MH_dev_309

Failure of atorvastatin to modulate P04141 REA HIV - 1 infection : results of a pilot study . BACKGROUND : HIV - 1 infection of the P04141 REA space is nearly universal in untreated systemic infection , and correlates strongly with intrathecal and systemic immunoactivation and P04141 REA pleocytosis . Based on the potential immunomodulatory and antiviral properties of P04035 REA inhibitors ( statins ) , we examined the effect of atorvastatin on P04141 REA HIV - 1 infection and associated P04141 REA abnormalities in a small pilot study . METHODS : Seven male HIV - 1 - infected , antiretroviral-naïve subjects with a mean blood P01730 REA + 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 REA 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 REA 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 REA virologic and inflammatory indices or in systemic HIV - 1 infection were observed during atorvastatin treatment despite potent reduction of blood lipids . CONCLUSION : DB01076 SUB showed no appreciable effect on P04141 REA 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 REA + T cell counts .

Q9GZX6 / IL - 22R1 axis and P05109 REA / 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 REA - related responses . METHODS : Q9GZX6 and IL - 22R1 expression was studied by RT-PCR and immunoblotting . Proliferation was measured by an ELISA kit . Q16552 REA receptors , p19IL - 23 and alarmins were analysed by RT-PCR . Q16552 REA receptor expression was evaluated by flow cytometry . P03956 REA and IL - 23 were measured by ELISA . P05109 REA / A9 expression was detected by immunofluorescence and ELISA . P40763 REA ( P40763 REA ) phosphorylation was quantified using a cell-based ELISA kit . RESULTS : Q9GZX6 and IL - 22R1 were expressed constitutively in FLSs . We demonstrated that P05109 REA and P06702 REA 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 REA and P05109 REA / A9 production . P40763 REA phosphorylation was induced after Q9GZX6 treatment and the stimulatory effect of Q9GZX6 on P05109 REA / A9 was reduced after the activities of O60674 REA ( O60674 REA ) and P52333 REA were blocked . We showed an inhibitory action of Q9GZX6 on IL - 23 and Q8NAC3 expression in RA FLSs and on Q96F46 REA 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 MEN - 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 REA 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 REA 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 REA Production , and IFN-γ T Cell Expression : Synergy with Conventional Immunosuppressive Agents . P04035 REA 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-CD 3/28- stimulated T-cell proliferation ( P < 0.01 ) , simvastatin significantly decreased intracellular P01730 REA ( + ) T-cell expression of IFN-γ ( P < 0.01 ) to levels similar to those induced by conventional immunosuppressives . DB01076 SUB and lovastatin also decreased IFN-γ expression , although to a lesser degree ( P < 0.05 ) . All three statins reduced levels of Q16552 REA production ( P < 0.01 ) . However , in response to anti-CD 3/28 stimulation , simvastatin significantly upregulated IL - 1β production ( P < 0.05 ) . The profile of cytokines produced in response to anti-CD 3/28 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 MEN , 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 MEN eluting silicone implants into a submuscular pocket in rats over a period of 3 months . Subsequently , key mediators of angiogenesis ( P01137 REA , P09038 REA , P02452 REA , P08253 REA , P14780 REA , P15692 REA and PDGF ) were established by immunohistological staining and RT-PCR and statistically evaluated . In comparison to uncoated silicone implants , DB04866 MEN eluting silicone implants lead to a significant local decrease of angiogenesis . DB04866 MEN eluting hybrid surface silicone implants have a significant local anti-angiogenic effect by down-regulating the expression activity of key mediators of angiogenesis .

PDE 4B5 , a novel , super-short , brain-specific DB02527 phosphodiesterase - 4 variant whose isoform-specifying N-terminal region is identical to that of DB02527 phosphodiesterase - 4D6 ( PDE 4D6 ) . 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 REA encoding a novel 5 ' terminus , which we label PDE 4B5 . 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 MEN ) . Confocal and subcellular fractionation analyses show that it is distributed predominantly and unevenly within the cytosol . The 16 novel N-terminal residues of PDE 4B5 are identical to the 16 N-terminal residues of the super-short isoform of Q08499 REA ( PDE 4D6 ) , which is also brain-specific . PDE 4B5 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 REA and Q07343 REA 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 REA 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 MEN ) , an inhibitor of P35968 REA , P00533 REA and P07949 REA tyrosine kinases , in an orthotopic model of MPM . We found that a human MPM cell line , EHMES - 10 , expressed P07949 REA / PTC 3 oncogenic rearrangement and a large amount of P15692 REA . DB05294 MEN 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 REA 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 REA - dependent tumor cell proliferation and survival and P35968 REA - dependent tumor angiogenesis may be promising against MPM expressing P07949 REA oncogenic rearrangement and P15692 REA .

The design and development of pegfilgrastim ( PEG-rmetHuG - P04141 REA , 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 MEN 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 MEN retains the same biological activity as filgrastim , and binds to the same Q99062 REA , 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 REA + T cells : predominant role of Q08499 REA . Type 4 phosphodiesterases ( DB05876 ) are critical regulators in TCR signaling by attenuating the negative constraint of DB02527 . In this study , we show that anti-CD 3 / P10747 REA stimulation of human primary P01730 REA ( + ) T cells increases the expression of the DB05876 subtypes P27815 REA , Q07343 REA , and Q08499 REA in a specific and time-dependent manner . P27815 REA and Q08499 REA mRNAs as well as enzyme activities were up-regulated within 5 days , Q07343 REA 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 REA or Q08499 REA inhibited P60568 REA release 24 h after stimulation ( time point of maximal P60568 REA concentrations ) to an extent similar to that observed with the panPDE 4 inhibitor RP73401 ( piclamilast ) . Substantial amounts of P01579 REA or P05113 REA were measured only at later time points . siRNA targeting Q08499 REA 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 REA - targeting siRNA alone was as effective as the panPDE 4 inhibitor , whereas P27815 REA or Q07343 REA 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 REA is the form likely playing a predominant role .

DB01076 SUB inhibits inflammatory angiogenesis in mice through down regulation of P15692 REA , P01375 REA and TGF-beta 1 . 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 SUB ( 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 REA ) , N-acetylglucosaminidase ( NAG ) and collagen . Relevant inflammatory , angiogenic and fibrogenic cytokines were also determined . DB01076 SUB treatment resulted in significant decrease in sponge vascularization ( Hb content ) and in P15692 REA levels at both doses . Neutrophil influx ( P05164 REA 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 REA ( MCP 1 - JE ) was decreased only with 0.6 mg / kg . DB01076 SUB was also able to reduce collagen deposition and the levels of transforming growth factor ( TGF-beta 1 ) 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 REA on P15692 REA , P01375 REA and TGF-beta 1 production .

Multiple arrhythmic syndromes in a newborn , owing to a novel mutation in Q14524 REA . BACKGROUND : Mutations in the Q14524 REA gene have been linked to Brugada syndrome ( BrS ) , conduction disease , Long QT syndrome ( LQT 3 ) , 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 REA . Na ( v ) 1.5 wild type ( WT ) and Q270K were expressed in CHO - P04264 REA 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 MENMAX DB00243 MEN reduced late I ( Na ) in WT and Q270K channels , while exerting minimal effects on peak I ( Na ) . CONCLUSION : The Q270K mutation in Q14524 REA 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 REA ( 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 REA ) . 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 REA / P29474 REA ratio . In conclusion , chronic treatment with an FPPS inhibitor improves the endothelial function in SHR , and the upregulation of phospho - P29474 REA / P29474 REA 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 REA ( O60674 REA ) inhibitors . We report the discovery of a series of 4 - aryl - 2 - aminoalkylpyrimidine derivatives as potent and selective O60674 REA 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 REA 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 MEN ) 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 REA + 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 REA 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 .

PDE 10 inhibition increases P42261 REA 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 ( Thr 197 ) 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 REA , 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 REA 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 PDE 10 with papaverine could improve cognitive function in HD mice . DB01113 MEN treatment improved spatial and object recognition memories in R6 / 1 mice , and significantly increased pGluA 1 and pCREB levels in R6 / 1 mice hippocampus . DB01113 MEN 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 PDE 10 improves cognition in R6 mice , at least in part through increased P42261 REA and CREB phosphorylation . Thus , PDE 10 might be a good therapeutic target to improve cognitive impairment in HD .

Pharmacological rescue of Ras signaling , P42261 REA - dependent synaptic plasticity , and learning deficits in a fragile X model . Fragile X syndrome , caused by the loss of Fmr 1 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-PI 3K / P31749 REA signaling input , P42261 REA - dependent synaptic plasticity , and learning in Fmr 1 knockout mice . Unexpectedly , combinations of these 5HT and DA compounds at low doses synergistically stimulate Ras-PI 3K / P31749 REA signal transduction and P42261 REA - dependent synaptic plasticity and remarkably restore normal learning in Fmr 1 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 REA 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 SUB ( 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 REA ) , microglia ( OX42 ) , inducible nitric oxide synthase ( P35228 REA ) , or endothelial nitric oxide synthase ( P29474 REA ) 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 SUB reduced TUNEL-positive cells , P35228 REA expression , and P05164 REA - positive or OX42 - positive cells in the perihematomal regions in a dose-dependent manner , whereas it increased P29474 REA 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 SUB 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 REA 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 SUB 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 REA - stimulated phosphorylation of Akt / P31749 REA was significantly increased in skeletal muscle of ATORVA _50 versus CONT in both lean and fatty rats . CONCLUSION : DB01076 SUB 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 REA - 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 REA . Patients with TNBC carry an unfavorable prognosis compared to other breast cancer subtypes given that endocrine or P04626 REA 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 REA , 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 MEN is a dual blocker of both the type - 1 and type - 2 isoform of P18405 REA 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 REA and HIF - 1α and increased chemosensitivity . CONCLUSION : Our results demonstrate that the P18405 REA - 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 REA ) - α and up-regulation of matrix metalloproteinase 9 ( P14780 REA ) , 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 SUB 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 REA - 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 REA . Similarly , P01375 REA - α-induced P14780 REA production was reduced in a dose-dependent manner in response to atorvastatin . Inhibition of extracellular-regulated kinase ( P29323 REA ) phosphorylation appears to be the mechanism responsible for inhibition of P14780 REA 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 .