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Glycation is a nonenzymatic posttranslational modification (PTM) known to be increased in the brains of hyperglycemic patients. Alpha-synuclein (αSN), a central player in the etiology of Parkinson's disease, can be glycated at lysine residues, thereby reducing αSN fibril formation in vitro and modulating αSN aggregation in cells. However, the molecular basis for these effects is unclear. To elucidate this, we investigated the aggregation of αSN modified by eight glycating agents, namely the dicarbonyl compound methylglyoxal (MGO) and the sugars ribose, fructose, mannose, glucose, galactose, sucrose, and lactose. We found that MGO and ribose modify αSN to the greatest extent, and these glycation products are the most efficient inhibitors of fibril formation. We show glycation primarily inhibits elongation rather than nucleation of αSN and has only a modest effect on the level of oligomerization. Furthermore, glycated αSN is not significantly incorporated into fibrils. For both MGO and ribose, we discovered that a level of ~5 modifications per αSN is optimal for inhibition of elongation. The remaining sugars showed a weak but optimal inhibition at ~2 modifications per αSN. We propose that this optimal level balances the affinity for the growing ends of the fibril (which decreases with the extent of modification) with the ability to block incorporation of subsequent αSN subunits (which increases with modification). Our results are not only relevant for other αSN PTMs but also for understanding PTMs affecting other fibrillogenic proteins and may thus open novel avenues for therapeutic intervention in protein aggregation disorders. [ABSTRACT FROM AUTHOR]

Aggregation of the 140-residue protein α-synuclein (αSN) is a key factor in the etiology of Parkinson's disease. Although the intensely anionic C-terminal domain (CTD) of αSN does not form part of the amyloid core region or affect membrane binding ability, truncation or reduction of charges in the CTD promotes fibrillation through as yet unknown mechanisms. Here, we study stepwise truncated CTDs and identify a threshold region around residue 121; constructs shorter than this dramatically increase their fibrillation tendency. Remarkably, these effects persist even when as little as 10% of the truncated variant is mixed with the full-length protein. Increased fibrillation can be explained by a substantial increase in self-replication, most likely via fragmentation. Paradoxically, truncation also suppresses toxic oligomer formation, and oligomers that can be formed by chemical modification show reduced membrane affinity and cytotoxicity. These remarkable changes correlate to the loss of negative electrostatic potential in the CTD and highlight a double-edged electrostatic safety guard. Farzadfard et al. present a comprehensive analysis of a range of C-terminal truncations of aSN, linking the importance of high C-terminus charge for decreased fibrillation rates. The ability to formation oligomers, to disrupt synthetic vesicles and cell toxicity was reduced with truncated aSN, aiding in understanding of the intramolecular interactions of aSN which promote/inhibit aggregation. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Complementary and alternative medicine has been increasingly used to treat chronic illnesses, such as diabetes mellitus. However, various limitations in terms of their application and efficacies exist. Furthermore, there is still much to be done to discover the right herbal medicine for diabetes. Aim of the study This paper aims to evaluate previous herbal studies on the management of diabetes mellitus, to address their strengths and weaknesses and propose a general framework for future studies. Approach and methods Data sources such as PubMed, ScienceDirect, Scopus, SpringerLink, and Wiley were searched, limited to Iran, using 36 search terms such as herbal, traditional, medicine, and phytopharmacy in combination with diabetes and related complications. Reviewed articles were evaluated regarding the use of botanical nomenclature and included information on (1) identity of plants and plant parts used, (2) the processing procedure, and (3) the extraction process. The main outcomes were extracted and then surveyed in terms of the efficacies of herbs in the management of diabetes mellitus. Then a comparative study was performed between Iranian and non-Iranian studies with respect to herbs best studied in Iran. Results Of the 82 herbs studied in Iran, only six herbs were endemic and 19 were studied in detail. Although most of the reviewed herbs were found to decrease the level of blood glucose (BG) and/or glycated hemoglobin (HbA1C) in both Iranian and non-Iranian studies, information on their pharmacological mechanisms is scarce. However, the level of HbA1C was measured in a limited number of clinical trials or animal studies. Available information on both short- and long-term use of studied herbs on diabetes related complications and functions of involved organs as well as comorbid depression and/or simultaneous changes in lifesyle is also insufficient. Furthermore, little or no information on their phytochemical, toxicological, and herb–drug interaction properties is available. It is worth noting that the efficacy of the reviewed herbs has been studied scarcely in both humans and animals regarding both Iranian and non-Iranian studies. A significant number of reviewed articles failed to cite the scientific name of herbs and include information on the processing procedure and the extraction process. Conclusions Treatment of diabetes mellitus as a multifactorial disease using herbal medicines requires a comprehensive approach. In order to discover the right herbal medicine for the management of diabetes many other important factors than the levels of BG, HbA1C and insulin should be considered. According to our criteria, all the reviewed herbs suffered from inadequate investigation in human, animal and in vitro models in this respect, whereas they are worth investigating further. However, more research on endemic plants and the traditional history of herbal medicine is warranted. In our opinion, the pharmacological, toxicological, and phytochemical information should be obtained before clinical trials. Furthermore, information such as botanical scientific nomenclature, side effects, and toxicity will improve the quality and validity of publications in herbal research. In particular, designing a database covering all valid information about herbs and/or diseases will decrease unnecessary costs and increase the efficiency of research. [ABSTRACT FROM AUTHOR]

Herein, an electrochemical label-free biosensor designed for the detection of glycated albumin (GA) using reduced graphene oxide/Au nanoparticles (RGO/AuNPs) modified by anti-GA aptamer. For fast and simple modification of the electrode, the aptamer chain was thiolated. Transition electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) techniques were used to the characterization of synthesized materials. Structural analysis of nanomaterials shows that graphene sheets were synthesized very fine by average thickness of 2.5 nm and Au nanoparticles distributed on the surface of graphene sheets uniformly. Cyclic voltammetry (CV) square wave voltammetry (SWV) and impedance spectroscopy (EIS) were used to electrochemical study of the decorated electrode. Electrochemical studies described the potential of fabricated rGO/AuNPs-aptamer electrode to selectively determine GA properly in buffer solution at the range of 2–10 μg mL−1 by the detection limit of 0.07 μg. mL−1 for GA. Image 1 • Simple and fast immobilization of aptamer on the surface of electrode. • Determination of GA in Hexacyanoferrate and buffer solutions. • Suitable selectivity and high sensitivity for GA. [ABSTRACT FROM AUTHOR]