scholarly journals The Synergistic Effect of Corticosteroids and Mycophenolic Acid on Chemokines in Orbital Cells From Patients With Graves’ Ophthalmopathy

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A845-A846
Author(s):  
Poupak Fallahi ◽  
Silvia Martina Ferrari ◽  
Francesca Ragusa ◽  
Giusy Elia ◽  
Ilaria Ruffilli ◽  
...  
Keyword(s):  
Synergistic Effect ◽  
Mycophenolic Acid ◽  
Response Rate ◽  
Primary Cultures ◽  
Inhibitory Effect ◽  
Graves Ophthalmopathy ◽  
Th2 Chemokines ◽  
Th1 And Th2 ◽  
Ifnγ And Tnfα

Abstract In recent studies, an improvement of the response rate to therapy has been reported with corticosteroids and mycophenolic acid in patients with Graves’ ophthalmopathy (GO). In GO, retro-orbital cells (fibroblasts, preadipocytes, and extraocular muscle cells) secrete Th1 and Th2 chemokines stimulated by cytokines. Until now, no studies are present in literature regarding the effect of corticosteroids and mycophenolic acid on the secretion of chemokines in GO orbital cells. For this reason, the effect of increasing concentrations of mycophenolic acid or corticosteroids on the secretion of either the Th1 (CXCL10) and Th2 (CCL2) chemokines was tested in primary cultures of myoblasts, preadipocytes and fibroblasts obtained from GO patients. CXCL10 was undetectable in the supernatants of the retro-orbital cells in primary cultures; its release was induced dose-dependently by IFNγ, while TNFα alone had no effect. On the contrary CCL2 release (that was produced in low amounts basally) was dose-dependently induced by TNFα, while IFNγ alone had no effect. In both cases the combination of TNFα and IFNγ had a significant synergistic effect on CXCL10 and CCL2 secretion. The release of these chemokines was dose-dependently inhibited by increasing concentrations of mycophenolic acid, or corticosteroids (in a pharmacological range), in presence of IFNγ and TNFα stimulation. Moreover, the association of corticosteroids and mycophenolic acid (in presence of IFNγ and TNFα) had a stronger inhibitory effect on the chemokines release. In conclusion, in GO orbital cells, mycophenolic acid and/or corticosteroids (in a pharmacological range) have an inhibitory role on the secretion of both Th1 (CXCL10) and Th2 (CCL2) chemokines. This suggests a possible therapeutic role of these drugs.

scholarly journals β (CCL2) and α (CXCL10) chemokine modulations by cytokines and peroxisome proliferator-activated receptor-α agonists in Graves' ophthalmopathy

2012 ◽  
Vol 213 (2) ◽  
pp. 183-191 ◽  
Author(s):  
Alessandro Antonelli ◽  
Silvia Martina Ferrari ◽  
Silvia Frascerra ◽  
Ilaria Ruffilli ◽  
Cinzia Pupilli ◽  
...  
Keyword(s):  
Interferon Γ ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Graves Ophthalmopathy ◽  
Primary Fibroblasts ◽  
Pparγ Agonists ◽  
Factor Α ◽  
Orbital Fibroblasts ◽  
Ifnγ And Tnfα

No data are present in the literature about the effect of cytokines on the prototype β chemokine (C-C motif) ligand 2 (CCL2) or of peroxisome proliferator-activated receptor α (PPARα (PPARA)) activation on CCL2 and CXCL10 chemokines secretion in fibroblasts or preadipocytes in Graves' ophthalmopathy (GO). We have tested the effect of interferon γ (IFNγ (IFNG)) and tumor necrosis factor α (TNFα) on CCL2, and for comparison on the prototype α chemokine (C-X-C motif) ligand 10 (CXCL10), and the possible modulatory role of PPARα activation on secretion of these chemokines in normal and GO fibroblasts or preadipocytes in primary cell cultures. This study shows that IFNγ alone, or in combination with TNFα, stimulates the secretion of CCL2 in primary orbital fibroblasts or preadipocytes from patients with GO at levels similar to those observed in controls. IFNγ and TNFα also stimulated CXCL10 chemokine secretion as expected. The presence of PPARα and PPARγ (PPARG) in primary fibroblasts or preadipocytes of patients with GO has been confirmed. PPARα activators were able to inhibit the secretion of CXCL10 and CCL2, while PPARγ activators were confirmed to be able to inhibit CXCL10 but had no effect on CCL2. PPARα activators were stronger inhibitors of chemokine secretions than PPARγ agonists. In conclusion, CCL2 and CXCL10 are modulated by IFNγ and TNFα in GO. PPARα activators inhibit the secretion of the main prototype α (CXCL10) and β (CCL2) chemokines in GO fibroblasts or preadipocytes, suggesting that PPARα may be involved in the modulation of the immune response in GO.

A probable role of dihydropyridine receptors in repression of Ca2+ sparks demonstrated in cultured mammalian muscle

2006 ◽  
Vol 290 (2) ◽  
pp. C539-C553 ◽  
Author(s):  
Jingsong Zhou ◽  
Jianxun Yi ◽  
Leandro Royer ◽  
Bradley S. Launikonis ◽  
Adom González ◽  
...  
Keyword(s):  
Ryanodine Receptors ◽  
Critical Role ◽  
Primary Cultures ◽  
Inhibitory Effect ◽  
Wild Type ◽  
Dihydropyridine Receptors ◽  
Skeletal Muscle Contraction ◽  
Probable Role ◽  
Emission Ratios

To activate skeletal muscle contraction, action potentials must be sensed by dihydropyridine receptors (DHPRs) in the T tubule, which signal the Ca2+ release channels or ryanodine receptors (RyRs) in the sarcoplasmic reticulum (SR) to open. We demonstrate here an inhibitory effect of the T tubule on the production of sparks of Ca2+ release. Murine primary cultures were confocally imaged for Ca2+ detection and T tubule visualization. After 72 h of differentiation, T tubules extended from the periphery for less than one-third of the myotube radius. Spontaneous Ca2+ sparks were found away from the region of cells where tubules were found. Immunostaining showed RyR1 and RyR3 isoforms in all areas, implying inhibition of both isoforms by a T tubule component. To test for a role of DHPRs in this inhibition, we imaged myotubes from dysgenic mice ( mdg) that lack DHPRs. These exhibited T tubule development similar to that of normal myotubes, but produced few sparks, even in regions where tubules were absent. To increase spark frequency, a high-Ca2+ saline with 1 mM caffeine was used. Wild-type cells in this saline plus 50 μM nifedipine retained the topographic suppression pattern of sparks, but dysgenic cells in high-Ca2+ saline did not. Shifted excitation and emission ratios of indo-1 in the cytosol or mag-indo-1 in the SR were used to image [Ca2+] in these compartments. Under the conditions of interest, wild-type and mdg cells had similar levels of free [Ca2+] in cytosol and SR. These data suggest that DHPRs play a critical role in reducing the rate of spontaneous opening of Ca2+ release channels and/or their susceptibility to Ca2+-induced activation, thereby suppressing the production of Ca2+ sparks.

A vH+-ATPase is present in cultured sheep ruminal epithelial cells

2006 ◽  
Vol 291 (6) ◽  
pp. G1171-G1179 ◽  
Author(s):  
Benjamin Etschmann ◽  
Katrin Sophie Heipertz ◽  
Annabelle von der Schulenburg ◽  
Monika Schweigel
Keyword(s):  
Epithelial Cells ◽  
Primary Cultures ◽  
Selective Inhibition ◽  
Protein Band ◽  
Inhibitory Effect ◽  
B Subunit ◽  
Initial Ph ◽  
Acid Load ◽  
Acid Loading

In this study, the existence and functional activity of a vacuolar-type H+-ATPase (vH+-ATPase) was explored in primary cultures of sheep ruminal epithelial cells (REC). The mRNA transcripts of the E and B subunits of vH+-ATPase were detectable in RNA from REC samples by RT-PCR. Immunoblotting of REC protein extractions with antibodies directed against the B subunit of yeast vH+-ATPase revealed a protein band of the expected size (60 kDa). Using the fluorescent indicator BCECF and selective inhibitors (foliomycin, HOE 694, S3226), the contribution of vH+-ATPase and Na+/H+ exchanger (NHE) subtype 1 and 3 activity to the regulation of intracellular pH (pHi) was determined in nominally HCO3−-free, HEPES-buffered NaCl medium containing 20 mM of the short-chain fatty acid butyrate as well as after reduction of the extracellular Cl− concentration ([Cl−]e) from 136 to 36 mM. The initial pHi of REC was 7.4 ± 0.1 in nominally HCO3−-free, HEPES-buffered NaCl medium and 7.0 ± 0.1 after acid loading with butyrate. Selective inhibition of the vH+-ATPase with foliomycin decreased pHi by 0.19 ± 0.03 pH units. On the basis of the observed decreases in pHi resulting from inhibition of vH+-ATPase as well as of subtypes 1 and 3 of NHE, vH+-ATPase activity appears to account for ∼30% of H+ extrusion, whereas the activities of NHE subtypes 3 and 1 account for 20 and 50% of H+ extrusion, respectively. Lowering of [Cl−]e induced a pHi decrease (−0.51 ± 0.03 pH units) and impaired pHi recovery from butyrate-induced acid load. Moreover, reduction of [Cl−]e abolished the inhibitory effect of foliomycin and markedly reduced the HOE 694- and S3226-sensitive components of pHi, indicating a role of Cl− in the function of these H+ extrusion mechanisms. We conclude that a vH+-ATPase is expressed in ovine REC and plays a considerable role in the pHi regulation of these cells.

scholarly journals Generation of Th1 and Th2 Chemokines by Human Eosinophils: Evidence for a Critical Role of TNF-α

2007 ◽  
Vol 179 (7) ◽  
pp. 4840-4848 ◽  
Author(s):  
Lin Ying Liu ◽  
Mary Ellen Bates ◽  
Nizar N. Jarjour ◽  
William W. Busse ◽  
Paul J. Bertics ◽  
...  
Keyword(s):  
Critical Role ◽  
Tnf Α ◽  
Th2 Chemokines ◽  
Th1 And Th2

Effect of Dipyridamole on Spontaneous Platelet Aggregation in Whole Blood Decreases with the Time After Venepuncture: Evidence for the Role of ADP

1987 ◽  
Vol 58 (02) ◽  
pp. 744-748 ◽  
Author(s):  
A R Saniabadi ◽  
G D O Lowe ◽  
J C Barbenel ◽  
C D Forbes
Keyword(s):  
Platelet Aggregation ◽  
Correlation Coefficient ◽  
Whole Blood ◽  
Blood Platelet ◽  
Inhibitory Effect ◽  
Time Interval ◽  
Adp Receptor ◽  
Spontaneous Platelet Aggregation

SummarySpontaneous platelet aggregation (SPA) was studied in human whole blood at 3, 5, 10, 20, 30, 40 and 60 minutes after venepuncture. Using a whole blood platelet counter, SPA was quantified by measuring the fall in single platelet count upon rollermixing aliquots of citrated blood at 37° C. The extent of SPA increased with the time after venepuncture, with a correlation coefficient of 0.819. The inhibitory effect of dipyridamole (Dipy) on SPA was studied: (a) 10 μM at each time interval; (b) 0.5-100 μM at 3 and 30 minutes and (c) 15 μM in combination with 100 μM adenosine, 8 μM 2-chloroadenosine (2ClAd, an ADP receptor blocker) and 50 μM aspirin. There was a rapid decrease in the inhibitory effect of Dipy with the time after venepuncture; the correlation coefficient was -0.533. At all the concentrations studied, Dipy was more effective at 3 minutes than at 30 minutes after venepuncture. A combination of Dipy with adenosine, 2ClAd or aspirin was a more effective inhibitor of SPA than either drug alone. However, when 15 μM Dipy and 10 μM Ad were added together, the inhibitory effect of Dipy was not increased significantly, suggesting that Dipy inhibits platelet aggregation independent of Ad. The increase in SPA with the time after venepuncture was abolished when blood was taken directly into the anticoagulant containing 5 μM 2ClAd. It is suggested that ADP released from the red blood cells is responsible for the increased platelet aggregability with the time after venepuncture and makes a serious contribution to the artifacts of in vitro platelet function studies.

Characteristics Of The Structure Formation Of Gypsum Binder Modified With Zinc Hydrosilicates

2020 ◽  
pp. 40-46
Keyword(s):  
Synergistic Effect ◽  
Physicochemical Properties ◽  
Structure Formation ◽  
Silicic Acid ◽  
Chemical Properties ◽  
Crystal Formation ◽  
Ability To Act ◽  
Chemical Factors ◽  
Sorption Characteristics

The authors' methodic for assessing the role of chemical and physic-chemical factors during the structure formation of gypsum stone is presented in the article. The methodic is also makes it possible to reveal the synergistic effect and to determine the ranges of variation of controls factors that ensure maximum values of such effect. The effect of a micro-sized modifier based on zinc hydro-silicates on the structure formation of building gypsum is analyzed and corresponding dependencies are found. It is shown that effects of influence of modifier on the properties of gypsum compositions are determined by chemical properties of modifier. Among the mentioned properties are sorption characteristics (which depend on the amount of silicic acid and its state) and physicochemical properties - the ability to act as a substrate during crystal formation. The proposed method can also be extended to other binding substances and materials. This article contributes to the understanding of the processes that occur during the structure formation of composites, which will make it possible to control the structure formation in the future, obtaining materials with a given set of properties.

Effect of human galanin on the response of circulating catecholamines to hypoglycemia in man

1995 ◽  
Vol 133 (6) ◽  
pp. 723-728 ◽  
Author(s):  
Ettore C degli Uberti ◽  
Maria R Ambrosio ◽  
Marta Bondanelli ◽  
Giorgio Transforini ◽  
Alberto Valentini ◽  
...  
Keyword(s):  
Heart Rate ◽  
Healthy Subjects ◽  
Sympathetic Nerve Activity ◽  
Heart Rate Response ◽  
Statistical Significance ◽  
Inhibitory Effect ◽  
Amino Acid Residues ◽  
Nerve Activity ◽  
Receptor Stimulation

degli Uberti EC, Ambrosio MR, Bondanelli M, Trasforini G, Valentini A, Rossi R, Margutti A, Campo M. Effect of human galanin on the response of circulating catecholamines to hypoglycemia in man. Eur J Endocrinol 1995;133:723–8. ISSN 0804–4643 Human galanin (hGAL) is a neuropeptide with 30 amino acid residues that has been found in the peripheral and central nervous system, where it often co-exists with catecholamines. In order to clarify the possible role of hGAL in the regulation of sympathoadrenomedullary function, the effect of a 60 min infusion of hGAL (80 pmol·kg−1 · min−1) on plasma epinephrine and norepinephrine responses to insulin-induced hypoglycemia in nine healthy subjects was investigated. Human GAL administration significantly reduced both the release of basal norepinephrine and the response to insulin-induced hypoglycemia, whereas it attenuated the epinephrine response by 26%, with the hGAL-induced decrease in epinephrine release failing to achieve statistical significance. Human GAL significantly increased the heart rate in resting conditions and clearly exaggerated the heart rate response to insulin-induced hypoglycemia, whereas it had no effect on the blood pressure. We conclude that GAL receptor stimulation exerts an inhibitory effect on basal and insulin-induced hypoglycemia-stimulated release of norepinephrine. These findings provide further evidence that GAL may modulate sympathetic nerve activity in man but that it does not play an important role in the regulation of adrenal medullary function. Ettore C degli Uberti, Chair of Endocrinology, University of Ferrara, Via Savonarola 9, I-44100 Ferrara, Italy

Biological role of AKT, and regulation of AKT signaling pathway by thymoquinone: perspectives in cancer therapeutics

2020 ◽  
Vol 20 ◽  
Author(s):  
Md. Junaid ◽  
Yeasmin Akter ◽  
Syeda Samira Afrose ◽  
Mousumi Tania ◽  
Md. Asaduzzaman Khan
Keyword(s):  
Clinical Trials ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Inhibitory Effect ◽  
Akt Signaling ◽  
Review Article ◽  
Therapeutic Drug ◽  
Akt Signaling Pathway ◽  
Anti Cancer

Background: AKT/PKB is an important enzyme with numerous biological functions, and its overexpression is related to the carcinogenesis. AKT stimulates different signaling pathways that are downstream of activated tyrosine kinases and phosphatidylinositol 3-kinase, hence functions as an important target for anti-cancer drugs. Objective: In this review article, we have interpreted the role of AKT signaling pathways in cancer and natural inhibitory effect of Thymoquinone (TQ) in AKT and its possible mechanism. Method: We have collected the updated information and data on AKT, their role in cancer and inhibitory effect of TQ in AKT signaling pathway from google scholar, PubMed, Web of Science, Elsevier, Scopus and many more. Results: There are many drugs already developed, which can target AKT, but very few among them have passed clinical trials. TQ is a natural compound, mainly found in black cumin, which has been found to have potential anti-cancer activities. TQ targets numerous signaling pathways, including AKT, in different cancers. In fact, many studies revealed that AKT is one of the major targets of TQ. The preclinical success of TQ suggests its clinical studies on cancer. Conclusion: This review article summarizes the role of AKT in carcinogenesis, its potent inhibitors in clinical trials, and how TQ acts as an inhibitor of AKT and TQ’s future as a cancer therapeutic drug.

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