interacts_with DB00191?
The emerging role of cannabinoid neuromodulators in symptom management . INTRODUCTION : The cannabinoids nabilone ( DB00486 ) and dronabinol ( Marinol ) are indicated for the management of chemotherapy-induced nausea and vomiting ( CINV ) in cancer patients who have failed to respond adequately to conventional antiemetic therapy . DISCUSSION : The endocannabinoid ( CB ) system interacts with numerous other systems and pharmaceutical cannabinoids target ubiquitous P21554 and CB2 receptors in the central nervous system and periphery , relieving nausea and vomiting and pain . SUMMARY : The benefits of this novel class of medications in cancer may extend beyond CINV , as indicated by data from preclinical studies and animal models . DB04956 . Tumour necrosis factor-alpha ( P01375 ) is well established as a key mediator in the inflammatory response seen in various disease processes including sepsis . P01375 is involved in virtually all features of septic shock and multiple organ failure . Anti- P01375 strategies are thus appealing and have been effective at reducing inflammation and morbidity in certain conditions including rheumatoid arthritis and Crohn 's disease . DB04956 is the F(ab')2 fragment of a murine anti- P01375 antibody , and has been evaluated in clinical trials in septic patients . The results suggest that the drug is well tolerated , and may be of benefit in certain groups of patients with sepsis . A large , randomised , clinical trial of afelimomab in patients with severe sepsis has recently been completed and the results are eagerly awaited . More work is necessary to identify a means of selecting which patients are most likely to benefit from this type of therapy in sepsis . Is phentermine an inhibitor of monoamine oxidase ? A critical appraisal . DB00191 produces a spectrum of concentration-dependent biochemical effects . It interacts with NE transporters at 0.1 microM , DA transporters at about 1 microM , 5-HT transporters at 15 microM and P21397 at about 100 microM . When administered at typical anorectic doses , phentermine primarily interacts with DA and NE transporters and does not produce biochemical or neurochemical effects which would occur if it were inhibiting P21397 . Some other explanation other than MAO inhibition must be sought to explain how oral phentermine increases platelet 5-HT , since platelet P27338 does not metabolize platelet 5-HT , and since amphetamine-type drugs are even weaker inhibitors of P27338 than P21397 . Clinical studies in humans have shown that amphetamine , which is a more potent inhibitor of P21397 than phentermine , does not inhibit P21397 at therapeutic doses . Neither phentermine alone , fluoxetine alone or their combined use have been associated with cardiac valvulopathy , and clinical experience has shown their combined use to be free of significant adverse effects . Viewed collectively , there appears to be no data to support the hypothesis that phentermine inhibits MAO at typical therapeutic doses . Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual 's response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome . Essential role for the ( hepatic ) P01130 in macrophage apolipoprotein E-induced reduction in serum cholesterol levels and atherosclerosis . P02649 ( apoE ) is a high affinity ligand for several receptor systems in the liver , including the low-density lipoprotein ( LDL ) receptor , and non- P01130 sites , like the P01130 -related protein ( Q14764 ) , the putative remnant receptor and/or proteoglycans . Although the liver is the major source of apoE synthesis , apoE is also produced by a wide variety of other cell types , including macrophages . In the present study , the role of the P01130 in the removal of lipoprotein remnants , enriched with macrophage-derived apoE from the circulation , was determined using the technique of bone marrow transplantation ( BMT ) . Reconstitution of macrophage apoE production in apoE-deficient mice resulted in a serum apoE concentration of only 2 % of the concentration in wild-type C57Bl/6 mice . This low level of apoE nevertheless reduced VLDL and LDL cholesterol 12-fold ( P < 0.001 ) and fourfold ( P < 0.001 ) , respectively , thereby reducing serum cholesterol levels and the susceptibility to atherosclerosis . In contrast , reconstitution of macrophage apoE synthesis in mice lacking both apoE and the P01130 induced only a twofold ( P < 0.001 ) reduction in VLDL cholesterol and had no significant effect on atherosclerotic lesion development , although serum apoE levels were 93 % of the concentration in normal C57Bl/6 mice . In conclusion , a functional ( hepatic ) P01130 is essential for the efficient removal of macrophage apoE-enriched lipoprotein remnants from the circulation and thus for normalization of serum cholesterol levels and protection against atherosclerotic lesion development in apoE-deficient mice . Current and future pharmacologic options for the management of patients unable to achieve low-density lipoprotein-cholesterol goals with statins . Low-density lipoprotein-cholesterol ( LDL-C ) lowering is the mainstay of the current treatment guidelines in the management of cardiovascular risk . P04035 inhibitors ( statins ) are currently the most effective LDL-C-lowering drugs . However , a substantial number of patients do not reach treatment targets with statins . Therefore , an unmet medical need exists for lipid-lowering drugs with novel mechanisms of action to reach the recommended cholesterol target levels , either by monotherapy or combination therapy . Upregulation of the P01130 with squalene synthase inhibitors has shown promising results in animal studies but the clinical development of the lead compound lapaquistat ( DB05317 ) has recently been discontinued . DB00973 combined with statins allowed significantly more patients to reach their LDL-C targets . Other inhibitors of intestinal cholesterol absorption such as disodium ascorbyl phytostanol phosphate ( DB05449 ) and bile acid transport inhibitors have shown positive results in early development trials , whereas the prospect of acyl coenzyme A : cholesterol acyltransferase inhibition in cardiovascular prevention is dire . Selective inhibition of messenger RNA ( mRNA ) by antisense oligonucleotides is a new approach to modify cholesterol levels . The inhibition of apolipoprotein B mRNA is in advanced development and mipomersen sodium ( ISIS 301012 ) has shown striking results in phase II studies both as monotherapy as well as in combination with statins . Genotype frequencies of 50 polymorphisms for 241 Japanese non-cancer patients . This paper lists the genotype frequencies of 50 polymorphisms of 37 genes ( P05091 , P07550 , P13945 , P21964 , P16671 , P25025 , P24385 , P35354 , P11509 , P05093 , P11511 , IGF1 , IL-1A , IL-1B , IL-1RN , IL-1R1 , P05231 , P10145 , P22301 , P41159 , Le , L-myc , P05164 , Q99707 , P42898 , P21397 , P15559 , O15527 , p53 , p73 , Se , P31213 , TGF-B , P01375 -A , P01375 -B , P18074 , and P18887 ) and 6 sets of combined genotype frequencies for 241 non-cancer Japanese outpatients . Though the genotype frequencies of 25 polymorphisms have already been reported in our previous papers , 15 polymorphisms ( P16671 A52C , P25025 C785T , P24385 G870A , IGF1 C/T at intron 2 and G2502T , IL-1A 46-bp VNTR , IL-1R1 C-116T , P05231 Ins/Del 17C , P10145 A-278T and C74T , IL- 10 T-819C , P41159 A-2548G , P31213 2-bp VNTR , P18074 Lys751Gln , and P18887 Arg399Gln ) and six sets of combined genotype frequencies ( IL-1B C-31T and IL-1A C-889T , IL-1B C-31T and IL-1RN 86-bp VNTR , IL-1B C-31T and IL-1R1 C-116T , P01375 -A G-308A and P01375 -B A252G , P31213 Val89Leu and 2-bp VNTR , and P18887 Arg399Gln and P18074 Lys751Gln ) were reported in this paper for the first time for Japanese . Although microarray technology will produce this kind of information in near future , this is the first document that reports the genotype/allele frequencies among Japanese for an archival purpose . Generation of human monoclonal anti-idiotypic antibodies with specificity to the murine monoclonal anti-CA 125 antibody DB04964 . Two human monoclonal antibodies , HID-7E7 and ROB-6F2 , were produced by EBV transformation of peripheral blood lymphocytes ( PBL ) . PBL were obtained from a patient with ovarian cancer who had been exposed several times to a Tc-99m labeled murine monoclonal anti-CA 125 antibody ( DB04964 , Biomira , Edmonton ) for immunoscintigraphy . The HID-7E7 and ROB-6F2 producing B-cells were cloned with a limiting dilution technique and have shown stable immunoglobulin secretion within a period of three years . The human monoclonal antibodies HID-7E7 and ROB-6F2 are of the IgG isotype , and bind with significant affinity to the murine monoclonal antibody DB04964 , which was used for immunoscintigraphy . Binding affinity of ROB-6F2 to other murine antibodies could not be detected . Cross reactivity of HID-7E7 to a murine anti- P06731 monoclonal antibody was observed . In order to verify the anti-idiotypic character of the generated human antibodies , the ability of HID-7E7 and ROB-6F2 , respectively , to inhibit the formation of the Q8WXI7 / DB04964 complex is demonstrated via an enzyme-linked immunosorbent assay . These human anti-idiotypic antibodies are possible candidates for immunotherapy of ovarian cancer in patients with a small tumor burden following surgery and/or chemotherapy . Interaction of early environment , gender and genes of monoamine neurotransmission in the aetiology of depression in a large population-based Finnish birth cohort . Objectives Depression is a worldwide leading cause of morbidity and disability . Genetic studies have recently begun to elucidate its molecular aetiology . The authors investigated candidate genes of monoamine neurotransmission and early environmental risk factors for depressiveness in the genetically isolated population-based Northern Finland Birth Cohort 1966 ( 12 058 live births ) . Design The authors ascertained and subdivided the study sample ( n=5225 ) based on measures of early development and of social environment , and examined candidate genes of monoamine neurotransmission , many of which have shown prior evidence of a gene-environment interaction for affective disorders , namely P31645 , Q8IWU9 , P21964 , P21397 and the dopamine receptor genes P21728 - P21918 . Results and conclusion The authors observed no major genetic effects of the analysed variants on depressiveness . However , when measures of early development and of social environment were considered , some evidence of interaction was observed . Allelic variants of P21964 interacted with high early developmental risk ( p=0.005 for rs2239393 and p=0.02 for rs4680 ) so that the association with depression was detected only in individuals at high developmental risk group ( p=0.0046 and β=0.056 for rs5993883-rs2239393-rs4680 risk haplotype CGG including Val158 ) , particularly in males ( p=0.0053 and β=0.083 for the haplotype CGG ) . Rs4274224 from P14416 interacted with gender ( p=0.017 ) showing a significant association with depressiveness in males ( p=0.0006 and β=0.0023 ; p=0.00005 and β=0.069 for rs4648318-rs4274224 haplotype GG ) . The results support the role of genes of monoamine neurotransmission in the aetiology of depression conditional on environmental risk and sex , but not direct major effects of monoaminergic genes in this unselected population . P43490 / P43490 /visfatin and cancer . P43490 / P43490 /visfatin is the rate-limiting enzyme that catalyzes the first step in NAD biosynthesis from nicotinamide and regulates growth , apoptosis and angiogenesis of mammalian cells . This enzyme was originally cloned as a putative cytokine shown to enhance the B cell precursor maturation in the presence of P13232 and stem cell factor . A number of cancers have increased expression of P43490 / P43490 /visfatin , which regulates a variety of different signaling pathways such as PI3K/Akt , P27361 /2 and P40763 . FK866/APO866 and CHS828/ DB05217 are two known inhibitors of P43490 / P43490 /visfatin and have been evaluated as anticancer agents in the clinic . This review will focus on its role in carcinogenesis and cancer progression and its inhibitors as therapeutic target for cancer treatment . Characterization of antihistamines using biphasic cutaneous reaction in BALB/c mice . Effects of 11 histamine H1 receptor antagonists on IgE-mediated biphasic cutaneous reaction in mice were examined . The immediate phase reaction ( IPR ) assessed at 1 hour after antigen application was significantly inhibited by all antihistamines examined . The inhibition of IPR by cetirizine and mequitazine were potent , but those by cyproheptadine and diphenhydramine were weak . The later phase reaction ( LPR ) assessed at 24 hours after antigen application was inhibited by chlorpheniramine , oxatomide , ketotifen , mequitazine , emedastine , terfenadine and azelastine . The inhibition of LPR by emedastine was potent , but those by ketotifen and terfenadine were only partial . DB01084 inhibited both IPR and LPR comparably . Present results indicate that H1 receptor activation is involved in the IPR of the biphasic cutaneous reaction , and that the blockade of H1 receptors at IPR does not contribute to the attenuation of following LPR . P35367 antagonists inhibiting the LPR have a property distinct from H1 receptor antagonism , which may have an additional benefit for the treatment of allergic diseases . DB01184 treatment for gastroparesis : demographic and pharmacogenetic characterization of clinical efficacy and side-effects . BACKGROUND : DB01184 is a useful alternative to metoclopramide for treatment of gastroparesis due to better tolerability . Effectiveness and side-effects from domperidone may be influenced by patient-related factors including polymorphisms in genes encoding drug-metabolizing enzymes , drug transporters , and domperidone targets . AIMS : The aim of this study was to determine if demographic and pharmacogenetic parameters of patients receiving domperidone are associated with response to treatment or side-effects . METHODS : Patients treated with domperidone for gastroparesis provided saliva samples from which DNA was extracted . Fourteen single-nucleotide polymorphisms ( SNPs ) in seven candidate genes ( P08183 , P10635 , P14416 , P15382 , Q9Y6J6 , Q12809 , P51787 ) were used for genotyping . SNP microarrays were used to assess single-nucleotide polymorphisms in the ADRA1A , P35368 , and P25100 loci . RESULTS : Forty-eight patients treated with domperidone participated in the study . DNA was successfully obtained from each patient . Age was associated with effectiveness of domperidone ( p=0.0088 ) . Genetic polymorphism in Q12809 was associated with effectiveness of domperidone ( p=0.041 ) . The efficacious dose was associated with polymorphism in P08183 gene ( p=0.0277 ) . The side-effects of domperidone were significantly associated with the SNPs in the promoter region of P25100 gene . CONCLUSIONS : Genetic characteristics associated with response to domperidone therapy included polymorphisms in the drug transporter gene P08183 , the potassium channel Q12809 gene , and α1D -- adrenoceptor P25100 gene . Age was associated with a beneficial response to domperidone . If verified in a larger population , this information might be used to help determine which patients with gastroparesis might respond to domperidone and avoid treatment in those who might develop side-effects . The receptor for urokinase regulates O60603 mediated inflammatory responses in neutrophils . The urokinase-type plasminogen activator receptor ( Q03405 ) , a glycosylphosphatidylinositol ( P06744 ) anchored membrane protein , regulates urokinase ( uPA ) protease activity , chemotaxis , cell-cell interactions , and phagocytosis of apoptotic cells . Q03405 expression is increased in cytokine or bacteria activated cell populations , including macrophages and monocytes . However , it is unclear if Q03405 has direct involvement in the response of inflammatory cells , such as neutrophils and macrophages , to Toll like receptor ( TLR ) stimulation . In this study , we found that Q03405 is required for optimal neutrophil activation after O60603 , but not O00206 stimulation . We found that the expression of P01375 -α and P05231 induced by O60603 engagement in Q03405 -/- neutrophils was less than that in Q03405 +/+ ( WT ) neutrophils . Pretreatment of neutrophils with PI- P98160 , which cleaves P06744 moieties , significantly decreased O60603 induced expression of P01375 -α in WT neutrophils , but demonstrated only marginal effects on P01375 -α expression in PAM treated Q03405 -/- neutrophils . IκB-α degradation and NF-κB activation were not different in Q03405 -/- or WT neutrophils after O60603 stimulation . However , Q03405 is required for optimal p38 MAPK activation after O60603 engagement . Consistent with the in vitro findings that Q03405 modulates O60603 engagement induced neutrophil activation , we found that pulmonary and systemic inflammation induced by O60603 , but not O00206 stimulation is reduced in Q03405 -/- mice compared to WT counterparts . Therefore , our data suggest that neutrophil associated Q03405 could be a potential target for treating acute inflammation , sepsis , and organ injury related to severe bacterial and other microbial infections in which O60603 engagement plays a major role . P35367 promotes atherosclerotic lesion formation by increasing vascular permeability for low-density lipoproteins . OBJECTIVE : Enhanced endothelial permeability leading to intimal accumulation of low-density lipoproteins ( LDL ) stimulates the formation of atherosclerotic lesions . DB11320 is known to increase vascular permeability . Whether this affects the formation of atherosclerotic lesions , however , remains elusive . METHODS AND RESULTS : P02649 -null ( ApoE(-/-) ) mice treated with a histamine H1 receptor but not an H2 receptor antagonist developed 40 % fewer atherosclerotic lesions in the aorta than placebo-treated controls . Similarly , genetic deletion of the H1 but not the H2 receptor resulted in a 60 % reduction of lesions compared with ApoE(-/-) controls . The H1 receptor enhanced LDL permeability and lipid accumulation in the aorta , whereas plasma lipoprotein levels remained unaltered . In contrast , the H1 receptor did not affect proliferation and migration of vascular smooth muscle cells . Bone marrow transplantation confirmed that the formation of atherosclerotic lesions depended on the H1 receptor in vascular cells , whereas its presence in bone marrow-derived cells was irrelevant for plaque development . Mice expressing the H1 receptor exhibited higher levels of the chemokine ( C-C motif ) ligand 5 and higher numbers of macrophages and T-helper lymphocytes in plaques , higher numbers of circulating lymphocytes , and larger spleens . CONCLUSION : These data indicate that H1 but not H2 receptor activation drives the formation of atherosclerotic lesions through an increased vascular permeability for LDL , which is associated with an enhanced secondary aortic and systemic inflammation . These data open novel perspectives for the prevention and treatment of atherosclerotic vascular disease . Expression of membrane complement regulators , P15529 , P08174 and P13987 , in mesothelial cells of patients on peritoneal dialysis therapy . We investigated the expression of membrane complement regulators ( CRegs ) , P15529 , P08174 and P13987 in human mesothelial cells , and correlated with clinical background and level of complement ( C ) activation products in peritoneal dialysis ( PD ) fluids ( PDF ) to clarify influence of the C activation system in PD patients . Expression of CRegs was assessed on primary cultures of mesothelial cells ( HPMC ) harvested from PD fluid of 31 PD patients . Because expression of P08174 but not P15529 and P13987 in mesothelial cells was significantly correlated to value of dialysate-to-plasma creatinine concentration ratio ( D/P Cre ) ( p < 0.005 ) as an indicator of peritoneal function , we focused on analysis of P08174 expression of HPMCs in comparison with levels of C activation products in the PDF of the PD patients , and their background factors . When comparing expression of the CRegs between systemic neutrophils and HPMC , no correlation was observed , supporting that change of CRegs ' expression in HPMC was independently occurring in the peritoneum . Expression of P08174 protein in HPMC was closely correlated with expression at the mRNA level ( p < 0.0001 ) and was inversely correlated with levels of sC5b-9 ( p < 0.05 ) , but not P01024 , C4 , P05231 and Q8WXI7 in the PDF . Complications of diabetes , usage of icodextrin and residual renal function were not correlated with change of P08174 expression in HPMCs . Our data show that the process of PD therapy modifies expression of P08174 on peritoneal mesothelium and triggers local C activation . These findings support efforts to modify PD therapy to limit effects on activation and regulation of the C system . 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 . ' Bridged ' stilbene derivatives as selective cyclooxygenase-1 inhibitors . DB02709 ( ( E ) - DB02709 ) , a phytoalexin found in various plants , shows non-selective cyclooxygenase-1 ( P23219 ) and cyclooxygenase-2 ( P35354 ) inhibition . In order to find more selective P36551 inhibitors a series of bridged stilbene derivatives was synthesized and evaluated for their ability to inhibit both P23219 and P35354 in vitro . The compounds showed a high rate of P23219 inhibition with the most potent compounds exhibiting submicromolar IC(50) values and high selectivity indices . A prediction model for P36551 -inhibiting activity was also developed using the classical LIE approach resulting in consistent docking data for our molecule sample . Phenyl substituted 1,2-dihydronaphthalene derivatives and 1H-indene derivatives therefore represent a novel class of highly selective P23219 inhibitors and land promising candidates for in vivo studies . Searching for a marker for Alzheimer 's disease- P02649 . The authors present their study of 10 patients affected by Alzheimer 's disease and 10 patients with multinfarctual dementia , who are already part of a P21554 study , senile dementia project , longitudinal study . The method adopted was that of DNA crossbreeding and amplification , so as to have a precise individualisation of alleles APo-E , Apo E-3 , Apo E-4 and of their various phenotype combinations . These isoforms are evaluated and compared with the disease studied , in order to help to identify a timely-marker for senile dementia . On the results obtained we hypothesised an association between Apo E-4 and the disease of about 40 % for Alzheimer 's disease , which leads us to increase our number of cases , regarding associations between demential diseases either Alzheimer or vascular and the presence of Apo E-4 . Multiple pathways of apolipoprotein E signaling in primary neurons . P02649 is a genetic risk factor for Alzheimer 's disease , and the apoE protein is associated with beta-amyloid deposits in Alzheimer 's disease brain . We examined signaling pathways stimulated by apoE in primary neurons in culture . ApoE and an apoE-derived peptide activated several intracellular kinases , including prominently extracellular signal-regulated kinase 1/2 ( P27361 /2 ) . P27361 /2 activation by apoE was blocked by an inhibitor of the low-density lipoprotein receptor family , the specific DB01221 glutamate receptor antagonist MK 801 and other calcium channel blockers . Activation of apoE receptors also induced tyrosine phosphorylation of Dab1 , an adaptor protein of apoE receptors , but experiments in Dab1 knockout neurons demonstrated that Dab1 was not necessary for P29323 activation . In contrast , apoE treatment of primary neurons decreased activation of c-Jun N-terminal kinase , a kinase that interacts with another apoE receptor adaptor protein , c-Jun N-terminal kinase-interacting protein . This change also depended on interactions with the low-density lipoprotein receptor family but was independent of calcium channels . c-Jun N-terminal kinase deactivation by apoE was blocked by gamma-secretase inhibitors and pertussis toxin . These results demonstrate that apoE affects several signaling cascades in neurons : increased disabled phosphorylation , activation of the P27361 /2 pathway ( dependent on calcium influx via the DB01221 receptor ) and inhibition of the P45983 /2 pathway ( dependent on gamma-secretase and G proteins ) .