interacts_with DB04844?
Alpha synuclein is transported into and out of the brain by the blood-brain barrier . P37840 ( α-Syn ) , a small protein with multiple physiological and pathological functions , is one of the dominant proteins found in Lewy Bodies , a pathological hallmark of Lewy body disorders , including Parkinson 's disease ( PD ) . More recently , α-Syn has been found in body fluids , including blood and cerebrospinal fluid , and is likely produced by both peripheral tissues and the central nervous system . Exchange of α-Syn between the brain and peripheral tissues could have important pathophysiologic and therapeutic implications . However , little is known about the ability of α-Syn to cross the blood-brain barrier ( BBB ) . Here , we found that radioactively labeled α-Syn crossed the BBB in both the brain-to-blood and the blood-to-brain directions at rates consistent with saturable mechanisms . P01130 -related protein-1 ( Q07954 ) , but not p-glycoprotein , may be involved in α-Syn efflux and lipopolysaccharide ( LPS ) -induced inflammation could increase α-Syn uptake by the brain by disrupting the BBB . Genetics and alcoholism . DB00898 is widely consumed ; however , excessive use creates serious physical , psychological and social problems and contributes to the pathogenesis of many diseases . DB00898 use disorders ( that is , alcohol dependence and alcohol abuse ) are maladaptive patterns of excessive drinking that lead to serious problems . Abundant evidence indicates that alcohol dependence ( alcoholism ) is a complex genetic disease , with variations in a large number of genes affecting a person 's risk of alcoholism . Some of these genes have been identified , including two genes involved in the metabolism of alcohol ( P00325 and P05091 ) that have the strongest known affects on the risk of alcoholism . Studies continue to reveal other genes in which variants affect the risk of alcoholism or related traits , including P47869 , P08172 , P48051 and Q8WXX7 . As more variants are analysed and studies are combined for meta-analysis to achieve increased sample sizes , an improved picture of the many genes and pathways that affect the risk of alcoholism will be possible . Generation and properties of a new human ventral mesencephalic neural stem cell line . Neural stem cells ( NSCs ) are powerful research tools for the design and discovery of new approaches to cell therapy in neurodegenerative diseases like Parkinson 's disease . Several epigenetic and genetic strategies have been tested for long-term maintenance and expansion of these cells in vitro . Here we report the generation of a new stable cell line of human neural stem cells derived from ventral mesencephalon ( hVM1 ) based on v-myc immortalization . The cells expressed neural stem cell and radial glia markers like nestin , vimentin and 3CB2 under proliferation conditions . After withdrawal of growth factors , proliferation and expression of v-myc were dramatically reduced and the cells differentiated into astrocytes , oligodendrocytes and neurons . hVM1 cells yield a large number of dopaminergic neurons ( about 12 % of total cells are TH+ ) after differentiation , which also produce dopamine . In addition to proneural genes ( Q9H2A3 , MASH1 ) , differentiated cells show expression of several genuine mesencephalic dopaminergic markers such as : Q8TE12 , O60663 , P48051 , P00325 , P43354 , O75364 , Q05940 and Q01959 , indicating that they retain their regional identity . Our data indicate that this cell line and its clonal derivatives may constitute good candidates for the study of development and physiology of human dopaminergic neurons in vitro , and to develop tools for Parkinson 's disease cell replacement preclinical research and drug testing . Monoclonal antibodies targeting P01584 reduce biomarkers of atherosclerosis in vitro and inhibit atherosclerotic plaque formation in P02649 -deficient mice . OBJECTIVE : Atherosclerosis is a condition that is increasingly contributing to worldwide mortality through complications such as stroke and myocardial infarction . IL-1β plays multiple direct , local roles in the formation and stability of the atheroma by eliciting the production of additional cytokines and proteolytic enzymes from macrophages , endothelial cells ( EC ) and smooth muscle cells ( SMC ) . We therefore tested whether an anti-IL-1β antibody , DB06062 , might inhibit the secretion of pro-atherogenic cytokines from macrophages in vitro and affect a positive outcome in the P02649 -deficient mouse ( ApoE(-/-) ) model of atherosclerosis in vivo . METHODS AND RESULTS : In an in vitro co-culture model , DB06062 inhibited macrophage-induced secretion of key atherogenic cytokines from EC and SMC , including P05231 , P10145 , P13500 and TNFα . The release of degradative enzymes , such as the matrix metalloproteinases P08254 and P14780 , was also decreased by DB06062 . In addition , DB06062 inhibited the secretion of P13232 from EC and P05112 from SMC , cytokines not previously reported to be driven by IL-1β in this context . In vivo , XMA052 MG1K , a chimeric murine version of DB06062 , inhibited the formation of atherosclerotic lesions in the ApoE(-/-) model at all three doses tested . This effect was comparable to that reported for complete genetic ablation of IL-1β or IL-1R1 on an ApoE(-/-) background and was associated with decreases in plasma non-HDL/HDL cholesterol ratio and plaque lipid content and macrophage infiltration . CONCLUSIONS : These results demonstrate for the first time that an antibody targeting IL-1β can inhibit the progression of atherosclerosis in vivo , highlighting the importance of this key cytokine in cardiovascular disease . Regulation of alpha-synuclein expression by liver X receptor ligands in vitro . P37840 is a lipid-binding protein expressed in neurons and oligodendrocytes which is increased in Parkinson 's disease . We identified two putative liver X receptor ( LXR ) response elements in the human alpha-synuclein gene and used synthetic ( TO901317 , GW3695 ) and physiological ( 27-hydroxycholesterol ) LXR activators to assess regulation of alpha-synuclein . LXR ligands upregulated alpha-synuclein mRNA by two-five-fold in human SK-N-SH neurons and three-six-fold in human Q03405 .13 oligodendrocytes . Significant 50 % to four-fold induction of alpha-synuclein protein was also detected . Under these conditions , mRNA for LXR-responsive gene O95477 was significantly upregulated 15-40-fold and 5-25-fold in neurons and oligodendrocytes , respectively . LXR may , therefore , contribute to the regulation of alpha-synuclein expression in neurons and oligodendrocytes . Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens . Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens ( NAc ) . In the past , different techniques have targeted dopamine levels in the NAc to establish a basal concentration . In this study , we used in vivo fast scan cyclic voltammetry ( FSCV ) in the NAc of awake , freely moving rats . The experiments were primarily designed to capture changes in dopamine caused by phasic firing - that is , the measurement of dopamine ' transients ' . These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc . A series of experiments were designed to probe regulation of extracellular dopamine . DB00281 was infused into the ventral tegmental area , the site of dopamine cell bodies , to arrest neuronal firing . While there was virtually no instantaneous change in dopamine concentration , longer sampling revealed a decrease in dopamine transients and a time-averaged decrease in the extracellular level . Dopamine transporter inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc . To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter ( Q05940 ) inhibitor , tetrabenazine , to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals . DB04844 almost abolished phasic dopamine release but increased extracellular dopamine to ∼500 nM , presumably by inducing reverse transport by dopamine transporter ( Q01959 ) . Taken together , data presented here show that average extracellular dopamine in the NAc is low ( 20-30 nM ) and largely arises from phasic dopamine transients . DB02424 attenuates 3‑nitropropionic acid‑induced apoptosis and JNK activation through the expression of HSP 70 in striatal cells . Although selective striatal cell death is a characteristic hallmark in the pathogenesis of Huntington 's disease ( HD ) , the underlying mechanism of striatal susceptibility remains to be clarified . Heat shock proteins ( HSPs ) have been reported to suppress the aggregate formation of mutant huntingtin and concurrent striatal cell death . In a previous study , we observed that heat shock transcription factor 1 ( Q00613 ) , a major transcription factor of HSPs , significantly attenuated 3‑nitropropionic acid (3NP)‑induced reactive oxygen species ( ROS ) production and apoptosis through the expression of HSP 70 in striatal cells . To investigate the differential roles of HSPs in 3NP‑induced striatal cell death , the effect of geldanamycin ( GA ) , an P08238 inhibitor , was examined in 3NP‑stimulated striatal cells . GA significantly attenuated 3NP‑induced striatal apoptosis and ROS production with an increased expression of HSP 70 . Triptolide ( TL ) , an HSP 70 inhibitor , abolished GA‑mediated protective effects in 3NP‑stimulated striatal cells . To understand the underlying mechanism by which GA‑mediated HSP 70 protects striatal cells against 3NP stimulation , the involvement of various signaling pathways was examined . GA significantly attenuated 3NP‑induced c‑Jun N‑terminal kinase ( JNK ) phosphorylation and subsequent c‑Jun phosphorylation in striatal cells . Taken together , the present study demonstrated that GA exhibits protective properties against 3NP‑induced apoptosis and JNK activation via the induction of HSP 70 in striatal cells , suggesting that expression of HSP 70 may be a valuable therapeutic target in the treatment of HD . [ Additive antiproteinuric effect of angiotensin II receptor antagonist and angiotensin-converting enzyme inhibitor in patients with chronic glomerulonephritis ] . P30556 blocker ( ARB ) and angiotensin-converting enzyme inhibitor ( ACEI ) have been thought to be effective for reducing proteinuria in patients with chronic glomerulonephritis . Recently , an additive effect of these two types of angiotensin blockers has been reported in patients with IgA nephropathy , but the mechanism responsible for the effect has not yet been determined . In this study , we examined additive effect of these two drugs in chronic glomerulonephritis patients . Ten patients with biopsy-proven primary glomerulonephritis ( eight IgA nephropathy patients , two membranous nephropathy patients ) , non-nephrotic proteinuria ( protein , 0.5 to 3.5 g/day ) received candesartan cilexetil ( 2 or 4 mg ) for 8 weeks . After the 8 weeks , a combination of perindopril erbumine ( 1 or 2 mg ) and candesartan cilexetil was administered to the patients . DB00790 was stopped after the 8-week administration of the two drugs . DB00796 alone reduced proteinuria by 13 % . Combination of these two drugs induced a more remarkable reduction of proteinuria ( 48 % ; p < 0.05 vs other periods ) . The decrease in mean blood pressure by the combination therapy was significantly correlated with the decrease in proteinuria . The combination of drugs also reduced the amount of urinary type-IV collagen excretion . An additive effect of ACEI and ARB on proteinuria and urinary type-IV collagen excretion was recognized in patients with chronic glomerulonephritis . P37840 A30P point-mutation generates age-dependent nigrostriatal deficiency in mice . Lewy bodies are mainly composed of alpha-synuclein ( P37840 ) and specific mutations in P37840 gene are related to familial forms of Parkinson 's disease ( PD ) . The purpose of our study was to generate a mouse line with A30P knock-in point mutation in P37840 gene and to test if a single point-mutation is able to turn otherwise normal P37840 into a toxic form . The behavioral profile of P37840 A30P mice was followed for 16 months . Generally , these mice are healthy and viable without any obvious abnormalities . Starting from the age of 13 months mice developed a significant deficit in motor performance tests related to nigrostriatal function ( ink-test and beam walk ) . In other tests ( motility boxes , rotarod ) mice continuously performed normally . Moreover , P37840 A30P mice expressed the altered sensitivity to Q05940 inhibitor reserpine , possibly reflecting a functional deficiency of dopamine . Indeed , mice at 15 months of age had significantly reduced levels of dopamine and its major metabolite DOPAC in the striatum , and reduced levels of dopamine in the mesolimbic system . The present study confirms that P37840 plays an important role in the development of PD and an insertion of a single point mutation is sufficient to generate age-related decline in specific motor performance . The generated mouse line has a potential to become a model for PD with comparable time course and phenotype . P00533 -directed monoclonal antibodies in non-small cell lung cancer . Several monoclonal antibodies directed against the epidermal growth factor receptor ( P00533 ) have been evaluated in patients with non-small cell lung cancer ( NSCLC ) . Cetuximab , a chimeric monoclonal antibody , has been studied in combination with first-line chemotherapy in phase II and two phase III trials in patients with advanced NSCLC . The phase III FLEX trial demonstrated an increase in survival for cisplatin/vinorelbine plus cetuximab compared to chemotherapy alone in patients with advanced P00533 -expressing NSCLC . Cetuximab added to carboplatin/paclitaxel failed to improve progression-free survival in the BMS099 phase III trial . However , a meta-analysis of four randomized trials confirmed a significant survival benefit for platinum-based chemotherapy plus cetuximab compared to chemotherapy alone . High P00533 expression of tumor cells was then shown to predict the benefit of cetuximab , whereas P01116 mutations and P00533 fluorescent in situ hybridization analysis were without predictive value . DB05101 and panitumumab have also been studied in phase II trials . DB09559 , a fully human monoclonal antibody , is currently evaluated in combination with chemotherapy in two phase III trials in patients with advanced NSCLC . Cetuximab is also studied in combination with chemoradiotherapy in patients with locally advanced NSCLC . New perspectives of vesicular monoamine transporter 2 chemical characteristics in mammals and its constant expression in type 1 diabetes rat models . Vesicular monoamine transporter 2 ( Q05940 ) has been exploited as a biomarker of β-cell mass in human islets . However , a current report suggested no immunoreactivity of Q05940 in the β cells of rat islets . To investigate the cellular localization of Q05940 in islets further , the pancreatic tissues from monkeys and humans were compared with those of rats and mice . The study was performed using among-species comparisons and a type 1 diabetes model ( T1DM ) for rats by Western blotting , double-label immunofluorescence , and confocal laser scanning microscopy . We found that Q05940 -immunoreactivity ( IR ) was distributed peripherally in the islets of rodents , but was widely scattered throughout the islets of primates . Consistent with rodent islets , Q05940 -IR did not exist in insulin ( P01308 ) -IR cells but was abundantly present in glucagon ( GLU ) -IR and pancreatic polypeptide ( PP ) -IR cells in monkey and human islets . Q05940 -IR had no colocalization with P01308 -IR in any part of the rat pancreas ( head , body , and tail ) . P01308 -IR cells were reduced dramatically in T1DM rat islets , but no significant alteration in the proportion of Q05940 -IR cells and GLU-IR cells was observed . Furthermore , a strong colocalization of Q05940 -IR with GLU-IR was distributed in the peripheral regions of diabetic islets . For the first time , the current study demonstrates the presence of Q05940 in α cells and PP cells but not in β cells in the islets of monkeys and humans . This study provides convinced morphologic evidence that Q05940 is not present in β cells . There needs to be studies for new markers for β cell mass . Dominant-positive Q00613 decreases alpha-synuclein level and alpha-synuclein-induced toxicity . P37840 aggregation and cytotoxicity are widely considered to play a critical role in the process of Parkinson 's disease . Heat shock proteins are a large family of cellular protective molecules in most kinds of cells . In this study , we examined the impact of dominant-positive heat shock transcription factor 1 ( Q00613 ) on alpha-synuclein over-expression cellular model of Parkinson 's disease . We found that over-expression of alpha-synuclein could form alpha-synuclein immunopositive inclusions and result in cell death ; dominant-positive Q00613 dramatically increased the expression of HSP70 in SH-SY5Y cells , and significantly decreased the level and cytotoxicity of alpha-synuclein . Taken together , these data indicate that dominant-positive Q00613 plays an important role in suppressing alpha-synuclein aggregation and toxicity in SH-SY5Y cells . Parkinson 's disease which is marked by alpha-synuclein aggregation may be treated by increasing a set of endogenous heat shock proteins . Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene-environment studies on cancer : data from population-based Japanese random samples . Knowledge of genetic polymorphisms in gene-environment studies may contribute to more accurate identification of avoidable risks and to developing tailor-made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene-environment studies on cancer in Japan . SNP typing was performed on middle-aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples . The molecular mechanisms underlying the reduction of LDL apoB-100 by ezetimibe plus simvastatin . The combination of ezetimibe , an inhibitor of Niemann-Pick C1-like 1 protein ( Q9UHC9 ) , and an P04035 inhibitor decreases cholesterol absorption and synthesis . In clinical trials , ezetimibe plus simvastatin produces greater LDL-cholesterol reductions than does monotherapy . The molecular mechanism for this enhanced efficacy has not been defined . P04114 ( apoB-100 ) kinetics were determined in miniature pigs treated with ezetimibe ( 0.1 mg/kg/day ) , ezetimibe plus simvastatin ( 10 mg/kg/day ) , or placebo ( n = 7/group ) . DB00973 decreased cholesterol absorption ( -79 % ) and plasma phytosterols ( -91 % ) , which were not affected further by simvastatin . DB00973 increased plasma lathosterol ( +65 % ) , which was prevented by addition of simvastatin . The combination decreased total cholesterol ( -35 % ) and LDL-cholesterol ( -47 % ) . VLDL apoB pool size decreased 26 % , due to a 35 % decrease in VLDL apoB production . LDL apoB pool size decreased 34 % due to an 81 % increase in the fractional catabolic rate , both of which were significantly greater than monotherapy . Combination treatment decreased hepatic microsomal cholesterol ( -29 % ) and cholesteryl ester ( -65 % ) and increased P01130 ( P01130 ) expression by 240 % . The combination increased Q9UHC9 expression in liver and intestine , consistent with increased Q12772 expression . DB00973 plus simvastatin decreases VLDL and LDL apoB-100 concentrations through reduced VLDL production and upregulation of P01130 -mediated LDL clearance . Catecholamine-producing cells in the synovial tissue during arthritis : modulation of sympathetic neurotransmitters as new therapeutic target . BACKGROUND : The proinflammatory and anti-inflammatory role of the sympathetic nervous system in early and late inflammation is an unresolved paradox . A drastic loss of sympathetic nerve fibres in the synovial tissue of patients with rheumatoid arthritis ( RA ) has previously been demonstrated . The presence of tyrosine hydroxylase ( TH ) -positive cells in RA and osteoarthritis ( OA ) has been determined , but the role of these cells in inflammation is still unclear . OBJECTIVE : To characterise TH-positive cells in inflamed RA and OA synovial tissue and to study their role in inflammation . METHODS : Synovial samples were obtained from 32 patients with OA and 19 patients with RA and from 10 control patients . Synovial tissue samples were used for immunofluorescence staining . Synovial cells were isolated by tissue digestion and immediately used for cell culture . For in vivo experiments , collagen type-II arthritis in DBA/1J mice was induced . RESULTS : TH+ cells were present only in inflamed tissue and not in controls . Catecholamine-storing vesicles and vesicular monoamine transporter 2 ( Q05940 ) were identified in the synovial tissue . Experimental increase of cytoplasmic catecholamines by Q05940 blockade strongly reduced tumour necrosis factor ( P01375 ) independently of canonical extracellular β-adrenergic signalling . In addition , Q05940 blockade increased cyclic AMP ( DB02527 ) and DB02527 responsive element binding protein , responsible for P01375 inhibition . In vivo , appearance of Q05940 positive cells was confirmed . Q05940 blockade ameliorated inflammation also in vivo . CONCLUSIONS : This study demonstrates that local catecholamine-producing cells start to replace sympathetic nerve fibres around the onset of disease , and modulation of locally produced catecholamines has strong anti-inflammatory effects in vivo and in vitro . The genetics of alcoholism : identifying specific genes through family studies . Alcoholism is a complex disorder with both genetic and environmental risk factors . Studies in humans have begun to elucidate the genetic underpinnings of the risk for alcoholism . Here we briefly review strategies for identifying individual genes in which variations affect the risk for alcoholism and related phenotypes , in the context of one large study that has successfully identified such genes . The Collaborative Study on the Genetics of Alcoholism ( COGA ) is a family-based study that has collected detailed phenotypic data on individuals in families with multiple alcoholic members . A genome-wide linkage approach led to the identification of chromosomal regions containing genes that influenced alcoholism risk and related phenotypes . Subsequently , single nucleotide polymorphisms ( SNPs ) were genotyped in positional candidate genes located within the linked chromosomal regions , and analyzed for association with these phenotypes . Using this sequential approach , COGA has detected association with P47869 , P08172 and P08319 ; these associations have all been replicated by other researchers . COGA has detected association to additional genes including Q99928 , Q9NYV7 , P37840 , P41145 and P01213 , results that are awaiting confirmation . These successes demonstrate that genes contributing to the risk for alcoholism can be reliably identified using human subjects . Engineering human T cells for resistance to methotrexate and mycophenolate mofetil as an in vivo cell selection strategy . Gene transfer and drug selection systems that enforce ongoing transgene expression in vitro and in vivo which are compatible with human pharmaceutical drugs are currently underdeveloped . Here , we report on the utility of incorporating human enzyme muteins that confer resistance to the lymphotoxic/immunosuppressive drugs methotrexate ( MTX ) and mycophenolate mofetil ( DB00688 ) in a multicistronic lentiviral vector for in vivo T lymphocyte selection . We found that co-expression of human dihydrofolate reductase ( P00374 (FS) ; L22F , F31S ) and inosine monophosphate dehydrogenase II ( P12268 (IY) ; T333I , S351Y ) conferred T cell resistance to the cytocidal and anti-proliferative effects of these drugs at concentrations that can be achieved clinically ( up to 0.1 µM MTX and 1.0 µM DB00603 ) . Furthermore , using a immunodeficient mouse model that supports the engraftment of central memory derived human T cells , in vivo selection studies demonstrate that huEGFRt(+) P00374 (FS+) P12268 (IY+) T cells could be enriched following adoptive transfer either by systemic administration of MTX alone ( 4.4 -fold ) , DB00688 alone ( 2.9-fold ) , or combined MTX and DB00688 ( 4.9-fold ) . These findings demonstrate the utility of both P00374 (FS)/MTX and P12268 (IY)/ DB00688 for in vivo selection of lentivirally transduced human T cells . Vectors incorporating these muteins in combination with other therapeutic transgenes may facilitate the selective engraftment of therapeutically active cells in recipients . P01308 -like growth factor-1 receptor inhibitor , Q99217 -479 , in cetuximab-refractory head and neck squamous cell carcinoma . BACKGROUND : Recurrent head and neck squamous cell carcinoma ( HNSCC ) remains a difficult cancer to treat . Here , we describe a patient with HNSCC who had complete response to methotrexate ( MTX ) after progressing on multiple cytotoxic agents , cetuximab , and Q99217 -479 ( monoclonal antibody against insulin-like growth factor-1 receptor [ IGF-1R ] ) . METHODS : The clinical information was collected by a retrospective medical record review under an Institutional Review Board-approved protocol . From 4 tumors and 2 normal mucosal epithelia , global gene expression , and IGF-1R and dihydrofolate reductase ( P00374 ) protein levels were determined . RESULTS : Effective target inhibition in the tumor was confirmed by the decreased protein levels of total and phospho-IGF-1R after treatment with Q99217 -479 . Decreased level of P00374 and conversion of a gene expression profile associated with cetuximab-resistance to cetuximab-sensitivity were also observed . CONCLUSION : This suggests that the combination of Q99217 -479 and MTX or cetuximab may be a promising therapeutic approach in refractory HNSCC . Association of a polymorphism of the apolipoprotein E gene with chronic kidney disease in Japanese individuals with metabolic syndrome . The purpose of the present study was to identify genetic variants that confer susceptibility to chronic kidney disease ( CKD ) in Japanese individuals with metabolic syndrome . The study population comprised 2150 Japanese individuals with metabolic syndrome , including 411 subjects with CKD [ estimated glomerular filtration rate ( eGFR ) < 50 mL/min/1.73m(2) ] and 1739 controls ( eGFR >/= 60 mL/min/1.73m(2) ) . The genotypes for 100 polymorphisms of 80 candidate genes were determined . The chi-square test , multivariable logistic regression analysis with adjustment for covariates , as well as a stepwise forward selection procedure revealed that nine polymorphisms of P02649 , O95477 , P23219 , P01375 , Q96IY4 , P30556 , Q8NGZ3 , and P16520 were associated ( P < 0.05 ) with the prevalence of CKD . Among these polymorphisms , the -219G --> T polymorphism of P02649 ( rs405509 ) was most significantly associated with CKD in Japanese individuals with metabolic syndrome . DB04864 ameliorates cognitive deficits in streptozotocin-induced diabetic rats . The present study was designed to probe the effects of DB04864 ( HupA ) on diabetes-associated cognitive decline ( DACD ) using a streptozotocin ( Q11206 ) -injected rat model . Diabetic rats were treated with HupA ( 0.05 and 0.1 mg/kg ) for seven weeks . Memory functions were evaluated by the water maze test . Nissl staining was selected for detecting neuronal loss . Protein and mRNA levels of brain-derived neurotrophic factor ( P23560 ) were analyzed by ELISA and real-time PCR , respectively . The activities of choline acetylase ( P28329 ) , P22303 ( P22303 ) , malondialdehyde ( MDA ) , superoxide dismutase ( SOD ) , glutathione peroxidase ( DB00143 -Px ) , catalase ( CAT ) , NF-κB p65 unit , P01375 -α , IL-1β , P05231 and caspase-3 were measured using corresponding kits . After seven weeks , diabetic rats exhibited remarkable reductions in : body weight , percentage of time spent in target quadrant , number of times crossing the platform , P28329 and P23560 levels , SOD , DB00143 -Px and CAT accompanied with increases in neuronal damage , plasma glucose levels , escape latency , mean path length , P22303 , MDA level as well as CAT , NF-κB p65 unit , P01375 -α , IL-1β , P05231 and caspase-3 in cerebral cortex and hippocampus . Supplementation with HupA significantly and dose-dependently reversed the corresponding values in diabetes . It is concluded that HupA ameliorates DACD via modulating P23560 , oxidative stress , inflammation and apoptosis . Suppression of rat breast cancer metastasis and reduction of primary tumour growth by the small synthetic urokinase inhibitor DB05476 . The serine protease uPA ( urokinase-type plasminogen activator ) and its receptor Q03405 ( CD87 ) are often elevated in malignant tumours , hence , inhibition of this tumour-associated plasminogen activation system provides an attractive target for therapeutic strategies . DB05476 , a derivative of 3-aminophenylalanine in the L-conformation with inhibitory antiproteolytic properties , was tested for its specificity spectrum using specific chromogenic paranitroanilide peptide substrates . The corresponding D-enantiomer of DB05476 was used as a control . The anti-tumour and anti-metastatic ( number of lung foci and weight of the axillary lymph nodes ) properties were studied by subcutaneous administration of DB05476 to Brown Norwegian ( BN ) rats carrying orthotopically transplanted BN472 rat breast tumours . DB05476 selectively inhibited tumour-related proteases from rats and humans such as uPA , plasmin , or thrombin in the sub or low micromolar range . The activity was stereoselective as the D-enantiomer of DB05476 inhibited uPA and plasmin at approximately 70-fold higher Ki values than the active L-form . Chronical administration of the L-enantiomer of WXUK1 impaired primary tumour growth and metastasis of BN472 rat breast cancer in a dose-dependent manner . The minimum inhibitory dosage with maximal effect was between 0.15 and 0.3 mg/kg/day . The inactive D-enatiomer of DB05476 was not active in this respect . Daily treatment with DB05476 for up to 35 days was well tolerated as judged by the unchanged body and organ weight development . In conclusion , our results provide evidence that DB05476 as a single agent inhibits breast tumour growth and metastasis in vivo , and thus is a promising candidate drug to treat human cancer . Transforming growth factor-alpha directly augments histidine decarboxylase and vesicular monoamine transporter 2 production in rat enterochromaffin-like cells . For the production and vesicle storage of histamine , Enterochromaffin-like ( ECL ) cells express histidine decarboxylase ( HDC ) and vesicular monoamine transporter 2 ( Q05940 ) . Although HDC and Q05940 show dynamic changes during gastric ulcer healing , the control system of their expression has not been fully investigated . In the present study , we investigated the effect of transforming growth factor-alpha ( TGF-alpha ) and proinflammatory cytokines on HDC and Q05940 expression in rat ECL cells . Time course changes in the expression of TGF-alpha during the healing of acetic acid-induced ulcers were studied . P01133 receptor ( P00533 ) expression was also examined in ECL cells , whereas the direct effects of TGF-alpha and proinflammatory cytokines on HDC and Q05940 expression in ECL cells were investigated using in vivo and in vitro models . During the process of ulcer healing , expression of TGF-alpha mRNA was markedly augmented . Furthermore , P00533 was identified in isolated ECL cells . TGF-alpha stimulated HDC and Q05940 mRNA expression and protein production and also increased histamine release from ECL cells . Selective P00533 tyrosine kinase inhibitor tyrphostin AG1478 almost completely inhibited HDC and Q05940 gene expression induced by TGF-alpha in vivo and in vitro . During gastric mucosal injury , TGF-alpha was found to stimulate ECL cell functions by increasing HDC and Q05940 expression .