interacts_with DB01098?
Role of monoamine oxidases in the exaggerated 5-hydroxytryptamine-induced tension development of human isolated preeclamptic umbilical artery . We investigated the role(s) of monoamine oxidases ( MAOs ) on the altered 5-hydroxytryptamine ( 5-HT , serotonin ) -induced tension development of the isolated umbilical artery of preeclamptic pregnancy of Chinese women . An enhanced 5-HT-induced tension development of the umbilical artery of preeclamptic pregnancy was observed when compared with that of normal pregnancy . The enhanced component of 5-HT-induced tension development was eradicated by clorgyline ( a P21397 inhibitor ) . Blockade of P29474 ( endothelial isoform nitric oxide synthase ) ( N(omega)-nitro-L-arginine methyl ester ) , 5-HT transporter ( citalopram ) , 5-HT receptor subtypes ( 5HT2B , SB 204741 ; P28335 , RS 102221 ; P34969 , SB 269970 ) , and endothelium denudation of the umbilical artery of normal pregnancy mimicked the enhanced 5-HT-induced tension development as observed in the preeclamptic tissues . In contrast , no apparent changes in 5-HT-induced tension development of the umbilical artery of preeclamptic pregnancy were observed with the same pharmacological manipulations . A decreased protein expression levels of P21397 and P29474 ( no P35228 and P27338 expression was detected ) and no change in caveolin-1 and 5-HT transporter expression were demonstrated in the umbilical artery ( endothelium intact ) lysate of preeclamptic pregnancy , compared to that of the umbilical artery of normal pregnancy . Thus , in the umbilical artery of preeclamptic pregnancy , a decrease of P21397 and P29474 protein expression levels are probably associated with , or responsible for , the exaggerated 5-HT-induced tension development . Regulation of porphyrin synthesis and photodynamic therapy in heavy metal intoxication . Protoporphyrin IX ( PpIX ) synthesis by malignant cells is successfully exploited for photodynamic therapy ( PDT ) following administration of 5-aminolevulinic acid ( ALA ) and light irradiation . The influence of two environmental heavy metal poisons , lead and gallium , on PpIX-synthesis and DB00855 was studied in two neu-ronal cell lines , SH-SY5Y neuroblastoma and PC12 pheochromocytoma . The heavy metal intoxication affected two of the heme-synthesis enzymes , ALA-dehydratase ( P13716 ) and porphobilinogen deaminase ( P08397 ) . The present results show that lead poisoning significantly decreased the P08397 cellular level and inhibited its enzymatic activity , whereas the effects of gallium were less prominent . Although , the protein levels were reduced , the mRNA levels of P08397 remained unchanged during metal intoxication . These findings show additional inhibitory activity of lead on top of its classical effect on P13716 . Proteasome activity was enhanced during lead treatment , as measured by the AMC fluorigenic proteasome assay . The reduction in P08397 levels was not a consequence of P08397 mRNA reduced synthesis , which remained unchanged as shown by RT-PCR analysis . As a result of the lead poisoning , marked alterations in the cell cycle were observed , including a decreased P55008 phase and an increased number of S phase cells . The efficacy of DB00855 was reduced in correlation with decreased activities of the enzymes during lead intoxication . We may conclude that lead poisoning adversely affects the outcome of ALA photodynamic therapy of cancer . Genetic deletion of P01375 receptor suppresses excitatory synaptic transmission via reducing AMPA receptor synaptic localization in cortical neurons . The distribution of postsynaptic glutamate receptors has been shown to be regulated by proimmunocytokine tumor necrosis factor α ( P01375 -α ) signaling . The role of P01375 -α receptor subtypes in mediating glutamate receptor expression , trafficking , and function still remains unclear . Here , we report that P01375 receptor subtypes ( P19438 and P20333 ) differentially modulate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor ( AMPAR ) clustering and function in cultured cortical neurons . We find that genetic deletion of P19438 decreases surface expression and synaptic localization of the AMPAR P42261 subunit , reduces the frequency of miniature excitatory postsynaptic current ( mEPSC ) , and reduces AMPA-induced maximal whole-cell current . In addition , these results are not observed in P20333 -deleted neurons . The decreased AMPAR expression and function in P19438 -deleted cells are not significantly restored by short ( 2 h ) or long ( 24 h ) term exposure to P01375 -α . In P20333 -deleted cells , P01375 -α promotes AMPAR trafficking to the synapse and increases mEPSC frequency . In the present study , we find no significant change in the Q05586 subunit of NMDAR clusters , location , and mEPSC . This includes applying or withholding the P01375 -α treatment in both P19438 - and P20333 -deleted neurons . Our results indicate that P01375 receptor subtype 1 but not 2 plays a critical role in modulating AMPAR clustering , suggesting that targeting P19438 gene might be a novel approach to preventing neuronal AMPAR-mediated excitotoxicity . ICE/ P29466 inhibitors as novel anti-inflammatory drugs . In recent years , several strategies that selectively inhibit pro-inflammatory cytokines , have yielded effective protein-based therapies for inflammatory disorders , validating the therapeutic hypothesis that intervention in cytokine signalling can provide clinical benefit . However , these protein-based products must be administered by injection , a constraint associated with inconvenience , adverse effects and expense for patients , caregivers and insurers . Besides interfering with the effects of cytokines such as P01375 or IL-1beta that have already been produced , inhibition of pro-inflammatory cytokine production or signalling with low-molecular weight orally-active drugs would combine the convenience of conventional pharmaceuticals with the focused efficacy of the protein therapies . Reducing IL-1beta and Q14116 production by inhibition of IL-1beta converting enzyme ( ICE , caspase-1 ) is one promising strategy because of the key roles of these cytokines in many inflammatory diseases . DB04875 , the first orally available , potent and selective ICE inhibitor to enter clinical trials , is currently under investigation in rheumatoid arthritis . In situ generation of nitric oxide by myenteric neurons but not by mononuclear cells of the human colon . 1. Production of nitric oxide ( NO ) is implicated in the pathogenesis of inflammatory bowel disease . However , the cells responsible for the production of NO in situ in the human colon remain unknown . 2 . Surgical samples from 12 patients with ulcerative colitis , eight patients with Crohn 's disease and 10 controls were studied . Possible generation of NO was visualized by reduced nicotinamide adenine dinucleotide phosphate ( NADPH ) diaphorase activity in human colon . Immunohistological staining for various NO synthase ( NOS ) isoforms ( endothelial , neuronal and inducible ) , nitrotyrosine and interleukin-2 was also performed . 3 . Reduced NADPH diaphorase activity was not found in lamina propria mononuclear cells , but was found in colonic epithelium , endothelium and myenteric neurons and their processes . 4 . The NADPH-diaphorase activity positive processes were significantly less common in colon from patients with Crohn 's disease compared with control colon . 5 . P29474 was constitutively expressed on colonic endothelium . 6 . P29475 was constitutively expressed on myenteric neurons . 7 . Expression of inducible NOS ( P35228 ) was increased in the epithelium and endothelium of the colon of patients with ulcerative colitis . 8 . No correlation was found between expression of P35228 and NADPH diaphorase activity . 9 . Nitrotyrosine was expressed by lamina propria leucocytes , but not by epithelium . 10 . P60568 was expressed on both leucocytes and myenteric neurons . 11 . Colonic epithelium , endothelium and myenteric neurons synthesize NO . Myenteric neurons were principally responsible for NO production and NO may act as a neurotransmitter in the enteric nervous system . IL-20 activates human lymphatic endothelial cells causing cell signalling and tube formation . IL-20 is an arteriogenic cytokine that remodels collateral networks in vivo , and plays a role in cellular organization . Here , we investigate its role in lymphangiogenesis using a lymphatic endothelial cell line , hTERT-HDLEC , which expresses the lymphatic markers Q9Y5Y7 and podoplanin . Upon stimulation of hTERT-HDLEC with IL-20 , we found an increase in the intracellular free calcium concentration , in Akt and P29474 phosphorylations as well as in perinuclear NO production . We found that P29474 phosphorylation and NO synthesis are highly dependent on the PI3K/Akt signalling pathway . We also found an IL-20 induced phosphorylation of Erk1/2 and P42345 , and using the MEK inhibitor PD98059 and P42345 complex inhibitor rapamycin we demonstrated the importance of these signalling pathways in IL-20-mediated proliferation . IL-20 triggered actin polymerization and morphological changes resulting in elongated cell structures , and in matrigels , IL-20 caused tube formations of hTERT-HDLEC in a PI3K- and P42345 dependent way . In a sprouting assay we found that IL-20 caused cell migration within 24 h at a rate comparable to P49767 , and this migration could be inhibited by wortmannin and rapamycin . These data show that IL-20 activates cell signalling resulting in lymphangiogenic processes including migration , proliferation and tube formation . Thus , IL-20 is a cytokine that has the potential of activating or modulating the formation of lymphatic vessels . Associations of patella lead with polymorphisms in the vitamin D receptor , delta-aminolevulinic acid dehydratase and endothelial nitric oxide synthase genes . A cross-sectional analysis was performed to evaluate associations of polymorphisms in the vitamin D receptor ( P11473 ) , delta-aminolevulinic acid dehydratase ( P13716 ) , and endothelial nitric oxide synthase ( P29474 ) genes with patella lead concentrations in 652 lead workers in the Republic of Korea . There was a wide range of patella lead ( from below detection limit to 946 microg Pb/g bone mineral ) , with a mean ( standard deviation ) of 75.2 ( 101.0 ) . There were no associations of P13716 or P29474 genotypes with patella lead , but workers with the P11473 B allele had significantly ( P value < 0.05 ) higher patella lead ( on average , 25 % or approximately 6.6 microg Pb/g bone mineral ) than lead workers with the P11473 bb genotype . There was evidence that the relation between age and patella lead was modified by both the P11473 and P29474 genotypes . DB01411 inhibits renal epithelial cyst progression via activation of AMP-activated protein kinase . Q9Y271 ( CysLT1 receptor ) antagonists were found to inhibit chloride secretion in human airway epithelial cells . Since chloride secretion in renal epithelial cells , which shares common mechanisms with airway epithelial cells , plays important roles in renal cyst progression in polycystic kidney disease ( Q15139 ) , this study was aimed to investigate effects of drugs acting as CysLT1 receptor antagonists on renal cyst progression and its underlying mechanisms . Effects of CysLT1 receptor antagonists on renal cyst growth and formation were determined using Madine Darby canine kidney ( MDCK ) cyst models . Mechanisms of actions of CysLT1 receptor antagonists were determined using short-circuit current measurement , assays of cell viability and cell proliferation , and immunoblot analysis of signaling proteins . Of the three drugs acting as CysLT1 receptor antagonists ( montelukast , pranlukast and zafirlukast ) tested , pranlukast was the most promising drug that inhibited MDCK cyst growth and formation without affecting cell viability . Its effect was independent of the inhibition of CysLT1 receptors . Instead , it reduced DB02527 -activated chloride secretion and proliferation of MDCK cells in an AMP-activated protein kinase ( AMPK ) -dependent manner and had no effect on P13569 protein expression . Interestingly , pranlukast enhanced AMPK activation via calcium/calmodulin-dependent protein kinase kinase beta ( CaMKKβ ) with consequent activation of acetyl- DB01992 carboxylase ( ACC ) and suppression of mammalian target of rapamycin ( P42345 ) pathway . These results indicate that pranlukast retards renal epithelial cyst progression by inhibiting DB02527 -activated chloride secretion and cell proliferation via CaMKKβ-AMPK- P42345 pathway . Therefore , pranlukast represents a class of known drugs that may have potential utility in Q15139 treatment . Mechanism of inhibition of the P42262 AMPA receptor channel opening by talampanel and its enantiomer : the stereochemistry of the 4-methyl group on the diazepine ring of 2,3-benzodiazepine derivatives . Stereoselectivity of 2,3-benzodiazepine compounds provides a unique way for the design of stereoisomers as more selective and more potent inhibitors as drug candidates for treatment of the neurological diseases involving excessive activity of AMPA receptors . Here we investigate a pair of enantiomers known as DB04982 and its ( + ) counterpart about their mechanism of inhibition and selectivity toward four AMPA receptor subunits or P42261 -4 . We show that DB04982 is the eutomer with the endismic ratio being 14 for the closed-channel and 10 for the open-channel state of P42262 . Kinetic evidence supports that DB04982 is a noncompetitive inhibitor and it binds to the same site for those 2,3-benzodiazepine compounds with the C-4 methyl group on the diazepine ring . This site , which we term as the " M " site , recognizes preferentially those 2,3-benzodiazepine compounds with the C-4 methyl group being in the R configuration , as in the chemical structure of DB04982 . Given that DB04982 inhibits P42261 and P42262 , but is virtually ineffective on the P42263 and P48058 AMPA receptor subunits , we hypothesize that the " M " site(s) on P42261 and P42262 to which DB04982 binds is different from that on P42263 and P48058 . If the molecular properties of the AMPA receptors and DB04982 are used for selecting an inhibitor as a single drug candidate for controlling the activity of all AMPA receptors in vivo , DB04982 is not ideal . Our results further suggest that addition of longer acyl groups to the N-3 position should produce more potent 2,3-benzodiazepine inhibitors for the " M " site . Traditional Korean Herbal Formula Samsoeum Attenuates Adipogenesis by Regulating the Phosphorylation of P27361 /2 in 3T3- Q9NUQ9 Cells . Adipogenesis is the cell differentiation process from preadipocytes into adipocytes and the critical action in the development of obesity . In the present study , we conducted in vitro analyses to investigate the inhibitory effects of Samsoeum ( SSE ) , a traditional herbal decoction . SSE had no significant cytotoxic effect against either the undifferentiated or differentiated 3T3- Q9NUQ9 cells . Oil Red O staining results showed that SSE significantly inhibited fat accumulation in adipocytes . SSE treatment consistently reduced the intracellular triglyceride content in the cells . SSE significantly inactivated glycerol-3-phosphate dehydrogenase ( GPDH ) , a major link between carbohydrate and lipid metabolisms in 3T3- Q9NUQ9 adipocytes , and markedly inhibited the production of leptin , an important adipokine , in differentiated cells . SSE markedly suppressed the mRNA expression of the adipogenesis-related genes peroxisome proliferator-activated receptor-gamma ( Q07869 -γ ) , CCAAT/enhancer binding protein-alpha ( C/EBP-α ) , fatty acid synthase ( FAS ) , lipoprotein lipase ( P06858 ) , and fatty acid binding protein 4 ( P15090 ) . Importantly , SSE increased the phosphorylation of P27361 /2 , but not p38 MAPK and JNK , in adipose cells . Overall , our results indicate that SSE exerts antiadipogenic activity and modulates expressions of adipogenesis-related genes and P27361 /2 activation in adipocytes . DB04901 : a review . IMPORTANCE OF THE FIELD : A significant number of patients relapse or do not respond to rituximab due to intrinsic or acquired resistance . Hence , mAbs targeting other cell surface antigens on B-cell lymphomas are being studied . P33681 is a glycoprotein expressed on Hodgkin 's lymphoma , mature B-cell lymphomas and immunoeffector cells which may have T-regulatory , in addition to direct antitumor activity . P33681 serves as an attractive target in the continued development of mAbs against lymphoma . AREAS COVERED IN THIS REVIEW : Preclinical studies with galiximab , an anti- P33681 primatized mAb , have been encouraging and have demonstrated antitumor activity against various B-cell lymphoma models , both as a single agent as well as in combination with rituximab . Data were reviewed from a PubMed literature search from 1975 to 2009 and also included a review of abstracts from published proceedings of annual meetings from the American Society of Hematology and International Conference of Malignant Lymphoma , Lugano . WHAT THE READER WILL GAIN : Readers will gain a better understanding of mechanisms of action ( both documented and proposed ) of galiximab . An update of currently available clinical data will be presented . TAKE HOME MESSAGE : Data from completed clinical trials are promising and galiximab is being studied in both upfront and relapsed settings with the potential of being incorporated into the future treatment of B-cell lymphoma . A phase-1 trial of bexarotene and denileukin diftitox in patients with relapsed or refractory cutaneous T-cell lymphoma . DB00004 , a genetically engineered fusion protein combining the enzymatically active domains of diphtheria toxin and the full-length sequence for interleukin-2 ( P60568 ) , efficiently targets lymphoma cells expressing the high-affinity P60568 receptor ( IL-2R ) consisting of the alpha/p55/CD25 , beta/p75/CD122 , and gamma/ P31785 /CD132 chains . In vitro studies demonstrated that the retinoid X receptor ( RXR ) retinoid , bexarotene , at biologically relevant concentrations of 10(-6) M to 10(-8) M , upregulated both the p55 and p75 subunits of the IL-2R and enhanced 5- to 10-fold the susceptibility of T-cell leukemia cells to denileukin diftitox . To determine whether this biomodulatory effect could be recapitulated in vivo , we treated 14 patients with relapsed or refractory cutaneous T-cell lymphoma with escalating doses of bexarotene ( 75 mg/day-300 mg/day ) and denileukin diftitox ( 18 mcg/kg per day x 3 days every 21 days ) in a phase 1 trial . Overall response was 67 % ( 4 complete responses , 4 partial responses ) . Modulation of IL-2R expression was observed at or above a bexarotene dose of 150 mg/day . Four patients experienced grade 2 or 3 leukopenia , and 2 had grade 4 lymphopenia . Our results demonstrate that the combination of denileukin diftitox and bexarotene is well tolerated and that even low doses ( 150 mg/day ) of bexarotene are capable of in vivo upregulation of CD25 expression on circulating leukemia cells . DB01098 , a new P04035 inhibitor , reduces the colonic inflammatory response in dextran sulfate sodium-induced colitis in mice . The aim of the present study was to elucidate the beneficial effects of rosuvastatin , a new P04035 inhibitor , on colonic mucosal damage and on the inflammatory response in a dextran sulfate sodium ( DSS ) colitis model . Acute colitis was induced using 8 % DSS in female BALB/c mice . Colonic mucosal inflammation was evaluated clinically , biochemically , and histologically . Mucosal protein contents and mRNA levels of tumor necrosis factor ( P01375 ) -alpha were determined by immunoassay and real time-PCR . The mRNA levels of endothelial nitric oxide synthase ( P29474 ) were determined by real-time PCR . Disease activity scores in DSS-induced colitis model mice , as determined by weight loss , stool consistency , and blood in stool , were significantly lower in the rosuvastatin-treated mice than in control mice . Shortening of the colon was significantly reversed by rosuvastatin . Increases in tissue-associated myeloperoxidase activity and thiobarbituric acid-reactive substances after DSS administration were both significantly inhibited by treatment with rosuvastatin . DB01098 also inhibited increases in intestinal P01375 protein and mRNA expression after DSS administration , respectively . The mucosal mRNA levels of P29474 were decreased after DSS administration , but preserved in mice treated with rosuvastatin . These results suggest that rosuvastatin prevents the development of DSS-induced colitis in mice via the inhibition of mucosal inflammatory responses associated with the preservation of P29474 transcription . Effects on thrombin generation of single injections of DB02351 in patients with calf vein thrombosis . STUDY OBJECTIVE : To determine whether single injections of DB02351 , a direct thrombin inhibitor , can inhibit thrombin generation in patients with calf vein thrombosis and , if so , if the inhibition is sustained . DESIGN : Phase II open label cohort study . SETTING : Tertiary-care referral centres , university affiliated hospitals . PATIENTS : 10 patients with venographically-demonstrated calf vein thrombosis . INTERVENTION : Patients received a single injection of DB02351 , either 1.0 mg/kg subcutaneously or 0.6 mg/kg as a 15 min intravenous infusion . P00734 fragment ( F1++2 ) levels , as an index of thrombin generation , were measured before as well as 6 h post- and 24 h post- DB02351 administration . Patients were followed with non-invasive tests to detect thrombus extension into the proximal veins . RESULTS : There was a significant reduction in the levels of F1+2 with both regimens , 6 h after DB02351 . The F1+2 levels 24 h post- DB02351 showed a significant increase relative to the 6 h post- DB02351 results . One patient developed thrombus extension into the popliteal vein and was treated with conventional anticoagulants . CONCLUSION : The single injections of DB02351 used in the study produced incomplete and temporary suppression of F1+2 . Complete and permanent inhibition of thrombin generation with DB02351 in patients with calf vein thrombosis may require higher doses , multiple subcutaneous injections and/or prolonged intravenous infusion . Maturation of dendritic cells by recombinant human P29965 -trimer leads to a homogeneous cell population with enhanced surface marker expression and increased cytokine production . Dendritic cells ( DC ) have been shown to be potent inducers of specific cytotoxic T-cell responses both in vivo and in vitro . Furthermore , exposure to cytokines such as tumour necrosis factor ( P01375 ) -alpha or P25942 triggering changes DC phenotype and cytokine production and may enhance the T-cell activating capacity of the DC . We studied DC phenotype and cytokine production as well as the T-cell proliferation and cytotoxic T lympocyte ( CTL ) activation induced by DC generated in vitro . In addition , the effect of exposure to recombinant human P29965 -trimer ( huCD40LT ) on these parameters was investigated . Effective differentiation of monocytes derived from freshly isolated peripheral blood mononuclear cells ( PBMC ) was obtained with granulocyte macrophage-colony stimulating factor ( GM- P04141 ) and interleukin ( IL ) -4 . The DC expression of human leucocyte antigen ( HLA ) molecules , P33681 , Q01151 , and P42081 was markedly enhanced by exposure to huCD40LT even compared to P01375 exposure . Only a moderate cytokine production was observed initially , while P01375 addition or P25942 triggering , especially , induced enhanced production of P05231 and IL-12 p40 . Surprisingly , comparable induction of T-cell proliferation by a DC allostimulus or through the presentation of PPD , and influenza M1-peptide specific CTL activity was obtained with nonmaturated ( Q01151 - ) and maturated ( Q01151 + ) DC . In conclusion , a final maturation of monocyte-derived DC through huCD40LT resulted in a highly homogeneous cell population with enhanced surface marker expression and high production of pro-inflammatory cytokines . In addition , the induction of responses to allo or recall antigens presented by huCD40LT maturated DC was comparable to the responses obtained with the DC maturated through P01375 exposure . Reduced satiating effect of d-fenfluramine in serotonin 5-HT(2C) receptor mutant mice . RATIONALE : d- DB00574 stimulates the release of serotonin ( 5-HT ) and is a potent inhibitor of the re-uptake of 5-HT into nerve terminals . Administration of d-fenfluramine suppresses food intake in both animals and humans . OBJECTIVE : We have investigated the role of the P28335 receptor in mediating the effect of d-fenfluramine on mouse food intake and the behavioural satiety sequence . METHODS : Mutant mice lacking serotonin P28335 receptors and wild-type animals were habituated to a daily presentation of wet mash . Animals were non-deprived and received d-fenfluramine ( 3-30 mg/kg ) 30 min prior to being assessed for the presence of stereotypy and presented with wet mash . The behaviour of animals was observed for the subsequent 40 min and food intake was recorded . RESULTS : d- DB00574 dose-dependently inhibited the consumption of a palatable wet mash by the mice . d- DB00574 ( 3 mg/kg ) significantly reduced the amount of wet mash consumed by wild-type mice and induced a temporal advance in the behavioural satiety sequence consistent with an enhancement of satiety . Mutant mice were less sensitive to the satiating effects of 3 mg/kg d-fenfluramine . Hence , this dose of d-fenfluramine had a reduced effect on both food consumption and the behavioural satiety sequence in the P28335 mutant mice . In contrast , mutant mice showed an increased sensitivity to the stereotypy induced by high doses of d-fenfluramine ( 10 , 30 mg/kg ) compared to that of wild-type littermates . CONCLUSION : These data demonstrate a role for the P28335 receptor in mediating d-fenfluramine-induced satiety . Determination of fenofibric acid concentrations by HPLC after anion exchange solid-phase extraction from human serum . Triglycerides are increasingly being recognized as a risk factor for cardiovascular disease . Research efforts to identify sources of variability in triglyceride-lowering response to the lipid-lowering drug fenofibrate require quantification of the active acidic form of this Q07869 agonist . Anion-exchange solid-phase extraction , in combination with reverse-phase high-performance liquid chromatography ( HPLC ) , rapidly and accurately determines steady-state fenofibric acid serum concentrations . Chromatographic separation under isocratic conditions , with use of ultraviolet detection at 285 nm , provides clean baseline and sharp peaks for clofibric acid , 1-napthyl acetic acid ( internal standards ) , and fenofibric acid . Commonly prescribed and over-the-counter nonsteroidal anti-inflammatory drugs ( NSAIDs ) were screened for assay interference , and the assay was employed to quantify fenofibric acid in more than 800 human subject specimens . DB01039 analysis was found to be linear over the range of 0.5 to 40 mg/L and was validated with either internal standard . Accuracies ranged from 98.65 % to 102.4 % , whereas the within- and between-day precisions ranged from 1.0 % to 2.2 % and 2.0 % to 6.2 % , respectively . NSAIDs had minimal interference with the assay , which succeeded in quantifying fenofibric acid in more than 843 of 846 serum samples from human subjects , many taking a variety of coadministered medications . Anion-exchange solid-phase extraction in combination with reverse-phase HPLC accurately determines steady-state fenofibric acid serum concentrations in humans without interference from NSAIDs or commonly administered medications . This method is suitable for quantification of fenofibric acid for clinical pharmacokinetic studies in patients with dyslipidemia . Inhibition of prothrombin kringle-2-induced inflammation by minocycline protects dopaminergic neurons in the substantia nigra in vivo . P00734 kringle-2 ( pKr-2 ) , a domain of prothrombin , can cause the degeneration of mesencephalic dopaminergic neurons through microglial activation . However , the chemical products that inhibit pKr-2-induced inflammatory activities in the brain are still not well known . The present study investigated whether minocycline , a semisynthetic tetracycline derivative , could inhibit pKr-2-induced microglial activation and prevent the loss of nigral dopaminergic ( DA ) neurons in vivo . To address this question , rats were administered a unilateral injection of pKr-2 in the substantia nigra in the presence or absence of minocycline . Our results show that pKr-2 induces the production of proinflammatory cytokines , such as tumor necrosis factor-α ( P01375 -α ) and interleukin-1β ( IL-1β ) , and inducible nitric oxide synthase from the activated microglia . In parallel , 7 days after pKr-2 injection , tyrosine hydroxylase immunocytochemical analysis and western blot analysis showed a significant loss of nigral DA neurons . This neurotoxicity was antagonized by minocycline and the observed neuroprotective effects were associated with the ability of minocycline to suppress the expression of tumor necrosis factor-α , interleukin-1β , and nitric oxide synthase . These results suggest that minocycline may be promising as a potential therapeutic agent for the prevention of DA neuronal degeneration associated with pKr-2-induced microglial activation . DB01098 improves endothelial function in db/db mice : role of angiotensin II type 1 receptors and oxidative stress . BACKGROUND AND PURPOSE : P04035 inhibitors , statins , with lipid-reducing properties combat against atherosclerosis and diabetes . The favourable modulation of endothelial function may play a significant role in this effect . The present study aimed to investigate the cellular mechanisms responsible for the therapeutic benefits of rosuvastatin in ameliorating diabetes-associated endothelial dysfunction . EXPERIMENTAL APPROACH : Twelve-week-old db/db diabetic mice were treated with rosuvastatin at 20 mg·kg⁻¹ ·day⁻¹ p.o.for 6 weeks . Isometric force was measured in isolated aortae and renal arteries . Protein expressions including angiotensin II type 1 receptor ( AT₁R ) , Q9NPH5 , O75935 (phox) , p67(phox) , Rac-1 , nitrotyrosine , phospho- P27361 /2 and phospho-p38 were determined by Western blotting , while reactive oxygen species ( ROS ) accumulation in the vascular wall was evaluated by dihydroethidium fluorescence and lucigenin assay . KEY RESULTS : DB01098 treatment of db/db mice reversed the impaired ACh-induced endothelium-dependent dilatations in both renal arteries and aortae and prevented the exaggerated contractions to angiotensin II and phenylephrine in db/db mouse renal arteries and aortae . DB01098 reduced the elevated expressions of AT₁R , O75935 (phox) and p67(phox) , Q9NPH5 , Rac1 , nitrotyrosine and phosphorylation of P27361 /2 and p38 MAPK and inhibited ROS production in aortae from db/db mice . CONCLUSIONS AND IMPLICATIONS : The vasoprotective effects of rosuvastatin are attributed to an increase in NO bioavailability , which is probably achieved by its inhibition of ROS production from the AT₁R-NAD(P)H oxidase cascade .