interacts_with DB04905?
Population pharmacokinetic study of memantine : effects of clinical and genetic factors . BACKGROUND AND OBJECTIVE : Memantine , a frequently prescribed anti-dementia drug , is mainly eliminated unchanged by the kidneys , partly via tubular secretion . Considerable inter-individual variability in plasma concentrations has been reported . We aimed to investigate clinical and genetic factors influencing memantine disposition . METHODS : A population pharmacokinetic study was performed including data from 108 patients recruited in a naturalistic setting . Patients were genotyped for common polymorphisms in renal cation transporters ( O15245 /2/5 , Q96FL8 , P08183 ) and nuclear receptors ( O75469 , Q14994 , RXR , Q07869 ) involved in transporter expression . RESULTS : The average clearance was 5.2 L/h with a 27 % inter-individual variability ( percentage coefficient of variation ) . Glomerular filtration rate ( p = 0.007 ) and sex ( p = 0.001 ) markedly influenced memantine clearance . O75469 rs1523130 was identified as the unique significant genetic covariate for memantine clearance ( p = 0.006 ) , with carriers of the O75469 rs1523130 CT/TT genotypes presenting a 16 % slower memantine elimination than carriers of the CC genotype . CONCLUSION : The better understanding of inter-individual variability of memantine disposition might be beneficial in the context of individual dose optimization . Safety and efficacy of panitumumab following cetuximab : retrospective review of the Memorial Sloan-Kettering experience . There are two highly selective antibodies to the epidermal growth factor receptor ( P00533 ) now available for use in metastatic colorectal cancer ( mCRC ) . In P01116 wild type patients , cetuximab ( Cmab ) -an IgG1 chimeric molecule -- has activity alone and in combination with chemotherapy for the first , second and third-line settings . DB01269 ( Pmab ) -- a fully humanized IgG2 molecule -- has activity as a single agent in chemorefractory mCRC and shows promising activity in combination with chemotherapy . It remains unclear which antibody to use . This retrospective review of our experience with Pmab in 13 P00533 antibody-naive patients and in 22 patients previously treated with Cmab for mCRC highlights a lack of hypersensitivity reactions ( HSR ) with Pmab , even in patients who experienced HSR to Cmab . In patients who received Cmab , 22 % developed grade 3-4 HSR . There were no HSR on subsequent treatment with Pmab . We demonstrate similar activity in 95 % of cases , between Cmab and Pmab both alone and in combination with chemotherapy in the treatment of mCRC . In one case we report unique sensitivity to Pmab after progression with Cmab . The expression of the solute carriers Q14973 and O75051 -1 is regulated by cholesterol in HepG2 cells . Drug disposition and response are greatly determined by the activities of drug-metabolizing enzymes and transporters . While the knowledge in terms of CYP enzymes and efflux ABC transporters ( such as P08183 , P-glycoprotein ) is quite extensive , influx transporters are increasingly being unveiled as key contributors to the process of drug disposition . There is little information on the regulation of these proteins in human cells , especially as regards the effect of endogenous compounds . In this study , we analysed the expression of P08684 and three uptake transporters Q14973 ( Q14973 ) , P46721 / P46721 ( P46721 ) and O75051 -1 ( O15245 ) in HepG2 cells following treatment with cholesterol . While P08684 and P46721 expression was unaffected , cholesterol treatment led to increased levels of Q14973 and O75051 -1 mRNAs . Alterations in the functional characteristics and/or expression levels of drug transporters in the liver may conceivably contribute to the variability in drug oral bioavailability often observed in the clinical settings . P04150 polymorphisms in major depression . Focus on glucocorticoid sensitivity and neurocognitive functioning . Previously , it has been suggested that hypothalamic-pituitary-adrenal ( Q9Y251 ) axis dysregulation and , as a consequence , increased cortisol levels , is not only a state phenomenon , but may also be a trait phenomenon in mood disorders . DB00741 exerts its effects mainly by binding to the glucocorticoid receptor ( GR ) and , of particular interest in certain brain regions , the mineralocorticoid receptor ( MR ) . Several GR polymorphisms have been shown to be associated with altered sensitivity of the Q9Y251 axis . Recently , the GR polymorphisms BclI and ER22/23EK have been associated with unipolar depression in several studies . In addition , the ER22/23EK polymorphism seems to be associated with a decreased risk of dementia in healthy individuals . Also , during a depressive episode , carriers of this ER22/23EK variant demonstrated a tendency toward better cognition , as measured by divided attention tests . In this overview , currently known clinically relevant GR and MR polymorphisms are discussed in relation to mood disorders ( both unipolar depression and bipolar disorder ) and cognitive function . Q96EB6 deacetylase promotes acquisition of genetic mutations for drug resistance in CML cells . P11274 - P00519 transforms bone marrow progenitor cells and promotes genome instability , leading to development of chronic myelogenous leukemia ( CML ) . The tyrosine kinase inhibitor imatinib effectively treats CML , but acquired resistance can develop because of P11274 - P00519 mutations . Mechanisms for acquisition of P11274 - P00519 mutations are not fully understood . Using a novel culture model of CML acquired resistance , we show that inhibition of Q96EB6 deacetylase by small molecule inhibitors or gene knockdown blocks acquisition of P11274 - P00519 mutations and relapse of CML cells on tyrosine kinase inhibitors . Q96EB6 knockdown also suppresses de novo genetic mutations of hypoxanthine phosphoribosyl transferase gene in CML and non-CML cells upon treatment with DNA damaging agent camptothecin . Although Q96EB6 can enhance cellular DNA damage response , it alters functions of DNA repair machineries in CML cells and stimulates activity of error-prone DNA damage repair , in association with acquisition of genetic mutations . These results reveal a previously unrecognized role of Q96EB6 for promoting mutation acquisition in cancer , and have implication for targeting Q96EB6 to overcome CML drug resistance . Effective dasatinib uptake may occur without human organic cation transporter 1 ( O15245 ) : implications for the treatment of imatinib-resistant chronic myeloid leukemia . We have previously shown that imatinib uptake into chronic myeloid leukemia ( CML ) cells is dependent on human organic cation transporter 1 ( O15245 ; O15245 ) , and that low O15245 expression is an important determinant of clinical outcome to imatinib treatment . We hypothesized that dasatinib might be transported differently than imatinib , possibly accounting for its favorable effects in imatinib-resistant patients . (14)C-dasatinib uptake was greater in KCL22-transfected cells with pcDNA3- O15245 plasmid ( high O15245 -expressing cells ) than in control cells ( P = .02 ) . However , hOCT inhibitors did not decrease dasatinib uptake into either control or primary cells , in contrast to their block on imatinib uptake . Dasa-tinib decreased the level of phosphorylated CrkL to 49.9 % in control and 40.3 % in high O15245 -expressing cells . Dasa-tinib efflux was investigated in confluent P08183 -transfected MDCKII cell monolayers . Both dasatinib and imatinib were transported from the basal to the apical layer , indicating that they were transported by P08183 , which was confirmed using the P08183 inhibitor PSC833 ( P = .001 and P < .001 , respectively ) . Compared with imatinib , dasatinib achieved superior intracellular levels and P11274 - P00519 suppression even in cells with low or blocked O15245 . Efflux of dasatinib and imatinib appear similar via P08183 . Dasatinib may therefore offer an advantage over imatinib in patients with low O15245 expression . Potential pancreatic lipase inhibitory activity of an endophytic Penicillium species . P16233 ( PL ) is considered as one of the safest target for diet-induced anti-obesity drug development . DB01083 is the only PL inhibitor approved for anti-obesity treatment till date . In the process of exploration of new PL inhibitors , we have screened culture filtrates of 70 endophytic fungi of medicinal plants using qualitative as well as quantitative in-vitro PL assays . The qualitative assays indicated potential PL inhibition in only three isolates , namely # 57 TBBALM , # 33 TBBALM and # 1 CSSTOT . Only ethyl acetate extracts of the culture filtrates of these isolates exhibited the PL inhibition . # 57 TBBLAM ethyl acetate extract of culture filtrate exhibited potential PL inhibition with an IC50 of 3.69 µg/ml which was comparable to the positive control , i.e. DB01083 exhibiting IC50 value of 2.73 µg/ml . Further molecular phylogenetic tools and morphological studies were used to identify the isolate # 57 TBBALM as Penicillium species . Personalized medicine and pharmacogenetic biomarkers : progress in molecular oncology testing . In the field of oncology , clinical molecular diagnostics and biomarker discoveries are constantly advancing as the intricate molecular mechanisms that transform a normal cell into an aberrant state in concert with the dysregulation of alternative complementary pathways are increasingly understood . Progress in biomarker technology , coupled with the companion clinical diagnostic laboratory tests , continue to advance this field , where individualized and customized treatment appropriate for each individual patient define the standard of care . Here , we discuss the current commonly used predictive pharmacogenetic biomarkers in clinical oncology molecular testing : P15056 V600E for vemurafenib in melanoma ; Q9HC35 - Q9UM73 for crizotinib and P00533 for erlotinib and gefitinib in non-small-cell lung cancer ; P01116 against the use of cetuximab and panitumumab in colorectal cancer ; P04626 ( P04626 /neu ) for trastuzumab in breast cancer ; P11274 - P00519 for tyrosine kinase inhibitors in chronic myeloid leukemia ; and P29590 /RARα for all-trans-retinoic acid and arsenic trioxide treatment for acute promyelocytic leukemia . Arundic acid ( DB05343 ) ameliorates delayed ischemic brain damage by preventing astrocytic overproduction of P04271 . After focal cerebral ischemia , the infarct volume increases rapidly within acute infarct expansion ( initial 12 to 24 h ) and continues slowly during delayed infarct expansion ( 25 to 168 h ) . While acute infarct expansion represents progressive necrosis within the ischemic core , delayed infarct expansion starts as disseminated apoptotic cell death in a narrow rim surrounding the infarct border , which gradually coalesces to form a larger infarct . Discovery of a distinct correlation between reactive astrogliosis along the infarct border and delayed infarct expansion in the rodent ischemia model led us to investigate the possible causal relationship between the two events . Specifically , the calcium binding protein P04271 exerts detrimental effects on cell survival through activation of various intracellular signaling pathways , resulting in altered protein expression . Arundic acid [ ( R ) -(-)-2-propyloctanoic acid , DB05343 ] is a novel agent that inhibits P04271 synthesis in cultured astrocytes . In the rodent ischemia model , this agent was shown to inhibit both the astrocytic overexpression of P04271 and the subsequent activation of signaling pathways in the peri-infarct area . Concurrently , delayed infarct expansion was prevented , and neurologic deficits were promptly ameliorated . The results of subsequent studies suggest that the efficacy of arundic acid is mediated by restoring the activity of astroglial glutamate transporters via enhanced genetic expression . Contribution of peroxisome-specific isoform of Lon protease in sorting PTS1 proteins to peroxisomes . Using an organelle proteomics approach , we previously studied the rat peroxisome in order to characterize the proteins participating in its biogenesis . A peroxisome-specific isoform of Lon ( pLon ) protein was accordingly identified . However , the precise role of pLon in peroxisomes remains to be elucidated . Here , we demonstrate that pLon plays a role in processing and activating a specific regulatory protein belonging to the peroxisome targeting signal ( Q03393 ) 1-containing proteins . Proteomic analysis of proteins co-immunoprecipitated with Lon suggested that Lon interacts with P28288 and several enzymes involved in beta-oxidation , including acyl- DB01992 oxidase ( Q15067 ) . The processing of Q15067 for its activation in peroxisomes was strongly inhibited in cells expressing a dominant negative form of pLon . Furthermore , a catalase possessing a modified PTS1 sequence was misdistributed in this cell line . pLon exhibits little , if any , in vitro Q15067 processing activity , and does not process PTS2-containing 3-ketoacyl-coenzyme A thiolase ( P16233 ) . Therefore , pLon may specifically control , sort and process PTS1 proteins . Based on the relationship between pLon and the beta-oxidation enzymes that regulate peroxisomal morphology , the observation of enlarged peroxisomes in cells expressing recombinant pLon suggests that pLon is a critical factor determining peroxisome morphology . Inhibition of the leukotriene synthetase of rat basophil leukemia cells by diethylcarbamazine , and synergism between diethylcarbamazine and piriprost , a P09917 inhibitor . DB00711 inhibited the formation of sulfidopeptide leukotrienes in rat basophil leukemia ( RBL ) cells ( 50 % inhibitory concentration , EC50 , 3 mM ) . Similar concentrations also inhibited the formation of leukotriene C4 ( LTC4 ) by LTC synthetase , a detergent-solubilized cell free particulate enzyme from RBL cells which is capable of coupling P09960 to glutathione . By contrast , the conversion of P09960 to LTC4 using enzymes from rat liver was at least ten times less sensitive to this inhibitor . The EC50 for inhibition of the leukotriene C synthetase of RBL cells was directly proportional to the P09960 concentration in the incubations , ranging from 1.5 mM at 10 microM P09960 to over 40 mM at 500 microM P09960 . Kinetic analysis revealed that the inhibition of the leukotriene C synthetase reaction by diethylcarbamazine was competitive with respect to P09960 . In contrast to diethylcarbamazine , piriprost ( U-60,257 ; 6,9-deepoxy-6,9-(phenylimino)-delta 6,8-prostaglandin I1 ) , which inhibits the formation of sulfidopeptide leuktrienes in RBL cells at the P09917 step ( EC50 5 microM ) , did not inhibit the leukotriene synthetase of these cells . On the other hand , low concentrations of piriprost , which had no demonstrable inhibitory activity on leukotriene formation by themselves , markedly synergized the inhibitory activity of diethylcarbamazine . These results are consistent with the interpretation that both piriprost and diethylcarbamazine inhibit leukotriene formation but that they act on sequential steps in the biosynthetic pathway in such a manner as to synergistically interfere with the availability or utilization of P09960 in the leukotriene C synthetase reaction . P15090 , a candidate progression marker of human transitional cell carcinoma of the bladder , is differentially regulated by Q07869 in urothelial cancer cells . Superficial pT1 bladder tumors are characterized by a high risk of recurrence and progression in grade and stage . Few studies provided evidence that loss of adipocyte-fatty acid binding protein ( P15090 ) expression was associated with bladder cancer progression . P15090 is a lipid binding protein playing a role in intracellular lipid transport and metabolism , as well as in signal transduction . We reported from bladder tumors that decrease of P15090 transcript level significantly correlated to tumor stage and to histologic grade ( p < 0.05 ) . Namely , in poor prognosis high grade pT1 tumors there was a loss of P15090 expression compared to good prognosis tumors suggesting that re-expression of P15090 could be a therapeutic approach in early stage bladder cancer to prevent disease progression . We demonstrated for the first time that this marker is upregulated by Peroxisome Proliferator-Activated Receptor ( Q07869 ) alpha , beta and gamma in T24 cells ( derived from an undifferentiated grade III carcinoma ) and only by PPARbeta in RT4 cells ( derived from a well differentiated grade I papillary tumor ) . This effect occurred through a Q07869 -dependent transcriptional mechanism without modifying mRNA stability and interestingly required de novo protein synthesis . Data as a whole suggest a prognostic significance of P15090 in bladder cancer outcome and the potential utility of overexpression of this protein by Q07869 agonists open up new perspectives in the treatment of bladder cancer . ( c ) 2008 Wiley-Liss , Inc . Effect of N9-methylation and bridge atom variation on the activity of 5-substituted 2,4-diaminopyrrolo[2,3-d]pyrimidines against dihydrofolate reductases from Pneumocystis carinii and Toxoplasma gondii . The effect of N9-methylation and bridge atom variation on inhibitory potency and selectivity of 2,4-diaminopyrrolo[2,3-d]pyrimidines against dihydrofolate reductases ( P00374 ) was studied . Specifically three nonclassical 2,4-diamino-5-((N-methylanilino)methyl)pyrrolo[2,3-d]pyrimidines with 2',5'-dimethoxyphenyl ( 2 ) , 3',4'-dichlorophenyl ( 3 ) , 1'-naphthyl ( 4 ) , one classical analogue with a 4'-L-glutamate substituent ( 10 ) , and four nonclassical 2,4-diamino-5-((phenylthio)methyl)pyrrolo[2,3-d]pyrimidines with 3',4'-dimethoxyphenyl ( 5 ) , 3',4'-dichlorophenyl ( 6 ) , 1'-naphthyl ( 7 ) , and 2'-naphthyl ( 8 ) substituents were synthesized . The classical and nonclassical analogues were obtained by displacement of the intermediate 2,4-diamino-5-bromomethylpyrrolo[2,3-d]pyrimidine , 14 , with appropriately substituted N-methylaniline , thiophenols , or 4-(N-methylamino)benzoyl-L-glutamate . Compounds 2-8 and 10 were evaluated against Pneumocystis carinii ( pc ) , Toxoplasma gondii ( tg ) , and rat liver ( rl ) DHFRs . The N-methyl and thiomethyl analogues were more inhibitory than their corresponding anilinomethyl analogues ( previously reported ) against all three DHFRs . The inhibitory potency of these analogues was greater against rlDHFR than against tgDHFR which resulted in a loss of selectivity for tgDHFR compared to the N9-H analogues . The classical N9-methyl analogue 10 was more potent and about 2-fold more selective against tgDHFR than its corresponding desmethyl analogue . All of the analogues , 2-8 and 10 , were more selective than trimetrexate ( DB01157 ) against pcDHFR ( except 4 ) and significantly more selective than DB01157 against tgDHFR . [ Molecular relapse of chronic myeloid leukemia after discontinuation of imatinib mesylate for maintaining complete molecular response for more than 2 years ] . Although imatinib mesylate therapy is effective for chronic myeloid leukemia ( CML ) patients , there are still some unanswered questions . It is unclear whether imatinib can actually cure CML and whether this therapy can be safely discontinued in patients showing complete cytogenetic and molecular responses . This report describes the clinical outcome of a patient with chronic phase CML who discontinued imatinib therapy after achieving molecular remission . This patient has shown a relapse based on transcription-mediated amplification-hybridization protection assay ( TMA- Q9Y251 ) to monitor P11274 - P00519 transcripts , highlighting the uncertainty of discontinuing imatinib therapy for five months . Enhancement of cytotoxicity of natural product drugs against multidrug resistant variant cell lines of human head and neck squamous cell carcinoma and breast carcinoma by tesmilifene . N,N-diethyl-2-[4-(phenylmethyl)phenoxyl]ethanamine ( tesmilifene ) , a tamoxifen derivative with antihistamine activity , greatly enhanced the survival of doxorubicin-treated , advanced stage breast cancer patients in a phase III trial . However , the molecular basis of tesmilifene action is not firmly established . The effects of tesmilifene on activity of several anticancer drugs was investigated using human head and neck squamous cell carcinoma ( HNSCC ) and breast carcinoma cell lines as a model system . Multidrug resistant ( MDR ) variants of an HNSCC cell line , HN-5a/V15e , and a breast carcinoma cell line , MCF-7/V25a , both highly overexpressed mdr1 ( P08183 ) mRNA and the proteins P-glycoprotein and glutathione transferase-pi . Drug sensitivities were measured by a vital stain after 4 days of continuous exposure to anticancer drug in the absence and presence of tesmilifene at a concentration that alone had no antiproliferative effect . DB04905 had minimal effect on drug cytotoxicity against the parental cell lines . However , the same tesmilifene treatment enhanced cytotoxicity of docetaxel , paclitaxel , epirubicin , doxorubicin , and vinorelbine against both MDR cell lines by up to 50 % . Flow cytometric measurement of annexin V/propidium iodide staining demonstrated that tesmilifene increased the killing of HN-5a/V15e cells caused by docetaxel after 24 and 48h exposure . DB04905 increased accumulation of radiolabelled vincristine in HN-5a/V15e cells , over 4h , by up to 100 % . The results suggest that tesmilifene might be effective in the treatment of tumors that are resistant to natural product drugs . The mechanism of enhancement appears to be related to expression of an ABC pump-dependent , MDR phenotype . PEGylation of growth hormone-releasing hormone ( P01286 ) analogues . Synthetically produced GRF1-29 ( DB00010 ) has an amino acid composition identical to the N-terminal 29 amino acids sequence of the natural hypothalamic GHRH1-44 ( Figure 1 ) . It maintains bioactivity in vitro and is almost equally effective in eliciting secretion of endogenous growth hormone in vivo . The main drawbacks associated with the pharmaceutical use of hGRF1-29 relate to its short half-life in plasma , about 10-20 min in humans , which is caused mostly by renal ultrafiltration and enzymatic degradation at the N terminus . PEGylation has been considered as one valid approach to obtain more stable forms of the peptide , with a longer in vivo half-life and ultimately with increased pharmacodynamic response along the somatotropic axis ( endogenous GH , DB01277 levels ) . Different PEGylated P01286 conjugates were obtained and their bioactivity was tested in vitro and in vivo by monitoring endogenous growth hormone ( GH ) serum levels after intravenous ( i.v. ) injection in rats , and intravenous and subcutaneous ( s.c. ) injection in pigs . It was found that P01286 -PEG conjugates are able to bind and activate the human Q02643 , although with different potency . The effect of PEG molecular weight , number of PEG chains bound and position of PEGylation site on P01286 activity were investigated . Mono-PEGylated isomers with a PEG5000 polymer chain linked to Lys 12 or Lys 21 residues , showed high biological activity in vitro , which is similar to that of hGRF1-29 , and a higher pharmacodynamic response as compared to unmodified P01286 molecule . Polyamines and membrane transporters . In recent years , our understanding of the importance of membrane transporters ( MTs ) in the disposition of and response to drugs has increased significantly . MTs are proteins that regulate the transport of endogenous molecules and xenobiotics across the cell membrane . In mammals , two super-families have been identified : DB00171 -binding cassette ( DB01048 ) and solute carrier ( O00585 ) transporters . There is evidence that MTs might mediate polyamines ( PA ) transport . PA are ubiquitous polycations which are found in all living cells . In mammalian cells , three major PA are synthesised : putrescine , spermidine and spermine ; whilst the decarboxylated arginine ( agmatine ) is not produced by mammals but is synthesised by plants and bacteria . In addition , research in the PA field suggests that PA are transported into cells via a specific transporter , the polyamine transport system(s) ( Q03393 ) . Although the Q03393 has not been fully defined , there is evidence that some of the known MTs might be involved in PA transport . In this mini review , eight O00585 transporters will be reviewed and their potential to mediate PA transport in human cells discussed . These transporters are O15245 , O15244 , O75751 , Q96FL8 , P30825 , P08195 , SLC12A8A , and Q86VW1 . Preliminary data from our laboratory have revealed that O15245 might be involved in the PA uptake ; in addition to one member of ABC superfamily ( P08183 protein ) might also mediate the efflux of polyamine like molecules . P00505 from rat heart is phosphorylated on Tyr19 in response to insulin stimulation . The cytosolic fatty acid-binding protein from rat heart ( P05413 , M(r) 15,000 ) as well as FABP from mouse adipocytes ( P15090 , 62 % homologous with P05413 ) contain a recognition sequence for protein tyrosine kinases , DB00174 - DB00120 - DB00128 - DB00128 -Tyr19 . P15090 has been shown by others to be partly phosphorylated on Tyr19 , thus encouraging experiments designed to search for phosphotyrosine in P05413 . For this purpose isolated cardiac myocytes were incubated with [32P]orthophosphate and analyzed by two-dimensional gel electrophoresis . A 15 kDa phosphoprotein present in the cytosolic protein fraction was specifically precipitated by a polyclonal antibody against rat heart FABP . Characterization of the phosphorylated FABP was facilitated by the development of an immunoaffinity purification procedure capable of isolating more than 200 micrograms FABP from four rat hearts in one step . Phosphoamino acid analysis and radiosequencing of the major tryptic phosphopeptide from immunopurified FABP revealed Tyr19 as the phosphorylated amino acid . Stimulation of cardiac myocytes with insulin in the presence of tyrosine phosphatase inhibitors led to a several-fold increase in the amount of phosphorylated FABP compared with a nearly undetectable level found without insulin stimulation , indicating that FABP may be a substrate for the insulin receptor tyrosine kinase . Phosphorylated FABP constitutes only a minor fraction compared to the large pool of FABP in the cardiac myocyte , thus obscuring the significance of this modification . However , as the phosphorylated Tyr19 residue is positioned within a helix-turn-helix-related domain of FABP , this modification may modulate a hitherto unknown DNA binding activity of FABP . A hypothesis is discussed in which phosphorylated FABP serves as a signalling molecule in the insulin signal transduction cascade . [ Circumventing multidrug resistance in human cancer by anti-ribozyme ] . The demonstration tha RNA can be cleavaged by cis-ribozyme ( catalytic RNAs , RNA enzyme ) has potentially important therapeutic implications . Ribozymes are effective for modulation of gene expression because of their simple structure , site-specific cleavage activity and catalytic potential . The targets of ribozyme-mediated gene modulation have ranged from cancer cells to foreign genes that cause infectious diseases . Additional target sites for ribozymes are in initial phases of development and design . Ribozymes have been targeted against myriad genes , including oncogenes ( ras , P11274 - P00519 ) and drug resistance genes ( MDR-1 , c-fos , P00374 ) . These ribozymes have cleaved the target RNAs in culture system ( in vitro ) and developed in vivo system . We reported that anti-fos ribozyme has altered the expression of c-fos and DNA repair genes in cisplatin-resistance cancer cells , and reversed the sensitivity to ciaplatin . Furthermore , we have developed high efficiency by the transfer system using an electroporation in vivo . DB02709 protects against peripheral deficits in a mouse model of Huntington 's disease . Sirtuins are NAD-dependent deacetylases that regulate important biologic processes including transcription , cell survival and metabolism . Activation of Q96EB6 , a mammalian sirtuin , extends longevity and increases neuronal survival . An important substrate of Q96EB6 is peroxisome proliferator-activated receptor gamma co-activator-1alpha ( P20142 -1alpha ) , a principal regulator of energy metabolism , whose function is significantly impaired in Huntington 's disease ( HD ) . We studied the effects of a pharmacological preparation of the Q96EB6 activator resveratrol ( DB05073 -M ) , in the N171-82Q transgenic mouse model of HD . We analyzed motor performance , survival , central and peripheral pathology and levels of P20142 -1alpha expression . Administration of DB05073 -M increased expression of P20142 -1alpha , as well as its downstream targets , nuclear respiratory factor-1 ( Q16656 ) and uncoupling protein-1 ( P25874 -1 ) in brown adipose tissue ( Q14032 ) , but there was no effect on P20142 -1alpha , Q16656 or the mitochondrial transcription factor ( Tfam ) in the striatum . DB05073 -M administration also reduced Q14032 vacuolation and decreased elevated blood glucose levels . However , there was no significant improvement in weight loss , motor performance , survival and striatal atrophy . Activation of the P20142 -1alpha signaling pathway via resveratrol-induced activation of Q96EB6 , therefore , is an effective therapy in Q14032 , but not in the central nervous system of HD transgenic mice . Effect of the hemoregulatory peptide (pEEDCK)2 (pyroGlu- DB00142 - DB00128 - DB00151 -Lys)2 and MIP-1alpha is reduced in bone marrow cultures from patients with chronic myeloid leukemia ( CML ) . The granulocyte-derived hemoregulatory peptide pyroGlu- DB00142 - DB00128 - DB00151 -Lys = pEEDCK is known to keep hematopoietic cells quiescent . When oxidized to its dimeric form (pEEDCK)2 , it activates growth of hematopoietic progenitors in association with stroma-derived cytokines . (pEEDCK)2 has a DB00151 - DB00151 motif which is also a typical feature of the macrophage inflammatory protein ( MIP-1alpha ) . The present study was designed to analyze differences between the response of normal and leukemic progenitor cells to (pEEDCK)2 or MIP-1alpha . When long-term bone marrow cultures ( LTBMCs ) were incubated with (pEEDCK)2 or MIP-1alpha and/or cytokines , the stimulatory effect on colony-forming units-granulocyte/erythroid/macrophage/megakaryocyte of LTBMC from chronic myeloid leukemia ( CML ) patients was less than 50 % compared to LTBMC from healthy humans . No difference in oncogene expression could be observed in LTBMC from CML patients regarding reduction of Philadelphia chromosome-associated transcription of the P11274 - P00519 gene . With respect to the expression of growth and differentiation-associated genes ( Galpha16 , P09917 , phospholipaseA2 , c-kit , and P28906 ) , which were analyzed from LTBMC by semiquantitative reverse transcriptase-polymerase chain reaction , the same transcription rate was observed in CML patients and healthy donors . However , two isoforms of a key enzyme of oxidative metabolism , carnitine palmitoyltransferase ( P50416 and Q92523 ) , showed 50-fold higher expression rates in LTBMC cells of healthy donors compared to CML patients . It is known that a decrease in oxidative metabolism is associated with an increase in redox equivalents in malignancy . This might result in a reduction of disulphide bonds in (pEEDCK)2 or MIP-1alpha , thus inducing a downregulation of these factors in bone marrow from CML patients . Reversible lipidization prolongs the pharmacological effect , plasma duration , and liver retention of octreotide . PURPOSE : DB00104 ( O75051 ) was reversibly lipidized to improve the pharmacological effect and to increase the plasma half-life and the liver retention of O75051 for greater therapeutic potential in the treatment of liver cancers such as hepatocellular carcinoma . METHODS : O75051 was chemically modified using reversible aqueous lipidization ( REAL ) technology . REAL-modified O75051 ( REAL- O75051 ) was characterized with high performance liquid chromatography ( HPLC ) and matrix-assisted laser desorption/ionization time-of-flight ( MALDI-TOF ) mass spectrometry . A single dose of O75051 or REAL- O75051 or vehicle only was subcutaneously administered to male Sprague-Dawley rats , and the plasma growth hormone ( GH ) levels were measured after an intravenous injection of 2.5 microg/kg of growth hormone releasing factor ( P01286 ) to assess the ability of REAL- O75051 on GH inhibition . Radio-iodinated Tyr3- O75051 ( TOC ) and REAL-TOC were used for pharmacokinetic studies . RESULTS : At 0.1 mg/kg , REAL- O75051 inhibited the P01286 -induced GH surge in rats for a greater than 24-h period in comparison to the 6-h period for O75051 . The distribution and elimination half-life for 125I-REAL-TOC were 1.4 h and 6.6 h , respectively , which were significantly longer than those of 125I-TOC . Sustained high blood concentrations and reduced in vivo degradation were observed for 125I-REAL-TOC . In addition , 125I-REAL-TOC appeared to be targeted to the liver with persistent high liver retention . CONCLUSIONS : REAL- O75051 has a significantly enhanced pharmacological effect , and this is most likely due to the favorable changes in the pharmacokinetic parameters upon lipidization . The observed liver targeting effect of REAL-TOC suggests that REAL- O75051 might be advantageous over O75051 in treating liver cancers . Oxidative stress and inflammatory response evoked by transient cerebral ischemia/reperfusion : effects of the Q07869 agonist WY14643 . This study investigated the effects of the selective peroxisome proliferator-activated receptor-alpha ( Q07869 ) agonist WY14643 on ischemia/reperfusion ( I/R ) injury in the rat hippocampus . Transient cerebral ischemia ( 30 min ) , followed by 1-24 h reperfusion , significantly increased the generation of reactive oxygen species , nitric oxide ( NO ) , and lipid peroxidation end-products , as well as markedly reducing levels of the endogenous antioxidant glutathione . Reperfusion for 3-6 h led to increased expression of the proteins heme oxygenase-1 ( P09601 ) , cyclooxygenase-2 ( P35354 ) , inducible NO synthase ( P35228 ) , and intercellular adhesion molecule-1 ( P05362 ) . Pretreatment with WY14643 suppressed oxidative stress and expression of P09601 , P35228 , and P05362 , but had no effect on P35354 . These effects are due to suppression of the activation of p38 mitogen-activated protein kinase and nuclear factor-kappaB . The Q07869 antagonist MK886 abolished the beneficial effects of WY14643 . The levels of P04271 protein , a marker of cerebral injury used in stroke trials to monitor injury , were high in the hippocampus of rats exposed to I/R , but markedly reduced by WY14643 . We propose that WY14643 protects the brain against excessive oxidative stress and inflammation and may thus be useful in treating stroke .