MH_dev_201

Thrombospondin 1 and its mimetic peptide DB05434 MEN decrease angiogenesis and inflammation in a murine model of inflammatory bowel disease . OBJECTIVE : Vascular abnormalities and expression of proangiogenic factors have been repeatedly reported in inflammatory bowel disease ( Q9UKU7 ) . Thrombospondin 1 ( P07996 REA - 1 ) is a protein well known for its antiangiogenic and anti-inflammatory properties . Using the dextran sulfate sodium ( DSS ) model , the role of P07996 REA - 1 in Q9UKU7 has been investigated in vivo . METHODS : P07996 REA - 1 - deficient mice ( P07996 REA - 1 - / - ) and WT mice were treated with DSS for 7 days . Disease activity indices , myeloperoxidase activity ( P05164 REA ) and histology were analyzed . Microvascular density ( P53602 REA ) was quantified using immunohistochemistry ( IMH ) with CD31 antibody . TGF-beta ( 1 ) , basic FGF , P15692 REA , P01375 REA and MMPs protein levels were evaluated by IMH and enzyme-linked immunoabsorbent assay ( ELISA ) . Mice were treated with DB05434 MEN ( Abbott Laboratories ) , an antiangiogenic P07996 REA peptide , using miniosmotic pumps for 7 days . RESULTS : P07996 REA - 1 ( - / - ) mice had a worse clinical outcome and exhibited severe signs of rectal bleeding compared to the WT controls . The P07996 REA - 1 - / - mice showed a higher level of crypt damage and deeper lesions . The grade of inflammation and the levels of P05164 REA activity were also significantly higher in colons of P07996 REA - 1 - / - mice . P07996 REA - 1 - / - mice displayed higher P53602 REA in focal areas of the colon after only 3 days of DSS treatment . Furthermore , clinical severity of the colitis and angiogenesis was significantly diminished when mice was treated with DB05434 MEN . CONCLUSIONS : These findings directly link P07996 REA - 1 as a protective factor in Q9UKU7 and suggest antiangiogenesis treatment , including compounds such as DB05434 MEN as an adjuvant therapy for Q9UKU7 .

DB00107 alleviates the neuroendocrine and cytokine response to bacterial endotoxin in healthy men . DB00107 is a hormone and neurotransmitter found to have anti-inflammatory functions in rodents . Here we used experimental bacterial endotoxinemia to examine the role of exogenous oxytocin administration on innate immune responses in humans . Ten healthy men received , in a randomized , placebo-controlled , crossover design , placebo , oxytocin , LPS , and LPS + oxytocin . DB00107 treatment resulted in a transient or prolonged reduction of endotoxin-induced increases in plasma DB01285 , cortisol , procalcitonin , P01375 REA , IL - 1 receptor antagonist , P05112 REA , P05231 REA , macrophage inflammatory protein - 1alpha , macrophage inflammatory protein - 1beta , monocyte chemoattractant protein - 1 ( P13500 REA ) , interferon-inducible protein 10 , and P15692 REA . In vitro , oxytocin had no impact on LPS effects in releasing P01375 REA , P05231 REA , and P13500 REA in monocytes and peripheral blood mononuclear cells from healthy human donors . In summary , oxytocin decreases the neuroendocrine and cytokine activation caused by bacterial endotoxin in men , possibly due to the pharmacological modulation of the cholinergic anti-inflammatory pathway . DB00107 might be a candidate for the therapy of inflammatory diseases and conditions associated with high cytokine and P15692 REA levels .

P08183 REA , Q9UNQ0 , and P60484 REA determine the response of glioblastoma to temozolomide and ABT - 888 therapy . PURPOSE : Little is known about the optimal clinical use of ABT - 888 ( veliparib ) for treatment of glioblastoma . ABT - 888 is a PARP inhibitor undergoing extensive clinical evaluation in glioblastoma , because it may synergize with the standard-of-care temozolomide ( DB00853 ) . We have elucidated important factors controlling ABT - 888 efficacy in glioblastoma . EXPERIMENTAL DESIGN : We used genetically engineered spontaneous glioblastoma mouse models and allograft models that were orthotopically transplanted into wild-type ( WT ) and Abcb 1 / Abcg 2 - deficient ( KO ) recipients . RESULTS : ABT - 888 / DB00853 is not efficacious against p53 ;p 16 ( Ink 4a ) / p19 ( Arf ); K-Ras ( v12 ); LucR allografts in wild-type recipients , indicating inherent resistance . Abcb 1 / Abcg 2 mediated efflux of ABT - 888 at the blood-brain barrier ( BBB ) causes a 5 - fold reduction of ABT - 888 brain penetration ( P < 0.0001 ) that was fully reversible by elacridar . Efficacy studies in WT and KO recipients and / or concomitant elacridar demonstrate that Abcb 1 / Abcg 2 at the BBB and in tumor cells impair DB00853 / ABT - 888 combination treatment efficacy . DB04881 MEN also markedly improved DB00853 / ABT - 888 combination treatment in the spontaneous p53 ;p 16 ( Ink 4a ) / p19 ( Arf ); K-Ras ( v12 ); LucR glioblastoma model . Importantly , ABT - 888 does enhance DB00853 efficacy in Pten deficient glioblastoma allografts and spontaneous tumors , even in Abcb 1 / Abcg 2 proficient wild-type mice . Loss of P60484 REA occurs frequently in glioblastoma ( 36 % ) and in silico analysis on patient with glioblastoma samples revealed that it is associated with a worse overall survival ( 310 days vs . 620 days , n = 117 ) . CONCLUSIONS : The potential of ABT - 888 in glioblastoma can best be demonstrated in patients with P60484 REA null tumors . Therefore , clinical trials with ABT - 888 should evaluate these patients as a separate group . Importantly , inhibition of P08183 REA and Q9UNQ0 ( by elacridar ) may improve the efficacy of DB00853 / ABT - 888 therapy in all glioblastoma patients .

Increase in intracellular Cl - concentration by DB02527 - and Ca2 + - dependent stimulation of M1 collecting duct cells . In the lungs of cystic fibrosis ( CF ) patients , mutations of the cystic fibrosis transmembrane conductance regulator ( P13569 REA ) lead to defective Cl - secretion and hyperabsorption of electrolytes . This may be a an important cause for the defective mucociliary clearance in CF lungs . Previous studies have suggested that inhibition of ENaC during activation of P13569 REA or by purinergic stimulation could be related to an increase in the intracellular [ Cl - ] i . This was examined in the present study using cultured mouse M1 collecting duct cells transfected with the chloride-sensitive enhanced yellow fluorescent protein YFP ( V163S ) . Calibration experiments showed a linear decrease of YFP fluorescence intensity with increasing [ Cl - ] i ( 0-100 mM ) . Activation of P13569 REA by isobutyl - 1 - methylxanthine ( DB07954 , 100 microM ) and forskolin ( 2 microM ) increased [ Cl - ] i by 9.6+ / -1.5 mM ( n = 35 ) . Similarly , DB00171 ( 100 microM ) increased [ Cl - ] i transiently by 9.5+ / -2.2 mM ( n = 17 ) . The increase in [ Cl - ] i was reduced by the Na + / K + / 2 Cl - - cortransporter - 1 ( P55011 REA ) blocker azosemide ( 100 microM ) , the P13569 REA blocker DB04941 MEN ( 50 microM ) , the blocker of Ca2 + - activated Cl - channels DIDS ( 100 microM ) or the ENaC blocker amiloride ( 10 microM ) . Changes in YFP ( V163S ) fluorescence were not due to changes in cell volume or intracellular pH . The present data thus demonstrate an increase in [ Cl - ] i following stimulation with secretagogues , which could participate in the inhibition of ENaC .

DB00227 SUB enhances gefitinib activity in glioblastoma cells irrespective of EGFRvIII and P60484 REA status . The epidermal growth factor receptor ( P00533 REA ) is commonly amplified and mutated in glioblastoma , making it a compelling therapeutic target . Recent reports have demonstrated clinical activity of the P00533 REA inhibitors gefitinib and erlotinib in a subset of glioblastoma patients . Co-expression of EGFRvIII , a constitutively active mutant receptor expressed in 50 % of tumours , and P60484 REA , an inhibitor of PI3K activity , by glioblastoma cells is associated with clinical response to these P00533 REA kinase inhibitors . P60484 REA loss and resulting increased PI3K pathway activity appears to act as a resistance factor . A critical therapeutic challenge is to identify agents that enhance the anti-cancer effects of these agents and promote responsiveness to P00533 REA kinase inhibitors in a broader spectrum of glioblastoma patients . For example , combining gefitinib with inhibitors of the PI3K / AKT pathway show enhanced cytotoxicity in glioblastoma derived cell lines . Here , we show that targeting P04035 REA with lovastatin , that can affect the activity of multiple cell signaling pathways , significantly enhanced the sensitivity of glioblastoma cells to the P00533 REA kinase inhibitor gefitinib in the five cell lines tested . In an isogenic model system , U87MG glioblastoma cells expressing EGFRvIII and P60484 REA in relevant combinations , we show that combined gefitinib and lovastatin treatments induce potent synergistic cytotoxicity irrespective of EGFRvIII and P60484 REA status . These studies demonstrate the potential of lovastatin to augment the cytotoxic effects of gefitinib and provide a rationale for combined statin / P00533 REA targeted therapies in glioblastoma patients .

Pathogenesis and treatment of thrombohemorrhagic diathesis in acute promyelocytic leukemia . Acute promyelocytic leukemia ( APL ) is a distinct subtype of myeloid leukemia characterized by t ( 15 ; 17 ) chromosomal translocation , which involves the retinoic acid receptor-alpha ( P10276 REA ) . APL typically presents with a life-threatening hemorrhagic diathesis . Before the introduction of all-trans retinoic acid ( DB00755 ) for the cure of APL , fatal hemorrhages due , at least in part , to the APL-associated coagulopathy , were a major cause of induction remission failure . The laboratory abnormalities of blood coagulation found in these patients indicate the occurrence of a hypercoagulable state . Major determinants of the coagulopathy of APL are endogenous factors expressed by the leukemic cells , including procoagulant factors , fibrinolytic proteins , and non-specific proteolytic enzymes . In addition , these cells have an increased capacity to adhere to the vascular endothelium , and to secrete inflammatory cytokines [ i . e . interleukin - 1beta ( IL - 1beta ) and tumor necrosis factor ( P01375 REA ) ] , which in turn stimulate the expression of prothrombotic activities by endothelial cells and leukocytes . DB00755 can interfere with each of the principal hemostatic properties of the leukemic cell , thus reducing the APL cell procoagulant potential , in parallel to the induction of cellular differentiation . This effect occurs in vivo , in the bone marrow of APL patients receiving DB00755 , and is associated with the improvement of the bleeding symptoms . Therapy with arsenic trioxide ( ATO ) also beneficially affects coagulation in APL . However , early deaths from bleeding still remain a major problem in APL and further research is required in this field . In this review , we will summarize our current knowledge of the pathogenesis of the APL-associated coagulopathy and will overview the therapeutic approaches for the management of this complication .

DB06268 MEN ( Q9Y6W8 REA - Texas Biotechnology ) . Q9Y6W8 REA - Texas Biotechnology is developing the endothelin A ( P25101 REA ) receptor antagonist , sitaxsentan , for the potential treatment of pulmonary hypertension , congestive heart failure ( CHF ) , chronic obstructive pulmonary disease and subarachnoid hemorrhage [ 205713 ] , [ 302200 ] . The compound is in phase IIa trials as an iv formulation for CHF and has completed phase I safety trials as an oral formulation [ 272071 ] . Phase II / III trials for pulmonary hypertension are planned for the first quarter of 2001 [ 3945711 ] . In June 2000 , Q9Y6W8 REA and Texas Biotechnology established a joint venture to develop and commercialize endothelin antagonists [ 370007 ] . US - 05591761 was issued to Texas in January 1997 , covering TBC - 11251 and several related isomers [ 2309301 .

DB00227 SUB , a 3 - hydroxy - 3 - methylglutaryl coenzyme A reductase inhibitor , induces apoptosis and differentiation in human anaplastic thyroid carcinoma cells . Although only 1 % of differentiated thyroid cancers transform into anaplastic thyroid cancer , this disease is always fatal . Differentiation therapy may provide a new therapeutic approach to increasing the survival rate in such patients . 3 - Hydroxy - 3 - methylglutaryl coenzyme A ( HMG - DB01992 ) reductase inhibitors are reported to promote cellular apoptosis and differentiation in many cancer cells ; these effects are unrelated to lipid reduction . Recently , we found that TNFalpha induces cytomorphological differentiation in anaplastic thyroid cancer cells and increases thyroglobulin expression ; however , P01375 REA is cytotoxic for normal human tissue . The aim of this study was to determine whether lovastatin , an P04035 REA inhibitor , could induce apoptosis and differentiation in anaplastic thyroid cancer cells . Anaplastic thyroid cancer cells were treated with lovastatin , then examined for cellular apoptosis and cytomorphological differentiation by DNA fragmentation , phosphatidylserine externalization / flow cytometry , and electron microscopy . Thyroglobulin levels in the culture medium were also measured . Our results showed that at a higher dose ( 50 micro M ) , lovastatin induced apoptosis of anaplastic thyroid cancer cells , whereas at a lower dose ( 25 micro M ) , it promoted 3 - dimensional cytomorphological differentiation . It also induced increased secretion of thyroglobulin by anaplastic cancer cells . Our results show that lovastatin not only induces apoptosis , but also promotes redifferentiation in anaplastic thyroid cancer cells , and suggest that it and other P04035 REA inhibitors merit further investigation as differentiation therapy for the treatment of anaplastic thyroid cancer .

Regulation of hepatic lecithin : retinol acyltransferase activity by retinoic acid receptor-selective retinoids . The microsomal enzyme O95237 REA esterifies retinol and has been implicated in the hepatic storage of vitamin A . Previously , we showed that hepatic O95237 REA activity is negligible during vitamin A deficiency and that all-trans-retinoic acid ( all-trans-RA ) rapidly induces the activity of liver O95237 REA in retinoid-deficient rats . In the present studies , we have examined the ability of natural and synthetic retinoids to induce liver O95237 REA activity in retinoid-deficient rats . The natural retinoids retinol , all-trans-RA ( 100 microg ) , 9 - DB00982 MEN , or equal molar amounts of other retinoids were injected ip and O95237 REA specific activity was measured in liver homogenates 17-18 h later . In retinoid-deficient rats , liver O95237 REA activity was extremely low [ 0.13 + / - 0.03 pmol retinyl ester ( RE ) / min / mg liver protein , mean + / - SE ] . The natural retinoids retinol and all-trans-RA strongly induced O95237 REA activity ( 12.71 + / - 1.09 and 13.10 + / - 1.55 pmol RE / min / mg , respectively ) , whereas 9 - DB00982 MEN induced a lower level of O95237 REA activity ( 3.96 + / - 1.88 pmol RE / min / mg , P < 0.001 vs all-trans-RA ) . The retinoic acid receptor ( RAR ) - selective analog ( RAR pan-agonist ) all-trans-UAB 8 and the P10276 REA - selective retinoid Am580 also strongly induced O95237 REA activity . In contrast , neither RXR-selective agonists nor retinoids having a retro structure were active . For retinoids with significant P10276 REA binding activity there was a strong direct correlation between receptor binding in vitro and the ability to induce hepatic O95237 REA activity in vivo ( r2 = 0.920 ) . These data implicate the RARs in the induction of hepatic O95237 REA and suggest a predominant role for P10276 REA - active ligands .

Administration of adenosine diphosphate-ribosyl transferase antagonist allows in vivo control of anti-dinitrophenyl response . DB03073 MEN ( 3MB ) is one of a series of chemical inhibitors of the nuclear enzyme adenosine diphosphate ( ADP ) - ribosyl transferase ( P09874 REA ) , which has been shown to inhibit cell differentiation in vitro , but has no effect on differentiation independent proliferation . Treatment of mice with an optimal concentration of 3MB ( 20 mg / kg body weight ) at or 1 day after dinitrophenyl-keyhole limpet haemocyanin ( DNP-KLH ) immunisation reduced anti-DNP plaque-forming cell ( P27918 REA ) numbers to less than 10 % of those of control animals . The period for maximum P27918 REA suppression showed a narrow time window relative to immunisation , suggesting that in vivo , as in vitro , 3 MB was acting only on those lymphocytes differentiating in response to antigen . Experimental findings showed that it was possible to select for P27918 REA derived from different populations of DNP-responsive lymphocytes by adjusting the time of 3MB treatment relative to immunisation . When 3MB was used with antigen priming , the residual P27918 REA showed a lower average affinity than P27918 REA in mice treated with 3MB 3 days after priming , suggesting a differential selection of those lymphocytes responding either ' early ' or ' late ' in the primary immune response .

DB00227 SUB overcomes gefitinib resistance in human non-small cell lung cancer cells with K-Ras mutations . DB00227 SUB is a 3 - hydroxy - 3 - methylglutaryl-coenzyme A ( HMG - DB01992 ) reductase inhibitor . Its inhibitory action on P04035 REA leads to depletion of isoprenoids , which inhibits post-translational modification of DB01367 . In this study , we investigated the effect of combining lovastatin with gefitinib on gefitinib-resistant human non-small cell lung cancer ( NSCLC ) cell lines with K-Ras mutations . Antitumor effects were measured by growth inhibition and 3 - ( 4,5- dimethylthiazol - 2 - yl ) -2,5- diphenyltetrazolium bromide assay . Effects on apoptosis were determined by flow cytometry , DNA fragmentation , and immunoblots . Protein levels of DB01367 , AKT / pAKT , and RAF / P27361 REA / 2 in cancer cells were analyzed by immunoblot . Compared with gefitinib alone , a combination of gefitinib with lovastatin showed significantly enhanced cell growth inhibition and cytotoxicity in gefitinib-resistant A549 and NCI-H 460 human NSCLC cells . In addition , lovastatin combination treatment significantly increased gefitinib-related apoptosis , as determined by fluorescence microscopy and flow cytometric analysis . These effects correlated with up-regulation of cleaved caspase - 3 , poly ( ADP-ribose ) polymerase ( PARP ) , and Bax and down-regulation of Bcl - 2 . The combination of lovastatin and gefitinib effectively down-regulated DB01367 protein and suppressed the phosphorylation of RAF , P27361 REA / 2 , AKT , and P00533 REA in both cell lines . Taken together , these results suggest lovastatin can overcome gefitinib resistance , in NSCLC cells with K-Ras mutations , by down regulation of DB01367 protein , which leads to inhibition of both RAF / P29323 REA and AKT pathways .

Tanshinone IIA inhibits endothelin - 1 production in P01375 REA - induced brain microvascular endothelial cells through suppression of endothelin-converting enzyme - 1 synthesis . AIM : To investigate the effects of tanshinone IIA ( Tan IIA ) on the regulation of the production of endothelin ( ET ) - 1 ( including large ET - 1 ) , mRNA levels of ET - 1 , endothelin-converting enzyme - 1 ( P42892 REA ) , endothelin-A receptor ( P25101 REA ) and endothelin-B receptor ( ETB ) induced by P01375 REA in rat brain microvascular endothelial cells ( BMVEC ) . METHODS : The ET - 1 release ( including large ET - 1 ) into the culture medium was determined by enzyme immunoassay . The levels of ET - 1 , P42892 REA , P25101 REA , and ETB mRNA were measured by RT-PCR . Endothelin receptor binding was also tested . RESULTS : The induction of ET - 1 release by P01375 REA from cultured BMVEC was dose-dependently reduced by Tan IIA , but large ET - 1 levels progressively increased in response to Tan IIA ; the mRNA expression of ET - 1 was unaffected . Tan IIA also caused a decrease in P25101 REA receptor mRNA and P42892 REA expression in a dose-dependent manner . Endothelin receptor binding was unaltered in BMVEC stimulated with P01375 REA alone or a combination of P01375 REA and Tan IIA . CONCLUSION : These findings suggest that Tan IIA may inhibit ET - 1 production in P01375 REA - induced BMVEC through the suppression of P42892 REA synthesis .

Suppression of dendritic cell maturation by Trichinella spiralis excretory / secretory products . Evidence from experimental studies indicates that during chronic infections with certain helminth species a regulatory network is induced that can down-modulate not only parasite-induced inflammation but also reduce other immunopathologies such as allergies and autoimmune diseases . The mechanisms however , and the molecules involved in this immunomodulation are unknown . Here , we focus on the effect of Trichinella spiralis excretory / secretory antigens ( TspES ) on the innate immune response by studying the effect of TspES on DC maturation in vitro . Bone marrow-derived DC from BALB / c mice were incubated with TspES either alone or in combination with LPS derived from two different bacteria . As indicators of DC maturation , the cytokine production ( IL - 1alpha , P05231 REA , P22301 REA , IL - 12p70 and P01375 REA ) and the expression of various surface molecules ( MHC-II , P25942 REA , P33681 REA and P42081 REA ) were measured . Results indicate that while TspES alone did not change the expression of the different surface molecules or the cytokine production , it completely inhibited DC maturation induced by Escherichia coli LPS ( E . coli LPS ) . In contrast , DC maturation induced by LPS from another bacterium , Neisseria meningitidis , was not affected by TspES . These results were confirmed using O00206 REA / Q9Y6Y9 REA / P08571 REA transfected P29320 REA 293 cells . In conclusion , T . spiralis ES antigens lead to suppression of DC maturation but this effect depends on the type of LPS used to activate these cells .

Mechanisms of atrial-selective block of Na ⁺ channels by ranolazine : I . Experimental analysis of the use-dependent block . Atrial-selective inhibition of cardiac Na ( + ) channel current ( I ( Na ) ) and I ( Na ) - dependent parameters has been shown to contribute to the safe and effective management of atrial fibrillation . The present study examined the basis for the atrial-selective actions of ranolazine . Whole cell I ( Na ) was recorded at 15 ° C in canine atrial and ventricular myocytes and in human embryonic kidney ( P29320 REA ) - 293 cells expressing Q14524 REA . Tonic block was negligible at holding potentials from - 140 to - 100 mV , suggesting minimal drug interactions with the closed state . Trains of 40 pulses were elicited over a range of holding potentials to determine use-dependent block . Guarded receptor formalism was used to analyze the development of block during pulse trains . Use-dependent block by ranolazine increased at more depolarized holding potentials , consistent with an interaction of the drug with either preopen or inactivated states , but was unaffected by longer pulse durations between 5 and 200 ms , suggesting a weak interaction with the inactivated state . Block was significantly increased at shorter diastolic intervals between 20 and 200 ms . Responses in atrial and ventricular myocytes and in P29320 REA - 293 cells displayed a similar pattern . DB00243 MENMAX DB00243 MEN is an open state blocker that unbinds from closed Na ( + ) channels unusually fast but is trapped in the inactivated state . Kinetic rates of ranolazine interactions with different states of atrial and ventricular Na ( + ) channels were similar . Our data suggest that the atrial selectivity of ranolazine is due to a more negative steady-state inactivation curve , less negative resting membrane potential , and shorter diastolic intervals in atrial cells compared with ventricular cells at rapid rates .

Antibodies to the epidermal growth factor receptor in non small cell lung cancer : current status of matuzumab and panitumumab . DB05101 MEN and panitumumab are antibodies against the epidermal growth factor receptor ( P00533 REA ) that are being evaluated in several malignancies including non-small cell lung cancer ( NSCLC ) . In phase I trials of single-agent matuzumab in patients with P00533 REA - positive cancer , three tumor responses were documented in esophageal squamous cell carcinoma as well as colorectal carcinoma . A phase I trial of matuzumab in combination with paclitaxel has been reported in 18 patients with P00533 REA - positive advanced NSCLC . Objective responses were seen in 4 of 18 ( 23 % ) patients . A randomized phase II trial is currently ongoing in second-line NSCLC with matuzumab in combination with pemetrexed . A large dose / schedule trial of single-agent panitumumab enrolled 96 patients with P00533 REA - positive solid tumors . No responses were seen in the 14 lung cancer patients evaluated ; 5 of 39 patients with colorectal cancers had objective responses . A randomized phase II trial of carboplatin / paclitaxel with or without panitumumab in 166 patients with previously untreated advanced stage IIIB / IV NSCLC did not find any benefit for the panitumumab arm compared with the chemotherapy alone arm with regard to response rates , time to disease progression , or median survival time . The lack of a biomarker to identify a subset of NSCLC patients who may derive benefit from this agent limits any potential enthusiasm for further trials of panitumumab at this time in NSCLC .

DB00207 fails to reduce inflammation in cystic fibrosis airway epithelial cells . Cystic fibrosis is a hereditary disease caused by a mutation in the Cystic Fibrosis Transmembrane conductance Regulator ( P13569 REA ) gene that encodes a chloride ( Cl ( - ) ) channel . Cystic fibrosis pulmonary pathophysiology is characterised by chronic inflammation and bacterial infections . DB00207 , a macrolide antibiotic , has shown promising anti-inflammatory properties in some inflammatory pulmonary diseases . Moreover , all clinical studies have presented an improvement of the respiratory condition of cystic fibrosis patients , but the molecular and cellular mechanisms remain unknown . The aim of this study was to investigate , in bronchial epithelial cells , the effects of azithromycin on inflammatory pathways involved in cystic fibrosis . We have analysed the effects of azithromycin on cystic fibrosis and non-cystic fibrosis bronchial epithelial cell lines but also in non-immortalized non-cystic fibrosis human glandular cells . To create an inflammatory context , cells were treated with Tumor Necrosis Factor ( P01375 REA ) - α or Interleukin ( IL ) 1 - β . Activation of the NF-κB pathway was investigated by luciferase assay , western blotting , and by Förster Resonance Energy Transfer imaging , allowing the detection of the interaction between the transcription factor and its inhibitor in live cells . In all conditions tested , azithromycin did not have an anti-inflammatory effect on the cystic fibrosis human bronchial epithelial cells and on P13569 REA - inhibited primary human bronchial glandular cells . More , our data showed no effect of azithromycin on IL - 1β - or P01375 REA - α-induced P10145 REA secretion and NF-κB pathway activation . Taken together , these data show that azithromycin is unable to decrease in vitro inflammation in cystic fibrosis cells from airways .

Differences in immune cell function between tuberculosis positive and negative Asian elephants . Tuberculosis is an important health concern for Asian elephant ( Elephas maximus ) populations worldwide , however , mechanisms underlying susceptibility to Mycobacterium tuberculosis are unknown . Proliferative responses assessed via brominated uridine incorporation and cytokine expression measured by real-time RT-PCR were evaluated in peripheral blood mononuclear cell ( PBMC ) cultures from 8 tuberculosis negative and 8 positive Asian elephants . Cultures were stimulated with Mycobacterium bovis purified protein derivative ( PPD-B ) , M . tuberculosis culture filtrate protein ( P27918 REA ) - 10 , and Mycobacterium avium PPD ( PPD-A ) . Following stimulation with PPD-B , proliferation was higher ( α = 0.005 ) in positive samples ; no significant differences were detected following P27918 REA - 10 or PPD-A stimulation . P01375 REA ( P01375 REA ) - α , interleukin ( IL ) - 12 , and interferon ( IFN ) - γ expression was greater in samples from positive elephants following stimulation with PPD-B ( α = 0.025 ) and P27918 REA - 10 ( α = 0.025 P01375 REA - α and IL - 12 ; α = 0.005 IFN-γ ) . Stimulation with PPD-A also produced enhanced IL - 12 expression in positive samples ( α = 0.025 ) . Findings suggested that differences in immune cell function exist between tuberculosis positive and negative elephants . Proliferative responses and expression of P01375 REA - α , IL - 12 , and IFN-γ in response to stimulation with PPD-B and P27918 REA - 10 differ between tuberculosis positive and negative elephants , suggesting these parameters may be important to tuberculosis immunopathogenesis in this species .

DB06626 MEN modulates hypoxia-induced blood-retina barrier permeability and expression of growth factors . This study investigates the effects of the multikinase inhibitor axitinib on the expression of vascular endothelial growth factor ( P15692 REA ) receptors 1/2 ( P17948 REA / 2 ) and platelet-derived growth factor ( PDGF ) receptor beta ( P09619 REA - β ) , hypoxia-induced increased tissue permeability , occludin , zonula occludens protein 1 ( ZO - 1 ) , P15692 REA , and PDGF expression of human retinal pigment epithelial ( Q96AT9 ) cells and human umbilical vein endothelial cells ( HUVECs ) . Primary human Q96AT9 cells and HUVECs were exposed to hypoxia and axitinib . Viability of cells , tissue permeability , and expression of occludin , ZO - 1 , P15692 REA , PDGF , P17948 REA / 2 and P09619 REA - β , and their mRNAs , were investigated by reverse transcription-polymerase chain reaction , enzyme-linked immunosorbent assay , western blotting , and immunohistochemistry . Treatment with axitinib reduced expression of P17948 REA / 2 and P09619 REA - β . Hypoxia decreased cell viability , occludin , and ZO - 1 expression and increased tissue permeability , expression , and secretion of P15692 REA and PDGF . DB06626 MEN significantly reduced hypoxia-induced effects on HUVEC and Q96AT9 cells . Our in vitro results suggest that axitinib may have promising properties as a potential treatment for diabetic macular edema .