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Wei X, Wang M, Dong X, He Y, Nan W, Ji S, Zhao M, Chang H, Wei H, Ding D, Chen H. Internal-External Homologous Drug-Loaded Exosome-Like Nanovesicles Released from Semi-IPN Hydrogel Enhancing Wound Healing of Chemoradiotherapy-Induced Oral Mucositis. Int J Nanomedicine 2025; 20:4105-4121. [PMID: 40201151 PMCID: PMC11977572 DOI: 10.2147/ijn.s508530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Accepted: 03/21/2025] [Indexed: 04/10/2025] Open
Abstract
Background Oral mucositis (OM) is a common acute side effect among patients undergoing chemotherapy and/or radiotherapy, with complex pathogenesis and limited current treatment efficacy. Rabdosia rubescens, a traditional Chinese herb, contains oridonin (ORI) with antibacterial and anti - inflammatory properties. However, ORI's poor solubility and low bioavailability hamper its clinical use. Medicinal plant - derived exosome - like nanovesicles (ENs) are emerging as a promising drug delivery system for wound repair. This study aimed to develop a novel therapeutic approach. Methods We fabricated internally-externally homologous drug-loaded exosome-like nanovesicles (ORI/ENs) derived from Rabdosia rubescens and encapsulated them in a semi-interpenetrating network hydrogel system (ORI/ENs/Gel) to repair chemoradiotherapy-induced OM. The morphology, biocompatibility, and antibacterial properties were evaluated. Moreover, the proliferative and migratory capacity were measured using L929 cells. In addition, the pro-healing effects and the underlying molecular mechanisms of ORI/ENs/Gel were assessed in vivo. Results ENs were extracted and purified from Rabdosia rubescens by sequential ultra-centrifugations. The encapsulation efficiency (EE) and loading capacity (LC) of ORI in ORI/ENs were 76.4 ± 3.2% and 9.21 ± 0.45%, respectively, suggesting that ENs had a high loading efficiency for homologous drug ORI. The evaluation of toxicity and antibacterial effects has been proven that ORI/ENs has biocompatibility and antibacterial properties. In vivo, ORI/ENs/Gel promoted collagen deposition, targeted NLRP3 to reduce inflammation, and accelerated OM wound healing. Conclusion The hydrogel composite incorporating internally-externally homologous drug-loaded ENs offers the potential to provide targeted therapy, improve bioavailability, and promote efficient healing of the OM.
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Affiliation(s)
- Xiangjuan Wei
- Clinical Medical Center of Tissue Engineering and Regeneration, The Third Affiliated Hospital, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, Henan, People’s Republic of China
| | - Mengyuan Wang
- Clinical Medical Center of Tissue Engineering and Regeneration, The Third Affiliated Hospital, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, Henan, People’s Republic of China
| | - Xiaocong Dong
- Clinical Medical Center of Tissue Engineering and Regeneration, The Third Affiliated Hospital, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, Henan, People’s Republic of China
| | - Yichen He
- Clinical Medical Center of Tissue Engineering and Regeneration, The Third Affiliated Hospital, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, Henan, People’s Republic of China
| | - Wenbin Nan
- Clinical Medical Center of Tissue Engineering and Regeneration, The Third Affiliated Hospital, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, Henan, People’s Republic of China
| | - Shenglu Ji
- Clinical Medical Center of Tissue Engineering and Regeneration, The Third Affiliated Hospital, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, Henan, People’s Republic of China
| | - Mengyuan Zhao
- Clinical Medical Center of Tissue Engineering and Regeneration, The Third Affiliated Hospital, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, Henan, People’s Republic of China
| | - Haodang Chang
- Clinical Medical Center of Tissue Engineering and Regeneration, The Third Affiliated Hospital, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, Henan, People’s Republic of China
| | - Hongliang Wei
- School of Chemistry and Chemical Engineering, Henan University of Technology, Zhengzhou, Henan, People’s Republic of China
| | - Dan Ding
- Key Laboratory of Bioactive Materials for the Ministry of Education, College of Life Sciences, Nankai University, Tianjin, People’s Republic of China
| | - Hongli Chen
- Clinical Medical Center of Tissue Engineering and Regeneration, The Third Affiliated Hospital, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, Henan, People’s Republic of China
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Kaur G, Tiwari P, Singla S, Panghal A, Jena G. The intervention of NLRP3 inflammasome inhibitor: oridonin against azoxymethane and dextran sulfate sodium-induced colitis-associated colorectal cancer in male BALB/c mice. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-03871-z. [PMID: 40035821 DOI: 10.1007/s00210-025-03871-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 01/31/2025] [Indexed: 03/06/2025]
Abstract
Colorectal cancer (CRC) ranks third globally in cancer diagnoses. The dysregulation of the NLRP3 inflammasome is prominently linked to several types of cancers. Oridonin, a principal component of Rabdosia rubescens, exhibits inhibitory activity against NLRP3 and is well-recognized for its diverse pharmacological benefits. However, its role in an animal model of colitis-associated colorectal cancer (CACC) remains unexplored. In the present study, the effectiveness of oridonin was investigated against CACC, developed using azoxymethane (AOM), a tumour initiator, and dextran sulphate sodium (DSS), a tumour promoter, in male BALB/c mice. The two-stage murine model of inflammation-associated cancer was established by administering AOM (10 mg/kg b.w.; i.p., once) followed by DSS (2% w/v) in drinking water (3 cycles, 7 days/cycle). Over a span of 10 weeks, the dose-dependent (2.5, 5, and 10 mg/kg, b.w.; i.p.) effects of oridonin were investigated in BALB/c mice. Oridonin significantly alleviated CACC severity, as evidenced by reduced DAI scores and restored body weight. Moreover, it attenuated surrogate markers of inflammation, including myeloperoxidase, nitrite, plasma LPS, TNF-α, IL-1β, and DNA damage. Histopathological examination revealed diminished tumorigenesis and apoptotic cells, corroborated by reduced Ki-67 and TNF-α, along with increased p53 expression in the colon. Following oridonin treatment, IHC/immunofluorescence analyses demonstrated a significantly reduced expression of the components of NLRP3 inflammasome including NLRP3, ASC-1, and caspase-1. Notably, the high dose of oridonin (10 mg/kg) consistently exhibited significant protective effects against CACC by modulating various molecular targets. Present findings confirmed the potential of oridonin in the protection of colitis-associated colorectal cancer, providing valuable insights into its mechanism of action and clinical significance.
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Affiliation(s)
- Gurpreet Kaur
- Facility of Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Punjab, 160062, India
| | - Priyanka Tiwari
- Facility of Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Punjab, 160062, India
| | - Shivani Singla
- Facility of Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Punjab, 160062, India
| | - Archna Panghal
- Facility of Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Punjab, 160062, India
| | - Gopabandhu Jena
- Facility of Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Punjab, 160062, India.
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Zhao CL, Zhang CY, Yang XM, Lam KH, Xia YX, Du YX, Pan LT, Zhang HJ. Design and synthesis of oridonin derivatives as cytotoxic agents. Nat Prod Res 2025; 39:550-558. [PMID: 37902442 DOI: 10.1080/14786419.2023.2275287] [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: 07/30/2023] [Revised: 09/26/2023] [Accepted: 10/16/2023] [Indexed: 10/31/2023]
Abstract
Oridonin is one of the ent-kaurane diterpenes that have been studied extensively for various bioactivities. In an effort to expand natural scaffold-based library as anticancer agents, we have designed and synthesised a number of novel oridonin derivatives and evaluated their bioactivities on a panel of human cancer cell lines (HCT116, A375, MCF-7, HepG2, and A549). Compound 4b bearing a 4-fluorophenyl moiety was found to be the most active compound with an IC50 value of 0.3 μM against MCF-7 cells, which was 7.4-fold more active than oridonin. This study could provide some insightful information for further synthesis of oridonin derivatives as anticancer agents.
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Affiliation(s)
- Chen-Liang Zhao
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, P. R. China
- Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, P. R. China
| | - Chi-Yuan Zhang
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, P. R. China
| | - Xiao-Min Yang
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, P. R. China
| | - Ka Hei Lam
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, P. R. China
| | - Yi-Xuan Xia
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, P. R. China
| | - Yin-Xiao Du
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, P. R. China
| | - Lu-Tai Pan
- Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, P. R. China
| | - Hong-Jie Zhang
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, P. R. China
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Liu J, Xu S, Li F, Zhang L, Gan Z, Chen J, Luo W, Wang S, Wang J. Genome assembly and multi-omics analyses of Isodon lophanthodies provide insights into the distribution of medicinal metabolites induced by exogenous methyl jasmonate. BMC PLANT BIOLOGY 2024; 24:1270. [PMID: 39731024 DOI: 10.1186/s12870-024-05979-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Accepted: 12/16/2024] [Indexed: 12/29/2024]
Abstract
BACKGROUND Isodon lophanthodies is a perennial herb and the whole plant has medicinal value distributed in southern China and southeast Asia. The absence of a reference genome has hindered evolution and genomic breeding research of this species. RESULTS In this study, we present a high-quality, chromosome-level genome assembly of I. lophanthodies with integrating PacBio and Hi-C sequencing data. We assembled a genome of 412.78 Mb with a scaffold N50 of ~ 33.43 Mb, organized into 12 pseudochromosomes. This assembly includes 36,324 genes and 209.51 Mb of repetitive sequences. Phylogenetic analysis revealed that I. lophanthodies and its sister species Isodon rubescens diverged approximately 9.99 million years ago (MYA), and shared a recent whole-genome duplication (WGD) event. Combined with the gene expression profile and metabolite fluctuation in response to methyl jasmonate, two key enzymes involved in salicin synthesis pathway were further identified. CONCLUSIONS This genome assembly provides an essential reference for future research on I. lophanthodies, and enhances our understanding of salicin synthesis and medicinal metabolite profiles in response to exogenous methyl jasmonate.
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Affiliation(s)
- Jieying Liu
- Guangdong Provincial Key Laboratory of Crops Genetics and Improvement, Crop Research Institute, Guangdong Academy of Agriculture Sciences, Guangzhou, 510640, China
- Guangdong Provincial Key Laboratory of Plant Molecular Breeding, State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, South China Agricultural University, Guangzhou, 510642, China
- Guangdong Provincial Engineering and Technology Research Center for Conservation and Utilization of the Genuine Southern Medicinal Resources, Guangzhou, 510640, China
| | - Shiqiang Xu
- Guangdong Provincial Key Laboratory of Crops Genetics and Improvement, Crop Research Institute, Guangdong Academy of Agriculture Sciences, Guangzhou, 510640, China
| | - Fangping Li
- Guangdong Provincial Key Laboratory of Crops Genetics and Improvement, Crop Research Institute, Guangdong Academy of Agriculture Sciences, Guangzhou, 510640, China
- Guangdong Provincial Key Laboratory of Plant Molecular Breeding, State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, South China Agricultural University, Guangzhou, 510642, China
| | - Long Zhang
- Guangdong Provincial Key Laboratory of Crops Genetics and Improvement, Crop Research Institute, Guangdong Academy of Agriculture Sciences, Guangzhou, 510640, China
| | - Zhenpeng Gan
- Guangdong Provincial Key Laboratory of Plant Molecular Breeding, State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, South China Agricultural University, Guangzhou, 510642, China
| | - Jiaxuan Chen
- Guangdong Provincial Key Laboratory of Plant Molecular Breeding, State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, South China Agricultural University, Guangzhou, 510642, China
| | - Wei Luo
- Guangdong Provincial Key Laboratory of Crops Genetics and Improvement, Crop Research Institute, Guangdong Academy of Agriculture Sciences, Guangzhou, 510640, China
| | - Shaokui Wang
- Guangdong Provincial Key Laboratory of Plant Molecular Breeding, State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, South China Agricultural University, Guangzhou, 510642, China
| | - Jihua Wang
- Guangdong Provincial Key Laboratory of Crops Genetics and Improvement, Crop Research Institute, Guangdong Academy of Agriculture Sciences, Guangzhou, 510640, China.
- Guangdong Provincial Engineering and Technology Research Center for Conservation and Utilization of the Genuine Southern Medicinal Resources, Guangzhou, 510640, China.
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Chen HT, Yuan XY, Wang ZY, Fan D, Luo XM, Yang JH, Ma YX, Liu J, Wang X, Wang ZM. Induction of apoptosis by oridonin in nonfunctioning pituitary adenoma cells. Drug Dev Res 2024; 85:e22251. [PMID: 39188035 DOI: 10.1002/ddr.22251] [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: 05/27/2024] [Revised: 08/01/2024] [Accepted: 08/09/2024] [Indexed: 08/28/2024]
Abstract
Nonfunctioning pituitary adenoma (NFPA) is one of the major subtypes of pituitary adenomas (PA) and its primary treatment is surgical resection. However, normal surgery fails to remove lesions completely and there remains in lack of frontline treatment, so the development of new drugs for NFPA is no doubt urgent. Oridonin (ORI) has been reported to have antitumor effects on a variety of tumors, but whether it could exhibit the same effect on NFPA requires to be further investigated. The effects of ORI on pituitary-derived folliculostellate cell line (PDFS) cell viability, colony formation, proliferation ability, migration, and invasion were examined by Cell Counting Kit-8, colony formation assay, 5‑Ethynyl‑2'‑deoxyuridine proliferation assay, wound-healing assay, and Transwell assay. The differentially expressed genes in the control and ORI-treated groups were screened by transcriptome sequencing analysis and analyzed by Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment. Cell cycle analysis was performed to detect changes in cell cycle. Annexin V-fluorescein isothiocyanate/propidium iodide staining was performed to detect apoptosis in ORI-treated cells. Western blot assay was performed to detect Bax, Bcl-2, and cleaved Caspase-3 protein expression. ORI inhibited PDFS cell viability and significantly suppressed cell proliferation, migration, and invasion. GO and KEGG results showed that ORI was associated with signaling pathways such as cell cycle and apoptosis in PDFS cells. In addition, ORI blocked cells in G2/M phase and induced apoptosis in PDFS cells. ORI can trigger cell cycle disruption and apoptosis collaboratively in PDFS cells, making it a promising and effective agent for NFPA therapy.
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Affiliation(s)
- Hui-Tong Chen
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, China
| | - Xing-Yi Yuan
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, China
| | - Zhong-Yu Wang
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, China
| | - Dong Fan
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, China
| | - Xiong-Ming Luo
- Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances, School of LifeSciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
- Department of Marine Pharmacy, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Jun-Hua Yang
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yu-Xin Ma
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, China
| | - Jing Liu
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, China
| | - Xin Wang
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, China
| | - Zong-Ming Wang
- Pituitary Tumor Center, Department of Neurosurgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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Ali MA, Khan N, Ali A, Akram H, Zafar N, Imran K, Khan T, Khan K, Armaghan M, Palma‐Morales M, Rodríguez‐Pérez C, Caunii A, Butnariu M, Habtemariam S, Sharifi‐Rad J. Oridonin from Rabdosia rubescens: An emerging potential in cancer therapy - A comprehensive review. Food Sci Nutr 2024; 12:3046-3067. [PMID: 38726411 PMCID: PMC11077219 DOI: 10.1002/fsn3.3986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 01/11/2024] [Accepted: 01/15/2024] [Indexed: 05/12/2024] Open
Abstract
Cancer incidences are rising each year. In 2020, approximately 20 million new cancer cases and 10 million cancer-related deaths were recorded. The World Health Organization (WHO) predicts that by 2024 the incidence of cancer will increase to 30.2 million individuals annually. Considering the invasive characteristics of its diagnostic procedures and therapeutic methods side effects, scientists are searching for different solutions, including using plant-derived bioactive compounds, that could reduce the probability of cancer occurrence and make its treatment more comfortable. In this regard, oridonin (ORI), an ent-kaurane diterpenoid, naturally found in the leaves of Rabdosia rubescens species, has been found to have antitumor, antiangiogenesis, antiasthmatic, antiinflammatory, and apoptosis induction properties. Extensive research has been performed on ORI to find various mechanisms involved in its anticancer activities. This review article provides an overview of ORI's effectiveness on murine and human cancer populations from 1976 to 2022 and provides insight into the future application of ORI in different cancer therapies.
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Affiliation(s)
| | - Noohela Khan
- Department of Nutrition SciencesRashid Latif Medical CollegeLahorePakistan
| | - Ahmad Ali
- Department of Food Science and Human NutritionUVASLahorePakistan
| | - Hira Akram
- Department of Food Science and Human NutritionUVASLahorePakistan
| | - Noushaba Zafar
- Department of Food Science and Human NutritionUVASLahorePakistan
| | - Kinza Imran
- Department of Food Science and Human NutritionUVASLahorePakistan
| | - Tooba Khan
- Department of Healthcare Biotechnology, Atta‐ur‐Rahman School of Applied BiosciencesNational University of Sciences and TechnologyIslamabadPakistan
| | | | - Muhammad Armaghan
- Department of Healthcare Biotechnology, Atta‐ur‐Rahman School of Applied BiosciencesNational University of Sciences and TechnologyIslamabadPakistan
| | - Marta Palma‐Morales
- Departamento de Nutrición y Bromatología, Facultad de FarmaciaUniversidad de GranadaGranadaSpain
- Instituto de Nutrición y Tecnología de los Alimentos ‘José Mataix’Universidad de GranadaGranadaSpain
| | - Celia Rodríguez‐Pérez
- Departamento de Nutrición y Bromatología, Facultad de FarmaciaUniversidad de GranadaGranadaSpain
- Instituto de Nutrición y Tecnología de los Alimentos ‘José Mataix’Universidad de GranadaGranadaSpain
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA)GranadaSpain
| | - Angela Caunii
- “Victor Babes” University of Medicine and PharmacyTimisoaraRomania
| | - Monica Butnariu
- University of Life Sciences "King Mihai I" from TimisoaraTimisoaraRomania
| | - Solomon Habtemariam
- Pharmacognosy Research & Herbal Analysis Services UKUniversity of GreenwichKentUK
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Badalamenti N, Maggio A, Fontana G, Bruno M, Lauricella M, D’Anneo A. Synthetic Derivatives of Natural ent-Kaurane Atractyligenin Disclose Anticancer Properties in Colon Cancer Cells, Triggering Apoptotic Cell Demise. Int J Mol Sci 2024; 25:3925. [PMID: 38612735 PMCID: PMC11011390 DOI: 10.3390/ijms25073925] [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: 03/06/2024] [Revised: 03/29/2024] [Accepted: 03/30/2024] [Indexed: 04/14/2024] Open
Abstract
The antitumor activity of different ent-kaurane diterpenes has been extensively studied. Several investigations have demonstrated the excellent antitumor activity of synthetic derivatives of the diterpene atractyligenin. In this research, a series of new synthetic amides and their 15,19-di-oxo analogues obtained from atractyligenin by modifying the C-2, C-15, and C-19 positions were designed in order to dispose of a set of derivatives with different substitutions at the amidic nitrogen. Using different concentrations of the obtained compounds (10-300 μM) a reduction in cell viability of HCT116 colon cancer cells was observed at 48 h of treatment. All the di-oxidized compounds were more effective than their alcoholic precursors. The di-oxidized compounds had already reduced the viability of two colon cancer cells (HCT116 and Caco-2) at 24 h when used at low doses (2.5-15 μM), while they turned out to be poorly effective in differentiated Caco-2 cells, a model of polarized enterocytes. The data reported here provide evidence that di-oxidized compounds induced apoptotic cell death, as demonstrated by the appearance of condensed and fragmented DNA in treated cells, as well as the activation of caspase-3 and fragmentation of its target PARP-1.
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Affiliation(s)
- Natale Badalamenti
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, 90128 Palermo, Italy; (A.M.); (G.F.); (M.B.); (A.D.)
- NBFC—National Biodiversity Future Center, Piazza Marina 60, 90133 Palermo, Italy
| | - Antonella Maggio
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, 90128 Palermo, Italy; (A.M.); (G.F.); (M.B.); (A.D.)
- NBFC—National Biodiversity Future Center, Piazza Marina 60, 90133 Palermo, Italy
| | - Gianfranco Fontana
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, 90128 Palermo, Italy; (A.M.); (G.F.); (M.B.); (A.D.)
- NBFC—National Biodiversity Future Center, Piazza Marina 60, 90133 Palermo, Italy
| | - Maurizio Bruno
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, 90128 Palermo, Italy; (A.M.); (G.F.); (M.B.); (A.D.)
- NBFC—National Biodiversity Future Center, Piazza Marina 60, 90133 Palermo, Italy
- Centro Interdipartimentale di Ricerca “Riutilizzo Bio-Based Degli Scarti da Matrici Agroalimentari” (RIVIVE), University of Palermo, Viale delle Scienze, 90128 Palermo, Italy
| | - Marianna Lauricella
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), Institute of Biochemistry, University of Palermo, Via del Vespro 129, 90127 Palermo, Italy;
| | - Antonella D’Anneo
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, 90128 Palermo, Italy; (A.M.); (G.F.); (M.B.); (A.D.)
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Kumar S, Das A. A Cocktail of Natural Compounds Holds Promise for New Immunotherapeutic Potential in Head and Neck Cancer. Chin J Integr Med 2024; 30:42-51. [PMID: 37118529 DOI: 10.1007/s11655-023-3694-0] [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] [Accepted: 09/05/2022] [Indexed: 04/30/2023]
Abstract
OBJECTIVE To obtain detailed understanding on the gene regulation of natural compounds in altering prognosis of head and neck squamous cell carcinomas (HNSC). METHODS Gene expression data of HNSC samples and peripheral blood mononuclear cells (PBMCs) of HNSC patients were collected from Gene Expression Omnibus (GEO). Differential gene expression analysis of GEO datasets were achieved by the GEO2R tool. Common differentially expressed gerres (DEGs) were screened by comparing DEGs of HNSC with those of PBMCs. The combination was further analyzed for regulating pathways and biological processes that were affected. RESULTS Totally 110 DEGs were retrieved and identified to be involved in biological processes related to tumor regulation. Then 102 natural compounds were screened for a combination such that the expression of all 110 commonly DEGs was altered. A combination of salidroside, ginsenoside Rd, oridonin, britanin, and scutellarein was chosen. A multifaceted, multi-dimensional tumor regression was showed by altering autophagy, apoptosis, inhibiting cell proliferation, angiogenesis, metastasis and inflammatory cytokines production. CONCLUSIONS This study has helped develop a unique combination of natural compounds that will markedly reduce the propensity of development of drug resistance in tumors and immune evasion by tumors. The result is crucial to developing a combinatorial natural therapeutic cocktail with accentuated immunotherapeutic potential.
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Affiliation(s)
- Sunil Kumar
- Department of Biotechnology, Delhi Technological University, Delhi, 110042, India
| | - Asmita Das
- Department of Biotechnology, Delhi Technological University, Delhi, 110042, India.
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Fang L, Zhang R, Shi L, Xie J, Ma L, Yang Y, Yan X, Fan K. Protein-Nanocaged Selenium Induces t(8;21) Leukemia Cell Differentiation via Epigenetic Regulation. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2300698. [PMID: 37888866 PMCID: PMC10724402 DOI: 10.1002/advs.202300698] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 08/13/2023] [Indexed: 10/28/2023]
Abstract
The success of arsenic in degrading PML-RARα oncoprotein illustrates the great anti-leukemia value of inorganics. Inspired by this, the therapeutic effect of inorganic selenium on t(8; 21) leukemia is studied, which has shown promising anti-cancer effects on solid tumors. A leukemia-targeting selenium nanomedicine is rationally built with bioengineered protein nanocage and is demonstrated to be an effective epigenetic drug for inducing the differentiation of t(8;21) leukemia. The selenium drug significantly induces the differentiation of t(8;21) leukemia cells into more mature myeloid cells. Mechanistic analysis shows that the selenium is metabolized into bioactive forms in cells, which drives the degradation of the AML1-ETO oncoprotein by inhibiting histone deacetylases activity, resulting in the regulation of AML1-ETO target genes. The regulation results in a significant increase in the expression levels of myeloid differentiation transcription factors PU.1 and C/EBPα, and a significant decrease in the expression level of C-KIT protein, a member of the type III receptor tyrosine kinase family. This study demonstrates that this protein-nanocaged selenium is a potential therapeutic drug against t(8;21) leukemia through epigenetic regulation.
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Affiliation(s)
- Long Fang
- Savaid Medical SchoolUniversity of Chinese Academy of SciencesBeijing100049China
- CAS Engineering Laboratory for NanozymeKey Laboratory of BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing100101China
| | - Ruofei Zhang
- CAS Engineering Laboratory for NanozymeKey Laboratory of BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing100101China
| | - Lin Shi
- Department of HematologyPeking University International HospitalBeijing102206China
| | - Jiaying Xie
- CAS Engineering Laboratory for NanozymeKey Laboratory of BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing100101China
| | - Long Ma
- CAS Engineering Laboratory for NanozymeKey Laboratory of BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing100101China
| | - Yili Yang
- China Regional Research CentreInternational Centre of Genetic Engineering and BiotechnologyTaizhou212200China
| | - Xiyun Yan
- CAS Engineering Laboratory for NanozymeKey Laboratory of BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing100101China
- Nanozyme Medical CenterSchool of Basic Medical SciencesZhengzhou UniversityZhengzhou450052China
| | - Kelong Fan
- CAS Engineering Laboratory for NanozymeKey Laboratory of BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing100101China
- Nanozyme Medical CenterSchool of Basic Medical SciencesZhengzhou UniversityZhengzhou450052China
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Chen Y, Jiang H, Zhan Z, Lu J, Gu T, Yu P, Liang W, Zhang X, Zhong S, Tang L. Oridonin restores hepatic lipid homeostasis in an LXRα-ATGL/EPT1 axis-dependent manner. J Pharm Anal 2023; 13:1281-1295. [PMID: 38174118 PMCID: PMC10759262 DOI: 10.1016/j.jpha.2023.08.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 08/01/2023] [Accepted: 08/10/2023] [Indexed: 01/05/2024] Open
Abstract
Hepatosteatosis is characterized by abnormal accumulation of triglycerides (TG), leading to prolonged and chronic inflammatory infiltration. To date, there is still a lack of effective and economical therapies for hepatosteatosis. Oridonin (ORI) is a major bioactive component extracted from the traditional Chinese medicinal herb Rabdosia rubescens. In this paper, we showed that ORI exerted significant protective effects against hepatic steatosis, inflammation and fibrosis, which was dependent on LXRα signaling. It is reported that LXRα regulated lipid homeostasis between triglyceride (TG) and phosphatidylethanolamine (PE) by promoting ATGL and EPT1 expression. Therefore, we implemented the lipidomic strategy and luciferase reporter assay to verify that ORI contributed to the homeostasis of lipids via the regulation of the ATGL gene associated with TG hydrolysis and the EPT1 gene related to PE synthesis in a LXRα-dependent manner, and the results showed the TG reduction and PE elevation. In detail, hepatic TG overload and lipotoxicity were reversed after ORI treatment by modulating the ATGL and EPT1 genes, respectively. Taken together, the data provide mechanistic insights to explain the bioactivity of ORI in attenuating TG accumulation and cytotoxicity and introduce exciting opportunities for developing novel natural activators of the LXRα-ATGL/EPT1 axis for pharmacologically treating hepatosteatosis and metabolic disorders.
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Affiliation(s)
- Yulian Chen
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Huanguo Jiang
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Zhikun Zhan
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Jindi Lu
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Tanwei Gu
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Ping Yu
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Weimin Liang
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Xi Zhang
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Shilong Zhong
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China
- Department of Pharmacy, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510515, China
| | - Lan Tang
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China
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11
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Chen F, Liao J, Wu P, Cheng L, Ma Y, Zhang L, Leng X, Zhu X, Liu Z, Xie F. Oridonin inhibits the occurrence and development of colorectal cancer by reversing the Warburg effect via reducing PKM2 dimer formation and preventing its entry into the nucleus. Eur J Pharmacol 2023; 954:175856. [PMID: 37321470 DOI: 10.1016/j.ejphar.2023.175856] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 06/12/2023] [Accepted: 06/12/2023] [Indexed: 06/17/2023]
Abstract
BACKGROUND The Warburg effect is prevalent in human cancer. Oridonin (ORI) has excellent anticancer effects, but its exact anticancer mechanism is still unclear. METHODS CCK8, EdU, and flow cytometry assay were performed to detect the effect of ORI on cell viability, proliferation and apoptosis, respectively. RNA-seq was carried out to search the underlying mechanisms. Total PKM2, dimeric PKM2, nuclear PKM2 was detected by Western blot. The epidermal growth factor receptor/extracellular signal regulated kinase (EGFR/ERK) signaling was assayed. The binding ability of Importin-α5 to PKM2 was performed by Co-IP experiments. The effect of ORI combined with cysteine (Cys) or fructose-1, 6-diphosphate (FDP) on cancer cells was detected. Mouse xenograft model was established to confirm the molecular mechanisms in vivo. RESULTS ORI inhibited viability, proliferation and promoted apoptosis of CRC cells. RNA-seq revealed ORI attenuated the Warburg effect in cancer cells. ORI reduced dimeric PKM2 and prevented it from entering the nucleus. ORI did not affect the EGFR/ERK signaling, but reduced Importin-α5 binding to the PKM2 dimer. Cys or FDP reversed or enhanced the effect of ORI. Animal model assay confirmed the molecular mechanisms in vivo. CONCLUSIONS Our study first shows that ORI could have anticancer activity by inhibiting the Warburg effect as a novel activator of PKM2.
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Affiliation(s)
- Fan Chen
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Gannan Medical University, Ganzhou, 341000, China
| | - Junnan Liao
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Gannan Medical University, Ganzhou, 341000, China
| | - Pinghui Wu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Gannan Medical University, Ganzhou, 341000, China
| | - Li Cheng
- School of Basic Medicine, Gannan Medical University, Ganzhou, 341000, China
| | - Yingchao Ma
- School of Basic Medicine, Gannan Medical University, Ganzhou, 341000, China
| | - Linghan Zhang
- School of Basic Medicine, Gannan Medical University, Ganzhou, 341000, China
| | - Xiaomin Leng
- School of Basic Medicine, Gannan Medical University, Ganzhou, 341000, China
| | - Xiuzhi Zhu
- School of Basic Medicine, Gannan Medical University, Ganzhou, 341000, China
| | - Zhiping Liu
- School of Basic Medicine, Gannan Medical University, Ganzhou, 341000, China.
| | - Fuhua Xie
- School of Basic Medicine, Gannan Medical University, Ganzhou, 341000, China.
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12
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Xu Y, Wang Z, Zhang L, Gao C, Li F, Li X, Ke Y, Liu HM, Hu Z, Wei L, Chen ZS. Differentiation of imatinib -resistant chronic myeloid leukemia cells with BCR-ABL-T315I mutation induced by Jiyuan Oridonin A. J Cancer 2023; 14:1182-1194. [PMID: 37215441 PMCID: PMC10197941 DOI: 10.7150/jca.83219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Accepted: 04/19/2023] [Indexed: 05/24/2023] Open
Abstract
Chronic myeloid leukemia (CML) results from BCR-ABL oncogene, which blocks CML cells differentiation and protects these cells from apoptosis. T315I mutated BCR-ABL is the main cause of the resistance mediated by imatinib and second generation BCR-ABL inhibitor. CML with the T315I mutation has been considered to have poor prognosis. Here, we determined the effect of Jiyuan oridonin A (JOA), an ent-kaurene diterpenoid compound, on the differentiation blockade in imatinib-sensitive, particularly, imatinib-resistant CML cells with BCR-ABL-T315I mutation by cell proliferation assay, apoptosis analysis, cell differentiation analysis, cell cycle analysis and colony formation assay. We also investigated the possible molecular mechanism by mRNA sequencing, qRT-PCR and Western blotting. We found that JOA at lower concentration significantly inhibited the proliferation of CML cells expressing mutant BCR-ABL (T315I mutation included) and wild-type BCR-ABL, which was due to that JOA induced the cell differentiation and the cell cycle arrest at G0/G1 phase. Interestingly, JOA possessed stronger anti-leukemia activity than its analogues such as OGP46 and Oridonin, which has been investigated extensively. Mechanistically, the cell differentiation mediated by JOA may be originated from the inhibition of BCR-ABL/c-MYC signaling in CML cells expressing wild-type BCR-ABL and BCR-ABL-T315I. JOA displayed the activity of inhibiting the BCR-ABL and promoted differentiation of not only imatinib -sensitive but also imatinib -resistant cells with BCR-ABL mutation, which could become a potent lead compound to overcome the imatinib -resistant induced by inhibitors of BCR-ABL tyrosine kinase in CML therapy.
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Affiliation(s)
- Yun Xu
- School of Pharmacy, Weifang Medical University, Weifang, 261053, China
| | - Ziting Wang
- School of Pharmacy, Weifang Medical University, Weifang, 261053, China
| | - Lei Zhang
- School of Pharmacy, Weifang Medical University, Weifang, 261053, China
| | - Congying Gao
- School of Pharmacy, Weifang Medical University, Weifang, 261053, China
| | - Fahui Li
- School of Pharmacy, Weifang Medical University, Weifang, 261053, China
| | - Xueming Li
- School of Pharmacy, Weifang Medical University, Weifang, 261053, China
| | - Yu Ke
- School of Pharmacy, Zhengzhou University, Zhengzhou, 450052, China
| | - Hong-Min Liu
- School of Pharmacy, Zhengzhou University, Zhengzhou, 450052, China
| | - Zhenbo Hu
- Laboratory for Stem Cell and Regenerative Medicine, Affiliated Hospital of Weifang Medical University, Weifang 261042, China
| | - Liuya Wei
- School of Pharmacy, Weifang Medical University, Weifang, 261053, China
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
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Tan Q, Hu K, Li XN, Yang XZ, Sun HD, Puno PT. Cytotoxic C-20 non-oxygenated ent-kaurane diterpenoids from Isodon wardii. Bioorg Chem 2023; 135:106512. [PMID: 37027948 DOI: 10.1016/j.bioorg.2023.106512] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 03/27/2023] [Accepted: 03/28/2023] [Indexed: 04/05/2023]
Abstract
Twenty new ent-kaurane diterpenoids, wardiisins A-T (1-20), along with two previously undescribed artefactual compounds (21 and 22) and twelve known analogues (23-34), were isolated from the aerial part of Isodon wardii. Their structures were elucidated by comprehensive analysis of spectroscopic data and single-crystal X-ray diffraction, and most of them were found to bear unusual C-12 oxygenation. Compounds 4, 7, 8, 19, 20, 21 exhibited remarkable cytotoxicity against the cancer cell lines HL-60, SMMC-7721, A-549, MDA-MB-231, and SW480, with IC50 values ranging from 0.3 to 5.2 μM. Moreover, 7 was found to induce G2/M cell cycle arrest and promote apoptosis in SW480 cell lines.
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14
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Costa RG, Silva SL, Dias IR, Oliveira MDS, Rodrigues ACBDC, Dias RB, Bezerra DP. Emerging drugs targeting cellular redox homeostasis to eliminate acute myeloid leukemia stem cells. Redox Biol 2023; 62:102692. [PMID: 37031536 PMCID: PMC10119960 DOI: 10.1016/j.redox.2023.102692] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 03/28/2023] [Accepted: 03/29/2023] [Indexed: 04/05/2023] Open
Abstract
Acute myeloid leukemia (AML) is a very heterogeneous group of disorders with large differences in the percentage of immature blasts that presently are classified according to the specific mutations that trigger malignant proliferation among thousands of mutations reported thus far. It is an aggressive disease for which few targeted therapies are available and still has a high recurrence rate and low overall survival. The main reason for AML relapse is believed to be due to leukemic stem cells (LSCs) that have unlimited self-renewal capacity and long residence in a quiescent state, which promote greater resistance to traditional therapies for this cancer. AML LSCs have low oxidative stress levels, which appear to be caused by a combination of low mitochondrial activity and high activity of ROS-removing pathways. In this sense, oxidative stress has been thought to be an important new potential target for the treatment of AML patients, targeting the eradication of AML LSCs. The aim of this review is to discuss some drugs that induce oxidative stress to direct new goals for future research focusing on redox imbalance as an effective strategy to eliminate AML LSCs.
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15
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Sun Y, Shao J, Liu H, Wang H, Wang G, Li J, Mao Y, Chen Z, Ma K, Xu L, Wang Y. A chromosome-level genome assembly reveals that tandem-duplicated CYP706V oxidase genes control oridonin biosynthesis in the shoot apex of Isodon rubescens. MOLECULAR PLANT 2023; 16:517-532. [PMID: 36518072 DOI: 10.1016/j.molp.2022.12.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 11/17/2022] [Accepted: 12/08/2022] [Indexed: 06/09/2023]
Abstract
The ent-kaurenoids (e.g., oridonin and enmein) from the Isodon genus (Lamiaceae) are one class of diterpenoids with rich structural diversity and intriguing pharmaceutical activity. In contrast to the well-established gibberellin pathway, oxidative modifications diversifying the ent-kaurene skeleton in Isodon have remained undetermined for half a century. Here we report a chromosome-level genome assembly of I. rubescens, a well-recognized oridonin producer long favored by Asian people as a traditional herb with antitumor effects. The shoot apex was confirmed to be the actual region actively producing ent-kaurene diterpenoids. Through comparative genomics and phylogenetic analyses, we discovered a cluster of tandem-duplicated CYP706V oxygenase-encoding genes located on an ancient genomic block widely distributed in eudicots, whereas almost exclusively emerged in Isodon plants. In the shoot apex, IrCYP706V2 and IrCYP706V7 oxidized the ent-kaurene core in the initial stage of oridonin biosynthesis. Loss of CYP706Vs in other Lamiaceae plants offered an explanation for the specific kaurenoid production in Isodon plants. Moreover, we found that the Isodon genomes encode multiple diterpenoid synthases that are potentially involved in generating diterpenoid diversity. These findings provided new insights into the evolution of the lineage-specific diterpenoid pathway and laid a foundation for improving production of bioactive ent-kaurene-type diterpenoids by molecular breeding and synthetic biology approaches.
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Affiliation(s)
- Yuwei Sun
- CAS-Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai 200032, China
| | - Jie Shao
- CAS-Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai 200032, China; University of Chinese Academy of Sciences, Beijing 100039, China
| | - Haili Liu
- CAS-Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai 200032, China
| | - Hua Wang
- National Key Laboratory of Plant Molecular Genetics, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai 200032, China
| | - Guangyi Wang
- CAS-Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai 200032, China; University of Chinese Academy of Sciences, Beijing 100039, China
| | - Jianhua Li
- CAS-Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai 200032, China
| | - Yaping Mao
- CAS-Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai 200032, China; University of Chinese Academy of Sciences, Beijing 100039, China
| | - Zhuo Chen
- CAS-Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai 200032, China; University of Chinese Academy of Sciences, Beijing 100039, China
| | - Ke Ma
- CAS-Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai 200032, China; University of Chinese Academy of Sciences, Beijing 100039, China
| | - Lin Xu
- National Key Laboratory of Plant Molecular Genetics, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai 200032, China
| | - Yong Wang
- CAS-Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai 200032, China.
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16
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Zhang X, Xing M, Ma Y, Zhang Z, Qiu C, Wang X, Zhao Z, Ji Z, Zhang JY. Oridonin Induces Apoptosis in Esophageal Squamous Cell Carcinoma by Inhibiting Cytoskeletal Protein LASP1 and PDLIM1. Molecules 2023; 28:805. [PMID: 36677861 PMCID: PMC9862004 DOI: 10.3390/molecules28020805] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Revised: 01/07/2023] [Accepted: 01/09/2023] [Indexed: 01/15/2023] Open
Abstract
Esophageal squamous cell carcinoma is a severe malignancy for its high mortality and poor prognosis. Mainstay chemotherapies cause serious side effects for their ways of inducing cell death. Oridonin is the main bioactive constituent from natural plants that has anticancer ability and weak side effects. The proteomics method is efficient to understand the anticancer mechanism. However, proteins identified by proteomics aimed at understanding oridonin's anticancer mechanism is seldom overlapped by different groups. This study used proteomics based on two-dimensional electrophoresis sodium dodecyl sulfate-polyacrylamide gel electrophoresis (2-DE SDS-PAGE) integrated with mass spectrometry and Gene Set Enrichment Analysis (GSEA) to understand the anticancer mechanism of oridonin on esophageal squamous cell carcinoma (ESCC). The results showed that oridonin induced ESCC cell death via apoptosis by decreasing the protein expression of LASP1 and PDLIM1.
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Affiliation(s)
- Xiaojun Zhang
- Department of Biological Sciences & Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX 79968, USA
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, China
| | - Mengtao Xing
- Department of Biological Sciences & Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX 79968, USA
| | - Yangcheng Ma
- Department of Biological Sciences & Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX 79968, USA
| | - Zhuangli Zhang
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, China
| | - Cuipeng Qiu
- Department of Biological Sciences & Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX 79968, USA
| | - Xiao Wang
- Department of Biological Sciences & Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX 79968, USA
| | - Zhihong Zhao
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, China
| | - Zhenyu Ji
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, China
| | - Jian-Ying Zhang
- Department of Biological Sciences & Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX 79968, USA
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17
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Feng H, Liu Y, Zhang M, Liu R, Wang J, Wang W, He P, Zhang P, Niu F. De Novo design of a humanized antiCD33 antibody-oridonin conjugate for acute myeloid leukemia therapy. Biochem Biophys Res Commun 2022; 629:152-158. [PMID: 36122452 DOI: 10.1016/j.bbrc.2022.09.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 08/26/2022] [Accepted: 09/07/2022] [Indexed: 11/02/2022]
Abstract
Acute myeloid leukemia (AML) is the most common blood cancer in adults. Patients' 5-year overall survival is less than 30% thus having a poor prognosis. To date, the development of novel target therapies is still necessary to ameliorate patients' survival. Antibody-drug conjugates (ADCs) represent a promising class of drugs for the treatment of AML. CD33 is highly expressed on AML cells, and the FDA-approved CD33-targeted ADC drug-gemtuzumab ozogamicin (GO) has proved the feasibility of CD33-targeted ADC drug design. In this study, we constructed a novel CD33-targeted ADC drug composed of a humanized anti-CD33 antibody and oridonin as a payload with a cleaved chemical linker. Oridonin is a natural product that has great cancer therapy potential while its poor bioavailability and targeting ability limited its clinical use. Herein, we demonstrated that antiCD33-oridonin specifically delivered oridonin in AML cells improved AML cells killing ability of oridonin. Meanwhile, it did not show any non-specific toxicity on CD33 negative cells. In summary, we developed a novel AML targeting ADC with clinical application potential, and therefore provided a new solution for the druggability improvement of oridonin.
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Affiliation(s)
- Hui Feng
- Department of Hematology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yi Liu
- Department of Hematology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Mengyao Zhang
- Department of Hematology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ruimin Liu
- Department of Hematology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jincheng Wang
- Department of Hematology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Wenjuan Wang
- Department of Hematology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Pengcheng He
- Department of Hematology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
| | - Penghui Zhang
- Institute of Basic Medicine and Cancer, Chinese Academy of Sciences, Hangzhou, China.
| | - Fan Niu
- Department of Hematology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
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Li F, Gao C, Li X, Wang J, Zhao Y, Ke Y, Liu Y, Liu HM, Hu Z, Wei L, Chen ZS. Jiyuan oridonin A induces differentiation of acute myeloid leukemia cells including leukemic stem-like cells. Front Pharmacol 2022; 13:1001552. [PMID: 36133825 PMCID: PMC9484275 DOI: 10.3389/fphar.2022.1001552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Accepted: 08/08/2022] [Indexed: 11/13/2022] Open
Abstract
Acute myeloid leukemia (AML) is an aggressive form of hematological neoplasia characterized by failure of myeloid differentiation. AML is a leading cause of death from leukemia. Cytarabine chemotherapy resistance is a major source of refractory/relapsed AML. A major obstacle to the successful treatment of AML results from residual disease maintained by leukemic stem cells (LSCs), which are mostly resistant to conventional chemotherapy. Here, we determined the effect of a natural compound, Jiyuan oridonin A (JOA), on the differentiation blockade in the M2 subtype [particularly t (8;21)] of AML cells, M3 subtype of AML cells (APL cells), and leukemic stem-like cells both in vitro and in vivo. We found that JOA induced cell differentiation and suppressed the colony formation capacity in various AML cell lines (Kasumi-1, KG-1, MUTZ-8, NB4, and HL-60) without eliciting apoptosis. The mechanism of JOA-induced cell differentiation depends on the specificity of cell type. JOA mediated the differentiation of Kasumi-1 cells by activating the hematopoietic cell lineage signaling pathway, while inhibition of c-MYC was involved in the JOA-induced differentiation of NB4 cells. Moreover, JOA was identified to target leukemic stem-like cells by induced cell differentiation in vivo. These findings demonstrated that JOA could inhibit the proliferation of M2 and M3 subtypes of AML cells and leukemic stem-like cells by overcoming the differentiation blockade, which may offer a novel therapeutic strategy for AML to overcome relapse and drug resistance in patients with AML. Our findings highlight the possibility of using compounds like JOA as a promising differentiation-induced agent for the treatment of AML.
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Affiliation(s)
- Fahui Li
- School of Pharmacy, Weifang Medical University, Weifang, China
| | - Congying Gao
- School of Pharmacy, Weifang Medical University, Weifang, China
| | - Xueming Li
- School of Pharmacy, Weifang Medical University, Weifang, China
| | - Jiangyun Wang
- School of Pharmacy, Weifang Medical University, Weifang, China
| | - Yao Zhao
- Laboratory for Stem Cell and Regenerative Medicine, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Yu Ke
- School of Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Ying Liu
- School of Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Hong-Min Liu
- School of Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Zhenbo Hu
- Laboratory for Stem Cell and Regenerative Medicine, Affiliated Hospital of Weifang Medical University, Weifang, China
- *Correspondence: Zhenbo Hu, ; Liuya Wei, ; Zhe-Sheng Chen,
| | - Liuya Wei
- School of Pharmacy, Weifang Medical University, Weifang, China
- *Correspondence: Zhenbo Hu, ; Liuya Wei, ; Zhe-Sheng Chen,
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY, United States
- *Correspondence: Zhenbo Hu, ; Liuya Wei, ; Zhe-Sheng Chen,
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Zhao X, Yang K, Song Z, He H, Zhang W. [Juglone induces proliferation inhibition and apoptosis of cervical cancer cells via promoting c-Myc ubiquitination]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2022; 42:1026-1031. [PMID: 35869765 DOI: 10.12122/j.issn.1673-4254.2022.07.09] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
OBJECTIVE To observe the expression of c-Myc protein in cervical cancer HeLa cells and explore the effect of juglone on the proliferation and apoptosis of HeLa cells by affecting c-Myc ubiquitination. METHODS HeLa cells treated with different concentrations (0, 10, 20, or 50 μmol/L) of juglone or with 20 μmol/L juglone for different time lengths were examined for expression of c-Myc protein with Western blotting. The half-life of c-Myc protein was determined using cycloheximide (CHX) and c-Myc protein degradation was detected using coimmunoprecipitation. We also assessed the effects of 20 μmol/L juglone combined with 0, 1.0 or 2.0 μmol/L MG132 (a proteasome inhibitor) on c-Myc expression. The effects of 20 μmol/L juglone on the proliferation and apoptosis of HeLa cells with RNA interference-mediated knockdown of c-Myc were evaluated with MTT assay and flow cytometry. RESULTS Treatment with juglone significantly lowered c-Myc protein expression in HeLa cells in a concentration-and time-dependent manner (P < 0.05). Juglone obviously shortened the half-life of c-Myc protein, and the addition of MG132 significantly up-regulated the expression level of c-Myc protein (P < 0.05). Juglone treatment also promoted ubiquitination of c-Myc protein in HeLa cells. Compared with the cells transfected with a negative control construct, the cells transfected with si-c-Myc showed significantly decreased proliferation inhibition and a lowered cell rate with early apoptosis after juglone treatment (P < 0.05). CONCLUSION Juglone inhibits proliferation and promotes apoptosis of HeLa cells by affecting the ubiquitination of c-Myc protein.
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Affiliation(s)
- X Zhao
- Department of Biochemistry, Jilin Medical College, Jilin 132013, China
| | - K Yang
- Department of Biochemistry, Jilin Medical College, Jilin 132013, China
| | - Z Song
- Department of Biochemistry, Jilin Medical College, Jilin 132013, China
| | - H He
- Department of Biochemistry, School of Basic Medicine, Yanbian University, Yanbian 133000, China
| | - W Zhang
- Department of Biochemistry, Jilin Medical College, Jilin 132013, China
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20
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An Y, Zhu J, Wang X, Sun X, Luo C, Zhang Y, Ye Y, Li X, Abulizi A, Huang Z, Zhang H, Yang B, Xie Z. Oridonin Delays Aging Through the AKT Signaling Pathway. Front Pharmacol 2022; 13:888247. [PMID: 35662728 PMCID: PMC9157590 DOI: 10.3389/fphar.2022.888247] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 04/29/2022] [Indexed: 12/18/2022] Open
Abstract
Aging is a major risk factor for chronic diseases and disability in humans. Nowadays, no effective anti-aging treatment is available clinically. In this study, oridonin was selected based on the drug screening strategy similar to Connectivity MAP (CMAP) but upon transcriptomes of 102 traditional Chinese medicines treated cell lines. Oridonin is a diterpenoid isolated from Rabdosia rubescens. As reported, Oridonin exhibits a variety of pharmacological activities, including antitumor, antibacterial and anti-inflammatory activities. Here, we found that oridonin inhibited cellular senescence in human diploid fibroblasts (2BS and WI-38), manifested by decreased senescence-associated β-galactosidase (SA-β-gal) staining. Compared with the elderly control group, the positive cell rate in the oridonin intervention group was reduced to 48.5%. Notably, oridonin prolonged the lifespan of yeast by 48.9%, and extended the average life span of naturally aged mice by 21.6%. Our mice behavior experiments exhibited that oridonin significantly improved the health status of naturally aged mice. In addition, oridonin also delayed doxorubicin-induced cellular senescence and mouse senescence. Compared with the model group, the percentage of SA-β-gal positive cells in the oridonin treatment group was reduced to 59.8%. It extended the average lifespan of mice by 53.8% and improved healthspan. Mechanistically, we showed that oridonin delayed aging through the AKT signaling pathway and reversed the genetic changes caused by doxorubicin-induced cell senescence. Therefore, oridonin is a potential candidate for the development of anti-aging drugs.
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Affiliation(s)
- Yongpan An
- Department of Pharmacology, School of Basic Medical Sciences, Peking University International Cancer Institute, Peking University, Beijing, China
| | - Jie Zhu
- Department of Pharmacology, School of Basic Medical Sciences, Peking University International Cancer Institute, Peking University, Beijing, China
| | - Xin Wang
- Department of Pharmacology, School of Basic Medical Sciences, Peking University International Cancer Institute, Peking University, Beijing, China
| | - Xinpei Sun
- Department of Pharmacology, School of Basic Medical Sciences, Peking University International Cancer Institute, Peking University, Beijing, China
| | - Chunxiong Luo
- School of Physics, Peking University, Beijing, China
| | - Yukun Zhang
- Department of Pharmacology, School of Basic Medical Sciences, Peking University International Cancer Institute, Peking University, Beijing, China
| | - Yuwei Ye
- Department of Pharmacology, School of Basic Medical Sciences, Peking University International Cancer Institute, Peking University, Beijing, China
| | - Xiaowei Li
- Department of Pharmacology, School of Basic Medical Sciences, Peking University International Cancer Institute, Peking University, Beijing, China
| | - Abudumijiti Abulizi
- Department of Pharmacology, School of Basic Medical Sciences, Peking University International Cancer Institute, Peking University, Beijing, China
| | - Zhizhen Huang
- Department of Pharmacology, School of Basic Medical Sciences, Peking University International Cancer Institute, Peking University, Beijing, China
| | - Hang Zhang
- Department of Pharmacology, School of Basic Medical Sciences, Peking University International Cancer Institute, Peking University, Beijing, China
| | - Baoxue Yang
- Department of Pharmacology, School of Basic Medical Sciences, Peking University International Cancer Institute, Peking University, Beijing, China
| | - Zhengwei Xie
- Department of Pharmacology, School of Basic Medical Sciences, Peking University International Cancer Institute, Peking University, Beijing, China.,Peking University-Yunnan Baiyao International Medical Research Center, Peking University Health Science Center, Peking University, Beijing, China.,Beijing Gigaceuticals Tech. Co. Ltd., Beijing, China
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21
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Structurally diverse diterpenoids from Isodon oresbius and their bioactivity. Bioorg Chem 2022; 124:105811. [DOI: 10.1016/j.bioorg.2022.105811] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/31/2022] [Accepted: 04/12/2022] [Indexed: 12/24/2022]
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22
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Hu JJ, Li BL, Xie JD, Liang HJ, Li QR, Yuan J, Wu JW. Two new 7,20-epoxy- ent-kaurane diterpenoids from the aerial parts of Isodon serra. Nat Prod Res 2022; 36:2021-2027. [PMID: 33131334 DOI: 10.1080/14786419.2020.1841189] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Two new compounds (1 and 2), belonging to C-20 oxygenated ent-kauranes-type diterpenoids, were identified from the aerial parts of Isodon serra. Their structures were elucidated by extensive analysis of HRESI-MS and NMR spectroscopic data. Both these two compounds possess a common 7,20-epoxy-ent-kauranes skeleton with a hydroxyl group rarely occurring at C-13. Compounds 1 and 2 were evaluated for their cytotoxic activity against Hela-60 and HepG2 as well as the antibacterial activity against Staphylococcus aureus, Bacillus cereus and Escherichia coli.
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Affiliation(s)
- Juan-Juan Hu
- Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, P. R. China
| | - Bai-Lin Li
- Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, P. R. China
| | - Jin-Dan Xie
- Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, P. R. China
| | - Hui-Jun Liang
- Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, P. R. China
| | - Qian-Ran Li
- Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, P. R. China
| | - Jie Yuan
- Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, P. R. China
| | - Jie-Wei Wu
- Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, P. R. China
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23
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Zhuang J, Xia L, Zou Z, Yin J. Blue light induces ROS mediated apoptosis and degradation of AML1-ETO oncoprotein in Kasumi-1 cells. Med Oncol 2022; 39:52. [PMID: 35150326 DOI: 10.1007/s12032-022-01650-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Accepted: 01/05/2022] [Indexed: 10/19/2022]
Abstract
Light-emitting diode (LED)-based therapies, particularly blue LEDs with wavelengths of 400-500 nm, have shown beneficial results in several cancers, including melanoma, lymphoid cells, and skin tumors. In this study, the cell viability and apoptosis of Kasumi-1 cells treated by blue light (BL) irradiation have been explored. Firstly, BL can specially inhibit the proliferation and promote the apoptosis of Kasumi-1 cells. Furthermore, the apoptosis was triggered by the production of reactive oxygen species and the decline of mitochondrial membrane potential which was regulated by the ratio of Bcl-2(Bcl-xL)/Bax; BL caused the cells' final apoptosis accompanied with the increased cleavage of caspase-3 and poly-ADP-ribose polymerase. Finally, BL induced the degradation of AML1-ETO dependent on the activation of caspase-3. These results are helpful for establishing a low toxicity and high efficiency strategy of BL irradiation for clinical treatment of Kasumi-1 cells.
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Affiliation(s)
- Jianjian Zhuang
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Cancer Center, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China
| | - Liping Xia
- College of Life Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, China
| | - Zheyu Zou
- College of Life Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, China
| | - Juxin Yin
- School of Information and Electrical Engineering, Zhejiang University City College, Hangzhou, 310015, People's Republic of China.
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24
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Yang YS, Wen D, Zhao XF. Preventive and therapeutic effect of intraportal oridonin on BALb/c nude mice hemispleen model of colon cancer liver metastasis. Transl Cancer Res 2022; 10:1324-1335. [PMID: 35116458 PMCID: PMC8798652 DOI: 10.21037/tcr-20-3042] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 01/27/2021] [Indexed: 01/15/2023]
Abstract
Background This study is to investigate the preventive and therapeutic effect of intraportal oridonin on colorectal cancer liver metastasis (CRCLM). Methods The inhibitory effect of oridonin on HT29 cells was determined by CCK-8 and MTT assays. The preventive and therapeutic effect of intraportal oridonin on CRCLM were investigated by establishing BALb/c nude mice hemispleen models of colon cancer liver metastasis. The microscopic characteristics of tumor tissues were observed by hematoxylin-eosin staining, immunohistochemistry and TUNEL staining. On the other hand, liver function enzymes, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP), were detected to evaluate the hepatotoxicity of intraportal oridonin. The serum levels of tumor markers, including carcinoembryonic antigen (CEA) and α-fetoprotein (AFP), were used to investigate the intervention effect of intraportal oridonin on CRCLM. Results Oridonin exerted an inhibitory effect on the proliferation of HT29 cells in vitro. Intraportal oridonin was found to effectively prevent the occurrence and formation of CRCLM, whilst intraportal oridonin can also exert a therapeutic effect on CRCLM. Additionally, liver enzymes testing indicated that intraportal oridonin possesses non-hepatotoxicity, instead can effectively alleviate liver injury caused by tumor. Furthermore, intraportal oridonin was also revealed to decrease the serum levels of AFP and CEA. Conclusions Intraportal oridonin can effectively inhibit the formation of liver metastatic tumor and exert a certain degree of preventive and therapeutic effect on CRCLM. These findings indicate intraportal oridonin to be a promising anti-metastasis agent for CRCLM.
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Affiliation(s)
- Yu-Shen Yang
- Department of General Surgery, Dalian University Affiliated Xinhua Hospital, Dalian, China
| | - Dan Wen
- Department of General Surgery, Dalian University Affiliated Xinhua Hospital, Dalian, China
| | - Xue-Feng Zhao
- Department of General Surgery, Dalian University Affiliated Xinhua Hospital, Dalian, China
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25
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Preparation, Characterization, and Evaluation of Liposomes Containing Oridonin from Rabdosia rubescens. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27030860. [PMID: 35164121 PMCID: PMC8839758 DOI: 10.3390/molecules27030860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/15/2022] [Accepted: 01/17/2022] [Indexed: 11/17/2022]
Abstract
Due to the remarkable anti-tumor activities of oridonin (Ori), research on Rabdosia rubescens has attracted more and more attention in the pharmaceutical field. The purpose of this study was to extract Ori from R. rubescens by ultrasound-assisted extraction (UAE) and prepare Ori liposomes as a novel delivery system to improve the bioavailability and biocompatibility. Response surface methodology (RSM), namely Box-Behnken design (BBD), was applied to optimize extraction conditions, formulation, and preparation process. The results demonstrated that the optimal extraction conditions were an ethanol concentration of 75.9%, an extraction time of 35.7 min, and a solid/liquid ratio of 1:32.6. Under these optimal conditions, the extraction yield of Ori was 4.23 mg/g, which was well matched with the predicted value (4.28 mg/g). The optimal preparation conditions of Ori liposomes by RSM, with an ultrasonic time of 41.1 min, a soybean phospholipids/drug ratio of 9.6 g/g, and a water bath temperature of 53.4 °C, had higher encapsulation efficiency (84.1%). The characterization studies indicated that Ori liposomes had well-dispersible spherical shapes and uniform sizes with a particle size of 137.7 nm, a polydispersity index (PDI) of 0.216, and zeta potential of −24.0 mV. In addition, Ori liposomes presented better activity than free Ori. Therefore, the results indicated that Ori liposomes could enhance the bioactivity of Ori, being proposed as a promising vehicle for drug delivery.
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26
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Oridonin Dose-Dependently Modulates the Cell Senescence and Apoptosis of Gastric Cancer Cells. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:5023536. [PMID: 34795783 PMCID: PMC8595004 DOI: 10.1155/2021/5023536] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 07/28/2021] [Accepted: 10/01/2021] [Indexed: 11/18/2022]
Abstract
Gastric cancer (GC) is the fourth most lethal cancer. Effective treatments are lacking, and our knowledge of the pathogenic mechanisms in play is poor. Oridonin from the Chinese herb Rabdosia rubescens exerts various anticancer activities. However, the dose-dependent effects of oridonin on human GC remain unclear. Here, we found that oridonin inhibited GC cell growth in a time- and dose-dependent manner. Low-dose oridonin induced GC cell cycle arrest at G0/G1 and cell senescence by suppressing the c-Myc-AP4 pathway and enhancing p53-p21 signaling. AP4 overexpression partly abrogated the oridonin-induced senescence of GC cells. High-dose oridonin induced apoptosis and autophagy, with the autophagy inhibitor BafA1 attenuating oridonin-induced apoptosis. Together, the findings indicate that oridonin at different doses modulates GC cell senescence and apoptosis; oridonin may thus usefully treat GC.
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27
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Wen D, Yang YS, Gao DZ, Wang Z, Jiang QW, Zhao XF. Oridonin Enhances the Anti-Metastasis Effect of Oxaliplatinliplatin on Colorectal Cancer Liver Metastasis. Bull Exp Biol Med 2021; 172:26-32. [PMID: 34792718 DOI: 10.1007/s10517-021-05324-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Indexed: 11/26/2022]
Abstract
The anti-metastasis effect of oridonin in combination with oxaliplatin on colorectal cancer liver metastasis was studied using a BALB/c nude mouse model. The liver condition, bloody ascites, cholestasis, and liver metastasis scores in the three groups receiving oxaliplatin combined with oridonin were significantly milder than in the control group and importantly the anti-migratory effect of oxaliplatin combined with oridonin was obviously the strongest (p<0.05). Oridonin possessed no hepatotoxicity; instead, it effectively alleviated liver injury caused by oxaliplatin. Oridonin alone or in combination with oxaliplatin significantly decreased serum levels of α-fetoprotein and carcinoembryonic antigen. Therefore, oridonin combined with oxaliplatin displays great potential to markedly increase the anti-metastasis effect of oxaliplatin in the treatment of liver metastases of colorectal cancer.
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Affiliation(s)
- D Wen
- Department of General Surgery, Dalian University Affiliated Xinhua Hospital, Dalian, China
| | - Y S Yang
- Department of General Surgery, Dalian University Affiliated Xinhua Hospital, Dalian, China
| | - D Z Gao
- Department of General Surgery, Dalian University Affiliated Xinhua Hospital, Dalian, China
| | - Z Wang
- Department of General Surgery, Dalian University Affiliated Xinhua Hospital, Dalian, China
| | - Q W Jiang
- Department of General Surgery, Dalian University Affiliated Xinhua Hospital, Dalian, China
| | - X F Zhao
- Department of General Surgery, Dalian University Affiliated Xinhua Hospital, Dalian, China.
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28
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Liao M, Dong Q, Chen R, Xu L, Jiang Y, Guo Z, Xiao M, He W, Cao C, Hu R, Sun W, Jiang H, Wang J. Oridonin inhibits DNMT3A R882 mutation-driven clonal hematopoiesis and leukemia by inducing apoptosis and necroptosis. Cell Death Discov 2021; 7:297. [PMID: 34663800 PMCID: PMC8523644 DOI: 10.1038/s41420-021-00697-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Revised: 09/14/2021] [Accepted: 10/05/2021] [Indexed: 01/10/2023] Open
Abstract
DNA (cytosine-5)-methyltransferase 3A (DNMT3A) mutations occur in ~20% of de novo acute myeloid leukemia (AML) patients, and >50% of these mutations in AML samples are heterozygous missense alterations within the methyltransferase domain at residue R882. DNMT3A R882 mutations in AML patients promote resistance to anthracycline chemotherapy and drive relapse. In this study, we performed high-throughput screening and identified that oridonin, an ent-kaurene diterpenoid extracted from the Chinese herb Rabdosia rubescens, inhibits DNMT3A R882 mutant leukemic cells at a low-micromolar concentration (IC50 = 2.1 µM) by activating both RIPK1-Caspase-8-Caspase-3-mediated apoptosis and RIPK1-RIPK3-MLKL-mediated necroptosis. The inhibitory effect of oridonin against DNMT3A R882 mutant leukemia cells can also be observed in vivo. Furthermore, oridonin inhibits clonal hematopoiesis of hematopoietic stem cells (HSCs) with Dnmt3a R878H mutation comparing to normal HSCs by inducing apoptosis and necroptosis. Overall, oridonin is a potential and promising drug candidate or lead compound targeting DNMT3A R882 mutation-driven clonal hematopoiesis and leukemia.
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Affiliation(s)
- Min Liao
- School of Pharmaceutical Sciences, Tsinghua University, 100084, Beijing, China
| | - Qiongye Dong
- Key Laboratory of Intelligent Information Processing, Advanced Computer Research Center, Institute of Computing Technology, Chinese Academy of Sciences, 100190, Beijing, China
| | - Ruiqing Chen
- School of Pharmaceutical Sciences, Tsinghua University, 100084, Beijing, China
| | - Liqian Xu
- School of Pharmaceutical Sciences, Tsinghua University, 100084, Beijing, China
| | - Yuxuan Jiang
- School of Pharmaceutical Sciences, Tsinghua University, 100084, Beijing, China
| | - Zhenxing Guo
- Department of Hematology/Oncology, First Hospital of Tsinghua University, 100016, Beijing, China
| | - Min Xiao
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China
| | - Wei He
- School of Pharmaceutical Sciences, Tsinghua University, 100084, Beijing, China
| | - Changcai Cao
- Shandong Hongmai Biotechnology Co., Ltd. Room 1201, building B, Research Institute of Tianjin University, No. 51, Lutai Avenue, Zibo High tech Zone, 255000, Tianjin, China
| | - Ronghua Hu
- Department of Hematology, Xuanwu Hospital, Capital Medical University, 100053, Beijing, China
| | - Wanling Sun
- Department of Hematology, Xuanwu Hospital, Capital Medical University, 100053, Beijing, China.
| | - Hong Jiang
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, 310003, Hangzhou, China.
| | - Jianwei Wang
- School of Pharmaceutical Sciences, Tsinghua University, 100084, Beijing, China.
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Abstract
Terpenoids are the largest class of natural products, most of which are derived from plants. Amongst their numerous biological properties, their anti-tumor effects are of interest for they are extremely diverse which include anti-proliferative, apoptotic, anti-angiogenic, and anti-metastatic activities. Recently, several in vitro and in vivo studies have been dedicated to understanding the 'terpenoid induced autophagy' phenomenon in cancer cells. Light has already been shed on the intricacy of apoptosis and autophagy relationship. This latter crosstalk is driven by the delicate balance between activating or silencing of certain proteins whereby the outcome is expressed via interrelated signaling pathways. In this review, we focus on nine of the most studied terpenoids and on their cell death and autophagic activity. These terpenoids are grouped in three classes: sesquiterpenoid (artemisinin, parthenolide), diterpenoids (oridonin, triptolide), and triterpenoids (alisol, betulinic acid, oleanolic acid, platycodin D, and ursolic acid). We have selected these nine terpenoids among others as they belong to the different major classes of terpenoids and our extensive search of the literature indicated that they were the most studied in terms of autophagy in cancer. These terpenoids alone demonstrate the complexity by which these secondary metabolites induce autophagy via complex signaling pathways such as MAPK/ERK/JNK, PI3K/AKT/mTOR, AMPK, NF-kB, and reactive oxygen species. Moreover, induction of autophagy can be either destructive or protective in tumor cells. Nevertheless, should this phenomenon be well understood, we ought to be able to exploit it to create novel therapies and design more effective regimens in the management and treatment of cancer.
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30
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Lei Y, Li Y, Tan Y, Qian Z, Zhou Q, Jia D, Sun Q. Novel Mechanistic Observations and NES-Binding Groove Features Revealed by the CRM1 Inhibitors Plumbagin and Oridonin. JOURNAL OF NATURAL PRODUCTS 2021; 84:1478-1488. [PMID: 33890470 DOI: 10.1021/acs.jnatprod.0c01231] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The protein chromosome region maintenance 1 (CRM1) is an important nuclear export factor and drug target in diseases such as cancer and viral infections. Several plant-derived CRM1 inhibitors including plumbagin and oridonin possess potent antitumor activities. However, their modes of CRM1 inhibition remain unclear. Here, a multimutant CRM1 was engineered to enable crystallization of these two small molecules in its NES groove. Plumbagin and oridonin share the same three conjugation sites in CRM1. In solution, these two inhibitors targeted more CRM1 sites and inhibited its activity through promoting its aggregation, in addition to directly targeting the NES groove. While the plumbagin-bound NES groove resembles the NES-bound groove state, the oridonin complex reveals for the first time a more open NES groove. The observed greater NES groove dynamics may improve cargo loading through a "capture-and-tighten" mechanism. This work thus provides new insights on the mechanism of CRM1 inhibition by two natural products and a structural basis for further development of these or other CRM1 inhibitors.
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Affiliation(s)
- Yuqin Lei
- Department of Pathology, State Key Laboratory of Biotherapy and Cancer Centre, West China Hospital, Sichuan University, and Collaborative Innovation Centre of Biotherapy, Chengdu 610041, People's Republic of China
| | - Yuling Li
- Department of Pathology, State Key Laboratory of Biotherapy and Cancer Centre, West China Hospital, Sichuan University, and Collaborative Innovation Centre of Biotherapy, Chengdu 610041, People's Republic of China
| | - Yuping Tan
- Department of Pathology, State Key Laboratory of Biotherapy and Cancer Centre, West China Hospital, Sichuan University, and Collaborative Innovation Centre of Biotherapy, Chengdu 610041, People's Republic of China
| | - Zhiyong Qian
- Department of Pathology, State Key Laboratory of Biotherapy and Cancer Centre, West China Hospital, Sichuan University, and Collaborative Innovation Centre of Biotherapy, Chengdu 610041, People's Republic of China
| | - Qiao Zhou
- Department of Pathology, State Key Laboratory of Biotherapy and Cancer Centre, West China Hospital, Sichuan University, and Collaborative Innovation Centre of Biotherapy, Chengdu 610041, People's Republic of China
| | - Da Jia
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Pediatrics, Division of Neurology, West China Second University Hospital, Sichuan University, Chengdu 610041, People's Republic of China
| | - Qingxiang Sun
- Department of Pathology, State Key Laboratory of Biotherapy and Cancer Centre, West China Hospital, Sichuan University, and Collaborative Innovation Centre of Biotherapy, Chengdu 610041, People's Republic of China
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31
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Zhao M, Wang J, Qu M, Zhao Y, Wang H, Ke Y, Liu Y, Lei ZN, Liu HM, Hu Z, Wei L, Chen ZS. OGP46 Induces Differentiation of Acute Myeloid Leukemia Cells via Different Optimal Signaling Pathways. Front Cell Dev Biol 2021; 9:652972. [PMID: 33748146 PMCID: PMC7969801 DOI: 10.3389/fcell.2021.652972] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 02/09/2021] [Indexed: 11/13/2022] Open
Abstract
Acute myelogenous leukemia (AML) is characterized by blockage of cell differentiation leading to the accumulation of immature cells, which is the most prevalent form of acute leukemia in adults. It is well known that all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) are the preferred drugs for acute promyelocytic leukemia (APL). However, they can lead to irreversible resistance which may be responsible for clinical failure after complete remission (CR). Moreover, the differentiation therapy of ATRA-based treatment has not been effective against AML with t(8;21) translocation. Here we aimed to identify the differentiation effect of OGP46 on AML cell lines (HL-60, NB4, and Kasumi-1) and explore its possible mechanisms. We found that OGP46 has significant inhibitory activity against these cells by triggering cell differentiation with cell-cycle exit at G1/G0 and inhibited the colony-formation capacity of the AML cells. It was shown that OGP46 induced the differentiation of NB4 cells via the transcriptional misregulation in cancer signaling pathway by PML-RARα depletion, while it was attributed to the hematopoietic cell lineage and phagosome pathway in Kasumi-1 cells, which are all critical pathways in cell differentiation. These results highlight that OGP46 is an active agent not only in the APL cell line NB4 but also in AML-M2 cell lines, especially Kasumi-1 with t(8;21) translocation. Therefore, OGP46 may be a potential compound for surmounting the differentiation blockage in AML.
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Affiliation(s)
- Min Zhao
- Laboratory for Stem Cell and Regenerative Medicine, Affiliated Hospital of Weifang Medical University, Weifang, China.,School of Pharmacy, Weifang Medical University, Weifang, China
| | - Jiangyun Wang
- Laboratory for Stem Cell and Regenerative Medicine, Affiliated Hospital of Weifang Medical University, Weifang, China.,School of Pharmacy, Weifang Medical University, Weifang, China
| | - Mei Qu
- Laboratory for Stem Cell and Regenerative Medicine, Affiliated Hospital of Weifang Medical University, Weifang, China.,School of Pharmacy, Weifang Medical University, Weifang, China
| | - Yao Zhao
- Laboratory for Stem Cell and Regenerative Medicine, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Haihua Wang
- Laboratory for Stem Cell and Regenerative Medicine, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Yu Ke
- School of Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Ying Liu
- School of Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Zi-Ning Lei
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, NY, United States.,School of Public Health, Guangzhou Medical University, Guangzhou, China
| | - Hong-Min Liu
- School of Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Zhenbo Hu
- Laboratory for Stem Cell and Regenerative Medicine, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Liuya Wei
- Laboratory for Stem Cell and Regenerative Medicine, Affiliated Hospital of Weifang Medical University, Weifang, China.,School of Pharmacy, Weifang Medical University, Weifang, China
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, NY, United States
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Zhang J, Duan D, Song ZL, Liu T, Hou Y, Fang J. Small molecules regulating reactive oxygen species homeostasis for cancer therapy. Med Res Rev 2021; 41:342-394. [PMID: 32981100 DOI: 10.1002/med.21734] [Citation(s) in RCA: 115] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Revised: 07/27/2020] [Accepted: 08/22/2020] [Indexed: 12/13/2022]
Abstract
Elevated intracellular reactive oxygen species (ROS) and antioxidant defense systems have been recognized as one of the hallmarks of cancer cells. Compared with normal cells, cancer cells exhibit increased ROS to maintain their malignant phenotypes and are more dependent on the "redox adaptation" mechanism. Thus, there are two apparently contradictory but virtually complementary therapeutic strategies for the regulation of ROS to prevent or treat cancer. The first strategy, that is, chemoprevention, is to prevent or reduce intracellular ROS either by suppressing ROS production pathways or by employing antioxidants to enhance ROS clearance, which protects normal cells from malignant transformation and inhibits the early stage of tumorigenesis. The second strategy is the ROS-mediated anticancer therapy, which stimulates intracellular ROS to a toxicity threshold to activate ROS-induced cell death pathways. Therefore, targeting the regulation of intracellular ROS-related pathways by small-molecule candidates is considered to be a promising treatment for tumors. We herein first briefly introduce the source and regulation of ROS, and then focus on small molecules that regulate ROS-related pathways and show efficacy in cancer therapy from the perspective of pharmacophores. Finally, we discuss several challenges in developing cancer therapeutic agents based on ROS regulation and propose the direction of future development.
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Affiliation(s)
- Junmin Zhang
- State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, and School of Pharmacy, Lanzhou University, Lanzhou, China
| | - Dongzhu Duan
- State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, and School of Pharmacy, Lanzhou University, Lanzhou, China
- Shaanxi Key Laboratory of Phytochemistry, Baoji University of Arts and Sciences, Baoji, China
| | - Zi-Long Song
- State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, and School of Pharmacy, Lanzhou University, Lanzhou, China
| | - Tianyu Liu
- State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, and School of Pharmacy, Lanzhou University, Lanzhou, China
| | - Yanan Hou
- State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, and School of Pharmacy, Lanzhou University, Lanzhou, China
| | - Jianguo Fang
- State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, and School of Pharmacy, Lanzhou University, Lanzhou, China
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Hu X, Wang Y, Gao X, Xu S, Zang L, Xiao Y, Li Z, Hua H, Xu J, Li D. Recent Progress of Oridonin and Its Derivatives for the Treatment of Acute Myelogenous Leukemia. Mini Rev Med Chem 2020; 20:483-497. [PMID: 31660811 DOI: 10.2174/1389557519666191029121809] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Revised: 03/13/2019] [Accepted: 09/06/2019] [Indexed: 01/03/2023]
Abstract
First stage human clinical trial (CTR20150246) for HAO472, the L-alanine-(14-oridonin) ester trifluoroacetate, was conducted by a Chinese company, Hengrui Medicine Co. Ltd, to develop a new treatment for acute myelogenous leukemia. Two patents, WO2015180549A1 and CN201410047904.X, covered the development of the I-type crystal, stability experiment, conversion rate research, bioavailability experiment, safety assessment, and solubility study. HAO472 hewed out new avenues to explore the therapeutic properties of oridonin derivatives and develop promising treatment of cancer originated from naturally derived drug candidates. Herein, we sought to overview recent progress of the synthetic, physiological, and pharmacological investigations of oridonin and its derivatives, aiming to disclose the therapeutic potentials and broaden the platform for the discovery of new anticancer drugs.
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Affiliation(s)
- Xu Hu
- Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China
| | - Yan Wang
- Valiant Co. Ltd., 11 Wuzhishan Road, YEDA Yantai, Shandong 264006, China
| | - Xiang Gao
- Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China
| | - Shengtao Xu
- Department of Medicinal Chemistry and State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China
| | - Linghe Zang
- School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China
| | - Yan Xiao
- Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China
| | - Zhanlin Li
- Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China
| | - Huiming Hua
- Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China
| | - Jinyi Xu
- Department of Medicinal Chemistry and State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China
| | - Dahong Li
- Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China
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Effect of microwave-drying on the quality and antioxidant properties of Ganoderma lucidum fermented sea-buckthorn tea. INTERNATIONAL JOURNAL OF FOOD ENGINEERING 2020. [DOI: 10.1515/ijfe-2019-0271] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Abstract
Effects of microwave power on the sensory properties (taste and aroma), chemical composition (catechins, caffeine, crude protein, and amino acid), active composition (flavones, triterpene, polysaccharide, and ergosterol) and antioxidant properties (superoxide free radical and hydroxyl radical scavenging abilities, reducing power) of Ganoderma lucidum fermented sea-buckthorn tea were investigated. G. lucidum fermented sea-buckthorn tea was dehydrated using microwaves at three power settings: 125, 250, and 500. After microwave treatment, a statistically significant difference in the chemical composition, active composition and antioxidant capacity (p < 0.05) of teas dried at different power settings was found. These results indicate that 250 W microwave treatments could effectively release and activate active components, improving the antioxidant activity of fermented tea.
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Fan Y, Li J, Yang Y, Zhao X, Liu Y, Jiang Y, Zhou L, Feng Y, Yu Y, Cheng Y. Resveratrol modulates the apoptosis and autophagic death of human lung adenocarcinoma A549 cells via a p53‑dependent pathway: Integrated bioinformatics analysis and experimental validation. Int J Oncol 2020; 57:925-938. [PMID: 32945383 PMCID: PMC7473753 DOI: 10.3892/ijo.2020.5107] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Accepted: 07/22/2020] [Indexed: 02/06/2023] Open
Abstract
Resveratrol (RSV) has been reported to exhibit cytotoxic activity in multiple types of malignant cells; however, the mechanisms underlying the antitumor effects of RSV in non-small-cell lung cancer (NSCLC) cells remain undetermined. Combining bioinformatics analysis with experimental validation, the present study aimed to examine the effects of RSV on the apoptosis and autophagy of A549 NSCLC cells, and to determine the potential underlying molecular mechanisms. Bioinformatics analysis was used to determine the differentially expressed genes (DEGs) and identify the enriched biological functions and pathways associated with these DEGs following RSV treatment. Cell viability was determined by MTT assay, and flow cytometry and TUNEL assay were used to evaluate cell apoptosis. Monodansylcadaverine staining combined with a transmission electron microscope were used to evaluate the extent of autophagy. The expression levels of apoptosis-, autophagy-, or pathway-associated molecular markers were measured by reverse transcription-quantitative PCR and/or western blot analysis. By bioinformatics analysis, a total of 1,031 DEGs were identified in the RSV-treated A549 cells, which were enriched in apoptosis-, or autophagy-related biological functions and the p53 signaling pathway. In validation experiments, RSV significantly reduced cell viability and initiated apoptosis, with an increase in the number of apoptotic cells; it also upregulated cleaved caspase-3 expression and Bax expression, and downregulated the Bcl-2 expression levels. Additionally, there was an increase in the accumulation of green dot-like structures, indicative of autophagic vesicles, observed under a fluorescence microscope, and an increase in the presence of autophagic vacuoles observed using a transmission electron microscope following RSV treatment. Furthermore, the expression levels of the autophagy-related proteins, LC3-II/LC3-I and Beclin-1, were increased and p62 expression was decreased. 3-methyladenine (3-MA), an inhibitor of autophagy, partially reversed the RSV-induced cytotoxic effects, but did not significantly alter the number of apoptotic cells. RSV elevated the p53 levels and decreased the phosphorylated (p-)Mdm2 and p-Akt levels. Pifithrin-α, an inhibitor of p53, partially reduced RSV-induced apoptosis and autophagy. On the whole, the results of the present study demonstrated that RSV initiates the apoptosis and autophagic death of A549 cells via the activation of the p53 signaling pathway, further highlighting the potential of RSV for the treatment of NSCLC.
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Affiliation(s)
- Yameng Fan
- School of Public Health, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Jiaqiao Li
- School of Public Health, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Yuxuan Yang
- School of Basic Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Xiaodan Zhao
- School of Basic Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Yamei Liu
- School of Public Health, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Yude Jiang
- School of Public Health, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Long Zhou
- School of Public Health, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Yang Feng
- School of Public Health, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Yan Yu
- School of Public Health, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Yilong Cheng
- School of Science, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
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Meng J, Ge Y, Xing H, Wei H, Xu S, Liu J, Yan D, Wen T, Wang M, Fang X, Ma L, Yang Y, Wang C, Wang J, Xu H. Synthetic CXCR4 Antagonistic Peptide Assembling with Nanoscaled Micelles Combat Acute Myeloid Leukemia. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2020; 16:e2001890. [PMID: 32608185 DOI: 10.1002/smll.202001890] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Revised: 05/22/2020] [Indexed: 06/11/2023]
Abstract
Acute myeloid leukemia (AML) is the most common adult acute leukemia with very low survival rate due to drug resistance and high relapse rate. The C-X-C chemokine receptor 4 (CXCR4) is highly expressed by AML cells, actively mediating chemoresistance and reoccurrence. Herein, a chemically synthesized CXCR4 antagonistic peptide E5 is fabricated to micelle formulation (M-E5) and applied to refractory AML mice, and its therapeutic effects and pharmacokinetics are investigated. Results show that M-E5 can effectively block the surface CXCR4 in leukemic cells separated from bone marrow (BM) and spleen, and inhibit the C-X-C chemokine ligand 12-mediated migration. Subcutaneous administration of M-E5 significantly inhibits the engraftment of leukemic cells in spleen and BM, and mobilizes residue leukemic cells into peripheral blood, reducing organs' burden and significantly prolonging the survival of AML mice. M-E5 can also increase the efficacy of combining regime of homoharringtonine and doxorubicin. Ribonucleic acid sequencing demonstrates that the therapeutic effect is contributed by inhibiting proliferation and enhancing apoptosis and differentiation, all related to the CXCR4 signaling blockade. M-E5 reaches the concentration peak at 2 h after administration with a half-life of 14.5 h in blood. In conclusion, M-E5 is a novel promising therapeutic candidate for refractory AML treatment.
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Affiliation(s)
- Jie Meng
- Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Yangyang Ge
- Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Haiyan Xing
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Hui Wei
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Shilin Xu
- Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Jian Liu
- Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Doudou Yan
- Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Tao Wen
- Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Min Wang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Xiaocui Fang
- CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Lilusi Ma
- CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yanlian Yang
- CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Chen Wang
- CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Jianxiang Wang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Haiyan Xu
- Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
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Ho PY, Ho CL, Wong WY. Recent advances of iridium(III) metallophosphors for health-related applications. Coord Chem Rev 2020. [DOI: 10.1016/j.ccr.2020.213267] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Oridonin Attenuates Myocardial Ischemia/Reperfusion Injury via Downregulating Oxidative Stress and NLRP3 Inflammasome Pathway in Mice. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:7395187. [PMID: 32565873 PMCID: PMC7277023 DOI: 10.1155/2020/7395187] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 04/27/2020] [Accepted: 05/15/2020] [Indexed: 12/18/2022]
Abstract
Oridonin (ORI), the major pharmacological component extracted from a traditional Chinese medicine, possesses a beneficial effect on myocardial ischemia/reperfusion (I/R) injury. However, the underlying molecular mechanism by which ORI effects take place is not completely known. Thus, whether ORI works via downregulating oxidative stress and nod-like receptor protein-3 (NLRP3) inflammasome pathway was investigated in this study. Mice underwent surgery to induce myocardial I/R injury, and some were administered ORI (10 mg/kg/day) pretreatment, while others were not. The myocardial enzymes' levels, infarct area, and inflammatory injury were measured. The activation situation of oxidative stress and NLRP3 inflammasome was also detected. We found that ORI pretreatment significantly alleviated CK-MB and cTnI levels and infarct size induced by I/R. ORI mitigated the inflammatory injury by decreasing the pathological damage and lowering TNF-α, IL-1β, and IL-18 levels. Moreover, the SOD1 and eNOS levels were significantly increased by ORI, while MDA and iNOS levels were relatively decreased. The oxidative stress was reversed using ORI pretreatment. Importantly, NLRP3 inflammasome pathway was also inhibited by ORI, as reflected by the lower protein levels of NLRP3, caspase-1, and IL-1β. In conclusion, ORI alleviates myocardial injury induced by I/R via inhibiting the oxidative stress and NLRP3 inflammasome pathway.
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Zhang HL, Zhang Y, Yan XL, Xiao LG, Hu DX, Yu Q, An LK. Secondary metabolites from Isodon ternifolius (D. Don) Kudo and their anticancer activity as DNA topoisomerase IB and Tyrosyl-DNA phosphodiesterase 1 inhibitors. Bioorg Med Chem 2020; 28:115527. [PMID: 32345458 DOI: 10.1016/j.bmc.2020.115527] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 04/17/2020] [Accepted: 04/20/2020] [Indexed: 12/21/2022]
Abstract
Based on DNA topoisomerase IB (TOP1) and tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibition of the ethanol extract of the roots of Isodon ternifolius (D. Don) Kudo (Labiatae), its secondary metabolites has been studied. Two new compounds, an ent-abietane diterpenoid isodopene A (1) and a 2,3-seco-triterpene isodopene B (13), along with 25 known compounds were isolated. Their structures were elucidated by spectroscopic analysis and theoretical calculations. The enzyme-based assays indicated that 1 and 13 showed strong (+++) and moderate (++) TOP1 inhibition, respectively. Two chalcone derivatives 11 and 12 were firstly found as dual TDP1 and TOP1 natural inhibitors, and showed synergistic effect with the clinical TOP1 inhibitors topotecan in MCF-7 cells. Compounds 8, 16, and 22 acted as TOP1 catalytic inhibitors with equipotent TOP1 inhibition to camptothecin (++++). Compounds 7 and 8 exhibited significant cytotoxicity against MCF-7, A549, and HCT116 cells with GI50 values in the range of 2.2-4.8 μM. This work would provide valuable information that secondary metabolites from I. ternifolius could be developed as anticancer agents.
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Affiliation(s)
- Hong-Li Zhang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Yu Zhang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Xue-Long Yan
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Long-Gao Xiao
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - De-Xuan Hu
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Qian Yu
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China; Clinical Pharmacy (School of Integrative Pharmacy, Institute of Integrative Pharmaceutical Research), Guangdong Pharmaceutical University, Guangzhou 510006, China.
| | - Lin-Kun An
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China; Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangzhou 510006, China.
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Holth TAD, Walters MA, Hutt OE, Georg GI. Diversity-Oriented Library Synthesis from Steviol and Isosteviol-Derived Scaffolds. ACS COMBINATORIAL SCIENCE 2020; 22:150-155. [PMID: 32065745 DOI: 10.1021/acscombsci.9b00186] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
The readily available natural product stevioside provides a unique diterpene core structure that can be explored for small molecule library development by diversity-oriented synthesis and functional group transformations. Validation arrays were prepared from steviol, isosteviol, and related analogues, derived from stevioside, to produce over 90 compounds. These compounds were submitted to the NIH Molecular Libraries Small Molecule Repository for screening in the Molecular Libraries Screening Center Network. Micromolar hits were identified in multiple high-throughput assays for several library members. A cheminformatics analysis of the compounds was performed that verified the expected diversity and complexity of this set of compounds. The screening results indicate that scaffolds-derived natural products can provide screening hits against multiple target proteins.
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Affiliation(s)
- Trinh A. D. Holth
- Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota, 717 Delaware Street Southeast, Minneapolis, Minnesota 55414, United States
| | - Michael A. Walters
- Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota, 717 Delaware Street Southeast, Minneapolis, Minnesota 55414, United States
| | - Oliver E. Hutt
- Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota, 717 Delaware Street Southeast, Minneapolis, Minnesota 55414, United States
| | - Gunda I. Georg
- Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota, 717 Delaware Street Southeast, Minneapolis, Minnesota 55414, United States
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Liu HC, Qiao LM, Zheng W, Xiang ZB, Chen HS, Yu SC, Zhang DZ, Wang T, Zhang YF, Jin YS. Synthesis and Cytotoxicity Assessment of Novel 7-O- and 14-O-Derivatives of Glaucocalyxin A. Anticancer Agents Med Chem 2020; 20:1241-1249. [PMID: 32116205 DOI: 10.2174/1871520620666200302114550] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 02/09/2020] [Accepted: 02/10/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Rabdosia japonica has been historically used in China as a popular folk medicine for the treatment of cancer, hepatitis, and gastricism. Glaucocalyxin A (GLA), an ent-kaurene diterpene isolated from Rabdosia japonica, is one of the main active ingredients showing potent inhibitory effects against several types of tumor cells. To the best of our knowledge, studies regarding the structural modification and Structure- Activity Relations (SAR) of this compound have not yet been reported. OBJECTIVE The aim of this study was to discover more potent derivatives of GLA and investigate their SAR and cytotoxicity mechanisms. METHODS Novel 7-O- and 14-O-derivatives of GLA were synthesized by condensation of acids or acyl chloride. The anti-tumor activities of these derivatives against various human cancer cell lines were evaluated in vitro by MTT assays. Apoptosis assays of compound 17 (7,14-diacylation product) were performed on A549 and HL-60 cells by flow cytometry and TUNNEL. The acute toxicity of this compound was tested on mice, at the dose of 300mg per kg body weight. RESULTS Seventeen novel 7-O- and 14-O-derivatives of GLA (1-17) were synthesized. These compounds showed potent cytotoxicity against the tested cancer cell lines, and almost all of them were found to be more cytotoxic than GLA and oridonin. Of the synthesized derivatives, compound 17 presented the greatest cytotoxicity, with IC50 values of 0.26μM and 1.10μM in HL-60 and CCRF-CEM cells, respectively. Furthermore, this compound induced weak apoptosis of A549 cells but showed great potential in stimulating the apoptosis of HL- 60 cells. Acute toxicity assays indicated that compound 17 is relatively safer. CONCLUSION The results reported herein indicate that the synthesized GLA derivatives exhibited greater cytotoxicity against leukemia cells than against other types of tumors. In particular, 7,14-diacylation product of GLA was found to be an effective anti-tumor agent. However, the cytotoxicity mechanism of this product in A549 cells is expected to be different than that in other tumor cell lines. Further research is needed to confirm this hypothesis.
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Affiliation(s)
- Hong-Chuan Liu
- Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China
| | - Li-Ming Qiao
- Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China
| | - Wei Zheng
- Department of Pharmacy, the 72nd Group Army Hospital of PLA, Huzhou, Zhejiang Province 313000, China
| | - Zhao-Bao Xiang
- Key Laboratory of Natural Medicine Research of Chongqing Education Commission, Chongqing Technology and Business University, Chongqing, 400067, China
| | - Hai-Sheng Chen
- Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China
| | - Shi-Chong Yu
- Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China
| | - Da-Zhi Zhang
- Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China
| | - Ting Wang
- Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China
| | - Yue-Fan Zhang
- Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China
| | - Yong-Sheng Jin
- Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China
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Hydrogen sulfide releasing oridonin derivatives induce apoptosis through extrinsic and intrinsic pathways. Eur J Med Chem 2020; 187:111978. [DOI: 10.1016/j.ejmech.2019.111978] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Revised: 12/12/2019] [Accepted: 12/16/2019] [Indexed: 02/06/2023]
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Tian L, Sheng D, Li Q, Guo C, Zhu G. Preliminary safety assessment of oridonin in zebrafish. PHARMACEUTICAL BIOLOGY 2019; 57:632-640. [PMID: 31545911 PMCID: PMC6764400 DOI: 10.1080/13880209.2019.1662457] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2023]
Abstract
Context: Oridonin, isolated from the leaves of Isodon rubescens (Hemsl.) H.Hara (Lamiaceae), has good antitumor activity. However, its safety in vivo is still unclear. Objective: To investigate the preliminary safety of oridonin in zebrafish. Materials and methods: Embryo, larvae and adult zebrafish (n = 40) were used. Low, medium and high oridonin concentrations (100, 200 and 400 mg/L for embryo; 150, 300 and 600 mg/L for larvae; 200, 400 and 800 mg/L for adult zebrafish) and blank samples were administered. At specific stages of zebrafish development, spontaneous movement, heartbeat, hatching rate, etc., were recorded to assess the developmental effects of oridonin. VEGFA, VEGFR2 and VEGFR3 gene expression were also examined. Results: Low-dose oridonin increased spontaneous movement and hatching rate with median effective doses (ED50) of 115.17 mg/L at 24 h post-fertilization (hpf) and 188.59 mg/L at 54 hpf, but these values decreased at high doses with half maximal inhibitory concentrations (IC50) of 209.11 and 607.84 mg/L. Oridonin decreased heartbeat with IC50 of 285.76 mg/L at 48 hpf, and induced malformation at 120 hpf with half maximal effective concentration (EC50) of 411.94 mg/L. Oridonin also decreased body length with IC50 of 324.78 mg/L at 144 hpf, and increased swimming speed with ED50 of 190.98 mg/L at 120 hpf. The effects of oridonin on zebrafish embryo development may be attributed to the downregulation of VEGFR3 gene expression. Discussions and conclusions: Oridonin showed adverse effects at early stages of zebrafish development. We will perform additional studies on mechanism of oridonin based on VEGFR3.
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Affiliation(s)
- Lili Tian
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Traditional Chinese Medicine Pharmacy, Zhejiang Hospital, Hangzhou, China
| | - Donglai Sheng
- Institute of Developmental and Regenerative Biology, Hangzhou Normal University, Hangzhou, China
| | - Qiushuang Li
- Center of Clinical Evaluation and Analysis, Zhejiang Provincial Hospital of Traditional Chinese Medicine, Hangzhou, China
| | - Chenxu Guo
- Department of Integrated Chinese and Western Medicine, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Guofu Zhu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- CONTACT Guofu Zhu School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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44
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Overview of thioredoxin system and targeted therapies for acute leukemia. Mitochondrion 2019; 47:38-46. [PMID: 31029641 DOI: 10.1016/j.mito.2019.04.010] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 03/15/2019] [Accepted: 04/24/2019] [Indexed: 12/11/2022]
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45
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Zhang W, Lu Y, Zhen T, Chen X, Zhang M, Liu P, Weng X, Chen B, Wang Y. Homoharringtonine synergy with oridonin in treatment of t(8; 21) acute myeloid leukemia. Front Med 2019; 13:388-397. [PMID: 30206768 DOI: 10.1007/s11684-018-0624-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Accepted: 12/06/2017] [Indexed: 02/07/2023]
Abstract
Collaboration of c-KIT mutations with AML1-ETO (AE) has been demonstrated to induce t(8; 21) acute myeloid leukemia (AML). Targeted therapies designed to eliminate AE and c-KIT oncoproteins may facilitate effective treatment of t(8; 21) AML. Homoharringtonine (HHT) features activity against tumor cells harboring c-KIT mutations, whereas oridonin can induce t(8; 21) AML cell apoptosis and AE cleavage. Therefore, studies should explore the efficacy of combination therapy with oridonin and HHT in t(8; 21) AML. In this study, we investigated the synergistic effects and mechanism of oridonin combined with HHT in t(8; 21) AML cell line and mouse model. The two drugs synergistically inhibited cell viability and induced significant mitochondrial membrane potential loss and apoptosis. Oridonin and HHT induced significant downregulation of c-KIT and its downstream signaling pathways and promoted AE cleavage. HHT increased intracellular oridonin concentration by modulating the expressions of MRP1 and MDR1, thus enhancing the effects of oridonin. The combination of oridonin and HHT prolonged t(8; 21) leukemia mouse survival. In conclusion, oridonin and HHTexert synergistic effects against t(8; 21) leukemia in vivo and in vitro, thereby indicating that their combination may be an effective therapy for t(8; 21) leukemia.
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Affiliation(s)
- Weina Zhang
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Ying Lu
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Tao Zhen
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Xinjie Chen
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Ming Zhang
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Ping Liu
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Xiangqin Weng
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Bing Chen
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yueying Wang
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
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46
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Li H, Gao X, Huang X, Wang X, Xu S, Uchita T, Gao M, Xu J, Hua H, Li D. Hydrogen sulfide donating ent-kaurane and spirolactone-type 6,7-seco-ent-kaurane derivatives: Design, synthesis and antiproliferative properties. Eur J Med Chem 2019; 178:446-457. [PMID: 31202992 DOI: 10.1016/j.ejmech.2019.06.016] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 06/03/2019] [Accepted: 06/04/2019] [Indexed: 01/15/2023]
Abstract
Motivated by our interest in hydrogen sulfide bio-chemistry and ent-kaurane diterpenoid chemistry, 14 hydrogen sulfide donating derivatives (9, 11a-c, 12a-c, 13, 14, 16a-c and 17a-b) of ent-kaurane and spirolactone-type 6,7-seco-ent-kaurane were designed and synthesized. Four human cancer cell lines (K562, Bel-7402, SGC-7901 and A549) and two normal cell lines (L-02 and PBMC) were selected for antiproliferative assay. Most derivatives showed more potent activities than the lead ent-kaurane oridonin. Among them, compound 12b exhibited the most potent antiproliferative activities, with IC50 values of 1.01, 0.88, 4.36 and 5.21 μM against above human cancer cell lines, respectively. Further apoptosis-related mechanism study indicated that 12b could arrest Bel-7402 cell cycle at G1 phase and induce apoptosis through mitochondria related pathway. Through Western blot assay, 12b was shown to influence the intrinsic pathway by increasing the expression of Bax, cleaved caspase-3, cytochrome c and cleaved PARP, meanwhile suppressing procaspase-3, Bcl-2, Bcl-xL and PARP.
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Affiliation(s)
- Haonan Li
- Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, PR China
| | - Xiang Gao
- Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, PR China
| | - Xiaofang Huang
- Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, PR China
| | - Xianhua Wang
- School of Public Health, Qingdao University, 38 Dengzhou Road, Qingdao, 266021, PR China
| | - Shengtao Xu
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, PR China
| | - Takahiro Uchita
- School of Pharmaceutical Sciences, Mukogawa Women's University, 11-68 Koshien, Nishinomiya, 663-8179, Japan
| | - Ming Gao
- School of Pharmaceutical Sciences, Mukogawa Women's University, 11-68 Koshien, Nishinomiya, 663-8179, Japan
| | - Jinyi Xu
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, PR China
| | - Huiming Hua
- Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, PR China
| | - Dahong Li
- Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, PR China.
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47
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Luo D, Yi Y, Peng K, Liu T, Yang J, Liu S, Zhao W, Qu X, Yu W, Gu Y, Wan S. Oridonin derivatives as potential anticancer drug candidates triggering apoptosis through mitochondrial pathway in the liver cancer cells. Eur J Med Chem 2019; 178:365-379. [PMID: 31200238 DOI: 10.1016/j.ejmech.2019.06.006] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Revised: 05/20/2019] [Accepted: 06/03/2019] [Indexed: 12/19/2022]
Abstract
The biological function of the natural ent-kaurene diterpenoid isolated from genus Isodon, oridonin, has been intensively studied. However, its mechanism studies and clinical applications were hampered by its moderate biological activities. In order to enlarge the applied range of oridonin and explore its mechanism of action, a series of derivatives were designed and synthesized based on the structure of oridonin. Some of the derivatives were significantly more potent than oridonin against four cancer cell lines. Especially, the most potent compound 20 markedly inhibited the proliferation of well differentiated HepG2 and poorly differentiated PLC/PRF/5 cells, with IC50 values as low as 1.36 μM and 0.78 μM respectively, while the IC50 values of oridonin are 8.12 μM and 7.41 μM. We found that compound 20 inhibited liver cancer cell proliferation via arresting cell cycle at G1 phase. Moreover, it induced liver cancer cell apoptosis by decreasing the mitochondrial membrane potential, increasing intracellular reactive oxygen species level and inducing the expression of apoptosis-related proteins. Furthermore, compound 20 significantly inhibited growth of PLC/PRF/5 xenograft tumors in nude mice and had no observable toxic effect. Altogether, these results indicated that compound 20 is a promising lead for liver cancer therapeutics.
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Affiliation(s)
- Dongdong Luo
- Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, and Yushan Road 5, Qingdao, 266003, China
| | - Yujiao Yi
- Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, and Yushan Road 5, Qingdao, 266003, China
| | - Kai Peng
- Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, and Yushan Road 5, Qingdao, 266003, China
| | - Tangrong Liu
- Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, and Yushan Road 5, Qingdao, 266003, China
| | - Jiayu Yang
- Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, and Yushan Road 5, Qingdao, 266003, China
| | - Shan Liu
- Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, and Yushan Road 5, Qingdao, 266003, China
| | - Wanzhou Zhao
- The Nanjing Han & Zaenker Cancer Institute (NHZCI), Nanjing OGpharma Co. Ltd., Nanjing, 210036, China
| | - Xianjun Qu
- Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Wengong Yu
- Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, and Yushan Road 5, Qingdao, 266003, China
| | - Yuchao Gu
- Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, and Yushan Road 5, Qingdao, 266003, China.
| | - Shengbiao Wan
- Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, and Yushan Road 5, Qingdao, 266003, China.
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48
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Xu M, Wan CX, Huang SH, Wang HB, Fan D, Wu HM, Wu QQ, Ma ZG, Deng W, Tang QZ. Oridonin protects against cardiac hypertrophy by promoting P21-related autophagy. Cell Death Dis 2019; 10:403. [PMID: 31127082 PMCID: PMC6534559 DOI: 10.1038/s41419-019-1617-y] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2018] [Revised: 04/22/2019] [Accepted: 04/29/2019] [Indexed: 02/06/2023]
Abstract
Autophagy is an endogenous protective process; the loss of autophagy could destabilize proteostasis and elevate intracellular oxidative stress, which is critically involved in the development of cardiac hypertrophy and heart failure. Oridonin, a natural tetracycline diterpenoid from the Chinese herb Rabdosia, has autophagy activation properties. In this study, we tested whether oridonin protects against cardiac hypertrophy in mice and cardiomyocytes. We implemented aortic banding to induce a cardiac hypertrophy mouse model, and oridonin was given by gavage for 4 weeks. Neonatal rat cardiomyocytes were stimulated with angiotensin II to simulate neurohumoural stress. Both in vivo and in vitro studies suggested that oridonin treatment mitigated pressure overload-induced cardiac hypertrophy and fibrosis, and also preserved heart function. Mice that received oridonin exhibited increased antioxidase activities and suppressed oxidative injury compared with the aortic banding group. Moreover, oridonin enhanced myocardial autophagy in pressure-overloaded hearts and angiotensin II-stimulated cardiomyocytes. Mechanistically, we discovered that oridonin administration regulated myocardial P21, and cytoplasmic P21 activated autophagy via regulating Akt and AMPK phosphorylation. These findings were further corroborated in a P21 knockout mouse model. Collectively, pressure overload-induced autophagy dysfunction causes intracellular protein accumulation, resulting in ROS injury while aggravating cardiac hypertrophy. Thus, our data show that oridonin promoted P21-related autophagic lysosomal degradation, hence attenuating oxidative injury and cardiac hypertrophy.
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Affiliation(s)
- Man Xu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.,Cardiovascular Research Institute of Wuhan University, Wuhan, 430060, China.,Hubei Key Laboratory of Cardiology, Wuhan, 430060, China
| | - Chun-Xia Wan
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.,Cardiovascular Research Institute of Wuhan University, Wuhan, 430060, China.,Hubei Key Laboratory of Cardiology, Wuhan, 430060, China
| | - Si-Hui Huang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.,Cardiovascular Research Institute of Wuhan University, Wuhan, 430060, China.,Hubei Key Laboratory of Cardiology, Wuhan, 430060, China
| | - Hui-Bo Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.,Cardiovascular Research Institute of Wuhan University, Wuhan, 430060, China.,Hubei Key Laboratory of Cardiology, Wuhan, 430060, China
| | - Di Fan
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.,Cardiovascular Research Institute of Wuhan University, Wuhan, 430060, China.,Hubei Key Laboratory of Cardiology, Wuhan, 430060, China
| | - Hai-Ming Wu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.,Cardiovascular Research Institute of Wuhan University, Wuhan, 430060, China.,Hubei Key Laboratory of Cardiology, Wuhan, 430060, China
| | - Qing-Qing Wu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.,Cardiovascular Research Institute of Wuhan University, Wuhan, 430060, China.,Hubei Key Laboratory of Cardiology, Wuhan, 430060, China
| | - Zhen-Guo Ma
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.,Cardiovascular Research Institute of Wuhan University, Wuhan, 430060, China.,Hubei Key Laboratory of Cardiology, Wuhan, 430060, China
| | - Wei Deng
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China. .,Cardiovascular Research Institute of Wuhan University, Wuhan, 430060, China. .,Hubei Key Laboratory of Cardiology, Wuhan, 430060, China.
| | - Qi-Zhu Tang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China. .,Cardiovascular Research Institute of Wuhan University, Wuhan, 430060, China. .,Hubei Key Laboratory of Cardiology, Wuhan, 430060, China.
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49
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Zhou B, Ye H, Xing C, Liang B, Li H, Chen L, Huang X, Wu Y, Gao S. Targeting miR-193a-AML1-ETO-β-catenin axis by melatonin suppresses the self-renewal of leukaemia stem cells in leukaemia with t (8;21) translocation. J Cell Mol Med 2019; 23:5246-5258. [PMID: 31119862 PMCID: PMC6653044 DOI: 10.1111/jcmm.14399] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 04/17/2019] [Accepted: 05/03/2019] [Indexed: 12/12/2022] Open
Abstract
AML1‐ETO, the most common fusion oncoprotein by t (8;21) in acute myeloid leukaemia (AML), enhances hematopoietic self‐renewal and leukemogenesis. However, currently no specific therapies have been reported for t (8;21) AML patients as AML1‐ETO is still intractable as a pharmacological target. For this purpose, leukaemia cells and AML1‐ETO‐induced murine leukaemia model were used to investigate the degradation of AML1‐ETO by melatonin (MLT), synthesized and secreted by the pineal gland. MLT remarkedly decreased AML1‐ETO protein in leukemic cells. Meanwhile, MLT induced apoptosis, decreased proliferation and reduced colony formation. Furthermore, MLT reduced the expansion of human leukemic cells and extended the overall survival in U937T‐AML1‐ETO‐xenografted NSG mice. Most importantly, MLT reduced the infiltration of leukaemia blasts, decreased the frequency of leukaemia stem cells (LSCs) and prolonged the overall survival in AML1‐ETO‐induced murine leukaemia. Mechanistically, MLT increased the expression of miR‐193a, which inhibited AML1‐ETO expression via targeting its putative binding sites. Furthermore, MLT decreased the expression of β‐catenin, which is required for the self‐renewal of LSC and is the downstream of AML1‐ETO. Thus, MLT presents anti‐self‐renewal of LSC through miR‐193a‐AML1‐ETO‐β‐catenin axis. In conclusion, MLT might be a potential treatment for t (8;21) leukaemia by targeting AML1‐ETO oncoprotein.
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Affiliation(s)
- Bin Zhou
- Laboratory of Internal Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Haige Ye
- Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Chongyun Xing
- Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Bin Liang
- Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Haiying Li
- Laboratory of Internal Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Linling Chen
- Department of Clinical Laboratory, The People's Hospital of Yuhuang County, Taizhou, China
| | - Xingzhou Huang
- Laboratory of Internal Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yanfei Wu
- Laboratory of Internal Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Shenmeng Gao
- Laboratory of Internal Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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50
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Oridonin inhibits LPS-induced inflammation in human gingival fibroblasts by activating PPARγ. Int Immunopharmacol 2019; 72:301-307. [PMID: 31005040 DOI: 10.1016/j.intimp.2019.04.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2018] [Revised: 04/01/2019] [Accepted: 04/02/2019] [Indexed: 02/07/2023]
Abstract
Oridonin, the major terpene isolated from Rabdosia rubescens, has been used as dietary supplement. Recently, it has been known to exhibit anti-inflammatory effect. This study we employed an in vitro model of LPS-stimulated human gingival fibroblasts to investigate the anti-inflammatory effects and mechanism of oridonin. Oridonin (10-30 μg/mL) was administrated 1 h before LPS treatment. The results showed that oridonin significantly inhibited inflammatory mediators PGE2, NO, IL-6, and IL-8 production. Immunoblotting experiments revealed that oridonin reduced the expression of phosphorylation levels of NF-κB p65 and IκBα. Furthermore, the expression of PPARγ was up-regulated by the treatment of oridonin. Further studies showed that PPARγ inhibitor GW9662 could reverse the inhibition of oridonin on PGE2, NO, IL-6, and IL-8 production. In conclusion, oridonin inhibited LPS-induced microglia activation through activating PPARγ.
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