MH_dev_250

Q07869 REA gamma 2 regulates adipose expression of the phosphoenolpyruvate carboxykinase gene . DB01819 MEN carboxykinase ( PEPCK ) is expressed at high levels in liver , kidney , and adipose tissue . This enzyme catalyzes the rate-limiting step in hepatic and renal gluconeogenesis and adipose glyceroneogenesis . The regulatory factors important for adipose expression of the PEPCK gene are not well defined . Previous studies with transgenic mice established that the region between bp - 2086 and - 888 is required for expression in adipose tissue but not for expression in liver or kidney tissue . We show here that a DNA fragment containing this region can function as an enhancer and direct differentiation-dependent expression of a chloramphenicol acetyltransferase gene from a heterologous promoter in cultured 3T3 - F442A preadipocytes and adipocytes . We further demonstrate that the adipocyte-specific transcription factor Q07869 REA gamma 2 , previously identified as a regulator of the adipocyte P2 enhancer , binds in a heterodimeric complex with RXR alpha to the PEPCK 5 ' - flanking region at two sites , termed P35558 REA ( bp - 451 to - 439 ) and Q16822 REA ( bp - 999 to - 987 ) . Forced expression of Q07869 REA gamma 2 and RXR alpha activates the PEPCK enhancer in non-adipose cells . This activation is potentiated by peroxisome proliferators and fatty acids but not by 9 - cis retinoic acid . Mutation of the Q07869 REA gamma 2 binding site ( Q16822 REA ) abolishes both the activity of the enhancer in adipocytes and its ability to be activated by Q07869 REA gamma 2 and RXR alpha . These results establish a role for Q07869 REA gamma 2 in the adipose expression of the PEPCK gene and suggest that this factor functions as a coordinate regulator of multiple adipocyte-specific genes .

Phosphorylation of the P06730 REA - binding protein Q13541 REA after exposure of PC12 cells to P01133 REA and P01138 REA . Q13541 REA or the Q13541 REA regulates the cap-binding activity of P06730 REA by sequestering P06730 REA . Binding of elF 4E to Q13541 REA is regulated by phosphorylation of Q13541 REA . PC12 cells were used to study the signal transduction pathway leading to phosphorylation of Q13541 REA . Both P01133 REA and P01138 REA induced phosphorylation of Q13541 REA . Wortmannin , a P19957 REA kinase inhibitor , staurosporine , a PKC inhibitor , and rapamycin , a P42345 REA inhibitor all blocked the phosphorylation of Q13541 REA . Of the three inhibitors , only wortmannin was able to inhibit MAPK phosphorylation . This excludes a role for MAPK in P01138 REA - and P01133 REA - induced Q13541 REA phosphorylation in PC12 cells . Apparently , Q13541 REA was phosphorylated in a P19957 REA kinase - , PKC - , and P42345 REA - dependent manner after P01133 REA or P01138 REA stimulation . Only P19957 REA kinase and P42345 REA are involved in the regulation of the basal level of Q13541 REA phosphorylation .

Fluorescence imaging reveals the nuclear behavior of peroxisome proliferator-activated receptor / retinoid X receptor heterodimers in the absence and presence of ligand . In a global approach combining fluorescence recovery after photobleaching ( P42345 REA ) , fluorescence correlation spectroscopy ( FCS ) , and fluorescence resonance energy transfer ( FRET ) , we address the behavior in living cells of the peroxisome proliferator-activated receptors ( PPARs ) , a family of nuclear receptors involved in lipid and glucose metabolism , inflammation control , and wound healing . We first demonstrate that unlike several other nuclear receptors , PPARs do not form speckles upon ligand activation . The subnuclear structures that may be observed under some experimental conditions result from overexpression of the protein and our immunolabeling experiments suggest that these structures are subjected to degradation by the proteasome . Interestingly and in contrast to a general assumption , PPARs readily heterodimerize with retinoid X receptor ( RXR ) in the absence of ligand in living cells . Q07869 REA diffusion coefficients indicate that all the receptors are engaged in complexes of very high molecular masses and / or interact with relatively immobile nuclear components . PPARs are not immobilized by ligand binding . However , they exhibit a ligand-induced reduction of mobility , probably due to enhanced interactions with cofactors and / or chromatin . Our study draws attention to the limitations and pitfalls of fluorescent chimera imaging and demonstrates the usefulness of the combination of FCS , P42345 REA , and FRET to assess the behavior of nuclear receptors and their mode of action in living cells .

Purification and characterization of mouse O15528 REA overproduced by an Escherichia coli system coexpressing molecular chaperonins GroEL / ES . The expression of mouse O15528 REA in Escherichia coli has been dramatically enhanced by coexpression of GroEL / ES . To reveal the enzymatic properties of O15528 REA , we measured its hydroxylation activity toward vitamin D3 and DB01436 MEN ( 1alpha ( OH ) D3 ) in addition to the physiological substrate DB00146 . Surprisingly , O15528 REA converted vitamin D3 to 1alpha , DB00146 . Both 1alpha - hydroxylation activity toward vitamin D3 , and 25 - hydroxylation activity toward 1alpha ( OH ) D3 were observed . The Km and Vmax values for 25 - hydroxylation activity toward 1alpha ( OH ) D3 were estimated to be 1.7 microM and 0.51 mol / min / mol P450 , respectively , while those for 1alpha - hydroxylation activity toward DB00146 were 0.050 microM and 2.73 mol / min / mol P450 , respectively . Note that the substrate must be fixed in the opposite direction in the substrate-binding pocket of O15528 REA between 1alpha - hydroxylation and 25 - hydroxylation . Based on these results and the fact that human Q02318 REA and Streptomyces CYP 105A1 also convert vitamin D3 to 1alpha , DB00146 , 1alpha - hydroxylation , and 25 - hydroxylation of vitamin D3 appear to be closely linked together .

DB06016 MEN , an orally active D2 / D3 receptor antagonist , for the potential treatment of schizophrenia , bipolar mania and depression . DB06016 MEN ( RGH - 188 ) , which is being codeveloped by Gedeon Richter Ltd , Forest Laboratories Inc and Mitsubishi Tanabe Pharma Corp , is a novel putative antipsychotic drug that exerts partial agonism at dopamine D2 / D3 receptors , with preferential binding to D3 receptors , and partial agonism at serotonin P08908 REA receptors . Its activity at D2 / D3 receptors may be lower than that of the prototype partial agonist aripiprazole . The antipsychotic activity of cariprazine was demonstrated in animal models , and data also suggest that the propensity for extrapyramidal side effects is low and that the drug may have procognitive properties . DB06016 MEN is rapidly absorbed , with high oral bioavailability and a long plasma elimination t1 / 2 . DB06016 MEN is in phase III clinical trials in patients with schizophrenia and in patients with bipolar disorder . Data from phase II trials in patients with schizophrenia and bipolar mania indicate that the drug has antipsychotic and antimanic properties that are superior to placebo . With its unique receptor affinity profile , cariprazine may represent a potential enrichment of the therapeutic armamentarium for schizophrenia and affective disorders . Its activity against the cognitive deficits associated with schizophrenia has to be carefully investigated .

[ DB01407 MEN in amyotrophic lateral sclerosis . No indication for a positive effect ] . The anabolic effects of clenbuterol have been recognized for a long time . DB01407 MEN augments the expression of specific muscle proteins with a differential effect on type I and type II fibres . Furthermore , clenbuterol induces the synthesis of endogenous nerve growth factor ( P01138 REA ) and may itself be a myotrophic factor released by neuron endings . Side effects include tremor and headache and dose dependent abnormalities of laboratory values ( hypokalemia , hypoglycemia ) . After long-term medication increasing fatigue of muscles has been observed . Decreased expression of beta 2 - adrenergic receptors may limit the expected functional improvement . The efficacy of clenbuterol as symptomatic treatment of amyotrophic lateral sclerosis has not been proved . Controlled treatment trials are warranted to assess this question .

Expression of Th2 - skewed pathology mediators in monocyte-derived type 2 of dendritic cells ( DC2 ) . The information conveyed from dendritic cells ( DCs ) to naïve P01730 REA ( + ) T cells has crucial influence on their differentiation toward effector T cells . In an effort to identify DC-derived molecules directly contributing to T cell differentiation , we searched for molecules distinctively expressed between two DC subtypes , which were differentiated from peripheral monocytes by cultivation with GM - P04141 REA ( for Q9NPG8 ) or P08700 REA ( for DC2 ) in the presence of P05112 REA and had the ability to induce naïve T cells to differentiate into Th1 or Th2 cells , respectively . As the first step to address this issue , we subtracted Q9NPG8 transcripts from those of DC2 and compiled the gene profile dominantly expressed in DC2 , whose products are known to reside in other than the nucleus . Intriguingly , many of them were molecules involved in Th2 - skewed disease pathologies , such as P02751 REA , P38570 REA , Q14956 REA , Q03405 REA , P25089 REA , Q8NHJ6 , P05121 REA , P16050 REA , P24557 REA , P19878 REA , P10147 REA , P18510 REA , P09486 REA , and Q9NY15 , suggesting that DCs function not only as antigen presenting cells but also as producers of Th2 pathology specific milieus leading to disease deteriorations . We also found that expressions of Q02318 REA , O14495 REA , Q8WXG1 , and O15438 REA were up-regulated in DC2 , implying their significant function in Th2 - deviated states . The identification of differentially expressed genes between DC subtypes provides new insights into their functions and our comparative gene expression profile will be highly useful for the identification of DC-derived key molecules for T cell differentiation .

Cholecystokinin mediates progression and metastasis of pancreatic cancer associated with dietary fat . BACKGROUND : Obesity and dietary fat are associated with increased risk of several malignancies including pancreatic cancer . The incidence of pancreatic cancer is increased in countries that consume diets high in fat . AIM : The purpose of this study was to assess the relationship and mechanism of action between dietary fat and endogenous cholecystokinin ( CCK ) on pancreatic tumor growth and metastasis in an immunocompetent animal model . METHODS : C57BL / 6 mice were placed on regular , low-fat , or high-fat diets for 8 weeks before establishment of Panc - 02 orthotopic pancreatic tumors . Mice were then treated with a P32238 REA antagonist , devazepide , or vehicle for an additional 2.5 weeks . Pancreas tumors were weighed and metastases counted . Blood CCK levels were measured by radioimmunoassay ( RIA ) . Tissues were examined histologically and studied for genes associated with metastasis by RT-PCR array . Effects of the CCK antagonist on Panc - 02 cells invasiveness was assessed in a Matrigel invasion assay . RESULTS : Mice that received the high-fat diet had larger tumors and tenfold higher serum CCK levels by RIA compared to normal diet controls ( p < 0.01 ) . Pancreatic tumors in high-fat diet mice treated with the antagonist had fewer intravascular tumor emboli and metastases compared to controls . The reduction in tumor emboli correlated with decreased vascular endothelial growth factor-A ( P15692 REA ) expression in tumors ( p < 6 × 10 ( - 9 ) ) . In vitro invasiveness of Panc - 02 cells also was reduced by P32238 REA antagonist treatment ( p = 1.33 × 10 ( - 6 ) ) . CONCLUSION : CCK is a mediator of dietary fat-associated pancreatic cancer . CCK is also involved in the invasiveness of pancreatic tumors through a mechanism involving P15692 REA .

Differential regulation of type I interferon and epidermal growth factor pathways by a human Respirovirus virulence factor . A number of paramyxoviruses are responsible for acute respiratory infections in children , elderly and immuno-compromised individuals , resulting in airway inflammation and exacerbation of chronic diseases like asthma . To understand the molecular pathogenesis of these infections , we searched for cellular targets of the virulence protein C of human parainfluenza virus type 3 ( hPIV 3 - C ) . We found that hPIV 3 - C interacts directly through its C-terminal domain with P42224 REA and P62993 REA , whereas C proteins from measles or Nipah viruses failed to do so . Binding to P42224 REA explains the previously reported capacity of hPIV 3 - C to block type I interferon signaling , but the interaction with P62993 REA was unexpected . This adaptor protein bridges Epidermal Growth Factor ( P01133 REA ) receptor to MAPK / P29323 REA pathway , a signaling cascade recently found to be involved in airway inflammatory response . We report that either hPIV 3 infection or transient expression of hPIV 3 - C both increase cellular response to P01133 REA , as assessed by Elk 1 transactivation and phosphorylation levels of P27361 REA / 2 , 40S ribosomal subunit protein S6 and translation initiation factor 4E ( P06730 REA ) . Furthermore , inhibition of MAPK / P29323 REA pathway with U0126 prevented viral protein expression in infected cells . Altogether , our data provide molecular basis to explain the role of hPIV 3 - C as a virulence factor and determinant of pathogenesis and demonstrate that Paramyxoviridae have evolved a single virulence factor to block type I interferon signaling and to boost simultaneous cellular response to growth factors .

Leukotriene A4 hydrolase . Inhibition by bestatin and intrinsic aminopeptidase activity establish its functional resemblance to metallohydrolase enzymes . DB03424 MEN , an inhibitor of aminopeptidases , was also a potent inhibitor of leukotriene ( LT ) A4 hydrolase . On isolated enzyme its effects were immediate and reversible with a Ki = 201 + / - 95 mM . With erythrocytes it inhibited LTB 4 formation greater than 90 % within 10 min ; with neutrophils it inhibited LTB 4 formation by only 10 % during the same period , increasing to 40 % in 2 h . DB03424 MEN inhibited P09960 REA hydrolase selectively ; neither P09917 REA nor 15 - lipoxygenase activity in neutrophil lysates was affected . Purified P09960 REA hydrolase exhibited an intrinsic aminopeptidase activity , hydrolyzing L-lysine-p-nitroanilide and L-leucine-beta-naphthylamide with apparent Km = 156 microM and 70 microM and Vmax = 50 and 215 nmol / min / mg , respectively . Both P09960 REA and bestatin suppressed the intrinsic aminopeptidase activity of P09960 REA hydrolase with apparent Ki values of 5.3 microM and 172 nM , respectively . Other metallohydrolase inhibitors tested did not reduce P09960 REA hydrolase / aminopeptidase activity , with one exception ; captopril , an inhibitor of angiotensin-converting enzyme , was as effective as bestatin . The results demonstrate a functional resemblance between P09960 REA hydrolase and certain metallohydrolases , consistent with a molecular resemblance at their putative Zn2 ( + ) - binding sites . The availability of a reversible , chemically stable inhibitor of P09960 REA hydrolase may facilitate investigations on the role of LTB 4 in inflammation , particularly the process termed transcellular biosynthesis .

DB01590 SUB ( RAD 001 ) : an P42345 REA inhibitor for the treatment of metastatic renal cell carcinoma . The recent introduction of drugs that inhibit angiogenesis or the P42345 REA has provided new options for the treatment of metastatic renal cell carcinoma , a disease which often has a poor prognosis . Chemotherapy and cytokine therapy are largely ineffective . The 5 - year survival rate is under 10 % . DB01590 SUB , an immunosuppressive drug widely used for the prevention of allograft rejection and an P42345 REA inhibitor , is one of the latest drugs undergoing clinical trials in metastatic renal cell carcinoma . It has been tested in patients with progressive disease after therapy with tyrosine kinase receptor inhibitors ( sunitinib , sorafenib or both ) , which interfere with signaling pathways , such as the P15692 REA pathway . Clinical efficacy results ( progression-free survival ) for everolimus are promising and the safety profile is good .

Clinical utilization of cinacalcet in hypercalcemic conditions . INTRODUCTION : DB01012 MEN has recently been introduced as a treatment for secondary hyperparathyroidism in dialysis patients and for parathyroid carcinoma . However , there has been an increasing interest in finding out whether cinacalcet can be used as a treatment for other parathyroid hormone ( PTH ) - dependent hypercalcemic conditions also . AREAS COVERED : The article reports the most relevant recent contributions dealing with calcium sensing receptor ( P41180 REA ) physiology as well as cinacalcet pharmacokinetics and pharmacodynamics . It also looks at the different hypercalcemic conditions where the use of cinacalcet has been proposed . This article was researched using clinical trials , case reports and outstanding basic research published in the last 3 years ( MEDLINE database up to 31 November 2010 ) . It provides the reader with an insight into the many unaddressed issues regarding cinacalcet that need to be resolved before it can be used in newly proposed fields . EXPERT OPINION : Since cinacalcet may not only have an effect on parathyroid P41180 REA but also on P41180 REA expressed at bone and renal levels , it can currently only be considered a good alternative to parathyroidectomy in PTH-dependent hypercalcemic conditions when surgical intervention is burdened by a high failure rate or when it can be considered a risky procedure . At present , cinacalcet can not be considered the first choice treatment in asymptomatic primary hyperparathyroidism or in mild-to-moderate forms of familial hypocalciuric hypocalcemia .

DB01590 SUB tablets for patients with subependymal giant cell astrocytoma . INTRODUCTION : Better understanding of aberrantly active molecular pathways in tumors offers potential to develop more specific and less toxic therapies . Abnormal mammalian target of rapamycin ( P42345 REA ) complex signaling and defects in Q92574 REA and P49815 REA have been associated with the development of subependymal giant cell astrocytomas ( SEGAs ) in tuberous sclerosis complex ( TSC ) patients . Recently , P42345 REA inhibitors such as everolimus have shown encouraging benefit for patients with SEGAs . AREAS COVERED : The authors discuss a molecular genetic pathway linked with TSC , specifically the role of two proteins whose functional absence is responsible for most SEGA tumors that arise in TSC patients . The authors also examine the rationale for targeted agents against this pathway therapeutically and describe the clinical evidence underlying the FDA approval of everolimus for patients with inoperable SEGAs . EXPERT OPINION : DB01590 SUB ( Afinitor ) selectively targets a molecular defect of SEGAs in TSC patients . Although surgery is effective , most SEGAs recur . An agent that inhibits an underlying molecular abnormality represents a particularly attractive therapeutic option for patients with inoperable or recurrent tumors . Studies are also underway to assess everolimus in treating other sequelae of TSC , and other gliomas . Finally , additional research aimed at better understanding aberrant cell signaling pathways may lead to the development of more effective therapeutics .

Interactome mapping of the phosphatidylinositol 3 - kinase-mammalian target of rapamycin pathway identifies deformed epidermal autoregulatory factor - 1 as a new glycogen synthase kinase - 3 interactor . The phosphatidylinositol 3 - kinase-mammalian target of rapamycin ( PI3K - P42345 REA ) pathway plays pivotal roles in cell survival , growth , and proliferation downstream of growth factors . Its perturbations are associated with cancer progression , type 2 diabetes , and neurological disorders . To better understand the mechanisms of action and regulation of this pathway , we initiated a large scale yeast two-hybrid screen for 33 components of the PI3K - P42345 REA pathway . Identification of 67 new interactions was followed by validation by co-affinity purification and exhaustive literature curation of existing information . We provide a nearly complete , functionally annotated interactome of 802 interactions for the PI3K - P42345 REA pathway . Our screen revealed a predominant place for glycogen synthase kinase - 3 ( GSK 3 ) A and B and the AMP-activated protein kinase . In particular , we identified the deformed epidermal autoregulatory factor - 1 ( O75398 ) transcription factor as an interactor and in vitro substrate of P49840 REA and P49841 REA . Moreover , GSK 3 inhibitors increased O75398 transcriptional activity on the P08908 REA serotonin receptor promoter . We propose that O75398 may represent a therapeutic target of lithium and other GSK 3 inhibitors used in bipolar disease and depression .

Cholecystokinin-related peptides , after systemic or central administration , prevent carbon monoxide-induced amnesia in mice . The neuroprotective actions of cholecystokinin ( CCK ) peptides were investigated in a mouse hypoxia model , in which the animals were successively exposed to CO gas . Working memory impairment 5 days after CO exposure was examined by using a Y-maze test ; delayed amnesia was examined 7 days after CO exposure , by using a step-down type passive avoidance test . DB00403 MEN ( 1-100 micrograms / kg , given s . c . 30 min before CO exposure ) significantly prevented the CO-induced impairment of performance in both tests , the improvement being correlated with the severity of hypoxia . This severity was increased by maintaining the body temperature at 38 degrees C . DB00403 MEN was less effective when injected immediately after a single CO exposure . The order of potency of the CCK-peptides administered systemically was : ceruletide > CCK - 8S > CCK - 8NS > > Q13308 . DB00403 MEN ( 0.03- 0.3 micrograms / mouse ) and CCK - 8S ( 0.03- 1 microgram / mouse ) prevented CO-induced amnesia after i . c . v . administration . Under all experimental conditions , dizocilpine [ MK - 801 , ( + ) - 5 - methyl -10,11- dihydro - 5H - dibenzo ( a , d ) cyclohepten -5,10- imine maleate , 500 micrograms / kg s . c . or 10 micrograms / mouse i . c . v . ] prevented completely the CO-induced amnesia . The protective effects of systemic ceruletide were blocked , partially but significantly , by the preadministration of L -364,718 ( 3S - ( - ) - N - [ 2,3- dihydro - 1 - methyl - 2 - oxo-S-phenyl - 1H -1,4- benzodiazepine - 3 - yl ] - 1H - indole - 2 - carboxamide , 1-10 mg / kg i . p . ) , a selective P32238 REA antagonist . L -365,260 ( [ 3R - ( + ) -2,3- dihydro - 1 - methyl - 2 - oxo - 5 - phenyl - 1H -1,4- benzodiazepine - 3 - yl ] - N ' - [ 3 - methyl-phenyl ] urea ) , a CCK-B antagonist , also decreased ceruletide-induced protection . ( ABSTRACT TRUNCATED AT 250 WORDS )

Activation of the p38 MAPK / Akt / P27361 REA / 2 signal pathways is required for the protein stabilization of Q99741 REA and cyclin D1 in low-dose arsenite-induced cell proliferation . DB01169 MEN ( ATO ) is a first-line anti-cancer agent for acute promyelocytic leukemia , and induces apoptosis in other solid cancer cell lines including breast cancer cells . However , as with arsenites found in drinking water and used as raw materials for wood preservatives , insecticides , and herbicides , low doses of ATO can induce carcinogenesis after long-term exposure . At 24 h after exposure , ATO ( 0.01- 1 µM ) significantly increased cell proliferation and promoted cell cycle progression from the P55008 to S / G2 phases in the non-tumorigenic MCF 10A breast epithelial cell line . The expression of 14 out of 96 cell-cycle-associated genes significantly increased , and seven of these genes including cell division cycle 6 ( Q99741 REA ) and cyclin D1 ( P24385 REA ) were closely related to cell cycle progression from P55008 to S phase . Low-dose ATO steadily increased gene transcript and protein levels of both Q99741 REA and cyclin D1 in a dose - and time-dependent manner . Low-dose ATO produced reactive oxygen species ( ROS ) , and activated the p38 MAPK , Akt , and P27361 REA / 2 pathways at different time points within 60 min . Small molecular inhibitors and siRNAs inhibiting the activation of p38 MAPK , Akt , and P27361 REA / 2 decreased the ATO-increased expression of Q99741 REA protein . Inhibiting the activation of Akt and P27361 REA / 2 , but not p38 MAPK , decreased the ATO-induced expression of cyclin D1 protein . This study reports for the first time that p38 MAPK / Akt / P27361 REA / 2 activation is required for the protein stabilization of Q99741 REA in addition to cyclin D1 in ATO-induced cell proliferation and cell cycle modulation from P55008 to S phase .

Prevention of atherosclerosis by the P42345 REA inhibitor everolimus in P01130 REA - / - mice despite severe hypercholesterolemia . DB01590 SUB inhibits the mammalian target of rapamycin ( P42345 REA ) in proliferating cells . It is widely used in transplant patients and has also been exploited by drug-eluting stents for the treatment of cardiovascular disease . However , there is only limited data on the pathophysiological effects of P42345 REA - inhibitors on the vascular wall . We aimed to unravel the effects of everolimus on cholesterol-induced atherosclerosis and on circulating cell mediators in LDL-receptor-deficient ( P01130 REA ( - / - ) ) mice . Male hypercholesterolemic P01130 REA ( - / - ) mice received either solvent ( group A ; n = 28 ) or everolimus at 0.05 mg / kg ( group B , n = 22 ) and 1.5 mg / kg ( group C , n = 29 ) per body weight per day by subcutaneously implanted osmotic minipumps for the study period of 12 weeks . Group B showed 44 % reduction of atherosclerotic lesions at the brachiocephalic artery ( BCA ) . In group C atherosclerotic lesions were reduced by 85 % in the BCA and by 60 % at the aortic root . This was associated with a significantly lower complexity of lesions in both treated groups ( p < 0.001 ) and despite a 40 % increase of plasma cholesterol . DB01590 SUB caused a significant reduction of circulating cell mediators such as interleukin - 1alpha , interleukin - 5 , GM - P04141 REA and interleukin - 12p40 . DB01590 SUB increased the plasma levels of KC but had no effect on eighteen other circulating cell mediators studied . DB01590 SUB strongly inhibits atherosclerosis development in LDL-receptor ( - / - ) mice despite severe hypercholesterolemia . DB01590 SUB application had only small effects on circulating cell mediators . The significant reduction of atherosclerotic lesions was associated with a delayed transition from early macrophages enriched lesions to advanced atherosclerotic plaques .

Antagonizing amyloid-β / calcium-sensing receptor signaling in human astrocytes and neurons : a key to halt Alzheimer ' s disease progression ? Astrocytes ' roles in late-onset Alzheimer ' s disease ( LOAD ) promotion are important , since they survive soluble or fibrillar amyloid-β peptides ( Aβs ) neurotoxic effects , undergo alterations of intracellular and intercellular Ca ( 2 + ) signaling and gliotransmitters release via the Aβ / α7 - nAChR ( α7 - nicotinic acetylcholine receptor ) signaling , and overproduce / oversecrete newly synthesized Aβ42 oligomers , NO , and P15692 REA via the Aβ / P41180 REA ( calcium-sensing receptor ) signaling . Recently , it was suggested that the NMDAR ( N-methyl-D-aspartate receptor ) inhibitor nitromemantine would block the synapse-destroying effects of Aβ / α7 - nAChR signaling . Yet , this and the progressive extracellular accrual and spreading of Aβ42 oligomers would be stopped well upstream by P0C0P6 REA 2143 , an allosteric P41180 REA antagonist ( calcilytic ) .

Map 4k4 suppresses Srebp - 1 and adipocyte lipogenesis independent of JNK signaling . Adipose tissue lipogenesis is paradoxically impaired in human obesity , promoting ectopic triglyceride ( TG ) deposition , lipotoxicity , and insulin resistance . We previously identified mitogen-activated protein kinase kinase kinase kinase 4 ( Map 4k4 ) , a sterile 20 protein kinase reported to be upstream of c-Jun NH2 - terminal kinase ( JNK ) signaling , as a novel negative regulator of insulin-stimulated glucose transport in adipocytes . Using full-genome microarray analysis we uncovered a novel role for Map 4k4 as a suppressor of lipid synthesis . We further report here the surprising finding that Map 4k4 suppresses adipocyte lipogenesis independently of JNK . Thus , while Map 4k4 silencing in adipocytes enhances the expression of lipogenic enzymes , concomitant with increased conversion of ( 14 ) C-glucose and ( 14 ) C-acetate into TGs and fatty acids , P45983 REA and P45984 REA depletion causes the opposite effects . Furthermore , high expression of Map 4k4 fails to activate endogenous JNK , while Map 4k4 depletion does not attenuate JNK activation by tumor necrosis factor α . Map 4k4 silencing in cultured adipocytes elevates both the total protein expression and cleavage of sterol-regulated element binding protein - 1 ( Srebp - 1 ) in a rapamycin-sensitive manner , consistent with Map 4k4 signaling via mechanistic target of rapamycin complex 1 ( mTORC 1 ) . We show Map 4k4 depletion requires Srebp - 1 upregulation to increase lipogenesis and further show that Map 4k4 promotes AMP-protein kinase ( AMPK ) signaling and the phosphorylation of mTORC 1 binding partner raptor ( Ser 792 ) to inhibit mTORC 1 . Our results indicate that Map 4k4 inhibits adipose lipogenesis by suppression of Srebp - 1 in an AMPK - and P42345 REA - dependent but JNK-independent mechanism .

DB01016 MEN exerts an antitumor activity through reactive oxygen species-c-jun NH2 - terminal kinase pathway in human gastric cancer cell line MGC - 803 . DB01016 MENMAX DB01016 MEN , a blocker of DB00171 - sensitive potassium ( K ( DB00171 ) ) channels , can suppress progression of many cancers , but the involved mechanism is unclear . Herein we reported that MGC - 803 cells expressed the K ( DB00171 ) channels composed of Kir 6.2 and Q09428 REA subunits . DB01016 MEN induced cellular viability decline , coupled with cell apoptosis and reactive oxygen species ( ROS ) generation in MGC - 803 cells . Meanwhile , glibenclamide increased NADPH oxidase catalytic subunit gp91 ( phox ) expression and superoxide anion ( O2 - ) generation , and caused mitochondrial respiration dysfunction in MGC - 803 cells , suggesting that glibenclamide induced an increase of ROS derived from NADPH oxidase and mitochondria . DB01016 MEN could also lead to loss of mitochondrial membrane potential , release of cytochrome c and apoptosis-inducing factor ( O95831 ) , and activation of c-jun NH2 - terminal kinase ( JNK ) in MGC - 803 cells . Pretreatment with antioxidant N-acetyl-l-cysteine ( Q9C000 REA ) prevented glibenclamide-induced JNK activation , apoptosis and cellular viability decline . Furthermore , glibenclamide greatly decreased the cellular viability , induced apoptosis and inhibited Akt activation in wild-type mouse embryonic fibroblast ( MEF ) cells but not in P45983 REA - / - or P45984 REA - / - MEF cells . Taken together , our study reveals that glibenclamide exerts an antitumor activity in MGC - 803 cells by activating ROS-dependent , JNK-driven cell apoptosis . These findings provide insights into the use of glibenclamide in the treatment of human gastric cancer .

ROS-mediated autophagy induced by dysregulation of lipid metabolism plays a protective role in colorectal cancer cells treated with gambogic acid . Gambogic acid ( GA ) , the main active component of gamboge resin , has potent antitumor activity both in vivo and in vitro . However , the underlying molecular mechanisms remain unclear . In this study , we found that GA could initiate autophagy in colorectal cancer cells , and inhibition of the autophagy process accelerated the effect of proliferative inhibition and apoptotic cell death induced by GA , implying a protective role of autophagy . Two-dimensional electrophoresis-based proteomics showed that GA treatment altered the expression of multiple proteins involved in redox signaling and lipid metabolism . Functional studies revealed that GA-induced dysregulation of lipid metabolism could activate P09917 REA ( 5 - P28300 REA ) , resulting in intracellular ROS accumulation , followed by inhibition of Akt - P42345 REA signaling and autophagy initiation . Finally , results using a xenograft model suggested ROS-induced autophagy protect against the antitumor effect of GA . Taken together , these data showed new biological activities of GA against colorectal cancer underlying the protective role of ROS-induced autophagy . This study will provide valuable insights for future studies regarding the anticancer mechanisms of GA .

Dependence on phosphoinositide 3 - kinase and DB01367 - RAF pathways drive the activity of RAF 265 , a novel RAF / P35968 REA inhibitor , and RAD 001 ( DB01590 SUB ) in combination . Activation of phosphatidylinositol - 3 - kinase ( PI3K ) - AKT and Kirsten rat sarcoma viral oncogene homologue ( P01116 REA ) can induce cellular immortalization , proliferation , and resistance to anticancer therapeutics such as epidermal growth factor receptor inhibitors or chemotherapy . This study assessed the consequences of inhibiting these two pathways in tumor cells with activation of P01116 REA , PI3K - AKT , or both . We investigated whether the combination of a novel RAF / vascular endothelial growth factor receptor inhibitor , RAF 265 , with a mammalian target of rapamycin ( P42345 REA ) inhibitor , RAD 001 ( everolimus ) , could lead to enhanced antitumoral effects in vitro and in vivo . To address this question , we used cell lines with different status regarding P01116 REA , P42336 REA , and P15056 REA mutations , using immunoblotting to evaluate the inhibitors , and MTT and clonogenic assays for effects on cell viability and proliferation . Subcutaneous xenografts were used to assess the activity of the combination in vivo . RAD 001 inhibited P42345 REA downstream signaling in all cell lines , whereas RAF 265 inhibited RAF downstream signaling only in P15056 REA mutant cells . In vitro , addition of RAF 265 to RAD 001 led to decreased AKT , S6 , and P06730 REA binding protein 1 phosphorylation in HCT 116 cells . In vitro and in vivo , RAD 001 addition enhanced the antitumoral effect of RAF 265 in HCT 116 and H460 cells ( both P01116 REA mut , P42336 REA mut ) ; in contrast , the combination of RAF 265 and RAD 001 yielded no additional activity in A549 and MDAMB 231 cells . The combination of RAF and P42345 REA inhibitors is effective for enhancing antitumoral effects in cells with deregulation of both DB01367 - RAF and PI3K , possibly through the cross-inhibition of 4E binding protein 1 and S6 protein .