MnSOD mimic compounds can counteract mechanical stress and islet beta cell apoptosis, although at appropriate concentration ranges.
Pancreatic islets are commonly isolated for research and transplantation without taking into consideration that they undergo mechanical or chemical stress during this process. In order to counteract both types of injuries, the compound AEOL10150, a novel MnSOD mimic, was added during isolation of islet at concentrations ranging from 18 to 100 microM. Mechanical or chemical stress-related pro-apoptotic signals were then studied. We demonstrate that this MnSOD mimic diminishes the negative effects of mechanical stress by blocking insulin impairment, production of non-specific islet beta-cell proteins, transcription of iNOS and FAS, activation of caspase-3 and -9 and, ultimately, apoptosis. Moreover, the effects of the MnSOD mimic on isolated islets were greatly influenced by dosage: the best dose able to fully counteract mechanical stress was found to be 100 microM; doses > or =150 microM were themselves highly toxic for islet cells. On the other hand, rIL-1beta-induced chemical stress is rather complex, and there was no protection in this scenario. Therefore, contrarily to what has been previously reported, MnSOD mimic administration is only capable of counteracting mechanical stress, and not cytokine-induced cytotoxicity, and that this drug acts within a limited concentration range.
Pedullà
Marcella
M
Department of Pediatrics, School of Medicine, Second University of Naples, Italy.
d'Aquino
Riccardo
R
Desiderio
Vincenzo
V
de Francesco
Francesco
F
Puca
Andrew
A
Papaccio
Gianpaolo
G
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D018929:Cell Culture Techniques; D002469:Cell Separation; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000096:biosynthesis; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D053583:Interleukin-1beta / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008665:Metalloporphyrins / Q000494:pharmacology* / Q000633:toxicity; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013314:Stress, Mechanical; D013482:Superoxide Dismutase / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
C472668:AEOL 10150; D000975:Antioxidants; D053222:Fas Ligand Protein; D007328:Insulin; D053583:Interleukin-1beta; D008665:Metalloporphyrins; D012333:RNA, Messenger; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D013482:Superoxide Dismutase; D020169:Caspases