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Sample records for underlying signaling pathways

  1. Mechanisms Underlying the Antidepressant Response of Acupuncture via PKA/CREB Signaling Pathway.

    Science.gov (United States)

    Jiang, Huili; Zhang, Xuhui; Wang, Yu; Zhang, Huimin; Li, Jing; Yang, Xinjing; Zhao, Bingcong; Zhang, Chuntao; Yu, Miao; Xu, Mingmin; Yu, Qiuyun; Liang, Xingchen; Li, Xiang; Shi, Peng; Bao, Tuya

    2017-01-01

    Protein kinase A (PKA)/cAMP response element-binding (CREB) protein signaling pathway, contributing to impaired neurogenesis parallel to depressive-like behaviors, has been identified as the crucial factor involved in the antidepressant response of acupuncture. However, the molecular mechanisms associated with antidepressant response of acupuncture, neurogenesis, and depressive-like behaviors ameliorating remain unexplored. The objective was to identify the mechanisms underlying the antidepressant response of acupuncture through PKA signaling pathway in depression rats by employing the PKA signaling pathway inhibitor H89 in in vivo experiments. Our results indicated that the expression of hippocampal PKA- α and p-CREB was significantly downregulated by chronic unpredicted mild stress (CUMS) procedures. Importantly, acupuncture reversed the downregulation of PKA- α and p-CREB. The expression of PKA- α was upregulated by fluoxetine, but not p-CREB. No significant difference was found between Acu and FLX groups on the expression of PKA- α and p-CREB. Interestingly, H89 inhibited the effects of acupuncture or fluoxetine on upregulating the expression of p-CREB, but not PKA- α . There was no significant difference in expression of CREB among the groups. Conclusively, our findings further support the hypothesis that acupuncture could ameliorate depressive-like behaviors by regulating PKA/CREB signaling pathway, which might be mainly mediated by regulating the phosphorylation level of CREB.

  2. Signaling pathway underlying the octopaminergic modulation of myogenic contraction in the cricket lateral oviduct.

    Science.gov (United States)

    Tamashiro, Hirotake; Yoshino, Masami

    2014-12-01

    Octopamine (OA), a biogenic monoamine, is a neurotransmitter and neuromodulator in invertebrates. Here, we report the effect of OA on the spontaneous rhythmic contractions (SRCs) of the lateral oviduct of the cricket Gryllus bimaculatus and the possible signaling pathway involved. Application of OA increased both the frequency and amplitude of SRCs in a dose-dependent manner. The effect of OA was inhibited by subsequent application of the OA receptor antagonist epinastine, indicating that the action of OA is mediated by OA receptor. To investigate the predominant signaling pathway underlying the action of OA, we first examined a possible involvement of the cAMP/cAMP-dependent protein kinase A (PKA) signaling pathway. Application of the membrane-permeable cAMP analog 8-Br-cAMP had little effect on SRCs and the effect of OA was not influenced by subsequent application of the PKA inhibitor H89, indicating that the cAMP/PKA signaling pathway is not the predominant pathway in the action of OA. Next, we examined a possible involvement of the second messenger inositol 1,4,5-trisphosphate in the action of OA. The effect of OA on SRCs was inhibited by subsequent application of the phosphoinositide-specific phospholipase C (PLC) inhibitor U73122, indicating that the PLC pathway is involved in the action of OA. The OA-induced increase in the frequency of SRCs was inhibited by pretreatment of the cell with the ryanodine receptor antagonist tetracaine but was not significantly affected by the IP3 receptor antagonist 2-aminoethoxydiphenyl borate (2-APB). On the other hand, the OA-induced increase in the amplitude of SRCs was inhibited by pretreatment of the cells with 2-APB but was not significantly affected by tetracaine. Taken together, these results suggest that the OA-induced excitatory effect on SRCs is mediated by the PLC signaling pathway: Ca2+ release from IP3 receptors may contribute to the modulation of the amplitude of SRCs, whereas Ca2+ release from ryanodine

  3. ROS signaling under metabolic stress: cross-talk between AMPK and AKT pathway.

    Science.gov (United States)

    Zhao, Yang; Hu, Xingbin; Liu, Yajing; Dong, Shumin; Wen, Zhaowei; He, Wanming; Zhang, Shuyi; Huang, Qiong; Shi, Min

    2017-04-13

    Cancer cells are frequently confronted with metabolic stress in tumor microenvironments due to their rapid growth and limited nutrient supply. Metabolic stress induces cell death through ROS-induced apoptosis. However, cancer cells can adapt to it by altering the metabolic pathways. AMPK and AKT are two primary effectors in response to metabolic stress: AMPK acts as an energy-sensing factor which rewires metabolism and maintains redox balance. AKT broadly promotes energy production in the nutrient abundance milieu, but the role of AKT under metabolic stress is in dispute. Recent studies show that AMPK and AKT display antagonistic roles under metabolic stress. Metabolic stress-induced ROS signaling lies in the hub between metabolic reprogramming and redox homeostasis. Here, we highlight the cross-talk between AMPK and AKT and their regulation on ROS production and elimination, which summarizes the mechanism of cancer cell adaptability under ROS stress and suggests potential options for cancer therapeutics.

  4. Up-regulation of abscisic acid signaling pathway facilitates aphid xylem absorption and osmoregulation under drought stress

    Science.gov (United States)

    Guo, Huijuan; Sun, Yucheng; Peng, Xinhong; Wang, Qinyang; Harris, Marvin; Ge, Feng

    2016-01-01

    The activation of the abscisic acid (ABA) signaling pathway reduces water loss from plants challenged by drought stress. The effect of drought-induced ABA signaling on the defense and nutrition allocation of plants is largely unknown. We postulated that these changes can affect herbivorous insects. We studied the effects of drought on different feeding stages of pea aphids in the wild-type A17 of Medicago truncatula and ABA signaling pathway mutant sta-1. We examined the impact of drought on plant water status, induced plant defense signaling via the abscisic acid (ABA), jasmonic acid (JA), and salicylic acid (SA) pathways, and on the host nutritional quality in terms of leaf free amino acid content. During the penetration phase of aphid feeding, drought decreased epidermis/mesophyll resistance but increased mesophyll/phloem resistance of A17 but not sta-1 plants. Quantification of transcripts associated with ABA, JA and SA signaling indicated that the drought-induced up-regulation of ABA signaling decreased the SA-dependent defense but increased the JA-dependent defense in A17 plants. During the phloem-feeding phase, drought had little effect on the amino acid concentrations and the associated aphid phloem-feeding parameters in both plant genotypes. In the xylem absorption stage, drought decreased xylem absorption time of aphids in both genotypes because of decreased water potential. Nevertheless, the activation of the ABA signaling pathway increased water-use efficiency of A17 plants by decreasing the stomatal aperture and transpiration rate. In contrast, the water potential of sta-1 plants (unable to close stomata) was too low to support xylem absorption activity of aphids; the aphids on sta-1 plants had the highest hemolymph osmolarity and lowest abundance under drought conditions. Taken together this study illustrates the significance of cross-talk between biotic-abiotic signaling pathways in plant-aphid interaction, and reveals the mechanisms leading to alter

  5. Survival pathways under stress

    Indian Academy of Sciences (India)

    First page Back Continue Last page Graphics. Survival pathways under stress. Bacteria survive by changing gene expression. pattern. Three important pathways will be discussed: Stringent response. Quorum sensing. Proteins performing function to control oxidative damage.

  6. Effect of ERK1/2 signal pathway on the expression of OPG/RANKL in cementoblasts under stress stimulation

    Directory of Open Access Journals (Sweden)

    Feng-xue YANG

    2015-01-01

    Full Text Available Objective To explore the effect of extracellular signal regulated kinase (ERK1/2 on the expression of osteoprotegerin/receptor activator of nuclear factor κB ligand (OPG/RANKL in cementoblasts under mechanical tensile stress stimulation. Methods Using Flexcell FX4000T tension loading system and the ERK1/2-specific inhibitor PD98059, cementoblasts OCCM30 were randomly divided into four groups: group A (without loading and inhibitor, group B (without loading but inhibitor, group C (loading but without inhibitor, and group D (with both loading and inhibitor. The phosphorylation level of ERK1/2 was measured by Western blotting after 5, 15, 30 and 60min loading. OPG and RANKL mRNA were analyzed with fluorescent quantitative RT-PCR after 12h loading. Results Mechanical tensile stress activated ERK1/2 signal pathway of group C rapidly, and the P-ERK1/2 levels were significantly higher in group C than in group A at 5, 15 and 30min (P<0.05, then the P-ERK1/2 level of group C resumed to similar level of group A at 60min. The P-ERK levels of group B and D were significantly reduced by inhibitor PD98059. Tension stress up-regulated the expression of RANKL mRNA, and down-regulated the expression of OPG mRNA in OCCM30, the RANKL/OPG ratio increased after tension loading. With PD98059, the expression of RANKL mRNA decreased, that of OPG mRNA increased, and the RANKL/OPG ratio decreased (P<0.05. Conclusion ERK1/2 may be a signal transduction pathway for the regulation of OPG and RANKL expression after tension stress loading, but it is not the only one of activation pathways, and there may be other common signal pathways involved in the regulation of OPG and RANKL expression. DOI: 10.11855/j.issn.0577-7402.2014.12.03

  7. ROS signaling under metabolic stress: cross-talk between AMPK and AKT pathway

    OpenAIRE

    Zhao, Yang; Hu, Xingbin; Liu, Yajing; Dong, Shumin; Wen, Zhaowei; He, Wanming; Zhang, Shuyi; Huang, Qiong; Shi, Min

    2017-01-01

    Cancer cells are frequently confronted with metabolic stress in tumor microenvironments due to their rapid growth and limited nutrient supply. Metabolic stress induces cell death through ROS-induced apoptosis. However, cancer cells can adapt to it by altering the metabolic pathways. AMPK and AKT are two primary effectors in response to metabolic stress: AMPK acts as an energy-sensing factor which rewires metabolism and maintains redox balance. AKT broadly promotes energy production in the nut...

  8. Crosstalk between adenylyl cyclase signaling pathway and Ca2+ regulatory mechanism under red blood cell microrheological changes.

    Science.gov (United States)

    Muravyov, Alexei V; Tikhomirova, Irina A; Maimistova, Alla A; Bulaeva, Svetlana V; Zamishlayev, Andrey V; Batalova, Ekaterina A

    2010-01-01

    There are evidences that red blood cell (RBC) deformation and aggregation change under their incubation with catecholamines and it is connected with activation of intracellular signaling pathways. The present study was designed to explore the adenylyl cyclase signaling pathway and Ca2+ regulatory mechanism of RBCs together with their microrheological changes. The washed RBCs were resuspended in PBS. In each of the three research sessions RBC suspensions were divided into two aliquots: 1) control (without drug) and 2) with an appropriate drug. After cell incubation RBC deformability (RBCD) and aggregation (RBCA) were estimated. RBC incubation with catecholamines resulted in RBCD changes by 18-30%. RBCs incubation with forskolin facilitated an increase of RBCD by 17% (p RBCA; whereas red cell deformability was changed only slightly. On the other hand, Ca2+ entry blocking into the cells by verapamil has led to significant RBCA decrease and RBCD rise. The obtained results make us believe that RBCD change was closely associated with Ca2+ control mechanisms. An effect of Ca2+ concentration increase on RBC microrheology was removed, if it was preliminary added to incubation medium EGTA as Ca2+ chelator. It was found that all four PDE inhibitors: IBMX, vinpocetine, rolipram, pentoxifylline decreased RBCA significantly and, quite the contrary, they increased red cell deformability. Our data have shown that Ca2+ entry increase was accompanied by red cell aggregation rise, while adenylyl cyclase-cAMP system stimulation led to red cell deformability increase and its aggregation lowered. The crosstalk between two intracellular signaling systems is probably connected with phosphodiesterase activity.

  9. Mechanisms underlying the perifocal neuroprotective effect of the Nrf2–ARE signaling pathway after intracranial hemorrhage

    Directory of Open Access Journals (Sweden)

    Yin XP

    2015-11-01

    Full Text Available Xiao-ping Yin,1,2 Zhi-ying Chen,2 Jun Zhou,1 Dan Wu,1,3 Bing Bao2 1Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China; 2Department of Neurology, Affiliated Hospital of Jiujiang University, Jiujiang, People’s Republic of China; 3Department of Neurology, The Sixth Hospital of Wuhan, Wuhan, People’s Republic of China Background: It has been found that nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2–ARE signaling pathway plays a role in antioxidative response, anti-inflammatory response, and neuron-protection in intracerebral hemorrhage (ICH. The aim of this study is to explore mechanisms underlying the perifocal neuroprotective effect of the Nrf2–ARE signaling pathway after ICH.Methods: There were a total of 90 rats with basal ganglia hemorrhage, which were randomly divided into the following four groups: ICH (Sprague–Dawley rats with autologous femoral arterial blood injection into the basal ganglia, sulforaphane (SFN (SFN was intraperitoneally administered into rats, retinoic acid (RA (RA was intraperitoneally administered into rats, and dimethyl sulfoxide (the rats were treated with dimethyl sulfoxide. We observed the neurological score of the rats in the different groups, and collected brain tissues for immunofluorescence, Western blot, and reverse transcription polymerase chain reaction to detect expression of Nrf2, heme oxygenase (HO-1, nuclear factor-κB (NF-κB, and tumor necrosis factor-α (TNF-α.Results: The results indicated that neurological dysfunction of rats was significantly improved in the SFN group, and the expressions of Nrf2 and HO-1 in tissues surrounding the hemorrhage were increased. Also, the level of NF-κB and TNF-α were reduced compared to the ICH group. The RA group exhibited more severe neurological dysfunction and lower levels of Nrf2 and HO-1 than the SFN and ICH groups. Compared to the ICH group, the NF

  10. Corruption of homeostatic mechanisms in the guanylyl cyclase C signaling pathway underlying colorectal tumorigenesis

    Science.gov (United States)

    Waldman, Scott A

    2010-01-01

    Colon cancer, the second leading cause of cancer-related mortality worldwide, originates from the malignant transformation of intestinal epithelial cells. The intestinal epithelium undergoes a highly organized process of rapid regeneration along the crypt-villus axis, characterized by proliferation, migration, differentiation and apoptosis, whose coordination is essential to maintaining the mucosal barrier. Disruption of these homeostatic processes predisposes cells to mutations in tumor suppressors or oncogenes, whose dysfunction provides transformed cells an evolutionary growth advantage. While sequences of genetic mutations at different stages along the neoplastic continuum have been established, little is known of the events initiating tumorigenesis prior to adenomatous polyposis coli (APC) mutations. Here, we examine a role for the corruption of homeostasis induced by silencing novel tumor suppressors, including the intestine-specific transcription factor CDX2 and its gene target guanylyl cyclase C (GCC), as early events predisposing cells to mutations in APC and other sequential genes that initiate colorectal cancer. CDX2 and GCC maintain homeostatic regeneration in the intestine by restricting cell proliferation, promoting cell maturation and adhesion, regulating cell migration and defending the intestinal barrier and genomic integrity. Elimination of CDX2 or GCC promotes intestinal tumor initiation and growth in aged mice, mice carrying APC mutations or mice exposed to carcinogens. The roles of CDX2 and GCC in suppressing intestinal tumorigenesis, universal disruption in their signaling through silencing of hormones driving GCC, and the uniform overexpression of GCC by tumors underscore the potential value of oral replacement with GCC ligands as targeted prevention and therapy for colorectal cancer. PMID:20592492

  11. Corruption of homeostatic mechanisms in the guanylyl cyclase C signaling pathway underlying colorectal tumorigenesis.

    Science.gov (United States)

    Li, Peng; Waldman, Scott A

    2010-08-01

    Colon cancer, the second leading cause of cancer-related mortality worldwide, originates from the malignant transformation of intestinal epithelial cells. The intestinal epithelium undergoes a highly organized process of rapid regeneration along the crypt-villus axis, characterized by proliferation, migration, differentiation and apoptosis, whose coordination is essential to maintaining the mucosal barrier. Disruption of these homeostatic processes predisposes cells to mutations in tumor suppressors or oncogenes, whose dysfunction provides transformed cells an evolutionary growth advantage. While sequences of genetic mutations at different stages along the neoplastic continuum have been established, little is known of the events initiating tumorigenesis prior to adenomatous polyposis coli (APC) mutations. Here, we examine a role for the corruption of homeostasis induced by silencing novel tumor suppressors, including the intestine-specific transcription factor CDX2 and its gene target guanylyl cyclase C (GCC), as early events predisposing cells to mutations in APC and other sequential genes that initiate colorectal cancer. CDX2 and GCC maintain homeostatic regeneration in the intestine by restricting cell proliferation, promoting cell maturation and adhesion, regulating cell migration and defending the intestinal barrier and genomic integrity. Elimination of CDX2 or GCC promotes intestinal tumor initiation and growth in aged mice, mice carrying APC mutations or mice exposed to carcinogens. The roles of CDX2 and GCC in suppressing intestinal tumorigenesis, universal disruption in their signaling through silencing of hormones driving GCC, and the uniform overexpression of GCC by tumors underscore the potential value of oral replacement with GCC ligands as targeted prevention and therapy for colorectal cancer.

  12. Extra- and intracellular signaling pathways under red blood cell aggregation and deformability changes.

    Science.gov (United States)

    Muravyov, Alexei V; Tikhomirova, Irina A; Maimistova, Alla A; Bulaeva, Svetlana V

    2009-01-01

    Exposure of red blood cells (RBCs) to catecholamines (epinephrine, phenylephrine, an agonist of alpha1-adrenergic receptors, clonidine, an agonist of alpha2-adrenergic receptors and isoproterenol, an agonist of beta-adrenergic receptors) led to change in the RBC microrheological properties. When forskolin (10 microM), an AC stimulator was added to RBC suspension, the RBC deformability (RBCD) was increased by 17% (pRBCA) was significantly decreased under these conditions (pRBCA reduction effect was found under cell incubation with pentoxifylline and inhibitor PDE1-vinpocetine. On the whole RBCA reduction averaged 36% (pRBCA, whereas red cell deformability was changed insignificantly. At the same time Ca2+ entry blocking into the red cells by verapamil or its chelating in medium by EGTA led to significant RBCA decrease and deformability rise (pRBCA decrease was mainly associated with an activation of the adenylyl-cyclase-cAMP system, while the red cell deformability was closely associated with Ca2+ control mechanisms.

  13. Quantitative Proteomic Analyses Identify ABA-related Proteins and Signal Pathways in Maize Leaves Under Drought Conditions

    Directory of Open Access Journals (Sweden)

    zhao Yulong

    2016-12-01

    Full Text Available Drought stress is one of major factors resulting in maize yield loss. The roles of abscisic acid (ABA have been widely studied in crops in response to drought stress. However, more attention is needed to identify key ABA-related proteins and also gain deeper molecular insights about drought stress in maize. Based on this need, the physiology and proteomics of the ABA-deficient maize mutant vp5 and its wild-type Vp5 under drought stress were examined and analyzed. Malondialdehyde content increased and quantum efficiency of photosystem II decreased under drought stress in both genotypes. However, the magnitude of the increase or decrease was significantly higher in vp5 than in Vp5. A total of 7051 proteins with overlapping expression patterns among three replicates in the two genotypes were identified by Multiplex run iTRAQ-based quantitative proteomic and liquid chromatography-tandem mass spectrometry methods, of which the expression of only 150 proteins (130 in Vp5, 27 in vp5 showed changes of at least 1.5-fold under drought stress. Among the 150 proteins, 67 and 60 proteins were up-regulated and down-regulated by drought stress in an ABA-dependent way, respectively. ABA was found to play active roles in regulating signaling pathways related to photosynthesis, oxidative phosphorylation (mainly related to ATP synthesis, and glutathione metabolism (involved in antioxidative reaction in the maize response to drought stress. Our results provide an extensive dataset of ABA-dependent, drought-regulated proteins in maize plants, which may help to elucidate the underlying mechanisms of ABA-enhanced tolerance to drought stress in maize.

  14. Critical nodes in signalling pathways

    DEFF Research Database (Denmark)

    Taniguchi, Cullen M; Emanuelli, Brice; Kahn, C Ronald

    2006-01-01

    Physiologically important cell-signalling networks are complex, and contain several points of regulation, signal divergence and crosstalk with other signalling cascades. Here, we use the concept of 'critical nodes' to define the important junctions in these pathways and illustrate their unique role...

  15. ins-7 Gene expression is partially regulated by the DAF-16/IIS signaling pathway in Caenorhabditis elegans under celecoxib intervention.

    Science.gov (United States)

    Zheng, Shanqing; Liao, Sentai; Zou, Yuxiao; Qu, Zhi; Liu, Fan

    2014-01-01

    DAF-16 target genes are employed as reporters of the insulin/IGF-1 like signal pathway (IIS), and this is notably true when Caenorhabditis elegans (C. elegans) is used to study the action of anti-aging compounds on IIS activity. However, some of these genes may not be specific to DAF-16, even if their expression levels are altered when DAF-16 is activated. Celecoxib was reported to extend the lifespan of C. elegans through activation of DAF-16. Our results confirmed the function of celecoxib on aging; however, we found that the expression of ins-7, a DAF-16 target gene, was abnormally regulated by celecoxib. ins-7 plays an important role in regulating aging, and its expression is suppressed in C. elegans when DAF-16 is activated. However, we found that celecoxib upregulated the expression of ins-7 in contrast to its role in DAF-16 activation. Our subsequent analysis indicated that the expression level of ins-7 in C. elegans was negatively regulated by DAF-16 activity. Additionally, its expression was also positively regulated by DAF-16-independent mechanisms, at least following external pharmacological intervention. Our study suggests that ins-7 is not a specific target gene of DAF-16, and should not be chosen as a reporter for IIS activity. This conclusion is important in the study of INSs on aging in C. elegans, especially under the circumstance of drug intervention.

  16. Retroactive signaling in short signaling pathways.

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    Jacques-Alexandre Sepulchre

    Full Text Available In biochemical signaling pathways without explicit feedback connections, the core signal transduction is usually described as a one-way communication, going from upstream to downstream in a feedforward chain or network of covalent modification cycles. In this paper we explore the possibility of a new type of signaling called retroactive signaling, offered by the recently demonstrated property of retroactivity in signaling cascades. The possibility of retroactive signaling is analysed in the simplest case of the stationary states of a bicyclic cascade of signaling cycles. In this case, we work out the conditions for which variables of the upstream cycle are affected by a change of the total amount of protein in the downstream cycle, or by a variation of the phosphatase deactivating the same protein. Particularly, we predict the characteristic ranges of the downstream protein, or of the downstream phosphatase, for which a retroactive effect can be observed on the upstream cycle variables. Next, we extend the possibility of retroactive signaling in short but nonlinear signaling pathways involving a few covalent modification cycles.

  17. Aberrant Signaling Pathways in Glioma

    International Nuclear Information System (INIS)

    Nakada, Mitsutoshi; Kita, Daisuke; Watanabe, Takuya; Hayashi, Yutaka; Teng, Lei; Pyko, Ilya V.; Hamada, Jun-Ichiro

    2011-01-01

    Glioblastoma multiforme (GBM), a WHO grade IV malignant glioma, is the most common and lethal primary brain tumor in adults; few treatments are available. Median survival rates range from 12–15 months. The biological characteristics of this tumor are exemplified by prominent proliferation, active invasiveness, and rich angiogenesis. This is mainly due to highly deregulated signaling pathways in the tumor. Studies of these signaling pathways have greatly increased our understanding of the biology and clinical behavior of GBM. An integrated view of signal transduction will provide a more useful approach in designing novel therapies for this devastating disease. In this review, we summarize the current understanding of GBM signaling pathways with a focus on potential molecular targets for anti-signaling molecular therapies

  18. Targeting Apoptosis Signaling Pathways for Anticancer Therapy

    International Nuclear Information System (INIS)

    Fulda, Simone

    2011-01-01

    Treatment approaches for cancer, for example chemotherapy, radiotherapy, or immunotherapy, primarily act by inducing cell death in cancer cells. Consequently, the inability to trigger cell death pathways or alternatively, evasion of cancer cells to the induction of cell death pathways can result in resistance of cancers to current treatment protocols. Therefore, in order to overcome treatment resistance a better understanding of the underlying mechanisms that regulate cell death and survival pathways in cancers and in response to cancer therapy is necessary to develop molecular-targeted therapies. This strategy should lead to more effective and individualized treatment strategies that selectively target deregulated signaling pathways in a tumor type- and patient-specific manner.

  19. Signaling pathways controlling skeletal muscle mass

    Science.gov (United States)

    Egerman, Marc A.

    2014-01-01

    The molecular mechanisms underlying skeletal muscle maintenance involve interplay between multiple signaling pathways. Under normal physiological conditions, a network of interconnected signals serves to control and coordinate hypertrophic and atrophic messages, culminating in a delicate balance between muscle protein synthesis and proteolysis. Loss of skeletal muscle mass, termed “atrophy”, is a diagnostic feature of cachexia seen in settings of cancer, heart disease, chronic obstructive pulmonary disease, kidney disease, and burns. Cachexia increases the likelihood of death from these already serious diseases. Recent studies have further defined the pathways leading to gain and loss of skeletal muscle as well as the signaling events that induce differentiation and post-injury regeneration, which are also essential for the maintenance of skeletal muscle mass. In this review, we summarize and discuss the relevant recent literature demonstrating these previously undiscovered mediators governing anabolism and catabolism of skeletal muscle. PMID:24237131

  20. Large-Scale microRNA Expression Profiling Identifies Putative Retinal miRNA-mRNA Signaling Pathways Underlying Form-Deprivation Myopia in Mice.

    Science.gov (United States)

    Tkatchenko, Andrei V; Luo, Xiaoyan; Tkatchenko, Tatiana V; Vaz, Candida; Tanavde, Vivek M; Maurer-Stroh, Sebastian; Zauscher, Stefan; Gonzalez, Pedro; Young, Terri L

    2016-01-01

    Development of myopia is associated with large-scale changes in ocular tissue gene expression. Although differential expression of coding genes underlying development of myopia has been a subject of intense investigation, the role of non-coding genes such as microRNAs in the development of myopia is largely unknown. In this study, we explored myopia-associated miRNA expression profiles in the retina and sclera of C57Bl/6J mice with experimentally induced myopia using microarray technology. We found a total of 53 differentially expressed miRNAs in the retina and no differences in miRNA expression in the sclera of C57BL/6J mice after 10 days of visual form deprivation, which induced -6.93 ± 2.44 D (p myopia. We also identified their putative mRNA targets among mRNAs found to be differentially expressed in myopic retina and potential signaling pathways involved in the development of form-deprivation myopia using miRNA-mRNA interaction network analysis. Analysis of myopia-associated signaling pathways revealed that myopic response to visual form deprivation in the retina is regulated by a small number of highly integrated signaling pathways. Our findings highlighted that changes in microRNA expression are involved in the regulation of refractive eye development and predicted how they may be involved in the development of myopia by regulating retinal gene expression.

  1. Large-Scale microRNA Expression Profiling Identifies Putative Retinal miRNA-mRNA Signaling Pathways Underlying Form-Deprivation Myopia in Mice.

    Directory of Open Access Journals (Sweden)

    Andrei V Tkatchenko

    Full Text Available Development of myopia is associated with large-scale changes in ocular tissue gene expression. Although differential expression of coding genes underlying development of myopia has been a subject of intense investigation, the role of non-coding genes such as microRNAs in the development of myopia is largely unknown. In this study, we explored myopia-associated miRNA expression profiles in the retina and sclera of C57Bl/6J mice with experimentally induced myopia using microarray technology. We found a total of 53 differentially expressed miRNAs in the retina and no differences in miRNA expression in the sclera of C57BL/6J mice after 10 days of visual form deprivation, which induced -6.93 ± 2.44 D (p < 0.000001, n = 12 of myopia. We also identified their putative mRNA targets among mRNAs found to be differentially expressed in myopic retina and potential signaling pathways involved in the development of form-deprivation myopia using miRNA-mRNA interaction network analysis. Analysis of myopia-associated signaling pathways revealed that myopic response to visual form deprivation in the retina is regulated by a small number of highly integrated signaling pathways. Our findings highlighted that changes in microRNA expression are involved in the regulation of refractive eye development and predicted how they may be involved in the development of myopia by regulating retinal gene expression.

  2. DMPD: Signal integration between IFNgamma and TLR signalling pathways in macrophages. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 16920490 Signal integration between IFNgamma and TLR signalling pathways in macroph...tml) (.csml) Show Signal integration between IFNgamma and TLR signalling pathways in macrophages. PubmedID 1...6920490 Title Signal integration between IFNgamma and TLR signalling pathways in

  3. Signalling pathways in pemphigus vulgaris.

    Science.gov (United States)

    Li, Xiaoguang; Ishii, Norito; Ohata, Chika; Furumura, Minao; Hashimoto, Takashi

    2014-03-01

    Acantholysis in pemphigus vulgaris is induced by binding of autoantibodies to desmoglein 3 (Dsg3). The roles of signalling pathways on development of acantholysis have recently been extensively studied. In the study by Sayar et al., recently published in Exp Dermatol, epidermal growth factor receptor (EGFR) signalling was activated in both in vivo and in vitro pemphigus vulgaris experimental models. However, while EGFR inhibitors suppressed activity of p38 mitogen-activated protein kinase (p38MAPK) linearly, they suppressed activity of c-Myc and acantholysis in a non-linear, V-shaped relationship. These findings indicated complicated interactions among EGFR, p38MAPK and c-Myc in pemphigus vulgaris pathology. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  4. Redox Signaling and CBF-Responsive Pathway Are Involved in Salicylic Acid-Improved Photosynthesis and Growth under Chilling Stress in Watermelon

    Science.gov (United States)

    Cheng, Fei; Lu, Junyang; Gao, Min; Shi, Kai; Kong, Qiusheng; Huang, Yuan; Bie, Zhilong

    2016-01-01

    Salicylic acid (SA) plays an important role in plant response to abiotic stresses. This study investigated the potential role of SA in alleviating the adverse effects of chilling stress on photosynthesis and growth in watermelon (Citrullus lanatus). Chilling stress induced the simultaneous accumulation of free and conjugated SA in watermelon plants, and the chilling-induced SA production was attributed to the phenylalanine ammonia-lyase pathway. Applying SA at moderate concentrations induced chilling tolerance, whereas inhibition of SA biosynthesis by L-α-aminooxy-β-phenylpropionic acid (AOPP) increased the photooxidation of PS II under chilling stress in watermelon, resulting in reduced photosynthesis and growth. Chilling induced a transient increase in the ratios of reduced to oxidized glutathione and reduced ascorbate to dehydroascorbate. Then, the expression of antioxidant genes was upregulated, and the activities of antioxidant enzymes were enhanced. Furthermore, SA-induced chilling tolerance was associated with cellular glutathione and ascorbate homeostasis, which served as redox signals to regulate antioxidant metabolism under chilling stress. AOPP treatment stimulated the chilling-induced expression of cold-responsive genes, particularly via C-repeat binding factors CBF3 and CBF4. These results confirm the synergistic role of SA signaling and the CBF-dependent responsive pathway during chilling stress in watermelon. PMID:27777580

  5. Redox Signaling and CBF-Responsive Pathway are Involved in Salicylic Acid-Improved Photosynthesis and Growth under Chilling Stress in Watermelon

    Directory of Open Access Journals (Sweden)

    Fei Cheng

    2016-10-01

    Full Text Available Salicylic acid (SA plays an important role in plant response to abiotic stresses. This study investigated the potential role of SA in alleviating the adverse effects of chilling stress on photosynthesis and growth in watermelon (Citrullus lanatus. Chilling stress induced the simultaneous accumulation of free and conjugated SA in watermelon plants, and the chilling-induced SA production was attributed to the phenylalanine ammonia-lyase pathway. Applying SA at moderate concentrations induced chilling tolerance, whereas inhibition of SA biosynthesis by L-ɑ-aminooxy-β-phenylpropionic acid (AOPP increased the photooxidation of PS II under chilling stress in watermelon, resulting in reduced photosynthesis and growth. Chilling induced a transient increase in the ratios of reduced to oxidized glutathione and reduced ascorbate to dehydroascorbate. Then, the expression of antioxidant genes was upregulated, and the activities of antioxidant enzymes were enhanced. Furthermore, SA-induced chilling tolerance was associated with cellular glutathione and ascorbate homeostasis, which served as redox signals to regulate antioxidant metabolism under chilling stress. AOPP treatment stimulated the chilling-induced expression of cold-responsive genes, particularly via C-repeat binding factors CBF3 and CBF4. These results confirm the synergistic role of SA signaling and the CBF-dependent responsive pathway during chilling stress in watermelon.

  6. Modularized study of human calcium signalling pathway

    Indian Academy of Sciences (India)

    PRAKASH KUMAR

    The idea is used here to break human calcium signalling pathway into simple entities known as ... [Nayak L and De R K 2007 Modularized study of human calcium signalling pathway; J. Biosci. 32 1009–1017] http://www.ias.ac.in/ ..... cellular physiology of intracellular calcium stores; Physiol. Rev. 74 595–636. Bertram R ...

  7. Signaling pathways in a Citrus EST database

    Directory of Open Access Journals (Sweden)

    Angela Mehta

    2007-01-01

    Full Text Available Citrus spp. are economically important crops, which in Brazil are grown mainly in the State of São Paulo. Citrus cultures are attacked by several pathogens, causing severe yield losses. In order to better understand this culture, the Millenium Project (IAC Cordeirópolis was launched in order to sequence Citrus ESTs (expressed sequence tags from different tissues, including leaf, bark, fruit, root and flower. Plants were submitted to biotic and abiotic stresses and investigated under different development stages (adult vs. juvenile. Several cDNA libraries were constructed and the sequences obtained formed the Citrus ESTs database with almost 200,000 sequences. Searches were performed in the Citrus database to investigate the presence of different signaling pathway components. Several of the genes involved in the signaling of sugar, calcium, cytokinin, plant hormones, inositol phosphate, MAPKinase and COP9 were found in the citrus genome and are discussed in this paper. The results obtained may indicate that similar mechanisms described in other plants, such as Arabidopsis, occur in citrus. Further experimental studies must be conducted in order to understand the different signaling pathways present.

  8. A genome-wide siRNA screen reveals multiple mTORC1 independent signaling pathways regulating autophagy under normal nutritional conditions.

    Science.gov (United States)

    Lipinski, Marta M; Hoffman, Greg; Ng, Aylwin; Zhou, Wen; Py, Bénédicte F; Hsu, Emily; Liu, Xuxin; Eisenberg, Jason; Liu, Jun; Blenis, John; Xavier, Ramnik J; Yuan, Junying

    2010-06-15

    Autophagy is a cellular catabolic mechanism that plays an essential function in protecting multicellular eukaryotes from neurodegeneration, cancer, and other diseases. However, we still know very little about mechanisms regulating autophagy under normal homeostatic conditions when nutrients are not limiting. In a genome-wide human siRNA screen, we demonstrate that under normal nutrient conditions upregulation of autophagy requires the type III PI3 kinase, but not inhibition of mTORC1, the essential negative regulator of starvation-induced autophagy. We show that a group of growth factors and cytokines inhibit the type III PI3 kinase through multiple pathways, including the MAPK-ERK1/2, Stat3, Akt/Foxo3, and CXCR4/GPCR, which are all known to positively regulate cell growth and proliferation. Our study suggests that the type III PI3 kinase integrates diverse signals to regulate cellular levels of autophagy, and that autophagy and cell proliferation may represent two alternative cell fates that are regulated in a mutually exclusive manner. Copyright 2010 Elsevier Inc. All rights reserved.

  9. Genes and (common pathways underlying drug addiction.

    Directory of Open Access Journals (Sweden)

    Chuan-Yun Li

    2008-01-01

    Full Text Available Drug addiction is a serious worldwide problem with strong genetic and environmental influences. Different technologies have revealed a variety of genes and pathways underlying addiction; however, each individual technology can be biased and incomplete. We integrated 2,343 items of evidence from peer-reviewed publications between 1976 and 2006 linking genes and chromosome regions to addiction by single-gene strategies, microrray, proteomics, or genetic studies. We identified 1,500 human addiction-related genes and developed KARG (http://karg.cbi.pku.edu.cn, the first molecular database for addiction-related genes with extensive annotations and a friendly Web interface. We then performed a meta-analysis of 396 genes that were supported by two or more independent items of evidence to identify 18 molecular pathways that were statistically significantly enriched, covering both upstream signaling events and downstream effects. Five molecular pathways significantly enriched for all four different types of addictive drugs were identified as common pathways which may underlie shared rewarding and addictive actions, including two new ones, GnRH signaling pathway and gap junction. We connected the common pathways into a hypothetical common molecular network for addiction. We observed that fast and slow positive feedback loops were interlinked through CAMKII, which may provide clues to explain some of the irreversible features of addiction.

  10. Modularized TGFbeta-Smad Signaling Pathway

    Science.gov (United States)

    Li, Yongfeng; Wang, M.; Carra, C.; Cucinotta, F. A.

    2011-01-01

    The Transforming Growth Factor beta (TGFbeta) signaling pathway is a prominent regulatory signaling pathway controlling various important cellular processes. It can be induced by several factors, including ionizing radiation. It is regulated by Smads in a negative feedback loop through promoting increases in the regulatory Smads in the cell nucleus, and subsequent expression of inhibitory Smad, Smad7 to form a ubiquitin ligase with Smurf targeting active TGF receptors for degradation. In this work, we proposed a mathematical model to study the radiation-induced Smad-regulated TGF signaling pathway. By modularization, we are able to analyze each module (subsystem) and recover the nonlinear dynamics of the entire network system. Meanwhile the excitability, a common feature observed in the biological systems, along the TGF signaling pathway is discussed by mathematical analysis and numerical simulation.

  11. Ral signaling pathway in health and cancer.

    Science.gov (United States)

    Moghadam, Adel Rezaei; Patrad, Elham; Tafsiri, Elham; Peng, Warner; Fangman, Benjamin; Pluard, Timothy J; Accurso, Anthony; Salacz, Michael; Shah, Kushal; Ricke, Brandon; Bi, Danse; Kimura, Kyle; Graves, Leland; Najad, Marzieh Khajoie; Dolatkhah, Roya; Sanaat, Zohreh; Yazdi, Mina; Tavakolinia, Naeimeh; Mazani, Mohammad; Amani, Mojtaba; Ghavami, Saeid; Gartell, Robyn; Reilly, Colleen; Naima, Zaid; Esfandyari, Tuba; Farassati, Faris

    2017-12-01

    The Ral (Ras-Like) signaling pathway plays an important role in the biology of cells. A plethora of effects is regulated by this signaling pathway and its prooncogenic effectors. Our team has demonstrated the overactivation of the RalA signaling pathway in a number of human malignancies including cancers of the liver, ovary, lung, brain, and malignant peripheral nerve sheath tumors. Additionally, we have shown that the activation of RalA in cancer stem cells is higher in comparison with differentiated cancer cells. In this article, we review the role of Ral signaling in health and disease with a focus on the role of this multifunctional protein in the generation of therapies for cancer. An improved understanding of this pathway can lead to development of a novel class of anticancer therapies that functions on the basis of intervention with RalA or its downstream effectors. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  12. Intraneuronal signaling pathways of metallothionein

    DEFF Research Database (Denmark)

    Asmussen, Johanne Wirenfeldt; Von Sperling, Marie Louise; Penkowa, Milena

    2009-01-01

    -protein-coupled pathway but not on protein tyrosine kinases or on receptor tyrosine kinases. Activation of phospholipase C was necessary for MT-induced neurite outgrowth, and furthermore it was shown that inhibition of several intracellular protein kinases, such as protein kinase A, protein kinase C, phosphatidylinositol...

  13. Signaling pathways regulating murine pancreatic development

    DEFF Research Database (Denmark)

    Serup, Palle

    2012-01-01

    The recent decades have seen a huge expansion in our knowledge about pancreatic development. Numerous lineage-restricted transcription factor genes have been identified and much has been learned about their function. Similarly, numerous signaling pathways important for pancreas development have...... been identified and the specific roles have been investigated by genetic and cell biological methods. The present review presents an overview of the principal signaling pathways involved in regulating murine pancreatic growth, morphogenesis, and cell differentiation....

  14. Mesenchymal Stem Cell Conditioned Medium Promotes Proliferation and Migration of Alveolar Epithelial Cells under Septic Conditions In Vitro via the JNK-P38 Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Jie Chen

    2015-11-01

    Full Text Available Background/Aims: Mesenchymal stem cell (MSC based therapies may be useful for treating acute respiratory distress syndrome (ARDS, but the underlying mechanisms are incompletely understood. We investigated the impact of human umbilical cord Wharton's jelly-derived MSC (hUC-MSC secreted factors on alveolar epithelial cells under septic conditions and determined the relevant intracellular signaling pathways. Methods: Human alveolar epithelial cells (AEC and primary human small airway epithelial cells (SAEC were subjected to lipopolysaccharide (LPS with or without the presence of hUC-MSC-conditioned medium (CM. Proliferation and migration of AEC and SAEC were determined via an MTT assay, a wound healing assay and a transwell migration assay (only for AEC. Protein phosphorylation was determined by western blot and the experiments were repeated in presence of small-molecule inhibitors. The hMSC-secretory proteins were identified by LC-MS/MS mass spectrometry. Results: MSC-CM enhanced proliferation and migration. Activation of JNK and P38, but not ERK, was required for the proliferation and migration of AEC and SAEC. Pretreatment of AEC or SAEC with SP600125, an inhibitor of JNK1 or SB200358, an inhibitor of P38, significantly reduced cell proliferation and migration. An array of proteins including TGF-beta receptor type-1, TGF-beta receptor type-2, Ras-related C3 botulinum toxin substrate 1 and Ras-related C3 botulinum toxin substrate 2 which influencing the proliferation and migration of AEC and SAEC were detected in MSC-CM. Conclusion: Our data suggest MSC promote epithelial cell repair through releasing a repertoire of paracrine factors via activation of JNK and P38 MAPK.

  15. Expression of conserved signalling pathway genes during

    Indian Academy of Sciences (India)

    Hence, we analysed the expression of Notch, Wnt and Sonic Hedgehog (Shh) pathway genes during differentiation of R1 cells into early vascular lineages. Notch-, Wnt-and Shh-mediated signalling is important during embryonic development. Regulation of gene expression through these signalling molecules is a frequently ...

  16. Intricacies of hedgehog signaling pathways: A perspective in tumorigenesis

    Energy Technology Data Exchange (ETDEWEB)

    Kar, Swayamsiddha; Deb, Moonmoon; Sengupta, Dipta; Shilpi, Arunima; Bhutia, Sujit Kumar [Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha 769008 (India); Patra, Samir Kumar, E-mail: samirp@nitrkl.ac.in [Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha 769008 (India)

    2012-10-01

    The hedgehog (HH) signaling pathway is a crucial negotiator of developmental proceedings in the embryo governing a diverse array of processes including cell proliferation, differentiation, and tissue patterning. The overall activity of the pathway is significantly curtailed after embryogenesis as well as in adults, yet it retains many of its functional capacities. However, aberration in HH signaling mediates the initiation, proliferation and continued sustenance of malignancy in different tissues to varying degrees through different mechanisms. In this review, we provide an overview of the role of constitutively active aberrant HH signaling pathway in different types of human cancer and the underlying molecular and genetic mechanisms that drive tumorigenesis in that particular tissue. An insight into the various modes of anomalous HH signaling in different organs will provide a comprehensive knowledge of the pathway in these tissues and open a window for individually tailored, tissue-specific therapeutic interventions. The synergistic cross talking of HH pathway with many other regulatory molecules and developmentally inclined signaling pathways may offer many avenues for pharmacological advances. Understanding the molecular basis of abnormal HH signaling in cancer will provide an opportunity to inhibit the deregulated pathway in many aggressive and therapeutically challenging cancers where promising options are not available.

  17. Targeting embryonic signaling pathways in cancer therapy.

    Science.gov (United States)

    Harris, Pamela Jo; Speranza, Giovanna; Dansky Ullmann, Claudio

    2012-01-01

    The embryonic signaling pathways (ESP), Hedgehog, Notch and Wnt, are critical for the regulation of normal stem cells and cellular development processes. They are also activated in the majority of cancers. ESP are operational in putative cancer stem cells (CSC), which drive initial tumorigenesis and sustain cancer progression and recurrence in non-CSC bulk subpopulations. ESP represent novel therapeutic targets. A variety of inhibitors and targeting strategies are being developed. This review discusses the rationale for targeting ESP for cancer treatment, as well as specific inhibitors under development; mainly focusing on those approaching clinical use and the challenges that lie ahead. The data sources utilized are several database search engines (PubMed, Google, Clinicaltrials.gov), and the authors' involvement in the field. CSC research is rapidly evolving. Expectations regarding their therapeutic targeting are rising quickly. Further definition of what constitutes a true CSC, proper validation of CSC markers, a better understanding of cross-talk among ESP and other pathways, and interactions with tumor non-CSC and the tumor microenvironment are needed. The appropriate patient population, the right clinical setting and combination strategies to test these therapies, as well as the proper pharmacodynamic markers to measure, need to be further established.

  18. Involvement of Hormone- and ROS-Signaling Pathways in the Beneficial Action of Humic Substances on Plants Growing under Normal and Stressing Conditions

    Science.gov (United States)

    García, Andrés Calderín; Olaetxea, Maite; Santos, Leandro Azevedo; Mora, Verónica; Baigorri, Roberto; Fuentes, Marta; Zamarreño, Angel Maria; Berbara, Ricardo Luis Louro; Garcia-Mina, José María

    2016-01-01

    The importance of soil humus in soil fertility has been well established many years ago. However, the knowledge about the whole mechanisms by which humic molecules in the rhizosphere improve plant growth remains partial and rather fragmentary. In this review we discuss the relationships between two main signaling pathway families that are affected by humic substances within the plant: one directly related to hormonal action and the other related to reactive oxygen species (ROS). In this sense, our aims are to try the integration of all these events in a more comprehensive model and underline some points in the model that remain unclear and deserve further research. PMID:27366744

  19. Signaling within Allosteric Machines: Signal Transmission Pathways Inside G Protein-Coupled Receptors.

    Science.gov (United States)

    Bartuzi, Damian; Kaczor, Agnieszka A; Matosiuk, Dariusz

    2017-07-15

    In recent years, our understanding of function of G protein-coupled receptors (GPCRs) has changed from a picture of simple signal relays, transmitting only a particular signal to a particular G protein heterotrimer, to versatile machines, capable of various responses to different stimuli and being modulated by various factors. Some recent reports provide not only the data on ligands/modulators and resultant signals induced by them, but also deeper insights into exact pathways of signal migration and mechanisms of signal transmission through receptor structure. Combination of these computational and experimental data sheds more light on underlying mechanisms of signal transmission and signaling bias in GPCRs. In this review we focus on available clues on allosteric pathways responsible for complex signal processing within GPCRs structures, with particular emphasis on linking compatible in silico- and in vitro-derived data on the most probable allosteric connections.

  20. Modularized study of human calcium signalling pathway

    Indian Academy of Sciences (India)

    PRAKASH KUMAR

    Modularization is a process by which we can break a network into small units for better analysis of the original network. The idea is used here to break human calcium signalling pathway into simple entities known as modules. Since there is no single definition of a module, we have followed certain criteria to create them.

  1. ERβ induces the differentiation of cultured osteoblasts by both Wnt/β-catenin signaling pathway and estrogen signaling pathways

    Energy Technology Data Exchange (ETDEWEB)

    Yin, Xinhua [Department of Spine Surgery, Xiangya Hospital of Central South University, Changsha (China); Wang, Xiaoyuan [Department of Nephrology, Xi An Honghui Hospital, Xi an (China); Hu, Xiongke; Chen, Yong; Zeng, Kefeng [Department of Spine Surgery, Xiangya Hospital of Central South University, Changsha (China); Zhang, Hongqi, E-mail: zhq9699@126.com [Department of Spine Surgery, Xiangya Hospital of Central South University, Changsha (China)

    2015-07-01

    Although 17β-estradial (E2) is known to stimulate bone formation, the underlying mechanisms are not fully understood. Recent studies have implicated the Wnt/β-catenin pathway as a major signaling cascade in bone biology. The interactions between Wnt/β-catenin signaling pathway and estrogen signaling pathways have been reported in many tissues. In this study, E2 significantly increased the expression of β-catenin by inducing phosphorylations of GSK3β at serine 9. ERβ siRNAs were transfected into MC3T3-E1 cells and revealed that ERβ involved E2-induced osteoblasts proliferation and differentiation via Wnt/β-catenin signaling. The osteoblast differentiation genes (BGP, ALP and OPN) and proliferation related gene (cyclin D1) expression were significantly induced by E2-mediated ERβ. Furthermore immunofluorescence and immunoprecipitation analysis demonstrated that E2 induced the accumulation of β-catenin protein in the nucleus which leads to interaction with T-cell-specific transcription factor/lymphoid enhancer binding factor (TCF/LEF) transcription factors. Taken together, these findings suggest that E2 promotes osteoblastic proliferation and differentiation by inducing proliferation-related and differentiation-related gene expression via ERβ/GSK-3β-dependent Wnt/β-catenin signaling pathway. Our findings provide novel insights into the mechanisms of action of E2 in osteoblastogenesis. - Highlights: • 17β-estradial (E2) promotes GSK3-β phosphorylation. • E2 activates the Wnt/β-catenin signaling pathway. • The Wnt/β-catenin signaling pathway interacts with estrogen signaling pathways. • E2-mediated ER induced osteoblast differentiation and proliferation related genes expression.

  2. ERβ induces the differentiation of cultured osteoblasts by both Wnt/β-catenin signaling pathway and estrogen signaling pathways

    International Nuclear Information System (INIS)

    Yin, Xinhua; Wang, Xiaoyuan; Hu, Xiongke; Chen, Yong; Zeng, Kefeng; Zhang, Hongqi

    2015-01-01

    Although 17β-estradial (E2) is known to stimulate bone formation, the underlying mechanisms are not fully understood. Recent studies have implicated the Wnt/β-catenin pathway as a major signaling cascade in bone biology. The interactions between Wnt/β-catenin signaling pathway and estrogen signaling pathways have been reported in many tissues. In this study, E2 significantly increased the expression of β-catenin by inducing phosphorylations of GSK3β at serine 9. ERβ siRNAs were transfected into MC3T3-E1 cells and revealed that ERβ involved E2-induced osteoblasts proliferation and differentiation via Wnt/β-catenin signaling. The osteoblast differentiation genes (BGP, ALP and OPN) and proliferation related gene (cyclin D1) expression were significantly induced by E2-mediated ERβ. Furthermore immunofluorescence and immunoprecipitation analysis demonstrated that E2 induced the accumulation of β-catenin protein in the nucleus which leads to interaction with T-cell-specific transcription factor/lymphoid enhancer binding factor (TCF/LEF) transcription factors. Taken together, these findings suggest that E2 promotes osteoblastic proliferation and differentiation by inducing proliferation-related and differentiation-related gene expression via ERβ/GSK-3β-dependent Wnt/β-catenin signaling pathway. Our findings provide novel insights into the mechanisms of action of E2 in osteoblastogenesis. - Highlights: • 17β-estradial (E2) promotes GSK3-β phosphorylation. • E2 activates the Wnt/β-catenin signaling pathway. • The Wnt/β-catenin signaling pathway interacts with estrogen signaling pathways. • E2-mediated ER induced osteoblast differentiation and proliferation related genes expression

  3. The JNK Signaling Pathway in Renal Fibrosis

    Directory of Open Access Journals (Sweden)

    Keren Grynberg

    2017-10-01

    Full Text Available Fibrosis of the glomerular and tubulointerstitial compartments is a common feature of chronic kidney disease leading to end-stage renal failure. This fibrotic process involves a number of pathologic mechanisms, including cell death and inflammation. This review focuses on the role of the c-Jun amino terminal kinase (JNK signaling pathway in the development of renal fibrosis. The JNK pathway is activated in response to various cellular stresses and plays an important role in cell death and inflammation. Activation of JNK signaling is a common feature in most forms of human kidney injury, evident in both intrinsic glomerular and tubular cells as well as in infiltrating leukocytes. Similar patterns of JNK activation are evident in animal models of acute and chronic renal injury. Administration of JNK inhibitors can protect against acute kidney injury and suppress the development of glomerulosclerosis and tubulointerstitial fibrosis. In particular, JNK activation in tubular epithelial cells may be a pivotal mechanism in determining the outcome of both acute kidney injury and progression of chronic kidney disease. JNK signaling promotes tubular epithelial cell production of pro-inflammatory and pro-fibrotic molecules as well as tubular cell de-differentiation toward a mesenchymal phenotype. However, the role of JNK within renal fibroblasts is less well-characterized. The JNK pathway interacts with other pro-fibrotic pathways, most notable with the TGF-β/SMAD pathway. JNK activation can augment TGF-β gene transcription, induce expression of enzymes that activate the latent form of TGF-β, and JNK directly phosphorylates SMAD3 to enhance transcription of pro-fibrotic molecules. In conclusion, JNK signaling plays an integral role in several key mechanisms operating in renal fibrosis. Targeting of JNK enzymes has therapeutic potential for the treatment of fibrotic kidney diseases.

  4. Signaling Pathways in Cardiac Myocyte Apoptosis

    Science.gov (United States)

    Xia, Peng; Liu, Yuening

    2016-01-01

    Cardiovascular diseases, the number 1 cause of death worldwide, are frequently associated with apoptotic death of cardiac myocytes. Since cardiomyocyte apoptosis is a highly regulated process, pharmacological intervention of apoptosis pathways may represent a promising therapeutic strategy for a number of cardiovascular diseases and disorders including myocardial infarction, ischemia/reperfusion injury, chemotherapy cardiotoxicity, and end-stage heart failure. Despite rapid growth of our knowledge in apoptosis signaling pathways, a clinically applicable treatment targeting this cellular process is currently unavailable. To help identify potential innovative directions for future research, it is necessary to have a full understanding of the apoptotic pathways currently known to be functional in cardiac myocytes. Here, we summarize recent progress in the regulation of cardiomyocyte apoptosis by multiple signaling molecules and pathways, with a focus on the involvement of these pathways in the pathogenesis of heart disease. In addition, we provide an update regarding bench to bedside translation of this knowledge and discuss unanswered questions that need further investigation. PMID:28101515

  5. Resveratrol increases nucleus pulposus matrix synthesis through activating the PI3K/Akt signaling pathway under mechanical compression in a disc organ culture.

    Science.gov (United States)

    Han, Xiaorui; Leng, Xiaoming; Zhao, Man; Wu, Mei; Chen, Amei; Hong, Guoju; Sun, Ping

    2017-12-22

    Disc nucleus pulposus (NP) matrix homeostasis is important for normal disc function. Mechanical overloading seriously decreases matrix synthesis and increases matrix degradation. The present study aims to investigate the effects of resveratrol on disc NP matrix homeostasis under a relatively high-magnitude mechanical compression and the potential mechanism underlying this process. Porcine discs were perfusion-cultured and subjected to a relatively high-magnitude mechanical compression (1.3 MPa at a frequency of 1.0 Hz for 2 h once per day) for 7 days in a mechanically active bioreactor. The non-compressed discs were used as controls. Resveratrol was added along with culture medium to observe the effects of resveratrol on NP matrix synthesis under mechanical load respectively. NP matrix synthesis was evaluated by histology, biochemical content (glycosaminoglycan (GAG) and hydroxyproline (HYP)), and expression of matrix macromolecules (aggrecan and collagen II). Results showed that this high-magnitude mechanical compression significantly decreased NP matrix content, indicated by the decreased staining intensity of Alcian Blue and biochemical content (GAG and HYP), and the down-regulated expression of NP matrix macromolecules (aggrecan and collagen II). Further analysis indicated that resveratrol partly stimulated NP matrix synthesis and increased activity of the PI3K/Akt pathway in a dose-dependent manner under mechanical compression. Together, resveratrol is beneficial for disc NP matrix synthesis under mechanical overloading, and the activation of the PI3K/Akt pathway may participate in this regulatory process. Resveratrol may be promising to regenerate mechanical overloading-induced disc degeneration. © 2017 The Author(s).

  6. SPV: a JavaScript Signaling Pathway Visualizer.

    Science.gov (United States)

    Calderone, Alberto; Cesareni, Gianni

    2018-03-24

    The visualization of molecular interactions annotated in web resources is useful to offer to users such information in a clear intuitive layout. These interactions are frequently represented as binary interactions that are laid out in free space where, different entities, cellular compartments and interaction types are hardly distinguishable. SPV (Signaling Pathway Visualizer) is a free open source JavaScript library which offers a series of pre-defined elements, compartments and interaction types meant to facilitate the representation of signaling pathways consisting of causal interactions without neglecting simple protein-protein interaction networks. freely available under Apache version 2 license; Source code: https://github.com/Sinnefa/SPV_Signaling_Pathway_Visualizer_v1.0. Language: JavaScript; Web technology: Scalable Vector Graphics; Libraries: D3.js. sinnefa@gmail.com.

  7. Obesity-Induced Hypertension: Brain Signaling Pathways

    Science.gov (United States)

    da Silva, Alexandre A.; Wang, Zhen; Fang, Taolin; Aberdein, Nicola; de Lara Rodriguez, Cecilia E. P.; Hall, John E.

    2017-01-01

    Obesity greatly increases the risk for cardiovascular, metabolic, and renal diseases and is one of the most significant and preventable causes of increased blood pressure (BP) in patients with essential hypertension. This review high-lights recent advances in our understanding of central nervous system (CNS) signaling pathways that contribute to the etiology and pathogenesis of obesity-induced hypertension. We discuss the role of excess adiposity and activation of the brain leptin-melanocortin system in causing increased sympathetic activity in obesity. In addition, we highlight other potential brain mechanisms by which increased weight gain modulates metabolic and cardiovascular functions. Unraveling the CNS mechanisms responsible for increased sympathetic activation and hypertension and how circulating hormones activate brain signaling pathways to control BP offer potentially important therapeutic targets for obesity and hypertension. PMID:27262997

  8. Purinergic Signaling Pathways in Endocrine System

    Science.gov (United States)

    Bjelobaba, Ivana; Janjic, Marija M.; Stojilkovic, Stanko S.

    2015-01-01

    Adenosine-5′-triphosphate is released by neuroendocrine, endocrine, and other cell types and acts as an extracellular agonist for ligand-gated P2X cationic channels and G protein-coupled P2Y receptors in numerous organs and tissues, including the endocrine system. The breakdown of ATP by ectonucleotidases not only terminates its extracellular messenger functions, but also provides a pathway for the generation of two additional agonists: adenosine 5′-diphosphate, acting via some P2Y receptors, and adenosine, a native agonist for G protein-coupled adenosine receptors, also expressed in the endocrine system. This article provides a review of purinergic signaling pathways in the hypothalamic magnocellular neurosecretory cells and neurohypophysis, hypothalamic parvocellular neuroendocrine system, adenohypophysis, and effector glands organized in five axes: hypothalamic-pituitary-gonadal, hypothalamic-pituitary-thyroid, hypothalamic-pituitary-adrenal, hypothalamic-pituitary-growth hormone, and hypothalamic-pituitary-prolactin. We attempted to summarize current knowledge of purinergic receptor subtypes expressed in the endocrine system, including their roles in intracellular signaling, hormone secretion, and other cell functions. We also briefly review the release mechanism for adenosine-5′-triphosphate by neuroendocrine, endocrine and surrounding cells, the enzymes involved in adenosine-5′-triphosphate hydrolysis to adenosine-5′-diphosphate and adenosine, and the relevance of this pathway for sequential activation of receptors and termination of signaling. PMID:25960051

  9. Purinergic signaling pathways in endocrine system.

    Science.gov (United States)

    Bjelobaba, Ivana; Janjic, Marija M; Stojilkovic, Stanko S

    2015-09-01

    Adenosine-5'-triphosphate is released by neuroendocrine, endocrine, and other cell types and acts as an extracellular agonist for ligand-gated P2X cationic channels and G protein-coupled P2Y receptors in numerous organs and tissues, including the endocrine system. The breakdown of ATP by ectonucleotidases not only terminates its extracellular messenger functions, but also provides a pathway for the generation of two additional agonists: adenosine 5'-diphosphate, acting via some P2Y receptors, and adenosine, a native agonist for G protein-coupled adenosine receptors, also expressed in the endocrine system. This article provides a review of purinergic signaling pathways in the hypothalamic magnocellular neurosecretory cells and neurohypophysis, hypothalamic parvocellular neuroendocrine system, adenohypophysis, and effector glands organized in five axes: hypothalamic-pituitary-gonadal, hypothalamic-pituitary-thyroid, hypothalamic-pituitary-adrenal, hypothalamic-pituitary-growth hormone, and hypothalamic-pituitary-prolactin. We attempted to summarize current knowledge of purinergic receptor subtypes expressed in the endocrine system, including their roles in intracellular signaling, hormone secretion, and other cell functions. We also briefly review the release mechanism for adenosine-5'-triphosphate by neuroendocrine, endocrine and surrounding cells, the enzymes involved in adenosine-5'-triphosphate hydrolysis to adenosine-5'-diphosphate and adenosine, and the relevance of this pathway for sequential activation of receptors and termination of signaling. Published by Elsevier B.V.

  10. Nongenomic Signaling Pathways of Estrogen Toxicity

    Science.gov (United States)

    Watson, Cheryl S.; Jeng, Yow-Jiun; Kochukov, Mikhail Y.

    2010-01-01

    Xenoestrogens can affect the healthy functioning of a variety of tissues by acting as potent estrogens via nongenomic signaling pathways or by interfering with those actions of multiple physiological estrogens. Collectively, our and other studies have compared a wide range of estrogenic compounds, including some closely structurally related subgroups. The estrogens that have been studied include environmental contaminants of different subclasses, dietary estrogens, and several prominent physiological metabolites. By comparing the nongenomic signaling and functional responses to these compounds, we have begun to address the structural requirements for their actions through membrane estrogen receptors in the pituitary, in comparison to other tissues, and to gain insights into their typical non-monotonic dose-response behavior. Their multiple inputs into cellular signaling begin processes that eventually integrate at the level of mitogen-activated protein kinase activities to coordinately regulate broad cellular destinies, such as proliferation, apoptosis, or differentiation. PMID:19955490

  11. MRF Family Genes Are Involved in Translation Control, Especially under Energy-Deficient Conditions, and Their Expression and Functions Are Modulated by the TOR Signaling Pathway[OPEN

    Science.gov (United States)

    Lee, Du-Hwa; Park, Seung Jun; Ahn, Chang Sook

    2017-01-01

    Dynamic control of protein translation in response to the environment is essential for the survival of plant cells. Target of rapamycin (TOR) coordinates protein synthesis with cellular energy/nutrient availability through transcriptional modulation and phosphorylation of the translation machinery. However, mechanisms of TOR-mediated translation control are poorly understood in plants. Here, we report that Arabidopsis thaliana MRF (MA3 DOMAIN-CONTAINING TRANSLATION REGULATORY FACTOR) family genes encode translation regulatory factors under TOR control, and their functions are particularly important in energy-deficient conditions. Four MRF family genes (MRF1-MRF4) are transcriptionally induced by dark and starvation (DS). Silencing of multiple MRFs increases susceptibility to DS and treatment with a TOR inhibitor, while MRF1 overexpression decreases susceptibility. MRF proteins interact with eIF4A and cofractionate with ribosomes. MRF silencing decreases translation activity, while MRF1 overexpression increases it, accompanied by altered ribosome patterns, particularly in DS. Furthermore, MRF deficiency in DS causes altered distribution of mRNAs in sucrose gradient fractions and accelerates rRNA degradation. MRF1 is phosphorylated in vivo and phosphorylated by S6 kinases in vitro. MRF expression and MRF1 ribosome association and phosphorylation are modulated by cellular energy status and TOR activity. We discuss possible mechanisms of the function of MRF family proteins under normal and energy-deficient conditions and their functional link with the TOR pathway. PMID:29084871

  12. MRF Family Genes Are Involved in Translation Control, Especially under Energy-Deficient Conditions, and Their Expression and Functions Are Modulated by the TOR Signaling Pathway.

    Science.gov (United States)

    Lee, Du-Hwa; Park, Seung Jun; Ahn, Chang Sook; Pai, Hyun-Sook

    2017-11-01

    Dynamic control of protein translation in response to the environment is essential for the survival of plant cells. Target of rapamycin (TOR) coordinates protein synthesis with cellular energy/nutrient availability through transcriptional modulation and phosphorylation of the translation machinery. However, mechanisms of TOR-mediated translation control are poorly understood in plants. Here, we report that Arabidopsis thaliana MRF (MA3 DOMAIN-CONTAINING TRANSLATION REGULATORY FACTOR) family genes encode translation regulatory factors under TOR control, and their functions are particularly important in energy-deficient conditions. Four MRF family genes ( MRF1 - MRF4 ) are transcriptionally induced by dark and starvation (DS). Silencing of multiple MRFs increases susceptibility to DS and treatment with a TOR inhibitor, while MRF1 overexpression decreases susceptibility. MRF proteins interact with eIF4A and cofractionate with ribosomes. MRF silencing decreases translation activity, while MRF1 overexpression increases it, accompanied by altered ribosome patterns, particularly in DS. Furthermore, MRF deficiency in DS causes altered distribution of mRNAs in sucrose gradient fractions and accelerates rRNA degradation. MRF1 is phosphorylated in vivo and phosphorylated by S6 kinases in vitro. MRF expression and MRF1 ribosome association and phosphorylation are modulated by cellular energy status and TOR activity. We discuss possible mechanisms of the function of MRF family proteins under normal and energy-deficient conditions and their functional link with the TOR pathway. © 2017 American Society of Plant Biologists. All rights reserved.

  13. Interleukin 4 signals through two related pathways.

    Science.gov (United States)

    Pernis, A; Witthuhn, B; Keegan, A D; Nelms, K; Garfein, E; Ihle, J N; Paul, W E; Pierce, J H; Rothman, P

    1995-08-15

    The interleukin 4 (IL-4) signaling pathway involves activation, by tyrosine phosphorylation, of two distinct substrates, a signal-transducing factor (STF-IL4) and the IL-4-induced phosphotyrosine substrate (4PS). It is not known whether the IL-4-mediated activation of these substrates occurs via related or distinct signaling pathways. We report that 32D cells, an IL-3-dependent myeloid progenitor cell line in which no phosphorylated 4PS is found, activate high levels of STF-IL4 in response to IL-4. Consistent with the known requirement for 4PS or insulin receptor substrate 1 (IRS-1) in IL-4-mediated mitogenesis, activation of STF-IL4 in 32D cells is not sufficient for IL-4-inducible c-myc expression. In addition, we have examined the ability of 32D cells transfected with different truncation mutants of the human IL-4 receptor to activate Jak-3 kinase and STF-IL4 in response to human IL-4. As in the case of 4PS/IRS-1, we have found that activation of both Jak-3 and STF-IL4 requires the presence of the IL-4 receptor region comprising aa 437-557. The finding that the same region of the IL-4 receptor is required for the induction of both 4PS/IRS-1 and STF-IL4 suggests that the IL-4-stimulated activation of these two substrates might involve common factors.

  14. Non-Smad pathways in TGF-β signaling

    OpenAIRE

    Zhang, Ying E

    2009-01-01

    Transforming growth factor-β utilizes a multitude of intracellular signaling pathways in addition to Smads to regulate a wide array of cellular functions. These non-canonical, non-Smad pathways are activated directly by ligand-occupied receptors to reinforce, attenuate, or otherwise modulate downstream cellular responses. These non-Smad pathways include various branches of MAP kinase pathways, Rho-like GTPase signaling pathways, and phosphatidylinositol-3-kinase/AKT pathways. This review focu...

  15. Cancer cachexia: mediators, signaling, and metabolic pathways.

    Science.gov (United States)

    Fearon, Kenneth C H; Glass, David J; Guttridge, Denis C

    2012-08-08

    Cancer cachexia is characterized by a significant reduction in body weight resulting predominantly from loss of adipose tissue and skeletal muscle. Cachexia causes reduced cancer treatment tolerance and reduced quality and length of life, and remains an unmet medical need. Therapeutic progress has been impeded, in part, by the marked heterogeneity of mediators, signaling, and metabolic pathways both within and between model systems and the clinical syndrome. Recent progress in understanding conserved, molecular mechanisms of skeletal muscle atrophy/hypertrophy has provided a downstream platform for circumventing the variations and redundancy in upstream mediators and may ultimately translate into new targeted therapies. Copyright © 2012 Elsevier Inc. All rights reserved.

  16. DMPD: When signaling pathways collide: positive and negative regulation of toll-likereceptor signal transduction. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18631453 When signaling pathways collide: positive and negative regulation of toll-...uction. PubmedID 18631453 Title When signaling pathways collide: positive and neg...l) Show When signaling pathways collide: positive and negative regulation of toll-likereceptor signal transd...likereceptor signal transduction. O'Neill LA. Immunity. 2008 Jul 18;29(1):12-20. (.png) (.svg) (.html) (.csm

  17. DMPD: LPS/TLR4 signal transduction pathway. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18304834 LPS/TLR4 signal transduction pathway. Lu YC, Yeh WC, Ohashi PS. Cytokine. ...2008 May;42(2):145-51. Epub 2008 Mar 4. (.png) (.svg) (.html) (.csml) Show LPS/TLR4 signal transduction path...way. PubmedID 18304834 Title LPS/TLR4 signal transduction pathway. Authors Lu YC, Yeh WC, Ohashi PS. Publica

  18. DMPD: Signaling pathways activated by microorganisms. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17303405 Signaling pathways activated by microorganisms. Takeuchi O, Akira S. Curr ...Opin Cell Biol. 2007 Apr;19(2):185-91. Epub 2007 Feb 15. (.png) (.svg) (.html) (.csml) Show Signaling pathways... activated by microorganisms. PubmedID 17303405 Title Signaling pathways activated by microorganisms. Auth

  19. DMPD: Regulation of mitochondrial antiviral signaling pathways. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18549796 Regulation of mitochondrial antiviral signaling pathways. Moore CB, Ting J...P. Immunity. 2008 Jun;28(6):735-9. (.png) (.svg) (.html) (.csml) Show Regulation of mitochondrial antiviral signaling pathways.... PubmedID 18549796 Title Regulation of mitochondrial antiviral signaling pathways. Author

  20. Signaling pathways in melanosome biogenesis and pathology.

    Science.gov (United States)

    Schiaffino, Maria Vittoria

    2010-07-01

    Melanosomes are the specialized intracellular organelles of pigment cells devoted to the synthesis, storage and transport of melanin pigments, which are responsible for most visible pigmentation in mammals and other vertebrates. As a direct consequence, any genetic mutation resulting in alteration of melanosomal function, either because affecting pigment cell survival, migration and differentiation, or because interfering with melanosome biogenesis, transport and transfer to keratinocytes, is immediately translated into color variations of skin, fur, hair or eyes. Thus, over 100 genes and proteins have been identified as pigmentary determinants in mammals, providing us with a deep understanding of this biological system, which functions by using mechanisms and processes that have parallels in other tissues and organs. In particular, many genes implicated in melanosome biogenesis have been characterized, so that melanosomes represent an incredible source of information and a model for organelles belonging to the secretory pathway. Furthermore, the function of melanosomes can be associated with common physiological phenotypes, such as variation of pigmentation among individuals, and with rare pathological conditions, such as albinism, characterized by severe visual defects. Among the most relevant mechanisms operating in melanosome biogenesis are the signal transduction pathways mediated by two peculiar G protein-coupled receptors: the melanocortin-1 receptor (MC1R), involved in the fair skin/red hair phenotype and skin cancer; and OA1 (GPR143), whose loss-of-function results in X-linked ocular albinism. This review will focus on the most recent novelties regarding the functioning of these two receptors, by highlighting emerging signaling mechanisms and general implications for cell biology and pathology. Copyright 2010 Elsevier Ltd. All rights reserved.

  1. Hypoxia-inducible factor-1α mediates the toll-like receptor 4 signaling pathway leading to anti-tumor effects in human hepatocellular carcinoma cells under hypoxic conditions.

    Science.gov (United States)

    Zhang, Xiaoyu; Li, Shuchen; Li, Mingrong; Huang, Haiying; Li, Jingyuan; Zhou, Changwei

    2016-08-01

    Hypoxia-inducible factor-1α (HIF-1α) and toll-like receptor 4 (TLR4) are involved in numerous mechanisms of cancer biology, including cell proliferation and survival; however the interaction of the two factors under hypoxic conditions remains unclear. The present study investigated the in vitro mechanism that results in the suppression of tumor cell growth and cellular functions when HIF-1α is silenced. In the present study, the human hepatocellular carcinoma HepG2 cell line was transfected with short hairpin RNA (shRNA) against HIF-1α and cultured under hypoxic conditions (1% O 2 for 24 h). The expression of HIF-1α and various growth factors, including epidermal growth factor (EGF), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2), were examined using quantitative polymerase chain reaction and immunoblotting. Tumor growth was measured using a Cell Counting Kit-8 assay and tumor activity was measured using tumor cell invasion and migration assays. Lipopolysaccharide and TAK-242 were used to activate and inhibit TLR4, respectively, to observe the role of TLR4 in the HIF-1α silenced tumor cells. The expression of TLR4 signaling pathway associates, including myeloid differentiation primary response gene 88 (MyD88), apoptosis signal-regulating kinase 1 (ASK1), p38 mitogen-activated protein kinases and HIF-1α, were analyzed by western blot assay. Under hypoxic conditions, silencing of HIF-1α expression suppressed tumor cell growth and regulated the expression of tumor growth-associated genes, including EGF, HGF, VEGF and FG2. Suppression of tumor cell invasion and migration was also observed in the HIF-1α silenced HepG2 cell line. In addition, TLR4 was identified to be involved in HIF-1α and MyD88 accumulation, and activation of ASK1 and p38 were demonstrated to be critical for TLR4-mediated HIF-1α pathway. In conclusion, silencing of HIF-1α expression may induce anti-tumor effects under hypoxic

  2. Enhancement of osteogenic differentiation of rat adipose tissue-derived mesenchymal stem cells by zinc sulphate under electromagnetic field via the PKA, ERK1/2 and Wnt/β-catenin signaling pathways.

    Directory of Open Access Journals (Sweden)

    Ezzatollah Fathi

    Full Text Available Zinc ion as an essential trace element and electromagnetic fields (EMFs has been reported to be involved in the regulation of bone metabolism. The aim of this study was to elucidate the effects of zinc sulphate (ZnSO4 on the osteogenic differentiation of adipose tissue-derived mesenchymal stem cells (ADSCs in the presence of EMF as a strategy in osteoporosis therapy. Alkaline phophatase (ALP activity measurement, calcium assay and expression of several osteoblastic marker genes were examined to assess the effect of ZnSO4 on the osteogenic differentiation of ADSCs under EMF. The expression of cAMP and PKA was evaluated by ELISA. The expression of β-catenin, Wnt1, Wnt3a, low-density lipoprotein receptor-related protein 5 (LRP5 and reduced dickkopf1 (DKK1 genes were used to detect the Wnt/β-catenin pathway. It was found that ZnSO4, in the presence of EMF, resulted in an increase in the expression of osteogenic genes, ALP activity and calcium levels. EMF, in the presence of ZnSO4, increased the cAMP level and protein kinase A (PKA activity. Treatment of ADSCs with (MAPK/ERK kinase 1/2 inhibitor, or PKA inhibitor, significantly inhibited the promotion of osteogenic markers, indicating that the induction of osteogenesis was dependent on the ERK and PKA signaling pathways. Real-time PCR analysis showed that ZnSO4, in the presence of EMF, increased the mRNA expressions of β-catenin, Wnt1, Wnt3a, LRP5 and DKK1. In this study, it was shown that 0.432 μg/ml ZnSO4, in the presence of 50 Hz, 20 mT EMF, induced the osteogenic differentiation of ADSCs via PKA, ERK1/2 and Wnt/β-catenin signaling pathways.

  3. Signaling pathways regulating red blood cell aggregation.

    Science.gov (United States)

    Muravyov, Alexei; Tikhomirova, Irina

    2014-01-01

    The exposure of red blood cells (RBC) to some hormones (epinephrine, insulin and glucagon) and agonists of α- and β-adrenergic receptors (phenylephrine, clonidine and isoproterenol) may modify RBC aggregation (RBCA). Prostaglandin E1 (PGE1) significantly decreased RBCA, and PGE2 had a similar but lesser effect. Adenylyl cyclase (AC) stimulator forskolin added to RBC suspension, caused a decrease of RBCA. More marked lowering of RBCA occurred after RBC treatment by dB-cAMP. Phosphodiesterase (PDE) inhibitors markedly reduced RBCA. Ca2+ influx stimulated by A23187 was accompanied by an increase of RBCA. The blocking of Ca2+ entry into the RBC by verapamil or the chelation of Ca2+ by EGTA led to a significant RBCA decrease. Lesser changes of aggregation were found after RBC incubation with protein kinase C stimulator phorbol 12-myristate 13-acetate (PMA). A significant inhibitory effect of tyrosine protein kinase (TPK) activator cisplatin on RBCA was revealed, while selective TPK inhibitor, lavendustin, eliminated the above mentioned effect. Taken together, the data demonstrate that changes in RBCA are connected with activation of different intracellular signaling pathways. We suggest that alterations in RBCA are mainly associated with the crosstalk between the adenylyl cyclase-cAMP system and Ca2+ control mechanisms.

  4. Deficient brain insulin signalling pathway in Alzheimer's disease and diabetes.

    Science.gov (United States)

    Liu, Ying; Liu, Fei; Grundke-Iqbal, Inge; Iqbal, Khalid; Gong, Cheng-Xin

    2011-09-01

    Brain glucose metabolism is impaired in Alzheimer's disease (AD), the most common form of dementia. Type 2 diabetes mellitus (T2DM) is reported to increase the risk for dementia, including AD, but the underlying mechanism is not understood. Here, we investigated the brain insulin-PI3K-AKT signalling pathway in the autopsied frontal cortices from nine AD, 10 T2DM, eight T2DM-AD and seven control cases. We found decreases in the levels and activities of several components of the insulin-PI3K-AKT signalling pathway in AD and T2DM cases. The deficiency of insulin-PI3K-AKT signalling was more severe in individuals with both T2DM and AD (T2DM-AD). This decrease in insulin-PI3K-AKT signalling could lead to activation of glycogen synthase kinase-3β, the major tau kinase. The levels and the activation of the insulin-PI3K-AKT signalling components correlated negatively with the level of tau phosphorylation and positively with protein O-GlcNAcylation, suggesting that impaired insulin-PI3K-AKT signalling might contribute to neurodegeneration in AD through down-regulation of O-GlcNAcylation and the consequent promotion of abnormal tau hyperphosphorylation and neurodegeneration. The decrease in brain insulin-PI3K-AKT signalling also correlated with the activation of calpain I in the brain, suggesting that the decrease might be caused by calpain over-activation. Our findings provide novel insight into the molecular mechanism by which type 2 diabetes mellitus increases the risk for developing cognitive impairment and dementia in Alzheimer's disease. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  5. Cerebral insulin, insulin signaling pathway, and brain angiogenesis.

    Science.gov (United States)

    Zeng, Yi; Zhang, Le; Hu, Zhiping

    2016-01-01

    Insulin performs unique non-metabolic functions within the brain. Broadly speaking, two major areas of these functions are those related to brain endothelial cells and the blood-brain barrier (BBB) function, and those related to behavioral effects, like cognition in disease states (Alzheimer's disease, AD) and in health. Recent studies showed that both these functions are associated with brain angiogenesis. These findings raise interesting questions such as how they are linked to each other and whether modifying brain angiogenesis by targeting certain insulin signaling pathways could be an effective strategy to treat dementia as in AD, or even to help secure healthy longevity. The two canonical downstream pathways involved in mediating the insulin signaling pathway, the phosphoinositide-3 kinase (PI3K), and mitogen-activated protein kinase (MAPK) cascades, in the brain are supposed to be similar to those in the periphery. PI3K and MAPK pathways play important roles in angiogenesis. Both are involved in stimulating hypoxia inducible factor (HIF) in angiogenesis and could be activated by the insulin signaling pathway. This suggests that PI3K and MAPK pathways might act as cross-talk between the insulin signaling pathway and the angiogenesis pathway in brain. But the cerebral insulin, insulin signaling pathway, and the detailed mechanism in the connection of insulin signaling pathway, brain angiogenesis pathway, and healthy aging or dementias are still mostly not clear and need further studies.

  6. Interleukins and their signaling pathways in the Reactome biological pathway database.

    Science.gov (United States)

    Jupe, Steve; Ray, Keith; Roca, Corina Duenas; Varusai, Thawfeek; Shamovsky, Veronica; Stein, Lincoln; D'Eustachio, Peter; Hermjakob, Henning

    2018-04-01

    There is a wealth of biological pathway information available in the scientific literature, but it is spread across many thousands of publications. Alongside publications that contain definitive experimental discoveries are many others that have been dismissed as spurious, found to be irreproducible, or are contradicted by later results and consequently now considered controversial. Many descriptions and images of pathways are incomplete stylized representations that assume the reader is an expert and familiar with the established details of the process, which are consequently not fully explained. Pathway representations in publications frequently do not represent a complete, detailed, and unambiguous description of the molecules involved; their precise posttranslational state; or a full account of the molecular events they undergo while participating in a process. Although this might be sufficient to be interpreted by an expert reader, the lack of detail makes such pathways less useful and difficult to understand for anyone unfamiliar with the area and of limited use as the basis for computational models. Reactome was established as a freely accessible knowledge base of human biological pathways. It is manually populated with interconnected molecular events that fully detail the molecular participants linked to published experimental data and background material by using a formal and open data structure that facilitates computational reuse. These data are accessible on a Web site in the form of pathway diagrams that have descriptive summaries and annotations and as downloadable data sets in several formats that can be reused with other computational tools. The entire database and all supporting software can be downloaded and reused under a Creative Commons license. Pathways are authored by expert biologists who work with Reactome curators and editorial staff to represent the consensus in the field. Pathways are represented as interactive diagrams that include as

  7. DMPD: Signalling pathways mediating type I interferon gene expression. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17904888 Signalling pathways mediating type I interferon gene expression. Edwards M...hways mediating type I interferon gene expression. PubmedID 17904888 Title Signalling pathways...R, Slater L, Johnston SL. Microbes Infect. 2007 Sep;9(11):1245-51. Epub 2007 Jul 1. (.png) (.svg) (.html) (.csml) Show Signalling pat

  8. Antagonism between Hedgehog and Wnt signaling pathways regulates tumorigenicity.

    Science.gov (United States)

    Ding, Mei; Wang, Xin

    2017-12-01

    The crosstalk of multiple cellular signaling pathways is crucial in animal development and tissue homeostasis, and its dysregulation may result in tumor formation and metastasis. The Hedgehog (Hh) and Wnt signaling pathways are both considered to be essential regulators of cell proliferation, differentiation and oncogenesis. Recent studies have indicated that the Hh and Wnt signaling pathways are closely associated and involved in regulating embryogenesis and cellular differentiation. Hh signaling acts upstream of the Wnt signaling pathway, and negative regulates Wnt activity via secreted frizzled-related protein 1 (SFRP1), and the Wnt/β-catenin pathway downregulates Hh activity through glioma-associated oncogene homolog 3 transcriptional regulation. This evidence suggests that the imbalance of Hh and Wnt regulation serves a crucial role in cancer-associated processes. The activation of SFRP1, which inhibits Wnt, has been demonstrated to be an important cross-point between the two signaling pathways. The present study reviews the complex interaction between the Hh and Wnt signaling pathways in embryogenesis and tumorigenicity, and the role of SFRP1 as an important mediator associated with the dysregulation of the Hh and Wnt signaling pathways.

  9. Research advances in Hedgehog signaling pathway in hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    LIU Jia

    2015-02-01

    Full Text Available Hedgehog (Hh signaling pathway is present in many animals and plays an important role in regulating embryonic development and differentiation. Aberrant activation of Hh signaling contributes to the pathogenesis of many malignancies. Recent studies have shown that dysregulated Hh signaling pathway participates in the tumorigenesis, tumor invasion, and metastasis of hepatocellular carcinoma (HCC. Investigation of the relationship between Hh signaling pathway and HCC will help elucidate the molecular mechanism of pathogenesis of HCC and provide a new insight into the development of novel anticancer therapy and therapeutic target.

  10. Myostatin and the skeletal muscle atrophy and hypertrophy signaling pathways.

    Science.gov (United States)

    Rodriguez, J; Vernus, B; Chelh, I; Cassar-Malek, I; Gabillard, J C; Hadj Sassi, A; Seiliez, I; Picard, B; Bonnieu, A

    2014-11-01

    Myostatin, a member of the transforming growth factor-β superfamily, is a potent negative regulator of skeletal muscle growth and is conserved in many species, from rodents to humans. Myostatin inactivation can induce skeletal muscle hypertrophy, while its overexpression or systemic administration causes muscle atrophy. As it represents a potential target for stimulating muscle growth and/or preventing muscle wasting, myostatin regulation and functions in the control of muscle mass have been extensively studied. A wealth of data strongly suggests that alterations in skeletal muscle mass are associated with dysregulation in myostatin expression. Moreover, myostatin plays a central role in integrating/mediating anabolic and catabolic responses. Myostatin negatively regulates the activity of the Akt pathway, which promotes protein synthesis, and increases the activity of the ubiquitin-proteasome system to induce atrophy. Several new studies have brought new information on how myostatin may affect both ribosomal biogenesis and translation efficiency of specific mRNA subclasses. In addition, although myostatin has been identified as a modulator of the major catabolic pathways, including the ubiquitin-proteasome and the autophagy-lysosome systems, the underlying mechanisms are only partially understood. The goal of this review is to highlight outstanding questions about myostatin-mediated regulation of the anabolic and catabolic signaling pathways in skeletal muscle. Particular emphasis has been placed on (1) the cross-regulation between myostatin, the growth-promoting pathways and the proteolytic systems; (2) how myostatin inhibition leads to muscle hypertrophy; and (3) the regulation of translation by myostatin.

  11. BMP2 and mechanical loading cooperatively regulate immediate early signalling events in the BMP pathway.

    Science.gov (United States)

    Kopf, Jessica; Petersen, Ansgar; Duda, Georg N; Knaus, Petra

    2012-04-30

    Efficient osteogenic differentiation is highly dependent on coordinated signals arising from growth factor signalling and mechanical forces. Bone morphogenetic proteins (BMPs) are secreted proteins that trigger Smad and non-Smad pathways and thereby influence transcriptional and non-transcriptional differentiation cues. Crosstalk at multiple levels allows for promotion or attenuation of signalling intensity and specificity. Similar to BMPs, mechanical stimulation enhances bone formation. However, the molecular mechanism by which mechanical forces crosstalk to biochemical signals is still unclear. Here, we use a three-dimensional bioreactor system to describe how mechanical forces are integrated into the BMP pathway. Time-dependent phosphorylation of Smad, mitogen-activated protein kinases and Akt in human fetal osteoblasts was investigated under loading and/or BMP2 stimulation conditions. The phosphorylation of R-Smads is increased both in intensity and duration under BMP2 stimulation with concurrent mechanical loading. Interestingly, the synergistic effect of both stimuli on immediate early Smad phosphorylation is reflected in the transcription of only a subset of BMP target genes, while others are differently affected. Together this results in a cooperative regulation of osteogenesis that is guided by both signalling pathways. Mechanical signals are integrated into the BMP signalling pathway by enhancing immediate early steps within the Smad pathway, independent of autocrine ligand secretion. This suggests a direct crosstalk of both mechanotransduction and BMP signalling, most likely at the level of the cell surface receptors. Furthermore, the crosstalk of both pathways over longer time periods might occur on several signalling levels.

  12. SPEECHLESS integrates brassinosteroid and stomata signalling pathways.

    NARCIS (Netherlands)

    Gudesblat, G.E.; Schneider-Pizon, J.; Betti, C.; Mayerhofer, J.; Vanhoutte, I.; Dongen, van W.M.A.M.; Boeren, J.A.; Zhiponova, M.; Vries, de S.C.; Jonak, C.; Russinova, E.T.

    2012-01-01

    Stomatal formation is regulated by multiple developmental and environmental signals, but how these signals are integrated to control this process is not fully understood1. In Arabidopsis thaliana, the basic helix-loop-helix transcription factor SPEECHLESS (SPCH) regulates the entry, amplifying and

  13. Expression of conserved signalling pathway genes during ...

    Indian Academy of Sciences (India)

    SEARCHU

    Notch signalling during embryonic develop- ment in mouse regulates vascular morphogenesis and remodelling (Krebs et al 2000). Aberrant Notch signalling is also implicated in many cancers and diseases including. T-cell acute lymphoblastic leukaemia (T-ALL), multiple sclerosis (MS), Alagille syndrome and Alzheimer's ...

  14. AKT/GSK3 signaling pathways and schizophrenia

    Directory of Open Access Journals (Sweden)

    Effat eEmamian

    2012-03-01

    Full Text Available Schizophrenia is a prevalent complex trait disorder manifested by severe neurocognitive dysfunctions and lifelong disability. During the past few years several studies have provided direct evidence for the involvement of different signaling pathways in schizophrenia. In this review, we mainly focus on AKT/GSK3 signaling pathways in schizophrenia. The original study on the involvement of this pathway in schizophrenia was published by Emamian et al in 2004. This study reported convergent evidence for a decrease in AKT1 protein levels and levels of phosphorylation of GSK3β in the peripheral lymphocytes and brains of individuals with schizophrenia; a significant association between schizophrenia and an AKT1 haplotype; and a greater sensitivity to the sensorimotor gating−disruptive effect of amphetamine, conferred by AKT1 deficiency. It also showed that haloperidol can induce a stepwise increase in regulatory phosphorylation of AKT1 in the brains of treated mice that could compensate for the impaired function of this signaling pathway in schizophrenia. Following this study, several independent studies were published that not only confirmed the association of this signaling pathway with schizophrenia across different populations, but also shed light on the mechanisms by which AKT/GSK3 pathway may contribute to the development of this complex disorder. In this review, following an introduction on the role of AKT in human diseases and its functions in neuronal & non-neuronal cells, a review on the results of studies published on AKT/GSK3 signaling pathway in schizophrenia after the original 2004 paper will be provided. A brief review on other signaling pathways involved in schizophrenia and the possible connections with AKT/GSK3 signaling pathway will be discussed. Moreover, some possible molecular mechanisms acting through this pathway will be discussed besides the mechanisms by which they may contribute to the pathogenesis of schizophrenia. Finally

  15. Robustness and fragility in the yeast high osmolarity glycerol (HOG) signal-transduction pathway.

    Science.gov (United States)

    Krantz, Marcus; Ahmadpour, Doryaneh; Ottosson, Lars-Göran; Warringer, Jonas; Waltermann, Christian; Nordlander, Bodil; Klipp, Edda; Blomberg, Anders; Hohmann, Stefan; Kitano, Hiroaki

    2009-01-01

    Cellular signalling networks integrate environmental stimuli with the information on cellular status. These networks must be robust against stochastic fluctuations in stimuli as well as in the amounts of signalling components. Here, we challenge the yeast HOG signal-transduction pathway with systematic perturbations in components' expression levels under various external conditions in search for nodes of fragility. We observe a substantially higher frequency of fragile nodes in this signal-transduction pathway than that has been observed for other cellular processes. These fragilities disperse without any clear pattern over biochemical functions or location in pathway topology and they are largely independent of pathway activation by external stimuli. However, the strongest toxicities are caused by pathway hyperactivation. In silico analysis highlights the impact of model structure on in silico robustness, and suggests complex formation and scaffolding as important contributors to the observed fragility patterns. Thus, in vivo robustness data can be used to discriminate and improve mathematical models.

  16. Aberrant signaling pathways in medulloblastomas: a stem cell connection

    Directory of Open Access Journals (Sweden)

    Carolina Oliveira Rodini

    2010-12-01

    Full Text Available Medulloblastoma is a highly malignant primary tumor of the central nervous system. It represents the most frequent type of solid tumor and the leading cause of death related to cancer in early childhood. Current treatment includes surgery, chemotherapy and radiotherapy which may lead to severe cognitive impairment and secondary brain tumors. New perspectives for therapeutic development have emerged with the identification of stem-like cells displaying high tumorigenic potential and increased radio- and chemo-resistance in gliomas. Under the cancer stem cell hypothesis, transformation of neural stem cells and/or granular neuron progenitors of the cerebellum are though to be involved in medulloblastoma development. Dissecting the genetic and molecular alterations associated with this process should significantly impact both basic and applied cancer research. Based on cumulative evidences in the fields of genetics and molecular biology of medulloblastomas, we discuss the possible involvement of developmental signaling pathways as critical biochemical switches determining normal neurogenesis or tumorigenesis. From the clinical viewpoint, modulation of signaling pathways such as TGFβ, regulating neural stem cell proliferation and tumor development, might be attempted as an alternative strategy for future drug development aiming at more efficient therapies and improved clinical outcome of patients with pediatric brain cancers.

  17. Exploiting the WNT Signaling Pathway for Clinical Purposes.

    Science.gov (United States)

    Johnson, Mark L; Recker, Robert R

    2017-06-01

    The goal of this paper is to evaluate critically the literature published over the past 3 years regarding the Wnt signaling pathway. The Wnt pathway was found to be involved in bone biology in 2001-2002 with the discovery of a (G171V) mutation in the lipoprotein receptor-related protein 5 (LRP5) that resulted in high bone mass and another mutation that completely inactivated Lrp5 function and resulted in osteoporosis pseudoglioma syndrome (OPPG). The molecular biology has been complex, and very interesting. It has provided many opportunities for exploitation to develop new clinical treatments, particularly for osteoporosis. More clinical possibilities include: treatments for fracture healing, corticosteroid osteoporosis, osteogenesis imperfecta, and others. In addition, we wish to provide historical information coming from distant publications (~350 years ago) regarding bone biology that have been confirmed by study of Wnt signaling. A recent finding is the development of an antibody to sclerostin that is under study as a treatment for osteoporosis. Development of treatments for other forms of osteoporosis, such as corticosteroid osteoporosis, is also underway. The full range of the applications of the work is not yet been achieved.

  18. Signaling Pathways in Pathogenesis of Diamond Blackfan Anemia

    Science.gov (United States)

    2015-12-01

    AWARD NUMBER: W81XWH-12-1-0590 TITLE: SIGNALING PATHWAYS IN PATHOGENESIS OF DIAMOND BLACKFAN ANEMIA PRINCIPAL INVESTIGATOR: KATHLEEN M...SUBTITLE 5a. CONTRACT NUMBER W81XWH-12-1-0590 SIGNALING PATHWAYS IN PATHOGENESIS OF DIAMOND BLACKFAN ANEMIA 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER...Unlimited 13. SUPPLEMENTARY NOTES None 14. ABSTRACT: Diamond Blackfan Anemia (DBA) is a disorder that results in pure red cell aplasia, congenital

  19. Dissection of the insulin signaling pathway via quantitative phosphoproteomics

    DEFF Research Database (Denmark)

    Krüger, Marcus; Kratchmarova, Irina; Blagoev, Blagoy

    2008-01-01

    spectrum of the tyrosine phosphorylation cascade, we have defined the tyrosine-phosphoproteome of the insulin signaling pathway, using high resolution mass spectrometry in combination with phosphotyrosine immunoprecipitation and stable isotope labeling by amino acids in cell culture (SILAC......The insulin signaling pathway is of pivotal importance in metabolic diseases, such as diabetes, and in cellular processes, such as aging. Insulin activates a tyrosine phosphorylation cascade that branches to create a complex network affecting multiple biological processes. To understand the full...

  20. Modelling and Analysis of Biochemical Signalling Pathway Cross-talk

    Directory of Open Access Journals (Sweden)

    Robin Donaldson

    2010-02-01

    Full Text Available Signalling pathways are abstractions that help life scientists structure the coordination of cellular activity. Cross-talk between pathways accounts for many of the complex behaviours exhibited by signalling pathways and is often critical in producing the correct signal-response relationship. Formal models of signalling pathways and cross-talk in particular can aid understanding and drive experimentation. We define an approach to modelling based on the concept that a pathway is the (synchronising parallel composition of instances of generic modules (with internal and external labels. Pathways are then composed by (synchronising parallel composition and renaming; different types of cross-talk result from different combinations of synchronisation and renaming. We define a number of generic modules in PRISM and five types of cross-talk: signal flow, substrate availability, receptor function, gene expression and intracellular communication. We show that Continuous Stochastic Logic properties can both detect and distinguish the types of cross-talk. The approach is illustrated with small examples and an analysis of the cross-talk between the TGF-b/BMP, WNT and MAPK pathways.

  1. Modulation of neurotrophic signaling pathways by polyphenols

    Directory of Open Access Journals (Sweden)

    Moosavi F

    2015-12-01

    Full Text Available Fatemeh Moosavi,1,2 Razieh Hosseini,1,2 Luciano Saso,3 Omidreza Firuzi1 1Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; 2Department of Pharmacology, School of Veterinary Medicine, Shiraz University, Shiraz, Iran; 3Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University of Rome, Rome, Italy Abstract: Polyphenols are an important class of phytochemicals, and several lines of evidence have demonstrated their beneficial effects in the context of a number of pathologies including neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease. In this report, we review the studies on the effects of polyphenols on neuronal survival, growth, proliferation and differentiation, and the signaling pathways involved in these neurotrophic actions. Several polyphenols including flavonoids such as baicalein, daidzein, luteolin, and nobiletin as well as nonflavonoid polyphenols such as auraptene, carnosic acid, curcuminoids, and hydroxycinnamic acid derivatives including caffeic acid phentyl ester enhance neuronal survival and promote neurite outgrowth in vitro, a hallmark of neuronal differentiation. Assessment of underlying mechanisms, especially in PC12 neuronal-like cells, reveals that direct agonistic effect on tropomyosin receptor kinase (Trk receptors, the main receptors of neurotrophic factors including nerve growth factor (NGF and brain-derived neurotrophic factor (BDNF explains the action of few polyphenols such as 7,8-dihydroxyflavone. However, several other polyphenolic compounds activate extracellular signal-regulated kinase (ERK and phosphoinositide 3-kinase (PI3K/Akt pathways. Increased expression of neurotrophic factors in vitro and in vivo is the mechanism of neurotrophic action of flavonoids such as scutellarin, daidzein, genistein, and fisetin, while compounds like apigenin and ferulic acid increase cyclic adenosine monophosphate

  2. Expression of conserved signalling pathway genes during ...

    Indian Academy of Sciences (India)

    However, though ES cells of different origins are regarded as equally pluripotent, their in vitro differentiation potential varies, suggesting that their response to developmental signals is different. The R1 cell line is widely used for gene manipulation due to its good growth characteristics and highly efficient germline ...

  3. Linking proteins to signaling pathways for experiment design and evaluation.

    Directory of Open Access Journals (Sweden)

    Illés J Farkas

    Full Text Available Biomedical experimental work often focuses on altering the functions of selected proteins. These changes can hit signaling pathways, and can therefore unexpectedly and non-specifically affect cellular processes. We propose PathwayLinker, an online tool that can provide a first estimate of the possible signaling effects of such changes, e.g., drug or microRNA treatments. PathwayLinker minimizes the users' efforts by integrating protein-protein interaction and signaling pathway data from several sources with statistical significance tests and clear visualization. We demonstrate through three case studies that the developed tool can point out unexpected signaling bias in normal laboratory experiments and identify likely novel signaling proteins among the interactors of known drug targets. In our first case study we show that knockdown of the Caenorhabditis elegans gene cdc-25.1 (meant to avoid progeny may globally affect the signaling system and unexpectedly bias experiments. In the second case study we evaluate the loss-of-function phenotypes of a less known C. elegans gene to predict its function. In the third case study we analyze GJA1, an anti-cancer drug target protein in human, and predict for this protein novel signaling pathway memberships, which may be sources of side effects. Compared to similar services, a major advantage of PathwayLinker is that it drastically reduces the necessary amount of manual literature searches and can be used without a computational background. PathwayLinker is available at http://PathwayLinker.org. Detailed documentation and source code are available at the website.

  4. Evaluation of Notch and Hypoxia Signaling Pathways in Chemically ...

    African Journals Online (AJOL)

    Hepatocellular carcinoma (HCC) is a common worldwide malignancy. Notch signaling pathway contributes to the genesis of diverse cancers, however, its role in HCC is unclear. Hypoxia is a common feature of HCC. Signal integration between Notch and hypoxia may be involved in HCC. The aim of this study was to ...

  5. Signal Transduction Pathways that Regulate CAB Gene Expression

    Energy Technology Data Exchange (ETDEWEB)

    Chory, Joanne

    2004-12-31

    The process of chloroplast differentiation, involves the coordinate regulation of many nuclear and chloroplast genes. The cues for the initiation of this developmental program are both extrinsic (e.g., light) and intrinsic (cell-type and plastid signals). During this project period, we utilized a molecular genetic approach to select for Arabidopsis mutants that did not respond properly to environmental light conditions, as well as mutants that were unable to perceive plastid damage. These latter mutants, called gun mutants, define two retrograde signaling pathways that regulate nuclear gene expression in response to chloroplasts. A major finding was to identify a signal from chloroplasts that regulates nuclear gene transcription. This signal is the build-up of Mg-Protoporphyrin IX, a key intermediate of the chlorophyll biosynthetic pathway. The signaling pathways downstream of this signal are currently being studied. Completion of this project has provided an increased understanding of the input signals and retrograde signaling pathways that control nuclear gene expression in response to the functional state of chloroplasts. These studies should ultimately influence our abilities to manipulate plant growth and development, and will aid in the understanding of the developmental control of photosynthesis.

  6. Signal Transduction Pathways that Regulate CAB Gene Expression

    Energy Technology Data Exchange (ETDEWEB)

    Chory, Joanne

    2006-01-16

    The process of chloroplast differentiation, involves the coordinate regulation of many nuclear and chloroplast genes. The cues for the initiation of this developmental program are both extrinsic (e.g., light) and intrinsic (cell-type and plastid signals). During this project period, we utilized a molecular genetic approach to select for Arabidopsis mutants that did not respond properly to environmental light conditions, as well as mutants that were unable to perceive plastid damage. These latter mutants, called gun mutants, define two retrograde signaling pathways that regulate nuclear gene expression in response to chloroplasts. A major finding was to identify a signal from chloroplasts that regulates nuclear gene transcription. This signal is the build-up of Mg-Protoporphyrin IX, a key intermediate of the chlorophyll biosynthetic pathway. The signaling pathways downstream of this signal are currently being studied. Completion of this project has provided an increased understanding of the input signals and retrograde signaling pathways that control nuclear gene expression in response to the functional state of chloroplasts. These studies should ultimately influence our abilities to manipulate plant growth and development, and will aid in the understanding of the developmental control of photosynthesis.

  7. Signaling pathway networks mined from human pituitary adenoma proteomics data

    Directory of Open Access Journals (Sweden)

    Zhan Xianquan

    2010-04-01

    Full Text Available Abstract Background We obtained a series of pituitary adenoma proteomic expression data, including protein-mapping data (111 proteins, comparative proteomic data (56 differentially expressed proteins, and nitroproteomic data (17 nitroproteins. There is a pressing need to clarify the significant signaling pathway networks that derive from those proteins in order to clarify and to better understand the molecular basis of pituitary adenoma pathogenesis and to discover biomarkers. Here, we describe the significant signaling pathway networks that were mined from human pituitary adenoma proteomic data with the Ingenuity pathway analysis system. Methods The Ingenuity pathway analysis system was used to analyze signal pathway networks and canonical pathways from protein-mapping data, comparative proteomic data, adenoma nitroproteomic data, and control nitroproteomic data. A Fisher's exact test was used to test the statistical significance with a significance level of 0.05. Statistical significant results were rationalized within the pituitary adenoma biological system with literature-based bioinformatics analyses. Results For the protein-mapping data, the top pathway networks were related to cancer, cell death, and lipid metabolism; the top canonical toxicity pathways included acute-phase response, oxidative-stress response, oxidative stress, and cell-cycle G2/M transition regulation. For the comparative proteomic data, top pathway networks were related to cancer, endocrine system development and function, and lipid metabolism; the top canonical toxicity pathways included mitochondrial dysfunction, oxidative phosphorylation, oxidative-stress response, and ERK/MAPK signaling. The nitroproteomic data from a pituitary adenoma were related to cancer, cell death, lipid metabolism, and reproductive system disease, and the top canonical toxicity pathways mainly related to p38 MAPK signaling and cell-cycle G2/M transition regulation. Nitroproteins from a

  8. TSLP signaling pathway map: a platform for analysis of TSLP-mediated signaling.

    Science.gov (United States)

    Zhong, Jun; Sharma, Jyoti; Raju, Rajesh; Palapetta, Shyam Mohan; Prasad, T S Keshava; Huang, Tai-Chung; Yoda, Akinori; Tyner, Jeffrey W; van Bodegom, Diederik; Weinstock, David M; Ziegler, Steven F; Pandey, Akhilesh

    2014-01-01

    Thymic stromal lymphopoietin (TSLP) is a four-helix bundle cytokine that plays a critical role in the regulation of immune responses and in the differentiation of hematopoietic cells. TSLP signals through a heterodimeric receptor complex consisting of an interleukin-7 receptor α chain and a unique TSLP receptor (TSLPR) [also known as cytokine receptor-like factor 2 (CRLF2)]. Cellular targets of TSLP include dendritic cells, B cells, mast cells, regulatory T (Treg) cells and CD4+ and CD8+ T cells. The TSLP/TSLPR axis can activate multiple signaling transduction pathways including the JAK/STAT pathway and the PI-3 kinase pathway. Aberrant TSLP/TSLPR signaling has been associated with a variety of human diseases including asthma, atopic dermatitis, nasal polyposis, inflammatory bowel disease, eosinophilic eosophagitis and, most recently, acute lymphoblastic leukemia. A centralized resource of the TSLP signaling pathway cataloging signaling events is not yet available. In this study, we present a literature-annotated resource of reactions in the TSLP signaling pathway. This pathway map is publicly available through NetPath (http://www.netpath.org/), an open access signal transduction pathway resource developed previously by our group. This map includes 236 molecules and 252 reactions that are involved in TSLP/TSLPR signaling pathway. We expect that the TSLP signaling pathway map will provide a rich resource to study the biology of this important cytokine as well as to identify novel therapeutic targets for diseases associated with dysregulated TSLP/TSLPR signaling. Database URL: http://www.netpath.org/pathways?path_id=NetPath_24.

  9. Purinergic Signaling Pathways in Endocrine System

    OpenAIRE

    Bjelobaba, Ivana; Janjic, Marija M.; Stojilkovic, Stanko S.

    2015-01-01

    Adenosine-5′-triphosphate is released by neuroendocrine, endocrine, and other cell types and acts as an extracellular agonist for ligand-gated P2X cationic channels and G protein-coupled P2Y receptors in numerous organs and tissues, including the endocrine system. The breakdown of ATP by ectonucleotidases not only terminates its extracellular messenger functions, but also provides a pathway for the generation of two additional agonists: adenosine 5′-diphosphate, acting via some P2Y receptors,...

  10. Epilepsy and the Wnt Signaling Pathway

    Science.gov (United States)

    2016-08-01

    Tufts University School of Medicine Boston, MA 02111 REPORT DATE: August 2016 TYPE OF REPORT: Final PREPARED FOR: U.S. Army Medical Research and...Medical Campus Building 500 Mail Stop F428, PO Box 6508 Aurora, CO 80045 Tufts University School of Medicine Dept. of DMCB Jaharis 614 150...delineating a time course for Wnt signaling in mouse to complement Audrey Yee’s studies in the rat. We have complementary evidence for the increase

  11. Predicting resistance by selection of signaling pathways

    Science.gov (United States)

    Rosell, Rafael; Molina, Miguel Angel; Viteri, Santiago

    2014-01-01

    Epidermal growth factor receptor (EGFR) mutations occur in 17% of non-small-cell lung cancer (NSCLC) patients with notable response to single agent therapy but with low complete remission rate and, eventually, disease progression. Priming BIM, a pro-apoptotic signaling BH3-only protein, induces sensitivity to erlotinib in EGFR-mutant cell lines. Synthetic lethal approaches and preemptive therapies based on the initial expression of BIM may significantly improve the treatment outcome. EGFR mutations result in transient pro-death imbalance of survival and apoptotic signaling in response to EGFR inhibition. SHP2 is essential to the balance between ERK and the phosphoinositide-3-kinase (PI3K)/AKT and signal transducer activator of transcription (STAT) activity, while mTOR can be an additional marker for patients with high BIM expression. Furthermore, stromal hepatocyte growth factor (HGF) confers EGFR tyrosine kinase inhibitor (TKI) resistance and induces interreceptor crosstalk with integrin-b4, Eph2, CUB domain-containing protein-1 (CDCP1), AXL and JAK1. Only by understanding better, and in more depth, complex cancer molecular biology will we have the information that will help us to design strategies to augment efficacy of EGFR TKIs and offer our patients the best, most correct therapeutic option. PMID:25806289

  12. Targeting Signaling Pathways in Epithelial Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    Johannes Haybaeck

    2013-05-01

    Full Text Available Ovarian carcinoma (OC is the most lethal gynecological malignancy. Response to platinum-based chemotherapy is poor in some patients and, thus, current research is focusing on new therapy options. The various histological types of OC are characterized by distinctive molecular genetic alterations that are relevant for ovarian tumorigenesis. The understanding of these molecular pathways is essential for the development of novel therapeutic strategies. Purpose: We want to give an overview on the molecular genetic changes of the histopathological types of OC and their role as putative therapeutic targets. In Depth Review of Existing Data: In 2012, the vascular endothelial growth factor (VEGF inhibitor, bevacizumab, was approved for OC treatment. Bevacizumab has shown promising results as single agent and in combination with conventional chemotherapy, but its target is not distinctive when analyzed before treatment. At present, mammalian target of rapamycin (mTOR inhibitors, poly-ADP-ribose polymerase (PARP inhibitors and components of the EGFR pathway are in the focus of clinical research. Interestingly, some phytochemical substances show good synergistic effects when used in combination with chemotherapy. Conclusion: Ongoing studies of targeted agents in conjunction with chemotherapy will show whether there are alternative options to bevacizumab available for OC patients. Novel targets which can be assessed before therapy to predict efficacy are needed. The assessment of therapeutic targets is continuously improved by molecular pathological analyses on tumor tissue. A careful selection of patients for personalized treatment will help to reduce putative side effects and toxicity.

  13. Segregation of Axial Motor and Sensory Pathways via Heterotypic Trans-Axonal Signaling

    Science.gov (United States)

    Gallarda, Benjamin W.; Bonanomi, Dario; Müller, Daniel; Brown, Arthur; Alaynick, William A.; Andrews, Shane E.; Lemke, Greg; Pfaff, Samuel L.; Marquardt, Till

    2011-01-01

    Execution of motor behaviors relies on circuitries effectively integrating immediate sensory feedback to efferent pathways controlling muscle activity. It remains unclear how, during neuromuscular circuit assembly, sensory and motor projections become incorporated into tightly coordinated, yet functionally separate pathways. We report that, within axial nerves, establishment of discrete afferent and efferent pathways depends on coordinate signaling between coextending sensory and motor projections. These heterotypic axon-axon interactions require motor axonal EphA3/EphA4 receptor tyrosine kinases activated by cognate sensory axonal ephrin-A ligands. Genetic elimination of trans-axonal ephrin-A → EphA signaling in mice triggers drastic motor-sensory miswiring, culminating in functional efferents within proximal afferent pathways. Effective assembly of a key circuit underlying motor behaviors thus critically depends on trans-axonal signaling interactions resolving motor and sensory projections into discrete pathways. PMID:18403711

  14. Autophagy and the nutritional signaling pathway

    Directory of Open Access Journals (Sweden)

    Long HE,Shabnam ESLAMFAM,Xi MA,Defa LI

    2016-09-01

    Full Text Available During their growth and development, animals adapt to tremendous changes in order to survive. These include responses to both environmental and physiological changes and autophagy is one of most important adaptive and regulatory mechanisms. Autophagy is defined as an autolytic process to clear damaged cellular organelles and recycle the nutrients via lysosomic degradation. The process of autophagy responds to special conditions such as nutrient withdrawal. Once autophagy is induced, phagophores form and then elongate and curve to form autophagosomes. Autophagosomes then engulf cargo, fuse with endosomes, and finally fuse with lysosomes for maturation. During the initiation process, the ATG1/ULK1 (unc-51-like kinase 1 and VPS34 (which encodes a class III phosphatidylinositol (PtdIns 3-kinase complexes are critical in recruitment and assembly of other complexes required for autophagy. The process of autophagy is regulated by autophagy related genes (ATGs. Amino acid and energy starvation mediate autophagy by activating mTORC1 (mammalian target of rapamycin and AMP-activated protein kinase (AMPK. AMPK is the energy status sensor, the core nutrient signaling component and the metabolic kinase of cells. This review mainly focuses on the mechanism of autophagy regulated by nutrient signaling especially for the two important complexes, ULK1 and VPS34.

  15. Racial differences in B cell receptor signaling pathway activation.

    Science.gov (United States)

    Longo, Diane M; Louie, Brent; Mathi, Kavita; Pos, Zoltan; Wang, Ena; Hawtin, Rachael E; Marincola, Francesco M; Cesano, Alessandra

    2012-06-06

    Single-cell network profiling (SCNP) is a multi-parametric flow cytometry-based approach that simultaneously measures basal and modulated intracellular signaling activity in multiple cell subpopulations. Previously, SCNP analysis of a broad panel of immune signaling pathways in cell subsets within PBMCs from 60 healthy donors identified a race-associated difference in B cell anti-IgD-induced PI3K pathway activity. The present study extended this analysis to a broader range of signaling pathway components downstream of the B cell receptor (BCR) in European Americans and African Americans using a subset of donors from the previously analyzed cohort of 60 healthy donors. Seven BCR signaling nodes (a node is defined as a paired modulator and intracellular readout) were measured at multiple time points by SCNP in PBMCs from 10 healthy donors [5 African Americans (36-51 yrs), 5 European Americans (36-56 yrs), all males]. Analysis of BCR signaling activity in European American and African American PBMC samples revealed that, compared to the European American donors, B cells from African Americans had lower anti-IgD induced phosphorylation of multiple BCR pathway components, including the membrane proximal proteins Syk and SFK as well as proteins in the PI3K pathway (S6 and Akt), the MAPK pathways (Erk and p38), and the NF-κB pathway (NF-κB). In addition to differences in the magnitude of anti-IgD-induced pathway activation, racial differences in BCR signaling kinetic profiles were observed. Further, the frequency of IgD+ B cells differed by race and strongly correlated with BCR pathway activation. Thus, the race-related difference in BCR pathway activation appears to be attributable at least in part to a race-associated difference in IgD+ B cell frequencies. SCNP analysis enabled the identification of statistically significant race-associated differences in BCR pathway activation within PBMC samples from healthy donors. Understanding race-associated contrasts in immune

  16. Racial differences in B cell receptor signaling pathway activation

    Directory of Open Access Journals (Sweden)

    Longo Diane M

    2012-06-01

    Full Text Available Abstract Background Single-cell network profiling (SCNP is a multi-parametric flow cytometry-based approach that simultaneously measures basal and modulated intracellular signaling activity in multiple cell subpopulations. Previously, SCNP analysis of a broad panel of immune signaling pathways in cell subsets within PBMCs from 60 healthy donors identified a race-associated difference in B cell anti-IgD-induced PI3K pathway activity. Methods The present study extended this analysis to a broader range of signaling pathway components downstream of the B cell receptor (BCR in European Americans and African Americans using a subset of donors from the previously analyzed cohort of 60 healthy donors. Seven BCR signaling nodes (a node is defined as a paired modulator and intracellular readout were measured at multiple time points by SCNP in PBMCs from 10 healthy donors [5 African Americans (36-51 yrs, 5 European Americans (36-56 yrs, all males]. Results Analysis of BCR signaling activity in European American and African American PBMC samples revealed that, compared to the European American donors, B cells from African Americans had lower anti-IgD induced phosphorylation of multiple BCR pathway components, including the membrane proximal proteins Syk and SFK as well as proteins in the PI3K pathway (S6 and Akt, the MAPK pathways (Erk and p38, and the NF-κB pathway (NF-κB. In addition to differences in the magnitude of anti-IgD-induced pathway activation, racial differences in BCR signaling kinetic profiles were observed. Further, the frequency of IgD+ B cells differed by race and strongly correlated with BCR pathway activation. Thus, the race-related difference in BCR pathway activation appears to be attributable at least in part to a race-associated difference in IgD+ B cell frequencies. Conclusions SCNP analysis enabled the identification of statistically significant race-associated differences in BCR pathway activation within PBMC samples from

  17. Systems Biomedicine of Rabies Delineates the Affected Signaling Pathways

    Science.gov (United States)

    Azimzadeh Jamalkandi, Sadegh; Mozhgani, Sayed-Hamidreza; Gholami Pourbadie, Hamid; Mirzaie, Mehdi; Noorbakhsh, Farshid; Vaziri, Behrouz; Gholami, Alireza; Ansari-Pour, Naser; Jafari, Mohieddin

    2016-01-01

    The prototypical neurotropic virus, rabies, is a member of the Rhabdoviridae family that causes lethal encephalomyelitis. Although there have been a plethora of studies investigating the etiological mechanism of the rabies virus and many precautionary methods have been implemented to avert the disease outbreak over the last century, the disease has surprisingly no definite remedy at its late stages. The psychological symptoms and the underlying etiology, as well as the rare survival rate from rabies encephalitis, has still remained a mystery. We, therefore, undertook a systems biomedicine approach to identify the network of gene products implicated in rabies. This was done by meta-analyzing whole-transcriptome microarray datasets of the CNS infected by strain CVS-11, and integrating them with interactome data using computational and statistical methods. We first determined the differentially expressed genes (DEGs) in each study and horizontally integrated the results at the mRNA and microRNA levels separately. A total of 61 seed genes involved in signal propagation system were obtained by means of unifying mRNA and microRNA detected integrated DEGs. We then reconstructed a refined protein–protein interaction network (PPIN) of infected cells to elucidate the rabies-implicated signal transduction network (RISN). To validate our findings, we confirmed differential expression of randomly selected genes in the network using Real-time PCR. In conclusion, the identification of seed genes and their network neighborhood within the refined PPIN can be useful for demonstrating signaling pathways including interferon circumvent, toward proliferation and survival, and neuropathological clue, explaining the intricate underlying molecular neuropathology of rabies infection and thus rendered a molecular framework for predicting potential drug targets. PMID:27872612

  18. CREB pathway links PGE2 signaling with macrophage polarization.

    Science.gov (United States)

    Luan, Bing; Yoon, Young-Sil; Le Lay, John; Kaestner, Klaus H; Hedrick, Susan; Montminy, Marc

    2015-12-22

    Obesity is thought to promote insulin resistance in part via activation of the innate immune system. Increases in proinflammatory cytokine production by M1 macrophages inhibit insulin signaling in white adipose tissue. In contrast, M2 macrophages have been found to enhance insulin sensitivity in part by reducing adipose tissue inflammation. The paracrine hormone prostaglandin E2 (PGE2) enhances M2 polarization in part through activation of the cAMP pathway, although the underlying mechanism is unclear. Here we show that PGE2 stimulates M2 polarization via the cyclic AMP-responsive element binding (CREB)-mediated induction of Krupple-like factor 4 (KLF4). Targeted disruption of CREB or the cAMP-regulated transcriptional coactivators 2 and 3 (CRTC2/3) in macrophages down-regulated M2 marker gene expression and promoted insulin resistance in the context of high-fat diet feeding. As re-expression of KLF4 rescued M2 marker gene expression in CREB-depleted cells, our results demonstrate the importance of the CREB/CRTC pathway in maintaining insulin sensitivity in white adipose tissue via its effects on the innate immune system.

  19. Using Proteomics To Elucidate Critical Signaling Pathways

    KAUST Repository

    Ahmed, Heba

    2012-11-01

    Despite important advances in the therapy of acute myeloid leukemia (AML) the majority of patients will die from their disease (Appelbaum, Rowe, Radich, & Dick, 2001). Characterization of the aberrant molecular pathways responsible for this malignancy provides a platform to discover alternative treatments to help alter the fate of patients. AML is characterized by a blockage in the differentiation of myeloid cells resulting in the accumulation of highly proliferating immature hematopoietic cells. Since treatments such as chemotherapy rarely destroy the leukemic cells entirely, differentiation induction therapy has become a very attractive treatment option. Interestingly, previous experiments have shown that ligation of CD44, a cell surface glycoprotein strongly expressed on all AML cells, with anti-CD44 monoclonal antibodies (mAbs) could reverse this block in differentiation of leukemic blasts regardless of the AML subtype. To expand the understanding of the cellular regulation and circuitry involved, we aim to apply quantitative phosphoproteomics to monitor dynamic changes in phosphorylation state in response to anti-CD44 treatment. Protein phosphorylation and dephosphorylation is a highly controlled biochemical process that responds to various intracellular and extracellular stimuli. As phosphorylation is a dynamic process, quantification of these phosphorylation events would be vastly insightful. The main objective of this project is to determine the differentiation-dependent phosphoproteome of AML cells upon treatment of cells with the anti-CD44 mAb.In these experiments, optimization of protein extraction, phosphopeptide enrichment and data processing and analysis has been achieved. The primary results show successful phosphoproteome extraction complemented with efficient phosphopeptide enrichment and informative data processing. Further quantification with stable isotope labeling techniques is anticipated to provide candidates for targeted therapy.

  20. The Spectrin cytoskeleton regulates the Hippo signalling pathway.

    Science.gov (United States)

    Fletcher, Georgina C; Elbediwy, Ahmed; Khanal, Ichha; Ribeiro, Paulo S; Tapon, Nic; Thompson, Barry J

    2015-04-01

    The Spectrin cytoskeleton is known to be polarised in epithelial cells, yet its role remains poorly understood. Here, we show that the Spectrin cytoskeleton controls Hippo signalling. In the developing Drosophila wing and eye, loss of apical Spectrins (alpha/beta-heavy dimers) produces tissue overgrowth and mis-regulation of Hippo target genes, similar to loss of Crumbs (Crb) or the FERM-domain protein Expanded (Ex). Apical beta-heavy Spectrin binds to Ex and co-localises with it at the apical membrane to antagonise Yki activity. Interestingly, in both the ovarian follicular epithelium and intestinal epithelium of Drosophila, apical Spectrins and Crb are dispensable for repression of Yki, while basolateral Spectrins (alpha/beta dimers) are essential. Finally, the Spectrin cytoskeleton is required to regulate the localisation of the Hippo pathway effector YAP in response to cell density human epithelial cells. Our findings identify both apical and basolateral Spectrins as regulators of Hippo signalling and suggest Spectrins as potential mechanosensors. © 2015 The Authors. Published under the terms of the CC BY 4.0 license.

  1. Evolution and Design Governing Signal Precision and Amplification in a Bacterial Chemosensory Pathway.

    Directory of Open Access Journals (Sweden)

    Mathilde Guzzo

    2015-08-01

    Full Text Available Understanding the principles underlying the plasticity of signal transduction networks is fundamental to decipher the functioning of living cells. In Myxococcus xanthus, a particular chemosensory system (Frz coordinates the activity of two separate motility systems (the A- and S-motility systems, promoting multicellular development. This unusual structure asks how signal is transduced in a branched signal transduction pathway. Using combined evolution-guided and single cell approaches, we successfully uncoupled the regulations and showed that the A-motility regulation system branched-off an existing signaling system that initially only controlled S-motility. Pathway branching emerged in part following a gene duplication event and changes in the circuit structure increasing the signaling efficiency. In the evolved pathway, the Frz histidine kinase generates a steep biphasic response to increasing external stimulations, which is essential for signal partitioning to the motility systems. We further show that this behavior results from the action of two accessory response regulator proteins that act independently to filter and amplify signals from the upstream kinase. Thus, signal amplification loops may underlie the emergence of new connectivity in signal transduction pathways.

  2. Roles of the Hedgehog Signaling Pathway in Epidermal and Hair Follicle Development, Homeostasis, and Cancer

    Directory of Open Access Journals (Sweden)

    Yoshinori Abe

    2017-11-01

    Full Text Available The epidermis is the outermost layer of the skin and provides a protective barrier against environmental insults. It is a rapidly-renewing tissue undergoing constant regeneration, maintained by several types of stem cells. The Hedgehog (HH signaling pathway is one of the fundamental signaling pathways that contributes to epidermal development, homeostasis, and repair, as well as to hair follicle development and follicle bulge stem cell maintenance. The HH pathway interacts with other signal transduction pathways, including those activated by Wnt, bone morphogenetic protein, platelet-derived growth factor, Notch, and ectodysplasin. Furthermore, aberrant activation of HH signaling is associated with various tumors, including basal cell carcinoma. Therefore, an understanding of the regulatory mechanisms of the HH signaling pathway is important for elucidating fundamental mechanisms underlying both organogenesis and carcinogenesis. In this review, we discuss the role of the HH signaling pathway in the development and homeostasis epidermis and hair follicles, and in basal cell carcinoma formation, providing an update of current knowledge in this field.

  3. Dissecting Major Signaling Pathways throughout the Development of Prostate Cancer

    Science.gov (United States)

    da Silva, Henrique B.; Amaral, Eduardo P.; Nolasco, Eduardo L.; de Victo, Nathalia C.; Atique, Rodrigo; Jank, Carina C.; Anschau, Valesca; Zerbini, Luiz F.; Correa, Ricardo G.

    2013-01-01

    Prostate cancer (PCa) is one of the most common malignancies found in males. The development of PCa involves several mutations in prostate epithelial cells, usually linked to developmental changes, such as enhanced resistance to apoptotic death, constitutive proliferation, and, in some cases, to differentiation into an androgen deprivation-resistant phenotype, leading to the appearance of castration-resistant PCa (CRPCa), which leads to a poor prognosis in patients. In this review, we summarize recent findings concerning the main deregulations into signaling pathways that will lead to the development of PCa and/or CRPCa. Key mutations in some pathway molecules are often linked to a higher prevalence of PCa, by directly affecting the respective cascade and, in some cases, by deregulating a cross-talk node or junction along the pathways. We also discuss the possible environmental and nonenvironmental inducers for these mutations, as well as the potential therapeutic strategies targeting these signaling pathways. A better understanding of how some risk factors induce deregulation of these signaling pathways, as well as how these deregulated pathways affect the development of PCa and CRPCa, will further help in the development of new treatments and prevention strategies for this disease. PMID:23738079

  4. POSTRANSLATIONAL MODIFICATIONS OF P53: UPSTREAM SIGNALING PATHWAYS.

    Energy Technology Data Exchange (ETDEWEB)

    ANDERSON,C.W.APPELLA,E.

    2003-10-23

    The p53 tumor suppressor is a tetrameric transcription factor that is posttranslational modified at >20 different sites by phosphorylation, acetylation, or sumoylation in response to various cellular stress conditions. Specific posttranslational modifications, or groups of modifications, that result from the activation of different stress-induced signaling pathways are thought to modulate p53 activity to regulate cell fate by inducing cell cycle arrest, apoptosis, or cellular senescence. Here we review recent progress in characterizing the upstream signaling pathways whose activation in response to various genotoxic and non-genotoxic stresses result in p53 posttranslational modifications.

  5. BMP2 and mechanical loading cooperatively regulate immediate early signalling events in the BMP pathway

    Directory of Open Access Journals (Sweden)

    Kopf Jessica

    2012-04-01

    Full Text Available Abstract Background Efficient osteogenic differentiation is highly dependent on coordinated signals arising from growth factor signalling and mechanical forces. Bone morphogenetic proteins (BMPs are secreted proteins that trigger Smad and non-Smad pathways and thereby influence transcriptional and non-transcriptional differentiation cues. Crosstalk at multiple levels allows for promotion or attenuation of signalling intensity and specificity. Similar to BMPs, mechanical stimulation enhances bone formation. However, the molecular mechanism by which mechanical forces crosstalk to biochemical signals is still unclear. Results Here, we use a three-dimensional bioreactor system to describe how mechanical forces are integrated into the BMP pathway. Time-dependent phosphorylation of Smad, mitogen-activated protein kinases and Akt in human fetal osteoblasts was investigated under loading and/or BMP2 stimulation conditions. The phosphorylation of R-Smads is increased both in intensity and duration under BMP2 stimulation with concurrent mechanical loading. Interestingly, the synergistic effect of both stimuli on immediate early Smad phosphorylation is reflected in the transcription of only a subset of BMP target genes, while others are differently affected. Together this results in a cooperative regulation of osteogenesis that is guided by both signalling pathways. Conclusions Mechanical signals are integrated into the BMP signalling pathway by enhancing immediate early steps within the Smad pathway, independent of autocrine ligand secretion. This suggests a direct crosstalk of both mechanotransduction and BMP signalling, most likely at the level of the cell surface receptors. Furthermore, the crosstalk of both pathways over longer time periods might occur on several signalling levels.

  6. Clinical Implications of Hedgehog Pathway Signaling in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Daniel L. Suzman

    2015-09-01

    Full Text Available Activity in the Hedgehog pathway, which regulates GLI-mediated transcription, is important in organogenesis and stem cell regulation in self-renewing organs, but is pathologically elevated in many human malignancies. Mutations leading to constitutive activation of the pathway have been implicated in medulloblastoma and basal cell carcinoma, and inhibition of the pathway has demonstrated clinical responses leading to the approval of the Smoothened inhibitor, vismodegib, for the treatment of advanced basal cell carcinoma. Aberrant Hedgehog pathway signaling has also been noted in prostate cancer with evidence suggesting that it may render prostate epithelial cells tumorigenic, drive the epithelial-to-mesenchymal transition, and contribute towards the development of castration-resistance through autocrine and paracrine signaling within the tumor microenvironment and cross-talk with the androgen pathway. In addition, there are emerging clinical data suggesting that inhibition of the Hedgehog pathway may be effective in the treatment of recurrent and metastatic prostate cancer. Here we will review these data and highlight areas of active clinical research as they relate to Hedgehog pathway inhibition in prostate cancer.

  7. YAP regulates neuronal differentiation through Sonic hedgehog signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Lin, Yi-Ting; Ding, Jing-Ya [Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan (China); Li, Ming-Yang [Department of Life Science, National Taiwan Normal University, Taipei 116, Taiwan (China); Yeh, Tien-Shun [Department of Anatomy and Cell Biology, National Yang-Ming University, Taipei 112, Taiwan (China); Wang, Tsu-Wei, E-mail: twwang@ntnu.edu.tw [Department of Life Science, National Taiwan Normal University, Taipei 116, Taiwan (China); Yu, Jenn-Yah, E-mail: jyyu@ym.edu.tw [Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan (China); Brain Research Center, National Yang-Ming University, Taipei 112, Taiwan (China)

    2012-09-10

    Tight regulation of cell numbers by controlling cell proliferation and apoptosis is important during development. Recently, the Hippo pathway has been shown to regulate tissue growth and organ size in Drosophila. In mammalian cells, it also affects cell proliferation and differentiation in various tissues, including the nervous system. Interplay of several signaling cascades, such as Notch, Wnt, and Sonic Hedgehog (Shh) pathways, control cell proliferation during neuronal differentiation. However, it remains unclear whether the Hippo pathway coordinates with other signaling cascades in regulating neuronal differentiation. Here, we used P19 cells, a mouse embryonic carcinoma cell line, as a model to study roles of YAP, a core component of the Hippo pathway, in neuronal differentiation. P19 cells can be induced to differentiate into neurons by expressing a neural bHLH transcription factor gene Ascl1. Our results showed that YAP promoted cell proliferation and inhibited neuronal differentiation. Expression of Yap activated Shh but not Wnt or Notch signaling activity during neuronal differentiation. Furthermore, expression of Yap increased the expression of Patched homolog 1 (Ptch1), a downstream target of the Shh signaling. Knockdown of Gli2, a transcription factor of the Shh pathway, promoted neuronal differentiation even when Yap was over-expressed. We further demonstrated that over-expression of Yap inhibited neuronal differentiation in primary mouse cortical progenitors and Gli2 knockdown rescued the differentiation defect in Yap over-expressing cells. In conclusion, our study reveals that Shh signaling acts downstream of YAP in regulating neuronal differentiation. -- Highlights: Black-Right-Pointing-Pointer YAP promotes cell proliferation and inhibits neuronal differentiation in P19 cells. Black-Right-Pointing-Pointer YAP promotes Sonic hedgehog signaling activity during neuronal differentiation. Black-Right-Pointing-Pointer Knockdown of Gli2 rescues the Yap

  8. Association study of the oestrogen signalling pathway genes in ...

    Indian Academy of Sciences (India)

    Association study of the oestrogen signalling pathway genes in relation to age at natural menopause. Li-Na He ... The Key Laboratory of Biomedical Information Engineering of Ministry of Education and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China ...

  9. Association study of the oestrogen signalling pathway genes in ...

    Indian Academy of Sciences (India)

    [He Li-Na, Xiong D.-H., Liu Y.-J., Zhang F., Recker R. R. and Deng H.-W. 2007 Association study of the oestrogen signalling pathway genes in relation to age at natural menopause. J. Genet. 86, 269–276]. Introduction. Age at natural menopause (AANM) is closely related to women's psychological and physical well being. It.

  10. Signaling Pathways in Cancer: a Matter of Dosage

    NARCIS (Netherlands)

    C.F.C. Gaspar (Claudia)

    2009-01-01

    textabstractThe main issue addressed in this thesis is how different levels of signaling activity of the Wnt and TGF-β/BMP pathways can affect transcriptional responses in particular relevant for self-renewal and differentiation both in homeostasis and in cancer. Chapter 1 presents an overview

  11. Endosomal "sort" of signaling control: The role of ESCRT machinery in regulation of receptor-mediated signaling pathways.

    Science.gov (United States)

    Szymanska, Ewelina; Budick-Harmelin, Noga; Miaczynska, Marta

    2018-02-01

    The endosomal sorting complexes required for transport (ESCRTs) machinery consists of four protein assemblies (ESCRT-0 to -III subcomplexes) which mediate various processes of membrane remodeling in the cell. In the endocytic pathway, ESCRTs sort cargo destined for degradation into intraluminal vesicles (ILVs) of endosomes. Cargos targeted by ESCRTs include various signaling molecules, mainly internalized cell-surface receptors but also some cytosolic proteins. It is therefore expected that aberrant trafficking caused by ESCRT dysfunction affects different signaling pathways. Here we review how perturbation of ESCRT activity alters intracellular transport of membrane receptors, causing their accumulation on endocytic compartments, decreased degradation and/or altered recycling to the plasma membrane. We further describe how perturbed trafficking of receptors impacts the activity of their downstream signaling pathways, with or without changes in transcriptional responses. Finally, we present evidence that ESCRT components can also control activity and intracellular distribution of cytosolic signaling proteins (kinases, other effectors and soluble receptors). The underlying mechanisms involve sequestration of such proteins in ILVs, their sorting for degradation or towards non-lysosomal destinations, and regulating their availability in various cellular compartments. All these ESCRT-mediated processes can modulate final outputs of multiple signaling pathways. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. [The state of receptor-dependent signal pathways in the agranulocytes from the peripheral blood of the reconvalescent patients following community-acquired pneumonia under the influence of microwave radiation].

    Science.gov (United States)

    Terekhov, I V; Bondar', S S; Khadartsev, A A

    2016-01-01

    The present article reports the study of the influence of low-intensity microwave radiation on the state of the JAK/STAT-signaling pathways in the mononuclear cells and the intercellular levels of the molecules maintaining the functioning of this pathway. The experiments on the model of intercellular interactions in the whole blood cell culture obtained during the convalescence phase of community-acquired bacterial pneumonia were designed to elucidate the effects of the cell-cell interactions in the culture exposed to electromagnetic radiation with a frequency of 1000 MHz and power flux density 0.1 mcW/cm2 on the intracellular levels of total and phosphorylated species of JAK-kinases, STAT-factors and SOCS-proteins. It is concluded that sensitivity of intracellular signaling systems to the effects of low-intensity microwave radiation manifests itself in the form of increased intracellular concentrations of Janus kinases and SOCS proteins with a simultaneous decrease in the level of STAT factors.

  13. Mitogen Activated Protein kinase signal transduction pathways in the prostate

    Directory of Open Access Journals (Sweden)

    Koul Sweaty

    2004-06-01

    Full Text Available Abstract The biochemistry of the mitogen activated protein kinases ERK, JNK, and p38 have been studied in prostate physiology in an attempt to elucidate novel mechanisms and pathways for the treatment of prostatic disease. We reviewed articles examining mitogen-activated protein kinases using prostate tissue or cell lines. As with other tissue types, these signaling modules are links/transmitters for important pathways in prostate cells that can result in cellular survival or apoptosis. While the activation of the ERK pathway appears to primarily result in survival, the roles of JNK and p38 are less clear. Manipulation of these pathways could have important implications for the treatment of prostate cancer and benign prostatic hypertrophy.

  14. Wolbachia as an infectious extrinsic factor manipulating host signalling pathways

    Directory of Open Access Journals (Sweden)

    Ilaria eNegri

    2012-01-01

    Full Text Available Wolbachia pipientis is a widespread endosymbiont of filarial nematodes and arthropods. While in worms the symbiosis is obligate, in arthropods Wolbachia induces several reproductive manipulations (i.e. cytoplasmic incompatibility, parthenogenesis, feminization of genetic males and male-killing in order to increase the number of infected females. These various phenotypic effects may be linked to differences in host physiology, and in particular to endocrine-related processes governing growth, development and reproduction. Indeed, a number of evidences links Wolbachia symbiosis to insulin and ecdysteroid signalling, two multilayered pathways known to work antagonistically, jointly or even independently for the regulation of different molecular networks. At present it is not clear whether Wolbachia manipulates one pathway, thus affecting other related metabolic networks, or if it targets both pathways, even interacting at several points in each of them. Interestingly, in view of the interplay between hormone signalling and epigenetic machinery, a direct influence of the infection on hormonal signalling involving ecdysteroids might be achievable through the manipulation of the host’s epigenetic pathways.

  15. The mTOR Signalling Pathway in Human Cancer

    Directory of Open Access Journals (Sweden)

    Paula Soares

    2012-02-01

    Full Text Available The conserved serine/threonine kinase mTOR (the mammalian target of rapamycin, a downstream effector of the PI3K/AKT pathway, forms two distinct multiprotein complexes: mTORC1 and mTORC2. mTORC1 is sensitive to rapamycin, activates S6K1 and 4EBP1, which are involved in mRNA translation. It is activated by diverse stimuli, such as growth factors, nutrients, energy and stress signals, and essential signalling pathways, such as PI3K, MAPK and AMPK, in order to control cell growth, proliferation and survival. mTORC2 is considered resistant to rapamycin and is generally insensitive to nutrients and energy signals. It activates PKC-α and AKT and regulates the actin cytoskeleton. Deregulation of multiple elements of the mTOR pathway (PI3K amplification/mutation, PTEN loss of function, AKT overexpression, and S6K1, 4EBP1 and eIF4E overexpression has been reported in many types of cancers, particularly in melanoma, where alterations in major components of the mTOR pathway were reported to have significant effects on tumour progression. Therefore, mTOR is an appealing therapeutic target and mTOR inhibitors, including the rapamycin analogues deforolimus, everolimus and temsirolimus, are submitted to clinical trials for treating multiple cancers, alone or in combination with inhibitors of other pathways. Importantly, temsirolimus and everolimus were recently approved by the FDA for the treatment of renal cell carcinoma, PNET and giant cell astrocytoma. Small molecules that inhibit mTOR kinase activity and dual PI3K-mTOR inhibitors are also being developed. In this review, we aim to survey relevant research, the molecular mechanisms of signalling, including upstream activation and downstream effectors, and the role of mTOR in cancer, mainly in melanoma.

  16. Signalling pathways involved in adult heart formation revealed by gene expression profiling in Drosophila.

    Directory of Open Access Journals (Sweden)

    Bruno Zeitouni

    2007-10-01

    Full Text Available Drosophila provides a powerful system for defining the complex genetic programs that drive organogenesis. Under control of the steroid hormone ecdysone, the adult heart in Drosophila forms during metamorphosis by a remodelling of the larval cardiac organ. Here, we evaluated the extent to which transcriptional signatures revealed by genomic approaches can provide new insights into the molecular pathways that underlie heart organogenesis. Whole-genome expression profiling at eight successive time-points covering adult heart formation revealed a highly dynamic temporal map of gene expression through 13 transcript clusters with distinct expression kinetics. A functional atlas of the transcriptome profile strikingly points to the genomic transcriptional response of the ecdysone cascade, and a sharp regulation of key components belonging to a few evolutionarily conserved signalling pathways. A reverse genetic analysis provided evidence that these specific signalling pathways are involved in discrete steps of adult heart formation. In particular, the Wnt signalling pathway is shown to participate in inflow tract and cardiomyocyte differentiation, while activation of the PDGF-VEGF pathway is required for cardiac valve formation. Thus, a detailed temporal map of gene expression can reveal signalling pathways responsible for specific developmental programs and provides here substantial grasp into heart formation.

  17. Signaling transduction pathways involved in basophil adhesion and histamine release

    DEFF Research Database (Denmark)

    Sha, Quan; Poulsen, Lars K.; Gerwien, Jens

    2006-01-01

    Little is known about basophil with respect to the different signaling transduction pathways involved in spontaneous, cytokine or anti-IgE induced adhesion and how this compares to IgE-dependent and IgE-independent mediator secretion. The purpose of the present study was to investigate the roles ...... of beta1 and beta2 integrins in basophil adhesion as well as hosphatidylinositol 3-kinase (PI3K), src-kinases and extracellular signal regulated kinase (ERK) 1/2 in basophil adhesion and histamine release (HR)....

  18. Shared signaling pathways in normal and breast cancer stem cells

    Directory of Open Access Journals (Sweden)

    Gautam K Malhotra

    2011-01-01

    Full Text Available Recent advances in our understanding of breast cancer biology have led to the identification of a subpopulation of cells within tumors that appear to be responsible for initiating and propagating the cancer. These tumor initiating cells are not only unique in their ability to generate tumors, but also share many similarities with elements of normal adult tissue stem cells, and have therefore been termed cancer stem cells (CSCs. These CSCs often inappropriately use many of the same signaling pathways utilized by their normal stem cell counterparts which may present a challenge to the development of CSC specific therapies. Here, we discuss three major stem cell signaling pathways (Notch, Wnt, and Hedgehog; with a focus on their function in normal mammary gland development and their misuse in breast cancer stem cell fate determination.

  19. Probing the canonicity of the Wnt/Wingless signaling pathway.

    Directory of Open Access Journals (Sweden)

    Alexandra Franz

    2017-04-01

    Full Text Available The hallmark of canonical Wnt signaling is the transcriptional induction of Wnt target genes by the beta-catenin/TCF complex. Several studies have proposed alternative interaction partners for beta-catenin or TCF, but the relevance of potential bifurcations in the distal Wnt pathway remains unclear. Here we study on a genome-wide scale the requirement for Armadillo (Arm, Drosophila beta-catenin and Pangolin (Pan, Drosophila TCF in the Wnt/Wingless(Wg-induced transcriptional response of Drosophila Kc cells. Using somatic genetics, we demonstrate that both Arm and Pan are absolutely required for mediating activation and repression of target genes. Furthermore, by means of STARR-sequencing we identified Wnt/Wg-responsive enhancer elements and found that all responsive enhancers depend on Pan. Together, our results confirm the dogma of canonical Wnt/Wg signaling and argue against the existence of distal pathway branches in this system.

  20. Use of mass spectrometry to study signaling pathways

    DEFF Research Database (Denmark)

    Pandey, A; Andersen, Jens S.; Mann, M

    2000-01-01

    biochemical assays have been used to identify molecules involved in signaling pathways. Lately, mass spectrometry, combined with elegant biochemical approaches, has become a powerful tool for identifying proteins and posttranslational modifications. With this protocol, we hope to bridge the gap between...... identification by matrix-assisted laser desorption/ionization (MALDI) mass spectrometry and nanoelectrospray tandem mass spectrometry. We discuss the special requirements for the identification of phosphorylation sites in proteins by mass spectrometry. We describe enrichment of phosphopeptides from unseparated...

  1. Regression of Pathological Cardiac Hypertrophy: Signaling Pathways and Therapeutic Targets

    Science.gov (United States)

    Hou, Jianglong; Kang, Y. James

    2012-01-01

    Pathological cardiac hypertrophy is a key risk factor for heart failure. It is associated with increased interstitial fibrosis, cell death and cardiac dysfunction. The progression of pathological cardiac hypertrophy has long been considered as irreversible. However, recent clinical observations and experimental studies have produced evidence showing the reversal of pathological cardiac hypertrophy. Left ventricle assist devices used in heart failure patients for bridging to transplantation not only improve peripheral circulation but also often cause reverse remodeling of the geometry and recovery of the function of the heart. Dietary supplementation with physiologically relevant levels of copper can reverse pathological cardiac hypertrophy in mice. Angiogenesis is essential and vascular endothelial growth factor (VEGF) is a constitutive factor for the regression. The action of VEGF is mediated by VEGF receptor-1, whose activation is linked to cyclic GMP-dependent protein kinase-1 (PKG-1) signaling pathways, and inhibition of cyclic GMP degradation leads to regression of pathological cardiac hypertrophy. Most of these pathways are regulated by hypoxia-inducible factor. Potential therapeutic targets for promoting the regression include: promotion of angiogenesis, selective enhancement of VEGF receptor-1 signaling pathways, stimulation of PKG-1 pathways, and sustention of hypoxia-inducible factor transcriptional activity. More exciting insights into the regression of pathological cardiac hypertrophy are emerging. The time of translating the concept of regression of pathological cardiac hypertrophy to clinical practice is coming. PMID:22750195

  2. Regression of pathological cardiac hypertrophy: signaling pathways and therapeutic targets.

    Science.gov (United States)

    Hou, Jianglong; Kang, Y James

    2012-09-01

    Pathological cardiac hypertrophy is a key risk factor for heart failure. It is associated with increased interstitial fibrosis, cell death and cardiac dysfunction. The progression of pathological cardiac hypertrophy has long been considered as irreversible. However, recent clinical observations and experimental studies have produced evidence showing the reversal of pathological cardiac hypertrophy. Left ventricle assist devices used in heart failure patients for bridging to transplantation not only improve peripheral circulation but also often cause reverse remodeling of the geometry and recovery of the function of the heart. Dietary supplementation with physiologically relevant levels of copper can reverse pathological cardiac hypertrophy in mice. Angiogenesis is essential and vascular endothelial growth factor (VEGF) is a constitutive factor for the regression. The action of VEGF is mediated by VEGF receptor-1, whose activation is linked to cyclic GMP-dependent protein kinase-1 (PKG-1) signaling pathways, and inhibition of cyclic GMP degradation leads to regression of pathological cardiac hypertrophy. Most of these pathways are regulated by hypoxia-inducible factor. Potential therapeutic targets for promoting the regression include: promotion of angiogenesis, selective enhancement of VEGF receptor-1 signaling pathways, stimulation of PKG-1 pathways, and sustention of hypoxia-inducible factor transcriptional activity. More exciting insights into the regression of pathological cardiac hypertrophy are emerging. The time of translating the concept of regression of pathological cardiac hypertrophy to clinical practice is coming. Copyright © 2012 Elsevier Inc. All rights reserved.

  3. Wnt/β-catenin signalling pathway mediated aberrant hippocampal neurogenesis in kainic acid-induced epilepsy.

    Science.gov (United States)

    Qu, Zhengyi; Su, Fang; Qi, Xueting; Sun, Jianbo; Wang, Hongcai; Qiao, Zhenkui; Zhao, Hong; Zhu, Yulan

    2017-10-01

    Temporal lobe epilepsy is a chronic disorder of nerve system, mainly characterized by hippocampal sclerosis with massive neuronal loss and severe gliosis. Aberrant neurogenesis has been shown in the epileptogenesis process of temporal lobe epilepsy. However, the molecular mechanisms underlying aberrant neurogenesis remain unclear. The roles of Wnt signalling cascade have been well established in neurogenesis during multiple aspects. Here, we used kainic acid-induced rat epilepsy model to investigate whether Wnt/β-catenin signalling pathway is involved in the aberrant neurogenesis in temporal lobe epilepsy. Immunostaining and western blotting results showed that the expression levels of β-catenin, Wnt3a, and cyclin D1, the key regulators in Wnt signalling pathway, were up-regulated during acute epilepsy induced by the injection of kainic acids, indicating that Wnt signalling pathway was activated in kainic acid-induced temporal lobe epilepsy. Moreover, BrdU labelling results showed that blockade of the Wnt signalling by knocking down β-catenin attenuated aberrant neurogenesis induced by kainic acids injection. Altogether, Wnt/β-catenin signalling pathway mediated hippocampal neurogenesis during epilepsy, which might provide new strategies for clinical treatment of temporal lobe epilepsy. Temporal lobe epilepsy is a chronic disorder of nerve system, mainly characterized by hippocampal sclerosis. Aberrant neurogenesis has been shown to involve in the epileptogenesis process of temporal lobe epilepsy. In the present study, we discovered that Wnt3a/β-catenin signalling pathway serves as a link between aberrant neurogenesis and underlying remodelling in the hippocampus, leading to temporal lobe epilepsy, which might provide new strategies for clinical treatment of temporal lobe epilepsy. Copyright © 2017 John Wiley & Sons, Ltd.

  4. [Sonic Hedgehog signaling pathway and regulation of inner ear development].

    Science.gov (United States)

    Chen, Zhi-Qiang; Han, Xin-Huan; Cao, Xin

    2013-09-01

    During inner ear development, Sonic Hedgehog (Shh) signaling pathway is involved in the ventral otic identity, cell fate determination of statoacoustic ganglion neurons and hair cell development. Shh protein, secreted from floor plate, antagonizes Wnt protein from roof plate, which refines and maintains dorsoventral axial patterning in the ear. Shh, served as a mitogen during neurogenesis, directly promotes the development of spiral ganglion neuron. After Shh signaling pathway is activated, Ngn1 is freed from Tbx1 repression. As a result, Shh indirectly upregulates the expression of Ngn1, thus regulating neurogenic patterning of inner ear. In addition, Shh regulates the differentiation of hair cells by influencing cell cycle of the progenitor cells located in the cochlea. The basal-to-apical wave of Shh decline ensures the normal devel- opment pattern of hair cells. It is confirmed by a quantity of researches conducted in both animals and patients with hereditary hearing impairment that abnormal Shh signaling results in aberrant transcription of target genes, disturbance of the proper development of inner ear, and human hearing impairment. In humans, diseases accompanied by hearing disorders caused by abnormal Shh signaling include Greig cephalopolysyndactyly syndrome (GCPS), Pallister-Hall syndrome (PHS), Waardenburg syndrome (WS) and medulloblastoma, etc. This review would provide a theoretical basis for further study of molecular mechanisms and clinical use of inner ear development.

  5. Nasopharyngeal Carcinoma Signaling Pathway: An Update on Molecular Biomarkers

    Directory of Open Access Journals (Sweden)

    Warut Tulalamba

    2012-01-01

    Full Text Available Nasopharyngeal carcinoma (NPC is an uncommon cancer, which has a distinctive ethnic and geographic distribution. Etiology of NPC is considered to be related with a complex interaction of environmental and genetic factors as well as Epstein-Barr virus infection. Since NPC is located in the silent painless area, the disease is usually therefore diagnosed at the advanced stages; hence early detection of NPC is difficult. Furthermore, understanding in molecular pathogenesis is still lacking, pondering the identification of effective prognostic and diagnostic biomarkers. Dysregulation of signaling molecules in intracellular signal transduction, which regulate cell proliferation, apoptosis, and adhesion, underlines the basis of NPC pathogenesis. In this paper, the molecular signaling pathways in the NPC are discussed for the holistic view of NPC development and progression. The important insights toward NPC pathogenesis may offer strategies for identification of novel biomarkers for diagnosis and prognosis.

  6. Methamphetamine addiction: involvement of CREB and neuroinflammatory signaling pathways.

    Science.gov (United States)

    Krasnova, Irina N; Justinova, Zuzana; Cadet, Jean Lud

    2016-05-01

    Addiction to psychostimulant methamphetamine (METH) remains a major public health problem in the world. Animal models that use METH self-administration incorporate many features of human drug-taking behavior and are very helpful in elucidating mechanisms underlying METH addiction. These models are also helping to decipher the neurobiological substrates of associated neuropsychiatric complications. This review summarizes our work on the influence of METH self-administration on dopamine systems, transcription and immune responses in the brain. We used the rat model of METH self-administration with extended access (15 h/day for eight consecutive days) to investigate the effects of voluntary METH intake on the markers of dopamine system integrity and changes in gene expression observed in the brain at 2 h-1 month after cessation of drug exposure. Extended access to METH self-administration caused changes in the rat brain that are consistent with clinical findings reported in neuroimaging and postmortem studies of human METH addicts. In addition, gene expression studies using striatal tissues from METH self-administering rats revealed increased expression of genes involved in cAMP response element binding protein (CREB) signaling pathway and in the activation of neuroinflammatory response in the brain. These data show an association of METH exposure with activation of neuroplastic and neuroinflammatory cascades in the brain. The neuroplastic changes may be involved in promoting METH addiction. Neuroinflammatory processes in the striatum may underlie cognitive deficits, depression, and parkinsonism reported in METH addicts. Therapeutic approaches that include suppression of neuroinflammation may be beneficial to addicted patients.

  7. Pentagone internalises glypicans to fine-tune multiple signalling pathways

    Science.gov (United States)

    Norman, Mark; Vuilleumier, Robin; Springhorn, Alexander; Gawlik, Jennifer; Pyrowolakis, George

    2016-01-01

    Tight regulation of signalling activity is crucial for proper tissue patterning and growth. Here we investigate the function of Pentagone (Pent), a secreted protein that acts in a regulatory feedback during establishment and maintenance of BMP/Dpp morphogen signalling during Drosophila wing development. We show that Pent internalises the Dpp co-receptors, the glypicans Dally and Dally-like protein (Dlp), and propose that this internalisation is important in the establishment of a long range Dpp gradient. Pent-induced endocytosis and degradation of glypicans requires dynamin- and Rab5, but not clathrin or active BMP signalling. Thus, Pent modifies the ability of cells to trap and transduce BMP by fine-tuning the levels of the BMP reception system at the plasma membrane. In addition, and in accordance with the role of glypicans in multiple signalling pathways, we establish a requirement of Pent for Wg signalling. Our data propose a novel mechanism by which morphogen signalling is regulated. DOI: http://dx.doi.org/10.7554/eLife.13301.001 PMID:27269283

  8. TRANSPATH: an information resource for storing and visualizing signaling pathways and their pathological aberrations.

    Science.gov (United States)

    Krull, Mathias; Pistor, Susanne; Voss, Nico; Kel, Alexander; Reuter, Ingmar; Kronenberg, Deborah; Michael, Holger; Schwarzer, Knut; Potapov, Anatolij; Choi, Claudia; Kel-Margoulis, Olga; Wingender, Edgar

    2006-01-01

    TRANSPATH is a database about signal transduction events. It provides information about signaling molecules, their reactions and the pathways these reactions constitute. The representation of signaling molecules is organized in a number of orthogonal hierarchies reflecting the classification of the molecules, their species-specific or generic features, and their post-translational modifications. Reactions are similarly hierarchically organized in a three-layer architecture, differentiating between reactions that are evidenced by individual publications, generalizations of these reactions to construct species-independent 'reference pathways' and the 'semantic projections' of these pathways. A number of search and browse options allow easy access to the database contents, which can be visualized with the tool PathwayBuildertrade mark. The module PathoSign adds data about pathologically relevant mutations in signaling components, including their genotypes and phenotypes. TRANSPATH and PathoSign can be used as encyclopaedia, in the educational process, for vizualization and modeling of signal transduction networks and for the analysis of gene expression data. TRANSPATH Public 6.0 is freely accessible for users from non-profit organizations under http://www.gene-regulation.com/pub/databases.html.

  9. Romidepsin targets multiple survival signaling pathways in malignant T cells

    International Nuclear Information System (INIS)

    Valdez, B C; Brammer, J E; Li, Y; Murray, D; Liu, Y; Hosing, C; Nieto, Y; Champlin, R E; Andersson, B S

    2015-01-01

    Romidepsin is a cyclic molecule that inhibits histone deacetylases. It is Food and Drug Administration-approved for treatment of cutaneous and peripheral T-cell lymphoma, but its precise mechanism of action against malignant T cells is unknown. To better understand the biological effects of romidepsin in these cells, we exposed PEER and SUPT1 T-cell lines, and a primary sample from T-cell lymphoma patient (Patient J) to romidepsin. We then examined the consequences in some key oncogenic signaling pathways. Romidepsin displayed IC 50 values of 10.8, 7.9 and 7.0 nm in PEER, SUPT1 and Patient J cells, respectively. Strong inhibition of histone deacetylases and demethylases, increased production of reactive oxygen species and decreased mitochondrial membrane potential were observed, which may contribute to the observed DNA-damage response and apoptosis. The stress-activated protein kinase/c-Jun N-terminal kinase signaling pathway and unfolded protein response in the endoplasmic reticulum were activated, whereas the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) and β-catenin pro-survival pathways were inhibited. The decreased level of β-catenin correlated with the upregulation of its inhibitor SFRP1 through romidepsin-mediated hypomethylation of its gene promoter. Our results provide new insights into how romidepsin invokes malignant T-cell killing, show evidence of its associated DNA hypomethylating activity and offer a rationale for the development of romidepsin-containing combination therapies

  10. Prevotella intermedia induces prostaglandin E2 via multiple signaling pathways.

    Science.gov (United States)

    Guan, S-M; Fu, S-M; He, J-J; Zhang, M

    2011-01-01

    Prostaglandin E(2) (PGE(2)) plays important roles in the bone resorption of inflammatory diseases such as rheumatoid arthritis and periodontitis via specific prostaglandin receptors (i.e., EP1-EP4). In this study, the authors examined whether Prevotella intermedia regulates PGE(2) production and EP expression in human periodontal ligament fibroblasts (hPDLs); they also explored the potential signaling pathways involved in PGE(2) production. P. intermedia induced PGE(2) production and cyclooxygenase-2 (COX-2) expression in a dose- and time-dependent manner. Indomethacin and NS-398 completely abrogated the P. intermedia-induced PGE(2) production without modulating COX-2 expression. Specific inhibitors of extracellular signal-regulated kinase, c-Jun N-terminal kinase, p38, phosphatidylinositol 3-kinase, and protein kinase C--but not c-AMP and protein kinase A--significantly attenuated the P. intermedia-induced COX-2 and PGE(2) expression. P. intermedia reduced EP1 expression in a concentration- and time-dependent manner. The results indicate that the COX-2-dependent induction of PGE(2) by P. intermedia in hPDLs is mediated by multiple signaling pathways.

  11. Emerging Role and Therapeutic Implication of Wnt Signaling Pathways in Autoimmune Diseases

    Science.gov (United States)

    Shi, Juan; Chi, Shuhong; Xue, Jing; Yang, Jiali; Li, Feng; Liu, Xiaoming

    2016-01-01

    The Wnt signaling pathway plays a key role in many biological aspects, such as cellular proliferation, tissue regeneration, embryonic development, and other systemic effects. Under a physiological condition, it is tightly controlled at different layers and arrays, and a dysregulated activation of this signaling has been implicated into the pathogenesis of various human disorders, including autoimmune diseases. Despite the fact that therapeutic interventions are available for ameliorating disease manifestations, there is no curative therapy currently available for autoimmune disorders. Increasing lines of evidence have suggested a crucial role of Wnt signaling during the pathogenesis of many autoimmune diseases; in addition, some of microRNAs (miRNAs), a class of small, noncoding RNA molecules capable of transcriptionally regulating gene expression, have also recently been demonstrated to possess both physiological and pathological roles in autoimmune diseases by regulating the Wnt signaling pathway. This review summarizes currently our understanding of the pathogenic roles of Wnt signaling in several major autoimmune disorders and miRNAs, those targeting Wnt signaling in autoimmune diseases, with a focus on the implication of the Wnt signaling as potential biomarkers and therapeutic targets in immune diseases, as well as miRNA-mediated regulation of Wnt signaling activation in the development of autoimmune diseases. PMID:27110577

  12. Emerging Role and Therapeutic Implication of Wnt Signaling Pathways in Autoimmune Diseases

    Directory of Open Access Journals (Sweden)

    Juan Shi

    2016-01-01

    Full Text Available The Wnt signaling pathway plays a key role in many biological aspects, such as cellular proliferation, tissue regeneration, embryonic development, and other systemic effects. Under a physiological condition, it is tightly controlled at different layers and arrays, and a dysregulated activation of this signaling has been implicated into the pathogenesis of various human disorders, including autoimmune diseases. Despite the fact that therapeutic interventions are available for ameliorating disease manifestations, there is no curative therapy currently available for autoimmune disorders. Increasing lines of evidence have suggested a crucial role of Wnt signaling during the pathogenesis of many autoimmune diseases; in addition, some of microRNAs (miRNAs, a class of small, noncoding RNA molecules capable of transcriptionally regulating gene expression, have also recently been demonstrated to possess both physiological and pathological roles in autoimmune diseases by regulating the Wnt signaling pathway. This review summarizes currently our understanding of the pathogenic roles of Wnt signaling in several major autoimmune disorders and miRNAs, those targeting Wnt signaling in autoimmune diseases, with a focus on the implication of the Wnt signaling as potential biomarkers and therapeutic targets in immune diseases, as well as miRNA-mediated regulation of Wnt signaling activation in the development of autoimmune diseases.

  13. Cell volume homeostatic mechanisms: effectors and signalling pathways

    DEFF Research Database (Denmark)

    Hoffmann, E K; Pedersen, Stine Helene Falsig

    2011-01-01

    Cell volume homeostasis and its fine-tuning to the specific physiological context at any given moment are processes fundamental to normal cell function. The understanding of cell volume regulation owes much to August Krogh, yet has advanced greatly over the last decades. In this review, we outline...... the historical context of studies of cell volume regulation, focusing on the lineage started by Krogh, Bodil Schmidt-Nielsen, Hans-Henrik Ussing, and their students. The early work was focused on understanding the functional behaviour, kinetics and thermodynamics of the volume-regulatory ion transport mechanisms....... Later work addressed the mechanisms through which cellular signalling pathways regulate the volume regulatory effectors or flux pathways. These studies were facilitated by the molecular identification of most of the relevant channels and transporters, and more recently also by the increased...

  14. Defects in Cytoskeletal Signaling Pathways, Arrhythmia, and Sudden Cardiac Death

    Science.gov (United States)

    Smith, Sakima; Curran, Jerry; Hund, Thomas J.; Mohler, Peter J.

    2012-01-01

    Ankyrin polypeptides are cellular adapter proteins that tether integral membrane proteins to the cytoskeleton in a host of human organs. Initially identified as integral components of the cytoskeleton in erythrocytes, a recent explosion in ankyrin research has demonstrated that these proteins play prominent roles in cytoskeletal signaling pathways and membrane protein trafficking/regulation in a variety of excitable and non-excitable cells including heart and brain. Importantly, ankyrin research has translated from bench to bedside with the discovery of human gene variants associated with ventricular arrhythmias that alter ankyrin–based pathways. Ankyrin polypeptides have also been found to play an instrumental role in various forms of sinus node disease and atrial fibrillation (AF). Mouse models of ankyrin-deficiency have played fundamental roles in the translation of ankyrin-based research to new clinical understanding of human sinus node disease, AF, and ventricular tachycardia. PMID:22586405

  15. Crosstalk between pathways enhances the controllability of signalling networks.

    Science.gov (United States)

    Wang, Dingjie; Jin, Suoqin; Zou, Xiufen

    2016-02-01

    The control of complex networks is one of the most challenging problems in the fields of biology and engineering. In this study, the authors explored the controllability and control energy of several signalling networks, which consisted of many interconnected pathways, including networks with a bow-tie architecture. On the basis of the theory of structure controllability, they revealed that biological mechanisms, such as cross-pathway interactions, compartmentalisation and so on make the networks easier to fully control. Furthermore, using numerical simulations for two realistic examples, they demonstrated that the control energy of normal networks with crosstalk is lower than in networks without crosstalk. These results indicate that the biological networks are optimally designed to achieve their normal functions from the viewpoint of the control theory. The authors' work provides a comprehensive understanding of the impact of network structures and properties on controllability.

  16. Sensors and signal transduction pathways in vertebrate cell volume regulation

    DEFF Research Database (Denmark)

    Hoffmann, Else K; Pedersen, Stine F

    2006-01-01

    to the identification of transporter binding partners such as protein kinases and phosphatases, cytoskeletal elements and lipids. Considerable progress has also been made recently in understanding the upstream elements in volume sensing and volume-sensitive signal transduction, and salient features of these systems...... will be discussed. In contrast to the simple pathway of osmosensing in yeast, cells from vertebrate organisms appear to exhibit multiple volume sensing systems, the specific mechanism(s) activated being cell type- and stimulus-dependent. Candidate sensors include integrins and growth factor receptors, while other...

  17. NOTCH1 activates the Wnt/β-catenin signaling pathway in colon cancer.

    Science.gov (United States)

    Ishiguro, Hideyuki; Okubo, Tomotaka; Kuwabara, Yoshiyuki; Kimura, Masahiro; Mitsui, Akira; Sugito, Nobuyoshi; Ogawa, Ryo; Katada, Takeyasu; Tanaka, Tatsuya; Shiozaki, Midori; Mizoguchi, Koji; Samoto, Yosuke; Matsuo, Yoichi; Takahashi, Hiroki; Takiguchi, Shuji

    2017-09-01

    The translocation of β-catenin/CTNNB1 to the nucleus activates Wnt signaling and cell proliferation; however, the precise mechanism underlying this phenomenon remains unknown. Previous reports have provided evidence that NOTCH1 is involved in the Wnt signaling pathway. Therefore, we sought to determine the mechanism by which NOTCH1 influences the Wnt/β-catenin pathway. We constructed a vector expressing the NOTCH1 intracellular domain (NICD1) and transfected the vector into HCT116 which has low expression of NICD1. Furthermore, inhibition of NOTCH signal pathway in SW480 which has abundant NICD1 expression, was performed by transfection of siNICD1 or DAPT, gamma secretase inhibitor, treatment. In addition, we evaluated NICD1 and β-catenin localization in colon cancer cell lines and in 189 colon cancer tissue samples and analyzed the correlation between the nuclear localization of NICD1 and the clinicopathological features of colon cancer patients. Immunohistochemical assays demonstrated that NICD1 and β-catenin exhibited a similar localization pattern in colon cancer tissues. In addition, we found that NICD1 induced the translocation of β-catenin to the nucleus and that NICD1 and β-catenin co-localized in the nucleus. Overexpression of NICD1 increased luciferase activity of Wnt signal pathway. On the other hand, reduction of NICD1 reduced luciferase activity of Wnt signaling pathway. In the 189 analyzed colon cancer cases, multivariate COX regression analysis demonstrated the independent prognostic impact of nuclear localization of NICD1(p=0.0376). NOTCH1 plays a key role in the Wnt pathway and activation of NOTCH1 is associated with the translocation of β-catenin to the nucleus.

  18. Heat-Responsive Photosynthetic and Signaling Pathways in Plants: Insight from Proteomics

    Directory of Open Access Journals (Sweden)

    Xiaoli Wang

    2017-10-01

    Full Text Available Heat stress is a major abiotic stress posing a serious threat to plants. Heat-responsive mechanisms in plants are complicated and fine-tuned. Heat signaling transduction and photosynthesis are highly sensitive. Therefore, a thorough understanding of the molecular mechanism in heat stressed-signaling transduction and photosynthesis is necessary to protect crop yield. Current high-throughput proteomics investigations provide more useful information for underlying heat-responsive signaling pathways and photosynthesis modulation in plants. Several signaling components, such as guanosine triphosphate (GTP-binding protein, nucleoside diphosphate kinase, annexin, and brassinosteroid-insensitive I-kinase domain interacting protein 114, were proposed to be important in heat signaling transduction. Moreover, diverse protein patterns of photosynthetic proteins imply that the modulations of stomatal CO2 exchange, photosystem II, Calvin cycle, ATP synthesis, and chlorophyll biosynthesis are crucial for plant heat tolerance.

  19. NF-kappaB signaling: a tale of two pathways in skeletal myogenesis.

    Science.gov (United States)

    Bakkar, Nadine; Guttridge, Denis C

    2010-04-01

    NF-kappaB is a ubiquitiously expressed transcription factor that plays vital roles in innate immunity and other processes involving cellular survival, proliferation, and differentiation. Activation of NF-kappaB is controlled by an IkappaB kinase (IKK) complex that can direct either canonical (classical) NF-kappaB signaling by degrading the IkappaB inhibitor and releasing p65/p50 dimers to the nucleus, or causes p100 processing and nuclear translocation of RelB/p52 via a noncanonical (alternative) pathway. Under physiological conditions, NF-kappaB activity is transiently regulated, whereas constitutive activation of this transcription factor typically in the classical pathway is associated with a multitude of disease conditions, including those related to skeletal muscle. How NF-kappaB functions in muscle diseases is currently under intense investigation. Insight into this role of NF-kappaB may be gained by understanding at a more basic level how this transcription factor contributes to skeletal muscle cell differentiation. Recent data from knockout mice support that the classical NF-kappaB pathway functions as an inhibitor of skeletal myogenesis and muscle regeneration acting through multiple mechanisms. In contrast, alternative NF-kappaB signaling does not appear to be required for myofiber conversion, but instead functions in myotube homeostasis by regulating mitochondrial biogenesis. Additional knowledge of these signaling pathways in skeletal myogenesis should aid in the development of specific inhibitors that may be useful in treatments of muscle disorders.

  20. G protein coupled receptors signaling pathways implicate in inflammatory and immune response of rheumatoid arthritis.

    Science.gov (United States)

    Shu, Jinling; Zhang, Feng; Zhang, Lingling; Wei, Wei

    2017-05-01

    G protein-coupled receptors (GPCRs) are transmembrane receptor proteins, which allow the transfer of signals across the membrane. Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovitis and accompanied with inflammatory and abnormal immune response. GPCRs signaling pathways play a significant role in inflammatory and immune response processes including RA. In this review, we have focused on the advances in GPCRs signaling pathway implicating the inflammatory and immune response of RA. The signaling pathways of GPCRs-adenylyl cyclase (AC)-cyclic adenosine 3', 5'-monophosphate (cAMP) include β 2 adrenergic receptors (β 2 -ARs)-AC-cAMP signaling pathways, E-prostanoid2/4 (EP2/4)-AC-cAMP signaling pathways and so on. Regulatory proteins, such as G protein-coupled receptor kinases (GRKs) and β-arrestins, play important modulatory roles in GPCRs signaling pathway. GPCRs signaling pathway and regulatory proteins implicate the pathogenesis process of inflammatory and immune response. GPCRs-AC-cAMP signal pathways involve in the inflammatory and immune response of RA. Different signaling pathways are mediated by different receptors, such as β 2 -AR, PGE2 receptor, chemokines receptor, and adenosine receptor. GRKs and β-arrestins are crucial proteins in the regulation of GPCRs signaling pathways. The potential therapeutic targets as well as strategies to modulate GPCRs signaling pathway are new development trends.

  1. Curcumin mediates anticancer effects by modulating multiple cell signaling pathways.

    Science.gov (United States)

    Kunnumakkara, Ajaikumar B; Bordoloi, Devivasha; Harsha, Choudhary; Banik, Kishore; Gupta, Subash C; Aggarwal, Bharat B

    2017-08-01

    Curcumin, a component of a spice native to India, was first isolated in 1815 by Vogel and Pelletier from the rhizomes of Curcuma longa (turmeric) and, subsequently, the chemical structure of curcumin as diferuloylmethane was reported by Milobedzka et al. [(1910) 43., 2163-2170]. Since then, this polyphenol has been shown to exhibit antioxidant, anti-inflammatory, anticancer, antiviral, antibacterial, and antifungal activities. The current review primarily focuses on the anticancer potential of curcumin through the modulation of multiple cell signaling pathways. Curcumin modulates diverse transcription factors, inflammatory cytokines, enzymes, kinases, growth factors, receptors, and various other proteins with an affinity ranging from the pM to the mM range. Furthermore, curcumin effectively regulates tumor cell growth via modulation of numerous cell signaling pathways and potentiates the effect of chemotherapeutic agents and radiation against cancer. Curcumin can interact with most of the targets that are modulated by FDA-approved drugs for cancer therapy. The focus of this review is to discuss the molecular basis for the anticancer activities of curcumin based on preclinical and clinical findings. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

  2. A SNP uncoupling Mina expression from the TGFβ signaling pathway.

    Science.gov (United States)

    Lian, Shang L; Mihi, Belgacem; Koyanagi, Madoka; Nakayama, Toshinori; Bix, Mark

    2018-03-01

    Mina is a JmjC family 2-oxoglutarate oxygenase with pleiotropic roles in cell proliferation, cancer, T cell differentiation, pulmonary inflammation, and intestinal parasite expulsion. Although Mina expression varies according to cell-type, developmental stage and activation state, its transcriptional regulation is poorly understood. Across inbred mouse strains, Mina protein level exhibits a bimodal distribution, correlating with inheritance of a biallelic haplotype block comprising 21 promoter/intron 1-region SNPs. We previously showed that heritable differences in Mina protein level are transcriptionally regulated. Accordingly, we decided to test the hypothesis that at least one of the promoter/intron 1-region SNPs perturbs a Mina cis-regulatory element (CRE). Here, we have comprehensively scanned for CREs across a Mina locus-spanning 26-kilobase genomic interval. We discovered 8 potential CREs and functionally validated 4 of these, the strongest of which (E2), residing in intron 1, contained a SNP whose BALB/c-but not C57Bl/6 allele-abolished both Smad3 binding and transforming growth factor beta (TGFβ) responsiveness. Our results demonstrate the TGFβ signaling pathway plays a critical role in regulating Mina expression and SNP rs4191790 controls heritable variation in Mina expression level, raising important questions regarding the evolution of an allele that uncouples Mina expression from the TGFβ signaling pathway. © 2017 The Authors. Immunity, Inflammation and Disease Published by John Wiley & Sons Ltd.

  3. MicroRNA-gene signaling pathways in pancreatic cancer

    Directory of Open Access Journals (Sweden)

    Alexandra Drakaki

    2013-10-01

    Full Text Available Pancreatic cancer is the fourth most frequent cause of cancer-related deaths and is characterized by early metastasis and pronounced resistance to chemotherapy and radiation therapy. Despite extensive esearch efforts, there is not any substantial progress regarding the identification of novel drugs against pancreatic cancer. Although the introduction of the chemotherapeutic agent gemcitabine improved clinical response, the prognosis of these patients remained extremely poor with a 5-year survival rate of 3-5%. Thus, the identification of the novel molecular pathways involved in pancreatic oncogenesis and the development of new and potent therapeutic options are highly desirable. Here, we describe how microRNAs control signaling pathways that are frequently deregulated during pancreatic oncogenesis. In addition, we provide evidence that microRNAs could be potentially used as novel pancreatic cancer therapeutics through reversal of chemotherapy and radiotherapy resistance or regulation of essential molecular pathways. Further studies should integrate the deregulated genes and microRNAs into molecular networks in order to identify the central regulators of pancreatic oncogenesis. Targeting these central regulators could lead to the development of novel targeted therapeutic approaches for pancreatic cancer patients.

  4. Signaling Pathways Involved in Lunar Dust Induced Cytotoxicity

    Science.gov (United States)

    Zhang, Ye; Lam, Chiu-Wing; Scully, Robert R.; Williams, Kyle; Zalesak, Selina; Wu, Honglu; James, John T.

    2014-01-01

    The Moon's surface is covered by a layer of fine, reactive dust. Lunar dust contain about 1-2% of very fine dust (pathways involved in lunar dust-induced toxicity. F344 rats were exposed for 4 weeks (6h/d; 5d/wk) in nose-only inhalation chambers to concentrations of 0 (control air), 2.1, 6.1, 21, and 61 mg/m(exp 3) of lunar dust. Five rats per group were euthanized 1 day, 1 week, 1 month, and 3 months after the last inhalation exposure. The total RNAs were isolated from the blood or lung tissue after being lavaged, using the Qigen RNeasy kit. The Rat Fibrosis RT2 Profile PCR Array was used to profile the expression of 84 genes relevant to fibrosis. The genes with significant expression changes are identified and the gene expression data were further analyzed using IPA pathway analysis tool to determine the signaling pathways with significant changes.

  5. TRANSPATH®: an information resource for storing and visualizing signaling pathways and their pathological aberrations

    Science.gov (United States)

    Krull, Mathias; Pistor, Susanne; Voss, Nico; Kel, Alexander; Reuter, Ingmar; Kronenberg, Deborah; Michael, Holger; Schwarzer, Knut; Potapov, Anatolij; Choi, Claudia; Kel-Margoulis, Olga; Wingender, Edgar

    2006-01-01

    TRANSPATH® is a database about signal transduction events. It provides information about signaling molecules, their reactions and the pathways these reactions constitute. The representation of signaling molecules is organized in a number of orthogonal hierarchies reflecting the classification of the molecules, their species-specific or generic features, and their post-translational modifications. Reactions are similarly hierarchically organized in a three-layer architecture, differentiating between reactions that are evidenced by individual publications, generalizations of these reactions to construct species-independent ‘reference pathways’ and the ‘semantic projections’ of these pathways. A number of search and browse options allow easy access to the database contents, which can be visualized with the tool PathwayBuilder™. The module PathoSign adds data about pathologically relevant mutations in signaling components, including their genotypes and phenotypes. TRANSPATH® and PathoSign can be used as encyclopaedia, in the educational process, for vizualization and modeling of signal transduction networks and for the analysis of gene expression data. TRANSPATH® Public 6.0 is freely accessible for users from non-profit organizations under . PMID:16381929

  6. Delayed cone-opponent signals in the luminance pathway.

    Science.gov (United States)

    Stockman, Andrew; Henning, G Bruce; Anwar, Sharif; Starba, Robert; Rider, Andrew T

    2018-02-01

    Cone signals in the luminance or achromatic pathway were investigated by measuring how the perceptual timing of M- or L-cone-detected flicker depended on temporal frequency and chromatic adaptation. Relative timings were measured, as a function of temporal frequency, by superimposing M- or L-cone-isolating flicker on "equichromatic" flicker (flicker of the same wavelength as the background) and asking observers to vary contrast and phase to cancel the perception of flicker. Measurements were made in four observers on up to 35 different backgrounds varying in wavelength and radiance. Observers showed substantial perceptual delays or advances of L- and M-cone flicker that varied systematically with cone class, background wavelength, and radiance. Delays were largest for M-cone-isolating flicker. Although complex, the results can be characterised by a surprisingly simple model in which the representations of L- and M-cone flicker are comprised not only of a fast copy of the flicker signal, but also of a slow copy that is delayed by roughly 30 ms and varies in strength and sign with both background wavelength and radiance. The delays, which are too large to be due to selective cone adaptation by the chromatic backgrounds, must arise postreceptorally. Clear evidence for the slow signals can also be found in physiological measurements of horizontal and magnocellular ganglion cells, thus placing the origin of the slow signals in the retina-most likely in an extended horizontal cell network. Luminance-equated stimuli chosen to isolate chromatic channels may inadvertently generate slow signals in the luminance channel.

  7. PSFC: a Pathway Signal Flow Calculator App for Cytoscape [version 2; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Lilit Nersisyan

    2017-04-01

    Full Text Available Cell signaling pathways are sequences of biochemical reactions that propagate an input signal, such as a hormone binding to a cell-surface receptor, into the cell to trigger a reactive process. Assessment of pathway activities is crucial for determining which pathways play roles in disease versus normal conditions. To date various pathway flow/perturbation assessment tools are available, however they are constrained to specific algorithms and specific data types. There are no accepted standards for evaluation of pathway activities or simulation of flow propagation events in pathways, and the results of different software are difficult to compare. Here we present Pathway Signal Flow Calculator (PSFC, a Cytoscape app for calculation of a pathway signal flow based on the pathway topology and node input data. The app provides a rich framework for customization of different signal flow algorithms to allow users to apply various approaches within a single computational framework.

  8. Inhibitory mechanisms of two Uncaria tomentosa extracts affecting the Wnt-signaling pathway.

    Science.gov (United States)

    Gurrola-Díaz, Carmen Magdalena; García-López, Pedro Macedonio; Gulewicz, Krzysztof; Pilarski, Radoslaw; Dihlmann, Susanne

    2011-06-15

    Uncaria tomentosa ("uña de gato"; "cat's claw"), a woody vine native to the Amazon rainforest, is commonly used in South American traditional medicine to treat a broad spectrum of diseases. Although recent studies have reported anti-inflammatory and anti-proliferative properties of different alkaloids extracted from this plant, the underlying molecular mechanisms of these effects have not been elucidated yet. Our study investigates the inhibitory mechanisms of Uncaria tomentosa extracts on the Wnt-signaling pathway, a central regulator of development and tissue homoeostasis. A modified cell-based luciferase assay for screening inhibitors of the Wnt-pathway was used for analysis. Three cancer cell lines displaying different levels of aberrant Wnt-signaling activity were transfected with Wnt-signaling responsive Tcf-reporter plasmids and treated with increasing concentrations of two Uncaria tomentosa bark extracts. Wnt-signaling activity was assessed by luciferase activity and by expression of Wnt-responsive target genes. We show that both, an aqueous and an alkaloid-enriched extract specifically inhibit Wnt-signaling activity in HeLa, HCT116 and SW480 cancer cells resulting in reduced expression of the Wnt-target gene: c-Myc. The alkaloid-enriched extract (B/S(rt)) was found to be more effective than the aqueous extract (B/W(37)). The strongest effect was observed in SW480 cells, displaying the highest endogenous Wnt-signaling activity. Downregulation of Wnt-signaling by a dominant negative-TCF-4 variant in non-cancer cells rendered the cells insensitive towards treatment with B/S(rt). B/Srt was less toxic in non-cancer cells than in cancer cells. Our data suggest that the broad spectrum of pharmacological action of Uncaria tomentosa involves inhibition of the Wnt-signaling pathway, downstream of beta-Catenin activity. Copyright © 2010 Elsevier GmbH. All rights reserved.

  9. Regulatory cross-talks and cascades in rice hormone biosynthesis pathways contribute to stress signaling

    Directory of Open Access Journals (Sweden)

    Arindam Deb

    2016-08-01

    Full Text Available Crosstalk among different hormone signaling pathways play an important role in modulating plant response to both biotic and abiotic stress. Hormone activity is controlled by its bio-availability, which is again influenced by its biosynthesis. Thus independent hormone biosynthesis pathways must be regulated and co-ordinated to mount an integrated response. One of the possibilities is to use cis-regulatory elements to orchestrate expression of hormone biosynthesis genes. Analysis of CREs, associated with differentially expressed hormone biosynthesis related genes in rice leaf under Magnaporthe oryzae attack and drought stress enabled us to obtain insights about cross-talk among hormone biosynthesis pathways at the transcriptional level. We identified some master transcription regulators that co-ordinate different hormone biosynthesis pathways under stress. We found that Abscisic acid and Brassinosteroid regulate Cytokinin conjugation; conversely Brassinosteroid biosynthesis is affected by both Abscisic acid and Cytokinin. Jasmonic acid and Ethylene biosynthesis may be modulated by Abscisic acid through DREB transcription factors. Jasmonic acid or Salicylic acid biosynthesis pathways are co-regulated but they are unlikely to influence each other’s production directly. Thus multiple hormones may modulate hormone biosynthesis pathways through a complex regulatory network, where biosynthesis of one hormone is affected by several other contributing hormones.

  10. Molecular mechanisms underlying phosphate sensing, signaling, and adaptation in plants.

    Science.gov (United States)

    Zhang, Zhaoliang; Liao, Hong; Lucas, William J

    2014-03-01

    As an essential plant macronutrient, the low availability of phosphorus (P) in most soils imposes serious limitation on crop production. Plants have evolved complex responsive and adaptive mechanisms for acquisition, remobilization and recycling of phosphate (Pi) to maintain P homeostasis. Spatio-temporal molecular, physiological, and biochemical Pi deficiency responses developed by plants are the consequence of local and systemic sensing and signaling pathways. Pi deficiency is sensed locally by the root system where hormones serve as important signaling components in terms of developmental reprogramming, leading to changes in root system architecture. Root-to-shoot and shoot-to-root signals, delivered through the xylem and phloem, respectively, involving Pi itself, hormones, miRNAs, mRNAs, and sucrose, serve to coordinate Pi deficiency responses at the whole-plant level. A combination of chromatin remodeling, transcriptional and posttranslational events contribute to globally regulating a wide range of Pi deficiency responses. In this review, recent advances are evaluated in terms of progress toward developing a comprehensive understanding of the molecular events underlying control over P homeostasis. Application of this knowledge, in terms of developing crop plants having enhanced attributes for P use efficiency, is discussed from the perspective of agricultural sustainability in the face of diminishing global P supplies. © 2014 Institute of Botany, Chinese Academy of Sciences.

  11. In vitro reconstitution of an abscisic acid signalling pathway

    KAUST Repository

    Fujii, Hiroaki

    2009-11-18

    The phytohormone abscisic acid (ABA) regulates the expression of many genes in plants; it has critical functions in stress resistance and in growth and development. Several proteins have been reported to function as ABA receptors, and many more are known to be involved in ABA signalling. However, the identities of ABA receptors remain controversial and the mechanism of signalling from perception to downstream gene expression is unclear. Here we show that by combining the recently identified ABA receptor PYR1 with the type 2C protein phosphatase (PP2C) ABI1, the serine/threonine protein kinase SnRK2.6/OST1 and the transcription factor ABF2/AREB1, we can reconstitute ABA-triggered phosphorylation of the transcription factor in vitro. Introduction of these four components into plant protoplasts results in ABA-responsive gene expression. Protoplast and test-tube reconstitution assays were used to test the function of various members of the receptor, protein phosphatase and kinase families. Our results suggest that the default state of the SnRK2 kinases is an autophosphorylated, active state and that the SnRK2 kinases are kept inactive by the PP2Cs through physical interaction and dephosphorylation. We found that in the presence of ABA, the PYR/PYL (pyrabactin resistance 1/PYR1-like) receptor proteins can disrupt the interaction between the SnRK2s and PP2Cs, thus preventing the PP2C-mediated dephosphorylation of the SnRK2s and resulting in the activation of the SnRK2 kinases. Our results reveal new insights into ABA signalling mechanisms and define a minimal set of core components of a complete major ABA signalling pathway. © 2009 Macmillan Publishers Limited. All rights reserved.

  12. New insights into mammalian signaling pathways using microfluidic pulsatile inputs and mathematical modeling

    Science.gov (United States)

    Sumit, M.; Takayama, S.; Linderman, J. J.

    2016-01-01

    Temporally modulated input mimics physiology. This chemical communication strategy filters the biochemical noise through entrainment and phase-locking. Under laboratory conditions, it also expands the observability space for downstream responses. A combined approach involving microfluidic pulsatile stimulation and mathematical modeling has led to deciphering of hidden/unknown temporal motifs in several mammalian signaling pathways and has provided mechanistic insights, including how these motifs combine to form distinct band-pass filters and govern fate regulation under dynamic microenvironment. This approach can be utilized to understand signaling circuit architectures and to gain mechanistic insights for several other signaling systems. Potential applications include synthetic biology and biotechnology, in developing pharmaceutical interventions, and in developing lab-on-chip models. PMID:27868126

  13. New insights into mammalian signaling pathways using microfluidic pulsatile inputs and mathematical modeling.

    Science.gov (United States)

    Sumit, M; Takayama, S; Linderman, J J

    2017-01-23

    Temporally modulated input mimics physiology. This chemical communication strategy filters the biochemical noise through entrainment and phase-locking. Under laboratory conditions, it also expands the observability space for downstream responses. A combined approach involving microfluidic pulsatile stimulation and mathematical modeling has led to deciphering of hidden/unknown temporal motifs in several mammalian signaling pathways and has provided mechanistic insights, including how these motifs combine to form distinct band-pass filters and govern fate regulation under dynamic microenvironment. This approach can be utilized to understand signaling circuit architectures and to gain mechanistic insights for several other signaling systems. Potential applications include synthetic biology and biotechnology, in developing pharmaceutical interventions, and in developing lab-on-chip models.

  14. Current Views of Toll-Like Receptor Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Masahiro Yamamoto

    2010-01-01

    Full Text Available On microbial invasion, the host immediately evokes innate immune responses. Recent studies have demonstrated that Toll-like receptors (TLRs play crucial roles in innate responses that lead not only to the clearance of pathogens but also to the efficient establishment of acquired immunity by directly detecting molecules from microbes. In terms of intracellular TLR-mediated signaling pathways, cytoplasmic adaptor molecules containing Toll/IL-1R (TIR domains play important roles in inflammatory immune responses through the production of proinflammatory cytokines, nitric oxide, and type I interferon, and upregulation of costimulatory molecules. In this paper, we will describe our current understanding of the relationship between TLRs and their ligands derived from pathogens such as viruses, bacteria, fungi, and parasites. Moreover, we will review the historical and current literature to describe the mechanisms behind TLR-mediated activation of innate immune responses.

  15. Use of glycolytic pathways for inhibiting or measuring oncogenic signaling

    Energy Technology Data Exchange (ETDEWEB)

    Onodera, Yasuhito; Bissell, Mina

    2017-06-27

    Disclosed are methods in which glucose metabolism is correlated to oncogenesis through certain specific pathways; inhibition of certain enzymes is shown to interfere with oncogenic signaling, and measurement of certain enzyme levels is correlated with patient survival. The present methods comprise measuring level of expression of at least one of the enzymes involved in glucose uptake or metabolism, wherein increased expression of the at least one of the enzymes relative to expression in a normal cell correlates with poor prognosis of disease in a patient. Preferably the genes whose expression level is measured include GLUT3, PFKP, GAPDH, ALDOC, LDHA and GFPT2. Also disclosed are embodiments directed towards downregulating the expression of some genes in glucose uptake and metabolism.

  16. Secretogranin III promotes angiogenesis through MEK/ERK signaling pathway.

    Science.gov (United States)

    Tang, Fen; Pacheco, Mario Thiego F; Chen, Ping; Liang, Dan; Li, Wei

    2018-01-01

    Secretogranin III (Scg3) was recently discovered as the first highly diabetic retinopathy-associated angiogenic factor, and its neutralizing antibody alleviated the disease with high efficacy in diabetic mice. Investigation of its molecular mechanisms will facilitate the translation of this novel therapy. Scg3 was reported to induce the phosphorylation of mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK). Here we characterized the importance of MEK/ERK activation to Scg3 angiogenic activity. Our results showed that MEK inhibitor PD98059 blocked Scg3-induced proliferation of human umbilical vein endothelial cells (HUVECs). This finding was corroborated by PD98059 inhibition of HUVEC migration and tube formation. Furthermore, ERK inhibitor SCH772984 also suppressed Scg3-induced proliferation and migration of HUVECs. Taken together, these findings suggest that MEK-ERK pathway plays an important role in Scg3-induced angiogenesis. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Phosphoinositide signal transduction pathway in rat liver mitochondria

    International Nuclear Information System (INIS)

    Pasupathy, K.; Krishna, M.; Bhattacharya, R.K.

    1997-01-01

    Phosphorylation of endogenous phospholipids of rat liver mitochondrial fractions with γ[ 32 P]ATP revealed formation of all the known inositol phospholipids, such as phosphatidylinositol, phosphatidylinositol phosphate and phosphatidylinositol bisphosphate. Additionally, a new inositol phospholipid was detected. Incorporation of [ 3 H]-labelled inositol followed a similar profile. Enzymatic experiments indicated that the new lipid could possibly be phosphatidylinositoltrisphosphate. The presence of phosphoinositides-generated second messengers such as diacylglycerol and inositol trisphosphate was also confirmed. Protein kinase C, which acts as mediator between second messengers and nuclear factors, was also found to be present in mitochondria in significant amount. These results suggest that phosphoinositide signal transduction pathway is operative in rat liver mitochondria. (author)

  18. Necroptotic Cell Death Signaling and Execution Pathway: Lessons from Knockout Mice

    Directory of Open Access Journals (Sweden)

    José Belizário

    2015-01-01

    Full Text Available Under stress conditions, cells in living tissue die by apoptosis or necrosis depending on the activation of the key molecules within a dying cell that either transduce cell survival or death signals that actively destroy the sentenced cell. Multiple extracellular (pH, heat, oxidants, and detergents or intracellular (DNA damage and Ca2+ overload stress conditions trigger various types of the nuclear, endoplasmic reticulum (ER, cytoplasmatic, and mitochondrion-centered signaling events that allow cells to preserve the DNA integrity, protein folding, energetic, ionic and redox homeostasis, thus escaping from injury. Along the transition from reversible to irreversible injury, death signaling is highly heterogeneous and damaged cells may engage autophagy, apoptotic, or necrotic cell death programs. Studies on multiple double- and triple- knockout mice identified caspase-8, flip, and fadd genes as key regulators of embryonic lethality and inflammation. Caspase-8 has a critical role in pro- and antinecrotic signaling pathways leading to the activation of receptor interacting protein kinase 1 (RIPK1, RIPK3, and the mixed kinase domain-like (MLKL for a convergent execution pathway of necroptosis or regulated necrosis. Here we outline the recent discoveries into how the necrotic cell death execution pathway is engaged in many physiological and pathological outcome based on genetic analysis of knockout mice.

  19. Identification of G protein-coupled receptor signaling pathway proteins in marine diatoms using comparative genomics.

    Science.gov (United States)

    Port, Jesse A; Parker, Micaela S; Kodner, Robin B; Wallace, James C; Armbrust, E Virginia; Faustman, Elaine M

    2013-07-24

    The G protein-coupled receptor (GPCR) signaling pathway plays an essential role in signal transmission and response to external stimuli in mammalian cells. Protein components of this pathway have been characterized in plants and simpler eukaryotes such as yeast, but their presence and role in unicellular photosynthetic eukaryotes have not been determined. We use a comparative genomics approach using whole genome sequences and gene expression libraries of four diatoms (Pseudo-nitzschia multiseries, Thalassiosira pseudonana, Phaeodactylum tricornutum and Fragilariopsis cylindrus) to search for evidence of GPCR signaling pathway proteins that share sequence conservation to known GPCR pathway proteins. The majority of the core components of GPCR signaling were well conserved in all four diatoms, with protein sequence similarity to GPCRs, human G protein α- and β-subunits and downstream effectors. There was evidence for the Gγ-subunit and thus a full heterotrimeric G protein only in T. pseudonana. Phylogenetic analysis of putative diatom GPCRs indicated similarity but deep divergence to the class C GPCRs, with branches basal to the GABAB receptor subfamily. The extracellular and intracellular regions of these putative diatom GPCR sequences exhibited large variation in sequence length, and seven of these sequences contained the necessary ligand binding domain for class C GPCR activation. Transcriptional data indicated that a number of the putative GPCR sequences are expressed in diatoms under various stress conditions in culture, and that many of the GPCR-activated signaling proteins, including the G protein, are also expressed. The presence of sequences in all four diatoms that code for the proteins required for a functional mammalian GPCR pathway highlights the highly conserved nature of this pathway and suggests a complex signaling machinery related to environmental perception and response in these unicellular organisms. The lack of evidence for some GPCR pathway

  20. Osteocytic signalling pathways as therapeutic targets for bone fragility.

    Science.gov (United States)

    Plotkin, Lilian I; Bellido, Teresita

    2016-10-01

    Osteocytes are differentiated osteoblasts that become surrounded by matrix during the process of bone formation. Acquisition of the osteocyte phenotype is achieved by profound changes in gene expression that facilitate adaptation to the changing cellular environment and constitute the molecular signature of osteocytes. During osteocytogenesis, the expression of genes that are characteristic of the osteoblast are altered and the expression of genes and/or proteins that impart dendritic cellular morphology, regulate matrix mineralization and control the function of cells at the bone surface are ordely modulated. The discovery of mutations in human osteocytic genes has contributed, in a large part, to our understanding of the role of osteocytes in bone homeostasis. Osteocytes are targets of the mechanical force imposed on the skeleton and have a critical role in integrating mechanosensory pathways with the action of hormones, which thereby leads to the orchestrated response of bone to environmental cues. Current, therapeutic approaches harness this accumulating knowledge by targeting osteocytic signalling pathways and messengers to improve skeletal health.

  1. Circadian period integrates network information through activation of the BMP signaling pathway.

    Directory of Open Access Journals (Sweden)

    Esteban J Beckwith

    2013-12-01

    Full Text Available Living organisms use biological clocks to maintain their internal temporal order and anticipate daily environmental changes. In Drosophila, circadian regulation of locomotor behavior is controlled by ∼150 neurons; among them, neurons expressing the PIGMENT DISPERSING FACTOR (PDF set the period of locomotor behavior under free-running conditions. To date, it remains unclear how individual circadian clusters integrate their activity to assemble a distinctive behavioral output. Here we show that the BONE MORPHOGENETIC PROTEIN (BMP signaling pathway plays a crucial role in setting the circadian period in PDF neurons in the adult brain. Acute deregulation of BMP signaling causes period lengthening through regulation of dClock transcription, providing evidence for a novel function of this pathway in the adult brain. We propose that coherence in the circadian network arises from integration in PDF neurons of both the pace of the cell-autonomous molecular clock and information derived from circadian-relevant neurons through release of BMP ligands.

  2. Renewable Fuel Pathways II Final Rule to Identify Additional Fuel Pathways under Renewable Fuel Standard Program

    Science.gov (United States)

    This final rule describes EPA’s evaluation of biofuels derived from biogas fuel pathways under the RFS program and other minor amendments related to survey requirements associated with ULSD program and misfueling mitigation regulations for E15.

  3. Functions and Signaling Pathways of Amino Acids in Intestinal Inflammation

    Directory of Open Access Journals (Sweden)

    Fang He

    2018-01-01

    Full Text Available Intestine is always exposed to external environment and intestinal microorganism; thus it is more sensitive to dysfunction and dysbiosis, leading to intestinal inflammation, such as inflammatory bowel disease (IBD, irritable bowel syndrome (IBS, and diarrhea. An increasing number of studies indicate that dietary amino acids play significant roles in preventing and treating intestinal inflammation. The review aims to summarize the functions and signaling mechanisms of amino acids in intestinal inflammation. Amino acids, including essential amino acids (EAAs, conditionally essential amino acids (CEAAs, and nonessential amino acids (NEAAs, improve the functions of intestinal barrier and expressions of anti-inflammatory cytokines and tight junction proteins but decrease oxidative stress and the apoptosis of enterocytes as well as the expressions of proinflammatory cytokines in the intestinal inflammation. The functions of amino acids are associated with various signaling pathways, including mechanistic target of rapamycin (mTOR, inducible nitric oxide synthase (iNOS, calcium-sensing receptor (CaSR, nuclear factor-kappa-B (NF-κB, mitogen-activated protein kinase (MAPK, nuclear erythroid-related factor 2 (Nrf2, general controlled nonrepressed kinase 2 (GCN2, and angiotensin-converting enzyme 2 (ACE2.

  4. Role of Notch signalling pathway in cancer and its association with ...

    Indian Academy of Sciences (India)

    The Notch signalling pathway is an evolutionarily conserved cell signalling pathway involved in the development of organisms as diverse as humans and fruit flies. It plays a pivotal role in cell fate determination. Dysregulated Notch signalling is oncogenic, inhibits apoptosis and promotes cell survival. Abnormal Notch ...

  5. Cherry Valley Ducks Mitochondrial Antiviral-Signaling Protein-Mediated Signaling Pathway and Antiviral Activity Research.

    Science.gov (United States)

    Li, Ning; Hong, Tianqi; Li, Rong; Wang, Yao; Guo, Mengjiao; Cao, Zongxi; Cai, Yumei; Liu, Sidang; Chai, Tongjie; Wei, Liangmeng

    2016-01-01

    Mitochondrial antiviral-signaling protein (MAVS), an adaptor protein of retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs)-mediated signal pathway, is involved in innate immunity. In this study, Cherry Valley duck MAVS (duMAVS) was cloned from the spleen and analyzed. duMAVS was determined to have a caspase activation and recruitment domain at N-terminal, followed by a proline-rich domain and a transmembrane domain at C-terminal. Quantitative real-time PCR indicated that duMAVS was expressed in all tissues tested across a broad expression spectrum. The expression of duMAVS was significantly upregulated after infection with duck Tembusu virus (DTMUV). Overexpression of duMAVS could drive the activation of interferon (IFN)-β, nuclear factor-κB, interferon regulatory factor 7, and many downstream factors (such as Mx, PKR, OAS, and IL-8) in duck embryo fibroblast cells. What is more, RNA interference further confirmed that duMAVS was an important adaptor for IFN-β activation. The antiviral assay showed that duMAVS could suppress the various viral replications (DTMUV, novel reovirus, and duck plague virus) at early stages of infection. Overall, these results showed that the main signal pathway mediated by duMAVS and it had a broad-spectrum antiviral ability. This research will be helpful to better understanding the innate immune system of ducks.

  6. Mechanism of attenuation of leptin signaling under chronic ligand stimulation

    Directory of Open Access Journals (Sweden)

    Bamberg-Lemper Simone

    2010-01-01

    Full Text Available Abstract Background Leptin is an adipocyte-derived hormone that acts via its hypothalamic receptor (LEPRb to regulate energy balance. A downstream effect essential for the weight-regulatory action of leptin is the phosphorylation and activation of the latent transcription factor STAT3 by LEPRb-associated Janus kinases (JAKs. Obesity is typically associated with chronically elevated leptin levels and a decreased ability of LEPRb to activate intracellular signal transduction pathways (leptin resistance. Here we have studied the roles of the intracellular tyrosine residues in the negative feedback regulation of LEPRb-signaling under chronic leptin stimulation. Results Mutational analysis showed that the presence of either Tyr985 and Tyr1077 in the intracellular domain of LEPRb was sufficient for the attenuation of STAT3 phosphorylation, whereas mutation of both tyrosines rendered LEPRb resistant to feedback regulation. Overexpression and RNA interference-mediated downregulation of suppressor of cytokine signaling 3 (SOCS3 revealed that both Tyr985 and Tyr1077 were capable of supporting the negative modulatory effect of SOCS3 in reporter gene assays. In contrast, the inhibitory effect of SOCS1 was enhanced by the presence of Tyr985 but not Tyr1077. Finally, the reduction of the STAT-phosphorylating activity of the LEPRb complex after 2 h of leptin stimulation was not accompanied by the dephosphorylation or degradation of LEPRb or the receptor-associated JAK molecule, but depended on Tyr985 and/or Tyr1077. Conclusions Both Tyr985 and Tyr1077 contribute to the negative regulation of LEPRb signaling. The inhibitory effects of SOCS1 and SOCS3 differ in the dependence on the tyrosine residues in the intracellular domain of LEPRb.

  7. Activation of the Notch signaling pathway promotes neurovascular repair after traumatic brain injury

    Directory of Open Access Journals (Sweden)

    Qi-shan Ran

    2015-01-01

    Full Text Available The Notch signaling pathway plays a key role in angiogenesis and endothelial cell formation, but it remains unclear whether it is involved in vascular repair by endothelial progenitor cells after traumatic brain injury. Therefore, in the present study, we controlled the Notch signaling pathway using overexpression and knockdown constructs. Activation of the Notch signaling pathway by Notch1 or Jagged1 overexpression enhanced the migration, invasiveness and angiogenic ability of endothelial progenitor cells. Suppression of the Notch signaling pathway with Notch1 or Jagged1 siRNAs reduced the migratory capacity, invasiveness and angiogenic ability of endothelial progenitor cells. Activation of the Notch signaling pathway in vivo in a rat model of mild traumatic brain injury promoted neurovascular repair. These findings suggest that the activation of the Notch signaling pathway promotes blood vessel formation and tissue repair after brain trauma.

  8. A model invalidation-based approach for elucidating biological signalling pathways, applied to the chemotaxis pathway in R. sphaeroides.

    Science.gov (United States)

    Roberts, Mark A J; August, Elias; Hamadeh, Abdullah; Maini, Philip K; McSharry, Patrick E; Armitage, Judith P; Papachristodoulou, Antonis

    2009-10-31

    Developing methods for understanding the connectivity of signalling pathways is a major challenge in biological research. For this purpose, mathematical models are routinely developed based on experimental observations, which also allow the prediction of the system behaviour under different experimental conditions. Often, however, the same experimental data can be represented by several competing network models. In this paper, we developed a novel mathematical model/experiment design cycle to help determine the probable network connectivity by iteratively invalidating models corresponding to competing signalling pathways. To do this, we systematically design experiments in silico that discriminate best between models of the competing signalling pathways. The method determines the inputs and parameter perturbations that will differentiate best between model outputs, corresponding to what can be measured/observed experimentally. We applied our method to the unknown connectivities in the chemotaxis pathway of the bacterium Rhodobacter sphaeroides. We first developed several models of R. sphaeroides chemotaxis corresponding to different signalling networks, all of which are biologically plausible. Parameters in these models were fitted so that they all represented wild type data equally well. The models were then compared to current mutant data and some were invalidated. To discriminate between the remaining models we used ideas from control systems theory to determine efficiently in silico an input profile that would result in the biggest difference in model outputs. However, when we applied this input to the models, we found it to be insufficient for discrimination in silico. Thus, to achieve better discrimination, we determined the best change in initial conditions (total protein concentrations) as well as the best change in the input profile. The designed experiments were then performed on live cells and the resulting data used to invalidate all but one of the

  9. A model invalidation-based approach for elucidating biological signalling pathways, applied to the chemotaxis pathway in R. sphaeroides

    Directory of Open Access Journals (Sweden)

    Hamadeh Abdullah

    2009-10-01

    Full Text Available Abstract Background Developing methods for understanding the connectivity of signalling pathways is a major challenge in biological research. For this purpose, mathematical models are routinely developed based on experimental observations, which also allow the prediction of the system behaviour under different experimental conditions. Often, however, the same experimental data can be represented by several competing network models. Results In this paper, we developed a novel mathematical model/experiment design cycle to help determine the probable network connectivity by iteratively invalidating models corresponding to competing signalling pathways. To do this, we systematically design experiments in silico that discriminate best between models of the competing signalling pathways. The method determines the inputs and parameter perturbations that will differentiate best between model outputs, corresponding to what can be measured/observed experimentally. We applied our method to the unknown connectivities in the chemotaxis pathway of the bacterium Rhodobacter sphaeroides. We first developed several models of R. sphaeroides chemotaxis corresponding to different signalling networks, all of which are biologically plausible. Parameters in these models were fitted so that they all represented wild type data equally well. The models were then compared to current mutant data and some were invalidated. To discriminate between the remaining models we used ideas from control systems theory to determine efficiently in silico an input profile that would result in the biggest difference in model outputs. However, when we applied this input to the models, we found it to be insufficient for discrimination in silico. Thus, to achieve better discrimination, we determined the best change in initial conditions (total protein concentrations as well as the best change in the input profile. The designed experiments were then performed on live cells and the resulting

  10. Regulatory Mechanisms of the Ihh/PTHrP Signaling Pathway in Fibrochondrocytes in Entheses of Pig Achilles Tendon

    Directory of Open Access Journals (Sweden)

    Xuesong Han

    2016-01-01

    Full Text Available This study is aimed at exploring the effect of stress stimulation on the proliferation and differentiation of fibrochondrocytes in entheses mediated via the Indian hedgehog (Ihh/parathyroid hormone-related protein (PTHrP signaling pathway. Differential stress stimulation on fibrochondrocytes in entheses was imposed. Gene expression and protein levels of signaling molecules including collagen type I (Col I, Col II, Col X, Ihh, and PTHrP in the cytoplasm of fibrochondrocytes were detected. Ihh signal blocking group was set up using Ihh signaling pathway-specific blocking agent cyclopamine. PTHrP enhancement group was set up using PTHrP reagent. Ihh/PTHrP double intervention group, as well as control group, was included to study the regulatory mechanisms of the Ihh/PTHrP signaling pathway in fibrochondrocytes. Under low cyclic stress tensile (CTS, PTHrP, Col I, and Col II gene expression and protein synthesis increased. Under high CTS, Ihh and Col X gene expression and protein synthesis increased. Blocking Ihh signaling with cyclopamine resulted in reduced PTHrP gene expression and protein synthesis and increased Col X gene expression and protein synthesis. Ihh and PTHrP coregulate fibrochondrocyte proliferation and differentiation in entheses through negative feedback regulation. Fibrochondrocyte is affected by the CTS. This phenomenon is regulated by stress stimulation through the Ihh/PTHrP signaling pathway.

  11. Nuclear Receptor Signaling Atlas: Opening Access to the Biology of Nuclear Receptor Signaling Pathways.

    Science.gov (United States)

    Becnel, Lauren B; Darlington, Yolanda F; Ochsner, Scott A; Easton-Marks, Jeremy R; Watkins, Christopher M; McOwiti, Apollo; Kankanamge, Wasula H; Wise, Michael W; DeHart, Michael; Margolis, Ronald N; McKenna, Neil J

    2015-01-01

    Signaling pathways involving nuclear receptors (NRs), their ligands and coregulators, regulate tissue-specific transcriptomes in diverse processes, including development, metabolism, reproduction, the immune response and neuronal function, as well as in their associated pathologies. The Nuclear Receptor Signaling Atlas (NURSA) is a Consortium focused around a Hub website (www.nursa.org) that annotates and integrates diverse 'omics datasets originating from the published literature and NURSA-funded Data Source Projects (NDSPs). These datasets are then exposed to the scientific community on an Open Access basis through user-friendly data browsing and search interfaces. Here, we describe the redesign of the Hub, version 3.0, to deploy "Web 2.0" technologies and add richer, more diverse content. The Molecule Pages, which aggregate information relevant to NR signaling pathways from myriad external databases, have been enhanced to include resources for basic scientists, such as post-translational modification sites and targeting miRNAs, and for clinicians, such as clinical trials. A portal to NURSA's Open Access, PubMed-indexed journal Nuclear Receptor Signaling has been added to facilitate manuscript submissions. Datasets and information on reagents generated by NDSPs are available, as is information concerning periodic new NDSP funding solicitations. Finally, the new website integrates the Transcriptomine analysis tool, which allows for mining of millions of richly annotated public transcriptomic data points in the field, providing an environment for dataset re-use and citation, bench data validation and hypothesis generation. We anticipate that this new release of the NURSA database will have tangible, long term benefits for both basic and clinical research in this field.

  12. Nuclear Receptor Signaling Atlas: Opening Access to the Biology of Nuclear Receptor Signaling Pathways.

    Directory of Open Access Journals (Sweden)

    Lauren B Becnel

    Full Text Available Signaling pathways involving nuclear receptors (NRs, their ligands and coregulators, regulate tissue-specific transcriptomes in diverse processes, including development, metabolism, reproduction, the immune response and neuronal function, as well as in their associated pathologies. The Nuclear Receptor Signaling Atlas (NURSA is a Consortium focused around a Hub website (www.nursa.org that annotates and integrates diverse 'omics datasets originating from the published literature and NURSA-funded Data Source Projects (NDSPs. These datasets are then exposed to the scientific community on an Open Access basis through user-friendly data browsing and search interfaces. Here, we describe the redesign of the Hub, version 3.0, to deploy "Web 2.0" technologies and add richer, more diverse content. The Molecule Pages, which aggregate information relevant to NR signaling pathways from myriad external databases, have been enhanced to include resources for basic scientists, such as post-translational modification sites and targeting miRNAs, and for clinicians, such as clinical trials. A portal to NURSA's Open Access, PubMed-indexed journal Nuclear Receptor Signaling has been added to facilitate manuscript submissions. Datasets and information on reagents generated by NDSPs are available, as is information concerning periodic new NDSP funding solicitations. Finally, the new website integrates the Transcriptomine analysis tool, which allows for mining of millions of richly annotated public transcriptomic data points in the field, providing an environment for dataset re-use and citation, bench data validation and hypothesis generation. We anticipate that this new release of the NURSA database will have tangible, long term benefits for both basic and clinical research in this field.

  13. Micro-RNA Feedback Loops Modulating the Calcineurin/NFAT Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Shichina Kannambath

    2016-05-01

    Full Text Available Nuclear factor of activated T cells (NFAT is a family of transcription factors important for innate and adaptive immune responses. NFAT activation is tightly regulated through the calcineurin/NFAT signaling pathway. There is increasing evidence on non-coding RNAs such as miRNAs playing a crucial role in regulating transcription factors and signaling pathways. However, not much is known about microRNAs (miRNAs targeting the calcineurin/NFAT signaling pathway involved in immune response in human. In this study, a comprehensive pathway level analysis has been carried out to identify miRNAs regulating the calcineurin/NFAT signaling pathway. Firstly, by incorporating experimental data and computational predictions, 191 unique miRNAs were identified to be targeting the calcineurin/NFAT signaling pathway in humans. Secondly, combining miRNA expression data from activated T cells and computational predictions, 32 miRNAs were observed to be induced by NFAT transcription factors. Finally, 11 miRNAs were identified to be involved in a feedback loop to modulate the calcineurin/NFAT signaling pathway activity. This data demonstrate the potential role of miRNAs as regulators of the calcineurin/NFAT signaling pathway. The present study thus emphasizes the importance of pathway level analysis to identify miRNAs and understands their role in modulating signaling pathways and transcription factor activity.

  14. Ski modulate the characteristics of pancreatic cancer stem cells via regulating sonic hedgehog signaling pathway.

    Science.gov (United States)

    Song, Libin; Chen, Xiangyuan; Gao, Song; Zhang, Chenyue; Qu, Chao; Wang, Peng; Liu, Luming

    2016-10-12

    Evidence from in vitro and in vivo studies shows that Ski may act as both a tumor proliferation-promoting factor and a metastatic suppressor in human pancreatic cancer and also may be a therapeutic target of integrative therapies. At present, pancreatic cancer stem cells (CSCs) are responsible for tumor recurrence accompanied by resistance to conventional therapies. Sonic hedgehog (Shh) signaling pathway is found to be aberrantly activated in CSCs. The objectives of this study were to investigate the role of Ski in modulating pancreatic CSCs and to examine the molecular mechanisms involved in pancreatic cancer treatment both in vivo and in vitro. In in vitro study, the results showed that enhanced Ski expression could increase the expression of pluripotency maintaining markers, such as CD24, CD44, Sox-2, and Oct-4, and also components of Shh signaling pathway, such as Shh, Ptch-1, Smo, Gli-1, and Gli-2, whereas depletion of Ski to the contrary. Then, we investigated the underlying mechanism and found that inhibiting Gli-2 expression by short interfering RNA (siRNA) can decrease the effects of Ski on the maintenance of pancreatic CSCs, indicating that Ski mediates the pluripotency of pancreatic CSCs mainly through Shh pathway. The conclusion is that Ski may be an important factor in maintaining the stemness of pancreatic CSCs through modulating Shh pathway.

  15. Dietary phytochemicals for possible preventive and therapeutic option of uterine fibroids: Signaling pathways as target.

    Science.gov (United States)

    Islam, Md Soriful; Segars, James H; Castellucci, Mario; Ciarmela, Pasquapina

    2017-02-01

    A growing interest has emerged on dietary phytochemicals to control diverse pathological conditions. Unfortunately, dietary phytochemical research in uterine fibroids is still under construction. Uterine fibroids/leiomyomas are benign tumors developing from the myometrium of the uterus in premenopausal women. They may occur in more than 70% of women, and approximately 25% of women show clinically significant symptoms. These include heavy and prolonged menstrual bleeding, pelvic pressure (urinary frequency, incontinence, and difficulty with urination), pelvic pain, pelvic mass, infertility, and reproductive dysfunction. Due to lack of medical treatments surgery has been definitive choice for fibroid management. Moreover, surgery negatively affects women's quality of life, and its associated cost appears to be expensive. The molecular mechanism of fibroids development and growth is not fully elucidated. However, accumulated evidence shows that several signaling pathways, including Smad 2/3, PI3K/AKT/mTOR, ERK 1/2 and β-catenin are involved in the leiomyoma pathogenesis, indicating that they could serve as targets for prevention and/or treatment of this tumor. Therefore, in this review, we discuss the involvement of signaling pathways in leiomyoma development and growth, and introduce some potential dietary phytochemicals that could modulate those signaling pathways. Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  16. Human Cytomegalovirus: Coordinating Cellular Stress, Signaling, and Metabolic Pathways.

    Science.gov (United States)

    Shenk, Thomas; Alwine, James C

    2014-11-01

    Viruses face a multitude of challenges when they infect a host cell. Cells have evolved innate defenses to protect against pathogens, and an infecting virus may induce a stress response that antagonizes viral replication. Further, the metabolic, oxidative, and cell cycle state may not be conducive to the viral infection. But viruses are fabulous manipulators, inducing host cells to use their own characteristic mechanisms and pathways to provide what the virus needs. This article centers on the manipulation of host cell metabolism by human cytomegalovirus (HCMV). We review the features of the metabolic program instituted by the virus, discuss the mechanisms underlying these dramatic metabolic changes, and consider how the altered program creates a synthetic milieu that favors efficient HCMV replication and spread.

  17. Functional comparison of innate immune signaling pathways in primates.

    Directory of Open Access Journals (Sweden)

    Luis B Barreiro

    2010-12-01

    Full Text Available Humans respond differently than other primates to a large number of infections. Differences in susceptibility to infectious agents between humans and other primates are probably due to inter-species differences in immune response to infection. Consistent with that notion, genes involved in immunity-related processes are strongly enriched among recent targets of positive selection in primates, suggesting that immune responses evolve rapidly, yet providing only indirect evidence for possible inter-species functional differences. To directly compare immune responses among primates, we stimulated primary monocytes from humans, chimpanzees, and rhesus macaques with lipopolysaccharide (LPS and studied the ensuing time-course regulatory responses. We find that, while the universal Toll-like receptor response is mostly conserved across primates, the regulatory response associated with viral infections is often lineage-specific, probably reflecting rapid host-virus mutual adaptation cycles. Additionally, human-specific immune responses are enriched for genes involved in apoptosis, as well as for genes associated with cancer and with susceptibility to infectious diseases or immune-related disorders. Finally, we find that chimpanzee-specific immune signaling pathways are enriched for HIV-interacting genes. Put together, our observations lend strong support to the notion that lineage-specific immune responses may help explain known inter-species differences in susceptibility to infectious diseases.

  18. Involvement of Notch1/Hes signaling pathway in ankylosing spondylitis.

    Science.gov (United States)

    Xu, Wei; Liang, Chao-Ge; Li, Yi-Fan; Ji, Yun-Han; Qiu, Wen-Jun; Tang, Xian-Zhong

    2015-01-01

    We aimed to investigate the role of Notch1/Hes signaling pathway in the pathogenesis of abnormal ossification of hip ligament in patients with ankylosing spondylitis (AS). 22 AS patients scheduled for artificial hip arthroplasty were randomly chosen as AS group. As controls, we used 4 patients diagnosed with transcervical fracture who underwent hip replacement surgery. Notch1 and Hes mRNA expressions were detected by real-time fluorescent quantitative polymerase chain reaction (RFQ-PCR). Immunohistochemistry (IHC) was used to detect Notch1 and Hes protein expression. Correlation analyses of Notch-l and Hes with AS-related clinical factors were conducted with spearman's correlation analysis and partial correlation analysis. RFQ-PCR results showed significant differences in Notch1 and Hes mRNA expressions between AS group and the control group (all Ppathways. Semi-quantitative IHC showed a higher Notch1 and Hes expression levels in AS group compared to the control group (all Ppathways mediated by Notch1-Hes may contribute to ligament ossification of hip joints in AS patients.

  19. Deficient brain insulin signalling pathway in Alzheimer’s disease and diabetes

    Science.gov (United States)

    Liu, Ying; Liu, Fei; Grundke-Iqbal, Inge; Iqbal, Khalid; Gong, Cheng-Xin

    2015-01-01

    Brain glucose metabolism is impaired in Alzheimer’s disease (AD), the most common form of dementia. Type 2 diabetes mellitus (T2DM) is reported to increase the risk for dementia, including AD, but the underlying mechanism is not understood. Here, we investigated the brain insulin–PI3K–AKT signalling pathway in the autopsied frontal cortices from nine AD, 10 T2DM, eight T2DM–AD and seven control cases. We found decreases in the levels and activities of several components of the insulin–PI3K–AKT signalling pathway in AD and T2DM cases. The deficiency of insulin–PI3K–AKT signalling was more severe in individuals with both T2DM and AD (T2DM–AD). This decrease in insulin–PI3K–AKT signalling could lead to activation of glycogen synthase kinase-3β, the major tau kinase. The levels and the activation of the insulin–PI3K–AKT signalling components correlated negatively with the level of tau phosphorylation and positively with protein O-GlcNAcylation, suggesting that impaired insulin–PI3K–AKT signalling might contribute to neurodegeneration in AD through down-regulation of O-GlcNAcylation and the consequent promotion of abnormal tau hyperphosphorylation and neurodegeneration. The decrease in brain insulin–PI3K–AKT signalling also correlated with the activation of calpain I in the brain, suggesting that the decrease might be caused by calpain over-activation. Our findings provide novel insight into the molecular mechanism by which type 2 diabetes mellitus increases the risk for developing cognitive impairment and dementia in Alzheimer’s disease. PMID:21598254

  20. Bacillus subtilis biofilm extends Caenorhabditis elegans longevity through downregulation of the insulin-like signalling pathway

    Science.gov (United States)

    Donato, Verónica; Ayala, Facundo Rodríguez; Cogliati, Sebastián; Bauman, Carlos; Costa, Juan Gabriel; Leñini, Cecilia; Grau, Roberto

    2017-01-01

    Beneficial bacteria have been shown to affect host longevity, but the molecular mechanisms mediating such effects remain largely unclear. Here we show that formation of Bacillus subtilis biofilms increases Caenorhabditis elegans lifespan. Biofilm-proficient B. subtilis colonizes the C. elegans gut and extends worm lifespan more than biofilm-deficient isogenic strains. Two molecules produced by B. subtilis — the quorum-sensing pentapeptide CSF and nitric oxide (NO) — are sufficient to extend C. elegans longevity. When B. subtilis is cultured under biofilm-supporting conditions, the synthesis of NO and CSF is increased in comparison with their production under planktonic growth conditions. We further show that the prolongevity effect of B. subtilis biofilms depends on the DAF-2/DAF-16/HSF-1 signalling axis and the downregulation of the insulin-like signalling (ILS) pathway. PMID:28134244

  1. DMPD: TLR signaling. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17275323 TLR signaling. Kawai T, Akira S. Semin Immunol. 2007 Feb;19(1):24-32. Epub... 2007 Feb 1. (.png) (.svg) (.html) (.csml) Show TLR signaling. PubmedID 17275323 Title TLR signaling. Author

  2. DMPD: TLR signaling. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 16410796 TLR signaling. Kawai T, Akira S. Cell Death Differ. 2006 May;13(5):816-25.... (.png) (.svg) (.html) (.csml) Show TLR signaling. PubmedID 16410796 Title TLR signaling. Authors Kawai T, A

  3. Primate fetal hepatic responses to maternal obesity: epigenetic signalling pathways and lipid accumulation.

    Science.gov (United States)

    Puppala, Sobha; Li, Cun; Glenn, Jeremy P; Saxena, Romil; Gawrieh, Samer; Quinn, Amy; Palarczyk, Jennifer; Dick, Edward J; Nathanielsz, Peter W; Cox, Laura A

    2018-03-07

    Maternal obesity (MO) increases offspring cardiometabolic disease risk. Altered fetal liver development in response to the challenge of MO has metabolic consequences underlying adverse offspring life-course health outcomes. Little is known about molecular pathways and potential epigenetic changes regulating primate fetal liver responses to MO. We hypothesized that MO would induce fetal baboon liver epigenetic changes resulting in dysregulation of key metabolic pathways that impact lipid metabolism. MO was induced prior to pregnancy by a high fat, high sucrose diet. Unbiased gene and microRNA (miRNA; small RNA Seq) abundance analyses were performed on fetal baboon livers at 0.9 gestation (G) and subjected to pathway analyses to identify fetal liver molecular responses to MO. Fetal baboon liver lipid and glycogen content were quantified by Computer Assisted Stereology Toolbox. In response to MO, fetal livers revealed dysregulation of TCA cycle, proteasome, oxidative phosphorylation, glycolysis and Wnt/β-catenin signalling pathways together with marked lipid accumulation supporting our hypothesis that multiple pathway dysregulation detrimentally impacts lipid management. This is the first study of MO programming of the nonhuman primate fetal liver using unbiased transcriptome analysis to detect changes in hepatic gene expression levels and identify potential miRNA epigenetic regulators of metabolic disruption. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  4. Analysis of diverse signal transduction pathways using the genetic model system Caenorhabditis elegans

    NARCIS (Netherlands)

    Moorman, Celine

    2003-01-01

    Signal transduction allows cells to respond to signals from their environment and is therefore important for most biological processes. The binding of an extracellular signalling molecule to a cell-surface receptor is the first step in most signal transduction pathways. Cell-surface receptors

  5. Regulation of muscle stem cell functions: a focus on the p38 MAPK signaling pathway

    Directory of Open Access Journals (Sweden)

    Jessica Segales

    2016-08-01

    Full Text Available Formation of skeletal muscle fibers (myogenesis during development and after tissue injury in the adult constitutes an excellent paradigm to investigate the mechanisms whereby environmental cues control gene expression programs in muscle stem cells (satellite cells by acting on transcriptional and epigenetic effectors. Here we will review the molecular mechanisms implicated in the transition of satellite cells throughout the distinct myogenic stages (i.e., activation from quiescence, proliferation, differentiation and self-renewal. We will also discuss recent findings on the causes underlying satellite cell functional decline with aging. In particular, our review will focus on the epigenetic changes underlying fate decisions and on how the p38 MAPK signaling pathway integrates the environmental signals at the chromatin to build up satellite cell adaptive responses during the process of muscle regeneration, and how these responses are altered in aging. A better comprehension of the signaling pathways connecting external and intrinsic factors will illuminate the path for improving muscle regeneration in the aged.

  6. Testosterone induces molecular changes in dopamine signaling pathway molecules in the adolescent male rat nigrostriatal pathway.

    Directory of Open Access Journals (Sweden)

    Tertia D Purves-Tyson

    Full Text Available Adolescent males have an increased risk of developing schizophrenia, implicating testosterone in the precipitation of dopamine-related psychopathology. Evidence from adult rodent brain indicates that testosterone can modulate nigrostriatal dopamine. However, studies are required to understand the role testosterone plays in maturation of dopamine pathways during adolescence and to elucidate the molecular mechanism(s by which testosterone exerts its effects. We hypothesized that molecular indices of dopamine neurotransmission [synthesis (tyrosine hydroxylase, breakdown (catechol-O-methyl transferase; monoamine oxygenase, transport [vesicular monoamine transporter (VMAT, dopamine transporter (DAT] and receptors (DRD1-D5] would be changed by testosterone or its metabolites, dihydrotestosterone and 17β-estradiol, in the nigrostriatal pathway of adolescent male rats. We found that testosterone and dihydrotestosterone increased DAT and VMAT mRNAs in the substantia nigra and that testosterone increased DAT protein at the region of the cell bodies, but not in target regions in the striatum. Dopamine receptor D2 mRNA was increased and D3 mRNA was decreased in substantia nigra and/or striatum by androgens. These data suggest that increased testosterone at adolescence may change dopamine responsivity of the nigrostriatal pathway by modulating, at a molecular level, the capacity of neurons to transport and respond to dopamine. Further, dopamine turnover was increased in the dorsal striatum following gonadectomy and this was prevented by testosterone replacement. Gene expression changes in the dopaminergic cell body region may serve to modulate both dendritic dopamine feedback inhibition and reuptake in the dopaminergic somatodendritic field as well as dopamine release and re-uptake dynamics at the presynaptic terminals in the striatum. These testosterone-induced changes of molecular indices of dopamine neurotransmission in males are primarily androgen

  7. Proteomics, pathway array and signaling network-based medicine in cancer

    Directory of Open Access Journals (Sweden)

    Xu Hong

    2009-10-01

    Full Text Available Abstract Cancer is a multifaceted disease that results from dysregulated normal cellular signaling networks caused by genetic, genomic and epigenetic alterations at cell or tissue levels. Uncovering the underlying protein signaling network changes, including cell cycle gene networks in cancer, aids in understanding the molecular mechanism of carcinogenesis and identifies the characteristic signaling network signatures unique for different cancers and specific cancer subtypes. The identified signatures can be used for cancer diagnosis, prognosis, and personalized treatment. During the past several decades, the available technology to study signaling networks has significantly evolved to include such platforms as genomic microarray (expression array, SNP array, CGH array, etc. and proteomic analysis, which globally assesses genetic, epigenetic, and proteomic alterations in cancer. In this review, we compared Pathway Array analysis with other proteomic approaches in analyzing protein network involved in cancer and its utility serving as cancer biomarkers in diagnosis, prognosis and therapeutic target identification. With the advent of bioinformatics, constructing high complexity signaling networks is possible. As the use of signaling network-based cancer diagnosis, prognosis and treatment is anticipated in the near future, medical and scientific communities should be prepared to apply these techniques to further enhance personalized medicine.

  8. Gene Regulation and Signal Transduction in the ICE-CBF-COR Signaling Pathway during Cold Stress in Plants.

    Science.gov (United States)

    Wang, Da-Zhi; Jin, Ya-Nan; Ding, Xi-Han; Wang, Wen-Jia; Zhai, Shan-Shan; Bai, Li-Ping; Guo, Zhi-Fu

    2017-10-01

    Low temperature is an abiotic stress that adversely affects the growth and production of plants. Resistance and adaptation of plants to cold stress is dependent upon the activation of molecular networks and pathways involved in signal transduction and the regulation of cold-stress related genes. Because it has numerous and complex genes, regulation factors, and pathways, research on the ICE-CBF-COR signaling pathway is the most studied and detailed, which is thought to be rather important for cold resistance of plants. In this review, we focus on the function of each member, interrelation among members, and the influence of manipulators and repressors in the ICE-CBF-COR pathway. In addition, regulation and signal transduction concerning plant hormones, circadian clock, and light are discussed. The studies presented provide a detailed picture of the ICE-CBF-COR pathway.

  9. Targeting Wnt signaling in colorectal cancer. A Review in the Theme: Cell Signaling: Proteins, Pathways and Mechanisms

    Science.gov (United States)

    Novellasdemunt, Laura; Antas, Pedro

    2015-01-01

    The evolutionarily conserved Wnt signaling pathway plays essential roles during embryonic development and tissue homeostasis. Notably, comprehensive genetic studies in Drosophila and mice in the past decades have demonstrated the crucial role of Wnt signaling in intestinal stem cell maintenance by regulating proliferation, differentiation, and cell-fate decisions. Wnt signaling has also been implicated in a variety of cancers and other diseases. Loss of the Wnt pathway negative regulator adenomatous polyposis coli (APC) is the hallmark of human colorectal cancers (CRC). Recent advances in high-throughput sequencing further reveal many novel recurrent Wnt pathway mutations in addition to the well-characterized APC and β-catenin mutations in CRC. Despite attractive strategies to develop drugs for Wnt signaling, major hurdles in therapeutic intervention of the pathway persist. Here we discuss the Wnt-activating mechanisms in CRC and review the current advances and challenges in drug discovery. PMID:26289750

  10. The octadecanoic pathway: signal molecules for the regulation of secondary pathways.

    Science.gov (United States)

    Blechert, S; Brodschelm, W; Hölder, S; Kammerer, L; Kutchan, T M; Mueller, M J; Xia, Z Q; Zenk, M H

    1995-05-09

    Plant defense against microbial pathogens and herbivores relies heavily on the induction of defense proteins and low molecular weight antibiotics. The signals between perception of the aggression, gene activation, and the subsequent biosynthesis of secondary compounds are assumed to be pentacylic oxylipin derivatives. The rapid, but transient, synthesis of cis-jasmonic acid was demonstrated after insect attack on a food plant and by microbial elicitor addition to plant suspension cultures. This effect is highly specific and not caused by a number of environmental stresses such as light, heavy metals, or cold or heat shock. Elicitation of Eschscholtzia cell cultures also led to a rapid alkalinization of the growth medium prior to jasmonate formation. Inhibition of this alkalinization process by the protein kinase inhibitor staurosporine also inhibited jasmonate formation. The induction of specific enzymes in the benzo[c]phenanthridine alkaloid pathway leading to the antimicrobial sanguinarine was induced to a qualitatively and quantitatively similar extent by fungal elicitor, methyl jasmonate, and its linolenic acid-derived precursor 12-oxophytodienoic acid. It is herein proposed that a second oxylipid cascade may exist in plants starting from linoleic acid via 15,16-dihydro-12-oxophytodienoic acid to 9,10-dihydrojasmonate. Experiments with synthetic trihomojasmonate demonstrated that beta-oxidation is not a prerequisite for biological activity and that 12-oxophytodienoic acid and derivatives are most likely fully active as signal transducers. Octadecanoic acid-derived compounds are essential elements in modulating the synthesis of antibiotic compounds and are thus integral to plant defense.

  11. Wnt and the Wnt signaling pathway in bone development and disease

    Science.gov (United States)

    Wang, Yiping; Li, Yi-Ping; Paulson, Christie; Shao, Jian-Zhong; Zhang, Xiaoling; Wu, Mengrui; Chen, Wei

    2014-01-01

    Wnt signaling affects both bone modeling, which occurs during development, and bone remodeling, which is a lifelong process involving tissue renewal. Wnt signals are especially known to affect the differentiation of osteoblasts. In this review, we summarize recent advances in understanding the mechanisms of Wnt signaling, which is divided into two major branches: the canonical pathway and the noncanonical pathway. The canonical pathway is also called the Wnt/β-catenin pathway. There are two major noncanonical pathways: the Wnt-planar cell polarity pathway (Wnt-PCP pathway) and the Wnt-calcium pathway (Wnt-Ca2+ pathway). This review also discusses how Wnt ligands, receptors, intracellular effectors, transcription factors, and antagonists affect both the bone modeling and bone remodeling processes. We also review the role of Wnt ligands, receptors, intracellular effectors, transcription factors, and antagonists in bone as demonstrated in mouse models. Disrupted Wnt signaling is linked to several bone diseases, including osteoporosis, van Buchem disease, and sclerosteosis. Studying the mechanism of Wnt signaling and its interactions with other signaling pathways in bone will provide potential therapeutic targets to treat these bone diseases. PMID:24389191

  12. Transistor Small Signal Analysis under Radiation Effects

    International Nuclear Information System (INIS)

    Sharshar, K.A.A.

    2004-01-01

    A Small signal transistor parameters dedicate the operation of bipolar transistor before and after exposed to gamma radiation (1 Mrad up to 5 Mrads) and electron beam(1 MeV, 25 mA) with the same doses as a radiation sources, the electrical parameters of the device are changed. The circuit Model has been discussed.Parameters, such as internal emitter resistance (re), internal base resistance, internal collector resistance (re), emitter base photocurrent (Ippe) and base collector photocurrent (Ippe). These parameters affect on the operation of the device in its applications, which work as an effective element, such as current gain (hFE≡β)degradation it's and effective parameter in the device operation. Also the leakage currents (IcBO) and (IEBO) are most important parameters, Which increased with radiation doses. Theoretical representation of the change in the equivalent circuit for NPN and PNP bipolar transistor were discussed, the input and output parameters of the two types were discussed due to the change in small signal input resistance of the two types. The emitter resistance(re) were changed by the effect of gamma and electron beam irradiation, which makes a change in the role of matching impedances between transistor stages. Also the transistor stability factors S(Ico), S(VBE) and S(β are detected to indicate the transistor operations after exposed to radiation fields. In low doses the gain stability is modified due to recombination of induced charge generated during device fabrication. Also the load resistance values are connected to compensate the effect

  13. Porcine Circovirus-Like Virus P1 Inhibits Wnt Signaling Pathway in Vivo and in Vitro.

    Science.gov (United States)

    Zhu, Xuejiao; Wen, Libin; Sheng, Shaoyang; Wang, Wei; Xiao, Qi; Qu, Meng; Hu, Yiyi; Liu, Chuanmin; He, Kongwang

    2018-01-01

    Porcine circovirus-like virus P1 is an important pathogen of the current pig industry, the infection mechanism is not entirely clear. Wnt signaling pathway plays an important role in the growth of young animals and infection of some viruses. This study was designed to demonstrate the effects of P1 infection on the Wnt signaling pathway. In vivo experiments, we demonstrated the down-regulatory effects of P1 infection in piglets and mice on the downstream components expression levels of Wnt signaling pathway, and the effects of Wnt signaling pathway activation on the pathogenesis of P1. In vitro studies, we found P1 infection down-regulated protein level of β-catenin and mRNA level of mmp2, prevented the β-catenin from entering into nucleus, abolished the TCF/LEF promoter activity, proved that P1 could inhibit the activation of Wnt signaling pathway in vitro . Finally, we found that VP1 of P1 virus also had the inhibitory effects on Wnt signaling pathway in vitro , elucidated the mechanism of P1's inhibitory effects on the Wnt signaling pathway and offered the possibility that the suppression of Wnt signaling pathway was involved in the post-weaning multisystemic wasting syndrome (PMWS), laying a foundation for elucidating the pathogenesis of P1.

  14. Porcine Circovirus-Like Virus P1 Inhibits Wnt Signaling Pathway in Vivo and in Vitro

    Directory of Open Access Journals (Sweden)

    Xuejiao Zhu

    2018-03-01

    Full Text Available Porcine circovirus-like virus P1 is an important pathogen of the current pig industry, the infection mechanism is not entirely clear. Wnt signaling pathway plays an important role in the growth of young animals and infection of some viruses. This study was designed to demonstrate the effects of P1 infection on the Wnt signaling pathway. In vivo experiments, we demonstrated the down-regulatory effects of P1 infection in piglets and mice on the downstream components expression levels of Wnt signaling pathway, and the effects of Wnt signaling pathway activation on the pathogenesis of P1. In vitro studies, we found P1 infection down-regulated protein level of β-catenin and mRNA level of mmp2, prevented the β-catenin from entering into nucleus, abolished the TCF/LEF promoter activity, proved that P1 could inhibit the activation of Wnt signaling pathway in vitro. Finally, we found that VP1 of P1 virus also had the inhibitory effects on Wnt signaling pathway in vitro, elucidated the mechanism of P1’s inhibitory effects on the Wnt signaling pathway and offered the possibility that the suppression of Wnt signaling pathway was involved in the post-weaning multisystemic wasting syndrome (PMWS, laying a foundation for elucidating the pathogenesis of P1.

  15. Dissecting blue light signal transduction pathway in leaf epidermis using a pharmacological approach

    NARCIS (Netherlands)

    Zivanovic, Branka D.; Shabala, Lana I.; Elzenga, Theo J. M.; Shabala, Sergey N.

    2015-01-01

    Blue light signalling pathway in broad bean leaf epidermal cells includes key membrane transporters: plasma- and endomembrane channels and pumps of H (+) , Ca (2+) and K (+) ions, and plasma membrane redox system. Blue light signalling pathway in epidermal tissue isolated from the abaxial side of

  16. Rac1 promotes chondrogenesis by regulating STAT3 signaling pathway.

    Science.gov (United States)

    Kim, Hyoin; Sonn, Jong Kyung

    2016-09-01

    The small GTPase protein Rac1 is involved in a wide range of biological processes including cell differentiation. Previously, Rac1 was shown to promote chondrogenesis in micromass cultures of limb mesenchyme. However, the pathways mediating Rac1's role in chondrogenesis are not fully understood. This study aimed to explore the molecular mechanisms by which Rac1 regulates chondrogenic differentiation. Phosphorylation of signal transducer and activator of transcription 3 (STAT3) was increased as chondrogenesis proceeded in micromass cultures of chick wing bud mesenchyme. Inhibition of Rac1 with NSC23766, janus kinase 2 (JAK2) with AG490, or STAT3 with stattic inhibited chondrogenesis and reduced phosphorylation of STAT3. Conversely, overexpression of constitutively active Rac1 (Rac L61) increased phosphorylation of STAT3. Rac L61 expression resulted in increased expression of interleukin 6 (IL-6), and treatment with IL-6 increased phosphorylation of STAT3. NSC23766, AG490, and stattic prohibited cell aggregation, whereas expression of Rac L61 increased cell aggregation, which was reduced by stattic treatment. Our studies indicate that Rac1 induces STAT3 activation through expression and action of IL-6. Overexpression of Rac L61 increased expression of bone morphogenic protein 4 (BMP4). BMP4 promoted chondrogenesis, which was inhibited by K02288, an activin receptor-like kinase-2 inhibitor, and increased phosphorylation of p38 MAP kinase. Overexpression of Rac L61 also increased phosphorylation of p38 MAPK, which was reduced by K02288. These results suggest that Rac1 activates STAT3 by expression of IL-6, which in turn increases expression and activity of BMP4, leading to the promotion of chondrogenesis. © 2016 International Federation for Cell Biology.

  17. Mast cell chemotaxis – Chemoattractants and signaling pathways

    Directory of Open Access Journals (Sweden)

    Ivana eHalova

    2012-05-01

    Full Text Available Migration of mast cells is essential for their recruitment within target tissues where they play an important role in innate and adaptive immune responses. These processes rely on the ability of mast cells to recognize appropriate chemotactic stimuli and react to them by a chemotactic response. Another level of intercellular communication is attained by production of chemoattractants by activated mast cells, which results in accumulation of mast cells and other hematopoietic cells at the sites of inflammation. Mast cells express numerous surface receptors for various ligands with properties of potent chemoattractants. They include the stem cell factor recognized by c-Kit, antigen, which binds to immunoglobulin E (IgE anchored to the high affinity IgE receptor (FcRI, highly cytokinergic IgE recognized by FcRI, lipid mediator sphingosine-1-phosphate (S1P, which binds to G-protein-coupled receptors (GPCRs. Other large groups of chemoattractants are eicosanoids [prostaglandin E2 and D2, leukotriene (LT B4, LTD4 and LTC4, and others] and chemokines (CC, CXC, C and CX3X, which also bind to various GPCRs. Further noteworthy chemoattractants are isoforms of transforming growth factor (TGF , which are sensitively recognized by TGF- serine/threonine type I and II  receptors, adenosine, C1q, C3a, and C5a components of the complement, 5-hydroxytryptamine, neuroendocrine peptide catestatin, interleukin-6, tumor necrosis factor- and others. Here we discuss the major types of chemoattractants recognized by mast cells, their target receptors, as well as signaling pathways they utilize. We also briefly deal with methods used for studies of mast cell chemotaxis and with ways of how these studies profited from the results obtained in other cellular systems.

  18. Trichoderma Biocontrol: Signal Transduction Pathways Involved in Host Sensing and Mycoparasitism

    Directory of Open Access Journals (Sweden)

    Susanne Zeilinger

    2007-01-01

    Full Text Available Fungi of the genus Trichoderma are used as biocontrol agents against several plant pathogenic fungi like Rhizoctonia spp., Pythium spp., Botrytis cinerea and Fusarium spp. which cause both soil-borne and leaf- or flower-borne diseases of agricultural plants. Plant disease control by Trichoderma is based on complex interactions between Trichoderma, the plant pathogen and the plant. Until now, two main components of biocontrol have been identified: direct activity of Trichoderma against the plant pathogen by mycoparasitism and induced systemic resistance in plants. As the mycoparasitic interaction is host-specific and not merely a contact response, it is likely that signals from the host fungus are recognised by Trichoderma and provoke transcription of mycoparasitism-related genes.In the last few years examination of signalling pathways underlying Trichoderma biocontrol started and it was shown that heterotrimeric G-proteins and mitogen-activated protein (MAP kinases affected biocontrol-relevant processes such as the production of hydrolytic enzymes and antifungal metabolites and the formation of infection structures. MAPK signalling was also found to be involved in induction of plant systemic resistance in Trichoderma virens and in the hyperosmotic stress response in Trichoderma harzianum. Analyses of the function of components of the cAMP pathway during Trichoderma biocontrol revealed that mycoparasitism-associated coiling and chitinase production as well as secondary metabolism are affected by the internal cAMP level; in addition, a cross talk between regulation of light responses and the cAMP signalling pathway was found in Trichoderma atroviride.

  19. DAMP signaling is a key pathway inducing immune modulation after brain injury.

    Science.gov (United States)

    Liesz, Arthur; Dalpke, Alexander; Mracsko, Eva; Antoine, Daniel J; Roth, Stefan; Zhou, Wei; Yang, Huan; Na, Shin-Young; Akhisaroglu, Mustafa; Fleming, Thomas; Eigenbrod, Tatjana; Nawroth, Peter P; Tracey, Kevin J; Veltkamp, Roland

    2015-01-14

    Acute brain lesions induce profound alterations of the peripheral immune response comprising the opposing phenomena of early immune activation and subsequent immunosuppression. The mechanisms underlying this brain-immune signaling are largely unknown. We used animal models for experimental brain ischemia as a paradigm of acute brain lesions and additionally investigated a large cohort of stroke patients. We analyzed release of HMGB1 isoforms by mass spectrometry and investigated its inflammatory potency and signaling pathways by immunological in vivo and in vitro techniques. Features of the complex behavioral sickness behavior syndrome were characterized by homecage behavior analysis. HMGB1 downstream signaling, particularly with RAGE, was studied in various transgenic animal models and by pharmacological blockade. Our results indicate that the cytokine-inducing, fully reduced isoform of HMGB1 was released from the ischemic brain in the hyperacute phase of stroke in mice and patients. Cytokines secreted in the periphery in response to brain injury induced sickness behavior, which could be abrogated by inhibition of the HMGB1-RAGE pathway or direct cytokine neutralization. Subsequently, HMGB1-release induced bone marrow egress and splenic proliferation of bone marrow-derived suppressor cells, inhibiting the adaptive immune responses in vivo and vitro. Furthermore, HMGB1-RAGE signaling resulted in functional exhaustion of mature monocytes and lymphopenia, the hallmarks of immune suppression after extensive ischemia. This study introduces the HMGB1-RAGE-mediated pathway as a key mechanism explaining the complex postischemic brain-immune interactions. Copyright © 2015 the authors 0270-6474/15/350583-16$15.00/0.

  20. Failure of signal transduction pathway of DNA damage in hereditary microcephaly

    International Nuclear Information System (INIS)

    Miyamoto, Tatsuo; Matsuura, Shinya

    2009-01-01

    Mechanisms underlying the brain size determination are considered from an aspect of DNA-damage signaling recently revealed by studies on hereditary microcephaly (M), in relation to the radiation-induced M. International Commission of Radiological Protection (ICRP) assesses the risk of M by in utero exposure as 40%/Sv, the threshold dose is about 0.2 Gy (deterministic effect), A-bomb M is conceived to be due to the exposure at 8-5 weeks of gestation, and M is induced by radiation at 10 days after fertilization in the mouse. Recent studies on causing genes of M have revealed its particular connection with signaling pathways: in ataxia-telangiectasia (AT), genes of ATM; in Seckel syndrome, of ATR (AT and Rad3-related) and pericentrin (PCNT); Nijmegen syndrome (NBS), of NBS1; NBS-like disease, of Rad50 and Mre11; AT-like disease, of Mre11; Lig4 syndrome, of Lig4; immunodeficiency combined with M, of XLF; primary M, of MCPH1, ASPM, CdkRap2, CENP-J and STIL. Single and double strand breaks of DNA respectively activate the signaling pathway of ATR where PCNT and MCPH1 participate, and pathway of ATM where NBS1, Mre11 and Rad50 do. PCNT is a major protein, pericentrin, composing the centrosome, of which defect results in the Seckel disease with spindle dysfunction. At present, M can be thus said to be of the cellular common features of failure of ATM/ATR signaling and of dysfunction of centrosome. As well, ASPM gene expression is recently reported to be suppressed by radiation. Thus future studies on M will spread to wider biological field of cell and development as well as radiation and inheritance. (K.T.)

  1. The role of the Hedgehog signaling pathway in cancer: A comprehensive review

    Directory of Open Access Journals (Sweden)

    Ana Marija Skoda

    2018-02-01

    Full Text Available The Hedgehog (Hh signaling pathway was first identified in the common fruit fly. It is a highly conserved evolutionary pathway of signal transmission from the cell membrane to the nucleus. The Hh signaling pathway plays an important role in the embryonic development. It exerts its biological effects through a signaling cascade that culminates in a change of balance between activator and repressor forms of glioma-associated oncogene (Gli transcription factors. The components of the Hh signaling pathway involved in the signaling transfer to the Gli transcription factors include Hedgehog ligands (Sonic Hh [SHh], Indian Hh [IHh], and Desert Hh [DHh], Patched receptor (Ptch1, Ptch2, Smoothened receptor (Smo, Suppressor of fused homolog (Sufu, kinesin protein Kif7, protein kinase A (PKA, and cyclic adenosine monophosphate (cAMP. The activator form of Gli travels to the nucleus and stimulates the transcription of the target genes by binding to their promoters. The main target genes of the Hh signaling pathway are PTCH1, PTCH2, and GLI1. Deregulation of the Hh signaling pathway is associated with developmental anomalies and cancer, including Gorlin syndrome, and sporadic cancers, such as basal cell carcinoma, medulloblastoma, pancreatic, breast, colon, ovarian, and small-cell lung carcinomas. The aberrant activation of the Hh signaling pathway is caused by mutations in the related genes (ligand-independent signaling or by the excessive expression of the Hh signaling molecules (ligand-dependent signaling – autocrine or paracrine. Several Hh signaling pathway inhibitors, such as vismodegib and sonidegib, have been developed for cancer treatment. These drugs are regarded as promising cancer therapies, especially for patients with refractory/advanced cancers.

  2. Signaling pathway-focused gene expression profiling in pressure overloaded hearts

    Directory of Open Access Journals (Sweden)

    Marco Musumeci

    2011-01-01

    Full Text Available The β-blocker propranolol displays antihypertrophic and antifibrotic properties in the heart subjected to pressure overload. Yet the underlying mechanisms responsible for these important effects remain to be completely understood. The purpose of this study was to determine signaling pathway-focused gene expression profile associated with the antihypertrophic action of propranolol in pressure overloaded hearts. To address this question, a focused real-time PCR array was used to screen left ventricular RNA expression of 84 gene transcripts representative of 18 different signaling pathways in C57BL/6 mice subjected to transverse aortic constriction (TAC or sham surgery. On the surgery day, mice received either propranolol (80 mg/kg/day or vehicle for 14 days. TAC caused a 49% increase in the left ventricular weight-to-body weight (LVW/BW ratio without changing gene expression. Propranolol blunted LVW/BW ratio increase by approximately 50% while causing about a 3-fold increase in the expression of two genes, namely Brca1 and Cdkn2a, belonging to the TGF-beta and estrogen pathways, respectively. In conclusion, after 2 weeks of pressure overload, TAC hearts show a gene expression profile superimposable to that of sham hearts. Conversely, propranolol treatment is associated with an increased expression of genes which negatively regulate cell cycle progression. It remains to be established whether a mechanistic link between gene expression changes and the antihypertrophic action of propranolol occurs.

  3. DMPD: Signal transduction pathways mediated by the interaction of CpG DNA withToll-like receptor 9. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 14751759 Signal transduction pathways mediated by the interaction of CpG DNA withTo...;16(1):17-22. (.png) (.svg) (.html) (.csml) Show Signal transduction pathways mediated by the interaction of... CpG DNA withToll-like receptor 9. PubmedID 14751759 Title Signal transduction pathways

  4. Role of SDF-1 and Wnt signaling pathway in the myocardial fibrosis of hypertensive rats.

    Science.gov (United States)

    Shao, Shuai; Cai, Wenwei; Sheng, Jing; Yin, Lingni

    2015-01-01

    To investigate the effects of stromal cell-derived factor-1 (SDF-1) and Wnt signaling pathway on the bioactivities of myofibroblasts (MFs) and the expressions of SDF-1 and components of Wnt signaling pathway in the myocardium of spontaneously hypertensive rats (SHR). BMSCs were induced to differentiate into MFs in vitro, and SDF-1 and Wnt signaling pathway were independently or simultaneously blocked. Then, the migration of MFs and the secretion of Col I and α-SMA were determined in MFs. Heart function, progression of myocardial fibrosis and structure of the heart were evaluated. The expression of SDF-1 and components of Wnt signaling pathway in SHR was detected. TGF-β could induce the differentiation of BMSCs into B-MFs; Blocking SDF-1/CXCR4 axis and/or Wnt signaling pathway was able to inhibit the MFs migration and Col I secretion; Blocking Wnt signaling pathway inhibited the differentiation of BMSCs into MFs; Serum SDF-1 increased with the increase in blood pressure, and serum β-catenin elevated with the fluctuation of blood pressure; Protein and mRNA expressions of SDF-1 in the myocardium increased, and those of DKK-1 (an inhibitor of Wnt signaling pathway) and GSK-3 reduced in SHR. SDF-1 and Wnt signaling pathway are involved in the differentiation of BMSCs into MFs, as well as the migration and collagen secretion of MFs; Hypertension affects the expressions of SDF-1 and components of Wnt signaling pathway. In the myocardium of SHR, SDF-1 expression increases, but the expression of inhibitor of Wnt signaling pathway reduces.

  5. Histone deacetylase regulates insulin signaling via two pathways in pancreatic β cells.

    Directory of Open Access Journals (Sweden)

    Yukina Kawada

    Full Text Available Recent studies demonstrated that insulin signaling plays important roles in the regulation of pancreatic β cell mass, the reduction of which is known to be involved in the development of diabetes. However, the mechanism underlying the alteration of insulin signaling in pancreatic β cells remains unclear. The involvement of epigenetic control in the onset of diabetes has also been reported. Thus, we analyzed the epigenetic control of insulin receptor substrate 2 (IRS2 expression in the MIN6 mouse insulinoma cell line. We found concomitant IRS2 up-regulation and enhanced insulin signaling in MIN6 cells, which resulted in an increase in cell proliferation. The H3K9 acetylation status of the Irs2 promoter was positively associated with IRS2 expression. Treatment of MIN6 cells with histone deacetylase inhibitors led to increased IRS2 expression, but this occurred in concert with low insulin signaling. We observed increased IRS2 lysine acetylation as a consequence of histone deacetylase inhibition, a modification that was coupled with a decrease in IRS2 tyrosine phosphorylation. These results suggest that insulin signaling in pancreatic β cells is regulated by histone deacetylases through two novel pathways affecting IRS2: the epigenetic control of IRS2 expression by H3K9 promoter acetylation, and the regulation of IRS2 activity through protein modification. The identification of the histone deacetylase isoform(s involved in these mechanisms would be a valuable approach for the treatment of type 2 diabetes.

  6. Histone deacetylase regulates insulin signaling via two pathways in pancreatic β cells.

    Science.gov (United States)

    Kawada, Yukina; Asahara, Shun-Ichiro; Sugiura, Yumiko; Sato, Ayaka; Furubayashi, Ayuko; Kawamura, Mao; Bartolome, Alberto; Terashi-Suzuki, Emi; Takai, Tomoko; Kanno, Ayumi; Koyanagi-Kimura, Maki; Matsuda, Tomokazu; Hashimoto, Naoko; Kido, Yoshiaki

    2017-01-01

    Recent studies demonstrated that insulin signaling plays important roles in the regulation of pancreatic β cell mass, the reduction of which is known to be involved in the development of diabetes. However, the mechanism underlying the alteration of insulin signaling in pancreatic β cells remains unclear. The involvement of epigenetic control in the onset of diabetes has also been reported. Thus, we analyzed the epigenetic control of insulin receptor substrate 2 (IRS2) expression in the MIN6 mouse insulinoma cell line. We found concomitant IRS2 up-regulation and enhanced insulin signaling in MIN6 cells, which resulted in an increase in cell proliferation. The H3K9 acetylation status of the Irs2 promoter was positively associated with IRS2 expression. Treatment of MIN6 cells with histone deacetylase inhibitors led to increased IRS2 expression, but this occurred in concert with low insulin signaling. We observed increased IRS2 lysine acetylation as a consequence of histone deacetylase inhibition, a modification that was coupled with a decrease in IRS2 tyrosine phosphorylation. These results suggest that insulin signaling in pancreatic β cells is regulated by histone deacetylases through two novel pathways affecting IRS2: the epigenetic control of IRS2 expression by H3K9 promoter acetylation, and the regulation of IRS2 activity through protein modification. The identification of the histone deacetylase isoform(s) involved in these mechanisms would be a valuable approach for the treatment of type 2 diabetes.

  7. Modulation of the TGFβ/Smad signaling pathway in mesangial cells by CTGF/CCN2

    International Nuclear Information System (INIS)

    Abdel Wahab, Nadia; Weston, Benjamin S.; Mason, Roger M.

    2005-01-01

    Transforming growth factor-beta (TGFβ) drives fibrosis in diseases such as diabetic nephropathy (DN). Connective tissue growth factor (CTGF; CCN2) has also been implicated in this, but the molecular mechanism is unknown. We show that CTGF enhances the TGFβ/Smad signaling pathway by transcriptional suppression of Smad 7 following rapid and sustained induction of the transcription factor TIEG-1. Smad 7 is a known antagonist of TGFβ signaling and TIEG-1 is a known repressor of Smad 7 transcription. CTGF enhanced TGFβ-induced phosphorylation and nuclear translocation of Smad 2 and Smad 3 in mesangial cells. Antisense oligonucleotides directed against TIEG-1 prevented CTGF-induced downregulation of Smad 7. CTGF enhanced TGFβ-stimulated transcription of the SBE4-Luc reporter gene and this was markedly reduced by TIEG-1 antisense oligonucleotides. Expression of the TGFβ-responsive genes PAI-1 and Col III over 48 h was maximally stimulated by TGFβ + CTGF compared to TGFβ alone, while CTGF alone had no significant effect. TGFβ-stimulated expression of these genes was markedly reduced by both CTGF and TIEG-1 antisense oligonucleotides, consistent with the endogenous induction of CTGF by TGFβ. We propose that under pathological conditions, where CTGF expression is elevated, CTGF blocks the negative feedback loop provided by Smad 7, allowing continued activation of the TGFβ signaling pathway

  8. Dynamic probabilistic threshold networks to infer signaling pathways from time-course perturbation data.

    Science.gov (United States)

    Kiani, Narsis A; Kaderali, Lars

    2014-07-22

    Network inference deals with the reconstruction of molecular networks from experimental data. Given N molecular species, the challenge is to find the underlying network. Due to data limitations, this typically is an ill-posed problem, and requires the integration of prior biological knowledge or strong regularization. We here focus on the situation when time-resolved measurements of a system's response after systematic perturbations are available. We present a novel method to infer signaling networks from time-course perturbation data. We utilize dynamic Bayesian networks with probabilistic Boolean threshold functions to describe protein activation. The model posterior distribution is analyzed using evolutionary MCMC sampling and subsequent clustering, resulting in probability distributions over alternative networks. We evaluate our method on simulated data, and study its performance with respect to data set size and levels of noise. We then use our method to study EGF-mediated signaling in the ERBB pathway. Dynamic Probabilistic Threshold Networks is a new method to infer signaling networks from time-series perturbation data. It exploits the dynamic response of a system after external perturbation for network reconstruction. On simulated data, we show that the approach outperforms current state of the art methods. On the ERBB data, our approach recovers a significant fraction of the known interactions, and predicts novel mechanisms in the ERBB pathway.

  9. Cross-regulation of signaling pathways: An example of nuclear hormone receptors and the canonical Wnt pathway

    International Nuclear Information System (INIS)

    Beildeck, Marcy E.; Gelmann, Edward P.; Byers, Stephen W.

    2010-01-01

    Predicting the potential physiological outcome(s) of any given molecular pathway is complex because of cross-talk with other pathways. This is particularly evident in the case of the nuclear hormone receptor and canonical Wnt pathways, which regulate cell growth and proliferation, differentiation, apoptosis, and metastatic potential in numerous tissues. These pathways are known to intersect at many levels: in the intracellular space, at the membrane, in the cytoplasm, and within the nucleus. The outcomes of these interactions are important in the control of stem cell differentiation and maintenance, feedback loops, and regulating oncogenic potential. The aim of this review is to demonstrate the importance of considering pathway cross-talk when predicting functional outcomes of signaling, using nuclear hormone receptor/canonical Wnt pathway cross-talk as an example.

  10. Aberrant Wnt signaling pathway in medial temporal lobe structures of Alzheimer's disease

    DEFF Research Database (Denmark)

    Riise, Jesper; Plath, Niels; Pakkenberg, Bente

    2015-01-01

    Cognitive decline is a cardinal feature of Alzheimer’s disease (AD) predominantly linked to synaptic failure, disrupted network connectivity and neurodegeneration. A large body of evidence associates the Wnt pathway with synaptic modulation and cognitive processes, suggesting a potential role...... for aberrant Wnt signaling in cognitive impairment. In fact, altered expression of key Wnt pathway components has been found in brains of AD patients as well as AD animal models supporting a deregulated pathway in AD. The evidence for deregulated Wnt signaling in AD, however, remains sparse and focused...... on isolated Wnt pathway components. Here, we provide the first comprehensive pathway-focused evaluation of the Wnt pathway in the entorhinal cortex and hippocampus of AD brains. Our data demonstrate altered Wnt pathway gene expression at all levels of the pathway in both medial temporal lobe regions...

  11. Identification of a Novel Gnao-Mediated Alternate Olfactory Signaling Pathway in Murine OSNs.

    Science.gov (United States)

    Scholz, Paul; Mohrhardt, Julia; Jansen, Fabian; Kalbe, Benjamin; Haering, Claudia; Klasen, Katharina; Hatt, Hanns; Osterloh, Sabrina

    2016-01-01

    It is generally agreed that in olfactory sensory neurons (OSNs), the binding of odorant molecules to their specific olfactory receptor (OR) triggers a cAMP-dependent signaling cascade, activating cyclic-nucleotide gated (CNG) channels. However, considerable controversy dating back more than 20 years has surrounded the question of whether alternate signaling plays a role in mammalian olfactory transduction. In this study, we demonstrate a specific alternate signaling pathway in Olfr73-expressing OSNs. Methylisoeugenol (MIEG) and at least one other known weak Olfr73 agonist (Raspberry Ketone) trigger a signaling cascade independent from the canonical pathway, leading to the depolarization of the cell. Interestingly, this pathway is mediated by Gnao activation, leading to Cl(-) efflux; however, the activation of adenylyl cyclase III (ACIII), the recruitment of Ca(2+) from extra-or intracellular stores, and phosphatidylinositol 3-kinase-dependent signaling (PI signaling) are not involved. Furthermore, we demonstrated that our newly identified pathway coexists with the canonical olfactory cAMP pathway in the same OSN and can be triggered by the same OR in a ligand-selective manner. We suggest that this pathway might reflect a mechanism for odor recognition predominantly used in early developmental stages before olfactory cAMP signaling is fully developed. Taken together, our findings support the existence of at least one odor-induced alternate signal transduction pathway in native OSNs mediated by Olfr73 in a ligand-selective manner.

  12. Identification of a novel Gnao-mediated alternate olfactory signaling pathway in murine OSNs

    Directory of Open Access Journals (Sweden)

    Paul eScholz

    2016-03-01

    Full Text Available It is generally agreed that in olfactory sensory neurons (OSNs, the binding of odorant molecules to their specific olfactory receptor (OR triggers a cAMP-dependent signaling cascade, activating cyclic-nucleotide gated (CNG channels. However, considerable controversy dating back more than 20 years has surrounded the question of whether alternate signaling plays a role in mammalian olfactory transduction. In this study, we demonstrate a specific alternate signaling pathway in Olfr73-expressing OSNs. Methylisoeugenol (MIEG and at least one other known weak Olfr73 agonist (Raspberry Ketone trigger a signaling cascade independent from the canonical pathway, leading to the depolarization of the cell. Interestingly, this pathway is mediated by Gnao activation, leading to Cl- efflux; however, the activation of adenylyl cyclase III (ACIII, the recruitment of Ca2+ from extra-or intracellular stores, and phosphatidylinositol 3-kinase-dependent signaling (PI signaling are not involved. Furthermore, we demonstrated that our newly identified pathway coexists with the canonical olfactory cAMP pathway in the same OSN and can be triggered by the same OR in a ligand-selective manner. We suggest that this pathway might reflect a mechanism for odor recognition predominantly used in early developmental stages before olfactory cAMP signaling is fully developed. Taken together, our findings support the existence of at least one odor-induced alternate signal transduction pathway in native OSNs mediated by Olfr73 in a ligand-selective manner.

  13. An alternative pathway for signal flow from rod photoreceptors to ganglion cells in mammalian retina.

    OpenAIRE

    DeVries, S H; Baylor, D A

    1995-01-01

    Rod signals in the mammalian retina are thought to reach ganglion cells over the circuit rod-->rod depolarizing bipolar cell-->AII amacrine cell-->cone bipolar cells-->ganglion cells. A possible alternative pathway involves gap junctions linking the rods and cones, the circuit being rod-->cone-->cone bipolar cells-->ganglion cells. It is not clear whether this second pathway indeed relays rod signals to ganglion cells. We studied signal flow in the isolated rabbit retina with a multielectrode...

  14. Evolution and Design Governing Signal Precision and Amplification in a Bacterial Chemosensory Pathway

    OpenAIRE

    Guzzo, Mathilde; Agrebi, Rym; Espinosa, Leon; Baronian, Gr?gory; Molle, Virginie; Mauriello, Emilia M. F.; Brochier-Armanet, C?line; Mignot, T?m

    2015-01-01

    Author Summary Deciphering the circuit design of signal transduction networks is a fundamental question in cell biology. This task is challenging because many pathways are branched and control multiple cellular processes in response to one or several environmental signals. Studying pathway diversification in bacteria could be a powerful approach because these organisms contain so-called chemosensory systems, modular signaling units that have been adapted multiple times independently to regula...

  15. Interactions among oscillatory pathways in NF-kappa B signaling

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    White Michael RH

    2011-02-01

    Full Text Available Abstract Background Sustained stimulation with tumour necrosis factor alpha (TNF-alpha induces substantial oscillations—observed at both the single cell and population levels—in the nuclear factor kappa B (NF-kappa B system. Although the mechanism has not yet been elucidated fully, a core system has been identified consisting of a negative feedback loop involving NF-kappa B (RelA:p50 hetero-dimer and its inhibitor I-kappa B-alpha. Many authors have suggested that this core oscillator should couple to other oscillatory pathways. Results First we analyse single-cell data from experiments in which the NF-kappa B system is forced by short trains of strong pulses of TNF-alpha. Power spectra of the ratio of nuclear-to-cytoplasmic concentration of NF-kappa B suggest that the cells' responses are entrained by the pulsing frequency. Using a recent model of the NF-kappa B system due to Caroline Horton, we carried out extensive numerical simulations to analyze the response frequencies induced by trains of pulses of TNF-alpha stimulation having a wide range of frequencies and amplitudes. These studies suggest that for sufficiently weak stimulation, various nonlinear resonances should be observable. To explore further the possibility of probing alternative feedback mechanisms, we also coupled the model to sinusoidal signals with a wide range of strengths and frequencies. Our results show that, at least in simulation, frequencies other than those of the forcing and the main NF-kappa B oscillator can be excited via sub- and superharmonic resonance, producing quasiperiodic and even chaotic dynamics. Conclusions Our numerical results suggest that the entrainment phenomena observed in pulse-stimulated experiments is a consequence of the high intensity of the stimulation. Computational studies based on current models suggest that resonant interactions between periodic pulsatile forcing and the system's natural frequencies may become evident for sufficiently

  16. Lung cancer, intracellular signaling pathways, and preclinical models

    International Nuclear Information System (INIS)

    Mordant, P.

    2012-01-01

    Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Activation of phosphatidylinositol-3-kinase (PI3K)-AKT and Kirsten rat sarcoma viral oncogene homologue (KRAS) 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 KRAS, PI3K-AKT, or both. We investigated whether the combination of a novel RAF/vascular endothelial growth factor receptor inhibitor, RAF265, with a mammalian target of rapamycin (mTOR) inhibitor, RAD001 (everolimus), could lead to enhanced anti-tumoral effects in vitro and in vivo. To address this question, we used cell lines with different status regarding KRAS, PIK3CA, and BRAF 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. RAD001 inhibited mTOR downstream signaling in all cell lines, whereas RAF265 inhibited RAF downstream signaling only in BRAF mutant cells. In vitro, addition of RAF265 to RAD001 led to decreased AKT, S6, and Eukaryotic translation initiation factor 4E binding protein 1 phosphorylation in HCT116 cells. In vitro and in vivo, RAD001 addition enhanced the anti-tumoral effect of RAF265 in HCT116 and H460 cells (both KRAS mut, PIK3CA mut); in contrast, the combination of RAF265 and RAD001 yielded no additional activity in A549 and MDAMB231 cells. The combination of RAF and mTOR inhibitors is effective for enhancing anti-tumoral effects in cells with deregulation of both RAS-RAF and PI3K, possibly through the cross-inhibition of 4E binding protein 1 and S6 protein. We then focus on animal models. Preclinical models of NSCLC require better clinical relevance to study disease mechanisms and innovative

  17. Vanillin Promotes the Germination of Antrodia camphorata Arthroconidia through PKA and MAPK Signaling Pathways

    Science.gov (United States)

    Lu, Zhen-Ming; Zhu, Qing; Li, Hua-Xiang; Geng, Yan; Shi, Jin-Song; Xu, Zheng-Hong

    2017-01-01

    Wild fruiting bodies of medicinal mushroom Antrodia camphorata are only found on the endemic species bull camphor tree, Cinnamomum kanehirae, in Taiwan. Despite the evident importance of the host components in promoting the growth of A. camphorata, insights into the underlying mechanisms are still lacking. Here, we first evaluated effects of the compounds from C. kanehirai, C. camphora, and A. camphorata, and their structural analogs on the germination rate of A. camphorata arthroconidia. Among the 54 tested compounds, vanillin (4-hydroxy-3-methoxybenzaldehyde) was determined as the optimum germination promoter, while o-vanillin and 1-octen-3-ol as major negative regulators of arthroconidia germination. Second, the protein patterns of arthroconidia after 24 h of incubation in the presence or absence of vanillin were compared via isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomics. Via bioinformatic analysis, it was found that 61 proteins might relate to the germination of arthroconidia, in which 16 proteins might involve in two potential protein kinase A (PKA) and mitogen-activated protein kinase (MAPK) signaling pathways in the vanillin-promoted germination of A. camphorata arthroconidia. Last, the mRNA expression levels of the 16 germination-related genes in the potential PKA and MAPK signaling pathways were analyzed by quantitative real time PCR. Together, our results are beneficial for the elucidation of molecular mechanisms underlying the germination of A. camphorata arthroconidia. PMID:29109709

  18. Vanillin Promotes the Germination of Antrodia camphorata Arthroconidia through PKA and MAPK Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Zhen-Ming Lu

    2017-10-01

    Full Text Available Wild fruiting bodies of medicinal mushroom Antrodia camphorata are only found on the endemic species bull camphor tree, Cinnamomum kanehirae, in Taiwan. Despite the evident importance of the host components in promoting the growth of A. camphorata, insights into the underlying mechanisms are still lacking. Here, we first evaluated effects of the compounds from C. kanehirai, C. camphora, and A. camphorata, and their structural analogs on the germination rate of A. camphorata arthroconidia. Among the 54 tested compounds, vanillin (4-hydroxy-3-methoxybenzaldehyde was determined as the optimum germination promoter, while o-vanillin and 1-octen-3-ol as major negative regulators of arthroconidia germination. Second, the protein patterns of arthroconidia after 24 h of incubation in the presence or absence of vanillin were compared via isobaric tags for relative and absolute quantitation (iTRAQ-based proteomics. Via bioinformatic analysis, it was found that 61 proteins might relate to the germination of arthroconidia, in which 16 proteins might involve in two potential protein kinase A (PKA and mitogen-activated protein kinase (MAPK signaling pathways in the vanillin-promoted germination of A. camphorata arthroconidia. Last, the mRNA expression levels of the 16 germination-related genes in the potential PKA and MAPK signaling pathways were analyzed by quantitative real time PCR. Together, our results are beneficial for the elucidation of molecular mechanisms underlying the germination of A. camphorata arthroconidia.

  19. Entada phaseoloides extract suppresses hepatic gluconeogenesis via activation of the AMPK signaling pathway.

    Science.gov (United States)

    Zheng, Tao; Hao, Xincai; Wang, Qibin; Chen, Li; Jin, Si; Bian, Fang

    2016-12-04

    The seed of Entada phaseoloides (L.) Merr. (Entada phaseoloides) has been long used as a folk medicine for the treatment of Diabetes mellitus by Chinese ethnic minorities. Recent reports have demonstrated that total saponins from Entada phaseoloides (TSEP) could reduce fasting blood glucose in type 2 diabetic rats. However, the mechanism has not been fully elucidated. The aim of this study was to explore the underlying mechanisms of TSEP on type 2 Diabetes mellitus (T2DM). Primary mouse hepatocytes and HepG2 cells were used to investigate the effects of TSEP on gluconeogenesis. After treatment with TSEP, glucose production, genes expression levels of Glucose-6-phosphatase (G6pase) and Phosphoenoylpyruvate carboxykinase (Pepck) were detected. The efficacy and underlying mechanism of TSEP on AMP-activated protein kinase (AMPK) signaling pathway were determinated. TSEP significantly inhibited glucose production and the gluconeogenic gene expression. Treatment with TSEP elevated the phosphorylation of AMPK, which in turn promoted the phosphorylation of acetyl coenzyme A (ACC) and Akt/glycogen synthase kinase 3β (GSK3β), respectively. Furthermore, TSEP reduced lipid accumulation and improved insulin sensitivity in hepatocytes. These findings provide evidence that TSEP exerts an antidiabetic effect by suppressing hepatic gluconeogenesis via the AMPK signaling pathway. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  20. The node-weighted Steiner tree approach to identify elements of cancer-related signaling pathways.

    Science.gov (United States)

    Sun, Yahui; Ma, Chenkai; Halgamuge, Saman

    2017-12-28

    Cancer constitutes a momentous health burden in our society. Critical information on cancer may be hidden in its signaling pathways. However, even though a large amount of money has been spent on cancer research, some critical information on cancer-related signaling pathways still remains elusive. Hence, new works towards a complete understanding of cancer-related signaling pathways will greatly benefit the prevention, diagnosis, and treatment of cancer. We propose the node-weighted Steiner tree approach to identify important elements of cancer-related signaling pathways at the level of proteins. This new approach has advantages over previous approaches since it is fast in processing large protein-protein interaction networks. We apply this new approach to identify important elements of two well-known cancer-related signaling pathways: PI3K/Akt and MAPK. First, we generate a node-weighted protein-protein interaction network using protein and signaling pathway data. Second, we modify and use two preprocessing techniques and a state-of-the-art Steiner tree algorithm to identify a subnetwork in the generated network. Third, we propose two new metrics to select important elements from this subnetwork. On a commonly used personal computer, this new approach takes less than 2 s to identify the important elements of PI3K/Akt and MAPK signaling pathways in a large node-weighted protein-protein interaction network with 16,843 vertices and 1,736,922 edges. We further analyze and demonstrate the significance of these identified elements to cancer signal transduction by exploring previously reported experimental evidences. Our node-weighted Steiner tree approach is shown to be both fast and effective to identify important elements of cancer-related signaling pathways. Furthermore, it may provide new perspectives into the identification of signaling pathways for other human diseases.

  1. Differential gene expressions of the MAPK signaling pathway in enterovirus 71-infected rhabdomyosarcoma cells

    Directory of Open Access Journals (Sweden)

    Weifeng Shi

    Full Text Available BACKGROUND: Mitogen-activated protein kinase (MAPK signaling pathway plays an important role in response to viral infection. The aim of this study was to explore the function and mechanism of MAPK signaling pathway in enterovirus 71 (EV71 infection of human rhabdomyosarcoma (RD cells. METHODS: Apoptosis of RD cells was observed using annexin V-FITC/PI binding assay under a fluorescence microscope. Cellular RNA was extracted and transcribed to cDNA. The expressions of 56 genes of MAPK signaling pathway in EV71-infected RD cells at 8 h and 20 h after infection were analyzed by PCR array. The levels of IL-2, IL-4, IL-10, and TNF-α in the supernatant of RD cells infected with EV71 at different time points were measured by ELISA. RESULTS: The viability of RD cells decreased obviously within 48 h after EV71 infection. Compared with the control group, EV71 infection resulted in the significantly enhanced releases of IL-2, IL-4, IL-10 and TNF-α from infected RD cells (p < 0.05. At 8 h after infection, the expressions of c-Jun, c-Fos, IFN-i, MEKK1, MLK3 and NIK genes in EV71-infected RD cells were up-regulated by 2.08-6.12-fold, whereas other 19 genes (e.g. AKT1, AKT2, E2F1, IKK and NF-κB1 exhibited down-regulation. However, at 20 h after infection, those MAPK signaling molecules including MEKK1, ASK1, MLK2, MLK3, NIK, MEK1, MEK2, MEK4, MEK7, ERK1, JNK1 and JNK2 were up-regulated. In addition, the expressions of AKT2, ELK1, c-Jun, c-Fos, NF-κB p65, PI3K and STAT1 were also increased. CONCLUSION: EV71 infection induces the differential gene expressions of MAPK signaling pathway such as ERK, JNK and PI3K/AKT in RD cells, which may be associated with the secretions of inflammatory cytokines and host cell apoptosis.

  2. Kaempferol induces hepatocellular carcinoma cell death via endoplasmic reticulum stress-CHOP-autophagy signaling pathway.

    Science.gov (United States)

    Guo, Haiqing; Lin, Wei; Zhang, Xiangying; Zhang, Xiaohui; Hu, Zhongjie; Li, Liying; Duan, Zhongping; Zhang, Jing; Ren, Feng

    2017-10-10

    Kaempferol is a flavonoid compound that has gained widespread attention due to its antitumor functions. However, the underlying mechanisms are still not clear. The present study investigated the effect of kaempferol on hepatocellular carcinoma and its underlying mechanisms. Kaempferol induced autophagy in a concentration- and time-dependent manner in HepG2 or Huh7 cells, which was evidenced by the significant increase of autophagy-related genes. Inhibition of autophagy pathway, through 3-methyladenine or Atg7 siRNA, strongly diminished kaempferol-induced apoptosis. We further hypothesized that kaempferol can induce autophagy via endoplasmic reticulum (ER) stress pathway. Indeed, blocking ER stress by 4-phenyl butyric acid (4-PBA) or knockdown of CCAAT/enhancer-binding protein homologous protein (CHOP) with siRNA alleviated kaempferol-induced HepG2 or Huh7 cells autophagy; while transfection with plasmid overexpressing CHOP reversed the effect of 4-PBA on kaempferol-induced autophagy. Our results demonstrated that kaempferol induced hepatocarcinoma cell death via ER stress and CHOP-autophagy signaling pathway; kaempferol may be used as a potential chemopreventive agent for patients with hepatocellular carcinoma.

  3. Targeting tissue-specific metabolic signaling pathways in aging: the promise and limitations.

    Science.gov (United States)

    Hu, Fang; Liu, Feng

    2014-01-01

    It has been well established that most of the age-related diseases such as insulin resistance, type 2 diabetes, hypertension, cardiovascular disease, osteoporosis, and atherosclerosis are all closely related to metabolic dysfunction. On the other hand, interventions on metabolism such as calorie restriction or genetic manipulations of key metabolic signaling pathways such as the insulin and mTOR signaling pathways slow down the aging process and improve healthy aging. These findings raise an important question as to whether improving energy homeostasis by targeting certain metabolic signaling pathways in specific tissues could be an effective anti-aging strategy. With a more comprehensive understanding of the tissue-specific roles of distinct metabolic signaling pathways controlling energy homeostasis and the cross-talks between these pathways during aging may lead to the development of more effective therapeutic interventions not only for metabolic dysfunction but also for aging.

  4. Comparison of growth factor signalling pathway utilisation in cultured normal melanocytes and melanoma cell lines

    International Nuclear Information System (INIS)

    Kim, Ji Eun; Stones, Clare; Joseph, Wayne R; Leung, Euphemia; Finlay, Graeme J; Shelling, Andrew N; Phillips, Wayne A; Shepherd, Peter R; Baguley, Bruce C

    2012-01-01

    The phosphatidylinositol-3-kinase (PI3K-PKB), mitogen activated protein kinase (MEK-ERK) and the mammalian target of rapamycin (mTOR- p70S6K), are thought to regulate many aspects of tumour cell proliferation and survival. We have examined the utilisation of these three signalling pathways in a number of cell lines derived from patients with metastatic malignant melanoma of known PIK3CA, PTEN, NRAS and BRAF mutational status. Western blotting was used to compare the phosphorylation status of components of the PI3K-PKB, MEK-ERK and mTOR-p70S6K signalling pathways, as indices of pathway utilisation. Normal melanocytes could not be distinguished from melanoma cells on the basis of pathway utilisation when grown in the presence of serum, but could be distinguished upon serum starvation, where signalling protein phosphorylation was generally abrogated. Surprisingly, the differential utilisation of individual pathways was not consistently associated with the presence of an oncogenic or tumour suppressor mutation of genes in these pathways. Utilisation of the PI3K-PKB, MEK-ERK and mTOR-p70S6K signalling pathways in melanoma, as determined by phosphorylation of signalling components, varies widely across a series of cell lines, and does not directly reflect mutation of genes coding these components. The main difference between cultured normal melanocytes and melanoma cells is not the pathway utilisation itself, but rather in the serum dependence of pathway utilisation

  5. Comprehensive logic based analyses of Toll-like receptor 4 signal transduction pathway.

    Directory of Open Access Journals (Sweden)

    Mahesh Kumar Padwal

    Full Text Available Among the 13 TLRs in the vertebrate systems, only TLR4 utilizes both Myeloid differentiation factor 88 (MyD88 and Toll/Interleukin-1 receptor (TIR-domain-containing adapter interferon-β-inducing Factor (TRIF adaptors to transduce signals triggering host-protective immune responses. Earlier studies on the pathway combined various experimental data in the form of one comprehensive map of TLR signaling. But in the absence of adequate kinetic parameters quantitative mathematical models that reveal emerging systems level properties and dynamic inter-regulation among the kinases/phosphatases of the TLR4 network are not yet available. So, here we used reaction stoichiometry-based and parameter independent logical modeling formalism to build the TLR4 signaling network model that captured the feedback regulations, interdependencies between signaling kinases and phosphatases and the outcome of simulated infections. The analyses of the TLR4 signaling network revealed 360 feedback loops, 157 negative and 203 positive; of which, 334 loops had the phosphatase PP1 as an essential component. The network elements' interdependency (positive or negative dependencies in perturbation conditions such as the phosphatase knockout conditions revealed interdependencies between the dual-specific phosphatases MKP-1 and MKP-3 and the kinases in MAPK modules and the role of PP2A in the auto-regulation of Calmodulin kinase-II. Our simulations under the specific kinase or phosphatase gene-deficiency or inhibition conditions corroborated with several previously reported experimental data. The simulations to mimic Yersinia pestis and E. coli infections identified the key perturbation in the network and potential drug targets. Thus, our analyses of TLR4 signaling highlights the role of phosphatases as key regulatory factors in determining the global interdependencies among the network elements; uncovers novel signaling connections; identifies potential drug targets for

  6. Comprehensive dissection of PDGF-PDGFR signaling pathways in PDGFR genetically defined cells.

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    Erxi Wu

    Full Text Available Despite the growing understanding of pdgf signaling, studies of pdgf function have encountered two major obstacles: the functional redundancy of PDGFRalpha and PDGFRbeta in vitro and their distinct roles in vivo. Here we used wild-type mouse embryonic fibroblasts (MEF, MEF null for either PDGFRalpha, beta, or both to dissect PDGF-PDGFR signaling pathways. These four PDGFR genetically defined cells provided us a platform to study the relative contributions of the pathways triggered by the two PDGF receptors. They were treated with PDGF-BB and analyzed for differential gene expression, in vitro proliferation and differential response to pharmacological effects. No genes were differentially expressed in the double null cells, suggesting minimal receptor-independent signaling. Protean differentiation and proliferation pathways are commonly regulated by PDGFRalpha, PDGFRbeta and PDGFRalpha/beta while each receptor is also responsible for regulating unique signaling pathways. Furthermore, some signaling is solely modulated through heterodimeric PDGFRalpha/beta.

  7. Optimal structural inference of signaling pathways from unordered and overlapping gene sets.

    Science.gov (United States)

    Acharya, Lipi R; Judeh, Thair; Wang, Guangdi; Zhu, Dongxiao

    2012-02-15

    A plethora of bioinformatics analysis has led to the discovery of numerous gene sets, which can be interpreted as discrete measurements emitted from latent signaling pathways. Their potential to infer signaling pathway structures, however, has not been sufficiently exploited. Existing methods accommodating discrete data do not explicitly consider signal cascading mechanisms that characterize a signaling pathway. Novel computational methods are thus needed to fully utilize gene sets and broaden the scope from focusing only on pairwise interactions to the more general cascading events in the inference of signaling pathway structures. We propose a gene set based simulated annealing (SA) algorithm for the reconstruction of signaling pathway structures. A signaling pathway structure is a directed graph containing up to a few hundred nodes and many overlapping signal cascades, where each cascade represents a chain of molecular interactions from the cell surface to the nucleus. Gene sets in our context refer to discrete sets of genes participating in signal cascades, the basic building blocks of a signaling pathway, with no prior information about gene orderings in the cascades. From a compendium of gene sets related to a pathway, SA aims to search for signal cascades that characterize the optimal signaling pathway structure. In the search process, the extent of overlap among signal cascades is used to measure the optimality of a structure. Throughout, we treat gene sets as random samples from a first-order Markov chain model. We evaluated the performance of SA in three case studies. In the first study conducted on 83 KEGG pathways, SA demonstrated a significantly better performance than Bayesian network methods. Since both SA and Bayesian network methods accommodate discrete data, use a 'search and score' network learning strategy and output a directed network, they can be compared in terms of performance and computational time. In the second study, we compared SA and

  8. Kaempferol Attenuates Cardiac Hypertrophy via Regulation of ASK1/MAPK Signaling Pathway and Oxidative Stress.

    Science.gov (United States)

    Feng, Hong; Cao, Jianlei; Zhang, Guangyu; Wang, Yanggan

    2017-07-01

    Kaempferol has been demonstrated to provide benefits for the treatment of atherosclerosis, coronary heart disease, hyperlipidemia, and diabetes through its antioxidant and anti-inflammatory properties. However, its role in cardiac hypertrophy remains to be elucidated. The aim of our study was to investigate the effects of kaempferol on cardiac hypertrophy and the underlying mechanism. Mice subjected to aorta banding were treated with or without kaempferol (100 mg/kg/d, p. o.) for 6 weeks. Echocardiography was performed to evaluate cardiac function. Mice hearts were collected for pathological observation and molecular mechanism investigation. H9c2 cardiomyocytes were stimulated with or without phenylephrine for in vitro study. Kaempferol significantly attenuated cardiac hypertrophy induced by aorta banding as evidenced by decreased cardiomyocyte areas and interstitial fibrosis, accompanied with improved cardiac functions and decreased apoptosis. The ASK1/MAPK signaling pathways (JNK1/2 and p38) were markedly activated in the aorta banding mouse heart but inhibited by kaempferol treatment. In in vitro experiments, kaempferol also inhibited the activity of ASK1/JNK1/2/p38 signaling pathway and the enlargement of H9c2 cardiomyocytes. Furthermore, our study revealed that kaempferol could protect the mouse heart and H9c2 cells from pathological oxidative stress. Our investigation indicated that treatment with kaempferol protects against cardiac hypertrophy, and its cardioprotection may be partially explained by the inhibition of the ASK1/MAPK signaling pathway and the regulation of oxidative stress. Georg Thieme Verlag KG Stuttgart · New York.

  9. DMPD: Calcium signaling in lymphocytes. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18515054 Calcium signaling in lymphocytes. Oh-hora M, Rao A. Curr Opin Immunol. 200...8 Jun;20(3):250-8. (.png) (.svg) (.html) (.csml) Show Calcium signaling in lymphocytes. PubmedID 18515054 Title Calcium sign

  10. Agrin as a Mechanotransduction Signal Regulating YAP through the Hippo Pathway

    Directory of Open Access Journals (Sweden)

    Sayan Chakraborty

    2017-03-01

    Full Text Available The Hippo pathway effectors YAP and TAZ act as nuclear sensors of mechanical signals in response to extracellular matrix (ECM cues. However, the identity and nature of regulators in the ECM and the precise pathways relaying mechanoresponsive signals into intracellular sensors remain unclear. Here, we uncover a functional link between the ECM proteoglycan Agrin and the transcriptional co-activator YAP. Importantly, Agrin transduces matrix and cellular rigidity signals that enhance stability and mechanoactivity of YAP through the integrin-focal adhesion- and Lrp4/MuSK receptor-mediated signaling pathways. Agrin antagonizes focal adhesion assembly of the core Hippo components by facilitating ILK-PAK1 signaling and negating the functions of Merlin and LATS1/2. We further show that Agrin promotes oncogenesis through YAP-dependent transcription and is clinically relevant in human liver cancer. We propose that Agrin acts as a mechanotransduction signal in the ECM.

  11. Role of CSL-dependent and independent Notch signaling pathways in cell apoptosis.

    Science.gov (United States)

    Zeng, Chong; Xing, Rui; Liu, Jing; Xing, Feiyue

    2016-01-01

    Apoptosis is a normally biological phenomenon in various organisms, involving complexly molecular mechanisms with a series of signaling processes. Notch signaling is found evolutionarily conserved in many species, playing a critical role in embryonic development, normal tissue homeostasis, angiogenesis and immunoregulation. The focus of this review is on currently novel advances about roles of CSL-dependent and independent Notch signaling pathways in cell apoptosis. The CSL can bind Notch intracellular domain (NIC) to act as a switch in mediating transcriptional activation or inactivation of the Notch signaling pathway downstream genes in the nucleus. It shows that CSL-dependent signaling regulates the cell apoptosis through Hes-1-PTEN-AKT-mTOR signaling, but rather the CSL-independent signaling mediates the cell apoptosis possibly via NIC-mTORC2-AKT-mTOR signaling, providing a new insight into apoptotic mechanisms.

  12. Antagonism between phytohormone signalling underlies the variation in disease susceptibility of tomato plants under elevated CO2.

    Science.gov (United States)

    Zhang, Shuai; Li, Xin; Sun, Zenghui; Shao, Shujun; Hu, Lingfei; Ye, Meng; Zhou, Yanhong; Xia, Xiaojian; Yu, Jingquan; Shi, Kai

    2015-04-01

    Increasing CO2 concentrations ([CO2]) have the potential to disrupt plant-pathogen interactions in natural and agricultural ecosystems, but the research in this area has often produced conflicting results. Variations in phytohormone salicylic acid (SA) and jasmonic acid (JA) signalling could be associated with variations in the responses of pathogens to plants grown under elevated [CO2]. In this study, interactions between tomato plants and three pathogens with different infection strategies were compared. Elevated [CO2] generally favoured SA biosynthesis and signalling but repressed the JA pathway. The exposure of plants to elevated [CO2] revealed a lower incidence and severity of disease caused by tobacco mosaic virus (TMV) and by Pseudomonas syringae, whereas plant susceptibility to necrotrophic Botrytis cinerea increased. The elevated [CO2]-induced and basal resistance to TMV and P. syringae were completely abolished in plants in which the SA signalling pathway nonexpressor of pathogenesis-related genes 1 (NPR1) had been silenced or in transgenic plants defective in SA biosynthesis. In contrast, under both ambient and elevated [CO2], the susceptibility to B. cinerea highly increased in plants in which the JA signalling pathway proteinase inhibitors (PI) gene had been silenced or in a mutant affected in JA biosynthesis. However, plants affected in SA signalling remained less susceptible to this disease. These findings highlight the modulated antagonistic relationship between SA and JA that contributes to the variation in disease susceptibility under elevated [CO2]. This information will be critical for investigating how elevated CO2 may affect plant defence and the dynamics between plants and pathogens in both agricultural and natural ecosystems. © The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology.

  13. Antagonism between phytohormone signalling underlies the variation in disease susceptibility of tomato plants under elevated CO2

    Science.gov (United States)

    Zhang, Shuai; Li, Xin; Sun, Zenghui; Shao, Shujun; Hu, Lingfei; Ye, Meng; Zhou, Yanhong; Xia, Xiaojian; Yu, Jingquan; Shi, Kai

    2015-01-01

    Increasing CO2 concentrations ([CO2]) have the potential to disrupt plant–pathogen interactions in natural and agricultural ecosystems, but the research in this area has often produced conflicting results. Variations in phytohormone salicylic acid (SA) and jasmonic acid (JA) signalling could be associated with variations in the responses of pathogens to plants grown under elevated [CO2]. In this study, interactions between tomato plants and three pathogens with different infection strategies were compared. Elevated [CO2] generally favoured SA biosynthesis and signalling but repressed the JA pathway. The exposure of plants to elevated [CO2] revealed a lower incidence and severity of disease caused by tobacco mosaic virus (TMV) and by Pseudomonas syringae, whereas plant susceptibility to necrotrophic Botrytis cinerea increased. The elevated [CO2]-induced and basal resistance to TMV and P. syringae were completely abolished in plants in which the SA signalling pathway nonexpressor of pathogenesis-related genes 1 (NPR1) had been silenced or in transgenic plants defective in SA biosynthesis. In contrast, under both ambient and elevated [CO2], the susceptibility to B. cinerea highly increased in plants in which the JA signalling pathway proteinase inhibitors (PI) gene had been silenced or in a mutant affected in JA biosynthesis. However, plants affected in SA signalling remained less susceptible to this disease. These findings highlight the modulated antagonistic relationship between SA and JA that contributes to the variation in disease susceptibility under elevated [CO2]. This information will be critical for investigating how elevated CO2 may affect plant defence and the dynamics between plants and pathogens in both agricultural and natural ecosystems. PMID:25657213

  14. Maternal Chromium Restriction Leads to Glucose Metabolism Imbalance in Mice Offspring through Insulin Signaling and Wnt Signaling Pathways

    Science.gov (United States)

    Zhang, Qian; Sun, Xiaofang; Xiao, Xinhua; Zheng, Jia; Li, Ming; Yu, Miao; Ping, Fan; Wang, Zhixin; Qi, Cuijuan; Wang, Tong; Wang, Xiaojing

    2016-01-01

    An adverse intrauterine environment, induced by a chromium-restricted diet, is a potential cause of metabolic disease in adult life. Up to now, the relative mechanism has not been clear. C57BL female mice were time-mated and fed either a control diet (CD), or a chromium-restricted diet (CR) throughout pregnancy and the lactation period. After weaning, some offspring continued the diet diagram (CD-CD or CR-CR), while other offspring were transferred to another diet diagram (CD-CR or CR-CD). At 32 weeks of age, glucose metabolism parameters were measured, and the liver from CR-CD group and CD-CD group was analyzed using a gene array. Quantitative real-time polymerase chain reaction (qPCR) and Western blot were used to verify the result of the gene array. A maternal chromium-restricted diet resulted in obesity, hyperglycemia, hyperinsulinemia, increased area under the curve (AUC) of glucose in oral glucose tolerance testing and homeostasis model assessment of insulin resistance (HOMA-IR). There were 463 genes that differed significantly (>1.5-fold change, p chromium deficiency influences glucose metabolism in pups through the regulation of insulin signaling and Wnt signaling pathways. PMID:27782077

  15. Making memories of stressful events: a journey along epigenetic, gene transcription and signaling pathways

    Directory of Open Access Journals (Sweden)

    Johannes M.H.M. eReul

    2014-01-01

    Full Text Available Strong psychologically stressful events are known to have a long-lasting impact on behavior. The consolidation of such, largely adaptive, behavioral responses to stressful events involves changes in gene expression in limbic brain regions such as the hippocampus and amygdala. The underlying molecular mechanisms however were until recently unresolved. More than a decade ago we started to investigate the role of these hormones in signaling and epigenetic mechanisms participating in the effects of stress on gene transcription in hippocampal neurons. We discovered a novel, rapid non-genomic mechanism in which glucocorticoids via glucocorticoid receptors (GRs facilitate signaling of the ERK MAPK signaling pathway to the downstream nuclear kinases MSK1 and Elk-1 in dentate gyrus (DG granule neurons. Activation of this signaling pathway results in serine10 (S10 phosphorylation and lysine14 (K14 acetylation at histone H3 (H3S10p-K14ac, leading to the induction of the immediate early genes c-Fos and Egr-1. In addition, we found a role of the DNA methylation status of gene promoters. A series of studies showed that these molecular mechanisms play a critical role in the long-lasting consolidation of behavioral responses in the forced swim test and Morris water maze. Furthermore, an important role of GABA was found in controlling the epigenetic and gene transcriptional responses to psychological stress. Thus, psychologically stressful events evoke a long-term impact on behavior through changes in hippocampal function brought about by distinct glutamatergic and glucocorticoid-driven changes in epigenetic regulation of gene transcription which are modulated by (local GABAergic interneurons and limbic afferent inputs. These epigenetic processes may play an important role in the etiology of stress-related mental disorders such as major depressive and anxiety disorders like PTSD.

  16. Expression patterns of genes critical for BMP signaling pathway in developing human primary tooth germs.

    Science.gov (United States)

    Dong, Xiuqing; Shen, Bin; Ruan, Ningsheng; Guan, Zhen; Zhang, Yanding; Chen, YiPing; Hu, Xuefeng

    2014-12-01

    The developing murine tooth has been used as an excellent model system to study the molecular mechanism of organ development and regeneration. While the expression patterns of numerous regulatory genes have been examined and their roles have begun to be revealed in the developing murine tooth, little is known about gene expression and function in human tooth development. In order to unveil the molecular mechanisms that regulate human tooth morphogenesis, we examined the expression patterns of the major BMP signaling pathway molecules in the developing human tooth germ at the cap and bell stages by in situ hybridization, immunohistochemistry, and real-time RT-PCR. Expression of BMP ligands and antagonist, including BMP2, BMP3, BMP4, BMP7, and NOOGGIN, exhibited uniform patterns in the tooth germs of incisor and molar at the cap and bell stages with stronger expression in the inner dental epithelium than that in the dental mesenchyme. Both type I and type II BMP receptors were present in widespread expression pattern in the whole-enamel organ and the dental mesenchyme with the strongest expression in inner dental epithelium at the cap and bell stages. SMAD4 and SMAD1/5/8 showed an expression pattern similar to that of BMP ligands with more intensive signals in the inner dental epithelium. Despite some unique and distinct patterns as compared to the mouse, the intensive expression of BMP signaling pathway molecules in the developing human tooth strongly suggests conserved functions of BMP signaling during human odontogenesis, such as in mediating tissue interactions and regulating differentiation and organization of odontogenic tissues. Our results provide an important set of documents for studying molecular regulatory mechanisms underlying tooth development and regeneration in humans.

  17. A computational approach for ordering signal transduction pathway components from genomics and proteomics Data

    Directory of Open Access Journals (Sweden)

    Zhao Hongyu

    2004-10-01

    Full Text Available Abstract Background Signal transduction is one of the most important biological processes by which cells convert an external signal into a response. Novel computational approaches to mapping proteins onto signaling pathways are needed to fully take advantage of the rapid accumulation of genomic and proteomics information. However, despite their importance, research on signaling pathways reconstruction utilizing large-scale genomics and proteomics information has been limited. Results We have developed an approach for predicting the order of signaling pathway components, assuming all the components on the pathways are known. Our method is built on a score function that integrates protein-protein interaction data and microarray gene expression data. Compared to the individual datasets, either protein interactions or gene transcript abundance measurements, the integrated approach leads to better identification of the order of the pathway components. Conclusions As demonstrated in our study on the yeast MAPK signaling pathways, the integration analysis of high-throughput genomics and proteomics data can be a powerful means to infer the order of pathway components, enabling the transformation from molecular data into knowledge of cellular mechanisms.

  18. Sex and hedgehog: roles of genes in the hedgehog signaling pathway in mammalian sexual differentiation.

    Science.gov (United States)

    Franco, Heather L; Yao, Humphrey H-C

    2012-01-01

    The chromosome status of the mammalian embryo initiates a multistage process of sexual development in which the bipotential reproductive system establishes itself as either male or female. These events are governed by intricate cell-cell and interorgan communication that is regulated by multiple signaling pathways. The hedgehog signaling pathway was originally identified for its key role in the development of Drosophila, but is now recognized as a critical developmental regulator in many species, including humans. In addition to its developmental roles, the hedgehog signaling pathway also modulates adult organ function, and misregulation of this pathway often leads to diseases, such as cancer. The hedgehog signaling pathway acts through its morphogenetic ligands that signal from ligand-producing cells to target cells over a specified distance. The target cells then respond in a graded manner based on the concentration of the ligands that they are exposed to. Through this unique mechanism of action, the hedgehog signaling pathway elicits cell fate determination, epithelial-mesenchymal interactions, and cellular homeostasis. Here, we review current findings on the roles of hedgehog signaling in the sexually dimorphic development of the reproductive organs with an emphasis on mammals and comparative evidence in other species.

  19. Signaling pathways regulating neuron-glia interaction and their implications in Alzheimer's disease.

    Science.gov (United States)

    Lian, Hong; Zheng, Hui

    2016-02-01

    Astrocytes are the most abundant cells in the central nervous system. They play critical roles in neuronal homeostasis through their physical properties and neuron-glia signaling pathways. Astrocytes become reactive in response to neuronal injury and this process, referred to as reactive astrogliosis, is a common feature accompanying neurodegenerative conditions, particularly Alzheimer's disease. Reactive astrogliosis represents a continuum of pathobiological processes and is associated with morphological, functional, and gene expression changes of varying degrees. There has been a substantial growth of knowledge regarding the signaling pathways regulating glial biology and pathophysiology in recent years. Here, we attempt to provide an unbiased review of some of the well-known players, namely calcium, proteoglycan, transforming growth factor β, NFκB, and complement, in mediating neuron-glia interaction under physiological conditions as well as in Alzheimer's disease. This review discusses the role of astrocytic NFκB and calcium as well as astroglial secreted factors, including proteoglycans, TGFβ, and complement in mediating neuronal function and AD pathogenesis through direct interaction with neurons and through cooperation with microglia. © 2015 International Society for Neurochemistry.

  20. Survival of corticostriatal neurons by Rho/Rho-kinase signaling pathway.

    Science.gov (United States)

    Kobayashi, Kenta; Sano, Hiromi; Kato, Shigeki; Kuroda, Keisuke; Nakamuta, Shinichi; Isa, Tadashi; Nambu, Atsushi; Kaibuchi, Kozo; Kobayashi, Kazuto

    2016-09-06

    Developing cortical neurons undergo a number of sequential developmental events including neuronal survival/apoptosis, and the molecular mechanism underlying each characteristic process has been studied in detail. However, the survival pathway of cortical neurons at mature stages remains largely uninvestigated. We herein focused on mature corticostriatal neurons because of their important roles in various higher brain functions and the spectrum of neurological and neuropsychiatric disorders. The small GTPase Rho is known to control diverse and essential cellular functions through some effector molecules, including Rho-kinase, during neural development. In the present study, we investigated the role of Rho signaling through Rho-kinase in the survival of corticostriatal neurons. We performed the conditional expression of Clostridium botulinum C3 ADP-ribosyltransferase (C3 transferase) or dominant-negative form for Rho-kinase (Rho-K DN), a well-known inhibitor of Rho or Rho-kinase, respectively, in corticostriatal neurons using a dual viral vector approach combining a neuron-specific retrograde gene transfer lentiviral vector and an adeno-associated virus vector. C3 transferase markedly decreased the number of corticostriatal neurons, which was attributed to caspase-3-dependent enhanced apoptosis. In addition, Rho-K DN produced phenotypic defects similar to those caused by C3 transferase. These results indicate that the Rho/Rho-kinase signaling pathway plays a crucial role in the survival of corticostriatal neurons. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  1. Weight control and cancer preventive mechanisms: role of insulin growth factor-1-mediated signaling pathways.

    Science.gov (United States)

    Xie, Linglin; Wang, Weiqun

    2013-02-01

    Overweight and obese not only increase the risk of cardiovascular disease and type-2 diabetes mellitus, but are also now known risk factors for a variety of cancers. Weight control, via dietary calorie restriction and/or exercise, has been demonstrated to be beneficial for cancer prevention in various experimental models, but the underlying mechanisms are still not well defined. Recent studies conducted in a mouse skin carcinogenesis model show that weight loss induced a significant reduction of the circulating levels of insulin growth factor (IGF)-1 and other hormones, including insulin and leptin, resulting in reduced IGF-1-dependent signaling pathways, i.e. Ras-MAPK proliferation and protein kinase B-phosphoinositide 3-kinase (Akt-PI3K) antiapoptosis. Selective targeting IGF-1 to Akt/mammalian target of rapamycin and AMP-activated protein kinase pathways, via negative energy balance, might inactivate cell cycle progression and ultimately suppress tumor development. This review highlights the current studies focused on the major role of reducing IGF-1-activated signaling via weight control as a potential cancer preventive mechanism.

  2. Role of Nodal-PITX2C signaling pathway in glucose-induced cardiomyocyte hypertrophy.

    Science.gov (United States)

    Su, Dongmei; Jing, Sun; Guan, Lina; Li, Qian; Zhang, Huiling; Gao, Xiaobo; Ma, Xu

    2014-06-01

    Pathological cardiac hypertrophy is a major cause of morbidity and mortality in cardiovascular disease. Recent studies have shown that cardiomyocytes, in response to high glucose (HG) stimuli, undergo hypertrophic growth. While much work still needs to be done to elucidate this important mechanism of hypertrophy, previous works have showed that some pathways or genes play important roles in hypertrophy. In this study, we showed that sublethal concentrations of glucose (25 mmol/L) could induce cardiomyocyte hypertrophy with an increase in the cellular surface area and the upregulation of the atrial natriuretic peptide (ANP) gene, a hypertrophic marker. High glucose (HG) treatments resulted in the upregulation of the Nodal gene, which is under-expressed in cardiomyocytes. We also determined that the knockdown of the Nodal gene resisted HG-induced cardiomyocyte hypertrophy. The overexpression of Nodal was able to induce hypertrophy in cardiomyocytes, which was associated with the upregulation of the PITX2C gene. We also showed that increases in the PITX2C expression, in response to Nodal, were mediated by the Smad4 signaling pathway. This study is highly relevant to the understanding of the effects of the Nodal-PITX2C pathway on HG-induced cardiomyocyte hypertrophy, as well as the related molecular mechanisms.

  3. The ABA-INSENSITIVE-4 (ABI4) transcription factor links redox, hormone and sugar signaling pathways.

    Science.gov (United States)

    Foyer, Christine H; Kerchev, Pavel I; Hancock, Robert D

    2012-02-01

    The cellular reduction-oxidation (redox) hub processes information from metabolism and the environment and so regulates plant growth and defense through integration with the hormone signaling network. One key pathway of redox control involves interactions with ABSCISIC ACID (ABA). Accumulating evidence suggests that the ABA-INSENSITIVE-4 (ABI4) transcription factor plays a key role in transmitting information concerning the abundance of ascorbate and hence the ability of cells to buffer oxidative challenges. ABI4 is required for the ascorbate-dependent control of growth, a process that involves enhancement of salicylic acid (SA) signaling and inhibition of jasmonic acid (JA) signaling pathways. Low redox buffering capacity reinforces SA- JA- interactions through the mediation of ABA and ABI4 to fine-tune plant growth and defense in relation to metabolic cues and environmental challenges. Moreover, ABI4-mediated pathways of sugar sensitivity are also responsive to the abundance of ascorbate, providing evidence of overlap between redox and sugar signaling pathways.

  4. MicroRNAs Regulating Signaling Pathways: Potential Biomarkers in Systemic Sclerosis

    Directory of Open Access Journals (Sweden)

    Yisha Li

    2015-08-01

    Full Text Available Systemic sclerosis (SSc is a multisystem fibrotic and autoimmune disease. Both genetic and epigenetic elements mediate SSc pathophysiology. This review summarizes the role of one epigenetic element, known as microRNAs (miRNAs, involved in different signaling pathways of SSc pathogenesis. The expression of key components in transforming growth factor-β (TGF-β signaling pathway has been found to be regulated by miRNAs both upstream and downstream of TGF-β. We are specifically interested in the pathway components upstream of TGF-β, while miRNAs in other signaling pathways have not been extensively studied. The emerging role of miRNAs in vasculopathy of SSc suggests a promising new direction for future investigation. Elucidation of the regulatory role of miRNAs in the expression of signaling factors may facilitate the discovery of novel biomarkers in SSc and improve the understanding and treatment of this disease.

  5. Multiple intracellular signaling pathways orchestrate adipocytic differentiation of human bone marrow stromal stem cells

    DEFF Research Database (Denmark)

    Ayesh Hafez Ali, Dalia; Abuelreich, Sarah; Alkeraishan, Nora

    2018-01-01

    Bone marrow adipocyte formation plays a role in bone homeostasis and whole body energy metabolism. However, the transcriptional landscape and signaling pathways associated with adipocyte lineage commitment and maturation are not fully delineated. Thus, we performed global gene expression profilin...

  6. Frequent alterations of SLIT2–ROBO1–CDC42 signalling pathway ...

    Indian Academy of Sciences (India)

    2016-09-07

    CDC42 signalling pathways in development of breast cancer (BC). Primary BC samples (n = 150), comprising of almost equal proportion of four subtypes were tested for molecu- lar alterations of SLIT2, ROBO1, ROBO2 and ...

  7. Regulation of phosphate transport and AMPK signal pathway by lower dietary phosphorus of broilers.

    Science.gov (United States)

    Miao, Zhiqiang; Feng, Yan; Zhang, Junzhen; Tian, Wenxia; Li, Jianhui; Yang, Yu

    2017-12-08

    Lower available P (aP) was used as a base value in nutritional strategies for mitigating P pollution by animal excreta. We hypothesized that the mechanism regulating phosphate transport under low dietary P might be related with the AMPK signal pathway. A total of 144 one-day-old Arbor Acres Plus broilers were randomly allocated to control (HP) or trial (LP) diets, containing 0.45 and 0.23% aP, respectively. Growth performance, blood, intestinal, and renal samples were tested in 21-day-old broilers. Results shown that LP decreased body weight gain and feed intake. Higher serum Ca and fructose, but lower serum P and insulin were detected in LP-fed broilers. NaPi-IIb mRNA expression in intestine and NaPi-IIa mRNA expression in kidney were higher in the LP group. AMP: ATP, p-AMPK: total AMPK, and p-ACC: total ACC ratios in the duodenal mucosa were decreased in the LP group, whereas the p-mTOR: total mTOR ratio increased. These findings suggested that the increase in phosphate transport owing to LP diet might be regulated either directly by higher mTOR activity or indirectly by the suppressive AMPK signal, with corresponding changes in blood insulin and fructose content. A novel viewpoint on the regulatory mechanism underlying phosphate transport under low dietary P conditions was revealed, which might provide theoretical guidelines for reducing P pollution by means of nutritional regulation.

  8. The Drosophila rolled locus encodes a MAP kinase required in the sevenless signal transduction pathway.

    OpenAIRE

    Biggs, W H; Zavitz, K H; Dickson, B; van der Straten, A; Brunner, D; Hafen, E; Zipursky, S L

    1994-01-01

    Mitogen-activated protein (MAP) kinases have been proposed to play a critical role in receptor tyrosine kinase (RTK)-mediated signal transduction pathways. Although genetic and biochemical studies of RTK pathways in Caenorhabditis elegans, Drosophila melanogaster and mammals have revealed remarkable similarities, a genetic requirement for MAP kinases in RTK signaling has not been established. During retinal development in Drosophila, the sevenless (Sev) RTK is required for development of the ...

  9. Molecular pathway profiling of T lymphocyte signal transduction pathways; Th1 and Th2 genomic fingerprints are defined by TCR and CD28-mediated signaling

    NARCIS (Netherlands)

    Smeets, Ruben L.; Fleuren, Wilco W. M.; He, Xuehui; Vink, Paul M.; Wijnands, Frank; Gorecka, Monika; Klop, Henri; Bauerschmidt, Sussane; Garritsen, Anja; Koenen, Hans J. P. M.; Joosten, Irma; Boots, Annemieke M. H.; Alkema, Wynand

    2012-01-01

    Background: T lymphocytes are orchestrators of adaptive immunity. Naive T cells may differentiate into Th1, Th2, Th17 or iTreg phenotypes, depending on environmental co-stimulatory signals. To identify genes and pathways involved in differentiation of Jurkat T cells towards Th1 and Th2 subtypes we

  10. Molecular pathway profiling of T lymphocyte signal transduction pathways; Th1 and Th2 genomic fingerprints are defined by TCR and CD28-mediated signaling.

    NARCIS (Netherlands)

    Smeets, R.L.; Fleuren, W.W.M.; He, X.; Vink, P.M.; Wijnands, F.; Gorecka, M.; Klop, H.; Bauerschmidt, S.; Garritsen, A.; Koenen, H.J.P.M.; Joosten, I.; Boots, A.M.H.; Alkema, W.

    2012-01-01

    BACKGROUND: T lymphocytes are orchestrators of adaptive immunity. Naive T cells may differentiate into Th1, Th2, Th17 or iTreg phenotypes, depending on environmental co-stimulatory signals. To identify genes and pathways involved in differentiation of Jurkat T cells towards Th1 and Th2 subtypes we

  11. Radiotracers For Lipid Signaling Pathways In Biological Systems

    Energy Technology Data Exchange (ETDEWEB)

    Gatley, S. J. [Northeastern Univ., Boston, MA (United States)

    2016-09-26

    enzymes such as fatty acid amide hydrolase, which may regulate endocannabinoid tone in animals. Early results were presented at the 2011 ICRS meeting, and at the 2012 Society for Neurosciences. Narachidonoylethanolamine is an endocannabinoid signaling messenger in animals and is known as “anandamide”. It is one of several families of signaling molecules derived from arachidonic acid, the principal omega-6 polyunsaturated fatty acids (PUFA’s) in animal species. Other derivatives of arachidonic acid include thromboxanes and prostaglandins. Full details of the studies with the ethanolamide isotopomers were a part of the PhD dissertation of Kun Hu (nee Qian), and were submitted for publication to Nuclear Medicine and Biology in August 2016. Syntheses of [14C]docosahexanoylethanolamine isotopomers and preliminary biological investigations Docosahexaenoic acid (DHA) is the omega-3 PUFA that can be regarded in some respects as the counterpart of arachidonic acid in the omega-6 series. While arachidonic acid is proinflammatory, DHA is anti-inflammatory, and foods high in DHA (or artificially enriched in DHA) are commonly regarded as promoting health. In contrast to the large literature on the Nethanolamide of arachidonic acid (i.e. the endocannabinoid anandamide) as of now (9/25/2016) there are only six papers on the corresponding ethanolamide of DHA, and when our studies under this grant began there were none. Beneficial actions of endogenously produced DHAethanolamine (“synaptamide”) have been indicated, and to help elucidate the possible roles of synaptamide, we have synthesized this molecule for the first time labeled with C-14 in either the ethanolamine moiety or the fatty acid moiety. Studies of the disposition of endogenously administered isotopomers of DHA-ethanolamine are in progress, to complement tissue culture experiments evaluation hypothesized protective effects of this DHA derivative.

  12. Multi-scale agent-based brain cancer modeling and prediction of TKI treatment response: Incorporating EGFR signaling pathway and angiogenesis

    OpenAIRE

    Sun Xiaoqiang; Zhang Le; Tan Hua; Bao Jiguang; Strouthos Costas; Zhou Xiaobo

    2012-01-01

    Abstract Background The epidermal growth factor receptor (EGFR) signaling pathway and angiogenesis in brain cancer act as an engine for tumor initiation, expansion and response to therapy. Since the existing literature does not have any models that investigate the impact of both angiogenesis and molecular signaling pathways on treatment, we propose a novel multi-scale, agent-based computational model that includes both angiogenesis and EGFR modules to study the response of brain cancer under ...

  13. Inferring the functional effect of gene expression changes in signaling pathways

    Science.gov (United States)

    Sebastián-León, Patricia; Carbonell, José; Salavert, Francisco; Sanchez, Rubén; Medina, Ignacio; Dopazo, Joaquín

    2013-01-01

    Signaling pathways constitute a valuable source of information that allows interpreting the way in which alterations in gene activities affect to particular cell functionalities. There are web tools available that allow viewing and editing pathways, as well as representing experimental data on them. However, few methods aimed to identify the signaling circuits, within a pathway, associated to the biological problem studied exist and none of them provide a convenient graphical web interface. We present PATHiWAYS, a web-based signaling pathway visualization system that infers changes in signaling that affect cell functionality from the measurements of gene expression values in typical expression microarray case–control experiments. A simple probabilistic model of the pathway is used to estimate the probabilities for signal transmission from any receptor to any final effector molecule (taking into account the pathway topology) using for this the individual probabilities of gene product presence/absence inferred from gene expression values. Significant changes in these probabilities allow linking different cell functionalities triggered by the pathway to the biological problem studied. PATHiWAYS is available at: http://pathiways.babelomics.org/. PMID:23748960

  14. A Transcriptome Analysis Suggests Apoptosis-Related Signaling Pathways in Hemocytes of Spodoptera litura After Parasitization by Microplitis bicoloratus

    Science.gov (United States)

    Zhang, Yan; Yu, Dongshuai; Yang, Minjun; Yang, Yang; Hu, Jiansheng; Luo, Kaijun

    2014-01-01

    Microplitis bicoloratus parasitism induction of apoptotic DNA fragmentation of host Spodoptera litura hemocytes has been reported. However, how M. bicoloratus parasitism regulates the host signaling pathways to induce DNA fragmentation during apoptosis remains unclear. To address this question, we performed a new RNAseq-based comparative analysis of the hemocytes transcriptomes of non-parasitized and parasitized S. litura. We were able to assemble a total of more than 11.63 Gbp sequence, to yield 20,571 unigenes. At least six main protein families encoded by M. bicoloratus bracovirus are expressed in the parasitized host hemocytes: Ankyrin-repeat, Ben domain, C-type lectin, Egf-like and Mucin-like, protein tyrosine phosphatase. The analysis indicated that during DNA fragmentation and cell death, 299 genes were up-regulated and 2,441 genes were down-regulated. Data on five signaling pathways related with cell death, the gap junctions, Ca2+, PI3K/Akt, NF-κB, ATM/p53 revealed that CypD, which is involved in forming a Permeability Transition Pore Complex (PTPC) to alter mitochondrial membrane permeabilization (MMP), was dramatically up-regulated. The qRT-PCR also provided that the key genes for cell survival were down-regulated under M. bicoloratus parasitism, including those encoding Inx1, Inx2 and Inx3 of the gap junction signaling pathway, p110 subunit of the PI3K/Akt signaling pathway, and the p50 and p65 subunit of the NF-κB signaling pathway. These findings suggest that M. bicoloratus parasitism may regulate host mitochondria to trigger internucleosomal DNA fragmentation. This study will facilitate the identification of immunosuppression-related genes and also improves our understanding of molecular mechanisms underlying polydnavirus-parasitoid-host interaction. PMID:25350281

  15. A SNARE-protein has opposing functions in penetration resistance and defence signalling pathways

    DEFF Research Database (Denmark)

    Zhang, Ziguo; Feechan, Angela; Pedersen, Carsten

    2007-01-01

    Penetration resistance is often the first line of defence against fungal pathogens. Subsequently induced defences are mediated by the programmed cell death (PCD) reaction pathway and the salicylic acid (SA), jasmonic acid (JA) and ethylene (ET) signalling pathways. We previously demonstrated...

  16. Dietary influence on MAPK-signaling pathways and risk of colon and rectal cancer.

    Science.gov (United States)

    Slattery, Martha L; Lundgreen, Abbie; Wolff, Roger K

    2013-01-01

    Mitogen-activated protein kinase (MAPK) pathways regulate cellular functions including cell proliferation, differentiation, migration, and apoptosis. Associations between genes in the DUSP, ERK1/2, JNK, and p38 MAPK-signaling pathways and dietary factors associated with growth factors, inflammation, and oxidative stress and risk of colon and rectal cancer were evaluated. Data include colon cases (n = 1555) and controls (n = 1956) and rectal cases (n = 754) and controls (n = 959). Statistically significant interactions were observed for the MAPK-signaling pathways after adjustment for multiple comparisons. DUSP genes interacted with carbohydrates, mutagen index, calories, calcium, vitamin D, lycopene, dietary fats, folic acid, and selenium. MAPK1, MAPK3, MAPK1, and RAF1 within the ERK1/2 MAPK-signaling pathway interacted with dietary fats and cruciferous vegetables. Within the JNK MAPK-signaling pathway, interactions between MAP3K7 and protein, vitamin C, iron, folic acid, carbohydrates, and cruciferous vegetables; MAP3K10 and folic acid; MAP3K9 and lutein/zeaxanthin; MAPK8 and calcium; MAP3K3 and calcium and lutein; MAP3K1 and cruciferous vegetables. Interaction within the p38-signaling pathway included MAPK14 with calories, carbohydrates saturated fat, selenium, vitamin C; MAP3K2 and carbohydrates, and folic acid. These data suggest that dietary factors involved in inflammation and oxidative stress interact with MAPK-signaling genes to alter risk of colorectal cancer.

  17. Characterization of the ABA signal transduction pathway in Vitis vinifera.

    Science.gov (United States)

    Boneh, Uri; Biton, Iris; Schwartz, Amnon; Ben-Ari, Giora

    2012-05-01

    The plant hormone abscisic acid (ABA) regulates many key processes in plants including the response to abiotic stress. ABA signal transduction consists of a double-negative regulatory mechanism, whereby ABA-bound PYR/RCARs inhibit PP2C activity, and PP2Cs inactivate SnRK2s. We studied and analyzed the various genes participating in the ABA signaling cascade of the grape (Vitis vinifera). The grape ABA signal transduction consists of at least six SnRK2s. Yeast two-hybrid system was used to test direct interactions between core components of grape ABA signal transduction. We found that a total of forty eight interactions can occur between the various components. Exogenous abscisic acid (ABA) and abiotic stresses such as drought, high salt concentration and cold, were applied to vines growing in a hydroponic system. These stresses regulated the expression of various grape SnRK2s as well as ABFs in leaves and roots. Based on the interactions between SnRK2s and its targets and the expression pattern, we suggest that VvSnRK2.1 and VvSnRK2.6, can be considered the major VvSnRK2 candidates involved in the stomata response to abiotic stress. Furthermore, we found that the expression pattern of the two grape ABF genes indicates organ specificity of these genes. The key role of ABA signaling in response to abiotic stresses makes the genes involve in this signaling potential candidates for manipulation in programs designed to improve fruit tree performance in extreme environments. © 2012 Elsevier Ireland Ltd. All rights reserved.

  18. Micropterus salmoides rhabdovirus (MSRV) infection induced apoptosis and activated interferon signaling pathway in largemouth bass skin cells.

    Science.gov (United States)

    Gao, E-Bin; Chen, Guifang

    2018-03-03

    Largemouth bass (Micropterus salmoides) rhabdovirus (MSRV) was isolated from infected juveniles of largemouth bass, and the infected fish exhibited corkscrew, irregular swimming, and crooked body. To our knowledge, the potential molecular mechanisms underlying the pathogenesis of MSRV infection remain largely unknown. In the current study, we found that MSRV infection in largemouth bass skin (LBS) cells induced typical apoptosis, evidenced by the presence of apoptotic bodies and caspase-3 activation. To further analyze the host factors involved in MSRV infection in LBS cells, the transcriptomic profiles during MSRV infection were uncovered using deep RNA sequencing technique, and several differentially expressed genes (DEGs) were validated by quantitative PCR. Our results showed that a total of 124483 unigenes were assembled. Among them, 34465 and 27273 had significant hits to those in the NR and SwissProt databases. After MSRV infection, a total of 2432 and 2480 genes which involved in multiples pathways including TNF signaling, NF-κB signaling, Toll-like receptor signaling and RIG-I signaling pathway were differentially expressed in MSRV infected LBS cells compared to mock-infected cells at 12 h, respectively. Furthermore, quantitative PCR showed that the expression levels of 9 differentially expressed genes (DEGs) related to apoptosis and interferon signaling pathway was consistent with that from transcriptomic profiles. Together, our results not only demonstrated that interferon signaling pathway and apoptosis pathway might exerted crucial roles during MSRV infection, but also provided a useful resource for subsequent investigation of other immune-related genes related to virus infection. Copyright © 2018. Published by Elsevier Ltd.

  19. Hypertrophy signaling pathways in experimental chronic aortic regurgitation

    DEFF Research Database (Denmark)

    Olsen, Niels Thue; Dimaano, Veronica L; Fritz-Hansen, Thomas

    2013-01-01

    The development of left ventricular hypertrophy and dysfunction in aortic regurgitation (AR) has only been sparsely studied experimentally. In a new model of chronic AR in rats, we examined activation of molecular pathways involved in myocardial hypertrophy. Chronic AR was produced by damaging one...... at both 2 and 12 weeks, while activation of calcium/calmodulin-dependent protein kinase II and extracellular regulated kinase 1/2 was unchanged. Expression of calcineurin and ANF was also unchanged. Eccentric hypertrophy and early cardiac dysfunction in experimental AR are associated with a pattern...... of activation of intracellular pathways different from that seen with pathological hypertrophy in pressure overload, and more similar to that associated with benign physiological hypertrophy....

  20. Signaling Pathways in Pathogenesis of Diamond Blackfan Anemia

    Science.gov (United States)

    2014-10-01

    hours in culture. Cells were sorted for green fluorescent protein (GFP) after 3 to 5 days and harvested for downstream assays as indicated in the...hours after transduction, and culture media was harvested 5 days after transduction. TNF-a was detected with a human TNF-a high sensitivity enzyme...cells involving p38 MAPK pathway, GATA-1 and FOG -1 downregulation and GATA-2 upregulation. Biochem Pharmacol. 2008;76(10):1229-1239. 19. Vassilev LT

  1. [The function of transcription factor P63 and its signaling pathway during limb development].

    Science.gov (United States)

    Ma, Wei; Tian, Wen

    2014-08-01

    The development of human limb is controlled by several transcription factors and signaling pathways, which are organized in precise time- and space-restricted manners. Recent studies showed that P63 and its signaling pathway play important roles in this process. Transcription factor P63, one member of the P53 family, is characterized by a similar amino acid domain, plays a crucial role in the development of limb and ectoderm differentiation, especially with its DNA binding domain, and sterile alpha motif domains. Mutated P63 gene may produce abnormal transcription factor P63 which can affect the signaling pathway. Furthermore, defective signaling protein in structure and/or quantity is synthesized though the pathway. Eventually, members of the signaling protein family are involved in the regulation of differentiation and development of stem cell, which causes deformity of limbs. In brief, three signaling pathways are related to the digit formation along three axes, including SHH-ZPA, FGFs-AER and Lmx1B-Wnt7a-En1. Each contains numerous signaling molecules which are integrated in self-regulatory modules that assure the acquisition or the correct digit complements. These finding has brought new clues for deciphering the etiology of congenital limb malformation and may provide alternatives for both prevention and treatment.

  2. Two zebrafish G2A homologs activate multiple intracellular signaling pathways in acidic environment

    Energy Technology Data Exchange (ETDEWEB)

    Ichijo, Yuta; Mochimaru, Yuta [Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571 (Japan); Azuma, Morio [Laboratory of Regulatory Biology, Graduate School of Science and Engineering, University of Toyama, 3190-Gofuku, Toyama 930-8555 (Japan); Satou, Kazuhiro; Negishi, Jun [Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571 (Japan); Nakakura, Takashi [Department of Anatomy, Graduate School of Medicine, Teikyo University, 2-11-1 Itabashi-Ku, Tokyo 173-8605 (Japan); Oshima, Natsuki [Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571 (Japan); Mogi, Chihiro; Sato, Koichi [Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512 (Japan); Matsuda, Kouhei [Laboratory of Regulatory Biology, Graduate School of Science and Engineering, University of Toyama, 3190-Gofuku, Toyama 930-8555 (Japan); Okajima, Fumikazu [Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512 (Japan); Tomura, Hideaki, E-mail: tomurah@meiji.ac.jp [Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571 (Japan)

    2016-01-01

    Human G2A is activated by various stimuli such as lysophosphatidylcholine (LPC), 9-hydroxyoctadecadienoic acid (9-HODE), and protons. The receptor is coupled to multiple intracellular signaling pathways, including the G{sub s}-protein/cAMP/CRE, G{sub 12/13}-protein/Rho/SRE, and G{sub q}-protein/phospholipase C/NFAT pathways. In the present study, we examined whether zebrafish G2A homologs (zG2A-a and zG2A-b) could respond to these stimuli and activate multiple intracellular signaling pathways. We also examined whether histidine residue and basic amino acid residue in the N-terminus of the homologs also play roles similar to those played by human G2A residues if the homologs sense protons. We found that the zG2A-a showed the high CRE, SRE, and NFAT activities, however, zG2A-b showed only the high SRE activity under a pH of 8.0. Extracellular acidification from pH 7.4 to 6.3 ameliorated these activities in zG2A-a-expressing cells. On the other hand, acidification ameliorated the SRE activity but not the CRE and NFAT activities in zG2A-b-expressing cells. LPC or 9-HODE did not modify any activity of either homolog. The substitution of histidine residue at the 174{sup th} position from the N-terminus of zG2A-a to asparagine residue attenuated proton-induced CRE and NFAT activities but not SRE activity. The substitution of arginine residue at the 32nd position from the N-terminus of zG2A-a to the alanine residue also attenuated its high and the proton-induced CRE and NFAT activities. On the contrary, the substitution did not attenuate SRE activity. The substitution of the arginine residue at the 10th position from the N-terminus of zG2A-b to the alanine residue also did not attenuate its high or the proton-induced SRE activity. These results indicate that zebrafish G2A homologs were activated by protons but not by LPC and 9-HODE, and the activation mechanisms of the homologs were similar to those of human G2A. - Highlights: • Zebrafish two G2A homologs are proton

  3. Signaling pathways regulated by Brassicaceae extract inhibit the ...

    African Journals Online (AJOL)

    Background: The goal of this study was identification signaling molecules mediated the formation of AGEs in brain of rats injected with CdCl2 and the role of camel whey proteins and Brassicaceae extract on formation of AGEs in brain. Methods: Ninety male rats were randomly grouped into five groups; Normal control (GpI) ...

  4. Four key signaling pathways mediating chemotaxis in Dictyostelium discoideum

    NARCIS (Netherlands)

    Veltman, Douwe M.; Keizer-Gunnink, Ineke; Van Haastert, Peter J. M.

    2008-01-01

    Chemotaxis is the ability of cells to move in the direction of an external gradient of signaling molecules. Cells are guided by actin-filled protrusions in the front, whereas myosin filaments retract the rear of the cell. Previous work demonstrated that chernotaxis of unpolarized amoeboid

  5. Signaling pathways and stem cells in uterus and fallopian tubes

    NARCIS (Netherlands)

    Y. Wang (Yongqian)

    2012-01-01

    textabstractDuring her fertile years, the endometrium of fertile women undergoes regular cycles of regeneration, differentiation and shedding, driven by changing concentrations of the steroid hormones estradiol and progesterone. In the present study, the role of Wnt/β-catenin signaling in relation

  6. Trigonelline and vildagliptin antidiabetic effect: improvement of insulin signalling pathway.

    Science.gov (United States)

    Aldakinah, Amat-Alrazaq A; Al-Shorbagy, Muhammad Y; Abdallah, Dalaal M; El-Abhar, Hanan S

    2017-07-01

    Trigonelline (TRG) is known to have an antidiabetic efficacy; however, its mechanism is not entirely elucidated. Hence, its effect on insulin signaling, besides its effectiveness in combination with vildagliptin (VLD) in a Type 2 diabetes model has been tested. TRG (50 mg/kg; p.o) lowered serum glucose, fructosamine, insulin, and HOMA-IR index and increased insulin sensitivity in soleus muscle via augmenting insulin receptor autophosphorylation (IR-PH), pT308-Akt, and glucose transporter 4 (GLUT4). Additionally, it reduced muscle advanced glycation end products and lipid peroxides with increased glutathione. TRG showed an anti-lipidemic effect lowering serum and/or muscle total cholesterol, triglycerides, and FFAs to decrease body weight, and visceral/epididymal indices. Furthermore, VLD (3 and 10 mg/kg, p.o) increased IR-PH, pT308-Akt, and GLUT4 to improve insulin signaling. The combined effect of TRG with the low dose of VLD was mostly confined to the reduction of the aberrant lipid profile. The beneficial effect of TRG on insulin sensitivity and glucose/ lipid homeostasis is mediated by the enhancement of the insulin signaling and antioxidant property. Moreover, the positive impact of VLD on pT308-Akt is an integral part in insulin signaling, and hence its antidiabetic effect. © 2017 Royal Pharmaceutical Society.

  7. Apoptotic Signaling Pathways in Glioblastoma and Therapeutic Implications

    Directory of Open Access Journals (Sweden)

    Silvia Anahi Valdés-Rives

    2017-01-01

    Full Text Available Glioblastoma multiforme (GBM is the most hostile type of brain cancer. Its aggressiveness is due to increased invasion, migration, proliferation, angiogenesis, and a decreased apoptosis. In this review, we discuss the role of key regulators of apoptosis in GBM and glioblastoma stem cells. Given their importance in the etiology and pathogenesis of GBM, these signaling molecules may represent potential therapeutic targets.

  8. Responses of the insulin signaling pathways in the brown adipose tissue of rats following cold exposure.

    Science.gov (United States)

    Wang, Xiaofei; Wahl, Richard

    2014-01-01

    The insulin signaling pathway is critical for the control of blood glucose levels. Brown adipose tissue (BAT) has also been implicated as important in glucose homeostasis. The effect of short-term cold exposure on this pathway in BAT has not been explored. We evaluated the effect of 4 hours of cold exposure on the insulin pathway in the BAT of rats. Whole genomic microarray chips were used to examine the transcripts of the pathway in BAT of rats exposed to 4°C and 22°C for 4 hours. The 4 most significantly altered pathways following 4 hours of cold exposure were the insulin signaling pathway, protein kinase A, PI3K/AKT and ERK/MAPK signaling. The insulin signaling pathway was the most affected. In the documented 142 genes of the insulin pathway, 42 transcripts (29.6%) responded significantly to this cold exposure with the least false discovery rate (Benjamini-Hochberg Multiple Testing: -log10 (p-value)  = 7.18). Twenty-seven genes (64%) were up-regulated, including the insulin receptor (Insr), insulin substrates 1 and 2 (Irs1 and Irs2). Fifteen transcripts (36%) were down-regulated. Multiple transcripts of the primary target and secondary effector targets for the insulin signaling were also up-regulated, including those for carbohydrate metabolism. Using western blotting, we demonstrated that the cold induced higher Irs2, Irs1, and Akt-p protein levels in the BAT than in the BAT of controls maintained at room temperature, and higher Akt-p protein level in the muscle. this study demonstrated that 4 hours of cold exposure stimulated the insulin signaling pathway in the BAT and muscle of overnight fasted rats. This raises the possibility that acute cold stimulation may have potential to improve glucose clearance and insulin sensitivity.

  9. Regulation of Cell Signaling Pathways and miRNAs by Resveratrol in Different Cancers.

    Science.gov (United States)

    Farooqi, Ammad Ahmad; Khalid, Sumbul; Ahmad, Aamir

    2018-02-26

    Genomic and proteomic studies have helped improve our understanding of the underlying mechanism(s) of cancer development and progression. Mutations, overexpressed oncogenes, inactivated/downregulated tumor suppressors, loss of apoptosis, and dysregulated signal transduction cascades are some of the well-studied areas of research. Resveratrol has gained considerable attention in the last two decades because of its pleiotropic anticancer activities. In this review, we have summarized the regulation of WNT, SHH (sonic hedgehog)/GLI (glioma-associated oncogene homolog), TGFβ1 (transforming growth factor beta 1)/SMAD, NOTCH, TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), STAT (signal transducer and activator of transcription), and microRNAs by resveratrol in different cancers. The importance of these signaling pathways in cancer progression, along with their modulation by resveratrol, is discussed. Further, we also evaluate the mechanisms and implications of the downregulation of oncogenic miRNAs and the upregulation of tumor suppressor miRNAs by resveratrol, both of which also define its ability to inhibit tumor growth and metastasis. It is envisioned that designing effective clinical trials will be helpful for the identification of resveratrol responders and non-responders and the elucidation of how this phytochemical can be combined with current therapeutic options to improve their clinical efficacy and reduce off-target effects.

  10. Parallel pathways of ethoxylated alcohol biodegradation under aerobic conditions

    International Nuclear Information System (INIS)

    Zembrzuska, Joanna; Budnik, Irena; Lukaszewski, Zenon

    2016-01-01

    Non-ionic surfactants (NS) are a major component of the surfactant flux discharged into surface water, and alcohol ethoxylates (AE) are the major component of this flux. Therefore, biodegradation pathways of AE deserve more thorough investigation. The aim of this work was to investigate the stages of biodegradation of homogeneous oxyethylated dodecanol C 12 E 9 having 9 oxyethylene subunits, under aerobic conditions. Enterobacter strain Z3 bacteria were chosen as biodegrading organisms under conditions with C 12 E 9 as the sole source of organic carbon. Bacterial consortia of river water were used in a parallel test as an inoculum for comparison. The LC-MS technique was used to identify the products of biodegradation. Liquid-liquid extraction with ethyl acetate was selected for the isolation of C 12 E 9 and metabolites from the biodegradation broth. The LC-MS/MS technique operating in the multiple reaction monitoring (MRM) mode was used for quantitative determination of C 12 E 9 , C 12 E 8 , C 12 E 7 and C 12 E 6 . Apart from the substrate, the homologues C 12 E 8 , C 12 E 7 and C 12 E 6 , being metabolites of C 12 E 9 biodegradation by shortening of the oxyethylene chain, as well as intermediate metabolites having a carboxyl end group in the oxyethylene chain (C 12 E 8 COOH, C 12 E 7 COOH, C 12 E 6 COOH and C 12 E 5 COOH), were identified. Poly(ethylene glycols) (E) having 9, 8 and 7 oxyethylene subunits were also identified, indicating parallel central fission of C 12 E 9 and its metabolites. Similar results were obtained with river water as inoculum. It is concluded that AE, under aerobic conditions, are biodegraded via two parallel pathways: by central fission with the formation of PEG, and by Ω-oxidation of the oxyethylene chain with the formation of carboxylated AE and subsequent shortening of the oxyethylene chain by a single unit. - Highlights: • Two parallel biodegradation pathways of alcohol ethoxylates have been discovered. • Apart from central

  11. The molecular mechanisms of signaling by cooperative assembly formation in innate immunity pathways.

    Science.gov (United States)

    Vajjhala, Parimala R; Ve, Thomas; Bentham, Adam; Stacey, Katryn J; Kobe, Bostjan

    2017-06-01

    The innate immune system is the first line of defense against infection and responses are initiated by pattern recognition receptors (PRRs) that detect pathogen-associated molecular patterns (PAMPs). PRRs also detect endogenous danger-associated molecular patterns (DAMPs) that are released by damaged or dying cells. The major PRRs include the Toll-like receptor (TLR) family members, the nucleotide binding and oligomerization domain, leucine-rich repeat containing (NLR) family, the PYHIN (ALR) family, the RIG-1-like receptors (RLRs), C-type lectin receptors (CLRs) and the oligoadenylate synthase (OAS)-like receptors and the related protein cyclic GMP-AMP synthase (cGAS). The different PRRs activate specific signaling pathways to collectively elicit responses including the induction of cytokine expression, processing of pro-inflammatory cytokines and cell-death responses. These responses control a pathogenic infection, initiate tissue repair and stimulate the adaptive immune system. A central theme of many innate immune signaling pathways is the clustering of activated PRRs followed by sequential recruitment and oligomerization of adaptors and downstream effector enzymes, to form higher-order arrangements that amplify the response and provide a scaffold for proximity-induced activation of the effector enzymes. Underlying the formation of these complexes are co-operative assembly mechanisms, whereby association of preceding components increases the affinity for downstream components. This ensures a rapid immune response to a low-level stimulus. Structural and biochemical studies have given key insights into the assembly of these complexes. Here we review the current understanding of assembly of immune signaling complexes, including inflammasomes initiated by NLR and PYHIN receptors, the myddosomes initiated by TLRs, and the MAVS CARD filament initiated by RIG-1. We highlight the co-operative assembly mechanisms during assembly of each of these complexes. Copyright

  12. Pathways of the Maillard reaction under physiological conditions.

    Science.gov (United States)

    Henning, Christian; Glomb, Marcus A

    2016-08-01

    Initially investigated as a color formation process in thermally treated foods, nowadays, the relevance of the Maillard reaction in vivo is generally accepted. Many chronic and age-related diseases such as diabetes, uremia, atherosclerosis, cataractogenesis and Alzheimer's disease are associated with Maillard derived advanced glycation endproducts (AGEs) and α-dicarbonyl compounds as their most important precursors in terms of reactivity and abundance. However, the situation in vivo is very challenging, because Maillard chemistry is paralleled by enzymatic reactions which can lead to both, increases and decreases in certain AGEs. In addition, mechanistic findings established under the harsh conditions of food processing might not be valid under physiological conditions. The present review critically discusses the relevant α-dicarbonyl compounds as central intermediates of AGE formation in vivo with a special focus on fragmentation pathways leading to formation of amide-AGEs.

  13. Curcumin and emodin down-regulate TGF-β signaling pathway in human cervical cancer cells.

    Directory of Open Access Journals (Sweden)

    Pooja Chandrakant Thacker

    Full Text Available Cervical cancer is the major cause of cancer related deaths in women, especially in developing countries and Human Papilloma Virus infection in conjunction with multiple deregulated signaling pathways leads to cervical carcinogenesis. TGF-β signaling in later stages of cancer is known to induce epithelial to mesenchymal transition promoting tumor growth. Phytochemicals, curcumin and emodin, are effective as chemopreventive and chemotherapeutic compounds against several cancers including cervical cancer. The main objective of this work was to study the effect of curcumin and emodin on TGF-β signaling pathway and its functional relevance to growth, migration and invasion in two cervical cancer cell lines, SiHa and HeLa. Since TGF-β and Wnt/β-catenin signaling pathways are known to cross talk having common downstream targets, we analyzed the effect of TGF-β on β-catenin (an important player in Wnt/β-catenin signaling and also studied whether curcumin and emodin modulate them. We observed that curcumin and emodin effectively down regulate TGF-β signaling pathway by decreasing the expression of TGF-β Receptor II, P-Smad3 and Smad4, and also counterbalance the tumorigenic effects of TGF-β by inhibiting the TGF-β-induced migration and invasion. Expression of downstream effectors of TGF-β signaling pathway, cyclinD1, p21 and Pin1, was inhibited along with the down regulation of key mesenchymal markers (Snail and Slug upon curcumin and emodin treatment. Curcumin and emodin were also found to synergistically inhibit cell population and migration in SiHa and HeLa cells. Moreover, we found that TGF-β activates Wnt/β-catenin signaling pathway in HeLa cells, and curcumin and emodin down regulate the pathway by inhibiting β-catenin. Taken together our data provide a mechanistic basis for the use of curcumin and emodin in the treatment of cervical cancer.

  14. Developmental biology informs cancer: the emerging role of the hedgehog signaling pathway in upper gastrointestinal cancers.

    Science.gov (United States)

    Xie, Keping; Abbruzzese, James L

    2003-10-01

    The hedgehog (Hh) signaling pathway plays many roles in invertebrate and vertebrate development. For example, specific inhibition of sonic Hh expression is critical during early stages of pancreas organogenesis, but an active Hh pathway appears to be required for maintenance of adult endocrine functions. Mutational inactivation of the Hh pathway has been demonstrated in human malignancies of the skin, cerebellum, and skeletal muscle. Now, two papers implicate aberrant Hh signaling in human upper gastrointestinal cancers including those developing from the esophagus, stomach, biliary tract, and pancreas.

  15. Effects of CD44 Ligation on Signaling and Metabolic Pathways in Acute Myeloid Leukemia

    KAUST Repository

    Madhoun, Nour Y.

    2017-04-01

    Acute myeloid leukemia (AML) is characterized by a blockage in the differentiation of myeloid cells at different stages. CD44-ligation using anti-CD44 monoclonal antibodies (mAbs) has been shown to reverse the blockage of differentiation and to inhibit the proliferation of blasts in most AML-subtypes. However, the molecular mechanisms underlying this property have not been fully elucidated. Here, we sought to I) analyze the effects of anti-CD44 mAbs on downstream signaling pathways, including the ERK1/2 (extracellular signal-regulated kinase 1 and 2) and mTOR (mammalian target of rapamycin) pathways and II) use state-of-the-art Nuclear Magnetic Resonance (NMR) technology to determine the global metabolic changes during differentiation induction of AML cells using anti-CD44 mAbs and other two previously reported differentiation agents. In the first objective (Chapter 4), our studies provide evidence that CD44-ligation with specific mAbs in AML cells induced an increase in ERK1/2 phosphorylation. The use of the MEK inhibitor (U0126) significantly inhibited the CD44-induced differentiation of HL60 cells, suggesting that ERK1/2 is critical for the CD44-triggered differentiation in AML. In addition, this was accompanied by a marked decrease in the phosphorylation of the mTORC1 and mTORC2 complexes, which are strongly correlated with the inhibition of the PI3K/Akt pathway. In the second objective (Chapter 5), 1H NMR experiments demonstrated that considerable changes in the metabolic profiles of HL60 cells were induced in response to each differentiation agent. These most notable metabolites that significantly changed upon CD44 ligation were involved in the tricarboxylic acid (TCA) cycle and glycolysis such as, succinate, fumarate and lactate. Therefore, we sought to analyze the mechanisms underlying their alterations. Our results revealed that anti-CD44 mAbs treatment induced upregulation in fumarate hydratase (FH) expression and its activity which was accompanied by a

  16. Behavioral Evidence for More than One Taste Signaling Pathway for Sugars in Rats.

    Science.gov (United States)

    Schier, Lindsey A; Spector, Alan C

    2016-01-06

    By conventional behavioral measures, rodents respond to natural sugars, such as glucose and fructose, as though they elicit an identical perceptual taste quality. Beyond that, the metabolic and sensory effects of these two sugars are quite different. Considering the capacity to immediately respond to the more metabolically expedient sugar, glucose, would seem advantageous for energy intake, the present experiment assessed whether experience consuming these two sugars would modify taste-guided ingestive responses to their yet unknown distinguishing orosensory properties. One group (GvF) had randomized access to three concentrations of glucose and fructose (0.316, 0.56, 1.1 m) in separate 30-min single access training sessions, whereas control groups received equivalent exposure to the three glucose or fructose concentrations only, or remained sugar naive. Comparison of the microstructural licking patterns for the two sugars revealed that GvF responded more positively to glucose (increased total intake, increased burst size, decreased number of pauses), relative to fructose, across training. As training progressed, GvF rats began to respond more positively to glucose in the first minute of the session when intake is principally taste-driven. During post-training brief-access taste tests, GvF rats licked more for glucose than for fructose, whereas the other training groups did not respond differentially to the two sugars. Additional brief access testing showed that this did not generalize to Na-saccharin or galactose. Thus, in addition to eliciting a common taste signal, glucose and fructose produce distinct signals that are apparently rendered behaviorally relevant and hedonically distinct through experience. The taste pathway(s) underlying this remain to be identified. The T1R2+T1R3 heterodimer is thought by many to be the only taste receptor for sugars. Although most sugars have been conventionally shown to correspondingly produce a unitary taste percept (sweet

  17. The cAMP Signaling and MAP Kinase Pathways in Plant Pathogenic Fungi

    NARCIS (Netherlands)

    Mehrabi, R.; Zhao, X.; Kim, Y.; Xu, J.R.

    2009-01-01

    The key components of the well conserved cyclic AMP signaling and MAP kinase pathways have been functionally characterized in the corn smut Ustilago maydis, rice blast fungus Magnaporthe grisea, and a few other fungal pathogens. In general, the cAMP signaling and the MAP kinase cascade homologous to

  18. Pan-cancer analysis of TCGA data reveals notable signaling pathways

    International Nuclear Information System (INIS)

    Neapolitan, Richard; Horvath, Curt M.; Jiang, Xia

    2015-01-01

    A signal transduction pathway (STP) is a network of intercellular information flow initiated when extracellular signaling molecules bind to cell-surface receptors. Many aberrant STPs have been associated with various cancers. To develop optimal treatments for cancer patients, it is important to discover which STPs are implicated in a cancer or cancer-subtype. The Cancer Genome Atlas (TCGA) makes available gene expression level data on cases and controls in ten different types of cancer including breast cancer, colon adenocarcinoma, glioblastoma, kidney renal papillary cell carcinoma, low grade glioma, lung adenocarcinoma, lung squamous cell carcinoma, ovarian carcinoma, rectum adenocarcinoma, and uterine corpus endometriod carcinoma. Signaling Pathway Impact Analysis (SPIA) is a software package that analyzes gene expression data to identify whether a pathway is relevant in a given condition. We present the results of a study that uses SPIA to investigate all 157 signaling pathways in the KEGG PATHWAY database. We analyzed each of the ten cancer types mentioned above separately, and we perform a pan-cancer analysis by grouping the data for all the cancer types. In each analysis several pathways were found to be markedly more significant than all the other pathways. We call them notable. Research has already established a connection between many of these pathways and the corresponding cancer type. However, some of our discovered pathways appear to be new findings. Altogether there were 37 notable findings in the separate analyses, 26 of them occurred in 7 pathways. These 7 pathways included the 4 notable pathways discovered in the pan-cancer analysis. So, our results suggest that these 7 pathways account for much of the mechanisms of cancer. Furthermore, by looking at the overlap among pathways, we identified possible regions on the pathways where the aberrant activity is occurring. We obtained 37 notable findings concerning 18 pathways. Some of them appear to be

  19. Vasculogenesis and angiogenesis initiation under normoxic conditions through Wnt/β-catenin pathway in gliomas.

    Science.gov (United States)

    Vallée, Alexandre; Guillevin, Rémy; Vallée, Jean-Noël

    2018-01-26

    The canonical Wnt/β-catenin pathway is up-regulated in gliomas and involved in proliferation, invasion, apoptosis, vasculogenesis and angiogenesis. Nuclear β-catenin accumulation correlates with malignancy. Hypoxia activates hypoxia-inducible factor (HIF)-1α by inhibiting HIF-1α prolyl hydroxylation, which promotes glycolytic energy metabolism, vasculogenesis and angiogenesis, whereas HIF-1α is degraded by the HIF prolyl hydroxylase under normoxic conditions. We focus this review on the links between the activated Wnt/β-catenin pathway and the mechanisms underlying vasculogenesis and angiogenesis through HIF-1α under normoxic conditions in gliomas. Wnt-induced epidermal growth factor receptor/phosphatidylinositol 3-kinase (PI3K)/Akt signaling, Wnt-induced signal transducers and activators of transcription 3 (STAT3) signaling, and Wnt/β-catenin target gene transduction (c-Myc) can activate HIF-1α in a hypoxia-independent manner. The PI3K/Akt/mammalian target of rapamycin pathway activates HIF-1α through eukaryotic translation initiation factor 4E-binding protein 1 and STAT3. The β-catenin/T-cell factor 4 complex directly binds to STAT3 and activates HIF-1α, which up-regulates the Wnt/β-catenin target genes cyclin D1 and c-Myc in a positive feedback loop. Phosphorylated STAT3 by interleukin-6 or leukemia inhibitory factor activates HIF-1α even under normoxic conditions. The activation of the Wnt/β-catenin pathway induces, via the Wnt target genes c-Myc and cyclin D1 or via HIF-1α, gene transactivation encoding aerobic glycolysis enzymes, such as glucose transporter, hexokinase 2, pyruvate kinase M2, pyruvate dehydrogenase kinase 1 and lactate dehydrogenase-A, leading to lactate production, as the primary alternative of ATP, at all oxygen levels, even in normoxic conditions. Lactate released by glioma cells via the monocarboxylate lactate transporter-1 up-regulated by HIF-1α and lactate anion activates HIF-1α in normoxic endothelial cells by

  20. Lrp4 modulates extracellular integration of cell signaling pathways in development.

    Directory of Open Access Journals (Sweden)

    Atsushi Ohazama

    Full Text Available The extent to which cell signaling is integrated outside the cell is not currently appreciated. We show that a member of the low-density receptor-related protein family, Lrp4 modulates and integrates Bmp and canonical Wnt signalling during tooth morphogenesis by binding the secreted Bmp antagonist protein Wise. Mouse mutants of Lrp4 and Wise exhibit identical tooth phenotypes that include supernumerary incisors and molars, and fused molars. We propose that the Lrp4/Wise interaction acts as an extracellular integrator of epithelial-mesenchymal cell signaling. Wise, secreted from mesenchyme cells binds to BMP's and also to Lrp4 that is expressed on epithelial cells. This binding then results in the modulation of Wnt activity in the epithelial cells. Thus in this context Wise acts as an extracellular signaling molecule linking two signaling pathways. We further show that a downstream mediator of this integration is the Shh signaling pathway.

  1. LPA, HGF, and EGF utilize distinct combinations of signaling pathways to promote migration and invasion of MDA-MB-231 breast carcinoma cells

    International Nuclear Information System (INIS)

    Harrison, Susan MW; Knifley, Teresa; Chen, Min; O’Connor, Kathleen L

    2013-01-01

    Various pathways impinge on the actin-myosin pathway to facilitate cell migration and invasion including members of the Rho family of small GTPases and MAPK. However, the signaling components that are considered important for these processes vary substantially within the literature with certain pathways being favored. These distinctions in signaling pathways utilized are often attributed to differences in cell type or physiological conditions; however, these attributes have not been systematically assessed. To address this question, we analyzed the migration and invasion of MDA-MB-231 breast carcinoma cell line in response to various stimuli including lysophosphatidic acid (LPA), hepatocyte growth factor (HGF) and epidermal growth factor (EGF) and determined the involvement of select signaling pathways that impact myosin light chain phosphorylation. LPA, a potent stimulator of the Rho-ROCK pathway, surprisingly did not require the Rho-ROCK pathway to stimulate migration but instead utilized Rac and MAPK. In contrast, LPA-stimulated invasion required Rho, Rac, and MAPK. Of these three major pathways, EGF-stimulated MDA-MB-231 migration and invasion required Rho; however, Rac was essential only for invasion and MAPK was dispensable for migration. HGF signaling, interestingly, utilized the same pathways for migration and invasion, requiring Rho but not Rac signaling. Notably, the dependency of HGF-stimulated migration and invasion as well as EGF-stimulated invasion on MAPK was subject to the inhibitors used. As expected, myosin light chain kinase (MLCK), a convergence point for MAPK and Rho family GTPase signaling, was required for all six conditions. These observations suggest that, while multiple signaling pathways contribute to cancer cell motility, not all pathways operate under all conditions. Thus, our study highlights the plasticity of cancer cells to adapt to multiple migratory cues

  2. Balancing act: matching growth with environment by the TOR signalling pathway.

    Science.gov (United States)

    Henriques, Rossana; Bögre, László; Horváth, Beátrix; Magyar, Zoltán

    2014-06-01

    One of the most fundamental aspects of growth in plants is its plasticity in relation to fluctuating environmental conditions. Growth of meristematic cells relies predominantly on protein synthesis, one of the most energy-consuming activities in cells, and thus is tightly regulated in accordance with the available nutrient and energy supplies. The Target of Rapamycin (TOR) signalling pathway takes a central position in this regulation. The core of the TOR signalling pathway is conserved throughout evolution, and can be traced back to the last eukaryotic common ancestor. In plants, a single complex constitutes the TOR signalling pathway. Manipulating the components of the TOR complex in Arabidopsis highlighted its common role as a major regulator of protein synthesis and metabolism, that is also involved in other biological functions such as cell-wall integrity, regulation of cell proliferation, and cell size. TOR, as an integral part of the auxin signalling pathway, connects hormonal and nutrient pathways. Downstream of TOR, S6 kinase and the ribosomal S6 protein have been shown to mediate several of these responses, although there is evidence of other complex non-linear TOR signalling pathway structures. © The Author 2014. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  3. Non Linear Programming (NLP formulation for quantitative modeling of protein signal transduction pathways.

    Directory of Open Access Journals (Sweden)

    Alexander Mitsos

    Full Text Available Modeling of signal transduction pathways plays a major role in understanding cells' function and predicting cellular response. Mathematical formalisms based on a logic formalism are relatively simple but can describe how signals propagate from one protein to the next and have led to the construction of models that simulate the cells response to environmental or other perturbations. Constrained fuzzy logic was recently introduced to train models to cell specific data to result in quantitative pathway models of the specific cellular behavior. There are two major issues in this pathway optimization: i excessive CPU time requirements and ii loosely constrained optimization problem due to lack of data with respect to large signaling pathways. Herein, we address both issues: the former by reformulating the pathway optimization as a regular nonlinear optimization problem; and the latter by enhanced algorithms to pre/post-process the signaling network to remove parts that cannot be identified given the experimental conditions. As a case study, we tackle the construction of cell type specific pathways in normal and transformed hepatocytes using medium and large-scale functional phosphoproteomic datasets. The proposed Non Linear Programming (NLP formulation allows for fast optimization of signaling topologies by combining the versatile nature of logic modeling with state of the art optimization algorithms.

  4. Identification of Potential Drug Targets in Cancer Signaling Pathways using Stochastic Logical Models.

    Science.gov (United States)

    Zhu, Peican; Aliabadi, Hamidreza Montazeri; Uludağ, Hasan; Han, Jie

    2016-03-18

    The investigation of vulnerable components in a signaling pathway can contribute to development of drug therapy addressing aberrations in that pathway. Here, an original signaling pathway is derived from the published literature on breast cancer models. New stochastic logical models are then developed to analyze the vulnerability of the components in multiple signalling sub-pathways involved in this signaling cascade. The computational results are consistent with the experimental results, where the selected proteins were silenced using specific siRNAs and the viability of the cells were analyzed 72 hours after silencing. The genes elF4E and NFkB are found to have nearly no effect on the relative cell viability and the genes JAK2, Stat3, S6K, JUN, FOS, Myc, and Mcl1 are effective candidates to influence the relative cell growth. The vulnerabilities of some targets such as Myc and S6K are found to vary significantly depending on the weights of the sub-pathways; this will be indicative of the chosen target to require customization for therapy. When these targets are utilized, the response of breast cancers from different patients will be highly variable because of the known heterogeneities in signaling pathways among the patients. The targets whose vulnerabilities are invariably high might be more universally acceptable targets.

  5. Non Linear Programming (NLP) formulation for quantitative modeling of protein signal transduction pathways.

    Science.gov (United States)

    Mitsos, Alexander; Melas, Ioannis N; Morris, Melody K; Saez-Rodriguez, Julio; Lauffenburger, Douglas A; Alexopoulos, Leonidas G

    2012-01-01

    Modeling of signal transduction pathways plays a major role in understanding cells' function and predicting cellular response. Mathematical formalisms based on a logic formalism are relatively simple but can describe how signals propagate from one protein to the next and have led to the construction of models that simulate the cells response to environmental or other perturbations. Constrained fuzzy logic was recently introduced to train models to cell specific data to result in quantitative pathway models of the specific cellular behavior. There are two major issues in this pathway optimization: i) excessive CPU time requirements and ii) loosely constrained optimization problem due to lack of data with respect to large signaling pathways. Herein, we address both issues: the former by reformulating the pathway optimization as a regular nonlinear optimization problem; and the latter by enhanced algorithms to pre/post-process the signaling network to remove parts that cannot be identified given the experimental conditions. As a case study, we tackle the construction of cell type specific pathways in normal and transformed hepatocytes using medium and large-scale functional phosphoproteomic datasets. The proposed Non Linear Programming (NLP) formulation allows for fast optimization of signaling topologies by combining the versatile nature of logic modeling with state of the art optimization algorithms.

  6. Identifying Novel Signaling Pathways: An Exercise Scientists Guide to Phosphoproteomics.

    Science.gov (United States)

    Wilson, Gary M; Blanco, Rocky; Coon, Joshua J; Hornberger, Troy A

    2018-01-15

    We propose that phosphoproteomic-based studies will radically advance our knowledge about exercise regulated signaling events. However, these studies utilize cutting-edge technologies that can be difficult for non-specialists to understand. Hence, this review is intended to help non-specialists: 1) understand the fundamental technologies behind phosphoproteomic analysis and 2) employ various bioinformatic tools that can be used to interrogate phosphoproteomic datasets.

  7. Functions and Signaling Pathways of Amino Acids in Intestinal Inflammation

    OpenAIRE

    Fang He; Chenlu Wu; Pan Li; Nengzhang Li; Dong Zhang; Quoqiang Zhu; Wenkai Ren; Yuanyi Peng

    2018-01-01

    Intestine is always exposed to external environment and intestinal microorganism; thus it is more sensitive to dysfunction and dysbiosis, leading to intestinal inflammation, such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), and diarrhea. An increasing number of studies indicate that dietary amino acids play significant roles in preventing and treating intestinal inflammation. The review aims to summarize the functions and signaling mechanisms of amino acids in intestin...

  8. Podocytes, Signaling Pathways, and Vascular Factors in Diabetic Kidney Disease

    Science.gov (United States)

    Brosius, Frank C.; Coward, Richard J.

    2014-01-01

    Alterations and injury to glomerular podocytes play a key role in the initiation and early progression of diabetic kidney disease. Multiple factors in the diabetic milieu cause abnormalities in podocyte signaling that lead to podocyte foot process effacement, hypertrophy, detachment, loss and death. Alterations in insulin action and mTOR activation have been well documented to lead to pathology. For example, reduced insulin action directly leads to albuminuria, increased glomerular matrix accumulation, thickening of the glomerular basement membrane, podocyte apoptosis and glomerulosclerosis. In addition, the podocyte generates factors that alter signaling in other glomerular cells. Prominent among these is VEGF-A which plays a complex role in maintaining glomerular endothelium viability but causes endothelial cell pathology when generated at too high a level. Finally, circulating vascular factors, such as activated protein C have a profound effect on podocyte stability and survival. This cytoprotective factor is critical for podocyte health and its deficiency promotes podocyte injury and apoptosis. Thus, the podocyte sits in the center of a network of paracrine and hormonal signaling systems that in health keep the podocyte adaptable and viable, but in diabetes can lead to pathologic changes, detachment and death. This podocyte injury is a critical determinant of the progression of diabetic kidney disease. PMID:24780459

  9. Lysophosphatidic acid targets vascular and oncogenic pathways via RAGE signaling

    Science.gov (United States)

    Touré, Fatouma; Chitayat, Seth; Pei, Renjun; Song, Fei; Li, Qing; Zhang, Jinghua; Rosario, Rosa; Ramasamy, Ravichandran; Chazin, Walter J.

    2012-01-01

    The endogenous phospholipid lysophosphatidic acid (LPA) regulates fundamental cellular processes such as proliferation, survival, motility, and invasion implicated in homeostatic and pathological conditions. Hence, delineation of the full range of molecular mechanisms by which LPA exerts its broad effects is essential. We report avid binding of LPA to the receptor for advanced glycation end products (RAGE), a member of the immunoglobulin superfamily, and mapping of the LPA binding site on this receptor. In vitro, RAGE was required for LPA-mediated signal transduction in vascular smooth muscle cells and C6 glioma cells, as well as proliferation and migration. In vivo, the administration of soluble RAGE or genetic deletion of RAGE mitigated LPA-stimulated vascular Akt signaling, autotaxin/LPA-driven phosphorylation of Akt and cyclin D1 in the mammary tissue of transgenic mice vulnerable to carcinogenesis, and ovarian tumor implantation and development. These findings identify novel roles for RAGE as a conduit for LPA signaling and suggest targeting LPA–RAGE interaction as a therapeutic strategy to modify the pathological actions of LPA. PMID:23209312

  10. Roles of TRAFs in NF-κB signaling pathways mediated by BAFF.

    Science.gov (United States)

    Tang, Xiaoyu; Zhang, Lingling; Wei, Wei

    2018-04-01

    B cell activating factor (BAFF) is an important cytokine for the maintenance of B cell development, survival and homeostasis. BAFF/BAFF-R could directly activate nuclear factor kappa B (NF-κB) pathway. Tumour necrosis factor receptor-associated factors (TRAFs) are key regulatory proteins in NF-κB signaling pathways. TRAF1 enhances the activation of tumor necrosis factor receptor 2 (TNF-R2) induced by NF-κB. TRAF2 and TRAF3 signal adapters act cooperatively to control the maturation and survival signals mediated by BAFF receptor. TRAF5 is most homologous to TRAF3, as well as most functionally similar to TRAF2. TRAF6 is also required for the BAFF-mediated activation of NF-κB signal pathway. TRAF7 is involved in signal transduction pathways that lead either to activation or repression of NF-κB transcription factor. In this article, we reviewed the roles of TRAFs in NF-κB signaling pathway mediated by BAFF. Copyright © 2018 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

  11. Gibberellic Acid Signaling Is Required to Induce Flowering of Chrysanthemums Grown under Both Short and Long Days.

    Science.gov (United States)

    Dong, Bin; Deng, Ye; Wang, Haibin; Gao, Ri; Stephen, Githeng'u K; Chen, Sumei; Jiang, Jiafu; Chen, Fadi

    2017-06-12

    Flower bud formation and flowering in chrysanthemums occur under short day conditions (SD), but the molecular basis for the switch to reproductive growth is less well understood than in model plants. Here, a spontaneous mutant able to flower under long days is described. In an attempt to reveal the pathway(s) involved in the formation of flower buds under contrasting daylengths, transcriptome sequencing was carried out in plants grown both under SD and long day conditions (LD). A number of differentially transcribed genes involved in the various known flowering pathways were identified. Both circadian clock genes and Chrysanthemum FLOWERING LOCUS T Like3 ( CmFTL3 ) were up-regulated under SD, thereby inducing floral bud formation and flowering. The gibberellin (GA) signaling pathway-related genes Gibberellin 20-oxidase ( GA20ox ) and Gibberellin receptor ( GID1 ) were up-regulated in the mutant under LD, while the catabolic genes Gibberellin 2-oxidase ( GA2ox ) and GA-INSENSITIVE ( GAI ) were down-regulated, thereby inducing the transcription of SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 ( SOC1 ) and LEAFY ( LFY ). The GA content of the leaf was higher in the mutant than in the wild type (WT) under LD and SD, and the mutant has more branching than WT plants under LD or SD. When treated with GA, the mutant flowered earlier under both SD and LD relative to WT, but there was no detectable phenotype difference between the two lines. The indication was that the photoperiod pathway majorly regulates flower bud formation and flowering time in chrysanthemums under SD. The GA signaling pathway only plays a subsidiary role for flowering. However, the GA signaling pathway predominated for flowering under LD.

  12. Discovery and characterization of a potent Wnt and hedgehog signaling pathways dual inhibitor.

    Science.gov (United States)

    Ma, Haikuo; Chen, Qin; Zhu, Fang; Zheng, Jiyue; Li, Jiajun; Zhang, Hongjian; Chen, Shuaishuai; Xing, Haimei; Luo, Lusong; Zheng, Long Tai; He, Sudan; Zhang, Xiaohu

    2018-04-10

    Embryonic stem cell pathways such as hedgehog and Wnt pathways are central to the tumorigenic properties of cancer stem cells (CSC). Since CSCs are characterized by their ability to self-renew, form differentiated progeny, and develop resistance to anticancer therapies, targeting the Wnt and hedgehog signaling pathways has been an important strategy for cancer treatment. Although molecules targeting either Wnt or hedgehog are common, to the best of our knowledge, those targeting both pathways have not been documented. Here we report a small molecule (compound 1) that inhibits both Wnt (IC 50  = 0.5 nM) and hedgehog (IC 50  = 71 nM) pathways based on reporter gene assays. We further identified that the molecular target of 1 for Wnt pathway inhibition was porcupine (a member of the membrane-bound O-acyltransferase family of proteins), a post-translational modification node in Wnt signaling; while the target of 1 mitigating hedgehog pathway was Smoothened, a key G protein coupled receptor (GPCR) mediating hedgehog signal transduction. Preliminary analysis of structure-activity-relationship identified key functional elements for hedgehog/Wnt inhibition. In in vivo studies, compound 1 demonstrated good oral exposure and bioavailability while eliciting no overt toxicity in mice. An important consideration in cancer treatment is the potential therapeutic escape through compensatory activation of an interconnected pathway when only one signaling pathway is inhibited. Toward this end, compound 1 may not only lead to the development of new therapeutics for Wnt and hedgehog related cancers, but may also help to develop potential cancer treatment which needs to target Wnt and hedgehog signaling simultaneously. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  13. Mitogen-activated protein kinase signaling pathways of the tangerine pathotype of Alternaria alternata

    Directory of Open Access Journals (Sweden)

    Kuang-Ren Chung

    2013-06-01

    Full Text Available Mitogen-activated protein kinase (MAPK- mediated signaling pathways have been known to have important functions in eukaryotic organisms. The mechanisms by which the filamentous fungus Alternaria alternata senses and responds to environmental signals have begun to be elucidated. Available data indicate that A. alternata utilizes the Fus3, Hog1 and Slt2 MAPK-mediated signaling pathways, either separately or in a cooperative manner, for conidia formation, resistance to oxidative and osmotic stress, and pathogenesis to citrus. This review provides an overview of our current knowledge of MAPK signaling pathways, in conjunction with the two-component histidine kinase and the Skn7 response regulator, in the tangerine pathotype of A. alternata.

  14. The ubiquitin–proteasome system and signal transduction pathways regulating Epithelial Mesenchymal transition of cancer

    Directory of Open Access Journals (Sweden)

    Voutsadakis Ioannis A

    2012-07-01

    Full Text Available Abstract Epithelial to Mesenchymal transition (EMT in cancer, a process permitting cancer cells to become mobile and metastatic, has a signaling hardwire forged from development. Multiple signaling pathways that regulate carcinogenesis enabling characteristics in neoplastic cells such as proliferation, resistance to apoptosis and angiogenesis are also the main players in EMT. These pathways, as almost all cellular processes, are in their turn regulated by ubiquitination and the Ubiquitin-Proteasome System (UPS. Ubiquitination is the covalent link of target proteins with the small protein ubiquitin and serves as a signal to target protein degradation by the proteasome or to other outcomes such as endocytosis, degradation by the lysosome or specification of cellular localization. This paper reviews signal transduction pathways regulating EMT and being regulated by ubiquitination.

  15. Broccoli consumption interacts with GSTM1 to perturb oncogenic signalling pathways in the prostate.

    Directory of Open Access Journals (Sweden)

    Maria Traka

    2008-07-01

    Full Text Available Epidemiological studies suggest that people who consume more than one portion of cruciferous vegetables per week are at lower risk of both the incidence of prostate cancer and of developing aggressive prostate cancer but there is little understanding of the underlying mechanisms. In this study, we quantify and interpret changes in global gene expression patterns in the human prostate gland before, during and after a 12 month broccoli-rich diet.Volunteers were randomly assigned to either a broccoli-rich or a pea-rich diet. After six months there were no differences in gene expression between glutathione S-transferase mu 1 (GSTM1 positive and null individuals on the pea-rich diet but significant differences between GSTM1 genotypes on the broccoli-rich diet, associated with transforming growth factor beta 1 (TGFbeta1 and epidermal growth factor (EGF signalling pathways. Comparison of biopsies obtained pre and post intervention revealed more changes in gene expression occurred in individuals on a broccoli-rich diet than in those on a pea-rich diet. While there were changes in androgen signalling, regardless of diet, men on the broccoli diet had additional changes to mRNA processing, and TGFbeta1, EGF and insulin signalling. We also provide evidence that sulforaphane (the isothiocyanate derived from 4-methylsuphinylbutyl glucosinolate that accumulates in broccoli chemically interacts with TGFbeta1, EGF and insulin peptides to form thioureas, and enhances TGFbeta1/Smad-mediated transcription.These findings suggest that consuming broccoli interacts with GSTM1 genotype to result in complex changes to signalling pathways associated with inflammation and carcinogenesis in the prostate. We propose that these changes may be mediated through the chemical interaction of isothiocyanates with signalling peptides in the plasma. This study provides, for the first time, experimental evidence obtained in humans to support observational studies that diets rich in

  16. Impact of laminitis on the canonical Wnt signaling pathway in basal epithelial cells of the equine digital laminae.

    Science.gov (United States)

    Wang, Le; Pawlak, Erica A; Johnson, Philip J; Belknap, James K; Eades, Susan; Stack, Sharon; Cousin, Helene; Black, Samuel J

    2013-01-01

    The digital laminae is a two layer tissue that attaches the distal phalanx to the inner hoof wall, thus suspending the horse's axial skeleton in the hoof capsule. This tissue fails at the epidermal:dermal junction in laminitic horses, causing crippling disease. Basal epithelial cells line the laminar epidermal:dermal junction, undergo physiological change in laminitic horses, and lose versican gene expression. Versican gene expression is purportedly under control of the canonical Wnt signaling pathway and is a trigger for mesenchymal-to-epithelial transition; thus, its repression in laminar epithelial cells of laminitic horses may be associated with suppression of the canonical Wnt signaling pathway and loss of the epithelial cell phenotype. In support of the former contention, we show, using laminae from healthy horses and horses with carbohydrate overload-induced laminitis, quantitative real-time polymerase chain reaction, Western blotting after sodium dodecylsulfate polyacrylamide gel electrophoresis, and immunofluorescent tissue staining, that positive and negative regulatory components of the canonical Wnt signaling pathway are expressed in laminar basal epithelial cells of healthy horses. Furthermore, expression of positive regulators is suppressed and negative regulators elevated in laminae of laminitic compared to healthy horses. We also show that versican gene expression in the epithelial cells correlates positively with that of β-catenin and T-cell Factor 4, consistent with regulation by the canonical Wnt signaling pathway. In addition, gene and protein expression of β-catenin correlates positively with that of integrin β4 and both are strongly suppressed in laminar basal epithelial cells of laminitic horses, which remain E-cadherin(+)/vimentin(-), excluding mesenchymal transition as contributing to loss of the adherens junction and hemidesmosome components. We propose that suppression of the canonical Wnt signaling pathway, and accompanying reduced

  17. Impact of laminitis on the canonical Wnt signaling pathway in basal epithelial cells of the equine digital laminae.

    Directory of Open Access Journals (Sweden)

    Le Wang

    Full Text Available The digital laminae is a two layer tissue that attaches the distal phalanx to the inner hoof wall, thus suspending the horse's axial skeleton in the hoof capsule. This tissue fails at the epidermal:dermal junction in laminitic horses, causing crippling disease. Basal epithelial cells line the laminar epidermal:dermal junction, undergo physiological change in laminitic horses, and lose versican gene expression. Versican gene expression is purportedly under control of the canonical Wnt signaling pathway and is a trigger for mesenchymal-to-epithelial transition; thus, its repression in laminar epithelial cells of laminitic horses may be associated with suppression of the canonical Wnt signaling pathway and loss of the epithelial cell phenotype. In support of the former contention, we show, using laminae from healthy horses and horses with carbohydrate overload-induced laminitis, quantitative real-time polymerase chain reaction, Western blotting after sodium dodecylsulfate polyacrylamide gel electrophoresis, and immunofluorescent tissue staining, that positive and negative regulatory components of the canonical Wnt signaling pathway are expressed in laminar basal epithelial cells of healthy horses. Furthermore, expression of positive regulators is suppressed and negative regulators elevated in laminae of laminitic compared to healthy horses. We also show that versican gene expression in the epithelial cells correlates positively with that of β-catenin and T-cell Factor 4, consistent with regulation by the canonical Wnt signaling pathway. In addition, gene and protein expression of β-catenin correlates positively with that of integrin β4 and both are strongly suppressed in laminar basal epithelial cells of laminitic horses, which remain E-cadherin(+/vimentin(-, excluding mesenchymal transition as contributing to loss of the adherens junction and hemidesmosome components. We propose that suppression of the canonical Wnt signaling pathway, and

  18. MiR-9-5p promotes MSC migration by activating β-catenin signaling pathway.

    Science.gov (United States)

    Li, Xianyang; He, Lihong; Yue, Qing; Lu, Junhou; Kang, Naixin; Xu, Xiaojing; Wang, Huihui; Zhang, Huanxiang

    2017-07-01

    Mesenchymal stem cells (MSCs) have the potential to treat various tissue damages, but the very limited number of cells that migrate to the damaged region strongly restricts their therapeutic applications. Full understanding of mechanisms regulating MSC migration will help to improve their migration ability and therapeutic effects. Increasing evidence shows that microRNAs play important roles in the regulation of MSC migration. In the present study, we reported that miR-9-5p was upregulated in hepatocyte growth factor -treated MSCs and in MSCs with high migration ability. Overexpression of miR-9-5p promoted MSC migration, whereas inhibition of endogenous miR-9-5p decreased MSC migration. To elucidate the underlying mechanism, we screened the target genes of miR-9-5p and report for the first time that CK1α and GSK3β, two inhibitors of β-catenin signaling pathway, were direct targets of miR-9-5p in MSCs and that overexpression of miR-9-5p upregulated β-catenin signaling pathway. In line with these data, inhibition of β-catenin signaling pathway by FH535 decreased the miR-9-5p-promoted migration of MSCs, while activation of β-catenin signaling pathway by LiCl rescued the impaired migration of MSCs triggered by miR-9-5p inhibitor. Furthermore, the formation and distribution of focal adhesions as well as the reorganization of F-actin were affected by the expression of miR-9-5p. Collectively, these results demonstrate that miR-9-5p promotes MSC migration by upregulating β-catenin signaling pathway, shedding light on the optimization of MSCs for cell replacement therapy through manipulating the expression level of miR-9-5p. Copyright © 2017 the American Physiological Society.

  19. The Cyclic AMP-Vfr Signaling Pathway in Pseudomonas aeruginosa Is Inhibited by Cyclic Di-GMP

    DEFF Research Database (Denmark)

    Almblad, Henrik; Harrison, Joe J; Rybtke, Morten

    2015-01-01

    : Our work suggests that cross talk between c-di-GMP and cAMP signaling pathways results in downregulation of acute virulence factors in P. aeruginosa biofilm infections. Knowledge about this cross-regulation adds to our understanding of virulence traits and immune evasion by P. aeruginosa in chronic......AMP), which is decreased in response to a high level of c-di-GMP. Mutations that cause reversion of the RSCV phenotype concomitantly reactivate Vfr-cAMP signaling. Attempts to uncover the mechanism underlying the observed c-di-GMP-mediated lowering of cAMP content provided evidence that it is not caused...

  20. Future changes in global warming potentials under representative concentration pathways

    Energy Technology Data Exchange (ETDEWEB)

    Reisinger, Andy [New Zealand Agricultural Greenhouse Gas Research Centre, PO Box 10002, Wellington 6143 (New Zealand); Meinshausen, Malte [Earth System Analysis, Potsdam Institute for Climate Impact Research (Germany); Manning, Martin, E-mail: andy.reisinger@nzagrc.org.nz [Climate Change Research Institute, Victoria University of Wellington (New Zealand)

    2011-04-15

    Global warming potentials (GWPs) are the metrics currently used to compare emissions of different greenhouse gases under the United Nations Framework Convention on Climate Change. Future changes in greenhouse gas concentrations will alter GWPs because the radiative efficiencies of marginal changes in CO{sub 2}, CH{sub 4} and N{sub 2}O depend on their background concentrations, the removal of CO{sub 2} is influenced by climate-carbon cycle feedbacks, and atmospheric residence times of CH{sub 4} and N{sub 2}O also depend on ambient temperature and other environmental changes. We calculated the currently foreseeable future changes in the absolute GWP of CO{sub 2}, which acts as the denominator for the calculation of all GWPs, and specifically the GWPs of CH{sub 4} and N{sub 2}O, along four representative concentration pathways (RCPs) up to the year 2100. We find that the absolute GWP of CO{sub 2} decreases under all RCPs, although for longer time horizons this decrease is smaller than for short time horizons due to increased climate-carbon cycle feedbacks. The 100-year GWP of CH{sub 4} would increase up to 20% under the lowest RCP by 2100 but would decrease by up to 10% by mid-century under the highest RCP. The 100-year GWP of N{sub 2}O would increase by more than 30% by 2100 under the highest RCP but would vary by less than 10% under other scenarios. These changes are not negligible but are mostly smaller than the changes that would result from choosing a different time horizon for GWPs, or from choosing altogether different metrics for comparing greenhouse gas emissions, such as global temperature change potentials.

  1. DNA Synthesis during Endomitosis Is Stimulated by Insulin via the PI3K/Akt and TOR Signaling Pathways in the Silk Gland Cells of Bombyx mori

    Directory of Open Access Journals (Sweden)

    Yaofeng Li

    2015-03-01

    Full Text Available Silk gland cells undergo multiple endomitotic cell cycles during silkworm larval ontogeny. Our previous study demonstrated that feeding is required for continued endomitosis in the silk gland cells of silkworm larvae. Furthermore, the insulin signaling pathway is closely related to nutritional signals. To investigate whether the insulin signaling pathway is involved in endomitosis in silk gland cells, in this study, we initially analyzed the effects of bovine insulin on DNA synthesis in endomitotic silk gland cells using 5-bromo-2'-deoxyuridine (BrdU labeling technology, and found that bovine insulin can stimulate DNA synthesis. Insulin signal transduction is mainly mediated via phosphoinositide 3-kinase (PI3K/Akt, the target of rapamycin (TOR and the extracellular signal-regulated kinase (ERK pathways in vertebrates. We ascertained that these three pathways are involved in DNA synthesis in endomitotic silk gland cells using specific inhibitors against each pathway. Moreover, we investigated whether these three pathways are involved in insulin-stimulated DNA synthesis in endomitotic silk gland cells, and found that the PI3K/Akt and TOR pathways, but not the ERK pathway, are involved in this process. These results provide an important theoretical foundation for the further investigations of the mechanism underlying efficient endomitosis in silk gland cells.

  2. Intraspecific evolution of the intercellular signaling network underlying a robust developmental system.

    Science.gov (United States)

    Milloz, Josselin; Duveau, Fabien; Nuez, Isabelle; Félix, Marie-Anne

    2008-11-01

    Many biological systems produce an invariant output when faced with stochastic or environmental variation. This robustness of system output to variation affecting the underlying process may allow for "cryptic" genetic evolution within the system without change in output. We studied variation of cell fate patterning of Caenorhabditis elegans vulva precursors, a developmental system that relies on a simple intercellular signaling network and yields an invariant output of cell fates and lineages among C. elegans wild isolates. We first investigated the system's genetic variation in C. elegans by means of genetic tools and cell ablation to break down its buffering mechanisms. We uncovered distinct architectures of quantitative variation along the Ras signaling cascade, including compensatory variation, and differences in cell sensitivity to induction along the anteroposterior axis. In the unperturbed system, we further found variation between isolates in spatio-temporal dynamics of Ras pathway activity, which can explain the phenotypic differences revealed upon perturbation. Finally, the variation mostly affects the signaling pathways in a tissue-specific manner. We thus demonstrate and characterize microevolution of a developmental signaling network. In addition, our results suggest that the vulva genetic screens would have yielded a different mutation spectrum, especially for Wnt pathway mutations, had they been performed in another C. elegans genetic background.

  3. Targeting the Mitotic Catastrophe Signaling Pathway in Cancer

    Science.gov (United States)

    Mc Gee, Margaret M.

    2015-01-01

    Mitotic catastrophe, as defined in 2012 by the International Nomenclature Committee on Cell Death, is a bona fide intrinsic oncosuppressive mechanism that senses mitotic failure and responds by driving a cell to an irreversible antiproliferative fate of death or senescence. Thus, failed mitotic catastrophe can promote the unrestrained growth of defective cells, thereby representing a major gateway to tumour development. Furthermore, the activation of mitotic catastrophe offers significant therapeutic advantage which has been exploited in the action of conventional and targeted anticancer agents. Yet, despite its importance in tumour prevention and treatment, the molecular mechanism of mitotic catastrophe is not well understood. A better understanding of the signals that determine cell fate following failed or defective mitosis will reveal new opportunities to selectively target and enhance the programme for therapeutic benefit and reveal biomarkers to predict patient response. This review is focused on the molecular mechanism of mitotic catastrophe induction and signalling and highlights current strategies to exploit the process in cancer therapy. PMID:26491220

  4. Signaling pathways and immune evasion mechanisms in classical Hodgkin lymphoma.

    Science.gov (United States)

    Liu, W Robert; Shipp, Margaret A

    2017-11-23

    Classical Hodgkin lymphoma (cHL) is an unusual B-cell-derived malignancy in which rare malignant Hodgkin and Reed-Sternberg (HRS) cells are surrounded by an extensive but ineffective inflammatory/immune cell infiltrate. This striking feature suggests that malignant HRS cells escape immunosurveillance and interact with immune cells in the cancer microenvironment for survival and growth. We previously found that cHLs have a genetic basis for immune evasion: near-uniform copy number alterations of chromosome 9p24.1 and the associated PD-1 ligand loci, CD274/PD-L1 and PDCD1LG2/PD-L2, and copy number-dependent increased expression of these ligands. HRS cells expressing PD-1 ligands are thought to engage PD-1 receptor-positive immune effectors in the tumor microenvironment and induce PD-1 signaling and associated immune evasion. The genetic bases of enhanced PD-1 signaling in cHL make these tumors uniquely sensitive to PD-1 blockade. © 2017 by The American Society of Hematology.

  5. Hydrogen peroxide induces activation of insulin signaling pathway via AMP-dependent kinase in podocytes

    Energy Technology Data Exchange (ETDEWEB)

    Piwkowska, Agnieszka, E-mail: apiwkowska@cmdik.pan.pl [Mossakowski Medical Research Centre, Polish Academy of Sciences, Laboratory of Molecular and Cellular Nephrology, Gdansk (Poland); Rogacka, Dorota; Angielski, Stefan [Mossakowski Medical Research Centre, Polish Academy of Sciences, Laboratory of Molecular and Cellular Nephrology, Gdansk (Poland); Jankowski, Maciej [Mossakowski Medical Research Centre, Polish Academy of Sciences, Laboratory of Molecular and Cellular Nephrology, Gdansk (Poland); Medical University of Gdansk, Department of Therapy Monitoring and Pharmacogenetics (Poland)

    2012-11-09

    (from 0.88 {+-} 0.04 to 1.29 {+-} 0.12 nmol/min/mg protein, P < 0.05), and this effect was attenuated by Compound C. Our results suggested that H{sub 2}O{sub 2} activated the insulin signaling pathway and glucose uptake via AMPK in cultured rat podocytes. This signaling may play a potential role in the prevention of insulin resistance under conditions associated with oxidative stress.

  6. Inflammatory stress increases hepatic CD36 translational efficiency via activation of the mTOR signalling pathway.

    Directory of Open Access Journals (Sweden)

    Chuan Wang

    Full Text Available Inflammatory stress is an independent risk factor for the development of non-alcoholic fatty liver disease (NAFLD. Although CD36 is known to facilitate long-chain fatty acid uptake and contributes to NAFLD progression, the mechanisms that link inflammatory stress to hepatic CD36 expression and steatosis remain unclear. As the mammalian target of rapamycin (mTOR signalling pathway is involved in CD36 translational activation, this study was undertaken to investigate whether inflammatory stress enhances hepatic CD36 expression via mTOR signalling pathway and the underlying mechanisms. To induce inflammatory stress, we used tumour necrosis factor alpha (TNF-α and interleukin-6 (IL-6 stimulation of the human hepatoblastoma HepG2 cells in vitro and casein injection in C57BL/6J mice in vivo. The data showed that inflammatory stress increased hepatic CD36 protein levels but had no effect on mRNA expression. A protein degradation assay revealed that CD36 protein stability was not different between HepG2 cells treated with or without TNF-α or IL-6. A polysomal analysis indicated that CD36 translational efficiency was significantly increased by inflammatory stress. Additionally, inflammatory stress enhanced the phosphorylation of mTOR and its downstream translational regulators including p70S6K, 4E-BP1 and eIF4E. Rapamycin, an mTOR-specific inhibitor, reduced the phosphorylation of mTOR signalling pathway and decreased the CD36 translational efficiency and protein level even under inflammatory stress resulting in the alleviation of inflammatory stress-induced hepatic lipid accumulation. This study demonstrates that the activation of the mTOR signalling pathway increases hepatic CD36 translational efficiency, resulting in increased CD36 protein expression under inflammatory stress.

  7. Parallel thalamic pathways for whisking and touch signals in the rat.

    Directory of Open Access Journals (Sweden)

    Chunxiu Yu

    2006-05-01

    Full Text Available In active sensation, sensory information is acquired via movements of sensory organs; rats move their whiskers repetitively to scan the environment, thus detecting, localizing, and identifying objects. Sensory information, in turn, affects future motor movements. How this motor-sensory-motor functional loop is implemented across anatomical loops of the whisker system is not yet known. While inducing artificial whisking in anesthetized rats, we recorded the activity of individual neurons from three thalamic nuclei of the whisker system, each belonging to a different major afferent pathway: paralemniscal, extralemniscal (a recently discovered pathway, or lemniscal. We found that different sensory signals related to active touch are conveyed separately via the thalamus by these three parallel afferent pathways. The paralemniscal pathway conveys sensor motion (whisking signals, the extralemniscal conveys contact (touch signals, and the lemniscal pathway conveys combined whisking-touch signals. This functional segregation of anatomical pathways raises the possibility that different sensory-motor processes, such as those related to motion control, object localization, and object identification, are implemented along different motor-sensory-motor loops.

  8. Wwox suppresses breast cancer cell growth through modulation of the hedgehog–GLI1 signaling pathway

    International Nuclear Information System (INIS)

    Xiong, Anwen; Wei, Li; Ying, Mingzhen; Wu, Hongmei; Hua, Jin; Wang, Yajie

    2014-01-01

    Highlights: • We investigated Gli1 as a novel partner of Wwox. • We observed a physical association between Wwox and the Gli1. • Wwox–Gli1 interaction affects Gli1 intracellular localization. • Gli1 Blocks Wwox-induced growth inhibition and apoptosis in T47D cells. - Abstract: Wwox is a tumor suppressor that is frequently deleted or altered in several cancer types, including breast cancer. Previous studies have shown that ectopic expression of Wwox inhibits proliferation of breast cancer cells. However, the underlying mechanism remains unclear. To better understand the molecular mechanisms of Wwox function, we investigated novel partners of this protein. Utilizing the coimmunoprecipitation assay, we observed a physical association between Wwox and the Gli1 zinc-finger transcription factor involved in the hedgehog pathway. Our results further demonstrated that Wwox expression triggered redistribution of nuclear Gli1 to the cytoplasm. Additionally, ectopic expression of Wwox reduced Gli1 expression in vitro. Furthermore, Gli1 Blocks Wwox-induced breast cancer cell growth inhibition. These findings suggest a functional crosstalk between Wwox and hedgehog–GLI1 signaling pathway in tumorigenesis

  9. Wwox suppresses breast cancer cell growth through modulation of the hedgehog–GLI1 signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Xiong, Anwen [Department of Oncology, Changhai Hospital, Second Military Medical University, Shanghai (China); Wei, Li [Department of Oncology, Changhai Hospital, Second Military Medical University, Shanghai (China); Department of Oncology, NO. 401 hospital of PLA, Qingdao, Shandong (China); Ying, Mingzhen; Wu, Hongmei; Hua, Jin [Department of Oncology, Changhai Hospital, Second Military Medical University, Shanghai (China); Wang, Yajie, E-mail: yajiewang@live.com [Department of Oncology, Changhai Hospital, Second Military Medical University, Shanghai (China)

    2014-01-24

    Highlights: • We investigated Gli1 as a novel partner of Wwox. • We observed a physical association between Wwox and the Gli1. • Wwox–Gli1 interaction affects Gli1 intracellular localization. • Gli1 Blocks Wwox-induced growth inhibition and apoptosis in T47D cells. - Abstract: Wwox is a tumor suppressor that is frequently deleted or altered in several cancer types, including breast cancer. Previous studies have shown that ectopic expression of Wwox inhibits proliferation of breast cancer cells. However, the underlying mechanism remains unclear. To better understand the molecular mechanisms of Wwox function, we investigated novel partners of this protein. Utilizing the coimmunoprecipitation assay, we observed a physical association between Wwox and the Gli1 zinc-finger transcription factor involved in the hedgehog pathway. Our results further demonstrated that Wwox expression triggered redistribution of nuclear Gli1 to the cytoplasm. Additionally, ectopic expression of Wwox reduced Gli1 expression in vitro. Furthermore, Gli1 Blocks Wwox-induced breast cancer cell growth inhibition. These findings suggest a functional crosstalk between Wwox and hedgehog–GLI1 signaling pathway in tumorigenesis.

  10. Are innate immune signaling pathways in plants and animals conserved?

    Science.gov (United States)

    Ausubel, Frederick M

    2005-10-01

    Although adaptive immunity is unique to vertebrates, the innate immune response seems to have ancient origins. Common features of innate immunity in vertebrates, invertebrate animals and plants include defined receptors for microbe-associated molecules, conserved mitogen-associated protein kinase signaling cascades and the production of antimicrobial peptides. It is commonly reported that these similarities in innate immunity represent a process of divergent evolution from an ancient unicellular eukaryote that pre-dated the divergence of the plant and animal kingdoms. However, at present, data suggest that the seemingly analogous regulatory modules used in plant and animal innate immunity are a consequence of convergent evolution and reflect inherent constraints on how an innate immune system can be constructed.

  11. Insulin-like growth factor-1 suppresses the Myostatin signaling pathway during myogenic differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Retamales, A.; Zuloaga, R.; Valenzuela, C.A. [Laboratorio de Biotecnología Molecular, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Santiago (Chile); Gallardo-Escarate, C. [Laboratory of Biotechnology and Aquatic Genomics, Universidad de Concepción, Concepción (Chile); Interdisciplinary Center for Aquaculture Research (INCAR), P.O. Box 160-C, Concepción (Chile); Molina, A. [Laboratorio de Biotecnología Molecular, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Santiago (Chile); Interdisciplinary Center for Aquaculture Research (INCAR), P.O. Box 160-C, Concepción (Chile); Valdés, J.A., E-mail: jvaldes@unab.cl [Laboratorio de Biotecnología Molecular, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Santiago (Chile); Interdisciplinary Center for Aquaculture Research (INCAR), P.O. Box 160-C, Concepción (Chile)

    2015-08-21

    Myogenic differentiation is a complex and well-coordinated process for generating mature skeletal muscle fibers. This event is autocrine/paracrine regulated by growth factors, principally Myostatin (MSTN) and Insulin-like Growth Factor-1 (IGF-1). Myostatin, a member of the transforming growth factor-β superfamily, is a negative regulator of skeletal muscle growth in vertebrates that exerts its inhibitory function by activating Smad transcription factors. In contrast, IGF-1 promotes the differentiation of skeletal myoblasts by activating the PI3K/Akt signaling pathway. This study reports on a novel functional crosstalk between the IGF-1 and MSTN signaling pathways, as mediated through interaction between PI3K/Akt and Smad3. Stimulation of skeletal myoblasts with MSTN resulted in a transient increase in the pSmad3:Smad3 ratio and Smad-dependent transcription. Moreover, MSTN inhibited myod gene expression and myoblast fusion in an Activin receptor-like kinase/Smad3-dependent manner. Preincubation of skeletal myoblasts with IGF-1 blocked MSTN-induced Smad3 activation, promoting myod expression and myoblast differentiation. This inhibitory effect of IGF-1 on the MSTN signaling pathway was dependent on IGF-1 receptor, PI3K, and Akt activities. Finally, immunoprecipitation assay analysis determined that IGF-1 pretreatment increased Akt and Smad3 interaction. These results demonstrate that the IGF-1/PI3K/Akt pathway may inhibit MSTN signaling during myoblast differentiation, providing new insight to existing knowledge on the complex crosstalk between both growth factors. - Highlights: • IGF-1 inhibits Myostatin canonical signaling pathway through IGF-1R/PI3K/Akt pathway. • IGF-1 promotes myoblast differentiation through a direct blocking of Myostatin signaling pathway. • IGF-1 induces the interaction of Akt with Smad3 in skeletal myoblast.

  12. Interactions between Trypanosoma cruzi Secreted Proteins and Host Cell Signaling Pathways

    Science.gov (United States)

    Watanabe Costa, Renata; da Silveira, Jose F.; Bahia, Diana

    2016-01-01

    Chagas disease is one of the prevalent neglected tropical diseases, affecting at least 6–7 million individuals in Latin America. It is caused by the protozoan parasite Trypanosoma cruzi, which is transmitted to vertebrate hosts by blood-sucking insects. After infection, the parasite invades and multiplies in the myocardium, leading to acute myocarditis that kills around 5% of untreated individuals. T. cruzi secretes proteins that manipulate multiple host cell signaling pathways to promote host cell invasion. The primary secreted lysosomal peptidase in T. cruzi is cruzipain, which has been shown to modulate the host immune response. Cruzipain hinders macrophage activation during the early stages of infection by interrupting the NF-kB P65 mediated signaling pathway. This allows the parasite to survive and replicate, and may contribute to the spread of infection in acute Chagas disease. Another secreted protein P21, which is expressed in all of the developmental stages of T. cruzi, has been shown to modulate host phagocytosis signaling pathways. The parasite also secretes soluble factors that exert effects on host extracellular matrix, such as proteolytic degradation of collagens. Finally, secreted phospholipase A from T. cruzi contributes to lipid modifications on host cells and concomitantly activates the PKC signaling pathway. Here, we present a brief review of the interaction between secreted proteins from T. cruzi and the host cells, emphasizing the manipulation of host signaling pathways during invasion. PMID:27065960

  13. Constraint-based modeling and kinetic analysis of the Smad dependent TGF-beta signaling pathway.

    Directory of Open Access Journals (Sweden)

    Zhike Zi

    Full Text Available BACKGROUND: Investigation of dynamics and regulation of the TGF-beta signaling pathway is central to the understanding of complex cellular processes such as growth, apoptosis, and differentiation. In this study, we aim at using systems biology approach to provide dynamic analysis on this pathway. METHODOLOGY/PRINCIPAL FINDINGS: We proposed a constraint-based modeling method to build a comprehensive mathematical model for the Smad dependent TGF-beta signaling pathway by fitting the experimental data and incorporating the qualitative constraints from the experimental analysis. The performance of the model generated by constraint-based modeling method is significantly improved compared to the model obtained by only fitting the quantitative data. The model agrees well with the experimental analysis of TGF-beta pathway, such as the time course of nuclear phosphorylated Smad, the subcellular location of Smad and signal response of Smad phosphorylation to different doses of TGF-beta. CONCLUSIONS/SIGNIFICANCE: The simulation results indicate that the signal response to TGF-beta is regulated by the balance between clathrin dependent endocytosis and non-clathrin mediated endocytosis. This model is useful to be built upon as new precise experimental data are emerging. The constraint-based modeling method can also be applied to quantitative modeling of other signaling pathways.

  14. Interactions between Trypanosoma cruzi secreted proteins and host cell signaling pathways

    Directory of Open Access Journals (Sweden)

    Renata Watanabe Costa

    2016-03-01

    Full Text Available Chagas disease is one of the prevalent neglected tropical diseases, affecting at least 6-7 million individuals in Latin America. It is caused by the protozoan parasite Trypanosoma cruzi (T. cruzi, which is transmitted to vertebrate hosts by blood-sucking insects. After infection, the parasite invades and multiplies in the myocardium, leading to acute myocarditis that kills around 5% of untreated individuals. T. cruzi secretes proteins that manipulate multiple host cell signaling pathways to promote host cell invasion. The primary secreted lysosomal peptidase in T. cruzi is cruzipain, which has been shown to modulate the host immune response. Cruzipain hinders macrophage activation during the early stages of infection by interrupting the NF-kB P65 mediated signaling pathway. This allows the parasite to survive and replicate, and may contribute to the spread of infection in acute Chagas disease. Another secreted protein P21, which is expressed in all of the developmental stages of T. cruzi, has been shown to modulate host phagocytosis signaling pathways. The parasite also secretes soluble factors that exert effects on host extracellular matrix, such as proteolytic degradation of collagens. Finally, secreted phospholipase A from T. cruzi contributes to lipid modifications on host cells and concomitantly activates the PKC signaling pathway. Here we present a brief review of the interaction between secreted proteins from T. cruzi and the host cells, emphasizing the manipulation of host signaling pathways during invasion.

  15. Modular and Stochastic Approaches to Molecular Pathway Models of ATM, TGF beta, and WNT Signaling

    Science.gov (United States)

    Cucinotta, Francis A.; O'Neill, Peter; Ponomarev, Artem; Carra, Claudio; Whalen, Mary; Pluth, Janice M.

    2009-01-01

    Deterministic pathway models that describe the biochemical interactions of a group of related proteins, their complexes, activation through kinase, etc. are often the basis for many systems biology models. Low dose radiation effects present a unique set of challenges to these models including the importance of stochastic effects due to the nature of radiation tracks and small number of molecules activated, and the search for infrequent events that contribute to cancer risks. We have been studying models of the ATM, TGF -Smad and WNT signaling pathways with the goal of applying pathway models to the investigation of low dose radiation cancer risks. Modeling challenges include introduction of stochastic models of radiation tracks, their relationships to more than one substrate species that perturb pathways, and the identification of a representative set of enzymes that act on the dominant substrates. Because several pathways are activated concurrently by radiation the development of modular pathway approach is of interest.

  16. Identification of T cell-signaling pathways that stimulate latent HIV in primary cells

    Science.gov (United States)

    Brooks, David G.; Arlen, Philip A.; Gao, Lianying; Kitchen, Christina M. R.; Zack, Jerome A.

    2003-01-01

    Eradication of HIV infection depends on the elimination of a small, but stable population of latently infected T cells. After the discontinuation of therapy, activation of latent virus can rekindle infection. To purge this reservoir, it is necessary to define cellular signaling pathways that lead to activation of latent HIV. We used the SCID-hu (Thy/Liv) mouse model of HIV latency to analyze a broad array of T cell-signaling pathways and show in primary, quiescent cells that viral induction depends on the activation of two primary intracellular signaling pathways, protein kinase C or nuclear factor of activated T cells (NF-AT). In contrast, inhibition or activation of other important T cell stimulatory pathways (such as mitogen-activated protein kinase, calcium flux, or histone deacetylation) do not significantly induce virus expression. We found that the activation of NF-κB is critical to viral reactivation; however, all pathways that stimulate NF-κBdonot reactivate latent virus. Our studies further show that inhibition of NF-κB does not prevent activation of HIV by NF-AT, indicating that these pathways can function independently to activate the HIV LTR. Thus, we define several molecular pathways that trigger HIV reactivation from latency and provide evidence that latent HIV infection is maintained by the functional lack of particular transcription factors in quiescent cells. PMID:14569007

  17. The primary nitrate response: a multifaceted signalling pathway.

    Science.gov (United States)

    Medici, Anna; Krouk, Gabriel

    2014-10-01

    Nitrate (NO3(-)) application strongly affects gene expression in plants. This regulation is thought to be crucial for their adaptation in response to a changing nutritional environment. Depending on the conditions preceding or concomitant with nitrate provision, the treatment can affect up to a 10th of genome expression in Arabidopsis thaliana. The early events occurring after NO3(-) provision are often called the Primary Nitrate Response (PNR). Despite this simple definition, PNR is a complex process that is difficult to properly delineate. Here we report the different concepts related to PNR, review the different molecular components known to control it, and show, using meta-analysis, that this concept/pathway is not monolithic. We especially bring our attention to the genome-wide effects of LBD37 and LBD38 overexpression, NLP7, and CHL1/NRT1.1 mutations. © The Author 2014. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  18. An interplay between 2 signaling pathways: Melatonin-cAMP and IP3–Ca2+ signaling pathways control intraerythrocytic development of the malaria parasite Plasmodium falciparum

    International Nuclear Information System (INIS)

    Furuyama, Wakako; Enomoto, Masahiro; Mossaad, Ehab; Kawai, Satoru; Mikoshiba, Katsuhiko; Kawazu, Shin-ichiro

    2014-01-01

    Highlights: • A melatonin receptor antagonist blocked Ca 2+ oscillation in P. falciparum and inhibited parasite growth. • P. falciparum development is controlled by Ca 2+ - and cAMP-signaling pathways. • The cAMP-signaling pathway at ring form and late trophozoite stages governs parasite growth of P. falciparum. - Abstract: Plasmodium falciparum spends most of its asexual life cycle within human erythrocytes, where proliferation and maturation occur. Development into the mature forms of P. falciparum causes severe symptoms due to its distinctive sequestration capability. However, the physiological roles and the molecular mechanisms of signaling pathways that govern development are poorly understood. Our previous study showed that P. falciparum exhibits stage-specific spontaneous Calcium (Ca 2+ ) oscillations in ring and early trophozoites, and the latter was essential for parasite development. In this study, we show that luzindole (LZ), a selective melatonin receptor antagonist, inhibits parasite growth. Analyses of development and morphology of LZ-treated P. falciparum revealed that LZ severely disrupted intraerythrocytic maturation, resulting in parasite death. When LZ was added at ring stage, the parasite could not undergo further development, whereas LZ added at the trophozoite stage inhibited development from early into late schizonts. Live-cell Ca 2+ imaging showed that LZ treatment completely abolished Ca 2+ oscillation in the ring forms while having little effect on early trophozoites. Further, the melatonin-induced cAMP increase observed at ring and late trophozoite stage was attenuated by LZ treatment. These suggest that a complex interplay between IP 3 –Ca 2+ and cAMP signaling pathways is involved in intraerythrocytic development of P. falciparum

  19. Molecular evolutionary patterns of NAD+/Sirtuin aging signaling pathway across taxa.

    Directory of Open Access Journals (Sweden)

    Uma Gaur

    Full Text Available A deeper understanding of the conserved molecular mechanisms in different taxa have been made possible only because of the evolutionary conservation of crucial signaling pathways. In the present study, we explored the molecular evolutionary pattern of selection signatures in 51 species for 10 genes which are important components of NAD+/Sirtuin pathway and have already been directly linked to lifespan extension in worms and mice. Selection pressure analysis using PAML program revealed that MRPS5 and PPARGC1A were under significant constraints because of their functional significance. FOXO3a also displayed strong purifying selection. All three sirtuins, which were SIRT1, SIRT2 and SIRT6, displayed a great degree of conservation between taxa, which is consistent with the previous report. A significant evolutionary constraint is seen on the anti-oxidant gene, SOD3. As expected, TP53 gene was under significant selection pressure in mammals, owing to its major role in tumor progression. Poly-ADP-ribose polymerase (PARP genes displayed the most sites under positive selection. Further 3D structural analysis of PARP1 and PARP2 protein revealed that some of these positively selected sites caused a change in the electrostatic potential of the protein structure, which may allow a change in its interaction with other proteins and molecules ultimately leading to difference in the function. Although the functional significance of the positively selected sites could not be established in the variants databases, yet it will be interesting to see if these sites actually affect the function of PARP1 and PARP2.

  20. KSHV ORF K9 (vIRF) is an oncogene which inhibits the interferon signaling pathway.

    Science.gov (United States)

    Gao, S J; Boshoff, C; Jayachandra, S; Weiss, R A; Chang, Y; Moore, P S

    1997-10-16

    Kaposi's sarcoma-associated herpesvirus (KSHV) is a gammaherpesvirus linked to the development of Kaposi's sarcoma and a rare B cell lymphoma, primary effusion lymphoma. The KSHV gene ORF K9 encodes vIRF which is a protein with low but significant homology to members of the interferon (IFN) regulatory factor (IRF) family responsible for regulating intracellular interferon signal transduction (Moore PS, Boshoff C, Weiss RA and Chang Y. (1996). Science, 274, 1739-1744). vIRF inhibits IFN-beta signal transduction as measured using an IFN-responsive ISG54 reporter construct co-transfected with ORF K9 into HeLa and 293 cells. vIRF also suppresses genes under IFN regulatory control as shown by inhibition of the IFN-beta inducibility of p21WAF1/CIP1, however, no direct DNA-binding or protein-protein interactions characteristic for IRF repressor proteins were identified. Stable transfectant NIH3T3 clones expressing vIRF grew in soft agar and at low serum concentrations, lost contact inhibition and formed tumors after injection into nude mice indicating that vIRF has the properties of a viral oncogene. Since vIRF is primarily expressed in KSHV-infected B cells, not KS spindle cells, this study suggests that vIRF is a transforming oncogene active in B cell neoplasias that may provide a unique immune escape mechanism for infected cells. This data is consistent with tumor suppressor pathways serving a dual function as host cell antiviral pathways.

  1. Putrescine stimulates the mTOR signaling pathway and protein synthesis in porcine trophectoderm cells.

    Science.gov (United States)

    Kong, Xiangfeng; Wang, Xiaoqiu; Yin, Yulong; Li, Xilong; Gao, Haijun; Bazer, Fuller W; Wu, Guoyao

    2014-11-01

    Insufficient placental growth is a major factor contributing to intrauterine growth retardation in mammals. There is growing evidence that putrescine produced from arginine (Arg) and proline via ornithine decarboxylase is a key regulator of angiogenesis, embryogenesis, as well as placental and fetal growth. However, the underlying mechanisms are largely unknown. The present study tested the hypothesis that putrescine stimulates protein synthesis by activating the mechanistic target of rapamycin (mTOR) signaling pathway in porcine trophectoderm cell line 2 cells. The cells were cultured for 2 to 4 days in customized Arg-free Dulbecco modified Eagle Ham medium containing 0, 10, 25, or 50 μM putrescine or 100 μM Arg. Cell proliferation, protein synthesis, and degradation, as well as the abundance of total and phosphorylated mTOR, ribosomal protein S6 kinase 1, and eukaryotic initiation factor 4E-binding protein-1 (4EBP1), were determined. Our results indicate that putrescine promotes cell proliferation and protein synthesis in a dose- and time-dependent manner, which was inhibited by difluoro-methylornithine (an inhibitor of ornithine decarboxylase). Moreover, supplementation of culture medium with putrescine increased the abundance of phosphorylated mTOR and its downstream targets, 4EBP1 and p70 S6K1 proteins. Collectively, these findings reveal a novel and important role for putrescine in regulating the mTOR signaling pathway in porcine placental cells. We suggest that dietary supplementation with or intravenous administration of putrescine may provide a new and effective strategy to improve survival and growth of embryos/fetuses in mammals. © 2014 by the Society for the Study of Reproduction, Inc.

  2. Naringin Stimulates Osteogenic Differentiation of Rat Bone Marrow Stromal Cells via Activation of the Notch Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Guo-yong Yu

    2016-01-01

    Full Text Available Naringin is a major flavonoid found in grapefruit and is an active compound extracted from the Chinese herbal medicine Rhizoma Drynariae. Naringin is a potent stimulator of osteogenic differentiation and has potential application in preventing bone loss. However, the signaling pathway underlying its osteogenic effect remains unclear. We hypothesized that the osteogenic activity of naringin involves the Notch signaling pathway. Rat bone marrow stromal cells (BMSCs were cultured in osteogenic medium containing-naringin, with or without DAPT (an inhibitor of Notch signaling, the effects on ALP activity, calcium deposits, osteogenic genes (ALP, BSP, and cbfa1, adipogenic maker gene PPARγ2 levels, and Notch expression were examined. We found that naringin dose-dependently increased ALP activity and Alizarin red S staining, and treatment at the optimal concentration (50 μg/mL increased mRNA levels of osteogenic genes and Notch1 expression, while decreasing PPARγ2 mRNA levels. Furthermore, treatment with DAPT partly reversed effects of naringin on BMSCs, as judged by decreases in naringin-induced ALP activity, calcium deposits, and osteogenic genes expression, as well as upregulation of PPARγ2 mRNA levels. These results suggest that the osteogenic effect of naringin partly involves the Notch signaling pathway.

  3. Parallel pathways of ethoxylated alcohol biodegradation under aerobic conditions

    Energy Technology Data Exchange (ETDEWEB)

    Zembrzuska, Joanna, E-mail: Joanna.Zembrzuska@put.poznan.pl; Budnik, Irena, E-mail: Irena.Budnik@gmail.com; Lukaszewski, Zenon, E-mail: zenon.lukaszewski@put.poznan.pl

    2016-07-01

    Non-ionic surfactants (NS) are a major component of the surfactant flux discharged into surface water, and alcohol ethoxylates (AE) are the major component of this flux. Therefore, biodegradation pathways of AE deserve more thorough investigation. The aim of this work was to investigate the stages of biodegradation of homogeneous oxyethylated dodecanol C{sub 12}E{sub 9} having 9 oxyethylene subunits, under aerobic conditions. Enterobacter strain Z3 bacteria were chosen as biodegrading organisms under conditions with C{sub 12}E{sub 9} as the sole source of organic carbon. Bacterial consortia of river water were used in a parallel test as an inoculum for comparison. The LC-MS technique was used to identify the products of biodegradation. Liquid-liquid extraction with ethyl acetate was selected for the isolation of C{sub 12}E{sub 9} and metabolites from the biodegradation broth. The LC-MS/MS technique operating in the multiple reaction monitoring (MRM) mode was used for quantitative determination of C{sub 12}E{sub 9}, C{sub 12}E{sub 8}, C{sub 12}E{sub 7} and C{sub 12}E{sub 6}. Apart from the substrate, the homologues C{sub 12}E{sub 8}, C{sub 12}E{sub 7} and C{sub 12}E{sub 6}, being metabolites of C{sub 12}E{sub 9} biodegradation by shortening of the oxyethylene chain, as well as intermediate metabolites having a carboxyl end group in the oxyethylene chain (C{sub 12}E{sub 8}COOH, C{sub 12}E{sub 7}COOH, C{sub 12}E{sub 6}COOH and C{sub 12}E{sub 5}COOH), were identified. Poly(ethylene glycols) (E) having 9, 8 and 7 oxyethylene subunits were also identified, indicating parallel central fission of C{sub 12}E{sub 9} and its metabolites. Similar results were obtained with river water as inoculum. It is concluded that AE, under aerobic conditions, are biodegraded via two parallel pathways: by central fission with the formation of PEG, and by Ω-oxidation of the oxyethylene chain with the formation of carboxylated AE and subsequent shortening of the oxyethylene chain by a

  4. Endocrine disruption via estrogen receptors that participate in nongenomic signaling pathways

    Science.gov (United States)

    Watson, Cheryl S.; Jeng, Yow-Juin; Guptarak, Jutatip

    2011-01-01

    When inappropriate (non-physiologic) estrogens affect organisms at critical times of estrogen sensitivity, disruption of normal endocrine functions can result. Non-physiologic estrogen mimetics (environmental, dietary, pharmaceutical) can signal rapidly and potently via the membrane versions of estrogen receptors, as can physiologic estrogens. Both physiologic and non-physiologic estrogens activate multiple signaling pathways, leading to altered cellular functions (eg. peptide release, cell proliferation or death, transport). Xenoestrogens’ mimicry of physiologic estrogens is imperfect. When superimposed, xenoestrogens can alter endogenous estrogens’ signaling and thereby disrupt normal signaling pathways, leading to malfunctions in many tissue types. Though these xenoestrogen actions occur rapidly via nongenomic signaling pathways, they can be sustained with continuing ligand stimulation, combinations of ligands, and signaling that perpetuates downstream, eventually also impinging on genomic regulation by controlling the activation state of transcription factors. Because via these pathways estrogens and xenoestrogens cause nonmonotonic stimulation patterns, they must be carefully tested for activity and toxicity over wide dose ranges. Nongenomic actions of xenoestrogens in combination with each other, and with physiologic estrogens, are still largely unexplored from these mechanistic perspectives. PMID:21300151

  5. The Wnt signalling pathway is upregulated in an in vitro model of acquired tamoxifen resistant breast cancer

    International Nuclear Information System (INIS)

    Loh, Yan Ni; Hedditch, Ellen L; Baker, Laura A; Jary, Eve; Ward, Robyn L; Ford, Caroline E

    2013-01-01

    Acquired resistance to Tamoxifen remains a critical problem in breast cancer patient treatment, yet the underlying causes of resistance have not been fully elucidated. Abberations in the Wnt signalling pathway have been linked to many human cancers, including breast cancer, and appear to be associated with more metastatic and aggressive types of cancer. Here, our aim was to investigate if this key pathway was involved in acquired Tamoxifen resistance, and could be targeted therapeutically. An in vitro model of acquired Tamoxifen resistance (named TamR) was generated by growing the estrogen receptor alpha (ER) positive MCF7 breast cancer cell line in increasing concentrations of Tamoxifen (up to 5 uM). Alterations in the Wnt signalling pathway and epithelial to mesenchymal transition (EMT) in response to Tamoxifen and treatment with the Wnt inhibitor, IWP-2 were measured via quantitative RT-PCR (qPCR) and TOP/FOP Wnt reporter assays. Resistance to Tamoxifen, and effects of IWP-2 treatment were determined by MTT proliferation assays. TamR cells exhibited increased Wnt signalling as measured via the TOP/FOP Wnt luciferase reporter assays. Genes associated with both the β-catenin dependent (AXIN2, MYC, CSNK1A1) and independent arms (ROR2, JUN), as well as general Wnt secretion (PORCN) of the Wnt signalling pathway were upregulated in the TamR cells compared to the parental MCF7 cell line. Treatment of the TamR cell line with human recombinant Wnt3a (rWnt3a) further increased the resistance of both MCF7 and TamR cells to the anti-proliferative effects of Tamoxifen treatment. TamR cells demonstrated increased expression of EMT markers (VIM, TWIST1, SNAI2) and decreased CDH1, which may contribute to their resistance to Tamoxifen. Treatment with the Wnt inhibitor, IWP-2 inhibited cell proliferation and markers of EMT. These data support the role of the Wnt signalling pathway in acquired resistance to Tamoxifen. Further research into the mechanism by which activated Wnt

  6. Ultrasonic signal processing for sizing under-clad flaws

    International Nuclear Information System (INIS)

    Shankar, R.; Paradiso, T.J.; Lane, S.S.; Quinn, J.R.

    1985-01-01

    Ultrasonic digital data were collected from underclad cracks in sample pressure vessel specimen blocks. These blocks were weld cladded under different processes to simulate actual conditions in US Pressure Water Reactors. Each crack was represented by a flaw-echo dynamic curve which is a plot of the transducer motion on the surface as a function of the ultrasonic response into the material. Crack depth sizing was performed by identifying in the dynamic curve the crack tip diffraction signals from the upper and lower tips. This paper describes the experimental procedure, digital signal processing methods used and algorithms developed for crack depth sizing

  7. Interleukin-6 Attenuates Serotonin 2A Receptor Signaling by Activating the JAK-STAT Pathway

    Science.gov (United States)

    Donegan, Jennifer J.; Patton, Michael S.; Chavera, Teresa S.; Berg, Kelly A.; Morilak, David A.

    2015-01-01

    The serotonin 2A (5-HT2A) receptor and the proinflammatory cytokine, interleukin-6 (IL-6), have both been implicated in psychiatric disorders. Previously, we demonstrated that these molecules both facilitate cognitive flexibility, a prefrontal cortex-mediated executive function impaired in multiple mental illnesses. In this study, we tested the hypothesis that IL-6 influences 5-HT2A receptor signaling, providing a potential mechanism by which this cytokine may influence behavior. We first demonstrated that 5-HT2A receptors and IL-6–mediated STAT3 phosphorylation colocalize in cells of the prefrontal cortex, providing the neuroanatomical substrate for a potential interaction. In the neuronally derived A1A1 cell line, which expresses both IL-6 and 5-HT2A receptors, we found that IL-6 attenuates inositol phosphate (IP) accumulation in response to the 5-HT2 agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI), suggesting that IL-6 can regulate 5-HT2A receptor function. To identify the signaling pathway(s) that mediate this effect, we measured DOI-mediated IP accumulation in the presence of IL-6 and either the JAK-STAT inhibitor 124 [(9β,10α,16α,23E)-2,16,20,25-tetrahydroxy-9-methyl-19-norlanosta-1,5,23-triene-3,11,22-trione], JSI-124, or the extracellular signal-regulated kinase inhibitor, 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD-98059). The IL-6 effect was blocked by JSI-124 but not PD-98059. Furthermore, silencing RNA knockdown of either JAK or STAT blocked the IL-6 effect, suggesting that IL-6–induced JAK-STAT activation can regulate 5-HT2A receptor signaling. Finally, to determine if IL-6 specifically regulates the 5-HT2A receptor system, we measured IP production mediated by another Gq-coupled receptor, bradykinin B2. IL-6 had no effect on bradykinin-mediated IP accumulation, suggesting that regulation may occur at the 5-HT2A receptor. These results may provide clues to the pathologic mechanisms underlying certain psychiatric disorders and may

  8. Differential and directional estrogenic signaling pathways induced by enterolignans and their precursors.

    Directory of Open Access Journals (Sweden)

    Yun Zhu

    Full Text Available Mammalian lignans or enterolignans are metabolites of plant lignans, an important category of phytochemicals. Although they are known to be associated with estrogenic activity, cell signaling pathways leading to specific cell functions, and especially the differences among lignans, have not been explored. We examined the estrogenic activity of enterolignans and their precursor plant lignans and cell signaling pathways for some cell functions, cell cycle and chemokine secretion. We used DNA microarray-based gene expression profiling in human breast cancer MCF-7 cells to examine the similarities, as well as the differences, among enterolignans, enterolactone and enterodiol, and their precursors, matairesinol, pinoresinol and sesamin. The profiles showed moderate to high levels of correlation (R values: 0.44 to 0.81 with that of estrogen (17β-estradiol or E2. Significant correlations were observed among lignans (R values: 0.77 to 0.97, and the correlations were higher for cell functions related to enzymes, signaling, proliferation and transport. All the enterolignans/precursors examined showed activation of the Erk1/2 and PI3K/Akt pathways, indicating the involvement of rapid signaling through the non-genomic estrogen signaling pathway. However, when their effects on specific cell functions, cell cycle progression and chemokine (MCP-1 secretion were examined, positive effects were observed only for enterolactone, suggesting that signals are given in certain directions at a position closer to cell functions. We hypothesized that, while estrogen signaling is initiated by the enterolignans/precursors examined, their signals are differentially and directionally modulated later in the pathways, resulting in the differences at the cell function level.

  9. Novel lipid signaling pathways in Alzheimer's disease pathogenesis.

    Science.gov (United States)

    Giannopoulos, Phillip F; Joshi, Yash B; Praticò, Domenico

    2014-04-15

    Alzheimer's disease (AD) is the most common cause of dementia in the elderly. With an increasing longevity and the absence of a cure, AD has become not only a major health problem but also a heavy social and economic burden worldwide. In addition to the presence of abundant intra- and extra-cellular neurotoxic amyloid β (Aβ) peptides, which form the amyloid plaques, and intracellular hyperphosphorylated tau protein, the main component of neurofibrillary tangles, consistent evidence indicates that the AD brain is characterized by extensive neuroinflammatory processes. The 5-lipoxygenase (5LO) is a pro-inflammatory enzymatic pathway widely distributed within the central nervous system and is up-regulated in AD. In the last five years our group has been involved in unraveling the neurobiology of this protein and investigating its relationship with cellular and molecular events of functional importance in AD pathogenesis. By using a combination of in vitro and in vivo experimental tools and implementing genetic as well as pharmacological approaches today we know that 5LO is likely an endogenous regulator of Aβ formation via the modulation of the γ-secretase complex, and tau metabolism by modulating its phosphorylation state at specific epitopes via the cyclin-dependent kinase-5 (cdk-5). In addition, 5LO influences synaptic function and integrity and by doing so significantly affects learning and memory in the Tg2576 and 3xTg AD transgenic mouse models. Taken together our data establish this protein as a pleiotropic contributor to the development of the full spectrum of the AD-like phenotype in these mouse models of the disease, making it a viable therapeutic target for the treatment of AD in humans. Copyright © 2013 Elsevier Inc. All rights reserved.

  10. HIV Tat Impairs Neurogenesis through Functioning As a Notch Ligand and Activation of Notch Signaling Pathway.

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    Fan, Yan; Gao, Xiang; Chen, Jinhui; Liu, Ying; He, Johnny J

    2016-11-02

    Alterations in adult neurogenesis have been noted in the brain of HIV-infected individuals and are likely linked to HIV-associated neurocognitive deficits, including those in learning and memory. But the underlying molecular mechanisms are not fully understood. In the study, we took advantage of doxycycline-inducible and astrocyte-specific HIV-1 Tat transgenic mice (iTat) and determined the relationship between Tat expression and neurogenesis. Tat expression in astrocytes was associated with fewer neuron progenitor cells (NPCs), fewer immature neurons, and fewer mature neurons in the dentate gyrus of the hippocampus of the mouse brain. In vitro NPC-derived neurosphere assays showed that Tat-containing conditioned media from astrocytes or recombinant Tat protein inhibited NPC proliferation and migration and altered NPC differentiation, while immunodepletion of Tat from Tat-containing conditioned media or heat inactivation of recombinant Tat abrogated those effects. Notch signaling downstream gene Hes1 promoter-driven luciferase reporter gene assay and Western blotting showed that recombinant Tat or Tat-containing conditioned media activated Hes1 transcription and protein expression, which were abrogated by Tat heat inactivation, immunodepletion, and cysteine mutation at position 30. Last, Notch signaling inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT) significantly rescued Tat-impaired NPC differentiation in vitro and neurogenesis in vivo Together, these results show that Tat adversely affects NPCs and neurogenesis through Notch signaling and point to the potential of developing Notch signaling inhibitors as HIV/neuroAIDS therapeutics. HIV infection of the CNS causes cognitive and memory deficits, which have become more prevalent in the era of combination antiretroviral therapy (cART). Neurogenesis is impaired in HIV-infected individuals. But the underlying molecular mechanisms remain largely unknown. In this study, we have

  11. Low Expression of CAPON in Glioma Contributes to Cell Proliferation via the Akt Signaling Pathway

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    Shangfeng Gao

    2016-11-01

    Full Text Available CAPON is an adapter protein for nitric oxide synthase 1 (NOS1. CAPON has two isoforms in the human brain: CAPON-L (long form of CAPON and CAPON-S (short form of CAPON. Recent studies have indicated the involvement of CAPON in tumorigenesis beyond its classical role in NOS1 activity regulation. In this study, we found that the protein levels of CAPON-S, but not than CAPON-L, were significantly decreased in glioma tissues. Therefore, we established lentivirus-mediated stable cell lines with CAPON-S overexpression or down-regulation, and investigated the role of CAPON-S in the proliferation of glioma cells by using CCK8, EdU, and flow cytometry assays. Overexpression of CAPON-S reduced the cell variability and the percentage of EdU-positive cells, and arrested the cells in the G1 phase in glioma cells. Silencing of CAPON by short-hairpin RNA showed the opposite effects. Furthermore, an intracellular signaling array revealed that overexpression of CAPON-S resulted in a remarkable reduction in the phosphorylation of Akt and S6 ribosomal protein in glioma cells, which was further confirmed by Western blot. These findings suggest that CAPON may function as a tumor suppressor in human brain glioma and that the inactivation of the Akt signaling pathway caused by CAPON-S overexpression may provide insight into the underlying mechanism of CAPON in glioma cell proliferation.

  12. CD38/cADPR Signaling Pathway in Airway Disease: Regulatory Mechanisms

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    Deepak A. Deshpande

    2018-01-01

    Full Text Available Asthma is an inflammatory disease in which proinflammatory cytokines have a role in inducing abnormalities of airway smooth muscle function and in the development of airway hyperresponsiveness. Inflammatory cytokines alter calcium (Ca2+ signaling and contractility of airway smooth muscle, which results in nonspecific airway hyperresponsiveness to agonists. In this context, Ca2+ regulatory mechanisms in airway smooth muscle and changes in these regulatory mechanisms encompass a major component of airway hyperresponsiveness. Although dynamic Ca2+ regulation is complex, phospholipase C/inositol tris-phosphate (PLC/IP3 and CD38-cyclic ADP-ribose (CD38/cADPR are two major pathways mediating agonist-induced Ca2+ regulation in airway smooth muscle. Altered CD38 expression or enhanced cyclic ADP-ribosyl cyclase activity associated with CD38 contributes to human pathologies such as asthma, neoplasia, and neuroimmune diseases. This review is focused on investigations on the role of CD38-cyclic ADP-ribose signaling in airway smooth muscle in the context of transcriptional and posttranscriptional regulation of CD38 expression. The specific roles of transcription factors NF-kB and AP-1 in the transcriptional regulation of CD38 expression and of miRNAs miR-140-3p and miR-708 in the posttranscriptional regulation and the underlying mechanisms of such regulation are discussed.

  13. Projecting Drivers of Human Vulnerability under the Shared Socioeconomic Pathways

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    Guillaume Rohat

    2018-03-01

    Full Text Available The Shared Socioeconomic Pathways (SSPs are the new set of alternative futures of societal development that inform global and regional climate change research. They have the potential to foster the integration of socioeconomic scenarios within assessments of future climate-related health impacts. To date, such assessments have primarily superimposed climate scenarios on current socioeconomic conditions only. Until now, the few assessments of future health risks that employed the SSPs have focused on future human exposure—i.e., mainly future population patterns—, neglecting future human vulnerability. This paper first explores the research gaps—mainly linked to the paucity of available projections—that explain such a lack of consideration of human vulnerability under the SSPs. It then highlights the need for projections of socioeconomic variables covering the wide range of determinants of human vulnerability, available at relevant spatial and temporal scales, and accounting for local specificities through sectoral and regional extended versions of the global SSPs. Finally, this paper presents two innovative methods of obtaining and computing such socioeconomic projections under the SSPs—namely the scenario matching approach and an approach based on experts’ elicitation and correlation analyses—and applies them to the case of Europe. They offer a variety of possibilities for practical application, producing projections at sub-national level of various drivers of human vulnerability such as demographic and social characteristics, urbanization, state of the environment, infrastructure, health status, and living arrangements. Both the innovative approaches presented in this paper and existing methods—such as the spatial disaggregation of existing projections and the use of sectoral models—show great potential to enhance the availability of relevant projections of determinants of human vulnerability. Assessments of future climate

  14. Discovery of GPCR ligands for probing signal transduction pathways.

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    Brogi, Simone; Tafi, Andrea; Désaubry, Laurent; Nebigil, Canan G

    2014-01-01

    G protein-coupled receptors (GPCRs) are seven integral transmembrane proteins that are the primary targets of almost 30% of approved drugs and continue to represent a major focus of pharmaceutical research. All of GPCR targeted medicines were discovered by classical medicinal chemistry approaches. After the first GPCR crystal structures were determined, the docking screens using these structures lead to discovery of more novel and potent ligands. There are over 360 pharmaceutically relevant GPCRs in the human genome and to date about only 30 of structures have been determined. For these reasons, computational techniques such as homology modeling and molecular dynamics simulations have proven their usefulness to explore the structure and function of GPCRs. Furthermore, structure-based drug design and in silico screening (High Throughput Docking) are still the most common computational procedures in GPCRs drug discovery. Moreover, ligand-based methods such as three-dimensional quantitative structure-selectivity relationships, are the ideal molecular modeling approaches to rationalize the activity of tested GPCR ligands and identify novel GPCR ligands. In this review, we discuss the most recent advances for the computational approaches to effectively guide selectivity and affinity of ligands. We also describe novel approaches in medicinal chemistry, such as the development of biased agonists, allosteric modulators, and bivalent ligands for class A GPCRs. Furthermore, we highlight some knockout mice models in discovering biased signaling selectivity.

  15. Discovery of GPCR ligands for probing signal transduction pathways

    Science.gov (United States)

    Brogi, Simone; Tafi, Andrea; Désaubry, Laurent; Nebigil, Canan G.

    2014-01-01

    G protein-coupled receptors (GPCRs) are seven integral transmembrane proteins that are the primary targets of almost 30% of approved drugs and continue to represent a major focus of pharmaceutical research. All of GPCR targeted medicines were discovered by classical medicinal chemistry approaches. After the first GPCR crystal structures were determined, the docking screens using these structures lead to discovery of more novel and potent ligands. There are over 360 pharmaceutically relevant GPCRs in the human genome and to date about only 30 of structures have been determined. For these reasons, computational techniques such as homology modeling and molecular dynamics simulations have proven their usefulness to explore the structure and function of GPCRs. Furthermore, structure-based drug design and in silico screening (High Throughput Docking) are still the most common computational procedures in GPCRs drug discovery. Moreover, ligand-based methods such as three-dimensional quantitative structure–selectivity relationships, are the ideal molecular modeling approaches to rationalize the activity of tested GPCR ligands and identify novel GPCR ligands. In this review, we discuss the most recent advances for the computational approaches to effectively guide selectivity and affinity of ligands. We also describe novel approaches in medicinal chemistry, such as the development of biased agonists, allosteric modulators, and bivalent ligands for class A GPCRs. Furthermore, we highlight some knockout mice models in discovering biased signaling selectivity. PMID:25506327

  16. Signaling Pathways in Exosomes Biogenesis, Secretion and Fate

    Directory of Open Access Journals (Sweden)

    Carla Emiliani

    2013-03-01

    Full Text Available Exosomes are small extracellular vesicles (30–100 nm derived from the endosomal system, which have raised considerable interest in the last decade. Several studies have shown that they mediate cell-to-cell communication in a variety of biological processes. Thus, in addition to cell-to-cell direct interaction or secretion of active molecules, they are now considered another class of signal mediators. Exosomes can be secreted by several cell types and retrieved in many body fluids, such as blood, urine, saliva and cerebrospinal fluid. In addition to proteins and lipids, they also contain nucleic acids, namely mRNA and miRNA. These features have prompted extensive research to exploit them as a source of biomarkers for several pathologies, such as cancer and neurodegenerative disorders. In this context, exosomes also appear attractive as gene delivery vehicles. Furthermore, exosome immunomodulatory and regenerative properties are also encouraging their application for further therapeutic purposes. Nevertheless, several issues remain to be addressed: exosome biogenesis and secretion mechanisms have not been clearly understood, and physiological functions, as well as pathological roles, are far from being satisfactorily elucidated.

  17. The evolutionary rate variation among genes of HOG-signaling pathway in yeast genomes.

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    Wu, Xuechang; Chi, Xiaoqin; Wang, Pinmei; Zheng, Daoqiong; Ding, Rui; Li, Yudong

    2010-07-10

    Responses to extracellular stress are required for microbes to survive in changing environments. Although the stress response mechanisms have been characterized extensively, the evolution of stress response pathway remains poorly understood. Here, we studied the evolution of High Osmolarity Glycerol (HOG) pathway, one of the important osmotic stress response pathways, across 10 yeast species and underpinned the evolutionary forces acting on the pathway evolution. Although the HOG pathway is well conserved across the surveyed yeast species, the evolutionary rate of the genes in this pathway varied substantially among or within different lineages. The fast divergence of MSB2 gene indicates that this gene is subjected to positive selection. Moreover, transcription factors in HOG pathway tend to evolve more rapidly, but the genes in conserved MAPK cascade underwent stronger functional selection. Remarkably, the dN/dS values are negatively correlated with pathway position along HOG pathway from Sln1 (Sho1) to Hog1 for transmitting external signal into nuclear. The increased gradient of selective constraints from upstream to downstream genes suggested that the downstream genes are more pleiotropic, being required for a wider range of pathways. In addition, protein length, codon usage, gene expression, and protein interaction appear to be important factors to determine the evolution of genes in HOG pathway. Taken together, our results suggest that functional constraints play a large role in the evolutionary rate variation in HOG pathway, but the genetic variation was influenced by quite complicated factors, such as pathway position, protein length and so on. These findings provide some insights into how HOG pathway genes evolved rapidly for responding to environmental osmotic stress changes. This article was reviewed by Han Liang (nominated by Laura Landweber), Georgy Bazykin (nominated by Mikhail Gelfand) and Zhenguo Lin (nominated by John Logsdon).

  18. The evolutionary rate variation among genes of HOG-signaling pathway in yeast genomes

    Directory of Open Access Journals (Sweden)

    Ding Rui

    2010-07-01

    Full Text Available Abstract Background Responses to extracellular stress are required for microbes to survive in changing environments. Although the stress response mechanisms have been characterized extensively, the evolution of stress response pathway remains poorly understood. Here, we studied the evolution of High Osmolarity Glycerol (HOG pathway, one of the important osmotic stress response pathways, across 10 yeast species and underpinned the evolutionary forces acting on the pathway evolution. Results Although the HOG pathway is well conserved across the surveyed yeast species, the evolutionary rate of the genes in this pathway varied substantially among or within different lineages. The fast divergence of MSB2 gene indicates that this gene is subjected to positive selection. Moreover, transcription factors in HOG pathway tend to evolve more rapidly, but the genes in conserved MAPK cascade underwent stronger functional selection. Remarkably, the dN/dS values are negatively correlated with pathway position along HOG pathway from Sln1 (Sho1 to Hog1 for transmitting external signal into nuclear. The increased gradient of selective constraints from upstream to downstream genes suggested that the downstream genes are more pleiotropic, being required for a wider range of pathways. In addition, protein length, codon usage, gene expression, and protein interaction appear to be important factors to determine the evolution of genes in HOG pathway. Conclusions Taken together, our results suggest that functional constraints play a large role in the evolutionary rate variation in HOG pathway, but the genetic variation was influenced by quite complicated factors, such as pathway position, protein length and so on. These findings provide some insights into how HOG pathway genes evolved rapidly for responding to environmental osmotic stress changes. Reviewers This article was reviewed by Han Liang (nominated by Laura Landweber, Georgy Bazykin (nominated by Mikhail Gelfand

  19. A pedagogical walkthrough of computational modeling and simulation of Wnt signaling pathway using static causal models in MATLAB.

    Science.gov (United States)

    Sinha, Shriprakash

    2016-12-01

    Simulation study in systems biology involving computational experiments dealing with Wnt signaling pathways abound in literature but often lack a pedagogical perspective that might ease the understanding of beginner students and researchers in transition, who intend to work on the modeling of the pathway. This paucity might happen due to restrictive business policies which enforce an unwanted embargo on the sharing of important scientific knowledge. A tutorial introduction to computational modeling of Wnt signaling pathway in a human colorectal cancer dataset using static Bayesian network models is provided. The walkthrough might aid biologists/informaticians in understanding the design of computational experiments that is interleaved with exposition of the Matlab code and causal models from Bayesian network toolbox. The manuscript elucidates the coding contents of the advance article by Sinha (Integr. Biol. 6:1034-1048, 2014) and takes the reader in a step-by-step process of how (a) the collection and the transformation of the available biological information from literature is done, (b) the integration of the heterogeneous data and prior biological knowledge in the network is achieved, (c) the simulation study is designed, (d) the hypothesis regarding a biological phenomena is transformed into computational framework, and (e) results and inferences drawn using d -connectivity/separability are reported. The manuscript finally ends with a programming assignment to help the readers get hands-on experience of a perturbation project. Description of Matlab files is made available under GNU GPL v3 license at the Google code project on https://code.google.com/p/static-bn-for-wnt-signaling-pathway and https: //sites.google.com/site/shriprakashsinha/shriprakashsinha/projects/static-bn-for-wnt-signaling-pathway. Latest updates can be found in the latter website.

  20. Developmental signalling pathways in renal fibrosis: the roles of Notch, Wnt and Hedgehog.

    Science.gov (United States)

    Edeling, Maria; Ragi, Grace; Huang, Shizheng; Pavenstädt, Hermann; Susztak, Katalin

    2016-07-01

    Kidney fibrosis is a common histological manifestation of functional decline in the kidney. Fibrosis is a reactive process that develops in response to excessive epithelial injury and inflammation, leading to myofibroblast activation and an accumulation of extracellular matrix. Here, we describe how three key developmental signalling pathways - Notch, Wnt and Hedgehog (Hh) - are reactivated in response to kidney injury and contribute to the fibrotic response. Although transient activation of these pathways is needed for repair of injured tissue, their sustained activation is thought to promote fibrosis. Excessive Wnt and Notch expression prohibit epithelial differentiation, whereas increased Wnt and Hh expression induce fibroblast proliferation and myofibroblastic transdifferentiation. Notch, Wnt and Hh are fundamentally different signalling pathways, but their choreographed activation seems to be just as important for fibrosis as it is for embryonic kidney development. Decreasing the activity of Notch, Wnt or Hh signalling could potentially provide a new therapeutic strategy to ameliorate the development of fibrosis in chronic kidney disease.

  1. A Survey of Strategies to Modulate the Bone Morphogenetic Protein Signaling Pathway: Current and Future Perspectives

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    Jonathan W. Lowery

    2016-01-01

    Full Text Available Bone morphogenetic proteins (BMPs constitute the largest subdivision of the TGF-β family of ligands and are unequivocally involved in regulating stem cell behavior. Appropriate regulation of canonical BMP signaling is critical for the development and homeostasis of numerous human organ systems, as aberrations in the BMP pathway or its regulation are increasingly associated with diverse human pathologies. In this review, we provide a wide-perspective on strategies that increase or decrease BMP signaling. We briefly outline the current FDA-approved approaches, highlight emerging next-generation technologies, and postulate prospective avenues for future investigation. We also detail how activating other pathways may indirectly modulate BMP signaling, with a particular emphasis on the relationship between the BMP and Activin/TGF-β pathways.

  2. ups1, an Arabidopsis thaliana camalexin accumulation mutant defective in multiple defence signalling pathways.

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    Denby, Katherine J; Jason, Laure J M; Murray, Shane L; Last, Robert L

    2005-03-01

    We report the characterization of an Arabidopsis thaliana mutant, ups1, isolated on the basis of reduced expression of phosphoribosylanthranilate transferase, a tryptophan biosynthetic enzyme. ups1 also exhibits defects in a wide range of defence responses. After infection with Pseudomonas syringae or Botrytis cinerea, the expression of genes regulated by both the salicylic acid and jasmonic acid/ethylene pathways is reduced in ups1 compared with wild type. Camalexin accumulation in ups1 is greatly reduced after infection with these two pathogens, as well as after amino acid starvation or oxidative stress. Reactive oxygen species (ROS)-mediated gene expression is also compromised in ups1 indicating that this mutant is defective in signalling pathways activated in response to both biotic and abiotic stress. The fact that all three major defence signalling pathways are disrupted in ups1, together with the oxidative stress phenotype, leads us to suggest that UPS1 is involved in ROS signal transduction.

  3. Phosphoproteomic Analysis Identifies Signaling Pathways Regulated by Curcumin in Human Colon Cancer Cells.

    Science.gov (United States)

    Sato, Tatsuhiro; Higuchi, Yutaka; Shibagaki, Yoshio; Hattori, Seisuke

    2017-09-01

    Curcumin, a major polyphenol of the spice turmeric, acts as a potent chemopreventive and chemotherapeutic agent in several cancer types, including colon cancer. Although various proteins have been shown to be affected by curcumin, how curcumin exerts its anticancer activity is not fully understood. Phosphoproteomic analyses were performed using SW480 and SW620 human colon cancer cells to identify curcumin-affected signaling pathways. Curcumin inhibited the growth of the two cell lines in a dose-dependent manner. Thirty-nine curcumin-regulated phosphoproteins were identified, five of which are involved in cancer signaling pathways. Detailed analyses revealed that the mTORC1 and p53 signaling pathways are main targets of curcumin. Our results provide insight into the molecular mechanisms of the anticancer activities of curcumin and future molecular targets for its clinical application. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  4. Role of Hedgehog signaling pathway in progression of non-alcoholic fatty liver fibrosis

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    AN Baiquan

    2015-03-01

    Full Text Available Obesity and related metabolic syndromes are prevalent on the global scale. Thus far, non-alcoholic fatty liver (NAFL disease has caused wide attention from domestic and overseas scholars. NAFL cirrhosis is considered to be the central part and inevitable stage of liver cirrhosis developed from simple fatty liver and non-alcoholic steatohepatitis. The effect of Hedgehog signaling pathway on hepatocytes in the progression of NAFL fibrosis was elucidated and investigated by a population study. Results showed that abnormal activation of the Hedgehog signaling pathway promoted the progression of NAFL fibrosis. In-depth study on the Hedgehog signaling pathway may provide a new approach for the treatment of NAFL fibrosis.

  5. Stem cell maintenance by manipulating signaling pathways: past, current and future

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    Chen, Xi; Ye, Shoudong; Ying, Qi-Long

    2015-01-01

    Pluripotent stem cells only exist in a narrow window during early embryonic development, whereas multipotent stem cells are abundant throughout embryonic development and are retainedin various adult tissues and organs. While pluripotent stem cell lines have been established from several species, including mouse, rat, and human, it is still challenging to establish stable multipotent stem cell lines from embryonic or adult tissues. Based on current knowledge, we anticipate that by manipulating extrinsic and intrinsic signaling pathways, most if not all types of stem cells can be maintained in a long-term culture. In this article, we summarize current culture conditions established for the long-term maintenance of authentic pluripotent and multipotent stem cells and the signaling pathways involved. We also discuss the general principles of stem cell maintenance and propose several strategies on the establishment of novel stem cell lines through manipulation of signaling pathways. [BMB Reports 2015; 48(12): 668-676] PMID:26497581

  6. PME-1 is regulated by USP36 in ERK and Akt signaling pathways.

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    Kim, Soo-Yeon; Choi, Jihye; Lee, Da-Hye; Park, Jun-Hyeok; Hwang, Young-Jae; Baek, Kwang-Hyun

    2018-03-25

    Deubiquitinating enzymes (DUBs) play an important role in the ubiquitin-proteasome system (UPS) by eliminating ubiquitins from substrates and inhibiting proteasomal degradation. Protein phosphatase methylesterase 1 (PME-1) inactivates protein phosphatase 2A (PP2A) and enhances the ERK and Akt signaling pathways, which increase cell proliferation and malignant cell transformation. In this study, we demonstrate that USP36 regulates PME-1 through its deubiquitinating enzyme activity. USP36 increases PME-1 stability, and depletion of USP36 decreases the PME-1 expression level. Furthermore, we demonstrate that USP36 promotes the ERK and Akt signaling pathways. In summary, it is suggested that USP36 regulates PME-1 as a DUB and participates in the ERK and Akt signaling pathways. © 2018 Federation of European Biochemical Societies.

  7. Induction of alternative respiratory pathway involves nitric oxide, hydrogen peroxide and ethylene under salt stress.

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    Wang, Huahua; Huang, Junjun; Bi, Yurong

    2010-12-01

    Alternative respiratory pathway (AP) plays an important role in plant thermogenesis, fruit ripening and responses to environmental stresses. AP may participate in the adaptation to salt stress since salt stress increased the activity of the AP. Recently, new evidence revealed that ethylene and hydrogen peroxide (H(2)O(2)) are involved in the salt-induced increase of the AP, which plays an important role in salt tolerance in Arabidopsis callus, and ethylene may be acting downstream of H(2)O(2). Recent observations also indicated both ethylene and nitric oxide (NO) act as signaling molecules in responses to salt stress, and ethylene may be a part of the downstream signal molecular in NO action. In this addendum, a hypothetical model for NO function in regulation of H(2)O(2)- and ethylene-mediated induction of AP under salt stress is presented.

  8. Climate Change and Health under the Shared Socioeconomic Pathway Framework

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    Samuel Sellers

    2017-12-01

    Full Text Available A growing body of literature addresses how climate change is likely to have substantial and generally adverse effects on population health and health systems around the world. These effects are likely to vary within and between countries and, importantly, will vary depending on different socioeconomic development patterns. Transitioning to a more resilient and sustainable world to prepare for and manage the effects of climate change is likely to result in better health outcomes. Sustained fossil fuel development will likely result in continued high burdens of preventable conditions, such as undernutrition, malaria, and diarrheal diseases. Using a new set of socioeconomic development trajectories, the Shared Socioeconomic Pathways (SSPs, along with the World Health Organization’s Operational Framework for Building Climate Resilient Health Systems, we extend existing storylines to illustrate how various aspects of health systems are likely to be affected under each SSP. We also discuss the implications of our findings on how the burden of mortality and the achievement of health-related Sustainable Development Goal targets are likely to vary under different SSPs.

  9. Managing coastal environments under climate change: Pathways to adaptation.

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    Sánchez-Arcilla, Agustín; García-León, Manuel; Gracia, Vicente; Devoy, Robert; Stanica, Adrian; Gault, Jeremy

    2016-12-01

    This paper deals with the question of how to manage vulnerable coastal systems so as to make them sustainable under present and future climates. This is interpreted in terms of the coastal functionality, mainly natural services and support for socio-economic activities. From here we discuss how to adapt for long term trends and for short terms episodic events using the DPSIR framework. The analysis is presented for coastal archetypes from Spain, Ireland and Romania, sweeping a range of meteo-oceanographic and socio-economic pressures, resulting in a wide range of fluxes among them those related to sediment. The analysis emphasizes the variables that provide a higher level of robustness. That means mean sea level for physical factors and population density for human factors. For each of the studied cases high and low sustainability practices, based on stakeholders preferences, are considered and discussed. This allows proposing alternatives and carrying out an integrated assessment in the last section of the paper. This assessment permits building a sequence of interventions called adaptation pathway that enhances the natural resilience of the studied coastal systems and therefore increases their sustainability under present and future conditions. Copyright © 2016 Elsevier B.V. All rights reserved.

  10. Genital Sensory Stimulation Shifts Estradiol Intraoviductal Signaling from Nongenomic to Genomic Pathways, Independently from Prolactin Surges

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    C PEÑARROJA-MATUTAN0

    2007-01-01

    Full Text Available Estradiol (E2 accelerates oviductal egg transport through nongenomic pathways involving oviductal protein phosphorylation in non-mated rats, and through genomic pathways in mated rats. Here we investigated the ability of cervico-vaginal stimulation (CVS to switch the mode of action of E2 in the absence of other male-associated components. Pro-estrous rats were subjected to CVS with a glass rod and 12 hours later were injected subcutaneously with E2 and intrabursally with the RNA synthesis inhibitor Actinomycin D or the protein phosphorylation inhibitor H-89. The number of eggs in the oviduct, assessed 24 h later, showed that Actinomycin D, but not H-89 blocked the E2-induced egg transport acceleration. This clearly indicates that CVS alone, without other mating-associated signals, is able to shift E2 signaling from nongenomic to genomic pathways. Since mating and CVS activate a neuroendocrine reflex that causes iterative prolactin (PRL surges, the involvement of PRL pathway in this phenomenon was evaluated. Prolactin receptor mRNA and protein expression in the rat oviduct was demonstrated by RT-PCR and Western blot, but their levels were not different on day 2 of the cycle (C2 or pregnancy (P2. Activated ST AT 5a/b (phosphorylated was detected by Western blot on P2 in the ovary, but not in the oviduct, showing that mating does not stimulate this PRL signalling pathway in the oviduct. Other rats subjected to CVS in the evening of pro-estrus were treated with bromoergocriptine to suppress PRL surges. In these rats, H-89 did not block the E2-induced acceleration of egg transport suggesting that PRL surges are not essential to shift E2 signaling pathways in the oviduct. We conclude that CVS is one of the components of mating that shifts E2 signaling in the oviduct from nongenomic to genomic pathways, and this effect is independent of PRL surges elicited by mating

  11. Connexin 32 affects doxorubicin resistance in hepatocellular carcinoma cells mediated by Src/FAK signaling pathway.

    Science.gov (United States)

    Yu, Meiling; Zou, Qi; Wu, Xiaoxiang; Han, Guangshu; Tong, Xuhui

    2017-11-01

    Doxorubicin (DOX) is first-line chemotherapy for hepatocellular carcinoma (HCC), but the effect is not satisfactory. The resistance of HCC cells to DOX is the main reason leading to treatment failure. Therefore, it is necessary to study the mechanism of DOX resistance in HCC. In this study, expression of connexin (Cx)32 was significantly decreased in HCC tissues compared with corresponding paracancerous tissues, and activity of the Src/focal adhesion kinase (FAK) signaling pathway was significantly enhanced. Expression of Cx32 was closely associated with activity of the Src/FAK signaling pathway, Cx32, and the Src/FAK signaling pathway was also correlated with degree of HCC differentiation. In DOX-resistant HepG2 cells, compared with DOX-sensitive HepG2 cells, expression of Cx32 was significantly reduced and activity of the Src/FAK pathway increased. After silencing Cx32 in HepG2 cells, activity of the Src/FAK pathway increased and sensitivity to DOX decreased. In contrast, overexpression of Cx32 in HepG2/DOX cells decreased activity of the Src/FAK pathway and increased sensitivity to DOX. Dasatinib and KX2-391, inhibitors of the Src/FAK pathway, significantly increased the sensitivity of HepG2/DOX cells to DOX. The results suggest that Src/FAK is a downstream regulator of Cx32 and Cx32 regulates the sensitivity of HCC cells to DOX via the Src/FAK signaling pathway. Our study demonstrates a potential mechanism of DOX resistance in HCC cells and supports that Cx32-Src/FAK is an important target for reversing drug resistance of HCC. Copyright © 2017. Published by Elsevier Masson SAS.

  12. Homocysteine enhances MMP-9 production in murine macrophages via ERK and Akt signaling pathways

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    Lee, Seung Jin; Lee, Yi Sle; Seo, Kyo Won; Bae, Jin Ung; Kim, Gyu Hee; Park, So Youn; Kim, Chi Dae, E-mail: chidkim@pusan.ac.kr

    2012-04-01

    Homocysteine (Hcy) at elevated levels is an independent risk factor of cardiovascular diseases, including atherosclerosis. In the present study, we investigated the effect of Hcy on the production of matrix metalloproteinases (MMP) in murine macrophages. Among the MMP known to regulate the activities of collagenase and gelatinase, Hcy exclusively increased the gelatinolytic activity of MMP-9 in J774A.1 cells as well as in mouse peritoneal macrophages. Furthermore, this activity was found to be correlated with Western blot findings in J774A.1 cells, which showed that MMP-9 expression was concentration- and time-dependently increased by Hcy. Inhibition of the ERK and Akt pathways led to a significant decrease in Hcy-induced MMP-9 expression, and combined treatment with inhibitors of the ERK and Akt pathways showed an additive effects. Activity assays for ERK and Akt showed that Hcy increased the phosphorylation of both, but these phosphorylation were not affected by inhibitors of the Akt and ERK pathways. In line with these findings, the molecular inhibition of ERK and Akt using siRNA did not affect the Hcy-induced phosphorylation of Akt and ERK, respectively. Taken together, these findings suggest that Hcy enhances MMP-9 production in murine macrophages by separately activating the ERK and Akt signaling pathways. -- Highlights: ► Homocysteine (Hcy) induced MMP-9 production in murine macrophages. ► Hcy induced MMP-9 production through ERK and Akt signaling pathways. ► ERK and Akt signaling pathways were activated by Hcy in murine macrophages. ► ERK and Akt pathways were additively act on Hcy-induced MMP-9 production. ► Hcy enhances MMP-9 production in macrophages via activation of ERK and Akt signaling pathways in an independent manner.

  13. Transcription Profiles Reveal Sugar and Hormone Signaling Pathways Mediating Flower Induction in Apple (Malus domestica Borkh.).

    Science.gov (United States)

    Xing, Li-Bo; Zhang, Dong; Li, You-Mei; Shen, Ya-Wen; Zhao, Cai-Ping; Ma, Juan-Juan; An, Na; Han, Ming-Yu

    2015-10-01

    Flower induction in apple (Malus domestica Borkh.) is regulated by complex gene networks that involve multiple signal pathways to ensure flower bud formation in the next year, but the molecular determinants of apple flower induction are still unknown. In this research, transcriptomic profiles from differentiating buds allowed us to identify genes potentially involved in signaling pathways that mediate the regulatory mechanisms of flower induction. A hypothetical model for this regulatory mechanism was obtained by analysis of the available transcriptomic data, suggesting that sugar-, hormone- and flowering-related genes, as well as those involved in cell-cycle induction, participated in the apple flower induction process. Sugar levels and metabolism-related gene expression profiles revealed that sucrose is the initiation signal in flower induction. Complex hormone regulatory networks involved in cytokinin (CK), abscisic acid (ABA) and gibberellic acid pathways also induce apple flower formation. CK plays a key role in the regulation of cell formation and differentiation, and in affecting flowering-related gene expression levels during these processes. Meanwhile, ABA levels and ABA-related gene expression levels gradually increased, as did those of sugar metabolism-related genes, in developing buds, indicating that ABA signals regulate apple flower induction by participating in the sugar-mediated flowering pathway. Furthermore, changes in sugar and starch deposition levels in buds can be affected by ABA content and the expression of the genes involved in the ABA signaling pathway. Thus, multiple pathways, which are mainly mediated by crosstalk between sugar and hormone signals, regulate the molecular network involved in bud growth and flower induction in apple trees. © The Author 2015. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists.

  14. ETHYLENE RESPONSE FACTOR1 Integrates Signals from Ethylene and Jasmonate Pathways in Plant DefenseW⃞

    Science.gov (United States)

    Lorenzo, Oscar; Piqueras, Raquel; Sánchez-Serrano, Jose J.; Solano, Roberto

    2003-01-01

    Cross-talk between ethylene and jasmonate signaling pathways determines the activation of a set of defense responses against pathogens and herbivores. However, the molecular mechanisms that underlie this cross-talk are poorly understood. Here, we show that ethylene and jasmonate pathways converge in the transcriptional activation of ETHYLENE RESPONSE FACTOR1 (ERF1), which encodes a transcription factor that regulates the expression of pathogen response genes that prevent disease progression. The expression of ERF1 can be activated rapidly by ethylene or jasmonate and can be activated synergistically by both hormones. In addition, both signaling pathways are required simultaneously to activate ERF1, because mutations that block any of them prevent ERF1 induction by any of these hormones either alone or in combination. Furthermore, 35S:ERF1 expression can rescue the defense response defects of coi1 (coronative insensitive1) and ein2 (ethylene insensitive2); therefore, it is a likely downstream component of both ethylene and jasmonate signaling pathways. Transcriptome analysis in Col;35S:ERF1 transgenic plants and ethylene/jasmonate-treated wild-type plants further supports the notion that ERF1 regulates in vivo the expression of a large number of genes responsive to both ethylene and jasmonate. These results suggest that ERF1 acts downstream of the intersection between ethylene and jasmonate pathways and suggest that this transcription factor is a key element in the integration of both signals for the regulation of defense response genes. PMID:12509529

  15. Epigenetic regulator Lid maintains germline stem cells through regulating JAK-STAT signaling pathway activity

    Directory of Open Access Journals (Sweden)

    Lama Tarayrah

    2015-11-01

    Full Text Available Signaling pathways and epigenetic mechanisms have both been shown to play essential roles in regulating stem cell activity. While the role of either mechanism in this regulation is well established in multiple stem cell lineages, how the two mechanisms interact to regulate stem cell activity is not as well understood. Here we report that in the Drosophila testis, an H3K4me3-specific histone demethylase encoded by little imaginal discs (lid maintains germline stem cell (GSC mitotic index and prevents GSC premature differentiation. Lid is required in germ cells for proper expression of the Stat92E transcription factor, the downstream effector of the Janus kinase signal transducer and activator of transcription (JAK-STAT signaling pathway. Our findings support a germ cell autonomous role for the JAK-STAT pathway in maintaining GSCs and place Lid as an upstream regulator of this pathway. Our study provides new insights into the biological functions of a histone demethylase in vivo and sheds light on the interaction between epigenetic mechanisms and signaling pathways in regulating stem cell activities.

  16. Novel mTORC1 and 2 Signaling Pathways in Polycystic Kidney Disease (PKD)

    Science.gov (United States)

    2017-09-01

    AWARD NUMBER: W81XWH-16-1-0172 TITLE: Novel mTORC1 and 2 Signaling Pathways in Polycystic Kidney Disease (PKD) PRINCIPAL INVESTIGATOR: Charles...TITLE AND SUBTITLE 5a. CONTRACT NUMBER W81XWH-16-1-0172 Novel mTORC1 and 2 Signaling Pathways in Polycystic Kidney Disease (PKD) 5b. GRANT NUMBER 5c...live PKD mice. 15. SUBJECT TERMS Polycystic kidney disease , PKD, mTORC1, mTORC2, Raptor, Rictor. 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF

  17. Advances in cell proliferation and apoptosis signal pathway and therapies of polycystic kidney disease

    Directory of Open Access Journals (Sweden)

    Xiao-ying LIAN

    2016-12-01

    Full Text Available Polycystic kidney disease (PKD is one of the monogenic inherited diseases. In PKD, excessive cell proliferation and fluid secretion, and disruption of the mechanisms controlling tubular diameter may all lead to cyst formation. Current evidence has demonstrated that intracellular calcium ion and cAMP imbalance drive both abnormal cell proliferation and apoptosis signal pathway. The present paper summarized the evidence implicating calcium ion and cAMP as central players in the signaling pathway of cell proliferation and apoptosis in PKD, and considered the potential therapeutic approaches targeted to slow cyst growth in PKD. DOI: 10.11855/j.issn.0577-7402.2016.11.13

  18. Sensitivity of Saccharomyces cerevisiae defective in TOR signaling pathway to carbonyl/oxidative stress

    Directory of Open Access Journals (Sweden)

    Valishkevych B. V.

    2014-09-01

    Full Text Available Aim. To investigate the influence of carbonyl/oxidative stress induced by glyoxal, methylglyoxal and hydrogen peroxide on the survival of Saccharomyces cerevisiae, defective for different parts of TOR- signaling pathway, grown on glucose or fructose. Methods. The assessment of number of colony-forming units to determine the yeast reproductive ability. Results. It was shown that at certain concentrations the mentioned above toxicants caused an increase in yeast survival, indicating the hormetic effect. Conclusions. The TOR signaling pathway is involved in the hormetic effect, but it is specific for each strain and depends on the type of carbohydrate in the incubation medium.

  19. Identification of Major Signaling Pathways in Prion Disease Progression Using Network Analysis.

    Directory of Open Access Journals (Sweden)

    Khalique Newaz

    Full Text Available Prion diseases are transmissible neurodegenerative diseases that arise due to conformational change of normal, cellular prion protein (PrPC to protease-resistant isofrom (rPrPSc. Deposition of misfolded PrpSc proteins leads to an alteration of many signaling pathways that includes immunological and apoptotic pathways. As a result, this culminates in the dysfunction and death of neuronal cells. Earlier works on transcriptomic studies have revealed some affected pathways, but it is not clear which is (are the prime network pathway(s that change during the disease progression and how these pathways are involved in crosstalks with each other from the time of incubation to clinical death. We perform network analysis on large-scale transcriptomic data of differentially expressed genes obtained from whole brain in six different mouse strain-prion strain combination models to determine the pathways involved in prion diseases, and to understand the role of crosstalks in disease propagation. We employ a notion of differential network centrality measures on protein interaction networks to identify the potential biological pathways involved. We also propose a crosstalk ranking method based on dynamic protein interaction networks to identify the core network elements involved in crosstalk with different pathways. We identify 148 DEGs (differentially expressed genes potentially related to the prion disease progression. Functional association of the identified genes implicates a strong involvement of immunological pathways. We extract a bow-tie structure that is potentially dysregulated in prion disease. We also propose an ODE model for the bow-tie network. Predictions related to diseased condition suggests the downregulation of the core signaling elements (PI3Ks and AKTs of the bow-tie network. In this work, we show using transcriptomic data that the neuronal dysfunction in prion disease is strongly related to the immunological pathways. We conclude that

  20. LeY oligosaccharide upregulates DAG/PKC signaling pathway in the human endometrial cells.

    Science.gov (United States)

    Li, Yali; Ma, Keli; Sun, Ping; Liu, Shuai; Qin, Huamin; Zhu, Zhengmei; Wang, Xiaoqi; Yan, Qiu

    2009-11-01

    LeY oligosaccharide is stage specifically expressed by the embryo and uterine endometrium, and it plays important roles in embryo implantation. In addition to participating in the recognition and adhesion on fetal-maternal interface, LeY potentially regulates the expression of some implantation-related factors. However, it remains elusive whether it can mediate the involved signaling pathway. In this study, agarose-LeY beads were used to mimic the embryos, and the effects of LeY oligosaccharide on DAG/PKC signaling pathway was studied in human endometrial epithelial cells. Results showed that LeY could significantly trigger the activation of cPKCalpha and cPKCbeta2, and their translocation from the cytosol to the plasma membrane. The cellular DAG content was also upregulated, and the activation of PLCgamma1 was promoted. On the contrary, DAG/PKC signaling pathway was significantly inhibited when anti-LeY antibody was used after confirmation of LeY expression in human endometrial epithelial cells by immunohistochemistry and flow cytometry. These results suggest that LeY oligosaccharide acts as a signal molecule to modulate DAG/PKC signaling pathway.

  1. Anti-apoptotic role of the sonic hedgehog signaling pathway in the proliferation of ameloblastoma.

    Science.gov (United States)

    Kanda, Shiori; Mitsuyasu, Takeshi; Nakao, Yu; Kawano, Shintaro; Goto, Yuichi; Matsubara, Ryota; Nakamura, Seiji

    2013-09-01

    Sonic hedgehog (SHH) signaling pathway is crucial to growth and patterning during organogenesis. Aberrant activation of the SHH signaling pathway can result in tumor formation. We examined the expression of SHH signaling molecules and investigated the involvement of the SHH pathway in the proliferation of ameloblastoma, the most common benign tumor of the jaws. We used immunohistochemistry on ameloblastoma specimens and immunocytochemistry and reverse transcription-PCR on the ameloblastoma cell line AM-1. We also used the inhibitors of SHH signaling, SHH neutralizing antibody and cyclopamine, to assess the effects of SHH on the proliferation of AM-1 cells. We detected expression of SHH, patched, GLI1, GLI2 and GLI3 in the ameloblastoma specimens and AM-1 cells. The proliferation of these cells was significantly inhibited in the presence of SHH neutralizing antibody or cyclopamine; this was confirmed by BrdU incorporation assays. Furthermore, in the presence of SHH neutralizing antibody, nuclear translocation of GLI1 and GLI2 was abolished, apoptosis was induced, BCL-2 expression decreased and BAX expression increased. Our results suggest that the SHH signaling pathway is constitutively active in ameloblastoma and plays an anti-apoptotic role in the proliferation of ameloblastoma cells through autocrine loop stimulation.

  2. miR-184 exhibits angiostatic properties via regulation of Akt and VEGF signaling pathways.

    Science.gov (United States)

    Park, Jong Kook; Peng, Han; Yang, Wending; Katsnelson, Julia; Volpert, Olga; Lavker, Robert M

    2017-01-01

    Corneal avascularity is critical for achieving transparency necessary for proper transmission of light to the lens and visual acuity. Although much is known about angiogenesis and angiostasis, the precise regulation of these processes in the cornea is unclear. MicroRNA (miR)-184, the most abundant corneal epithelial miRNA, has been suggested to function in corneal angiostasis by altering VEGF signaling; however, the mechanism(s) underlying this regulation have not been addressed. Using a combination of in vitro and in vivo assays to evaluate angiogenesis, we demonstrated that human limbal epithelial keratinocytes (HLEKs) engineered to overexpress miR-184 secreted lower amounts of angiogenic mitogens. Human dermal microvascular cells exposed to conditioned medium from miR-184-overexpressing HLEKs were less proliferative and failed to seal linear scratch wounds. The in vivo Matrigel plug assay showed that conditioned medium from miR-184-expressing HLEKs elicited a lesser degree of neovascularization compared with controls. We found that miR-184 directly targets and represses the proangiogenic factors, friend of Gata 2 (FOG2), platelet-derived growth factor (PDGF)-β, and phosphatidic acid phosphatase 2b (PPAP2B). FOG2 regulates VEGF expression, whereas PDGF-β and PPAP2B regulate Akt activity. By attenuating both VEGF and Akt signaling, miR-184 acts as a broad-spectrum negative regulator of corneal angiogenesis.-Park, J. K., Peng, H., Yang, W., Katsnelson, J., Volpert, O., Lavker, R. M. miR-184 exhibits angiostatic properties via regulation of Akt and VEGF signaling pathways. © FASEB.

  3. Loss of wobble uridine modification in tRNA anticodons interferes with TOR pathway signaling.

    Science.gov (United States)

    Scheidt, Viktor; Jüdes, André; Bär, Christian; Klassen, Roland; Schaffrath, Raffael

    2014-11-29

    Previous work in yeast has suggested that modification of tRNAs, in particular uridine bases in the anticodon wobble position (U34), is linked to TOR (target of rapamycin) signaling. Hence, U34 modification mutants were found to be hypersensitive to TOR inhibition by rapamycin. To study whether this involves inappropriate TOR signaling, we examined interaction between mutations in TOR pathway genes ( tip41 ∆, sap190 ∆, ppm1 ∆, rrd1 ∆) and U34 modification defects ( elp3 ∆, kti 12∆, urm1 ∆, ncs2 ∆) and found the rapamycin hypersensitivity in the latter is epistatic to drug resistance of the former. Epistasis, however, is abolished in tandem with a gln3 ∆ deletion, which inactivates transcription factor Gln3 required for TOR-sensitive activation of NCR (nitrogen catabolite repression) genes. In line with nuclear import of Gln3 being under control of TOR and dephosphorylation by the Sit4 phosphatase, we identify novel TOR-sensitive sit4 mutations that confer rapamycin resistance and importantly, mislocalise Gln3 when TOR is inhibited. This is similar to gln3 ∆ cells, which abolish the rapamycin hypersensitivity of U34 modification mutants, and suggests TOR deregulation due to tRNA undermodification operates through Gln3. In line with this, loss of U34 modifications ( elp3 ∆, urm1 ∆) enhances nuclear import of and NCR gene activation ( MEP2 , GAP1 ) by Gln3 when TOR activity is low. Strikingly, this stimulatory effect onto Gln3 is suppressed by overexpression of tRNAs that usually carry the U34 modifications. Collectively, our data suggest that proper TOR signaling requires intact tRNA modifications and that loss of U34 modifications impinges on the TOR-sensitive NCR branch via Gln3 misregulation.

  4. Modulation of the beta-catenin signaling pathway by the dishevelled-associated protein Hipk1.

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    Sarah H Louie

    Full Text Available BACKGROUND: Wnts are evolutionarily conserved ligands that signal through beta-catenin-dependent and beta-catenin-independent pathways to regulate cell fate, proliferation, polarity, and movements during vertebrate development. Dishevelled (Dsh/Dvl is a multi-domain scaffold protein required for virtually all known Wnt signaling activities, raising interest in the identification and functions of Dsh-associated proteins. METHODOLOGY: We conducted a yeast-2-hybrid screen using an N-terminal fragment of Dsh, resulting in isolation of the Xenopus laevis ortholog of Hipk1. Interaction between the Dsh and Hipk1 proteins was confirmed by co-immunoprecipitation assays and mass spectrometry, and further experiments suggest that Hipk1 also complexes with the transcription factor Tcf3. Supporting a nuclear function during X. laevis development, Myc-tagged Hipk1 localizes primarily to the nucleus in animal cap explants, and the endogenous transcript is strongly expressed during gastrula and neurula stages. Experimental manipulations of Hipk1 levels indicate that Hipk1 can repress Wnt/beta-catenin target gene activation, as demonstrated by beta-catenin reporter assays in human embryonic kidney cells and by indicators of dorsal specification in X. laevis embryos at the late blastula stage. In addition, a subset of Wnt-responsive genes subsequently requires Hipk1 for activation in the involuting mesoderm during gastrulation. Moreover, either over-expression or knock-down of Hipk1 leads to perturbed convergent extension cell movements involved in both gastrulation and neural tube closure. CONCLUSIONS: These results suggest that Hipk1 contributes in a complex fashion to Dsh-dependent signaling activities during early vertebrate development. This includes regulating the transcription of Wnt/beta-catenin target genes in the nucleus, possibly in both repressive and activating ways under changing developmental contexts. This regulation is required to modulate gene

  5. Signaling Mechanisms Underlying Resistance Responses: What Have We Learned, and How Is It Being Applied?

    Science.gov (United States)

    Kachroo, Aardra; Vincelli, Paul; Kachroo, Pradeep

    2017-12-01

    Plants have evolved highly specific mechanisms to resist pathogens including preformed barriers and the induction of elaborate signaling pathways. Induced signaling requires recognition of the pathogen either via conserved pathogen-derived factors or specific pathogen-encoded proteins called effectors. Recognition of these factors by host encoded receptor proteins can result in the elicitation of different tiers of resistance at the site of pathogen infection. In addition, plants induce a type of systemic immunity which is effective at the whole plant level and protects against a broad spectrum of pathogens. Advances in our understanding of pathogen-recognition mechanisms, identification of the underlying molecular components, and their significant conservation across diverse plant species has enabled the development of novel strategies to combat plant diseases. This review discusses key advances in plant defense signaling that have been adapted or have the potential to be adapted for plant protection against microbial diseases.

  6. Modulation of the Inflammasome Signaling Pathway by Enteropathogenic and Enterohemorrhagic Escherichia coli.

    Science.gov (United States)

    Yen, Hilo; Karino, Masaki; Tobe, Toru

    2016-01-01

    Innate immunity is an essential component in the protection of a host against pathogens. Enteropathogenic and enterohemorrhagic Escherichia coli (EPEC and EHEC, respectively) are known to modulate the innate immune responses of infected cells. The interference is dependent on their type III secretion system (T3SS) and T3SS-dependent effector proteins. Furthermore, these cytosolically injected effectors have been demonstrated to engage multiple immune signaling pathways, including the IFN/STAT, MAPK, NF-κB, and inflammasome pathways. In this review, recent work describing the interaction between EPEC/EHEC and the inflammasome pathway will be discussed.

  7. The octadecanoic pathway: signal molecules for the regulation of secondary pathways.

    OpenAIRE

    Blechert, S; Brodschelm, W; Hölder, S; Kammerer, L; Kutchan, T M; Mueller, M J; Xia, Z Q; Zenk, M H

    1995-01-01

    Plant defense against microbial pathogens and herbivores relies heavily on the induction of defense proteins and low molecular weight antibiotics. The signals between perception of the aggression, gene activation, and the subsequent biosynthesis of secondary compounds are assumed to be pentacylic oxylipin derivatives. The rapid, but transient, synthesis of cis-jasmonic acid was demonstrated after insect attack on a food plant and by microbial elicitor addition to plant suspension cultures. Th...

  8. Role of Insulin-Induced Reactive Oxygen Species in the Insulin Signaling Pathway

    OpenAIRE

    GOLDSTEIN, BARRY J.; MAHADEV, KALYANKAR; WU, XIANGDONG; ZHU, LI; MOTOSHIMA, HIROYUKI

    2005-01-01

    Oxidants, including hydrogen peroxide (H2O2), have been recognized for years to mimic insulin action on glucose transport in adipose cells. Early studies also demonstrated the complementary finding that H2O2 was elaborated during treatment of cells with insulin, suggesting that cellular H2O2 generation was integral to insulin signaling. Recently, reactive oxygen species elicited by various hormones and growth factors have been shown to affect signal transduction pathways in various cell types...

  9. Crocin inhibits RANKL‑induced osteoclastogenesis by regulating JNK and NF‑κB signaling pathways.

    Science.gov (United States)

    Shi, Liping; Zhao, Suping; Chen, Qian; Wu, Youwei; Zhang, Jian; Li, Na

    2018-03-29

    Receptor activator of nuclear factor‑κB ligand (RANKL), a member of the tumor necrosis factor receptor-ligand family, is a crucial factor involved in osteoclast differentiation. Crocin, a pharmacologically active component of Crocus sativus L., has been reported to attenuate ovariectomy‑induced osteoporosis in rats. However, the molecular mechanism underlying the effect of crocin on osteoclast formation remains to be determined. The present study aimed to investigate the effect of crocin on RANKL‑induced osteoclastogenesis and its underlying molecular mechanism. Results demonstrated that crocin decreased osteoclastogenesis in bone marrow‑derived macrophages (BMMs). In addition, the expression levels of osteoclast marker proteins were downregulated by crocin. Mechanistically, crocin inhibited RANKL‑induced activation of nuclear factor‑κB (NF‑κB) by suppressing inhibitor of κBα degradation and preventing NF‑κB p65 subunit nuclear translocation, and by activating c‑Jun N‑terminal kinase (JNK) in BMMs. In summary, the results of the present study suggested that crocin downregulates osteoclast differentiation via inhibition of JNK and NF‑κB signaling pathways. Thus, crocin may be a potential therapeutic agent for the treatment of osteoclast‑associated diseases, including osteoporosis.

  10. Effects of thyroid hormone on the GH signal transduction pathway.

    Science.gov (United States)

    Ocaranza, Paula; Lammoglia, Juan Javier; Iñiguez, Germán; Román, Rossana; Cassorla, Fernando

    2014-02-01

    The importance of thyroid hormone on growth and development in children is well recognized. In addition, linear growth is highly dependent on the response of peripheral tissues to growth hormone, a process known as GH sensitivity, but little is known about the possible effects of T4 on this process. We determined the effect of stimulation with recombinant human GH (rhGH; 200 ng/mL) alone or in combination with two different concentrations of T4 (250 nM and 500 nM for 24 h) on JAK2 and STAT5 activation in skin fibroblast cultures obtained from prepubertal boys with normal height. JAK2 and STAT5 were activated under co-incubation with T4 (at both concentrations) and rhGH in the non-nuclear fraction of the fibroblasts. In addition, after 24h of co-incubation with rhGH and T4 (500 nM), we observed an increase in phospho-STAT5 in the nuclear fraction, when compared to GH and T4 stimulation alone. This effect was not observed when the fibroblasts were co-incubated with GH and the lower concentration of T4 (250 nM). Combined stimulation with GH and T4 at a concentration of 500 nM increases synergistically nuclear phospho-STAT5 in skin fibroblasts, which may amplify tissue sensitivity to GH. These findings may help to explain the effect of T4 administration on growth velocity in some children with idiopathic short stature. Copyright © 2014 Elsevier Ltd. All rights reserved.

  11. Cartography of Pathway Signal Perturbations Identifies Distinct Molecular Pathomechanisms in Malignant and Chronic Lung Diseases.

    Science.gov (United States)

    Arakelyan, Arsen; Nersisyan, Lilit; Petrek, Martin; Löffler-Wirth, Henry; Binder, Hans

    2016-01-01

    Lung diseases are described by a wide variety of developmental mechanisms and clinical manifestations. Accurate classification and diagnosis of lung diseases are the bases for development of effective treatments. While extensive studies are conducted toward characterization of various lung diseases at molecular level, no systematic approach has been developed so far. Here we have applied a methodology for pathway-centered mining of high throughput gene expression data to describe a wide range of lung diseases in the light of shared and specific pathway activity profiles. We have applied an algorithm combining a Pathway Signal Flow (PSF) algorithm for estimation of pathway activity deregulation states in lung diseases and malignancies, and a Self Organizing Maps algorithm for classification and clustering of the pathway activity profiles. The analysis results allowed clearly distinguish between cancer and non-cancer lung diseases. Lung cancers were characterized by pathways implicated in cell proliferation, metabolism, while non-malignant lung diseases were characterized by deregulations in pathways involved in immune/inflammatory response and fibrotic tissue remodeling. In contrast to lung malignancies, chronic lung diseases had relatively heterogeneous pathway deregulation profiles. We identified three groups of interstitial lung diseases and showed that the development of characteristic pathological processes, such as fibrosis, can be initiated by deregulations in different signaling pathways. In conclusion, this paper describes the pathobiology of lung diseases from systems viewpoint using pathway centered high-dimensional data mining approach. Our results contribute largely to current understanding of pathological events in lung cancers and non-malignant lung diseases. Moreover, this paper provides new insight into molecular mechanisms of a number of interstitial lung diseases that have been studied to a lesser extent.

  12. Involvement of salicylate and jasmonate signaling pathways in Arabidopsis interaction with Fusarium graminearum.

    Science.gov (United States)

    Makandar, Ragiba; Nalam, Vamsi; Chaturvedi, Ratnesh; Jeannotte, Richard; Sparks, Alexis A; Shah, Jyoti

    2010-07-01

    Fusarium graminearum is the principal causative agent of Fusarium head blight (FHB), a devastating disease of wheat and barley. This fungus can also colonize Arabidopsis thaliana. Disease resistance was enhanced in transgenic wheat and Arabidopsis plants that constitutively overexpress the NONEXPRESSOR OF PATHOGENESIS-RELATED GENES 1 (NPR1) gene, which regulates salicylic acid (SA) signaling and modulates the activation of jasmonic acid (JA)-dependent defenses. Here, we provide several lines of evidence that reveal an important role for SA and JA signaling in Arabidopsis defense against F. graminearum. SA level was elevated in fungus-inoculated leaves, and SA application and biologically activated systemic acquired resistance enhanced resistance. Furthermore, the disruption of SA accumulation and signaling in the sid2 mutant and NahG transgenic plant, and the npr1 and wrky18 mutants, respectively, resulted in heightened susceptibility to this fungus in leaves and inflorescence. JA signaling was activated in parallel with SA signaling in the fungus-challenged plants. However, the hyperresistance of the JA pathway mutants opr3, coi1, and jar1 indicates that this pathway contributes to susceptibility. Genetic and biochemical experiments indicate that the JA pathway promotes disease by attenuating the activation of SA signaling in fungus-inoculated plants. However, the hypersusceptibility of the jar1 npr1 double mutant compared with the npr1 mutant suggests that JAR1 also contributes to defense, signifying a dichotomous role of JA and a JAR1-dependent mechanism in this interaction.

  13. Natural Antioxidant-Isoliquiritigenin Ameliorates Contractile Dysfunction of Hypoxic Cardiomyocytes via AMPK Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Xiaoyu Zhang

    2013-01-01

    Full Text Available Isoliquiritigenin (ISL, a simple chalcone-type flavonoid, is derived from licorice compounds and is mainly present in foods, beverages, and tobacco. Reactive oxygen species (ROS is a critical factor involved in modulating cardiac stress response signaling during ischemia and reperfusion. We hypothesize that ISL as a natural antioxidant may protect heart against ischemic injury via modulating cellular redox status and regulating cardioprotective signaling pathways. The fluorescent probe H2DCFDA was used to measure the level of intracellular ROS. The glucose uptake was determined by 2-deoxy-D-glucose-3H accumulation. The IonOptix System measured the contractile function of isolated cardiomyocytes. The results demonstrated that ISL treatment markedly ameliorated cardiomyocytes contractile dysfunction caused by hypoxia. ISL significantly stimulated cardioprotective signaling, AMP-activated protein kinase (AMPK, and extracellular signal-regulated kinase (ERK signaling pathways. The ROS fluorescent probe H2DCFDA determination indicated that ISL significantly reduced cardiac ROS level during hypoxia/reoxygenation. Moreover, ISL reduced the mitochondrial potential (Δψ of isolated mouse cardiomyocytes. Taken together, ISL as a natural antioxidant demonstrated the cardioprotection against ischemic injury that may attribute to the activation of AMPK and ERK signaling pathways and balance of cellular redox status.

  14. Pattern-recognition receptors: signaling pathways and dysregulation in canine chronic enteropathies-brief review.

    Science.gov (United States)

    Heilmann, Romy M; Allenspach, Karin

    2017-11-01

    Pattern-recognition receptors (PRRs) are expressed by innate immune cells and recognize pathogen-associated molecular patterns (PAMPs) as well as endogenous damage-associated molecular pattern (DAMP) molecules. With a large potential for synergism or convergence between their signaling pathways, PRRs orchestrate a complex interplay of cellular mediators and transcription factors, and thus play a central role in homeostasis and host defense. Aberrant activation of PRR signaling, mutations of the receptors and/or their downstream signaling molecules, and/or DAMP/PAMP complex-mediated receptor signaling can potentially lead to chronic auto-inflammatory diseases or development of cancer. PRR signaling pathways appear to also present an interesting new avenue for the modulation of inflammatory responses and to serve as potential novel therapeutic targets. Evidence for a dysregulation of the PRR toll-like receptor (TLR)2, TLR4, TLR5, and TLR9, nucleotide-binding oligomerization domain-containing protein (NOD)2, and the receptor of advanced glycation end products (RAGE) exists in dogs with chronic enteropathies. We describe the TLR, NOD2, and RAGE signaling pathways and evaluate the current veterinary literature-in comparison to human medicine-to determine the role of TLRs, NOD2, and RAGE in canine chronic enteropathies.

  15. A modulator based regulatory network for ERα signaling pathway.

    Science.gov (United States)

    Wu, Heng-Yi; Zheng, Pengyue; Jiang, Guanglong; Liu, Yunlong; Nephew, Kenneth P; Huang, Tim H M; Li, Lang

    2012-01-01

    Estrogens control multiple functions of hormone-responsive breast cancer cells. They regulate diverse physiological processes in various tissues through genomic and non-genomic mechanisms that result in activation or repression of gene expression. Transcription regulation upon estrogen stimulation is a critical biological process underlying the onset and progress of the majority of breast cancer. ERα requires distinct co-regulator or modulators for efficient transcriptional regulation, and they form a regulatory network. Knowing this regulatory network will enable systematic study of the effect of ERα on breast cancer. To investigate the regulatory network of ERα and discover novel modulators of ERα functions, we proposed an analytical method based on a linear regression model to identify translational modulators and their network relationships. In the network analysis, a group of specific modulator and target genes were selected according to the functionality of modulator and the ERα binding. Network formed from targets genes with ERα binding was called ERα genomic regulatory network; while network formed from targets genes without ERα binding was called ERα non-genomic regulatory network. Considering the active or repressive function of ERα, active or repressive function of a modulator, and agonist or antagonist effect of a modulator on ERα, the ERα/modulator/target relationships were categorized into 27 classes. Using the gene expression data and ERα Chip-seq data from the MCF-7 cell line, the ERα genomic/non-genomic regulatory networks were built by merging ERα/ modulator/target triplets (TF, M, T), where TF refers to the ERα, M refers to the modulator, and T refers to the target. Comparing these two networks, ERα non-genomic network has lower FDR than the genomic network. In order to validate these two networks, the same network analysis was performed in the gene expression data from the ZR-75.1 cell. The network overlap analysis between two

  16. Autoimmunity and autoinflammation: A systems view on signaling pathway dysregulation profiles.

    Directory of Open Access Journals (Sweden)

    Arsen Arakelyan

    Full Text Available Autoinflammatory and autoimmune disorders are characterized by aberrant changes in innate and adaptive immunity that may lead from an initial inflammatory state to an organ specific damage. These disorders possess heterogeneity in terms of affected organs and clinical phenotypes. However, despite the differences in etiology and phenotypic variations, they share genetic associations, treatment responses and clinical manifestations. The mechanisms involved in their initiation and development remain poorly understood, however the existence of some clear similarities between autoimmune and autoinflammatory disorders indicates variable degrees of interaction between immune-related mechanisms.Our study aims at contributing to a holistic, pathway-centered view on the inflammatory condition of autoimmune and autoinflammatory diseases. We have evaluated similarities and specificities of pathway activity changes in twelve autoimmune and autoinflammatory disorders by performing meta-analysis of publicly available gene expression datasets generated from peripheral blood mononuclear cells, using a bioinformatics pipeline that integrates Self Organizing Maps and Pathway Signal Flow algorithms along with KEGG pathway topologies.The results reveal that clinically divergent disease groups share common pathway perturbation profiles. We identified pathways, similarly perturbed in all the studied diseases, such as PI3K-Akt, Toll-like receptor, and NF-kappa B signaling, that serve as integrators of signals guiding immune cell polarization, migration, growth, survival and differentiation. Further, two clusters of diseases were identified based on specifically dysregulated pathways: one gathering mostly autoimmune and the other mainly autoinflammatory diseases. Cluster separation was driven not only by apparent involvement of pathways implicated in adaptive immunity in one case, and inflammation in the other, but also by processes not explicitly related to immune

  17. Lidocaine induces apoptosis via the mitochondrial pathway independently of death receptor signaling

    NARCIS (Netherlands)

    Werdehausen, Robert; Braun, Sebastian; Essmann, Frank; Schulze-Osthoff, Klaus; Walczak, Henning; Lipfert, Peter; Stevens, Markus F.

    2007-01-01

    BACKGROUND: Local anesthetics, especially lidocaine, can lead to persistent cauda equina syndrome after spinal anesthesia. Recently, lidocaine has been reported to trigger apoptosis, although the underlying mechanisms remain unknown. To elucidate the pathway of lidocaine-induced apoptosis, the

  18. CHARACTERISTICS OF SIGNALING PATHWAYS MEDIATING A CYTOTOXIC EFFECT OF DENDRITIC CELLS UPON ACTIVATED Т LYMPHOCYTES AND NK CELLS

    Directory of Open Access Journals (Sweden)

    T. V. Tyrinova

    2012-01-01

    Full Text Available Abstract. Cytotoxic/pro-apoptogenic effects of IFNα-induced dendritic cells (IFN-DCs directed against Т-lymphocytes and NK cells were investigated in healthy donors. Using an allogenic MLC system, it was revealed that IFN-DCs induce apoptosis of both activated CD4+ and CD8+ T-lymphocytes, and NK cells. Apoptosis of CD4+ and CD8+ T-lymphocytes induced by their interaction with IFN-DCs was mediated by various signaling pathways. In particular, activated CD4+Т-lymphocytes were most sensitive to TRAIL- и Fas/ FasL-transduction pathways, whereas activated CD8+ T-lymphocytes were induced to apoptosis via TNFα-mediated pathway. PD-1/B7-H1-signaling pathway also played a distinct role in cytotoxic activity of IFNDCs towards both types of T lymphocytes and activated NK cells. The pro-apoptogenic/cytotoxic activity of IFN-DC against activated lymphocytes may be regarded as a mechanism of a feedback regulation aimed at restriction of immune response and maintenance of immune homeostasis. Moreover, upregulation of proapoptogenic molecules on DCs under pathological conditions may lead to suppression of antigen-specific response, thus contributing to the disease progression.

  19. Transcript profile analysis reveals important roles of jasmonic acid signalling pathway in the response of sweet potato to salt stress.

    Science.gov (United States)

    Zhang, Huan; Zhang, Qian; Zhai, Hong; Li, Yan; Wang, Xiangfeng; Liu, Qingchang; He, Shaozhen

    2017-01-13

    Sweet potato is an important food and bio-energy crop, and investigating the mechanisms underlying salt tolerance will provide information for salt-tolerant breeding of this crop. Here, the root transcriptomes of the salt-sensitive variety Lizixiang and the salt-tolerant line ND98 were compared to identify the genes and pathways involved in salt stress responses. In total, 8,744 and 10,413 differentially expressed genes (DEGs) in Lizixiang and ND98, respectively, were involved in salt responses. A lower DNA methylation level was detected in ND98 than in Lizixiang. In both genotypes, the DEGs, which function in phytohormone synthesis and signalling and ion homeostasis, may underlie the different degrees of salt tolerance. Significant up-regulations of the genes involved in the jasmonic acid (JA) biosynthesis and signalling pathways and ion transport, more accumulation of JA, a higher degree of stomatal closure and a lower level of Na + were found in ND98 compared to Lizixiang. This is the first report on transcriptome responses to salt tolerance in sweet potato. These results reveal that the JA signalling pathway plays important roles in the response of sweet potato to salt stress. This study provides insights into the mechanisms and genes involved in the salt tolerance of sweet potato.

  20. Regulating Cdc42 and Its Signaling Pathways in Cancer: Small Molecules and MicroRNA as New Treatment Candidates.

    Science.gov (United States)

    Xiao, Xing-Hua; Lv, Lin-Chen; Duan, Jing; Wu, Ye-Meng; He, Shu-Jin; Hu, Zhen-Zhen; Xiong, Li-Xia

    2018-03-29

    Despite great improvements in the diagnosis and treatment of neoplasms, metastatic disease is still the leading cause of death in cancer patients, with mortality rates still rising. Given this background, new ways to treat cancer will be important for development of improved cancer control strategies. Cdc42 is a member of the Rho GTPase family and plays an important role in cell-to-cell adhesion, formation of cytoskeletal structures, and cell cycle regulation. It thus influences cellular proliferation, transformation, and homeostasis, as well as the cellular migration and invasion processes underlying tumor formation. Cdc42 acts as a collection point for signal transduction and regulates multiple signaling pathways. Moreover, recent studies show that in most human cancers Cdc42 is abnormally expressed and promoting neoplastic growth and metastasis. Regarding possible new treatments for cancer, miRNA and small molecules targeting Cdc42 and related pathways have been recently found to be effective on cancer. In this review, we analyze the newly recognized regulation mechanisms for Cdc42 and Cdc42-related signal pathways, and particularly new treatments using small molecules and miRNAs to inhibit the abnormal overexpression of Cdc42 that may slow down the metastasis process, improve cancer therapy and lead to novel strategies for development of antineoplastic drugs.

  1. The effects of telmisartan on the nuclear factor of activated T lymphocytes signalling pathway in hypertensive patients.

    Science.gov (United States)

    Huang, Sha-Sha; He, Si-Li; Zhang, Yuan-Ming

    2016-01-01

    Previous studies provide links between the nuclear factor of activated T lymphocytes (NFAT) signalling pathway and the development of hypertension. Our preliminary studies indicate that telmisartan can block Kv1.3 potassium channels and effectively inhibit potassium current densities, along with Kv1.3 mRNA and protein expression levels. This paper aims to investigate whether telmisartan has an inhibitory effect on the NFAT signalling pathway after activation and proliferation of peripheral blood T lymphocytes in Kazakh patients with essential hypertension (EH) from Xinjiang, China. T lymphocytes were isolated using the immunomagnetic cell sorting method (MACS). The mRNA expression of NFATc1, IL-6 and TNF-α was measured by quantitative polymerase chain reaction (qRT-PCR) and relative protein levels were evaluated by Western blot. T cell samples from 50 hypertensive Kazakh patients from Xinjiang were randomly divided into control, telmisartan, cyclosporin A (CsA), VIVIT, and 4-aminopytidine (4-AP) groups. Peripheral blood T lymphocytes were first activated and proliferated in vitro, then incubated for 48 h under different treatment conditions before determination of protein and mRNA expression of NFATc1, IL-6, and TNF-α by Western blot and qRT-PCR analyses, respectively. There were no significant differences in cardiovascular risk factors among the patients with samples assigned to the five groups (p > 0.05). Expression of NFATc1, IL-6, and TNF-α mRNA and protein was significantly reduced in T lymphocytes in all treatment groups (telmisartan, CsA, VIVIT, and 4-AP) compared with controls. Antihypertensive function and inhibitory effects of telmisartan on the T lymphocyte NFAT signalling pathway are unlikely to affect the normal immune function of hypertensive patients. Telmisartan may exert anti-inflammatory effects by inhibition of the NFAT signalling pathway in the T lymphocytes of hypertensive patients. © The Author(s) 2016.

  2. Pterygium epithelium abnormal differentiation related to activation of extracellular signal-regulated kinase signaling pathway in vitro

    Directory of Open Access Journals (Sweden)

    Juan Peng

    2015-12-01

    Full Text Available AIM: To investigate whether the abnormal differentiation of the pterygium epithelium is related to the extracellular signal-regulated kinase (ERK signaling pathway in vitro. METHODS: The expression levels of phosphorylated ERK (P-ERK, keratin family members including K19 and K10 and the ocular master control gene Pax-6 were measured in 16 surgically excised pterygium tissues and 12 eye bank conjunctiva. In colony-forming cell assays, the differences in clone morphology and in K10, K19, P-ERK and Pax-6 expression between the head and body were investigated. When cocultured with the ERK signaling pathway inhibitor PD98059, the changes in clone morphology, colony-forming efficiency, differentiated marker K10, K19 and Pax-6 expression and P-ERK protein expression level were examined by immunoreactivity and Western blot analysis. RESULTS: The expression of K19 and Pax-6 decreased in the pterygium, especially in the head. No staining of K10 was found in the normal conjunctiva epithelium, but it was found to be expressed in the superficial cells in the head of the pterygium. Characteristic upregulation of P-ERK was observed by immunohistochemistry. The clone from the head with more differentiated cells in the center expressed more K10, and the clone from the body expressed more K19. The P-ERK protein level increased in the pterygium epithelium compared with conjunctiva and decreased when cocultured with PD98059. The same medium with the ERK inhibitor PD98059 was more effective in promoting clonal growth than conventional medium with 3T3 murine feeder layers. It was observed that the epithelium clone co-cultured with the inhibitor had decreased K10 expression and increased K19 and Pax-6 expression. CONCLUSION: We suggest ERK signaling pathway activation might play a role in the pterygium epithelium abnormal differentiation.

  3. Overexpression of protein O-fucosyltransferase 1 accelerates hepatocellular carcinoma progression via the Notch signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Ma, Lijie [Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai (China); Dong, Pingping [Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai (China); Liu, Longzi; Gao, Qiang; Duan, Meng [Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai (China); Zhang, Si; Chen, She [Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai (China); Xue, Ruyi, E-mail: xue.ruyi@zs-hospital.sh.cn [Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai (China); Wang, Xiaoying, E-mail: xiaoyingwang@fudan.edu.cn [Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai (China)

    2016-04-29

    Aberrant activation of Notch signaling frequently occurs in liver cancer, and is associated with liver malignancies. However, the mechanisms regulating pathologic Notch activation in hepatocellular carcinoma (HCC) remain unclear. Protein O-fucosyltransferase 1 (Pofut1) catalyzes the addition of O-linked fucose to the epidermal growth factor-like repeats of Notch. In the present study, we detected the expression of Pofut1 in 8 HCC cell lines and 253 human HCC tissues. We reported that Pofut1 was overexpressed in HCC cell lines and clinical HCC tissues, and Pofut1 overexpression clinically correlated with the unfavorable survival and high disease recurrence in HCC. The in vitro assay demonstrated that Pofut1 overexpression accelerated the cell proliferation and migration in HCC cells. Furthermore, Pofut1 overexpression promoted the binding of Notch ligand Dll1 to Notch receptor, and hence activated Notch signaling pathway in HCC cells, indicating that Pofut1 overexpression could be a reason for the aberrant activation of Notch signaling in HCC. Taken together, our findings indicated that an aberrant activated Pofut1-Notch pathway was involved in HCC progression, and blockage of this pathway could be a promising strategy for the therapy of HCC. - Highlights: • Pofut1 overexpression in HCC was correlated with aggressive tumor behaviors. • Pofut1 overexpression in HCC was associated with poor prognosis. • Pofut1 promoted cell proliferation, migration and invasion in hepatoma cells. • Pofut1 activated Notch signaling pathway in hepatoma cells.

  4. p38 Mapk signal pathway involved in anti-inflammatory effect of ...

    African Journals Online (AJOL)

    In conclusion, CSS and SLBZS might work as a significant anti-inflammatory effect on hepatocyte of NASH by inhibiting the activation of TLR4, p-p38 MAPK and p38 MAPK involved in p38 MAPK signal pathway. Conclusion: To some extent, CSS and SLBZS may be a potential alternative and complementary medicine to ...

  5. Angoline: a selective IL-6/STAT3 signaling pathway inhibitor isolated from Zanthoxylum nitidum.

    Science.gov (United States)

    Liu, Jiawei; Zhang, Qing; Ye, Yushan; Li, Wuguo; Qiu, Junxin; Liu, Jingli; Zhan, Ruoting; Chen, Weiwen; Yu, Qiang

    2014-01-01

    STAT3 signaling pathway is an important target for human cancer therapy. Thus, the identification of small-molecules that target STAT3 signaling will be of great interests in the development of anticancer agents. The aim of this study was to identify novel inhibitors of STAT3 pathway from the roots of Zanthoxylum nitidum (Roxb.) DC. The bioassay-guided fractionation of MeOH extract of Z. nitidum using a STAT3-responsive gene reporter assay led to the isolation of angoline (1) as a potent and selective inhibitor of the STAT3 signaling pathway (IC50=11.56 μM). Angoline inhibited STAT3 phosphorylation and its target gene expression and consequently induced growth inhibition of human cancer cells with constitutively activated STAT3 (IC50=3.14-4.72 μM). This work provided a novel lead for the development of anti-cancer agents targeting the STAT3 signaling pathway. Copyright © 2014 Elsevier GmbH. All rights reserved.

  6. Expression of the cholinergic signal-transduction pathway components during embryonic rat heart development

    NARCIS (Netherlands)

    Franco, D.; Moorman, A. F.; Lamers, W. H.

    1997-01-01

    BACKGROUND: Previous studies showed that acetylcholinesterase (AChE) activity is present in the downstream (arterial) part of the embryonic chick and rat heart, but its functional significance was unclear. To establish whether other components of a cholinergic signal-transduction pathway are present

  7. Insulin signaling pathways in a patient with insulin resistance of difficult management - a case report

    OpenAIRE

    Taboada, Giselle F; de Freitas, Marta S; da S Corr?a, Fernanda H; Junior, Carlos RMA; de B Gomes, Mar?lia

    2009-01-01

    Insulin signalling pathways were investigated in a 33 year-old woman with immunologic insulin resistance. Her past medical history was remarkable for intermittent use of insulin and allergic reactions to several drugs, and measure of plasma anti-insulin antibodies level corroborated the clinical suspicion of immune mediated insulin resistance (8074 nU/ml - RIA - Ref value:

  8. Tyrosinase kinetics in epidermal melanocytes: analysis of DAG-PKC-dependent signaling pathway

    Science.gov (United States)

    Stolnitz, Mikhail M.; Peshkova, Anna Y.

    2001-05-01

    Tyrosinase is the key enzyme of melanogenesis with unusual enzyme kinetics. Protein kinase C plays an important role in regulating of tyrosinase activity. In the paper the mathematical model of PKC-DAG-dependent signal transduction pathway for UV-radiation is presented.

  9. Effects of matrine on JAK-STAT signaling transduction pathways in ...

    African Journals Online (AJOL)

    The current study aims to investigate the effects of matrine on the JAK-STAT signaling transduction pathways in bleomycin (BLM)-induced pulmonary fibrosis (PF) and to explore its action mechanism. A total of 72 male C57BL/6 mice were randomized into the control, model, and treatment groups. PF models were ...

  10. Role of Notch signalling pathway in cancer and its association with ...

    Indian Academy of Sciences (India)

    screening, detection, diagnosis, staging and risk stratification of various cancers. DNA methylation can be therapeutically reversed and demethylating drugs have proven to be promising in cancer treatment. This review focusses on the methylation status of genes in Notch signalling pathway from various cancers and how ...

  11. Wnt signaling, a novel pathway regulating blood pressure? State of the art review.

    Science.gov (United States)

    Abou Ziki, Maen D; Mani, Arya

    2017-07-01

    Recent antihypertensive trials show conflicting results on blood pressure (BP) targets in patient populations with different metabolic profiles, with lowest benefit from tight BP control observed in patients with type 2 diabetes mellitus. This paradox could arise from the heterogeneity of study populations and underscores the importance of precision medicine initiatives towards understanding and treating hypertension. Wnt signaling pathways and genetic variations in its signaling peptides have been recently associated with metabolic syndrome, hypertension and diabetes, generating a breakthrough for advancement of precision medicine in the field of hypertension. We performed a review of PubMed for publications addressing the contributions of Wnt to BP regulation and hypertension. In addition, we performed a manual search of the reference lists for relevant articles, and included unpublished observations from our laboratory. There is emerging evidence for Wnt's role in BP regulation and its involvement in the pathogenesis of hypertension. Wnt signaling has pleiotropic effects on distinct pathways that involve vascular smooth muscle plasticity, and cardiac, renal, and neural physiology. Hypertension is a heterogeneous disease with unique molecular pathways regulating its response to therapy. Recognition of these pathways is a prerequisite to identify novel targets for drug development and personalizing medicine. A review of Wnt signaling reveals its emerging role in BP regulation and as a target for novel drug development that has the potential to transform the therapy of hypertension in specific populations. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Involvement of wnt signaling pathways in the metamorphosis of the bryozoan bugula neritina

    KAUST Repository

    Wong, Yue Him

    2012-03-20

    In this study, we analyzed the metamorphosis of the marine bryozoan Bugula neritina. We observed the morphogenesis of the ancestrula. We defined three distinct pre-ancestrula stages based on the anatomy of the developing polypide and the overall morphology of pre-ancestrula. We then used an annotation based enrichment analysis tool to analyze the B. neritina transcriptome and identified over-representation of genes related to Wnt signaling pathways, suggesting its involvement in metamorphosis. Finally, we studied the temporal-spatial gene expression studies of several Wnt pathway genes. We found that one of the Wnt ligand, BnWnt10, was expressed spatially opposite to the Wnt antagonist BnsFRP within the blastemas, which is the presumptive polypide. Down-stream components of the canonical Wnt signaling pathway were exclusively expressed in the blastemas. Bn?catenin and BnFz5/8 were exclusively expressed in the blastemas throughout the metamorphosis. Based on the genes expression patterns, we propose that BnWnt10 and BnsFRP may relate to the patterning of the polypide, in which the two genes served as positional signals and contributed to the polarization of the blastemas. Another Wnt ligand, BnWnt6, was expressed in the apical part of the pre-ancestrula epidermis. Overall, our findings suggest that the Wnt signaling pathway may be important to the pattern formation of polypide and the development of epidermis. © 2012 Wong et al.

  13. Eight paths of ERK1/2 signalling pathway regulating hepatocyte ...

    Indian Academy of Sciences (India)

    2011-12-05

    Dec 5, 2011 ... proliferation and how. In this study, using isolated hepatocytes, Rat Genome. 230 2.0 Array, bioinformatics and systems biology meth- ods, we evaluated expression changes of genes related to. ERK1/2 signalling pathway and its paths at the transcrip- tional level, which is helpful to explore the relevance of.

  14. Overexpression of protein O-fucosyltransferase 1 accelerates hepatocellular carcinoma progression via the Notch signaling pathway

    International Nuclear Information System (INIS)

    Ma, Lijie; Dong, Pingping; Liu, Longzi; Gao, Qiang; Duan, Meng; Zhang, Si; Chen, She; Xue, Ruyi; Wang, Xiaoying

    2016-01-01

    Aberrant activation of Notch signaling frequently occurs in liver cancer, and is associated with liver malignancies. However, the mechanisms regulating pathologic Notch activation in hepatocellular carcinoma (HCC) remain unclear. Protein O-fucosyltransferase 1 (Pofut1) catalyzes the addition of O-linked fucose to the epidermal growth factor-like repeats of Notch. In the present study, we detected the expression of Pofut1 in 8 HCC cell lines and 253 human HCC tissues. We reported that Pofut1 was overexpressed in HCC cell lines and clinical HCC tissues, and Pofut1 overexpression clinically correlated with the unfavorable survival and high disease recurrence in HCC. The in vitro assay demonstrated that Pofut1 overexpression accelerated the cell proliferation and migration in HCC cells. Furthermore, Pofut1 overexpression promoted the binding of Notch ligand Dll1 to Notch receptor, and hence activated Notch signaling pathway in HCC cells, indicating that Pofut1 overexpression could be a reason for the aberrant activation of Notch signaling in HCC. Taken together, our findings indicated that an aberrant activated Pofut1-Notch pathway was involved in HCC progression, and blockage of this pathway could be a promising strategy for the therapy of HCC. - Highlights: • Pofut1 overexpression in HCC was correlated with aggressive tumor behaviors. • Pofut1 overexpression in HCC was associated with poor prognosis. • Pofut1 promoted cell proliferation, migration and invasion in hepatoma cells. • Pofut1 activated Notch signaling pathway in hepatoma cells.

  15. Protein conservation and variation suggest mechanisms of cell type-specific modulation of signaling pathways.

    Directory of Open Access Journals (Sweden)

    Martin H Schaefer

    2014-06-01

    Full Text Available Many proteins and signaling pathways are present in most cell types and tissues and yet perform specialized functions. To elucidate mechanisms by which these ubiquitous pathways are modulated, we overlaid information about cross-cell line protein abundance and variability, and evolutionary conservation onto functional pathway components and topological layers in the pathway hierarchy. We found that the input (receptors and the output (transcription factors layers evolve more rapidly than proteins in the intermediary transmission layer. In contrast, protein expression variability decreases from the input to the output layer. We observed that the differences in protein variability between the input and transmission layer can be attributed to both the network position and the tendency of variable proteins to physically interact with constitutively expressed proteins. Differences in protein expression variability and conservation are also accompanied by the tendency of conserved and constitutively expressed proteins to acquire somatic mutations, while germline mutations tend to occur in cell type-specific proteins. Thus, conserved core proteins in the transmission layer could perform a fundamental role in most cell types and are therefore less tolerant to germline mutations. In summary, we propose that the core signal transmission machinery is largely modulated by a variable input layer through physical protein interactions. We hypothesize that the bow-tie organization of cellular signaling on the level of protein abundance variability contributes to the specificity of the signal response in different cell types.

  16. Mitigation of TGF-β/Smad signaling pathway-associated liver fibrosis ...

    African Journals Online (AJOL)

    The hydroxyproline content of proteins was measured as an indirect way of assessing collagen deposition. TGF-β1 levels and TGF-β/Smad signaling pathway-related genes and proteins were analyzed by quantitative polymerase chain reaction (qPCR) assay and Western blot assay. Results: After PF administration, serum ...

  17. A structured approach for the engineering of biochemical network models, illustrated for signalling pathways

    NARCIS (Netherlands)

    Breitling, Rainer; Gilbert, David; Heiner, Monika; Orton, Richard

    Quantitative models of biochemical networks (signal transduction cascades, metabolic pathways, gene regulatory circuits) are a central component of modern systems biology. Building and managing these complex models is a major challenge that can benefit from the application of formal methods adopted

  18. Helicobacter pylori infection causes hepatic insulin resistance by the c-Jun/miR-203/SOCS3 signaling pathway.

    Science.gov (United States)

    Zhou, Xiaoying; Liu, Wei; Gu, Min; Zhou, Hongwen; Zhang, Guoxin

    2015-10-01

    Epidemiological studies have indicated that patients with chronic Helicobacter pylori infection have an increased risk of developing type 2 diabetes mellitus, but the underlying mechanisms remain largely unknown. This study aimed to investigate whether H. pylori infection contributes to the development of insulin resistance, as well as the underlying mechanisms both in vivo and in vitro. The effect of H. pylori infection on glucose metabolism was evaluated in humans and mouse models. The role of the c-Jun/miR-203/suppressor of cytokine signaling 3 (SOCS3) pathway in H. pylori-induced insulin resistance was determined in vitro and was validated in vivo. Average fasting glucose levels were increased in patients (P = 0.012) and mice (P = 0.004) with H. pylori infection. Diabetic mice with H. pylori infection showed impaired glucose metabolism and insulin tolerance and hyperinsulinemia. Furthermore, H. pylori infection impaired insulin signaling in primary hepatocytes. H. pylori infection could upregulate SOCS3, a well-known insulin signaling inhibitor, by downregulating miR-203. SOCS3 overexpression interfered with insulin signaling proteins, and knockdown of SOCS3 alleviated H. pylori-induced impairment of insulin signaling. The transcription factor c-Jun, which affects gene expression, was induced by H. pylori infection and suppressed miR-203 expression. Our results demonstrated that H. pylori infection induced hepatic insulin resistance by the c-Jun/miR-203/SOCS3 signaling pathway and provide possible implications with regard to resolving insulin resistance.

  19. Regulator of G protein signaling-1 modulates paraquat-induced oxidative stress and longevity via the insulin like signaling pathway in Caenorhabditis elegans.

    Science.gov (United States)

    Wu, Mingyu; Kang, Xin; Wang, Qiang; Zhou, Chunyu; Mohan, Chandra; Peng, Ai

    2017-05-05

    Insulin or insulin like signaling (IIS) pathway is a crucial pathway in Caenorhabditis elegans associated with mediating longevity, and stress resistance. Regulators of G protein signaling (RGS) also modulate stress resistance and longevity in multiple in vitro and in vivo models. However, the mechanism underlying RGS mediating stress resistance and longevity remains largely unclear. Here we report that rgs-1, an important member of rgs family, is a novel modulator of IIS pathway in C. elegans. We found that the loss of rgs-1 dramatically promoted paraquat resistance in C. elegans. Further genetic analyses demonstrated that rgs-1 acted downstream of daf-2 and upstream of age-1, pdk-1, daf-16. Instead of affecting those IIS-associated genes in transcriptional process, loss of rgs-1 promoted DAF-16's nucleus translocation and subset genes' expression in paraquat-induced oxidative status. By this way, rgs-1 mutant worms exhibited lower ROS damage and longer survival time than wild type worms when both exposed to paraquat. Other than paraquat exposure, rgs-1 mutant also promoted lifespan and cadmium resistance relying on daf-16. As rgs is evolutionarily conserved, our findings open a new insight into rgs family and its role in paraquat-induced oxidative stress and longevity in C. elegans or even mammals. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Adapting the Stress Response: Viral Subversion of the mTOR Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Valerie Le Sage

    2016-05-01

    Full Text Available The mammalian target of rapamycin (mTOR is a central regulator of gene expression, translation and various metabolic processes. Multiple extracellular (growth factors and intracellular (energy status molecular signals as well as a variety of stressors are integrated into the mTOR pathway. Viral infection is a significant stress that can activate, reduce or even suppress the mTOR signaling pathway. Consequently, viruses have evolved a plethora of different mechanisms to attack and co-opt the mTOR pathway in order to make the host cell a hospitable environment for replication. A more comprehensive knowledge of different viral interactions may provide fruitful targets for new antiviral drugs.

  1. Dicer-2-Dependent Activation of Culex Vago Occurs via the TRAF-Rel2 Signaling Pathway

    Science.gov (United States)

    Paradkar, Prasad N.; Duchemin, Jean-Bernard; Voysey, Rhonda; Walker, Peter J.

    2014-01-01

    Despite their importance as vectors of human and livestock diseases, relatively little is known about innate antiviral immune pathways in mosquitoes and other insects. Previous work has shown that Culex Vago (CxVago), which is induced and secreted from West Nile virus (WNV)-infected mosquito cells, acts as a functional homolog of interferon, by activating Jak-STAT pathway and limiting virus replication in neighbouring cells. Here we describe the Dicer-2-dependent pathway leading to WNV-induced CxVago activation. Using a luciferase reporter assay, we show that a NF-κB-like binding site in CxVago promoter region is conserved in mosquito species and is responsible for induction of CxVago expression following WNV infection. Using dsRNA-based gene knockdown, we show that the NF-κB ortholog, Rel2, plays significant role in the signaling pathway that activates CxVago in mosquito cells in vitro and in vivo. Using similar approaches, we also show that TRAF, but not TRAF-3, is involved in activation of Rel2 after viral infection. Overall the study shows that a conserved signaling pathway, which is similar to mammalian interferon activation pathway, is responsible for the induction and antiviral activity of CxVago. PMID:24762775

  2. Dicer-2-dependent activation of Culex Vago occurs via the TRAF-Rel2 signaling pathway.

    Directory of Open Access Journals (Sweden)

    Prasad N Paradkar

    2014-04-01

    Full Text Available Despite their importance as vectors of human and livestock diseases, relatively little is known about innate antiviral immune pathways in mosquitoes and other insects. Previous work has shown that Culex Vago (CxVago, which is induced and secreted from West Nile virus (WNV-infected mosquito cells, acts as a functional homolog of interferon, by activating Jak-STAT pathway and limiting virus replication in neighbouring cells. Here we describe the Dicer-2-dependent pathway leading to WNV-induced CxVago activation. Using a luciferase reporter assay, we show that a NF-κB-like binding site in CxVago promoter region is conserved in mosquito species and is responsible for induction of CxVago expression following WNV infection. Using dsRNA-based gene knockdown, we show that the NF-κB ortholog, Rel2, plays significant role in the signaling pathway that activates CxVago in mosquito cells in vitro and in vivo. Using similar approaches, we also show that TRAF, but not TRAF-3, is involved in activation of Rel2 after viral infection. Overall the study shows that a conserved signaling pathway, which is similar to mammalian interferon activation pathway, is responsible for the induction and antiviral activity of CxVago.

  3. Targeting the Sonic Hedgehog Signaling Pathway: Review of Smoothened and GLI Inhibitors

    Directory of Open Access Journals (Sweden)

    Tadas K. Rimkus

    2016-02-01

    Full Text Available The sonic hedgehog (Shh signaling pathway is a major regulator of cell differentiation, cell proliferation, and tissue polarity. Aberrant activation of the Shh pathway has been shown in a variety of human cancers, including, basal cell carcinoma, malignant gliomas, medulloblastoma, leukemias, and cancers of the breast, lung, pancreas, and prostate. Tumorigenesis, tumor progression and therapeutic response have all been shown to be impacted by the Shh signaling pathway. Downstream effectors of the Shh pathway include smoothened (SMO and glioma-associated oncogene homolog (GLI family of zinc finger transcription factors. Both are regarded as important targets for cancer therapeutics. While most efforts have been devoted towards pharmacologically targeting SMO, developing GLI-targeted approach has its merit because of the fact that GLI proteins can be activated by both Shh ligand-dependent and -independent mechanisms. To date, two SMO inhibitors (LDE225/Sonidegib and GDC-0449/Vismodegib have received FDA approval for treating basal cell carcinoma while many clinical trials are being conducted to evaluate the efficacy of this exciting class of targeted therapy in a variety of cancers. In this review, we provide an overview of the biology of the Shh pathway and then detail the current landscape of the Shh-SMO-GLI pathway inhibitors including those in preclinical studies and clinical trials.

  4. Janus kinase/signal transducer and activator of transcription pathways in spondyloarthritis.

    Science.gov (United States)

    Raychaudhuri, Smriti K; Raychaudhuri, Siba P

    2017-07-01

    Cytokines are major drivers of autoimmunity, and biologic agents targeting cytokines have revolutionized the treatment of immune-mediated diseases. Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway represents a group of several intracellular molecules with a key role in signal pathways activated by growth factors and cytokines. These kinase proteins are associated with the signaling process of multiple key cytokines, which regulates various T-cell subpopulations and their effector cytokines. Development of novel drugs to inhibit this kinase cascade is an emerging field in clinical immunology. Thus, it is essential to have insights about the regulatory role of the JAK-STAT cytokine signaling in relation to autoimmune diseases and its applications in spondyloarthritis. JAK-STAT kinase signaling proteins have been extensively studied in rheumatoid arthritis. Initial observations suggest that JAK-STAT kinase signaling cascade regulates activation and proliferation of the IL17 effector memory T cells and thus has a potential role in the pathogenesis of psoriasis, psoriatic arthritis and ankylosing spondylitis. Here, we provide an overview of the clinical rheumatologists about the significance of JAK-STAT signaling system in rheumatic diseases and introduce the potential application of JAK and STAT inhibitors in spondyloarthritis.

  5. High-frequency deregulated expression of Wnt signaling pathway members in breast carcinomas.

    Science.gov (United States)

    Khan, Zahid; Arafah, Maha; Shaik, Jilani Purusottapatnam; Mahale, Alka; Alanazi, Mohammad Saud

    2018-01-01

    Breast carcinoma is the most common malignancy and leading cause of cancer-related deaths in women worldwide including Saudi Arabia. Breast cancer in Saudi women develops at a much early age with median age of onset of 49 years compared to 62 years observed in patients from USA. Aberrations in wingless and integration site growth factor (Wnt) signaling pathway have been pathologically implicated in development of breast cancers and hence its role was examined in Saudi patients. We immunohistochemically examined various components of Wnt signaling pathway including β-catenin, tumor suppressor proteins, adenomatous polyposis coli (APC), and Axin, expression of naturally occurring pathway antagonists such as Dickkopf Wnt signaling pathway inhibitor 3 (DKK3), FRP2, and WIF1, as well as Wnt target cyclin D1 and c-Myc to establish if the pathway is constitutively activated in breast cancers arising in Saudi women. Cytoplasmic β-catenin, indicative of activation of the pathway, was observed in 24% of cases. Expression of APC and Axin, which are components of β-catenin destruction complex, was lost in 5% and 10% of tumors, respectively. Additionally, Wnt signaling inhibitors DKK3, FRP2, and Wnt inhibitory factor 1 (WIF1) were not expressed in 8%, 14%, and 5% breast tumors, respectively. Overall, accumulation of cytoplasmic β-catenin and downregulation of other Wnt pathway proteins (APC/Axin/DKK3/FRP2/WIF1) were found in approximately half of the breast cancers (47%) in our cohort. Consistent with this, analysis of Wnt target genes demonstrated moderate-to-strong expression of c-Myc in 58% and cyclin D1 in 50% of breast cancers. Deregulation of Wnt pathway was not associated with age of onset of the disease, tumor grade, and triple-negative status of breast cancers. High level of deregulated expression of Wnt pathway proteins suggests its important role in pathogenesis of breast cancers arising in Saudi women who may benefit from development of therapeutic drugs

  6. Road Impedance Model Study under the Control of Intersection Signal

    Directory of Open Access Journals (Sweden)

    Yunlin Luo

    2015-01-01

    Full Text Available Road traffic impedance model is a difficult and critical point in urban traffic assignment and route guidance. The paper takes a signalized intersection as the research object. On the basis of traditional traffic wave theory including the implementation of traffic wave model and the analysis of vehicles’ gathering and dissipating, the road traffic impedance model is researched by determining the basic travel time and waiting delay time. Numerical example results have proved that the proposed model in this paper has received better calculation performance compared to existing model, especially in flat hours. The values of mean absolute percentage error (MAPE and mean absolute deviation (MAD are separately reduced by 3.78% and 2.62 s. It shows that the proposed model has feasibility and availability in road traffic impedance under intersection signal.

  7. Association of single nucleotide polymorphisms in Wnt signaling pathway genes with breast cancer in Saudi patients.

    Directory of Open Access Journals (Sweden)

    Mohammad Saud Alanazi

    Full Text Available Breast cancer is a complex heterogeneous disease involving genetic and epigenetic alterations in genes encoding proteins that are components of various signaling pathways. Candidate gene approach have identified association of genetic variants in the Wnt signaling pathway genes and increased susceptibility to several diseases including breast cancer. Due to the rarity of somatic mutations in key genes of Wnt pathway, we investigated the association of genetic variants in these genes with predisposition to breast cancers. We performed a case-control study to identify risk variants by examining 15 SNPs located in 8 genes associated with Wnt signaling. Genotypic analysis of individual locus showed statistically significant association of five SNPs located in β-catenin, AXIN2, DKK3, SFRP3 and TCF7L2 with breast cancers. Increased risk was observed only with the SNP in β-catenin while the other four SNPs conferred protection against breast cancers. Majority of these associations persisted after stratification of the cases based on estrogen receptor status and age of on-set of breast cancer. The rs7775 SNP in exon 6 of SFRP3 gene that codes for either arginine or glycine exhibited very strong association with breast cancer, even after Bonferroni's correction. Apart from these five variants, rs3923086 in AXIN2 and rs3763511 in DKK4 that did not show any association in the overall population were significantly associated with early on-set and estrogen receptor negative breast cancers, respectively. This is the first study to utilize pathway based approach to identify association of risk variants in the Wnt signaling pathway genes with breast cancers. Confirmation of our findings in larger populations of different ethnicities would provide evidence for the role of Wnt pathway as well as screening markers for early detection of breast carcinomas.

  8. Endodermal Hedgehog signals modulate Notch pathway activity in the developing digestive tract mesenchyme.

    Science.gov (United States)

    Kim, Tae-Hee; Kim, Byeong-Moo; Mao, Junhao; Rowan, Sheldon; Shivdasani, Ramesh A

    2011-08-01

    The digestive tract epithelium and its adjoining mesenchyme undergo coordinated patterning and growth during development. The signals they exchange in the process are not fully characterized but include ligands of the Hedgehog (Hh) family, which originate in the epithelium and are necessary for mesenchymal cells to expand in number and drive elongation of the developing gut tube. The Notch signaling pathway has known requirements in fetal and adult intestinal epithelial progenitors. We detected Notch pathway activity in the embryonic gut mesenchyme and used conditional knockout mice to study its function. Selective disruption of the Notch effector gene RBP-Jκ (Rbpj) in the mesenchyme caused progressive loss of subepithelial fibroblasts and abbreviated gut length, revealing an unexpected requirement in this compartment. Surprisingly, constitutive Notch activity also induced rapid mesenchymal cell loss and impaired organogenesis, probably resulting from increased cell death and suggesting the need for a delicate balance in Notch signaling. Because digestive tract anomalies in mouse embryos with excess Notch activity phenocopy the absence of Hh signaling, we postulated that endodermal Hh restrains mesenchymal Notch pathway activity. Indeed, Hh-deficient embryos showed Notch overactivity in their defective gut mesenchyme and exposure to recombinant sonic hedgehog could override Notch-induced death of cultured fetal gut mesenchymal cells. These results reveal unexpected interactions between prominent signals in gastrointestinal development and provide a coherent explanation for Hh requirements in mesenchymal cell survival and organ growth.

  9. Toll-Like Receptor 4 Signaling Pathway Mediates Inhalant Organic Dust-Induced Bone Loss.

    Directory of Open Access Journals (Sweden)

    Elizabeth Staab

    Full Text Available Agriculture workers have increased rates of airway and skeletal disease. Inhalant exposure to agricultural organic dust extract (ODE induces bone deterioration in mice; yet, mechanisms underlying lung-bone crosstalk remain unclear. Because Toll-like receptor 2 (TLR2 and TLR4 are important in mediating the airway consequences of ODE, this study investigated their role in regulating bone responses. First, swine facility ODE stimulated wild-type (WT bone marrow macrophages to form osteoclasts, and this finding was inhibited in TLR4 knock-out (KO, but not TLR2 KO cells. Next, using an established intranasal inhalation exposure model, WT, TLR2 KO and TLR4 KO mice were treated daily with ODE or saline for 3 weeks. ODE-induced airway neutrophil influx and cytokine/chemokine release were similarly reduced in TLR2 and TLR4 KO animals as compared to WT mice. Utilizing micro-computed tomography (CT, analysis of tibia showed loss of bone mineral density, volume and deterioration of bone micro-architecture and mechanical strength induced by ODE in WT mice were significantly reduced in TLR4 but not TLR2 KO animals. Bone marrow osteoclast precursor cell populations were analyzed by flow cytometry from exposed animals. In WT animals, exposure to inhalant ODE increased osteoclast precursor cell populations as compared to saline, an effect that was reduced in TLR4 but not TLR2 KO mice. These results show that TLR2 and TLR4 pathways mediate ODE-induced airway inflammation, but bone deterioration consequences following inhalant ODE treatment is strongly dependent upon TLR4. Thus, the TLR4 signaling pathway appears critical in regulating the lung-bone inflammatory axis to microbial component-enriched organic dust exposures.

  10. Benzoquinone activates the ERK/MAPK signaling pathway via ROS production in HL-60 cells

    International Nuclear Information System (INIS)

    Ruiz-Ramos, Ruben; Cebrian, Mariano E.; Garrido, Efrain

    2005-01-01

    Benzene (BZ) is a class I carcinogen and its oxidation to reactive intermediates is a prerequisite of hematoxicity and myelotoxicity. The generated metabolites include hydroquinone, which is further oxidized to the highly reactive 1,4-benzoquinone (BQ) in bone marrow. Therefore, we explored the mechanisms underlying BQ-induced HL-60 cell proliferation by studying the role of BQ-induced reactive oxygen species (ROS) in the activation of the ERK-MAPK signaling pathway. BQ treatment (0.01-30 μM) showed that doses below 10 μM did not significantly reduce viability. ROS production after 3 μM BQ treatment increased threefold; however, catalase addition reduced ROS generation to basal levels. FACS analysis showed that BQ induced a fivefold increase in the proportion of cells in S-phase. We also observed a high proportion of Bromodeoxyuridine (BrdU) stained cells, indicating a higher DNA synthesis rate. BQ also produced rapid and prolonged phosphorylation of ERK1/2 proteins. Simultaneous treatment with catalase or PD98059, a potent MEK protein inhibitor, reduced cell recruitment into the S-phase and also abolished the ERK1/2 protein phosphorylation induced by BQ, suggesting that MEK/ERK is an important pathway involved in BQ-induced ROS mediated proliferation. The prolonged activation of ERK1/2 contributes to explain the increased S-phase cell recruitment and to understand the leukemogenic processes associated with exposure to benzene metabolites. Thus, the possible mechanism by which BQ induce HL-60 cells to enter the cell cycle and proliferate is linked to ROS production and its growth promoting effects by specific activation of regulating genes known to be activated by redox mechanisms

  11. Altered Expression of Wnt Signaling Pathway Components in Osteogenesis of Mesenchymal Stem Cells in Osteoarthritis Patients.

    Directory of Open Access Journals (Sweden)

    Pilar Tornero-Esteban

    Full Text Available Osteoarthritis (OA is characterized by altered homeostasis of joint cartilage and bone, whose functional properties rely on chondrocytes and osteoblasts, belonging to mesenchymal stem cells (MSCs. WNT signaling acts as a hub integrating and crosstalking with other signaling pathways leading to the regulation of MSC functions. The aim of this study was to evaluate the existence of a differential signaling between Healthy and OA-MSCs during osteogenesis.MSCs of seven OA patients and six healthy controls were isolated, characterised and expanded. During in vitro osteogenesis, cells were recovered at days 1, 10 and 21. RNA and protein content was obtained. Expression of WNT pathway genes was evaluated using RT-qPCR. Functional studies were also performed to study the MSC osteogenic commitment and functional and post-traslational status of β-catenin and several receptor tyrosine kinases.Several genes were downregulated in OA-MSCs during osteogenesis in vitro. These included soluble Wnts, inhibitors, receptors, co-receptors, several kinases and transcription factors. Basal levels of β-catenin were higher in OA-MSCs, but calcium deposition and expression of osteogenic genes was similar between Healthy and OA-MSCs. Interestingly an increased phosphorylation of p44/42 MAPK (ERK1/2 signaling node was present in OA-MSCs.Our results point to the existence in OA-MSCs of alterations in expression of Wnt pathway components during in vitro osteogenesis that are partially compensated by post-translational mechanisms modulating the function of other pathways. We also point the relevance of other signaling pathways in OA pathophysiology suggesting their role in the maintenance of joint homeostasis through modulation of MSC osteogenic potential.

  12. Altered Expression of Wnt Signaling Pathway Components in Osteogenesis of Mesenchymal Stem Cells in Osteoarthritis Patients.

    Science.gov (United States)

    Tornero-Esteban, Pilar; Peralta-Sastre, Ascensión; Herranz, Eva; Rodríguez-Rodríguez, Luis; Mucientes, Arkaitz; Abásolo, Lydia; Marco, Fernando; Fernández-Gutiérrez, Benjamín; Lamas, José Ramón

    2015-01-01

    Osteoarthritis (OA) is characterized by altered homeostasis of joint cartilage and bone, whose functional properties rely on chondrocytes and osteoblasts, belonging to mesenchymal stem cells (MSCs). WNT signaling acts as a hub integrating and crosstalking with other signaling pathways leading to the regulation of MSC functions. The aim of this study was to evaluate the existence of a differential signaling between Healthy and OA-MSCs during osteogenesis. MSCs of seven OA patients and six healthy controls were isolated, characterised and expanded. During in vitro osteogenesis, cells were recovered at days 1, 10 and 21. RNA and protein content was obtained. Expression of WNT pathway genes was evaluated using RT-qPCR. Functional studies were also performed to study the MSC osteogenic commitment and functional and post-traslational status of β-catenin and several receptor tyrosine kinases. Several genes were downregulated in OA-MSCs during osteogenesis in vitro. These included soluble Wnts, inhibitors, receptors, co-receptors, several kinases and transcription factors. Basal levels of β-catenin were higher in OA-MSCs, but calcium deposition and expression of osteogenic genes was similar between Healthy and OA-MSCs. Interestingly an increased phosphorylation of p44/42 MAPK (ERK1/2) signaling node was present in OA-MSCs. Our results point to the existence in OA-MSCs of alterations in expression of Wnt pathway components during in vitro osteogenesis that are partially compensated by post-translational mechanisms modulating the function of other pathways. We also point the relevance of other signaling pathways in OA pathophysiology suggesting their role in the maintenance of joint homeostasis through modulation of MSC osteogenic potential.

  13. Partial promoter substitutions generating transcriptional sentinels of diverse signaling pathways in embryonic stem cells and mice

    Science.gov (United States)

    Serup, Palle; Gustavsen, Carsten; Klein, Tino; Potter, Leah A.; Lin, Robert; Mullapudi, Nandita; Wandzioch, Ewa; Hines, Angela; Davis, Ashley; Bruun, Christine; Engberg, Nina; Petersen, Dorthe R.; Peterslund, Janny M. L.; MacDonald, Raymond J.; Grapin-Botton, Anne; Magnuson, Mark A.; Zaret, Kenneth S.

    2012-01-01

    SUMMARY Extracellular signals in development, physiology, homeostasis and disease often act by regulating transcription. Herein we describe a general method and specific resources for determining where and when such signaling occurs in live animals and for systematically comparing the timing and extent of different signals in different cellular contexts. We used recombinase-mediated cassette exchange (RMCE) to test the effect of successively deleting conserved genomic regions of the ubiquitously active Rosa26 promoter and substituting the deleted regions for regulatory sequences that respond to diverse extracellular signals. We thereby created an allelic series of embryonic stem cells and mice, each containing a signal-responsive sentinel with different fluorescent reporters that respond with sensitivity and specificity to retinoic acids, bone morphogenic proteins, activin A, Wnts or Notch, and that can be adapted to any pathway that acts via DNA elements. PMID:22888097

  14. Differential detectability of polymorphic warning signals under varying light environments.

    Science.gov (United States)

    Rojas, Bibiana; Rautiala, Petri; Mappes, Johanna

    2014-11-01

    The striking colour-pattern variation of some aposematic species is paradoxical because selection by predators is expected to favour signal uniformity. Although the mechanisms allowing for the maintenance of such variation are not well understood, possible explanations include both non-adaptive processes like drift and gene flow; and adaptive processes, such as an interaction between natural and sexual selection, spatial and temporal variation in selection, a link between behaviour or other fitness-related traits and phenotype, and predators' ability to generalise among different signals. Here we test whether warning-signal polymorphisms, such as that of dyeing poison frogs (Dendrobates tinctorius), could be maintained by differences in detectability among morphs. We did experiments in the wild using wax models with different aposematic colour patterns vs. cryptic ones, and examined the attack rates by wild predators over time. We also tested the detectability of different aposematic morphs by 'human predators' under different light environments. We found that cryptic frog models were attacked more than aposematic models, but there were no differences in bird attack rates towards the different aposematic morphs. However, we found that detectability of different morphs depends both on predator experience and light environment. We suggest that the interaction between differential detectability and signal efficiency among morphs in different light conditions could be a mechanism aiding to the maintenance of warning-signal polymorphisms. Our results highlight the importance of considering the light environment at which predators have their first encounters with aposematic prey for future studies on predation in the wild. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. Dibenzocyclooctadiene lignans, gomisins J and N inhibit the Wnt/β-catenin signaling pathway in HCT116 cells

    International Nuclear Information System (INIS)

    Kang, Kyungsu; Lee, Kyung-Mi; Yoo, Ji-Hye; Lee, Hee Ju; Kim, Chul Young; Nho, Chu Won

    2012-01-01

    Graphical abstract: Schematic diagram of the possible molecular mechanism underlying the inhibition of the Wnt/β-catenin signaling pathway and the induction of G0/G1-phase arrest by gomisins J and N, derived from the fruits of S. chinensis, in HCT116 human colon cancer cells. Highlights: ► Gomisins J and N inhibited Wnt/β-catenin signaling pathway in HCT116 cells. ► Gomisins J and N disrupted the binding of β-catenin to specific DNA sequences, TBE. ► Gomisins J and N inhibited the HCT116 cell proliferation through G0/G1 phase arrest. ► Gomisins J and N inhibited the expression of Cyc D1, a Wnt/β-catenin target gene. -- Abstract: Here, we report that gomisin J and gomisin N, dibenzocyclooctadiene type lignans isolated from Schisandra chinensis, inhibit Wnt/β-catenin signaling in HCT116 cells. Gomisins J and N appear to inhibit Wnt/β-catenin signaling by disrupting the interaction between β-catenin and its specific target DNA sequences (TCF binding elements, TBE) rather than by altering the expression of the β-catenin protein. Gomisins J and N inhibit HCT116 cell proliferation by arresting the cell cycle at the G0/G1 phase. The G0/G1 phase arrest induced by gomisins J and N appears to be caused by a decrease in the expression of Cyclin D1, a representative target gene of the Wnt/β-catenin signaling pathway, as well as Cdk2, Cdk4, and E2F-1. Therefore, gomisins J and N, the novel Wnt/β-catenin inhibitors discovered in this study, may serve as potential agents for the prevention and treatment of human colorectal cancers.

  16. Dibenzocyclooctadiene lignans, gomisins J and N inhibit the Wnt/{beta}-catenin signaling pathway in HCT116 cells

    Energy Technology Data Exchange (ETDEWEB)

    Kang, Kyungsu; Lee, Kyung-Mi; Yoo, Ji-Hye; Lee, Hee Ju [Functional Food Center, Korea Institute of Science and Technology, Gangneung 210-340 (Korea, Republic of); Kim, Chul Young [Functional Food Center, Korea Institute of Science and Technology, Gangneung 210-340 (Korea, Republic of); College of Pharmacy, Hanyang University, Ansan 426-791 (Korea, Republic of); Nho, Chu Won, E-mail: cwnho@kist.re.kr [Functional Food Center, Korea Institute of Science and Technology, Gangneung 210-340 (Korea, Republic of)

    2012-11-16

    Graphical abstract: Schematic diagram of the possible molecular mechanism underlying the inhibition of the Wnt/{beta}-catenin signaling pathway and the induction of G0/G1-phase arrest by gomisins J and N, derived from the fruits of S. chinensis, in HCT116 human colon cancer cells. Highlights: Black-Right-Pointing-Pointer Gomisins J and N inhibited Wnt/{beta}-catenin signaling pathway in HCT116 cells. Black-Right-Pointing-Pointer Gomisins J and N disrupted the binding of {beta}-catenin to specific DNA sequences, TBE. Black-Right-Pointing-Pointer Gomisins J and N inhibited the HCT116 cell proliferation through G0/G1 phase arrest. Black-Right-Pointing-Pointer Gomisins J and N inhibited the expression of Cyc D1, a Wnt/{beta}-catenin target gene. -- Abstract: Here, we report that gomisin J and gomisin N, dibenzocyclooctadiene type lignans isolated from Schisandra chinensis, inhibit Wnt/{beta}-catenin signaling in HCT116 cells. Gomisins J and N appear to inhibit Wnt/{beta}-catenin signaling by disrupting the interaction between {beta}-catenin and its specific target DNA sequences (TCF binding elements, TBE) rather than by altering the expression of the {beta}-catenin protein. Gomisins J and N inhibit HCT116 cell proliferation by arresting the cell cycle at the G0/G1 phase. The G0/G1 phase arrest induced by gomisins J and N appears to be caused by a decrease in the expression of Cyclin D1, a representative target gene of the Wnt/{beta}-catenin signaling pathway, as well as Cdk2, Cdk4, and E2F-1. Therefore, gomisins J and N, the novel Wnt/{beta}-catenin inhibitors discovered in this study, may serve as potential agents for the prevention and treatment of human colorectal cancers.

  17. A Leak Pathway for Luminal Protons in Endosomes Drives Oncogenic Signaling in Glioblastoma

    Science.gov (United States)

    Kondapalli, Kalyan C.; Llongueras, Jose P.; Capilla-González, Vivian; Prasad, Hari; Hack, Anniesha; Smith, Christopher; Guerrero-Cázares, Hugo; Quiñones-Hinojosa, Alfredo; Rao, Rajini

    2015-01-01

    Epidermal growth factor receptor (EGFR) signaling is a potent driver of glioblastoma, a malignant and lethal form of brain cancer. Disappointingly, inhibitors targeting receptor tyrosine kinase activity are not clinically effective, and EGFR persists on the plasma membrane to maintain tumor growth and invasiveness. Here we show that endolysosomal pH is critical for receptor sorting and turnover. By functioning as a leak pathway for protons, the Na+/H+ exchanger NHE9 limits luminal acidification to circumvent EGFR turnover and prolong downstream signaling pathways that drive tumor growth and migration. In glioblastoma, NHE9 expression is associated with stem/progenitor characteristics, radiochemoresistance, poor prognosis and invasive growth in vitro and in vivo. Silencing or inhibition of NHE9 in brain tumor initiating cells attenuates tumorsphere formation and improves efficacy of EGFR inhibitor. Thus, NHE9 mediates inside-out control of oncogenic signaling and is a highly druggable target for pan-specific receptor clearance in cancer therapy. PMID:25662504

  18. The EBI2 signalling pathway plays a role in cellular crosstalk between astrocytes and macrophages.

    Science.gov (United States)

    Rutkowska, Aleksandra; O'Sullivan, Sinead A; Christen, Isabelle; Zhang, Juan; Sailer, Andreas W; Dev, Kumlesh K

    2016-05-11

    EBI2 is a G protein-coupled receptor activated by oxysterol 7α, 25-dihydroxycholesterol (7α25HC) and regulates T cell-dependant antibody response and B cell migration. We recently found EBI2 is expressed in human astrocytes, regulates intracellular signalling and modulates astrocyte migration. Here, we report that LPS treatment of mouse astrocytes alters mRNA levels of EBI2 and oxysterols suggesting that the EBI2 signalling pathway is sensitive to LPS-mediated immune challenge. We also find that conditioned media obtained from LPS-stimulated mouse astrocytes induces macrophage migration, which is inhibited by the EBI2 antagonist NIBR189. These results demonstrate a role for the EBI2 signalling pathway in astrocytes as a sensor for immune challenge and for communication with innate immune cells such as macrophages.

  19. Feedback Activation of Basic Fibroblast Growth Factor Signaling via the Wnt/β-Catenin Pathway in Skin Fibroblasts.

    Science.gov (United States)

    Wang, Xu; Zhu, Yuting; Sun, Congcong; Wang, Tao; Shen, Yingjie; Cai, Wanhui; Sun, Jia; Chi, Lisha; Wang, Haijun; Song, Na; Niu, Chao; Shen, Jiayi; Cong, Weitao; Zhu, Zhongxin; Xuan, Yuanhu; Li, Xiaokun; Jin, Litai

    2017-01-01

    Skin wound healing is a complex process requiring the coordinated behavior of many cell types, especially in the proliferation and migration of fibroblasts. Basic fibroblast growth factor (bFGF) is a member of the FGF family that promotes fibroblast migration, but the underlying molecular mechanism remains elusive. The present RNA sequencing study showed that the expression levels of several canonical Wnt pathway genes, including Wnt2b , Wnt3 , Wnt11 , T-cell factor 7 (TCF7) , and Frizzled 8 ( FZD8 ) were modified by bFGF stimulation in fibroblasts. Enzyme-linked immunosorbent assay (ELISA) analysis also showed that Wnt pathway was activated under bFGF treatment. Furthermore, treatment of fibroblasts with lithium chloride or IWR-1, an inducer and inhibitor of the Wnt signaling pathway, respectively, promoted and inhibited cell migration. Also, levels of cytosolic glycogen synthase kinase 3 beta phosphorylated at serine 9 (pGSK3β Ser 9 ) and nuclear β-catenin were increased upon exposure to bFGF. Molecular and biochemical assays indicated that phosphoinositide 3-kinase (PI3K) signaling activated the GSK3β/β-catenin/Wnt signaling pathway via activation of c-Jun N-terminal kinase (JNK), suggesting that PI3K and JNK act at the upstream of β-catenin. In contrast, knock-down of β -catenin delayed fibroblast cell migration even under bFGF stimulation. RNA sequencing analysis of β -catenin knock-down fibroblasts demonstrated that β-catenin positively regulated the transcription of bFGF and FGF21. Moreover, FGF21 treatment activated AKT and JNK, and accelerated fibroblast migration to a similar extent as bFGF does. In addition, ELISA analysis demonstrated that both of bFGF and FGF21 were auto secretion factor and be regulated by Wnt pathway stimulators. Taken together, our analyses define a feedback regulatory loop between bFGF (FGF21) and Wnt signaling acting through β-catenin in skin fibroblasts.

  20. Proximity of signallers can maintain sexual signal variation under stabilizing selection.

    Science.gov (United States)

    van Wijk, Michiel; Heath, Jeremy; Lievers, Rik; Schal, Coby; Groot, Astrid T

    2017-12-22

    How sexual communication systems can evolve under stabilizing selection is still a paradox in evolutionary biology. In moths, females emit a species-specific sex pheromone, consisting of a blend of biochemically related components, to which males are attracted. Although males appear to exert strong stabilizing selection on female pheromone, these blends seem to have evolved rapidly, as evidenced by ~120,000 moth species. Here we propose and test a "proximity model" wherein two females that vary in their relative attractiveness to males, can both benefit from calling in close proximity to each other. In a field study, we show that (1) artificially selected unattractive females can achieve mating rates comparable to attractive females if they signal in close proximity to attractive females, and (2) attractive females benefit from higher mating rates when signalling in close proximity to unattractive females. We propose that frequency-dependent behavioural and spatial interactions can sustain signal variation within populations even when these signals are under stabilizing selection.

  1. Schisantherin A suppresses osteoclast formation and wear particle-induced osteolysis via modulating RANKL signaling pathways

    Energy Technology Data Exchange (ETDEWEB)

    He, Yi; Zhang, Qing; Shen, Yi; Chen, Xia; Zhou, Feng; Peng, Dan, E-mail: xyeypd@163.com

    2014-07-04

    Highlights: • Schisantherin A suppresses osteoclasts formation and function in vitro. • Schisantherin A impairs RANKL signaling pathway. • Schisantherin A suppresses osteolysis in vivo. • Schisantherin A may be used for treating osteoclast related diseases. - Abstract: Receptor activator of NF-κB ligand (RANKL) plays critical role in osteoclastogenesis. Targeting RANKL signaling pathways has been a promising strategy for treating osteoclast related bone diseases such as osteoporosis and aseptic prosthetic loosening. Schisantherin A (SA), a dibenzocyclooctadiene lignan isolated from the fruit of Schisandra sphenanthera, has been used as an antitussive, tonic, and sedative agent, but its effect on osteoclasts has been hitherto unknown. In the present study, SA was found to inhibit RANKL-induced osteoclast formation and bone resorption. The osteoclastic specific marker genes induced by RANKL including c-Src, SA inhibited OSCAR, cathepsin K and TRAP in a dose dependent manner. Further signal transduction studies revealed that SA down-regulate RANKL-induced nuclear factor-kappaB (NF-κB) signaling activation by suppressing the phosphorylation and degradation of IκBα, and subsequently preventing the NF-κB transcriptional activity. Moreover, SA also decreased the RANKL-induced MAPKs signaling pathway, including JNK and ERK1/2 posphorylation while had no obvious effects on p38 activation. Finally, SA suppressed the NF-κB and MAPKs subsequent gene expression of NFATc1 and c-Fos. In vivo studies, SA inhibited osteoclast function and exhibited bone protection effect in wear-particle-induced bone erosion model. Taken together, SA could attenuate osteoclast formation and wear particle-induced osteolysis by mediating RANKL signaling pathways. These data indicated that SA is a promising therapeutic natural compound for the treatment of osteoclast-related prosthesis loosening.

  2. Schisantherin A suppresses osteoclast formation and wear particle-induced osteolysis via modulating RANKL signaling pathways

    International Nuclear Information System (INIS)

    He, Yi; Zhang, Qing; Shen, Yi; Chen, Xia; Zhou, Feng; Peng, Dan

    2014-01-01

    Highlights: • Schisantherin A suppresses osteoclasts formation and function in vitro. • Schisantherin A impairs RANKL signaling pathway. • Schisantherin A suppresses osteolysis in vivo. • Schisantherin A may be used for treating osteoclast related diseases. - Abstract: Receptor activator of NF-κB ligand (RANKL) plays critical role in osteoclastogenesis. Targeting RANKL signaling pathways has been a promising strategy for treating osteoclast related bone diseases such as osteoporosis and aseptic prosthetic loosening. Schisantherin A (SA), a dibenzocyclooctadiene lignan isolated from the fruit of Schisandra sphenanthera, has been used as an antitussive, tonic, and sedative agent, but its effect on osteoclasts has been hitherto unknown. In the present study, SA was found to inhibit RANKL-induced osteoclast formation and bone resorption. The osteoclastic specific marker genes induced by RANKL including c-Src, SA inhibited OSCAR, cathepsin K and TRAP in a dose dependent manner. Further signal transduction studies revealed that SA down-regulate RANKL-induced nuclear factor-kappaB (NF-κB) signaling activation by suppressing the phosphorylation and degradation of IκBα, and subsequently preventing the NF-κB transcriptional activity. Moreover, SA also decreased the RANKL-induced MAPKs signaling pathway, including JNK and ERK1/2 posphorylation while had no obvious effects on p38 activation. Finally, SA suppressed the NF-κB and MAPKs subsequent gene expression of NFATc1 and c-Fos. In vivo studies, SA inhibited osteoclast function and exhibited bone protection effect in wear-particle-induced bone erosion model. Taken together, SA could attenuate osteoclast formation and wear particle-induced osteolysis by mediating RANKL signaling pathways. These data indicated that SA is a promising therapeutic natural compound for the treatment of osteoclast-related prosthesis loosening

  3. A Novel Rac1-GSPT1 Signaling Pathway Controls Astrogliosis Following Central Nervous System Injury*

    Science.gov (United States)

    Ishii, Taiji; Shigyo, Michiko; Kohta, Masaaki; Kondoh, Takeshi; Kuboyama, Tomoharu; Uebi, Tatsuya; Hamada, Takeshi; Gutmann, David H.; Aiba, Atsu; Kohmura, Eiji; Tohda, Chihiro; Saito, Naoaki

    2017-01-01

    Astrogliosis (i.e. glial scar), which is comprised primarily of proliferated astrocytes at the lesion site and migrated astrocytes from neighboring regions, is one of the key reactions in determining outcomes after CNS injury. In an effort to identify potential molecules/pathways that regulate astrogliosis, we sought to determine whether Rac/Rac-mediated signaling in astrocytes represents a novel candidate for therapeutic intervention following CNS injury. For these studies, we generated mice with Rac1 deletion under the control of the GFAP (glial fibrillary acidic protein) promoter (GFAP-Cre;Rac1flox/flox). GFAP-Cre;Rac1flox/flox (Rac1-KO) mice exhibited better recovery after spinal cord injury and exhibited reduced astrogliosis at the lesion site relative to control. Reduced astrogliosis was also observed in Rac1-KO mice following microbeam irradiation-induced injury. Moreover, knockdown (KD) or KO of Rac1 in astrocytes (LN229 cells, primary astrocytes, or primary astrocytes from Rac1-KO mice) led to delayed cell cycle progression and reduced cell migration. Rac1-KD or Rac1-KO astrocytes additionally had decreased levels of GSPT1 (G1 to S phase transition 1) expression and reduced responses of IL-1β and GSPT1 to LPS treatment, indicating that IL-1β and GSPT1 are downstream molecules of Rac1 associated with inflammatory condition. Furthermore, GSPT1-KD astrocytes had cell cycle delay, with no effect on cell migration. The cell cycle delay induced by Rac1-KD was rescued by overexpression of GSPT1. Based on these results, we propose that Rac1-GSPT1 represents a novel signaling axis in astrocytes that accelerates proliferation in response to inflammation, which is one important factor in the development of astrogliosis/glial scar following CNS injury. PMID:27941025

  4. Targeting multiple pro-apoptotic signaling pathways with curcumin in prostate cancer cells.

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    Mariela Rivera

    Full Text Available Curcumin, an extract from the turmeric rhizome (Curcuma longa, is known to exhibit anti-inflammatory, antioxidant, chemopreventive and antitumoral activities against aggressive and recurrent cancers. Accumulative data indicate that curcumin may induce cancer cell death. However, the detailed mechanism underlying its pro-apoptotic and anti-cancer effects remains to be elucidated. In the present study, we examined the signaling pathways triggered by curcumin, specifically, the exact molecular mechanisms of curcumin-induced apoptosis in highly metastatic human prostate cancer cells. The effect of curcumin was evaluated using for the first time in prostate cancer, a gel-free shotgun quantitative proteomic analysis coupled with Tandem Mass Tag isobaric labeling-based-signaling networks. Results were confirmed at the gene expression level by qRT-PCR and at the protein expression level by western blot and flow cytometry. Our findings revealed that curcumin induced an Endoplasmic Reticulum stress-mediated apoptosis in PC3. The mechanisms by which curcumin promoted cell death in these cells were associated with cell cycle arrest, increased reactive oxygen species, autophagy and the Unfolded Protein Response. Furthermore, the upregulation of ER stress was measured using key indicators of ER stress: Glucose-Regulated Protein 78, Inositol-Requiring Enzyme 1 alpha, Protein Disulfide isomerase and Calreticulin. Chronic ER stress induction was concomitant with the upregulation of pro-apoptotic markers (caspases 3,9,12 and Poly (ADP-ribose polymerase. The downregulated proteins include anti-apoptotic and anti-tumor markers, supporting their curcumin-induced pro-apoptotic role in prostate cancer cells. Taken together, these data suggest that curcumin may serve as a promising anticancer agent by inducing a chronic ER stress mediated cell death and activation of cell cycle arrest, UPR, autophagy and oxidative stress responses.

  5. Targeting multiple pro-apoptotic signaling pathways with curcumin in prostate cancer cells

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    Rivera, Mariela; Ramos, Yanilda; Rodríguez-Valentín, Madeline; López-Acevedo, Sheila; Cubano, Luis A.; Zou, Jin; Zhang, Qiang; Wang, Guangdi

    2017-01-01

    Curcumin, an extract from the turmeric rhizome (Curcuma longa), is known to exhibit anti-inflammatory, antioxidant, chemopreventive and antitumoral activities against aggressive and recurrent cancers. Accumulative data indicate that curcumin may induce cancer cell death. However, the detailed mechanism underlying its pro-apoptotic and anti-cancer effects remains to be elucidated. In the present study, we examined the signaling pathways triggered by curcumin, specifically, the exact molecular mechanisms of curcumin-induced apoptosis in highly metastatic human prostate cancer cells. The effect of curcumin was evaluated using for the first time in prostate cancer, a gel-free shotgun quantitative proteomic analysis coupled with Tandem Mass Tag isobaric labeling-based-signaling networks. Results were confirmed at the gene expression level by qRT-PCR and at the protein expression level by western blot and flow cytometry. Our findings revealed that curcumin induced an Endoplasmic Reticulum stress-mediated apoptosis in PC3. The mechanisms by which curcumin promoted cell death in these cells were associated with cell cycle arrest, increased reactive oxygen species, autophagy and the Unfolded Protein Response. Furthermore, the upregulation of ER stress was measured using key indicators of ER stress: Glucose-Regulated Protein 78, Inositol-Requiring Enzyme 1 alpha, Protein Disulfide isomerase and Calreticulin. Chronic ER stress induction was concomitant with the upregulation of pro-apoptotic markers (caspases 3,9,12) and Poly (ADP-ribose) polymerase. The downregulated proteins include anti-apoptotic and anti-tumor markers, supporting their curcumin-induced pro-apoptotic role in prostate cancer cells. Taken together, these data suggest that curcumin may serve as a promising anticancer agent by inducing a chronic ER stress mediated cell death and activation of cell cycle arrest, UPR, autophagy and oxidative stress responses. PMID:28628644

  6. Modulation of bacterial Type III secretion system by a spermidine transporter dependent signaling pathway.

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    Lian Zhou

    Full Text Available BACKGROUND: Many gram-negative bacterial pathogens employ Type III secretion systems (T3SS to inject effector proteins into host cells in infectious processes. METHODOLOGY/PRINCIPAL FINDINGS: By screening a transposon mutant library of P. aeruginosa, we found that mutation of spuDEFGH, which encode a major spermidine uptake system, abolished the expression of the exsCEBA operon that codes for key T3SS regulators under inducing conditions (low calcium. Whole genome microarray analysis revealed that inactivation of the spermidine uptake system significantly decreased the transcriptional expression of most, if not all, T3SS genes. Consistently, the spermidine uptake mutants showed decreased expression of the T3SS genes in responding to host cell extract and attenuated cytotoxicity. Furthermore, exogenous addition of spermidine to the wild type strain PAO1 enhanced the expression of exsCEBA and also the effector protein genes. CONCLUSION/SIGNIFICANCE: Cumulatively, these data have depicted a novel spermidine transporter-dependent signaling pathway, which appears to play an essential role in modulation of T3SS expression in P. aeruginosa.

  7. Resveratrol Protects PC12 Cell against 6-OHDA Damage via CXCR4 Signaling Pathway

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    Jing Zhang

    2015-01-01

    Full Text Available Resveratrol, herbal nonflavonoid polyphenolic compound naturally derived from grapes, has long been acknowledged to possess extensive biological and pharmacological properties including antioxidant and anti-inflammatory ones and may exert a neuroprotective effect on neuronal damage in neurodegenerative diseases. However, the underlying molecular mechanisms remain undefined. In the present study, we intended to investigate the neuroprotective effects of resveratrol against 6-OHDA-induced neurotoxicity of PC12 cells and further explore the possible mechanisms involved. For this purpose, PC12 cells were exposed to 6-OHDA in the presence of resveratrol (0, 12.5, 25, and 50 μM. The results showed that resveratrol increased cell viability, alleviated the MMP reduction, and reduced the number of apoptotic cells as measured by MTT assay, JC-1 staining, and Hoechst/PI double staining (all p<0.01. Immunofluorescent staining and Western blotting revealed that resveratrol averts 6-OHDA induced CXCR4 upregulation (p<0.01. Our results demonstrated that resveratrol could effectively protect PC12 cells from 6-OHDA-induced oxidative stress and apoptosis via CXCR4 signaling pathway.

  8. Genomics in cardiovascular diseases: analysis of the importance of the toll-like receptor signaling pathway

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    Bustamante J

    2012-10-01

    Full Text Available J Bustamante,1 E Tamayo,2 J Herreros3,41Department of Cardiovascular Surgery, Hospital Universitario La Princesa, Madrid, 2Department of Anesthesiology and Intensive Care, Hospital Clinico Universitario de Valladolid, Valladolid, 3Department of Cardiovascular Surgery, Hospital Universitario Valdecilla, Santander, 4Biomedical Engineering Institute of Santander, Santander, SpainAbstract: The development of techniques for genomics study makes it possible for us to further our knowledge about the physiopathology of various immunological or infectious diseases. These techniques improve our understanding of the development and evolution of such diseases, including those of cardiovascular origin, whilst they help to bring about the design of new therapeutic strategies. We are reviewing the genetic alterations of immunity in said field, and focusing on the signaling pathway of toll-like receptors because not only does this play a decisive role in response to microorganisms, it is also heavily involved in modulating the inflammatory response to tissue damage, a side effect of numerous cardiovascular diseases. These alterations in tissue homeostasis are present under a wide range of circumstances, such as reperfusion ischemia (myocardial infarction phenomena, arteriosclerosis, or valvulopathy.Keywords: genome-wide association study, single-nucleotide polymorphism, innate immune system, ischemic/reperfusion, myocardial infarction

  9. Autophagy protects intestinal epithelial cells against deoxynivalenol toxicity by alleviating oxidative stress via IKK signaling pathway.

    Science.gov (United States)

    Tang, Yulong; Li, Jianjun; Li, Fengna; Hu, Chien-An A; Liao, Peng; Tan, Kunrong; Tan, Bie; Xiong, Xia; Liu, Gang; Li, Tiejun; Yin, Yulong

    2015-12-01

    Autophagy is an intracellular process of homeostatic degradation that promotes cell survival under various stressors. Deoxynivalenol (DON), a fungal toxin, often causes diarrhea and disturbs the homeostasis of the intestinal system. To investigate the function of intestinal autophagy in response to DON and associated mechanisms, we firstly knocked out ATG5 (autophagy-related gene 5) in porcine intestinal epithelial cells (IPEC-J2) using CRISPR-Cas9 technology. When treated with DON, autophagy was induced in IPEC-J2 cells but not in IPEC-J2.Atg5ko cells. The deficiency in autophagy increased DON-induced apoptosis in IPEC-J2.atg5ko cells, in part, through the generation of reactive oxygen species (ROS). The cellular stress response can be restored in IPEC-J2.atg5ko cells by overexpressing proteins involved in protein folding. Interestingly, we found that autophagy deficiency downregulated the expression of endoplasmic reticulum folding proteins BiP and PDI when IPEC-J2.atg5ko cells were treated with DON. In addition, we investigated the molecular mechanism of autophagy involved in the IKK, AMPK, and mTOR signaling pathway and found that Bay-117082 and Compound C, specific inhibitors for IKK and AMPK, respectively, inhibited the induction of autophagy. Taken together, our results suggest that autophagy is pivotal for protection against DON in pig intestinal cells. Copyright © 2015 Elsevier Inc. All rights reserved.

  10. Sulfuretin Attenuates MPP+-Induced Neurotoxicity through Akt/GSK3β and ERK Signaling Pathways

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    Ramesh Pariyar

    2017-12-01

    Full Text Available Parkinson’s disease (PD is the second most common neurodegenerative disease. It is caused by the death of dopaminergic neurons in the substantia nigra pars compacta. Oxidative stress and mitochondrial dysfunction contribute to the loss of dopaminergic neurons in PD. Sulfuretin is a potent antioxidant that is reported to be beneficial in the treatment of neurodegenerative diseases. In this study, we examined the protective effect of sulfuretin against 1-methyl-4-phenyl pyridinium (MPP+-induced cell model of PD in SH-SY5Y cells and the underlying molecular mechanisms. Sulfuretin significantly decreased MPP+-induced apoptotic cell death, accompanied by a reduction in caspase 3 activity and polyADP-ribose polymerase (PARP cleavage. Furthermore, it attenuated MPP+-induced production of intracellular reactive oxygen species (ROS and disruption of mitochondrial membrane potential (MMP. Consistently, sulfuretin decreased p53 expression and the Bax/Bcl-2 ratio. Moreover, sulfuretin significantly increased the phosphorylation of Akt, GSK3β, and ERK. Pharmacological inhibitors of PI3K/Akt and ERK abolished the cytoprotective effects of sulfuretin against MPP+. An inhibitor of GSK3β mimicked sulfuretin-induced protection against MPP+. Taken together, these results suggest that sulfuretin significantly attenuates MPP+-induced neurotoxicity through Akt/GSK3β and ERK signaling pathways in SH-SY5Y cells. Our findings suggest that sulfuretin might be one of the potential candidates for the treatment of PD.

  11. Curcumin inhibits MCF-7 cells by modulating the NF-κB signaling pathway.

    Science.gov (United States)

    Liu, Jun-Li; Pan, Yan-Yan; Chen, Ou; Luan, Yun; Xue, Xia; Zhao, Jing-Jie; Liu, Ling; Jia, Hong-Ying

    2017-11-01

    The present study investigated the inhibitory effect of curcumin on human breast cancer MCF-7 cells and investigated the potential underlying molecular mechanisms. MCF-7 cells were cultured with curcumin at different concentrations and time points. The effects of curcumin treatment on breast cancer cell proliferation were studied using a MTT assay. Reverse transcription-quantitative polymerase chain reaction and western blot analysis were used to assess the mRNA and protein expression levels of B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X (Bax), nuclear factor-κ-light-chain-enhancer of activated B cells (NF-κB) and inhibitor of NF-κB-α (IκBα). The proliferation of MCF-7 cells in the group treated with curcumin was markedly decreased compared with the control, with the greatest inhibitory effect at a concentration of 20 µM. The expression of Bax mRNA was increased and Bcl-2 mRNA expression was decreased compared with the control. Additionally, protein expression of NF-κB and IκB was increased. The data indicate that curcumin is able to inhibit breast cancer cell proliferation, possibly by regulating the NF-κB signaling pathway.

  12. The effect of phosphate deficiency on quorum sensing signaling pathway of Sinorhizobium meliloti

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    Najmeh Pakdaman

    2015-02-01

    Full Text Available   Introduction : Phosphorus is one of the most essential macroelements for bacterial cells. Since phosphate (PO4-3 limitation is frequently encountered in soils, bacteria developed some mechanisms in response to this sever condition. Phosphate transporter (PstS and proteins involved in quorum sensing (QS signaling pathway are affected by mediating PhoB, response regulator, following phosphate starvation. QS system of Sinorhizobium meliloti composed of at least three genes of sinI (autoinducer synthase, sinR and expR (autoinducer activated receptor which involved in its free living and symbiotic functions .   Materials and method s: The optical density (OD600 of different S. meliloti transformed strains carrying pLK004 (a pstS promoter-egfp fusion, pLK64 (a sinI promoter-egfp fusion, pLK65 (a sinR promoter-egfp fusion, pLK66 (an expR promoter-egfp fusion and control (promoterless-egfp fusion plasmids were read under different phosphate concentrations of 0.1 (phosphate deficiency, 0.5 and 2 mM (sufficient phosphate at several time points of 16, 24 and 40h. The promoter activity of different genes of pstS, sinI, sinR and expR were measured as emitted fluorescence per bacterial cell density (OD600 under different phosphate concentrations .   Results : By reducing phosphate concentration in the medium, the growth rate of transformed bacteria decreased, especially at 40h. The promoter activity of pstS, sinI and sinR, but not expR, genes was activated following phosphate starvation .   Discussion and conclusion : S. meliloti can upregulate PstS to partly compensate phosphate deficiency in the environment. The gene of sinR is also activated in a PhoB dependent manner as phosphate starvation is encountered. SinR is the activator of sinI, so the upregulation of QS pathway under phosphate deficiency may be facilitate free living and symbiotic bacterial functions .

  13. The function of BTG3 in colorectal cancer cells and its possible signaling pathway.

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    Lv, Chi; Wang, Heling; Tong, Yuxin; Yin, Hongzhuan; Wang, Dalu; Yan, Zhaopeng; Liang, Yichao; Wu, Di; Su, Qi

    2018-02-01

    B-cell translocation gene 3 (BTG3) has been identified as a candidate driver gene for various cancers, but its specific role in colorectal cancer (CRC) is poorly understood. We aimed to investigate the relationship between expression of BTG3 and clinicopathological features and prognosis, as well as to explore the effects and the role of a possible BTG3 molecular mechanism on aggressive colorectal cancer behavior. BTG3 expression was assessed by immunohistochemistry (IHC) on specimens from 140 patients with CRC. The association of BTG3 expression with clinicopathological features was examined. To confirm the biological role of BTG3 in CRC, two CRC cell lines expressing BTG3 were used and BTG3 expression was knocked down by shRNA. CCK-8, cell cycle, apoptosis, migration, and invasion assays were performed. The influence of BTG3 knockdown was further investigated by genomic microarray to uncover the potential molecular mechanisms underlying BTG3-mediated CRC development and progression. BTG3 was downregulated in colorectal cancer tissues and positively correlated with pathological classification (p = 0.037), depth of invasion (p = 0.016), distant metastasis (p = 0.024), TNM stage (p = 0.007), and overall survival (OS) and disease-free survival (DFS). BTG3 knockdown promoted cell proliferation, migration, invasion, relieved G2 arrest, and inhibited apoptosis in HCT116 and LoVo cells. A genomic microarray analysis showed that numerous tumor-associated signaling pathways and oncogenes were altered by BTG3 knockdown. At the mRNA level, nine genes referred to the extracellular-regulated kinase/mitogen-activated protein kinase pathway were differentially expressed. Western blotting revealed that BTG3 knockdown upregulated PAK2, RPS6KA5, YWHAB, and signal transducer and activator of transcription (STAT)3 protein levels, but downregulated RAP1A, DUSP6, and STAT1 protein expression, which was consistent with the genomic microarray data. BTG3 expression might

  14. Beta-arrestins - scaffolds and signalling elements essential for WNT/Frizzled signalling pathways?

    Czech Academy of Sciences Publication Activity Database

    Schulte, G.; Schambony, A.; Bryja, Vítězslav

    2010-01-01

    Roč. 159, č. 5 (2010), s. 1051-1058 ISSN 0007-1188 R&D Projects: GA ČR(CZ) GC204/09/J030 Grant - others:GA ČR(CZ) GA204/09/0498; GA AV ČR(CZ) KJB501630801 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : beta-arrestin * Wnt signaling * dishevelled Subject RIV: BO - Biophysics Impact factor: 4.925, year: 2010

  15. NO2inhalation causes tauopathy by disturbing the insulin signaling pathway.

    Science.gov (United States)

    Yan, Wei; Ku, Tingting; Yue, Huifeng; Li, Guangke; Sang, Nan

    2016-12-01

    Air pollution has been evidenced as a risk factor for neurodegenerative tauopathies. NO 2 , a primary component of air pollution, is negatively linked to neurodegenerative disorders, but its independent and direct association with tau lesion remains to be elucidated. Considering the fact that the insulin signaling pathway can be targeted by air pollutants and regulate tau function, this study focused on the role of insulin signaling in this NO 2 -induced tauopathy. Using a dynamic inhalation treatment, we demonstrated that exposure to NO 2 induced a disruption of insulin signaling in skeletal muscle, liver, and brain, with associated p38 MAPK and/or JNK activation. We also found that in parallel with these kinase signaling cascades, the compensatory hyperinsulinemia triggered by whole-body insulin resistance (IR) further attenuated the IRS-1/AKT/GSK-3β signaling pathway in the central nervous system, which consequently increased the phosphorylation of tau and reduced the expression of synaptic proteins that contributed to the development of the tau pathology. These findings provide new insight into the possible mechanisms involved in the etiopathogenesis of NO 2 -induced tauopathy, suggesting that the targeting of insulin signaling may be a promising therapeutic strategy to prevent this disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

  16. Molecular pathway profiling of T lymphocyte signal transduction pathways; Th1 and Th2 genomic fingerprints are defined by TCR and CD28-mediated signaling

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    Smeets Ruben L

    2012-03-01

    Full Text Available Abstract Background T lymphocytes are orchestrators of adaptive immunity. Naïve T cells may differentiate into Th1, Th2, Th17 or iTreg phenotypes, depending on environmental co-stimulatory signals. To identify genes and pathways involved in differentiation of Jurkat T cells towards Th1 and Th2 subtypes we performed comprehensive transcriptome analyses of Jurkat T cells stimulated with various stimuli and pathway inhibitors. Results from these experiments were validated in a human experimental setting using whole blood and purified CD4+ Tcells. Results Calcium-dependent activation of T cells using CD3/CD28 and PMA/CD3 stimulation induced a Th1 expression profile reflected by increased expression of T-bet, RUNX3, IL-2, and IFNγ, whereas calcium-independent activation via PMA/CD28 induced a Th2 expression profile which included GATA3, RXRA, CCL1 and Itk. Knock down with siRNA and gene expression profiling in the presence of selective kinase inhibitors showed that proximal kinases Lck and PKCθ are crucial signaling hubs during T helper cell activation, revealing a clear role for Lck in Th1 development and for PKCθ in both Th1 and Th2 development. Medial signaling via MAPkinases appeared to be less important in these pathways, since specific inhibitors of these kinases displayed a minor effect on gene expression. Translation towards a primary, whole blood setting and purified human CD4+ T cells revealed that PMA/CD3 stimulation induced a more pronounced Th1 specific, Lck and PKCθ dependent IFNγ production, whereas PMA/CD28 induced Th2 specific IL-5 and IL-13 production, independent of Lck activation. PMA/CD3-mediated skewing towards a Th1 phenotype was also reflected in mRNA expression of the master transcription factor Tbet, whereas PMA/CD28-mediated stimulation enhanced GATA3 mRNA expression in primary human CD4+ Tcells. Conclusions This study identifies stimulatory pathways and gene expression profiles for in vitro skewing of T helper cell

  17. MAPK/ERK signaling pathway-induced hyper-O-GlcNAcylation enhances cancer malignancy.

    Science.gov (United States)

    Zhang, Xinling; Ma, Leina; Qi, Jieqiong; Shan, Hui; Yu, Wengong; Gu, Yuchao

    2015-12-01

    Dysregulated MAPK/ERK signaling is implicated in one-third of human tumors and represents an attractive target for the development of anticancer drugs. Similarly, elevated protein O-GlcNAcylation and O-GlcNAc transferase (OGT) are detected in various cancers and serve as attractive novel cancer-specific therapeutic targets. However, the potential connection between them remains unexplored. Here, a positive correlation was found between the activated MAPK/ERK signaling and hyper-O-GlcNAcylation in various cancer types and inhibition of the MAPK/ERK signaling by 10 µM U0126 significantly decreased the expression of OGT and O-GlcNAcylation in H1299, BPH-1 and DU145 cells; then, the pathway analysis of the potential regulators of OGT obtained from the UCSC Genome Browser was done, and ten downstream targets of ERK pathway were uncovered; the following results showed that ELK1, one of the ten targets of ERK pathway, mediated ERK signaling-induced OGT upregulation; finally, the MTT assay and the soft agar assay showed that the inhibition of MAPK/ERK signaling reduced the promotion effect of hyper-O-GlcNAcylation on cancer cell proliferation and anchorage-independent growth. Taken together, our data originally provided evidence for the regulatory mechanism of hyper-O-GlcNAcylation in tumors, which will be helpful for the development of anticancer drugs targeting to hyper-O-GlcNAcylation. This study also provided a new mechanism by which MAPK/ERK signaling-enhanced cancer malignancy. Altogether, the recently discovered oncogenic factor O-GlcNAc was linked to the classical MAPK/ERK signaling which is essential for the maintenance of malignant phenotype of cancers.

  18. Utilizing ras signaling pathway to direct selective replication of herpes simplex virus-1.

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    Weihong Pan

    Full Text Available Re-engineering the tropism of viruses is an attractive translational strategy for targeting cancer cells. The Ras signal transduction pathway is a central hub for a variety of pro-oncogenic events with a fundamental role in normal and neoplastic physiology. In this work we were interested in linking Ras activation to HSV-1 replication in a direct manner in order to generate a novel oncolytic herpes virus which can target cancer cells. To establish such link, we developed a mutant HSV-1 in which the expression of ICP4 (infected cell protein-4, a viral protein necessary for replication is controlled by activation of ELK, a transcription factor down-stream of the Ras pathway and mainly activated by ERK (extracellular signal-regulated kinase, an important Ras effector pathway. This mutant HSV-1 was named as Signal-Smart 1 (SS1. A series of prostate cells were infected with the SS1 virus. Cells with elevated levels of ELK activation were preferentially infected by the SS1 virus, as demonstrated by increased levels of viral progeny, herpetic glycoprotein C and overall SS1 viral protein production. Upon exposure to SS1, the proliferation, invasiveness and colony formation capabilities of prostate cancer cells with increased ELK activation were significantly decreased (p<0.05, while the rate of apoptosis/necrosis in these cells was increased. Additionally, high Ras signaling cells infected with SS1 showed a prominent arrest in the G1 phase of the cell cycle as compared to cells exposed to parental HSV-1. The results of this study reveal the potential for re-modeling the host-herpes interaction to specifically interfere with the life of cancer cells with increased Ras signaling. SS1 also serves as a "prototype" for development of a family of signal-smart viruses which can target cancer cells on the basis of their signaling portfolio.

  19. Improved Protein Arrays for Quantitative Systems Analysis of the Dynamics of Signaling Pathway Interactions

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Chin-Rang [National Inst. of Health (NIH), Bethesda, MD (United States). National Heart, Lung and Blood Inst.

    2013-12-11

    Astronauts and workers in nuclear plants who repeatedly exposed to low doses of ionizing radiation (IR, <10 cGy) are likely to incur specific changes in signal transduction and gene expression in various tissues of their body. Remarkable advances in high throughput genomics and proteomics technologies enable researchers to broaden their focus from examining single gene/protein kinetics to better understanding global gene/protein expression profiling and biological pathway analyses, namely Systems Biology. An ultimate goal of systems biology is to develop dynamic mathematical models of interacting biological systems capable of simulating living systems in a computer. This Glue Grant is to complement Dr. Boothman’s existing DOE grant (No. DE-FG02-06ER64186) entitled “The IGF1/IGF-1R-MAPK-Secretory Clusterin (sCLU) Pathway: Mediator of a Low Dose IR-Inducible Bystander Effect” to develop sensitive and quantitative proteomic technology that suitable for low dose radiobiology researches. An improved version of quantitative protein array platform utilizing linear Quantum dot signaling for systematically measuring protein levels and phosphorylation states for systems biology modeling is presented. The signals are amplified by a confocal laser Quantum dot scanner resulting in ~1000-fold more sensitivity than traditional Western blots and show the good linearity that is impossible for the signals of HRP-amplification. Therefore this improved protein array technology is suitable to detect weak responses of low dose radiation. Software is developed to facilitate the quantitative readout of signaling network activities. Kinetics of EGFRvIII mutant signaling was analyzed to quantify cross-talks between EGFR and other signaling pathways.

  20. Utilizing ras signaling pathway to direct selective replication of herpes simplex virus-1.

    Science.gov (United States)

    Pan, Weihong; Bodempudi, Vidya; Esfandyari, Tuba; Farassati, Faris

    2009-08-04

    Re-engineering the tropism of viruses is an attractive translational strategy for targeting cancer cells. The Ras signal transduction pathway is a central hub for a variety of pro-oncogenic events with a fundamental role in normal and neoplastic physiology. In this work we were interested in linking Ras activation to HSV-1 replication in a direct manner in order to generate a novel oncolytic herpes virus which can target cancer cells. To establish such link, we developed a mutant HSV-1 in which the expression of ICP4 (infected cell protein-4, a viral protein necessary for replication) is controlled by activation of ELK, a transcription factor down-stream of the Ras pathway and mainly activated by ERK (extracellular signal-regulated kinase, an important Ras effector pathway). This mutant HSV-1 was named as Signal-Smart 1 (SS1). A series of prostate cells were infected with the SS1 virus. Cells with elevated levels of ELK activation were preferentially infected by the SS1 virus, as demonstrated by increased levels of viral progeny, herpetic glycoprotein C and overall SS1 viral protein production. Upon exposure to SS1, the proliferation, invasiveness and colony formation capabilities of prostate cancer cells with increased ELK activation were significantly decreased (p<0.05), while the rate of apoptosis/necrosis in these cells was increased. Additionally, high Ras signaling cells infected with SS1 showed a prominent arrest in the G1 phase of the cell cycle as compared to cells exposed to parental HSV-1. The results of this study reveal the potential for re-modeling the host-herpes interaction to specifically interfere with the life of cancer cells with increased Ras signaling. SS1 also serves as a "prototype" for development of a family of signal-smart viruses which can target cancer cells on the basis of their signaling portfolio.

  1. Effects of the Notch1 signaling pathway on human lung cancer A549 cells.

    Science.gov (United States)

    Zeng, Yun; Yin, Bijian; Wang, Xinwei; Xia, Guohao; Shen, Zhengjie; Gu, Wenzhe; Wu, Mianhua

    To evaluate the effects of the Notch1 signaling pathway on human lung cancer A549 cells. A549 cells were transfected with recombinant plasmids. Cell proliferation was detected by MTT assay. A tumor-bearing mouse model was established for intratumoral gene injection. Apoptosis-related factors were detected by immunohistochemical assay. Caspase-8, caspase-3, caspase-9, PI3K, pAkt and pSTAT3 expressions were detected by Western blotting. Compared with A549-GFP and A549 cells, A549-ICN cell growth in mice decelerated, tumor volume significantly reduced (p A549 cell proliferation decelerated, growth was significantly inhibited (p A549-ICN cell growth time- and dose-dependently. After treatment for 24 h or longer, TRAIL induced apoptosis of more A549-ICN cells. Cleaved caspase-3 and cleaved caspase-9 were detected only in A549-ICN cells after 6 h of 40 ng/mL TRAIL treatment, but cleaved caspase-8 was not detected. Combining Notch1 signal with TRAIL inhibited PI3K, phosphorylated Akt and phosphorylated STAT3 expressions. The Notch1 signaling pathway may inhibit A549 cell growth in vitro and in vivo by regulating cell cycle-related and anti-apoptotic protein expressions. Notch1 activation also suppressed A549 cell apoptosis by inhibiting the PI3K/pAkt pathway and activating the caspase-3 pathway in cooperation with TRAIL.

  2. Molecular alterations in signal pathways of melanoma and new personalized treatment strategies: Targeting of Notch

    Directory of Open Access Journals (Sweden)

    Julija Mozūraitienė

    2015-01-01

    Full Text Available Despite modern achievements in therapy of malignant melanomas new treatment strategies are welcomed in clinics for survival of patients. Now it is supposed that personalized molecular therapies for each patient are needed concerning a specificity of molecular alterations in patient's tumors. In human melanoma, Notch signaling interacts with other pathways, including MAPK, PI3K-AKT, NF-kB, and p53. This article discusses mutated genes and leading aberrant signal pathways in human melanoma which are of interest concerning to their perspective for personalized treatment strategies in melanoma. We speculate that E3 ubiquitin ligases MDM2 and MDM4 can be attractive therapeutic target for p53 and Notch signaling pathways in malignant melanoma by using small molecule inhibitors. It is possible that restoration of p53-MDM2-NUMB complexes in melanoma can restore wild type p53 function and positively modulate Notch pathway. In this review we summarize recent data about novel US Food and Drug Administration approved target drugs for metastatic melanoma treatment, and suppose model for treatment strategy by targeting Notch.

  3. Natural compounds targeting major cell signaling pathways: a novel paradigm for osteosarcoma therapy

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    Pablo Angulo

    2017-01-01

    Full Text Available Abstract Osteosarcoma is the most common primary bone cancer affecting children and adolescents worldwide. Despite an incidence of three cases per million annually, it accounts for an inordinate amount of morbidity and mortality. While the use of chemotherapy (cisplatin, doxorubicin, and methotrexate in the last century initially resulted in marginal improvement in survival over surgery alone, survival has not improved further in the past four decades. Patients with metastatic osteosarcoma have an especially poor prognosis, with only 30% overall survival. Hence, there is a substantial need for new therapies. The inability to control the metastatic progression of this localized cancer stems from a lack of complete knowledge of the biology of osteosarcoma. Consequently, there has been an aggressive undertaking of scientific investigation of various signaling pathways that could be instrumental in understanding the pathogenesis of osteosarcoma. Here, we review these cancer signaling pathways, including Notch, Wnt, Hedgehog, phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K/AKT, and JAK/STAT, and their specific role in osteosarcoma. In addition, we highlight numerous natural compounds that have been documented to target these pathways effectively, including curcumin, diallyl trisulfide, resveratrol, apigenin, cyclopamine, and sulforaphane. We elucidate through references that these natural compounds can induce cancer signaling pathway manipulation and possibly facilitate new treatment modalities for osteosarcoma.

  4. Whole Genome Expression Profiling and Signal Pathway Screening of MSCs in Ankylosing Spondylitis.

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    Li, Yuxi; Wang, Peng; Xie, Zhongyu; Huang, Lin; Yang, Rui; Gao, Liangbin; Tang, Yong; Zhang, Xin; Ye, Jichao; Chen, Keng; Cai, Zhaopeng; Wu, Yanfeng; Shen, Huiyong

    2014-01-01

    The pathogenesis of dysfunctional immunoregulation of mesenchymal stem cells (MSCs) in ankylosing spondylitis (AS) is thought to be a complex process that involves multiple genetic alterations. In this study, MSCs derived from both healthy donors and AS patients were cultured in normal media or media mimicking an inflammatory environment. Whole genome expression profiling analysis of 33,351 genes was performed and differentially expressed genes related to AS were analyzed by GO term analysis and KEGG pathway analysis. Our results showed that in normal media 676 genes were differentially expressed in AS, 354 upregulated and 322 downregulated, while in an inflammatory environment 1767 genes were differentially expressed in AS, 1230 upregulated and 537 downregulated. GO analysis showed that these genes were mainly related to cellular processes, physiological processes, biological regulation, regulation of biological processes, and binding. In addition, by KEGG pathway analysis, 14 key genes from the MAPK signaling and 8 key genes from the TLR signaling pathway were identified as differentially regulated. The results of qRT-PCR verified the expression variation of the 9 genes mentioned above. Our study found that in an inflammatory environment ankylosing spondylitis pathogenesis may be related to activation of the MAPK and TLR signaling pathways.

  5. Whole Genome Expression Profiling and Signal Pathway Screening of MSCs in Ankylosing Spondylitis

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    Yuxi Li

    2014-01-01

    Full Text Available The pathogenesis of dysfunctional immunoregulation of mesenchymal stem cells (MSCs in ankylosing spondylitis (AS is thought to be a complex process that involves multiple genetic alterations. In this study, MSCs derived from both healthy donors and AS patients were cultured in normal media or media mimicking an inflammatory environment. Whole genome expression profiling analysis of 33,351 genes was performed and differentially expressed genes related to AS were analyzed by GO term analysis and KEGG pathway analysis. Our results showed that in normal media 676 genes were differentially expressed in AS, 354 upregulated and 322 downregulated, while in an inflammatory environment 1767 genes were differentially expressed in AS, 1230 upregulated and 537 downregulated. GO analysis showed that these genes were mainly related to cellular processes, physiological processes, biological regulation, regulation of biological processes, and binding. In addition, by KEGG pathway analysis, 14 key genes from the MAPK signaling and 8 key genes from the TLR signaling pathway were identified as differentially regulated. The results of qRT-PCR verified the expression variation of the 9 genes mentioned above. Our study found that in an inflammatory environment ankylosing spondylitis pathogenesis may be related to activation of the MAPK and TLR signaling pathways.

  6. Imipramine protects retinal ganglion cells from oxidative stress through the tyrosine kinase receptor B signaling pathway

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    Ming-lei Han

    2016-01-01

    Full Text Available Retinal ganglion cell (RGC degeneration is irreversible in glaucoma and tyrosine kinase receptor B (TrkB-associated signaling pathways have been implicated in the process. In this study, we attempted to examine whether imipramine, a tricyclic antidepressant, may protect hydrogen peroxide (H 2 O 2 -induced RGC degeneration through the activation of the TrkB pathway in RGC-5 cell lines. RGC-5 cell lines were pre-treated with imipramine 30 minutes before exposure to H 2 O 2 . Western blot assay showed that in H 2 O 2 -damaged RGC-5 cells, imipramine activated TrkB pathways through extracellular signal-regulated protein kinase/TrkB phosphorylation. TUNEL staining assay also demonstrated that imipramine ameliorated H 2 O 2 -induced apoptosis in RGC-5 cells. Finally, TrkB-IgG intervention was able to reverse the protective effect of imipramine on H 2 O 2 -induced RGC-5 apoptosis. Imipramine therefore protects RGCs from oxidative stress-induced apoptosis through the TrkB signaling pathway.

  7. TEC protein tyrosine kinase is involved in the Erk signaling pathway induced by HGF.

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    Li, Feifei; Jiang, Yinan; Zheng, Qiping; Yang, Xiaoming; Wang, Siying

    2011-01-07

    TEC, a member of the TEC family of non-receptor type protein tyrosine kinases, has recently been suggested to play a role in hepatocyte proliferation and liver regeneration. This study aims to investigate the putative mechanisms of TEC kinase regulation of hepatocyte differentiation, i.e. to explore which signaling pathway TEC is involved in, and how TEC is activated in hepatocyte after hepatectomy and hepatocyte growth factor (HGF) stimulation. We performed immunoprecipitation (IP) and immunoblotting (IB) to examine TEC tyrosine phosphorylation after partial hepatectomy in mice and HGF stimulation in WB F-344 hepatic cells. The TEC kinase activity was determined by in vitro kinase assay. Reporter gene assay, antisense oligonucleotide and TEC dominant negative mutant (TEC(KM)) were used to examine the possible signaling pathways in which TEC is involved. The cell proliferation rate was evaluated by (3)H-TdR incorporation. TEC phosphorylation and kinase activity were increased in 1 h after hepatectomy or HGF treatment. TEC enhanced the activity of Elk and serum response element (SRE). Inhibition of MEK1 suppressed TEC phosphorylation. Blocking TEC activity dramatically decreased the activation of Erk. Reduced TEC kinase activity also suppressed the proliferation of WB F-344 cells. These results suggest TEC is involved in the Ras-MAPK pathway and acts between MEK1 and Erk. TEC promotes hepatocyte proliferation and regeneration and is involved in HGF-induced Erk signaling pathway. Copyright © 2010 Elsevier Inc. All rights reserved.

  8. A systematic screen reveals MicroRNA clusters that significantly regulate four major signaling pathways.

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    Lindsey E Becker

    Full Text Available MicroRNAs (miRNAs are encoded in the genome as individual miRNA genes or as gene clusters transcribed as polycistronic units. About 50% of all miRNAs are estimated to be co-expressed with neighboring miRNAs. Recent studies have begun to illuminate the importance of the clustering of miRNAs from an evolutionary, as well as a functional standpoint. Many miRNA clusters coordinately regulate multiple members of cellular signaling pathways or protein interaction networks. This cooperative method of targeting could produce effects on an overall process that are much more dramatic than the smaller effects often associated with regulation by an individual miRNA. In this study, we screened 366 human miRNA minigenes to determine their effects on the major signaling pathways culminating in AP-1, NF-κB, c-Myc, or p53 transcriptional activity. By stratifying these data into miRNA clusters, this systematic screen provides experimental evidence for the combined effects of clustered miRNAs on these signaling pathways. We also verify p53 as a direct target of miR-200a. This study is the first to provide a panoramic view of miRNA clusters' effects on cellular pathways.

  9. The signaling pathways by which the Fas/FasL system accelerates oocyte aging.

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    Zhu, Jiang; Lin, Fei-Hu; Zhang, Jie; Lin, Juan; Li, Hong; Li, You-Wei; Tan, Xiu-Wen; Tan, Jing-He

    2016-02-01

    In spite of great efforts, the mechanisms for postovulatory oocyte aging are not fully understood. Although our previous work showed that the FasL/Fas signaling facilitated oocyte aging, the intra-oocyte signaling pathways are unknown. Furthermore, the mechanisms by which oxidative stress facilitates oocyte aging and the causal relationship between Ca2+ rises and caspase-3 activation and between the cell cycle and apoptosis during oocyte aging need detailed investigations. Our aim was to address these issues by studying the intra-oocyte signaling pathways for Fas/FasL to accelerate oocyte aging. The results indicated that sFasL released by cumulus cells activated Fas on the oocyte by increasing reactive oxygen species via activating NADPH oxidase. The activated Fas triggered Ca2+ release from the endoplasmic reticulum by activating phospholipase C-γ pathway and cytochrome c pathway. The cytoplasmic Ca2+ rises activated calcium/calmodulin-dependent protein kinase II (CaMKII) and caspase-3. While activated CaMKII increased oocyte susceptibility to activation by inactivating maturation-promoting factor (MPF) through cyclin B degradation, the activated caspase-3 facilitated further Ca2+releasing that activates more caspase-3 leading to oocyte fragmentation. Furthermore, caspase-3 activation and fragmentation were prevented in oocytes with a high MPF activity, suggesting that an oocyte must be in interphase to undergo apoptosis.

  10. Creating and analyzing pathway and protein interaction compendia for modelling signal transduction networks

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    Kirouac Daniel C

    2012-05-01

    Full Text Available Abstract Background Understanding the information-processing capabilities of signal transduction networks, how those networks are disrupted in disease, and rationally designing therapies to manipulate diseased states require systematic and accurate reconstruction of network topology. Data on networks central to human physiology, such as the inflammatory signalling networks analyzed here, are found in a multiplicity of on-line resources of pathway and interactome databases (Cancer CellMap, GeneGo, KEGG, NCI-Pathway Interactome Database (NCI-PID, PANTHER, Reactome, I2D, and STRING. We sought to determine whether these databases contain overlapping information and whether they can be used to construct high reliability prior knowledge networks for subsequent modeling of experimental data. Results We have assembled an ensemble network from multiple on-line sources representing a significant portion of all machine-readable and reconcilable human knowledge on proteins and protein interactions involved in inflammation. This ensemble network has many features expected of complex signalling networks assembled from high-throughput data: a power law distribution of both node degree and edge annotations, and topological features of a “bow tie” architecture in which diverse pathways converge on a highly conserved set of enzymatic cascades focused around PI3K/AKT, MAPK/ERK, JAK/STAT, NFκB, and apoptotic signaling. Individual pathways exhibit “fuzzy” modularity that is statistically significant but still involving a majority of “cross-talk” interactions. However, we find that the most widely used pathway databases are highly inconsistent with respect to the actual constituents and interactions in this network. Using a set of growth factor signalling networks as examples (epidermal growth factor, transforming growth factor-beta, tumor necrosis factor, and wingless, we find a multiplicity of network topologies in which receptors couple to downstream

  11. Regulation of PGE2 signaling pathways and TNF-alpha signaling pathways on the function of bone marrow-derived dendritic cells and the effects of CP-25.

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    Li, Ying; Sheng, Kangliang; Chen, Jingyu; Wu, Yujing; Zhang, Feng; Chang, Yan; Wu, Huaxun; Fu, Jingjing; Zhang, Lingling; Wei, Wei

    2015-12-15

    This study was to investigate PGE2 and TNF-alpha signaling pathway involving in the maturation and activation of bone marrow dendritic cells (DCs) and the effect of CP-25. Bone marrow DCs were isolated and stimulated by PGE2 and TNF-alpha respectively. The markers of maturation and activation expressed on DCs, such as CD40, CD80, CD83, CD86, MHC-II, and the ability of antigen uptake of DCs were analyzed by flow cytometry. The proliferation of T cells co-cultured with DCs, the signaling pathways of PGE2-EP4-cAMP and TNF-alpha-TRADD-TRAF2-NF-κB in DCs were analyzed. The results showed that both PGE2 and TNF-alpha up-regulated the expressions of CD40, CD80, CD83, CD86, and MHC-II, decreased the antigen uptake of DCs, and DCs stimulated by PGE2 or TNF-alpha could increase T cell proliferation. CP-25 (10(-5), 10(-6), and 10(-7)mol/l) decreased significantly the expressions of CD40, CD80, CD83, CD86 and MHC-II, increased the antigen uptake of DCs, and suppressed T cell proliferation induced by DCs. PGE2 increased the expressions of EP4, NF-κB and down-regulated cAMP level of DCs. TNF-alpha could also up-regulate TNFR1, TRADD, TRAF2, and NF-κB expression of DCs. CP-25 (10(-5), 10(-6), and 10(-7)mol/l) decreased the expressions of EP4 and NF-κB, increased cAMP level in DCs stimulated by PGE2. CP-25 (10(-5), 10(-6), and 10(-7)mol/l) also could down-regulate significantly TNFR1, TRADD, TRAF2, and NF-κB expression in DCs stimulated by TNF-alpha. These results demonstrate that PGE2 and TNF-alpha could enhance DCs functions by mediating PGE2-EP4-cAMP pathway, TNF-alpha-TNFR1-TRADD-TRAF2-NF-κB pathway respectively. CP-25 might inhibit the function of DCs through regulating PGE2-EP4-cAMP and TNF-alpha-TNFR1-TRADD-TRAF2-NF-κB pathways. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. Signal transduction pathway mediated by the novel regulator LoiA for low oxygen tension induced Salmonella Typhimurium invasion.

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    Jiang, Lingyan; Feng, Lu; Yang, Bin; Zhang, Wenwen; Wang, Peisheng; Jiang, Xiaohan; Wang, Lei

    2017-06-01

    Salmonella enterica serovar Typhimurium (S. Typhimurium) is a major intestinal pathogen of both humans and animals. Salmonella pathogenicity island 1 (SPI-1)-encoded virulence genes are required for S. Typhimurium invasion. While oxygen (O2) limitation is an important signal for SPI-1 induction under host conditions, how the signal is received and integrated to the central SPI-1 regulatory system in S. Typhimurium is not clear. Here, we report a signal transduction pathway that activates SPI-1 expression in response to low O2. A novel regulator encoded within SPI-14 (STM14_1008), named LoiA (low oxygen induced factor A), directly binds to the promoter and activates transcription of hilD, leading to the activation of hilA (the master activator of SPI-1). Deletion of loiA significantly decreased the transcription of hilA, hilD and other representative SPI-1 genes (sipB, spaO, invH, prgH and invF) under low O2 conditions. The response of LoiA to the low O2 signal is mediated by the ArcB/ArcA two-component system. Deletion of either arcA or arcB significantly decreased transcription of loiA under low O2 conditions. We also confirmed that SPI-14 contributes to S. Typhimurium virulence by affecting invasion, and that loiA is the virulence determinant of SPI-14. Mice infection assays showed that S. Typhimurium virulence was severely attenuated by deletion of either the entire SPI-14 region or the single loiA gene after oral infection, while the virulence was not affected by either deletion after intraperitoneal infection. The signal transduction pathway described represents an important mechanism for S. Typhimurium to sense and respond to low O2 conditions of the host intestinal tract for invasion. SPI-14-encoded loiA is an essential element of this pathway that integrates the low O2 signal into the SPI-1 regulatory system. Acquisition of SPI-14 is therefore crucial for the evolution of S. Typhimurium as an intestinal pathogen.

  13. Signal transduction pathway mediated by the novel regulator LoiA for low oxygen tension induced Salmonella Typhimurium invasion.

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    Lingyan Jiang

    2017-06-01

    Full Text Available Salmonella enterica serovar Typhimurium (S. Typhimurium is a major intestinal pathogen of both humans and animals. Salmonella pathogenicity island 1 (SPI-1-encoded virulence genes are required for S. Typhimurium invasion. While oxygen (O2 limitation is an important signal for SPI-1 induction under host conditions, how the signal is received and integrated to the central SPI-1 regulatory system in S. Typhimurium is not clear. Here, we report a signal transduction pathway that activates SPI-1 expression in response to low O2. A novel regulator encoded within SPI-14 (STM14_1008, named LoiA (low oxygen induced factor A, directly binds to the promoter and activates transcription of hilD, leading to the activation of hilA (the master activator of SPI-1. Deletion of loiA significantly decreased the transcription of hilA, hilD and other representative SPI-1 genes (sipB, spaO, invH, prgH and invF under low O2 conditions. The response of LoiA to the low O2 signal is mediated by the ArcB/ArcA two-component system. Deletion of either arcA or arcB significantly decreased transcription of loiA under low O2 conditions. We also confirmed that SPI-14 contributes to S. Typhimurium virulence by affecting invasion, and that loiA is the virulence determinant of SPI-14. Mice infection assays showed that S. Typhimurium virulence was severely attenuated by deletion of either the entire SPI-14 region or the single loiA gene after oral infection, while the virulence was not affected by either deletion after intraperitoneal infection. The signal transduction pathway described represents an important mechanism for S. Typhimurium to sense and respond to low O2 conditions of the host intestinal tract for invasion. SPI-14-encoded loiA is an essential element of this pathway that integrates the low O2 signal into the SPI-1 regulatory system. Acquisition of SPI-14 is therefore crucial for the evolution of S. Typhimurium as an intestinal pathogen.

  14. Differences in gene expression profiles and signaling pathways in rhabdomyolysis-induced acute kidney injury.

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    Geng, Xiaodong; Wang, Yuanda; Hong, Quan; Yang, Jurong; Zheng, Wei; Zhang, Gang; Cai, Guangyan; Chen, Xiangmei; Wu, Di

    2015-01-01

    Rhabdomyolysis is a threatening syndrome because it causes the breakdown of skeletal muscle. Muscle destruction leads to the release of myoglobin, intracellular proteins, and electrolytes into the circulation. The aim of this study was to investigate the differences in gene expression profiles and signaling pathways upon rhabdomyolysis-induced acute kidney injury (AKI). In this study, we used glycerol-induced renal injury as a model of rhabdomyolysis-induced AKI. We analyzed data and relevant information from the Gene Expression Omnibus database (No: GSE44925). The gene expression data for three untreated mice were compared to data for five mice with rhabdomyolysis-induced AKI. The expression profiling of the three untreated mice and the five rhabdomyolysis-induced AKI mice was performed using microarray analysis. We examined the levels of Cyp3a13, Rela, Aldh7a1, Jun, CD14. And Cdkn1a using RT-PCR to determine the accuracy of the microarray results. The microarray analysis showed that there were 1050 downregulated and 659 upregulated genes in the rhabdomyolysis-induced AKI mice compared to the control group. The interactions of all differentially expressed genes in the Signal-Net were analyzed. Cyp3a13 and Rela had the most interactions with other genes. The data showed that Rela and Aldh7a1 were the key nodes and had important positions in the Signal-Net. The genes Jun, CD14, and Cdkn1a were also significantly upregulated. The pathway analysis classified the differentially expressed genes into 71 downregulated and 48 upregulated pathways including the PI3K/Akt, MAPK, and NF-κB signaling pathways. The results of this study indicate that the NF-κB, MAPK, PI3K/Akt, and apoptotic pathways are regulated in rhabdomyolysis-induced AKI.

  15. Role of TWEAK/Fn14 signalling pathway in lupus nephritis and other clinical settings

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    Diego A. González-Sánchez

    2017-03-01

    Full Text Available Knowledge of the signalling pathways involved in various diseases has enabled advances in the understanding of pathophysiological, diagnostic and therapeutic models of several inflammatory and autoimmune diseases. Systemic lupus erythematosus is a widely studied autoimmune disease that can affect multiple organs, with a major impact on morbidity and mortality when it involves the kidneys. Over the past 10 years, interest in the role of the TWEAK/Fn14 signalling pathway in lupus nephritis, as well as other clinical settings, has increased. By reviewing the literature, this article assesses the role of this pathway in lupus nephritis, underlines the importance of TWEAK in urine (uTWEAK as a biomarker of the disease and stresses the favourable results published in the literature from the inhibition of the TWEAK/Fn14 pathway as a therapeutic target in experimental animal models, demonstrating its potential application in other settings. Results of ongoing clinical trials and future research will give us a better understanding of the real benefit of blocking this pathway in the clinical course of several conditions.

  16. Domain altering SNPs in the human proteome and their impact on signaling pathways.

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    Yichuan Liu

    Full Text Available Single nucleotide polymorphisms (SNPs constitute an important mode of genetic variations observed in the human genome. A small fraction of SNPs, about four thousand out of the ten million, has been associated with genetic disorders and complex diseases. The present study focuses on SNPs that fall on protein domains, 3D structures that facilitate connectivity of proteins in cell signaling and metabolic pathways. We scanned the human proteome using the PROSITE web tool and identified proteins with SNP containing domains. We showed that SNPs that fall on protein domains are highly statistically enriched among SNPs linked to hereditary disorders and complex diseases. Proteins whose domains are dramatically altered by the presence of an SNP are even more likely to be present among proteins linked to hereditary disorders. Proteins with domain-altering SNPs comprise highly connected nodes in cellular pathways such as the focal adhesion, the axon guidance pathway and the autoimmune disease pathways. Statistical enrichment of domain/motif signatures in interacting protein pairs indicates extensive loss of connectivity of cell signaling pathways due to domain-altering SNPs, potentially leading to hereditary disorders.

  17. Activation of stress signalling pathways enhances tolerance of fungi to chemical fungicides and antifungal proteins.

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    Hayes, Brigitte M E; Anderson, Marilyn A; Traven, Ana; van der Weerden, Nicole L; Bleackley, Mark R

    2014-07-01

    Fungal disease is an increasing problem in both agriculture and human health. Treatment of human fungal disease involves the use of chemical fungicides, which generally target the integrity of the fungal plasma membrane or cell wall. Chemical fungicides used for the treatment of plant disease, have more diverse mechanisms of action including inhibition of sterol biosynthesis, microtubule assembly and the mitochondrial respiratory chain. However, these treatments have limitations, including toxicity and the emergence of resistance. This has led to increased interest in the use of antimicrobial peptides for the treatment of fungal disease in both plants and humans. Antimicrobial peptides are a diverse group of molecules with differing mechanisms of action, many of which remain poorly understood. Furthermore, it is becoming increasingly apparent that stress response pathways are involved in the tolerance of fungi to both chemical fungicides and antimicrobial peptides. These signalling pathways such as the cell wall integrity and high-osmolarity glycerol pathway are triggered by stimuli, such as cell wall instability, changes in osmolarity and production of reactive oxygen species. Here we review stress signalling induced by treatment of fungi with chemical fungicides and antifungal peptides. Study of these pathways gives insight into how these molecules exert their antifungal effect and also into the mechanisms used by fungi to tolerate sub-lethal treatment by these molecules. Inactivation of stress response pathways represents a potential method of increasing the efficacy of antifungal molecules.

  18. Role of TWEAK/Fn14 signalling pathway in lupus nephritis and other clinical settings.

    Science.gov (United States)

    González-Sánchez, Diego A; Álvarez, Cristian M; Vásquez, Gloria; Gómez-Puerta, José A

    Knowledge of the signalling pathways involved in various diseases has enabled advances in the understanding of pathophysiological, diagnostic and therapeutic models of several inflammatory and autoimmune diseases. Systemic lupus erythematosus is a widely studied autoimmune disease that can affect multiple organs, with a major impact on morbidity and mortality when it involves the kidneys. Over the past 10 years, interest in the role of the TWEAK/Fn14 signalling pathway in lupus nephritis, as well as other clinical settings, has increased. By reviewing the literature, this article assesses the role of this pathway in lupus nephritis, underlines the importance of TWEAK in urine (uTWEAK) as a biomarker of the disease and stresses the favourable results published in the literature from the inhibition of the TWEAK/Fn14 pathway as a therapeutic t