Magnesium orotate elicits acute cardioprotection at reperfusion in isolated and in vivo rat hearts

2013 ◽  
Vol 91 (2) ◽  
pp. 108-115 ◽  
Author(s):  
Silvia N. Mirica ◽  
Oana M. Duicu ◽  
Simona L. Trancota ◽  
Ovidiu Fira-Mladinescu ◽  
Denis Angoulvant ◽  
...  
Keyword(s):  
Beneficial Effect ◽  
Orotic Acid ◽  
Myocardial Function ◽  
Ex Vivo ◽  
Control Group ◽  
Mptp Opening ◽  
Rat Hearts ◽  
Magnesium Orotate

Orotic acid and its salts chronically administered have been shown to significantly improve cardiac function in pathological settings associated with ischemia–reperfusion (I/R) injury. The aim of our study was to investigate the effect of magnesium orotate (Mg-Or) administration at the onset of post-ischemic reperfusion on myocardial function and infarct size (IS). Ex-vivo experiments performed on isolated perfused rat hearts were used to compare Mg-Or administration with a control group (buffer treated), ischemic post-conditioning, orotic acid treatment, and MgCl2 treatment. Mg-Or administration was also investigated in an in-vivo model of regional I/R performed in rats undergoing reversible coronary ligation. The effect of Mg-Or on mitochondrial permeability transition pore (mPTP) opening after I/R was investigated in vitro to gain mechanistic insights. Both ex-vivo and in-vivo experiments showed a beneficial effect from Mg-Or administration at the onset of reperfusion on myocardial function and IS. In-vitro assays showed that Mg-Or significantly delayed mPTP opening after I/R. Our data suggest that Mg-Or administered at the very onset of reperfusion may preserve myocardial function and reduce IS. This beneficial effect may be related to a significant reduction of mPTP opening, a usual trigger of cardiac cell death following I/R.

Beneficial effect of 3,4,5,6-tetrahydroxyxanthone on dyslipidemia in apolipoprotein E-deficient mice

2008 ◽  
Vol 86 (12) ◽  
pp. 815-826 ◽  
Author(s):  
Hong-Bo Xiao ◽  
Zhi-Liang Sun ◽  
Xiang-Yang Lu ◽  
Da-Zhi Li ◽  
Jian-Ping Xu ◽  
...  
Keyword(s):  
Beneficial Effect ◽  
Apolipoprotein E ◽  
Density Lipoprotein ◽  
Control Group ◽  
Elevated Expression ◽  
Plasma High Density ◽  
Adipose Tissue Lipoprotein Lipase ◽  
Xanthone Compound

Previous investigations have shown that decreased expression of angiopoietin-like protein 3 (Angptl3) is protective against dyslipidemia in atherosclerosis. The present study was conducted to test the effect of 3,4,5,6-tetrahydroxyxanthone, a xanthone compound, on dyslipidemia in apolipoprotein E-deficient (ApoE−/−) mice. Forty mice were randomly divided into 4 groups (n = 10): control group (C57BL/6J mice), ApoE−/− mice group, and two groups of ApoE−/− mice treated with 3,4,5,6-tetrahydroxyxanthone (10 or 30 mg/kg per day). Eight weeks after treatment, lipid levels in the blood and liver, expression of hepatic Angptl3, and adipose tissue lipoprotein lipase (LPL) were determined. Treatment with 3,4,5,6-tetrahydroxyxanthone (10 or 30 mg/kg) significantly decreased plasma and hepatic total cholesterol and triglyceride concentrations, increased plasma high-density lipoprotein cholesterol, and significantly downregulated expression of Angptl3 mRNA and protein concomitantly with upregulated expression of LPL mRNA. In addition, T0901317 (a liver X receptor ligand) caused elevated expression of hepatic Angptl3 mRNA and protein, and the effect of T0901317 was also abrogated by 3,4,5,6-tetrahydroxyxanthone in vivo and in vitro. The present results suggest that the beneficial effect of 3,4,5,6-tetrahydroxyxanthone on dyslipidemia may be related to reduced expression of Angptl3.

scholarly journals The Diverse Potential of Gluten from Different Durum Wheat Varieties in Triggering Celiac Disease: A Multilevel In Vitro, Ex Vivo and In Vivo Approach

Nutrients ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3566
Author(s):  
Federica Gaiani ◽  
Sara Graziano ◽  
Fatma Boukid ◽  
Barbara Prandi ◽  
Lorena Bottarelli ◽  
...  
Keyword(s):  
Immune Response ◽  
Celiac Disease ◽  
Durum Wheat ◽  
Ex Vivo ◽  
Diet Group ◽  
Control Group ◽  
Wheat Varieties ◽  
Before And After

The reasons behind the increasing prevalence of celiac disease (CD) worldwide are still not fully understood. This study adopted a multilevel approach (in vitro, ex vivo, in vivo) to assess the potential of gluten from different wheat varieties in triggering CD. Peptides triggering CD were identified and quantified in mixtures generated from simulated gastrointestinal digestion of wheat varieties (n = 82). Multivariate statistics enabled the discrimination of varieties generating low impact on CD (e.g., Saragolla) and high impact (e.g., Cappelli). Enrolled subjects (n = 46) were: 19 healthy subjects included in the control group; 27 celiac patients enrolled for the in vivo phase. Celiacs were divided into a gluten-free diet group (CD-GFD), and a GFD with Saragolla-based pasta group (CD-Sar). The diet was followed for 3 months. Data were compared between CD-Sar and CD-GFD before and after the experimental diet, demonstrating a limited ability of Saragolla to trigger immunity, although not comparable to a GFD. Ex vivo studies showed that Saragolla and Cappelli activated immune responses, although with great variability among patients. The diverse potential of durum wheat varieties in triggering CD immune response was demonstrated. Saragolla is not indicated for celiacs, yet it has a limited potential to trigger adverse immune response.

T-cell redirected killing and cure of pancreatic and gastric cancer xenografts by targeting Trop-2.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 262-262
Author(s):  
David M. Goldenberg ◽  
Edmund A. Rossi ◽  
Diane L Rossi ◽  
Thomas M. Cardillo ◽  
Chien-Hsing Chang
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Ex Vivo ◽  
Control Group ◽  
Calcium Signal ◽  
Target Cells ◽  
Normal Tissues

262 Background: Trop-2 [also called tumor-associated calcium signal transducer 2 (TACSTD2), EGP-1 (epithelial glycoprotein-1), GA733-1, or M1S1]is a 35 kDa transmembrane glycoprotein that is overexpressed relative to normal tissues in a variety of human cancers, including pancreatic and gastric carcinomas, where increased expression correlates with poor prognosis. Trop-2 appears to be more tumor-specific than the related molecule, EpCAM (Trop-1). MT110, the EpCAM antibody x CD3 bispecific T-cell engager (BiTE), is currently undergoing a Phase I study in various solid tumors, including lung, gastric, colorectal, breast, prostate, and ovarian cancers. We produced a similar T-cell redirecting bispecific tandem scFv, E1-3, using the variable domains of hRS7 (humanized anti-Trop-2 mAb) and Okt-3 (anti-CD3 mAb). Methods: T-cell activation, cytokine induction and cytotoxicity were evaluated ex vivo using PBMCs or purified T cells with human pancreatic (Capan-1 and BxPC3) and gastric (NCI-N87) cancer cell lines as target cells. In vivo activity was assayed with NCI-N87 xenografts that were inoculated s.c. in a mixture with twice the number of human PBMCs and matrigel. Results: In the presence of target cells and PBMCs, E1-3 potently induced T-cell activation, proliferation, and dose-dependent cytokine production of IL-2 (>2 ng/mL), IL-6 (>1 ng/mL), IL-10 (>7 ng/mL), TNF-α (>1 ng/mL) and IFN-γ (>50 ng/mL). In vitro, E1-3 mediated a highly potent T-cell lysis of BxPC3 [IC50=0.09(±0.04) pM], Capan-1 [IC50=1.2(±1.1) pM] and NCI-N87 [IC50=1.2(±1.2) pM] target cells. In vivo, two 50-µg doses of E1-3 given three days apart cured all of the mice (N=8) bearing NCI-N87 xenografts (P=0.0005; Log-Rank). Tumors in the control group (PBMCs only) reached the endpoint (TV>1 cm3) with a median of 39.5 days. All mice remained tumor-free in the E1-3 group at 78 days. Conclusions: Trop-2 is an attractive target for T-cell-mediated killing of pancreatic, gastric and other epithelial cancers.

scholarly journals Tegavivint and the β-Catenin/ALDH Axis in Chemotherapy-Resistant and Metastatic Osteosarcoma

2019 ◽  
Vol 111 (11) ◽  
pp. 1216-1227 ◽  
Author(s):  
Motonari Nomura ◽  
Nino Rainusso ◽  
Yi-Chien Lee ◽  
Brian Dawson ◽  
Cristian Coarfa ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Cell Lines ◽  
Ex Vivo ◽  
Statistical Tests ◽  
Control Group ◽  
Gene And Protein Expression ◽  
Relative Mrna Expression ◽  
Pdx Models

Abstract Background The Wnt/β-catenin pathway is closely associated with osteosarcoma (OS) development and metastatic progression. We investigated the antitumor activity of Tegavivint, a novel β-catenin/transducin β-like protein 1 (TBL1) inhibitor, against OS employing in vitro, ex vivo, and in vivo cell line and patient-derived xenograft (PDX) models that recapitulate high risk disease. Methods The antitumor efficacy of Tegavivint was evaluated in vitro using established OS and PDX-derived cell lines. Use of an ex vivo three-dimensional pulmonary metastasis assay assessed targeting of β-catenin activity during micro- and macrometastatic development. The in vivo activity of Tegavivint was evaluated using chemoresistant and metastatic OS PDX models. Gene and protein expression were quantified by quantitative Reverse transcription polymerase chain reaction or immunoblot analysis. Bone integrity was determined via microCT. All statistical tests were two-sided. Results Tegavivint exhibited antiproliferative activity against OS cells in vitro and actively reduced micro- and macrometastatic development ex vivo. Multiple OS PDX tumors (n = 3), including paired patient primary and lung metastatic tumors with inherent chemoresistance, were suppressed by Tegavivint in vivo. We identified that metastatic lung OS cell lines (n = 2) exhibited increased stem cell signatures, including enhanced concomitant aldehyde dehydrogenase (ALDH1) and β-catenin expression and downstream activity, which were suppressed by Tegavivint (ALDH1: control group, mean relative mRNA expression = 1.00, 95% confidence interval [CI] = 0.68 to 1.22 vs Tegavivint group, mean = 0.011, 95% CI = 0.0012 to 0.056, P < .001; β-catenin: control group, mean relative mRNA expression = 1.00, 95% CI = 0.71 to 1.36 vs Tegavivint group, mean = 0.45, 95% CI = 0.36 to 0.52, P < .001). ALDH1high PDX-derived lung OS cells, which demonstrated enhanced metastatic potential compared with ALDHlow cells in vivo, were sensitive to Tegavivint. Toxicity studies revealed decreased bone density in male Tegavivint-treated mice (n = 4 mice per group). Conclusions Tegavivint is a promising therapeutic agent for advanced stages of OS via its targeting of the β-catenin/ALDH1 axis.

scholarly journals Targeted delivery of pentagalloyl glucose inhibits matrix metalloproteinase activity and preserves elastin in emphysematous lungs

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Vaideesh Parasaram ◽  
Xiaoying Wang ◽  
Pantrika Krisanarungson ◽  
Narendra Vyavahare
Keyword(s):  
Matrix Metalloproteinase ◽  
Tidal Volume ◽  
Targeted Delivery ◽  
Ex Vivo ◽  
Lung Damage ◽  
Control Group ◽  
Elastin Degradation ◽  
Pentagalloyl Glucose

Abstract Background Elastin degradation has been established as one of the driving factors of emphysema. Elastin-derived peptides (EDPs) are shown to act as a chemoattractant for monocytes. Effectively shielding elastin from elastolytic damage and regenerating lost elastin are two important steps in improving the mechanical function of damaged lungs. Pentagalloyl glucose (PGG) has been shown to preserve elastin in vascular tissues from elastolytic damage in vivo and aid in elastin deposition in vitro. Methods We created emphysema by elastase inhalation challenge in mice. Albumin nanoparticles loaded with PGG, conjugated with elastin antibody, were delivered to target degraded elastin in lungs. We investigated matrix metalloproteinase-12 activity and lung damage by measuring dynamic compliance and tidal volume changes. Results Ex-vivo experiments demonstrated elastin preservation in PGG treated samples compared to controls. Inhaled nanoparticles conjugated with elastin antibody retained for extended periods in lungs. Further, mice treated with PGG nanoparticles showed a significant suppression of MMP-12 activity measured in the lungs. We observed suppression of emphysema in terms of dynamic lung compliance and tidal volume change compared to the control group. The histological examination further confirmed elastin preservation in the lungs. Conclusion These results demonstrate successful targeted delivery of nanoparticles loaded with PGG to inhibit MMP-12 activity and preserve elastin in the lungs. Such targeted PGG therapy has potential therapeutic use in the management of emphysema.

scholarly journals Biocompatible Dialysis Solutions Preserve Peritoneal Mesothelial Cell and Vessel Wall Integrity. A Case-Control Study on Human Biopsies

2016 ◽  
Vol 36 (2) ◽  
pp. 129-134 ◽  
Author(s):  
Gloria del Peso ◽  
José Antonio Jiménez-Heffernan ◽  
Rafael Selgas ◽  
César Remón ◽  
Marta Ossorio ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Mesothelial Cell ◽  
Cell Loss ◽  
Control Group ◽  
Peritoneal Fibrosis ◽  
Morphological Alterations ◽  
Peritoneal Function

IntroductionChronic exposure to conventional peritoneal dialysis (PD) solutions has been related to peritoneal function alterations in PD patients, and associated with mesothelial cell loss, submesothelial fibrosis, vasculopathy, and angiogenesis. In vitro and ex vivo analyses, as well as studies with animal models, have demonstrated that biocompatible PD solutions attenuate these morphological alterations. Our aim was to confirm the morphological benefits of biocompatible solutions in PD patients.MethodsWe analyzed biopsies from 23 patients treated with biocompatible solutions (study group, SG), and compared them with a control group ( n = 23) treated with conventional solutions (CG), matched for time on PD.ResultsA total of 56.5% of SG patients showed total or partial preservation of mesothelial cells monolayer, in contrast with 26.1% of patients in CG ( p = 0.036). Peritoneal fibrosis was not significantly less frequent in SG patients (47.8% SG vs 69.6% CG; p = 0.13). In patients without previous peritonitis, a significantly lower prevalence of fibrosis was present in SG patients (41.7% SG vs 77.8% CG; p = 0.04). Hyalinizing vasculopathy (HV) was significantly lower in SG (4.3% SG vs 30.4% CG; p = 0.02). Cytokeratin-positive fibroblast-like cells were detected in 10 patients (22%), but the prevalence was not significantly lower in SG. In the univariate regression analysis, the use of biocompatible solutions was associated with mesothelial monolayer integrity ( p = 0.04) and an absence of vasculopathy ( p = 0.04).ConclusionThe present study demonstrates in vivo in human biopsies that biocompatible solutions are better tolerated by the peritoneum in the medium and long term than conventional solutions.

The Role of Polyphenols in the Modulation of Plasma Non-Enzymatic Antioxidant Capacity (NEAC)

2012 ◽  
Vol 82 (3) ◽  
pp. 228-232 ◽  
Author(s):  
Mauro Serafini ◽  
Giuseppa Morabito
Keyword(s):  
Antioxidant Capacity ◽  
Dietary Intervention ◽  
Ex Vivo ◽  
The Body ◽  
Dietary Polyphenols ◽  
Enzymatic Antioxidant ◽  
Endogenous Antioxidant

Dietary polyphenols have been shown to scavenge free radicals, modulating cellular redox transcription factors in different in vitro and ex vivo models. Dietary intervention studies have shown that consumption of plant foods modulates plasma Non-Enzymatic Antioxidant Capacity (NEAC), a biomarker of the endogenous antioxidant network, in human subjects. However, the identification of the molecules responsible for this effect are yet to be obtained and evidences of an antioxidant in vivo action of polyphenols are conflicting. There is a clear discrepancy between polyphenols (PP) concentration in body fluids and the extent of increase of plasma NEAC. The low degree of absorption and the extensive metabolism of PP within the body have raised questions about their contribution to the endogenous antioxidant network. This work will discuss the role of polyphenols from galenic preparation, food extracts, and selected dietary sources as modulators of plasma NEAC in humans.

In-vitro- und In-vivo-Wirkung von Schilddrüsenhormon auf das Wachstum von Neuroblastomzellen

1990 ◽  
Vol 29 (03) ◽  
pp. 120-124
Author(s):  
R. P. Baum ◽  
E. Rohrbach ◽  
G. Hör ◽  
B. Kornhuber ◽  
E. Busse
Keyword(s):  
Cell Differentiation ◽  
Neuroblastoma Cells ◽  
Control Group ◽  
Initial Value ◽  
Initial Rise ◽  
Biphasic Effect ◽  
Contrast Microscopy ◽  
Morphological Sign

The effect of triiodothyronine (T3) on the differentiation of cultured neuroblastoma (NB) cells was studied after 9 days of treatment with a dose of 10-4 M/106 cells per day. Using phase contrast microscopy, 30-50% of NB cells showed formation of neurites as a morphological sign of cellular differentiation. The initial rise of the mitosis rate was followed by a plateau. Changes in cyclic nucleotide content, in the triphosphates and in the activity of the enzyme ornithine decarboxylase (ODC) were assessed in 2 human and 2 murine cell lines to serve as biochemical parameters of the cell differentiation induced by T3. Whereas the cAMP level increased significantly (3 to 7 fold compared with its initial value), the cGMP value dropped to 30 to 50% of that of the control group. ATP and GTP increased about 200%, the ODC showed a decrease of about 50%. The present studies show a biphasic effect of T3 on neuroblastoma cells: the initial rise of mitotic activity is followed by increased cell differentiation starting from day 4 of the treatment.

Significance of Platelet β-Adrenoceptors for Platelet Responses In Vivo and In Vitro

1992 ◽  
Vol 68 (06) ◽  
pp. 687-693 ◽  
Author(s):  
P T Larsson ◽  
N H Wallén ◽  
A Martinsson ◽  
N Egberg ◽  
P Hjemdahl
Keyword(s):  
Ex Vivo ◽  
High Dose ◽  
Platelet Aggregability ◽  
Adrenoceptor Agonist ◽  
Dose Infusion ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Factor Antigen

SummaryThe significance of platelet β-adrenoceptors for platelet responses to adrenergic stimuli in vivo and in vitro was studied in healthy volunteers. Low dose infusion of the β-adrenoceptor agonist isoprenaline decreased platelet aggregability in vivo as measured by ex vivo filtragometry. Infusion of adrenaline, a mixed α- and β-adrenoceptor agonist, increased platelet aggregability in vivo markedly, as measured by ex vivo filtragometry and plasma β-thromboglobulin levels. Adrenaline levels were 3–4 nM in venous plasma during infusion. Both adrenaline and high dose isoprenaline elevated plasma von Willebrand factor antigen levels β-Blockade by propranolol did not alter our measures of platelet aggregability at rest or during adrenaline infusions, but inhibited adrenaline-induced increases in vWf:ag. In a model using filtragometry to assess platelet aggregability in whole blood in vitro, propranolol enhanced the proaggregatory actions of 5 nM, but not of 10 nM adrenaline. The present data suggest that β-adrenoceptor stimulation can inhibit platelet function in vivo but that effects of adrenaline at high physiological concentrations are dominated by an α-adrenoceptor mediated proaggregatory action.

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