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Find video protocols related to scientific articles indexed in Pubmed.
Candidate Pathway-Based GWAS Identifies Novel Associations of Genomic Variants in the Complement System Associated with Coronary Artery Disease.
Circ Cardiovasc Genet
PUBLISHED: 09-25-2014
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-Genomic variants identified by genome-wide association studies (GWAS) explain <20% of heritability of coronary artery disease (CAD), thus many risk variants remain missing for CAD. Identification of new variants may unravel new biological pathways and genetic mechanisms for CAD. To identify new variants associated with CAD, we developed a candidate pathway-based GWAS by integrating expression quantitative loci (eQTL) analysis and mining of GWAS data with variants in a candidate pathway.
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Histone demethylase KDM2A promotes tumor cell growth and migration in gastric cancer.
Tumour Biol.
PUBLISHED: 07-15-2014
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Histone demethylase KDM2A has been reported to be dysregulated in lung cancer. However, its function in gastric cancer remains poorly understood. Here, it was found that the expression level of KDM2A was increased in gastric cancer tissues. Moreover, forced expression of KDM2A in gastric cancer cells promoted cell growth and migration, while the knockdown expression of KDM2A inhibited the tumorigenicity of gastric cancer cells. Mechanistically, KDM2A regulated the growth and motility of gastric cancer cells through downregulating the expression of programmed cell death 4 (PDCD4), a known tumor suppressor in the progression of gastric cancer. Taken together, our study suggested that upregulation of KDM2A was very important in the progression of gastric cancer, and KDM2A might be a promising therapeutic target.
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Adiponectin retards the progression of diabetic nephropathy in db/db mice by counteracting angiotensin II.
Physiol Rep
PUBLISHED: 02-01-2014
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Adiponectin is a multifunctional adipokine with insulin-sensitizing, anti-inflammatory, and vasoprotective properties. Epidemiology studies have, however, shown that high levels of serum adiponectin are associated with kidney disease progression. We, therefore, examined the effect of adiponectin administration on the progression of glomerulosclerosis in the obese diabetic (db/db) mouse, a model of type II diabetes. Recombinant human adiponectin was administered intraperitoneally at a dose of 30 or 150 ?g per day from weeks 18 to 20. Rosiglitazone administered by gavage at 20 mg/kg body weight (BW) daily served as a therapeutic control. Untreated uninephrectomized db/db mice developed progressive albuminuria and glomerular matrix expansion, associated with increased expression of transforming growth factor beta 1 (TGF?1), plasminogen activator inhibitor type 1 (PAI-1), collagen I (Col I), and fibronectin (FN). Treatment with adiponectin at either dose reduced the increases in albuminuria and markers of renal fibrosis seen in db/db mice, without affecting BW and blood glucose. Renal expressions of tumor necrosis factor-? (TNF-?) and monocyte-chemoattractant protein-1 (MCP-1) and urinary TNF-? levels, the markers of renal inflammation, were increased in diabetic mice, whereas adiponectin treatment significantly reduced the levels of these markers. Furthermore, adiponectin obliterated the stimulatory effects of angiotensin II (Ang II), but not the total effect of TGF?1, on the mRNA expression of PAI-1, Col I, and FN by cultured glomerular mesangial cells. These observations suggest that adiponectin treatment reduces glomerulosclerosis resulting from type II diabetes probably through its anti-inflammatory and angiotensin-antagonistic effects. Thus, adiponectin has therapeutic implications in the prevention of progression of diabetic nephropathy.
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A plasminogen activator inhibitor type 1 mutant retards diabetic nephropathy in db/db mice by protecting podocytes.
Exp. Physiol.
PUBLISHED: 01-17-2014
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A mutant non-inhibiting plasminogen activator inhibitor type 1 (PAI-1), termed PAI-1R, which reduces endogenous PAI-1 activity, has been shown to inhibit albuminuria and reduce glomerulosclerosis in experimental diabetes. The mechanism of the reduction of albuminuria is unclear. This study sought to determine whether the administration of PAI-1R protected podocytes from injury directly, thereby reducing albuminuria in the db/db mouse, a model of type 2 diabetes. Untreated uninephrectomized db/db mice developed significant mesangial matrix expansion and albuminuria at week 22 of age, associated with segmental podocyte foot-process effacement, reduction of renal nephrin, podocin and zonula occludin-1 production and induction of renal desmin and B7-1 generation. In contrast, treatment with PAI-1R at 0.5 mg (kg body weight)(-1) i.p., twice daily from week 20 to 22, reduced glomerular matrix accumulation, fibronectin and collagen production and albuminuria by 36, 62, 65 and 31%, respectively (P < 0.05), without affecting blood glucose level or body weight. Podocyte morphology and protein markers were also significantly attenuated by PAI-1R administration. Importantly, recombinant PAI-1 downregulated nephrin and zonula occludin-1 but increased desmin and B7-1 mRNA expression and protein production by podocytes in vitro, similar to the effects of transforming growth factor-?1. These observations provide evidence that PAI-1, in a manner similar to transforming growth factor-?1, directly induces podocyte injury, particularly in the setting of diabetes, where elevated PAI-1 may contribute to the progression of albuminuria. Reducing the increased PAI-1 activity by administration of PAI-1R, in fact, reduces podocyte injury, thereby reducing albuminuria. Therefore, PAI-1R provides an additional therapeutic effect in slowing the progression of diabetic nephropathy via the protection of podocytes.
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Regulation of CARD8 expression by ANRIL and association of CARD8 single nucleotide polymorphism rs2043211 (p.C10X) with ischemic stroke.
Stroke
PUBLISHED: 01-02-2014
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ANRIL has long been considered as the strongest candidate gene at the 9p21 locus, robustly associated with stroke and coronary artery disease. However, the underlying molecular mechanism remains unknown. The present study works to elucidate such a mechanism.
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Noncontiguous lumbar vertebral hemangiomas treated by posterior decompression, intraoperative kyphoplasty, and segmental fixation.
J Neurosurg Spine
PUBLISHED: 11-15-2013
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Vertebral hemangiomas are benign lesions and are often asymptomatic. Most vertebral hemangiomas that cause cord compression and neurological symptoms are located in the thoracic spine and involve a single vertebra. The authors report the rare case of lumbar hemangiomas in a 60-year-old woman presenting with severe back pain and rapidly progressive neurological signs attributable to 2 noncontiguous lesions. After embolization of the feeding arteries, no improvement was noted. Thus, the authors performed open surgery using a combination of posterior decompression, intraoperative kyphoplasty, and segmental fixation. The patient experienced relief from back and leg pain immediately after surgery. At 3 months postoperatively, her symptoms and neurological deficits had improved completely. To the authors knowledge, this is the first description of 2 noncontiguous extensive lumbar hemangiomas presenting with neurological symptoms managed by such combined treatment. The combined management seems to be an effective method for treating symptomatic vertebral hemangiomas.
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BRG1 variant rs1122608 on chromosome 19p13.2 confers protection against stroke and regulates expression of pre-mRNA-splicing factor SFRS3.
Hum. Genet.
PUBLISHED: 08-10-2013
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A single nucleotide polymorphism (SNP) rs1122608 on chromosome 19p13.2 and in the BRG1/SMARCA4 gene was previously associated with coronary artery disease (CAD). CAD and ischemic stroke are both associated with atherosclerosis. Thus, we tested the hypothesis that rs1122608 is associated with ischemic stroke. Further studies were used to identify the most likely mechanism by which rs1122608 regulates atherosclerosis. For case-control association studies, two independent Chinese Han GeneID cohorts were used, including a Central cohort with 1,075 cases and 2,685 controls and the Northern cohort with 1,208 cases and 824 controls. eQTL and real-time RT-PCR analyses were used to identify the potential candidate gene(s) affected by rs1122608. The minor allele T of SNP rs1122608 showed significant association with a decreased risk of ischemic stroke in the Central GeneID cohort (adjusted P adj = 2.1 × 10(-4), OR 0.61). The association was replicated in an independent Northern GeneID cohort (P adj = 6.00 × 10(-3), OR 0.69). The association became more significant in the combined population (P adj = 7.86 × 10(-5), OR 0.73). Allele T of SNP rs1122608 also showed significant association with a decreased total cholesterol level (P adj = 0.013). Allele T of rs1122608 was associated with an increased expression level of SFRS3 encoding an mRNA splicing regulator, but not with the expression of BRG1/SMARCA4 or LDLR (located 36 kb from rs1122608). Increased expression of SFSR3 may decrease IL-1? expression and secretion, resulting in reduced risk of atherosclerosis and stroke. This is the first study that demonstrates that rs1122608 confers protection against ischemic stroke and implicates splicing factor SFSR3 in the disease process.
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Meta-analysis identifies robust association between SNP rs17465637 in MIA3 on chromosome 1q41 and coronary artery disease.
Atherosclerosis
PUBLISHED: 06-15-2013
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Several large-scale meta-GWAS identified significant association between SNP rs17465637 in the MIA3 gene and coronary artery disease (CAD) in the European ancestry populations. However, three follow-up replication studies in the Chinese populations yielded inconsistent results. In order to unequivocally determine whether SNP rs17465637 is associated with CAD, we performed an independent case control association study in the Chinese Han population and a follow-up large scale meta-analysis for SNP rs17465637. Our study included 2503 CAD patients and 2920 non-CAD controls of the Chinese Han origin. A significant association was found between SNP rs17465637 and CAD (P = 0.01, OR = 1.11). Meta-analysis included 7263 CAD patients and 8347 controls combined from five Asian populations. The association between SNP rs17465637 and CAD became highly significant (P = 4.97 × 10(-5), OR = 1.11). Similar analysis also identified significant association between SNP rs17465637 and MI (2424 cases vs. 6,536controls; P = 5.00 × 10(-3), OR = 1.10). We conclude that SNP rs17465637 in MIA3 is indeed a genetic risk factor for CAD across different ethnic populations.
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Totally cystic schwannoma of the lumbar spine.
Orthopedics
PUBLISHED: 05-16-2013
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A schwannoma is a benign tumor arising from a schwann cell and occurs mainly in the nerve sheath in the intradural extramedullary region. Schwannomas have been well described as occurring in the lumbar spine, but total cystic degeneration of schwannomas is rarely reported. The authors describe the clinical and radiographic evaluations and treatment of a rare case of an intraextradural totally cystic schwannoma on the lumbar spine.Two patients reported a history of 6 to 12 months of pain accompanied by weakness in the lower extremities. On examination, 1 patient had bilateral lower-extremity muscle strength graded at 4/5, and magnetic resonance imaging revealed a cystic schwannoma (1.5 × 2.0 cm in the sagittal dimension) at L2-L3. The other patient had a right lower-extremity muscle strength graded at 3/5, and magnetic resonance imaging revealed a cystic schwannoma (2.0 × 3.0 cm in the sagittal dimension) at L4-L5. The patients underwent operative treatment, and the tumors were completely removed, as were the filum terminale adhered to the tumor. Pedicle screws were used to maintain stability of the lumbar spine. Gross examination of the tumors showed yellowish-white soft contents. Histologic examination confirmed that they were benign totally cystic schwannomas. Postoperatively, the patients neurologic symptoms completely resolved.Cystic schwannomas can be diagnosed using preoperative magnetic resonance imaging. The filum terminale cut off the tumor walls did not cause the clinical symptoms in the 2 patients.
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Combining angiotensin II blockade and renin receptor inhibition results in enhanced antifibrotic effect in experimental nephritis.
Am. J. Physiol. Renal Physiol.
PUBLISHED: 07-27-2011
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The limited antifibrotic effect of therapeutic angiotensin blockade, the fact that angiotensin blockade dramatically elevates renin levels, and recent evidence that renin has an angiotensin-independent, receptor-mediated profibrotic action led us to hypothesize that combining renin receptor inhibition and ANG II blockade would increase the antifibrotic effect of angiotensin blockade alone. Using cultured nephritic glomeruli from rats with anti-Thy-1-induced glomerulonephritis, the maximally effective dose of enalaprilate was determined to be 10(-4) M, which reduced mRNAs for transforming growth factor (TGF)-?1, fibronectin (FN), and plasminogen activator inhibitor-1 (PAI-1) by 49, 65, and 56% and production of TGF-?1 and FN proteins by 60 and 49%, respectively. Disease alone caused 6.8-fold increases in ANG II levels that were reduced 64% with enalaprilate. In contrast, two- and threefold disease-induced increases in renin mRNA and activity were further increased 2- and 3.7-fold with 10(-4) M enalaprilate treatment. Depressing the renin receptor by 80% with small interfering (si) RNA alone reduced fibrotic markers in a manner remarkably similar to enalaprilate alone but had no effect on glomerular renin expression. Enalaprilate and siRNA combination therapy further reduced disease markers. Notably, elevated TGF-?1 and FN production was reduced by 73 and 81%, respectively. These results support the notion of a receptor-mediated profibrotic action of renin, suggest that the limited effectiveness of ANG II blockade may be due, at least in part, to the elevated renin they induce, and support our hypothesis that adding renin receptor inhibitor to ANG II blockade in patients may have therapeutic potential.
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[Cloning and expression of fibrinolytic enzyme cDNA sequence from Eupolyphaga sinensis].
Zhongguo Zhong Yao Za Zhi
PUBLISHED: 10-12-2010
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To obtain the cDNA sequence encoding fibrinolytic enzyme from Eupolyphaga sinensis and express it in prokaryotic and eukaryotic expression system.
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Minor allele C of chromosome 1p32 single nucleotide polymorphism rs11206510 confers risk of ischemic stroke in the Chinese Han population.
Stroke
PUBLISHED: 06-24-2010
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Genome-wide association studies found that the common allele T of single nucleotide polymorphism rs11206510 on chromosome 1p32 was associated with increased low-density lipoprotein-cholesterol levels (LDL-C) and with risk of coronary artery disease (CAD) in white populations. The goals of this study are to determine whether rs11206510 is associated with LDL-C and CAD in a different ethnic population, namely a Chinese cohort, and to investigate whether rs11206510 is associated with ischemic stroke.
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Infusion of angiotensin-(1-7) reduces glomerulosclerosis through counteracting angiotensin II in experimental glomerulonephritis.
Am. J. Physiol. Renal Physiol.
PUBLISHED: 12-23-2009
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Recent identification of a counterregulatory axis of the renin-angiotensin system, called angiotensin-converting enzyme 2-angiotensin-(1-7) [ANG-(1-7)]-Mas receptor, may offer new targets for the treatment of renal fibrosis. We hypothesized that therapy with ANG-(1-7) would improve glomerulosclerosis through counteracting ANG II in experimental glomerulonephritis. Disease was induced in rats with the monoclonal anti-Thy-1 antibody, OX-7. Based on a three-dose pilot study, 576 microg x kg(-1) x day(-1) ANG-(1-7) was continuously infused from day 1 using osmotic pumps. Measures of glomerulosclerosis include semiquantitative scoring of matrix proteins stained for periodic acid Schiff, collagen I, and fibronectin EDA+ (FN). ANG-(1-7) treatment reduced disease-induced increases in proteinuria by 75%, glomerular periodic acid Schiff staining by 48%, collagen I by 24%, and FN by 25%. The dramatic increases in transforming growth factor-beta1, plasminogen activator inhibitor-1, FN, and collagen I mRNAs seen in disease control animals compared with normal rats were all significantly reduced by ANG-(1-7) administration (P < 0.05). These observations support our hypothesis that ANG-(1-7) has therapeutic potential for reversing glomerulosclerosis. Several results suggest ANG-(1-7) acts by counteracting ANG II effects: 1) renin expression in ANG-(1-7)-treated rats was dramatically increased as it is with ANG II blockade therapy; and 2) in vitro data indicate that ANG II-induced increases in mesangial cell proliferation and plasminogen activator inhibitor-1 overexpression are inhibited by ANG-(1-7) via its binding to a specific receptor known as Mas.
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Accelerated detection of intracranial space-occupying lesions with CUDA based on statistical texture atlas in brain HRCT.
Conf Proc IEEE Eng Med Biol Soc
PUBLISHED: 12-08-2009
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In this paper, we present a method that detects intracranial space-occupying lesions in two-dimensional (2D) brain high-resolution CT images. Use of statistical texture atlas technique localizes anatomy variation in the gray level distribution of brain images, and in turn, identifies the regions with lesions. The statistical texture atlas involves 147 HRCT slices of normal individuals and its construction is extremely time-consuming. To improve the performance of atlas construction, we have implemented the pixel-wise texture extraction procedure on Nvidia 8800GTX GPU with Compute Unified Device Architecture (CUDA) platform. Experimental results indicate that the extracted texture feature is distinctive and robust enough, and is suitable for detecting uniform and mixed density space-occupying lesions. In addition, a significant speedup against straight forward CPU version was achieved with CUDA.
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[Computer-aided surgery planning for implantation of artificial ear].
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi
PUBLISHED: 10-10-2009
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In conventional ear implantation surgery, clinical physicians usually make a surgery planning based on their observation on series of 2D X-ray images or CT images. Such a planning method requires the physicians to have a high level of clinical experience. Besides, the whole operation is unintuitive, and might have certain risk. Considering these facts, we have developed a computer-aided system for the surgery planning of the implantation of artificial ear based on CT imaging and 3D reconstruction techniques. The system effectively overcomes the main drawbacks in conventional surgery planning techniques, and it makes the surgery planning procedure more precise, safe, and intuitive.
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Mechanisms underlying the antifibrotic properties of noninhibitory PAI-1 (PAI-1R) in experimental nephritis.
Am. J. Physiol. Renal Physiol.
PUBLISHED: 07-22-2009
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Administration of a mutant, noninhibitory PAI-1 (PAI-1R), reduces disease in experimental glomerulonephritis. Here we investigated the importance of vitronectin (Vn) binding, PAI-1 stability and protease binding in this therapeutic effect using a panel of PAI-1 mutants differing in half-life, protease binding, and Vn binding. PAI-1R binds Vn normally but does not inhibit proteases. PAI-1AK has a complete defect in Vn binding but retains full inhibitory activity, with a short half-life similar to wild-type (wt)-PAI-1. Mutant 14-lb is identical to wt-PAI-1 but with a longer half-life. PAI-1K has defective Vn binding, inhibits proteases normally, and has a long half-life. In vitro wt-PAI-1 dramatically inhibited degradation of mesangial cell ECM while the AK mutant had much less effect. Mutants 14-1b and PAI-1K, like wt-PAI-1, inhibited matrix degradation but PAI-1R failed to reverse this inhibition although PAI-1R reversed the wt-PAI-1-induced inhibition of ECM degradation in a plasmin-, time-, and dose-dependent manner. Thus the ability of PAI-1 to inhibit ECM degradation is dependent both on its antiproteinase activity and on maintaining an active conformation achieved either by Vn binding or mutation to a stable form. Administration of these PAI-1 mutants to nephritic rats confirmed the in vitro data; only PAI-1R showed therapeutic effects. PAI-1K did not bind to nephritic kidney, indicating that Vn binding is essential to the therapeutic action of PAI-1R. The ability of PAI-1R to remain bound to Vn even in a high-protease environment is very likely the key to its therapeutic efficacy. Furthermore, because both PAI-1R and 14-1b bound to the nephritic kidney in the same pattern and differ only in their ability to bind proteases, lack of protease inhibition is also keyed to PAI-1Rs therapeutic action.
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A novel splice site mutation in the dentin sialophosphoprotein gene in a Chinese family with dentinogenesis imperfecta type II.
Mutat. Res.
PUBLISHED: 05-19-2009
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Twenty-four individuals were investigated that spanned six generations in a Chinese family affected with an apparently autosomal dominant form of dentinogenesis imperfecta type II (DGI-II, OMIM #125490). All affected individuals presented with typical, clinical and radiographic features of DGI-II, but without bilateral progressive high-frequency sensorineural hearing loss. To investigate the mutated molecule, a positional candidate approach was used to determine the mutated gene in this family. Genomic DNA was obtained from 24 affected individuals, 18 unaffected relatives of the family and 50 controls. Haplotype analysis was performed using leukocyte DNA for 6 short tandem repeat (STR) markers present in chromosome 4 (D4S1534, GATA62A11, DSPP, DMP1, SPP1 and D4S1563). In the critical region between D4S1534 and DMP1, the dentin sialophosphoprotein (DSPP) gene (OMIM *125485) was considered as the strongest candidate gene. The first four exons and exon/intron boundaries of the gene were analyzed using DNA from 24 affected individuals and 18 unaffected relatives of the same family. DNA sequencing revealed a heterozygous deletion mutation in intron 2 (at positions -3 to -25), which resulted in a frameshift mutation, that changed the acceptor site sequence from CAG to AAG (IVS2-3C-->A) and may also have disrupted the branch point consensus sequence in intron 2. The mutation was found in the 24 affected individuals, but not in the 18 unaffected relatives and 50 controls. The deletion was identified by allele-specific sequencing and denaturing high-performance liquid chromatography (DHPLC) analysis. We conclude that the heterozygous deletion mutation contributed to the pathogenesis of DGI-II.
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Cytotoxicity and oxidative stress study in cultured rat Sertoli cells with methyl tert-butyl ether (MTBE) exposure.
Reprod. Toxicol.
PUBLISHED: 01-20-2009
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Cultured Sertoli cells were tested for their cytotoxicity and oxidative stress induced by methyl tert-butyl ether (MTBE) which has been extensively used as a gasoline additive. In cytotoxic experiments, Sertoli cells were cultured with medium alone (control), 5, 500, or 50,000 microM MTBE. Lactate dehydrogcnase (LDH) leakage assay, staining with fluorescein diacetate (FDA) and propidium iodide (PI), and flow cytometric analyses were used. In oxidative stress experiments, Sertoli cells were cultured with medium alone (control), 0.5, 50, or 5000 microM MTBE. The production of reactive oxygen species (ROS), maleic dialdehyde (MDA) content and the level of superoxide dismutase (SOD) activity in cell supernatants were measured. Meanwhile, the expression level of 8-oxoguanine DNA glycosidase (OGG1) and extracellular form of superoxide dismutase (SOD(EX)) in Sertoli cells were determined by RT-PCR. We also compared the current findings with the previous findings in rat spermatogenic cells exposed to MTBE. The present data indicate that high dose MTBE may exert a direct toxic effect on Sertoli cells. Oxidative stress induced by MTBE is a possible mechanism of cytotoxicity.
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Nonylphenol induces apoptosis in rat testicular Sertoli cells via endoplasmic reticulum stress.
Toxicol. Lett.
PUBLISHED: 01-06-2009
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Nonylphenol (NP) is a widely distributed environment contaminant and has been documented to disrupt testicular development and decrease male fertility. Amongst possible targets of this compound are testicular Sertoli cells, which play a crucial role in supporting and nourishing sperm cells. In the present study, we found that NP treatment could cause dramatic morphological changes as well as decreased cell viability of Sertoli cells, while the following Annexin V-PI staining demonstrated that NP treatment led to increased proportion of cell apoptosis, which was evidenced again by the detection of condensation and marginal changes of chromatins using Hoechst staining and transmission microscopy observation. In addition, increased intracellular Ca(2+) levels and changes of endoplasmic reticulum (ER) ultrastructure were also observed in NP-treated groups, indicating the action of NP on ER. The subsequent data showed that the expressions of ER-stress signaling targeted genes GRP78 and gadd153 were elevated, suggesting the activation of ER-stress signal pathway. Furthermore, the detection of ER-stress related proteins by western blotting revealed that the expression of gadd153 was upregulated by NP, whereas the expressions of GRP78 and ERp57 were both first upregulated and then inhibited. Taken together, it is suggested that NP can induce ER stress in Sertoli cells, which may plays an important role in the induction of apoptosis.
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Targeting reduction of proteinuria in glomerulonephritis: Maximizing the antifibrotic effect of valsartan by protecting podocytes.
J Renin Angiotensin Aldosterone Syst
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Although angiotensin (Ang) II blockade has become a standard antifibrotic therapy in kidney disease, the therapeutic efficacy of Ang II blockade is yet to be optimized. Considering the prognostic impact of proteinuria reduction, we hypothesized that titration of Ang II blockade for optimal anti-proteinuric effect would improve renoprotection. One day after induction of Thy 1.1 glomeruonephritis, rats were treated with increasing doses of the Ang II receptor blocker valsartan in drinking water. Six days after disease induction, the therapeutic effect on proteinuria, podocyte injury and glomerular fibrosis was evaluated. Increasing doses of valsartan resulted in increasing reduction of proteinuria. The maximally effective dose of valsartan was determined to be 1000 mg/l, which reduced proteinuria by 80% and maximally reduced glomerular matrix expansion, fibronectin, collagen I and collagen III staining and glomerular mRNAs for TGFß1, PAI-1, FN and collagen I. Notably, valsartan given at this dose prevented podocyte dysfunction by preserving expression of podocin and nephrin and the counter-regulating molecule B7-1 that is involved in podocyte injury. These results support the hypothesis that higher doses of valsartan are required to optimize proteinuria reduction and glomerulosclerosis amelioration. Further, the optimal dose of valsartan also provides an additional therapeutic effect by preventing podocyte dysfunction.
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MRI study of the position of the conus medullaris in patients with lumbar spinal stenosis.
Orthopedics
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Substantial data exist from cadaveric and magnetic resonance imaging studies regarding the position of the conus medullaris in normally developed adults. However, no large studies have documented the position of the conus medullaris in patients with diagnosed lumbar spinal stenosis. To goal of the current study was to determine the position of the conus medullaris within a living adult population with existing pathology of lumbar spinal stenosis. In a retrospective study, 234 patients (110 women and 124 men; mean age, 48.8 years) with diagnosed lumbar spinal stenosis had their T2-weighted, midline, sagittal, spin-echo magnetic resonance imaging studies compared to assess and confirm the position of the conus medullaris. A straight line perpendicular to the long axis of the spinal cord in the median sagittal sequence was subtended to the adjacent vertebra or disk space, and the position was defined in relation to the vertebra or disk space. The conus medullaris position was labeled in relation to the upper, middle, and lower segments of the adjacent vertebral body or the adjacent disk space and assigned numerical values from 1 to 12. The position of the conus medullaris in patients with lumbar spinal stenosis followed a normal distribution. The mean conus medullaris position was mainly within the lower third of the L1 vertebral body (ranged from the middle third of T12 to the upper third of L3). No significant differences existed between men and women with lumbar spinal stenosis. The conus medullaris position was found to be unaffected by the pathology of lumbar spinal stenosis.
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Receptor-mediated nonproteolytic activation of prorenin and induction of TGF-?1 and PAI-1 expression in renal mesangial cells.
Am. J. Physiol. Renal Physiol.
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While elevated plasma prorenin levels are commonly found in diabetic patients and correlate with diabetic nephropathy, the pathological role of prorenin, if any, remains unclear. Prorenin binding to the (pro)renin receptor [(p)RR] unmasks prorenin catalytic activity. We asked whether elevated prorenin could be activated at the site of renal mesangial cells (MCs) through receptor binding without being proteolytically converted to renin. Recombinant inactive rat prorenin and a mutant prorenin that is noncleavable, i.e., cannot be activated proteolytically, are produced in 293 cells. After MCs were incubated with 10(-7) M native or mutant prorenin for 6 h, cultured supernatant acquired the ability to generate angiotensin I (ANG I) from angiotensinogen, indicating both prorenins were activated. Small interfering RNA (siRNA) against the (p)RR blocked their activation. Furthermore, either native or mutant rat prorenin at 10(-7) M alone similarly and significantly induced transforming growth factor-?(1), plasminogen activator inhibitor-1 (PAI-1), and fibronectin mRNA expression, and these effects were blocked by (p)RR siRNA, but not by the ANG II receptor antagonist, saralasin. When angiotensinogen was also added to cultured MCs with inactive native or mutant prorenin, PAI-1 and fibronectin were further increased significantly compared with prorenin or mutant prorenin alone. This effect was blocked partially by treatment with (p)RR siRNA or saralasin. We conclude that prorenin binds the (p)RR on renal MCs and is activated nonproteolytically. This activation leads to increased expression of PAI-1 and transforming growth factor-?(1) via ANG II-independent and ANG II-dependent mechanisms. These data provide a mechanism by which elevated prorenin levels in diabetes may play a role in the development of diabetic nephropathy.
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Valsartan slows the progression of diabetic nephropathy in db/db mice via reduction in podocyte injury and renal oxidative stress and inflammation.
Clin. Sci.
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Higher doses of angiotensin II blockade are usually required to optimize albuminuria reduction than for blood pressure control in chronic kidney disease. However, the long-term renoprotection of high-dose angiotensin II blockade has yet to be defined. This study sought to determine whether doses of angiotensin II receptor blocker (ARB) that maximally reduce proteinuria could slow the progression of glomerulosclerosis in the uninephrectomized db/db mouse, a model of type 2 diabetes. Untreated uninephrectomized db/db mice had normal blood pressure but developed progressive albuminuria and mesangial matrix expansion between weeks 18 and 22, associated with increased renal expression of TGFß1, PAI-1, type IV collagen and fibronectin. Treatment with valsartan in drinking water from weeks 18 to 22 at a dose that maximally reduced proteinuria determined previously prevented the increases in albuminuria and markers of renal fibrosis seen in db/db mice. In addition, WT-1 immunopositive podocyte numbers were found to be lower in the untreated diabetic glomeruli. The expression of podocin and nephrin was continually decreased in diabetes between weeks 18 and 22. Valsartan administration substantially ameliorated these changes that are indicative of podocyte injury. Renal expressions of TNF-?, MCP-1, Nox2, p22phox and p47phox and urine TBARS levels, the markers of renal inflammation and oxidative stress, were increased during disease progression in diabetic mice. Valsartan treatment reduced these markers. Thus, high dose of valsartan not only reduces albuminuria maximally but also halts the progression of glomerulosclerosis resulting from type 2 diabetes via reduction in podocyte injury and renal oxidative stress and inflammation.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.