MH_dev_230

Low-intensity laser irradiation at 660 nm stimulates transcription of genes involved in the electron transport chain . BACKGROUND DATA : Low-intensity laser irradiation ( LILI ) has been shown to stimulate cellular functions leading to increased adenosine triphosphate ( DB00171 ) synthesis . This study was undertaken to evaluate the effect of LILI on genes involved in the mitochondrial electron transport chain ( ETC , complexes I-IV ) and oxidative phosphorylation ( DB00171 synthase ) . METHODS : Four human skin fibroblast cell models were used in this study : normal non-irradiated cells were used as controls while wounded , diabetic wounded , and ischemic cells were irradiated . Cells were irradiated with a 660 nm diode laser with a fluence of 5 J / cm ( 2 ) and gene expression determined by quantitative real-time reverse transcription ( RT ) polymerase chain reaction ( PCR ) . RESULTS : LILI upregulated cytochrome c oxidase subunit VIb polypeptide 2 ( Q6YFQ2 ) , cytochrome c oxidase subunit VIc ( P09669 REA ) , and pyrophosphatase ( inorganic ) 1 ( Q15181 REA ) in diabetic wounded cells ; P09669 REA , DB00171 synthase , H + transporting , mitochondrial Fo complex , subunit B1 ( P24539 REA ) , nicotinamide adenine dinucleotide ( DB00157 MEN ) dehydrogenase ( ubiquinone ) 1 alpha subcomplex , 11 ( Q86Y39 REA ) , and DB00157 MEN dehydrogenase ( ubiquinone ) Fe - Q15517 REA 7 ( O75251 REA ) in wounded cells ; and ATPase , H + / K + exchanging , beta polypeptide ( P51164 REA ) , and DB00171 synthase , H + transporting , mitochondrial Fo complex , subunit P06681 REA ( subunit 9 ) ( Q06055 REA ) in ischemic cells . CONCLUSIONS : LILI at 660 nm stimulates the upregulation of genes coding for subunits of enzymes involved in complexes I and IV and DB00171 synthase .

Lactobacillus protects the integrity of intestinal epithelial barrier damaged by pathogenic bacteria . Pathogens invade intestinal mucosal barrier through phagocytosis of antigen presenting cells ( dendritic cell , microfold cells ) , or through the invasion into the intestinal epithelial directly . Some pathogens could damage the cell junction between epithelial cells and use the paracellular pathway as an entrance to invade . Moreover , some Lactobacillus could inhibit the adhesion of the pathogens and protect the integrity of the cell junction and mucosal barrier . This research focused on the potential therapeutic effect of Lactobacillus fructosus ( L . fructosus ) P06681 REA to attenuate ETEC K88 or S . typhimurium SL1344 induced changes to mucosal barrier . The results demonstrated that treatment of polarized Caco - 2 cells with L . fructosus P06681 REA reduced the permeation of dextran , and expression of P10145 REA , p - P29323 REA , and p-JNK when cells were infected with pathogenic bacteria . The findings indicated that L . fructosus P06681 REA exerted a protective effect against the damage to the integrity of Caco - 2 cells by ETEC or S . typhimurium infection .

P29323 REA activation of P38936 REA activated kinase - 1 ( Pak 1 ) is critical for medulloblastoma cell migration . We previously identified that overexpression of the platelet-derived growth factor receptor ( P09619 REA ) is associated with metastatic medulloblastoma ( MB ) and showed that PDGF treatment increases P29323 REA activity and promotes MB cell migration . In this study , we investigated whether P29323 REA regulates Rac 1 / Pak 1 signaling and is critically linked to MB cell migration . Herein we demonstrate that DB00102 MEN treatment of MB cells induces concomitant activation of PDGFRβ , Q02750 REA / P29323 REA , Rac 1 and Pak 1 , but suppresses Rho activity , which together significantly promotes cell migration . Conversely , cells transfected with either PDGFRβ or Pak 1 siRNA or treated with an inhibitor of Rac 1 ( NSC 23766 ) or N-myristoyltransferase - 1 ( DB03754 - dipalladium ) are unable to activate Rac 1 or Pak 1 in response to PDGF , and consequently , are unable to undergo PDGF-mediated cell migration . Furthermore , we also demonstrate that either chemical inhibition of MEK / P29323 REA ( U0126 ) or stable downregulation of PDGFRβ by shRNA similarly results in the loss of PDGF-induced P29323 REA phosphorylation and abolishes Rac 1 / Pak 1 activation and cell migration in response to PDGF . However , specific depletion of Pak 1 by siRNA has no effect on PDGF-induced P29323 REA phosphorylation , indicating that in MB cells P29323 REA signaling is Pak 1 - independent , but PDGF-induced migration is dependent on P29323 REA - mediated activation of Pak 1 . Finally , using tissue microarrays , we detect phosphorylated Pak 1 in 53 % of medulloblastomas and show that immunopositivity is associated with unfavorable outcome . We conclude that Rac 1 / Pak 1 signaling is critical to MB cell migration and is functionally dependent on PDGFRβ / P29323 REA activity .

Ras-dependent P29323 REA activation by the human G ( s ) - coupled serotonin receptors Q13639 REA ( b ) and P34969 REA ( a ) . Receptor tyrosine kinases activate mitogen-activated protein ( Q96HU1 ) kinases through Ras , P04049 REA , and MEK . Receptor tyrosine kinases can be transactivated by G protein-coupled receptors coupling to G ( i ) and G ( q ) . The human G protein-coupled serotonin receptors 5 - HT ( 4 ( b ) ) and 5 - HT ( 7 ( a ) ) couple to G ( s ) and elevate intracellular DB02527 . Certain G ( s ) - coupled receptors have been shown to activate Q96HU1 kinases through a protein kinase A - and Rap 1 - dependent pathway . We report the activation of the extracellular signal-regulated kinases ( ERKs ) 1 and 2 ( Q8TCB0 and Q8NFH3 Q96HU1 kinase ) through the human serotonin receptors 5 - HT ( 4 ( b ) ) and 5 - HT ( 7 ( a ) ) in COS - 7 and human embryonic kidney HEK 293 cells . In transfected HEK 293 cells , 5 - HT-induced activation of P27361 REA / 2 is sensitive to H89 , which indicates a role for protein kinase A . The observed activation of P27361 REA / 2 does not require transactivation of epidermal growth factor receptors . Furthermore , 5 - HT induced activation of both Ras and Rap 1 . Whereas the presence of P47736 REA did not influence the 5 - HT-mediated activation of P27361 REA / 2 , the activation of P27361 REA / 2 was abolished in the presence of dominant negative Ras ( RasN 17 ) . P27361 REA / 2 activation was reduced in the presence of " dominant negative " Raf 1 ( RafS 621A ) and slightly reduced by dominant negative B-Raf , indicating the involvement of one or more Raf isoforms . These findings suggest that activation of P27361 REA / 2 through the human G ( s ) - coupled serotonin receptors 5 - HT ( 4 ( b ) ) and 5 - HT ( 7 ( a ) ) in HEK 293 cells is dependent on Ras , but independent of Rap 1 .

Comparative effects of cytokines on constitutive and inducible expression of the gene encoding for the cytochrome P450 3A6 isoenzyme in cultured rabbit hepatocytes : consequences on progesterone 6beta - hydroxylation . Cultured rabbit hepatocytes were used to compare the relative activities of cytokines to inhibit the constitutive or rifampicin ( Q9HBH0 ) - induced expression of the cytochrome P450 3A6 gene ( CYP 3A6 ) . Human recombinant cytokines tested were interleukin - 1beta ( IL - 1beta ) ( 2 U / mL ) , interleukin - 2 ( P60568 REA ) ( 5,000 U / mL ) and interferon-gamma ( P01579 REA ) ( 50 U / mL ) . Hepatocytes were cultured in the presence or absence of 25 microM Q9HBH0 for 24 hr , with or without cytokines alone or in combination . All these cytokines inhibited Q9HBH0 - induced P4503A6 expression without apparent cellular toxicity . By contrast , only P01579 REA treatment provided a significant decrease ( 41 % ) in the constitutive P4503A6 protein level . Moreover , cytokines differed in their ability to repress Q9HBH0 - dependent transcriptional induction of CYP 3A6 : IL - 1beta and P60568 REA were approximately equipotent , causing an almost 40-50 % suppression of CYP 3A6 mRNA and protein levels , whereas P01579 REA exerted repressive effects only on P4503A6 - related erythromycin N-demethylase activity and inducible protein expression . In fact , although strongly reducing P4503A6 protein content ( an approximate 70 % decrease ) , P01579 REA did not exhibit any influence on CYP 3A6 mRNAs with the exception of its association with interleukins . All these results suggest that IL - 1beta and P60568 REA mainly promote a transcriptional repression mechanism , given the absence of effect of these cytokines on the basal P4503A6 level , whereas P01579 REA exerts a post-transcriptional suppressive action on both induced and constitutive P4503A6 expression . Consequently , P4503A6 - dependent progesterone 6beta - hydroxylase activity also presented a cytokine-specific pattern of inhibition , with a much greater sensitivity than P4503A6 immunoreactive protein to IL - 1beta and P60568 REA + P01579 REA treatments . Thus , this study underlines the significant impact of inflammation on steroid metabolism .

P15056 REA inhibitors suppress apoptosis through off-target inhibition of JNK signaling . DB08881 SUB and dabrafenib selectively inhibit the P15056 REA ( P15056 REA ) kinase , resulting in high response rates and increased survival in melanoma . Approximately 22 % of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma ( cSCC ) during therapy . The prevailing explanation for this is drug-induced paradoxical P29323 REA activation , resulting in hyperproliferation . Here we show an unexpected and novel effect of vemurafenib / PLX 4720 in suppressing apoptosis through the inhibition of multiple off-target kinases upstream of c-Jun N-terminal kinase ( JNK ) , principally Q9NYL2 . JNK signaling is suppressed in multiple contexts , including in cSCC of vemurafenib-treated patients , as well as in mice . Expression of a mutant Q9NYL2 that can not be inhibited reverses the suppression of JNK activation and apoptosis . Our results implicate suppression of JNK-dependent apoptosis as a significant , independent mechanism that cooperates with paradoxical P29323 REA activation to induce cSCC , suggesting broad implications for understanding toxicities associated with P15056 REA inhibitors and for their use in combination therapies . DOI : http://dx.doi.org/10.7554/eLife.00969.001 .

Activation of c-fos by lipopolysaccharide in glial cells via p38 mitogen-activated protein kinase-dependent activation of serum or cyclic AMP / calcium response element . Pathological conditions such as ischaemic stroke and inflammatory disorders cause c-fos activation in the brain . This activation contributes to the initiation of the brain ' s inflammatory response , orchestrated by activated glial cells . The inflammatory signalling cascades leading to c-fos activation in glial cells are not well characterized . Thus , we have attempted a detailed analysis of the cis-acting elements , transcription factors and upstream kinase pathways involved in the activation of c-fos by lipopolysaccharide ( LPS ) in primary rat cortical glial cells . We found that ( 1 ) LPS-induced c-fos mRNA levels were sensitive to p38 mitogen-activated protein kinase ( MAPK ) inhibitors but not to mitogen-activated / extracellular signal-regulated kinase ( P29323 REA ) or calcium-calmodulin-dependent kinase inhibitors , ( 2 ) LPS activated both serum response element ( SRE ) and cyclic AMP / calcium response element ( CRE ) - driven luciferase reporters in transient transfection assays , ( 3 ) LPS induced the phosphorylation of Elk 1 CRE-binding protein ( CREB ) / activated transcription factor - 1 ( P39905 REA - 1 ) and the activation of GAL 4 - Elk 1 and GAL 4 - CREB chimeric proteins , and ( 4 ) mutation of both SRE and CRE elements was necessary and sufficient to completely abolish LPS induction of a rat c-fos proximal promoter-luciferase reporter . Thus , c-fos activation by LPS in glial cells occurs via the SRE or CRE in an independent manner , and involves the Elk 1 or CREB / P39905 REA - 1 transcription factors . Elk 1 - mediated transactivation was dependent on p38 MAPK , suggesting a crucial role of these factors in mediating inflammatory responses in the CNS .

P62158 - mediated effects of loperamide on chloride transport by brush border membrane vesicles from human ileum . We investigated whether the synthetic opiate loperamide-HCl is able to regulate specific transport systems for sodium and chloride in brush border membrane vesicles ( BBMVs ) from human ileum and whether such activities are mediated by calcium / calmodulin . In BBMVs we studied Na + / H + antiport , Cl + / OH - antiport , Na + / Cl - cotransport , and the Cl - conductive pathway . Brush border membrane vesicles were incubated with 10 microM loperamide over 4 h at 5 degrees C before the uptake experiments . In ileal BBMVs , loperamide stimulated intravesicular accumulation of Na + in the presence of Cl - and vice versa . After 1 min of incubation , the stimulatory effect was 35 % + / - 5 % ( p less than 0.005 ) of the control without loperamide . DB00836 MEN also stimulated Cl - / OH - antiport by 30 % + / - 5 % ( p less than 0.005 ) in BBMVs of ileum . In addition , we studied the role of Ca2 + / calmodulin in the action of loperamide on chloride transport by human BBMVs . In loperamide-pretreated BBMVs , calmodulin activity was significantly decreased ( 12 + / - 2 vs . 38 + / - 4 pmol / mg protein ) . When loperamide-pretreated vesicles were incubated with 2 microM calcium ( free concentration ) plus 5 microM calmodulin for 1 h at 5 degrees C , complete inhibition of the stimulatory effect of loperamide on Cl - / OH - antiport and Na + / Cl - cotransport was observed . Increasing the Ca2 + / calmodulin activity of loperamide-pretreated BBMVs with 2 microM calcium plus 5 microM calmodulin led to a significant inhibition of Cl - / OH - antiport and Na + / Cl - cotransport by 40 % + / - 5 % ( p less than 0.005 ) .

PARP and CHK inhibitors interact to cause DNA damage and cell death in mammary carcinoma cells . The present studies examined viability and DNA damage levels in mammary carcinoma cells following P09874 REA and O14757 REA inhibitor drug combination exposure . P09874 REA inhibitors [ AZD 2281 ; ABT 888 ; DB02690 MEN ; AG014699 ] interacted with O14757 REA inhibitors [ P55089 REA - 01 ; AZD 7762 ; LY2603618 ] to kill mammary carcinoma cells . P09874 REA and O14757 REA inhibitors interacted to increase both single strand and double strand DNA breaks that correlated with increased γ P16104 REA phosphorylation . Treatment of cells with O14757 REA inhibitors increased the phosphorylation of O14757 REA and P27361 REA / 2 . Knock down of Q13315 REA suppressed the drug-induced increases in O14757 REA and P27361 REA / 2 phosphorylation and enhanced tumor cell killing by P09874 REA and O14757 REA inhibitors . Expression of dominant negative Q02750 REA enhanced drug-induced DNA damage whereas expression of activated Q02750 REA suppressed both the DNA damage response and tumor cell killing . Collectively our data demonstrate that P09874 REA and O14757 REA inhibitors interact to kill mammary carcinoma cells and that increased DNA damage is a surrogate marker for the response of cells to this drug combination .

DB01628 MEN - induced fixed drug eruption with positive lesional patch tests . Fixed drug eruption ( FDE ) is most commonly associated with antibiotics , anticonvulsants , and nonnarcotic analgens , including nonsteroidal anti-inflammatory drugs ( NSAIDs ) . However , the newer cyclooxygenase 2 ( P35354 REA ) inhibitors have been rarely reported to cause FDE . We report the case of a 52 - year-old Caucasian woman with erythematous pruritic plaques on the neck , left forearm , and second finger of the right hand , healing with hyperpigmentation and recurring in the same locations . The patient was sporadically taking oral etoricoxib 90 mg for her back pain and noticed the relation between administration of the drug and skin lesions , the time interval decreasing progressively from 1 week to 30 minutes . No other signs , symptoms , or drug intake was mentioned . The patch tests with etoricoxib 1 % and 5 % in petrolatum were positive at the location of the lesions and negative on the back ( nonlesional skin ) . Standard European and NSAID series were negative . Patch tests of 10 healthy controls with etoricoxib 1 % and 5 % in petrolatum were negative . After the avoidance of the drug , no relapse was mentioned . The patch test was reliable for the diagnosis of FDE , avoiding the need for subsequent oral provocation testing and therefore preventing the possible adverse effects . Despite being regarded as a safe drug , the occurrence of cutaneous adverse reactions to etoricoxib should be considered , especially in the setting of its increasing use in pain control .

The selective 5 - hydroxytryptamine ( 5 - HT ) 4 - receptor agonist RS67506 enhances lower intestinal propulsion in mice . Interactions of gastrointestinal prokinetic benzamides with 5 - hydroxytryptamine ( 5 - HT ) 3 and Q13639 REA receptors and the relation to their effects on gastrointestinal propulsion were investigated . DB04917 MEN and zacopride potently inhibited 5 - Q9H205 REA - receptor-mediated contractions in the guinea pig colon , whereas RS67506 ( 1 - ( 4 - amino - 5 - chloro - 2 - methoxyphenyl ) - 3 - [ 1 - ( 2 - methyl sulphonylamino ) ethyl - 4 - piperidinyl ] - 1 - propanone hydrochloride ) , a selective Q13639 REA - receptor agonist , showed no inhibition . RS67506 , renzapride and zacopride all exerted Q13639 REA receptor-mediated relaxation in the carbachol-precontracted rat oesophagus . In mice , RS67506 shortened the whole gut transit time , whereas renzapride and zacopride were reported to prolong it . Gastrointestinal prokinetic benzamides , which are selective for Q13639 REA - receptor agonistic over 5 - Q9H205 REA - receptor antagonistic action , may be useful in treating gastrointestinal disorders associated with impaired lower intestinal propulsion such as constipation .

Activity , pharmacological inhibition and biological regulation of 3 - hydroxy - 3 - methylglutaryl coenzyme A reductase in Trypanosoma brucei . Activity of hydroxymethylglutaryl-coenzyme A ( HMG - DB01992 ) reductase , the key enzyme in the biosynthesis of steroids and polyisoprenoids in mammalian cells , has been detected in both the bloodstream form and the culture-adapted procyclic form of Trypanosoma brucei ( 3.7 + / - 0.6 and 12.7 + / - 1.8 pmol mevalonate produced min - 1 ( mg cell protein ) - 1 , respectively ) . The enzyme activity is enriched 6 - fold in microsomal fractions . Several competitive inhibitors of mammalian P04035 REA , including synvinolin ( simvastatin ) , inhibit the multiplication of both forms of trypanosome in vitro ( IC50 , approx . 25-50 microM after 2-3 days ) . This growth inhibition is potentiated by agents interfering with the exogenous supply of cholesterol , such as antibodies blocking the low-density lipoprotein ( LDL ) receptor , or 5 microM chloroquine . Conversely , growth inhibition by synvinolin can be largely reverted either by 300 nM LDL or by products of the mevalonate pathway , such as 20 mM mevalonate and in procyclics by 100 microM squalene or cholesterol . In procyclics , low concentrations of synvinolin selectively inhibit the incorporation of [ 14C ] acetate into sterols , but not into fatty acids . These results argue for a critical role in trypanosomes of a mevalonate pathway , that is involved in the biosynthesis of sterol and probably of other metabolites . The P04035 REA activity is decreased 2 - fold in procyclics incubated with 4 mM mevalonate and increased 2 - fold in the presence of 2.5 microM synvinolin . DB00641 MEN also upregulates LDL binding up to 4 - fold . These data suggest that P04035 REA and P01130 REA expression are regulated in T . brucei as in mammalian cells , to ensure sterol homeostasis .

Compound FLZ inhibits lipopolysaccharide-induced inflammatory effects via down-regulation of the P50750 REA - IKK and P50750 REA - JNK / p38MAPK pathways in RAW 264.7 macrophages . AIM : The aim of this study was to investigate the effect of the squamosamide derivative FLZ ( N - 2 - ( 4 - hydroxy-phenyl ) - ethyl - 2 - ( 2,5- dimethoxy-phenyl ) - 3 - ( 3 - methoxy - 4 - hydroxy-phenyl ) - acrylamide ) on lipopolysaccharide ( LPS ) - induced inflammatory mediator production and the underlying mechanism in RAW 264.7 macrophages . METHODS : RAW 264.7 cells were preincubated with non-toxic concentrations of compound FLZ ( 1 , 5 , and 10 micromol / L ) for 30 min and then stimulated with 10 microg / L LPS . The production of nitric oxide ( NO ) , the expression of inducible nitric oxide synthase ( P35228 REA ) and cyclooxygenase 2 ( P35354 REA ) , and the activation of nuclear factor kappa-B ( NF-kappaB ) and mitogen-activated protein kinase ( MAPK ) pathways were examined . RESULTS : FLZ significantly inhibited the LPS-induced production of NO , as well as the expression of P35228 REA and P35354 REA at both the RNA and the protein levels in RAW 264.7 cells . The LPS-induced increase in the DNA binding activity of NF-kappaB and activator protein 1 ( AP - 1 ) , the nuclear translocation of NF-kappaB p65 , the degradation of the inhibitory kappaBalpha protein ( P25963 REA ) and the phosphorylation of P25963 REA , O15111 REA ( IKK ) alpha / beta , c-Jun NH ( 2 ) - terminal kinase ( JNK ) and p38 MAPKs were all suppressed by FLZ . However , the phosphorylation of extracellular signal-regulated kinase ( P29323 REA ) was not affected . Further study revealed that FLZ inhibited the phosphorylation of transforming growth factor-beta ( TGF-beta ) - activated kinase 1 ( TAK 1 ) , which is an upstream signaling molecule required for IKKalpha / beta , JNK and p38 activation . CONCLUSION : FLZ inhibited the LPS-induced production of inflammatory mediators at least partly through the downregulation of the P50750 REA - IKK and P50750 REA - JNK / p38MAPK pathways .

A novel mutation in the human complex I O75251 REA subunit associated with Leigh syndrome . Defects in DB00157 MEN : ubiquinone oxidoreductase , the complex I of the mitochondrial respiratory chain represents the most frequent cause of mitochondrial diseases and is associated with a wide clinical spectrum varying from severe lactic acidosis in infants to muscle weakness in adults . Here , we report a patient with Leigh syndrome ( LS ) , born to consanguineous parents , with severe complex I defect and a novel mutation in the O75251 REA gene subunit . The homozygous mutation at nucleotide ( nt ) 434 G > A resulted in the modification of the arginine 145 to histidine in a highly conserved region of the protein . Parents were heterozygous carriers for this mutation . The mutation was absent from over than 100 healthy controls from the same ethnic origin . Identifying nuclear mutations as a cause of respiratory chain disorders will enhance the possibility of prenatal diagnosis and help us to understand how moleculardefects can lead to complex I deficiency .

Inhibition of mutant P15056 REA splice variant signaling by next-generation , selective RAF inhibitors . DB08881 SUB and dabrafenib block MEK - P27361 REA / 2 signaling and cause tumor regression in the majority of advanced-stage P15056 REA ( V600E ) melanoma patients ; however , acquired resistance and paradoxical signaling have driven efforts for more potent and selective RAF inhibitors . Next-generation RAF inhibitors , such as PLX 7904 ( PB04 ) , effectively inhibit RAF signaling in P15056 REA ( V600E ) melanoma cells without paradoxical effects in wild-type cells . Furthermore , PLX 7904 blocks the growth of vemurafenib-resistant P15056 REA ( V600E ) cells that express mutant P01111 REA . Acquired resistance to vemurafenib and dabrafenib is also frequently driven by expression of mutation P15056 REA splice variants ; thus , we tested the effects of PLX 7904 and its clinical analog , PLX 8394 ( PB03 ) , in P15056 REA ( V600E ) splice variant-mediated vemurafenib-resistant cells . We show that paradox-breaker RAF inhibitors potently block MEK - P27361 REA / 2 signaling , P55008 / S cell cycle events , survival and growth of vemurafenib / PLX 4720 - resistant cells harboring distinct P15056 REA ( V600E ) splice variants . These data support the further investigation of paradox-breaker RAF inhibitors as a second-line treatment option for patients failing on vemurafenib or dabrafenib .

Gambogic acid inhibits angiogenesis through suppressing vascular endothelial growth factor-induced tyrosine phosphorylation of P35968 REA / Flk - 1 . Previous studies revealed that gambogic acid ( GA ) , the major active ingredient of gamboge , a brownish to orange resin exuded from Garcinia hanburryi tree in Southeast Asia , possessed significant anticancer activity both in vitro and in vivo . In this study , we explored the high antiangiogenic activities of GA for the first time . GA inhibits the P15692 REA - stimulated proliferation , migration and tube formation of human umbilical vein endothelial cells ( HUVECs ) as well as microvessel sprouting from rat aortic rings in vitro . Moreover , GA inhibits vessel growth in matrigel plugs and P62158 in vivo and transplanted tumor in mice . The results also indicated that GA decreases P15692 REA production of cultured tumor cells and inhibits P15692 REA - induced tyrosine phosphorylation of P35968 REA / Flk - 1 . This inhibition of receptor phosphorylation is correlated with a significant decrease in P15692 REA - triggered phosphorylated forms of P29323 REA , AKT and p38 . Taken together , these findings strongly suggest that GA might be a structurally novel angiogenesis inhibitor .

Adenoviral expression of a urokinase receptor-targeted protease inhibitor inhibits neointima formation in murine and human blood vessels . BACKGROUND : Smooth muscle cell migration , in addition to proliferation , contributes to a large extent to the neointima formed in humans after balloon angioplasty or bypass surgery . P00747 REA activator / plasmin-mediated proteolysis is an important mediator of this smooth muscle cell migration . Here , we report the construction of a novel hybrid protein designed to inhibit the activity of cell surface-bound plasmin , which can not be inhibited by its natural inhibitors , such as alpha ( 2 ) - antiplasmin . This hybrid protein , consisting of the receptor-binding amino-terminal fragment of uPA ( P39905 REA ) , linked to the potent protease inhibitor bovine pancreas trypsin inhibitor ( DB06692 MEN ) , can inhibit plasmin activity at the cell surface . METHODS AND RESULTS : The effect of adenovirus-mediated P39905 REA . DB06692 MEN expression on neointima formation was tested in human saphenous vein organ cultures . Infection of human saphenous vein segments with Ad.CMV . P39905 REA . DB06692 MEN ( 5x10 ( 9 ) pfu / mL ) resulted in 87.5+ / -3.8 % ( mean + / - SEM , n = 10 ) inhibition of neointima formation after 5 weeks , whereas Ad.CMV . P39905 REA or Ad.CMV . DB06692 MEN virus had only minimal or no effect on neointima formation . The efficacy of P39905 REA . DB06692 MEN in vivo was demonstrated in a murine model for neointima formation . Neointima formation in the femoral artery of mice , induced by placement of a polyethylene cuff , was strongly inhibited ( 93.9+ / - 2 % ) after infection with Ad.CMV.mATF . DB06692 MEN , a variant of P39905 REA . DB06692 MEN able to bind specifically to murine uPA receptor ; Ad.CMV.mATF and Ad.CMV . DB06692 MEN had no significant effect . CONCLUSIONS : These data provide evidence that adenoviral transfer of a hybrid protein that binds selectively to the uPA receptor and inhibits plasmin activity directly on the cell surface is a powerful approach to inhibiting neointima formation and restenosis .

Attenuation of anti-tuberculosis therapy induced hepatotoxicity by Spirulina fusiformis , a candidate food supplement . Therapy using Isoniazid ( DB00951 ) and DB01045 MENMAX DB01045 MEN ( Q9HBH0 ) leads to induction of hepatotoxicity in some individuals undergoing anti-tuberculosis treatment . In this study , we assessed the effect of Spirulina fusiformis on DB00951 and Q9HBH0 induced hepatotoxicity in rats compared with hepatoprotective drug Silymarin . Induction of hepatotoxicity was measured by changes in the liver marker enzymes ( aspartate transaminase , alanine transaminase , and alkaline phosphatase ) . The antioxidant status was also analyzed in liver tissue homogenate and plasma by measurement of superoxide dismutase , catalase , glutathione-S-transferase , glutathione reductase , and lipid peroxidation levels . We also aimed to study the binding and interactions of the transcription factors Pregnane X Receptor ( O75469 REA ) and Farnesoid X Receptor ( Q96RI1 ) with DB00951 , Q9HBH0 , and representative active compounds of Spirulina fusiformis by in silico methods . The administration of DB00951 and Q9HBH0 resulted in significant ( p < 0.05 ) decrease in the antioxidant levels and total protein levels . There was also a significant ( p < 0.05 ) increase in the levels of liver marker enzymes . Spirulina fusiformis was seen to protect the parameters from significant changes upon challenge with DB00951 and Q9HBH0 in a dose-dependent manner . This was corroborated by histological examination of the liver . The results of the in silico analyses further support the wet lab results .

5 - Aminoimidazole - 4 - carboxamide ribonucleoside stabilizes low density lipoprotein receptor mRNA in hepatocytes via P29323 REA - dependent Q15717 binding to an AU-rich element . OBJECTIVE : 5 - Aminoimidazole - 4 - carboxamide ribonucleoside ( AICAR ) has pleiotropic and beneficial effects on metabolic disorders . However , the effects of AICAR on low density lipoprotein ( LDL ) metabolism are poorly understood . METHODS AND RESULTS : AICAR induces increased P01130 REA mRNA levels and increased P01130 REA protein production in hepatocytes . The AICAR-dependent P01130 REA mRNA increase was partially mediated by mRNA stabilization in an extracellular signal-regulated kinase 1/2 ( P27361 REA / 2 ) - dependent manner , but not by the AMP-activated protein kinase ( AMPK ) activation . Reporter assays using a variety of constructs harboring the 3 ' - untranslated region ( UTR ) of human P01130 REA mRNA revealed that the most upstream AU-rich element ( ARE ) was critical for these AICAR effects . Using UV cross-linking assays , we found increased binding of three cytoplasmic proteins to this ARE region in response to AICAR and identified a 35 - kDa protein as Human antigen R ( Q15717 ) . Blocking P29323 REA signaling pathway activation resulted in attenuated Q15717 binding . Silencing Q15717 expression by RNA interference hindered AICAR-induced P01130 REA mRNA stability , whereas its overexpression stabilized this mRNA . CONCLUSIONS : AICAR-dependent P01130 REA mRNA stabilization is mediated , at least in part , by Q15717 binding to the ARE 1 region . Given that AICAR enhanced LDL uptake in hepatocytes , our findings warrant further studies using animal models to develop a novel LDL-cholesterol lowering agent as a possible strategy to treat atherosclerosis-related cardiovascular diseases .

Algorithm for the management of metastatic cutaneous melanoma . Over the last 4 years , various drugs have been approved for the treatment of metastatic cutaneous melanoma . DB06186 , an anti - P16410 REA inhibitor that stimulates antitumor immunity , was the first agent to improve overall survival both in first line and in previously treated patients . DB06186 results in long term disease control in approximately 20 % of the patients . DB08881 SUB was the first P15056 REA inhibitor ( BRAFi ) approved and also resulted in improved overall survival compared with dacarbazine in patients with P15056 REA mutated metastatic melanoma . More recently , another BRAFi , dabrafenib , and a MEK inhibitor , trametinib , were approved either alone or in combination as they each showed significant antitumor activity relative to dacarbazine and the combination appeared superior to dabrafenib monotherapy . The major feature of such tumor targeted therapy is its high response rate ( 40-70 % ) and the rapidity of the responses , resulting in prompt clinical improvement . However , unlike immunotherapy , targeted therapy does not result in long-term treatment free survival . In this paper , we discuss how best to integrate the currently available treatment options including high-dose interleukin - 2 ( HD P60568 REA ) , systemic chemotherapy , ipilimumab and tumor targeted therapy in various clinical scenarios .