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한국응용약물학회> Biomolecules & Therapeutics(구 응용약물학회지)> Behavioral Deficits in Adolescent Mice after Sub-Chronic Administration of NMDA during Early Stage of Postnatal Development

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Behavioral Deficits in Adolescent Mice after Sub-Chronic Administration of NMDA during Early Stage of Postnatal Development

Keremkleroo Jym Adil , Chilly Gay Remonde , Edson Luck Gonzales , Kyung-jun Boo , Kyong Ja Kwon , Dong Hyun Kim , Hee Jin Kim , Jae Hoon Cheong , Chan Young Shin , Se Jin Jeon
  • : 한국응용약물학회
  • : Biomolecules & Therapeutics(구 응용약물학회지) 30권4호
  • : 연속간행물
  • : 2022년 07월
  • : 320-327(8pages)
Biomolecules & Therapeutics(구 응용약물학회지)

DOI


목차

INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
ACKNOWLEDGMENTS
REFERENCES

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초록 보기

Neurodevelopmental disorders are complex conditions that pose difficulty in the modulation of proper motor, sensory and cognitive function due to dysregulated neuronal development. Previous studies have reported that an imbalance in the excitation/ inhibition (E/I) in the brain regulated by glutamatergic and/or GABAergic neurotransmission can cause neurodevelopmental and neuropsychiatric behavioral deficits such as autism spectrum disorder (ASD). NMDA acts as an agonist at the NMDA receptor and imitates the action of the glutamate on that receptor. NMDA however, unlike glutamate, only binds to and regulates the NMDA receptor subtypes and not the other glutamate receptors. This study seeks to determine whether NMDA administration in mice i.e., over-activation of the NMDA system would result in long-lasting behavioral deficits in the adolescent mice. Both gender mice were treated with NMDA or saline at early postnatal developmental period with significant synaptogenesis and synaptic maturation. On postnatal day 28, various behavioral experiments were conducted to assess and identify behavioral characteristics. NMDAtreated mice show social deficits, and repetitive behavior in both gender mice at adolescent periods. However, only the male mice but not female mice showed increased locomotor activity. This study implies that neonatal exposure to NMDA may illicit behavioral features similar to ASD. This study also confirms the validity of the E/I imbalance theory of ASD and that NMDA injection can be used as a pharmacologic model for ASD. Future studies may explore the mechanism behind the gender difference in locomotor activity as well as the human relevance and therapeutic significance of the present findings.

UCI(KEPA)

간행물정보

  • : 의약학분야  > 약화학
  • : KCI등재
  • : SCOPUS
  • : 격월
  • : 1976-9148
  • : 2005-4483
  • : 학술지
  • : 연속간행물
  • : 1993-2023
  • : 1842


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1Enhancing Anti-Cancer Therapy with Selective Autophagy Inhibitors by Targeting Protective Autophagy

저자 : Min Ju Lee , Jae-sung Park , Seong Bin Jo , Young Ae Joe

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 31권 1호 발행 연도 : 2023 페이지 : pp. 1-15 (15 pages)

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Autophagy is a process of eliminating damaged or unnecessary proteins and organelles, thereby maintaining intracellular homeostasis. Deregulation of autophagy is associated with several diseases including cancer. Contradictory dual roles of autophagy have been well established in cancer. Cytoprotective mechanism of autophagy has been extensively investigated for overcoming resistance to cancer therapies including radiotherapy, targeted therapy, immunotherapy, and chemotherapy. Selective autophagy inhibitors that directly target autophagic process have been developed for cancer treatment. Efficacies of autophagy inhibitors have been tested in various pre-clinical cancer animal models. Combination therapies of autophagy inhibitors with chemotherapeutics are being evaluated in clinal trials. In this review, we will focus on genetical and pharmacological perturbations of autophagy-related proteins in different steps of autophagic process and their therapeutic benefits. We will also summarize combination therapies of autophagy inhibitors with chemotherapies and their outcomes in pre-clinical and clinical studies. Understanding of current knowledge of development, progress, and application of cytoprotective autophagy inhibitors in combination therapies will open new possibilities for overcoming drug resistance and improving clinical outcomes.

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2The Trend of Organic Based Nanoparticles in the Treatment of Diabetes and Its Perspectives

저자 : Vijayakumar Natesan , Sung-jin Kim

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 31권 1호 발행 연도 : 2023 페이지 : pp. 16-26 (11 pages)

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Diabetes is an untreatable metabolic disorder characterized by alteration in blood sugar homeostasis, with submucosal insulin therapy being the primary treatment option. This route of drug administration is attributed to low patient comfort due to the risk of pain, distress, and local inflammation/infections. Nanoparticles have indeed been suggested as insulin carriers to allow the drug to be administered via less invasive routes other than injection, such as orally or nasally. The organic-based nanoparticles can be derived from various organic materials (for instance, polysaccharides, lipids, and so on) and thus are prevalently used to enhance the physical and chemical consistency of loaded bioactive compounds (drug) and thus their bioavailability. This review presents various forms of organic nanoparticles (for example, chitosan, dextron, gums, nanoemulsion, alginate, and so on) for enhanced hypoglycemic drug delivery relative to traditional therapies.

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36-Shogaol and 10-Shogaol Synergize Curcumin in Ameliorating Proinflammatory Mediators via the Modulation of TLR4/TRAF6/MAPK and NFκB Translocation

저자 : Xian Zhou , Ahmad Al-khazaleh , Sualiha Afzal , Ming-hui tim Kao , Gerald Münch , Hans Wohlmuth , David Leach , Mitchell Low , Chun Guang Li

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 31권 1호 발행 연도 : 2023 페이지 : pp. 27-41 (15 pages)

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Extensive research supported the therapeutic potential of curcumin, a naturally occurring compound, as a promising cytokine-suppressive anti-inflammatory drug. This study aimed to investigate the synergistic anti-inflammatory and anti-cytokine activities by combining 6-shogaol and 10-shogaol to curcumin, and associated mechanisms in modulating lipopolysaccharides and interferon-ɣ-induced proinflammatory signaling pathways. Our results showed that the combination of 6-shogaol-10-shogaolcurcumin synergistically reduced the production of nitric oxide, inducible nitric oxide synthase, tumor necrosis factor and inter-lukin-6 in lipopolysaccharides and interferon-γ-induced RAW 264.7 and THP-1 cells assessed by the combination index model. 6-shogaol-10-shogaol-curcumin also showed greater inhibition of cytokine profiling compared to that of 6-shogaol-10-shogaol or curcumin alone. The synergistic anti-inflammatory activity was associated with supressed NFκB translocation and downregulated TLR4-TRAF6-MAPK signaling pathway. In addition, SC also inhibited microRNA-155 expression which may be relevant to the inhibited NFκB translocation. Although 6-shogaol-10-shogaol-curcumin synergistically increased Nrf2 activity, the anti-inflammatory mechanism appeared to be independent from the induction of Nrf2. 6-shogaol-10-shogaol-curcumin provides a more potent therapeutic agent than curcumin alone in synergistically inhibiting lipopolysaccharides and interferon-γ induced proinflammatory mediators and cytokine array in macrophages. The action was mediated by the downregulation of TLR4/TRAF6/MAPK pathway and NFκB translocation.

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4Loganin Prevents Hepatic Steatosis by Blocking NLRP3 Inflammasome Activation

저자 : Joo Hyeon Jang , Gabsik Yang , Jin Kyung Seok , Han Chang Kang , Yong-yeon Cho , Hye Suk Lee , Joo Young Lee

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 31권 1호 발행 연도 : 2023 페이지 : pp. 40-47 (8 pages)

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Activation of the NLRP3 inflammasome is a necessary process to induce fibrosis in nonalcoholic fatty liver disease (NAFLD). Nonalcoholic steatohepatitis (NASH) is a kind of NAFLD that encompasses the spectrum of liver disease. It is characterized by inflammation and ballooning of hepatocytes during steatosis. We tested whether inhibiting the NLRP3 inflammasome could prevent the development and pathology of NASH. We identified loganin as an inhibitor of the NLRP3 inflammasome and investigated whether in vivo administration of loganin prevented NASH symptoms using a methionine-choline deficient (MCD) diet model in mice. We found that loganin inhibited the NLRP3 inflammasome activation triggered by ATP or nigericin, as shown by suppression of the production of interleukin (IL)-1β and caspase-1 (p10) in mouse primary macrophages. The speck formation of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) was blocked by loganin, showing that the assembly of the NLRP3 inflammasome complex was impaired by loganin. Administration of loganin reduced the clinical signs of NASH in mice fed the MCD diet, including hepatic inflammation, fat accumulation, and fibrosis. In addition, loganin reduced the expression of NLRP3 inflammasome components in the liver. Our findings indicate that loganin alleviates the inflammatory symptoms associated with NASH, presumably by inhibiting NLRP3 inflammasome activation. In summary, these findings imply that loganin may be a novel nutritional and therapeutic treatment for NASH-related inflammation.

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5Identification of Small GTPases That Phosphorylate IRF3 through TBK1 Activation Using an Active Mutant Library Screen

저자 : Jae-hyun Yu , Eun-yi Moon , Jiyoon Kim , Ja Hyun Koo

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 31권 1호 발행 연도 : 2023 페이지 : pp. 48-59 (12 pages)

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Interferon regulatory factor 3 (IRF3) integrates both immunological and non-immunological inputs to control cell survival and death. Small GTPases are versatile functional switches that lie on the very upstream in signal transduction pathways, of which duration of activation is very transient. The large number of homologous proteins and the requirement for site-directed mutagenesis have hindered attempts to investigate the link between small GTPases and IRF3. Here, we constructed a constitutively active mutant expression library for small GTPase expression using Gibson assembly cloning. Small-scale screening identified multiple GTPases capable of promoting IRF3 phosphorylation. Intriguingly, 27 of 152 GTPases, including ARF1, RHEB, RHEBL1, and RAN, were found to increase IRF3 phosphorylation. Unbiased screening enabled us to investigate the sequence-activity relationship between the GTPases and IRF3. We found that the regulation of IRF3 by small GTPases was dependent on TBK1. Our work reveals the significant contribution of GTPases in IRF3 signaling and the potential role of IRF3 in GTPase function, providing a novel therapeutic approach against diseases with GTPase overexpression or active mutations, such as cancer.

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6Thrombin Induced Apoptosis through Calcium-Mediated Activation of Cytosolic Phospholipase A2 in Intestinal Myofibroblasts

저자 : Mi Ja Park , Jong Hoon Won , Dae Kyong Kim

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 31권 1호 발행 연도 : 2023 페이지 : pp. 59-67 (9 pages)

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Thrombin is a serine protease that participates in a variety of biological signaling through protease-activated receptors. Intestinal myofibroblasts play central roles in maintaining intestinal homeostasis. In this study, we found that thrombin-induced apoptosis is mediated by the calcium-mediated activation of cytosolic phospholipase A2 in the CCD-18Co cell. Thrombin reduced cell viability by inducing apoptosis and proteinase-activated receptor-1 antagonist attenuated thrombin-induced cell death. Endogenous ceramide did not affect the cell viability itself, but a ceramide-mediated pathway was involved in thrombin-induced cell death. Thrombin increased intracellular calcium levels and cytosolic phospholipase A2 activity. The ceramide synthase inhibitor Fumonisin B1, intracellular calcium chelator BAPTA-AM, and cytosolic phospholipase A2 inhibitor AACOCF3 inhibited thrombin-induced cell death. Thrombin stimulated arachidonic acid release and reactive oxygen species generation, which was blocked by AACOCF3, BAPTA-AM, and the antioxidant reagent Trolox. Taken together, thrombin triggered apoptosis through calcium-mediated activation of cytosolic phospholipase A2 in intestinal myofibroblasts.

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7MS-5, a Naphthalene Derivative, Induces Apoptosis in Human Pancreatic Cancer BxPC-3 Cells by Modulating Reactive Oxygen Species

저자 : Suman Giri , Gyu Hwan Park , Joon-seok Choi , Eunsook Ma , Kyung-soo Chun , Sang Hoon Joo

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 31권 1호 발행 연도 : 2023 페이지 : pp. 68-73 (6 pages)

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Pancreatic cancer is one of the most fatal cancers with a poor prognosis. Standard chemotherapies have proven largely ineffective because of their toxicity and the development of resistance. Therefore, there is an urgent need to develop novel therapies. In this study, we investigated the antitumor activity of MS-5, a naphthalene derivative, on BxPC-3, a human pancreatic cancer cell line. We observed that MS-5 was cytotoxic to BxPC-3 cells, as well as inhibited the growth of cells in a concentration- and time- dependent manner. Flow cytometry analysis revealed that the percentage of annexin V-positive cells increased after MS-5 treatment. We also observed cleavage of caspases and poly (ADP-ribose) polymerase, and downregulation of Bcl-xL protein. Flow cytometry analysis of intracellular levels of reactive oxygen species (ROS) and mitochondrial superoxide suggested that MS-5 induced the generation of mitochondrial superoxide while lowering the overall intracellular ROS levels. Thus, MS-5 may be potential candidate for pancreatic cancer treatment.

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8MHY2251, a New SIRT1 Inhibitor, Induces Apoptosis via JNK/p53 Pathway in HCT116 Human Colorectal Cancer Cells

저자 : Yong Jung Kang , Young Hoon Kwon , Jung Yoon Jang , Jun Ho Lee , Sanggwon Lee , Yujin Park , Hyung Ryong Moon , Hae Young Chung , Nam Deuk Kim

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 31권 1호 발행 연도 : 2023 페이지 : pp. 73-81 (9 pages)

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Sirtuins (SIRTs) belong to the nicotinamide adenine dinucleotide (NAD+)-dependent class III histone deacetylase family. They are key regulators of cellular and physiological processes, such as cell survival, senescence, differentiation, DNA damage and stress response, cellular metabolism, and aging. SIRTs also influence carcinogenesis, making them potential targets for anticancer therapeutic strategies. In this study, we investigated the anticancer properties and underlying molecular mechanisms of a novel SIRT1 inhibitor, MHY2251, in human colorectal cancer (CRC) cells. MHY2251 reduced the viability of various human CRC cell lines, especially those with wild-type TP53. MHY2251 inhibited SIRT1 activity and SIRT1/2 protein expression, while promoting p53 acetylation, which is a target of SIRT1 in HCT116 cells. MHY2251 treatment triggered apoptosis in HCT116 cells. It increased the percentage of late apoptotic cells and the sub-G1 fraction (as detected by flow cytometric analysis) and induced DNA fragmentation. In addition, MHY2251 upregulated the expression of FasL and Fas, altered the ratio of Bax/Bcl-2, downregulated the levels of pro-caspase-8, -9, and -3 proteins, and induced subsequent poly(ADP-ribose) polymerase cleavage. The induction of apoptosis by MHY2251 was related to the activation of the caspase cascade, which was significantly attenuated by pre-treatment with ZVAD-FMK, a pan-caspase inhibitor. Furthermore, MHY2251 stimulated the phosphorylation of c-Jun N-terminal kinase (JNK), and MHY2251-triggered apoptosis was blocked by pre-treatment with SP600125, a JNK inhibitor. This finding indicated the specific involvement of JNK in MHY2251-induced apoptosis. MHY2251 shows considerable potential as a therapeutic agent for targeting human CRC via the inhibition of SIRT1 and activation of JNK/p53 pathway.

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9Functional Characterization of Drosophila melanogaster CYP6A8 Fatty Acid Hydroxylase

저자 : Sang-a Lee , Vitchan Kim , Byoungyun Choi , Hyein Lee , Young-jin Chun , Kyoung Sang Cho , Donghak Kim

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 31권 1호 발행 연도 : 2023 페이지 : pp. 82-90 (9 pages)

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Genomic analysis indicated that the genome of Drosophila melanogaster contains more than 80 cytochrome P450 genes. To date, the enzymatic activity of these P450s has not been extensively studied. Here, the biochemical properties of CYP6A8 were characterized. CYP6A8 was cloned into the pCW vector, and its recombinant enzyme was expressed in Escherichia coli and purified using Ni2+-nitrilotriacetate affinity chromatography. Its expression level was approximately 130 nmol per liter of culture. Purified CYP6A8 exhibited a low-spin state in the absolute spectra of the ferric forms. Binding titration analysis indicated that lauric acid and capric acid produced type l spectral changes, with Kd values 28 ± 4 and 144 ± 20 μM, respectively. Ultra-performance liquid chromatography-mass spectrometry analysis showed that the oxidation reaction of lauric acid produced (ω-1)-hydroxylated lauric acid as a major product and ω-hydroxy-lauric acid as a minor product. Steady-state kinetic analysis of lauric acid hydroxylation yielded a kcat value of 0.038 ± 0.002 min-1 and a Km value of 10 ± 2 μM. In addition, capric acid hydroxylation of CYP6A8 yielded kinetic parameters with a kcat value of 0.135 ± 0.007 min-1 and a Km value of 21 ± 4 μM. Because of the importance of various lipids as carbon sources, the metabolic analysis of fatty acids using CYP6A8 in this study can provide an understanding of the biochemical roles of P450 enzymes in many insects, including Drosophila melanogaster.

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10Growth Factors Upregulated by Uric Acid Affect Guanine Deaminase-Induced Melanogenesis

저자 : Nan-hyung Kim , Ai-young Lee

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 31권 1호 발행 연도 : 2023 페이지 : pp. 89-97 (9 pages)

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Uric acid produced by guanine deaminase (GDA) is involved in photoaging and hyperpigmentation. Reactive oxygen species (ROS) generated by uric acid plays a role in photoaging. However, the mechanism by which uric acid stimulates melanogenesis in GDA-overexpressing keratinocytes is unclear. Keratinocyte-derived paracrine factors have been identified as important mechanisms of ultraviolet-induced melanogenesis. Therefore, the role of paracrine melanogenic growth factors in GDA-induced hypermelanosis mediated by uric acid was examined. The relationships between ROS and these growth factors were examined. Primary cultured normal keratinocytes overexpressed with wild type or mutant GDA and those treated with xanthine or uric acid in the presence or absence of allopurinol, H2O2, or N-acetylcysteine (NAC) were used in this study. Intracellular and extracellular bFGF and SCF levels were increased in keratinocytes by wild type, but not by loss-of-function mutants of GDA overexpression. Culture supernatants from GDA-overexpressing keratinocytes stimulated melanogenesis, which was restored by anti-bFGF and anti-SCF antibodies. Allopurinol treatment reduced the expression levels of bFGF and SCF in both GDA-overexpressing and normal keratinocytes exposed to exogenous xanthine; the exogenous uric acid increased their expression levels. H2O2-stimulated tyrosinase expression and melanogenesis were restored by NAC pretreatment. However, H2O2 or NAC did not upregulate or downregulate bFGF or SCF, respectively. Overall, uric acid could be involved in melanogenesis induced by GDA overexpression in keratinocytes via bFGF and SCF upregulation not via ROS generation.

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1Strategies for Manipulating T Cells in Cancer Immunotherapy

저자 : Hyang-mi Lee

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 4호 발행 연도 : 2022 페이지 : pp. 299-308 (10 pages)

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T cells are attractive targets for the development of immunotherapy to treat cancer due to their biological features, capacity of cytotoxicity, and antigen-specific binding of receptors. Novel strategies that can modulate T cell functions or receptor reactivity provide effective therapies, including checkpoint inhibitor, bispecific antibody, and adoptive transfer of T cells transduced with tumor antigen-specific receptors. T cell-based therapies have presented successful pre-clinical/clinical outcomes despite their common immune-related adverse effects. Ongoing studies will allow us to advance current T cell therapies and develop innovative personalized T cell therapies. This review summarizes immunotherapeutic approaches with a focus on T cells. Anti-cancer T cell therapies are also discussed regarding their biological perspectives, efficacy, toxicity, challenges, and opportunities.

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2Metabolic Bone Diseases and New Drug Developments

저자 : Vijayakumar Natesan , Sung-jin Kim

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 4호 발행 연도 : 2022 페이지 : pp. 309-319 (11 pages)

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Metabolic bone diseases are serious health issues worldwide, since several million individuals over the age of 50 are at risk of bone damage and should be worried about their bone health. One in every two women and one in every four men will break a bone during their lifetime due to a metabolic bone disease. Early detection, raising bone health awareness, and maintaining a balanced healthy diet may reduce the risk of skeletal fractures caused by metabolic bone diseases. This review compiles information on the most common metabolic bone diseases (osteoporosis, primary hyperparathyroidism, osteomalacia, and fluorosis disease) seen in the global population, including their symptoms, mechanisms, and causes, as well as discussing their prevention and the development of new drugs for treatment. A large amount of research literature suggests that balanced nutrition and balanced periodic supplementation of calcium, phosphate, and vitamin D can improve re-absorption and the regrowth of bones, and inhibit the formation of skeletal fractures, except in the case of hereditary bone diseases. Meanwhile, new and improved drug formulations, such as raloxifene, teriparatide, sclerostin, denosumab, and abaloparatide, have been successfully developed and administered as treatments for metabolic bone diseases, while others (romososumab and odanacatib) are in various stages of clinical trials.

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3Behavioral Deficits in Adolescent Mice after Sub-Chronic Administration of NMDA during Early Stage of Postnatal Development

저자 : Keremkleroo Jym Adil , Chilly Gay Remonde , Edson Luck Gonzales , Kyung-jun Boo , Kyong Ja Kwon , Dong Hyun Kim , Hee Jin Kim , Jae Hoon Cheong , Chan Young Shin , Se Jin Jeon

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 4호 발행 연도 : 2022 페이지 : pp. 320-327 (8 pages)

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Neurodevelopmental disorders are complex conditions that pose difficulty in the modulation of proper motor, sensory and cognitive function due to dysregulated neuronal development. Previous studies have reported that an imbalance in the excitation/ inhibition (E/I) in the brain regulated by glutamatergic and/or GABAergic neurotransmission can cause neurodevelopmental and neuropsychiatric behavioral deficits such as autism spectrum disorder (ASD). NMDA acts as an agonist at the NMDA receptor and imitates the action of the glutamate on that receptor. NMDA however, unlike glutamate, only binds to and regulates the NMDA receptor subtypes and not the other glutamate receptors. This study seeks to determine whether NMDA administration in mice i.e., over-activation of the NMDA system would result in long-lasting behavioral deficits in the adolescent mice. Both gender mice were treated with NMDA or saline at early postnatal developmental period with significant synaptogenesis and synaptic maturation. On postnatal day 28, various behavioral experiments were conducted to assess and identify behavioral characteristics. NMDAtreated mice show social deficits, and repetitive behavior in both gender mice at adolescent periods. However, only the male mice but not female mice showed increased locomotor activity. This study implies that neonatal exposure to NMDA may illicit behavioral features similar to ASD. This study also confirms the validity of the E/I imbalance theory of ASD and that NMDA injection can be used as a pharmacologic model for ASD. Future studies may explore the mechanism behind the gender difference in locomotor activity as well as the human relevance and therapeutic significance of the present findings.

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4Repeated Morphine Administration Increases TRPV1 mRNA Expression and Autoradiographic Binding at Supraspinal Sites in the Pain Pathway

저자 : Thi-lien Nguyen , Yun-son Nam , Seok-yong Lee , Choon-gon Jang

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 4호 발행 연도 : 2022 페이지 : pp. 328-333 (6 pages)

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Repeated morphine administration induces tolerance to its analgesic effects. A previous study reported that repeated morphine treatment activates transient receptor potential vanilloid type 1 (TRPV1) expression in the sciatic nerve, dorsal root ganglion, and spinal cord, contributing to morphine tolerance. In the present study, we analyzed TRPV1 expression and binding sites in supraspinal pain pathways in morphine-tolerant mice. The TRPV1 mRNA levels and binding sites were remarkably increased in the cortex and thalamus of these animals. Our data provide additional insights into the effects of morphine on TRPV1 in the brain and suggest that changes in the expression of, and binding to TRPV1 in the brain are involved in morphine tolerance.

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5Peroxiredoxin 6 Overexpression Induces Anxiolytic and Depression-Like Behaviors by Regulating the Serotonergic Pathway in Mice

저자 : Sun Mi Gu , Eunhye Yu , Young Eun Kim , Seong Shoon Yoon , Dohyun Lee , Jin Tae Hong , Jaesuk Yun

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 4호 발행 연도 : 2022 페이지 : pp. 334-339 (6 pages)

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Peroxiredoxin 6 (PRDX6) is a bifunctional protein with both glutathione peroxidase and calcium-independent phospholipase activity. Recently, we reported that PRDX6 plays an important role in dopaminergic neurodegeneration in Parkinson's disease. However, the relationship between PRDX6 function and emotional behavior remains elusive. In the present study, we examined depression- and anxiety-like behaviors in PRDX6-overexpressing transgenic (PRDX6-Tg) mice using the forced swim test, tail suspension test, open field paradigm, and elevated plus-maze. PRDX6-Tg mice exhibited depression-like behaviors and low anxiety. In particular, female PRDX6-Tg mice exhibited anxiolytic behavior in the open field test. Furthermore, the serotonin content in the cortex and 5-hydroxytryptophan-induced head twitch response were both reduced in PRDX6-Tg mice. Interestingly, levels of dopa decarboxylase expression in the cortex were decreased in male PRDX6-Tg mice but not in female mice. Our findings provide novel insights into the role of PRDX6 in 5-HT synthesis and suggest that PRDX6 overexpression can induce depression-like behaviors via downregulation of the serotonergic neuronal system.

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6PRR16/Largen Induces Epithelial-Mesenchymal Transition through the Interaction with ABI2 Leading to the Activation of ABL1 Kinase

저자 : Gyeoung Jin Kang , Jung Ho Park , Hyun Ji Kim , Eun Ji Kim , Boram Kim , Hyun Jung Byun , Lu Yu , Tuan Minh Nguyen , Thi Ha Nguyen , Kyung Sung Kim , Hiệu Phùng Huy , Mostafizur Rahman , Ye Hyeon Kim ,

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 4호 발행 연도 : 2022 페이지 : pp. 340-347 (8 pages)

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Advanced or metastatic breast cancer affects multiple organs and is a leading cause of cancer-related death. Cancer metastasis is associated with epithelial-mesenchymal metastasis (EMT). However, the specific signals that induce and regulate EMT in carcinoma cells remain unclear. PRR16/Largen is a cell size regulator that is independent of mTOR and Hippo signalling pathways. However, little is known about the role PRR16 plays in the EMT process. We found that the expression of PRR16 was increased in mesenchymal breast cancer cell lines. PRR16 overexpression induced EMT in MCF7 breast cancer cells and enhances migration and invasion. To determine how PRR16 induces EMT, the binding proteins for PRR16 were screened, revealing that PRR16 binds to Abl interactor 2 (ABI2). We then investigated whether ABI2 is involved in EMT. Gene silencing of ABI2 induces EMT, leading to enhanced migration and invasion. ABI2 is a gene that codes for a protein that interacts with ABL proto-oncogene 1 (ABL1) kinase. Therefore, we investigated whether the change in ABI2 expression affected the activation of ABL1 kinase. The knockdown of ABI2 and PRR16 overexpression increased the phosphorylation of Y412 in ABL1 kinase. Our results suggest that PRR16 may be involved in EMT by binding to ABI2 and interfering with its inhibition of ABL1 kinase. This indicates that ABL1 kinase inhibitors may be potential therapeutic agents for the treatment of PRR16-related breast cancer.

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7Benzyl Isothiocyanate-Induced Cytotoxicity via the Inhibition of Autophagy and Lysosomal Function in AGS Cells

저자 : Wah Wah Po , Won Seok Choi , Tin Myo Khing , Ji-yun Lee , Jong Hyuk Lee , Joon Seok Bang , Young Sil Min , Ji Hoon Jeong , Uy Dong Sohn

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 4호 발행 연도 : 2022 페이지 : pp. 348-359 (12 pages)

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Gastric adenocarcinoma is among the top causes of cancer-related death and is one of the most commonly diagnosed carcinomas worldwide. Benzyl isothiocyanate (BITC) has been reported to inhibit the gastric cancer metastasis. In our previous study, BITC induced apoptosis in AGS cells. The purpose of the present study was to investigate the effect of BITC on autophagy mechanism in AGS cells. First, the AGS cells were treated with 5, 10, or 15 μM BITC for 24 h, followed by an analysis of the autophagy mechanism. The expression level of autophagy proteins involved in different steps of autophagy, such as LC3B, p62/SQSTM1, Atg5-Atg12, Beclin1, p-mTOR/mTOR ratio, and class III PI3K was measured in the BITC-treated cells. Lysosomal function was investigated using cathepsin activity and Bafilomycin A1, an autophagy degradation stage inhibitor. Methods including qPCR, western blotting, and immunocytochemistry were employed to detect the protein expression levels. Acridine orange staining and omnicathepsin assay were conducted to analyze the lysosomal function. siRNA transfection was performed to knock down the LC3B gene. BITC reduced the level of autophagy protein such as Beclin 1, class III PI3K, and Atg5-Atg12. BITC also induced lysosomal dysfunction which was shown as reducing cathepsin activity, protein level of cathepsin, and enlargement of acidic vesicle. Overall, the results showed that the BITC-induced AGS cell death mechanism also comprises the inhibition of the cytoprotective autophagy at both initiation and degradation steps.

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8Characterization of KRC-108 as a TrkA Kinase Inhibitor with Anti-Tumor Effects

저자 : Hyo Jeong Lee , Yeongyu Moon , Jungil Choi , Jeong Doo Heo , Sekwang Kim , Hari Krishna Nallapaneni , Young-won Chin , Jongkook Lee , Sun-young Han

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 4호 발행 연도 : 2022 페이지 : pp. 360-367 (8 pages)

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Tropomyosin receptor kinase A (TrkA) protein is a receptor tyrosine kinase encoded by the NTRK1 gene. TrkA signaling mediates the proliferation, differentiation, and survival of neurons and other cells following stimulation by its ligand, the nerve growth factor. Chromosomal rearrangements of the NTRK1 gene result in the generation of TrkA fusion protein, which is known to cause deregulation of TrkA signaling. Targeting TrkA activity represents a promising strategy for the treatment of cancers that harbor the TrkA fusion protein. In this study, we evaluated the TrkA-inhibitory activity of the benzoxazole compound KRC-108. KRC-108 inhibited TrkA activity in an in vitro kinase assay, and suppressed the growth of KM12C colon cancer cells harboring an NTRK1 gene fusion. KRC-108 treatment induced cell cycle arrest, apoptotic cell death, and autophagy. KRC-108 suppressed the phosphorylation of downstream signaling molecules of TrkA, including Akt, phospholipase Cγ, and ERK1/2. Furthermore, KRC-108 exhibited antitumor activity in vivo in a KM12C cell xenograft model. These results indicate that KRC-108 may be a promising therapeutic agent for Trk fusion-positive cancers.

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9High Levels of Hyaluronic Acid Synthase-2 Mediate NRF2-Driven Chemoresistance in Breast Cancer Cells

저자 : Bo-hyun Choi , Ingeun Ryoo , Kyeong Hwa Sim , Hyeon-jin Ahn , Youn Ju Lee , Mi-kyoung Kwak

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 4호 발행 연도 : 2022 페이지 : pp. 368-379 (12 pages)

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Hyaluronic acid (HA), a ligand of CD44, accumulates in some types of tumors and is responsible for tumor progression. The nuclear factor erythroid 2-like 2 (NRF2) regulates cytoprotective genes and drug transporters, which promotes therapy resistance in tumors. Previously, we showed that high levels of CD44 are associated with NRF2 activation in cancer stem like-cells. Herein, we demonstrate that HA production was increased in doxorubicin-resistant breast cancer MCF7 cells (MCF7-DR) via the upregulation of HA synthase-2 (HAS2). HA incubation increased NRF2, aldo-keto reductase 1C1 (AKR1C1), and multidrug resistance gene 1 (MDR1) levels. Silencing of HAS2 or CD44 suppressed NRF2 signaling in MCF7-DR, which was accompanied by increased doxorubicin sensitivity. The treatment with a HAS2 inhibitor, 4-methylumbelliferone (4-MU), decreased NRF2, AKR1C1, and MDR1 levels in MCF7-DR. Subsequently, 4-MU treatment inhibited sphere formation and doxorubicin resistance in MCF7-DR. The Cancer Genome Atlas (TCGA) data analysis across 32 types of tumors indicates the amplification of HAS2 gene is a common genetic alteration and is negatively correlated with the overall survival rate. In addition, high HAS2 mRNA levels are associated with increased NRF2 signaling and poor clinical outcome in breast cancer patients. Collectively, these indicate that HAS2 elevation contributes to chemoresistance and sphere formation capacity of drug-resistant MCF7 cells by activating CD44/ NRF2 signaling, suggesting a potential benefit of HAS2 inhibition.

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10Snail Promotes Cancer Cell Proliferation via Its Interaction with the BIRC3

저자 : Seung Bae Rho , Hyun-jung Byun , Boh-ram Kim , Chang Hoon Lee

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 4호 발행 연도 : 2022 페이지 : pp. 380-388 (9 pages)

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Snail is implicated in tumour growth and metastasis and is up-regulated in various human tumours. Although the role of Snails in epithelial-mesenchymal transition, which is particularly important in cancer metastasis, is well known, how they regulate tumour growth is poorly described. In this study, the possible molecular mechanisms of Snail in tumour growth were explored. Baculoviral inhibitor of apoptosis protein (IAP) repeat-containing protein 3 (BIRC3), a co-activator of cell proliferation during tumourigenesis, was identified as a Snail-binding protein via a yeast two-hybrid system. Since BIRC3 is important for cell survival, the effect of BIRC3 binding partner Snail on cell survival was investigated in ovarian cancer cell lines. Results revealed that Bax expression was activated, while the expression levels of anti-apoptotic proteins were markedly decreased by small interfering RNA (siRNA) specific for Snail (siSnail). siSnail, the binding partner of siBIRC3, activated the tumour suppressor function of p53 by promoting p53 protein stability. Conversely, BIRC3 could interact with Snail, for this reason, the possibility of BIRC3 involvement in EMT was investigated. BIRC3 overexpression resulted in a decreased expression of the epithelial marker and an increased expression of the mesenchymal markers. siSnail or siBIRC3 reduced the mRNA levels of matrix metalloproteinase (MMP)-2 and MMP-9. These results provide evidence that Snail promotes cell proliferation by interacting with BIRC3 and that BIRC3 might be involved in EMT via binding to Snail in ovarian cancer cells. Therefore, our results suggested the novel relevance of BIRC3, the binding partner of Snail, in ovarian cancer development.

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