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      Podophyllotoxin Exposure Causes Spindle Defects and DNA Damage-Induced Apoptosis in Mouse Fertilized Oocytes and Early Embryos

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          Abstract

          Podophyllotoxin (PPT) is a kind of lignans extracted from the roots and stems of the genus Podophyllum from the tiller family, and it has been widely used in the treatment of condyloma acuminatum, multiple superficial epithelioma in the clinics. However, PPT has been reported to be toxic and can cause liver defects and other organ poisoning. In addition, emerging evidences also indicate that PPT has reproductive toxicity and causes female reproduction disorders. In this study, we used fertilized oocytes and tried to explore the effects of PPT on the early embryonic development with the mouse model. The results showed that exposure to PPT had negative effects on the cleavage of zygotes. Further analysis indicated that PPT could disrupt the organization of spindle and chromosome arrangement at the metaphase of first cleavage. We also found that PPT exposure to the zygotes induced excessive reactive oxygen species (ROS), suggesting the occurrence of oxidative stress. Moreover, in the PPT-exposed embryos, there was positive γH2A.X and Annexin-V signals, indicating that PPT induced embryonic DNA damage and early apoptosis. In conclusion, our results suggested that PPT could affect spindle formation and chromosome alignment during the first cleavage of mouse embryos, and its exposure induced DNA damage-mediated oxidative stress which eventually led to embryonic apoptosis, indicating the toxic effects of PPT on the early embryo development.

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          Most cited references38

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          Apoptosis: A Basic Biological Phenomenon with Wide-ranging Implications in Tissue Kinetics

          The term apoptosis is proposed for a hitherto little recognized mechanism of controlled cell deletion, which appears to play a complementary but opposite role to mitosis in the regulation of animal cell populations. Its morphological features suggest that it is an active, inherently programmed phenomenon, and it has been shown that it can be initiated or inhibited by a variety of environmental stimuli, both physiological and pathological. The structural changes take place in two discrete stages. The first comprises nuclear and cytoplasmic condensation and breaking up of the cell into a number of membrane-bound, ultrastructurally well-preserved fragments. In the second stage these apoptotic bodies are shed from epithelial-lined surfaces or are taken up by other cells, where they undergo a series of changes resembling in vitro autolysis within phagosomes, and are rapidly degraded by lysosomal enzymes derived from the ingesting cells. Apoptosis seems to be involved in cell turnover in many healthy adult tissues and is responsible for focal elimination of cells during normal embryonic development. It occurs spontaneously in untreated malignant neoplasms, and participates in at least some types of therapeutically induced tumour regression. It is implicated in both physiological involution and atrophy of various tissues and organs. It can also be triggered by noxious agents, both in the embryo and adult animal. Images Fig. 8-10 Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 6 Fig. 7 Fig. 11-14 Fig. 15-18 Fig. 19 Fig. 20-22 Fig. 23 and 24
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            Role of Mitochondrial Reverse Electron Transport in ROS Signaling: Potential Roles in Health and Disease

            Reactive Oxygen Species (ROS) can cause oxidative damage and have been proposed to be the main cause of aging and age-related diseases including cancer, diabetes and Parkinson's disease. Accordingly, mitochondria from old individuals have higher levels of ROS. However, ROS also participate in cellular signaling, are instrumental for several physiological processes and boosting ROS levels in model organisms extends lifespan. The current consensus is that low levels of ROS are beneficial, facilitating adaptation to stress via signaling, whereas high levels of ROS are deleterious because they trigger oxidative stress. Based on this model the amount of ROS should determine the physiological effect. However, recent data suggests that the site at which ROS are generated is also instrumental in determining effects on cellular homeostasis. The best example of site-specific ROS signaling is reverse electron transport (RET). RET is produced when electrons from ubiquinol are transferred back to respiratory complex I, reducing NAD+ to NADH. This process generates a significant amount of ROS. RET has been shown to be instrumental for the activation of macrophages in response to bacterial infection, re-organization of the electron transport chain in response to changes in energy supply and adaptation of the carotid body to changes in oxygen levels. In Drosophila melanogaster, stimulating RET extends lifespan. Here, we review what is known about RET, as an example of site-specific ROS signaling, and its implications for the field of redox biology.
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              Insight into tubulin regulation from a complex with colchicine and a stathmin-like domain.

              Microtubules are cytoskeletal polymers of tubulin involved in many cellular functions. Their dynamic instability is controlled by numerous compounds and proteins, including colchicine and stathmin family proteins. The way in which microtubule instability is regulated at the molecular level has remained elusive, mainly because of the lack of appropriate structural data. Here, we present the structure, at 3.5 A resolution, of tubulin in complex with colchicine and with the stathmin-like domain (SLD) of RB3. It shows the interaction of RB3-SLD with two tubulin heterodimers in a curved complex capped by the SLD amino-terminal domain, which prevents the incorporation of the complexed tubulin into microtubules. A comparison with the structure of tubulin in protofilaments shows changes in the subunits of tubulin as it switches from its straight conformation to a curved one. These changes correlate with the loss of lateral contacts and provide a rationale for the rapid microtubule depolymerization characteristic of dynamic instability. Moreover, the tubulin-colchicine complex sheds light on the mechanism of colchicine's activity: we show that colchicine binds at a location where it prevents curved tubulin from adopting a straight structure, which inhibits assembly.
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                Author and article information

                Contributors
                Journal
                Front Cell Dev Biol
                Front Cell Dev Biol
                Front. Cell Dev. Biol.
                Frontiers in Cell and Developmental Biology
                Frontiers Media S.A.
                2296-634X
                19 November 2020
                2020
                : 8
                : 600521
                Affiliations
                Reproductive Medicine Center, The Affiliated Hospital of Youjiang Medical University for Nationalities , Baise, China
                Author notes

                Edited by: Shao-Chen Sun, Nanjing Agricultural University, China

                Reviewed by: Qinghua Zhang, Monash University, Australia; Qianqian Sha, Guangdong Second Provincial General Hospital, China; Li-Jun Huo, Huazhong Agricultural University, China

                *Correspondence: Jun-Li Wang, baisewangjunli@ 123456163.com
                Xiao-Qiong Luo, nongbb@ 123456126.com

                This article was submitted to Cell Growth and Division, a section of the journal Frontiers in Cell and Developmental Biology

                Article
                10.3389/fcell.2020.600521
                7710938
                4ca0449d-5eee-4308-a628-0d4d7e57f14d
                Copyright © 2020 Hu, Liao, Wei, Ling, Wei, Liu, Luo and Wang.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 30 August 2020
                : 21 October 2020
                Page count
                Figures: 5, Tables: 0, Equations: 0, References: 38, Pages: 9, Words: 0
                Categories
                Cell and Developmental Biology
                Original Research

                oocyte,embryo,spindle,oxidative stress,dna damage, apoptosis
                oocyte, embryo, spindle, oxidative stress, dna damage, apoptosis

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