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Tang X, Ravikumar Y, Zhang G, Yun J, Zhao M, Qi X. D-allose, a typical rare sugar: properties, applications, and biosynthetic advances and challenges. Crit Rev Food Sci Nutr 2024:1-28. [PMID: 38764407 DOI: 10.1080/10408398.2024.2350617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/21/2024]
Abstract
D-allose, a C-3 epimer of D-glucose and an aldose-ketose isomer of D-allulose, exhibits 80% of sucrose's sweetness while being remarkably low in calories and nontoxic, making it an appealing sucrose substitute. Its diverse physiological functions, particularly potent anticancer and antitumor effects, render it a promising candidate for clinical treatment, garnering sustained attention. However, its limited availability in natural sources and the challenges associated with chemical synthesis necessitate exploring biosynthetic strategies to enhance production. This overview encapsulates recent advancements in D-allose's physicochemical properties, physiological functions, applications, and biosynthesis. It also briefly discusses the crucial role of understanding aldoketose isomerase structure and optimizing its performance in D-allose synthesis. Furthermore, it delves into the challenges and future perspectives in D-allose bioproduction. Early efforts focused on identifying and characterizing enzymes responsible for D-allose production, followed by detailed crystal structure analysis to improve performance through molecular modification. Strategies such as enzyme immobilization and implementing multi-enzyme cascade reactions, utilizing more cost-effective feedstocks, were explored. Despite progress, challenges remain, including the lack of efficient high-throughput screening methods for enzyme modification, the need for food-grade expression systems, the establishment of ordered substrate channels in multi-enzyme cascade reactions, and the development of downstream separation and purification processes.
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Affiliation(s)
- Xinrui Tang
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang, China
| | - Yuvaraj Ravikumar
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang, China
| | - Guoyan Zhang
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang, China
| | - Junhua Yun
- School of Life Sciences, Guangzhou University, Guangzhou, China
| | - Mei Zhao
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang, China
| | - Xianghui Qi
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang, China
- School of Life Sciences, Guangzhou University, Guangzhou, China
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2
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Sharma S, Patel SN, Singh SP. A novel thermotolerant L-rhamnose isomerase variant for biocatalytic conversion of D-allulose to D-allose. Appl Microbiol Biotechnol 2024; 108:279. [PMID: 38564031 PMCID: PMC10987364 DOI: 10.1007/s00253-024-13074-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 01/24/2024] [Accepted: 02/13/2024] [Indexed: 04/04/2024]
Abstract
A novel L-rhamnose isomerase was identified and cloned from an extreme-temperature aquatic habitat metagenome. The deduced amino acid sequence homology suggested the possible source of this metagenomic sequence to be Chloroflexus islandicus. The gene expression was performed in a heterologous host, Escherichia coli, and the recombinant protein L-rhamnose isomerase (L-RIM) was extracted and purified. The catalytic function of L-RIM was characterized for D-allulose to D-allose bioconversion. D-Allose is a sweet, rare sugar molecule with anti-tumour, anti-hypertensive, cryoprotective, and antioxidative properties. The characterization experiments showed L-RIM to be a Co++- or Mn++-dependent metalloenzyme. L-RIM was remarkably active (~ 80%) in a broad spectrum of pH (6.0 to 9.0) and temperature (70 to 80 °C) ranges. Optimal L-RIM activity with D-allulose as the substrate occurred at pH 7.0 and 75 °C. The enzyme was found to be excessively heat stable, displaying a half-life of about 12 days and 5 days at 65 °C and 70 °C, respectively. L-RIM catalysis conducted at slightly acidic pH of 6.0 and 70 °C achieved biosynthesis of about 30 g L-1 from 100 g L-1 D-allulose in 3 h. KEY POINTS: • The present study explored an extreme temperature metagenome to identify a novel gene that encodes a thermostable l-rhamnose isomerase (L-RIM) • L-RIM exhibits substantial (80% or more) activity in a broad spectrum of pH (6.0 to 9.0) and temperature (70 to 80 °C) ranges • L-RIM is excessively heat stable, displaying a half-life of about 12 days and 5 days at 65 °C and 70 °C, respectively.
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Affiliation(s)
- Sweety Sharma
- Center of Innovative and Applied Bioprocessing, Biotechnology Research and Innovation Council (Department of Biotechnology, Government of India), NABI Campus, SAS Nagar, Sector 81, Mohali, India, 140306
- Indian Institute of Science Education and Research Mohali, SAS Nagar, Sector 81, Mohali, India, 140306
| | - Satya Narayan Patel
- Center of Innovative and Applied Bioprocessing, Biotechnology Research and Innovation Council (Department of Biotechnology, Government of India), NABI Campus, SAS Nagar, Sector 81, Mohali, India, 140306
| | - Sudhir P Singh
- Center of Innovative and Applied Bioprocessing, Biotechnology Research and Innovation Council (Department of Biotechnology, Government of India), NABI Campus, SAS Nagar, Sector 81, Mohali, India, 140306.
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Wu K, Gong W, Sun H, Li W, Chen L, Duan Y, Zhu J, Zhang H, Ke H. SMAD4 inhibits glycolysis in ovarian cancer through PI3K/AKT/HK2 signaling pathway by activating ARHGAP10. Cancer Rep (Hoboken) 2024; 7:e1976. [PMID: 38230565 PMCID: PMC10849991 DOI: 10.1002/cnr2.1976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 11/01/2023] [Accepted: 12/28/2023] [Indexed: 01/18/2024] Open
Abstract
BACKGROUND ARHGAP10 is a tumor-suppressor gene related to ovarian cancer (OC) progression; however, its specific mechanism is unclear. AIMS To investigate the effect of ARHGAP10 on OC cell migration, invasion, and glycolysis. METHODS AND RESULTS Quantitative real-time PCR (qRT-PCR) quantified mRNA and protein expressions of AKT, p-AKT, HK2, and SMAD4 were tested by Western blot. EdU, Wound healing, and Transwell assay were utilized to evaluate OC cell proliferation, migration, and invasion. We used a Seahorse XF24 Extracellular Flux Analyzer to monitor cellular oxygen consumption rates (OCR) and extracellular acidification rates (ECAR). Chromatin immunoprecipitation (ChIP) was used to analyze the transcriptional regulation of ARHGAP10 by SMAD4. ARHGAP10 expression in OC tissues was detected by immunohistochemistry. Our results showed that ARHGAP10 expression was negatively related to lactate levels in human OC tissues. ARHGAP10 overexpression can inhibit the migration, proliferation, and invasion of OC cells, and this function can be blocked by 2-Deoxy-D-glucose. Moreover, we found that ARHGAP10 expression can be rescued with the AKT inhibitor LY294002. CONCLUSIONS This study revealed that the antitumor effects of ARHGAP10 in vivo and in vitro possibly suppress oncogenic glycolysis through the PI3K/AKT/HK2-regulated glycolysis metabolism pathway.
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Affiliation(s)
- Kui Wu
- Department of Obstetrics and Gynecology, Shanghai Pudong HospitalFudan University Pudong Medical CenterShanghaiPR China
| | - Wei Gong
- Department of Obstetrics and Gynecology, Shanghai Pudong HospitalFudan University Pudong Medical CenterShanghaiPR China
| | - Huanmei Sun
- Department of Obstetrics and Gynecology, Shanghai Pudong HospitalFudan University Pudong Medical CenterShanghaiPR China
| | - Wenjiao Li
- Department of Obstetrics and Gynecology, Shanghai Pudong HospitalFudan University Pudong Medical CenterShanghaiPR China
| | - Li Chen
- Department of Obstetrics and Gynecology, Shanghai Pudong HospitalFudan University Pudong Medical CenterShanghaiPR China
| | - Yingchun Duan
- Department of Obstetrics and Gynecology, Shanghai Pudong HospitalFudan University Pudong Medical CenterShanghaiPR China
| | - Jianlong Zhu
- Department of Obstetrics and Gynecology, Shanghai Pudong HospitalFudan University Pudong Medical CenterShanghaiPR China
| | - Hu Zhang
- Department of Obstetrics and Gynecology, Shanghai Pudong HospitalFudan University Pudong Medical CenterShanghaiPR China
| | - Huihui Ke
- Department of Obstetrics and Gynecology, Shanghai Pudong HospitalFudan University Pudong Medical CenterShanghaiPR China
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Mahmood S, Iqbal MW, Tang X, Zabed HM, Chen Z, Zhang C, Ravikumar Y, Zhao M, Qi X. A comprehensive review of recent advances in the characterization of L-rhamnose isomerase for the biocatalytic production of D-allose from D-allulose. Int J Biol Macromol 2024; 254:127859. [PMID: 37924916 DOI: 10.1016/j.ijbiomac.2023.127859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 10/05/2023] [Accepted: 11/01/2023] [Indexed: 11/06/2023]
Abstract
D-Allose and D-allulose are two important rare natural monosaccharides found in meager amounts. They are considered to be the ideal substitutes for table sugar (sucrose) for, their significantly lower calorie content with around 80 % and 70 % of the sweetness of sucrose, respectively. Additionally, both monosaccharides have gained much attention due to their remarkable physiological properties and excellent health benefits. Nevertheless, D-allose and D-allulose are rare in nature and difficult to produce by chemical methods. Consequently, scientists are exploring bioconversion methods to convert D-allulose into D-allose, with a key enzyme, L-rhamnose isomerase (L-RhIse), playing a remarkable role in this process. This review provides an in-depth analysis of the extractions, physiological functions and applications of D-allose from D-allulose. Specifically, it provides a detailed description of all documented L-RhIse, encompassing their biochemical properties including, pH, temperature, stabilities, half-lives, metal ion dependence, molecular weight, kinetic parameters, specific activities and specificities of the substrates, conversion ratio, crystal structure, catalytic mechanism as well as their wide-ranging applications across diverse fields. So far, L-RhIses have been discovered and characterized experimentally by numerous mesophilic and thermophilic bacteria. Furthermore, the crystal forms of L-RhIses from E. coli and Stutzerimonas/Pseudomonas stutzeri have been previously cracked, together with their catalytic mechanism. However, there is room for further exploration, particularly the molecular modification of L-RhIse for enhancing its catalytic performance and thermostability through the directed evolution or site-directed mutagenesis.
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Affiliation(s)
- Shahid Mahmood
- School of Food & Biological Engineering, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, Jiangsu Province, China
| | - Muhammad Waheed Iqbal
- School of Food & Biological Engineering, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, Jiangsu Province, China
| | - Xinrui Tang
- School of Food & Biological Engineering, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, Jiangsu Province, China
| | - Hossain M Zabed
- School of Life Sciences, Guangzhou University, 230 Wai Huan Xi Road, Guangzhou 510006, Guangdong, China
| | - Ziwei Chen
- School of Food & Biological Engineering, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, Jiangsu Province, China
| | - Cunsheng Zhang
- School of Food & Biological Engineering, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, Jiangsu Province, China
| | - Yuvaraj Ravikumar
- School of Food & Biological Engineering, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, Jiangsu Province, China
| | - Mei Zhao
- School of Food & Biological Engineering, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, Jiangsu Province, China.
| | - Xianghui Qi
- School of Food & Biological Engineering, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, Jiangsu Province, China; School of Life Sciences, Guangzhou University, 230 Wai Huan Xi Road, Guangzhou 510006, Guangdong, China.
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Hong H, Luo B, Xie Z, Li M, Xu Q, He Z, Peng Z. Retracted: Britannin mediates apoptosis and glycolysis of T-cell lymphoblastic lymphoma cells by AMPK-dependent autophagy. J Biochem Mol Toxicol 2023; 37:e23211. [PMID: 36120848 DOI: 10.1002/jbt.23211] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 06/13/2022] [Accepted: 08/29/2022] [Indexed: 11/08/2022]
Abstract
The above article, published online on 19 September 2022 in Wiley Online Library (https://onlinelibrary.wiley.com/doi/abs/10.1002/jbt.23211), has been retracted by agreement between the authors, the journal Editor in Chief, Hari Bhat, and Wiley Periodicals, LLC. The article is being retracted at the authors' request because some of the data underlying this article refer to a different cell line from the one reported in it. As a result, the article's conclusions do not accurately reflect the full data and cannot be considered reliable.
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Affiliation(s)
- Haoyuan Hong
- Department of Hematology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Bin Luo
- Department of Hematology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, China
| | - Zucheng Xie
- Department of Hematology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Meiwei Li
- Department of Hematology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Qingyuan Xu
- Department of Hematology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Zhendong He
- Department of Hematology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Zhigang Peng
- Department of Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
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Kao TW, Bai GH, Wang TL, Shih IM, Chuang CM, Lo CL, Tsai MC, Chiu LY, Lin CC, Shen YA. Novel cancer treatment paradigm targeting hypoxia-induced factor in conjunction with current therapies to overcome resistance. J Exp Clin Cancer Res 2023; 42:171. [PMID: 37460927 DOI: 10.1186/s13046-023-02724-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 05/29/2023] [Indexed: 07/20/2023] Open
Abstract
Chemotherapy, radiotherapy, targeted therapy, and immunotherapy are established cancer treatment modalities that are widely used due to their demonstrated efficacy against tumors and favorable safety profiles or tolerability. Nevertheless, treatment resistance continues to be one of the most pressing unsolved conundrums in cancer treatment. Hypoxia-inducible factors (HIFs) are a family of transcription factors that regulate cellular responses to hypoxia by activating genes involved in various adaptations, including erythropoiesis, glucose metabolism, angiogenesis, cell proliferation, and apoptosis. Despite this critical function, overexpression of HIFs has been observed in numerous cancers, leading to resistance to therapy and disease progression. In recent years, much effort has been poured into developing innovative cancer treatments that target the HIF pathway. Combining HIF inhibitors with current cancer therapies to increase anti-tumor activity and diminish treatment resistance is one strategy for combating therapeutic resistance. This review focuses on how HIF inhibitors could be applied in conjunction with current cancer treatments, including those now being evaluated in clinical trials, to usher in a new era of cancer therapy.
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Affiliation(s)
- Ting-Wan Kao
- Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 110301, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, 110301, Taiwan
| | - Geng-Hao Bai
- Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei City, 100225, Taiwan
| | - Tian-Li Wang
- Departments of Pathology, Oncology and Gynecology and Obstetrics, Johns Hopkins Medical Institutions, 1550 Orleans StreetRoom 306, Baltimore, MD, CRB221231, USA
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ie-Ming Shih
- Departments of Pathology, Oncology and Gynecology and Obstetrics, Johns Hopkins Medical Institutions, 1550 Orleans StreetRoom 306, Baltimore, MD, CRB221231, USA
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Chi-Mu Chuang
- Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei, 112304, Taiwan
- Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, 112201, Taiwan
- Department of Midwifery and Women Health Care, National Taipei University of Nursing and Health Sciences, Taipei, 112303, Taiwan
| | - Chun-Liang Lo
- Department of Biomedical Engineering, National Yang-Ming Chiao Tung University, Taipei, 112304, Taiwan
- Medical Device Innovation and Translation Center, National Yang Ming Chiao Tung University, Taipei, 112304, Taiwan
| | - Meng-Chen Tsai
- Department of General Medicine, Taipei Medical University Hospital, Taipei, 110301, Taiwan
| | - Li-Yun Chiu
- Department of General Medicine, Mackay Memorial Hospital, Taipei, 104217, Taiwan
| | - Chu-Chien Lin
- Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 110301, Taiwan
- School of Medicine, College of Medicine, Taipei Medical University, Taipei City, 110301, Taiwan
| | - Yao-An Shen
- Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 110301, Taiwan.
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, 110301, Taiwan.
- International Master/Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei, 110301, Taiwan.
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7
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Targeting metabolism to overcome cancer drug resistance: A promising therapeutic strategy for diffuse large B cell lymphoma. Drug Resist Updat 2022; 61:100822. [DOI: 10.1016/j.drup.2022.100822] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 02/21/2022] [Accepted: 02/27/2022] [Indexed: 02/07/2023]
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Kalli M, Li R, Mills GB, Stylianopoulos T, Zervantonakis IK. Mechanical Stress Signaling in Pancreatic Cancer Cells Triggers p38 MAPK- and JNK-Dependent Cytoskeleton Remodeling and Promotes Cell Migration via Rac1/cdc42/Myosin II. Mol Cancer Res 2022; 20:485-497. [PMID: 34782370 PMCID: PMC8898300 DOI: 10.1158/1541-7786.mcr-21-0266] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 09/24/2021] [Accepted: 11/04/2021] [Indexed: 11/16/2022]
Abstract
Advanced or metastatic pancreatic cancer is highly resistant to existing therapies, and new treatments are urgently needed to improve patient outcomes. Current studies focus on alternative treatment approaches that target the abnormal microenvironment of pancreatic tumors and the resulting elevated mechanical stress in the tumor interior. Nevertheless, the underlying mechanisms by which mechanical stress regulates pancreatic cancer metastatic potential remain elusive. Herein, we used a proteomic assay to profile mechanical stress-induced signaling cascades that drive the motility of pancreatic cancer cells. Proteomic analysis, together with selective protein inhibition and siRNA treatments, revealed that mechanical stress enhances cell migration through activation of the p38 MAPK/HSP27 and JNK/c-Jun signaling axes, and activation of the actin cytoskeleton remodelers: Rac1, cdc42, and myosin II. In addition, mechanical stress upregulated transcription factors associated with epithelial-to-mesenchymal transition and stimulated the formation of stress fibers and filopodia. p38 MAPK and JNK inhibition resulted in lower cell proliferation and more effectively blocked cell migration under mechanical stress compared with control conditions. The enhanced tumor cell motility under mechanical stress was potently reduced by cdc42 and Rac1 silencing with no effects on proliferation. Our results highlight the importance of targeting aberrant signaling in cancer cells that have adapted to mechanical stress in the tumor microenvironment, as a novel approach to effectively limit pancreatic cancer cell migration. IMPLICATIONS Our findings highlight that mechanical stress activated the p38 MAPK and JNK signaling axis and stimulated pancreatic cancer cell migration via upregulation of the actin cytoskeleton remodelers cdc42 and Rac1.
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Affiliation(s)
- Maria Kalli
- Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus
| | - Ruxuan Li
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Gordon B. Mills
- Knight Cancer Institute, Oregon Health Sciences University, Oregon, Pennsylvania
| | - Triantafyllos Stylianopoulos
- Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus
| | - Ioannis K. Zervantonakis
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania
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Cheng HY, Li LF, Wu WJ, Zhang QW, Liu M, Wong TL, Kong HY, Lai CH, Bao WR, Huo CY, Zheng HM, Hou QK, Xu J, Zhou Y, Han QB. Qualitative and quantitative analysis of agar in edible bird's nest and related products based on a daughter oligosaccharide-marker approach using LC-QTOF-MS. Food Control 2022. [DOI: 10.1016/j.foodcont.2021.108514] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
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10
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Bu D, Tu ZC, Wang H, Hu YM, Sun Q, Liu GX. Insight into the mechanism of d-allose in reducing the allergenicity and digestibility of ultrasound-pretreated α-lactalbumin by high-resolution mass spectrometry. Food Chem 2021; 374:131616. [PMID: 34815116 DOI: 10.1016/j.foodchem.2021.131616] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 10/30/2021] [Accepted: 11/11/2021] [Indexed: 12/12/2022]
Abstract
The mechanism of d-allose in reducing the allergenicity and digestibility of ultrasound-pretreated α-lactalbumin (α-LA) was studied. The intensity reduction and peak red shift occurred in fluorescence spectra of glycated samples. Enzyme-linked immunosorbent assay and basophil degranulation analysis showed that d-allose significantly reduced the allergenicity of α-LA, and ultrasound-pretreated α-LA showed the lowest allergenicity after glycation. Compared with α-LA, the degree of hydrolysis decreased in glycated samples. Size-exclusion high-performance liquid chromatography showed that the glycated α-LA was resistant to digestive enzymes. The glycated sites and average degree of substitution per peptide molecule were determined using LC Orbitrap MS/MS. These results suggested that the masking of linear allergenic epitopes by glycation could reduce the allergenicity. Therefore, the combination of ultrasound pretreatment and glycation is a potential method to reduce protein allergenicity in food processing and provides a useful approach for the application of rare sugars in food processing.
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Affiliation(s)
- Dan Bu
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, Jiangxi 330047, China
| | - Zong-Cai Tu
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, Jiangxi 330047, China; National R&D Center of Freshwater Fish Processing, Jiangxi Normal University, Nanchang 330022, China; Engineering Research Center of Freshwater Fish High-value Utilization of Jiangxi Province, Jiangxi Normal University, Nanchang 330022, China
| | - Hui Wang
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, Jiangxi 330047, China.
| | - Yue-Ming Hu
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, Jiangxi 330047, China
| | - Qing Sun
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, Jiangxi 330047, China
| | - Guang-Xian Liu
- Jiangxi Academy of Agricultural Sciences, Nanchang 330299, China.
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11
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Estaras M, Gonzalez A. Modulation of cell physiology under hypoxia in pancreatic cancer. World J Gastroenterol 2021; 27:4582-4602. [PMID: 34366624 PMCID: PMC8326256 DOI: 10.3748/wjg.v27.i28.4582] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 05/28/2021] [Accepted: 06/22/2021] [Indexed: 02/06/2023] Open
Abstract
In solid tumors, the development of vasculature is, to some extent, slower than the proliferation of the different types of cells that form the tissue, both cancer and stroma cells. As a consequence, the oxygen availability is compromised and the tissue evolves toward a condition of hypoxia. The presence of hypoxia is variable depending on where the cells are localized, being less extreme at the periphery of the tumor and more severe in areas located deep within the tumor mass. Surprisingly, the cells do not die. Intracellular pathways that are critical for cell fate such as endoplasmic reticulum stress, apoptosis, autophagy, and others are all involved in cellular responses to the low oxygen availability and are orchestrated by hypoxia-inducible factor. Oxidative stress and inflammation are critical conditions that develop under hypoxia. Together with changes in cellular bioenergetics, all contribute to cell survival. Moreover, cell-to-cell interaction is established within the tumor such that cancer cells and the microenvironment maintain a bidirectional communication. Additionally, the release of extracellular vesicles, or exosomes, represents short and long loops that can convey important information regarding invasion and metastasis. As a result, the tumor grows and its malignancy increases. Currently, one of the most lethal tumors is pancreatic cancer. This paper reviews the most recent advances in the knowledge of how cells grow in a pancreatic tumor by adapting to hypoxia. Unmasking the physiological processes that help the tumor increase its size and their regulation will be of major relevance for the treatment of this deadly tumor.
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Affiliation(s)
- Matias Estaras
- Department of Physiology, Institute of Molecular Pathology Biomarkers, University of Extremadura, Caceres 10003, Spain
| | - Antonio Gonzalez
- Department of Physiology, Cell Biology and Communication Research Group, University of Extremadura, Caceres 10003, Spain
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Mijailovic N, Nesler A, Perazzolli M, Aït Barka E, Aziz A. Rare Sugars: Recent Advances and Their Potential Role in Sustainable Crop Protection. Molecules 2021; 26:molecules26061720. [PMID: 33808719 PMCID: PMC8003523 DOI: 10.3390/molecules26061720] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 03/15/2021] [Accepted: 03/16/2021] [Indexed: 02/06/2023] Open
Abstract
Rare sugars are monosaccharides with a limited availability in the nature and almost unknown biological functions. The use of industrial enzymatic and microbial processes greatly reduced their production costs, making research on these molecules more accessible. Since then, the number of studies on their medical/clinical applications grew and rare sugars emerged as potential candidates to replace conventional sugars in human nutrition thanks to their beneficial health effects. More recently, the potential use of rare sugars in agriculture was also highlighted. However, overviews and critical evaluations on this topic are missing. This review aims to provide the current knowledge about the effects of rare sugars on the organisms of the farming ecosystem, with an emphasis on their mode of action and practical use as an innovative tool for sustainable agriculture. Some rare sugars can impact the plant growth and immune responses by affecting metabolic homeostasis and the hormonal signaling pathways. These properties could be used for the development of new herbicides, plant growth regulators and resistance inducers. Other rare sugars also showed antinutritional properties on some phytopathogens and biocidal activity against some plant pests, highlighting their promising potential for the development of new sustainable pesticides. Their low risk for human health also makes them safe and ecofriendly alternatives to agrochemicals.
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Affiliation(s)
- Nikola Mijailovic
- Induced Resistance and Plant Bioprotection, USC RIBP 1488, University of Reims, UFR Sciences, CEDEX 02, 51687 Reims, France; (N.M.); (E.A.B.)
- Bi-PA nv, Londerzee l1840, Belgium;
| | | | - Michele Perazzolli
- Department of Sustainable Agro-Ecosystems and Bioresources, Research and Innovation Centre, Fondazione Edmund Mach, 38010 San Michele all’Adige, Italy;
- Center Agriculture Food Environment (C3A), University of Trento, 38098 San Michele all’Adige, Italy
| | - Essaid Aït Barka
- Induced Resistance and Plant Bioprotection, USC RIBP 1488, University of Reims, UFR Sciences, CEDEX 02, 51687 Reims, France; (N.M.); (E.A.B.)
| | - Aziz Aziz
- Induced Resistance and Plant Bioprotection, USC RIBP 1488, University of Reims, UFR Sciences, CEDEX 02, 51687 Reims, France; (N.M.); (E.A.B.)
- Correspondence: ; Tel.: +33-326-918-525
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13
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Hypoxia-Mediated Decrease of Ovarian Cancer Cells Reaction to Treatment: Significance for Chemo- and Immunotherapies. Int J Mol Sci 2020; 21:ijms21249492. [PMID: 33327450 PMCID: PMC7764929 DOI: 10.3390/ijms21249492] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 11/30/2020] [Accepted: 12/08/2020] [Indexed: 12/20/2022] Open
Abstract
Hypoxia, a common factor ruling the microenvironment composition, leads to tumor progression. In this hypoxic context, cytokines and cells cooperate to favor cancer development and metastasis. Tumor hypoxia is heterogeneously distributed. Oxygen gradients depend on the vicinity, functionality of blood vessels, and oxygen ability to diffuse into surrounding tissues. Thus, the vasculature state modulates the microenvironment of the tumor cells. Cells sense and react to small variations in oxygen tension, which explains the lack of tumor cells’ unicity in their reaction to drugs. Ovarian cancers are highly hypoxia-dependent, ascites worsening the access to oxygen, in their reactions to both chemotherapy and new immunotherapy. Consequently, hypoxia affects the results of immunotherapy, and is thus, crucial for the design of treatments. Controlling key immunosuppressive factors and receptors, as well as immune checkpoint molecule expression on tumor, immune and stromal cells, hypoxia induces immunosuppression. Consequently, new approaches to alleviate hypoxia in the tumor microenvironment bring promises for ovarian cancer immunotherapeutic strategies. This review focuses on the effects of hypoxia in the microenvironment and its consequences on tumor treatments. This opens the way to innovative combined treatments to the advantage of immunotherapy outcome in ovarian cancers.
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Tilekar K, Upadhyay N, Iancu CV, Pokrovsky V, Choe JY, Ramaa CS. Power of two: combination of therapeutic approaches involving glucose transporter (GLUT) inhibitors to combat cancer. Biochim Biophys Acta Rev Cancer 2020; 1874:188457. [PMID: 33096154 PMCID: PMC7704680 DOI: 10.1016/j.bbcan.2020.188457] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 10/16/2020] [Accepted: 10/16/2020] [Indexed: 12/20/2022]
Abstract
Cancer research of the Warburg effect, a hallmark metabolic alteration in tumors, focused attention on glucose metabolism whose targeting uncovered several agents with promising anticancer effects at the preclinical level. These agents' monotherapy points to their potential as adjuvant combination therapy to existing standard chemotherapy in human trials. Accordingly, several studies on combining glucose transporter (GLUT) inhibitors with chemotherapeutic agents, such as doxorubicin, paclitaxel, and cytarabine, showed synergistic or additive anticancer effects, reduced chemo-, radio-, and immuno-resistance, and reduced toxicity due to lowering the therapeutic doses required for desired chemotherapeutic effects, as compared with monotherapy. The combinations have been specifically effective in treating cancer glycolytic phenotypes, such as pancreatic and breast cancers. Even combining GLUT inhibitors with other glycolytic inhibitors and energy restriction mimetics seems worthwhile. Though combination clinical trials are in the early phase, initial results are intriguing. The various types of GLUTs, their role in cancer progression, GLUT inhibitors, and their anticancer mechanism of action have been reviewed several times. However, utilizing GLUT inhibitors as combination therapeutics has received little attention. We consider GLUT inhibitors agents that directly affect glucose transporters by binding to them or indirectly alter glucose transport by changing the transporters' expression level. This review mainly focuses on summarizing the effects of various combinations of GLUT inhibitors with other anticancer agents and providing a perspective on the current status.
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Affiliation(s)
- Kalpana Tilekar
- Department of Pharmaceutical Chemistry, Bharati Vidyapeeth’s College of Pharmacy, Navi Mumbai, Maharashtra, India
| | - Neha Upadhyay
- Department of Pharmaceutical Chemistry, Bharati Vidyapeeth’s College of Pharmacy, Navi Mumbai, Maharashtra, India
| | - Cristina V. Iancu
- East Carolina Diabetes and Obesity Institute, Department of Chemistry, East Carolina University, Greenville, North Carolina, USA
| | - Vadim Pokrovsky
- Laboratory of Combined Therapy, N.N. Blokhin Cancer Research Center, Moscow, Russia
- Department of Biochemistry, People’s Friendship University, Moscow, Russia
| | - Jun-yong Choe
- East Carolina Diabetes and Obesity Institute, Department of Chemistry, East Carolina University, Greenville, North Carolina, USA
| | - C. S. Ramaa
- Department of Pharmaceutical Chemistry, Bharati Vidyapeeth’s College of Pharmacy, Navi Mumbai, Maharashtra, India
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15
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Hu Y, Deng K, Pan M, Liu S, Li W, Huang J, Yao J, Zuo J. Down-regulation of PCK2 inhibits the invasion and metastasis of laryngeal carcinoma cells. Am J Transl Res 2020; 12:3842-3857. [PMID: 32774739 PMCID: PMC7407686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 05/31/2020] [Indexed: 06/11/2023]
Abstract
Laryngeal carcinoma is one of the common malignancies of head and neck. However, the pathogenesis of laryngeal cancer has been not completely clear. To identify the effects of hypoxia on the invasion, metastasis, and metabolism of laryngeal carcinoma, iTRAQ-labeling-with-LC-MS/MS analysis was performed to identify differentially expressed proteins of the SCC10A cells under hypoxia and normoxia, while metabolites were examined by metabolic profiling. 155 proteins and 180 metabolites were identified and the PCK2 protein was selected for validation by Western Blotting. Immunohistochemistry (IHC) was performed to analyze the expression of PCK2 in formalin-fixed paraffin-embedded (FFPE) tissue sections, including laryngeal squamous cell carcinoma tissues from various stages. Collectively, we report that down-regulation of PCK2 inhibits the invasion, migration, and proliferation of laryngeal cancer under hypoxia and down-regulation of PCK2 may be used as a new strategy for laryngeal cancer therapy.
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Affiliation(s)
- Yun Hu
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, The Laboratory of Translational Medicine, Hunan Provincial Key Laboratory of Tumour Microenvironment Responsive Drug Research, Hengyang Medical School, University of South ChinaHengyang 421002, Hunan, P. R. China
| | - Kun Deng
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, The Laboratory of Translational Medicine, Hunan Provincial Key Laboratory of Tumour Microenvironment Responsive Drug Research, Hengyang Medical School, University of South ChinaHengyang 421002, Hunan, P. R. China
| | - Meihong Pan
- The Affiliated Nanhua Hospital of University of South ChinaHengyang 421002, Hunan, P. R. China
| | - Shanyan Liu
- The Affiliated Nanhua Hospital of University of South ChinaHengyang 421002, Hunan, P. R. China
| | - Wenda Li
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, The Laboratory of Translational Medicine, Hunan Provincial Key Laboratory of Tumour Microenvironment Responsive Drug Research, Hengyang Medical School, University of South ChinaHengyang 421002, Hunan, P. R. China
| | - Jialu Huang
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, The Laboratory of Translational Medicine, Hunan Provincial Key Laboratory of Tumour Microenvironment Responsive Drug Research, Hengyang Medical School, University of South ChinaHengyang 421002, Hunan, P. R. China
| | - Jinwei Yao
- The Third Affiliated Hospital of University of South ChinaHengyang 421900, Hunan, P. R. China
| | - Jianhong Zuo
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, The Laboratory of Translational Medicine, Hunan Provincial Key Laboratory of Tumour Microenvironment Responsive Drug Research, Hengyang Medical School, University of South ChinaHengyang 421002, Hunan, P. R. China
- The Affiliated Nanhua Hospital of University of South ChinaHengyang 421002, Hunan, P. R. China
- The Third Affiliated Hospital of University of South ChinaHengyang 421900, Hunan, P. R. China
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16
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Kumar S, Principe DR, Singh SK, Viswakarma N, Sondarva G, Rana B, Rana A. Mitogen-Activated Protein Kinase Inhibitors and T-Cell-Dependent Immunotherapy in Cancer. Pharmaceuticals (Basel) 2020; 13:E9. [PMID: 31936067 PMCID: PMC7168889 DOI: 10.3390/ph13010009] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 01/02/2020] [Accepted: 01/04/2020] [Indexed: 12/13/2022] Open
Abstract
Mitogen-activated protein kinase (MAPK) signaling networks serve to regulate a wide range of physiologic and cancer-associated cell processes. For instance, a variety of oncogenic mutations often lead to hyperactivation of MAPK signaling, thereby enhancing tumor cell proliferation and disease progression. As such, several components of the MAPK signaling network have been proposed as viable targets for cancer therapy. However, the contributions of MAPK signaling extend well beyond the tumor cells, and several MAPK effectors have been identified as key mediators of the tumor microenvironment (TME), particularly with respect to the local immune infiltrate. In fact, a blockade of various MAPK signals has been suggested to fundamentally alter the interaction between tumor cells and T lymphocytes and have been suggested a potential adjuvant to immune checkpoint inhibition in the clinic. Therefore, in this review article, we discuss the various mechanisms through which MAPK family members contribute to T-cell biology, as well as circumstances in which MAPK inhibition may potentiate or limit cancer immunotherapy.
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Affiliation(s)
- Sandeep Kumar
- Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, IL 60612, USA; (S.K.); (D.R.P.); (S.K.S.); (N.V.); (G.S.); (B.R.)
- Jesse Brown VA Medical Center, Chicago, IL 60612, USA
| | - Daniel R. Principe
- Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, IL 60612, USA; (S.K.); (D.R.P.); (S.K.S.); (N.V.); (G.S.); (B.R.)
- Medical Scientist Training Program, University of Illinois College of Medicine, Chicago, IL 60612, USA
| | - Sunil Kumar Singh
- Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, IL 60612, USA; (S.K.); (D.R.P.); (S.K.S.); (N.V.); (G.S.); (B.R.)
- Jesse Brown VA Medical Center, Chicago, IL 60612, USA
| | - Navin Viswakarma
- Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, IL 60612, USA; (S.K.); (D.R.P.); (S.K.S.); (N.V.); (G.S.); (B.R.)
- Jesse Brown VA Medical Center, Chicago, IL 60612, USA
| | - Gautam Sondarva
- Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, IL 60612, USA; (S.K.); (D.R.P.); (S.K.S.); (N.V.); (G.S.); (B.R.)
- Jesse Brown VA Medical Center, Chicago, IL 60612, USA
| | - Basabi Rana
- Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, IL 60612, USA; (S.K.); (D.R.P.); (S.K.S.); (N.V.); (G.S.); (B.R.)
- Jesse Brown VA Medical Center, Chicago, IL 60612, USA
- University of Illinois Hospital & Health Sciences System Cancer Center, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Ajay Rana
- Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, IL 60612, USA; (S.K.); (D.R.P.); (S.K.S.); (N.V.); (G.S.); (B.R.)
- Jesse Brown VA Medical Center, Chicago, IL 60612, USA
- University of Illinois Hospital & Health Sciences System Cancer Center, University of Illinois at Chicago, Chicago, IL 60612, USA
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17
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Kumari S, Khan S, Sekhri R, Mandil H, Behrman S, Yallapu MM, Chauhan SC, Jaggi M. Protein kinase D1 regulates metabolic switch in pancreatic cancer via modulation of mTORC1. Br J Cancer 2019; 122:121-131. [PMID: 31819177 PMCID: PMC6964700 DOI: 10.1038/s41416-019-0629-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 08/01/2019] [Accepted: 10/23/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Protein kinase D1 (PKD1) is a serine-threonine kinase that regulates various functions within the cell. Herein, we report the significance of PKD1 expression in glucose metabolism resulting in pancreatic cancer (PanCa) progression and chemo-resistance. METHODS PKD1 expression in PanCa was investigated by using immunohistochemistry. Functional and metabolic assays were utilised to analyse the effect of PKD1 expression/knockdown on associated cellular/molecular changes. RESULTS PKD1 expression was detected in human pancreatic intraepithelial neoplasia lesions (MCS = 12.9; P < 0.0001) and pancreatic ductal adenocarcinoma samples (MCS = 15, P < 0.0001) as compared with faint or no expression in normal pancreatic tissues (MCS = 1.54; P < 0.0001). Our results determine that PKD1 enhances glucose metabolism in PanCa cells, by triggering enhanced tumorigenesis and chemo-resistance. We demonstrate that mTORC1 activation by PKD1 regulates metabolic alterations in PanCa cells. siRNA knockdown of Raptor or treatment with rapamycin inhibited PKD1-accelerated lactate production as well as glucose consumption in cells, which confirms the association of mTORC1 with PKD1-induced metabolic alterations. CONCLUSION This study suggests a novel role of PKD1 as a key modulator of the glucose metabolism in PanCa cells accelerating tumorigenesis and chemo-resistance. The remodelling of PKD1-dysregulated glucose metabolism can be achieved by regulation of mTORC1 for development of novel therapeutic strategies.
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Affiliation(s)
- Sonam Kumari
- Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Sheema Khan
- Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA. .,Department of Immunology and Microbiology, University of Texas Rio Grande Valley, McAllen, TX, USA.
| | - Radhika Sekhri
- Department of Pathology, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Hassan Mandil
- Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Stephen Behrman
- Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Murali M Yallapu
- Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA.,Department of Immunology and Microbiology, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Subhash C Chauhan
- Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA.,Department of Immunology and Microbiology, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Meena Jaggi
- Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA. .,Department of Immunology and Microbiology, University of Texas Rio Grande Valley, McAllen, TX, USA.
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18
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Zhang J, Chen Q, Du D, Wu T, Wen J, Wu M, Zhang Y, Yan W, Zhou S, Li Y, Jin Y, Luo A, Wang S. Can ovarian aging be delayed by pharmacological strategies? Aging (Albany NY) 2019; 11:817-832. [PMID: 30674710 PMCID: PMC6366956 DOI: 10.18632/aging.101784] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Accepted: 01/15/2019] [Indexed: 12/31/2022]
Abstract
Aging has been regarded as a treatable condition, and delaying aging could prevent some diseases. Ovarian aging, a special type of organ senescence, is the earliest-aging organ, as ovaries exhibit an accelerated rate of aging with characteristics of gradual declines in ovarian follicle quantity and quality since birth, compared to other organs. Ovarian aging is considered as the pacemaker of female body aging, which drives the aging of multiple organs of the body. Hence, anti-ovarian aging has become a research topic broadly interesting to both biomedical scientists and pharmaceutical industry. A marked progress has been made in exploration of possible anti-ovarian agents or approaches, such as calorie restriction mimetics, antioxidants, autophagy inducers etc., over the past years. This review is attempted to discuss recent advances in the area of anti-ovarian aging pharmacology and to offer new insights into our better understanding of molecular mechanisms underlying ovarian aging, which might be informative for future prevention and treatment of ovarian aging and its related diseases.
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Affiliation(s)
- Jinjin Zhang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Qian Chen
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Dingfu Du
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Tong Wu
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jingyi Wen
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Meng Wu
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yan Zhang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Wei Yan
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Su Zhou
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yan Li
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yan Jin
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Aiyue Luo
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Shixuan Wang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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Shi D, Zhao D, Niu P, Zhu Y, Zhou J, Chen H. Glycolysis inhibition via mTOR suppression is a key step in cardamonin-induced autophagy in SKOV3 cells. Altern Ther Health Med 2018; 18:317. [PMID: 30514289 PMCID: PMC6278091 DOI: 10.1186/s12906-018-2380-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Accepted: 11/20/2018] [Indexed: 01/22/2023]
Abstract
Background Autophagy occurs in cells that undergoing nutrient deprivation. Glycolysis rapidly supplies energy for the proliferation of cancer cells. Cardamonin inhibits proliferation and enhances autophagy by mTORC1 suppression in ovarian cancer cells. Here, we investigate the relationship between cardamonin-triggered autophagy and glycolysis inhibition via mTORC1 suppression. Methods Treated with indicated compounds, ATP content and the activity of hexokinase (HK) and lactate dehydrogenase (LDH) were analyzed by the assay kits. Autophagy was detected by monodansylcadaverin (MDC) staining. The relationship between cardamonin-triggered autophagy and glycolysis inhibition via mTORC1 suppression was analyzed by Western blot. Results We found that cardamonin inhibited the lactate secretion, ATP production, and the activity of HK and LDH. The results demonstrated that cardamonin enhanced autophagy in SKOV3 cells, as indicated by acidic compartments accumulation, microtubule-associated protein 1 Light Chain 3-II (LC3-II) and lysosome associated membrane protein 1 up-regulation. Our results showed that the activation of mTORC1 signaling and the expression HK2 were reduced by cardamonin; whereas the phosphorylation of AMPK (AMP-activated protein kinase) was increased. We also confirmed that the AMPK inhibitor, Compound C, reversed cardamonin-induced upregulation of LC3-II. Conclusion These results suggest that cardamonin-induced autophagy is associated with inhibition on glycolysis by down-regulating the activity of mTORC1 in ovarian cancer cells.
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20
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Bousseau S, Vergori L, Soleti R, Lenaers G, Martinez MC, Andriantsitohaina R. Glycosylation as new pharmacological strategies for diseases associated with excessive angiogenesis. Pharmacol Ther 2018; 191:92-122. [DOI: 10.1016/j.pharmthera.2018.06.003] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2018] [Accepted: 06/01/2018] [Indexed: 02/07/2023]
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21
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Thermal degradation of agar: Mechanism and toxicity of products. Food Chem 2018; 264:277-283. [DOI: 10.1016/j.foodchem.2018.04.098] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Revised: 03/26/2018] [Accepted: 04/23/2018] [Indexed: 12/12/2022]
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22
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Guo X, Ding X. Dioscin suppresses the viability of ovarian cancer cells by regulating the VEGFR2 and PI3K/AKT/MAPK signaling pathways. Oncol Lett 2018; 15:9537-9542. [PMID: 29805675 DOI: 10.3892/ol.2018.8454] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2016] [Accepted: 09/28/2017] [Indexed: 02/07/2023] Open
Abstract
Diosgenin is a natural steroidal saponin that is extracted from a range of sources, including from fenugreek. It is a critical raw material in the synthesis of steroid hormone drugs, exhibiting antitumor, anti-inflammatory, antioxidation and a number of other significant pharmacological actions, possessing high pharmaceutical value. The aim of the present study was to investigate the effects of dioscin suppression on ovarian cancer cell growth and the mechanism of apoptosis induction by dioscin in ovarian cancer cells. The results of the present study demonstrated that dioscin decreased viability and induced apoptosis in SKOV3 human ovarian cancer cells in a dose-dependent manner. Dioscin significantly increased caspase-3 and caspase-9 activity, and increased the protein expression of Bax and cleaved poly(ADP-ribose) polymerase in SKOV3 cells. In addition, dioscin significantly suppressed vascular endothelial growth factor receptor (VEGFR)2, phosphoinositide 3-kinase (PI3K), phosphorylated AKT and phosphorylated p38 mitogen-activated protein kinase (MAPK) protein expression in SKOV3 cells. Taken together, to the best of our knowledge, the present study demonstrated for the first time that dioscin suppresses cell viability in ovarian cancer cells by regulating the VEGFR2 and PI3K/AKT/MAPK signaling pathways.
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Affiliation(s)
- Xianqing Guo
- Department of Pharmaceuticals, Qilu Hospital of Shandong University, Qingdao, Shandong 266035, P.R. China
| | - Xiao Ding
- Department of Gynecology and Obstetrics, Qilu Hospital of Shandong University, Qingdao, Shandong 266035, P.R. China
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23
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Chen Z, Chen J, Zhang W, Zhang T, Guang C, Mu W. Recent research on the physiological functions, applications, and biotechnological production of D-allose. Appl Microbiol Biotechnol 2018; 102:4269-4278. [PMID: 29577167 DOI: 10.1007/s00253-018-8916-6] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 03/05/2018] [Accepted: 03/06/2018] [Indexed: 02/06/2023]
Abstract
D-Allose is a rare monosaccharide, which rarely appears in the natural environment. D-Allose has an 80% sweetness relative to table sugar but is ultra-low calorie and non-toxic and is thus an ideal candidate to take the place of table sugar in food products. It displays unique health benefits and physiological functions in various fields, including food systems, clinical treatment, and the health care fields. However, it is difficult to produce chemically. The biotechnological production of D-allose has become a research hotspot in recent years. Therefore, an overview of recent studies on the physiological functions, applications, and biotechnological production of D-allose is presented. In this review, the physiological functions of D-allose are introduced in detail. In addition, the different types of D-allose-producing enzymes are compared for their enzymatic properties and for the biotechnological production of D-allose. To date, very little information is available on the molecular modification and food-grade expression of D-allose-producing enzymes, representing a very large research space yet to be explored.
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Affiliation(s)
- Ziwei Chen
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, 214122, China
| | - Jiajun Chen
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, 214122, China
| | - Wenli Zhang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, 214122, China
| | - Tao Zhang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, 214122, China.,International Joint Laboratory on Food Safety, Jiangnan University, Wuxi, 214122, China
| | - Cuie Guang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, 214122, China
| | - Wanmeng Mu
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, 214122, China. .,International Joint Laboratory on Food Safety, Jiangnan University, Wuxi, 214122, China.
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24
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Niccoli S, Boreham DR, Phenix CP, Lees SJ. Non-radioactive 2-deoxy-2-fluoro-D-glucose inhibits glucose uptake in xenograft tumours and sensitizes HeLa cells to doxorubicin in vitro. PLoS One 2017; 12:e0187584. [PMID: 29095925 PMCID: PMC5667878 DOI: 10.1371/journal.pone.0187584] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Accepted: 10/23/2017] [Indexed: 12/23/2022] Open
Abstract
A glucose analog called 2-deoxy-D-glucose (2DG) has been successfully used to sensitize cancer cells to ROS-inducing cancer treatments such as ionizing radiation, through the inhibition of glycolysis. However, the use of 2DG can be limited by several factors such as availability, non-specific cytotoxicity, and chemoresistance under hypoxic conditions. The purpose of this study was to investigate the use of non-radioactive 2-deoxy-2-fluoro-D-glucose (19FDG), a drug that potentially addresses current limitations of 2DG. The effectiveness of using either 2DG or 19FDG in combination with doxorubicin (Dox) in HeLa cells was determined in both normoxia and hypoxia. We have also shown that under both oxygen conditions, 19FDG-treated cells produce less lactate than 2DG-treated cells, an important finding that suggests improved inhibition of glycolysis, the preferential pathway for cancerous cells. When used in combination with Dox, we have demonstrated a significant decrease in the number of viable cells, with the effect of 19FDG remaining stable across both normoxic and hypoxic conditions. Moreover, the assessment of apoptosis and necrosis revealed that 19FDG maintained its ability to sensitize HeLa cells to Dox in hypoxia, but 2DG was only effective under normoxic conditions. The retained effectiveness of 19FDG in combination with Dox under hypoxic conditions, suggests that 19FDG may be efficacious for sensitizing hypoxic regions of solid tumour masses. Importantly, the ability of 19FDG to inhibit glucose uptake in vivo was also confirmed using positron emission tomography (PET) of xenograft tumours. The results displayed here suggest 19FDG is a promising combination therapy, which may lead to decreased ROS scavenging via glycolysis, and enhanced treatment success.
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Affiliation(s)
- Sarah Niccoli
- Medical Sciences, Lakehead University Faculty of Medicine, Thunder Bay, Ontario, Canada
| | - Douglas R. Boreham
- Medical Sciences Division, Northern Ontario School of Medicine, Thunder Bay, Ontario, Canada
| | - Christopher P. Phenix
- Chemistry, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
- Thunder Bay Regional Health Research Institute, Thunder Bay, Ontario, Canada
| | - Simon J. Lees
- Medical Sciences, Lakehead University Faculty of Medicine, Thunder Bay, Ontario, Canada
- Medical Sciences Division, Northern Ontario School of Medicine, Thunder Bay, Ontario, Canada
- Biology, Lakehead University, Thunder Bay, Ontario, Canada
- * E-mail:
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Broecker-Preuss M, Becher-Boveleth N, Bockisch A, Dührsen U, Müller S. Regulation of glucose uptake in lymphoma cell lines by c-MYC- and PI3K-dependent signaling pathways and impact of glycolytic pathways on cell viability. J Transl Med 2017; 15:158. [PMID: 28724379 PMCID: PMC5517804 DOI: 10.1186/s12967-017-1258-9] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Accepted: 07/04/2017] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Changes in glucose and energy metabolism contribute to the altered phenotype of cancer cells and are the basis for positron emission tomography with 18F-fluoro-2-deoxy-D-glucose (FDG) to visualize tumors in vivo. The molecular background of the enhanced glucose uptake and its regulation in lymphoma cells is not fully clarified and may provide new possibilities to reverse the altered metabolism. Thus in this study we investigated regulation of glucose uptake by different signaling pathways. Furthermore, the effect of the glucose analog 2-deoxy-D-glucose (2-DG) alone and in combination with other inhibitors on cell survival was studied. METHODS An FDG uptake assay was established and uptake of FDG by lymphoma cells was determined after incubation with inhibitors of the c-MYC and the PI3K signalling pathways that are known to be activated in lymphoma cells and able to regulate glucose metabolism. Inhibitors of MAPK signalling pathways whose role in altered metabolism is still unclear were also investigated. Expression of mRNAs of the glucose transporter 1 (GLUT1), hexokinase 2 (HK2), glucose-6-phosphatase (G6Pase) and lactate dehydrogenase A (LDHA) and of the glucose metabolism-regulating micro RNAs (miRNA) miR21, -23a, -133a, -133b, -138-1 and -143 was determined by RT-PCR. Cell viability was analysed by MTT assay. RESULTS Treatment with the c-MYC inhibitor 10058-F4 and inhibitors of the PI3K/mTOR pathway diminished uptake of FDG in all three cell lines, while inhibition of MAPK pathways had no effect on glucose uptake. Expression of glycolysis-related genes and miRNAs were diminished, although to a variable degree in the three cell lines. The c-MYC inhibitor, the PI3K inhibitor LY294002, the mTOR inhibitor Rapamycin and 2-DG all diminished the number of viable cells. Interestingly, in combination with 2-DG, the c-MYC inhibitor, LY294002 and the p38 MAPK inhibitor SB203580 had synergistic effects on cell viability in all three cell lines. CONCLUSIONS c-MYC- and PI3K/mTOR-inhibitors decreased viability of the lymphoma cells and led to decreased glucose uptake, expression of glycolysis-associated genes, and glucose metabolism-regulating miRNAs. Inhibition of HK by 2-DG reduced cell numbers as a single agent and synergistically with inhibitors of other intracellular pathways. Thus, targeted inhibition of the pathways investigated here could be a strategy to suppress the glycolytic phenotype of lymphoma cells and reduce proliferation.
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Affiliation(s)
- Martina Broecker-Preuss
- Department of Nuclear Medicine, University Hospital Essen, Hufelandstr. 55, 45122, Essen, Germany. .,Department of Clinical Chemistry, University Hospital Essen, Hufelandstr. 55, 45122, Essen, Germany.
| | - Nina Becher-Boveleth
- Department of Nuclear Medicine, University Hospital Essen, Hufelandstr. 55, 45122, Essen, Germany.,Department of Hematology, University Hospital Essen, Hufelandstr. 55, 45122, Essen, Germany.,Institute of Pathology, University Hospital Essen, Hufelandstr. 55, 45122, Essen, Germany
| | - Andreas Bockisch
- Department of Nuclear Medicine, University Hospital Essen, Hufelandstr. 55, 45122, Essen, Germany
| | - Ulrich Dührsen
- Department of Hematology, University Hospital Essen, Hufelandstr. 55, 45122, Essen, Germany
| | - Stefan Müller
- Department of Nuclear Medicine, University Hospital Essen, Hufelandstr. 55, 45122, Essen, Germany
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Huang H, Liu N, Liao Y, Liu N, Cai J, Xia X, Guo Z, Li Y, Wen Q, Yin Q, Liu Y, Wu Q, Rajakumar D, Sheng X, Liu J. Platinum-containing compound platinum pyrithione suppresses ovarian tumor proliferation through proteasome inhibition. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2017; 36:79. [PMID: 28619062 PMCID: PMC5471884 DOI: 10.1186/s13046-017-0547-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Accepted: 05/31/2017] [Indexed: 12/17/2022]
Abstract
BACKGROUND Ovarian carcinoma is one of the most aggressive gynecological malignant neoplasms and makes up 25-30% of all cancer cases of the female genital tract. Currently, resistance to traditional chemotherapy is a great challenge for patients with Epithelial ovarian cancer (EOC). Therefore, identifying novel agents for EOC treatment is essential and urgent. METHOD MTS assay was used to analyze the cell viability and proliferation of cancer cells. Flow cytometry was employed to analyze cell cycle distribution and cell apoptosis. Protein signaling pathways were detected by western blot and immunohistochemical staining. Nude mouse experiment was performed to test the in vivo effect of platinum pyrithione (PtPT). RESULTS PtPT is a chemically well-characterized synthetic complex of platinum that potently inhibits proteasome-associated deubiquitinases USP14 and UCHL5 activity and shows selective cytotoxicity to multiple cancer cells without damaging DNA. We found that PtPT significantly accumulated ubquitinated-proteins and suppressed the proliferation of multiple EOC cells. Additionally, PtPT induced G2 phase arrest and apoptosis in both A2780 and SKOV3 cells. More importantly, animal experiments showed that PtPT dramatically suppressed the growth of EOC xenografts without obvious side effects. CONCLUSION These results suggest that through proteasome inhibition, PtPT significantly suppressed the proliferation of EOC in vitro and in vivo and could be developed as a novel agent for EOC treatment in the future.
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Affiliation(s)
- Hongbiao Huang
- Key Laboratory of Protein Modification and Degradation, Department of Obsterics and Gynecology, The Third Affiliated Hospital, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Guangzhou, Guangdong, 510510, China.,Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences and Affiliated Cancer Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 511436, China
| | - Ni Liu
- Key Laboratory of Protein Modification and Degradation, Department of Obsterics and Gynecology, The Third Affiliated Hospital, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Guangzhou, Guangdong, 510510, China.,Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences and Affiliated Cancer Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 511436, China
| | - Yuning Liao
- Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences and Affiliated Cancer Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 511436, China
| | - Ningning Liu
- Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences and Affiliated Cancer Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 511436, China.,Guangzhou Institute of Cardiovascular Disease, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510260, China
| | - Jianyu Cai
- Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences and Affiliated Cancer Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 511436, China
| | - Xiaohong Xia
- Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences and Affiliated Cancer Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 511436, China
| | - Zhiqiang Guo
- Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences and Affiliated Cancer Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 511436, China
| | - Yanling Li
- Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences and Affiliated Cancer Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 511436, China
| | - Qirong Wen
- Key Laboratory of Protein Modification and Degradation, Department of Obsterics and Gynecology, The Third Affiliated Hospital, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Guangzhou, Guangdong, 510510, China
| | - Qi Yin
- Key Laboratory of Protein Modification and Degradation, Department of Obsterics and Gynecology, The Third Affiliated Hospital, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Guangzhou, Guangdong, 510510, China
| | - Yan Liu
- Key Laboratory of Protein Modification and Degradation, Department of Obsterics and Gynecology, The Third Affiliated Hospital, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Guangzhou, Guangdong, 510510, China
| | - Qingxia Wu
- Key Laboratory of Protein Modification and Degradation, Department of Obsterics and Gynecology, The Third Affiliated Hospital, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Guangzhou, Guangdong, 510510, China
| | - Dhivya Rajakumar
- Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences and Affiliated Cancer Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 511436, China
| | - Xiujie Sheng
- Key Laboratory of Protein Modification and Degradation, Department of Obsterics and Gynecology, The Third Affiliated Hospital, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Guangzhou, Guangdong, 510510, China.
| | - Jinbao Liu
- Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences and Affiliated Cancer Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 511436, China.
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Characterization of a novel thermostable l-rhamnose isomerase from Thermobacillus composti KWC4 and its application for production of d-allose. Process Biochem 2017. [DOI: 10.1016/j.procbio.2016.11.025] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Noguchi C, Kamitori K, Hossain A, Hoshikawa H, Katagi A, Dong Y, Sui L, Tokuda M, Yamaguchi F. D-Allose Inhibits Cancer Cell Growth by Reducing GLUT1 Expression. TOHOKU J EXP MED 2016; 238:131-41. [PMID: 26829886 DOI: 10.1620/tjem.238.131] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Glucose is a major energy source for mammalian cells and is transported into cells via cell-specific expression of various glucose transporters (GLUTs). Especially, cancer cells require massive amounts of glucose as an energy source for their dysregulated growth and thus over-express GLUTs. d-allose, a C-3 epimer of d-glucose, is one of rare sugars that exist in small quantities in nature. We have shown that d-allose induces the tumor suppressor gene coding for thioredoxin interacting protein (TXNIP) and inhibits cancer cell growth by G1 cell cycle arrest. It has also been reported that GLUTs including GLUT1 are over-expressed in many cancer cell lines, which may contribute to larger glucose utilization. Since d-allose suppresses the growth of cancer cells through the upregulation of TXNIP expression, our present study focused on whether d-allose down-regulates GLUT1 expression via TXNIP expression and thus suppresses cancer cell growth. Western blot and real-time PCR analyses revealed that d-allose significantly induced TXNIP expression and inhibited GLUT1 expression in a dose-dependent manner in three human cancer cell lines: hepatocellular carcinoma (HuH-7), Caucasian breast adenocarcinoma (MDA-MB-231), and neuroblastoma (SH-SY5Y). In these cell lines, d-allose treatment inhibited cell growth. Importantly, d-allose treatment decreased glucose uptake, as measured by the uptake of 2-deoxy d-glucose. Moreover, the reporter assays showed that d-allose decreased the expression of luciferase through the hypoxia response element present in the tested promoter region. These results suggest that d-allose may cause the inhibition of cancer growth by reducing both GLUT1 expression and glucose uptake.
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Affiliation(s)
- Chisato Noguchi
- Department of Cell Physiology, Faculty of Medicine, Kagawa University
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Muniruzzaman S, McIntosh M, Hossain A, Izumori K, Bhattacharjee PS. A novel rare sugar inhibitor of murine herpes simplex keratitis. J Pharmacol Sci 2016; 131:126-30. [PMID: 27262904 PMCID: PMC5499707 DOI: 10.1016/j.jphs.2016.05.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Revised: 05/12/2016] [Accepted: 05/12/2016] [Indexed: 12/26/2022] Open
Abstract
Purpose To determine the therapeutic efficacy of a novel rare sugar, L-psicose, for the treatment of HSV-1 induced herpetic stromal keratitis (HSK) in a mouse eye model. Methods One rare sugar L-psicose was assayed for HSV-1 inhibition of in vitro virus adsorption. The IC50 and IC90 values of L-psicose were determined using plaque reduction assay (PRA) in CV-1 cell. Female Balb/c mice were corneally infected with HSV-1, strain KOS-GFP; A topical eye drop treatment of L-psicose was started 24 h after infection and continued four times daily for ten consecutive days. The severity of HSK was monitored by slit lamp examination in a masked fashion and Infectious HSV-1 shedding was determined by PRA. Results L-psicose was found to have anti-viral activity in vitro at an IC50 dose of 99.5 mM and an IC90 dose of 160 mM. Topical eye drop treatment with 200 mM L-psicose in PBS solution significantly reduced the severity of HSK compared to the mock treatment group. The in vivo mouse ocular model results of L-psicose therapy correlated with accelerated clearance of virus from eye swabs. Conclusion The results suggest that topical treatment with rare sugar L-psicose has efficacy against HSK through inhibition of HSV-1.
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Affiliation(s)
- Syed Muniruzzaman
- Department of Biology, Xavier University of Louisiana, New Orleans, LA, USA
| | | | - Ahamed Hossain
- Department of Biology, Xavier University of Louisiana, New Orleans, LA, USA
| | - Ken Izumori
- Rare Sugar Research Center, Kagawa University, 2393 Ikenobe, Miki, Takamatsu 761-0795, Japan
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Yang LJ, Tang Q, Wu J, Chen Y, Zheng F, Dai Z, Hann SS. Inter-regulation of IGFBP1 and FOXO3a unveils novel mechanism in ursolic acid-inhibited growth of hepatocellular carcinoma cells. J Exp Clin Cancer Res 2016; 35:59. [PMID: 27036874 PMCID: PMC4815122 DOI: 10.1186/s13046-016-0330-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Accepted: 03/21/2016] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Ursolic acid (UA), a natural pentacyclic triterpenoid, exerts anti-tumor effects in various cancer types including hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying this remain largely unknown. METHODS Cell viability and cell cycle were examined by MTT and Flow cytometry assays. Western blot analysis was performed to measure the phosphorylation and protein expression of p38 MAPK, insulin-like growth factor (IGF) binding protein 1 (IGFBP1) and forkhead box O3A (FOXO3a). Quantitative real-time PCR (qRT-PCR) was used to examine the mRNA levels of IGFBP1 gene. Small interfering RNAs (siRNAs) method was used to knockdown IGFBP1 gene. Exogenous expressions of IGFBP1 and FOXO3a were carried out by transient transfection assays. IGFBP1 promoter activity was measured by Secrete-Pair™ Dual Luminescence Assay Kit . In vivo nude mice xenograft model and bioluminescent imaging system were used to confirm the findings in vitro. RESULTS We showed that UA stimulated phosphorylation of p38 MAPK. In addition, UA increased the protein, mRNA levels, and promoter activity of IGFBP1, which was abrogated by the specific inhibitor of p38 MAPK (SB203580). Intriguingly, we showed that UA increased the expression of FOXO3a and that overexpressed FOXO3a enhanced phosphorylation of p38 MAPK, all of which were not observed in cells silencing of endogenous IGFBP1 gene. Moreover, exogenous expressed IGFBP1 strengthened UA-induced phosphorylation of p38 MAPK and FOXO3a protein expression, and more importantly, restored the effect of UA-inhibited growth in cells silencing of endogenous IGFBP1 gene. Consistent with these, UA suppressed tumor growth and increased phosphorylation of p38 MAPK, protein expressions of IGFBP1 and FOXO3a in vivo. CONCLUSION Collectively, our results show that UA inhibits growth of HCC cells through p38 MAPK-mediated induction of IGFBP1 and FOXO3a expression. The interactions between IGFBP1 and FOXO3a, and feedback regulatory loop of p38 MAPK by IGFBP1 and FOXO3a resulting in reciprocal pathways, contribute to the overall effects of UA. This in vitro and in vivo study corroborates a potential novel mechanism by which UA controls HCC growth and implies that the rational targeting IGFBP1 and FOXO3a can be potential for the therapeutic strategy against HCC.
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Affiliation(s)
- Li Jun Yang
- />Laboratory of Tumor Biology and Target Therapy, The Second Clinical Medical Collage, University of Guangzhou Traditional Chinese Medicine, Guangzhou, Guangdong Province 510120 China
| | - Qing Tang
- />Laboratory of Tumor Biology and Target Therapy, The Second Clinical Medical Collage, University of Guangzhou Traditional Chinese Medicine, Guangzhou, Guangdong Province 510120 China
| | - Jingjing Wu
- />Laboratory of Tumor Biology and Target Therapy, The Second Clinical Medical Collage, University of Guangzhou Traditional Chinese Medicine, Guangzhou, Guangdong Province 510120 China
| | - Yuqing Chen
- />Laboratory of Tumor Biology and Target Therapy, The Second Clinical Medical Collage, University of Guangzhou Traditional Chinese Medicine, Guangzhou, Guangdong Province 510120 China
| | - Fang Zheng
- />Laboratory of Tumor Biology and Target Therapy, The Second Clinical Medical Collage, University of Guangzhou Traditional Chinese Medicine, Guangzhou, Guangdong Province 510120 China
| | - Zhenhui Dai
- />Department of Radiation Therapy, Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical Medical Collage, University of Guangzhou Traditional Chinese Medicine, Guangzhou, Guangdong Province 510120 China
| | - Swei Sunny Hann
- />Laboratory of Tumor Biology and Target Therapy, The Second Clinical Medical Collage, University of Guangzhou Traditional Chinese Medicine, Guangzhou, Guangdong Province 510120 China
- />No. 55, Neihuan West Road, Higher Education Mega Center, Panyu District, Guangzhou, Guangdong Province 510006 P. R. China
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31
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Xu W, Zhang W, Zhang T, Jiang B, Mu W. l-Rhamnose isomerase and its use for biotechnological production of rare sugars. Appl Microbiol Biotechnol 2016; 100:2985-92. [DOI: 10.1007/s00253-016-7369-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2015] [Revised: 01/27/2016] [Accepted: 01/30/2016] [Indexed: 10/22/2022]
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Walsh M, Fais S, Spugnini EP, Harguindey S, Abu Izneid T, Scacco L, Williams P, Allegrucci C, Rauch C, Omran Z. Proton pump inhibitors for the treatment of cancer in companion animals. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2015; 34:93. [PMID: 26337905 PMCID: PMC4559889 DOI: 10.1186/s13046-015-0204-z] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Accepted: 08/10/2015] [Indexed: 12/15/2022]
Abstract
The treatment of cancer presents a clinical challenge both in human and veterinary medicine. Chemotherapy protocols require the use of toxic drugs that are not always specific, do not selectively target cancerous cells thus resulting in many side effects. A recent therapeutic approach takes advantage of the altered acidity of the tumour microenvironment by using proton pump inhibitors (PPIs) to block the hydrogen transport out of the cell. The alteration of the extracellular pH kills tumour cells, reverses drug resistance, and reduces cancer metastasis. Human clinical trials have prompted to consider this as a viable and safe option for the treatment of cancer in companion animals. Preliminary animal studies suggest that the same positive outcome could be achievable. The purpose of this review is to support investigations into the use of PPIs for cancer treatment cancer in companion animals by considering the evidence available in both human and veterinary medicine.
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Affiliation(s)
- Megan Walsh
- School of Veterinary Medicine and Science, University of Nottingham, College Road, Sutton Bonington, LE12 5RD, UK.
| | - Stefano Fais
- Department of Therapeutic Research and Medicines Evaluation, National Institute of Health, Viale Regina Elena 299, 00161, Rome, Italy.
| | | | - Salvador Harguindey
- Institute for Clinical Biology and Metabolism, c) Postas 13, 01004, Vitoria, Spain.
| | - Tareq Abu Izneid
- College of Pharmacy, Umm Al-Qura University, Al-Abidiyya, 21955, Makkah, Kingdom of Saudi Arabia.
| | - Licia Scacco
- Equivet Roma Hospital, Equine Veterinary Clinic, Via di Torre di Sant'Anastasia 83, 00134, Rome, Italy
| | - Paula Williams
- School of Veterinary Medicine and Science, University of Nottingham, College Road, Sutton Bonington, LE12 5RD, UK.
| | - Cinzia Allegrucci
- School of Veterinary Medicine and Science, University of Nottingham, College Road, Sutton Bonington, LE12 5RD, UK.
| | - Cyril Rauch
- School of Veterinary Medicine and Science, University of Nottingham, College Road, Sutton Bonington, LE12 5RD, UK.
| | - Ziad Omran
- College of Pharmacy, Umm Al-Qura University, Al-Abidiyya, 21955, Makkah, Kingdom of Saudi Arabia.
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Dando I, Dalla Pozza E, Biondani G, Cordani M, Palmieri M, Donadelli M. The metabolic landscape of cancer stem cells. IUBMB Life 2015; 67:687-93. [DOI: 10.1002/iub.1426] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Accepted: 08/14/2015] [Indexed: 12/11/2022]
Affiliation(s)
- Ilaria Dando
- Department of Life and Reproduction Sciences; Section of Biochemistry, University of Verona; Verona Italy
| | - Elisa Dalla Pozza
- Department of Life and Reproduction Sciences; Section of Biochemistry, University of Verona; Verona Italy
| | - Giulia Biondani
- Department of Life and Reproduction Sciences; Section of Biochemistry, University of Verona; Verona Italy
| | - Marco Cordani
- Department of Life and Reproduction Sciences; Section of Biochemistry, University of Verona; Verona Italy
| | - Marta Palmieri
- Department of Life and Reproduction Sciences; Section of Biochemistry, University of Verona; Verona Italy
| | - Massimo Donadelli
- Department of Life and Reproduction Sciences; Section of Biochemistry, University of Verona; Verona Italy
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Mu W, Yu L, Zhang W, Zhang T, Jiang B. Isomerases for biotransformation of D-hexoses. Appl Microbiol Biotechnol 2015; 99:6571-84. [DOI: 10.1007/s00253-015-6788-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2015] [Revised: 06/18/2015] [Accepted: 06/19/2015] [Indexed: 10/23/2022]
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