MH_dev_18

Q03181 REA is up-regulated during vascular lesion formation and promotes post-confluent cell proliferation in vascular smooth muscle cells . Although peroxisome proliferator-activated receptor ( Q07869 REA ) delta is widely expressed in many tissues , the role of PPARdelta is poorly understood . In this study , we report that PPARdelta was up-regulated in vascular smooth muscle cells ( VSMC ) during vascular lesion formation . By using Northern blot analysis , we demonstrated that PPARdelta was increased by 3-4- fold in VSMC treated with platelet-derived growth factor ( PDGF ) ( 20 ng / ml ) . In addition , PDGF-induced PPARdelta mRNA expression neither needs de novo protein synthesis nor affects the stability of PPARdelta mRNA in VSMC . Preincubation of VSMC with phosphatidylinositol 3 - kinase inhibitor ( LY294002 , 50 micromol / liter ) or infection of VSMC with an adenovirus carrying the gene for a dominant negative form of Akt abrogated PDGF-induced PPARdelta mRNA expression , suggesting that phosphatidylinositol 3 - kinase / Akt signaling pathway is involved in the regulation of PDGF-induced PPARdelta mRNA expression in VSMC . To explore the role of PPARdelta in VSMC , we generated rat vascular smooth muscle cells ( A7r5 ) stably overexpressing PPARdelta and the control green fluorescent protein . Overexpression of PPARdelta in VSMC increased post-confluent cell proliferation by increasing the cyclin A and P24941 REA as well as decreasing p57 ( kip 2 ) . Taken together , the results suggest that PPARdelta plays an important role in the pathology of diseases associated with VSMC proliferation , such as primary atherosclerosis and restenosis .

DB01393 SUB restores the inhibition of DB00094 - induced follicular development and steroidogenesis by tumor necrosis factor-alpha through peroxisome proliferator-activated receptor-gamma pathway in an in vitro mouse preantral follicle culture . We recently reported that bezafibrate , a lipid-lowering drug of the fibrate class , administered in addition to clomiphene citrate ( CC ) successfully induced ovulation in CC-resistant polycystic ovary syndrome ( PCOS ) patients . We hypothesized that bezafibrate may directly affect ovarian follicle development . P01308 REA resistance and compensatory hyperinsulinemia are important for the pathogenesis of PCOS . In this study , we first examined the effects of tumor necrosis factor-alpha ( P01375 REA ) , which plays a role in insulin resistance , on follicle development by using the follicle culture system . P01375 REA significantly inhibited follicle-stimulating hormone ( DB00094 ) - induced follicle development , 17beta - estradiol ( E2 ) secretion , and ovulation rate in a dose-dependent manner . We then examined whether bezafibrate treatment could rescue the inhibition of DB00094 - induced follicle development and steroidogenesis by P01375 REA . DB01393 SUB treatment rescued inhibition of follicle development , secretion of E2 , and ovulation rate by P01375 REA . We examined the expression of peroxisome proliferator-activated receptor ( Q07869 REA ) subtypes in mouse preantral follicles . As the protein expression of only P37231 REA was observed in mouse preantral follicles , we examined whether bezafibrate could affect follicle development and steroidogenesis through P37231 REA pathways . Treatment with GW1929 , a selective P37231 REA agonist , restored inhibition of DB00094 - induced follicle development and steroidogenesis by P01375 REA , whereas treatment with GW9662 , a selective P37231 REA antagonist , canceled the restorative effects of bezafibrate . Collectively , the results in this study suggest that bezafibrate may directly exhibit a restorative effect on the inhibition of ovarian follicle development and steroidogenesis by P01375 REA through the P37231 REA pathway .

P06401 REA level as a predictor of response to megestrol acetate in advanced breast cancer : a retrospective study . DB00351 MEN ( 160 mg / day ) produced a response rate of 44 % in a retrospective series of 39 evaluable patients with advanced breast cancer . The estrogen-receptor ( ER ) level was greater than 10 fmols / mg of protein in 28 patients , and the progesterone-receptor ( PR ) level was greater than 10 fmols / mg of protein in 26 patients . ER and PR levels , age , and disease-free interval were analyzed for their relationship to response . The PR was the single best predictor of response to megestrol acetate ; the addition of ER added 2 % to the predictive accuracy rate of PR alone .

P62937 REA - deficient mice are resistant to immunosuppression by cyclosporine . DB00091 MENMAX DB00091 MEN is an immunosuppressive drug that is widely used to prevent organ transplant rejection . Known intracellular ligands for cyclosporine include the cyclophilins , a large family of phylogenetically conserved proteins that potentially regulate protein folding in cells . Immunosuppression by cyclosporine is thought to result from the formation of a drug-cyclophilin complex that binds to and inhibits calcineurin , a serine / threonine phosphatase that is activated by TCR engagement . Amino acids within the cyclophilins that are critical for binding to cyclosporine have been identified . Most of these residues are highly conserved within the 15 mammalian cyclophilins , suggesting that many are potential targets for the drug . We examined the effects of cyclosporine on immune cells and mice lacking Ppia , the gene encoding the prototypical cyclophilin protein cyclophilin A . TCR-induced proliferation and signal transduction by Ppia ( - / - ) P01730 REA ( + ) T cells were resistant to cyclosporine , an effect that was attributable to diminished calcineurin inhibition . Immunosuppressive doses of cyclosporine failed to block the responses of Ppia ( - / - ) mice to allogeneic challenge . Rag 2 ( - / - ) mice reconstituted with Ppia ( - / - ) splenocytes were also cyclosporine resistant , indicating that this property is intrinsic to Ppia ( - / - ) immune cells . Thus , among multiple potential ligands , CypA is the primary mediator of immunosuppression by cyclosporine .

The glial cell modulator and phosphodiesterase inhibitor , DB05066 MEN ( ibudilast ) , attenuates prime - and stress-induced methamphetamine relapse . Stress and renewed contact with drug ( a " slip " ) have been linked to persisting relapse of methamphetamine abuse . Human brain microglial activation has been linked with methamphetamine abuse , and inhibitors of glial cell activation , certain phosphodiesterase ( PDE ) inhibitors , and glial cell derived neurotrophic factor ( P39905 REA ) have been reported to modulate drug abuse effects . Our objective was to determine whether the glial cell attenuator , 3 - isobutyryl - 2 - isopropylpyrazolo - [ 1,5- a ] pyridine ( DB05066 MEN , ibudilast ) , a non-selective PDE inhibitor and promoter of P39905 REA , could reduce stress - and methamphetamine prime-induced reinstatement of methamphetamine-seeking behavior . Male Long-Evans hooded rats were trained to lever press reinforced with 0.1 mg / kg i . v . methamphetamine infusion according to fixed-ratio 1 ( FR1 ) reinforcement schedules during daily , 2 - hour experimental sessions . After performance had stabilized , lever pressing was extinguished for 12 consecutive sessions and doses of 0 ( vehicle ) , 2.5 and 7.5 mg / kg DB05066 MEN were then administered intraperitoneally b . i . d . on the last 2 days of extinction and then once on the testday to separate groups of 12 rats . During testing , the rats were given 15 min of intermittent footshock or a 1 mg / kg i . p . methamphetamine prime followed by a 2 - hour reinstatement test session . DB05066 MEN significantly reduced response levels of footshock-induced ( 2.5 and 7.5 mg / kg ) and prime-induced ( 7.5 mg / kg ) reinstatement of extinguished methamphetamine-maintained responding . DB05066 MEN has properties consistent with the ability to attenuate relapse precipitated by stress and methamphetamine " slips " during abstinence . These results thus reinforce interest in atypical neurobiological mechanisms which could be exploited for developing novel medications for treating drug abuse disorders .

Anti-allergic function and regulatory mechanisms of KR62980 in allergen-induced airway inflammation . The ligand-activated transcription factor , peroxisome proliferator-activated receptor ( Q07869 REA ) gamma , and its ligands inhibit pro-inflammatory cytokine production by immune cells , thus exerting anti-inflammatory activity . As a non-thiazolidinedione PPARgamma ligand , KR62980 has anti-diabetic and anti-adipogenic activities , but its anti-inflammatory function has yet to be characterized . In this study , we investigated the functions and mechanisms of KR62980 in the activation and differentiation of P01730 REA + T helper ( Th ) cells by comparing its effects with those of a thiazolidinedione PPARgamma ligand , rosiglitazone . KR62980 dose-dependently and significantly suppressed TCR-triggered Th cell proliferation by suppressing P60568 REA / IL - 2Ralpha - mediated signaling . Both KR62980 and rosiglitazone suppressed IFNgamma production in a dose-dependent manner , whereas P05112 REA gene expression was specifically suppressed by only KR62980 . In addition , sustained KR62980 treatment diminished Th2 cytokine production by inhibiting c-Maf expression . In vivo administration of KR62980 in a model of allergic asthma significantly attenuated eotaxin-induced eosinophil infiltration , allergic cytokine production and collagen deposition in the lung . KR62980 also decreased goblet cell hyperplasia in the airway and mucous cell metaplasia in nasal epithelium , concurrent with decreases of allergic Th2 cytokines and Q16552 REA in the draining lymph node . In conclusion , a novel PPARgamma ligand , KR62980 , suppresses in vitro Th2 cell differentiation and attenuates in vivo OVA-induced airway inflammation , suggesting a beneficial role for KR62980 in the treatment of allergic asthma and allergic rhinitis .

Effects of Q07869 REA agonists on proliferation and differentiation in human urothelium . Systemic treatment of rats with peroxisome proliferator-activated receptor ( Q07869 REA ) agonists ( mainly of dual alpha / gamma activity ) has indicated that they may invoke non-genotoxic carcinogenesis in the epithelial lining of the urinary tract ( urothelium ) . Although there is evidence in the male rat to support an indirect effect via a crystaluria-induced urothelial damage response , there is other evidence to indicate a direct signalling effect on the urothelium and hence the full implication for using these drugs in man is unclear . Numerous reports have demonstrated that PPARs are expressed within the urothelium of different species , including man , and from an early developmental stage . We have developed methods to maintain normal human urothelial ( NHU ) cells in culture , where the cells retain Q07869 REA expression and express a highly proliferative phenotype , mediated via autocrine stimulation of the epidermal growth factor ( P01133 REA ) receptor . We have shown that specific activation of PPARgamma results in a programme of gene expression changes associated with late / terminal cytodifferentiation , including induction of cytokeratins CK13 and CK20 , tight junction-associated claudin 3 , and uroplakins UPK 1a and O00526 , but this is dependent upon inhibition of the signalling cascade downstream of the P01133 REA receptor . This indicates a subtle balance in the regulation of proliferation and differentiation in urothelium , with PPARgamma agonists promoting differentiation . Our data indicate that human urothelium is a target tissue for PPARgamma signalling , but it has yet to be determined whether dual agonists could have a modulatory effect on the proliferation / differentiation balance .

Blocking cannabinoid P21554 REA receptors for the treatment of nicotine dependence : insights from pre-clinical and clinical studies . Tobacco use is one of the leading preventable causes of death in developed countries . Since existing medications are only partially effective in treating tobacco smokers , there is a great need for improved medications for smoking cessation . It has been recently proposed that cannabinoid CB ( 1 ) receptor antagonists represent a new class of therapeutic agents for drug dependence , and notably , nicotine dependence . Here , we will review current evidence supporting the use of this class of drugs for smoking cessation treatment . Pre-clinical studies indicate that nicotine exposure produces changes in endocannabinoid content in the brain . In experimental animals , N-piperidinyl - 5 - ( 4 - chlorophenyl ) - 1 - ( 2,4- dichlorophenyl ) - DB01213 - 3 - carboxamide ( rimonabant , SR141716 ) and N - ( piperidin - 1 - yl ) - 5 - ( 4 - iodophenyl ) - 1 - ( 2,4- dichlorophenyl ) - 4 - methyl - 1H - pyrazole - 3 - carboxamide ( AM251 ) , two cannabinoid CB ( 1 ) receptor antagonists , block nicotine self-administration behavior , an effect that may be related to the blockade of the dopamine-releasing effects of nicotine in the brain . DB06155 MEN also seems efficacious in decreasing the influence of nicotine-associated stimuli over behavior , suggesting that it may act on two distinct neuronal pathways , those implicated in drug-taking behavior and those involved in relapse phenomena . The utility of rimonabant has been evaluated in several clinical trials . It seems that rimonabant is an efficacious treatment for smoking cessation , although its efficacy does not exceed that of nicotine-replacement therapy and its use may be limited by emotional side effects ( nausea , anxiety and depression , mostly ) . DB06155 MEN also appears to decrease relapse rates in smokers . These findings indicate significant , but limited , utility of rimonabant for smoking cessation .

Coadministrating luteolin minimizes the side effects of the aromatase inhibitor letrozole . P11511 REA inhibitors ( AIs ) have been used as adjuvant therapeutic agents for breast cancer . Their adverse side effect on blood lipid is well documented . Some natural compounds have been shown to be potential AIs . In the present study , we compared the efficacy of the flavonoid luteolin to the clinically approved AI letrozole ( DB01006 MEN ; Novartis Pharmaceuticals , East Hanover , NJ ) in a cell and a mouse model . In the in vitro experimental results for aromatase inhibition , the Ki values of luteolin and letrozole were estimated to be 2.44 µM and 0.41 nM , respectively . Both letrozole and luteolin appeared to be competitive inhibitors . Subsequently , an animal model was used for the comparison . P11511 REA - expressing MCF - 7 cells were transplanted into ovariectomized athymic mice . Luteolin was given by mouth at 5 , 20 , and 50 mg / kg , whereas letrozole was administered by intravenous injection . Similar to letrozole , luteolin administration reduced plasma estrogen concentrations and suppressed the xenograft proliferation . The regulation of cell cycle and apoptotic proteins-such as a decrease in the expression of Bcl-xL , cyclin-A / D1 / E , P24941 REA / 4 , and increase in that of Bax-was about the same in both treatments . The most significant disparity was on blood lipids . In contrast to letrozole , luteolin increased fasting plasma high-density lipoprotein concentrations and produced a desirable blood lipid profile . These results suggested that the flavonoid could be a coadjuvant therapeutic agent without impairing the action of AIs .

25 - Hydroxycholesterol is not a ligand for the orphan nuclear receptor steroidogenic factor - 1 ( Q13285 REA ) . The orphan nuclear receptor steroidogenic factor - 1 ( Q13285 REA ) is involved in the transcriptional regulation of all the steroid hydroxylase genes , and also regulates the transcription of the genes for Müllerian Inhibitory substance ( P03971 REA ) , alpha subunit of glycoprotein hormone , LHbeta , oxytocin , P30968 REA , Q01718 REA , prolactin receptor , DAX - 1 , and steroidogenic acute regulatory protein . Other members of the nuclear receptor gene family , including steroid hormone , thyroid hormone , retinoic acid , Q07869 REA , and vitamin D receptors must bind ligand to activate transcription , but Q13285 REA has been considered to be an orphan nuclear receptor because , when identified , it had no known ligand . A recent publication suggested that transcriptional regulation by Q13285 REA , expressed in a non-steroidogenic CV - 1 cells , could be activated by oxysterols suggesting that these compounds could serve as natural ligands for Q13285 REA . We now demonstrate that 25 - hydroxycholesterol , either added exogenously or synthesized endogenously in steroidogenic mouse Leydig MA - 10 cells , did not act as a ligand for Q13285 REA , as it did not increase transcription from six different Q13285 REA - dependent DNA sequences . Furthermore , the abundance of these oxysterols in MA - 10 cells was much less than concentrations needed for activation of Q13285 REA in CV - 1 cells , indicating that Q13285 REA is not constitutively bound by ligand in MA - 10 cells . Thus , in steroidogenic cells , transcriptional regulation of the steroid hydroxylase genes by Q13285 REA does not depend upon the presence of 25 - hydroxycholesterol , and is not modified by its presence .

P60568 REA suppression by 2 - arachidonyl glycerol is mediated through peroxisome proliferator-activated receptor gamma independently of cannabinoid receptors 1 and 2 . 2 - Arachidonyl glycerol ( 2 - AG ) is an endogenous arachidonic acid derivative that binds cannabinoid receptors P21554 REA and CB2 and is hence termed an endocannabinoid . 2 - AG also modulates a variety of immunological responses , including expression of the autocrine / paracrine T cell growth factor interleukin ( IL ) - 2 . The objective of the present studies was to determine the mechanism responsible for P60568 REA suppression by 2 - AG . Because of the labile properties of 2 - AG , 2 - AG ether , a nonhydrolyzable analog of 2 - AG , was also used . Both 2 - AG and 2 - AG ether suppressed P60568 REA expression independently of P21554 REA and CB2 , as demonstrated in leukocytes derived from P21554 REA / CB2 - null mice . Moreover , we demonstrated that both 2 - AG and 2 - AG ether treatment activated peroxisome proliferator-activated receptor gamma ( PPARgamma ) , as evidenced by forced differentiation of 3T3 - Q9NUQ9 cells into adipocytes , induction of aP2 mRNA levels , and activation of a PPARgamma-specific luciferase reporter in transiently transfected 3T3 - Q9NUQ9 cells . Consequently , the putative role of PPARgamma in P60568 REA suppression by 2 - AG and 2 - AG ether was examined in Jurkat T cells . Concordant with PPARgamma involvement , the PPARgamma-specific antagonist 2 - chloro - 5 - nitro-N - ( 4 - pyridyl ) - benzamide ( T0070907 ) blocked 2 - AG - and 2 - AG ether-mediated P60568 REA suppression . Likewise , 2 - AG suppressed the transcriptional activity of two transcription factors crucial for P60568 REA expression , nuclear factor of activated T cells and nuclear factor kappaB , in the absence but not in the presence of T0070907 . 2 - AG treatment also induced PPARgamma binding to a Q07869 REA response element in activated Jurkat T cells . Together , the aforementioned studies identify PPARgamma as a novel intracellular target of 2 - AG , which mediates the suppression of P60568 REA by 2 - AG in a manner that is independent of P21554 REA and / or CB2 .

Traditional Korean Herbal Formula Samsoeum Attenuates Adipogenesis by Regulating the Phosphorylation of P27361 REA / 2 in 3T3 - Q9NUQ9 Cells . Adipogenesis is the cell differentiation process from preadipocytes into adipocytes and the critical action in the development of obesity . In the present study , we conducted in vitro analyses to investigate the inhibitory effects of Samsoeum ( SSE ) , a traditional herbal decoction . SSE had no significant cytotoxic effect against either the undifferentiated or differentiated 3T3 - Q9NUQ9 cells . Oil Red O staining results showed that SSE significantly inhibited fat accumulation in adipocytes . SSE treatment consistently reduced the intracellular triglyceride content in the cells . SSE significantly inactivated glycerol - 3 - phosphate dehydrogenase ( GPDH ) , a major link between carbohydrate and lipid metabolisms in 3T3 - Q9NUQ9 adipocytes , and markedly inhibited the production of leptin , an important adipokine , in differentiated cells . SSE markedly suppressed the mRNA expression of the adipogenesis-related genes peroxisome proliferator-activated receptor-gamma ( Q07869 REA - γ ) , CCAAT / enhancer binding protein-alpha ( C / EBP-α ) , fatty acid synthase ( FAS ) , lipoprotein lipase ( P06858 REA ) , and fatty acid binding protein 4 ( P15090 REA ) . Importantly , SSE increased the phosphorylation of P27361 REA / 2 , but not p38 MAPK and JNK , in adipose cells . Overall , our results indicate that SSE exerts antiadipogenic activity and modulates expressions of adipogenesis-related genes and P27361 REA / 2 activation in adipocytes .

Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender-dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti-estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element-driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 REA ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 REA protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 REA expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 REA and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .

DB00644 antagonist in the management of prostate cancer . DB00044 - releasing hormone ( P01148 REA ) agonist therapy to induce medical castration has become the most common form of hormonal therapy for advanced and metastatic prostate cancer . When treatment is started , P01148 REA agonists initially stimulate the release of LH , causing a surge in serum testosterone that can precipitate a " flare " phenomenon or worsening of disease , particularly in patients with bone metastatic disease . DB00644 ( DB00644 ) receptor antagonism represents a newer approach to medical castration . DB00106 MEN is a pure P30968 REA antagonist that is devoid of any P01148 REA agonist activity . Results from 1 phase II and 3 phase III clinical trials demonstrate that abarelix produces medical castration more quickly and without causing testosterone surge , as compared with P01148 REA agonists with or without a nonsteroidal antagonist . The safety profile in terms of adverse events is comparable between the 2 types of treatment , but the lack of testosterone surge with abarelix might confer a safety advantage by abolishing the risk of a disease flare .

Effects of peroxisome proliferator-activated receptor ligands , bezafibrate and fenofibrate , on adiponectin level . OBJECTIVE : Q15848 REA is adipose-specific secretory protein and acts as anti-diabetic and anti-atherosclerotic molecule . We previously found peroxisome proliferators response element in adiponectin promoter region , suggesting that peroxisome proliferator-activated receptor ( Q07869 REA ) ligands elevate adiponectin . Fibrates are known to be PPARalpha ligands and were shown to reduce risks of diabetes and cardiovascular disease . Effect of fibrates on adiponectin has not been clarified , whereas thiazolidinediones enhance adiponectin . Thus , we explored the possibility and mechanism that fibrates enhance adiponectin in humans , mice , and cells . METHODS AND RESULTS : Significant increase of serum adiponectin was observed in bezafibrate-treated subjects compared with placebo group in patients enrolled in The DB01393 SUB Infarction Prevention study . Higher baseline adiponectin levels were strongly associated with reduced risk of new diabetes . Fibrates , bezafibrate and fenofibrate , significantly elevated adiponectin levels in wild-type mice and 3T3 - Q9NUQ9 adipocytes . Such an effect was not observed in PPARalpha-deficient mice and adipocytes . Fibrates activated adiponectin promoter but failed to enhance its activity when the point mutation occurred in peroxisome proliferators response element site and the endogenous PPARalpha was knocked down by PPARalpha-RNAi . CONCLUSIONS : Our results suggest that fibrates enhance adiponectin partly through adipose PPARalpha and measurement of adiponectin might be a useful tool for searching subjects at high risk for diabetes .

Regulation of activating transcription factor - 2 in early stage of the adipocyte differentiation program . p38beta mitogen-activated protein kinase activity is required for the differentiation of 3T3 - Q9NUQ9 fibroblasts into adipocytes . Activating transcription factor - 2 ( P39905 REA - 2 ) is efficiently phosphorylated and activated by p38beta kinase . These findings led us to examine a regulatory role of P39905 REA - 2 in adipocyte differentiation . The induction of P39905 REA - 2 protein precedes the expression of the transcription factors , peroxisome proliferator-activated receptor ( Q07869 REA ) gamma and CCAAT / enhancer-binding protein ( C / EBP ) alpha . Consistent with early activation of p38beta kinase , the phosphorylation of P39905 REA - 2 was also detected in early stage of adipocyte differentiation . P39905 REA - 2 regulated gene transcription of PPARgamma , which was synergistically enhanced by p38beta kinase and C / EBPbeta proteins expression . Ectopic expression of P39905 REA - 2 in 3T3 - Q9NUQ9 cells induced the endogenous PPARgamma protein levels . These results suggest that P39905 REA - 2 plays a role in a primary regulator of adipocyte differentiation with C / EBPbeta through promoting adipogenesis-inducing transcription factors including PPARgamma and becomes associated earlier in the differentiation program as mitotic clonal expansion proceeds and the cells become initially differentiated .

Pharmacologic activation of mitochondrial biogenesis exerts widespread beneficial effects in a transgenic mouse model of Huntington ' s disease . There is substantial evidence that impairment of peroxisome proliferator-activated receptor ( Q07869 REA ) - γ-coactivator 1α ( P20142 - 1α ) levels and activity play an important role in Huntington ' s disease ( HD ) pathogenesis . We tested whether pharmacologic treatment with the pan - Q07869 REA agonist bezafibrate would correct a deficiency of P20142 - 1α and exert beneficial effects in a transgenic mouse model of HD . We found that administration of bezafibrate in the diet restored levels of P20142 - 1α , PPARs and downstream genes to levels which occur in wild-type mice . There were significant improvements in phenotype and survival . In the striatum , astrogliosis and neuronal atrophy were attenuated and numbers of mitochondria were increased . DB01393 SUB treatment prevented conversion of type I oxidative to type II glycolytic muscle fibers and increased the numbers of muscle mitochondria . Finally , bezafibrate rescued lipid accumulation and apparent vacuolization of brown adipose tissue in the HD mice . These findings provide strong evidence that treatment with bezafibrate exerts neuroprotective effects which may be beneficial in the treatment of HD .

Inhibition of the T790M gatekeeper mutant of the epidermal growth factor receptor by EXEL - 7647 . PURPOSE : Agents inhibiting the epidermal growth factor receptor ( P00533 REA ) have shown clinical benefit in a subset of non-small cell lung cancer patients expressing amplified or mutationally activated P00533 REA . However , responsive patients can relapse as a result of selection for P00533 REA gene mutations that confer resistance to DB00171 competitive P00533 REA inhibitors , such as erlotinib and gefitinib . We describe here the activity of EXEL - 7647 ( DB05007 MEN ) , a novel spectrum-selective kinase inhibitor with potent activity against the P01133 REA and vascular endothelial growth factor receptor tyrosine kinase families , against both wild-type ( WT ) and mutant P00533 REA in vitro and in vivo . EXPERIMENTAL DESIGN : The activity of P00533 REA inhibitors against WT and mutant EGFRs and their effect on downstream signal transduction was examined in cellular assays and in vivo using A431 and MDA-MB - 231 ( WT P00533 REA ) and H1975 ( L858R and T790M mutant P00533 REA ) xenograft tumors . RESULTS : EXEL - 7647 shows potent and long-lived inhibition of the WT P00533 REA in vivo . In addition , EXEL - 7647 inhibits cellular proliferation and P00533 REA pathway activation in the erlotinib-resistant H1975 cell line that harbors a double mutation ( L858R and T790M ) in the P00533 REA gene . In vivo efficacy studies show that EXEL - 7647 substantially inhibited the growth of H1975 xenograft tumors and reduced both tumor P00533 REA signaling and tumor vessel density . Additionally , EXEL - 7647 , in contrast to erlotinib , substantially inhibited the growth and vascularization of MDA-MB - 231 xenografts , a model which is more reliant on signaling through vascular endothelial growth factor receptors . CONCLUSIONS : These studies provide a preclinical basis for clinical trials of DB05007 MEN in solid tumors and in patients bearing tumors that are resistant to existing P00533 REA - targeted therapies .

Peroxisome proliferator-activated receptor-gamma is a target of nonsteroidal anti-inflammatory drugs mediating cyclooxygenase-independent inhibition of lung cancer cell growth . Nonsteroidal anti-inflammatory drugs ( NSAIDs ) inhibit the growth of different cancer cell types , suggesting a broad role for their cyclooxygenase ( P36551 REA ) targets and eicosanoid products in tumor cell growth . Sulindac sulfide , a P36551 REA inhibitor , inhibited the growth of non-small-cell lung cancers ( NSCLC ) both in soft agar and as xenografts in nude mice . Importantly , the concentration of sulindac sulfide required to inhibit NSCLC cell growth greatly exceeded the concentration required to inhibit prostaglandin ( PG ) E ( 2 ) synthesis in NSCLC cells , suggesting that NSAID inhibition of cell growth is mediated by additional targets distinct from P36551 REA . Both sulindac sulfide and ciglitazone , a defined peroxisome proliferator-activated receptor-gamma ( PPARgamma ) agonist , stimulated a promoter construct containing a Q07869 REA response element linked to luciferase and potently inhibited NSCLC cell growth at similar concentrations , indicating a role for PPARgamma as a target of NSAID action in these cells . Overexpression of PPARgamma in NSCLC cells strongly inhibited the transformed growth properties of the cells , providing a molecular confirmation of the results obtained with the PPARgamma agonists . Increased expression of PPARgamma , as well as ciglitazone and sulindac sulfide induced expression of P12830 REA , which has been linked to increased differentiation of NSCLC . Despite the fact that SCLC cell lines expressed little or no cytosolic phospholipase A ( 2 ) , P23219 REA , or P35354 REA , sulindac sulfide and PPARgamma agonists also inhibited the transformed growth of these lung cancer cells . We propose that PPARgamma serves as a target for NSAIDs that accounts for P36551 REA - independent inhibition of lung cancer cell growth .

Inhibition of functional HER family members increases the sensitivity to docetaxel in human ovarian cancer cell lines . Human epidermal growth factor ( HER ) family-targeted therapy combined with standard cytotoxic agents might improve the treatment of ovarian cancer . Human ovarian cancer cell lines OVCAR - 3 , IGROV - 1 , and SKOV - 3 with differential P00533 REA , P04626 REA , and P21860 REA expression levels were used to study whether P00533 REA - directed ( cetuximab ) or P04626 REA - directed ( trastuzumab , pertuzumab ) monoclonal antibodies inhibited cell growth and abrogated activated receptor signaling routes . Possible increase of antiproliferative effects and further activation of caspase - 3 as a read-out for apoptosis were analyzed when monoclonal antibodies were combined with docetaxel . Cetuximab alone inhibited cell growth in OVCAR - 3 and IGROV - 1 , which was more pronounced when combined with pertuzumab in OVCAR - 3 . SKOV - 3 cell growth was not significantly affected by any of the antibodies . Cetuximab increased the 50 % growth-inhibiting effects of docetaxel in OVCAR - 3 and IGROV - 1 , but not in SKOV - 3 . Coaddition of pertuzumab to cetuximab plus docetaxel in OVCAR - 3 and IGROV - 1 , and , to a lesser extent trastuzumab in OVCAR - 3 , inhibited cell growth even further . P42574 REA activation by docetaxel was enhanced after addition of cetuximab in OVCAR - 3 and after addition of cetuximab plus pertuzumab in IGROV - 1 and SKOV - 3 . Functional P00533 REA - signaling , P04626 REA - signaling , and P21860 REA - signaling routes as shown from abrogation of P01133 REA - stimulated and heregulin-stimulated phosphorylated P27361 REA / 2 by cetuximab , trastuzumab , and pertuzumab , respectively , were shown in OVCAR - 3 and IGROV - 1 , but hardly in SKOV - 3 . DB06366 MEN was able to abrogate phosphorylated P04626 REA by P01133 REA and heregulin , except in SKOV - 3 . In conclusion , a combination of docetaxel with inhibitors of HER family members , such as cetuximab plus pertuzumab , may be considered for a clinical trial in ovarian carcinomas with functional receptors .

Novel phenolic antioxidants as multifunctional inhibitors of inducible P19320 REA expression for use in atherosclerosis . A series of novel phenolic compounds has been discovered as potent inhibitors of P01375 REA - inducible expression of vascular cell adhesion molecule - 1 ( P19320 REA ) with concurrent antioxidant and lipid-modulating properties . Optimization of these multifunctional agents led to the identification of 3a ( DB05399 MEN ) as a clinical candidate with demonstrated efficacies in animal models of atherosclerosis and hyperlipidemia .