Publications by authors named "Nami Kim"

51 Publications

Cis P-tau underlies vascular contribution to cognitive impairment and dementia and can be effectively targeted by immunotherapy in mice.

Sci Transl Med 2021 06;13(596)

Division of Translational Therapeutics, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.

Compelling evidence supports vascular contributions to cognitive impairment and dementia (VCID) including Alzheimer's disease (AD), but the underlying pathogenic mechanisms and treatments are not fully understood. Cis P-tau is an early driver of neurodegeneration resulting from traumatic brain injury, but its role in VCID remains unclear. Here, we found robust cis P-tau despite no tau tangles in patients with VCID and in mice modeling key aspects of clinical VCID, likely because of the inhibition of its isomerase Pin1 by DAPK1. Elimination of cis P-tau in VCID mice using cis-targeted immunotherapy, brain-specific Pin1 overexpression, or DAPK1 knockout effectively rescues VCID-like neurodegeneration and cognitive impairment in executive function. Cis mAb also prevents and ameliorates progression of AD-like neurodegeneration and memory loss in mice. Furthermore, single-cell RNA sequencing revealed that young VCID mice display diverse cortical cell type-specific transcriptomic changes resembling old patients with AD, and the vast majority of these global changes were recovered by cis-targeted immunotherapy. Moreover, purified soluble cis P-tau was sufficient to induce progressive neurodegeneration and brain dysfunction by causing axonopathy and conserved transcriptomic signature found in VCID mice and patients with AD with early pathology. Thus, cis P-tau might play a major role in mediating VCID and AD, and antibody targeting it may be useful for early diagnosis, prevention, and treatment of cognitive impairment and dementia after neurovascular insults and in AD.
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http://dx.doi.org/10.1126/scitranslmed.aaz7615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8272885PMC
June 2021

Personal Profiles, Family Environment, Patterns of Smartphone Use, Nomophobia, and Smartphone Addiction across Low, Average, and High Perceived Academic Performance Levels among High School Students in the Philippines.

Int J Environ Res Public Health 2021 05 14;18(10). Epub 2021 May 14.

Department of Addiction Science, Sahmyook University Graduate School, Seoul 01795, Korea.

(1) Background: Problematic smartphone use in adolescents has become a major concern among parents and educators. This study aimed to determine the factors associated with, and the predictors of, low, average, and high perceived academic performance (PAP). (2) Methods: Descriptive and comparative analyses were employed in this cross-sectional study among 3374 Filipino high school students through an online Google forms survey. (3) Results: We found that age, grade level, father's education, time spent daily on weekends, frequency of use on weekdays, purpose of use, nomophobia (NMP), and smartphone addiction (SA) were significantly associated with low PAP, while frequency of use on weekends and type of internet access had a significant association with high PAP. Gender was a significant predictor of low, average, and high PAP. Father's education and SA were also significant predictors for both low and average PAP. (4) Conclusions: This study shows the significant association between personal profiles, family environment, patterns of smartphone use, NMP, and SA contributing to a significant impact on Filipino high school students' PAP. This suggests that proper guidelines for smartphone use should be provided at home and in school settings to raise awareness of the adverse effects of SA on students' academic performance.
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http://dx.doi.org/10.3390/ijerph18105219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156849PMC
May 2021

Inhibition of death-associated protein kinase 1 attenuates cis P-tau and neurodegeneration in traumatic brain injury.

Prog Neurobiol 2021 Aug 9;203:102072. Epub 2021 May 9.

Division of Translational Therapeutics, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA. Electronic address:

Traumatic brain injury (TBI) is the leading cause of mortality and disability in young people and may lead to the development of progressive neurodegeneration, such as that observed in chronic traumatic encephalopathy. We have recently found that the conformation-specific cis phosphorylated form of tau (cis P-tau) is a major early driver of neurodegeneration after TBI. However, not much is known about how cis P-tau is regulated in TBI. In this study, we demonstrated a novel critical role of death-associated protein kinase 1 (DAPK1) in regulating cis P-tau induction after TBI. We found that DAPK1 is significantly upregulated in mouse brains after TBI and subsequently promotes cis P-tau induction. Genetic deletion of DAPK1 in mice not only significantly decreases cis P-tau expression, but also effectively attenuates neuropathology development and rescues behavioral impairments after TBI. Mechanistically, DAPK1-mediated cis P-tau induction is regulated by the phosphorylation of Pin1 at Ser71, a unique prolyl isomerase known to control the conformational status of P-tau. Furthermore, pharmacological suppression of DAPK1 kinase activity dramatically decreases the levels of Pin1 phosphorylated at Ser71 as well as cis P-tau after neuronal stress. Thus, DAPK1 is a novel regulator of TBI that, in combination with its downstream targets, has a major impact on the development and/or outcome of TBI, and targeting DAPK1 might offer a potential therapeutic impact on TBI-related neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.pneurobio.2021.102072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217320PMC
August 2021

Melatonin directly binds and inhibits death-associated protein kinase 1 function in Alzheimer's disease.

J Pineal Res 2020 Sep 27;69(2):e12665. Epub 2020 May 27.

Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, China.

Death-associated protein kinase 1 (DAPK1) is upregulated in the brains of human Alzheimer's disease (AD) patients compared with normal subjects, and aberrant DAPK1 regulation is implicated in the development of AD. However, little is known about whether and how DAPK1 function is regulated in AD. Here, we identified melatonin as a critical regulator of DAPK1 levels and function. Melatonin significantly decreases DAPK1 expression in a post-transcriptional manner in neuronal cell lines and mouse primary cortical neurons. Moreover, melatonin directly binds to DAPK1 and promotes its ubiquitination, resulting in increased DAPK1 protein degradation through a proteasome-dependent pathway. Furthermore, in tau-overexpressing mouse brain slices, melatonin treatment and the inhibition of DAPK1 kinase activity synergistically decrease tau phosphorylation at multiple sites related to AD. In addition, melatonin and DAPK1 inhibitor dramatically accelerate neurite outgrowth and increase the assembly of microtubules. Mechanistically, melatonin-mediated DAPK1 degradation increases the activity of Pin1, a prolyl isomerase known to play a protective role against tau hyperphosphorylation and tau-related pathologies. Finally, elevated DAPK1 expression shows a strong correlation with the decrease in melatonin levels in human AD brains. Combined, these results suggest that DAPK1 regulation by melatonin is a novel mechanism that controls tau phosphorylation and function and offers new therapeutic options for treating human AD.
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http://dx.doi.org/10.1111/jpi.12665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890046PMC
September 2020

Gaudichaudione H Inhibits Inflammatory Responses in Macrophages and Dextran Sodium Sulfate-Induced Colitis in Mice.

Front Pharmacol 2019 17;10:1561. Epub 2020 Jan 17.

School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.

Macrophages-involved inflammation is considered to induce the damage in various diseases. Herein, novel therapeutics inhibiting over-activation of macrophages could prove an effective strategy to prevent inflammation-related diseases. Gaudichaudione H (GH), which is a natural small molecular compound isolated from Merr. (Clusiaceae) has previously been demonstrated its anti-cancer effects on several cancer cell lines. However, no report has been published about the anti-inflammatory effect of GH to date. This study aims to examine the anti-inflammatory effects and potential molecular mechanism of GH, and provide new insights toward the treatment of inflammation. GH inhibited nitric oxide (NO) production, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression, cytokine interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) production, and messenger RNA (mRNA) expression to attenuate inflammatory responses in lipopolysaccharide (LPS)-induced RAW 264.7 cells or stimulated bone marrow-derived macrophages (BMDMs). GH inhibited nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways, the nuclear translocation of transcription factors NF-κB and activator protein 1 (AP-1), as well as upstream signaling of the toll-like receptor 4 (TLR4)-myeloid differentiation primary response 88 (MyD88) pathway in stimulated macrophages. Furthermore, the result of the intracellular signaling array showed that the phosphorylation of adenosine 5'-monophosphate-activated protein kinase-α (AMPKα), proline-rich Akt substrate of 40 kDa (PRAS40), and p38 could be down regulated by GH in BMDMs, indicating that the mechanism by which GH inhibited inflammation may be also associated with the energy metabolism pathway, PRAS40-mediated NF-κB pathway, cell proliferation, apoptosis, and autophagy, etc. In addition, GH alleviated dextran sodium sulfate (DSS)-induced colitis in mice by ameliorating weight loss, stool consistency change, blood in the stool, and colon shortening. GH decreased the protein and mRNA levels of IL-6 and TNF-α, iNOS and COX-2 mRNA expression, the activation of NF-κB and MAPK pathways, the phosphorylation of AMPKα and PRAS40, histological damage, and infiltration of macrophages in the colons of mice with DSS-induced colitis. Taken together, our results support that GH exerts the anti-inflammatory effects in macrophages through regulation of NF-κB and MAPK pathways, and DSS-induced colitis mouse model These findings suggest that GH may be a promising candidate in treating macrophage-related inflammatory disease.
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http://dx.doi.org/10.3389/fphar.2019.01561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978770PMC
January 2020

Effect of Cacao Nip Extracts (CEs) on Quality Characteristics of Pork Patties during Cold Storage Period.

Food Sci Anim Resour 2019 Dec 31;39(6):918-933. Epub 2019 Dec 31.

Department of Food Service Management and Nutrition,Kongju National University, Yesan 32439, Korea.

Cacao has been shown to have antioxidant effects and health benefits. However, the applicability of cacao as a meat preservative has not been thoroughly evaluated. Here, we examined the effects of cacao nib extracts (CEs) on suppression of fat oxidation and enhancement of quality characteristics of pork patties. Cacao nib powder was extracted in distilled water or 50%, 70%, or 99% ethanol. CEs prepared using 70% ethanol had the highest total phenolic and total flavonoid contents, and the highest 1,1-diphenyl-2-picrylhytdrazyl radical and 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) radical scavenging activities. Decompression-concentrated CEs prepared using 70% ethanol and 0.1% ascorbic acid were added to pork patties, and the physiochemical properties of the patties were measured. The pH of all pork patties increased during storage, but tended to decrease according to the CEs content. CEs enhanced the preservation of redness and texture of the pork patties during storage. Analysis of thiobarbituric acid reactive substances (TBARS) in patties revealed that fat oxidation was highly suppressed in all treatment groups containing CEs during storage, and TBARS values decreased according to CE content. Treatment with 0.1% CE reduced fat oxidation to a level similar to that of treatment with 0.1% ascorbic acid. Consumer flavor preference increased according to CE content, and overall preference was the highest for patties prepared with 0.05% and 0.075% CEs. Overall, 70% ethanol was found to be the optimal concentration for extraction of cacao nibs, and adding 0.05% or 0.075% CEs to pork patties yielded the highest quality.
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http://dx.doi.org/10.5851/kosfa.2019.e77DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949522PMC
December 2019

Safranal Alleviates Dextran Sulfate Sodium-Induced Colitis and Suppresses Macrophage-Mediated Inflammation.

Front Pharmacol 2019 1;10:1281. Epub 2019 Nov 1.

School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.

(saffron) is widely used in China, Iran, and India for dyeing and as a food additive and medicinal plant. Safranal, as one of the main constituents of saffron, is responsible for its aroma and has been reported to have anticancer, antioxidant, and anti-inflammation properties. In this study, we investigated the anti-inflammatory effects of Safranal in RAW264.7 cells, bone marrow-derived macrophages (BMDMs), and dextran sulfate sodium (DSS)-induced colitis mice. Safranal toxicity was determined using an MTT assay. We evaluated the inhibitory effect of nitric oxide (NO) and levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in RAW264.7 cells and BMDMs. We assessed the inhibitory effect of pro-inflammatory cytokines, and the mRNA expressions of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), classical inflammatory pathways (MAPK and NF-κB), and the nuclear translocation factors AP-1 and NF-κB p65 were investigated. The anti-inflammatory effects of Safranal were assessed in a DSS-induced colitis model. DSS3.5% was used to induce colitis in mice with or without Safranal for 7 days; weight and disease activity index (DAI) were recorded daily. At the end of the experiment, the colon, mesenteric lymph nodes (MLNs), and spleen were collected for flow cytometry, ELISA, and Western blot analysis. Safranal suppressed NO production, iNOS, and COX-2 in lipopolysaccharide (LPS)-stimulated RAW264.7 cells and BMDMs. Safranal decreased the production and mRNA expression of IL-6 and TNF-α in the RAW264.7 cell line and inhibited the phosphorylation and nuclear translocation of components of the MAPK and NF-κB pathways. Safranal alleviated clinical symptoms in the DSS-induced colitis model, and colon histology showed decreased severity of inflammation, depth of inflammatory involvement, and crypt damage. Immunohistochemical staining and flow cytometry showed reduced macrophage infiltration in colonic tissues and macrophage numbers in MLNs and the spleen. The levels of colonic IL-6 and TNF-α also decreased in Safranal-treated colitis mice. This study elucidates the anti-inflammation activity of Safranal, which may be a candidate for inflammatory bowel syndrome (IBD) therapy.
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http://dx.doi.org/10.3389/fphar.2019.01281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838343PMC
November 2019

Effect of Cacao Bean Husk Powder on the Quality Properties of Pork Sausages.

Food Sci Anim Resour 2019 Oct 31;39(5):742-755. Epub 2019 Oct 31.

Department of Food and Nutrition, Sookmyung Women's University, Seoul 04310, Korea.

Cacao bean husk ( L.) contains a high level of dietary fiber and therefore can be used as raw material in food processing. The objective of the present study was to measure the physicochemical properties and sensory traits of emulsion-type pork sausages with various levels of cacao bean husk powder (0.25%, 0.5%, 0.75%, 1%, and 2%). The moisture content in cooked sausages increased as the level of cacao bean husk power increased, whereas the protein content decreased (p<0.05). With respect to color, as the level of cacao bean husk power increased, there was a decrease in lightness and yellowness, but there was a considerable increase in redness (p<0.05). Cacao bean husk powder exhibited a positive effect on emulsion stability and apparent viscosity. In the sensory evaluation, increased level of cacao bean husk increased flavor acceptability; the 0.75% and 1% treatment groups showed significantly high overall acceptability (p<0.05). The thiobarbituric acid reactive species content of cooked sausages indicated that with the addition of cacao bean husk powder significantly inhibited lipid oxidation in the sausages during refrigerated storage (p<0.05). Overall, the findings of the present study suggest that adding 0.75% and 1% cacao bean husk powder as a natural ingredient in sausages can help develop meat products with excellent qualities.
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http://dx.doi.org/10.5851/kosfa.2019.e62DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6837902PMC
October 2019

Implementation of Laboratory Review of Test Builds Within the Electronic Health Record Reduces Errors.

Arch Pathol Lab Med 2020 06 24;144(6):742-747. Epub 2019 Oct 24.

From the Departments of Information Technology (Ms Barry) and Pathology (Drs Edmonston and Bierl) and the Division of Medical Informatics & Care Delivery Innovation (Drs Gandhi, Ganti, and Kim), Cooper University Hospital, Camden, New Jersey. Dr Bierl is currently affiliated with the Central Laboratory and Phlebotomy Services at the Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, and the Department of Pathology and Laboratory Medicine at Perelman School of Medicine at the University of Pennsylvania, Philadelphia.

Context.—: As electronic health records (EHRs) become more ubiquitous, physicians have come to expect that laboratory data from a variety of sources will be incorporated into the EHR in a structured format. The Clinical Laboratory Improvement Amendments have standards for data transmission traditionally met by pathologist review of their own hospital laboratory information system transmissions. However, with third-party laboratory data now being sent through external (nonhospital laboratory) interfaces, ownership of this review is less clear. Lack of an expert laboratory review process prior to changes being implemented can result in mapping and interfacing errors that could lead to misinterpretation and diagnostic errors.

Objective.—: To determine the impact of retrospective and prospective laboratorian-assisted review on the volume of interface errors and new builds.

Design.—: A seminal event led to a restructuring of the process for review of EHR laboratory builds, using laboratory expertise.

Results.—: A review of 26 500 test result fields found 61 of 4282 (1.4%) unique codes that could have led to misinterpretation. These were corrected and a process for proactive review and maintenance by laboratory experts was implemented. This resulted in monthly decreases in outbound error message from 4270 to 1820 (57.4%), in new test builds from 586 to 274 (53.2%), and in new result builds from 1116 to 552 (50.5%).

Conclusions.—: Regular review and maintenance of external laboratory test builds in EHRs by a laboratory review team reduces interface error messages and reduces the number of new builds required for results to file into the EHR.
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http://dx.doi.org/10.5858/arpa.2019-0239-OADOI Listing
June 2020

Eicosapentaenoic Acid (EPA) Modulates Glucose Metabolism by Targeting AMP-Activated Protein Kinase (AMPK) Pathway.

Int J Mol Sci 2019 Sep 25;20(19). Epub 2019 Sep 25.

Department of Anatomy, Korea University College of Medicine, Seoul 136-701, Korea.

EPA, an omega-3 polyunsaturated fatty acid, exerts beneficial effects on human health. However, the molecular mechanisms underlying EPA function are poorly understood. The object was to illuminate molecular mechanism underlying EPA's role. Here, H-NMR-based metabolic analysis showed enhanced branched-chain amino acids (BCAAs) and lactate following EPA treatment in skeletal muscle cells. EPA regulated mitochondrial oxygen consumption rate. Furthermore, EPA induced calcium/calmodulin-dependent protein kinase kinase (CaMKK) through the generation of intracellular calcium. This induced the phosphorylation of AMP-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (p38 MAPK) that led to glucose uptake, and the translocation of glucose transporter type 4 (GLUT4) in muscles. In conclusion, EPA exerts benign effects on glucose through the activation of AMPK-p38 MAPK signaling pathways in skeletal muscles.
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http://dx.doi.org/10.3390/ijms20194751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801536PMC
September 2019

Andrographolide inhibits inflammatory responses in LPS-stimulated macrophages and murine acute colitis through activating AMPK.

Biochem Pharmacol 2019 12 20;170:113646. Epub 2019 Sep 20.

School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, People's Republic of China; Institute of Cardiovascular Disease of Integrated Traditional Chinese and Western Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, People's Republic of China. Electronic address:

Andrographolide (Andro), a well-known labdane diterpenoid of Andrographis paniculata, has been reported to have anti-inflammatory effects in various inflammatory disease models. Despite ongoing efforts to elucidate the anti-inflammatory mechanism of Andro, its specific mechanism is not entirely clear. In this study, we confirmed the inhibitory effect of Andro on inflammatory activity and studied its mechanism in depth to find potential anti-inflammatory targets of Andro using lipopolysaccharide (LPS)-induced macrophages in vitro and a dextran sulfate sodium (DSS)-induced mouse model of acute colitis in vivo. We found that Andro significantly reduced proinflammatory cytokines by suppressing nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK) and their upstream signaling pathways and activating the AMP activated protein kinase (AMPK) pathway in LPS-induced macrophages. Interestingly, Andro could not regulate the activation of the AMPK/NF-κB/MAPK pathway nor inhibit NF-κB and activator protein 1 (AP-1) nuclear translocation and nitric oxide (NO) production following knockdown of AMPKα2. Moreover, Andro attenuated DSS-induced intestinal barrier dysfunction and inflammation by suppressing the NF-κB and MAPK pathways in colon tissues while activating the AMPK pathway. In conclusion, our study demonstrates that Andro effectively inhibits LPS-induced inflammatory responses via AMPK activation in macrophages, whereby Andro can ameliorate DSS-induced acute colitis in mice.
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http://dx.doi.org/10.1016/j.bcp.2019.113646DOI Listing
December 2019

Optimization of the Order Menu in the Electronic Health Record Facilitates Test Patterns Consistent With Recommendations in the Choosing Wisely Initiative.

Am J Clin Pathol 2020 01;153(1):94-98

Department of Pathology, Cooper University Health Care, Camden, NJ.

Objectives: Thyroid and rheumatologic autoimmune testing are areas where evidence-based guidance from specialty organizations and Choosing Wisely support utilizing screening tests for autoimmune and thyroid disorders prior to more specialized testing. Adjustment of the orderable options in the electronic health record (EHR) can influence ordering patterns without requiring manual review or additional effort by the clinician.

Methods: The menu was adjusted to reflect recommendations from Choosing Wisely to favor screening tests that automatically reflex to specialized testing on primary care providers' preference lists. Effectiveness was evaluated by reviewing total orders for individual tests.

Results: Shifts in ordering from individual screening tests (antinuclear antibody and thyrotropin) to ones that reflexed to specialized testing were observed in parallel with significant reductions in the corresponding specialized testing.

Conclusions: Optimization of the EHR laboratory ordering menu can be used to shift ordering patterns toward Choosing Wisely recommendations.
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http://dx.doi.org/10.1093/ajcp/aqz134DOI Listing
January 2020

Death-Associated Protein Kinase 1 Phosphorylation in Neuronal Cell Death and Neurodegenerative Disease.

Int J Mol Sci 2019 Jun 26;20(13). Epub 2019 Jun 26.

Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China.

Regulated neuronal cell death plays an essential role in biological processes in normal physiology, including the development of the nervous system. However, the deregulation of neuronal apoptosis by various factors leads to neurodegenerative diseases such as ischemic stroke and Alzheimer's disease (AD). Death-associated protein kinase 1 (DAPK1) is a calcium/calmodulin (Ca/CaM)-dependent serine/threonine (Ser/Thr) protein kinase that activates death signaling and regulates apoptotic neuronal cell death. Although DAPK1 is tightly regulated under physiological conditions, DAPK1 deregulation in the brain contributes to the development of neurological disorders. In this review, we describe the molecular mechanisms of DAPK1 regulation in neurons under various stresses. We also discuss the role of DAPK1 signaling in the phosphorylation-dependent and phosphorylation-independent regulation of its downstream targets in neuronal cell death. Moreover, we focus on the major impact of DAPK1 deregulation on the progression of neurodegenerative diseases and the development of drugs targeting DAPK1 for the treatment of diseases. Therefore, this review summarizes the DAPK1 phosphorylation signaling pathways in various neurodegenerative diseases.
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http://dx.doi.org/10.3390/ijms20133131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6651373PMC
June 2019

Dibenzoylmethane ameliorates lipid-induced inflammation and oxidative injury in diabetic nephropathy.

J Endocrinol 2019 02;240(2):169-179

Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea.

Dibenzoylmethane (DBM) is a beta-diketone analog of curcumin. Numerous studies have shown the beneficial effects of curcumin on diabetes, obesity and diabetic complications including diabetic nephropathy. Recently, we investigated the beneficial metabolic effects of DBM on high-fat diet-induced obesity. However, the effects and mechanisms of action of DBM in the kidney are currently unknown. To investigate the renoprotective effects of DBM in type 2 diabetes, we administered DBM (100 mg/kg) orally for 12 weeks to high-fat diet-induced diabetic model mice. We used mouse renal mesangial (MES13) and macrophage (RAW 264.7) cells to examine the mechanism of action of DBM (20 μM). After DBM treatment, the albumin-to-creatinine ratio was significantly decreased compared to that of the high-fat-diet group. Moreover, damaged renal ultra-structures and functions including increased glomerular volume, glomerular basement membrane thickness and inflammatory signals were ameliorated after DBM treatment. Stimulation of MES13 and RAW264.7 cells by palmitate or high-dose glucose with lipopolysaccharides increased inflammatory signals and macrophage migration. However, these changes were reversed by DBM treatment. In addition, DBM inhibited NADPH oxidase 2 and 4 expression and oxidative DNA damage. Collectively, these data suggested that DBM prevented diabetes-induced renal injury through its anti-inflammatory and antioxidant effects.
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http://dx.doi.org/10.1530/JOE-18-0206DOI Listing
February 2019

Lipidomic profiling reveals free fatty acid alterations in plasma from patients with atrial fibrillation.

PLoS One 2018 3;13(5):e0196709. Epub 2018 May 3.

Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul, Republic of Korea.

Atrial fibrillation (AF) is the most common cardiac arrhythmia, and its incidence is increasing worldwide. One method used to restore sinus rhythm is direct current cardioversion (DCCV). Despite the high success rate of DCCV, AF typically recurs within the first 2 weeks. However, our understanding of the pathophysiology of AF recurrence, incidence, and progression are highly limited. Lipidomic profiling was applied to identify altered lipids in plasma from patients with AF using ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry coupled with multivariate statistical analysis. Partial least-squares discriminant analysis revealed a clear separation between AF patients and healthy controls. The levels of several lipid species, including fatty acids and phospholipids, were different between AF patients and healthy controls, indicating that oxidative stress and inflammation are associated with the pathogenesis of AF. Similar patterns were also detected between recurrent and non-recurrent AF patients. These results suggest that the elevated saturated fatty acid and reduced polyunsaturated fatty acid levels in AF patients may be associated with enhanced inflammation and that free fatty acid levels may play a crucial role in the development and progression of AF.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0196709PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933795PMC
August 2018

Effect of green tea on hepatic lipid metabolism in mice fed a high-fat diet.

J Nutr Biochem 2018 01 19;51:1-7. Epub 2017 Sep 19.

Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul 03759, Republic of Korea.; Department of Chemistry & Nanoscience, Ewha Womans University, Seoul 03760, Republic of Korea.. Electronic address:

Green tea (GT) is a widely consumed beverage with health benefits, including antiobesity effects; however, the efficacy of GT on lipid levels associated with obesity is not clearly understood. Here, we examined the impact of GT consumption on lipid metabolism in the livers of high-fat diet (HFD)-induced obese mice. We performed lipid profiling using ultraperformance liquid chromatography quadrupole time-of-flight mass spectrometry in C57BL/6J mice fed a normal diet (ND), HFD and HFD with GT for 12 weeks. The partial least squares discriminant analysis score plot showed a difference among the groups and revealed that the levels of several lipid metabolites were altered in mice fed HFD with GT. The decreased levels of lysophospholipids (LPLs), such as lysophosphatidylcholine, lysophosphatidylethanolamine and lysophosphatidylserine, in HFD mice compared to those of the ND group were recovered by supplementation of GT. In agreement with these lipid metabolites changes, hepatic lysophosphatidylcholine acyltransferase 2/4 was significantly increased in HFD mice. This study showed abnormal changes in lipid species associated with obesity, and these levels were attenuated by GT intake, suggesting a relationship between the reduction of hepatic LPL levels and inflammation in obesity.
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http://dx.doi.org/10.1016/j.jnutbio.2017.09.002DOI Listing
January 2018

Myocardial metabolic alterations in mice with diet-induced atherosclerosis: linking sulfur amino acid and lipid metabolism.

Sci Rep 2017 10 19;7(1):13597. Epub 2017 Oct 19.

Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul, 03759, Republic of Korea.

Atherosclerosis is a leading cause of cardiovascular disease (CVD), but the effect of diet on the atherosclerotic heart's metabolism is unclear. We used an integrated metabolomics and lipidomics approach to evaluate metabolic perturbations in heart and serum from mice fed an atherogenic diet (AD) for 8, 16, and 25 weeks. Nuclear magnetic resonance (NMR)-based metabolomics revealed significant changes in sulfur amino acid (SAA) and lipid metabolism in heart from AD mice compared with heart from normal diet mice. Higher SAA levels in AD mice were quantitatively verified using liquid chromatography-mass spectrometry (LC/MS). Lipidomic profiling revealed that fatty acid and triglyceride (TG) levels in the AD group were altered depending on the degree of unsaturation. Additionally, levels of SCD1, SREBP-1, and PPARγ were reduced in AD mice after 25 weeks, while levels of reactive oxygen species were elevated. The results suggest that a long-term AD leads to SAA metabolism dysregulation and increased oxidative stress in the heart, causing SCD1 activity suppression and accumulation of toxic TGs with a low degree of unsaturation. These findings demonstrate that the SAA metabolic pathway is a promising therapeutic target for CVD treatment and that metabolomics can be used to investigate the metabolic signature of atherosclerosis.
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http://dx.doi.org/10.1038/s41598-017-13991-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5648757PMC
October 2017

Angiotensin II affects inflammation mechanisms via AMPK-related signalling pathways in HL-1 atrial myocytes.

Sci Rep 2017 09 4;7(1):10328. Epub 2017 Sep 4.

Department of Anatomy, Korea University College of Medicine, Seoul, 02841, Republic of Korea.

Inflammation is a common cause of cardiac arrhythmia. Angiotensin ІІ (Ang ІІ) is a major contributing factor in the pathogenesis of cardiac inflammation; however, its underlying molecular mechanism remains unclear. Here, we explored the effect of Ang ІІ on inflammatory mechanisms and oxidative stress using HL-1 atrial myocytes. We showed that Ang ІІ activated c-Jun N-terminal kinase (JNK) phosphorylation and other inflammatory markers, such as transforming growth factor-β1 (TGF-β1) and tumor necrosis factor-α (TNF-α). Ang ІІ decreased oxygen consumption rate, which resulted in reactive oxygen species (ROS) generation and inhibition of ROS blocked Ang II-mediated JNK phosphorylation and TGF-β1 induction. Ang ІІ induced the expression of its specific receptor, AT1R. Ang II-induced intracellular calcium production associated with Ang ІІ-mediated signalling pathways. In addition, the generated ROS and calcium stimulated AMPK phosphorylation. Inhibiting AMPK blocked Ang II-mediated JNK and TGF-β signalling pathways. Ang ІІ concentration, along with TGF-β1 and tumor necrosis factor-α levels, was slightly increased in plasma of patients with atrial fibrillation. Taken together, these results suggest that Ang ІІ induces inflammation mechanisms through an AMPK-related signalling pathway. Our results provide new molecular targets for the development of therapeutics for inflammation-related conditions, such as atrial fibrillation.
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http://dx.doi.org/10.1038/s41598-017-09675-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5583339PMC
September 2017

Snail reprograms glucose metabolism by repressing phosphofructokinase PFKP allowing cancer cell survival under metabolic stress.

Nat Commun 2017 02 8;8:14374. Epub 2017 Feb 8.

Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul 03722, Korea.

Dynamic regulation of glucose flux between aerobic glycolysis and the pentose phosphate pathway (PPP) during epithelial-mesenchymal transition (EMT) is not well-understood. Here we show that Snail (SNAI1), a key transcriptional repressor of EMT, regulates glucose flux toward PPP, allowing cancer cell survival under metabolic stress. Mechanistically, Snail regulates glycolytic activity via repression of phosphofructokinase, platelet (PFKP), a major isoform of cancer-specific phosphofructokinase-1 (PFK-1), an enzyme involving the first rate-limiting step of glycolysis. The suppression of PFKP switches the glucose flux towards PPP, generating NADPH with increased metabolites of oxidative PPP. Functionally, dynamic regulation of PFKP significantly potentiates cancer cell survival under metabolic stress and increases metastatic capacities in vivo. Further, knockdown of PFKP rescues metabolic reprogramming and cell death induced by loss of Snail. Thus, the Snail-PFKP axis plays an important role in cancer cell survival via regulation of glucose flux between glycolysis and PPP.
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http://dx.doi.org/10.1038/ncomms14374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5309788PMC
February 2017

Piperine regulates UCP1 through the AMPK pathway by generating intracellular lactate production in muscle cells.

Sci Rep 2017 01 24;7:41066. Epub 2017 Jan 24.

Department of Anatomy, Korea University College of Medicine, Seoul 136-701, Korea.

This study characterizes the human metabolic response to piperine, a curcumin extract, and the details of its underlying molecular mechanism. Using H-NMR-based metabolome analysis, we showed the metabolic effect of piperine on skeletal muscle and found that piperine increased the level of intracellular lactate, an important metabolic intermediate that controls expression of several genes involved in mitochondrial activity. Piperine also induced the phosphorylation of AMP-activated protein kinase (AMPK) and its downstream target, acetyl-CoA carboxylase (ACC), while additionally stimulating glucose uptake in an AMPK dependent manner. Piperine also stimulates the p38 mitogen-activated protein kinase (p38 MAPK), an effect that was reversed by pretreatment with compound C, an AMPK inhibitor. Inhibition of p38 MAPK resulted in no piperine-induced glucose uptake. Increased level of lactate resulted in increased expression of mitochondrial uncoupling protein 1 (UCP1), which regulates energy expenditure, thermogenesis, and fat browning. Knock-down of AMPK blocked piperine-induced UCP1 up-regulation, demonstrating the required role of AMPK in this effect. Taken together, these results suggest that piperine leads to benign metabolic effects by activating the AMPK-p38 MAPK signaling pathway and UCP1 expression by activating intracellular lactate production in skeletal muscle.
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http://dx.doi.org/10.1038/srep41066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5259784PMC
January 2017

Resistin, a fat-derived secretory factor, promotes metastasis of MDA-MB-231 human breast cancer cells through ERM activation.

Sci Rep 2016 Jan 5;6:18923. Epub 2016 Jan 5.

Department of Anatomy, Korea University College of Medicine, Seoul, Korea.

Resistin, an adipocyte-secreted factor, is known to be elevated in breast cancer patients. However, the molecular mechanism by which resistin acts is not fully understood. The aim of this study was to investigate whether resistin could stimulate invasion and migration of breast cancer cells. Here, we report that resistin stimulated invasion and migration of breast cancer cells as well as phosphorylation of c-Src. Inhibition of c-Src blocked resistin-induced breast cancer cell invasion. Resistin increased intracellular calcium concentration, and chelation of intracellular calcium blocked resistin-mediated activation of Src. Resistin also induced phosphorylation of protein phosphatase 2A (PP2A). Inhibition of c-Src blocked resistin-mediated PP2A phosphorylation. In addition, resistin increased phosphorylation of PKCα. Inhibition of PP2A enhanced resistin-induced PKCα phosphorylation, demonstrating that PP2A activity is critical for PKCα phosphorylation. Resistin also increased phosphorylation of ezrin, radixin, and moesin (ERM). Additionally, ezrin interacted with PKCα, and resistin promoted co-localization of ezrin and PKCα. Either inhibition of c-Src and PKCα or knock-down of ezrin blocked resistin-induced breast cancer cells invasion. Moreover, resistin increased expression of vimentin, a key molecule for cancer cell invasion. Knock-down of ezrin abrogated resistin-induced vimentin expression. These results suggest that resistin play as a critical regulator of breast cancer metastasis.
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http://dx.doi.org/10.1038/srep18923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4700449PMC
January 2016

AMPK, a metabolic sensor, is involved in isoeugenol-induced glucose uptake in muscle cells.

J Endocrinol 2016 Feb 19;228(2):105-14. Epub 2015 Nov 19.

Department of AnatomyKorea University College of Medicine, Seoul 136-701, South KoreaDepartment of MedicineKorea University College of Medicine, Seoul, South KoreaIntegrated Metabolomics Research GroupKorea Basic Science Institute (KBSI), Western Seoul Center, Seoul, South KoreaDepartment of Life ScienceEwha Womans University, Seoul, South Korea

Isoeugenol exerts various beneficial effects on human health. However, the mechanisms underlying these effects are poorly understood. In this study, we observed that isoeugenol activated AMP-activated protein kinase (AMPK) and increased glucose uptake in rat L6 myotubes. Isoeugenol-induced increase in intracellular calcium concentration and glucose uptake was inhibited by STO-609, an inhibitor of calcium/calmodulin-dependent protein kinase kinase (CaMKK). Isoeugenol also increased the phosphorylation of protein kinase C-α (PKCα). Chelation of calcium with BAPTA-AM blocked isoeugenol-induced AMPK phosphorylation and glucose uptake. Isoeugenol stimulated p38MAPK phosphorylation that was inhibited after pretreatment with compound C, an AMPK inhibitor. Isoeugenol also increased glucose transporter type 4 (GLUT4) expression and its translocation to the plasma membrane. GLUT4 translocation was not observed after the inhibition of AMPK and CaMKK. In addition, isoeugenol activated the Akt substrate 160 (AS160) pathway, which is downstream of the p38MAPK pathway. Knockdown of the gene encoding AS160 inhibited isoeugenol-induced glucose uptake. Together, these results indicate that isoeugenol exerts beneficial health effects by activating the AMPK/p38MAPK/AS160 pathways in skeletal muscle.
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http://dx.doi.org/10.1530/JOE-15-0302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4705517PMC
February 2016

Paclitaxel suppresses the viability of breast tumor MCF7 cells through the regulation of EF1α and FOXO3a by AMPK signaling.

Int J Oncol 2015 Nov 10;47(5):1874-80. Epub 2015 Sep 10.

Department of Anatomy, Korea University College of Medicine, Seoul 136-701, Republic of Korea.

Paclitaxel (Taxol), a potent drug of natural origin isolated from the bark of the Pacific yew, is widely used for treating ovarian, lung and breast cancers. Currently, there is little information regarding the specific mechanism underlying the anticancer activity of paclitaxel. In the present study, we found that 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR), a well-known activator of adenosine monophosphate (AMP)-activated protein kinase (AMPK), downregulated the protein and mRNA levels of elongation factor 1 α (EF1α) in breast cancer MCF7 cells. Paclitaxel increased the phosphorylation of AMPK and also downregulated the expression of EF1α in MCF7 cells. In addition, paclitaxel increased the expression, as well as the phosphorylation of forkhead box O3a (FOXO3a). Phosphorylation of FOXO3a was suppressed in the presence of compound C, a specific AMPK inhibitor, suggesting the involvement of AMPK in paclitaxel-induced FOXO3a phosphorylation. The induction and phosphorylation of FOXO3a by paclitaxel were not observed in EF1α and AMPK knockdown cells. Co-treatment with AICAR resulted in increased susceptibility of cancer cells to paclitaxel-induced suppression of their viability and further enhanced paclitaxel-induced FOXO3a phosphorylation. These results suggest that the antitumor effects of paclitaxel in breast cancer are mediated by activation of the AMPK/EF1α/FOXO3a signaling pathway.
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http://dx.doi.org/10.3892/ijo.2015.3153DOI Listing
November 2015

Endogenous Ligand for GPR120, Docosahexaenoic Acid, Exerts Benign Metabolic Effects on the Skeletal Muscles via AMP-activated Protein Kinase Pathway.

J Biol Chem 2015 Aug 1;290(33):20438-47. Epub 2015 Jul 1.

From the Department of Anatomy, Korea University College of Medicine, Seoul 136-701, Korea

Docosahexaenoic acid (DHA) is an endogenous ligand of G protein-coupled receptor 120 (GPR120). However, the mechanisms underlying DHA action are poorly understood. In this study, DHA stimulated glucose uptake in the skeletal muscles in an AMP-activated protein kinase (AMPK)-dependent manner. GPR120-mediated increase in intracellular Ca(2+) was critical for DHA-mediated AMPK phosphorylation and glucose uptake. In addition, DHA stimulated GLUT4 translocation AMPK-dependently. Inhibition of AMPK and Ca(2+)/calmodulin-dependent protein kinase kinase blocked DHA-induced glucose uptake. DHA and GW9508, a GPR120 agonist, increased GPR120 expression. DHA-mediated glucose uptake was not observed in GPR120 knockdown conditions. DHA increased AMPK phosphorylation, glucose uptake, and intracellular Ca(2+) concentration in primary cultured myoblasts. Taken together, these results indicated that the beneficial metabolic role of DHA was attributed to its ability to regulate glucose via the GPR120-mediated AMPK pathway in the skeletal muscles.
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http://dx.doi.org/10.1074/jbc.M115.657379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536449PMC
August 2015

Cognitive Function and Control of Type 2 Diabetes Mellitus in Young Adults.

N Am J Med Sci 2015 May;7(5):220-6

Cooper Research Institute, Cooper Medical School of Rowan University, Camden, New Jersey, USA.

Background: Type 2 diabetes mellitus (T2DM) has been associated with impairment of cognitive function. Studies show a strong negative correlation between the levels of glycosylated hemoglobin and cognitive function in adult patients above the mean age of 60 years. In healthy adults, age-related cognitive impairment is mostly reported after the age of 60 years, hence the decline in cognitive function can be a part of normal aging without diabetes. Since the majority of patients with diabetes are between the ages of 40 and 59 years, it is crucial to ascertain whether the levels of glycosylated hemoglobin negatively correlate with the levels of cognitive function scores in adult patients of age 60 years or younger, similar to the way it correlates in patients older than 60 years of age, or not.

Aims: We observed the relationship between the levels of glycosylated hemoglobin and the levels of cognitive function in patients of age 60 years or younger with T2DM.

Materials And Methods: Eighty-two patients with T2DM underwent cognitive assessment testing by using a Modified Mini-Mental State Examination (3MS), and their cognitive function scores were correlated with their glycosylated hemoglobin levels, durations of diabetes, and levels of education.

Results: Cognitive impairment was observed in 19.5% of the studied patients. We found a weakly negative relationship between the glycosylated hemoglobin level and cognitive function score (r = -0.292), a moderately negative relationship between the duration of diabetes and cognitive function score (r = -0.303), and a weakly positive relationship between the level of education and cognitive function score (r = 0.277).

Conclusion: Cognitive impairment affects one-fifth of the patients of age 60 years or younger with T2DM. It is weakly negatively related to the glycosylated hemoglobin level, moderately negatively related to the duration of diabetes, and weakly positively related to the level of education.
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http://dx.doi.org/10.4103/1947-2714.157627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4462818PMC
May 2015

Visfatin, a novel adipokine, stimulates glucose uptake through the Ca2 +-dependent AMPK-p38 MAPK pathway in C2C12 skeletal muscle cells.

J Mol Endocrinol 2015 Jun;54(3):251-62

Department of Anatomy Korea University College of Medicine, 126-1, Anam-dong 5-ga, Seongbuk-gu, Seoul, Korea

Visfatin is a novel adipocytokine produced by visceral fat. In the present study, visfatin increased AMP-activated protein kinase (AMPK) phosphorylation in mouse C2C12 skeletal muscle cells. It also increased phosphorylation of the insulin receptor, whose knockdown blocked visfatin-induced AMPK phosphorylation and glucose uptake. Visfatin stimulated glucose uptake in differentiated skeletal muscle cells. However, inhibition of AMPKα2 with an inhibitor or with knockdown of AMPKα2 using siRNA blocked visfatin-induced glucose uptake, which indicates that visfatin stimulates glucose uptake through the AMPKα2 pathway. Visfatin increased the intracellular Ca(2) (+) concentration. STO-609, a calmodulin-dependent protein kinase kinase inhibitor, blocked visfatin-induced AMPK phosphorylation and glucose uptake. Visfatin-mediated activation of p38 MAPK was AMPKα2-dependent. Furthermore, both inhibition and knockdown of p38 MAPK blocked visfatin-induced glucose uptake. Visfatin increased glucose transporter type 4 (GLUT4) mRNA and protein levels. In addition, visfatin stimulated the translocation of GLUT4 to the plasma membrane, and this effect was suppressed by AMPKα2 inhibition. The present results indicate that visfatin plays an important role in glucose metabolism via the Ca(2) (+)-mediated AMPK-p38 MAPK pathway.
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http://dx.doi.org/10.1530/JME-14-0274DOI Listing
June 2015

Promoter hypermethylation of membrane type 3 matrix metalloproteinase is associated with cell migration in colorectal adenocarcinoma.

Cancer Genet 2015 May 1;208(5):261-70. Epub 2015 May 1.

Institute of Human Genetics, Department of Anatomy, Korea University College of Medicine, Seoul, Republic of Korea. Electronic address:

The gene MT3-MMP (also known as MMP16) encodes the membrane type 3 matrix metalloproteinase, which is a member of the matrix metalloproteinase (MMP) gene family. Several MMPs are associated with migration in colorectal cancer (CRC). However, the methylation status of the MT3-MMP promoter in CRC has not been reported. The methylation status and expression levels of MT3-MMP were investigated in primary tumor tissues and adjacent normal tissues in 105 patients with CRC, one normal colon cell line (CCD18Co), and three CRC cell lines (SW480, DLD-1, and LoVo) by quantitative methylation-specific PCR and real-time PCR. MT3-MMP was hypermethylated in 82 of 105 CRC tissues (78%), 30 of 105 adjacent normal tissues (29%), and two of 11 normal colon tissues (18%). MT3-MMP mRNA was significantly reduced in CRC compared with that in adjacent normal tissues (P < 0.05). The methylation-mediated downregulation of MT3-MMP was restored by treatment with 5-aza-2'-deoxycytidine in two CRC cell lines, and MT3-MMP promoter activity was significantly reduced by methylation. The knockdown of MT3-MMP induced cell migration, but overexpressed MT3-MMP reduced cell migration in CRC cells. These results demonstrate that the MT3-MMP promoter is frequently hypermethylated in CRC and that downregulation of MT3-MMP may be important for cell migration in CRC.
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http://dx.doi.org/10.1016/j.cancergen.2015.04.009DOI Listing
May 2015

The effect of applying ethnicity-specific spirometric reference equations to Asian migrant workers in Korea.

Ann Occup Environ Med 2015 18;27:14. Epub 2015 May 18.

Department of Occupational and Environmental Medicine & Institute of Environmental and Occupational Medicine, Inje University Busan Paik Hospital, Bokji-ro 75, Busanjin-gu, Busan, Republic of Korea.

Objectives: Asian migrant workers in Korea have various ethnicities. The purpose of this study was to evaluate the difference in spirometric interpretation made using the set of third National Health and Nutrition Examination Survey (NHANES III) reference equations and the relevant ethnicity-specific reference sets.

Methods: Spirometry was performed on 166 migrant and 498 Korean male workers between March and November 2012. We analyzed the spirometric data of healthy never-smokers. Spirometric patterns were evaluated using the NHANES III reference set and some relevant ethnicity-specific equations (Eom's equation for Koreans, Ip's equation for East Asians, Crapo's equation for Central Asians, Memon's equation for South Asians, and Gnanou's equation for Southeast Asian people).

Results: In all migrant groups except the Central Asian group, the forced expiratory volume in 1 second percentage (FEV1%) and forced vital capacity percentage (FVC%) calculated using each of the ethnicity-specific reference equations considered were significantly higher than those calculated using the NHANES III reference set. This study showed that in the evaluation of the spirometric result of subjects from Southeast Asia or South Asia, the percentage of cases with an abnormal FEV1 or FVC increased when the NHANES III set of equations was used as compared to when the ethnicity-specific equations were used.

Conclusions: We found that the spirometric results of all ethnic groups were higher and the composition of the abnormal spirometric result was lower when the ethnicity-specific reference equations were used instead of the NHANES III reference set.
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http://dx.doi.org/10.1186/s40557-015-0065-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4437438PMC
May 2015

The effect of high glucose levels on the hypermethylation of protein phosphatase 1 regulatory subunit 3C (PPP1R3C) gene in colorectal cancer.

J Genet 2015 Mar;94(1):75-85

Department of Anatomy, Korea University Anam Hospital, Korea University College of Medicine, 126-1, Anam-dong 5-ga, Seongbuk-gu, Seoul, South Korea.

DNA methylation is an epigenetic event that occurs frequently in colorectal cancer (CRC). Increased glucose level is a strong risk factor for CRC. Protein phosphatase 1 regulatory subunit 3C (PPP1R3C) modulates glycogen metabolism, particularly glycogen synthesis. The aim of this study was to investigate the effect of high glucose levels on DNA methylation of PPP1R3C in CRC. PPP1R3C was significantly hypermethylated in CRC tissues (76/105, 72.38%, P <0.05) and colon cancer cell lines (P < 0.05). CRC tissues obtained from patients with high glucose levels showed that the methylation of PPP1R3C was lower than in patients who had normal levels of glucose. When DLD-1 cells were cultured under conditions of high glucose, the methylation of PPP1R3C was repressed. The expression of PPP1R3C was inversely related to methylation status. In addition, a promoter luciferase assay showed that the transcriptional activity of PPP1R3C was increased in high glucose culture conditions. The number of cells decreased when PPP1R3C was silenced in DLD-1 cells. These results suggest that PPP1R3C, a novel hypermethylated gene in CRC, may play a critical role in cancer cell growth in association with glucose levels.
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http://dx.doi.org/10.1007/s12041-015-0492-2DOI Listing
March 2015

Irisin, a Novel Myokine, Regulates Glucose Uptake in Skeletal Muscle Cells via AMPK.

Mol Endocrinol 2015 Jun 31;29(6):873-81. Epub 2015 Mar 31.

Department of Anatomy (H.J.L., J.O.L., N.K., J.K.K., H.I.K., Y.W.L., S.J.K., S.H.P., H.S.K.), Korea University College of Medicine, Seoul, Korea 136-705; Division of Cardiology (J.-I.C.), Department of Internal Medicine, Korea University Medical Center, Seoul, Korea; College of Nursing (Y.O.), Korea University, Seoul, Korea 136-705; College of Pre-Pharm·Med (J.H.K.), DukSung Women's University, Seoul, Korea 132-714; and College of Pharmacy (S.-H.), University of Rhode Island, Kingston, Rhode Island 02881.

Irisin is a novel myokine produced by skeletal muscle. However, its metabolic role is poorly understood. In the present study, irisin induced glucose uptake in differentiated skeletal muscle cells. It increased AMP-activated protein kinase (AMPK) phosphorylation and the inhibition of AMPK blocked glucose uptake. It also increased reactive oxygen species (ROS) generation. N-acetyl cysteine, a ROS scavenger, blocked irisin-induced AMPK phosphorylation. Moreover, irisin activated p38 MAPK in an AMPK-dependent manner. The inhibition and knockdown of p38 MAPK blocked irisin-induced glucose uptake. A colorimetric absorbance assay showed that irisin stimulated the translocation of glucose transporter type 4 to the plasma membrane and that this effect was suppressed in cells pretreated with a p38 MAPK inhibitor or p38 MAPK small interfering RNA. In primary cultured myoblast cells, irisin increased the concentration of intracellular calcium. STO-609, a calcium/calmodulin-dependent protein kinase kinase inhibitor, blocked irisin-induced AMPK phosphorylation, implying that calcium is involved in irisin-mediated signaling. Our results suggest that irisin plays an important role in glucose metabolism via the ROS-mediated AMPK pathway in skeletal muscle cells.
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http://dx.doi.org/10.1210/me.2014-1353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5414737PMC
June 2015