453 results on '"Ha, Hunjoo"'
Search Results
152. High Glucose Increases Inducible NO Production in Cultured Rat Mesangial Cells
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Noh, Hyunjin, primary, Ha, Hunjoo, additional, Yu, Mi Ra, additional, Kang, Shin Wook, additional, Choi, Kyu Hun, additional, Han, Dae Suk, additional, and Lee, Ho Yung, additional
- Published
- 2001
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153. Biocompatibility of New Peritoneal Dialysis Solutions
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Lee, Hi Bahl, primary, Ha, Hunjoo, additional, and Lindholm, Bengt, additional
- Published
- 2000
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154. Effects of Conventional and New Peritoneal Dialysis Solutions on Human Peritoneal Mesothelial Cell Viability and Proliferation
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Ha, Hunjoo, primary, Yu, Mi Ra, additional, Choi, Hoo Nam, additional, Cha, Mi Kyung, additional, Kang, Hyun Seung, additional, Kim, Mi Ho, additional, and Lee, Hi Bahl, additional
- Published
- 2000
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155. Effect of High Glucose on Peritoneal Mesothelial Cell Biology
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Ha, Hunjoo, primary and Lee, Hi Bahl, additional
- Published
- 2000
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156. Synthesis and Anti-Renal FibrosisActivity of ConformationallyLocked Truncated 2-Hexynyl-N6-Substituted-(N)-Methanocarba-nucleosidesas A3Adenosine Receptor Antagonists and Partial Agonists.
- Author
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Nayak, Akshata, Chandra, Girish, Hwang, Inah, Kim, Kyunglim, Hou, Xiyan, Kim, Hea Ok, Sahu, Pramod K., Roy, Kuldeep K., Yoo, Jakyung, Lee, Yoonji, Cui, Minghua, Choi, Sun, Moss, Steven M., Phan, Khai, Gao, Zhan-Guo, Ha, Hunjoo, Jacobson, Kenneth A., and Jeong, Lak Shin
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- 2014
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157. Future of Interventions in Diabetic Nephropathy: Antioxidants
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Ha, Hunjoo, primary and Kim, Kyung H., additional
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- 1999
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158. A High Glucose Concentration Stimulates the Expression of Monocyte Chemotactic Peptide 1 in Human Mesangial Cells
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Ihm, Chun-Gyoo, primary, Park, Jae-Kyung, additional, Hong, Seong-Pyo, additional, Lee, Tae-Won, additional, Cho, Byoung-Soo, additional, Kim, Myung-Jae, additional, Cha, Dae-Ryong, additional, and Ha, Hunjoo, additional
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- 1998
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159. High glucose can induce lipid peroxidation in the isolated rat glomeruli
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Ha, Hunjoo, primary, Yoon, Suck Jong, additional, and Kim, Kyung Hwan, additional
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- 1994
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160. Amelioration of diabetic microalbuminuria and lipid peroxidation by captopril
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Ha, HunJoo, primary and Kim, Kyung Hwan, additional
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- 1992
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161. Determination of daumone in mouse plasma by HPLC/MS-MS.
- Author
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Noh, Keumhan, Park, Jong Hee, Kim, Minkyu, Jung, Mankil, Lee, Hwa Jeong, Kwon, Kwang-il, Kang, Wonku, and Ha, Hunjoo
- Abstract
ABSTRACT Daumone, a pheromone secreted by Caenorhabditis elegans, is an essential regulator of chemosensory processes in development and aging. A quantification method using HPLC/MS-MS was developed for the determination of daumone in mouse plasma. After simple protein precipitation with acetonitrile including methaqualone (an internal standard), the analytes were chromatographed on a reversed-phase column and detected by liquid chromatography/tandem mass spectrometry with electrospray ionization. The accuracy and precision of the assay were in accordance with FDA regulations for validation of bioanalytical methods. This method was applied to measure the plasma daumone concentrations following a 5-week repeated oral administration of daumone in mice. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]
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- 2012
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162. Fractional mictopuncture studies of filtration and reabsorption of albumin and low-molecular-weight proteins (LMWP) in rat kidney.
- Author
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Tojo, Akihiro, primary, Ha, Hunjoo, additional, and Endou, Hitoshi, additional
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- 1991
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163. Carvedilol Inhibits Platelet-Derived Growth Factor-Induced Extracellular Matrix Synthesis by Inhibiting Cellular Reactive Oxygen Species and Mitogen-Activated Protein Kinase Activation
- Author
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Park, Jehyun, Ha, Hunjoo, Kim, Myoung Soo, Ahn, Hyung Joon, Huh, Kyu Ha, and Kim, Yu Seun
- Subjects
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ANTIHYPERTENSIVE agents , *CARDIOVASCULAR agents , *PLATELET-derived growth factor , *BLOOD proteins , *GROWTH factors , *HOMOGRAFTS - Abstract
Background: Vascular smooth muscle cell (VSMC) proliferation, migration, and extracellular matrix (ECM) synthesis are major pathologic features of chronic allograft vasculopathy. Carvedilol, an anti-hypertensive agent, might be an effective agent for preventing the development and progression of chronic allograft vasculopathy, since it can inhibit VSMC proliferation and migration. The present study was designed to examine the effect of carvedilol on platelet-derived growth factor (PDGF)-induced ECM synthesis in rat VSMCs. Furthermore, we evaluated whether carvedilol inhibits PDGF-induced cellular reactive oxygen species (ROS) and the activation of mitogen-activated protein kinase (MAPK). Methods: Primary cultured rat VSMCs were stimulated with PDGF-BB (10 ng/ml) in the presence or absence of carvedilol, and the effects of carvedilol were compared with those of ROS or MAPK inhibitors. Fibronectin secretion, proliferating cell nuclear antigen (PCNA) expression, and each MAPK activation were determined by Western blot analysis, total collagen synthesis by [3H]-proline incorporation, and cellular ROS by flow cytometry. Results: PDGF significantly increased PCNA expression, fibronectin secretion, total collagen synthesis, cellular ROS, and MAPK activation in rat VSMCs. Carvedilol at doses that inhibited PDGF-induced cell proliferation, inhibited ECM synthesis, cellular ROS, or subsequent MAPK activation. Structurally different anti-oxidants and extracellular signal-regulated protein kinase or p38 MAPK inhibitor effectively inhibited PDGF-induced fibronectin secretion and total collagen synthesis. Conclusions: These results suggest that carvedilol inhibits PDGF-induced VSMC proliferation and matrix protein synthesis by inhibiting cellular ROS and the subsequent activation of MAPK. Thus the targeted inhibition of cellular ROS and MAPK might provide an effective therapeutic strategy to treat chronic allograft vasculopathy. [Copyright &y& Elsevier]
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- 2006
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164. Dual Actions of A 2A and A 3 Adenosine Receptor Ligand Prevents Obstruction-Induced Kidney Fibrosis in Mice.
- Author
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Pak, Eun Seon, Jeong, Lak Shin, Hou, Xiyan, Tripathi, Sushil K., Lee, Jiyoun, and Ha, Hunjoo
- Subjects
RENAL fibrosis ,ADENOSINES ,LABORATORY mice ,CHRONIC kidney failure ,REACTIVE oxygen species ,URETERIC obstruction - Abstract
Kidney fibrosis is the final outcome of chronic kidney disease (CKD). Adenosine plays a significant role in protection against cellular damage by activating four subtypes of adenosine receptors (ARs), A
1 AR, A2A AR, A2B AR, and A3 AR. A2A AR agonists protect against inflammation, and A3 AR antagonists effectively inhibit the formation of fibrosis. Here, we showed for the first time that LJ-4459, a newly synthesized dual-acting ligand that is an A2A AR agonist and an A3 AR antagonist, prevents the progression of tubulointerstitial fibrosis. Unilateral ureteral obstruction (UUO) surgery was performed on 6-week-old male C57BL/6 mice. LJ-4459 (1 and 10 mg/kg) was orally administered for 7 days, started at 1 day before UUO surgery. Pretreatment with LJ-4459 improved kidney morphology and prevented the progression of tubular injury as shown by decreases in urinary kidney injury molecular-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) excretion. Obstruction-induced tubulointerstitial fibrosis was attenuated by LJ-4459, as shown by a decrease in fibrotic protein expression in the kidney. LJ-4459 also inhibited inflammation and oxidative stress in the obstructed kidney, with reduced macrophage infiltration, reduced levels of pro-inflammatory cytokines, as well as reduced levels of reactive oxygen species (ROS). These data demonstrate that LJ-4459 has potential as a therapeutic agent against the progression of tubulointerstitial fibrosis. [ABSTRACT FROM AUTHOR]- Published
- 2021
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165. High Glucose Increases Inducible NO Production in Cultured Rat Mesangial Cells
- Author
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Noh, Hyunjin, Ha, Hunjoo, Yu, Mi Ra, Kang, Shin Wook, Choi, Kyu Hun, Han, Dae Suk, and Lee, Ho Yung
- Abstract
Background/Aim:Increased nitric oxide (NO) generation and action have been suggested to be associated with glomerular hyperfiltration and increased vascular permeability early in diabetes. However, previous studies have primarily focused on the constitutive nitric oxide synthase (cNOS) pathway present in endothelial cells, and the role of the inducible NOS (iNOS) pathway in diabetic nephropathy has remained unclear. This study examined whether high glucose modulates NO synthesis by the iNOS pathway in rat mesangial cells. In addition, the effect of inhibition of the iNOS pathway on fibronectin production was determined to examine the role of the iNOS pathway in high glucose-induced extracellular expansion by mesangial cells. Methods:NO synthesis by the iNOS pathway was evaluated by nitrite and iNOS mRNA and protein productions. The effects of protein kinase C (PKC) inhibitor and aldose reductase inhibitor on the iNOS mRNA expression and aminoguanidine, a relatively specific inhibitor of the iNOS on fibronectin protein production were examined. Results:High 30 mMglucose concentration led to significant increases in nitrite production of rat mesangial cells upon stimulation with lipopolysaccharide (LPS) plus interferon-γ (IFN-γ) compared with control 5.6 mMglucose concentration. Mesangial iNOS mRNA expression and protein production also increased significantly in response to high glucose. The addition of calphostin C, a PKC inhibitor, and 6-bromo-1,3-dioxo-1H-benz[d,e]isoquinoline-2(3H)-acetic acid, an aldose reductase inhibitor, significantly suppressed the enhancement of iNOS mRNA expression in high glucose concentration. High glucose also significantly increased fibronectin protein production of mesangial cells upon stimulation with LPS plus IFN-γ compared to control glucose. Aminoguanidine reversed this high glucose-induced fibronectin production at dose inhibiting iNOS mRNA expression. Conclusions:These results indicate that high glucose enhances cytokine-induced NO production by rat mesangial cells, and that the activation of PKC and aldose reductase pathway may play a role in this enhancement. In addition, high glucose-induced NO production by the iNOS pathway may promote extracellular matrix accumulation by mesangial cells under certain condition.
- Published
- 2002
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166. Prospects of Marine Sterols against Pathobiology of Alzheimer's Disease: Pharmacological Insights and Technological Advances.
- Author
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Rahman, Md. Ataur, Dash, Raju, Sohag, Abdullah Al Mamun, Alam, Mahboob, Rhim, Hyewhon, Ha, Hunjoo, Moon, Il Soo, Uddin, Md Jamal, Hannan, Md. Abdul, Rauter, Amélia Pilar, and Bandarra, Narcisa M.
- Abstract
Alzheimer's disease (AD) is a degenerative brain disorder characterized by a progressive decline in memory and cognition, mostly affecting the elderly. Numerous functional bioactives have been reported in marine organisms, and anti-Alzheimer's agents derived from marine resources have gained attention as a promising approach to treat AD pathogenesis. Marine sterols have been investigated for several health benefits, including anti-cancer, anti-obesity, anti-diabetes, anti-aging, and anti-Alzheimer's activities, owing to their anti-inflammatory and antioxidant properties. Marine sterols interact with various proteins and enzymes participating via diverse cellular systems such as apoptosis, the antioxidant defense system, immune response, and cholesterol homeostasis. Here, we briefly overview the potential of marine sterols against the pathology of AD and provide an insight into their pharmacological mechanisms. We also highlight technological advances that may lead to the potential application of marine sterols in the prevention and therapy of AD. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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167. Associations of Circulating Irisin with FNDC5 Expression in Fat and Muscle in Type 1 and Type 2 Diabetic Mice.
- Author
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Jiang, Songling, Piao, Lingjuan, Ma, Eun Bi, Ha, Hunjoo, and Huh, Joo Young
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FAT ,METABOLIC regulation ,MICE ,HIGH-fat diet ,METABOLIC disorders - Abstract
Irisin is an exercise-induced myokine, suggested to exert beneficial effects on metabolism. However, the studies on the regulation of irisin secretion and the expression of its precursor FNDC5 have shown conflicting data. The discrepancies among previous correlation studies in humans are related to the heterogeneity of the study population. The fact that irisin is not only a myokine but also an adipokine leads to the further complexity of the role of irisin in metabolic regulation. In this study, we examined the regulation of FNDC5 expression and irisin in circulation in both type 1 and type 2 diabetic mice, and their potential relationships with metabolic parameters. In streptozotocin (STZ)-induced type 1 diabetic mice, high-fat diet (HFD)-induced obese mice and db/db mice, the circulating irisin as well as FNDC5 gene expression in subcutaneous fat was downregulated. Muscle FNDC5 expression was only significantly lower in STZ mice, and epididymal fat FNDC5 expression was unaltered. It is interesting to note that plasma irisin levels correlated positively with subcutaneous fat FNDC5 expression, but not epididymal fat or muscle. Moreover, both irisin levels and subcutaneous fat FNDC5 correlated negatively with markers of insulin resistance. These results suggest a regulatory role for subcutaneous fat-derived FNDC5/irisin in metabolic disease. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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168. Pharmacotherapy against Oxidative Stress in Chronic Kidney Disease: Promising Small Molecule Natural Products Targeting Nrf2-HO-1 Signaling.
- Author
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Uddin, Md Jamal, Kim, Ee Hyun, Hannan, Md. Abdul, Ha, Hunjoo, Jung, Yi-Sook, and Shim, Sang Hee
- Subjects
CHRONIC kidney failure ,NATURAL products ,OXIDATIVE stress ,ANIMAL disease models ,KIDNEY diseases - Abstract
The global burden of chronic kidney disease (CKD) intertwined with cardiovascular disease has become a major health problem. Oxidative stress (OS) plays an important role in the pathophysiology of CKD. The nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant responsive element (ARE) antioxidant system plays a critical role in kidney protection by regulating antioxidants during OS. Heme oxygenase-1 (HO-1), one of the targets of Nrf2-ARE, plays an important role in regulating OS and is protective in a variety of human and animal models of kidney disease. Thus, activation of Nrf2-HO-1 signaling may offer a potential approach to the design of novel therapeutic agents for kidney diseases. In this review, we have discussed the association between OS and the pathogenesis of CKD. We propose Nrf2-HO-1 signaling-mediated cell survival systems be explored as pharmacological targets for the treatment of CKD and have reviewed the literature on the beneficial effects of small molecule natural products that may provide protection against CKD. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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169. Dojuksan ameliorates tubulointerstitial fibrosis through irisin-mediated muscle-kidney crosstalk.
- Author
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Jiang, Songling, Oh, Dal-Seok, Dorotea, Debra, Son, Eunjung, Kim, Dong-Seon, and Ha, Hunjoo
- Abstract
Background: Sarcopenia progresses in chronic kidney disease (CKD) and is positively correlated with mortality in end-stage kidney disease patients. Circulating irisin, an exercise-induced myokine, gradually decreases during CKD stage progression. Irisin inhibits the progression of kidney fibrosis, which is the final common outcome of CKD. Our preliminary study with C2C12 cells showed that Dojuksan, a herbal decoction, increases the expression of PGC1α (a regulator of irisin) and FNDC5 (a precursor of irisin).Hypothesis: Dojuksan may increase circulating irisin and prevent the progression of kidney fibrosis.Study Design and Methods: Unilateral ureteral obstruction (UUO) was performed on seven-week-old male C57BL/6 mice to induce kidney tubulointerstitial fibrosis. Dojuksan (50, 100, or 200 mg/kg/day) or losartan (1.5 mg/kg/day), a standard clinical treatment for CKD, was administered orally one day prior to surgery and continued for seven days thereafter. To determine the role of irisin released from muscles, TGFβ-stimulated murine proximal tubular epithelial cells (mProx24 cells) were treated with conditioned media (CM) from Dojuksan-treated C2C12 muscle cells transfected with FNDC5 siRNA.Results: UUO mice exhibited muscle wasting along with progressive kidney injury. Similar to losartan, Dojuksan ameliorated kidney inflammation and fibrosis in UUO mice. Dojuksan, but not losartan, increased plasma irisin concentration in UUO mice. Dojuksan significantly increased basal FNDC5 expression and inhibited TNFα-induced and indoxyl sulfate-induced FNDC5 down-regulation in C2C12 cells. The TGFβ-induced collagen I (COL1) up-regulation in mProx24 cells was effectively inhibited by CM from C2C12 cells after Dojuksan treatment. Moreover, irisin inhibited TGFβ-induced COL1 in mProx24 cells, which was not affected by CM from C2C12 cells transfected with FNDC5 siRNA.Conclusion: Dojuksan ameliorates kidney fibrosis through irisin-mediated muscle-kidney crosstalk, suggesting that Dojuksan may be used as an alternative therapeutic agent against CKD. [ABSTRACT FROM AUTHOR]- Published
- 2021
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170. Inhibition of Src Family Kinases Ameliorates LPS-Induced Acute Kidney Injury and Mitochondrial Dysfunction in Mice.
- Author
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Pak, Eun Seon, Uddin, Md Jamal, and Ha, Hunjoo
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ACUTE kidney failure ,LIPOPOLYSACCHARIDES ,KIDNEY injuries ,KINASES ,TREATMENT effectiveness ,EPITHELIAL cells - Abstract
Acute kidney injury (AKI), a critical syndrome characterized by a rapid decrease of kidney function, is a global health problem. Src family kinases (SFK) are proto-oncogenes that regulate diverse biological functions including mitochondrial function. Since mitochondrial dysfunction plays an important role in the development of AKI, and since unbalanced SFK activity causes mitochondrial dysfunction, the present study examined the role of SFK in AKI. Lipopolysaccharides (LPS) inhibited mitochondrial biogenesis and upregulated the expression of NGAL, a marker of tubular epithelial cell injury, in mouse proximal tubular epithelial (mProx) cells. These alterations were prevented by PP2, a pan SFK inhibitor. Importantly, PP2 pretreatment significantly ameliorated LPS-induced loss of kidney function and injury including inflammation and oxidative stress. The attenuation of LPS-induced AKI by PP2 was accompanied by the maintenance of mitochondrial biogenesis. LPS upregulated SFK, especially Fyn and Src, in mouse kidney as well as in mProx cells. These data suggest that Fyn and Src kinases are involved in the pathogenesis of LPS-induced AKI, and that inhibition of Fyn and Src kinases may have a potential therapeutic effect, possibly via improving mitochondrial biogenesis. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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171. Where are we now in diabetic research?
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Kwak, Mi-Kyoung and Ha, Hunjoo
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- 2013
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172. Evaluation of Anti-Tumor Effects of Whole-Body Low-Dose Irradiation in Metastatic Mouse Models.
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Song, Kyung-Hee, Jung, Seung-Youn, Park, Jeong-In, Ahn, Jiyeon, Park, Jong-Kuk, Hwang, Sang-Gu, Kim, Eun-Ho, Nam, Seon Young, Park, Seungwoo, Ha, Hunjoo, and Song, Jie-Young
- Subjects
ANIMAL experimentation ,BIOLOGICAL models ,CELL lines ,LUNG tumors ,METASTASIS ,MICE ,RADIATION doses ,T cells ,TREATMENT effectiveness - Abstract
Low-dose irradiation (LDI) has recently been shown to have various beneficial effects on human health, such as on cellular metabolic activities, DNA repair, antioxidant activity, homeostasis potency, and immune activation. Although studies on the immunogenic effects of LDI are rapidly accumulating, clinical trials for cancer treatment are considered premature owing to the lack of available preclinical results and protocols. Here, we aim to investigate anti-tumor and anti-metastatic effects of whole-body LDI in several tumor-bearing mouse models. Mice were exposed to single or fractionated whole-body LDI prior to tumor transplantation, and tumor growth and metastatic potential were determined, along with analysis of immune cell populations and expression of epithelial–mesenchymal transition (EMT) markers. Whole-body fractionated-LDI decreased tumor development and lung metastasis not only by infiltration of CD4
+ , CD8+ T-cells, and dendritic cells (DCs) but also by attenuating EMT. Moreover, a combination of whole-body LDI with localized high-dose radiation therapy reduced the non-irradiated abscopal tumor growth and increased infiltration of effector T cells and DCs. Therefore, whole-body LDI in combination with high-dose radiation therapy could be a potential therapeutic strategy for treating cancer. [ABSTRACT FROM AUTHOR]- Published
- 2020
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173. Urinary myo-inositol is associated with the clinical outcome in focal segmental glomerulosclerosis.
- Author
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An, Jung Nam, Hyeon, Jin Seong, Jung, Youngae, Choi, Young Wook, Kim, Jin Hyuk, Yang, Seung Hee, Oh, Sohee, Kwon, Soie, Lee, Sang-Ho, Cho, Jang-Hee, Park, Sun-Hee, Ha, Hunjoo, Kim, Dong Ki, Lee, Jung Pyo, and Hwang, Geum-Sook
- Subjects
FOCAL segmental glomerulosclerosis ,NUCLEAR magnetic resonance spectroscopy ,HISTOLOGY ,PATIENTS ,BIOPSY - Abstract
Focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) have similar initial histological findings; however, their prognoses are distinct. Therefore, it is of great importance to discriminate FSGS from MCD in the early phase of disease and predict clinical prognosis. A discovery set of 184 urine samples (61 healthy control, 80 MCD, and 43 FSGS) and a validation set of 61 urine samples (12 healthy control, 26 MCD, and 23 FSGS) were collected at the time of kidney biopsy. Metabolic profiles were examined using nuclear magnetic resonance spectroscopy. Of 70 urinary metabolites, myo-inositol was significantly higher in FSGS patients than in control patients (discovery set, 2.34-fold, P < 0.001; validation set, 2.35-fold, P = 0.008) and MCD patients (discovery set, 2.48-fold, P = 0.002; validation set, 1.69-fold, P = 0.042). Myo-inositol showed an inverse relationship with the initial estimated glomerular filtration rate (eGFR) and was associated with the plasma level of soluble urokinase-type plasminogen activator receptor in FSGS patients. Myo-inositol treatment ameliorated the decreased expression of ZO-1 and synaptopodin in an in vitro FSGS model, and as myo-inositol increased, myo-inositol oxygenase tissue expression decreased proportionally to eGFR. Furthermore, urinary myo-inositol exhibited an increase in the power to discriminate FSGS patients, and its addition could better predict the response to initial treatment. In conclusion, urinary myo-inositol may be an important indicator in the diagnosis and treatment of FSGS patients. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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174. Fumarate modulates phospholipase A2 receptor autoimmunity-induced podocyte injury in membranous nephropathy
- Author
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Jo, Hyung Ah, Hyeon, Jin Seong, Yang, Seung Hee, Jung, Youngae, Ha, Hunjoo, Jeong, Chang Wook, Kwak, Cheol, Kim, Yaerim, Lee, Hajeong, Lee, Jung Pyo, Joo, Kwon Wook, Lim, Chun Soo, Kim, Yon Su, Hwang, Geum-Sook, and Kim, Dong Ki
- Abstract
Downstream mechanisms that lead to podocyte injury following phospholipase A2 receptor (PLA2R) autoimmunity remain elusive. To help define this we compared urinary metabolomic profiles of patients with PLA2R-associated membranous nephropathy (MN) at the time of kidney biopsy with those of patients with minimal change disease (MCD) and to healthy individuals. Among the metabolites differentially expressed in patients with PLA2R-associated MN compared to healthy individuals, fumarate was the only significant differentially expressed metabolite in PLA2R-associated MN compared to MCD [fold-difference vs. healthy controls and vs. MCD: 1.76 and 1.60, respectively]. High urinary fumarate levels could predict the composite outcome of PLA2R-associated MN. Fumarate hydratase, which hydrolyzes fumarate, colocalized with podocalyxin, and its expression was lower in glomerular sections from patients with PLA2R-associated MN than in those from healthy individuals, patients with non-PLA2R-associated MN or MCD. Podocytes stimulated with IgG purified from serum with a high anti-PLA2R titer (MN-IgG) decreased expression of fumarate hydratase and increased fumarate levels. These changes were coupled to alterations in the expression of molecules involved in the phenotypic profile of podocytes (WT1, ZO-1, Snail, and fibronectin), an increase in albumin flux across the podocyte layer and the production of reactive oxygen species in podocytes. However, overexpression of fumarate hydratase ameliorated these alterations. Furthermore, knockdown of fumarate hydratase exhibited synergistic effects with MN-IgG treatment. Thus, fumarate may promote changes in the phenotypic profiles of podocytes after the development of PLA2R autoimmunity. These findings suggest that fumarate could serve as a potential target for the treatment of PLA2R-associated MN.
- Published
- 2021
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175. Network-based integrated analysis of omics data reveal novel players of TGF-β1-induced EMT in human peritoneal mesothelial cells.
- Author
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Han, Soo Min, Ryu, Hye-Myung, Suh, Jinjoo, Lee, Kong-Joo, Choi, Soon-Youn, Choi, Sangdun, Kim, Yong-Lim, Huh, Joo Young, and Ha, Hunjoo
- Abstract
Long-term peritoneal dialysis is associated with progressive fibrosis of the peritoneum. Epithelial-mesenchymal transition (EMT) of mesothelial cells is an important mechanism involved in peritoneal fibrosis, and TGF-β1 is considered central in this process. However, targeting currently known TGF-β1-associated pathways has not proven effective to date. Therefore, there are still gaps in understanding the mechanisms underlying TGF-β1-associated EMT and peritoneal fibrosis. We conducted network-based integrated analysis of transcriptomic and proteomic data to systemically characterize the molecular signature of TGF-β1-stimulated human peritoneal mesothelial cells (HPMCs). To increase the power of the data, multiple expression datasets of TGF-β1-stimulated human cells were employed, and extended based on a human functional gene network. Dense network sub-modules enriched with differentially expressed genes by TGF-β1 stimulation were prioritized and genes of interest were selected for functional analysis in HPMCs. Through integrated analysis, ECM constituents and oxidative stress-related genes were shown to be the top-ranked genes as expected. Among top-ranked sub-modules, TNFAIP6, ZC3H12A, and NNT were validated in HPMCs to be involved in regulation of E-cadherin, ZO-1, fibronectin, and αSMA expression. The present data shows the validity of network-based integrated analysis in discovery of novel players in TGF-β1-induced EMT in peritoneal mesothelial cells, which may serve as new prognostic markers and therapeutic targets for peritoneal dialysis patients. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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176. Orally active, species-independent novel A3 adenosine receptor antagonist protects against kidney injury in db/db mice.
- Author
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Dorotea, Debra, Cho, Ahreum, Lee, Gayoung, Kwon, Guideock, Lee, Junghwa, Sahu, Pramod K., Jeong, Lak Shin, Cha, Dae Ryong, and Ha, Hunjoo
- Published
- 2018
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177. Role of reactive oxygen species in the pathogenesis of diabetic nephropathy
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Ha, Hunjoo, Hwang, In-A, Park, Jong Hee, and Lee, Hi Bahl
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DIABETIC nephropathies , *OXYGEN in the body , *OXIDATIVE stress , *HYPERGLYCEMIA , *PROTEIN kinase C , *DIABETES complications , *THERAPEUTICS - Abstract
Abstract: There is an increasing evidence that reactive oxygen species (ROS) play a major role in the development of diabetic complications. Oxidative stress is increased in diabetes and the overproduction of ROS in diabetes is a direct consequence of hyperglycemia. Various types of vascular cells including renal cells are able to produce ROS under hyperglycemic condition. Both NADPH oxidase and mitochondrial electron gradient play roles in hyperglycemia-induced ROS generation. In addition to their ability to directly inflict macromolecular damage, ROS can function as signaling molecules. ROS mediate hyperglycemia-induced activation of signal transduction cascades and transcription factors leading to transcriptional activation of profibrotic genes in the kidney. Furthermore, ROS-activated signaling molecules generate and signal through ROS and thus ROS act as a signal amplifier. Intensive glycemic control and inhibition of angiotensin II delay the onset and progression of diabetic nephropathy, in part, through prevention of overproduction of ROS. Conventional and catalytic antioxidants have been shown to prevent or delay the onset of diabetic nephropathy. Combination of strategies to prevent overproduction of ROS and to increase the removal of preformed ROS may prove to be effective in preventing the development and progression of diabetic nephropathy. [Copyright &y& Elsevier]
- Published
- 2008
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178. MYCOPHENOLIC ACID INHIBITS MESANGIAL CELL ACTIVATION THROUGH P38 MAPK INHIBITION.
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Ha, Hunjoo, Kim, Joon Ye, Park, Jehyun, Kim, Myoung Soo, Ahn, Hyung Joon, and Kim, Yu Seun
- Published
- 2006
179. Reactive oxygen species mediate TGF-<f>β1</f>-induced plasminogen activator inhibitor-1 upregulation in mesangial cells
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Jiang, Zongpei, Seo, Ji Yeon, Ha, Hunjoo, Lee, Eun Ah, Kim, Yu Seun, Han, Dong Cheol, Uh, Soo Tack, Park, Choon Sik, and Lee, Hi Bahl
- Subjects
- *
GROWTH factors , *EXTRACELLULAR matrix , *PLASMINOGEN , *GENE expression - Abstract
Transforming growth factor-
β1 (TGF-β1 ) promotes tissue fibrosis by upregulating genes encoding extracellular matrix proteins and by increasing the synthesis of plasminogen activator inhibitor-1 (PAI-1). TGF-β1 induces cellular reactive oxygen species (ROS) and PAI-1 promoter region has binding sites for redox sensitive transcription factors. We, therefore, hypothesized that TGF-β1 -induced upregulation of PAI-1 is ROS-dependent. Using cultured glomerular mesangial cells, we confirmed that TGF-β1 induces cellular ROS, upregulates PAI-1 mRNA and protein expression, and suppresses plasmin activity. We further demonstrated that H2O2 stimulates PAI-1 expression and suppresses plasmin activity and that N-acetylcysteine effectively reverses TGF-β1 - and H2O2-induced changes in PAI-1 expression and plasmin activity. Basal as well as TGF-β1 - and H2O2-induced PAI-1 expression was upregulated by depletion of intracellular GSH. The present data demonstrate that TGF-β1 -induced PAI-1 in mesangial cells is ROS-dependent and imply that cellular ROS may be potential therapeutic targets in glomerular fibrosis. [Copyright &y& Elsevier]- Published
- 2003
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180. The impaired redox balance in peroxisomes of catalase knockout mice accelerates nonalcoholic fatty liver disease through endoplasmic reticulum stress.
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Hwang, Inah, Uddin, Md Jamal, Pak, Eun Seon, Kang, Hyeji, Jin, Eun-Jung, Jo, Suin, Kang, Dongmin, Lee, Hyukjin, and Ha, Hunjoo
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FATTY liver , *ENDOPLASMIC reticulum , *KNOCKOUT mice , *LIPID metabolism , *PEROXISOMES , *HIGH-fat diet , *REACTIVE oxygen species - Abstract
Peroxisomes are essential organelles for maintaining the homeostasis of lipids and reactive oxygen species (ROS). While oxidative stress-induced endoplasmic reticulum (ER) stress plays an important role in nonalcoholic fatty liver disease (NAFLD), the role of peroxisomes in ROS-mediated ER stress in the development of NAFLD remains elusive. We investigated whether an impaired peroxisomal redox state accelerates NAFLD by activating ER stress by inhibiting catalase, an antioxidant expressed exclusively in peroxisomes. Wild-type (WT) and catalase knockout (CKO) mice were fed either a normal diet or a high-fat diet (HFD) for 11 weeks. HFD-induced phenotype changes and liver injury accompanied by ER stress and peroxisomal dysfunction were accelerated in CKO mice compared to WT mice. Interestingly, these changes were also significantly increased in CKO mice fed a normal diet. Inhibition of catalase by 3-aminotriazole in hepatocytes resulted in the following effects: (i) increased peroxisomal H 2 O 2 levels as measured by a peroxisome-targeted H 2 O 2 probe (HyPer-P); (ii) elevated intracellular ROS; (iii) decreased peroxisomal biogenesis; (iv) activated ER stress; (v) induced lipogenic genes and neutral lipid accumulation; and (vi) suppressed insulin signaling cascade associated with JNK activation. N-acetylcysteine or 4-phenylbutyric acid effectively prevented those alterations. These results suggest that a redox imbalance in peroxisomes perturbs cellular metabolism through the activation of ER stress in the liver. Image 1 • Catalase deficiency accelerates nonalcoholic fatty liver disease (NAFLD) in mice. • Catalase deficiency impairs redox balance of peroxisomes in NAFLD. • Peroxisomal redox imbalance accelerates ER stress-mediated NAFLD. [ABSTRACT FROM AUTHOR]
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- 2020
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181. Impaired Peroxisomal Fitness in Obese Mice, a Vicious Cycle Exacerbating Adipocyte Dysfunction via Oxidative Stress.
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Piao, Lingjuan, Dorotea, Debra, Jiang, Songling, Koh, Eun Hee, Oh, Goo Taeg, and Ha, Hunjoo
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FAT cells , *WHITE adipose tissue , *METABOLIC syndrome , *OXIDATIVE stress , *FATTY acid oxidation , *CATALASE , *ADIPOSE tissue physiology - Abstract
Aims: Peroxisome is a critical organelle for fatty acid oxidation (FAO) and metabolism of reactive oxygen species (ROS). Increased oxidative stress in adipose tissue contributes to the development of insulin resistance and metabolic syndrome in obesity. This study aimed to investigate the role of peroxisomal fitness in maintaining adipocyte function, which has been under-rated in the obesity research area. Results: Reduced peroxisomal gene expressions in white adipose tissue (WAT) of obese mice suggested a close correlation between peroxisomes and obesity. Peroxisomal biogenesis factor 5 siRNA increased cellular ROS and inflammatory mediators in 3T3-L1 adipocytes. On the contrary, hydrogen peroxide or tumor necrosis factor-α treatment significantly decreased biogenesis- and function-related peroxisomal proteins, suggesting a positive feedback loop of ROS/inflammation and peroxisomal dysfunction. Correspondingly, catalase (a major peroxisomal antioxidant)-knockout mice fed with high-fat diet (HFD) exhibited suppressed peroxisomal proteins along with increased oxidative stress and accelerated obesity. In response to fenofibrate (a peroxisomal proliferator) treatment, WAT of HFD-fed wild-type mice showed not only increases in peroxisomal biogenesis and FAO but also attenuated features of adipocyte dysfunction and obesity. However, these results were not observed in peroxisome proliferator-activated receptor-alpha null obese mice. Innovation: Impaired peroxisomal fitness enhanced oxidative stress and inflammation in adipocytes, which exacerbates obesity. Conclusion: Adipose tissue peroxisomal homeostasis plays an important role in attenuating the features of obesity, and it can be a potential therapeutic target of obesity. [ABSTRACT FROM AUTHOR]
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- 2019
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182. Ablation of catalase promotes non-alcoholic fatty liver via oxidative stress and mitochondrial dysfunction in diet-induced obese mice.
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Shin, Su-Kyung, Cho, Hyun-Woo, Song, Seung-Eun, Bae, Jae-Hoon, Im, Seung-Soon, Hwang, Inha, Ha, Hunjoo, and Song, Dae-Kyu
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CATALASE , *FATTY liver , *OXIDATIVE stress , *LIVER mitochondria , *HYDROGEN peroxide , *MITOCHONDRIAL DNA , *MICE , *ANIMAL experimentation - Abstract
Hydrogen peroxide (H2O2) produced endogenously can cause mitochondrial dysfunction and metabolic complications in various cell types by inducing oxidative stress. In the liver, oxidative and endoplasmic reticulum (ER) stress affects the development of non-alcoholic fatty liver disease (NAFLD). Although a link between both stresses and fatty liver diseases has been suggested, few studies have investigated the involvement of catalase in fatty liver pathogenesis. We examined whether catalase is associated with NAFLD, using catalase knockout (CKO) mice and the catalase-deficient human hepatoma cell line HepG2. Hepatic morphology analysis revealed that the fat accumulation was more prominent in high-fat diet (HFD) CKO mice compared to that in age-matched wild-type (WT) mice, and lipid peroxidation and H2O2 release were significantly elevated in CKO mice. Transmission electron micrographs indicated that the liver mitochondria from CKO mice tended to be more severely damaged than those in WT mice. Likewise, mitochondrial DNA copy number and cellular ATP concentrations were significantly lower in CKO mice. In fatty acid-treated HepG2 cells, knockdown of catalase accelerated cellular lipid accumulation and depressed mitochondrial biogenesis, which was recovered by co-treatment with N-acetyl cysteine or melatonin. This effect of antioxidant was also true in HFD-fed CKO mice, suppressing fatty liver development and improving hepatic mitochondrial function. Expression of ER stress marker proteins and hepatic fat deposition also increased in normal-diet, aged CKO mice compared to WT mice. These findings suggest that H2O2 production may be an important event triggering NAFLD and that catalase may be an attractive therapeutic target for preventing NAFLD. [ABSTRACT FROM AUTHOR]
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- 2019
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183. Effects of low-dose irradiation on mice with Escherichia coli-induced sepsis.
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Song, Kyung-Hee, Jung, Seung-Youn, Kho, Seong-Ho, Hwang, Sang-Gu, Ha, Hunjoo, Nam, Seon Young, and Song, Jie-Young
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PHYSIOLOGICAL effects of radiation , *SEPTICEMIA treatment , *ESCHERICHIA coli , *IMMUNE response , *TOTAL body irradiation , *LABORATORY mice - Abstract
Although favorable immune responses to low-dose irradiation (LDI) have been observed in normal mice, i.e., a hormesis effect, little is known about the effects of LDI in infectious diseases. In this study, we examined the effects of LDI on mice with sepsis, a severe and often lethal hyperinflammatory response to bacteria. Female C57BL/6 mice were whole-body irradiated with 10 cGy 48 h before Escherichia coli infection, and survival, bacterial clearance, cytokines, and antioxidants were quantified. LDI pretreatment significantly increased survival from 46.7% in control mice to 75% in mice with sepsis. The bacterial burden was significantly lower in the blood, spleen, and kidney of LDI-treated mice than in those of control septic mice. The levels of pro-inflammatory cytokines, e.g., IL-1β and IL-6, as well as anti-inflammatory IL-10 were markedly reduced in pre-LDI septic mice. Nitric oxide production by peritoneal macrophages was also reduced in pre-LDI septic mice. Immune cells in the spleen increased and Nrf2 and HO-1 were induced in pre-LDI septic mice. LDI stimulates the immune response and minimizes lethality in septic mice via enhanced bacterial clearance and reduced initial proinflammatory responses. [ABSTRACT FROM AUTHOR]
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- 2017
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184. Daumone fed late in life improves survival and reduces hepatic inflammation and fibrosis in mice.
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Park, Jong Hee, Chung, Hae Young, Kim, Minkyu, Lee, Jung Hwa, Jung, Mankil, and Ha, Hunjoo
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AGE factors in disease , *HEPATITIS prevention , *HEPATIC fibrosis , *LABORATORY mice , *PHEROMONES , *AGING prevention , *LOW-calorie diet , *ANTI-inflammatory agents - Abstract
The liver is one of the most susceptible organs to aging, and hepatic inflammation and fibrosis increase with age. Chronic inflammation has been proposed as the major molecular mechanism underlying aging and age-related diseases, whereas calorie restriction has been shown to be the most effective in extending mammalian lifespan and to have anti-aging effects through its anti-inflammatory action. Thus, it is necessary to develop effective calorie restriction mimetics. Daumone [(2)-(6R)-(3,5-dihydroxy-6-methyltetrahydropyran-2-yloxy)heptanoic acid], a pheromone secreted by Caenorhabditis elegans, forces them to enter the dauer stage when facing inadequate conditions. Because Caenorhabditis elegans live longer during the dauer stage under energy deprivation, it was hypothesized that daumone may improve survival in mammals by mimicking calorie restriction. Daumone (2 mg kg−1 day−1) was administered orally for 5 months to 24-month-old male C57BL/6J mice. Daumone was found to reduce the risk of death by 48% compared with age-matched control mice, and the increased plasma insulin normally presented in old mice was significantly reduced by daumone. The increased hepatic hypertrophy, senescence-associated β-galactosidase activity, insulin resistance, lipid accumulation, inflammation, oxidative stress, and fibrosis in old mice were significantly attenuated by daumone. From a mechanistic view, daumone reduced the phosphorylation of the IκBα and upregulation of Rela and Nfkbia mRNA in the livers of old mice. The anti-inflammatory effect of daumone was confirmed in lipopolysaccharide-induced liver injury model. Oral administration of daumone improves survival in mice and delivers anti-aging effects to the aged liver by modulating chronic inflammation, indicating that daumone could be developed as an anti-aging compound. [ABSTRACT FROM AUTHOR]
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- 2014
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185. Carnosic acid, a phenolic diterpene from rosemary, prevents UV-induced expression of matrix metalloproteinases in human skin fibroblasts and keratinocytes.
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Park, Miyoung, Han, Jiwon, Lee, Chang Seok, Heung Soo, Baek, Lim, Kyung‐Min, and Ha, Hunjoo
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PHYSIOLOGICAL effects of ultraviolet radiation , *REACTIVE oxygen species , *EPIDERMAL growth factor receptors , *CARNOSIC acid , *ROSEMARY , *FIBROBLASTS - Abstract
Exposure of the skin to ultraviolet ( UV) irradiation induces photoageing through the up-regulation of matrix metalloproteinases ( MMPs) and subsequent breakdown of extracellular matrices. Reactive oxygen species ( ROS) and epidermal growth factor receptor ( EGFR) activation play central roles in UV-induced MMP expression through initiating extracellular signal-regulated kinase ( ERK)-mediated AP-1 signalling. We aimed to explore the effects of carnosic acid ( CA), a phenolic diterpene from rosemary, on UV-induced MMP expression in human skin cells. Molecular mechanism underlying the effects of CA was also examined in the aspect of MMP expression, ERK/ AP-1 pathway, ROS generation and EGFR activation. Human dermal fibroblast cell line (Hs68), primary normal human dermal fibroblasts ( HDFs) and normal human epidermal keratinocytes ( HEKs) were employed, and antiphotoageing effects of CA were assessed by Western blotting, quantitative real-time PCR and enzyme assays. CA significantly inhibited UVA- and UVB-induced expression of MMP-1, MMP-3 and MMP-9 in a concentration-dependent manner in Hs68 cells. UVB-induced ERK activation and the formation of transcription factor, AP-1, were significantly suppressed by CA. Among the upstream events of MMP expression, UVB-induced ROS generation was attenuated by CA, while EGFR activation was not affected. Confirming the antiphotoageing effects of CA through the suppression of UV-induced ROS generation, UVB-enhanced GADD45 expression, a marker for oxidative DNA damages was significantly reduced by CA. Inhibitory effects of CA on UVB-induced MMP expression could be also seen in HDFs and HEKs. Collectively, our study demonstrates that CA inhibits the UV-enhanced MMPs in human skin cells through the inhibition of ROS and the suppression of ERK/ AP-1 activation. [ABSTRACT FROM AUTHOR]
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- 2013
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186. 8-Hydroxy-2-deoxyguanosine prevents plaque formation and inhibits vascular smooth muscle cell activation through Rac1 inactivation
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Huh, Joo Young, Son, Dong Ju, Lee, Yoonji, Lee, Junghyun, Kim, Boyeon, Lee, Hwan Myung, Jo, Hanjoong, Choi, Sun, Ha, Hunjoo, and Chung, Myung-Hee
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DEOXYGUANOSINE , *VASCULAR smooth muscle , *OXIDATIVE stress , *NEUTROPHILS , *MACROPHAGES , *REACTIVE oxygen species , *ASPARTATE aminotransferase , *EXTRACELLULAR matrix - Abstract
Abstract: 8-Hydroxy-2-deoxyguanosine (8-OHdG), a marker of oxidative stress, has been recently rediscovered to inhibit Rac1 in neutrophils and macrophages, thereby inhibiting Rac1-linked functions of these cells, including reactive oxygen species production through NADPH oxidase activation, phagocytosis, chemotaxis, and cytokine release. In vascular smooth muscle cells (VSMCs), reactive oxygen species also induce abnormal proliferation and migration leading to progression of atherosclerosis. Based upon the involvement of reactive oxygen species in phagocytic cells and VSMCs during the atherosclerotic process, we hypothesized that 8-OHdG could have antiatherosclerotic action and tested this hypothesis in an experimentally induced atherosclerosis in mice. Partially ligated ApoE knockout mice, a more physiologically relevant model of low and oscillatory flow, developed an advanced lesion in 2 weeks, and orally administered 8-OHdG significantly reduced plaque formation along with reduced superoxide formation, monocyte/macrophage infiltration, and extracellular matrix (ECM) accumulation. The effects of 8-OHdG observed in primary VSMCs were consistent with the in vivo effects of 8-OHdG and were inhibitory to angiotensin II or platelet-derived growth factor-induced production of reactive oxygen species, proliferation, migration, and ECM production. Also, angiotensin II-induced Rac1 activity in VSMCs was significantly inhibited by 8-OHdG, and transfection of constitutively active Rac1 reversed the inhibitory effect of 8-OHdG on VSMC activation. Molecular docking study showed that 8-OHdG stabilizes Rac1–GEF complex, indicating the physical contact of 8-OHdG with Rac1. These findings highly suggest that the antiatherosclerotic effect of 8-OHdG is mediated by inhibition of Rac1 activity. In conclusion, our results show a novel action of orally active 8-OHdG in suppressing atherosclerotic plaque formation in vivo and VSMC activation in vitro through inhibition of Rac1, which emphasizes a new therapeutic avenue to benefit atherosclerosis. [Copyright &y& Elsevier]
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- 2012
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187. Renoprotective antioxidant effect of alagebrium in experimental diabetes.
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Park, Jehyun, Kwon, Min Kyung, Huh, Joo Young, Choi, Won Jun, Jeong, Lak Shin, Nagai, Ryoji, Kim, Wan Young, Kim, Jin, Lee, Geun Taek, Lee, Hi Bahl, and Ha, Hunjoo
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ANTIOXIDANTS , *DIABETES , *KIDNEY diseases , *OXIDATIVE stress , *DRUG administration , *ALBUMINS , *NAD+ synthase , *LABORATORY mice - Abstract
Background. Despite the beneficial effects of alagebrium (ALA), a putative advanced glycation end-product (AGE) breaker, on diabetic nephropathy, its renoprotective mechanisms are incompletely understood. Since oxidative stress exacerbates diabetic renal injury through interaction with AGE, the present study examined the antioxidative property of ALA in db/db mice, mesangial cells cultured under high glucose or H2O2 and a test tube.Methods. ALA (2 mg/kg/day) was administered intraperitoneally for 12 weeks to 8-week-old db/m and db/db (DALAE) mice or for 4 weeks to 16-week-old db/db mice (DALAL). Oxidative stress markers (nitrotyrosine accumulation, expression and translocation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits, cellular DCF-DA fluorescence) together with urinary albumin excretion and histological changes including mesangial expansion were measured. The concentration of H2O2 in the presence and absence of ALA was measured by iodometric analysis in a test tube.Results. ALA significantly reduced not only urinary albumin excretion and renal pathological changes but also accumulation of pentosidine and nitrotyrosine and expression of NADPH oxidase subunits in db/db mice regardless of treatment protocol. In mesangial cells, ALA effectively prevented not only high glucose- but also H2O2-induced membrane translocation of NADPH oxidase subunit (p47 phox, p67 phox and rac1) and protein kinase C isoform (α, βI and βII) and Nox4 messenger RNA expression concomitant with cellular reactive oxygen species. Furthermore, ALA directly decreased H2O2 in a test tube.Conclusion. ALA has both direct and indirect antioxidant effects that may play important roles in ALA’s renoprotective effect in diabetic kidneys. [ABSTRACT FROM AUTHOR]
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- 2011
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188. Quantitative determination of daumone in rat plasma by liquid chromatography–mass spectrometry
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Noh, Keumhan, Park, Jung Hyun, Park, Jong Hee, Kim, Minkyu, Jung, Mankil, Ha, Hunjoo, Kwon, Kwang-il, Lee, Hwa Jeong, and Kang, Wonku
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PHEROMONES , *BLOOD plasma , *HEPTANE , *LABORATORY rats , *LIQUID chromatography , *ELECTROSPRAY ionization mass spectrometry , *QUANTITATIVE chemical analysis - Abstract
Abstract: Daumone, 6-(3,5-dihydroxy-6-methyl-tetrahydro-pyran-2-yloxy)-heptanoic acid is a pheromone secreted by Caenorhabditis elegans, and has been known as a pivotal regulator of chemosensory processes in development and ageing. A quantification method using mass spectrometry was developed for the determination of daumone in rat plasma. After simple protein precipitation with acetonitrile including an internal standard, the analytes were chromatographed on a reversed-phase column and detected by liquid chromatography/tandem mass spectrometry with electrospray ionization. The accuracy and precision of the assay were in accordance with FDA regulations for validation of bioanalytical methods. This method was applied to measure the plasma daumone concentrations after a single intravenous administration of daumone in rats. [Copyright &y& Elsevier]
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- 2011
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189. The role of plasminogen activator inhibitor 1 in renal and cardiovascular diseases.
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Hunjoo Ha, Oh, Eun Y., Lee, Hi B., and Ha, Hunjoo
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PLASMINOGEN activators , *GLYCOPROTEINS , *KIDNEY diseases , *CARDIOVASCULAR diseases , *UROKINASE , *REACTIVE oxygen species , *DISEASE risk factors , *SERINE proteinases - Abstract
The 50 kDa glycoprotein plasminogen activator inhibitor 1 (PAI-1) is the major physiological inhibitor of tissue-type and urokinase-type plasminogen activator. These two molecules convert inactive plasminogen into its fibrin-degrading form, plasmin. Plasma and tissue concentrations of PAI-1 are extremely low under normal circumstances but increase under pathologic conditions. This increase is mediated by many factors, including reactive oxygen species. Increased PAI-1 activity is associated with an increased risk of ischemic cardiovascular events and tissue fibrosis. Whereas the antifibrinolytic property of PAI-1 derives mainly from its inhibition of serine proteases, its profibrotic actions seem to derive from a capacity to stimulate interstitial macrophage recruitment and increase transcription of profibrotic genes, as well as from inhibition of serine proteases. Despite studies in mice that lack or overexpress PAI-1, the biological effects of this molecule in humans remain incompletely understood because of the complexity of the PAI-1-plasminogen-activator-plasmin system. The cardioprotective and renoprotective properties of some currently available drugs might be attributable in part to inhibition of PAI-1. The development of an orally active, high-affinity PAI-1 inhibitor will provide a potentially important pharmacological tool for further investigation of the role of PAI-1 and might offer a novel therapeutic strategy in renal and cardiovascular diseases. [ABSTRACT FROM AUTHOR]
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- 2009
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190. Exercise-Induced Irisin Decreases Inflammation and Improves NAFLD by Competitive Binding with MD2.
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Zhu, Weiwei, Sahar, Namood E, Javaid, Hafiz Muhammad Ahmad, Pak, Eun Seon, Liang, Guang, Wang, Yi, Ha, Hunjoo, and Huh, Joo Young
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NON-alcoholic fatty liver disease , *TREADMILL exercise , *IRISIN , *HIGH-fat diet , *FATTY liver , *HEPATIC fibrosis , *INFLAMMATION - Abstract
Non-alcoholic fatty liver disease (NAFLD) is a global clinical problem. The MD2-TLR4 pathway exacerbates NAFLD progression by promoting inflammation. Long-term exercise is considered to improve NAFLD but the underlying mechanism is still unclear. In this study, we examined the protective effect and molecular mechanism of exercise on high-fat diet (HFD)-induced liver injury. In an HFD-induced NAFLD mouse model, exercise training significantly decreased hepatic steatosis and fibrosis. Interestingly, exercise training blocked the binding of MD2-TLR4 and decreased the downstream inflammatory response. Irisin is a myokine that is highly expressed in response to exercise and exerts anti-inflammatory effects. We found that circulating irisin levels and muscle irisin expression were significantly increased in exercised mice, suggesting that irisin could mediate the effect of exercise on NAFLD. In vitro studies showed that irisin improved lipid metabolism, fibrosis, and inflammation in palmitic acid (PA)-stimulated AML12 cells. Moreover, binding assay results showed that irisin disturbed MD2-TLR4 complex formation by directly binding with MD2 but not TLR4, and interfered with the recognition of stimuli such as PA and lipopolysaccharide with MD2. Our study provides novel evidence that exercise-induced irisin inhibits inflammation via competitive binding with MD2 to improve NAFLD. Thus, irisin could be considered a potential therapy for NAFLD. [ABSTRACT FROM AUTHOR]
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- 2021
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191. Lithospermic acid B ameliorates the development of diabetic nephropathy in OLETF rats
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Kang, Eun Seok, Lee, Geun Taek, Kim, Beom Seok, Kim, Chul Hoon, Seo, Gi Ho, Han, Seung Jin, Hur, Kyu Yeon, Ahn, Chul Woo, Ha, Hunjoo, Jung, Mankil, Ahn, Young Soo, Cha, Bong Soo, and Lee, Hyun Chul
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DIABETES complications , *DIABETES , *KIDNEY diseases , *TYPE 2 diabetes - Abstract
Abstract: Lithospermic acid B (LAB), an active component isolated from Salvia miltiorrhizae, has been reported to have renoprotective effects in type 1 diabetic animal models. In the present study we investigated the effects of LAB on the prevention of diabetic nephropathy in type 2 diabetic Otsuka Long-Evans-Tokushima Fatty (OLETF) rats. LAB (20 mg/kg) was given orally once daily to 10-week-old male OLETF rats for 28 weeks. Treatment of OLETF rats with LAB had little effects on body weight and blood glucose levels. Treatment with LAB resulted in significant reduction in blood pressure. LAB markedly attenuated albuminuria and significantly lowered levels of lipid peroxidation, monocyte chemoattractant protein-1 (MCP-1), and transforming growth factor-β (TGF-β1) expression in renal tissues of OLETF rats. In addition, LAB inhibited the progression of glomerular hypertrophy, mesangial expansion, and expansion of the extracellular matrix in the renal cortex. Collectively, these results suggest that LAB has beneficial effects on the diabetic nephropathy in OLETF rats by decreasing blood pressure, oxidative stress, and MCP-1 expression. Our results suggest that LAB might be a new therapeutic agent for the prevention of nephropathy in type 2 diabetes. [Copyright &y& Elsevier]
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- 2008
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192. HORMONES - CYTOKINES - SIGNALING Reactive oxygen species amplify protein kinase C signaling in high glucose-induced fibronectin expression by human peritoneal mesothelial cells.
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Lee, Hi Bahl, Yu, Mi Ra, Song, Jae Sook, and Ha, Hunjoo
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FIBRONECTINS , *GLUCOSE , *DIABETES , *PROTEIN kinases , *OXIDATIVE stress , *PERITONEAL dialysis - Abstract
Reactive oxygen species amplify protein kinase C signaling in high glucose-induced fibronectin expression by human peritoneal mesothelial cells. Background. We previously demonstrated that high glucose up-regulates fibronectin mRNA and protein expression by human peritoneal mesothelial cells (HPMC) through activation of protein kinase C (PKC). PKC is known to induce cellular reactive oxygen species (ROS) and PKC-dependent activation of the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase has recently been shown to be responsible, in part, for increased oxidative stress in diabetes. On the other hand, high glucose-induced mitochondrial overproduction of superoxide anion was found to activate PKC. We, therefore, hypothesized that high glucose-induced activation of PKC in HPMC may increase cellular ROS and ROS, in turn, may activate PKC and thus provide signal amplification in high glucose-induced fibronectin up-regulation in HPMC. Methods. The role of ROS in high glucose- and PKC-induced fibronectin expression was examined by quantification of cellular ROS after stimulation with high glucose and phorbol 12-myristate 13-acetate (PMA), by the effect of hydrogen peroxide (H2O2) and PMA on fibronectin expression, and finally by inhibition of ROS and PKC. The source of cellular ROS was further examined by inhibition of NADPH oxidase and mitochondrial metabolism. Results. d-glucose increased dichlorofluorescein (DCF)-sensitive cellular ROS in HPMC in a dose-dependent manner. l-glucose did not induce ROS generation and cytochalasin B completely blocked high glucose-induced ROS generation, suggesting that glucose uptake, but not media hyperosmolality, is required in ROS generation in HPMC. PMA increased cellular ROS and fibronectin secretion. A single dose of H2O2 or H2O2 continuously generated by glucose oxidase fibronectin expression. Antioxidants trolox and catalase inhibited high glucose- and PMA-induced fibronectin mRNA and protein expression. Inhibition of PKC inhibited high glucose- and H2O2-induced fibronectin secretion. NADPH oxidase inhibitors (diphenyleneiodinium and apocynin) and an inhibitor of mitochondrial electron transport chain subunit I (rotenone) all effectively inhibited high glucose-induced cellular ROS generation and fibronectin secretion. Conclusion. The present data demonstrate that high glucose increases cellular ROS in HPMC through activation of PKC, NADPH oxidase, and mitochondrial metabolism and that ROS, thus generated, up-regulate fibronectin expression by HPMC. ROS are not only downstream but also upstream signaling molecules to PKC and provide signal amplification in high glucose-induced fibronectin expression by HPMC. The present data imply that cellular ROS may be potential therapeutic targets in progressive accumulation of extracellular matrix in the peritoneal tissue of long-term peritoneal dialysis patients using high glucose-containing peritoneal dialysis solutions. [ABSTRACT FROM AUTHOR]
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- 2004
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193. Protective Effects of Black Cumin (Nigella sativa) and Its Bioactive Constituent, Thymoquinone against Kidney Injury: An Aspect on Pharmacological Insights.
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Hannan, Md. Abdul, Zahan, Md. Sarwar, Sarker, Partha Protim, Moni, Akhi, Ha, Hunjoo, and Uddin, Md Jamal
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BLACK cumin , *ACUTE kidney failure , *KIDNEY injuries , *KIDNEYS , *OILSEEDS , *CHRONIC kidney failure , *CASPASES - Abstract
The prevalence of chronic kidney disease (CKD) is increasing worldwide, and a close association between acute kidney injury (AKI) and CKD has recently been identified. Black cumin (Nigella sativa) has been shown to be effective in treating various kidney diseases. Accumulating evidence shows that black cumin and its vital compound, thymoquinone (TQ), can protect against kidney injury caused by various xenobiotics, namely chemotherapeutic agents, heavy metals, pesticides, and other environmental chemicals. Black cumin can also protect the kidneys from ischemic shock. The mechanisms underlying the kidney protective potential of black cumin and TQ include antioxidation, anti-inflammation, anti-apoptosis, and antifibrosis which are manifested in their regulatory role in the antioxidant defense system, NF-κB signaling, caspase pathways, and TGF-β signaling. In clinical trials, black seed oil was shown to normalize blood and urine parameters and improve disease outcomes in advanced CKD patients. While black cumin and its products have shown promising kidney protective effects, information on nanoparticle-guided targeted delivery into kidney is still lacking. Moreover, the clinical evidence on this natural product is not sufficient to recommend it to CKD patients. This review provides insightful information on the pharmacological benefits of black cumin and TQ against kidney damage. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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194. Prospective Pharmacological Potential of Resveratrol in Delaying Kidney Aging.
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Uddin, Md Jamal, Farjana, Mithila, Moni, Akhi, Hossain, Khandkar Shaharina, Hannan, Md. Abdul, and Ha, Hunjoo
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RESVERATROL , *KIDNEYS , *PROTEIN kinases , *SIRTUINS , *AGING prevention , *KIDNEY diseases , *PLANT polyphenols - Abstract
Aging is an unavoidable part of life. The more aged we become, the more susceptible we become to various complications and damages to the vital organs, including the kidneys. The existing drugs for kidney diseases are mostly of synthetic origins; thus, natural compounds with minimal side-effects have attracted growing interest from the scientific community and pharmaceutical companies. A literature search was carried out to collect published research information on the effects of resveratrol on kidney aging. Recently, resveratrol has emerged as a potential anti-aging agent. This versatile polyphenol exerts its anti-aging effects by intervening in various pathologies and multi-signaling systems, including sirtuin type 1, AMP-activated protein kinase, and nuclear factor-κB. Researchers are trying to figure out the detailed mechanisms and possible resveratrol-mediated interventions in divergent pathways at the molecular level. This review highlights (i) the causative factors implicated in kidney aging and the therapeutic aspects of resveratrol, and (ii) the effectiveness of resveratrol in delaying the aging process of the kidney while minimizing all possible side effects. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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195. AZD7648, a DNA-PKcs inhibitor, overcomes radioresistance in Hep3B xenografts and cells under tumor hypoxia.
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Ha J, Park M, Lee Y, Choi SH, Kim BS, Ha H, and Jeong YK
- Abstract
Radiation therapy is one of the most commonly used cancer treatments. However, it has important concerns such as damage to normal tissues around cancers and radioresistance. To overcome these problems, combination therapy using radiosensitizer and radiotherapy will be a good alternative. The present study investigated the effects of AZD7648 on overcoming radioresistance as well as radiosensitizing in Hep3B xenografts and cells. The results showed that AZD7648 enhanced ionizing radiation (IR)-induced tumor growth not only in radiosensitive but also radioresistant tumors. In particular, the combination of AZD7648 with radiation reduced the expression of hypoxia induce factor-1α (HIF-1α) in radioresistant tumors. In vitro studies, AZD7648 plus IR increased IR-induced G2/M arrest and regulated cell cycle checkpoints such as cyclinB1, p-cdc2 in normoxia but not in hypoxia. AZD7648 induced more radiation-mediated ROS than radiation only under normoxia, but these ROS were not altered by AZD7648 under hypoxia. Interestingly, AZD7648 downregulated HIF-1α expression level under CoCl
2 -treated hypoxic condition but not in normoxic condition. In conclusion, AZD7648 synergistically increased radiosensitivity through accumulating IR-induced G2/M arrest and further improved radioresistance via regulation of HIF-1α. The present data suggest that AZD7648 may be a strong radiosensitizer in radioresistant as well as radiosensitive cancers., Competing Interests: None., (AJCR Copyright © 2023.)- Published
- 2023
196. Editorial: The role of oxidative stress and systemic inflammation in diabetes and chronic kidney disease.
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Chanda D, Ha H, and Lee IK
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- Humans, Oxidative Stress, Diabetes Mellitus, Renal Insufficiency, Chronic
- Abstract
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
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- 2023
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197. Peroxisomal Fitness: A Potential Protective Mechanism of Fenofibrate against High Fat Diet-Induced Non-Alcoholic Fatty Liver Disease in Mice.
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Jiang S, Uddin MJ, Yu X, Piao L, Dorotea D, Oh GT, and Ha H
- Subjects
- Mice, Male, Animals, Diet, High-Fat adverse effects, PPAR alpha agonists, Mice, Inbred C57BL, Fatty Acids metabolism, Lipids, Fenofibrate pharmacology, Fenofibrate therapeutic use, Non-alcoholic Fatty Liver Disease drug therapy, Non-alcoholic Fatty Liver Disease etiology, Non-alcoholic Fatty Liver Disease prevention & control, Chemical and Drug Induced Liver Injury, Chronic
- Abstract
Background: Non-alcoholic fatty liver disease (NAFLD) has been increasing in association with the epidemic of obesity and diabetes. Peroxisomes are single membrane-enclosed organelles that play a role in the metabolism of lipid and reactive oxygen species. The present study examined the role of peroxisomes in high-fat diet (HFD)-induced NAFLD using fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist., Methods: Eight-week-old male C57BL/6J mice were fed either a normal diet or HFD for 12 weeks, and fenofibrate (50 mg/kg/day) was orally administered along with the initiation of HFD., Results: HFD-induced liver injury as measured by increased alanine aminotransferase, inflammation, oxidative stress, and lipid accumulation was effectively prevented by fenofibrate. Fenofibrate significantly increased the expression of peroxisomal genes and proteins involved in peroxisomal biogenesis and function. HFD-induced attenuation of peroxisomal fatty acid oxidation was also significantly restored by fenofibrate, demonstrating the functional significance of peroxisomal fatty acid oxidation. In Ppara deficient mice, fenofibrate failed to maintain peroxisomal biogenesis and function in HFD-induced liver injury., Conclusion: The present data highlight the importance of PPARα-mediated peroxisomal fitness in the protective effect of fenofibrate against NAFLD.
- Published
- 2022
- Full Text
- View/download PDF
198. Adenosine receptors as emerging therapeutic targets for diabetic kidney disease.
- Author
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Pak ES, Cha JJ, Cha DR, Kanasaki K, and Ha H
- Abstract
Diabetic kidney disease (DKD) is now a pandemic worldwide, and novel therapeutic options are urgently required. Adenosine, an adenosine triphosphate metabolite, plays a role in kidney homeostasis through interacting with four types of adenosine receptors (ARs): A1AR, A2AAR, A2BAR, and A3AR. Increasing evidence highlights the role of adenosine and ARs in the development and progression of DKD: 1) increased adenosine in the plasma and urine of diabetics with kidney injury, 2) increased expression of each of the ARs in diabetic kidneys, 3) the protective effect of coffee, a commonly ingested nonselective AR antagonist, on DKD, and 4) the protective effect of AR modulators in experimental DKD models. We propose AR modulators as a new therapeutic option to treat DKD. Detailed mechanistic studies on the pharmacology of AR modulators will help us to develop effective first-in-class AR modulators against DKD.
- Published
- 2022
- Full Text
- View/download PDF
199. Pan-Src kinase inhibitor treatment attenuates diabetic kidney injury via inhibition of Fyn kinase-mediated endoplasmic reticulum stress.
- Author
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Dorotea D, Jiang S, Pak ES, Son JB, Choi HG, Ahn SM, and Ha H
- Subjects
- Animals, Endoplasmic Reticulum Stress, Fibrosis, Humans, Kidney pathology, Losartan, Mice, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-fyn genetics, Proto-Oncogene Proteins c-fyn metabolism, Rats, src-Family Kinases metabolism, Diabetes Mellitus, Experimental complications, Diabetes Mellitus, Experimental drug therapy, Diabetes Mellitus, Experimental pathology, Diabetic Nephropathies drug therapy, Diabetic Nephropathies pathology
- Abstract
Src family kinases (SFKs) have been implicated in the pathogenesis of kidney fibrosis. However, the specific mechanism by which SFKs contribute to the progression of diabetic kidney disease (DKD) remains unclear. Our preliminary transcriptome analysis suggested that SFK expression was increased in diabetic kidneys and that the expression of Fyn (a member of the SFKs), along with genes related to unfolded protein responses from the endoplasmic reticulum (ER) stress signaling pathway, was upregulated in the tubules of human diabetic kidneys. Thus, we examined whether SFK-induced ER stress is associated with DKD progression. Mouse proximal tubular (mProx24) cells were transfected with Fyn or Lyn siRNA and exposed to high glucose and palmitate (HG-Pal). Streptozotocin-induced diabetic rats were treated with KF-1607, a novel pan-Src kinase inhibitor (SKI) with low toxicity. The effect of KF-1607 was compared to that of losartan, a standard treatment for patients with DKD. Among the SFK family members, the Fyn and Lyn kinases were upregulated under diabetic stress. HG-Pal induced p70S6 kinase and JNK/CHOP signaling and promoted tubular injury. Fyn knockdown but not Lyn knockdown inhibited this detrimental signaling pathway. In addition, diabetic rats treated with KF-1607 showed improved kidney function and decreased ER stress, inflammation, and fibrosis compared with those treated with losartan. Collectively, these findings indicate that Fyn kinase is a specific member of the SFKs implicated in ER stress activation leading to proximal tubular injury in the diabetic milieu and that pan-SKI treatment attenuates kidney injury in diabetic rats. These data highlight Fyn kinase as a viable target for the development of therapeutic agents for DKD., (© 2022. The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
200. Kidney protective potential of lactoferrin: pharmacological insights and therapeutic advances.
- Author
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Zahan MS, Ahmed KA, Moni A, Sinopoli A, Ha H, and Uddin MJ
- Abstract
Kidney disease is becoming a global public health issue. Acute kidney injury (AKI) and chronic kidney disease (CKD) have serious adverse health outcomes. However, there is no effective therapy to treat these diseases. Lactoferrin (LF), a multi-functional glycoprotein, is protective against various pathophysiological conditions in various disease models. LF shows protective effects against AKI and CKD. LF reduces markers related to inflammation, oxidative stress, apoptosis, and kidney fibrosis, and induces autophagy and mitochondrial biogenesis in the kidney. Although there are no clinical trials of LF to treat kidney disease, several clinical trials and studies on LF-based drug development are ongoing. In this review, we discussed the possible kidney protective mechanisms of LF, as well as the pharmacological and therapeutic advances. The evidence suggests that LF may become a potent pharmacological agent to treat kidney diseases.
- Published
- 2022
- Full Text
- View/download PDF
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