EDS1-Dependent Cell Death and the Antioxidant System in Arabidopsis Leaves is Deregulated by the Mammalian Bax

Cell death is the ultimate end of a cell cycle that occurs in all living organisms during development or responses to biotic and abiotic stresses. In the course of evolution, plants and animals evolve various molecular mechanisms to regulate cell death; however, some of them are conserved among both these kingdoms. It was found that mammalian proapoptotic BCL-2 associated X (Bax) protein, when expressed in plants, induces cell death, similar to hypersensitive response (HR). It was also shown that changes in the expression level of genes encoding proteins involved in stress response or oxidative status regulation mitigate Bax-induced plant cell death. In our study, we focused on the evolutional compatibility of animal and plant cell death molecular mechanisms. Therefore, we studied the deregulation of reactive oxygen species burst and HR-like propagation in Arabidopsis thaliana expressing mammalian Bax. We were able to diminish Bax-induced oxidative stress and HR progression through the genetic cross with plants mutated in ENHANCED DISEASE SUSCEPTIBILITY 1 (EDS1), which is a plant-positive HR regulator. Plants expressing the mouse Bax gene in eds1-1 null mutant background demonstrated less pronounced cell death and exhibited higher antioxidant system efficiency compared to Bax-expressing plants. Moreover, eds1/Bax plants did not show HR marker genes induction, as in the case of the Bax-expressing line. The present study indicates some common molecular features between animal and plant cell death regulation and can be useful to better understand the evolution of cell death mechanisms in plants and animals.

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Protective Effect of Psoralea corylifolia L. Seed Extract against Palmitate-Induced Neuronal Apoptosis in PC12 Cells

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2016/5410419 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 3

Author(s):

Yunkyoung Lee ◽

Hee-Sook Jun ◽

Yoon Sin Oh

Keyword(s):

Pc12 Cells ◽

Molecular Mechanisms ◽

Neuronal Cell ◽

Marker Genes ◽

Heme Oxygenase 1 ◽

Mrna Levels ◽

Protective Effects ◽

Psoralea Corylifolia ◽

Antioxidant Genes ◽

Bax Protein

The extract of Psoralea corylifolia seeds (PCE) has been widely used as a herbal medicine because of its beneficial effect on human health. In this study, we investigated the protective effects and molecular mechanisms of PCE on palmitate- (PA-) induced toxicity in PC12 cells, a neuron-like cell line. PCE significantly increased cell viability in PA-treated PC12 cells and showed antiapoptotic effects, as evidenced by decreased expression of cleaved caspase-3, cleaved poly(ADP-ribose) polymerase, and bax protein as well as increased expression of bcl-2 protein. In addition, PCE treatment reduced PA-induced reactive oxygen species production and upregulated mRNA levels of antioxidant genes such as nuclear factor (erythroid-derived 2)-like 2 and heme oxygenase 1. Moreover, PCE treatment recovered the expression of autophagy marker genes such as beclin-1 and p62, which was decreased by PA treatment. Treatment with isopsoralen, one of the major components of PCE extract, also recovered the expression of autophagy marker genes and reduced PA-induced apoptosis. In conclusion, PCE exerts protective effects against lipotoxicity via its antioxidant function, and this effect is mediated by activation of autophagy. PCE might be a potential pharmacological agent to protect against neuronal cell injury caused by oxidative stress or lipotoxicity.

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Age-associated features of the expression level of apoptosis markers in cardiomyocytes of patients with dilated cardiomyopathy

Успехи геронтологии ◽

10.34922/ae.2021.34.6.010 ◽

2022 ◽

pp. 885-890

Author(s):

К.П. Кравченко ◽

К. Л. Козлов ◽

А.О. Дробинцева ◽

Д.С. Медведев ◽

В.О. Полякова

Keyword(s):

Cell Death ◽

Dilated Cardiomyopathy ◽

Molecular Mechanisms ◽

Molecular Level ◽

Confocal Laser ◽

Control Group ◽

Cellular Mechanisms ◽

Apoptosis Pathway ◽

Bax Protein

Для понимания патогенеза дилатационной кардиомиопатии (ДКМП) необходимо установить молекулярно-клеточные механизмы старения миокарда, в том числе связанные с программируемой клеточной гибелью, молекулярные механизмы которого практически не изучены. Цель работы - изучение маркеров апоптоза в кардиомиоцитах у пациентов с ДКМП in vitro. В работе использовали метод первичных диссоциированных клеточных культур и метод иммунофлюоресцентной конфокальной лазерной микроскопии. Для моделирования клеточного старения использовали клетки 3-го и 14-го пассажей, соответствующие «молодым» и «старым» культурам. На молекулярном уровне старение клеток кардиомиоцитов сопровождалось повышением экспрессии р16 в 2 раза по сравнению с «молодыми культурами» как в контрольной, так и в группе с ДКМП. Также установлено, что экспрессия р16 в культурах, взятых от пациентов с патологией, была в 2 раза выше, чем в аналогичных культурах от здоровых пациентов. Экспрессия р21 была повышена в группе с ДКМП по сравнению с контрольной группой, однако при старении культуры экспрессия p21 не изменялась, оставаясь на высоком уровне. Наиболее значимые различия были получены при сравнении экспрессии Bax в культуре клеток кардиомиоцитов из группы с ДКМП в «молодой» культуре с нормой - в 3,2 раза. Старение клеток миокарда на молекулярном уровне проявлялось в повышении экспрессии белка Baх, именно он является запускающим механизмом митохондриального пути апоптоза. Возможно, этот путь клеточной гибели является превалирующем при ДКМП. To understand the pathogenesis of dilated cardiomyopathy (DCMP), it is necessary to establish the molecular-cellular mechanisms of myocardial aging, including those associated with programmed cell death, the molecular mechanisms of which have not been practically studied. The aim of this work is to study markers of apoptosis in cardiomyocytes of patients with DCMP in vitro. We used the method of primary dissociated cell cultures and the method of immunofluorescence confocal laser microscopy. Cells of the 3 and 14 passages, corresponding to «young» and «old» cultures, were used to simulate cellular senescence. Results. At the molecular level, aging of cardiomyocyte cells was accompanied by a twofold increase in the expression of p16 compared to «young cultures» both in the control group and in the group with DCMP. It was also found that the expression of p16 in cultures taken from patients with pathology was 2 times higher than in similar cultures from healthy patients. The expression of p21 was increased in the group with DCMP compared to the control; however, with aging of the culture, the expression of p21 did not change, remaining at a significant level. The most significant differences were obtained when comparing the expression of Bax in the cell culture of cardiomyocytes from the group with DCMP in a «young» culture compared with the norm, 3,2 times. Aging of myocardial cells at the molecular level was manifested in an increase in the expression of the Bax protein, which is the triggering mechanism of the mitochondrial apoptosis pathway. It is possible that this pathway of cell death is prevalent in DCMP.

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Cell Death Mechanisms Induced by INNO-406, a Novel Tyrosine Kinase Inhibitor for Imatinib-Resistant Ph+ Leukemia.

Blood ◽

10.1182/blood.v108.11.2177.2177 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2177-2177

Author(s):

Yuri Kamitsuji ◽

Souichi Adachi ◽

Motonobu Watanabe ◽

Hiroshi Matsubara ◽

Yasuhiro Mizushima ◽

...

Keyword(s):

Cell Death ◽

Dna Fragmentation ◽

Cell Lines ◽

Molecular Mechanisms ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Cellular Growth ◽

Caspase Activity ◽

Apoptosis Pathway ◽

Cell Death Mechanisms

Abstract The blockade of Bcr-Abl signaling suppresses cellular growth and induces cell death in Bcr-Abl-positive (Bcr-Abl+) cells. We herein assessed the cell death mechanisms induced by INNO-406 (formerly NS-187; Kimura et al, Blood 2005), in four CML-derived Bcr-Abl+ cell lines (K562, KT-1, BV173 and MYL), and Ba/F3 harboring wild type bcr-abl (Ba/F3/wt bcr-abl). When cells are treated by INNO-406, the accumulation of subG1 fraction was seen in all five cell lines. This cell death was accompanied by loss of mitochondrial membrane potential and was inhibited by over-expression of Bcl-2, indicating that INNO-406-induced cell death is mainly mediated by mitochondria-dependent apoptosis. Caspase-3 activation in INNO-406-treated cell was also common among all cell lines. However, the inhibition of caspase activity by ZVAD-fmk (ZVAD), a pan-caspase inhibitor, was variable in the cell lines tested. In K562, KT-1 and BV173 cells treated with INNO-406, ZVAD almost completely prevented apoptosis (i.e. showing atypical feature for apoptosis, no DNA fragmentation and no accumulation of subG1 fraction), with cell death resulting from morphologically non-apoptotic cell death. The percentages of non-apoptotic cells under ZVAD co-treated with INNO-406 varied among the three cell lines, suggesting that the dependence on non-apoptotic cell death is variable. While, in MYL and Ba/F3/wt bcr-abl cells, despite the sufficient inhibition of caspases’ activity, the inhibition of the cell death by ZVAD was only partial and these cell lines still underwent apoptosis (i.e. showing DNA fragmentation and the accumulation of subG1 population), suggesting the presence of caspase-independent apoptotic machineries. In addition, assay data for apoptosome activities (complex of Apaf-1, cytochrome c and caspase-9 that initiates and drives cysteine protease activities of caspase in mitochondrial-mediated pathway) suggested that cell types could be largely subdivided into two groups, namely those cells with high apoptosome activity (K562, KT-1 and BV173) that undergo non-apoptotic, and, those cells with low apoptosome activity (MYL and Ba/F3/wt bcr-abl.) that undergo caspase-independent apoptosis when caspase activity was blocked by ZVAD. These data indicate that there is a common initial pathway for cell death due to INNO-406, while the pathway for cell death commitment (i.e. dependence on apoptosome/caspases-mediated apoptosis pathway that has been commonly believed to be central for apoptosis execution) vary among cellular context in Bcr-Abl+ leukemic cells. Moreover, in a mouse model of primary human CML in blast crisis, INNO-406 caused cell death with fragmented nuclei typical to apoptosis and “necklace-like” nuclei not typical of apoptosis, further implicating the significance of involvement of caspase-independent, non-apoptotic cell death in vivo. Further studies of the role of caspase-independent cell death in patient-derived Bcr-Abl+ cells and the molecular mechanisms that lead to mitochondrial-depolarization and caspase-independent apoptotic and/or non-apoptotic cell death may help the development of novel therapeutic strategies against Bcr-Abl+ leukemias.

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Ca2+-Operated Transcriptional Networks: Molecular Mechanisms and In Vivo Models

Physiological Reviews ◽

10.1152/physrev.00041.2005 ◽

2008 ◽

Vol 88 (2) ◽

pp. 421-449 ◽

Cited By ~ 110

Author(s):

Britt Mellström ◽

Magali Savignac ◽

Rosa Gomez-Villafuertes ◽

Jose R. Naranjo

Keyword(s):

Molecular Mechanisms ◽

Critical Role ◽

Transcriptional Networks ◽

Calcium Signal ◽

In Vivo Models ◽

Cellular Processes ◽

Calcium Sensors ◽

Genes Encoding ◽

Living Organisms

Calcium is the most universal signal used by living organisms to convey information to many different cellular processes. In this review we present well-known and recently identified proteins that sense and decode the calcium signal and are key elements in the nucleus to regulate the activity of various transcriptional networks. When possible, the review also presents in vivo models in which the genes encoding these calcium sensors-transducers have been modified, to emphasize the critical role of these Ca2+-operated mechanisms in many physiological functions.

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Tocotrienols Modulate a Life or Death Decision in Cancers

International Journal of Molecular Sciences ◽

10.3390/ijms20020372 ◽

2019 ◽

Vol 20 (2) ◽

pp. 372 ◽

Cited By ~ 6

Author(s):

Shiau-Ying Tham ◽

Hwei-San Loh ◽

Chun-Wai Mai ◽

Ju-Yen Fu

Keyword(s):

Cell Death ◽

Cell Survival ◽

Anticancer Agents ◽

Molecular Mechanisms ◽

Treatment Strategies ◽

Promising Alternative ◽

Cancer Cell Death ◽

Survival Pathways ◽

Cell Death Mechanisms ◽

A Minor

Malignancy often arises from sophisticated defects in the intricate molecular mechanisms of cells, rendering a complicated molecular ground to effectively target cancers. Resistance toward cell death and enhancement of cell survival are the common adaptations in cancer due to its infinite proliferative capacity. Existing cancer treatment strategies that target a single molecular pathway or cancer hallmark fail to fully resolve the problem. Hence, multitargeted anticancer agents that can concurrently target cell death and survival pathways are seen as a promising alternative to treat cancer. Tocotrienols, a minor constituent of the vitamin E family that have previously been reported to induce various cell death mechanisms and target several key survival pathways, could be an effective anticancer agent. This review puts forward the potential application of tocotrienols as an anticancer treatment from a perspective of influencing the life or death decision of cancer cells. The cell death mechanisms elicited by tocotrienols, particularly apoptosis and autophagy, are highlighted. The influences of several cell survival signaling pathways in shaping cancer cell death, particularly NF-κB, PI3K/Akt, MAPK, and Wnt, are also reviewed. This review may stimulate further mechanistic researches and foster clinical applications of tocotrienols via rational drug designs.

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Live Imaging of muscle histolysis inDrosophilametamorphosis

10.1101/047761 ◽

2016 ◽

Author(s):

Yadav Kuleesha ◽

Wee Choo Puah ◽

Martin Wasser

Keyword(s):

Cell Death ◽

Molecular Mechanisms ◽

Cysteine Proteinase ◽

Cathepsin L ◽

Time Lapse ◽

Live Imaging ◽

Dominant Negative ◽

Muscle Size ◽

Genes Encoding

Background:The contribution of programmed cell death (PCD) to muscle wasting disorders remains a matter of debate.Drosophila melanogastermetamorphosis offers the opportunity to study muscle cell death in the context of development. Using live cell imaging of the abdomen, two groups of larval muscles can be observed, doomed muscles that undergo histolysis and persistent muscles that are remodelled and survive into adulthood.Method:To identify and characterize genes that control the decision between survival and cell death of muscles, we developed a method comprisingin vivoimaging, targeted gene perturbation and time-lapse image analysis. Our approach enabled us to study the cytological and temporal aspects of abnormal cell death phenotypes.Results:In a previous genetic screen for genes controlling muscle size and cell death in metamorphosis, we identified gene perturbations that induced cell death of persistent or inhibit histolysis of doomed larval muscles. RNA interference (RNAi) of the genes encoding the helicase Rm62 and the lysosomal Cathepsin-L homolog Cysteine proteinase 1 (Cp1) caused premature cell death of persistent muscle in early and mid-pupation, respectively. Silencing of the transcriptional co-repressorAtrophininhibited histolysis of doomed muscles. Overexpression of dominant-negative Target of Rapamycin (TOR) delayed the histolysis of a subset of doomed and induced ablation of all persistent muscles. RNAi ofAMPKα,which encodes a subunit of the AMPK protein complex that senses AMP and promotes ATP formation, led to loss of attachment and a spherical morphology. None of the perturbations affected the survival of newly formed adult muscles, suggesting that the method is useful to find genes that are crucial for the survival of metabolically challenged muscles, like those undergoing atrophy. The ablation of persistent muscles did not affect eclosion of adult flies.Conclusions:Live imaging is a versatile approach to uncover gene functions that are required for the survival of muscle undergoing remodelling, yet are dispensable for other adult muscles. Our approach promises to identify molecular mechanisms that can explain the resilience of muscles to PCD.

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Autophagy Regulation and Photodynamic Therapy: Insights to Improve Outcomes of Cancer Treatment

Frontiers in Oncology ◽

10.3389/fonc.2020.610472 ◽

2021 ◽

Vol 10 ◽

Author(s):

Waleska K. Martins ◽

Renata Belotto ◽

Maryana N. Silva ◽

Daniel Grasso ◽

Maynne D. Suriani ◽

...

Keyword(s):

Cell Death ◽

Photodynamic Therapy ◽

Cancer Therapy ◽

Cancer Treatment ◽

Tumor Cells ◽

Molecular Mechanisms ◽

Light Sources ◽

Regulated Cell Death ◽

Age Related ◽

Cell Death Mechanisms

Cancer is considered an age-related disease that, over the next 10 years, will become the most prevalent health problem worldwide. Although cancer therapy has remarkably improved in the last few decades, novel treatment concepts are needed to defeat this disease. Photodynamic Therapy (PDT) signalize a pathway to treat and manage several types of cancer. Over the past three decades, new light sources and photosensitizers (PS) have been developed to be applied in PDT. Nevertheless, there is a lack of knowledge to explain the main biochemical routes needed to trigger regulated cell death mechanisms, affecting, considerably, the scope of the PDT. Although autophagy modulation is being raised as an interesting strategy to be used in cancer therapy, the main aspects referring to the autophagy role over cell succumbing PDT-photoinduced damage remain elusive. Several reports emphasize cytoprotective autophagy, as an ultimate attempt of cells to cope with the photo-induced stress and to survive. Moreover, other underlying molecular mechanisms that evoke PDT-resistance of tumor cells were considered. We reviewed the paradigm about the PDT-regulated cell death mechanisms that involve autophagic impairment or boosted activation. To comprise the autophagy-targeted PDT-protocols to treat cancer, it was underlined those that alleviate or intensify PDT-resistance of tumor cells. Thereby, this review provides insights into the mechanisms by which PDT can be used to modulate autophagy and emphasizes how this field represents a promising therapeutic strategy for cancer treatment.

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Natural Peptides Inducing Cancer Cell Death: Mechanisms and Properties of Specific Candidates for Cancer Therapeutics

Molecules ◽

10.3390/molecules26247453 ◽

2021 ◽

Vol 26 (24) ◽

pp. 7453

Author(s):

Plinio A. Trinidad-Calderón ◽

Carlos Daniel Varela-Chinchilla ◽

Silverio García-Lara

Keyword(s):

Cell Death ◽

Molecular Mechanisms ◽

Bioactive Peptides ◽

Treatment Options ◽

Cancer Therapeutics ◽

New Drugs ◽

Tumor Cell Death ◽

Cancer Cell Death ◽

Anticancer Effects ◽

Cell Death Mechanisms

Nowadays, cancer has become the second highest leading cause of death, and it is expected to continue to affect the population in forthcoming years. Additionally, treatment options will become less accessible to the public as cases continue to grow and disease mechanisms expand. Hence, specific candidates with confirmed anticancer effects are required to develop new drugs. Among the novel therapeutic options, proteins are considered a relevant source, given that they have bioactive peptides encrypted within their sequences. These bioactive peptides, which are molecules consisting of 2–50 amino acids, have specific activities when administered, producing anticancer effects. Current databases report the effects of peptides. However, uncertainty is found when their molecular mechanisms are investigated. Furthermore, analyses addressing their interaction networks or their directly implicated mechanisms are needed to elucidate their effects on cancer cells entirely. Therefore, relevant peptides considered as candidates for cancer therapeutics with specific sequences and known anticancer mechanisms were accurately reviewed. Likewise, those features which turn certain peptides into candidates and the mechanisms by which peptides mediate tumor cell death were highlighted. This information will make robust the knowledge of these candidate peptides with recognized mechanisms and enhance their non-toxic capacity in relation to healthy cells and further avoid cell resistance.

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CBIO-25. INTEGRATED MOLECULAR AND BH3 PROFILING OF THE INTRINSIC APOPTOTIC MACHINERY IDENTIFIES THERAPEUTIC VULNERABILITIES IN GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa215.085 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii21-ii21

Author(s):

Elizabeth Fernandez ◽

Wilson Mai ◽

Nicholas Bayley ◽

Christopher Tse ◽

Linda Liau ◽

...

Keyword(s):

Cell Death ◽

Molecular Mechanisms ◽

Functional Characterization ◽

Standard Of Care ◽

Molecular Data ◽

Dependent Manner ◽

Intrinsic Apoptosis ◽

Apoptosis Resistance ◽

Molecular Features ◽

P53 Signaling

Abstract Resistance to apoptosis is a hallmark of cancer. However, the underlying molecular mechanisms of intrinsic-apoptotic resistance in glioblastoma (GBM) are largely unknown. Here we performed integrated molecular and functional characterization (via BH3 profiling) of the intrinsic apoptotic machinery in 50 GBM patient specimens. We found that, despite significant genetic heterogeneity of our GBM samples, all GBMs have a cross compensatory reliance on BCLXL and MCL1 for basal survival. Treatment with standard of care (e.g., temozolomide or radiation) caused minimal apoptosis, yet ablated the MCL-1 block in a p53-dependent manner, thus creating an exclusive dependence on BCLXL for survival in p53 wild-type GBM tumors (65% of GBM tumors). Consequently, BCLXL inhibition caused synergistic cell death with IR/TMZ in GBM tumors with intact p53 signaling. Importantly, the degree of synergistic cell kill was best predicted by combining molecular features with BH3 profiling, providing an integrated predictive signature of response to this novel therapeutic approach. Collectively, these studies identify mechanisms of intrinsic apoptosis resistance in both basal and treatment states of GBM and demonstrate how functional and molecular data can be complementary to robustly predict therapy-induced cell death.

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