Effect of Ginsenoside Rg2 and Rh1 on Macrophage Inflammation-Mediated Liver Damage

Diem Thi Ngoc Huynh, Thuy Le Lam Nguyen, Kyung-Sun Heo 충남대학교 약학대학 의약품개발연구소 2021 藥學論文集 Vol.36 No.-

Ginsenosides have been reported to display diverse pharmacological effects, such as immune regulation and anticancer activity. In this study, we investigated the protective effect of a combination of ginsenoside Rg2 and Rh1 (G-Rg2 and -Rh1) on macrophages and liver function during septic shock induced by lip-opolysaccharide (LPS). In vitro experiments were performed using RAW264.7 cell line, and an in vivo model of inflammation was established using LPS-treated ICR mice. We assessed 3-(4,5-dimethylthiazole-2-yl)-2, 5-diphe- nyltetrazolium bromide assay, Western blot analysis, quantitative reverse transcription-polymerase chain reaction, and hematoxylin and eosin staining to evaluate the effect of G-Rg2 and -Rh1. We found that G-Rg2 and -Rh1 significantly inhibited LPS-caused nuclear factor kappa B (NF-κB) p65 activation in macrophages. Moreover, the combination treatment strongly abolished the mRNA expression of tumor necrosis factor-alpha and interleukin-1 beta induced by LPS in both RAW264.7 cells and peritoneal macrophages. Furthermore, signal transducer and activator of transcription 1 (STAT1) phosphorylation increased by LPS was dose-dependently decreased by G-Rg2 and -Rh1 treatment. Notably, the 20 mg/kg ginsenoside treatment significantly reduced LPS-induced acute liver inflammation levels in vivo, as indicated by the histological changes in liver tissue sections and the levels of aspartate transaminase, a biochemical marker for liver function from mouse serum. Taken together, our data demonstrated that G-Rg2 and -Rh1 exerted a key role in prevention of LPS-induced acute inflammation and liver damage by suppressing pro-inflammatory cytokine-mediated STAT1 activation through the inhibition of NF-κB acti- vation in macrophages.

2D siloxene supported NiO/Co3O4 electrocatalyst for the stable and efficient hydrogen evolution reaction

Huynh Ngoc-Diem,Jana Jayasmita,Nivetha Ravi,Van Phuc Tran,정진석,허승현 한국물리학회 2022 Current Applied Physics Vol.44 No.-

The activity of NiO/Co3O4 for the hydrogen evolution reaction (HER) during water splitting was increased by depositing these metal oxides on siloxene multi-sheets. The improvement in active sites due to siloxene was used to increase the catalytic activity. The hierarchical structure of the composite with the synergistic effect of metal oxides helped enhance the catalytic activity to show a low overpotential of 110 mV at 10 mA/cm2 in 1 M KOH and stability at 10 mA/cm2 over 20 h without an obvious change in voltage. The as-prepared catalyst can be a promising electrocatalyst for the HER owing to the low cost of transition metal oxides, the abundance of silicon on Earth, and the simplicity of the synthesis process.

Therapeutic targets for endothelial dysfunction in vascular diseases

Diem Thi Ngoc Huynh,Kyung‑Sun Heo 대한약학회 2019 Archives of Pharmacal Research Vol.42 No.10

Vascular endothelial cells are located on thesurface of the blood vessels. It has been recognized as animportant barrier to the regulation of vascular homeostasisby regulating the blood flow of micro- or macrovascular vessels. Indeed, endothelial dysfunction is an initial stage ofvascular diseases and is an important prognostic indicatorof cardiovascular and metabolic diseases such as atherosclerosis,hypertension, heart failure, or diabetes. Therefore, inorder to develop therapeutic targets for vascular diseases, itis important to understand the key factors involved in maintainingendothelial function and the signaling pathwaysaffecting endothelial dysfunction. The purpose of this reviewis to describe the function and underlying signaling pathwayof oxidative stress, inflammatory factors, shear stress, andepigenetic factors in endothelial dysfunction, and introducerecent therapeutic targets for the treatment of cardiovasculardiseases.

Therapeutic targets and drugs for hyper-proliferation of vascular smooth muscle cells

Huynh Diem Thi Ngoc,Jin Yujin,Heo Kyung-Sun 한국약제학회 2020 Journal of Pharmaceutical Investigation Vol.50 No.4

Background Vascular smooth muscle cells (VSMCs) play an important role in the biosynthetic, proliferative, and contractile functions of vessel walls. Hyper-proliferation of VSMCs is a crucial event associated with the pathogenesis of various vascular diseases including hypertension, atherosclerosis, and re-stenosis. Area covered A variety of studies have been performed to identify the signaling molecular targets or inhibitory drugs to suppress hyper-proliferation of VSMCs. Emerging studies have highlighted the relevance of targeting various signaling pathways, miRNAs, and post-translational modifications in controlling the hyper-proliferation of VSMCs. Expert opinion This review will introduce various inhibitors, a wide range of miRNAs, and different histone deacetylases related to the molecular targets and underlying signaling pathways involved in the regulation of VSMC hyper-proliferation. This will contribute to the development of promising approaches for the treatment of vascular diseases.

Therapeutic effects of ginsenosides on breast cancer growth and metastasis

Yujin Jin,Diem Thi Ngoc Huynh,Thuy Le Lam Nguyen,Hyesu Jeon,Kyung-Sun Heo 대한약학회 2020 Archives of Pharmacal Research Vol.43 No.8

Breast cancer is the most common cause ofcancer-related deaths among women worldwide. Thus, thedevelopment of new and eff ective low-toxicity drugs is vital. The specifi c characteristics of breast cancer have allowed forthe development of targeted therapy towards each breast cancersubtype. Nevertheless, increasing drug resistance is displayedby the changing phenotype and microenvironmentsof the tumor through mutation or dysregulation of variousmechanisms. Recently, emerging data on the therapeuticpotential of biocompounds isolated from ginseng have beenreported. Therefore, in this review, various roles of ginsenosidesin the treatment of breast cancer, including apoptosis,autophagy, metastasis, epithelial-mesenchymal transition,epigenetic changes, combination therapy, and drug deliverysystem, have been discussed.

Inhibition of p90RSK activation sensitizes triple-negative breast cancer cells to cisplatin by inhibiting proliferation, migration and EMT

( Yujin Jin ),( Diem Thi Ngoc Huynh ),( Keon Wook Kang ),( Chang-seon Myung ),( Kyung-sun Heo ) 생화학분자생물학회(구 한국생화학분자생물학회) 2019 BMB Reports Vol.52 No.12

Cisplatin (Cis-DDP) is one of the most widely used anti-cancer drugs. It is applicable to many types of cancer, including lung, bladder, and breast cancer. However, its use is now limited because of drug resistance. p90 ribosomal S6 kinase (p90RSK) is one of the downstream effectors in the extracellular signalregulated protein kinases 1 and 2 (ERK1/2) pathway and high expression of p90RSK is observed in human breast cancer tissues. Therefore, we investigated the role of p90RSK in the Cis-DDP resistance-related signaling pathway and epithelial-mesenchymal transition (EMT) in breast cancer cells. First, we discovered that MDA-MB-231 cells exhibited more Cis-DDP resistance than other breast cancer cells, including MCF-7 and BT549 cells. Cis-DDP increased p90RSK activation, whereas the inactivation of p90RSK using a small interfering RNA (siRNA) or dominant-negative kinase mutant plasmid overexpression significantly reduced Cis-DDP-induced cell proliferation and migration via the inhibition of matrix metallopeptidase (MMP)2 and MMP9 in MDA-MB-231 cells. In addition, p90RSK activation was involved in EMT via the upregulation of mRNA expression, including that of Snail, Twist, ZEB1, N-cadherin, and vimentin. We also investigated NF-κB, the upstream regulator of EMT markers, and discovered that Cis-DDP treatment led to NF-κB translocation in the nucleus as well as its promoter activity. Our results suggest that targeting p90RSK would be a good strategy to increase Cis-DDP sensitivity in triple-negative breast cancers. [BMB Reports 2019; 52(12): 706-711]

Role of p90RSK Activation on Angiotensin II-Stimulated Proliferation of Vascular Smooth Muscle Cells

Yujin Jin,Diem Thi Ngoc Huynh,Kyung-Sun Heo 충남대학교 약학대학 의약품개발연구소 2020 藥學論文集 Vol.35 No.-

Inhibitory Effect of Metformin on Angiotensin II Induced RASMC Migration

Sohyun Sim,Diem Thi Ngoc Huynh,Yujin Jin,Kyung-Sun Heo 충남대학교 약학대학 의약품개발연구소 2019 藥學論文集 Vol.34 No.-

Angiotensin II (Ang II) contribute a vascular smooth muscle cells (VSMC) proliferation and migration that lead progression of cardiovascular disease including atherosclerosis and restenosis. Metformin (Met) is anti- diabetic drugs extensively used in the treatment of type 2 diabetes mellitus (T2D) patients. Recent study has suggested that Met has protective effects on vascular diseases but signaling pathway related to cell migration remains unclear. Therefore, we investigated the role of Met on Ang II-induced cell migration and its underlying signaling pathway in rat aortic VSMC (RASMC). First, activations of mitogen-activated protein kinase (MAPK) and Akt were evaluated in Ang II and Met treated cells using western blot analysis. Ang II induced activation of Akt, ERK1/2, and p38 at 25 nM within 1 min, whereas Met inhibited Ang II-stimulated activation of ERK1/2 and p38 in RASMC. Next, we examined effect of Met on protein and mRNA expression level of Ang II-induced matrix metalloproteinase 2 (MMP2), Intercellular Adhesion Molecule (ICAM-1), and vascular cell adhesion protein-1 (VCAM-1) using western blot and qRT-PCR analysis. Interestingly, Met completely inhibited both protein and mRNA expression level of Ang II-increased ICAM-1, VCAM-1 and MMP2. To confirm the effect of Met on Ang II-induced cell migration, we performed wound healing assay and found that 1 mM Met completely inhibited cell migration stimulated by 100 nM Ang II for 24 hrs. Together, our data demonstrates that Met regulates VSMC migration through down-regulation of ERK1/2 and p38 kinase activation and migratory gene expression, such as ICAM-1, VCAM-1 and MMP2.

Ginsenoside Rh1 inhibits tumor growth in MDA-MB-231 breast cancer cells via mitochondrial ROS and ER stress-mediated signaling pathway

Yujin Jin,Diem Thi Ngoc Huynh,Kyung-Sun Heo 대한약학회 2022 Archives of Pharmacal Research Vol.45 No.3

Ginsenoside-Rh1 (Rh1) is a ginseng-derivedcompound that has been reported to exert anticancer eff ectsby regulating cell cycle arrest and apoptosis according toreactive oxygen species (ROS) production. However, theeff ects of Rh1 on mitochondrial dysfunction are involved intriple negative breast cancer (TNBC) cell apoptosis, and therelated molecular mechanisms remain unknown. Rh1 treatmentinduced cell toxicity less than 50% at 50 μM. In addition,Rh1 induced apoptosis in TNBC cells through cleavedcaspase-3 activation and G1/S arrest. The Rh1-treatedTNBC cells showed a signifi cant increase in mitochondrialROS (mtROS), which in turn increased protein expressionof mitochondrial molecules, such as Bak and cytochromeC, and caused the loss of mitochondrial membrane potential. Pretreatment with mitochondria-targeted antioxidantMito-TEMPO alters the Rh1-reduced rate of mito- andglycol-ATP. Furthermore, Rh1 induces ER stress-mediatedcalcium accumulation via PERK/eIF2α/ATF4/CHOP pathway. Inhibition of ATF4 by siRNA transfection signifi cantlyinhibited Rh1-mediated apoptosis and calcium production. Interestingly, Mito-TEMPO treatment signifi cantly reducedapoptosis and ER stress induced by Rh1. Finally, Rh1 at5 mg/kg suppressed tumor growth through increased levelsof ROS production, cleaved caspase-3, and ATF4 more than5-fl uorouracil treated group. Overall, our results suggest thatRh1 has potential for use in TNBC treatment.

Protective effects of ginsenoside-Rg2 and -Rh1 on liver function through inhibiting TAK1 and STAT3-mediated inflammatory activity and Nrf2/ARE-mediated antioxidant signaling pathway

Thuy Le Lam Nguyen,Diem Thi Ngoc Huynh,Yujin Jin,Hyesu Jeon,Kyung-Sun Heo 대한약학회 2021 Archives of Pharmacal Research Vol.44 No.2

Systemic or hepatic infl ammation is caused byintraperitoneal application of lipopolysaccharide (LPS). Inthis study, we investigated anti-infl ammatory and antioxidantproperties of combination of ginsenoside-Rg2 (G-Rg2) and-Rh1 (G-Rh1) on liver function under LPS challenging. Wefi rst confi rmed that G-Rg2 and -Rh1 at 100 μg/ml did notshow cytotoxicity in HepG2 cells. G-Rg2 and -Rh1 treatmentsignifi cantly inhibited activation of STAT3 and TAK1,and infl ammatory factors including iNOS, TNF-α, and IL-1βin peritoneal macrophages. In HepG2 cells, G-Rg2 and -Rh1treatment inhibited activation of STAT3 and TAK1/c-JunN-terminal kinase, and down-regulated nuclear translocationof NF-κB transcription factor. In addition, LPS-inducedmitochondrial dysfunction was restored by treatment withG-Rg2 and -Rh1. Interestingly, pretreatment with G-Rg2 and-Rh1 eff ectively inhibited mitochondrial damage-mediatedROS production induced by LPS stimulation, and alterationsof Nrf2 nuclear translocation and ARE promotor activitywere involved in G-Rg2 and -Rh1 eff ects on balancingROS levels. In liver tissues of LPS-treated mice, G-Rg2and -Rh1 treatment protected liver damages and increasedNrf2 expression while reducing CD45 expression. Takentogether, G-Rg2 and -Rh1 exerts a protective effect onliver function by increasing antioxidant through Nrf2 and anti-inflammatory activities through STAT3/TAK1 andNF-κB signaling pathways in liver cells and macrophages.