Amyloid cross-seeding between Ab and hIAPP in relation to the pathogenesis of Alzheimer and type 2 diabetes

Amyloid cross-seeding of different amyloid proteins is considered as a highly possible mechanism for exacerbating the transmissible pathogenesis of protein misfolding disease(PMDs)and for explaining a molecular link between different PMDs,including Alzheimer disease(AD)and type 2 diabetes(T2D),AD and Parkinson disease(PD),and AD and prion disease.Among them,AD and T2D are the most prevalent PMDs,affecting millions of people globally,while Ab and hIAPP are the causative peptides responsible for AD and T2D,respectively.Increasing clinical and epidemiological evidences lead to a hypothesis that the cross-seeding of Ab and hIAPP is more biologically responsible for a pathological link between AD and T2D.In this review,we particularly focus on(i)the most recent and important findings of amyloid cross-seeding between Ab and hIAPP from in vitro,in vivo,and in silico studies,(ii)a mechanistic role of structural compatibility and sequence similarity of amyloid proteins(beyond Ab and hIAPP)in amyloid cross-seeding,and(iii)several current challenges and future research directions in this lessstudied field.Review of amyloid cross-seeding hopefully provides some mechanistic understanding of amyloidogenesis and inspires more efforts for the better design of next-generation drugs/strategies to treat different PMDs simultaneously.

Supramolecular approaches for insulin stabilization without prolonged duration of action

Aggregation represents a significant challenge for the long-term formulation stability of insulin therapeutics.The supramolecular PEGylation of insulin with conjugates of cucurbit[7]uril and polyethylene glycol(CB[7]-PEG)has been shown to stabilize insulin formulations by reducing aggregation propensity.Yet prolonged in vivo duration of action,arising from sustained complex formation in the subcutaneous depot,limits the application scope for meal-time insulin uses and could increase hypoglycemic risk several hours after a meal.Supramolecular affinity of CB[7]in binding the B1-Phe residue on insulin is central to supramolecular PEGylation using this approach.Accordingly,here we synthesized N-terminal acid-modified insulin analogs to reduce CB[7]interaction affinity at physiological pH and reduce the duration of action by decreasing the subcutaneous depot effect of the formulation.These insulin analogs show weak to no interaction with CB[7]-PEG at physiological pH but demonstrate high formulation stability at reduced pH.Accordingly,N-terminal modified analogs have in vitro and in vivo bioactivity comparable to native insulin.Furthermore,in a rat model of diabetes,the acid-modified insulin formulated with CB[7]-PEG offers a reduced duration of action compared to native insulin formulated with CB[7]-PEG.This work extends the application of supramolecular PEGylation of insulin to achieve enhanced stability while reducing the risks arising from a subcutaneous depot effect prolonging in vivo duration of action.

A multiscale polymerization framework towards network structure and fracture of double-network hydrogels

Double-network(DN)hydrogels,consisting of two contrasting and interpenetrating polymer networks,are considered as perhaps the toughest soft-wet materials.Current knowledge of DN gels from synthesis methods to toughening mechanisms almost exclusively comes from chemically-linked DN hydrogels by experiments.Molecular modeling and simulations of inhomogeneous DN structure in hydrogels have proved to be extremely challenging.Herein,we developed a new multiscale simulation platform to computationally investigate the early fracture of physically-chemically linked agar/polyacrylamide(agar/PAM)DN hydrogels at a long timescale.A“random walk reactive polymerization”(RWRP)was developed to mimic a radical polymerization process,which enables to construct a physically-chemically linked agar/PAM DN hydrogel from monomers,while conventional and steered MD simulations were conducted to examine the structural-dependent energy dissipation and fracture behaviors at the relax and deformation states.Collective simulation results revealed that energy dissipation of agar/PAM hydrogels was attributed to a combination of the pulling out of agar chains from the DNs,the disruption of massive hydrogen bonds between and within DN structures,and the strong association of water molecules with both networks,thus explaining a different mechanical enhancement of agar/PAM hydrogels.This computational work provided atomic details of network structure,dynamics,solvation,and interactions of a hybrid DN hydrogel,and a different structural-dependent energy dissipation mode and fracture behavior of a hybrid DN hydrogel,which help to design tough hydrogels with new network structures and efficient energy dissipation modes.Additionally,the RWRP algorithm can be generally applied to construct the radical polymerization-produced hydrogels,elastomers,and polymers.