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Find video protocols related to scientific articles indexed in Pubmed.
Inflammatory stimuli induce inhibitory S-nitrosylation of the deacetylase SIRT1 to increase acetylation and activation of p53 and p65.
Sci Signal
PUBLISHED: 11-13-2014
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Inflammation increases the abundance of inducible nitric oxide synthase (iNOS), leading to enhanced production of nitric oxide (NO), which can modify proteins by S-nitrosylation. Enhanced NO production increases the activities of the transcription factors p53 and nuclear factor ?B (NF-?B) in several models of disease-associated inflammation. S-nitrosylation inhibits the activity of the protein deacetylase SIRT1. SIRT1 limits apoptosis and inflammation by deacetylating p53 and p65 (also known as RelA), a subunit of NF-?B. We showed in multiple cultured mammalian cell lines that NO donors or inflammatory stimuli induced S-nitrosylation of SIRT1 within CXXC motifs, which inhibited SIRT1 by disrupting its ability to bind zinc. Inhibition of SIRT1 reduced deacetylation and promoted activation of p53 and p65, leading to apoptosis and increased expression of proinflammatory genes. In rodent models of systemic inflammation, Parkinson's disease, or aging-related muscular atrophy, S-nitrosylation of SIRT1 correlated with increased acetylation of p53 and p65 and activation of p53 and NF-?B target genes, suggesting that S-nitrosylation of SIRT1 may represent a proinflammatory switch common to many diseases and aging.
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Expression of androgen and estrogen signaling components and stem cell markers to predict cancer progression and cancer-specific survival in patients with metastatic prostate cancer.
Clin. Cancer Res.
PUBLISHED: 07-01-2014
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Genes of androgen and estrogen signaling cells and stem cell-like cells play crucial roles in prostate cancer. This study aimed to predict clinical failure by identifying these prostate cancer-related genes.
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Pravastatin and olmesartan synergistically ameliorate renal failure-induced vascular calcification.
J. Atheroscler. Thromb.
PUBLISHED: 05-19-2014
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Vascular calcification is a critical problem in patients with chronic kidney disease (CKD). In this study, we examined the effects of a HMG Co-A reductase inhibitor (statin) and an angiotensin ? type 1 receptor blocker (ARB) on renal failure-induced vascular calcification.
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Large-scale analysis reveals a functional single-nucleotide polymorphism in the 5'-flanking region of PRDM16 gene associated with lean body mass.
Aging Cell
PUBLISHED: 04-05-2014
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Genetic factors are important for the development of sarcopenia, a geriatric disorder characterized by low lean body mass. The aim of this study was to search for novel genes that regulate lean body mass in humans. We performed a large-scale search for 250K single-nucleotide polymorphisms (SNPs) associated with bone mineral density (BMD) using SNP arrays in 1081 Japanese postmenopausal women. We focused on an SNP (rs12409277) located in the 5'-flanking region of the PRDM16 (PRD1-BF-1-RIZ1 homologous domain containing protein 16) gene that showed a significant P value in our screening. We demonstrated that PRDM16 gene polymorphisms were significantly associated with total body BMD in 1081 postmenopausal Japanese women. The rs12409277 SNP affected the transcriptional activity of PRDM16. The subjects with one or two minor allele(s) had a higher lean body mass than the subjects with two major alleles. Genetic analyses uncovered the importance of the PRDM16 gene in the regulation of lean body mass.
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Systemic identification of estrogen-regulated genes in breast cancer cells through cap analysis of gene expression mapping.
Biochem. Biophys. Res. Commun.
PUBLISHED: 03-23-2014
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To explore the estrogen-regulated genes genome-widely in breast cancer, cap analysis of gene expression (CAGE) sequencing was performed in MCF-7 cells under estrogen treatment. Estrogen-regulated expressional changes were found in 1537 CAGE tag clusters (TCs) (?1.5 or ?0.66-folds). Among them, 15 TCs were situated in the vicinity of (?10 kb) reported estrogen receptor-binding sites. Knockdown experiments of the 15 TC-associated genes demonstrated that the genes such as RAMP3, ISOC1 and GPRC5C potentially regulate the growth or migration of MCF-7 cells. These results suggest that CAGE sequencing will reveal novel estrogen target genes in breast cancer.
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Development of a simple screening test for sarcopenia in older adults.
Geriatr Gerontol Int
PUBLISHED: 01-24-2014
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To develop a simple screening test to identify older adults at high risk for sarcopenia.
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Metabolic Syndrome, Sarcopenia and Role of Sex and Age: Cross-Sectional Analysis of Kashiwa Cohort Study.
PLoS ONE
PUBLISHED: 01-01-2014
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Recent epidemiological evidence suggests that effects of cardiovascular risk factors may vary depending on sex and age. In this study, we assessed the associations of metabolic syndrome (MetS) with sarcopenia and its components in older adults, and examined whether the associations vary by sex and age. We also tested if any one of the MetS components could explain the associations. We conducted a cross-sectional analysis of the baseline data from the cohort study conducted in Kashiwa city, Chiba, Japan in 2012 which included 1971 functionally-independent, community-dwelling Japanese adults aged 65 years or older (977 men, 994 women). Sarcopenia was defined based on appendicular skeletal muscle mass, grip strength and usual gait speed. MetS was defined based on the National Cholesterol Education Program's Adult Treatment Panel-III criteria. The prevalence of sarcopenia was 14.2% in men and 22.1% in women, while the prevalence of MetS was 43.6% in men and 28.9% in women. After adjustment for potential confounders, MetS was positively associated with sarcopenia in men aged 65 to 74 years (odds ratio 5.5; 95% confidence interval 1.9-15.9) but not in older men or women. Among the sarcopenia components, MetS was associated with lower muscle mass and grip strength, particularly in men aged 65 to 74 years. The associations of MetS with sarcopenia and its components were mainly driven by abdominal obesity regardless of sex or age. In conclusion, MetS is positively associated with sarcopenia in older men. The association is modified by sex and age, but abdominal obesity is the main contributor to the association across sex and age.
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Liver-specific ?-glutamyl carboxylase-deficient mice display bleeding diathesis and short life span.
PLoS ONE
PUBLISHED: 01-01-2014
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Vitamin K is a fat-soluble vitamin that plays important roles in blood coagulation and bone metabolism. One of its functions is as a co-factor for ?-glutamyl carboxylase (Ggcx). Conventional knockout of Ggcx causes death shortly after birth in homozygous mice. We created Ggcx-floxed mice by inserting loxP sequences at the sites flanking exon 6 of Ggcx. By mating these mice with albumin-Cre mice, we generated Ggcx-deficient mice specifically in hepatocytes (Ggcx(?liver/?liver) mice). In contrast to conventional Ggcx knockout mice, Ggcx(?liver/?liver) mice had very low activity of Ggcx in the liver and survived several weeks after birth. Furthermore, compared with heterozygous mice (Ggcx(+/?liver) ), Ggcx(?liver/?liver) mice had shorter life spans. Ggcx(?liver/?liver) mice displayed bleeding diathesis, which was accompanied by decreased activity of coagulation factors II and IX. Ggcx-floxed mice can prove useful in examining Ggcx functions in vivo.
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Polymorphism of SLC25A32, the folate transporter gene, is associated with plasma folate levels and bone fractures in Japanese postmenopausal women.
Geriatr Gerontol Int
PUBLISHED: 10-23-2013
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Elevation of homocysteine is associated with an increased risk for bone fractures. We previously reported that the methylenetetrahydrofolate reductase (MTHFR) gene polymorphism is associated with homocysteine levels and fracture. The association between the fracture and folate levels or their related gene polymorphisms is not completely clear. We speculated that the SLC25A32 gene, the mitochondrial inner membrane folate transporter, also could be implicated in the regulation of folate metabolism and fracture.
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[Approaches to sarcopenia].
Clin Calcium
PUBLISHED: 09-26-2013
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Frailty is one of the features of geriatric syndrome, and the prevention from frailty and sarcopenia is a major problem in elderly population. Recent findings suggest that sarcopenia is caused by multiple processes that may involve decreased hormone levels, malnutrition, inflammatory status. Nutritional, pharmacological intervention and exercise training may be promising candidates for the treatment of sarcopenia.
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Respiratory dysrhythmia in dementia with Lewy bodies: a cross-sectional study.
BMJ Open
PUBLISHED: 09-12-2013
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Dementia with Lewy bodies (DLB) is the second most common form of neurodegenerative dementia after Alzheimers disease (AD). DLB is characterised by intracytoplasmic inclusions called Lewy bodies that are often seen in the brainstem. Because modulation of the respiratory rhythm is one of the most important functions of the brainstem, patients with DLB may exhibit dysrhythmic breathing. This hypothesis has not yet been systematically studied. Therefore, we evaluated the association between DLB and dysrhythmic breathing.
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trans-Resveratrol in Gnetum gnemon protects against oxidative-stress-induced endothelial senescence.
J. Nat. Prod.
PUBLISHED: 07-16-2013
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Gnetum gnemon is an arboreal dioecious plant that is cultivated in Indonesia. The seeds of this species mainly contain dimeric stilbenoid compounds [gnetin C (1), gnemonoside A (2), and gnemonoside D (3)] along with trans-resveratrol (4). trans-Resveratrol has been reported to have antiaging, anticancer, and antidiabetic effects, as well as being a calorie restriction mimetic. SIRT1 exerts a protective effect against vascular senescence. In this study, the effects of these four main stilbenoid derivatives of a G. gnemon seed endosperm ethanolic extract on endothelial senescence were investigated. In streptozotocin-induced diabetic mice, administration of the G. gnemon ethanolic extract increased SIRT1 and decreased endothelial senescence. The concentration of 1 in blood plasma was 6-fold higher than 4 in these mice. Next, the in vitro effects of the four main stilbenoid derivatives of G. gnemon seeds were investigated. Senescent human umbilical vein endothelial cells were induced by hydrogen peroxide. Endothelial senescence was inhibited by 4, which increased the expression of endothelial nitric oxide synthase and SIRT1, whereas 1-3 had no effect. These results indicated that the ethanolic extract of G. gnemon seeds inhibits endothelial senescence, suggesting that 4 plays a critical role in the prevention of endothelial senescence.
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Androgen-responsive long noncoding RNA CTBP1-AS promotes prostate cancer.
EMBO J.
PUBLISHED: 04-04-2013
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High-throughput techniques have identified numerous antisense (AS) transcripts and long non-coding RNAs (ncRNAs). However, their significance in cancer biology remains largely unknown. Here, we report an androgen-responsive long ncRNA, CTBP1-AS, located in the AS region of C-terminal binding protein 1 (CTBP1), which is a corepressor for androgen receptor. CTBP1-AS is predominantly localized in the nucleus and its expression is generally upregulated in prostate cancer. CTBP1-AS promotes both hormone-dependent and castration-resistant tumour growth. Mechanistically, CTBP1-AS directly represses CTBP1 expression by recruiting the RNA-binding transcriptional repressor PSF together with histone deacetylases. CTBP1-AS also exhibits global androgen-dependent functions by inhibiting tumour-suppressor genes via the PSF-dependent mechanism thus promoting cell cycle progression. Our findings provide new insights into the functions of ncRNAs that directly contribute to prostate cancer progression.
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Association of decreased sympathetic nervous activity with mortality of older adults in long-term care.
Geriatr Gerontol Int
PUBLISHED: 03-10-2013
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To investigate the relationship between physical function, mortality and autonomic nervous activity measured by heart rate variability of elderly in long-term care.
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Clinical significance of amyloid precursor protein in patients with testicular germ cell tumor.
Adv Urol
PUBLISHED: 02-13-2013
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Introduction. The biological role of amyloid precursor protein (APP) is not well understood, especially in testicular germ cell tumors (TGCTs). Therefore, we aimed to investigate the immunoreactivity (IR) and expression of APP in TGCTs and evaluated its clinical relevance. Materials and Methods. We performed an analysis of immunohistochemistry and mRNA expression of APP in 64 testicular specimens and 21 snap-frozen samples obtained from 1985 to 2004. We then evaluated the association between APP expression and clinicopathological status in TGCTs. Results. Positive APP IR was observed in 9.8% (4/41) of seminomatous germ cell tumors (SGCTs) and 39.1% (9/23) of nonseminomatous germ cell tumors (NGCTs). NGCTs showed significantly more cases of positive IR (P = 0.00870) and a higher mRNA expression level compared with those of SGCTs (P = 0.0140). Positive APP IR was also significantly associated with ? -fetoprotein ( ? FP) elevation (P = 0.00870) and venous invasion (P = 0.0414). Conclusion. We observed an elevated APP expression in TGCTs, especially in NGCTs. APP may be associated with a more aggressive cancer in TGCTs.
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Vitamin?K: Novel molecular mechanisms of action and its roles in osteoporosis.
Geriatr Gerontol Int
PUBLISHED: 02-13-2013
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Vitamin?K is a fat-soluble vitamin, which is involved in blood coagulation mediated by maintaining the activity of coagulation factors in the liver. Vitamin?K also has extrahepatic actions and has been shown to prevent bone fractures in clinical studies. In addition, epidemiological studies suggest that a lack of vitamin?K is associated with several geriatric diseases, including osteoporosis, osteoarthritis, dementia and arteriosclerosis. It has also been shown that vitamin?K contributes to the prevention and treatment of some kinds of malignancies. Recently, we discovered a novel role for vitamin?K as a ligand of the nuclear receptor, steroid and xenobiotic receptor (SXR), and its murine ortholog, pregnane X receptor (PXR). In addition to its established roles as a cofactor of ?-glutamyl carboxylase (GGCX) in mediating post-transcriptional modifications, vitamin?K has a different mode of action mediated by transcriptional regulation of SXR/PXR target genes. Analysis of bone tissue from PXR-deficient mice showed that the bone protective effects of vitamin?K are partially mediated by SXR/PXR-dependent signaling. The discoveries of a novel mode of vitamin?K action have opened up new possibilities that vitamin?K might be useful for prevention or treatment of a variety of diseases that affect the geriatric population. Geriatr Gerontol Int 2013; ??: ??-??.
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C-reactive protein, bone strength, and nine-year fracture risk: data from the Study of Womens Health Across the Nation (SWAN).
J. Bone Miner. Res.
PUBLISHED: 01-26-2013
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Higher levels of C-reactive protein (CRP), an inflammatory marker, are associated with increased fracture risk, although previous studies on CRP and bone mineral density (BMD) have yielded conflicting results. We aimed to test the hypotheses that composite indices of femoral neck strength relative to load, which are inversely associated with fracture risk, would also be inversely associated with CRP, and would explain part of the association between CRP and fracture risk. We analyzed data from a multisite, multiethnic prospective cohort of 1872 community-dwelling women, premenopausal or early perimenopausal at baseline. Femoral neck composite strength indices in three failure modes were calculated using dual-energy X-ray absorptiometry (DXA)-derived femoral neck width (FNW), femoral neck axis length (FNAL), femoral neck BMD and body size at baseline, as BMD*FNW/weight for compression strength, BMD*(FNW)(2) /(FNAL*weight) for bending strength, and BMD*FNW*FNAL/(height*weight) for impact strength. Incident nondigital, noncraniofacial fractures were ascertained annually over a median follow-up of 9 years. In analyses adjusted for age, race/ethnicity, diabetes, menopause transition stage, body mass index, smoking, alcohol use, physical activity, medications, prior fracture, and study site, CRP was associated inversely with each composite strength index (0.035-0.041 SD decrement per doubling of CRP, all p?
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Involvement of ASK1-p38 pathway in the pathogenesis of diabetes triggered by pancreatic ß cell exhaustion.
Biochim. Biophys. Acta
PUBLISHED: 01-24-2013
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Diabetes mellitus is characterized by high blood glucose levels. Pancreatic ß cell death contributes to type 1 and type 2 diabetes. Akita mice, which harbor a human permanent neonatal diabetes-linked mutation (Cys96Tyr) in the insulin gene, are well established as an animal model of diabetes caused by pancreatic ß cell exhaustion. Mutant Insulin 2 protein (Ins2(C96Y)) induces endoplasmic reticulum (ER) stress and pancreatic ß cell death in Akita mice, although the molecular mechanism of Ins(C96Y)-induced cell death remains unclear.
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RNA sequencing of MCF-7 breast cancer cells identifies novel estrogen-responsive genes with functional estrogen receptor-binding sites in the vicinity of their transcription start sites.
Horm Cancer
PUBLISHED: 01-16-2013
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Estrogen receptor ? (ER?) is a key transcription factor in breast cancer, which plays an essential role in the pathophysiology of the disease by regulating the expression of various target genes. In the present study, we performed deep RNA sequencing (RNA-seq) as an unbiased high-throughput technique for comprehensive transcriptome analysis in ER?-positive human breast cancer MCF-7 cells, to facilitate the elucidation of ER? regulatory gene networks. From the 17,336 mapped RefSeq genes from the sequenced fragments of the cell samples treated with estrogen time dependently, substantial numbers of sequence reads were observed in 3,386 genes (>100 tags per million reads per sample at any of the six time points studied). ER? occupancy within and in the proximal regions of the genes (<10-kb upstream and downstream regions) was significantly enriched in the subgroup of the 3,386 genes compared to the whole 17,336 RefSeq genes. Of the 3,386 genes, we focused on 29 genes, which included ER? occupancy adjacent to their transcription start sites and whose expression was estrogen dependently altered by >3-fold. Knockdown studies using siRNAs specific to the 29 genes validated that prototypic ER? targets V-myc myelocytomatosis viral oncogene homolog and cyclin D1 promote both proliferation and migration of MCF-7 cells and further identified novel candidate ER? targets EIF3A and tumor protein D52-like 1, which will also facilitate the proliferation or migration of MCF-7 cells. Taken together, the present findings provide a valuable dataset that will elucidate ER? regulatory mechanisms in breast cancer biology, based on the integrative analysis of RNA-seq combined with the genome-wide information for ER? occupancy.
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Priorities of health care outcomes for the elderly.
J Am Med Dir Assoc
PUBLISHED: 01-12-2013
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Physicians are uncertain about what medical services should be provided to older and/or disabled patients. Better understanding of health outcome prioritization among health care providers and recipients may help the process of decision- and policy-making. For this purpose, surveys were conducted on priorities of health care outcomes for the elderly.
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Acute exogenous lipoid pneumonia caused by accidental kerosene ingestion in an elderly patient with dementia: a case report.
Geriatr Gerontol Int
PUBLISHED: 01-05-2013
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Acute exogenous lipoid pneumonia is an uncommon condition caused by aspiration of oil-based substances, occurring mainly in children. Here, we report the case of an 83-year-old patient with Alzheimers disease who presented with coughing and hypoxia. The diagnosis of acute exogenous lipoid pneumonia caused by accidental kerosene ingestion was made on the basis of the patients clinical history, and typical radiological and cytological findings. The patients cognitive impairment and an unsafe environment, in which the patients 91-year-old husband stored kerosene in an old shochu bottle, were responsible for the accidental ingestion. Acute exogenous lipoid pneumonia should be considered in the differential diagnosis for acute respiratory disorders in the rapidly aging population.
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Polypharmacy as a risk for fall occurrence in geriatric outpatients.
Geriatr Gerontol Int
PUBLISHED: 12-23-2011
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To investigate the predictors of falls, such as comorbidity and medication, in geriatric outpatients in a longitudinal observational study.
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Clinical significance of steroid and xenobiotic receptor and its targeted gene CYP3A4 in human prostate cancer.
Cancer Sci.
PUBLISHED: 11-27-2011
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The steroid and xenobiotic receptor (SXR) regulates cytochrome P450 (CYP) enzymes, which are key inactivators of testosterone in the liver and prostate. In the present study, we investigated SXR expression in human prostate tissues. We determined SXR immunoreactivity using an anti-SXR antibody in benign (n = 78) and cancerous (n = 106) tissues obtained by radical prostatectomy. Stained slides were evaluated for the proportion and staining intensity of immunoreactive cells. Total immunoreactivity (IR) scores (range: 0-8) were calculated as the sum of the proportion and intensity scores. Associations between the clinicopathological features of the patients, SXR status, and CYP3A4 immunoreactivity were analyzed. Western blot analyses validated the specificity of the anti-SXR antibody in 293T cells transfected with pcDNA-FLAG-SXR. Positive (IR score: ? 2) nuclear SXR staining was observed in 91% (71/78) of benign foci and 47% (50/106) of cancerous lesions. Immunoreactivity scores were significantly lower in the cancerous lesions than in the benign foci (P < 0.0001). Clinicopathological analyses showed that cancer-specific survival in patients with high SXR IR scores (? 4) was significantly increased (P = 0.046). Combined data of present and previous studies showed that high IR scores for both the SXR and CYP3A4 correlated with significantly better cancer-specific survival rates in multivariate regression analyses (hazard ratio: 2.15, 95% confidence interval: 1.25-3.55, P = 0.007). We showed differential SXR expression in human prostate tissues. The high expression of the SXR and CYP3A4 is a strong prognostic indicator of favorable outcomes in prostate cancer, and could be a therapeutic target.
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PROX1 suppresses vitamin K-induced transcriptional activity of Steroid and Xenobiotic Receptor.
Genes Cells
PUBLISHED: 10-26-2011
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Steroid and Xenobiotic Receptor (SXR) belongs to nuclear receptor superfamily. It was shown that secondary bile acids such as lithocholic acid and several chemical compounds such as rifampicin could be ligands for this receptor. Recently, we have demonstrated that vitamin K2 also serves as a ligand for SXR and activation of SXR by vitamin K2 suppressed proliferation and motility of hepatocellular carcinoma (HCC) cells. To analyze function of SXR in HCC cells, we overexpressed exogenous SXR double-tagged with FLAG and HA in a HCC cell line, HepG2 cells, and purified SXR-binding molecules by immunoprecipitation from the nuclear extracts of these cells. Several binding molecules were identified by TOF-MS analyses. One of the SXR-binding molecules was a transcription factor PROX1. We confirmed the interaction of PROX1 and SXR in HEK293 cells. Then, we have shown that AF2 domain of SXR is necessary for binding with PROX1. We further demonstrated that PROX1 negatively regulated the transcriptional activity of SXR by promoter analyses of SXR target gene. These results suggest that PROX1 could negatively regulate SXR signals in some tumor cells, such as HCC cells, where both SXR and PROX1 are expressed.
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Sirtuin 1 retards hyperphosphatemia-induced calcification of vascular smooth muscle cells.
Arterioscler. Thromb. Vasc. Biol.
PUBLISHED: 06-30-2011
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Arterial calcification is associated with cardiovascular disease as a complication of advanced atherosclerosis. Aged vascular cells manifest some morphological features of a senescent phenotype. Recent studies have demonstrated that mammalian sirtuin 1 (SIRT1), a histone deacetylase, is an exciting target for cardiovascular disease management. Here, we investigated the role of SIRT1 in a calcification model of vascular smooth muscle cells (SMCs).
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Association of polypharmacy with fall risk among geriatric outpatients.
Geriatr Gerontol Int
PUBLISHED: 05-05-2011
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To investigate the association of fall risk with comorbidities and medications in geriatric outpatients in a cross-sectional design.
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[Inflammatory control on lifestyle-related diseases and bone metabolism].
Clin Calcium
PUBLISHED: 05-03-2011
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Recent findings suggest that chronic inflammation is involved in lifestyle related diseases and osteoporosis. Members of nuclear receptor superfamily have regulatory effects on inflammatory processes and cytokine responses which contribute to prevention and treatment of above diseases. Here, recent studies are described that these nuclear receptors have regulatory roles called transrepression in chronic inflammatory diseases through their interactions with transcription factors and cell-signaling systems.
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Risk stratification based on metabolic syndrome as well as non- metabolic risk factors in the assessment of carotid atherosclerosis.
J. Atheroscler. Thromb.
PUBLISHED: 03-18-2011
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We aimed to develop a new approach to risk stratification using metabolic syndrome as well as traditional non-metabolic risk factors, and to examine its validity in carotid atherosclerosis.
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Oct1 regulates cell growth of LNCaP cells and is a prognostic factor for prostate cancer.
Int. J. Cancer
PUBLISHED: 02-15-2011
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The androgen receptor (AR) plays a critical role in the development and the progression of prostate cancer. Alterations in the expression of AR coregulators lead to AR hypersensitivity, which is one of the mechanisms underlying the progression of prostate cancer into a castrate-resistant state. Octamer transcription factor 1 (Oct1) is a ubiquitous member of the POU-homeodomain family that functions as a coregulator of AR. In our study, the contribution of Oct1 to prostate cancer development was examined. Immunocytochemistry analysis showed that Oct1 is expressed in the nuclei of LNCaP cells. siRNA-mediated silencing of Oct1 expression inhibited LNCaP cell proliferation. Immunohistochemical analysis of Oct1 expression in tumor specimens obtained from 102 patients with prostate cancer showed a positive correlation of Oct1 immunoreactivity with a high Gleason score and AR immunoreactivity (p = 0.0042 and p < 0.0001, respectively). Moreover, patients with high immunoreactivity of Oct1 showed a low cancer-specific survival rate, and those patients with high immunoreactivities of both Oct1 and AR exhibited poorer cancer-specific prognosis. Multivariate hazard analysis revealed a significant correlation between high Oct1 immunoreactivity and poor cancer-specific survival (p = 0.012). These results demonstrate that Oct1 can be a prognostic factor in prostate cancer as a coregulator of AR and may lead to the development of a new therapeutic intervention for prostate cancer.
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ARFGAP3, an androgen target gene, promotes prostate cancer cell proliferation and migration.
Int. J. Cancer
PUBLISHED: 01-10-2011
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ADP ribosylation factor GTPase-activating protein 3 (ARFGAP3) is a GTPase-activating protein that associates with the Golgi apparatus and regulates the vesicular trafficking pathway. In the present study, we examined the contribution of ARFGAP3 to prostate cancer cell biology. We showed that ARFGAP3 expression was induced by 100 nM of dihydrotestosterone (DHT) at both the mRNA and protein levels in androgen-sensitive LNCaP cells. We generated stable transfectants of LNCaP cells with FLAG-tagged ARFGAP3 or a control empty vector and showed that ARFGAP3 overexpression promoted cell proliferation and migration compared with control cells. We found that ARFGAP3 interacted with paxillin, a focal adhesion adaptor protein that is important for cell mobility and migration. Small interfering RNA (siRNA)-mediated knockdown of ARFGAP3 showed that ARFGAP3 siRNA markedly reduced LNCaP cell growth. Androgen receptor (AR)-dependent transactivation activity on prostate-specific antigen (PSA) enhancer was synergistically promoted by exogenous ARFGAP3 and paxillin expression, as shown by luciferase assay in LNCaP cells. Thus, our results suggest that ARFGAP3 is a novel androgen-regulated gene that can promote prostate cancer cell proliferation and migration in collaboration with paxillin.
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Plasma sex hormone levels and mortality in disabled older men and women.
Geriatr Gerontol Int
PUBLISHED: 12-10-2010
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To investigate the relationship between circulating sex hormone levels and subsequent mortality in disabled elderly.
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[Can statins slow the process of vascular calcification? Possibilities of lipid-lowering therapy and pleiotropic effect by statin treatment].
Clin Calcium
PUBLISHED: 11-02-2010
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Widespread vascular calcification is a ubiquitous feature of aging and is prevalent in association with several atherosclerotic diseases. HMG-CoA reductase inhibitors (statins) have been shown to exert protective potentials against cardiovascular diseases via the lipid-lowering and/or their independent pleiotropic effects. Recently, statins have been extensively investigated as potential therapeutic agents capable of slowing the progression of vascular and valvular calcification. However, accumulating recent evidences show that there are conflicting data regarding beneficial effects of statins on progression of cardiovascular calcification. In particular, regarding coronary artery calcification, which is shown to can predict coronary events, it still remains unclear and controversial. To address the positioning of statins as therapeutic strategy for cardiovascular calcification more clearly, clinical studies by intensive therapy using statins throughout long-term period is indispensable in near future. In addition, future investigation about the detailed molecular mechanisms how statins affect calcification process in vascular cells is necessary.
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[Molecular mechanism of vascular aging: impact of vascular smooth muscle cell calcification via cellular senescence].
Clin Calcium
PUBLISHED: 11-02-2010
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Atherosclerotic vascular damage associated with aging manifest several features, namely atherosis, sclerosis and calcified change, finally leading to cardiovascular (CV) events. Accumulating recent reports show the importance of cellular senescence in atherosclerogenesis; however, few reports have addressed whether cellular senescence is associated with smooth muscle cells (SMC) calcification. Recent report has demonstrated the association of senescent phenotypic change with osteoblastic trans-differentiation in VSMC. In addition, our new findings show that the possibility of dynamic action of sirtuin, which is well known as a longevity gene, as a negative regulator in the cellular senescence-related vascular calcification. Strategies how to manage senescent phenotypic change in VSMC may provide novel therapeutic opportunities for the prevention of vascular calcification.
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Pregnane X receptor knockout mice display osteopenia with reduced bone formation and enhanced bone resorption.
J. Endocrinol.
PUBLISHED: 09-27-2010
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The steroid and xenobiotic receptor (SXR) and its murine ortholog pregnane X receptor (PXR) are nuclear receptors that are expressed mainly in the liver and intestine where they function as xenobiotic sensors. In addition to its role as a xenobiotic sensor, previous studies in our laboratories and elsewhere have identified a role for SXR/PXR as a mediator of bone homeostasis. Here, we report that systemic deletion of PXR results in marked osteopenia with mechanical fragility in female mice as young as 4 months old. Bone mineral density (BMD) of PXR knockout (PXRKO) mice was significantly decreased compared with the BMD of wild-type (WT) mice. Micro-computed tomography analysis of femoral trabecular bones revealed that the three-dimensional bone volume fraction of PXRKO mice was markedly reduced compared with that of WT mice. Histomorphometrical analysis of the trabecular bones in the proximal tibia showed a remarkable reduction in bone mass in PXRKO mice. As for bone turnover of the trabecular bones, bone formation is reduced, whereas bone resorption is enhanced in PXRKO mice. Histomorphometrical analysis of femoral cortical bones revealed a larger cortical area in WT mice than that in PXRKO mice. WT mice had a thicker cortical width than PXRKO mice. Three-point bending test revealed that these morphological phenotypes actually caused mechanical fragility. Lastly, serum levels of phosphate, calcium, and alkaline phosphatase were unchanged in PXRKO mice compared with WT. Consistent with our previous results, we conclude that SXR/PXR promotes bone formation and suppresses bone resorption thus cementing a role for SXR/PXR as a key regulator of bone homeostasis.
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Visceral fat accumulation and metabolic risk factor clustering in older adults.
J Am Geriatr Soc
PUBLISHED: 09-25-2010
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To examine the relationship between visceral fat area (VFA) evaluated using computed tomography (CT) scans and the number of metabolic risk factors in older adults.
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Induction of endothelial nitric oxide synthase, SIRT1, and catalase by statins inhibits endothelial senescence through the Akt pathway.
Arterioscler. Thromb. Vasc. Biol.
PUBLISHED: 08-12-2010
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Statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) have pleiotropic vascular protective effects besides cholesterol lowering. Recently, experimental and clinical studies have indicated that senescence of endothelial cells is involved in endothelial dysfunction and atherogenesis. Therefore, the present study was performed to determine whether statins would reduce endothelial senescence and to clarify the molecular mechanisms underlying the antisenescent property of statins.
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Identification of non-synonymous polymorphisms in the WDSOF1 gene as novel susceptibility markers for low bone mineral density in Japanese postmenopausal women.
Bone
PUBLISHED: 05-19-2010
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Genetic factors are important for the development of osteoporosis. During the search for novel markers of single-nucleotide polymorphisms (SNPs) associated with bone mineral density (BMD) by performing a large-scale SNP screen with 251 Japanese postmenopausal women utilizing 50K SNP array, we here focused on the rs1370005 in the WD repeats and SOF1 domain-containing (WDSOF1) gene because we could found common non-synonymous variants in this WDSOF1 gene. The analysis of linkage disequilibrium (LD) in the WDSOF1 gene revealed that rs1370005 and 3 other non-synonymous SNPs (Arg47Ser, Pro108Leu and Ile194Val) lie in a 30-kb region of high LD. Quantitative real-time PCR (qRT-PCR) analysis showed that WDSOF1 mRNA was expressed in mouse primary osteoblasts and osteoclasts, suggesting that WDSOF1 plays some roles in the bone metabolism. We examined the 3 non-synonymous SNPs in WDSOF1 gene in 750 Japanese postmenopausal women. A trend test showed that Arg47Ser, Pro108Leu, and Ile194Val genotypes were significant associated with total body BMD (Arg47Ser; P=0.021, Pro108Leu; P=0.022 and Ile194Val; P=0.009). We also compared Z scores for total body BMD between the subjects bearing at least one minor allele and those lacking the minor allele using unpaired t test. Subjects with the one or two minor alleles had significantly lower Z scores for total body BMD (Arg47Ser; P=0.010, Pro108Leu; P=0.019 and Ile194Val; P=0.003). The present study suggests that these non-synonymous WDSOF1 polymorphisms play a role in the genetic susceptibility to osteoporosis.
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Effects of dehydroepiandrosterone supplementation on cognitive function and activities of daily living in older women with mild to moderate cognitive impairment.
Geriatr Gerontol Int
PUBLISHED: 05-17-2010
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There is little evidence that dehydroepiandrosterone (DHEA) has beneficial effects on physical and psychological functions in older women. We investigated the effect of DHEA supplementation on cognitive function and ADL in older women with cognitive impairment.
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Single-nucleotide polymorphism in the hyaluronan and proteoglycan link protein 1 (HAPLN1) gene is associated with spinal osteophyte formation and disc degeneration in Japanese women.
Eur Spine J
PUBLISHED: 04-02-2010
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Spinal osteoarthritis including disc degeneration is a very common condition in the axial skeletons of aged people. Recently, spinal osteoarthritis has been shown to be influenced by specific genetic risk factors. Vertebral osteophytes, endplate sclerosis, and intervertebral disc narrowing are recognized as radiographic features of spinal disc degeneration. HAPLN1 is a key component of the cartilage extracellular matrix; thus, variations in this gene may affect the pathogenesis of cartilage-related diseases such as spinal degeneration. Here, we examine the association between an HAPLN1 gene polymorphism and the radiographic features of spinal degeneration. We evaluated the degree of endplate sclerosis, osteophyte formation, and disc space narrowing in 622 Japanese postmenopausal women. Four SNPs in the HAPLN1 gene-in the 5 flanking region, intron 1, intron 2, and intron 4-were analyzed using the TaqMan polymerase chain reaction method. We found that compared to subjects with the CC or CT genotype, those with the TT genotype for an SNP at intron 2 (rs179851) were significantly overrepresented among the subjects with higher scores for osteophyte formation (P = 0.0001; odds ratio 2.12; 95% confidence interval 1.45-3.11, as determined by logistic regression analysis) and disc space narrowing (P = 0.0057; odds ratio 1.83; 95% confidence interval 1.19-2.83). Consistent with the involvement of the HAPLN1 gene in cartilage metabolism, a variation in a specific HAPLN1 gene locus may be associated with spinal degeneration.
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[A case of limbic encephalitis with small cell lung carcinoma in which the cognitive function improved and redeteriorated during tumor therapy].
Nihon Ronen Igakkai Zasshi
PUBLISHED: 03-27-2010
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We report the findings regarding a 70-year-old man with paraneoplastic limbic encephalitis. He presented with a chief complaint of inability to recall any events. He had been well until one month before admission, and then he abruptly began to show progressive amnesia. At admission, the patients score on the Revised Hasegawa Dementia Scale (HDS-R) showed a decline to 13/30, thus indicating the existence of severe disorientation and an impaired memory. The brain CT and EEG showed no specific abnormalities and an analysis of cerebrospinal fluid showed only a mild increase in the total protein level. A chest X-ray film revealed a mass in the right hilum, while a histological analysis of the biopsied specimen finally established a diagnosis of small cell lung carcinoma. The FDG-PET and the enhanced brain MRI showed a single small metastatic lesion in the cerebellum. After the 1st course of chemotherapy and whole brain radiation, cognitive function, especially the short-term memory, remarkably improved and the HDS-R score increased to 21/30. However, the tumor again increased in size during the 3(rd) and 4(th) courses of chemotherapy. Interestingly, cognitive function also worsened again and the score of HDS-R declined to 15/30, 20 weeks after the start of chemotherapy. Limbic encephalitis can be associated with malignant tumors, such as small cell lung carcinoma, and some reported cases have shown a cognitive improvement after tumor therapy. In our case, we also observed a reworsening of the cognitive function in association with the acquired chemoresistence.
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Association of low testosterone with metabolic syndrome and its components in middle-aged Japanese men.
Hypertens. Res.
PUBLISHED: 03-26-2010
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Epidemiological studies have shown that low testosterone is associated with metabolic syndrome (MetS) in Caucasian men. We investigated whether testosterone level is related to the prevalence of MetS in middle-aged Japanese men. A cross-sectional survey was conducted in 194 men aged 30-64 years (49+/-9). Blood sampling was performed in the morning after a 12-h fast, and the relationship between plasma hormone and MetS was analyzed. Low total testosterone was associated with MetS according to the Japanese criteria (HRs of 2.02 by quartile of testosterone; 95% CI=1.43-2.87) and the International Diabetes Federation criteria (HRs of 1.68 by quartile of testosterone; 95% CI=1.25-2.25). Age-adjusted regression analyses revealed that testosterone was significantly related to the MetS parameters of obesity (beta=-0.365 and -0.343 for waist circumference and body mass index, respectively), hypertension (beta=-0.278 and -0.157 for systolic and diastolic blood pressure, respectively), dyslipidemia (beta=-0.242 and 0.228 for triglycerides and high-density lipoprotein cholesterol, respectively), insulin resistance (beta=-0.253 and -0.333 for fasting plasma glucose and homeostasis model assessment of insulin resistance, respectively) and adiponectin (beta=0.216). Inclusion of waist circumference into the model largely weakened the association of testosterone with other metabolic risk factors. In contrast, high estradiol was associated with MetS and its parameters, mostly attributing to the positive correlation between estradiol and obesity. Dehydroepiandrosterone sulfate was not associated with MetS or its parameters. These results suggest that low testosterone is associated with MetS and its parameters in middle-aged Japanese men. The association between estradiol and MetS needs further investigation.
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SIRT1/eNOS axis as a potential target against vascular senescence, dysfunction and atherosclerosis.
J. Atheroscler. Thromb.
PUBLISHED: 03-09-2010
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Sir2 (silent information regulator-2), an NAD(+)-dependent histone deacetylase, is highly conserved in organisms ranging from archaea to humans. Yeast Sir2 is responsible for silencing at repeated DNA sequences in mating-type loci, telomeres and rDNA, and plays critical roles in DNA repair, stress resistance and longevity.The phenomenon of human aging is known to be a critical cardiovascular risk factor. Senescence of endothelial cells has been proposed to be involved in vascular dysfunction and atherogenesis. Recent studies have demonstrated that mammalian Sirt1 NAD(+)-dependent protein deacetylase, the closest homologue of Sir2, regulates vascular angiogenesis, homeostasis and senescence. This review focuses on SIRT1 as a potential therapeutic target against atherosclerosis.
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Androgen receptor-dependent activation of endothelial nitric oxide synthase in vascular endothelial cells: role of phosphatidylinositol 3-kinase/akt pathway.
Endocrinology
PUBLISHED: 03-01-2010
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The mechanisms of testosterone-induced vasodilatation are not fully understood. This study investigated the effect of testosterone on nitric oxide (NO) synthesis and its molecular mechanism using human aortic endothelial cells (HAEC). Testosterone at physiological concentrations (1-100 nm) induced a rapid (15-30 min) increase in NO production, which was associated with phosphorylation and activation of endothelial NO synthase (eNOS). Then, the involvement of the androgen receptor (AR), which is abundantly expressed in HAEC, was examined. The effect of testosterone on eNOS activation and NO production were abolished by pretreatment with an AR antagonist nilutamide and by transfection with AR small interference RNA. In contrast, testosterone-induced eNOS phosphorylation was unchanged by pretreatment with an aromatase inhibitor or by transfection with ERalpha small interference RNA. 5alpha-Dihydrotestosterone, a nonaromatizable androgen, also stimulated eNOS phosphorylation. Next, the signaling cascade that leads to eNOS phosphorylation was explored. Testosterone stimulated rapid phosphorylation of Akt in a time- and dose-dependent manner, with maximal response at 15-60 min. The rapid phosphorylation of eNOS or NO production induced by testosterone was inhibited by Akt inhibitor SH-5 or by phosphatidylinositol (PI) 3-kinase inhibitor wortmannin. Co-immunoprecipitation assays revealed a testosterone-dependent interaction between AR and the p85alpha subunit of PI3-kinase. In conclusion, testosterone rapidly induces NO production via AR-dependent activation of eNOS in HAEC. Activation of PI3-kinase/Akt signaling and the direct interaction of AR with p85alpha are involved, at least in part, in eNOS phosphorylation.
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Glucocorticoid-induced gene tripartite motif-containing 63 (TRIM63) promotes differentiation of osteoblastic cells.
Endocr. J.
PUBLISHED: 02-20-2010
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Glucocorticoids exert their function by regulating glucocorticoid-responsive genes through interaction with glucocorticoid receptor alpha (GRalpha), a nuclear receptor. Glucocorticoids also affect bone metabolism; this is evidenced by the fact that GRalpha is expressed in several kinds of cells in bone tissue, including osteoblasts, osteocytes, osteoclasts, mononuclear cells in bone marrow, and hypertrophic chondrocytes. Glucocorticoids are known to induce osteoblastic differentiation and bone formation. However, this effect of glucocorticoids on bone tissue is still controversial since long-term use of glucocorticoids results in osteoporosis in vivo. To identify glucocorticoid-regulated genes in human osteoblastic cells, SaOS2 cells were treated with dexamethasone (10(-8) M) for 6 hours, and were then subjected to microarray analysis. Genes such as C/EBPdelta, DUSP1, Per1 and TRIM63 were found to be induced by dexamethasone. The induction of mRNAs of these genes by dexamethasone (10(-8) M, 10(-7) M, and 10(-6) M) was confirmed by quantitative real-time polymerase chain reaction (PCR). TRIM63, also called muscle-specific ring finger protein 1 (MuRF1), was reported to be an E3 ubiquitin ligase expressed mainly in muscular tissue. SaOS2 cells overexpressing exogenous TRIM63 showed increased expression of an osteoblastic differentiation marker gene, alkaline phosphatase, with reduced proliferation. These results suggest that TRIM63 is a candidate for genes mediating the glucocorticoid-induced promotion of osteoblastic differentiation.
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Involvement of androgen receptor in nitric oxide production induced by icariin in human umbilical vein endothelial cells.
FEBS Lett.
PUBLISHED: 02-09-2010
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Icariin, a flavonoid isolated from Epimedii herba, stimulated phosphorylation of endothelial nitric oxide synthase (eNOS) at Ser1177, Akt (Ser473) and ERK1/2 (Thr202/Tyr204). The icariin-induced eNOS phosphorylation was abolished by an androgen receptor (AR) antagonist, nilutamide in human umbilical vein endothelial cells (HUVECs). Furthermore, it was also reduced in the cells transfected with small interfering RNA in which the expression of AR was broken down. The icariin-induced eNOS phosphorylation was inhibited by wortmannin, a phosphatidylinositol 3-kinase (PI3K) inhibitor and partially attenuated by PD98059, an upstream inhibitor for ERK1/2. These data suggest that icariin stimulates release of NO by AR-dependent activation of eNOS in HUVECs. PI3K/Akt and MAPK-ERK kinase (MEK)/ERK1/2 pathways were involved in the phosphorylation of eNOS by icariin.
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Age-related changes in plasma androgen levels and their association with cardiovascular risk factors in male Japanese office workers.
Geriatr Gerontol Int
PUBLISHED: 01-28-2010
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To assess the age-related change in plasma androgen levels in healthy middle-aged men and whether any clinical parameters are associated with the hormonal change.
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Androgen receptor-dependent transactivation of growth arrest-specific gene 6 mediates inhibitory effects of testosterone on vascular calcification.
J. Biol. Chem.
PUBLISHED: 01-04-2010
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Recent epidemiological studies have found that androgen deficiency is associated with a higher incidence of cardiovascular disease in men. However, little is known about the mechanism underlying the cardioprotective effects of androgens. Here we show the inhibitory effects of testosterone on vascular calcification and a critical role of androgen receptor (AR)-dependent transactivation of growth arrest-specific gene 6 (Gas6), a key regulator of inorganic phosphate (P(i))-induced calcification of vascular smooth muscle cells (VSMC). Testosterone and nonaromatizable androgen dihydrotestosterone inhibited P(i)-induced calcification of human aortic VSMC in a concentration-dependent manner. Androgen inhibited P(i)-induced VSMC apoptosis, an essential process for VSMC calcification. The effects on VSMC calcification were mediated by restoration of P(i)-induced down-regulation of Gas6 expression and a subsequent reduction of Akt phosphorylation. These effects of androgen were blocked by an AR antagonist, flutamide, but not by an estrogen receptor antagonist, ICI 182,780. We then explored the mechanistic role of the AR in Gas6 expression and found an abundant expression of AR predominantly in the nucleus of VSMC and two consensus ARE sequences in the Gas6 promoter region. Dihydrotestosterone stimulated Gas6 promoter activity, and this effect was abrogated by flutamide and by AR siRNA. Site-specific mutation revealed that the proximal ARE was essential for androgen-dependent transactivation of Gas6. Furthermore, chromatin immunoprecipitation assays demonstrated ligand-dependent binding of the AR to the proximal ARE of Gas6. These results indicate that AR signaling directly regulates Gas6 transcription, which leads to inhibition of vascular calcification, and provides a mechanistic insight into the cardioprotective action of androgens.
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Differential expression of estrogen-related receptors beta and gamma (ERRbeta and ERRgamma) and their clinical significance in human prostate cancer.
Cancer Sci.
PUBLISHED: 11-27-2009
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Estrogen-related receptor (ERR) is a nuclear receptor that modulates the estrogen-signaling pathway. Here, we investigated the expression of both ERRbeta and ERRgamma in human prostate tissues. Using original rabbit polyclonal anti-ERRbeta and anti-ERRgamma antibodies, the expression of ERRbeta and ERRgamma was evaluated by immunohistochemical analysis of cancerous lesions (n = 107) and benign foci (n = 92), obtained by radical prostatectomy. Stained slides were evaluated for the proportion of immunoreactive cells and their staining intensity. Total immunoreactivity scores (IR scores; range, 0-8) were calculated as the sum of the proportion and intensity scores. The relationship between the clinicopathological characteristics of the patients and the expression of the three ERRs (ERRalpha, ERR beta, and ERR gamma) was evaluated. IR scores for ERRbeta and ERRgamma were significantly lower in cancerous lesions than that in benign foci (P < 0.0001, for both). Clinicopathological analyses revealed that the patients with low ERRgamma IR scores (
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[A case of a primary effusion lymphoma in the elderly].
Nihon Ronen Igakkai Zasshi
PUBLISHED: 10-28-2009
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We report a 90-year-old man who was given a diagnosis of pleural effusion lymphoma (PEL) based on the detailed immunochemical and DNA analyses of the pleural effusion. He was bed-ridden and on enteral nutrition due to severe Alzheimers disease, and also had diabetes mellitus. He was transferred to our hospital with fever and massive pleural effusion. A cytological examination of the pleural effusion revealed class 5 atypical lymphocytes with a high nucleus/cytoplasm ratio. The origin of the atypical cells could not be determined by flow cytometry of the pleural effusion, which only suggested the existence of inflammatory changes. Considering his general physical status, further investigations were not performed. The respiratory failure progressed, and he died on the 45(th) hospital day. At autopsy, no atypical cells were identified in his organs other than in the right thoracic space. We conducted immunochemical staining after making a cell block from the effusion sample. Most of the atypical cells were CD30 positive, with human herpes virus-8 (HHV-8)-associated protein. A PCR analysis of the immunoglobulin heavy chain gene detected monoclonal rearrangement, thus indicating the atypical cells to be involved in the B-cell lineage. These findings led to a final diagnosis of PEL. PEL is a rare type of lymphoma confined to the body cavities without any prominent tumor mass, and its pathogenesis is related to HHV-8 infection. PEL develops mostly in immunocompromised patients, such as those with AIDS. However, it may also occur in elderly patients as well. We should therefore also consider the possibility of PEL in elderly patients presenting with pleural effusion of unknown origin.
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Association of plasma sex hormone levels with functional decline in elderly men and women.
Geriatr Gerontol Int
PUBLISHED: 08-26-2009
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We aimed to determine whether plasma sex hormone levels are associated with activities of daily living (ADL), cognition, depression and vitality in elderly individuals with functional decline.
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Association of a single nucleotide polymorphism in the constitutive androstane receptor gene with bone mineral density.
Geriatr Gerontol Int
PUBLISHED: 08-26-2009
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Nuclear receptors play an important role in bone metabolism. In bone cells, the vitamin D receptor (VDR) and the steroid and xenobiotic receptor (SXR) are activated by vitamin D and vitamin K2, respectively. VDR and SXR are the NR1I subfamily members of nuclear receptors. We speculated that the constitutive androstane receptor (CAR), the third member of the NR1I subfamily, also could be implicated in the regulation of bone metabolism. Therefore, we analyzed expression of CAR mRNA in osteoblasts and then examined association of a single nucleotide polymorphism (SNP) in the human CAR gene at intron 2 (IVS2-99C>T, rs2502815) with bone mineral density (BMD).
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Low testosterone level as a predictor of cardiovascular events in Japanese men with coronary risk factors.
Atherosclerosis
PUBLISHED: 08-25-2009
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Recent epidemiological studies have found that testosterone deficiency is associated with higher mortality largely due to cardiovascular (CV) disease in community-dwelling older men. We investigated whether a low plasma testosterone level could predict cardiovascular events in middle-aged Japanese men with coronary risk factors.
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Aortic arch calcification detectable on chest X-ray is a strong independent predictor of cardiovascular events beyond traditional risk factors.
Atherosclerosis
PUBLISHED: 07-29-2009
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Arterial calcification makes the management of hemodynamics more difficult. Some reports have previously shown that simple assessment of aortic calcification using plain radiography is associated with cardiovascular (CV) events; however, these studies simply assessed whether aortic calcification was present or absent only, without considering its extent. Here, we evaluated validity of grading aortic arch calcification (AAC) to predict new CV events.
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A1330V variant of the low-density lipoprotein receptor-related protein 5 (LRP5) gene decreases Wnt signaling and affects the total body bone mineral density in Japanese women.
Endocr. J.
PUBLISHED: 07-01-2009
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Wnt signaling is an important regulator of bone homeostasis. The Wnt co-receptor, namely, low-density lipoprotein receptor-related protein 5 (LRP5), initiates Wnt signal transduction. Recently, we and several other groups have shown that there is a single nucleotide polymorphism (SNP) located in the exon 18 of the LRP5 gene that leads to an amino acid change (3989C > T, A1330V), and is associated with lumbar spine, femoral neck, and radial bone mineral density (BMD), and incidence of fracture. These data suggest that the A1330V variation in the LRP5 gene may affect the pathogenesis of osteoporosis. However, the functional basis of the A1330V variation remains unclear. In the present study, we analyzed the effect of the A1330V variation on Wnt activity. We also investigated the association between this LRP5 SNP and total body BMD using 739 postmenopausal women. LRP5 with the A1330V SNP were transiently coexpressed with Wnt3a in 293T cells and their activity was evaluated by the TCF-Lef reporter assay. In vitro, the TCF-Lef activity in presence of Wnt3a in cells expressing LRP5 and carrying the T allele (Valine at 1330 (V1330)) of exon 18 was significantly reduced as compared to the wild-type allele. The association between the A1330V SNP and total body BMD were replicated in 739 postmenopausal Japanese women (AA vs. VV; P = 0.0026). These data suggest that the V1330 variant in the LRP5 gene decreases Wnt activity, which in turn decreases the BMD.
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Validity and usefulness of aortic arch calcification in chest X-ray.
J. Atheroscler. Thromb.
PUBLISHED: 06-25-2009
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Arterial calcification is associated with cardiovascular (CV) disease, to be leading to vessel wall stiffness and causing the management of hemodynamics in the elderly more difficult. Here, we compared the extent of calcification in the aortic arch by reviewing chest X-rays to that in the abdominal aorta as assessed by more detailed examinations. In addition, the validity of the grading and the relationship of this useful grading to clinical risk factors were evaluated.
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Vitamin K2 suppresses proliferation and motility of hepatocellular carcinoma cells by activating steroid and xenobiotic receptor.
Endocr. J.
PUBLISHED: 06-24-2009
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Vitamin K2, known as a cofactor for gamma-carboxylase, also serves as a ligand of a nuclear receptor, Steroid and Xenobiotic Receptor (SXR). Several clinical trials revealed that vitamin K2 reduced de novo formation and recurrence of hepatocellular carcinoma (HCC). To examine the role of SXR in HCC as a receptor activated by vitamin K2, the cells stably overexpressing SXR were established using a HCC cell line, HuH7. Overexpression of SXR resulted in reduced proliferation and motility of the cells. Further suppression of proliferation and motility was observed when SXR overexpressing clones were treated with vitamin K2. These results suggest that the activation of SXR could contribute to tumor suppressive effects of vitamin K2 on HCC cells.
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TRIM44 interacts with and stabilizes terf, a TRIM ubiquitin E3 ligase.
Biochem. Biophys. Res. Commun.
PUBLISHED: 03-24-2009
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Terf/TRIM17 is a member of the TRIM family of proteins, which is characterized by the RING finger, B-box, and coiled-coil domains. In the present study, we found that terf interacts with TRIM44. Terf underwent ubiquitination in vitro in the presence of the E2 enzyme UbcH6; this suggests that terf exhibits E3 ubiquitin ligase activity. It was also found that terf was conjugated with polyubiquitin chains and stabilized by the proteasome inhibitor in mammalian cells; this suggested that terf rendered itself susceptible to proteasomal degradation through polyubiquitination. We also found that TRIM44 inhibited ubiquitination of terf, and thus stabilized the protein. The N-terminal region of TRIM44 contains a zinc-finger domain found in ubiquitin hydrolases (ZF UBP) and ubiquitin specific proteases (USPs). Thus, we proposed that TRIM44 may function as a new class of the "USP-like-TRIM" which regulates the activity of associated TRIM proteins.
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Association of estrogen receptor alpha and histone deacetylase 6 causes rapid deacetylation of tubulin in breast cancer cells.
Cancer Res.
PUBLISHED: 03-24-2009
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Estrogen receptor alpha (ERalpha) is a nuclear receptor that functions as a ligand-activated transcription factor. Besides its genomic action in nuclei, ERalpha could exert nongenomic actions at the plasma membrane. To investigate the mechanism underlying the nongenomic action of ERalpha in breast cancer cells, we generated a construct of membrane-targeted ERalpha (memER), an expression vector of ERalpha without the nuclear localizing signal and including instead the membrane-targeting sequence of Src kinase. MemER was stably expressed in human breast cancer MCF-7 cells. Cell migration test and tumorigenic assay in nude mice revealed that the in vitro motility and the in vivo proliferation activity of MCF-7 cells expressing memER were significantly enhanced compared with those of vector-transfected cells. Interestingly, the acetylation level of tubulin in memER-overexpressing cells was lower than that in control cells. We found that histone deacetylase (HDAC) 6 translocated to the plasma membrane shortly after estrogen stimulation, and rapid tubulin deacetylation subsequently occurred. We also showed that memER associated with HDAC6 in a ligand-dependent manner. Although tamoxifen is known for its antagonistic role in the ERalpha genomic action in MCF-7 cells, the agent showed an agonistic function in the memER-HDAC6 association and tubulin deacetylation. These findings suggest that ERalpha ligand dependently forms a complex with HDAC6 and tubulin at the plasma membrane. Estrogen-dependent tubulin deacetylation could provide new evidence for the nongenomic action of estrogen, which potentially contributes to the aggressiveness of ERalpha-positive breast cancer cells.
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Bone mass effects of a Smad6 gene polymorphism in Japanese postmenopausal women.
J. Bone Miner. Metab.
PUBLISHED: 03-10-2009
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Smad6 plays pivotal roles in the negative regulation of transforming growth factor beta (TGFbeta) family signaling as one of the feedback molecules. Here, we analyzed whether the human Smad6 gene is involved in the regulation of bone mass, using association analysis between bone mineral density (BMD) and single-nucleotide polymorphism (SNP) in the Smad6 gene. Association of an SNP at IVS3+26115A>C (intron 3, rs755451) in the Smad6 gene with BMD was examined in 721 Japanese postmenopausal Japanese women (age 65.2 +/- 9.6 years; mean +/- SD). The subjects bearing at least one variant C allele (CC +/- AC; n = 387) had significantly lower Z-scores for total body and lumbar BMD than the subjects with no C allele (AA; n = 334) (total body, 0.23 +/- 0.98 versus 0.50 +/- 1.07; P = 0.0004; lumbar spine, -0.20 +/- 1.38 versus 0.10 +/- 1.48; P = 0.0050). These findings suggest that the Smad6 gene is a candidate for the genetic determinants of BMD in postmenopausal women, and this SNP could be useful as a genetic marker for predicting the risk of osteoporosis.
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Sirolimus and everolimus induce endothelial cellular senescence via sirtuin 1 down-regulation: therapeutic implication of cilostazol after drug-eluting stent implantation.
J. Am. Coll. Cardiol.
PUBLISHED: 01-27-2009
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The aim of this study was to compare the effects of paclitaxel, sirolimus, and everolimus on the senescent phenotype in human endothelial cells, and to further investigate possible involvement of mammalian sirtuin 1 (Sirt1) down-regulation as a mechanism.
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Comparison of the effects of the kinase inhibitors imatinib, sorafenib, and transforming growth factor-beta receptor inhibitor on extravasation of nanoparticles from neovasculature.
Cancer Sci.
PUBLISHED: 01-24-2009
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There are a number of kinase inhibitors that regulate components of the neovasculature. We previously reported the use of transforming growth factor (TGF)-beta inhibitor on neovasculature in stroma-rich tumor models to increase the intratumoral distribution of nanoparticles. Here, we compared the effects of two other kinase inhibitors, imatinib and sorafenib, with TGF-beta inhibitor (LY364947) on extravasation of a modeled nanoparticle, 2 MDa dextran. We first used a mouse model of neoangiogenesis, the Matrigel plug assay, to compare neovasculature formed inside of and around Matrigel plugs (intraplug and periplug regions, respectively). Intraplug vasculature was more strongly pericyte covered, whereas periplug vasculature was less covered. In this model, TGF-beta inhibitor exhibited the most potent effect on intraplug vasculature in increasing the extravasation of dextran, whereas sorafenib had the strongest effect on periplug vasculature. Although imatinib and TGF-beta inhibitor each reduced pericyte coverage, imatinib also reduced the density of endothelium, resulting in a decrease in overall delivery of nanoparticles. These findings were confirmed in two tumor models, the CT26 colon cancer model and the BxPC3 pancreatic cancer model. The vasculature phenotype in the CT26 model resembled that in the periplug region, whereas the latter resembled that in the intraplug region. Consistent with this, sorafenib most potently enhanced the accumulation of nanoparticles in the CT26 model, whereas TGF-beta inhibitor did in the BxPC3 model. In conclusion, the appropriate strategy for optimization of tumor vasculature for nanoparticles may differ depending on tumor type, and in particular on the degree of pericyte coverage around the vasculature.
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Estrogen receptor-binding fragment-associated gene 9 expression and its clinical significance in human testicular cancer.
Int. J. Urol.
PUBLISHED: 01-20-2009
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We previously demonstrated that estrogen receptor-binding fragment-associated gene 9 (EBAG9) is a tumor promoting factor in renal cell carcinoma (Ogushi T, Cancer Res. 2005; 65: 3700). Here, we evaluated EBAG9 expression and its clinical significance in normal and malignant human testicular tissues.
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Expression of cytochrome P450 3A4 and its clinical significance in human prostate cancer.
Urology
PUBLISHED: 01-17-2009
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To evaluate CYP3A4 expression in human prostrate cancer (PCa) tissues. Enzymes of the cytochrome P450 (CYP) family are key inactivators of testosterone in the liver and prostate. We previously reported that CYP2B6 is a growth-inhibitory and prognostic factor in human PCa; however, the status of CYP3A4 in PCa remains unclear.
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EBAG9 is a tumor-promoting and prognostic factor for bladder cancer.
Int. J. Cancer
PUBLISHED: 01-15-2009
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Upregulation of EBAG9 expression has been observed in several malignant tumors such as advanced breast and prostate cancers, indicating that EBAG9 may contribute to tumor proliferation. In the present study, we assess the role of EBAG9 in bladder cancer. We generated human bladder cancer EJ cells stably expressing FLAG-tagged EBAG9 (EJ-EBAG9) or empty vector (EJ-vector), and investigated whether EBAG9 overexpression modulates cell growth and migration in vitro as well as the in vivo tumor formation of EJ transfectants in xenograft models of BALB/c nude mice. EBAG9 overexpression promoted EJ cell migration, while the effect of EBAG9 to cultured cell growth was rather minimal. Tumorigenic experiments in nude mice showed that the size of EJ-EBAG9-derived tumors was significantly larger than EJ-vector-derived tumors. Loss-of-function study for EBAG9 using small interfering RNA (siRNA) in xenografts with parental EJ cells showed that the intra-tumoral injection of EBAG9 siRNA markedly reduced the EJ tumor formation compared with control siRNA. Furthermore, immunohistochemical study for EBAG9 expression was performed in 60 pathological bladder cancer specimens. Intense and diffuse cytoplasmic immunostaining was observed in 45% of the bladder cancer cases. Positive EBAG9 immunoreactivity was closely correlated with poor prognosis of the patients (p = 0.0001) and it was an independent prognostic predictor for disease-specific survival in multivariate analysis (p = 0.003). Our results indicate that EBAG9 would be a crucial regulator of tumor progression and a potential prognostic marker for bladder cancer.
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Association of HTRA1 promoter polymorphism with spinal disc degeneration in Japanese women.
J. Bone Miner. Metab.
PUBLISHED: 01-09-2009
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HTRA1 (high-temperature requirement A1) has been implicated in the modulation of various disease pathologies. HTRA1 expression is upregulated in osteoarthritic joints, suggesting that it may contribute to the development of this debilitating disease. Moreover, recent reports have shown that the rs11200638, a single nucleotide polymorphism (SNP) in the promoter region of the HTRA1 gene, is strongly associated with an increased prevalence of age-related macular degeneration (AMD). In the present study, we examined the expression of the HTRA1 in human primary chondrocytes and an association between the rs11200638 SNP and radiographic features of spinal disc degeneration in 513 postmenopausal Japanese women. HTRA1 mRNA was detected and increased by TGF-beta treatment in human primary chondrocytes. As an association study of rs11200638 SNP in the HTRA1 gene, the subjects without the G allele (AA; n = 89) had a significantly higher spinal disc space narrowing score than the subjects bearing at least one G allele (GG + GA; n = 424) (P = 0.0292). We found that subjects without the G allele (AA) were significantly overrepresented in the subjects having a higher (> or =4) disc space narrowing score (P = 0.013; odds ratio 1.97; 95% confidence interval 1.15-3.37 by logistic regression analysis). A genetic variation at the HTRA1 gene promoter locus is associated with spinal disc degeneration, suggesting an involvement of the HTRA1 gene in osteoarthritis.
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Amyloid precursor protein is a primary androgen target gene that promotes prostate cancer growth.
Cancer Res.
PUBLISHED: 01-02-2009
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Androgen receptor (AR) is a critical transcription factor that regulates various target genes and contributes to the pathophysiology of prostate cancer hormone dependently. Here, we identify amyloid precursor protein (APP) as a primary androgen target through chromatin immunoprecipitation (ChIP) combined with genome tiling array analysis (ChIP-chip). ChIP-treated DNA were obtained from prostate cancer LNCaP cells with R1881 or vehicle treatment using AR or acetylated histone H3 antibodies. Ligand-dependent AR binding was further enriched by PCR subtraction. Using chromosome 21/22 arrays, we identified APP as one of the androgen-regulated genes with adjacent functional AR binding sites. APP expression is androgen-inducible in LNCaP cells and APP immunoreactivity was correlated with poor prognosis in patients with prostate cancer. Gain-of-function and loss-of-function studies revealed that APP promotes the tumor growth of prostate cancer. The present study reveals a novel APP-mediated pathway responsible for the androgen-dependent growth of prostate cancer. Our findings will indicate that APP could be a potential molecular target for the diagnosis and treatment of prostate cancer.
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A selective estrogen receptor modulator inhibits TNF-alpha-induced apoptosis by activating ERK1/2 signaling pathway in vascular endothelial cells.
Vascul. Pharmacol.
PUBLISHED: 01-01-2009
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Tumor necrosis factor (TNF-alpha) is a pleiotropic cytokine exerting both inflammatory and cell death activity and is thought to play a role in the pathogenesis of atherosclerosis. The present study was designed to examine whether the raloxifene analogue, LY117018 could inhibit TNF-alpha-induced apoptosis in vascular endothelial cells and to clarify the involved mechanisms. Apoptosis of endothelial cells was determined by DNA fragmentation assay and the activation of caspase-3. LY117018 significantly inhibited TNF-alpha-induced caspase-3 activation and cell DNA fragmentation levels in bovine carotid artery endothelial cells. The inhibitory effect of LY117018 was abolished by an estrogen receptor antagonist ICI 182,780. p38 MAPK, JNK, ERK1/2 and Akt have been shown to act as apoptotic or anti-apoptotic signals. TNF-alpha stimulated the phosphorylation levels of p38 MAPK, JNK, ERK1/2 and Akt in vascular endothelial cells. TNF-alpha-induced apoptosis was significantly decreased by SB203580, a p38 MAPK inhibitor or SP600125, a JNK inhibitor, but was enhanced by an ERK1/2 pathway inhibitor, PD98059 or a PI3-kinase/Akt pathway inhibitor, wortmannin. The anti-apoptotic effect of LY117018 was abrogated only by PD98059 but was not affected by the inhibitors for p38 MAPK, JNK, or Akt. LY117018 stimulated the further increase in phosphorylation of ERK1/2 in TNF-alpha treated endothelial cells but it did not affect phosphorylation levels of p38 MAPK, JNK or Akt. These results suggest that LY 110718 prevents caspase-3 dependent apoptosis induced by TNF-alpha in vascular endothelial cells through activation of the estrogen receptors and the ERK1/2 signaling pathway.
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Thrombomodulin, a novel molecule regulating inorganic phosphate-induced vascular smooth muscle cell calcification.
J. Mol. Cell. Cardiol.
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Hyperphosphatemia has emerged as a cardiovascular risk factor that stimulates calcification in vessels. We explored molecules that were induced by inorganic phosphate (Pi) at an early stage in vascular smooth muscle cells (VSMC). In the present study, we examined the role of thrombomodulin (TM) in Pi-induced VSMC calcification based on the results of DNA microarray analysis. Both mRNA and protein expression of TM were markedly augmented in Pi-induced calcification. Conversely, knockdown of TM by siRNA significantly inhibited calcification, in addition to Pi-induced apoptosis which plays critical roles in VSMC calcification. We further found that TM suppressed both of mRNA and protein expression of growth arrest-specific gene 6 (Gas6), a key molecule regulating apoptosis. Recombinant extracellular epidermal growth factor (EGF)-repeat domain of TM exaggerated calcification and this effect was abrogated by a neutralizing antibody for EGF receptor, suggesting that the cleaved and secreted form of TM may activate EGF receptor. We also found that downregulation of Gas6 by TM/EGF receptor axis was mediated by ERK in VSMC calcification. In the aorta of adenine-fed rat, a typical medial calcification model with hyperphosphatemia, we found that TM expression was increased. Furthermore, in human calcified aorta, increased TM expression was also observed. These results indicate that TM is a novel molecule that promotes apoptosis and vascular calcification by regulation of Gas6, presumably via EGF receptor/ERK axis.
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Ginsenoside Rb1 Prevents MPP(+)-Induced Apoptosis in PC12 Cells by Stimulating Estrogen Receptors with Consequent Activation of ERK1/2, Akt and Inhibition of SAPK/JNK, p38 MAPK.
Evid Based Complement Alternat Med
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Ginsenoside Rb1 shows neuroprotective effects in various neurons, including dopaminergic cells. However, the precise mechanisms of action are uncertain. In this paper, we examine whether Rb1 has a neuroprotective effect on MPP(+)-induced apoptosis and attempt to clarify the signaling pathway in PC12 cells. Apoptosis of PC12 cells was determined by DNA fragmentation assay, the activation of caspase-3, or by the inactivation of Bcl-xL. Rb1 inhibited MPP(+)-induced caspase-3 activation and DNA fragmentation and activated Bcl-xL in MPP(+)-treated PC12 cells. These antiapoptotic effect was abrogated in PC12 cells transfected with estrogen receptor siRNA. Levels of DNA fragmentation were increased by wortmannin or PD 98059, while they were decreased by SB 203580 or SP 600125 in MPP(+)-treated PC12 cells. Rb1 increased phosphorylation levels of ERK1/2 or Akt in MPP(+)-treated PC12 cells, while it reduced phosphorylated p38 or SAPK/JNK. The increased phosphorylation of ERK/1/2 or Akt by Rb1 was abrogated by estrogen receptor siRNA. Rb1-induced inhibition of SAPK/JNK or p38 phosphorylation was also abolished by estrogen receptor siRNA. These results suggest that ginsenoside Rb1 protects PC12 cells from caspase-3-dependent apoptosis through stimulation of estrogen receptor with consequent activation of ERK1/2 and Akt and inhibition of SAPK/JNK and p38.
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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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