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Find video protocols related to scientific articles indexed in Pubmed.
Disruption of the Posterior Medial Network during the Acute Stage of Transient Global Amnesia: A Preliminary Study.
Clin EEG Neurosci
PUBLISHED: 11-14-2014
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Acute perturbation of the corticohippocampal circuitry is a primary pathophysiological mechanism underlying transient global amnesia (TGA). With regard to memory, 2 distinct corticohippocampal circuitries potentially exist: the anterior temporal network and the posterior medial network. We used electroencephalography (EEG) spectral analysis to determine which network is disrupted during the acute stage of TGA. Patients with TGA who visited Seoul National University Bundang Hospital within 24 hours after symptom onset were retrospectively identified. Twenty patients underwent EEG twice, once in the acute stage (<24 hours after symptom onset) and once in the resolved stage (>2 months after symptom onset). A fast Fourier transform was applied to compute the spectral power of the 6 frequency bands: delta, theta, alpha, beta 1, beta 2, and gamma. We assumed that the frontocentral and temporal regions belonged to the anterior temporal network, whereas the parieto-occipital regions belonged to the posterior medial network. A paired Student's t test was used to evaluate the difference in the regional spectral powers in each frequency band between the acute and resolved TGA stages. Compared with the resolved stage, relative theta power in the left parieto-occipital region was increased and relative alpha power in the right parieto-occipital region was reduced during the acute stage of TGA, with a statistical significance of P < .05 (uncorrected). The cortical regions that belonged to the posterior medial network showed alterations of neuronal activity, which reflects disruption of the posterior medial network during the acute stage of TGA.
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EVpedia: A Community Web Portal for Extracellular Vesicles Research.
Dae-Kyum Kim, Jaewook Lee, Sae Rom Kim, Dong-Sic Choi, Yae Jin Yoon, Ji Hyun Kim, Gyeongyun Go, Dinh Nhung, Kahye Hong, Su Chul Jang, Si-Hyun Kim, Kyong-Su Park, Oh Youn Kim, Hyun Taek Park, Ji Hye Seo, Elena Aikawa, Monika Baj-Krzyworzeka, Bas W M van Balkom, Mattias Belting, Lionel Blanc, Vincent Bond, Antonella Bongiovanni, Francesc E Borràs, Luc Buée, Edit I Buzás, Lesley Cheng, Aled Clayton, Emanuele Cocucci, Charles S Dela Cruz, Dominic M Desiderio, Dolores Di Vizio, Karin Ekström, Juan M Falcon-Perez, Chris Gardiner, Bernd Giebel, David W Greening, Julia Christina Gross, Dwijendra Gupta, An Hendrix, Andrew F Hill, Michelle M Hill, Esther Nolte-'t Hoen, Do Won Hwang, Jameel Inal, Medicharla V Jagannadham, Muthuvel Jayachandran, Young-Koo Jee, Malene Jørgensen, Kwang Pyo Kim, Yoon-Keun Kim, Thomas Kislinger, Cecilia Lässer, Dong Soo Lee, Hakmo Lee, Johannes van Leeuwen, Thomas Lener, Ming-Lin Liu, Jan Lötvall, Antonio Marcilla, Suresh Mathivanan, Andreas Möller, Jess Morhayim, François Mullier, Irina Nazarenko, Rienk Nieuwland, Diana N Nunes, Ken Pang, Jaesung Park, Tushar Patel, Gabriella Pocsfalvi, Hernando Del Portillo, Ulrich Putz, Marcel I Ramirez, Marcio L Rodrigues, Tae-Young Roh, Felix Royo, Susmita Sahoo, Raymond Schiffelers, Shivani Sharma, Pia Siljander, Richard J Simpson, Carolina Soekmadji, Philip Stahl, Allan Stensballe, Ewa Stępień, Hidetoshi Tahara, Arne Trummer, Hadi Valadi, Laura J Vella, Sun Nyunt Wai, Kenneth Witwer, María Yáñez-Mó, Hyewon Youn, Reinhard Zeidler, Yong Song Gho.
Bioinformatics
PUBLISHED: 11-13-2014
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Extracellular vesicles are spherical bilayered proteolipids, harboring various bioactive molecules. Due to the complexity of the vesicular nomenclatures and components, online searches for extracellular vesicle-related publications and vesicular components are currently challenging.
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Reduction of Regulatory T cells by Mogamulizumab, a Defucosylated Anti-CC Chemokine Receptor 4 Antibody, in Patients with Aggressive/Refractory Mycosis Fungoides and Sézary Syndrome.
Clin. Cancer Res.
PUBLISHED: 11-08-2014
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Purpose:The CC chemokine receptor 4 (CCR4) is expressed on malignant T-cells in cutaneous T-cell lymphoma (CTCL) as well as on regulatory T cells (Treg). When mogamulizumab, a defucosylated monoclonal antibody, binds to CCR4, it induces antibody-dependent cellular cytotoxicity against CCR4+malignant T-cells. The goal of this study was to determine the effect of mogamulizumab on CCR4+Treg cells in CTCL patients. Experimental Design:Peripheral blood of 24 CTCL patients participating in a Phase 1/2 trial was analyzed for CCR4 expression on different T-cell subsets by flow cytometry, before and after one course of mogamulizumab. The number and function of NK cells were also analyzed. Lesional biopsies were examined for CCR4, Foxp3, and CD16 expression by immunohistochemistry. Results:Malignant T-cells in peripheral blood were 20.8-100% positive for CCR4 at baseline. Fourteen patients who achieved a response in blood had high baseline CCR4 expression on malignant T-cells. Treg cells in blood were 58.6-100% positive for CCR4 at baseline and showed decreased numbers and CCR4 expression after treatment. CD8+T-cells in blood were 3.2-23.2% positive for CCR4 at baseline and showed limited reduction of CCR4 expression with increased percentages of CD8+T-cells after treatment. Of 14 patients tested for NK cells in blood, 10 showed increased percentages after treatment. Four of 6 patients tested showed increased NK cell cytotoxicity. Sixteen of 18 patients who had CCR4+lymphocytes in baseline lesions, showed decreased numbers after treatment. Conclusions:Mogamulizumab reduces levels of CCR4+malignant T-cells and also CCR4+Treg cells in CTCL patients, which may in turn improve immune profiles.
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Ectopic presence of tooth within the mandibular condyle.
J Oral Facial Pain Headache
PUBLISHED: 10-28-2014
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This article describes the case of a 41-year-old woman who presented with the complaint of crepitation sound and mild pain in the left temporomandibular joint area. Panoramic radiographs taken to rule out degenerative or arthritic changes in the joints demonstrated a radiopaque mass within the left condyle. Cone beam computed tomography scans revealed an ectopic tooth located centrally within the left condyle. Thus, while considered rare, the mandibular condyle can be a possible location of an ectopic tooth.
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Characteristics of pulmonary vein enlargement in non-valvular atrial fibrillation patients with stroke.
Yonsei Med. J.
PUBLISHED: 10-18-2014
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The association between pulmonary vein (PV) dilatation and stroke in non-valvular atrial fibrillation (AF) patients remains unknown.
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Lipoprotein-associated phospholipase a? is related to plaque stability and is a potential biomarker for acute coronary syndrome.
Yonsei Med. J.
PUBLISHED: 10-18-2014
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Plasma lipoprotein-associated phospholipase A? (Lp-PLA?) binds to low-density lipoprotein. The levels of Lp-PLA? reflect the plaque burden, and are upregulated in acute coronary syndrome (ACS). We investigated the diagnostic value of Lp-PLA2 levels and found that it might be a potential biomarker for ACS.
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Role of Fractalkine in the Pathogenesis of Primary Sjögren Syndrome: Increased Serum Levels of Fractalkine, Its Expression in Labial Salivary Glands, and the Association with Clinical Manifestations.
J. Rheumatol.
PUBLISHED: 10-17-2014
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To investigate the expression of fractalkine and identify the clinical effects of fractalkine and its receptor (CX3CR1) in patients with primary Sjögren syndrome (pSS).
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Anti-Inflammatory Effect of Methylpenicinoline from a Marine Isolate of Penicillium sp. (SF-5995): Inhibition of NF-?B and MAPK Pathways in Lipopolysaccharide-Induced RAW264.7 Macrophages and BV2 Microglia.
Molecules
PUBLISHED: 09-25-2014
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In the course of a search for anti-inflammatory metabolites from marine-derived fungi, methylpenicinoline (1) was isolated from a marine isolate of Penicillin sp. Compound 1 inhibited lipopolysaccharide (LPS)-stimulated nitric oxide (NO) production by suppressing the expression of inducible NO synthase (iNOS) in RAW264.7 macrophages and BV2 microglia. It also attenuated prostaglandin E2 (PGE2) production by suppressing cyclooxygenase-2 (COX-2) expression in a concentration-dependent manner (from 10 ?M to 80 ?M) without affecting cell viability. In addition, compound 1 reduced the production of the pro-inflammatory cytokine interleukin-1? (IL-1?). In a further study designed to elucidate the mechanism of its anti-inflammatory effects, compound 1 was shown to block nuclear factor-kappa B (NF-?B) activation in LPS-induced RAW264.7 macrophages and BV2 microglia by inhibiting the phosphorylation of inhibitor kappa B-? (I?B-?), thereby suppressing the nuclear translocation of NF-?B dimers, namely p50 and p65, that are known to be crucial molecules associated with iNOS and COX-2 expression. In addition, compound 1 inhibited the activation of mitogen-activated protein kinase (MAPK) pathways. Taken together, the results suggest that compound 1 might be a valuable therapeutic agent for the treatment of anti-inflammatory and anti-neuroinflammatory diseases.
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Non-Hodgkin's lymphomas, version 4.2014.
J Natl Compr Canc Netw
PUBLISHED: 09-06-2014
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Non-Hodgkin's lymphomas (NHL) are a heterogeneous group of lymphoproliferative disorders originating in B lymphocytes, T lymphocytes, or natural killer cells. Mantle cell lymphoma (MCL) accounts for approximately 6% of all newly diagnosed NHL cases. Radiation therapy with or without systemic therapy is a reasonable approach for the few patients who present with early-stage disease. Rituximab-based chemoimmunotherapy followed by high-dose therapy and autologous stem cell rescue (HDT/ASCR) is recommended for patients presenting with advanced-stage disease. Induction therapy followed by rituximab maintenance may provide extended disease control for those who are not candidates for HDT/ASCR. Ibrutinib, a Bruton tyrosine kinase inhibitor, was recently approved for the treatment of relapsed or refractory disease. This manuscript discusses the recommendations outlined in the NCCN Guidelines for NHL regarding the diagnosis and management of patients with MCL.
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Curcumin Reverse Methicillin Resistance in Staphylococcus aureus.
Molecules
PUBLISHED: 09-05-2014
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Curcumin, a natural polyphenolic flavonoid extracted from the rhizome of Curcuma longa L., was shown to possess superior potency to resensitize methicillin-resistant Staphylococcus aureus (MRSA) to antibiotics. Previous studies have shown the synergistic activity of curcumin with ?-lactam and quinolone antibiotics. Further, to understand the anti-MRSA mechanism of curcumin, we investigated the potentiated effect of curcumin by its interaction in diverse conditions. The mechanism of anti-MRSA action of curcumin was analyzed by the viability assay in the presence of detergents, ATPase inhibitors and peptidoglycan (PGN) from S. aureus, and the PBP2a protein level was analyzed by western blotting. The morphological changes in the curcumin-treated MRSA strains were investigated by transmission electron microscopy (TEM). We analyzed increased susceptibility to MRSA isolates in the presence of curcumin. The optical densities at 600 nm (OD600) of the suspensions treated with the combinations of curcumin with triton X-100 and Tris were reduced to 63% and 59%, respectively, compared to curcumin without treatment. N,N'-dicyclohexylcarbodiimide (DCCD) and sodium azide (NaN3) were reduced to 94% and 55%, respectively. When peptidoglycan (PGN) from S. aureus was combined with curcumin, PGN (0-125 ?g/mL) gradually blocked the antibacterial activity of curcumin (125 ?g/mL); however, at a concentration of 125 µg/mL PGN, it did not completely block curcumin. Curcumin has a significant effect on the protein level of PBP2a. The TEM images of MRSA showed damage of the cell wall, disruption of the cytoplasmic contents, broken cell membrane and cell lysis after the treatment of curcumin. These data indicate a remarkable antibacterial effect of curcumin, with membrane permeability enhancers and ATPase inhibitors, and curcumin did not directly bind to PGN on the cell wall. Further, the antimicrobial action of curcumin involved in the PBP2a-mediated resistance mechanism was investigated.
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Amomum tsao-ko suppresses lipopolysaccharide-induced inflammatory responses in RAW264.7 macrophages via Nrf2-dependent heme oxygenase-1 expression.
Am. J. Chin. Med.
PUBLISHED: 09-01-2014
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Amomum tsao-ko Crevost et Lemaire, used as a spice in Asia, is an important source of Chinese cuisine and traditional Chinese medicines. A. tsao-ko is reported to exert a variety of biological and pharmacological activities, including anti-proliferative, anti-oxidative and neuroprotective effects. In this study, NNMBS227, consisting of the ethanol extract of A. tsao-ko, exhibited potent anti-inflammatory activities in RAW264.7 macrophages. We investigated the effect of NNMBS227 in the suppression of pro-inflammatory mediators, including pro-inflammatory enzymes (inducible nitric oxide synthase and cyclooxygenase-2) and cytokines (tumor necrosis factor-? and interleukin-1?) in LPS stimulated macrophages. NNMBS227 also inhibited the phosphorylation and degradation of I?B-?, as well as the nuclear translocation of nuclear factor kappa B (NF-?B) p65 caused by stimulation with LPS. In addition, NNMBS227 induced heme oxygenase (HO)-1 expression through the nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) in macrophages. Using tin protoporphyrin (SnPP), an HO activity inhibitor, we confirmed an association between the anti-inflammatory effects of NNMBS227 and the up-regulation of HO-1. These findings suggest that Nrf2-dependent increases in the expression of HO-1 induced by NNMBS227 conferred anti-inflammatory activities in LPS stimulated RAW264.7 macrophages.
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Opuntia humifusa ameliorated cerulein-induced acute pancreatitis.
Pancreas
PUBLISHED: 08-16-2014
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The aim of this study was to evaluate the effects of Opuntia humifusa (OH) on cerulein-induced acute pancreatitis (AP).
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Clinicopathologic differences between prostate cancers detected during initial and repeat transrectal ultrasound-guided biopsy in Korea.
Korean J Urol
PUBLISHED: 08-04-2014
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The aim of this study was to investigate clinicopathologic differences between prostate cancer (PCa) detected at initial and repeat transrectal ultrasound-guided prostate biopsy in a large Korean cohort.
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Primary Cutaneous Gamma-Delta T-Cell Lymphoproliferative Disorder in a 3-Year-Old Boy.
Am J Dermatopathol
PUBLISHED: 07-30-2014
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: Primary cutaneous gamma-delta T-cell lymphoma (PCGD-TCL) is a rare disorder, constituting less than 1% of primary cutaneous lymphomas. Most cases occur in adults and may present as plaques or nodules with ulceration. Here we describe an unusual case of PCGD-TCL in a 3-year-old boy who presented with asymptomatic subcutaneous nodules. To our knowledge, this report represents one of the youngest reported patients with gamma-delta lymphoma/lymphoproliferative disorder. In addition, our patient has an indolent clinical presentation with greater than 1 year clinical follow-up. Because gamma-delta T-cell lymphomas are exceedingly rare in children, we acknowledge that the clinical course/outcome in young patients is still unclear. We hope to add to the recognition that PCGD-TCLs demonstrate a wide clinical spectrum of disease with relatively indolent presentations in some cases.
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Red ginseng extract ameliorates autoimmune arthritis via regulation of STAT3 pathway, Th17/Treg balance, and osteoclastogenesis in mice and human.
Mediators Inflamm.
PUBLISHED: 07-23-2014
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Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic joint inflammation. Red ginseng is a steamed and dried Panax ginseng C.A. Meyer, which has been used as alternative medicine for thousands of years. This study was undertaken to investigate the effects of red ginseng extracts (RGE) on autoimmune arthritis in mice and humans and to delineate the underlying mechanism. RGE was orally administered three times a week to mice with arthritis. Oral administration of RGE markedly ameliorated clinical arthritis score and histologically assessed joint inflammation in mice with CIA. A significant reduction in STAT3 phosphorylation and a decrease in the number of Th17 cells were observed with RGE treatment. There was also a marked reduction in RANKL-induced osteoclastogenesis with treatment of RGE. The inhibitory effect of RGE on Th17 differentiation and osteoclastogenesis observed in mice was also confirmed in the subsequent experiments performed using human peripheral blood mononuclear cells. Our findings provide the first evidence that RGE can regulate Th17 and reciprocally promote Treg cells by inhibiting the phosphorylation of STAT3. Therefore, RGE can ameliorate arthritis in mice with CIA by targeting pathogenic Th17 and osteoclast differentiation, suggesting a novel therapy for treatment of RA.
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Extracellular vesicles as emerging intercellular communicasomes.
BMB Rep
PUBLISHED: 07-18-2014
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All living cells release extracellular vesicles having pleiotropic functions in intercellular communication. Mammalian extracellular vesicles, also known as exosomes and microvesicles, are spherical bilayered proteolipids composed of various bioactive molecules, including RNAs, DNAs, proteins, and lipids. Extracellular vesicles directly and indirectly control a diverse range of biological processes by transferring membrane proteins, signaling molecules, mRNAs, and miRNAs, and activating receptors of recipient cells. The active interaction of extracellular vesicles with other cells regulates various physiological and pathological conditions, including cancer, infectious diseases, and neurodegenerative disorders. Recent developments in high-throughput proteomics, transcriptomics, and lipidomics tools have provided ample data on the common and specific components of various types of extracellular vesicles. These studies may contribute to the understanding of the molecular mechanism involved in vesicular cargo sorting and the biogenesis of extracellular vesicles, and, further, to the identification of disease-specific biomarkers. This review focuses on the components, functions, and therapeutic and diagnostic potential of extracellular vesicles under various pathophysiological conditions. [BMB Reports 2014; 47(10): 531-539].
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A case-control study to identify risk factors for totally implantable central venous port-related bloodstream infection.
Cancer Res Treat
PUBLISHED: 07-15-2014
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To date, the risk factors for central venous port-related bloodstream infection (CVPBSI) in solid cancer patients have not been fully elucidated. We conducted this study in order to determine the risk factors for CVP-BSI in patients with solid cancer.
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Isocudraxanthone K induces growth inhibition and apoptosis in oral cancer cells via hypoxia inducible factor-1?.
Biomed Res Int
PUBLISHED: 07-03-2014
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Isocudraxanthone K (IK) is a novel, natural compound from a methanol extract of the root bark of Cudrania tricuspidata. It has not been shown previously that IK possessed antitumor activity. We investigated the antitumor effects and molecular mechanism of IK and related signal transduction pathway(s) in oral squamous cell carcinoma cells (OSCCCs). The MTT assay revealed that IK had an antiproliferative effect on OSCCCs, in a dose- and time-dependent manner. IK induced apoptosis in OSCCCs, as identified by a cell-cycle analysis, annexin V-FITC and propidium iodide staining, and the nuclear morphology in cell death. IK caused time-dependent phosphorylation of Akt, p38, and ERK (extracellular signal-regulated kinase). In addition, IK increased the cytosolic to nuclear translocation of nuclear factor-?B (NF-?B) p65 and the degradation and phosphorylation of I?B-? in HN4 and HN12 cells. Furthermore, IK treatment downregulated hypoxia-inducible factor 1? (HIF-1?) and its target gene, vascular endothelial growth factor (VEGF). Cobalt chloride (CoCl2), a HIF-1? activator, attenuated the IK-induced growth-inhibiting and apoptosis-inducing effects, and blocked IK-induced expression of apoptosis regulatory proteins, such as Bax, Bcl-2, caspase-3, caspase-8, and caspase-9, and cytochrome c. Collectively, these data provide the first evidence of antiproliferative and apoptosis-inducing effects of IK as a HIF-1? inhibitor and suggest it may be a drug candidate for chemotherapy against oral cancer.
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In vivo Kinetic Biodistribution of Nano-Sized Outer Membrane Vesicles Derived from Bacteria.
Small
PUBLISHED: 06-20-2014
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Evaluation of kinetic distribution and behaviors of nanoparticles in vivo provides crucial clues into their roles in living organisms. Extracellular vesicles are evolutionary conserved nanoparticles, known to play important biological functions in intercellular, inter-species, and inter-kingdom communication. In this study, the first kinetic analysis of the biodistribution of outer membrane vesicles (OMVs)-bacterial extracellular vesicles-with immune-modulatory functions is performed. OMVs, injected intraperitoneally, spread to the whole mouse body and accumulate in the liver, lung, spleen, and kidney within 3 h of administration. As an early systemic inflammation response, increased levels of TNF-? and IL-6 are observed in serum and bronchoalveolar lavage fluid. In addition, the number of leukocytes and platelets in the blood is decreased. OMVs and cytokine concentrations, as well as body temperature are gradually decreased 6 h after OMV injection, in concomitance with the formation of eye exudates, and of an increase in ICAM-1 levels in the lung. Following OMV elimination, most of the inflammatory signs are reverted, 12 h post-injection. However, leukocytes in bronchoalveolar lavage fluid are increased as a late reaction. Taken together, these results suggest that OMVs are effective mediators of long distance communication in vivo.
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A Case of Ventriculitis Associated with Renal Abscess Caused by Serotype K1 Klebsiella pneumoniae.
Infect Chemother
PUBLISHED: 06-20-2014
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Recently, serotype K1 Klebsiella pneumoniae has been a major agent of an invasive syndrome characterized by liver abscess and its metastatic infection. Extrahepatic infection and its characteristics in patients with renal abscess caused by K. pneumoniae are poorly understood, and few cases of central nervous system infection have been reported. This is a report of 80-year-old woman with uncontrolled type 2 diabetes mellitus with renal abscess caused by serotype K1 K. pneumoniae, complicated with ventriculitis despite of appropriate use of antibiotics. Physicians need to be aware of possibility of metastatic infection in patients with serotype K1 K. pneumoniae infection, if they develop neurologic symptom and focus of infection is still present.
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Non-Hodgkin's lymphomas, version 2.2014.
J Natl Compr Canc Netw
PUBLISHED: 06-14-2014
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Non-Hodgkin's lymphomas (NHLs) are a heterogeneous group of lymphoproliferative disorders originating in B lymphocytes, T lymphocytes, or natural killer cells. Follicular lymphoma (FL) is the most common subtype of indolent NHL, accounting for approximately 22% of all newly diagnosed cases of NHL. The incorporation of rituximab to chemotherapy regimens has become a widely accepted standard of care for first-line therapy for patients with FL. Maintenance and consolidation therapy with rituximab and radioimmunotherapy have also been associated with improved progression-free survival in patients experiencing response to first-line therapy. Despite therapeutic advances that have improved outcomes, FL is generally considered a chronic disease characterized by multiple recurrences with current therapies. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with FL.
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Anti-fibrotic effect of PF2401-SF, a standardized fraction of Salvia miltiorrhiza, in thioacetamide-induced experimental rats liver fibrosis.
Arch. Pharm. Res.
PUBLISHED: 06-11-2014
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We previously reported the in vitro and in vivo hepatoprotective and anti-fibrotic effects of PF2401-SF, a standardized fraction of Salvia miltiorrhiza, against acute and subacute liver injury. The aim of this study was to investigate the effect of PF2401-SF on liver fibrosis induced by thioacetamide (TAA), a chronic liver injury model (12 weeks) that closely resembles fibrosis and cirrhosis in humans. Hepatoprotective activity was indicated by low serum levels of the markers aspartate amino transferase and alanine amino transferase .In addition, compared to the TAA-group livers, the PF2401-SF-treated liver tissues showed no fibrous tissue deposition in the portal areas, hepatocyte morphology more closely resembling normal tissue morphology, and significantly reduced collagen deposition. Furthermore, downregulation of collagen 1(?) and tissue inhibitor of metalloproteinase (TIMP)1 protein and mRNA expression also supports PF2401-SF's anti-fibrotic effect. We also observed reduced expression of ?-smooth muscle actin (?-SMA), an important marker of hepatic stellate cells (HSCs) activation. From these results, we conclude that PF2401-SF's anti-fibrotic mechanism in the TAA model involves reduced HSC activation, and may be mediated by downregulation of central markers of fibrosis, including collagen 1(?), TIMP1, and ?-SMA.
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Ginsenoside compound K-bearing glycol chitosan conjugates: synthesis, physicochemical characterization, and in vitro biological studies.
Carbohydr Polym
PUBLISHED: 06-10-2014
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Ginsenosides are triterpenoids found in Panax ginseng and have a numerous structural, functional, and pharmacological properties. The purpose of this study was to develop hydrophilic polymer functionalized ginsenoside conjugates to enhance water solubility and targeted delivery. To this end, hydrophobic ginsenoside compound K (CK) was covalently conjugated to the backbone of hydrophilic glycol chitosan (GC) through an acid-labile linkage. The resulting GC-CK conjugates formed self-assembled spherical nanoparticles in an aqueous solution, and their particles sizes were (296 nm and 255 nm) dependent on the degree of CK substitution. The nanoparticles were stable in the physiological buffer (pH 7.4) over a period of 8 days, whereas they were readily degraded under acidic conditions (pH 5.0) mimicking the intracellular pH-conditions. From in vitro release experiment, it was found that CK released slowly from the self-assembled nanoparticles in the physiological buffer (pH 7.4). On the other hand, the release rate of CK was rapidly increased under the acidic condition (pH 5.0). In vitro cytotoxicity assays revealed that GC-CK conjugates exhibited higher cytotoxicity than CK in HT29, and similar cytotoxicity in HepG2, and HT22 cell lines. Moreover, RAW264.7 cells treated with GC-CK maintained good cell viability and exhibited decreased lipopolysaccharide-induced NO production. Taken together, these results suggest that the GC-CK conjugate may be potentially useful as a tumor-specific delivery vehicle.
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Prevalence of systemic lupus erythematosus in South Korea: an administrative database study.
J Epidemiol
PUBLISHED: 05-24-2014
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Systemic lupus erythematosus (SLE) is a rare autoimmune disease for which a population-based survey on the prevalence of the disease in South Korea has not yet been conducted. Our goal was to estimate the nationwide prevalence of SLE.
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Cudarflavone B provides neuroprotection against glutamate-induced mouse hippocampal HT22 cell damage through the Nrf2 and PI3K/Akt signaling pathways.
Molecules
PUBLISHED: 05-21-2014
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Oxidative cell damage contributes to neuronal degeneration in many central nervous system (CNS) diseases such as Alzheimer's disease, Parkinson's disease, and ischemia. Nrf2 signaling-mediated heme oxygenase (HO)-1 expression acts against oxidants that are thought to play a key role in the pathogenesis of neuronal diseases. Cudraflavone B is a prenylated flavone isolated from C. tricuspidata which has shown anti-proliferative activity, mouse brain monoamine oxidase (MAO) inhibitory effects, apoptotic actions in human gastric carcinoma cells and mouse melanoma cells, and hepatoprotective activity. In this study, cudraflavone B showed neuroprotective effects and reactive oxygen species (ROS) inhibition against glutamate-induced neurotoxicity by inducing the expression of HO-1 in mouse hippocampal HT22 cells. Furthermore, cudraflavone B caused the nuclear accumulation of nuclear factor-E2-related factor 2 (Nrf2) and increased the promoter activity of antioxidant response elements (ARE) in mouse hippocampal HT22 cells. In addition, we found that the Nrf2-midiated HO-1 expression by cudraflavone B is involved in the cell protective response and ROS reductions, and cudraflavone B-induced expression of HO-1 was mediated through the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in HT22 cells. Our results demonstrated the potential application of naturally occurring cudraflavone B as a therapeutic agent from neurodegenerative disease.
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Saussurea lappa extract suppresses TPA-induced cell invasion via inhibition of NF-?B-dependent MMP-9 expression in MCF-7 breast cancer cells.
BMC Complement Altern Med
PUBLISHED: 05-13-2014
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Saussurea lappa (SL) has been used as a traditional herbal medicine to treat abdominal pain and tenesmus, and has been suggested to possess various biological activities, including anti-tumor, anti-ulcer, anti-inflammatory, anti-viral, and cardiotonic activities. The effect of SL on breast cancer metastasis, however, is unknown. Cell migration and invasion are crucial in neoplastic metastasis. Matrix metalloproteinase-9 (MMP-9), which degrades the extracellular matrix, is a major component in cancer cell invasion.
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Intralymphatic cutaneous anaplastic large cell lymphoma/lymphomatoid papulosis: expanding the spectrum of CD30-positive lymphoproliferative disorders.
Am. J. Surg. Pathol.
PUBLISHED: 05-09-2014
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Intravascular large B-cell lymphomas and EBV NK/T-cell lymphomas commonly follow an aggressive clinical course. We recently reported an entirely intravascular anaplastic large cell lymphoma (ALCL) in the skin with a surprisingly indolent clinical course; interestingly, this lymphoma involved the lymphatic rather than the blood vasculature. We hypothesized that intravascular skin-limited ALCL is distinct from aggressive systemic intravascular lymphomas in its intralymphatic localization and clinical course. We now describe 18 cases of cutaneous intravascular large cell lymphoproliferations from 4 institutions. All 12 intravascular large T-cell lesions were intralymphatic; the majority (9) were CD30 T-cell lymphoproliferative disorders (TLPDs), 5 further classified as intravascular ALK ALCL. One ALK ALCL and 2 benign microscopic intravascular T-cell proliferations were also intralymphatic. A single case of otherwise typical cutaneous follicle center lymphoma contained intralymphatic centroblasts. The clinical and pathologic characteristics of the CD30 TLPDs were similar to those of their extravascular counterparts, including extralymphatic dermal involvement in a subset, DUSP22-IRF4 translocations in half of tested ALK ALCLs, and associated mycosis fungoides in 1; most were skin-limited at baseline and remained so at relapse. All 5 cases of intravascular large B-cell lymphoma involved the blood vasculature and behaved in a clinically aggressive manner; the ALK ALCL, although intralymphatic, was systemic and clinically aggressive. We propose that cutaneous ALK ALCL and related CD30 ALK TLPDs involving the lymphatics are part of an expanding spectrum of CD30 TLPDs. The identification of intralymphatic as distinct from blood vascular localization may provide critical prognostic and therapeutic information.
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Outcomes after diagnosis of mycosis fungoides and Sézary syndrome before 30 years of age: a population-based study.
JAMA Dermatol
PUBLISHED: 04-11-2014
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Mycosis fungoides and Sézary syndrome (MF/SS) are rare in children and young adults, and thus the incidence and outcomes in this patient population are not well studied.
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Home blood pressure is the predictor of subclinical target organ damage like ambulatory blood pressure monitoring in untreated hypertensive patients.
Anadolu Kardiyol Derg
PUBLISHED: 04-08-2014
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Home blood pressure (HBP) measurements are known as an important adjunct to office blood pressure (OBP) measurements in clinical practice. But little is known about the relationship between HBP and subclinical target organ damage (TOD) other than left ventricular hypertrophy (LVH). So we investigated the relationship of HBP measurements with subclinical TOD in untreated hypertensive patients.
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Lignan and flavonoids from the stems of Zea mays and their anti-inflammatory and neuroprotective activities.
Arch. Pharm. Res.
PUBLISHED: 04-02-2014
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The stems of Zea mays L., otherwise known as cornstalks, were extracted with 80 % aqueous MeOH, and the concentrated extract was successively partitioned with ethyl acetate (EtOAc), normal butanol, and water. From the EtOAc fraction, a new lignan along with three known flavonoids, tricin (1), salcolin A (2), and salcolin B (3), were isolated. The chemical structure of the lignan was determined to be tetrahydro-4,6-bis(4-hydroxy-3-methoxyphenyl)-1H,3H-furo[3,4-c]furan-1-one (4) through spectroscopic data analyses including NMR, MS, and IR. All compounds were isolated for the first time from this plant. The isolated compounds were evaluated for their inhibitory activity against NO production in Lipopolysaccharide-induced RAW 264.7 cells and their protective activity in glutamate-induced cell death in HT22 cells. The compounds 1, 2 and 4 showed anti-inflammatory effects with IC50 values of 2.63, 14.65, and 18.91 ?M, respectively, as well as neuroprotective effects with EC50 values of 25.14, 47.44, and >80 ?M, respectively.
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Multidetector computed tomography for the evaluation of coronary artery disease; the diagnostic accuracy in calcified coronary arteries, comparing with IVUS imaging.
Yonsei Med. J.
PUBLISHED: 04-01-2014
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Contrast enhanced multidetector computed tomography (MDCT) has been used as an alternative to coronary angiography for the assessment of coronary artery disease in the patient of the intermediate risk group. However, coronary calcium is a known limiting factor for MDCT evaluation. We investigated the diagnostic accuracy of 64-channel MDCT with each coronary artery calcium score (CACS) by compared with intravascular ultrasound (IVUS) imaging.
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The cytoprotective effect of sulfuretin against tert-butyl hydroperoxide-induced hepatotoxicity through Nrf2/ARE and JNK/ERK MAPK-mediated heme oxygenase-1 expression.
Int J Mol Sci
PUBLISHED: 03-26-2014
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Sulfuretin is one of the major flavonoid components in Rhus verniciflua Stokes (Anacardiaceae) isolates. In this study, we investigated the protective effects of sulfuretin against tert-butyl hydroperoxide (t-BHP)-induced oxidative injury. The results indicated that the addition of sulfuretin before t-BHP treatment significantly inhibited cytotoxicity and reactive oxygen species (ROS) production in human liver-derived HepG2 cells. Sulfuretin up-regulated the activity of the antioxidant enzyme heme oxygenase (HO)-1 via nuclear factor E2-related factor 2 (Nrf2) translocation into the nucleus and increased the promoter activity of the antioxidant response element (ARE). Moreover, sulfuretin exposure enhanced the phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase 1/2 (ERK1/2), which are members of the mitogen-activated protein kinase (MAPK) family. Furthermore, cell treatment with a JNK inhibitor (SP600125) and ERK inhibitor (PD98059) reduced sulfuretin-induced HO-1 expression and decreased its protective effects. Taken together, these results suggest that the protective effect of sulfuretin against t-BHP-induced oxidative damage in human liver-derived HepG2 cells is attributable to its ability to scavenge ROS and up-regulate the activity of HO-1 through the Nrf2/ARE and JNK/ERK signaling pathways. Therefore, sulfuretin could be advantageous as a bioactive source for the prevention of oxidative injury.
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Risk factors for mortality in patients with Pseudomonas aeruginosa bacteremia; retrospective study of impact of combination antimicrobial therapy.
BMC Infect. Dis.
PUBLISHED: 03-19-2014
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Whether the combination of antimicrobial therapy is a factor in mortality in Pseudomonas aeruginosa bacteremia remains to be elucidated. This study investigated the risk factors for mortality in P. aeruginosa bacteremia patients and the influence of adequate antimicrobial therapy and combination therapy on clinical outcomes.
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Beneficial Effects of Fractions of Nardostachys jatamansi on Lipopolysaccharide-Induced Inflammatory Response.
Evid Based Complement Alternat Med
PUBLISHED: 02-28-2014
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It has been previously shown that Nardostachys jatamansi (NJ) exhibits anti-inflammatory properties against lipopolysaccharide (LPS) challenges. However, the potency of NJ constituents against LPS-induced inflammatory responses has not been examined. In this present study, we determined which NJ extract fractions exhibit inhibitory effects against LPS-induced inflammatory responses. Among the NJ fractions, NJ-1, NJ-3, NJ-4, and NJ-6 inhibited LPS-induced production of NO. The NJ-3, NJ-4, and NJ-6 fractions also inhibited the production of cytokines, such as IL-1 ? , IL-6, and TNF- ? . However, NJ-1, NJ-3, NJ-4, and NJ-6 showed differential inhibitory mechanisms against LPS-induced inflammatory responses. NJ-1, NJ-3, and NJ-4 inhibited LPS-induced activation of c-jun NH2-terminal kinase (JNK) and p38 but did not affect activation of extracellular signal-regulated kinase (ERK) or NF- ? B. On the other hand, NJ-6 inhibited activation of MAPKs and NF- ? B. In addition, in vivo experiments revealed that administration of NJ-1, NJ-3, NJ-4, and NJ-6 reduced LPS-induced endotoxin shock, with NJ-6 especially showing a marked protective effect. Taken together, these results provide the evidence for the potential of selective NJ fractions against LPS-induced inflammation. Thus, it will be advantageous to further isolate and determine single effective compounds from these potent fractions.
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Inhibitory effects of Pericarpium zanthoxyli extract on adipocyte differentiation.
Int. J. Mol. Med.
PUBLISHED: 02-20-2014
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Obesity is a risk factor associated with numerous disorders, such as type 2 diabetes, hypertension, dyslipidemia and coronary heart disease. In this study, we investigated the inhibitory effects of Pericarpium zanthoxyli extract (PZE) on the adipocytic differentiation of OP9 cells. During adipocyte differentiation, the OP9 cells were treated with 0, 10 and 20 µg/ml of PZE at various time intervals, followed by the examination of lipid droplet formation and the mRNA expression of adipogenesis-related genes. The cells treated with PZE during the early period (days 0-2) showed a significant reduction in the accumulation of lipid droplets, which were induced by a standard adipogenic cocktail, as well as a decrease in the expression of the adipogenesis-related transcription factor, peroxisome proliferator-activated receptor ? (PPAR?) and PPAR?-target genes, such as adipocyte protein 2 (aP2), fatty acid synthase (FAS) and other adipocyte markers. Adipocyte differentiation was not inhibited by treatment with PZE during the late stage of differentiation (days 3-5). Thus, the inhibitory effects of PZE on adipocyte differentiation occurred during the early stages of adipogenesis, which was confirmed by the decrease in the levels of CCAAT/enhancer-binding protein ? (C/EBP?) in a dose-dependent manner when the OP9 cells were exposed to PZE. Taken together, our results indicate that PZE inhibit the early stages of adipogenic differentiation by inhibiting C/EBP? expression.
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Recurrent bilateral breast abscess due to nontuberculous mycobacterial infection.
J Breast Cancer
PUBLISHED: 02-19-2014
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Since recurrent bilateral breast infection due to nontuberculous mycobacterium (NTM) is rare, its diagnosis is easily overlooked; in addition, complete recovery is often difficult to achieve. We report a case of recurrent bilateral infection in a 35-year-old woman who had completed treatment for NTM. Although various infectious diseases show similar clinical conditions and imaging findings, recurrences should raise suspicion of NTM infection, and this possibility should be considered in differential diagnoses.
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Clinical impact of body mass index on bactibilia and bacteremia.
BMC Gastroenterol
PUBLISHED: 02-19-2014
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The aim of this study was to evaluate the association between obesity and infected bile or bacteremia in patients with acute calculous cholecystitis.
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9-Hydroxy-6,7-dimethoxydalbergiquinol inhibits osteoclast differentiation through down-regulation of Akt, c-Fos and NFATc1.
Int. Immunopharmacol.
PUBLISHED: 02-19-2014
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Recently, natural plant-derived products have been recognized as one of the main sources for drug discovery and development in human disease. 9-Hydroxy-6,7-dimethoxydalbergiquinol (HDDQ) isolated from the heart wood of Dalbergia odorifera is widely used in oriental medicine, however, the pharmacological effect of HDDQ in osteoclast-associated diseases remains unknown. In this study, HDDQ dose-dependently inhibited the early stage of RANKL-mediated osteoclast differentiation in bone marrow macrophages (BMMs) without cytotoxicity. HDDQ strongly inhibited Akt phosphorylation in RANKL-stimulated BMMs and did not show any effects on p38, JNK, and I?B phosphorylation and I?B degradation. Interestingly, we found that HDDQ down-regulated the induction by RANKL of c-Fos protein by suppressing its translation. Also, ectopic overexpression of c-Fos and NFATc1 rescued the inhibition of osteoclast differentiation by HDDQ. Furthermore, the Akt/c-Fos/NFATc1-regulated expression of genes required for osteoclastogenesis, such as OSCAR and TRAP, was inhibited by HDDQ. These findings suggest that HDDQ prevents osteoclast differentiation via down-regulation of Akt, c-Fos, and NFATc1 signaling molecules, suggesting a potential therapeutic value of HDDQ for bone disorders associated with increased bone resorption.
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Combined use of multiple computational intracranial EEG analysis techniques for the localization of epileptogenic zones in Lennox-Gastaut syndrome.
Clin EEG Neurosci
PUBLISHED: 02-18-2014
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Traditionally, identification of epileptogenic zones primarily relied on visual inspection of intracranial electroencephalography (iEEG) recordings by experienced epileptologists; however, removal of epileptogenic zones identified by iEEG does not always guarantee favorable surgical outcomes. To confirm visual inspection results, and assist in making decisions about surgical resection areas, computational iEEG analysis methods have recently been used for the localization of epileptogenic zones. In this study, we have proposed a new approach for the localization of epileptogenic zones in Lennox-Gastaut syndrome (LGS), and have investigated whether the proposed approach could confirm surgical resection areas and predict seizure outcome before surgery. The proposed approach simultaneously used results of 2 iEEG analysis methods, directed transfer function (DTF) and time delay estimation, to enhance localization accuracy. This new combined method was applied to patients who became seizure-free after resective epilepsy surgery, as well as those who had unsuccessful surgery. A quantitative metric was also introduced that can measure how well the localized epileptogenic zones coincided with the surgical resection areas, with the aim of verifying whether the approach could confirm surgical resection areas determined by epileptologists. The estimated epileptogenic zones more strongly coincided with surgical resection areas in patients with successful, compared to those with unsuccessful surgical outcomes. Both qualitative and quantitative analyses showed that the combined use of 2 iEEG analyses resulted in a more accurate estimate of epileptogenic zones in LGS than the use of a single method. A combination of multiple iEEG analyses could not only enhance overall accuracy of localizing epileptogenic zones in LGS, but also has the potential to predict outcomes before resective surgery.
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Localization of epileptogenic zones in Lennox-Gastaut syndrome (LGS) using graph theoretical analysis of ictal intracranial EEG: A preliminary investigation.
Brain Dev.
PUBLISHED: 02-13-2014
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Introduction: Precise localization of epileptogenic zones is essential for the successful surgical treatment of refractory epilepsy including Lennox-Gastaut syndrome (LGS). The surgical resection areas are generally determined by epileptologists based on diverse neuroimaging modalities; however, exact epileptogenic zones cannot be accurately localized in many patients with LGS using the conventional methods. Therefore, new reliable algorithms are still required for enhancing the success rate of the resective epilepsy surgery. In the present study, we introduce an approach to localize epileptogenic zones in LGS based on the graph theoretical analysis of ical intracranial EEG (iEEG). Methods: Four patients with LGS who became seizure-free after the resective epilepsy surgery were selected. Before the surgery, their epileptogenic zones were delineated using EEG, iEEG, and several conventional imaging modalities. Phase locking value (PLV) analysis was applied to construct functional connectivity networks during ictal events, and then several graph theoretical indices including betweenness centrality (BC) were evaluated for each iEEG sensor to find the primary hubs of the ictal epileptic network. The graph theoretical index values were then overlaid on 3D individual cortical surface. Results: The iEEG channels with high BC values coincided well with the surgical resection areas. Among various graph theoretical measures such as local efficiency, participation coefficient, and eigenvector centrality, only BC showed fair correspondence with the surgical resection areas. Conclusions: The primary hubs in the ictal epileptic networks coincided well with areas of surgical resection in LGS patients with successful surgical outcomes. This observation warrants further studies to determine if the graph theoretical network analysis of ictal iEEG recordings can serve as a new auxiliary tool to localize epileptogenic zones in LGS.
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The Antibacterial Assay of Tectorigenin with Detergents or ATPase Inhibitors against Methicillin-Resistant Staphylococcus aureus.
Evid Based Complement Alternat Med
PUBLISHED: 02-12-2014
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Tectorigenin (TTR) is an O-methylated isoflavone derived from the rhizome of Belamacanda chinensis (L.) DC. It is known to perform a wide spectrum of biological activities such as antioxidant, anti-inflammatory, anti-tumor. The aim of this study is to examine the mechanism of antibacterial activity of TTR against methicillin-resistant Staphylococcus aureus (MRSA). The anti-MRSA activity of TTR was analyzed in combination assays with detergent, ATPase inhibitors, and peptidoglycan (PGN) derived from S. aureus. Transmission electron microscopy (TEM) was used to monitor survival characteristics and changes in S. aureus morphology. The MIC values of TTR against all the tested strains were 125? ? g/mL. The OD(600) of each suspension treated with a combination of Triton X-100, DCCD, and NaN3 with TTR (1/10 × MIC) had been reduced from 68% to 80%, compared to the TTR alone. At a concentration of 125? ? g/mL, PGN blocked antibacterial activity of TTR. This study indicates that anti-MRSA action of TTR is closely related to cytoplasmic membrane permeability and ABC transporter, and PGN at 125? ? g/mL directly bind to and inhibit TTR at 62.5? ? g/mL. These results can be important indication in study on antimicrobial activity mechanism against multidrug resistant strains.
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Lignans and neolignans from the stems of Vibrunum erosum and their neuroprotective and anti-inflammatory activity.
Arch. Pharm. Res.
PUBLISHED: 02-10-2014
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A new lignan, (7'S,8S,8'S)-3,5'-dimethoxy-3',4,9'-trihydroxy-7',9-epoxy-8,8'-lignan, named vibruresinol (1), was isolated from the stems of Viburnum erosum by silica gel, ODS, and Sephadex LH-20 column chromatography. In addition, four other known lignans, (7'R,8S,8'S)-3,5'-dimethoxy-3',4,8',9'-tetrahydroxy-7',9-epoxy-8,8'-lignan (2), (+)-syringaresinol (3), (+)-pinoresinol (4), and (+)-pinoresinol-4-O-?-D-glucopyranoside (5), and five known neolignans, herpetol (6), vibsanol (7), (-)-dehydrodiconiferyl alcohol (8), icariside E4 (9), and dihydrodehydrodiconiferyl alcohol (10), were isolated in the same manner. The chemical structures of the compounds were determined based on spectroscopic data including NMR, MS, and IR. All of the compounds described above were isolated from V. erosum for the first time. The isolated compounds 3, 4, and 6 were evaluated for neuroprotective activity on glutamate-induced cell death in HT22 cells and had EC50 values of 6.33 ± 1.22, 6.96 ± 0.65, and 9.15 ± 0.36 ?M, respectively. Likewise, the same compounds had inhibitory activity on NO production in LPS-induced RAW 264.7 cells with IC50 values of 8.30 ± 1.56, 7.89 ± 1.22, and 9.32 ± 0.36 ?M, respectively.
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Ethanol Extract of Alismatis rhizome Inhibits Adipocyte Differentiation of OP9 Cells.
Evid Based Complement Alternat Med
PUBLISHED: 02-06-2014
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The rhizome of Alisma orientale (Alismatis rhizome) has been used in Asia for promoting diuresis to eliminate dampness from the lower-jiao and to expel heat. In this study, an ethanol extract of the rhizome of Alisma orientale (AOE) was prepared and its effects on adipocyte differentiation of OP9 cells were investigated. Treatment with AOE in a differentiation medium for 5 days resulted in dose-dependent inhibition of lipid droplet formation in OP9 cells. Furthermore, AOE significantly inhibited adipocyte differentiation by downregulating the expression of the master transcription factor of adipogenesis, peroxisome proliferation-activity receptor ? (PPAR ? ), and related genes, including CCAAT/enhancer binding protein ? (C/EBP ? ), fatty acid-binding protein (aP2), and fatty acid synthase (FAS). AOE exerted its inhibitory effects primarily during the early adipogenesis stage (days 1-2), at which time it also exerted dose-dependent inhibition of the expression of C/EBP ? , a protein related to the inhibition of mitotic clonal expansion. Additionally, AOE decreased the expression of autophagy-related proteins, including beclin 1, and the autophagy-related genes, (Atg) 7 and Atg12. Our results indicate that AOE's inhibitory effects on adipocyte differentiation of OP9 cells are mediated by reduced C/EBP ? expression, causing inhibition of mitotic clonal expansion and autophagy.
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Different contribution of extent of myocardial injury to left ventricular systolic and diastolic function in early reperfused acute myocardial infarction.
Cardiovasc Ultrasound
PUBLISHED: 02-06-2014
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We sought to investigate the influence of the extent of myocardial injury on left ventricular (LV) systolic and diastolic function in patients after reperfused acute myocardial infarction (AMI).
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(2S)-2'-Methoxykurarinone inhibits osteoclastogenesis and bone resorption through down-regulation of RANKL signaling.
Biol. Pharm. Bull.
PUBLISHED: 02-05-2014
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(2S)-2'-Methoxykurarinone (MK), a compound isolated from the roots of Sophora flavescens, has various physiological properties, such as anti-inflammatory, antipyretic, antidiabetic, and antineoplastic effects. However, the effect of S. flavescens-derived MK on osteoclastogenesis remains unknown. Therefore, we examined the effect and mechanism of action of MK on receptor activator of nuclear factor-?B ligand (RANKL)-induced osteoclast differentiation and bone resorption. MK inhibited osteoclast differentiation in bone marrow cell-osteoblast cocultures but did not affect the RANKL-to-osteoprotegerin ratio induced by osteoclastogenic factors in osteoblasts. MK also inhibited RANKL-induced osteoclast differentiation from bone marrow macrophages in a dose-dependent manner, without cytotoxicity. Pretreatment with MK significantly suppressed the Akt, p38, c-Jun N terminal kinase (JNK), c-Fos, and nuclear factor of activated T cells c1 (NFATc1) pathways and inhibited the bone-resorbing activity of mature osteoclasts. These results collectively suggest that MK inhibits osteoclast differentiation and bone resorption through RANKL-induced mitogen-activated protein kinases (MAPKs) and c-Fos-NFATc1 signaling pathways.
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The neoflavonoid latifolin isolated from MeOH extract of Dalbergia odorifera attenuates inflammatory responses by inhibiting NF-?B activation via Nrf2-mediated heme oxygenase-1 expression.
Phytother Res
PUBLISHED: 01-01-2014
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In Korea and China, the heartwood of Dalbergia odorifera T. Chen is an important traditional medicine used to treat blood disorders, ischemia, swelling, and epigastric pain. In this study, we investigated the inhibitory effects of latifolin, a major neoflavonoid component isolated from the MeOH extract of D.?odorifera, on the inflammatory reaction of thioglycollate-elicited peritoneal macrophages exposed to lipopolysaccharide, with a particular focus on heme oxygenase-1 (HO-1) expression and nuclear factor-?B (NF-?B) signaling. Latifolin significantly inhibited the protein and mRNA expression of inducible nitric oxide synthase and COX-2, reduced NO, prostaglandins E2, tumor necrosis factor-?, and interleukin-1? production in primary murine peritoneal macrophages exposed to lipopolysaccharide. Latifolin also suppressed inhibitor ?B-? levels, NF-?B nuclear translocation, and NF-?B DNA-binding activity. Furthermore, latifolin upregulated HO-1 expression via nuclear transcription factor-E2-related factor 2 (Nrf2) nuclear translocation. In addition, using inhibitor tin protoporphyrin IX (SnPP), an inhibitor of HO-1, it was verified that the inhibitory effects of latifolin on the proinflammatory mediators and NF-?B DNA-binding activity were associated with the HO-1 expression. These results suggested that the latifolin-mediated up-regulation of HO-1 expression played a critical role in anti-inflammatory effects in macrophages. This study therefore identified potent therapeutic effects of latifolin, which warrants further investigation as a potential treatment for inflammatory diseases.
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Results of an open-label multicenter phase II trial of lenalidomide monotherapy in refractory mycosis fungoides and Sezary syndrome.
Blood
PUBLISHED: 12-11-2013
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A phase II multicenter trial was performed to evaluate single-agent lenalidomide in advanced, refractory mycosis fungoides/Sézary syndrome. Thirty-two patients were enrolled with a median of six prior treatment regimens, including a median of four systemic therapies. Patients achieved an overall response rate of 28% (9 patients); all partial responses. Median overall survival was 43 months, median progression-free survival was 8 months, and median duration of response was 10 months. No grade 4 toxicities occurred. Grade 3 adverse events included fatigue (22%), infection (9%), and leukopenia (3%). Patients were frequently unable to tolerate the 25mg starting dose of lenalidomide used in other hematologic malignancies due to fatigue, pain and transient flare reaction (TFR) as a contributory factor. TFR appeared to correlate with clinical response, but the small sample size limited definitive conclusions, and the underlying mechanisms of this reaction are not known. Data from correlative studies on peripheral blood samples suggest that the effects of lenalidomide could be associated with decreased circulating CD25+ T-cells and CD4+ T-cell numbers. Skin lesions showed a trend for increased CD8, CD25 and FoxP3 expression with decreased CD4:CD8 ratio. In conclusion, lenalidomide monotherapy demonstrated activity in refractory CTCL, along with acceptable toxicity. This study is registered at ClinicalTrials.gov, identifier NCT00466921.
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Minimal residual disease monitoring with high-throughput sequencing of T cell receptors in cutaneous T cell lymphoma.
Sci Transl Med
PUBLISHED: 12-06-2013
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Mycosis fungoides (MF) and the leukemic presentation Sézary syndrome (SS) are clonal T cell lymphomas arising from the skin and are considered noncurable with standard therapies. To develop a specific and sensitive monitoring tool, we tested the ability of high-throughput sequencing (HTS) of T cell receptors (TCRB) to monitor minimal residual disease (MRD) after allogeneic hematopoietic cell transplantation. Genomic DNA was extracted from peripheral blood mononuclear cells (PBMCs) or skin samples. The rearranged TCR? loci were amplified using V?- and J?-specific primers, followed by HTS, to generate up to 1,000,000 reads spanning the CDR3 region of individual cells. Malignant clones were identified in diagnostic samples in all cases by a dominant CDR3 sequence. Before transplant, four patients had circulating Sézary cells by the routine flow cytometry, which was confirmed by TCRB HTS. Although the flow cytometry found no detectable Sézary cells, malignant clones were detected by TCRB HTS in all other six cases. Five patients achieved "molecular remission" in blood between +30 and +540 days after transplant. Four of these patients also achieved molecular clearance in skin after transplant. Experiments using blood samples spiked with purified Sézary cells demonstrated that TCRB HTS can detect Sézary cells at the level of 1 in 50,000 PBMCs, which is more sensitive than standard diagnostics. We have thus demonstrated the utility of TCRB HTS to assess MRD with increased sensitivity and specificity compared to other current methodologies, and to monitor response to therapy in this MF/SS patient population.
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Liver abscess due to Klebsiella pneumoniae: Risk factors for metastatic infection.
Scand. J. Infect. Dis.
PUBLISHED: 11-15-2013
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Abstract Introduction: Klebsiella pneumoniae-associated liver abscess (KPLA) is often accompanied by extrahepatic complications. We investigated the clinical features and outcomes of patients with and without metastatic infections and compared the 2 groups. Methods: We retrospectively reviewed the medical records of 161 patients with KPLA who were admitted to 2 tertiary referral hospitals in Korea. Results: In total, 9.9% had a metastatic infection. The most commonly involved distant sites were the eyes (n = 7) and the lungs (n = 6). In multivariate analysis, diabetes mellitus as an underlying disease (odds ratio (OR) 2.30, 95% confidence interval (CI) 1.05-9.51; p = 0.03) and a platelet count < 80,000/mm(3) (OR 11.60, 95% CI 2.53-53.26; p = 0.002) were associated with metastatic infection. Extended-spectrum beta-lactamase (ESBL) production was not observed in K. pneumoniae from patients with metastatic infection, whereas 3.4% of the bacteria in patients without metastatic infection had ESBL production. However, this difference was not statistically significant (p = 0.45). The in-hospital mortality rate was not significantly different (0% vs. 2.8%; p = 0.52). By multivariate analysis, the Acute Physiology and Chronic Health Evaluation II (APACHE II) score was independently associated with mortality among patients with KPLA (OR 1.5, 95% CI 1.12-2.00; p = 0.006). Conclusions: Clinicians must be aware of potential metastatic infections in patients with KPLA, especially if they have diabetes mellitus and thrombocytopenia. The APACHE II score was predictive of mortality in patients with KPLA.
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Penicillinolide A: a new anti-inflammatory metabolite from the marine fungus Penicillium sp. SF-5292.
Mar Drugs
PUBLISHED: 10-09-2013
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In the course of studies on bioactive metabolites from marine fungi, a new 10-membered lactone, named penicillinolide A (1) was isolated from the organic extract of Penicillium sp. SF-5292 as a potential anti-inflammatory compound. The structure of penicillinolide A (1) was mainly determined by analysis of NMR and MS data and Moshers method. Penicillinolide A (1) inhibited the production of NO and PGE2 due to inhibition of the expression of iNOS and COX-2. Penicillinolide A (1) also reduced TNF-?, IL-1? and IL-6 production, and these anti-inflammatory effects were shown to be correlated with the suppression of the phosphorylation and degradation of I?B-?, NF-?B nuclear translocation, and NF-?B DNA binding activity. In addition, using inhibitor tin protoporphyrin (SnPP), a competitive inhibitor of HO activity, it was verified that the inhibitory effects of compound 1 on the production of pro-inflammatory mediators and NF-?B DNA binding activity were partially associated with HO-1 expression through Nrf2 nuclear translocation.
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Increased Th17 differentiation in aged mice is significantly associated with high IL-1? level and low IL-2 expression.
Exp. Gerontol.
PUBLISHED: 09-16-2013
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Aging has been reported to be associated with changes in immune function. Although frequent infection and the development of malignancy suggest the decline of immune function with aging, changes toward proinflammatory conditions also develop at the same time. Th17 cells are well known CD4(+) T cell subpopulation closely linked to chronic inflammation and autoimmunity. In this study, changes in the Th17 population were investigated to elucidate a possible mechanism for this response with aging.
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Anti-inflammatory effect of neoechinulin a from the marine fungus Eurotium sp. SF-5989 through the suppression of NF-?B and p38 MAPK Pathways in lipopolysaccharide-stimulated RAW264.7 macrophages.
Molecules
PUBLISHED: 09-13-2013
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In the course of a bioassay-guided study of metabolites from the marine fungus Eurotium sp. SF-5989, two diketopiperazine type indole alkaloids, neoechinulins A and B, were isolated. In this study, we investigated the anti-inflammatory effects of neoechinulins A (1) and B (2) on lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Neoechinulin A (1) markedly suppressed the production of nitric oxide (NO) and prostaglandin E2 (PGE2) and the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in a dose dependent manner ranging from 12.5 µM to 100 µM without affecting the cell viability. On the other hand, neoechinulin B (2) affected the cell viability at 25 µM although the compound displayed similar inhibitory effect of NO production to neoechinulin A (1) at lower doses. Furthermore, neoechinulin A (1) decreased the secretion of pro-inflammatory cytokines, such as tumor necrosis factor-? (TNF-?) and interleukin-1? (IL-1?). We also confirmed that neoechinulin A (1) blocked the activation of nuclear factor-kappaB (NF-?B) in LPS-stimulated RAW264.7 macrophages by inhibiting the phosphorylation and degradation of inhibitor kappa B (I?B)-?. Moreover, neoechinulin A (1) decreased p38 mitogen-activated protein kinase (MAPK) phosphorylation. Therefore, these data showed that the anti-inflammatory effects of neoechinulin A (1) in LPS-stimulated RAW264.7 macrophages were due to the inhibition of the NF-?B and p38 MAPK pathways, suggesting that neoechinulin A (1) might be a potential therapeutic agent for the treatment of various inflammatory diseases.
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Treating rheumatoid arthritis to target: recommendations assessment questionnaire in Korea.
Clin. Rheumatol.
PUBLISHED: 09-13-2013
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Treat rheumatoid arthritis (RA) to target (T2T) is an international initiative to provide the rheumatology community with clear direction on treatment targets for RA. We performed a nationwide survey in Korea among rheumatologists to measure the levels of agreement with international T2T recommendations and to assess their practical application in Korea. A questionnaire was administered to 111 physicians. Responses were assessed using a 10-point Likert scale for the level of agreement with each of 10 recommendations and a 4-point Likert scale for the degree to which each recommendation was being applied in current daily practice. Respondents were also asked whether these recommendations would result in a change in their practice. This report outlines the consensus reached for T2T in Korea and compares those results with data obtained internationally. Agreement with T2T recommendations was high with average response scores above 8.3. The majority of respondents indicated they applied the recommendations "always" and "very often" in daily practice. More than half of the participants not currently applying these recommendations were willing to change their practice, but the percentage of Korean physicians willing to change was consistently more than the international average. The results of this survey of T2T recommendations in Korean rheumatologists revealed a good correlation with the views of the international rheumatology community. These results could be utilized to define key issues for better disease control in daily practice and used as a reference to improve the treatment environment.
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The inhibition of JNK MAPK and NF-?B signaling by tenuifoliside A isolated from Polygala tenuifolia in lipopolysaccharide-induced macrophages is associated with its anti-inflammatory effect.
Eur. J. Pharmacol.
PUBLISHED: 09-04-2013
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The root of Polygala tenuifolia Willd. (Polygalaceae) is well known for its use in the treatment of neurasthenia, amnesia, and inflammation. In this study, we isolated phenyl propanoid type metabolite tenuifoliside A, one of the phenylpropanoids from P. tenuifolia, and investigated its anti-inflammatory effects in lipopolysaccharide (LPS)-stimulated RAW264.7 and murine peritoneal macrophages. The results showed that tenuifoliside A inhibited the production of nitric oxide (NO), inducible nitric oxide synthase (iNOS), prostaglandin E2 (PG E2), and cyclooxygenase (COX)-2. In addition, tenuifoliside A suppressed the production of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-? and interleukin (IL)-1?. We also evaluated the effects of tenuifoliside A on the activation of nuclear factor-kappaB (NF-?B). Tenuifoliside A inhibited the translocation of the NF-?B subunit p65 into the nucleus by interrupting the phosphorylation and degradation of inhibitor kappa B (I?B)-? in LPS-stimulated murine peritoneal macrophages. Moreover, we confirmed that the suppression of the inflammatory process by tenuifoliside A was mediated through the mitogen-activated protein kinases (MAPKs) pathway based on the fact that tenuifoliside A significantly decreased p-c-Jun N-terminal kinase (p-JNK) protein expression in LPS-stimulated murine peritoneal macrophages. Taken together, the anti-inflammatory effects of tenuifoliside A were mediated by the inhibition of the NF-?B and MAPK pathways. This study is the first report on the anti-inflammatory effects of tenuifoliside A, and the strong anti-inflammatory effects of tenuifoliside A provide potential compound to be developed as therapeutic for inflammatory diseases.
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Bioinspired Exosome-Mimetic Nanovesicles for Targeted Delivery of Chemotherapeutics to Malignant Tumors.
ACS Nano
PUBLISHED: 09-04-2013
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Exosomes, the endogenous nanocarriers that can deliver biological information between cells, were recently introduced as new kind of drug delivery system. However, mammalian cells release relatively low quantities of exosomes, and purification of exosomes is difficult. Here, we developed bioinspired exosome-mimetic nanovesicles that deliver chemotherapeutics to the tumor tissue after systemic administration. The chemotherapeutics-loaded nanovesicles were produced by the breakdown of monocytes or macrophages using a serial extrusion through filters with diminishing pore sizes (10, 5, and 1 ?m). These cell-derived nanovesicles have similar characteristics with the exosomes but have 100-fold higher production yield. Furthermore, the nanovesicles have natural targeting ability of cells by maintaining the topology of plasma membrane proteins. In vitro, chemotherapeutic drug-loaded nanovesicles induced TNF-?-stimulated endothelial cell death in a dose-dependent manner. In vivo, experiments in mice showed that the chemotherapeutic drug-loaded nanovesicles traffic to tumor tissue and reduce tumor growth without the adverse effects observed with equipotent free drug. Furthermore, compared with doxorubicin-loaded exosomes, doxorubicin-loaded nanovesicles showed similar in vivo antitumor activity. However, doxorubicin-loaded liposomes that did not carry targeting proteins were inefficient in reducing tumor growth. Importantly, removal of the plasma membrane proteins by trypsinization eliminated the therapeutic effects of the nanovesicles both in vitro and in vivo. Taken together, these studies suggest that the bioengineered nanovesicles can serve as novel exosome-mimetics to effectively deliver chemotherapeutics to treat malignant tumors.
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Neolignans from the fruits of Magnolia obovata and their inhibition effect on NO production in LPS-induced RAW 264.7 cells.
Planta Med.
PUBLISHED: 08-22-2013
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Three new neolignans, named 9-methoxyobovatol (6), magnobovatol (7), and 2-hydroxyobovaaldehyde (9), along with six known ones, magnolol (1), honokiol (2), isomagnolol (3), obovatol (4), obovatal (5), and obovaaldehyde (8), were isolated from the fruits of Magnolia obovata using silica gel and ODS column chromatography. From the results of spectroscopic data including EIMS, IR, 1H- and 13C-NMR, DEPT, and 2D-NMR (gCOSY, gHSQC, gHMBC), the chemical structures were determined. All isolated compounds were evaluated for inhibition activity on nitric oxide production in LPS-induced RAW 264.7 cells, and compounds 1-4, 6, 7, and 9 showed significant activity with IC50 values of 15.8 ± 0.3, 3.3 ± 1.2, 14.1 ± 0.9, 6.2 ± 1.2, 14.8 ± 2.3, 14.2 ± 1.2, and 14.8 ± 3.2 µM, respectively, without any visible toxic effect.
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Secondary metabolites isolated from Castilleja rubra exert anti-inflammatory effects through NF-?B inactivation on lipopolysaccharide-induced RAW264.7 macrophages.
Arch. Pharm. Res.
PUBLISHED: 08-05-2013
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8-Epiloganin (1), mussaenoside (2), and 5-O-caffeoylshikimic acid (3) have been isolated from Castilleja rubra, and the anti-inflammatory properties of these metabolites in a cell culture system were investigated. Compounds 1-3 suppressed not only the production of nitric oxide (NO) and prostaglandin E2, but also the expression of inducible NO synthase and cyclooxygenase-2 induced by lipopolysaccharide (LPS) in the RAW264.7 murine macrophage cell line. Compounds 1-3 also inhibited the release of pro-inflammatory cytokines induced by LPS, namely, tumor necrosis factor-? and interleukin-1?. The underlying mechanism of the anti-inflammatory action of compounds 1-3 was associated with downregulation of nuclear factor-?B.
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Clonal identity and differences in primary cutaneous B-cell lymphoma occurring at different sites or time points in the same patient.
Am J Dermatopathol
PUBLISHED: 07-28-2013
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Primary cutaneous B-cell lymphomas (PCBCL) are rare. Marginal zone lymphomas and follicle center lymphomas (FCL) represent a majority of these cases, and a significant number of cases present with multiple lesions. It is unclear whether multiple lesions in PCBCL represent dissemination of a single clone or multiple new primary lymphomas. In the current study, we analyzed paired samples from 20 PCBCL patients at more than 1 site (16) or at the same site at different time points (4) and 12 patients with benign lymphoid infiltrates to investigate for the presence or absence of a clone, and if present, whether the clones were identical. Both IGH@ and IGK@ rearrangements were tested using the BIOMED-2 protocol. We identified a clone (IGH@ and/or IGK@) in 19 of 20 (95%) PCBCL patients and 2 of 12 (17%) benign lymphoid infiltrate patients. The B-cell clones were proven to be identical in 11 of 20 (55%) PCBCL patients, including 7 of 16(44%) biopsies from patients with 2 different sites and 4 of 4 biopsies (100%) from patients at the same site but different time points. In 4 cases (3 FCL and 1 marginal zone lymphoma), different clones were detected at different sites, suggesting the possibility of a second simultaneous primary lymphoma. Our results indicate that the presence of identical clones is highly suggestive of lymphoma. To our knowledge, this is the first report to investigate the detection of identical clones in 2 distinct biopsies in PCBCL patients. Although the study is small and the results need to be confirmed in a larger study, these findings suggest that a subset of PCBCL at different sites may represent different primary tumors rather than occurrence of a single disease.
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Simultaneous analysis and peroxynitrite-scavenging activity of galloylated flavonoid glycosides and ellagic acid in Euphorbia supina.
Arch. Pharm. Res.
PUBLISHED: 07-27-2013
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The herbs of Euphorbia supina (Euphorbiaceae) have been used to treat hemorrhage, chronic bronchitis, hepatitis, jaundice, diarrhea, gastritis, and hemorrhoids as a medicinal herb. This work is aimed to qualitatively and quantitatively analyze the polyphenols with peroxynitrite-scavenging activities. The eight compounds: gallic acid, methyl gallate, avicularin, astragalin, juglanin, isoquercitrin 6?-gallate, astragalin 6?-gallate, and ellagic acid, were isolated from E. supina and used for HPLC analysis and peroxynitrite (ONOO(-))-scavenging assay. Simultaneous analysis of the eight compounds was performed on MeOH extract and its fractions. The contents in MeOH extract and peroxynitrite-scavenging activities of the dimer of gallic acid, ellagic acid (15.64 mg/g; IC50 0.89 ?M), and two galloylated flavonoid glycosides, astragalin 6?-gallate (13.72 mg/g; IC50 1.43 ?M) and isoquercitrin 6?-gallate (16.99 mg/g; IC50 1.75 ?M), were high, compared to other compounds. The legendary uses of E. supina could be attributed to the high content of polyphenols, particularly ellagic acid, isoquercitrin 6?-gallate, and astragalin 6?-gallate as active principles.
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Growth inhibition and apoptosis-inducing effects of cudraflavone B in human oral cancer cells via MAPK, NF-?B, and SIRT1 signaling pathway.
Planta Med.
PUBLISHED: 07-23-2013
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The goal of this study was to investigate the effect and molecular mechanism of cudraflavone B, a prenylated flavonoid isolated from the root bark of Cudrania tricuspidata, against oral squamous cell carcinoma cells. We observed that cudraflavone B inhibited proliferation of these cells in a time- and dose-dependent manner. At 15 µM, cudraflavone B induced cell death via apoptosis (characterized by the appearance of nuclear morphology) and increased the accumulation of the sub-G1 peak (portion of apoptotic annexin V positive cells). Treatment with cudraflavone B triggered the mitochondrial apoptotic pathway (indicated by induction of the proapoptotic protein p53 and the p21 and p27 effector proteins), downregulation of cell cycle regulatory proteins (e.g., p-Rb, changing Bax/Bcl-2 ratios, cytochrome-c release), and caspase-3 activation. Cudraflavone B time-dependently activated NF-?B, the MAP kinases p38, and ERK, and induced the expression of SIRT1. SIRT1 activator, resveratrol, dose-dependently attenuated the growth-inhibitory and apoptosis-inducing effect of cudraflavone B and blocked cudraflavone B-induced regulatory protein expressions in the mitochondrial pathway such as p53, p21, p27, Bax, caspase-3, and cytochrome-c. Conversely, treatment with SIRT1 inhibitor sirtinol caused opposite effects. These results demonstrate for the first time that the molecular mechanism underlying the antitumor effect in oral squamous cell carcinoma cells is related to the activation of MAPK/and NF-?B as well as of the SIRT1 pathway. Therefore, cudraflavone B may be a lead for the development of a potential candidate for human oral squamous cell carcinoma cells.
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A new sulfonic acid derivative, (Z)-4-methylundeca-1,9-diene-6-sulfonic acid, isolated from the cold water sea urchin inhibits inflammatory responses through JNK/p38 MAPK and NF-?B inactivation in RAW 264.7.
Arch. Pharm. Res.
PUBLISHED: 07-08-2013
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In this study, we isolated a new sulfonic acid derivative, (Z)-4-methylundeca-1,9-diene-6-sulfonic acid (1), from the sea urchin collected from the Sea of Okhotsk. We established the structure of this new compound by analysis of NMR and HRMS data, along with comparison of the data with those of the related compounds reported in the literature. In addition, we investigated its anti-inflammatory effects in LPS-stimulated RAW264.7 macrophages. Compound 1 inhibited the production of NO, iNOS, PGE2, and COX-2, and it also suppressed the production of pro-inflammatory cytokines, such as TNF-? and IL-1?. It inhibited the translocation of the NF-?B subunit p65 into the nucleus by interrupting the phosphorylation and degradation of I?B-?. In addition, compound 1 significantly decreased the phosphorylation of JNK and p38 in LPS-stimulated RAW264.7 macrophages, suggesting that suppression of the inflammation process by compound 1 was mediated through the MAPK pathway. Taken together, this study showed that the anti-inflammatory effects of a new sulfonic acid derivative, (Z)-4-methylundeca-1,9-diene-6-sulfonic acid were mediated through the inhibition of NF-?B and JNK/p38 MAPK signaling pathways.
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Phenolic components from Rhus parviflora fruits and their inhibitory effects on lipopolysaccharide-induced nitric oxide production in RAW 264.7 macrophages.
Nat. Prod. Res.
PUBLISHED: 07-04-2013
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Nine phenolic compounds, phloracetophenone-4-O-?-d-glucopyranoside (1), p-hydroxybenzoic acid-4-O-?-d-glucopyranoside (2), leonuriside A (3), 3-methoxy-4-hydroxyphenol-1-O-?-d-glucopyranoside (4), cis-p-coumaric acid-4-O-?-d-glucopyranoside (5), trans-p-coumaric acid-4-O-?-d-glucopyranoside (6), trans-p-coumaric acid-9-O-?-d-glucopyranoside (7), (-)-shikimic acid (8) and (-)-methyl shikimate (9), were isolated for the first time from the fruits of Rhus parviflora. Compounds 1, 3-6 and 8 inhibited lipopolysaccharide-stimulated nitric oxide (NO) production and inducible NO synthase expression in RAW 264.7 macrophages with IC50 values of 9.24 ± 1.20, 21.37 ± 2.02, 23.07 ± 1.58, 9.86 ± 0.98, 19.05 ± 1.66 and 11.3 ± 1.54 ?M, respectively. The results indicated possible use of compounds for the treatment of inflammatory diseases.
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In vivo action of IL-27: reciprocal regulation of Th17 and Treg cells in collagen-induced arthritis.
Exp. Mol. Med.
PUBLISHED: 07-03-2013
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Interleukin (IL)-27 is a novel cytokine of the IL-6/IL-12 family that has been reported to be involved in the pathogenesis of autoimmune diseases and has a pivotal role as both a pro- and anti-inflammatory cytokine. We investigated the in vivo effects of IL-27 on arthritis severity in a murine collagen-induced arthritis (CIA) model and its mechanism of action regarding control of regulatory T (Tregs) and IL-17-producing T helper 17 (Th17) cells. IL-27-Fc-treated CIA mice showed a lower severity of arthritis. IL-17 expression in the spleens was significantly decreased in IL-27-Fc-treated CIA mice compared with that in the CIA model. The Th17 population was decreased in the spleens of IL-27-Fc-treated CIA mice, whereas the CD4(+)CD25(+)Foxp3(+) Treg population increased. In vitro studies revealed that IL-27 inhibited IL-17 production in murine CD4(+) T cells, and the effect was associated with retinoic acid-related orphan receptor ?T and signal transducer and activator of transcription 3 inhibition. In contrast, fluorescein isothiocyanate-labeled forkhead box P3 (Foxp3) and IL-10 were profoundly augmented by IL-27 treatment. Regarding the suppressive capacity of Treg cells, the proportions of CTLA-4(+) (cytotoxic T-lymphocyte antigen 4), PD-1(+) (programmed cell death protein 1) and GITR(+) (glucocorticoid-induced tumor necrosis factor receptor) Tregs increased in the spleens of IL-27-Fc-treated CIA mice. Furthermore, in vitro differentiated Treg cells with IL-27 exerted a more suppressive capacity on T-cell proliferation. We found that IL-27 acts as a reciprocal regulator of the Th17 and Treg populations in CD4(+) cells isolated from healthy human peripheral blood mononuclear cells (PBMCs), as well as from humans with rheumatoid arthritis (RA) PBMCs. Our study suggests that IL-27 has the potential to ameliorate overwhelming inflammation in patients with RA through a reciprocal regulation of Th17 and Treg cells.
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PTP1B inhibitory secondary metabolites from marine-derived fungal strains Penicillium spp. and Eurotium sp.
J. Microbiol. Biotechnol.
PUBLISHED: 06-18-2013
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The selective inhibition of PTP1B has been widely recognized as a potential drug target for the treatment of type 2 diabetes and obesity. In the course of screening for PTP1B inhibitory fungal metabolites, the organic extracts of several fungal species isolated from marine environments were found to exhibit significant inhibitory effects, and the bioassay-guided investigation of these extracts resulted in the isolation of fructigenine A (1), cyclopenol (2), echinulin (3), flavoglaucin (4), and viridicatol (5). The structures of these compounds were determined mainly by analysis of NMR and MS data. These compounds inhibited PTP1B activity with 50% inhibitory concentration values of 10.7, 30.0, 29.4, 13.4, and 64.0 micrometer, respectively. Furthermore, the kinetic analysis of PTP1B inhibition by compounds 1 and 5 suggested that compound 1 inhibited PTP1B activity in a noncompetitive manner, whereas compound 5 inhibited PTP1B activity in a competitive manner.
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Inhibitory effect of 9-hydroxy-6,7-dimethoxydalbergiquinol from Dalbergia odorifera on the NF-?B-related neuroinflammatory response in lipopolysaccharide-stimulated mouse BV2 microglial cells is mediated by heme oxygenase-1.
Int. Immunopharmacol.
PUBLISHED: 05-07-2013
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The heartwood of Dalbergia odorifera T. Chen (Leguminosae) is an important source of traditional Korean and Chinese medicines. 9-Hydroxy-6,7-dimethoxydalbergiquinol (HDDQ), a compound isolated from D. odorifera, has various biological activities. The aim of this study was to determine the efficacy of HDDQ in modulating the regulation of anti-inflammatory activity through the upregulation of heme oxygenase (HO)-1 in BV2 microglia. HDDQ inhibited the protein expression of inducible nitric oxide synthase (iNOS), iNOS-derived nitric oxide (NO), and the production of cyclooxygenase (COX)-2 and COX-2-derived prostaglandin E2 (PGE2) in lipopolysaccharide (LPS)-stimulated mouse BV2 microglia. HDDQ also reduced tumor necrosis factor-? (TNF-?) and interleukin-1? (IL-1?) production, and suppressed the phosphorylation and degradation of I?B-? and the nuclear translocation of p65 in mouse BV2 microglia in response to LPS. Furthermore, HDDQ upregulated HO-1 expression via nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) in mouse BV2 microglia. Using tin protoporphyrin (SnPP), an HO activity inhibitor, we verified that the inhibitory effects of HDDQ on the proinflammatory mediators NO, PGE2, TNF-?, and IL-1?, and nuclear factor kappa B (NF-?B) DNA-binding activity are associated with the induction of HO-1 expression. Our data suggest that HDDQ has therapeutic potential against neurodegenerative diseases caused by neuroinflammation.
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Pulchellamin G, an amino acid-sesquiterpene lactone, from Saussurea pulchella suppresses lipopolysaccharide-induced inflammatory responses via heme oxygenase-1 expression in murine peritoneal macrophages.
Eur. J. Pharmacol.
PUBLISHED: 04-26-2013
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Saussurea pulchella (Asteraceae) is widely distributed in Korea and has been used in Korean folk medicine for the treatment of inflammation, hypertension, hepatitis, and arthritis. Pulchellamin G is an amino acid-sesquiterpene lactone conjugate isolated from S. pulchella. In the present study, we focused on the anti-inflammatory effect of pulchellamin G, which acts by inducing the expression of heme oxygenase (HO)-1. HO-1 plays important roles in cytoprotection since it has antioxidant, anti-inflammatory, antiproliferative, and antiapoptotic properties. Pulchellamin G inhibited the mRNA and protein expression of inducible nitric oxide synthase (iNOS), iNOS-derived nitric oxide (NO), and cyclooxygenase (COX)-2 and COX-derived prostaglandin E2 (PGE2) production in lipopolysaccharide (LPS)-stimulated murine peritoneal macrophages. The compound also reduced tumor necrosis factor-? (TNF-?) and interleukin-1? (IL-1?) production and suppressed the phosphorylation and degradation of I?B-? and nuclear translocation of p65 in murine peritoneal macrophages in response to LPS stimulus. The inhibitory effects of pulchellamin G on nuclear factor kappa B (NF-?B) translocation was impaired by co-treatment of the cells with HO activity inhibitor tin protoporphyrin (SnPP). By using SnPP, we verified that the inhibitory effects of pulchellamin G on the pro-inflammatory mediators NO, PGE2, TNF-?, and IL-1? are associated with induction of HO-1 expression. Our data suggest that pulchellamin G might have potent therapeutic effects and it should be considered in the development of treatments for various inflammatory diseases.
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Immunization with Escherichia coli outer membrane vesicles protects bacteria-induced lethality via Th1 and Th17 cell responses.
J. Immunol.
PUBLISHED: 03-20-2013
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Outer membrane vesicles (OMVs), secreted from Gram-negative bacteria, are spherical nanometer-sized proteolipids enriched with outer membrane proteins. OMVs, also known as extracellular vesicles, have gained interests for use as nonliving complex vaccines and have been examined for immune-stimulating effects. However, the detailed mechanism on how OMVs elicit the vaccination effect has not been studied extensively. In this study, we investigated the immunological mechanism governing the protective immune response of OMV vaccines. Immunization with Escherichia coli-derived OMVs prevented bacteria-induced lethality and OMV-induced systemic inflammatory response syndrome. As verified by adoptive transfer and gene-knockout studies, the protective effect of OMV immunization was found to be primarily by the stimulation of T cell immunity rather than B cell immunity, especially by the OMV-Ag-specific production of IFN-? and IL-17 from T cells. By testing the bacteria-killing ability of macrophages, we also demonstrated that IFN-? and IL-17 production is the main factor promoting bacterial clearances. Our findings reveal that E. coli-derived OMV immunization effectively protects bacteria-induced lethality and OMV-induced systemic inflammatory response syndrome primarily via Th1 and Th17 cell responses. This study therefore provides a new perspective on the immunological detail regarding OMV vaccination.
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Non-Hodgkins lymphomas, version 1.2013.
J Natl Compr Canc Netw
PUBLISHED: 03-15-2013
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These NCCN Guidelines Insights summarize several key updates to the NCCN Guidelines for Non-Hodgkins Lymphomas (NHL) and provide a discussion of the clinical evidence that support the updates. The updates discussed in this article feature recommendations for additional treatment options in patients with chronic lymphocytic leukemia and guidance surrounding the management of hepatitis virus reactivation/infections in high-risk patients with NHL undergoing antitumor therapy.
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Intravascular ALK-negative anaplastic large cell lymphoma with localized cutaneous involvement and an indolent clinical course: toward recognition of a distinct clinicopathologic entity.
Am. J. Surg. Pathol.
PUBLISHED: 03-14-2013
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Intravascular large T-cell or NK-cell lymphomas rarely present with cutaneous involvement. Intravascular cytotoxic T or NK lymphomas presenting in the skin (cIT/NKL) are often EBV, and reported cases follow a highly aggressive clinical course. Intravascular anaplastic large cell lymphoma (ALCL) by contrast is extraordinarily rare and, when it presents in the skin, raises the question of aggressive clinical behavior in the manner of cIT/NKL versus indolent clinical behavior in the manner of primary cutaneous ALCL. Here we describe a case of localized cutaneous intravascular anaplastic lymphoma kinase-negative ALCL (cIALCL) with a very indolent clinical course. The patient experienced a single cutaneous relapse and remains alive without disease 4 years after diagnosis. Review of the literature reveals multiple clinicopathologic differences between cIALCL and cIT/NKL: distribution (cIALCL, single skin region, P=0.021, Fisher exact test); histology (cIALCL, cohesive with necrosis, P=0.005); immunophenotype (cIALCL, strongly CD30, P=0.021; cIT/NKL, CD56 and/or EBV, P=0.003); and indolent clinical behavior with a trend toward better overall survival (P=0.067, Kaplan-Meier survival analysis). Our index case of cIALCL and 1 other tested case were immunohistochemically confirmed to be intralymphatic (contained within D2-40+vessels) as compared with the blood vessel localization of cIT/NKL. Recognition of cIALCLs as a distinct clinicopathologic entity, and in particular their distinction from aggressive, usually EBV cIT/NKLs, may be possible on the basis of a combination of clinicopathologic criteria, allowing for localized therapy in a subset of patients.
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