interacts_with DB00977?
The N-end rule pathway counteracts cell death by destroying proapoptotic protein fragments . In the course of apoptosis , activated caspases cleave ∼500 to ∼1,000 different proteins in a mammalian cell . The dynamics of apoptosis involve a number of previously identified , caspase-generated proapoptotic protein fragments , defined as those that increase the probability of apoptosis . In contrast to activated caspases , which can be counteracted by inhibitor of apoptosis proteins , there is little understanding of antiapoptotic responses to proapoptotic protein fragments . One possibility is the regulation of proapoptotic fragments through their selective degradation . The previously identified proapoptotic fragments DB00151 - Q13546 , DB00151 - Q13077 , DB00128 - P38398 , DB00149 - P53667 , DB00135 - Q14511 , DB00125 - P55957 , DB00128 -BCL(XL) , DB00125 - O43521 (EL) , DB00128 - P54764 , and DB00135 -MET bear destabilizing N-terminal residues . Tellingly , the destabilizing nature ( but not necessarily the actual identity ) of N-terminal residues of proapoptotic fragments was invariably conserved in evolution . Here , we show that these proapoptotic fragments are short-lived substrates of the DB00125 /N-end rule pathway . Metabolic stabilization of at least one such fragment , DB00151 - Q13546 , greatly augmented the activation of the apoptosis-inducing effector caspase-3 . In agreement with this understanding , even a partial ablation of the DB00125 /N-end rule pathway in two specific N-end rule mutants is shown to sensitize cells to apoptosis . We also found that caspases can inactivate components of the DB00125 /N-end rule pathway , suggesting a mutual suppression between this pathway and proapoptotic signaling . Together , these results identify a mechanistically specific and functionally broad antiapoptotic role of the DB00125 /N-end rule pathway . In conjunction with other apoptosis-suppressing circuits , the DB00125 /N-end rule pathway contributes to thresholds that prevent a transient or otherwise weak proapoptotic signal from reaching the point of commitment to apoptosis . Signaling cascade that mediates endothelial nitric oxide synthase activation induced by atrial natriuretic peptide . Atrial natriuretic peptide ( P01160 ) induces activation of nitric oxide-synthase ( NOS ) . AIMS : to identify the isoform of NOS involved in P01160 effects , to study whether P01160 modifies NOS expression and to investigate the signaling pathways and receptors involved in NOS stimulation . NOS activation induced by P01160 would be mediated by endothelial NOS ( P29474 ) since neuronal or inducible NOS inhibition did not alter P01160 effect . The peptide induced no changes in P29474 protein expression . NOS activity stimulated by P01160 , in the kidney , aorta and left ventricle , was partially abolished by the P16066 /B antagonist , as well as PKG inhibition , but no difference in atria was observed . 8-Br-cGMP partially mimicked the effect of P01160 on NOS in all tissues . NOS stimulation by P01160 in atria disappeared when G protein was inhibited , but this effect was partial in the other tissues . P62158 antagonist abolished NOS stimulation via P01160 . Inhibition of the P98160 , PKC or P19957 kinase/Akt pathway failed to alter NOS activation induced by P01160 . P01160 would activate P29474 in the aorta , heart and kidney without modifying the expression of the enzyme . P01160 would interact with P17342 coupled via G proteins leading to the activation of Ca(2+)-calmodulin-dependent NOS in atria ; while in ventricle , aorta and kidney , P01160 could also interact with P16066 /B , increasing cGMP , which in turns activates PKG to stimulate P29474 . DB04958 , a humanized anti- P20273 antibody , in aggressive non-Hodgkin 's lymphoma : phase I/II clinical trial results . PURPOSE : We conducted a single-center , dose-escalation study evaluating the safety , pharmacokinetics , and efficacy of epratuzumab , an anti- P20273 humanized monoclonal antibody , in patients with aggressive non-Hodgkin 's lymphoma . EXPERIMENTAL DESIGN : DB04958 was administered once weekly for 4 weeks at 120-1000-mg/m2 doses to 56 patients [ most ( n = 35 ) with diffuse large B-cell lymphoma ] . RESULTS : Patients were heavily pretreated ( median , 4 prior therapies ) , 25 % received prior high-dose chemotherapy with stem cell transplant , and 84 % had bulky disease ( > or =5 cm ) . DB04958 was well tolerated , with no dose-limiting toxicity . Most ( 95 % ) infusions were completed within 1 h . The mean serum half-life was 23.9 days . Across all dose levels and histologies , objective responses ( ORs ) were observed in five patients ( 10 % ; 95 % confidence interval , 3-21 % ) , including three complete responses . In patients with diffuse large B-cell lymphoma , 15 % had ORs . Overall , 11 ( 20 % ) patients experienced some tumor mass reduction . Median duration of OR was 26.3 weeks , and median time to progression for responders was 35 weeks . Two responses are ongoing at > or =34 months , including one rituximab-refractory patient . CONCLUSIONS : These data demonstrate that epratuzumab has a good safety profile and exerts antitumor activity in aggressive non-Hodgkin 's lymphoma at doses of > or =240 mg/m2 , thus warranting further evaluation in this clinical setting . Altered regulation of renal nitric oxide , atrial natriuretic peptide and cyclooxygenase systems in aldosterone escape in rats . The present study was aimed to determine whether there is an altered role of local nitric oxide ( NO ) , atrial natriuretic peptide ( P01160 ) and cyclooxygenase ( P36551 ) systems in the kidney in association with the aldosterone escape . Male Sprague-Dawley rats were used . DB04630 ( 200 microg/day ) was infused through entire time course . The control group was kept on a low sodium diet ( 0.02 mEq/day ) , and the experimental group was supplied with a higher sodium diet ( 2. /day ) . Four days after beginning the regimen , the kidneys were taken . The protein expression of NO synthase ( NOS ) and P36551 isoforms was determined by semiquantitative immunoblotting . The mRNA expression of components of P01160 system was determined by real-time polymerase chain reaction . The activities of soluble and particulate guanylyl cyclases were determined by the amount of cGMP generated in responses to sodium nitroprusside and P01160 , respectively . There developed aldosterone escape in the experimental group . Accordingly , the renal content and the urinary excretion of NO increased . The expression of P29475 was increased in the inner medulla . Neither the expression of P29474 nor that of P35228 was changed . The expression and the catalytic activity of soluble guanylyl cyclase remained unaltered . The mRNA expression of P01160 was increased . Neither the expression of P16066 or P17342 nor the activity of particulate guanylyl cyclase was altered in the papilla . The protein expression of P35354 was increased in the inner medulla , while that of P23219 remained unchanged . In conclusion , the upregulation of P29475 , P01160 , and P35354 may be causally related with the aldosterone escape . DB01645 potentiates the P01160 effect on a K(+)-conductance in P29320 -293 cells . P29320 -293 cells are known to reflect many features of the late distal tubule . Furthermore , they have the ability to release urodilatin , the structural analog to P01160 . RT-PCR was performed to test for the expression of natriuretic peptide receptors . While the mRNA for the human P01160 receptor ( P16066 , P16066 ) could be amplified , the P09543 -specific receptor P20594 ( P20594 ) and the receptor specific for guanylins , P25092 , could not be detected . In patch clamp experiments the effects of P01160 ( 10 nM ) on membrane voltage ( V(m) ) were monitored and P29320 -293 cells depolarized by 2.3 +/- 0.5 mV ( n=14 ) . In the presence of the P01133 receptor blocker genistein ( 10 microM ) the effect of P01160 was increased by 65 % to 3.9 +/- 0.8 mV ( n=14 ) . After removal of genistein the P01160 -mediated depolarization further increased by 147 % to 5.7 +/- 1.0 mV ( n=14 ) . P01160 given repetitively without genistein had no increasing depolarizing effect in P29320 -293 cells with time . The P01160 effect could be fully blocked by 1 mM Ba(2+) and by 1 microM of the specific PKG inhibitor KT5823 indicating that P01160 inhibits a K(+)-conductance via a cGMP-dependent protein kinase . DB01645 itself hyperpolarized the membrane voltage of P29320 -293 cells by -3.9 +/- 0.6 mV ( n=11 ) and this effect could also be fully blocked by Ba(2+) ( -0.3 +/- 0.1 mV , n=5 ) , indicating that genistein activates a K(+)-conductance which contributes significantly to the membrane potential of P29320 -293 cells . Clinical development of eniluracil : current status . DB03516 is a potent inactivator of dihydropyrimidine dehydrogenase ( Q12882 ) , which is the first enzyme in the degradative pathway of systemically administered 5-fluorouracil ( DB00544 ) . Two completely oral regimens of eniluracil plus DB00544 are being evaluated in clinical trials : ( 1 ) a chronic schedule with both agents administered P55957 in a 10:1 ratio for 28 days of a 5-week course , and ( 2 ) a 5-day schedule of eniluracil once daily on days 1 through 7 and DB00544 once daily on days 2 through 6 . The clinical development of eniluracil is being pursued in several tumor types , including colorectal cancer , breast cancer , and pancreatic cancer . Response rates achieved in a phase II study of the chronic schedule of oral eniluracil/ DB00544 in patients with colorectal cancer compare favorably with those obtained in trials of intravenous DB00544 and leucovorin , while results from other trials are awaited . Safety analysis for the 28-day schedule has revealed a low incidence of severe toxicities , particularly as compared with standard DB00544 regimens . The cloning and reintroduction into animal cells of a functional CAD gene , a dominant amplifiable genetic marker . Rodent cells resistant to DB03459 , a specific inhibitor of the aspartate transcarbamylase activity of the multifunctional P27708 , overproduce CAD as a result of amplification of the CAD gene . We cloned a functional CAD gene from Syrian hamster cells using a cosmid vector . Two independently isolated cosmids containing CAD genes have inserts 40 and 45 kb long . We introduced the cloned genes into CAD-deficient Chinese hamster ovary ( CHO ) cell mutants by fusing them with protoplasts of Escherichia coli containing the cosmids . We also introduced the cloned genes into wild-type CHO cells by selecting cells that became resistant to high concentrations of DB03459 following protoplast fusion . The transformants of the mutant and wild-type CHO cells contain multiple active copies of the donated Syrian hamster CAD genes . The cloned genes in three independent transformants are integrated into host-cell chromosomes at single locations identified by in situ hybridization . In two of these transformants , the genes are located in one X chromosome or in a chromosome resembling the X . In the third case , the genes are located in a small metacentric or rearranged chromosome . Characterization of the StcE protease activity of Escherichia coli O157:H7 . The StcE zinc metalloprotease is secreted by enterohemorrhagic Escherichia coli ( EHEC ) O157:H7 and contributes to intimate adherence of this bacterium to host cells , a process essential for mammalian colonization . StcE has also been shown to localize the inflammatory regulator P05155 ( DB05341 ) to cell membranes . We tried to more fully characterize StcE activity to better understand its role in EHEC pathogenesis . StcE was active at pH 6.1 to 9.0 , in the presence of NaCl concentrations ranging from 0 to 600 mM , and at 4 degrees C to 55 degrees C . Interestingly , antisera against StcE or DB05341 did not eliminate StcE cleavage of DB05341 . Treatment of StcE with the proteases trypsin , chymotrypsin , human neutrophil elastase , and Pseudomonas aeruginosa elastase did not eliminate StcE activity against DB05341 . After StcE was kept at 23 degrees C for 65 days , it exhibited full proteolytic activity , and it retained 30 % of its original activity after incubation for 8 days at 37 degrees C . Together , these results show the StcE protease is a stable enzyme that is probably active in the environment of the colon . Additionally , k(cat)/K(m) data showed that StcE proteolytic activity was 2.5-fold more efficient with the secreted mucin Q8TAX7 than with the complement regulator DB05341 . This evidence supports a model which includes two roles for StcE during infection , in which StcE acts first as a mucinase and then as an anti-inflammatory agent by localizing DB05341 to cell membranes . Glucocorticoid-induced surface expression of annexin 1 blocks beta2-integrin adhesion of human eosinophils to intercellular adhesion molecule 1 surrogate protein . BACKGROUND : Glucocorticoids attenuate the population of eosinophils and T lymphocytes in asthmatic airways . The decrease in airway eosinophilia is caused both by accelerated cell death and by induction of blockade of integrin adhesion . In this study , we examined the hypothesis that annexin 1 surface expression , which is upregulated by the glucocorticoid receptor , prevents integrin adhesion essential to cell migration by blocking intracellular translocation of cytosolic group IV phospholipase A2 ( P47712 ) . OBJECTIVE : To examine the relationship of the glucocorticoid on annexin 1 expression and the effect of blockade of annexin 1 activity on adhesion of human eosinophils in vitro . To determine the relationship between annexin 1surface expression and nuclear membrane translocation of P47712 . METHODS : Eosinophils isolated from human peripheral blood were pretreated with fluticasone propionate ( FP ) , and beta2-integrin adhesion was measured after stimulation with P05113 or eotaxin . Effects of FP on P47712 expression , phosphorylation , and translocation were determined . The role of annexin 1 was examined by using annexin 1 blocking antibody and/or mimetic peptides . RESULTS : DB00588 decreased stimulated eosinophil adhesion and caused 4-fold increase in annexin 1 expression on the plasma membrane . Inhibition of adhesion by FP was blocked with annexin 1 blocking antibody . Annexin 1 N-terminal mimetic peptide also blocked beta2-integrin adhesion . Translocation of P47712 to the nuclear membrane was significantly blocked by incubation with FP . Blockade was reversed with annexin 1 blocking antibody . CONCLUSION : Blockade of beta2-integrin adhesion by glucocorticoid is regulated by annexin 1 , which blocks P47712 translocation to nuclear membrane . Q8NFH3 / Q8TCB0 mitogen-activated protein kinases inhibit atrial natriuretic peptide mRNA transcription in P40189 -mediated hypertrophic ventricular myocytes . OBJECTIVE : To understand the role of P01160 mRNA transcription regulation in P40189 -mediated cardiomyocyte hypertrophy , and the involved mitogen-activated protein kinase kinase ( MEK ) -extracellular signal-regulated kinase ( P29323 , also called Q8NFH3 / Q8TCB0 MAPK ) signaling pathway . METHODS : Isolated neonatal ventricular myocytes were treated with different concentrations of Q16619 ( 10(-9) , 10(-8)and 10(-7)mol/L ) . MTT was used to analyze the viability and RT-PCR was used to detect P01160 mRNA levels in cardiomyocyte . To inhibit Q8NFH3 / Q8TCB0 MAPK activity in hypertrophic cardiomyocytes , the cells were pretreated with a specific Q02750 inhibitor . RESULTS : Q16619 significantly induced P01160 mRNA expression and the viability of cardiomyocytes in a dose- and time-dependent manner . Furthermore , blocking Q8NFH3 / Q8TCB0 MAPK activity by the special Q02750 inhibitor upregulated the P01160 mRNA . CONCLUSIONS : Q8NFH3 / Q8TCB0 MAPK have an important role in suppressing P01160 mRNA transcription and cell activity in P40189 -mediated hypertrophic ventricular myocytes . Functional analysis of human Q8TAX7 mucin gene 5'-flanking region in lung epithelial cells . The human Q8TAX7 gene encodes a low-molecular-mass mucin glycoprotein that functions in modulation of microbial flora in the oral cavity and respiratory tracts . Q8TAX7 gene expression is tissue- and cell-specific , with dominant expression in salivary gland acinar cells . To begin to understand the molecular mechanisms responsible for controlling Q8TAX7 gene expression , we analyzed the promoter activity of Q8TAX7 5'-flanking region in a human lung epithelial cell line A549 . We demonstrated that Q8TAX7 gene is expressed constitutively in this cell line and is upregulated by P01375 stimulation . The promoter activities of a 2,762-bp fragment of the human genomic DNA ( -2,732/+30 bp ) and its deletion series , subcloned into a luciferase reporter vector , were characterized at the basal level and under stimulation by P01375 . The results indicated that the minimal functional Q8TAX7 promoter is in the region of -138/+30 bp . This region also revealed the greatest increase in the promoter activity upon P01375 stimulation . Two putative P05412 -binding elements and one NF-kappaB-binding element were identified within the proximal promoter . Further analyses demonstrated that mutations of these elements dramatically reduced specific DNA-protein binding ability and reporter gene expression . P05412 elements played an essential role in the constitutive expression , while the NF-kappaB element was crucially important in the response to P01375 stimulation , demonstrating that P01375 activates Q8TAX7 transcription via NF-kappaB signaling pathway . Neuronal influence behind the central nervous system regulation of the immune cells . Central nervous system ( CNS ) has a highly specialized microenvironment , and despite being initially considered an immune privileged site , this immune status is far from absolute because it varies with age and brain topography . The brain monitors immune responses by several means that act in parallel ; one pathway involves afferent nerves ( vagal nerve ) and the other resident cells ( neurons and glia ) . These cell populations exert a strong role in the regulation of the immune system , favoring an immune-modulatory environment in the CNS . Neurons control glial cell and infiltrated T-cells by contact-dependent and -independent mechanisms . Contact-dependent mechanisms are provided by several membrane immune modulating molecules such as Sema-7A , P48023 , P20273 , P41217 , Q08722 , P13591 , Q9UMF0 , and cadherins ; which can inhibit the expression of microglial inflammatory cytokines , induce apoptosis or inactivate infiltrated T-cells . On the other hand , soluble neuronal factors like Sema-3A , cytokines , neurotrophins , neuropeptides , and neurotransmitters attenuate microglial and/or T-cell activation . In this review , we focused on all known mechanism driven only by neurons in order to control the local immune cells . DB01373 /calmodulin-dependent protein kinase II increases glutamate and noradrenaline release from synaptosomes . A variety of evidence indicates that calcium-dependent protein phosphorylation modulates the release of neurotransmitter from nerve terminals . For instance , the injection of rat calcium/calmodulin-dependent protein kinase II ( Ca2+/ P62158 -dependent PK II ) into the preterminal digit of the squid giant synapse leads to an increase in the release of a so-far unidentified neurotransmitter induced by presynaptic depolarization . But until now , it has not been demonstrated that Ca2+/ P62158 -dependent PK II can also regulate neurotransmitter release in the vertebrate nervous system . Here we report that the introduction of Ca2+/ P62158 -dependent PK II , autoactivated by thiophosphorylation , into rat brain synaptosomes ( isolated nerve terminals ) increases the initial rate of induced release of two neurotransmitters , glutamate and noradrenaline . We also show that introduction of a selective peptidergic inhibitor of Ca2+/ P62158 -dependent PK II inhibits the initial rate of induced glutamate release . These results support the hypothesis that activation of Ca2+/ P62158 -dependent PK II in the nerve terminal removes a constraint on neurotransmitter release . Immunohistochemical analysis in ethinylestradiol-treated breast cancers after prior long-term estrogen-deprivation therapy . BACKGROUND : P03372 ( ER ) positive breast cancer can often be treated by hormone therapy ; however a certain population of ER-positive patients become resistant to hormone therapy after long-term hormone treatment . DB00977 ( EE2 ) is a derivative of estrogen , which has shown promising effects in these patients . METHODS : We successfully obtained tissue samples from 6 patients undergoing EE2 treatment and examined 13 well-known breast cancer-related factors by immunohistochemistry . Of the 6 patients , 5 responded but one patient did not . RESULTS : Before EE2 treatment , staining for both ER and androgen receptor ( AR ) was strong in the nucleus , and the progesterone receptor ( PgR ) was almost no staining . EE2 treatment significantly down-regulated ER and up-regulated PgR while nuclear and cytosolic AR were oppositely down- and up-regulated , respectively . Cytosolic staining of P38398 was significantly up-regulated by EE2 whereas nuclear staining tended to decrease . Individual comparisons suggested less induction of PgR and decreasing AKT but increasing pAKT in the non-responder following EE2 treatment . CONCLUSIONS : Our observations revealed that EE2 activated ER downstream genes ; however it did not stimulate cell growth . This suggests that hormone resistant cells might receive growth signals from a non-genomic pathway and this may be reflected in their sensitivity to EE2 treatment . Vampire bat plasminogen activator DB04925 -alpha-1 ( desmoteplase ) : a thrombolytic drug optimized by natural selection . P00747 activators are enzymes found in all vertebrate species investigated so far . Their physiological function is the generation of localized proteolysis in the context of tissue remodeling , wound healing and neuronal plasticity . The common vampire bat ( Desmodus rotundus ) is a New World species that feeds exclusively on blood . Its saliva contains highly potent plasminogen activators , specialized in rapid lysis of fresh blood clots . Biochemical and pharmacological evidence indicates that these plasminogen activators represent a new class of thrombolytics with pharmacological and toxicological properties superior to human tissue-type plasminogen activator , the clot dissolving agent now most frequently used in medicine . A form of the enzyme produced by recombinant DNA technology is currently employed to test this hypothesis in clinical studies . [ Level of neuropeptide Y in serum of patients with chronic congestive heart failure ] . The purpose of the study was to measure plasma concentrations of neuropeptide Y ( P01303 ) , endothelin-1,2 ( ET-1,2 ) , alpha atrial natriuretic polypeptide ( P01160 ) and noradrenaline ( NA ) in relation to cardiac index ( CI ) and left ventricular ejection fraction ( LVEF ) in patients with congestive heart failure ( CHF ) . There were significant increases in venous blood concentrations of P01303 , Na , ET-1,2 , P01160 in the patients with CHF . Plasma concentrations of P01303 correlated with plasma NA concentrations but plasma noradrenaline concentrations alone correlated with CI and LVEF . In patients with CHF plasma NA concentrations seems to be more sensitive index of cardiac dysfunction then the concentrations of neuropeptide Y . Differential display RT-PCR reveals genes associated with lithium-induced neuritogenesis in SK-N-MC cells . DB01356 is shown to be neurotrophic and protective against variety of environmental stresses both in vitro as well as in vivo . In view of the wider clinical applications , it is necessary to examine alterations in levels of expression of genes affected by lithium . DB01356 induces neuritogenesis in human neuroblastoma cell line SK-N-MC . Our aim was to elucidate genes involved in lithium-induced neuritogenesis using SK-N-MC cells . The differential display reverse transcriptase polymerase chain reaction ( DD-RT-PCR ) technique was used to study gene expression profiles in SK-N-MC cells undergoing lithium-induced neuritogenesis . Differential expression of genes in control and lithium ( 2.5 mM , 24 h ) -treated cells was compared by display of cDNAs generated by reverse transcription of mRNA followed by PCR using arbitrary primers . Expression of four genes was altered in lithium-treated cells . Real-time PCR was done to confirm the levels of expression of each of these genes using specific primers . DB01356 significantly up-regulated P13591 , a molecule known to stimulate neuritogenesis , occludin , a molecule participating in tight junctions and PKD2 , a molecule known to modulate calcium transport . P01160 32c , a gene whose function is not fully known yet , was found to be down-regulated by lithium . This is the first report demonstrating altered levels of expression of these genes in lithium-induced neuritogenesis and contributes four hitherto unreported candidates possibly involved in the process . Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen DB00977 ( EE ) and bisphenol-A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( DB00603 ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER-labelled neurons were higher in males than in females in the ARC and DB00603 . EE and Q03001 increased ER-labelled neurons in the ARC and DB00603 . At P01160 90 , females showed higher ER-labelled neurons in the VMH . EE and Q03001 increased ER-labelled neurons in the DB00603 in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats . Isolation and characterization of P62333 . A novel ATPase family component of the yeast 26 S proteasome . Using a genetic strategy designed to find proteins involved in the function of the Saccharomyces cerevisiae transcriptional activator GAL4 , we isolated mutants in two genes which rescue a class of gal4 activation domain mutants . One of these genes , P62195 , encodes a member of a large family of putative ATPases , the Conserved ATPase containing Domain ( CAD ) proteins ( also known as AAA proteins ) that are involved in a wide variety of cellular functions . Subsequently , P62195 was identified as a subunit of the 26 S proteasome . We have now cloned the gene defined by the second complementation group . P62333 encodes an essential 49-kDa protein that is also a member of the CAD family and is 43 % identical to P62195 . The mutation in sug2-1 , like that in sug1-1 , is found in the CAD near the highly conserved ATPase motif . We present biochemical and genetic evidence that P62333 is associated in vivo with P62195 and is a novel P27708 subunit of the 26 S proteasome . With its highly conserved mammalian homologs , human Q8NFH3 and ground squirrel CADp44 , P62333 defines a new class of proteasomal CAD proteins . The response of striatal neuropeptide Y and cholinergic neurons to excitatory amino acid agonists . The effect of excitatory amino acid antagonists on antagonist on neuropeptide Y ( P01303 ) and cholinergic neurons in the striatum of the rat was studied by means of P01303 immunocytochemistry , DB00677 histochemistry for acetylcholinesterase ( P22303 ) , and biochemical determinations of choline acetyltransferase ( P28329 ) . Intrastriatal infusion of drugs revealed that striatal neurons containing P01303 are more sensitive than cholinergic neurons to the neurotoxic actions of kainic acid ( KA ) , quinolinic acid ( QA ) and L-glutamic acid ( GA ) ; all 3 compounds produced a marked loss of P01303 neurons , but only a moderate decrease in the number of P22303 neurons or P28329 activity . Co-injection experiments showed that the neurotoxicity of QA and GA , but not that of KA , can be antagonized by the specific N-methyl-D-aspartate ( DB01221 ) receptor antagonist 3-((+/-)-2-(carboxypiperazine-4-yl))-propyl-1-phosphonic acid ( CPP ) . Destruction of the glutamatergic corticostriatal projection by cerebral decortication protected striatal P01303 and cholinergic neurons against KA neurotoxicity . These results indicate that striatal P01303 and cholinergic neurons receive prominent cortical amino acid afferents , and that the neurotoxic effect of QA and GA on these neurons is mediated through DB01221 receptors . Rationalizing cyclooxygenase ( P36551 ) inhibition for maximal efficacy and minimal adverse events . New information indicates that cyclooxygenase-2 ( P35354 ) is constitutively expressed in several tissues , including brain , lung , pancreas , kidney , and ovary , and plays an important role in renal and gastrointestinal function . Selective P35354 inhibition has been associated in animal studies with impairment of ulcer healing and renal function and inhibition of prostacyclin , an effect that inhibits vasodilation without inhibiting platelet aggregation . The clinical consequences , if any , of these effects remain to be determined in long-term studies in humans . The premise that selective P35354 inhibitors will cause less gastrointestinal toxicity than nonsteroidal antiinflammatory drugs that inhibit both P36551 isoforms needs to take into account the low toxicity of nabumetone . The gastrointestinal safety profile of this nonacidic , dual P36551 inhibitor that does not undergo enterohepatic circulation has been evaluated in extensive clinical trials . The data submitted to the US Food and Drug Administration in the New Drug Application for nabumetone ( DB00461 ) , the comparative trials subsequently completed , the published databases of the comparative gastrointestinal toxicity of various nonsteroidal anti-inflammatory drugs ( NSAIDs ) , and the meta-analysis published in this issue of The American Journal of Medicine ( Schoenfeld , page 48S ) indicate that nabumetone has the lowest incidence of gastrointestinal toxicity among the extensively studied NSAIDs . Overall , the incidence is approximately 10-fold less than with comparator drugs . This rate is an appropriate current reference against which the gastrointestinal toxicity of P35354 inhibitors can be compared . Encapsulation of viral vectors for gene therapy applications . In gene therapy , a number of viruses are currently being used as vectors to provide transient expression of therapeutic proteins . A drawback of using free virus is that it gives a potent immune response , which reduces gene transfer and limits re-administration . An alternative delivery system is to encapsulate the virus in poly(lactide-co-glycolide) ( P00747 ) microspheres prior to administration . A recombinant adenovirus ( Ad ) expressing green fluorescent protein ( GFP ) was used to test the transduction efficiency of Ad encapsulated in microspheres on target cells . The number of infected cells that expressed GFP was measured by flow cytometry . It was demonstrated that encapsulated viral vectors could successfully transduce target cells with encapsulation efficiencies up to 23 % and that the level of transduction could be controlled by varying both the quantity of microspheres and the amount of Ad in the microspheres . High transduction efficiencies and its recognized biocompatibility make P00747 -encapsulated Ad an attractive alternative to the use of free virus in gene therapy applications . The infectivity of Ad was found to be significantly influenced by the processing conditions and changes in environmental factors . Free Ad and encapsulated Ad were able to infect both E1 complimenting cells ( P29320 293 ) and non-complimenting cells ( A549 ) , with the viral expression in P29320 293 cells being 2.1 times greater than for A549 cells . Prevention of airway inflammation with topical cream containing imiquimod and small interfering RNA for natriuretic peptide receptor . BACKGROUND : Asthma is a complex disease , characterized by reversible airway obstruction , hyperresponsiveness and chronic inflammation . Principle pharmacologic treatments for asthma include bronchodilating beta2-agonists and anti-inflammatory glucocorticosteroids ; but these agents do not target the main cause of the disease , the generation of pathogenic Th2 cells . We previously reported reduction in allergic inflammation in mice deficient in the P01160 receptor NPRA . Here we determined whether siRNA for natriuretic peptide receptor A ( siNPRA ) protected against asthma when administered transdermally . METHODS : Imiquimod cream mixed with chitosan nanoparticles containing either siRNA green indicator ( siGLO ) or siNPRA was applied to the skin of mice . Delivery of siGLO was confirmed by fluorescence microscopy . The anti-inflammatory activity of transdermal siNPRA was tested in OVA-sensitized mice by measuring airway hyperresponsiveness , eosinophilia , lung histopathology and pro-inflammatory cytokines . RESULTS : SiGLO appearing in the lung proved the feasibility of transdermal delivery . In a mouse asthma model , BALB/c mice treated with imiquimod cream containing siNPRA chitosan nanoparticles showed significantly reduced airway hyperresponsiveness , eosinophilia , lung histopathology and pro-inflammatory cytokines P05112 and P05113 in lung homogenates compared to controls . CONCLUSION : These results demonstrate that topical cream containing imiquimod and siNPRA nanoparticles exerts an anti-inflammatory effect and may provide a new and simple therapy for asthma . Molecular targets and regulators of cardiac hypertrophy . Cardiac hypertrophy is one of the main ways in which cardiomyocytes respond to mechanical and neurohormonal stimuli . It enables myocytes to increase their work output , which improves cardiac pump function . Although cardiac hypertrophy may initially represent an adaptive response of the myocardium , ultimately , it often progresses to ventricular dilatation and heart failure which is one of the leading causes of mortality in the western world . A number of signaling modulators that influence gene expression , apoptosis , cytokine release and growth factor signaling , etc. are known to regulate heart . By using genetic and cellular models of cardiac hypertrophy it has been proved that pathological hypertrophy can be prevented or reversed . This finding has promoted an enormous drive to identify novel and specific regulators of hypertrophy . In this review , we have discussed the various molecular signal transduction pathways and the regulators of hypertrophic response which includes calcineurin , cGMP , NFAT , natriuretic peptides , histone deacetylase , P05231 cytokine family , Gq/ P49842 signaling , PI3K , MAPK pathways , Na/H exchanger , DB01367 , polypeptide growth factors , P01160 , NO , P01375 , Q07869 and JAK/ P35610 pathway , microRNA , Cardiac angiogenesis and gene mutations in adult heart . Augmented knowledge of these signaling pathways and their interactions may potentially be translated into pharmacological therapies for the treatment of various cardiac diseases that are adversely affected by hypertrophy . The purpose of this review is to provide the current knowledge about the molecular pathogenesis of cardiac hypertrophy , with special emphasis on novel researches and investigations .