Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
Volume 37 , Issue 12
Showing 1-22 articles out of 22 articles from the selected issue
Regular Articles
  • Jin Young Choi, Kyeheui Lee, Seung Min Lee, Sun Hong Yoo, Seong Gyu Hw ...
    2014 Volume 37 Issue 12 Pages 1853-1859
    Published: December 01, 2014
    Released: December 01, 2014
    [Advance publication] Released: October 09, 2014
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    Human placental extract (HPE) is a traditional medicine that has been used for the symptomatic treatment of liver disease without any verifying clinical evidence. This study aimed to evaluate the efficacy and safety of HPE in patients with alcoholic or nonalcoholic steatohepatitis (ASH or NASH). We designed this clinical trial as a multicenter, open-label, randomized, comparative noninferiority study to improve the reliability of analyses. The enrollment criteria were limited to ASH or NASH patients with serum alanine aminotransferase (ALT) 1.5-fold higher than the normal level. Patients in the control group were treated with a commercially available mixture of liver extract and flavin adenine dinucleotide (LE–FAD). Intention-to-treat (ITT) analysis was applied to 194 patients, and per-protocol (PP) analysis was available for 154 patients. The rate of primary goal achievement of treatment efficacy was arbitrarily defined as 20% or greater improvement in ALT level compared with the pretreatment level and did not differ significantly between the HPE and control groups [62.9% (44/70) vs. 48.8% (41/84); p=0.0772]. ITT and modified ITT analysis showed results similar to those of PP analysis. Adverse drug reactions (ADRs) of minimal to moderate degree occurred in 3.1% of patients. The ADR and treatment compliance rates were similar in both groups. In conclusion, the clinical value of HPE in the treatment of ASH and NASH is equivalent to that of LE–FAD.
  • Takahiro Hayashi, Saori Ikehata, Haruna Matsuzaki, Kimio Yasuda, Toshi ...
    2014 Volume 37 Issue 12 Pages 1860-1865
    Published: December 01, 2014
    Released: December 01, 2014
    [Advance publication] Released: October 02, 2014
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    Morphine, oxycodone, and fentanyl are commonly used to control cancer pain. Because these drugs have differences in receptor affinity or pharmacokinetic parameters, changing the opioid formulation may result in an unexpected outcome, depending on the patient’s condition. This study investigated whether low serum protein levels influence the effectiveness of opioid rotation by determining the impact of serum albumin levels on the analgesic effect before and after opioid rotation from morphine or oxycodone to fentanyl in cancer patients. The patients were classified into 3 groups according to their serum albumin levels before opioid rotation: group 1, <2.5 g/dL; group 2, from 2.5 g/dL to <3.0 g/dL; and group 3, ≥3.0 g/dL. There was no significant change in the percentage of patients with good pain control after rotation in group 1 or group 2; however, the percentage of patients with good pain control increased significantly in group 3. When the percentage of patients whose numerical rating scale scores increased, were unchanged, or decreased after rotation were compared, a significant difference in the percentage of those showing improvement was noted among the 3 groups and between groups 1 and 3. These findings suggest that monitoring serum albumin levels during fentanyl therapy is useful for pain management, and that the effectiveness of opioid rotation to fentanyl in patients with serum albumin levels of <2.5 g/dL should be carefully evaluated after rotation.
  • Hirokazu Wakuda, Shinya Uchida, Masahiko Ikeda, Masaki Tabuchi, Yasumi ...
    2014 Volume 37 Issue 12 Pages 1866-1871
    Published: December 01, 2014
    Released: December 01, 2014
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    Although hyperlipidemia, high blood pressure, and diabetes increase the risk of arteriosclerosis, it is not clear whether hyperuricemia increases the risk of arteriosclerosis or not. We examined the effects of uric acid and curative drugs for hyperuricemia on atherosclerosis-susceptible C57BL/6J apolipoprotein E-deficient (apoE−/−) mice. Male apoE−/− mice (age: 6 weeks) were fed a normal diet (normal diet group) or a uric acid-enriched diet. Mice fed the uric acid-enriched diet were divided into three groups and administered a drinking vehicle (high uric acid diet group), allopurinol (20 mg·kg−1·d−1), or benzbromarone (20 mg·kg−1·d−1) for 10 weeks. Serum uric acid concentrations were higher in the high uric acid diet group than in the normal diet group, and concentrations in the allopurinol and benzbromarone groups were lower than in the high uric acid diet group. Serum total cholesterol and triglyceride levels were lower in the allopurinol group than in the high uric acid diet group. Oxidative stress was lower in the benzbromarone group than in the high uric acid diet group. Atherosclerotic lesion areas were smaller in the allopurinol and benzbromarone groups than in the high uric acid diet group. Thus, hyperuricemia may not be an independent risk factor for arteriosclerosis; however, the administration of allopurinol and benzbromarone prevented the development of atherosclerosis in apoE−/− mice fed a uric acid-enriched diet. The anti-atherosclerotic effect was in part due to lower total cholesterol and oxidative stress in the serum. Other possible mechanisms underlying this effect should be investigated.
  • Masafumi Taki, Isao Tsuboi, Tomonori Harada, Michiko Naito, Hiroyuki H ...
    2014 Volume 37 Issue 12 Pages 1872-1881
    Published: December 01, 2014
    Released: December 01, 2014
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    Hematopoiesis in the bone marrow (BM) and spleen is controlled by stromal cells. Inflammation promotes myelopoiesis and simultaneously suppresses B lymphopoiesis. However, the role of the reciprocal regulation of myelopoiesis and B lymphopoiesis by stromal cells during inflammation is not fully understood. We investigated inflammation-induced alteration of hematopoietic regulation in lipopolysaccharide (LPS)-treated mice. C57BL/6 female mice were intravenously injected with a single, 5-µg dose of LPS, which induced a rapid decrease in the number of granulocyte-macrophage progenitors (colony-forming unit granulocyte-macrophage; CFU-GM) and B cell progenitors (CFU-preB) in BM. The CFU-GM count rapidly recovered, whereas the recovery of CFU-preB was delayed. LPS induced a marked increase in the number of CFU-GM but not in the number of CFU-preB in spleen. After LPS treatment, gene expression levels of positive regulators of myelopoiesis such as granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF) in BM and spleen were markedly upregulated whereas levels of positive regulators for B lymphopoiesis such as stromal cell-derived factor (SDF)-1, stem cell factor (SCF), and IL-7 remained unchanged. Meanwhile, the negative regulator of B lymphopoiesis tumor necrosis factor (TNF)-α was markedly up-regulated. The number of CFU-GM in S-phase in BM increased after LPS treatment, whereas the number of CFU-preB in S-phase decreased. These results suggest that LPS-activated stromal cells induce positive-dominant regulation of myelopoiesis and negative-dominant regulation of B lymphopoiesis, which facilitates emergency myelopoiesis during inflammation by suppressing B lymphopoiesis, thereby contributing to the host defense against infection.
  • Jian-ling Xia, Li-qun Wang, Li-li Wu, Qiao-bing Huang
    2014 Volume 37 Issue 12 Pages 1882-1890
    Published: December 01, 2014
    Released: December 01, 2014
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    Doxycycline hyclate (DOX-h) attenuates inflammatory conditions independent of its antimicrobial effect. This study aimed to observe the effects of DOX-h on lipopolysaccharide (LPS)-induced endothelial barrier dysfunction. The endothelial monolayer permeability of human umbilical vein endothelial cells (HUVECs) was monitored by transendothelial electrical resistance (TEER). The phosphorylation of mitogen-activated protein kinases (MAPKs) and the arrangement of F-actin were detected. The results showed that both pretreatment and simultaneous treatment with DOX-h markedly attenuated the LPS-induced reduction in TEER and the disorganization of F-actin on HUVECs in a dose- and time-dependent manner. LPS mediated the phosphorylation of all three MAPKs (p38, extracellular signal-regulated kinase (ERK)1/2, and c-Jun N-terminal kinase (JNK)), but DOX-h was only able to inhibit the LPS-induced phosphorylation of p38 and JNK. The data further suggested that DOX-h alleviated LPS-evoked TEER reduction and F-actin redistribution by inhibiting the phosphorylation of p38 and its downstream target, heat shock protein (HSP)27. Thus, DOX-h attenuates LPS-induced endothelial barrier dysfunction via inhibition of the p38 MAPK-HSP27-F-actin pathway.
  • Chenghong Sun, Xinqiang Lai, Xiuyan Huang, Yaoying Zeng
    2014 Volume 37 Issue 12 Pages 1891-1898
    Published: December 01, 2014
    Released: December 01, 2014
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    Ginsenoside Rg1 (Rg1), one of the active ingredients in Panax ginseng, has been known to regulate many cellular processes. The purpose of this study was to investigate the protective effects of Rg1 on apoptosis in mouse cultured astrocytes in vitro and a mouse model of cerebral ischemia and reperfusion in vivo. The cell apoptosis was measured by fluorescence microplate reader and xCELLigence system and the Ca2+ overload was recorded by confocal microscopy. The mitochondrial membrane potential and reactive oxygen species (ROS) were determined by flow cytometry. BALB/c mice were subjected to transient middle cerebral artery occlusion (MCAO) and randomly divided into four groups: Sham (sham-operated +0.9% saline), MCAO (MCAO+0.9% saline), Rg1-L (MCAO+Rg1 20 mg/kg) and Rg1-H (MCAO+Rg1 40 mg/kg). Neurological deficit scores, brain water content and infarct volume were evaluated at 24 h after reperfusion. The results showed that Rg1 significantly attenuated H2O2-induced apoptosis in astrocytes. Rg1 efficiently inhibited intracellular Ca2+ overload, loss of mitochondrial membrane potential, and ROS production in astrocytes. In vivo study, it was also observed that Rg1 markedly reduced the neurological deficit scores, brain edema, and infarct volume in the model mice. These results suggest that Rg1 possesses significant neuroprotective effects, which might be related to the prevention of astrocytes from apoptosis.
  • Jong-Sik Jin, Mutsumi Touyama, Shin Yamada, Takashi Yamazaki, Yoshimi ...
    2014 Volume 37 Issue 12 Pages 1899-1906
    Published: December 01, 2014
    Released: December 01, 2014
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    The human intestinal microbiota (HIM) settles from birth and continues to change phenotype by some factors (e.g. host’s diet) throughout life. However, the effect of extreme life environment on human HIM composition is not well known. To understand HIM fluctuation under extreme life environment in humans, fecal samples were collected from six Japanese men on a long Antarctic expedition. They explored Antarctica for 3 months and collected their fecal samples at once-monthly intervals. Using terminal restriction fragment length polymorphism (T-RFLP) and real time polymerase chain reaction (PCR) analysis, the composition of HIM in six subjects was investigated. Three subjects presented restoration of HIM after the expedition compared versus before and during the expedition. Two thirds samples collected during the expedition belonged to the same cluster in dendrogram. However, all through the expedition, T-RFLP patterns showed interindividual variability. Especially, Bifidobacterium spp. showed a tendency to decrease during and restore after the expedition. A reduction of Bifidobacterium spp. was observed in five subjects the first 1 month of the expedition. Bacteroides thetaiotaomicron, which is thought to proliferate during emotional stress, significantly decreased in one subject, indicating that other factors in addition to emotional stress may affect the composition of HIM in this study. These findings could be helpful to understand the effect of extreme life environment on HIM.
  • Hitoshi Matsui, Tomohiro Noguchi, Kaoru Takakusaki, Makoto Kashiwayana ...
    2014 Volume 37 Issue 12 Pages 1907-1912
    Published: December 01, 2014
    Released: December 01, 2014
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    TRPV2, a member of the transient receptor potential family, has been isolated as a capsaicin-receptor homolog and is thought to respond to noxious heat. Here we show that TRPV2 mRNA is predominantly expressed in the subpopulation of olfactory sensory neurons (OSNs). We carried out histochemical analyses of TRPV2 and insulin-like growth factor-I receptor (IGF-IR) using in situ hybridization and immunofluorescence in the adult olfactory system. In olfactory mucosa, intensive TRPV2 immunostaining was observed at the olfactory axon bundles but not at the soma. TRPV2-positive labeling was preferentially found in the olfactory nerve layer in the olfactory bulb (OB). Furthermore, we demonstrated that a positive signal for IGF-IR mRNA was detected in OSNs expressing TRPV2 mRNA. In embryonic stages, TRPV2 immunoreactivity was observed on axon bundles of developing OSNs in the nasal region starting from 12.5 d of gestation and through fetal development. Observations in this study suggest that TRPV2 coupled with IGF-IR localizes to growing olfactory axons in the OSNs.
  • Tomohiko Kotaka, Shoji Kimura, Makoto Kashiwayanagi, Jun Iwamoto
    2014 Volume 37 Issue 12 Pages 1913-1918
    Published: December 01, 2014
    Released: December 01, 2014
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    Application of camphor to the skin has been empirically thought to improve blood circulation. However, camphor’s effects on blood circulation to the skin and on thermal sensation have not been well elucidated. In this study, we examined its effects on the quality of sensation as well as on skin and muscle blood flow in human. Nine adults (average age 37±9.4 years) participated in the study. Petroleum jelly containing 5%, 10%, 20% camphor, or 2% menthol was separately applied to the skin on the medial side of one forearm of each subject. Just after the application, camphor at each concentration induced a cold sensation in a dose-dependent manner. Within 10 min, each subject reported that the cold sensation had faded, after which it was replaced by a warm sensation. As reported previously, a cold sensation was induced by application of 2% menthol, but the subjects did not adapt to that sensation. In addition, menthol did not induce a warm sensation at all. Application of menthol has been shown to increase blood flow in the skin. Finally, we measured blood flow in skin and muscle after the application of camphor or menthol. Application of camphor or menthol separately induced increases in local blood flow in the skin and muscle. The present results indicate that camphor induces both cold and warm sensations and improves blood circulation.
  • Binbin Li, Hao Liu, Shengnan Jia
    2014 Volume 37 Issue 12 Pages 1919-1925
    Published: December 01, 2014
    Released: December 01, 2014
    [Advance publication] Released: October 09, 2014
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    We investigated the effect of puerarin on bone mass and marrow adiposity in ovariectomy (OVX)-induced osteoporosis. The rats were divided into four groups: control; OVX; OVX+estradiol (OVX-E); and OVX+puerarin treatment (OVX-GE). In vivo, bone mineral density (BMD) and histomorphometry were measured under microCT. The mechanical properties of tibia were obtained in 3-point bending test. Plasma osteocalcin and adiponectin were determined using enzyme-linked immunosorbent assay (ELISA). Alkaline phosphatase (ALP) were measured using biochemical methods. In vitro, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Oil Red O staining were used to compare osteoblast proliferation and adipocyte differentiation, respectively. Osteocalcin and adiponectin in culture supernatants were determined using ELISA. The results showed that puerarin significantly enhanced bone volume density and trabecular number compared with OVX and OVX-E groups (p<0.05, p<0.05, respectively). Puerarin increased energy to ultimate load, plasma osteocalcin and ALP (p<0.01). However, BMD in OVX-GE group was less than that in control (p<0.01) and OVX-E groups (p<0.05). The culture supernatants from OVX-GE group showed increased osteocalcin compared with those from OVX (p<0.01) and OVX-E groups (p<0.05). Puerarin lowered adiponectin in culture supernatant compared with supernatant from OVX group and inhibited the increase in adipocytes caused by OVX (p<0.01). However, the amount of lipids did not differ between OVX-GE and OVX groups. These findings suggest that puerarin likely enhances bone formation by stimulating the proliferation and differentiation of osteoblasts while slightly inhibiting the adipotic differentiation.
  • Golam Kibria, Hiroto Hatakeyama, Kosuke Akiyama, Kyoko Hida, Hideyoshi ...
    2014 Volume 37 Issue 12 Pages 1926-1935
    Published: December 01, 2014
    Released: December 01, 2014
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    Multi-drug resistance (MDR) of cancers to chemotherapy including doxorubicin (DOX) is mediated by several factors. To design an effective therapy for the treatment of chemotherapy-resistant cancers, it is essential to explore the elements responsible for mediating MDR. However, exploring these factors in detail in a wide range of tumor types is challenging as several critical analytical steps are involved. Here, we demonstrated the way of exploring the factors mediating MDR in the tumor types without performing the analysis at the molecular level of cells. The sensitivities of 15 different types of cancer cells to DOX were evaluated, and the role of P-glycoprotein (P-gp), one of the major efflux-pumps, was explored. A correlation curve was developed between the intracellular amounts of DOX and the sensitivities of cells, and, based on this correlation, the cells were classified in response to the involvement of P-gp that mediates MDR. P-gp plays an active role in mediating MDR of cancer cells where a correlation between the sensitivities of cells and the accumulated DOX exists. In contrast, in cells that show a resistance to DOX but whose sensitivities are independent of the amount of accumulated drug, it was reasonably presumed that mechanisms other than P-gp are likely to be involved in mediating MDR. Based on the correlation between the availability of a drug and cell sensitivity, it would be reasonable to explore the factors governing cancer MDR, which is essential in designing an effective therapeutic approach for treating chemotherapy-resistant cancers using chemotherapeutic drugs.
  • Worranan Rangsimawong, Praneet Opanasopit, Theerasak Rojanarata, Tanas ...
    2014 Volume 37 Issue 12 Pages 1936-1943
    Published: December 01, 2014
    Released: December 01, 2014
    [Advance publication] Released: October 08, 2014
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    We investigated the effect of PEGylated liposomes (PLs) containing a terpene on the penetration of a hydrophilic compound through porcine skin. PLs composed of N-(carbonyl-methoxypolyethyleneglycol-2000)–1,2-distearoyl-sn-glycero-3-phosphoethanolamine (PEG2000–DSPE), the sodium salt of PEG2000–DSPE, phosphatidylcholine (PC), cholesterol (Chol), Tween 20, and d-limonene were prepared as carriers for fluorescein sodium (NaFI). The physicochemical characteristics of PLs and their effects on in vitro skin penetration were evaluated. Tape stripping was used to evaluate NaFI deposition in skin layers, and confocal laser scanning microscopy (CLSM) was used to investigate the depth of skin penetration and the pathways used by NaFI-loaded vesicles. PLs containing d-limonene were smaller and conferred higher entrapment efficiency and skin penetration on NaFI than did PLs and conventional liposomes (CLs). The deposition of NaFI from PLs with d-limonene was greater in epidermis and dermis (6.10±1.74 µg) than stratum corneum (2.06±0.47 µg). CLSM images revealed that NaFI penetrated into the deepest skin layer with maximum fluorescence intensity. NaFI penetrated deeper (180 µm) in follicular than nonfollicular regions (145 µm), suggesting a transfollicular pathway predominates in skin penetration by NaFI-loaded PLs. In conclusion, grafting PEG onto ultra-deformable liposomes may enhance transdermal NaFI delivery and may be used as a carrier to prolong liposome circulation time.
  • Sayaka Kazami, Masak Takaine, Hiroyasu Itoh, Takaaki Kubota, Jun’ichi ...
    2014 Volume 37 Issue 12 Pages 1944-1947
    Published: December 01, 2014
    Released: December 01, 2014
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    Iejimalides (IEJLs) A–D are 24-membered macrolides isolated from a tunicate Eudistoma cf. rigida, and exhibit potent cytotoxicity in vitro and antitumor activity in vivo. We previously reported that the molecular target of IEJL-A and -B was the vacuolar-type H+-ATPases (V-ATPases). However IEJL-C and -D, which are sulfonylated IEJL-A and -B, respectively, show more potent antitumor activity, and their molecular targets remain to be discovered. Here, we report that IEJL-C is also a potent V-ATPase inhibitor by binding in a site similar to the bafilomycin-binding site. Two-hour treatment with IEJL-C resulted in the complete disappearance of acidic organelles in HeLa cells. Interestingly, after 24-h treatment, small actin aggregates were observed instead of actin fibers. The same actin reorganization was also observed in cells treated with another V-ATPase inhibitor, bafilomycin A1. Because IEJLs did not inhibit actin polymerization in vitro, these results suggest that the primary target of IEJL-C, as well as IEJL-A and -B, is V-ATPase, and actin reorganizations are probably caused by the disruption of pH homeostasis via V-ATPase inhibition.
  • Sureewan Duangjit, Leilah Maria Mehr, Mont Kumpugdee-Vollrath, Tanasai ...
    2014 Volume 37 Issue 12 Pages 1948-1957
    Published: December 01, 2014
    Released: December 01, 2014
    [Advance publication] Released: October 03, 2014
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    Microemulsions (ME) have gained attention as an alternative pharmaceutical formulation for transdermal delivery systems. However, the complicated relationships between various ME compositions (causal factors) and their characteristics (response variable) have not been fully comprehended. To overcome this problem, the design and development of ME for transdermal delivery was performed in our study using Design Expert® Software. The model formulations of ME were prepared according to the ME region obtained from pseudo-ternary phase diagrams using the simplex lattice design as an optimization technique. In this study, ketoprofen-loaded ME composed of oleic acid, Cremophor® RH40, ethanol and water were prepared, and their characteristics (e.g., size, charge, conductivity, pH, viscosity, drug content, loading capacity and skin permeation flux) were evaluated. The ME having an appropriate skin permeation flux was used as the basis for optimization. The skin permeation flux of the experimental ME was very close to the flux predicted by Design Expert® Software and was significantly greater than that for the commercial product. Possible mechanisms for the enhancement of the skin permeation of the ME were also investigated using Fourier transform infrared (FT-IR) spectroscopy and X-ray diffraction (XRD). This finding provided an understanding of the relationship between the causal factors and response variables, as shown in the response surfaces. Moreover, these results indicated that the simple lattice design was beneficial for the pharmaceutical development of ME for transdermal delivery.
  • Yosuke Kamatsuka, Manami Fukagawa, Takahiro Furuta, Akihiro Ohishi, Ke ...
    2014 Volume 37 Issue 12 Pages 1958-1962
    Published: December 01, 2014
    Released: December 01, 2014
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    We previously demonstrated that the P2X7 receptor (P2X7R), a purinergic receptor, expressed by mouse cultured cortical astrocytes is constitutively activated without any exogenous stimulus, differing from the case of neurons. It is well known that astrocytic morphology differs between in vitro and in vivo situations, implying different functionalities. Brain acute slices are widely accepted as an in vitro experimental system that reflects in vivo cell conditions better than in vitro cell culture ones. We examined whether astrocytic P2X7Rs exhibited constitutive activation in mouse cortical slices. In acute cortical slices, P2X7R-immunoreactivity was detected in both glial fibrillary acidic protein-immunopositive astrocytes and microtubule-associated protein 2-immunopositive neurons. Astrocytic, but not neuronal, spontaneous uptake of propidium iodide, an indicator of P2X7R channel/pore activity, was inhibited by representative antagonists of P2X7R, but they had no effect on the uptake by astrocytes in membrane-permeabilized fixed slices. These findings indicate that astrocytes, but not neurons, in acute cortical slices exhibit constitutive activation of P2X7Rs under non-stimulated resting conditions as in the case of cell culture systems.
  • Jae-Suk Choi, Eun Jin Cheon, Tae-Uk Kim, Woi-Sook Moon, Joo-Wan Kim, M ...
    2014 Volume 37 Issue 12 Pages 1963-1970
    Published: December 01, 2014
    Released: December 01, 2014
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    Rice bran oil extracted by supercritical CO2 extraction (RB-SCE) reportedly exhibits pharmacological activities such as antioxidant and in vivo hair growth-inducing effects. Such activities raise the possibility of the development of novel hair growth-inducing agents using RB-SCE. The aim of this study was to investigate the potential genotoxic effects of RB-SCE in three short-term mutagenicity assays (bacterial reverse mutation assay, in vitro mammalian chromosomal aberration test, and in vivo micronucleus assay). RB-SCE showed no genotoxicity in the bacterial reverse mutation assay up to 5000 mg/plate and in the in vivo micronucleus test up to 600 mg/kg body weight. However, at 120 µg/mL with S9 mix and 200 µg/mL without S9 mix RB-SCE showed significantly different genotoxicity than the negative control in the in vitro chromosome aberration test. The induction of chromosomal aberrations under the present conditions may have no biological significance. We have herein demonstrated that RB-SCE can be regarded as a non-genotoxic material based on the available in vivo and in vitro results.
Notes
  • Fumi Karino, Nobuhiro Nishimura, Noriyuki Ishihara, Hidehiko Moriyama, ...
    2014 Volume 37 Issue 12 Pages 1971-1976
    Published: December 01, 2014
    Released: December 01, 2014
    [Advance publication] Released: October 08, 2014
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    This study aimed to clarify the efficacy, safety, and pharmacokinetics of piperacillin–tazobactam (PIPC–TAZ) in late elderly Japanese patients. This is the first antimicrobial pilot study in late elderly patients with nursing and healthcare associated pneumonia. After PIPC–TAZ administration, PIPC concentrations in plasma were measured chromatographically and the pharmacokinetic parameters were estimated. Efficacy, safety, and bacteriological evaluations were also carried out. The mean age was 85.0 years old and most of the patients were late elderly. Chest X-rays, body temperature, white blood cell count, and C reactive protein all improved significantly, and a high efficacy ratio of 90.9% was observed. Serious nephrotoxicity was observed in 4 cases (18.2%) after administration of PIPC–TAZ. Creatinine clearance (mean±S.D.) measured before PIPC–TAZ therapy was significantly lower in the nephrotoxicity group (32.5±4.4 mL/min) than in the non-nephrotoxicity group (46.1±16.7 mL/min), although the ages were not different between the 2 groups. In the pharmacokinetic parameters for PIPC, total clearance was slightly lower in the nephrotoxicity group than in the non-nephrotoxicity group. However, no significant difference was observed in plasma PIPC levels between the 2 groups. In patients with renal impairment, especially with a creatinine clearance of <40 mL/min, renal impairment was found to be an influencing factor for severe nephrotoxicity following PIPC–TAZ administration. In conclusion, the results suggest that physicians should pay close attention in order to avoid possible toxicity, and that deliberate administration planning and careful follow-up are required in late elderly patients with comprised organ dysfunction.
  • Daiying Zhou, Ning Ding, Suqing Zhao, Dongli Li, Jeremiah Van Doren, Y ...
    2014 Volume 37 Issue 12 Pages 1977-1981
    Published: December 01, 2014
    Released: December 01, 2014
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    Indanones are very useful molecules as starting building blocks for the synthesis of biologically active compounds. A series of novel curcumin-related compounds containing indan-2-one were synthesized and screened for anticancer activities. The structures were confirmed by spectral data (IR, NMR, and Mass). Inhibitory effects of these compounds on the growth of prostate cancer PC-3 cells, pancreatic cancer BxPC-3 cells, colon cancer HT-29 cells, lung cancer H1299 cells and non-tumorigenic human prostate epithelial RWPE-1 cells were determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The IC50 for compound IND-4 was lower than 1 µM in the four cancer cell lines. The present study indicates that IND-4 may have useful effects on human cancer cells.
  • Kota Makino, Runa Omachi, Hiroka Suzuki, Koji Tomobe, Tsuyoshi Kawashi ...
    2014 Volume 37 Issue 12 Pages 1982-1985
    Published: December 01, 2014
    Released: December 01, 2014
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    The bursa of Fabricius (BF) is a unique primary lymphoid organ, and among vertebrates is unique to birds. Despite its importance to the immune systems of various avian species, little is known of the molecular mechanisms underlying early BF development. In the present study, we demonstrated that apoptosis occurs during early development of the bursa of Fabricius in chicken embryos. Initial histological analyses of BF morphogenesis in chicken embryos led to the hypothesis that formation of the bursal lumen correlates with fusion of vacuoles, which appear in the cloacal epithelial bud. Using terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL) analysis and immunostaining with an anti-cleaved (activated) caspase-3 antibody, we detected multiple apoptotic cells around these vacuoles. In further experiments, treatments with a caspase inhibitor caused abnormal bursal lumen in vivo. The present data indicate that apoptosis may play important roles in BF morphogenesis in chickens.
  • Akane Morita, Tsutomu Nakahara, Hiroko Ushikubo, Asami Mori, Kenji Sak ...
    2014 Volume 37 Issue 12 Pages 1986-1989
    Published: December 01, 2014
    Released: December 01, 2014
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    We have previously reported that treatment of newborn mice with KRN633, a vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, delayed retinal vascularization leading to abnormal retinal vascular growth and patterns. To determine whether similar abnormalities are observed in newborn mice treated with other VEGF receptor tyrosine kinase inhibitors, we administered axitinib to mice on the day of birth and on the following day. When compared with control pups, a significant delay in retinal vascularization was observed in pups treated with axitinib (5 mg/kg). Axitinib-treated pups had a very dense capillary network on postnatal day (P) 6 and fewer central arteries and veins on P8 and P12. Central veins, but not arteries, were significantly enlarged on P8. These abnormalities were similar to those observed in KRN633-treated pups and probably represent a common phenotype induced by short-term treatment with VEGF receptor inhibitors in newborn mice. Therefore, mice treated postnatally with VEGFR inhibitors could serve as an animal model for studying the mechanisms of retinal vascular formation and patterning.
  • Hiroki Yamamoto, Yasushi Habu, Ikuko Yano, Junko Ozaki, Yoshihiko Kimu ...
    2014 Volume 37 Issue 12 Pages 1990-1993
    Published: December 01, 2014
    Released: December 01, 2014
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    The package insert of the antithrombotic agent warfarin warns users of its interaction with azole antifungals. However, information on the frequency or degree of these interactions is limited. In particular, the time to onset of azole-mediated prothrombin time prolongation, expressed as the international normalized ratio (INR), is poorly characterized. Therefore, we retrospectively examined the INR in 29 patients administered warfarin with fluconazole (FLCZ), voriconazole (VRCZ), or itraconazole (ITCZ). INRs in 18 patients taking FLCZ and in 5 patients taking VRCZ significantly increased from 1.40 to 2.94 and from 1.95 to 2.89, respectively. The warfarin sensitivity index (WSI), calculated as INR/daily warfarin dose, also significantly increased from 1.06 to 1.89 with FLCZ and showed an upward trend from 1.13 to 2.23 with VRCZ. ITCZ had no influence on the INR or WSI in 6 patients. The INRs observed when warfarin was coadministered with azoles (Y) correlated significantly with those observed in the absence of azoles (X): FLCZ, Y=4.94X−3.96, r2=0.80; VRCZ, Y=2.13X−1.27, r2=0.93. Moreover, in all 8 patients with closely monitored INRs, the WSI increased within 1 week of FLCZ or VRCZ coadministration. In conclusion, FLCZ and VRCZ augmented the anticoagulant activity of warfarin. The INR should be closely monitored within 1 week of initiating FLCZ or VRCZ coadministration with warfarin, especially in patients with high INRs.
  • Fang-Yi Zhang, Feng-Jian Yang, Jiu-Lin Yang, Liang Wang, Yan Zhang
    2014 Volume 37 Issue 12 Pages 1994-1997
    Published: December 01, 2014
    Released: December 01, 2014
    [Advance publication] Released: October 01, 2014
    JOURNALS FREE ACCESS FULL-TEXT HTML
    The skeletal renin–angiotensin system (RAS) is involved in the progression of osteoporosis and the active peptide within the RAS, angiotensin II (ANG II), has deleterious effects on bones. This study was performed to investigate whether suppression of the rate-limiting step of the RAS cascade by the renin inhibitor aliskiren has a benefit on trabecular bone in osteoporotic mice. A postmenopausal osteoporosis model was induced by bilateral ovariectomy. The ovariectomized (OVX) mice were treated with a low (5 mg/kg) or high (25 mg/kg) dose of aliskiren for 6 weeks. Micro-computed tomography was performed to detect trabecular bone parameters of lumbar vertebra and to obtain 3-dimensional (3D) images. Treatment with aliskiren markedly increased bone volume over total volume (p<0.05), trabecular bone number (p<0.05), connectivity density (p<0.05), and bone mineral density (p<0.05) and reduced trabecular bone separation (p<0.05) compared to vehicle-treated OVX mice. Similarly, the 3D images were consistent with the quantitative data that showed aliskiren could markedly reverse the ovariectomy-induced pathological changes of trabecular bone. Thus, this study indicated that the treatment of estrogen-deficient mice with aliskiren could markedly increase bone mass and improve trabecular bone structure, suggesting its potential application in treating postmenopausal osteoporosis.
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