• Environmental Analysis Health and Toxicology
• /
• v.31
• /
• pp.16.1-16.9
• /
• 2016

Objectives Banha-sasim-tang (BST), which consists of seven different herbs, is one of the most popular herbal formulae for treating gastrointestinal disorders in Eastern Asia. The commonly used herbal medicine is often co-administered with other therapeutic drugs, which raises the possibility of herb-drug interactions and may modify the clinical safety profile of therapeutic drugs. Methods We investigated the potential herb-drug interactions between BST extract and midazolam (MDZ) in mice. The area under the plasma concentration-time curve (AUC) of MDZ and 1'-hydroxymidazolam (1'-OH-MDZ) was evaluated for both oral and intraperitoneal administration of MDZ, following oral administration of BST (0.5 and 1 g/kg). Results It was found that the AUC of MDZ and 1'-OH-MDZ was lower in case of oral administration of MDZ. Administration of BST extract was not associated with hepatic cytochrome P450 activity. BST extract induced a strong reduction in pH and it has been reported that oral mucosal absorption of MDZ is lower at low pH. The decreased absorption rate of MDZ might be caused by the ingredients of BST and may not be related to other factors such as increased excretion of MDZ by P-glycoprotein. Conclusions The altered pharmacokinetics of midazolam caused by co-administration with BST in vivo could be attributed to a decrease in pH and subsequent reduction of MDZ absorption rate.

• Toxicological Research
• /
• v.34 no.1
• /
• pp.23-29
• /
• 2018

Ethanol-induced fat accumulation, the earliest and most common response of the liver to ethanol exposure, may be involved in the pathogenesis of liver diseases. Isoliquiritigenin (ISL), an important constituent of Glycyrrhizae Radix, is a chalcone derivative that exhibits antioxidant, anti-inflammatory, and phytoestrogenic activities. However, the effect of ISL treatment on lipid accumulation in hepatocytes and alcoholic hepatitis remains unclear. Therefore, we evaluated the effect and underlying mechanism of ISL on ethanol-induced hepatic steatosis by treating AML-12 cells with 200 mM ethanol and/or ISL ($0{\sim}50{\mu}M$) for 72 hr. Lipid accumulation was assayed by oil red O staining, and the expression of sirtuin1 (SIRT1), sterol regulatory element-binding protein-1c (SREBP-1c), AMP-activated protein kinase (AMPK), and peroxisome proliferator-activated receptor alpha ($PPAR{\alpha}$) was studied by western blotting. Our results indicated that ISL treatment upregulated SIRT1 expression and downregulated SREBP-1c expression in ethanol-treated cells. Similarly, oil red O staining revealed a decrease in ethanol-induced fat accumulation upon co-treatment of ethanol-treated cells with 10, 20, and $50{\mu}M$ of ISL. These findings suggest that ISL can reduce ethanol induced-hepatic lipogenesis by activating the SIRT1-AMPK pathway and thus improve lipid metabolism in alcoholic fatty livers.

• Mass Spectrometry Letters
• /
• v.10 no.2
• /
• pp.61-65
• /
• 2019

Korean ginseng (Panax ginseng Meyer) is a traditional herb used across the world to treat various diseases. Although, red ginseng is this herb's most famous product and has demonstrated diverse pharmacological activities, white ginseng (WG) is another ginseng product that is made fresh and individually regulated in Eastern Asia. Red and white ginseng show different characteristics due to distinct processing steps despite originating from the same plant, and the drug interactions induced by WG have not been well documented. Selegiline is a selective monoamine oxidase (MAO) inhibitor used as an antidyskinetic and antiparkinsonian agent. Here we developed a quantification method for selegiline in mouse plasma using a C8 stationary phase in triple quadrupole-mass spectrometry (LC-MS/MS) with multiple reaction monitoring (MRM). The validated LC-MS/MS method was successfully applied to determine the potential interaction with WG extract (0.1 g/kg/day) pre-administered for 4 weeks. The $AUC_{0-240min}$ of selegiline was altered due to a decrease in the absorption of selegiline with repeated administration of WG extract.

• IMMUNE NETWORK
• /
• v.14 no.2
• /
• pp.73-80
• /
• 2014

Because autoimmune diseases (AIDs) result from a complex combination of genetic and epigenetic factors, as well as an altered immune response to endogenous or exogenous antigens, systems biology approaches have been widely applied. The use of multi-omics approaches, including blood transcriptomics, genomics, epigenetics, proteomics, and metabolomics, not only allow for the discovery of a number of biomarkers but also will provide new directions for further translational AIDs applications. Systems biology approaches rely on high-throughput techniques with data analysis platforms that leverage the assessment of genes, proteins, metabolites, and network analysis of complex biologic or pathways implicated in specific AID conditions. To facilitate the discovery of validated and qualified biomarkers, better-coordinated multi-omics approaches and standardized translational research, in combination with the skills of biologists, clinicians, engineers, and bioinformaticians, are required.

• Animal Bioscience
• /
• v.34 no.8
• /
• pp.1271-1282
• /
• 2021

Genome-wide studies provide considerable insights into the genetic background of animals; however, the inheritance of several heritable factors cannot be elucidated. Epigenetics explains these heritabilities, including those of genes influenced by environmental factors. Knowledge of the mechanisms underlying epigenetics enables understanding the processes of gene regulation through interactions with the environment. Recently developed next-generation sequencing (NGS) technologies help understand the interactional changes in epigenetic mechanisms. There are large sets of NGS data available; however, the integrative data analysis approaches still have limitations with regard to reliably interpreting the epigenetic changes. This review focuses on the epigenetic mechanisms and profiling methods and multi-omics integration methods that can provide comprehensive biological insights in animal genetic studies.

• Genomics & Informatics
• /
• v.19 no.2
• /
• pp.13.1-13.8
• /
• 2021

Ranked in the topmost position among the deadliest diseases in the world, cardiovascular diseases (CVDs) are a global burden with alterations in heart and blood vessels. Early diagnostics and prognostics could be the best possible solution in CVD management. OMICS (genomics, proteomics, transcriptomics, and metabolomics) approaches could be able to tackle the challenges against CVDs. Genome-wide association studies along with next-generation sequencing with various computational biology tools could lead a new sight in early detection and possible therapeutics of CVDs. Human cardiac proteins are also characterized by mass spectrophotometry which could open the scope of proteomics approaches in CVD. Besides this, regulation of gene expression by transcriptomics approaches exhibits a new insight while metabolomics is the endpoint on the downstream of multi-omics approaches to confront CVDs from the early onset. Although a lot of challenges needed to overcome in CVD management, OMICS approaches are certainly a new prospect.

• International Journal of Oncology
• /
• v.54 no.4
• /
• pp.1327-1336
• /
• 2019

Endothelial progenitor cells (EPCs) are bone marrow (BM)-derived progenitor cells that can differentiate into mature endothelial cells, contributing to vasculogenesis in the blood vessel formation process. Runt-related transcription factor 3 (RUNX3) belongs to the Runt domain family and is required for the differentiation of specific immune cells and neurons. The tumor suppressive role of RUNX3, via the induction of apoptosis and cell cycle arrest in a variety of cancers, and its deletion or frequent silencing by epigenetic mechanisms have been studied extensively; however, its role in the differentiation of EPCs is yet to be investigated. Therefore, in the present study, adult BM-derived hematopoietic stem cells (HSCs) were isolated from Runx3 heterozygous (Rx3^+/-) or wild-type (WT) mice. The differentiation of EPCs from the BM-derived HSCs of Rx3^+/- mice was found to be significantly increased compared with those of the WT mice, as determined by the number of small or large colony-forming units. The migration and tube formation abilities of Rx3^+/- EPCs were also observed to be significantly increased compared with those of WT EPCs. Furthermore, the number of circulating EPCs, defined as CD34⁺/vascular endothelial growth factor receptor 2 (VEGFR2)⁺ cells, was also significantly increased in Rx3^+/- mice. Hypoxia-inducible factor (HIF)-1α was upregulated in Rx3^+/- EPCs compared with WT EPCs, even under normoxic conditions. Furthermore, in a hindlimb ischemic mouse models, the recovery of blood flow was observed to be highly stimulated in Rx3^+/- mice compared with WT mice. Also, in a Lewis lung carcinoma cell allograft model, the tumor size in Rx3^+/- mice was significantly larger than that in WT mice, and the EPC cell population (CD34⁺/VEGFR2⁺ cells) recruited to the tumor was greater in the Rx3^+/- mice compared with the WT mice. In conclusion, the present study revealed that Runx3 inhibits vasculogenesis via the inhibition of EPC differentiation and functions via the suppression of HIF-1α activity.

• BMB Reports
• /
• v.55 no.9
• /
• pp.465-471
• /
• 2022

Understanding and monitoring virus-mediated infections has gained importance since the global outbreak of the coronavirus disease 2019 (COVID-19) pandemic. Studies of high-throughput omics-based immune profiling of COVID-19 patients can help manage the current pandemic and future virus-mediated pandemics. Although COVID-19 is being studied since past 2 years, detailed mechanisms of the initial induction of dynamic immune responses or the molecular mechanisms that characterize disease progression remains unclear. This study involved comprehensively collected biospecimens and longitudinal multi-omics data of 300 COVID-19 patients and 120 healthy controls, including whole genome sequencing (WGS), single-cell RNA sequencing combined with T cell receptor (TCR) and B cell receptor (BCR) sequencing (scRNA(+scTCR/BCR)-seq), bulk BCR and TCR sequencing (bulk TCR/BCR-seq), and cytokine profiling. Clinical data were also collected from hospitalized COVID-19 patients, and HLA typing, laboratory characteristics, and COVID-19 viral genome sequencing were performed during the initial diagnosis. The entire set of biospecimens and multi-omics data generated in this project can be accessed by researchers from the National Biobank of Korea with prior approval. This distribution of large-scale multi-omics data of COVID-19 patients can facilitate the understanding of biological crosstalk involved in COVID-19 infection and contribute to the development of potential methodologies for its diagnosis and treatment.

• Mass Spectrometry Letters
• /
• v.7 no.3
• /
• pp.69-73
• /
• 2016

High-resolution quadrupole-Orbitrap mass spectrometry (HRMS), with high-resolution (> 10,000 at full-width at half-maximum) and accurate mass (< 5 ppm deviation) capabilities, plays an important role in the structural elucidation of drug metabolites in the pharmaceutical industry. ML106, a derivative of imidazobenzimidazole, decreased melanin content and tyrosinase activity in a dose-dependent manner. Here, we investigated the phase 1 metabolic pathway of ML106 using HRMS in human liver microsomes (HLMs) and recombinant cDNA-expressed cytochrome P450 (CYP). After the incubation of ML106 with pooled HLMs and recombinant cDNA-expressed CYP in the presence of NADPH, five phase 1 metabolites, including three mono-hydroxylated metabolites (M1-3) and two di-hydroxylated metabolites (M4 and M5), were investigated. The metabolite structures were postulated by the elucidation of protonated mass spectra using HRMS. The CYP isoforms related to the hydroxylation of ML106 were studied after incubation with recombinant cDNA-expressed CYP. Here, we identified the phase 1 metabolic pathway of ML106 induced by CYP in HLMs.

• BMB Reports
• /
• v.52 no.4
• /
• pp.271-276
• /
• 2019

Zingerone (ZGR), a phenolic alkanone isolated from ginger, has been reported to possess pharmacological activities such as anti-inflammatory and anti-apoptotic effects. This study was initiated to determine whether ZGR could modulate renal functional damage in a mouse model of sepsis and to elucidate the underlying mechanisms. The potential of ZGR treatment to reduce renal damage induced by cecal ligation and puncture (CLP) surgery in mice was measured by assessment of serum creatinine, blood urea nitrogen (BUN), lipid peroxidation, total glutathione, glutathione peroxidase activity, catalase activity, and superoxide dismutase activity. Treatment with ZGR resulted in elevated plasma levels of BUN and creatinine, and of protein in urine in mice with CLP-induced renal damage. Moreover, ZGR inhibited nuclear $factor-{\kappa}B$ activation and reduced the induction of nitric oxide synthase and excessive production of nitric acid. ZGR treatment also reduced the plasma levels of interleukin-6 and tumor necrosis $factor-{\alpha}$, reduced lethality due to CLP-induced sepsis, increased lipid peroxidation, and markedly enhanced the antioxidant defense system by restoring the levels of superoxide dismutase, glutathione peroxidase, and catalase in kidney tissues. Our study showed renal suppressive effects of zingerone in a mouse model of sepsis, suggesting that ZGR protects mice against sepsis-triggered renal injury.