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1.
J Cell Physiol ; 239(6): e31245, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38497504

ABSTRACT

Parathyroid hormone (PTH) serves dual roles in bone metabolism, exhibiting both anabolic and catabolic effects. The anabolic properties of PTH have been utilized in the treatment of osteoporosis with proven efficacy in preventing fractures. Despite these benefits, PTH can be administered therapeutically for up to 2 years, and its use in patients with underlying malignancies remains a subject of ongoing debate. These considerations underscore the need for a more comprehensive understanding of the underlying mechanisms. p21-activated kinase 4 (PAK4) is involved in bone resorption and cancer-associated osteolysis; however, its role in osteoblast function and PTH action remains unknown. Therefore, in this study, we aimed to clarify the role of PAK4 in osteoblast function and its effects on PTH-induced anabolic activity. PAK4 enhanced MC3T3-E1 osteoblast viability and proliferation and upregulated cyclin D1 expression. PAK4 also augmented osteoblast differentiation, as indicated by increased mineralization found by alkaline phosphatase and Alizarin Red staining. Treatment with PTH (1-34), an active PTH fragment, stimulated PAK4 expression and phosphorylation in a protein kinase A-dependent manner. In addition, bone morphogenetic protein-2 (which is known to promote bone formation) increased phosphorylated PAK4 (p-PAK4) and PAK4 levels. PAK4 regulated the expression of both phosphorylated and total ß-catenin, which are critical for osteoblast proliferation and differentiation. Moreover, p-PAK4 directly interacted with ß-catenin, and disruption of ß-catenin's binding to T-cell factor impaired PAK4- and PTH-induced osteoblast differentiation. Our findings elucidate the effect of PAK4 on enhancing bone formation in osteoblasts and its pivotal role in the anabolic activity of PTH mediated through its interaction with ß-catenin. These insights improve the understanding of the mechanisms underlying PTH activity and should inform the development of more effective and safer osteoporosis treatments.


Subject(s)
Cell Differentiation , Cell Proliferation , Osteoblasts , Parathyroid Hormone , beta Catenin , p21-Activated Kinases , Animals , Humans , Mice , beta Catenin/metabolism , beta Catenin/genetics , Calcification, Physiologic/drug effects , Cell Differentiation/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Cyclin D1/metabolism , Cyclin D1/genetics , Osteoblasts/drug effects , Osteoblasts/metabolism , Osteogenesis/drug effects , p21-Activated Kinases/metabolism , p21-Activated Kinases/genetics , Parathyroid Hormone/pharmacology , Parathyroid Hormone/metabolism , Phosphorylation/drug effects , Signal Transduction/drug effects , Cells, Cultured
2.
Clin Exp Pharmacol Physiol ; 49(3): 341-349, 2022 03.
Article in English | MEDLINE | ID: mdl-34729812

ABSTRACT

An imbalance of osteoclasts and osteoblasts can result in a variety of bone-related diseases, including osteoporosis. Thus, decreasing the activity of osteoclastic bone resorption is the main therapeutic method for treating osteoporosis. 2E-Decene-4, 6-diyn-1-ol-acetate (DDA) is a natural bioactive compound with anti-inflammatory and anti-cancer properties. However, its effects on osteoclastogenesis are unknown. Murine bone marrow-derived macrophages (BMMs) or RAW264.7 cells were treated with DDA, followed by evaluation of cell viability, RANKL-induced osteoclast differentiation, and pit formation assay. Effects of DDA on RANKL-induced phosphorylation of MAPKs were assayed by western blot analysis. Expression of osteoclast-specific genes was examined with reverse transcription-PCR (RT-PCR) and western blot analysis. In this study, DDA significantly inhibited RANKL-induced osteoclast differentiation in RAW264.7 cells as well as in BMMs without cytotoxicity. DDA also strongly blocked the resorbing capacity of BMM on calcium phosphate-coated plates. DDA inhibited RANKL-induced phosphorylation of ERK, JNK and p38 MAPKs, as well as expression of c-Fos and NFATc1, which are essential transcription factors for osteoclastogenesis. In addition, DDA decreased expression levels of osteoclastogenesis-specific genes, including matrix metalloproteinase-9 (MMP-9), tartrate-resistant acid phosphatase (TRAP), and receptor activator of NF-κB (RANK) in RANKL-induced RAW264.7 cells. Collectively, these findings indicated that DDA attenuates RANKL-induced osteoclast formation by suppressing the MAPKs-c-Fos-NFATc1 signalling pathway and osteoclast-specific genes. These results indicate that DDA may be a potential candidate for bone diseases associated with abnormal osteoclast formation and function.


Subject(s)
Biological Products/pharmacology , Extracellular Signal-Regulated MAP Kinases/metabolism , Genes, fos/physiology , Macrophages/drug effects , NFATC Transcription Factors/metabolism , Osteogenesis/drug effects , Animals , Aster Plant/chemistry , Biological Products/chemistry , Cell Differentiation/drug effects , Extracellular Signal-Regulated MAP Kinases/drug effects , Gene Expression Regulation/drug effects , Genes, fos/genetics , Mice , NFATC Transcription Factors/genetics , Osteoclasts , RANK Ligand/genetics , RANK Ligand/metabolism , RAW 264.7 Cells
3.
Molecules ; 27(6)2022 Mar 09.
Article in English | MEDLINE | ID: mdl-35335156

ABSTRACT

In this paper, we studied the effects of the intersection angle between the inlet channels on the droplet diameter using a COMSOL Multiphysics® simulation. We employed the level-set method to study the droplet generation process inside a microfluidic flow device. A flow-focusing geometry was integrated into a microfluidics device and used to study droplet formation in liquid-liquid systems. Droplets formed by this flow-focusing technique are typically smaller than the upstream capillary tube and vary in size with the flow rates. Different intersection angles were modeled with a fixed width of continuous and dispersed channels, orifices, and expansion channels. Numerical simulations were performed using the incompressible Navier-Stokes equations for single-phase flow in various flow-focusing geometries. As a result of modeling, when the dispersed flow rate and the continuous flow rate were increased, the flow of the continuous flow fluid interfered with the flow of the dispersed flow fluid, which resulted in a decrease in the droplet diameter. Variations in the droplet diameter can be used to change the intersection angle and fluid flow rate. In addition, it was predicted that the smallest diameter droplet would be generated when the intersection angle was 90°.


Subject(s)
Microfluidic Analytical Techniques , Computer Simulation , Lab-On-A-Chip Devices
4.
Cancer Sci ; 108(11): 2176-2186, 2017 Nov.
Article in English | MEDLINE | ID: mdl-28859238

ABSTRACT

Lipocalin 2 (LCN2), a member of the lipocalin superfamily, plays an important role in oncogenesis and progression in various types of cancer. However, the expression pattern and functional role of LCN2 in colorectal cancer (CRC) is still poorly understood. The purpose of the present study was to investigate whether LCN2 is associated with proliferation and the epithelial-mesenchymal transition (EMT) in CRC and to elucidate the underlying signaling pathways. LCN2 was preferentially expressed in CRC cells compared to normal tissues. However, LCN2 expression was significantly lower in metastatic or advanced-stage CRC than in non-metastatic or early stage CRC. Knockdown of LCN2 using small interfering RNA (siRNA) in CRC cells expressing a high level of LCN2 induced cell proliferation and a morphological switch from an epithelial to mesenchymal state. Furthermore, downregulation of LCN2 in CRC cells increased cell migration and invasion involved in the regulation of EMT markers. Knockdown of LCN2 also induced glucose consumption and lactate production, accompanied by an increase in energy metabolism-related genes. Taken together, our findings indicated that LCN2 negatively modulated proliferation, EMT and energy metabolism in CRC cells. Accordingly, LCN2 may be a candidate metastasis suppressor and potential therapeutic target in CRC.


Subject(s)
Cell Proliferation/genetics , Colorectal Neoplasms/genetics , Energy Metabolism/genetics , Epithelial-Mesenchymal Transition/genetics , Lipocalin-2/genetics , Aged , Cell Line, Tumor , Cell Movement/genetics , Colorectal Neoplasms/pathology , Female , Gene Expression Regulation, Neoplastic , Gene Knockdown Techniques , Glucose/metabolism , Humans , Male , Signal Transduction
5.
Biomolecules ; 12(12)2022 12 01.
Article in English | MEDLINE | ID: mdl-36551228

ABSTRACT

The inner shell of the chestnut (Castanea crenata) has long been used in Asia as a medicinal herb for improving digestion and blood circulation, and treating diarrhea. However, most chestnut shells are now treated as waste materials in industrial peeling processes. In this study, we examined the metabolite variation among major cultivars of C. crenata shells using mass spectrometry. Among five representative cultivars, Okkwang, Porotan, and Ishizuuchi had higher levels of bioactive compounds, such as ellagic acid derivatives, ellagitannins, flavonoids, and gallic acid derivatives. Their antioxidant capacity was positively correlated with their chemical composition. The byproducts (whole shells) from the industrial peeling process were re-evaluated in comparison with the inner shell, a rich source of phenolic compounds. The phenolic acids and flavonoid glucoside derivatives were significantly higher in the whole shells, whereas the levels of flavonoids were higher in the inner shells. In addition, the whole shell extracts significantly reduced cellular reactive oxygen species production compared to the inner shell extracts. This study demonstrated the different biochemical benefits of different C. crenata cultivars through metabolic profiling and suggests that the whole shell could be used as a functional ingredient, as it has the highest levels of bioactive products and antioxidant effects.


Subject(s)
Antioxidants , Fagaceae , Antioxidants/chemistry , Nuts/chemistry , Plant Extracts/chemistry , Phenols/analysis , Flavonoids/chemistry , Fagaceae/chemistry
6.
Cell Biochem Funct ; 29(2): 126-34, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21287578

ABSTRACT

Hypoxia-inducible transcription factors (HIFs) play a pivotal role in the response of cells to hypoxia. HIFs are dimers of an oxygen-sensitive α-subunit (HIF-1α or HIF-2α), and a constitutively expressed ß-subunit. In normoxia, HIF-1α is destabilized by post-translational hydroxylation of Pro-564 and Pro-402 by a family of oxygen-sensitive dioxygenases. Prolyl hydroxylation leads to von Hippel­Lindau protein-dependent ubiquitination and rapid degradation of HIF-1α. We previously reported that KRH102053, an activator of PHD2, rapidly decreased HIF-1α and eventually inhibited angiogenesis. Here, we report a potent activator of PHD2, KRH102140, which has a structure similar to KRH102053. KRH102140 more efficiently suppressed HIF-1α than KRH102053 in human osteosarcoma cells under hypoxia. Furthermore, KRH102140 decreased the mRNA levels of HIF-regulated downstream target genes associated with angiogenesis and energy metabolism such as vascular endothelial growth factor, adrenomedullin, Glut1, aldolase A, enolase 1 and monocarboxylate transporter 4. KRH102140 also inhibited tube formation in human umbilical vein endothelium cells. The results suggest that KRH102140 has potential therapeutic effects in alleviating various diseases associated with HIFs.


Subject(s)
Benzopyrans/pharmacology , Benzylamines/pharmacology , Down-Regulation , Enzyme Activators/pharmacology , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Neovascularization, Pathologic/metabolism , Osteosarcoma/metabolism , Procollagen-Proline Dioxygenase/metabolism , Cell Line, Tumor , Enzyme Activation/drug effects , Gene Expression Regulation, Neoplastic , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Hypoxia-Inducible Factor-Proline Dioxygenases , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/enzymology , Neovascularization, Pathologic/genetics , Osteosarcoma/drug therapy , Osteosarcoma/enzymology , Osteosarcoma/genetics , Procollagen-Proline Dioxygenase/genetics
7.
Sci Rep ; 11(1): 6988, 2021 03 26.
Article in English | MEDLINE | ID: mdl-33772044

ABSTRACT

The International Federation of Gynecology and Obstetrics (FIGO) cervical cancer staging system was modified in 2018, introducing new stage IB subdivisions and new lymph node status considerations in stage IIIC. We compared cervical cancer survival outcomes according to the 2014 and 2018 FIGO staging systems. We selected 10% of cervical cancer cases (2010-2015) from the Korean national cancer registry (2010-2015) through a systematic sampling method. We collected information using a collaborative stage data collection system and evaluated the results according to both staging systems. The log-rank test was used to analyze overall survival differences. No significant difference in survival was observed between 2018 subdivisions IB1/IB2/IB3 (P = 0.069), whereas a considerable difference was observed between these subdivisions according to histological subtypes. In the 2018 FIGO staging system, stage IIIC had better survival than stage IIIA/IIIB (P < 0.001). We observed considerable heterogeneity in 2018 stage IIIC related to the corresponding stages of the 2014 staging system (stages IA1-IIIB). The size of the primary cervical mass was related to survival (P < 0.001). In conclusion, using lymph node status to define stage IIIC captured a broad range of prognoses. The inclusion of primary tumor size considerations may improve the staging accuracy of advanced cervical cancer.


Subject(s)
Cervix Uteri/pathology , Uterine Cervical Neoplasms/mortality , Uterine Cervical Neoplasms/pathology , Adult , Aged , Female , Humans , Lymph Nodes/physiology , Middle Aged , Neoplasm Staging/methods , Prognosis , Retrospective Studies , Uterine Cervical Neoplasms/therapy
8.
J Microbiol Biotechnol ; 30(9): 1387-1394, 2020 Sep 28.
Article in English | MEDLINE | ID: mdl-32699197

ABSTRACT

Clam worms (Marphysa sanguinea) are a rich source of bioactive components such as the antibacterial peptide, perinerin. In the present study, we explored the physiological activities of a novel NCWPFQGVPLGFQAPP peptide (NCW peptide), which was purified from clam worm extract through high-performance liquid chromatography. Tandem mass spectrometry (MS/MS) revealed that NCW was a new peptide with a molecular weight of 1757.86 kDa. Moreover, NCW peptide exhibited significant antioxidant effects, causing a 50% inhibition of DPPH radical at a concentration of 20 µM without showing any cytotoxicity. These were associated with a reduction in the activity of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and malondialdehyde (MDA) in LPS-stimulated RAW264. 7 cells. Furthermore, NCW peptide exhibited anti-inflammatory effects in LPS-stimulated RAW264.7 macrophages via inhibition of the abnormal production of pro-inflammatory cytokines including nitric oxide (NO), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). These anti-inflammatory effects of NCW peptide were associated with the inhibition of interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α). Our results therefore suggest that this novel NCW peptide with antioxidant and anti-inflammatory effects could be a good therapeutic agent against inflammation-related diseases.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Antioxidants/pharmacology , Peptides/pharmacology , Polychaeta/chemistry , Amino Acid Sequence , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/isolation & purification , Antioxidants/chemistry , Antioxidants/isolation & purification , Antioxidants/metabolism , Cell Survival/drug effects , Cyclooxygenase 2/metabolism , Cytokines/metabolism , Inflammation , Inflammation Mediators/metabolism , Macrophages/drug effects , Macrophages/metabolism , Mice , Molecular Weight , Nitric Oxide Synthase Type II/metabolism , Nitrites/metabolism , Peptides/chemistry , Peptides/isolation & purification , RAW 264.7 Cells
9.
Sci Rep ; 10(1): 14758, 2020 Sep 08.
Article in English | MEDLINE | ID: mdl-32901051

ABSTRACT

Halide vacancy defect is one of the major origins of non-radiative recombination in the lead halide perovskite light emitting devices (LEDs). Hence the defect passivation is highly demanded for the high-performance perovskite LEDs. Here, we demonstrated that FA doping led to the enrichment of Br in Cs1-xFAxPbBr3 QDs. Due to the defect passivation by the enriched Br, the trap density in Cs1-xFAxPbBr3 significantly decreased after FA doping, and which improved the optical properties of Cs1-xFAxPbBr3 QDs and their QD-LEDs. PLQY of Cs1-xFAxPbBr3 QDs increased from 76.8% (x = 0) to 85.1% (x = 0.04), and Lmax and CEmax of Cs1-xFAxPbBr3 QD-LEDs were improved from Lmax = 2880 cd m-2 and CEmax = 1.98 cd A-1 (x = 0) to Lmax = 5200 cd m-2 and CEmax = 3.87 cd A-1 (x = 0.04). Cs1-xFAxPbBr3 QD-LED device structure was optimized by using PVK as a HTL and ZnO modified with b-PEI as an ETL. The energy band diagram of Cs1-xFAxPbBr3 QD-LEDs deduced by UPS analyses.

10.
J Microbiol Biotechnol ; 30(10): 1543-1551, 2020 Oct 28.
Article in English | MEDLINE | ID: mdl-32807758

ABSTRACT

Panax ginseng has a wide range of activities including a neuroprotective effect, skin protective effects, enhanced DNA repairing, anti-diabetic activity, and protective effects against vascular inflammation. In the present study, we sought to discover the inhibitory effects of a mixture of natural products containing Panax ginseng, Ziziphus jujube, Rubi fructus, Artemisiae asiaticae and Scutellaria baicalensis (PZRAS) on osteoclastogenesis and bone remodeling, as neither the effects of a mixture containing Panax ginseng extract, nor its molecular mechanism on bone inflammation, have been clarified yet. PZRAS upregulated the levels of catalase (CAT), superoxide dismutase (SOD), glutathione reductase (GSH-R) and glutathione peroxidase (GSH-Px) and reduced malondialdehyde (MDA) in LPS-treated RAW264.7 cells. Moreover, treatment with PZRAS decreased the production of IL-1ß and TNF-α. PZRAS also inhibited osteoclast differentiation through inhibiting osteoclastspecific genes like MMP-2, 9, cathepsin K, and TRAP in RANKL-treated RAW264.7 cells. Additionally, PZRAS has inhibitory functions on the RANKL-stimulated activation of ERK and JNK, which lead to a decrease in the expression of NFATc1 and c-Fos. In an in vivo study, bone resorption induced by LPS was recovered by treatment with PZRAS in bone volume per tissue volume (BV/TV) compared to control. Furthermore, the ratio of eroded bone surface of femurs was significantly increased in LPStreated mice compared to vehicle group, but this ratio was significantly reversed in PZRAS-treated mice. These results suggest that PZRAS could prevent or treat disorders with abnormal bone loss.


Subject(s)
Bone Resorption/prevention & control , Inflammation/prevention & control , Osteogenesis/drug effects , Plant Extracts/pharmacology , Animals , Cathepsin K/genetics , Cathepsin K/metabolism , Cell Differentiation/drug effects , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Lipopolysaccharides/toxicity , Matrix Metalloproteinase 2/genetics , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/genetics , Matrix Metalloproteinase 9/metabolism , Mice , Mice, Inbred ICR , NFATC Transcription Factors/genetics , NFATC Transcription Factors/metabolism , Proto-Oncogene Proteins c-fos/genetics , Proto-Oncogene Proteins c-fos/metabolism , RANK Ligand/genetics , RANK Ligand/metabolism , RAW 264.7 Cells , Tartrate-Resistant Acid Phosphatase/genetics , Tartrate-Resistant Acid Phosphatase/metabolism , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism
11.
Cancer Res Treat ; 52(2): 335-350, 2020 Apr.
Article in English | MEDLINE | ID: mdl-32178489

ABSTRACT

PURPOSE: This study reports the cancer statistics and temporal trends in Korea on a nationwide scale, including incidence, survival, prevalence, and mortality in 2017. MATERIALS AND METHODS: The incidence, survival, and prevalence rates of cancer were evaluated using data from the Korea National Cancer Incidence Database from 1999 to 2017 with follow-up until December 31, 2018. Deaths from cancer were assessed using cause-of-death data from 1983 to 2017, obtained from Statistics Korea. Crude and age-standardized rates (ASRs) for incidence, mortality, and prevalence, and 5-year relative survival rates were calculated and trend analysis was performed. RESULTS: In 2017, newly diagnosed cancer cases and deaths from cancer numbered 232,255 (ASR, 264.4 per 100,000) and 78,863 (ASR, 76.6 per 100,000), respectively. The overall cancer incidence rates increased annually by 3.5% from 1999 to 2011 and decreased by 2.7% annually thereafter. Cancer mortality rates have been decreasing since 2002, by 2.8% annually. The 5-year relative survival rate for all patients diagnosed with cancer between 2013 and 2017 was 70.4%, which contributed to a prevalence of approximately 1.87 million cases by the end of 2017. CONCLUSION: The burden of cancer measured by incidence and mortality rates have improved in Korea, with the exception of a few particular cancers that are associated with increasing incidence or mortality rates. However, cancer prevalence is increasing rapidly, with the dramatic improvement in survival during the past several years. Comprehensive cancer control strategies and efforts should continue, based on the changes of cancer statistics.


Subject(s)
Neoplasms/epidemiology , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Female , History, 21st Century , Humans , Incidence , Infant , Infant, Newborn , Male , Middle Aged , Neoplasms/mortality , Prevalence , Republic of Korea/epidemiology , Survival Rate , Young Adult
12.
J Phys Condens Matter ; 21(19): 195405, 2009 May 13.
Article in English | MEDLINE | ID: mdl-21825483

ABSTRACT

Using the full-potential linearized augmented plane wave method, we have investigated the oxygen vacancy defect induced ferromagnetism in both rutile and anatase TiO(2). It has been found that the oxygen vacancy induces lattice distortion in rutile TiO(2), whereas there is no such meaningful change in the anatase structure. Interestingly, the lattice distorted rutile TiO(2) shows an oxygen vacancy induced ferromagnetic state with a magnetic moment of 0.22 µ(B) in the Ti atom neighboring the vacancy site, while only 0.06 µ(B) is observed in the Ti atom in anatase TiO(2). We attribute the sizable magnetic moment due to the oxygen vacancy in rutile TiO(2) to the charge redistribution owing to lattice distortion. Experimentally measured magnetic hysteresis curves for undoped rutile and anatase TiO(2) films clearly display ferromagnetic behavior at room temperature. The observed magnetic strength of the rutile sample turns out to be larger than that of the anatase sample, in accordance with the theoretical calculations.

13.
Pathol Oncol Res ; 25(3): 953-959, 2019 Jul.
Article in English | MEDLINE | ID: mdl-29532406

ABSTRACT

MiRNAs are non-coding RNAs that play important roles in the pathogenesis of human diseases by regulating target gene expression in specific cells or tissues. Previously we identified colorectal cancer (CRC) associated MIR196B, which was specifically up-regulated in CRC cells and tissue. We also identified 18 putative MIR196B target genes by comparing the mRNAs down-regulated in MIR196B-overexpressed cells with MIR196B target genes predicted by public bioinformatics tools. In this study, we verified the association between MIR196B and three genes, HOXA5, HOXB6 and GLTP. HOXA5, HOXB6 and GLTP transcripts were directly down-regulated by MIR196B. The mRNA and proteins levels of HOXA5, HOXB6 and GLTP were also down-regulated in CRC cells by the up-regulated MIR196B. GLTP protein expression was decreased in CRC tissues compared to adjacent non-tumor tissues. These results suggest that HOXA5, HOXB6, and GLTP were direct target genes of MIR196B in CRC cells, and that the up-regulated MIR196B in CRC tissue regulates the expression levels of HOXA5, HOXB6, and GLTP during colorectal carcinogenesis.


Subject(s)
Carrier Proteins/genetics , Colorectal Neoplasms/genetics , Gene Expression Regulation, Neoplastic/genetics , Homeodomain Proteins/genetics , MicroRNAs/genetics , Aged , Cell Line, Tumor , Cell Movement/genetics , Down-Regulation/genetics , Humans , Middle Aged , RNA, Messenger/genetics , Up-Regulation/genetics
14.
Eur J Pharmacol ; 865: 172772, 2019 Dec 15.
Article in English | MEDLINE | ID: mdl-31697934

ABSTRACT

Vascular calcification increases the risk of morbidity and mortality in patients with cardiovascular diseases, chronic kidney diseases, and diabetes. However, viable therapeutic methods to target vascular calcification are limited. Aloe-emodin (AE), an anthraquinone is a natural compound found in the leaves of Aloe-vera. In this study, we investigated the underlying mechanism of AE in the calcification of vascular smooth muscle cells (VSMCs) and murine thoracic aorta. We demonstrate that AE repressed not only the phenotypes of Ca2+ induced calcification but also level of calcium in VSMCs. AE has no effect on cell viability in VSMC cells. Alizarin red, von Kossa stainings and calcium quantification showed that Ca2+ induced vascular calcification is significantly decreased by AE in a concentration-dependent manner. In contrast, AE attenuated Ca2+ induced calcification through inhibiting osteoblast differentiation genes such as SMAD4, collagen 1α, osteopontin (OPN), Runt-related transcription factor (RUNX-2) and Osterix. AE also suppressed Ca2+ induced osteoblast-related protein expression including collagen 1α, bone morphogenic protein 2 (BMP-2), RUNX-2 and smooth muscle actin (SMA). Furthermore, Alizarin red, von Kossa stainings and calcium quantification showed that AE significantly inhibited the calcification of ex vivo ring formation in murine thoracic aorta, and markedly inhibited vitamin D3 induced medial aorta calcification in vivo. Taken together, our findings suggest that AE may have therapeutic potential for the prevention of vascular calcification program.


Subject(s)
Anthraquinones/pharmacology , Calcification, Physiologic/drug effects , Myocytes, Smooth Muscle/drug effects , Animals , Aorta, Thoracic/cytology , Bone Morphogenetic Protein 2/metabolism , Calcium/metabolism , Male , Mice, Inbred ICR , Muscle, Smooth, Vascular/cytology , Myocytes, Smooth Muscle/physiology , Osteogenesis/drug effects , Smad4 Protein/genetics
15.
Int J Oncol ; 54(5): 1897, 2019 05.
Article in English | MEDLINE | ID: mdl-30864690

ABSTRACT

Following the publication of this article, an interested reader drew to our attention that Fig. 1C contained an important flaw. The Figure shows a western blot for LCN2, DR4, DR5, and actin, and it was noted that the identical bands shown for actin were also featured in a paper by the same authors published in 2017 [Lipocalin 2 negatively regulates cell proliferation and epithelial to mesenchymal transition through changing metabolic gene expression in colorectal cancer. Kim SL, Lee ST, Min IS, Park YR, Lee JH, Kim DG and Kim SW: Cancer Sci 108: 2176­2186, 2017], except that the lanes for the cell lines HCT116 and SW620 were depicted the other way around in the International Journal of Oncology article. Upon investigating the matter with the authors, they were able to confirm that the lanes were labelled incorrectly in the Figure itself; moreover, the incorrect control bands were included with the Figure. The corrected version of Fig. 1 is shown opposite, including the correct control data for Fig. 1C. This error did not have an impact on the overall meaning of the paper, or on the reported conclusions of this study. The authors regret that this error was introduced into the printed version of the paper, and apologize to the readership for any inconvenience caused. [the original article was published in International Journal of Oncology 53: 2789­2799, 2018; DOI: 10.3892/ijo.2018.4562].

16.
Cancer Genet ; 231-232: 22-31, 2019 02.
Article in English | MEDLINE | ID: mdl-30803553

ABSTRACT

MicroRNA-9 (miR-9) has been reported to play a suppressive or promoting role according to cancer type. In this study, we investigated the effects of anoctamin-1 (ANO1) and miR-9 on colorectal cancer (CRC) cell proliferation, migration, and invasion and determined the underlying molecular mechanisms. Thirty-two paired CRC tissues and adjacent normal tissues were analyzed for ANO1 expression using quantitative real-time PCR (qRT-PCR). HCT116 cells were transiently transfected with miR-9 mimic, miR-9 inhibitor, or si-ANO1. Cell proliferation was determined by MTT, and flow cytometric analysis, while cell migration and invasion were assayed by trans-well migration and invasion assay in HCT116 cells. ANO1 was validated as a target of miR-9 using luciferase reporter assay and bioinformatics algorithms. We found that ANO1 expression was up-regulated in CRC tissues compared with adjacent normal tissues. ANO1 expression was associated with advanced tumor stage and lymph node metastasis, and there was an inverse relationship between miR-9 and ANO1 mRNA expression in CRC specimens, but no significant difference was found between miR-9 and ANO1 expression. ANO1 is a direct target of miR-9, and overexpression of miR-9 suppressed both mRNA and protein expression of ANO1 and inhibited cell proliferation, migration, and invasion of HCT116 cells. We also showed that overexpression of miR-9 suppressed expression of p-AKT, cyclin D1, and p-ERK in HCT116 cells. We conclude that miR-9 inhibits CRC cell proliferation, migration, and invasion by directly targeting ANO1, and miR-9/ANO1 could be a potential therapeutic target for CRC.


Subject(s)
Anoctamin-1/genetics , Colorectal Neoplasms/genetics , Down-Regulation/genetics , Epithelial-Mesenchymal Transition/genetics , Gene Expression Regulation, Neoplastic , MicroRNAs/genetics , Neoplasm Proteins/genetics , Anoctamin-1/metabolism , Apoptosis/genetics , Base Sequence , Cell Cycle Checkpoints/genetics , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation/genetics , Colorectal Neoplasms/pathology , Cyclin D1/metabolism , Extracellular Signal-Regulated MAP Kinases/metabolism , Female , Humans , Lymphatic Metastasis/genetics , Male , MicroRNAs/metabolism , Middle Aged , Neoplasm Invasiveness , Neoplasm Proteins/metabolism , Neoplasm Staging , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Up-Regulation/genetics
17.
Int J Oncol ; 53(6): 2789-2799, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30221676

ABSTRACT

TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis through death receptors (DRs)4 and/or 5 expressed on the cell surface. Multiple clinical trials are underway to evaluate the antitumor activity of recombinant human TRAIL and agonistic antibodies to DR4 or DR5. However, their therapeutic potential is limited by the high frequency of cancer resistance. In this study, we provide evidence demonstrating the role of lipocalin 2 (LCN2) in the TRAIL-mediated apoptosis of human colorectal cancer (CRC). By analyzing the mRNA expression data of 71 CRC tissues from patients, we found that DR5 was preferentially expressed in CRC tissues with a low LCN2 expression level compared to tissues with a high LCN2 expression level. Moreover, we analyzed the association between DR5 and LCN2 expression and this analysis revealed that DR5 expression in CRC tended to be inversely associated with LCN2 expression. By contrast, no association was found between the DR4 and LCN2 expression levels. The expression patterns of LCN2 in human CRC cell lines also exhibited an inverse association with DR5 expression. The knockdown of LCN2 by siRNA in the TRAIL­resistant CRC cells expressing high levels of LCN2 led to a significant increase in TRAIL-induced apoptosis through the upregulation of DR5 protein and mRNA expression. The mechanism through which LCN2 silencing sensitized the CRC cells to TRAIL was dependent on the extrinsic pathway of apoptosis. In addition, we identified that the knockdown of LCN2 enhanced the sensitivity of the cells to TRAIL through the p38 MAPK/CHOP-dependent upregulation of DR5. Taken together, the findings of this study suggest that LCN2 is responsible for TRAIL sensitivity and LCN2 may thus prove to be a promising target protein in DR-targeted CRC therapy.


Subject(s)
Colorectal Neoplasms/metabolism , Drug Resistance, Neoplasm , Lipocalin-2/genetics , MAP Kinase Signaling System/drug effects , Receptors, TNF-Related Apoptosis-Inducing Ligand/genetics , TNF-Related Apoptosis-Inducing Ligand/pharmacology , Cell Line, Tumor , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Down-Regulation , Drug Resistance, Neoplasm/drug effects , Female , Gene Expression Regulation, Neoplastic/drug effects , Gene Knockdown Techniques , HCT116 Cells , HT29 Cells , Humans , Lipocalin-2/metabolism , Male , Middle Aged , Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism
18.
Biosci Rep ; 38(5)2018 10 31.
Article in English | MEDLINE | ID: mdl-30135139

ABSTRACT

MiRNA (miR)-206 plays a tumor suppressor role in various cancer types. Here, we investigated whether miR-206 is involved in prostaglandin E2 (PGE2)-induced epithelial-mesenchymal transition (EMT) in colorectal cancer (CRC) cells through the targetting of transmembrane 4 L six family member 1 (TM4SF1).The effect of PGE2 on growth and apoptosis of CRC cells was evaluated using the MTT assay and flow cytometry analysis, respectively. TM4SF1 and miR-206 expression levels were determined with quantitative polymerase chain reaction (qRT-PCR) in CRC tissues and cell lines. The concentration of PGE2 in the serum of CRC patients and healthy controls was measured with an ELISA kit. A miR-206 or TM4SF1 construct was transfected into cells with PGE2. Transwell migration and invasion assays were used to examine cell migration and invasion properties. Additionally, a luciferase assay was performed to determine whether TM4SF1 was directly targetted by miR-206.We found that miR-206 was down-regulated and TM4SF1 was up-regulated in human CRC tissues and cell lines. Moreover, miR-206 was negatively correlated with TM4SF1 expression. Bioinformatics analysis and a luciferase reporter assay revealed that miR-206 directly targetted the 3'-untranslated region (UTR) of TM4SF1, and TM4SF1 expression was reduced by miR-206 overexpression at both the mRNA and protein levels. Additionally, PGE2 significantly suppressed the expression of miR-206 and increased the expression of TM4SF1 in CRC cells. PGE2 induction led to enhanced CRC cell proliferation, migration, and invasion. Moreover, the overexpression of miR-206 decreased CRC cell proliferation, migration, and invasion compared with control group in PGE2-induced cells, and these effects could be recovered by the overexpression of TM4SF1. Overexpression of miR-206 also suppressed the expression of ß-catenin, VEGF, MMP-9, Snail, and Vimentin and enhanced E-cadherin expression in PGE2-induced cells. These results could be reversed by the overexpression of TM4SF1. At last, up-regulation of miR-206 suppressed expression of p-AKT and p-ERK by targetting TM4SF1 in PGE2-induced cells.Our results provide further evidence that miR-206 has a protective effect on PGE2-induced colon carcinogenesis.


Subject(s)
Antigens, Surface/genetics , Cell Proliferation/genetics , Colorectal Neoplasms/genetics , MicroRNAs/genetics , Neoplasm Proteins/genetics , Aged , Apoptosis/genetics , Cadherins/genetics , Cell Line, Tumor , Cell Movement/genetics , Colorectal Neoplasms/blood , Colorectal Neoplasms/pathology , Dinoprostone/blood , Dinoprostone/genetics , Epithelial-Mesenchymal Transition/genetics , Female , Gene Expression Regulation, Neoplastic/genetics , Humans , Male , Middle Aged , Neoplasm Invasiveness/genetics , Neoplasm Invasiveness/pathology , Neoplasm Staging
19.
Int J Oncol ; 51(6): 1809-1820, 2017 Dec.
Article in English | MEDLINE | ID: mdl-29075793

ABSTRACT

Activation of hypoxia-inducible factor 1α (HIF­1α) is frequently observed in solid tumors and it has been associated with various pathophysiological processes, including epithelial­mesenchymal transition (EMT). Previously, we reported that parthenolide (PT), an inhibitor of nuclear factor-κB (NF-κB), is a promising anticancer agent because it promotes apoptosis of human colorectal cancer (CRC). Here, we investigated a new molecular mechanism by which PT acts on HIF­1α and hypoxia contributing to EMT by NF­κB inhibition. Cell viability, DNA binding activity, vascular cell tube formation and cell motility were studied after treatment of PT in hypoxic or normoxic condition. Moreover, effects of PT on hypoxia signaling and hypoxia-induced EMT signaling were investigated. We also examined the inhibitory effect of PT on CRC progression in xenografts. We demonstrated that PT markedly inhibits hypoxia dependent HIF­1α activity and angiogenesis by preventing NF-κB activation. We also report that PT decreases the level of proteins associated with glucose metabolism, angiogenesis, development and survival that are regulated by HIF­1α. Furthermore, we verified that PT protects the morphological change from epithelial to mesenchymal state, inhibits matrix metalloproteinase (MMP) enzyme activity and decreases cell motility involved in the -regulation of the hypoxia-induced EMT markers. In addition, PT inhibits growth in CRC xenograft models and regulates NF­κB, HIF­1α and EMT specific marker in tissue specimens. Our data demonstrated that PT can inhibit HIF­1α signaling and hypoxia-induced EMT, suggesting a novel molecular mechanism for HIF­1α mediated cancer progression and metastasis.


Subject(s)
Colonic Neoplasms/drug therapy , Colonic Neoplasms/metabolism , Epithelial-Mesenchymal Transition/drug effects , Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors , Sesquiterpenes/pharmacology , Animals , Cell Hypoxia/drug effects , Colonic Neoplasms/blood supply , Colonic Neoplasms/pathology , Down-Regulation/drug effects , Female , HCT116 Cells , HT29 Cells , Human Umbilical Vein Endothelial Cells , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Mice , Mice, Nude , NF-kappa B/metabolism , Neoplasm Invasiveness , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/pathology , Signal Transduction/drug effects , Xenograft Model Antitumor Assays
20.
Intest Res ; 15(2): 174-181, 2017 Apr.
Article in English | MEDLINE | ID: mdl-28522946

ABSTRACT

BACKGROUND/AIMS: Parthenolide (PT), a principle component derived from feverfew (Tanacetum parthenium), is a promising anticancer agent and has been shown to promote apoptotic cell death in various cancer cells. In this study, we focused on its functional role in apoptosis, migration, and invasion of human colorectal cancer (CRC) cells. METHODS: SW620 cells were employed as representative human CRC cells. We performed the MTT assay and cell cycle analysis to measure apoptotic cell death. The wound healing, Transwell migration, and Matrigel invasion assays were performed to investigate the effect of PT on cell migration/invasion. Western blotting was used to establish the signaling pathway of apoptosis and cell migration/invasion. RESULTS: PT exerts antiproliferative effect and induces apoptotic cell death of SW620 cells. In addition, PT prevents cell migration and invasion in a dose-dependent manner. Moreover, PT markedly suppressed migration/invasion-related protein expression, including E-cadherin, ß-catenin, vimentin, Snail, cyclooxygenase-2, matrix metalloproteinase-2 (MMP-2), and MMP-9 in SW620 cells. PT also inhibited the expression of antiapoptotic proteins (Bcl-2 and Bcl-xL) and activated apoptosis terminal factor (caspase-3) in a dose-dependent manner. CONCLUSIONS: Our results suggest that PT is a potential novel therapeutic agent for aggressive CRC treatment.

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