• Oncology Letters
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• v.18 no.6
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• pp.6361-6370
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• 2019

Angiogenesis is an essential step in cancer progression and metastasis. Changes in the microRNA (miRNA or miR) expression profiles of endothelial cells (ECs) elicited by cancer cells promote angiogenesis. Vascular endothelial growth factor (VEGF), a key pro-angiogenic factor, influences miRNA expression in ECs; however, the exact role that VEGF serves in miRNA regulation during angiogenesis is poorly defined. The present study aimed to demonstrate the differential angiogenic effects on human umbilical vein endothelial cells (HUVECs) of five different colorectal cancer (CRC) cell lines by in vitro HUVEC migration and angiogenesis assays in response to CRC-conditioned medium (CM). Among the tested CMs, LoVo was the most effective cell line in eliciting HUVEC angiogenic phenotypes, at least partially due to its high VEGF level. It was also observed that pro-angiogenesis-regulatory miRNAs (angio-miRNA) miR-296, miR-132, miR-105 and miR-200 were upregulated in the VEGF-rich LoVo CM compared with the VEGF-scarce SW620 CM. In addition, treatment with VEGF receptor 2 inhibitor downregulated the pro-angio-miRNAs, with the exception of miR-132, suggesting that VEGF, as well as additional signaling, is required for angio-miRNA expression. Quantitative analyses on pro-angio-miRNA target expression suggested that independent pathways may be involved in the regulation of their expression. Overall, the data from the present study indicated that multiple paracrine factors, including VEGF secreted by CRCs, effectively modulated angio-miRNA expression, thus impacting their target expression and the angiogenic phenotypes of HUVECs.

• Nutrition Research and Practice
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• v.17 no.4
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• pp.682-697
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• 2023

BACKGROUND/OBJECTIVES: Tibetan tea is a kind of dark tea, due to the inherent complexity of natural products, the chemical composition and beneficial effects of Tibetan tea are not fully understood. The objective of this study was to unravel the composition of Tibetan tea using knowledge-guided multilayer network (KGMN) techniques and explore its potential antioxidant and hypolipidemic mechanisms in mice. MATERIALS/METHODS: The C57BL/6J mice were continuously gavaged with Tibetan tea extract (T group), green tea extract (G group) and ddH2O (H group) for 15 days. The activity of total antioxidant capacity (T-AOC) and superoxide dismutase (SOD) in mice was detected. Transcriptome sequencing technology was used to investigate the molecular mechanisms underlying the antioxidant and lipid-lowering effects of Tibetan tea in mice. Furthermore, the expression levels of liver antioxidant and lipid metabolism related genes in various groups were detected by the real-time quantitative polymerase chain reaction (qPCR) method. RESULTS: The results showed that a total of 42 flavonoids are provisionally annotated in Tibetan tea using KGMN strategies. Tibetan tea significantly reduced body weight gain and increased T-AOC and SOD activities in mice compared with the H group. Based on the results of transcriptome and qPCR, it was confirmed that Tibetan tea could play a key role in antioxidant and lipid lowering by regulating oxidative stress and lipid metabolism related pathways such as insulin resistance, P53 signaling pathway, insulin signaling pathway, fatty acid elongation and fatty acid metabolism. CONCLUSIONS: This study was the first to use computational tools to deeply explore the composition of Tibetan tea and revealed its potential antioxidant and hypolipidemic mechanisms, and it provides new insights into the composition and bioactivity of Tibetan tea.

• Toxicological Research
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• v.23 no.1
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• pp.55-63
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• 2007

Diethylnitrosamine (DEN) is a nitrosamine compound that can induce a variety of liver lesions including hepatic carcinoma, forming DNA-carcinogen adducts. In the present study, microarray analyses were performed with Affymetrix Murine Genome 430A Array in order to identify the gene-expression profiles for DEN and to provide valuable information for the evaluation of potential hepatotoxicity. C57BL/6NCrj mice were orally administered once with DEN at doses of 0, 3, 7 and 20 mg/kg. Liver from each animal was removed 2, 4, 8 and 24 hrs after the administration. The histopathological analysis and serum biochemical analysis showed no significant difference in DEN-treated groups compared to control group. Conversely, the principal component analysis (PCA) profiles demonstrated that a specific normal gene expression profile in control groups differed clearly from the expression profiles of DEN-treated groups. Within groups, a little variance was found between individuals. Student's t-test on the results obtained from triplicate hybridizations was performed to identify those genes with statistically significant changes in the expression. Statistical analysis revealed that 11 genes were significantly downregulated and 28 genes were upregulated in all three animals after 2 h treatment at 20 mg/kg. The upregulated group included genes encoding Gdf15, JunD1, and Mdm2, while the genes including Sox6, Shmt2, and SIc6a6 were largely down regulated. Hierarchical clustering of gene expression also allowed the identification of functionally related clusters that encode proteins related to metabolism, and MAPK signaling pathway. Taken together, this study suggests that match with a toxicant signature can assign a putative mechanism of action to the test compound if is established a database containing response patterns to various toxic compounds.

• Animal Bioscience
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• v.37 no.1
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• pp.28-38
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• 2024

Objective: Tibetan chickens, which have unique adaptations to extreme high-altitude environments, exhibit phenotypic and physiological characteristics that are distinct from those of lowland chickens. However, the mechanisms underlying hypoxic adaptation in the liver of chickens remain unknown. Methods: RNA-sequencing (RNA-Seq) technology was used to assess the differentially expressed genes (DEGs) involved in hypoxia adaptation in highland chickens (native Tibetan chicken [HT]) and lowland chickens (Langshan chicken [LS], Beijing You chicken [BJ], Qingyuan Partridge chicken [QY], and Chahua chicken [CH]). Results: A total of 352 co-DEGs were specifically screened between HT and four native lowland chicken breeds. Gene ontology and Kyoto encyclopedia of genes and genomes enrichment analyses indicated that these co-DEGs were widely involved in lipid metabolism processes, such as the peroxisome proliferator-activated receptors (PPAR) signaling pathway, fatty acid degradation, fatty acid metabolism and fatty acid biosynthesis. To further determine the relationship from the 352 co-DEGs, protein-protein interaction network was carried out and identified eight genes (ACSL1, CPT1A, ACOX1, PPARC1A, SCD, ACSBG2, ACACA, and FASN) as the potential regulating genes that are responsible for the altitude difference between the HT and other four lowland chicken breeds. Conclusion: This study provides novel insights into the molecular mechanisms regulating hypoxia adaptation via lipid metabolism in Tibetan chickens and other highland animals.

• Korean Chemical Engineering Research
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• v.57 no.3
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• pp.305-312
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• 2019

The discovery of nitric oxide (NO) as a major signaling molecule in a number of pathophysiological processes - vasodilation, immune response, platelet aggregation, wound repair, and cancer biology - has led to the development of various exogeneous NO delivery systems. However, the development of ideal delivery system for human body application is still left as a challenge due to its high reactivity and short half-life in physiological condition. In this article, an overview of several nano-structures as potential NO delivery system will be presented, along with their recent research results and biomedical applications. Nano-size delivery system has immense advantages compared to others due to its high surface-to-volume ratio and capability for surface modification; thus, it has been proven to be effective in delivering nitric oxide with enhanced performance. Through this novel nano-structure delivery system, we are expecting to achieve sustained release of nitric oxide within adequate range of concentration, which ensures desired drug effects at the target site. Among different nano-structures, in particular, nanoparticle, microemulsion and nanofilm will be reviewed and compared to each other in respect of nitric oxide release profile. The proposed nano-structures for exogeneous NO delivery have a biological significance in that it can be further utilized in diverse biomedical fields as a highly promising therapeutic method.

• Nutrition Research and Practice
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• v.16 no.6
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• pp.729-744
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• 2022

BACKGROUND/OBJECTIVES: 4-Hydroxy-2-nonenal (HNE) is a biomarker for oxidative stress to induce inflammation. Methionine is an essential sulfur-containing amino acid with antioxidative activity. On the other hand, the evidence on whether and how methionine can depress HNE-derived inflammation is lacking. In particular, the link between the regulation of the nuclear factor-κB (NF-κB) signaling pathway and methionine intake is unclear. This study examined the link between depression from HNE accumulation and the anti-inflammatory function of ⳑ-methionine in rats. MATERIALS/METHODS: Male Wistar rats (3-week-old, weighing 70-80 g) were administered different levels of ⳑ-methionine orally at 215.0, 268.8, 322.5, and 430.0 mg/kg body weight for two weeks. The control group was fed commercial pellets. The hepatic HNE contents and the protein expression and mRNA levels of the inflammatory mediators were measured. The interleukin-10 (IL-10) and glutathione S-transferase (GST) levels were also estimated. RESULTS: Compared to the control group, hepatic HNE levels were reduced significantly in all groups fed ⳑ-methionine, which were attributed to the stimulation of GST by ⳑ-methionine. With decreasing HNE levels, ⳑ-methionine inhibited the activation of NF-κB by up-regulating inhibitory κBα and depressing phosphoinositide 3 kinase/protein kinase B. The mRNA levels of the inflammatory mediators (cyclooxygenase-2, interleukin-1β, interleukin-6, inducible nitric oxide synthase, tumor necrotic factor alpha) were decreased significantly by ⳑ-methionine. In contrast, the protein expression of these inflammatory mediators was effectively down regulated by ⳑ-methionine. The anti-inflammatory action of ⳑ-methionine was also reflected by the up-regulation of IL-10. CONCLUSIONS: This study revealed a link between the inhibition of HNE accumulation and the depression of inflammation in growing rats, which was attributed to ⳑ-methionine availability. The anti-inflammatory mechanism exerted by ⳑ-methionine was to inhibit NF-κB activation and to up-regulate GST.

• Bulletin of the Korean Chemical Society
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• v.30 no.9
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• pp.2083-2086
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• 2009

Human vascular endothelial growth factor receptor 2 (hVEGFR2) is an important signaling protein involved in angiogenesis and attractive drug target in cancer therapy. It has been reported that flavonols, a class of flavonoids, have anti-angiogenic activity in various cancer cell lines. We performed receptor-oriented pharmacophore based in silico screening for identification of hVEGFR2 inhibitors from flavonol database. By comparing with three X-ray complex structures of hVEGFR2 and its inhibitors, we evaluated the specific interactions between inhibitors and receptors and determined a single pharmacophore map. This map consisted of four features, a hydrogen bonding acceptor (HBA) on Cys917, two hydrogen bonding donors on Glu917 (HBD1) and Glu883 (HBD2), and one hydrophobic interaction (Lipo) with Val846, Ala864, Val897, Val914 and Phe1045 of hVEGFR2. Using this map, we searched a flavonol database including 9 typical flavonols and proposed that five flavonols, kaempferol, quercetin, fisetin, morin, and rhamnetin can be potent inhibitors of hVEGFR2. 3-OH of C-ring and 4’-OH of B-ring of flavonols are the essential features for hVEGFR2 inhibition. This study will be helpful for understanding the mechanism of inhibition of hVEGFR2 by natural products.

• Journal of Microbiology and Biotechnology
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• v.30 no.1
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• pp.31-37
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• 2020

We previously identified a new heparinase inhibitor fungal metabolite, named CRM646-A, which showed inhibition of heparinase and telomerase activities in an in vitro enzyme assay and antimetastatic activity in a cell-based assay. In this study, we elucidated the mechanism by which CRM646-A rapidly induced nucleus condensation, plasma membrane disruption and morphological changes by increasing intracellular Ca²⁺ levels. Furthermore, PD98059, a mitogen-activated protein kinase (MEK) inhibitor, inhibited CRM646-A-induced nucleus condensation through ERK1/2 activation in rat 3Y1 fibroblast cells. We identified CRM646-A as a Ca²⁺ ionophore-like agent with a distinctly different chemical structure from that of previously reported Ca²⁺ ionophores. These results indicate that CRM646-A has the potential to be used as a new and effective antimetastatic drug.

• Korean Chemical Engineering Research
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• v.58 no.4
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• pp.514-523
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• 2020

Plants are exposed to various types of stresses in their surroundings, and stress-resistant and regulatory proteins are produced as defense mechanisms. Abscisic acid is well known for its important role in stress signals as a phytohormone and is also involved in the physiological reactions of plants such as leaf senescence and seed dormancy. In particular, it has been found to perform a variety of functions in other biological systems, such as animals and microalgae, not plants. In this review, the biosynthesis and signaling process of abscisic acid and its function were investigated and the future prospects for the industrial application of abscisic acid in various biotechnologies, including agriculture, biomedical and industrial biotechnology, have been proposed based on study of emerging applications such as increased crop yields, disease treatment development and bioenergy production.

• Bulletin of the Korean Chemical Society
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• v.32 no.12
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• pp.4397-4402
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• 2011

The NF-${\kappa}B$ system of transcription factors plays a crucial role in inflammatory diseases, making it an important drug target. We combined quantitative structure activity relationships for predicting the activity of new compounds and quantitative dynamic models for the NF-${\kappa}B$ network with intracellular concentration models. GFA-MLR QSAR analysis was employed to determine the optimal QSAR equation. To validate the predictability of the $IKK{\beta}$ QSAR model for an external set of inhibitors, a set of ordinary differential equations and mass action kinetics were used for modeling the NF-${\kappa}B$ dynamic system. The reaction parameters were obtained from previously reported research. In the IKKb QSAR model, good cross-validated $q^2$ (0.782) and conventional $r^2$ (0.808) values demonstrated the correlation between the descriptors and each of their activities and reliably predicted the $IKK{\beta}$ activities. Using a developed simulation model of the NF-${\kappa}B$ signaling pathway, we demonstrated differences in $I{\kappa}B$ mRNA expression between normal and different inhibitory states. When the inhibition efficiency increased, inhibitor 1 (PS-1145) led to long-term oscillations. The combined computational modeling and NF-${\kappa}B$ dynamic simulations can be used to understand the inhibition mechanisms and thereby result in the design of mechanism-based inhibitors.