Insulin glycation coupled with liposomal lipid peroxidation and microglial cell death

Sabokdast, M; Habibi-Rezaei, Mehran; Poursasan, Najmeh; Sabouni, Farzaneh; Ferdousi, Maryam; Azimzadeh-Irani, Effat; Moosavi-Movahedi, Ali Akbar

doi:10.1039/c4ra16420b

RSC Adv.

2015

DOI: 10.1039/c4ra16420b

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Insulin glycation coupled with liposomal lipid peroxidation and microglial cell death

M Sabokdast

Mehran Habibi-Rezaei

Najmeh Poursasan

et al.

Abstract: Type 2 diabetes is characterized jointly by hyperglycemia and hyperinsulinemia, which make insulin prone to glycation then fibrillation.

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Cited by 3 publications

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Enhancing thermal stability of a highly concentrated insulin formulation with Pluronic F-127 for long-term use in microfabricated implantable devices

Chu

et al. 2017

Drug Deliv. and Transl. Res.

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Development of highly concentrated formulations of protein and peptide drugs is a major challenge due to increased susceptibility to aggregation and precipitation. Numerous drug delivery systems including implantable and wearable controlled-release devices require thermally stable formulations with high concentrations due to limited device sizes and long-term use. Herein we report a highly concentrated insulin gel formulation (up to 80 mg/mL, corresponding to 2200 IU/mL), stabilized with a non-ionic amphiphilic triblock copolymer (i.e., Pluronic F-127 (PF-127)). Chemical and physical stability of insulin was found to be improved with increasing polymer concentration, as evidenced by reduced insulin fibrillation, formation of degradation products, and preserved secondary structure as measured by HPLC and circular dichroism spectroscopy, respectively. This formulation exhibits excellent insulin stability for up to 30 days in vitro under conditions of continuous shear at 37 °C, attributable to the amphiphilic properties of the copolymer and increased formulation viscosity. The mechanism of stabilizing insulin structure by PF-127 was investigated by coarse-grained molecular dynamics (CG-MD), all-atom MD, and molecular docking simulations. The computation results revealed that PF-127 could reduce fibrillation of insulin by stabilizing the secondary structure of unfolded insulin and forming hydrophobic interaction with native insulin. The gel formulations contained in microfabricated membrane-reservoir devices released insulin at a constant rate dependent on both membrane porosity and copolymer concentration. Subcutaneous implantation of the gel formulation-containing devices into diabetic rats resulted in normal blood glucose levels for the duration of drug release. These findings suggest that the thermally stable gel formulations are suitable for long-term and implantable drug delivery applications.

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Enhancing thermal stability of a highly concentrated insulin formulation with Pluronic F-127 for long-term use in microfabricated implantable devices

Chu

et al. 2017

Drug Deliv. and Transl. Res.

View full text Add to dashboard Cite

show abstract

Amorphous aggregate adducts of linker histone H1 turn highly immunologic in the cancers of oesophagus, stomach, gall bladder and ovary

Mir

Moinuddin

Habib

2017

International Journal of Biological Macromolecules

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Toxicity of serum albumin on microglia upon seeding effect of amyloid peptide

et al. 2016

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We demonstrate in vitro cross-seeding of bovine serum albumin (BSA) in the presence of Aβ and their cytotoxic effects on microglial cells. To investigate the cross-seeding of BSA in the presence of Aβ fibrils, we examined how Aβ fibrils can function as seeds to trigger and accelerate BSA fibrillogenesis using ThT, intrinsic fluorescence, ANS fluorescence and transmission electron microscopy (TEM). Moreover, the effects of these fibrils on microglial viability were measured using MTT and Annexin V/propidium iodide (PI) staining. Although Aβ is toxic against microglia, it acted as seed and affected the aggregation pathway and accelerated the fibrillogenesis of BSA in vitro, resulted in an enhanced cytotoxic effect in comparison with Aβ or BSA alone. These observations thought to be helpful to understand the molecular mechanism of enhanced toxicity due to the coexistence of the aggregation prone proteins/peptides,. then cross-seeding effect on microglial cells that may involve in neurodegenerative diseases such as Alzheimer's disease (AD).

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Insulin glycation coupled with liposomal lipid peroxidation and microglial cell death

Abstract: Type 2 diabetes is characterized jointly by hyperglycemia and hyperinsulinemia, which make insulin prone to glycation then fibrillation.

Cited by 3 publications

References 41 publications

Enhancing thermal stability of a highly concentrated insulin formulation with Pluronic F-127 for long-term use in microfabricated implantable devices

Enhancing thermal stability of a highly concentrated insulin formulation with Pluronic F-127 for long-term use in microfabricated implantable devices

Amorphous aggregate adducts of linker histone H1 turn highly immunologic in the cancers of oesophagus, stomach, gall bladder and ovary

Toxicity of serum albumin on microglia upon seeding effect of amyloid peptide

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