摘要 :
The endangered Yangtze finless porpoise is found in the middle and lower reaches of the Yangtze River and its adjoining big lakes. To explore the major histocompatibility complex (MHC) genetic diversity and allelic distribution pa...
展开
The endangered Yangtze finless porpoise is found in the middle and lower reaches of the Yangtze River and its adjoining big lakes. To explore the major histocompatibility complex (MHC) genetic diversity and allelic distribution patterns across its range, we investigated variation at DQB exon 2. From 76 porpoises, we identified 18 DQB sequences. The freshwater Yangtze populations had much higher allelic diversity than marine populations. Among these freshwater populations, the middle-reach population had higher allelic diversity than the lower-reach population. The high DQB diversity level, relative to that of a neutral mtDNA locus, suggests that balancing selection is acting at the DQB gene and that rapid evolution and local positive selection play critical roles in generating and retaining high MHC diversity in the freshwater population. As the balancing selection might be driven by environmental pathogens, we suggest that maintaining MHC variation should be a high priority in the conservation and management of this endangered population, especially as an ex situ conservation strategy.
收起
摘要 :
BACKGROUND: Stanniocalcin 1 (STC1) is a secreted glycoprotein hormone. High expression of STC1 has been associated with several cancers including ovarian cancer, but its role in the development of ovarian cancer is not clear. METH...
展开
BACKGROUND: Stanniocalcin 1 (STC1) is a secreted glycoprotein hormone. High expression of STC1 has been associated with several cancers including ovarian cancer, but its role in the development of ovarian cancer is not clear. METHODS: We used five human ovarian epithelial cancer cell lines (OVCA420, OVCA432, OVCA433, SKOV3, and HEY), immortalized human ovarian surface epithelial cells (T29 and T80), ovarian cancer tissues from 342 patients, serum from 73 ovarian cancer patients and from58 control subjects, and 116 mice, with six or eight per group. Protein expression was assessed. Cells overexpressing STC1 protein were generated by ectopic expression of human STC1 cDNA. STC1 expression was silenced by using small interfering RNA against STC1. Cell proliferation, migration, colony formation, and apoptosis were assessed. Xenograft tumor growth in mice was studied. Neutralizing anti-STC1 antibody was used to inhibit STC1 function. All statistical tests were two-sided. RESULTS: STC1 protein expression was higher in all human ovarian cancer cell lines examined than in immortalized human ovarian epithelial cell lines, higher in ovarian cancer tissue than in normal ovarian tissue (P < .001), and higher in serum from ovarian cancer patients than from control subjects (P = .021). Ovarian cancer cells with STC1 overexpression, compared with corresponding control cells, had increased cell proliferation, migration, and colony formation in cell culture and increased growth of xenograft tumors in mice. These activities in normal or malignant ovarian cells with STC1 overexpression, compared with control cells, were also accompanied by increased expression of cell cycle regulatory proteins and antiapoptotic proteins but decreased cleavage of several caspases. Within 24 hours of treatment, apoptosis in cultures of HEY ovarian cancer cells treated with neutralizing anti-STC1 monoclonal antibody was higher (17.3% apoptotic cells) than that in cultures treated with mouse IgG control cells (4.4%) (12.9% difference, 95% confidence interval = 11.6% to 14.2%). CONCLUSIONS: STC1 protein may be involved in ovarian tumorigenesis.
收起
摘要 :
Image-based computational models for atherosclerotic plaques have been developed to perform mechanical analysis to quantify critical flow and stress/strain conditions related to plaque rupture which often leads directly to heart a...
展开
Image-based computational models for atherosclerotic plaques have been developed to perform mechanical analysis to quantify critical flow and stress/strain conditions related to plaque rupture which often leads directly to heart attack or stroke. An important modeling issue is how to determine zero stress state from in vivo plaque geometries. This paper presents a method to quantify human carotid artery axial and inner circumferential shrinkages by using patient-specific ex vivo and in vivo MRI images. A shrink-stretch process based on patient-specific in vivo plaque morphology and shrinkage data was introduced to shrink the in vivo geometry first to find the zero-stress state (opening angle was ignored to reduce the complexity), and then stretch and pressurize to recover the in vivo plaque geometry with computed initial stress, strain, flow pressure and velocity conditions. Effects of the shrink-stretch process on plaque stress/strain distributions were demonstrated based on patient-specific data using 3D models with fluid-structure interactions (FSI). The average artery axial and inner circumferential shrinkages were 25% and 7.9%, respectively, based on a data set obtained from 10 patients. Maximum values of maximum principal stress and strain increased 349.8% and 249% respectively with 33% axial stretch. Influence of inner circumferential shrinkage (7.9%) was not very noticeable under 33% axial stretch, but became more noticeable under smaller axial stretch. Our results indicated that accurate knowledge of artery shrinkages and the shrink-stretch process will considerably improve the accuracy of computational predictions made based on results from those in vivo MRI-based FSI models.
收起
摘要 :
RATIONAL: Vascular smooth muscle cells (VSMCs) switching from a contractile/differentiated to a synthetic/dedifferentiated phenotype has an essential role in atherosclerosis, postangioplastic restenosis and hypertension. However, ...
展开
RATIONAL: Vascular smooth muscle cells (VSMCs) switching from a contractile/differentiated to a synthetic/dedifferentiated phenotype has an essential role in atherosclerosis, postangioplastic restenosis and hypertension. However, how normal VSMCs maintain the differentiated state is less understood. OBJECTIVE: We aimed to indentify the effect of cartilage oligomeric matrix protein (COMP), a normal vascular extracellular matrix, on modulation of VSMCs phenotype. METHODS AND RESULTS: We demonstrated that COMP was associated positively with the expression of VSMC differentiation marker genes during phenotype transition. Knockdown of COMP by small interfering (si)RNA favored dedifferentiation. Conversely, adenoviral overexpression of COMP markedly suppressed platelet-derived growth factor-BB-elicited VSMC dedifferentiation, characterized by altered VSMC morphology, actin fiber organization, focal adhesion assembly, and the expression of phenotype-dependent markers. Whereas alpha(7) integrin coimmunoprecipitated with COMP in normal rat VSMCs and vessels, neutralizing antibody or siRNA against alpha(7) integrin inhibited VSMC adhesion to COMP, which indicated that alpha(7)beta(1) integrin is a potential receptor for COMP. As well, blocking or interference by siRNA of alpha(7) integrin completely abolished the effect of COMP on conserving the contractile phenotype. In accordance, ectopic adenoviral overexpression of COMP greatly retarded VSMC phenotype switching, rescued contractility of carotid artery ring, and inhibited neointima formation in balloon-injured rats. CONCLUSIONS: Our data suggest that COMP is essential for maintaining a VSMC contractile phenotype and the protective effects of COMP are mainly mediated through interaction with alpha(7)beta(1) integrin. Investigations to identify the factors affecting the expression and integrity of COMP may provide a novel therapeutic target for vascular disorders.
收起
摘要 :
In this study, we compared four decellularization protocols and finally developed an optimized one through which a porcine bladder acellular matrix (BAM) with well-preserved extracellular bioactive factors had been prepared. In th...
展开
In this study, we compared four decellularization protocols and finally developed an optimized one through which a porcine bladder acellular matrix (BAM) with well-preserved extracellular bioactive factors had been prepared. In this protocol, the intact bladder was treated with trypsin/ethylenediaminetetraacetic acid to remove the urothelium, then with hypotonic buffer and Triton X-100 in hypertonic buffer to remove the membranous and cytoplasmic materials, and finally with nuclease to degrade the cellular nuclear components. Bladder distention and mechanical agitation were simultaneously used to facilitate cell removal. Meanwhile, several preservative techniques, including limitation of wash time, supplement with inhibitors of proteinase, control of the pH value and temperature of the wash buffer, ethylene oxide sterilization, and lyophilization of the scaffold for storage, were used to protect the extracellular bioactive factors. This decellularization protocol had completely removed the cellular materials and well preserved the extracellular collagen, sulfated glycosaminoglycan (GAG), and bioactive factors. The preserved bioactive factors had a great potential of promoting the proliferation and migration of both human bladder smooth muscle cell and human umbilical vein endothelial cell. It was also found that the amount of two representative bioactive factors, platelet-derived growth factor BB and vascular endothelial growth factor, was positively correlated with the sulfated GAG content in the porcine BAM, implying that the amount of sulfated GAG might be a determinant for preservation of bioactive factors in the decellularized tissues. In conclusion, the porcine BAM with well-preserved extracellular bioactive factors might be a favorable scaffold for tissue engineering applications.
收起
摘要 :
Scutellaria barbata (SB) has been used in Chinese medicine to treat various cancers. This study investigated the effects of SB on prostate cancer prevention. Male TRansgenic Adenocarcinoma Mouse Prostate (TRAMP) mice at 9 weeks we...
展开
Scutellaria barbata (SB) has been used in Chinese medicine to treat various cancers. This study investigated the effects of SB on prostate cancer prevention. Male TRansgenic Adenocarcinoma Mouse Prostate (TRAMP) mice at 9 weeks were randomly divided into four groups and given daily oral feedings of 8, 16, or 32 mg SB or sterilized water. In the control group, palpable tumors initially appeared at 19 weeks of age and were present in all mice by 32 weeks. In the respective treatment groups, palpable tumor development was delayed by 2, 4, and 7 weeks and 22, 30, and 38% of the mice were free of palpable tumors. Palpable tumor development in 50% of the mice occurred at 25 weeks in the placebo group, 29 weeks in the low-dose and mid-dose treatment groups, and 33 weeks in the high-dose group (log rank, P = 0.0211). Histological assessment further showed that the SB treatment (32 mg) delayed prostate tumor progression in the TRAMP mice. Caspase 3 activation was observed in SB-treated prostate tissue. Positive TUNEL assay results were detected in TRAMP-C1 and LNCaP cells treated with SB (1 mg/ml), which indicated significant apoptosis induction. Western blotting of SB-treated LNCaP cells also showed elevated expression of Bax, p53, Akt, and JNK. In-vivo data showed that the SB delayed tumor development in TRAMP mice. Complementary in-vitro data indicated that SB might exert this function by upregulating the apoptotic pathway and downregulating the survival pathway in prostate cancer cells, thus suggesting that SB possesses chemopreventive properties and has potential for cancer treatment.
收起
摘要 :
MicroRNA-1 (miR-1) is preferentially expressed in cardiac muscles, and the expression has been demonstrated to be involved in cardiac development and cardiovascular diseases. Here we report that miR-1 is closely related with ische...
展开
MicroRNA-1 (miR-1) is preferentially expressed in cardiac muscles, and the expression has been demonstrated to be involved in cardiac development and cardiovascular diseases. Here we report that miR-1 is closely related with ischemia/reperfusion injury in a rat model. The level of miR-1 is inversely correlated with Bcl-2 protein expression in cardiomyocytes of the I/R rat model. In vitro, the level of miR-1 was dramatically increased in response to H(2)O(2). Overexpression of miR-1 facilitated H(2)O(2)-induced apoptosis in cardiomyocytes. Inhibition of miR-1 by antisense inhibitory oligonucleotides caused marked resistance to H(2)O(2). Through bioinformatics, we identified the potential target sites for miR-1 on the 3' UTR of Bcl-2. miR-1 significantly reduced the expression of Bcl-2 in the levels of mRNA and protein. The post-transcriptional repression of Bcl-2 was further confirmed by luciferase reporter experiments. These data demonstrated that miR-1 plays an important role in the regulation of cardiomyocyte apoptosis, which is involved in post-transcriptional repression of Bcl-2.
收起
摘要 :
Evaluating biliary excretion, a major elimination pathway for many compounds, is important in drug discovery. The bile duct-cannulated (BDC) rat model is commonly used to determine the percentage of dose excreted as intact parent ...
展开
Evaluating biliary excretion, a major elimination pathway for many compounds, is important in drug discovery. The bile duct-cannulated (BDC) rat model is commonly used to determine the percentage of dose excreted as intact parent into bile. However, a study using BDC rats is time-consuming and cost-ineffective. The present report describes a computational model that has been established to predict biliary excretion of intact parent in rats as a percentage of dose. The model was based on biliary excretion data of 50 Bristol-Myers Squibb Co. compounds with diverse chemical structures. The compounds were given intravenously at <10 mg/kg to BDC rats, and bile was collected for at least 8 h after dosing. Recoveries of intact parents in bile were determined by liquid chromatography with tandem mass spectrometry. Biliary excretion was found to have a fairly good correlation with polar surface area (r = 0.76) and with free energy of aqueous solvation (DeltaG(solv aq)) (r = -0.67). In addition, biliary excretion was also highly corrected with the presence of a carboxylic acid moiety in the test compounds (r = 0.87). An equation to calculate biliary excretion in rats was then established based on physiochemical properties via a multiple linear regression. This model successfully predicted rat biliary excretion for 50 BMS compounds (r = 0.94) and for 25 previously reported compounds (r = 0.86) whose structures are markedly different from those of the 50 BMS compounds. Additional calculations were conducted to verify the reliability of this computation model.
收起
摘要 :
Early growth response 1 (Egr-1) over-expression has been demonstrated in myocardial ischemia-reperfusion injury, which is closely associated with endothelial dysfunction. In the present study we investigated the expression of Egr-...
展开
Early growth response 1 (Egr-1) over-expression has been demonstrated in myocardial ischemia-reperfusion injury, which is closely associated with endothelial dysfunction. In the present study we investigated the expression of Egr-1 on cultured cardiac microvascular endothelial cells (CMECs) to help define the mechanism of myocardial ischemia-reperfusion injury. A model of cultured CMECs exposed to hypoxia-reoxygenation was developed in which synthesized Egr-1 sense and antisense oligodeoxyribonucleotide were transfected into the cells. The expression of Egr-1 was examined by Western blot analysis. Lactate dehydrogenase, malondialdehyde, superoxide dismutase, tumor necrosis factor alpha, and intercellular adhesion molecule 1 were measured after hypoxia-reoxygenation to assess cell function and injury. Cell morphology, cell viability, and neutrophil adhesion to the CMECs were measured to assess the degree of injury and inflammation. Only cells transfected with Egr-1 antisense oligodeoxyribonucleotide showed a significant reduction in Egr-1 protein expression following hypoxia-reoxygenation. Consistent with the down-regulation of Egr-1 expression, other forms of cell injury were significantly reduced in this group of cells, as evidenced by less alteration in cell morphology, a decrease in expression of tumor necrosis factor alpha and intercellular adhesion molecule 1, improved cell survival, and reduced neutrophil adhesion.
收起
摘要 :
The lack of effective anti-tumor therapy for renal cell carcinoma (RCC) has stimulated the search for novel target whose inhibition could block tumorigenesis. Recently, reduced DLC-1 has been shown to be associated with aggressive...
展开
The lack of effective anti-tumor therapy for renal cell carcinoma (RCC) has stimulated the search for novel target whose inhibition could block tumorigenesis. Recently, reduced DLC-1 has been shown to be associated with aggressive and highly metastatic renal cell carcinoma. In this study, the biological role of DLC-1 on cell growth, migration and cell cycle progression in RCC cells was investigated. Over-expression of DLC-1 was associated with a marked inhibition of cell growth (P<0.01). The inhibitory effect was partly due to the induction of apoptosis and cell cycle arrest in G(0)/G(1) accompanied by up-regulation of the intracellular signal proteins of p27 and down-regulation of cyclin D1 and cyclin E. Furthermore, DLC-1 induced FAK dephosphorylation of focal adhesion proteins inhibited cell migration (P<0.05). Decreased DLC-1 expression strongly correlated with proliferative activity, as indicated by the elevated levels of Ki67. Restoration of DLC-1 expression in RCC cells led to Bcl-2 and caspase-3 mediated apoptosis as well as attenuated the ability of the cells to form RCC tumors in athymic nude mice (P<0.05). Taken together, these results suggest that DLC-1 plays a crucial role in signal transduction pathway regulating the cell proliferation, migration, and carcinogenesis of human RCC.
收起
原文获取