The Statistics of Synergism

Slinker, Bryan K.

doi:10.1006/jmcc.1998.0655

Cited by 237 publications

(212 citation statements)

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“…A complete isobolographic analysis requires the acquisition of multiple data points using several drug proportions that produce the exact same effect on energy balance, followed by regression analysis (Tallarida, 2001). Two-way ANOVA is a superior (and somewhat more rigorous) method for analysis of drug interactions in behavioral pharmacology because it does not require acquisition of multiple data points and has a simple visual and statistical interpretation of data that can be used to identify significant synergistic or additive effects (Slinker, 1998).…”

Section: Discussionmentioning

confidence: 99%

“…For two-way ANOVA analysis, data (food intake or body weight) were plotted using Prism Software (Graph-Pad Software). The F-statistic for an interaction effect in a two-way ANOVA is mathematically comparable to testing the null hypothesis (for a review, see Slinker, 1998); therefore, a significant interaction between drugtreated animals (Po0.05) was considered indicative of a synergistic interaction (Slinker, 1998). (e) BUP caused a dose-dependent increase in locomotor activity that was independent of food intake (n ¼ 8/group).…”

Section: Analysis Of Drug Additivity/synergymentioning

confidence: 99%

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Inhibition of Dopamine and Norepinephrine Reuptake Produces Additive Effects on Energy Balance in Lean and Obese Mice

Billes

Cowley

2006

Neuropsychopharmacol

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Although originally developed as an antidepressant, long-term bupropion (BUP) treatment was recently shown to cause 5-8% weight loss over placebo in clinical trials with obese adults. BUP's antidepressant properties probably stem from its ability to increase extracellular brain dopamine (DA) and norepinephrine (NE) levels by inhibiting their reuptake, although the mechanism of BUP-induced weight loss is unknown. Consequently, the acute effects of DA and NE reuptake inhibition on energy homeostasis were determined by measuring food intake and body weight in mice following peripheral (intraperitoneal (i.p.)) administration of either BUP, a selective DA (GBR12783), or a selective NE (nisoxetine (NIS)) reuptake inhibitor. BUP, GBR12783, and NIS all dose-dependently decreased acute food intake in fasted lean mice. The ability of BUP to decrease food intake was independent of its ability to cause a temporary increase in locomotor activity. The inhibitory effects of acute GBR12783 and NIS on short-term food intake were additive. Subchronic (via miniosmotic pump) administration of GBR12783 and NIS produced a transient nonadditive effect on food intake, but produced an additive reduction in body weight (8-10%). Because obesity can affect catecholaminergic signaling, we determined the effects of i.p. BUP, GBR12783, and NIS on short-term food intake in obese mice. Acute BUP, GBR12783, and NIS dose-dependently reduced acute food intake, and the additive effect of GBR12783 and NIS on acute food intake was preserved in obese mice. These results demonstrate that combined DA and NE reuptake inhibition produces additive effects on energy balance in lean and obese mice on both standard and high-fat diet, providing a foundation for further research on the effects of BUP and similar compounds on energy balance in mice.

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Section: Discussionmentioning

confidence: 99%

Section: Analysis Of Drug Additivity/synergymentioning

confidence: 99%

Inhibition of Dopamine and Norepinephrine Reuptake Produces Additive Effects on Energy Balance in Lean and Obese Mice

Billes

Cowley

2006

Neuropsychopharmacol

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“…Statistical synergy identifies a physical intersection between two signaling pathways, producing a greater than additive response (40). To this end, we initially sought to confirm the synergistic regulation of gene expression by FSH and exogenous IGF-1, focusing on three FSH-and PI3K-dependent genes required for follicle maturation and female fertility: Inha (inhibin-␣) (41), Lhcgr (luteinizing hormone (LH) receptor) (42), and Cyp11a1 (P450scc (p450 side chain cleavage)) (reviewed in Ref.…”

Section: Fsh and Igf-1 Synergistically Regulate Gene Expression In Amentioning

confidence: 99%

“…Analysis by two-way ANOVA was necessary to test for the interaction between IGF-1 and FSH or FSH plus Myr-PKI. A synergistic relationship, or an intersection between two signaling pathways, is identified quantitatively by significance under a twoway ANOVA (p Ͻ 0.05) and qualitatively by departure of graphed treatment groups from parallel (40).…”

mentioning

confidence: 99%

Insulin Receptor Substrate 1, the Hub Linking Follicle-stimulating Hormone to Phosphatidylinositol 3-Kinase Activation

Law

Hunzicker-Dunn

2016

Journal of Biological Chemistry

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The ubiquitous phosphatidylinositol 3-kinase (PI3K) signaling pathway regulates many cellular functions. However, the mechanism by which G protein-coupled receptors (GPCRs) signal to activate PI3K is poorly understood. We have used ovarian granulosa cells as a model to investigate this pathway, based on evidence that the GPCR agonist follicle-stimulating hormone (FSH) promotes the protein kinase A (PKA)-dependent phosphorylation of insulin receptor substrate 1 (IRS1) on tyrosine residues that activate PI3K. We report that in the absence of FSH, granulosa cells secrete a subthreshold concentration of insulin-like growth factor-1 (IGF-1) that primes the IGF-1 receptor (IGF-1R) but fails to promote tyrosine phosphorylation of IRS1. FSH via PKA acts to sensitize IRS1 to the tyrosine kinase activity of the IGF-1R by activating protein phosphatase 1 (PP1) to promote dephosphorylation of inhibitory Ser/Thr residues on IRS1, including Ser 789 . Knockdown of PP1␤ blocks the ability of FSH to activate PI3K in the presence of endogenous IGF-1. Activation of PI3K thus requires both PKA-mediated relief of IRS1 inhibition and IGF-1R-dependent tyrosine phosphorylation of IRS1. Treatment with FSH and increasing concentrations of exogenous IGF-1 triggers synergistic IRS1 tyrosine phosphorylation at PI3K-activating residues that persists downstream through protein kinase B (AKT) and FOXO1 (forkhead box protein O1) to drive synergistic expression of genes that underlies follicle maturation. Based on the ability of GPCR agonists to synergize with IGFs to enhance gene expression in other cell types, PP1 activation to relieve IRS1 inhibition may be a more general mechanism by which GPCRs act with the IGF-1R to activate PI3K/AKT.The phosphatidylinositol-3 kinase (PI3K) signaling pathway regulates transcription, translation, proliferation, and apoptosis (1, 2). Whereas PI3K is classically activated by receptor tyrosine kinases, such as the insulin-like growth factor-1 receptor (IGF-1R), 2 PI3K is also activated in many cells by G-proteincoupled receptors (GPCRs). However, the mechanisms by which GPCRs signal to activate PI3K are much less understood compared with classical activation by receptor tyrosine kinases (1). We have used rat ovarian granulosa cells (GCs) as a model to elucidate the mechanism by which the GPCR agonist folliclestimulating hormone (FSH) activates PI3K, based on prior evidence that FSH activates PI3K in a protein kinase A (PKA)-dependent manner (3). FSH is an obligatory regulator of ovarian follicle maturation. During the menstrual cycle, preantral follicles that encompass developing oocytes mature to a preovulatory stage in response to elevated levels of FSH (4). Administration of exogenous FSH also restores follicle development in anovulatory women (5). Finally, mice harboring null alleles for either the FSH receptor or FSH␤ lack preovulatory follicles and are infertile (6, 7). Traditionally, FSH has thus been considered both necessary and sufficient to promote follicle maturation.FSH acts exclusively on GCs wit...

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“…Consequently, treatment of the cells with plant extract (without irradiation) slightly reduces cellular survival to 97% and 89% at a dose of 5 and 15µg/ml, respectively, compared to untreated control cells. Plant extract treatment and gamma-radiation synergistically impact cellular survival (p=0.03) (Slinker, 1998). Moreover, the combined effect of D scandens extract and radiation on cellular survival was determined from CI values ( Table 1).…”

Section: Scandens Extract Synergistically Sensitizes Ht-29 Cells Tomentioning

confidence: 99%

Ethanolic Extract from Derris scandens Benth Mediates Radiosensitzation via Two Distinct Modes of Cell Death in Human Colon Cancer HT-29 Cells

Hematulin

Ingkaninan²,

Limpeanchob³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Enhancing of radioresponsiveness of tumors by using radiosensitizers is a promising approach to increase the efficacy of radiation therapy. Recently, the ethanolic extract of the medicinal plant, Derris scandens Benth has been identified as a potent radiosensitizer of human colon cancer HT29 cells. However, cell death mechanisms underlying radiosensitization activity of D scandens extract have not been identified. Here, we show that treatment of HT-29 cells with D scandens extract in combination with gamma irradiation synergistically sensitizes HT-29 cells to cell lethality by apoptosis and mitotic catastrophe. Furthermore, the extract was found to decrease Erk1/2 activation. These findings suggest that D scandens extract mediates radiosensitization via at least two distinct modes of cell death and silences pro-survival signaling in HT-29 cells.

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The Statistics of Synergism

Cited by 237 publications

References 1 publication

Inhibition of Dopamine and Norepinephrine Reuptake Produces Additive Effects on Energy Balance in Lean and Obese Mice

Inhibition of Dopamine and Norepinephrine Reuptake Produces Additive Effects on Energy Balance in Lean and Obese Mice

Insulin Receptor Substrate 1, the Hub Linking Follicle-stimulating Hormone to Phosphatidylinositol 3-Kinase Activation

Ethanolic Extract from Derris scandens Benth Mediates Radiosensitzation via Two Distinct Modes of Cell Death in Human Colon Cancer HT-29 Cells

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