Protective mechanisms of CA074-me (other than cathepsin-B inhibition) against programmed necrosis induced by global cerebral ischemia/reperfusion injury in rats

Xu, Yang; Wang, Jingye; Song, Xinghui; Wei, Rui-Li; He, Fangping; Peng, Guoping; Luo, Benyan

doi:10.1016/j.brainresbull.2015.11.007

Cited by 37 publications

(22 citation statements)

References 43 publications

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“…How ever, the lysosomal CathB level decreased significantly by 25.4 ± 4.7% and 43.9 ± 6.3% after 30 and 60 min of MILH treat ment respectively, demonstrating that leakage of lysosome content is an early event occurring concomitantly with the generation of lysosomal ROS. Of note, RFP Lamp1 and GFP CathB fluorescence intensities, other LMP markers [29], decreased respectively by 20 ± 2.4% and 16.5 ± 6.6% from 30 min of AMF exposure (Fig. S7), strongly sug gesting that the changes in RFP Lamp1 and GFP CathB fluorescence represent respectively lysosomal rupture and CathB leakage from ly sosome into the cytosol and that both events occur early in the signaling cascade leading to cell death.…”

Section: Milh Enhanced Ros Production Within Lysosomes Causes Lysosommentioning

confidence: 87%

Targeted Magnetic Intra-Lysosomal Hyperthermia produces lysosomal reactive oxygen species and causes Caspase-1 dependent cell death

Clerc

Jeanjean

Hallali

et al. 2018

Journal of Controlled Release

103

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Therapeutic strategies using drugs which cause Lysosomal Cell Death have been proposed for eradication of resistant cancer cells. In this context, nanotherapy based on Magnetic Intra-Lysosomal Hyperthermia (MILH) generated by magnetic nanoparticles (MNPs) that are grafted with ligands of receptors overexpressed in tumors appears to be a very promising therapeutic option. However, mechanisms whereby MILH induces cell death are still elusive. Herein, using Gastrin-grafted MNPs specifically delivered to lysosomes of tumor cells from different cancers, we provide evidences that MILH causes cell death through a non-apoptotic signaling pathway. The mechanism of cell death involves a local temperature elevation at the nanoparticle periphery which enhances the production of reactive oxygen species through the lysosomal Fenton reaction. Subsequently, MILH induces lipid peroxidation, lysosomal membrane permeabilization and leakage of lysosomal enzymes into the cytosol, including Cathepsin-B which activates Caspase-1 but not apoptotic Caspase-3. These data highlight the clear potential of MILH for the eradication of tumors overexpressing receptors.

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Section: Milh Enhanced Ros Production Within Lysosomes Causes Lysosommentioning

confidence: 87%

Targeted Magnetic Intra-Lysosomal Hyperthermia produces lysosomal reactive oxygen species and causes Caspase-1 dependent cell death

Clerc

Jeanjean

Hallali

et al. 2018

Journal of Controlled Release

103

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“…11d, e), all of this contribute to the cells to improve their mitochondria function, reducing cytochrome C release and increasing their anti-apoptotic capacity to prevent OGD/R injury (Boonyarat et al 2014). RIP3 is a key Bswitch^molecule in programmed necrosis, overexpression, and nuclear translocation of RIP3 that plays a critical role in the hippocampal neuronal programmed necrosis induced I/R injury (Yin et al 2015;Xu et al 2016;Vieira et al 2014). These were consistent with our research that RIP3 level significantly increased after OGD/R injury, indicating OGDR-induced RIP3 activation and trigger necroptosis.…”

Section: Discussionmentioning

confidence: 99%

Ginkgolides and bilobalide protect BV2 microglia cells against OGD/reoxygenation injury by inhibiting TLR2/4 signaling pathways

Zhou

Wang

et al. 2016

Cell Stress and Chaperones

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Ginkgolide and bilobalide are major trilactone constituent of Ginkgo biloba leaves and have been shown to exert powerful neuroprotective properties. The aims of this study were to observe the inhibitory effects of ginkgolide and bilobalide on the activation of microglial cells induced by oxygen-glucose deprivation and reoxygenation (OGD/R) and the specific mechanisms by which these effects are mediated. For detecting whether ginkgolide and bilobalide increased cell viability in a dose-dependent manner, BV2 cells were subjected to oxygen-glucose deprivation for 4 h followed by 3 h reoxygenation with various concentrations of drugs (6.25, 12.5, 25, 50, and 100 μg/ml). The extent of apoptosis effect of OGD/R with or without ginkgolide and bilobalide treatment were also measured by Annexin V-FITC/PI staining. Similarly, the levels of pro-inflammatory cytokines TNF-α, IL-1β, IL-6, IL-8, and IL-10 were detected using a specific Bio-Plex Pro™ Reagent Kit. The effects of ginkgolide and bilobalide on protein levels of TLR2/4, MyD88, p-TAK1, p-IKKβ, p-IkBα, NF-κB p65, Bcl-2, Bax, Bak, RIP3, cleaved-Caspase-3, cleaved PARP-1 and cellular localization of NF-κB p65 were evaluated by Western blot and double-labeled immunofluorescence staining, respectively. OGD/R significantly decreased the cell viability and increased the release of IL-1β, IL-6, IL-8, IL-10, TNF-α in BV2 microglia cells; these effects were suppressed by ginkgolide and bilobalide. Meanwhile, ginkgolide and bilobalide also attenuated the OGD/R-induced increases in TLR2, TLR4, MyD88, Bak, RIP3 levels and reversed cleaved caspase-3/caspase-3, Bax/Bcl-2 and cleaved PARP-1/PARP-1 ratio. Furthermore, ginkgolide and bilobalide also downregulated p-TAK1, p-IkBα, and p-IKKβ and inhibited the OGD/R-induced transfer of NF-κB p65 from cytoplasm to nucleus in BV2 microglia cells. The results showed that ginkgolide and bilobalide can inhibit OGD/R-induced production of inflammatory factors in BV2 microglia cells by regulating the TLRs/MyD88/NF-κB signaling pathways and attenuating inflammatory response. The possible mechanism of anti-inflammatory and neuroprotective effects of ginkgolides results from the synergistic reaction among each monomer constituents.

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“…Upon the stimulation of TNF-like cytokines, death receptors are triggered and the caspase cascade is activated, leading to apoptotic cell death ( 30 ). Previous studies have indicated that the inhibition of caspase activity by specific caspase inhibitors, such as zVAD, is able to lead to apotosis-independent cell death, namely programmed necrosis (necroptosis) ( 31 – 33 ). Necroptosis has been demonstrated to be regulated by two key kinases, RIP1 and RIP3 ( 29 ).…”

Section: Discussionmentioning

confidence: 99%

Receptor-interacting protein kinase 3-mediated programmed cell necrosis in rats subjected to focal cerebral ischemia-reperfusion injury

Dong

Cui-fen

et al. 2016

Molecular Medicine Reports

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In the current study, the activation of tumor necrosis factor-α receptor 1 (TNFR1) and receptor-interacting protein kinase 3 (RIP3) were investigated following cerebral ischemia-reperfusion injury (CIRI). Healthy SD rats were randomly divided into 3 groups: Sham operation group, model group and inhibitor group. The model group and inhibitor group were further divided into 4 subgroups of 6, 12, 24 and 72 h following CIRI. Using right middle cerebral artery embolization, the CIRI model was generated. To confirm that the CIRI model was established, neurological scores, TTC staining and brain water content measurements were conducted. Immunohistochemistry and western blotting were conducted to investigate the expression of TNFR1 and RIP3 in the cerebral cortex. It was observed that nerve cell necrosis occurred following 6 h of CIRI. The appearance of necrotic cells was gradually increased with increasing CIRI duration. TNFR1 and RIP3 were positively expressed following 6 h of CIRI. With increasing durations of CIRI, the protein expression levels of TNFR1 and RIP3 were significantly increased. Pre-administration with Z-VAD-FMK (zVAD) significantly increased the protein level of RIP3, however, had no effect on the levels of TNFR1, and was accompanied by a reduction in necrosis. In conclusion, RIP3-mediated cell necrosis was enhanced by caspase blockade zVAD and the function of zVAD was independent of TNFR1 signaling following IR.

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Protective mechanisms of CA074-me (other than cathepsin-B inhibition) against programmed necrosis induced by global cerebral ischemia/reperfusion injury in rats

Cited by 37 publications

References 43 publications

Targeted Magnetic Intra-Lysosomal Hyperthermia produces lysosomal reactive oxygen species and causes Caspase-1 dependent cell death

Targeted Magnetic Intra-Lysosomal Hyperthermia produces lysosomal reactive oxygen species and causes Caspase-1 dependent cell death

Ginkgolides and bilobalide protect BV2 microglia cells against OGD/reoxygenation injury by inhibiting TLR2/4 signaling pathways

Receptor-interacting protein kinase 3-mediated programmed cell necrosis in rats subjected to focal cerebral ischemia-reperfusion injury

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