MH_dev_47

Target genes discovery through copy number alteration analysis in human hepatocellular carcinoma . High-throughput short-read sequencing of exomes and whole cancer genomes in multiple human hepatocellular carcinoma ( HCC ) cohorts confirmed previously identified frequently mutated somatic genes , such as P04637 REA , P35222 REA and O15169 REA , and identified several novel genes with moderate mutation frequencies , including O14497 REA , Q68CP9 , Q03164 REA , MLL 2 , Q8NEZ4 , MLL 4 , P14316 REA , Q13315 REA , CDKN 2A , O95750 REA , P42336 REA , P51812 REA , P23458 REA , Q14145 REA , Q16236 , Q7Z3J2 REA , LEPR , P15153 REA , and P40189 REA . Functional classification of these mutated genes suggested that alterations in pathways participating in chromatin remodeling , Wnt / β-catenin signaling , JAK / P35610 REA signaling , and oxidative stress play critical roles in HCC tumorigenesis . Nevertheless , because there are few druggable genes used in HCC therapy , the identification of new therapeutic targets through integrated genomic approaches remains an important task . Because a large amount of HCC genomic data genotyped by high density single nucleotide polymorphism arrays is deposited in the public domain , copy number alteration ( Q08209 REA ) analyses of these arrays is a cost-effective way to reveal target genes through profiling of recurrent and overlapping amplicons , homozygous deletions and potentially unbalanced chromosomal translocations accumulated during HCC progression . Moreover , integration of CNAs with other high-throughput genomic data , such as aberrantly coding transcriptomes and non-coding gene expression in human HCC tissues and rodent HCC models , provides lines of evidence that can be used to facilitate the identification of novel HCC target genes with the potential of improving the survival of HCC patients .

beta-Carotene induces apoptosis and up-regulates peroxisome proliferator-activated receptor gamma expression and reactive oxygen species production in MCF - 7 cancer cells . Although the pharmacological role of beta-carotene in the prevention and treatment of many cancer cells has received increasing attention , the molecular mechanisms underlying such chemopreventive activity are not clear . Since peroxisome proliferator-activated receptor gamma ( P37231 REA ) has been implicated in regulating breast cancer cell differentiation and apoptosis , the effects of beta-carotene on the P37231 REA - mediated pathway and its association with reactive oxygen species production in MCF - 7 cells were investigated in the present study . The results demonstrated that beta-carotene significantly increased P37231 REA mRNA and protein levels in time-dependent manner . In addition , beta-carotene increased the cyclin-dependent kinase inhibitor P38936 REA ( P38936 REA / CIP 1 ) expression and decreased the prostanoid synthesis rate-limiting enzyme cyclooxygenase - 2 expression . DB07863 MEN ( GW9662 ) , an irreversible P37231 REA antagonist , partly attenuated the cell death caused by beta-carotene . Further , reactive oxygen species ( ROS ) production was induced by beta-carotene , resulting in mitochondrial dysfunction and cytochrome C release . DB00143 ( DB00143 ) treatment decreases the intracellular ROS and prevents cytochrome C release and cell apoptosis induced by beta-carotene . In total , these observations suggest that the synergistic effect of P37231 REA expression and ROS production may account for beta-carotene-mediated anticancer activities .

Glucocorticoids enhance regeneration of murine olfactory epithelium . CONCLUSION : Glucocorticoid ( GC ) administration enhanced apoptotic changes in mature olfactory receptor neurons ( ORNs ) . GC administration may enhance regeneration of olfactory epithelium ( OE ) . OBJECTIVES : The mechanism underlying olfactory epithelial cells turnover involves apoptosis replaced by new ORNs . On regeneration of OE , we evaluated the apoptotic changes in OE . Our aim was to corroborate the enhancement of apoptosis of ORNs induced by GCs that are generally administered locally or systemically to patients with olfactory dysfunction . MATERIALS AND METHODS : For the in vitro study , we established cultured murine ORNs . DB00620 MEN acetonide was added to culture supernatants . ORNs were then cultured for another 2 weeks . In the in vivo study , triamcinolone acetonide was administered to mice 5 or 10 times . The mice were dissected 3 days after the final injection , and the olfactory regions were removed and embedded in paraffin . All samples were examined by immunohistochemical staining and the TdT-mediated dUTP-biotin nick-end labeling ( TUNEL ) method . RESULTS : P04150 REA ( GR ) expression of cultured murine ORNs was observed among ORNs at the mature stage . Expression of GRs by murine OE was localized on mature ORNs and supporting cells . Administration of GC to both cultured ORNs and mice resulted in proportions of apoptotic cells that were significantly higher than those in the control groups .

Poly ( ADP-ribose ) polymerase - 1 : a novel therapeutic target in necrotizing enterocolitis . Necrotizing enterocolitis ( NEC ) is the most common gastrointestinal disease of infancy , afflicting 11 % of infants born 22-28 wk GA . Both inflammation and oxidation may be involved in NEC pathogenesis through reactive nitrogen species production , protein oxidation , and DNA damage . Poly ( ADP-ribose ) polymerase - 1 ( P09874 REA ) is a critical enzyme activated to facilitate DNA repair using nicotinamide adenine dinucleotide ( NAD + ) as a substrate . However , in the presence of severe oxidative stress and DNA damage , P09874 REA overactivation may ensue , depleting cells of NAD + and DB00171 , killing them by metabolic catastrophe . Here , we tested the hypothesis that NO dysregulation in intestinal epithelial cells during NEC leads to marked P09874 REA expression and that administration of a P09874 REA inhibitor ( nicotinamide ) attenuates intestinal injury in a newborn rat model of NEC . In this model , 56 % of control pups developed NEC ( any stage ) versus 14 % of pups receiving nicotinamide . Forty-four percent of control pups developed high-grade NEC ( grades 3-4 ) , whereas only 7 % of pups receiving nicotinamide developed high-grade NEC . DB02701 MEN treatment protects pups against intestinal injury incurred in the newborn rat NEC model . We speculate that P09874 REA overactivation in NEC may drive mucosal cell death in this disease and that P09874 REA may be a novel therapeutic target in NEC .

Effects of inhaled prostacyclin analogue on chronic hypoxic pulmonary hypertension . Inhaled DB01240 has been reported to elicit pulmonary vasodilation , but whether it is also effective in treating chronic hypoxic pulmonary hypertension is still uncertain . We designed this study to address the in vivo effectiveness of inhaled DB05229 MEN , a stable DB01240 analogue , on pulmonary vascular tone during hypoxic exposure in normoxic ( N ) and chronically hypoxic ( CH ) rats . Pulmonary vasodilation was observed by low-dose inhaled DB05229 MEN in N rats , but not in CH rats . It was not until higher doses of DB05229 MEN were given that pulmonary vasodilation was obtained in CH rats . When the agent was continuously administered by an intravascular route at the inhaled dose , it elicited no vasodilation in N rats . On the contrary , it elicited profound vasodilation in CH rats , although a concomitant systemic hypotension was observed . The P43119 REA mRNA expression was unchanged in the lungs of CH rats compared with that of N rats . We conclude that low doses of aerosolized DB05229 MEN may reduce pulmonary vascular tone in rats without preexisting lung diseases . In contrast , when hypoxic pulmonary hypertension is present , the threshold of DB05229 MEN inhalation was elevated to provoke pulmonary vasodilation .

15d - PGJ 2 and rosiglitazone suppress Janus kinase - P35610 REA inflammatory signaling through induction of suppressor of cytokine signaling 1 ( O15524 REA ) and O14543 REA in glia . Peroxisome proliferator-activated receptor ( Q07869 REA ) - gamma agonists are now emerging as therapeutic drugs for various inflammatory diseases . However , their molecular mechanism of action remains to be elucidated . Here we report a novel mechanism that underlies the P37231 REA agonist-mediated suppression of brain inflammation . We show that 15 - deoxy-Delta 12,14- prostaglandin J ( 2 ) ( 15d - PGJ ( 2 ) ) and rosiglitazone reduce the phosphorylation of P42224 REA and P40763 REA as well as P23458 REA ( P23458 REA ) and O60674 REA in activated astrocytes and microglia . The P37231 REA agonist-mediated reduction in phosphorylation leads to the suppression of JAK - P35610 REA - dependent inflammatory responses . The effects of 15d - PGJ ( 2 ) and rosiglitazone are not mediated by activation of P37231 REA . 15d - PGJ ( 2 ) and rosiglitazone rapidly induce the transcription of suppressor of cytokine signaling ( Q9NSE2 ) 1 and 3 , which in turn inhibit JAK activity in activated glial cells . In addition , Src homology 2 domain-containing protein phosphatase 2 ( SHP 2 ) , another negative regulator of JAK activity , is also involved in their anti-inflammatory action . Our data suggest that 15d - PGJ ( 2 ) and rosiglitazone suppress the initiation of JAK - P35610 REA inflammatory signaling independently of P37231 REA , thus attenuating brain inflammation .

P09874 REA deficiency blocks P05113 REA expression through calpain-dependent degradation of P35610 REA - 6 in a murine asthma model . BACKGROUND : We recently showed that poly ( ADP-ribose ) polymerase - 1 ( P09874 REA ) may play a role in allergen ( ovalbumin ) - induced airway eosinophilia , potentially through a specific effect on P05113 REA production . We also reported that while P05113 REA replenishment promotes reversal of eosinophilia in lungs of P09874 REA ( - / - ) mice , P05112 REA or Immunoglobulin E replenishment do not , suggesting a potentially significant regulatory relationship between P09874 REA and P05113 REA . OBJECTIVE : To explore the mechanism by which P09874 REA regulates P05113 REA production and to determine how P09874 REA inhibition blocks allergen-induced eosinophilia . METHODS : This study was conducted using a murine model of allergic airway inflammation and primary splenocytes . RESULTS : P09874 REA knockout-associated reduction in P05113 REA upon allergen exposure occurs at the mRNA level . Such an effect appears to take place after P05112 REA receptor activation as P09874 REA inhibition exerted no effect on P23458 REA / P52333 REA activation . Signal transducer and activator of transcription - 6 ( P35610 REA - 6 ) protein was severely downregulated in spleens of P09874 REA ( - / - ) mice without any effect on mRNA levels , suggesting an effect on protein integrity rather than gene transcription . Interestingly , the degradation of P35610 REA - 6 in P09874 REA ( - / - ) mice required allergen stimulation . Additionally , P09874 REA enzymatic activity appears to be required for P35610 REA - 6 integrity . The downregulation of P35610 REA - 6 coincided with mRNA and protein reduction of GATA-binding protein - 3 and occupancy of its binding site on the P05113 REA gene promoter . P05112 REA was sufficient to induce P35610 REA - 6 downregulation in both P09874 REA ( - / - ) mice and isolated splenocytes . Such degradation may be mediated by calpain , but not by proteasomes . CONCLUSION : These results demonstrate a novel function of P09874 REA in regulating P05113 REA expression during allergen-induced inflammation and explain the underlying mechanism by which P09874 REA inhibition results in P05113 REA reduction .

The polymorphisms S503P and Q576R in the interleukin - 4 receptor alpha gene are associated with atopy and influence the signal transduction . P05112 REA ( P05112 REA ) plays a major role in immunoglobulin E ( IgE ) production . Its signal is conferred to effector cells through binding to the alpha chain of the P05112 REA receptor ( IL - 4Ralpha ) . We present further evidence for polymorphisms in the IL - 4Ralpha gene having an effect on IgE regulation . For two of four common polymorphisms , S503P and Q576R , we found an association with lowered total IgE concentrations ( P= 0.0008 if occurring together ) . The polymorphism S503P has not yet been described and is located within the I4R motif of the receptor . In vitro analyses using synthetic peptides of this region showed that the tyrosine kinase P23458 REA ( P23458 REA ) , as well as P35568 REA and Q9Y4H2 REA bind to the I4R motif irrespective of the polymorphism or a tyrosine phosphorylation . In vivo immunoassays using T cells of four different groups of individuals ( S503 / Q576 ; P503 / Q576 ; S503 / R576 ; P503 / R576 ) revealed that only in case of both polymorphisms the phosphorylation of P35568 REA and Q9Y4H2 REA , but not P23458 REA was increased . We found no binding of P42226 REA to the I4R synthetic peptides ; however , the phosphorylation was reduced in the presence of any of the two polymorphisms , including P503 alone . We discuss possible conformational changes of the receptor leading to the observed effects on the phosphorylation status of P35568 REA , Q9Y4H2 REA and P42226 REA , in addition to previous findings that Q576R alters P42226 REA binding . We conclude that P503 and R576 influence the signal transduction pathways through the IL - 4Ralpha , an effect that is magnified by the presence of both polymorphisms . This could explain the observed association effects with lowered total IgE concentrations .

Differential role of two P11473 REA coactivators , Q15648 REA and Q9Y6Q9 REA , in keratinocyte proliferation and differentiation . Cell programs such as proliferation and differentiation involve the selective activation and repression of gene expression . The vitamin D receptor ( P11473 REA ) , through 1,25 ( OH ) ( 2 ) D ( 3 ) , controls the proliferation and differentiation of keratinocytes . Previously , we have identified two P11473 REA binding coactivator complexes . In proliferating keratinocytes P11473 REA bound preferentially to the DRIP complex , whereas in differentiated keratinocytes the P12931 REA complex was preferred . We proposed that different coactivators are required for sequential gene regulation in the transition from proliferation to differentiation . Here we examined the roles of Q15648 REA and Q9Y6Q9 REA in this transition . Silencing of Q15648 REA and P11473 REA caused hyperproliferation of keratinocytes , demonstrated by increased XTT and BrdU incorporation . Q9Y6Q9 REA silencing , on the other hand , did not have an effect on proliferation . In contrast , Q9Y6Q9 REA as well as Q15648 REA and P11473 REA silencing blocked keratinocyte differentiation as shown by decreased expression of keratin 1 and filaggrin . These results are consistent with the differential localization of Q15648 REA and Q9Y6Q9 REA in skin . These results indicate that Q15648 REA is required for keratinocyte proliferation . Both Q15648 REA and Q9Y6Q9 REA are required for the keratinocyte differentiation . These results support the concept that the selective use of coactivators by P11473 REA underlies the selective regulation of gene expression in keratinocyte proliferation and differentiation .

DB08877 SUB for the treatment of primary myelofibrosis . PURPOSE : The pharmacology , pharmacokinetics , pharmacogenomics , clinical efficacy , and safety profile of ruxolitinib for the treatment of primary myelofibrosis are reviewed . SUMMARY : DB08877 SUB , an oral tyrosine kinase inhibitor that targets the Janus-associated kinases ( JAKs ) 1 and 2 , has been recently approved for the treatment of patients with intermediate - or high-risk myelofibrosis . Unlike previous treatment options for patients with myelofibrosis , ruxolitinib offers a targeted therapy option for these patients who often suffer with severe and debilitating symptoms associated with the disease process . After oral administration , ruxolitinib is rapidly absorbed and can be given without regard to meals . DB08877 SUB is primarily metabolized by the cytochrome P - 450 ( CYP ) 3A4 isoenzyme system ; therefore , if concomitant use with a strong P08684 REA inhibitor is unavoidable , an initial dosage reduction is warranted . Two Phase III randomized trials comparing ruxolitinib to either placebo or best available therapy found a rapid and sustained response in the reduction of spleen size and improvements in constitutional symptoms and quality of life , with one study demonstrating an improvement in overall survival . The most commonly reported serious adverse effects of ruxolitinib are anemia and thrombocytopenia . DB08877 SUB is administered as an oral tablet given twice daily , with the initial starting dosage based on the baseline platelet count . Dosage reductions are based on the development of thrombocytopenia . CONCLUSION : By directly targeting both P23458 REA and O60674 REA through small-molecule inhibition , ruxolitinib elicits a reduction in splenomegaly and disease-related symptoms in patients with intermediate - or high-risk myelofibrosis while maintaining an acceptable toxicity profile and a low treatment-discontinuation rate .

P43119 REA - induced P40763 REA phosphorylation in human erythroleukemia cells is mediated via Galpha ( s ) and Galpha ( 16 ) hybrid signaling . Human prostacyclin receptor ( hIP ) stimulates P40763 REA via pertussis toxin-insensitive G proteins in human erythroleukemia ( HEL ) cells . Since hIP can utilize G ( s ) and G ( q ) proteins for signal transduction and that both G proteins can induce P40763 REA phosphorylation and activation via complex signaling networks , we sought to determine if one of them is predominant in mediating the hIP signal . Stimulation of P40763 REA DB00135 ( 705 ) and DB00133 ( 727 ) phosphorylations by the IP-specific agonist , cicaprost , was sensitive to inhibition of protein kinase A , phospholipase Cbeta , protein kinase C , calmodulin-dependent protein kinase II and O60674 REA / 3 . Unlike Galpha ( 16 ) - mediated regulation of P40763 REA in the same cells , cicaprost-induced P40763 REA DB00135 ( 705 ) phosphorylation was resistant to inhibition of Src and MEK while P40763 REA DB00133 ( 727 ) phosphorylation distinctly required phosphatidylinositol - 3 kinase . This unique inhibitor-sensitivity pattern of P40763 REA phosphorylation was reproduced in HEL cells by stimulating the G ( 16 ) - coupled C5a receptor in the presence of dibutyryl - DB02527 , suggesting that the change in inhibitor-sensitivity was due to activation of the G ( s ) pathway . This postulation was confirmed by expressing constitutively active Galpha ( 16 ) QL and Galpha ( s ) QL in human embryonic kidney 293 cells and the inhibitor-sensitivity of Galpha ( 16 ) QL-induced P40763 REA phosphorylations could be converted by the mere presence of Galpha ( s ) QL to resemble that obtained with cicaprost in HEL cells . In addition , the restoration of the Galpha ( 16 ) - mediated inhibitor-sensitivity upon cicaprost induction in Galpha ( s ) - knocked down HEL cells again verified the pivotal role of G ( s ) signal . Taken together , our observations illustrate that co-stimulation of G ( s ) and G ( q ) can result in the fine-tuning of P40763 REA activation status , and this may provide the basis for cell type-specific responses following activation of hIP .

Met 326Ile aminoacid polymorphism in the human p8 5 alpha gene has no major impact on early insulin signaling in type 2 diabetes . Class I alpha phosphatidylinositol ( PI ) 3 - kinase is an important enzyme in the early insulin signaling cascade , and plays a key role in insulin-mediated glucose transport . Despite extensive investigation , the genes responsible for the development of the common forms of type 2 diabetes remain unknown . This study was performed to identify variants in the coding region of p8 5 alpha , the regulatory subunit of PI 3 - kinase . Fibroblasts from skin biopsies from type 2 diabetics and controls were established to address this issue . P8 5 alpha cDNA was sequenced , and a single point mutation at codon 326 was found . This mutation resulted in a homozygous missense amino acid change DB00134 --> DB00167 MEN in one subject with type 2 diabetes and heterozygous variant in two other diabetic patients and one with severe insulin resistance . Interestingly , those patients revealed an impaired insulin-mediated insulin receptor substrate ( P41252 REA ) - 1 binding to p8 5 alpha without any alteration in Q9Y4H2 REA / p8 5 alpha association . Furthermore , P35568 REA , Q9Y4H2 REA , p8 5 alpha and MAPK protein contents were not significantly changed , and neither were MAPK or Akt phosphorylation . We conclude from our data that this variant may have only minor impact on signaling events ; however , in combination with variants in other genes encoding signaling proteins , this may have a functional impact on early insulin signaling .

Retinoic acid receptors in retinoid responsive ovarian cancer cell lines detected by polymerase chain reaction following reverse transcription . The growth inhibitory effects of all-trans and 13 - cis retinoic acid ( RA ) and of the synthetic retinoids DB02877 MEN , DB02877 MEN - ethylester and TTNN were studied on seven human epithelial ovarian cancer cell lines and one ovarian teratocarcinoma cell line . Six of seven ovarian adenocarcinoma cell lines were inhibited in their growth by RA and by synthetic retinoids in a dose dependent manner . No response to these substances was observed for the ovarian teratocarcinoma cell line . The knowledge that RA and retinoids exert their action on the cells via nuclear receptors led us to examine the expression of P10276 REA , - beta and - gamma mRNA by these cell lines by polymerase chain reaction following reverse transcription . All cell lines expressed P10276 REA and - gamma mRNA and six of the eight cell lines were found to express additionally P10826 REA mRNA , among them the ovarian teratocarcinoma cell line . Our data indicate that there was no direct association between the presence of RAR subtype transcripts and the response to retinoids in ovarian cancer cell lines .

Interactions Between Ataxia Telangiectasia Mutated Kinase Inhibition , Poly ( ADP-ribose ) Polymerase - 1 Inhibition and P38398 REA Status in Breast Cancer Cells . BACKGROUND : Cells harboring P38398 REA / P51587 REA mutations are hypersensitive to inhibition of poly ( ADP-ribose ) polymerase - 1 ( P09874 REA ) . We recently showed that interference with P09874 REA activity by DB02690 MEN is strongly cytotoxic for P38398 REA - positive BT - 20 cells but not P38398 REA - deficient SKBr - 3 cells . These unexpected observations prompted speculation that other P09874 REA inhibitor ( s ) may be more cytotoxic towards SKBr - 3 cells . In addition , interference with the DNA damage signaling pathway via ( for instance ) Q13315 REA ( Q13315 REA ) kinase inhibition may induce synthetic lethality in DNA repair-deficient breast cancer cells and pharmacological interference with Q13315 REA activity may sensitize breast cancer cells to P09874 REA inactivation . METHODS : We determined drug cytotoxicity in human MCF - 7 and SKBr - 3 breast cancer cells using the CellTiterGLO Luminescent cell viability assay and a Tecan multi-label , multitask plate counter to measure generated luminescence . Changes in cell cycle progression were monitored by flow cytometric measurement of DNA content in cells stained with propidium iodide . RESULTS : Unlike DB02690 MEN , AZD 2461 , a new P09874 REA inhibitor , markedly reduced the numbers of living MCF - 7 and SKBr - 3 cells . Q13315 REA kinase inhibition ( CP466722 ) was also cytotoxic for both MCF - 7 and SKBr - 3 cells . Furthermore , AZD 2461 enhanced the cytotoxicity of CP466722 in both cell lines by inducing apoptosis , and concurrent inhibition of Q13315 REA and P09874 REA reduced cell proliferation more strongly than either single treatment . CONCLUSIONS : Our data show that inhibition of P09874 REA by AZD 2461 is synthetically lethal for DB02690 MEN - resistant MCF - 7 and SKBr - 3 breast cancer cells . They also indicate that DNA damage signaling is essential for survival of both SKBr - 3 and MCF - 7 cells , especially after inactivation of P09874 REA .

Inhibition of related JAK / P35610 REA pathways with molecular targeted drugs shows strong synergy with ruxolitinib in chronic myeloproliferative neoplasm . This study aimed to assess the antitumour effects , molecular mechanisms of action , and potential synergy of ruxolitinib with sorafenib , KNK 437 , dasatinib , and perifosine , in Philadelphia-negative chronic myeloproliferative neoplasms ( Q9BQR3 ) . Cytotoxic and cytostatic effects of the different compounds were determined in the O60674 REA V617F - positive cell lines , HEL and Ba / P13726 REA ( JAK 2V617F P19235 REA ) , and in primary mononuclear and bone marrow P28906 REA - positive cells from 19 Q9BQR3 patients . DB08877 SUB [ 50 % inhibitory concentration ( IC50 ) ( PV ) = 15 nmol / l ] , as well as sorafenib ( IC50 PV = 8μmol / l ) , KNK 437 ( IC50 PV = 100μmol / l ) , and perifosine ( IC50 PV = 15μmol / l ) , were able to inhibit proliferation in cell line models and in primary cells from Q9BQR3 patients . Dasatinib , KNK 437 , and sorafenib showed a strong synergistic effect in combination with ruxolitinib [ combination index ( CI ) ( PV ) < 0 · 3 ] . Western blot confirmed that ruxolitinib blocked P29323 REA , and consequently P42229 REA activation , sorafenib inhibited P29323 REA , O75791 REA and P42229 REA , dasatinib blocked P12931 REA and P42229 REA , and KNK 437 decreased the stability of the O60674 REA protein , reducing its expression . Inhibiting O60674 REA - related proliferative pathways has the potential to inhibit cell proliferation in MPNs . Furthermore , the combination of ruxolitinib with inhibitors that target these pathways has a strong synergistic effect , which may be due to decreased activation of the common effector , P42229 REA .

Conditional ablation of mediator subunit MED 1 ( MED 1 / Q15648 REA ) gene in mouse liver attenuates glucocorticoid receptor agonist dexamethasone-induced hepatic steatosis . P04150 REA ( GR ) agonist dexamethasone ( DB00514 ) induces hepatic steatosis and enhances constitutive androstane receptor ( CAR ) expression in the liver . CAR is known to worsen hepatic injury in nonalcoholic hepatic steatosis . Because transcription coactivator MED 1 / Q15648 REA gene is required for GR - and CAR-mediated transcriptional activation , we hypothesized that disruption of MED 1 / Q15648 REA gene in liver cells would result in the attenuation of DB00514 - induced hepatic steatosis . Here we show that liver-specific disruption of MED 1 gene ( MED 1 ( delta Liv ) ) improves DB00514 - induced steatotic phenotype in the liver . In wild-type mice DB00514 induced severe hepatic steatosis and caused reduction in medium - and short-chain acyl - DB01992 dehydrogenases that are responsible for mitochondrial beta-oxidation . In contrast , DB00514 did not induce hepatic steatosis in mice conditionally null for hepatic MED 1 , as it failed to inhibit fatty acid oxidation enzymes in the liver . MED 1 ( delta Liv ) livers had lower levels of GR-regulated CAR mRNA compared to wild-type mouse livers . Microarray gene expression profiling showed that absence of MED 1 affects the expression of the GR-regulated genes responsible for energy metabolism in the liver . These results establish that absence of MED 1 in the liver diminishes DB00514 - induced hepatic steatosis by altering the GR - and CAR-dependent gene functions .

The JAK inhibitor , tofacitinib , reduces the T cell stimulatory capacity of human monocyte-derived dendritic cells . OBJECTIVE : DB08895 MEN , which is a Janus kinase ( JAK ) inhibitor , has shown clinical effects in the treatment of rheumatoid arthritis . JAKs are important kinases in lymphocyte differentiation ; however , their function in dendritic cells ( DCs ) is unknown . In this study , the function of JAKs in DCs was investigated with tofacitinib . METHODS : The effects of tofacitinib on the maturation of human monocyte-derived DCs induced by lipopolysaccharide ( LPS ) stimulation were investigated . In addition , its effects on T cell stimulatory capability was investigated by coculturing with naïve CD45RA - positive T cells . RESULTS : DB08895 MENMAX DB08895 MEN decreased expression of P33681 REA / P42081 REA in a concentration-dependent manner in LPS-stimulated DCs ; however , it did not affect HLA-DR expression . DB08895 MEN suppressed tumour necrosis factor , interleukin ( IL ) - 6 and IL - 1β production without affecting transforming growth factor ( TGF ) - β and P22301 REA production . Meanwhile , P33681 REA / P42081 REA expression in DCs was enhanced by type I interferon ( IFN ) stimulation , and the LPS-induced P33681 REA / P42081 REA expression was inhibited by an antibody to type I IFN receptor . Furthermore , tofacitinib suppressed production of type I IFN and activation of interferon regulatory factor ( Q969Q1 REA ) - 7 , which is a transcription factor involved in P33681 REA / P42081 REA and type I IFN expression . DB08895 MEN also decreased the T cell stimulatory capability of DCs and increased expression of indoleamine 2,3- dioxygenase ( P14902 REA ) - 1 and Q6ZQW0 . CONCLUSIONS : DB08895 MEN , a P23458 REA / P52333 REA inhibitor , affected the activities of human DCs . It decreased P33681 REA / P42081 REA expression and T cell stimulatory capability through suppression of type I IFN signalling . These results suggest a novel mode of action for tofacitinib and a pivotal role for JAKs in the differentiation of DCs .

Sequencing a mouse acute promyelocytic leukemia genome reveals genetic events relevant for disease progression . Acute promyelocytic leukemia ( APL ) is a subtype of acute myeloid leukemia ( AML ) . It is characterized by the t ( 15 ; 17 ) ( q22 ; q11 . 2 ) chromosomal translocation that creates the promyelocytic leukemia-retinoic acid receptor α ( P29590 REA - P10276 REA ) fusion oncogene . Although this fusion oncogene is known to initiate APL in mice , other cooperating mutations , as yet ill defined , are important for disease pathogenesis . To identify these , we used a mouse model of APL , whereby P29590 REA - P10276 REA expressed in myeloid cells leads to a myeloproliferative disease that ultimately evolves into APL . Sequencing of a mouse APL genome revealed 3 somatic , nonsynonymous mutations relevant to APL pathogenesis , of which 1 ( Jak 1 V657F ) was found to be recurrent in other affected mice . This mutation was identical to the P23458 REA V658F mutation previously found in human APL and acute lymphoblastic leukemia samples . Further analysis showed that P23458 REA V658F cooperated in vivo with P29590 REA - P10276 REA , causing a rapidly fatal leukemia in mice . We also discovered a somatic 150 - kb deletion involving the lysine ( K ) - specific demethylase 6A ( Kdm 6a , also known as Utx ) gene , in the mouse APL genome . Similar deletions were observed in 3 out of 14 additional mouse APL samples and 1 out of 150 human AML samples . In conclusion , whole genome sequencing of mouse cancer genomes can provide an unbiased and comprehensive approach for discovering functionally relevant mutations that are also present in human leukemias .

The heme oxygenase system rescues hepatic deterioration in the condition of obesity co-morbid with type - 2 diabetes . The prevalence of non-alcoholic fatty-liver disease ( NAFLD ) is increasing globally . NAFLD is a spectrum of related liver diseases that progressive from simple steatosis to serious complications like cirrhosis . The major pathophysiological driving of NAFLD includes elevated hepatic adiposity , increased hepatic triglycerides / cholesterol , excessive hepatic inflammation , and hepatocyte ballooning injury is a common histo-pathological denominator . Although heme-oxygenase ( HO ) is cytoprotective , its effects on hepatocyte ballooning injury have not been reported . We investigated the effects of upregulating HO with hemin or inhibiting it with stannous-mesoporphyrin ( DB04912 MEN ) on hepatocyte ballooning injury , hepatic adiposity and inflammation in Zucker-diabetic-fatty rats ( ZDFs ) , an obese type - 2 - diabetic model . DB03404 administration to ZDFs abated hepatic / plasma triglycerides and cholesterol , and suppressed several pro-inflammatory cytokines and chemokines including , P01375 REA - α , P05231 REA , IL - 1β , macrophage-inflammatory-protein - 1α ( MIP - 1α ) and macrophage-chemoattractant-protein - 1 ( P13500 REA ) , with corresponding reduction of the pro-inflammatory M1 - phenotype marker , Q92838 REA and hepatic macrophage infiltration . Correspondingly , hemin concomitantly potentiated the protein expression of several markers of the anti-inflammatory macrophage-M 2 - phenotype including ED2 , P22301 REA and CD - 206 , alongside components of the HO-system including P09601 REA , HO-activity and cGMP , whereas the HO-inhibitor , DB04912 MEN abolished the effects . Furthermore , hemin attenuated liver histo-pathological lesions like hepatocyte ballooning injury and fibrosis , and reduced extracellular-matrix / profibrotic proteins implicated in liver injury such as osteopontin , TGF-β 1 , fibronectin and collagen-IV . We conclude that hemin restore hepatic morphology by abating hepatic adiposity , suppressing macrophage infiltration , inflammation and fibrosis . The selective enhancement of anti-inflammatory macrophage-M 2 - phenotype with parallel reduction of pro-inflammatory macrophage-M 1 - phenotype and related chemokines / cytokines like P01375 REA - α , P05231 REA , IL - 1β , MIP - 1α and P13500 REA are among the multifaceted mechanisms by which hemin restore hepatic morphology .

Constitutive NF-kappaB activation confers interleukin 6 ( P05231 REA ) independence and resistance to dexamethasone and Janus kinase inhibitor DB08877 SUB in murine plasmacytoma cells . Myeloma cells are dependent on P05231 REA for their survival and proliferation during the early stages of disease , and independence from P05231 REA is associated with disease progression . The role of the NF-κB pathway in the P05231 REA - independent growth of myeloma cells has not been studied . Because human herpesvirus 8 - encoded P13646 REA selectively activates the NF-κB pathway , we have used it as a molecular tool to examine the ability of the NF-κB pathway to confer P05231 REA independence on murine plasmacytomas . We demonstrated that ectopic expression of P13646 REA , but not its NF-κB-defective mutant or a structural homolog , protected plasmacytomas against P05231 REA withdrawal-induced apoptosis and resulted in emergence of P05231 REA - independent clones that could proliferate long-term in vitro in the absence of P05231 REA and form abdominal plasmacytomas with visceral involvement when injected intraperitoneally into syngeneic mice . These P05231 REA - independent clones were dependent on NF-κB activity for their survival and proliferation but were resistant to dexamethasone and DB08877 SUB , a selective P23458 REA / 2 inhibitor . Ectopic expression of human T cell leukemia virus 1 - encoded Tax protein , which resembles P13646 REA in inducing constitutive NF-κB activation , similarly protected plasmacytoma cells against P05231 REA withdrawal-induced apoptosis . Although P13646 REA is known to up-regulate P05231 REA gene expression , its protective effect was not due to induction of endogenous P05231 REA production but instead was associated with sustained expression of several antiapoptotic members of the Bcl 2 family upon P05231 REA withdrawal . Collectively , these results demonstrate that NF-κB activation can not only promote the emergence of P05231 REA independence during myeloma progression but can also confer resistance to dexamethasone and DB08877 SUB .