Artykuły w czasopismach na temat „Apoptosis”
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Cutrona, Giovanna, Nicolò Leanza, Massimo Ulivi, Giovanni Melioli, Vito L. Burgio, Giovanni Mazzarello, Giovanni Gabutti, Silvio Roncella i Manlio Ferrarini. "Expression of CD10 by Human T Cells That Undergo Apoptosis Both In Vitro and In Vivo". Blood 94, nr 9 (1.11.1999): 3067–76. http://dx.doi.org/10.1182/blood.v94.9.3067.
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Abstract This study shows that human postthymic T cells express CD10 when undergoing apoptosis, irrespective of the signal responsible for initiating the apoptotic process. Cells from continuous T-cell lines did not normally express CD10, but became CD10+ when induced into apoptosis by human immunodeficiency virus (HIV) infection and exposure to CD95 monoclonal antibody, etoposide, or staurosporin. Inhibitors of caspases blocked apoptosis and CD10 expression. Both CD4+ and CD8+ T cells purified from normal peripheral blood expressed CD10 on apoptotic induction. CD10 was newly synthesized by the apoptosing cells because its expression was inhibited by exposure to cycloheximide and CD10 mRNA became detectable by reverse transcription-polymerase chain reaction in T cells cultured under conditions favoring apoptosis. To show CD10 on T cells apoptosing in vivo, lymph node and peripheral blood T cells from HIV+ subjects were used. These suspensions were composed of a substantial, although variable, proportion of apoptosing T cells that consistently expressed CD10. In contrast, CD10+ as well as spontaneously apoptosing T cells were virtually absent in peripheral blood from normal individuals. Collectively, these observations indicate that CD10 may represent a reliable marker for identifying and isolating apoptosing T cells in vitro and ex vivo and possibly suggest novel functions for surface CD10 in the apoptotic process of lymphoid cells.
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Cutrona, Giovanna, Nicolò Leanza, Massimo Ulivi, Giovanni Melioli, Vito L. Burgio, Giovanni Mazzarello, Giovanni Gabutti, Silvio Roncella i Manlio Ferrarini. "Expression of CD10 by Human T Cells That Undergo Apoptosis Both In Vitro and In Vivo". Blood 94, nr 9 (1.11.1999): 3067–76. http://dx.doi.org/10.1182/blood.v94.9.3067.421a32_3067_3076.
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This study shows that human postthymic T cells express CD10 when undergoing apoptosis, irrespective of the signal responsible for initiating the apoptotic process. Cells from continuous T-cell lines did not normally express CD10, but became CD10+ when induced into apoptosis by human immunodeficiency virus (HIV) infection and exposure to CD95 monoclonal antibody, etoposide, or staurosporin. Inhibitors of caspases blocked apoptosis and CD10 expression. Both CD4+ and CD8+ T cells purified from normal peripheral blood expressed CD10 on apoptotic induction. CD10 was newly synthesized by the apoptosing cells because its expression was inhibited by exposure to cycloheximide and CD10 mRNA became detectable by reverse transcription-polymerase chain reaction in T cells cultured under conditions favoring apoptosis. To show CD10 on T cells apoptosing in vivo, lymph node and peripheral blood T cells from HIV+ subjects were used. These suspensions were composed of a substantial, although variable, proportion of apoptosing T cells that consistently expressed CD10. In contrast, CD10+ as well as spontaneously apoptosing T cells were virtually absent in peripheral blood from normal individuals. Collectively, these observations indicate that CD10 may represent a reliable marker for identifying and isolating apoptosing T cells in vitro and ex vivo and possibly suggest novel functions for surface CD10 in the apoptotic process of lymphoid cells.
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Park, Cheol, Cheng-Yun Jin, Tae Hyun Choi, Su Hyun Hong i Yung Hyun Choi. "Effect of Proapoptotic Bcl-2 on Naringenin-induced Apoptosis in Human Leukemia U937 Cells". Journal of Life Science 23, nr 9 (30.09.2013): 1118–25. http://dx.doi.org/10.5352/jls.2013.23.9.1118.
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Lizama, Carlos, Diego Rojas-Benítez, Marcelo Antonelli, Andreas Ludwig, Ximena Bustamante-Marín, Jurriaan Brouwer-Visser i Ricardo D. Moreno. "TACE/ADAM17 is involved in germ cell apoptosis during rat spermatogenesis". REPRODUCTION 140, nr 2 (sierpień 2010): 305–17. http://dx.doi.org/10.1530/rep-10-0104.
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The pathways leading to male germ cell apoptosisin vivoare poorly understood, but are highly relevant for the comprehension of sperm production regulation by the testis. In this work, we show the evidence of a mechanism where germ cell apoptosis is induced through the inactivation and shedding of the extracellular domain of KIT (c-kit) by the protease TACE/a disintegrin and metalloprotease 17 (ADAM17) during the first wave of spermatogenesis in the rat. We show that germ cells undergoing apoptosis lacked the extracellular domain of the KIT receptor. TACE/ADAM17, a membrane-bound metalloprotease, was highly expressed in germ cells undergoing apoptosis as well. On the contrary, cell surface presence of ADAM10, a closely related metalloprotease isoform, was not associated with apoptotic germ cells. Pharmacological inhibition of TACE/ADAM17, but not ADAM10, significantly prevented germ cell apoptosis in the male pubertal rat. Induction of TACE/ADAM17 by the phorbol-ester phorbol 12-myristate 13-acetate (PMA) induced germ cell apoptosis, which was prevented when an inhibitor of TACE/ADAM17 was present in the assay.Ex-vivorat testis culture showed that PMA induced the cleavage of the KIT extracellular domain. Isolation of apoptotic germ cells showed that even though protein levels of TACE/ADAM17 were higher in apoptotic germ cells than in nonapoptotic cells, the contrary was observed for ADAM10. These results suggest that TACE/ADAM17 is one of the elements triggering physiological germ cell apoptosis during the first wave of spermatogenesis.
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GETTI, G. T., R. A. CHEKE i D. P. HUMBER. "Induction of apoptosis in host cells: a survival mechanism forLeishmaniaparasites?" Parasitology 135, nr 12 (8.09.2008): 1391–99. http://dx.doi.org/10.1017/s0031182008004915.
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SUMMARYLeishmaniaparasites invade host macrophages, causing infections that are either limited to skin or spread to internal organs. In this study, 3 species causing cutaneous leishmaniasis,L. major,L. aethiopicaandL. tropica, were tested for their ability to interfere with apoptosis in host macrophages in 2 different lines of human monocyte-derived macrophages (cell lines THP-1 and U937) and the results confirmed in peripheral blood mononuclear cells (PBMC). All 3 species induced early apoptosis 48 h after infection (expression of phosphatidyl serine on the outer membrane). There were significant increases in the percentage of apoptotic cells both for U937 and PBMC following infection with each of the 3 species. Early apoptotic events were confirmed by mitochondrial membrane permeabilization detection and caspase activation 48 and 72 h after infection. Moreover, the percentage of infected THP-1 and U937 macrophages increased significantly (up to 100%) following treatment with an apoptosis inducer. Since phosphatidyl serine externalization on apoptosing cells acts as a signal for engulfment by macrophages, induction of apoptosis in the parasitized cells could actively participate in spreading the infection. In summary, parasite-containing apoptotic bodies with intact membranes could be released and phagocytosed by uninfected macrophages.
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Langrová, Tereza, Zbyšek Sládek i Dušan Ryšánek. "The effect of the bacterial pathogens Staphylococcus aureus and Streptococcus uberis on morphological features of apoptosis of heifers mammary gland neutrophils". Acta Universitatis Agriculturae et Silviculturae Mendelianae Brunensis 53, nr 4 (2005): 61–74. http://dx.doi.org/10.11118/actaun200553040061.
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The aim of the student thesis was to review the effect of the significant bacterial pathogens,Staphylococcus aureusand Steptococcus uberis on programmed cell death – apoptosisin vitro, and to determine the dynamic of morphological changes during aging neutrophil granulocytes of heifers mammary glandin vitro. Using light and electron microscopy we have noted characteristic alterations of apoptotic neutrophils. These are running in three consequential phases. We found out, that the interaction of bacterial pathogens with neutrophils during the incubation have lead in expressive quantitative and qualitative changes in apoptotic cells proportion. Concretely, the influence of both pathogens on mammary gland neutrophils caused the defer of apoptosis expression. Here,S. aureuscaused lower number of apoptotic neutrophils in comprasion withS. uberis. The outcomes testified, thatS. aureusandS. uberisinteraction with heifers mammary gland neutrophilsin vitrocauses alterations relating to apoptosis of these cells. Looking at the results of the study, we can conclude, that the pathogensS. aureusandS. uberisare not only significant heifers mammary gland – affection causers, but they significantly influence the cells of defensive system in their functions too. They significantly decrease the appereance of morphological apoptosis manifestations on neotrophils of tissue pool of the heifers mammary gland. The numbers of apoptotic cells in neutrophil population confirm, that during the interaction with mentioned pathogens the defer of morphological apoptosis manifestations happens. Then, higher number of apoptotic neutrophils in stages of apoptotic corpuscles implies increasing dynamic of this process. Beside that, the dynamic of apoptotic process is influenced by the specifity of certain bacterious actor too.
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Aravani, Dimitra, Kirsty Foote, Nichola Figg, Alison Finigan, Anna Uryga, Murray Clarke i Martin Bennett. "Cytokine regulation of apoptosis-induced apoptosis and apoptosis-induced cell proliferation in vascular smooth muscle cells". Apoptosis 25, nr 9-10 (5.07.2020): 648–62. http://dx.doi.org/10.1007/s10495-020-01622-4.
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Abstract Vascular smooth muscle cells (VSMCs) are the main structural cell of blood vessels, and VSMC apoptosis occurs in vascular disease, after injury, and in vessel remodeling during development. Although VSMC apoptosis is viewed as silent, recent studies show that apoptotic cells can promote apoptosis-induced compensatory proliferation (AICP), apoptosis-induced apoptosis (AIA), and migration of both local somatic and infiltrating inflammatory cells. However, the effects of VSMC apoptosis on adjacent VSMCs, and their underlying signaling and mechanisms are unknown. We examined the consequences of VSMC apoptosis after activating extrinsic and intrinsic death pathways. VSMCs undergoing apoptosis through Fas/CD95 or the protein kinase inhibitor staurosporine transcriptionally activated interleukin 6 (IL-6) and granulocyte-macrophage colony stimulating factor (GM-CSF), leading to their secretion. Apoptosis induced activation of p38MAPK, JNK, and Akt, but neither p38 and JNK activation nor IL-6 or GM-CSF induction required caspase cleavage. IL-6 induction depended upon p38 activity, while Fas-induced GM-CSF expression required p38 and JNK. Conditioned media from apoptotic VSMCs induced VSMC apoptosis in vitro, and IL-6 and GM-CSF acted as pro-survival factors for AIA. VSMC apoptosis was studied in vivo using SM22α-DTR mice that express the diphtheria toxin receptor in VSMCs only. DT administration induced VSMC apoptosis and VSMC proliferation, and also signficantly induced IL-6 and GM-CSF. We conclude that VSMC apoptosis activates multiple caspase-independent intracellular signaling cascades, leading to release of soluble cytokines involved in regulation of both cell proliferation and apoptosis. VSMC AICP may ameliorate while AIA may amplify the effects of pro-apoptotic stimuli in vessel remodeling and disease.
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Hassan, Mohamed, Hidemichi Watari, Ali AbuAlmaaty, Yusuke Ohba i Noriaki Sakuragi. "Apoptosis and Molecular Targeting Therapy in Cancer". BioMed Research International 2014 (12.06.2014): 1–23. http://dx.doi.org/10.1155/2014/150845.
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Apoptosis is the programmed cell death which maintains the healthy survival/death balance in metazoan cells. Defect in apoptosis can cause cancer or autoimmunity, while enhanced apoptosis may cause degenerative diseases. The apoptotic signals contribute into safeguarding the genomic integrity while defective apoptosis may promote carcinogenesis. The apoptotic signals are complicated and they are regulated at several levels. The signals of carcinogenesis modulate the central control points of the apoptotic pathways, including inhibitor of apoptosis (IAP) proteins and FLICE-inhibitory protein (c-FLIP). The tumor cells may use some of several molecular mechanisms to suppress apoptosis and acquire resistance to apoptotic agents, for example, by the expression of antiapoptotic proteins such as Bcl-2 or by the downregulation or mutation of proapoptotic proteins such as BAX. In this review, we provide the main regulatory molecules that govern the main basic mechanisms, extrinsic and intrinsic, of apoptosis in normal cells. We discuss how carcinogenesis could be developed via defective apoptotic pathways or their convergence. We listed some molecules which could be targeted to stimulate apoptosis in different cancers. Together, we briefly discuss the development of some promising cancer treatment strategies which target apoptotic inhibitors including Bcl-2 family proteins, IAPs, and c-FLIP for apoptosis induction.
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LaBelle, James L., Jill K. Fisher, Samuel G. Katz, Gregory H. Bird, Chelsea E. Lawrence, Amy M. Silverstein i Loren D. Walensky. "Pharmacologic Replacement of BIM BH3 Reactivates Apoptosis in Hematologic Cancer and Lymphoproliferative Disease." Blood 110, nr 11 (16.11.2007): 524. http://dx.doi.org/10.1182/blood.v110.11.524.524.
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Abstract Selective targeting of deregulated apoptotic protein networks is a promising pharmacologic strategy for subverting diseases of unrestrained cellular survival, such as cancer. BCL-2 family protein interactions constitute a critical control point for the regulation of apoptosis. Whereas multidomain anti-apoptotic proteins such as BCL-2 guard against cell death, multidomain pro-apoptotic proteins such as BAX constitute a gateway to cell death through mitochondrial damage. The BH3-only proteins function as death sentinels situated throughout the cell, poised to transmit signals of cellular injury to multidomain members. BH3-only proteins deliver their death messages via their conserved alpha-helical BH3 domains. Whereas the indirect activator class of BH3-only proteins (e.g. BAD) counteract anti-apoptotic proteins, the direct activator subgroup (e.g. BIM) is believed to trigger apoptosis both by neutralizing anti-apoptotics and by directly activating the mitochondrial executioners BAX and BAK. The essential roles of BH3-only proteins in maintaining cellular homeostasis is highlighted by the development of autoimmune disease and cancer in mouse models of BH3-only protein deficiency. By inserting hydrocarbon “staples” into native BH3 peptide sequences, we have produced a chemical toolbox of stabilized alpha-helices of BCL-2 domains (SAHBs) to dissect apoptotic signaling pathways in vivo and explore the pharmacodynamic effects of “BH3 replacement” in cancer cells and mouse models of deregulated apoptosis. Whereas SAHBs display high affinity binding to anti-apoptotic targets, BID and BIM SAHBs also directly engage BAX and are thus especially potent in inducing apoptosis of a panel of leukemia and lymphoma cell lines. To evaluate the impact of selective BH3 replacement in vivo, we tested the capacity of BIM SAHB to reactivate apoptosis in the lymphoproliferative disease of Bim-/- mice. Strikingly, Bim-/- mice treated with BIM SAHB displayed marked influx of tingible-body macrophages into the lymphoid infiltrates of affected organs, with scattered cells throughout the infiltrate robustly positive for activated caspase-3, suggestive of SAHB induced apoptosis induction. Our studies highlight the therapeutic potential of BH3 replacement to circumvent apoptotic blockade and restore the death pathway in hematologic cancer and lymphoproliferative disease.
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Resanović, Ivana, Emina Sudar-Milovanović, Nikola Bogdanović, Aleksandra Jovanović, Sonja Zafirović, Anastasija Panić i Esma Isenović. "Fundamentals of apoptosis". Medicinska istrazivanja 49, nr 3 (2015): 42–45. http://dx.doi.org/10.5937/medist1502042r.
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Apoptosis is evolutionary conserved, programmed pattern of cell death with an essential role in various physiological processes, such as normal cell turnover and embryonic development, hormone-regulated cell demise, aging, immune system functioning and development and removal of defective and harmful cells. There are two general pathways for activation of apoptosis: the intrinsic and extrinsic pathways. While the intrinsic apoptotic pathway can be triggered by a cytotoxic accumulation of intracellular Ca 2+ , followed permeabilization of mitochondrial membrane and release of pro-apoptotic proteins into the cytosol from mitochondria, the extrinsic mechanisms of apoptosis include the participation of death receptors of tumor necrosis factor-a (TNF-a), receptor superfamily such as TNFR-1, Fas, and TNF-related apoptosis-inducing ligand receptors (TRAIL-R) located on the plasma membrane. There is also the perforin-granzyme pathway that involves T-cell mediated cytotoxicity. All three pathways converge on the same execution pathway, resulting in DNA fragmentation, degradation of cytoskeletal and nuclear proteins, cross-linking of proteins, formation of apoptotic bodies, expression of ligands for phagocytic cell receptors and finally uptake by phagocytic cells. In this review we summarize data from recent studies focusing on apoptotic proteins that have been identified and molecular mechanisms of apoptosis. Understanding apoptotic mechanism might provide useful information and a new approach to prevention and development of new therapies for variety of diseases.
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Li, Fu-Lun, Rong Xu, Qing-chun Zeng, Xin Li, Jie Chen, Yi-Fei Wang, Bin Fan, Lin Geng i Bin Li. "Tanshinone IIA Inhibits Growth of Keratinocytes through Cell Cycle Arrest and Apoptosis: Underlying Treatment Mechanism of Psoriasis". Evidence-Based Complementary and Alternative Medicine 2012 (2012): 1–14. http://dx.doi.org/10.1155/2012/927658.
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The aim of the present investigation was to elucidate the cellular mechanisms whereby Tanshinone IIA (Tan IIA) leads to cell cycle arrest and apoptosisin vitroin keratinocytes, the target cells in psoriasis. Tan IIA inhibited proliferation of mouse keratinocytes in a dose- and time-dependent manner and induced apoptosis, resulting in S phase arrest accompanied by down-regulation of pCdk2 and cyclin A protein expression. Furthermore, Tan IIA-induced apoptosis and mitochondrial membrane potential changes were also further demonstrated by DNA fragmentation, single-cell gel electrophoresis assay (SCGE), and flow cytometry methods. Apoptosis was partially blocked by the caspase-3 inhibitor Ac-DEVD-CHO. Mitochondrial regulation of apoptosis further downstream was investigated, showing changes in the mitochondrial membrane potential, cytochrome c release into the cytoplasm, and enhanced activation of cleaved caspase-3 and Poly ADP-ribose polymerase (PARP). There was also no translocation of apoptosis-inducing factor (AIF) from mitochondria to the nucleus in apoptotic keratinocytes, indicating Tan IIA-induced apoptosis occurs mainly through the caspase pathway. Our findings provide the molecular mechanisms by which Tan IIA can be used to treat psoriasis and support the traditional use ofSalvia miltiorrhiza Bungee (Labiatae)for psoriasis and related skin diseases.
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Liu, Kai, Dongdong Lin, Yabo Ouyang, Lijun Pang, Xianghua Guo, Shanshan Wang, Yunjin Zang i Dexi Chen. "Amphiregulin impairs apoptosis-stimulating protein 2 of p53 overexpression–induced apoptosis in hepatoma cells". Tumor Biology 39, nr 3 (marzec 2017): 101042831769502. http://dx.doi.org/10.1177/1010428317695026.
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Overexpression of apoptosis-stimulating protein 2 of p53 (ASPP2) induces apoptotic cell death in hepatoma cells (e.g. HepG2 cells) by enhancing the transactivation activity of p53, but long-term ASPP2 overexpression fails to induce more apoptosis since activation of the epidermal growth factor/epidermal growth factor receptor/SOS1 pathway impairs the pro-apoptotic role of ASPP2. In this study, in recombinant adenovirus-ASPP2-infected HepG2 cells, ASPP2 overexpression induces amphiregulin expression in a p53-dependent manner. Although amphiregulin initially contributes to ASPP2-induced apoptosis, it eventually impairs the pro-apoptotic function of ASPP2 by activating the epidermal growth factor/epidermal growth factor receptor/SOS1 pathway, leading to apoptosis resistance. Moreover, blocking soluble amphiregulin with a neutralizing antibody also significantly increased apoptotic cell death of HepG2 cells due to treatment with methyl methanesulfonate, cisplatin, or a recombinant p53 adenovirus, suggesting that the function of amphiregulin involved in inhibiting apoptosis may be a common mechanism by which hepatoma cells escape from stimulus-induced apoptosis. Thus, our data elucidate an apoptosis-evasion mechanism in hepatocellular carcinoma and have potential implications for hepatocellular carcinoma therapy.
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Arisanty, Dessy. "In Vitro Cytotoxic Study and Detection of Apoptosis on Breast Cancer Cell lines MDA-MB 231 after Exposed to Azadirachta Indica A. Juss (neem) Extract". Jurnal Kesehatan Andalas 2, nr 2 (1.05.2013): 80. http://dx.doi.org/10.25077/jka.v2i2.125.
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AbstrakSuatu senyawa obat dapat menjadi kemoterapi kanker adalah dengan cara menskrining terlebih dahulu tumbuhan obat yang berpotensi sebagai obat antikanker. Salah satunya adalah tanaman obat daun nimba (Azadirachta indica L.Juss) yang terbukti secara significant menyebabkan apoptosis pada beberapa jenis sel line kanker. Dalam penelitian ini, ekstrak ethanol dari A. indica dipelajari untuk melihat efeknya pada pertumbuhan sel kanker payudara manusia jenis MDA-MB-231 dengan menggunakan tes untuk proliferasi yaitu MTT assai dan untuk mengetahui perubahan morphologi dari apoptosis selnya dengan menggunakan TUNEL assay Ekstrak daun nimba (A. indica) dapat menurunkan keberadaan jumlah sel kanker dengan cara menghambat perkembangan daripada sel tersebut dan menginduksi proses apoptosis pada sel kanker tersebut. Hasil pemeriksaan MTT assai didapatkan nilai IC50 nya adalah 55 ug / mL. Kematian MDA-MB231 sel yang disebabkan oleh ekstrak daun nimba (A.indica) ditemukan melalui mekanisme apoptosis yang secara morfologinya menunjukan ciri ciri dari kematian secara apoptosis seperti kondensasi dari nucleus, membrane nukleus yang melebur dan akhirnya terjadinya fragmentasi dari DNA. Analisis struktur dalaman sel juga mengungkapkan karakteristik apoptosis yaitu marginasi dari kromosom yang disertai dengan fragmentasi DNA dan selanjutnya akan terbentuk badan apoptotik pada sel kanker yang diinkubasi dengan ekstrak tersebut. Pada penelitian ini juga dijumpai peningkatan jumlah sel apoptosis dari hari 1 sampai hari 3 inkubasi oleh ekstrak nimba. Ekstrak ethanol A.indica mungkin mengandung senyawa bioaktif(s) yang menyebabkan kanker payudara MDA-MNB 231 mengalami kematian sel secara apoptosis. Penelitian lebih lanjut masih diperlukan untuk mengetahui mekanisme tumbuhan ini membunuh sel kanker MDA-MB 231.Kata kunci: Studi In vitro, Azadirachta indica, apoptosis, TUNEL assayAbstractA screening is conducted on plants that have potential as anticancer is a promising way for discovering novel chemotherapeutic compound. A medicinal plant neem leaf (Azadirachta indica L.Juss) intake has been shown to induce significant levels of apoptosis in various cancer cells. In this present study, ethanol extract of Azadirachta indica was studied for its effects on growth in MDA-MB 231 human breast cancer cells using assays for proliferation (MTT assay) and mechanisme of cell apoptosis using TUNEL assay. Neem leaf extract decreased cell viability, inhibited cell proliferation, and induced cell apoptosis. Result of MTT assay was 55 μg/mL of neem remarkably reduced cell viability of MDA-MB 231 cells. MDA-MB231 cell death elicited by the extract was found to be apoptotic in nature based the indication of nucleus condensation, shrinkage of nucleus membrane and also DNA fragmentation which are a hallmark of apoptosis. In addition, ultrastructural analysis also revealed apoptotic characteristics which are the presence of chromatin margination and apoptotic bodies in the extract-treated cells. There was an increase in the number of apoptotic cells from day 1 to day 3 post incubation with neem extract. Thus, the results from this study strongly suggest that the ethanol extract of A.indica may contain bioactive compound(s) that caused breast carcinoma, MDA-MNB 231 cell death by apoptosis. It’s needed to do advance research to know more deeply the mechanism this plant on breast cancer cell line MDA-MB.Keywords:In vitro study, Azadirachta indica, apoptosis, TUNEL assay
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Sanfilippo, Christine M., i John A. Blaho. "ICP0 Gene Expression Is a Herpes Simplex Virus Type 1 Apoptotic Trigger". Journal of Virology 80, nr 14 (15.07.2006): 6810–21. http://dx.doi.org/10.1128/jvi.00334-06.
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ABSTRACT Apoptosis is a highly regulated programmed cell death process which is activated during normal development and by various stimuli, such as viral infection, which disturb cellular metabolism and physiology. That herpes simplex virus type 1 (HSV-1) induces apoptosis but then prevents its killing of infected cells is well-established. However, little is known about the viral factor/event which triggers the apoptotic process. We previously reported that infections with either (i) a temperature-sensitive virus at its nonpermissive temperature which does not inject viral DNA into nuclei or (ii) various UV-inactivated wild-type viruses do not result in the induction of apoptosis (C. M. Sanfilippo, F. N. W. Chirimuuta, and J. A. Blaho, J. Virol. 78:224-239, 2004). This indicates that virus receptor binding/attachment to cells, membrane fusion, virion disassembly/tegument dispersal, virion RNAs, and capsid translocation to nuclei are not responsible for induction and implicates viral immediate-early (IE) gene expression in the process. Here, we systematically evaluated the contribution of each IE gene to the stimulation of apoptosis. Using a series of viruses individually deleted for α27, α4, and α22, we determined that these genes are not required for apoptosis induction but rather that their products play roles in its prevention, likely through regulatory effects. Sole expression of α0 acted as an “apoptoxin” that was necessary and sufficient to trigger the cell death cascade. Importantly, results using a recombinant virus which contains a stop codon in α0 showed that it was not the ICP0 protein which acted as the apoptotic inducer. Based on these findings, we propose that α0 gene expression acts as an initial inducer of apoptosis during HSV-1 infection. This represents the first description of apoptosis induction in infected cells triggered as a result of expression of a single viral gene. Expression of apoptotic viral genes is a unique mechanism through which human pathogens may modulate interactions with their host cells.
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McCarthy, Justin V. "Apoptosis and development". Essays in Biochemistry 39 (1.10.2003): 11–24. http://dx.doi.org/10.1042/bse0390011.
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Apoptosis is an evolutionarily conserved process used by multicellular organisms to developmentally regulate cell number or to eliminate cells that are potentially detrimental to the organism. The large diversity of regulators of apoptosis in mammalian cells and their numerous interactions complicate the analysis of their individual functions, particularly in development. The remarkable conservation of apoptotic mechanisms across species has allowed the genetic pathways of apoptosis determined in lower species, such as the nematode Caenorhabditis elegans and the fruitfly Drosophila melanogaster, to act as models for understanding the biology of apoptosis in mammalian cells. Though many components of the apoptotic pathway are conserved between species, the use of additional model organisms has revealed several important differences and supports the use of model organisms in deciphering complex biological processes such as apoptosis.
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Ward, Carol, Adriano G. Rossi, Christopher Haslett i Ian Dransfield. "Apoptosis: future perspectives". Essays in Biochemistry 39 (1.10.2003): 155–62. http://dx.doi.org/10.1042/bse0390155.
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The field of apoptosis has expanded to include research in almost all subject areas of cell biology. Despite this growth, there are still many unanswered questions, some of which are fundamental to the development of therapeutic strategies. Most importantly, the underlying mechanisms involved in conferring specificity of apoptotic signals must be determined. This will allow the development of treatments to delete injured or transformed cells and minimize damage to other tissues. Such information is also necessary to combat degenerative diseases, to prevent critical loss of cells. In addition, it would be of therapeutic benefit to selectively induce apoptosis in specific cells where removal of unwanted cells is required (e.g. tumour cells in malignant tissue or inflammatory cells responsible for tissue damage in chronic inflammatory disease). Therefore we have to understand how the full complement of signalling pathways, and survival and apoptotic proteins determine the end effect of an apoptotic signal. Apoptotic cells are known to functionally influence phagocytes that ingest them, but little is known of the effect of apoptosis on neighbouring cells or of signals generated during the apoptotic process itself. Although the processes of mitosis and apoptosis would appear to be diametrically opposed, cell-cycle proteins are involved in apoptosis, and may be able to influence cell-death mechanisms; conversely, proliferation may be caspase-dependent in some cells. Further study is necessary to discover how these pathways are interlinked since such knowledge would be particularly useful in cancer treatment. The link between pathogen-survival strategies and apoptotic mechanisms will also reward further work. Viruses, in particular, exploit cellular survival and death pathways for replication purposes and may represent a targeting approach for specific treatments.
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Legesse-Miller, Aster, Irene Raitman, Erin M. Haley, Albert Liao, Lova L. Sun, David J. Wang, Nithya Krishnan i in. "Quiescent fibroblasts are protected from proteasome inhibition–mediated toxicity". Molecular Biology of the Cell 23, nr 18 (15.09.2012): 3566–81. http://dx.doi.org/10.1091/mbc.e12-03-0192.
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Proteasome inhibition is used as a treatment strategy for multiple types of cancers. Although proteasome inhibition can induce apoptotic cell death in actively proliferating cells, it is less effective in quiescent cells. In this study, we used primary human fibroblasts as a model system to explore the link between the proliferative state of a cell and proteasome inhibition–mediated cell death. We found that proliferating and quiescent fibroblasts have strikingly different responses to MG132, a proteasome inhibitor; proliferating cells rapidly apoptosed, whereas quiescent cells maintained viability. Moreover, MG132 treatment of proliferating fibroblasts led to increased superoxide anion levels, juxtanuclear accumulation of ubiquitin- and p62/SQSTM1-positive protein aggregates, and apoptotic cell death, whereas MG132-treated quiescent cells displayed fewer juxtanuclear protein aggregates, less apoptosis, and higher levels of mitochondrial superoxide dismutase. In both cell states, reducing reactive oxygen species with N-acetylcysteine lessened protein aggregation and decreased apoptosis, suggesting that protein aggregation promotes apoptosis. In contrast, increasing cellular superoxide levels with 2-methoxyestradiol treatment or inhibition of autophagy/lysosomal pathways with bafilomycin A1 sensitized serum-starved quiescent cells to MG132-induced apoptosis. Thus, antioxidant defenses and the autophagy/lysosomal pathway protect serum-starved quiescent fibroblasts from proteasome inhibition–induced cytotoxicity.
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Zhang, Xu Dong, Susan K. Gillespie i Peter Hersey. "Staurosporine induces apoptosis of melanoma by both caspase-dependent and -independent apoptotic pathways". Molecular Cancer Therapeutics 3, nr 2 (1.02.2004): 187–97. http://dx.doi.org/10.1158/1535-7163.187.3.2.
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Abstract Staurosporine has long been used in vitro as an initiator of apoptosis in many different cell types, but the mechanism involved remains poorly understood. In the present study, we have examined the apoptosis-inducing potential of staurosporine in cultured melanoma cell lines and dissected the staurosporine-induced apoptotic signaling pathway. We report that although staurosporine activated Bax and the mitochondrial caspase-dependent apoptotic pathway, it also induced apoptosis of melanoma by caspase-independent pathways. The caspase-dependent apoptotic pathway was activated relatively soon after exposure to staurosporine and was associated with release of cytochrome c and Smac/DIABLO from mitochondria and cleavage of poly(ADP-ribose) polymerase and inhibitor of caspase-activated DNase. This pathway was inhibitable by broad caspase inhibitors. A second apoptotic pathway that appeared to be involved in late apoptotic events was caspase independent in that inhibitors of caspases did not prevent the late onset of apoptosis. Overexpression of Bcl-2 inhibited the early onset of apoptosis but not the later, caspase-independent pathway. Apoptosis-inducing factor may be responsible for the late apoptotic execution in that its translocation from mitochondria into the nucleus coincided with the late onset of apoptosis and could not be inhibited by either a pan-caspase inhibitor or overexpression of Bcl-2. Our results indicate that staurosporine is able to bypass resistance of melanoma cells to mitochondrial caspase-dependent apoptotic pathways; hence, derivatives of staurosporine may warrant further evaluation either alone or with other apoptosis-inducing agents.
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Barbaste, Audrey, Sonia Schott, Corinne Benassayag i Magali Suzanne. "Dissecting morphogenetic apoptosis through a genetic screen in Drosophila". Life Science Alliance 6, nr 10 (26.07.2023): e202301967. http://dx.doi.org/10.26508/lsa.202301967.
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Apoptosis is an essential cellular process both in normal development and pathological contexts. Screens performed to date have focused on the cell autonomous aspect of the process, deciphering the apoptotic cascade leading to cell destruction through the activation of caspases. However, the nonautonomous aspect of the apoptotic pathway, including signals regulating the apoptotic pattern or those sent by the apoptotic cell to its surroundings, is still poorly understood. Here, we describe an unbiased RNAi-based genetic screen whose goal is to identify elements of the “morphogenetic apoptosis pathway” in an integrated model system, theDrosophilaleg. We screened about 1,400 candidates, using adult joint morphology, morphogenetic fold formation, and apoptotic pattern as readouts for the identification of potential apoptosis-related genes. We identified 41 genes potentially involved in specific aspects of morphogenetic apoptosis: (1) regulation of the apoptotic process; (2) formation, extrusion, and elimination of apoptotic bodies; and (3) contribution to morphogenesis downstream of apoptosis.
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Feng, Ying, Yan Zhang, Zhiqing Lin, Xiaolei Ye, Xue Lin, Lixiu Lv, Yi Lin, Shenfei Sun, Yun Qi i Xinhua Lin. "Chromatin remodeler Dmp18 regulates apoptosis by controlling H2Av incorporation in Drosophila imaginal disc development". PLOS Genetics 18, nr 9 (27.09.2022): e1010395. http://dx.doi.org/10.1371/journal.pgen.1010395.
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Programmed Cell Death (PCD) or apoptosis is a highly conserved biological process and plays essential roles both in the development and stress context. In Drosophila, expression of pro-apoptotic genes, including reaper (rpr), head involution defective (hid), grim, and sickle (skl), is sufficient to induce cell death. Here, we demonstrate that the chromatin remodeler Dmp18, the homolog of mammalian Znhit1, plays a crucial role in regulating apoptosis in eye and wing development. We showed that loss of Dmp18 disrupted eye and wing development, up-regulated transcription of pro-apoptotic genes, and induced apoptosis. Inhibition of apoptosis suppressed the eye defects caused by Dmp18 deletion. Furthermore, loss of Dmp18 disrupted H2Av incorporation into chromatin, promoted H3K4me3, but reduced H3K27me3 modifications on the TSS regions of pro-apoptotic genes. These results indicate that Dmp18 negatively regulates apoptosis by mediating H2Av incorporation and histone H3 modifications at pro-apoptotic gene loci for transcriptional regulation. Our study uncovers the role of Dmp18 in regulating apoptosis in Drosophila eye and wing development and provides insights into chromatin remodeling regulating apoptosis at the epigenetic levels.
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Ortiz, Rocío, Leticia Corté, Humberto Gonz´lez–M´rquez, José Luis Gómez, Cristina Gonz´lez i Edith Cortés. "Flow cytometric analysis of spontaneous and dexamethasone-induced apoptosis in thymocytes from severely malnourished rats". British Journal of Nutrition 86, nr 5 (listopad 2001): 545–48. http://dx.doi.org/10.1079/bjn2001446.
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Severe malnutrition is widely distributed throughout the world, showing a high prevalence in developing countries. Experimental animal models have been useful to study the effects of malnutrition at different levels and ages. Apoptosis is a well recognised process of cell death occurring under several physiological and pathological conditions. It represents the principal mechanism involved in cell selection in the thymus. Thymocyte apoptosis induction by dexamethasone is one of the best characterised experimental models of programmed cell death. The aim of the present study was to determine whether severe malnutrition increased spontaneous and/or dexamethasone-induced apoptosisin vivoin thymocytes of experimentally malnourished rats during lactation. Thymocytes were obtained from malnourished rats at weaning (21d of age). Apoptosis frequency was estimated by the terminal transferase-mediated dUTP nick end labelling assay. Spontaneous apoptosis was 1·9 (SD 1·0) % IN WELL NOURISHED RATS IN CONTRAST TO 13·3 (sd 3·8) % in malnourished animals; this is seven times greater (P<0·001). Interestingly, the frequency of dexamethasone-induced apoptosis was similar in both groups of animals (47·9 (sd 10·1) % in well nourished rats and 53·8 (sd 8·0) % in malnourished rats). The results obtained in the present study indicate that malnutrition is associated with a significant increase of spontaneously apoptotic cells. In addition, the data showed that the fraction of thymocytes susceptible to dexamethasone-induced apoptosis was similar in well nourished and malnourished animals. The greater levels of spontaneously apoptotic cells associated with malnutrition could be related to alterations of the microenvironment of the thymus and/or to an obstruction of early thymocyte maturation.
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Jan, Rehmat, i Gul-e.-Saba Chaudhry. "Understanding Apoptosis and Apoptotic Pathways Targeted Cancer Therapeutics". Advanced Pharmaceutical Bulletin 9, nr 2 (1.06.2019): 205–18. http://dx.doi.org/10.15171/apb.2019.024.
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Various physiological processes involve appropriate tissue developmental process and homeostasis - the pathogenesis of several diseases connected with deregulatory apoptosis process. Apoptosis plays a crucial role in maintaining a balance between cell death and division, evasion of apoptosis results in the uncontrolled multiplication of cells leading to different diseases such as cancer. Currently, the development of apoptosis targeting anticancer drugs has gained much interest since cell death induced by apoptosis causes minimal inflammation. The understanding of complexities of apoptosis mechanism and how apoptosis is evolved by tumor cells to oppose cell death has focused research into the new strategies designed to induce apoptosis in cancer cells. This review focused on the underlying mechanism of apoptosis and the dysregulation of apoptosis modulators involved in the extrinsic and intrinsic apoptotic pathway, which include death receptors (DRs) proteins, cellular FLICE inhibitory proteins (c-FLIP), anti-apoptotic Bcl-2 proteins, inhibitors of apoptosis proteins (IAPs), tumor suppressor (p53) in cancer cells along with various current clinical approaches aimed to selectively induce apoptosis in cancer cells.
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Holubec, Hana, Claire M. Payne, Harris Bernstein, Katerina Dvorakova, Carol Bernstein, Caroline N. Waltmire, James A. Warneke i Harinder Garewal. "Assessment of Apoptosis by Immunohistochemical Markers Compared to Cellular Morphology in Ex Vivo-stressed Colonic Mucosa". Journal of Histochemistry & Cytochemistry 53, nr 2 (luty 2005): 229–35. http://dx.doi.org/10.1369/jhc.4a6386.2005.
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Apoptosis competence is central to the prevention of cancer. Frequency of apoptotic cells, after a sample of colonic tissue is stressed, can be used to gauge apoptosis competence and, thus, possible susceptibility to colon cancer. The gold standard for assessment of apoptosis is morphological evaluation, but this requires an experienced microscopist. Easier-to-use immunohistochemical markers of apoptosis, applicable in archived paraffin-embedded tissue, have been commercially developed. Potentially useful apoptosis markers include cleaved cytokeratin-18 (c-CK18), cleaved caspase-3 (c-cas-3), cleaved lamin A (c-lam-A), phosphorylated histone H2AX (γH2AX), cleaved poly(ADP ribose) polymerase (c-PARP), and translocation of apoptosis-inducing factor (AIF). When tissue samples from freshly resected colon segments were challenged ex vivo with the bile acid deoxycholate, ∼50% of goblet cells became apoptotic by morphologic criteria. This high level of morphologic apoptosis allowed quantitative comparison with the usefulness and specificity of immunohistochemical markers of apoptosis. The antibody to c-CK18 was almost as useful and about as specific as morphology for identifying apoptotic colonic epithelial cells. Antibodies to c-cas-3, c-lam-A, and γH2AX, though specific for apoptotic cells, were less useful. The antibody to c-PARP, though specific for apoptotic cells, had low usefulness, and the antibody to AIF was relatively nonspecific, under our conditions.
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Velde, L. F. te, I. Vermes, C. Haanen, C. P. M. Reutelingsperger i C. H. H. ten Napel. "Apoptotic cell death, detectedex vivoin peripheral blood lymphocytes of HIV-1 infected persons". Mediators of Inflammation 5, nr 5 (1996): 379–81. http://dx.doi.org/10.1155/s0962935196000543.
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In HIV-1 infection the ongoing depletion of CD4+ T-lymphocytes is believed, to a large extent, to be due to apoptosis. Until now quantitative information aboutin vivoapoptosis of lymphocytes in HIV-patients is scarce because of the very nature of the apoptotic process. Successful detection of apoptosisex vivorequires the recognition of the initial phase of this process, because at a later stage the cells may not remain any longer in the circulation. We measured quantitatively the amount of early apoptotic peripheral blood lymphocytes directlyex vivoin HIV-1 infected patients using a recently described flow cytometric assay. With this method we observed in an unselected heterogenous group of twelve HIV-infected individuals a median percentage of apoptotic lymphocytes to be significantly higher than in ten healthy controls. To the best of our knowledge this is the first report ofex vivoobserved increased apoptosis of peripheral blood lymphocytes in HIV-infected persons.
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Chrysis, D., EM Ritzen i L. Savendahl. "Growth retardation induced by dexamethasone is associated with increased apoptosis of the growth plate chondrocytes". Journal of Endocrinology 176, nr 3 (1.03.2003): 331–37. http://dx.doi.org/10.1677/joe.0.1760331.
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Glucocorticoids cause significant growth retardation in mammals and humans and decreased proliferation of chondrocytes has been considered as the main local mechanism. Death by apoptosis is an important regulator of homeostasis in multicellular organisms. Here we chose to study the role of apoptosis in growth retardation caused by glucocorticoid treatment. We treated 7-week-old male rats with dexamethasone (5 mg/kg/day) for 7 days. Apoptosis was studied in tibiae growth plates by the TUNEL method. Immunoreactivity for parathyroid hormone-related peptide (PTHrP), caspase-3, and the anti-apoptotic proteins Bcl-2 and Bcl-x was also studied. Apoptosis was mainly localized in terminal hypertropic chondrocytes (THCs) in both control and dexamethasone-treated animals. Dexamethasone caused an increase in apoptosis which was fourfold in THCs (2.45+/-0.12 vs 0.62+/-0.09 apoptotic cells/mm growth plate, P<0.001), and 18-fold in proliferative chondrocytes (0.18+/-0.04 vs 0.01+/-0.007 apoptotic cells/mm growth plate, P<0.001). Increased apoptosis after dexamethasone treatment was accompanied by increased immunoreactivity for caspase-3 and decreased immunoreactivity for the anti-apoptotic proteins Bcl-2 and Bcl-x, which further supports our apoptosis results. Dexamethasone also decreased the immunoreactivity for PTHrP, suggesting a role in the mechanism by which glucocorticoids induce apoptosis in the growth plate. We conclude that apoptosis is one mechanism involved in growth retardation induced by glucocorticoids. Premature loss of resting/proliferative chondrocytes by apoptosis could contribute to incomplete catch-up seen after prolonged glucocorticoid treatment.
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Madeo, Frank, Eleonore Fröhlich, Martin Ligr, Martin Grey, Stephan J. Sigrist, Dieter H. Wolf i Kai-Uwe Fröhlich. "Oxygen Stress: A Regulator of Apoptosis in Yeast". Journal of Cell Biology 145, nr 4 (17.05.1999): 757–67. http://dx.doi.org/10.1083/jcb.145.4.757.
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Oxygen radicals are important components of metazoan apoptosis. We have found that apoptosis can be induced in the yeast Saccharomyces cerevisiae by depletion of glutathione or by low external doses of H2O2. Cycloheximide prevents apoptotic death revealing active participation of the cell. Yeast can also be triggered into apoptosis by a mutation in CDC48 or by expression of mammalian bax. In both cases, we show oxygen radicals to accumulate in the cell, whereas radical depletion or hypoxia prevents apoptosis. These results suggest that the generation of oxygen radicals is a key event in the ancestral apoptotic pathway and offer an explanation for the mechanism of bax-induced apoptosis in the absence of any established apoptotic gene in yeast.
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Rezaei Zarnaghi, Mahsa, Zahra Bahroudi, Melika Izadpanah, Abbas Majdi Seghinsara i Ali Abedelahi. "Novel Approaches Used for Decreasing Apoptosis Rate in Ovarian Tissue Cryopreservation and Transplantation". ImmunoAnalysis 4 (6.05.2024): 2. http://dx.doi.org/10.34172/ia.4055.
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Apoptosis is the main cause of atresia in ovarian follicles. In oxidative stress (OS) conditions, an imbalance between pro-apoptotic and anti-apoptotic genes can increase the apoptosis rate. In some diseases, such as cancers, patients lose fertility due to chemotherapy and radiotherapy. One way to maintain fertility in these patients is ovarian tissue cryopreservation and transplantation (OTC/T). Studies show that OTC/T also increases apoptosis due to hypoxia and ischemia but fortunately new findings show that applying new approaches could decrease apoptosis in these procedures considerably. This article reviewed follicular atresia, apoptosis during cryopreservation and transplantation, and factors affecting the reduction of apoptosis.
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Nagata, Shigekazu. "Apoptosis and Clearance of Apoptotic Cells". Annual Review of Immunology 36, nr 1 (26.04.2018): 489–517. http://dx.doi.org/10.1146/annurev-immunol-042617-053010.
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Halder, Kalpataru. "Apoptosis: From Oncogenesis to Oncotherapy". International Journal of Experimental Research and Review 40, Spl Volume (30.06.2024): 200–216. http://dx.doi.org/10.52756/ijerr.2024.v40spl.017.
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Cell death is critical in maintaining the balance between cell proliferation and elimination in all living organisms. Among the different modalities of regulated cell death, apoptosis remains the most extensively studied and interesting pathway for targeted carcinogenesis therapy. Dysfunctions in apoptotic pathways contribute to the development and progression of cancer, and targeting these pathways is essential for effective cancer therapy. This review provides an overview of different types of apoptotic pathways and their significance in the development and progression of cancer. We also discuss the present oncotherapy strategies targeting different cell death pathways and mechanisms and the challenges associated with apoptosis-based therapies. This review highlights the need for the development of 3-D cellular models to study the interaction between tumor cells and their microenvironment, reduced in-vivo toxicity, and increased specificity for certain drugs targeting p53 or inhibitor of apoptosis proteins (IAPs). Overall, this review provides a comprehensive understanding of the significance of apoptosis in oncogenesis and oncotherapy and the potential of targeting apoptotic pathways for effective cancer treatment.Cell death is critical in maintaining the balance between cell proliferation and elimination in all living organisms. Among the different modalities of regulated cell death, apoptosis remains the most extensively studied and interesting pathway for targeted carcinogenesis therapy. Dysfunctions in apoptotic pathways contribute to the development and progression of cancer, and targeting these pathways is essential for effective cancer therapy. This review provides an overview of different types of apoptotic pathways and their significance in the development and progression of cancer. We also discuss the present oncotherapy strategies targeting different cell death pathways and mechanisms and the challenges associated with apoptosis-based therapies. This review highlights the need for the development of 3-D cellular models to study the interaction between tumor cells and their microenvironment, reduced in-vivo toxicity, and increased specificity for certain drugs targeting p53 or inhibitor of apoptosis proteins (IAPs). Overall, this review provides a comprehensive understanding of the significance of apoptosis in oncogenesis and oncotherapy and the potential of targeting apoptotic pathways for effective cancer treatment.
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Andreu-Vieyra, C. V., i H. R. Habibi. "Factors controlling ovarian apoptosis". Canadian Journal of Physiology and Pharmacology 78, nr 12 (1.12.2000): 1003–12. http://dx.doi.org/10.1139/y00-101.
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Apoptosis is a form of programmed cell death that is essential for the development of the embryo and adult tissue plasticity. In adults, it is observed mainly in those tissues undergoing active differentiation such as the hematopoietic system, testis, ovary, and intestinal epithelium. Apoptosis can be triggered by many factors, such as hormones, cytokines, and drugs, depending on the type of the cell. While the intracellular signaling mechanisms may vary in different cells, they all display similar morphological and biochemical features at the later stages of the apoptotic process. This review focuses on the factors controlling ovarian apoptosis, emphasizing observations made on GnRH-induced apoptotic process in goldfish follicles.Key words: apoptosis, ovary, GnRH.
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Fan, Xueping, i Bernard Robaire. "Orchidectomy Induces a Wave of Apoptotic Cell Death in the Epididymis*". Endocrinology 139, nr 4 (1.04.1998): 2128–36. http://dx.doi.org/10.1210/endo.139.4.5888.
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Abstract The epididymis is the site where spermatozoa are matured and stored. After orchidectomy, this tissue loses up to 80% of its weight. In the prostate, androgen withdrawal by orchidectomy is associated with apoptotic cell death. The objective of the present study was to investigate whether apoptotic cell death is involved in the androgen-dependent weight loss found in the rat epididymis after orchidectomy. Adult male Sprague-Dawley rats were orchidectomized, and apoptotic cells were identified by in situ TUNEL (TdT-mediated dUTP-digoxigenin nick end-labeling) apoptosis detection. Apoptosis first appeared in the epithelium of the initial segment of the epididymis 18 h after orchidectomy, reached a maximum on day 2, and disappeared by day 5 postorchidectomy. In the caput epididymidis, apoptosis was first found after 24 h, reached a maximum by day 3, and was detectable until day 5. In the corpus epididymidis, apoptosis was first seen on day 4, peaked on day 5, and was undetectable by day 6 postorchidectomy. In the cauda epididymidis, apoptosis was first seen on day 5, peaked on day 6, and was occasionally detected on day 7. Throughout the rat epididymis, apoptotic cell death was localized specifically to principal cells. The presence of apoptosis was confirmed with the observation of a ladder of nucleosomal sized DNA fragmentation by using agarose gel electrophoresis. Androgen replacement therapy after orchidectomy demonstrated that apoptosis in the caput, corpus, and cauda epididymidis was androgen dependent. However, androgens alone could not completely prevent apoptosis in the initial segment of the epididymis. Efferent duct ligation induced a similar pattern of apoptosis in the initial segment of the epididymis as that seen after orchidectomy, but there were fewer apoptotic cells in the caput epididymidis, and no apoptotic cell death in the corpus and cauda epididymidis. We conclude that withdrawal of androgen by orchidectomy induces a wave of apoptotic cell death in the epididymis; we hypothesize that apoptosis in the initial segment is caused primarily by withdrawal of androgen as well as by luminal components coming from the testis.
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Niesler, CU, B. Urso, JB Prins i K. Siddle. "IGF-I inhibits apoptosis induced by serum withdrawal, but potentiates TNF-alpha-induced apoptosis, in 3T3-L1 preadipocytes". Journal of Endocrinology 167, nr 1 (1.10.2000): 165–74. http://dx.doi.org/10.1677/joe.0.1670165.
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We have previously shown that human preadipocytes in primary culture undergo apoptosis in response to serum deprivation and addition of tumour necrosis factor alpha (TNF-alpha), and have proposed that regulation of preadipocyte apoptosis in vivo may contribute to the overall control of adipose mass. In the present study we have investigated both pro- and anti-apoptotic factors, and the signalling pathways by which they act, in murine 3T3-L1 preadipocytes. Apoptotic indices (fraction of cells undergoing apoptosis) were determined by microscopic examination of acridine orange-stained cells, fluorescence-activated cell sorting of propidium iodide-stained cells, or phase-contrast video microscopy. Murine 3T3-L1 cells were more susceptible to apoptosis than human preadipocytes. In medium containing 10% newborn calf serum, the basal apoptotic index was very low (<2%), but the number of apoptotic cells increased significantly following serum withdrawal (10% after 24 h). Addition of TNF-alpha (6 nM) stimulated apoptosis in both serum-containing and serum-free media (apoptotic indices of 12% and 20% respectively after 24 h). IGF-I inhibited by approximately 50% the apoptosis induced by serum withdrawal, but increased by 25% the apoptosis induced by TNF-alpha in serum-free medium. It was shown by using specific inhibitors of lipid and protein kinases (LY294002, rapamycin, PD98059, SB203580) that both phosphoinositide 3-kinase and MAP kinase pathways contribute to the anti-apoptotic action of IGF-I on serum-starved cells, while phosphoinositide 3-kinase but not MAP kinase activity is required for the paradoxical pro-apoptotic action of IGF-I in the presence of TNF-alpha. We conclude that, in addition to its previously described anti-apoptotic action, IGF-I can also be pro-apoptotic in 3T3-L1 cells in the presence of TNF-alpha, and that both the anti- and pro-apoptotic effects of IGF-I require the activation of phosphoinositide 3-kinase.
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Stewart, Katherine, You Chi Tang, Maxwell E. R. Shafer, Adda-Lee Graham-Paquin i Maxime Bouchard. "Modulation of apoptotic response by LAR family phosphatases–cIAP1 signaling during urinary tract morphogenesis". Proceedings of the National Academy of Sciences 114, nr 43 (9.10.2017): E9016—E9025. http://dx.doi.org/10.1073/pnas.1707229114.
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The elimination of unwanted cells by apoptosis is necessary for tissue morphogenesis. However, the cellular control of morphogenetic apoptosis is poorly understood, notably the modulation of cell sensitivity to apoptotic stimuli. Ureter maturation, the process by which the ureter is displaced to the bladder wall, represents an exquisite example of morphogenetic apoptosis, requiring the receptor protein tyrosine phosphatases (RPTPs): LAR and RPTPσ. Here we show that LAR-RPTPs act through cellular inhibitor of apoptosis protein 1 (cIAP1) to modulate caspase 3,7-mediated ureter maturation. Pharmacologic or genetic inactivation of cIAP1 reverts the apoptotic deficit of LAR-RPTP–deficient embryos. Moreover, Birc2 (cIAP1) inactivation generates excessive apoptosis leading to vesicoureteral reflux in newborns, which underscores the importance of apoptotic modulation during urinary tract morphogenesis. We finally demonstrate that LAR-RPTP deficiency increases cIAP1 stability during apoptotic cell death. Together these results identify a mode of cIAP1 regulation playing a critical role in the cellular response to apoptotic pathway activation in the embryo.
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Brajuskovic, Goran. "Apoptosis in malignant diseases". Archive of Oncology 13, nr 1 (2005): 19–22. http://dx.doi.org/10.2298/aoo0501019b.
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Apoptosis is a special type of cell death essentially different from necrosis in nature and biological significance. It is an active process of genetically regulated cell auto destruction and in most cases has a homeostatic function. Apoptotic cells may be characterized by specific morphological and biochemical changes. A great number of genes are known today, whose protein products take part in regulation of the apoptotic process. Apoptosis or programmed cell death has been implicated in a wide range of pathological conditions. Studies of the correlation of programmed cell death with proliferation and the multistage carcinogenesis process are in the focus of modern research. Mutations and deletions of apoptotic genes play important roles in carcinogenesis, tumor growth, and tumor regression. This article reviews the current knowledge on mutations of apoptosis genes involved in pathogenesis of human cancers. Finally, we have recently summarized achievements in cancer therapy with a focus on the apoptotic genes.
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Morsi, Rami Z., Rouba Hage-Sleiman, Hadile Kobeissy i Ghassan Dbaibo. "Noxa: Role in Cancer Pathogenesis and Treatment". Current Cancer Drug Targets 18, nr 10 (13.11.2018): 914–28. http://dx.doi.org/10.2174/1568009618666180308105048.
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The B-cell lymphoma 2 (Bcl-2) family proteins play an important role in regulating apoptosis, or programmed cell death, in response to several extracellular and intracellular signals. These proteins are either pro-apoptotic or anti-apoptotic. The pro-apoptotic Noxa is a Bcl-2 family protein that belongs to a subclass of BH3-only proteins. Noxa induces apoptosis via p53-dependent and/or p53-independent mechanisms. While Noxa may play a limited role in apoptosis, it is a crucial player that interacts with several proteins in the apoptosis pathway, highlighting its importance in the pathogenesis and treatment of certain cancers. In this review, we will elucidate the mechanisms by which Noxa regulates apoptosis and review the roles of chemotherapeutic drugs in relation to Noxa.
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Sandra, Ferry. "Targeting Ameloblatoma into Apoptosis". Indonesian Biomedical Journal 10, nr 1 (29.04.2018): 35. http://dx.doi.org/10.18585/inabj.v10i1.354.
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BACKGROUND: Generally ameloblastoma is a locally aggressive, slow growing, non-metastatic epithelial odontogenic benign tumor. However, rarely some ameloblastoma can metastasize in spite of a benign histologic appearance. Targeting ameloblastoma by inducing it into apoptosis could be a beneficial strategy, since many ameloblastoma cases were reported recurrent after surgical therapy.CONTENT: To investigate ameloblastoma in cellular aspect,cytological pattern of ameloblastoma was divided intoouter layer/peripheral and inner layer/central cells. Tumor necrosis factor (TNF)-α, Fas ligand (FasL), TNF receptor (TNFR)1/death receptor (DR)1, TNFR2/DR2, DR4, DR5andFas were highly expressed in central than peripheral cells. Despite inducing apoptosis, TNF-α can induce PI3K leading to Akt and p44/42 mitogen-activated protein kinases (MAPK) activation in AM-1 cells, which later induce cell survival and proliferation. Therefore apoptotic induction in ameloblastoma should be suggested in higher TNF-α concentration. Expression of FasL and Fas are closely associated with squamous metaplasia and granular transformation of the tumor cells, suggesting that apoptosis induced by FasL may play a role in the terminally differentiated or degenerative ameloblastoma cells. TNF-related apoptosis-inducing ligand (TRAIL) has emerged as an apoptotic inducing anticancer agent in tumor cells specifically. TRAIL induced activation of caspases, lowering mitochondrial membrane potential, high number of apoptotic cells in ameloblastoma cells. Therefore, TRAIL could be a potential agent for targeting ameloblastoma, although further study should be explored.SUMMARY: Targeting ameloblastoma by inducing it into apoptosis could be achieved effectively, although some criteria should be considered. Therefore understanding the underlying apoptosis signaling pathways are necessary for inducing ameloblasotma into apoptosis. Investigations on other apoptosis-related molecules, potential apoptosis-inducing natural products, and novel approach in reprogramming, are important in the future for a better anagement of ameloblastoma.KEYWORDS: ameloblastoma, apoptosis, TNF, Fas, TRAIL, Akt, MAPK, caspase
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Feng, Jinzhou, Tao Tao, Weiping Yan, Cindy Si Chen i Xinyue Qin. "Curcumin Inhibits Mitochondrial Injury and Apoptosis from the Early Stage in EAE Mice". Oxidative Medicine and Cellular Longevity 2014 (2014): 1–10. http://dx.doi.org/10.1155/2014/728751.
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The exact pathophysiological change concerning mitochondrial injury and oligodendrocyte apoptosis in MS and EAE model is still unknown. Whether curcumin is able to inhibit mitochondrial injury and suppress the apoptosis in the early stages of MS/EAE is still unclear. We first explored mitochondrial injury and apoptosis at different time points p.i. in C57 BL/6 EAE mice. We then explored the effects of curcumin on mitochondria and apoptosis. Results showed that mitochondrial injury can be observed 3 days p.i. Apoptosis in the spinal cord occurred 3 days p.i. and the apoptotic cells were shown to be oligodendrocytes and neuronal cells. Curcumin significantly reduced the number of apoptotic cells and inhibited the upregulation of cyt-c, caspase-9, and caspase-3 at 7 days p.i. in the EAE mice. These observations demonstrate that mitochondrial injury and oligodendrocyte/neuronal apoptosis occur in the early stages of EAE. Curcumin can inhibit apoptosis in EAE mice which maybe act through protection of mitochondrial injury and inhibition of the intrinsic apoptotic pathway.
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Yu, Qianlong, Minghui Wang, Xuemeng Ding, Jiachen Han, Hancheng Ma, Jie Li, Guiling Zheng, Bin Zhang i Changyou Li. "The Expression of P35 Plays a Key Role in the Difference in Apoptosis Induced by AcMNPV Infection in Different Spodoptera exigua Cell Lines". International Journal of Molecular Sciences 24, nr 17 (25.08.2023): 13228. http://dx.doi.org/10.3390/ijms241713228.
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Baculovirus infection induces apoptosis in host cells, and apoptosis significantly affects virus production. Autographa californica multiple nucleopolyhedrovirus (AcMNPV) can regulate apoptosis, but the regulatory mechanism is unclear. Here, we found that AcMNPV infection induced different apoptosis responses in different Spodoptera exigua cell lines. In the early stages of viral infection (1–6 h), Se-1 cells underwent severe apoptosis, while Se-3 cells underwent very slight apoptosis. In the late stages of viral infection (12–72 h), Se-1 cells continued to undergo apoptosis and formed a large number of apoptotic bodies, while the apoptosis of Se-3 cells was inhibited and no apoptotic bodies were formed. To determine the reasons for the apoptosis differences in the two cell lines, we measured the expression of the six S. exigua cysteine-dependent aspartate specific protease genes (SeCaspase-1 to -6) and the three AcMNPV antiapoptotic protein genes (iap1, iap2 and p35) during viral infection. We found that SeCaspase-1 to -6 were all activated in Se-1 cells and inhibited in Se-3 cells, whereas iap1, iap2 and p35 were all inhibited in Se-1 cells and normally expressed in Se-3 cells. And p35 was expressed earlier than iap1 and iap2 in Se-3 cells. Otherwise, Se-1 and Se-3 cells would all be apoptotic when infected with the recombinant p35 knockout AcMNPV, whereas only Se-1 cells were apoptotic, but Se-3 cells were not apoptotic when infected with the recombinant p35 repair AcMNPV. Combined with the fact that the expression of P35 protein is inhibited in Se-1 cells but normally expressed in Se-3 cells during the infection of recombinant p35 repair AcMNPV, we proposed that the different expression of P35 is an important reason for the apoptosis differences between the two cell lines. We also found that some genes associated with apoptosis can probably regulate the expression of P35. However, the major upstream regulators of P35 and their mechanisms are still unclear and will be studied in the future.
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Vaahtokari, A., T. Aberg i I. Thesleff. "Apoptosis in the developing tooth: association with an embryonic signaling center and suppression by EGF and FGF-4". Development 122, nr 1 (1.01.1996): 121–29. http://dx.doi.org/10.1242/dev.122.1.121.
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Apoptosis was localized in developing mouse teeth from initiation of morphogenesis to completion of cusp formation by using modified TUNEL method for serial sections and Nile Blue staining for whole mounts. Apoptosis was first detected at bud stage (E12-E13) in the central cells of the invaginating dental epithelium suggesting involvement of cell death in epithelial budding morphogenesis. During cusp development, apoptotic cells were located in the enamel knots, which are transient clusters of dental epithelial cells proposed to act as signaling centers directing the morphogenesis of tooth cusps. Apoptosis was also detected in other restricted epithelial cell populations including the dental lamina, ameloblasts, as well as stratum intermedium and stellate reticulum cells suggesting that the removal of these epithelial cells occurs by apoptosis. Apoptotic cells, presumably osteoclasts, were also located on the surfaces of the developing alveolar bone. When dissected E13 dental epithelium or mesenchyme were cultured in isolation, apoptotic cells were abundant throughout the tissues, whereas when cultured together, apoptosis was inhibited in both tissues close to their interface indicating that epithelial-mesenchymal tissue interactions prevent apoptosis. Epidermal growth factor (EGF) and fibroblast growth factor-4 (FGF-4) inhibited apoptosis in the dental mesenchyme when applied locally using agarose or heparin-coated acrylic beads, suggesting involvement of these or related growth factors in the prevention of apoptosis in dental tissues in vivo. The spatially and temporally restricted distribution patterns of apoptotic cells suggest multiple roles for programmed cell death in dental development. Of particular interest is the removal of the enamel knots by apoptosis which may terminate their tasks as regulators of the patterning of the tooth cusps. The apical ectodermal ridge (AER) of the limb bud has similar signaling characteristics as the enamel knot, and it also undergoes apoptosis. Hence, apoptosis may be a general mechanism for the silencing of embryonic signaling centers.
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Dastoor, Z., i J. L. Dreyer. "Potential role of nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase in apoptosis and oxidative stress". Journal of Cell Science 114, nr 9 (1.05.2001): 1643–53. http://dx.doi.org/10.1242/jcs.114.9.1643.
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Recent studies indicating a role of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in apoptosis or oxidative stress has been reported. Using confocal laser-scanning microscopy, we have investigated the cellular distribution of GAPDH in central nervous system (CNS)-derived cells (neuroblastoma mNB41A3), in non-CNS derived cells (R6 fibroblast) and in an apoptosis-resistant Bcl2 overexpressing cell line (R6-Bcl2). Induction of apoptosis by staurosporine or MG132 and oxidative stress by H(2)O(2) or FeCN enhanced the nuclear translocation of endogenous GAPDH in all cell types, as detected by immunocytochemistry. In apoptotic cells, GAPDH expression is three times higher than in non-apoptotic cells. Consistent with a role for GAPDH in apoptosis, overexpression of a GAPDH-green fluorescent protein (GAPDH-GFP) hybrid increased nuclear import of GAPDH-GFP into transfected cells and the number of apoptotic cells, and made them more sensitive to agents that induce apoptosis. Bcl2 overexpression prevents nuclear translocation of GAPDH and apoptosis in untransfected cells, but not in transfected cells that overexpress GAPDH-GFP. Our observations indicate that nuclear translocation of GAPDH may play a role in apoptosis and oxidative stress, probably related to the activity of GAPDH as a DNA repair enzyme or as a nuclear carrier for pro-apoptotic molecules.
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HUNG, Wen-Chun, Hui-Chiu CHANG i Lea-Yea CHUANG. "Activation of caspase-3-like proteases in apoptosis induced by sphingosine and other long-chain bases in Hep3B hepatoma cells". Biochemical Journal 338, nr 1 (8.02.1999): 161–66. http://dx.doi.org/10.1042/bj3380161.
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Sphingosine and other long-chain bases (including sphinganine, dimethylsphingosine and stearylamine), but not octylamine (a short-chain analogue of sphinganine), induced apoptosis in Hep3B hepatoma cells. Because both d- and l-erythrosphingosine and stearylamine exert potent apoptotic effects on Hep3B cells, it is possible that these long-chain bases may activate apoptosis by inhibiting protein kinase C (PKC) activity. However, pretreatment with the PKC activator PMA could not rescue cells from apoptosis triggered by long-chain bases. Therefore the involvement of PKC in this apoptotic process requires further characterization. We also investigated whether these long-chain bases might be metabolized into ceramide in order to elicit their apoptotic action. We found that long-chain bases acted independently of ceramide in the induction of apoptosis, since addition of fumonisin B1, a fungal agent which effectively inhibits ceramide synthesis from sphingosine, did not protect against apoptosis. Additionally, we found that sphingosine-induced apoptosis was accompanied by activation of caspases. The functional role of caspases in this apoptotic process was examined by using specific caspase inhibitors. The general caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp fluoromethyl ketone, which exhibits a broad specificity for caspase-family proteases, effectively blocked sphingosine-induced apoptosis. Furthermore, our results indicate that caspase-3-like proteases, but not caspase-1, are activated during apoptosis triggered by sphingosine. Enhancement of caspase-3-like activity and cleavage of poly(ADP-ribose) polymerase, an in vivo substrate for caspase-3, was clearly demonstrated in sphingosine-treated Hep3B cells. Considered together, these results suggest that caspase-3-like proteases participate in apoptotic cell death induced by sphingosine.
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Rumble, Julie M., Mathieu J. M. Bertrand, Rebecca A. Csomos, Casey W. Wright, Lori Albert, Tak W. Mak, Philip A. Barker i Colin S. Duckett. "Apoptotic sensitivity of murine IAP-deficient cells". Biochemical Journal 415, nr 1 (12.09.2008): 21–25. http://dx.doi.org/10.1042/bj20081188.
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Although numerous studies have implicated the IAPs (inhibitor of apoptosis proteins) in the control of apoptotic cell death, analyses of murine Iap-targeted cells have not revealed significant differences in their susceptibility to apoptosis. In the present study, we show that, under defined conditions, murine cells lacking XIAP (X-linked inhibitor of apoptosis) and c-IAP (cellular IAP) 2, but not c-IAP1, exhibit heightened apoptotic sensitivity to both intrinsic and extrinsic apoptotic stimuli.
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Leveille, Etienne, i Nathalie A. Johnson. "Genetic Events Inhibiting Apoptosis in Diffuse Large B Cell Lymphoma". Cancers 13, nr 9 (30.04.2021): 2167. http://dx.doi.org/10.3390/cancers13092167.
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Diffuse large B cell lymphoma (DLBCL) is curable with chemoimmunotherapy in ~65% of patients. One of the hallmarks of the pathogenesis and resistance to therapy in DLBCL is inhibition of apoptosis, which allows malignant cells to survive and acquire further alterations. Inhibition of apoptosis can be the result of genetic events inhibiting the intrinsic or extrinsic apoptotic pathways, as well as their modulators, such as the inhibitor of apoptosis proteins, P53, and components of the NF-kB pathway. Mechanisms of dysregulation include upregulation of anti-apoptotic proteins and downregulation of pro-apoptotic proteins via point mutations, amplifications, deletions, translocations, and influences of other proteins. Understanding the factors contributing to resistance to apoptosis in DLBCL is crucial in order to be able to develop targeted therapies that could improve outcomes by restoring apoptosis in malignant cells. This review describes the genetic events inhibiting apoptosis in DLBCL, provides a perspective of their interactions in lymphomagenesis, and discusses their implication for the future of DLBCL therapy.
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Choi, Diana, i Minna Woo. "Executioners of apoptosis in pancreatic β-cells: not just for cell death". American Journal of Physiology-Endocrinology and Metabolism 298, nr 4 (kwiecień 2010): E735—E741. http://dx.doi.org/10.1152/ajpendo.00696.2009.
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Pancreatic β-cell mass is dynamic and is regulated by β-cell proliferation, neogenesis, and apoptosis. Under physiological conditions, apoptosis is tightly regulated with a slow, net rise in β-cell mass over time. Excessive β-cell apoptosis is an important contributor to both type 1 and type 2 diabetes development. Therefore, much effort has been given recently to better understand the mechanisms of apoptosis that occur both during physiological homeostasis and during the course of both types of diabetes. Caspases are the executioners of apoptosis that ultimately result in cell suicide. In mammals, there are 14 caspases, of which many participate in the apoptotic pathways. Genetic mouse models have been important tools for elucidation of the specific apoptotic pathways that play an essential role in β-cell apoptosis under physiological and pathological conditions. This review focuses on the diverse roles of each of the specific caspases and their regulators, unveiling both the classical apoptotic roles as well as emerging nonapoptotic roles.
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Putri, Mustika Anggiane, Patwa Amani, Donna Adriani i Rita Khairani. "Importance of Exercise in Mitigating Age-Related Cardiac Apoptosis". Sriwijaya Journal of Medicine 6, nr 3 (20.12.2023): 94–101. http://dx.doi.org/10.32539/sjm.v6i3.208.
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Aging causes a progressive decline in heart function. Loss of cardiomyocytes through programmed cell death or apoptosis is a critical factor contributing to this age-related damage. As we age, the heart undergoes structural changes, such as loss of cardiomyocytes, cardiomyocyte hypertrophy, and increased connective tissue with changes in heart geometry. It is widely known that mitochondria are vital sites of apoptosis. Mitochondrial-mediated apoptotic pathways are important regulators of apoptosis with aging. Mitochondrial dysfunction and oxidative stress also contribute to the cardiac remodeling and apoptosis associated with the aging process. On the other hand, exercise can improve heart function and reduce the risk of heart disease. Recent studies suggest that aging increases apoptotic signaling in the left ventricle. However, chronic exercise reduces this mitochondrial-mediated apoptotic signaling pathway in the aging heart. This review will describe the impacts of aging and exercise on cardiac apoptosis, highlighting the importance of exercise in reducing age-related cardiac apoptosis.
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McComb, Scott, Pik Ki Chan, Anna Guinot, Holmfridur Hartmannsdottir, Silvia Jenni, Maria Pamela Dobay, Jean-Pierre Bourquin i Beat C. Bornhauser. "Efficient apoptosis requires feedback amplification of upstream apoptotic signals by effector caspase-3 or -7". Science Advances 5, nr 7 (lipiec 2019): eaau9433. http://dx.doi.org/10.1126/sciadv.aau9433.
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Apoptosis is a complex multi-step process driven by caspase-dependent proteolytic cleavage cascades. Dysregulation of apoptosis promotes tumorigenesis and limits the efficacy of chemotherapy. To assess the complex interactions among caspases during apoptosis, we disrupted caspase-8, -9, -3, -7, or -6 and combinations thereof, using CRISPR-based genome editing in living human leukemia cells. While loss of apical initiator caspase-8 or -9 partially blocked extrinsic or intrinsic apoptosis, respectively, only combined loss of caspase-3 and -7 fully inhibited both apoptotic pathways, with no discernible effect of caspase-6 deficiency alone or in combination. Caspase-3/7 double knockout cells exhibited almost complete inhibition of caspase-8 or -9 activation. Furthermore, deletion of caspase-3 and -7 decreased mitochondrial depolarization and cytochrome c release upon apoptosis activation. Thus, activation of effector caspase-3 or -7 sets off explosive feedback amplification of upstream apoptotic events, which is a key feature of apoptotic signaling essential for efficient apoptotic cell death.
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Auner, Holger W., Christine Beham-Schmid, Niall Dillon i Pierangela Sabbattini. "ER Stress and Inhibition of Key Apoptotic Caspases Regulate the Life Span of Short-Lived Plasma Cells". Blood 112, nr 11 (16.11.2008): 2554. http://dx.doi.org/10.1182/blood.v112.11.2554.2554.
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Abstract Plasma cells (PCs) are the terminally differentiated effector cells of the humoral immune system. The majority of PCs are short-lived and undergo programmed cell death in the form of apoptosis after a few days of intensive immunoglobulin secretion. Despite potentially wide-ranging implications for infection control, auto-immunity, and PC dyscrasias, the mechanisms that govern the initiation and execution of PC apoptosis are poorly understood. We used two well-established murine systems of PC differentiation and immunohistochemistry of human lymphoid tissue sections to study the regulation of PC apoptosis. IgM-secreting post-mitotic CD138+B220− PCs were differentiated in vitro from primary mouse splenic B cells using cytokines and LPS and purified by magnetic selection. Murine I.29mu+ B lymphoma cells were induced to undergo plasmacytic differentiation by stimulation with LPS. In both systems, terminal PC differentiation is followed by spontaneous apoptosis of half of the PCs within 48h, similar to PC apoptosis in vivo. We found that a sharp increase in endoplasmatic reticulum (ER) stress, which is caused by an imbalance between secretory load and capacity in the ER, occurs in PCs that have completed differentiation and begin to undergo apoptosis. In parallel, susceptibility specifically to ER stress-induced apoptosis but not to other apoptotic stimuli increases substantially in differentiated PCs, despite an ongoing ER stress response and expansion of the secretory machinery. Caspase-12, which has been linked specifically to ER stress-induced apoptosis, is activated and processed during programmed PC death. Using the specific inhibitor of caspase-12, zATADfmk, we found that caspase-12 mediates apoptotic DNA fragmentation and chromatin condensation in PCs undergoing apoptosis but not in B cells undergoing tunicamycin-induced apoptosis. In contrast, the major apoptotic effector caspases (caspase-9, caspase-3, caspase-7) downstream of the mitochondria become resistant to activation by apoptotic ER stress during terminal PC differentiation and are not activated during PC apoptosis. We observed that he pan-caspase inhibitor, zVADfmk, completely blocks tunicamycin-induced apoptosis in B cells but does not inhibit PC apoptosis or tunicamycin-induced cell death in PCs. Using the small molecule PAC-1, which specifically activates caspase-3 by targeting a “safety-catch” amino acid sequence that keeps caspase-3 inactive, we found that caspase-3 is stabilized in its inactive form in PCs and human myeloma cell lines, but not in B cells. Immunohistochemistry of human lymphoid tissue sections demonstrated that most primary reactive PCs and extramedullary myeloma cells undergo spontaneous apoptosis in vivo without activation of caspase-3. Thus, ER stress plays a major role in limiting the life span of short-lived PCs and activates caspase-12, which mediates nuclear apoptosis specifically in PCs. The major apoptotic effector caspases, however, become resistant to activation during terminal PC differentiation, and PC apoptosis is largely independent of caspases downstream of the mitochondria. These observations lead us to propose that developmentally regulated inhibition of key apoptotic caspases, which rapidly execute apoptosis in most cells, has evolved in PCs as a means to delay apoptosis under conditions of increasing ER stress linked to immunoglobulin secretion. Overwhelming ER stress ultimately limits the life span of short-lived PCs by inducing apoptosis using alternative mechanism involving caspase-12, which is redundant for the execution of ER stress-induced apoptosis in cells that can activate the classical effector caspases.
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Henriques, S., E. Silva, S. Cruz, M. F. Silva, G. Ferreira-Dias, L. Lopes-da-Costa i L. Mateus. "Oestrous cycle-dependent expression of Fas and Bcl2 family gene products in normal canine endometrium". Reproduction, Fertility and Development 28, nr 9 (2016): 1307. http://dx.doi.org/10.1071/rd14245.
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During the oestrous cycle canine endometrium undergoes cyclical cellular proliferation, apoptosis and differentiation. To study the regulation of endometrial apoptosis and proliferation events the expression of apoptosis-related genes was analysed by real-time polymerase chain reaction and cellular expression of their proteins was identified through immunohistochemistry. Cellular apoptosis and proliferation events were detected by TdT-mediated dUTP-biotin nick end labeling (TUNEL) and proliferation marker Ki67 immunostaining, respectively. The highest proliferative index was observed in the follicular phase (all endometrial cellular components) and at early dioestrus (basal glands). This was associated with a low apoptotic index and a strong expression of anti- (Bcl2) and pro-apoptotic proteins (Fas, FasL, Bax). Subsequently (Days 11–45 of dioestrus), basal glandular epithelium experienced the highest apoptotic index, coincidental with a decrease of Bcl2 expression and a low ratio of Bcl2/Bax transcription. An increase in the apoptotic index of crypts, stromal and endothelial cells was observed at late dioestrus and the beginning of anoestrus. These results indicate that pro- and anti-apoptotic proteins regulate the balance between cell proliferation and death in the canine endometrium during the oestrous cycle. High Bcl2 expression in both the follicular and early dioestrous phases stimulate glandular proliferation and prevent apoptosis but, in the non-pregnant uterus, a decrease in Bcl2 expression together with an increase in pro-apoptotic proteins induces apoptosis of basal glandular epithelium cells.
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Jiang, Wei, Liang Chen i Sika Zheng. "Global Reprogramming of Apoptosis-Related Genes during Brain Development". Cells 10, nr 11 (27.10.2021): 2901. http://dx.doi.org/10.3390/cells10112901.
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To enable long-term survival, mammalian adult neurons exhibit unique apoptosis competence. Questions remain as to whether and how neurons globally reprogram the expression of apoptotic genes during development. We systematically examined the in vivo expression of 1923 apoptosis-related genes and associated histone modifications at eight developmental ages of mouse brains. Most apoptotic genes displayed consistent temporal patterns across the forebrain, midbrain, and hindbrain, suggesting ubiquitous robust developmental reprogramming. Although both anti- and pro-apoptotic genes can be up- or downregulated, half the regulatory events in the classical apoptosis pathway are downregulation of pro-apoptotic genes. Reduced expression in initiator caspases, apoptosome, and pro-apoptotic Bcl-2 family members restrains effector caspase activation and attenuates neuronal apoptosis. The developmental downregulation of apoptotic genes is attributed to decreasing histone-3-lysine-4-trimethylation (H3K4me3) signals at promoters, where histone-3-lysine-27-trimethylation (H3K27me3) rarely changes. By contrast, repressive H3K27me3 marks are lost in the upregulated gene groups, for which developmental H3K4me3 changes are not predictive. Hence, developing brains remove epigenetic H3K4me3 and H3K27me3 marks on different apoptotic gene groups, contributing to their downregulation and upregulation, respectively. As such, neurons drastically alter global apoptotic gene expression during development to transform apoptosis controls. Research into neuronal cell death should consider maturation stages as a biological variable.
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Adamkov, Marian. "Logical complexity of Bcl-2 family proteins function in the intrinsic apoptosis". Srpski arhiv za celokupno lekarstvo 147, nr 1-2 (2019): 99–104. http://dx.doi.org/10.2298/sarh190124010a.
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Apoptosis (type of programmed cell death) is an active process of cellular self-destruction in multicellular organisms. It is characterized by distinctive histomorphological, biochemical, and molecular features. Multiple cellular pathways trigger apoptosis, two of them are the best known: intrinsic and extrinsic. Multiple cellular signals and interactions can influence the course of apoptotic pathways. Bcl-2 family proteins play a key role in regulatory mechanisms of intrinsic apoptosis. Mitochondrial outer membrane permeabilization (MOMP) is an essential step for intrinsic apoptosis that is controlled by pro-apoptotic and anti-apoptotic members of Bcl-2 protein family. Pro-apoptotic effector proteins Bax and Bak represent the only Bcl-2 proteins inducing formation of MOMP, whose pores facilitate the subsequent releasing of several pro-apoptotic proteins from mitochondrial intermembrane space into cytosol. These proteins initiate a caspase cascade, resulting in rapid elimination of the doomed cells.