scholarly journals GPR120: A bi-potential mediator to modulate the osteogenic and adipogenic differentiation of BMMSCs

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Bo Gao ◽  
Qiang Huang ◽  
Qiang Jie ◽  
Wei-Guang Lu ◽  
Long Wang ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Unsaturated Fatty Acids ◽  
Adipogenic Differentiation ◽  
Dependent Manner ◽  
Signalling Molecules ◽  
Low Concentrations ◽  
High Concentrations ◽  
High Doses ◽  
Dose Dependent

Abstract Free fatty acids display diverse effects as signalling molecules through GPCRs in addition to their involvement in cellular metabolism. GPR120, a G protein-coupled receptor for long-chain unsaturated fatty acids, has been reported to mediate adipogenesis in lipid metabolism. However, whether GPR120 also mediates osteogenesis and regulates BMMSCs remain unclear. In this study, we showed that GPR120 targeted the bi-potential differentiation of BMMSCs in a ligand dose-dependent manner. High concentrations of TUG-891 (a highly selective agonist of GPR120) promoted osteogenesis via the Ras-ERK1/2 cascade, while low concentrations elevated P38 and increased adipogenesis. The fine molecular regulation of GPR120 was implemented by up-regulating different integrin subunits (α1, α2 and β1; α5 and β3). The administration of high doses of TUG-891 rescued oestrogen-deficient bone loss in vivo, further supporting an essential role of GPR120 in bone metabolism. Our findings, for the first time, showed that GPR120-mediated cellular signalling determines the bi-potential differentiation of BMMSCs in a dose-dependent manner. Additionally, the induction of different integrin subunits was involved in the cytoplasmic regulation of a seesaw-like balance between ERK and p38 phosphorylation. These findings provide new hope for developing novel remedies to treat osteoporosis by adjusting the GPR120-mediated differentiation balance of BMMSCs.

scholarly journals Biphasic Dose–Response Induced by PCB150 and PCB180 in HeLa Cells and Potential Molecular Mechanisms

Dose-Response ◽  
2020 ◽  
Vol 18 (1) ◽  
pp. 155932582091004
Author(s):  
Ainy Zehra ◽  
Muhammad Zaffar Hashmi ◽  
Abdul Majid Khan ◽  
Tariq Malik ◽  
Zaigham Abbas
Keyword(s):  
Hela Cells ◽  
Molecular Mechanisms ◽  
Dependent Manner ◽  
Genotoxic Effects ◽  
Species Formation ◽  
Low Concentrations ◽  
Extracellular Signal ◽  
High Concentrations ◽  
High Doses ◽  
Dose Dependent

The polychlorinated biphenyls (PCBs) are persistent and their dose-dependent toxicities studies are not well-established. In this study, cytotoxic and genotoxic effects of PCB150 and PCB180 in HeLa cells were studied. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay indicated that the cell proliferation was stimulated at low doses (10−3 and 10−2 µg/mL for 12, 24, 48, and 72 hours) and inhibited at high doses (10 and 15 µg/mL for 24, 48, and 72 hours) for both PCBs. Increase in reactive oxygen species formation was observed in the HeLa cells in a time- and dose-dependent manner. Malondialdehyde and superoxide dismutase showed increased levels at high concentrations of PCBs over the time. Glutathione peroxidase expression was downregulated after PCBs exposure, suggested that both PCB congeners may attributable to cytotoxicity. Comet assay elicited a significant increase in genotoxicity at high concentrations of PCBs as compared to low concentrations indicating genotoxic effects. PCB150 and PCB180 showed decrease in the activity of extracellular signal–regulated kinase 1/2 and c-Jun N-terminal kinase at high concentrations after 12 and 48 hours. These findings may contribute to understanding the mechanism of PCBs-induced toxicity, thereby improving the risk assessment of toxic compounds in humans.

Effects of polymethoxylated flavone metabolites on apoB100 secretion and MTP activity in Huh7.5 cells

2021 ◽  
Vol 18 ◽  
Author(s):  
Danielle R. Gonçalves ◽  
Thais B. Cesar ◽  
John A. Manthey ◽  
Paulo I. Costa
Keyword(s):  
Lipid Synthesis ◽  
Dependent Manner ◽  
Transfer Protein ◽  
Low Concentrations ◽  
Wide Range ◽  
Cell Assays ◽  
Polymethoxylated Flavones ◽  
High Concentrations

Background: Citrus polymethoxylated flavones (PMFs) reduce the synthesis of liver lipoproteins in animal and in vitro cell assays, but few studies have evaluated the direct effects of their metabolites on this highly regulated process. Objective: To investigate the effects of representative metabolites of PMF on the secretion of liver lipoproteins using the mammalian cell Huh7.5. Method: In this study, the influences of three PMFs and five previously isolated PMF metabolites on hepatic apoB-100 secretion and microsomal transfer protein (MTP) activity were evaluated. Tangeretin (TAN), nobiletin (NOB) and 3,5,6,7,8,3′,4′-heptamethoxyflavone (HMF), and their glucuronides (TAN-Gluc, NOB-Gluc and HMF-Gluc) and oxidatively demethylated metabolites (TAN-OH, NOB-OH, HMF-OH) were incubated with Huh7.5 cells to measure their inhibitory effects on lipid synthesis. Results: The results showed that TAN, HMF and TAN-OH reduced the secretion of apoB-100 in a dose-dependent manner, while NOB and the other tested metabolites showed no inhibition. MTP activity in the Huh7.5 cells was significantly reduced in the presence of low concentrations of TAN, and in high concentrations of NOB-OH. This study also showed that PMFs and PMF metabolites produced a wide range of effects on apoB-100 secretion and MTP activity. Conclusion: The results suggest that while PMFs and their metabolites control dyslipidemia in vivo, the inhibition of MTP activity cannot be the only pathway influenced by these compounds.

Unsaturated fatty acids and cyclooxygenase inhibitors: effects on pial arterioles

1982 ◽  
Vol 242 (4) ◽  
pp. H629-H632
Author(s):  
W. I. Rosenblum
Keyword(s):  
Fatty Acids ◽  
Unsaturated Fatty Acids ◽  
Eicosatrienoic Acid ◽  
Inhibitory Effect ◽  
Cyclooxygenase Inhibitors ◽  
Dependent Manner ◽  
Double Bonds ◽  
Pial Arterioles ◽  
Dose Dependent

Cerebral surface arterioles of the mouse were constricted in a dose-dependent manner by three different unsaturated fatty acids each with one of its double bonds in the n-6 position: arachidonate, linoleic, and 11,14,17-eicosatrienoic acid (ETA) in doses of 10-200 micrograms/ml. The constriction was transient, and its magnitude was significantly reduced by pretreatment of the mice with intraperitoneal injections of indomethacin (5 mg/kg), aspirin (100 mg/kg), or sodium 2-amino-3-(4 chlorobenzyl)-phenylacetate (AHR-6293, 100 mg/kg). The inhibitory effect of these cyclooxygenase inhibitors suggests that this enzyme is involved in the response to these fatty acids and is in keeping with suggestions in the literature stating that such unsaturated fatty acids may interact with cyclooxygenase even when they cannot form prostaglandin (PG) endoperoxides, The PG endoperoxide formed by arachidonate or the analogous hydroperoxy compounds formed by linoleic or 11,14,17 ETA, may then alter cerebrovascular tone by production of reactive, O2-containing species. Alternate explanations for the data are also proposed.

scholarly journals Stimulation of prostaglandin E2 synthesis by exogenous phospholipase A2 and C in rabbit kidney medulla slices

1984 ◽  
Vol 218 (1) ◽  
pp. 69-74 ◽  
Author(s):  
Y Fujimoto ◽  
N Akamatsu ◽  
A Hattori ◽  
T Fujita
Keyword(s):  
Fatty Acids ◽  
Prostaglandin E2 ◽  
Phospholipase A2 ◽  
Phospholipase C ◽  
Unsaturated Fatty Acids ◽  
Rabbit Kidney ◽  
Dependent Manner ◽  
Kidney Medulla ◽  
Diacylglycerol Lipase ◽  
Dose Dependent

We have investigated the effects of phospholipase A2 and C on the synthesis of prostaglandin E2 in rabbit kidney medulla and the release of fatty acids from the medulla slices. Exogenous phospholipase A2 [from Naja naja (Indian cobra) venom] and phospholipase C (from Clostridium welchii) stimulated prostaglandin E2 production in a dose-dependent manner. At the maximal effective concentrations (0.5 unit of phospholipase A2/ml, 2 units of phospholipase C/ml), phospholipase C increased prostaglandin E2 formation to the level observed with phospholipase A2. Phospholipase A2 enhanced the release only of unsaturated fatty acids, whereas phospholipase C stimulated the release of individual free fatty acids (C 16:0, C 18:0, C 18:1, C 18:2 and C 20:4). Moreover, p-bromophenacyl bromide inhibited phospholipase A2-stimulated prostaglandin E2 production and the release of fatty acids, but it had no influence on prostaglandin E2 formation and the release of fatty acids increased by phospholipase C, indicating that the stimulatory effect of phospholipase C is not mediated through the activation of endogenous phospholipase A2. These results suggest the presence of diacylglycerol lipase and monoacylglycerol lipase in the kidney and the importance of this pathway in prostaglandin synthesis by the kidney.

scholarly journals Unsaturated Fatty Acids Stimulate LH Secretion via Novel PKCε and -θ in Gonadotrope Cells and Inhibit GnRH-Induced LH Release

Endocrinology ◽  
2011 ◽  
Vol 152 (10) ◽  
pp. 3905-3916 ◽  
Author(s):  
Ghislaine Garrel ◽  
Violaine Simon ◽  
Chantal Denoyelle ◽  
Céline Cruciani-Guglielmacci ◽  
Stéphanie Migrenne ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Cell Cultures ◽  
Unsaturated Fatty Acids ◽  
Reproductive Function ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Lh Release ◽  
Lh Secretion

The activity of pituitary gonadotrope cells, crucial for reproductive function, is regulated by numerous factors including signals related to nutritional status. In this work, we demonstrated, for the first time, that in vivo central exposure of rats to lipids intracarotid infusion of a heparinized triglyceride emulsion selectively increases the expression of pituitary LH subunit genes without any alteration of pituitary GnRH receptor and hypothalamic GnRH or Kiss-1 transcript levels. Furthermore, we showed that unsaturated fatty acids (UFA), oleate and linoleate, increase LH release in a dose-dependent manner as well as LHβ mRNA levels in both immortalized LβT2 gonadotrope cell line and rat primary cell cultures. In contrast, the saturated palmitate was ineffective. ACTH or TSH secretion was unaffected by UFA treatment. We demonstrated in LβT2 cells that linoleate effect is mediated neither by activation of membrane fatty acid (FA) receptors GPR40 or GPR120 although we characterized these receptors in LβT2 cells, nor through nuclear peroxisome proliferator-activated receptors. Furthermore, linoleate β-oxidation is not required for its action on LH secretion. In contrast, pharmacological inhibition of protein kinase C (PKC) or ERK pathways significantly prevented linoleate-stimulated LH release. Accordingly, linoleate was shown to activate novel PKC isoforms, PKCε and -θ, as well as ERK1/2 in LβT2 cells. Lastly, unsaturated, but not saturated, FA inhibited GnRH-induced LH secretion in LβT2 cells as well as in pituitary cell cultures. Altogether, these results suggest that the pituitary is a relevant site of FA action and that UFA may influence reproduction by directly interfering with basal and GnRH-dependent gonadotrope activity.

Inhibitory effects of gossypol on adrenal function

1991 ◽  
Vol 124 (6) ◽  
pp. 672-678 ◽  
Author(s):  
Yan-Wan Wu ◽  
Constance L. Chik ◽  
Barry D. Albertson ◽  
W. Marston Linehan ◽  
Richard A. Knazek
Keyword(s):  
Adrenal Function ◽  
Dependent Manner ◽  
Inhibitory Effects ◽  
Acth Stimulation ◽  
Adrenal Steroidogenesis ◽  
Cortisol Responses ◽  
Corticosterone Response ◽  
High Doses ◽  
Dose Dependent

Abstract. Gossypol, an antifertility agent, has inhibitory actions on many membrane-associated enzymes, suggesting that this agent might have a generalized effect on cell membranes. This hypothesis was examined in the present study using membranes and dispersed cells prepared from human and rat adrenal glands. Four parameters were determined: microviscosity as measured by fluorescence polarization of human adrenal microsomal- and mitochondrial-enriched membranes, adrenal steroidogenic enzymes; and cAMP and cortisol responses to ACTH. It was found that gossypol increased the polarization constants of microsomes and mitochondria in a dose-dependent manner. Of the three adrenal enzymes tested, both 3β-hydroxysteroid dehydrogenase Δ5-Δ4 isomerase and 11-hydroxylase were inhibited by gossypol, but not 21-hydroxylase. Using intact human adrenocortical cells, high doses of gossypol also inhibited the ACTH-stimulated cAMP and cortisol levels. The in vivo corticosterone response to ACTH in rats subjected to chronic gossypol treatment was also found to be reduced. These findings suggest that gossypol has multiple effects on adrenal function. Its effects on membrane microviscosity, adrenal steroidogenesis, cAMP and corticosterone responses to ACTH stimulation probably occur through a generalized membrane effect.

scholarly journals Effects of oleic acid

2015 ◽  
Vol 2 (1) ◽  
pp. 125-132
Author(s):  
Kayihan Karacor ◽  
Meryem Cam
Keyword(s):  
Fatty Acids ◽  
Oleic Acid ◽  
Unsaturated Fatty Acids ◽  
Oil Composition ◽  
Phagocytic Capacity ◽  
Beneficial Effects ◽  
High Concentrations ◽  
Negative Impacts ◽  
Neu Oncogene

Content of fatty diet plays a significant role in the development and progression of chronic diseases. Generally, it is accepted that unsaturated fatty acids are beneficial. According to literature review, oleic acid (C18:1n-9) has positive impacts on various tissues in general and has negative impacts rarely. Olive oil composition includes high amount oleic acid. Considering of the effects of oleic acid on the cardiovascular system, it was determined that decreasing of the myocardial infarction rate, platelet aggregation and secretion of TXA2, plus reduce of the systolic blood pressure. LDL cholesterol was decreased. In terms of effects on the liver, while some studies suggest that oleic acid has beneficial effects, unlike other studies proved that exposed to oleic acid of hepatocytes induce ER (endoplasmic reticulum) stress in long - term period. The several studies which were investigating the efficacy of the oleic acid on the tumor tissue proved that OA increased to hepato-tumorigenesis in vivo as a potential. On te other hand, another research showed that oleic acid blocked the action of HER-2 / neu oncogene that led to breast cancer. Although some researchers reported that OA develop neutrophil phagocytic capacity and candidacidal activity, other researchers point out that these fatty acids didn’t cause any changes on bactericidal activity and fatty acids caused moderate decreases on phagocytosis and chemotaxis only in extremely high concentrations, and they suppressed to T lymphocytes. Although, most of studies have indicated to beneficial effects of oleic acids, also the adverse effects of oleic acid have been reported in a few studies. This situation requires further researches for detail information about oleic acid

Mechanisms of dorsal-ventral patterning in noggin-induced neural tissue

Development ◽  
1997 ◽  
Vol 124 (12) ◽  
pp. 2477-2488 ◽  
Author(s):  
A.K. Knecht ◽  
R.M. Harland
Keyword(s):  
Neural Tissue ◽  
Bmp Signaling ◽  
Cell Interactions ◽  
Dependent Manner ◽  
Low Doses ◽  
Morphogenetic Protein ◽  
High Doses ◽  
Dose Dependent ◽  
Cell Cell

We have investigated mechanisms of dorsal-ventral patterning of neural tissue, using Xenopus ectoderm neuralized by noggin protein. This tissue appears to be patterned dorsoventrally; cp1-1, a gene expressed in the dorsal brain, and etr-1, a gene largely excluded from the dorsal brain, are expressed in separate territories in noggin-treated explants (Knecht, A. K., Good, P. J., Dawid, I. B. and Harland, R. M. (1995) Development 121, 1927–1936). Here we show further evidence that this pattern represents a partial dorsal-ventral organization. Additionally, we test two mechanisms that could account for this pattern: a dose-dependent response to a gradient of noggin protein within the explant, and regulative cell-cell interactions. We show that noggin exhibits concentration-dependent effects, inducing cp1-1 at low doses but repressing it at high doses. Since noggin acts by antagonizing Bone Morphogenetic Protein (BMP) signaling, this result suggests that BMPs also may act in a dose-dependent manner in vivo. However, in the absence of a noggin gradient, regulative cell-cell interactions can also pattern the tissue. Such regulation is facilitated by increased motility of noggin-treated cells. Finally, the response of cells to both of these patterning mechanisms is ultimately controlled by a third process, the changing competence of the responding tissue.

High-Dose Calcitriol Modulates the Expression and Activity of Tissue Factor and Thrombomodulin in Tumor Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 921-921
Author(s):  
Enriqueta Coll-Sangrona ◽  
Ali Amirkhosravi ◽  
Alshad S. Lalani ◽  
Liza Robles ◽  
Hina Desai ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Endothelial Cells ◽  
Tumor Cells ◽  
High Dose ◽  
Dependent Manner ◽  
High Concentrations ◽  
Dose Dependent ◽  
A549 Lung

Abstract Calcitriol, the hormonally-active metabolite of Vitamin D3, plays critical roles in calcium homeostasis, cell growth and differentiation, and immunoregulation. The anti-tumor activities of high-dose calcitriol have been demonstrated in a variety of preclinical models of solid tumors, leukemias and lymphomas. Recently, a new dose-intense formulation of calcitriol, termed DN-101 (Asentar™), was developed specifically for cancer therapy which allows for supraphysiological concentrations of calcitriol to be safely delivered in vivo to patients with cancer. In a recent Phase 2 clinical trial, DN-101 significantly increased overall survival and also reduced the incidence of thromboembolic events in men with androgen-independent prostate cancer receiving docetaxel-based chemotherapy. Based on previous observations we hypothesized that calcitriol’s anti-thrombotic effects in vivo may be due to the downregulation of Tissue Factor (TF) antigen and activity and/or upregulation of Thrombomodulin (TM). To test this hypothesis, we incubated A549 lung carcinoma, A375-C15 metastatic melanoma, THP-1 monocytic leukemia, and Eahy926 endothelial cells with increasing concentrations of calcitriol for 24 hrs. For TF induction, tumor cells were stimulated with TNFα for 5 hrs and activity was measured by a clotting assay and a thrombin generation assay (TGA). TM activity was measured by a chromogenic assay. TF and TM surface antigen were assessed by flow cytometry. Calcitriol prevented the induction of TF in TNFα-stimulated THP-1 cells in a dose-dependent manner (from 33% at 1 nM to 94% at 100 nM) as evidenced by a prolongation of plasma clotting time, a decrease in endogenous thrombin potential (ETP), and a reduction of surface TF antigen. In addition, the activity and surface expression of TM on THP-1 cells was increased significantly (40% and 3-fold respectively, P < 0.01) following 100 nM calcitriol treatment. Similarly, in TNFα-stimulated melanoma cells, calcitriol prevented the induction of TF activity (from 26% at 1 nM to 60% at 1 μM) and expression in a dose-dependent manner. High-dose calcitriol treatment also increased melanoma cell TM activity between 8% and 62%. In contrast, constitutively expressed TF activity and antigen were less affected by calcitriol in A549 lung carcinoma cells (12 to 28% reduction at concentrations between 1–100 nM) whilst TM activity and antigen were unaffected. In comparison to the tumor cells, calcitriol had no significant effect on TM or TF activity or antigen in TNFα-stimulated EAhy926 endothelial cells. In conclusion, we have demonstrated that high concentrations of calcitriol inhibit the induction of surface TF expression and upregulates TM in multiple tumor cell lines in vitro. The degree of the inhibition is proportional to the extent of TF induction by TNF-α. These in vitro results provide further support for the anticoagulant properties associated with high concentrations of calcitriol and may provide a rationale for understanding the lower incidence of thromboembolic complications observed in patients with metastatic prostate cancer treated with DN-101.

scholarly journals Effects of sublethal doses of gossypol on haematological properties and biochemical metabolites of male rabbit

2019 ◽  
Vol 27 (4) ◽  
pp. 237
Author(s):  
T.A. Ramadan ◽  
A.M. Rashad
Keyword(s):  
Fatty Acids ◽  
Blood Plasma ◽  
Unsaturated Fatty Acids ◽  
Saturated Fatty Acids ◽  
Recovery Period ◽  
High Dose ◽  
Dependent Manner ◽  
Male Rabbit ◽  
Sublethal Doses ◽  
Dose Dependent

The purpose of this study was to investigate the effects of two sublethal doses of gossypol (GOS) (4 and 20 mg/kg of body weight), administered every other day, on some haematological, biochemical, enzymatic and electrolytic properties and amino and fatty acids in male rabbit blood plasma. The experiment lasted for 16 wk and included two phases: 1) administration period; rabbits were given the experimental doses of GOS for 8 wk; and 2) recovery period; rabbits were allowed 8 wk for complete withdrawal of drugs from the plasma. Results showed that low levels of gossypol increased (<em>P</em>&lt;0.01) haemoglobin, mean corpuscular haemoglobin and white blood cells compared to control. Plasma total protein was increased (<em>P</em>&lt;0.01) by the low GOS dose in both experimental phases. Likewise, glucose concentration was increased (<em>P</em>&lt;0.01) by the high GOS dose during the recovery period. Aspartate aminotransferase and alanine aminotransferase enzymes were increased (<em>P</em>&lt;0.01) by the high dose of GOS treatment only. Low GOS dose increased (<em>P</em>&lt;0.01) blood plasma Na+ concentration in the recovery period only. Results revealed that total essential amino acids (EAA), and EAA/non-EAA ratio were not affected in a dose-dependent manner during the treatment phase expect for plasma proline, which was increased along with non-EAA (<em>P</em>&lt;0.01) by high GOS dose. Additionally, GOS administration did not affect total unsaturated fatty acids (USFA), total saturated fatty acids (SFA) and SFA/USFA ratio in a dose-dependent manner. In conclusion, Gossypol treatment affected rabbit haematological parameters and biochemical properties of blood plasma in a dose-dependent manner.

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