interacts_with DB00266?
Protein-repairing methionine sulfoxide reductases in photosynthetic organisms : gene organization , reduction mechanisms , and physiological roles . DB00134 oxidation to methionine sulfoxide ( MetSO ) is reversed by two types of methionine sulfoxide reductases ( MSRs ) , A and B , specific to the S- and R-diastereomers of MetSO , respectively . Q9UBK8 genes are found in most organisms from bacteria to human . In the current review , we first compare the organization of the Q9UBK8 gene families in photosynthetic organisms from cyanobacteria to higher plants . The analysis reveals that MSRs constitute complex families in higher plants , bryophytes , and algae compared to cyanobacteria and all non-photosynthetic organisms . We also perform a classification , based on gene number and structure , position of redox-active cysteines and predicted sub-cellular localization . The various catalytic mechanisms and potential physiological electron donors involved in the regeneration of Q9UBK8 activity are then described . Data available from higher plants reveal that MSRs fulfill an essential physiological function during environmental constraints through a role in protein repair and in protection against oxidative damage . Taking into consideration the expression patterns of Q9UBK8 genes in plants and the known roles of these genes in non-photosynthetic cells , other functions of MSRs are discussed during specific developmental stages and ageing in photosynthetic organisms . A transgenic platform for testing drugs intended for reversal of cardiac remodeling identifies a novel 11βHSD1 inhibitor rescuing hypertrophy independently of re-vascularization . RATIONALE : Rescuing adverse myocardial remodeling is an unmet clinical goal and , correspondingly , pharmacological means for its intended reversal are urgently needed . OBJECTIVES : To harness a newly-developed experimental model recapitulating progressive heart failure development for the discovery of new drugs capable of reversing adverse remodeling . METHODS AND RESULTS : A P15692 -based conditional transgenic system was employed in which an induced perfusion deficit and a resultant compromised cardiac function lead to progressive remodeling and eventually heart failure . Ability of candidate drugs administered at sequential remodeling stages to reverse hypertrophy , enlarged LV size and improve cardiac function was monitored . Arguing for clinical relevance of the experimental system , clinically-used drugs operating on the P00797 -Angiotensin- DB04630 -System ( RAAS ) , namely , the P12821 inhibitor Enalapril and the direct renin inhibitor Aliskerin fully reversed remodeling . Remodeling reversal by these drugs was not accompanied by neovascularization and reached a point-of-no-return . Similarly , the PPARγ agonist Pioglitazone was proven capable of reversing all aspects of cardiac remodeling without affecting the vasculature . Extending the arsenal of remodeling-reversing drugs to pathways other than RAAS , a specific inhibitor of 11β-hydroxy-steroid dehydrogenase type 1 ( 11β HSD1 ) , a key enzyme required for generating active glucocorticoids , fully rescued myocardial hypertrophy . This was associated with mitigating the hypertrophy-associated gene signature , including reversing the myosin heavy chain isoform switch but in a pattern distinguishable from that associated with neovascularization-induced reversal . CONCLUSIONS : A system was developed suitable for identifying novel remodeling-reversing drugs operating in different pathways and for gaining insights into their mechanisms of action , exemplified here by uncoupling their vascular affects . DB09078 : first global approval . DB09078 ( Lenvima™ ) is a multitargeted receptor kinase inhibitor that inhibits the kinase activities of vascular endothelial-derived growth factor receptors 1 , 2 and 3 , fibroblast growth factor receptors 1 , 2 , 3 and 4 , platelet-derived growth factor receptor α , P07949 and P10721 . In addition to their role in normal cellular function , these kinases have been implicated in pathogenic angiogenesis , tumour growth and cancer progression . DB09078 is being developed by Eisai Co . Ltd for the treatment of solid tumours , primarily for differentiated thyroid cancer , and other malignancies . A capsule formulation of the drug has received approval in the USA for use in locally recurrent or metastatic , progressive , radioactive iodine-refractory differentiated thyroid cancer . DB09078 is in pre-registration for this indication in the EU , Australia , Brazil , Canada , Japan , South Korea , Russia , Singapore and Switzerland , and is in phase 3 development in Argentina , Chile and Thailand . DB09078 has orphan designation in the EU and Japan for use in differentiated thyroid cancer . In addition , an ongoing global , phase 3 trial is evaluating the use of lenvatinib as first-line treatment in unresectable hepatocellular carcinoma . This article summarizes the milestones in the development of lenvatinib leading to this first approval in locally recurrent or metastatic , progressive , radioactive iodine-refractory differentiated thyroid cancer . Pivotal role of the P06681 domain of the Smurf1 ubiquitin ligase in substrate selection . The P06681 -WW-HECT-type ubiquitin ligases Smurf1 and Smurf2 play a critical role in embryogenesis and adult bone homeostasis via regulation of bone morphogenetic protein , Wnt , and RhoA signaling pathways . The intramolecular interaction between P06681 and HECT domains autoinhibits the ligase activity of Smurf2 . However , the role of the Smurf1 P06681 domain remains elusive . Here , we show that the P06681 -HECT autoinhibition mechanism is not observed in Smurf1 , and instead its P06681 domain functions in substrate selection . The Smurf1 P06681 domain exerts a key role in localization to the plasma membrane and endows Smurf1 with differential activity toward RhoA versus Q99717 and Runx2 . Crystal structure analysis reveals that the Smurf1 P06681 domain possesses a typical anti-parallel β-sandwich fold . Examination of the sulfate-binding site analysis reveals two key lysine residues , Lys-28 and Lys-85 , within the P06681 domain that are important for Smurf1 localization at the plasma membrane , regulation on cell migration , and robust ligase activity toward RhoA , which further supports a Ca(2+)-independent localization mechanism for Smurf1 . These findings demonstrate a previously unidentified role of the Smurf1 P06681 domain in substrate selection and cellular localization . P37268 inhibitors suppress triglyceride biosynthesis through the farnesol pathway in rat hepatocytes . We recently demonstrated that squalene synthase ( P37268 ) inhibitors reduce plasma triglyceride through an P01130 -independent mechanism in Watanabe heritable hyperlipidemic rabbits ( Hiyoshi et al. 2001. Eur. J. Pharmacol. 431 : 345-352 ) . The present study deals with the mechanism of the inhibition of triglyceride biosynthesis by the P37268 inhibitors ER-27856 and RPR-107393 in rat primary cultured hepatocytes . DB01076 , an P04035 inhibitor , had no effect on triglyceride biosynthesis , but reversed the inhibitory effect of the P37268 inhibitors . A squalene epoxidase inhibitor , NB-598 , affected neither triglyceride biosynthesis nor its inhibition by ER-27856 and RPR-107393 . The reduction of triglyceride biosynthesis by ER-27856 and RPR-107393 was potentiated by mevalonolactone supplementation . Treatment of hepatocytes with farnesol and its derivatives reduced triglyceride biosynthesis . In addition , we found that ER-27856 and RPR-107393 significantly reduced the incorporation of [1-(14)C]acetic acid into oleic acid , but not the incorporation of [1-(14)C]oleic acid into triglyceride . Though ER-27856 and RPR-107393 increased mitochondrial fatty acid beta-oxidation , the inhibition of beta-oxidation by RS-etomoxir had little effect on their inhibition of triglyceride biosynthesis . These results suggest that P37268 inhibitors reduce triglyceride biosynthesis by suppressing fatty acid biosynthesis via an increase in intracellular farnesol and its derivatives . Identification of microRNAs involved in the modulation of pro-angiogenic factors in atherosclerosis by a polyphenol-rich extract from propolis . New vessel formation plays a critical role in the progression and vulnerability of atherosclerotic lesions . It has been shown that polyphenols from propolis attenuate the progression of atherosclerosis and also exert inhibitory effects on angiogenic factors . However , the mechanisms underlying these effects are not completely understood . Thus , this study aimed to identify microRNAs ( miRNAs ) involved in the modulation of pro-angiogenic factors in the atherosclerotic plaques of P01130 gene knockout mice treated with a polyphenol-rich extract of Chilean propolis . The progression of the atherosclerotic lesions was significantly attenuated in treated mice compared with control mice . Using microarray analysis and a bioinformatic approach , we identified 29 differentially expressed miRNAs . Many of these miRNAs were involved in biological processes associated with angiogenesis , such as the cell cycle , cell migration , cell growth and proliferation . Among them , three miRNAs ( miR-181a , miR-106a and miR-20b ) were over-expressed and inversely related to the expression of Vegfa ( vascular endothelial growth factor A ) and Hif1a ( hypoxia inducible factor 1 alpha ) . In addition , P15692 protein expression was attenuated in histological sections obtained from the aortic sinuses of treated mice . P15692 is a key pro-angiogenic factor in atherosclerotic plaques , and Hif1a , which is expressed in the necrotic nucleus of the atheroma , is its main inducer . We found a correlation between the over-expression of miR-181a , miR-106a and miR-20b and their target genes , Hif1a and Vegfa , which is consistent with attenuation of the atherosclerotic lesion . In conclusion , our data analysis provides evidence that the anti-angiogenic effects of polyphenols from Chilean propolis can be modulated by miRNAs , in particular miR-181a , miR-106a and miR-20b . Treatment of cardiovascular dysfunction associated with the metabolic syndrome and type 2 diabetes . Our previous studies have shown vascular dysfunction in small coronary and mesenteric arteries in Zucker obese rats , a model of the metabolic syndrome , and Zucker Diabetic Fatty ( ZDF ) rats , a model of type 2 diabetes . Because of their lipid lowering action and antioxidant activity , we predicted that treatment with DB01098 , an P04035 inhibitor ( statin ) or Enalapril , an angiotensin converting enzyme ( P12821 ) inhibitor would improve vascular dysfunction associated with the metabolic syndrome and type 2 diabetes . METHODS : 20-week-old Zucker obese and 16-week-old ZDF rats were treated with DB01098 ( 25 mg/kg/day ) or Enalapril ( 20 mg/kg/day ) for 12 weeks . We examined metabolic parameters , indices of oxidative stress and vascular dysfunction in ventricular and mesenteric small arteries ( 75-175 microm intraluminal diameter ) from lean , Zucker obese and ZDF rats ( untreated and treated ) . RESULTS : Endothelial dependent responses were attenuated in coronary vessels from Zucker obese and ZDF rats compared to responses from lean rats . Both drugs improved metabolic parameters , oxidative stress , and vascular dysfunction in Zucker obese rats , however , only partial improvement was observed in ZDF rats , suggesting more aggressive treatment is needed when hyperglycemia is involved . CONCLUSION : Vascular dysfunction is improved when Zucker obese and , to a lesser degree , when ZDF rats were treated with DB01098 or Enalapril . Efficacy and safety of repeated dosing of netupitant , a neurokinin-1 receptor antagonist , in treating overactive bladder . AIM : NK-1 receptors in sensory nerves , the spinal cord and bladder smooth muscle participate in complex sensory mechanisms that regulate bladder activity . This study was designed to assess the efficacy and safety of a new P25103 antagonist , netupitant , in patients with OAB . METHODS : This was a phase II , multicenter , double-blind study in which adults with OAB symptoms > 6 months were randomized to receive 1 of 3 doses of netupitant ( 50 , 100 , 200 mg ) or placebo once daily for 8 weeks . The primary efficacy endpoint was percentage change from baseline in average number of daily micturitions at week 8 . Urinary incontinence , urge urinary incontinence ( UUI ) , and urgency episodes were also assessed . RESULTS : The primary efficacy endpoint was similar in the treatment groups ( -13.85 for placebo to -16.17 in the netupitant 200 mg group ) with no statistically significant differences between netupitant and placebo . The same was true for most secondary endpoints although a significant difference for improvement in UUI episodes and a trend for the greatest decrease in urgency episodes were seen in the netupitant 100 mg group . DB09048 was well tolerated with most treatment emergent adverse events ( AEs ) being mild . While the overall incidence of AEs increased with netupitant dose , there was no evidence for this dose dependency based on relationship to treatment , intensity , or time to onset . CONCLUSIONS : The study failed to demonstrate superiority of netupitant versus placebo in decreasing OAB symptoms , despite a trend favoring netupitant 100 mg . There were no safety concerns with daily administration of netupitant over 8 weeks . Gene expression studies provide clues to the pathogenesis of uterine leiomyoma : new evidence and a systematic review . BACKGROUND : Uterine leiomyomas are extremely common and a major cause of pelvic pain , bleeding , infertility , and the leading indication for hysterectomy . Familial and epidemiological studies provide compelling evidence that genetic alterations play an important role in leiomyoma development . METHODS : Using Affymetrix U133A GeneChip we analysed expression profiles of 22,283 genes in paired samples of leiomyoma and adjacent normal myometrium . We compared our results with previously published data on gene expression in uterine leiomyoma and identified the overlapping gene alterations . RESULTS : We detected 80 genes with average differences of > or = 2-fold and false discovery rates of < 5 % ( 14 overexpressed and 66 underexpressed ) . A comparative analysis including eight previous gene expression studies revealed eight prominent genes ( P07327 , P18847 , P29373 , O00622 , Q07507 , P42262 , P01344 , Q5EB52 ) identified by at least five different studies , eleven genes ( P00352 , P25063 , P29279 , O43602 , P28562 , P01100 , O60829 , P24592 , P41222 , P43115 , P04818 ) reported by four studies , twelve genes ( ABCA , P04083 , Q15847 , O00585 , P38936 , Q14194 , P54849 , P03372 , FY , Q99683 , P37173 , P35625 ) identified by three studies , and 40 genes reported by two different studies . CONCLUSIONS : Review of gene expression data revealed concordant changes in genes regulating retinoid synthesis , IGF metabolism , TGF-beta signaling and extracellular matrix formation . Gene expression studies provide clues to the relevant pathways of leiomyoma development . DB05294 improves anti-tumor effects of L19mTNFalpha in xenograft models of esophageal cancer . PURPOSE : Targeting the tumor vasculature by vascular disrupting agents ( VDAs ) has shown therapeutic activity in mouse models . In most cases , however , VDA efficacy is substantially compromised by the inability of these drugs to completely kill tumor cells located at the periphery of the tumor mass . In this study , we investigated anti-tumor effects of L19mTNFα , a fusion protein composed of Q9Y2K2 ( scFv ) , specific for the angiogenesis-associated ED-B containing fibronectin isoform , and murine TNFα , in xenograft models of esophageal cancer . EXPERIMENTAL DESIGN : We evaluated ED-B expression in esophageal cancer samples . Subsequently , we generated subcutaneous xenografts from primary tumors , treated them with the L19mTNFα scFv , and determined effects on tumor vasculature , viability and proliferation , and P15692 expression and infiltration by hematopoietic cells . To overcome tumor resistance , L19mTNFα scFv was combined with vandetanib , a tyrosine kinase inhibitor of P15692 receptor , epidermal growth factor receptor , and P07949 signaling . RESULTS : ED-B was broadly expressed by esophageal cancer cell lines , as well as xenografts and primary surgical samples of esophageal cancer . Administration of L19mTNFα acutely damaged tumor vasculature and increased necrosis , indicating a VDA-like activity of this immunoconjugate . This event was followed , however , by rapid tumor growth recovery associated with increased expression of P15692 and recruitment of CD11b+Gr1+ myeloid cells into tumors . Combination of L19mTNFα with vandetanib severely impaired vascular functions in tumors , leading to a reduction of cell proliferation and increased necrosis , without apparent signs of toxicity . CONCLUSION : These findings indicate that a combination of vascular damaging agents with anti-angiogenic drugs could represent a promising therapeutic strategy for esophageal cancer . Integrin αvβ3 and P16070 pathways in metastatic prostate cancer cells support osteoclastogenesis via a Runx2/Smad 5/receptor activator of NF-κB ligand signaling axis . BACKGROUND : Bone loss and pathological fractures are common skeletal complications associated with androgen deprivation therapy and bone metastases in prostate cancer patients . We have previously demonstrated that prostate cancer cells secrete receptor activator of NF-kB ligand ( O14788 ) , a protein essential for osteoclast differentiation and activation . However , the mechanism(s) by which O14788 is produced remains to be determined . The objective of this study is to gain insight into the molecular mechanisms controlling O14788 expression in metastatic prostate cancer cells . RESULTS : We show here that phosphorylation of Smad 5 by integrin αvβ3 and Q13950 by P16070 signaling , respectively , regulates O14788 expression in human-derived PC3 prostate cancer cells isolated from bone metastasis . We found that Q13950 intranuclear targeting is mediated by phosphorylation of Smad 5 . Indeed , Q99717 knock-down via RNA interference and inhibition of Smad 5 phosphorylation by an αv inhibitor reduced Q13950 nuclear localization and O14788 expression . Similarly , knockdown of P16070 or Q13950 attenuated the expression of O14788 . As a result , conditioned media from these cells failed to support osteoclast differentiation in vitro . Immunohistochemistry analysis of tissue microarray sections containing primary prostatic tumor ( grade2-4 ) detected predominant localization of Q13950 and phosphorylated Smad 5 in the nuclei . Immunoblotting analyses of nuclear lysates from prostate tumor tissue corroborate these observations . CONCLUSIONS : Collectively , we show that P16070 signaling regulates phosphorylation of Q13950 . Localization of Q13950 in the nucleus requires phosphorylation of Smad-5 by integrin αvβ3 signaling . Our results suggest possible integration of two different pathways in the expression of O14788 . These observations imply a novel mechanistic insight into the role of these proteins in bone loss associated with bone metastases in patients with prostate cancer . DB09210 defines a new binding site for allosteric modulators of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid ( AMPA ) receptors . Glutamate receptors are the most prevalent excitatory neurotransmitter receptors in the vertebrate central nervous system and are important potential drug targets for cognitive enhancement and the treatment of schizophrenia . Allosteric modulators of AMPA receptors promote dimerization by binding to a dimer interface and reducing desensitization and deactivation . The pyrrolidine allosteric modulators , piracetam and aniracetam , were among the first of this class of drugs to be discovered . We have determined the structure of the ligand binding domain of the AMPA receptor subtypes P42262 and P42263 with piracetam and a corresponding structure of P42263 with aniracetam . Both drugs bind to P42262 and P42263 in a very similar manner , suggesting little subunit specificity . However , the binding sites for piracetam and aniracetam differ considerably . DB04599 binds to a symmetrical site at the center of the dimer interface . DB09210 binds to multiple sites along the dimer interface with low occupation , one of which is a unique binding site for potential allosteric modulators . This new site may be of importance in the design of new allosteric regulators . O95760 augments DB05875 -induced P15692 secretion from human mast cells and is increased in psoriatic skin . The peptide DB05875 ( SP ) has been implicated in inflammatory conditions , such as psoriasis , where mast cells and P15692 are increased . A relationship between SP and P15692 has not been well studied , nor has any interaction with the proinflammatory cytokines , especially O95760 . Here we report that SP ( 0.1-10 microM ) induces gene expression and secretion of P15692 from human LAD2 mast cells and human umbilical core blood-derived cultured mast cells ( hCBMCs ) . This effect is significantly increased by coadministration of O95760 ( 5-100 ng/mL ) in both cell types . The effect of SP on P15692 release is inhibited by treatment with the P25103 antagonist 733,060 . SP rapidly increases cytosolic calcium , and so does O95760 to a smaller extent ; the addition of O95760 augments the calcium increase . SP-induced P15692 production involves calcium-dependent PKC isoforms , as well as the P29323 and JNK MAPKs . Gene expression of O95760 and histidine decarboxylase ( HDC ) , an indicator of mast cell presence/activation , is significantly increased in affected and unaffected ( at least 15 cm away from the lesion ) psoriatic skin , as compared with normal control skin . Immunohistochemistry indicates that O95760 is associated with endothelial cells in both the unaffected and affected sites , but is stronger and also associated with immune cells in the affected site . These results imply that functional interactions among SP , O95760 , and mast cells leading to P15692 release contribute to inflammatory conditions , such as the psoriasis , a nonallergic hyperproliferative skin inflammatory disorder with a neurogenic component . DB00898 dose-dependently elicits opposing regulatory effects on hippocampal AMPA receptor P42262 subunits through a zeta inhibitory peptide-sensitive kinase in adolescent and adult Sprague-Dawley rats . AMPA receptor P42262 subunits are strongly implicated in cognition , and prior work suggests that these subunits may be regulated by atypical protein kinase C ( aPKC ) isoforms . The present study assessed whether hippocampal and cortical AMPA receptor P42262 subunit regulation may be an underlying factor in known age-related differences to cognitive-impairing doses of ethanol , and if aPKC isoforms modulate such responses . Hippocampal AMPA receptor P42262 subunit , protein kinase Mζ ( PKMζ ) , and PKCι/λ expression were elevated during adolescence compared to adults . 1 h following a low-dose ( 1.0-g/kg ) ethanol exposure , hippocampal AMPA receptor P42262 subunit serine 880 phosphorylation was decreased in adolescents , but was increased in adults . Age-dependent changes in P42262 subunit phosphorylation were paralleled by alterations in aPKC isoforms , and zeta inhibitory peptide ( Q8N5A5 ) administration prevented ethanol-induced increases in both in adults . DB00898 -induced changes in P42262 subunit phosphorylation were associated with delayed regulation in synaptosomal P42262 subunit expression 24 h later . A higher ethanol dose ( 3.5-g/kg ) failed to elicit changes in most measures in the hippocampus at either age . Similar to the hippocampus , analysis of cerebral cortical tissue also revealed age-related declines . However , no demonstrable effects were found following a low-dose ethanol exposure at either age . High-dose ethanol exposure reduced adolescent P42262 subunit phosphorylation and aPKC isoform expression that were again accompanied by delayed reductions in synaptosomal P42262 subunit expression . Together , these results suggest that P42262 -containing AMPA receptor modulation by aPKC isoforms is age- , region- and dose-dependently regulated , and may potentially be involved in developmentally regulated ethanol-induced cognitive impairment and other ethanol behaviors . P10997 -driven metabolic reprogramming induces regression of p53-deficient tumours in vivo . P04637 is commonly altered in human cancer , and Tp53 reactivation suppresses tumours in vivo in mice ( P04637 and Tp53 are also known as p53 ) . This strategy has proven difficult to implement therapeutically , and here we examine an alternative strategy by manipulating the p53 family members , Tp63 and Tp73 ( also known as p63 and p73 , respectively ) . The acidic transactivation-domain-bearing ( TA ) isoforms of p63 and p73 structurally and functionally resemble p53 , whereas the ΔN isoforms ( lacking the acidic transactivation domain ) of p63 and p73 are frequently overexpressed in cancer and act primarily in a dominant-negative fashion against p53 , TAp63 and TAp73 to inhibit their tumour-suppressive functions . The p53 family interacts extensively in cellular processes that promote tumour suppression , such as apoptosis and autophagy , thus a clear understanding of this interplay in cancer is needed to treat tumours with alterations in the p53 pathway . Here we show that deletion of the ΔN isoforms of p63 or p73 leads to metabolic reprogramming and regression of p53-deficient tumours through upregulation of P10997 , the gene that encodes amylin , a 37-amino-acid peptide co-secreted with insulin by the β cells of the pancreas . We found that P10997 is causally involved in this tumour regression and that amylin functions through the calcitonin receptor ( CalcR ) and receptor activity modifying protein 3 ( O60896 ) to inhibit glycolysis and induce reactive oxygen species and apoptosis . DB01278 , a synthetic analogue of amylin that is currently used to treat type 1 and type 2 diabetes , caused rapid tumour regression in p53-deficient thymic lymphomas , representing a novel strategy to target p53-deficient cancers . Crystallization and preliminary X-ray studies of ferric uptake regulator from Magnetospirillum gryphiswaldense . Magnetosomes in magnetotactic bacteria have been widely used in studies of magnetic domains and in commercial applications . The iron content of magnetotactic bacteria is ∼100 times higher than that of Escherichia coli . Magnetospirillum gryphiswaldense Q9UBK8 -1 can still take up iron even at high intracellular concentrations . Ferric uptake regulator ( Fur ) is a global iron-responsive regulator that affects magnetosome formation , iron transport and oxygen metabolism . However , the mechanism of iron uptake and homeostasis by M. gryphiswaldense Q9UBK8 -1 Fur is not clear . Here , the expression , purification and crystallization of apo and SeMet Fur from M. gryphiswaldense Q9UBK8 -1 are reported . The crystals belonged to space group P06681 . Matthews coefficient analysis and size-exclusion chromatography showed that the asymmetric unit probably contains one dimer of Fur . Diffraction data were optimized to 1.58 Å resolution for apo Fur and to 1.9 Å resolution for SeMet Fur . DB11582 suppresses osteoclastogenesis induced by O14788 and cancer cells through inhibition of inflammatory pathways : a new use for an old drug . BACKGROUND AND PURPOSE : Most patients with cancer die not because of the tumour in the primary site , but because it has spread to other sites . Common tumours , such as breast , multiple myeloma , and prostate tumours , frequently metastasize to the bone . To search for an inhibitor of cancer-induced bone loss , we investigated the effect of thiocolchicoside , a semi-synthetic colchicoside derived from the plant Gloriosa superba and clinically used as a muscle relaxant , on osteoclastogenesis induced by receptor activator of NF-κB ligand ( O14788 ) and tumour cells . EXPERIMENTAL APPROACH : We used RAW 264.7 ( murine macrophage ) cells , a well-established system for osteoclastogenesis , and evaluated the effect of thiocolchicoside on O14788 -induced NF-κB signalling and osteoclastogenesis as well as on osteoclastogenesis induced by tumour cells . KEY RESULTS : DB11582 suppressed osteoclastogenesis induced by O14788 , and by breast cancer and multiple myeloma cells . Inhibition of the NF-κB pathway was responsible for this effect since the colchicoside inhibited O14788 -induced NF-κB activation , activation of IκB kinase ( IKK ) and suppressed inhibitor of NF-κBα ( IκBα ) phosphorylation and degradation , an inhibitor of NF-κB . Furthermore , an inhibitor of the IκBα kinase γ or NF-κB essential modulator , the regulatory component of the IKK complex , demonstrated that the NF-κB signalling pathway is mandatory for osteoclastogenesis induced by O14788 . CONCLUSIONS AND IMPLICATIONS : Together , these data suggest that thiocolchicoside significantly suppressed osteoclastogenesis induced by O14788 and tumour cells via the NF-κB signalling pathway . Thus , thiocolchicoside , a drug that has been used for almost half a century to treat muscle pain , may also be considered as a new treatment for bone loss . The bone morphogenetic protein signaling pathway is upregulated in a mouse model of total parenteral nutrition . Total parenteral nutrition ( O15533 ) results in intestinal mucosal atrophic changes due to an absence of enteral nutrition ; however , the mechanisms responsible for this are not fully understood . It has been shown that bone morphogenetic protein ( BMP ) activation inhibits intestinal epithelial cell ( EC ) proliferation . Therefore , we hypothesized that the BMP pathway could be upregulated by O15533 . To address this , we randomly assigned mice to receive O15533 or to be enterally fed ( control ) for 7 d . Mucosal EC isolates were harvested from the entire length of small intestine for RNA and protein measurements . Q8N1N2 -thickness , mid-small bowel was processed for histological examination . O15533 increased the abundance of P12643 , P12644 , and Q13873 at the RNA and protein levels . Phosphorylation of Q15797 , Q99717 , and Smad8 also was greater in the O15533 group than in the control , which helped to confirm activation of this pathway . Interestingly , the O15533 and control groups did not differ in the mRNA expression of the extracellular soluble bmp antagonists , noggin , gremlin , chordin , or follistatin . Compared to the control group , the expression of c-Myc ( cellular myelocytomatosis ) mRNA was lower , whereas the level of P38936 ( P38936 /CIP1) was greater , in the O15533 group . Because the BMP family may function through suppression of Wnt-beta-catenin signaling , this pathway was also examined . mRNA expression of Wnt 3 , Wnt5a , and the Wnt receptor Lrp5 were lower in the O15533 group compared to controls . The results suggest that the BMP signaling pathway may be involved in the development of intestinal mucosal atrophy due to O15533 administration . P04637 mutation , epithelial-mesenchymal transition , and stemlike features in breast cancer subtypes . Altered p53 protein is prevalently associated with the pathologic class of triple-negative breast cancers and loss of p53 function has recently been linked to the induction of an epithelial-mesenchymal transition ( EMT ) and acquisition of stemness properties . We explored the association between P04637 mutational status and expression of some genes involved in the canonical TGF-β signaling pathway ( the most potent EMT inducer ) and in two early EMT associated events : loss of cell polarity and acquisition of stemness-associated features . We used a publicly accessible microarray dataset consisting of 251 p53-sequenced primary breast cancers . Statistical analysis indicated that mutant p53 tumors ( especially those harboring a severe mutation ) were consistent with the aggressive class of triple-negative cancers and that , differently from cell cultures , surgical tumors underexpressed some TGF-β related transcription factors known as involved in EMT ( P41134 , P47928 , P84022 , Q13485 , Q99717 , P37275 ) . These unexpected findings suggest an interesting relationship between p53 mutation , mammary cell dedifferentiation , and the concomitant acquisition of stemlike properties ( as indicated by the overexpression of O43490 and P46531 genes ) , which improve tumor cells aggressiveness as indicated by the overexpression of genes associated with cell proliferation ( P11802 , Q00534 , P46013 ) and migration ( P61073 , P03956 ) . Targeting eIF4GI translation initiation factor affords an attractive therapeutic strategy in multiple myeloma . BACKGROUND : Deregulation of protein synthesis is integral to the malignant phenotype and translation initiation is the rate limiting stage . Therefore , eIF4F translation initiation complex components are attractive therapeutic targets . METHODS : Protein lysates of myeloma cells ( cell lines/patients ' bone marrow samples ) untreated/treated with bevacizumab were assayed for eIF4GI expression , regulation ( P15559 /proteosome dependent fragmentation ) ( WB , DB00266 , qPCR ) and targets (WB). eIF4GI was inhibited by knockdown and 4EGI-1 . Cells were tested for viability ( ELISA ) , death ( FACS ) and eIF4GI targets ( WB ) . RESULTS : Previously , we have shown that manipulation of P15692 in myeloma cells attenuated P06730 dependent translation initiation . Here we assessed the significance of eIF4GI to MM cells . We demonstrated increased expression of eIF4GI in myeloma cells and its attenuation upon P15692 inhibition attributed to elevated P15559 /proteasome dependent fragmentation and diminished mRNA levels . Knockdown of eIF4GI was deleterious to myeloma cells phenotype and expression of specific molecular targets ( Q99717 /ERα/HIF1α/c-Myc ) . Finally , we showed that the small molecule 4EGI-1 inhibits eIF4GI and causes a reduction in expression of its molecular targets in myeloma . CONCLUSION : Our findings substantiate that translation initiation of particular targets in MM is contingent on the function of eIF4GI , critical to cell phenotype , and mark it as a viable target for pharmacological intervention .