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.
* Corresponding 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.
* Corresponding 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
* Corresponding 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.
* Corresponding 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.
* Corresponding 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.
* Corresponding 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.
* Corresponding 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.
* Corresponding 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.
* Corresponding 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.
* Corresponding 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.
* Corresponding 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
* Corresponding 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.
* Corresponding 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
* Corresponding author: jiantan198@hotmail.com
Equal contributors
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DOI: 10.1186/s11658-018-0083-3 Volume 23 (2018)
Authors Ruijie Gong1, Xiaofei Lv3 and Fengqiong Liu1,2*
Abstract Background: The miRNA cluster miR-17-92 is known to act as an oncogene in various cancers. Members of this cluster were also found to be involved in some other pathological process, such as steatosis, which is a pivotal event in the initiation and progression of nonalcoholic fatty liver disease (NAFLD). This study aimed to explore whether miR-17, one of the most functional miRNAs in the miR-17-92 family, participates in the process of steatosis in hepatoma cells.
Methods: We developed both a miR-17-expressing transgenic mouse model and a miR-17-expressing HepG2 cell model, the latter was established via stable transfection. Real-time PCR and western blot were applied to measure the expression levels of miR-17 and the potential target gene CYP7A1. The luciferase assay was used to confirm direct binding of miR-17 and CYP7A1. The oleic acid induction assay and Oil-Red-O staining were performed to support the determination of steatotic changes in HepG2 cell.
Results: Extensive steatotic changes were observed in the livers of transgenic mice. Fewer were seen in the wild-type animals. CYP7A1 was confirmed as a target gene of miR-17, and the expression of CYP7A1 was found to be negatively regulated in both the transgenic mice liver cells and the miR-17-expressing HepG2 cells. CYP7A1 was found to participate in miR-17-induced steatosis, as its repressed expression in miR-17 HepG2 cells exacerbated steatotic change. Re-introduction of CYP7A1 into miR-17 HepG2 cell partially alleviated steatosis.
Conclusions: miR-17 is a novel regulator of CYP7A1 signaling in hepatic lipid metabolism, suggesting a potential therapeutic approach for fatty liver.
Keywords MiRNA-17, Steatosis, Fatty liver, CYP7A1
Address and Contact Information 1Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou, Fujian 350008, People’s Republic of China.
2 Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, Fujian, China.
3 Department of Internal Medicine, Guangdong Women and Children’s Hospital, Guangzhou Medical University, 521 Xingnan Road, Guangzhou, China.
* Corresponding author: meimei20061986@126.com
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DOI: 10.1186/s11658-018-0082-4 Volume 23 (2018)
Authors Gabriela Sánchez1, Omar Estrada1, Giovana Acha1, Alfonso Cardozo2, Franshelle Peña1, Marie Christine Ruiz1, Fabián Michelangeli1 and Claudia Alvarado-Castillo1,3*
Abstract Background: The leaves of Annona purpurea have yielded several alkaloids with anti-aggregation activities against rabbit platelets. This is promising in the search for agents that might act against platelets and reduce the incidence of cardiovascular diseases. Since significant differences in platelet function have been reported between human and animal platelets, a study focusing on the effect of A. purpurea extracts against human platelet activation is necessary.
Methods: The compounds in an A. purpurea ethanolic extract underwent bio-guided fractionation and were used for in vitro human platelet aggregation assays to isolate the compounds with anti-platelet activity. The bioactive compounds were identified by spectroscopic analysis. Additional platelet studies were performed to characterize their action as inhibitors of human platelet activation.
Results: The benzylisoquinoline alkaloid norpurpureine was identified as the major anti-platelet compound. The IC50 for norpurpureine was 80 μM against platelets when stimulated with adenosine 5′-diphosphate (ADP), collagen and thrombin. It was pharmacologically effective from 20 to 220 μM. Norpurpureine (220 μM) exhibited its in vitro effectiveness in samples from 30 healthy human donors who did not take any drugs during the 2 weeks prior to the collection. Norpurpureine also gradually inhibited granule secretion and adhesion of activated platelets to immobilized fibrinogen. At the intra-platelet level, norpurpureine prevented agonist-stimulated calcium mobilization and cAMP reduction. Structure–activity relationship analysis indicates that the lack of a methyl group at the nitrogen seems to be key in the ability of the compound to interact with its molecular target.
Conclusion: Norpurpureine displays a promising in vitro pharmacological profile as an inhibitor of human platelet activation. Its molecular target could be a common effector between Ca2+ and cAMP signaling, such as the PLC-PKC-Ca2+ pathway and PDEs. This needs further evaluation at the protein isoform level.
Keywords Annona purpurea, Alkaloids, Norpurpureine, Human platelets
Address and Contact Information 1 Centro de Biofísica y Bioquímica (CBB), Instituto Venezolano de Investigaciones Científicas (IVIC), Caracas, Bolivarian Republic of Venezuela.
2 Laboratorio de Botánica Sistemática, Facultad de Agronomía, Universidad Central de Venezuela (UCV), Maracay, Bolivarian Republic of Venezuela.
3 Laboratorio de Hemostasia y Genética Vascular, Centro de Biofísica y Bioquímica, Instituto Venezolano de Investigaciones Científicas, Apartado 20632, K11 de la Carretera Panamericana, Caracas 1020-A, Bolivarian Republic of Venezuela.
* Corresponding author: cpilar.alvarado@gmail.com; calvarad@ivic.gob.ve
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DOI: 10.1186/s11658-018-0070-8 Volume 23 (2018)
Authors Jing Liu1, Chunxia Yang1, Yufang Gu2, Chong Li1, Huamei Zhang1, Wenfang Zhang1, Xueqing Wang1, Nan Wu1 and Chunyan Zheng3*
Abstract Background:, Epstein–Barr virus (EBV) infection is causatively associated with a variety of human cancers, including gastric cancer (GC), which has one of the highest mortality rates of all human cancers. Long non-coding RNAs (lncRNAs) show important regulatory roles in human GC. SNHG8 is a recently identified lncRNA that was reported to show abnormal expression pattern in GC. However, little is known of its biological function in EBV-associated GC.
Methods: We used cell viability, colony formation and cell cycle assays to investigate the roles of lncRNA SNHG8 in the cell growth of EBV-associated GC.
Results: The transcript levels of SNHG8 in the cultured EBV-associated GC cells were significantly higher in the cultured EBV-associated GC cells compared with the levels in normal human gastric mucosal cells and EBV-negative GC cells. Knockdown of SNHG8 with specific shRNAs inhibited cell proliferation and colony formation and arrested the cell cycle in the G0/G1 phase in vitro. We also found that knockdown of SNHG8 suppressed tumor growth in vivo.
Conclusions: These data indicate the pro-oncogenic potential of SNHG8 in EBV-associated GC, meaning it is a latent therapeutic target for the treatment of this type of cancer.
Keywords SNHG8, Cell growth, shRNA, Epstein-Barr virus-associated gastric carcinoma
Address and Contact Information 1 Department of Nephology, Zibo, China.
2 Department of Gastrointestinal Surgery, Zibo, China.
3 Department of Medical Care, Zibo Central Hospital, 54 Gongqingtuan Rd, Zibo, Shandong 255036, People’s Republic of China.
* Corresponding author: Chunyanzheng2017@163.com
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DOI: /10.1186/s11658-018-0084-2 Volume 23 (2018)
Authors Bihua Liang1†, Liqian Peng1,2†, Runxiang Li1, Huaping Li1, Ziyin Mo1,2, Xinyue Dai1, Na Jiang3, Qing Liu4, Erting Zhang5, Huiyan Deng1, Zhenjie Li1* and Huilan Zhu1*
Abstract Background: Lycium barbarum polysaccharide (LBP) is considered an antioxidant agent. NF-E2-related factor-2 (Nrf2) is an important regulator for protection against UV damage. In this study, we verified the performance of LBP and the correlation between LBP and Nrf2.
Methods: HSF cells were treated with LBP to determine dose and time dependencies. An antioxidant response element (ARE) reporter was designed to monitor the activity of the Nrf2 antioxidant pathway.
Results: For HSF cells, the optimal LBP treatment was 300 μg/ml for 3 h. The ARE-reporter assay showed that LBP could increase the robustness of p-Nrf2. Treatments with genistein and LY294002 reduced of nuclear p-Nrf2 after 24 h. LBP increased the level of nuclear Nrf2, which functions by both phosphorylation and nuclear translocation. Silencing Nrf2 led to increased reactive oxygen species (ROS) levels, lower cell viability, and decreased superoxide dismutase (SOD) and glutathione peroxidase (GSP-PX) levels. This induced a higher level of lipid peroxide (LPO). However, LBP could decrease the levels of ROS and LPO and enhance the levels of SOD and GSP-PX.
Conclusion: LBP protects HSF cells against UV damage via the regulation of Nrf2.
Keywords Ultraviolet damage, Lycium barbarum, Polysaccharide, Nrf2
Address and Contact Information 1 Guangzhou Institute of Dermatology, Guangzhou, China.
2 Guangzhou Medical University, Guangzhou, China.
3 Guangzhou First People’s Hospital, Guangzhou, China.
4 The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
5 The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
* Corresponding author: lizhen3564@163.com; zhlhuilan@126.com
Equal contributors
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DOI: 10.1186/s11658-018-0086-0 Volume 23 (2018)
Authors Renguo Xu1, Zhen Liu1, Jiande Hou1, Tao Huang2 and Ming Yang1*
Abstract Background: Osthole is a natural product that has multiple bioactive functions and has been reported to exert potent immunosuppressive effects. However, the therapeutic effect of osthole on arthritis has not been explored. In the present study, a collagen-induced arthritis rat model, IL-1β-stimulated SW982 cells, and RA-like fibroblast-like synoviocytes (FLS) were employed to investigate the effect and possible mechanism of osthole on arthritis in vivo and in vitro.
Results: 20 and 40 mg/kg osthole significantly alleviated collagen-induced arthritic symptoms based on histopathology and clinical arthritis scores, and improved erosion using HE staining. 20 and 40 mg/kg osthole decreased the level of IL-1β, TNF-α and IL-6 in rats and ameliorated oxidative stress in serum evaluated using ELISA kits. In addition, treatment with 50 and 100 μM osthole for 48 h inhibited 10 ng/ml IL-1β-stimulated proliferation and migration of SW982, and significantly inhibited the expression of matrix metalloproteinases, such as MMP-1, MMP-3 and MMP-13, as detected by western blot. 50 and 100 μM osthole also blocked the generation of IL-6 and TNF-α in IL-1β-stimulated SW982 cells. The NF-κB and MAPK pathways were also inhibited by osthole in IL-1β-treated SW982 cells.
Conclusion: These results collectively demonstrated that osthole improves collagen-induced arthritis in a rat model and IL-1β-treated SW982 cells through inhibiting inflammation and cellular stress in vivo and in vitro, and osthole might be a promising therapeutic agent for RA.
Keywords Osthole, Collagen-induced arthritis, Synovial fibroblasts, Inflammation, NF-κB
Address and Contact Information 1 Department of Osteology, YeDa Hospital, Taishan Road No. 11 Economic and Technological District of Yantai, Yantai 264006, China.
2 School of Pharmacy, Jiangsu university, Zhenjiang 212000, China.
* Corresponding author: doctoryangming1@163.com
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DOI: 10.1186/s11658-018-0088-y Volume 23 (2018)
Authors Mokgadi Violet Gwangwa, Anna Margaretha Joubert and Michelle Helen Visagie*
Abstract Tumourigenic tissue uses modified metabolic signalling pathways in order to support hyperproliferation and survival. Cancer-associated aerobic glycolysis resulting in lactic acid production was described nearly 100 years ago. Furthermore, increased reactive oxygen species (ROS) and lactate quantities increase metabolic, survival and proliferation signalling, resulting in increased tumourigenesis. In order to maintain redox balance, the cell possesses innate antioxidant defence systems such as superoxide dismutase, catalase and glutathione. Several stimuli including cells deprived of nutrients or failure of antioxidant systems result in oxidative stress and cell death induction. Among the cell death machinery is autophagy, a compensatory mechanism whereby energy is produced from damaged and/or redundant organelles and proteins, which prevents the accumulation of waste products, thereby maintaining homeostasis. Furthermore, autophagy is maintained by several pathways including phosphoinositol 3 kinases, the mitogen-activated protein kinase family, hypoxia-inducible factor, avian myelocytomatosis viral oncogene homolog and protein kinase receptor-like endoplasmic reticulum kinase. The persistent potential of cancer metabolism, redox regulation and the crosstalk with autophagy in scientific investigation pertains to its ability to uncover essential aspects of tumourigenic transformation. This may result in clinical translational possibilities to exploit tumourigenic oxidative status and autophagy to advance our capabilities to diagnose, monitor and treat cancer.
Keywords Warburg effect, Autophagy, Oxidative stress, Cancer
Address and Contact Information Department of Physiology, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Arcadia 0007, South Africa
* Corresponding author: michelle.visagie@up.ac.za
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DOI: 10.1186/s11658-018-0085-1 Volume 23 (2018)
Authors Xisong Wang and Qing Song*
Abstract Background: Post-infarction cardiac injury is closely associated with cardiac remodeling and heart dysfunction. Mammalian STE20-like kinase 1 (Mst1), a regulator of cellular apoptosis, is involved in cardiac remodeling in post-infarction heart, but the mechanisms remain poorly defined. We aimed to explore the role of Mst1 in regulating chronic post-infarction cardiac injury, with a focus on mitochondrial homoeostasis.
Methods: Wild-type (WT) and Mst1-knockout mice were as the cardiac myocardial infarction model. Cardiac fibrosis, myocardial inflammation response, heart dysfunction and cardiomyocyte death were measured in vivo using immunohistochemistry, immunofluorescence, western blot, qPCR and TUNEL assays. Cardiomyocytes were isolated from WT and Mst1-knockout mice, and a chronic hypoxia model was used to induce damage. Mitochondrial function was determined via JC1 staining, ROS measurement, cyt-c leakage detection and mitochondrial apoptotic pathways analysis. Mitochondrial fission was observed using immunofluorescence. A pathway activator and inhibitor were applied to establish the signaling pathways involved in regulating mitochondrial homeostasis.
Results: Our study demonstrated that Mst1 expression was significantly upregulated in the heart post-infarction. Activated Mst1 induced cardiac fibrosis, an excessive inflammatory response, and cardiomyocyte death, whereas the genetic ablation of Mst1 protected the myocardium against chronic post-infarction injury. Function assays showed that upregulation of Mst1 activity contributed to JNK pathway activation, which led to Drp1 migration from the cytoplasm onto the surface of the mitochondria, indicative of mitochondrial fission activation. Excessive mitochondrial fission caused mitochondrial fragmentation, resulting in mitochondrial potential collapse, ROS overproduction, mitochondrial pro-apoptotic leakage into the cytoplasm, and the initiation of caspase-9-mediated mitochondrial apoptosis. By contrast, Mst1 deletion helped to maintain mitochondrial structure and function, sending pro-survival signals to the cardiomyocytes.
Conclusions: Our results identify Mst1 as a malefactor in the development of post-infarction cardiac injury and that it acts through the JNK-Drp1-mitochondrial fission pathway.
Keywords Cardiac post-infarction injury, Mst1, Mitochondrial fission, JNK-Drp1 pathway, Cardiomyocyte death
Address and Contact Information Department of Critical Care Medicine, the Chinese PLA General Hospital, Beijing, China
* Corresponding author: zhengdehuang198@hotmail.com
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DOI: 10.1186/s11658-018-0089-x Volume 23 (2018)
Authors Xiaowei Wang*, Haiying Jin, Shifeng Jiang and Yanlan Xu
Abstract Background: MicroRNAs (miRNAs) have physiological and pathophysiological functions that are involved in the regulation of cardiac fibrosis. This study aimed to investigate the effects of miR-495 on high glucose-induced cardiac fibrosis in human cardiac fibroblasts (CFs) and to establish the mechanism underlying these effects.
Methods: Human CFs were transfected with an miR-495 inhibitor or mimic and incubated with high glucose. The levels of NOD1 and miR-495 were then determined via quantitative RT-PCR. Pro-inflammatory cytokine levels, cell differentiation and extracellular matrix accumulation were respectively detected using ELISA, quantitative RT-PCR and western blot assays. The luciferase reporter assay, quantitative RT-PCR and western blot were used to explore whether NOD1 was a target of miR-495. The effects of miR-495 on the NF-κB and TGF-β1/Smad signaling pathways were also detected via western blot.
Results: Our results show that high glucose can significantly increase the expression of NOD1 in a time-dependent manner. Upregulation of miR-495 significantly alleviated the high glucose-induced increases in cell differentiation and collagen accumulation of CFs. Moreover, the bioinformatics analysis predicted that NOD1 was a potential target gene for miR-495. The luciferase reporter assay showed that miR-495 can directly target NOD1. The introduction of miR-495 could significantly inhibit the high glucose-activated NF-κB and TGF-β1/Smad signaling pathways.
Conclusion: Upregulation of miR-495 ameliorates the high glucose-induced inflammatory, cell differentiation and extracellular matrix accumulation of human CFs by modulating both the NF-κB and TGF-β1/Smad signaling pathways through downregulation of NOD1 expression. These results provide further evidence for the protective effect of miR-495 overexpression in cases of high glucose-induced cardiac fibrosis.
Keywords MicroRNA-495, Human cardiac fibroblasts, High glucose, Cardiac fibrosis, NOD1
Address and Contact Information Department of Geriatrics, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Qingpu District, No.1158, Park East Road, Shanghai 201707, People’s Republic of China
* Corresponding author: wangxiaoweifudan@163.com
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DOI: 10.1186/s11658-018-0087-z Volume 23 (2018)
Authors Jing-jing Zhao, Xiao-Li Lou, Hong-wei Chen, Feng-ting Zhu and Yan-Qiang Hou*
Abstract The levels of decoy receptor 3 (DcR3), soluble urokinase type plasminogen activator receptor (suPAR) and procalcitonin (PCT) are significantly increased in sepsis. We investigated the diagnostic value of DcR3 combined with suPAR and PCT in sepsis. Patients with sepsis, non-infectious systemic inflammatory response comprehensive syndrome (SIRS) and healthy controls were recruited according to the diagnostic standard. We measured DcR3, suPAR, PCT, interleukin-6 (IL-6) and C-reactive protein (CRP), and the diagnostic value was evaluated by receiver operating characteristics (ROC) curves. In our analysis, serum DcR3, suPAR and PCT levels of the sepsis group were significantly higher than those of the SIRS and control groups. However, IL-6, CRP and WBC showed no significant difference between the SIRS group and the sepsis group. The serum DcR3 level was positively correlated with the serum suPAR level (r = 0.37, p = 0.0022) and PCT level (r = 0.37, p = 0.0021). Using DcR3, suPAR and PCT to distinguish SIRS from sepsis, the area under the curve (AUC) values were 0.892, 0.778 and 0.692. When DcR3, suPAR and PCT combined were used for diagnosis of sepsis, the AUC was 0.933, at a cut-off point of 0.342. This combination improved the sensitivity and specificity of diagnosis of sepsis, suggesting that use of the combination of three indexes enhanced the efficiency of sepsis diagnosis.
Keywords Sepsis, SIRS, DcR3, suPAR, PCT
Address and Contact Information Department of Central Laboratory, Songjiang Hospital Affiliated First People’s Hospital, Shanghai Jiao Tong University, Shanghai 201600, China
* Corresponding author: houyanqiang@aliyun.com
Equal contributors
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DOI: 10.1186/s11658-018-0091-3 Volume 23 (2018)
Authors Yanfen Zhang, Wenjing Zhang, Caijun Zha and Yanhong Liu*
Abstract Background: Patients with anti-β2GPI antibodies display significantly higher platelet activation/aggregation and vascular endothelial cell damage. The mechanism underlying the correlation between platelet activation, vascular endothelial cell dysfunctions and anti-β2GPI antibodies remains unknown.
Methods: In this study, we derived miR-96 and -26a from platelets activated by the anti- β2GPI/β2GPI complex and explored their role in modulating human umbilical vein endothelial cell (HUVEC) migration and tube formation.
Results: Anti-β2GPI/β2GPI complex induces the release of platelet-derived microparticles (p-MPs). The amounts of miR-96 and -26a in these p-MPs were also higher than for the control group. Co-incubation of HUVECs with p-MPs resulted in the transfer of miR-96 and -26a into HUVECs, where they inhibited migration and tube formation. The targeting role of these miRNAs was further validated by directly downregulating targeted selectin-P (SELP) and platelet-derived growth factor receptor alpha (PDGFRA) via luciferase activity assay.
Conclusion: Our study suggests that miR-96 and -26a in p-MPs can inhibit HUVEC behavior by targeting SELP and PDGFRA.
Keywords Platelet-derived microparticles, MicroRNA, Endothelial cells
Address and Contact Information Department of Laboratory Diagnosis, The Second Affliated Hospital of Harbin Medical University, Harbin, China
* Corresponding author: 460205012@qq.com
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DOI: 10.1186/s11658-018-0090-4 Volume 23 (2018)
Authors Aixia Sun1†, Hongwei Zhang1*†, Feng Pang1, Guifen Niu2, Jianzhong Chen3, Fei Chen3 and Jian Zhang4
Abstract Background: Although significant advances have been made in understanding the mechanisms of macrophage response to Staphylococcus aureus infection, the molecular details are still elusive. Identification of the essential genes and biological processes of macrophages that are specifically changed at different durations of S. aureus exposure is of great clinical significance.
Methods: We aimed to identify the significantly changed genes and biological processes of S. aureus-exposed macrophages. We systematically analyzed the macrophage gene expression profile GSE 13670 database with 8 h, 24 h or 48 h S. aureus infection. The results were further confirmed by western blot and quantitative polymerase chain reaction (qPCR) analyses.
Results: After 8 h of S. aureus infection, the expression of 624 genes was significantly changed. Six hundred thirteen differentially expressed genes (DEGs) were identified after 24 h of S. aureus infection. Two hundred fifty-three genes were significantly changed after 48 h of S. aureus infection. STAT1 was consistently up-regulated in these three treatments. TP53, JAK2, CEBPA, STAT3, MYC, CTNNB1 and PRKCA were only identified in the 8 h or 24 h S. aureus infection groups. CTNNB1 and PRKCA were for the first time identified as potential essential genes in S. aureus infection of macrophages. In the Gene Ontology (GO) term analysis, the defense response was shown to be the most significantly changed biological process among all processes; KEGG pathway analysis identified the JAK-STAT signaling pathway involved in early infection.
Conclusions: Our systematic analysis identified unique gene expression profiles and specifically changed biological processes of the macrophage response to different S. aureus exposure times.
Keywords Macrophage, Staphylococcus aureus, Bio-informatics
Address and Contact Information 1 Department of Clinical Laboratory, Liaocheng People’s Hospital, 67 West Dongchang Road, Liaocheng 252000, Shandong Province, People’s Republic of China.
2 Department of Endocrinology, Liaocheng People’s Hospital, 67 West Dongchang Road, Liaocheng 252000, Shandong Province, People’s Republic of China.
3 Department of Clinical Pharmacy, Liaocheng People’s Hospital, 67 West Dongchang Road, Liaocheng 252000, Shandong Province, People’s Republic of China.
4 Outpatient Vaccination Service, Center for Disease Control and Prevention of Liaocheng, Liaocheng 252000, Shandong Province, People’s Republic of China.
* Corresponding author: 13310659996@189.cn
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DOI: 10.1186/s11658-018-0077-1 Volume 23 (2018)
Authors Wenming Feng1*, Tao Xue2, Sanxiong Huang3, Qilin Shi4, Chengwu Tang1, Ge Cui4, Guanghui Yang5, Hui Gong2 and Huihui Guo2
Abstract Background: Hypoxia plays a critical role in many cancers. Hypoxia inducible factor-1α (HIF-1α) is an important mediator of the hypoxia response. It regulates the expression of various chemokines involved in tumor growth, angiogenesis and metastasis but the associated pathway needs further investigation.
Methods: The expression level of HIF-1α was determined in hepatocellular carcinoma (HCC) cells. The correlation of interleukin-8 (IL-8) and HIF-1α was assessed by knocking down HIF-1α. These cells were also used to assess its influence on HCC cell migration and invasion was checked. Pyrrolidinedithiocarbamate (PDTC), an inhibitor of NF-κB, was used to confirm the associated signaling pathway.
Results: HIF-1α was significantly expressed in HCC cells and found to promote HCC cell migration and invasion in an IL-8-dependent manner. NF-κB was confirmed to be involved in the process.
Conclusions: HIF-1α promotes HCC cell migration and invasion by modulating IL-8 via the NF-κB pathway.
Keywords Hepatocellular carcinoma, Hypoxia, HIF-1α, IL-8, NF-κB
Address and Contact Information 1 Department of Hepatobiliary Pancreatic Surgery, The First People’s Hospital of Huzhou, No. 158 Guangchanghou Road, Huzhou, Zhejiang Province 313000, People’s Republic of China.
2 Central Laboratory, The First People’s Hospital of Huzhou, No. 158 Guangchanghou Road, Huzhou, Zhejiang Province 313000, People’s Republic of China.
3 Department of General Surgery, The First People’s Hospital of Huzhou, No. 158 Guangchanghou Road, Huzhou, Zhejiang Province 313000, People’s Republic of China.
4 Department of Pathology, The First People’s Hospital of Huzhou, No. 158 Guangchanghou Road, Huzhou, Zhejiang Province 313000, People’s Republic of China.
5 Department of Pharmacy, The First People’s Hospital of Huzhou, No. 158 Guangchanghou Road, Huzhou, Zhejiang Province 313000, People’s Republic of China.
* Corresponding author: wenmingfeng2017@163.com
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DOI: 10.1186/s11658-018-0092-2 Volume 23 (2018)
Authors Hongxia Li1, Yi Cui2, Fuyan Li3, Wenqi Shi4, Wenjing Gao2, Xiao Wang2 and Qingshi Zeng2*
Abstract Background: Radiotherapy is among the commonly applied treatment options for glioma, which is one of the most common types of primary brain tumor. To evaluate the effect of radiotherapy noninvasively, it is vital for oncologists to monitor the effects of X-ray irradiation on glioma cells. Preliminary research had showed that PKC-ι expression correlates with tumor cell apoptosis induced by X-ray irradiation. It is also believed that the lactate-to-creatine (Lac/Cr) ratio can be used as a biomarker to evaluate apoptosis in glioma cells after X-ray irradiation. In this study, we evaluated the relationships between the Lac/Cr ratio, apoptotic rate, and protein kinase C iota (PKC-ι) expression in glioma cells.
Methods: Cells of the glioma cell lines C6 and U251 were randomly divided into 4 groups, with every group exposed to X-ray irradiation at 0, 1, 5, 10 and 15 Gy. Single cell gel electrophoresis (SCGE) was conducted to evaluate the DNA damage. Flow cytometry was performed to measure the cell cycle blockage and apoptotic rates. Western blot analysis was used to detect the phosphorylated PKC-ι (p-PKC-ι) level. 1H NMR spectroscopy was employed to determine the Lac/Cr ratio.
Results: The DNA damage increased in a radiation dose-dependent manner (p < 0.05). With the increase in X-ray irradiation, the apoptotic rate also increased (C6, p < 0.01; U251, p < 0.05), and the p-PKC-ι level decreased (C6, p < 0.01; U251, p < 0.05). The p-PKC-ι level negatively correlated with apoptosis, whereas the Lac/Cr ratio positively correlated with the p-PKC-ι level.
Conclusion: The Lac/Cr ratio decreases with an increase in X-ray irradiation and thus can be used as a biomarker to reflect the effects of X-ray irradiation in glioma cells.
Keywords DNA damage, P-PKC-ι, Lactate, Glioma, X-ray irradiation, Apoptosis
Address and Contact Information 1 Department of Radiology, the Second Hospital of Shandong University, Jinan, China.
2 Department of Radiology, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, Jinan 250012, China.
3 Department of Radiology, Shandong Medical Imaging Research Institute, Jinan, China.
4 Department of Radiology, the Third Affiliated Hospital, Sun Yat- Sen University, Guangzhou, China.
* Corresponding author: zengqingshi@sina.com
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