https://scholar.dgist.ac.kr/handle/20.500.11750/1170 2026-04-04T15:19:37Z https://scholar.dgist.ac.kr/handle/20.500.11750/59346 Title: Neurotherapeutic effects of Vutiglabridin as a Paraoxonase-2 modulator in preclinical models of Parkinson's disease Author(s): An, Heeyoung; Kang, Sora; Shin, Jaejin; Kim, Purum; Kim, Sunpil; Im, Suyeol; Kim, Ji Hwan; Lee, Keun Woo; Kim, Dong Hwan; Park, Jung Hee; Park, Min-Ho; Lee, Jaemin; Park, Sun Kyung; Kim, Kwang Pyo; Lee, Hyeong Min; Lee, Jae Ho; Choi, Leo S.; Jeon, Hyun Ju; Kim, Suyeon Yellena; Hwang, In Young; Bhalla, Mridula; Won, Woojin; Park, Hyung Soon; Yoo, Sang-Ku; Lee, Byoung Dae; Lee, C. Justin; Pak, Youngmi Kim Abstract: BackgroundParkinson's disease (PD) is the second most prevalent neurodegenerative disease characterized by motor impairment resulting from the degeneration of dopaminergic neurons in the substantia nigra, alongside alpha -synuclein (alpha-syn) accumulation, mitochondrial dysfunction, and oxidative stress. Recent studies on PD treatment have focused primarily on exploring oxidative stress and mitochondrial function as ways to restore dopamine release. Notably, previous studies have demonstrated that Paraoxonase 2 (PON2) plays a critical role in neuroprotection and neuroinflammation by reducing oxidative stress in striatal neurons and astrocytes.MethodsIn this study, we investigated the potential therapeutic effect of a newly developed drug, Vutiglabridin, which is demonstrated to augment the activity of PON2 in the mouse model of PD. We assessed the impact of Vutiglabridin in a PD model induced by MPP+ treatment and overexpression of the A53T mutated alpha-syn. Furthermore, we administered Vutiglabridin subsequent to PON2 gene knockdown through PON2-shRNA overexpression to elucidate the interplay between PON2 and Vutiglabridin.ResultVutiglabridin effectively crosses the blood-brain barrier (BBB) and maintains a presence in the brain for over 24 h, achieving concentrations up to 2.5 times higher than in the bloodstream. It successfully binds to PON2 in both its (R) and (S) forms. Vutiglabridin reversed mitochondrial dysfunction, reduced oxidative stress, improved motor functions, and protected dopaminergic neurons against MPP+-induced damage. Similarly, in alpha-syn A53T overexpressed PD models, it not only reduced astrocytic reactivity and microglia activation but also doubled the tyrosine hydroxylase positive neurons /dopa decarboxylase positive neurons (TH+/DDC+) ratio, signifying enhanced neuronal health. However, these positive outcomes were absent in PON2-knockdown mice, underscoring Vutiglabridin's reliance on PON2 for its neuroprotective effects.ConclusionThese findings indicate that Vutiglabridin may serve as a promising therapeutic approach for reducing reactive oxygen species (ROS) levels by modulating PON2 activity in Parkinson's diseases. 2025-09-30T15:00:00Z https://scholar.dgist.ac.kr/handle/20.500.11750/58308 Title: Engineered extracellular vesicles with surface FGF21 and enclosed miR-223 for treating metabolic dysfunction-associated steatohepatitis Author(s): Cho, Hanchae; Ju, Hyunji; Ahn, Yongdeok; Jang, Juhee; Cho, Juhyeong; Park, Eunju; Kang, Sung-Min; Lee, Jaemin; Seo, Daeha; Baek, Moon-Chang; Yea, Kyungmoo Abstract: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disorder with a complex pathogenesis that requires combination therapies rather than monotherapies. Extracellular vesicles (EVs) exhibit inherently efficient delivery to the liver and can be engineered to carry various therapeutic substances, making them promising agents. In this study, EVs were engineered to display fibroblast growth factor 21 (FGF21) on their surface and encapsulate miR-223 (223/F-EVs), aiming to improve steatosis and alleviate inflammation and fibrosis, respectively. Introducing the 223/F-EVs into human liver cell lines significantly reduced both basal and induced levels of lipid storage, inflammation, and fibrosis markers. Furthermore, using an FGF21-blocking antibody or miR-223 inhibitor effectively diminished the efficacy of the 223/F-EVs, confirming the essential roles of FGF21 and miR-223 in these processes. In a Choline-Deficient, L-Amino acid-defined, High-Fat Diet (CDAHFD)-fed mouse model, intravenously administered 223/F-EVs demonstrated liver-preferential delivery and a marked reduction in the MASH phenotype without compromising bone density, unlike conventional FGF21 treatment. Collectively, 223/F-EVs convey FGF21 and miR-223 exclusively to the liver, offering strategic advantages by mitigating MASH progression via multiple pathways. This study lays a solid foundation for further investigation of engineered EVs as a transformative therapeutic approach for treating MASH. © 2025 Elsevier Ltd 2025-09-30T15:00:00Z https://scholar.dgist.ac.kr/handle/20.500.11750/57386 Title: Exploring Renal Pyruvate Metabolism as a Therapeutic Avenue for Diabetic Kidney Injury Author(s): Lee, Jaemin Abstract: [No Abstract Available] 2024-04-30T15:00:00Z https://scholar.dgist.ac.kr/handle/20.500.11750/56936 Title: ER stress and unfolded protein response (UPR) signaling modulate GLP-1 receptor signaling in the pancreatic islets Author(s): Gao, Yurong; Ryu, Hanguk; Lee, Hyejin; Kim, Young-Joon; Lee, Ji-Hye; Lee, Jaemin Abstract: Insulin is essential for maintaining normoglycemia and is predominantly secreted in response to glucose stimulation by β-cells. Incretin hormones, such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide, also stimulate insulin secretion. However, as obesity and type 2 diabetes worsen, glucose-dependent insulinotropic polypeptide loses its insulinotropic efficacy, whereas GLP-1 receptor (GLP-1R) agonists continue to be effective owing to its signaling switch from Gs to Gq. Herein, we demonstrated that endoplasmic reticulum (ER) stress induced a transition from Gs to Gq in GLP-1R signaling in mouse islets. Intriguingly, chemical chaperones known to alleviate ER stress, such as 4-PBA and TUDCA, enforced GLP-1R's Gq utilization rather than reversing GLP-1R's signaling switch induced by ER stress or obese and diabetic conditions. In addition, the activation of X-box binding protein 1 (XBP1) or activating transcription factor 6 (ATF6), 2 key ER stress-associated signaling (unfolded protein response) factors, promoted Gs utilization in GLP-1R signaling, whereas Gq employment by ER stress was unaffected by XBP1 or ATF6 activation. Our study revealed that ER stress and its associated signaling events alter GLP-1R's signaling, which can be used in type 2 diabetes treatment. © 2023 The Authors 2023-12-31T15:00:00Z