MH_dev_183

Alpha synuclein is transported into and out of the brain by the blood-brain barrier . P37840 REA ( 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 REA - related protein - 1 ( Q07954 REA ) , 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 MENMAX DB00898 MEN is widely consumed ; however , excessive use creates serious physical , psychological and social problems and contributes to the pathogenesis of many diseases . DB00898 MEN 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 REA and P05091 REA ) 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 REA , P08172 REA , P48051 REA 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 ( hVM 1 ) 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 . hVM 1 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 , MASH 1 ) , differentiated cells show expression of several genuine mesencephalic dopaminergic markers such as : Q8TE12 , O60663 , P48051 REA , P00325 REA , P43354 REA , O75364 , Q05940 REA and Q01959 REA , 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 REA reduce biomarkers of atherosclerosis in vitro and inhibit atherosclerotic plaque formation in P02649 REA - 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 MEN , might inhibit the secretion of pro-atherogenic cytokines from macrophages in vitro and affect a positive outcome in the P02649 REA - deficient mouse ( ApoE ( - / - ) ) model of atherosclerosis in vivo . METHODS AND RESULTS : In an in vitro co-culture model , DB06062 MEN inhibited macrophage-induced secretion of key atherogenic cytokines from EC and SMC , including P05231 REA , P10145 REA , P13500 REA and TNFα . The release of degradative enzymes , such as the matrix metalloproteinases P08254 REA and P14780 REA , was also decreased by DB06062 MEN . In addition , DB06062 MEN inhibited the secretion of P13232 REA from EC and P05112 REA from SMC , cytokines not previously reported to be driven by IL - 1β in this context . In vivo , XMA 052 MG1K , a chimeric murine version of DB06062 MEN , 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 REA 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 REA . 13 oligodendrocytes . Significant 50 % to four-fold induction of alpha-synuclein protein was also detected . Under these conditions , mRNA for LXR-responsive gene O95477 REA 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 GBR 12909 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 REA ) inhibitor , tetrabenazine , to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals . DB04844 SUB almost abolished phasic dopamine release but increased extracellular dopamine to ∼ 500 nM , presumably by inducing reverse transport by dopamine transporter ( Q01959 REA ) . 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 MEN 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 REA ) , 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 REA 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 REA 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 MEN 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 REA A30P point-mutation generates age-dependent nigrostriatal deficiency in mice . Lewy bodies are mainly composed of alpha-synuclein ( P37840 REA ) and specific mutations in P37840 REA 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 REA gene and to test if a single point-mutation is able to turn otherwise normal P37840 REA into a toxic form . The behavioral profile of P37840 REA 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 REA A30P mice expressed the altered sensitivity to Q05940 REA 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 REA 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 REA - directed monoclonal antibodies in non-small cell lung cancer . Several monoclonal antibodies directed against the epidermal growth factor receptor ( P00533 REA ) 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 REA - expressing NSCLC . Cetuximab added to carboplatin / paclitaxel failed to improve progression-free survival in the BMS 099 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 REA expression of tumor cells was then shown to predict the benefit of cetuximab , whereas P01116 REA mutations and P00533 REA fluorescent in situ hybridization analysis were without predictive value . DB05101 and panitumumab have also been studied in phase II trials . DB09559 MEN , 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 REA ) has been exploited as a biomarker of β-cell mass in human islets . However , a current report suggested no immunoreactivity of Q05940 REA in the β cells of rat islets . To investigate the cellular localization of Q05940 REA 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 REA - immunoreactivity ( IR ) was distributed peripherally in the islets of rodents , but was widely scattered throughout the islets of primates . Consistent with rodent islets , Q05940 REA - IR did not exist in insulin ( P01308 REA ) - IR cells but was abundantly present in glucagon ( GLU ) - IR and pancreatic polypeptide ( PP ) - IR cells in monkey and human islets . Q05940 REA - IR had no colocalization with P01308 REA - IR in any part of the rat pancreas ( head , body , and tail ) . P01308 REA - IR cells were reduced dramatically in T1DM rat islets , but no significant alteration in the proportion of Q05940 REA - IR cells and GLU-IR cells was observed . Furthermore , a strong colocalization of Q05940 REA - 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 REA 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 REA is not present in β cells . There needs to be studies for new markers for β cell mass .

Dominant-positive Q00613 REA decreases alpha-synuclein level and alpha-synuclein-induced toxicity . P37840 REA 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 REA ) 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 REA dramatically increased the expression of HSP 70 in SH-SY 5Y cells , and significantly decreased the level and cytotoxicity of alpha-synuclein . Taken together , these data indicate that dominant-positive Q00613 REA plays an important role in suppressing alpha-synuclein aggregation and toxicity in SH-SY 5Y 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 REA , Q16678 REA , P11712 REA , P33261 REA , P05181 REA , P05093 REA , P11511 REA , P35869 REA , P03372 REA , Q92731 REA , ERRRG , P06401 REA , P07099 REA , P34913 REA , P37059 REA , P37058 REA , P28161 REA , P21266 REA , GSTT 2 , P09211 REA , NAT 1 , NAT 2 , P21964 REA , P07327 REA , P00325 REA , P00326 REA , P05091 REA , P35228 REA , NOS 3 , P01583 REA , P01584 REA , O15527 REA , P36639 REA [ P36639 REA ] , P14416 REA , P35462 REA , P21917 REA , P31645 REA , P04150 REA [ GCCR ] , P42898 REA , and P15559 REA . 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 REA 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 REA ( 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 MEN decreased cholesterol absorption ( - 79 % ) and plasma phytosterols ( - 91 % ) , which were not affected further by simvastatin . DB00973 MEN 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 REA ( P01130 REA ) expression by 240 % . The combination increased Q9UHC9 expression in liver and intestine , consistent with increased Q12772 REA expression . DB00973 MEN plus simvastatin decreases VLDL and LDL apoB - 100 concentrations through reduced VLDL production and upregulation of P01130 REA - 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 REA ) were identified in the synovial tissue . Experimental increase of cytoplasmic catecholamines by Q05940 REA blockade strongly reduced tumour necrosis factor ( P01375 REA ) independently of canonical extracellular β-adrenergic signalling . In addition , Q05940 REA blockade increased cyclic AMP ( DB02527 ) and DB02527 responsive element binding protein , responsible for P01375 REA inhibition . In vivo , appearance of Q05940 REA positive cells was confirmed . Q05940 REA 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 REA , P08172 REA and P08319 REA ; these associations have all been replicated by other researchers . COGA has detected association to additional genes including Q99928 REA , Q9NYV7 , P37840 REA , P41145 REA and P01213 REA , 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 MEN ) in a multicistronic lentiviral vector for in vivo T lymphocyte selection . We found that co-expression of human dihydrofolate reductase ( P00374 REA ( FS ) ; L22F , F31S ) and inosine monophosphate dehydrogenase II ( P12268 REA ( 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 REA ( FS + ) P12268 REA ( IY + ) T cells could be enriched following adoptive transfer either by systemic administration of MTX alone ( 4.4 - fold ) , DB00688 MEN alone ( 2.9- fold ) , or combined MTX and DB00688 MEN ( 4.9- fold ) . These findings demonstrate the utility of both P00374 REA ( FS ) / MTX and P12268 REA ( IY ) / DB00688 MEN 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 REA - like growth factor - 1 receptor inhibitor , Q99217 REA - 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 REA - 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 REA ) 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 REA - 479 . Decreased level of P00374 REA 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 REA - 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 / 1.73 m ( 2 ) ] and 1739 controls ( eGFR > /= 60 mL / min / 1.73 m ( 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 REA , O95477 REA , P23219 REA , P01375 REA , Q96IY4 , P30556 REA , Q8NGZ3 , and P16520 REA were associated ( P < 0.05 ) with the prevalence of CKD . Among these polymorphisms , the - 219G --> T polymorphism of P02649 REA ( rs405509 ) was most significantly associated with CKD in Japanese individuals with metabolic syndrome .

DB04864 MEN ameliorates cognitive deficits in streptozotocin-induced diabetic rats . The present study was designed to probe the effects of DB04864 MEN ( HupA ) on diabetes-associated cognitive decline ( DACD ) using a streptozotocin ( Q11206 REA ) - 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 REA ) were analyzed by ELISA and real-time PCR , respectively . The activities of choline acetylase ( P28329 REA ) , P22303 REA ( P22303 REA ) , malondialdehyde ( MDA ) , superoxide dismutase ( SOD ) , glutathione peroxidase ( DB00143 - Px ) , catalase ( CAT ) , NF-κB p65 unit , P01375 REA - α , IL - 1β , P05231 REA 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 REA and P23560 REA levels , SOD , DB00143 - Px and CAT accompanied with increases in neuronal damage , plasma glucose levels , escape latency , mean path length , P22303 REA , MDA level as well as CAT , NF-κB p65 unit , P01375 REA - α , IL - 1β , P05231 REA 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 REA , oxidative stress , inflammation and apoptosis .

Suppression of rat breast cancer metastasis and reduction of primary tumour growth by the small synthetic urokinase inhibitor DB05476 MEN . The serine protease uPA ( urokinase-type plasminogen activator ) and its receptor Q03405 REA ( CD87 ) are often elevated in malignant tumours , hence , inhibition of this tumour-associated plasminogen activation system provides an attractive target for therapeutic strategies . DB05476 MEN , 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 MEN 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 MEN to Brown Norwegian ( BN ) rats carrying orthotopically transplanted BN472 rat breast tumours . DB05476 MEN 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 MEN inhibited uPA and plasmin at approximately 70 - fold higher Ki values than the active L-form . Chronical administration of the L-enantiomer of WXUK 1 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 MEN was not active in this respect . Daily treatment with DB05476 MEN 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 MEN 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 REA ) . Although HDC and Q05940 REA 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 REA 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 REA receptor ( P00533 REA ) expression was also examined in ECL cells , whereas the direct effects of TGF-alpha and proinflammatory cytokines on HDC and Q05940 REA 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 REA was identified in isolated ECL cells . TGF-alpha stimulated HDC and Q05940 REA mRNA expression and protein production and also increased histamine release from ECL cells . Selective P00533 REA tyrosine kinase inhibitor tyrphostin AG1478 almost completely inhibited HDC and Q05940 REA 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 REA expression .