Publications by authors named "Hyun-Shik Lee"

119 Publications

Overexpression of Lin28a Aggravates Psoriasis-Like Phenotype by Regulating the Proliferation and Differentiation of Keratinocytes.

J Inflamm Res 2021 30;14:4299-4312. Epub 2021 Aug 30.

School of Life Sciences, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu, Korea.

Purpose: Psoriasis is a common and well-studied autoimmune skin disease, which is characterized by plaques. The formation of psoriasis plaques occurs through the hyperproliferation and abnormal differentiation of keratinocytes, infiltration of numerous immune cells into the dermis, increased subepidermal angiogenesis, and various autoimmune-associated cytokines and chemokines. According to previous research, Lin28 regulates the let-7 family, and let-7b is associated with psoriasis. However, the link between Lin28 and psoriasis is unclear. In this study, an association was identified between and psoriasis progression, which promoted the pathological characteristic of psoriasis in epidermal keratinocytes.

Patients And Methods: This study aims to investigate the role of Lin28a and its underlying mechanism in psoriasis through in vivo and in vitro models, which include the Lin28a-overexpressing transgenic (TG) mice and Lin28a-overexpressing human keratinocyte (HaCaT) cell lines, respectively.

Results: In vivo and in vitro results revealed that overexpression of downregulated microRNA let-7 expression levels and caused hyperproliferation and abnormal differentiation in keratinocytes. In imiquimod (IMQ)-induced psoriasis-like inflammation, overexpressing transgenic (TG) mice exhibited more severe symptoms of psoriasis.

Conclusion: Mechanistically, exacerbated psoriasis-like inflammation through the activation of the extracellular-signal-regulated kinase (ERK) and signal transducer and activator of transcription 3 signaling (STAT 3) by targeting proinflammatory cytokine interleukin-6 (IL-6).
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http://dx.doi.org/10.2147/JIR.S312963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8415766PMC
August 2021

2-IPMA Ameliorates PM2.5-Induced Inflammation by Promoting Primary Ciliogenesis in RPE Cells.

Molecules 2021 Sep 6;26(17). Epub 2021 Sep 6.

BK21 FOUR KNU Creative BioResearch Group, School of Life Sciences, Kyungpook National University, Daegu 41566, Korea.

Primary cilia mediate the interactions between cells and external stresses. Thus, dysregulation of primary cilia is implicated in various ciliopathies, e.g., degeneration of the retina caused by dysregulation of the photoreceptor primary cilium. Particulate matter (PM) can cause epithelium injury and endothelial dysfunction by increasing oxidative stress and inflammatory responses. Previously, we showed that PM disrupts the formation of primary cilia in retinal pigment epithelium (RPE) cells. In the present study, we identified 2-isopropylmalic acid (2-IPMA) as a novel inducer of primary ciliogenesis from a metabolite library screening. Both ciliated cells and primary cilium length were increased in 2-IPMA-treated RPE cells. Notably, 2-IPMA strongly promoted primary ciliogenesis and restored PM2.5-induced dysgenesis of primary cilia in RPE cells. Both excessive reactive oxygen species (ROS) generation and activation of a stress kinase, JNK, by PM2.5 were reduced by 2-IPMA. Moreover, 2-IPMA inhibited proinflammatory cytokine production, i.e., IL-6 and TNF-α, induced by PM2.5 in RPE cells. Taken together, our data suggest that 2-IPMA ameliorates PM2.5-induced inflammation by promoting primary ciliogenesis in RPE cells.
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http://dx.doi.org/10.3390/molecules26175409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8433925PMC
September 2021

Anti-inflammatory effect of Ailanthus altissima (Mill.) Swingle leaves in lipopolysaccharide-stimulated astrocytes.

J Ethnopharmacol 2021 Jul 13:114258. Epub 2021 Jul 13.

Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul, 06974, Republic of Korea. Electronic address:

Ethnopharmacological Relevance: Activated astrocytes are involved in the progression of neurodegenerative diseases. Traditionally, Ailanthus altissima (Mill.) Swingle, widely distributed in East Asia, has been used as a medicine for the treatment of fever, gastric diseases, and inflammation. Although A. altissima has been reported to play an anti-inflammatory role in peripheral tissues or cells, its role in the central nervous system (CNS) remains unclear.

Aim Of The Study: In the present study, we investigated the anti-inflammatory effects and mechanism of action of A. altissima in primary astrocytes stimulated by lipopolysaccharide (LPS).

Materials And Methods: A nitrite assay was used to measure nitric oxide (NO) production, and the tetrazolium salt 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay was performed to determine cytotoxicity. The expression levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and mitogen-activated protein kinase (MAPK) were determined with western blotting. Reverse-transcription PCR was used to assess the expression of inflammatory cytokines. The levels of reactive oxygen species were measured using 2,7-dichlorodihydrofluorescein diacetate. Luciferase assay and immunocytochemistry were used for assessing nuclear factor-kappa B (NF-κB) transcription and p65 localization, respectively. Memory and social interaction were analyzed using the Y-maze and three-chamber tests, respectively.

Results: The ethanol extract of A. altissima leaves (AAE) inhibited iNOS and COX-2 expression in LPS-stimulated astrocytes. Moreover, AAE reduced the transcription of various proinflammatory mediators, hindered NF-κB activation, and suppressed extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) activation without p38 activation. Ultra-high performance liquid chromatography with mass spectrometry analysis revealed that AAE comprised ethyl gallate, quercetin, and kaempferol, along with luteolin, which has anti-inflammatory properties, and repressed LPS-induced nitrite levels and the nuclear translocation of p65. Finally, oral administration of AAE attenuated LPS-induced memory and social impairment in mice and repressed LPS-induced ERK and JNK activation in the cortices of mice.

Conclusion: AAE could have therapeutic uses in the treatment of neuroinflammatory diseases via suppression of astrocyte activation.
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http://dx.doi.org/10.1016/j.jep.2021.114258DOI Listing
July 2021

Depletion of HNRNPA1 induces peroxisomal autophagy by regulating PEX1 expression.

Biochem Biophys Res Commun 2021 03 3;545:69-74. Epub 2021 Feb 3.

School of Life Sciences, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu, 41566, South Korea. Electronic address:

Peroxisomes play an essential role in cellular homeostasis by regulating lipid metabolism and the conversion of reactive oxygen species (ROS). Several peroxisomal proteins, known as peroxins (PEXs), control peroxisome biogenesis and degradation. Various mutations in the PEX genes are genetic causes for the development of inheritable peroxisomal-biogenesis disorders, such as Zellweger syndrome. Among the peroxins, PEX1 defects are the most common mutations in Zellweger syndrome. PEX1 is an AAA-ATPase that regulates the recycling of PEX5, which is essential for importing peroxisome matrix proteins. However, the post-transcriptional regulation of PEX1 is largely unknown. Here, we showed that heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) controls PEX1 expression. In addition, we found that depletion of HNRNPA1 induces autophagic degradation of peroxisome, which is blocked in ATG5-knockout cells. In addition, depletion of HNRNPA1 increased peroxisomal ROS levels. Inhibition of the generation of peroxisomal ROS by treatment with NAC significantly suppressed pexophagy in HNRNPA1-deficient cells. Taken together, our results suggest that depletion of HNRNPA1 increases peroxisomal ROS and pexophagy by downregulating PEX1 expression.
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http://dx.doi.org/10.1016/j.bbrc.2021.01.083DOI Listing
March 2021

Mediates Posterior Development by Regulating Cell Death during Embryogenesis.

Antioxidants (Basel) 2020 Dec 12;9(12). Epub 2020 Dec 12.

KNU-Center for Nonlinear Dynamics, CMRI, BK21 Plus KNU Creative BioResearch Group, School of Life Sciences, College of Natural Sciences, Kyungpook National University, Daegu 41566, Korea.

Glutathione peroxidase 3 (GPx3) belongs to the glutathione peroxidase family of selenoproteins and is a key antioxidant enzyme in multicellular organisms against oxidative damage. Downregulation of GPx3 affects tumor progression and metastasis and is associated with liver and heart disease. However, the physiological significance of GPx3 in vertebrate embryonic development remains poorly understood. The current study aimed to investigate the functional roles of during embryogenesis. To this end, we determined 's spatiotemporal expression using as a model organism. Using reverse transcription polymerase chain reaction (RT-PCR), we demonstrated the zygotic nature of this gene. Interestingly, the expression of enhanced during the tailbud stage of development, and whole mount in situ hybridization (WISH) analysis revealed localization in prospective tail region of developing embryo. knockdown using antisense morpholino oligonucleotides (MOs) resulted in short post-anal tails, and these malformed tails were significantly rescued by glutathione peroxidase mimic ebselen. The gene expression analysis indicated that knockdown significantly altered the expression of genes associated with Wnt, Notch, and bone morphogenetic protein (BMP) signaling pathways involved in tailbud development. Moreover, RNA sequencing identified that plays a role in regulation of cell death in the developing embryo. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and phospho-histone 3 (PH3) staining confirmed the association of knockdown with increased cell death and decreased cell proliferation in tail region of developing embryos, establishing the involvement of in tailbud development by regulating the cell death. Furthermore, these findings are inter-related with increased reactive oxygen species (ROS) levels in knockdown embryos, as measured by using a redox-sensitive fluorescent probe HyPer. Taken together, our results suggest that plays a critical role in posterior embryonic development by regulating cell death and proliferation during vertebrate embryogenesis.
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http://dx.doi.org/10.3390/antiox9121265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764483PMC
December 2020

Peroxiredoxin 2 deficiency reduces white adipogenesis due to the excessive ROS generation.

Cell Biol Int 2020 Oct 16;44(10):2086-2093. Epub 2020 Jul 16.

School of Life Sciences, BK21 Plus KNU Creative Bioresearch Group, Kyungpook National University, Daegu, Republic of Korea.

Reactive oxygen species (ROS) act as signaling molecules to regulate various cell functions. Numerous studies have demonstrated ROS to be essential for the differentiation of adipocytes. Peroxiredoxins (Prxs) are a ubiquitous family of antioxidant enzymes in mammalian cells. Prx2 is present in the cytoplasm and cell membranes and demonstrates ROS scavenging activity. We focused on Prx2 involvement in regulating adipogenesis and lipid accumulation and demonstrated that Prx2 expression was upregulated during adipocyte differentiation. In addition, the silencing of Prx2 (shPrx2) inhibited adipogenesis by modulating adipogenic gene expression, and cell death was enhanced via increased ROS production in shPrx2-3T3-L1 cells. These results demonstrate that shPrx2 triggers adipocyte cell death and weakens adipocyte function via ROS production. Taken together, our data suggest the participation of Prx2 in adipocyte function and differentiation. Our results also imply that the downregulation of Prx2 activity could help prevent obesity. Overall, findings support the development of ROS-based therapeutic solutions for the treatment of obesity and obesity-related metabolic disorders.
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http://dx.doi.org/10.1002/cbin.11417DOI Listing
October 2020

Dach1 regulates neural crest migration during embryonic development.

Biochem Biophys Res Commun 2020 07 16;527(4):896-901. Epub 2020 May 16.

KNU-Center for Nonlinear Dynamics, CMRI, School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University, Daegu, 41566, South Korea. Electronic address:

Dachshund 1(Dach1) is a key component of the retinal determination gene network that plays significant roles in cell fate regulation. The vertebrate homolog of Drosophila dachshund has gained considerable importance as an essential regulator of development, but its functions during embryonic development remain elusive. We investigated the functional significance of dach1 during Xenopus embryogenesis using loss-of-function studies. Reverse transcription-polymerase chain reaction demonstrated the maternal nature of dach1, showing enhanced expression at the neurula stage of development, and morpholino oligonucleotide injection of dach1 induced phenotypic anomalies of microcephaly and reduced body length. Animal cap assays followed by whole-mount in-situ hybridization indicated the perturbed expression of neural and neural crest (NC) markers. Our data suggest the prerequisite functions of dach1 in NC migration during Xenopus embryogenesis. However, the developmental pathways regulated by dach1 during embryogenesis require further elucidation.
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http://dx.doi.org/10.1016/j.bbrc.2020.05.009DOI Listing
July 2020

Peroxiredoxin 4 attenuates glutamate-induced neuronal cell death through inhibition of endoplasmic reticulum stress.

Free Radic Res 2020 Apr 5;54(4):207-220. Epub 2020 May 5.

School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea;

High concentrations of glutamate induce neurotoxicity by eliciting reactive oxygen species (ROS) generation and intracellular Ca influx. The disruption of Ca homeostasis in the endoplasmic reticulum (ER) evokes ER stress, ultimately resulting in neuronal dysfunction. Additionally, glutamate participates in the development of neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. Peroxiredoxins (Prxs) are members of a family of antioxidant enzymes that protect cells from neurotoxic factor-induced apoptosis by scavenging hydrogen peroxide (HO). Prx4 is located in the ER and controls the redox condition within the ER. The present study investigated the protective effects of Prx4 against glutamate-induced neurotoxicity linked to ER stress. HT22 cells in which Prx4 was either overexpressed or silenced were used to elucidate the protective role of Prx4 against glutamate toxicity. The expression of Prx4 in HT22 cells was significantly increased in response to glutamate treatment, while ROS scavengers and ER chemical chaperones reduced Prx4 levels. Moreover, Prx4 overexpression reduces glutamate-induced apoptosis of HT22 cells by inhibiting ROS formation, Ca influx, and ER stress. Therefore, we conclude that Prx4 has protective effects against glutamate-induced HT22 cell damage. Collectively, these results suggest that Prx4 could contribute to the treatment of neuronal disorders.
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http://dx.doi.org/10.1080/10715762.2020.1745201DOI Listing
April 2020

Peroxiredoxin 4 inhibits insulin-induced adipogenesis through regulation of ER stress in 3T3-L1 cells.

Mol Cell Biochem 2020 May 17;468(1-2):97-109. Epub 2020 Mar 17.

School of Life Sciences, BK21 Plus KNU Creative Bioresearch Group, Kyungpook National University, Daegu, Republic of Korea.

Obesity was originally considered a disease endemic to developed countries but has since emerged as a global health problem. Obesity is characterized by abnormal or excessive lipid accumulation (World Health Organization, WHO) resulting from pre-adipocyte differentiation (adipogenesis). The endoplasmic reticulum (ER) produces proteins and cholesterol and shuttles these compounds to their target sites. Many studies have implicated ER stress, indicative of ER dysfunction, in adipogenesis. Reactive oxygen species (ROS) are also known to be involved in pre-adipocyte differentiation. Prx4 specific to the ER lumen exhibits ROS scavenging activity, and we thereby focused on ER-specific Prx4 in tracking changes in adipocyte differentiation and lipid accumulation. Overexpression of Prx4 reduced ER stress and suppressed lipid accumulation by regulating adipogenic gene expression during adipogenesis. Our results demonstrate that Prx4 inhibits ER stress, lowers ROS levels, and attenuates pre-adipocyte differentiation. These findings suggested enhancing the activity of Prx4 may be helpful in the treatment of obesity; the data also support the development of new therapeutic approaches to obesity and obesity-related metabolic disorders.
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http://dx.doi.org/10.1007/s11010-020-03714-wDOI Listing
May 2020

Polyozellin alleviates atopic dermatitis-like inflammatory and pruritic responses in activated keratinocytes and mast cells.

Biomed Pharmacother 2020 Feb 30;122:109743. Epub 2019 Dec 30.

Cell & Matrix Research Institute, Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea. Electronic address:

Polyozellus multiplex is an edible mushroom that offers beneficial pharmacological effects against intestinal inflammation and cancer. Previous studies have demonstrated that polyozellin, a major component of P. multiplex, has therapeutic activities against inflammation, cancer, and oxidative stress-related disorders. This study aimed to determine the pharmacological effects of polyozellin on inflammatory and pruritic responses, the major symptoms of atopic dermatitis (AD), and to define its underlying mechanism of action. Our results showed that polyozellin inhibited the expression of inflammatory cytokines and chemokines through blockade of signal transducer and activator of transcription 1 and nuclear factor-κB in activated keratinocytes, the major cells involved in AD progression. Based on the histological and immunological analyses, oral treatment with polyozellin attenuated the Dermatophagoides farinae extract (DFE)/2,4-dinitrochlorobenzene (DNCB)-induced atopic inflammatory symptoms in the skin. Pruritus is an unpleasant sensation for AD patients that causes scratching behavior and ultimately exacerbates the severity of AD. To find a possible explanation for the anti-pruritic effects of polyozellin, we investigated its effects on mast cells and mast cell-derived histamines. Oral treatment with polyozellin reduced the DFE/DNCB-induced tissue infiltration of mast cells, the serum histamine levels, and the histaminergic scratching behaviors. Additionally, polyozellin decreased the immunoglobulin E-stimulated degranulation of mast cells. Taken together, the findings of this study provide us with novel insights into the potential pharmacological targets of polyozellin for treating AD by inhibiting the inflammatory and pruritic responses.
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http://dx.doi.org/10.1016/j.biopha.2019.109743DOI Listing
February 2020

Cathepsin K inhibition-induced mitochondrial ROS enhances sensitivity of cancer cells to anti-cancer drugs through USP27x-mediated Bim protein stabilization.

Redox Biol 2020 02 31;30:101422. Epub 2019 Dec 31.

Department of Immunology, School of Medicine, Keimyung University, 1095 Dalgubeoldaero, Dalseo-Gu, Daegu, 42601, South Korea. Electronic address:

Cathepsin K (Cat K) is expressed in cancer cells, but the effect of Cat K on apoptosis is still elusive. Here, we showed that inhibition of Cat K sensitized the human carcinoma cells to anti-cancer drug through up-regulation of Bim. Inhibition of Cat K increased USP27x expression, and knock down of USP27x markedly blocked Cat K-induced up-regulation of Bim expression. Furthermore, inhibition of Cat K induced proteasome-dependent degradation of regulatory associated protein of mammalian target of rapamycin (Raptor). Down-regulation of Raptor expression increased mitochondrial ROS production, and mitochondria specific superoxide scavengers prevented USP27x-mediated stabilization of Bim by inhibition of Cat K. Moreover, combined treatment with Cat K inhibitor (odanacatib) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) reduced tumor growth and induced cell death in a xenograft model. Our results demonstrate that Cat K inhibition enhances anti-cancer drug sensitivity through USP27x-mediated the up-regulation of Bim via the down-regulation of Raptor.
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http://dx.doi.org/10.1016/j.redox.2019.101422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948260PMC
February 2020

Curcumin Ameliorates Nonalcoholic Fatty Liver Disease through Inhibition of -GlcNAcylation.

Nutrients 2019 Nov 8;11(11). Epub 2019 Nov 8.

School of Life Science and Biotechnology, BK21 Plus KNU Creative BioResearch Group, College of Natural Science, Kyungpook National University, Daegu 41566, Korea.

The cause of progression to non-alcoholic fatty liver disease (NAFLD) is not fully understood. In the present study, we aimed to investigate how curcumin, a natural phytopolyphenol pigment, ameliorates NAFLD. Initially, we demonstrated that curcumin dramatically suppresses fat accumulation and hepatic injury induced in methionine and choline-deficient (MCD) diet mice. The severity of hepatic inflammation was alleviated by curcumin treatment. To identify the proteins involved in the pathogenesis of NAFLD, we also characterized the hepatic proteome in MCD diet mice. As a result of two-dimensional proteomic analysis, it was confirmed that thirteen proteins including antioxidant protein were differentially expressed in hepatic steatosis. However, the difference in expression was markedly improved by curcumin treatment. Interestingly, eight of the identified proteins are known to undergo -GlcNAcylation modification. Thus, we further focused on elucidating how the regulation of -linked β--acetylglucosamine (-GlcNAc) modification is associated with the progression of hepatic steatosis leading to hepatitis in MCD diet mice. In parallel with lipid accumulation and inflammation, the MCD diet significantly up-regulated hexosamine biosynthetic pathway (HBP) and -GlcNAc transferase (OGT) via ER stress. Curcumin treatment alleviates the severity of hepatic steatosis by relieving the dependence of -GlcNAcylation on nuclear factor-κB (NF-κB) in inflammation signaling. Conversely, the expressions of superoxide dismutase 1 (SOD1) and SIRT1 were significantly upregulated by curcumin treatment. In conclusion, curcumin inhibits -GlcNAcylation pathway, leading to antioxidant responses in non-alcoholic steatohepatitis (NASH) mice. Therefore, curcumin will be a promising therapeutic agent for diseases involving hyper--GlcNAcylation, including cancer.
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http://dx.doi.org/10.3390/nu11112702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893521PMC
November 2019

Increasing ERK phosphorylation by inhibition of p38 activity protects against cadmium-induced apoptotic cell death through ERK/Drp1/p38 signaling axis in spermatocyte-derived GC-2spd cells.

Toxicol Appl Pharmacol 2019 12 30;384:114797. Epub 2019 Oct 30.

School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea; School of Life Sciences & Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea. Electronic address:

Many studies report that cadmium chloride (CdCl)-induces oxidative stress is associated with male reproductive damage in the testes. CdCl also induces mitochondrial fission by increasing dynamin-related protein 1 (Drp1) expression as well as the mitochondria-dependent apoptosis pathway by extracellular signal-regulated kinase (ERK) activation. However, it remains unclear whether mechanisms linked to the mitochondrial damage signal via CdCl-induced mitogen-activated protein kinases (MAPK) cause damage to spermatocytes. In this study, increased intracellular and mitochondrial reactive oxygen species (ROS) levels, mitochondrial membrane potential (∆Ψm) depolarization, and mitochondrial fragmentation and swelling were observed at 5 μM of CdCl exposure, resulting in increased apoptotic cell death. Moreover, CdCl-induced cell death is closely associated with the ERK/Drp1/p38 signaling axis. Interestingly, SB203580, a p38 inhibitor, effectively prevented CdCl-induced apoptotic cell death by reducing ∆Ψm depolarization and intracellular and mitochondrial ROS levels. Knockdown of Drp1 expression diminished CdCl-induced mitochondrial deformation and ROS generation and protected GC-2spd cells from apoptotic cell death. In addition, electron microscopy showed that p38 inhibition reduced CdCl2-induced mitochondrial interior damage more effectively than N-acetyl-L-cysteine (NAC), an ROS scavenger; ERK inhibition; or Drp1 knockdown. Therefore, these results demonstrate that inhibition of p38 activity prevents CdCl-induced apoptotic GC-2spd cell death by reducing depolarization of mitochondrial membrane potential and mitochondrial ROS levels via ERK phosphorylation in a signal pathway different from the CdCl-induced ERK/Drp1/p38 axis and suggest a therapeutic strategy for CdCl-induced male infertility.
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http://dx.doi.org/10.1016/j.taap.2019.114797DOI Listing
December 2019

PKCδ Mediates NF-κB Inflammatory Response and Downregulates SIRT1 Expression in Liver Fibrosis.

Int J Mol Sci 2019 Sep 17;20(18). Epub 2019 Sep 17.

School of Life Science and Biotechnology, BK21 Plus KNU Creative BioResearch Group, College of Natural Science, Kyungpook National University, Daegu 41566, Korea.

The precise mechanism of hepatic cirrhosis remains largely unclear. In particular, a potential regulatory mechanism by which protein kinase C-delta (PKCδ ) affects profibrogenic gene expression involved in hepatic cirrhosis has never been explored. In the present study, we investigated whether PKCδ activation is involved in liver inflammatory fibrosis in both lipopolysaccharide (LPS)-treated RAW 264.7 and CCl-treated mice. PKCδ was strongly activated by LPS or CCl treatment and consequently stimulated nuclear factor (NF)-κB inflammatory response. Interestingly, the activation of PKCδ negatively regulated sirtuin-1 (SIRT1) expression, whereas PKCδ suppression by PKCδ peptide inhibitor V1-1 or siRNA dramatically increased SIRT1 expression. Furthermore, we showed that the negative regulation of PKCδ leads to a decrease in SIRT1 expression. To our knowledge, these results are the first demonstration of the involvement of PKCδ in modulating NF-κB through SIRT1 signaling in fibrosis in mice, suggesting a novel role of PKCδ in inflammatory fibrosis. The level of NF-κB p65 in the nucleus was also negatively regulated by SIRT1 activity. We showed that the inhibition of PKCδ promoted SIRT1 expression and decreased p65 levels in the nucleus through deacetylation. Moreover, the inactivation of PKCδ with V1-1 dramatically suppressed the inflammatory fibrosis, indicating that PKCδ represents a promising target for treating fibrotic diseases like hepatic cirrhosis.
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http://dx.doi.org/10.3390/ijms20184607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770793PMC
September 2019

Peroxiredoxin 5 ameliorates obesity-induced non-alcoholic fatty liver disease through the regulation of oxidative stress and AMP-activated protein kinase signaling.

Redox Biol 2020 01 3;28:101315. Epub 2019 Sep 3.

School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, South Korea; School of Life Sciences & Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu, South Korea. Electronic address:

Non-alcoholic fatty liver disease (NAFLD) is becoming the most common chronic liver disease globally. NAFLD-which can develop into liver fibrosis, nonalcoholic steatohepatosis, cirrhosis, and hepatocellular carcinoma-is defined as an excess accumulation of fat caused by abnormal lipid metabolism and excessive reactive oxygen species (ROS) generation in hepatocytes. Recently, we reported that Peroxiredoxin 5 (Prx5) plays an essential role in regulating adipogenesis and suggested the need to further investigation on the potential curative effects of Prx5 on obesity-induced fatty liver disease. In the present study, we focused on the role of Prx5 in fatty liver disease. We found that Prx5 overexpression significantly suppressed cytosolic and mitochondrial ROS generation. Additionally, Prx5 regulated the AMP-activated protein kinase pathway and lipogenic gene (sterol regulatory element binding protein-1 and FAS) expression; it also inhibited lipid accumulation, resulting in the amelioration of free fatty acid-induced hepatic steatosis. Silence of Prx5 triggered de novo lipogenesis and abnormal lipid accumulation in HepG2 cells. Concordantly, Prx5 knockout mice exhibited a high susceptibility to obesity-induced hepatic steatosis. Liver sections of Prx5-deletion mice fed on a high-fat diet displayed Oil Red O-stained dots and small leaky shapes due to immoderate fat deposition. Collectively, our findings suggest that Prx5 functions as a protective regulator in fatty liver disease and that it may be a valuable therapeutic target for the management of obesity-related metabolic diseases.
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http://dx.doi.org/10.1016/j.redox.2019.101315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736789PMC
January 2020

Reactive oxygen species-mediated senescence is accelerated by inhibiting Cdk2 in Idh2-deficient conditions.

Aging (Albany NY) 2019 09 10;11(17):7242-7256. Epub 2019 Sep 10.

School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea.

Among the many factors that promote cellular senescence, reactive oxygen species (ROS) are a focus of intense research because of their critical role in accelerating cellular senescence and initiating senescence-related diseases that can be fatal. Therefore, maintaining the proper balance of ROS in cells is a key method to alleviate senescence. Recent studies have found that isocitrate dehydrogenase 2 (IDH2), a critical enzyme of the tricarboxylic acid cycle, participates in ROS generation and in cellular dysfunction that is induced by excessive levels of ROS. Loss of IDH2 induces mitochondrial dysfunction that promotes excessive ROS generation and the development of several diseases. The results of this study suggest that Idh2 plays an important role in cellular senescence. Idh2 deficiency resulted in senescence-associated phenotypes and increased levels of senescence marker proteins in mouse embryonic fibroblasts and tissues. Furthermore, excessive ROS were generated in Idh2-deficient conditions, promoting cellular senescence by inducing cell cycle arrest through cyclin-dependent kinase 2. These results indicate that loss of Idh2 is a critical factor in regulating cellular senescence. Taken together, our findings contribute to the field of senescence research and suggest that IDH2 is a potential target of future anti-senescence studies.
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http://dx.doi.org/10.18632/aging.102259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756887PMC
September 2019

Interplay Between Mitochondrial Peroxiredoxins and ROS in Cancer Development and Progression.

Int J Mol Sci 2019 Sep 7;20(18). Epub 2019 Sep 7.

KNU-Center for Nonlinear Dynamics, CMRI, School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University, Daegu 41566, Korea.

Mitochondria are multifunctional cellular organelles that are major producers of reactive oxygen species (ROS) in eukaryotes; to maintain the redox balance, they are supplemented with different ROS scavengers, including mitochondrial peroxiredoxins (Prdxs). Mitochondrial Prdxs have physiological and pathological significance and are associated with the initiation and progression of various cancer types. In this review, we have focused on signaling involving ROS and mitochondrial Prdxs that is associated with cancer development and progression. An upregulated expression of Prdx3 and Prdx5 has been reported in different cancer types, such as breast, ovarian, endometrial, and lung cancers, as well as in Hodgkin's lymphoma and hepatocellular carcinoma. The expression of Prdx3 and Prdx5 in different types of malignancies involves their association with different factors, such as transcription factors, micro RNAs, tumor suppressors, response elements, and oncogenic genes. The microenvironment of mitochondrial Prdxs plays an important role in cancer development, as cancerous cells are equipped with a high level of antioxidants to overcome excessive ROS production. However, an increased production of Prdx3 and Prdx5 is associated with the development of chemoresistance in certain types of cancers and it leads to further complications in cancer treatment. Understanding the interplay between mitochondrial Prdxs and ROS in carcinogenesis can be useful in the development of anticancer drugs with better proficiency and decreased resistance. However, more targeted studies are required for exploring the tumor microenvironment in association with mitochondrial Prdxs to improve the existing cancer therapies and drug development.
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http://dx.doi.org/10.3390/ijms20184407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770548PMC
September 2019

Parkin in early stage LPS-stimulated BV-2 cells regulates pro-inflammatory response and mitochondrial quality via mitophagy.

J Neuroimmunol 2019 11 28;336:577044. Epub 2019 Aug 28.

School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Republic of Korea; School of Life Sciences and Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu 41566, Republic of Korea. Electronic address:

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http://dx.doi.org/10.1016/j.jneuroim.2019.577044DOI Listing
November 2019

Comparative Analysis of the Developmental Toxicity in Xenopus laevis and Danio rerio Induced by Al O Nanoparticle Exposure.

Environ Toxicol Chem 2019 12 16;38(12):2672-2681. Epub 2019 Oct 16.

KNU-Center for Nonlinear Dynamics, CMRI, School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University, Daegu, South Korea.

Engineered aluminum oxide nanoparticles (Al O NPs) having high-grade thermal stability and water-dispersion properties are extensively used in different industries and personal care products. Toxicological response evaluation of these NPs is indispensable in assessing the health risks and exposure limits because of their industrial disposal into the aquatic environment. We assessed and compared the developmental toxicity of Al O NPs in Xenopus laevis and Danio rerio over a period of 96 h using the frog embryo teratogenic assay Xenopus and a fish embryo toxicity assay. Engineered Al O NP exposure produced dose-dependent embryonic mortality and decreased the embryo length, indicating a negative effect on growth. Moreover, Al O NPs induced various malformations, such as small head size, a bent/deformed axis, edema, and gut malformation, dose-dependently and altered the expression of heart- and liver-specific genes in both X. laevis and D. rerio, as revealed by whole-mount in-situ hybridization and reverse transcriptase polymerase chain reaction. In conclusion, the toxicological data suggest that Al O NPs are developmentally toxic and teratogenic and negatively affect the embryonic development of X. laevis and D. rerio. Our study can serve as a model for the toxicological evaluation of nanomaterial exposure on vertebrate development that is critical to ensure human and environmental safety. Environ Toxicol Chem 2019;38:2672-2681. © 2019 SETAC.
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http://dx.doi.org/10.1002/etc.4584DOI Listing
December 2019

Gomisin M2 Inhibits Mast Cell-Mediated Allergic Inflammation Attenuation of FcεRI-Mediated Lyn and Fyn Activation and Intracellular Calcium Levels.

Front Pharmacol 2019 2;10:869. Epub 2019 Aug 2.

Cell & Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, South Korea.

Mast cells are effector cells that induce allergic inflammation by secreting inflammatory mediators. Gomisin M2 (G.M2) is a lignan isolated from (Turcz). Baill. exhibiting anti-cancer activities. We aimed to investigate the anti-allergic effects and the underlying mechanism of G.M2 in mast cell-mediated allergic inflammation. For the study, we used mouse bone marrow-derived mast cells, RBL-2H3, and rat peritoneal mast cells. G.M2 inhibited mast cell degranulation upon immunoglobulin E (IgE) stimulation by suppressing the intracellular calcium. In addition, G.M2 inhibited the secretion of pro-inflammatory cytokines. These inhibitory effects were dependent on the suppression of FcεRI-mediated activation of signaling molecules. To confirm the anti-allergic effects of G.M2 , IgE-mediated passive cutaneous anaphylaxis (PCA) and ovalbumin-induced active systemic anaphylaxis (ASA) models were utilized. Oral administration of G.M2 suppressed the PCA reactions in a dose-dependent manner. In addition, G.M2 reduced the ASA reactions, including hypothermia, histamine, interleukin-4, and IgE production. In conclusion, G.M2 exhibits anti-allergic effects through suppression of the Lyn and Fyn pathways in mast cells. According to these findings, we suggest that G.M2 has potential as a therapeutic agent for the treatment of allergic inflammatory diseases suppression of mast cell activation.
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http://dx.doi.org/10.3389/fphar.2019.00869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688163PMC
August 2019

Peroxiredoxin 5 prevents diethylhexyl phthalate-induced neuronal cell death by inhibiting mitochondrial fission in mouse hippocampal HT-22 cells.

Neurotoxicology 2019 09 10;74:242-251. Epub 2019 Aug 10.

School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea. Electronic address:

Diethylhexyl phthalate (DEHP) is used in many plastic products, such as perfumes, lunch boxes, bags, and building materials. As DEHP is not covalently bound to the plastic, humans can be easily exposed to it. DEHP induces neurobehavioral changes and neuronal cell death; however, the exact mechanism behind this is still unclear. We hypothesized that the neurotoxic mechanism is related to DEHP-induced oxidative stress leading to apoptosis through mitochondrial fission. We demonstrated that DEHP-induced oxidative stress triggers neuronal cell death via mitochondrial fission in mouse hippocampal HT-22 cells. Furthermore, we identified that peroxiredoxin 5 (Prx5), an antioxidant enzyme induced by DEHP, prevents DEHP-induced mitochondrial fission by inhibiting the production of reactive oxygen species. We conclude that Prx5 may be a promising therapeutic target for mitigating DEHP-induced neuronal cell death.
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http://dx.doi.org/10.1016/j.neuro.2019.08.003DOI Listing
September 2019

Peroxiredoxin 5 Inhibits Glutamate-Induced Neuronal Cell Death through the Regulation of Calcineurin-Dependent Mitochondrial Dynamics in HT22 Cells.

Mol Cell Biol 2019 10 27;39(20). Epub 2019 Sep 27.

School of Life Science, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea

Glutamate is an essential neurotransmitter in the central nervous system (CNS). However, high glutamate concentrations can lead to neurodegenerative diseases. A hallmark of glutamate toxicity is high levels of reactive oxygen species (ROS), which can trigger Ca influx and dynamin-related protein 1 (Drp1)-mediated mitochondrial fission. Peroxiredoxin 5 (Prx5) is a well-known cysteine-dependent peroxidase enzyme. However, the precise effects of Prx5 on glutamate toxicity are still unclear. In this study, we investigated the role of Prx5 in glutamate-induced neuronal cell death. We found that glutamate treatment induces endogenous Prx5 expression and Ca/calcineurin-dependent dephosphorylation of Drp1, resulting in mitochondrial fission and neuronal cell death. Our results indicate that Prx5 inhibits glutamate-induced mitochondrial fission through the regulation of Ca/calcineurin-dependent dephosphorylation of Drp1, and it does so by scavenging cytosolic and mitochondrial ROS. Therefore, we suggest that Ca/calcineurin-dependent mitochondrial dynamics are deeply associated with glutamate-induced neurotoxicity. Consequently, Prx5 may be used as a potential agent for developing therapies against glutamate-induced neurotoxicity and neurodegenerative diseases where it plays a key role.
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http://dx.doi.org/10.1128/MCB.00148-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6766699PMC
October 2019

Peroxiredoxin 4 ameliorates amyloid beta oligomer-mediated apoptosis by inhibiting ER-stress in HT-22 hippocampal neuron cells.

Cell Biol Toxicol 2019 12 30;35(6):573-588. Epub 2019 May 30.

School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea.

Alzheimer's disease (AD) is a neurodegenerative disorder caused by amyloid beta oligomers (AβO), which induce cell death by triggering oxidative stress and endoplasmic reticulum (ER) stress. Oxidative stress is regulated by antioxidant enzymes, including peroxiredoxins. Peroxiredoxins (Prx) are classified into six subtypes, based on their localization and cysteine residues, and protect cells by scavenging hydrogen peroxide (HO). Peroxiredoxin 4 (Prx4) is unique in being localized to the ER; however, whether Prx4 protects neuronal cells from AβO-induced toxicity remains unclear, although Prx4 expression is upregulated in AβO-induced oxidative stress and ER stress. In this study, we established HT-22 cells in which Prx4 was either overexpressed or silenced to investigate its role in AβO-induced toxicity. AβO-stimulation of HT-22 cells with overexpressed Prx4 caused decreases in both AβO-induced ROS and ER stress (followed by ER expansion). In contrast, AβO stimulation caused increases in both ROS and ER stress that were notably higher in HT-22 cells with silenced Prx4 expression than in HT-22 cells. Consequently, Prx4 overexpression decreased apoptotic cell death and ameliorated the AβO-induced increase in intracellular Ca. Therefore, we conclude that Prx4 has a protective effect against AβO-mediated oxidative stress, ER stress, and neuronal cell death. Furthermore, these results suggest that Prx4 may be a target for preventing AβO toxicity in AD. Graphical abstract .
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http://dx.doi.org/10.1007/s10565-019-09477-5DOI Listing
December 2019

Inhibitory effect of ethanol extract of Ampelopsis brevipedunculata rhizomes on atopic dermatitis-like skin inflammation.

J Ethnopharmacol 2019 Jun 4;238:111850. Epub 2019 Apr 4.

Cell and Matrix Research Institute, Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea. Electronic address:

Ethnopharmacological Relevance: Extracts from various parts of Ampelopsis brevipedunculata has been used as anti-inflammatory agents in Asian folk medicine.

Aim Of The Study: To demonstrate the medicinal effect of the A. brevipedunculata in skin inflammation, specifically atopic dermatitis (AD).

Materials And Methods: The effect of ethanol extract of A. brevipedunculata rhizomes (ABE) on AD was examined using an AD-like skin inflammation model induced by repeated exposure to house dust mite (Dermatophagoides farinae extract, DFE) and 2,4-dinitrochlorobenzene (DNCB). The mechanism study was performed using tumor necrosis factor (TNF)-α and interferon (IFN)-γ-activated human keratinocytes (HaCaT). Serum histamine and immunoglobulin levels were quantified using enzymatic kits, while the gene expression of cytokines and chemokines was analyzed using quantitative real time polymerase chain reaction. The expression of signaling molecules was detected using Western blot.

Results: Oral administration of ABE alleviated DFE/DNCB-induced ear thickening and clinical symptoms, as well as immune cell infiltration (mast cells and eosinophils) into the dermal layer. Serum Immunoglobulin (Ig) E, DFE-specific IgE, IgG2a, and histamine levels were decreased after the administration of ABE. ABE also inhibited CD4IFN-γ and CD4IL-4 lymphocyte polarization in lymph nodes and expression of TNF-α, IFN-γ, IL-4, IL-13, and IL-31 in the ear tissue. In TNF-α/INF-γ-stimulated keratinocytes, ABE inhibited the gene expression of TNF-α, IL-6, IL-1β, and CCL17. In addition, ABE decreased the nuclear localization of signal transducer and activator of transcription 1 and nuclear factor-κB, and the phosphorylation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase.

Conclusion: Collectively, our data demonstrate the pharmacological role and signaling mechanism of ABE in the regulation of skin allergic inflammation, which supports our suggestion that ABE could be developed as a potential therapeutic agent for the treatment of AD.
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http://dx.doi.org/10.1016/j.jep.2019.111850DOI Listing
June 2019

Development of finasteride polymer microspheres for systemic application in androgenic alopecia.

Int J Mol Med 2019 Jun 28;43(6):2409-2419. Epub 2019 Mar 28.

KNU‑Center for Nonlinear Dynamics, CMRI, School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, College of Natural Science Kyungpook National University, Daegu 41566, Republic of Korea.

The use of finasteride for alleviating hair loss has been investigated, and it has been applied as an oral dose medication. However, due to the inconvenience of daily drug administration over long period of time, novel controllable finasteride delivery has been actively investigated. As a novel method of finasteride delivery, the development of finasteride‑loaded microspheres for subcutaneous administration is becoming increasingly pharmaceutically important. Therefore, the present study aimed to use finasteride‑loaded microspheres in a controlled manner in an attempt to overcome the limitations of the oral administration of finasteride and to cause fewer adverse effects. Finasteride‑loaded microspheres containing poly(lactic‑co‑glycolic acid) and finasteride at a ratio of 4:1 were prepared, and a testosterone‑induced androgenic alopecia mouse model was used. Following observation for 10 weeks, the percentage hair growth was 86.7% (total hair growth 60%, partial hair growth 26.7%) in the orally‑applied finasteride‑treated group as a positive control, and 93.3% (total hair growth 60%, partial hair growth 33.3%) in the finasteride‑loaded microspheres‑treated group. Serum dihydrotestosterone levels began to decrease at week 6 in the orally‑applied finasteride‑ and finasteride‑loaded microsphere‑treated groups. In addition, the finasteride‑loaded microspheres‑treated group exhibited similar follicular number, follicular length, anagen/telogen ratio and hair bulb diameter values to those of the orally‑applied finasteride‑treated group. Furthermore, the finasteride‑loaded microspheres increased the activities of phosphoinositide 3‑kinase/protein kinase B and Wnt/β‑catenin in relation to hair follicle cell growth signaling in mouse skin, and suppressed the apoptosis of hair follicle cells by reducing the expression of transforming growth factor‑β2 and caspase‑3, which are indicators of apoptosis. In conclusion, the administration of a single injection of finasteride‑loaded microspheres was effective in treating testosterone‑induced alopecia. Furthermore, it led to equivalent hair growth effects when compared with orally‑applied finasteride, thus revealing the possibility of effective treatment via different routes of administration.
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http://dx.doi.org/10.3892/ijmm.2019.4149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488187PMC
June 2019

Structural basis for substrate binding to human pyridoxal 5'-phosphate phosphatase/chronophin by a conformational change.

Int J Biol Macromol 2019 Jun 23;131:912-924. Epub 2019 Mar 23.

School of Life Science and Biotechnology, KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Republic of Korea. Electronic address:

Human pyridoxal 5'-phosphate phosphatase (PLPP), also known as a chronophin, is a phosphatase belonging to subfamily II of the HAD phosphatases, characterized by a large cap domain. As a member of the subfamily, its cap-open conformation is expected for substrate binding. We determined apo and PLP-bound PLPP/chronophin structures showing a cap-closed conformation. The active site, in which a PLP molecule was found, is too small to accommodate a phospho-cofilin peptide, the substrate of chronophin. A conformational change to a cap-open conformation may be required for substrate binding. The core and cap domains are joined through linker peptide hinges that change conformation to open the active site. The crystal structures reveal that a disulphide bond between the cap and core domains restricts the hinge motion. The enzyme displays PLP dephosphorylation activity in the cap-closed conformation with the disulphide bond and even in the crystal state, in which repositioning of the cap and core domains is restricted. Structural analysis suggests that a small substrate such as PLP can bind to the active site through a small movement of a local motif. However, a change to the cap-open conformation is required for binding of larger substrates such as phosphopeptides to the active site.
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http://dx.doi.org/10.1016/j.ijbiomac.2019.03.097DOI Listing
June 2019

Oxalomalate reduces tumor progression in melanoma via ROS-dependent proapoptotic and antiangiogenic effects.

Biochimie 2019 Mar 9;158:165-171. Epub 2019 Jan 9.

School of Life Sciences and Biotechnology, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University, Taegu, South Korea. Electronic address:

The potent cytotoxicity of reactive oxygen species (ROS) can cause various diseases, however, it may also serve as a powerful chemotherapeutic strategy capable of killing cancer cells. Oxalomalate (OMA, α-hydroxy-β-oxalosuccinic acid), a tricarboxylic acid intermediate, is a well-known competitive inhibitor of two classes of NADP-dependent isocitrate dehydrogenase (IDH) isoenzymes, which serve as the major antioxidants and redox regulators in the mitochondria and cytosol. In this study, we investigated the therapeutic effects of OMA in melanoma and elucidated the associated underlying mechanisms of action using in vitro and in vivo models. OMA targeting IDH enzymes suppressed melanoma growth through activation of apoptosis and inhibition of angiogenesis. Mechanistically, our findings showed that OMA activated p53-mediated apoptosis through ROS-dependent ATM-Chk2 signaling and reduced the expression of vascular endothelial growth factor through ROS-dependent E2F1-mediated hypoxia inducible factor-1α degradation. In particular, OMA-induced suppression of IDH activity resulted in induction of ROS stress response, ultimately leading to apoptotic cell death and antiangiogenic effects in melanoma cells. Thus, OMA might be a potential candidate drug for melanoma skin cancer therapy.
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http://dx.doi.org/10.1016/j.biochi.2019.01.004DOI Listing
March 2019

Lysine demethylase 3a in craniofacial and neural development during Xenopus embryogenesis.

Int J Mol Med 2019 Feb 11;43(2):1105-1113. Epub 2018 Dec 11.

Cell and Matrix Research Institute, Kyungpook National University‑Center for Nonlinear Dynamics, School of Life Sciences, Brain Korea 21 Plus Kyungpook National University Creative BioResearch Group, College of Natural Sciences, Kyungpook National University, Daegu 41566, Republic of Korea.

Epigenetic modifier lysine demethylase 3a (Kdm3a) specifically demethylates mono‑ and di‑methylated ninth lysine of histone 3 and belongs to the Jumonji domain‑containing group of demethylases. Kdm3a serves roles during various biological and pathophysiological processes, including spermatogenesis and metabolism, determination of sex, androgen receptor‑mediated transcription and embryonic carcinoma cell differentiation. In the present study, physiological functions of Kdm3a were evaluated during embryogenesis of Xenopus laevis. Spatiotemporal expression pattern indicated that kdm3a exhibited its expression from early embryonic stages until tadpole stage, however considerable increase of kdm3a expression was observed during the neurula stage of Xenopus development. Depleting kdm3a using kdm3a antisense morpholino oligonucleotides induced anomalies, including head deformities, small‑sized eyes and abnormal pigmentation. Whole‑mount in situ hybridization results demonstrated that kdm3a knockdown was associated with defects in neural crest migration. Further, quantitative polymerase chain reaction revealed abnormal expression of neural markers in kdm3a morphants. RNA sequencing of kdm3a morphants indicated that kdm3a was implicated in mesoderm formation, cell adhesion and metabolic processes of embryonic development. In conclusion, the results of the present study indicated that Kdm3a may serve a role in neural development during Xenopus embryogenesis and may be targeted for treatment of developmental disorders. Further investigation is required to elucidate the molecular mechanism underlying the regulation of neural development by Kdm3a.
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http://dx.doi.org/10.3892/ijmm.2018.4024DOI Listing
February 2019

Physiological effects of KDM5C on neural crest migration and eye formation during vertebrate development.

Epigenetics Chromatin 2018 12 6;11(1):72. Epub 2018 Dec 6.

KNU-Center for Nonlinear Dynamics, CMRI, School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University, Daegu, 41566, South Korea.

Background: Lysine-specific histone demethylase 5C (KDM5C) belongs to the jumonji family of demethylases and is specific for the di- and tri-demethylation of lysine 4 residues on histone 3 (H3K4 me2/3). KDM5C is expressed in the brain and skeletal muscles of humans and is associated with various biologically significant processes. KDM5C is known to be associated with X-linked mental retardation and is also involved in the development of cancer. However, the developmental significance of KDM5C has not been explored yet. In the present study, we investigated the physiological roles of KDM5C during Xenopus laevis embryonic development.

Results: Loss-of-function analysis using kdm5c antisense morpholino oligonucleotides indicated that kdm5c knockdown led to small-sized heads, reduced cartilage size, and malformed eyes (i.e., small-sized and deformed eyes). Molecular analyses of KDM5C functional roles using whole-mount in situ hybridization, β-galactosidase staining, and reverse transcription-polymerase chain reaction revealed that loss of kdm5c resulted in reduced expression levels of neural crest specifiers and genes involved in eye development. Furthermore, transcriptome analysis indicated the significance of KDM5C in morphogenesis and organogenesis.

Conclusion: Our findings indicated that KDM5C is associated with embryonic development and provided additional information regarding the complex and dynamic gene network that regulates neural crest formation and eye development. This study emphasizes the functional significance of KDM5C in Xenopus embryogenesis; however, further analysis is needed to explore the interactions of KDM5C with specific developmental genes.
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http://dx.doi.org/10.1186/s13072-018-0241-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282277PMC
December 2018

Drp1-dependent mitochondrial fission regulates p62-mediated autophagy in LPS-induced activated microglial cells.

Biosci Biotechnol Biochem 2019 Mar 26;83(3):409-416. Epub 2018 Nov 26.

a School of Life Sciences and Biotechnology , BK21 Plus KNU Creative BioResearch Group, Kyungpook National University , Daegu , Republic of Korea.

Microglial activation is known to be an important event during innate immunity, but microglial inflammation is also thought to play a role in the etiology of neurodegenerative diseases. Recently, it was reported that autophagy could influence inflammation and activation of microglia. However, little is known about the regulation of autophagy during microglial activation. In this study, we demonstrated that mitochondrial fission-induced ROS can promote autophagy in microglia. Following LPS-induced autophagy, GFP-LC3 puncta were increased, and this was suppressed by inhibiting mitochondrial fission and mitochondrial ROS. Interestingly, inhibition of mitochondrial fission and mitochondrial ROS also resulted in decreased p62 expression, but Beclin1 and LC3B were unaffected. Taken together, these results indicate that ROS induction due to increased LPS-stimulated mitochondrial fission triggers p62 mediated autophagy in microglial cells. Our findings provide the first important clues towards understanding the correlation between mitochondrial ROS and autophagy. Abbreviations: Drp1; Dynamin related protein 1, LPS; Lipopolysaccharide, ROS; Reactive Oxygen Species, GFP; Green Fluorescent Protein, CNS; Central Nervous System, AD; Alzheimer's Disease, PD; Parkinson's Disease, ALIS; Aggresome-like induced structures, iNOS; inducible nitric oxide synthase, Cox-2; Cyclooxygenase-2, MAPK; Mitogen-activated protein kinase; SODs; Superoxide dismutase, GPXs; Glutathione Peroxidase, Prxs; Peroxiredoxins.
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http://dx.doi.org/10.1080/09168451.2018.1549933DOI Listing
March 2019
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