MH_dev_299

P13726 REA - independent effects of recombinant factor VIIa on hemostasis . The molecular mechanisms responsible for the hemostatic efficacy of recombinant activated factor VII ( DB00036 MEN ; NovoSeven , Novo Nordisk , Bagsvaerd , Denmark ) in platelet-related bleeding disorders remain unclear . The general concept is that DB00036 MEN locally enhances thrombin generation at the site of injury , where tissue factor ( TF ) has become exposed . However , a growing amount of evidence shows that DB00036 MEN is also able to exert its activity in a manner independent of TF . Using an in vitro flow model , we recently showed that TF-independent thrombin generation is responsible for increased platelet deposition onto injured vessels following DB00036 MEN administration . Furthermore , it has been shown that DB00036 MEN can restore platelet aggregation in Glanzmann ' s thrombasthenia ( GT ) patients via TF-independent thrombin generation . However , the mechanism behind TF-independent thrombin generation remains to be elucidated . It is postulated that , in vivo , both the TF-dependent and TF-independent thrombin generation induced by DB00036 MEN contribute to the control of hemorrhage in patients with platelet-related bleeding disorders and , perhaps , other causes of hemorrhagic diatheses .

Regulation of Con A-dependent cytokine production from P01730 REA + and CD8 + T lymphocytes by autosecretion of histamine . OBJECTIVES : Previously we have shown that both P01730 REA + T cells and CD8 + T cells produce histamine when activated with Con A . The aim of this study was to examine whether cytokine production by these cells is regulated by autosecretion of histamine . MATERIALS : P01730 REA + and CD8 + T cells were separated from spleen cells of C57BL / 6 mice and mice lacking the H1 receptor ( P35367 REA ) or P25021 REA , using anti - P01730 REA + - and anti-CD 8 + - coupled magnetic beads , respectively . RESULTS : Depletion of the P35367 REA resulted in decreases in the release of P60568 REA and P22301 REA from both P01730 REA + and CD8 + cells and increases in the release of P05112 REA from P01730 REA + T cells and P01579 REA from CD8 + cells . Mice lacking the P25021 REA showed up-regulation of P01579 REA secretion from CD8 + cells and of P05112 REA from P01730 REA + and CD8 + T cells . Release of P60568 REA and P22301 REA from P01730 REA + as well as CD8 + cells was down-regulated in these mice . Both P01730 REA + and CD8 + T cell fractions synthesized histamine , which was enhanced in the P35367 REA - deficient CD8 + T cells . Treatment of the cells with alpha-fluoromethyl-histidine , a specific inhibitor of HDC , or histaminase increased P01579 REA from CD8 + cells , whereas it had no appreciable effect on P05112 REA secretion from P01730 REA + cells . CONCLUSION : These results suggest that cytokine production by P01730 REA + and CD8 + T lymphocytes is regulated by autosecretion of histamine .

Antiaging gene Q9UEF7 regulates endothelin - 1 levels and endothelin receptor subtype B expression in kidneys of spontaneously hypertensive rats . OBJECTIVE : Q9UEF7 is an antiaging gene and is predominately expressed in kidneys . The endothelin system is critical in the regulation of kidney function . The objective of this study is to assess whether klotho affects the renal endothelin system in spontaneously hypertensive rats ( SHRs ) . METHOD : Four groups of male SHRs and one group of male Wistar-Kyoto ( WKY ) rats were used . In-vivo expression of klotho was achieved by AAV 2 delivery of mouse klotho full-length cDNA ( AAV.mKL ) . Four groups of SHRs were given ( intravenously ) AAV.mKL , AAV.LacZ , AAV.GFP , and phosphate-buffered saline , respectively . The WKY group was given phosphate-buffered saline and served as a control . At the end of week 12 after gene delivery , all animals were euthanized . RESULTS : Plasma endothelin - 1 ( ET - 1 ) and renal ET - 1 levels were increased in SHRs vs . WKY rats . In-vivo expression of klotho reversed the elevated ET - 1 levels in SHRs . ETB receptor protein expression was decreased in both kidney cortex and medulla of SHRs . Interestingly , in-vivo expression of klotho abolished the downregulation of ETB protein expression in SHRs , suggesting that klotho regulates ETB receptor expression . Q9UEF7 gene delivery also eliminated the increase in the ratio of P25101 REA / ETB in SHRs . Mitochondrial superoxide dismutase ( Mn-SOD ) protein expression was decreased in kidneys of SHRs , which was rescued by in-vivo expression of klotho . CONCLUSION : Q9UEF7 gene delivery abolished the upregulation of ET - 1 levels and the downregulation of ETB and Mn-SOD expression in kidneys of SHRs . These findings revealed a previously unidentified role of klotho in the regulation of the renal ET system and Mn-SOD in SHRs .

Blockage of the neurokinin 1 receptor and capsaicin-induced ablation of the enteric afferent nerves protect SCID mice against T-cell-induced chronic colitis . BACKGROUND : The neurotransmitter DB05875 ( SP ) released by , and the transient receptor potential vanilloid ( Q8NER1 ) , expressed by afferent nerves , have been implicated in mucosal neuro-immune-regulation . To test if enteric afferent nerves are of importance for the development of chronic colitis , we examined antagonists for the high-affinity neurokinin 1 ( NK - 1 ) SP receptor and the Q8NER1 receptor agonist capsaicin in a T-cell transfer model for chronic colitis . METHODS : Chronic colitis was induced in SCID mice by injection of P01730 REA ( + ) CD25 ( - ) T cells . The importance of NK - 1 signaling and Q8NER1 expressing afferent nerves for disease development was studied in recipient SCID mice systemically treated with either high-affinity P25103 REA antagonists or neurotoxic doses of capsaicin . In addition , we studied the colitis-inducing effect of P25103 REA deleted P01730 REA ( + ) CD25 ( - ) T cells . RESULTS : Treatment with the P25103 REA antagonist P62158 4092 reduced the severity of colitis , but colitis was induced by P25103 REA - deleted T cells , suggesting that SP in colitis targets the recipient mouse cells and not the colitogenic donor T cells . DB06774 - induced depletion of nociceptive afferent nerves prior to P01730 REA ( + ) CD25 ( - ) T-cell transfer completely inhibited the development of colitis . CONCLUSIONS : Our data demonstrate the importance of an intact enteric afferent nerve system and NK - 1 signaling in mucosal inflammation and may suggest new treatment modalities for patients suffering from inflammatory bowel disease .

Endothelin @25 - new agonists , antagonists , inhibitors and emerging research frontiers : IUPHAR Review 12 . Since the discovery of endothelin ( ET ) - 1 in 1988 , the main components of the signalling pathway have become established , comprising three structurally similar endogenous 21 - amino acid peptides , ET - 1 , P20800 REA and P14138 REA , that activate two GPCRs , P25101 REA and ETB . Our aim in this review is to highlight the recent progress in ET research . The ET-like domain peptide , corresponding to prepro-ET -193-166 , has been proposed to be co-synthesized and released with ET - 1 , to modulate the actions of the peptide . ET - 1 remains the most potent vasoconstrictor in the human cardiovascular system with a particularly long-lasting action . To date , the major therapeutic strategy to block the unwanted actions of ET in disease , principally in pulmonary arterial hypertension , has been to use antagonists that are selective for the P25101 REA receptor ( ambrisentan ) or that block both receptor subtypes ( DB00559 ) . DB08932 MEN represents the next generation of antagonists , being more potent than DB00559 , with longer receptor occupancy and it is converted to an active metabolite ; properties contributing to greater pharmacodynamic and pharmacokinetic efficacy . A second strategy is now being more widely tested in clinical trials and uses combined inhibitors of ET-converting enzyme and neutral endopeptidase such as SLV 306 ( daglutril ) . A third strategy based on activating the ETB receptor , has led to the renaissance of the modified peptide agonist IRL 1620 as a clinical candidate in delivering anti-tumour drugs and as a pharmacological tool to investigate experimental pathophysiological conditions . Finally , we discuss biased signalling , epigenetic regulation and targeting with monoclonal antibodies as prospective new areas for ET research .

Elevated TGF-β 1 levels might protect HCV / HIV-coinfected patients from liver fibrosis . BACKGROUND : HIV accelerates hepatitis C virus ( HCV ) - induced liver fibrosis by mechanisms not well understood . As HIV dysregulates transforming growth factor-β 1 ( TGF-β 1 ) and T regulatory ( Treg ) cells , both of which are involved in hepatic fibrogenesis , herein we describe their influence on liver fibrosis staging in patients with chronic hepatitis C with and without HIV coinfection . METHODS : Eighty-eight subjects ( 42 HIV / HCV co-infected patients , 20 HCV-monoinfected patients , and 26 healthy controls ) were examined . Treg cells ( P01730 REA + Foxp 3 + ) were measured in peripheral blood using flow cytometry . An enzyme immunoassay was used to measure TGF-β 1 in plasma . Liver fibrosis staging was estimated using elastometry and advanced liver fibrosis was considered for ≥ 9 · 5 kPa ( P13726 REA - F4 Metavir estimates ) . RESULTS : Treg cells were increased in HIV / HCV-coinfected patients compared with HCV-monoinfected patients ( P = 0 · 004 ) , whereas TGF-β 1 levels were similar in both groups of patients . While Treg cells levels were similar in both null-mild and advanced liver fibrosis patients , a high level of TGF-β 1 was found in patients with low levels of liver fibrosis compared with those with advanced liver fibrosis [ 14 · 9 ng mL ( - 1 ) ( 5 · 6-37 · 9 ) vs . 5 · 5 ng mL ( - 1 ) ( 1 · 9-7 · 9 ) respectively P = 0 · 007 ] . In a multivariate logistic regression model , elevated TGF-β 1 levels were significantly associated with not having advanced liver fibrosis [ OR : 0 · 13 ( 95 % CI : 0 · 02-0 · 71 ) , P = 0 · 019 ] . CONCLUSIONS : While Treg cells do not influence liver fibrosis staging , elevated TGF-β 1 , probably through its anti-inflammatory effects , might protect HCV / HIV-coinfected patients from liver fibrosis .

Passive smoke effects on cough and airways in young guinea pigs : role of brainstem DB05875 . Children raised with extended exposure to environmental tobacco smoke ( ETS ) experience increased cough and wheeze . This study was designed to determine whether extended ETS exposure enhances citric acid-induced cough and bronchoconstriction in young guinea pigs via a neurokinin - 1 ( NK - 1 ) receptor mechanism at the first central synapse of lung afferent neurons , the nucleus tractus solitarius . Guinea pigs were exposed to ETS from 1 to 6 weeks of age . At 5 weeks of age , guide cannulae were implanted bilaterally in the medial nucleus tractus solitarius at a site that produced apnea in response to the glutamate agonist D , L-homocysteic acid . At 6 weeks of age , either vehicle or a P25103 REA antagonist , DB05790 MEN , was injected into the nucleus tractus solitarius of the conscious guinea pigs who were then exposed to citric acid aerosol . ETS exposure significantly enhanced citric acid-induced cough by 56 % and maximal Penh ( a measure of airway obstruction ) by 43 % , effects that were attenuated by the P25103 REA antagonist in the nucleus tractus solitarius . We conclude that in young guinea pigs extended exposure to ETS increases citric acid-induced cough and bronchoconstriction in part by an P25103 REA mechanism in the nucleus tractus solitarius .

Antihistamine effects on prefrontal cortex activity during working memory process in preschool children : a near-infrared spectroscopy ( NIRS ) study . P35367 REA antagonists ( antihistamines ) are widely used for the treatment of allergic disorders in young children . This study examined the effects of antihistamine on prefrontal cortex activity in preschool children using near-infrared spectroscopy ( NIRS ) , an emerging brain-imaging method suitable for psychological experiments , especially in young children . We examined the changes of oxygenated hemoglobin concentration in the prefrontal cortex while children performed a spatial working memory task , 3h after taking a first-generation antihistamine ( ketotifen ) , second-generation antihistamine ( epinastine ) , or placebo . Fifteen healthy preschool children ( mean age , 5.5 years ) participated . DB00920 MEN significantly impaired behavioral performance and cortical activation at the lateral prefrontal cortex in the working memory task , compared with epinastine and placebo . There were no sedative effects on neural response or behavioral performance after epinastine administration . This paper demonstrates for the first time differential sedation effects of first - and second-generation antihistamines on brain hemodynamic response in young children . Also discussed is the utility of the NIRS technique in neuropsychopharmacological studies of children .

Does computational biology help us to understand the molecular phylogenetics and evolution of cluster of differentiation ( CD ) proteins ? Cluster of differentiation ( CD ) is a group of proteins with highly immunological and medical importance , and some are established therapeutics . These membrane proteins are used to investigate of cell surface molecules of blood cells especially WBC . We selected a population of fifteen members with most medical importance , which includes P06729 REA , P01730 REA , P06127 , P30203 , P09564 , P21926 REA , P08571 REA , CD16 , P15391 REA , P20273 REA , P10747 REA , P20138 REA , P16671 REA , P28907 REA , and P16070 REA and performed in silico analysis using algorithm analysis and mathematical models . The results suggest that LEU ( L ) is well aligned . CD16 is rooted with P20273 REA and likewise , P01730 REA is closely related to P16070 REA . Notably , highest number of highly conserved amino acids is recorded in P20273 REA . WebLogo were formed up to 350 amino acid position and DB00134 ( M ) is found to be tallest logo . Our results would be useful for upcoming researchers to obtain fundamental idea about the particular regions CD proteins which is having the structural and functional significance related to the evolutionary biology .

Statin Modulation of Human T-Cell Proliferation , IL - 1β and Q16552 REA Production , and IFN-γ T Cell Expression : Synergy with Conventional Immunosuppressive Agents . P04035 REA inhibitors ( statins ) have been demonstrated to be immunomodulatory for human immune-mediated disease and in experimental models . The aim of this study was to compare statin-mediated immunosuppressive effects on human T-cell responses in vitro with those of conventional immunosuppressives ( dexamethasone , cyclosporin A ( DB00091 ) , mycophenolate , and rapamycin ) . Statins ( atorvastatin , lovastatin , and simvastatin ) were investigated for their modulatory effects on human PBMC viability , cytokine profiles , and T-cell proliferation . At concentrations that inhibited anti-CD 3/28- stimulated T-cell proliferation ( P < 0.01 ) , simvastatin significantly decreased intracellular P01730 REA ( + ) T-cell expression of IFN-γ ( P < 0.01 ) to levels similar to those induced by conventional immunosuppressives . DB01076 SUB and lovastatin also decreased IFN-γ expression , although to a lesser degree ( P < 0.05 ) . All three statins reduced levels of Q16552 REA production ( P < 0.01 ) . However , in response to anti-CD 3/28 stimulation , simvastatin significantly upregulated IL - 1β production ( P < 0.05 ) . The profile of cytokines produced in response to anti-CD 3/28 stimulation was similar when both atorvastatin and dexamethasone were added as compared with dexamethasone alone , suggesting that atorvastatin can synergise with dexamethasone with respect to immunomodulation of cytokines . This data supports the hypothesis of selective statin-mediated immunomodulatory effects on human immune cells .

P04035 REA inhibitors up-regulate anti-aging klotho mRNA via RhoA inactivation in IMCD 3 cells . OBJECTIVE : Q9UEF7 is thought to play a critical role in the development of age-related disorders including arteriosclerosis . Statins may exert vascular protective effects , independent of the lowering of plasma cholesterol levels . We investigated the impact of statins on mRNA expression of the age-suppressor gene , klotho in mIMCD 3 cells . METHODS AND RESULTS : Q9UEF7 mRNA levels were evaluated with real-time RT-PCR . DB01076 SUB and pitavastatin increased the expression of klotho mRNA in a dose-dependent manner . This stimulatory effect was abolished by the addition of mevalonate , GGPP and FPP , essential molecules for isoprenylation of the small GTPase Rho . As was the case with the statin treatment , inhibition of Rho-kinase by Y27632 up-regulated klotho mRNA . In contrast to the statin treatment , stimulation with angiotensin II down-regulated klotho mRNA expression without obvious morphological changes . Furthermore , pretreatment with atorvastatin blunted the angiotensin II-induced response and ameliorated the decrease in klotho mRNA expression towards basal levels . RhoA activity was further evaluated by detection of its translocation . Angiotensin II activated RhoA , whereas statins potently inactivated RhoA and blocked RhoA activation by angiotensin II . CONCLUSION : Statins inactivate the RhoA pathway , resulting in over-expression of klotho mRNA , which may contribute to the novel pleiotropic effects of statins towards vascular protection .

Human bronchial smooth muscle cells express adenylyl cyclase isoforms 2 , 4 , and 6 in distinct membrane microdomains . Adenylyl cyclases ( AC ) are important regulators of airway smooth muscle function , because β-adrenergic receptor ( AR ) agonists stimulate AC activity and increase airway diameter . We assessed expression of AC isoforms in human bronchial smooth muscle cells ( hBSMC ) . Reverse transcriptase-polymerase chain reaction and immunoblot analyses detected expression of AC2 , AC4 , and AC6 . DB02587 MEN - stimulated AC activity in membranes from hBSMC displayed Ca ( 2 + ) - inhibited and G ( βγ ) - stimulated AC activity , consistent with expression of AC6 , AC2 , and AC4 . DB01064 - stimulated AC activity was inhibited by Ca ( 2 + ) but unaltered by G ( βγ ) , whereas butaprost-stimulated AC activity was stimulated by G ( βγ ) but unaffected by Ca ( 2 + ) addition . Using sucrose density centrifugation to isolate lipid raft fractions , we found that only AC6 localized in lipid raft fractions , whereas AC2 and AC4 localized in nonraft fractions . Immunoisolation of caveolae using caveolin - 1 antibodies yielded Ca ( 2 + ) - inhibited AC activity ( consistent with AC6 expression ) , whereas the nonprecipitated material displayed G ( βγ ) - stimulated AC activity ( consistent with expression of AC2 and / or AC4 ) . Overexpression of AC6 enhanced DB02527 production in response to isoproterenol and beraprost but did not increase responses to prostaglandin E ( 2 ) or butaprost . β ( 2 ) AR , but not prostanoid EP ( 2 ) or EP ( 4 ) receptors , colocalized with O95622 REA / 6 in lipid raft fractions . Thus , particular G protein-coupled receptors couple to discreet AC isoforms based , in part , on their colocalization in membrane microdomains . These different DB02527 signaling compartments in airway smooth muscle cells are responsive to different hormones and neurotransmitters and can be regulated by different coincident signals such as Ca ( 2 + ) and G ( βγ ) .

Exome sequencing of three cases of familial exceptional longevity . Exceptional longevity ( EL ) is a rare phenotype that can cluster in families , and co-segregation of genetic variation in these families may point to candidate genes that could contribute to extended lifespan . In this study , for the first time , we have sequenced a total of seven exomes from exceptionally long-lived siblings ( probands ≥ 103 years and at least one sibling ≥ 97 years ) that come from three separate families . We have focused on rare functional variants ( RFVs ) which have ≤ 1 % minor allele frequency according to databases and that are likely to alter gene product function . Based on this , we have identified one candidate longevity gene carrying RFVs in all three families , P04114 REA . Interestingly , P04114 REA is a component of lipoprotein particles together with P02649 REA , and variants in the genes encoding these two proteins have been previously associated with human longevity . Analysis of nonfamilial EL cases showed a trend , without reaching statistical significance , toward enrichment of P04114 REA RFVs . We have also identified candidate longevity genes shared between two families ( 5-13 ) or within individual families ( 66-156 genes ) . Some of these genes have been previously linked to longevity in model organisms , such as Q9UBK2 , Q02297 REA , P43351 REA , Q06609 REA , O75376 REA , and O95622 REA genes . This work provides an initial catalog of genes that could contribute to exceptional familial longevity .

An acetylcholinesterase inhibitor , eserine , induces long-term depression at P07451 REA - P00915 REA synapses in the hippocampus of adult rats . Studies in humans and rodents support a role for muscarinic ACh receptor ( mAChR ) and nicotinic AChR in learning and memory , and both regulate hippocampal synaptic plasticity using complex and often times opposing mechanisms . P22303 REA ( P22303 REA ) inhibitors are commonly prescribed to enhance cholinergic signaling in Alzheimer ' s disease in hopes of rescuing cognitive function , caused , in part , by degeneration of cholinergic innervation to the hippocampus and cortex . Unfortunately , therapeutic efficacy is moderate and inconsistent , perhaps due to unanticipated mechanisms . M1 mAChRs bidirectionally control synaptic strength at P07451 REA - P00915 REA synapses ; weak pharmacological activation using carbachol ( CCh ) facilitates potentiation , whereas strong agonism induces muscarinic long-term depression ( mLTD ) via an P29323 REA - dependent mechanism . Here , we tested the prediction that accumulation of extracellular ACh via inhibition of P22303 REA is sufficient to induce LTD at P07451 REA - P00915 REA synapses in hippocampal slices from adult rats . Although P22303 REA inhibition with eserine induces LTD , it unexpectedly does not share properties with mLTD induced by CCh , as reported previously . DB00981 MEN - LTD was prevented by the M3 mAChR-preferring antagonist 1,1- dimethyl - 4 - diphenylacetoxypiperidinium iodide ( 4 - DAMP ) , and pharmacological inhibition of MEK was completely ineffective . Additionally , pharmacological inhibition of p38 MAPK prevents mLTD but has no effect on eserine-LTD . Finally , long-term expression of eserine-LTD is partially dependent on a decrease in presynaptic release probability , likely caused by tonic activation of mAChRs by the sustained increase in extracellular ACh . Thus these findings extend current literature by showing that pharmacological P22303 REA inhibition causes a prolonged decrease in presynaptic glutamate release at P07451 REA - P00915 REA synapses , in addition to inducing a likely postsynaptic form of LTD .

Q07869 REA gene variants influence progression of coronary atherosclerosis and risk of coronary artery disease . BACKGROUND : Q07869 REA ( PPARalpha ) regulates the expression of genes involved in lipid metabolism and inflammation , making it a candidate gene for atherosclerosis and ischemic heart disease ( IHD ) . METHODS AND RESULTS : We investigated the association between the leucine 162 to valine ( L162V ) polymorphism and a G to C transversion in intron 7 of the PPARalpha gene and progression of atherosclerosis in the DB01241 MENMAX DB01241 MEN Coronary Angiography Trial ( LOCAT ) , a trial examining the effect of gemfibrozil treatment on progression of atherosclerosis after bypass surgery and on risk of IHD in the second Northwick Park Heart Study ( Q9NP85 ) , a prospective study of healthy middle-aged men in the United Kingdom . There was no association with plasma lipid concentrations in either study . Both polymorphisms influenced progression of atherosclerosis and risk of IHD . V162 allele carriers had less progression of diffuse atherosclerosis than did L162 allele homozygotes with a similar trend for focal atherosclerosis . Intron 7 C allele carriers had greater progression of atherosclerosis than did G allele homozygotes . The V162 allele attenuated the proatherosclerotic effect of the intron 7 C allele . Homozygotes for the intron 7 C allele had increased risk of IHD , an effect modulated by the L162V polymorphism CONCLUSIONS : The PPARalpha gene affects progression of atherosclerosis and risk of IHD . Absence of association with plasma lipid concentrations suggests that PPARalpha affects atherosclerotic progression directly in the vessel wall .

Molecular basis of organ fibrosis : potential therapeutic approaches . Fibrosis , a non-physiological wound healing in multiple organs , is associated with end-stage pathological symptoms of a wide variety of vascular injury and inflammation related diseases . In response to chemical , immunological and physical insults , the body ' s defense system and matrix synthetic machinery respond to healing the wound and maintain tissue homeostasis . However , uncontrolled wound healing leads to scarring or fibrosis , a pathological condition characterized by excessive synthesis and accumulation of extracellular matrix proteins , loss of tissue homeostasis and organ failure . Understanding the actual cause of pathological wound healing and identification of igniter ( s ) of fibrogenesis would be helpful to design novel therapeutic approaches to control pathological wound healing and to prevent fibrosis related morbidity and mortality . In this article , we review the significance of a few key cytokines ( TGF-β , IFN-γ , P22301 REA ) transcriptional activators ( Sp1 , Egr - 1 , P8 4022 ) , repressors ( O15105 REA , Fli - 1 , Q07869 REA - γ , p53 , Q9UEF7 ) and epigenetic modulators ( acetyltransferase , methyltransferases , deacetylases , microRNAs ) involved in major matrix protein collagen synthesis under pathological stage of wound healing , and the potentiality of these regulators as therapeutic targets for fibrosis treatment . The significance of endothelial to mesenchymal transition ( EndMT ) and senescence , two newly emerged fields in fibrosis research , has also been discussed .

DB01076 SUB stimulates the production of osteoprotegerin by human osteoblasts . Recently , P04035 REA inhibitors ( statins ) , potent inhibitors of cholesterol biosynthesis , have been linked to protective effects on bone metabolism . Because of their widespread use , prevention of bone loss and fractures would be a desirable side effect . However , the mechanisms how statins may affect bone metabolism are poorly defined . Here , we evaluated the effect of atorvastatin on osteoblastic production of receptor activator of nuclear factor-kappaB ligand ( O14788 REA ) and osteoprotegerin ( O00300 REA ) , cytokines that are essential for osteoclast cell biology . While O14788 REA enhances osteoclast formation and activation , thereby , promoting bone loss , O00300 REA acts as a soluble decoy receptor and antagonizes the effects of O14788 REA . In primary human osteoblasts ( hOB ) , atorvastatin increased O00300 REA mRNA levels and protein secretion by hOB by up to three fold in a dose-dependent manner with a maximum effect at 10 ( - 6 ) M ( P < 0.001 ) . Time course experiments indicated a time-dependent stimulatory effect of atorvastatin on O00300 REA mRNA levels after 24 h and on O00300 REA protein secretion after 48-72 h ( P < 0.001 ) . Treatment of hOB with substrates of cholesterol biosynthesis that are downstream of the P04035 REA reaction ( mevalonate , geranylgeranyl pyrophosphate ) reversed atorvastatin-induced enhancement of O00300 REA production . Of note , atorvastatin abrogated the inhibitory effect of glucocorticoids on O00300 REA production . Treatment of hOB with atorvastatin enhanced the expression of osteoblastic differentiation markers , alkaline phosphatase and osteocalcin . In summary , our data suggest that atorvastatin enhances osteoblastic differentiation and production of O00300 REA . This may contribute to the bone-sparing effects of statins .

DB00480 MEN inhibits osteoclastogenesis , survival factors and bone-remodeling markers in multiple myeloma . Osteolytic bone disease in multiple myeloma ( MM ) is caused by enhanced osteoclast ( OCL ) activation and inhibition of osteoblast function . DB00480 MEN and bortezomib have shown promising response rates in relapsed and newly diagnosed MM , and bortezomib has recently been reported to inhibit OCLs . We here investigated the effect of lenalidomide on OCL formation and osteoclastogenesis in comparison with bortezomib . Both drugs decreased alpha V beta 3 - integrin , tartrate-resistant acid phosphatase-positive cells and bone resorption on dentin disks . In addition , both agents decreased receptor activator of nuclear factor-kappaB ligand ( O14788 REA ) secretion of bone marrow stromal cells ( BMSCs ) derived from MM patients . We identified PU . 1 and pERK as major targets of lenalidomide , and nuclear factor of activated T cells of bortezomib , resulting in inhibition of osteoclastogenesis . Furthermore , downregulation of cathepsin K , essential for resorption of the bone collagen matrix , was observed . We demonstrated a significant decrease of growth and survival factors including macrophage inflammatory protein-alpha , B-cell activating factor and a proliferation-inducing ligand . Importantly , in serum from MM patients treated with lenalidomide , the essential bone-remodeling factor O14788 REA , as well as the O14788 REA / O00300 REA ratio , were significantly reduced , whereas osteoprotegerin ( O00300 REA ) was increased . We conclude that both agents specifically target key factors in osteoclastogenesis , and could directly affect the MM-OCL-BMSCs activation loop in osteolytic bone disease .

Monoclonal antibodies in acute lymphoblastic leukemia . With modern intensive combination polychemotherapy , the complete response ( CR ) rate in adults with acute lymphoblastic leukemia ( ALL ) is 80 % to 90 % , and the cure rate is 40 % to 50 % . Hence , there is a need to develop effective salvage therapies and combine novel agents with standard effective chemotherapy . ALL leukemic cells express several surface antigens amenable to target therapies , including P11836 , P20273 REA , and P15391 REA . Monoclonal antibodies target these leukemic surface antigens selectively and minimize off-target toxicity . When added to frontline chemotherapy , rituximab , an antibody directed against P11836 , increases cure rates of adults with Burkitt leukemia from 40 % to 80 % and those with pre-B ALL from 35 % to 50 % . Inotuzumab ozogamicin , a P20273 REA monoclonal antibody bound to calicheamicin , has resulted in marrow CR rates of 55 % and a median survival of 6 to 7 months when given to patients with refractory-relapsed ALL . DB09052 MEN , a biallelic T cell engaging the CD3 - P15391 REA monoclonal antibody , also resulted in overall response rates of 40 % to 50 % and a median survival of 6.5 months in a similar refractory-relapsed population . Other promising monoclonal antibodies targeting P11836 ( ofatumumab and obinutuzumab ) or P15391 REA or P11836 and bound to different cytotoxins or immunotoxins are under development . Combined modalities of chemotherapy and the novel monoclonal antibodies are under investigation .

Prolonged inhibition of cholesterol synthesis by atorvastatin inhibits apo B - 100 and triglyceride secretion from HepG 2 cells . DB01076 SUB is a new P04035 REA inhibitor that strongly lowers plasma cholesterol and triglyceride ( TG ) levels in humans and animals . Since previous data indicated that atorvastatin has prolonged inhibition of hepatic cholesterol synthesis , we tested whether this longer duration of inhibitory effect on cholesterol synthesis decreased hepatic lipoprotein secretion in vitro . We used the HepG 2 hepatoma cell line to : ( 1 ) determine the time required until levels of secreted apo B - 100 and TG declined significantly , ( 2 ) examine the relation to the mass of cellular cholesteryl ester ( CE ) and ( 3 ) test microsomal triglyceride transfer protein ( P55157 REA ) activity which leads to decreased apo B - 100 production . Although atorvastatin significantly inhibited cholesterol synthesis in HepG 2 cells regardless of treatment duration ( 1 , 14 or 24 h ) , it did not inhibit TG synthesis . P04114 REA and TG secretion were unchanged after 1 - h atorvastatin treatment , but declined significantly after 24 - h treatment . DB01076 SUB treatment also reduced cellular CE mass , exhibiting both time - and dose-dependency . Mevalonolactone , a product of P04035 REA , attenuated the inhibitory effects of atorvastatin . DB01076 SUB strongly reduced mRNA levels of P55157 REA , whereas it did not inhibit P55157 REA activity as measured by TG transfer assay between liposomes . Simvastatin also induced treatment - and time-dependent reductions in apo B - 100 , whereas the P55157 REA inhibitor BMS - 201038 exhibited no time dependency , instead inhibiting this variable even on 1 - h treatment . These results indicate that reduced apo B - 100 secretion caused by atorvastatin is a secondary result owing to decreased lipid availability , and that atorvastatin ' s efficacy depends on the duration of cholesterol synthesis inhibition in the liver .

DB01076 SUB attenuates bleomycin-induced pulmonary fibrosis via suppressing P35228 REA expression and the P29279 REA ( P29279 REA ) / P29323 REA signaling pathway . Pulmonary fibrosis is a progressive and fatal lung disorder with high mortality rate . To date , despite the fact that extensive research trials are ongoing , pulmonary fibrosis continues to have a poor response to available medical therapy . Statins , P04035 REA inhibitors , known for its broad pharmacological activities , remains a remedy against multiple diseases . The present study investigated the antifibrotic potential of atorvastatin against bleomycin-induced lung fibrosis and to further explore the possible underlying mechanisms . Our results showed that atorvastatin administration significantly ameliorated the bleomycin mediated histological alterations and blocked collagen deposition with parallel reduction in the hydroxyproline level . DB01076 SUB reduced malondialdehyde ( MDA ) level and lung indices . DB01076 SUB also markedly decreased the expression of inducible nitric oxide synthase ( P35228 REA ) in lung tissues and , thus , prevented nitric oxide ( NO ) release in response to bleomycin challenge . Furthermore , atorvastatin exhibited target down-regulation of connective tissue growth factor ( P29279 REA ( P29279 REA ) ) and phosphorylation extracellular regulated protein kinases ( p - P29323 REA ) expression . Taken together , atorvastatin significantly ameliorated bleomycin-induced pulmonary fibrosis in rats , via the inhibition of P35228 REA expression and the P29279 REA ( P29279 REA ) / P29323 REA signaling pathway . The present study provides evidence that atorvastatin may be a potential therapeutic reagent for the treatment of lung fibrosis .