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Immunotoxicological Effects of Aripiprazole: In vivo and In vitro Studies

  • Baek, Kwang-Soo;Ahn, Shinbyoung;Lee, Jaehwi;Kim, Ji Hye;Kim, Han Gyung;Kim, Eunji;Kim, Jun Ho;Sung, Nak Yoon;Yang, Sungjae;Kim, Mi Seon;Hong, Sungyoul;Kim, Jong-Hoon;Cho, Jae Youl
    • The Korean Journal of Physiology and Pharmacology
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    • v.19 no.4
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    • pp.365-372
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    • 2015
  • Aripiprazole (ARI) is a commonly prescribed medication used to treat schizophrenia and bipolar disorder. To date, there have been no studies regarding the molecular pathological and immunotoxicological profiling of aripiprazole. Thus, in the present study, we prepared two different formulas of aripiprazole [Free base crystal of aripiprazole (ARPGCB) and cocrystal of aripiprazole (GCB3004)], and explored their effects on the patterns of survival and apoptosis-regulatory proteins under acute toxicity and cytotoxicity test conditions. Furthermore, we also evaluated the modulatory activity of the different formulations on the immunological responses in macrophages primed by various stimulators such as lipopolysaccharide (LPS), pam3CSK, and poly(I:C) via toll-like receptor 4 (TLR4), TLR2, and TLR3 pathways, respectively. In liver, both ARPGCB and GCB3004 produced similar toxicity profiles. In particular, these two formulas exhibited similar phospho-protein profiling of p65/nuclear factor $(NF)-{\kappa}B$, c-Jun/activator protein (AP)-1, ERK, JNK, p38, caspase 3, and bcl-2 in brain. In contrast, the patterns of these phospho-proteins were variable in other tissues. Moreover, these two formulas did not exhibit any cytotoxicity in C6 glioma cells. Finally, the two formulations at available in vivo concentrations did not block nitric oxide (NO) production from activated macrophage-like RAW264.7 cells stimulated with LPS, pam3CSK, or poly(I:C), nor did they alter the morphological changes of the activated macrophages. Taken together, our present work, as a comparative study of two different formulas of aripiprazole, suggests that these two formulas can be used to achieve similar functional activation of brain proteins related to cell survival and apoptosis and immunotoxicological activities of macrophages.

Biomechanical Comparison of Inter-fragmentary Compression Pressures : Lag Screw versus Herbert Screw for Anterior Odontoid Screw Fixation

  • Park, Jin-Woo;Kim, Kyoung-Tae;Sung, Joo-Kyung;Park, Seong-Hyun;Seong, Ki-Woong;Cho, Dae-Chul
    • Journal of Korean Neurosurgical Society
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    • v.60 no.5
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    • pp.498-503
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    • 2017
  • Objective : The purpose of the present study was to compare inter-fragmentary compression pressures after fixation of a simulated type II odontoid fracture with the headless compression Herbert screw and a half threaded cannulated lag screw. Methods : We compared inter-fragmentary compression pressures between 40- and 45-mm long 4.5-mm Herbert screws (n=8 and n=9, respectively) and 40- and 45-mm long 4.0-mm cannulated lag screws (n=7 and n=10, respectively) after insertion into rigid polyurethane foam test blocks (Sawbones, Vashon, WA, USA). A washer load cell was placed between the two segments of test blocks to measure the compression force. Because the total length of each foam block was 42 mm, the 40-mm screws were embedded in the cancellous foam, while the 45-mm screws penetrated the denser cortical foam at the bottom. This enabled us to compare inter-fragmentary compression pressures as they are affected by the penetration of the apical dens tip by the screws. Results : The mean compression pressures of the 40- and 45-mm long cannulated lag screws were $50.48{\pm}1.20N$ and $53.88{\pm}1.02N$, respectively, which was not statistically significant (p=0.0551). The mean compression pressures of the 40-mm long Herbert screw was $52.82{\pm}2.17N$, and was not statistically significant compared with the 40-mm long cannulated lag screw (p=0.3679). However, 45-mm Herbert screw had significantly higher mean compression pressure ($60.68{\pm}2.03N$) than both the 45-mm cannulated lag screw and the 40-mm Herbert screw (p=0.0049 and p=0.0246, respectively). Conclusion : Our results showed that inter-fragmentary compression pressures of the Herbert screw were significantly increased when the screw tip penetrated the opposite dens cortical foam. This can support the generally recommended surgical technique that, in order to facilitate maximal reduction of the fracture gap using anterior odontoid screws, it is essential to penetrate the apical dens tip with the screw.

Supplementation of Microalgae (Tetradesmus sp.) to Pre-Starter Diet for Broiler Chickens (초기 육계 사료 내 미세조류(Tetradesmus sp.) 첨가에 따른 장관환경 변화)

  • Rim, Chae Yun;Jung, Hui-su;An, Su Hyun;Joo, Sang Seok;Kim, Z-Hun;Kong, Changsu;Kim, Myunghoo
    • Korean Journal of Poultry Science
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    • v.49 no.2
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    • pp.125-137
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    • 2022
  • This study aimed to determine the effects of dietary microalgae (Tetradesmus sp. (TO)) on intestinal immunity and microbiota of pre-starter broilers. One hundred and twenty 1-day-old birds (Ross 308) were allocated to two dietary treatment groups with six blocks in a randomized complete block design. The two experimental diets consisted of a corn-soybean meal-based basal diet and a diet with 0.5% TO powder instead of cornstarch in the basal diet. After feeding the experimental diets for ten days, all birds' body weight and feed intake were measured, and representative eight birds were selected from each treatment group. Small intestinal lamina propria cells were isolated using flow cytometry to examine the frequency of immune cells. Cecal feces were harvested for 16s rRNA gut microbiota analysis and fecal IgA levels. Here, we found that 0.5% TO supplementation increased CD3+CD4+ T cells in the small intestine, but decreased CD3+CD8+ T cells in the small intestine. Gut microbial analysis showed that TO supplementation significantly increased the alpha diversity of the gut microbiome. Taxonomic analysis showed that TO treatment increased the abundance of Firmicutes and decreased that of Bacteroidetes at the phylum level. The distribution of Enterobacteriaceae containing many harmful bacteria at the family level, was lower in the TO group. In the LEfSe analysis, the TO group had a significantly enriched abundance of Agathobaculum at the genus level. Overall, results show that Tetradesmus sp. supplementation influences intestinal T-cell immunity and induces the expansion of beneficial gut microbes in pre-starter broiler chickens.

A Study of Electro-Optical Properties of Polyester Acrylate-Based Polymer-Dispersed Liquid Crystals Using TIZO/Ag/TIZO Multilayer Transparent Electrodes (TIZO/Ag/TIZO 다층막 투명전극을 이용한 폴리에스터 아크릴레이트 기반 고분자분산액정의 전기광학적 특성 연구)

  • Cho, Jung-Dae;Heo, Gi-Seok;Hong, Jin-Who
    • Applied Chemistry for Engineering
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    • v.33 no.1
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    • pp.50-57
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    • 2022
  • Ti-In-Zn-O (TIZO)/Ag/TIZO multilayer transparent electrodes were prepared on glass substrates at room temperature using RF/DC magnetron sputtering. Obtained multilayer structure comprising TIZO/Ag/TIZO (10 nm/10 nm/40 nm) with the total thickness of 60 nm showed a transmittance of 86.5% at 650 nm and a sheet resistance of 8.1 Ω/□. The multilayer films were expected to be applicable for use in energy-saving smart window based on polymer-dispersed liquid crystal (PDLC) because of their transmittance properties to effectively block infrared rays (heat rays). We investigated the effects of the content ratio of prepolymer, the thickness of the PDLC coating layer, and the ultraviolet (UV) light intensity on electro-optical properties, and the surface morphology of polyester acrylate-based PDLC systems using new TIZO/Ag/TIZO transparent conducting electrodes. A PDLC cell with a thickness of 15 ㎛ PDLC layer photocured at an UV intensity of 1.5 mW/cm2 exhibited good driving voltage, favorable on-state transmittance, and excellent off-haze. The LC droplets formed on the surface of the polymer matrix of the PDLC composite had a size range of 1 to 3 ㎛ capable of efficiently scattering incident light. Also, the PDLC-based smart window manufactured using TIZO/Ag/TIZO multi-layered transparent electrodes in this study exhibited a light brown, which will have an advantage in terms of aesthetics.

THE EFFECTS OF POLYTETRAFLUOROETHYLENE MEMBRANE AND MILLIPORE FILTER COMBINED WITH FIBRIN ON THE REGENERATION OF PERIODONTIUM IN DOGS (Polytetrafluoroethylene membrane 및 millipore filter를 섬유소와 병용사용시 성견 치주조직 재생에 미치는 영향)

  • Joo, Sang-Don;Park, Jae-Wan;Suh, Jo-Young
    • Journal of Periodontal and Implant Science
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    • v.23 no.3
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    • pp.577-594
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    • 1993
  • The ultimate goal of periodontal therapy is the regeneration of the periodontium that have been destroyed as a result of periodontal disease. This study were done in order to determine the healing status of periodontium under Polytetrafluoroethylene and millipore fillter combined with fibrin and the effect of the guided tissue regeneration procedures were performed as follows : 1) flap operation using PTFE membrane(control group) 2) flap operation using PTFE membrane which was fixed with fibrin(experimental group 1) 3) flap operation using millipore filter which was fixed with suture(experimental group II) 4) flap operation using millipore filter which was fixed with fibrin(experimental group II) After 1, 2, 4, 8, 12 weeks, dogs were sacrificed by perfusion technique and tissue block was excised including the tooth and prepared for light microscope with H-E & Masson’s trichrome staining. The result were as follows : In control and experimental group, there is no siginificant difference on epithelial cell down growth within 1st week, but more epithelial cell downgrowth in millipore or millipore combined with fibrin group. In this experiment, there were no significant difference in new cementum and alveolar bone formation whether PTFE membrane was fixed with suture or fibrin. In control and each experimental group, bone maturation appeared in 4 weeks, bone width increased bucco-lingually in control and experimental 1 group especially. Both control group and experimental group showed mild mew cementum formation on root surface and irregular arrangement of collagen fiber at 4 weeks, that showed obvious increased cementum formation at 8 weeks, and that was observed the functional arrangement of collagen fiber between new cementum and new alveolar bone at 12 weeks.

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Do Paneth Cells Regulate the Zinc Body Burden? (Zinc 대사와 관련된 Paneth 세포활성의 변화에 관한 조직화학적 연구)

  • Jo, Seung-Mook;Kim, Sung-Jun;Park, Seung-Kook;Kang, Tae-Cheon;Won, Moo-Ho
    • Applied Microscopy
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    • v.30 no.4
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    • pp.357-365
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    • 2000
  • Paneth cells have been suggested to contribute to the elimination of excess metals into the intestinal lumen. The purpose of this study wat to investigate the changes of the zinc pools in rats subjected to functional loading with zinc salt by mean of both light and electron microscopical autometallography (AMG). Wistar rats 4 were administrated with zinc chloride (20 mg/kg body weight) intraperitoneally dissolved in 1 ml distilled water. The control group received 1 ml saline IP. After further one hour the animals were transcardially perfused with 0.4% sodium sulphide dissolved in 0.1 M PB fellowed by 3% glutaraldehyde solution for 10 minutes. Pieces of ileum were frozen with solid $CO_2$ and sectioned on a cryostat. The sections $(20{\mu}m)$ were autometallographically developed. Sections selected for EM were reembedded on top of a blank Epon block, from which ultrathin sections (100 nm) were cut. The ultrathin sections were double stained with uranyl acetate (30 min) and lead citrate (5 min), then examined under electron microscope. Studies of comparable sections from control and zinc loaded animals with the AMG selenium method gave quite different results. The control animals demonstrated a weakly positive staining in the cytoplasm of the Paneth cells. In the electron microscope the AMG silver grains were found to be located in the cytoplasm, while the electron dense secretary granules and other cell organelles were void of staining. Few AMG grains were located at the apical surface of the Paneth cells. In sections from zinc loaded rats, the AMG grains were seen in abundance in the lumen of the Lieberkuhn crypts at light microscopic levels. At EM levels the zinc revealing silver grains were located in the cytoplasm as in the controls, but much more AMG grains were shifted into the secretary granules. Furthermore, profound AMG grains were found in the lumen of the crypts and surrounding vessels. And a few grains were seen in the endothelium. The AMG technique demonstrated a pattern of AMG grains in the Paneth cells that strongly suggests a transport of zinc ions through these cells.

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Characterization of Microsomal $Ca^{2+}$ Uptake in Tomato Root Tissues (토마토 뿌리조직에서 분리한 마이크로솜의 $Ca^{2+}$ 흡수 특성)

  • Cho, Kwang-Hyun;Kim, Young-Kee
    • Applied Biological Chemistry
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    • v.42 no.2
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    • pp.116-122
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    • 1999
  • In order to characterize the property of $Ca^{2+}$ transport in plant cell, microsomes were prepared from the roots of tomato and microsomal $^{45}Ca^{2+}$ uptake was measured. When 1 mM vanadate, a selective inhibitor of P-type ATPases, 50 mM $NO_3^-$, a specific inhibitor of vacuolar $H^{+}-ATPase$, and both of these inhibitors were treated, the microsomal $^{45}Ca^{2+}$ uptakes were inhibited by 20, 33 and 47%, respectively. The inhibitory effects of these two inhibitors were investigated by using a protonophore, gramicidin. When the chemical gradient of $H^{+}$ was relieved by gramicidin, the uptake was decreased by 30%, implying the presence of $Ca^{2+}/H^+$ antiporter in the microsomal membrane. In the $^{45}Ca^{2+}$ uptake experiment, the effect of gramicidin was independent of vanadate-induced inhibition. However, when the activity of vacuolar $H^{+}-ATPase$ was inhibited by $NO_3^-$, the effect of gramicidin was severely decreased. Meanwhile, thapsigargin, a specific antagonist of ER/SR-type $Ca^{2+}-ATPase$, inhibited the microsomal $^{45}Ca^{2+}$ uptake and the maximum inhibitory effect was obtained at $10\;{\mu}M$. The effect of thapsigargin was blocked by $NO_3^-$ and gramicidin, but not by vanadate. These results imply that vanadate directly inhibits the activity of $Ca^{2+}-ATPase$; however, $NO_3^-$ and thapsigargin block the activity of $Ca^{2+}/H^+$ antiporter by inhibiting the vacuolar $H^{+}-ATPase$. In conclusion, the microsomal $^{45}Ca^{2+}$ uptakes are mediated by two major enzymes, $Ca^{2+}-ATPase$ and $Ca^{2+}/H^+$ antiporter in tomato root tissue.

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The effects of the standardized extracts of Ginkgo biloba on steroidogenesis pathways and aromatase activity in H295R human adrenocortical carcinoma cells

  • Kim, Mijie;Park, Yong Joo;Ahn, Huiyeon;Moon, Byeonghak;Chung, Kyu Hyuck;Oh, Seung Min
    • Environmental Analysis Health and Toxicology
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    • v.31
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    • pp.10.1-10.8
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    • 2016
  • Objectives Aromatase inhibitors that block estrogen synthesis are a proven first-line hormonal therapy for postmenopausal breast cancer. Although it is known that standardized extract of Ginkgo biloba (EGb761) induces anti-carcinogenic effects like the aromatase inhibitors, the effects of EGb761 on steroidogenesis have not been studied yet. Therefore, the effects of EGb761 on steroidogenesis and aromatase activity was studied using a H295R cell model, which was a good in vitro model to predict effects on human adrenal steroidogenesis. Methods Cortisol, aldosterone, testosterone, and $17{\beta}$-estradiol were evaluated in the H295R cells by competitive enzyme-linked immunospecific assay after exposure to EGb761. Real-time polymerase chain reaction were performed to evaluate effects on critical genes in steroid hormone production, specifically cytochrome P450 (CYP11/ 17/19/21) and the hydroxysteroid dehydrogenases ($3{\beta}$-HSD2 and $17{\beta}$-HSD1/4). Finally, aromatase activities were measured with a tritiated water-release assay and by western blotting analysis. Results H295R cells exposed to EGb761 (10 and $100{\mu}g/mL$) showed a significant decrease in $17{\beta}$-estradiol and testosterone, but no change in aldosterone or cortisol. Genes (CYP19 and $17{\beta}$-HSD1) related to the estrogen steroidogenesis were significantly decreased by EGb761. EGb761 treatment of H295R cells resulted in a significant decrease of aromatase activity as measured by the direct and indirect assays. The coding sequence/Exon PII of CYP19 gene transcript and protein level of CYP19 were significantly decreased by EGb761. Conclusions These results suggest that EGb761 could regulate steroidogenesis-related genes such as CYP19 and $17{\beta}$-HSD1, and lead to a decrease in $17{\beta}$-estradiol and testosterone. The present study provides good information on potential therapeutic effects of EGb761 on estrogen dependent breast cancer.

Effects of dietary enzyme cocktail on diarrhea and immune responses of weaned pigs

  • Kang, Joowon;Cho, Jeeyeon;Jang, Kibeom;Kim, Junsu;Kim, Sheena;Mun, Daye;Kim, Byeonghyeon;Kim, Younghwa;Park, Juncheol;Choe, Jeehwan;Song, Minho
    • Korean Journal of Agricultural Science
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    • v.44 no.4
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    • pp.525-530
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    • 2017
  • Weaning is the most stressful event for nursery pigs because they are moved from familiar to unfamiliar environments. In addition, weaned pigs have immature digestive and immune systems. This situation makes weaned pigs susceptible to diseases and makes the absorption of nutrients from diets difficult. A feed approach, such as dietary enzyme supplementation, can be considered a solution. This study investigated the effects of dietary enzyme cocktail on diarrhea and immune responses of weaned pigs. A total 36 weaned pigs ($5.92{\pm}0.48kg\;BW$; 28 d old) were randomly allotted to 2 dietary treatments (3 pigs/pen, 6 replicates/treatment) in a randomized complete block design. The dietary treatments were a typical diet based on corn and soybean meal (CON) and CON with 0.05% enzyme cocktail (Cocktail; combination of xylanase, ${\alpha}-amylase$, protease, ${\beta}-glucanase$, and pectinase). Pigs were fed their respective diets for 6 wk. Incidence of diarrhea, packed cell volume (PCV), white blood cells (WBC) count, and immunoglobulin content were measured. A significantly lower incidence of diarrhea (p < 0.05) was observed in the Cocktail group as compared with the CON group. The Cocktail group also showed a decreased PCV (p < 0.1) on d 3 after weaning than the CON group. However, no differences were observed for number of WBC and contents of immunoglobulin G, M, and A between the Cocktail and CON groups. Consequently, inclusion of an enzyme cocktail in diets for weaned pigs had a positive influence on gut health by reducing the incidence of diarrhea in the present study.

Absorbable Guided Bone Regeneration Membrane Fabricated from Dehydrothermal Treated Porcine Collagen (Dehydrothermal Treatment로 제작한 흡수성 콜라겐 골유도재생술 차단막)

  • Pang, Kang-Mi;Choung, Han-Wool;Kim, Sung-Po;Yang, Eun-Kyung;Kim, Ki-Ho;Kim, Soung-Min;Kim, Myung-Jin;Jahng, Jeong-Won;Lee, Jong-Ho
    • Maxillofacial Plastic and Reconstructive Surgery
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    • v.33 no.2
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    • pp.112-119
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    • 2011
  • Purpose: Collagen membranes are used extensively as bioabsorbable barriers in guided bone regeneration. However, collagen has different effects on tissue restoration depending on the type, structure, degree of cross-linking and chemical treatment. The purpose of this study was to evaluate the inflammatory reaction, bone formation, and degradation of dehydrothermal treated porcine type I atelocollagen (CollaGuide$^{(R)}$) compared to of the non-crosslinked porcine type I, III collagen (BioGide$^{(R)}$) and the glutaldehyde cross-linked bovine type I collagen (BioMend$^{(R)}$) in surgically created bone defects in rat mandible. Methods: Bone defect model was based upon 3 mm sized full-thickness transcortical bone defects in the mandibular ramus of Sprague-Dawley rats. The defects were covered bucolingually with CollaGuide$^{(R)}$, BioMend$^{(R)}$, or BioGide$^{(R)}$ (n=12). For control, the defects were not covered by any membrane. Lymphocyte, multinucleated giant cell infiltration, bone formation over the defect area and membrane absorption were evaluated at 4 weeks postimplantation. For comparison of the membrane effect over the bone augmentation, rats received a bone graft plus different covering of membrane. A $3{\times}4$ mm sized block graft was harvested from the mandibular angle and was laid and stabilized with a microscrew on the naturally existing curvature of mandibular inferior border. After 10 weeks postimplantation, same histologic analysis were done. Results: In the defect model at 4 weeks post-implantation, the amount of new bone formed in defects was similar for all types of membrane. Bio-Gide$^{(R)}$ membranes induced significantly greater inflammatory response and membrane resorption than other two membranes; characterized by lymphocytes and multinucleated giant cells. At 10 weeks postoperatively, all membranes were completely resorbed. Conclusion: Dehydrotheramal treated cross-linked collagen was safe and effective in guiding bone regeneration in alveolar ridge defects and bone augmentation in rats, similar to BioGide$^{(R)}$ and BioMend$^{(R)}$, thus, could be clinically useful.