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Luo J, Chen K, Nong X. Potential regulation of artesunate on bone metabolism through suppressing inflammatory infiltration in type 2 diabetes mellitus. Immunopharmacol Immunotoxicol 2025; 47:147-158. [PMID: 39762719 DOI: 10.1080/08923973.2024.2444953] [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: 01/24/2024] [Accepted: 12/15/2024] [Indexed: 03/29/2025]
Abstract
OBJECTIVE Osteoimmunology is an emerging field that explores the interplay between bone and the immune system. The immune system plays a critical role in the pathogenesis of diabetes and significantly affects bone homeostasis. Artesunate, a first-line treatment for malaria, is known for its low toxicity and multifunctional properties. Increasing evidence suggests that artesunate possesses anti-inflammatory, immunoregulatory, and osteogenic effects. This review aims to explore the relationship between immune regulation and bone metabolism in type 2 diabetes (T2DM) and to investigate the potential therapeutic application of artesunate. METHODS This review systematically examines literature from PubMed/Medline, Elsevier, Web of Science, Embase, the International Diabetes Federation, and other relevant databases. RESULTS This review synthesizes evidence from multiple sources to delineate the relationship between T lymphocytes and T2DM, the regulation of T lymphocyte subsets in bone metabolism, and the effects of artesunate on both T lymphocytes and bone metabolism. Recent studies suggest a bidirectional regulatory relationship between T2DM and T lymphocytes (CD4+ T and CD8+ T) during the onset and progression of the disease, with inflammatory and anti-inflammatory cytokines serving as key mediators. T lymphocyte subsets and their cytokines play a pivotal role in regulating osteogenesis and osteoclastogenesis in pathological conditions. Furthermore, artesunate has shown promise in modulating inflammatory infiltration and bone metabolism. CONCLUSION The accumulated evidence indicates that artesunate exerts regulatory effects on bone metabolism in T2DM by influencing T lymphocyte differentiation.
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Affiliation(s)
- Jinghong Luo
- Department of Oral & Maxillofacial Surgery, College of Stomatology, Guangxi Medical University, Nanning, Guangxi, China
| | - Kun Chen
- Department of Oral & Maxillofacial Surgery, College of Stomatology, Guangxi Medical University, Nanning, Guangxi, China
| | - Xiaolin Nong
- Department of Oral & Maxillofacial Surgery, College of Stomatology, Guangxi Medical University, Nanning, Guangxi, China
- Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Medical University, Nanning, Guangxi, China
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Qiao Y, Liang J, Jiang D. State of the ART: Drug Screening Reveals Artesunate as a Promising Anti-Fibrosis Therapy. JOURNAL OF RESPIRATORY BIOLOGY AND TRANSLATIONAL MEDICINE 2025; 2:10023. [PMID: 39925974 PMCID: PMC11800322 DOI: 10.70322/jrbtm.2024.10023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/11/2025]
Abstract
Fibrosis is a progressive pathological process that severely impairs normal organ function. Current treatments for fibrosis are extremely limited, with no curative approaches available. In a recent article published in Cell, Zhang and colleagues employed drug screening using ACTA2 reporter iPSC-derived cardiac fibroblasts and identified artesunate as a potent antifibrotic drug by targeting MD2/TLR4 signaling. This study provides new insights into strategies for exploiting existing drugs to treat fibrosis.
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Affiliation(s)
- Yujie Qiao
- Division of Pulmonary, Women’s Guild Lung Institute,
Department of Medicine, Los Angeles, CA 90048, USA
- Department of Respiratory and Critical Care Medicine,
Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Jiurong Liang
- Division of Pulmonary, Women’s Guild Lung Institute,
Department of Medicine, Los Angeles, CA 90048, USA
| | - Dianhua Jiang
- Division of Pulmonary, Women’s Guild Lung Institute,
Department of Medicine, Los Angeles, CA 90048, USA
- Department of Biomedical Sciences, Cedars-Sinai Medical
Center, Los Angeles, CA 90048, USA
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Zhang H, Thai PN, Shivnaraine RV, Ren L, Wu X, Siepe DH, Liu Y, Tu C, Shin HS, Caudal A, Mukherjee S, Leitz J, Wen WTL, Liu W, Zhu W, Chiamvimonvat N, Wu JC. Multiscale drug screening for cardiac fibrosis identifies MD2 as a therapeutic target. Cell 2024; 187:7143-7163.e22. [PMID: 39413786 PMCID: PMC11645214 DOI: 10.1016/j.cell.2024.09.034] [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: 12/05/2023] [Revised: 08/13/2024] [Accepted: 09/19/2024] [Indexed: 10/18/2024]
Abstract
Cardiac fibrosis impairs cardiac function, but no effective clinical therapies exist. To address this unmet need, we employed a high-throughput screening for antifibrotic compounds using human induced pluripotent stem cell (iPSC)-derived cardiac fibroblasts (CFs). Counter-screening of the initial candidates using iPSC-derived cardiomyocytes and iPSC-derived endothelial cells excluded hits with cardiotoxicity. This screening process identified artesunate as the lead compound. Following profibrotic stimuli, artesunate inhibited proliferation, migration, and contraction in human primary CFs, reduced collagen deposition, and improved contractile function in 3D-engineered heart tissues. Artesunate also attenuated cardiac fibrosis and improved cardiac function in heart failure mouse models. Mechanistically, artesunate targeted myeloid differentiation factor 2 (MD2) and inhibited MD2/Toll-like receptor 4 (TLR4) signaling pathway, alleviating fibrotic gene expression in CFs. Our study leverages multiscale drug screening that integrates a human iPSC platform, tissue engineering, animal models, in silico simulations, and multiomics to identify MD2 as a therapeutic target for cardiac fibrosis.
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Affiliation(s)
- Hao Zhang
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
| | - Phung N Thai
- Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, Davis, CA 95616, USA; David Geffen School of Medicine at University of California, Los Angeles, CA 90095, USA
| | | | - Lu Ren
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Xuekun Wu
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Dirk H Siepe
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Yu Liu
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Chengyi Tu
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Hye Sook Shin
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Arianne Caudal
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | | | - Jeremy Leitz
- Greenstone Biosciences, Palo Alto, CA 94305, USA
| | - Wilson Tan Lek Wen
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Wenqiang Liu
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Wenjuan Zhu
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Nipavan Chiamvimonvat
- Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, Davis, CA 95616, USA; Department of Basic Medical Sciences and Translational Cardiovascular Research Center, University of Arizona College of Medicine, Phoenix, AZ 85004, USA
| | - Joseph C Wu
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
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Pierre-Louis E, Kelley J, Patel D, Carlson C, Talundzic E, Jacobson D, Barratt JLN. Geo-classification of drug-resistant travel-associated Plasmodium falciparum using Pfs47 and Pfcpmp gene sequences (USA, 2018-2021). Antimicrob Agents Chemother 2024; 68:e0120324. [PMID: 39530682 PMCID: PMC11619247 DOI: 10.1128/aac.01203-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 10/18/2024] [Indexed: 11/16/2024] Open
Abstract
Travel-related malaria is regularly encountered in the United States, and the U.S. Centers for Disease Control and Prevention (CDC) characterizes Plasmodium falciparum drug-resistance genotypes routinely for travel-related cases. An important aspect of antimalarial drug resistance is understanding its geographic distribution. However, specimens submitted to CDC laboratories may have missing, incomplete, or inaccurate travel data. To complement genotyping for drug-resistance markers Pfcrt, Pfmdr1, Pfk13, Pfdhps, Pfdhfr, and PfcytB at CDC, amplicons of Pfs47 and Pfcpmp are also sequenced as markers of geographic origin. Here, a bi-allele likelihood (BALK) classifier was trained using Pfs47 and Pfcpmp sequences from published P. falciparum genomes of known geographic origin to classify clinical genotypes to a continent. Among P. falciparum-positive blood samples received at CDC for drug-resistance genotyping from 2018 to 2021 (n = 380), 240 included a travel history with the submission materials, though 6 were excluded due to low sequence quality. Classifications obtained for the remaining 234 were compared to their travel histories. Classification results were over 96% congruent with reported travel for clinical samples, and with collection sites for field isolates. Among travel-related samples, only two incongruent results occurred; a specimen submitted citing Costa Rican travel classified to Africa, and a specimen with travel referencing Sierra Leone classified to Asia. Subsequently, the classifier was applied to specimens with unreported travel histories (n = 140; 5 were excluded due to low sequence quality). For the remaining 135 samples, geographic classification data were paired with results generated using CDC's Malaria Resistance Surveillance (MaRS) protocol, which detects single-nucleotide polymorphisms in and generates haplotypes for Pfcrt, Pfmdr1, Pfk13, Pfdhps, Pfdhfr, and PfcytB. Given the importance of understanding the geographic distribution of antimalarial drug resistance, this work will complement domestic surveillance efforts by expanding knowledge on the geographic origin of drug-resistant P. falciparum entering the USA.
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Affiliation(s)
- Edwin Pierre-Louis
- Laboratory Science and Diagnostics Branch, Division of Parasitic Diseases and Malaria, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
- Oak Ridge Institute for Science and Education, Oak Ridge, Tennessee, USA
| | - Julia Kelley
- Laboratory Science and Diagnostics Branch, Division of Parasitic Diseases and Malaria, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Dhruviben Patel
- Laboratory Science and Diagnostics Branch, Division of Parasitic Diseases and Malaria, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
- Williams Consulting LLC, Atlanta, Georgia, USA
| | - Christina Carlson
- Laboratory Science and Diagnostics Branch, Division of Parasitic Diseases and Malaria, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Eldin Talundzic
- Laboratory Science and Diagnostics Branch, Division of Parasitic Diseases and Malaria, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - David Jacobson
- Laboratory Science and Diagnostics Branch, Division of Parasitic Diseases and Malaria, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Joel Leonard Nicholas Barratt
- Laboratory Science and Diagnostics Branch, Division of Parasitic Diseases and Malaria, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
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Long Z, Xiang W, Xiao W, Min Y, Qu F, Zhang B, Zeng L. Advances in the study of artemisinin and its derivatives for the treatment of rheumatic skeletal disorders, autoimmune inflammatory diseases, and autoimmune disorders: a comprehensive review. Front Immunol 2024; 15:1432625. [PMID: 39524446 PMCID: PMC11543433 DOI: 10.3389/fimmu.2024.1432625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 09/16/2024] [Indexed: 11/16/2024] Open
Abstract
Artemisinin and its derivatives are widely recognized as first-line treatments for malaria worldwide. Recent studies have demonstrated that artemisinin-based antimalarial drugs, such as artesunate, dihydroartemisinin, and artemether, not only possess excellent antimalarial properties but also exhibit antitumor, antifungal, and immunomodulatory effects. Researchers globally have synthesized artemisinin derivatives like SM735, SM905, and SM934, which offer advantages such as low toxicity, high bioavailability, and potential immunosuppressive properties. These compounds induce immunosuppression by inhibiting the activation of pathogenic T cells, suppressing B cell activation and antibody production, and enhancing the differentiation of regulatory T cells. This review summarized the mechanisms by which artemisinin and its analogs modulate excessive inflammation and immune responses in rheumatic and skeletal diseases, autoimmune inflammatory diseases, and autoimmune disorders, through pathways including TNF, Toll-like receptors, IL-6, RANKL, MAPK, PI3K/AKT/mTOR, JAK/STAT, and NRF2/GPX4. Notably, in the context of the NF-κB pathway, artemisinin not only inhibits NF-κB expression by disrupting upstream cascades and/or directly binding to NF-κB but also downregulates multiple downstream genes controlled by NF-κB, including inflammatory chemokines and their receptors. These downstream targets regulate various immune cell functions, apoptosis, proliferation, signal transduction, and antioxidant responses, ultimately intervening in systemic autoimmune diseases and autoimmune responses in organs such as the kidneys, nervous system, skin, liver, and biliary system by modulating immune dysregulation and inflammatory responses. Ongoing multicenter randomized clinical trials are investigating the effects of these compounds on rheumatic, inflammatory, and autoimmune diseases, with the aim of translating promising preclinical data into clinical applications.
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Affiliation(s)
- Zhiyong Long
- Department of Physical Medicine and Rehabilitation, The Affiliated Panyu Central Hospital, Guangzhou Medical University, Guangzhou, China
| | - Wang Xiang
- Department of Rheumatology, Changde Hospital, Xiangya School of Medicine, Central South University, Changde, China
| | - Wei Xiao
- Department of Rheumatology, Changde Hospital, Xiangya School of Medicine, Central South University, Changde, China
| | - Yu Min
- Department of Physical Medicine and Rehabilitation, The Affiliated Panyu Central Hospital, Guangzhou Medical University, Guangzhou, China
| | - Fei Qu
- Department of Acupuncture and Massage, The Affiliated Panyu Central Hospital, Guangzhou Medical University, Guangzhou, China
| | | | - Liuting Zeng
- Department of Physical Medicine and Rehabilitation, The Affiliated Panyu Central Hospital, Guangzhou Medical University, Guangzhou, China
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Fan X, Yan Y, Li Y, Song Y, Li B. Anti-tumor mechanism of artesunate. Front Pharmacol 2024; 15:1483049. [PMID: 39525639 PMCID: PMC11549674 DOI: 10.3389/fphar.2024.1483049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 10/14/2024] [Indexed: 11/16/2024] Open
Abstract
Artesunate (ART) is a classic antimalarial drug with high efficiency, low toxicity and tolerance. It has been shown to be safe and has good anti-tumor effect. Existing clinical studies have shown that the anti-tumor mechanisms of ART mainly include inducing apoptosis and autophagy of tumor cells, affecting tumor microenvironment, regulating immune response, overcoming drug resistance, as well as inhibiting tumor cell proliferation, migration, invasion, and angiogenesis. ART has been proven to fight against lung cancer, hepatocarcinoma, lymphoma, multiple myeloma, leukemia, colorectal cancer, ovarian cancer, cervical cancer, malignant melanoma, oral squamous cell carcinoma, bladder cancer, prostate cancer and other neoplasms. In this review, we highlight the effects of ART on various tumors with an emphasis on its anti-tumor mechanism, which is helpful to propose the potential research directions of ART and expand its clinical application.
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Affiliation(s)
| | | | | | | | - Bo Li
- Department of Oral Anatomy and Physiology, Jilin Provincial Key Laboratory of Oral Biomedical Engineering, Hospital of Stomatology, Jilin University, Changchun, China
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de Azevedo Teotônio Cavalcanti M, Da Silva Menezes KJ, De Oliveira Viana J, de Oliveira Rios É, Corrêa de Farias AG, Weber KC, Nogueira F, Dos Santos Nascimento IJ, de Moura RO. Current trends to design antimalarial drugs targeting N-myristoyltransferase. Future Microbiol 2024; 19:1601-1618. [PMID: 39440556 DOI: 10.1080/17460913.2024.2412397] [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: 05/20/2024] [Accepted: 10/01/2024] [Indexed: 10/25/2024] Open
Abstract
Malaria is a disease caused by Plasmodium spp., of which Plasmodium falciparum and Plasmodium vivax are the most prevalent. Unfortunately, traditional and some current treatment regimens face growing protozoan resistance. Thus, searching for and exploring new drugs and targets is necessary. One of these is N-myristoyltransferase (NMT). This enzyme is responsible for the myristoylation of several protein substrates in eukaryotic cells, including Plasmodium spp., thus enabling the assembly of protein complexes and stabilization of protein-membrane interactions. Given the importance of this target in developing new antiparasitic drugs, this review aims to explore the recent advances in the design of antimalarial drugs to target Plasmodium NMT.
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Affiliation(s)
- Misael de Azevedo Teotônio Cavalcanti
- Postgraduate Program of Pharmaceutical Sciences, Pharmacy Department, State University of Paraíba, Campina, Grande-PB, Brazil
- Drug Development & Synthesis Laboratory, Department of Pharmacy, State University of Paraíba, Campina, Grande, 58429-500, Brazil
| | - Karla Joane Da Silva Menezes
- Drug Development & Synthesis Laboratory, Department of Pharmacy, State University of Paraíba, Campina, Grande, 58429-500, Brazil
- Postgraduate Program of Drug Development & Technology Innovation, Federal University of Paraíba, João Pessoa, 58051-900, Brazil
| | - Jéssika De Oliveira Viana
- Postgraduate Program of Chemistry, Department of Chemistry, Federal University of Paraíba, João Pessoa, 58051-970, Brazil
| | | | - Arthur Gabriel Corrêa de Farias
- Drug Development & Synthesis Laboratory, Department of Pharmacy, State University of Paraíba, Campina, Grande, 58429-500, Brazil
| | - Karen Cacilda Weber
- Postgraduate Program of Chemistry, Department of Chemistry, Federal University of Paraíba, João Pessoa, 58051-970, Brazil
| | - Fatima Nogueira
- Universidade NOVA de Lisboa, UNL, Global Health & Tropical Medicine, GHTM, Associate Laboratory in Translation & Innovation Towards Global Health, LAREAL, Instituto de Higiene e Medicina Tropical, IHMT, Rua da Junqueira 100, 1349-008, Lisboa, Portugal
- LAQV-REQUIMTE, MolSyn, IHMT, Universidade NOVA de Lisboa, UNL, Rua da Junqueira 100, 1349-008, Lisboa, Portugal
| | - Igor José Dos Santos Nascimento
- Postgraduate Program of Pharmaceutical Sciences, Pharmacy Department, State University of Paraíba, Campina, Grande-PB, Brazil
- Drug Development & Synthesis Laboratory, Department of Pharmacy, State University of Paraíba, Campina, Grande, 58429-500, Brazil
- Cesmac University Center, Pharmacy Department, Maceió, 57051-180, Brazil
| | - Ricardo Olimpio de Moura
- Postgraduate Program of Pharmaceutical Sciences, Pharmacy Department, State University of Paraíba, Campina, Grande-PB, Brazil
- Drug Development & Synthesis Laboratory, Department of Pharmacy, State University of Paraíba, Campina, Grande, 58429-500, Brazil
- Postgraduate Program of Drug Development & Technology Innovation, Federal University of Paraíba, João Pessoa, 58051-900, Brazil
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Xu M, Zhang D, Yan J. Targeting ferroptosis using Chinese herbal compounds to treat respiratory diseases. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 130:155738. [PMID: 38824825 DOI: 10.1016/j.phymed.2024.155738] [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: 02/01/2024] [Revised: 04/27/2024] [Accepted: 05/14/2024] [Indexed: 06/04/2024]
Abstract
BACKGROUND Respiratory diseases pose a grave threat to human life. Therefore, understanding their pathogenesis and therapeutic strategy is important. Ferroptosis is a novel type of iron-dependent programmed cell death, distinct from apoptosis, necroptosis, and autophagy, characterised by iron, reactive oxygen species, and lipid peroxide accumulation, as well as glutathione (GSH) depletion and GSH peroxidase 4 (GPX4) inactivation. A close association between ferroptosis and the onset and progression of respiratory diseases, including chronic obstructive pulmonary disease, acute lung injury, bronchial asthma, pulmonary fibrosis, and lung cancer, has been reported. Recent studies have shown that traditional Chinese medicine (TCM) compounds exhibit unique advantages in the treatment of respiratory diseases owing to their natural properties and potential efficacy. These compounds can effectively regulate ferroptosis by modulating several key signalling pathways such as system Xc- -GSH-GPX4, NCOA4-mediated ferritinophagy, Nrf2-GPX4, and Nrf2/HO-1, thus playing a positive role in improving respiratory diseases. PURPOSE This comprehensive review systematically outlines the regulatory role of ferroptosis in the onset and progression of respiratory diseases and provides evidence for treating respiratory diseases by targeting ferroptosis with TCM compounds. These insights aim to offer potential remedies for the clinical prevention and treatment of respiratory diseases. STUDY DESIGN AND METHODS We searched scientific databases PubMed, Web of Science, Scopus, and CNKI using keywords such as "ferroptosis","respiratory diseases","chronic obstructive pulmonary disease","bronchial asthma","acute lung injury","pulmonary fibrosis","lung cancer","traditional Chinese medicine","traditional Chinese medicine compound","monomer", and "natural product" to retrieve studies on the therapeutic potential of TCM compounds in ameliorating respiratory diseases by targeting ferroptosis. The retrieved data followed PRISMA criteria (preferred reporting items for systematic review). RESULTS TCM compounds possess unique advantages in treating respiratory diseases, stemming from their natural origins and proven clinical effectiveness. TCM compounds can exert therapeutic effects on respiratory diseases by regulating ferroptosis, which mainly involves modulation of pathways such as system Xc- -GSH-GPX4,NCOA4-mediated ferritinophagy, Nrf2-GPX4, and Nrf2/HO-1. CONCLUSION TCM compounds have demonstrated promising potential in improving respiratory diseases through the regulation of ferroptosis. The identification of specific TCM-related inducers and inhibitors of ferroptosis holds great significance in developing more effective strategies. However, current research remains confined to animal and cellular studies, emphasizing the imperative for further verifications through high-quality clinical data.
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Affiliation(s)
- Mengjiao Xu
- Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102, China
| | - Di Zhang
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Jun Yan
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China.
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Fazilani SA, An W, Li S, Hassan MF, Ishfaq M, Lakho SA, Farooque M, Shoaib M, Zhang X. Unrevealing the therapeutic potential of artesunate against emerging zoonotic Babesia microti infection in the murine model. Front Vet Sci 2024; 11:1383291. [PMID: 38784653 PMCID: PMC11111996 DOI: 10.3389/fvets.2024.1383291] [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: 02/07/2024] [Accepted: 04/01/2024] [Indexed: 05/25/2024] Open
Abstract
Babesiosis, a zoonotic blood protozoal disease, threatens humans and animals and is difficult to treat due to growing antimicrobial resistance. The study aimed to investigate the therapeutic efficacy of artesunate (AS), a well-known derivative of artemisinin, against Babesia microti (B. microti) using a murine infection model. Male BALB/c mice (6 weeks old; 15 per group) were chosen and randomly divided into 1) the control group, 2) the B. microti group, and 3) the B. microti + artesunate treatment groups. AS treatment at 2 mg/kg, 4 mg/kg, and 8 mg/kg of body weight significantly (p < 0.05) reduced the B. microti load in blood smears in a dose-dependent manner. Additionally, AS treatment mitigated the decrease in body weight and restored the normal state of the liver and spleen viscera index compared to the B. microti-infected group after 28 days. Hematological analysis revealed significant increases in RBC, WBC, and PLT counts post-AS treatment compared to the B. microti-infected group. Furthermore, AS administration resulted in significant reductions in total protein, bilirubin, ALT, AST, and ALP levels, along with reduced liver and spleen inflammation and lesions as observed through histopathological analysis. AS also elicited dose-dependent changes in mRNA and protein expression levels of apoptotic, proinflammatory, and anti-inflammatory cytokines in the liver compared to the control and B. microti-infected groups. Immunolabeling revealed decreased expression of apoptotic and inflammation-related proteins in AS-treated hepatic cytoplasm compared to the B. microti-infected group. AS also in dose-dependent manner decreased apoptotic protein and increased Bcl-2. Overall, these findings underscore the potential of AS as an anti-parasitic candidate in combating B. microti pathogenesis in an in vivo infection model, suggesting its promise for clinical trials as a treatment for babesiosis.
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Affiliation(s)
- Saqib Ali Fazilani
- Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development. Faculty of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
- Department of Veterinary Pharmacology and Toxicology, Faculty of Biosciences, Shaheed Benazir Bhutto University of Veterinary and Animal Sciences, Sakrand, Pakistan
| | - Wei An
- Technical Centre of Chengdu Customs, Chengdu, China
| | - Sihong Li
- College of Animal Science and Technology and College of Veterinary Medicine of Zhejiang A&F University, Hangzhou, China
| | - Mohammad Farooque Hassan
- Department of Veterinary Pathology, Faculty of Veterinary Sciences, Shaheed Benazir Bhutto University of Veterinary and Animal Sciences, Sakrand, Pakistan
| | | | - Shakeel Ahmed Lakho
- Department of Veterinary Parasitology, Faculty of Veterinary Sciences, Shaheed Benazir Bhutto University of Veterinary and Animal Sciences, Sakrand, Pakistan
| | - Muhammad Farooque
- Faculty of Veterinary and Animal Sciences, Ziauddin University Karachi, Karachi, Pakistan
| | - Muhammad Shoaib
- Key Laboratory of New Animal Drug Project, Gansu Province/Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of Chinese Academy of Agriculture Sciences, Lanzhou, China
| | - Xiuying Zhang
- Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development. Faculty of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
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Ortiz-Perez E, Vazquez-Jimenez LK, Paz-Gonzalez AD, Delgado-Maldonado T, González-González A, Gaona-Lopez C, Moreno-Herrera A, Vazquez K, Rivera G. Advances in the Development of Carbonic Anhydrase Inhibitors as New Antiprotozoal Agents. Curr Med Chem 2024; 31:6735-6759. [PMID: 37909441 DOI: 10.2174/0109298673249553231018070920] [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: 02/16/2023] [Revised: 06/19/2023] [Accepted: 09/14/2023] [Indexed: 11/03/2023]
Abstract
BACKGROUND Parasitic diseases are a public health problem despite the existence of drugs for their treatment. These treatments have variable efficacy and, in some cases, serious adverse effects. There has been interest in the enzyme carbonic anhydrase (CA) in the last two decades since it is essential in the life cycle of various parasites due to its important participation in processes such as pyrimidine synthesis, HCO3 - transport across cell membranes, and the maintenance of intracellular pH and ion transport (Na+, K+, and H+), among others. OBJECTIVE In this review, CA was analyzed as a pharmacological target in etiological agents of malaria, American trypanosomiasis, leishmaniasis, amoebiasis, and trichomoniasis. The CA inhibitors´ design, binding mode, and structure-activity relationship are also discussed. CONCLUSION According to this review, advances in discovering compounds with potent inhibitory activity suggest that CA is a candidate for developing new antiprotozoal agents.
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Affiliation(s)
- Eyra Ortiz-Perez
- Laboratorio de Biotecnología Farmacéutica, Centro de Biotecnología Genómica, Instituto Politécnico Nacional, Reynosa 88710, Tamaulipas, México
| | - Lenci K Vazquez-Jimenez
- Laboratorio de Biotecnología Farmacéutica, Centro de Biotecnología Genómica, Instituto Politécnico Nacional, Reynosa 88710, Tamaulipas, México
| | - Alma D Paz-Gonzalez
- Laboratorio de Biotecnología Farmacéutica, Centro de Biotecnología Genómica, Instituto Politécnico Nacional, Reynosa 88710, Tamaulipas, México
| | - Timoteo Delgado-Maldonado
- Laboratorio de Biotecnología Farmacéutica, Centro de Biotecnología Genómica, Instituto Politécnico Nacional, Reynosa 88710, Tamaulipas, México
| | - Alonzo González-González
- Laboratorio de Biotecnología Farmacéutica, Centro de Biotecnología Genómica, Instituto Politécnico Nacional, Reynosa 88710, Tamaulipas, México
| | - Carlos Gaona-Lopez
- Laboratorio de Biotecnología Farmacéutica, Centro de Biotecnología Genómica, Instituto Politécnico Nacional, Reynosa 88710, Tamaulipas, México
| | - Antonio Moreno-Herrera
- Laboratorio de Biotecnología Farmacéutica, Centro de Biotecnología Genómica, Instituto Politécnico Nacional, Reynosa 88710, Tamaulipas, México
| | - Karina Vazquez
- Departamento de Biotecnología Farmacéutica, Facultad de Medicina Veterinaria y Zootecnia, Universidad Autónoma de Nuevo León, Gral. Escobedo, 66050, México
| | - Gildardo Rivera
- Laboratorio de Biotecnología Farmacéutica, Centro de Biotecnología Genómica, Instituto Politécnico Nacional, Reynosa 88710, Tamaulipas, México
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11
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Munnik BL, Kaschula CH, Harding CR, Chellan P. Investigation of new ferrocenyl-artesunate derivatives as antiparasitics. Dalton Trans 2023; 52:15786-15797. [PMID: 37681434 PMCID: PMC10628858 DOI: 10.1039/d3dt02254d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 08/30/2023] [Indexed: 09/09/2023]
Abstract
Artesunate (Ars) is a semisynthetic antimalarial drug and is a part of the artemisinin-based combination therapy arsenal employed for malaria treatment. The drug functions mainly by activation of its endoperoxide bridge leading to increased oxidative stress in malaria parasites. The purpose of this study was to ascertain the antiparasitic effects of combining ferrocene and Arsvia short or long chain ester or amide linkages (C1-C4). The compounds were evaluated for growth inhibition activity on the apicomplexan parasites, Plasmodium falciparum (P. falciparum) and Toxoplasma gondii (T. gondii). All the complexes demonstrated good activity against T. gondii with IC50 values in the low micromolar range (0.28-1.2 μM) and good to excellent antimalarial activity against a chloroquine sensitive strain of P. falciparum (NF54). Further investigations on T. gondii revealed that the likely mode of action (MoA) is through the generation of reactive oxygen species. Additionally, immunofluorescence microscopy suggested a novel change in the morphology of the parasite by complex C3, an artesunate-ferrocenyl ethyl amide complex. The complexes were not cytotoxic or showed low cytotoxicity to two normal cell lines tested.
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Affiliation(s)
- Brandon L Munnik
- Department of Chemistry and Polymer Science, Stellenbosch University, Stellenbosch, Western Cape, South Africa.
| | - Catherine H Kaschula
- Department of Chemistry and Polymer Science, Stellenbosch University, Stellenbosch, Western Cape, South Africa.
| | - Clare R Harding
- Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and inflammation, University of Glasgow, UK
| | - Prinessa Chellan
- Department of Chemistry and Polymer Science, Stellenbosch University, Stellenbosch, Western Cape, South Africa.
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12
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Lin L, Huang Z, Jianchi M, Guo Z, Shi Z, Tang Z, Guo Q, Xiong H. Artesunate alleviates psoriasis-like dermatitis by reducing interleukin-23 expression in tumor necrosis factor-alpha-induced HaCaT cells. Clin Exp Pharmacol Physiol 2023; 50:903-913. [PMID: 37635387 DOI: 10.1111/1440-1681.13816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 06/29/2023] [Accepted: 08/06/2023] [Indexed: 08/29/2023]
Abstract
Artesunate (ART), an antimalarial drug with a multifunctional immunomodulatory effect, reduces psoriasis disease. ART can alleviate psoriasis-like dermatitis in mice but has no effect on proinflammatory cytokines in the blood. Thus, we hypothesized that the skin might be the target tissue of ART during the treatment of psoriasis. The interleukin (IL)-23/IL-17 axis has a key role in the pathogenesis of psoriasis. However, whether and how ART manipulates the IL-23 signal during psoriasis is unknown. This study found that IL-23 is highly expressed in the epidermis of psoriasis lesions and positively correlated with histological neutrophil infiltration and clinical psoriasis area and severity index (PASI) scores. Furthermore, ART inhibits the migration and cell cycle, as well as tumor necrosis factor-alpha (TNF-α)-induced IL-23 expression in HaCaT cells in a dose-dependent manner, probably through interference with the nuclear factor kappa B (NF-κB) signalling pathway. Animal experiments in imiquimod (IMQ)-induced psoriasis-like mice model also suggested that ART dose-dependently reduces IL-23 in the epidermis and ameliorates neutrophil infiltration. These findings thus provide further molecular evidence supporting ART as a promising drug for psoriasis in clinic.
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Affiliation(s)
- Lixian Lin
- Department of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhongzhou Huang
- Department of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ma Jianchi
- Department of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhixuan Guo
- Department of Dermatology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Zhenrui Shi
- Department of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zengqi Tang
- Department of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qing Guo
- Department of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Hui Xiong
- Department of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
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13
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Yuan Y, Hua L, Zhou J, Liu D, Ouyang F, Chen X, Long S, Huang Y, Liu X, Zheng J, Zhou H. The effect of artesunate to reverse CLP-induced sepsis immunosuppression mice with secondary infection is tightly related to reducing the apoptosis of T cells via decreasing the inhibiting receptors and activating MAPK/ERK pathway. Int Immunopharmacol 2023; 124:110917. [PMID: 37716165 DOI: 10.1016/j.intimp.2023.110917] [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: 04/10/2023] [Revised: 08/12/2023] [Accepted: 09/06/2023] [Indexed: 09/18/2023]
Abstract
T cells play an important role in regulating immune system balance. Sepsis-associated immunosuppression causes apoptosis of T cells and a decrease in their number. Previously, artesunate was found to have an immunomodulatory effect on immunosuppression in model mice with cecal ligation and puncture (CLP)-induced sepsis. In the present study, mouse sepsis models of CLP and CLP with secondary infection were established and treated with artesunate in order to examine the effect of artesunate on adaptive immune response in sepsis-related immunosuppression. The results showed that artesunate treatment could increase the survival rate of CLP mice with secondary Pseudomonas aeruginosa infection, increase the bacterial clearance rate, and also increase the level of the pro-inflammatory cytokine TNF-α. In addition, artesunate resulted in an increase in the number of T cells, CD4+ T cells and CD8+ T cells, and inhibited CD4+ and CD8+ T-cell apoptosis. Artesunate was also found to inhibit the expression of the inhibitory receptors of PD-1, CTLA-4, and BTLA, but it did not affect the expression of Tim-3. Additionally, artesunate significantly increased the phosphorylated ERK level of CD4+ T cells and CD8+ T cells and inhibited mitochondrial pathway-mediated apoptosis in CLP mice with Pseudomonas aeruginosa infection. These findings reveal that artesunate has an immunomodulatory effect on the adaptive immune response in sepsis. These effects include an increase in the numbers of T cells, CD4+ T cells, and CD8+ T cells through inhibition of the expression of inhibitory receptors and promotion of the MAPK/ERK pathway.
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Affiliation(s)
- Yue Yuan
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Ling Hua
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Jun Zhou
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Dan Liu
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Fumin Ouyang
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Xuemin Chen
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Shujuan Long
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Yasi Huang
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Xin Liu
- Medical Research Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Jiang Zheng
- Medical Research Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Hong Zhou
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, China.
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14
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Gao L, Wang ZF, Wang LW, Tang HT, Mo ZY, He MX. Electrochemical selenium-catalyzed para-amination of N-aryloxyamides: access to polysubstituted aminophenols. Org Biomol Chem 2023; 21:7895-7899. [PMID: 37747203 DOI: 10.1039/d3ob01116j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/26/2023]
Abstract
Aminophenols are a class of important compounds with various pharmacological activities such as anticancer, anti-inflammatory, antimalarial, and antibacterial activities. Herein, we introduce a mild and efficient electrochemical selenium-catalyzed strategy to synthesize polysubstituted aminophenols. High atom efficiency and transition metal-free and oxidant-free conditions are the striking features of this protocol. By merging electrochemical and organoselenium-catalyzed processes, the intramolecular rearrangement of N-aryloxyamides produces para-amination products at room temperature in a simple undivided cell.
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Affiliation(s)
- Lei Gao
- Guangxi Key Laboratory of Drug Discovery and Optimization, Guangxi Engineering Research Center for Pharmaceutical Molecular Screening and Druggability Evaluation, Pharmacy School of Guilin Medical University, Guilin 541199, People's Republic of China.
| | - Zhi-Feng Wang
- Guangxi Key Laboratory of Drug Discovery and Optimization, Guangxi Engineering Research Center for Pharmaceutical Molecular Screening and Druggability Evaluation, Pharmacy School of Guilin Medical University, Guilin 541199, People's Republic of China.
- Department of Burn, Wound Repair Surgery and Plastic Surgery, Department of Aesthetic Surgery, Affiliated Hospital of Guilin Medical University, Guilin 541001, People's Republic of China
| | - Lin-Wei Wang
- Guangxi Key Laboratory of Drug Discovery and Optimization, Guangxi Engineering Research Center for Pharmaceutical Molecular Screening and Druggability Evaluation, Pharmacy School of Guilin Medical University, Guilin 541199, People's Republic of China.
| | - Hai-Tao Tang
- Guangxi Key Laboratory of Drug Discovery and Optimization, Guangxi Engineering Research Center for Pharmaceutical Molecular Screening and Druggability Evaluation, Pharmacy School of Guilin Medical University, Guilin 541199, People's Republic of China.
| | - Zu-Yu Mo
- Guangxi Key Laboratory of Drug Discovery and Optimization, Guangxi Engineering Research Center for Pharmaceutical Molecular Screening and Druggability Evaluation, Pharmacy School of Guilin Medical University, Guilin 541199, People's Republic of China.
- Key Laboratory of Agricultural Resources Chemistry and Biotechnology, College of Chemistry and Food Science of Yulin Normal University, Yulin 537000, People's Republic of China
| | - Mu-Xue He
- Guangxi Key Laboratory of Drug Discovery and Optimization, Guangxi Engineering Research Center for Pharmaceutical Molecular Screening and Druggability Evaluation, Pharmacy School of Guilin Medical University, Guilin 541199, People's Republic of China.
- Key Laboratory of Agricultural Resources Chemistry and Biotechnology, College of Chemistry and Food Science of Yulin Normal University, Yulin 537000, People's Republic of China
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15
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Del Gaudio A, Covello C, Di Vincenzo F, De Lucia SS, Mezza T, Nicoletti A, Siciliano V, Candelli M, Gasbarrini A, Nista EC. Drug-Induced Acute Pancreatitis in Adults: Focus on Antimicrobial and Antiviral Drugs, a Narrative Review. Antibiotics (Basel) 2023; 12:1495. [PMID: 37887196 PMCID: PMC10604068 DOI: 10.3390/antibiotics12101495] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 09/26/2023] [Accepted: 09/26/2023] [Indexed: 10/28/2023] Open
Abstract
Acute pancreatitis (AP) is an acute inflammation of the pancreas caused by the activation of digestive enzymes in the pancreatic tissue. The main causes of AP are cholelithiasis and alcohol abuse; less commonly, it can be caused by drugs, with a prevalence of up to 5%. Causal associations between drugs and pancreatitis are largely based on case reports or case series with limited evidence. We reviewed the available data on drug-induced AP, focusing on antimicrobial drugs and antivirals, and discussed the current evidence in relation to the classification systems available in the literature. We found 51 suspected associations between antimicrobial and antiviral drugs and AP. The drugs with the most evidence of correlation are didanosine, protease inhibitors, and metronidazole. In addition, other drugs have been described in case reports demonstrating positive rechallenge. However, there are major differences between the various classifications available, where the same drug being assigned to different probability classes. It is likely that the presence in multiple case reports of an association between acute pancreatitis and a drug should serve as a basis for conducting prospective randomized controlled trials to improve the quality of the evidence.
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Affiliation(s)
- Angelo Del Gaudio
- Center for Diagnosis and Treatment of Digestive Diseases, Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy; (A.D.G.); (C.C.); (F.D.V.)
| | - Carlo Covello
- Center for Diagnosis and Treatment of Digestive Diseases, Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy; (A.D.G.); (C.C.); (F.D.V.)
| | - Federica Di Vincenzo
- Center for Diagnosis and Treatment of Digestive Diseases, Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy; (A.D.G.); (C.C.); (F.D.V.)
| | - Sara Sofia De Lucia
- Center for Diagnosis and Treatment of Digestive Diseases, Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy; (A.D.G.); (C.C.); (F.D.V.)
| | - Teresa Mezza
- Pancreas Unit, Centro Malattie Apparato Digerente, Medicina Interna e Gastroenterologia, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy; (T.M.); (A.N.)
| | - Alberto Nicoletti
- Pancreas Unit, Centro Malattie Apparato Digerente, Medicina Interna e Gastroenterologia, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy; (T.M.); (A.N.)
| | - Valentina Siciliano
- Laboratory and Infectious Diseases Sciences, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy;
| | - Marcello Candelli
- Emergency, Anesthesiological and Reanimation Sciences, Fondazione Policlinico Universitario Agostino Gemelli—IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy;
| | - Antonio Gasbarrini
- Center for Diagnosis and Treatment of Digestive Diseases, Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy; (A.D.G.); (C.C.); (F.D.V.)
| | - Enrico Celestino Nista
- Pancreas Unit, Centro Malattie Apparato Digerente, Medicina Interna e Gastroenterologia, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy; (T.M.); (A.N.)
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16
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Guan L, Wang H, Xu X, Fan H. Therapeutical Utilization and Repurposing of Artemisinin and Its Derivatives: A Narrative Review. Adv Biol (Weinh) 2023; 7:e2300086. [PMID: 37178448 DOI: 10.1002/adbi.202300086] [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: 02/22/2023] [Revised: 04/08/2023] [Indexed: 05/15/2023]
Abstract
Artemisinin (ART) and its derivatives have great therapeutical utility as antimalarials and can be repurposed for other indications, such as viral infections, autoimmune diseases, and cancer. This review presents a comprehensive overview of the therapeutic effects of ART-based drugs, beyond their antimalarial effects. This review also summarizes the information on their repurposing in other pathologies, with the hope that it will guide the future optimization of the use of ART-based drugs and of the treatment strategies for the listed diseases. By reviewing related literature, ART extraction and structure as well as the synthesis and structure of its derivatives are presented. Subsequently, the traditional roles of ART and its derivatives against malaria are reviewed, including antimalarial mechanism and occurrence of antimalarial resistance. Finally, the potential of ART and its derivatives to be repurposed for the treatment of other diseases are summarized. The great repurposing potential of ART and its derivatives may be useful for the control of emerging diseases with corresponding pathologies, and future research should be directed toward the synthesis of more effective derivatives or better combinations.
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Affiliation(s)
- Lin Guan
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, P. R. China
| | - Huiyong Wang
- Wuhan Humanwell Pharmaceutical Co. Ltd., Wuhan, 430206, P. R. China
| | - Xiaolong Xu
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, Beijing, 100010, P. R. China
| | - Huahao Fan
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, P. R. China
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17
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Hore R, Hasan N, Mäder K, Kressler J. Synthesis and Characterization of Dimeric Artesunate Glycerol Monocaprylate Conjugate and Formulation of Nanoemulsion Preconcentrate. Molecules 2023; 28:5208. [PMID: 37446870 DOI: 10.3390/molecules28135208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 06/30/2023] [Accepted: 07/01/2023] [Indexed: 07/15/2023] Open
Abstract
Malaria is one of the major life-threatening health problems worldwide. Artesunate is the most potent antimalarial drug to combat severe malaria. However, development of drug resistance, short plasma half-life, and poor bioavailability limit the efficacy of this drug. Here, we applied the dimerization concept to synthesize dimeric artesunate glycerol monocaprylate conjugate (D-AS-GC) by conjugating artesunate (AS) with glycerol monocaprylate (GC) via esterification reaction. D-AS-GC conjugate, AS, and GC were well characterized by 1H NMR, attached proton test (APT) 13C NMR and 2D NMR spectroscopy. D-AS-GC conjugate was further analyzed by ESI-TOF MS. Finally, a series of nanoemulsion preconcentrate (F1-F6) of D-AS-GC was prepared by mixing different ratios of oil and surfactant/cosurfactant and evaluated after dilution with an aqueous phase. The optimized formulation (F6) exhibits a clear nanoemulsion and the hydrodynamic diameter of the dispersed phase was determined by DLS and DOSY NMR spectroscopy. The morphology of the nanoemulsion droplets of F6 was investigated by AFM, which revealed the formation of tiny nanoemulsion droplets on a hydrophilic mica substrate. Moreover, using a less polar silicon wafer led to the formation of larger droplets with a spherical core shell-like structure. Overall, the rational design of the dimeric artesunate-based nanoemulsion preconcentrate could potentially be used in more efficient drug delivery systems.
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Affiliation(s)
- Rana Hore
- Department of Chemistry, Martin Luther University Halle-Wittenberg, Von-Danckelmann-Platz 4, D-06099 Halle (Saale), Germany
| | - Nazmul Hasan
- Department of Chemistry, Martin Luther University Halle-Wittenberg, Von-Danckelmann-Platz 4, D-06099 Halle (Saale), Germany
| | - Karsten Mäder
- Institute of Pharmacy, Martin Luther University Halle-Wittenberg, D-06099 Halle (Saale), Germany
| | - Jörg Kressler
- Department of Chemistry, Martin Luther University Halle-Wittenberg, Von-Danckelmann-Platz 4, D-06099 Halle (Saale), Germany
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18
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Du Y, Li C, Zhang Y, Xiong W, Wang F, Wang J, Zhang Y, Deng L, Li X, Chen W, Cui W. In Situ-Activated Phospholipid-Mimic Artemisinin Prodrug via Injectable Hydrogel Nano/Microsphere for Rheumatoid Arthritis Therapy. RESEARCH (WASHINGTON, D.C.) 2022; 2022:0003. [PMID: 39290968 PMCID: PMC11407526 DOI: 10.34133/research.0003] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 10/19/2022] [Indexed: 09/19/2024]
Abstract
In situ-activated therapy is a decent option for localized diseases with improved efficacies and reduced side effects, which is heavily dependent on the local conversion or activation of bioinert components. In this work, we applied a phospholipid-mimic artemisinin prodrug (ARP) for preparing an injectable nano/microsphere to first realize an in situ-activated therapy of the typical systemically administrated artemisinin-based medicines for a localized rheumatoid arthritis (RA) lesion. ARP is simultaneously an alternative of phospholipids and an enzyme-independent activable prodrug, which can formulate "drug-in-drug" co-delivery liposomes with cargo of partner drugs (e.g., methotrexate). To further stabilize ARP/methotrexate "drug-in-drug" liposomes (MTX/ARPL) for a long-term intra-articular retention, a liposome-embedded hydrogel nano/microsphere (MTX/ARPL@MS) was prepared. After the local injection, the MTX/ARPL could be slowly released because of imine hydrolysis and targeted to RA synovial macrophages and fibroblasts simultaneously. ARP assembly is relatively stable before cellular internalization but disassembled ARP after lysosomal escape and converted into dihydroartemisinin rapidly to realize the effective in situ activation. Taken together, phospholipid-mimic ARP was applied for the firstly localized in situ-activated RA therapy of artemisinin-based drugs, which also provided a brand-new phospholipid-mimic strategy for other systemically administrated prodrugs to realize a remodeling therapeutic schedule for localized diseases.
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Affiliation(s)
- Yawei Du
- Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China
| | - Chao Li
- Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China
- Department of Orthopaedic Surgery, the Third Hospital of Hebei Medical University, No. 139 Ziqiang Road, Shijiazhuang 050051, China
| | - Yu Zhang
- Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China
| | - Wei Xiong
- Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China
| | - Fei Wang
- Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China
| | - Juan Wang
- Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China
| | - Yingze Zhang
- Department of Orthopaedic Surgery, the Third Hospital of Hebei Medical University, No. 139 Ziqiang Road, Shijiazhuang 050051, China
| | - Lianfu Deng
- Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China
| | - Xinsong Li
- School of Chemistry and Chemical Engineering, Southeast University, 2 Southeast University Road, Nanjing 211189, China
| | - Wei Chen
- Department of Orthopaedic Surgery, the Third Hospital of Hebei Medical University, No. 139 Ziqiang Road, Shijiazhuang 050051, China
| | - Wenguo Cui
- Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China
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19
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Akide Ndunge OB, Kilian N, Salman MM. Cerebral Malaria and Neuronal Implications of Plasmodium Falciparum Infection: From Mechanisms to Advanced Models. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2202944. [PMID: 36300890 PMCID: PMC9798991 DOI: 10.1002/advs.202202944] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 09/22/2022] [Indexed: 06/01/2023]
Abstract
Reorganization of host red blood cells by the malaria parasite Plasmodium falciparum enables their sequestration via attachment to the microvasculature. This artificially increases the dwelling time of the infected red blood cells within inner organs such as the brain, which can lead to cerebral malaria. Cerebral malaria is the deadliest complication patients infected with P. falciparum can experience and still remains a major public health concern despite effective antimalarial therapies. Here, the current understanding of the effect of P. falciparum cytoadherence and their secreted proteins on structural features of the human blood-brain barrier and their involvement in the pathogenesis of cerebral malaria are highlighted. Advanced 2D and 3D in vitro models are further assessed to study this devastating interaction between parasite and host. A better understanding of the molecular mechanisms leading to neuronal and cognitive deficits in cerebral malaria will be pivotal in devising new strategies to treat and prevent blood-brain barrier dysfunction and subsequent neurological damage in patients with cerebral malaria.
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Affiliation(s)
- Oscar Bate Akide Ndunge
- Department of Internal MedicineSection of Infectious DiseasesYale University School of Medicine300 Cedar StreetNew HavenCT06510USA
| | - Nicole Kilian
- Centre for Infectious Diseases, ParasitologyHeidelberg University HospitalIm Neuenheimer Feld 32469120HeidelbergGermany
| | - Mootaz M. Salman
- Department of PhysiologyAnatomy and GeneticsUniversity of OxfordOxfordOX1 3QUUK
- Kavli Institute for NanoScience DiscoveryUniversity of OxfordOxfordUK
- Oxford Parkinson's Disease CentreUniversity of OxfordOxfordUK
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20
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Luan Y, Bao Y, Wang F. Artesunate regulates the proliferation and differentiation of neural stem cells by activating the JAK‑2/STAT‑3 signaling pathway in ischemic stroke. Exp Ther Med 2022; 25:2. [PMID: 36561626 PMCID: PMC9748661 DOI: 10.3892/etm.2022.11701] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Accepted: 07/04/2022] [Indexed: 11/17/2022] Open
Abstract
Ischemic stroke is one of the most common causes of disability and death globally; therefore, the repair and reconstruction of the central nervous system (CNS) after stroke is very important. Neural stem/progenitor cells (NSPCs) may be the key to cell replacement therapy to treat CNS damage. It has previously been reported that artesunate (ART) is involved in the regulation of the biological functions of NSPCs; however, the mechanism of action of ART remains unclear. In the present study, different concentrations of ART were used to treat NSPCs following oxygen-glucose deprivation (OGD). Cell viability and apoptosis were analyzed using Cell Counting Kit-8 assay and flow cytometry, respectively, whereas immunofluorescence analysis was used to measure the expression levels of the differentiation-related molecule doublecortin (DCX) and proliferating cell nuclear antigen (PCNA). Western blotting was performed to analyze the expression levels of molecules related to the JAK-2/STAT-3 signaling pathway. The present results indicated that treatment with ART following OGD significantly promoted the viability of NSPCs, inhibited the apoptosis of NSPCs, and promoted the expression of PCNA and DCX. Moreover, ART significantly downregulated the protein expression levels of phosphorylated (p)-JAK-2 and p-STAT-3. Furthermore, activation of the JAK-2/STAT-3 signaling pathway and treatment with ART reversed the effects of ART on the proliferation, apoptosis and differentiation of NSPCs. In conclusion, the present data suggested that ART may promote the proliferation and differentiation of NSPCs, and reduce the apoptosis of NSPCs, by inhibiting the JAK-2/STAT-3 signaling pathway. ART may potentially be used for the treatment of ischemic stroke.
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Affiliation(s)
- Yumin Luan
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Yanan Bao
- Department of Thoracic Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Fei Wang
- Department of Intensive Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China,Correspondence to: Professor Fei Wang, Department of Intensive Medicine, The First Affiliated Hospital of Kunming Medical University, 295 Xichang Road, Kunming, Yunnan 650032, P.R. China
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21
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Chen W, Ma Z, Yu L, Mao X, Ma N, Guo X, Yin X, Jiang F, Wang Q, Wang J, Fang M, Lin N, Zhang Y. Preclinical investigation of artesunate as a therapeutic agent for hepatocellular carcinoma via impairment of glucosylceramidase-mediated autophagic degradation. EXPERIMENTAL & MOLECULAR MEDICINE 2022; 54:1536-1548. [PMID: 36123535 PMCID: PMC9535011 DOI: 10.1038/s12276-022-00780-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 03/10/2022] [Accepted: 03/29/2022] [Indexed: 12/09/2022]
Abstract
Artesunate (ART) has been indicated as a candidate drug for hepatocellular carcinoma (HCC). Glucosylceramidase (GBA) is required for autophagic degradation. Whether ART regulates autophagic flux by targeting GBA in HCC remains to be defined. Herein, our data demonstrated that the dramatic overexpression of GBA was significantly associated with aggressive progression and short overall survival times in HCC. Subsequent experiments revealed an association between autophagic activity and GBA expression in clinical HCC samples, tumor tissues from a rat model of inflammation-induced HCC and an orthotopic mouse model, and human HCC cell lines. Interestingly, probe labeling identified GBA as an ART target, which was further verified by both a glutathione-S-transferase pulldown assay and surface plasmon resonance analysis. The elevated protein expression of LC3B, the increased numbers of GFP-LC3B puncta and double-membrane vacuoles, and the enhanced expression of SQSTM1/p62 indicated that the degradation of autophagosomes in HCC cells was inhibited by ART treatment. Both the in vitro and in vivo data revealed that autophagosome accumulation through targeting of GBA was responsible for the anti-HCC effects of ART. In summary, this preclinical study identified GBA as one of the direct targets of ART, which may have promising potential to inhibit lysosomal autophagy for HCC therapy. Confirmation that the malaria drug artesunate targets a key enzyme overexpressed in aggressive liver cancer suggests it may be a novel therapeutic option for the disease. High levels of an enzyme called glucosylceramidase (GBA) are associated with poor prognosis in liver cancer, according to research conducted by Yanqiong Zhang and Na Lin at the Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, and co-workers. In experiments on rat and mouse models and human cell lines, the team demonstrated that high GBA levels over activated autophagic flux, accelerated the rate at which cellular material may be degraded and recycled in balanced, healthy cells. This disturbance enables liver cancer to progress. The researchers found that artesunate can suppress GBA expression levels and restore normal autophagic flux, boosting the drug’s anticancer activity.
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Affiliation(s)
- Wenjia Chen
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Zhaochen Ma
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Lingxiang Yu
- The Fifth Medical Centre, Chinese PLA General Hospital, Beijing, 100039, China
| | - Xia Mao
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Nan Ma
- Artemisinin Research Center, China Academy of Chinese Medical Sciences, 100700, Beijing, China
| | - Xiaodong Guo
- The Fifth Medical Centre, Chinese PLA General Hospital, Beijing, 100039, China
| | - Xiaoli Yin
- College of Life Science, South China Normal University, Guangzhou, 510631, China
| | - Funeng Jiang
- Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, South China University of Technology, Guangzhou, 510631, China
| | - Qian Wang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Jigang Wang
- Artemisinin Research Center, China Academy of Chinese Medical Sciences, 100700, Beijing, China
| | - Mingliang Fang
- Nanyang Technology University of Singapore, APT11-04, Singapore, Singapore
| | - Na Lin
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
| | - Yanqiong Zhang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
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22
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Gashe F, Wynendaele E, De Spiegeleer B, Suleman S. Degradation kinetics of artesunate for the development of an ex-tempore intravenous injection. Malar J 2022; 21:256. [PMID: 36068561 PMCID: PMC9450271 DOI: 10.1186/s12936-022-04278-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Accepted: 08/24/2022] [Indexed: 11/10/2022] Open
Abstract
Background Artesunate is recommended by the World Health Organization (WHO) for parenteral treatment of severe Plasmodium falciparum malaria. However, artesunate is inherently unstable in an aqueous solution and hydrolyses rapidly after its preparation for injection. Therefore, the aim of the study was to evaluate the stabilizing effects of phosphate buffer and mannitol against short-term (ex-tempore) artesunate hydrolysis. Methods A HPLC–UV isocratic method was developed using a reversed-phase fused core column (HALO RP-C18) and a mobile phase consisting of a mixture of 45% ammonium formate 10 mM in water (pH 4.5) and 55% methanol. Artesunate was formulated as aqueous solutions using a design of experiment (DOE) to investigate the artesunate stabilizing effects of pH (8–10), phosphate buffer strength (0.3–0.5 M), and mannitol (0–0.22 mmol/mL). The solutions were incubated at predefined temperatures (5, 25, and 40 °C) with subsequent analysis. Arrhenius equation was applied to model and evaluate the stability results. Results The developed HPLC-based method using fused-core stationary phase allowed to selectively quantify artesunate in the presence of its main hydrolysis degradants; namely β-dihydroartemisinin (β-DHA) and α-dihydroartemisinin (α-DHA) within 10 min. By applying the Arrhenius equation, the rate of hydrolysis of the drug increased approximately by 3.4 as the temperature raised by 10 °C. Buffer strength was found to be the main factor affecting the hydrolysis rate constants at 5 and 25 °C (p < 0.05), the activation energy (p = 0.009), and the frequency factor (p = 0.045). However, the effect of the buffer was predominant on the activation energy and hydrolysis rate constants, revealing its stabilizing effect on the drug at lower buffer strength (0.3 M). Within the investigated range (pH = 8–10), pH was found to influence the activation energy, with a positive stabilizing effect in the pH range of 8–9. The addition of mannitol as stabilizing agent into artesunate aqueous formulation did not show an improved response. Conclusion Phosphate buffer was the main stability determining factor of artesunate in the aqueous intravenous (i.v.) formulation and was found to be more effective in stabilizing artesunate at a buffer strength of 0.3 M in pH 8–9, while mannitol lacked stabilizing effect. Supplementary Information The online version contains supplementary material available at 10.1186/s12936-022-04278-4.
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Affiliation(s)
- Fanta Gashe
- Jimma University Laboratory of Drug Quality (JuLaDQ) and School of Pharmacy, Jimma University, PO Box 378, Jimma, Ethiopia.,Drug Quality and Registration (DruQuaR) Group, Faculty of Pharmaceutical Sciences, Ghent University, Harelbekestraat 72, 9000, Ghent, Belgium
| | - Evelien Wynendaele
- Drug Quality and Registration (DruQuaR) Group, Faculty of Pharmaceutical Sciences, Ghent University, Harelbekestraat 72, 9000, Ghent, Belgium
| | - Bart De Spiegeleer
- Drug Quality and Registration (DruQuaR) Group, Faculty of Pharmaceutical Sciences, Ghent University, Harelbekestraat 72, 9000, Ghent, Belgium
| | - Sultan Suleman
- Jimma University Laboratory of Drug Quality (JuLaDQ) and School of Pharmacy, Jimma University, PO Box 378, Jimma, Ethiopia.
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23
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Synthesis, Structure and Antileishmanial Evaluation of Endoperoxide–Pyrazole Hybrids. Molecules 2022; 27:molecules27175401. [PMID: 36080174 PMCID: PMC9457810 DOI: 10.3390/molecules27175401] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 08/19/2022] [Accepted: 08/22/2022] [Indexed: 11/17/2022] Open
Abstract
Leishmaniases are among the most impacting neglected tropical diseases. In attempts to repurpose antimalarial drugs or candidates, it was found that selected 1,2,4-trioxanes, 1,2,4,5-tetraoxanes, and pyrazole-containing chemotypes demonstrated activity against Leishmania parasites. This study reports the synthesis and structure of trioxolane–pyrazole (OZ1, OZ2) and tetraoxane–pyrazole (T1, T2) hybrids obtained from the reaction of 3(5)-aminopyrazole with endoperoxide-containing building blocks. Interestingly, only the endocyclic amine of 3(5)-aminopyrazole was found to act as nucleophile for amide coupling. However, the fate of the reaction was influenced by prototropic tautomerism of the pyrazole heterocycle, yielding 3- and 5-aminopyrazole containing hybrids which were characterized by different techniques, including X-ray crystallography. The compounds were evaluated for in vitro antileishmanial activity against promastigotes of L. tropica and L. infantum, and for cytotoxicity against THP-1 cells. Selected compounds were also evaluated against intramacrophage amastigote forms of L. infantum. Trioxolane–pyrazole hybrids OZ1 and OZ2 exhibited some activity against Leishmania promastigotes, while tetraoxane–pyrazole hybrids proved inactive, most likely due to solubility issues. Eight salt forms, specifically tosylate, mesylate, and hydrochloride salts, were then prepared to improve the solubility of the corresponding peroxide hybrids and were uniformly tested. Biological evaluations in promastigotes showed that the compound OZ1•HCl was the most active against both strains of Leishmania. Such finding was corroborated by the results obtained in assessments of the L. infantum amastigote susceptibility. It is noteworthy that the salt forms of the endoperoxide–pyrazole hybrids displayed a broader spectrum of action, showing activity in both strains of Leishmania. Our preliminary biological findings encourage further optimization of peroxide–pyrazole hybrids to identify a promising antileishmanial lead.
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24
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Looker O, Dans MG, Bullen HE, Sleebs BE, Crabb BS, Gilson PR. The Medicines for Malaria Venture Malaria Box contains inhibitors of protein secretion in
Plasmodium falciparum
blood stage parasites. Traffic 2022; 23:442-461. [PMID: 36040075 PMCID: PMC9543830 DOI: 10.1111/tra.12862] [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: 05/04/2022] [Revised: 07/17/2022] [Accepted: 07/26/2022] [Indexed: 11/27/2022]
Abstract
Plasmodium falciparum parasites which cause malaria, traffic hundreds of proteins into the red blood cells (RBCs) they infect. These exported proteins remodel their RBCs enabling host immune evasion through processes such as cytoadherence that greatly assist parasite survival. As resistance to all current antimalarial compounds is rising new compounds need to be identified and those that could inhibit parasite protein secretion and export would both rapidly reduce parasite virulence and ultimately lead to parasite death. To identify compounds that inhibit protein export we used transgenic parasites expressing an exported nanoluciferase reporter to screen the Medicines for Malaria Venture Malaria Box of 400 antimalarial compounds with mostly unknown targets. The most potent inhibitor identified in this screen was MMV396797 whose application led to export inhibition of both the reporter and endogenous exported proteins. MMV396797 mediated blockage of protein export and slowed the rigidification and cytoadherence of infected RBCs—modifications which are both mediated by parasite‐derived exported proteins. Overall, we have identified a new protein export inhibitor in P. falciparum whose target though unknown, could be developed into a future antimalarial that rapidly inhibits parasite virulence before eliminating parasites from the host.
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Affiliation(s)
| | - Madeline G. Dans
- Burnet Institute Melbourne Australia
- School of Medicine Deakin University Geelong Australia
| | - Hayley E. Bullen
- Burnet Institute Melbourne Australia
- Department of Immunology and Microbiology University of Melbourne Melbourne Australia
| | - Brad E. Sleebs
- The Walter and Eliza Hall Institute of Medical Research Parkville Victoria Australia
- Department of Medical Biology The University of Melbourne Parkville Victoria Australia
| | - Brendan S. Crabb
- Burnet Institute Melbourne Australia
- Department of Immunology and Microbiology University of Melbourne Melbourne Australia
- Department of Immunology and Pathology Monash University Melbourne Australia
| | - Paul R. Gilson
- Burnet Institute Melbourne Australia
- Department of Immunology and Microbiology University of Melbourne Melbourne Australia
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25
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Travi BL. Current status of antihistamine drugs repurposing for infectious diseases. MEDICINE IN DRUG DISCOVERY 2022. [DOI: 10.1016/j.medidd.2022.100140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
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26
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Jin J, Guo D, Wang Y, Jiao W, Li D, He Y. Artesunate Inhibits the Development of Esophageal Cancer by Targeting HK1 to Reduce Glycolysis Levels in Areas With Zinc Deficiency. Front Oncol 2022; 12:871483. [PMID: 35646662 PMCID: PMC9133444 DOI: 10.3389/fonc.2022.871483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 04/11/2022] [Indexed: 11/13/2022] Open
Abstract
Esophageal cancer (EC) threatens many lives in China, especially in areas with high incidences of EC. Our previous studies proved that zinc deficiency (ZD) promotes the cell cycle, thus promoting the progression of EC in areas with a high incidence of EC. Artesunate could inhibit the cell cycle, thereby inhibiting the progression of EC. In this study, we first demonstrated the mechanism by which artesunate inhibits EC in vitro and then demonstrated that artesunate could reverse the ZD-promoted progression of EC before EC occurred in vivo. The results showed that artesunate could inhibit the cell cycle, metastasis, and glycolysis of EC cells. Artesunate could target HK1, promote HK1 degradation, and reduce the levels of HIF-1α and PKM2 expression, which are key glycolysis enzymes. The in vivo results showed that ZD could increase the expression of HK1 and increase the incidence of EC. Artesunate reduced the incidence of EC and decreased the level of HK1 expression before EC occurred. Artesunate has an anti-EC effect by inhibiting aerobic glycolysis and has the potential to be a drug that prevents EC in areas with a high risk of EC.
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Affiliation(s)
- Jing Jin
- Cancer Institute, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Dongli Guo
- Cancer Institute, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yingying Wang
- Cancer Institute, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Wenpeng Jiao
- Cancer Institute, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Daojuan Li
- Cancer Institute, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yutong He
- Cancer Institute, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
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27
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Recent Advances in the Therapeutic Efficacy of Artesunate. Pharmaceutics 2022; 14:pharmaceutics14030504. [PMID: 35335880 PMCID: PMC8951414 DOI: 10.3390/pharmaceutics14030504] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 02/02/2022] [Accepted: 02/03/2022] [Indexed: 11/17/2022] Open
Abstract
Artesunate, a semisynthetic artemisinin derivative, is well-known and used as the first-line drug for treating malaria. Apart from treating malaria, artesunate has also been found to have biological activity against a variety of cancers and viruses. It also exhibits antidiabetic, anti-inflammatory, anti-atherosclerosis, immunosuppressive activities, etc. During its administration, artesunate can be loaded in liposomes, alone or in combination with other therapeutic agents. Administration routes include intragastrical, intravenous, oral, and parenteral. The biological activity of artesunate is based on its ability to regulate some biological pathways. This manuscript reports a critical review of the recent advances in the therapeutic efficacy of artesunate.
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28
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Wang Q, Tang Y, Pan Z, Yuan Y, Zou Y, Zhang H, Guo X, Guo W, Huang X, Wu Z, Li C, Xu Q, Song J, Deng C. RNA-seq-based transcriptome analysis of the anti-inflammatory effect of artesunate in the early treatment of the mouse cerebral malaria model. Mol Omics 2022; 18:716-730. [DOI: 10.1039/d1mo00491c] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The present study provides new insights into the molecular mechanisms by which artesunate improves prognosis in cerebral malaria, in particular inhibition of host cytokine storm.
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Affiliation(s)
- Qi Wang
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
- Institute of Pulmonary Disease, Guangzhou Chest Hospital, Guangzhou, Guangdong, P. R. China
| | - Yexiao Tang
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
- Guangzhou Eighth People’s Hospital, Guangzhou Medical University, Guangzhou, P. R. China
| | - Ziyi Pan
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
| | - Yueming Yuan
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
- Institute of Science and Technology, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
| | - Yuanyuan Zou
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
| | - Hongying Zhang
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
- Institute of Science and Technology, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
| | - Xueying Guo
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
| | - Wenfeng Guo
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
| | - Xinan Huang
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
| | - Zhibin Wu
- Institute of Science and Technology, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
| | - Changqing Li
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
| | - Qin Xu
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
| | - Jianping Song
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
| | - Changsheng Deng
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P. R. China
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29
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Nordmann T, Borrmann S, Ramharter M. Drug-induced hypersensitivity to artemisinin-based therapies for malaria. Trends Parasitol 2021; 38:136-146. [PMID: 34561157 DOI: 10.1016/j.pt.2021.08.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 08/27/2021] [Accepted: 08/30/2021] [Indexed: 12/13/2022]
Abstract
In the early 2000s, artemisinin-based combination therapy (ACT) was introduced as first-line treatment for uncomplicated Plasmodium falciparum malaria in virtually all endemic countries. However, despite the well-known excellent tolerability of ACTs, hypersensitivity to artemisinin derivatives remains a repeatedly documented adverse drug reaction of still unknown frequency. The clinical features of an artemisinin-induced hypersensitivity reaction range from mild to life-threatening severity, and a significant number of cases may pass unnoticed. In this review, we discuss the medical importance of hypersensitivity to artemisinin derivatives and we review data on the presumed frequency and its potential underlying mechanisms. Furthermore, we advocate to make alternative non-artemisinin-based drugs available for patients who do not tolerate artemisinin derivatives and to continue investing in the development of novel non-artemisinin-based combination regimens.
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Affiliation(s)
- Tamara Nordmann
- Department of Tropical Medicine, Bernhard Nocht Institute for Tropical Medicine and I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Centre for Infection Research (DZIF), partner site Hamburg-Luebeck-Borstel, Hamburg, Germany
| | - Steffen Borrmann
- Institute for Tropical Medicine, Eberhard Karls University of Tübingen, Tübingen, Germany; Centre de Recherches Médicale de Lambaréné (CERMEL), Lambaréné, Gabon
| | - Michael Ramharter
- Department of Tropical Medicine, Bernhard Nocht Institute for Tropical Medicine and I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Centre for Infection Research (DZIF), partner site Hamburg-Luebeck-Borstel, Hamburg, Germany; Centre de Recherches Médicale de Lambaréné (CERMEL), Lambaréné, Gabon.
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30
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Güiza J, Arriagada J, Rodríguez L, Gutiérrez C, Duarte Y, Sáez JC, Vega JL. Anti-parasitic drugs modulate the non-selective channels formed by connexins or pannexins. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166188. [PMID: 34102257 DOI: 10.1016/j.bbadis.2021.166188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 05/03/2021] [Accepted: 05/31/2021] [Indexed: 10/21/2022]
Abstract
The proteins connexins, innexins, and pannexins are the subunits of non-selective channels present in the cell membrane in vertebrates (connexins and pannexins) and invertebrates (innexins). These channels allow the transfer of ions and molecules across the cell membrane or, and in many cases, between the cytoplasm of neighboring cells. These channels participate in various physiological processes, particularly under pathophysiological conditions, such as bacterial, viral, and parasitic infections. Interestingly, some anti-parasitic drugs also block connexin- or pannexin-formed channels. Their effects on host channels permeable to molecules that favor parasitic infection can further explain the anti-parasitic effects of some of these compounds. In this review, the effects of drugs with known anti-parasitic activity that modulate non-selective channels formed by connexins or pannexins are discussed. Previous studies that have reported the presence of these proteins in worms, ectoparasites, and protozoa that cause parasitic infections have also been reviewed.
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Affiliation(s)
- Juan Güiza
- Laboratory of Gap Junction and Parasitic Diseases (GaPaL), Instituto Antofagasta, Universidad de Antofagasta, Antofagasta, Chile
| | - Javiera Arriagada
- Laboratory of Gap Junction and Parasitic Diseases (GaPaL), Instituto Antofagasta, Universidad de Antofagasta, Antofagasta, Chile
| | - Luis Rodríguez
- Laboratory of Gap Junction and Parasitic Diseases (GaPaL), Instituto Antofagasta, Universidad de Antofagasta, Antofagasta, Chile
| | - Camila Gutiérrez
- Laboratory of Gap Junction and Parasitic Diseases (GaPaL), Instituto Antofagasta, Universidad de Antofagasta, Antofagasta, Chile
| | - Yorley Duarte
- Instituto de Neurociencias, Centro Interdisciplinario de Neurociencia de Valparaíso, Universidad de Valparaíso, Valparaíso, Chile; Center for Bioinformatics and Integrative Biology, Facultad de Ciencias de la Vida, Universidad Andrés Bello, Av. República 330, Santiago 8370146, Chile
| | - Juan C Sáez
- Instituto de Neurociencias, Centro Interdisciplinario de Neurociencia de Valparaíso, Universidad de Valparaíso, Valparaíso, Chile
| | - José L Vega
- Laboratory of Gap Junction and Parasitic Diseases (GaPaL), Instituto Antofagasta, Universidad de Antofagasta, Antofagasta, Chile.
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Romero-Cordero S, Kirwan R, Noguera-Julian A, Cardellach F, Fortuny C, Morén C. A Mitocentric View of the Main Bacterial and Parasitic Infectious Diseases in the Pediatric Population. Int J Mol Sci 2021; 22:3272. [PMID: 33806981 PMCID: PMC8004694 DOI: 10.3390/ijms22063272] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 03/13/2021] [Accepted: 03/16/2021] [Indexed: 01/04/2023] Open
Abstract
Infectious diseases occur worldwide with great frequency in both adults and children. Both infections and their treatments trigger mitochondrial interactions at multiple levels: (i) incorporation of damaged or mutated proteins to the complexes of the electron transport chain, (ii) mitochondrial genome (depletion, deletions, and point mutations) and mitochondrial dynamics (fusion and fission), (iii) membrane potential, (iv) apoptotic regulation, (v) generation of reactive oxygen species, among others. Such alterations may result in serious adverse clinical events with great impact on children's quality of life, even resulting in death. As such, bacterial agents are frequently associated with loss of mitochondrial membrane potential and cytochrome c release, ultimately leading to mitochondrial apoptosis by activation of caspases-3 and -9. Using Rayyan QCRI software for systematic reviews, we explore the association between mitochondrial alterations and pediatric infections including (i) bacterial: M. tuberculosis, E. cloacae, P. mirabilis, E. coli, S. enterica, S. aureus, S. pneumoniae, N. meningitidis and (ii) parasitic: P. falciparum. We analyze how these pediatric infections and their treatments may lead to mitochondrial deterioration in this especially vulnerable population, with the intention of improving both the understanding of these diseases and their management in clinical practice.
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Affiliation(s)
- Sonia Romero-Cordero
- Faculty of Medicine, Pompeu Fabra University and Universitat Autònoma de Barcelona, 08002 Barcelona, Spain;
| | - Richard Kirwan
- School of Biological and Environmental Sciences, Liverpool John Moores University, Liverpool L2 2QP, UK
| | - Antoni Noguera-Julian
- Malalties Infeccioses i Resposta Inflamatòria Sistèmica en Pediatria, Unitat d’Infeccions, Servei de Pediatria, Institut de Recerca Pediàtrica Hospital Sant Joan de Déu, 08950 Barcelona, Spain; (A.N.-J.); (C.F.)
- Faculty of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, Spain;
- Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), 28029 Madrid, Spain
- Red de Investigación Translacional en Infectología Pediátrica (RITIP), 28029 Madrid, Spain
| | - Francesc Cardellach
- Faculty of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, Spain;
- Muscle Research and Mitochondrial Function Laboratory, Cellex-IDIBAPS, Faculty of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (ISCIII), 28029 Madrid, Spain
- Internal Medicine Department-Hospital Clínic of Barcelona (HCB), 08036 Barcelona, Spain
| | - Clàudia Fortuny
- Malalties Infeccioses i Resposta Inflamatòria Sistèmica en Pediatria, Unitat d’Infeccions, Servei de Pediatria, Institut de Recerca Pediàtrica Hospital Sant Joan de Déu, 08950 Barcelona, Spain; (A.N.-J.); (C.F.)
- Faculty of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, Spain;
- Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), 28029 Madrid, Spain
- Red de Investigación Translacional en Infectología Pediátrica (RITIP), 28029 Madrid, Spain
| | - Constanza Morén
- Faculty of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, Spain;
- Muscle Research and Mitochondrial Function Laboratory, Cellex-IDIBAPS, Faculty of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (ISCIII), 28029 Madrid, Spain
- Internal Medicine Department-Hospital Clínic of Barcelona (HCB), 08036 Barcelona, Spain
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Forcados GE, Adamu VO, Abdulsalam MT, Aminu NA, Anjuwon TM, Otor M, Riki JR, Muhammad A. Toxicological implications of sequential administration of herbal and conventional medicines: Evidence from an in vivo study on Azadirachta indica and artesunate in male Wistar rats. TOXICOLOGY RESEARCH AND APPLICATION 2021. [DOI: 10.1177/2397847321999302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
In most parts of West Africa and other developing countries, herbal medicines are sometimes used by patients concomitantly receiving conventional drugs, which can result in potentially serious adverse effects. This study examined in vivo cytotoxic effects of Azadirachta indica extracts followed by artesunate administration on some markers of liver and kidney toxicity. Serum ALT, GGT, urea, creatinine, interleukin 1β, tumor necrosis factor α, tissue malondialdehyde and glutathione levels and liver and kidney histology in healthy male Wistar rats administered 100 and 200 mg/kg A. indica for 5 days followed by 10 mg/kg Artesunate for 5 days was determined. Results showed significantly ( p < 0.05) higher serum ALT, GGT, urea, creatinine, interleukin 1β and tumor necrosis factor α levels with proportional increase of 16.5, 21.7, 9.2, 6.9, 9.1 and 9.1% respectively when compared to normal control was observed. Malondialdehyde levels were significantly ( p < 0.05) higher with a proportional increase of 57.8%, while glutathione levels were significantly ( p < 0.05) lower with a proportional decrease of 13.4% in liver homogenates of the treated rats relative to normal control. Histological examination of the liver and kidney of the co-treated rats showed vascular congestion and necrosis. Collectively, the results suggest that administration of A. indica followed by artesunate could predispose to liver and kidney associated cytotoxicity. These findings could have implications for people who habitually use herbal preparations and conventional drugs in sequential fashion.
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Affiliation(s)
- GE Forcados
- Department of Biochemistry, Faculty of Life Sciences, Ahmadu Bello University, Zaria, Nigeria
| | - VO Adamu
- Department of Biochemistry, Faculty of Life Sciences, Ahmadu Bello University, Zaria, Nigeria
| | - MT Abdulsalam
- Department of Biochemistry, Faculty of Life Sciences, Ahmadu Bello University, Zaria, Nigeria
| | - NA Aminu
- Department of Biochemistry, Faculty of Life Sciences, Ahmadu Bello University, Zaria, Nigeria
| | - TM Anjuwon
- Department of Biochemistry, Faculty of Life Sciences, Ahmadu Bello University, Zaria, Nigeria
| | - M Otor
- National Veterinary Research Institute, Vom, Nigeria
| | - JR Riki
- National Veterinary Research Institute, Vom, Nigeria
| | - A Muhammad
- Department of Biochemistry, Faculty of Life Sciences, Ahmadu Bello University, Zaria, Nigeria
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New drug approvals for 2020: Synthesis and clinical applications. Eur J Med Chem 2021; 215:113284. [PMID: 33611190 DOI: 10.1016/j.ejmech.2021.113284] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 02/03/2021] [Accepted: 02/03/2021] [Indexed: 02/06/2023]
Abstract
53 New drugs including 38 chemical entities and 15 biologics were approved by the U.S. Food and Drug Administration during 2020. Among the marketed drugs, 34 new small molecule drugs and 4 new diagnostic agents with privileged structures and novel clinical applications represent as promising leads for the development of new drugs with the similar indications and improved therapeutic efficacy. This review is mainly focused on the clinical applications and synthetic methods of 34 small-molecule drugs newly approved by the FDA in 2020.
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