Insulin aggregation starts at dynamic triple interfaces, originating from solution agitation

Chouchane, Karim; Frachon, Thibaut; Marichal, Laurent; Nault, Laurent; Vendrely, Charlotte; Maze, Antoine; Brückert, Franz; Weidenhaupt, Marianne

doi:10.1016/j.colsurfb.2022.112451

Cited by 7 publications

(10 citation statements)

References 49 publications

(69 reference statements)

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“…We neglected the difference of PP surface curvature in both geometries, but we kept a motion period that reproduces the conditions of the rotating wheel set-up. No significant protein loss was observed in the dip-coating experiments (Table S5 ), contrary to the observations reported in the case of insulin solutions 24 . Therefore, drying at the triple line zone with PP is certainly not the process responsible for the protein loss measured in the rotating wheel experiment.…”

Section: Resultscontrasting

confidence: 79%

“…It suggests that S/L interface, once passivated by proteins, has a minor effect on proteins destabilization in solution (Table 1 ) and that A/L and/or A/L/S are the determining interfaces. Different studies 24 suggest that the A/L/S moving triple line defines a zone of complex drying phenomena that can induce strong laterals forces 25 and ‘shear’ damage to proteins 3 . To test this hypothesis, we changed the geometry of the system and used a dip coater setup with a PP plate that was vertically immersed and withdrawn in order to reproduce the condition encountered in the rotating wheel agitation experiments at the triple A/L/S line interface (Scheme S2 ).…”

Section: Resultsmentioning

confidence: 99%

“…We are considering here a gentle agitation process. However, the shearing, even if it cannot alter the protein directly, can have two effects: (i) it can increase and decrease transiently the amount of A/L interface (the wavy behaviour 29 ) thus favouring the aggregation at A/L; (ii) it may favour the desorption of adsorbed native or destabilized proteins from the S/L or A/L interfaces 24 , 30 .…”

Section: Resultsmentioning

confidence: 99%

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A proteome scale study reveals how plastic surfaces and agitation promote protein aggregation

Schvartz

Saudrais

Devineau

et al. 2023

Sci Rep

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Protein aggregation in biotherapeutics can reduce their activity and effectiveness. It may also promote immune reactions responsible for severe adverse effects. The impact of plastic materials on protein destabilization is not totally understood. Here, we propose to deconvolve the effects of material surface, air/liquid interface, and agitation to decipher their respective role in protein destabilization and aggregation. We analyzed the effect of polypropylene, TEFLON, glass and LOBIND surfaces on the stability of purified proteins (bovine serum albumin, hemoglobin and α-synuclein) and on a cell extract composed of 6000 soluble proteins during agitation (P = 0.1–1.2 W/kg). Proteomic analysis revealed that chaperonins, intrinsically disordered proteins and ribosomes were more sensitive to the combined effects of material surfaces and agitation while small metabolic oligomers could be protected in the same conditions. Protein loss observations coupled to Raman microscopy, dynamic light scattering and proteomic allowed us to propose a mechanistic model of protein destabilization by plastics. Our results suggest that protein loss is not primarily due to the nucleation of small aggregates in solution, but to the destabilization of proteins exposed to material surfaces and their subsequent aggregation at the sheared air/liquid interface, an effect that cannot be prevented by using LOBIND tubes. A guidance can be established on how to minimize these adverse effects. Remove one of the components of this combined stress - material, air (even partially), or agitation - and proteins will be preserved.

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Section: Resultscontrasting

confidence: 79%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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A proteome scale study reveals how plastic surfaces and agitation promote protein aggregation

Schvartz

Saudrais

Devineau

et al. 2023

Sci Rep

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“…Insulin aggregates’ growth rate was recently found to be proportional to shear stress under agitation, with the insulin aggregation rate correlating with the amount of dynamic triple interfaces, which arise from the contact between air–liquid interfaces with solid surfaces. In these conditions, the meniscus’s continuous movement during agitation leads to the generation of transiently dry areas, causing the partial dehydration of adsorbed proteins that may then aggregate more easily [ 52 ]. Similarly, fibrillation is promoted by mechanical shocks and cavitation, which can occur when pressure waves of sufficient amplitude produce gas bubbles within liquids that rapidly expand and collapse, generating localized regions of high energy dissipation [ 43 ].…”

Section: Insulin Fibrillationmentioning

confidence: 99%

Peptide Inhibitors of Insulin Fibrillation: Current and Future Challenges

Rosetti

Marchesan

2023

IJMS

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Amyloidoses include a large variety of local and systemic diseases that share the common feature of protein unfolding or refolding into amyloid fibrils. The most studied amyloids are those directly involved in neurodegenerative diseases, while others, such as those formed by insulin, are surprisingly far less studied. Insulin is a very important polypeptide that plays a variety of biological roles and, first and foremost, is at the basis of the therapy of diabetic patients. It is well-known that it can form fibrils at the site of injection, leading to inflammation and immune response, in addition to other side effects. In this concise review, we analyze the current knowledge on insulin fibrillation, with a focus on the development of peptide-based inhibitors, which are promising candidates for their biocompatibility but still pose challenges to their effective use in therapy.

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“…After establishing the antioxidant properties of the polymers, we have next examined their insulin fibril inhibiting effects which were initially assessed by fluorescence measurements using a Thioflavin T (ThT) dye. [39,40] ThT-based assay is a commonly used technique to detect the formation of amyloid fibrils as ThT molecules can specifically bind with amyloid protein aggregated species, not with native protein. In the ThT-based fluorescence assay, ThT shows an enhancement in emission intensity upon binding with amyloid fibrils that is relatively proportional to the extent of the formation of fibrils.…”

Section: Thioflavin T (Tht) Fluorescence Measurementsmentioning

confidence: 99%

Antioxidant Polymers with Enhanced Neuroprotection Against Insulin Fibrillation

Bera

Ghosh

et al. 2023

Macromolecular Bioscience

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Lipoic acid (LA) and dihydrolipoic acid (DHLA) are well established antioxidants to scavenge reactive oxygen species (ROS). However, they are carboxylates with ≈4.7 pKa making them negatively charged at physiological pH (7.4) reducing their passive diffusion through cell membranes. LA is known to be capable of reducing protein fibrillation. Incorporation of LA and especially DHLA in polymer side chains are scarce. Herein, the first examples of the anti‐amyloidogenic effect of LA and DHLA incorporated into the side‐chain of a block copolymer with a water‐soluble poly(polyethylene glycol methyl ether methacrylate) (PPEGMA) segment are presented. The resultant polymers show improved ROS scavenging activity and improved ability to reduce insulin fibrillation compared to free LA and DHLA. Furthermore, the resultant polymers are also capable of disintegrating preformed insulin firbrils. Interestingly, polymers with dihydro‐lipoate moieties showed 93% free radical scavenging activity with 91% anti‐fibrillating efficacies for insulin protein confirmed by 2,2‐diphenyl‐1‐picrylhydrazyl (DPPH) assay and Thioflavin T (ThT) dye binding study, respectively. Further, the antioxidant polymers increase the cell viability against fibrillar insulin aggregates that may be involved in the etiology of several diseases. Overall, this work reveals that antioxidant polymer‐based therapeutic agents can serve as a powerful modulation strategy for developing novel drugs in future against amyloid‐related disorders.

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Insulin aggregation starts at dynamic triple interfaces, originating from solution agitation

Cited by 7 publications

References 49 publications

A proteome scale study reveals how plastic surfaces and agitation promote protein aggregation

A proteome scale study reveals how plastic surfaces and agitation promote protein aggregation

Peptide Inhibitors of Insulin Fibrillation: Current and Future Challenges

Antioxidant Polymers with Enhanced Neuroprotection Against Insulin Fibrillation

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