interacts_with DB01050?
Effect of milk hydrolysates on inflammation markers and drug-induced transcriptional alterations in cell-based models . Nonsteroidal anti-inflammatory drugs ( NSAID ) are associated with gastrointestinal inflammation and subsequent damage to the intestinal tissue . Earlier studies in our laboratory have found that specific casein hydrolysates ( CH ) might be useful in the treatment of gastrointestinal wounds . The underlying mechanisms that support inflammation and wound healing are not completely understood , but transcriptional alterations may be used as markers for inflammation and wound healing . The bioactivity of 3 CH prepared by treatment of commercial casein with pepsin ( 60 min ) followed by corolase ( 0 , 10 , or 60 min ) were investigated in intestinal epithelial cells treated with the NSAID indomethacin . The bioactivity was evaluated as transcriptional alterations of transforming growth factor-β1 ( TGF-β1 ) , cyclooxygenase-2 ( P35354 ) , peroxisome proliferator-activated receptor-γ ( Q07869 -γ ) and nuclear factor κB ( NFκB ) by real-time PCR . Furthermore , the effect of CH on lipopolysaccharide-induced inflammation was evaluated in macrophages by measuring PG E(2) levels . Casein hydrolysates treated with corolase for 10 or 60 min after pepsin treatment downregulated transcription of TGF-β1 and NFκB ( P < 0.05 ) compared with the hydrolysate treated with pepsin only . Hydrolysate prepared by corolase treatment for 60 min after pepsin hydrolysis downregulated transcription of P35354 ( P < 0.05 ) compared with hydrolysate treated with corolase for only 10 min whereas transcription of Q07869 -γ was not affected ( P > 0.05 ) . Additionally , the hydrolysate prepared by pepsin treatment only ( 0 min corolase ) had a pro-inflammatory effect on macrophages via PG E(2) stimulation ( P < 0.05 ) . In conclusion , CH produced by a combination of pepsin and corolase treatments downregulated the transcription levels of TGF-β1 , P35354 , and NFκB . P00734 kringle-2 induces death of mesencephalic dopaminergic neurons in vivo and in vitro via microglial activation . We have shown that prothrombin kringle-2 ( pKr-2 ) , a domain of human prothrombin distinct from thrombin could activate cultured rat brain microglia in vitro . However , little is known whether pKr-2-induced microglial activation could cause neurotoxicity on dopaminergic ( DA ) neurons in vivo . To address this question , pKr-2 was injected into the rat substantia nigra ( SN ) . Tyrosine hydroxylase ( TH ) immunohistochemistry experiments demonstrate significant loss of DA neurons seven days after injection of pKr-2 . In parallel , pKr-2-activated microglia were detected in the SN with OX-42 and OX-6 immunohistochemistry . Reverse transcription PCR and double-label immunohistochemistry revealed that activated microglia in vivo exhibit early and transient expression of inducible nitric oxide synthase ( P35228 ) , cyclooxygenase-2 ( P35354 ) and several proinflammatory cytokines . The pKr-2-induced loss of SN DA neurons was partially inhibited by the NOS inhibitor N(G)-nitro-L-arginine methyl ester hydrochloride , and the P35354 inhibitor DuP-697 . P27361 /2 , c-Jun N-terminal kinase and p38 mitogen-activated protein kinase were activated in the SN as early as 1 hr after pKr-2 injection , and localized within microglia . Inhibition of these kinases led to attenuation of mRNA expression of P35228 , P35354 and several proinflammatory cytokines , and rescue of DA neurons in the SN . Intriguingly , following treatment with pKr-2 in vitro , neurotoxicity was detected exclusively in co-cultures of mesencephalic neurons and microglia , but not microglia-free neuron-enriched mesencephalic cultures , indicating that microglia are required for pKr-2 neurotoxicity . Our results strongly suggest that microglia activated by endogenous compound(s) , such as pKr-2 , are implicated in the DA neuronal cell death in the SN . A real time quantitative PCR analysis and correlation of P23219 and P35354 enzymes in inflamed dental pulps following administration of three different NSAIDs . Dental pain is encountered daily by clinicians . Nonsteroidal anti-inflammatory drugs ( NSAIDs ) commonly used for pain management are traditionally cyclooxygenase-1 ( P23219 ) and cyclooxygenase-2 ( P35354 ) inhibitors , and more recently selective P35354 inhibitors . This study was designed to identify and quantify P23219 and P35354 gene expression level in inflamed rat molar pulps after administration of three NSAIDs : DB00482 , Vioxx , and DB01050 . Fifty male Wistar rats had their first and second molar pulps exposed and sealed with Cavit for 4 days . Rats were randomly divided into the three drug groups and two control groups . RNA was isolated from the rat pulps . Real Time Quantitative Reverse Transcriptase-Polymerase Chain Reaction assay , a relatively new PCR technique , was used to quantify P23219 and P35354 mRNA . Statistical analysis demonstrated no significant differences in P23219 and P35354 levels among the drug groups . However , Vioxx and DB01050 significantly reduced P35354 expression levels compared to inflamed ( positive control ) pulps ( p < 0.05 ) . A phase-1 trial of bexarotene and denileukin diftitox in patients with relapsed or refractory cutaneous T-cell lymphoma . DB00004 , a genetically engineered fusion protein combining the enzymatically active domains of diphtheria toxin and the full-length sequence for interleukin-2 ( P60568 ) , efficiently targets lymphoma cells expressing the high-affinity P60568 receptor ( IL-2R ) consisting of the alpha/p55/CD25 , beta/p75/CD122 , and gamma/ P31785 /CD132 chains . In vitro studies demonstrated that the retinoid X receptor ( RXR ) retinoid , bexarotene , at biologically relevant concentrations of 10(-6) M to 10(-8) M , upregulated both the p55 and p75 subunits of the IL-2R and enhanced 5- to 10-fold the susceptibility of T-cell leukemia cells to denileukin diftitox . To determine whether this biomodulatory effect could be recapitulated in vivo , we treated 14 patients with relapsed or refractory cutaneous T-cell lymphoma with escalating doses of bexarotene ( 75 mg/day-300 mg/day ) and denileukin diftitox ( 18 mcg/kg per day x 3 days every 21 days ) in a phase 1 trial . Overall response was 67 % ( 4 complete responses , 4 partial responses ) . Modulation of IL-2R expression was observed at or above a bexarotene dose of 150 mg/day . Four patients experienced grade 2 or 3 leukopenia , and 2 had grade 4 lymphopenia . Our results demonstrate that the combination of denileukin diftitox and bexarotene is well tolerated and that even low doses ( 150 mg/day ) of bexarotene are capable of in vivo upregulation of CD25 expression on circulating leukemia cells . [ P35354 inhibitor non-steroidal anti-inflammatory drugs , myth or reality ? ] . The discovery of two isoforms of cyclooxygenase , Cox-1 constitutive and Cox-2 inducible , has prompted the development of new molecules with high Cox-2 selectivity . These new NSAIDs belong to the coxib class and have theoretically a better digestive tolerability than classical NSAID have . In Belgium , rofecoxib ( ( Vioxx ) and celecoxib ( DB00482 ) are commercialized . DB00533 is indicated in the symptomatic treatment of osteoarthritis ( 12.5 to 25 mg/d ) and celecoxib is indicated in osteoarthritis ( 200 mg/d ) and in rheumatoid arthritis ( 200 to 400 mg/d ) . Several studies have demonstrated their efficacy , similarly to classical NSAID as diclofenac ( Voltaren ) , naproxen ( Naprosyne ) , ibuprofen ( DB01050 ) and their superiority compared to placebo . Their safety profile for gastrointestinal events is proven in patients without ulcer history compared to classical NSAID . However , the concomitant use of aspirin decreases the benefit as demonstrated for celecoxib at 400 mg/d but not investigated for rofecoxib . The selective inhibition of Cox-2 with no effect on Cox-1 favors cardiovascular events in patients at risk . Other side effects are similar to classical NSAID . Thus Cox-2 inhibitors NSAID are interesting molecules for their sparing gastrointestinal activity . They must be used with caution in patients with ulcer history , in the elderly and in patients requiring aspirin for cardiovascular prophylaxis . Regulation of cyclooxygenase-2 expression by heat : a novel aspect of heat shock factor 1 function in human cells . The heat-shock response , a fundamental defense mechanism against proteotoxic stress , is regulated by a family of heat-shock transcription factors ( HSF ) . In humans Q00613 is considered the central regulator of heat-induced transcriptional responses . The main targets for Q00613 are specific promoter elements ( HSE ) located upstream of heat-shock genes encoding cytoprotective heat-shock proteins ( HSP ) with chaperone function . In addition to its cytoprotective function , Q00613 was recently hypothesized to play a more complex role , regulating the expression of non-HSP genes ; however , the non-canonical role of Q00613 is still poorly understood . Herein we report that heat-stress promotes the expression of cyclooxygenase-2 ( P35354 ) , a key regulator of inflammation controlling prostanoid and thromboxane synthesis , resulting in the production of high levels of prostaglandin-E(2) in human cells . We show that heat-induced P35354 expression is regulated at the transcriptional level via Q00613 -mediated signaling and identify , by in-vitro reporter gene activity assay and deletion-mutant constructs analysis , the P35354 heat-responsive promoter region and a new distal cis-acting HSE located at position -2495 from the transcription start site . As shown by ChIP analysis , Q00613 is recruited to the P35354 promoter rapidly after heat treatment ; by using shRNA-mediated Q00613 suppression and HSE-deletion from the P35354 promoter , we demonstrate that Q00613 plays a central role in the transcriptional control of P35354 by heat . Finally , P35354 transcription is also induced at febrile temperatures in endothelial cells , suggesting that Q00613 -dependent P35354 expression could contribute to increasing blood prostaglandin levels during fever . The results identify P35354 as a human non-classical heat-responsive gene , unveiling a new aspect of Q00613 function . Heart allograft protection with low-dose carbon monoxide inhalation : effects on inflammatory mediators and alloreactive T-cell responses . BACKGROUND : DB11588 ( CO ) , a byproduct of heme catalysis , has lately received considerable attention as a regulatory molecule in cellular and biological processes . CO has been shown to provide potent protection against a variety of tissue injuries . We hypothesized in this study that low concentration CO would be beneficial for organ allografts , which frequently undergo several types of injury such as ischemia/reperfusion , alloimmune reaction , and inflammation METHODS : The efficacy of low-dose CO was examined in a fully allogeneic LEW to BN rat heterotopic heart transplantation ( HHTx ) model . Recipients were kept in air or exposed to low-dose CO ( 20 ppm ) for 14 , 28 , or 100 days after HHTx under short-course tacrolimus RESULTS : CO treatment ( d0-28 , 0-100 ) was remarkably effective in prolonging heart allograft survival to a median of > 100 from 45 days in the air-control group , with significant reductions of arteritis , fibrosis , and cellular infiltration , including macrophages and T cells . CO inhibited intragraft upregulation of Th1 type cytokines ( P60568 , IFNgamma ) , proinflammatory mediators ( IL-1beta , TNFalpha , P05231 , P35354 ) , and adhesion molecule . Shorter CO exposure in early ( 0-13d ) and late ( 14-28d ) posttransplant periods also prolonged graft survival , with a significant inhibition of inflammatory mediators CONCLUSIONS : These results show that low dose CO inhalation protects heart allografts and can considerably prolong their survival . CO appears to function via multiple mechanisms , including direct inhibition of Th1 type cytokine production and regulation of inflammatory responses . Effects of external calcium on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229-7 . DB01373 is a known signalling molecule in eukaryotic cells and plays a central role in the regulation of many cellular processes . In the following study , we report on the effect of external calcium treatments on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229-7 . We observed that the intracellular calcium content of P. bainier 229-7 mycelia was increased in response to exposure to high external Ca(2+) concentrations . Both ginsenoside Rd biotransformation and β-glucosidase activity were both found to be dependent on the external calcium concentration . At an optimal Ca(2+) concentration of 45 mM , maximal ginsenoside Rd bioconversion rate of 92.44 % was observed and maximal β-glucosidase activity of 0.1778 U was reached in a 72-h biotransformation . The Ca(2+) channel blocker Verapamil blocked the trans-membrane influx of calcium and decreased ginsenoside Rd biotransformatiom . In addition , β-glucosidase activity and ginsenoside Rd content decreased by 36.0 and 29.2 % respectively after a 72-h incubation in the presence of 0.05 mM P62158 ( P62158 ) antagonist DB00850 . These results suggest that both Ca(2+) channels and P62158 are involved in ginsenoside Rd biotransformation via regulation of β-glucosidase activity . This is the first report regarding the effects of calcium signal transduction on biotransformation and enzyme activity in fungi . Preliminary evidence of ethnic divergence in associations of putative genetic variants for methamphetamine dependence . Research into the biological processes that increase susceptibility to methamphetamine dependence has been conducted primarily in Asian populations . Using a case-control design this study 's purpose was to explore , among a population of methamphetamine-dependent Caucasians , six putative single nucleotide polymorphisms previously found to be associated with methamphetamine dependence in Asian populations . A total of 193 non-psychotic males ( 117 methamphetamine-dependent and 76 controls ) were genotyped for variants located in six genes ( P31749 , P32121 , P23560 , P21964 , P09211 , P35372 ) . Genotypic and allelic frequencies , odds ratios , and 95 % confidence intervals were calculated . None of the putative gene associations was significantly replicated in our sample of Caucasian men . Effect size comparisons suggest a trend toward allelic divergence for arrestin beta 2 ( P32121 ) and glutathione S-transferase P1 ( P09211 ) and allelic convergence for brain-derived neurotrophic factor ( P23560 ) . Results provide preliminary support for further exploration and validation of candidate single nucleotide polymorphisms ( SNPs ) for methamphetamine ( METH ) dependence reported among Asian populations across other ethnic/ancestral groups . DB03758 activates heat shock protein expression and cardioprotection in neonatal rat cardiomyocytes . Heat shock proteins ( HSPs ) constitute an endogenous cellular defense mechanism against environmental stresses . In the past few years , studies have shown that overexpression of HSPs can protect cardiac myocytes against ischemia-reperfusion injury . In an attempt to increase the HSPs in cardiac tissue , we used the compound radicicol that activates HSP expression by binding to the P08238 kDa ( HSP90 ) . HSP90 is the main component of the cytosolic molecular chaperone complex , which has been implicated in the regulation of the heat shock factor 1 ( Q00613 ) . Q00613 is responsible for the transcriptional activation of the heat shock genes . In the present study , we show that radicicol induces HSP expression in neonatal rat cardiomyocytes , and this increase in HSPs confers cardioprotection to these cardiomyocytes . We also show that radicicol induction of the HSP and cardioprotection is dependent on the inhibition of HSP90 in cardiomyocytes . These results indicate that modulation of the active HSP90 protein level plays an important role in cardioprotection . Therefore , compounds , such as radicicol and its possible derivatives that inhibit the function of HSP90 in the cell may represent potentially useful cardioprotective agents . P35372 and P20813 gene variants as risk factors in methadone-related deaths . DB00333 is a medication valued for its effectiveness in the treatment of heroin addiction ; however , many fatal poisonings associated with its use have been reported over the years . We have examined the association between P20813 and micro-opioid receptor ( P35372 ) gene variations and apparent susceptibility to methadone poisoning . Genomic DNA was extracted from postmortem whole blood of 40 individuals whose deaths were attributed to methadone poisoning . The presence of P20813 *4,*9 , and *6 alleles and the P35372 A118G variant was determined by SNP genotyping . P20813 *4 , *9 , and *6 alleles were found to be associated with higher postmortem methadone concentrations in blood ( P < or = 0.05 ) . P35372 A118G was also associated with higher postmortem methadone concentrations in blood but not to a level of statistical significance ( P = 0.39 ) . In these methadone-related deaths , P35372 118GA was associated with higher postmortem benzodiazepine concentrations ( P = 0.04 ) , a finding not associated with morphine-related deaths . The risk of a methadone-related fatality during treatment may be evaluated in part by screening for P20813 *6 and A118G . Interpretation of point-of-care INR results in patients treated with dabigatran . BACKGROUND : Point-of-care devices for measurement of the international normalized ratio ( INR ) are commonly used to monitor therapy and maintain therapeutic levels of anticoagulation in patients treated with vitamin K antagonists . DB06695 , a new oral , reversible direct thrombin inhibitor approved for stroke prevention in patients with atrial fibrillation does not require routine coagulation monitoring . However , case reports have identified falsely elevated point-of-care INR levels in patients treated with dabigatran using one of these devices ( Hemochron ) . This in vitro study was designed to verify this issue . METHODS : We compared INR levels in whole blood and plasma using a Hemochron Jr . Signature+ point-of-care device ( International Technidyne Corporation , Edison , NJ ) with routine laboratory monitoring , using blood from healthy volunteers that was spiked with increasing concentrations of dabigatran . RESULTS : P00734 time and INR levels were increased about 2- to 4-fold with the point-of-care device compared with laboratory measures across the plasma dabigatran concentration range 50-1400 ng/mL . At plasma concentrations of dabigatran likely to be observed in patients , at a dose of 150 mg twice daily ( 60-275 ng/mL ) , whole blood point-of-care INR values increased from 1.7 to 4.0 , versus 1.1 to 1.5 measured with the laboratory coagulometer . Similar differences in prothrombin time were observed in plasma samples . CONCLUSIONS : INR levels in patients taking dabigatran are substantially higher using a Hemochron Jr. point-of-care device compared with laboratory values . We discourage the use of these devices specifically , as well as the use of the INR in general , for measuring the anticoagulant effect of dabigatran . Dietary phytochemicals alter epigenetic events and signaling pathways for inhibition of metastasis cascade : phytoblockers of metastasis cascade . Cancer metastasis is a multistep process in which a cancer cell spreads from the site of the primary lesion , passes through the circulatory system , and establishes a secondary tumor at a new nonadjacent organ or part . Inhibition of cancer progression by dietary phytochemicals ( DPs ) offers significant promise for reducing the incidence and mortality of cancer . Consumption of DPs in the diet has been linked to a decrease in the rate of metastatic cancer in a number of preclinical animal models and human epidemiological studies . DPs have been reported to modulate the numerous biological events including epigenetic events ( noncoding micro-RNAs , histone modification , and DNA methylation ) and multiple signaling transduction pathways ( Wnt/β-catenin , Notch , Sonic hedgehog , P35354 , P00533 , MAPK- P29323 , JAK- P35610 , Akt/PI3K/ P42345 , NF-κB , AP-1 , etc. ) , which can play a key role in regulation of metastasis cascade . Extensive studies have also been performed to determine the molecular mechanisms underlying antimetastatic activity of DPs , with results indicating that these DPs have significant inhibitory activity at nearly every step of the metastatic cascade . DPs have anticancer effects by inducing apoptosis and by inhibiting cell growth , migration , invasion , and angiogenesis . Growing evidence has also shown that these natural agents potentiate the efficacy of chemotherapy and radiotherapy through the regulation of multiple signaling pathways . In this review , we discuss the variety of molecular mechanisms by which DPs regulate metastatic cascade and highlight the potentials of these DPs as promising therapeutic inhibitors of cancer . The analgesic efficacy of valdecoxib vs. oxycodone/acetaminophen after oral surgery . BACKGROUND : The authors conducted two studies to compare the analgesic efficacy and safety of the cyclooxygenase , or P36551 , -2-specific inhibitor , valdecoxib , with oxycodone/ acetaminophen in patients who have undergone oral surgery . METHODS : In total , 205 eligible subjects in Study A and 201 in Study B were randomized to receive a single oral dose of valdecoxib ( 20 or 40 milligrams ) , a combination of oxycodone 10 mg/acetaminophen 1,000 mg or placebo . Eligible subjects experienced moderate-to-severe pain within six hours of surgery during which two or more impacted third molars were extracted . Analgesic efficacy was assessed over 24 hours or until the patient required rescue analgesia . RESULTS : In both studies , subjects receiving either dose of valdecoxib experienced a rapid onset of analgesia and ( among those who received valdecoxib 40 mg ) a level of pain relief comparable with that of those who received oxycodone/ acetaminophen . Both valdecoxib doses had a significantly longer duration of analgesic effect than did oxycodone/acetaminophen . Pooled safety data demonstrated that each valdecoxib dose had a tolerability profile superior to that of oxycodone/ acetaminophen and similar to that of placebo . CONCLUSIONS : Orally administered valdecoxib is as rapidly acting and effective as oxycodone/acetaminophen , and it has a superior duration of analgesic effect in patients after oral surgery . DB00580 has a tolerability profile superior to that of oxycodone/acetaminophen . CLINICAL IMPLICATIONS : The current standard of care for alleviating acute pain after oral surgery has rested largely on conventional nonsteroidal anti-inflammatory drugs or opioid/analgesic combination products . The studies reported here suggest that the P35354 -specific inhibitor valdecoxib offers an efficacious and safe alternative to other analgesics used to treat pain after oral surgery . P62158 -mediated effects of loperamide on chloride transport by brush border membrane vesicles from human ileum . We investigated whether the synthetic opiate loperamide-HCl is able to regulate specific transport systems for sodium and chloride in brush border membrane vesicles ( BBMVs ) from human ileum and whether such activities are mediated by calcium/calmodulin . In BBMVs we studied Na+/H+ antiport , Cl+/OH- antiport , Na+/Cl- cotransport , and the Cl- conductive pathway . Brush border membrane vesicles were incubated with 10 microM loperamide over 4 h at 5 degrees C before the uptake experiments . In ileal BBMVs , loperamide stimulated intravesicular accumulation of Na+ in the presence of Cl- and vice versa . After 1 min of incubation , the stimulatory effect was 35 % +/- 5 % ( p less than 0.005 ) of the control without loperamide . DB00836 also stimulated Cl-/OH- antiport by 30 % +/- 5 % ( p less than 0.005 ) in BBMVs of ileum . In addition , we studied the role of Ca2+/calmodulin in the action of loperamide on chloride transport by human BBMVs . In loperamide-pretreated BBMVs , calmodulin activity was significantly decreased ( 12 +/- 2 vs. 38 +/- 4 pmol/mg protein ) . When loperamide-pretreated vesicles were incubated with 2 microM calcium ( free concentration ) plus 5 microM calmodulin for 1 h at 5 degrees C , complete inhibition of the stimulatory effect of loperamide on Cl-/OH- antiport and Na+/Cl- cotransport was observed . Increasing the Ca2+/calmodulin activity of loperamide-pretreated BBMVs with 2 microM calcium plus 5 microM calmodulin led to a significant inhibition of Cl-/OH- antiport and Na+/Cl- cotransport by 40 % +/- 5 % ( p less than 0.005 ) . DB01411 inhibits renal epithelial cyst progression via activation of AMP-activated protein kinase . Q9Y271 ( CysLT1 receptor ) antagonists were found to inhibit chloride secretion in human airway epithelial cells . Since chloride secretion in renal epithelial cells , which shares common mechanisms with airway epithelial cells , plays important roles in renal cyst progression in polycystic kidney disease ( Q15139 ) , this study was aimed to investigate effects of drugs acting as CysLT1 receptor antagonists on renal cyst progression and its underlying mechanisms . Effects of CysLT1 receptor antagonists on renal cyst growth and formation were determined using Madine Darby canine kidney ( MDCK ) cyst models . Mechanisms of actions of CysLT1 receptor antagonists were determined using short-circuit current measurement , assays of cell viability and cell proliferation , and immunoblot analysis of signaling proteins . Of the three drugs acting as CysLT1 receptor antagonists ( montelukast , pranlukast and zafirlukast ) tested , pranlukast was the most promising drug that inhibited MDCK cyst growth and formation without affecting cell viability . Its effect was independent of the inhibition of CysLT1 receptors . Instead , it reduced DB02527 -activated chloride secretion and proliferation of MDCK cells in an AMP-activated protein kinase ( AMPK ) -dependent manner and had no effect on P13569 protein expression . Interestingly , pranlukast enhanced AMPK activation via calcium/calmodulin-dependent protein kinase kinase beta ( CaMKKβ ) with consequent activation of acetyl- DB01992 carboxylase ( ACC ) and suppression of mammalian target of rapamycin ( P42345 ) pathway . These results indicate that pranlukast retards renal epithelial cyst progression by inhibiting DB02527 -activated chloride secretion and cell proliferation via CaMKKβ-AMPK- P42345 pathway . Therefore , pranlukast represents a class of known drugs that may have potential utility in Q15139 treatment . Association between P29274 and P14416 polymorphisms and caffeine-induced anxiety . Caffeine produces mild psychostimulant and sometimes anxiogenic effects by antagonizing adenosine at A(1) and A(2A) receptors , and perhaps through interactions with other transmitter systems . DB00640 receptors are colocalized and functionally interact with dopamine receptors in the brain . Thus , functional polymorphisms in the genes for either adenosine or dopamine receptors may affect responses to caffeine . In this study , we examined associations between self-reported anxiogenic effects of caffeine and variation in the genes for A(2A) ( P29274 ) and DRD(2) ( P14416 ) receptors . Healthy male and female individuals ( n=102 ) , who consumed less than 300 mg caffeine per week , ingested capsules containing 0 , 50 , 150 , and 450 mg caffeine under double-blind conditions in four separate experimental sessions . Subjective anxiety was measured before and at repeated times after capsules were consumed . At the 150 mg dose of caffeine , we found a significant association between caffeine-induced anxiety ( Visual Analog Scales , VAS ) and P29274 rs5751876 ( 1976C/T ) , rs2298383 ( intron 1a ) and rs4822492 ( 3'-flank ) , and P14416 rs1110976 ( intron 6 ) . Caffeine-induced anxiety ( VAS ) was also associated with two-loci interactions of selected P29274 and P14416 polymorphisms . The lowest dose of caffeine did not increase ratings of anxiety while the highest dose increased anxiety in the majority of subjects . These findings provide support for an association between an P29274 polymorphism and self-reported anxiety after a moderate dose of caffeine . It is likely that other P29274 and P14416 polymorphisms also contribute to responses to caffeine . Anti-inflammatory activity of Taraxacum officinale . Taraxacum officinale has been widely used as a folkloric medicine for the treatment of diverse diseases . The dried plant was extracted with 70 % ethanol to generate its ethanol extract ( TEE ) . For some experiments , ethyl acetate ( EA ) , n-butanol ( BuOH ) and aqueous ( Aq ) fractions were prepared in succession from TEE . TEE showed a scavenging activity in the 1,1-diphenyl-2-picrylhydrazyl ( DPPH ) assay , a diminishing effect on intracellular reactive oxygen species ( ROS ) level , and an anti-angiogenic activity in the chicken chorioallantoic ( P62158 ) assay . In the carrageenan-induced air pouch model , TEE inhibited production of exudate , and significantly diminished nitric oxide ( NO ) and leukocyte levels in the exudate . It also possessed an inhibitory effect on acetic acid-induced vascular permeability and caused a dose-dependent inhibition on acetic acid-induced abdominal writhing in mice . Suppressive effects of TEE on the production of NO and expression of inducible nitric oxide synthase ( P35228 ) and cyclooxygenase-2 ( P35354 ) in lipopolysaccharide ( LPS ) -stimulated macrophages were also assessed . Among the fractions , the n-butanol fraction ( BuOH ) was identified to be most effective in the P62158 assay . Collectively , Taraxacum officinale contains anti-angiogenic , anti-inflammatory and anti-nociceptive activities through its inhibition of NO production and P35354 expression and/or its antioxidative activity . LG839 : anti-obesity effects and polymorphic gene correlates of reward deficiency syndrome . INTRODUCTION : This study systematically assessed the weight management effects of a novel experimental DNA-customized nutraceutical , LG839 ( LifeGen , Inc. , La Jolla , CA , USA ) . METHODS : A total of 1058 subjects who participated in the overall D.I.E.T. study were genotyped and administered an LG839 variant based on polymorphic outcomes . A subset of 27 self-identified obese subjects of Dutch descent , having the same DNA pattern of four out of the five candidate genes tested ( chi-square analysis ) as the entire data set , was subsequently evaluated . Simple t tests comparing a number of weight management parameters before and after 80 days of treatment with LG839 were performed . RESULTS : Significant results were observed for weight loss , sugar craving reduction , appetite suppression , snack reduction , reduction of late night eating ( all P < 0.01 ) , increased perception of overeating , enhanced quality of sleep , increased happiness ( all P < 0.05 ) , and increased energy ( P < 0.001 ) . Polymorphic correlates were obtained for a number of genes ( P41159 , Q07869 -gamma2 , P42898 , 5- Q13049 , and P14416 genes ) with positive clinical parameters tested in this study . Of all the outcomes and gene polymorphisms , only the P14416 gene polymorphism ( A1 allele ) had a significant Pearson correlation with days on treatment ( r=0.42 , P=0.045 ) . CONCLUSION : If these results are confirmed in additional rigorous , controlled studies , we carefully suggest that DNA-directed targeting of certain regulator genes , along with customized nutraceutical intervention , provides a unique framework and strategic modality to combat obesity . Inhibition of Akt/ P31749 by a P35354 inhibitor induces apoptosis in gastric cancer cells . BACKGROUND/AIM : Inhibition of cyclooxygenase-2 has been proposed to be a potential mechanism for the chemoprevention of gastrointestinal tumors by nonsteroidal anti-inflammatory drugs . This study investigates the mechanisms by which the cyclooxygenase-2 inhibitor SC236 induces apoptosis of gastric cancer cell lines and its downstream signaling pathway . METHODS : Two gastric cancer cell lines , AGS and MKN28 , were treated with SC236 and assessed for cell growth and apoptosis . The involvement of mitogen-activated protein kinase and Akt kinase/protein kinase B ( Akt/ P31749 ) pathways and their downstream signalings were studied in the AGS cell line . RESULTS : SC236 treatment induced apoptosis in gastric cancer cells and caused activation of p38 and stress-activated protein kinase/jun kinase , but down-regulated Akt/ P31749 . The specific p38 inhibitor SB203580 and the dominant-negative stress-activated protein kinase/jun kinase both failed , while the constitutively active form of Akt/ P31749 was able to block SC236-induced apoptosis . SC236-induced apoptosis was coupled with release of cytochrome c and activation of caspases . CONCLUSION : One of the pathways involved in SC-236-induced apoptosis in gastric cancer cells is through downregulation of Akt and then release of cytochrome c .