MH_dev_48

P00797 REA angiotensin system modulates P42345 REA pathway through AT2R in HIVAN . P42345 REA ( P42345 REA ) has been reported to contribute to the development of HIV-associated nephropathy ( HIVAN ) . We hypothesized that HIV may be activating renal tissue P42345 REA pathway through renin angiotensin system ( DB01367 ) via Angiotensin Receptor Type II receptor ( AT2R ) . Renal tissues of Vpr transgenic and Tg26 ( HIVAN ) mice displayed enhanced phosphorylation of P42345 REA and p70S6K . DB09026 MEN , a renin inhibitor attenuated phosphorylation of both P42345 REA and p70S6K in renal tissues of HIVAN mice . Interestingly , Angiotensin Receptor Type I ( AT1R ) blockade did not modulate renal tissue phosphorylation of P42345 REA in HIVAN mice ; on the other hand , AT2R blockade attenuated renal tissue phosphorylation of P42345 REA in HIVAN mice . In vitro studies , both renin and Ang II displayed enhanced mouse tubular cell ( P04629 REA ) phosphorylation of p70S6K in a dose dependent manner . HIV / P04629 REA also displayed enhanced phosphorylation of both P42345 REA and p70S6K ; interestingly this effect of HIV was further enhanced by losartan ( an AT1R blocker ) . On the other hand , AT2R blockade attenuated HIV-induced tubular cell phosphorylation of P42345 REA and p70S6K , whereas , AT2R agonist enhanced phosphorylation of P42345 REA and p70S6K . These findings indicate that HIV stimulates P42345 REA pathway in HIVAN through the activation of renin angiotensin system via AT2R .

First report of warfarin dose requirements in patients possessing the P11712 REA * 12 allele . BACKGROUND : DB00682 MENMAX DB00682 MEN is the most frequently prescribed anticoagulant in North America and Europe . It is administered as a racemate , but S-warfarin is principally responsible for its anticoagulant activity . Cytochrome P450 ( CYP ) 2C9 is the enzyme primarily responsible for the metabolism of S-warfarin . Numerous variant alleles of P11712 REA have been identified . The P11712 REA * 12 ( rs9332239 ) allele harbors a P489S substitution in P11712 REA which has been shown to result in a 40 % decline in catalytic activity in vitro . CASES : Four Caucasian patients with a low mean weekly warfarin dose ( MWWD ) were genotyped for P11712 REA , Q9BQB6 and P02649 REA variant alleles . None of the four patients carried the common P11712 REA variant alleles ( * 2 , * 3 , * 5 , * 6 , * 7 , * 8 , * 9 , * 11 , * 13 ) despite a relatively low MWWD ( 23.4 ± 7.94 mg ) compared to 208 patients carrying the CYP 29C9 * 1 genotype ( 32.2 ± 12.65 mg ) . Given that P11712 REA * 12 confers decreased in vitro activity to the enzyme , we investigated whether these patients carried this allele . All four patients were P11712 REA * 12 CT heterozygotes . Individual comparisons with patients possessing the same Q9BQB6 and P02649 REA genotypes also demonstrated lower dose requirements in the patients that possessed P11712 REA * 12 allele . CONCLUSIONS : There are no reports of the clinical impact of rs9332239 on P11712 REA substrates . This is the first report of patients with the rare P11712 REA * 12 genotype and lower warfarin dose requirements .

Novel systemic markers for patients with Alzheimer disease ? - a pilot study . Almost 2 % of the population of western industrialized countries are affected by Alzheimer ' s disease ( AD ) . Nevertheless the pathogenetic process leading to this neurodegenerative disease is widely unknown . Thus , we focus on novel pathophysiological aspects of AD . We hypothesize that AD patients reveal increased levels of peripheral blood mononuclear cells ( PBMCs ) expressing proinflammatory ( P35354 REA , P01375 REA , P25942 REA ) , proapoptotic ( P09874 REA ) , adhesion-relevant ( P28907 REA ) or AD associated ( C99 , P56817 REA , P49768 REA ) proteins as well as elevated proinflammatory biochemical plasma parameters . Therefore , PBMCs of AD patients and age-matched control subjects were studied by two color fluorescence-activated cell sorter ( FACS ) analysis . Furthermore , concentration of plasma oxidized low-density lipoprotein ( oxLDL ) and P01375 REA were measured by enzyme-linked immunosorbent assay ( ELISA ) . We found a significantly increased percentage of P01375 REA , P35354 REA , P09874 REA , P28907 REA , C99 or presenilin - 1 positive PBMCs in AD patients compared with healthy subjects . FACS analyses revealed that the percentage of C99 or presenilin - 1 positive PBMCs , which also express P01375 REA , P35354 REA , P09874 REA or P28907 REA is also increased in AD patients . Additionally , AD patients had significantly increased plasma oxLDL and P01375 REA levels . Furthermore , we found positive correlations between plasma oxLDL or P01375 REA concentrations and the percentage of TNFalpha + , P35354 REA + or P09874 REA + , as well as P49768 REA + , C99 + or P56817 REA + PBMCs . Our findings suggest that immunocytological investigations , based on immunophenotyping of AD relevant proteins combined with measurement of proinflammatory , proapoptotic and adhesion-relevant proteins in PBMCs may provide more insight into the pathophysiology of AD .

Accumulation of autophagosomes contributes to enhanced amyloidogenic P05067 REA processing under insulin-resistant conditions . Alzheimer disease ( AD ) is sometimes referred to as type III diabetes because of the shared risk factors for the two disorders . P01308 REA resistance , one of the major components of type II diabetes mellitus ( T2DM ) , is a known risk factor for AD . P01308 REA resistance increases amyloid-β peptide ( Aβ ) generation , but the exact mechanism underlying the linkage of insulin resistance to increased Aβ generation in the brain is unknown . In this study , we investigated the effect of insulin resistance on amyloid β ( A4 ) precursor protein ( P05067 REA ) processing in mice fed a high-fat diet ( HFD ) , and diabetic db / db mice . We found that insulin resistance promotes Aβ generation in the brain via altered insulin signal transduction , increased P56817 REA / β-secretase and γ-secretase activities , and accumulation of autophagosomes . Using an in vitro model of insulin resistance , we found that defects in insulin signal transduction affect autophagic flux by inhibiting the mechanistic target of rapamycin ( P42345 REA ) pathway . The insulin resistance-induced autophagosome accumulation resulted in alteration of P05067 REA processing through enrichment of secretase proteins in autophagosomes . We speculate that the insulin resistance that underlies the pathogenesis of T2DM might alter P05067 REA processing through autophagy activation , which might be involved in the pathogenesis of AD . Therefore , we propose that insulin resistance-induced autophagosome accumulation becomes a potential linker between AD and T2DM .

[ Quantitative analysis of P11387 REA activity in human and rat glioma : characterization and mechanism of resistance to antitopoisomerase chemical , camptothecin - 11 ] . DB00762 MEN ( CPT - 11 ) is a new derivation of camptothecin , a plant alkaloid antitumor agent . Previous studies indicated that antitumor activity of CPT - 11 was mediated through interaction of the drugs with its target enzyme , P11387 REA ( topo I ) . In this study , we studied the relation between sensitivity to CPT - 11 and topo I activity of glioma cells . Furthermore , we established CPT - 11 resistant cell lines in order to elucidate potential mechanisms of drug resistance . A clear correlation between the sensitivities to CPT - 11 and topo I activities in surgical glioma specimens was demonstrated . Activities of topo I in CPT - 11 sensitive group ( IC50 values for CPT - 11 ; < 50 micrograms / ml ) tended to be higher than those in CPT - 11 resistant group ( IC50 values ; > or = 50 ) . Topo I activity may serve as a novel marker to predict the sensitivity of gliomas to topo inhibitors . CPT - 11 resistance cell lines ( T98G / CPT - 11 and P13671 REA ) respectively exhibit a 5.4- and 7.3- fold increase in resistance to CPT - 11 . No differences in topo I activity and intracellular accumulation of CPT - 11 were observed between parent and CPT - 11 resistant lines . On the other hand , topo I from T98G / CPT - 11 and P13671 REA / CPT - 11 cells were at least 4 - and 2 - fold resistant to the inhibitory effect of the CPT - 11 on the relaxation activity of topo I in comparison with their parent lines . This enzymological difference may be responsible for the resistance to CPT - 11 .

DB01098 MEN , a new P04035 REA inhibitor , reduces the colonic inflammatory response in dextran sulfate sodium-induced colitis in mice . The aim of the present study was to elucidate the beneficial effects of rosuvastatin , a new P04035 REA inhibitor , on colonic mucosal damage and on the inflammatory response in a dextran sulfate sodium ( DSS ) colitis model . Acute colitis was induced using 8 % DSS in female BALB / c mice . Colonic mucosal inflammation was evaluated clinically , biochemically , and histologically . Mucosal protein contents and mRNA levels of tumor necrosis factor ( P01375 REA ) - alpha were determined by immunoassay and real time-PCR . The mRNA levels of endothelial nitric oxide synthase ( P29474 REA ) were determined by real-time PCR . Disease activity scores in DSS-induced colitis model mice , as determined by weight loss , stool consistency , and blood in stool , were significantly lower in the rosuvastatin-treated mice than in control mice . Shortening of the colon was significantly reversed by rosuvastatin . Increases in tissue-associated myeloperoxidase activity and thiobarbituric acid-reactive substances after DSS administration were both significantly inhibited by treatment with rosuvastatin . DB01098 MEN also inhibited increases in intestinal P01375 REA protein and mRNA expression after DSS administration , respectively . The mucosal mRNA levels of P29474 REA were decreased after DSS administration , but preserved in mice treated with rosuvastatin . These results suggest that rosuvastatin prevents the development of DSS-induced colitis in mice via the inhibition of mucosal inflammatory responses associated with the preservation of P29474 REA transcription .

Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 REA , P21397 REA , P23560 REA , NOS 3 , P05231 REA , P12036 , P31645 REA , P21964 REA , P48454 REA and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .

Potentiator ivacaftor abrogates pharmacological correction of ΔF508 P13569 REA in cystic fibrosis . Cystic fibrosis ( CF ) is caused by mutations in the CF transmembrane conductance regulator ( P13569 REA ) . Newly developed " correctors " such as DB09280 MEN ( VX - 809 ) that improve P13569 REA maturation and trafficking and " potentiators " such as ivacaftor ( VX - 770 ) that enhance channel activity may provide important advances in CF therapy . Although VX - 770 has demonstrated substantial clinical efficacy in the small subset of patients with a mutation ( G551D ) that affects only channel activity , a single compound is not sufficient to treat patients with the more common P13569 REA mutation , ΔF508 . Thus , patients with ΔF508 will likely require treatment with both correctors and potentiators to achieve clinical benefit . However , whereas the effectiveness of acute treatment with this drug combination has been demonstrated in vitro , the impact of chronic therapy has not been established . In studies of human primary airway epithelial cells , we found that both acute and chronic treatment with VX - 770 improved P13569 REA function in cells with the G551D mutation , consistent with clinical studies . In contrast , chronic VX - 770 administration caused a dose-dependent reversal of VX - 809 - mediated P13569 REA correction in ΔF508 homozygous cultures . This result reflected the destabilization of corrected ΔF508 P13569 REA by VX - 770 , markedly increasing its turnover rate . Chronic VX - 770 treatment also reduced mature wild-type P13569 REA levels and function . These findings demonstrate that chronic treatment with P13569 REA potentiators and correctors may have unexpected effects that can not be predicted from short-term studies . Combining these drugs to maximize rescue of ΔF508 P13569 REA may require changes in dosing and / or development of new potentiator compounds that do not interfere with P13569 REA stability .

Ceramide stabilizes beta-site amyloid precursor protein-cleaving enzyme 1 and promotes amyloid beta-peptide biogenesis . The lipid second messenger ceramide regulates several biochemical events that occur during aging . In addition , its level is highly elevated in the amyloid-burdened brains of Alzheimer ' s disease patients . Here , we analyzed the impact of aberrant ceramide levels on amyloid beta-peptide ( Abeta ) generation by using a cell-permeable analog of ceramide , P13671 REA - ceramide , and several biochemical inhibitors of the sphingomyelin / glycosphingolipid biosynthetic pathway . We found that P13671 REA - ceramide increased the biogenesis of Abeta by affecting beta-but not gamma-cleavage of the amyloid precursor protein . Similarly to P13671 REA - ceramide , increased levels of endogenous ceramide induced by neutral sphingomyelinase treatment also promoted the biogenesis of Abeta . Conversely , fumonisin B1 , which inhibits the biosynthesis of endogenous ceramide , reduced Abeta production . Exogenous P13671 REA - ceramide restored both intracellular ceramide levels and Abeta generation in fumonisin B1 - treated cells . These events were specific for amyloid precursor protein and were not associated with apoptotic cell death . Pulse-chase and time-course degradation experiments showed that ceramide post-translationally stabilizes the beta-secretase P56817 REA . Taken together , these data indicate that the lipid second messenger ceramide , which is elevated in the brains of Alzheimer ' s disease patients , increases the half-life of P56817 REA and thereby promotes Abeta biogenesis .

Biophysical and pharmacological characterization of hypotonically activated chloride currents in cortical astrocytes . Rat cortical astrocytes regulate their cell volume in response to hypotonic challenge . This regulation is believed to depend largely on the release of chloride or organic osmolytes through anion channels . Using whole-cell recordings , we identified weakly outwardly rectifying chloride currents that could be activated in response to hypotonic challenge . These currents exhibited the following permeability sequence upon replacement of chloride in the bathing solution with various anions : I - > NO3 - > Cl - > Gluc - > or = MeS - > Ise - . Interestingly , extracellular I - , albeit showing the greatest permeability , blocked the currents with an IC50 of approximately 50 mM . Currents were almost completely inhibited by 123 microM P16860 and partially inhibited by 200 microM niflumic acid or 200 microM DIDS . Additionally , the total number of Cl - ions effluxed through the hypotonically activated channels was markedly similar to the total solute efflux during volume regulation . We therefore propose the hypotonically activated chloride channel as a major contributor to volume regulation of astrocytes . To examine potential candidate chloride channel genes expressed by astrocytes , we employed RT-PCR to demonstrate the presence of transcripts for P51788 REA , 3 , 4 , 5 , and 7 , as well as for P21796 REA and P13569 REA in cultured astrocytes . Moreover , we performed immunostaining with antibodies against each of these channels and showed the strongest expression of P51788 REA and P51790 REA , strong expression of P51795 REA and P21796 REA , weak expression of P51798 REA and very weak expression of P51793 REA and P13569 REA . Intriguingly , although we found at least seven Cl - channel proteins from three different gene families in astrocytes , none appeared to be active in resting cells .

[ DB00707 MEN sodium ( Photofrin-II ) ] . DB00707 MEN sodium ( DB00707 MEN ) is a photosensitizer which distributes selectively to tumor tissues , and causes tumor cell death by combination with light irradiation . Photodynamic therapy ( PDT ) by combination of porfimer sodium and laser was developed as a new cancer therapy . Tumor selectivity of porfimer sodium are based on the following reasons ; 1 ) high affinity for lipoprotein , especially , low density lipoprotein ( LDL ) , 2 ) elevation of P01130 REA activity in cancer tissue , and 3 ) lack or imcompleteness of lymphatic system in cancer tissue . DB00707 MEN sodium is activated by laser irradiation at 630 nm , which can reacts with tissue oxygen to produce highly reactive excited siglet oxygen ( 1O2 ) . This highly reactive molecule is subsequently capable of killing tumor cells through oxidation of cellular component like mitochondrial enzymes . In addition , this highly reactive intermediate causes destruction of the tumor capillaries , which accelerates tumor cell death . The growth suppression or lethal damage to tumor cells by PDT of porfimer sodium and excimer dye laser were observed in experimental tumor models . In human clinical trials , the rates of complete response ( CR ) for roentgenographically occult lung cancer , stage I lung cancer , superficial esophageal cancer , superficial gastric cancer and carcinoma in situ or dysplasia of the cervix were 84.8 % , 50.0 % , 90.0 % , 87.5 % and 94.4 % , respectively . The major side effects were cutaneous symptoms e . g . photosensitivity , pigmentation , increasing GOT , GPT but these symptoms were not severe . PDT using porfimer sodium and excimer dye laser must be clinically useful for the treatment of inoperable early cancer or conservation of organ functions .

Herpes simplex virus infection causes cellular beta-amyloid accumulation and secretase upregulation . It is uncertain whether environmental factors contribute to the formation of senile plaques and neurofibrillary tangles , the abnormal features that define the Alzheimer ' s disease ( AD ) brain . We previously proposed that herpes simplex virus type 1 ( HSV 1 ) is a strong risk factor for AD when it is present in the brains of people who possess the type 4 allele of the apolipoprotein E gene ( P02649 REA - epsilon 4 ) ; however a direct biochemical link between viral infection and the development of the AD pathological features has never previously been examined . Here we show that infection of cultured neuronal and glial cells with HSV 1 leads to a dramatic increase in the intracellular levels of beta-amyloid ( Abeta ) 1-40 and 1-42 , whilst levels of amyloid precursor protein ( P05067 REA ) in cells decrease . Similarly , Abeta 1-42 deposits are present in mouse brain after HSV 1 infection . In the cultured cells the mechanism involves increased Abeta production , rather than merely greater retention of cellular Abeta , as levels of beta-site P05067 REA - cleaving enzyme ( P56817 REA - 1 ) and of nicastrin , a component of gamma-secretase , both increase in HSV 1 - infected cells . These novel data show that HSV 1 can directly contribute to the development of senile plaques .

The influence of costimulation and regulatory P01730 REA + T cells on intestinal IgA immune responses . It is thought that IgA B-cell differentiation is highly dependent on activated P01730 REA + T cells . In particular , cell-cell interactions in the Peyer ' s patches involving P25942 REA and / or P33681 REA / P42081 REA have been implicated in germinal-center formation and IgA B-cell development . Also soluble factors , such as P05112 REA , P05113 REA , P05231 REA , and TGF beta may be critical for IgA B-cell differentiation in vivo . Here we report on some paradoxical findings with regard to IgA B-cell differentiation and specific mucosal immune responses that we have recently made using gene knockout mice . More specifically , we have investigated to what extent absence of P01730 REA + T cells , relevant cytokines , or T-cell-B-cell interactions would influence IgA B-cell differentiation in vivo . Using P01730 REA - or P05112 REA - gene knockout mice or mice made transgenic for DB01281 MEN , we found that , although specific responses were impaired , total IgA production and IgA B-cell differentiation appeared to proceed normally . However , a poor correlation was found between , on the one hand , GC formation and IgA differentiation and , on the other hand , the ability to respond to T-cell-dependent soluble protein antigens in these mice . Thus , despite the various deficiencies in P01730 REA + T-cell functions seemingly intact IgA B-cell development was observed .

P01130 REA - related protein promotes amyloid precursor protein trafficking to lipid rafts in the endocytic pathway . The major defining pathological hallmark of Alzheimer ' s disease ( AD ) is the accumulation of amyloid beta protein ( Abeta ) , a small peptide derived from beta - and gamma-secretase cleavages of the amyloid precursor protein ( P05067 REA ) . Recent studies have shown that beta - and gamma-secretase activities of P56817 REA and presenilin , respectively , are concentrated in intracellular lipid raft microdomains . However , the manner in which P05067 REA normally traffics to lipid rafts is unknown . In this study , using transient transfection and immuno-precipitation assays , we show that the cytoplasmic domain of low-density lipoprotein receptor-related protein ( Q14764 REA ) interacts with P05067 REA and increases Abeta secretion and P05067 REA beta-CTF ( C-terminal fragment ) generation by promoting P56817 REA - P05067 REA interaction . We also employed discontinuous sucrose density gradient ultracentrifugation to show that the Q14764 REA cytoplasmic domain-mediated effect was accompanied by greatly increased localization of P05067 REA and P56817 REA to lipid raft membranes , where beta - and gamma-secretase activities are highly enriched . Moreover , we provide evidence that endogenous Q14764 REA is required for the normal delivery of P05067 REA to lipid rafts and Abeta generation primarily in the endocytic but not secretory pathway . These results may provide novel insights to block Abeta generation by targeting Q14764 REA - mediated delivery of P05067 REA to raft microdomains .

Splice variants : a homology modeling approach . Splice variants play an important role within the cell in both increasing the proteome diversity and in cellular function . Splice variants are also associated with disease states and may play a role in their etiology . Information about splice variants has , until now , mostly been derived from the primary transcript or through cellular studies . In this study information from the transcript and other studies is combined with tertiary structure information derived from homology models . Through this method we have determined that it is possible to effectively model splice variants . Forty models of splice variants for fourteen proteins were produced . Analysis of the models shows that deletions produce superior model validation values . Additions to sequences where there is little homology become increasingly difficult to model with increasing sequence length . Many of the splicing events are associated with post-translational modification either in the N-terminal region by changing the signal peptide or by affecting the number or availability of glycosylation sites . Often the alternative exon combinations are associated with loss or gain of whole structural units , as opposed to just changing small loop regions . Losing part of the secondary structure may destabilize neighboring parts of the same secondary structure . Detailed analysis is given of four biomedically relevant proteins ( Beta-site Amyloid Precursor Protein Cleaving enzyme ( P56817 REA ) , P05112 REA , Frataxin and Q30201 REA ) and their associated splice variant models . The visualization of these possible structures provides new insights about their functionality and the possible etiology of associated diseases .

Fetzima ( levomilnacipran ) , a drug for major depressive disorder as a dual inhibitor for human serotonin transporters and beta-site amyloid precursor protein cleaving enzyme - 1 . Pharmacological management of Major Depressive Disorder includes the use of serotonin reuptake inhibitors which targets serotonin transporters ( P31645 REA ) to increase the synaptic concentrations of serotonin . Beta-site amyloid precursor protein cleaving enzyme - 1 ( P56817 REA - 1 ) is responsible for amyloid β plaque formation . Hence it is an interesting target for Alzheimer ' s disease ( AD ) therapy . This study describes molecular interactions of a new Food and Drug Administration approved antidepressant drug named ' Fetzima ' with P56817 REA - 1 and P31645 REA . Fetzima is chemically known as levomilnacipran . The study has explored a possible link between the treatment of Depression and AD . ' Autodock 4.2 ' was used for docking study . The free energy of binding ( ΔG ) values for ' levomilnacipran - P31645 REA ' interaction and ' levomilnacipran - P56817 REA ' interaction were found to be -7.47 and -8.25 kcal / mol , respectively . DB08918 SUB was found to interact with S438 , known to be the most important amino acid residue of serotonin binding site of P31645 REA during ' levomilnacipran - P31645 REA ' interaction . In the case of ' levomilnacipran - P56817 REA ' interaction , levomilnacipran interacted with two very crucial aspartic acid residues of P56817 REA - 1 , namely , D32 and D228 . These residues are accountable for the cleavage of amyloid precursor protein and the subsequent formation of amyloid β plaques in AD brain . Hence , Fetzima ( levomilnacipran ) might act as a potent dual inhibitor of P31645 REA and P56817 REA - 1 and expected to form the basis of a future dual therapy against depression and AD . It is an established fact that development of AD is associated with Major Depressive Disorder . Therefore , the design of new P56817 REA - 1 inhibitors based on antidepressant drug scaffolds would be particularly beneficial .

Apoptogenic interactions of plasmalemmal type - 1 P21796 REA and Aβ peptides via GxxxG motifs induce Alzheimer ' s disease - a basic model of apoptosis ? Human type - 1 porin / P21796 REA ( voltage-dependent anion channel ) carries a GxxxG motif in its N-terminal part , traversing the β-barrel , while the Alzheimer ' s disease ( AD ) relevant amyloid peptides Aβ1 - 42 and Aβ1 - 40 show a series of corresponding motifs close to their C-terminus . GxxxG motifs are established as aggregation / membrane perturbation motifs . These peptide primary structure data support a proposal I recently made on the basis of a synopsis of recent literature . Accordingly , amyloid Aβ , cut from P05067 REA by beta-secretase P56817 REA and gamma-secretase , has been insinuated to induce Alzheimer ' s disease via apoptosis by opening type - 1 porin / P21796 REA in cell membranes of hypometabolic neuronal cells . Considering the ubiquitous expression modus of P05067 REA , beta - and gamma-secretases and type - 1 P21796 REA / eukaryotic porin a basic model of apoptosis might be given .

Is phentermine an inhibitor of monoamine oxidase ? A critical appraisal . DB00191 MEN produces a spectrum of concentration-dependent biochemical effects . It interacts with NE transporters at 0.1 microM , DA transporters at about 1 microM , 5 - HT transporters at 15 microM and P21397 REA at about 100 microM . When administered at typical anorectic doses , phentermine primarily interacts with DA and NE transporters and does not produce biochemical or neurochemical effects which would occur if it were inhibiting P21397 REA . Some other explanation other than MAO inhibition must be sought to explain how oral phentermine increases platelet 5 - HT , since platelet P27338 REA does not metabolize platelet 5 - HT , and since amphetamine-type drugs are even weaker inhibitors of P27338 REA than P21397 REA . Clinical studies in humans have shown that amphetamine , which is a more potent inhibitor of P21397 REA than phentermine , does not inhibit P21397 REA at therapeutic doses . Neither phentermine alone , fluoxetine alone or their combined use have been associated with cardiac valvulopathy , and clinical experience has shown their combined use to be free of significant adverse effects . Viewed collectively , there appears to be no data to support the hypothesis that phentermine inhibits MAO at typical therapeutic doses .

Cluster analysis of risk factor genetic polymorphisms in Alzheimer ' s disease . Multiple genetic variants may contribute to the risk of developing Alzheimer ' s disease . We have analyzed polymorphisms in 9 genes to determine whether particular combinations would contribute to this risk . The genes were P02649 REA , LDLr , P01034 REA , P07339 REA , P01375 REA , P56817 REA , P10636 REA , Q8IWL8 , P29474 REA , and Q12800 . Three risk groups for the disease were identified . Risk group I was younger , was heterozygous for the P01034 REA ( GA ) , CTSD 2936 ( AG ) , P01375 REA - 308 ( AG ) genetic variants . Risk group II was older , was homozygous for the - 427 P02649 REA promoter polymorphism ( TT ) , and heterozygous for the P10636 REA deletion and for the Q8IWL8 variant ( QR ) . Group III had both the youngest and oldest subjects , were heterozygous for the - 863 ( AC ) and - 1031 ( CT ) P01375 REA promoter polymorphisms . All three groups carried the P02649 REA 4 allele and were heterozygous for both P56817 REA polymorphisms . The control groups were carriers of the P02649 REA 3 allele and were homozygous for the P56817 REA genetic variants .

DB00588 MEN - induced regulation of the balance within macrophage subpopulations . In asthma , treatment with inhaled corticosteroids reduces chronic peribronchial inflammation and restores the balance within macrophage subpopulations . This study investigates whether corticosteroids can regulate monocyte differentiation in vitro and thereby influence the balance of functionally distinct macrophages . Graded doses of fluticasone propionate ( FP ) were added to cultures of normal peripheral blood monocytes in the presence or absence of P05112 REA . Cells were harvested after 7 days ' culture . Double immunofluorescence studies were performed on cytospins of differentiated macrophages using the MoAbs RFD 1 and RFD 7 to distinguish inductive and suppressive macrophages by their respective phenotypes . Macrophage function was determined by quantifying allostimulation in a mixed leucocyte reaction and by measuring tumour necrosis factor-alpha ( P01375 REA ) production . FP reduced the number of mature cells with a D1 + antigen-presenting phenotype and up-regulated the development of cells with the D1 / D7 + and D7 + phenotypes . Functionally , this was associated with reduced stimulation of T cell proliferation in a mixed leucocyte reaction ( P08235 REA ) . DB00588 MEN also reversed the increase in both D1 + expression and P01375 REA production induced by P05112 REA . The effect of FP persisted for 24 h after removal of FP from the culture medium . These results suggest that FP treatment of asthmatics may have a direct beneficial effect by normalizing the macrophage subset imbalance that contributes to the chronic peribronchial inflammation present in this condition .