interacts_with DB01076?
Failure of atorvastatin to modulate P04141 HIV-1 infection : results of a pilot study . BACKGROUND : HIV-1 infection of the P04141 space is nearly universal in untreated systemic infection , and correlates strongly with intrathecal and systemic immunoactivation and P04141 pleocytosis . Based on the potential immunomodulatory and antiviral properties of P04035 inhibitors ( statins ) , we examined the effect of atorvastatin on P04141 HIV-1 infection and associated P04141 abnormalities in a small pilot study . METHODS : Seven male HIV-1-infected , antiretroviral-naïve subjects with a mean blood P01730 + T cell count of 473 cells/muL were studied in an open-label , single-arm pilot study to assess the effects of 80 mg atorvastatin daily for 8 weeks . The primary endpoint was the change in P04141 HIV-1 RNA levels , both absolutely and relative to plasma HIV-1 RNA , at 4 and 8 weeks of treatment . Other outcome measures included P04141 white blood cell counts and neopterin concentrations as indices of intrathecal immunoactivation , and blood HIV-1 RNA levels , neopterin concentrations , and T lymphocyte counts . Effects on blood lipids were used to monitor the established biologic effects of atorvastatin and treatment adherence . RESULTS : No significant changes in P04141 virologic and inflammatory indices or in systemic HIV-1 infection were observed during atorvastatin treatment despite potent reduction of blood lipids . CONCLUSION : DB01076 showed no appreciable effect on P04141 HIV-1 infection or intrathecal immunoactivation in this small uncontrolled study and thus appears to have little promise as an immunomodulatory adjuvant therapy for CNS HIV-1 infection , at least in neuroasymptomatic subjects with preserved P01730 + T cell counts . Q9GZX6 /IL-22R1 axis and P05109 /A9 alarmins in human osteoarthritic and rheumatoid arthritis synovial fibroblasts . OBJECTIVES : Fibroblast-like synoviocytes ( FLSs ) are crucial players in the pathogenesis of synovitis in rheumatic diseases . Targeting FLS activation represents an approach to the development of therapeutic strategies . Our aim was to investigate whether the microenvironment of inflamed joints could modulate the expression of Q9GZX6 and IL-22R1 on OA and RA FLSs . We also examined the effect of Q9GZX6 on FLS activation as well as on their Q16552 -related responses . METHODS : Q9GZX6 and IL-22R1 expression was studied by RT-PCR and immunoblotting . Proliferation was measured by an ELISA kit . Q16552 receptors , p19IL-23 and alarmins were analysed by RT-PCR . Q16552 receptor expression was evaluated by flow cytometry . P03956 and IL-23 were measured by ELISA . P05109 /A9 expression was detected by immunofluorescence and ELISA . P40763 ( P40763 ) phosphorylation was quantified using a cell-based ELISA kit . RESULTS : Q9GZX6 and IL-22R1 were expressed constitutively in FLSs . We demonstrated that P05109 and P06702 were synthesized in FLSs . We reported that inflammatory mediators increased the expression of the Q9GZX6 /IL-22R1 axis , amplifying FLS activation . Q9GZX6 enhanced FLS proliferation and up-regulated P03956 and P05109 /A9 production . P40763 phosphorylation was induced after Q9GZX6 treatment and the stimulatory effect of Q9GZX6 on P05109 /A9 was reduced after the activities of O60674 ( O60674 ) and P52333 were blocked . We showed an inhibitory action of Q9GZX6 on IL-23 and Q8NAC3 expression in RA FLSs and on Q96F46 in OA FLSs . CONCLUSION : Therapies based on the pharmacological disruption signalling of Q9GZX6 could be beneficial for the treatment of rheumatic diseases . The restricted expression of IL-22R1 to non-lymphoid cells could lead to a reduction of side effects mediated by immune responses . DB00399 -induced IPP/ApppI production in vivo . Bisphosphonates are currently the most important class of anti-resorptive drugs used for the treatment of diseases involving excess bone resorption . Recently we discovered a new mechanism of action for bisphosphonates . Previously it has been shown that nitrogen-containing bisphosphonates ( N-BPs ) are not metabolized . However , our studies revealed that N-BPs induce formation of a novel pro-apoptotic DB00171 analog ( ApppI ) , as a consequence of the inhibition of P14324 in the mevalonate pathway , and the subsequent accumulation of isopentenyl pyrophosphate ( IPP ) in vitro . The primary aim of the current study was to determine whether zoledronic acid ( a N-BP ) induces IPP/ApppI formation in vivo . Mass spectrometry was used to identify whether in vivo administration of zoledronic acid-induced IPP/ApppI production by mouse peritoneal macrophages or bone marrow cells . IPP/ApppI could be detected in extracts from peritoneal macrophages isolated from zoledronic acid-treated animals . Increasing IPP/ApppI accumulation was determined up to 7 days after drug injection , indicating prolonged P14324 inhibition by zoledronic acid . Importantly , this is the first report of in vivo production of ApppI , supporting the biological significance of this molecule . Statin Modulation of Human T-Cell Proliferation , IL-1β and Q16552 Production , and IFN-γ T Cell Expression : Synergy with Conventional Immunosuppressive Agents . P04035 inhibitors ( statins ) have been demonstrated to be immunomodulatory for human immune-mediated disease and in experimental models . The aim of this study was to compare statin-mediated immunosuppressive effects on human T-cell responses in vitro with those of conventional immunosuppressives ( dexamethasone , cyclosporin A ( DB00091 ) , mycophenolate , and rapamycin ) . Statins ( atorvastatin , lovastatin , and simvastatin ) were investigated for their modulatory effects on human PBMC viability , cytokine profiles , and T-cell proliferation . At concentrations that inhibited anti-CD3/28-stimulated T-cell proliferation ( P < 0.01 ) , simvastatin significantly decreased intracellular P01730 (+) T-cell expression of IFN-γ ( P < 0.01 ) to levels similar to those induced by conventional immunosuppressives . DB01076 and lovastatin also decreased IFN-γ expression , although to a lesser degree ( P < 0.05 ) . All three statins reduced levels of Q16552 production ( P < 0.01 ) . However , in response to anti-CD3/28 stimulation , simvastatin significantly upregulated IL-1β production ( P < 0.05 ) . The profile of cytokines produced in response to anti-CD3/28 stimulation was similar when both atorvastatin and dexamethasone were added as compared with dexamethasone alone , suggesting that atorvastatin can synergise with dexamethasone with respect to immunomodulation of cytokines . This data supports the hypothesis of selective statin-mediated immunomodulatory effects on human immune cells . Local inhibition of angiogenesis by halofuginone coated silicone materials . Anti-angiogenic therapy is a promising approach for the treatment of increased angiogenesis in certain diseases . We aimed to investigate the local anti-angiogenic effect of silicone implants coated with DB04866 , an angiogenesis inhibitor that inhibits synthesis of collagen-type-I and matrix metalloproteinases . The degree of angiogenesis was observed after implantation of surface modified DB04866 eluting silicone implants into a submuscular pocket in rats over a period of 3 months . Subsequently , key mediators of angiogenesis ( P01137 , P09038 , P02452 , P08253 , P14780 , P15692 and PDGF ) were established by immunohistological staining and RT-PCR and statistically evaluated . In comparison to uncoated silicone implants , DB04866 eluting silicone implants lead to a significant local decrease of angiogenesis . DB04866 eluting hybrid surface silicone implants have a significant local anti-angiogenic effect by down-regulating the expression activity of key mediators of angiogenesis . PDE4B5 , a novel , super-short , brain-specific DB02527 phosphodiesterase-4 variant whose isoform-specifying N-terminal region is identical to that of DB02527 phosphodiesterase-4D6 ( PDE4D6 ) . The DB02527 -specific phosphodiesterase-4 ( DB05876 ) gene family is the target of several potential selective therapeutic inhibitors . The four DB05876 genes generate several distinct protein-coding isoforms through the use of alternative promoters and 5'-coding exons . Using mouse transcripts , we identified a novel , super-short isoform of human Q07343 encoding a novel 5' terminus , which we label PDE4B5 . The protein-coding region of the novel 5' exon is conserved across vertebrates , chicken , zebrafish , and fugu . Reverse-transcription-polymerase chain reaction ( PCR ) and quantitative ( PCR ) measurements show that this isoform is brain-specific . The novel protein is 58 +/- 2 kDa ; it has DB02527 hydrolyzing enzymatic activity and is inhibited by DB05876 -selective inhibitors rolipram and cilomilast ( DB03849 ) . Confocal and subcellular fractionation analyses show that it is distributed predominantly and unevenly within the cytosol . The 16 novel N-terminal residues of PDE4B5 are identical to the 16 N-terminal residues of the super-short isoform of Q08499 ( PDE4D6 ) , which is also brain-specific . PDE4B5 is able to bind the scaffold protein Q9NRI5 , whose gene has been linked to schizophrenia . Microarray expression profiling of the DB05876 gene family shows that specific DB05876 genes are enriched in muscle and blood fractions ; however , only by monitoring the individual isoforms is the brain specificity of the super-short Q08499 and Q07343 isoforms revealed . Understanding the distinct tissue specificity of DB05876 isoforms will be important for understanding phosphodiesterase biology and opportunities for therapeutic intervention . Novel dual targeting strategy with vandetanib induces tumor cell apoptosis and inhibits angiogenesis in malignant pleural mesothelioma cells expressing P07949 oncogenic rearrangement . Malignant pleural mesothelioma ( MPM ) is an aggressive malignancy with a poor prognosis , therefore development of novel effective therapies is urgent . In the present study , we investigated the therapeutic efficacy of vandetanib ( DB05294 ) , an inhibitor of P35968 , P00533 and P07949 tyrosine kinases , in an orthotopic model of MPM . We found that a human MPM cell line , EHMES-10 , expressed P07949 /PTC3 oncogenic rearrangement and a large amount of P15692 . DB05294 induced the apoptosis and inhibited the proliferation of EHMES-10 cells in vitro ( IC(50)=0.3 microM ) . Once-daily oral treatment with vandetanib inhibited tumor angiogenesis , and reduced significantly the growth of thoracic tumors and the production of pleural effusions , resulting in the prolonged survival of mice in EHMES-10 orthograft model . In contrast , the selective P00533 tyrosine kinase inhibitor , gefitinib , had no effect against EHMES-10 cells both in vitro and in vivo . Our results suggest that using vandetanib to target P07949 -dependent tumor cell proliferation and survival and P35968 -dependent tumor angiogenesis may be promising against MPM expressing P07949 oncogenic rearrangement and P15692 . The design and development of pegfilgrastim ( PEG-rmetHuG- P04141 , Neulasta ) . Recombinant protein technology produces drugs for human therapy in unprecedented quantity and quality . Research is now focusing on the relationship between pharmacokinetic and pharmacodynamic properties of molecules , with the aim of engineering proteins that possess enhanced therapeutic characteristics in contrast to being used as simple replacements for the natural equivalent . The addition of a polyethylene glycol ( PEG ) moiety to filgrastim ( rmetHu- DB00099 , Neupogen ) resulted in the development of pegfilgrastim . DB00019 is a long-acting form of filgrastim that requires only once-per-cycle administration for the management of chemotherapy-induced neutropenia . The covalent attachment of PEG to the N-terminal amine group of the parent molecule was attained using site-directed reductive alkylation . Pegylation increases the size of filgrastim so that it becomes too large for renal clearance . Consequently , neutrophil-mediated clearance predominates in elimination of the drug . This extends the median serum half-life of pegfilgrastim to 42 hours , compared with between 3.5 and 3.8 hours for DB00099 , though in fact the half-life is variable , depending on the absolute neutrophil count , which in turn reflects of the ability of pegfilgrastim to sustain production of those same cells . The clearance of the molecule is thus dominated by a self-regulating mechanism . DB00019 retains the same biological activity as filgrastim , and binds to the same Q99062 , stimulating the proliferation , differentiation and activation of neutrophils . Once-per-chemotherapy cycle administration of pegfilgrastim reduces the duration of severe neutropenia as effectively as daily treatment with filgrastim . In clinical trials , patients receiving pegfilgrastim also had a lower observed incidence of febrile neutropenia than patients receiving filgrastim . Differential expression and function of phosphodiesterase 4 ( DB05876 ) subtypes in human primary P01730 + T cells : predominant role of Q08499 . Type 4 phosphodiesterases ( DB05876 ) are critical regulators in TCR signaling by attenuating the negative constraint of DB02527 . In this study , we show that anti-CD3/ P10747 stimulation of human primary P01730 (+) T cells increases the expression of the DB05876 subtypes P27815 , Q07343 , and Q08499 in a specific and time-dependent manner . P27815 and Q08499 mRNAs as well as enzyme activities were up-regulated within 5 days , Q07343 showed a transient up-regulation with highest levels after 24 h . The induction was shown to be independent of different stimulation conditions and was similar in naive and memory T cell subpopulations . To elucidate the functional impact of individual DB05876 subtypes on T cell function , we used DB05876 subtype-specific short-interfering RNAs ( siRNAs ) . Knockdown of either Q07343 or Q08499 inhibited P60568 release 24 h after stimulation ( time point of maximal P60568 concentrations ) to an extent similar to that observed with the panPDE4 inhibitor RP73401 ( piclamilast ) . Substantial amounts of P01579 or P05113 were measured only at later time points . siRNA targeting Q08499 showed a predominant inhibitory effect on these cytokines measured after 72 h . However , the inhibition of all cytokines was most effective when DB05876 siRNAs were applied in combination . Although the effect of DB05876 inhibition on T cell proliferation is small , the Q08499 -targeting siRNA alone was as effective as the panPDE4 inhibitor , whereas P27815 or Q07343 siRNAs had hardly an effect . In summary , individual DB05876 subtypes have overall nonredundant , but complementary , time-dependent roles in propagating various T cell functions and Q08499 is the form likely playing a predominant role . DB01076 inhibits inflammatory angiogenesis in mice through down regulation of P15692 , P01375 and TGF-beta1 . While compelling evidence indicates beneficial effects of statins on inflammatory processes , besides their cholesterol-lowering activities , the actions on angiogenesis are less clear-cut . Our aim was to investigate the effects of atorvastatin on key components of inflammatory angiogenesis in the murine sponge model . Polyester-polyurethane sponges , used as a framework for fibrovascular tissue growth , were implanted in Swiss mice . DB01076 ( 0.6 , 3 mg/kg/day ) was given orally for 8 days in drinking water . The implants collected at day 9 postimplantation were processed for the assessment of hemoglobin , myeloperoxidase ( P05164 ) , N-acetylglucosaminidase ( NAG ) and collagen . Relevant inflammatory , angiogenic and fibrogenic cytokines were also determined . DB01076 treatment resulted in significant decrease in sponge vascularization ( Hb content ) and in P15692 levels at both doses . Neutrophil influx ( P05164 activity ) was not affected by the compound whereas macrophage recruitment ( NAG activity ) was inhibited , suggesting a degree of selectivity by atorvastatin for this cell population . The level of P13500 ( MCP1-JE ) was decreased only with 0.6 mg/kg . DB01076 was also able to reduce collagen deposition and the levels of transforming growth factor ( TGF-beta1 ) intraimplant , dose-dependently . The inhibitory function of atorvastatin on multiple parameters of main components of inflammatory angiogenesis revealed in this study is clearly associated with the modulatory effects of P04035 on P15692 , P01375 and TGF-beta1 production . Multiple arrhythmic syndromes in a newborn , owing to a novel mutation in Q14524 . BACKGROUND : Mutations in the Q14524 gene have been linked to Brugada syndrome ( BrS ) , conduction disease , Long QT syndrome ( LQT3 ) , atrial fibrillation ( AF ) , and to pre- and neonatal ventricular arrhythmias . OBJECTIVE : The objective of this study is to characterize a novel mutation in Na(v)1.5 found in a newborn with fetal chaotic atrial tachycardia , post-partum intraventricular conduction delay , and QT interval prolongation . METHODS : Genomic DNA was isolated and all exons and intron borders of 15 ion-channel genes were sequenced , revealing a novel missense mutation ( Q270K ) in Q14524 . Na(v)1.5 wild type ( WT ) and Q270K were expressed in CHO- P04264 with and without the Na(v)β1 subunit . Results . Patch-clamp analysis showed ∼40 % reduction in peak sodium channel current ( I(Na) ) density for Q270K compared with WT . Fast and slow decay of I(Na) were significantly slower in Q270K . Steady-state activation and inactivation of Q270K channels were shifted to positive potentials , and window current was increased . The tetrodotoxin-sensitive late I(Na) was increased almost 3-fold compared with WT channels . DB00243 reduced late I(Na) in WT and Q270K channels , while exerting minimal effects on peak I(Na) . CONCLUSION : The Q270K mutation in Q14524 reduces peak I(Na) while augmenting late I(Na) , and may thus underlie the development of atrial tachycardia , intraventricular conduction delay , and QT interval prolongation in an infant . Chronic inhibition of farnesyl pyrophosphate synthase improves endothelial function in spontaneously hypertensive rats . P14324 ( FPPS , EC 2.5.1.10 ) , an essential enzyme in the mevalonate pathway , catalyzes the synthesis of isoprenoid intermediates . The isoprenoid intermediates are needed for protein isoprenylation of RhoA for its function on regulation of endothelial nitric oxide synthase ( P29474 ) . We previously reported that FPPS were upregulated in spontaneously hypertensive rats ( SHR ) when compared with Wistar-Kyoto rats ( WKY ) , and this was accompanied by development of endothelial dysfunction . Five-week-old male rats were daily gavaged with vehicle or an FPPS inhibitor ( alendronate , 1 or 10mg/kg ) . After 12-week administration of alendronate , endothelium-dependent and -independent vasorelaxation were measured in isolated aortic rings . Twelve-week of alendronate ( 10mg/kg/day ) treatment restored the impaired endothelium-dependent vasodilation in SHR . Furthermore , long-term treatment with an FPPS inhibitor significantly suppressed RhoA activation and increased phospho- P29474 / P29474 ratio . In conclusion , chronic treatment with an FPPS inhibitor improves the endothelial function in SHR , and the upregulation of phospho- P29474 / P29474 ratio with inhibition of RhoA activation may be an important mechanism . SAR and in vivo evaluation of 4-aryl-2-aminoalkylpyrimidines as potent and selective O60674 ( O60674 ) inhibitors . We report the discovery of a series of 4-aryl-2-aminoalkylpyrimidine derivatives as potent and selective O60674 inhibitors . High throughput screening of our in-house compound library led to the identification of hit 1 , from which optimization resulted in the discovery of highly potent and selective O60674 inhibitors . Advanced lead 10d demonstrated a significant dose-dependent pharmacodynamic and antitumor effect in a mouse xenograft model . Based upon the desirable profile of 10d ( DB05243 ) it was advanced into clinical trials . Relationship of Kaposi sarcoma ( KS ) -associated herpesvirus viremia and KS disease in Zimbabwe . The relationship between Kaposi sarcoma-associated herpesvirus ( KSHV ) viremia and KS disease was investigated in 500 subjects who received treatment in Harare , Zimbabwe . Subjects were grouped by results of human immunodeficiency virus ( HIV ) type 1 serological tests , KS diagnosis , and KS clinical stage . The plasma KSHV DNA concentration was associated with concomitant KS and HIV-1 infection ( AIDS-KS ; P < .001 ) and AIDS-KS clinical stage ( P=.01 ) . Plasma KSHV DNA levels were greater in AIDS-KS than in matched HIV-1-seronegative KS ( P=.04 ) . The plasma KSHV DNA level was not associated with age , sex , systemic symptoms , or P01730 + lymphocyte count . Plasma and peripheral blood mononuclear cell KSHV DNA concentrations were linearly related ( r2=.44 ; P < .001 ) , and the nucleotide sequence of the P04264 gene highly variable region was identical in both compartments . These findings provide evidence that KSHV viremia is common in advanced AIDS-KS in Zimbabwe and suggest a relationship between KSHV lytic replication and untreated HIV-1 infection . PDE10 inhibition increases P42261 and CREB phosphorylation and improves spatial and recognition memories in a Huntington 's disease mouse model . Huntington 's disease ( HD ) causes motor disturbances , preceded by cognitive impairment , in patients and mouse models . We showed that increased hippocampal DB02527 -dependent protein kinase ( PKA ) signaling disrupts recognition and spatial memories in R6 HD mouse models . However , unchanged levels of hippocampal phosphorylated ( p ) DB02527 -responsive element-binding protein ( CREB ) suggested unaltered nuclear PKA activity in R6 mice . Here , we extend this finding by showing that nuclear pPKA catalytic subunit ( Thr197 ) and pPKA substrate levels were unaltered in the hippocampus of R6/1 mice . Phosphodiesterases ( PDEs ) play an important role in the regulation of PKA activity . Q9Y233 , a DB02527 /cGMP dual-substrate PDE , was reported to be restricted to the nuclear region in nonstriatal neurons . Using cell fractionation we confirmed that Q9Y233 was enriched in nuclear fractions , both in wild-type and R6/1 mice hippocampus , without differences in its levels or intracellular distribution between genotypes . We next investigated whether inhibition of PDE10 with papaverine could improve cognitive function in HD mice . DB01113 treatment improved spatial and object recognition memories in R6/1 mice , and significantly increased pGluA1 and pCREB levels in R6/1 mice hippocampus . DB01113 likely acted through the activation of the PKA pathway as the phosphorylation level of distinct cGMP-dependent kinase ( cGK ) substrates was not modified in either genotype . Moreover , hippocampal DB02527 , but not cGMP , levels were increased after acute papaverine injection . Our results show that inhibition of PDE10 improves cognition in R6 mice , at least in part through increased P42261 and CREB phosphorylation . Thus , PDE10 might be a good therapeutic target to improve cognitive impairment in HD . Pharmacological rescue of Ras signaling , P42261 -dependent synaptic plasticity , and learning deficits in a fragile X model . Fragile X syndrome , caused by the loss of Fmr1 gene function , is the most common form of inherited mental retardation , with no effective treatment . Using a tractable animal model , we investigated mechanisms of action of a few FDA-approved psychoactive drugs that modestly benefit the cognitive performance in fragile X patients . Here we report that compounds activating serotonin ( 5HT ) subtype 2B receptors ( 5HT2B-Rs ) or dopamine ( DA ) subtype 1-like receptors ( D1-Rs ) and/or those inhibiting 5HT2A-Rs or D2-Rs moderately enhance Ras-PI3K/ P31749 signaling input , P42261 -dependent synaptic plasticity , and learning in Fmr1 knockout mice . Unexpectedly , combinations of these 5HT and DA compounds at low doses synergistically stimulate Ras-PI3K/ P31749 signal transduction and P42261 -dependent synaptic plasticity and remarkably restore normal learning in Fmr1 knockout mice without causing anxiety-related side effects . These findings suggest that properly dosed and combined FDA-approved psychoactive drugs may effectively treat the cognitive impairment associated with fragile X syndrome . P04035 inhibitor , atorvastatin , promotes sensorimotor recovery , suppressing acute inflammatory reaction after experimental intracerebral hemorrhage . BACKGROUND AND PURPOSE : Statins have neuroprotective effects on ischemic stroke . They modify the endothelial function , increase blood flow , and inhibit thrombus formation , which are independent of lipid-lowering effects . However , whether statins have a protective effect toward hemorrhagic stroke is yet unknown . To test this possibility , we attempted to determine the effect of atorvastatin on experimental intracerebral hemorrhage ( ICH ) . METHODS : ICH was induced using stereotaxic infusion of collagenase into the left basal ganglia in adult rats . DB01076 ( 1 mg/kg or 10 mg/kg ) or phosphate-buffered saline was administered for 2 weeks . To monitor the sensorimotor deficits , limb placing and Rotorod tests were performed . Hematoma volume , brain water content , and hemispheric atrophy were analyzed . Immunohistochemical staining for myeloperoxidase ( P05164 ) , microglia ( OX42 ) , inducible nitric oxide synthase ( P35228 ) , or endothelial nitric oxide synthase ( P29474 ) was performed . Perihematomal cell death was determined by TUNEL staining . RESULTS : The atorvastatin-treated ICH group showed better performance on Rotorod and limb placing tests when compared with the vehicle-treated group ( P < 0.01 ) . The hematoma volumes between groups were not different , but the brain water content and hemispheric atrophy were reduced in the atorvastatin-treated ICH group . DB01076 reduced TUNEL-positive cells , P35228 expression , and P05164 -positive or OX42-positive cells in the perihematomal regions in a dose-dependent manner , whereas it increased P29474 expression . CONCLUSIONS : The present study shows that atorvastatin reduces the perihematomal cell death via antiinflammation , which is associated with sensorimotor recovery after experimental ICH . DB01076 induces insulin sensitization in Zucker lean and fatty rats . BACKGROUND : The 3-hydroxy-3-methyl glutaryl coenzyme A ( HMG- DB01992 ) reductase inhibitors ( ' statins ' ) have been implicated in preventing new onset type 2 diabetes , whereas the mechanism of this effect is not known . We investigated the effects of an P04035 inhibitor , atorvastatin , on insulin sensitization in Zucker lean and fatty rats . METHODS AND RESULTS : In vivo studies of insulin sensitization were performed in chow fed Zucker lean and fatty rats treated with atorvastatin 50mg/kg/day ( ATORVA_50 ) and results were compared to Zucker lean and fatty rats treated with drug vehicle only ( CONT ) . Additional Zucker lean rats were treated with an intermediate dose of atorvastatin 25mg/kg/day ( ATORVA_25 ) . Treatment with atorvastatin resulted in a dose-dependent improvement in whole body insulin sensitivity in both lean and fatty rats , with an approximately two-fold increase in glucose infusion rate and glucose disposal ( Rd ) in ATORVA_50 versus CONT ( p < 0.01 ) . DB01076 50mg/kg/day resulted in an increase in DB08831 ( 2-DOG ) uptake by skeletal muscles ( approximately two-fold increase in 2-DOG uptake in quadriceps ( p=0.06 ) and gastrocnemius ( p < 0.01 ) ) in lean Zucker rats . P01308 -stimulated phosphorylation of Akt/ P31749 was significantly increased in skeletal muscle of ATORVA_50 versus CONT in both lean and fatty rats . CONCLUSION : DB01076 induces insulin sensitization in Zucker lean and fatty rats . This may be a clinically important pleiotropic effect if confirmed in insulin resistant humans . The anti-androgen drug dutasteride renders triple negative breast cancer cells more sensitive to chemotherapy via inhibition of HIF-1α-/ P15692 -signaling . BACKGROUND : Triple negative breast cancer ( TNBC ) is characterized by lack of expression of both estrogen and progesterone receptor as well as lack of amplification of P04626 . Patients with TNBC carry an unfavorable prognosis compared to other breast cancer subtypes given that endocrine or P04626 targeted therapies are not effective , rendering chemotherapy the sole effective treatment option to date . Therefore , there is a high demand for additional novel treatment options . FINDINGS : We previously published a list of genes showing both higher gene expression rates in TNBC and , in addition , are known to encode targets of non-oncologic drugs . P18405 , which encodes the type-1 isoform of the steroid-5alpha-reductase , which is involved in androgen metabolism , was found to be one of these genes . DB01126 is a dual blocker of both the type-1 and type-2 isoform of P18405 and is indicated in the treatment of benign prostate hyperplasia . Treatment of TNBC cell lines with dutasteride was associated with a dose-dependent decrease in cell viability , altered protein expression of P15692 and HIF-1α and increased chemosensitivity . CONCLUSION : Our results demonstrate that the P18405 -corresponding anti-androgenic drug dutasteride might act as a combinatorial therapeutic option besides standard chemotherapy in highly aggressive TNBC . The role of atorvastatin in regulating the immune response leading to vascular damage in a model of Kawasaki disease . Superantigens have been implicated in a number of diseases including Kawasaki disease ( KD ) , a multi-system vasculitis resulting in coronary artery aneurysms . We have characterized a murine disease model in which coronary arteritis is induced by a novel superantigen found in Lactobacillus casei cell wall extract ( LCWE ) . Using this animal model of KD , we have identified three pathogenic steps leading to coronary artery aneurysm formation . These steps include T cell activation and proliferation , production of the proinflammatory cytokine tumour necrosis factor ( P01375 ) -α and up-regulation of matrix metalloproteinase 9 ( P14780 ) , an elastolytic protease . In addition to their cholesterol-lowering effects , 3-hydroxy-3-methylglutaryl ( HMG ) coenzyme A ( DB01992 ) reductase inhibitors ( statins ) have pleotropic immunomodulatory properties . Thus , we examined the effect of atorvastatin in modulating each of these three critical pathogenic processes leading to aneurysm formation in the disease model . DB01076 inhibited lymphocyte proliferation in response to superantigen stimulation in a dose-dependent manner . This inhibition was also observed for production of soluble mediators of inflammation including interleukin ( IL ) -2 and P01375 -α . The inhibitory effect on proliferation was rescued completely by mevalonic acid , confirming that the mechanism responsible for this inhibitory activity on immune activation was inhibition of P04035 . Similarly , P01375 -α-induced P14780 production was reduced in a dose-dependent manner in response to atorvastatin . Inhibition of extracellular-regulated kinase ( P29323 ) phosphorylation appears to be the mechanism responsible for inhibition of P14780 production . In conclusion , atorvastatin is able to inhibit critical steps known to be important in the development of coronary aneurysms , suggesting that statins may have therapeutic benefit in patients with KD .