MH_dev_168

Steatohepatitis in laboratory opossums exhibiting a high lipemic response to dietary cholesterol and fat . Plasma VLDL and LDL cholesterol were markedly elevated ( > 40 - fold ) in high-responding opossums , but moderately elevated ( 6 - fold ) in low-responding opossums after they had consumed a high-cholesterol and high-fat diet for 24 wk . In both high - and low-responding opossums , plasma triglycerides were slightly elevated , threefold and twofold , respectively . Dietary challenge also induced fatty livers in high responders , but not in low responders . We studied the lipid composition , histopathological features , and gene expression patterns of the fatty livers . Free cholesterol ( 2 - fold ) , esterified cholesterol ( 11 - fold ) , and triglycerides ( 2 - fold ) were higher in the livers of high responders than those in low responders , whereas free fatty acid levels were similar . The fatty livers of high responders showed extensive lobular disarray by histology . Inflammatory cells and ballooned hepatocytes were also present , as were perisinusoidal fibrosis and ductular proliferation . In contrast , liver histology was normal in low responders . Hepatic gene expression revealed differences associated with the development of steatohepatitis in high responders . The accumulation of hepatic cholesterol was concomitant with upregulation of the P04035 REA gene and downregulation of the Q02318 REA , Q9H221 REA , and P21439 REA genes . Genes involved in inflammation ( P01375 REA , P19838 REA , and P35354 REA ) and in oxidative stress ( P13498 REA and P14598 REA ) were upregulated . Upregulation of the growth factor genes ( PDGF and P01137 REA ) and collagen genes ( Col 1A1 , Col 3A1 , and Col 4A1 ) was consistent with fibrosis . Some of the histological characteristics of the fatty livers of high-responding opossums imitate those in the livers of humans with nonalcoholic steatohepatitis .

The potential role of PD0332991 ( DB09073 MEN ) in the treatment of multiple myeloma . INTRODUCTION : Multiple myeloma ( MM ) remains an incurable malignancy indicating a need for continued investigation of novel therapies . Recent studies have highlighted the role of cyclin-dependent kinases ( CDK ) in the pathogenesis of MM . PD0332991 ( DB09073 MEN ) is an orally bioavailable , highly selective inhibitor of the P11802 REA / 6 - cyclin complex and downstream retinoblastoma protein ( Rb ) activation pathway that induces cell cycle arrest in the P55008 phase . AREAS COVERED : In this review , the authors summarize the role of the P11802 REA / 6 signaling pathway in MM . They also summarize the development of PD0332991 as a specific inhibitor of P11802 REA / 6 , and the reported preclinical and clinical data supporting the potential role of PD0332991 in MM . EXPERT OPINION : While PD0332991 is essentially cytostatic , inducing prolonged P55008 arrest , it enhances the cytotoxic effect of other agents effective in MM , including bortezomib and lenalidomide , as confirmed in early phase clinical trials . However , with a plethora of other drugs of different classes being tested in MM , further development of PD0332991 will depend on defining the most efficacious combination with least toxicity . An unexplored opportunity remains the potential protective effect of PD0332991 against lytic bone lesions of MM . The next few years are likely to better define the place of PD0332991 in the treatment of MM .

Celecoxib with chemotherapy in colorectal cancer . P35354 REA ( P35354 REA ) is the enzyme that normally synthesizes prostaglandins during an inflammatory response . Many primary and metastatic cancers express P35354 REA , and its presence is correlated with tumor angiogenesis , more invasive tumor phenotype , resistance to apoptosis , and systemic immunosuppression . The expression of P35354 REA is associated with a worse prognosis . Inhibition of prostaglandin synthesis may be beneficial in human malignancy . Regular consumption of nonsteroidal anti-inflammatory drugs ( NSAIDs ) decreases the incidence of , and mortality rate resulting from , a number of types of gastrointestinal cancers . Premalignant colonic lesions regress following the administration of nonspecific P36551 REA inhibitors , such as sulindac ( DB00605 ) . Advanced solid tumor patients treated with indomethacin ( DB00328 SUB ) survive twice as long as do such patients who receive supportive care alone . The U . S . Food and Drug Administration has approved specific P35354 REA inhibitors for the treatment of arthritis , pain , and familial adenomatous polyposis . Preclinical studies show that these drugs block angiogenesis , suppress solid tumor metastases , and slow the growth of implanted gastrointestinal cancer cell lines . The P35354 REA inhibitors have safely and effectively been combined with chemotherapeutic agents in experimental studies . Ongoing clinical trials are currently assessing the potential therapeutic role of P35354 REA inhibitors in both prevention and treatment of a diverse range of human cancers .

Toll-like receptor expression in human keratinocytes : nuclear factor kappaB controlled gene activation by Staphylococcus aureus is toll-like receptor 2 but not toll-like receptor 4 or platelet activating factor receptor dependent . Cultured primary human keratinocytes were screened for their expression of various members of the toll-like receptor ( TLR ) family . Keratinocytes were found to constitutively express Q15399 REA , O60603 REA , O15455 REA , O60602 REA , and Q9NR96 but not O00206 REA , Q9Y2C9 REA , Q9NYK1 , Q9NR97 , or Q9BXR5 as shown by polymerase chain reaction analysis . The expression of the crucial receptor for signaling of staphylococcal compounds O60603 REA was also confirmed by immunohistochemistry , in contrast to O00206 REA , which showed a negative staining pattern . Next , we analyzed the activation of the proinflammatory nuclear transcription factor kappaB by Staphylococcus aureus strain 8325-4 . Using nuclear extract gel shifts , RelA staining , and luciferase reporter transfection plasmids we found a clear induction of nuclear factor kappaB translocation by the bacteria . This translocation induced the transcription of nuclear factor kappaB controlled genes such as inducible nitric oxide synthetase , P35354 REA , and interleukin - 8 . Transcription of these genes was followed by production of increased amounts of interleukin - 8 protein and NO . Inhibition experiments using monoclonal antibodies and the specific platelet activating factor receptor inhibitor CV3988 showed that nuclear factor kappaB activation by S . aureus was O60603 REA but not O00206 REA or platelet activating factor receptor dependent . In line , the purified staphylococcal cell wall components lipoteichoic acid and peptidoglycan , known to signal through O60603 REA , also showed nuclear factor kappaB translocation in human keratinocytes , indicating a crucial role of the staphylococcal cell wall in the innate immune stimulation of human keratinocytes . These results help to explain the complex activation of human keratinocytes by S . aureus and its cell wall components in various inflammatory disorders of the skin .

P00797 REA inhibition reduces atherosclerotic plaque neovessel formation and regresses advanced atherosclerotic plaques . OBJECTIVE : The interaction between the renin-angiotensin system and toll-like receptors ( TLRs ) in the pathogenesis of advanced atherosclerotic plaques is not well understood . We studied the effects of the renin inhibitor aliskiren on the progression of advanced atherosclerotic plaque in apolipoprotein E-deficient ( ApoE ( - / - ) ) mice with a special focus on plaque neovessel formation . METHODS AND RESULTS : Four-wk-old ApoE ( - / - ) mice were fed a high-fat diet for 8 wks , and the mice were randomly assigned to one of three groups and administered a vehicle , hydralazine , or aliskiren for an additional 12 wks . DB09026 MEN reduced the atherosclerotic plaque area and plaque neovessel density . It increased the plaque collagen and elastin contents , and reduced plasma angiotensin II levels and plaque macrophage infiltration and cathepsin S ( CatS ) protein . DB09026 MENMAX DB09026 MEN also decreased the levels of AT1R , gp91phox , O60603 REA , monocyte chemotactic protein - 1 , and CatS mRNAs in the aortic roots . DB01275 had no beneficial vascular effects , although its administration resulted in the same degree of blood pressure reduction as aliskiren . CatS deficiency mimicked the aliskiren-mediated vasculoprotective effect in the ApoE ( - / - ) mice , but aliskiren showed no further benefits in ApoE ( - / - ) CatS ( - / - ) mice . In vitro , O60603 REA silencing reduced CatS expression induced by angiotensin II . Moreover , aliskiren or the inhibition of CatS impaired the endothelial cell angiogenic action in vitro or / and ex vivo . CONCLUSION : P00797 REA inhibition appears to inhibit advanced plaque neovessel formation in ApoE ( - / - ) mice and to decrease the vascular inflammatory action and extracellular matrix degradation , partly by reducing AT1R / O60603 REA - mediated CatS activation and activity , thus regressing advanced atherosclerosis .

DB01095 MEN inhibits growth and alters the malignant phenotype of the P13671 REA glioma cell line . BACKGROUND : DB01095 MEN is a member of the family of P04035 REA inhibitors ( statins ) extensively used in medical practice . Increasing evidence suggests that fluvastatin may be implicated in suppression of cancer growth and development . The aim of the present study was to investigate the anti-cancer potential of fluvastatin in P13671 REA rat malignant glioma cells . METHODS : First , the effects of fluvastatin on cell viability ( MTT assay ) , proliferation ( BrdU assay ) , cell morphology , and cytoskeleton were examined . Subsequently , its effect on extracellular signal regulated kinase 1 and 2 ( P27361 REA / 2 ) and P45983 REA and 2 ( JNK 1/2 ) expression was estimated by Western blot . Finally , the influence of fluvastatin on cell migration and production of P14780 REA and P15692 REA was determined using a wound-healing assay and ELISA test , respectively . RESULTS : The results obtained showed that fluvastatin had a remarkable inhibitory and cytotoxic effect on tumor P13671 REA cells ( IC ( 50 ) = 8.6 μM , 48 h ) , but did not inhibit the growth of normal neuronal cells . The concentrations from 1 to 10 μM induced marked morphologic alterations typical for apoptosis including shrinkage of cytoplasm , chromatin condensation , and nucleus breakdown . CONCLUSION : The inhibitory effects of fluvastatin on cell proliferation seemed to be associated with decreased p - P27361 REA / 2 expression , upregulation of p - P45983 REA / 2 , and reduction in the P14780 REA and P15692 REA concentrations in culture media . The high anticancer ( antiproliferative , proapoptotic , antiinvasive ) activity of fluvastatin and lack of its toxicity against normal cells indicate a potential use of this statin in the treatment of malignant glioma .

A transgenic platform for testing drugs intended for reversal of cardiac remodeling identifies a novel 11βHSD1 inhibitor rescuing hypertrophy independently of re-vascularization . RATIONALE : Rescuing adverse myocardial remodeling is an unmet clinical goal and , correspondingly , pharmacological means for its intended reversal are urgently needed . OBJECTIVES : To harness a newly-developed experimental model recapitulating progressive heart failure development for the discovery of new drugs capable of reversing adverse remodeling . METHODS AND RESULTS : A P15692 REA - based conditional transgenic system was employed in which an induced perfusion deficit and a resultant compromised cardiac function lead to progressive remodeling and eventually heart failure . Ability of candidate drugs administered at sequential remodeling stages to reverse hypertrophy , enlarged LV size and improve cardiac function was monitored . Arguing for clinical relevance of the experimental system , clinically-used drugs operating on the P00797 REA - Angiotensin - DB04630 - System ( RAAS ) , namely , the P12821 REA inhibitor Enalapril and the direct renin inhibitor Aliskerin fully reversed remodeling . Remodeling reversal by these drugs was not accompanied by neovascularization and reached a point-of-no-return . Similarly , the PPARγ agonist Pioglitazone was proven capable of reversing all aspects of cardiac remodeling without affecting the vasculature . Extending the arsenal of remodeling-reversing drugs to pathways other than RAAS , a specific inhibitor of 11β - hydroxy-steroid dehydrogenase type 1 ( 11β HSD 1 ) , a key enzyme required for generating active glucocorticoids , fully rescued myocardial hypertrophy . This was associated with mitigating the hypertrophy-associated gene signature , including reversing the myosin heavy chain isoform switch but in a pattern distinguishable from that associated with neovascularization-induced reversal . CONCLUSIONS : A system was developed suitable for identifying novel remodeling-reversing drugs operating in different pathways and for gaining insights into their mechanisms of action , exemplified here by uncoupling their vascular affects .

Evaluation of pharmacological profile of meloxicam as an anti-inflammatory agent , with particular reference to its relative selectivity for cyclooxygenase - 2 over cyclooxygenase - 1 . We studied the anti-inflammatory activity of meloxicam on rat carrageenin-induced pleurisy and its toxicity for rat gastric mucosa , relative to its in vitro inhibitory potency against partially purified cyclooxygenase ( P36551 REA ) - 1 and P35354 REA preparations in order to clarify the pharmacological profile of the compound as an anti-inflammatory agent . In rat carrageenin-induced pleurisy , the plasma exudation rate peaked at 5 h , at which time P35354 REA was detectable in cells from the pleural exudate . Meloxicam and piroxicam ( 1 and 3 mg / kg ) and NS - 398 ( 3 mg / kg ) showed almost equal anti-inflammatory potency against 5 - hour pleurisy . A single oral administration of the compounds caused a dose-dependent increase in the number of rats with gastric mucosal erosion . The ED50 value for meloxicam ( 5.92 mg / kg ) was significantly higher than that for piroxicam ( 1.76 mg / kg ) , indicating that meloxicam is safer . DB00328 SUB showed intermediate safety ( 2.59 mg / kg ) . In in vitro experiments , indometacin inhibited P23219 REA about 1.7 times more potently than P35354 REA . NS - 398 inhibited P35354 REA with an IC50 of 0.32 microM , but never affected P23219 REA activity , even at 100 microM . In the same assay system , meloxicam inhibited P35354 REA about 12 times more selectively than P23219 REA . Piroxicam , however , inhibited both isoforms almost equally . These results indicate that meloxicam is a potent anti-inflammatory agent with low gastric toxicity . One reason for its in vivo pharmacological profile may be related to its relative selectivity for P35354 REA over P23219 REA . Thus , meloxicam may belong to a group of P35354 REA selective anti-inflammatory agents with a better safety profile than conventional P23219 REA and P35354 REA nonselective anti-inflammatory agents .

The protective effect of rebamipide on paracellular permeability of rat gastric epithelial cells . BACKGROUND : Barrier function in gastric epithelial cells is essential for the gastric defence mechanism against acid back-diffusion into the mucosal layer . Our previous study indicated that trans-epithelial resistance ( Q9NZ01 ) of rat gastric epithelial cells was rapidly increased when the cells were exposed to acid . This response to acid was diminished by indometacin . AIM : Evaluate the effects of a mucoprotective agent , rebamipide , on the nonsteroidal anti-inflammatory drug ( NSAID ) - induced increase of gastric epithelial permeability . METHODS : Rat gastric epithelial cells were plated on tissue culture inserts . Cells were exposed to a NSAID ( indometacin , 10-7 M ) . Trans-epithelial permeability was measured by Q9NZ01 and diffusion rate of 14C - mannitol . The effect of rebamipide was evaluated by measuring Q9NZ01 . Endogenous prostaglandin E2 ( DB00917 ) production in culture medium was also measured . RESULTS : DB00328 SUB gradually and significantly decreased Q9NZ01 and increased 14C - manitol permeability . Rebamipide reversed the indometacin-induced changes in epithelial permeability and induced DB00917 synthesis . This induction was blocked by either indometacin or a Cyclooxygenase ( P36551 REA ) - 2 specific inhibitor . CONCLUSIONS : P36551 REA inhibitors such as indometacin inhibit regulation of epithelial permeability by reducing DB00917 . P23219 REA has an important role in the gastric defense mechanism . Rebamipide suppressed an indometacin-induced increase in gastric epithelial permeability by increasing DB00917 levels in a P35354 REA dependent manner .

P01116 REA , P00533 REA , P09619 REA - α , P10721 REA and P35354 REA status in carcinoma showing thymus-like elements ( CASTLE ) . BACKGROUND : CASTLE ( Carcinoma showing thymus-like elements ) is a rare malignant neoplasm of the thyroid resembling lymphoepithelioma-like and squamous cell carcinoma of the thymus with different biological behaviour and a better prognosis than anaplastic carcinoma of the thyroid . METHODS : We retrospectively investigated 6 cases of this very rare neoplasm in order to investigate the mutational status of P01116 REA , P00533 REA , P09619 REA - α and P10721 REA , as well as the immunohistochemical expression pattern of CD117 , P00533 REA and P35354 REA , and possibly find new therapeutic targets . RESULTS : Diagnosis was confirmed by a moderate to strong expression of P06127 , CD117 and CK5 / 6 , whereas thyroglobulin , calcitonin and Q15669 REA - 1 were negative in all cases . Tumors were also positive for P35354 REA and in nearly all cases for P00533 REA . In four cases single nucleotide polymorphisms ( SNPs ) could be detected in exon 12 of the P09619 REA - α gene ( rs1873778 ) , in three cases SNPs were found in exon 20 of the P00533 REA gene ( rs1050171 ) . No mutations were found in the P10721 REA and P01116 REA gene . CONCLUSIONS : All tumors showed a P35354 REA expression as well as an P00533 REA expression except for one case and a wild-type P01116 REA status . No activating mutations in the P00533 REA , P10721 REA and P09619 REA - α gene could be detected . Our data may indicate a potential for targeted therapies , but if these therapeutic strategies are of benefit in CASTLE remains to be determined . VIRTUAL SLIDES : The virtual slide ( s ) for this article can be found here : http://www.diagnosticpathology.diagnomx.eu/vs/1658499296115016 .

DB00328 SUB ameliorates high glucose-induced proliferation and invasion via modulation of e-cadherin in pancreatic cancer cells . DB00328 SUB , an inhibitor of cyclooxygenase - 2 ( P35354 REA ) , has been shown to exert anticancer effects in a variety of cancers . However , the effect and mechanism of indometacin on high glucose ( HG ) - induced proliferation and invasion of pancreatic cancer ( PC ) cells remain unclear . Multiple lines of evidence suggest that a large portion of pancreatic cancer ( PC ) patients suffer from either diabetes or HG which contributing PC progression . In this study , we report that indometacin down-regulated HG-induced proliferation and invasion via up-regulating P12830 REA but not P35354 REA in PC cells . Additionally , the P12830 REA transcriptional repressors , Snail and Slug , were also involved in the process . Furthermore , the proliferation and invasion of PC cells , incubated in HG medium and treated with indometacin were significantly increased when P12830 REA was knocked down ( Si-E-cad ) . Moreover , the protein levels of P08253 REA , P14780 REA , and P15692 REA were increased in PC cells transfected with Si-E-cad . Finally , the activation of the PI3K / AKT / GSK - 3β signaling pathway was demonstrated to be involved in indometacin reversing HG-induced cell proliferation and invasion in PC cells . In conclusion , these results suggest that indometacin plays a key role in down-regulating HG-induced proliferation and invasion in PC cells . Our findings indicate that indometacin could be used as a novel therapeutic strategy to treat PC patients who simultaneously suffer from diabetes or HG .

Dissection of the phenotypic and genotypic associations with nicotinic dependence . INTRODUCTION : Strong evidence demonstrates that nicotine dependence is associated with 4 genetic variants rs16969968 , rs6474412 , rs3733829 , and rs1329650 in large-scale Genome-Wide Association Studies . We examined how these identified genetic variants relate to nicotine dependence defined by different categorical and dimensional measures . METHODS : Four genetic variants were analyzed in 2,047 subjects of European descent ( 1,062 cases and 985 controls ) . DB00184 MEN dependence was assessed with multiple smoking measures , including the Fagerström Test for DB00184 MEN Dependence , the Diagnostic and Statistical Manual for Mental Disorders-IV ( DSM-IV ) nicotine dependence , the DB00184 MEN Dependence Syndrome Scale , and the Wisconsin Inventory of Smoking Dependence Motives . Single-item measures of cigarettes per day ( O75976 REA ) and time to first cigarette ( Q15669 REA ) in the morning were also examined . RESULTS : Among the variants , association effect sizes were largest for rs16969968 , with measures of craving and heavy smoking , especially cigarettes smoked per day , showing the largest effects . Significant but weaker associations were found for rs6474412 and rs3733729 but not for rs1329650 . None of the more comprehensive measures of smoking behaviors yielded stronger genetic associations with these variants than did O75976 REA . CONCLUSIONS : O75976 REA is an important simple measure that captures in part the genetic associations of P30532 REA and nicotine dependence , even when other more comprehensive measures of smoking behaviors are examined . The P30532 REA gene is associated with heavy compulsive smoking and craving ; this should inform the mission to improve the diagnostic validity of DSM-V .

DB01095 MEN enhances the inhibitory effects of a selective AT1 receptor blocker , valsartan , on atherosclerosis . We investigated the effects of a P04035 REA inhibitor ( statin ) on the inhibitory effects of an angiotensin II type - 1 receptor ( AT1 ) blocker on atherosclerosis and explored cellular mechanisms . We gave apolipoprotein E null mice a high-cholesterol diet for 10 weeks and measured atherosclerotic plaque area and lipid deposition . Neither 1 mg / kg per day of valsartan nor 3 mg / kg per day of fluvastatin had any effect on blood pressure or cholesterol concentration ; however , both drugs decreased plaque area and lipid deposition after 10 weeks . We then reduced the doses of both drugs to 0.1 mg / kg per day and 1 mg / kg per day , respectively . At these doses , neither drug had an effect on atherosclerotic lesions . When both drugs were combined at these doses , a significant reduction in atherosclerotic lesions was observed . Similar inhibitory effects of valsartan or fluvastatin on the expressions of nicotinamide-adenine dinucleotide / nicotinamide-adenine dinucleotide phosphate oxidase subunits P13498 REA and p47phox , production of superoxide anion , the expression of monocyte chemoattractant protein - 1 , and intercellular adhesion molecule - 1 expression were observed . These results suggest that concomitant AT1 receptor and cholesterol biosynthesis blockade , particularly when given concomitantly , blunts oxidative stress and inflammation independent of blood pressure or cholesterol-related effects .

A field synopsis and meta-analysis of genetic association studies in peripheral arterial disease : The CUMAGAS-PAD database . In an electronic search of the literature , the authors systematically retrieved all published studies that investigated genetic susceptibility to peripheral arterial disease ( PAD ) . They created a comprehensive database of all eligible studies , collecting detailed genetic and bioinformatics data on each polymorphism . Data from eligible studies were synthesized using meta-analysis techniques . Gene variants were classified into distinct pathophysiologic pathways , and their potential involvement in PAD pathogenesis was determined . Forty-one publications that examined 44 gene polymorphisms were included . For 37 polymorphisms , the variant form had a functional effect . Twenty-three polymorphisms in 22 potential PAD candidate genes ( F2 , P02675 REA , P42898 REA , P05106 REA , P12821 REA , AGT , P05231 REA , P13500 REA , P05362 REA , P16581 REA , P14780 REA , P37231 REA , P03956 REA , P35611 REA , Q9H244 REA , P11150 REA , Q13093 REA , Q8WTV0 , P08254 REA , P55157 REA , P08519 REA , P32297 REA ) showed a significant association in individual studies . Eighty-eight percent of the studies had statistical power of less than 50 % , and in 15 studies the genotype distribution in the control group did not conform to Hardy-Weinberg equilibrium . Data on 12 polymorphisms ( P12259 REA 1691 G / A , P42898 REA 677C / T , F2 20210 G / A , P05106 REA 1565 T / C , P12821 REA I / D , AGT 704C / T , AGT - 6G / A , AGT 733C / T , P05231 REA - 174 G / C , P14780 REA - 1562C / T , P05362 REA 1462A / G , P32297 REA 831C / T ) were synthesized , and a positive association was found for 3 ( P05231 REA - 174 G / C , P05362 REA 1462A / G , P32297 REA 831C / T ) .

DB00184 MEN consumption is regulated by a human polymorphism in dopamine neurons . Smoking is the most important preventable cause of morbidity and mortality worldwide . Recent genome-wide association studies highlighted a human haplotype on chromosome 15 underlying the risk for tobacco dependence and lung cancer . Several polymorphisms in the P32297 REA - P30532 REA - P30926 REA cluster coding for the nicotinic acetylcholine receptor ( nAChR ) α3 , α5 and β4 subunits were implicated . In mouse models , we define a key role in the control of sensitivity to nicotine for the α5 subunit in dopaminergic ( DAergic ) neurons of the ventral tegmental area ( VTA ) . We first investigated the reinforcing effects of nicotine in drug-naive α5 ( - / - ) mice using an acute intravenous nicotine self-administration task and ex vivo and in vivo electrophysiological recordings of nicotine-elicited DA cell activation . We designed lentiviral re-expression vectors to achieve targeted re-expression of wild-type or mutant α5 in the VTA , in general , or in DA neurons exclusively . Our results establish a crucial role for α5 * - nAChRs in DAergic neurons . These receptors are key regulators that determine the minimum nicotine dose necessary for DA cell activation and thus nicotine reinforcement . Finally , we demonstrate that a single-nucleotide polymorphism , the non-synonymous α5 variant rs16969968 , frequent in many human populations , exhibits a partial loss of function of the protein in vivo . This leads to increased nicotine consumption in the self-administration paradigm . We thus define a critical link between a human predisposition marker , its expression in DA neurons and nicotine intake .

P00797 REA inhibition with aliskiren . 1 . Initial attempts to inhibit renin in humans have faced numerous difficulties . Molecular modelling and X-ray crystallography of the active site of renin have led to the development of new orally active renin inhibitors , such as aliskiren . 2 . DB09026 MEN has a low bioavailability ( between 2.6 and 5.0 % ) compensated by its high potency to inhibit renin ( IC50 : 0.6 nmol / L ) and a long plasma half-life ( 23-36 h ) , which makes it suitable for once-daily dosing . 3 . The once-daily administration of aliskiren to hypertensive patients lowers BP as strongly as standard doses of established angiotensin II type 1 ( AT1 ) receptor blockers ( losartan , valsartan , irbesartan ) , hydrochlorothiazide , angiotensin converting enzyme inhibitors ( ramipril and lisinopril ) or long acting calcium channel blockers ( amlodipine ) . In combination therapy , aliskiren further decreases blood pressure when combined with either hydrochlorothiazide , amlodipine , irbesartan or ramipril . 4 . The biochemical consequences of renin inhibition differ from those of angiotensin I-converting enzyme ( P12821 REA ) inhibition and Ang II antagonism , particularly in terms of angiotensin profiles and interactions with the bradykinin-nitric oxide-cyclic guanosine monophosphate pathway and possibly the ( pro ) renin receptor . 5 . Blockade of the renin angiotensin system ( DB01367 ) with P12821 REA inhibitors , AT1 receptor blockers or a combination of these drugs has become one of the most successful therapeutic approaches in medicine . However , it remains unclear how to optimize DB01367 blockade to maximize cardiovascular and renal benefits . In this context , renin inhibition to render the DB01367 fully quiescent is a new possibility requiring further study .

DB00316 MEN - inhibitable P35354 REA . Although paracetamol potently reduces pain and fever , its mechanism of action has so far not been satisfactorily explained . It inhibits both P23219 REA and P35354 REA weakly in vitro , but reduces prostaglandin synthesis markedly in vivo . In mouse macrophage J774 . 2 cells , P35354 REA induced for 48 hr with high concentrations of NSAIDs is more sensitive to inhibition with paracetamol than endotoxin-induced P35354 REA . In the rat pleurisy model of inflammation , a second peak of P35354 REA protein appears 48 hr after administration of the inflammatory stimulus , during the resolution phase of the inflammatory process . Inhibition of the activity of this late-appearing P35354 REA with indomethacin or a selective P35354 REA inhibitor , delays resolution and the inflammation is prolonged . Cultured lung fibroblasts also express P35354 REA activity after stimulation with IL - 1beta which is highly sensitive to inhibition with paracetamol . Thus , evidence is accumulating for the existence of a P35354 REA variant or a new P36551 REA enzyme which can be inhibited with paracetamol .

JTE - 522 , a selective P35354 REA inhibitor , inhibits cell proliferation and induces apoptosis in RL95 - 2 cells . AIM : To investigate whether JTE - 522 [ 4 - ( 4 - cyclohexyl - 2 - methyloxazol - 5 - yl ) - 2 - fluorobenzenesulfonamide ] , a selective P35354 REA inhibitor , can induce apoptosis and inhibit cell proliferation in human endometrial cancer cell line RL95 - 2 cells and to explore the molecular mechanisms . METHODS : [ 3 - ( 4,5 ) - dimethylthiazol - 2 - yl ] -2,5- diphenyl tetrazolium bromide ( MTT ) , DNA ladder , enzyme-linked immunosorbent assay ( ELISA ) , flow cytometry , RT-PCR , and Western blot analysis were employed to investigate effect of JTE - 522 on human endometrial cancer cell line RL95 - 2 cells and the related molecular mechanisms . RESULTS : JTE - 522 inhibited the growth of RL95 - 2 cells and induced the apoptosis . Furthermore , it arrested G0 / P55008 phase and inhibited S phase in RL95 - 2 cells . JTE - 522 inhibited the expressions of P35354 REA mRNA , phosphorylated Rb , and P11802 REA proteins , while increased the levels of p53 , P38936 REA , cyclin D1 proteins , and the activity of caspase - 3 in RL95 - 2 cells . CONCLUSION : JTE - 522 inhibits cell proliferation and induces apoptosis in RL95 - 2 cells , which may be associated with the activation of caspase - 3 - like proteases , down-regulation of the expression of P35354 REA mRNA , phosphorylated Rb , and P11802 REA proteins , and up-regulation of the expressions of p53 , P38936 REA , and cyclin D1 proteins .