Evaluation of the thrombospondin-1 analogue ABT-510 in the APCMin/+ mouse intestinal adenoma model

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13545-13545 ◽  
Author(s):  
D. E. Joyce ◽  
G. Mulji ◽  
L. S. Gutierrez ◽  
F. J. Castellino
Keyword(s):  
Matrix Protein ◽  
Combined Treatment ◽  
Extracellular Matrix Protein ◽  
Rank Test ◽  
Tumor Vascularity ◽  
Angiogenic Switch ◽  
Treatment Groups ◽  
Significant Difference ◽  
Thrombospondin 1 ◽  
Intestinal Adenoma

13545 Background: The extracellular matrix protein Thrombospondin-1 (TSP-1) affects the angiogenic balance in cancer to suppress tumor growth. Exogenous TSP-1 or the peptide derivative ABT-510 (Abbott, Chicago, IL) can reverse this angiogenic switch from adenoma to carcinoma. We evaluated treatment effects of ABT-510 in the APCMin/+ mouse spontaneous intestinal adenoma model. This study determined reduction in intestinal adenoma number after ABT-510 or the combined treatment of ABT-510/bevacizumab (Genentech) compared to no treatment in APCMin/+. Proliferation, vascularity, and dysplasia were also compared. Methods: 90 day old APCMin/+ mice (familial adenomatous polyposis, 5q21 termination), Jackson Laboratory (Bar Harbor, ME)) received drug for three weeks: 1.) ABT-510, 60 mg/Kg/day s.c. pump for 2 weeks then i.p. daily for the last 7 days, 2.) Anti-VEGF antibody bevacizumab 10 mg/Kg i.p. twice per week in combination with ABT-510, and 3.) untreated controls. After 21 days mice were sacrificed, intestines harvested and adenomas enumerated. Immunohistochemistry (PCNA, vWF/CD31) was performed. Studies were IACUC approved. Wilcoxon signed-rank test was used to compare results. Results: Twenty one mice were evaluated with no adverse effects. Comparisons were made to untreated APCMin/+ controls. Untreated controls (N=7) demonstrated a mean of 7.7±1.25 polyps. ABT-510 treated APCMin/+ (N=8) demonstrated a mean of 3.4±1.8 polyps, significantly different from controls (p<0.004). Combined bevacizumab and ABT-510 treatment demonstrated a mean of 4.7 ±3.0 polyps (p<0.008). There was no significant difference between the ABT-510 and combined ABT-510/bevacizumab treated groups. Immunohistochemistry for tumor vascularity (anti-CD31/anti-vWF) and for proliferation (PCNA) demonstrated enhanced vascular and PCNA staining in polyps, but no differences were detected in tumor dysplasia or immunohistochemistry compared across control and treatment groups. Conclusions: Significant reduction in APCMin/+ polyp number was seen with ABT-510 and the combination ABT-510/bevacizumab treatment groups compared to untreated controls. Tumor-specific vascularity and proliferation was characteristically no different across control and treated groups. [Table: see text]

scholarly journals Thrombospondin 1 Mediates High-Fat Diet-Induced Muscle Fibrosis and Insulin Resistance in Male Mice

Endocrinology ◽  
2013 ◽  
Vol 154 (12) ◽  
pp. 4548-4559 ◽  
Author(s):  
Mayumi Inoue ◽  
Yibin Jiang ◽  
Richard H. Barnes ◽  
Masakuni Tokunaga ◽  
Gabriel Martinez-Santibañez ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
High Fat Diet ◽  
Skeletal Muscles ◽  
Matrix Protein ◽  
Extracellular Matrix Protein ◽  
Male Mice ◽  
High Fat ◽  
Adipose Tissues ◽  
Early Stages ◽  
Thrombospondin 1

Thrombospondin 1 (THBS1 or TSP-1) is a circulating glycoprotein highly expressed in hypertrophic visceral adipose tissues of humans and mice. High-fat diet (HFD) feeding induces the robust increase of circulating THBS1 in the early stages of HFD challenge. The loss of Thbs1 protects male mice from diet-induced weight gain and adipocyte hypertrophy. Hyperinsulinemic euglycemic clamp study has demonstrated that Thbs1-null mice are protected from HFD-induced insulin resistance. Tissue-specific glucose uptake study has revealed that the insulin-sensitive phenotype of Thbs1-null mice is mostly mediated by skeletal muscles. Further assessments of the muscle phenotype using RNA sequencing, quantitative PCR, and histological studies have demonstrated that Thbs1-null skeletal muscles are protected from the HFD-dependent induction of Col3a1 and Col6a1, coupled with a new collagen deposition. At the same time, the Thbs1-null mice display a better circadian rhythm and higher amplitude of energy expenditure with a browning phenotype in sc adipose tissues. These results suggest that THBS1, which circulates in response to a HFD, may induce insulin resistance and fibrotic tissue damage in skeletal muscles as well as the de-browning of sc adipose tissues in the early stages of a HFD challenge. Our study may shed new light on the pathogenic role played by a circulating extracellular matrix protein in the cross talk between adipose tissues and skeletal muscles during obesity progression.

scholarly journals Thrombospondin 1 mediates renal dysfunction in a mouse model of high-fat diet-induced obesity

2013 ◽  
Vol 305 (6) ◽  
pp. F871-F880 ◽  
Author(s):  
Wenpeng Cui ◽  
Hasiyeti Maimaitiyiming ◽  
Xinyu Qi ◽  
Heather Norman ◽  
Shuxia Wang
Keyword(s):  
Mouse Model ◽  
Renal Dysfunction ◽  
Matrix Protein ◽  
Transforming Growth Factor ◽  
Mesangial Cells ◽  
Kidney Diseases ◽  
Extracellular Matrix Protein ◽  
Obese Mouse ◽  
Wild Type ◽  
Thrombospondin 1

Obesity is prevalent worldwide and is a major risk factor for many diseases including renal complications. Thrombospondin 1 (TSP1), a multifunctional extracellular matrix protein, plays an important role in diabetic kidney diseases. However, whether TSP1 plays a role in obesity-related kidney disease is unknown. In the present studies, the role of TSP1 in obesity-induced renal dysfunction was determined by using a diet-induced obese mouse model. The results demonstrated that TSP1 was significantly upregulated in the kidney from obese mice. The increased TSP1 was localized in the glomerular mesangium as well as in the tubular system from obese wild-type mice. Obese wild-type mice developed renal hypertrophy and albuminuria, which was associated with increased kidney macrophage infiltration, augmented kidney inflammation, and activated transforming growth factor (TGF)-β signaling and renal fibrosis. In contrast, obese TSP1-deficient mice did not develop these kidney damages. Furthermore, in vitro studies demonstrated that leptin treatment stimulated the expression of TSP1, TGF-β1, fibronectin, and collagen type IV in mesangial cells isolated from wild-type mice. These leptin-stimulated effects were abolished in TSP1-deficient mesangial cells. Taken together, these data suggest that TSP1 is an important mediator for obesity- or hyperleptinemia-induced kidney dysfunction.

scholarly journals Investigation of Tenascin Expression in Endometriosis

2012 ◽  
Vol 2012 ◽  
pp. 1-5
Author(s):  
Zehra Sema Ozkan ◽  
Hasan Cilgin ◽  
Remzi Atilgan ◽  
Mehmet Simsek ◽  
Bengu Cobanoglu ◽  
...  
Keyword(s):  
Matrix Protein ◽  
Expression Patterns ◽  
Serum Levels ◽  
Extracellular Matrix Protein ◽  
Secretory Phase ◽  
Tissue Samples ◽  
Intense Staining ◽  
Tissue Levels ◽  
Significant Difference ◽  
Ectopic Endometrium

Objective. To evaluate the serum and tissue levels and local expression pattern of tenascin, a high molecular weight extracellular matrix protein, in eutopic and ectopic endometrium from patients with and without endometriosis and to compare the proliferative and secretory phase differences. Materials and Methods. Thirty women with endometriosis and fifteen women without endometriosis undergoing surgery for benign indications were included in the study. Serum and tissue levels and proliferative and secretory phase expression patterns of tenascin in the ectopic and eutopic endometrium were analyzed with immunohistochemistry and immunoassays. The results were compared with Mann-Whitney U test. P values <0.05 were considered as statistically significant. Results. Tenascin expression was detected in both of eutopic and ectopic endometrium of women with and without endometriosis. In immunohistochemical staining, intense staining of tenascin was observed in glandular cells of eutopic and ectopic endometrial tissue samples of both groups during secretory phase (P<0.01). Eutopic and ectopic tissue levels of tenascin were higher than serum tenascin levels only secretory phase (P=0.02). There was no significant difference between groups for tissue and serum levels of tenascin during cycle phases. Conclusion. Tenascin expression showed cyclic change on eutopic and ectopic endometrium.

scholarly journals The importance of aminoguanidine and methylprednisolone administration in lung contusion after chest trauma

2021 ◽  
Vol 38 (4) ◽  
pp. 504-510
Author(s):  
Fatih ÇALIŞKAN ◽  
Hızır Ufuk AKDEMİR ◽  
Celal KATI ◽  
Latif DURAN ◽  
Tolga GÜVENÇ
Keyword(s):  
Combined Treatment ◽  
Serum Levels ◽  
The Other ◽  
Pulmonary Contusion ◽  
Sprague Dawley ◽  
Treatment Groups ◽  
Sprague Dawley Rats ◽  
Combined Use ◽  
Significant Difference ◽  
All Treatment

This study aims to evaluate the effect of the antioxidant and anti-inflammatory properties of aminoguanidine and metylprednisolone (MP) on lung tissue in a pulmonary contusion model of rats and evaluate whether their combined use improves treatment efficacy. This study included 35 female Sprague Dawley rats weighing 250-300 grams. The rats were divided into five groups as following: Sham; Pulmonary Contusion (PC); PC+MP, PC group treated with i.p methylprednisolone; PC+AG, PC group treated with i.p Aminoguanidine; and PC+AG+MP, PC group treated with Aminoguanidine and methylprednisolone. Each group had seven animals. Blood and lung tissues were studied biochemically and histopathologically. When compared groups according to serum levels of biomarkers, serum YKL-40, nitrate-nitrite, catalase, and TBARS levels were significant different. Serum YKL-40 levels were decreased after treatments in three groups. The serum YKL-40 levels in PC+AG group were lower than the other treatment groups, especially compared to PC + MP (p=0.028). Serum nitrate-nitrite levels were decreased in all treatment groups (PC+MP, PC+AG and PC+MP+AG). The lowest levels were measured in PC+MP+AG; but there was no statistically significant difference compared to PC group (p>0.05). Serum catalase levels were increased in all treatment groups. The higher levels were measured in PC+MP+AG than the other single treatment groups; however, PC+MP+AG and PC+MP were statistically significant different compared to PC group (p=0.001 and p=0.002 respectively). Serum TBARS levels were decreased in all treatment groups compared to Sham group (p<0.001) and PC group (p<0.001). The lowest levels were measured in PC+MP+AG compared to PC group (p<0.001). Histopathologic and immunohistochemical staining scores were decreased at all the treatment groups, especially PC+MP+AG. We suggest the use of combined treatment of methylprednisolone and aminoguanidine for the treatment of pulmonary contusion.

Efficacy of Fenbendazole and Ivermectin against Trichuris spp. in African Green Monkeys (Chlorocebus sabaeus) in Barbados West Indies

2021 ◽  
Author(s):  
Kamara JR Rhynd ◽  
Daniel P Walsh ◽  
Linnell CM Arthur-Banfield
Keyword(s):  
Natural Infection ◽  
Combined Treatment ◽  
Control Group ◽  
Treatment Groups ◽  
Significant Difference ◽  
The Mean ◽  
And Control ◽  
Bayesian Generalized Linear Model ◽  
Proportional Reduction ◽  
Green Monkeys

Trichuris spp. are common helminths in NHP, and benzimidazoles and avermectins have both been used to treat theseintestinal parasites. The current study compared the efficacy of fenbendazole and ivermectin against natural infection ofTrichuris spp. in African green monkeys (Chlorocebus sabaeus). Anthelmintic-naive animals (n = 65) were randomly assignedto 4 groups: an untreated control group, and 3 groups treated with either fenbendazole, ivermectin, or both compounds. Fecalsamples were collected before treatment and on days 7, 14, 28, and 60 after treatment, and fecal egg counts (FEC) were determined by using fecal flotation. The mean percentages of FEC reduction at day 60 were 100%, 86%, and 100% for treatmentwith fenbendazole, ivermectin, and both compounds, respectively. Analyzing the time series of FEC by using a Bayesian generalized linear model showed no significant difference in the proportional reduction in FEC among the 3 treatment groups, although all FEC from treated groups were significantly lower than the FEC of the control group. In contrast, the probability of shedding was highest in the ivermectin group and the lowest in the animals treated with both compounds. The probability of shedding differed significantly between the fenbendazole and ivermectin groups and between the ivermectin and combined-treatment groups. In conclusion, both fenbendazole and ivermectin are effective anthelmintics in treating Trichuris spp. infection in African green monkeys. All treatment groups showed significant reductions in FEC when compared with baseline counts and control animals; however, fenbendazole may be more effective than ivermectin when used solely or in combination with other anthelmintic treatments.

Phase III Study Comparing a Semimonthly With a Monthly Regimen of Fluorouracil and Leucovorin As Adjuvant Treatment for Stage II and III Colon Cancer Patients: Final Results of GERCOR C96.1

2007 ◽  
Vol 25 (24) ◽  
pp. 3732-3738 ◽  
Author(s):  
Thierry André ◽  
Emmanuel Quinaux ◽  
Christophe Louvet ◽  
Philippe Colin ◽  
Erik Gamelin ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Adjuvant Treatment ◽  
Disease Free Survival ◽  
International Study ◽  
Stage Ii ◽  
Phase Iii ◽  
Rank Test ◽  
Treatment Groups ◽  
Metastatic Relapse ◽  
Significant Difference

PurposeThis randomized, 2 × 2 factorial study compared a semimonthly regimen (fluorouracil [FU] and leucovorin [LV] semi-monthly is LV5FU2) with a monthly regimen of FU and LV (mFU/LV) as well as 24 weeks versus 36 weeks of each regimen as adjuvant treatment of stage II and III colon cancer.Patients and MethodsLV5FU2 was administered semimonthly for 2 days as racemate (dl) or levogyre (l-; 200 or 100 mg/m2) as a 2-hour infusion, followed by 400 mg/m2FU bolus and a 600-mg/m2FU 22-hour continuous infusion. FU and LV were administered monthly (mFU/LV) for 5 days as dl- or l-LV 15-minute infusion, followed by a 400 mg/m2FU 15-minute infusion. The primary end point was disease-free survival (DFS).ResultsBetween September 1996 and November 1999, 905 patients with stage II (43%) and III (57%) colon cancer were enrolled. The median follow-up was 6 years. There was no statistically significant difference between mFU/LV and LV5FU2 in terms of DFS (150 v 148 events; hazard ratio [HR],1.01; 95% CI, 0.806 to 1.269; P = .94) and overall survival (OS; 104 v 103 events; HR,1.02; 95% CI, 0.77 to 1.34; P = .91). No statistical difference was observed between 24 or 36 weeks of chemotherapy. Median survival from metastatic relapse was 24 months. The survival of patients with metastatic relapse (n = 243) was significantly longer for patients with a longer time from random assignment to relapse (< 1, 1 to 2, ≥ 2 years; log-rank test for trend P, .0497).ConclusionDFS and OS were not statistically different between treatment groups and treatment durations. These data confirm the value of LV5FU2 as control arm in the Multicenter International Study of Oxaliplatin/5FU-LV in the Adjuvant Treatment of Colon Cancer and Pan-European Trials in Adjuvant Colon Cancer studies.

scholarly journals Vascular smooth muscle cell growth arrest on blockade of thrombospondin-1 requires p21Cip1/WAF1

1999 ◽  
Vol 277 (3) ◽  
pp. H1100-H1106 ◽  
Author(s):  
Donghui Chen ◽  
Kun Guo ◽  
Jihong Yang ◽  
William A. Frazier ◽  
Jeffrey M. Isner ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Matrix Protein ◽  
Molecular Mechanisms ◽  
Cellular Proliferation ◽  
Growth Arrest ◽  
Inhibitory Effect ◽  
Extracellular Matrix Protein ◽  
Inhibitory Protein ◽  
Thrombospondin 1

Abnormal proliferation of vascular smooth muscle cells (VSMCs) is thought to play an important role in the pathogenesis of atherosclerosis and restenosis. Previous studies have implicated the extracellular matrix protein thrombospondin-1 (TSP1) in mitogen-dependent proliferation of VSMCs. In this study, we investigated the molecular mechanisms involved in TSP1-mediated regulation of VSMC growth. Neutralizing A4.1 anti-TSP1 antibody inhibited the activity of the G1/S cyclin-dependent kinase 2 (cdk2) and blocked the induction of S-phase entry, which normally occurs in serum-stimulated VSMCs. This growth-inhibitory effect was associated with a marked induction of p21Cip1/WAF1(p21) expression in A4.1-treated VSMCs. Moreover, addition of A4.1 antibody to VSMCs markedly increased the level of p21 bound to cdk2. Thus growth arrest on antibody blockade of TSP1 may be mediated by the cdk inhibitory protein p21. Consistent with this notion, anti-TSP1 antibody inhibited [3H]-thymidine incorporation in wild-type but not in p21-deficient mouse embryonic fibroblasts (MEFs). Together, these data suggest that p21 plays an important role in TSP1-mediated control of cellular proliferation.

scholarly journals Thrombospondin 1 and Its Diverse Roles as a Regulator of Extracellular Matrix in Fibrotic Disease

2019 ◽  
Vol 67 (9) ◽  
pp. 683-699 ◽  
Author(s):  
Joanne E. Murphy-Ullrich
Keyword(s):  
Extracellular Matrix ◽  
Stress Responses ◽  
Transforming Growth Factor Beta ◽  
Renal Fibrosis ◽  
Matrix Protein ◽  
Transforming Growth Factor ◽  
Extracellular Matrix Protein ◽  
Matrix Remodeling ◽  
Matrix Assembly ◽  
Thrombospondin 1

Thrombospondin 1 (TSP1) is a matricellular extracellular matrix protein that has diverse roles in regulating cellular processes important for the pathogenesis of fibrotic diseases. We will present evidence for the importance of TSP1 control of latent transforming growth factor beta activation in renal fibrosis with an emphasis on diabetic nephropathy. Other functions of TSP1 that affect renal fibrosis, including regulation of inflammation and capillary density, will be addressed. Emerging roles for TSP1 N-terminal domain regulation of collagen matrix assembly, direct effects of TSP1–collagen binding, and intracellular functions of TSP1 in mediating endoplasmic reticulum stress responses in extracellular matrix remodeling and fibrosis, which could potentially affect renal fibrogenesis, will also be discussed. Finally, we will address possible strategies for targeting TSP1 functions to treat fibrotic renal disease.

scholarly journals β1 Integrin Cytoplasmic Variants Differentially Regulate Expression of the Antiangiogenic Extracellular Matrix Protein Thrombospondin 1

2009 ◽  
Vol 69 (13) ◽  
pp. 5374-5382 ◽  
Author(s):  
Hira Lal Goel ◽  
Loredana Moro ◽  
Joanne E. Murphy-Ullrich ◽  
Chung-Cheng Hsieh ◽  
Chin-Lee Wu ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Matrix Protein ◽  
Extracellular Matrix Protein ◽  
Β1 Integrin ◽  
Thrombospondin 1

scholarly journals Periodontal condition in growing subjects with Marfan Syndrome: a case-control study

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e6606
Author(s):  
Nicolò Venza ◽  
Carlotta Danesi ◽  
Diego Contò ◽  
Francesco Fabi ◽  
Gianluca Mampieri ◽  
...  
Keyword(s):  
Marfan Syndrome ◽  
Matrix Protein ◽  
Mean Value ◽  
Extracellular Matrix Protein ◽  
Control Group ◽  
Depth Information ◽  
Gingival Thickness ◽  
Periodontal Condition ◽  
Significant Difference ◽  
The Mean

Background Marfan’s syndrome (MFS) is a systemic disorder of connective tissue caused by mutations in the extracellular matrix protein fibrillin-1. Orofacial characteristics may be useful in identification of the syndrome. Severe periodontitis is sometimes observed in MFS patients, but no in-depth information has been reported in Italian groups of growing subjects with MFS. The aim of this study was to analyze the periodontal condition on a group of growing subjects affected by MFS, in comparison with a typically developed control group. Methods A group of 16 subjects with diagnosed MFS were recruited from the Centre for Rare Diseases for Marfan Syndrome and Related Disorders of Tor Vergata University Hospital. The Marfan Group (MG) was compared with a Control Group (CG) composed by 20 nonsyndromic subjects. The periodontal clinical parameters like Marginal Gingival Thickness (GT), Plaque Index (PI), Bleeding On Probing (BOP) and Modified Periodontal Screening and Recording (PSR) were assessed. Results The mean value of PI in MG was 59%, instead in CG it reached 21%. Analysis showed a significant difference between MG and CG also for the BOP. In MG the mean value of BOP attained 36% and in CG it reached 16%. A statistical significant difference of distribution of PSR index between the two groups was found for all sextant examined. Discussion Patients with Marfan syndrome reveal a higher presence of plaque and consequently a generalized inflammation in the oral cavity when compared with a control group.

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