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1.
Cells ; 11(19)2022 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-36231015

RESUMO

Mitochondrial disruption leads to the release of cytochrome c to activate caspase-9 and the downstream caspase cascade for the execution of apoptosis. However, cell death can proceed efficiently in the absence of caspase-9 following mitochondrial disruption, suggesting the existence of caspase-9-independent cell death mechanisms. Through a genome-wide siRNA library screening, we identified a network of genes that mediate caspase-9-independent cell death, through ROS production and Alox5-dependent membrane lipid peroxidation. Erk1-dependent phosphorylation of Alox5 is critical for targeting Alox5 to the nuclear membrane to mediate lipid peroxidation, resulting in nuclear translocation of cytolytic molecules to induce DNA damage and cell death. Consistently, double knockouts of caspase-9 and Alox5 in mice, but not deletion of either gene alone, led to significant T cell expansion with inhibited cell death, indicating that caspase-9- and Alox5-dependent pathways function in parallel to regulate T cell death in vivo. This unbiased whole-genome screening reveals an Erk1-Alox5-mediated pathway that promotes membrane lipid peroxidation and nuclear translocation of cytolytic molecules, leading to the execution of cell death in parallel to the caspase-9 signaling cascade.


Assuntos
Citocromos c , Mitocôndrias , Animais , Araquidonato 5-Lipoxigenase/metabolismo , Caspase 9/metabolismo , Caspases/metabolismo , Morte Celular/fisiologia , Citocromos c/metabolismo , Camundongos , Mitocôndrias/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo
2.
Mol Cell ; 82(20): 3760-3762, 2022 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-36270246

RESUMO

The dietary factor vitamin K has been found to protect against ferroptosis, a form of cell death driven by lipid peroxidation. This reveals new dietary links to cancers and degenerative conditions and a key factor involved in warfarin poisoning.


Assuntos
Ferroptose , Ferroptose/genética , Vitamina K , Varfarina , Peroxidação de Lipídeos , Morte Celular/fisiologia
3.
Methods Cell Biol ; 172: 37-50, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36064225

RESUMO

Lipid peroxidation occurs under conditions where reactive oxygen species (ROS) readily react with vulnerable lipids on cell membranes. Polyunsaturated fatty acids (PUFAs) are highly susceptible to lipid peroxidation because of their unstable double bonds. Because the cell membrane is particularly rich in PUFAs, it is often the site at which many lipid peroxidation chain reactions occur. Lipid peroxidation is considered the ultimate trigger of ferroptosis, an iron-dependent form of non-apoptotic cell death. Radiotherapy is a common cancer treatment that uses high-energy ionizing radiation to kill cancer cells, and radiation-induced cell death is partially attributed to lipid peroxidation-driven ferroptosis. Here, we describe methods to assess lipid peroxidation in irradiated cells. The same techniques can be applied to a variety of lipid peroxidation measurements under different treatment conditions.


Assuntos
Ferro , Morte Celular/fisiologia , Membrana Celular/metabolismo , Ferro/metabolismo , Peroxidação de Lipídeos/fisiologia , Espécies Reativas de Oxigênio/metabolismo
4.
J Chem Neuroanat ; 125: 102147, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36028204

RESUMO

BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) is a major cause of stroke that causes high rates of disability and mortality in adults. Tenascin C (TNC) protein, one of the matricellular proteins associated with platelet-derived growth factor receptor (PDGFR) activation, has been reported to induce neuronal apoptosis. However, the role and underlying mechanisms of TNC in ICH-induced secondary brain injury (SBI) have not yet been fully explained. The main purpose of this study was to explore the role of TNC and its potential mechanisms in ICH. METHODS: An ICH model was established by injecting autologous blood into the right basal ganglia in male Sprague Dawley (SD) rats, and imatinib, an inhibitor of PDGFR, was used to inhibit the release of TNC. RESULTS: We found that TNC protein was significantly increased in the brain tissues after ICH and expressed in both neurons and microglia. We also found that the TNC level was elevated in the cerebrospinal fluid (CSF) after ICH. Additionally, we observed that the infiltration of activated microglia and the release of TNFα and IL-1ß induced by ICH were decreased after inhibition of the protein levels of TNC and cleaved-TNC by a chemical inhibitor (imatinib). Furthermore, imatinib improved neuronal cell death and neurobehavioral abnormalities induced by ICH. CONCLUSION: In summary, our study revealed that TNC protein plays an important role in ICH-induced SBI, and inhibition of TNC could alleviate ICH-induced neuroinflammation, neuronal cell death, and neurobehaviour. Therefore, TNC may be a potential therapeutic target for ICH-induced SBI.


Assuntos
Lesões Encefálicas , Tenascina , Animais , Ratos , Masculino , Tenascina/metabolismo , Ratos Sprague-Dawley , Mesilato de Imatinib/farmacologia , Doenças Neuroinflamatórias , Hemorragia Cerebral/complicações , Hemorragia Cerebral/metabolismo , Morte Celular/fisiologia , Lesões Encefálicas/complicações , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/metabolismo , Modelos Animais de Doenças
5.
Methods Mol Biol ; 2510: 53-63, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35776319

RESUMO

For many years the P2X7 receptor (P2X7R) was considered the prototypic cytolytic receptor due to its ability to cause dramatic changes in plasma membrane permeability, eventually leading to cell death. However, later studies revealed that controlled P2X7R activation has beneficial effects on cell metabolism and nowadays our perception of the physiological role of this receptor has radically changed. Some of the biochemical pathways underlying the trophic effect of the P2X7R are being unveiled, thus disclosing an unanticipated role of P2X7Rs in mitochondrial and glycolytic metabolism. We provide here an update of the effects of the P2X7R on cell energy metabolism.


Assuntos
Glicólise , Receptores Purinérgicos P2X7 , Morte Celular/fisiologia , Permeabilidade da Membrana Celular , Mitocôndrias , Receptores Purinérgicos P2X7/genética
6.
Int J Mol Sci ; 23(13)2022 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-35806303

RESUMO

Differential evolution of apoptosis, programmed necrosis, and autophagy, parthanatos is a form of cell death mediated by poly(ADP-ribose) polymerase 1 (PARP1), which is caused by DNA damage. PARP1 hyper-activation stimulates apoptosis-inducing factor (AIF) nucleus translocation, and accelerates nicotinamide adenine dinucleotide (NAD+) and adenosine triphosphate (ATP) depletion, leading to DNA fragmentation. The mechanisms of parthanatos mainly include DNA damage, PARP1 hyper-activation, PAR accumulation, NAD+ and ATP depletion, and AIF nucleus translocation. Now, it is reported that parthanatos widely exists in different diseases (tumors, retinal diseases, neurological diseases, diabetes, renal diseases, cardiovascular diseases, ischemia-reperfusion injury...). Excessive or defective parthanatos contributes to pathological cell damage; therefore, parthanatos is critical in the therapy and prevention of many diseases. In this work, the hallmarks and molecular mechanisms of parthanatos and its related disorders are summarized. The questions raised by the recent findings are also presented. Further understanding of parthanatos will provide a new treatment option for associated conditions.


Assuntos
Parthanatos , Trifosfato de Adenosina , Fator de Indução de Apoptose/genética , Fator de Indução de Apoptose/metabolismo , Morte Celular/fisiologia , NAD/metabolismo , Poli(ADP-Ribose) Polimerase-1/metabolismo
7.
Int J Biol Sci ; 18(10): 4260-4274, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35844784

RESUMO

Ferroptosis is a novel type of cell death characterized by iron-dependent lipid peroxidation that involves a variety of biological processes, such as iron metabolism, lipid metabolism, and oxidative stress. A growing body of research suggests that ferroptosis is associated with cancer and neurodegenerative diseases, such as glioblastoma, Alzheimer's disease, Parkinson's disease, and stroke. Building on these findings, we can selectively induce ferroptosis for the treatment of certain cancers, or we can treat neurodegenerative diseases by inhibiting ferroptosis. This review summarizes the relevant advances in ferroptosis, the regulatory mechanisms of ferroptosis, the participation of ferroptosis in brain tumors and neurodegenerative diseases, and the corresponding drug therapies to provide new potential targets for its treatment.


Assuntos
Ferroptose , Neoplasias , Doenças Neurodegenerativas , Morte Celular/fisiologia , Humanos , Ferro/metabolismo , Peroxidação de Lipídeos , Neoplasias/metabolismo , Doenças Neurodegenerativas/tratamento farmacológico
8.
Comput Math Methods Med ; 2022: 7906218, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35866036

RESUMO

An injury to the spinal cord results in a crucial central nervous system event that further causes irreversible impairment or loss of motor, autonomic, and sensory functions. A progressive pathophysiological cascade following spinal cord injury (SCI) includes ischemia/reperfusion injury, oxidative stress, proapoptotic signaling, peripheral inflammatory cell infiltration, and glutamate-mediated excitotoxicity, and regulated cell death. These complex pathological and physiological changes continue to cause cell injury over the long-term and severely limit the efficacy of clinical treatment strategies in restoring the injured nervous system. Ferroptosis is a nonapoptotic, iron-regulated kind of cell death that has recently been discovered. It is distinguished by iron overload-induced toxic lipid peroxidation associated with mitochondrial morphological changes during the cell death process. For example, after SCI, iron overload activates the reactive oxygen species generation, dysregulation of glutathione/glutathione peroxidase 4 (GSH/GPX4) metabolism, and accumulation of lipid peroxides, which cause lipid membrane deterioration and ferroptosis. Conversely, knockout or differential expression of key genes and application of lipid peroxidation inhibitors and iron chelators (e.g., deferoxamine) (e.g., SRS-16-86) can block ferroptosis and promote neuronal repair for functional recovery after SCI. Although the findings of numerous investigations have been confirmed the importance of ferroptosis in several human neurologic sicknesses and its potential in SCI, the mechanism of ferroptosis and its application in SCI has not been elucidated. This review highlights current ferroptosis research and its impact on SCI, as well as the key molecular mechanism of ferroptosis in promoting the recovery from SCI. Understanding ferroptosis' process and function in SCI could provide useful insight into the treatment and avoidance of such a destructive injury.


Assuntos
Ferroptose , Sobrecarga de Ferro , Traumatismos da Medula Espinal , Morte Celular/fisiologia , Humanos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Traumatismos da Medula Espinal/tratamento farmacológico
9.
ACS Biomater Sci Eng ; 8(6): 2508-2517, 2022 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-35648631

RESUMO

Ferroptosis is a novel type of regulated cell death characterized by the accumulation of lipid peroxides to lethal levels. Most tumor cells are extremely vulnerable to ferroptosis due to the high levels of reactive oxygen species (ROS) produced by their active metabolism. Therefore, tumor cells rely on glutathione (GSH) to reduce lipid peroxides catalyzed by glutathione peroxidase 4 (GPX4), and this pathway is also an important target for a variety of drugs that promote tumor cell ferroptosis. Herein, RSL3@PCA was designed to simultaneously deplete intracellular GSH and inhibit the activity of GPX4, thereby significantly promoting tumor cell ferroptosis. RSL3@PCA was successfully prepared by encapsulating a selective inhibitor of GPX4 into acid-responsive nanoparticle PCA. After being taken up by tumor cells, the acid-responsive nanoparticle gradually degraded to release cinnamaldehyde (CA) and the encapsulated RSL3. CA and RSL3 block the reduction of lipid peroxides in cells, thereby inducing ferroptosis. By a cytotoxicity assay and 4T1 cell xenotransplantation model, we confirmed that RSL3@PCA has excellent inhibition of tumor growth without significant toxicity to normal cells and tissues and still has a good therapeutic effect on tumor cells that are resistant to conventional chemotherapy drugs. This work provides new drug combinations for promoting ferroptosis in tumor cells without severe side effects in normal organs.


Assuntos
Ferroptose , Acroleína/análogos & derivados , Carbolinas/farmacologia , Morte Celular/fisiologia , Peroxidação de Lipídeos/fisiologia , Peróxidos Lipídicos/farmacologia , Micelas
10.
Int J Mol Sci ; 23(12)2022 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-35743026

RESUMO

Ferroptosis is a recently recognized form of nonapoptotic cell death that is triggered by reactive oxidative species (ROS) due to iron overload, lipid peroxidation accumulation, or the inhibition of phospholipid hydroperoxidase glutathione peroxidase 4 (GPX4). Recent studies have reported that ferroptosis plays a vital role in the pathophysiological process of multiple systems such as the nervous, renal, and pulmonary systems. In particular, the kidney has higher rates of O2 consumption in its mitochondria than other organs; therefore, it is susceptible to imbalances between ROS and antioxidants. In ischemia/reperfusion (I/R) injury, which is damage caused by the restoring blood flow to ischemic tissues, the release of ROS and reactive nitrogen species is accelerated and contributes to subsequent inflammation and cell death, such as ferroptosis, as well as apoptosis and necrosis being induced. At the same time, I/R injury is one of the major causes of acute kidney injury (AKI), causing significant morbidity and mortality. This review highlights the current knowledge on the involvement of ferroptosis in AKI via oxidative stress.


Assuntos
Injúria Renal Aguda , Ferroptose , Traumatismo por Reperfusão , Injúria Renal Aguda/metabolismo , Morte Celular/fisiologia , Humanos , Peroxidação de Lipídeos , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/metabolismo
11.
Methods Mol Biol ; 2447: 193-204, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35583783

RESUMO

In plants, the hypersensitive response (HR) is a programmed cell death modality that occurs upon recognition of harmful non-self. It occurs at the site of pathogen infection, thus preventing pathogens to live off plant tissue and proliferate. Shedding light on the molecular constituents underlying this process requires robust and quantitative methods that can determine whether plants lacking functional genes are defective in HR execution compared to wild-type controls. In this chapter, we provide two quantitative protocols in which we measure cell death from Arabidopsis thaliana leaves infected with avirulent HR-causing bacterial strains. Firstly, we use trypan blue staining to quantify the stained area of leaves upon bacterial infection using a personalized macro in the Image J (Fiji) software. Alternately, we incorporate an electrolyte leakage protocol in order to measure HR caused by different avirulent bacterial strains at different bacterial titers. We encourage users to perform a combination of both methods when assessing HR in different plant genotypes.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Bactérias/metabolismo , Morte Celular/fisiologia , Doenças das Plantas/genética , Doenças das Plantas/microbiologia , Folhas de Planta/metabolismo , Pseudomonas syringae
12.
Cell Death Dis ; 13(5): 423, 2022 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-35501340

RESUMO

Distinct types of immune responses are activated by infections, which cause the development of type I, II, or III inflammation, regulated by Th1, Th2, Th17 helper T cells and ILC1, ILC2 and ILC3 cells, respectively. While the classification of immune responses to different groups of pathogens is widely accepted, subtypes of the immune response elicited by sterile inflammation have not yet been detailed. Necroinflammation is associated with the release of damage-associated molecular patterns (DAMP) from dying cells. In this review, we present that the distinct molecular mechanisms activated during apoptosis, necroptosis, pyroptosis, and ferroptosis lead to the release of different patterns of DAMPs and their suppressors, SAMPs. We summarize the currently available data on how regulated cell death pathways and released DAMPs and SAMPs direct the differentiation of T helper and ILC cells. Understanding the subtypes of necroinflammation can be crucial in developing strategies for the treatment of sterile inflammatory diseases caused by cell death processes.


Assuntos
Imunidade Inata , Linfócitos , Alarminas/metabolismo , Morte Celular/fisiologia , Humanos , Inflamação , Linfócitos/metabolismo
13.
Cell Death Dis ; 13(5): 509, 2022 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-35637197

RESUMO

Interest in the lysosome's potential role in anticancer therapies has recently been appreciated in the field of immuno-oncology. Targeting lysosomes triggers apoptotic pathways, inhibits cytoprotective autophagy, and activates a unique form of apoptosis known as immunogenic cell death (ICD). This mechanism stimulates a local and systemic immune response against dead-cell antigens. Stressors that can lead to ICD include an abundance of ROS which induce lysosome membrane permeability (LMP). Dying cells express markers that activate immune cells. Dendritic cells engulf the dying cell and then present the cell's neoantigens to T cells. The discovery of ICD-inducing agents is important due to their potential to trigger autoimmunity. In this review, we discuss the various mechanisms of activating lysosome-induced cell death in cancer cells specifically and the strategies that current laboratories are using to selectively promote LMP in tumors.


Assuntos
Morte Celular Imunogênica , Neoplasias , Morte Celular/fisiologia , Humanos , Imunoterapia , Lisossomos/metabolismo , Neoplasias/patologia
14.
Cell Death Differ ; 29(6): 1094-1106, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35422492

RESUMO

Ferroptosis is a recently defined form of regulated cell death, which is biochemically and morphologically distinct from traditional forms of programmed cell death such as apoptosis or necrosis. It is driven by iron, reactive oxygen species, and phospholipids that are oxidatively damaged, ultimately resulting in mitochondrial damage and breakdown of membrane integrity. Numerous cellular signaling pathways and molecules are involved in the regulation of ferroptosis, including enzymes that control the cellular redox status. Alterations in the ferroptosis-regulating network can contribute to the development of various diseases, including cancer. Evidence suggests that ferroptosis is commonly suppressed in cancer cells, allowing them to survive and progress. However, cancer cells which are resistant to common chemotherapeutic drugs seem to be highly susceptible to ferroptosis inducers, highlighting the great potential of pharmacologic modulation of ferroptosis for cancer treatment. Non-coding RNAs (ncRNAs) are considered master regulators of various cellular processes, particularly in cancer where they have been implicated in all hallmarks of cancer. Recent work also demonstrated their involvement in the molecular control of ferroptosis. Hence, ncRNA-based therapeutics represent an exciting alternative to modulate ferroptosis for cancer therapy. This review summarizes the ncRNAs implicated in the regulation of ferroptosis in cancer and highlights their underlying molecular mechanisms in the light of potential therapeutic applications.


Assuntos
Ferroptose , Neoplasias , Apoptose/genética , Morte Celular/fisiologia , Ferroptose/genética , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Oxirredução , Espécies Reativas de Oxigênio/metabolismo
15.
Viruses ; 14(4)2022 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-35458404

RESUMO

Virus infection of adrenal glands can disrupt secretion of mineralocorticoids, glucocorticoids, and sex hormones from the cortex and catecholamines from the medulla, leading to a constellation of symptoms such as fatigue, dizziness, weight loss, nausea, and muscle and joint pain. Specifically, varicella zoster virus (VZV) can produce bilateral adrenal hemorrhage and adrenal insufficiency during primary infection or following reactivation. However, the mechanisms by which VZV affects the adrenal glands are not well-characterized. Herein, we determined if primary human adrenal cortical cells (HAdCCs) infected with VZV support viral replication and produce a proinflammatory environment. Quantitative PCR showed VZV DNA increasing over time in HAdCCs, yet no cell death was seen at 3 days post-infection by TUNEL staining or Western Blot analysis with PARP and caspase 9 antibodies. Compared to conditioned supernatant from mock-infected cells, supernatant from VZV-infected cells contained significantly elevated IL-6, IL-8, IL-12p70, IL-13, IL-4, and TNF-α. Overall, VZV can productively infect adrenal cortical cells in the absence of cell death, suggesting that these cells may be a potential reservoir for ongoing viral replication and proinflammatory cytokine production, leading to chronic adrenalitis and dysfunction.


Assuntos
Morte Celular , Herpes Zoster , Viroses , Córtex Suprarrenal , Morte Celular/imunologia , Morte Celular/fisiologia , Herpes Zoster/metabolismo , Herpes Zoster/patologia , Herpesvirus Humano 3/fisiologia , Humanos , Inflamação/metabolismo , Interleucinas/metabolismo , Cultura Primária de Células , Fator de Necrose Tumoral alfa/metabolismo , Replicação Viral
16.
Int J Mol Sci ; 23(7)2022 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-35409251

RESUMO

Calpains are a family of calcium-activated proteases involved in numerous disorders. Notably, previous studies have shown that calpain activity was substantially increased in various models for inherited retinal degeneration (RD). In the present study, we tested the capacity of the calpain-specific substrate t-BOC-Leu-Met-CMAC to detect calpain activity in living retina, in organotypic retinal explant cultures derived from wild-type mice, as well as from rd1 and RhoP23H/+ RD-mutant mice. Test conditions were refined until the calpain substrate readily detected large numbers of cells in the photoreceptor layer of RD retina but not in wild-type retina. At the same time, the calpain substrate was not obviously toxic to photoreceptor cells. Comparison of calpain activity with immunostaining for activated calpain-2 furthermore suggested that individual calpain isoforms may be active in distinct temporal stages of photoreceptor cell death. Notably, calpain-2 activity may be a relatively short-lived event, occurring only towards the end of the cell-death process. Finally, our results support the development of calpain activity detection as a novel in vivo biomarker for RD suitable for combination with non-invasive imaging techniques.


Assuntos
Degeneração Retiniana , Animais , Biomarcadores/metabolismo , Calpaína/metabolismo , Morte Celular/fisiologia , Camundongos , Células Fotorreceptoras de Vertebrados/metabolismo , Retina/metabolismo , Degeneração Retiniana/diagnóstico , Degeneração Retiniana/metabolismo
17.
Trends Mol Med ; 28(4): 258-269, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35260343

RESUMO

Parkinson's disease (PD) is characterized by dopaminergic (DA) neuron loss and the formation of cytoplasmic protein inclusions. Although the exact pathogenesis of PD is unknown, iron dyshomeostasis has been proposed as a potential contributing factor. Emerging evidence suggests that glial cell activation plays a pivotal role in ferroptosis and subsequent neurodegeneration. We review the association between iron deposition, glial activation, and neuronal death, and discuss whether and how ferroptosis affects α-synuclein aggregation and DA neuron loss. We examine the possible roles of different types of glia in mediating ferroptosis in neurons. Lastly, we review current PD clinical trials targeting iron homeostasis. Although clinical trials are already evaluating ferroptosis modulation in PD, much remains unknown about metal ion metabolism and regulation in PD pathogenesis.


Assuntos
Ferroptose , Doença de Parkinson , Morte Celular/fisiologia , Neurônios Dopaminérgicos/metabolismo , Humanos , Neuroglia/metabolismo , Doença de Parkinson/metabolismo , alfa-Sinucleína/metabolismo
18.
J Exp Bot ; 73(12): 3991-4007, 2022 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-35303096

RESUMO

Multiple disease resistance (MDR) in maize has attracted increasing attention. However, the interplay between cell death and metabolite changes and their contributions to MDR remains elusive in maize. In this study, we identified a mutant named as lesion mimic 30 (les30) that showed 'suicidal' lesion formation in the absence of disease and had enhanced resistance to the fungal pathogen Curvularia lunata. Using map-based cloning, we identified the causal gene encoding pheophorbide a oxidase (PAO), which is known to be involved in chlorophyll degradation and MDR, and is encoded by LETHAL LEAF SPOT1 (LLS1). LLS1 was found to be induced by both biotic and abiotic stresses. Transcriptomics analysis showed that genes involved in defense responses and secondary metabolite biosynthesis were mildly activated in leaves of the les30 mutant without lesions, whilst they were strongly activated in leaves with lesions. In addition, in les30 leaves with lesions, there was overaccumulation of defense-associated phytohormones including jasmonic acid and salicylic acid, and of phytoalexins including phenylpropanoids, lignin, and flavonoids, suggesting that their biosynthesis was activated in a lesion-dependent manner. Taken together, our study implies the existence of an interactive amplification loop of interrupted chlorophyll degradation, cell death, expression of defense-related genes, and metabolite changes that results in suicidal lesion formation and MDR, and this has the potential to be exploited by genetic manipulation to improve maize disease resistance.


Assuntos
Resistência à Doença , Zea mays , Alelos , Morte Celular/fisiologia , Clorofila/metabolismo , Resistência à Doença/genética , Humanos , Oxilipinas/metabolismo , Doenças das Plantas/genética , Doenças das Plantas/microbiologia , Folhas de Planta/genética , Folhas de Planta/metabolismo , Proteínas de Plantas/genética , Zea mays/metabolismo
19.
Sci Rep ; 12(1): 5118, 2022 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-35332201

RESUMO

Nigratine (also known as 6E11), a flavanone derivative of a plant natural product, was characterized as highly specific non-ATP competitive inhibitor of RIPK1 kinase, one of the key components of necroptotic cell death signaling. We show here that nigratine inhibited both necroptosis (induced by Tumor Necrosis Factor-α) and ferroptosis (induced by the small molecules glutamate, erastin, RSL3 or cumene hydroperoxide) with EC50 in the µM range. Taken together, our data showed that nigratine is a dual inhibitor of necroptosis and ferroptosis cell death pathways. These findings open potential new therapeutic avenues for treating complex necrosis-related diseases.


Assuntos
Ferroptose , Apoptose , Morte Celular/fisiologia , Humanos , Necroptose , Necrose , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
20.
Cells ; 11(5)2022 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-35269533

RESUMO

Excitotoxicity is a form of neuronal death characterized by the sustained activation of N-methyl-D-aspartate receptors (NMDARs) triggered by the excitatory neurotransmitter glutamate. NADPH-diaphorase neurons (also known as nNOS (+) neurons) are a subpopulation of aspiny interneurons, largely spared following excitotoxic challenges. Unlike nNOS (-) cells, nNOS (+) neurons fail to generate reactive oxygen species in response to NMDAR activation, a critical divergent step in the excitotoxic cascade. However, additional mechanisms underlying the reduced vulnerability of nNOS (+) neurons to NMDAR-driven neuronal death have not been explored. Using functional, genetic, and molecular analysis in striatal cultures, we indicate that nNOS (+) neurons possess distinct NMDAR properties. These specific features are primarily driven by the peculiar redox milieu of this subpopulation. In addition, we found that nNOS (+) neurons exposed to a pharmacological maneuver set to mimic chronic excitotoxicity alter their responses to NMDAR-mediated challenges. These findings suggest the presence of mechanisms providing long-term dynamic regulation of NMDARs that can have critical implications in neurotoxic settings.


Assuntos
Neurônios , Receptores de N-Metil-D-Aspartato , Morte Celular/fisiologia , Corpo Estriado/metabolismo , Ácido Glutâmico , Neurônios/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo
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