Vol. 23 (2018)

DOI: 10.1186/s11658-017-0063-z Volume 23 (2018)
Authors Yanan Li1, Yu Yan2, Fang Liu1, Ming Wang1, Fumin Feng1 and Yonghong Xiao1*
Abstract Background: Our previous study showed that during in vitro experiments changes in calcium concentration were associated with apoptosis. We presumed that the calcium ion might play a role as intermediate messenger for apoptosis-related genes. No such evidence has been reported in the literature. Here, we investigate the effect of calcium ionophore A23187 on the apoptosis of rat hepatic stellate cells (HSCs) stimulated by transforming growth factor-β1 (TGF-β1) to explore the mechanism of apoptosis through the endoplasmic reticulum stress pathway.
Methods: The apoptotic rate was determined using flow cytometry. The changes in Ca2+ level in HSCs were examined with laser confocal microscopy. The expressions of caspase-12 GRP78 and caspase-9 were assayed via western blot.
Results: The respective apoptosis rates for the blank group, the TGF-β1 group and the TGF-β1 + low, medium and high dose calcium ionophore A23187 groups were 3.40 ± 0.10%, 1.76 ± 0.12%, 5.86 ± 0.31%, 11.20 ± 0.48% and 15.08 ± 0.75%, with significant differences between the groups (p < 0.05). The concentration of Ca2+ and the expression of the GRP78, caspase-9 and caspase-12 proteins significantly increased with increasing calcium ionophore A23187 doses (p < 0.05).
Conclusion: Calcium ionophore A23187 increased intracellular Ca2+ and activated endoplasmic reticulum stress, which promoted HSC apoptosis.
Keywords Hepatic fibrosis, Hepatic stellate cells, Calcium ionophore A23187, Apoptosis
Address and Contact Information 1 Department of School of Public Health, North China University of Science and Technology, Hebei, Tang Shan 063000, China.
2 Department of School of Basic Medical Science, North China University of Science and Technology, Hebei,Tang Shan 063000, China.
* Correspondence author: 1619747081@qq.com
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DOI: 10.1186/s11658-017-0058-9 Volume 23 (2018)
Authors Ying Chen1,2,3*, Lei Zhang1,2,3, Wen-xin Liu1 and Ke Wang1
Abstract Background: Anti-angiogenesis therapy that targets VEGF is one of the important treatment strategies in advanced ovarian cancer. However, depending on the pharmaceutical agent, treatment can have undesirable side effects. SEMA4D has recently gained interest for its role in promoting angiogenesis. Here, we try to further understand the mechanism by which SEMA4D promotes angiogenesis in ovarian cancer.
Methods: Correlation and western blot assaya were used to detect the relationship between VEGF and SEMA4D in clinical tissues and cells. Vasculogenic mimicry and transwell migration analyses were used to detect the roles of VEGF, SEMA4D and plexin-B1 on vasculogenic mimicry and migration. Vascular density and SEMA4D expression was determined using immunofluorescence staining in clinical tissues of EOC. Western blot was used to detect the expressions of CD31, MMP2 and VE-cadherin. We also analyzed the relationship between VEGF-SEMA4D and malignant tumor prognosis.
Results: We found that knockdown of VEGF could suppress SEMA4D expression and that the expressions of VEGF and SEMA4D have a positive correlation in EOC cancer tissues. Vasculogenic mimicry and transwell migration analyses showed that SEMA4D and VEGF have a synergistic effect on the promotion of angiogenesis in A2780 and HUVEC cells. Soluble SEMA4D (sSEMA4D) could promote VM and migration in A2780 and HUVEC cells via the SEMA4D/plexin-B1 pathway, but the effect was not noted in stably transfected shR-plexin-B1 cells. In clinical tissues of EOC, the vascular density and SEMA4D/plexin-B1 expression were higher. When VEGF, SEMA4D and plexin-B1 was knocked down, the expression of CD31, MMP2 and VE-cadherin, which are the markers and initiators of angiogenesis and the epithelial–mesenchymal transition (EMT) process were reduced. VEGF and SEMA4D had a positive correlation with the malignant degree of ovarian cancer, and SEMA4D can serve as an independent prognostic factor.
Conclusions: VEGF and SEMA4D have synergistic effects on the promotion of angiogenesis in epithelial ovarian cancer. Targeting VEGF and the SEMA4D signaling pathway could be important for the therapy for EOC.
Keywords SEMA4D, Vegf, Angiogenesis, Tumor growth, Epithelial ovarian cancer
Address and Contact Information 1Department of Gynecologic Oncology, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Hexi District, Tianjin 300060, China.
2 Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
3 National Clinical Research Centre of Cancer, Tianjin 300060, China.
* Correspondence author: chenying912a@126.com
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DOI: 10.1186/s11658-017-0068-7 Volume 23 (2018)
Authors Paul Chen, Saifuddin Sheikh, Ateeq Ahmad, Shoukath M. Ali, Moghis U. Ahmad and Imran Ahmad*
Abstract Endoxifen, an active metabolite of tamoxifen, has been shown to be an effective anti-estrogenic agent in estrogen receptor-positive breast cancer patients. In melanoma, estrogen receptor expression is shown to be associated with disease progression. However, the therapeutic benefit of endoxifen in melanoma has not yet been evaluated. Here, we present the first demonstration of the anti-melanogenic activity of endoxifen in vitro and in vivo.
The in vitro cytotoxic effect of endoxifen was tested using a cell viability assay. The in vivo anti-melanogenic activity was evaluated in B16F10 cell-bearing C57BL/6 mice, a mouse melanoma model. The general toxicity was tested in Swiss albino mice. Endoxifen exhibited greater activity against melanoma cell lines. Treatment of B16F10 mouse and SK-MEL-5 human melanoma cell lines with 10 μM of endoxifen for 48 h respectively resulted in 93.6 and 92.5% cell death. Orally administered endoxifen, at dose levels of 4 and 8 mg/kg body weight/day for 20 consecutive days, respectively reduced metastatic melanoma nodules in the lungs by 26.7 and 82.7%.
Endoxifen was found to be a safe and effective anti-melanogenic agent in animal studies.
Keywords Endoxifen, Melanoma tumor model, Tamoxifen, Safety, Efficacy
Address and Contact Information Jina Pharmaceuticals, Inc., 28100 N. Ashley Circle, Suite 103, Libertyville, IL 60048, USA
* Correspondence author: imran@jinapharma.com
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DOI: Volume 23 (2018)
Authors Shaohua Wang1*, Hongxing Dang2, Feng Xu2, Jian Deng1 and Xuemei Zheng1
Abstract Background: Calcitonin gene-related peptide (CGRP) can protect against hyperoxia-induced lung injury, making the upregulation of CGRP a potential therapeutic approach for this type of injury. However, the effects of CGRP on the Wnt7b/β-catenin signaling pathway are unclear. In this study, we investigated the roles of CGRP and the Wnt7b/β-catenin signaling pathway in hyperoxia-induced lung injury.
Methods: Premature Sprague Dawley (SD) rats were exposed to 21, 40, 60 and 95% oxygen for 3, 7 and 14 days. The animals’ body weights, survival rates and endogenous CGRP levels were measured. Lung samples were harvested for histological analyses and measurements of malondialdehyde (MDA) concentration and total antioxidant capacity (TAOC). We also assessed the MDA concentration and TAOC in the lung tissues after administration of 200 nmol/kg CGRP8–37 (a CGRP antagonist). Finally, alveolar epithelial type II (AEC II) cells were isolated from premature rats, exposed to 21 or 95% oxygen for 3, 7 and 14 days, and treated with 10−8 mol/l exogenous CGRP. The protein expressions of Wnt7b and β-catenin were assessed using western blotting, and TCF and c-myc mRNA expressions were assessed using qPCR.
Results: Rats exposed to 60 and 95% oxygen had significantly lower body weights and survival rates than the 21 and 40% groups, and the decrease was time dependent. Endogenous CGRP was elevated in the lung tissues of premature rats exposed to 95% oxygen. CGRP8–37 induced apparent inflammation in the lung tissue and alveolar structural remodeling. In addition, the expression levels of Wnt7b and β-catenin were markedly increased after exposure for 3 days. They peaked at 7 days, then declined at 14 days. The levels of TCF/c-myc in AEC II cells increased significantly after CGRP treatment when compared with cells that had only undergone hyperoxia.
Conclusions: CGRP protected against hyperoxia-induced lung injury in premature rats. This process involves the Wnt7b/β-catenin signaling pathway.
Keywords CGRP, Lung injury, Wnt7b, β-catenin
Address and Contact Information 1 Neonatal Intensive Care Unit, Women and Children Health Institute of Futian, University of South China, Jintian South Road No. 2002, Futian district, Shen Zhen 518045, China.
2 Pediatric Intensive Care Unit, Children’s Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, Yu Zhong, Chongqing 400014, China.
* Correspondence author: wangshua2017@163.com
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DOI: 10.1186/s11658-018-0073-5 Volume 23 (2018)
Authors Nazli F. Eskici1, Sevim Erdem-Ozdamar2 and Didem Dayangac-Erden1*
Abstract Background: Perineuronal nets (PNNs), which are localized around neurons during development, are specialized forms of neural extracellular matrix with neuroprotective and plasticity-regulating roles. Hyaluronan and proteoglycan link protein 1 (HAPLN1), tenascin-R (TNR) and aggrecan (ACAN) are key elements of PNNs. In diseases characterized by neuritogenesis defects, the expression of these proteins is known to be downregulated, suggesting that PNNs may have a role in neural differentiation.
Methods: In this study, the mRNA and protein levels of HAPLN1, TNR and ACAN were determined and compared at specific time points of neural differentiation. We used PC12 cells as the in vitro model because they reflect this developmental process.
Results: On day 7, the HAPLN1 mRNA level showed a 2.9-fold increase compared to the non-differentiated state. However, the cellular HAPLN1 protein level showed a decrease, indicating that the protein may have roles in neural differentiation, and may be secreted during the early period of differentiation. By contrast, TNR mRNA and protein levels remained unchanged, and the amount of cellular ACAN protein showed a 3.7-fold increase at day 7. These results suggest that ACAN may be secreted after day 7, possibly due to its large amount of post-translational modifications.
Conclusions: Our results provide preliminary data on the expression of PNN elements during neural differentiation. Further investigations will be performed on the role of these elements in neurological disease models.
Keywords Perineuronal nets, HAPLN1, Tenascin-R, Aggrecan, PC12 differentiation
Address and Contact Information 1 Faculty of Medicine Department of Medical Biology, Hacettepe University, Ankara, Turkey. 2Faculty of Medicine Department of Neurology, Hacettepe University, Ankara, Turkey.
* Correspondence author: didayan@hacettepe.edu.tr
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DOI: 10.1186/s11658-017-0067-8 Volume 23 (2018)
Authors Guodong Li1†, Xiaoling Hu2†, Lu Sun1, Xin Li1, Jianfeng Li1, Tongli Li1* and Xiaohui Zhang3*
Abstract Background: Laryngeal cancer tends to have a very poor prognosis due to the unsatisfactory efficacy of chemotherapy for this cancer. Multidrug resistance (MDR) is the main cause of chemotherapy failure. The proto-oncogene c-fos has been shown to be involved in the development of MDR in several tumor types, but few studies have evaluated the relationship between c-fos and MDR in laryngeal cancer. We investigated the role of c-fos in MDR development in laryngeal cancer cells (cell line: human epithelial type 2, HEp-2) using the chemotherapeutic vincristine (VCR).
Methods: HEp-2/VCR drug resistance was established by selection against an increasing drug concentration gradient. The expressions of c-fos and multidrug resistance 1 (mdr1) were measured using qPCR and western blot. C-fos overexpression or knockdown was performed in various cells. The intracellular rhodamine-123 (Rh-123) accumulation assay was used to detect the transport capacity of P-glycoprotein (P-gp, which is encoded by the mdr1 gene).
Results: HEp-2 cells with VCR-induced resistance (HEp-2/VCR cells) were not only resistant to VCR but also evolved cross-resistance to other chemotherapeutic drugs. The expressions of the c-fos and mdr1genes were significantly higher in the HEp-2/VCR cells than in control cells. C-fos overexpression in HEp-2 cells (c-fos WT) resulted in increased P-gp expression and increased the IC50 for 5-FU. C-fos knockdown in the HEp-2/VCR cells (c-fos shRNA) resulted in decreased P-gp expression and decreased IC50 for 5-FU. An intracellular Rh-123 accumulation assay showed that the mean intracellular fluorescence intensity (MFI) was lower in the HEp-2/VCR cells than in HEp-2 cells. C-fos WT cells also showed lower MFI. By contrast, c-fos shRNA cells exhibited a higher MFI than the control group.
Conclusion: C-fos increased the expression of P-gp and mdr1 in the HEp-2/VCR cells, and enhanced the efflux function of the cells, thereby contributing to the development of MDR.
Keywords C-fos, P-glycoprotein, Multidrug resistance, Laryngeal carcinoma
Address and Contact Information 1 Department of Otorhinolaryngology, Shanxi Provincial People’s Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi 030012, China.
2 Department of Pharmacology, Shanxi Medical University, Taiyuan, Shanxi, China.
3 Artificial Livers Treatment Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China.
* Correspondence author: t.l.li@163.com;zhangxiaohui_111@163.com
Equal contributors
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DOI: 10.1186/s11658-018-0072-6 Volume 23 (2018)
Authors Hao Yang1, Di Wu1, Hua Li1, Nan Chen1 and Yongjun Shang2*
Abstract Background: Osteoarthritis is characterized by the continuous degradation of the articular cartilage. The microRNA miR-448 has been found to be broadly involved in cellular processes, including proliferation, apoptosis, invasion and EMT. While aberrant expression of miR-448 has been found in multiple cancers, its level in osteoarthritis cartilage and its role in the progression of this disease are still unknown. Here, we examined the functional roles of miR-448 and its expression in osteoarthritis tissues, including IL-1β-stimulated osteoarthritis chondrocytes.
Methods: Chondrocytes were isolated from human articular cartilage and stimulated with IL-1β. The expression levels of miR-448 in the cartilage and chondrocytes were both determined. After transfection with an miR-448 mimic or inhibitor, the mRNA levels of aggrecan, type II collagen and MMP-13 were determined. Luciferase reporter assay, qRT-PCR and western blot were performed to explore whether matrilin-3 was a target of miR-448. Furthermore, we co-transfected chondrocytes with miR-448 inhibitor and siRNA for matrilin-3 and then stimulated them with IL-1β to determine whether miR-448-mediated IL-1β-induced cartilage matrix degradation resulted from directly targeting matrilin-3.
Results: The level of miR-448 was significantly higher and matrilin-3 expression was significantly lower in osteoarthritis cartilage and IL-1β-induced chondrocytes than in normal tissues and cells. Furthermore, matrilin-3 expression was reduced by miR-448 overexpression. MiR-448 downregulation significantly alleviated the IL-1β-induced downregulation of aggrecan and type II collagen expression, and upregulation of MMP-13 expression. MiR-448 overexpression had the opposite effects. Knockdown of matrilin-3 reversed the effects of the miR-448 inhibitor on the expressions of aggrecan, type II collagen and MMP-13.
Conclusion: The findings showed that miR-448 contributed to the progression of osteoarthritis by directly targeting matrilin-3. This indicates that it has potential as a therapeutic target for the treatment of osteoarthritis.
Keywords Osteoarthritis, MicroRNA-448, Interleukin-1 beta, Chondrocyte, Extracellular matrix, Matrilin-3
Address and Contact Information 1 Department of Orthopedics, First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, People’s Republic of China.
2 Department of Orthopedics, Dalian University Affiliated Xinhua Hospital, No. 156 Xinhua Street, Shahekou District, Dalian 116021, Liaoning Province, People’s Republic of China.
* Correspondence author: shangyongjundalian@yahoo.com
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DOI: 10.1186/s11658-018-0075-3 Volume 23 (2018)
Authors Tomoaki Kinjo1,3, Chuanhai Sun1,4, Tomomi Ikeda2, Takako Ikegami2, Yuhki Tada1,5, Tadayuki Akagi1, Takashi Yokota1 and Hiroshi Koide1,2*
Abstract Background: Platelet-derived growth factor-C (PDGF-C) has been shown to be involved in several biological processes, such as embryonic development, wound healing and angiogenesis, as well as in diseases including tumor formation and fibrotic diseases. However, its role in fibrosarcoma and embryonic stem (ES) cells has not been elucidated.
Methods: The expression level of PDGF-C was measured using RT-PCR. The activity of PDGF-C was suppressed using RNA interference or a neutralizing antibody and the effect on cell growth was examined using the WST and soft agar assays.
Results: In the tumor cell lines studied, the highest level of PDGF-C expression was in human HT1080 fibrosarcoma cells. In ES cells, it was highly expressed in the self-renewal state but not in the differentiated state. PDGF-C knockdown suppressed anchorage-dependent and -independent growth of HT1080 and ES cells. In addition, the suppression of PDGF-C activity by a neutralizing antibody retarded ES cell growth.
Conclusion: Our results suggest that PDGF-C plays an important role in the proliferation of fibrosarcoma and ES cells.
Keywords Embryonic stem cells, Cancer, PDGF-C, Fibrosarcoma, Anchorage-independent growth
Address and Contact Information 1Department of Stem Cell Biology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan.
2 Laboratory of Molecular and Biochemical Research, Research Support Center, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
3 Present address: Department of Diagnostic Imaging and Nuclear Medicine, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
4 Present address: Neusoft Xikang Healthcare Technology Co., Ltd., Shenyang, China.
5 Present address: RIKEN BioResource Center, Tsukuba, Ibaraki, Japan.
* Correspondence author: h-koide@juntendo.ac.jp
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DOI: 10.1186/s11658-018-0076-2 Volume 23 (2018)
Authors Seungwoo Kim1, Hyosoon Cheon1, Sam-Moon Kim1 and Young-Youl Kim2*
Abstract Background: Previous studies indicated that cadmium (Cd) increases PI3-kinase/Akt phosphorylation, resulting in an alteration in GSK-3β activity. However, the mechanism of Cd-induced endoplasmic reticulum (ER) stress in neuronal cells has yet to be studied in needs further elucidation. We examined the role of GSK-3β in Cd-induced neuronal cell death and the related downstream signaling pathways.
Methods: SH-SY5Y human neuroblastoma cells were treated with 10 or 20 μM BAPTA-AM and 1 μM wortmannin for 30 min and then incubated with 25 μM Cd for 12 h. Apoptotic cells were visualized via DAPI and PI staining. Data were evaluated with one-way analysis of variance (ANOVA) followed by Student’s t-test. Data are expressed as the means ± SD of experiments performed at least three times.
Results: Treatment of human neuronal SH-SY5Y cells with Cd induced ER, stress as evidenced by the increased expression of GRP78, which is a marker of ER stress. Cd exposure significantly increased the phosphorylation of Akt at thr308 and ser473 and that of GSK-3β at ser9 in a time-dependent manner, while the total protein levels of GSK-3β and Akt did not change. Cd-induced apoptosis was higher in GSK-3β-knockdown cells than in normal cells.
Conclusions: Our data suggest that Akt/GSK-3β signaling activated by Cd is involved in neuronal cell survival.
Keywords Cadmium, ER-stress, GSK-3β
Address and Contact Information 1 Division of Brain Diseases, Center for Biomedical Science, National Institute of Health, Center for Disease Control & Prevention, Osong Health Technology Administration Complex, 187, Osongsaengmyeong2-ro, Osong-eup, Heungdeok-gu, Cheongju-si, South Korea.
2 Division of Biobank for Health Sciences, Center for Genome Science, National Institute of Health, Center for Disease Control & Prevention, 200 Osongsaengmyeong2-ro, Osong-eup, Heungdeok-gu, Cheongju-si, South Korea.
* Correspondence author: youngyk@nih.go.kr
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DOI: 10.1186/s11658-018-0080-6 Volume 23 (2018)
Authors Ghmkin Hassan1*, Mohammad Bahjat2, Issam Kasem2,3, Chadi Soukkarieh2,3 and Majd Aljamali1,2,3*
Abstract Purpose: Articular cartilage has a poor capacity for self-repair, and thus still presents a major challenge in orthopedics. Mesenchymal stem cells (MSCs) are multipotent stem cells with the potential to differentiate into chondrocytes in the presence of transforming growth factor beta (TGF-β). Platelet lysate (PL) contains a relatively large number of growth factors, including TGF-β, and has been shown to ameliorate cartilage repair. Here, we investigated the ability of PL to direct chondrogenic differentiation of MSCs along with other standard differentiation components in a pellet culture system.
Methods: We isolated and expanded MSCs from human umbilical cords using a PL-supplemented medium and characterized the cells based on immunophenotype and potential for differentiation to adipocytes and osteocytes. We further cultured MSCs as pellets in a chondrogenic-differentiation medium supplemented with PL. After 21 days, the pellets were processed for histological analysis and stained with alician blue and acridine orange. The expression of SOX9 was investigated using RT-PCR.
Results: MSCs maintained their stemness characteristics in the PL-supplemented medium. However, the distribution of cells in the pellets cultured in the PL-supplemented chondrogenic differentiation medium had a greater similarity to cartilage tissue-derived chondrocytes than to the negative control. The intense alician blue staining indicated an increased production of mucopolysaccharides in the differentiated pellets, which also showed elevated expression of SOX9.
Conclusions: Our data suggest that MSCs could be differentiated to chondrocytes in the presence of PL and absence of exogenous TGF-β. Further research needs to be conducted to understand the exact role and potential of PL in chondrogenic differentiation and chondrocyte regeneration.
Keywords Platelet lysate, Mesenchymal stem cells, Chondrogenic differentiation, Cartilage
Address and Contact Information 1 Faculty of Pharmacy, Damascus University, Damascus, Syria.
2 Faculty of Sciences, Damascus University, Damascus, Syria.
3 National Commission for Biotechnology (NCBT), Damascus, Syria.
* Correspondence author: hsn.ghmkin@gmail.com; maljamali@gmail.com
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DOI: 10.1186/s11658-018-0079-z Volume 23 (2018)
Authors Laura Susan Boyd1, Devrim Gozuacik2 and Anna Margaretha Joubert1*
Abstract Background: The majority of novel chemotherapeutics target the cell cycle, aiming to effect arrest and cause apoptosis. One such agent, 2-methoxyestradiol (2ME), has been shown to possess anticancer properties against numerous cancer types, both in vitro and in vivo. Despite its promise, 2ME has exhibited limitations, including low oral bioavailability and rapid hepatic enzymatic inactivation in vivo. A novel sulphamoylated estrogen analog, 2-ethyl-3-O-sulphamoyl-estra-1,3,5(10)16-tetraene (ESE-16), was in silico-designed in our laboratory to overcome these issues. It was then synthesized by a pharmaceutical company and used in an in vitro antiproliferative effect study on a human cervical carcinoma (HeLa) cell line.
Results: Cell proliferation data obtained from the crystal violet assay and real-time cell analysis demonstrated that 0.2 μM of ESE-16 had a significant inhibitory effect on the HeLa cells 24 h post-exposure. Immunofluorescence showed that ESE-16 is a microtubule disruptor that causes cells to undergo a mitotic block. Qualitative morphological studies using polarization-optical transmitted light differential interference contrast (PlasDIC) and light microscopy revealed a decrease in cell density and an increase in the number of cells arrested in metaphase. After ESE-16 exposure, hallmarks of apoptosis were also observed, including membrane blebbing, chromatin condensation and the presence of apoptotic bodies. Flow cytometry provided quantitative results from cell cycle progression analysis, indicating cells undergoing apoptosis and cells in the G2/M phase of the cell cycle, confirming cell cycle arrest in metaphase after ESE-16 treatment. Quantification of the ESE-16-mediated upregulation of cyclin B in HeLa cells and spectrophotometric and flow cytometric confirmation of cell death via apoptosis further confirmed the substance’s impact.
Conclusion: ESE-16 exerts its antiproliferative effects through microtubule disruption, which induces a mitotic block culminating in apoptosis. This research provided information on ESE-16 as a potential antitumor agent and on cellular targets that could aid in the design of prospective microtubule-disrupting compounds. Further in vitro and in vivo investigations of this novel compound are needed.
Keywords Estradiol analog, ESE-16, Antiproliferative, Metaphase block, Cervical carcinoma
Address and Contact Information 1Department of Physiology, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Arcadia 0007, Pretoria, South Africa.
2 Faculty of Engineering and Natural Sciences, Molecular Biology Genetics and Bioengineering Program, Sabanci University, Orhanli-Tuzla 3495, Istanbul, Turkey.
* Correspondence author: annie.joubert@up.ac.za
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DOI: 10.1186/s11658-018-0078-0 Volume 23 (2018)
Authors Michaela Galoczova*, Philip Coates and Borivoj Vojtesek
Abstract Signal Transducer and Activator of Transcription 3 (STAT3) is a transcription factor with many important functions in the biology of normal and transformed cells. Its regulation is highly complex as it is involved in signaling pathways in many different cell types and under a wide variety of conditions. Besides other functions, STAT3 is an important regulator of normal stem cells and cancer stem cells. p63 which is a member of the p53 protein family is also involved in these functions and is both physically and functionally connected with STAT3. This review summarizes STAT3 function and regulation, its role in stem cell and cancer stem cell properties and highlights recent reports about its relationship to p63.
Keywords STAT3, Stem cells, Cancer stem cells, p63
Address and Contact Information Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53 Brno, Czech Republic
* Correspondence author: michaela.galoczova@mou.cz
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DOI: 10.1186/s11658-018-0074-4 Volume 23 (2018)
Authors Yuanyuan Sun1, Chen Wang2, Ligang Wang2, Zhibo Dai2 and Kongbin Yang2*
Abstract Background: Arsenic trioxide (As2O3) has a dramatic therapeutic effect on acute promyelocytic leukemia (APL) patients. It can also cause apoptosis in various tumor cells. This study investigated whether As2O3 has an antitumor effect on glioma and explored the underlying mechanism.
Results: MTT and trypan blue assays showed that As2O3 remarkably inhibited growth of C6 and 9 L glioma cells. Cell viability decreased in glioma cells to a greater extent than in normal glia cells. The annexin V-FITC/PI and Hoechest/PI staining assays revealed a significant increase in apoptosis that correlated with the duration of As2O3 treatment and occurred in glioma cells to a greater extent than in normal glial cells. As2O3 treatment induced reactive oxygen species (ROS) production in C6 and 9 L cells in a time-dependent manner. Cells pretreated with the antioxidant N-acetylcysteine (NAC) showed significantly lower As2O3-induced ROS generation. As2O3 significantly inhibited the expression of the anti-apoptotic gene Bcl-2, and upregulated the proapoptotic gene Bax in both C6 and 9 L glioma cells in a time-dependent manner.
Conclusions: As2O3 can significantly inhibit the growth of glioma cells and it can induce cell apoptosis in a time- and concentration-dependent manner. ROS were found to be responsible for apoptosis in glioma cells induced by As2O3. These results suggest As2O3 is a promising agent for the treatment of glioma.
Keywords Arsenic trioxide (As2O3), Reactive oxygen species (ROS), Glioma, Apoptosis
Address and Contact Information 1 Nursing Support Center, First Affiliated Hospital, Harbin Medical University, Harbin 150000, China.
2 Neurosurgery Department, First Affiliated Hospital, Harbin Medical University, Nangang District, Harbin 150000, China.
* Correspondence author: dk5732@163.com; ykbnewrosurgery@sina.com
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DOI: 10.1186/s11658-018-0081-5 Volume 23 (2018)
Authors Qingyun Lei, Jian Tan, Shangqing Yi, Na Wu, Yilin Wang and Heng Wu*
Abstract Background: The regulation of microglial function via mitochondrial homeostasis is important in the development of neuroinflammation. The underlying mechanism for this regulatory function remains unclear. In this study, we investigated the protective role of mitochonic acid 5 (MA-5) in microglial mitochondrial apoptosis following TNFα-induced inflammatory injury.
Methods: TNFα was used to induce inflammatory injury in mouse microglial BV-2 cells with and without prior MA-5 treatment. Cellular apoptosis was assessed using the MTT and TUNEL assays. Mitochondrial functions were evaluated via mitochondrial membrane potential JC-1 staining, ROS flow cytometry analysis, mPTP opening assessment, and immunofluorescence of cyt-c. Mitophagy was examined using western blots and immunofluorescence. The pathways analysis was carried out using western blots and immunofluorescence with a pathway blocker.
Results: Our results demonstrated that TNFα induced apoptosis in the microglial BV-2 cell line by activating the caspase-9-dependent mitochondrial apoptotic pathway. Mechanistically, inflammation reduced mitochondrial potential, induced ROS production, and contributed to the leakage of mitochondrial pro-apoptotic factors into the cytoplasm. The inflammatory response reduced cellular energy metabolism and increased oxidative stress. By contrast, treatment with MA-5 reduced mitochondrial apoptosis via upregulation of mitophagy. Increased mitophagy degraded damaged mitochondria, disrupting mitochondrial apoptosis, neutralizing ROS overproduction, and improving cellular energy production. We also identified that MA-5 regulated mitophagy via Bnip3 through the MAPK–ERK–Yap signaling pathway. Inhibiting this signaling pathway or knocking down Bnip3 expression prevented MA-5 from having beneficial effects on mitochondrial homeostasis and increased microglial apoptosis.
Conclusions: After TNFα-induced inflammatory injury, MA-5 affects microglial mitochondrial homeostasis in a manner mediated via the amplification of protective, Bnip3-related mitophagy, which is mediated via the MAPK–ERK–Yap signaling pathway.
Keywords MA-5, Inflammatory injury, Mitophagy, Microglia, Mitochondria, MAPK–ERK– yap signaling pathway
Address and Contact Information Department of Neurology, First Hospital Affiliated to University of South China, Hunan, China
* Correspondence author: jiantan198@hotmail.com
Equal contributors
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