Publications by authors named "Hwa Young Kim"

124 Publications

Structural Insights into a Bifunctional Peptide Methionine Sulfoxide Reductase MsrA/B Fusion Protein from .

Antioxidants (Basel) 2021 Mar 5;10(3). Epub 2021 Mar 5.

Department of Biotechnology, Korea University, Seoul 02841, Korea.

Methionine sulfoxide reductase (Msr) is a family of enzymes that reduces oxidized methionine and plays an important role in the survival of bacteria under oxidative stress conditions. MsrA and MsrB exist in a fusion protein form (MsrAB) in some pathogenic bacteria, such as (), , and . To understand the fused form instead of the separated enzyme at the molecular level, we determined the crystal structure of MsrAB at 2.2 Å, which showed that a linker region (, 193-205) between two domains interacted with each MsrA or MsrB domain via three salt bridges (E193-K107, D197-R103, and K200-D339). Two acetate molecules in the active site pocket showed an planar electron density map in the crystal structure, which interacted with the conserved residues in fusion MsrABs from the pathogen. Biochemical and kinetic analyses revealed that is required to increase the catalytic efficiency of MsrAB. Two salt bridge mutants (D193A and E199A) were located at the entrance or tailgate of . Therefore, the linker region of the MsrAB fusion enzyme plays a key role in the structural stability and catalytic efficiency and provides a better understanding of why MsrAB exists in a fused form.
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http://dx.doi.org/10.3390/antiox10030389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000184PMC
March 2021

Importance of extracutaneous organ involvement in determining the clinical severity and prognosis of incontinentia pigmenti caused by mutations in the IKBKG gene.

Exp Dermatol 2021 Mar 2. Epub 2021 Mar 2.

Department of Pediatrics, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.

Incontinentia pigmenti (IP) is a rare X-linked skin disease caused by mutations in the IKBKG gene, which is required for activation of the nuclear factor-kappa B signalling pathway. Multiple systems can be affected with highly variable phenotypic expressivity. We aimed to clarify the clinical characteristics observed in molecularly confirmed Korean IP patients. The medical records of 25 females confirmed as IP by molecular genetic analysis were retrospectively reviewed. The phenotypic score of extracutaneous manifestations was calculated to assess the disease severity. The IKBKG gene partial deletion or intragenic mutations were investigated using long-range PCR, multiplex ligation-dependent probe amplification and direct sequencing methods. Among the 25 individuals, 18 (72%) were sporadic cases. All patients showed typical skin manifestations at birth or during the neonatal period. Extracutaneous findings were noted in 17 (68%) patients; ocular manifestations (28%), neurological abnormalities (28%), hair abnormalities (20%), dental anomalies (12%), nail dystrophy (8%). The common exon 4-10 IKBKG deletion was observed in 20 (80%) patients. In addition, five intragenic sequence variants were identified, including three novel variants. The phenotype scores were highly variable, ranging from abnormal skin pigmentation only to one or more extracutaneous features, although no significant difference was observed for each clinical characteristic between the group with sequence variants and that with common large deletion. Our cohort with IP showed heterogeneity of extracutaneous manifestations and high incidence of sporadic cases. Long-term monitoring with multidisciplinary management is essential for evaluating the clinical status, providing adequate genetic counselling and understanding the genotype-phenotype correlation in IP.
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http://dx.doi.org/10.1111/exd.14313DOI Listing
March 2021

Antiobesity Effect of a Novel Herbal Formulation in High-Fat Diet-Induced Obese Mice.

Evid Based Complement Alternat Med 2021 8;2021:6612996. Epub 2021 Feb 8.

Department of Biomedical Science, Cheongju University, Cheongju 28503, Republic of Korea.

A variety of natural products have been explored for their antiobesity potential and widely used to develop dietary supplements for the prevention of weight gain from excess body fat. In an attempt to find a natural antiobesity agent, this study was designed to evaluate the antiobesity activity of a novel herbal formulation composed of extracts from three medicinal plants in high-fat diet- (HFD-) induced obese mice. After the thirteen-week oral administration of the test materials to mice, the body weight gain, whole-body fat mass, adipose tissue weight, and the expression levels of obesity-related proteins were measured. Our results indicated that can suppress body weight gain and lower whole-body fat mass in HFD-induced obese mice. Significant decreases in epididymal and retroperitoneal fat mass were observed in -treated groups compared with the HFD-fed control group ( < 0.05). Furthermore, the oral administration of caused significant decreases in the expression level of adipogenic (C/EBP and PPAR) and lipogenic (ACC) markers and notable increases in the production level of thermogenetic (AMPK, PGC1 and UCP1) and lipolytic (HSL) proteins. These findings suggest that holds great promise for a novel herbal formulation with antiobesity activities, preventing body fat accumulation and altering lipid metabolism.
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http://dx.doi.org/10.1155/2021/6612996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886504PMC
February 2021

Cardiac autonomic dysfunction is associated with hypothalamic damage in patients with childhood-onset craniopharyngioma.

PLoS One 2021 16;16(2):e0246789. Epub 2021 Feb 16.

Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.

Background: Autonomic nervous system dysfunction is implicated in the development of hypothalamic obesity. We investigated the relationship between hypothalamic involvement (HI), central obesity, and cardiac autonomic dysfunction by assessing heart rate variability (HRV) indices in patients with childhood-onset craniopharyngioma.

Methods: A cross-sectional study of 48 patients (28 males, 10-30 years old) with hypothalamic damage after childhood-onset craniopharyngioma was performed. Postoperative HI was graded as mild (n = 19) or extensive (n = 29) on magnetic resonance imaging. Anthropometry, body composition and HRV indices including the standard deviation of all normal R-R intervals (SDNN) and total power (TP) as overall variability markers, root-mean square differences of successive R-R intervals (RMSSD) and high frequency (HF) as parasympathetic modulation markers, and low frequency (LF) as a sympathetic/sympathovagal modulation marker were measured.

Results: Patients with extensive HI had increased means of body mass index, waist circumference, and fat mass than those with mild HI (P < 0.05, for all). Centrally obese patients had a lower mean HF, a parasympathetic modulation marker, than centrally non-obese patients (P < 0.05). The extensive HI group had lower means of overall variability (SDNN and TP), parasympathetic modulation (HF), and sympathetic/sympathovagal modulation (LF) than the mild HI group (P < 0.05, for all). The interaction effect of HI and central obesity on HRV indices was not significant. In models adjusted for age, sex, and family history of cardiometabolic disease, the means of the overall variability indices (P < 0.05 for both SDNN and TP) and a sympathetic/sympathovagal modulation index (P < 0.05 for LF) were lower with extensive HI, without differences according to central obesity.

Conclusions: The reduced HRV indices with extensive HI suggests that hypothalamic damage may contribute to cardiac autonomic dysfunction, underscoring the importance of minimizing hypothalamic damage in patients with childhood-onset craniopharyngioma.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246789PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886170PMC
February 2021

Methionine sulfoxide reductase B3 deficiency inhibits the development of diet-induced insulin resistance in mice.

Redox Biol 2021 Jan 1;38:101823. Epub 2020 Dec 1.

Department of Physiology, College of Medicine, Yeungnam University, Daegu, 42415, Republic of Korea; Smart-Aging Convergence Research Center, College of Medicine, Yeungnam University, Daegu, 42415, Republic of Korea. Electronic address:

Oxidative and endoplasmic reticulum (ER) stress are involved in mediating high-fat diet (HFD)-induced insulin resistance. As the ER-localized methionine sulfoxide reductase B3 (MsrB3) protects cells against oxidative and ER stress, we hypothesized that MsrB3 might be associated with HFD-induced insulin resistance. To test this hypothesis, we examined the effect of MsrB3 deficiency on HFD-induced insulin resistance using MsrB3 knockout (KO) mice. Mice were fed a control diet or HFD for 12 weeks and insulin sensitivity was measured using a hyperinsulinemic-euglycemic clamp. HFD consumption increased the body weight of both wild-type and MsrB3 KO mice, and no significant difference was observed between the genotypes. The HFD increased oxidative stress and induced insulin resistance in the skeletal muscle of wild-type mice, but did not affect either in MsrB3 KO mice. The unfolded protein response (UPR) was increased in MsrB3 KO mice upon consumption of HFD, but not in wild-type mice. Mitochondrial oxidative phosphorylation proteins and the levels of superoxide dismutase 2 and glutathione peroxidase 1 were increased in MsrB3 KO mice upon HFD consumption. The respiratory control ratio was reduced in wild-type mice consuming HFD but not in MsrB3 KO mice. The levels of calcium/calmodulin-dependent protein kinase kinase β, phosphorylated AMP-activated protein kinase, and peroxisome proliferator-activated receptor gamma coactivator 1α were increased in MsrB3 KO mice following HFD consumption. These results suggest that MsrB3 deficiency inhibits HFD-induced insulin resistance, and the increased mitochondrial biogenesis and antioxidant induction might be the mechanisms underlying this phenomenon.
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http://dx.doi.org/10.1016/j.redox.2020.101823DOI Listing
January 2021

Monothiol and dithiol glutaredoxin-1 from : identification of domain-swapped structures by NMR, X-ray crystallography and HDX mass spectrometry.

IUCrJ 2020 Nov 19;7(Pt 6):1019-1027. Epub 2020 Sep 19.

Department of Biotechnology, School of Life Sciences and Biotechnology for BK21 PLUS, Institute of Life Science and Natural Resources, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea.

Protein dimerization or oligomerization resulting from swapping part of the protein between neighboring polypeptide chains is known to play a key role in the regulation of protein function and in the formation of protein aggregates. Glutaredoxin-1 from (cGrx1) was used as a model to explore the formation of multiple domain-swapped conformations, which were made possible by modulating several hinge-loop residues that can form a pivot for domain swapping. Specifically, two alternative domain-swapped structures were generated and analyzed using nuclear magnetic resonance (NMR), X-ray crystallography, circular-dichroism spectroscopy and hydrogen/deuterium-exchange (HDX) mass spectrometry. The first domain-swapped structure (β3-swap) was formed by the hexameric cGrx1-cMsrA complex. The second domain-swapped structure (β1-swap) was formed by monothiol cGrx1 (C16S) alone. In summary, the first domain-swapped structure of an oxidoreductase in a hetero-oligomeric complex is presented. In particular, a single point mutation of a key cysteine residue to serine led to the formation of an intramolecular disulfide bond, as opposed to an intermolecular disulfide bond, and resulted in modulation of the underlying free-energy landscape of protein oligomerization.
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http://dx.doi.org/10.1107/S2052252520011598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642778PMC
November 2020

Clinical and Genetic Characteristics of 23 Korean Patients with Haploinsufficiency of the Short-stature Homeobox-containing Gene.

Exp Clin Endocrinol Diabetes 2020 Sep 15. Epub 2020 Sep 15.

Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul.

Background: The short-stature homeobox-containing gene () is one of the major growth genes in humans. The clinical spectrum of haploinsufficiency ranges from Léri-Weill dyschondrosteosis to idiopathic short stature. Herein, we describe the clinical and genetic characteristics of 23 Korean patients with deficiency disorders.

Methods: Medical records of 23 patients (19 females and 4 males) from 15 unrelated families who were genetically confirmed to have deficiency were retrospectively reviewed. gene deletions or mutations were determined by sequence analyses using multiplex ligation-dependent probe amplification, chromosomal microarray, and/or Sanger sequencing methods.

Results: In the 15 families, 9 probands were cases. All 23 patients showed mesomelia. Madelung deformity and tibia vara were observed in 13 (56.5%) and 3 (13.1%) patients, respectively. Genetically, 11 (73.3%) of the 15 families showed deletions of various sizes, and the other 4 families harboured sequence variants. Four patients had undergone orthopaedic surgeries (3 for tibia vara and 1 for Madelung deformity). Among 7 patients who had received growth hormone treatment for ≥1 year, 5 showed good responses, with a median first-year change-in-height standard deviation score of +0.6. There were no significant differences in the clinical characteristics of the deletion and point mutation groups.

Conclusions: A high index of suspicion and the genetic confirmation of deficiency are helpful for the timely management of the condition and are needed to provide genetic counselling to the family members of the patients.
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http://dx.doi.org/10.1055/a-1247-4863DOI Listing
September 2020

Correction: Autonomic Dysfunction is Associated with Increased Cardiometabolic Risk in Patients with Childhood-Onset Craniopharyngioma.

Horm Metab Res 2020 Jul 16;52(7):e2. Epub 2020 Jun 16.

Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea.

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http://dx.doi.org/10.1055/a-1192-5447DOI Listing
July 2020

Autonomic Dysfunction is Associated with Increased Cardiometabolic Risk in Patients with Childhood-Onset Craniopharyngioma.

Horm Metab Res 2020 Jul 8;52(7):500-508. Epub 2020 Jun 8.

Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea.

Patients with craniopharyngioma are susceptible to autonomic dysfunction as a result of hypothalamic damage. We evaluated indices of heart rate variability (HRV) in patients with childhood-onset craniopharyngioma to investigate autonomic function and its relationship with components of the metabolic syndrome (MetS). This cross-sectional, case-only study included 53 patients (10-30 years of age). We measured the standard deviation of all normal R-R intervals (SDNN) and total power indicating overall HRV, the root-mean square of the difference of successive R-R intervals (RMSSD) and high frequency indicating parasympathetic modulation, and low frequency. These indices were compared according to the presence of the MetS. During the mean 10.8 years of follow-up, 25% of patients were diagnosed with the MetS. Patients with the MetS showed significantly lower levels of SDNN (29.0 vs. 40.6 ms), total power (416.1 vs. 1129.6 ms), RMSSD (20.1 vs. 34.5 ms), high frequency (94.7 vs. 338.5 ms), and low frequency (94.5 vs. 289.4 ms) than those without (p <0.05, for all). Individual components of the MetS including insulin resistance, serum triglycerides levels, and systolic blood pressure were inversely associated with SDNN, total power, RMSSD and high frequency. Higher overall variability and parasympathetic modulation were related to decreased odds ratios for having the MetS (OR 0.91, p=0.029 for SDNN; OR 0.91, p=0.032 for total power). In conclusion, autonomic dysfunction, as evidenced by reduced HRV indices, is associated with increased cardiometabolic risk in patients with childhood-onset craniopharyngioma.
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http://dx.doi.org/10.1055/a-1169-0307DOI Listing
July 2020

Generation of embryonic stem cells derived from the inner cell mass of blastocysts of outbred ICR mice.

Anim Cells Syst (Seoul) 2020 16;24(2):91-98. Epub 2020 Apr 16.

Department of Animal Life Science, Kangwon National University, Chuncheon, Korea.

Embryonic stem cells (ESCs) derived from outbred mice which share several genetic characteristics similar to humans have been requested for developing stem cell-based bioengineering techniques directly applicable to humans. Here, we report the generation of ESCs derived from the inner cell mass of blastocysts retrieved from 9-week-old female outbred ICR mice mated with 9-week-old male outbred ICR mice (ESCs). Similar to those from 129/Ola mouse blastocysts (ESCs), the established ESCs showed inherent characteristics of ESCs except for partial and weak protein expression and activity of alkaline phosphatase. Moreover, ESCs were not originated from embryonic germ cells or pluripotent cells that may co-exist in outbred ICR strain-derived mouse embryonic fibroblasts (MEFs) used for deriving colonies from inner cell mass of outbred ICR mouse blastocysts. Furthermore, instead of outbred MEFs, hybrid MEFs as feeder cells could sufficiently support maintenance of ESC self-renewal. Additionally, ESC-specific characteristics (self-renewal, pluripotency, and chromosomal normality) were observed in ESCs cultured for 40th subpassages (164 days) on MEFs without any alterations. These results confirmed the successful establishment of ESCs derived from outbred ICR mice, and indicated that self-renewal and pluripotency of the established ESCs could be maintained on MEFs in culture.
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http://dx.doi.org/10.1080/19768354.2020.1752306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241472PMC
April 2020

Prenatal and early childhood phthalate exposures and thyroid function among school-age children.

Environ Int 2020 08 22;141:105782. Epub 2020 May 22.

Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; Division of Public Health and Preventive Medicine, Seoul National University Hospital, Seoul, Republic of Korea; Institute of Environmental Medicine, Seoul National University Medical Research Center, Seoul, Republic of Korea. Electronic address:

Background: Limited studies have investigated the association between prenatal and early childhood phthalate exposures and thyroid function among children.

Objectives: To investigate the association between early life phthalate exposure and thyroid function among school-age children, considering both prenatal and early childhood exposures, using longitudinal data from an established prospective cohort.

Methods: We measured urinary phthalate metabolite levels during pregnancy and at 2, 4, and 6 years of age and conducted thyroid function tests at 6 years of age. We assessed the associations between phthalate metabolite levels and thyroid function using linear regression and Bayesian kernel machine regression (BKMR) models (n = 492).

Results: In linear regression models, a doubling of urinary mono-n-butyl phthalate (MnBP) levels, measured during pregnancy and at 4 years of age, was associated with lower thyroid-stimulating hormone (TSH) levels at 6 years of age (-5.0%, 95% confidence interval [CI]: -8.8%, -1.0% and -5.7%, 95% CI: -9.7%, -1.5%, respectively). A similar association was found between mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) levels at 4 years of age and TSH levels at 6 years of age (-5.5%, 95% CI: -9.7%, -1.1%). Urinary mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) (2.3%, 95% CI: 0.1%, 4.5%) and MEOHP levels at 2 years of age (2.2%, 95% CI: 0.1%, 4.4%) and mono-2-ethyl-5-carboxypentyl phthalate (1.4%, 95% CI: 0.1%, 2.7%) and mono-benzyl phthalate levels at 6 years of age (1.1%, 95% CI: 0.4%, 1.9%) were associated with higher triiodothyronine (T3) levels at 6 years of age. Urinary MnBP during pregnancy, MEHHP, MEOHP, and MnBP at 4 years of age were also associated with lower free thyroxine (fT4) × TSH. In BKMR models, urinary MnBP levels during pregnancy were associated with lower TSH levels and fT4 × TSH (both posterior inclusion probabilities: 0.99).

Conclusions: Our findings suggest that early life phthalate exposure influences subsequent thyroid function. However, the results should be interpreted cautiously, because a single spot urine sample was used to quantify the phthalate exposures at each time point.
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http://dx.doi.org/10.1016/j.envint.2020.105782DOI Listing
August 2020

The Relationship Between Perfluoroalkyl Substances Concentrations and Thyroid Function in Early Childhood: A Prospective Cohort Study.

Thyroid 2020 11 2;30(11):1556-1565. Epub 2020 Jun 2.

Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.

Exposure to perfluoroalkyl substances (PFAS) has been suggested to affect thyroid function; however, data on early-life exposure and thyroid function in early childhood are scarce. We investigated the cross-sectional and longitudinal relationships of early-life exposure to PFAS with thyroid function at 2, 4, and 6 years of age. This study used data on PFAS exposure and thyroid function from the Environment and Development of Children (EDC) cohort study. A total of 660 children who visited at least once at 2, 4, or 6 years of age (381 children aged 2 years, 569 children aged 4 years, and 511 children aged 6 years) were included in this study. Serum thyrotropin (TSH) levels were measured at 2, 4, and 6 years of age. The relationship of serum PFAS (sPFAS) concentrations with TSH levels at the three time points was assessed by repeated-measure analysis using linear mixed models. The serum levels of free thyroxine (fT4) and triiodothyronine (T3) were measured once (at 6 years of age). The relationship of sPFAS with fT4 and T3 levels at 6 years of age was investigated by linear regression analyses. None complained of hyper- or hypothyroid symptoms with normal fT4 and T3 levels. Repeated-measure analysis showed that TSH levels at 2, 4, and 6 years of age were inversely associated with serum perfluorononanoic acid (sPFNA), after adjusting for age, sex, and/or dietary iodine intake ( < 0.05). When stratified by sex, TSH levels were inversely associated with serum perfluorooctanoic acid (sPFOA) in boys and sPFNA in girls ( < 0.05 for both). fT4 levels at 6 years of age were positively related to sPFNA and serum perfluorohexane sulfonic acid at 2 years of age and sPFOA at 6 years of age, and T3 levels at 6 years of age showed positive relationships with serum perfluorodecanoic acid and serum perfluorooctane sulfonic acid at 6 years of age ( < 0.05 for all). When stratified by sex, similar positive relationships for sPFAS with fT4 and T3 levels were significant among boys only. A significant relationship was found between early-life exposure to PFAS and thyroid function. Early-life exposure to PFAS was associated with decreased TSH and increased fT4 or T3 levels among preschool-age children.
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http://dx.doi.org/10.1089/thy.2019.0436DOI Listing
November 2020

Effect of overhang and stiffness on accessibility of catheter tip to lung defects under surgical constraints.

Ann Transl Med 2020 Mar;8(5):169

Department of Thoracic and Cardiovascular Surgery, Pusan National University Hospital, Medical Research Institution, Busan, South Korea.

Background: Steering a catheter tip to a defective spot on a lung during fibrin glue application under pleurography (FGAP) constitutes a very challenging task. Accurate control of tip position/slope of steerable catheters is critical for providing glue to air-leaking defects on lung during FGAP. Steerable catheters are composed of multiple segments with different flexural rigidities and experience nonlinear deformation. Therefore, predicting tip position with accuracy is difficult. The purpose of this paper is to present a novel method that can accurately control the tip of the catheter, and thus enhance its target accessibility.

Methods: The tip position of a deflected steerable catheter can be accurately predicted using a simulation tool depicting the curvature of a bent catheter based on a mechanics of materials analysis. The proposed method utilizes the simulation tool to enhance the target accessibility of the catheter's tip. This assists medical doctors to not only select the optimal catheter prior to operation, but also to steer the catheter to the defects effectively. Simulation reliability is tested by performing a catheter deflection experiment and measuring the tip position.

Results: The simulation result accurately predicts the location of the catheter tip with an error of less than 5 mm to the experimental results.

Conclusions: Controlling pull-wire tensions and overhang lengths based on simulation results substantially improves the target accessibility of the catheter tip.
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http://dx.doi.org/10.21037/atm.2020.02.22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154481PMC
March 2020

Cardiac autonomic neuropathy in nonobese young adults with type 1 diabetes.

Ann Pediatr Endocrinol Metab 2019 Sep 30;24(3):180-186. Epub 2019 Sep 30.

Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea.

Purpose: The aim of this study was to evaluate the prevalence and risk factors for cardiac autonomic neuropathy (CAN) in nonobese nonobese young type 1 diabetes mellitus (T1DM) patients without micro- or macrovascular complications.

Methods: CAN was assessed in 95 patients with T1DM, aged 18-29 years, using standard cardiovascular reflex tests - heart rate response to deep breathing, standing, and the Valsalva maneuver and blood pressure response to standing. Furthermore, power spectral analyses of overall heart rate variability (HRV), standard deviation of NN intervals (SDNN), and total power (TP) were tested with DiCAN. CAN was defined as abnormal results for at least 1 of the 4 cardiovascular reflex tests.

Results: The prevalence of CAN was 12.6%. The frequency of one and 2 abnormal reflex tests was 10.5% and 2.1%, respectively. No significant differences were observed in age, sex, mean hemoglobin A1c (HbA1c) level, and duration of diabetes with respect to presence of CAN. Patients with CAN exhibited lower overall HRV parameters (SDNN and TP) compared with those without CAN even though there was no statistical significance. In multivariable analyses, higher mean HbA1c level was significantly associated with lower overall HRV (β=-44.42, P=0.002 for SDNN and β=-2.82, P<0.001 for TP).

Conclusion: CAN can be detected in 12.6% of young adult T1DM patients even without other micro- or macrovascular complications. Glycemic control is the main determinant to maintain overall HRV and prevent CAN.
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http://dx.doi.org/10.6065/apem.2019.24.3.180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790876PMC
September 2019

Noxa mitochondrial targeting domain induces necrosis via VDAC2 and mitochondrial catastrophe.

Cell Death Dis 2019 07 8;10(7):519. Epub 2019 Jul 8.

Department of Biochemistry and Molecular Biology, Chosun University School of Medicine, 309 Pilmoon-Daero, Dong-Gu, Gwang-Ju, 61452, Korea.

Noxa, a Bcl-2 homology 3 (BH3)-only protein of the Bcl-2 family, is responsive to cell stresses and triggers apoptosis by binding the prosurvival Bcl-2-like proteins Mcl1, Bcl, and Bcl2A1. Although the Noxa BH3 domain is necessary to induce apoptosis, the mitochondrial targeting domain (MTD) of Noxa functions as a pronecrotic domain, an inducer of mitochondrial fragmentation, and delivery to mitochondria. In this study, we demonstrate that the extended MTD (eMTD) peptide induces necrotic cell death by interaction with the VDAC2 protein. The eMTD peptide penetrates the cell membrane, causing cell membrane blebbing, cytosolic calcium influx, and mitochondrial swelling, fragmentation, and ROS generation. The MTD domain binds VDACs and opens the mitochondrial permeability transition pore (mPTP) in a CypD-independent manner. The opening of mPTP induced by eMTD is inhibited either by down-regulation of VDAC2 or by the VDACs inhibitor DIDS. These results indicate that the MTD domain of Noxa causes mitochondrial damage by opening mPTP through VDACs, especially VDAC2, during necrotic cell death.
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http://dx.doi.org/10.1038/s41419-019-1753-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614423PMC
July 2019

Identification of integrin heterodimers functioning on the surface of undifferentiated porcine primed embryonic stem cells.

Cell Biol Int 2018 Sep 20;42(9):1221-1227. Epub 2018 Jun 20.

Department of Animal Life Science, Kangwon National University, Chuncheon, 24341, Korea.

In vitro expansion of undifferentiated porcine primed embryonic stem (ES) cells is facilitated by use of non-cellular niches that mimic three-dimensional (3D) microenvironments enclosing an inner cell mass of porcine blastocysts. Therefore, we investigated the integrin heterodimers on the surface of undifferentiated porcine primed ES cells for the purpose of developing a non-cellular niche to support in vitro maintenance of the self-renewal ability of porcine primed ES cells. Immunocytochemistry and a fluorescence immunoassay were performed to assess integrin α and β subunit levels, and attachment and antibody inhibition assays were used to evaluate the function of integrin heterodimers. The integrin α , α , α , α , α , and β subunits, but not the α , α , α , α , and α subunits, were identified on the surface of undifferentiated porcine primed ES cells. Subsequently, significant increase of their adhesion to fibronectin, tenascin C, and vitronectin were observed and functional blocking of integrin heterodimer α β , α β , or α β showed significantly inhibited adhesion to fibronectin, tenascin C, or vitronectin. No integrin α β heterodimer-mediated adhesion to laminin was detected. These results demonstrate that active α β , α β , and α β integrin heterodimers are present on the surface of undifferentiated porcine primed ES cells, together with inactive integrin α (presumed) and α subunits.
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http://dx.doi.org/10.1002/cbin.10993DOI Listing
September 2018

Effects of Mutation on Stringent Response-Mediated Bacterial Growth, Toxin Production, and Motility in .

J Microbiol Biotechnol 2018 May;28(5):816-820

Freshwater Bioresources Utilization Division, Nakdonggang National Institute of Biological Resources, Sangju 37242, Republic of Korea.

The stringent response (SR), which is activated by accumulation of (p)ppGpp under conditions of growth-inhibiting stresses, plays an important role on growth and virulence in . Herein, we carried out a genome-wide screen using transposon random mutagenesis to identify genes controlled by SR in a (p)ppGpp-overproducing mutant strain. One of the identified SR target genes was encoding flagellin. Genetic studies using and SR mutants demonstrated that FlaC was involved in bacterial growth, toxin production, and normal flagellum function under conditions of high (p)ppGpp levels, suggesting FlaC plays an important role in SR-induced pathogenicity in .
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http://dx.doi.org/10.4014/jmb.1712.12040DOI Listing
May 2018

Guanosine tetra- and pentaphosphate increase antibiotic tolerance by reducing reactive oxygen species production in .

J Biol Chem 2018 04 23;293(15):5679-5694. Epub 2018 Feb 23.

From the Department of Microbiology and Immunology, Brain Korea 21 PLUS Project for Medical Science, and

The pathogen is the causative agent of cholera. Emergence of antibiotic-resistant strains is increasing, but the underlying mechanisms remain unclear. Herein, we report that the stringent response regulator and stress alarmone guanosine tetra- and pentaphosphate ((p)ppGpp) significantly contributes to antibiotic tolerance in We found that N16961, a pandemic strain, and its isogenic (p)ppGpp-overexpressing mutant ΔΔ are both more antibiotic-resistant than (p)ppGpp (ΔΔΔ) and Δ mutants, which cannot produce or utilize (p)ppGpp, respectively. We also found that additional disruption of the aconitase B-encoding and tricarboxylic acid (TCA) cycle gene in the (p)ppGpp mutant increases its antibiotic tolerance. Moreover, expression of TCA cycle genes, including , was increased in (p)ppGpp, but not in the antibiotic-resistant ΔΔ mutant, suggesting that (p)ppGpp suppresses TCA cycle activity, thereby entailing antibiotic resistance. Importantly, when grown anaerobically or incubated with an iron chelator, the (p)ppGpp mutant became antibiotic-tolerant, suggesting that reactive oxygen species (ROS) are involved in antibiotic-mediated bacterial killing. Consistent with that hypothesis, tetracycline treatment markedly increased ROS production in the antibiotic-susceptible mutants. Interestingly, expression of the Fe(III) ABC transporter substrate-binding protein FbpA was increased 10-fold in (p)ppGpp, and gene deletion restored viability of tetracycline-exposed (p)ppGpp cells. Of note, FbpA expression was repressed in the (p)ppGpp-accumulating mutant, resulting in a reduction of intracellular free iron, required for the ROS-generating Fenton reaction. Our results indicate that (p)ppGpp-mediated suppression of central metabolism and iron uptake reduces antibiotic-induced oxidative stress in .
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http://dx.doi.org/10.1074/jbc.RA117.000383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5900777PMC
April 2018

A lack of association between vitamin D-binding protein and 25-hydroxyvitamin D concentrations in pediatric type 1 diabetes without microalbuminuria.

Ann Pediatr Endocrinol Metab 2017 Dec 31;22(4):247-252. Epub 2017 Dec 31.

Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea.

Purpose: Vitamin D deficiency is reported to be more common in type 1 diabetes patients and might be associated with the increased urinary loss of vitamin D binding protein (VDBP) consequent to impaired 25-hydroxyvitamin D (25(OH)D) circulation. We aimed to evaluate the possible increased urinary loss of VDBP, a correlation between VDBP and circulating 25(OH)D level, and risk factors influencing low vitamin D level in pediatric type 1 diabetes patients without microalbuminuria.

Methods: This is a cross-sectional study of subjects who visited Seoul National University Children's Hospital between January and March 2013. Forty-two type 1 diabetes patients and 29 healthy controls were included. Biochemical parameters including serum and urine VDBP concentrations were analyzed.

Results: There was no significant difference in the frequency of vitamin D deficiency or serum 25(OH)D level between the 2 groups. The serum and urine VDBP concentrations did not show any difference between the 2 groups. Serum 25(OH) D level did not correlate with serum or urine VDBP. Multivariate regression analysis revealed that daylight outdoor hours (=2.948, =0.003) and vitamin D intake (=2.865, =0.003) affected the 25(OH)D level; the presence of type 1 diabetes or urinary VDBP excretion was not significant.

Conclusions: In pediatric type 1 diabetes patients, urinary VDBP excretion did not contribute to low serum 25(OH)D level in the setting of normoalbuminuria. The factors associated with 25(OH)D level during winter periods were daylight outdoor hours and vitamin D intake. Further studies including both micro- and macroalbuminuria patients with type 1 diabetes are warranted.
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http://dx.doi.org/10.6065/apem.2017.22.4.247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5769838PMC
December 2017

Selenoprotein MsrB1 deficiency exacerbates acetaminophen-induced hepatotoxicity via increased oxidative damage.

Arch Biochem Biophys 2017 11 3;634:69-75. Epub 2017 Oct 3.

Department of Biochemistry and Molecular Biology, Yeungnam University College of Medicine, Daegu 42415, Republic of Korea. Electronic address:

Acetaminophen (APAP) overdose induces acute liver damage and failure via reactive oxygen species production and glutathione (GSH) depletion. Methionine sulfoxide reductase B1 (MsrB1) is an antioxidant selenoenzyme that specifically catalyzes the reduction of methionine R-sulfoxide residues. In this study, we used MsrB1 gene-knockout mice and primary hepatocytes to investigate the effect of MsrB1 on APAP-induced hepatotoxicity. Analyses of histological alterations and serum indicators of liver damage showed that MsrB1 mice were more susceptible to APAP-induced acute liver injury than wild-type (MsrB1) mice. Consistent with the in vivo results, primary MsrB1 hepatocytes displayed higher susceptibility to APAP-induced cytotoxicity than MsrB1 cells. MsrB1 deficiency increased hepatic oxidative stress after APAP challenge such as hydrogen peroxide production, lipid peroxidation, and protein oxidation levels. Additionally, basal and APAP-induced ratios of reduced-to-oxidized GSH (GSH/GSSG) were significantly lower in MsrB1 than in MsrB1 livers. Nrf2 nuclear accumulation and heme oxygenase-1 expression levels after APAP challenge were lower in MsrB1 than in MsrB1 livers, suggesting that MsrB1 deficiency attenuates the APAP-induced activation of Nrf2. Collectively, the results of this study suggest that selenoprotein MsrB1 plays a protective role against APAP-induced hepatotoxicity via its antioxidative function.
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http://dx.doi.org/10.1016/j.abb.2017.09.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5807074PMC
November 2017

The Role of Overweight and Obesity on Bone Health in Korean Adolescents with a Focus on Lean and Fat Mass.

J Korean Med Sci 2017 Oct;32(10):1633-1641

Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea.

As the associations between pediatric overweight/obesity and bone health remain controversial, we investigated the effects of overweight/obesity as well as lean mass (LM) and fat mass (FM) on bone parameters in adolescents. Bone parameters were evaluated using dual-energy X-ray absorptiometry (DXA) data of 982 adolescents (aged 12-19 years) from the Korea National Health and Nutrition Examination Survey (2009-2010). Z-scores for LM, FM, bone mass, bone mineral density (BMD), and bone mineral apparent density (BMAD) using Korean pediatric reference values were used for analysis. Adolescents with overweight/obesity had significantly higher bone mass and density of the total-body-less-head (TBLH), lumbar spine, and femur neck than underweight or normal-weight adolescents (P < 0.001) after adjusting for vitamin D deficiency, calcium intake, and insulin resistance in both sexes. LM was positively associated with bone parameters at all skeletal sites in both sexes (P < 0.001). FM was negatively related to TBLH BMD in boys (P = 0.018) but was positively associated to BMD and BMAD of the lumbar spine and femur neck in girls. In conclusion, overweight/obesity and LM play a positive role in bone health in adolescents. The effect of FM on bone parameters is sex- and site-specific.
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http://dx.doi.org/10.3346/jkms.2017.32.10.1633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5592177PMC
October 2017

Methionine sulfoxide reductase A protects against lipopolysaccharide-induced septic shock via negative regulation of the proinflammatory responses.

Arch Biochem Biophys 2017 10 10;631:42-48. Epub 2017 Aug 10.

Department of Biochemistry and Molecular Biology, Yeungnam University College of Medicine, Daegu, Republic of Korea. Electronic address:

Methionine sulfoxide reductase A (MsrA) is a major antioxidant enzyme that specifically catalyzes the reduction of methionine S-sulfoxide. In this study, we used MsrA gene-knockout (MsrA) mice and bone marrow-derived macrophages (BMDMs) to investigate the role of MsrA in the regulation of inflammatory responses induced by lipopolysaccharide (LPS). MsrA mice were more susceptible to LPS-induced lethal shock than wild-type (MsrA) mice. Serum levels of the proinflammatory cytokines IL-6 and TNF-α induced by LPS were higher in MsrA than in MsrA mice. MsrA deficiency in the BMDMs also increased the LPS-induced cytotoxicity as well as TNF-α level. Basal and LPS-induced reactive oxygen species (ROS) levels were higher in MsrA than in MsrA BMDMs. Phosphorylation levels of p38, JNK, and ERK were higher in MsrA than in MsrA BMDMs in response to LPS, suggesting that MsrA deficiency increases MAPK activation. Furthermore, MsrA deficiency increased the expression and nuclear translocation of NF-κB and the expression of inducible nitric oxide synthase, a target gene of NF-κB, in response to LPS. Taken together, our results suggest that MsrA protects against LPS-induced septic shock, and negatively regulates proinflammatory responses via inhibition of the ROS-MAPK-NF-κB signaling pathways.
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http://dx.doi.org/10.1016/j.abb.2017.08.008DOI Listing
October 2017

Effect of Alpha-Linolenic Acid on Oocyte Maturation and Embryo Development in Pigs.

Dev Reprod 2017 Jun 30;21(2):205-213. Epub 2017 Jun 30.

College of Animal Life Sciences, Kangwon National University, Chunchoen 24341, Republic of Korea.

The aim of this study was to determine the effect of additional alpha-linolenic acid (ALA) supplementation during maturation (IVM) and culture (IVC) on nucleic maturation and embryo development of pigs. Cumulus-oocyte complexes (COCs) were incubated in IVM medium containing different concentration of ALA (25, 50 and 100 μM) for 44 h. After maturation, nuclear maturation of oocytes were evaluated by aceto-orcein stain. Mature oocytes with 50 μM ALA were fertilized and cultured in IVC medium with ALA (25, 50 and 100 μM) during early-embryogenesis (48 hours after fertilization). Then, embryos were cultured with 25 μM ALA during early embryogenesis and/or late embryogenesis (120 hours after early-embryogenesis). In results, oocyte maturation were significantly increased by 50 μM ALA treatment groups compared with control groups (<0.05). Treatment of 25 μM ALA during early-embryogenesis enhanced cleavage rate of embryo compared with other groups (<0.05), whereas formation and total cell number of blastocyst had no significant difference. Similarly, cleavage rate of embryos were increased by 25 μM ALA supplement during early- or late-embryogenesis than ALA treatment both stage of embryogenesis (<0.05), but did not influence to blastocyst formation. Interestingly, total cell number of blastocyst were enhanced in ALA treatment group during early-embryogenesis. These findings indicated that ALA supplement enhance the nuclear maturation of oocyte and embryo development, however, excessive ALA could negatively influence. Therefore, we suggest that ALA is used for improvement of production of mammalian embryo and further study regarding with functional mechanism of ALA is needed.
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http://dx.doi.org/10.12717/DR.2017.21.2.205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5532312PMC
June 2017

Selenoprotein MsrB1 promotes anti-inflammatory cytokine gene expression in macrophages and controls immune response in vivo.

Sci Rep 2017 07 11;7(1):5119. Epub 2017 Jul 11.

Division of Genetics, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.

Post-translational redox modification of methionine residues often triggers a change in protein function. Emerging evidence points to this reversible protein modification being an important regulatory mechanism under various physiological conditions. Reduction of oxidized methionine residues is catalyzed by methionine sulfoxide reductases (Msrs). Here, we show that one of these enzymes, a selenium-containing MsrB1, is highly expressed in immune-activated macrophages and contributes to shaping cellular and organismal immune responses. In particular, lipopolysaccharide (LPS) induces expression of MsrB1, but not other Msrs. Genetic ablation of MsrB1 did not preclude LPS-induced intracellular signaling in macrophages, but resulted in attenuated induction of anti-inflammatory cytokines, such as interleukin (IL)-10 and the IL-1 receptor antagonist. This anomaly was associated with excessive pro-inflammatory cytokine production as well as an increase in acute tissue inflammation in mice. Together, our findings suggest that MsrB1 controls immune responses by promoting anti-inflammatory cytokine expression in macrophages. MsrB1-dependent reduction of oxidized methionine in proteins may be a heretofore unrecognized regulatory event underlying immunity and inflammatory disease, and a novel target for clinical applications.
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http://dx.doi.org/10.1038/s41598-017-05230-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5506048PMC
July 2017

Methionine sulfoxide reductase A protects hepatocytes against acetaminophen-induced toxicity via regulation of thioredoxin reductase 1 expression.

Biochem Biophys Res Commun 2017 06 23;487(3):695-701. Epub 2017 Apr 23.

Department of Biochemistry and Molecular Biology, Yeungnam University College of Medicine, Daegu, Republic of Korea. Electronic address:

Thioredoxin reductase 1 (TXNRD1) is associated with susceptibility to acetaminophen (APAP)-induced liver damage. Methionine sulfoxide reductase A (MsrA) is an antioxidant and protein repair enzyme that specifically catalyzes the reduction of methionine S-sulfoxide residues. We have previously shown that MsrA deficiency exacerbates acute liver injury induced by APAP. In this study, we used primary hepatocytes to investigate the underlying mechanism of the protective effect of MsrA against APAP-induced hepatotoxicity. MsrA gene-deleted (MsrA) hepatocytes showed higher susceptibility to APAP-induced cytotoxicity than wild-type (MsrA) cells, consistent with our previous in vivo results. MsrA deficiency increased APAP-induced glutathione depletion and reactive oxygen species production. APAP treatment increased Nrf2 activation more profoundly in MsrA than in MsrA hepatocytes. Basal TXNRD1 levels were significantly higher in MsrA than in MsrA hepatocytes, while TXNRD1 depletion in both MsrA and MsrA cells resulted in increased resistance to APAP-induced cytotoxicity. In addition, APAP treatment significantly increased TXNRD1 expression in MsrA hepatocytes, while no significant change was observed in MsrA cells. Overexpression of MsrA reduced APAP-induced cytotoxicity and TXNRD1 expression levels in APAP-treated MsrA hepatocytes. Collectively, our results suggest that MsrA protects hepatocytes from APAP-induced cytotoxicity through the modulation of TXNRD1 expression.
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http://dx.doi.org/10.1016/j.bbrc.2017.04.119DOI Listing
June 2017

MsrB3 deficiency induces cancer cell apoptosis through p53-independent and ER stress-dependent pathways.

Arch Biochem Biophys 2017 05 5;621:1-5. Epub 2017 Apr 5.

Department of Biochemistry and Molecular Biology, Yeungnam University College of Medicine, Daegu, Republic of Korea. Electronic address:

We have previously shown that down-regulation of methionine sulfoxide reductase B3 (MsrB3) induces cancer cell apoptosis through the activation of the intrinsic mitochondrial pathway. However, the mechanism through which MsrB3 deficiency results in cancer cell death is poorly understood. In this study, we investigated whether p53 and endoplasmic reticulum (ER) stress are involved in MsrB3 deficiency-induced cancer cell apoptosis using breast and colon cancer cells. MsrB3 depletion resulted in p53 down-regulation at the post-transcriptional level. MsrB3 deficiency induced cell death to a similar extent in both p53 wild-type (p53) and null (p53) cancer cells, suggesting that MsrB3 deficiency-induced apoptosis occurs independently of p53. MsrB3 deficiency significantly increased ER stress, which resulted in apoptosis. In addition, MsrB3 depletion activated the pro-apoptotic Bim molecule, which is essential for ER stress-induced apoptosis. MsrB3 deficiency increased cytosolic calcium levels, suggesting that MsrB3 down-regulation leads to a disturbance of calcium homeostasis in the ER, which consequently triggers ER stress. MsrB3 overexpression in MsrB3-depleted cells reduced ER stress, and was accompanied by at least partial recovery of cell viability. Taken together, our results suggest that MsrB3 plays a critical role in cancer cell apoptosis through the modulation of ER stress status.
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http://dx.doi.org/10.1016/j.abb.2017.04.001DOI Listing
May 2017

Methionine Sulfoxide Reductase A Deficiency Exacerbates Cisplatin-Induced Nephrotoxicity via Increased Mitochondrial Damage and Renal Cell Death.

Antioxid Redox Signal 2017 Oct 20;27(11):727-741. Epub 2017 Mar 20.

1 Department of Anatomy and BK21 Plus, Kyungpook National University School of Medicine , Junggu, Daegu, Republic of Korea.

Aims: Methionine sulfoxide reductase A (MsrA), which is abundantly localized in the mitochondria, reduces methionine-S-sulfoxide, scavenging reactive oxygen species (ROS). Cisplatin, an anticancer drug, accumulates at high levels in the mitochondria of renal cells, causing mitochondrial impairment that ultimately leads to nephrotoxicity. Here, we investigated the role of MsrA in cisplatin-induced mitochondrial damage and kidney cell death using MsrA gene-deleted (MsrA) mice.

Results: Cisplatin injection resulted in increases of ROS production, methionine oxidation, and oxidative damage in the kidneys. This oxidative stress was greater in MsrA mouse kidneys than in wild-type (MsrA) mouse kidneys. MsrA gene deletion exacerbated cisplatin-induced reductions in the expression and activity of MsrA and MsrBs, and the expression of thioredoxin 1, glutathione peroxidase 1 and 4, mitochondrial superoxide dismutase, cystathionine-β-synthase, and cystathionine-γ-lyase. Cisplatin induced swelling, cristae loss, and fragmentation of mitochondria with increased lipid peroxidation, more so in MsrA than in MsrA kidneys. The ratio of mitochondrial fission regulator (Fis1) to fusion regulator (Opa1) was higher in MsrA than MsrA mice. MsrA deletion exacerbated cisplatin-induced increases in Bax to Bcl-2 ratio, cleaved caspase-3 level, and apoptosis, whereas MsrA overexpression attenuated cisplatin-induced oxidative stress and apoptosis.

Innovation: MsrA gene deletion in mice exacerbates cisplatin-induced renal injury through increases of mitochondrial susceptibility, whereas MsrA overexpression protects cells against cisplatin.

Conclusion: This study demonstrates that MsrA protects kidney cells against cisplatin-induced methionine oxidation, oxidative stress, mitochondrial damage, and apoptosis, suggesting that MsrA could be a useful target protein for the treatment of cisplatin-induced nephrotoxicity. Antioxid. Redox Signal. 27, 727-741.
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http://dx.doi.org/10.1089/ars.2016.6874DOI Listing
October 2017

Methionine sulfoxide reductase A deficiency exacerbates acute liver injury induced by acetaminophen.

Biochem Biophys Res Commun 2017 02 16;484(1):189-194. Epub 2017 Jan 16.

Department of Biochemistry and Molecular Biology, Yeungnam University College of Medicine, Daegu, 42415, Republic of Korea. Electronic address:

Acetaminophen (APAP) overdose induces acute liver injury via enhanced oxidative stress and glutathione (GSH) depletion. Methionine sulfoxide reductase A (MsrA) acts as a reactive oxygen species scavenger by catalyzing the cyclic reduction of methionine-S-sulfoxide. Herein, we investigated the protective role of MsrA against APAP-induced liver damage using MsrA gene-deleted mice (MsrA). We found that MsrA mice were more susceptible to APAP-induced acute liver injury than wild-type mice (MsrA). The central lobule area of the MsrA liver was more impaired with necrotic lesions. Serum alanine transaminase, aspartate transaminase, and lactate dehydrogenase levels were significantly higher in MsrA than in MsrA mice after APAP challenge. Deletion of MsrA enhanced APAP-induced hepatic GSH depletion and oxidative stress, leading to increased susceptibility to APAP-induced liver injury in MsrA-deficient mice. APAP challenge increased Nrf2 activation more profoundly in MsrA than in MsrA livers. Expression and nuclear accumulation of Nrf2 and its target gene expression were significantly elevated in MsrA than in MsrA livers after APAP challenge. Taken together, our results demonstrate that MsrA protects the liver from APAP-induced toxicity. The data provided herein constitute the first in vivo evidence of the involvement of MsrA in hepatic function under APAP challenge.
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http://dx.doi.org/10.1016/j.bbrc.2017.01.025DOI Listing
February 2017

Down-regulation of MsrB3 induces cancer cell apoptosis through reactive oxygen species production and intrinsic mitochondrial pathway activation.

Biochem Biophys Res Commun 2017 01 19;483(1):468-474. Epub 2016 Dec 19.

Department of Biochemistry and Molecular Biology, Yeungnam University College of Medicine, Daegu, Republic of Korea. Electronic address:

Methionine sulfoxide reductase B3 (MsrB3) is a protein repair enzyme that specifically catalyzes the reduction of methionine-R-sulfoxide residues and has an antioxidant function. We have previously shown that depletion of MsrB3 suppresses the proliferation of normal mammalian cells by arresting cell cycle. In this study, we report the crucial role of MsrB3 in cancer cell death. Deficiency of MsrB3 induced cancer cell death, while MsrB3 overexpression stimulated cancer cell proliferation. MsrB3 depletion resulted in apoptotic cancer cell death through the activation of the intrinsic mitochondrial pathway. MsrB3 deficiency increased the levels of cellular reactive oxygen species (ROS) and led to redox imbalance, and also increased the Bax to Bcl-2 ratio and cytochrome c release, leading to caspase activation. Treatment of MsrB3-depleted cells with N-acetylcysteine, an ROS scavenger, prevented cell death, suggesting that MsrB3 deficiency-induced cell death is associated with increased ROS production. In addition, MsrB3 depletion activated poly(ADP ribose) polymerase-1 (PARP-1) and led to the translocation of apoptosis-inducing factor (AIF) to the nucleus. Taken together, our results suggest that MsrB3 plays an important role in cancer cell survival through the modulation of the intrinsic apoptosis pathway.
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http://dx.doi.org/10.1016/j.bbrc.2016.12.120DOI Listing
January 2017

Selective and Efficient Elimination of with a Chemical Modulator that Targets Glucose Metabolism.

Front Cell Infect Microbiol 2016 16;6:156. Epub 2016 Nov 16.

Department of Microbiology and Immunology, Yonsei University College of MedicineSeoul, South Korea; Brain Korea 21 Project for Medical Science, Yonsei University College of MedicineSeoul, South Korea; Institute for Immunology and Immunological Diseases, Yonsei University College of MedicineSeoul, South Korea.

, a Gram-negative bacterium, is the causative agent of pandemic cholera. Previous studies have shown that the survival of the pandemic El Tor biotype strain N16961 requires production of acetoin in a glucose-rich environment. The production of acetoin, a neutral fermentation end-product, allows to metabolize glucose without a pH drop, which is mediated by the production of organic acid. This finding suggests that inhibition of acetoin fermentation can result in elimination by causing a pH imbalance under glucose-rich conditions. Here, we developed a simple high-throughput screening method and identified an inducer of medium acidification (iMAC). Of 8364 compounds screened, we identified one chemical, 5-(4-chloro-2-nitrobenzoyl)-6-hydroxy-1,3-dimethylpyrimidine-2,4(1H,3H)-dione, that successfully killed glucose-metabolizing N16961 by inducing acidic stress. When N16961 was grown with abundant glucose in the presence of iMAC, acetoin production was completely suppressed and concomitant accumulation of lactate and acetate was observed. Using a beta-galactosidase activity assay with a single-copy p reporter fusion, we show that that iMAC likely inhibits acetoin production at the transcriptional level. Thin-layer chromatography revealed that iMAC causes a significantly reduced accumulation of intracellular (p)ppGpp, a bacterial stringent response alarmone known to positively regulate acetoin production. bacterial colonization and fluid accumulation were also markedly decreased after iMAC treatment. Finally, we demonstrate iMAC-induced bacterial killing for 22 different strains belonging to diverse serotypes. Together, our results suggest that iMAC, acting as a metabolic modulator, has strong potential as a novel antibacterial agent for treatment against cholera.
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http://dx.doi.org/10.3389/fcimb.2016.00156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5111416PMC
September 2017