التفاصيل البيبلوغرافية
| العنوان: |
Hemocompatible L-Type amino acid transporter 1 (LAT1)-Utilizing prodrugs of perforin inhibitors can accumulate into the pancreas and alleviate inflammation-induced apoptosis. |
| المؤلفون: |
Tampio, Janne1 (AUTHOR), Markowicz-Piasecka, Magdalena2 (AUTHOR), Huttunen, Kristiina M.1 (AUTHOR) kristiina.huttunen@uef.fi |
| المصدر: |
Chemico-Biological Interactions. Aug2021, Vol. 345, pN.PAG-N.PAG. 1p. |
| مصطلحات موضوعية: |
*ERYTHROCYTES, *PANCREAS, *AMINO acids, *CELL death, *TYPE 1 diabetes, *PRODRUGS |
| مستخلص: |
Cytolytic pore-forming protein, perforin, has been associated with autoimmune destruction of pancreatic β-cells in type 1 diabetes mellitus (T1DM) once released from CD8+ T cells. Curiously, perforinopathy has also been implicated in numerous brain diseases. Therefore, inhibitors of perforin have been in demand with targeted delivery in mind. l -Type amino acid transporter 1 (LAT1) is known to be expressed in both the above-mentioned target tissues, in the pancreas as well as in the brain. Thus, in the present study, the distribution of two LAT1-utilizing prodrugs of investigational perforin inhibitors into the pancreas was explored after intraperitoneal (i.p., 30 μmol/kg) bolus injection to mice. The effects of prodrug 1 were also studied in lipopolysaccharide (LPS)-induced in vitro (50 μg/mL) and in vivo (250 μg/kg x 3 days) apoptosis and pancreatitis models by determining the cellular apoptotic levels with human umbilical vein endothelial cells (HUVEC) and pancreatic caspase-3/-7 activity in mice. Furthermore, the biocompatibility of prodrug 1 was explored in human plasma and towards red blood cells. According to the results, both prodrugs were accumulated more effectively into the pancreas than their parent drugs (in addition to the brain that has been previously reported). Prodrug 1 (30 μmol/kg) also decreased the pancreatic caspase-3/-7 activity (52%) and with 2.5 μM concentration, the number of early and late apoptotic cells (32–53%). Since prodrug 1 was also found to be hemocompatible and not affecting human plasma hemostasis or inducing hemolysis of erythrocytes at the concentration <50 μM, it can be considered biocompatible in systemic circulation and ready to be studied in the future as a dual-acting drug candidate (in the pancreas and brain) in diseases like T1DM with neurodegenerative comorbidities. [Display omitted] • L-type amino acid transporter 1 (LAT1) is highly expressed in the pancreas. • Therefore, LAT1-utilizing prodrugs are accumulated effectively into the pancreas. • LAT1-prodrug of inhibitor of cytolytic perforin reduced induced cellular apoptosis. • The prodrug also decreased pancreatic caspase activity in mice with pancreatitis. • This prodrug was found hemocompatible and safe to be used in systemic circulation. [ABSTRACT FROM AUTHOR] |
| قاعدة البيانات: |
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