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1
Pirkl, Martin, Elisabeth Hand, Dieter Kube, and Rainer Spang. "Analyzing synergistic and non-synergistic interactions in signalling pathways using Boolean Nested Effect Models." Bioinformatics 32, no. 6 (2015): 893–900. http://dx.doi.org/10.1093/bioinformatics/btv680.
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Abstract Motivation: Understanding the structure and interplay of cellular signalling pathways is one of the great challenges in molecular biology. Boolean Networks can infer signalling networks from observations of protein activation. In situations where it is difficult to assess protein activation directly, Nested Effect Models are an alternative. They derive the network structure indirectly from downstream effects of pathway perturbations. To date, Nested Effect Models cannot resolve signalling details like the formation of signalling complexes or the activation of proteins by multiple alternative input signals. Here we introduce Boolean Nested Effect Models (B-NEM). B-NEMs combine the use of downstream effects with the higher resolution of signalling pathway structures in Boolean Networks. Results: We show that B-NEMs accurately reconstruct signal flows in simulated data. Using B-NEM we then resolve BCR signalling via PI3K and TAK1 kinases in BL2 lymphoma cell lines. Availability and implementation: R code is available at https://github.com/MartinFXP/B-NEM (github). The BCR signalling dataset is available at the GEO database (http://www.ncbi.nlm.nih.gov/geo/) through accession number GSE68761. Contact: martin-franz-xaver.pirkl@ukr.de, Rainer.Spang@ukr.de Supplementary information: Supplementary data are available at Bioinformatics online.
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Guerrero-Alba, Raquel, Eduardo E. Valdez-Morales, Nestor N. Jimenez-Vargas, et al. "Stress activates pronociceptive endogenous opioid signalling in DRG neurons during chronic colitis." Gut 66, no. 12 (2016): 2121–31. http://dx.doi.org/10.1136/gutjnl-2016-311456.
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Aims and backgroundPsychological stress accompanies chronic inflammatory diseases such as IBD, and stress hormones can exacerbate pain signalling. In contrast, the endogenous opioid system has an important analgesic action during chronic inflammation. This study examined the interaction of these pathways.MethodsMouse nociceptive dorsal root ganglia (DRG) neurons were incubated with supernatants from segments of inflamed colon collected from patients with chronic UC and mice with dextran sodium sulfate (cDSS)-induced chronic colitis. Stress effects were studied by adding stress hormones (epinephrine and corticosterone) to dissociated neurons or by exposing cDSS mice to water avoidance stress. Changes in excitability of colonic DRG nociceptors were measured using patch clamp and Ca2+imaging techniques.ResultsSupernatants from patients with chronic UC and from colons of mice with chronic colitis caused a naloxone-sensitive inhibition of neuronal excitability and capsaicin-evoked Ca2+responses. Stress hormones decreased signalling induced by human and mouse supernatants. This effect resulted from stress hormones signalling directly to DRG neurons and indirectly through signalling to the immune system, leading to decreased opioid levels and increased acute inflammation. The net effect of stress was a change endogenous opioid signalling in DRG neurons from an inhibitory to an excitatory effect. This switch was associated with a change in G protein-coupled receptor excitatory signalling to a pathway sensitive to inhibitors of protein kinase A-protein, phospholipase C-protein and G protein βϒ subunits.ConclusionsStress hormones block the inhibitory actions of endogenous opioids and can change the effect of opioid signalling in DRG neurons to excitation. Targeting these pathways may prevent heavy opioid use in IBD.
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Wang, Yishu, Enhang Lu, Riqiang Bao, et al. "Notch signalling regulates steroidogenesis in mouse ovarian granulosa cells." Reproduction, Fertility and Development 31, no. 6 (2019): 1091. http://dx.doi.org/10.1071/rd18281.
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The Notch signalling pathway in the mammalian ovary regulates granulosa cell proliferation. However, the effects of Notch signalling on steroidogenesis are unclear. In this study we cultured mouse ovarian granulosa cells from preantral follicles invitro and observed the effect of Notch signalling on steroidogenesis through overexpression, knockdown and inhibition of Notch signalling. Activation of Notch signalling decreased progesterone and oestrogen secretion. In contrast, inhibition of Notch signalling increased the production of progesterone and oestrogen. Expression of the genes for steroidogenic-related enzymes, including 3β-hydroxysteroid dehydrogenase, p450 cholesterol side-chain cleavage enzyme and aromatase, was repressed after stimulation of Notch signalling. The expression of upstream transcription factors, including steroidogenic factor 1 (SF1), Wilms’ tumour 1 (Wt1), GATA-binding protein 4 (Gata4) and Gata6, was also inhibited after stimulation of Notch signalling. Production of interleukin (IL)-6 was positively correlated with Notch signalling and negatively correlated with the expression of these transcription factors and enzymes. In conclusion, Notch signalling regulated progesterone and oestrogen secretion by affecting the expression of upstream transcription factors SF1, Wt1, Gata4 and Gata6, as well as downstream steroidogenic-related enzymes. IL-6, which may be regulated directly by Notch signalling, may contribute to this process. Our findings add to the understanding of the diverse functions of Notch signalling in the mammalian ovary.
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Šrámek, Jan, Vlasta Němcová-Fürstová та Jan Kovář. "Molecular Mechanisms of Apoptosis Induction and Its Regulation by Fatty Acids in Pancreatic β-Cells". International Journal of Molecular Sciences 22, № 8 (2021): 4285. http://dx.doi.org/10.3390/ijms22084285.
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Pancreatic β-cell failure and death contribute significantly to the pathogenesis of type 2 diabetes. One of the main factors responsible for β-cell dysfunction and subsequent cell death is chronic exposure to increased concentrations of FAs (fatty acids). The effect of FAs seems to depend particularly on the degree of their saturation. Saturated FAs induce apoptosis in pancreatic β-cells, whereas unsaturated FAs are well tolerated and are even capable of inhibiting the pro-apoptotic effect of saturated FAs. Molecular mechanisms of apoptosis induction by saturated FAs in β-cells are not completely elucidated. Saturated FAs induce ER stress, which in turn leads to activation of all ER stress pathways. When ER stress is severe or prolonged, apoptosis is induced. The main mediator seems to be the CHOP transcription factor. Via regulation of expression/activity of pro- and anti-apoptotic Bcl-2 family members, and potentially also through the increase in ROS production, CHOP switches on the mitochondrial pathway of apoptosis induction. ER stress signalling also possibly leads to autophagy signalling, which may activate caspase-8. Saturated FAs activate or inhibit various signalling pathways, i.e., p38 MAPK signalling, ERK signalling, ceramide signalling, Akt signalling and PKCδ signalling. This may lead to the activation of the mitochondrial pathway of apoptosis, as well. Particularly, the inhibition of the pro-survival Akt signalling seems to play an important role. This inhibition may be mediated by multiple pathways (e.g., ER stress signalling, PKCδ and ceramide) and could also consequence in autophagy signalling. Experimental evidence indicates the involvement of certain miRNAs in mechanisms of FA-induced β-cell apoptosis, as well. In the rather rare situations when unsaturated FAs are also shown to be pro-apoptotic, the mechanisms mediating this effect in β-cells seem to be the same as for saturated FAs. To conclude, FA-induced apoptosis rather appears to be preceded by complex cross talks of multiple signalling pathways. Some of these pathways may be regulated by decreased membrane fluidity due to saturated FA incorporation. Few data are available concerning molecular mechanisms mediating the protective effect of unsaturated FAs on the effect of saturated FAs. It seems that the main possible mechanism represents a rather inhibitory intervention into saturated FA-induced pro-apoptotic signalling than activation of some pro-survival signalling pathway(s) or metabolic interference in β-cells. This inhibitory intervention may be due to an increase of membrane fluidity.
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Gleeson, Deborah J. "Context-dependent effect of social environment on immune response and sexual signalling in male zebra finches." Australian Journal of Zoology 54, no. 6 (2006): 375. http://dx.doi.org/10.1071/zo06001.
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Variation in avian immune response can be influenced by social environment. This is of particular interest in the context of immunomediated sexual behaviour because social environment may subsequently affect a bird’s relative investment in immunocompetence versus sexual signalling. I tested whether the effect of social environment on immune response and sexual signalling depends on socio-sexual status using male zebra finches (Taeniopygia guttata). To do this, I manipulated social environment (‘same sex’ versus ‘dual sex’) and socio-sexual status (‘high’ versus ‘low’) of the males. I then determined what effect these manipulations had on an index of immunocompetence, namely cell-mediated immune response, and two indices of sexual signalling (bill colour and song rate). I found that social environment influenced cell-mediated immune response and sexual signalling in low-status males. These males had lower immune responses and increased sexual signalling in the dual-sex environment compared with the same-sex environment. In contrast, high-status males had similar immune responses and sexual signalling regardless of social environment. These results suggest that social environment can influence immune response and sexual signalling; however, the nature of this effect was context-dependent, with low-status males more affected than high-status males.
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Benzler, Jonas, Goutham K. Ganjam, Manon Krüger та ін. "Hypothalamic glycogen synthase kinase 3β has a central role in the regulation of food intake and glucose metabolism". Biochemical Journal 447, № 1 (2012): 175–84. http://dx.doi.org/10.1042/bj20120834.
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GSK3β (glycogen synthase kinase 3β) is a ubiquitous kinase that plays a key role in multiple intracellular signalling pathways, and increased GSK3β activity is implicated in disorders ranging from cancer to Alzheimer's disease. In the present study, we provide the first evidence of increased hypothalamic signalling via GSK3β in leptin-deficient Lepob/ob mice and show that intracerebroventricular injection of a GSK3β inhibitor acutely improves glucose tolerance in these mice. The beneficial effect of the GSK3β inhibitor was dependent on hypothalamic signalling via PI3K (phosphoinositide 3-kinase), a key intracellular mediator of both leptin and insulin action. Conversely, neuron-specific overexpression of GSK3β in the mediobasal hypothalamus exacerbated the hyperphagia, obesity and impairment of glucose tolerance induced by a high-fat diet, while having little effect in controls fed standard chow. These results demonstrate that increased hypothalamic GSK3β signalling contributes to deleterious effects of leptin deficiency and exacerbates high-fat diet-induced weight gain and glucose intolerance.
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Strembitska, Anastasiya, Sarah Mancini, Jonathan Gamwell, Timothy Palmer, George Baillie, and Ian Salt. "A769662 Inhibits Insulin-Stimulated Akt Activation in Human Macrovascular Endothelial Cells Independent of AMP-Activated Protein Kinase." International Journal of Molecular Sciences 19, no. 12 (2018): 3886. http://dx.doi.org/10.3390/ijms19123886.
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Protein kinase B (Akt) is a key enzyme in the insulin signalling cascade, required for insulin-stimulated NO production in endothelial cells (ECs). Previous studies have suggested that AMP-activated protein kinase (AMPK) activation stimulates NO synthesis and enhances insulin-stimulated Akt activation, yet these studies have largely used indirect activators of AMPK. The effects of the allosteric AMPK activator A769662 on insulin signalling and endothelial function was therefore examined in cultured human macrovascular ECs. Surprisingly, A769662 inhibited insulin-stimulated NO synthesis and Akt phosphorylation in human ECs from umbilical veins (HUVECs) and aorta (HAECs). In contrast, the AMPK activators compound 991 and AICAR had no substantial inhibitory effect on insulin-stimulated Akt phosphorylation in ECs. Inhibition of AMPK with SBI-0206965 had no effect on the inhibition of insulin-stimulated Akt phosphorylation by A769662, suggesting the inhibitory action of A769662 is AMPK-independent. A769662 decreased IGF1-stimulated Akt phosphorylation yet had no effect on VEGF-stimulated Akt signalling in HUVECs, suggesting that A769662 attenuates early insulin/IGF1 signalling. The effects of A769662 on insulin-stimulated Akt phosphorylation were specific to human ECs, as no effect was observed in the human cancer cell lines HepG2 or HeLa, as well as in mouse embryonic fibroblasts (MEFs). A769662 inhibited insulin-stimulated Erk1/2 phosphorylation in HAECs and MEFs, an effect that was independent of AMPK in MEFs. Therefore, despite being a potent AMPK activator, A769662 has effects unlikely to be mediated by AMPK in human macrovascular ECs that reduce insulin sensitivity and eNOS activation.
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BHATTACHARYYA, Asima, Shresh PATHAK, Simanti DATTA, Santanu CHATTOPADHYAY, Joyoti BASU та Manikuntala KUNDU. "Mitogen-activated protein kinases and nuclear factor-κB regulate Helicobacter pylori-mediated interleukin-8 release from macrophages". Biochemical Journal 368, № 1 (2002): 121–29. http://dx.doi.org/10.1042/bj20020555.
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Gastric infection, as well as inflammation, caused by Helicobacter pylori, activates the production of cytokines and chemokines by mononuclear cells; interleukin-8 (IL-8) is one of the major inflammatory chemokines. Since H. pylori does not invade mucosal tissue, we observed the effect of the water extract of H. pylori (HPE), containing shed factors, on the production of IL-8 by human peripheral blood monocytes and the human monocyte cell line THP-1. HPE-treatment induced activation of the mitogen-activated protein kinases (MAPKs) ERK (extracellular signal-regulated kinase), p38 and JNK (c-Jun N-terminal kinase), an effect which was not dependent on the presence of the cag pathogenicity island. p38 MAPK activation was sustained. The specific inhibitors, U0126 (for ERK1/2 signalling) and SB203580 (for p38 MAPK signalling), both abrogated IL-8 secretion from HPE-treated THP-1. Dominant-negative mutants of the upstream kinases MEK1 (MAPK/ERK kinase 1), MKK (MAPK kinase) 6 and MKK7 also inhibited IL-8 secretion, pointing to a role of all three MAPKs in HPE-mediated IL-8 release. The inhibitory effects of polymyxin B and anti-CD14 antibody suggested that the effect of HPE on MAPKs was mediated by H. pylori lipopolysaccharide (LPS). By analysis of IL-8-promoter-driven luciferase gene expression, we observed that the effects of HPE-induced nuclear factor-κB (NF-κB) activation and MAPK signalling were mediated at the level of the IL-8 promoter. While ERK1/2 activation could be linked to enhanced DNA binding of activator protein-1 (AP-1), p38 MAPK signalling did not affect AP-1 DNA binding. Taken together, these results provide the first evidence that LPS from H. pylori stimulates IL-8 release from cells of the monocytic lineage through activation of NF-κB and signalling along MAPK cascades. The stimulation of MAPK signalling in macrophages by LPS of H. pylori amplifies the inflammatory response associated with gastric H. pylori infection and needs to be taken into consideration when developing therapeutics based on these signalling pathways.
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Elbialy, Abdalla. "The role of antioxidants in restoring MAPK 14 and a DNA damage marker level following autophagy suppression." Open Biology 10, no. 12 (2020): 200253. http://dx.doi.org/10.1098/rsob.200253.
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Autophagy is a lysosomal degradation mechanism for elimination and recycling of damaged intracellular organelles and proteins. Recent studies have shown that autophagy could help reduce oxidative stress by removing oxidized proteins and damaged mitochondria. Autophagy deficiency is associated with the disruption of many intracellular biological processes. Using bioinformatics tools and fibroblast immunostaining technology, I tried to investigate whether oxidative stress is involved in mediating the effect of autophagy suppression on certain cell biological processes and signalling pathways. Many pharmaceutical components have different modes of action to suppress autophagy. In this study, I performed analysis on autophagy suppression induced by neutralizing lysosomal pH (NH 4 Cl and bafilomycin A1). Bioinformatics analysis of GEO data, GSE60570 accession number, revealed that p38 signalling induction and DNA damage response are among the main disrupted signalling pathways in bafilomycin A1-treated RPE-1 cells. Likewise, fibroblast immunostaining showed that autophagy deficiency established by ammonium chloride (NH 4 Cl) has significantly increased P38 signalling, DNA damage marker (H2A.X), and oxidative stress marker (dityrosine). I therefore investigated the role of oxidative stress and whether antioxidants treatment could reverse autophagy suppression effects on p38 signalling and DNA damage response. Importantly, antioxidant treatment clearly restored P38 signalling and H2A.X levels in autophagy-suppressed fibroblast cells. Indicating that oxidative stress might be associated with the harmful effect of autophagy suppression.
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Zhang, Jiandi. "Resveratrol inhibits insulin responses in a SirT1-independent pathway." Biochemical Journal 397, no. 3 (2006): 519–27. http://dx.doi.org/10.1042/bj20050977.
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Resveratrol mimics calorie restriction to extend lifespan of Caenorhabditis elegans, yeast and Drosophila, possibly through activation of Sir2 (silent information regulator 2), a NAD+-dependent histone deacetylase. In the present study, resveratrol is shown to inhibit the insulin signalling pathway in several cell lines and rat primary hepatocytes in addition to its broad-spectrum inhibition of several signalling pathways. Resveratrol effectively inhibits insulin-induced Akt and MAPK (mitogen-activated protein kinase) activation mainly through disruption of the interactions between insulin receptor substrates and its downstream binding proteins including p85 regulatory subunit of phosphoinositide 3-kinase and Grb2 (growth factor receptor-bound protein 2). The inhibitory effect of resveratrol on insulin signalling is also demonstrated at mRNA level, where resveratrol reverses insulin effects on phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, fatty acid synthase and glucokinase. In addition, RNA interference experiment shows that the inhibitory effect of resveratrol on insulin signalling pathway is not weakened in cells with reduced expression of SirT1, the mammalian counterpart of Sir2. These observations raise the possibility that resveratrol may additionally modulate lifespan through inhibition of insulin signalling pathway, independently of its activation of SirT1 histone deacetylase. Furthermore, the present study may help to explain a wide range of biological effects of resveratrol, and provides further insight into the molecular basis of calorie restriction.
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Birch, Michala Rosa, Steen Dissing, Niels E. Skakkebæk, and Anders Rehfeld. "Finasteride interferes with prostaglandin-induced CatSper signalling in human sperm." Reproduction 161, no. 5 (2021): 561–72. http://dx.doi.org/10.1530/rep-20-0287.
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Ca2+ signalling controls human sperm functions necessary for successful fertilization. Multiple endocrine-disrupting chemicals have been found to activate the CatSper Ca2+ channel and thereby interfering with Ca2+ signalling in human sperm. Finasteride is prescribed to men in the fertile age to treat hair loss and its use has been associated with impaired male fertility. Due to the structural relatedness of finasteride to the endogenous CatSper ligand progesterone, this study aimed to investigate whether finasteride affects human sperm in a progestogen-like manner. The effect of finasteride on Ca2+ signalling via CatSper in human sperm was investigated in cell suspensions by single-cell imaging. Additionally, effects on sperm penetration into viscous medium and acrosome reaction were assessed. Finasteride alone caused a minor transient rise in the intracellular, free Ca2+ concentration ([Ca2+]i) at physiologically relevant concentrations. Ca2+ signals induced by PGE1 were inhibited by finasteride displaying mixed type of inhibition consistent with multiple binding sites. Finasteride did not interfere with progesterone-induced Ca2+ signalling and no effect on acrosome reaction or sperm viability was found. Finasteride significantly decreased PGE1-induced penetration into viscous medium but in concentrations above what is measured in blood and seminal fluids during regular finasteride administration. In conclusion, the use of finasteride may affect Ca2+ signalling in human sperm through an interaction with the PGE1-binding site, but to which extend it alters the chances of a successful fertilization needs further investigation. It remains to be investigated whether finasteride administration may give rise to side effects by interfering with prostaglandin signalling elsewhere in the human body.
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Gutierrez-Castillo, Emilio, Hao Ming, Brittany Foster, et al. "Effect of vitrification on global gene expression dynamics of bovine elongating embryos." Reproduction, Fertility and Development 33, no. 5 (2021): 338. http://dx.doi.org/10.1071/rd20285.
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Embryo vitrification involves exposure to high concentrations of cryoprotectants and osmotic stress during cooling and warming in the cryopreservation process. Many of these factors can potentially affect gene expression. In this study, invitro-produced bovine embryos at the blastocyst stage were subjected to vitrification. Four recipients each were used for transferring non-vitrified (n=80) and vitrified (n=80) embryos. A total of 12 non-vitrified and 9 vitrified viable day-14 (D14) embryos were recovered by uterine flushing. RNA-seq analysis of the whole embryo or isolated trophectoderm (TE) from vitrified and fresh recovered D14 embryos revealed a total of 927 and 4376 genes with changed expression in embryos and TE isolates, respectively, as a result of vitrification. In addition, we found 671 and 61 genes commonly up- or downregulated in both vitrified whole embryos and TE. Commonly upregulated pathways by vitrification included epithelial adherens junctions, sirtuin signalling, germ cell–sertoli cell junction, ATM signalling, NER and protein ubiquitination pathways. The commonly downregulated pathways included EIF2 signalling, oxidative phosphorylation, mitochondrial dysfunction, regulation of eIF4 and p70S6K signalling and mTOR signalling pathways. Our analysis identified specific pathways and implicated specific gene expression patterns affecting embryo developmental competence that are important to cryopreservation.
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Li, Chunyu, Yongfu He, Ling Peng, and Denghua Yuan. "How manufacturer brand erosion shapes consumer assortment perceptions." Asia Pacific Journal of Marketing and Logistics 32, no. 4 (2019): 922–39. http://dx.doi.org/10.1108/apjml-04-2019-0235.
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Purpose Recently, the popularity of store brands has resulted in some manufacturer brands being removed from shelves. The current literature lacks empirical work on the effect of manufacturer brand erosion on consumer assortment perception and repatronage intention. Based on signalling theory, the purpose of this paper is to manufacturer brands play a signalling role and contend that manufacturer brand erosion has detrimental effects on the assortment perception due to reduced signalling efficacy. Design/methodology/approach A 3 (low manufacturer brand erosion vs high manufacturer brand erosion vs manufacturer brand dominance) ×2 (assortment size: small vs large) between-subject experiment was conducted. Findings Manufacturer brand erosion exerts a negative effect on assortment attractiveness and consumers’ repatronage intention; the greater the erosion, the larger the negative effect. These negative effects are mediated by reduced consumer perceptions of assortment quality and variety. A large (vs small) assortment size attenuates the negative effect of manufacturer brand erosion by improving perceived assortment quality. Practical implications To engage in strategic positioning through efficient assortment management, retailers should cooperate with brand manufacturers, instead of promoting their own private labels. Nevertheless, a large assortment dominated by store brands signals that the retailer has built a strong private brand, which in turn gains a differentiation advantage. Originality/value This paper is among the first to take the signalling perspective and explicitly investigate whether and how manufacturer brand erosion exerts a significant impact on assortment perception.
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Wang, Mingyang, Weiwei Wu, Lin Li, et al. "Analysis of the miRNA Expression Profiles in the Zearalenone-Exposed TM3 Leydig Cell Line." International Journal of Molecular Sciences 20, no. 3 (2019): 635. http://dx.doi.org/10.3390/ijms20030635.
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Zearalenone (ZEN), an important environmental pollutant, can cause serious harm to human and animal health. The aim of our study was to examine the effect of zearalenone (ZEN) on miRNA expression profiles in the mouse Leydig cell line (TM3 Leydig cell line) by miRNA sequencing. The effect of ZEN on the viability of TM3 Leydig cells was verified by Cell Counting Kit-8 (CCK-8). MiRNA sequencing was performed 24 h after the exposure of TM3 Leydig cells with 50 μmol/L of ZEN. Bioinformatics predicted the miRNA target genes, performed Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, and conducted miRNA-gene-pathway mapping to show the relationship between miRNA, the target gene, and the signalling pathway. The expression levels of miRNA and the miRNA target genes associated with ZEN toxicology were verified by quantitative real-time polymerase chain reaction. The miRNA sequencing revealed a significant change (p < 0.05) in the 197 miRNAs in the ZEN-treated and control groups, among which 86 were up-regulated and 111 were down-regulated. GO analysis of the target genes of these miRNAs indicated various biological functions. KEGG analysis showed that the predicted miRNA target genes were involved in signalling pathways, such as cancer, apoptosis, and oxidation, namely, the Ras signalling pathway, Rap1 signalling pathway, PI3K-AKT signalling pathway, Foxo signalling pathway, and AMPK signalling pathway. These results suggest that ZEN, as an estrogen-like toxin, is regulated by microRNAs. Our results can help to examine the toxicological effects of ZEN-regulated miRNAs on germ cells.
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Koelink, Pim J., Felicia M. Bloemendaal, Bofeng Li, et al. "Anti-TNF therapy in IBD exerts its therapeutic effect through macrophage IL-10 signalling." Gut 69, no. 6 (2019): 1053–63. http://dx.doi.org/10.1136/gutjnl-2019-318264.
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ObjectiveMacrophage interleukin (IL)-10 signalling plays a critical role in the maintenance of a regulatory phenotype that prevents the development of IBD. We have previously found that anti-tumour necrosis factor (TNF) monoclonal antibodies act through Fcγ-receptor (FcγR) signalling to promote repolarisation of proinflammatory intestinal macrophages to a CD206+ regulatory phenotype. The role of IL-10 in anti-TNF-induced macrophage repolarisation has not been examined.DesignWe used human peripheral blood monocytes and mouse bone marrow-derived macrophages to study IL-10 production and CD206+ regulatory macrophage differentiation. To determine whether the efficacy of anti-TNF was dependent on IL-10 signalling in vivo and in which cell type, we used the CD4+CD45Rbhigh T-cell transfer model in combination with several genetic mouse models.ResultsAnti-TNF therapy increased macrophage IL-10 production in an FcγR-dependent manner, which caused differentiation of macrophages to a more regulatory CD206+ phenotype in vitro. Pharmacological blockade of IL-10 signalling prevented the induction of these CD206+ regulatory macrophages and diminished the therapeutic efficacy of anti-TNF therapy in the CD4+CD45Rbhigh T-cell transfer model of IBD. Using cell type-specific IL-10 receptor mutant mice, we found that IL-10 signalling in macrophages but not T cells was critical for the induction of CD206+ regulatory macrophages and therapeutic response to anti-TNF.ConclusionThe therapeutic efficacy of anti-TNF in resolving intestinal inflammation is critically dependent on IL-10 signalling in macrophages.
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Pacherník, Jiří, V. Horváth, L. Kubala, P. Dvořák, A. Kozubík, and A. Hampl. "Neural Differentiation Potentiated by the Leukaemia Inhibitory Factor through STAT3 Signalling in Mouse Embryonal Carcinoma Cells." Folia Biologica 53, no. 5 (2007): 157–63. https://doi.org/10.14712/fb2007053050157.
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LIF is a cytokine playing a key role in the regulation of self-renewal and maintenance of undifferentiated state in mouse ES cells. The response of pluripotent cells to LIF is mediated mainly by the STAT3 and ERK signalling pathways. Recently, we have shown that LIF potentiated retinoic acid-induced neural differentiation of pluripotent mouse embryonal carcinoma P19 cells. Here we demonstrate that pro-neural effects of LIF and partially also of retinoic acid are abolished by inhibition of the JAK2->STAT3 signalling pathway. In contrast, inhibition of the MEK1->ERK signalling pathway does not exhibit any effect. These results suggest that in neurogenic regions, cooperative action of LIF and other neuro-differentiation-inducing factors, such as retinoic acid, may be mediated by the STAT3 signalling pathway.
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Lapeikaite, Indre, Vilmantas Pupkis, Vladas Neniskis, Osvaldas Ruksenas, and Vilma Kisnieriene. "Glutamate and NMDA affect cell excitability and action potential dynamics of single cell of macrophyte Nitellopsis obtusa." Functional Plant Biology 47, no. 12 (2020): 1032. http://dx.doi.org/10.1071/fp20074.
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The effect of glutamate and N-methyl-d-aspartate (NMDA) on electrical signalling – action potentials (AP) and excitation current transients – was studied in intact macrophyte Nitellopsis obtusa (Characeaen) internodal cell. Intracellular glass electrode recordings of single cell in current clamp and two-electrode voltage clamp modes indicate that glutamate (Glu, 0.1–1.0 mM) and NMDA (0.01–1.0 mM) increase electrically induced AP amplitude by hyperpolarising excitation threshold potential (Eth) and prolong AP fast repolarisation phase. Amplitude of Cl– current transient, as well as its activation and inactivation durations were also increased. Both Glu and NMDA act in a dose-dependent manner. The effect of NMDA exceeds that of Glu. Ionotropic glutamate receptor inhibitors AP-5 (NMDA-type receptors) and DNQX (AMPA/Kainate-type) have no effect on Nitellopsis cell electrical signalling per se, yet robustly inhibit excitatory effect of NMDA. This study reinforces NMDA as an active component in glutamatergic signalling at least in some plants and stresses the elaborate fine-tuning of electrical signalling.
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Ai Chin, Wong, Wan Ahmad Jaafar Wan Yahaya, and Balakrishnan Muniandy. "Virtual Science Laboratory (Vislab): The Effect of Visual Signalling Principles towards Students’ Perceived Motivation." International Journal of Engineering & Technology 7, no. 3.30 (2018): 289. http://dx.doi.org/10.14419/ijet.v7i3.30.18262.
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The purpose of this study is to investigate the effect of Virtual Science Laboratory (ViSLab) on visual signalling principles towards students’ perceived motivation. Motivation can be identified as a dimension that determines learning success and causes the high failure rate among online learners, especially in VR environments. Cognitive load researchers need to determine the motivational effects of instructional conditions, and identify strategies that maintain students’ awareness of the learning materials without their being distracted by the world outside, as well as help out instructional designers to distinguish the power of VR learning environments in enhancing the motivation of learners. The lesson of the science laboratory safety is developed in two different modes, Virtual Reality with Signalling (VRS) and Virtual Reality Non Signalling (VRNS). 2x2 quasi experimental factorial design is adopted in this research. The independent variables were the two modes of presentation. The moderator variable is the spatial ability. The dependant variable is the perceived motivation. The study sample consisted of 141 students. The Instructional Material Motivational Scale (IMMS) from Keller was used to determine students’ perceived motivation. ANOVA was carried out to determine if a significant difference occurred between the two groups in their motivation towards instructional materials. The findings of this study showed that the use of Virtual Reality with Signalling (VRS) treatment mode helped pupils perform significantly better than Virtual Reality Non Signalling (VRNS) in learning science laboratory safety. Overall, visual signalling principle needs to be considered in the design and development of Virtual Science Laboratory (ViSLab) to promote more effective learning.
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Plomp, Florence. "Een Empirisch Onderzoek Naar Het Effect Van Lexicale Structuurmarkeringen op Tekstbegrip in de Eerste en in de Tweede Taal." Toegepaste Taalwetenschap in Artikelen 56 (January 1, 1997): 47–62. http://dx.doi.org/10.1075/ttwia.56.05plo.
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In reading research, it has regularly been claimed that the signalling of coherence relations by means of connectives (However, because) or signalling phrases (The solution to this problem is...) facilitates the processing of expository texts and increases recall from texts. In this paper a reading experiment is presented that aimed at the role of signalling in both L1 (first language) and L2 (second language) reading. Twenty-three Dutch university students who had specialised in Italian language and literature participated in the experiment. Two variables were manipulated: signalling (implicit vs. explicit) and the language in which the text was written (Dutch vs. Italian). Subjects read two expository texts, either in L1 or in L2, verified statements, and were given both an immediate and a delayed free-recall task. The results showed a positive tendency towards a signalling effect in both the L1 and the L2 conditions.
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Martínez-Padilla, Jesús, François Mougeot, Lorenzo Pérez-Rodríguez, and Gary R. Bortolotti. "Nematode parasites reduce carotenoid-based signalling in male red grouse." Biology Letters 3, no. 2 (2007): 161–64. http://dx.doi.org/10.1098/rsbl.2006.0593.
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Carotenoids determine the yellow–red colours of many ornaments, which often function as signals of quality. Carotenoid-based signalling may reliably advertise health and should be particularly sensitive to parasite infections. Nematodes are among the commonest parasites of vertebrates, with well-documented negative effects on their hosts. However, to date, little is known about the effects that these parasites may have on carotenoid-based signalling. Tetraonid birds (grouse) exhibit supra-orbital combs, which are bright integumentary ornaments pigmented by carotenoids. We tested the effect of the nematode parasite Trichostrongylus tenuis on signalling in free-living male red grouse Lagopus lagopus scoticus . We show that experimentally reduced nematode infection increases plasma carotenoid concentration and comb redness, demonstrating for the first time that nematodes can influence carotenoid-based signals.
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Conzelmann, Michael, Elena Rodionova, Michael Hess, et al. "Complementary JAK/STAT Signalling Is Required for the Pro-Inflammatory Effects of CD40 Ligation: Differential Effects in Human Myeloid and B Cells." Blood 110, no. 11 (2007): 2413. http://dx.doi.org/10.1182/blood.v110.11.2413.2413.
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Abstract CD40L represents a strong endogenous danger signal that induces pro-inflammatory activation of CD40-expressing cells such as dendritic cells (DC), monocytes, and B cells. However, since CD40 activation alone is insufficient to induce pro-inflammatory cytokines such as IL-12p70, we studied whether CD40-mediated pro-inflammatory activity might be dependent on co-signalling pathways involving JAK/STAT. Using quantitative Western blotting, we demonstrate that JAK/STAT signalling is induced by cytokines such as IL-4, GM-CSF and IFNg, whereas CD40 activation mediates NFkB signalling. CD40L-induced IL-12p70 and IL-10 secretion in human DC, monocytes, B cells, and chronic lymphocytic leukemia (CLL) cells was measured upon complementary JAK/STAT activation by IL-4, GM-CSF and IFNg in the presence and absence of specific inhibitors of JAK2, JAK3, and pan-JAK. Whereas IL-12p70 could not be induced by CD40 ligation or by cytokines alone, IL-12p70 secretion and suppression of IL-10 was reproducibly observed after co-stimulation of CD40L with IL-4, GM-CSF, or IFNg. This effect could be completely reversed by pan-JAK inhibition. Persistence of IL-4/GM-CSF/IFNg-mediated JAK/STAT signalling as late as 12 hours following cellular activation via CD40 was required for IL-12p70 secretion as shown by the effects of delayed JAK inhibition. Similarly, persistence between 12 and 24 hours of IL-12p35 and p40 mRNA expression correlated best with the level of IL-12p70 secretion. Specific inhibition of JAK2 and JAK3 further revealed a context-dependent action of the distinct JAK family members: JAK2 showed a strong co-dominant effect in the setting of IL-4-induced JAK/STAT activity. Both, JAK2 and JAK3 were required for IL-12p70 secretion, whereas JAK2 alone was sufficient to modulate IL-10 secretion. However, in the context of IFNg-induced JAK/STAT signalling in DC, neither JAK2 nor JAK3 inhibition had effects on IL-12p70. Here, only inhibition by the pan-JAK inhibitor involving JAK1 abrogated IL-12p70 secretion, indicating that in IFNg-dependent signalling, JAK2 is apparently sub-dominant to JAK1 and had only a small enhancing effect on IL-10. This context dependence markedly differed in myeloid cells and B cells, as normal and malignant (CLL) B cells maintain a co-dominant JAK2 activity in the context of IFNg-induced JAK/STAT-signalling. In conclusion, complementary JAK/STAT signalling is required for the pro-inflammatory effects of CD40 ligation in humans, with different JAK subset predominance in myeloid and B cells. These results may open new ways of lineage-specific interfering with CD40 signals by modulating JAK/STAT activity using tyrosine kinase inhibitors.
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Tihanov, Galin. "STUDY ON THE EFFECT OF THE TYPE OF FULL HOPPER SIGNALLING USED IN GRAIN HARVESTERS ON THE TIME FOR THE GRAIN HOPPER UNLOADING." Applied Researches in Technics, Technologies and Education 6, no. 4 (2018): 294–99. http://dx.doi.org/10.15547/artte.2018.04.002.
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The paper has established the length of the time for unloading hoppers in harvesters using a different signaling mode for full hopper: without automatic signalling - 245.35 s; with one level of automatic signalling - 224.5 s; with two levels of automatic signalling - 208.82 s and for harvesters unloading in the vehicle located at the end of the field - 301.46 s. Dispersion analysis has been carried out proving the effect of the type of signalling for full hopper used on the total time for unloading the hopper at a significance level of a = 0.05. Through it the interaction between the factor: type of signalling used on the time for unloading the hopper tp has also been established.
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Pejchal, Jaroslav, Jan Österreicher, Jiří Kassa, et al. "Soman and VX: different effect on cellular signalling." Journal of Applied Biomedicine 10, no. 1 (2012): 51–61. http://dx.doi.org/10.2478/v10136-011-0018-z.
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Bird, Graham. "The credibility and signalling effect of IMF programmes." Journal of Policy Modeling 24, no. 9 (2002): 799–811. http://dx.doi.org/10.1016/s0161-8938(02)00168-0.
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Pereira, Vitor Silva, Angélica C. D. Romano Suavinha, Gregers Wegener, and Sâmia R. L. Joca. "Prelimbic neuronal nitric oxide synthase inhibition exerts antidepressant-like effects independently of BDNF signalling cascades." Acta Neuropsychiatrica 31, no. 03 (2019): 143–50. http://dx.doi.org/10.1017/neu.2018.39.
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AbstractObjectivesNMDA antagonists and nitric oxide synthase (NOS) inhibitors induce antidepressant-like effects and may represent treatment options for depression. The behavioural effects of NMDA antagonists seem to depend on Tyrosine kinase B receptor (TrkB) activation by BDNF and on mechanistic target of rapamycin (mTOR), in the medial prefrontal cortex (mPFC). However, it is unknown whether similar mechanisms are involved in the behavioural effects of NOS inhibitors. Therefore, this work aimed at determining the role of TrkB and mTOR signalling in the prelimbic area of the ventral mPFC (vmPFC-PL) in the antidepressant-like effect of NOS inhibitors.MethodsPharmacological treatment with LY235959 or ketamine (NMDA antagonists), NPA or 7-NI (NOS inhibitors), BDNF, K252a (Trk antagonist) and rapamycin (mTOR inhibitor) injected systemically or into vmPFC-PL followed by behavioural assessment.ResultsWe found that bilateral injection of BDNF into the vmPFC-PL induced an antidepressant-like effect, which was blocked by pretreatment with K252a and rapamycin. Microinjection of LY 235959 into the vmPFC-PL induced antidepressant-like effect that was suppressed by local rapamycin but not by K252a pretreatment. Microinjection of NPA induced an antidepressant-like effect insensitive to both K252a and rapamycin. Similarly, the antidepressant-like effects of a systemic injection of ketamine or 7-NI were not affected by blockade of mTOR or Trk receptors in the vmPFC-PL.ConclusionOur data support the hypothesis that NMDA blockade induces an antidepressant-like effect that requires mTOR but not Trk signalling into the vmPFC-PL. The antidepressant-like effect induced by local NOS inhibition is independent on both Trk and mTOR signalling in the vmPFC-PL.
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Chen, Yunlong, and Mianhua Wu. "Demethoxycurcumin inhibits the growth of human lung cancer cells by targeting of PI3K/AKT/m-TOR signalling pathway, induction of apoptosis and inhibition of cell migration and invasion." Tropical Journal of Pharmaceutical Research 20, no. 4 (2022): 687–93. http://dx.doi.org/10.4314/tjpr.v20i4.4.
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 Purpose: To determine the antitumor effect of demethoxycurcumin on lung cancer cells, as well as its effect on PI3K/AKT/m-TOR signalling, cellular apoptosis, cell migration and cell invasion.
 Methods: Cell viability was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, while AO/EB and annexin V/PI staining assays were used for apoptosis analysis in demethoxycurcumin-treated A-549 lung cancer cells. Transwell chamber assay was used to determine the effect of demethoxycurcumin on migration and invasion of A-549 cells. The expression levels of PI3K/AKT/m-TOR signalling and apoptosis-associated proteins in A-549 cells post- demethoxycurcumin treatment were determined by Western blotting assay.
 Results: Demethoxycurcumin markedly inhibited the proliferation of A-549 cells in a dose- and time- reliant fashion. The antiproliferative effect of demethoxycurcumin occurred via stimulation of apoptosis. The expression levels of Bax, Caspase-3 and Caspase-9 increased significantly, while Bcl-2 was significantly decreased in A-549 cells post-demethoxycurcumin treatment. Demethoxycurcumin substantially inhibited migration and invasion of A-549 cells, and blocked PI3K/AKT/m-TOR signalling pathway in these cells.
 Conclusion: Demethoxycurcumin induces anticancer effects on A-549 cells via targeting PI3K/AKT/mTOR signalling pathway. It induces cellular apoptosis and inhibits migration and invasion of A-549 cells. Thus, it is a promising anti-lung cancer agent.
 
 
 
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Horvat, Luka, Mariastefania Antica, and Maja Matulić. "The Effect of Casein Kinase 2 Inhibition on three Leukemic Cell Lines." Current Drug Therapy 15, no. 3 (2020): 209–15. http://dx.doi.org/10.2174/1574885514666190724111509.
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Background:: Casein Kinase 2 (CK2) is a Ser/Thr protein kinase that coregulates a great number of signalling pathways in the cell. It is involved in cell cycle regulation and cell proliferation, apoptosis, DNA damage response and gene transcription. Its substrates are numerous kinases and transcription factors. It was found to be upregulated in different tumours, and certain types of leukaemia are very sensitive to its inhibition. Objective:: We analysed the effects of casein kinase 2 inhibition on three leukaemia cell lines of B and T cell origin: Jurkat, a T cell line, CLL, a chronic B lymphocytic leukaemia cell line and 697, a pre-B acute lymphocytic leukaemia cell line. Besides cell proliferation and cytotoxicity analysis, the aim was to investigate the influence of CK2 inhibition on elements of the Notch signalling pathway. Notch signalling has an important role in blood cell differentiation, and CK2 regulates Ikaros, a tumour suppressor interfering with Notch signalling Methods:: and T leukaemia cells were treated with different concentrations of the CK2 inhibitor, CX-4945, for 6 days, and cell viability and proliferation were determined by Trypan Blue Exclusion Method. Analysis of gene expression was performed by RT-qPCR. Results:: All three cell lines were sensitive to CK2 inhibition and among them, 697 cells had two times lower IC50. In Jurkat and CLL cells changes in c-Myc and Notch pathway gene expression were found. Conclusion:: As CK2 is involved in numerous signalling circuits, we concluded that each cell type could have a cell-specific response in gene expression.
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Romic, Snjezana, Snezana Tepavcevic, Zorica Zakula, et al. "Does oestradiol attenuate the damaging effects of a fructose-rich diet on cardiac Akt/endothelial nitric oxide synthase signalling?" British Journal of Nutrition 109, no. 11 (2012): 1940–48. http://dx.doi.org/10.1017/s0007114512004114.
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Fructose-rich diets (FRD) cause cardiac insulin resistance manifested by impairment of Akt/endothelial NO synthase (eNOS) signalling. In contrast, oestradiol (E2) activates this signalling pathway in the heart. To study the ability of E2 to revert the detrimental effect of fructose on cardiac Akt/eNOS, female rats were subjected to a FRD and ovariectomy followed with or without E2 replacement. We also analysed the effects of the FRD and E2 on cardiac extracellular signal-regulated kinase (Erk 1/2) signalling related to their role in cardiac hypertrophy development. Expression of Akt, eNOS and Erk 1/2, as well as regulatory phosphorylations of these molecules were determined. The protein expression of cardiac Akt and eNOS was not affected by the diet or E2 treatment. However, the FRD was accompanied by a decrease in Akt phosphorylation at Ser473 and Thr308, and eNOS at Ser1177, while the phosphorylation of eNOS at Thr495 was increased. E2 replacement in ovariectomised fructose-fed rats caused a reversion of the diet effect on Akt and eNOS serine phosphorylation, but mostly had no effect on threonine phosphorylation of the molecules. The FRD and E2 treatment did not influence Erk 1/2 expression and phosphorylation and heart mass as well. The data show that E2 selectively suppress the negative effects of a FRD on Akt/eNOS signalling and probably point to the different effects of E2 on kinase/phosphatase pathways responsible for phosphorylation/dephosphorylation of Akt and eNOS. Furthermore, the results suggest that the heart of females in the reproductive period is partially protected against the damaging effects of increased fructose intake.
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Gunther, Lisa M., and Ralph R. Miller. "Prevention of the degraded-contingency effect by signalling training trials." Quarterly Journal of Experimental Psychology Section B 53, no. 2b (2000): 97–119. http://dx.doi.org/10.1080/713932719.
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Presentation of unsignalled unconditioned stimuli (USs) interspersed among Pavlovian excitatory conditioning trials weakens conditioned responding to a target conditioned stimulus (CS; Rescorla, 1968). However, signalling these intertrial USs with another cue (a cover stimulus) has been shown to alleviate this degraded-contingency effect (e.g. Durlach, 1982, 1983). In contrast to signalling the inter-trial USs, the present experiments examined the effect on the degraded-contingency effect of signalling the target CS-US pairings. Experiment 1, using parameters selected to avoid overshadowing, found that consistently presenting a cover stimulus immediately prior to the target CS-US pairings during degraded-contingency training alleviated the degraded-contingency effect. Experiment 2 examined the underlying mechanism responsible for this cover-stimulus effect through posttraining associative inflation of the cover stimulus or the context, and found that inflation of the cover stimulus attenuated responding to the target CS (i.e. empirical retrospective revaluation). The results are discussed in terms of various acquisition- and expression-focused models of acquired responding.
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Yim, Grace, Helena Huimi Wang, and Julian Davies FRS. "Antibiotics as signalling molecules." Philosophical Transactions of the Royal Society B: Biological Sciences 362, no. 1483 (2007): 1195–200. http://dx.doi.org/10.1098/rstb.2007.2044.
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We present the argument that the majority of low-molecular-weight organic compounds made and secreted by microbes play roles as cell-signalling molecules in the environment. Of the large number of compounds isolated to date, only a small fraction have been shown to possess useful therapeutic antibiotic activity. However, most microbial metabolites modulate gene transcription at low concentrations, and this is proposed to be the primary effect of the compounds in the maintenance of microbial communities in the environment. Thus, microbial metabolites constitute a large collection of cell-signalling molecules that regulate gene expression in microbial populations and possibly the interactions of these populations with the surrounding organisms.
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Slaninova, Vera, Michaela Krafcikova, Raquel Perez-Gomez, et al. "Notch stimulates growth by direct regulation of genes involved in the control of glycolysis and the tricarboxylic acid cycle." Open Biology 6, no. 2 (2016): 150155. http://dx.doi.org/10.1098/rsob.150155.
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Glycolytic shift is a characteristic feature of rapidly proliferating cells, such as cells during development and during immune response or cancer cells, as well as of stem cells. It results in increased glycolysis uncoupled from mitochondrial respiration, also known as the Warburg effect. Notch signalling is active in contexts where cells undergo glycolytic shift. We decided to test whether metabolic genes are direct transcriptional targets of Notch signalling and whether upregulation of metabolic genes can help Notch to induce tissue growth under physiological conditions and in conditions of Notch-induced hyperplasia. We show that genes mediating cellular metabolic changes towards the Warburg effect are direct transcriptional targets of Notch signalling. They include genes encoding proteins involved in glucose uptake, glycolysis, lactate to pyruvate conversion and repression of the tricarboxylic acid cycle. The direct transcriptional upregulation of metabolic genes is PI3K/Akt independent and occurs not only in cells with overactivated Notch but also in cells with endogenous levels of Notch signalling and in vivo . Even a short pulse of Notch activity is able to elicit long-lasting metabolic changes resembling the Warburg effect. Loss of Notch signalling in Drosophila wing discs as well as in human microvascular cells leads to downregulation of glycolytic genes. Notch-driven tissue overgrowth can be rescued by downregulation of genes for glucose metabolism. Notch activity is able to support growth of wing during nutrient-deprivation conditions, independent of the growth of the rest of the body. Notch is active in situations that involve metabolic reprogramming, and the direct regulation of metabolic genes may be a common mechanism that helps Notch to exert its effects in target tissues.
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Tsay, Gregory J., Fei-Hung Hsieh, Ting-Yin Xue та ін. "Hydroxychloroquine enhances efferocytosis and inhibits IL-6 and TNF-α productions through upregulating both Gas6/Axl and MFG-E8/TG2 Signaling pathways in Pristine-induced lupus mice". Journal of Immunology 204, № 1_Supplement (2020): 236.18. http://dx.doi.org/10.4049/jimmunol.204.supp.236.18.
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Abstract Objectives Impaired clearance of apoptotic cells (efferocytosis) plays an important role in the pathogenesis of autoimmune diseases, especially systemic lupus erythematosus (SLE). Hydroxychloroquine (HCQ) has been widely used to treat autoimmune diseases. We aimed to investigate the underlying mechanism of efferocytosis in the action of HCQ. Methods Eighteen 6-week-old female BALB/c mice were treated Intraperitoneally with pristine in Pristine-induced lupus mice (PIL). Efferocytosis was performed using mouse cell lines EL4 as apoptotic cells and co-cultured with RAW 264.7 and peritoneal macrophages of PIL to investigate the effect of HCQ on efferocytosis which was analyzed with fluorescent microscopy and flow cytometry. Real time PCR was performed to investigate molecular mRNA expressions of signalling pathways. Protein level was measured by ELISA. Results HCQ could enhance efferocytosis with dose-dependent manner in both RAW264.7 cell lines and peritoneal macrophages of PIL with increased expression of GAS6 and MFG-E8 signallings. Both Gas6/Axl and MFG-E8/TG2 Signalling pathways play important roles in HCQ-enhanced efferocytosis. In HCQ-treated mice of PIL, HCQ reduced of IL-6 (p&lt;0.0036) and TNF-α (p&lt;0.06) protein levels in their ascites. Conclusions Our study shows that HCQ can enhance efferocytosis through both Gas6/Axl and MFG-E8/TG2 Signalling pathways and suppress the production of IL-6 and TNF-α. Our findings provide novel insights into understanding the mechanisms of HCQ, which could have the long-term beneficial effects on the therapy of SLE.
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Mao, Yiwen, Yan Li, Han Gao, and Xinda Lin. "The Direct Interaction between E93 and Kr-h1 Mediated Their Antagonistic Effect on Ovary Development of the Brown Planthopper." International Journal of Molecular Sciences 20, no. 10 (2019): 2431. http://dx.doi.org/10.3390/ijms20102431.
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The juvenile hormone (JH) signalling and ecdysone signalling pathways are crucial endocrine signalling pathways that orchestrate the metamorphosis of insects. The metamorphic process, the morphological change from the immature to adult forms, is orchestrated by the dramatic reduction of JH and downstream transcription factors. The Krüppel-homologue 1 (Kr-h1), a downstream transcription factor of the JH signalling pathway, represses E93 expression with an anti-metamorphic effect. However, the biochemical interaction between Kr-h1 and E93 and how the interaction regulates ovary development, a sensitive readout for endocrine regulation, remain unknown. In brown planthopper, Nilaparvata lugens, we found that the downregulation of Kr-h1 partially recovered the deteriorating effect of E93 knock-down on metamorphosis. Dual knock down of E93 and Kr-h1 increased ovary development and the number of eggs laid when compared to the effects of the knock down of E93 alone, indicating that the knock down of Kr-h1 partially recovered the deteriorating effect of the E93 knock-down on ovary development. In summary, our results indicated that E93 and Kr-h1 have antagonistic effects on regulating metamorphosis and ovary development. We tested the biochemical interaction between these two proteins and found that these molecules interact directly. Kr-h1 V and E93 II undergo strong and specific interactions, indicating that the potential interacting domain may be located in these two regions. We inferred that the nuclear receptor interaction motif (NR-box) and helix-turn-helix DNA binding motifs of the pipsqueak family (RHF1) are candidate domains responsible for the protein–protein interaction between E93 and Kr-h1. Moreover, the HA-tagged E93 and FLAG-tagged Kr-h1 were co-localized in the nucleus, and the expression of E93 was increased when Kr-h1 was downregulated, supporting that these two proteins may interact antagonistically. JH and ecdysone signalling are critical for the control of ovary development and pest populations. Our result is important for understanding the interactions between E93 and related proteins, which makes it possible to identify potential targets and develop new pesticides for pest management.
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Uvdal, Petter, and Sviatlana Shashkova. "The Effect of Calorie Restriction on Protein Quality Control in Yeast." Biomolecules 13, no. 5 (2023): 841. http://dx.doi.org/10.3390/biom13050841.
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Initially, protein aggregates were regarded as a sign of a pathological state of the cell. Later, it was found that these assemblies are formed in response to stress, and that some of them serve as signalling mechanisms. This review has a particular focus on how intracellular protein aggregates are related to altered metabolism caused by different glucose concentrations in the extracellular environment. We summarise the current knowledge of the role of energy homeostasis signalling pathways in the consequent effect on intracellular protein aggregate accumulation and removal. This covers regulation at different levels, including elevated protein degradation and proteasome activity mediated by the Hxk2 protein, the enhanced ubiquitination of aberrant proteins through Torc1/Sch9 and Msn2/Whi2, and the activation of autophagy mediated through ATG genes. Finally, certain proteins form reversible biomolecular aggregates in response to stress and reduced glucose levels, which are used as a signalling mechanism in the cell, controlling major primary energy pathways related to glucose sensing.
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Krejčí, Alena. "Metabolic sensors and their interplay with cell signalling and transcription." Biochemical Society Transactions 40, no. 2 (2012): 311–23. http://dx.doi.org/10.1042/bst20110767.
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There is an intimate, yet poorly understood, link between cellular metabolic status, cell signalling and transcription. Central metabolic pathways are under the control of signalling pathways and, vice versa, the cellular metabolic profile influences cell signalling through the incorporation of various metabolic sensors into the signalling networks. Thus information about nutrients availability directly and crucially influences crucial cell decisions. In the present review, I summarize our current knowledge of various metabolic sensors and give some examples of the integration of metabolically derived inputs into the signalling system and the regulation of transcription. I also discuss the Warburg effect where the cross-talk between metabolism and signalling is used to orchestrate rapid cell growth and division. It is becoming clear that future research will concentrate on the collection of small-molecule metabolites, whose concentration fluctuates in response to cellular energy levels, searching for their sensors that connect them to the signalling and transcriptional networks.
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Palma-Nicolas, Jose P., Edith López, and Ana María López-Colomé. "PKC isoenzymes differentially modulate the effect of thrombin on MAPK-dependent RPE proliferation." Bioscience Reports 28, no. 6 (2008): 307–17. http://dx.doi.org/10.1042/bsr20080083.
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Thrombin signalling through PAR (protease-activated receptor)-1 is involved in cellular processes, such as proliferation, differentiation and cell survival. Following traumatic injury to the eye, thrombin signalling may participate in disorders, such as PVR (proliferative vitreoretinopathy), a human eye disease characterized by the uncontrolled proliferation, transdifferentiation and migration of otherwise quiescent RPE (retinal pigment epithelium) cells. PARs activate the Ras/Raf/MEK/ERK MAPK pathway (where ERK is extracellular-signal-regulated kinase, MAPK is mitogen-activated protein kinase and MEK is MAPK/ERK kinase) through the activation of Gα and Gβγ heterotrimeric G-proteins, and the downstream stimulation of the PLC (phospholipase C)-β/PKC (protein kinase C) and PI3K (phosphoinositide 3-kinase) signalling axis. In the present study, we examined the molecular signalling involved in thrombin-induced RPE cell proliferation, using rat RPE cells in culture as a model system for PVR pathogenesis. Our results showed that thrombin activation of PAR-1 induces RPE cell proliferation through Ras-independent activation of the Raf/MEK/ERK1/2 MAPK signalling cascade. Pharmacological analysis revealed that the activation of ‘conventional’ PKC isoforms is essential for proliferation, although thrombin-induced phosphorylation of ERK1/2 requires the activation of atypical PKCζ by PI3K. Consistently, thrombin-induced ERK1/2 activation and RPE cell proliferation were prevented completely by PI3K or PKCζ inhibition. These results suggest that thrombin induces RPE cell proliferation by joint activation of PLC-dependent and atypical PKC isoforms and the Ras-independent downstream stimulation of the Raf/MEK/ERK1/2 MAPK cascade. The present study is the first report demonstrating directly thrombin-induced ERK phosphorylation in the RPE, and the involvement of atypical PKCζ in this process.
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Koblas, T., I. Leontovyč, K. Zacharovová, et al. "Activation of the Jak/Stat Signalling Pathway by Leukaemia Inhibitory Factor Stimulates Trans-differentiation of Human Non-Endocrine Pancreatic Cells into Insulin-Producing Cells." Folia Biologica 58, no. 3 (2012): 98–105. http://dx.doi.org/10.14712/fb2012058030098.
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Differentiation of pancreatic β-cells is regulated by a wide range of signalling pathways. The aim of our current work was to evaluate the effect of the Jak/Stat signalling pathway on the differentiation of human non-endocrine pancreatic cells into insulin-producing cells. Activation of the Jak/Stat signalling pathway by leukaemia inhibitory factor (LIF) stimulated differentiation of C-peptide-negative human non-endocrine pancreatic cells into insulin-producing cells in 6.3 ± 2.0 % cells (N = 5) and induced expression of pro-endocrine transcription factor neurogenin 3, Notch signalling pathway suppressor HES6 and stimulator of β-cell neogenesis REG3A. The expression of the REG3A gene and increased rate of differentiation into insulin-producing cells (10.2 ± 2.1 %) were further stimulated by a combination of LIF with nicotinamide and dexamethasone. Glucose-stimulated (5 vs. 20 mM) C-peptide secretion confirmed proper insulin secretory function of trans-differentiated insulin-producing cells (0.51 vs. 2.03 pmol C-peptide/μg DNA, P < 0.05). Our results indicate that Jak/Stat signalling critically contributes to trans-differentiation of non-endocrine pancreatic cells into functional insulin-producing cells. The positive effect of the Jak/Stat signalling pathway on trans-differentiation is mediated by the key genes that activate differentiation of pancreatic β-cells.
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Lee, Yu-Hsuan. "Does oridonin inhibit the growth of small-cell lung cancer?" Theoretical and Natural Science 6, no. 1 (2023): 205–10. http://dx.doi.org/10.54254/2753-8818/6/20230224.
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Research Question: Can oridonin inhibit small cell lung cancer growth by blocking the Notch signalling? Purpose: Small cell lung cancer (SCLC) is an aggressive illness with a low 5-year survival rate. Oridonin is a Chinese medicine extracted from the leaves of the Rabdosia rubescens, a traditional Chinese medicinal herb, which has been proven to have many medical effects in opposition to the tumour. Notch signalling is an essential pathway in multicellular organisms and transfers information into living organisms. Methods: This study will use a human small-cell lung cancer cell line (H1688). Migration assay will test the influence of oridonin on cell migration. A Xenograft mouse tumour model is created to determine the effect of oridonin on tumour growth. Annexin V will test cell apoptosis, and a western blot is used to test whether Notch signalling is activated. All the assays are repeated three times, and the statistics are analyzed by calculating the means and doing the student's t-test. Possible results: There are three main possible results:(1) Oridonin can inhibit SCLC growth by blocking the notch signalling. (2) Oridonin can inhibit the tumour growth of SCLC cells but not by blocking notch signalling. (3) Oridonin cannot inhibit tumour growth but can block the notch signalling. Conclusion: The study will show whether oridonin can inhibit the growth of SCLC by blocking the notch signalling. It will provide a new method of treatment for those with SCLCs.
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Hallett, Maurice B. "Localisation of Intracellular Signals and Responses during Phagocytosis." International Journal of Molecular Sciences 24, no. 3 (2023): 2825. http://dx.doi.org/10.3390/ijms24032825.
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Phagocytosis is one of the most polarised of all cellular activities. Both the stimulus (the target for phagocytosis) and the response (its internalisation) are focussed at just one part of the cell. At the locus, and this locus alone, pseudopodia form a phagocytic cup around the particle, the cytoskeleton is rearranged, the plasma membrane is reorganised, and a new internal organelle, the phagosome, is formed. The effect of signals from the stimulus must, thus, both be complex and yet be restricted in space and time to enable an effective focussed response. While many aspects of phagocytosis are being uncovered, the mechanism for the restriction of signalling or the effects of signalling remains obscure. In this review, the details of the problem of restricting chemical intracellular signalling are presented, with a focus on diffusion into the cytosol and of signalling lipids along the plasma membrane. The possible ways in which simple diffusion is overcome so that the restriction of signalling and effective phagocytosis can be achieved are discussed in the light of recent advances in imaging, biophysics, and cell biochemistry which together are providing new insights into this area.
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Jiang, Z., E. Gutierrez, H. Ming, et al. "31 Effect of vitrification on global gene expression dynamics of bovine elongating embryos." Reproduction, Fertility and Development 32, no. 2 (2020): 141. http://dx.doi.org/10.1071/rdv32n2ab31.
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The ability to cryopreserve gametes and embryos has been a valuable tool for reproductive management in all mammalian species, especially livestock. Embryo vitrification involves exposure to high concentrations of cryoprotectants and osmotic stress during cooling and warming. These factors have to affect gene expression. The elongating embryo is a stage of embryo development that can be recovered noninvasively in the cow on day (D) 14 and represents a critical stage of development when many embryos die. In this study, we aimed to evaluate the effect of vitrification on the transcriptome dynamics of D14 embryos by RNA sequencing (RNA-seq). Invitro blastocyst-stage embryos were vitrified by exposure to dimethyl sulfoxide and ethylene glycol solution, followed by placing on Cryo Loks and plunging in liquid nitrogen. After warming, embryos were loaded into straws and transferred into eight synchronized recipients, four cows received nonvitrified embryos and four cows received vitrified embryos (20 embryos per cow). Embryo flushing yielded 12 nonvitrified and 9 vitrified viable D14 embryos. Whole embryos (six nonvitrified and two vitrified embryos) or isolated trophectoderm (TE; four nonvitrified and seven vitrified) were processed for RNA-seq. The Smart-sEqn 2 protocol was followed to prepare RNA-seq libraries. Sequencing reads were prefiltered and aligned to the bovine genome, and gene expression values were calculated as fragments per kilobase of transcript per million mapped reads. Genes were deemed differentially expressed between treatments if they showed a false discovery rate P-value&lt;0.05 and fold-change &gt;2. Ingenuity pathway analysis was used to reveal gene ontology and pathways. Expression of 927 genes was changed in D14 embryos as a result of vitrification, with 782 and 145 genes upregulated and downregulated, respectively. In TE, vitrification resulted in 4096 and 280 upregulated or downregulated genes, respectively. Several pathways were upregulated by vitrification in both whole embryos and TE, including epithelial adherens junctions, sirtuin signalling, germ cell-Sertoli cell junction, ATM signalling, nucleotide excision repair, and protein ubiquitination pathways. Downregulated pathways included EIF2 signalling, oxidative phosphorylation, mitochondrial dysfunction, regulation of eIF4 and p70S6K signalling, mammalian target of rapamycin signalling, sirtuin singling, and nucleotide excision repair pathways. In addition, we found 671 and 61 genes upregulated and downregulated in both vitrified whole embryos and TE. Mitochondrial dysfunction and oxidative phosphorylation signalling were upregulated, whereas epithelial adherens junction and sirtuin signalling were downregulated, suggesting mitochondrial function and energy production were impaired in TE after vitrification. Our analysis identified specific pathways and implicated specific genes affected by cryopreservation and potentially affecting embryo developmental competence.
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Silva, Praneeth, та Devi Atukorallaya. "Characterising the Effect of Wnt/β-Catenin Signalling on Melanocyte Development and Patterning: Insights from Zebrafish (Danio rerio)". International Journal of Molecular Sciences 24, № 13 (2023): 10692. http://dx.doi.org/10.3390/ijms241310692.
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Zebrafish (Danio rerio) is a well-established model organism for studying melanocyte biology due to its remarkable similarity to humans. The Wnt signalling pathway is a conserved signal transduction pathway that plays a crucial role in embryonic development and regulates many aspects of the melanocyte lineage. Our study was designed to investigate the effect of Wnt signalling activity on zebrafish melanocyte development and patterning. Stereo-microscopic examinations were used to screen for changes in melanocyte count, specific phenotypic differences, and distribution in zebrafish, while microscopic software tools were used to analyse the differences in pigment dispersion of melanocytes exposed to LiCl (Wnt enhancer) and W-C59 (Wnt inhibitor). Samples exposed to W-C59 showed low melanocyte densities and defects in melanocyte phenotype and patterning, whereas LiCl exposure demonstrated a stimulatory effect on most aspects of melanocyte development. Our study demonstrates the crucial role of Wnt signalling in melanocyte lineage and emphasises the importance of a balanced Wnt signalling level for proper melanocyte development and patterning.
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Zhao, Qinglan, Murli Manohar, Yi Wei, Stephen J. Pandol, and Aida Habtezion. "STING signalling protects against chronic pancreatitis by modulating Th17 response." Gut 68, no. 10 (2019): 1827–37. http://dx.doi.org/10.1136/gutjnl-2018-317098.
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ObjectiveChronic pancreatitis (CP) is an inflammatory disease with progressive fibrosis leading to exocrine and endocrine dysfunction. Currently, there are no approved effective therapies for CP. Stimulator of interferon genes (STING) signalling is a key innate immune sensor of DNA. In this study, we evaluated the role of STING signalling in CP.DesignWe used an experimental model of CP to test the effect of STING signalling in STING wild-type and knockout mice as well as bone marrow chimaeras (BMCs). STING was activated using a pharmacological agent. Since we found changes in Th17 cells, we used neutralising and control antibodies to determine the role of IL-17A. The effect of STING signalling was further explored in IL-17A generation and we examined the effect of IL-17A on pancreatic stellate cells (PSCs). Human pancreas from patients with CP and without CP were also stained for IL-17A.ResultsSTING activation decreased CP-associated pancreatic inflammation and fibrosis, whereas absence of STING led to worsening of the disease. BMCs showed that leucocytes play an important role in STING signalling–mediated amelioration of experimental CP. STING deletion was associated with increased Th17 cell infiltration in the pancreas, whereas STING agonist limited this Th17 response. Importantly, anti-IL-17A antibody treatment mitigated the severity of CP in the absence of STING signalling. STING deficiency promoted Th17 polarisation and PSCs express functional IL-17 receptor by upregulating fibrosis genes. Compared with tumour margins, pancreas from patients with CP had significant increase in IL-17A+ cells.ConclusionUnlike acute pancreatitis, STING activation is protective in CP. STING signalling is important in regulating adaptive immune responses by diminishing generation of IL-17A during CP and presents a novel therapeutic target for CP.
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Lim, Chung Thong, Blerina Kola, and Márta Korbonits. "AMPK as a mediator of hormonal signalling." Journal of Molecular Endocrinology 44, no. 2 (2009): 87–97. http://dx.doi.org/10.1677/jme-09-0063.
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AMP-activated protein kinase (AMPK) is a key molecular player in energy homeostasis at both cellular and whole-body levels. AMPK has been shown to mediate the metabolic effects of hormones such as leptin, ghrelin, adiponectin, glucocorticoids and insulin as well as cannabinoids. Generally, activated AMPK stimulates catabolic pathways (glycolysis, fatty acid oxidation and mitochondrial biogenesis) and inhibits anabolic pathways (gluconeogenesis, glycogen, fatty acid and protein synthesis), and has a direct appetite-regulating effect in the hypothalamus. Drugs that activate AMPK, namely metformin and thiazolidinediones, are often used to treat metabolic disorders. Thus, AMPK is now recognised as a potential target for the treatment of obesity and associated co-morbidities.
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Navarrete, Marta, Adolfo Díez, and Alfonso Araque. "Astrocytes in endocannabinoid signalling." Philosophical Transactions of the Royal Society B: Biological Sciences 369, no. 1654 (2014): 20130599. http://dx.doi.org/10.1098/rstb.2013.0599.
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Astrocytes are emerging as integral functional components of synapses, responding to synaptically released neurotransmitters and regulating synaptic transmission and plasticity. Thus, they functionally interact with neurons establishing tripartite synapses: a functional concept that refers to the existence of communication between astrocytes and neurons and its crucial role in synaptic function. Here, we discuss recent evidence showing that astrocytes are involved in the endocannabinoid (ECB) system, responding to exogenous cannabinoids as well as ECBs through activation of type 1 cannabinoid receptors, which increase intracellular calcium and stimulate the release of glutamate that modulates synaptic transmission and plasticity. We also discuss the consequences of ECB signalling in tripartite synapses on the astrocyte-mediated regulation of synaptic function, which reveal novel properties of synaptic regulation by ECBs, such as the spatially controlled dual effect on synaptic strength and the lateral potentiation of synaptic efficacy. Finally, we discuss the potential implications of ECB signalling for astrocytes in brain pathology and animal behaviour.
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Nölting, Svenja, Edwin Garcia, Ghassan Alusi, et al. "Combined blockade of signalling pathways shows marked anti-tumour potential in phaeochromocytoma cell lines." Journal of Molecular Endocrinology 49, no. 2 (2012): 79–96. http://dx.doi.org/10.1530/jme-12-0028.
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Currently, there is no completely effective therapy available for metastatic phaeochromocytomas (PCCs) and paragangliomas. In this study, we explore new molecular targeted therapies for these tumours, using one more benign (mouse phaeochromocytoma cell (MPC)) and one more malignant (mouse tumour tissue (MTT)) mouse PCC cell line – both generated from heterozygous neurofibromin 1 knockout mice. Several PCC-promoting gene mutations have been associated with aberrant activation of PI3K/AKT, mTORC1 and RAS/RAF/ERK signalling. We therefore investigated different agents that interfere specifically with these pathways, including antagonism of the IGF1 receptor by NVP-AEW541. We found that NVP-AEW541 significantly reduced MPC and MTT cell viability at relatively high doses but led to a compensatory up-regulation of ERK and mTORC1 signalling at suboptimal doses while PI3K/AKT inhibition remained stable. We subsequently investigated the effect of the dual PI3K/mTORC1/2 inhibitor NVP-BEZ235, which led to a significant decrease of MPC and MTT cell viability at doses down to 50 nM but again increased ERK signalling. Accordingly, we next examined the combination of NVP-BEZ235 with the established agent lovastatin, as this has been described to inhibit ERK signalling. Lovastatin alone significantly reduced MPC and MTT cell viability at therapeutically relevant doses and inhibited both ERK and AKT signalling, but increased mTORC1/p70S6K signalling. Combination treatment with NVP-BEZ235 and lovastatin showed a significant additive effect in MPC and MTT cells and resulted in inhibition of both AKT and mTORC1/p70S6K signalling without ERK up-regulation. Simultaneous inhibition of PI3K/AKT, mTORC1/2 and ERK signalling suggests a novel therapeutic approach for malignant PCCs.
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Shin, Yeun-Kyung, Qiang Liu, Suresh K. Tikoo, Lorne A. Babiuk, and Yan Zhou. "Effect of the phosphatidylinositol 3-kinase/Akt pathway on influenza A virus propagation." Journal of General Virology 88, no. 3 (2007): 942–50. http://dx.doi.org/10.1099/vir.0.82483-0.
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The phosphatidylinositol 3-kinase (PI3K)/Akt signalling pathway has attracted much recent interest due to its central role in modulating diverse downstream signalling pathways associated with cell survival, proliferation, differentiation, morphology and apoptosis. An increasing amount of information has demonstrated that many viruses activate the PI3K/Akt pathway to augment their efficient replication. In this study, the effect of the PI3K/Akt signalling pathway on influenza virus propagation was investigated. It was found that Akt phosphorylation was elevated in the late phase of influenza A/PR/8/34 infection in human lung carcinoma cells (A549). The PI3K-specific inhibitor LY294002 could suppress Akt phosphorylation, suggesting that influenza A virus-induced Akt phosphorylation is PI3K-dependent. UV-irradiated influenza virus failed to induce Akt phosphorylation, indicating that viral attachment and entry were not sufficient to trigger PI3K/Akt pathway activation. Blockage of PI3K/Akt activation by LY294002 and overexpression of the general receptor for phosphoinositides-1 PH domain (Grp1-PH) led to a reduction in virus yield. Moreover, in the presence of LY294002, viral RNA synthesis and viral protein expression were suppressed and, possibly as a consequence of low NP and M1 protein level, viral RNP nuclear export was also suppressed. These data suggest that the PI3K/Akt signalling pathway plays a role in influenza virus propagation.
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Fälker, Knut, Linda Haglund, Peter Gunnarsson, Martina Nylander, Tomas L. Lindahl, and Magnus Grenegård. "Protease-activated receptor 1 (PAR1) signalling desensitization is counteracted via PAR4 signalling in human platelets." Biochemical Journal 436, no. 2 (2011): 469–80. http://dx.doi.org/10.1042/bj20101360.
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PARs (protease-activated receptors) 1 and 4 belong to the family of G-protein-coupled receptors which induce both Gα12/13 and Gαq signalling. By applying the specific PAR1- and PAR4-activating hexapeptides, SFLLRN and AYPGKF respectively, we found that aggregation of isolated human platelets mediated via PAR1, but not via PAR4, is abolished upon homologous receptor activation in a concentration- and time-dependent fashion. This effect was not due to receptor internalization, but to a decrease in Ca2+ mobilization, PKC (protein kinase C) signalling and α-granule secretion, as well as to a complete lack of dense granule secretion. Interestingly, subthreshold PAR4 activation rapidly abrogated PAR1 signalling desensitization by differentially reconstituting these affected signalling events and functional responses, which was sufficient to re-establish aggregation. The lack of ADP release and P2Y12 receptor-induced Gαi signalling accounted for the loss of the aggregation response, as mimicking Gαi/z signalling with 2-MeS-ADP (2-methylthioadenosine-5′-O-diphosphate) or epinephrine (adrenaline) could substitute for intermediate PAR4 activation. Finally, we found that the re-sensitization of PAR1 signalling-induced aggregation via PAR4 relied on PKC-mediated release of both ADP from dense granules and fibrinogen from α-granules. The present study elucidates further differences in human platelet PAR signalling regulation and provides evidence for a cross-talk in which PAR4 signalling counteracts mechanisms involved in PAR1 signalling down-regulation.
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Xu, Chen, Xingji You, Weina Liu та ін. "Prostaglandin F2α regulates the expression of uterine activation proteins via multiple signalling pathways". REPRODUCTION 149, № 1 (2015): 139–46. http://dx.doi.org/10.1530/rep-14-0479.
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Prostaglandin F2α (PGF2A) has multiple roles in the birth process in addition to its vital contractile role. Our previous study has demonstrated that PGF2A can modulate uterine activation proteins (UAPs) in cultured pregnant human myometrial smooth muscle cells (HMSMCs). The objective of this study was to define the signalling pathways responsible for PGF2A modulation of UAPs in myometrium. It was found that PGF2A stimulated the expression of (GJA1) connexin 43 (CX43), prostaglandin endoperoxide synthase 2 (PTGS2) and oxytocin receptor (OTR) in cultured HMSMCs. The inhibitors of phospholipase C (PLC) and protein kinase C (PKC) blocked PGF2A-stimulated expression of CX43. The inhibitors of ERK, P38 and NFκB also blocked the effect of PGF2A on CX43 expression, whereas PI3K and calcineurin/nuclear factor of activated T-cells (NFAT) pathway inhibitors did not reverse the effect of PGF2A on CX43. For PTGS2 and OTR, PLC, PI3K, P38 and calcineurin/NFAT signalling pathways were involved in PGF2A action, whereas PKC and NFκB signalling were not involved. In addition, PGF2A activated NFAT, PI3K, NFκB, ERK and P38 signalling pathways. Our data suggest that PGF2A stimulates CX43, PTGS2 and OTR through divergent signalling pathways.
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Pfirrmann, Thorsten, and Christoph Gerhardt. "Life-Saver or Undertaker: The Relationship between Primary Cilia and Cell Death in Vertebrate Embryonic Development." Journal of Developmental Biology 10, no. 4 (2022): 52. http://dx.doi.org/10.3390/jdb10040052.
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The development of multicellular organisms requires a tightly coordinated network of cellular processes and intercellular signalling. For more than 20 years, it has been known that primary cilia are deeply involved in the mediation of intercellular signalling and that ciliary dysfunction results in severe developmental defects. Cilia-mediated signalling regulates cellular processes such as proliferation, differentiation, migration, etc. Another cellular process ensuring proper embryonic development is cell death. While the effect of cilia-mediated signalling on many cellular processes has been extensively studied, the relationship between primary cilia and cell death remains largely unknown. This article provides a short review on the current knowledge about this relationship.
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Bobenhausen, Nils-Christian, and Astrid Juliane Salzmann. "Discount, transparency and announcements effects of equity rights offerings: international evidence." Journal of Business Economics 91, no. 5 (2021): 733–58. http://dx.doi.org/10.1007/s11573-020-01023-8.
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AbstractEquity rights offerings and their respective announcement effects have been studied extensively in the literature. Our study expands upon these studies and focuses on those announcement effects and the relation between the discount of an equity rights offering and the announcement effect. Previous theoretical and empirical analyses show that firms can signal their quality via the discount in an equity rights offering and demonstrate a negative relation between the discount and the announcement effect. We argue that this link is only relevant in environments where signalling is possible and necessary. These are financial markets with a particularly low level of capital market transparency, i.e. high information asymmetry. We calculate announcement effects for an international sample of equity rights offerings and show that the negative effect of the discount on announcement effects can only be observed in environments with a low capital market transparency. Hence, our study estimates announcement effects across several different countries and is thus among the first to analyse signalling considerations for equity rights offerings in different transparency environments.