MH_dev_144

A diarylheptanoid from lesser galangal ( Alpinia officinarum ) inhibits proinflammatory mediators via inhibition of mitogen-activated protein kinase , Q8TCB0 / 42 , and transcription factor nuclear factor-kappa B . The diarylheptanoid 7 - ( 4 ' - hydroxy - 3 ' - methoxyphenyl ) - 1 - phenylhept - 4 - en - 3 - one ( Q16891 REA ) is a naturally occurring phytochemical found in lesser galangal ( Alpinia officinarum ) . In the present study , we have demonstrated the anti-inflammatory properties of this compound on mouse macrophage cell line ( RAW 264.7 ) and human peripheral blood mononuclear cells ( PBMCs ) in vitro . Treatment of RAW 264.7 cells with Q16891 REA ( 6.25- 25 microM ) significantly inhibited lipopolysaccharide ( LPS ) - stimulated nitric oxide ( NO ) production . This compound also inhibited the release of LPS-induced proinflammatory cytokines interleukin - 1 beta ( P01584 REA ) and tumor necrosis factor-alpha ( P01375 REA ) from human PB-MCs in vitro . In addition , Western blotting and reverse transcription-polymerase chain reaction analysis demonstrated that Q16891 REA decreased LPS-induced inducible nitric-oxide synthase ( P35228 REA ) and cyclooxygenase - 2 ( P35354 REA ) protein and mRNA expression in RAW 264.7 cells . Furthermore , Q16891 REA treatment also reduced nuclear factor-kappa B ( NF-kappa B ) DNA binding induced by LPS in RAW 264.7 cells . To elucidate the molecular mechanism for inhibition of proinflammatory mediators by Q16891 REA ( 25 microM ) , we have studied the effect of Q16891 REA on LPS-induced p38 and Q8TCB0 / 42 mitogen-activated protein kinase ( MAPK ) . We observed that the phosphorylation of Q8TCB0 / 42 MAPK in LPS-stimulated RAW 264.7 cells was markedly inhibited by Q16891 REA , whereas activation of p38 MAPK was not affected . These results suggested that Q16891 REA from lesser galangal suppressed the LPS-induced production of NO , P01584 REA , and P01375 REA and expression of P35228 REA and P35354 REA gene expression by inhibiting NF-kappa B activation and phosphorylation of Q8TCB0 / 42 MAPK .

Methodological challenges in monitoring new treatments for rare diseases : lessons from the cryopyrin-associated periodic syndrome registry . BACKGROUND : The Q96P20 REA - Associated Periodic Syndromes ( CAPS ) are a group of rare hereditary autoinflammatory diseases and encompass Familial Cold Autoinflammatory Syndrome ( FCAS ) , Muckle-Wells Syndrome ( MWS ) , and Neonatal Onset Multisystem Inflammatory Disease ( NOMID ) . DB06168 SUB is a monoclonal antibody directed against P01584 REA and approved for CAPS patients but requires post-approval monitoring due to low and short exposures during the licensing process . Creative approaches to observational methodology are needed , harnessing novel registry strategies to ensure Health Care Provider reporting and patient monitoring . METHODS : A web-based registry was set up to collect information on long-term safety and effectiveness of canakinumab for CAPS . RESULTS : Starting in November 2009 , this registry enrolled 241 patients in 43 centers and 13 countries by December 31 , 2012 . One-third of the enrolled population was aged < 18 ; the overall population is evenly divided by gender . Enrolment is ongoing for children . CONCLUSIONS : Innovative therapies in orphan diseases require post-approval structures to enable in depth understanding of safety and natural history of disease . The rarity and distribution of such diseases and unpredictability of treatment require innovative methods for enrolment and follow-up . Broad international practice-based recruitment and web-based data collection are practical .

Effect of canagliflozin on renal threshold for glucose , glycemia , and body weight in normal and diabetic animal models . BACKGROUND : DB08907 MEN is a sodium glucose co-transporter ( SGLT ) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus ( T2DM ) . METHODS : ( 14 ) C-alpha-methylglucoside uptake in Chinese hamster ovary-K cells expressing human , rat , or mouse SGLT 2 or P13866 REA ; ( 3 ) H - 2 - deoxy-d-glucose uptake in Q9BTT4 myoblasts ; and 2 - electrode voltage clamp recording of oocytes expressing human SGLT 3 were analyzed . Graded glucose infusions were performed to determine rate of urinary glucose excretion ( UGE ) at different blood glucose ( BG ) concentrations and the renal threshold for glucose excretion ( RT ( G ) ) in vehicle or canagliflozin-treated Zucker diabetic fatty ( ZDF ) rats . This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity . RESULTS : Treatment with canagliflozin 1 mg / kg lowered RT ( G ) from 415 ± 12 mg / dl to 94 ± 10 mg / dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RT ( G ) . DB08907 MEN dose-dependently decreased BG concentrations in db / db mice treated acutely . In ZDF rats treated for 4 weeks , canagliflozin decreased glycated hemoglobin ( HbA 1c ) and improved measures of insulin secretion . In obese animal models , canagliflozin increased UGE and decreased BG , body weight gain , epididymal fat , liver weight , and the respiratory exchange ratio . CONCLUSIONS : DB08907 MEN lowered RT ( G ) and increased UGE , improved glycemic control and beta-cell function in rodent models of T2DM , and reduced body weight gain in rodent models of obesity .

A case study of acenocoumarol sensitivity and genotype-phenotype discordancy explained by combinations of polymorphisms in Q9BQB6 and P11712 REA . To determine the cause of a genotype-phenotype discordancy for acenocoumarol sensitivity . Methods A patient , highly sensitive to acenocoumarol , and previously determined to carry only a single P11712 REA * 3 allele , was genotyped for additional functionally defective alleles in the P11712 REA and Q9BQB6 genes . Family members were also analyzed to trace the pedigree . Results The acenocoumarol-sensitive patient was found to possess , in addition to P11712 REA * 3 allele , a P11712 REA * 11 allele and the Q9BQB6 AA diplotype which were all traced back through the parental lines . Conclusions DB01418 MEN sensitivity in this subject is the consequence of inheritance of multiple functionally defective alleles in both the P11712 REA and Q9BQB6 genes . The study provides additional data in support of diminished P11712 REA activity due to the presence of the rare * 11 allele .

[ 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 MEN ) 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 .

Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene-environment studies on cancer : data from population-based Japanese random samples . Knowledge of genetic polymorphisms in gene-environment studies may contribute to more accurate identification of avoidable risks and to developing tailor-made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene-environment studies on cancer in Japan . SNP typing was performed on middle-aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 REA , Q16678 REA , P11712 REA , P33261 REA , P05181 REA , P05093 REA , P11511 REA , P35869 REA , P03372 REA , Q92731 REA , ERRRG , P06401 REA , P07099 REA , P34913 REA , P37059 REA , P37058 REA , P28161 REA , P21266 REA , GSTT 2 , P09211 REA , NAT 1 , NAT 2 , P21964 REA , P07327 REA , P00325 REA , P00326 REA , P05091 REA , P35228 REA , NOS 3 , P01583 REA , P01584 REA , O15527 REA , P36639 REA [ P36639 REA ] , P14416 REA , P35462 REA , P21917 REA , P31645 REA , P04150 REA [ GCCR ] , P42898 REA , and P15559 REA . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .

Erosive arthritis and hepatic granuloma formation induced by peptidoglycan polysaccharide in rats is aggravated by prasugrel treatment . Administration of the thienopyridine Q9H244 REA receptor antagonist , clopidogrel , increased the erosive arthritis induced by peptidoglycan polysaccharide ( PG-PS ) in rats or by injection of the arthritogenic K / BxN serum in mice . To determine if the detrimental effects are caused exclusively by clopidogrel , we evaluated prasugrel , a third-generation thienopyridine pro-drug , that contrary to clopidogrel is mostly metabolized into its active metabolite in the intestine . Prasugrel effects were examined on the PG-PS-induced arthritis rat model . Erosive arthritis was induced in Lewis rats followed by treatment with prasugrel for 21 days . Prasugrel treated arthritic animals showed a significant increase in the inflammatory response , compared with untreated arthritic rats , in terms of augmented macroscopic joint diameter associated with significant signs of inflammation , histomorphometric measurements of the hind joints and elevated platelet number . Moreover , fibrosis at the pannus , assessed by immunofluorescence of connective tissue growth factor , was increased in arthritic rats treated with prasugrel . In addition to the arthritic manifestations , hepatomegaly , liver granulomas and giant cell formation were observed after PG-PS induction and even more after prasugrel exposure . Cytokine plasma levels of P01584 REA , P05231 REA , MIP 1 alpha , MCP 1 , Q16552 REA and RANTES were increased in arthritis-induced animals . P22301 REA plasma levels were significantly decreased in animals treated with prasugrel . Overall , prasugrel enhances inflammation in joints and liver of this animal model . Since prasugrel metabolites inhibit neutrophil function ex-vivo and the effects of both clopidogrel and prasugrel metabolites on platelets are identical , we conclude that the thienopyridines metabolites might exert non-platelet effects on other immune cells to aggravate inflammation .

DB00819 MEN inhibits osmotic water permeability by interaction with aquaporin - 1 . DB09145 channel proteins , known as aquaporins , are transmembrane proteins that mediate osmotic water permeability . In a previous study , we found that acetazolamide could inhibit osmotic water transportation across Xenopus oocytes by blocking the function of aquaporin - 1 ( P29972 REA ) . The purpose of the current study was to confirm the effect of acetazolamide on water osmotic permeability using the human embryonic kidney 293 ( HEK 293 ) cells transfected with pEGFP / P29972 REA and to investigate the interaction between acetazolamide and P29972 REA . The fluorescence intensity of HEK 293 cells transfected with pEGFP / P29972 REA , which corresponds to the cell volume when the cells swell in a hyposmotic solution , was recorded under confocal laser fluorescence microscopy . The osmotic water permeability was assessed by the change in the ratio of cell fluorescence to certain cell area . DB00819 MEN , at concentrations of 1 and 10muM , inhibited the osmotic water permeability in HEK 293 cells transfected with pEGFP / P29972 REA . The direct binding between acetazolamide and P29972 REA was detected by surface plasmon resonance . P29972 REA was prepared from rat red blood cells and immobilized on a CM5 chip . The binding assay showed that acetazolamide could directly interact with P29972 REA . This study demonstrated that acetazolamide inhibited osmotic water permeability through interaction with P29972 REA .

DB00501 MEN induces interleukin - 18 production through H2 - agonist activity in monocytes . The present study demonstrates a possible mechanism for the improvement of gastrointestinal cancer patients ' prognosis by the histamine receptor type 2 ( P25021 REA ) antagonist cimetidine . This agent , but not the P25021 REA antagonists ranitidine and famotidine , induced the production of an antitumor cytokine , interleukin ( IL ) - 18 , by human monocytes and dendritic cells ( DC ) . In fact , ranitidine and famotidine antagonized cimetidine-induced Q14116 REA production . DB00501 MEN induced the activation of caspase - 1 , which is reported to modify immature Q14116 REA to mature / active Q14116 REA , and the elevation of intracellular DB02527 , leading to the activation of protein kinase A ( PKA ) . The PKA inhibitor H89 abolished the Q14116 REA production induced by cimetidine . Moreover , the effects of cimetidine on Q14116 REA production were reproduced in peripheral blood mononuclear cells from wild-type mice , but not in those from P25021 REA knockout mice . In conclusion , cimetidine , a partial agonist for P25021 REA , has a pharmacological profile different from ranitidine and famotidine , possibly contributing to its antitumor activity on gastrointestinal cancers .

Molecular discrimination of responders and nonresponders to anti - P01375 REA alpha therapy in rheumatoid arthritis by etanercept . INTRODUCTION : About 30 % of rheumatoid arthritis patients fail to respond adequately to TNFalpha-blocking therapy . There is a medical and socioeconomic need to identify molecular markers for an early prediction of responders and nonresponders . METHODS : RNA was extracted from peripheral blood mononuclear cells of 19 rheumatoid arthritis patients before the first application of the TNFalpha blocker etanercept as well as after 72 hours . Clinical response was assessed over 3 months using the 28 - joint-count Disease Activity Score and X-ray scans . Supervised learning methods were applied to Affymetrix Human Genome U133 microarray data analysis to determine highly selective discriminatory gene pairs or triplets with prognostic relevance for the clinical outcome evinced by a decline of the 28 - joint-count Disease Activity Score by 1.2 . RESULTS : Early downregulation of expression levels secondary to TNFalpha neutralization was associated with good clinical responses , as shown by a decline in overall disease activity 3 months after the start of treatment . Informative gene sets include genes ( for example , P25963 REA , P13236 REA , P10145 REA , P01584 REA , P21580 REA , Q07343 REA , O75807 REA and P35318 REA ) involved in different pathways and cellular processes such as TNFalpha signalling via NFkappaB , NFkappaB-independent signalling via DB02527 , and the regulation of cellular and oxidative stress response . Pairs and triplets within these genes were found to have a high prognostic value , reflected by prediction accuracies of over 89 % for seven selected gene pairs and of 95 % for 10 specific gene triplets . CONCLUSION : Our data underline that early gene expression profiling is instrumental in identifying candidate biomarkers to predict therapeutic outcomes of anti-TNFalpha treatment regimes .

Inflammasomes and host defenses against bacterial infections . The inflammasome has emerged as an important molecular protein complex which initiates proteolytic processing of pro-IL - 1β and pro - Q14116 REA into mature inflammatory cytokines . In addition , inflammasomes initiate pyroptotic cell death that may be independent of those cytokines . Inflammasomes are central to elicit innate immune responses against many pathogens , and are key components in the induction of host defenses following bacterial infection . Here , we review recent discoveries related to Q9C000 REA , Q96P20 REA , Q9NPP4 , P59044 , Q8WX94 , P59046 and O14862 REA - mediated recognition of bacteria . Mechanisms for inflammasome activation and regulation are now suggested to involve kinases such as P19525 REA and PKCδ , ligand binding proteins such as the NAIPs , and caspase - 11 and caspase - 8 in addition to caspase - 1 . Future research will determine how specific inflammasome components pair up in optimal responses to specific bacteria .

Salacia oblonga extract increases glucose transporter 4 - mediated glucose uptake in Q9BTT4 rat myotubes : role of mangiferin . BACKGROUND AND AIMS : To evaluate if the antidiabetic properties of Salacia oblonga extract are mediated not only by inhibiting intestinal alpha-glycosidases but also by enhancing glucose transport in muscle and adipose cells . METHODS : S . oblonga extract effects on 2 - deoxy-D-glucose uptake were assayed in muscle Q9BTT4 - myotubes and 3T3 - adipocytes . In Q9BTT4 - myotubes , the amount and translocation of glucose transporters were assayed . A fractionation of the extract was carried out to identify the active compounds . Furthermore , we analyzed the phosphorylation status of key components of signaling pathways that are involved in the molecular mechanisms regulating glucose uptake . RESULTS : S . oblonga extract increased 2 - deoxy-D-glucose uptake by 50 % in Q9BTT4 - myotubes and 3T3 - adipocytes . In Q9BTT4 - myotubes , the extract increased up to a 100 % the P14672 REA content , activating P14672 REA promoter transcription and its translocation to the plasma membrane . Mangiferin was identified as the bioactive compound . Furthermore , mangiferin effects were concomitant with the phosphorylation of DB00131 - activated protein kinase without the activation of P31749 REA / Akt . The effect of mangiferin on 2 - deoxy-D-glucose uptake was blocked by GW9662 , an irreversible P37231 REA antagonist . CONCLUSIONS : S . oblonga extract and mangiferin may exert their antidiabetic effect by increasing P14672 REA expression and translocation in muscle cells . These effects are probably mediated through two independent pathways that are related to DB00131 - activated protein kinase and P37231 REA .

Critical role of aquaporins in interleukin 1β ( IL - 1β ) - induced inflammation . Rapid changes in cell volume characterize macrophage activation , but the role of water channels in inflammation remains unclear . We show here that , in vitro , aquaporin ( AQP ) blockade or deficiency results in reduced IL - 1β release by macrophages activated with a variety of Q96P20 REA activators . Inhibition of AQP specifically during the regulatory volume decrease process is sufficient to limit IL - 1β release by macrophages through the Q96P20 REA inflammasome axis . The immune-related activity of AQP was confirmed in vivo in a model of acute lung inflammation induced by crystals . P29972 REA deficiency is associated with a marked reduction of both lung IL - 1β release and neutrophilic inflammation . We conclude that AQP-mediated water transport in macrophages constitutes a general danger signal required for Q96P20 REA - related inflammation . Our findings reveal a new function of AQP in the inflammatory process and suggest a novel therapeutic target for anti-inflammatory therapy .

Cross-talk between PKA-Cβ and p65 mediates synergistic induction of Q07343 REA by roflumilast and NTHi . Phosphodiesterase 4B ( Q07343 REA ) plays a key role in regulating inflammation . DB01656 MENMAX DB01656 MEN , a phosphodiesterase ( PDE ) 4 - selective inhibitor , has recently been approved for treating severe chronic obstructive pulmonary disease ( P48444 REA ) patients with exacerbation . However , there is also clinical evidence suggesting the development of tachyphylaxis or tolerance on repeated dosing of roflumilast and the possible contribution of Q07343 REA up-regulation , which could be counterproductive for suppressing inflammation . Thus , understanding how Q07343 REA is up-regulated in the context of the complex pathogenesis and medications of P48444 REA may help improve the efficacy and possibly ameliorate the tolerance of roflumilast . Here we show that roflumilast synergizes with nontypeable Haemophilus influenzae ( NTHi ) , a major bacterial cause of P48444 REA exacerbation , to up-regulate PDE 4B2 expression in human airway epithelial cells in vitro and in vivo . Up-regulated PDE 4B2 contributes to the induction of certain important chemokines in both enzymatic activity-dependent and activity-independent manners . We also found that protein kinase A catalytic subunit β ( PKA-Cβ ) and nuclear factor-κB ( NF-κB ) p65 subunit were required for the synergistic induction of PDE 4B2 . PKA-Cβ phosphorylates p65 in a DB02527 - dependent manner . Moreover , Ser 276 of p65 is critical for mediating the PKA-Cβ-induced p65 phosphorylation and the synergistic induction of PDE 4B2 . Collectively , our data unveil a previously unidentified mechanism underlying synergistic up-regulation of PDE 4B2 via a cross-talk between PKA-Cβ and p65 and may help develop new therapeutic strategies to improve the efficacy of DB05876 inhibitor .

Characterization of the aggregation responses of camel platelets . BACKGROUND : Despite evidence of active hemostasis , camel platelets barely respond to common aggregating agents at standard doses used for human platelet aggregation . OBJECTIVES : The purpose of the study was to find out whether camel platelets can be activated by high doses or combinations of aggregation agonists , and to characterize the receptor that mediates the aggregation response to adenosine diphosphate ( ADP ) , the most potent agonist for camel platelets known so far . METHODS : Aggregation studies were performed with platelet-rich plasma ( PRP ) in response to multiple doses or combinations of ADP , epinephrine ( P08473 REA ) , collagen , and arachidonic acid ( AA ) . Aggregation responses to ADP were performed before and after the addition of the ADP receptor ( Q9H244 REA ) antagonist DB00758 MEN . RESULTS : Camel platelets responded to ADP at doses higher than the standard dose for human platelets , and to combinations of P08473 REA and other agonists , while no aggregation was elicited with P08473 REA or AA alone . DB00758 MEN blocked the ADP-induced aggregation responses in a dose-dependent fashion in vitro . CONCLUSIONS : Camel platelet aggregation can be activated by increasing the dose of some agonists such as ADP , but not AA or P08473 REA . Irreversible aggregation of camel platelets could also be triggered by a combination of P08473 REA and ADP , and collagen and AA . Inhibition with clopidogrel suggests that camel platelets express the ADP receptor , Q9H244 REA . Understanding platelet function in camels will add to the understanding of platelet function in health and disease .

Estradiol or genistein prevent Alzheimer ' s disease-associated inflammation correlating with an increase Q07869 REA gamma expression in cultured astrocytes . Inflammation has been implicated in neurodegenerative disorders such as Alzheimer ' s disease ( AD ) . The main inflammatory players in AD are the glial cells which initiate the inflammatory response . One of the earliest neuropathological changes in AD is the accumulation of astrocytes at sites of A beta deposition . It is desirable to find methods of tipping the balance towards anti-inflammatory state . Estrogenic compounds have shown anti-inflammatory and also antioxidant activity . Astrocytes were pretreated with 17 - beta estradiol or with genistein , and 48 h later treated with 5 microM amyloid beta ( A beta ) for 24 h . We found that A beta induces inflammatory mediators , such as cyclooxygenase 2 ( P35354 REA ) , inducible nitric oxide synthase ( P35228 REA ) , interleukin 1 beta ( P01584 REA ) and tumor necrosis factor alpha ( P01375 REA ) . All these effects were prevented when cells were pretreated with estradiol or genistein , demonstrating anti-inflammatory effects of estradiol or genistein in astrocytes in primary culture . The A beta-stimulated expression of pro-inflammatory genes in cells is antagonized by the action of the PPARs ( peroxisome proliferator activated receptors ) . Here we detected an increase in P37231 REA expression in astrocytes in primary culture treated with A beta and estradiol or soy isoflavone genistein . Thus , some of the anti-inflammatory effects of estrogenic compounds may be mediated and activated by PPARs suppressing a diverse array of inflammatory responses caused by A beta in astrocytes in primary culture .