Inhibition of PLA2G4E/cPLA2 promotes survival of random skin flaps by alleviating Lysosomal membrane permeabilization-Induced necroptosis

Lou, Junsheng; Wang, Xiangyang; Zhang, Haojie; Yu, Gaoxiang; Ding, Jian; Zhu, Xuwei; Li, Yao; Wu, Yaosen; Xu, Hui; Xu, Huazi; Gao, Weiyang; Xiao, Jian; Zhou, Kailiang

doi:10.1080/15548627.2021.2002109

Cited by 40 publications

(33 citation statements)

References 70 publications

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“…Previous studies have found that PLA2G4E was related to necroptosis. Inhibition of PLA2G4E by microRNA Mir504-5p reduced necroptosis of skin and prolonged survival of skin cells [50]. Previous studies have found that inactivated function of RIPK1, RIPK3, and MLKL, especially by the necroptosis inhibitor Nec-1, protected neurons from being damaged, degenerated, and keeping the viability of neural cells in these neurodegenerative diseases [51][52][53][54][55].…”

Section: Discussionmentioning

confidence: 95%

Differential Expression of Necroptosis-Related Genes with regulating lncRNA in Triple Negative Breast Cancer to Predict Prognosis and Immunotherapy Response

2023

Ann med clin Oncol

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Purpose: Necroptosis is essential in tumor biology in which lncRNAs play an important role but related studies in triple negative breast cancer (TNBC) were insufficient. We aim to screen remarkable necroptosis-related lncRNA and construct a lncNRA-related risk model for precision of immunotherapy. Methods: Transcriptional data were acquired from TCGA database. Differentially expressed genes (DEGs) related to necroptosis were obtained in TNBC samples. LncRNAs related to DEGs were analyzed by following Cox and least absolute shrinkage and selection operator regression analysis. Prognosis-associated lncRNAs were brought into a model which divided training and testing samples into high-/low-risk subgroups. Survival analysis between these subgroups were conducted and independent variables of prognosis were selected. Nomogram was then created to predict prognosis of selected patients. Comparisons of immune landscape, tumor microenvironment, and immunotherapy response were performed between the two subgroups. Results: Seven necroptosis-related DEGs (NRGs) were found in TNBC. Six of 153 NRG-related lncRNAs were brought into model. Forecast performance was validated in testing datasets. Immune cell infiltration and T-cell activity was weaker in high-risk group compared with that in low-risk counterparts. Innate and adaptive immune cell abundance was inversely proportional to risk score. Compared with low-risk group, patients in high-risk group had lower immune/stromal/ESTIMATE score, lower expression of immune checkpoint molecules, and worse immunotherapy response. Conclusion: Six NRG-related lncRNAs were potential targets for future precision therapy of TNBC. Our model was effective in predicting the prognosis of TNBC patients and beneficial for decision-making of immunotherapy.

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Section: Discussionmentioning

confidence: 95%

Differential Expression of Necroptosis-Related Genes with regulating lncRNA in Triple Negative Breast Cancer to Predict Prognosis and Immunotherapy Response

2023

Ann med clin Oncol

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“…In addition, lysosomal dysfunction is primarily characterized by LMP, which released lysosomal cathepsins into the cytoplasm that destroy intracellular components 33 . To date, many pathogenic factors, including ROS, lysosomotropic drugs, bacterial and viral products, have been identi ed to cause LMP 27,34 . However, correlations between the excessive mechanical load and LMP were not well demonstrated.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies revealed that the lysophospholipids exhibit properties similar to detergents and may induce the lysosomal membrane to rupture 19 . The LMP caused by cPLA2 in neurons and endothelial cells resulted in cell death 19,27 . Recent studies have shown that Piezo1 activates cPLA2 via calcium in ux 21,22 .…”

Section: Discussionmentioning

confidence: 99%

“…These results suggested that cPLA2was activated in lysosomes following Piezo1 activation via calcium in ux. cPLA2 may directly cause loss of membrane integrity and participate in LMP 19,27 . To investigate the roles of cPLA2 in mechanical stretch mediated LMP, speci c siRNA was used to knockdown cPLA2 expression in chondrocytes (Supplementary Fig.…”

Section: Piezo1 Mediates Excessive Mechanical Stretch-induced Apoptos...mentioning

confidence: 99%

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Excessive mechanical stress mediated Piezo1 activation regulates lysosomal membrane permeabilization-induced chondrocyte apoptosis in mouse osteoarthritis model

Yan

et al. 2022

Preprint

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Excessive mechanical stress is closely associated with progression of osteoarthritis (OA). Pathological mechanical stress can lead to chondrocyte apoptosis and subsequent cartilage degeneration. Piezo1 is a recently identified mechanosensitive ion channel that mediates chondrocyte response to mechanical stress. Here, we investigated the potential role of Piezo1 in chondrocyte apoptosis and cartilage degeneration induced by excessive mechanical stress. The primary mouse chondrocytes were subjected to mechanical stretch stress for 0, 6, 12 and 24 h, respectively. Western blot, quantitative real-time polymerase chain reaction, immunofluorescence, lysosomes and acridine orange staining were applied to examine levels of Piezo1, lysosomal function, chondrocyte apoptosis and cartilage degeneration. In vivo studies, DMM mouse model was performed to explore the protective effects and underlying mechanisms of Piezo1 inhibition on chondrocyte apoptosis and articular cartilage degradation. Exposure of chondrocytes to excessive mechanical loading caused lysosomal membrane permeabilization (LMP), which increased chondrocyte apoptosis and cartilage degeneration. Moreover, Piezo1 was upregulated in mechanical stress treated chondrocytes, and Piezo1 inhibition by siRNA or pharmacological inhibitor attenuated LMP, chondrocyte apoptosis and cartilage degeneration. We also found that Piezo1 activated cPLA2 through the calcium signaling, and cPLA2 subsequently caused the occurrence of LMP. Finally, the DMM mouse model revealed that Piezo1 inhibition reduced cPLA2 induced LMP, thereby ameliorated the surgery induced chondrocyte apoptosis and cartilage degradation, and attenuated OA pathological process. In summary, our study indicates that activity of Piezo1 was the culprit in the excessive mechanical stress-induced LMP and cartilage degradation, and Piezo1 inhibition may be a promising strategy for OA treatment.

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“…Mechanistically, nuclear CTSB accumulation causes DNA damage and subsequent activation of the stimulator of interferon response cGAMP interactor 1 (STING1/STING)-dependent DNA sensor pathway, which ultimately leads to ferroptosis [ 114 ]. Lysosomal membrane permeabilization (LMP) plays an indispensable role in the regulation of necroptosis [ 115 ].…”

Section: Interactions Between Sting Signalling and Different Types Of...mentioning

confidence: 99%

Emerging role of STING signalling in CNS injury: inflammation, autophagy, necroptosis, ferroptosis and pyroptosis

Zhang

et al. 2022

J Neuroinflammation

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Stimulator of interferons genes (STING), which is crucial for the secretion of type I interferons and proinflammatory cytokines in response to cytosolic nucleic acids, plays a key role in the innate immune system. Studies have revealed the participation of the STING pathway in unregulated inflammatory processes, traumatic brain injury (TBI), spinal cord injury (SCI), subarachnoid haemorrhage (SAH) and hypoxic–ischaemic encephalopathy (HIE). STING signalling is markedly increased in CNS injury, and STING agonists might facilitate the pathogenesis of CNS injury. However, the effects of STING-regulated signalling activation in CNS injury are not well understood. Aberrant activation of STING increases inflammatory events, type I interferon responses, and cell death. cGAS is the primary pathway that induces STING activation. Herein, we provide a comprehensive review of the latest findings related to STING signalling and the cGAS–STING pathway and highlight the control mechanisms and their functions in CNS injury. Furthermore, we summarize and explore the most recent advances toward obtaining an understanding of the involvement of STING signalling in programmed cell death (autophagy, necroptosis, ferroptosis and pyroptosis) during CNS injury. We also review potential therapeutic agents that are capable of regulating the cGAS–STING signalling pathway, which facilitates our understanding of cGAS–STING signalling functions in CNS injury and the potential value of this signalling pathway as a treatment target.

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Inhibition of PLA2G4E/cPLA2 promotes survival of random skin flaps by alleviating Lysosomal membrane permeabilization-Induced necroptosis

Cited by 40 publications

References 70 publications

Differential Expression of Necroptosis-Related Genes with regulating lncRNA in Triple Negative Breast Cancer to Predict Prognosis and Immunotherapy Response

Differential Expression of Necroptosis-Related Genes with regulating lncRNA in Triple Negative Breast Cancer to Predict Prognosis and Immunotherapy Response

Excessive mechanical stress mediated Piezo1 activation regulates lysosomal membrane permeabilization-induced chondrocyte apoptosis in mouse osteoarthritis model

Emerging role of STING signalling in CNS injury: inflammation, autophagy, necroptosis, ferroptosis and pyroptosis

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