Publications by authors named "Joon Shin"

67 Publications

Loganin Attenuates the Severity of Acute Kidney Injury Induced by Cisplatin through the Inhibition of ERK Activation in Mice.

Int J Mol Sci 2021 Jan 31;22(3). Epub 2021 Jan 31.

Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University, Iksan, Jeonbuk 54538, Korea.

Cisplatin is the most widely used chemotherapeutic agent. However, it often causes nephrotoxicity, which results in acute kidney injury (AKI). Therefore, we urgently need a drug that can reduce the nephrotoxicity induced by cisplatin. Loganin is a major iridoid glycoside isolated from Corni fructus that has been used as an anti-inflammatory agent in various pathological models. However, the renal protective activity of loganin remains unclear. In this study, to examine the protective effect of loganin on cisplatin-induced AKI, male C57BL/6 mice were orally administered with loganin (1, 10, and 20 mg/kg) 1 h before intraperitoneal injection of cisplatin (10 mg/kg) and sacrificed at three days after the injection. The administration of loganin inhibited the elevation of blood urea nitrogen (BUN) and creatinine (CREA) in serum, which are used as biomarkers of AKI. Moreover, histological kidney injury, proximal tubule damages, and renal cell death, such as apoptosis and ferroptosis, were reduced by loganin treatment. Also, pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, reduced by loganin treatment. Furthermore, loganin deactivated the extracellular signal-regulated kinases (ERK) 1 and 2 during AKI. Taken together, our results suggest that loganin may attenuate cisplatin-induced AKI through the inhibition of ERK1/2.
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http://dx.doi.org/10.3390/ijms22031421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866969PMC
January 2021

Atomic structure of, and valine binding to the regulatory ACT domain of the Mycobacterium tuberculosis Rel protein.

FEBS J 2020 Oct 17. Epub 2020 Oct 17.

School of Biological Sciences, Nanyang Technological University, Singapore City, Singapore.

The stringent response, regulated by the bifunctional (p)ppGpp synthetase/hydrolase Rel in mycobacteria, is critical for long-term survival of the drug-tolerant dormant state of Mycobacterium tuberculosis. During amino acid starvation, MtRel senses a drop in amino acid concentration and synthesizes the messengers pppGpp and ppGpp, collectively called (p)ppGpp. Here, we investigate the role of the regulatory 'Aspartokinase, Chorismate mutase and TyrA' (ACT) domain in MtRel. Using NMR spectroscopy approaches, we report the high-resolution structure of dimeric MtRel ACT which selectively binds to valine out of all other branched-chain amino acids tested. A set of MtRel ACT mutants were generated to identify the residues required for maintaining the head-to-tail dimer. Through NMR titrations, we determined the crucial residues for binding of valine and show structural rearrangement of the MtRel ACT dimer in the presence of valine. This study suggests the direct involvement of amino acids in (p)ppGpp accumulation mediated by MtRel independent to interactions with stalled ribosomes. Database Structural data are available in the PDB database under the accession number 6LXG.
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http://dx.doi.org/10.1111/febs.15600DOI Listing
October 2020

Protective effects of Coenzyme Q10 against acute pancreatitis.

Int Immunopharmacol 2020 Nov 20;88:106900. Epub 2020 Aug 20.

Department of Herbology, School of Korean Medicine, Wonkwang University, Iksan-daero 460, Iksan, Jeollabuk-do 54538, Republic of Korea; Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University, Iksan-daero 460, Iksan, Jeollabuk-do 54538, Republic of Korea. Electronic address:

Acute pancreatitis (AP) refers to inflammation in the pancreas, which may lead to death in severe cases. Coenzyme Q10 (Q10), generally known to generate energy, plays an important role as an anti-oxidant and anti-inflammatory effector. Here, we showed the effect of Q10 on inflammatory response in murine AP model. For this study, we induced AP by injection of cerulein intraperitoneally or pancreatic duct ligation (PDL) in mice. The level of cytokines and digestive enzymes were measured in pancreas, and blood. All pancreatic tissues were excised for investigation such as histological changes, infiltration of immune cells. Administration of Q10 attenuated the severity of AP and its associated pulmonary complication as shown by reduction of acinar cell death, parenchymal edema, inflammatory cell infiltration and alveolar thickening in both cerulein-induced AP and PDL-induced AP. Moreover, reduction of the cytokines such as interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α were observed in pancreas and pancreatic acinar cells by Q10. Furthermore, Q10 reduced the infiltration of immune cells such as monocytes and neutrophils and augmentation of chemokines such as CC chemokine-2 (CCL2) and C-X-C chemokine-2 (CXCL2) in pancreas of AP mice. In addition, Q10 deactivates the phosphorylation of extracellular signal-regulated kinase (ERK) and c-jun NH-terminal kinase (JNK) in pancreas. In conclusion, these observations suggest that Q10 could attenuate the pancreatic damage and its associated pulmonary complications via inhibition of inflammatory cytokines and inflammatory cell infiltration and that the deactivation of ERK and JNK by Q10 might contribute to the attenuation of AP.
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http://dx.doi.org/10.1016/j.intimp.2020.106900DOI Listing
November 2020

A systematic assessment of mycobacterial F -ATPase subunit ε's role in latent ATPase hydrolysis.

FEBS J 2021 Feb 4;288(3):818-836. Epub 2020 Jul 4.

School of Biological Sciences, Nanyang Technological University, Singapore City, Singapore.

In contrast to most bacteria, the mycobacterial F F -ATP synthase (α :β :γ:δ:ε:a:b:b':c ) does not perform ATP hydrolysis-driven proton translocation. Although subunits α, γ and ε of the catalytic F -ATPase component α :β :γ:ε have all been implicated in the suppression of the enzyme's ATPase activity, the mechanism remains poorly defined. Here, we brought the central stalk subunit ε into focus by generating the recombinant Mycobacterium smegmatis F -ATPase (MsF -ATPase), whose 3D low-resolution structure is presented, and its ε-free form MsF αβγ, which showed an eightfold ATP hydrolysis increase and provided a defined system to systematically study the segments of mycobacterial ε's suppression of ATPase activity. Deletion of four amino acids at ε's N terminus, mutant MsF αβγε , revealed similar ATP hydrolysis as MsF αβγ. Together with biochemical and NMR solution studies of a single, double, triple and quadruple N-terminal ε-mutants, the importance of the first N-terminal residues of mycobacterial ε in structure stability and latency is described. Engineering ε's C-terminal mutant MsF αβγε and MsF αβγε with deletion of the C-terminal residue D121 and the two C-terminal ɑ-helices, respectively, revealed the requirement of the very C terminus for communication with the catalytic α β -headpiece and its function in ATP hydrolysis inhibition. Finally, we applied the tools developed during the study for an in silico screen to identify a novel subunit ε-targeting F-ATP synthase inhibitor.
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http://dx.doi.org/10.1111/febs.15440DOI Listing
February 2021

Body mass index as an indicator of the likelihood of ultrasound visualization of the appendix in pregnant women with suspicion of appendicitis.

Abdom Radiol (NY) 2020 09 8;45(9):2637-2646. Epub 2020 Jun 8.

Department of Radiology, Northwestern Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.

Purpose: To determine if clinical characteristics of pregnant women are associated with the likelihood of ultrasound (US) visualization of the appendix in cases where there is a clinical suspicion of appendicitis.

Materials And Methods: A retrospective study of 471 pregnant patients with suspicion of appendicitis from 2009 to 2018 were studied. Patients underwent sonography of the appendix as their initial imaging study. The association of body mass index (BMI) and gestational age with sonographic visualization of the appendix was analyzed using logistic regression. Cut-off values were determined for BMI to predict visualization of the appendix.

Results: The rate of visualization of the appendix on US was 16% (95% CI 12% to 19%). When stratified by trimester of pregnancy, rebound pain on compression US examination in the 1st trimester and BMI in the 2nd and 3rd trimesters were identified as predictors of US visualization. Applying BMI cut-off values rounded to the nearest whole number, 36, 30, and 26 in the 1st, 2nd, and 3rd trimesters, non-visualization rates would be reduced by 16% (95% CI 10% to 25%), 35% (95% CI 29% to 42%), and 67% (95% CI 58% to 74%). Using BMI index cut-off values would reduce the number of primary US examinations by 35% (95% CI 30% to 39%) and increase the rate of visualization by 6% (95% CI 0.02% to 12%, P = 0.04).

Conclusion: Using BMI cut-off values for determining the efficaciousness of US visualization of the appendix in pregnant women with suspicion of appendicitis could significantly reduce the non-visualization rate.
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http://dx.doi.org/10.1007/s00261-020-02610-7DOI Listing
September 2020

Preventive Effects of on Cerulein-Induced Chronic Pancreatitis.

Am J Chin Med 2020 20;48(4):987-1003. Epub 2020 May 20.

Department of Herbology, Wonkwang University School of Korean Medicine, Iksan 54538, Republic of Korea.

Our previous report revealed that (GJ) has protective effects against acute pancreatitis. So, we examined whether aqueous extract of GJ has anti-inflammation and antifibrotic effects even against cerulein-induced chronic pancreatitis (CP). CP was induced in mice by an intraperitoneal injection of a stable cholecystokinin (CCK) analogue, cerulein, six times a day, four days per week for three weeks. GJ extract (0.1 or 1[Formula: see text]g/kg) or saline (control group) were intraperitoneally injected 1[Formula: see text]h before first cerulein injection. After three weeks of stimulation, the pancreas was harvested for the examination of several fibrotic parameters. In addition, pancreatic stellate cells (PSCs) were isolated using gradient methods to examine the antifibrogenic effects of GJ. In the cerulein-induced CP mice, the histological features of the pancreas showed severe tissue damage such as enlarged interstitial spaces, inflammatory cell infiltrate and glandular atrophy, and tissue fibrosis. However, treatment of GJ reduced the severity of CP such as pancreatic edema and inflammatory cell infiltration. Furthermore, treatment of GJ increased pancreatic acinar cell survival, and reduced pancreatic fibrosis and activation of PSC and . In addition, GJ treatment inhibited the activation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated protein kinase (ERK) in the PSCs. These results suggest that GJ attenuated the severity of CP and the pancreatic fibrosis by inhibiting JNK and ERK activation during CP.
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http://dx.doi.org/10.1142/S0192415X20500470DOI Listing
September 2020

Discovery of a Novel Mycobacterial F-ATP Synthase Inhibitor and its Potency in Combination with Diarylquinolines.

Angew Chem Int Ed Engl 2020 08 26;59(32):13295-13304. Epub 2020 May 26.

School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551, Republic of Singapore.

The F F -ATP synthase is required for growth and viability of Mycobacterium tuberculosis and is a validated clinical target. A mycobacterium-specific loop of the enzyme's rotary γ subunit plays a role in the coupling of ATP synthesis within the enzyme complex. We report the discovery of a novel antimycobacterial, termed GaMF1, that targets this γ subunit loop. Biochemical and NMR studies show that GaMF1 inhibits ATP synthase activity by binding to the loop. GaMF1 is bactericidal and is active against multidrug- as well as bedaquiline-resistant strains. Chemistry efforts on the scaffold revealed a dynamic structure activity relationship and delivered analogues with nanomolar potencies. Combining GaMF1 with bedaquiline or novel diarylquinoline analogues showed potentiation without inducing genotoxicity or phenotypic changes in a human embryonic stem cell reporter assay. These results suggest that GaMF1 presents an attractive lead for the discovery of a novel class of anti-tuberculosis F-ATP synthase inhibitors.
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http://dx.doi.org/10.1002/anie.202002546DOI Listing
August 2020

Pyrazinamide triggers degradation of its target aspartate decarboxylase.

Nat Commun 2020 04 3;11(1):1661. Epub 2020 Apr 3.

Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

Pyrazinamide is a sterilizing first-line tuberculosis drug. Genetic, metabolomic and biophysical analyses previously demonstrated that pyrazinoic acid, the bioactive form of the prodrug pyrazinamide (PZA), interrupts biosynthesis of coenzyme A in Mycobacterium tuberculosis by binding to aspartate decarboxylase PanD. While most drugs act by inhibiting protein function upon target binding, we find here that pyrazinoic acid is only a weak enzyme inhibitor. We show that binding of pyrazinoic acid to PanD triggers degradation of the protein by the caseinolytic protease ClpC1-ClpP. Thus, the old tuberculosis drug pyrazinamide exerts antibacterial activity by acting as a target degrader, a mechanism of action that has recently emerged as a successful strategy in drug discovery across disease indications. Our findings provide the basis for the rational discovery of next generation PZA.
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http://dx.doi.org/10.1038/s41467-020-15516-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125159PMC
April 2020

Unique structural and mechanistic properties of mycobacterial F-ATP synthases: Implications for drug design.

Prog Biophys Mol Biol 2020 05 16;152:64-73. Epub 2019 Nov 16.

Nanyang Technological University, School of Biological Sciences, 60 Nanyang Drive, Singapore, 637551, Republic of Singapore. Electronic address:

The causative agent of Tuberculosis (TB) Mycobacterium tuberculosis (Mtb) encounters unfavourable environmental conditions in the lungs, including nutrient limitation, low oxygen tensions and/or low/high pH values. These harsh conditions in the host triggers Mtb to enter a dormant state in which the pathogen does not replicate and uses host-derived fatty acids instead of carbohydrates as an energy source. Independent to the energy source, the bacterium's energy currency ATP is generated by oxidative phosphorylation, in which the FF-ATP synthase uses the proton motive force generated by the electron transport chain. This catalyst is essential in Mtb and inhibition by the diarylquinoline class of drugs like Bedaquilline, TBAJ-587, TBAJ-876 or squaramides demonstrated that this engine is an attractive target in TB drug discovery. A special feature of the mycobacterial F-ATP synthase is its inability to establish a significant proton gradient during ATP hydrolysis, and its latent ATPase activity, to prevent energy waste and to control the membrane potential. Recently, unique epitopes of mycobacterial FF-ATP synthase subunits absent in their prokaryotic or mitochondrial counterparts have been identified to contribute to the regulation of the low ATPase activity. Most recent structural insights into individual subunits, the F domain or the entire mycobacterial enzyme added to the understanding of mechanisms, regulation and differences of the mycobacterial FF-ATP synthase compared to other bacterial and eukaryotic engines. These novel insights provide the basis for the design of new compounds targeting this engine and even novel regimens for multidrug resistant TB.
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http://dx.doi.org/10.1016/j.pbiomolbio.2019.11.006DOI Listing
May 2020

Disrupting coupling within mycobacterial F-ATP synthases subunit ε causes dysregulated energy production and cell wall biosynthesis.

Sci Rep 2019 11 14;9(1):16759. Epub 2019 Nov 14.

Nanyang Technological University, School of Biological Sciences, 60 Nanyang Drive, Singapore, 637551, Republic of Singapore.

The dynamic interaction of the N- and C-terminal domains of mycobacterial F-ATP synthase subunit ε is proposed to contribute to efficient coupling of H-translocation and ATP synthesis. Here, we investigate crosstalk between both subunit ε domains by introducing chromosomal atpC missense mutations in the C-terminal helix 2 of ε predicted to disrupt inter domain and subunit ε-α crosstalk and therefore coupling. The ε mutant εR105A,R111A,R113A,R115A (ε) showed decreased intracellular ATP, slower growth rates and lower molar growth yields on non-fermentable carbon sources. Cellular respiration and metabolism were all accelerated in the mutant strain indicative of dysregulated oxidative phosphorylation. The ε mutant exhibited an altered colony morphology and was hypersusceptible to cell wall-acting antimicrobials suggesting defective cell wall biosynthesis. In silico screening identified a novel mycobacterial F-ATP synthase inhibitor disrupting ε's coupling activity demonstrating the potential to advance this regulation as a new area for mycobacterial F-ATP synthase inhibitor development.
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http://dx.doi.org/10.1038/s41598-019-53107-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856130PMC
November 2019

Chloroquine modulates inflammatory autoimmune responses through Nurr1 in autoimmune diseases.

Sci Rep 2019 10 29;9(1):15559. Epub 2019 Oct 29.

Molecular Neurobiology Laboratory, Department of Psychiatry and McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, Massachusetts, 02478, USA.

For over a half-century the anti-malarial drug chloroquine (CQ) has been used as a therapeutic agent, alone or in combination, to treat autoimmune diseases. However, neither the underlying mechanism(s) of action nor their molecular target(s) are well defined. The orphan nuclear receptor Nurr1 (also known as NR4A2) is an essential transcription factor affecting the development and maintenance of midbrain dopaminergic neurons. In this study, using in vitro T cell differentiation models, we demonstrate that CQ activates T cell differentiation and induces Foxp3 gene expression in a Nurr1-dependent manner. Remarkably, CQ appears to induce Nurr1 function by two distinct mechanisms: firstly, by direct binding to Nurr1's ligand-binding domain and promoting its transcriptional activity and secondly by upregulation of Nurr1 expression through the CREB signaling pathway. In contrast, CQ suppressed gene expression and differentiation of pathogenic T17 cells. Importantly, using a valid animal model of inflammatory bowel disease (IBD), we demonstrated that CQ promotes Foxp3 expression and differentiation of T cells in a Nurr1-dependent manner, leading to significant improvement of IBD-related symptoms. Taken together, these data suggest that CQ ameliorates autoimmune diseases via regulating Nurr1 function/expression and that Nurr1 is a promising target for developing effective therapeutics of human inflammatory autoimmune diseases.
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http://dx.doi.org/10.1038/s41598-019-52085-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820774PMC
October 2019

Comparison of psychiatric disturbances in patients with multiple sclerosis and neuromyelitis optica.

Medicine (Baltimore) 2019 Sep;98(38):e17184

Department of Neurology, Seoul National University Hospital.

Although both multiple sclerosis (MS) and neuromyelitis optica (NMO) are demyelinating diseases, their psychiatric disturbances may differ given differences in the neurological manifestations. We used subjective and objective measurements to compare the psychiatric disturbances in patients with MS and NMO.Psychiatric disturbances were assessed in 24 MS and 35 NMO patients using the Beck Hopelessness Scale, Symptom Checklist-95 and the brief version of World Health Organization Quality of Life. Personality was assessed using the Big Five Inventory-10. Disease-related function was assessed using the Fatigue Severity Scale, Short-Form McGill Pain Questionnaire, and the Global Assessment of Function. Positivity offset (PO) and negativity bias (NB) and heart rate variability (HRV) were measured using a modified implicit affect test and photoplethysmograph, respectively. Data were analyzed using analysis of covariance with age and sex as covariates.MS patients had higher levels of depression, anxiety, panic attacks, obsessive-compulsiveness, aggression, paranoia, interpersonal sensitivity, self-regulation problems, stress vulnerability, and lower psychological quality of life (QOL) compared with NMO patients. The PO and NB and HRV values were not significantly different between groups. However, NMO patients had lower QOL, and higher levels of hopelessness, suicidality, and fatigue than the normal range. Disease duration was associated with hopelessness in NMO patients and with several psychiatric disturbances, but not hopelessness, in MS patients.Subjective psychiatric disturbances were more severe in patients with MS than in those with NMO, whereas PO and NB and HRV in patients with NMO were comparable with those of MS patients. Our findings highlight the need for different clinical approaches to assess and treat psychiatric disturbances in patients with MS and NMO.
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http://dx.doi.org/10.1097/MD.0000000000017184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756707PMC
September 2019

Inflammatory mimickers of pancreatic adenocarcinoma.

Abdom Radiol (NY) 2020 05;45(5):1387-1396

Department of Radiology, Northwestern Memorial Hospital, Northwestern University Feinberg School of Medicine, 676 N. St. Clair St. Suite 800, Chicago, IL, 60611, USA.

Pancreatic ductal adenocarcinoma can be a difficult imaging diagnosis early in its course given its subtle imaging findings such as focal pancreatic duct dilatation, abrupt duct cut-off, and encasement of vasculature. A variety of pancreatitidies have imaging findings that mimic pancreatic ductal adenocarcinoma and lead to mass formation making diagnosis even more difficult on imaging alone. These conditions include acute focal pancreatitis, chronic pancreatitis, autoimmune pancreatitis, and paraduodenal ("groove") pancreatitis. This review will focus on imaging findings that can help differentiate these inflammatory processes from pancreatic ductal adenocarcinoma.
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http://dx.doi.org/10.1007/s00261-019-02233-7DOI Listing
May 2020

8α-Hydroxypinoresinol isolated from Nardostachys jatamansi ameliorates cerulein-induced acute pancreatitis through inhibition of NF-κB activation.

Mol Immunol 2019 10 19;114:620-628. Epub 2019 Sep 19.

Department of Herbology, School of Korean Medicine, Wonkwang University, Iksandaero 460, Iksan, Jeonbuk 54538, South Korea; Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University, Iksandaero 460, Iksan, Jeonbuk 54538, South Korea. Electronic address:

Acute pancreatitis (AP) is a severe inflammatory condition of the pancreas, with no specific treatment available. We have previously reported that Nardostachys jatamansi (NJ) ameliorates cerulein-induced AP. However, the specific compound responsible for this inhibitory effect has not been identified. Therefore, in the present study, we focused on a single compound, 8α-hydroxypinoresinol (HP), from NJ. The aim of this study was to determine the effect of HP on the development of pancreatitis in mice and to explore the underlying mechanism(s). AP was induced by the injection of cerulein (50 μg/kg/h) for 6 h. HP (0.5, 5 or 10 mg/kg, i.p.) was administered 1 h prior to and 1, 3 or 5 h after the first cerulein injection, with vehicle- and DMSO-treated groups as controls. Blood samples were collected to determine serum levels of amylase, lipase, and cytokines. The pancreas was removed for morphological examination, myeloperoxidase (MPO) assays, cytokine assays, and assessment of nuclear factor (NF)-κB activation. The lungs were removed for morphological examination and MPO assays. Administration of HP dramatically improved pancreatic damage and pancreatitis-associated lung damage and also reduced amylase and lipase activities in serum. Moreover, administration of HP reduced the production of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in the pancreas and serum during AP. In addition, the administration of HP inhibited degradation of inhibitory κ-Bα (Iκ-Bα), NF-κB p65 translocation into nucleus and NF-κB binding activity in the pancreas. Our results suggest that HP exerted therapeutic effects on pancreatitis and these beneficial effects may be due to the inhibition of NF-κB activation.
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http://dx.doi.org/10.1016/j.molimm.2019.09.002DOI Listing
October 2019

Differentiation of focal autoimmune pancreatitis from pancreatic ductal adenocarcinoma.

Abdom Radiol (NY) 2020 05;45(5):1371-1386

Department of Radiology, Northwestern Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.

Autoimmune pancreatitis (AIP) is an inflammatory process of the pancreas that occurs most commonly in elderly males and clinically can mimic pancreatic adenocarcinoma and present with jaundice, weight loss, and abdominal pain. Mass-forming lesions in the pancreas are seen in the focal form of AIP and both clinical and imaging findings can overlap those of pancreatic cancer. The accurate distinction of AIP from pancreatic cancer is of utmost importance as it means avoiding unnecessary surgery in AIP cases or inaccurate steroid treatment in patients with pancreatic cancer. Imaging concomitantly with serological examinations (IgG4 and Ca 19-9) plays an important role in the distinction between these entities. Characteristic extra-pancreatic manifestations as well as favorable good response to treatment with steroids are characteristic of AIP. This paper will review current diagnostic parameters useful in differentiating between focal AIP and pancreatic adenocarcinoma.
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http://dx.doi.org/10.1007/s00261-019-02210-0DOI Listing
May 2020

TBAJ-876 Retains Bedaquiline's Activity against Subunits c and ε of F-ATP Synthase.

Antimicrob Agents Chemother 2019 10 23;63(10). Epub 2019 Sep 23.

Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

The antituberculosis drug bedaquiline (BDQ) inhibits F-ATP synthase by interfering with two subunits. Drug binding to the c subunit stalls the rotation of the c ring, while binding to the ε subunit blocks coupling of c ring rotation to ATP synthesis at the catalytic α:β headpiece. BDQ is used for the treatment of drug-resistant tuberculosis. However, the drug is highly lipophilic, displays a long terminal half-life, and has a cardiotoxicity liability by causing QT interval prolongation. Recent medicinal chemistry campaigns have resulted in the discovery of 3,5-dialkoxypyridine analogues of BDQ that are less lipophilic, have higher clearance, and display lower cardiotoxic potential. TBAJ-876, which is a new developmental compound of this series, shows attractive antitubercular activity and efficacy in a murine tuberculosis model. Here, we asked whether TBAJ-876 and selected analogues of the compound retain BDQ's mechanism of action. Biochemical assays showed that TBAJ-876 is a potent inhibitor of mycobacterial F-ATP synthase. Selection of spontaneous TBAJ-876-resistant mutants identified missense mutations at BDQ's binding site on the c subunit, suggesting that TBAJ-876 retains BDQ's targeting of the c ring. Susceptibility testing against a strain overexpressing the ε subunit and a strain harboring an engineered mutation in BDQ's ε subunit binding site suggest that TBAJ-876 retains BDQ's activity on the ε subunit. Nuclear magnetic resonance (NMR) titration studies confirmed that TBAJ-876 binds to the ε subunit at BDQ's binding site. We show that TBAJ-876 retains BDQ's antimycobacterial mode of action. The developmental compound inhibits the mycobacterial F-ATP synthase via a dual-subunit mechanism of interfering with the functions of both the enzyme's c and ε subunits.
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http://dx.doi.org/10.1128/AAC.01191-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761534PMC
October 2019

Effect of the additional cysteine 503 of vancomycin-resistant Enterococcus faecalis (V583) alkylhydroperoxide reductase subunit F (AhpF) and the mechanism of AhpF and subunit C assembling.

Free Radic Biol Med 2019 07 30;138:10-22. Epub 2019 Apr 30.

Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), 30 Biopolis Street, #07-01 Matrix, Singapore, 138671, Republic of Singapore; Nanyang Technological University, School of Biological Sciences, 60 Nanyang Drive, Singapore, 637551, Republic of Singapore. Electronic address:

The vancomycin-resistant Enterococcus faecalis alkyl hydroperoxide reductase complex (AhpR) with its subunits AhpC (EfAhpC) and AhpF (EfAhpF) is of paramount importance to restore redox homeostasis. Therefore, knowledge about this defense system is essential to understand its antibiotic-resistance and survival in hosts. Recently, we described the crystallographic structures of EfAhpC, the two-fold thioredoxin-like domain of EfAhpF, the novel phenomenon of swapping of the catalytic domains of EfAhpF as well as the unique linker length, connecting the catalytically active N-and C-terminal domains of EfAhpF. Here, using mutagenesis and enzymatic studies, we reveal the effect of an additional third cysteine (C503) in EfAhpF, which might optimize the functional adaptation of the E. faecalis enzyme under various physiological conditions. The crystal structure and solution NMR data of the engineered C503A mutant of the thioredoxin-like domain of EfAhpF were used to describe alterations in the environment of the additional cysteine residue during modulation of the redox-state. To glean insight into the epitope and mechanism of EfAhpF and -AhpC interaction as well as the electron transfer from the thioredoxin-like domain of EfAhpF to AhpC, NMR-titration experiments were performed, showing a coordinated disappearance of peaks in the thioredoxin-like domain of EfAhpF in the presence of full length EfAhpC, and indicating a stable EfAhpF-AhpC-complex. Combined with docking studies, the interacting residues of EfAhpF were identified and a mechanism of electron transfer of the EfAhpF donor to the electron acceptor EfAhpC is described.
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http://dx.doi.org/10.1016/j.freeradbiomed.2019.04.036DOI Listing
July 2019

Heme oxygenase-1 induced by desoxo-narchinol-A attenuated the severity of acute pancreatitis via blockade of neutrophil infiltration.

Int Immunopharmacol 2019 Apr 7;69:225-234. Epub 2019 Feb 7.

Department of Herbology, School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 54538, South Korea; Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University, Iksan, Jeonbuk 54538, South Korea. Electronic address:

Heme oxygenase-1 (HO-1) has an anti-inflammatory action in acute pancreatitis (AP). However, its mechanism of action and natural compounds/drugs to induce HO-1 in pancreas are not well understood. In this study, we investigated the regulatory mechanisms of HO-1 during AP using desoxo-narchinol-A (DN), the natural compound inducing HO-1 in the pancreas. Female C57/BL6 Mice were intraperitoneally injected with supramaximal concentrations of cerulein (50 μg/kg) hourly for 6 h to induce AP. DMSO or DN was administered intraperitoneally, then mice were sacrificed 6 h after the final cerulein injection. Administration of DN increased pancreatic HO-1 expression through activation of activating protein-1, mediated by mitogen-activated protein kinases. Furthermore, DN treatment reduced the pancreatic weight-to-body weight ratio as well as production of digestive enzymes and pro-inflammatory cytokines. Inhibition of HO-1 by tin protoporphyrin IX abolished the protective effects of DN on pancreatic damage. Additionally, DN treatment inhibited neutrophil infiltration into the pancreas via regulation of chemokine (C-X-C motif) ligand 2 (CXCL2) by HO-1. Our results suggest that DN is an effective inducer of HO-1 in the pancreas, and that HO-1 regulates neutrophil infiltration in AP via CXCL2 inhibition.
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http://dx.doi.org/10.1016/j.intimp.2019.01.051DOI Listing
April 2019

Structure and function of Mycobacterium-specific components of F-ATP synthase subunits α and ε.

J Struct Biol 2018 12 17;204(3):420-434. Epub 2018 Oct 17.

Nanyang Technological University, School of Biological Sciences, 60 Nanyang Drive, Singapore 637551, Republic of Singapore. Electronic address:

The Mycobacterium tuberculosis (Mtb) FF-ATP synthase (α:β:γ:δ:ε:a:b:b':c) is an essential enzyme that supplies energy for both the aerobic growing and the hypoxic dormant stage of the mycobacterial life cycle. Employing the heterologous F-ATP synthase model system α:β:γ we showed previously, that transfer of the C-terminal domain (CTD) of Mtb subunit α (Mtα) to a standard F-ATP synthase α subunit suppresses ATPase activity. Here we determined the 3D reconstruction from electron micrographs of the α:β:γ complex reconstituted with the Mtb subunit ε (Mtε), which has been shown to crosstalk with the CTD of Mtα. Together with the first solution shape of Mtb subunit α (Mtα), derived from solution X-ray scattering, the structural data visualize the extended C-terminal stretch of the mycobacterial subunit α. In addition, Mtε mutants MtεR62L, MtεE87A, Mtε, and Mtε, reconstituted with α:β:γ provided insight into their role in coupling and in trapping inhibiting MgADP. NMR solution studies of MtεE87A gave insights into how this residue contributes to stability and crosstalk between the N-terminal domain (NTD) and the CTD of Mtε. Analyses of the N-terminal mutant Mtε highlight the differences of the NTD of mycobacterial subunit ε to the well described Geobacillus stearothermophilus or Escherichia coli counterparts. These data are discussed in context of a crosstalk between the very N-terminal amino acids of Mtε and the loop region of one c subunit of the c-ring turbine for coupling of proton-translocation and ATP synthesis activity.
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http://dx.doi.org/10.1016/j.jsb.2018.10.006DOI Listing
December 2018

Molecular diversity and function of jasmintides from Jasminum sambac.

BMC Plant Biol 2018 Jul 11;18(1):144. Epub 2018 Jul 11.

School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551, Singapore.

Background: Jasmintides jS1 and jS2 from Jasminum sambac were previously identified as a novel family of cysteine-rich peptides (CRPs) with an unusual disulfide connectivity. However, very little else is known about jasmintides, particularly their molecular diversity and functions. Here, we report the discovery and characterization of a novel suite of jasmintides from J. sambac using transcriptomic, peptidomic, structural and functional tools.

Results: Transcriptomic analysis of leaves, flowers and roots revealed 14 unique jasmintide precursors, all of which possess a three-domain architecture comprising a signal peptide, a pro-domain and a mature jasmintide domain. Peptidomic analysis, using fractionated mixtures of jasmintides and chemical derivatization of cysteine to pseudolysine, trypsin digestion and MS/MS sequencing, revealed an additional 86 jasmintides, some of which were post-translationally modified. NMR analysis showed that jasmintide jS3 has three anti-parallel β-strands with a three-disulfide connectivity of CysI-CysV, CysII-CysIV and CysIII-CysVI, which is similar to jasmintide jS1. Jasmintide jS3 was able to withstand thermal, acidic and enzymatic degradation and, importantly, exhibited antifeedant activity against mealworm Tenebrio molitor.

Conclusion: Together, this study expands the existing library of jasmintides and furthers our understanding of the molecular diversity and cystine framework of CRPs as scaffolds and tools for engineering peptides targeting pests.
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http://dx.doi.org/10.1186/s12870-018-1361-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6042386PMC
July 2018

Synesthesia Occurring after the Use of Japanese Kiken Drugs: a Case Report.

Psychiatr Danub 2018 Jun;30(2):223-226

Department of Neuropsychiatry, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.

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http://dx.doi.org/10.24869/psyd.2018.223DOI Listing
June 2018

The NMR solution structure of Mycobacterium tuberculosis F-ATP synthase subunit ε provides new insight into energy coupling inside the rotary engine.

FEBS J 2018 03 6;285(6):1111-1128. Epub 2018 Feb 6.

Nanyang Technological University, School of Biological Sciences, Singapore, Singapore.

Mycobacterium tuberculosis (Mt) F F ATP synthase (α :β :γ:δ:ε:a:b:b':c ) is essential for the viability of growing and nongrowing persister cells of the pathogen. Here, we present the first NMR solution structure of Mtε, revealing an N-terminal β-barrel domain (NTD) and a C-terminal domain (CTD) composed of a helix-loop-helix with helix 1 and -2 being shorter compared to their counterparts in other bacteria. The C-terminal amino acids are oriented toward the NTD, forming a domain-domain interface between the NTD and CTD. The Mtε structure provides a novel mechanistic model of coupling c-ring- and ε rotation via a patch of hydrophobic residues in the NTD and residues of the CTD to the bottom of the catalytic α β -headpiece. To test our model, genome site-directed mutagenesis was employed to introduce amino acid changes in these two parts of the epsilon subunit. Inverted vesicle assays show that these mutations caused an increase in ATP hydrolysis activity and a reduction in ATP synthesis. The structural and enzymatic data are discussed in light of the transition mechanism of a compact and extended state of Mtε, which provides the inhibitory effects of this coupling subunit inside the rotary engine. Finally, the employment of these data with molecular docking shed light into the second binding site of the drug Bedaquiline.

Database: Structural data are available in the PDB under the accession number 5YIO.
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http://dx.doi.org/10.1111/febs.14392DOI Listing
March 2018

Comparison of Fixed-dose Combinations of Amlodipine/Losartan Potassium/Chlorthalidone and Amlodipine/Losartan Potassium in Patients With Stage 2 Hypertension Inadequately Controlled With Amlodipine/Losartan Potassium: A Randomized, Double-blind, Multicenter, Phase III Study.

Clin Ther 2017 Oct 19;39(10):2049-2060. Epub 2017 Sep 19.

Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea. Electronic address:

Purpose: The goal of this study was to compare the efficacy and safety of fixed-dose combinations of amlodipine/losartan potassium/chlorthalidone (A/L/C) and A/L in Korean patients with stage 2 hypertension inadequately controlled by A/L.

Methods: This study was an 8-week, randomized double-blind, multicenter, phase III clinical trial. Three hundred forty volunteer patients with stage 2 hypertension were randomized to receive A/L/C or A/L. The primary end point was a change in sitting systolic blood pressure (SitSBP) after 8 weeks of treatment. As secondary end points, the change in SitSBP after 2 weeks of treatment and the change in sitting diastolic blood pressure (SitDBP) were compared between treatment groups. All patients were assessed for adverse events, clinical laboratory data, and vital signs.

Findings: Of 330 patients from 33 medical centers, 328 patients who had available efficacy data were analyzed. After 8 weeks of double-blind treatment, the mean (SD) changes in SitSBP at 8 weeks were -16.4 (0.9) mm Hg and -6.9 (1.0) mm Hg in the A/L/C and A/L groups, respectively. A/L/C had a statistically superior blood pressure-lowering effect compared with that of A/L (mean [SD] difference, 9.5 [1.3] mm Hg; P < 0.001). The mean (SD) change in SitDBP at 8 weeks was significantly greater with A/L/C (-8.0 [0.6] mm Hg) than with A/L (-3.6 [0.6] mm Hg) (P < .001). In terms of the mean (SD) change in SitDBP at 2 weeks compared with baseline, A/L/C (-5.9 [0.5] mm Hg) was statistically different from A/L (-2.9 [0.5] mm Hg) (P < .001). Mean (SD) SitSBP change from baseline to week 2 was -13.2 (0.9) and -5.5 (0.9) in the A/L/C and A/L groups, respectively, with a statistically significant blood pressure-lowering effect (P < 0.001). The number of participants who achieved target blood pressure at week 8 was significantly higher in the A/L/C group (93 patients [55.7%]) than in the A/L group (48 [29.8%]) (P < 0.001). Adverse drug reactions were observed in 23 patients (7.0%), and the incidence of dizziness was significantly higher in the A/L/C group than in the A/L group (4.8% vs 0.6%, P = 0.037) There were no serious adverse events associated with the study drugs.

Implications: The results of this study suggest that A/L/C had a significantly increased blood pressure-lowering efficacy compared with that of A/L and had a good safety profile. ClinicalTrials.gov identifier: NCT02916602.
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http://dx.doi.org/10.1016/j.clinthera.2017.08.013DOI Listing
October 2017

Stroke Impact Scale 3.0: Reliability and Validity Evaluation of the Korean Version.

Ann Rehabil Med 2017 Jun 29;41(3):387-393. Epub 2017 Jun 29.

Department of Rehabilitation Medicine, National Rehabilitation Center, Seoul, Korea.

Objective: To establish the reliability and validity the Korean version of the Stroke Impact Scale (K-SIS) 3.0.

Methods: A total of 70 post-stroke patients were enrolled. All subjects were evaluated for general characteristics, Mini-Mental State Examination (MMSE), the National Institutes of Health Stroke Scale (NIHSS), Modified Barthel Index, Hospital Anxiety and Depression Scale (HADS). The SF-36 and K-SIS 3.0 assessed their health-related quality of life. Statistical analysis after evaluation, determined the reliability and validity of the K-SIS 3.0.

Results: A total of 70 patients (mean age, 54.97 years) participated in this study. Internal consistency of the SIS 3.0 (Cronbach's alpha) was obtained, and all domains had good co-efficiency, with threshold above 0.70. Test-retest reliability of SIS 3.0 required correlation (Spearman's rho) of the same domain scores obtained on the first and second assessments. Results were above 0.5, with the exception of social participation and mobility. Concurrent validity of K-SIS 3.0 was assessed using the SF-36, and other scales with the same or similar domains. Each domain of K-SIS 3.0 had a positive correlation with corresponding similar domain of SF-36 and other scales (HADS, MMSE, and NIHSS).

Conclusion: The newly developed K-SIS 3.0 showed high inter-intra reliability and test-retest reliabilities, together with high concurrent validity with the original and various other scales, for patients with stroke. K-SIS 3.0 can therefore be used for stroke patients, to assess their health-related quality of life and treatment efficacy.
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http://dx.doi.org/10.5535/arm.2017.41.3.387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5532343PMC
June 2017

AhpC of the mycobacterial antioxidant defense system and its interaction with its reducing partner Thioredoxin-C.

Sci Rep 2017 07 11;7(1):5159. Epub 2017 Jul 11.

Nanyang Technological University, School of Biological Sciences, 60 Nanyang Drive, Singapore, 637551, Republic of Singapore.

Despite the highly oxidative environment of the phagosomal lumen, the need for maintaining redox homeostasis is a critical aspect of mycobacterial biology. The pathogens are equipped with the sophisticated thioredoxin- (Trx) and peroxiredoxin system, including TrxC and the alkyl hydroperoxide reductase subunit C (AhpC), whereby TrxC is one of the reducing partners of AhpC. Here we visualize the redox modulated dodecamer ring formation of AhpC from Mycobacterium bovis (BCG strain; MbAhpC) using electron microscopy and present novel insights into the unique N-terminal epitope (40 residues) of mycobacterial AhpC. Truncations and amino acid substitutions of residues in the unique N-terminus of MbAhpC provide insights into their structural and enzymatic roles, and into the evolutionary divergence of mycobacterial AhpC versus that of other bacteria. These structural details shed light on the epitopes and residues of TrxC which contributes to its interaction with AhpC. Since human cells lack AhpC, the unique N-terminal epitope of mycobacterial AhpC as well as the MbAhpC-TrxC interface represent an ideal drug target.
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http://dx.doi.org/10.1038/s41598-017-05354-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5505994PMC
July 2017

Structural and mechanistic insights into Mycothiol Disulphide Reductase and the Mycoredoxin-1-alkylhydroperoxide reductase E assembly of Mycobacterium tuberculosis.

Biochim Biophys Acta Gen Subj 2017 Sep 10;1861(9):2354-2366. Epub 2017 May 10.

Nanyang Technological University, School of Biological Sciences, 60 Nanyang Drive, Singapore 637551, Republic of Singapore. Electronic address:

Mycobacteria employ a versatile machinery of the mycothiol-dependent system, containing the proteins mycothiol disulfide reductase (Mtr), the oxido-reductase Mycoredoxin-1 (Mrx-1) and the alkyl-hydroperoxide subunit E (AhpE). The mycothiol-dependent protein ensemble regulates the balance of oxidized-reduced mycothiol, to ensure a reductive intracellular environment for optimal functioning of its proteins even upon exposure to oxidative stress. Here, we determined the first low-resolution solution structure of Mycobacterium tuberculosis Mtr (MtMtr) derived from small-angle X-ray scattering data, which provides insight into its dimeric state. The solution shape reveals the two NADPH-binding domains inside the dimeric MtMtr in different conformations. NMR-titration shows that the MtMtr-MtMrx-1 interaction is characterized by a fast exchange regime and critical residues involved in the protein-protein interaction were identified. Using NMR spectroscopy and docking studies, the epitopes of MtMrx-1 and MtAhpE interaction are described, shedding new light into the interaction interface and mechanism of action. Finally, the essential residue of MtMrx-1 identified in the interaction with MtMtr and MtAhpE form a platform for structure-guided drug design against the versatile enzyme machinery of the mycothiol-dependent system inside M. tuberculosis.
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http://dx.doi.org/10.1016/j.bbagen.2017.05.007DOI Listing
September 2017

Structural features of NS3 of Dengue virus serotypes 2 and 4 in solution and insight into RNA binding and the inhibitory role of quercetin.

Acta Crystallogr D Struct Biol 2017 May 19;73(Pt 5):402-419. Epub 2017 Apr 19.

School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.

Dengue virus (DENV), which has four serotypes (DENV-1 to DENV-4), is the causative agent of the viral infection dengue. DENV nonstructural protein 3 (NS3) comprises a serine protease domain and an RNA helicase domain which has nucleotide triphosphatase activities that are essential for RNA replication and viral assembly. Here, solution X-ray scattering was used to provide insight into the overall structure and flexibility of the entire NS3 and its recombinant helicase and protease domains for Dengue virus serotypes 2 and 4 in solution. The DENV-2 and DENV-4 NS3 forms are elongated and flexible in solution. The importance of the linker residues in flexibility and domain-domain arrangement was shown by the compactness of the individual protease and helicase domains. Swapping of the PPAVP linker stretch of the related Hepatitis C virus (HCV) NS3 into DENV-2 NS3 did not alter the elongated shape of the engineered mutant. Conformational alterations owing to RNA binding are described in the protease domain, which undergoes substantial conformational alterations that are required for the optimal catalysis of bound RNA. Finally, the effects of ATPase inhibitors on the enzymatically active DENV-2 and DENV-4 NS3 and the individual helicases are presented, and insight into the allosteric effect of the inhibitor quercetin is provided.
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http://dx.doi.org/10.1107/S2059798317003849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5417341PMC
May 2017

Prenatal Exposure to Perfluorinated Compounds Affects Birth Weight Through GSTM1 Polymorphism.

J Occup Environ Med 2016 06;58(6):e198-205

Department of Preventive Medicine, School of Medicine, Ewha Womans University, Seoul, South Korea (Ms Kwon, Drs Kim, Kulkarni, Park, Ha); Department of Pediatrics, School of Medicine, Ewha Womans University, Seoul, South Korea (Dr Park); Department of Obstetrics and Gynecology, School of Medicine, Ewha Womans University, Seoul, South Korea (Ms Kwon, Dr Kim); Department of Health, Environment & Safety, Eulji University, Seongnam, South Korea (Dr Kho); Cancer Policy Branch (Dr Kim), National Cancer Center, Goyang, South Korea; and Chicago Medical School (Mr Shin), Rosalind Franklin University of Medicine and Science, Lake County, Illinois.

Objective: The aim of this study was to investigate the effect of genetic polymorphisms on the association of prenatal exposure to perfluorinated compounds (PFCs) with birth weight.

Methods: We analyzed the level of eight PFCs in cord blood and two genetic polymorphisms in maternal blood of 268 subjects.

Results: Concentrations of perfluorooctanoic acid, perfluorooctane sulfonate, perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUnDA) showed significant association with a decrease in birth weight (P < 0.05). In mothers with glutathione S-transferase M1 (GSTM1) null genotype, concentrations of PFNA, PFDA, and PFUnDA showed significantly negative association with birth weight (P < 0.05).

Conclusion: Our findings indicated that GSTM1 polymorphism might affect the association between exposure to PFCs and birth weight, suggesting the effect of genetic susceptibility on the relationship between prenatal PFCs exposure and birth outcomes.
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http://dx.doi.org/10.1097/JOM.0000000000000739DOI Listing
June 2016

Impact of the β-1 adrenergic receptor polymorphism on tolerability and efficacy of bisoprolol therapy in Korean heart failure patients: association between β adrenergic receptor polymorphism and bisoprolol therapy in heart failure (ABBA) study.

Korean J Intern Med 2016 Mar 16;31(2):277-87. Epub 2016 Feb 16.

Department of Internal Medicine, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.

Background/aims: We evaluated the association between coding region variants of adrenergic receptor genes and therapeutic effect in patients with congestive heart failure (CHF).

Methods: One hundred patients with stable CHF (left ventricular ejection fraction [LVEF] < 45%) were enrolled. Enrolled patients started 1.25 mg bisoprolol treatment once daily, then up-titrated to the maximally tolerable dose, at which they were treated for 1 year.

Results: Genotypic analysis was carried out, but the results were blinded to the investigators throughout the study period. At position 389 of the β-1 adrenergic receptor gene (ADRB1), the observed minor Gly allele frequency (Gly389Arg + Gly389Gly) was 0.21, and no deviation from Hardy-Weinberg equilibrium was observed in the genotypic distribution of Arg389Gly (p = 0.75). Heart rate was reduced from 80.8 ± 14.3 to 70.0 ± 15.0 beats per minute (p < 0.0001). There was no significant difference in final heart rate across genotypes. However, the Arg389Arg genotype group required significantly more bisoprolol compared to the Gly389X (Gly389Arg + Gly389Gly) group (5.26 ± 2.62 mg vs. 3.96 ± 2.05 mg, p = 0.022). There were no significant differences in LVEF changes or remodeling between two groups. Also, changes in exercise capacity and brain natriuretic peptide level were not significant. However, interestingly, there was a two-fold higher rate of readmission (21.2% vs. 10.0%, p = 0.162) and one CHF-related death in the Arg389Arg group.

Conclusions: The ADRB1 Gly389X genotype showed greater response to bisoprolol than the Arg389Arg genotype, suggesting the potential of individually tailoring β-blocker therapy according to genotype.
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http://dx.doi.org/10.3904/kjim.2015.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4773723PMC
March 2016

Structural basis of nucleic acid recognition by FK506-binding protein 25 (FKBP25), a nuclear immunophilin.

Nucleic Acids Res 2016 Apr 13;44(6):2909-25. Epub 2016 Jan 13.

School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, 637551, Singapore Department of Genetic Engineering, College of Life Sciences, Kyung Hee University Yongin-si, Gyeonggi-do 446-701, Republic of Korea

The nuclear immunophilin FKBP25 interacts with chromatin-related proteins and transcription factors and is suggested to interact with nucleic acids. Currently the structural basis of nucleic acid binding by FKBP25 is unknown. Here we determined the nuclear magnetic resonance (NMR) solution structure of full-length human FKBP25 and studied its interaction with DNA. The FKBP25 structure revealed that the N-terminal helix-loop-helix (HLH) domain and C-terminal FK506-binding domain (FKBD) interact with each other and that both of the domains are involved in DNA binding. The HLH domain forms major-groove interactions and the basic FKBD loop cooperates to form interactions with an adjacent minor-groove of DNA. The FKBP25-DNA complex model, supported by NMR and mutational studies, provides structural and mechanistic insights into the nuclear immunophilin-mediated nucleic acid recognition.
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http://dx.doi.org/10.1093/nar/gkw001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4824100PMC
April 2016