• Molecules and Cells
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• v.41 no.2
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• pp.119-126
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• 2018

microRNA (miR)-612 shows anticancer activity in several types of cancers, yet its function in melanoma is still unclear. This study was undertaken to investigate the expression of miR-612 and its biological relevance in melanoma cell growth, invasion, and tumorigenesis. The expression and prognostic significance of miR-612 in melanoma were examined. The effects of miR-612 overexpression on cell proliferation, colony formation, tumorigenesis, and invasion were determined. Rescue experiments were conducted to identify the functional target gene(s) of miR-612. miR-612 was significantly downregulated in melanoma tissues compared to adjacent normal tissues. Low miR-612 expression was significantly associated with melanoma thickness, lymph node metastasis, and shorter overall, and disease-free survival of patients. Overexpression of miR-612 significantly decreased cell proliferation, colony formation, and invasion of SK-MEL-28 and A375 melanoma cells. In vivo tumorigenic studies confirmed that miR-612 overexpression retarded the growth of A375 xenograft tumors, which was coupled with a decline in the percentage of Ki-67-positive proliferating cells. Mechanistically, miR-612 targeted Espin in melanoma cells. Overexpression of Espin counteracted the suppressive effects of miR-612 on melanoma cell proliferation, invasion, and tumorigenesis. A significant inverse correlation (r = -0.376, P = 0.018) was observed between miR-612 and Espin protein expression in melanoma tissues. In addition, overexpression of miR-612 and knockdown of Espin significantly increased the sensitivity of melanoma cells to doxorubicin. Collectively, miR-612 suppresses the aggressive phenotype of melanoma cells through downregulation of Espin. Delivery of miR-612 may represent a novel therapeutic strategy against melanoma.

• Molecules and Cells
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• v.41 no.6
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• pp.575-581
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• 2018

Postmenopausal osteoporosis (PMOP) is a common systemic skeletal disease characterized by reduced bone mass and microarchitecture deterioration. Although differentially expressed SOX5 has been found in bone marrow from ovariectomized mice, its role in osteogenic differentiation in human mesenchymal stem cells (hMSCs) from bone marrow in PMOP remains unknown. In this study, we investigated the biological function of SOX5 and explore its molecular mechanism in hMSCs from patients with PMOP. Our findings showed that the mRNA and protein expression levels of SOX5 were upregulated in hMSCs isolated from bone marrow samples of PMOP patients. We also found that SOX5 overexpression decreased the alkaline phosphatase (ALP) activity and the gene expression of osteoblast markers including Collagen I, Runx2 and Osterix, which were increased by SOX5 knockdown using RNA interference. Furthermore, $TNF-{\alpha}$ notably upregulated the SOX5 mRNA expression level, and SOX5 knockdown reversed the effect of $TNF-{\alpha}$ on osteogenic differentiation of hMSCs. In addition, SOX5 overexpression increased Kruppel-like factor 4 (KLF4) gene expression, which was decreased by SOX5 silencing. KLF4 knockdown abrogated the suppressive effect of SOX5 overexpression on osteogenic differentiation of hMSCs. Taken together, our results indicated that $TNF-{\alpha}$-induced SOX5 upregulation inhibited osteogenic differentiation of hMSCs through KLF4 signal pathway, suggesting that SOX5 might be a novel therapeutic target for PMOP treatment.

• Molecules and Cells
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• v.41 no.8
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• pp.771-780
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• 2018

Angiogenesis must be precisely controlled because uncontrolled angiogenesis is involved in aggravation of disease symptoms. Vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR-2) signaling is a key pathway leading to angiogenic responses in vascular endothelial cells (ECs). Therefore, targeting VEGF/VEGFR-2 signaling may be effective at modulating angiogenesis to alleviate various disease symptoms. Oleanolic acid was verified as a VEGFR-2 binding chemical from anticancer herbs with similar binding affinity as a reference drug in the Protein Data Bank (PDB) entry 3CJG of model A coordination. Oleanolic acid effectively inhibited VEGF-induced VEGFR-2 activation and angiogenesis in HUVECs without cytotoxicity. We also verified that oleanolic acid inhibits in vivo angiogenesis during the development and the course of the retinopathy of prematurity (ROP) model in the mouse retina. Taken together, our results suggest a potential therapeutic benefit of oleanolic acid for inhibiting angiogenesis in proangiogenic diseases, including retinopathy.

• Journal of Society of Preventive Korean Medicine
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• v.12 no.3
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• pp.81-90
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• 2008

Objectives : The pathophysiology of ICH is not fully understood, therefore, the fundamental therapeutic strategies for ICH also not well inspected either. The genetic profile for the effect of Carthami Flos extract on cerebral hemorrhage in rat brain tissue was measured using microarray technique. Genes displaying expressional change on brain damage were selected and the functional analysis on these genes was conducted. Methods : Rats were placed in a stereotaxic frame after intraperitoneal injection of chloralhydrate, and ICH was induced by injection of collagenase type IV and Carthami Flos extract was administered orally. The molecular profile of cerebral hemorrhage in rat brain tissue was measured using microarray technique to identify up- or down- regulated genes in brain tissue. Results : Upon treatment with Carthami Flos extract on the rat having brain damage, many genes show expressional change. The pattern of gene expressional change can be classified into 8 classes in which two types of classes were composed of recovered genes from up or down-regulation by brain damage, respectively. Conclusions : Further analysis using protein interaction database identified some key molecules that can be used for elucidation of therapeutical mechanism of Carthami Flos extract in future.

• Restorative Dentistry and Endodontics
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• v.45 no.3
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• pp.31.1-31.20
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• 2020

Matrix metalloproteinases (MMPs) are enzymes that can degrade collagen in hybrid layer and reduce the longevity of adhesive restorations. As scientific understanding of the MMPs has advanced, useful strategies focusing on preventing these enzymes' actions by MMP inhibitors have quickly developed in many medical fields. However, in restorative dentistry, it is still not well established. This paper is an overview of the strategies to inhibit MMPs that can achieve a long-lasting material-tooth adhesion. Literature search was performed comprehensively using the electronic databases: PubMed, ScienceDirect and Scopus including articles from May 2007 to December 2019 and the main search terms were "matrix metalloproteinases", "collagen", and "dentin" and "hybrid layer". MMPs typical structure consists of several distinct domains. MMP inhibitors can be divided into 2 main groups: synthetic (synthetic-peptides, non-peptide molecules and compounds, tetracyclines, metallic ions, and others) and natural bioactive inhibitors mainly flavonoids. Selective inhibitors of MMPs promise to be the future for specific targeting of preventing dentin proteolysis. The knowledge about MMPs functionality should be considered to synthesize drugs capable to efficiently and selectively block MMPs chemical routes targeting their inactivation in order to overcome the current limitations of the therapeutic use of MMPs inhibitors, i.e., easy clinical application and long-lasting effect.

• Natural Product Sciences
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• v.22 no.1
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• pp.70-75
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• 2016

A phytoformula containing the root barks of Morus alba, the fructus of Schizandra sinensis and the roots of Asparagus cochinchinensis (MSA) was prepared as a potential new herbal remedy, and its therapeutic potential for alleviating inflammatory lung conditions was examined. For in vivo evaluation, an animal model of lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice was used. With oral administration of 6 - 60 mg/kg, MSA potently and dose-dependently inhibited bronchitis-like symptoms in acute lung injury induced by intranasal treatment of LPS as judged by the number of cells in the bronchoalveolar lavage fluid (BALF) and histological observation. The inhibitory potency was comparable with that of dexamethasone. For in vitro assay, the effects on the production of proinflammatory molecules in lung epithelial cells and alveolar macrophages were examined. Although MSA inhibited IL-6 production in IL-$1{\beta}$-treated lung epithelial cells (A549) only at a high concentration ($300{\mu}g/ml$), the formula strongly and concentration-dependently inhibited NO production in LPS-treated alveolar macrophages (MH-S) at $20-300{\mu}g/ml$. Based on all of these findings, the new phytoformula MSA is suggested to have the potential to control inflammatory lung diseases including bronchitis, at least in part, by inhibiting inducible nitric oxide synthase-catalyzed NO production.

• Korean Journal of Pharmacognosy
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• v.44 no.3
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• pp.257-262
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• 2013

Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis, the bone mineral density is reduced, bone microarchitecture deteriorates, and the amount and variety of proteins in bone are altered. $It^{\circ}{\emptyset}s$ caused by the imbalance between born resorption and born formation. Recently natural products from plants have been extensively studied as therapeutic drugs to treat and prevent various diseases. Wheat bran is the hard outer layers of wheat grain and produced as a by-product of milling in the production of refined grains. In oriental medicines, Bu So Maek (Tritici Immaturi Semen) with wheat bran has been used as bronchitis, sedatives and anti-sweating effects. However effects of wheat bran butanol fraction (WBB, 50 ${\mu}g/ml$) in osteoclast differentiation remains unknown yet. Thus we investigated the effects of WBB on RANKL induced osteoclast differentiation. WBB inhibited osteoclast differentiation by downregulating the RANKL-induced activations of MAP kinases. Moreover mRNA expression of osteoclast-mediating molecules such as c-Fos, NFATc1 and DC-STAMP were attenuated by WBB during osteoclast differentiation. The finding of this study show that WBB and its components might prevent osteoclast-related bone loss.

• Toxicological Research
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• v.33 no.4
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• pp.325-332
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• 2017

3-Bromo-4,5-dihydroxybenzaldehyde (BDB) is a natural bromophenol compound that is most commonly isolated from red algae. The present study was designed to investigate the anti-inflammatory properties of BDB on atopic dermatitis (AD) in mice induced by 2,4-dinitrochlorobenzene (DNCB) and on lipopolysaccharide (LPS)-stimulated murine macrophages. BDB treatment (100 mg/kg) resulted in suppression of the development of AD symptoms compared with the control treatment (induction-only), as demonstrated by reduced immunoglobulin E levels in serum, smaller lymph nodes with reduced thickness and length, a decrease in ear edema, and reduced levels of inflammatory cell infiltration in the ears. In RAW 264.7 murine macrophages, BDB (12.5, 25, 50, and $100{\mu}M$) suppressed the production of interleukin-6, a proinflammatory cytokine, in a dose-dependent manner. BDB also had an inhibitory effect on the phosphorylation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-${\kappa}B$) and signal transducer and activator of transcription 1 (STAT1; Tyr 701), two major signaling molecules involved in cellular inflammation. Taken together, the results show that BDB treatment alleviates inflammatory responses in an atopic dermatitis mouse model and RAW 264.7 macrophages. These results suggest that BDB may be a useful therapeutic strategy for treating conditions involving allergic inflammation such as atopic dermatitis.

• Biomolecules & Therapeutics
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• v.25 no.3
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• pp.249-258
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• 2017

To examine the effect of biflorin, a component of Syzygium aromaticum, on memory deficit, we introduced a scopolamine-induced cognitive deficit mouse model. A single administration of biflorin increased latency time in the passive avoidance task, ameliorated alternation behavior in the Y-maze, and increased exploration time in the Morris water maze task, indicating the improvement of cognitive behaviors against cholinergic dysfunction. The biflorin-induced reverse of latency in the scopolamine-treated group was attenuated by MK-801, an NMDA receptor antagonist. Biflorin also enhanced cognitive function in a naïve mouse model. To understand the mechanism of biflorin for memory amelioration, we performed Western blot. Biflorin increased the activation of protein kinase C-${\zeta}$ and its downstream signaling molecules in the hippocampus. These results suggest that biflorin ameliorates drug-induced memory impairment by modulation of protein kinase C-${\zeta}$ signaling in mice, implying that biflorin could function as a possible therapeutic agent for the treatment of cognitive problems.

• Molecules and Cells
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• v.37 no.3
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• pp.234-240
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• 2014

Cisplatin is one of the most potent chemotherapy agents. However, its use is limited due to its toxicity in normal tissues, including the kidney and ear. In particular, nephrotoxicity induced by cisplatin is closely associated with oxidative stress and inflammation. Heme oxygenase-1(HO-1), the rate-limiting enzyme in the heme metabolism, has been implicated in a various cellular processes, such as inflammatory injury and anti-oxidant/oxidant homeostasis. Capsaicin is reported to have therapeutic potential in cisplatin-induced renal failures. However, the mechanisms underlying its protective effects on cisplatin-induced nephrotoxicity remain largely unknown. Herein, we demonstrated that administration of capsaicin ameliorates cisplatin-induced renal dysfunction by assessing the levels of serum creatinine and blood urea nitrogen (BUN) as well as tissue histology. In addition, capsaicin treatment attenuates the expression of inflammatory mediators and oxidative stress markers for renal damage. We also found that capsaicin induces HO-1 expression in kidney tissues and HK-2 cells. Notably, the protective effects of capsaicin were completely abrogated by treatment with either the HO inhibitor ZnPP IX or HO-1 knockdown in HK-2 cells. These results suggest that capsaicin has protective effects against cisplatin-induced renal dysfunction through induction of HO-1 as well as inhibition oxidative stress and inflammation.