• Molecules and Cells
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• v.43 no.11
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• pp.945-952
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• 2020

Hypoxia induces the expression of several genes through the activation of a master transcription factor, hypoxia-inducible factor (HIF)-1α. This study shows that hypoxia strongly induced the expression of two carboxypeptidases (CP), CPA4 and CPE, in an HIF-1α-dependent manner. The hypoxic induction of CPA4 and CPE gene was accompanied by the recruitment of HIF-1α and upregulation in the active histone modification, H3K4me3, at their promoter regions. The hypoxic responsiveness of CPA4 and CPE genes was observed in human adipocytes, human adipose-derived stem cells, and human primary fibroblasts but not mouse primary adipocyte progenitor cells. CPA4 and CPE have been identified as secreted exopeptidases that degrade and process other secreted proteins and matrix proteins. This finding suggests that hypoxia changes the microenvironment of the obese hypoxic adipose tissue by inducing the expression of not only adipokines but also peptidases such as CPA4 and CPE.

• Bulletin of the Korean Chemical Society
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• v.33 no.11
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• pp.3835-3837
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• 2012

• Korean Journal of Plant Resources
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• v.35 no.3
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• pp.391-398
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• 2022

Ulcerative colitis (UC) is a typical inflammatory colon disorder. Platycodon grandiflorum (PG) is known to exert various beneficial effects including anti-oxidative and anti-bacterial properties and improvements in liver function. However, the improving effect and mechanism of PG on intestinal inflammation are not fully understood. The present research was designed to investigate the effect of PG on the clinical signs of DSS-induced colitis in mice. The ameliorative effects of PG on inflammatory cytokine expression and the activation of hypoxia-inducible-factor (HIF)-1α in DSS-treated colon tissue were also determined. Our results showed that mice treated with DSS displayed the main clinical symptoms of colitis, including weight loss, bloody stools, decrease in colon length and diarrhea and PG treatment significantly improved the clinical features induced by DSS in mice. PG inhibited the increase in the levels of inflammatory cytokines caused by DSS in colon tissues. We also showed that the anti-inflammatory mechanism of PG involved suppressing the activation of HIF-1α in DSS-treated colon tissues. Collectively, the findings of this study indicate the prospect of developing new drugs from PG for UC treatment.

• Journal of Gastric Cancer
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• v.21 no.4
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• pp.439-456
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• 2021

Purpose: Gastric cancer (GC) has high morbidity and mortality and is a serious threat to public health. The flavonoid compound vitexin is known to exhibit anti-tumor activity. In this study, we explored the therapeutic potential of vitexin in GC and its underlying mechanism. Materials and Methods: The viability, migration, and invasion of GC cells were determined using MTT, scratch wound healing, and transwell assays, respectively. Target molecule expression was determined by western blotting. Tumor growth and liver metastasis were evaluated in vivo using nude mice. Protein expression in the tumor tissues was examined by immunohistochemistry. Results: Vitexin inhibited GC cell viability, migration, invasion, and epithelial-mesenchymal transition (EMT) in a dose-dependent manner. Vitexin treatment led to the inactivation of phosphatidylinositol-3-kinase (PI3K)/AKT/hypoxia-inducible factor-1α (HIF-1α) pathway by repressing HMGB1 expression. Vitexin-mediated inhibition in proliferation, migration, invasion and EMT of GC cells were counteracted by hyper-activation of PI3K/AKT/HIF-1α pathway or HMGB1 overexpression. Finally, vitexin inhibited the xenograft tumor growth and liver metastasis in vivo by suppressing HMGB1 expression. Conclusions: Vitexin inhibited the malignant progression of GC in vitro and in vivo by suppressing HMGB1-mediated activation of PI3K/Akt/HIF-1α signaling pathway. Thus, vitexin may serve as a promising therapeutic agent for the treatment of GC.

• Journal of the Korea Academia-Industrial cooperation Society
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• v.11 no.3
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• pp.1133-1138
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• 2010

The purpose of our study was to evaluate the correlation between expression of VEGF, HIF-$1{\alpha}$, E-cadherin, and p53 and pathologic stage. We retrospectively reviewed the medical records of the 101 patients who underwent surgery of thyroid nodules from 2000 to 2007. Expression of VEGF, HIF-$1{\alpha}$, E-cadherin, and p53 were examinated immunohistochemically. Papillary thyroid carcinoma in this study included 54 cases of more than 45 years old. Each expression of VEGF, HIF-$1{\alpha}$, E-cadherin, and p53 was analysed. Only expression loss of E-cadherin was associated with the stage. High HIF-1 expression was significantly associated with VEGF immunoreactivity (p<0.05). Expression loss of E-cadherin was independent unfavorable factors. It is suggested that high HIF-$1{\alpha}$ expression may be associated with intratumoral neovascularization possibly through HIF-VEGF pathway.

• 한국체육학회지인문사회과학편
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• v.51 no.3
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• pp.363-372
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• 2012

One of the major ocular complications of diabetes mellitus(DM) is retinopathy, which is characterized by increased neovascularization and neural degeneration in the retina. In the present study, we investigated the effects of treadmill exercise on retinopathy in the rats with DM. Thirty-two male Sprague-Dawley rats were divided into four groups(n = 8 in each group): control group, exercise group, DM-induction group, and DM-induction and exercise group. DM was induced by intraperitoneal injection of streptozotocin. The rats in the exercise groups were made to run on the treadmill for 30 min five times per a week, during 12 weeks. The expressions of phosphoinositide 3-kinase(PI3K), phospho-protein kinase B(pAkt), hypoxia inducible factor-1α(HIF-1α), and vascular endothelial growth factor(VEGF) in the retina were determined using western blot analysis and immunohistochemistry. In the present results, the expressions of PI3K, pAkt, HIF-1α, and VEGF in the retina of the diabetic rats were increased. Treadmill exercise suppressed HIF-1α and VEGF expressions through inhibition of PI3K/pAkt pathway in the diabetic rats. These results suggest that treadmill exercise may ameliorate the progression of diabetes-induced retinopathy by inhibiting neovascularization in the retina.

• Journal of the Korean Applied Science and Technology
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• v.38 no.3
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• pp.750-761
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• 2021

This study was performed to observe the responses of angiogenesis-related protein expression in skeletal muscle of aged rats by regular resistance exercise training with aerobic exercise. For the purpose of the study, naturally aged SD rats (20-24 months, N=18) were used and divided into control (CON, n=6), resistance exercise (RE, n=6), and resistance + aerobic exercise (RE + AE, n=6) groups. RE group performed 3 sets × 4 exercises each session using a ladder for laboratory animals, and RE +AE group performed 2 sets × 3 times of ladder climbing and additional treadmill running (30 min) each session. After 8 weeks of exercise training, soleus muscle and extensor digitorum longus muscle (EDL) were extracted and used for analysis. Western blot was performed to analyze the expression levels of angiogenesis-related proteins (HIF-1α, VEGF, FLK-1, Ang-1, Ang-2) in skeletal muscle. As a result of the study, the expression of HIF-1α, VEGF, FLK-1, Ang-1, and Ang-2 proteins in soleus muscle (type I muscle) was higher in RE +AE than in CON group, and HIF-1α, VEGF, Ang-1, Ang-2 protein expression of RE group was higher than that of CON group. Furthermore, Ang-2 to Ang-1 ratio of RE + AE group was higher than that of RE group, showing differences by exercise type. In EDL muscle (type II muscle), HIF-1α was increased only by RE group, whereas VEGF and FLK-1 protein expressions were increased in both training types, and no difference was observed between the types of exercise training. In addition, there was no difference in angiopoieitin protein expressions in EDL muscle by exercise training. Therefore, in aging, regular exercise training induces skeletal muscle angiogenic response regardless of exercise type, and in particular, the combination of aerobic exercise with resistance exercise may have an additional positive effect on angiogenesis in type I muscle.

• Molecules and Cells
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• v.27 no.2
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• pp.243-250
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• 2009

Recent studies suggest a novel role of $HIF-1{\alpha}$ under nonhypoxic conditions, including antibacterial and antiviral innate immune responses. However, the identity of the pathogen-associated molecular pattern which triggers $HIF-1{\alpha}$ activation during the antiviral response remains to be identified. Here, we demonstrate that cellular administration of double-stranded nucleic acids, the molecular mimics of viral genomes, results in the induction of $HIF-1{\alpha}$ protein level as well as the increase in $HIF-1{\alpha}$ target gene expression. Whole-genome DNA microarray analysis revealed that double-stranded nucleic acid treatment triggers induction of a number of hypoxia-inducible genes, and induction of these genes are compromised upon siRNA-mediated $HIF-1{\alpha}$ knock-down. Interestingly, $HIF-1{\alpha}$ knock-down also resulted in down-regulation of a number of genes involved in antiviral innate immune responses. Our study demonstrates that $HIF-1{\alpha}$ activation upon nucleic acid-triggered antiviral innate immune responses plays an important role in regulation of genes involved in not only hypoxic response, but also immune response.

• BMB Reports
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• v.42 no.11
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• pp.737-742
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• 2009

Hypoxia-inducible factor-$1{\alpha}/{\beta}$ (HIF-$1{\alpha}/{\beta}$) is a heterodimeric transcriptional activator that mediates gene expression in response to hypoxia. HIF-$1{\alpha}$ has been noted as an effective therapeutic target for ischemic diseases such as myocardiac infarction, stroke and cancer. By using a yeast two-hybrid system and a random peptide library, we found a 16-mer peptide named F29 that directly interacts with the bHLH-PAS domain of HIF-$1{\alpha}$. We found that F29 facilitates the interaction of the HIF-$1{\alpha/\beta}$ heterodimer with its target DNA sequence, hypoxia-responsive element (HRE). The transient transfection of an F29-expressing plasmid increases the expression of both an HRE-driven luciferase gene and the endogenous HIF-1 target gene, vascular endothelial growth factor (VEGF). Taken together, we conclude that F29 increases the DNA-binding ability of HIF-$1{\alpha}$, leading to increased expression of its target gene VEGF. Our results suggest that F29 can be a lead compound that directly targets HIF-$1{\alpha}$ and increases its activity.

• Biomedical Science Letters
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• v.29 no.2
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• pp.58-65
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• 2023

Pu-erh tea, a popular and traditional Chinese tea, possesses various health-promoting effects, including inhibiting tumor cell progression and preventing type II diabetes and neurodegenerative disorders. However, the precise anti-inflammatory mechanisms are not well understood. In present study, we elucidated the anti-inflammatory mechanism of Pu-erh tea in lipopolysaccharide (LPS)-activated RAW264.7 cells. We explored the effects of Pu-erh tea on the levels of inflammatory-related genes, including inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2 and prostaglandin E₂ (PGE₂) in LPS-activated RAW264.7 cells. Moreover, we investigated its regulatory effects on nuclear factor-kappa B (NF)-κB and hypoxia-inducible-factor (HIF)-1α activation. The findings of this study demonstrated that Pu-erh tea inhibited the LPS-increased inflammatory cytokines and PGE₂ release, as well as COX-2 and iNOS expression. Moreover, we confirmed that the anti-inflammatory mechanism of Pu-erh tea occurs via the inhibition of NF-κB and HIF-1α activation. Conclusively, these findings provide experimental evidence that Pu-erh tea may be useful candidate in the treatment of inflammatory-related diseases.