interacts_with DB00630?
P00750 ( tPA ) promotes M1 macrophage survival through p90 ribosomal S6 kinase ( RSK ) and p38 mitogen-activated protein kinase ( MAPK ) pathway . Macrophage accumulation is one of the hallmarks of progressive kidney disease . Resting macrophages have a finite lifespan , but become resistant to apoptosis in response to pathogenic cues , whereas the underlying mechanism remains unknown . P00750 ( tPA ) , a protease up-regulated in the kidneys with chronic injury , has been shown to promote macrophage accumulation and renal inflammation . We hypothesized that tPA may be the endogenous factor that promotes macrophage survival and extends their lifespan that leads to their accumulation in the injured kidneys . We examined the role of tPA in macrophage survival , and found that tPA protected macrophages from both staurosporine and H2O2-induced apoptosis . tPA promoted the survival of both resting and lipopolysaccharide- or interferon-γ-induced M1 macrophages , but failed to do so in the interleukin 4 ( P05112 ) -induced M2 macrophages . In the kidneys with unilateral ureteral obstruction , there were significantly more apoptotic M1 macrophages in tPA-deficient mice than their wild-type counterparts , and obstruction-induced M1 macrophages accumulation and M1 chemokine expression were markedly reduced in these knock-out mice . The cytoprotective effect of tPA required its receptor , P01130 -related protein-1 ( Q07954 ) . tPA induced the phosphorylation of Erk1/2 , p90 ribosomal S6 kinase ( RSK ) , and p38 in a temporal order . The tPA-mediated macrophage survival was eliminated by PD98059 , BI-D1870 , or sc68376 , the specific inhibitors for Erk1/2 , p90RSK , or p38 , respectively . Thus , it is clear that tPA promoted M1 macrophage survival through its receptor Q07954 -mediated novel signaling cascade involving Erk1/2 , p90RSK , and p38 , which leads to the accumulation of these cells in the injured kidneys . Q9Y6X2 negatively regulates O14788 -mediated osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblasts . Cytokine signaling via various transcription factors regulates receptor activator of nuclear factor ( NF ) -kappaB ligand ( O14788 ) -mediated osteoclast differentiation from monocyte/macrophage lineage cells involved in propagation and resolution of inflammatory bone destruction . Protein inhibitor of activated P40763 ( Q9Y6X2 ) was initially identified as a molecule that inhibits DNA binding of P40763 and regulates many transcription factors through distinct mechanisms . To analyze Q9Y6X2 function in osteoclasts in vivo , we have generated transgenic mice in which Q9Y6X2 is specifically expressed in the osteoclast lineage using the tartrate-resistant acid phosphatase ( TRAP ) gene promoter . Q9Y6X2 transgenic mice showed an osteopetrotic phenotype due to impairment of osteoclast differentiation . Overexpression of Q9Y6X2 in RAW264.7 cells suppressed O14788 -induced osteoclastogenesis by inhibiting the expression of c-Fos and O95644 . Interestingly , Q9Y6X2 inhibits the transcriptional activity of microphthalmia-associated transcription factor ( O75030 ) independent of sumoylation . Down-regulation of Q9Y6X2 markedly enhances O14788 -mediated osteoclastogenesis in RAW264.7 cells . Furthermore , overexpression of Q9Y6X2 in mouse primary osteoblast ( DB00925 ) , down-regulates O14788 expression induced by interleukin-6 ( P05231 ) cytokine family , and inhibits osteoclast formation from bone marrow macrophages ( BMMs ) in vitro coculture system . Down-regulation of Q9Y6X2 leads to the accelerated expression of O14788 in DB00925 stimulated with P05231 and soluble P05231 receptor ( sIL-6R ) . Taken together , our results clearly indicate that Q9Y6X2 negatively regulates O14788 -mediated osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblasts . Drug-induced activation of SREBP-controlled lipogenic gene expression in CNS-related cell lines : marked differences between various antipsychotic drugs . BACKGROUND : The etiology of schizophrenia is unknown , but neurodevelopmental disturbances , myelin- and oligodendrocyte abnormalities and synaptic dysfunction have been suggested as pathophysiological factors in this severe psychiatric disorder . DB04540 is an essential component of myelin and has proved important for synapse formation . Recently , we demonstrated that the antipsychotic drugs clozapine and haloperidol stimulate lipogenic gene expression in cultured glioma cells through activation of the sterol regulatory element-binding protein ( SREBP ) transcription factors . We here compare the action of chlorpromazine , haloperidol , clozapine , olanzapine , risperidone and ziprasidone on SREBP activation and SREBP-controlled gene expression ( ACAT2 , P04035 , Q01581 , P14324 , O75845 , Q9UBM7 , P01130 , P49327 and SCD1 ) in four CNS-relevant human cell lines . RESULTS : There were marked differences in the ability of the antipsychotic drugs to activate the expression of SREBP target genes , with clozapine and chlorpromazine as the most potent stimulators in a context of therapeutically relevant concentrations . Glial-like cells ( GaMg glioma and CCF-STTG1 astrocytoma cell lines ) displayed more pronounced drug-induced SREBP activation compared to the response in Q9UL51 human cortical neurons and SH-SY5Y neuroblastoma cells , indicating that antipsychotic-induced activation of lipogenesis is most prominent in glial cells . CONCLUSION : Our present data show a marked variation in the ability of different antipsychotics to induce SREBP-controlled transcriptional activation of lipogenesis in cultured human CNS-relevant cells . We propose that this effect could be relevant for the therapeutic efficacy of some antipsychotic drugs . Mechanism of aminobisphosphonate action : characterization of alendronate inhibition of the isoprenoid pathway . DB00630 ( ALN ) , an aminobisphosphonate compound used for the treatment of osteoporosis and other disorders of bone resorption , has been suggested to act by inhibition of the formation of GGPP . In the present study we used an S(10) homogenate fraction of rat liver to show that ALN causes a dose-dependent inhibition of [(3)H]MVA incorporation into sterols and a concomitant increase in incorporation of radiolabel into IPP and DMAPP . We further show that ALN is a potent inhibitor of cytosolic trans-prenyltransferase ( P14324 ) . The inhibition is competitive with respect to allylic pyrophosphate substrates , but not IPP , suggesting that ALN acts as an allylic pyrophosphate analog and binds to the free enzyme . The K(i) is in the 0.5 microM range . Genome-wide analysis of DNA copy number alterations and gene expression in gastric cancer . Genomic copy number aberrations ( CNAs ) are believed to play a major role in the development and progression of human cancers . Although many CNAs have been reported in gastric cancer , their genome-wide transcriptional consequences are poorly understood . In this study , to reveal the impact of CNAs on genome-wide expression in gastric cancer , we analysed 30 cases of gastric cancers for their CNAs by array comparative genomic hybridization ( array CGH ) and 24 of these 30 cases for their expression profiles by oligonucleotide-expression microarray . We found that with the application of laser microdissection , most CNAs were detected at higher frequency than in previous studies . Notably , gain at 20q13 was detected in almost all cases ( 97 % ) , suggesting that this may play an important role in the pathogenesis of gastric cancer . By comparing the array CGH data with expression profiles of the same samples , we showed that both genomic amplification and deletion strongly influence the expression of genes in altered genomic regions . Furthermore , we identified 125 candidate genes , consisting of 114 up-regulated genes located in recurrent regions ( > 10 % ) of amplification and 11 down-regulated genes located in recurrent regions of deletion . Up-regulation of several candidate genes , such as Q99741 , P60059 , Q9BTT0 , Q13895 and P37268 , was confirmed by immunohistochemistry . Interestingly , some candidate genes were localized at genomic loci adjacent to well-known genes such as P00533 , P04626 and Q13485 , and concordantly deregulated by genomic alterations . Based on these results , we propose that our list of candidate genes may contain novel genes involved in the pathogenesis of advanced gastric cancer . Small interfering RNA knocks down the molecular target of alendronate , farnesyl pyrophosphate synthase , in osteoclast and osteoblast cultures . P14324 ( FPPS ) , an enzyme in the mevalonate pathway , is the inhibition target of alendronate , a potent FDA-approved nitrogen-containing bisphosphonate ( N-BP ) drug , at the molecular level . DB00630 not only inhibits osteoclasts but also has been reported to positively affect osteoblasts . This study assesses the knockdown effects of siRNA targeting FPPS compared with alendronate in both osteoclast and osteoblast cultures . Primary murine bone marrow cell-induced osteoclasts and the preosteoblast MC3T3-E1 cell line were used to assess effects of anti-FPPS siRNA compared with alendronate . Results show that both FPPS mRNA message and protein knockdown in serum-based culture is correlated with reduced osteoclast viability . FPPS siRNA is more potent than 10 μM alendronate , but less potent than 50 μM alendronate on reducing osteoclast viability . Despite FPPS knockdown , no significant changes were observed in osteoblast proliferation . FPPS knockdown promotes osteoblast differentiation significantly but not cell mineral deposition . However , compared with 50 μM alendronate dosing , FPPS siRNA does not exhibit cytotoxic effects on osteoblasts while producing significant effects on ostoblast differentiation . Both siRNA and alendronate at tested concentrations do not have significant effects on cultured osteoblast mineralization . Overall , results indicate that siRNA against FPPS could be useful for selectively inhibiting osteoclast-mediated bone resorption and improving bone mass maintenance by influencing both osteoclasts and osteoblasts in distinct ways . Role of xanthine oxidoreductase and NAD(P)H oxidase in endothelial superoxide production in response to oscillatory shear stress . Oscillatory shear stress occurs at sites of the circulation that are vulnerable to atherosclerosis . Because oxidative stress contributes to atherosclerosis , we sought to determine whether oscillatory shear stress increases endothelial production of reactive oxygen species and to define the enzymes responsible for this phenomenon . Bovine aortic endothelial cells were exposed to static , laminar ( 15 dyn/cm2 ) , and oscillatory shear stress ( +/-15 dyn/cm2 ) . Oscillatory shear increased superoxide ( O2.- ) production by more than threefold over static and laminar conditions as detected using electron spin resonance ( P03372 ) . This increase in O2*- was inhibited by oxypurinol and culture of endothelial cells with tungsten but not by inhibitors of other enzymatic sources . DB05262 also prevented H2O2 production in response to oscillatory shear stress as measured by dichlorofluorescin diacetate and Amplex Red fluorescence . DB02134 -dependent O2*- production was increased in homogenates of endothelial cells exposed to oscillatory shear stress . This was associated with decreased xanthine dehydrogenase ( P47989 ) protein levels and enzymatic activity resulting in an elevated ratio of xanthine oxidase ( XO ) to P47989 . We also studied endothelial cells lacking the p47phox subunit of the NAD(P)H oxidase . These cells exhibited dramatically depressed O2*- production and had minimal XO protein and activity . Transfection of these cells with p47phox restored XO protein levels . Finally , in bovine aortic endothelial cells , prolonged inhibition of the NAD(P)H oxidase with apocynin decreased XO protein levels and prevented endothelial cell stimulation of O2*- production in response to oscillatory shear stress . These data suggest that the NAD(P)H oxidase maintains endothelial cell XO levels and that XO is responsible for increased reactive oxygen species production in response to oscillatory shear stress . Caenorhabditis elegans expressed sequence tags identify gene families and potential disease gene homologues . A database containing mapped partial cDNA sequences from Caenorhabditis elegans will provide a ready starting point for identifying nematode homologues of important human genes and determining their functions in C. elegans . A total of 720 expressed sequence tags ( ESTs ) have been generated from 585 clones randomly selected from a mixed-stage C. elegans cDNA library . Comparison of these ESTs with sequence databases identified 422 new C. elegans genes , of which 317 are not similar to any sequences in the database . Twenty-six new genes have been mapped by YAC clone hybridization . Members of several gene families , including cuticle collagens , GTP-binding proteins , and RNA helicases were discovered . Many of the new genes are similar to known or potential human disease genes , including P13569 and the P01130 . In vivo analysis of folate coenzymes and their compartmentation in Saccharomyces cerevisiae . In eukaryotes , enzymes responsible for the interconversion of one-carbon units exist in parallel in both mitochondria and the cytoplasm . Strains of Saccharomyces cerevisiae were constructed that possess combinations of gene disruptions at the SHM1 [ mitochondrial serine hydroxymethyltransferase ( SHMTm ) ] , SHM2 [ cytoplasmic SHMT ( SHMTc ) ] , MIS1 [ mitochondrial C1- DB00116 synthase ( C1-THFSm ) ] , ADE3 [ cytoplasmic P11586 ( C1-THFSc ) ] , GCV1 [ glycine cleavage system ( GCV ) protein T ] , and the GLY1 ( involved in glycine synthesis ) loci . Analysis of the in vivo growth characteristics and phenotypes was used to determine the contribution to cytoplasmic nucleic acid and amino acid anabolism by the mitochondrial enzymes involved in the interconversion of folate coenzymes . The data indicate that mitochondria transport formate to the cytoplasmic compartment and mitochondrial synthesis of formate appears to rely primarily on SHMTm rather than the glycine cleavage system . The glycine cleavage system and SHMTm cooperate to specifically synthesize serine . With the inactivation of SHM1 , however , the glycine cleavage system can make an observable contribution to the level of mitochondrial formate . Inactivation of SHM1 , SHM2 and ADE3 is required to render yeast auxotrophic for P54849 and methionine , suggesting that P54849 synthesized in mitochondria may be available to the cytoplasmic compartment . Inhibition of farnesylpyrophosphate synthase prevents angiotensin II-induced hypertrophic responses in rat neonatal cardiomyocytes : involvement of the RhoA/Rho kinase pathway . The RhoA/Rho-kinase ( ROCK ) pathway is involved in angiotensin ( Ang ) II-induced cardiac hypertrophy . However , it is still unclear whether inhibition of farnesylpyrophosphate ( FPP ) synthase can attenuate Ang II-induced hypertrophic responses , and whether it involves the RhoA/ROCK pathway . The anti-hypertrophic effects of inhibition of P14324 with alendronate in Ang II-cultured neonatal cardiomyocytes were partially reversed by geranylgeranyol ( GGOH ) and were mimicked by GGTI-286 , a geranylgeranyl transferase-I inhibitor , P01024 exoenzyme , an inhibitor of Rho , or Y-27632 , an inhibitor of ROCK . Pull-down assay showed alendronate reduced-active RhoA by Ang II was also partially antagonized by GGOH . This study revealed that the inhibition of P14324 by alendronate reduces RhoA activation by diminishing geranylgeranylation which prevents Ang II-induced hypertrophic responses in neonatal cardiomyocytes . Phenotypic and molecular evaluation of a chromosome 1q region with linkage and association to type 2 diabetes in humans . OBJECTIVE : Linkage to type 2 diabetes ( T2D ) is well replicated on chromosome 1q21-q23 . Within this region , T2D was associated with common single nucleotide polymorphisms that marked an extended linkage disequilibrium block , including the liver pyruvate kinase gene ( P30613 ) , in several European-derived populations . In this study we sought to determine the molecular basis for the association and the phenotypic consequences of the risk haplotype . RESEARCH DESIGN AND METHODS : Genes surrounding P30613 were resequenced in European-American and African-American cases and controls , and association with T2D was tested . Copy number variants ( CNVs ) were tested for four regions with real-time PCR . Expression of genes in the region was tested in adipose and muscle from nondiabetic subjects with each genotype . P01308 secretion , insulin sensitivity , and hepatic glucose production were tested in nondiabetic individuals with each haplotype combination . RESULTS : No coding variant in the region was associated with T2D . CNVs were rare and not associated with T2D . P30613 was not expressed in available tissues , but expression of genes Q9P1Z3 , P49760 , O14828 , and P14324 was not associated with haplotype combinations in adipose or muscle . Haplotype combinations were not associated with insulin secretion or peripheral insulin sensitivity , but homozygous carriers of the risk haplotype had increased hepatic glucose production during hyperinsulinemia . CONCLUSIONS : Noncoding variants in the P30613 region likely alter gene expression of one or more genes . Our extensive physiological and molecular studies suggest increased hepatic glucose production and reduced hepatic insulin sensitivity , thus pointing to P30613 itself as the most likely candidate gene in this population . Design of novel potent antihyperlipidemic agents with antioxidant/anti-inflammatory properties : exploiting phenothiazine 's strong antioxidant activity . Because atherosclerosis is an inflammatory process involving a series of pathological events such as dyslipidemia , oxidative stress , and blood clotting mechanisms , we hereby report the synthesis and evaluation of novel compounds in which antioxidant , anti-inflammatory , and squalene synthase ( P37268 ) inhibitory/hypolipidemic activities are combined in simple molecules through design . The coupling of two different pharmacophores afforded compounds 1-12 , whose biological profile was markedly improved compared to those of parent lead structures ( i.e. , the hypolipidemic 2-hydroxy-2-aryl-(benzo)oxa ( or thia ) zine and the antioxidant phenothiazine ) . Most derivatives strongly inhibited in vitro microsomal lipid and LDL peroxidation , exhibiting potent free-radical scavenging activity . They further significantly inhibited P37268 activity and showed remarkable antidyslipidemic activity in vivo in animal models of acute and high-fat-induced hyperlipidemia . Finally , several compounds showed anti-inflammatory activity in vitro , inhibiting cycloxygenase ( P23219 /2 ) activity . The multimodal properties of the new compounds and especially their combined antioxidant/ P37268 / P36551 inhibitory activity render them interesting lead compounds for further evaluation against atherosclerosis . 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 ) 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 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 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 ) blocker azosemide ( 100 microM ) , the P13569 blocker DB04941 ( 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 . Clinical outcome and cyclo-oxygenase-2 expression in five dogs with solar dermatitis/actinic keratosis treated with firocoxib . BACKGROUND : The conversion of arachidonic acid into prostaglandin is catalysed by the cyclo-oxygenases ( P23219 / P35354 ) . Several studies indicate that P35354 is overexpressed in actinic keratosis in humans and dogs . DB09217 is a P35354 -selective inhibitor that blocks the biochemical activity of P35354 . HYPOTHESIS/OBJECTIVES : To evaluate the efficacy of firocoxib ( 5 mg/kg orally once daily ) for the treatment of dogs with solar dermatitis/actinic keratosis . METHODS : DB09217 5 mg/kg was given orally once daily for 180 days to five dogs with clinical signs and histopathological lesions consistent with solar dermatitis/actinic keratosis . On days 0 , 50 and 180 , the severity of erythema , skin shine , induration and the number of comedones were evaluated by a clinical scoring system . On the same days , samples were collected for histopathology from ' target lesions ' and P35354 expression was evaluated by immunohistochemistry . RESULTS : The clinical follow-up showed that four of five dogs improved with the treatment ; improvement in terms of histological findings was correlated with the regularization of the epidermal proliferation rather than the recovery of dermal changes . CONCLUSIONS AND CLINICAL IMPORTANCE : A role for P35354 might thus be hypothesized in the pathogenesis of canine solar dermatitis . DB00072 emtansine : the first targeted chemotherapy for treatment of breast cancer . DB00072 emtansine ( DB05773 ) is a novel antibody-drug conjugate , comprised of a potent cytotoxic drug connected via a stable linker to the anti- P04626 antibody , trastuzumab , thereby primarily targeting chemotherapy delivery to cells overexpressing the P04626 receptor . A Phase II randomized trial of DB05773 in the front-line metastatic breast cancer setting revealed promising activity and improved safety compared with standard chemotherapy plus trastuzumab . Subsequently , a Phase III trial in patients with trastuzumab-pretreated metastatic breast cancer showed DB05773 to be associated with prolonged progression-free and overall survival compared with lapatinib plus capecitabine . DB05773 represents a major shift in the treatment of patients with breast cancer as it replaces traditional nontargeted chemotherapy with a ' smart ' medication that directs the cytotoxic therapy to cancer cells by using a known biomarker . Gene therapy-mediated delivery of targeted cytotoxins for glioma therapeutics . Restricting the cytotoxicity of anticancer agents by targeting receptors exclusively expressed on tumor cells is critical when treating infiltrative brain tumors such as glioblastoma multiforme ( GBM ) . GBMs express an P35225 receptor ( IL13Rα2 ) that differs from the physiological P24394 /IL13R receptor . We developed a regulatable adenoviral vector ( Ad.mhIL-4.TRE.mhIL-13-PE ) encoding a mutated human P35225 fused to Pseudomonas exotoxin ( mhIL-13-PE ) that specifically binds to IL13Rα2 to provide sustained expression , effective anti-GBM cytotoxicity , and minimal neurotoxicity . The therapeutic Ad also encodes mutated human P05112 that binds to the physiological P24394 /IL13R without interacting with IL13Rα2 , thus inhibiting potential binding of mhIL-13-PE to normal brain cells . Using intracranial GBM xenografts and syngeneic mouse models , we tested the Ad.mhIL-4.TRE.mhIL-13-PE and two protein formulations , hIL-13-PE used in clinical trials ( DB05305 ) and a second-generation mhIL-13-PE . DB05305 doubled median survival without eliciting long-term survival and caused severe neurotoxicity ; mhIL-13-PE led to ∼40 % long-term survival , eliciting severe neurological toxicity at the high dose tested . In contrast , Ad-mediated delivery of mhIL-13-PE led to tumor regression and long-term survival in over 70 % of the animals , without causing apparent neurotoxicity . Although DB05305 was originally developed to target GBM , when tested in a phase III trial it failed to achieve clinical endpoints and revealed neurotoxicity . Limitations of DB05305 include its short half-life , which demanded frequent or continued administration , and binding to P24394 /IL13R , present in normal brain cells . These shortcomings were overcome by our therapeutic Ad , thus representing a significant advance in the development of targeted therapeutics for GBM . 13C nuclear magnetic resonance detection of interactions of serine hydroxymethyltransferase with C1- DB00116 synthase and glycine decarboxylase complex activities in Arabidopsis . In P01024 plants , serine synthesis is associated with photorespiratory glycine metabolism involving the DB00116 ( DB00116 ) -dependent activities of the glycine decarboxylase complex ( P16260 ) and serine hydroxymethyl transferase ( SHMT ) . Alternatively , DB00116 -dependent serine synthesis can occur via the P11586 /SHMT pathway . We used 13C nuclear magnetic resonance to examine serine biosynthesis by these two pathways in Arabidopsis thaliana ( L. ) Heynh . Columbia wild type . We confirmed the tight coupling of the P16260 / SHMT system and observed directly in a higher plant the flux of formate through the P11586 /SHMT system . The accumulation of 13C-enriched serine over 24 h from the P16260 /SHMT activities was 4-fold greater than that from P11586 /SHMT activities . Our experiments strongly suggest that the two pathways operate independently in Arabidopsis . Plants exposed to methotrexate and sulfanilamide , powerful inhibitors of DB00116 biosynthesis , reduced serine synthesis by both pathways . The results suggest that continuous supply of DB00116 is essential to maintain high rates of serine metabolism . Nuclear magnetic resonance is a powerful tool for the examination of DB00116 -mediated metabolism in its natural cellular environment . A novel bisphosphonate inhibitor of squalene synthase combined with a statin or a nitrogenous bisphosphonate in vitro . Statins and nitrogenous bisphosphonates ( NBP ) inhibit 3-hydroxy-3-methylglutaryl-coenzyme-A reductase ( P04035 ) and farnesyl diphosphate synthase ( P14324 ) , respectively , leading to depletion of farnesyl diphosphate ( FPP ) and disruption of protein prenylation . P37268 ( P37268 ) utilizes FPP in the first committed step from the mevalonate pathway toward cholesterol biosynthesis . Herein , we have identified novel bisphosphonates as potent and specific inhibitors of P37268 , including the tetrasodium salt of 9-biphenyl-4,8-dimethyl-nona-3,7-dienyl-1,1-bisphosphonic acid ( compound 5 ) . Compound 5 reduced cholesterol biosynthesis and lead to a substantial intracellular accumulation of FPP without reducing cell viability in HepG2 cells . At high concentrations , lovastatin and zoledronate impaired protein prenylation and decreased cell viability , which limits their potential use for cholesterol depletion . When combined with lovastatin , compound 5 prevented lovastatin-induced FPP depletion and impairment of protein farnesylation . Compound 5 in combination with the NBP zoledronate completely prevented zoledronate-induced impairment of both protein farnesylation and geranylgeranylation . Cotreatment of cells with compound 5 and either lovastatin or zoledronate was able to significantly prevent the reduction of cell viability caused by lovastatin or zoledronate alone . The combination of an P37268 inhibitor with an P04035 or P14324 inhibitor provides a rational approach for reducing cholesterol synthesis while preventing nonsterol isoprenoid depletion . [ mRNA expression of lipogenic genes in mouse mammary gland in different lactation stages ] . To investigate the expression pattern of lipogenic genes in mammary gland of mouse in different lactation stages , the relative mRNA abundance and expression of 20 genes involved in milk fat synthesis and secretion of lactating mammary tissues were assessed using real-time PCR . Results revealed the significant upregulation of mRNA expression for both high abundant genes ( abundance > 5 % ) , such as P06858 , Q13085 , O00767 , P47989 , Q13410 , and Q99541 and moderate abundant genes ( 5 % > abundance > 1 % ) , such as P16671 , P49327 , Q86UL3 , and O75907 in lactation stages compared to pregnancy ( P < 0.05 ) . The mRNA expression of lipogenic enzyme genes for Q13085 , O00767 , P49327 , Q86UL3 , and O75907 exhibited lower expression lever in early ( 6 d ) and late ( 18 d ) lactation stages but higher expression level at middle stage ( 12 d ) , demonstrating a low-high-low pattern . Besides , the mRNA levels of some gene regulators were also measured . The mRNA expression of SREBF gene increased gradually along with the lactation , which showed a 10-fold elevation at middle stage ( 12 d ) . The expression pattern of SREBF gene was the same as lipogenic enzyme genes , suggesting that SREBF may play an important role in the regulation of lipogenic enzyme genes in the lactating mammary gland . P01308 -like growth factor-I is a serum component stimulating growth of human neuroblastoma . Human non-autocrine neuroblastoma cells SK-N-SH and LF require serum for proliferation in vitro . We wished to determine the role of serum-borne insulin-like growth factor I ( P05019 ) as mitogen for these cells . Introduction of the monoclonal antibody alpha-IR3 against human P08069 reduced proliferation in the presence of fetal bovine serum ( FBS ) . P05019 ( 5 nM ) was as effective as FBS ( 10 % ) in stimulating proliferation . DB00071 mimicked the effects of P05019 , but at a 1000-fold higher concentration . The antibody alpha-IR3 reduced growth stimulated by P05019 more effectively than growth stimulated by insulin . Thus , proliferation of human non-autocrine neuroblastoma cells can be effectively manipulated by exogenous P05019 . Effect of postponed treatment with an anti-tumour necrosis factor ( P01375 ) F(ab')2 fragment on endotoxin-induced cytokine and neutrophil responses in chimpanzees . P01375 is considered to be an intermediate factor in endotoxin-induced release of other cytokines and endotoxin-induced neutrophil degranulation . Little is known about the effect of postponed treatment with anti- P01375 in primate endotoxin models . To assess the effect of delayed treatment with anti- P01375 in endotoxaemia , six healthy adult chimpanzees were intravenously injected with Escherichia coli endotoxin ( 4 ng/kg ) . In three of these animals the administration of endotoxin was followed after 30 min by a bolus i.v. injection of the anti- P01375 F(ab')2 fragment DB04956 ( 0.1 mg/kg ) . Post-treatment with DB04956 completely prevented the appearance of P01375 activity in serum elicited by endotoxin , and markedly reduced the rises in the serum concentrations of P05231 and P10145 . In addition , the endotoxin-induced increases in the type I and type II soluble P01375 receptors were also profoundly inhibited by DB04956 , suggesting that P01375 is involved in the release of its own soluble receptors in endotoxaemia . Neutrophilic leucocytosis was not affected by DB04956 . In contrast , DB04956 did significantly abrogate neutrophil degranulation , as measured by the plasma concentrations of lactoferrin . These results indicate that treatment with anti- P01375 30 min after the administration of endotoxin is still effective in attenuating the induction of the cytokine network and of neutrophil degranulation . Differential effects of endotoxin and fibrinogen degradation products ( P14324 ) on liver synthesis of fibrinogen and albumin : evidence for the involvement of a novel monokine in the stimulation of fibrinogen synthesis induced by P14324 . 1. Administration of endotoxin or fibrinogen degradation products ( FDPs ) in rats increase fibrinogen synthesis comparable to that found during the acute phase response . 2 . An increased fibrinogen synthesis is also found in co-cultures of hepatocytes with peripheral blood mononuclear cells upon administration of endotoxin or FDPs , but not in primary cultures of hepatocytes alone . 3 . However , the increased synthesis of fibrinogen by FDPs is not accompanied by a decreased albumin synthesis , as in the case of stimulated fibrinogen synthesis induced by endotoxin in vivo and in co-cultures of hepatocytes with peripheral blood mononuclear cells , or induced by monocytic products in vivo and in primary cultures of hepatocytes alone . 4 . Since IL-1 and/or P05231 could not be accounted for the stimulation of fibrinogen synthesis without a decreased albumin synthesis , a novel monokine produced by mononuclear cells upon Q9NRC9 administration might be involved . DB00338 , a gastric proton pump inhibitor , inhibits melanogenesis by blocking Q04656 trafficking . DB00338 is a proton pump inhibitor used in the treatment of peptic ulcer disease and gastrosophageal reflux disease and acts by irreversibly blocking P20648 , a P-type H+/K+ ATPase in gastric parietal cells . We found that omeprazole and its closely related congeners inhibited melanogenesis at micromolar concentrations in B16 mouse melanoma cells , normal human epidermal melanocytes , and in a reconstructed human skin model . DB00338 topically applied to the skin of UV-irradiated human subjects significantly reduced pigment levels after 3 weeks compared with untreated controls . DB00338 had no significant inhibitory effect on the activities of purified human tyrosinase or on the mRNA levels of tyrosinase , dopachrome tautomerase , Pmel17 , or O75030 mRNA levels . Although melanocytes do not express P20648 , they do express Q04656 , a copper transporting P-type ATPase in the trans-Golgi network that is required for copper acquisition by tyrosinase . Q04656 relocalization from the trans-Golgi network to the plasma membrane in response to elevated copper concentrations in melanocytes was inhibited by omeprazole . DB00338 treatment increased the proportion of EndoH sensitive tyrosinase , indicating that tyrosinase maturation was impaired . In addition , omeprazole reduced tyrosinase protein abundance in the presence of cycloheximide , suggestive of increased degradation . Our findings are consistent with the hypothesis that omeprazole reduces melanogenesis by inhibiting Q04656 and by enhancing degradation of tyrosinase . [ Genetics and pharmacogenetics of osteoporosis ] . Osteoporosis is a serious disease characterized by high morbidity and mortality due to atraumatic fractures . In pathogenesis of osteoporosis , except environment , internal factors , such as hormonal dysbalance and genetic background , are also in play . In this review , candidate genes for osteoporosis are classified according to metabolic or hormonal pathways , which regulate bone mineral density/and or quality ( estrogen , O14788 / Q9Y6Q6 / O00300 , mevalonate , Wnt circuit , genes for collagen and vitamin D ) . Authors discuss the perspectives of practical utilization of pharmacogenetics ( identification of single candidate genes using PCR ) or pharmacogenomics ( using genome wide association studies ) in choice of optimal treatment of osteoporosis . Potentional predictors of effectivity of antiresorption therapy are genes ER , P14324 , Cyp19A1 , P11473 , Col1A1 and gene of Wnt pathway . Moreover , polymorphisms of CYP2C gene , but also P14324 may identify patients with high risk of undesirable effects of bisphosphonates ( osteonecrosis of jaw ) . Unfortunately , results of the most association studies has not been confirmed by other investigators . The controversial results could be explained by different methodic approaches in individual studies ( different sample size , homogenity of investigated groups , ethnic differences or linkage disquilibrium between genes ) . Key cliff of association studies is low variability ( 7-10 % ) of bone phenotypes associated with investigated genes . Nevertheless , identification of new genes and verification their association with bone density and/or quality using both PCR and genome wide association studies remain to be a great challenge targeting optimal prevention and treatment of osteoporosis .