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Find video protocols related to scientific articles indexed in Pubmed.
Angiotensin II type 1 receptor blockade ameliorates proteinuria in puromycin aminonucleoside nephropathy by inhibiting the reduction of NEPH1 and nephrin.
J. Nephrol.
PUBLISHED: 07-28-2014
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The precise pathogenic mechanism and role of angiotensin II (Ang II) action in the development of proteinuria in minimal change nephrotic syndrome (MCNS) is uncertain.
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Therapeutic effect of anti-C-X-C motif chemokine 10 (CXCL10) antibody on C protein-induced myositis mouse.
Arthritis Res. Ther.
PUBLISHED: 06-06-2014
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C-X-C motif chemokine 10 (CXCL10) is a chemokine that plays a critical role in the infiltration of T cells in autoimmune diseases and is reported to be expressed in muscle tissue of polymyositis. To determine the therapeutic efficacy of CXCL10 blockade, we investigated the role of CXCL10 and the effect of anti-CXCL10 antibody treatment in C protein-induced myositis (CIM), an animal model of polymyositis.
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Therapeutic target for nephrotic syndrome: Identification of novel slit diaphragm associated molecules.
World J Nephrol
PUBLISHED: 03-26-2014
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The slit diaphragm bridging the neighboring foot processes functions as a final barrier of glomerular capillary wall for preventing the leak of plasma proteins into primary urine. It is now accepted that the dysfunction of the sit diaphragm contributes to the development of proteinuria in several glomerular diseases. Nephrin, a gene product of NPHS1, a gene for a congenital nephrotic syndrome of Finnish type, constitutes an extracellular domain of the slit diaphragm. Podocin was identified as a gene product of NPHS2, a gene for a familial steroid-resistant nephrotic syndrome of French. Podocin binds the cytoplasmic domain of nephrin. After then, CD2 associated protein, NEPH1 and transient receptor potential-6 were also found as crucial molecules of the slit diaphragm. In order to explore other novel molecules contributing to the development of proteinuria, we performed a subtraction hybridization assay with a normal rat glomerular RNA and a glomerular RNA of rats with a puromycin aminonucleoside nephropathy, a mimic of a human minimal change type nephrotic syndrome. Then we have found that synaptic vesicle protein 2B, ephrin-B1 and neurexin were already downregulated at the early stage of puromycin aminonucleoside nephropathy, and that these molecules were localized close to nephrin. It is conceivable that these molecules are the slit diaphragm associated molecules, which participate in the regulation of the barrier function. These molecules could be targets to establish a novel therapy for nephrotic syndrome.
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Changes in the microvascular structure of mucosal squamous cell carcinoma of the esophagus and their significance in tumor progression.
J. Med. Dent. Sci.
PUBLISHED: 01-28-2014
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To identify the clinical T stage by endoscopy is a major diagnostic goal for superficial esophageal squamous cell carcinoma (ESCC). The completion of a microvascular morphological study of mucosal lesions is necessary to optimize therapy.
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Intracellular Propionibacterium acnes infection in glandular epithelium and stromal macrophages of the prostate with or without cancer.
PLoS ONE
PUBLISHED: 01-01-2014
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Recent reports on Propionibacterium acnes (P. acnes) suggest that this bacterium is prevalent in the prostate, is associated with acute and chronic prostatic inflammation, and might have a role in prostate carcinogenesis.
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Twisted gastrulation, a BMP antagonist, exacerbates podocyte injury.
PLoS ONE
PUBLISHED: 01-01-2014
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Podocyte injury is the first step in the progression of glomerulosclerosis. Previous studies have demonstrated the beneficial effect of bone morphogenetic protein 7 (Bmp7) in podocyte injury and the existence of native Bmp signaling in podocytes. Local activity of Bmp7 is controlled by cell-type specific Bmp antagonists, which inhibit the binding of Bmp7 to its receptors. Here we show that the product of Twisted gastrulation (Twsg1), a Bmp antagonist, is the central negative regulator of Bmp function in podocytes and that Twsg1 null mice are resistant to podocyte injury. Twsg1 was the most abundant Bmp antagonist in murine cultured podocytes. The administration of Bmp induced podocyte differentiation through Smad signaling, whereas the simultaneous administration of Twsg1 antagonized the effect. The administration of Bmp also inhibited podocyte proliferation, whereas simultaneous administration of Twsg1 antagonized the effect. Twsg1 was expressed in the glomerular parietal cells (PECs) and distal nephron of the healthy kidney, and additionally in damaged glomerular cells in a murine model of podocyte injury. Twsg1 null mice exhibited milder hypoalbuminemia and hyperlipidemia, and milder histological changes while maintaining the expression of podocyte markers during podocyte injury model. Taken together, our results show that Twsg1 plays a critical role in the modulation of protective action of Bmp7 on podocytes, and that inhibition of Twsg1 is a promising means of development of novel treatment for podocyte injury.
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Characterization of perineural invasion as a component of colorectal cancer staging.
Am. J. Surg. Pathol.
PUBLISHED: 09-13-2013
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Perineural invasion (PN) in colorectal cancer (CRC) is a site-specific prognostic marker, as mentioned by the AJCC Cancer Staging Manual, but it remains to be clearly defined. We aimed to identify an optimal characterization of PN as a component of cancer staging. On the basis of the anatomic features of the nervous system of the large bowel, site-specific pathologic criteria were assigned to PN according to the location of PN. Multi-institutional pathologic review based on these criteria was performed for 962 patients with stage I to III CRC at 2 institutions (1999 to 2004, cohort 1) and 1883 patients from 8 other institutions (2000 to 2004, cohort 2). In cohort 1, intramural and extramural PN were observed in 152 and 101 patients, respectively, which had a different impact on disease-free survival (hazard ratio, 2.6 [1.9 to 3.5] vs. 4.7 [3.4 to 6.5], respectively). A 3-tiered grading system (Pn0; Pn1a, intramural PN; Pn1b, extramural PN) distinguished 5-year disease-free survival as 88%, 70%, and 48%, respectively; and multivariate analysis identified PN grade as a significant prognostic marker independent of T or N stage. These results were similar in cohort 2. Interinstitutional difference of the prognostic impact of PN grade was acceptably small among all institutions. Interobserver study among 6 gastrointestinal pathologists showed superior judgment reproducibility for PN compared with vascular invasion. The results of our study indicate that PN is an important prognostic marker in CRC. The value of cancer staging could be enhanced by PN assessment using site-specific criteria and a simple grading system based on PN location within the bowel.
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Planar cell polarity pathway regulates nephrin endocytosis in developing podocytes.
J. Biol. Chem.
PUBLISHED: 07-03-2013
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The noncanonical Wnt/planar cell polarity (PCP) pathway controls a variety of cell behaviors such as polarized protrusive cell activity, directional cell movement, and oriented cell division and is crucial for the normal development of many tissues. Mutations in the PCP genes cause malformation in multiple organs. Recently, the PCP pathway was shown to control endocytosis of PCP and non-PCP proteins necessary for cell shape remodeling and formation of specific junctional protein complexes. During formation of the renal glomerulus, the glomerular capillary becomes enveloped by highly specialized epithelial cells, podocytes, that display unique architecture and are connected via specialized cell-cell junctions (slit diaphragms) that restrict passage of protein into the urine; podocyte differentiation requires active remodeling of cytoskeleton and junctional protein complexes. We report here that in cultured human podocytes, activation of the PCP pathway significantly stimulates endocytosis of the core slit diaphragm protein, nephrin, via a clathrin/?-arrestin-dependent endocytic route. In contrast, depletion of the PCP protein Vangl2 leads to an increase of nephrin at the cell surface; loss of Vangl2 functions in Looptail mice results in disturbed glomerular maturation. We propose that the PCP pathway contributes to podocyte development by regulating nephrin turnover during junctional remodeling as the cells differentiate.
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?-Glutamylcyclotransferase as a novel immunohistochemical biomarker for the malignancy of esophageal squamous tumors.
Hum. Pathol.
PUBLISHED: 05-22-2013
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Recently, overexpression of ?-glutamylcyclotransferase (GGCT) has been reported in various cancer tissues suggesting that it has significant potential as a diagnostic marker. The aim of this study was to examine the suitability of GGCT for the detection of high-risk lesions at an early stage of esophageal squamous cell carcinoma (ESCC). A total of 200 lesions, including 120 invasive ESCC, 80 esophageal squamous intraepithelial neoplasia consisting of 40 low-grade intraepithelial neoplasia (LGIEN) and 40 high-grade intraepithelial neoplasia (HGIEN), as well as 20 confounding lesions, were examined by immunohistochemical (IHC) staining for GGCT. IHC staining for Ki-67 and p53 was also performed in esophageal squamous intraepithelial neoplasia to compare the diagnostic power of GGCT. Increased expression of GGCT was common in invasive ESCC and HGIEN (87.5% and 85.0%, respectively), but was much less frequently observed in LGIEN (17.5%). GGCT expression significantly correlated with the presence of lymph node metastasis and the degree of differentiation. In the differential diagnosis of LGIEN and HGIEN, GGCT possessed both high sensitivity and high specificity, while Ki-67 and p53 only possessed either high sensitivity or high specificity. Additionally, GGCT expression was higher in 7 out of 8 ESCC cell lines (KYSE series) than in a normal esophageal squamous cell line (Het-1A). The expression levels strongly correlated with enzymatic activity (r=.92; P<.001). These results indicate that overexpressed GGCT retains its enzymatic activity and can become a valuable biomarker for the diagnosis of HGIEN that is likely to progress to subepithelial invasion.
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Tyrosine kinases inhibition by Imatinib slows progression in chronic anti-thy1 glomerulosclerosis of the rat.
BMC Nephrol
PUBLISHED: 04-07-2013
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Chronic progressive mesangioproliferative nephropathy represents a major cause of end-stage renal disease worldwide. Until now, effective approaches to stop or even slow its progression are limited. We tested the effects of an inhibitor of PDGF receptor, abl and c-kit tyrosine kinases, Imatinib, in a chronic progressive model of mesangioproliferative glomerulosclerosis.
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Histogenesis and prognostic value of myenteric spread in colorectal cancer: a Japanese multi-institutional study.
J. Gastroenterol.
PUBLISHED: 02-14-2013
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BACKGROUND: The histogenesis of the pattern of cancer spread along Auerbachs plexus (myenteric spread: MS) remains unclear and its prognostic value in colorectal cancer (CRC) has not been thoroughly investigated. METHODS: Pathology slides of 2845 pT2/pT3/pT4 CRCs stained with hematoxylin-eosin (H&E) were reviewed at 10 institutions. MS was classified into 2 groups depending on whether it was accompanied by the finding of perineural invasion (PN) within the lesion. In addition, immunohistochemical staining (D2-40, S100, CD56, synaptophysin) was performed for serially sectioned specimens from 50 CRCs diagnosed as having PN-negative MS. RESULTS: MS was observed in 504 patients (17.7 %); 360 patients were classified as having PN-positive MS and 144 as having PN-negative MS. The 5-year disease-free survival rate of patients with MS was lower than that of patients without MS (63.3 vs 82.7 %, P < 0.0001); however, there was no significant difference in survival outcome according to the presence or absence of intralesion PN in MS. Multivariate analysis showed that the prognostic impact of MS was independent of conventional prognosticators including T and N stages, vascular invasion and extramural PN. In all the tumors having PN-negative MS, remnants of neural tissue were identified within or around cancer nests located at the leading edge of MS. CONCLUSIONS: MS is an important prognostic factor for CRC. This feature is the result of cancer development with replacement of Auerbachs plexus and can be classified as intramural PN. The clinical significance of "Pn1" in the UICC/AJCC TNM classification could be enhanced by individual assessment both intramurally and extramurally.
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CD49f(high) cells retain sphere-forming and tumor-initiating activities in human gastric tumors.
PLoS ONE
PUBLISHED: 01-01-2013
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Identification of gastric tumor-initiating cells (TICs) is essential to explore new therapies for gastric cancer patients. There are reports that gastric TICs can be identified using the cell surface marker CD44 and that they form floating spheres in culture, but we could not obtain consistent results with our patient-derived tumor xenograft (PDTX) cells. We thus searched for another marker for gastric TICs, and found that CD49f(high) cells from newly-dissected gastric cancers formed tumors with histological features of parental ones while CD49f(low) cells did not when subcutaneously injected into immunodeficient mice. These results indicate that CD49f, a subunit of laminin receptors, is a promising marker for human gastric TICs. We established a primary culture system for PDTX cells where only CD49f(high) cells could grow on extracellular matrix (ECM) to form ECM-attaching spheres. When injected into immunodeficient mice, these CD49f(high) sphere cells formed tumors with histological features of parental ones, indicating that only TICs could grow in the culture system. Using this system, we found that some sphere-forming TICs were more resistant than gastric tumor cell lines to chemotherapeutic agents, including doxorubicin, 5-fluorouracil and doxifluridine. There was a patient-dependent difference in the tumorigenicity of sphere-forming TICs and their response to anti-tumor drugs. These results suggest that ECM plays an essential role for the growth of TICs, and that this culture system will be useful to find new drugs targeting gastric TICs.
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Early treatment with everolimus exerts nephroprotective effect in rats with adriamycin-induced nephrotic syndrome.
Nephrol. Dial. Transplant.
PUBLISHED: 10-29-2011
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Nephrotic syndrome (NS) is a clinical state characterized by massive proteinuria and excessive fluid retention. The effects of early versus late treatment with low or high doses of oral everolimus, a mammalian target of rapamycin inhibitor, on proteinuria in NS have not been previously described.
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Actual status of distribution and prognostic impact of extramural discontinuous cancer spread in colorectal cancer.
J. Clin. Oncol.
PUBLISHED: 05-16-2011
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To clarify the prognostic impact of tumor nodules without residual lymph node (LN) structure (ND) in colorectal cancer and to determine optimal categorization of ND in tumor staging.
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Angiotensin II type I receptor blockade suppresses glomerular renin-angiotensin system activation, oxidative stress, and progressive glomerular injury in rat anti-glomerular basement membrane glomerulonephritis.
Transl Res
PUBLISHED: 05-11-2011
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Excessive renin-angiotensin system (RAS) activation within the kidney induces not only renal oxidative stress but also renal scarring and dysfunction. This study examined the effects of an angiotensin II (Ang II) type I receptor (AT1R) blocker (ARB) on the progression of renal injury in rat anti-glomerular basement membrane glomerulonephritis (GN), with a particular focus on the participation of glomerular RAS activation in glomerular structural alterations, inflammation, and oxidative stress. Nephritic rats were divided into 2 groups and treated with vehicle or ARB until day 28. Treatment with ARB improved proteinuria significantly in nephritic rats. Vehicle-treated nephritic rats developed crescentic GN accompanied by marked macrophage infiltration and the enhanced expression of glomerular ?-smooth muscle actin (?-SMA), angiotensinogen (AGT), Ang II, AT1R, and NADPH oxidase (Nox2) on days 7 and 28 of GN. ARB improved pathologic alterations such as crescent formation and glomerulosclerosis, and it had a significant inhibitory effect on the levels of these parameters on day 28 of GN. Enhanced superoxide production in nephritic glomeruli was decreased also by ARB. Moreover, Ang II and transforming growth factor beta (TGF-?) in the supernatant of cultured glomeruli was increased significantly in vehicle-treated nephritic rats whereas ARB inhibited the production of these compounds significantly on day 28. These results indicate that increased glomerular RAS activity and the resulting Ang II play important roles in progressive glomerular injury-the induction of oxidative stress and TGF-? expression, and they suggest that AT1R blockade attenuates proteinuria and progressive glomerular remodeling via the suppression of glomerular RAS activation in GN.
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Osteoplastic bone metastasis in esophageal squamous cell cancer: report of a case.
Surg. Today
PUBLISHED: 03-22-2011
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This report presents a case of esophageal squamous cell cancer with osteoplastic bone metastasis. A 58-year-old male patient underwent multimodality treatment for esophageal cancer. Sclerotic changes resembling bone metastasis from prostate cancer were detected in the 4th thoracic and the 5th lumber vertebral body soon after the adjuvant chemoradiotherapy. Systemic examinations revealed no primary cancer as a cause of osteoplastic bone metastasis and no esophageal cancer recurrence. A needle biopsy revealed metastases of esophageal squamous cell cancer with osteoplastic changes. Multiple sclerotic changes were detected in the systemic bones at that time, and new carcinomatous bilateral pleural effusion developed. The drastic systemic progression of the cancer caused the rapid deterioration of the patients general condition.
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Curcumin ameliorates macrophage infiltration by inhibiting NF-?B activation and proinflammatory cytokines in streptozotocin induced-diabetic nephropathy.
Nutr Metab (Lond)
PUBLISHED: 03-18-2011
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Chronic inflammation plays an important role in the progression of diabetic nephropathy (DN) and that the infiltration of macrophages in glomerulus has been implicated in the development of glomerular injury. We hypothesized that the plant polyphenolic compound curcumin, which is known to exert potent anti-inflammatory effect, would ameliorate macrophage infiltration in streptozotocin (STZ)-induced diabetic rats.
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[Langerhans cell histiocytosis of the rib in adult male].
Kyobu Geka
PUBLISHED: 03-11-2011
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A 57-year-old man was admitted to our hospital with an abnormal shadow on chest X-ray film. Computed tomography (CT) scanning demonstrated a low-density, destructive mass on the right 8th rib. The maximum standardized uptake value of the tumor measured by positron emission tomography (PET) was 2.9, indicating malignancy. Wide resection of the tumor, including the right 8th rib and the 7th to 8th intercostal muscle, was performed. Chest wall reconstruction was achieved with Composix Mesh. The histologic findings revealed proliferation of histiocytes and eosinophil infiltration. No malignant cells were detected in the tumor. Histiocytes stained for S-100 protein and CD1a, compatible with a diagnosis of Langerhans cell histiocytosis (LCH). LCH in the ribs is very rare and difficult to diagnose using CT or PET. Tumor biopsy or resection is needed to diagnose LCH.
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Analysis of intestinal fibrosis in chronic colitis in mice induced by dextran sulfate sodium.
Pathol. Int.
PUBLISHED: 03-03-2011
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Fibrogenic mesenchymal cells including fibroblasts and myofibroblasts play a key role in intestinal fibrosis, however, their precise role is largely unknown. To investigate their role in intestinal fibrosis, we analyzed the lesions of chronic colitis in C57BL/6 (B6) mice induced by dextran sulfate sodium (DSS). B6 mice exposed to single cycle administration of DSS for 5 days developed acute colitis that progressed to severe chronic inflammation with dense infiltrates of mononuclear cells, irregular epithelial structure, thickening of colonic wall, and persistent deposits of collagen. Increased mRNA expressions of proinflammatory cytokines are correlated with extensive cellular infiltration, and the mRNA expressions of collagen 1, transforming growth factor (TGF)-?, and matrix metalloproteinases were also enhanced in the colon. In the colon of chronic DSS colitis, fibroblasts (vimentin(+), ?-smooth muscle actin (?-SMA)(-)) were increased in both mucosal and submucosal layers, while myofibroblasts (vimentin(+), ?-SMA(+)) were increased in mucosal but not in submucosal layers. Primary mouse subcutaneous fibroblast cultures experiments revealed that exogenously added TGF-? 1 substantially augmented the expressions of both vimentin and ?-SMA proteins with increased production of collagen. In conclusion, profibrogenic mesenchymal cells play an important role in the development of intestinal fibrosis in this chronic DSS-induced colitis model.
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Identification of alternatively activated macrophages in new-onset paediatric and adult immunoglobulin A nephropathy: potential role in mesangial matrix expansion.
Histopathology
PUBLISHED: 02-18-2011
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New onset of the clinical symptoms of immunoglobulin A (IgA) nephropathy (IgAN) manifests with proliferative glomerular lesions in children, whereas adults exhibit mesangial matrix expansion and interstitial fibrosis. Alternatively, activated (M2) macrophages have been implicated in promoting tissue fibrosis in some settings. Therefore, the aim of this study was to investigate whether M2 macrophages are present in new-onset IgAN and if they are related to pathological differences between paediatric and adult disease.
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Neurexin-1, a presynaptic adhesion molecule, localizes at the slit diaphragm of the glomerular podocytes in kidneys.
Am. J. Physiol. Regul. Integr. Comp. Physiol.
PUBLISHED: 11-03-2010
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The slit diaphragm connecting the adjacent foot processes of glomerular epithelial cells (podocytes) is the final barrier of the glomerular capillary wall and serves to prevent proteinuria. Podocytes are understood to be terminally differentiated cells and share some common features with neurons. Neurexin is a presynaptic adhesion molecule that plays a role in synaptic differentiation. Although neurexin has been understood to be specifically expressed in neuronal tissues, we found that neurexin was expressed in several organs. Several forms of splice variants of neurexin-1? were detected in the cerebrum, but only one form of neurexin-1? was detected in glomeruli. Immunohistochemical study showed that neurexin restrictedly expressed in the podocytes in kidneys. Dual-labeling analyses showed that neurexin was colocalized with CD2AP, an intracellular component of the slit diaphragm. Immunoprecipitation assay using glomerular lysate showed that neurexin interacted with CD2AP and CASK. These observations indicated that neurexin localized at the slit diaphragm area. The staining intensity of neurexin in podocytes was clearly lowered, and their staining pattern shifted to a more discontinuous patchy pattern in the disease models showing severe proteinuria. The expression and localization of neurexin in these models altered more clearly and rapidly than that of other slit diaphragm components. We propose that neurexin is available as an early diagnostic marker to detect podocyte injury. Neurexin coincided with nephrin, a key molecule of the slit diaphragm detected in a presumptive podocyte of the developing glomeruli and in the glomeruli for which the slit diaphragm is repairing injury. These observations suggest that neurexin is involved in the formation of the slit diaphragm and the maintenance of its function.
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[A case of stage IV breast cancer with bone metastases that responded well for long-term to hormonal therapy].
Gan To Kagaku Ryoho
PUBLISHED: 10-15-2010
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A case was a 48 years old woman. She was aware of a lump in her left breast and visited our hospital. We diagnosed it as an invasive ductal carcinoma. Immunostaining for both ER and PgR was strongly positive. CT of the initial consultation showed multiple bone metastases (thoracic vertebrae, lumbar vertebrae, and iliac bone). After AC followed by docetaxel and tamoxifen, LH-RH analogue was started. We used anastrozole after menopause. The bisphosphonate has been used from the beginning of the treatment. After the chemotherapy, the clinical response of primary tumor was judged as partial response. For six years, the size of primary tumor has not been changed, and PET-CT has not showed another metastasis. Anastrozole was superior to tamoxifen with respect to TTP (median values of 10.7 and 6.4 months for anastrozole and tamoxifen, respectively) in postmenopausal women with ER and/or PgR receptor positive tumors. Our study indicated that many patients responding to hormonal therapy appear to have been increasing from now on.
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[Pilot study of radiofrequency ablation (RFA) therapy in patients with early breast cancer].
Gan To Kagaku Ryoho
PUBLISHED: 10-15-2010
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A recent breast cancer operation appears to have become more simplified, and we may cure an early stage breast cancer without a surgery in the future. This study was approved by our institutional review board and all patients received the study information. We started a radiofrequency ablation (RFA) in April 2008 for breast cancer patients without extensive ductal spreads and the tumor size of 2 cm or less measured by magnetic resonance imaging (MRI). At first, we performed five patients from a clinical viewpoint of technique and safety. All cases were performed safely. There was no complication such as burns. At the mid observation period of 22 months in average (range 21-24), no local recurrence and distant metastases were occurred after RFA. Cosmetic after RFA was excellent in all cases.
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Ameliorating effects of L-carnitine on diabetic podocyte injury.
J Med Food
PUBLISHED: 10-14-2010
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High glucose levels can change podocyte gene expression and subsequently induce podocyte damage through altered glucose metabolism. l-Carnitine is known to play a beneficial role in diabetes; however, there are no studies on the effects of l-carnitine on podocyte alteration under high glucose conditions. This study investigated whether l-carnitine can attenuate diabetic podocyte injury through the prevention of loss of slit diaphragm proteins. The l-carnitine treatment group showed increased glucose uptakes compared to the control group, suggesting that glucose utilization in the podocytes was increased by l-carnitine. l-Carnitine treatment also prevented decreased mRNA expressions of nephrin and podocin in the high glucose-stimulated podocytes. However, mRNA expressions of CD2AP and ?-actinin-4 were not significantly changed by the high glucose conditions. When these data are taken together, l-carnitine can increase glucose uptake in podocytes under high glucose conditions, and its mechanism may be at least partly related to the up-regulation of nephrin and podocin. Our results help clarify the beneficial effects of l-carnitine in diabetic nephropathy.
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Defective glycosylation of ?-dystroglycan contributes to podocyte flattening.
Kidney Int.
PUBLISHED: 10-13-2010
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In addition to skeletal muscle and the nervous system, ?-dystroglycan is found in the podocyte basal membrane, stabilizing these cells on the glomerular basement membrane. Fukutin, named after the gene responsible for Fukuyama-type congenital muscular dystrophy, is a putative glycosyltransferase required for the post-translational modification of ?-dystroglycan. Chimeric mice targeted for both alleles of fukutin develop severe muscular dystrophy; however, these mice do not have proteinuria. Despite the lack of a functional renal defect, we evaluated glomerular structure and found minor abnormalities in the chimeric mice by light microscopy. Electron microscopy revealed flattening of podocyte foot processes, the number of which was significantly lower in the chimeric compared to wild-type mice. A monoclonal antibody against the laminin-binding carbohydrate residues of ?-dystroglycan did not detect ?-dystroglycan glycosylation in the glomeruli by immunoblotting or immunohistochemistry. In contrast, expression of the core ?-dystroglycan protein was preserved. There was no statistical difference in dystroglycan mRNA expression or in the amount of nephrin and ?3-integrin protein in the chimeric compared to the wild-type mice as judged by immunohistochemistry and real-time RT-PCR. Thus, our results indicate that appropriate glycosylation of ?-dystroglycan has an important role in the maintenance of podocyte architecture.
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Allogenic fetal membrane-derived mesenchymal stem cells contribute to renal repair in experimental glomerulonephritis.
Am. J. Physiol. Renal Physiol.
PUBLISHED: 08-25-2010
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Mesenchymal stem cells (MSC) have been reported to be an attractive therapeutic cell source for the treatment of renal diseases. Recently, we reported that transplantation of allogenic fetal membrane-derived MSC (FM-MSC), which are available noninvasively in large amounts, had a therapeutic effect on a hindlimb ischemia model (Ishikane S, Ohnishi S, Yamahara K, Sada M, Harada K, Mishima K, Iwasaki K, Fujiwara M, Kitamura S, Nagaya N, Ikeda T. Stem Cells 26: 2625-2633, 2008). Here, we investigated whether allogenic FM-MSC administration could ameliorate renal injury in experimental glomerulonephritis. Lewis rats with anti-Thy1 nephritis intravenously received FM-MSC obtained from major histocompatibility complex-mismatched ACI rats (FM-MSC group) or a PBS (PBS group). Nephritic rats exhibited an increased urinary protein excretion in the PBS group, whereas the FM-MSC group rats had a significantly lower level of increase (P < 0.05 vs. PBS group). FM-MSC transplantation significantly reduced activated mesangial cell (MC) proliferation, glomerular monocyte/macrophage infiltration, mesangial matrix accumulation, as well as the glomerular expression of inflammatory or extracellular matrix-related genes including TNF-?, monocyte chemoattractant protein 1 (MCP-1), type I collagen, TGF-?, type 1 plasminogen activator inhibitor (PAI-1) (P < 0.05 vs. PBS group). In vitro, FM-MSC-derived conditioned medium significantly attenuated the expression of TNF-? and MCP-1 in rat MC through a prostaglandin E(2)-dependent mechanism. These data suggest that transplanted FM-MSC contributed to the healing process in injured kidney tissue by producing paracrine factors. Our results indicate that allogenic FM-MSC transplantation is a potent therapeutic strategy for the treatment of acute glomerulonephritis.
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Peroxisome proliferator-activated receptor-? agonist rosiglitazone prevents albuminuria but not glomerulosclerosis in experimental diabetes.
Am. J. Nephrol.
PUBLISHED: 07-01-2010
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Renal inflammation and nephrin downregulation contribute to albuminuria in diabetes. We studied, in streptozotocin-induced diabetic rats, the effect of rosiglitazone (RSG), a peroxisome proliferator-activated receptor-? agonist, on renal macrophage infiltration, MCP1, and nephrin expression in relation to albuminuria.
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Effects of mineralocorticoid and angiotensin II receptor blockers on proteinuria and glomerular podocyte protein expression in a model of minimal change nephrotic syndrome.
Nephrology (Carlton)
PUBLISHED: 05-18-2010
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Several proteins constituting the slit diaphragm are considered important for maintaining capillary wall permselectivity. Early intervention with blockers of angiotensin II receptors (AR) and mineralocorticoid receptors (MR) is effective against proteinuria in models of chronic hypertensive and protein-induced renal damage. However, the effects of AR and/or MR blockers in a model of acute nephrotic syndrome remain unknown. The effects of AR and MR blockers were examined in puromycin aminonucleoside (PAN)-treated rats.
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Rectal administration of tranilast ameliorated acute colitis in mice through increased expression of heme oxygenase-1.
Pathol. Int.
PUBLISHED: 04-20-2010
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Mast cells play a key role in the pathophysiology of inflammatory bowel disease (IBD). Tranilast, a mast cell stabilizer, has been empirically used for IBD in Japan, but its precise role in the treatment of IBD is largely unknown. To investigate the role of tranilast for the treatment of IBD, tranilast was administered intrarectally to mice with dextran sulfate sodium (DSS)-induced colitis. Tranilast ameliorated DSS colitis clinically and pathologically, as demonstrated by decreased number and degranulation of mast cells in the colon. mRNA expression was increased for tumor necrosis factor-alpha, interferon-gamma and interleukin (IL)-6, and decreased for IL-10 in the colon of DSS colitis mice. In contrast, tranilast markedly decreased expression of mRNAs for the pro-inflammatory cytokines, and increased that of the anti-inflammatory cytokines. Moreover, tranilast increased heme oxygenase (HO)-1 expression on colonic epithelial cells as well as on colon-infiltrating cells of DSS colitis. In conclusion, tranilast ameliorated DSS colitis by regulating mast cell degranulation, decreasing inflammatory cytokines and increasing anti-inflammatory cytokines. Tranilast might exert these effects partly through enhanced HO-1 expression in the colon, suggesting a potential adjunctive therapy for IBD.
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Frequent silencing of protocadherin 17, a candidate tumour suppressor for esophageal squamous cell carcinoma.
Carcinogenesis
PUBLISHED: 03-03-2010
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Protocadherins are a subfamily of the cadherin superfamily, but little is known about their functions. We identified a homozygous loss of protocadherin (PCDH) 17 in the course of a program to screen a panel of esophageal squamous cell carcinoma (ESCC) cell lines for genomic copy number aberrations. PCDH17 messenger RNA was expressed in normal esophageal tissue but not in the majority of ESCC cell lines without a homozygous deletion of this gene and restored in gene-silenced ESCC cells after treatment with 5-aza-2-deoxycytidine. The DNA methylation status of the PCDH17 CpG island correlated inversely with the PCDH17 expression, and a putative methylation target region showed promoter activity. The methylation of the PCDH17 promoter was also associated with the silencing of gene expression in primary ESCC partly. Among primary ESCC cases, the silencing of PCDH17 protein expression was associated with a poorer differentiation status of ESCC cells and possibly with prognosis in a subset of this tumour. Restoration of PCDH17 expression in ESCC cells reduced cell proliferation and migration/invasion. These results suggest that silencing of PCDH17 expression through hypermethylation of the promoter or other mechanisms leads to loss of its tumour-suppressive activity, which may be a factor in the carcinogenesis of a subgroup of ESCCs.
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Loss of the BMP antagonist USAG-1 ameliorates disease in a mouse model of the progressive hereditary kidney disease Alport syndrome.
J. Clin. Invest.
PUBLISHED: 02-08-2010
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The glomerular basement membrane (GBM) is a key component of the filtering unit in the kidney. Mutations involving any of the collagen IV genes (COL4A3, COL4A4, and COL4A5) affect GBM assembly and cause Alport syndrome, a progressive hereditary kidney disease with no definitive therapy. Previously, we have demonstrated that the bone morphogenetic protein (BMP) antagonist uterine sensitization-associated gene-1 (USAG-1) negatively regulates the renoprotective action of BMP-7 in a mouse model of tubular injury during acute renal failure. Here, we investigated the role of USAG-1 in renal function in Col4a3-/- mice, which model Alport syndrome. Ablation of Usag1 in Col4a3-/- mice led to substantial attenuation of disease progression, normalization of GBM ultrastructure, preservation of renal function, and extension of life span. Immunohistochemical analysis revealed that USAG-1 and BMP-7 colocalized in the macula densa in the distal tubules, lying in direct contact with glomerular mesangial cells. Furthermore, in cultured mesangial cells, BMP-7 attenuated and USAG-1 enhanced the expression of MMP-12, a protease that may contribute to GBM degradation. These data suggest that the pathogenetic role of USAG-1 in Col4a3-/- mice might involve crosstalk between kidney tubules and the glomerulus and that inhibition of USAG-1 may be a promising therapeutic approach for the treatment of Alport syndrome.
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Contrasting effects of steroids and mizoribine on macrophage activation and glomerular lesions in rat thy-1 mesangial proliferative glomerulonephritis.
Am. J. Nephrol.
PUBLISHED: 01-27-2010
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Macrophages with a pro-inflammatory (M1) phenotype mediate renal injury in proliferative forms of glomerulonephritis, while alternatively activated (M2) macrophages are thought to be anti-inflammatory and promote repair. Glucocorticoids, the mainstay therapy for proliferative glomerulonephritis, can induce alternative macrophage activation in vitro, but it is unknown whether this occurs in vivo and if this is required for glucocorticoid responsiveness. In addition, clinical studies have suggested that the ability of mizoribine (MZR) to suppress steroid-resistant proliferative glomerulonephritis may operate via inhibiting pro-inflammatory macrophage activation.
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CD28 superagonist-induced regulatory T cell expansion ameliorates mesangioproliferative glomerulonephritis in rats.
Clin. Exp. Nephrol.
PUBLISHED: 01-19-2010
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Naturally occurring regulatory T cells (Treg) are essential for the prevention of autoimmunity and overshooting immune responses to pathogens; however, the involvement of Treg in mesangioproliferative glomerulonephritis, a major cause of chronic kidney disease, remains unclear. Superagonistic CD28-specific monoclonal antibodies (CD28SA) are highly effective activators of Treg in rats.
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Endocytoscopic observation of esophageal squamous cell carcinoma.
Dig Endosc
PUBLISHED: 01-19-2010
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The endocytoscopy system (ECS), adapted for clinical use in 2003, is an ultra-high-power magnifying endoscope that allows observations at the cell level. ECS is based on the technology of light-contact microscopy. The most evident use of ECS is for real-time, high-resolution diagnosis of nuclear abnormalities, mainly in patients with esophageal cancer. Up to now, three different types of ECS have been available. This diagnostic tool makes it possible to omit histological examination of biopsy samples in approximately 84% of esophageal squamous cell carcinoma, as evidence for both an increase of cell density and nuclear abnormalities is considered to be convincing proof that a lesion is malignant. Here we describe the features of ECS and the background that led to its development, and review the published literature pertaining to the observation of esophageal neoplasms using ECS.
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p21-activated kinases regulate actin remodeling in glomerular podocytes.
Am. J. Physiol. Renal Physiol.
PUBLISHED: 01-13-2010
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The tyrosine phosphorylation of nephrin is reported to regulate podocyte morphology via the Nck adaptor proteins. The Pak family of kinases are regulators of the actin cytoskeleton and are recruited to the plasma membrane via Nck. Here, we investigated the role of Pak in podocyte morphology. Pak1/2 were expressed in cultured podocytes. In mouse podocytes, Pak2 was predominantly phosphorylated, concentrated at the tips of the cellular processes, and its expression and/or phosphorylation were further increased when differentiated. Overexpression of rat nephrin in podocytes increased Pak1/2 phosphorylation, which was abolished when the Nck binding sites were mutated. Furthermore, dominant-negative Nck constructs blocked the Pak1 phosphorylation induced by antibody-mediated cross linking of nephrin. Transient transfection of constitutively kinase-active Pak1 into differentiated mouse podocytes decreased stress fibers, increased cortical F-actin, and extended the cellular processes, whereas kinase-dead mutant, kinase inhibitory construct, and Pak2 knockdown by shRNA had the opposite effect. In a rat model of puromycin aminonucleoside nephrosis, Pak1/2 phosphorylation was decreased in glomeruli, concomitantly with a decrease of nephrin tyrosine phosphorylation. These results suggest that Pak contributes to remodeling of the actin cytoskeleton in podocytes. Disturbed nephrin-Nck-Pak interaction may contribute to abnormal morphology of podocytes and proteinuria.
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ERK5 activation enhances mesangial cell viability and collagen matrix accumulation in rat progressive glomerulonephritis.
Am. J. Physiol. Renal Physiol.
PUBLISHED: 10-21-2009
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The mitogen-activated protein kinase (MAPK) cascade plays an important role in the regulation of various cellular functions in glomerulonephritis (GN). Here, we investigated whether extracellular signal-regulated kinase 5 (ERK5), a member of the MAPK family, is involved in the pathogenesis of chronic mesangioproliferative GN, using a rat model induced by uninephrectomy and anti-Thy-1 antibody injection. Immunostaining of kidneys obtained at different time points revealed that phospho-ERK5 was weakly expressed in control glomeruli but dramatically increased in a typical mesangial pattern after 28 and 56 days of GN. A semiquantitative assessment indicated that glomerular phospho-ERK5 expression closely paralleled the accumulation of extracellular matrix (ECM), collagen type I, as well as glomerular expression of reactive oxygen species (ROS) and ANG II. On the other hand, phospho-ERK1/2 expression increased on day 7 during the phase of enhanced mesangial cell (MC) proliferation and decreased thereafter. H(2)O(2) and ANG II each induced ERK5 phosphorylation by cultured rat MCs. Costimulation with both H(2)O(2) and ANG II synergistically increased ERK5 phosphorylation in MCs. Cultured MCs transfected with ERK5-specific small interference RNA showed a significant decrease in H(2)O(2) or ANG II-induced cell viability and soluble collagen secretion compared with control cells. Treatment of GN rats with an ANG II type 1 receptor blocker resulted in significant decreases in phospho-ERK5 expression and collagen accumulation accompanied by remarkable histological improvement. Taken together, these results suggest that MC ERK5 phosphorylation by ANG II or H(2)O(2) enhances cell viability and ECM accumulation in an experimental model of chronic GN.
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Relationship between mucin expression of gastric intramucosal signet ring cell carcinoma and its background mucosa.
J. Med. Dent. Sci.
PUBLISHED: 08-25-2009
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The intramucosal lesion of gastric signet ring cell carcinoma (SIG) is known to form a layered structure (LS) that simulates mucin expression in ordinary gastric mucosa. In this study, we suspected the influence of background mucosa on the formation of LS and performed histopathological analysis. We examined 35 cases of intramucosal SIG with a maximum diameter of 30 mm or less. The LS patterns were classified into those with a layer of MUC6-positive cells (complete pattern, CP) and those lacking this layer (incomplete pattern, ICP). The relationship between LS patterns and the characteristics of the background mucosa, the expression of MUC2 (intestinal-type mucin antigen), MUC5AC (foveolar-type mucin antigen), and Ki-67 (the marker of cell proliferation activity) was examined by histochemistry and immunohistochemistry. Intestinal metaplasia in the background mucosa and MUC2 expression were frequently observed in cases with ICP. Ki-67-positive cells were much more and they were distributed more widely in the lesion of cases with ICP alone than in the other cases. Mucin expression and LS formation of gastric SIG are strongly influenced by its background mucosa. The cases completely lacking MUC6 expression may have higher malignant potential.
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Therapeutic targets in the podocyte: findings in anti-slit diaphragm antibody-induced nephropathy.
J. Nephrol.
PUBLISHED: 08-08-2009
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Recent studies have demonstrated that the slit diaphragm of the glomerular epithelial cell (podocyte) is the structure likely to be the barrier in the glomerular capillary wall. Murine monoclonal antibody against nephrin, a molecule constituting the extracellular site of the slit diaphragm, caused severe proteinuria if injected into rats, in a complement- or inflammatory cell-independent manner. In this proteinuric state, not only nephrin but also other slit diaphragm-associated molecules are down-regulated. These observations suggest that the antibody alters the molecular composition of the slit diaphragm and, thereby, affects the glomerular permeability barrier. Recently, it was found that IP-10, SV2B, ephrin B1 and the receptors of angiotensin II were expressed in the podocyte, and that their expressions were clearly altered in anti-nephrin antibody-induced nephropathy. It is conceivable that these molecules are involved in the development of proteinuria in this model. IP-10 is assumed to play a role in maintaining the slit diaphragm function by regulating the cell cycle balance of the podocyte. SV2B and ephrin B1 play pivotal roles in the proper localization of the slit diaphragm component. In vivo and in vitro studies demonstrated that angiotensin II type 2 receptor-mediated action enhanced the expression of nephrin. We propose that these molecules could be novel therapeutic targets for proteinuria.
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Rac1 contributes to actin organization in glomerular podocytes.
Nephron Exp. Nephrol.
PUBLISHED: 06-18-2009
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Background/Aims: The function of glomerular podocytes is closely associated with the actin cytoskeleton. In this study, we studied the role of the small Rho-GTPase, Rac1, in actin organization in podocytes. Methods: Conditionally immortalized mouse podocytes (MP) stably expressing nephrin or control plasmid were used. Results: In MP, Rac1 activity increased significantly at 1 week of differentiation. MP stably expressing nephrin showed Rac1 activity significantly higher and more sustained than vector-expressing control cells. Antibody-mediated cross-linking of nephrin also activated Rac1. Differentiated MP showed more distinct lamellipodia/cellular processes, as compared with undifferentiated cells, which was further augmented by nephrin expression. Transient transfection of constitutively active Rac1 markedly increased the number of lamellipodia/cellular processes in undifferentiated MP, while the Rac1 inhibitor caused actin cytoskeleton derangement in differentiating MP. In the rat model of puromycin aminonucleoside nephrosis, RhoA activity was increased at Day 7 (at the peak of proteinuria), while Rac1 activity increased significantly only at Day 14, when the recovery process had started. Conclusion: Rac1 is activated in differentiating MP and nephrin potentiates Rac1 activation. Rac1 likely contributes to lamellipodia formation in differentiating MP and may contribute to process formation in podocytes recovering from injuries.
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Multi-center survey regarding the management of anticoagulation and antiplatelet therapy for endoscopic procedures in Japan.
J. Gastroenterol. Hepatol.
PUBLISHED: 05-08-2009
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A guideline on the management of anticoagulation and antiplatelet therapy for endoscopic procedures has been established from Japan Gastroenterological Endoscopy Society in 2005. However, it is unknown whether consensus on the management of these conditions is obtained among endoscopists in daily practice owing to the guideline.
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Tolvaptan, a selective oral vasopressin V2 receptor antagonist, ameliorates podocyte injury in puromycin aminonucleoside nephrotic rats.
Clin. Exp. Nephrol.
PUBLISHED: 04-20-2009
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Proteinuria caused by glomerular disease is characterized by podocyte injury. Vasopressin V2 receptor antagonists are effective in reducing albuminuria, although their actions on glomerular podocytes have not been explored. The objective of this study was to evaluate the effects of tolvaptan, a selective oral V2 receptor antagonist, on podocytes in a puromycin aminonucleoside (PAN)-induced nephrosis rat model.
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Active vitamin D and its analogue, 22-oxacalcitriol, ameliorate puromycin aminonucleoside-induced nephrosis in rats.
Nephrol. Dial. Transplant.
PUBLISHED: 03-18-2009
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Recent studies have demonstrated that podocyte injury, which results in proteinuria, leads to tubulointerstitial fibrosis. Although some studies have revealed that vitamin D administration protects renal structure and function in mesangial cell proliferative and/or excessive matrix productive models, the effects of vitamin D on podocyte injury have remained uncertain.
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HPV infection in an HIV-positive patient with primary squamous cell carcinoma of rectum.
Int. J. Clin. Oncol.
PUBLISHED: 02-23-2009
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Primary squamous cell carcinoma (SCC) of the colorectum is a rare malignancy of unknown etiology and pathogenesis. We report a case of primary SCC of the rectum. A 55-year-old man with a rectal tumor and human immunodeficiency virus (HIV) infection was referred to our hospital. Histopathology of biopsy specimens showed characteristics of SCC. We diagnosed the patient as having primary moderately differentiated SCC of the rectum according to the criteria proposed by Cooper. Human papillomavirus (HPV) DNA was amplified by polymerase chain reaction analysis of unfixed tumor biopsy specimens. In addition, no p53 overexpression or nuclear staining of retinoblastoma protein (Rb) was observed in neoplastic cells by immunohistochemical staining. We suggest from our case that HPV infection following the inactivation of the cellular tumor suppressor Rb and the immune suppression induced by HIV infection play an etiologic role in the pathogenesis of rectal SCC, consistent with the well-established concept of HPV-associated anal carcinogenesis.
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Slit diaphragm dysfunction in proteinuric states: identification of novel therapeutic targets for nephrotic syndrome.
Clin. Exp. Nephrol.
PUBLISHED: 02-05-2009
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Several recent studies have demonstrated that the slit diaphragm of the glomerular epithelial cell (podocyte) is the structure likely to be the principal barrier in the glomerular capillary wall. Nephrin identified as a gene product mutated in congenital nephrotic syndrome located at the outer leaflet of plasma membranes of the slit diaphragm. The anti-nephrin antibody is capable of inducing massive proteinuria, which indicates that nephrin is a key functional molecule in the slit diaphragm. Expression of nephrin was reduced in glomeruli of minimal change nephrotic syndrome. Some recent studies demonstrated that podocin, CD2-associated protein and NEPH1 are also functional molecules in the slit diaphragm, and their expressions are altered in membranous nephropathy and also in focal glomerulosclerosis. These observations suggested that the alteration of the molecular arrangement in the slit diaphragm is involved in the development of proteinuria in several kinds of glomerular diseases. Recent studies of our group have demonstrated that type 1 receptor-mediated angiotensin II action reduced the expression of the slit diaphragm-associated molecules and that type 1 receptor blockade ameliorated proteinuria by preventing the function of angiotensin II on the slit diaphragm. By the subtraction hybridization techniques using glomerular cDNA of normal and proteinuric rats, we detected that synaptic vesicle protein 2B and ephrin B1 are involved in the maintenance of the barrier function of the slit diaphragm.
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Angiotensin II receptor blockade inhibits acute glomerular injuries with the alteration of receptor expression.
Lab. Invest.
PUBLISHED: 01-12-2009
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Angiotensin II receptor blockade (ARB) suppresses the progression of chronic kidney disease. However, the renoprotective effect of ARB in the active phase of glomerulonephritis (GN) has not been evaluated in detail. We examined the alteration of angiotensin II receptors expression and the action of ARB on acute glomerular injuries in GN. Thy-1 GN was induced in rats that were divided into three groups (n=7, in each group); high dose (3 mg/kg/day) or low dose (0.3 mg/kg/day) olmesartan (Thy-1 GN+HD- or LD-ARB group), and vehicle (Thy-1 GN group). Renal function and histopathology were assessed by week 2. In the Thy-1 GN group, diffuse mesangiolysis and focal aneurysmal ballooning developed by day 3. Marked mesangial proliferation and activation progressed with glomerular epithelial injury. We confirmed that both angiotensin II type 1 receptor (AT1R) and type 2 receptor (AT2R) were expressed on glomerular endothelial, mesangial, epithelial cells, and macrophages, and increased 7 days after disease induction. However, ARB treatment caused a decrease in AT1R and a further increase in AT2R expression in glomeruli. ARB prevented capillary destruction and preserved eNOS expression after diffuse mesangiolysis. Mesangial proliferation and activation was suppressed markedly with low levels of PDGF-B expression. Glomerular desmin expression, which is a marker for injured glomerular epithelial cells, was diminished significantly with retained expression of nephrin and podoplanin. Glomerular macrophage infiltration was also inhibited. Proteinuria was suppressed significantly. Furthermore, these effects of ARB showed dose dependency. These results provide insights that ARB affects individual glomerular cells and macrophages through angiotensin II receptors, with the alteration of both AT1R and AT2R expressions, and leads to inhibition of the acute destructive and proliferative glomerular lesions in GN.
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[A long-surviving case of HER2-positive breast cancer with brain metastasis treated by multidisciplinary therapy].
Gan To Kagaku Ryoho
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We present a case of a 55-year-old woman who visited our hospital aware of a lump in her right breast. We diagnosed it as bilateral breast cancer [Rt: ABCDE, T3N1M0, ER (-), PgR (-), HER2: 3+, Stage IIIA; Lt: C, T2N0M0, ER (-), PgR (-), HER2: 1+, Stage IIA]. She underwent NAC with EC followed by docetaxel. After cPR, an operation (Rt Bt+Ax, Lt Bp+Ax) was performed. Liver metastases were identified 9 months after the operation, and she was administered weekly paclitaxel+trastuzumab for 12 courses. After cPR, the treatment was changed to trastuzumab only. Because a cerebellar metastasis appeared in postoperative month 19, she underwent an operation using a gamma-knife. Because a new cerebellar metastasis appeared in postoperative month 26, she underwent another gamma-knife operation. Furthermore, liver metastases were diagnosed as PD, and treatment was changed to vinorelbine and trastuzumab. Because third new cerebellar metastasis appeared in postoperative month 45, she underwent another gamma-knife operation. Lung metastases were identified 59 months after the operation, and the therapy was changed to lapatinib and capecitabine. There was no subsequent growth of metastatic tumors, and good control was obtained.
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Curcumin alleviates oxidative stress, inflammation, and renal fibrosis in remnant kidney through the Nrf2-keap1 pathway.
Mol Nutr Food Res
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We hypothesized that curcumin, by increasing the expression of nuclear factor-erythroid-2-related factor 2 (Nrf2), could reduce oxidative stress, inflammation, and renal fibrosis in remnant kidney.
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The hyperglycemia stimulated myocardial endoplasmic reticulum (ER) stress contributes to diabetic cardiomyopathy in the transgenic non-obese type 2 diabetic rats: a differential role of unfolded protein response (UPR) signaling proteins.
Int. J. Biochem. Cell Biol.
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It has been well demonstrated that excessive blood glucose level could be detrimental to the myocardial function through the variety of mechanisms, of which endoplasmic reticulum stress (ERS) could play an unprecedented role through the activation of unfolded protein response (UPR). Recently, reports are coming out with the evidences that UPR signaling proteins are regulated differentially depend on the experimental conditions and cell types. In addition, ERS has been proposed to be closely associated with the regulation of lipogenesis. Therefore, in this study we tried to find out the expressions of myocardial UPR signaling proteins as well as proteins involved in lipid and glucose metabolism in non-obese type 2 diabetic mellitus (DM) condition using Spontaneous Diabetic Torii (SDT) rat. We have found the significant up-regulation of oxidative, nitrosative and ERS marker proteins in the myocardium of the SDT rats, in comparison to its normal (Sprague-Dawley - SD) rats. In addition, the sub-arm of UPR signaling proteins, such as p-PERK, p-eIF2?, ATF6, CHOP/GADD153, TRAF2, apoptotic signaling proteins, such as BAD, cytochrome C, cleaved caspase-7 and -12, were significantly up-regulated in the SDT rats, in comparison to the SD rats. Interestingly, there were no significant changes in the phosphorylation of IRE-1?, and XBP-1 protein expression. In addition, the proteins involved in lipid and glucose metabolisms, such as PPAR?, PPAR?, CPT1, PGC-1? except GLUT4, and the proteins involved in insulin signaling, such as p-Akt and p-PI3K were shown significant attenuation in its expressions in the SDT rats, when compared with the SD rats. Taken together, it is suggested that the activation of PERK and ATF6 pathway are the major determinant rather than the IRE-1?-XBP1 pathway for the ERS-mediated metabolic dysfunction, which might eventually leads to diabetic cardiomyopathy in non-obese type 2 DM.
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Irsogladine maleate ameliorates inflammation and fibrosis in mice with chronic colitis induced by dextran sulfate sodium.
Med Mol Morphol
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Intestinal fibrosis is a common and severe complication of inflammatory bowel disease (IBD), especially Crohns disease (CD). To investigate the therapeutic approach to intestinal fibrosis, we have developed a mouse model of intestinal fibrosis by administering dextran sulfate sodium (DSS) and examining the effects of irsogladine maleate (IM) [2,4-diamino-6-(2,5-dichlorophenyl)-s-triazine maleate], which has been widely used as an antiulcer drug for gastric mucosa in Japan, on DDS-induced chronic colitis. In this experimental colitis lesion, several pathognomonic changes were found: increased deposition of collagen, increased number of profibrogenic mesenchymal cells such as fibroblasts (vimentin(+), ?-SMA(-)) and myofibroblasts (vimentin(+), ?-SMA(+)) in both mucosa and submucosa of the colon with infiltrating inflammatory cells, and increased mRNA expressions of collagen type I, transforming growth factor (TGF)-?, matrix metalloproteinase (MMP)-2, and tissue inhibitor of matrix metalloproteinase (TIMP)-1. When IM was administered intrarectally to this colitis, all these pathological changes were significantly decreased or suppressed, suggesting a potential adjunctive therapy for intestinal fibrosis. IM could consequently reduce fibrosis in DSS colitis by direct or indirect effect on profibrogenic factors or fibroblasts. Therefore, the precise effect of IM on intestinal fibrosis should be investigated further.
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Significance of stromal decorin expression during the progression of breast cancer.
Oncol. Rep.
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Decorin, a small leucine-rich proteoglycan and important component of the extracellular matrix (ECM), is a natural anticancer agent that modulates several receptors involved in cell growth and survival. Reductions in decorin expression may weaken the ECM and enhance the effectiveness of these receptors and may, consequently, lead to tumor spreading. To determine the contribution of stromal decorin regulation in the development of breast cancer and in tumor invasiveness, immunohistochemistry was used to examine the expression of stromal decorin in 120 breast cancer tissue samples. In patients with invasive breast carcinoma (IBC), stromal decorin expression was highest in normal gland tissue, lower in in situ components and the lowest in invasive components. Stromal decorin expression adjacent to malignant cells in IBC tumors was also significantly weaker compared to that in pure ductal carcinoma in situ (DCIS). These findings indicate that there is a striking difference in the stromal decorin expression around normal glands and around DCIS or IBC tumors. Reduced levels of decorin were associated with more aggressive disease; this finding was consistent with the view that reduced decorin expression may facilitate tumorigenesis, tumor invasion and/or tumor growth. Given these and other reported findings, evaluating stromal decorin expression may be useful in assessing prognosis and malignant potential; therefore, a large-scale study of decorin expression is warranted.
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Curcumin decreases renal triglyceride accumulation through AMPK-SREBP signaling pathway in streptozotocin-induced type 1 diabetic rats.
J. Nutr. Biochem.
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Diabetic kidney disease has been associated with the presence of lipid deposits. We assumed that curcumin, a polyphenol, would attenuate the tissue dyslipidemic condition through activation of 5 adenosine monophosphate (AMP)-activated protein kinase (AMPK) phosphorylation and suppression of sterol regulatory element-binding protein (SREBP)-1c in the kidney and would prevent renal progression in experimental type 1 diabetic rats. Diabetes was induced with streptozotocin (STZ) (55 mg/kg) by intraperitoneal injection in male Sprague-Dawley rats. Three weeks after STZ injection, rats were divided into three groups, namely, control, diabetic and diabetic treated with curcumin (100 mg/kg/day) by gavage for 8 weeks. We found that curcumin decreased plasma triglyceride and the amount of renal triglyceride significantly. Furthermore, treatment of diabetic rats with curcumin increased the phosphorylation of AMPK and prevented the increased renal expression of SREBP-1c and, as a result, decreased the expression of acetyl CoA carboxylase and fatty acid synthase as well as adipose differentiation-related protein, a marker of cytoplasmic droplets. We also demonstrate that curcumin significantly suppressed the increased expression of transforming growth factor ?, vascular endothelial growth factor and extracellular matrix proteins such as type IV collagen and fibronectin. In addition, curcumin treatment increased nephrin expression to near-normal levels in diabetic rats. These results demonstrated that curcumin protects against the development of diabetic nephropathy through the AMPK-SREBP pathway and the reduction of renal triglyceride accumulation which could be a possible mechanism by which curcumin preserves renal function in diabetes.
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"Crawling-type" adenocarcinoma of the stomach: a distinct entity preceding poorly differentiated adenocarcinoma.
Gastric Cancer
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Gastric "crawling-type" adenocarcinoma (CTAC) is a neoplasm histologically comprising irregularly fused glands with low-grade cellular atypia that tends to spread laterally in the mucosa. It is necessary to elucidate the clinicopathological characteristics of CTAC.
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Localization of propionibacterium acnes in granulomas supports a possible etiologic link between sarcoidosis and the bacterium.
Mod. Pathol.
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Sarcoidosis likely results from the exposure of a genetically susceptible subject to an environmental agent, possibly an infectious one. Mycobacterial and propionibacterial organisms are the most commonly implicated potential etiologic agents. Propionibacterium acnes is the only microorganism, however, found in sarcoid lesions by bacterial culture. To evaluate the pathogenic role of this indigenous bacterium, we screened for the bacterium in sarcoid and non-sarcoid tissues using immunohistochemical methods with novel P. acnes-specific monoclonal antibodies that react with cell-membrane-bound lipoteichoic acid (PAB antibody) and ribosome-bound trigger-factor protein (TIG antibody). We examined formalin-fixed and paraffin-embedded samples of lungs and lymph nodes from 196 patients with sarcoidosis, and corresponding control samples from 275 patients with non-sarcoidosis diseases. The samples were mostly from Japanese patients, with 64 lymph node samples from German patients. Immunohistochemistry with PAB antibody revealed small round bodies within sarcoid granulomas in 20/27 (74%) video-assisted thoracic surgery lung samples, 24/50 (48%) transbronchial lung biopsy samples, 71/81 (88%) Japanese lymph node samples, and 34/38 (89%) German lymph node samples. PAB antibody did not react with non-sarcoid granulomas in any of the 45 tuberculosis samples or the 34 samples with sarcoid reaction. In nongranulomatous areas, small round bodies detected by PAB antibody were found in alveolar macrophages of lungs and paracortical macrophages of lymph nodes from many sarcoid and some non-sarcoid patients. Large-spheroidal acid-fast bodies, Hamazaki-Wesenberg bodies, which were found in 50% of sarcoid and 15% of non-sarcoid lymph node samples, reacted with both PAB and TIG antibodies. Electron microscopy revealed that these Hamazaki-Wesenberg bodies had a single bacterial structure and lacked a cell wall with occasional protrusions from the body. The high frequency and specificity of P. acnes, detected by PAB antibody within sarcoid granulomas, indicates that this indigenous bacterium might be the cause of granuloma formation in many sarcoid patients.
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Development of lymphatic vasculature and morphological characterization in rat kidney.
Clin. Exp. Nephrol.
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The mechanisms and morphological characteristics of lymphatic vascular development in embryonic kidneys remain uncertain.
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Genomic copy-number alterations of MYC and FHIT genes are associated with survival in esophageal squamous-cell carcinoma.
Cancer Sci.
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Esophageal squamous-cell carcinoma (ESCC) is one of the most common cancers and is associated with a poor prognosis. Studies are warranted on the clinical relevance of its genomic copy-number alterations (CNA) as prognosticators for ESCC. In the present study, we first screened recurrent CNA by array-based comparative genomic hybridization using an in-house focused bacterial artificial chromosome-based array for 108 loci in 45 ESCC specimens. We detected 14 regions showing recurrent (>20%) CNA (4 losses and 10 gains) by array-based comparative genomic hybridization in the first cohort. Among them, loss of 3p14.2 and gain of 8q24.21 for the FHIT and MYC genes, respectively, and the accumulation of those two CNA (higher FM-CNA scores) were significantly associated with a worse overall survival (OS) in the first cohort (P = 0.0273, P = 0.0356 and P = 0.0089, respectively). In the independent validation cohort of 92 resected ESCC cases, loss of FHIT, gain of MYC and higher FM-CNA scores determined by a quantitative genomic PCR-based copy-number analysis were associated with a worse OS (P = 0.0011, P = 0.0104 and P = 0.0008, respectively) and disease-free survival (P = 0.0038, P = 0.0132 and P = 0.0021, respectively). In addition, the Cox model showed the presence of either CNA to be an independent prognosticator for OS and disease-free survival in the validation cohort (P = 0.0120 and P = 0.0255, respectively). These results suggest that CNA of MYC and FHIT are poor prognostic markers, and risk stratification based on the copy-number status of those genes is useful to select the optimal treatment strategy in resected ESCC patients.
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Optimal colorectal cancer staging criteria in TNM classification.
J. Clin. Oncol.
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Histologic components of the TNM classification system have been repeatedly revised since the fifth edition (TNM5). TNM classification revisions provide different criteria for categorizing tumor nodules without residual lymph node structure (ND). However, there are few systematic evaluations regarding the effectiveness of these revisions.
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Reduction of NOTCH1 expression pertains to maturation abnormalities of keratinocytes in squamous neoplasms.
Lab. Invest.
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Notch is a transmembrane receptor functioning in the determination of cell fate. Abnormal Notch signaling promotes tumor development, showing either oncogenic or tumor suppressive activity. The uncertainty about the exact role of Notch signaling, partially, stems from inconsistencies in descriptions of Notch expression in human cancers. Here, we clarified basal-cell dominant expression of NOTCH1 in squamous epithelium. NOTCH1 was downregulated in squamous neoplasms of oral mucosa, esophagus and uterine cervix, compared with the normal basal cells, although the expression tended to be retained in cervical lesions. NOTCH1 downregulation was observed even in precancers, and there was little difference between cancers and high-grade precancerous lesions, suggesting its minor contribution to cancer-specific events such as invasion. In culture experiments, reduction of NOTCH1 expression resulted in downregulation of keratin 13 and keratin 15, and upregulation of keratin 17, and NOTCH1 knockdown cells formed a dysplastic stratified epithelium mimicking a precancerous lesion. The NOTCH1 downregulation and the concomitant alterations of those keratin expressions were confirmed in the squamous neoplasms both by immunohistochemical and cDNA microarray analyses. Our data indicate that reduction of NOTCH1 expression directs the basal cells to cease terminal differentiation and to form an immature epithelium, thereby playing a major role in the histopathogenesis of epithelial dysplasia. Furthermore, downregulation of NOTCH1 expression seems to be an inherent mechanism for switching the epithelium from a normal and mature state to an activated and immature state, suggesting its essential role in maintaining the epithelial integrity.
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Local delivery of a direct renin inhibitor into the kidney ameliorates progression of experimental glomerulonephritis.
Clin. Exp. Nephrol.
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Increasing evidence indicates that locally blocking renin-angiotensin system activity exerts a beneficial effect on glomerulonephritis (GN) progression leading to irreversible glomerulosclerosis. This is the first study on the pharmacological effect of the renal delivery of aliskiren, a direct renin inhibitor, in a progressive model of anti-Thy-1 GN.
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Early treatment with olmesartan prevents juxtamedullary glomerular podocyte injury and the onset of microalbuminuria in type 2 diabetic rats.
Am. J. Hypertens.
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Studies were performed to determine if early treatment with an angiotensin II (Ang II) receptor blocker (ARB), olmesartan, prevents the onset of microalbuminuria by attenuating glomerular podocyte injury in Otsuka Long-Evans Tokushima Fatty (OLETF) rats with type 2 diabetes mellitus.
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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.