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Mitochondrial-Encoded Peptide MOTS-c, Diabetes, and Aging-Related Diseases
공병수,Lee Changhan,조영민 대한당뇨병학회 2023 Diabetes and Metabolism Journal Vol.47 No.3
Mitochondria are complex metabolic organelles with manifold pathophysiological implications in diabetes. Currently published mitochondrial-encoded peptides, which are expressed from the mitochondrial open reading frame of the 12S ribosomal RNA type-c (MOTS-c), 16S rRNA (humanin and short humanin like peptide 1-6 [SHLP1-6]), or small human mitochondrial open reading frame over serine tRNA (SHMOOSE) are associated with regulation of cellular metabolism and insulin action in age-related diseases, such as type 2 diabetes mellitus. This review focuses mainly on recent advances in MOTS-c research with regards to diabetes, including both type 1 and type 2. The emerging understanding of MOTS-c in diabetes may provide insight into the development of new therapies for diabetes and other age or senescence-related diseases.
김예슬,김가영,공병수,이지은,오유미,현재원,김수현,정애란,김병준,최경호,김호진 대한신경과학회 2017 Journal of Clinical Neurology Vol.13 No.2
Background and Purpose The detection of aquaporin 4-IgG (AQP4-IgG) is now a critical diagnostic criterion for neuromyelitis optica spectrum disorder (NMOSD). To evaluate the serostatus of NMOSD patients based on the 2015 new diagnostic criteria using a new in-house cell-based assay (CBA). Methods We generated a stable cell line using internal ribosome entry site-containing bicistronic vectors, which allow the simultaneous expression of two proteins (AQP4 and green fluorescent protein) separately from the same RNA transcript. We performed in-house CBA using serum from 386 patients: 178 NMOSD patients diagnosed according to the new diagnostic criteria without AQP4-IgG, 63 high risk NMOSD patients presenting 1 of the 6 core clinical characteristics of NMOSD but not fulfilling dissemination in space, and 145 patients with other neurological diseases, including 66 with multiple sclerosis. The serostatus of 111 definite and high risk NMOSD patients were also tested using a commercial CBA kit with identical serum to evaluate the correlation between the 2 methods. All assays were performed by two independent and blinded investigators. Results Our in-house assay yielded a specificity of 100% and sensitivities of 80% (142 of 178) and 76% (48 of 63) when detecting definite- and high risk NMOSD patients, respectively. The comparison with the commercial CBA kit revealed a correlation for 102 of the 111 patients: no correlation was present in 7 patients who were seronegative using the commercial method but seropositive using the in-house method, and in 2 patients who were seropositive using the commercial method but seronegative using the in-house method Conclusions These results demonstrate that our in-house CBA is a highly specific and sensitive method for detecting AQP4-IgG in NMOSD patients.
Neutralizing Antibodies Against Interferon-Beta in Korean Patients with Multiple Sclerosis
현재원,김가영,김예슬,공병수,정애란,박나영,장현민,신현준,김수현,안석원,신하영,허소영,김우준,박민수,김병조,김병준,오지영,김호진 대한신경과학회 2018 Journal of Clinical Neurology Vol.14 No.2
Background and Purpose Patients treated with interferon-beta (IFN-β) can develop neutralizingantibodies (NAbs) against IFN-β that can negatively affect the therapeutic response. This study assessed the prevalence of NAbs and the impact of NAb positivity on the therapeuticresponse to IFN-β in Korean patients with multiple sclerosis (MS). Methods This was a multicenter study involving 150 MS patients from 9 Korean medicalcenters who were treated with IFN-β for at least 6 months. Sera that had not been influencedby acute treatment were assessed for NAbs using a luciferase reporter gene assay. To evaluatethe association between persistent positivity for NAbs and disease activity, NAbs were tested at2 different time points in 75 of the 150 patients. Disease activity was defined as the presence ofclinical exacerbations and/or active MRI lesions during a 1-year follow-up after NAb positivitywas confirmed. Results NAbs were found in 39 of the 150 (26%) MS patients: 30 of the 85 (35%) who weretreated with subcutaneous IFN-β-1b, 9 of the 60 (15%) who were treated with subcutaneousIFN-β-1a, and 0 of the 5 (0%) who were treated with intramuscular IFN-β-1a. Thirty of the 39patients exhibiting NAb positivity were tested at different time points, and 20 of them exhibitedpersistent NAb positivity. Disease activity was observed more frequently in patients with persistentNAb positivity than in those with transient positivity or persistent negativity [16/20 (80%)vs. 4/55 (7%), respectively; p<0.001]. When disease activity was compared between patientswith persistent and transient NAb positivity, the difference was unchanged and remained statisticallysignificant [16/20 (80%) vs. 2/10 (20%), p=0.004]. Conclusions These results further support that persistent NAb positivity is associated withdisease activity in MS patients treated with IFN-β.
The Role of Foxo3 in Leydig Cells
최영숙,이은직,송주은,공병수,홍재원,Silvia Novelli 연세대학교의과대학 2015 Yonsei medical journal Vol.56 No.6
Purpose: Foxo3 in female reproduction has been reported to regulate proliferation of granulose cells that form follicles. There are no reports so far that discuss on the role of Foxo3 in males. This study was designed to outline the role of Foxo3 in the testes. Materials and Methods: Testes from mice at birth to postpartum week (PPW) 5 were isolated and examined for the expression of Foxo3 using immunostaining. To elucidate role of Foxo3 in Leydig cells, R2C cells were treated with luteinizing hormone (LH) and the phosphorylation of Foxo3. Testosterone and steroidogenic acute regulatory (StAR) protein levels were measured after constitutive active [triple mutant (TM)] human FOXO3 adenovirus was transduced and StAR promoter assay was performed. Results: Foxo3 expression in the testicles started from birth and lasted until PPW 3. After PPW 3, most Foxo3 expression occurred in the nuclei of Leydig cells; however, at PPW 5, Foxo3 was expressed in both the nucleus and cytoplasm. When R2C cells were treated with luteinizing hormone, Foxo3 phosphorylation levels by AKT increased. After blocking the PI3K pathway, LH-induced phosphorylated Foxo3 levels decreased, indicating that LH signaling regulates Foxo3 localization. When active FOXO3-TM adenoviruswas introduced into a Leydig tumor cell line, the concentrations of testosterone and StAR protein decreased. When FOXO3 and a StAR promoter vector were co-transfected into HEK293 cells for a reporter assay, FOXO3 inhibited the StAR promoter. Conclusion: FOXO3 affects testosterone synthesis by inhibiting the formation of StAR protein. LH hormone, meanwhile, influencesFoxo3 localization, mediating its function.