Browsing by Author "Kim, Hyeong-Geug"
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Item Biomarkers of Oxidative Stress and Endogenous Antioxidants for Patients with Chronic Subjective Dizziness(Nature Research, 2020-01-30) Fang, Zhigang; Huang, Keer; Gil, Chang-Hyun; Jeong, Jin-Woo; Yoo, Ho-Ryong; Kim, Hyeong-Geug; Biochemistry and Molecular Biology, School of MedicineAs a neurotologic disorder of persistent non-vertiginous dizziness, chronic subjective dizziness (CSD) arises unsteadily by psychological and physiological imbalance. The CSD is hypersensitivity reaction due to exposure to complex motions visual stimuli. However, the pathophysiological features and mechanism of the CSD still remains unclearly. The present study was purposed to establish possible endogenous contributors of the CSD using serum samples from patients with the CSD. A total 199 participants were gathered and divided into two groups; healthy (n = 152, male for 61, and female for 91) and CSD (n = 47, male for 5, female for 42), respectively. Oxidative stress parameters such as, hydrogen peroxide and reactive substances were significantly elevated (p < 0.01 or p < 0.001), whereas endogenous antioxidant components including total glutathione contents, and activities of catalase and superoxide dismutase were significantly deteriorated in the CSD group (p < 0.01 or p < 0.001) as comparing to the healthy group, respectively. Serum levels of tumor necrosis factor -α and interferon-γ were significantly increased in the CSD participants (p < 0.001). Additionally, emotional stress related hormones including cortisol, adrenaline, and serotonin were abnormally observed in the serum levels of the CSD group (p < 0.01 or p < 0.001). Our results confirmed that oxidative stress and antioxidants are a critical contributor of pathophysiology of the CSD, and that is first explored to establish features of redox system in the CSD subjects compared to a healthy population.Item Discordant regulation of eIF2 kinase GCN2 and mTORC1 during nutrient stress(Oxford University Press, 2021-06-04) Misra, Jagannath; Holmes, Michael J.; Mirek, Emily T.; Langevin, Michael; Kim, Hyeong-Geug; Carlson, Kenneth R.; Watford, Malcolm; Dong, X. Charlie; Anthony, Tracy G.; Wek, Ronald C.; Biochemistry and Molecular Biology, School of MedicineAppropriate regulation of the Integrated stress response (ISR) and mTORC1 signaling are central for cell adaptation to starvation for amino acids. Halofuginone (HF) is a potent inhibitor of aminoacylation of tRNAPro with broad biomedical applications. Here, we show that in addition to translational control directed by activation of the ISR by general control nonderepressible 2 (GCN2), HF increased free amino acids and directed translation of genes involved in protein biogenesis via sustained mTORC1 signaling. Deletion of GCN2 reduced cell survival to HF whereas pharmacological inhibition of mTORC1 afforded protection. HF treatment of mice synchronously activated the GCN2-mediated ISR and mTORC1 in liver whereas Gcn2-null mice allowed greater mTORC1 activation to HF, resulting in liver steatosis and cell death. We conclude that HF causes an amino acid imbalance that uniquely activates both GCN2 and mTORC1. Loss of GCN2 during HF creates a disconnect between metabolic state and need, triggering proteostasis collapse.Item Ethyl Acetate Fraction of Amomum villosum var. xanthioides Attenuates Hepatic Endoplasmic Reticulum Stress-Induced Non-Alcoholic Steatohepatitis via Improvement of Antioxidant Capacities(MDPI, 2021-06-23) Cho, Jung-Hyo; Lee, Jong-Suk; Kim, Hyeong-Geug; Lee, Hye Won; Fang, Zhigang; Kwon, Hyeok-Hee; Kim, Dong Woon; Lee, Chang-Min; Jeong, Jin-Woo; Biochemistry and Molecular Biology, School of MedicineNon-alcoholic fatty liver disease (NAFLD), including non-alcoholic steatohepatitis (NASH), affects 25% of the global population. Despite the prevalence of NAFLD worldwide, effective therapeutics are currently lacking. Amomum villosum var. xanthioides (Wall. ex Baker) T.L.Wu & S.J.Chen (AX) is a medicinal herb traditionally used for treating digestive tract disorders in countries across Asia. We aimed to examine the pharmacological effects of the ethyl acetate fraction of AX (AXEF) against tunicamycin (TM)-induced ER stress in a NASH mouse model using C57/BL6J male mice. Following TM injections (2 mg/kg), the mice were orally administrated AXEF (12.5, 25, or 50 mg/kg), silymarin (50 mg/kg), or distilled water daily for 5 days, and the outcomes for fatty liver, inflammation, and oxidative stress were measured in serum or liver tissue levels. AXEF drastically attenuated hepatic ER stress-induced NASH as indicated by decreases in lipid droplet accumulations, serum liver enzymes, hepatic inflammations, and cell death signals in the hepatic tissue and/or serum levels. Interestingly, AXEF showed potent antioxidant effects by quenching reactive oxidative stress and its final product lipid peroxide in the hepatic tissue, specifically an increase in metallothionein (MT). To confirm the underlying actions of AXEF, we observed that AXEF increases MT1 gene promoter activities in the physiological levels. Collectively, AXEF showed antioxidant properties on TM-induced ER stress in a NASH mice model through the improvement of MTs.Item FOXO transcription factors protect against the diet-induced fatty liver disease(SpringerNature, 2017-03-16) Pan, Xiaoyan; Zhang, Yang; Kim, Hyeong-Geug; Liangpunsakul, Suthat; Dong, X. Charlie; Department of Biochemistry & Molecular Biology, IU School of MedicineForkhead O transcription factors (FOXOs) have been implicated in glucose and lipid homeostasis; however, the role of FOXOs in the development of nonalcoholic fatty liver disease (NAFLD) is not well understood. In this study, we designed experiments to examine the effects of two different diets-very high fat diet (HFD) and moderately high fat plus cholesterol diet (HFC)-on wildtype (WT) and liver-specific Foxo1/3/4 triple knockout mice (LTKO). Both diets induced severe hepatic steatosis in the LTKO mice as compared to WT controls. However, the HFC diet led to more severe liver injury and fibrosis compared to the HFD diet. At the molecular levels, hepatic Foxo1/3/4 deficiency triggered a significant increase in the expression of inflammatory and fibrotic genes including Emr1, Ccl2, Col1a1, Tgfb, Pdgfrb, and Timp1. Thus, our data suggest that FOXO transcription factors play a salutary role in the protection against the diet-induced fatty liver disease.Item GCN2 eIF2 kinase promotes prostate cancer by maintaining amino acid homeostasis(eLife Sciences, 2022-09-15) Cordova, Ricardo A.; Misra, Jagannath; Amin, Parth H.; Klunk, Anglea J.; Damayanti, Nur P.; Carlson, Kenneth R.; Elmendorf, Andrew J.; Kim, Hyeong-Geug; Mirek, Emily T.; Elzey, Bennet D.; Miller, Marcus J.; Dong, X. Charlie; Cheng, Liang; Anthony, Tracy G.; Pili, Roberto; Wek, Ronald C.; Staschke, Kirk A.; Biochemistry and Molecular Biology, School of MedicineA stress adaptation pathway termed the integrated stress response has been suggested to be active in many cancers including prostate cancer (PCa). Here, we demonstrate that the eIF2 kinase GCN2 is required for sustained growth in androgen-sensitive and castration-resistant models of PCa both in vitro and in vivo, and is active in PCa patient samples. Using RNA-seq transcriptome analysis and a CRISPR-based phenotypic screen, GCN2 was shown to regulate expression of over 60 solute-carrier (SLC) genes, including those involved in amino acid transport and loss of GCN2 function reduces amino acid import and levels. Addition of essential amino acids or expression of 4F2 (SLC3A2) partially restored growth following loss of GCN2, suggesting that GCN2 targeting of SLC transporters is required for amino acid homeostasis needed to sustain tumor growth. A small molecule inhibitor of GCN2 showed robust in vivo efficacy in androgen-sensitive and castration-resistant mouse models of PCa, supporting its therapeutic potential for the treatment of PCa.Item KDM2A Deficiency in the Liver Promotes Abnormal Liver Function and Potential Liver Damage(MDPI, 2023-09-27) Martin, Matthew; Motolani, Aishat; Kim, Hyeong-Geug; Collins, Amy M.; Alipourgivi, Faranak; Jin, Jiamin; Wei, Han; Wood, Barry A.; Ma, Yao-Ying; Dong, X. Charlie; Mirmira, Raghavendra G.; Lu, Tao; Pharmacology and Toxicology, School of MedicineDysregulation of metabolic functions in the liver impacts the development of diabetes and metabolic disorders. Normal liver function can be compromised by increased inflammation via the activation of signaling such as nuclear factor (NF)-κB signaling. Notably, we have previously identified lysine demethylase 2A (KDM2A)—as a critical negative regulator of NF-κB. However, there are no studies demonstrating the effect of KDM2A on liver function. Here, we established a novel liver-specific Kdm2a knockout mouse model to evaluate KDM2A’s role in liver functions. An inducible hepatic deletion of Kdm2a, Alb-Cre-Kdm2afl/fl (Kdm2a KO), was generated by crossing the Kdm2a floxed mice (Kdm2afl/fl) we established with commercial albumin-Cre transgenic mice (B6.Cg-Tg(Alb-cre)21Mgn/J). We show that under a normal diet, Kdm2a KO mice exhibited increased serum alanine aminotransferase (ALT) activity, L-type triglycerides (TG) levels, and liver glycogen levels vs. WT (Kdm2afl/fl) animals. These changes were further enhanced in Kdm2a liver KO mice in high-fat diet (HFD) conditions. We also observed a significant increase in NF-κB target gene expression in Kdm2a liver KO mice under HFD conditions. Similarly, the KO mice exhibited increased immune cell infiltration. Collectively, these data suggest liver-specific KDM2A deficiency may enhance inflammation in the liver, potentially through NF-κB activation, and lead to liver dysfunction. Our study also suggests that the established Kdm2afl/fl mouse model may serve as a powerful tool for studying liver-related metabolic diseases.Item Pharmacological Properties of Jaeumgeonbi-Tang on Redox System and Stress-Related Hormones in Chronic Subjective Dizziness: A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Trial(MDPI, 2022-11-09) Kim, Chan-young; Kim, Hyeong-Geug; Lee, Hye Won; Seol, In-Chan; Kim, Yoon-Sik; Choi, Hyung Il; Park, Miso S.; Yoo, Ho-Ryong; Biochemistry and Molecular Biology, School of MedicineJaeumgeonbi-Tang (JGT), a traditional herbal medicine, has been used to treat dizziness and vertigo in Korea and China for hundreds of years. The purpose of this study was to evaluate the pharmacological properties of JGT in chronic subjective dizziness (CSD) patients. A randomized, double-blind, parallel-group and placebo-controlled trial was performed with a total of 50 CSD patients. The patients were randomly assigned to one of two groups: JGT or placebo (n = 25 for each). All participants received the treatment (placebo or JGT, 24 g/day) for 4 weeks. We analyzed the serum levels of oxidative stressors, antioxidants, and stress hormones. Serum levels of lipid peroxidation, but not nitric oxide, were significantly decreased in the JGT group. JGT not only prevented the decline of serum total glutathione contents and total antioxidant capacity, but it also increased superoxide dismutase and catalase activities. Serum levels of stress hormones including cortisol, adrenaline, and serotonin were notably normalized by JGT treatment, but noradrenaline levels were not affected. Regarding the safety and tolerability of JGT, we found no allergic, adverse, or side effects in any of the participants. JGT showed beneficial effects on CSD patients by improving redox status and balancing psycho-emotional stress hormones.Item Sestrin Proteins Protect Against Lipotoxicity-Induced Oxidative Stress in the Liver via Suppression of C-Jun N-Terminal Kinases(Elsevier, 2021) Fang, Zhigang; Kim, Hyeong-Geug; Huang, Menghao; Chowdhury, Kushan; Li, Ming O.; Liangpunsakul, Suthat; Dong, X. Charlie; Biochemistry and Molecular Biology, School of MedicineBackground & aims: Sestrin 1/2/3 (Sesn1/2/3) belong to a small family of proteins that have been implicated in the regulation of metabolic homeostasis and oxidative stress. However, the underlying mechanisms remain incompletely understood. The aim of this work was to illustrate the collective function of Sesn1/2/3 in the protection against hepatic lipotoxicity. Methods: We used Sesn1/2/3 triple knockout (TKO) mouse and cell models to characterize oxidative stress and signal transduction under lipotoxic conditions. Biochemical, histologic, and physiological approaches were applied to illustrate the related processes. Results: After feeding with a Western diet for 8 weeks, TKO mice developed remarkable metabolic associated fatty liver disease that was manifested by exacerbated hepatic steatosis, inflammation, and fibrosis compared with wild-type counterparts. Moreover, TKO mice exhibited higher levels of hepatic lipotoxicity and oxidative stress. Our biochemical data revealed a critical signaling node from sestrins to c-Jun N-terminal kinases (JNKs) in that sestrins interact with JNKs and mitogen-activated protein kinase kinase 7 and suppress the JNK phosphorylation and activity. In doing so, sestrins markedly reduced palmitate-induced lipotoxicity and oxidative stress in both mouse and human hepatocytes. Conclusions: The data from this study suggest that Sesn1/2/3 play an important role in the protection against lipotoxicity-associated oxidative stress and related pathology in the liver.Item SIRT6 controls hepatic lipogenesis by suppressing LXR, ChREBP, and SREBP1(Elsevier, 2021) Zhu, Chaoyu; Huang, Menghao; Kim, Hyeong-Geug; Chowdhury, Kushan; Gao, Jing; Liu, Sheng; Wan, Jun; Wei, Li; Dong, X. Charlie; Biochemistry and Molecular Biology, School of MedicineFatty liver disease is the most prevalent chronic liver disorder, which is manifested by hepatic triglyceride elevation, inflammation, and fibrosis. Sirtuin 6 (Sirt6), an NAD+-dependent deacetylase, has been implicated in hepatic glucose and lipid metabolism; however, the underlying mechanisms are incompletely understood. The aim of this study was to identify and characterize novel players and mechanisms that are responsible for the Sirt6-mediated metabolic regulation in the liver. We generated and characterized Sirt6 liver-specific knockout mice regarding its role in the development of fatty liver disease. We used cell models to validate the molecular alterations observed in the animal models. Biochemical and molecular biological approaches were used to illustrate protein-protein interactions and gene regulation. Our data show that Sirt6 liver-specific knockout mice develop more severe fatty liver disease than wild-type mice do on a Western diet. Hepatic Sirt6 deficiency leads to elevated levels and transcriptional activities of carbohydrate response element binding protein (ChREBP) and sterol regulatory element binding protein 1 (SREBP1). Mechanistically, our data reveal protein-protein interactions between Sirt6 and liver X receptor α (LXRα), ChREBP, or SREBP1c in hepatocytes. Moreover, Sirt6 suppresses transcriptional activities of LXRα, ChREBP, and SREBP1c through direct deacetylation. In conclusion, this work has identified a key mechanism that is responsible for the salutary function of Sirt6 in the inhibition of hepatic lipogenesis by suppressing LXR, ChREBP, and SREBP1.Item SIRT6 Protects Against Liver Fibrosis by Deacetylation and Suppression of SMAD3 in Hepatic Stellate Cells(Elsevier, 2020-04-17) Zhong, Xiaolin; Huang, Menghao; Kim, Hyeong-Geug; Zhang, Yang; Chowdhury, Kushan; Cai, Wenjie; Saxena, Romil; Schwabe, Robert F.; Liangpunsakul, Suthat; Dong, X. Charlie; Biochemistry and Molecular Biology, School of Medicine