MH_dev_7

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-β 1 ( TGF-β 1 ) , cyclooxygenase - 2 ( P35354 REA ) , peroxisome proliferator-activated receptor-γ ( Q07869 REA - 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-β 1 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 REA ( P < 0.05 ) compared with hydrolysate treated with corolase for only 10 min whereas transcription of Q07869 REA - 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-β 1 , P35354 REA , and NFκB .

P00734 REA 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 REA ) , cyclooxygenase - 2 ( P35354 REA ) 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 REA inhibitor DuP - 697 . P27361 REA / 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 REA , P35354 REA 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 REA and P35354 REA 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 REA ) and cyclooxygenase - 2 ( P35354 REA ) inhibitors , and more recently selective P35354 REA inhibitors . This study was designed to identify and quantify P23219 REA and P35354 REA gene expression level in inflamed rat molar pulps after administration of three NSAIDs : DB00482 , Vioxx , and DB01050 SUB . 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 REA and P35354 REA mRNA . Statistical analysis demonstrated no significant differences in P23219 REA and P35354 REA levels among the drug groups . However , Vioxx and DB01050 SUB significantly reduced P35354 REA 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 MEN , a genetically engineered fusion protein combining the enzymatically active domains of diphtheria toxin and the full-length sequence for interleukin - 2 ( P60568 REA ) , efficiently targets lymphoma cells expressing the high-affinity P60568 REA receptor ( IL - 2R ) consisting of the alpha / p55 / CD25 , beta / p75 / CD122 , and gamma / P31785 REA / 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 REA 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 SUB ) 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 REA is considered the central regulator of heat-induced transcriptional responses . The main targets for Q00613 REA 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 REA was recently hypothesized to play a more complex role , regulating the expression of non-HSP genes ; however , the non-canonical role of Q00613 REA is still poorly understood . Herein we report that heat-stress promotes the expression of cyclooxygenase - 2 ( P35354 REA ) , 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 REA expression is regulated at the transcriptional level via Q00613 REA - mediated signaling and identify , by in-vitro reporter gene activity assay and deletion-mutant constructs analysis , the P35354 REA 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 REA is recruited to the P35354 REA promoter rapidly after heat treatment ; by using shRNA-mediated Q00613 REA suppression and HSE-deletion from the P35354 REA promoter , we demonstrate that Q00613 REA plays a central role in the transcriptional control of P35354 REA by heat . Finally , P35354 REA transcription is also induced at febrile temperatures in endothelial cells , suggesting that Q00613 REA - dependent P35354 REA expression could contribute to increasing blood prostaglandin levels during fever . The results identify P35354 REA as a human non-classical heat-responsive gene , unveiling a new aspect of Q00613 REA 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 REA , IFNgamma ) , proinflammatory mediators ( IL - 1beta , TNFalpha , P05231 REA , P35354 REA ) , and adhesion molecule . Shorter CO exposure in early ( 0-13 d ) and late ( 14-28 d ) 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 MEN . 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 REA , P32121 REA , P23560 REA , P21964 REA , P09211 REA , P35372 REA ) . 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 REA ) and glutathione S-transferase P1 ( P09211 REA ) and allelic convergence for brain-derived neurotrophic factor ( P23560 REA ) . 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 MEN 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 REA kDa ( HSP 90 ) . HSP 90 is the main component of the cytosolic molecular chaperone complex , which has been implicated in the regulation of the heat shock factor 1 ( Q00613 REA ) . Q00613 REA 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 HSP 90 in cardiomyocytes . These results indicate that modulation of the active HSP 90 protein level plays an important role in cardioprotection . Therefore , compounds , such as radicicol and its possible derivatives that inhibit the function of HSP 90 in the cell may represent potentially useful cardioprotective agents .

P35372 REA and P20813 REA gene variants as risk factors in methadone-related deaths . DB00333 MEN 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 REA and micro-opioid receptor ( P35372 REA ) 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 REA * 4 , * 9 , and * 6 alleles and the P35372 REA A118G variant was determined by SNP genotyping . P20813 REA * 4 , * 9 , and * 6 alleles were found to be associated with higher postmortem methadone concentrations in blood ( P < or = 0.05 ) . P35372 REA 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 REA 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 REA * 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 MENMAX DB06695 MEN , 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 REA 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 REA , P00533 REA , MAPK - P29323 REA , JAK - P35610 REA , Akt / PI3K / P42345 REA , 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 REA , - 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 MEN 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 REA - 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 MEN 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 MEN inhibits renal epithelial cyst progression via activation of AMP-activated protein kinase . Q9Y271 REA ( CysLT 1 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 REA ) , this study was aimed to investigate effects of drugs acting as CysLT 1 receptor antagonists on renal cyst progression and its underlying mechanisms . Effects of CysLT 1 receptor antagonists on renal cyst growth and formation were determined using Madine Darby canine kidney ( MDCK ) cyst models . Mechanisms of actions of CysLT 1 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 CysLT 1 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 CysLT 1 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 REA 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 REA ) pathway . These results indicate that pranlukast retards renal epithelial cyst progression by inhibiting DB02527 - activated chloride secretion and cell proliferation via CaMKKβ-AMPK - P42345 REA pathway . Therefore , pranlukast represents a class of known drugs that may have potential utility in Q15139 REA treatment .

Association between P29274 REA and P14416 REA 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 MEN 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 REA ) and DRD ( 2 ) ( P14416 REA ) 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 REA rs5751876 ( 1976C / T ) , rs2298383 ( intron 1a ) and rs4822492 ( 3 ' - flank ) , and P14416 REA rs1110976 ( intron 6 ) . Caffeine-induced anxiety ( VAS ) was also associated with two-loci interactions of selected P29274 REA and P14416 REA 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 REA polymorphism and self-reported anxiety after a moderate dose of caffeine . It is likely that other P29274 REA and P14416 REA 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 REA ) and cyclooxygenase - 2 ( P35354 REA ) 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 REA 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 REA , Q07869 REA - gamma 2 , P42898 REA , 5 - Q13049 REA , and P14416 REA genes ) with positive clinical parameters tested in this study . Of all the outcomes and gene polymorphisms , only the P14416 REA 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 REA by a P35354 REA 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 MKN 28 , 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 REA ) 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 REA . 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 REA 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 .