Ultrastructural Patterns of the Activated Cell Death Programs in the Human Brain

Pais, Viorel; Dănăilă, L; E, Pais

doi:10.3109/01913123.2012.751949

Cited by 10 publications

(9 citation statements)

References 13 publications

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“…The preliminary observations in this study focus on the high incidence of autophagy and paraptosis in the GCL where RGCs die by this nonapoptotic pathway. The roles of individual types of cell death and the coexistence of multiple cell death types (paraptosis, autophagy and apoptosis) have been reported in recent studies concerning ischemic injury, neurodegeneration and viral infection ( 25 , 27 , 29 , 30 ). For the identification of the type of cell death, and even for the quantification of certain processes, EM remains one of the most accurate methods; for example, paraptosis was first discovered by TEM ( 15 ).…”

Section: Discussionmentioning

confidence: 98%

Activation of autophagy and paraptosis in retinal ganglion cells after retinal ischemia and reperfusion injury in rats

Wei

Kang

et al. 2014

Experimental and Therapeutic Medicine

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Glaucoma is a neurodegenerative disease characterized by elevated intraocular pressure (IOP), which causes retinal ischemia and progressive neuronal death. Retinal ischemia/reperfusion (RIR) injury is a common clinical condition representing the main cause of irreversible visual field defects in humans. The aim of this study was to investigate whether non-apoptotic forms of programmed cell death (PCD) have an effect on RIR injury in an experimental model that replicates features of acute hypertensive glaucoma and to explore the possible underlying mechanisms. The activation of autophagy was investigated in retinal ganglion cells (RGCs) following RIR in comparison with a control group, using immunofluorescence against microtubule-associated protein 1 light chain 3 (LC3). RIR injury increased LC3 expression in the cytoplasm of RGCs in the ganglion cell layer (GCL) 6 h after the insult, and the increased expression was sustained throughout the experimental period. Following RIR insult, the number of neurons in the GCL significantly decreased. Ultra-structural analyses showed that double- or multiple-membrane autophagosomes were markedly accumulated in the cytoplasm of RGCs following IOP elevation. Since there are no known markers for paraptosis, its identification was based on morphological criteria. Electron microscopy (EM) analysis revealed severe structural alterations associated with cytoplasmatic vacuolization within the 6 h after RIR injury and RGC death. EM also revealed that vacuoles were derived predominantly from the progressive swelling of the endoplasmic reticulum (ER) and/or mitochondria in RGCs after RIR injury. The results provide novel evidence implicating an important role of autophagy and paraptosis in the pathogenesis of RIR injury. Autophagy and paraptosis take place during developmental cell death in the nervous system as well as in certain cases of neurodegeneration. Therefore, targeting autophagy and paraptosis could have therapeutic potential for the prevention of glaucoma involving RIR injury.

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Section: Discussionmentioning

confidence: 98%

Activation of autophagy and paraptosis in retinal ganglion cells after retinal ischemia and reperfusion injury in rats

Wei

Kang

et al. 2014

Experimental and Therapeutic Medicine

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“…Moreover, paraptosis was found to be a relevant cell death process in the brain tissue of GBM patients. 23 …”

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confidence: 99%

Fungal metabolite ophiobolin A as a promising anti-glioma agent: In vivo evaluation, structure–activity relationship and unique pyrrolylation of primary amines

Dasari¹,

Masi

Lisy

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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Glioblastoma, the most common form of malignant primary brain tumor, is characterized by resistance to apoptosis, which is largely responsible for the low effectiveness of the classical chemotherapeutic approaches based on apoptosis induction in cancer cells. Previously, a fungal secondary metabolite ophiobolin A was found to have significant activity against apoptosis-resistant glioblastoma cells through the induction of a non-apoptotic cell death, thus, offering an innovative strategy to combat this type of cancer. The current work describes the results of a preliminary evaluation of ophiobolin A in an in vivo glioblastoma model and its chemical derivatization to establish first synthetically generated structure-activity relationship. The synthetic work has also led to the discovery of a unique reaction of ophiobolin A with primary amines suggesting the possibility of pyrrolylation of lysine residues on its intracellular target protein(s).

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“…13, 16 Paraptotic cells in brain tissues were observed to be filled with small and large vacuoles. 17 In addition, various stimuli, including paclitaxel, 18 curcumin 3, 19 and ophiobolin A, 20 reportedly induce paraptosis or paraptosis-like cell death in resistant malignant cancer cells, suggesting that paraptosis may provide a strategy for overcoming innate and acquired resistance to the current pro-apoptotic anticancer therapies. However, the molecular basis of paraptosis is still poorly defined, and additional evidence is required to confirm the authentic biochemical markers of this process.…”

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confidence: 99%

Stronger proteasomal inhibition and higher CHOP induction are responsible for more effective induction of paraptosis by dimethoxycurcumin than curcumin

et al. 2014

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Although curcumin suppresses the growth of a variety of cancer cells, its poor absorption and low systemic bioavailability have limited its translation into clinics as an anticancer agent. In this study, we show that dimethoxycurcumin (DMC), a methylated, more stable analog of curcumin, is significantly more potent than curcumin in inducing cell death and reducing the clonogenicity of malignant breast cancer cells. Furthermore, DMC reduces the tumor growth of xenografted MDA-MB 435S cells more strongly than curcumin. We found that DMC induces paraptosis accompanied by excessive dilation of mitochondria and the endoplasmic reticulum (ER); this is similar to curcumin, but a much lower concentration of DMC is required to induce this process. DMC inhibits the proteasomal activity more strongly than curcumin, possibly causing severe ER stress and contributing to the observed dilation. DMC treatment upregulates the protein levels of CCAAT-enhancer-binding protein homologous protein (CHOP) and Noxa, and the small interfering RNA-mediated suppression of CHOP, but not Noxa, markedly attenuates DMC-induced ER dilation and cell death. Interestingly, DMC does not affect the viability, proteasomal activity or CHOP protein levels of human mammary epithelial cells, suggesting that DMC effectively induces paraptosis selectively in breast cancer cells, while sparing normal cells. Taken together, these results suggest that DMC triggers a stronger proteasome inhibition and higher induction of CHOP compared with curcumin, giving it more potent anticancer effects on malignant breast cancer cells.

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Ultrastructural Patterns of the Activated Cell Death Programs in the Human Brain

Cited by 10 publications

References 13 publications

Activation of autophagy and paraptosis in retinal ganglion cells after retinal ischemia and reperfusion injury in rats

Activation of autophagy and paraptosis in retinal ganglion cells after retinal ischemia and reperfusion injury in rats

Fungal metabolite ophiobolin A as a promising anti-glioma agent: In vivo evaluation, structure–activity relationship and unique pyrrolylation of primary amines

Stronger proteasomal inhibition and higher CHOP induction are responsible for more effective induction of paraptosis by dimethoxycurcumin than curcumin

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