Cell Death
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2021 ◽  
Vol 11 ◽  
Author(s):  
Yan Zhao ◽  
Zineng Huang ◽  
Hongling Peng

Cell death is essential for the normal metabolism of human organisms. Ferroptosis is a unique regulated cell death (RCD) mode characterized by excess accumulation of iron-dependent lipid peroxide and reactive oxygen species (ROS) compared with other well-known programmed cell death modes. It has been currently recognized that ferroptosis plays a rather important role in the occurrence, development, and treatment of traumatic brain injury, stroke, acute kidney injury, liver damage, ischemia–reperfusion injury, tumor, etc. Of note, ferroptosis may be explained by the expression of various molecules and signaling components, among which iron, lipid, and amino acid metabolism are the key regulatory mechanisms of ferroptosis. Meanwhile, tumor cells of hematological malignancies, such as leukemia, lymphoma, and multiple myeloma (MM), are identified to be sensitive to ferroptosis. Targeting potential regulatory factors in the ferroptosis pathway may promote or inhibit the disease progression of these malignancies. In this review, a systematic summary was conducted on the key molecular mechanisms of ferroptosis and the current potential relationships of ferroptosis with leukemia, lymphoma, and MM. It is expected to provide novel potential therapeutic approaches and targets for hematological malignancies.


2021 ◽  
Vol 11 ◽  
Author(s):  
Emad Matanes ◽  
Vanessa M. López-Ozuna ◽  
David Octeau ◽  
Tahira Baloch ◽  
Florentin Racovitan ◽  
...  

BackgroundPoly ADP-ribose glycohydrolase (PARG) is responsible for the catabolism of PARP-synthesized PAR to free ADP-ribose. Inhibition of PARG leads to DNA repair interruption and consequently induces cell death. This study aims to evaluate the effect of a PARG inhibitor (PARGi) on epithelial ovarian cancer (OC) cell lines, alone and in combination with a PARP inhibitor (PARPi) and/or Cisplatin.MethodsPARG mRNA levels were studied in three different OC datasets: TCGA, Hendrix, and Meyniel. PARG protein levels were assessed in 100 OC specimens from our bio-bank. The therapeutic efficacy of PARGi was assessed using cell migration and clonogenic formation assays. Flow cytometry was used to evaluate the cell apoptosis rate and the changes in the cell cycle.ResultsPARG protein was highly expressed in 34% of the OC tumors and low expression was found in another 9%. Similarly, Hendrix, Meyneil and TCGA databases showed a significant up-regulation in PARG mRNA expression in OC samples as compared to normal tissue (P=0.001, P=0.005, P=0.005, respectively). The use of PARGi leads to decreased cell migration. PARGi in combination with PARPi or Cisplatin induced decreased survival of cells as compared to each drug alone. In the presence of PARPi and Cisplatin, PARG knockdown cell lines showed significant G2/M cell cycle arrest and cell death induction.ConclusionsPARG inhibition appears as a complementary strategy to PARP inhibition in the treatment of ovarian cancer, especially in the presence of homologous recombination defects.


Author(s):  
Christine E. Broster Reix ◽  
Miharisoa Rijatiana Ramanantsalama ◽  
Carmelo Di Primo ◽  
Laëtitia Minder ◽  
Mélanie Bonhivers ◽  
...  

Trypanosoma brucei belongs to a group of important zoonotic parasites. We investigated how these organisms develop their cytoskeleton (the internal skeleton that controls cell shape) and focused on an essential protein (BILBO1) first described in T. brucei .


2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Lindsey M. Ludwig ◽  
Katrina M. Hawley ◽  
David B. Banks ◽  
Anika T. Thomas-Toth ◽  
Bruce R. Blazar ◽  
...  

AbstractBH3 mimetics are increasingly used as anti-cancer therapeutics either alone or in conjunction with other chemotherapies. However, mounting evidence has also demonstrated that BH3 mimetics modulate varied amounts of apoptotic signaling in healthy immune populations. In order to maximize their clinical potential, it will be essential to understand how BH3 mimetics affect discrete immune populations and to determine how BH3 mimetic pressure causes immune system adaptation. Here we focus on the BCL-2 specific inhibitor venetoclax (ABT-199) and its effects following short-term and long-term BCL-2 blockade on T cell subsets. Seven day “short-term” ex vivo and in vivo BCL-2 inhibition led to divergent cell death sensitivity patterns in CD8+ T cells, CD4+ T cells, and Tregs resulting in shifting of global T cell populations towards a more memory T cell state with increased expression of BCL-2, BCL-XL, and MCL-1. However, twenty-eight day “long-term” BCL-2 blockade following T cell-depleted bone marrow transplantation did not lead to changes in the global T cell landscape. Despite the lack of changes in T cell proportions, animals treated with venetoclax developed CD8+ and CD4+ T cells with high levels of BCL-2 and were more resistant to apoptotic stimuli following expansion post-transplant. Further, we demonstrate through RNA profiling that T cells adapt while under BCL-2 blockade post-transplant and develop a more activated genotype. Taken together, these data emphasize the importance of evaluating how BH3 mimetics affect the immune system in different treatment modalities and disease contexts and suggest that venetoclax should be further explored as an immunomodulatory compound.


2021 ◽  
Vol 11 ◽  
Author(s):  
Sayeda Yasmin-Karim ◽  
Jana Wood ◽  
Johanna Wirtz ◽  
Michele Moreau ◽  
Noella Bih ◽  
...  

Effective in situ cancer vaccines require both a means of tumor cell death and a source of adjuvant to activate local dendritic cells. Studies have shown that the use of radiotherapy (RT) to induce tumor cell death and anti-CD40 to activate dendritic cells can result in in situ vaccination in animal models. Here, investigations are carried out on potential strategies to enhance such in situ vaccination. Strategies investigated include the use of smart immunogenic biomaterials (IBM) loaded with anti-CD40 in different tumor types including immunologically cold tumors like pancreatic and prostate tumors. The use of downstream checkpoint inhibitors to further boost such in situ vaccination is also examined. Results indicate that the use of IBM to deliver the anti-CD40 significantly enhances the effectiveness of in situ vaccination with anti-CD40 compared with direct injection in pancreatic and prostate cancers (p < 0.001 and p < 0.0001, respectively). This finding is consistent with significant increase in infiltration of antigen-presenting cells in the treated tumor, and significant increase in the infiltration of CD8+ cytotoxic T lymphocyte into distant untreated tumors. Moreover, in situ vaccination with IBM is consistently observed across different tumor types. Meanwhile, the addition of downstream immune checkpoint inhibitors further enhances overall survival when using the IBM approach. Overall, the findings highlight potential avenues for enhancing in situ vaccination when combining radiotherapy with anti-CD40.


2021 ◽  
Vol 8 ◽  
Author(s):  
Zhenzhen Chen ◽  
Youyou Yan ◽  
Chao Qi ◽  
Jia Liu ◽  
Longbo Li ◽  
...  

Cardiovascular diseases (CVDs) are the leading cause of deaths worldwide with regulated cell death playing an important role in cardiac pathophysiology. However, the classical mode of cell death cannot fully explain the occurrence and development of heart disease. In recent years, much research has been performed on ferroptosis, a new type of cell death that causes cell damage and contributes to the development of atherosclerosis, myocardial infarction, heart failure, and other diseases. In this review, we discuss the role of different organelles in ferroptosis and also focus on the relationship between autophagy and ferroptosis. Additionally, we describe the specific mechanism by which ferroptosis contributes to the development of CVD. Finally, we summarize the current research on ferroptosis-related pathway inhibitors and the applications of clinically beneficial cardiovascular drugs.


2021 ◽  
Vol 12 ◽  
Author(s):  
Deepak Duhan ◽  
Shivani Gajbhiye ◽  
Rajdeep Jaswal ◽  
Ravindra Pal Singh ◽  
Tilak Raj Sharma ◽  
...  

Alternaria brassicae is an important necrotrophic pathogen that infects the Brassicaceae family. A. brassicae, like other necrotrophs, also secretes various proteinaceous effectors and metabolites that cause cell death to establish itself in the host. However, there has been no systematic study of A. brassicae effectors and their roles in pathogenesis. The availability of the genome sequence of A. brassicae in public domain has enabled the search for effectors and their functional characterization. Nep1-like proteins (NLPs) are a superfamily of proteins that induce necrosis and ethylene biosynthesis. They have been reported from a variety of microbes including bacteria, fungi, and oomycetes. In this study, we identified two NLPs from A. brassicae viz. AbrNLP1 and AbrNLP2 and functionally characterized them. Although both AbrNLPs were found to be secretory in nature, they localized differentially inside the plant. AbrNLP2 was found to induce necrosis in both host and non-host species, while AbrNLP1 could not induce necrosis in both species. Additionally, AbrNLP2 was shown to induce pathogen-associated molecular pattern (PAMP)-triggered immunity in both host and non-host species. Overall, our study indicates that AbrNLPs are functionally and spatially (subcellular location) distinct and may play different but important roles during the pathogenesis of A. brassicae.


Author(s):  
Yikun Wang ◽  
Shiyu Qiu ◽  
Hong Wang ◽  
Jiangtao Cui ◽  
Xiaoting Tian ◽  
...  

Ferroptosis is an iron- and lipid peroxidation-dependent form of regulated cell death. The release of labile iron is one of the important factors affecting sensitivity to ferroptosis. Yes-associated protein (YAP) controls intracellular iron levels by affecting the transcription of ferritin heavy chain (FTH) and transferrin receptor (TFRC). However, whether YAP regulates iron metabolism through other target genes remains unknown. Here, we observed that the system Xc– inhibitor erastin inhibited the binding of the WW domain and PSY motif between YAP and transcription factor CP2 (TFCP2), and then suppressed the transcription of ferritin light chain (FTL) simultaneously mediated by YAP, TFCP2 and forkhead box A1 (FOXA1). Furthermore, inhibition of FTL expression abrogated ferroptosis-resistance in cells with sustained YAP expression. Unlike FTH, which exhibited first an increase and then a decrease in transcription, FTL transcription continued to decline after the addition of erastin, and a decrease in lysine acetyltransferase 5 (KAT5)-dependent acetylation of FTL was also observed. In lung adenocarcinoma (LUAD) tissues, lipid peroxidation and labile iron decreased, while YAP, TFCP2 and FTL increased compared to their adjacent normal tissues, and the lipid peroxidation marker 4-hydroxynonenal (4-HNE) was negatively correlated with the level of FTL or the degree of LUAD malignancy, but LUAD tissues with lower levels of 4-HNE showed a higher sensitivity to ferroptosis. In conclusion, the findings from this study indicated that the suppression of FTL transcription through the inhibition of the YAP-TFCP2-KAT5 complex could be another mechanism for elevating ferroptosis sensitivity and inducing cell death, and ferroptotic therapy is more likely to achieve better results in LUAD patients with a lower degree of lipid peroxidation.


2021 ◽  
Vol 12 ◽  
Author(s):  
Yonghao Yang ◽  
Hao Huang ◽  
Tiepeng Li ◽  
Quanli Gao ◽  
Yongping Song ◽  
...  

Owing to broad and notable clinical anti-tumor activity, anti-programmed cell death-1 (PD-1)/anti-programmed cell death-ligand 1 (PD-L1) antibodies have been indicated for almost all types of cancer, and form a part of the current standard of care. However, a large proportion of patients do not respond to anti-PD-1/PD-L1 therapy (primary resistance), and responders often develop progressive disease (acquired resistance). The mechanisms of resistance are complex and largely unknown; therefore, overcoming resistance remains clinically challenging, and data on reversing anti-PD-1 resistance are scarce. Herein, we report the case of a 58-year-old woman with renal cell carcinoma associated with Xp11.2 translocation/transcription factor E3 gene fusion, who had already showed resistance to both anti-PD-1 monotherapy and standard-dose axitinib. However, she finally achieved a partial response with a continuous combination therapy comprising low-dose axitinib and anti-PD-1. We speculate that axitinib played a key role in reversing the primary resistance to anti-PD-1 therapy. Interestingly, we observed that the number of peripheral regulatory T cells increased after the standard-dose axitinib therapy, with accompanied tumor enlargement; however, after the dose was reduced, the number of regulatory T cells decreased gradually, and the tumor regressed. We also reviewed relevant literature, which supported the fact that low-dose axitinib might be more beneficial than standard-dose axitinib in assisting immunotherapy. Given that this is a single-case report, the immunomodulatory effect of axitinib requires further investigation.


2021 ◽  
Author(s):  
Ishaan S Nanal ◽  
Linxi Wang ◽  
Luke Y Zhao ◽  
Andrew Looka ◽  
Marianne Bezaire

Parkinson′s Disease (PD) is a debilitating neurodegenerative condition that affects over 10 million people across the world, causing tremors and muscle weakness. Its mechanisms are unknown, but one key feature is selective cell death: neurons in the Substantia Nigra Pars Compacta (SNc) die, but their neighbors, the cells in the Ventral Tegmental Area (VTA), remain healthy. To study this phenomenon, we used an established single neuron model of the SNc, adapting its biophysical and bioenergetic properties to match that of the VTA. We discovered that reducing calcium influx correlates with higher ATP and lower ROS concentrations in the cell, suggesting in silico the importance of calcium influx in metabolic stress and selective vulnerability for Parkinson′s Disease. Future efforts may target calcium channel inhibition as a therapeutic strategy, although caution is needed with potential metabolic side effects.


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