p = 0.036 for MMSE and t =2.724 , p= 0.011 for IADL , respectively ) . DB00989 was improved both the scores of MMSE and IADL in elderly patients with LOAD , but there was no significance or correlation between HOMA scores and cognitive status . CONCLUSION : In conclusion , inhibition of both BuChE and P22303 with rivastigmine was improved the cognition without affecting on the peripheral IR in the elderly patients with LOAD by HOMA . Due to the complexity of disease pathogenesis , it is too early to make general comments , and further longitudinal and long-term studies on this issue are needed . Effect of canagliflozin on renal threshold for glucose , glycemia , and body weight in normal and diabetic animal models . BACKGROUND : DB08907 is a sodium glucose co-transporter ( SGLT ) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus ( T2DM ) . METHODS : (14)C-alpha-methylglucoside uptake in Chinese hamster ovary-K cells expressing human , rat , or mouse SGLT2 or P13866 ; (3)H-2-deoxy-d-glucose uptake in Q9BTT4 myoblasts ; and 2-electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed . Graded glucose infusions were performed to determine rate of urinary glucose excretion ( UGE ) at different blood glucose ( BG ) concentrations and the renal threshold for glucose excretion ( RT(G) ) in vehicle or canagliflozin-treated Zucker diabetic fatty ( ZDF ) rats . This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity . RESULTS : Treatment with canagliflozin 1 mg/kg lowered RT(G) from 415±12 mg/dl to 94±10 mg/dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RT(G) . DB08907 dose-dependently decreased BG concentrations in db/db mice treated acutely . In ZDF rats treated for 4 weeks , canagliflozin decreased glycated hemoglobin ( HbA1c ) and improved measures of insulin secretion . In obese animal models , canagliflozin increased UGE and decreased BG , body weight gain , epididymal fat , liver weight , and the respiratory exchange ratio . CONCLUSIONS : DB08907 lowered RT(G) and increased UGE , improved glycemic control and beta-cell function in rodent models of T2DM , and reduced body weight gain in rodent models of obesity . Activity of retinoic acid receptor-gamma selectively binding retinoids alone and in combination with interferon-gamma in breast cancer cell lines . Retinoids modulate several cell functions and especially inhibit the growth of a wide variety of cells including breast cancer . Retinoic acid receptor-gamma ( P13631 ) has been shown to mediate the antiproliferative activity of retinoids . To further test this hypothesis we examined the effects of different P13631 selectively binding retinoids ( CD2325 , CD2247 , CD666 and CD437 ) on breast cancer cell lines . With exception of CD2247 , all retinoids inhibited proliferation of MCF-7 , SKBR-3 , T47D and ZR-75-1 breast cancer cell lines , similar to the natural compound all-trans retinoic acid ( DB00755 ) . In addition , all 4 compounds were able to act synergistically with interferon-gamma ( P01579 ) in all breast cancer cell lines including the retinoid-resistant BT-20 and 734-B lines . In functional transactivation assays we demonstrated that only in the MCF-7 cell line , TPA-mediated AP-1 activity was suppressed only by DB00755 and CD2325 , whereas in SKBR-3 , another RA-sensitive breast cancer cell line , it was not . The synergistic antiproliferative activity involving retinoids and P01579 could not be explained by an enhanced anti-AP-1 activity . No correlation was found between expression of RARs and cellular retinoic acid binding proteins ( CRABPs ) and antiproliferative effects of the retinoids . P13631 selectively binding retinoids are potent inhibitors of breast cancer cell proliferation , alone and in combination with P01579 . For this reason and because of a possible low toxicity , as compared with retinoic acid , we speculate that these P13631 selective binding retinoids might be of clinical importance . Antiinflammatory and analgesic efficacy of P35354 specific inhibition : from investigational trials to clinical experience . Research strongly indicates that increased expression of the isoenzyme cyclooxygenase-2 ( P35354 ) is responsible for elevated production of prostaglandins in inflamed joint tissues and is involved in the mediation of pain . In contrast , P23219 is a constitutively produced isoenzyme that is involved in the synthesis of eicosanoids that have important homeostatic functions , for example , in the gastric mucosa and platelets . This new knowledge led to the development of drugs that are highly specific inhibitors of P35354 while not inhibiting P23219 at maximally efficacious dosages . The first P35354 specific agent approved for clinical use in the United States was celecoxib . Large multicenter trials have shown that celecoxib at dosages of 100 mg P55957 and 200 mg P55957 is as effective as naproxen 500 mg P55957 in patients with osteoarthritis of the knee or hip . Another large multicenter trial also demonstrated that celecoxib 200 mg P43251 and 400 mg P55957 is as effective as naproxen 500 mg P55957 in patients with rheumatoid arthritis ( RA ) . A comparative trial showed that celecoxib 200 mg P55957 is as effective as diclofenac SR 75 mg P55957 in patients with RA . The potential of P35354 specific inhibitors to provide antiinflammatory and analgesic efficacy equivalent to that of conventional nonsteroidal antiinflammatory drugs without the adverse gastrointestinal mucosal and platelet effects associated with nonspecific P36551 inhibitors promises to revolutionize the clinical care of arthritis patients . NT-702 ( parogrelil hydrochloride , DB05505 ) , a novel and potent phosphodiesterase inhibitor , improves reduced walking distance and lowered hindlimb plantar surface temperature in a rat experimental intermittent claudication model . NT-702 ( parogrelil hydrochloride , DB05505 ) , 4-bromo-6-[3-(4-chlorophenyl)propoxy]-5-[(pyridin-3-ylmethyl)amino]pyridazin-3(2H)-one hydrochloride , a novel phosphodiesterase ( PDE ) inhibitor synthesized as a potent vasodilatory and antiplatelet agent , is being developed for the treatment of intermittent claudication ( IC ) in patients with peripheral arterial disease . We assessed the efficacy of NT-702 in an experimental IC model as compared with cilostazol and additionally investigated the pharmacological property in vitro and ex vivo . NT-702 selectively inhibited PDE3 ( IC(50)=0.179 and 0.260 nM for Q14432 and 3B ) more potently than cilostazol ( IC(50)=231 and 237 nM for Q14432 and 3B ) among recombinant human PDE1 to PDE6 . NT-702 inhibited in vitro human platelet aggregation induced by various agonists ( IC(50)=11 to 67 nM ) and phenylephrine-induced rat aortic contraction ( IC(50)=24 nM ) . Corresponding results for cilostazol were 4.1 to 17 microM and 1.0 microM , respectively . NT-702 ( 3 mg/kg or more ) significantly inhibited ex vivo rat platelet aggregation after a single oral dose . For cilostazol , 300 mg/kg was effective . In a rat femoral artery ligation model , NT-702 at 5 and 10 mg/kg repeated oral doses twice a day ( P55957 ) for 13 days significantly improved the reduced walking distance while the lowered plantar surface temperature was improved at 2.5 mg/kg and more . DB01166 also improved the walking distance and surface temperature at 300 mg/kg P55957 but significant difference was only observed for surface temperature on day 8 . These results suggest that NT-702 can be expected to have therapeutic advantage for IC . Microarray analysis of cytokine activation of apoptosis pathways in the thyroid . It has been suggested that Fas-mediated apoptosis plays an important role in the pathogenesis of autoimmune thyroid diseases . Our previous studies have demonstrated that normal primary thyroid epithelial cells are resistant to Fas-mediated apoptosis , but the resistance can be overcome by pretreatment with a combination of interferon-gamma ( P01579 ) and IL-1beta . To understand the molecular mechanism responsible for the P01579 /IL-1beta effects , we profiled changes in the transcription induced by these two cytokines in normal human thyroid cells , using cDNA microarrays . We found that P01579 /IL-1beta showed a significant increase in apoptosis-related genes such as inducible nitric oxide synthase ( P35228 ) , receptor-interacting protein 2 ( O43353 ) , and caspases 10 . These increases were confirmed by other methods , including real-time PCR and Western blot . Furthermore , the sensitization of primary thyroid epithelial cells to Fas-mediated apoptosis by P01579 /IL-1beta was significantly blocked by a general caspase inhibitor , z-VAD , or by the combination of two specific individual caspase inhibitors . In addition , our results showed that P01579 /IL-1beta enhance p38 MAPK phosphorylation and that SB 203580 , a p38 MAPK inhibitor , can inhibit P01579 /IL-1beta-induced p38 MAPK phosphorylation . SB 203580 also significantly prevented cytokine-induced P35228 expression and caspase activation and thus blocked Fas-mediated apoptosis of thyroid cells sensitized by P01579 /IL-1beta . In conclusion , our data suggest that both p38 MAPK and P35228 are involved in P01579 /IL-1beta-induced sensitization of the thyroid cells to Fas-mediated apoptosis via the activation of caspases 3 , 7 , and 10 and that this pathway may be further activated by P55957 . This hints that inflammatory cytokines regulate death-receptor-mediated apoptosis at multiple points in the process . DB00909 block of cloned human T-type voltage-gated calcium channels . DB00909 ( ZNS ) is a multi-target antiepileptic drug reported to be efficient in the treatment of both partial and generalized seizures , with T-type Ca(2+) channel blockade being one of its proposed mechanisms of action . In this study , we systematically investigated electrophysiological effects of ZNS on cloned human Ca(v)3.1-3.3 Ca(2+) channels in a heterologous P29320 -293 expression system using whole cell patch-clamp technique . Concentration-response studies were performed in the range from 5 microM to 2mM for Ca(v)3.2 Ca(2+) channels exhibiting a 15.4-30.8 % reduction of Ca(2+) influx within the maximum therapeutic plasma range ( 50-200 microM ZNS ) . The other T-type Ca(2+) channel entities , Ca(v)3.1 and Q9P0X4 , were even less sensitive to ZNS . Both voltage- and concentration-dependence of inactivation kinetics remained unchanged for Ca(v)3.2 VGCC , whereas Ca(v)3.1 and Q9P0X4 exhibited minor , though significant reduction of inactivation-tau . Interestingly , ZNS block of Ca(v)3.2 VGCCs was not use-dependent and remained unaffected by changes in the holding potential . Steady-state inactivation studies did not display a significant shift in steady-state availability of Ca(v)3.2 channels at 100 microM ZNS ( DeltaV(1/2)=3.1mV , p=0.071 ) . Our studies indicate that ZNS is a moderate blocker of human Ca(v)3 T-type Ca(2+) channels with little or no effect on Ca(v)3.2 Ca(2+) channel inactivation kinetics , use- and state-dependence of blockade . These results suggest that T-type Ca(2+) channel inhibition only partially contributes to the anti-absence activity of ZNS antiepileptic drug . Inhibition of phosphatidylinositol 3'-kinase/AKT signaling promotes apoptosis of primary effusion lymphoma cells . PURPOSE : Phosphatidylinositol 3'-kinase ( P19957 '-kinase ) can be activated by the P04264 protein of Kaposi sarcoma-associated herpes virus ( KSHV ) . However , the role of P19957 '-kinase in KSHV-associated primary effusion lymphoma ( PEL ) is not known . To assess this , we studied survival and apoptosis in PEL cell lines following inhibition of P19957 '-kinase . EXPERIMENTAL DESIGN : Constitutive activation of several targets of P19957 -kinase and apoptotic proteins were determined by Western blot analysis using specific antibodies . We used LY294002 to block P19957 '-kinase/AKT activation and assess apoptosis by flow cytometric analysis . RESULTS : Blocking P19957 '-kinase induced apoptosis in PEL cells , including BC1 , BC3 , BCBL1 , and HBL6 , whereas BCP1 was refractory to LY294002-induced apoptosis . LY294002-induced apoptosis did not seem to involve Fas/Fas-L but had an additive effect to CH11-mediated apoptosis . We also show that AKT/ P31749 is constitutively activated in all PELs and treatment with LY294002 causes complete dephosphorylation in all cell lines except BCP1 where a residual AKT phosphorylation remained after 24 hours of treatment . Q12778 and GSK3 were also constitutively phosphorylated in PELs and treatment with LY294002 caused their dephosphorylation . Although inhibition of P19957 '-kinase induced cleavage of P55957 in all cell lines , cytochrome c was released from the mitochondria and caspase-9 and caspase-3 were activated in LY294002-induced apoptotic BC1 but not in resistant BCP1 . Similarly , P98170 , a target of AKT , was down-regulated after LY294002 treatment only in sensitive PEL cells . CONCLUSIONS : Our data show that the P19957 '-kinase pathway plays a major role in survival of PEL cells and suggest that this cascade may be a promising target for therapeutic intervention in primary effusion lymphomas . DB01645 potentiates the P01160 effect on a K(+)-conductance in P29320 -293 cells . P29320 -293 cells are known to reflect many features of the late distal tubule . Furthermore , they have the ability to release urodilatin , the structural analog to P01160 . RT-PCR was performed to test for the expression of natriuretic peptide receptors . While the mRNA for the human P01160 receptor ( P16066 , P16066 ) could be amplified , the P09543 -specific receptor P20594 ( P20594 ) and the receptor specific for guanylins , P25092 , could not be detected . In patch clamp experiments the effects of P01160 ( 10 nM ) on membrane voltage ( V(m) ) were monitored and P29320 -293 cells depolarized by 2.3 +/- 0.5 mV ( n=14 ) . In the presence of the P01133 receptor blocker genistein ( 10 microM ) the effect of P01160 was increased by 65 % to 3.9 +/- 0.8 mV ( n=14 ) . After removal of genistein the P01160 -mediated depolarization further increased by 147 % to 5.7 +/- 1.0 mV ( n=14 ) . P01160 given repetitively without genistein had no increasing depolarizing effect in P29320 -293 cells with time . The P01160 effect could be fully blocked by 1 mM Ba(2+) and by 1 microM of the specific PKG inhibitor KT5823 indicating that P01160 inhibits a K(+)-conductance via a cGMP-dependent protein kinase . DB01645 itself hyperpolarized the membrane voltage of P29320 -293 cells by -3.9 +/- 0.6 mV ( n=11 ) and this effect could also be fully blocked by Ba(2+) ( -0.3 +/- 0.1 mV , n=5 ) , indicating that genistein activates a K(+)-conductance which contributes significantly to the membrane potential of P29320 -293 cells . Synergism between bosutinib ( DB06616 ) and the Chk1 inhibitor ( PF-00477736 ) in highly imatinib-resistant P11274 /ABL⁺ leukemia cells . Interactions between the dual P11274 / P00519 and Src inhibitor bosutinib and the Chk1 inhibitor PF-00477736 were examined in P11274 / P00519 (+) leukemia cells , particularly imatinib-resistant cells , including those with the T315I mutation . Bosutinib blocked PF-00477736-induced P27361 /2 activation and sharply increased apoptosis in association with Mcl-1 inhibition , p34(cdc2) dephosphorylation , BimEL up-regulation , and DNA damage in imatinib-resistant CML or Ph(+) ALL cell lines . Inhibition of Src or Q02750 by shRNA significantly enhanced PF-0047736 lethality . Bosutinib/PF-00477736 co-treatment also potentiated cell death in P28906 (+) CML patient samples , including dasatinib-resistant blast crisis cells exhibiting both T315I and E355G mutations , but was minimally toxic to normal P28906 (+) cells . Finally , combined in vivo treatment significantly suppressed BaF3/T315I tumor growth and prolonged survival in an allogeneic mouse model . Together , these findings suggest that this targeted combination strategy warrants attention in IM-resistant CML or Ph(+) ALL . Prevention of thrombus formation and growth by antithrombin III and heparin cofactor II-dependent thrombin inhibitors : importance of heparin cofactor II . DB01109 ( HEP ) prevents thrombus formation ( TF ) and thrombus growth ( TG ) , by accelerating thrombin ( THR ) inhibition by antithrombin III ( P01008 ) . Recent studies suggest that dermatan sulphate which catalyzes thrombin inhibition by heparin cofactor II ( HCII ) , can inhibit TF and TG as effectively as HEP . This study compared the antithrombotic effects of HEP and another agent , DB06271 ( SLX ) which catalyzes thrombin inhibition by P01008 and HCII simultaneously . TF was induced in rabbit jugular veins , using the stasis/hypercoagulation model . TG was measured as the accretion of 125I-fibrin onto existing thrombi in rabbit jugular veins . HEP and SLX inhibited TF when given in doses of 10 and 5 anti-thrombin U/kg , respectively . SLX ( 16 anti-thrombin U/kg or 260 micrograms/kg ) was more effective than HEP ( 120 anti-thrombin U/kg or 800 micrograms/kg ) in preventing TG when administered either as a bolus or by continuous infusion . These data suggest that agents which accelerate THR inhibition by both P01008 and HCII simultaneously , can inhibit TF and TG with less systemic anticoagulation than comparable antithrombotic doses of HEP . DB00575 prevents insulin resistance and hypertension in obese dogs . The role that the central sympathetic nervous system plays in the development of obesity hypertension and insulin was evaluated by feeding dogs a high fat diet with or without clonidine treatment . Thirteen adult mongrel dogs were chronically instrumented and randomly assigned to receive either a high fat diet and no clonidine ( n=6 ) or a high fat diet plus clonidine ( n=7 ) , 0.3 mg P55957 . Blood pressure , heart rate , plasma insulin , and electrolytes were measured daily . P01308 resistance was assessed with a multiple-dose euglycemic clamp ( 1 , 2 , and 30 mU. kg-1. min-1 ) before and after 1 , 3 , and 6 weeks of the high fat diet . DB00575 prevented the hypertension , tachycardia , and insulin resistance associated with feeding dogs the high fat diet but did not affect weight gain . The present study suggests that the central sympathetic nervous system plays a critical role in the development of both insulin resistance and hypertension associated with feeding dogs a high fat diet . Expression of angiogenesis- and apoptosis-related genes in chorionic villi derived from recurrent pregnancy loss patients . Angiogenesis takes place during embryogenesis , characterized by the formation of new blood vessels from pre-existing ones . This biological process is also found in the female reproductive system , wound healing , and cancer development . Apoptosis , programmed cell death , is a physiological process in development , tissue homeostasis , and disease . Apoptosis is a normal event in several reproductive tissues including human placenta . In these studies , we investigated whether aberrant angiogenesis and apoptosis are associated with recurrent pregnancy loss ( RPL ) . We compared the gene expression level for angiogenesis- and apoptosis-related genes in chorionic villi from RPL patients and those from normal controls . Semi-quantitative reverse transcriptase-polymerase chain reaction ( RT-PCR ) analysis revealed that 7 angiogenesis- and 12 apoptosis-related genes were abnormally expressed in chorionic villi from RPL patients . Angiogenesis-related genes that showed aberrant expression level are matrix metalloproteinase-2 ( P08253 ) , plasminogen activator inhibitor ( P05121 ) , integrin , transforming growth factor-beta ( TGF-beta ) , vascular endothelial growth factor ( P15692 ) , basic fibroblast growth factor ( P09038 ) , and leptin receptor . Expression levels for these genes , except for leptin receptor , showed less in chorionic villi from RPL patients than those from normal controls . In contrast , higher expression levels of 12 apoptosis-related genes ( caspase 3 , 6 , 7 , 8 , 9 , 10 , 12 , Q92934 , Q07812 , P55957 , Fas , and P48023 ) were shown in chorionic villi from RPL patients than those from normal controls . Taken all together , it is likely that the lower expression of angiogenesis-related genes and the excessive expression of apoptosis-related genes are associated with RPL . Salacia oblonga extract increases glucose transporter 4-mediated glucose uptake in Q9BTT4 rat myotubes : role of mangiferin . BACKGROUND AND AIMS : To evaluate if the antidiabetic properties of Salacia oblonga extract are mediated not only by inhibiting intestinal alpha-glycosidases but also by enhancing glucose transport in muscle and adipose cells . METHODS : S. oblonga extract effects on 2-deoxy-D-glucose uptake were assayed in muscle Q9BTT4 -myotubes and 3T3-adipocytes . In Q9BTT4 -myotubes , the amount and translocation of glucose transporters were assayed . A fractionation of the extract was carried out to identify the active compounds . Furthermore , we analyzed the phosphorylation status of key components of signaling pathways that are involved in the molecular mechanisms regulating glucose uptake . RESULTS : S. oblonga extract increased 2-deoxy-D-glucose uptake by 50 % in Q9BTT4 -myotubes and 3T3-adipocytes . In Q9BTT4 -myotubes , the extract increased up to a 100 % the P14672 content , activating P14672 promoter transcription and its translocation to the plasma membrane . Mangiferin was identified as the bioactive compound . Furthermore , mangiferin effects were concomitant with the phosphorylation of DB00131 -activated protein kinase without the activation of P31749 /Akt . The effect of mangiferin on 2-deoxy-D-glucose uptake was blocked by GW9662 , an irreversible P37231 antagonist . CONCLUSIONS : S. oblonga extract and mangiferin may exert their antidiabetic effect by increasing P14672 expression and translocation in muscle cells . These effects are probably mediated through two independent pathways that are related to DB00131 -activated protein kinase and P37231 . DB00316 -inhibitable P35354 . Although paracetamol potently reduces pain and fever , its mechanism of action has so far not been satisfactorily explained . It inhibits both P23219 and P35354 weakly in vitro , but reduces prostaglandin synthesis markedly in vivo . In mouse macrophage J774.2 cells , P35354 induced for 48 hr with high concentrations of NSAIDs is more sensitive to inhibition with paracetamol than endotoxin-induced P35354 . In the rat pleurisy model of inflammation , a second peak of P35354 protein appears 48 hr after administration of the inflammatory stimulus , during the resolution phase of the inflammatory process . Inhibition of the activity of this late-appearing P35354 with indomethacin or a selective P35354 inhibitor , delays resolution and the inflammation is prolonged . Cultured lung fibroblasts also express P35354 activity after stimulation with IL-1beta which is highly sensitive to inhibition with paracetamol . Thus , evidence is accumulating for the existence of a P35354 variant or a new P36551 enzyme which can be inhibited with paracetamol . DB01285 releasing hormone ( P06850 ) antagonist attenuates adjuvant induced arthritis : role of P06850 in peripheral inflammation . OBJECTIVE : To determine whether a corticotropin releasing hormone ( P06850 ) type 1-specific receptor antagonist , antalarmin , would alter the progression of inflammation in adjuvant induced arthritis ( AIA ) susceptible LEW/N rats by blocking local P06850 mediated inflammatory responses or render AIA resistant F344/N rats more susceptible to AIA by blocking central P06850 , thus reducing secretion of endogenous glucocorticoids . METHODS : F344/N and LEW/N rats were assigned to either drug or vehicle groups and treated with 20 mg/kg antalarmin or vehicle alone P55957 for 25 days by intraperitoneal injection . Arthritis was induced in both antalarmin and vehicle treated LEW/N and F344/N rats by subcutaneous injections at the base of the tail of incomplete Freund 's adjuvant containing 10 mg/ml heat killed Mycobacterium tuberculosis . Control F344/N and LEW/N rats were maintained on either antalarmin or vehicle . RESULTS : Chronic blockade of P34998 with systemic antalarmin significantly ameliorated AIA in LEW/N rats , reducing the severity of inflammation in peripheral joints , evidenced by clinical and histopathology scores , and weight loss associated with disease onset . Antalarmin neither induced nor exacerbated arthritis expression in F344/N or LEW/N rats , despite suppression of levels of adjuvant induced corticosterone , the major antiinflammatory glucocorticoid in rats . CONCLUSION : Systemic blockade of P06850 -RI appeared to predominantly block peripheral proinflammatory effects of immune P06850 , rather than the systemic glucocorticoid mediated antiinflammatory effects of hypothalamic P06850 . Results indicate that chronic treatment with a P06850 antagonist attenuates progressive inflammation induced degeneration of synovia , cartilage , and bone in arthritic joints , suggesting that antalarmin may have therapeutic potential in treatment of human autoimmune and inflammatory disorders . P50591 -activated stress kinases suppress apoptosis through transcriptional upregulation of Q8WXI8 -1 . P01375 -related apoptosis-inducing ligand ( P50591 ) is a potentially useful anticancer agent with exquisite selectivity for cancer cells . Unfortunately , many cancers show or acquire resistance to P50591 . In this study we report that P50591 activates a O43318 --> mitogen-activated protein kinase ( MAPK ) kinase 3 ( P46734 ) / P52564 --> p38 pathway in prostate cancer cells that transcriptionally upregulates expression of the antiapoptotic BCL-2 family member Q8WXI8 -1 . P50591 alone triggered robust formation of the ' death-inducing signaling complex ' ( DISC ) , activation of the initiator caspase-8 , and truncation of the Q7L3V2 P55957 ( tBID ) . Nevertheless , simultaneous disruption of the p38 MAPK pathway was required to suppress Q8WXI8 -1 expression , thereby allowing tBID to activate the proapoptotic BCL-2 family member Q16611 and stimulate mitochondrial outer membrane permeabilization ( MOMP ) . Release of the inhibitor-of-apoptosis ( IAP ) antagonist , Q9NR28 / Q9NR28 , from the intermembrane space was sufficient to promote P50591 -induced apoptosis , whereas release of cytochrome c and activation of the apoptosome was dispensable . Even after MOMP , however , mitochondrial-generated reactive oxygen species ( ROS ) activated a secondary signaling pathway , involving c-Jun N-terminal kinases ( JNKs ) , that similarly upregulated Q8WXI8 -1 expression and partially rescued some cells from death . Thus , stress kinases activated at distinct steps , before and after mitochondrial injury , mediate P50591 resistance through maintenance of Q8WXI8 -1 expression . Hepatocellular apoptosis in mice is associated with early upregulation of mitochondrial glucose metabolism . Hepatocyte death due to apoptosis is a hallmark of almost every liver disease . Manipulation of cell death regulatory steps during the apoptotic process is therefore an obvious goal of biomedical research . To clarify whether metabolic changes occur prior to the characteristic apoptotic events , we used ex vivo multinuclear NMR-spectroscopy to study metabolic pathways of [U-(13)C]glucose in mouse liver during Fas-induced apoptosis . We addressed whether these changes could be associated with protection against apoptosis afforded by Epidermal Growth Factor ( P01133 ) . Our results show that serum alanine and aspartate aminotransferase levels , caspase-3 activity , P55957 cleavage and changes in cellular energy stores were not observed before 3 h following anti-Fas injection . However , as early as 45 min after anti-Fas treatment , we observed upregulation of carbon entry ( i.e. flux ) from glucose into the Krebs-cycle via pyruvate dehydrogenase ( PDH ) and pyruvate carboxylase ( PC ) ( up to 139 % and 123 % of controls , respectively , P < 0.001 ) . This was associated with increased glutathione synthesis . P01133 treatment significantly attenuated Fas-induced apoptosis , liver injury and the late decrease in energy stores , as well as the early fluxes through PDH and PC which were comparable to untreated controls . Using ex vivo multinuclear NMR-spectroscopic analysis , we have shown that Fas receptor activation in mouse liver time-dependently affects specific metabolic pathways of glucose . These early upregulations in glucose metabolic pathways occur prior to any visible signs of apoptosis and may have the potential to contribute to the initiation of apoptosis by maintaining mitochondrial energy production and cellular glutathione stores .