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Find video protocols related to scientific articles indexed in Pubmed.
E2F1 suppresses cardiac neovascularization by down-regulating VEGF and PlGF expression.
Cardiovasc. Res.
PUBLISHED: 10-23-2014
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The E2F transcription factors are best characterized for their roles in cell-cycle regulation, cell growth, and cell death. Here we investigated the potential role of E2F1 in cardiac neovascularization.
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Nanoceria based electrochemical sensor for hydrogen peroxide detection.
Biointerphases
PUBLISHED: 10-05-2014
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Oxidative stress is a condition when the concentration of free radicals and reactive molecular species rise above certain level in living systems. This condition not only perturbs the normal physiology of the system but also has been implicated in many diseases in humans and other animals. Hydrogen peroxide (H2O2) is known to be involved in induction of oxidative stress and has also been linked to a variety of ailments such as inflammation, rheumatoid arthritis, diabetes, and cancer in humans. It is one of the more stable reactive molecular species present in living systems. Because of its stability and links with various diseases, sensing the level of H2O2 can be of great help in diagnosing these diseases, thereby easing disease management and amelioration. Nanoceria is a potent candidate in free radical scavenging as well as sensing because of its unique redox properties. These properties have been exploited, in the reported work, to sense and quantify peroxide levels. Nanoceria has been synthesized using different capping agents: Hexamethylene-tetra-amine (HMTA) and fructose. CeO2-HMTA show rhombohedral and cubic 6.4 nm particles whereas CeO2-fructose are found to be spherical with average particle diameter size 5.8 nm. CeO2-HMTA, due to the better exposure of the active (200) and (220) planes relative to (111) plane, exhibits superior electrocatalytic activity toward H2O2 reduction. Amperometric responses were measured by increasing H2O2 concentration. The authors observed a sensitivity of 21.13 and 9.6??A?cm(-2)?mM(-1) for CeO2-HMTA and CeO2-fructose, respectively. The response time of 4.8 and 6.5 s was observed for CeO2-HMTA and CeO2-fructose, respectively. The limit of detection is as low as 0.6 and 2.0??M at S/N ratio 3 for CeO2-HMTA and CeO2-fructose, respectively. Ceria-HMTA was further tested for its antioxidant activity in an animal cell line in vitro and the results confirmed its activity.
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Electricity from the silk cocoon membrane.
Sci Rep
PUBLISHED: 06-05-2014
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Silk cocoon membrane (SCM) is an insect engineered structure. We studied the electrical properties of mulberry (Bombyx mori) and non-mulberry (Tussar, Antheraea mylitta) SCM. When dry, SCM behaves like an insulator. On absorbing moisture, it generates electrical current, which is modulated by temperature. The current flowing across the SCM is possibly ionic and protonic in nature. We exploited the electrical properties of SCM to develop simple energy harvesting devices, which could operate low power electronic systems. Based on our findings, we propose that the temperature and humidity dependent electrical properties of the SCM could find applications in battery technology, bio-sensor, humidity sensor, steam engines and waste heat management.
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Enhanced potency of cell-based therapy for ischemic tissue repair using an injectable bioactive epitope presenting nanofiber support matrix.
J. Mol. Cell. Cardiol.
PUBLISHED: 04-23-2014
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The translation of cell-based therapies for ischemic tissue repair remains limited by several factors, including poor cell survival and limited target site retention. Advances in nanotechnology enable the development of specifically designed delivery matrices to address these limitations and thereby improve the efficacy of cell-based therapies. Given the relevance of integrin signaling for cellular homeostasis, we developed an injectable, bioactive peptide-based nanofiber matrix that presents an integrin-binding epitope derived from fibronectin, and evaluated its feasibility as a supportive artificial matrix for bone marrow-derived pro-angiogenic cells (BMPACs) used as a therapy in ischemic tissue repair. Incubation of BMPACs with these peptide nanofibers in vitro significantly attenuated apoptosis while enhancing proliferation and adhesion. Pro-angiogenic function was enhanced, as cells readily formed tubes. These effects were, in part, mediated via p38, and p44/p42 MAP kinases, which are downstream pathways of focal adhesion kinase. In a murine model of hind limb ischemia, an intramuscular injection of BMPACs within this bioactive peptide nanofiber matrix resulted in greater retention of cells, enhanced capillary density, increased limb perfusion, reduced necrosis/amputation, and preserved function of the ischemic limb compared to treatment with cells alone. This self-assembling, bioactive peptide nanofiber matrix presenting an integrin-binding domain of fibronectin improves regenerative efficacy of cell-based strategies in ischemic tissue by enhancing cell survival, retention, and reparative functions.
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Day case laparoscopic cholecystectomy in children: A review of 11 cases.
J Indian Assoc Pediatr Surg
PUBLISHED: 04-18-2014
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The aim of this paper is to study the outcome of day case laparoscopic cholecystectomy (DCLC) in children.
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TNF-TNFR2/p75 signaling inhibits early and increases delayed nontargeted effects in bone marrow-derived endothelial progenitor cells.
J. Biol. Chem.
PUBLISHED: 04-07-2014
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TNF-?, a pro-inflammatory cytokine, is highly expressed after being irradiated (IR) and is implicated in mediating radiobiological bystander responses (RBRs). Little is known about specific TNF receptors in regulating TNF-induced RBR in bone marrow-derived endothelial progenitor cells (BM-EPCs). Full body ?-IR WT BM-EPCs showed a biphasic response: slow decay of p-H2AX foci during the initial 24 h and increase between 24 h and 7 days post-IR, indicating a significant RBR in BM-EPCs in vivo. Individual TNF receptor (TNFR) signaling in RBR was evaluated in BM-EPCs from WT, TNFR1/p55KO, and TNFR2/p75KO mice, in vitro. Compared with WT, early RBR (1-5 h) were inhibited in p55KO and p75KO EPCs, whereas delayed RBR (3-5 days) were amplified in p55KO EPCs, suggesting a possible role for TNFR2/p75 signaling in delayed RBR. Neutralizing TNF in ?-IR conditioned media (CM) of WT and p55KO BM-EPCs largely abolished RBR in both cell types. ELISA protein profiling of WT and p55KO EPC ?-IR-CM over 5 days showed significant increases in several pro-inflammatory cytokines, including TNF-?, IL-1? (Interleukin-1 alpha), RANTES (regulated on activation, normal T cell expressed and secreted), and MCP-1. In vitro treatments with murine recombinant (rm) TNF-? and rmIL-1?, but not rmMCP-1 or rmRANTES, increased the formation of p-H2AX foci in nonirradiated p55KO EPCs. We conclude that TNF-TNFR2 signaling may induce RBR in naïve BM-EPCs and that blocking TNF-TNFR2 signaling may prevent delayed RBR in BM-EPCs, conceivably, in bone marrow milieu in general.
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Adsorption studies of chromium (VI) removal from water by lanthanum diethanolamine hybrid material.
Environ Technol
PUBLISHED: 03-21-2014
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In the present research work, lanthanum diethanolamine hybrid material is synthesized by co-precipitation method and used for the removal of Cr(VI) from synthetic dichromate solution and hand pump water sample. The sorption experiments were carried out in batch mode to optimize various influencing parameters such as adsorbent dose, contact time, pH, competitive anions and temperature. The characterization of the material and mechanism of Cr(VI) adsorption on the material was studied by using scanning electron microscope, Fourier transform infrared, X-ray diffraction, Brunauer-Emmett-Teller and thermogravimetric analysis-differential thermal analysis. Adsorption kinetics studies reveal that the adsorption process followed first-order kinetics and intraparticle diffusion model with correlation coefficients (R2) of 0.96 and 0.97, respectively. The adsorption data were best fitted to linearly transformed Langmuir isotherm with correlation coefficient (R2) of 0.997. The maximum removal of Cr(VI) is found to be 99.31% at optimal condition: pH = 5.6 of the solution, adsorbent dose of 8 g L(-1) with initial concentration of 10mgL(-1) of Cr(VI) solution and an equilibrium time of 50 min. The maximum adsorption capacity of the material is 357.1 mg g(-1). Thermodynamic parameters were evaluated to study the effect of temperature on the removal process. The study shows that the adsorption process is feasible and endothermic in nature. The value of E (260.6 kJ mol(-1)) indicates the chemisorption nature of the adsorption process. The material is difficult to be regenerated. The above studies indicate that the hybrid material is capable of removing Cr(VI) from water.
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Hypersensitivity to pollen of four different species of Brassica: a clinico-immunologic evaluation in patients of respiratory allergy in India.
Asia Pac Allergy
PUBLISHED: 01-31-2014
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Rapeseed-mustard is the second most important source of edible oil in India. Several species of Brassica are grown in different parts of country for its oilseeds.
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Sensitive and reliable ascorbic acid sensing by lanthanum oxide/reduced graphene oxide nanocomposite.
Appl. Biochem. Biotechnol.
PUBLISHED: 01-15-2014
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A simple strategy for the detection and estimation of ascorbic acid (AA), using lanthanum oxide-reduced graphene oxide nanocomposite (LO/RGO) on indium tin oxide (ITO) substrate, is reported. LO/RGO displays high catalytic activity toward the oxidation of AA, and the synergism between lanthanum oxide and reduced graphene oxide was attributed to the successful and efficient detection. Detection mechanism and sensing efficacy of LO/RGO nanocomposite are investigated by electrochemical techniques. Chronoamperometric results under optimal conditions show a linear response range from 14 to 100 ?M for AA detection. Commercially available vitamin C tablets were also analyzed using the proposed LO/RGO sensor, and the remarkable recovery percentage (97.64-99.7) shows the potential application in AA detection.
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Immunological evaluation of mannosylated chitosan nanoparticles based foot and mouth disease virus DNA vaccine, pVAC FMDV VP1-OmpA in guinea pigs.
Biologicals
PUBLISHED: 01-09-2014
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A DNA vaccine for foot and mouth disease (FMD) based on mannosylated chitosan nanoparticles was evaluated in guinea pigs. The DNA construct was comprised of FMD virus full length-VP1 gene and outer membrane protein A (Omp A) gene of Salmonella typhimurium as a Toll-like receptor (TLR)-ligand in pVAC vector. Groups of guinea pigs immunized either intramuscularly or intra-nasally were evaluated for induction of virus neutralizing antibodies, Th1(IgG2) and Th2 (IgG1) responses, lymphocyte proliferation, reactive nitrogen intermediate production, secretory IgA for naso-mucosal immune response and protection upon homotypic type O virulent FMD virus challenge. The results indicate the synergistic effect of OmpA on the immunogenic potential of FMD DNA vaccine construct delivered using mannosylated chitosan nano-particles by different routes of administration. These observations suggest the substantial improvement in all the immunological parameters with enhanced protection in guinea pigs.
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Cardiovascular risks associated with low dose ionizing particle radiation.
PLoS ONE
PUBLISHED: 01-01-2014
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Previous epidemiologic data demonstrate that cardiovascular (CV) morbidity and mortality may occur decades after ionizing radiation exposure. With increased use of proton and carbon ion radiotherapy and concerns about space radiation exposures to astronauts on future long-duration exploration-type missions, the long-term effects and risks of low-dose charged particle irradiation on the CV system must be better appreciated. Here we report on the long-term effects of whole-body proton (1H; 0.5 Gy, 1 GeV) and iron ion (56Fe; 0.15 Gy, 1GeV/nucleon) irradiation with and without an acute myocardial ischemia (AMI) event in mice. We show that cardiac function of proton-irradiated mice initially improves at 1 month but declines by 10 months post-irradiation. In AMI-induced mice, prior proton irradiation improved cardiac function restoration and enhanced cardiac remodeling. This was associated with increased pro-survival gene expression in cardiac tissues. In contrast, cardiac function was significantly declined in 56Fe ion-irradiated mice at 1 and 3 months but recovered at 10 months. In addition, 56Fe ion-irradiation led to poorer cardiac function and more adverse remodeling in AMI-induced mice, and was associated with decreased angiogenesis and pro-survival factors in cardiac tissues at any time point examined up to 10 months. This is the first study reporting CV effects following low dose proton and iron ion irradiation during normal aging and post-AMI. Understanding the biological effects of charged particle radiation qualities on the CV system is necessary both for the mitigation of space exploration CV risks and for understanding of long-term CV effects following charged particle radiotherapy.
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Therapeutic non-toxic doses of TNF induce significant regression in TNFR2-p75 knockdown Lewis lung carcinoma tumor implants.
PLoS ONE
PUBLISHED: 01-01-2014
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Tumor necrosis factor-alpha (TNF) binds to two receptors: TNFR1/p55-cytotoxic and TNFR2/p75-pro-survival. We have shown that tumor growth in p75 knockout (KO) mice was decreased more than 2-fold in Lewis lung carcinoma (LLCs). We hypothesized that selective blocking of TNFR2/p75 LLCs may sensitize them to TNF-induced apoptosis and affect the tumor growth. We implanted intact and p75 knockdown (KD)-LLCs (>90%, using shRNA) into wild type (WT) mice flanks. On day 8 post-inoculation, recombinant murine (rm) TNF-? (12.5 ng/gr of body weight) or saline was injected twice daily for 6 days. Tumor volumes (tV) were measured daily and tumor weights (tW) on day 15, when study was terminated due to large tumors in LLC+TNF group. Tubular bones, spleens and peripheral blood (PB) were examined to determine possible TNF toxicity. There was no significant difference in tV or tW between LLC minus (-) TNF and p75KD/LLC-TNF tumors. Compared to 3 control groups, p75KD/LLC+TNF showed >2-5-fold decreases in tV (p<0.001) and tW (p<0.0001). There was no difference in tV or tW end of study vs. before injections in p75KD/LLC+TNF group. In 3 other groups tV and tW were increased 2.7-4.5-fold (p<0.01, p<0.0002 and p<0.0001). Pathological examination revealed that 1/3 of p75KD/LLC+rmTNF tumors were 100% necrotic, the remaining revealed 40-60% necrosis. No toxicity was detected in bone marrow, spleen and peripheral blood. We concluded that blocking TNFR2/p75 in LLCs combined with intra-tumoral rmTNF injections inhibit LLC tumor growth. This could represent a novel and effective therapy against lung neoplasms and a new paradigm in cancer therapeutics.
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Removal efficiency of fluoride by novel Mg-Cr-Cl layered double hydroxide by batch process from water.
J Environ Sci (China)
PUBLISHED: 11-14-2013
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The fluoride ion removal from aqueous solution using synthesized Mg-Cr-Cl layered double hydroxide has been reported. Mg-Cr-Cl was characterized by X-ray powder diffraction, Fourier-transform infrared, thermo-gravimetric analysis, differential thermal analysis, and scanning electron microscope. Adsorption experiments were carried out in batch mode as a function of adsorption dosages, contact time, pH, and initial fluoride concentration to get optimum adsorption capacity. The adsorption kinetic study showed that the adsorption process followed first order kinetics. The fluoride removal was 88.5% and 77.4% at pH 7 with an adsorbent dose of 0.6 g/100 mL solution and initial fluoride concentration of 10 mg/L and 100 mg/L, respectively. The equilibrium was established at 40 min. Adsorption experiment data were fitted well with Langmuir isotherm with R2 = 0.9924. Thermodynamic constants were also measured and concluded that the adsorption process was spontaneous and endothermic in nature. The removal percentage decreased slowly with increasing pH. This process is suitable for industrial effluents. The regeneration of the material is not possible.
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Morphology controlled synthesis of nanoporous Co3O4 nanostructures and their charge storage characteristics in supercapacitors.
ACS Appl Mater Interfaces
PUBLISHED: 10-24-2013
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Cubic spinel Co3O4 nanoparticles with spherical (0D) and hexagonal platelet (2D) morphologies were synthesized using a simple solvothermal method by tuning the reaction time. XRD and HRTEM analyses revealed pure phase with growth of Co3O4 particles along [111] and [110] directions. UV-vis studies showed two clear optical absorption peaks corresponding to two optical band gaps in the range of 400-500 nm and 700-800 nm, respectively, related to the ligand to metal charge transfer events (O(2-) ? Co(2+,3+)). Under the electrochemical study in two electrode assembly system (Co3O4/KOH/Co3O4) without adding any large area support or a conductive filler, the hexagonal platelet Co3O4 particles exhibited comparatively better characteristics with high specific capacitance (476 F g(-1)), energy density 42.3 Wh kg(-1) and power density 1.56 kW kg(-1) at current density of 0.5 Ag(-1), that suited for potential applications in supercapacitors. The observed better electrochemical properties of the nanoporous Co3O4 particles is attributed to the layered platelet structural arrangement of the hexagonal platelet and the presence of exceptionally high numbers of regularly ordered pores.
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Divergent modification of low-dose ??Fe-particle and proton radiation on skeletal muscle.
Radiat. Res.
PUBLISHED: 10-17-2013
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It is unknown whether loss of skeletal muscle mass and function experienced by astronauts during space flight could be augmented by ionizing radiation (IR), such as low-dose high-charge and energy (HZE) particles or low-dose high-energy proton radiation. In the current study adult mice were irradiated whole-body with either a single dose of 15 cGy of 1 GeV/n ??Fe-particle or with a 90 cGy proton of 1 GeV/n proton particles. Both ionizing radiation types caused alterations in the skeletal muscle cytoplasmic Ca²? ([Ca²?]i) homeostasis. ??Fe-particle irradiation also caused a reduction of depolarization-evoked Ca²? release from the sarcoplasmic reticulum (SR). The increase in the [Ca²?]i was detected as early as 24 h after ??Fe-particle irradiation, while effects of proton irradiation were only evident at 72 h. In both instances [Ca²?]i returned to baseline at day 7 after irradiation. All ??Fe-particle irradiated samples revealed a significant number of centrally localized nuclei, a histologic manifestation of regenerating muscle, 7 days after irradiation. Neither unirradiated control or proton-irradiated samples exhibited such a phenotype. Protein analysis revealed significant increase in the phosphorylation of Akt, Erk1/2 and rpS6k on day 7 in ??Fe-particle irradiated skeletal muscle, but not proton or unirradiated skeletal muscle, suggesting activation of pro-survival signaling. Our findings suggest that a single low-dose ??Fe-particle or proton exposure is sufficient to affect Ca²? homeostasis in skeletal muscle. However, only ??Fe-particle irradiation led to the appearance of central nuclei and activation of pro-survival pathways, suggesting an ongoing muscle damage/recovery process.
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Enhanced efferocytosis of apoptotic cardiomyocytes through myeloid-epithelial-reproductive tyrosine kinase links acute inflammation resolution to cardiac repair after infarction.
Circ. Res.
PUBLISHED: 07-08-2013
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Efficient clearance of apoptotic cells (efferocytosis) is a prerequisite for inflammation resolution and tissue repair. After myocardial infarction, phagocytes are recruited to the heart and promote clearance of dying cardiomyocytes. The molecular mechanisms of efferocytosis of cardiomyocytes and in the myocardium are unknown. The injured heart provides a unique model to examine relationships between efferocytosis and subsequent inflammation resolution, tissue remodeling, and organ function.
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Alcohol consumption negates estrogen-mediated myocardial repair in ovariectomized mice by inhibiting endothelial progenitor cell mobilization and function.
J. Biol. Chem.
PUBLISHED: 05-03-2013
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We have shown previously that estrogen (estradiol, E2) supplementation enhances voluntary alcohol consumption in ovariectomized female rodents and that increased alcohol consumption impairs ischemic hind limb vascular repair. However, the effect of E2-induced alcohol consumption on post-infarct myocardial repair and on the phenotypic/functional properties of endothelial progenitor cells (EPCs) is not known. Additionally, the molecular signaling of alcohol-estrogen interactions remains to be elucidated. This study examined the effect of E2-induced increases in ethanol consumption on post-infarct myocardial function/repair. Ovariectomized female mice, implanted with 17?-E2 or placebo pellets were given access to alcohol for 6 weeks and subjected to acute myocardial infarction. Left ventricular functions were consistently depressed in mice consuming ethanol compared with those receiving only E2. Alcohol-consuming mice also displayed significantly increased infarct size and reduced capillary density. Ethanol consumption also reduced E2-induced mobilization and homing of EPCs to injured myocardium compared with the E2-alone group. In vitro, exposure of EPCs to ethanol suppressed E2-induced proliferation, survival, and migration and markedly altered E2-induced estrogen receptor-dependent cell survival signaling and gene expression. Furthermore, ethanol-mediated suppression of EPC biology was endothelial nitric oxide synthase-dependent because endothelial nitric oxide synthase-null mice displayed an exaggerated response to post-acute myocardial infarction left ventricular functions. These data suggest that E2 modulation of alcohol consumption, and the ensuing EPC dysfunction, may negatively compete with the beneficial effects of estrogen on post-infarct myocardial repair.
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Contrasting roles of E2F2 and E2F3 in endothelial cell growth and ischemic angiogenesis.
J. Mol. Cell. Cardiol.
PUBLISHED: 03-28-2013
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The growth of new blood vessels after ischemic injury requires endothelial cells (ECs) to divide and proliferate, and the E2F transcription factors are key regulators of the genes responsible for cell-cycle progression; however, the specific roles of individual E2Fs in ECs are largely unknown. To determine the roles of E2F2 and E2F3 in EC proliferation and the angiogenic response to ischemic injury, hind-limb ischemia was surgically induced in E2F2(-/-) mice, endothelial-specific E2F3-knockout (EndoE2F3(?/?)) mice, and their littermates with wild-type E2F2 and E2F3 expression. Two weeks later, Laser-Doppler perfusion measurements, capillary density, and endothelial proliferation were significantly greater in E2F2(-/-) mice and significantly lower in EndoE2F3(?/?) mice than in their littermates, and EndoE2F3(?/?) mice also developed toe and limb necrosis. The loss of E2F2 expression was associated with increases in the proliferation and G1/S-phase gene expression of isolated ECs, while the loss of E2F3 expression led to declines in these parameters. Thus E2F2 impairs, and endothelial E2F3 promotes, the angiogenic response to peripheral ischemic injury through corresponding changes in EC cell-cycle progression.
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Development and properties of surfactant-free water-dispersible Cu2ZnSnS4 nanocrystals: a material for low-cost photovoltaics.
Chemphyschem
PUBLISHED: 03-25-2013
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A simple, yet novel hydrothermal method has been developed to synthesize surfactant-free Cu2ZnSnS4 nanocrystal ink in water. The environmentally friendly, 2-4 nm ultrafine particles are stable in water for several weeks. Detailed X-ray diffraction (XRD) and high-resolution transmission electron microscopy revealed the formation of single-crystalline-kesterite-phase Cu2ZnSnS4. Elemental mapping by scanning electron microscopy/energy dispersive spectrometry corroborated the presence of all four elements in a stoichiometric ratio with minor sulfur deficiency. Finally, Raman spectroscopy ruled out the possible presence of impurities of ZnS, Cu2SnS3, SnS, SnS2, Cu(2-x)S, or Sn2S3, which often interfere with the XRD and optical spectra of Cu2ZnSnS4. X-ray photoelectron spectroscopic studies of the as-synthesized samples confirmed that the oxidation states of the four elements match those of the bulk sample. Optical absorption analyses of thin film and solution samples showed high absorption efficiency (>10(4) cm(-1)) across the visible and near-infrared spectral regions and a band gap E(g) of 1.75 eV for the as-synthesized sample. A non-ohmic asymmetric rectifying response was observed in the I-V measurement at room temperature. The nonlinearity was more pronounced for this p-type semiconductor when the resistance was measured against temperature in the range 180-400 K, which was detected in the hot-point probe measurement.
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Co-administration of flagellin augments immune responses to inactivated foot-and-mouth disease virus (FMDV) antigen.
Res. Vet. Sci.
PUBLISHED: 03-03-2013
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Foot-and-mouth disease virus (FMDV) is one of the most contagious animal virus known that affects livestock health and production. This study aimed to investigate the effect of flagellin, a toll-like receptor 5 agonist, on the immune responses to inactivated FMDV antigen in guinea pig model. Our results showed that the co-administration of flagellin with FMDV antigen through intradermal route induces earlier and higher anti-FMDV neutralizing antibody responses as compared to FMDV antigen alone. Both IgG1 and IgG2 antibody-isotype responses were enhanced, but the IgG1/IgG2 ratios were relatively low, indicative of TH1 type of immune activation. On live viral challenge, flagellin+FMDV immunized guinea pigs showed 70% (7 out of 10) protection rate as compared to 40% (4 out of 10) in FMDV alone immunized guinea pigs. The results demonstrate that the co-administration of flagellin augments immune responses (preferably TH1 type) and protective efficacy against FMDV in guinea pigs.
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Bone marrow progenitor cell therapy-mediated paracrine regulation of cardiac miRNA-155 modulates fibrotic response in diabetic hearts.
PLoS ONE
PUBLISHED: 01-24-2013
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Diabetes is associated with a higher incidence of myocardial infarction (MI) and increased risk for adverse vascular and fibrogenic events post-MI. Bone marrow-derived progenitor cell (BMPC) therapy has been shown to promote neovascularization, decrease infarct area and attenuate left ventricular (LV) dysfunction after MI. Unlike vascular effects, the anti-fibrosis mechanisms of BMPC, specifically under diabetic conditions, are poorly understood. We demonstrated that intramyocardial delivery of BMPCs in infarcted diabetic db/db mice significantly down-regulates profibrotic miRNA-155 in the myocardium and improves LV remodeling and function. Furthermore, inhibition of paracrine factor hepatocyte growth factor (HGF) signaling in vivo suppressed the BMPC-mediated inhibition of miR-155 expression and the associated protective effect on cardiac fibrosis and function. In vitro studies confirmed that the conditioned media of BMPC inhibited miR-155 expression and profibrotic signaling in mouse cardiac fibroblasts under diabetic conditions. However, neutralizing antibodies directed against HGF blocked these effects. Furthermore, miR-155 over-expression in mouse cardiac fibroblasts inhibited antifibrotic Sloan-Kettering Institute proto-oncogene (Ski) and Ski-related novel gene, non-Alu-containing (SnoN) signaling and abrogated antifibrogenic response of HGF. Together, our data demonstrates that paracrine regulation of cardiac miRNAs by transplanted BMPCs contributes to the antifibrotic effects of BMPC therapy. BMPCs release HGF, which inhibits miR-155-mediated profibrosis signaling, thereby preventing cardiac fibrosis. These data suggest that targeting miR-155 might serve as a potential therapy against cardiac fibrosis in the diabetic heart.
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Quantum-chemical studies on thermodynamic feasibility of 1-methyl-2,4,5-trinitroimidazole processes.
J Mol Model
PUBLISHED: 01-19-2013
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1-Methyl-2,4,5-trinitro imidazole (MTNI) is a well-known melt cast explosive possessing good thermal stability and impact insensitivity. MTNI has been synthesized from multi-step nitration followed by methylation of imidazole exhibiting low yield. It is desirable to screen the process thermodynamically for evaluating feasibility of the process. In the present investigations, B3LYP method in combination with 3-21G** basis set has been chosen to evaluate the enthalpy of formation for reaction species by designing reasonable isodesmic reactions. Thermodynamic feasibility of the processes has been worked out assuming free energies of reactions as derived from standard enthalpy and entropy of the reaction species. All possible synthesis routes for the target molecule, MTNI has been conceptualized from different precursors/intermediates viz. imidazole, 2-nitroimidazole, 4-nitroimidazole, 1-methyl imidazole and 2,4,5-triiodoimidazole. Various nitrating agents have been employed and their effect studied for deciding the feasibility of the reaction. It has been found that reaction entropy and enthalpy are favorable on usage of NO2BF4 as nitrating agent. The charge on nitro group (-QNO2) has been used for better understanding of the reactivity of substrates/intermediates. Overall, the study helped in screening several possible routes for MTNI synthesis and identified the thermodynamically feasible process by using NO2BF4 as nitrating agent.
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Contrasting roles of E2F2 and E2F3 in cardiac neovascularization.
PLoS ONE
PUBLISHED: 01-01-2013
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Insufficient neovascularization, characterized by poor endothelial cell (EC) growth, contributes to the pathogenesis of ischemic heart disease and limits cardiac tissue preservation and regeneration. The E2F family of transcription factors are critical regulators of the genes responsible for cell-cycle progression and growth; however, the specific roles of individual E2Fs in ECs are not well understood. Here we investigated the roles of E2F2 and E2F3 in EC growth, angiogenesis, and their functional impact on myocardial infarction (MI). An endothelial-specific E2F3-deficient mouse strain VE-Cre; E2F3(fl/fl) was generated, and MI was surgically induced in VE-Cre; E2F3(fl/fl) and E2F2-null (E2F2 KO) mice and their wild-type (WT) littermates, VE-Cre; E2F3(+/+) and E2F2 WT, respectively. The cardiac function, infarct size, and vascular density were significantly better in E2F2 KO mice and significantly worse in VE-Cre; E2F3(fl/fl) mice than in their WT littermates. The loss of E2F2 expression was associated with an increase in the proliferation of ECs both in vivo and in vitro, while the loss of E2F3 expression led to declines in EC proliferation. Thus, E2F3 promotes while E2F2 suppresses ischemic cardiac repair through corresponding changes in EC proliferation; and differential targeting of specific E2F members may provide a novel strategy for therapeutic angiogenesis of ischemic heart disease.
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Global gene expression profiling in PAI-1 knockout murine heart and kidney: molecular basis of cardiac-selective fibrosis.
PLoS ONE
PUBLISHED: 01-01-2013
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Fibrosis is defined as an abnormal matrix remodeling due to excessive synthesis and accumulation of extracellular matrix proteins in tissues during wound healing or in response to chemical, mechanical and immunological stresses. At present, there is no effective therapy for organ fibrosis. Previous studies demonstrated that aged plasminogen activator inhibitor-1 (PAI-1) knockout mice develop spontaneously cardiac-selective fibrosis without affecting any other organs. We hypothesized that differential expressions of profibrotic and antifibrotic genes in PAI-1 knockout hearts and unaffected organs lead to cardiac selective fibrosis. In order to address this prediction, we have used a genome-wide gene expression profiling of transcripts derived from aged PAI-1 knockout hearts and kidneys. The variations of global gene expression profiling were compared within four groups: wildtype heart vs. knockout heart; wildtype kidney vs. knockout kidney; knockout heart vs. knockout kidney and wildtype heart vs. wildtype kidney. Analysis of illumina-based microarray data revealed that several genes involved in different biological processes such as immune system processing, response to stress, cytokine signaling, cell proliferation, adhesion, migration, matrix organization and transcriptional regulation were affected in hearts and kidneys by the absence of PAI-1, a potent inhibitor of urokinase and tissue-type plasminogen activator. Importantly, the expressions of a number of genes, involved in profibrotic pathways including Ankrd1, Pi16, Egr1, Scx, Timp1, Timp2, Klf6, Loxl1 and Klotho, were deregulated in PAI-1 knockout hearts compared to wildtype hearts and PAI-1 knockout kidneys. While the levels of Ankrd1, Pi16 and Timp1 proteins were elevated during EndMT, the level of Timp4 protein was decreased. To our knowledge, this is the first comprehensive report on the influence of PAI-1 on global gene expression profiling in the heart and kidney and its implication in fibrogenesis and several other biological processes. The significance of these observations in the light of heart-specific profibrotic signaling and fibrogenesis are discussed.
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Rosuvastatin enhances angiogenesis via eNOS-dependent mobilization of endothelial progenitor cells.
PLoS ONE
PUBLISHED: 01-01-2013
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Circulating endothelial progenitor cells (circEPCs) of bone marrow (BM) origin contribute to postnatal neovascularization and represent a potential therapeutic target for ischemic disease. Statins are beneficial for ischemia disease and have been implicated to increase neovascularization via mechanisms independent of lipid lowering. However, the effect of Statins on EPC function is not completely understood. Here we sought to investigate the effects of Rosuvastatin (Ros) on EPC mobilization and EPC-mediated neovascularization during ischemic injury. In a mouse model of surgically-induced hindlimb ischemia (HLI), treatment of mice with low dose (0.1 mg/kg) but not high dose (5 mg/kg) significantly increased capillary density and accelerated blood flow recovery, as compared to saline-treated group. When HLI was induced in mice that had received Tie2/LacZ BM transplantation, Ros treatment led a significantly larger amount of endothelial cells (ECs) of BM origin incorporated at ischemic sites than saline. After treatment of mice with a single low dose of Ros, circEPCs significantly increased from 2 h, peaked at 4 h, declined until 8 h. In a growth-factor reduced Matrigel plug-in assay, Ros treatment for 5 d induced endothelial lineage differentiation in vivo. Interestingly, the enhanced circEPCs and post-HLI neovascularization stimulated by Ros were blunted in mice deficient in endothelial nitric oxide synthase (eNOS), and Ros increased p-Akt/p-eNOS levels in EPCs in vitro, indicating these effects of Ros are dependent on eNOS activity. We conclude that Ros increases circEPCs and promotes their de novo differentiation through eNOS pathway.
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Interleukin-10 deficiency impairs bone marrow-derived endothelial progenitor cell survival and function in ischemic myocardium.
Circ. Res.
PUBLISHED: 09-29-2011
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Endothelial progenitor cell (EPC) survival and function in the injured myocardium is adversely influenced by hostile microenvironment such as ischemia, hypoxia, and inflammatory response, thereby compromising full benefits of EPC-mediated myocardial repair.
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Laparoscopic management of congenital H-type urethroanal fistula.
J Laparoendosc Adv Surg Tech A
PUBLISHED: 08-20-2011
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Laparoscopic management in a case of congenital urethroanal fistula with a normal anterior urethra in a 5-month-old male child is reported. A congenital H-type urethroanal fistula is a rare entity. Management of such fistula has always been surgical, ranging from perineal dissection, posterior saggital approach, to abdomino-perineal approach. We describe a minimally invasive laparoscopic method for approaching such fistula, which has not been described in the literature and is being reported for the first time.
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Exosomes from human CD34(+) stem cells mediate their proangiogenic paracrine activity.
Circ. Res.
PUBLISHED: 08-11-2011
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Transplantation of human CD34(+) stem cells to ischemic tissues has been associated with reduced angina, improved exercise time, and reduced amputation rates in phase 2 clinical trials and has been shown to induce neovascularization in preclinical models. Previous studies have suggested that paracrine factors secreted by these proangiogenic cells are responsible, at least in part, for the angiogenic effects induced by CD34(+) cell transplantation.
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Improvement of cardiac function in mouse myocardial infarction after transplantation of epigenetically-modified bone marrow progenitor cells.
PLoS ONE
PUBLISHED: 05-24-2011
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To study usefulness of bone marrow progenitor cells (BPCs) epigenetically altered by chromatin modifying agents in mediating heart repair after myocardial infarction in mice.
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Computational design and structure-property relationship studies on heptazines.
J Mol Model
PUBLISHED: 01-04-2011
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This study aimed to design novel nitrogen-rich heptazine derivatives as high energy density materials (HEDM) by exploiting systematic structure-property relationships. Molecular structures with diverse energetic substituents at varying positions in the basic heptazine ring were designed. Density functional techniques were used for prediction of gas phase heat of formation by employing an isodesmic approach, while crystal density was assessed by packing calculations. The results reveal that nitro derivatives of heptazine possess a high heat of formation and further enhancement was achieved by the substitution of nitro heterocycles. The crystal packing density of the designed compounds varied from 1.8 to 2 g cm(-3), and hence, of all the designed molecules, nitro derivatives of heptazine exhibit better energetic performance characteristics in terms of detonation velocity and pressure. The calculated band gap of the designed molecules was analyzed to establish sensitivity correlations, and the results reveal that, in general, amino derivatives possess better insensitivity characteristics. The overall performance of the designed compounds was moderate, and such compounds may find potential applications in gas generators and smoke-free pyrotechnic fuels as they are rich in nitrogen content.
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CXCR4-mediated bone marrow progenitor cell maintenance and mobilization are modulated by c-kit activity.
Circ. Res.
PUBLISHED: 09-16-2010
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The mobilization of bone marrow (BM) progenitor cells (PCs) is largely governed by interactions between stromal cell-derived factor (SDF)-1 and CXC chemokine receptor (CXCR)4. Ischemic injury disrupts the SDF-1-CXCR4 interaction and releases BM PCs into the peripheral circulation, where the mobilized cells are recruited to the injured tissue and contribute to vessel growth. BM PCs can also be mobilized by the pharmacological CXCR4 antagonist AMD3100, but the other components of the SDF-1-CXCR4 signaling pathway are largely unknown. c-kit, a membrane-bound tyrosine kinase and the receptor for stem cell factor, has also been shown to play a critical role in BM PC mobilization and ischemic tissue repair.
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Inhibition of melanoma angiogenesis by telomere homolog oligonucleotides.
J Oncol
PUBLISHED: 05-06-2010
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Telomere homolog oligonucleotides (T-oligos) activate an innate telomere-based program that leads to multiple anticancer effects. T-oligos act at telomeres to initiate signaling through the Werner protein and ATM kinase. We wanted to determine if T-oligos have antiangiogenic effects. We found that T-oligo-treated human melanoma (MM-AN) cells had decreased expression of vascular endothelial growth factor (VEGF), VEGF receptor 2, angiopoeitin-1 and -2 and decreased VEGF secretion. T-oligos activated the transcription factor E2F1 and inhibited the activity of the angiogenic transcription factor, HIF-1alpha. T-oligos inhibited EC tubulogenesis and total tumor microvascular density matrix invasion by MM-AN cells and ECs in vitro. In melanoma SCID xenografts, two systemic T-oligo injections decreased by 60% (P < .004) total tumor microvascular density and the functional vessels density by 80% (P < .002). These findings suggest that restriction of tumor angiogenesis is among the hosts innate telomere-based anticancer responses and provide further evidence that T-oligos may offer a powerful new approach for melanoma treatment.
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Myocardial knockdown of mRNA-stabilizing protein HuR attenuates post-MI inflammatory response and left ventricular dysfunction in IL-10-null mice.
FASEB J.
PUBLISHED: 03-10-2010
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Prolonged inflammatory response is associated with left ventricular (LV) dysfunction and adverse remodeling following myocardial infarction (MI). IL-10 inhibits inflammation by suppressing HuR-mediated mRNA stabilization of proinflammatory cytokines. Here we report that following MI, IL-10(-/-) mice showed exaggerated LV dysfunction, fibrosis, and cardiomyocyte apoptosis. Short-hairpin RNA (shRNA)-mediated knockdown of HuR in the myocardium significantly reversed MI-induced LV dysfunctions and LV remodeling. HuR knockdown significantly reduced MI-induced cardiomyocyte apoptosis concomitant with reduced p53 expression. Moreover, HuR knockdown significantly reduced infarct size and fibrosis area, which in turn was associated with decreased TGF-beta expression. In vitro, stable knockdown of HuR in mouse macrophage cell line RAW 264.7 corroborated in vivo data and revealed reduced mRNA expression of TNF-alpha, TGF-beta, and p53 following LPS challenge, which was associated with a marked reduction in the mRNA stability of these genes. Taken together, our studies suggest that HuR is a direct target of IL-10, and HuR knockdown mimics anti-inflammatory effects of IL-10.
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Sonic hedgehog induces angiogenesis via Rho kinase-dependent signaling in endothelial cells.
J. Mol. Cell. Cardiol.
PUBLISHED: 02-11-2010
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The morphogen Sonic hedgehog (Shh) promotes neovascularization in adults by inducing pro-angiogenic cytokine expression in fibroblasts; however, the direct effects of Shh on endothelial cell (EC) function during angiogenesis are unknown. Our findings indicate that Shh promotes capillary morphogenesis (tube length on Matrigel increased to 271+/-50% of the length in untreated cells, p=0.00003), induces EC migration (modified Boyden chamber assay, 191+/-35% of migration in untreated cells, p=0.00009), and increases EC expression of matrix metalloproteinase 9 (MMP-9) and osteopontin (OPN) mRNA (real-time RT-PCR), which are essential for Shh-induced angiogenesis both in vitro and in vivo. Shh activity in ECs is mediated by Rho, rather than through the "classic" Shh signaling pathway, which involves the Gli transcription factors. The Rho dependence of Shh-induced EC angiogenic activity was documented both in vitro, with dominant-negative RhoA and Rho kinase (ROCK) constructs, and in vivo, with the ROCK inhibitor Y27632 in the mouse corneal angiogenesis model. Finally, experiments performed in MMP-9- and OPN-knockout mice confirmed the roles of the ROCK downstream targets MMP-9 and OPN in Shh-induced angiogenesis. Collectively, our results identify a "nonclassical" pathway by which Shh directly modulates EC phenotype and angiogenic activity.
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Neutralization of red mud using CO2 sequestration cycle.
J. Hazard. Mater.
PUBLISHED: 01-29-2010
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A laboratory study was conducted to investigate the ability of neutralization of red mud (RM) using carbon dioxide gas sequestration cycle at ambient conditions. The neutralized red mud (NRM) was characterized by XRD, SEM, EDX, FT-IR and auto titration method. X-ray diffraction pattern of NRM was revealed that the intensity of gibbsite was increased prominently and formed ilmenite due to dissolution of minerals. EDX analysis was showed that the %(w/w) of Na, C, O, Si were higher in the carbonated filtrate as compared to the RM and NRM. The permanently sequestered CO(2)%(w/w) per 10 g of red mud were approximately 26.33, approximately 58.01, approximately 55.37, and approximately 54.42 in NRM and first, second, third cycles of carbonated filtrate, respectively. The pH of red mud was decreased from approximately 11.8 to approximately 8.45 and alkalinity was decreased from approximately 10,789 to approximately 178 mg/L. The acid neutralizing capacity of NRM was approximately 0.23 mol H(+)/kg of red mud. The specific advantages of these cyclic processes are that, large amount of CO(2) can be captured as compared to single step.
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Polypodium leucotomos extract decreases UV-induced Cox-2 expression and inflammation, enhances DNA repair, and decreases mutagenesis in hairless mice.
Am. J. Pathol.
PUBLISHED: 10-01-2009
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UV-irradiated skin and UV-induced tumors overexpress the inducible isoform of cyclooxygenase-2 (Cox-2), and Cox-2 inhibition reduces photocarcinogenesis. To evaluate photoprotective effects of Polypodium leucotomos extract (PL), hairless Xpc(+/-) mice were fed for 10 days with PL (300 mg/kg) or vehicle then UV-irradiated, once. By 24 hours, UV-induced Cox-2 levels were increased in vehicle-fed and PL-fed mice, whereas by 48 and 72 hours, Cox-2 levels were four- to fivefold lower in PL-fed mice (P < 0.05). p53 expression/activity was increased in PL-fed versus vehicle-fed then UV-irradiated mice. UV-induced inflammation was decreased in PL-fed mice, as shown by approximately 60% decrease (P < 0.001) in neutrophil infiltration at 24 hours, and macrophages by approximately 50% (<0.02) at 24 and 48 hours. By 72 hours, 54 +/- 5% cyclobutane pyrimidine dimers remained in vehicle-fed versus 31 +/- 5% in PL-fed skin (P < 0.003). The number of 8-hydroxy-2-deoxyguanosine-positive cells were decreased before UV irradiation by approximately 36% (P < 0.01), suggesting that PL reduces constitutive oxidative DNA damage. By 6 and 24 hours, the number of 8-hydroxy-2-deoxyguanosine-positive cells were approximately 59% (P < 0.01) and approximately 79% (P < 0.03) lower in PL-fed versus vehicle-fed mice. Finally, UV-induced mutations in PL-fed-mice were decreased by approximately 25% when assessed 2 weeks after the single UV exposure. These data demonstrate that PL extract supplementation affords the following photoprotective effects: p53 activation and reduction of acute inflammation via Cox-2 enzyme inhibition, increased cyclobutane pyrimidine dimer removal, and reduction of oxidative DNA damage.
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Regulation of vascular contractility and blood pressure by the E2F2 transcription factor.
Circulation
PUBLISHED: 09-14-2009
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Recent studies have identified a polymorphism in the endothelin-converting enzyme (ECE)-1b promoter (-338C/A) that is strongly associated with hypertension in women. The polymorphism is located in a consensus binding sequence for the E2F family of transcription factors. E2F proteins are crucially involved in cell-cycle regulation, but their roles in cardiovascular function are poorly understood. Here, we investigated the potential role of E2F2 in blood pressure regulation.
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Hypoxic preconditioning enhances the benefit of cardiac progenitor cell therapy for treatment of myocardial infarction by inducing CXCR4 expression.
Circ. Res.
PUBLISHED: 04-30-2009
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Myocardial infarction rapidly depletes the endogenous cardiac progenitor cell pool, and the inefficient recruitment of exogenously administered progenitor cells limits the effectiveness of cardiac cell therapy. Recent reports indicate that interactions between the CXC chemokine stromal cell-derived factor 1 and its receptor CXC chemokine receptor 4 (CXCR4) critically mediate the ischemia-induced recruitment of bone marrow-derived circulating stem/progenitor cells, but the expression of CXCR4 in cardiac progenitor cells is very low. Here, we studied the influence of hypoxia on CXCR4 expression in cardiac progenitor cells, on the recruitment of intravenously administered cells to ischemic heart tissue, and on the preservation of heart function in a murine myocardial infarction model. We found that hypoxic preconditioning increased CXCR4 expression in CLK (cardiosphere-derived, Lin(-)c-kit(+) progenitor) cells and markedly augmented CLK cell migration (in vitro) and recruitment (in vivo) to the ischemic myocardium. Four weeks after surgically induced myocardial infarction, infarct size and heart function were significantly better in mice administered hypoxia-preconditioned CLK cells than in mice treated with cells cultured under normoxic conditions. Furthermore, these effects were largely abolished by the addition of a CXCR4 inhibitor, indicating that the benefits of hypoxic preconditioning are mediated by the stromal cell-derived factor 1/CXCR4 axis, and that therapies targeting this axis may enhance cardiac-progenitor cell-based regenerative therapy.
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Essential thrombocythaemia presenting with subclavian artery thrombosis and multiple embolic events.
BMJ Case Rep
PUBLISHED: 03-17-2009
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The present report describes a case of in situ thrombosis of the left subclavian artery complicated by posterior circulation stroke, left arm ischaemia and possibly ischaemic pancreatitis. Essential thrombocythaemia was found to be the underlying cause.
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IL-10 inhibits inflammation and attenuates left ventricular remodeling after myocardial infarction via activation of STAT3 and suppression of HuR.
Circ. Res.
PUBLISHED: 02-13-2009
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Persistent inflammatory response has adverse effects on left ventricular (LV) function and remodeling following acute myocardial infarction. We hypothesized that suppression of inflammation with interleukin (IL)-10 treatment attenuates LV dysfunction and remodeling after acute myocardial infarction. After the induction of acute myocardial infarction, mice were treated with either saline or recombinant IL-10, and inflammatory response and LV functional and structural remodeling changes were evaluated. IL-10 significantly suppressed infiltration of inflammatory cells and expression of proinflammatory cytokines in the myocardium. These changes were associated with IL-10-mediated inhibition of p38 mitogen-activated protein kinase activation and repression of the cytokine mRNA-stabilizing protein HuR. IL-10 treatment significantly improved LV functions, reduced infarct size, and attenuated infarct wall thinning. Myocardial infarction-induced increase in matrix metalloproteinase (MMP)-9 expression and activity was associated with increased fibrosis, whereas IL-10 treatment reduced both MMP-9 activity and fibrosis. Small interfering RNA knockdown of HuR mimicked IL-10-mediated reduction in MMP-9 expression and activity in NIH3T3 cells. Moreover, IL-10 treatment significantly increased capillary density in the infarcted myocardium which was associated with enhanced STAT3 phosphorylation. Taken together, our studies demonstrate that IL-10 suppresses inflammatory response and contributes to improved LV function and remodeling by inhibiting fibrosis via suppression of HuR/MMP-9 and by enhancing capillary density through activation of STAT3.
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Formulation and evaluation of flurbiprofen-loaded genipin cross-linked gelatin microspheres for intra-articular delivery.
J Drug Target
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Oral and parenteral formulations are challenging to produce therapeutic concentration of flurbiprofen in the joints. This encourages for the development of formulation for long term drug retention in the joint through intra-articular (i. a.) administration. In this study, genipin cross-linked gelatin microspheres of flurbiprofen were prepared for i. a. delivery. The microspheres were prepared using emulsification-homogenization-cross-linking method by changing the experimental variables such as concentration of cross-linker, cross-linking time and cross-linking temperature. The microspheres showed drug entrapment up to 76.19% with a mean particle size range of 5.91-8.19 µm. The degree of cross-linking and water-soluble fraction were 8.27-59.33% and 12.29-81.23%, respectively. SEM confirmed smooth surface and spherical shape of the microspheres. FTIR and (13)C-NMR confirmed cross-linking of gelatin by genipin. No chemical change in encapsulated drug was observed by FTIR and TGA. DSC and XRD indicated the molecular dispersion of drug within microspheres. Optimized microspheres could prolong the drug release for more than 108 h with anomalous transport. Histopathology confirmed the biocompatibility of microspheres in the rat (Wistar) knee joint. After 96 h of i. a. injection, significant higher amount (42.56%) of administered drug in cross-linked microspheres was recovered than uncross-linked microspheres (8.27%) confirming better drug retention efficiency (p < 0.01).
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The angiogenic factor secretoneurin induces coronary angiogenesis in a model of myocardial infarction by stimulation of vascular endothelial growth factor signaling in endothelial cells.
Circulation
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Secretoneurin is a neuropeptide located in nerve fibers along blood vessels, is upregulated by hypoxia, and induces angiogenesis. We tested the hypothesis that secretoneurin gene therapy exerts beneficial effects in a rat model of myocardial infarction and evaluated the mechanism of action on coronary endothelial cells.
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Elucidation of a novel pathway through which HDAC1 controls cardiomyocyte differentiation through expression of SOX-17 and BMP2.
PLoS ONE
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Embryonic Stem Cells not only hold a lot of potential for use in regenerative medicine, but also provide an elegant and efficient way to study specific developmental processes and pathways in mammals when whole animal gene knock out experiments fail. We have investigated a pathway through which HDAC1 affects cardiovascular and more specifically cardiomyocyte differentiation in ES cells by controlling expression of SOX17 and BMP2 during early differentiation. This data explains current discrepancies in the role of HDAC1 in cardiovascular differentiation and sheds light into a new pathway through which ES cells determine cardiovascular cell fate.
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Induced pluripotent cells in cardiovascular biology: epigenetics, promises, and challenges.
Prog Mol Biol Transl Sci
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Cardiovascular diseases are still the leading cause of death worldwide. Despite the improvement shown in the prognosis of patients with acute MI, there remains still a significant mortality risk. Since the main underlying problem after an MI is the loss of cardiomyocytes and microvasculature, treatment strategies aimed at preserving or regenerating myocardial tissue have been examined as potential therapeutic modalities. Toward this goal, many cell types are being investigated as potent sources of cardiomyocytes for cell transplantation. The progress made toward the generation of induced Pluripotent Stem (iPS) cells hold great potential for future use in myocardial repair. We review critical aspects of these cells potential, such as their generation, their differentiating ability, the known epigenetic mechanisms that allow for their reprogramming, maintenance of pluripotency, their cardiovascular differentiation and therapeutic potential, and the possibility of an epigenetic memory. Understanding the molecular circuitry of these cells will provide a better understanding of their potential as well as limitations in future clinical use.
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Histone deacetylase 1 deficiency impairs differentiation and electrophysiological properties of cardiomyocytes derived from induced pluripotent cells.
Stem Cells
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Epigenetic and chromatin modifications play particularly important roles in embryonic and induced pluripotent stem cells (ESCs and iPSCs) allowing for the cells to both differentiate and dedifferentiate back to a pluripotent state. We analyzed how the loss of a key chromatin-modifying enzyme, histone deacetylase 1 (HDAC1), affects early and cardiovascular differentiation of both ESCs and iPSCs. We also investigated potential differences between these two cell types when differentiation is induced. Our data indicate an essential role for HDAC1 in deacetylating regulatory regions of key pluripotency-associated genes during early differentiation. Although HDAC1 functions primarily as a HDAC, its loss also affects DNA methylation in ESCs and iPSCs both during pluripotency and differentiation. We show that HDAC1 plays a crucial, nonredundant role in cardiomyocyte differentiation and maturation. Our data also elucidate important differences between ESCs and iPSCs, when levels of this enzyme are reduced, that affect their ability to differentiate into functional cardiomyocytes. As varying levels of chromatin-modifying enzymes are likely to exist in patient-derived iPSCs, understanding the molecular circuitry of these enzymes in ESCs and iPSCs is critical for their potential use in cardiovascular therapeutic applications
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Interleukin-10 treatment attenuates pressure overload-induced hypertrophic remodeling and improves heart function via signal transducers and activators of transcription 3-dependent inhibition of nuclear factor-?B.
Circulation
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Inflammation plays a critical role in adverse cardiac remodeling and heart failure. Therefore, approaches geared toward inhibiting inflammation may provide therapeutic benefits. We tested the hypotheses that genetic deletion of interleukin-10 (IL-10), a potent antiinflammatory cytokine, exacerbates pressure overload-induced adverse cardiac remodeling and hypertrophy and that IL-10 therapy inhibits this pathology.
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Formulation, characterization and in vitro-in vivo evaluation of flurbiprofen-loaded nanostructured lipid carriers for transdermal delivery.
Drug Dev Ind Pharm
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Flurbiprofen is used in the treatment of arthritis. However, its multiple dosing due to short elimination half life is a concern for such treatment. This work aims to develop nanostructured lipid carriers (NLCs) of flurbiprofen and evaluate their potential for transdermal delivery. The NLCs were prepared by the optimized o/w emulsification-homogenization-sonication technique using coconut oil (liquid lipid). The NLCs were found to be spherical with uniform size (214 nm). The entrapment efficiency and zeta potential were 92.58% and -30.70 mV, respectively. Differential scanning calorimetry (DSC) showed the amorphous state of flurbiprofen encapsulated in NLCs. The percentage cumulative drug release through the excised rat skin from NLCs was biphasic and significantly prolonged compared with the commercial gel. DSC of the treated skin indicated that the NLCs penetrate into follicles of the skin and accumulate in the dermis. The bioavailability of flurbiprofen from NLCs was more than 1.7-fold that of the commercial gel. The NLCs showed a quick onset and sustained anti-inflammatory effect over period of 24 h for carrageenan-induced rat paw edema than the commercial gel. The stability data revealed that the NLCs were more stable when stored at 5°C. In conclusion, prepared NLCs have potential for skin targeting and sustained drug release.
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Enhanced angiogenic and cardiomyocyte differentiation capacity of epigenetically reprogrammed mouse and human endothelial progenitor cells augments their efficacy for ischemic myocardial repair.
Circ. Res.
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Although bone marrow endothelial progenitor cell (EPC)-based therapies improve the symptoms in patients with ischemic heart disease, their limited plasticity and decreased function in patients with existing heart disease limit the full benefit of EPC therapy for cardiac regenerative medicine.
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Sonic hedgehog-modified human CD34+ cells preserve cardiac function after acute myocardial infarction.
Circ. Res.
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Ischemic cardiovascular disease represents one of the largest epidemics currently facing the aging population. Current literature has illustrated the efficacy of autologous, stem cell therapies as novel strategies for treating these disorders. The CD34+ hematopoetic stem cell has shown significant promise in addressing myocardial ischemia by promoting angiogenesis that helps preserve the functionality of ischemic myocardium. Unfortunately, both viability and angiogenic quality of autologous CD34+ cells decline with advanced age and diminished cardiovascular health.
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Roles of STATs signaling in cardiovascular diseases.
JAKSTAT
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In cardiac and many other systems, chronic stress activates avfamily of structurally and functionally conserved receptors and their downstream signaling molecules that entail tyrosine, serine or threonine phosphorylation to transfer the messages to the genetic machinery. However, the activation of the Janus kinases (JAKs) and their downstream signal transducer and activator of transcription (STATs) proteins is both characteristic of and unique to cytokine and growth factor signaling which plays a central role in heart physiology. Dysregulation of JAK-STAT signaling is associated with various cardiovascular diseases. The molecular signaling and specificity of the JAK-STAT pathway are modulated at many levels by distinct regulatory proteins. Here, we review recent studies on the regulation of the STAT signaling pathway that will enhance our ability to design rational therapeutic strategies for stress-induced heart failure.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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