• Biomolecules & Therapeutics
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• v.28 no.2
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• pp.163-171
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• 2020

Silibinin exhibits antidiabetic potential by preserving the mass and function of pancreatic β-cells through up-regulation of estrogen receptor-α (ERα) expression. However, the underlying protective mechanism of silibinin in pancreatic β-cells is still unclear. In the current study, we sought to determine whether ERα acts as the target of silibinin for the modulation of antioxidative response in pancreatic β-cells under high glucose and high fat conditions. Our in vivo study revealed that a 4-week oral administration of silibinin (100 mg/kg/day) decreased fasting blood glucose with a concurrent increase in levels of serum insulin in high-fat diet/streptozotocin-induced type 2 diabetic rats. Moreover, expression of ERα, NF-E2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) in pancreatic β-cells in pancreatic islets was increased by silibinin treatment. Accordingly, silibinin (10 μM) elevated viability, insulin biosynthesis, and insulin secretion of high glucose/palmitate-treated INS-1 cells accompanied by increased expression of ERα, Nrf2, and HO-1 as well as decreased reactive oxygen species production in vitro. Treatment using an ERα antagonist (MPP) in INS-1 cells or silencing ERα expression in INS-1 and NIT-1 cells with siRNA abolished the protective effects of silibinin. Our study suggests that silibinin activates the Nrf2-antioxidative pathways in pancreatic β-cells through regulation of ERα expression.

• Journal of Microbiology and Biotechnology
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• v.31 no.10
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• pp.1358-1365
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• 2021

To clarify the role of long intergenic nonprotein-coding RNA 1232 (LINC01232) in the progression of gastric cancer and the potential mechanism, we analyzed the expression of LINC01232 in TCGA database using the GEPIA online tool, and the LINC01232 level in gastric cancer cell lines was detected by quantitative real time-polymerase chain reaction (qRT-PCR) as well. Cell proliferation assay, colony formation assay, transwell assay and tumor formation experiment in nude mice were conducted to observe the biological behavior changes of gastric cancer cells through the influence of LINC01232 knockdown. LncATLAS database and subcellular isolation assay were used for subcellular distribution of LINC01232 in gastric cancer cells. The interaction among LINC01232, zeste homolog 2 (EZH2) and kruppel-like factor 2 (KLF2) was clarified by RNA-protein interaction prediction (RPISeq), RNA immunoprecipitation (RIP), qRT-PCR and chromatin immunoprecipitation (ChIP) assay. Rescue experiments were further conducted to elucidate the biological function of LINC01232/KLF2 axis in the progression of gastric cancer. LINC01232 was upregulated in stomach adenocarcinoma (STAD) tissues and gastric cancer lines. LINC01232 knockdown inhibited the proliferative capacities of gastric cancer cells in vitro, and impaired in vivo tumorigenicity. LINC01232 was mainly distributed in the cell nucleus where it epigenetically repressed KLF2 expression via binding to the enhancer of EZH2, which was capable of binding to promoter regions of KLF2 to induce histone H3 lysine 27 trimethylation (H3K27me3). LINC01232 exerts oncogenic activities in gastric cancer via inhibition of KLF2, and therefore, the knockdown of KLF2 could reverse the regulatory effect of LINC01232 in the proliferative ability of gastric cancer cells.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.22
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• pp.9805-9812
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• 2014

Radixin, a member of the ERM (ezrin-radixin-moesin) family, plays important roles in cell motility, invasion and tumor progression. It is expressed in a variety of normal and neoplastic cells, including many types of epithelial and lymphoid examples. However, its function in glioblastomas remains elusive. Thus, in this study, radixin gene expression was first examined in the glioblastoma cells, then suppressed with a lentivirus-mediated short-hairpin RNA (shRNA) method.We found that there were high levels of radixin expression in glioblastoma U251cells. Radixin shRNA caused down-regulation of radixin gene expression and when radixin-silenced cells were implanted into nude mice, tumor growth was significantly inhibited as compared to blank control cells or nonsense shRNA cells. In addition, microvessel density in the tumors was significantly reduced. Thrombospondin-1 (TSP-1) and E-cadherin were up-regulated in radixin- suppressed glioblastoma U251 cells. In contrast, MMP9 was down-regulated. Taken together, our findings suggest that radixin is involved in GBM cell migration and invasion, and implicate TSP-1, E-cadherin and MMP9 as metastasis-inducing factors.

• Journal of Pharmaceutical Investigation
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• v.40 no.3
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• pp.139-153
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• 2010

Nitrosative stress is defined as pathophysiological conditions that are related to covalent modifications of proteins by nitration/nitrosylation by forms of nitrogen oxide ($NO_x$), leading to DNA damage, ultimately, cell death. This type of stress condition appears to be associated with a number of disease states, including diabetes, inflammation and neurodegenerative diseases. Since these pathological conditions are frequently chronic in nature and, thus, require long-term treatment, changes in pharmacokinetics are likely to affect the therapy. Transporters are membrane proteins that facilitate the movement of substrates, including drugs, across plasma membranes of epithelial / endothelial cells. Since it is now increasingly evident that transporters are pharmacokinetically significant, functional alteration of transporters by this stress condition may have therapeutic relevance. In this review, experimental techniques that are used to study both in vivo and in vitro nitrosative stress are summarized and discussed, along with available literature information on the functional implication of transporters under conditions of nitrosative stress conditions. In the literature, both functional induction and impa irment were apparently present for both drug transporter families [i.e., ATP-binding cassette (ABC) and solute carrier families (SLC)]. Furthermore, a change in the function of a certain transporter appears to have temporal dependency by impairment in the early phase of nitrosative stress and induction thereafter, suggesting that the role of nitrosative stress is complex in terms of functional implications of the transporters. Although the underlying mechanisms for these alterations are not fully understood, protein nitration/nitrosylation appears to be involved in the functional impairment whereas transcript factor(s) activated by nitrosative stress may play a role, at least in part, in functional induction. Interestingly, functional induction under conditions of nitrosative stress has not been observed for SLC transporters while such impairment has been documented for both ABC and SLC transporters. Further investigations appear to be necessary to fully delineate the underlying reasons for these differences on the impact and importance of nitrosative stress conditions.

• Journal of Microbiology and Biotechnology
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• v.32 no.7
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• pp.877-884
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• 2022

Probiotics are microorganisms that can benefit host health when ingested in a live state, and lactic acid bacteria are the most common type. Among fungi, Saccharomyces boulardii (SB) is the only strain known to have a probiotic function with beneficial effects on colitis; however, information on other probiotic yeast strains is limited. Therefore, this study aimed to discover yeast strains expressing intestinal anti-inflammatory activities by exhibiting probiotic properties in dextran sodium sulfate (DSS)-induced colitis mice model. Nuruk (Korean traditional fermentation starter) containing various microbial strains was used as a source for yeast strains, and S. cerevisiae 28-7 (SC28-7) strain was selected with in vitro and in vivo characteristics to enable survival in the intestines. After 14 days of pretreatment with the yeast strains, DSS was co-administered for six days to induce colitis in mice. The results revealed that the disease activity index score was lowered by SC28-7 treatment compared to the DSS group, and the colon length and weight/length ratio were recovered in a pattern similar to that of the normal group. SC28-7 administration significantly reduced the secretion of pro-inflammatory cytokines in the serum and modified the mRNA expression of inflammatory cytokines (interleukin-1β, transforming growth factor-β, and interferon-γ) and proteins involved in gut barrier functions (mucin 2, mucin 3, zonula occludens-1, and occludin) in colon tissues. These results indicate that SC28-7 attenuates DSS-induced colon damage and inflammation, supporting its future use as a probiotic yeast for treating and preventing intestinal inflammatory diseases such as inflammatory bowel disease.

• Biomolecules & Therapeutics
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• v.26 no.2
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• pp.109-114
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• 2018

Liquiritigenin (LQ) is a flavonoid that can be isolated from Glycyrrhiza radix. It is frequently used as a tranditional oriental medicine herbal treatment for swelling and injury and for detoxification. However, the effects of LQ on cognitive function have not been fully explored. In this study, we evaluated the memory-enhancing effects of LQ and the underlying mechanisms with a focus on the N-methyl-D-aspartic acid receptor (NMDAR) in mice. Learning and memory ability were evaluated with the Y-maze and passive avoidance tests following administration of LQ. In addition, the expression of NMDAR subunits 1, 2A, and 2B; postsynaptic density-95 (PSD-95); phosphorylation of $Ca^{2+}$/calmodulin-dependent protein kinase II (CaMKII); phosphorylation of extracellular signal-regulated kinase 1/2 (ERK 1/2); and phosphorylation of cAMP response element binding (CREB) proteins were examined by Western blot. In vivo, we found that treatment with LQ significantly improved memory performance in both behavioral tests. In vitro, LQ significantly increased NMDARs in the hippocampus. Furthermore, LQ significantly increased PSD-95 expression as well as CaMKII, ERK, and CREB phosphorylation in the hippocampus. Taken together, our results suggest that LQ has cognition enhancing activities and that these effects are mediated, in part, by activation of the NMDAR and CREB signaling pathways.

• Biomolecules & Therapeutics
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• v.25 no.6
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• pp.641-647
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• 2017

Galangin (3,5,7-trihydroxyflavone) is a polyphenolic compound abundant in honey and medicinal herbs, such as Alpinia officinarum. In this study, we investigated the anti-inflammatory effects of galangin under in vitro and in vivo neuroinflammatory conditions caused by polyinosinic-polycytidylic acid (poly(I:C)), a viral mimic dsRNA analog. Galangin suppressed the production of nitric oxide, reactive oxygen species, and pro-inflammatory cytokines in poly(I:C)-stimulated BV2 microglia. On the other hand, galangin enhanced anti-inflammatory interleukin (IL)-10 production. Galangin also suppressed the expression of pro-inflammatory markers in poly(I:C)-injected mouse brains. Further mechanistic studies showed that galangin inhibited poly(I:C)-induced nuclear factor (NF)-${\kappa}B$ activity and phosphorylation of Akt without affecting MAP kinases. Interestingly, galangin increased the expression and transcriptional activity of peroxisome proliferator-activated receptor (PPAR)-${\gamma}$, known to play an anti-inflammatory role. To investigate whether PPAR-${\gamma}$ is involved in the anti-inflammatory function of galangin, BV2 cells were pre-treated with PPAR-${\gamma}$ antagonist before treatment of galangin. We found that PPAR-${\gamma}$ antagonist significantly blocked galangin-mediated upregulation of IL-10 and attenuated the inhibition of tumor necrosis factor (TNF)-${\alpha}$ and IL-6 in poly(I:C)-stimulated microglia. In conclusion, our data suggest that PI3K/Akt, NF-${\kappa}B$, and PPAR-${\gamma}$ play a pivotal role in mediating the anti-inflammatory effects of galangin in poly(I:C)-stimulated microglia.

• Biomolecules & Therapeutics
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• v.31 no.5
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• pp.484-495
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• 2023

Idiopathic pulmonary fibrosis (IPF) can be defined as a progressive chronic pulmonary disease showing scarring in the lung parenchyma, thereby resulting in increase in mortality and decrease in the quality of life. The pathophysiologic mechanism of fibrosis in IPF is still unclear. Repetitive microinjuries to alveolar epithelium with genetical predisposition and an abnormal restorative reaction accompanied by excessive deposition of collagens are involved in the pathogenesis. Although the two FDA-approved drugs, pirfenidone and nintedanib, are under use for retarding the decline in lung function of patients suffered from IPF, they are not able to improve the survival rate or quality of life. Therefore, a novel therapeutic agent acting on the major steps of the pathogenesis of disease and/or, at least, managing the clinical symptoms of IPF should be developed for the effective regulation of this incurable disease. In the present review, we tried to find a potential of managing the clinical symptoms of IPF by natural products derived from medicinal plants used for controlling the pulmonary inflammatory diseases in traditional Asian medicine. A multitude of natural products have been reported to exert an antifibrotic effect in vitro and in vivo through acting on the epithelial-mesenchymal transition pathway, transforming growth factor (TGF)- β-induced intracellular signaling, and the deposition of extracellular matrix. However, clinical antifibrotic efficacy of these natural products on IPF have not been elucidated yet. Thus, those effects should be proven by further examinations including the randomized clinical trials, in order to develop the ideal and optimal candidate for the therapeutics of IPF.

• Mycobiology
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• v.46 no.2
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• pp.159-167
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• 2018

This study evaluated the in vitro and in vivo hypolipidemic effects of the medicinal mushroom Phellinus pini. The methanol extract (ME) of the fruiting body of Ph. pini was active against pancreatic lipase and cholesterol esterase with 99.14% and 67.23% inhibited activity at 1.0 mg/mL, respectively. It also inhibited 81.81% and 55.33% of ${\alpha}$-glucosidase and ${\alpha}$-amylase activities, respectively, at 2.0 mg/mL. Hyperlipidemia as induced by feeding rats with a high fat and cholesterol diet (HFC). HFC supplemented with a 5% fruiting body powder of Ph. pini (HFC + PhP) significantly reduced plasma total cholesterol, low-density lipoprotein cholesterol, and triglycerides in rats compared with HFC. The reduced levels were comparable to rats fed the normal control diet (NC). The atherogenic index of HFC + PhP rats was significantly lower than that of the HFC rats. The excretion of fecal total lipid and cholesterol in the HFC + PhP rats was significantly higher than those in the NC and HFC rats. Histopathological examinations demonstrated scant deposition of lipids in the liver of rats fed HFC + PhP. The dietary supplementation with the fruiting body powder provided natural plasma lipid and glucose lowering effects in experimental rats without adverse effects on the plasma biochemical parameters and liver function related enzyme activities. Therefore, the hypolipidemic effects of Ph. pini may be due to the inhibitory effects on pancreatic lipase, cholesterol esterase, ${\alpha}$-glucosidase, and ${\alpha}$-amylase, and excretion of excess lipids and cholesterol in the feces.

• Molecules and Cells
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• v.45 no.6
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• pp.376-387
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• 2022

Extracellular vesicles (EVs) play an essential role in the communication between cells and the tumor microenvironment. However, the effect of tumor-derived EVs on the growth and metastasis of lung adenocarcinoma (LUAD) remains to be explored. This study aimed to elucidate the role of miR-153-3p-EVs in the invasion and migration capabilities of LUAD cells and explore its mechanism through in vivo and in vitro experiments. We found that miR-153-3p was specifically and highly expressed in LUAD and its secreted EVs. Furthermore, the expression of BANCR was negatively regulated by miR-153-3p and identified as a target gene of miR-153-3p using luciferase reporter assays. Through further investigation, we found that the downregulation of BANCR activates the PI3K/AKT pathway and accelerates the process of epithelial-mesenchymal transition (EMT), which ultimately leads to the aggravation of LUAD. The orthotopic xenograft mouse model was established to illustrate the effect of miR-153-3p-EVs on LUAD. Animal studies showed that miR-153-3p-EVs accelerated tumor growth in mice. Besides, we found that miR-153-3p-EVs could damage the respiratory ability of mice and produce a mass of inflammatory cells around the lung tissue of mice. Nevertheless, antagomir-153-3p treatment could inhibit the deterioration of respiratory function and inhibit the growth of lung tumors in mice. In conclusion, our study reveals the potential molecular mechanism of miR-153-3p-EVs in the development of LUAD and provides a potential strategy for the treatment of LUAD.