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1.
Sci Rep ; 14(1): 7410, 2024 03 28.
Article in English | MEDLINE | ID: mdl-38548749

ABSTRACT

Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) has recently emerged as a promising therapeutic target in cancer. In this study, we explored the biological function of MAP4K4 in radioresistant breast cancer cells using two MAP4K4 inhibitors, namely PF06260933 and GNE-495. Radioresistant SR and MR cells were established by exposing SK-BR-3 and MCF-7 breast cancer cells to 48-70 Gy of radiation delivered at 4-5 Gy twice a week over 10 months. Surprisingly, although radioresistant cells were derived from two different subtypes of breast cancer cell lines, MAP4K4 was significantly elevated regardless of subtype. Inhibition of MAP4K4 with PF06260933 or GNE-495 selectively targeted radioresistant cells and improved the response to irradiation. Furthermore, MAP4K4 inhibitors induced apoptosis through the accumulation of DNA damage by inhibiting DNA repair systems in radioresistant cells. Notably, Inhibition of MAP4K4 suppressed the expressions of ACSL4, suggesting that MAP4K4 functioned as an upstream effector of ACSL4. This study is the first to report that MAP4K4 plays a crucial role in mediating the radioresistance of breast cancer by acting upstream of ACSL4 to enhance DNA damage response and inhibit apoptosis. We hope that our findings provide a basis for the development of new drugs targeting MAP4K4 to overcome radioresistance.


Subject(s)
Breast Neoplasms , Humans , Female , Breast Neoplasms/genetics , Cell Line, Tumor , Radiation Tolerance/genetics , DNA Repair , MCF-7 Cells , Apoptosis/radiation effects , Protein Serine-Threonine Kinases/metabolism , Intracellular Signaling Peptides and Proteins/metabolism
2.
Adv Mater ; 36(18): e2309708, 2024 May.
Article in English | MEDLINE | ID: mdl-38251443

ABSTRACT

Insects can efficiently perform object motion detection via a specialized neural circuit, called an elementary motion detector (EMD). In contrast, conventional machine vision systems require significant computational resources for dynamic motion processing. Here, a fully memristive EMD (M-EMD) is presented that implements the Hassenstein-Reichardt (HR) correlator, a biological model of the EMD. The M-EMD consists of a simple Wye (Y) configuration, including a static resistor, a dynamic memristor, and a Mott memristor. The resistor and dynamic memristor introduce different signal delays, enabling spatio-temporal signal integration in the subsequent Mott memristor, resulting in a direction-selective response. In addition, a neuromorphic system is developed employing the M-EMDs to predict a lane-changing maneuver by vehicles on the road. The system achieved a high accuracy (> 87%) in predicting future lane-changing maneuvers on the Next Generation Simulation (NGSIM) dataset while reducing the computational cost by 92.9% compared to the conventional neuromorphic system without the M-EMD, suggesting its strong potential for edge-level computing.

3.
IUBMB Life ; 75(9): 765-777, 2023 09.
Article in English | MEDLINE | ID: mdl-37492896

ABSTRACT

Chemotherapy failure is often caused by drug resistance, for which no effective treatment strategy has been established. Many studies have been undertaken with the aim of overcoming drug resistance using natural products. Arctigenin (ATG), a natural product, has been investigated for its anti-cancer effects in HER2-overexpressing, ER-positive, and triple-negative breast cancer cells. We investigated the efficacy of ATG against self-established doxorubicin (DOX)-resistant breast cancer cells (MCF-DR and MDA-DR cells) derived from MCF-7 and MDA-MB-231 cells, respectively. ATG was found to increase DOX intracellular levels by downregulating multidrug Resistance 1 (MDR1) mRNA expression in DOX-resistant cells. In addition, combined treatment with DOX and ATG (DOX/ATG) reduced the viability of and colony formation by DOX-resistant cells. DOX/ATG also significantly induced G2/M cell cycle arrest by suppressing the Cyclin D1/CDK4/RB pathways and suppressed the expressions of MDR1 and Cyclin D1 by inhibiting the Mitogen-activated protein kinase (MAPK)/Activating protein-1 (AP-1) signaling pathways. Furthermore, DOX/ATG induced DNA damage and attenuated the expressions of RAD51 and Ku80. However, PARP1 (Poly [ADP-ribose] polymerase1) cleavage and AIF (Apoptosis-inducing factor) induced apoptosis did not occur despite DNA damage-induced cell death. Rather, flow cytometry showed that DOX/ATG caused necrosis. In summary, DOX/ATG increased intracellular DOX levels by inhibiting MDR1 and inducing G2/M arrest by inhibiting the Cyclin D1/CDK4/RB pathways and causing necrosis by damaging DNA. Our results suggest that ATG might be used as an adjuvant to enhance the efficacy of DOX in DOX-resistant breast cancer.


Subject(s)
Breast Neoplasms , Humans , Female , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Cyclin D1 , Apoptosis , Cell Line, Tumor , Drug Resistance, Neoplasm/genetics , G2 Phase Cell Cycle Checkpoints , Doxorubicin/pharmacology , Cell Cycle Checkpoints , Necrosis
4.
Pharmaceuticals (Basel) ; 16(5)2023 Apr 29.
Article in English | MEDLINE | ID: mdl-37242455

ABSTRACT

Considerable emphasis is being placed on combinatorial chemotherapeutic/natural treatments for breast cancer. This study reveals the synergistic anti-tumor activity of morin and Doxorubicin (Dox) co-treatment on MDA-MB-231 triple-negative breast cancer (TNBC) cell proliferation. Morin/Dox treatment promoted Dox uptake and induced DNA damage and formation of nuclear foci of p-H2A.X. Furthermore, DNA repair proteins, RAD51 and survivin, and cell cycle proteins, cyclin B1 and forkhead Box M1 (FOXM1), were induced by Dox alone but attenuated by morin/Dox co-treatment. In addition, Annexin V/7-AAD analysis revealed that necrotic cell death after co-treatment and apoptotic cell death by Dox alone were associated with the induction of cleaved PARP and caspase-7 without Bcl-2 family involvement. FOXM1 inhibition by thiostrepton showed that co-treatment caused FOXM1-mediated cell death. Furthermore, co-treatment downregulated the phosphorylation of EGFR and STAT3. Flow cytometry showed that the accumulation of cells in the G2/M and S phases might be linked to cellular Dox uptake, p21 upregulation, and cyclin D1 downregulation. Taken together, our study shows that the anti-tumor effect of morin/Dox co-treatment is due to the suppression of FOXM1 and attenuation of EGFR/STAT3 signaling pathways in MDA-MB-231 TNBC cells, which suggests that morin offers a means of improving therapeutic efficacy in TNBC patients.

5.
Pharmaceuticals (Basel) ; 17(1)2023 Dec 22.
Article in English | MEDLINE | ID: mdl-38256858

ABSTRACT

Anthocyanin oligomers (AOs) are phytochemicals synthesized by fermenting anthocyanins extracted from grape skins and are more biologically active than monomeric anthocyanins. In this study, we evaluate the effects of an AO on triple-negative MDA-MB-231 and HER2-overexpressing SK-BR-3 breast cancer cells. The cell viability of MDA-MB-231 and SK-BR-3 cells was significantly inhibited in a concentration-dependent manner by AO treatment for 24 h, while delphinidin (a monomeric anthocyanin) had no effect on cell viability. In addition, the AO increased H2A.X phosphorylation (a marker of DNA damage), reduced RAD51 (a DNA repair protein) and survivin (a cell survival factor) protein levels, and induced apoptosis by caspase-3-dependent PARP1 cleavage in both cell lines. Surprisingly, the AO induced autophagy by increasing intracellular LC3-II puncta and LC3-II and p62 protein levels. In addition, the AO inhibited the mTOR pathway in MDA-MB-231 and SK-BR-3 cells by suppressing the HER2, EGFR1, and AKT pathways. These results demonstrate that the anti-cancer effect of the AO was due to the induction of apoptosis and autophagy via cleaved caspase-3-mediated PARP1 cleavage and mTOR pathway inhibition, respectively. Furthermore, our results suggest that anthocyanin oligomers could be considered potential candidates for breast cancer treatment.

6.
Cancer Biother Radiopharm ; 37(7): 544-552, 2022 Sep.
Article in English | MEDLINE | ID: mdl-33259733

ABSTRACT

Background: Recently, several clinical studies have reported that combination treatments of radiation therapy (RT) and immunotherapy in patients with multiple lesions can improve tumor regression at a distance from the irradiated site, known as the abscopal effect. However, when RT and immunotherapy are concurrently applied, it is hard to distinguish the pure systemic effects of RT from those of the immunotherapy drug. In this preclinical study, the authors investigated the systemic antitumor effects of RT alone according to fraction dose size and splitting schedules. Materials and Methods: 4T1 mouse breast cancer cells were implanted into the right and left sides of mammary gland fat pads of BALB/c mice, followed by irradiation with 6 Gy × 3, 8 Gy × 2, and 13 Gy × 1 fractions when the right-side tumors were palpable. Results: The different irradiation schedules produced similar antitumor effects in irradiated right-side tumors and unirradiated left-side tumors. However, 8 Gy × 2 and 13 Gy × 1 fractions exhibited better antimetastatic potential than that from irradiation using 6 Gy × 3 fractions. Furthermore, 8 Gy × 2 and 13 Gy × 1 fractions produced higher expressions of HMGB1 and lower expressions of the proinflammatory cytokines, IFN-γ, TNF-α, IL-6, and IL-1ß, from the irradiated tumor tissues. Conclusions: These findings suggest that 8 Gy × 2 and 13 Gy × 1 fractions can provide better systemic antitumor effects than 6 Gy × 3 fractions. The authors hope these results provide clues to optimize RT dose regimens to make the abscopal effect clinically more relevant in future combination treatments.


Subject(s)
Immunotherapy , Neoplasms , Animals , Mice , Mice, Inbred BALB C , Tumor Necrosis Factor-alpha
7.
Biochem Pharmacol ; 192: 114718, 2021 10.
Article in English | MEDLINE | ID: mdl-34358518

ABSTRACT

The development of radioresistance during radiotherapy is a major cause of tumor recurrence and metastasis. To provide new insights of the mechanisms underlying radioresistance, we established radioresistant cell lines derived from two different subtypes of breast cancer cells, HER2-positive SK-BR-3 and ER-positive MCF-7 breast cancer cells, by exposing cells to 48 ~ 70 Gy of radiation delivered at 4-5 Gy twice weekly over 9 ~ 10 months. The established radioresistant SK-BR-3 (SR) and MCF-7 (MR) cells were resistant not only to a single dose of radiation (2 Gy or 4 Gy) but also to fractionated radiation delivered at 2 Gy/day for 5 days. Furthermore, these cells exhibited tumor-initiating potential in vivo and high CD24-/CD44 + ratio. To identify novel therapeutic molecular targets, we analyzed differentially expressed genes in both radioresistant cell lines and found that the expression of ACSL4 was significantly elevated in both cell lines. Targeting ACSL4 improved response to irradiation and inhibited migration activities. Furthermore, inhibition of ACLS4 using ASCL4 siRNA or triacsin C suppressed FOXM1 expression, whereas inhibition of FOXM1 using thiostrepton did not affect ACSL4 expression. Targeting the ACSL4-FOXM1 signaling axis by inhibiting ASCL4 or FOXM1 overcame the radioresistance by suppressing DNA damage responses and inducing apoptosis. This is the first study to report that ACSL4 plays a crucial role in mediating the radioresistance of breast cancer by regulating FOXM1. We propose the ACSL4-FOXM1 signaling axis be considered a novel therapeutic target in radioresistant breast cancer and suggest treatment strategies targeting this signaling axis might overcome breast cancer radioresistance.


Subject(s)
Breast Neoplasms/metabolism , Breast Neoplasms/radiotherapy , Coenzyme A Ligases/metabolism , Forkhead Box Protein M1/metabolism , Radiation Tolerance/physiology , Animals , Coenzyme A Ligases/antagonists & inhibitors , Female , Forkhead Box Protein M1/antagonists & inhibitors , Humans , MCF-7 Cells , Mice , Mice, Inbred BALB C , Mice, Nude
8.
Oncol Rep ; 46(1)2021 Jul.
Article in English | MEDLINE | ID: mdl-33982761

ABSTRACT

Morin (2',3,4',5,7­pentahydroxyflavone), a flavonoid isolated from members of the Moraceae family and the leaves of Cudranaia tricuspidata Buread, is a well­known natural substance with anti­inflammatory, antioxidative, antimetastasis, and anticancer effects. However, its anticancer activity has not been comprehensively investigated in human epidermal growth factor receptor 2 (HER2)­overexpressing breast cancer cells. Here, we evaluated the effects of morin on metastasis and cell viability in HER­2­overexpressing human breast cancer SK­BR­3 cells. Our results revealed that morin (150­200 µM) prevented endothelial growth factor (EGF)­induced metastatic potential and suppressed cell migration and MMP­9 activity by inhibiting the EGFR signaling pathway in SK­BR­3 cells by gelatin zymography, wound healing assay and western blotting. Interestingly, morin­induced reductions in cell viability were found to be associated with inhibition of the HER2/EGFR signaling pathway by sulforhodamine B assay and western blotting. Morin also induced the phosphorylation of H2A.X and downregulated the expression levels of RAD51 and survivin, which implied morin­induced DNA damage and that this damage accumulated in HER­2­overexpressing SK­BR­3 cells. Western blot analysis and fluorescent immunocytochemisty showed that morin also activated autophagy after 24 h of treatment and this was maintained at 48 h when activation of apoptosis via PARP cleavage resulted in the activation of caspase­3 and ­7, which was associated with the release of cytochrome c to the cytosol from mitochondria. In addition, the phosphorylation of p38 and JNK was enhanced in the HER­2­overexpressing SK­BR­3 cells by morin after 24 and 48 h of treatment, which suggested p38 and JNK participate in morin­induced cell death. Taken together, the present investigation indicates that morin is a powerful therapeutic candidate for the treatment of HER2­overexpressing breast cancer because it suppresses the EGFR signaling pathway, induces cell death by inhibiting the HER2/EGFR signaling pathway, and suppresses metastatic potential.


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Breast Neoplasms/metabolism , Flavonoids/pharmacology , Receptor, ErbB-2/metabolism , Breast Neoplasms/drug therapy , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Epidermal Growth Factor/pharmacology , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Matrix Metalloproteinase 9/metabolism , Neoplasm Metastasis/drug therapy , Signal Transduction/drug effects , Up-Regulation/drug effects
9.
Pharmacol Rep ; 73(5): 1315-1327, 2021 Oct.
Article in English | MEDLINE | ID: mdl-33993438

ABSTRACT

BACKGROUND: Morin, a flavonoid extracted from Moraceace family and exhibits several pharmacological activities including anti-cancer activity. Although the anticancer activity of morin in breast cancer was estimated in some investigations, the pharmaceutical mechanism has not been fully elucidated. Therefore, we investigated to unveil the detail signaling pathway in morin-treated in MDA-MB-231 triple-negative breast cancer cells. METHODS: The cytotoxicity of morin in MDA-MB-231 cells was confirmed by sulforhodamine B (SRB) assay and colony formation assay. Flow cytometry was performed to examine the cell cycle and cell death patterns and the protein expression and phosphorylation were detected by western blotting. RESULTS: Our results showed that morin inhibited MDA-MB-231 cells proliferation in time and concentration-dependent manner. Morphological changes were observed when treated with various concentration of morin in MDA-MB-231 cells. In regard to protein expression, morin induced the phosphorylation of ERK and p-H2A.X and decreased the level of DNA repair markers, RAD51 and survivin. In addition, flow cytometry showed S and G2/M arrest by morin that was associated with the decrease in the protein expression of cyclin A2 and cyclin B1 and upregulation of p21. Interestingly, annexin V/PI staining result clearly showed that morin induced cell death without apoptosis. Furthermore, attenuated FoxM1 by morin was co-related with cell cycle regulators including p21, cyclin A2 and cyclin B1. CONCLUSION: Taken together, our study indicates that morin-induced cell death of MDA-MB-231 is caused by sustained cell cycle arrest via the induction of p21 expression by activation of ERK and repression of FOXM1 signaling pathways.


Subject(s)
Apoptosis/drug effects , Cell Cycle Checkpoints/drug effects , Flavonoids/pharmacology , Triple Negative Breast Neoplasms , Antioxidants/pharmacology , Autophagy/drug effects , Butadienes/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Enzyme Inhibitors/pharmacology , Female , Humans , Molecular Structure , Nitriles/pharmacology
10.
J Ethnopharmacol ; 274: 114081, 2021 Jun 28.
Article in English | MEDLINE | ID: mdl-33798660

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Chaga mushrooms (Inonotus obliquus) are commonly used in traditional treatments in Eastern Europe and Asia due to their diverse pharmacological effects, including anti-tumor and immunologic effects. Thus, many cancer patients take Chaga mushrooms as a complementary medicine, even during chemotherapy or radiotherapy. However, few studies have investigated the effects or molecular targets of Chaga mushrooms in breast cancer. AIM OF THE STUDY: Herein, we examined the anticancer effects of Chaga mushrooms in different types of breast cancer cell lines, and explored the underlying molecular mechanism to better understand their effects and benefits. MATERIALS AND METHODS: Chaga mushroom extract (CME) was prepared by extracting Chaga mushrooms with 70% ethanol. The cytotoxic effects of CME were assessed by MTT assay and protein expressions were evaluated by western blotting. To evaluate in vivo anti-tumor effects of CME, CME (2 g/kg) was orally administered to 4T1 tumor-bearing BALB/c mice every other day over 30 days (15 administrations), and tumor sizes were measured. Silica gel column chromatography was used to fractionate CME, and major constituents responsible for cytotoxic effects of CME were identified by 1H/13C-NMR and LC-MS. RESULTS: CME inhibited the proliferation of 4T1 mouse breast cancer cells in a dose and time-dependent manner. The expression of LC3 and phosphorylation of AMPK were increased by CME, while the phosphorylation of mTOR, S6, and S6K1 were suppressed, suggesting that CME induced autophagy by activating AMPK and inhibiting mTOR signaling pathways. Consistent with its observed cytotoxic effect in vitro, CME effectively suppressed tumor growth in 4T1 tumor-bearing BALB/c mice. In addition, inotodiol and trametenolic acid were identified as the major constituents responsible for the cytotoxic effects of CME on breast cancer cells. Moreover, inotodiol and trametenolic acid-enriched fractions both exhibited cytotoxic effects regardless of breast cancer cell subtypes and did not interfere with the cytotoxic effects of conventional drugs. CONCLUSIONS: Taken together, Chaga mushroom extract induced autophagy by activating AMPK and inhibiting the mTOR signaling pathway. Our data suggest Chaga mushrooms may be a beneficial complementary medicine for breast cancer patients.


Subject(s)
Agaricales , Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Complex Mixtures/therapeutic use , AMP-Activated Protein Kinases/metabolism , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Autophagy/drug effects , Breast Neoplasms/metabolism , Cell Line, Tumor , Cell Survival/drug effects , Complex Mixtures/chemistry , Complex Mixtures/pharmacology , Female , Humans , Lanosterol/analogs & derivatives , Lanosterol/analysis , Lanosterol/pharmacology , Mice, Inbred BALB C , Signal Transduction/drug effects , TOR Serine-Threonine Kinases/metabolism , Triterpenes/analysis , Triterpenes/pharmacology
11.
Pharmacol Rep ; 73(2): 629-641, 2021 Apr.
Article in English | MEDLINE | ID: mdl-33677703

ABSTRACT

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) is well-known as the therapeutic marker in breast cancer. Therefore, we evaluated anti-cancer activity of arctigenin (ATG) on in SK-BR-3 HER2-overexpressing human breast cancer cells. METHODS: Cell viability and cytotoxicity were analyzed with MTT and colony-forming assay and cell cycle analysis was performed by flow cytometry. The expression and/or phosphorylation of proteins in whole cell lysate and mitochondrial fraction were analyzed by Western blotting. Cellular levels of LC3 and sequestosome 1 (SQSTM1/P62) were observed by immunofluorescence analysis. RESULTS: The result showed that ATG decreased cell viability of SK-BR-3 cells in a concentration-dependent manner. Moreover, ATG increased the sub G1 population linked to the suppression of HER2/EGFR1 signaling pathway. Furthermore, ATG increased the phosphorylation of H2AX and down-regulated RAD51 and survivin expressions, indicating that ATG induced DNA damage and inhibited the DNA repair system. We also found that cleavages of caspase-7 and PARP by releasing mitochondrial cytochrome c into the cytoplasm were induced by ATG treatment for 72 h through the reduction of Bcl-2 and Bcl-xL levels in mitochondria. In contrast, the levels of LC-3 and SQSTM1/P62 were increased by ATG for 24 h through the Akt/mTOR and AMPK signaling pathway. CONCLUSIONS: Taken together, this study indicates that autophagy-linked apoptosis is responsible for the anti-cancer activity of ATG in SK-BR-3 cells, and suggests that ATG is considered a potential therapeutic for the treatment of HER2-overexpressing breast cancer.


Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Furans/pharmacology , Lignans/pharmacology , Receptor, ErbB-2/antagonists & inhibitors , Apoptosis/drug effects , Autophagy/drug effects , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Survival/drug effects , Female , Gene Expression Regulation, Neoplastic , Humans , Receptor, ErbB-2/genetics , Signal Transduction/drug effects
12.
Int J Mol Sci ; 21(8)2020 Apr 23.
Article in English | MEDLINE | ID: mdl-32340377

ABSTRACT

Several reports have described the anti-cancer activity of arctigenin, a lignan extracted from Arctium lappa L. Here, we investigated the effect of arctigenin (ATG) on doxorubicin (DOX)-induced cell death using MDA-MB-231 human breast cancer cells. The results showed that DOX-induced cell death was enhanced by ATG/DOX co-treatment in a concentration-dependent manner and that this was associated with increased DOX uptake and the suppression of multidrug resistance-associated protein 1 (MRP1) gene expression in MDA-MB-231 cells. ATG enhanced DOX-induced DNA damage and decreased the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and the expressions of RAD51 and survivin. Cell death caused by ATG/DOX co-treatment was mediated by the nuclear translocation of apoptosis inducing factor (AIF), reductions in cellular and mitochondrial Bcl-2 and Bcl-xL, and increases in mitochondrial BAX levels. However, caspase-3 and -7 did not participate in DOX/ATG-induced cell death. We also found that DOX/ATG-induced cell death was linked with activation of the p38 signaling pathway and suppressions of the phosphorylations and expressions of Akt and c-Jun N-terminal kinase. Taken together, these results show that ATG enhances the cytotoxic activity of DOX in MDA-MB-231 human breast cancer cells by inducing prolonged p21 expression and p38-mediated AIF-dependent cell death. In conclusion, our findings suggest that ATG might alleviate the side effects and improve the therapeutic efficacy of DOX.


Subject(s)
Antibiotics, Antineoplastic/pharmacology , Doxorubicin/pharmacology , Furans/pharmacology , Lignans/pharmacology , Apoptosis/drug effects , Biomarkers, Tumor , Cell Line, Tumor , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Synergism , Gene Expression Regulation, Neoplastic/drug effects , Humans , MAP Kinase Signaling System/drug effects , Mitochondria/drug effects , Mitochondria/genetics , Mitochondria/metabolism , Phosphorylation
13.
Mol Med Rep ; 21(3): 1374-1382, 2020 03.
Article in English | MEDLINE | ID: mdl-32016480

ABSTRACT

Arctigenin is a natural lignan that is found in burdock with anti­viral, ­oxidative, ­inflammatory and anti­tumor activities. In the current study, the effect of arctigenin on metastatic potential was examined in 4T­1 mouse triple­negative breast cancer cells. The results indicated that arctigenin inhibited cell motility and invasiveness, which was determined using wound healing and transwell invasion assays. Arctigenin suppressed matrix metalloprotease­9 (MMP­9) activity via gelatin zymography, and protein expression of cyclooxygenase­2 (COX­2) and MMP­3. Furthermore, arctigenin attenuated the mRNA expression of metastatic factors, including MMP­9, MMP­3 and COX­2. Based on these results, the effect of arctigenin on the mitogen­activated protein kinase (MAPK)/activating protein­1 (AP­1) signaling pathway was assessed in an attempt to identify the regulatory mechanism responsible for its anti­metastatic effects. Arctigenin was demonstrated to inhibit the phosphorylation of extracellular signal­regulated protein kinase (ERK) and c­Jun N­terminal kinase (JNK), and the nuclear translocations of the AP­1 subunits, c­Jun and c­Fos. In summary, the present study demonstrated that in 4T­1 mouse triple­negative breast cancer cells the anti­metastatic effect of arctigenin is mediated by the inhibition of MMP­9 activity and by the inhibition of the metastasis­enhancing factors MMP­9, MMP­3 and COX­2, due to the suppression of the MAPK/AP­1 signaling pathway. The results of the current study demonstrated that arctigenin exhibits a potential for preventing cell migration and invasion in triple negative breast cancer.


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Arctium/chemistry , Furans/pharmacology , Lignans/pharmacology , MAP Kinase Signaling System , Matrix Metalloproteinase Inhibitors/pharmacology , Transcription Factor AP-1/metabolism , Triple Negative Breast Neoplasms/drug therapy , Animals , Cell Line, Tumor , Cell Movement/drug effects , Female , Humans , Matrix Metalloproteinase 9/genetics , Matrix Metalloproteinase 9/metabolism , Mice , Neoplasm Invasiveness , Phosphorylation/drug effects , Signal Transduction/drug effects
14.
Asian-Australas J Anim Sci ; 32(7): 956-965, 2019 Jul.
Article in English | MEDLINE | ID: mdl-30744366

ABSTRACT

OBJECTIVE: The main goal of this study was to provide a morphological indicator that could be used to select high-quality oocytes of appropriate meiotic and developmental capabilities in pig. The higher quality of immature oocytes, the higher success rates of in vitro maturation (IVM) and in vitro fertilization (IVF). Thus, prior to the IVM culture, it is important to characterize oocytes morphologically and biochemically in order to assess their quality. Two of the largest indicators of oocyte quality are the presence of cumulus cells and status of chromatin. To investigate the effects of porcine oocyte chromatin configurations on the developmental capacity of blastocysts, we assessed oocyte chromatin status according to follicle size and measured the developmental potency of blastocysts. METHODS: To sort by follicle size, we divided the oocytes into three groups (less than 1 mm, 1 to 3 mm, and more than 3 mm in diameter). To assess chromatin configuration, the oocytes were assessed for their stages (surrounded nucleolus [SN] germinal vesicle [GV], non-surrounded nucleolus [NSN] GV, GV breakdown, metaphase I [MI], pro-metaphase II [proMII], and metaphase II [MII]) at different maturation times (22, 44, and 66 h). To assess the development rate, oocytes of each follicle size were subjected to parthenogenetic activation for further development. Finally, GV oocytes were grouped by their chromatin configuration (SN, SN/NSN, and NSN) and their global transcriptional levels were measured. RESULTS: SN GV oocytes were more suitable for IVF than NSN GV oocytes. Moreover, oocytes collected from the larger follicles had a greater distribution of SN GV oocytes and a higher developmental capacity during IVM, reaching MII more quickly and developing more often to blastocysts. CONCLUSION: Porcine oocytes with high-level meiotic and developmental capacity were identified by analyzing the relationship between follicle size and chromatin configuration. The porcine oocytes from large follicles had a significantly higher SN status in which the transcription level was low and could be better in the degree of meiotic progression and developmental capacity.

15.
Int J Oncol ; 54(2): 744-752, 2019 02.
Article in English | MEDLINE | ID: mdl-30483758

ABSTRACT

Fewer than 20% of patients diagnosed with pancreatic cancer can be treated with surgical resection. The effects of proton beam irradiation were evaluated on the cell viabilities in Panc­1 and Capan­1 pancreatic cancer cells. The cells were irradiated with proton beams at the center of Bragg peaks with a 6­cm width using a proton accelerator. Cell proliferation was assessed with the MTT assay, gene expression was analyzed with semi­quantitative or quantitative reverse transcription­polymerase chain reaction analyses and protein expression was evaluated by western blotting. The results demonstrated that Capan­1 cells had lower cell viability than Panc­1 cells at 72 h after proton beam irradiation. Furthermore, the cleaved poly (ADP­ribose) polymerase protein level was increased by irradiation in Capan­1 cells, but not in Panc­1 cells. Additionally, it was determined that histone H2AX phosphorylation in the two cell lines was increased by irradiation. Although a 16 Gy proton beam was only slightly up­regulated cyclin­dependent kinase inhibitor 1 (p21) protein expression in Capan­1 cells, p21 expression levels in Capan­1 and Panc­1 cells were significantly increased at 72 h after irradiation. Furthermore, it was observed that the expression of DNA repair protein RAD51 homolog 1 (RAD51), a homogenous repair enzyme, was decreased in what appeared to be a dose­dependent manner by irradiation in Capan­1 cells. Contrastingly, the transcription of survivin in Panc­1 was significantly enhanced. The results suggest that RAD51 and survivin are potent markers that determine the therapeutic efficacy of proton beam therapy in patients with pancreatic cancer.


Subject(s)
Pancreatic Neoplasms/radiotherapy , Rad51 Recombinase/genetics , Radiation Tolerance/genetics , Survivin/genetics , Apoptosis/radiation effects , Cell Line, Tumor , Cell Proliferation/radiation effects , Cell Survival/radiation effects , Humans , Pancreatic Neoplasms/pathology , Proton Therapy
16.
Biomed Pharmacother ; 111: 282-291, 2019 Mar.
Article in English | MEDLINE | ID: mdl-30590316

ABSTRACT

Ultraviolet light (UV) is a major inducer of skin cancer. Therefore, recovery and removal of UV-damaged skin cells are important in the prevention of skin carcinogenesis. Here, we investigated the effect of deep sea water (DSW) in HaCaT keratinocyte exposed by UVB (λ = 290∼320 nm). The result showed that UVB-induced cell death was reinforced by DSW treatment in a hardness-dependent manner. Furthermore, the increase of cell death by DSW was associated with the down-regulation of survivin and RAD51 expressions induced by UVB. Moreover, we confirmed the inhibition of H2 A.X phosphorylation, a marker for double-stranded DNA damage, and the enhancement of LC3-II and SQSTM1/p62 expressions by DSW administration in UVB-radiated HaCaT keratinocyte. The results imply that the enhancement of UVB-induced cell death by DSW is associated with autophagy. Therefore, we further explored the regulation of autophagy-regulating proteins and apoptosis-related factors expression. Phosphorylation of mammalian target of rapamycin (mTOR), ribosomal protein S6, and S6 kinase by UVB radiation were regressed via DSW treatment, underlying the increase of AMP-activated protein kinase (AMPK) phosphorylation. Furthermore, UVB-enhanced nuclear factor κB (NF-κB) and c-Jun N-terminal kinase (JNK) phosphorylations were increased with DSW treatment. Contrastingly, DSW lessened the Ser15 phosphorylation of p53 and cleavage of poly (ADP-ribose) polymerase induced by UVB radiation. Consequently, the results demonstrate that DSW enhances UVB-damaged skin cell clearance through the activation of autophagic cell death underlying the regulation of AMP-activated protein kinase (AMPK)/mTOR signaling as well as NF-κB and JNK phosphorylations. In conclusion, this investigation suggests that DSW is a potent candidate for the prevention of UV-induced skin cancer development.


Subject(s)
Autophagy/radiation effects , Carcinogenesis/radiation effects , Keratinocytes/radiation effects , Seawater , Skin Neoplasms/prevention & control , Ultraviolet Rays/adverse effects , Autophagy/physiology , Carcinogenesis/pathology , Cell Line , Cell Survival/physiology , Cell Survival/radiation effects , Humans , Keratinocytes/pathology , Skin Neoplasms/etiology , Skin Neoplasms/pathology
17.
Cardiovasc Drugs Ther ; 32(4): 329-338, 2018 08.
Article in English | MEDLINE | ID: mdl-29956042

ABSTRACT

BACKGROUND/AIMS: The progression and development of congestive heart failure is still considered a large problem despite the existence of revascularization therapies and optimal, state-of-the-art medical services. An acute myocardial infarction (AMI) is a major cause of congestive heart failure, so researchers are investigating techniques to complement primary percutaneous coronary intervention (PCI) or thrombolytic therapy to prevent congestive heart failure after AMI. METHODS: Twenty-six patients with successful PCI for acute ST-segment elevation anterior wall myocardial infarction were assigned to either a control group (n = 12) or a bone marrow mesenchymal stem cells (BM-MSC) group (n = 14). The control group received optimum post-infarction treatment, and the BMSC group received intracoronary delivery of autologous BMSC at 1 month after PCI with the optimum medical treatment. The primary endpoint was a left ventricular ejection fraction (LVEF) change from baseline to 4-month follow-up, as determined via myocardial single-photon emission computed tomography (SPECT). RESULTS: The global LVEF at baseline (determined 3.5 ± 1.5 days after PCI) was 35.4 ± 3.0% in the control group and 33.6 ± 4.7% in the BM-MSC group. BMSC transfer enhanced left ventricular systolic function primarily in anterior wall myocardial segments adjacent to the LAD infarcted area. Four months later, via SPECT, global LVEF had increased by 4.8 ± 1.9% in the control group and 8.8 ± 2.9% in the BM-MSC group (p = 0.031). The cell transfer did not increase the risk of adverse clinical events, in-stent restenosis, or proarrhythmic effects. The echocardiographic evaluation also revealed a significant increase in the LVEF value from baseline to the 4-month (9.0 ± 4.7 and 5.3 ± 2.6%, p = 0.023) and 12-month (9.9 ± 5.2% and 6.5 ± 2.7%, p = 0.048) follow-up in the BM-MSC group but not in the control group. CONCLUSIONS: Intracoronary administration of autologous BM-MSC was tolerable and safe with significant improvement in LVEF at 4-month (SPECT and echocardiography result) and 12-month (echocardiography result only) follow-up in patients with anterior AMI.


Subject(s)
Anterior Wall Myocardial Infarction/surgery , Heart Failure/prevention & control , Mesenchymal Stem Cell Transplantation , ST Elevation Myocardial Infarction/surgery , Stroke Volume , Ventricular Function, Left , Aged , Anterior Wall Myocardial Infarction/complications , Anterior Wall Myocardial Infarction/diagnostic imaging , Anterior Wall Myocardial Infarction/physiopathology , Echocardiography , Female , Heart Failure/etiology , Heart Failure/physiopathology , Humans , Male , Mesenchymal Stem Cell Transplantation/adverse effects , Middle Aged , Percutaneous Coronary Intervention , Recovery of Function , Republic of Korea , Risk Factors , ST Elevation Myocardial Infarction/complications , ST Elevation Myocardial Infarction/diagnostic imaging , ST Elevation Myocardial Infarction/physiopathology , Time Factors , Tomography, Emission-Computed, Single-Photon , Treatment Outcome
18.
Surg Endosc ; 32(7): 3282-3289, 2018 07.
Article in English | MEDLINE | ID: mdl-29344790

ABSTRACT

BACKGROUNDS/AIMS: Although post-polypectomy bleeding is the most frequent complication after colonoscopic polypectomy, only few studies have investigated the incidence of bleeding prospectively. The aim of this study was to investigate the incidence of delayed post-polypectomy bleeding and its associated risk factors prospectively. METHODS: Patients who underwent colonoscopic polypectomy at Kangbuk Samsung Hospital from January 2013 to December 2014 were prospectively enrolled in this study. Trained nurses contacted patients via telephone 7 and 30 days after polypectomy and completed a standardized questionnaire regarding the development of bleeding. Delayed post-polypectomy bleeding was categorized as minor or major and early or late bleeding. Major delayed bleeding was defined as a > 2-g/dL drop in the hemoglobin level, requiring hospitalization for control of bleeding or blood transfusion; late delayed bleeding was defined as bleeding occurring later than 24 h after polypectomy. RESULTS: A total of 8175 colonoscopic polypectomies were performed in 3887 patients. Overall, 133 (3.4%) patients developed delayed post-polypectomy bleeding. Among them, 90 (2.3%) and 43 (1.1%) patients developed minor and major delayed bleeding, respectively, and 39 (1.0%) patients developed late delayed bleeding. In the polyp-based multivariate analysis, young age (< 50 years; odds ratio [OR] 2.10; 95% confidence interval [CI] 1.18-3.68), aspirin use (OR 2.78; 95% CI 1.23-6.31), and polyp size of > 10 mm (OR 2.45; 95% CI 1.38-4.36) were significant risk factors for major delayed bleeding, while young age (< 50 years; OR 2.6; 95% CI 1.35-5.12) and immediate bleeding (OR 3.3; 95% CI 1.49-7.30) were significant risk factors for late delayed bleeding. CONCLUSIONS: Young age, aspirin use, polyp size, and immediate bleeding were found to be independent risk factors for delayed post-polypectomy bleeding.


Subject(s)
Colonic Polyps/surgery , Colonoscopy/adverse effects , Gastrointestinal Hemorrhage/epidemiology , Postoperative Hemorrhage/epidemiology , Rectal Diseases/surgery , Adult , Aged , Blood Transfusion , Colorectal Neoplasms/prevention & control , Female , Gastrointestinal Hemorrhage/etiology , Humans , Incidence , Male , Middle Aged , Multivariate Analysis , Odds Ratio , Postoperative Hemorrhage/etiology , Prospective Studies , Risk Factors
19.
Biomed Pharmacother ; 97: 1331-1340, 2018 Jan.
Article in English | MEDLINE | ID: mdl-29156522

ABSTRACT

Atopic dermatitis (AD) is a chronic inflammatory skin disease caused by environmental and chemical allergens. Despite the complexity of its pathogenesis, many investigations have shown that substances having anti-inflammatory activities alleviated the pathology of AD. Here, we evaluated the effects of mineral-balanced deep sea water (DSW) on AD-like skin damage in both in vitro and in vivo. The results showed that mineral-balanced DSW regressed inflammatory chemokines, such as macrophage-derived chemokine (MDC), thymus- and activation-regulated chemokine (TARC) and regulated on activation, normal T-cell expressed and secreted (RANTES), and cytokines, interleukin (IL)-6 and granulocyte-macrophage colony-stimulating factor (GM-CSF) mRNA expression in HaCaT immortal human keratinocyte treated with tumor necrosis factor (TNF)-α/ interferon (IFN)-γ mixture. Furthermore, increased cyclooxygenase (COX)-2 protein expressions were also reversed, filaggrin gene expression was enhanced and decreased involucrin transcriptions was recovered by mineral-balanced DSW in TNF-α/IFN-γ mixture-treated HaCaT human keratinocyte. Moreover, we revealed that the inhibitory effects of mineral-balanced DSW were mediated with the suppression of signal transducer and activator of transcription (STAT) 1 phosphorylation. In animal experiments, we showed that hardness 2000 of mineral-balanced DSW decreased the serum levels of IgE, IL-4, and histamine, and alleviated the severity score and numbers of scratching in dinitrochlorobezene (DNCB)-treated Nc/Nga mice. Furthermore, increased epidermal thickness and mast cell infiltration by DNCB treatment were reversed by the application of hardness 2000 mineral-balanced DSW. Taken together, the present investigation indicates that mineral-balanced DSW is a potent substance with anti-atopic dermatitis activity.


Subject(s)
Dermatitis, Atopic/prevention & control , Inflammation/prevention & control , Keratinocytes/drug effects , Mineral Waters/administration & dosage , Animals , Anti-Inflammatory Agents/pharmacology , Cell Line , Chemokines/metabolism , Cytokines/metabolism , Dermatitis, Atopic/pathology , Disease Models, Animal , Filaggrin Proteins , Gene Expression Regulation , Humans , Inflammation/pathology , Interferon-gamma/administration & dosage , Interferon-gamma/metabolism , Keratinocytes/metabolism , Male , Mast Cells/metabolism , Mice , Seawater/chemistry , Tumor Necrosis Factor-alpha/administration & dosage , Tumor Necrosis Factor-alpha/metabolism
20.
Dig Dis Sci ; 62(8): 2113-2119, 2017 08.
Article in English | MEDLINE | ID: mdl-28500589

ABSTRACT

BACKGROUND: The risks of minor adverse events (MAEs) such as abdominal pain and bloating after colon polypectomy (CP) are less clearly documented than major adverse events. However, these complications may cause significant discomfort during the performance of normal activities. We aimed to estimate the incidence of MAE, associated risk factors, and healthcare resource utilization after CP. METHODS: Patients who underwent CP were prospectively enrolled in this study. Trained nurses contacted patients by telephone at 7 and 30 days after the CP and administered a standardized questionnaire to obtain information regarding the development of complications. MAEs were defined as any discomfort the patient experienced after CP excluding major bleeding, perforation, and post-polypectomy coagulation syndrome. RESULTS: Among a total of 2716 patients, 2253 patients completed the interview at 7 and 30 days. MAEs occurred in 263 patients (11.7%) before day 7, among which the most common were abdominal pain (4.5%), rectal bleeding (2.8%), and bloating (2.6%). Cumulative incidence of MAEs was in 267 patients (11.9%) at 30 days. On multivariate analysis, female sex (odds ratio [OR] 2.24, 95% confidence interval [CI] 1.58-3.18) and use of meperidine (OR 1.54, 95% CI 1.04-2.27) were risk factors for the occurrence of MAEs. Two patients (0.7%) required hospital admission, 117 patients (43.8%) were treated medically in the outpatient clinic, and the majority at 148 patients (55.4%) experienced resolution of symptoms after observation. CONCLUSIONS: The post-CP MAE rate was as low as 11.8%. The MAEs occurred mainly in the first seven postoperative days and resulted in little use of healthcare resources.


Subject(s)
Colonic Polyps/surgery , Colonoscopy/adverse effects , Postoperative Complications/epidemiology , Abdominal Pain/epidemiology , Abdominal Pain/etiology , Analgesics, Opioid/adverse effects , Colonoscopy/methods , Female , Gastrointestinal Hemorrhage/epidemiology , Gastrointestinal Hemorrhage/etiology , Humans , Male , Meperidine/adverse effects , Middle Aged , Postoperative Complications/etiology , Postoperative Period , Prospective Studies , Rectum , Risk Factors , Sex Factors , Time Factors
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