Publications by authors named "Hyoung-Chin Kim"

87 Publications

Two base pair deletion in IL2 receptor γ gene in NOD/SCID mice induces a highly severe immunodeficiency.

Lab Anim Res 2020 14;36:27. Epub 2020 Aug 14.

Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141 Korea.

Genome editing has recently emerged as a powerful tool for generating mutant mice. Small deletions of nucleotides in the target genes are frequently found in CRISPR/Cas9 mediated mutant mice. However, there are very few reports analyzing the phenotypes in small deleted mutant mice generated by CRISPR/Cas9. In this study, we generated a mutant by microinjecting sgRNAs targeting the IL2 receptor γ gene and Cas9 protein, into the cytoplasm of IVF-derived NOD.CB17/Prkdcscid/JKrb (NOD/SCID) mice embryos, and further investigated whether a 2 bp deletion of the IL2 receptor γ gene affects severe deficiency of immune cells as seen in NOD/LtSz-scid IL2 receptor γ (NSG) mice. Our results show that the thymus weight of mutant mice is significantly less than that of NOD/SCID mice, whereas the spleen weight was marginally less. T and B cells in the mutant mice were severely deficient, and NK cells were almost absent. In addition, tumor growth was exceedingly increased in the mutant mice transplanted with HepG2, Raji and A549 cells, but not in nude and NOD/SCID mice. These results suggest that the NOD/SCID mice with deletion of 2 bp in the IL2 receptor γ gene shows same phenotype as NSG mice. Taken together, our data indicates that small deletions by genome editing is sufficient to generate null mutant mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s42826-020-00048-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427935PMC
August 2020

Importin-11 is Essential for Normal Embryonic Development in Mice.

Int J Med Sci 2020 12;17(6):815-823. Epub 2020 Mar 12.

Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Yeonjudanji-ro 30, Chungbuk 28116, Korea.

Importin-11 (Ipo11) is a novel member of the human importin family of transport receptors (karyopherins), which are known to mediate the nucleocytoplasmic transport of protein and RNA cargos. Despite its role in the transport of protein, we found that knockout of Ipo11 nuclear import factor affects normal embryonic development and govern embryo-lethal phenotypes in mice. In this study, we for the first time produced a mouse line containing null mutation in gene utilized by gene trapping. The embryos showed an embryonic lethal phenotype. The embryos showed a reduced size at embryonic day 10.5 (E10.5) when compared with or embryos and died by E11.5. Whereas mice were healthy and fertile, and there was no detectable changes in embryonic lethality and phenotype when reviewed. In the X-gal staining with the or embryos, strong X-gal staining positivity was detected systematically in the whole mount embryos at E10.5, although almost no X-gal positivity was detected at E9.5, indicating that the embryos die soon after the process of Ipo11 expression started. These results indicate that Ipo11 is essential for the normal embryonic development in mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/ijms.40697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085267PMC
December 2020

Critical Roles of E2F3 in Growth and Musculo-skeletal Phenotype in Mice.

Int J Med Sci 2019 21;16(12):1557-1563. Epub 2019 Oct 21.

Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Yeonjudanji-ro 30, Chungbuk 28116, Korea.

E2F3, a member of the E2F family, plays a critical role in cell cycle and proliferation by targeting downstream, retinoblastoma (RB) a tumor suppressor family protein. The purpose of this study, was to investigate the role and function of E2F3 . We examined phenotypic abnormalities, by deletion of the gene in mice. Complete ablation of the E2F3 was fully penetrant, in the pure C57BL/6N background. The mouse embryo developed normally without fatal disorder. However, they exhibited reduced body weight, growth retardation, skeletal imperfection, and poor grip strength ability. Findings suggest that E2F3 has a pivotal role in muscle and bone development, and affect normal mouse growth.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/ijms.39068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6909802PMC
April 2020

Cisplatin-induced ototoxicity involves interaction of PRMT3 and cannabinoid system.

Arch Toxicol 2019 08 29;93(8):2335-2346. Epub 2019 Jun 29.

College of Veterinary Medicine (BK21 Plus Project Team), Chonnam National University, Gwangju, 61186, Republic of Korea.

This study investigated whether protein arginine methyltransferase (PRMT) and the cannabinoid system are involved in cisplatin-induced ototoxicity. Cisplatin increased cytosine-cytosine-adenosine-adenosine-thymidine-enhancer-binding protein homologous protein expression. This effect is indicative of an increase in endoplasmic reticulum (ER) stress, and apoptosis signaling including cleavage of caspase-3, caspase-9, poly-adenosine diphosphate-ribose polymerase, and phospho-p53, as well as expression of PRMT3, PRMT4 and fatty acid amide hydrolase (FAAH)1 in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells. In addition, overexpression of PRMT3 or PRMT4 increased the expression of FAAH1 expression, apoptosis, and ER stress signaling in HEI-OC1 cells, whereas PRMT3 or PRMT4 knockdown had the opposite effect. Furthermore, overexpression of FAAH1 increased apoptosis and ER stress, but expression of the PRMTs was unchanged. In addition, a cannabinoid 1 receptor agonist and FAAH inhibitor attenuated apoptosis and ER stress, while cisplatin increased the binding of PRMT3 with FAAH1. In the in vivo experiments, cisplatin was injected intraperitoneally at 6 mg/kg/day into C57BL/6 mice, and 7 days later, this study confirmed that PRMT3 and PRMT4 were upregulated in the organ of Corti of the mice. These results indicate that cisplatin-induced ototoxicity was correlated with PRMT3, PRMT4 and the cannabinoid system, and PRMT3 binding with FAAH1 was increased by cisplatin in HEI-OC1 cells. Therefore, this study suggests that PRMT3 mediates cisplatin-induced ototoxicity via interaction with FAAH1 in vitro and in vivo.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00204-019-02507-5DOI Listing
August 2019

Nonclinical toxicology studies with sodium taurodeoxycholate: acute and subacute toxicity in dogs.

Drug Chem Toxicol 2021 Mar 19;44(2):161-169. Epub 2019 Jun 19.

Graduate School of Translational Medicine, College of Medicine, Seoul National University, Seoul, Republic of Korea.

Sodium taurodeoxycholate (TDCA) has been investigated for various inflammatory disorders such as sepsis. We recently evaluated nonclinical safety profile of TDCA using rats infused intravenously. As a series of preclinical safety investigations, we further conducted toxicity studies with TDCA delivered to dogs intravenous administration under Good Laboratory Practice regulation in this study. In dose range-finding study (dose escalation study), dogs given with TDCA at a dose of 150 mg/kg showed marked changes in clinical signs, hematology, and serum biochemistry. And biochemical markers of liver damage and local skin lesions were observed following intravenous infusion of 100 mg/kg TDCA, suggesting that 100 mg/kg was chosen as the highest dose of TDCA for 4-week repeated-dose toxicity study using dogs. Despite no treatment-related significant changes in body weight, food consumption, ophthalmoscopy, and urinalysis, skin lesions were observed at the injection site of animals administered with higher than 50 mg/kg of TDCA along with biochemical and histopathological changes associated with liver injury. However, most of off-target effects were found to be reversible since these were recovered after stopping TDCA infusion. These findings indicate that the no-observed-adverse-effect-level (NOAEL) for TDCA in dogs was considered to be 5 mg/kg/d. Taken together, our results provide important toxicological profiles regarding the safe dose of TDCA for drug development or clinical application.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/01480545.2019.1566352DOI Listing
March 2021

Melatonin attenuates cisplatin-induced acute kidney injury in rats via induction of anti-aging protein, Klotho.

Food Chem Toxicol 2019 Jul 27;129:201-210. Epub 2019 Apr 27.

College of Veterinary Medicine (BK21 Plus Project Team), Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju, 61186, Republic of Korea. Electronic address:

This study investigated the protective effects of melatonin (MT) against cisplatin (CP)-induced acute kidney injury in rats as well as its possible mechanism of action associated with anti-aging protein Klotho. The following four experimental groups were evaluated: vehicle control, CP (7 mg/kg), CP&MT20 (20 mg/kg/day), and CP&MT40 (40 mg/kg/day). The concomitant administration of MT significantly ameliorated CP-induced acute kidney injury in rats, as evidenced by increased kidney weight, increased serum levels of blood urea nitrogen and creatinine, and increased incidence of histopathological alterations with renal tubular cell apoptosis. In addition, MT treatment protected kidney tissue against oxidative damages and significantly upregulated the expression level of Klotho decreased by CP treatment, resulting in reduced phosphorylation of protein kinase B (AKT) and forkhead box O (FOXO) as well as reduced expression levels of B-cell lymphoma 2-associated X protein (Bax) and caspase-3. MT not only partially regulated oxidative stress via AKT/FOXO signaling, but also reduced apoptosis caused by CP by inhibiting the Bax/caspase-3 pathway. Our results indicated that MT could prevent acute kidney injury induced by CP in rats, presumably through upregulating the expression of Klotho, resulting in elevated anti-oxidant and anti-apoptotic properties.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.fct.2019.04.049DOI Listing
July 2019

Preclinical study of safety of Dendropanax morbifera Leveille leaf extract: General and genetic toxicology.

J Ethnopharmacol 2019 Jun 13;238:111874. Epub 2019 Apr 13.

Department of Experimental Animal Research, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea; Biomedical Center for Animal Resource and Development, Seoul National University College of Medicine, Seoul, Republic of Korea; Graduate School of Translational Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; Designed Animal and Transplantation Research Institute, Institute of GreenBio Science Technology, Seoul National University, Pyeongchang-gun, Gangwon-do, Republic of Korea. Electronic address:

Ethnopharmacology Relevance: Dendropanax morbifera Leveille (DM) has been used in traditional medicines for infectious and skin diseases, and dysmenorrhea. It exhibits a diverse therapeutic potential including anti-cancer, anti-thrombotic, anti-diabetic, anti-oxidant, and anti-inflammatory activities.

Aim Of The Study: Despite promising health benefits of DM, knowledge of its potential adverse effects is very limited. The current study focused on the investigation of subchronic toxicity and genotoxicity of extract obtained from DM according to the test guidelines published by the Organization for Economic Cooperation and Development.

Materials And Methods: We conducted a toxicological evaluation of DM extracts using 14-day repeated-dose toxicity study and 13-week repeated-dose toxicity study in Sprague-Dawley rats administered orally at doses of 500, 1000, or 2000 mg/kg/day. The clastogenicity of DM extract was also evaluated by in vitro chromosome aberration assay and in vivo micronucleus assay.

Results: Assessment of subchronic toxicity of DM extract by oral administration in rats revealed unremarkable treatment-related findings with respect to food/water consumption, body weight, mortality, urinalysis, hematology, serum biochemistry, necropsy, organ weight and histopathology at doses of 500, 1000, and 2000 mg/kg. Accordingly, the level of no-observed-adverse-effect for DM extract in 13-week subchronic toxicity study was considered to be 2000 mg/kg/day in rats. The data observed from in vitro chromosome aberration assay and in vivo micronucleus assay exclude any clastogenicity of DM extract.

Conclusion: The results suggest that the oral consumption of DM extract has no adverse effects in humans and represents a safe traditional medicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jep.2019.111874DOI Listing
June 2019

Genetic and morphometric characteristics of Korean wild mice (KWM/Hym) captured at Chuncheon, South Korea.

Lab Anim Res 2018 Dec 31;34(4):311-316. Epub 2018 Dec 31.

Department of Medical Genetics, College of Medicine, Hallym University, Chuncheon, Korea.

Laboratory inbred mice are used widely and commonly in biomedical research, but inbred mice do not have a big enough gene pool for the research. In this study, genetic and morphometric analyses were performed to obtain data on the characteristics of a newly developing inbred strain (KWM/Hym) captured from Chuncheon, Korea. All of five Korean wild male mice have the zinc-finger Y () gene. Also, all of 19 Korean wild mice used in this analysis have the AKV-type murine leukemia virus gene, indicating that Korean wild mice might be . To identify the genetic polymorphism in KWM/Hym, SNP analysis was performed. In a comparison with 28 SNP markers, there was a considerable difference between KWM/Hym and several inbred strains. The homogeneity between KWM/Hym and the inbred strains was as follows: C57BL/6J (39.3%), BALB/c AJic (42.9%), and DBA/2J (50%). KWM/Hym is most similar to the PWK/PhJ inbred strain (96.4%) derived from wild mice (Czech Republic). To identify the morphometric characteristics of KWM/Hym, the external morphology was measured. The tail ratio of male and female was 79.60±3.09 and 73.55±6.14%, respectively. KWM/Hym has short and agouti-colored hairs and its belly is white with golden hair. Taking these results together, KWM/Hym, a newly developing inbred mouse originated from wild mouse, might be use as new genetic resources to overcome the limitations of the current laboratory mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5625/lar.2018.34.4.311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333606PMC
December 2018

The Use of Normal Stem Cells and Cancer Stem Cells for Potential Anti-Cancer Therapeutic Strategy.

Tissue Eng Regen Med 2018 Aug 21;15(4):365-380. Epub 2018 Jun 21.

1Department of Biotechnology, The Catholic University of Korea, 43 Jibongro, Bucheon, 14662 Republic of Korea.

Background: Despite recent advance in conventional cancer therapies including surgery, radiotherapy, chemotherapy, and immunotherapy to reduce tumor size, unfortunately cancer mortality and metastatic cancer incidence remain high. Along with a deeper understanding of stem cell biology, cancer stem cell (CSC) is important in targeted cancer therapy. Herein, we review representative patents using not only normal stem cells as therapeutics themselves or delivery vehicles, but also CSCs as targets for anti-cancer strategy.

Methods: Relevant patent literatures published between 2005 and 2017 are discussed to present developmental status and experimental results on using normal stem cells and CSCs for cancer therapy and explore potential future directions in this field.

Results: Stem cells have been considered as important element of regenerative therapy by promoting tissue regeneration. Particularly, there is a growing trend to use stem cells as a target drug-delivery system to reduce undesirable side effects in non-target tissues. Noteworthy, studies on CSC-specific markers for distinguishing CSCs from normal stem cells and mature cancer cells have been conducted as a selective anti-cancer therapy with few side effects. Many researchers have also reported the development of various substances with anticancer effects by targeting CSCs from cancer tissues.

Conclusion: There has been a continuing increase in the number of studies on therapeutic stem cells and CSC-specific markers for selective diagnosis and therapy of cancer. This review focuses on the current status in the use of normal stem cells and CSCs for targeted cancer therapy. Future direction is also proposed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13770-018-0128-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6171655PMC
August 2018

Determination of Penicillium griseofulvum-oriented pyripyropene A, a selective inhibitor of acyl-coenzyme A:cholesterol acyltransferase 2, in mouse plasma using liquid chromatography-tandem mass spectrometry and its application to pharmacokinetic studies.

Biomed Chromatogr 2019 Feb 30;33(2):e4388. Epub 2018 Oct 30.

Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Chungbuk, South Korea.

In this study, we developed a method for the determination of Penicillium griseofulvum-oriented pyripyropene A (PPPA), a selective inhibitor of acyl-coenzyme A:cholesterol acyltransferase 2, in mouse and human plasma and validated it using liquid chromatography-tandem mass spectrometry. Pyripyropene A (PPPA) and an internal standard, carbamazepine, were separated using a Xterra MS C18 column with a mixture of acetonitrile and 0.1% formic acid as the mobile phase. The ion transitions monitored in positive-ion mode [M + H] of multiple-reaction monitoring (MRM) were m/z 148.0 from m/z 584.0 for PPPA and m/z 194.0 from m/z 237.0 for the internal standard. The detector response was specific and linear for PPPA at concentrations within the range from 1 to 5,000 ng/mL. The intra-/inter-day precision and accuracy of the method was acceptable by the criteria for assay validation. The matrix effects of PPPA ranged from 97.6 to 104.2% and from 93.3 to 105.3% in post-preparative mouse and human plasma samples, respectively. PPPA was also stable under various processing and/or handling conditions. Finally, PPPA concentrations in the mouse plasma samples could be measured after intravenous, intraperitoneal, or oral administration of PPPA, suggesting that the assay is useful for pharmacokinetic studies on mice and applicable to human studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/bmc.4388DOI Listing
February 2019

Assessment of acute, 14-day, and 13-week repeated oral dose toxicity of Tiglium seed extract in rats.

BMC Complement Altern Med 2018 Sep 12;18(1):251. Epub 2018 Sep 12.

Department of Experimental Animal Research, Biomedical Research Institute, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.

Background: Seed of mature Croton tiglium Linne, also known as Tiglium seed (TS), has been widely used as a natural product due to its several health beneficial properties including anti-tumor and antifungal activities. Despite its ethnomedicinal beneficial properties, toxicological information regarding TS extract, especially its long-term toxicity, is currently limited. Therefore, the objective of the present study was to evaluate acute and subchronic toxicity of TS extract in rats after oral administration following test guidelines of the Organization for Economic Cooperation and Development (OECD).

Methods: Toxicological properties of TS extract were evaluated by toxicity assays to determine its single-dose acute toxicity (125, 250, 500, 1000, or 2000 mg/kg), 14-day repeated-dose toxicity (125, 250, 500, 1000, or 2000 mg/kg) and 13-week repeated-dose toxicity (31.25, 62.5, 125, 250, and 500 mg/kg) in Sprague-Dawley rats and F344 rats. Hematological, serum biochemical, and histopathological parameters were analyzed to determine its median lethal dose (LD) and no-observed-adverse-effect-level (NOAEL).

Results: Oral single dose up to 2000 mg/kg of TS extract resulted in no mortalities or abnormal clinical signs. In 13-week toxicity study, TS extract exhibited no dose-related changes (mortality, body weight, food/water consumption, hematology, clinical biochemistry, organ weight, or histopathology) at dose up to 500 mg/kg, the highest dosage level suggested based on 14-day repeat-dose oral toxicity study.

Conclusion: Acute oral LD of TS extract in rats was estimated to be greater than 2000 mg/kg. NOAEL of TS extract administered orally was determined to be 500 mg/kg/day in both male and female rats. Results from these acute and subchronic toxicity assessments of TS extract under Good Laboratory Practice regulations indicate that TS extract appears to be safe for human consumption.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12906-018-2315-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134578PMC
September 2018

Copper nanoparticles induce early fibrotic changes in the liver via TGF-β/Smad signaling and cause immunosuppressive effects in rats.

Nanotoxicology 2018 08 30;12(6):637-651. Epub 2018 May 30.

b College of Veterinary Medicine BK21 Plus Team , Chonnam National University , Gwangju , Republic of Korea.

Copper nanoparticles (Cu NPs) have various uses, including as additives in polymers/plastics, lubricants for metallic coating, and biomedical applications. We investigated the role of transforming growth factor (TGF)-β1 signaling in hepatic damage caused by Cu NPs and explored the effects of a 28-day repeated oral administration to Cu NPs on the immune response. The exposure to Cu NPs caused a dose-dependent increase in Cu levels in the liver and spleen. Cu NPs caused hepatic damage and markedly increased oxidative stress in liver tissues. Cu NPs induced activation of TGF-β1/Smad signaling by induction of vascular endothelial growth factor and matrix metalloproteinase-9. Exposure to Cu NPs also induced activation of Smad-independent pathways, phosphorylation of mitogen-activated protein kinases (MAPKs) and Akt/FoxO3. Consistent with the activation of TGF-β1/Smad-dependent and -independent pathways, Cu NPs markedly increased the deposition and induction of extracellular matrix components, α-smooth muscle actin, and collagens in liver tissues. In addition, repeated exposure to Cu NPs suppressed the proliferation of mitogenically stimulated T- or B-lymphocytes and decreased CD3 (particularly, CD3CD4CD8) and CD45 population, followed by decreased levels of immunoglobulins and Th1/Th2 type cytokines. Collectively, Cu NPs caused hepatic damage and induced pro-fibrotic changes, which were closely related to the activation of oxidative stress-mediated TGF-β1/Smad-dependent and -independent pathways (MAPKs and Akt/FoxO3). We confirmed the immunosuppressive effect of Cu NPs via the inhibition of mitogen-stimulated spleen-derived lymphocyte proliferation and suppression of B- or T-lymphocyte-mediated immune responses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17435390.2018.1472313DOI Listing
August 2018

In vitro and in vivo safety studies of cinnamon extract (Cinnamomum cassia) on general and genetic toxicology.

Regul Toxicol Pharmacol 2018 Jun 6;95:115-123. Epub 2018 Mar 6.

Department of Experimental Animal Research, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea; Biomedical Center for Animal Resource and Development, Seoul National University College of Medicine, Seoul, Republic of Korea; Graduate School of Translational Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; Designed Animal and Transplantation Research Institute, Institute of GreenBio Science Technology, Seoul National University, Pyeongchang-gun, Gangwon-do, Republic of Korea. Electronic address:

Cinnamomum cassia has been widely used as a natural product to treat diseases in Asia due to its diverse pharmacological functions including anti-inflammatory, anti-oxidant, anti-microbial, anti-diabetic, and anti-tumor effects. Despite its ethnomedicinal benefits, little information regarding its toxicity is currently available. The aim of this study was to evaluate its potential long-term toxicity and genotoxicity in compliance with test guidelines of the Organization for Economic Cooperation and Development. A 13-week repeat-dose oral toxicity study revealed that body weights of rats were normal after receiving cinnamon extract at up to 2000 mg/kg. High-dose intake of cinnamon extract (2000 mg/kg) showed potential nephrotoxicity and hepatotoxicity to both males and females as evidenced by obvious increases of kidney/liver weight along with a small but statistically elevation of total cholesterol level. Overall findings from genetic toxicity testing battery including Ames test, in vitro mammalian cell micronucleus assay, and in vivo bone marrow micronucleus assay indicated that cinnamon extract was not mutagenic or clastogenic. In conclusion, cinnamon extract may possess potential nephrotoxicity and hepatotoxicity at dose higher than its recommended daily safe dose. Further study is needed to clarify the mechanism involved in its induction of liver and kidney injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yrtph.2018.02.017DOI Listing
June 2018

Fryl deficiency is associated with defective kidney development and function in mice.

Exp Biol Med (Maywood) 2018 03 6;243(5):408-417. Epub 2018 Feb 6.

1 Laboratory Animal Resource Center, 204180 Korea Research Institute of Bioscience and Biotechnology , Chungbuk 28116, Korea.

FRY like transcription coactivator ( Fryl) gene located on chromosome 5 is a paralog of FRY microtubule binding protein ( Fry) in vertebrates. It encodes a protein with unknown functions. Fryl gene is conserved in various species ranging from eukaryotes to human. Although there are several reports on functions of Fry gene, functions of Fryl gene remain unclear. A mouse line containing null mutation in Fryl gene by gene trapping was produced in this study for the first time. The survival and growth of Fryl mice were observed. Fryl gene expression levels in mouse tissues were determined and histopathologic analyses were conducted. Most Fryl mice died soon after birth. Rare Fryl survivors showed growth retardation with significantly lower body weight compared to their littermate controls. Although they could breed, more than half of Fryl survivors died of hydronephrosis before age 1. No abnormal histopathologic lesion was apparent in full-term embryo or adult tissues except the kidney. Abnormal lining cell layer detachments from walls of collecting and convoluted tubules in kidneys were apparent in Fryl neonates and full-term embryos. Fryl gene was expressed in renal tubular tissues including the glomeruli and convoluted and collecting tubules. This indicates that defects in tubular systems are associated with Fryl functions and death of Fryl neonates. Fryl protein is required for normal development and functional maintenance of kidney in mice. This is the first report of in vivo Fryl gene functions. Impact statement FRY like transcription coactivator ( Fryl) gene is conserved in various species ranging from eukaryotes to human. It expresses a protein with unknown function. We generated a Fryl gene mutant mouse line and found that most homozygous mice died soon after their birth. Rare Fryl survivors showed growth retardation with significantly lower body weight compared to their littermate controls. Although they could breed, more than half of Fryl survivors died of hydronephrosis before age 1. Full-term mutant embryos showed abnormal collecting and convoluted tubules in kidneys where Fryl gene was expressed. Collectively, these results indicate that Fryl protein is required for normal development and functional maintenance of kidney in mice. To the best of our knowledge, this is the first report on in vivo Fryl gene functions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1535370218758249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882029PMC
March 2018

Collagen-Induced Arthritis Analysis in Knockout Mouse.

Biomol Ther (Seoul) 2018 May;26(3):298-305

Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Cheongwon 28116, Republic of Korea.

Rhomboid family member 2 gene () is an inactive homologue lacking essential catalytic residues of rhomboid intramembrane serine proteases. The protein is necessary for maturation of tumor necrosis factor-alpha (TNF-α) converting enzyme, which is the molecule responsible for the release of TNF-α. In this study, knockout (KO) mice were produced by CRISPR/CAS9. To see the effects of the failure of TNF-α release induced by gene KO, collagen-induced arthritis (CIA), which is the representative TNF-α related disease, was induced in the mutant mouse using chicken collagen type II. The severity of the CIA was measured by traditional clinical scores and histopathological analysis of hind limb joints. A rota-rod test and grip strength test were employed to evaluate the severity of CIA based on losses of physical functions. The results indicated that mutant mice showed clear alleviation of the clinical severity of CIA as demonstrated by the significantly lower severity indexes. Moreover, a grip strength test was shown to be useful for the evaluation of physical functional losses by CIA. Overall, the results showed that the gene has a significant effect on the induction of CIA, which is related to TNF-α.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4062/biomolther.2017.103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933897PMC
May 2018

Age-Related Changes in Sulfur Amino Acid Metabolism in Male C57BL/6 Mice.

Biomol Ther (Seoul) 2018 Mar;26(2):167-174

College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea.

Alterations in sulfur amino acid metabolism are associated with an increased risk of a number of common late-life diseases, which raises the possibility that metabolism of sulfur amino acids may change with age. The present study was conducted to understand the age-related changes in hepatic metabolism of sulfur amino acids in 2-, 6-, 18- and 30-month-old male C57BL/6 mice. For this purpose, metabolite profiling of sulfur amino acids from methionine to taurine or glutathione (GSH) was performed. The levels of sulfur amino acids and their metabolites were not significantly different among 2-, 6- and 18-month-old mice, except for plasma GSH and hepatic homocysteine. Plasma total GSH and hepatic total homocysteine levels were significantly higher in 2-month-old mice than those in the other age groups. In contrast, 30-month-old mice exhibited increased hepatic methionine and cysteine, compared with all other groups, but decreased hepatic S-adenosylmethionine (SAM), S-adenosylhomocysteine and homocysteine, relative to 2-month-old mice. No differences in hepatic reduced GSH, GSH disulfide, or taurine were observed. The hepatic changes in homocysteine and cysteine may be attributed to upregulation of cystathionine β-synthase and down-regulation of γ-glutamylcysteine ligase in the aged mice. The elevation of hepatic cysteine levels may be involved in the maintenance of hepatic GSH levels. The opposite changes of methionine and SAM suggest that the regulatory role of SAM in hepatic sulfur amino acid metabolism may be impaired in 30-month-old mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4062/biomolther.2017.054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839495PMC
March 2018

Lectin, Galactoside-Binding Soluble 3 Binding Protein Promotes 17-N-Allylamino-17-demethoxygeldanamycin Resistance through PI3K/Akt Pathway in Lung Cancer Cell Line.

Mol Cancer Ther 2017 07 23;16(7):1355-1365. Epub 2017 Mar 23.

College of Pharmacy, Gachon University, Incheon, Republic of Korea.

Heat shock protein 90 (HSP90) stabilizing oncoproteins has been an attractive target in cancer therapy. 17-N-Allylamino-17-demethoxygeldanamycin (17-AAG), an HSP90 inhibitor, was tested in phase II/III clinical trials, but due to lack of efficacy, clinical evaluation of 17-AAG has achieved limited success, which led to resistance to 17-AAG. However, the mechanism of 17-AAG resistance has not clearly been identified. Here, we identified LGALS3BP (Lectin, galactoside-binding soluble 3 binding protein), a secretory glycoprotein, as a 17-AAG resistance factor. In the clinical reports, it was suggested that LGALS3BP was associated with low survival rate, development of cancer progression, and enhancement of metastasis in human cancers. As we confirmed that the LGALS3BP level was increased in 17-AAG-resistant cells (H1299_17R) compared with that of the parental cell line (H1299_17P), knockdown of LGALS3BP expression increased sensitivity to 17-AAG in H1299_17R cells. Overexpression of LGALS3BP also augmented PI3K/Akt and ERK signaling pathways. Furthermore, we determined that the PI3K/Akt signaling pathway was involved in LGALS3BP-mediated 17-AAG resistance and , demonstrating that LGALS3BP mediates the resistance against 17-AAG through PI3K/Akt activation rather than ERK activation. These findings suggest that LGALS3BP would be a target to overcome resistance to 17-AAG in lung cancer. For example, the combination of 17-AAG and PI3K/Akt inhibitor would effectively suppress acquired resistance to 17-AAG. In conclusion, targeting of LGALS3BP-mediated-specific survival signaling pathway in resistant cells may provide a novel therapeutic model for the cancer therapy. .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-16-0574DOI Listing
July 2017

Picroside II Attenuates Airway Inflammation by Downregulating the Transcription Factor GATA3 and Th2-Related Cytokines in a Mouse Model of HDM-Induced Allergic Asthma.

PLoS One 2016 21;11(11):e0167098. Epub 2016 Nov 21.

Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, Chungbuk, Republic of Korea.

Picroside II isolated from Pseudolysimachion rotundum var. subintegrum has been used as traditional medicine to treat inflammatory diseases. In this study, we assessed whether picroside II has inhibitory effects on airway inflammation in a mouse model of house dust mite (HDM)-induced asthma. In the HDM-induced asthmatic model, picroside II significantly reduced inflammatory cell counts in the bronchoalveolar lavage fluid (BALF), the levels of total immunoglobulin (Ig) E and HDM-specific IgE and IgG1 in serum, airway inflammation, and mucus hypersecretion in the lung tissues. ELISA analysis showed that picroside II down-regulated the levels of Th2-related cytokines (including IL-4, IL-5, and IL-13) and asthma-related mediators, but it up-regulated Th1-related cytokine, IFNγ in BALF. Picroside II also inhibited the expression of Th2 type cytokine genes and the transcription factor GATA3 in the lung tissues of HDM-induced mice. Finally, we demonstrated that picroside II significantly decreased the expression of GATA3 and Th2 cytokines in developing Th2 cells, consistent with in vivo results. Taken together, these results indicate that picroside II has protective effects on allergic asthma by reducing GATA3 expression and Th2 cytokine bias.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0167098PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5117775PMC
June 2017

Comparative toxicity and biodistribution assessments in rats following subchronic oral exposure to copper nanoparticles and microparticles.

Part Fibre Toxicol 2016 10 28;13(1):56. Epub 2016 Oct 28.

College of Veterinary Medicine BK21 Plus Project Team, Chonnam National University, Gwangju, 61186, Republic of Korea.

Background: Copper nanoparticles (Cu NPs) have great potential in electronics and biomedical fields because of their efficient thermodynamic and anti-microbial properties. However, their potential toxic effects and kinetic data following repeated exposure are still unclear.

Methods: We evaluated the physicochemical properties of Cu NPs (25 nm) and copper microparticles (Cu MPs, 14-25 μm). Comparative in vivo toxicity of Cu NPs and Cu MPs was evaluated by conducting a 28-day repeated oral dose study at equivalent dose levels of 0, 100, 200, and 400 mg/kg/day (vehicle, 1 % hydroxypropyl methylcellulose). We determined Cu levels in the blood, tissues, urine, and feces by using inductively coupled plasma mass spectrometry.

Results: The solubility of Cu NPs and Cu MPs was 84.5 and 17.2 %, respectively, in an acidic milieu; however, they scarcely dissolved in vehicle or intestinal milieus. The specific surface area of Cu NPs and Cu MPs was determined to be 14.7 and 0.16 m/g, respectively. Cu NPs exhibited a dose-dependent increase of Cu content in the blood and tested organs, with particularly high levels of Cu in the liver, kidney, and spleen. Only for liver and kidney increased Cu levels were found in Cu MPs-treated rats. Cu NPs caused a dose-related increase in Cu levels in urine, whereas Cu MPs did not affect the urine Cu levels. Extremely high levels of Cu were detected in the feces of Cu MPs-treated rats, whereas much lower levels were detected in the feces of Cu NPs-treated rats. A comparative in vivo toxicity study showed that Cu NPs caused damages to red blood cells, thymus, spleen, liver, and kidney at ≥200 mg/kg/days, but Cu MPs did not cause any adverse effects even at the highest dose.

Conclusions: Overall, the in vivo repeated dose toxicity study of Cu NPs and Cu MPs demonstrated that large surface area and high solubility in physiological milieus could directly influence the toxicological responses and biodistribution of Cu particles when administered orally. Under these experimental conditions, the no-observed-adverse-effect levels of Cu NPs and Cu MPs were determined to be 100 and ≥400 mg/kg/day, respectively.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12989-016-0169-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5084351PMC
October 2016

Hepatic expression of cytochrome P450 in Zucker diabetic fatty rats.

Food Chem Toxicol 2016 Oct 11;96:244-53. Epub 2016 Aug 11.

College of Pharmacy, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, 34134, Republic of Korea. Electronic address:

In this study, the hepatic expression of cytochrome P450 (CYP) enzymes, including CYP1A1/2, 2B1, 2C11, 2E1, 3A1/2, and 4A, was investigated in 5-week-old (insulinresistant state) and 11-week-old (diabetic) Zucker diabetic fatty (ZDF) rats. Serum glucose and glycated hemoglobin levels were increased in 11-week-old ZDF rats, but not in 5-weekold ZDF rats. Hyperinsulinemia was observed in both age groups. The microsomal protein, total CYP, CYP reductase, CYP1A1/2, and CYP3A1 levels did not differ between 5- and 11-week-old ZDF rats and their respective control rats, while CYP4A was up-regulated in both groups. Hepatic levels of cytochrome b5, CYP2B1, CYP2C11, CYP2E1, and CYP3A2 were decreased in 5-week-old ZDF rats, but not in 11-week-old ZDF rats. Similarly, pentoxyresorufin O-depentylase, testosterone 2α- and 16α-hydroxylase, chlorzoxazone 6- hydroxylase, and midazolam 1'- and 4-hydroxylase activities were decreased only in 5-weekold ZDF rats. Based on these results, the 5-week-old ZDF rats exhibited down-regulation of the major CYP enzymes. These results suggest that hepatic expression of CYP enzymes may be dysregulated during development in ZDF rats. With the exception of CYP2B1 and CYP4A, the hepatic levels and activities of CYP were comparable between 11-week-old ZDF and control rats, suggesting that xenobiotic metabolism is normally regulated in the early diabetic state.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.fct.2016.08.010DOI Listing
October 2016

miR-204 downregulates EphB2 in aging mouse hippocampal neurons.

Aging Cell 2016 Apr 22;15(2):380-8. Epub 2016 Jan 22.

Department of New Biology, DGIST, Daegu, 711-873, Korea.

Hippocampal synaptic function and plasticity deteriorate with age, often resulting in learning and memory deficits. As MicroRNAs (miRNAs) are important regulators of neuronal protein expression, we examined whether miRNAs may contribute to this age-associated decline in hippocampal function. We first compared the small RNA transcriptome of hippocampal tissues from young and old mice. Among 269 hippocampal miRNAs, 80 were differentially expressed (≥ twofold) among the age groups. We focused on 36 miRNAs upregulated in the old mice compared with those in the young mice. The potential targets of these 36 miRNAs included 11 critical Eph/Ephrin synaptic signaling components. The expression levels of several genes in the Eph/Ephrin pathway, including EphB2, were significantly downregulated in the aged hippocampus. EphB2 is a known regulator of synaptic plasticity in hippocampal neurons, in part by regulating the surface expression of the NMDA receptor NR1 subunit. We found that EphB2 is a direct target of miR-204 among miRNAs that were upregulated with age. The transfection of primary hippocampal neurons with a miR-204 mimic suppressed both EphB2 mRNA and protein expression and reduced the surface expression of NR1. Transfection of miR-204 also decreased the total expression of NR1. miR-204 induces senescence-like phenotype in fully matured neurons as evidenced by an increase in p16-positive cells. We suggest that aging is accompanied by the upregulation of miR-204 in the hippocampus, which downregulates EphB2 and results in reduced surface and total NR1 expression. This mechanism may contribute to age-associated decline in hippocampal synaptic plasticity and the related cognitive functions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/acel.12444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4783348PMC
April 2016

Genetically obese (ob/ob) mice are resistant to the lethal effects of thioacetamide hepatotoxicity.

Toxicol Appl Pharmacol 2016 Jan 15;291:38-45. Epub 2015 Dec 15.

Department of Veterinary Pathology, College of Veterinary Medicine, Chungnam National University, Daejeon, South Korea. Electronic address:

Obesity increases the risk of chronic liver diseases, including viral hepatitis, alcohol-induced liver disease, and non-alcoholic steatohepatitis. In this study, we investigated the effects of obesity in acute hepatic failure using a murine model of thioacetamide (TA)-induced liver injury. Genetically obese ob/ob mice, together with non-obese ob/+ littermates, were subjected to a single intraperitoneal injection of TA, and examined for signs of hepatic injury. ob/ob mice showed a significantly higher survival rate, lower levels of serum alanine aminotransferase and aspartate aminotransferase, and less hepatic necrosis and apoptosis, compared with ob/+ mice. In addition, ob/ob mice exhibited significantly lower levels of malondialdehyde and significantly higher levels of glutathione and antioxidant enzyme activities compared with their ob/+ counterparts. Bioactivation analyses revealed reduced plasma clearance of TA and covalent binding of [(14)C]TA to liver macromolecules in ob/ob mice. Together, these data demonstrate that genetically obese mice are resistant to TA-induced acute liver injury through diminished bioactivation of TA and antioxidant effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.taap.2015.12.001DOI Listing
January 2016

Time-course and molecular mechanism of hepatotoxicity induced by 1,3-dichloro-2-propanol in rats.

Environ Toxicol Pharmacol 2015 Jul 10;40(1):191-8. Epub 2015 Jun 10.

College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Republic of Korea. Electronic address:

This study investigated the time-course of 1,3-dichloro-2-propanol (1,3-DCP)-induced hepatotoxicity and the molecular mechanism of its oxidative stress and apoptotic changes in rats. Thirty-six male rats were randomly assigned to six groups of six rats each and were administered a single oral dose of 1,3-DCP (90 mg/kg) or its vehicle. 1,3-DCP caused acute hepatic damage, as evidenced by marked increases in serum aminotransferase, alkaline phosphatase, and histopathological alterations. These functional and histopathological changes in the liver peaked at 12h after administration and then decreased progressively. Oxidative stress indices were increased significantly at 6h, peaked at 12h, and then decreased progressively. The number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)- and caspase-3-positive cells increased after 6h, peaked at 12 and 24h, and then decreased. The protein levels of phosphorylated mitogen-activated protein kinases (MAPKs) including p-Erk1/2 and p-JNK showed a similar trend to the numbers of TUNEL- and caspase-3-positive cells. These results indicate that 1,3-DCP increases oxidative stress, nuclear translocation of Nrf2, and expression of Nrf2-targeted genes, followed by increased functional and histopathological alterations in the liver. The increase in hepatocellular apoptosis induced by 1,3-DCP may be related to oxidative stress-mediated MAPK activation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.etap.2015.06.011DOI Listing
July 2015

An age-dependent alteration of the respiratory exchange ratio in the db/db mouse.

Lab Anim Res 2015 Mar 20;31(1):1-6. Epub 2015 Mar 20.

Laboratory Animal Resource Center, KRIBB, Cheongju, Korea.

The leptin receptor-deficient db/db mouse is a rodent model of type 2 diabetes and obesity. Diabetes in db/db mice shows an age-dependent progression, with early insulin resistance followed by an insulin secretory defect resulting in profound hyperglycemia. However, there is insufficient data on agedependent changes of energy metabolism in db/db mice. We demonstrated an age-dependent decrease in the respiratory exchange ratio (RER), calculated by a ratio of VO2/VCO2, in db/db mice. The RER determined by indirect calorimetry, was 1.03 in db/db mice under 6 weeks of age, which were similar to those in heterozygote (db/+) and wild-type (+/+) mice. However, RER decreased from approximately 0.9 to 0.8 by 10 weeks of age and subsequently returned to approximately 0.9 at 22 weeks of age. The changes in RER were concurrent with the alterations in body weight and blood glucose level. However, other metabolic indicators such as glucose tolerance, changes in body fat mass, and urinary glucose levels, did not change with age. The results suggested that the energy source utilized in db/db mice changed with the age-related progression of diabetes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5625/lar.2015.31.1.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4371472PMC
March 2015

Helicobacter apodemus sp. nov., a new Helicobacter species identified from the gastrointestinal tract of striped field mice in Korea.

J Vet Sci 2015 ;16(4):475-81

Laboratory of Developmental Biology and Genomics, College of Veterinary Medicine, BIO-MAX Institute, Program for Cancer Biology, and Interdisciplinary Program for Bioinformatics, BK21Plus Program fo.

A novel Helicobacter species was identified from the gastrointestinal tract of the Korean striped field mouse (Apodemus agrarius). Biochemical testing, ultrastructure characterization, and 16S rRNA gene sequence analysis suggested that this bacterium represents a distinct taxon. The bacterium was positive for urease activity, susceptible to cephalothin and nalidixic acid, and weakly positive for oxidase and catalase activity. Electron microscopy revealed that the bacterium has spirally curved rod morphology with singular bipolar nonsheathed flagella. Genotypically, the isolated bacterial strains (YMRC 000215, YMRC 000216, and YMRC 000419) were most closely related to a reference strain of Helicobacter mesocricetorum (97.25%, 97.32%, and 97.03% 16S rRNA sequence similarities, respectively). The 16S rRNA sequences of these strains were deposited into GenBank under accession numbers AF284754, AY009129, and AY009130, respectively. We propose the name Helicobacter apodemus for this novel species.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4142/jvs.2015.16.4.475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4701740PMC
September 2016

Diallyl Disulfide Prevents Cyclophosphamide-Induced Hemorrhagic Cystitis in Rats through the Inhibition of Oxidative Damage, MAPKs, and NF-κB Pathways.

Biomol Ther (Seoul) 2015 Mar 1;23(2):180-8. Epub 2015 Mar 1.

College of Veterinary Medicine, Chonnam National University, Gwangju 500-757.

This study investigated the possible effects and molecular mechanisms of diallyl disulfide (DADS) against cyclophosphamide (CP)-induced hemorrhagic cystitis (HC) in rats. Inflammation response was assessed by histopathology and serum cytokines levels. We determined the protein expressions of nuclear transcription factor kappa-B (NF-κB), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and tumor necrosis factor-α (TNF-α), oxidative stress, urinary nitrite-nitrate, malondialdehyde (MDA), and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Finally, we studied the involvement of mitogen-activated protein kinases (MAPKs) signaling in the protective effects of DADS against CP-induced HC. CP treatment caused a HC which was evidenced by an increase in histopathological changes, proinflammatory cytokines levels, urinary nitrite-nitrate level, and the protein expression of NF-κB, COX-2, iNOS, TNF-α, p-c-Jun N-terminal kinase (JNK), and p-extracellular signal regulated kinase (ERK). The significant decreases in glutathione content and glutathione-S-transferase and glutathione reductase activities, and the significant increase in MDA content and urinary MDA and 8-OHdG levels indicated that CP-induced bladder injury was mediated through oxidative DNA damage. In contrast, DADS pretreatment attenuated CP-induced HC, including histopathological lesion, serum cytokines levels, oxidative damage, and urinary oxidative DNA damage. DADS also caused significantly decreased the protein expressions of NF-κB, COX-2, iNOS, TNF-α, p-JNK, and p-ERK. These results indicate that DADS prevents CP-induced HC and that the protective effects of DADS may be due to its ability to regulate proinflammatory cytokines production by inhibition of NF-κB and MAPKs expressions, and its potent anti-oxidative capability through reduction of oxidative DNA damage in the bladder.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4062/biomolther.2014.126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354320PMC
March 2015

Effects of age increase on hepatic expression and activity of cytochrome P450 in male C57BL/6 mice.

Arch Pharm Res 2015 25;38(5):857-64. Epub 2014 Jul 25.

College of Pharmacy, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, 305-764, Republic of Korea.

Effects of aging on hepatic expression and activity of cytochrome P450 (CYP) isoforms were investigated in male mice aged 2, 6, 18, and 30 months. Microsomal protein, total CYP, cytochrome b5 and NADPH-dependent cytochrome P450 reductase contents in liver were fully expressed in young (2-month-old) mice. Neither Cyp1a1 nor Cyp2c was detected in any aged mice. And Cyp1a2 was maximally expressed at 2 months and decreased with age. Hepatic levels of Cyp2b10 and Cyp3a11 were decreased in 30-month-old mice. Hepatic Cyp2e1 levels were constantly maintained from 2-month to 30-month old mice. Hepatic activities of ethoxyresorufin-O-deethylase and methoxyresorufin-O-demethylase were gradually decreased after 6 months. The 30-month-old mice exhibited the lowest activity of midazolam 1'-hydroxylase. Pentoxyresorufin-O-depenthylase activity was decreased in 30-month-old mice, but not statistically significant. There were no significant differences in hepatic activities of chlorzoxazone 6-hydroxylase and midazolam 4-hydroxylase. The present study shows that increasing age, especially 30-month-old mice, leads to decrease in expression and activity of hepatic CYP isoforms, suggesting that aging mice exhibit poor hepatic drug-metabolizing capacity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12272-014-0452-zDOI Listing
February 2016

The adipokine Retnla modulates cholesterol homeostasis in hyperlipidemic mice.

Nat Commun 2014 Jul 15;5:4410. Epub 2014 Jul 15.

Department of Life Sciences, Ewha Womans University, Seoul 120-750, Republic of Korea.

Hyperlipidemia is a well-recognized risk factor for atherosclerosis and can be regulated by adipokines. Expression of the adipokine resistin-like molecule alpha (Retnla) is regulated by food intake; whether Retnla has a role in the pathogenesis of hyperlipidemia and atherosclerosis is unknown. Here we report that Retnla has a cholesterol-lowering effect and protects against atherosclerosis in low-density lipoprotein receptor-deficient mice. On a high-fat diet, Retnla deficiency promotes hypercholesterolaemia and atherosclerosis, whereas Retnla overexpression reverses these effects and improves the serum lipoprotein profile, with decreased cholesterol in the very low-density lipoprotein fraction concomitant with reduced serum apolipoprotein B levels. We show that Retnla upregulates cholesterol-7-α-hydroxylase, a key hepatic enzyme in the cholesterol catabolic pathway, through induction of its transcriptional activator liver receptor homologue-1, leading to increased excretion of cholesterol in the form of bile acids. These findings define Retnla as a novel therapeutic target for treating hypercholesterolaemia and atherosclerosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms5410DOI Listing
July 2014