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Lee ASY, Lin TH, Liu YY, Wang YH, Cheng SC, Li TS, Sun CY, Chen YH. Growth inhibition and toxicity assessments of cis-3,4-diaryl-α-methylene-γ-butyrolactams in cultured human renal cancer cells and zebrafish embryos. Biochim Biophys Acta Gen Subj 2025; 1869:130761. [PMID: 39788219 DOI: 10.1016/j.bbagen.2025.130761] [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: 06/01/2024] [Revised: 12/15/2024] [Accepted: 01/06/2025] [Indexed: 01/12/2025]
Abstract
This study aimed to compare and evaluate the growth inhibition effects of eight previously synthesized compounds, cis-3,4-diaryl-α-methylene-γ-butyrolactams (compounds 1-8), on two human renal carcinoma cell (RCC) lines: CRL-1932 (rapid growth) and HTB-44 (slow growth). MTT assays and flow cytometry were conducted, revealing that compounds 5 and 6 had the potential to induce cell death in the slow-growing RCC cells (HTB-44), while compound 8 demonstrated effectiveness in both RCC lines (HTB-44 and CRL-1932). Additionally, a non-transformed HEK293 cell line and a transgenic zebrafish with a green fluorescent kidney Tg(wt1b:egfp) were used to assess the toxicities of compounds 5, 6, and 8. The findings suggested that compound 8 was relatively non-toxic compared to the others. Western blot analysis indicated that compounds 5, 6, and 8 may interact with the P53/mTOR pathways. Based on these results, we concluded that compound 8 exhibits RCC growth inhibition properties and has lower toxicity, making it a candidate for further investigation in mammalian models.
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Affiliation(s)
- Adam Shih-Yuan Lee
- Department of Chemistry, Tamkang University, 151, Yingzhuan Road, Danshui Dist., New Taipei City 25137, Taiwan
| | - Ta-Hsien Lin
- Division of Basic Research, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Biochemistry and Molecular Biology, National Ying Ming Chiao Tung University, Taipei, Taiwan
| | - Yen-Yu Liu
- Department of Chemistry, Tamkang University, 151, Yingzhuan Road, Danshui Dist., New Taipei City 25137, Taiwan
| | - Yun-Hsin Wang
- Department of Chemistry, Tamkang University, 151, Yingzhuan Road, Danshui Dist., New Taipei City 25137, Taiwan
| | - Shu-Chun Cheng
- Division of Nephrology, Department of Internal Medicine, Keelung Chang Gung Memorial Hospital, Keelung 204, Taiwan
| | - Tao-Sheng Li
- Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, Japan
| | - Chiao-Yin Sun
- Division of Nephrology, Department of Internal Medicine, Keelung Chang Gung Memorial Hospital, Keelung 204, Taiwan; College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.
| | - Yau-Hung Chen
- Department of Chemistry, Tamkang University, 151, Yingzhuan Road, Danshui Dist., New Taipei City 25137, Taiwan.
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Raj AK, Lokhande KB, Prasad TK, Nandangiri R, Choudhary S, Pal JK, Sharma NK. Intracellular Ellagic Acid Derived from Goat Urine DMSO Fraction (GUDF) Predicted as an Inhibitor of c-Raf Kinase. Curr Mol Med 2024; 24:264-279. [PMID: 36642883 DOI: 10.2174/1566524023666230113141032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 11/12/2022] [Accepted: 11/22/2022] [Indexed: 01/17/2023]
Abstract
BACKGROUND Dietary chemicals and their gut-metabolized products are explored for their anti-proliferative and pro-cell death effects. Dietary and metabolized chemicals are different from ruminants such as goats over humans. METHODS Loss of cell viability and induction of death due to goat urine DMSO fraction (GUDF) derived chemicals were assessed by routine in vitro assays upon MCF-7 breast cancer cells. Intracellular metabolite profiling of MCF-7 cells treated with goat urine DMSO fraction (GUDF) was performed using an in-house designed vertical tube gel electrophoresis (VTGE) assisted methodology, followed by LC-HRMS. Next, identified intracellular dietary chemicals such as ellagic acid were evaluated for their inhibitory effects against transducers of the c-Raf signaling pathway employing molecular docking and molecular dynamics (MD) simulation. RESULTS GUDF treatment upon MCF-7 cells displayed significant loss of cell viability and induction of cell death. A set of dietary and metabolized chemicals in the intracellular compartment of MCF-7 cells, such as ellagic acid, 2-hydroxymyristic acid, artelinic acid, 10-amino-decanoic acid, nervonic acid, 2,4-dimethyl-2-eicosenoic acid, 2,3,4'- Trihydroxy,4-Methoxybenzophenone and 9-amino-nonanoic acid were identified. Among intracellular dietary chemicals, ellagic acid displayed a strong inhibitory affinity (-8.7 kcal/mol) against c-Raf kinase. The inhibitory potential of ellagic acid was found to be significantly comparable with a known c-Raf kinase inhibitor sorafenib with overlapping inhibitory site residues (ARG450, GLU425, TRP423, VA403). CONCLUSION Intracellular dietary-derived chemicals such as ellagic acid are suggested for the induction of cell death in MCF-7 cells. Ellagic acid is predicted as an inhibitor of c-Raf kinase and could be explored as an anti-cancer drug.
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Affiliation(s)
- Ajay Kumar Raj
- Cancer and Translational Research Lab, Dr. D.Y. Patil Biotechnology & Bioinformatics Institute, Dr. D.Y. Patil Vidyapeeth, Pimpri, Pune, Maharashtra, 411033, India
| | - Kiran Bharat Lokhande
- Bioinformatics Research Laboratory, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pimpri, Pune, Maharashtra, 411033, India
| | - Tanay Kondapally Prasad
- Cancer and Translational Research Lab, Dr. D.Y. Patil Biotechnology & Bioinformatics Institute, Dr. D.Y. Patil Vidyapeeth, Pimpri, Pune, Maharashtra, 411033, India
| | - Rasika Nandangiri
- Cancer and Translational Research Lab, Dr. D.Y. Patil Biotechnology & Bioinformatics Institute, Dr. D.Y. Patil Vidyapeeth, Pimpri, Pune, Maharashtra, 411033, India
| | - Sumitra Choudhary
- Cancer and Translational Research Lab, Dr. D.Y. Patil Biotechnology & Bioinformatics Institute, Dr. D.Y. Patil Vidyapeeth, Pimpri, Pune, Maharashtra, 411033, India
| | - Jayanta Kumar Pal
- Cancer and Translational Research Lab, Dr. D.Y. Patil Biotechnology & Bioinformatics Institute, Dr. D.Y. Patil Vidyapeeth, Pimpri, Pune, Maharashtra, 411033, India
| | - Nilesh Kumar Sharma
- Cancer and Translational Research Lab, Dr. D.Y. Patil Biotechnology & Bioinformatics Institute, Dr. D.Y. Patil Vidyapeeth, Pimpri, Pune, Maharashtra, 411033, India
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Letafati A, Mozhgani SH, Marjani A, Amiri A, Siami Z, Mohammaditabar M, Molaverdi G, Hedayatyaghoobi M. Decoding dysregulated angiogenesis in HTLV-1 asymptomatic carriers compared to healthy individuals. Med Oncol 2023; 40:317. [PMID: 37792095 DOI: 10.1007/s12032-023-02177-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Accepted: 08/29/2023] [Indexed: 10/05/2023]
Abstract
Human T-cell lymphotropic virus type 1 (HTLV-1) is the first identified human retrovirus responsible for two significant diseases: HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukemia/lymphoma (ATLL). Although the majority of infected individuals remain asymptomatic carriers, a small percentage may develop ATLL or HAM/TSP. In tumorigenesis, a crucial process is angiogenesis, which involves the formation of new blood vessels. However, the precise mechanism of HTLV-1 associated angiogenesis remains unclear. This study aims to investigate the gene regulation involved in the angiogenesis signaling pathway associated with HTLV-1 infection. The research enrolled 20 male participants, including asymptomatic carriers and healthy individuals. Blood samples were collected and screened using ELISA for HTLV-1 confirmation, and PCR was performed for both Tax and HBZ for validation. RNA extraction and cDNA synthesis were carried out, followed by RT-qPCR analysis targeting cellular genes involved in angiogenesis. Our findings indicate that gene expression related to angiogenesis was elevated in HTLV-1 ACs patients. However, the differences in gene expression of the analyzed genes, including HSP27, Paxillin, PDK1, PTEN, RAF1, SOS1, and VEGFR2 between ACs and healthy individuals were not statistically significant. This suggests that although angiogenesis-related genes may show increased expression in HTLV-1 infection, they might not be robust indicators of ATLL progression in asymptomatic carriers. The results of our study demonstrate that angiogenesis gene expression is altered in ACs of HTLV-1, indicating potential involvement of angiogenesis in the early stages before ATLL development. While we observed elevated angiogenesis gene expression in ACs, the lack of statistical significance between ACs and healthy individuals suggests that these gene markers may not be sufficient on their own to predict the development of ATLL in asymptomatic carriers.
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Affiliation(s)
- Arash Letafati
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
- Research Center for Clinical Virology, Tehran University of Medical Sciences, Tehran, Iran
| | - Sayed-Hamidreza Mozhgani
- Department of Microbiology and Virology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran.
| | - Arezoo Marjani
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Abdollah Amiri
- Student Research Committee, Alborz University of Medical Sciences, Karaj, Iran
| | - Zeinab Siami
- Department of Infectious Diseases, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
| | | | - Ghazale Molaverdi
- Student Research Committee, Alborz University of Medical Sciences, Karaj, Iran
| | - Mojtaba Hedayatyaghoobi
- Department of Infectious Diseases, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran.
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Wang T, You Y, Wang ZH, Zhao JQ, Zhang YP, Yin JQ, Zhou MQ, Cui BD, Yuan WC. Copper-Catalyzed Diastereo- and Enantioselective Decarboxylative [3 + 2] Cyclization of Alkyne-Substituted Cyclic Carbamates with Azlactones: Access to γ-Butyrolactams Bearing Two Vicinal Tetrasubstituted Carbon Stereocenters. Org Lett 2023. [PMID: 36800376 DOI: 10.1021/acs.orglett.3c00075] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/18/2023]
Abstract
A copper-catalyzed diastereo- and enantioselective decarboxylative [3 + 2] cyclization reaction of alkyne-substituted cyclic carbamates with azlactones has been established. A range of optically pure γ-butyrolactams bearing two vicinal tetrasubstituted carbon stereocenters were obtained in high yields with good to excellent stereoselectivities (up to 99% yield, 99:1 dr, and 99% ee). This is the first example of asymmetric synthesis γ-butyrolactams containing sterically congested vicinal tetrasubstituted stereocenters via a decarboxylative cyclization pathway.
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Affiliation(s)
- Ting Wang
- Innovation Research Center of Chiral Drugs, Institute for Advanced Study, Chengdu University, Chengdu 610106, China.,School of Pharmacy, Zunyi Medical University, Zunyi 563006, China
| | - Yong You
- Innovation Research Center of Chiral Drugs, Institute for Advanced Study, Chengdu University, Chengdu 610106, China
| | - Zhen-Hua Wang
- Innovation Research Center of Chiral Drugs, Institute for Advanced Study, Chengdu University, Chengdu 610106, China
| | - Jian-Qiang Zhao
- Innovation Research Center of Chiral Drugs, Institute for Advanced Study, Chengdu University, Chengdu 610106, China
| | - Yan-Ping Zhang
- Innovation Research Center of Chiral Drugs, Institute for Advanced Study, Chengdu University, Chengdu 610106, China
| | - Jun-Qing Yin
- Innovation Research Center of Chiral Drugs, Institute for Advanced Study, Chengdu University, Chengdu 610106, China
| | - Ming-Qiang Zhou
- National Engineering Research Center of Chiral Drugs, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
| | - Bao-Dong Cui
- School of Pharmacy, Zunyi Medical University, Zunyi 563006, China
| | - Wei-Cheng Yuan
- Innovation Research Center of Chiral Drugs, Institute for Advanced Study, Chengdu University, Chengdu 610106, China
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Pseurotin D inhibits delayed type IV hypersensitivity response. Chem Biol Interact 2022; 368:110241. [DOI: 10.1016/j.cbi.2022.110241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Revised: 10/14/2022] [Accepted: 10/24/2022] [Indexed: 11/18/2022]
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Ali ES, Akter S, Ramproshad S, Mondal B, Riaz TA, Islam MT, Khan IN, Docea AO, Calina D, Sharifi-Rad J, Cho WC. Targeting Ras-ERK cascade by bioactive natural products for potential treatment of cancer: an updated overview. Cancer Cell Int 2022; 22:246. [PMID: 35941592 PMCID: PMC9358858 DOI: 10.1186/s12935-022-02666-z] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 07/27/2022] [Indexed: 12/11/2022] Open
Abstract
MAPK (mitogen-activated protein kinase) or ERK (extracellular-signal-regulated kinase) pathway is an important link in the transition from extracellular signals to intracellular responses. Because of genetic and epigenetic changes, signaling cascades are altered in a variety of diseases, including cancer. Extant studies on the homeostatic and pathologic behavior of MAPK signaling have been conducted; however, much remains to be explored in preclinical and clinical research in terms of regulation and action models. MAPK has implications for cancer therapy response, more specifically in response to experimental MAPK suppression, compensatory mechanisms are activated. The current study investigates MAPK as a very complex cell signaling pathway that plays roles in cancer treatment response, cellular normal conduit maintenance, and compensatory pathway activation. Most MAPK inhibitors, unfortunately, cause resistance by activating compensatory feedback loops in tumor cells and tumor microenvironment components. As a result, innovative combinatorial treatments for cancer management must be applied to limit the likelihood of alternate pathway initiation as a possibility for generating novel therapeutics based on incorporation in translational research. We summarize current knowledge about the implications of ERK (MAPK) in cancer, as well as bioactive products from plants, microbial organisms or marine organisms, as well as the correlation with their chemical structures, which modulate this pathway for the treatment of different types of cancer.
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Affiliation(s)
- Eunus S. Ali
- College of Medicine and Public Health, Flinders University, Bedford Park, 5042 Australia
| | - Shamima Akter
- Department of Bioinformatics and Computational Biology, George Mason University, Fairfax, VA 22030 USA
| | - Sarker Ramproshad
- Department of Pharmacy, Ranada Prasad Shaha University, Narayanganj, 1400 Bangladesh
| | - Banani Mondal
- Department of Pharmacy, Ranada Prasad Shaha University, Narayanganj, 1400 Bangladesh
| | - Thoufiqul Alam Riaz
- Department of Pharmacology and Institute of New Drug Development, Jeonbuk National University Medical School, Jeonju, 54907 Republic of Korea
| | - Muhammad Torequl Islam
- Department of Pharmacy, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, 8100 Bangladesh
| | - Ishaq N. Khan
- Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, 25100 Pakistan
| | - Anca Oana Docea
- Department of Toxicology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Daniela Calina
- Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | | | - William C. Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong
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Zhang R, Wang H, Chen B, Dai H, Sun J, Han J, Liu H. Discovery of Anti-MRSA Secondary Metabolites from a Marine-Derived Fungus Aspergillus fumigatus. Mar Drugs 2022; 20:302. [PMID: 35621953 PMCID: PMC9146929 DOI: 10.3390/md20050302] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 04/23/2022] [Accepted: 04/25/2022] [Indexed: 12/30/2022] Open
Abstract
Methicillin-resistant Staphylococcus aureus (MRSA), a WHO high-priority pathogen that can cause great harm to living beings, is a primary cause of death from antibiotic-resistant infections. In the present study, six new compounds, including fumindoline A-C (1-3), 12β, 13β-hydroxy-asperfumigatin (4), 2-epi-tryptoquivaline F (17) and penibenzophenone E (37), and thirty-nine known ones were isolated from the marine-derived fungus Aspergillus fumigatus H22. The structures and the absolute configurations of the new compounds were unambiguously assigned by spectroscopic data, mass spectrometry (MS), electronic circular dichroism (ECD) spectroscopic analyses, quantum NMR and ECD calculations, and chemical derivatizations. Bioactivity screening indicated that nearly half of the compounds exhibit antibacterial activity, especially compounds 8 and 11, and 33-38 showed excellent antimicrobial activities against MRSA, with minimum inhibitory concentration (MIC) values ranging from 1.25 to 2.5 μM. In addition, compound 8 showed moderate inhibitory activity against Mycobacterium bovis (MIC: 25 μM), compound 10 showed moderate inhibitory activity against Candida albicans (MIC: 50 μM), and compound 13 showed strong inhibitory activity against the hatching of a Caenorhabditis elegans egg (IC50: 2.5 μM).
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Affiliation(s)
- Rui Zhang
- Key Laboratory of Structure-Based Drug Design & Discovery of Education, College of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China; (R.Z.); (H.W.)
- State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; (B.C.); (H.D.); (J.S.)
| | - Haifeng Wang
- Key Laboratory of Structure-Based Drug Design & Discovery of Education, College of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China; (R.Z.); (H.W.)
| | - Baosong Chen
- State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; (B.C.); (H.D.); (J.S.)
| | - Huanqin Dai
- State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; (B.C.); (H.D.); (J.S.)
| | - Jingzu Sun
- State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; (B.C.); (H.D.); (J.S.)
| | - Junjie Han
- State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; (B.C.); (H.D.); (J.S.)
| | - Hongwei Liu
- Key Laboratory of Structure-Based Drug Design & Discovery of Education, College of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China; (R.Z.); (H.W.)
- State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; (B.C.); (H.D.); (J.S.)
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Dmitriev MV, Sabitov AA, Maslivets AN. Three-Component Reaction of 1H-Pyrrole-2,3-diones with Malononitrile and Phthalhydrazide. RUSSIAN JOURNAL OF ORGANIC CHEMISTRY 2022. [DOI: 10.1134/s1070428021120289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Mosejová E, Bosnjakovic R, Kubala L, Vašíček O. Pseurotin D Induces Apoptosis through Targeting Redox Sensitive Pathways in Human Lymphoid Leukemia Cells. Antioxidants (Basel) 2021; 10:antiox10101576. [PMID: 34679711 PMCID: PMC8533295 DOI: 10.3390/antiox10101576] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 09/23/2021] [Accepted: 10/01/2021] [Indexed: 01/23/2023] Open
Abstract
Chronic lymphocytic leukemia (CLL) is the most prevalent lymphoid malignancy in many geographical regions of the world. Pseurotin D, a secondary metabolite of fungi, represents a group of bioactive natural products with a newly ascribed range of interesting biological activities. The purpose of this study was to bring new insights into the mechanism behind the effects of pseurotin D on MEC-1 cells as a representative CLL cell line, with a particular focus on selected signaling pathways important in the proliferation of cells and targeting mitochondrial metabolism. Our results showed that pseurotin D was able to significantly inhibit the proliferation of MEC-1 cells and arrested them in the G2/M cell cycle phase. In addition, pseurotin D was able to induce apoptosis. We found that all of these effects were associated with a change in mitochondrial membrane potential and the production of mitochondrial reactive oxygen species (ROS). We showed for the first time that pseurotin D suppresses MEC-1 cell proliferation and induces apoptotic cell death via induction of the collapse of the mitochondria respiratory chain and the ROS-related caspase pathway. Our results show the pseurotins family as promising compounds which could serve as a basis for the development of new compounds in the treatment of lymphoma.
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Affiliation(s)
- Eva Mosejová
- Institute of Biophysics of the Czech Academy of Sciences, 612 65 Brno, Czech Republic; (E.M.); (R.B.); (L.K.)
| | - Rebeka Bosnjakovic
- Institute of Biophysics of the Czech Academy of Sciences, 612 65 Brno, Czech Republic; (E.M.); (R.B.); (L.K.)
| | - Lukáš Kubala
- Institute of Biophysics of the Czech Academy of Sciences, 612 65 Brno, Czech Republic; (E.M.); (R.B.); (L.K.)
- Institute of Experimental Biology, Faculty of Science, Masaryk University, 625 00 Brno, Czech Republic
- International Clinical Research Center, St. Anne’s University Hospital, 656 91 Brno, Czech Republic
| | - Ondřej Vašíček
- Institute of Biophysics of the Czech Academy of Sciences, 612 65 Brno, Czech Republic; (E.M.); (R.B.); (L.K.)
- Institute of Experimental Biology, Faculty of Science, Masaryk University, 625 00 Brno, Czech Republic
- Correspondence: ; Tel.: +420-541-517-207
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Pseurotin D Inhibits the Activation of Human Lymphocytes. Int J Mol Sci 2021; 22:ijms22041938. [PMID: 33669259 PMCID: PMC7920033 DOI: 10.3390/ijms22041938] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 02/05/2021] [Accepted: 02/09/2021] [Indexed: 12/11/2022] Open
Abstract
Background: Pseurotins, a family of secondary metabolites of different fungi characterized by an unusual spirocyclic furanone-lactam core, are suggested to have different biological activities including the modulation of immune response. Purpose: Complex characterization of the effects of pseurotin D on human lymphocyte activation in order to understand the potential of pseurotin to modulate immune response in humans. Methods: CD4+ and CD8+ T cells and CD19+ B cells isolated from human blood were activated by various activators simultaneously with pseurotin D treatment. The effects of pseurotin were tested on the basis of changes in cell viability, apoptosis, activation of signal transducers and activators of transcription (STAT) signaling pathways, production of tumor necrosis factor (TNF)-α by T cells, expression of activation markers CD69 and CD25 on T cells and Human Leukocyte Antigen–DR isotype (HLA-DR) on B cells, and the differentiation markers CD20, CD27, CD38, and immunoglobulin (Ig) D on B cells. Results: Pseurotin D significantly inhibited the activation of both CD4+ and CD8+ human T cells complemented by the inhibition of TNF-α production without significant acute toxic effects. The Pseurotin D-mediated inhibition of T-cell activation was accompanied by the induction of the apoptosis of T cells. This corresponded with the inhibited phosphorylation of STAT3 and STAT5. In human B cells, pseurotin D did not significantly inhibit their activation; however, it affected their differentiation. Conclusions: Our results advance the current mechanistic understanding of the pseurotin-induced inhibition of lymphocytes and suggest pseurotins as new attractive chemotypes for future research in the context of immune-modulatory drugs.
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Kobayashi K, Tanaka III K, Kogen H. Highly Oxidized γ-Lactam-Containing Natural Products: Total Synthesis and Biological Evaluation. HETEROCYCLES 2021. [DOI: 10.3987/rev-20-944] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
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Vasicek O, Rubanova D, Chytkova B, Kubala L. Natural pseurotins inhibit proliferation and inflammatory responses through the inactivation of STAT signaling pathways in macrophages. Food Chem Toxicol 2020; 141:111348. [PMID: 32376338 DOI: 10.1016/j.fct.2020.111348] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 02/29/2020] [Accepted: 04/09/2020] [Indexed: 01/13/2023]
Abstract
BACKGROUND Natural pseurotins, secondary metabolites of fungi, commonly produced by various species such as Aspergillus flavus with suggested significant biological effects. However, little is known about effects of pseurotins on immune system functions. METHODS Effects of pseurotin A and D on proliferation and viability of macrophage RAW 264.7 cells were evaluated together with mitochondrial respiration and glycolysis. Macrophage response to lipopolysaccharide was analyzed based on determination of nitric oxide (NO) production, expression of inducible NO synthase (iNOS), interleukin 6 (IL-6) and tumor necrosis factor production. Activation of selected signaling pathways, particularly STAT and MAPK, as well as expression of cyclins were determined. RESULTS Natural pseurotins A and D in concentrations of up to 50 μM significantly inhibit proliferation of RAW 264.7 macrophages which was not complemented by induction of cell toxicity. The inhibition of cell proliferation was accompanied by downregulation of expression of cyclins and mitochondrial respiration via inhibition of particularly STAT3 phosphorylation. Both pseurotins significantly inhibited production of NO, expression of iNOS and IL-6 production. CONCLUSION Our results advance the current mechanistic understanding of the pseurotin-induced inhibition of proliferation, metabolic respiration and functional responses in macrophages by linking the effect to JAK/STAT signaling pathway.
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Affiliation(s)
- Ondrej Vasicek
- Institute of Biophysics of the Czech Academy of Sciences, 612 65, Brno, Czech Republic; International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic
| | - Daniela Rubanova
- Institute of Biophysics of the Czech Academy of Sciences, 612 65, Brno, Czech Republic
| | - Barbora Chytkova
- Institute of Biophysics of the Czech Academy of Sciences, 612 65, Brno, Czech Republic
| | - Lukas Kubala
- Institute of Biophysics of the Czech Academy of Sciences, 612 65, Brno, Czech Republic; International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.
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Heravi MM, Janati F, Zadsirjan V. Applications of Knoevenagel condensation reaction in the total synthesis of natural products. MONATSHEFTE FUR CHEMIE 2020. [DOI: 10.1007/s00706-020-02586-6] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Vašíček O, Fedr R, Skoroplyas S, Chalupa D, Sklenář M, Tharra PR, Švenda J, Kubala L. Natural pseurotins and analogs thereof inhibit activation of B-cells and differentiation into the plasma cells. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2020; 69:153194. [PMID: 32146299 DOI: 10.1016/j.phymed.2020.153194] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 01/29/2020] [Accepted: 02/21/2020] [Indexed: 06/10/2023]
Abstract
BACKGROUND The frequency of allergic diseases is constantly rising. Dysregulated production of isotype E immunoglobulins is one of the key factors behind allergic reactions and its modulation is therefore an important target for pharmacological intervention. Natural products of the pseurotin family were reported to be inhibitors of IgE production in B-cells. Mechanistic details underlying these effects are however not well understood. PURPOSE In the present study, we synthesized new analogs of natural pseurotins and extensively investigated their inhibitory effects on activation, proliferation and differentiation of B-cells, as well as on the production of IgE. STUDY DESIGN Effects of two natural pseurotins (pseurotins A and D) and a collection of fully synthetic pseurotin analogs were studied on mouse B-cells stimulated by the combination of IL-4 and E. coli lipopolysaccharide. The IgE production was determined along with cell viability and cell proliferation. The phosphorylation of selected members of the STAT transcription factor family was subsequently investigated. Finally, the in vivo effect of pseurotin D on the ovalbumin-induced delayed type hypersensitivity response was tested in mice. RESULTS We discovered that several fully synthetic pseurotin analogs were able to decrease the production of IgE in stimulated B-cells with potency comparable to that of pseurotins A and D. We found that the two natural pseurotins and the active synthetic analogs inhibited the phosphorylation of STAT3, STAT5 and STAT6 proteins in stimulated B-cells, resulting in the inhibition of B-cell proliferation and differentiation into the plasma cells. In vivo, pseurotin D decreased ovalbumin-induced foot pad edema. CONCLUSION Our results advance the current mechanistic understanding of the pseurotin-induced inhibition of IgE production in B-cells by linking the effect to STAT signaling, and associated modulation of B-cell proliferation and differentiation. Together with our finding that structurally simpler pseurotin analogs were able to reproduce the effects of natural pseurotins, the presented work has implications for the future research on these secondary metabolites in the context of allergic diseases.
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Affiliation(s)
- Ondřej Vašíček
- Institute of Biophysics of the Czech Academy of Sciences, Brno 612 65, Czech Republic; International Clinical Research Center, St. Anne's University Hospital, Brno 656 91, Czech Republic
| | - Radek Fedr
- Institute of Biophysics of the Czech Academy of Sciences, Brno 612 65, Czech Republic; International Clinical Research Center, St. Anne's University Hospital, Brno 656 91, Czech Republic
| | - Svitlana Skoroplyas
- Institute of Biophysics of the Czech Academy of Sciences, Brno 612 65, Czech Republic; Institute of Experimental Biology, Faculty of Science, Masaryk University, Brno 625 00, Czech Republic
| | - David Chalupa
- Department of Chemistry, Faculty of Science, Masaryk University, Brno 625 00, Czech Republic
| | - Matěj Sklenář
- Department of Chemistry, Faculty of Science, Masaryk University, Brno 625 00, Czech Republic
| | - Prabhakara Rao Tharra
- Department of Chemistry, Faculty of Science, Masaryk University, Brno 625 00, Czech Republic
| | - Jakub Švenda
- International Clinical Research Center, St. Anne's University Hospital, Brno 656 91, Czech Republic; Department of Chemistry, Faculty of Science, Masaryk University, Brno 625 00, Czech Republic.
| | - Lukáš Kubala
- Institute of Biophysics of the Czech Academy of Sciences, Brno 612 65, Czech Republic; International Clinical Research Center, St. Anne's University Hospital, Brno 656 91, Czech Republic; Institute of Experimental Biology, Faculty of Science, Masaryk University, Brno 625 00, Czech Republic.
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Moroz AA, Zhulanov VE, Dmitriev MV, Maslivets AN. Diversity-oriented synthesis of three skeletally diverse iminolactones from isocyanides, activated acetylenes and 1H-pyrrole-2,3-diones via [3+2] and [4+1] cycloaddition reactions. Tetrahedron 2020. [DOI: 10.1016/j.tet.2019.130880] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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Abstract
We completed a nine-step total synthesis of (-)-FD-838 and (-)-cephalimysin A. Our synthesis features a biogenetically guided assembly of the highly oxidized spirocyclic core by Snider-type tandem epoxidations of the chiral substrate derived from an amino acid derivative. Our synthetic approach provides a general and versatile solution to access spirocyclic PKS-NRPS-based secondary fungal metabolites.
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Affiliation(s)
- Deokhee Jo
- Department of Chemistry , Korea Advanced Institute of Science and Technology (KAIST) , Daejeon 34141 , Korea
| | - Sunkyu Han
- Department of Chemistry , Korea Advanced Institute of Science and Technology (KAIST) , Daejeon 34141 , Korea.,Center for Catalytic Hydrocarbon Functionalizations , Institute for Basic Science (IBS) , Daejeon 34141 , Korea
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17
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Hirasawa S, Mukai K, Sakai S, Wakamori S, Hasegawa T, Souma K, Kanomata N, Ogawa N, Aizawa M, Emoto M. Elucidation of Racemization Process of Azaspirene Skeleton in Neutral Aqueous Media. J Org Chem 2018; 83:14457-14464. [DOI: 10.1021/acs.joc.8b02223] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Affiliation(s)
- Shun Hirasawa
- Department of Chemistry and Biochemistry, Waseda University, 3-4-1, Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
| | - Ken Mukai
- Department of Chemistry and Biochemistry, Waseda University, 3-4-1, Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
| | - Shinnosuke Sakai
- Department of Chemistry and Biochemistry, Waseda University, 3-4-1, Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
| | - Shinnosuke Wakamori
- Department of Chemistry and Biochemistry, Waseda University, 3-4-1, Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
| | - Takahiro Hasegawa
- Department of Chemistry and Biochemistry, Waseda University, 3-4-1, Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
| | - Kazunori Souma
- Department of Applied Chemistry, Meiji University, 1-1-1 Higashimita, Tama-ku, Kawasaki 214-8571, Japan
| | - Nobuhiro Kanomata
- Department of Chemistry and Biochemistry, Waseda University, 3-4-1, Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
- Department of Applied Chemistry, Meiji University, 1-1-1 Higashimita, Tama-ku, Kawasaki 214-8571, Japan
| | - Narihito Ogawa
- Department of Chemistry and Biochemistry, Waseda University, 3-4-1, Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
- Department of Applied Chemistry, Meiji University, 1-1-1 Higashimita, Tama-ku, Kawasaki 214-8571, Japan
| | - Mamoru Aizawa
- Department of Applied Chemistry, Meiji University, 1-1-1 Higashimita, Tama-ku, Kawasaki 214-8571, Japan
| | - Makoto Emoto
- Clinical Research Center and Division of Preventive Medicine, Fukuoka Sanno Hospital, International University of Health and Welfare, 3-6-45 Momochihama, Sawara-ku, Fukuoka 814-0001, Japan
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Jo D, Han S. Total syntheses of spirocyclic PKS-NRPS-based fungal metabolites. Chem Commun (Camb) 2018; 54:6750-6758. [PMID: 29873347 DOI: 10.1039/c8cc02315h] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Since the first isolation of pseurotin A in 1976, over twenty five spirocyclic PKS-NRPS-based (polyketide synthase-nonribosomal peptide synthetase-based) fungal natural products have been discovered to date. The common 1-oxa-7-azaspiro[4.4]non-2-ene-4,6-dione core of this family of natural products has served as a platform for the development of novel chemistry and resulted in the development of numerous new reactivities and synthetic strategies. Herein, we delineate all reported syntheses of spirocyclic PKS-NRPS-based fungal metabolites including our own recent contributions on this subject. We showcase how a biosynthetic consideration could lead to concise synthetic routes to this family of natural products.
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Affiliation(s)
- Deokhee Jo
- Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea.
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19
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Affiliation(s)
- Taeho Kang
- Department
of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea
| | - Deokhee Jo
- Department
of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea
- Center
for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, Korea
| | - Sunkyu Han
- Department
of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea
- Center
for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, Korea
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Chalupa D, Vojáčková P, Partl J, Pavlović D, Nečas M, Švenda J. Enantioselective Synthesis of Cephalimysins B and C. Org Lett 2017; 19:750-753. [DOI: 10.1021/acs.orglett.6b03373] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Affiliation(s)
- David Chalupa
- Department
of Chemistry, Masaryk University, Brno, 625 00, Czech Republic
| | - Petra Vojáčková
- Department
of Chemistry, Masaryk University, Brno, 625 00, Czech Republic
| | - Jiří Partl
- Department
of Chemistry, Masaryk University, Brno, 625 00, Czech Republic
| | - Dražen Pavlović
- Department
of Chemistry, Masaryk University, Brno, 625 00, Czech Republic
- International
Clinical Research Center, St. Anne’s University Hospital, Brno, 656 91, Czech Republic
| | - Marek Nečas
- Department
of Chemistry, Masaryk University, Brno, 625 00, Czech Republic
| | - Jakub Švenda
- Department
of Chemistry, Masaryk University, Brno, 625 00, Czech Republic
- International
Clinical Research Center, St. Anne’s University Hospital, Brno, 656 91, Czech Republic
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Abstract
We describe the total synthesis of (±)-berkeleyamide D using a strategy stemmed from biosynthetic considerations of γ-hydroxy/methoxy-γ-lactam-based fungal metabolites.
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Affiliation(s)
- Deokhee Jo
- Department of Chemistry
- Korea Advanced Institute of Science and Technology (KAIST)
- Daejeon 34141
- Republic of Korea
- Center for Catalytic Hydrocarbon Functionalizations
| | - Sunkyu Han
- Department of Chemistry
- Korea Advanced Institute of Science and Technology (KAIST)
- Daejeon 34141
- Republic of Korea
- Center for Catalytic Hydrocarbon Functionalizations
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RQN-18690A (18-deoxyherboxidiene) targets SF3b, a spliceosome component, and inhibits angiogenesis. J Antibiot (Tokyo) 2015; 69:121-3. [PMID: 26350783 DOI: 10.1038/ja.2015.94] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Revised: 08/11/2015] [Accepted: 08/20/2015] [Indexed: 01/05/2023]
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Ding Q, Tian XG, Li Y, Wang QZ, Zhang CQ. Carvedilol may attenuate liver cirrhosis by inhibiting angiogenesis through the VEGF-Src-ERK signaling pathway. World J Gastroenterol 2015; 21:9566-76. [PMID: 26327764 PMCID: PMC4548117 DOI: 10.3748/wjg.v21.i32.9566] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Revised: 05/15/2015] [Accepted: 07/08/2015] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the effect of carvedilol on angiogenesis and the underlying signaling pathways. METHODS The effect of carvedilol on angiogenesis was examined using a human umbilical vascular endothelial cell (HUVEC) model. The effect of carvedilol on cell viability was measured by CCK8 assay. Flow cytometry was used to assess the effect of carvedilol on cell cycle progression. Cell migration, transwell migration and tube formation assays were performed to analyze the effect of carvedilol on HUVEC function. Vascular endothelial growth factor (VEGF) induced activation of HUVECs, which were pretreated with different carvedilol concentrations or none. Western blot analysis detected the phosphorylation levels of three cell signaling pathway proteins, VEGFR-2, Src, and extracellular signal-regulated kinase (ERK). The specific Src inhibitor PP2 was used to assess the role of Src in the VEGF-induced angiogenic pathway. RESULTS Carvedilol inhibited HUVEC proliferation in a dose-dependent manner (IC50 = 38.5 mmol/L). The distribution of cells in the S phase decreased from 43.6% to 37.2%, 35.6% and 17.8% by 1, 5 and 10 μmol/L carvedilol for 24 h, respectively. Carvedilol (10 μmol/L) reduced VEGF-induced HUVEC migration from 67.54 ± 7.83 to 37.11 ± 3.533 (P < 0.001). Carvedilol concentrations of 5 μmol/L and 10 μmol/L reduced cell invasion from 196.3% ± 18.76% to 114.0% ± 12.20% and 51.68% ± 8.28%, respectively. VEGF-induced tube formation was also reduced significantly by 5 μmol/L and 10 μmol/L carvedilol from 286.0 ± 36.72 to 135.7 ± 18.13 (P < 0.05) and 80.27 ± 11.16 (P < 0.01) respectively. We investigated several intracellular protein levels to determine the reason for these reductions. Treatment with 10 μmol/L carvedilol reduced VEGF-induced tyrosine phosphorylation of VEGFR-2 from 175.5% ± 8.54% to 52.67% ± 5.33% (P < 0.01). Additionally, 10 μmol/L carvedilol reduced VEGF-induced ERK 1/2 phosphorylation from 181.9% ± 18.61% to 56.45% ± 7.64% (P < 0.01). The VEGF-induced increase in Src kinase activity was alleviated by carvedilol [decreased from 141.8% ± 15.37% to 53.57 ± 7.18% (P < 0.01) and 47.04% ± 9.74% (P < 0.01) at concentrations of 5 and 10 μmol/L, respectively]. Pretreatment of HUVECs with Src kinase inhibitor almost completely prevented the VEGF-induced ERK upregulation [decreased from 213.2% ± 27.68% to 90.96% ± 17.16% (P < 0.01)]. CONCLUSION Carvedilol has an anti-angiogenic effect on HUVECs. This inhibitory effect is mediated by VEGF-induced Src-ERK signaling pathways.
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Kim NH, Jung HI, Choi WS, Son BW, Seo YB, Choi JS, Kim GD. Toluhydroquinone, the secondary metabolite of marine algae symbiotic microorganism, inhibits angiogenesis in HUVECs. Biomed Pharmacother 2015; 70:129-39. [DOI: 10.1016/j.biopha.2015.01.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Accepted: 01/04/2015] [Indexed: 01/08/2023] Open
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Andrographolide inhibits tumor angiogenesis via blocking VEGFA/VEGFR2-MAPKs signaling cascade. Chem Biol Interact 2014; 218:99-106. [DOI: 10.1016/j.cbi.2014.04.020] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2013] [Revised: 03/12/2014] [Accepted: 04/28/2014] [Indexed: 01/11/2023]
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26
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Mo X, Li Q, Ju J. Naturally occurring tetramic acid products: isolation, structure elucidation and biological activity. RSC Adv 2014. [DOI: 10.1039/c4ra09047k] [Citation(s) in RCA: 114] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Natural products containing the tetramic acid core scaffold have been isolated from an assortment of terrestrial and marine species and often display wide ranging and potent biological activities including antibacterial, antiviral and antitumoral activities.
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Affiliation(s)
- Xuhua Mo
- Shandong Key Laboratory of Applied Mycology
- School of Life Sciences
- Qingdao Agricultural University
- Qingdao, China
- CAS Key Laboratory of Tropical Marine Bio-resources and Ecology
| | - Qinglian Li
- CAS Key Laboratory of Tropical Marine Bio-resources and Ecology
- Guangdong Key Laboratory of Marine Materia Medica
- RNAM Center for Marine Microbiology
- South China Sea Institute of Oceanology
- Chinese Academy of Sciences
| | - Jianhua Ju
- CAS Key Laboratory of Tropical Marine Bio-resources and Ecology
- Guangdong Key Laboratory of Marine Materia Medica
- RNAM Center for Marine Microbiology
- South China Sea Institute of Oceanology
- Chinese Academy of Sciences
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Violaceols function as actin inhibitors inducing cell shape elongation in fibroblast cells. Biosci Biotechnol Biochem 2012; 76:1431-7. [PMID: 22878183 DOI: 10.1271/bbb.120074] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Violaceol-I and -II were isolated from a fractionated library of marine-derived fungal metabolites. These compounds increased the calcium ion concentration inside the cell and caused F-actin aggregation in rat fibroblast 3Y1 cells within 3 h resulting in cell shape elongation. Calcium chelator BAPTA-AM (1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis (acetoxymethyl ester) inhibited violaceol-I and -II induced F-actin aggregation in 3Y1 cells, and hence violaceol-I and -II act in a calcium dependent manner. Violaceol-I and -II inhibited G-actin polymerization in vitro in a dose-dependent manner and strongly associated with G-actin, at dissociation equilibrium constants of 1.44 × 10(-8) M and 2.52 × 10(-9) M respectively. Here we report the identification of a novel function of violaceol-I and -II as actin inhibitors. Violaceol-I and -II induced cell shape elongation through F-actin aggregation in 3Y1 fibroblasts. These compounds may give researchers new insights into the role of actin in tumorigenesis and lead to the development of additional anti-tumor drugs.
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Asami Y, Jang JH, Soung NK, He L, Moon DO, Kim JW, Oh H, Muroi M, Osada H, Kim BY, Ahn JS. Protuboxepin A, a marine fungal metabolite, inducing metaphase arrest and chromosomal misalignment in tumor cells. Bioorg Med Chem 2012; 20:3799-806. [DOI: 10.1016/j.bmc.2012.04.039] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2012] [Revised: 04/19/2012] [Accepted: 04/19/2012] [Indexed: 11/30/2022]
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The Chick Embryo Chorioallantoic Membrane as an In Vivo Assay to Study Antiangiogenesis. Pharmaceuticals (Basel) 2010; 3:482-513. [PMID: 27713265 PMCID: PMC4033966 DOI: 10.3390/ph3030482] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2010] [Revised: 01/29/2010] [Accepted: 03/02/2010] [Indexed: 12/15/2022] Open
Abstract
Antiangiogenesis, e.g., inhibition of blood vessel growth, is being investigated as a way to prevent the growth of tumors and other angiogenesis-dependent diseases. Pharmacological inhibition interferes with the angiogenic cascade or the immature neovasculature with synthetic or semi-synthetic substances, endogenous inhibitors or biological antagonists.The chick embryo chorioallantoic membrane (CAM) is an extraembryonic membrane, which serves as a gas exchange surface and its function is supported by a dense capillary network. Because its extensive vascularization and easy accessibility, CAM has been used to study morphofunctional aspects of the angiogenesis process in vivo and to study the efficacy and mechanism of action of pro- and anti-angiogenic molecules. The fields of application of CAM in the study of antiangiogenesis, including our personal experience, are illustrated in this review article.
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Kakeya H, Nishimura S. Novel Natural Products Open the Door of Chemical Biology and Medicinal Chemistry. J SYN ORG CHEM JPN 2010. [DOI: 10.5059/yukigoseikyokaishi.68.490] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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Total synthesis and determination of the absolute configuration of FD-838, a naturally occurring azaspirobicyclic product. Bioorg Med Chem Lett 2009; 19:3863-5. [DOI: 10.1016/j.bmcl.2009.03.154] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2009] [Revised: 03/27/2009] [Accepted: 03/30/2009] [Indexed: 11/24/2022]
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Nay B, Riache N, Evanno L. Chemistry and biology of non-tetramic gamma-hydroxy-gamma-lactams and gamma-alkylidene-gamma-lactams from natural sources. Nat Prod Rep 2009; 26:1044-62. [PMID: 19636449 DOI: 10.1039/b903905h] [Citation(s) in RCA: 100] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Natural products containing non-tetramic gamma-hydroxy-gamma-lactams and gamma-alkylidene-gamma-lactams are usually but not exclusively derived from the mixed polyketide-non-ribosomal peptide biosynthetic pathway. Often they are fungal metabolites, although some plant- and marine-derived exceptions exist. Owing to their unique structures and biological properties, they have gained interest in the chemical and biological communities. In this review, we aim to emphasize the structural originality of these compounds, their biological properties and the synthetic efforts developed to reach them; 157 references are cited.
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Affiliation(s)
- Bastien Nay
- Unité Molécules de Communication et Adaptation de Micro-organismes, Muséum National d'Histoire Naturelle-CNRS (FRE 3206), 57 rue Cuvier (CP 54), 75005 Paris, France.
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