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Abstract Prostate cancer (PCa) is the most common invasive malignancy for men in the USA. The incidence and mortality rates of PCa are significantly higher among African American men, as compared to those in Caucasian men. Betulinic acid (BA) is a penta-cyclic triterpenoid that is often found in the bark of several species of plants. It possesses a variety of biological activities, including anti-cancer activities. We examined the cytotoxic effects and endoplasmic reticulum (ER) stress induced by BA and its ionic derivatives with PCa cells derived from African Americans and Caucasian men. The viability of all PCa cells was reduced by the BA compounds, and the cytotoxicity of these BA compounds was independent of ethnicity and androgen dependency. The BA compounds induced modest effects on ER stress proteins when compared with ER stress inducers, tunicamycin and thapsigargin. The induction of glucose regulated protein 78 (GRP78) was largely correlated with the expression of C/EBP homologous protein (CHOP) and cleaved poly [ADP-ribose] polymerase (PARP)/caspase-3 in the PCa cells. In summary, our data demonstrated that BA compounds impaired the growth of PCa cells regardless of ethnicity – through GRP78- and CHOP-independent pathways.
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The Role of NMDA Receptor Partial Antagonist, Carbamathione, as a Therapeutic Agent for Transient Global Ischemia
Carbamathione (Carb), an NMDA glutamate receptor partial antagonist, has potent neuroprotective functions against hypoxia- or ischemia-induced neuronal injury in cell- or animal-based stroke models. We used PC-12 cell cultures as a cell-based model and bilateral carotid artery occlusion (BCAO) for stroke. Whole-cell patch clamp recording in the mouse retinal ganglion cells was performed. Key proteins involved in apoptosis, endoplasmic reticulum (ER) stress, and heat shock proteins were analyzed using immunoblotting. Carb is effective in protecting PC12 cells against glutamate- or hypoxia-induced cell injury. Electrophysiological results show that Carb attenuates NMDA-mediated glutamate currents in the retinal ganglion cells, which results in activation of the AKT signaling pathway and increased expression of pro-cell survival biomarkers, e.g., Hsp 27, P-AKT, and Bcl2 and decreased expression of pro-cell death markers, e.g., Beclin 1, Bax, and Cleaved caspase 3, and ER stress markers, e.g., CHOP, IRE1, XBP1, ATF 4, and eIF2α. Using the BCAO animal stroke model, we found that Carb reduced the brain infarct volume and decreased levels of ER stress markers, GRP 78, CHOP, and at the behavioral level, e.g., a decrease in asymmetric turns and an increase in locomotor activity. These findings for Carb provide promising and rational strategies for stroke therapy.
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- Award ID(s):
- 2126141
- PAR ID:
- 10521658
- Editor(s):
- Fregni, F
- Publisher / Repository:
- MDPI
- Date Published:
- Journal Name:
- Biomedicines
- Edition / Version:
- 1
- Volume:
- 11
- Issue:
- 7
- ISSN:
- 2227-9059
- Page Range / eLocation ID:
- 1885
- Subject(s) / Keyword(s):
- Carbamathione (Carb) glutamate hypoxia endoplasmic reticulum (ER) stress PC-12 cell culture stroke whole-cell patch clamp and bilateral carotid artery occlusion (BCAO)
- Format(s):
- Medium: X Size: 5.2 Other: cxv
- Size(s):
- 5.2
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.3390/biomedicines11071885
