MH_dev_199

[ Synthesis of ( 2 ' - bromo - 4 ' , 5 ' - dimethoxy-phenyl ) - ( 2,3- dibromo -4,5- dimethoxy-phenyl ) - methane as P18031 REA inhibitor ] . OBJECTIVE : To synthesize ( 2 ' - bromo - 4 ' , 5 ' - dimethoxy-phenyl ) - ( 2,3- dibromo -4,5- dimethoxy-phenyl ) - methane ( 6 ) as protein tyrosine phosphatase 1B ( P18031 REA ) inhibitor . METHOD : DB04088 MEN was synthesized by Friedel-Crafts reaction , bromination and decarbonylation and screened inhibitory activity against P18031 REA by the colorimetric assay . The structure of synthetic intermediates and target product were identified on the basis of spectral analysis . RESULT : DB04088 MEN was synthesized successfully in four steps and evaluated for its P18031 REA inhibitory activity , the screening result shown that compound 6 displayed good inhibitory activity against P18031 REA . CONCLUSION : The target compound 6 was synthesized with the overall yield of 20 % , which was a new compound and shown good inhibitory activity against P18031 REA ( inhibition 40.16 % at 5 mg x L ( - 1 ) ) .

Histone deacetylase inhibitors increase microRNA - 146a expression and enhance negative regulation of interleukin - 1β signaling in osteoarthritis fibroblast-like synoviocytes . OBJECTIVE : MiR - 146a exerts negative control on inflammatory responses by suppressing cytokine-induced expression of interleukin - 1 receptor-associated kinase - 1 ( P51617 REA ) and tumor necrosis factor receptor-associated factor 6 ( Q9Y4K3 REA ) by impairing NF-κB activity and inhibiting the expression of target genes . Recent study suggests that histone deacetylases ( HDACs ) are involved in the regulation of microRNA ( miRNA ) expression . Therefore , we determined whether HDAC inhibitors can increase miR - 146a expression , thereby inhibiting interleukin - 1β ( IL - 1β ) - induced signaling in osteoarthritis fibroblast-like synoviocytes ( OA-FLS ) . METHOD : MiRNA expression was analyzed using real-time PCR . IL - 1β - induced downstream signals and cytokine expression were evaluated using Western blotting and ELISA . Transcription factors regulating promoter activation were identified using chromatin immunoprecipitation assays . RESULTS : IL - 1β treatment of OA-FLS induced a mild ( 1.7- fold ) increase in miR - 146a expression that was unable to appropriately downregulate P51617 REA and Q9Y4K3 REA expression . HDAC inhibitors , DB02546 SUB ( vorinostat ) , and LBH 589 ( DB06603 ) significantly ( 6.1- and 5.4- fold ) elevated miR - 146a expression by increasing the binding of the transcription factor NF-κB to the miR - 146a promoter , and negatively regulated IL - 1β - induced IKK / IκB / p65 phosphorylation signaling and P05231 REA secretion . The increase in miR - 146a expression induced by the HDAC inhibitors was prevented by transfection of miR - 146a inhibitor or Q13547 REA ( class I HDAC ) , P56524 REA ( class IIa HDAC ) , and Q9UBN7 ( class IIb HDAC ) overexpression , suggesting that they were due to inhibition of HDAC activity . CONCLUSIONS : Our study demonstrated that HDAC inhibitor treatment in OA-FLS significantly increased miR - 146a expression and mediated markedly negative regulation to inhibit IL - 1β - induced signaling and cytokine secretion . Our results indicate the potential rationale of anti-inflammatory effects for HDAC inhibitors .

DB00107 MEN predominantly excites putative oxytocin neurons in the rat supraoptic nucleus in vitro . To determine the oxytocin ( P01178 REA ) sensitivity of neurons in the supraoptic nucleus ( P18583 ) , extracellular recordings were made from the rat hypothalamic slice preparation . P01178 REA added to the bathing medium ( 3 X 10 ( - 7 ) M ) excited 13 ( 93 % ) of 14 cells which fired continuously ( average 4.9 + / - 0.7 spikes / s ) and 26 ( 81 % ) of 32 cells which fired slowly and irregularly ( average 1.4 + / - 0.4 spikes / s ) . By contrast , only 2 ( 8 % ) of 26 phasically firing neurons were excited and none of the P18583 cells tested were inhibited . The excitation was reversibly antagonized by a synthetic P01178 REA analogue , 1 - deamino - [ 2 - ( O-methyltyrosine ) , 4 - valine , 8-D - arginine ] vasopressin . The results suggest that P01178 REA exerts predominantly excitatory effects in the P18583 and that putative P01178 REA cells are more likely to be affected than putative vasopressin cells .

Effect of thymoglobulin induction on HIV-infected renal transplant recipients : differences between HIV-positive and HIV-negative patients . The best immunosuppressive regimen in HIV-infected renal transplant recipients has not been established . DB00098 MEN has been associated with an increased risk of serious bacterial infections in HIV-negative patients and , for this reason , there is some concern over its use in the HIV-infected population . We describe three consecutive HIV-infected renal transplant recipients who received thymoglobulin as induction therapy , and we compared their progress with a cohort of 23 HIV-negative recipients . Median follow-up was 24 and 11 months , respectively . Nadir lymphocytopenia was observed at 1 week in both groups , and their absolute lymphocyte count recovery was similar . An early and deep ( < 30 cells / mm ( 3 ) ) P01730 REA ( + ) T cell lymphocytopenia was seen in two of the three HIV-infected patients . No opportunistic infections were diagnosed in HIV-positive patients . One HIV-positive patient had a bacterial infection and five HIV-negative patients had one or more bacterial infections . DB00098 MEN was safe in our three HIV-infected renal transplant recipients . Until those data are confirmed in larger studies , close monitoring is recommended during the thymoglobulin-induced P01730 REA ( + ) T cell lymphocytopenia period .

Age-related changes in rat bone-marrow mesenchymal stem cell plasticity . BACKGROUND : The efficacy of adult stem cells is known to be compromised as a function of age . This therefore raises questions about the effectiveness of autologous cell therapy in elderly patients . RESULTS : We demonstrated that the expression profile of stemness markers was altered in BM-MSCs derived from old rats . BM-MSCs from young rats ( 4 months ) expressed Q01860 REA , Sox - 2 and Q9H9S0 REA , but we failed to detect Sox - 2 and Q9H9S0 REA in BM-MSCs from older animals ( 15 months ) . Chondrogenic , osteogenic and adipogenic potential is compromised in old BM-MSCs . Stimulation with a cocktail mixture of bone morphogenetic protein ( P12643 REA ) , fibroblast growth factor ( P09038 REA ) and insulin-like growth factor ( DB01277 MEN ) induced cardiomyogenesis in young BM-MSCs but not old BM-MSCs . Significant differences in the expression of gap junction protein connexin - 43 were observed between young and old BM-MSCs . Young and old BM-MSCs fused with neonatal ventricular cardiomyocytes in co-culture and expressed key cardiac transcription factors and structural proteins . Cells from old animals expressed significantly lower levels of P15692 REA , IGF , P01133 REA , and DB00099 . Significantly higher levels of DNA double strand break marker γ - P16104 REA and diminished levels of telomerase activity were observed in old BM-MSCs . CONCLUSION : The results suggest age related differences in the differentiation capacity of BM-MSCs . These changes may affect the efficacy of BM-MSCs for use in stem cell therapy .

Combined effects of C225 and 125 - iodine seed radiation on colorectal cancer cells . BACKGROUND : To characterize the effect of combined treatment of the anti-epidermal growth factor receptor ( P00533 REA ) monoclonal antibody C225 and 125 - iodine ( 125I ) seed radiation in human colorectal cancer . METHODS : We treated LS180 cells with 125I continuous low dose rate radiation in the presence and absence of 100 nM C225 . The clonogenic capacity , cellular proliferation , cell cycle distribution , apoptosis , and molecular pathways of the cells following the treatments were analyzed in vitro . RESULTS : The sensitizer enhancement ratio of C225 was approximately 1.4 . Treatment with C225 and radiation alone produced significant inhibition of cell growth , but combination therapy produced greater inhibition than either treatment administered alone . C225 increased the radiation-induced apoptosis and the fraction of γ - P16104 REA foci positive cells at 48 h after treatment . The Akt phosphorylation level was lower in the cells receiving the combination treatment than in the cells treated with radiation or C225 alone . CONCLUSIONS : These findings indicate that C225 sensitizes LS180 cells to 125I seed radiation . Growth inhibition is mediated by inducing apoptosis and not cell cycle arrest . Additionally , we confirmed that C225 impairs DNA repair by reducing the cellular level of the P78527 REA and P12956 REA proteins . Furthermore , the inhibition of Akt signaling activation may be responsible for the C225 - mediated radiosensitization .

Transcriptional alterations of ET - 1 axis and DNA damage in lung tissue of a rat obesity model . Obesity has been implicated in the development of many cancers . This can lead to genome damage , especially in the form of double-strand break , the presence of which is now easily detected through nuclear phosphorylation of histone P16104 REA ( γ - P16104 REA ) focus assay . Recently , the endothelin ( ET ) axis has also been shown to have a role in the growth and progression of several tumors , including lung cancer . The aim of this study was to evaluate the ET - 1 system transcriptional alterations and γ - P16104 REA in lung tissue of Zucker rats subdivided into obese ( O , n = 22 ) and controls ( CO , n = 18 ) rats : under either fasting conditions ( CO ( fc ) - O ( fc ) ) or acute hyperglycemia ( CO ( AH ) - O ( AH ) ) . Significantly higher prepro-ET - 1 ( p= 0.05 ) and ET-converting enzyme ( ECE ) - 2 mRNA expression was observed in O with respect to CO . A significant positive association was observed between prepro-ET - 1 and P25101 REA in the whole rat population ( p= 0.009 ) or in the obese group alone ( p= 0.007 ) . The levels of γ - P16104 REA in O and in O ( AH ) rats were significantly higher ( p= 0.019 ) than in the corresponding CO and CO ( AH ) rats ( p= 0.038 ) . The study shows an inappropriate secretion of ET - 1 in O animals with a parallel DNA damage in their lungs , providing novel mechanisms by which ET receptor antagonist may exert organ protection .

The novel phospho-non-steroidal anti-inflammatory drugs , P01178 REA - 328 , MDC - 22 and MDC - 917 , inhibit adjuvant-induced arthritis in rats . BACKGROUND AND PURPOSE : The use of non-steroidal anti-inflammatory drugs ( NSAIDs ) in the treatment of rheumatoid arthritis ( RA ) is limited by their toxicity . We evaluated the anti-inflammatory efficacy and safety of three novel modified NSAIDs , phospho-aspirin , phospho-ibuprofen and phospho-sulindac . EXPERIMENTAL APPROACH : We determined the anti-inflammatory effects and gastrointestinal safety of the phospho-NSAIDs in the rat adjuvant arthritis model and studied their mechanism of action in cultured cells , Cytokines were measured with elisa and activation of nuclear factor-κB ( NF-κB ) by immunohistochemistry . KEY RESULTS : All three phospho-NSAIDs showed less gastrointestinal toxicity than their parent compounds and demonstrated strong anti-inflammatory effects , essentially reversing joint inflammation and oedema . They have a broad but not uniform effect on the expression of relevant cytokines , in general decreasing P05231 REA and IL - 1β and increasing P22301 REA levels in rat plasma and cultured cells . Phospho-sulindac and phospho-ibuprofen but not phospho-aspirin suppressed PGE ( 2 ) production in vitro , whereas phospho-aspirin ( in contrast to aspirin ) showed the same effect in vivo . In joint tissues , phospho-aspirin inhibited NF-κB activation , and suppressed inflammation and bone resorption . Phospho-aspirin also inhibited Jurkat T cell proliferation . In general , phospho-aspirin had greater efficacy but different effects upon inflammatory mediators compared with aspirin . The chemical modification of the parent NSAIDs seems crucial for their safety and efficacy . CONCLUSIONS AND IMPLICATIONS : Phospho-aspirin , phospho-ibuprofen and phospho-sulindac were safer than their parent NSAIDs , were highly effective in rat adjuvant arthritis and inhibited many key mediators in the pathophysiology of RA . These novel compounds are promising candidate drugs for the treatment of RA and merit further evaluation .

DB09341 and fructose have sugar-specific effects in both liver and skeletal muscle in vivo : a role for liver fructokinase . We examined glucose and fructose effects on serine phosphorylation levels of a range of proteins in rat liver and muscle cells . For this , healthy adult rats were subjected to either oral glucose or fructose loads . A mini-array system was utilized to determine serine phosphorylation levels of liver and skeletal muscle proteins . A glucose oral load of 125 mg / 100 g body weight ( G 1/2 ) did not induce changes in phosphorylated serines of the proteins studied . Loading with 250 mg / 100 g body weight of fructose ( Fr ) , which induced similar glycemia levels as G 1/2 , significantly increased serine phosphorylation of liver cyclin D3 , P19957 REA kinase / p8 5 , P28482 REA , PTP 2 and clusterin . The G 1/2 increased serine levels of the skeletal muscle proteins cyclin H , Cdk 2 , P51617 REA , total PKC , P18031 REA , c-Raf 1 , Ras and the β-subunit of the insulin receptor . The Fr induced a significant increase only in muscle serine phosphorylation of P19957 REA kinase / p8 5 . The incubation of isolated rat hepatocytes with 10 mM glucose for 5 min significantly increased serine phosphorylation of 31 proteins . In contrast , incubation with 10 mM fructose produced less intense effects . Incubation with 10 mM glucose plus 75 µM fructose counteracted the effects of the incubation with glucose alone , except those on P04049 REA and Ras . Less marked effects were detected in cultured muscle cells incubated with 10 mM glucose or 10 mM glucose plus 75 µM fructose . Our results suggest that glucose and fructose act as specific functional modulators through a general mechanism that involves liver-generated signals , like micromolar fructosemia , which would inform peripheral tissues of the presence of either glucose - or fructose-derived metabolites .

DB08932 MEN ( Opsumit ) for the treatment of pulmonary arterial hypertension . The endothelin pathway is a key pathway for the pathogenesis of pulmonary arterial hypertension ( PAH ) . Antagonism of this pathway is recommended as initial therapy in low-risk patient with PAH to inhibit fibrosis , cell proliferation , and inflammation caused by endothelin . Prior to October 2013 , ambrisentan , a selective P25101 REA receptor antagonist and DB00559 , a dual P25101 REA / ETB antagonist , were the only currently available agents for PAH targeting the endothelin pathway . Based on the results of the SERAPHIN trial , macitentan ( brand name Opsumit ® ) , a new P25101 REA / ETB antagonist , has been US FDA approved to delay disease progression and reduce hospitalizations for PAH . SERAPHIN is the first ERA trial to use an event-driven strategy with a composite primary end point of morbidity or mortality . Previous trials have focused on short-term outcomes , such as improved 6 - min walk distance and WHO functional class .

Safety profile of almotriptan , a new antimigraine agent . Effects on central nervous system , renal function and respiratory dynamics . DB00918 MEN ( 3 - [ 2 - ( dimethylamino ) ethyl ] - 5 - ( pyrrolidin - 1 - ylsulfonylmethyl ) - 1H - indole , CAS 154323-57- 6 ) is a new P28222 REA / 1D agonist whose clinical efficacy has been demonstrated in Phase III clinical trials . This study aimed to evaluate the safety of almotriptan with respect to the central nervous system , renal function and respiratory dynamics using preclinical animal models . The results indicate that almotriptan does not cross the blood-brain barrier , since no effects on / interaction with spontaneous locomotor activity , hexobarbital-induced sleeping time , caffeine-induced increase of spontaneous locomotor activity , or hypothermia ( caused by stimulation of central P28221 REA receptors ) was observed following treatment . DB00918 MEN had a mild antiemetic effect and a slight , transient diuretic effect in dogs , although the latter effect is probably of no clinical relevance . In addition , no effect on the respiratory system of conscious guinea pigs was observed following almotriptan treatment . These results indicate that almotriptan has a favourable safety profile with respect to the central nervous , renal and respiratory systems .

Calorie restriction promotes mammalian cell survival by inducing the Q96EB6 deacetylase . A major cause of aging is thought to result from the cumulative effects of cell loss over time . In yeast , caloric restriction ( CR ) delays aging by activating the Sir 2 deacetylase . Here we show that expression of mammalian Sir 2 ( Q96EB6 ) is induced in CR rats as well as in human cells that are treated with serum from these animals . P01308 REA and insulin-like growth factor 1 ( DB01277 MEN ) attenuated this response . Q96EB6 deacetylates the DNA repair factor P12956 REA , causing it to sequester the proapoptotic factor Bax away from mitochondria , thereby inhibiting stress-induced apoptotic cell death . Thus , CR could extend life-span by inducing Q96EB6 expression and promoting the long-term survival of irreplaceable cells .

Selective inhibition of histone deacetylase 6 ( Q9UBN7 ) induces DNA damage and sensitizes transformed cells to anticancer agents . Q9UBN7 ( Q9UBN7 ) is structurally and functionally unique among the 11 human zinc-dependent histone deacetylases . Here we show that chemical inhibition with the Q9UBN7 - selective inhibitor tubacin significantly enhances cell death induced by the topoisomerase II inhibitors etoposide and doxorubicin and the pan-HDAC inhibitor DB02546 SUB ( vorinostat ) in transformed cells ( LNCaP , MCF - 7 ) , an effect not observed in normal cells ( human foreskin fibroblast cells ) . The inactive analogue of tubacin , nil-tubacin , does not sensitize transformed cells to these anticancer agents . Further , we show that down-regulation of Q9UBN7 expression by shRNA in LNCaP cells enhances cell death induced by etoposide , doxorubicin , and DB02546 SUB . Tubacin in combination with DB02546 SUB or etoposide is more potent than either drug alone in activating the intrinsic apoptotic pathway in transformed cells , as evidenced by an increase in PARP cleavage and partial inhibition of this effect by the pan-caspase inhibitor Z-VAD-fmk . Q9UBN7 inhibition with tubacin induces the accumulation of γ P16104 REA , an early marker of DNA double-strand breaks . Tubacin enhances DNA damage induced by etoposide or DB02546 SUB as indicated by increased accumulation of γ P16104 REA and activation of the checkpoint kinase Chk 2 . Tubacin induces the expression of P35638 REA ( P35638 REA / P35638 REA ) , a transcription factor up-regulated in response to cellular stress . P35638 REA induction is further increased when tubacin is combined with DB02546 SUB . These findings point to mechanisms by which Q9UBN7 - selective inhibition can enhance the efficacy of certain anti-cancer agents in transformed cells .

Identification of an acetylation-dependant P12956 REA / FLIP complex that regulates FLIP expression and HDAC inhibitor-induced apoptosis . FLIP is a potential anti-cancer therapeutic target that inhibits apoptosis by blocking caspase 8 activation by death receptors . We report a novel interaction between FLIP and the DNA repair protein P12956 REA that regulates FLIP protein stability by inhibiting its polyubiquitination . Furthermore , we found that the histone deacetylase ( HDAC ) inhibitor DB02546 SUB ( DB02546 SUB ) enhances the acetylation of P12956 REA , thereby disrupting the FLIP / P12956 REA complex and triggering FLIP polyubiquitination and degradation by the proteasome . Using in vitro and in vivo colorectal cancer models , we further demonstrated that DB02546 SUB - induced apoptosis is dependant on FLIP downregulation and caspase 8 activation . In addition , an Q9UBN7 - specific inhibitor Tubacin recapitulated the effects of DB02546 SUB , suggesting that Q9UBN7 is a key regulator of P12956 REA acetylation and FLIP protein stability . Thus , HDAC inhibitors with anti - Q9UBN7 activity act as efficient post-transcriptional suppressors of FLIP expression and may , therefore , effectively act as ' FLIP inhibitors ' .

P01308 REA action on H292 bronchial carcinoma cells as compared to normal bronchial epithelial cells . DB00030 MENMAX DB00030 MEN may contribute to bronchial carcinoma due to P08069 REA activation by high local concentrations . Therefore , effects of insulin and P05019 REA on human bronchial carcinoma cells ( H292 ) and normal bronchial epithelium cells ( P02100 REA ) were studied . TGF-β was included since it also influences carcinoma progression . H292 and P02100 REA cells expressed both the insulin receptor and the P08069 REA ; in H292 cells an additional , shorter , splicing variant ( IR-A ) of the insulin receptor was present . P06213 REA expression was around four to five times higher in H292 than in P02100 REA cells at mRNA and protein levels . P01308 REA and TGF-β exerted contrary actions on proliferation and gene expression in H292 cells . Genes regulated by insulin , P05019 REA , and TGF-β were linked to inflammation , cell adhesion , muscle contraction and differentiation . P01308 REA and P05019 REA also suppressed DNA repair genes . EC ( 50 ) for insulin-induced proliferation was around 5 nM in H292 and around 30 nM P02100 REA cells . The EC ( 50 ) values for gene expression ranged from 9 to 90 nM in both cell types , dependent on the gene studied . In H292 cells , the proliferative response was much stronger if TGF-β was present . In P02100 REA cells this interaction of insulin and TGF-β was not observed , and changes in gene expression were mostly lower by at least 10 - fold as compared to H292 . All in all , the insulin effects in H292 were generally much stronger than in P02100 REA cells and - with regard to proliferation - occurred at lower concentrations . Thus , insulin will hardly induce cancer from normal bronchial cells but may favour progression of pre-existing tumours .

The chronic oral administration of arginine aspartate decreases secretion of DB01277 MEN and P17936 REA in healthy volunteers . To investigate the effect of chronic oral arginine aspartate on the growth hormone ( GH ) , GH-releasing hormone ( P01286 REA ) , insulin-like growth factor - 1 ( DB01277 MEN ) and IGF-binding protein - 3 ( P17936 REA ) secretions in healthy volunteers . Twenty-three healthy non-athlete volunteer males were administered arginine aspartate ( 30 g ) orally once daily at 21:00 h for 21 consecutive days . Subjects were hospitalized on days 0 , 1 , 3 , 5 , 7 , 14 and 21 of treatment . At each hospitalization , concentrations of P01286 REA , GH , DB01277 MEN and P17936 REA were measured over 4 h after arginine aspartate intake . GH , DB01277 MEN and P17936 REA concentrations were also determined over 12 h at days 0 , 1 and 21 . Compared with day 1 , 4 h GH levels dropped at day 5 and subsequently rose to levels not significantly different from initial ones . The latter was substantiated by 12 h GH levels that did not significantly change from days 1 to 21 . P01286 REA levels were not statistically different , although there was a trend in median values that seemed to inversely mirror those of GH . This dynamic over the course of the study for GH and P01286 REA was accompanied by a general decrease in DB01277 MEN and P17936 REA . In healthy volunteers , a chronic oral treatment with 30 g / day arginine aspartate is followed by a decrease in DB01277 MEN and P17936 REA secretions .

A phase I pharmacokinetic study of matuzumab in combination with paclitaxel in patients with P00533 REA - expressing advanced non-small cell lung cancer . DB05101 MEN is a humanized IgG 1 P00533 REA monoclonal antibody . This phase I study investigated the tolerability , safety and pharmacokinetics ( PK ) of matuzumab in combination with paclitaxel in patients with P00533 REA - expressing advanced non-small cell lung cancer ( NSCLC ) . Six dose levels / schedules of matuzumab were explored in combination with paclitaxel . Dose was escalated from 100 mg to 1,600 mg on a modified Fibonacci scheme according to the incidence of dose-limiting toxicity ( DLT ) over the first two cycles . DLT was assessed in patients who completed the first two treatment cycles or who stopped treatment because of a DLT during those cycles . Patients with non-progressive disease could then continue to receive study treatment for up to 6 months . The safety population comprised 44 patients , with DLT evaluable in 33 . The maximum tolerated dose was not reached , with only one DLT reported at the 1,600 mg 3 - weekly dose level . The most frequent grade 3/4 adverse events across all cycles were dyspnea ( 23 % ) and neutropenia ( 11 % ) . DB05101 MEN exhibited non-linear PK , with accumulation after escalation and repeated dosing . Tumor growth control was seen in 15/44 ( 34 % ) patients , including 5/9 ( 56 % ) at the 800 mg weekly dose level . DB05101 MEN combined with paclitaxel was generally well tolerated in patients with advanced NSCLC . There was some evidence of anticancer activity in relation to the matuzumab 800 mg weekly dose .

P40189 REA - linked signal transduction promotes the differentiation and maturation of dendritic cells . In order to explore the role of P40189 REA - linked signal transduction in the differentiation and maturation of dendritic cells ( DC ) , the mAb , B - P28222 REA , an agonist of P40189 REA , was used for the activation of P40189 REA on DC . The effects of cytokines and of anti - P40189 REA mAb on the proliferation of DC , and their expression of IL - 12 and P33681 REA ( P33681 REA - 1 ) by DC were evaluated . DC differentiating from peripheral blood mononuclear cells did not express the P05231 REA receptor alpha chain , but expressed P40189 REA . Anti - P40189 REA mAb promoted the proliferation of DC , induced by P05112 REA and granulocyte macrophage colony stimulating factor ( GM - P04141 REA ) , by up-regulating the GM - P04141 REA receptor on DC . DC induced by P40189 REA mAb and cytokines expressed DC-derived CC chemokine , as measured by RT-PCR . Induced DC also stimulated strong proliferation of autologous T cells in mixed lymphocyte reaction since an up-regulated expression of IL - 12 and P33681 REA ( P33681 REA - 1 ) was observed in DC activated by anti - P40189 REA mAb . Thus , P40189 REA signal transduction is important for the differentiation and maturation of DC .

P12956 REA and ku80 null mutants improve the gene targeting frequency in Monascus ruber M7 . Normally , gene targeting by homologous recombination occurs rarely during a transformation process since non-homologous recombination is predominant in filamentous fungi . In our previous researches , the average gene replacement frequency ( P01286 REA ) in Monascus ruber M7 was as low as 15 % . To develop a highly efficient gene targeting system for M . ruber M7 , two M . ruber M7 null mutants of ku70 ( MrΔku 70 ) and ku80 ( MrΔku 80 ) were constructed which had no apparent defects in the development including vegetative growth , colony phenotype , microscopic morphology and spore yield compared with M . ruber M7 . In addition , the production of some significant secondary metabolites such as pigments and citrinin had no differences between the two disruptants and the wild-type strain . Further results revealed that the GRFs of triA ( encoding a putative acetyltransferase ) were 42.2 % and 61.5 % in the MrΔku 70 and MrΔku 80 strains , respectively , while it was only about 20 % in M . ruber M7 . Furthermore , GRFs of these two disruptants at other loci ( the pigE , fmdS genes in MrΔku 70 and the ku70 gene in MrΔku 80 ) were investigated , and the results indicated that GRFs in the MrΔku 70 strain and the MrΔku 80 strain were doubled and tripled compared with that in M . ruber M7 , respectively . Therefore , the ku70 and ku80 null mutants of M . ruber M7 , especially the ku80 - deleted strain , will be excellent hosts for efficient gene targeting .

DB06693 MEN and simvastatin , but not pravastatin , induce bone morphogenetic protein - 2 in human osteosarcoma cells . Bone morphogenetic protein ( BMP ) - 2 , a member of the BMP family , plays an important role in osteoblast differentiation and bone formation . To discover small molecules that induce P12643 REA , a luciferase reporter vector containing the 5 ' - flanking promoter region of the human P12643 REA gene was constructed and transfected into human osteosarcoma ( Q9UKB1 ) cells . By the screening of an in-house natural product library with stably transfected Q9UKB1 cells , a fungal metabolite , compactin , known as an inhibitor of 3 - hydroxy - 3 - methylglutaryl coenzyme A ( HMG - DB01992 ) reductase , was isolated . The stimulation of the promoter activity by compactin seemed to be specific for P12643 REA gene in Q9UKB1 cells , since it had little effect on P12644 REA or SV40 promoter activity and the stimulation was not observed in Chinese hamster ovary ( CHO ) cells . RT-PCR analysis and alkaline phosphatase assay revealed that compactin induced an increase in the expression of P12643 REA mRNA and protein . Like compactin , simvastatin also activated the P12643 REA promoter , whereas pravastatin did not . The statin-mediated activation of P12643 REA promoter was completely inhibited by the downstream metabolite of P04035 REA , mevalonate , indicating that the activation was a result of the inhibition of the enzyme . These results suggest that statins , if they are selectively targeted to bone , have beneficial effects in the treatment of osteoporosis or bone fracture .

Selective targeting of the repressive transcription factors P25490 REA and cMyc to disrupt quiescent human immunodeficiency viruses . Quiescent HIV - 1 infection of resting P01730 REA ( + ) T cells is an obstacle to eradication of HIV - 1 infection . These reservoirs are maintained , in part , by repressive complexes that bind to the HIV - 1 long terminal repeat ( LTR ) and recruit histone deacetylases ( HDACs ) . cMyc and P25490 REA are two transcription factors that are recruited as part of well-described , distinct complexes to the HIV - 1 LTR and in turn recruit HDACs . In prior studies , depletion of single factors that recruit Q13547 REA in various cell lines was sufficient to upregulate LTR activity . We used short hairpin RNAs ( shRNAs ) to test the effect of targeted disruption of a single transcription factor on quiescent proviruses in T cell lines . In this study , we found that depletion of P25490 REA significantly increases mRNA and protein expression from the HIV - 1 promoter in some contexts , but does not affect Q13547 REA , Q92769 REA , O15379 REA , or acetylated histone 3 occupancy of the HIV - 1 LTR . Conversely , depletion of cMyc or cMyc and P25490 REA does not significantly alter the level of transcription from the LTR or affect recruitment of HDACs to the HIV - 1 LTR . Furthermore , global inhibition of HDACs with the HDAC inhibitor suberoylanilide hydroxamic acid ( DB02546 SUB ) enhanced the increase in LTR transcription in cells that were depleted of P25490 REA . These findings show that despite prior isolated findings , redundancy in repressors of HIV - 1 LTR expression will require selective targeting of multiple restrictive mechanisms to comprehensively induce the escape of quiescent proviruses from latency .