Jaheon Kang

TGFβ mediates activation of transglutaminase 2 in response to oxidative stress that leads to protein aggregation

Transglutaminase 2 (TGase2) is a ubiquitously expressed enzyme that catalyzes irreversible post‐translational modification of protein, forming cross‐linked protein aggregates. We previously reported that intracellular TGase2 is activated by oxidative stress. To elucidate the functional role of TGase2 activation in cells under the oxidatively stressed condition, we identified the mediator that activates TGase2. In this study, we showed that low levels of oxidative stress trigger the release of TGFβ, which subsequently activates TGase2 through the nuclear translocation of Smad3. Analysis of substrate proteins reveals that TGase2‐mediated protein modification results in a decrease of protein solubility and a collapse of intermediate filament network, which leads to aggregation of proteins. We confirm these results using lens tissues from TGase2‐deficient mice. Among several antioxidants tried, only N‐acetylcysteine effectively inhibits TGFβ‐mediated activation of TGase2. These results indicate that TGFβ mediates oxidative stress‐induced protein aggregation through activation of TGase2 and suggest that the formation of protein aggregation may not be a passive process of self‐assembly of oxidatively damaged proteins but may be an active cellular response to oxidative stress. Therefore, TGFP‐TGase2 pathway may have implications for both the pathogenesis of age‐related degenerative diseases and the development of pharmaceutics.—Shin, D.‐M., Jeon, J.‐H., Kim, C.‐W., Cho, S.‐Y., Lee, H.‐J., Jang, G.‐Y., Jeong, E. M., Lee, D.‐S., Kang, J.‐H., Melino, G., Park, S.‐C., Kim, I.‐G. TGFβ mediates activation of transglutaminase 2 in response to oxidative stress that leads to protein aggregation. FASEB J. 22, 2498–2507 (2008)

Inhibition of NF-κB prevents high glucose-induced proliferation and plasminogen activator inhibitor-1 expression in vascular smooth muscle cells

Recent epidemiologic studies clearly showed that early intensive glucose control has a legacy effect for preventing diabetic macrovascular complications. However, the cellular and molecular processes by which high glucose leads to macrovascular complications are poorly understood. Vascular smooth muscle cell (VSMC) dysfunction due to high glucose is a characteristic of diabetic vascular complications. Activation of nuclear factor-κB (NF-κB) may play a key role in the regulation of inflammation and proliferation of VSMCs. We examined whether VSMC proliferation and plasminogen activator inhibitor-1 (PAI-1) expression induced by high glucose were mediated by NF-κB activation. Also, we determined whether selective inhibition of NF-κB would inhibit proliferation and PAI-1 expression in VSMCs. VSMCs of the aorta of male SD rats were treated with various concentrations of glucose (5.6, 11.1, 16.7, and 22.2 mM) with or without an inhibitor of NF-κB or expression of a recombinant adenovirus vector encoding an IκB-α mutant (Ad-IκBαM). VSMC proliferation was examined using an MTT assay. PAI-1 expression was assayed by real-time PCR and PAI-1 protein in the media was measured by ELISA. NF-κB activation was determined by immunohistochemical staining, NF-κB reporter assay, and immunoblotting. We found that glucose stimulated VSMC proliferation and PAI-1 expression in a dose-dependent manner up to 22.2 mM. High glucose (22.2 mM) alone induced an increase in NF-κB activity. Treatment with inhibitors of NF-κB such as MG132, PDTC or expression of Ad-IκB-αM in VSMCs prevented VSMC proliferation and PAI-1 expression induced by high glucose. In conclusion, inhibition of NF-κB activity prevented high glucose-induced VSMC proliferation and PAI-1 expression.

Fulminant Type 1 diabetes in a pregnant woman as an initial manifestation of the insulin autoimmune syndrome.

Diabet. Med. 29, 1335–1338 (2012)

Risk factors for the progression of intima-media thickness of carotid arteries: a 2-year follow-up study in patients with newly diagnosed type 2 diabetes.

Background Intima-media thickness (IMT) of the carotid arteries is known to have a positive correlation with the risk of cardiovascular disease. This study was designed to identify risk factors affecting the progression of carotid IMT in patients with type 2 diabetes mellitus (T2DM). Methods Patients with newly diagnosed T2DM with carotid IMT measurements were enrolled, and their clinical data and carotid IMT results at baseline and 2 years later were compared. Results Of the 171 patients, 67.2% of males and 50.8% of females had abnormal baseline IMT of the left common carotid artery. At baseline, systolic blood pressure, body mass index and smoking in male participants, and fasting plasma glucose and glycated hemoglobin levels in females were significantly higher in patients with abnormal IMT than in those with normal IMT. Low density lipoprotein cholesterol (LDL-C) levels in males and high density lipoprotein cholesterol (HDL-C) levels in females at the 2-year follow-up were significantly different between the nonprogression and the progression groups. Reduction of the United Kingdom Prospective Diabetes Study (UKPDS) 10-year coronary heart disease (CHD) risk score after 2 years was generally higher in the nonprogression group than the progression group. Conclusion LDL-C levels in males and HDL-C levels in females at the 2-year follow-up were significantly different between participants with and without progression of carotid IMT. Furthermore, a reduction in the UKPDS 10-year CHD risk score appeared to delay the advancement of atherosclerosis. Therefore, the importance of establishing the therapeutic goal of lipid profiles should be emphasized to prevent the progression of carotid IMT in newly diagnosed T2DM patients.

Development of an LCD-Based Visual Field System.

Background The present study investigated the diagnostic effectiveness of an LCD-based visual field testing system (LVF) in comparison with the standard automated perimetry Humphrey Field Analyzer II-750i (HFA). Methods A randomized controlled crossover study was conducted with 202 normal and 128 glaucomatous eyes using both LVF and HFA. The visual field testing systems were compared in terms of mean deviation (MD), pattern standard deviation (PSD), and area under the receiver operating characteristics curve (AUC) of MD and PSD differentiating the normal and glaucomatous eyes. Results Significant correlations were found between MD measurements from LVF and those from HFA for normal eyes (r = 0.342) and glaucomatous eyes (r = 0.796); slightly higher significant correlations were identified between PSD measurements from LVF and those from HFA for normal eyes (r = 0.363) and glaucomatous eyes (r = 0.828). Furthermore, high AUCs of MD were found as 0.786 for LVF and 0.868 for HFA and AUCs of PSD as 0.913 for LVF and 0.932 for HFA. Conclusion The comparison results of the present study support the competence of LVF compared with HFA in visual field testing for early detection of glaucoma.

The Effect of Visual Attention Factors on Visual Field Testing for Maintenance of Gaze Fixation

The maintenance of gaze fixation during visual field testing is needed to accurately measure the functionality of the optic nerve. The present study is intended to analyze the performance of gaze fixation and evaluate five gaze fixation induction methods (GFIM) including black dot (BD; conventional method), changing color dot (CCD), alphanumeric characters (AC), flashing black dot (FBD), and bulls-eye with cross hair (BECH). Recruiting 32 participants (16 in 20s and 16 in 30s), the experiment was conducted in four steps: (1) preparation, (2) exercising the visual field testing, (3) main experiment for five GFIMs, and (4) debriefing. The performance of gaze fixation was analyzed in terms of correct fixation rate (CFR), and subjective satisfaction was evaluated in terms of ease of gaze fixation (EGF), eye fatigue (EF), and overall satisfaction (OS) using a 11-point Likert bipolar scale. The CFRs of the four new GFIMs were all higher than that of BD (BD = 86.7%, CCD = 87.9%, AC = 88.8%, FBD = 91.5%, and BECH = 88.0%). However, there was no statistically significant difference among the CFR averages of the five GFIMs, but the variances of CFR of the newly proposed GFIMs were all lower than that of BD. The subjective satisfaction of BECH (EGF = 2.0, EF = -0.4, OS = 1.6) was highest. Therefore, BECH was recommended for an effective GFIM to maintain the examinee’s gaze fixation during a visual field testing in both aspects of the performance and the subjective satisfaction.

Spontaneous corneal perforation in Terrienʼs marginal degeneration in childhood: A case report

Rationale: Terriens marginal corneal degeneration (TMD) is characterized by progressive peripheral corneal thinning. It appears primarily above the age of 40 years and is rare at younger ages. Spontaneous corneal perforation in TMD is a rare, but serious complication that may occur in childhood. Patient concerns: This review presents the case of a 16-year-old girl presented with blurred vision in the right eye on awakening in the morning. Slit-lamp examination revealed superior corneal thinning with a corneal perforation. Diagnoses: The best-corrected visual acuity (BCVA) was 20/50 in the right eye and 20/20 in the left eye. Intraocular pressures were 5 and 18 mm Hg in the right and left eyes, respectively, measured using a noncontact tonometer. Slit-lamp examination revealed superior corneal thinning with superficial pannus. A 1-mm corneal perforation was observed at the 11 o’clock position. The anterior chamber of the right eye was flat and the Seidel test result was positive. The left eye showed no apparent abnormality on slit-lamp examination. Corneal topography showed 4.3 D of against-the-rule astigmatism, and anterior segment optical coherence tomography revealed superior corneal thinning. We diagnosed it as childhood onset TMD. Interventions: Multilayered amniotic membrane transplantation was performed over the perforation site and a bandage contact lens was placed. Outcomes: At 1 week postoperatively, the BCVA of the right eye improved to 20/32, the amniotic membrane graft was well-attached, and the anterior chamber remained deep. At 2 months postoperatively, the BCVA was 20/25 and the anterior chamber depth was maintained. Lessons: Spontaneous corneal perforation due to TMD is rare, but may occur in childhood. The possibility of corneal perforation should be considered even in childhood and good surgical results can be obtained with amniotic membrane transplantation.

The Effect of Gaze Fixation Induction Method on Visual Field Testing

A visual field tester using a fixation target with a lack of distinctiveness decreases accuracy and usability in visual field testing. The present study is intended to develop various induction methods of gaze fixation for effective visual field testing. Proposed were four new gaze fixation induction methods (color changing dot; alphanumeric characters; flashing black dot; and bulls eye and cross hair, BECH) by considering visual attention factors such as color, meaning, flashing, and shape and the proposed methods were compared with the existing black dot (BD) method in terms of gaze fixation performance and subjective satisfaction by 32 participants in their 20s to 30s. BECH was found most preferred by increasing gaze fixation performance by 4.8% and subjective satisfaction by 0.4 to 2.0 in a 7-point scale compared to BD. BECH can be applied to tests such as visual field testing and macular pigment optical density testing in which gaze fixation is crucial for accuracy and usability.

Contribution of TNF-α-308 gene polymorphisms to susceptibility to the development of uveitis in Korean patients with HLA-B27-positive ankylosing spondylitis

Human leucocyte antigen (HLA)-B27-associated anterior uveitis (AU) is significantly associated with ankylosing spondylitis (AS), with up to 50% of AS patients developing acute AU (1). The prevalence of HLA-B27 in patients with AU is about 50% (2). HLA-B27 may be an important but not a sufficient predisposing factor to uveitis. Therefore, other non-HLA-B27 factors could contribute to the pathophysiology of uveitis. Recent studies suggest that single nucleotide polymorphisms within the tumour necrosis factor (TNF)-a promoter region play a role in uveitis (3–6). In this study we investigated the association of TNFa promoter gene polymorphisms (1031T>C, –863C>A, –857C>T, –308G>A, and –238G>A) with developing uveitis in Korean patients with HLA-B27-positive AS. We reviewed the clinical characteristics of 398 HLAB27-positive Korean AS patients who visited our Department of Rheumatology and Ophthalmology between May 2006 and October 2009. The participants enrolled were 116 Korean patients with AS. Of these,