MH_dev_313

AM2389 , a high-affinity , in vivo potent P21554 REA - receptor-selective cannabinergic ligand as evidenced by drug discrimination in rats and hypothermia testing in mice . RATIONALE : The endocannabinoid signaling system ( ECS ) has been targeted for developing novel therapeutics since ECS dysfunction has been implicated in various pathologies . Current focus is on chemical modifications of the hexahydrocannabinol ( HHC ) nabilone ( DB00486 MENMAX DB00486 MEN ( ® ) ) . OBJECTIVE : To characterize the novel , high-affinity cannabinoid receptor 1 ( CB ( 1 ) R ) HHC-ligand AM2389 [ 9β - hydroxy - 3 - ( 1 - hexyl-cyclobut - 1 - yl ) - hexahydrocannabinol in two rodent pre-clinical assays . MATERIALS AND METHODS : CB ( 1 ) R mediation of AM2389 - induced hypothermia in mice was evaluated with AM251 , a CB ( 1 ) R-selective antagonist / inverse agonist . Additionally , two groups of rats discriminated the full cannabinergic aminoalkylindole AM5983 ( 0.18 and 0.56 mg / kg ) from vehicle 20 min post-injection in a two-choice operant conditioning task motivated by 0.1 % saccharin / water . Generalization / substitution tests were conducted with AM2389 , AM5983 , and Δ ( 9 ) - tetrahydrocannabinol ( Δ ( 9 ) - THC ) . RESULTS : Δ ( 9 ) - THC ( 30 mg / kg ) - induced hypothermia exhibited a faster onset and shorter duration of action compared with AM2389 ( 0.1 and 0.3 mg / kg ) . AM251 ( 3 and 10 mg / kg ) attenuated / blocked hypothermia induced by 0.3 mg / kg AM2389 . In drug discrimination , the order of potency was AM2389 > AM5983 > Δ ( 9 ) - THC with ED ( 50 ) values of 0.0025 , 0.0571 , and 0.2635 mg / kg , respectively , in the low-dose condition . The corresponding ED ( 50 ) values in the high-dose condition were 0.0069 , 0.1246 , and 0.8438 mg / kg , respectively . Onset of the effects of AM2389 was slow with a protracted time-course ; the functional , perceptual in vivo half-life was approximately 17 h . CONCLUSIONS : This potent cannabinergic HHC exhibited a slow onset of action with a protracted time-course . The AM2389 chemotype appears well suited for further drug development , and AM2389 currently is used to probe behavioral consequences of sustained ECS activation .

Pharmacodynamics and pharmacokinetics of DB05225 MEN , a novel inhibitor of P09917 REA - activating protein ( P20292 REA ) . The P09917 REA - activating protein ( P20292 REA ) gene and an increase in leukotriene ( LT ) production are linked to the risk of asthma , myocardial infarction , and stroke . We evaluated the pharmacodynamics , pharmacokinetics , and tolerability of 3 - [ 3 - tert-butylsulfanyl - 1 - [ 4 - ( 6 - methoxy-pyridin - 3 - yl ) - benzyl ] - 5 - ( pyridin - 2 - ylmethoxy ) - 1H - indol - 2 - yl ] -2,2- dimethyl-propionic acid ( DB05225 MEN ) , a novel P20292 REA inhibitor , in healthy subjects . Single and multiple doses of DB05225 MEN demonstrated dose-dependent inhibition of blood Q06643 REA ( 4 ) production and dose-related inhibition of urinary LTE ( 4 ) . After a single oral dose ( 50-1 , 000 mg ) of DB05225 MEN , the maximum concentration ( C ( max ) ) and area under the curve ( AUC ) in plasma increased in a dose-dependent manner . After multiple-dose administration ( 50-1 , 000 mg once daily for 11 days ) , there were no significant differences in the pharmacokinetic parameters between the first and last days of treatment . DB05225 MEN was well tolerated at all doses in both the single - and multiple-dose cohorts . Further clinical trials with DB05225 MEN in inflammatory diseases are warranted .

Genetic mechanism of aspirin-induced urticaria / angioedema . PURPOSE OF REVIEW : DB00945 - induced urticaria / angioedema is a major aspirin-related hypersensitivity often associated with aspirin-intolerant asthma . Genetic studies on aspirin-intolerant asthma have shown chronic overproduction of cysteinyl leukotrienes . The genetic analysis of aspirin-induced urticaria / angioedema is limited , however . RECENT FINDINGS : A recent study on HLA genotypes has suggested that the HLA alleles DRB 11302 and DQB 10609 may be genetic markers for aspirin-induced urticaria / angioedema . A polymorphism study that examined nine single-nucleotide polymorphisms of five leukotriene-related genes [ P09917 REA ( encoding P09917 REA ) , P20292 REA ( P09917 REA - activating protein ) , P35354 REA ( cyclooxygenase 2 ) , Q16873 REA ( leukotriene C4 synthase ) , and Q9Y271 REA ( cysteinyl leukotriene receptor 1 ) ] found that promoter polymorphisms of P09917 REA ( - 1708A > G ) and Q9Y271 REA ( - 634C > T ) were significantly different between aspirin-intolerant asthma and aspirin-induced urticaria / angioedema , suggesting different contributions to the lipoxygenase pathway . A second polymorphism study , conducted on histamine-related genes , did not find any significant associations with aspirin-induced urticaria / angioedema for the genes P50135 REA ( encoding histamine N-methyltransferase ) , P35367 REA or P25021 REA ( encoding histamine receptor types 1 and 2 respectively ) , or the gene encoding high-affinity IgE receptor Ibeta ( FcepsilonRIbeta ) ; however , the FcepsilonRIalpha gene promoter polymorphism was significantly associated with aspirin-induced urticaria / angioedema . This finding has been supported by in vitro functional studies . SUMMARY : The HLA alleles DRB 11302 and DQB 10609 , and the P09917 REA and FcepsilonRIalpha promoter polymorphisms , may contribute to the pathogenesis of aspirin-induced urticaria / angioedema . Further investigation to identify candidate genetic markers would help to elucidate the pathogenic mechanism of this condition .

CCK 1 - receptor stimulation protects against gut mediator-induced lung damage during endotoxemia . BACKGROUND / AIMS : Cholecystokinin 1 - receptor ( P32238 REA ) activation by long chain fatty acid ( LCFA ) absorption stimulates vago-vagal reflex pathways in the brain stem . The present study determines whether this reflex also activates the cholinergic anti-inflammatory pathway , a pathway known to modulate cytokine release during endotoxemia . METHODS : Mesenteric lymph was obtained from wild type ( WT ) and P32238 REA knockout ( P32238 REA ( - / - ) ) mice intraperitoneally challenged with Lipopolysaccharid ( LPS ) ( endotoxemic lymph , EL ) and intestinally infused with vehicle or LCFA-enriched solution . The lymph was analyzed for TNFα , P05231 REA and P22301 REA concentration and administered to healthy recipient mice via jugular infusion . Alveolar wall thickness , myeloperoxidase ( P05164 REA ) and TUNEL positive cells were determined in lung tissue of recipient mice . RESULTS : LCFA infusion in WT mice reduced TNFα concentration in EL by 49 % compared to vehicle infusion , but had no effect in P32238 REA ( - / - ) mice . EL significantly increased the alveolar wall thickness , the number of P05164 REA - positive and TUNEL-positive cells compared to control lymph administration . LCFA infusion in WT , but not in CCK 1R ( - / - ) mice , significantly reduced these pathological effects of EL . CONCLUSION : During endotoxemia enteral LCFA absorption reduces TNFα release into mesenteric lymph and attenuates histomorphologic parameters of lung dysfunction . Failure to elicit this effect in CCK 1R ( - / - ) mice demonstrates that anti-inflammatory properties of LCFAs are mediated through CCK 1 - Rs .

DB00092 MEN ( anti - P06729 REA ) causes a selective reduction in circulating effector memory T cells ( Tem ) and relative preservation of central memory T cells ( Tcm ) in psoriasis . BACKGROUND : DB00092 MEN ( anti - P06729 REA ) biological therapy selectively targets effector memory T cells ( Tem ) in psoriasis vulgaris , a model Type 1 autoimmune disease . METHODS : Circulating leukocytes were phenotyped in patients receiving alefacept for moderate to severe psoriasis . RESULTS : In all patients , this treatment caused a preferential decrease in effector memory T cells ( P32248 REA - CD45RA - ) ( mean 63 % reduction ) for both P01730 REA + and CD8 + Tem , while central memory T cells ( Tcm ) ( P32248 REA + CD45RA - ) were less affected , and naïve T cells ( P32248 REA + CD45RA + ) were relatively spared . Circulating CD8 + effector T cells and Type 1 T cells ( P01579 REA - producing ) were also significantly reduced . CONCLUSION : DB00092 MEN causes a selective reduction in circulating effector memory T cells ( Tem ) and relative preservation of central memory T cells ( Tcm ) in psoriasis .

Stimulation of the peroxisome proliferator-activated receptor gamma ( Q07869 REA gamma ) and the expression of selected blood monocyte cytokine genes in diabetic macroangiopathy . Monocytes and macrophages play a key role in the progression of atheromatous changes . The peroxisome proliferator-activated receptor gamma ( Q07869 REA gamma ) can limit macroangiopathy through the control of cytokine transcription . The objectives of this study were to examine the influence of Q07869 REA gamma and its agonist ( rosiglitazone ) on the TNFalpha , P05231 REA , P10145 REA and P22301 REA gene expression in monocytes of patients with diabetic macroangiopathy and to analyse obtained results in context of selected atherogenic factors ant direct indicators of endothelial lesion . TNFalpha , P05231 REA , P10145 REA , P22301 REA and Q07869 REA gamma gene expression was assessed in peripheral blood monocytes in 45 patients with type 2 diabetes before and following 22 weeks of rosiglitazone therapy ( real-time PCR [ Applied Biosystems ] ) . As indicators of endothelial lesion , concentration of thrombomodulin ( immunoassay [ Diagnostica Stago ] ) and amount of circulating blood endothelial cells ( immunofluorescence method with MoAb Q8N0X4 - HEC 19 ) were determined . Following rosiglitazone therapy , a statistically significant downward tendency of TNFalpha ( p= 0.026 ) and P10145 REA ( p= 0.008 ) gene expression was noted . Before and following rosiglitazone treatment , Q07869 REA gamma , P05231 REA and P22301 REA gene expression was undetectable in studied monocytes in vivo . In conclusion , TNFalpha and P10145 REA play an important role in monocyte atherogenic activity . Rosiglitazone reduces monocyte proinflammatory readiness by influencing the expression of selected atherogenic cytokines ( Q07869 REA gamma-independent pathway ) .

Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c-Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 REA ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen-presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 REA - mediated NF-ĸB signaling of DCs remain poorly defined . METHODS : Bone-marrow ( BM ) - derived DCs ( BM-DCs ) were treated with P35367 REA inverse agonists to interrupt basal P35367 REA - mediated signaling . The crosstalk of P35367 REA - mediated signaling and the NF-ĸB pathway was examined by NF-ĸB cellular activity using a luciferase reporter assay , NF-ĸB subunit analysis using Western blotting and P01375 REA - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 REA signaling by inverse agonists significantly inhibited P01375 REA - α and P05231 REA production of BM-DCs . P35367 REA - specific agonists were able to enhance P01375 REA - α production , but this overexpression was significantly inhibited by NF-ĸB inhibitor . The P35367 REA inverse agonist ketotifen also suppressed cellular NF-ĸB activity , suggesting crosstalk between P35367 REA and NF-ĸB signaling in DCs . After comprehensive analysis of NF-ĸB subunits , c-Rel protein expression was significantly down-regulated in ketotifen-treated BM-DCs , which led to inhibition of the promoter activity of P01375 REA - α . Finally , adoptive transfer of the ketotifen-treated BM-DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c-Rel controls P35367 REA - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 REA - mediated signaling and NF-ĸB pathway crosstalk in allergic inflammation .

Clinical and genetic factors associated with nausea and vomiting in cancer patients receiving opioids . BACKGROUND : This study investigates whether demographical , disease-related and genetic factors contribute to inter-individual differences in nausea and vomiting among patients receiving opioids for cancer pain . METHODS : Cancer patients receiving opioids were included from 17 centres in 11 European countries . Intensities of nausea and vomiting were reported by 1579 patients on four-point categorical scales . In stratified regression models including demographical and disease-related factors as covariates , 96 single nucleotide polymorphisms ( SNPs ) in 16 candidate genes related to opioid - or nausea / vomiting signalling pathways ( P08183 REA , P35372 REA , P41145 REA , P32121 REA , P42226 REA , P21964 REA , P20309 REA , P08912 REA , P35367 REA , P14416 REA , P35462 REA , P25103 REA , P46098 REA , O95264 REA , Q8WXA8 , P21554 REA ) were analysed for association with nausea and vomiting . FINDINGS : Age , body mass index , Karnofsky Performance Status , gender , use of antiemetics , type of opioid , type of cancer and eight SNPs were associated with the inter-individual differences in nausea and vomiting among cancer patients treated with opioids ( p < 0.01 ) . The SNPs were rs1176744 , rs3782025 and rs1672717 in O95264 REA ; rs165722 , rs4680 and rs4633 in P21964 REA ; rs10802789 and rs685550 in P20309 REA . Only the SNP rs1672717 in O95264 REA passed the Benjamini-Hochberg criterion for a 10 % false discovery rate . INTERPRETATION : Clinical characteristics and SNPs within the O95264 REA , P21964 REA and P20309 REA genes may be associated with the variability in nausea and vomiting among cancer patients receiving opioids . This knowledge may help to identify patients at particular risk for nausea and vomiting during treatment with opioids for cancer pain .

P05231 REA ( P05231 REA ) and / or soluble P05231 REA receptor down-regulation of human type II collagen gene expression in articular chondrocytes requires a decrease of Sp1 . Sp3 ratio and of the binding activity of both factors to the P02458 REA promoter . Type II collagen is composed of alpha 1 ( II ) chains encoded by the P02458 REA gene . Alteration of this cartilage marker is a common feature of osteoarthritis . P05231 REA ( P05231 REA ) is a pro-inflammatory cytokine that needs a soluble form of receptor called sIL - 6R to exert its effects in some cellular models . In that case , sIL - 6R exerts agonistic action . This mechanism can make up for the partial or total absence of membrane-anchored P05231 REA receptors in some cell types , such as chondrocytes . Our study shows that P05231 REA , sIL - 6R , or both inhibit type II collagen production by rabbit articular chondrocytes through a transcriptional control . The cytokine and / or sIL - 6R repress P02458 REA transcription by a - 63 / - 35 sequence that binds Sp1 . Sp3 . Indeed , P05231 REA and / or sIL - 6R inhibit Sp1 and Sp3 expression and their binding activity to the 63 - bp promoter . In chromatin immunoprecipitation experiments , P05231 REA . sIL - 6R induced an increase in Sp3 recruitment to the detriment of Sp1 . Knockdown of Sp1 . Sp3 by small interference RNA and decoy strategies were found to prevent the P05231 REA - and / or sIL - 6R - induced inhibition of P02458 REA transcription , indicating that each of these Sp proteins is required for down-regulation of the target gene and that a heterotypic Sp1 . Sp3 complex is involved . Additionally , Sp1 was shown to interact with Sp3 and Q13547 REA . Indeed , overexpression of a full-length Sp3 cDNA blocked the Sp1 up-regulation of the 63 - bp P02458 REA promoter activity , and by itself , inhibits P02458 REA transcription . We can conclude that P05231 REA , sIL - 6R , or both in combination decrease both the Sp1 . Sp3 ratio and DNA-binding activities , thus inhibiting P02458 REA transcription .

Possible role of cholecystokinin-A receptors in regulation of thyrotropin ( DB00024 ) secretion in male rats . We studied the importance of cholecystokinin ( CCK ) system in the regulation of thyrotropin ( DB00024 ) and prolactin ( PRL ) secretion in male rats . To this end , we tested the effects of both unselective CCK agonists CCK - 8 and caerulein , and CCK-B selective agonists Q13308 and pentagastrin as well as the selective CCK antagonists ( devazepide and L -365,260 ) at wide dose-ranges on the cold-stimulated and TRH-induced DB00024 and PRL secretion . DB00403 MEN , given s . c . 15 min before sacrifice , decreased DB00024 levels at 5 micrograms / kg . In time course-studies , the maximum inhibition was seen at 15 min but the effect lasted at least 30 , but less than 60 min . Also CCK - 8 decreased DB00024 levels at the doses of 20 and 50 micrograms / kg at 15 min . Devazepide and L -365,260 did not affect DB00024 or PRL levels at any dose . The effect of caerulein ( 5 micrograms / kg ) was antagonized by devazepide , a CCK-A antagonist , at 100 micrograms / kg , but not by a CCK-B antagonist L -365,260 tested at a wide dose range . PRL levels were not affected by any treatment . DB00403 MEN ( 5 micrograms / kg ) , given at the same time as TRH ( 500 ng / kg ) , inhibited the TRH-induced DB00024 levels at 15 min , but not at 30 or 60 min . CCK - 8 ( 50 micrograms / kg ) , Q13308 ( 100 micrograms / kg ) and pentagastrin ( 500 micrograms / kg ) did not affect the TRH-induced DB00024 secretion . The results probably indicate that P32238 REA stimulation inhibits DB00024 secretion at the level of the anterior pituitary gland . PRL levels in male rats are not affected by CCK system .

Role of nitrative and oxidative DNA damage in inflammation-related carcinogenesis . Chronic inflammation induced by biological , chemical , and physical factors has been found to be associated with the increased risk of cancer in various organs . We revealed that infectious agents including liver fluke , Helicobacter pylori , and human papilloma virus and noninfectious agents such as asbestos fiber induced P35228 REA - dependent formation of 8 - nitroguanine and 8 - oxo - 7 , 8-d ihydro - 2 ' - deoxyguanosine ( 8 - oxodG ) in cancer tissues and precancerous regions . Our results with the colocalization of phosphorylated Q13315 REA and γ - P16104 REA with 8 - oxodG and 8 - nitroguanine in inflammation-related cancer tissues suggest that DNA base damage leads to double-stranded breaks . It is interesting from the aspect of genetic instability . We also demonstrated P05231 REA - modulated P35228 REA expression via P40763 REA and P00533 REA in Epstein-Barr-virus-associated nasopharyngeal carcinoma and found promoter hypermethylation in several tumor suppressor genes . Such epigenetic alteration may occur by controlling the DNA methylation through P05231 REA - mediated JAK / P40763 REA pathways . Collectively , 8 - nitroguanine would be a useful biomarker for predicting the risk of inflammation-related cancers .

Enhanced goblet cell hyperplasia in HDC knockout mice with allergic airway inflammation . BACKGROUND : DB11320 is known to have immunoregulatory roles in allergic reactions through histamine receptor 1 ( P35367 REA ) , P25021 REA , Q9Y5N1 REA and Q9H3N8 REA . However , its role in goblet cell hyperplasia in the airways of asthma patients is yet to be clarified . OBJECTIVE : This study was designed to examine the role of histamine in goblet cell hyperplasia using histamine-deficient mice ( Hdc - / - mice ) with allergic airway inflammation . METHODS : Wild-type and Hdc - / - C57BL / 6 mice were sensitized with ovalbumin ( OVA ) . After a 2 - week exposure to OVA , goblet cell hyperplasia was evaluated . Cell differentials and cytokines in BALF were analyzed . The mRNA levels of P98088 REA and Gob - 5 gene were determined quantitatively . RESULTS : The number of eosinophils in BALF increased in both the sensitized wild-type mice and Hdc - / - mice with OVA inhalation . In addition , the numbers of alveolar macrophages and lymphocytes in BALF increased significantly in the sensitized Hdc - / - mice with OVA inhalation compared to the wild-type mice under the same conditions . The concentrations of P05112 REA ( P05112 REA ) , P05113 REA , P35225 REA , Interferon-gamma ( P01579 REA ) , tumor necrosis factor-alpha ( P01375 REA ) and P60568 REA in the BALF all increased significantly in both groups compared to those exposed to saline . In particular , the concentration of P01375 REA in the Hdc - / - mice exposed to OVA was significantly higher than that in the wild-type mice under the same conditions . The mRNA levels of Gob - 5 and P98088 REA , and the ratio of the goblet cells in the airway epithelium significantly increased in Hdc - / - mice exposed to OVA compared to wild-type mice . CONCLUSIONS : These results suggested that histamine may play a regulatory role in goblet cell hyperplasia in allergic airway inflammation .

P35367 REA antagonist cetirizine impairs working memory processing speed , but not episodic memory . BACKGROUND AND PURPOSE : The histaminergic neurotransmitter system is currently under investigation as a target for drug treatment of cognitive deficits in clinical disorders . The therapeutic potential of new drugs may initially be screened using a model of histaminergic dysfunction , for example , as associated with the use of centrally active antihistamines . Of the selective second generation antihistamines , cetirizine has been found to have central nervous system effects . The aim of the present study was to determine whether cetirizine can be used as a tool to model cognitive deficits associated with histaminergic hypofunction . EXPERIMENTAL APPROACH : The study was conducted according to a three-way , double-blind , cross-over design . Treatments were single oral doses of cetirizine 10 and 20 mg and placebo . Effects on cognition were assessed using tests of word learning , memory scanning , vigilance , divided attention , tracking and visual information processing speed . KEY RESULTS : DB00341 SUB 10 mg impaired tracking performance and both doses impaired memory scanning speed . None of the other measures indicated impaired performance . CONCLUSION AND IMPLICATIONS : DB00341 SUB affects information processing speed , but these effects were not sufficient to serve as a model for cognitive deficits in clinical disorders .

Change of redox status and modulation by thiol replenishment in retinal photooxidative damage . PURPOSE : Cellular or tissue reduction-oxidation ( redox ) is crucial in various diseases . The present study was conducted to analyze how tissue redox status is affected by photooxidative stress and whether the exogenous thiol antioxidant DB06151 ( Q9C000 REA ) affects photooxidative stress-induced retinal damage . METHODS : Mice were intraperitoneally injected with either Q9C000 REA ( 250 mg / kg ) or phosphate-buffered saline ( PBS ) and exposed to white fluorescent light ( 8000 lux ) for 2 hours . Levels of thioredoxin ( TRX ) , glutaredoxin ( P35754 REA ) , and glutathione ( DB00143 MEN ) , endogenous regulators of redox ; 4 - hydroxy - 2 - nonenal ( HNE ) - modified protein , a marker of lipid peroxidation ; and nuclear factor ( NF ) - kappaB , a redox-sensitive transcription factor in retinal samples , was measured by immunohistochemistry and Western blot or enzymatic recycling assay . Light-induced retinal damage estimated by electroretinography and quantitative immunohistochemistry for 8 - hydroxy - 2 - deoxyguanosine ( 8OHdG index ) , a marker of oxidative stress-induced DNA damage , was compared in Q9C000 REA - and PBS-treated mice . RESULTS : Upregulation of TRX and HNE-modified protein , decrease of DB00143 MEN , and nuclear translocation of NF-kappaB were noted after light exposure in PBS-treated mice . These changes were suppressed in Q9C000 REA - treated mice compared with PBS-treated mice . P35754 REA was not upregulated after light exposure in any mice . The a - and b-wave amplitudes were significantly higher , and the 8OHdG index was significantly lower after light exposure in Q9C000 REA - treated mice than in PBS-treated mice . CONCLUSIONS : Retinal redox status is altered by intense light and is normalized partially by the effect of Q9C000 REA on TRX and DB00143 MEN tissue levels . Manipulation of the tissue redox state by exogenous thiol replenishment may be a useful strategy to prevent retinal photooxidative damage .

Differences in hepatotoxicity and gene expression profiles by anti-diabetic Q07869 REA gamma agonists on rat primary hepatocytes and human HepG 2 cells . Agonists of peroxisome proliferator-activated receptor gamma ( PPARgamma ) are a new class of oral drugs designed to treat insulin-resistant diabetes ( i . e . , type 2 diabetes ) . However , troglitazone , the first compound in the class approved by the US Food and Drug Administration ( FDA ) in 1997 was found to be hepatotoxic and was withdrawn from the market after reports of severe liver failure . The mechanism of Q07869 REA gamma agonist-induced hepatotoxicity remains unknown . In this study , we examined the hepatotoxic effects of five Q07869 REA gamma agonists ( ciglitazone , pioglitazone , rosiglitazone , troglitazone , and DB04971 MEN ) on rat primary hepatocytes and human HepG 2 cells . We also compared the gene expression profiles of rat primary hepatocytes after exposure to Q07869 REA gamma agonists by using the Rat Genome Survey Microarray system from Applied Biosystems in order to understand the mechanisms of hepatotoxicities induced by PPARgamma agonists . Consistent with the hepatotoxicity data , our results demonstrate that the gene expression profiles affected by troglitazone and ciglitazone can be clearly distinguished from those by pioglitazone and rosiglitazone . Genes that are differentially expressed between the more toxic troglitazone / ciglitazone group and the less toxic rosiglitazone / pioglitazone group are involved in necrotic , apoptotic , and cell proliferative pathways . The five compounds were also clustered based on a set of molecular descriptors . The clustering based on chemical structural information is in good agreement with the clustering of compounds based on cytotoxicity or gene expression data , indicating a strong relationship between chemical structure and biological endpoints . Our work suggests that microarray analysis together with toxicological observations can be used to rank drugs for hepatotoxicity and to evaluate the safety of new compounds .

Rindopepimut , a 14 - mer injectable peptide vaccine against EGFRvIII for the potential treatment of glioblastoma multiforme . Celldex Therapeutics is developing rindopepimut ( DB05374 MEN ) , a 14 - mer injectable peptide vaccine for the potential treatment of glioblastoma multiforme ( GBM ) . Rindopepimut specifically targets a novel junctional epitope of the P00533 REA deletion mutant EGFRvIII , which is a constitutively active receptor that is expressed in approximately 60 to 70 % of patients with GBM . EGFRvIII expression is correlated with worse prognosis and reduced overall survival . Importantly , EGFRvIII is not expressed in normal brain tissue , making it an excellent therapeutic target . Preclinical studies demonstrated lasting tumor regression and increased survival times , as well as efficient generation of EGFRvIII-specific humoral and cellular immune responses , in animals expressing EGFRvIII and vaccinated with rindopepimut . Phase I and II clinical trials in patients with GBM demonstrated significantly increased median time to progression and overall survival time in those vaccinated with rindopepimut compared with matched historical controls . Only limited side effects have been observed in patients . Given these results , rindopepimut is an extremely promising therapy for patients with GBM . Phase I and II clinical trials in patients with GBM were ongoing at the time of publication . In the future , it may be beneficial to combine rindopepimut with other treatment modalities to further prolong survival .

DB05578 MEN : a novel antiangiogenic agent . DB05578 MEN ( IMC - 1121B ) is a fully humanized monoclonal antibody that binds to P35968 REA and can inhibit angiogenesis , a quintessential mechanism for promoting tumor growth and metastasis . Several antiangiogenesis agents are already approved for cancer therapy ; however , ramucirumab ' s selectivity for P35968 REA makes it interesting . The selectivity of an agent can improve safety and efficacy . This article describes the mechanism of action , pharmacokinetics , safety and clinical trial results of ramucirumab with particular emphasis on gastric cancer .

Differential expression of glutaredoxin and thioredoxin during monocytic differentiation . Macrophages generate reactive oxygen intermediates ( ROIs ) as the effectors of anti-bacterial defense mechanism . Intracellular ROIs and reduction / oxidation ( redox ) status play crucial roles in signal transduction . We therefore investigated the expression of redox-regulating proteins such as glutaredoxin ( P35754 REA ) and thioredoxin ( TRX ) during the differentiation of murine monocytic leukemia cell line M1 cells and human monocytic leukemia cell line U937 cells . When M1 cells were treated by P05231 REA , P35754 REA mRNA markedly increased and TRX mRNA also increased slightly . In contrast , there was no increase of P35754 REA mRNA in D-cell , which is a sub-cell line derived from M1 lacking in the capacity of differentiation . P35754 REA mRNA also increased in U937 cells differentiated by phorbol 12 - myristate 13 - acetate ( PMA ) . By immunohistochemistry , unstimulated M1 cells showed strong staining of TRX and marginal staining of P35754 REA . In contrast , TRX expression in P05231 REA treated M1 cells is as strong as in unstimulated M1 cells , whereas P35754 REA expression is slightly enhanced in P05231 REA treated M1 cells . Phagocytosis is markedly enhanced and hydrogen peroxide production is slightly enhanced in P05231 REA treated M1 cells . These results showed that TRX is steadily expressed whereas P35754 REA is induced in association with the differentiation in macrophage-like cell line cells , suggesting differential roles of these redox regulators in macrophage lineage .

Discovery of ( 2E ) - 3 - { 2 - butyl - 1 - [ 2 - ( diethylamino ) ethyl ] - 1H - benzimidazol - 5 - yl } - N-hydroxyacrylamide ( DB05223 MEN ) , an orally active histone deacetylase inhibitor with a superior preclinical profile . A series of 3 - ( 1,2- disubstituted - 1H - benzimidazol - 5 - yl ) - N-hydroxyacrylamides ( 1 ) were designed and synthesized as HDAC inhibitors . Extensive SARs have been established for in vitro potency ( Q13547 REA enzyme and COLO 205 cellular IC ( 50 ) ) , liver microsomal stability ( t ( 1/2 ) ) , cytochrome P450 inhibitory ( 3A4 IC ( 50 ) ) , and clogP , among others . These parameters were fine-tuned by carefully adjusting the substituents at positions 1 and 2 of the benzimidazole ring . After comprehensive in vitro and in vivo profiling of the selected compounds , DB05223 MEN ( 3 ) was identified as a preclinical development candidate . 3 is a potent pan-HDAC inhibitor with excellent druglike properties , is highly efficacious in in vivo tumor models ( HCT - 116 , PC - 3 , A2780 , MV4 - 11 , Ramos ) , and has high and dose-proportional oral exposures and very good ADME , safety , and pharmaceutical properties . When orally dosed to tumor-bearing mice , 3 is enriched in tumor tissue which may contribute to its potent antitumor activity and prolonged duration of action . 3 is currently being tested in phase I and phase II clinical trials .

Benzyl isothiocyanate suppresses pancreatic tumor angiogenesis and invasion by inhibiting HIF-α / P15692 REA / Rho-GTPases : pivotal role of P35610 REA - 3 . Our previous studies have shown that benzyl isothiocyanate ( BITC ) suppresses pancreatic tumor growth by inhibiting P35610 REA - 3 ; however , the exact mechanism of tumor growth suppression was not clear . Here we evaluated the effects and mechanism of BITC on pancreatic tumor angiogenesis . Our results reveal that BITC significantly inhibits neovasularization on rat aorta and Chicken-Chorioallantoic membrane . Furthermore , BITC blocks the migration and invasion of BxPC - 3 and PanC - 1 pancreatic cancer cells in a dose dependant manner . Moreover , secretion of P15692 REA and P08253 REA in normoxic and hypoxic BxPC - 3 and PanC - 1 cells was significantly suppressed by BITC . Both P15692 REA and P08253 REA play a critical role in angiogenesis and metastasis . Our results reveal that BITC significantly suppresses the phosphorylation of P35968 REA ( DB00135 - 1175 ) , and expression of HIF-α . Rho-GTPases , which are regulated by P15692 REA play a crucial role in pancreatic cancer progression . BITC treatment reduced the expression of RhoC whereas up-regulated the expression of tumor suppressor RhoB . P35610 REA - 3 over-expression or P05231 REA treatment significantly induced HIF - 1α and P15692 REA expression ; however , BITC substantially suppressed P35610 REA - 3 as well as P35610 REA - 3 - induced HIF - 1α and P15692 REA expression . Finally , in vivo tumor growth and matrigel-plug assay show reduced tumor growth and substantial reduction of hemoglobin content in the matrigel plugs and tumors of mice treated orally with 12 µmol BITC , indicating reduced tumor angiogenesis . Immunoblotting of BITC treated tumors show reduced expression of P35610 REA - 3 phosphorylation ( DB00135 - 705 ) , HIF-α , P35968 REA , P15692 REA , P08253 REA , CD31 and RhoC . Taken together , our results suggest that BITC suppresses pancreatic tumor growth by inhibiting tumor angiogenesis through P35610 REA - 3 - dependant pathway .

P35367 REA antagonism by cetirizine in isolated guinea pig tissues : influence of receptor reserve and dissociation kinetics . We characterised histamine H ( 1 ) receptor antagonism by cetirizine and its enantiomers on isolated guinea pig ileum and trachea . Competitive or mixed ( competitive and apparent noncompetitive ) antagonism profiles were observed . The order of potency was : chlorpheniramine > or = mepyramine > levocetirizine > cetirizine > or = terfenadine > loratadine > dextrocetirizine . The inhibitory effects of cetirizine , levocetirizine , terfenadine and loratadine were slowly reversible compared to those of dextrocetirizine or mepyramine . DB00341 SUB and its enantiomers were inactive on L-type Ca ( 2 + ) channels . Reduction of the histamine H ( 1 ) receptor reserve by dibenamine in the ileum ( 100 - fold higher than in the trachea ) showed a gradual change from the competitive profile of dextrocetirizine and mepyramine to a mixed profile . The present results show that cetirizine and levocetirizine are selective competitive but slowly reversible histamine H ( 1 ) receptor antagonists . Their mixed antagonism profile observed in the trachea can be explained by the small receptor reserve present in this tissue compared to the ileum and their very slow dissociation rate from the histamine H ( 1 ) receptor .