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Thrombospondin-1 (TSP-1) is a known inhibitor of angiogenesis; however, a skeletal muscle phenotype of TSP-1 null mice has not been investigated. The purposes of this study were to compare and contrast TSP-1 null and wild-type mice by examining the following: (1) capillarity in the skeletal and cardiac muscles; (2) fibre type composition and oxidative enzyme activity in the hindlimb; and (3) the consequences of TSP-1 gene deletion for exercise capacity. In TSP-1 null mice, maximal running speed was 11% greater and time to exhaustion during submaximal endurance running was 67% greater compared with wild-type mice. Morphometric analyses revealed that TSP-1 null mice had higher ( P < 0.05) capillarity in the heart and skeletal muscle than wild-type mice, whereas no differences for fibre type composition or oxidative enzyme activity were present between the two groups. Cardiac function, as measured by transthoracic echocardiography, revealed no difference in myocardial contractility but greater left ventricular end-diastolic and systolic dimensions, corresponding to an elevated heart mass in the TSP-1 null mice. The results of this study indicate that TSP-1 is an important endogenous negative regulator of angiogenesis that prevents excessive capillarization in the heart and skeletal muscles. The increased capillarity alone was sufficient to increase ( P < 0.05) exercise capacity. These data demonstrate that the capillary-to-muscle interface is a critical factor that limits oxygen transport during exercise. 相似文献
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Hyperglycemia increases oxidative stress in various tissues and leads to diabetic cardiovascular complication. Dyslipidemia,
such as an increase in oxidized low-density lipoprotein (LDL), is well recognized in diabetic patients with hyperglycemia.
However, the mechanism by which hyperglycemia causes the increased LDL oxidation remains unclear. Albumin is the most abundant
protein in the circulation, and can function as an antioxidant. Therefore, we examined whether glycoxidative modification
inhibits the antioxidant activity of albumin to LDL oxidation and clarified the mechanism by which this modification may suppress
its antioxidant activity. Human serum albumin (HSA) was incubated in phosphate-buffered saline with and without glucose at
37°C for up to 8 weeks under aerobic conditions (referred to as glycoxidation (goHSA) and oxidation (oHSA), respectively).
Metal chelator-treated, nonoxidative HSA (chHSA) and freshly prepared HSA (fHSA) were used as controls. N
ε-(carboxymethyl)lysine (CML), a glycoxidative product, was determined by enzyme-linked immunosorbent assay. Oxidation was
estimated by measuring the thiols of the HSA molecule. Copper-mediated oxidation of LDL was conducted in the presence or absence
of modified HSAs at 37°C for 6 days. Malondialdehyde and negative charge of LDL were measured. To clarify the mechanism of
reduced antioxidant activity of HSA, we examined firstly the binding activity of modified HSAs to copper, and secondly the
effects of free radical scavengers on the formation of malondialdehyde. CML was formed in goHSA in a time- and concentration-dependent
manner. Both goHSA and oHSA significantly decreased the contents of free thiol groups compared to ch- and fHSAs. The antioxidant
activity of goHSA to LDL oxidation was the lowest among various modified HSAs. The oHSA showed a moderate decrease in antioxidant
activity. The binding activity of go- and oHSAs to copper was lower than that of ch- and fHSAs. The formation of MDA from
LDL oxidation in the presence of goHSA was completely inhibited by Tiron (1,2-dihydroxy-3,5-benzenedisulfonic acid) and superoxide
dismutase. In contrast, catalase and mannitol had no effect. Our results indicate that in vitro glycoxidation of HSA induced
a marked loss of antioxidant activity of this molecule to copper-mediated oxidation of LDL, which may be caused by the generation
of superoxide.
Received: December 17, 2001 / Accepted: June 28, 2002
Acknowledgments The authors thank Drs. Ryoji Nagai and Seikoh Horiuchi (Department of Biochemistry, Kumamoto University School of Medicine,
Kumamoto, Japan) and Drs. Hiroyuki Itabe and Tatsuya Takano (Department of Microbiology and Molecular Pathology, Faculty of
Pharmaceutical Sciences, Teikyo University, Sagamiko, Kanagawa, Japan) for kindly supplying antibodies. We also thank Associate
Professor Takeo Yamaguchi (Department of Chemistry, Faculty of Science, Fukuoka University) for the ESR experiment and Miss
Satoko Nagano for her excellent technical assistance. This work was supported by a Grant-in-Aid from the Ministry of Education,
Science, Sports and Culture of Japan (No. 14570171) and in part by funds from the Central Research Institute of Fukuoka University
(No. 016004).
Correspondence to N. Sakata 相似文献
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Salah Eldin M. E. Hassan Mohamed Alamin Ahmed Sabir Taha Hussein Abdallah Elamin Elsheikh Moh. Mah. Fadel Alla Eljack Mazin SalahEldien Hassan Haroun Khabab Abbasher Hussien Mohamed Ahmed Mohammed Eltahier Abdalla Omer Ghassan Elfatih Mustafa 《Clinical Case Reports》2022,10(1)
A 3‐year‐old child presented with recurrent chest pain for 3 months, echocardiography showed a thorn inside the left ventricle, the patient was diagnosed with foreign body complicated with infective endocarditis and received proper treatment, and operation was performed after inflammatory reaction subsided. 相似文献
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Genomic Understanding Reveals the Important Role of FGFR2 as Paeoniflorin Target for Circumventing Breast Cancer Resistance to Tamoxifen
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Moh Arikus WibowoEri Prasetyo NugrohoAdam Hermawan 《Asian Pacific journal of cancer prevention》2021,22(12):3949-3958
Objectives: Paeoniflorin (PF), a compound found in Paeonia lactiflora and Paeonia suffruticosa, has anticancer potential, particularly in inhibiting migration and invasion, the resistant cancer cells hallmarks. To date, the mechanism of overcoming tamoxifen resistance in breast cancer is not yet elucidated. This research aims to explore the potential target of PF as a co-treatment for circumventing breast cancer resistance to tamoxifen with a genomic understanding-bioinformatics. Methods: Microarray data originating from GSE67916 and GSE85871 in the NCBI GEO database was analyzed to obtain differentially expressed genes (DEGs). Further analyses were performed on DEGs using the DAVID v6.8, STRING-DB v11.0, the Cytoscape, and cBioportal. Gene expression analysis validation in breast cancer cells and tamoxifen-resistant breast cancer cells was accomplished using GEPIA and ONCOMINE databases. Survival rate analysis of selected genes was conducted using Kaplan–Meier. Results: We obtained 175 DEGs from the two samples (tamoxifen-resistant and paeoniflorin-treated). DEG involves in 70 biological processes, 26 cellular components, and 18 molecular functions, and three pathways relevant to breast cancer. The PPI network analysis and hub genes selection obtained 10 genes with the highest degree scores. Genetic changes for selected genes, including IFNB1, CDK6, FGFR2, OAS1, BCL2, and STAT2 were found from 0.5% to 7% of the case population per patient case. Additional analysis using cBioportal revealed FGFR signaling pathway through Ras is important for the PF mechanism in circumventing breast cancer resistance to tamoxifen. ONCOMINE and GEPIA analysis emphasized the importance of selected genes in the tamoxifen-resistance mechanism. Conclusion: PF has potential to be used as a co-treatment for circumventing breast cancer resistance to tamoxifen by targeting FGFR2 signaling, but further validation is needed. 相似文献
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Claire Rutherford Winston Martin Moh Salame Martin Carrier Erik ngg rd Gordon Ferns 《Atherosclerosis》1997,130(1-2):45-51
Thirty percent of patients undergoing percutaneous transluminal coronary angioplasty develop recurrent disease within a year. This is usually due to the rapid accumulation of intimal smooth muscle cells and extracellular matrix, which causes luminal narrowing, and is probably orchestrated by several mitogenic and chemotactic factors, of which platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) appear to be particularly important. We have investigated the effects of administering a combination of neutralizing antibodies directed against PDGF-BB and bFGF on neo-intima development following balloon catheter injury in the rat carotid artery. Purified sheep anti-PDGF-BB and anti-bFGF immunoglobulins (IgGs) were administered singly and in combination prior to mechanical injury and daily until sacrifice, 8 days later. Plasma titres of exogenous anti-PDGF-BB and anti-bFGF were maintained at levels 10–20-fold higher than those required to neutralise the mitogenic and chemotactic effects of 20 ng/ml of PDGF-BB, or 10 ng/ml bFGF in vitro. Used singly, anti-PDGF IgG treatment was associated with a 47% reduction in intimal thickness and a 59% reduction in intimal:medial area ratio; anti-bFGF IgG administration caused a 53% reduction in intimal thickness, and a 50% reduction in intimal:medial area ratio. Treatment with a combination of these antibodies resulted in a 83.8% reduction in intimal thickness (P<0.05), and a 91% reduction in intimal:medial area ratio (P<0.01). The latter treatment was also associated with a significantly higher intimal cell density (14.2±1.6×103 nuclei/mm2) compared to animals receiving non-immune IgG (7.8±0.8×103 nuclei/mm2; P<0.025), although intimal and medial cell proliferation indices were not significantly different between the groups (P>0.05). Our results suggest that in this particular model, PDGF-BB and bFGF are the major factors controlling neointimal hyperplasia, and that these growth factors are operating principally via an effect on smooth muscle cell migration and extracellular matrix protein accumulation. 相似文献