Search

The human islet amyloid polypeptide (hIAPP) tends to misfold and self-assemble to form amyloid fibrils, which has been associated with the loss of function and viability of pancreatic β-cells in type 2 diabetes mellitus (T2DM). The role of hIAPP in the development of insulin resistance (a hallmark of T2DM) in skeletal muscles - the major sites for glucose utilization - needs further investigation. Even though, insulin-resistant conditions have been known to stimulate hIAPP aggregation, the events that lead to the development of insulin resistance due to hIAPP aggregation in skeletal muscles remain unidentified. Here, we have attempted to identify metabolic perturbations in L6 myotubes that were exposed to increasing concentrations of recombinant hIAPP for different time durations. It was observed that hIAPP exposure was associated with increased mitochondrial and cellular ROS levels, loss in mitochondrial membrane potential and viability of the myotubes. Metabolomic investigations of hIAPP-treated myotubes revealed significant perturbations in o-phosphocholine, sn-glycero-3-phosphocholine and dimethylamine levels (p < 0.05). Therefore, we anticipate that defects in glycerophospholipid metabolism and the associated oxidative stress and membrane damage may play key roles in the development of insulin resistance due to protein misfolding in skeletal muscles. In summary, the perturbed metabolites and their pathways have not only the potential to be used as early biomarkers to predict the onset of insulin resistance and T2DM but also as therapeutic targets for the effective management of the same., Competing Interests: Declaration of Competing Interest The authors declare no financial/personal interest or belief that could affect the objectivity and results of this manuscript., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Few synthetic ion transporters have been reported incorporating indole as the core moiety. We have developed a novel bisindole-based transporter capable of efficient transmembrane anion antiport. This system induced cytotoxicity in MCF-7 breast cancer cells via chloride ion homeostasis disruption and the associated ROS generation, mitochondrial membrane depolarization, and lysosomal deacidification.

A novel cis -dioxomolybdenum(VI)-maltolate [MoO 2 (Mal) 2 ] (1) is prepared as a stable molybdopterin model for the biomimetic catalysis of the oxidation of hypoxanthine in acetonitrile-water at room temperature. Compound 1 efficiently catalyzes the oxidation reaction of toluene, diphenylmethane, and styrene. Cyto- and oral-toxicity studies suggest its tremendous potential for application as a molybdenum supplement.

NAD(P)H:quinone acceptor oxidoreductase 1 (NQO1), a detoxifying enzyme overexpressed in tumors, plays a key role in protecting cancer cells against oxidative stress and thus has been considered an attractive candidate for activating prodrug(s). Herein, we report the first use of NQO1 for the selective activation of 'protransporter' systems in cancer cells leading to the induction of apoptosis. Salicylamides, easily synthesizable small molecules, have been effectively used for efficient H + /Cl - symport across lipid membranes. The ion transport activity of salicylamides was efficiently abated by caging the OH group with NQO1 activatable quinones via either ether or ester linkage. The release of active transporters, following the reduction of quinone caged 'protransporters' by NQO1, was verified. Both the transporters and protransporters exhibited significant toxicity towards the MCF-7 breast cancer line, mediated via the induction of oxidative stress, mitochondrial membrane depolarization, and lysosomal deacidification. Induction of cell death via intrinsic apoptotic pathway was verified by monitoring PARP1 cleavage., (© 2023 Wiley-VCH GmbH.)

Fluctuations in the intracellular chloride ion concentration, mediated by synthetic ion transporters, have been known to induce cytotoxicity in cells by disrupting ionic homeostasis. However, the activity of these transporters in modulating autophagy remains largely unexplored. Here, we report a benzoylbenzohydrazide ( 1c ) that self-assembles to form a supramolecular nanochannel lumen that allows selective and efficient transport of chloride ions across the cell membranes, disrupts ion homeostasis, and thus leads to the induction of apoptosis in cancer cells. It is important to note that the transporter was relatively nontoxic to cells of noncancerous origin. 1c was also shown to induce the deacidification of lysosomes, thereby disrupting autophagy in cancer cells. Taken together, these findings provide a rare example of an artificial ion channel that specifically targets cancer cells by induction of apoptosis via disruption of autophagy.

Type 2 diabetes mellitus (T2DM) and other metabolic disorders are often silent and go unnoticed in patients because of the lack of suitable prognostic and diagnostic markers. The current therapeutic regimens available for managing T2DM do not reverse diabetes; instead, they delay the progression of diabetes. Their efficacy (in principle) may be significantly improved if implemented at earlier stages. The misfolding and aggregation of human islet amyloid polypeptide (hIAPP) or amylin has been associated with a gradual decrease in pancreatic β-cell function and mass in patients with T2DM. Hence, hIAPP has been recognized as a therapeutic target for managing T2DM. This review summarizes hIAPP's role in mediating dysfunction and apoptosis in pancreatic β-cells via induction of endoplasmic reticulum stress, oxidative stress, mitochondrial dysfunction, inflammatory cytokine secretion, autophagy blockade, etc. Furthermore, it explores the possibility of using intermediates of the hIAPP aggregation pathway as potential drug targets for T2DM management. Finally, the effects of common antidiabetic molecules and repurposed drugs; other hIAPP mimetics and peptides; small organic molecules and natural compounds; nanoparticles, nanobodies, and quantum dots; metals and metal complexes; and chaperones that have demonstrated potential to inhibit and/or reverse hIAPP aggregation and can, therefore, be further developed for managing T2DM have been discussed., (© 2022 The Author(s).)

α-Synuclein (α-Syn) is an intrinsically disordered presynaptic protein, whose aggregation is critically involved in Parkinson's disease (PD). Many of the currently available drugs for the treatment of PD are not sufficiently effective in preventing progress of the disease and have multiple side-effects. With this background, efficient drug candidates, sulfated polysaccharides from Chlamydomonas reinhardtii (Cr-SPs) were isolated and investigated for their effect on inhibition of α-Syn fibrillation and dissolution of preformed α-Syn fibrillar structures through a combination of spectroscopic and microscopic techniques. The kinetics of α-Syn fibrillation demonstrates that Cr-SPs are very effective in inhibiting α-Syn fibrillation. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis gel-image shows presence of soluble protein in the presence of Cr-SPs after completion of the fibrillation process. The morphological changes associated with fibrillation monitored by transmission electron microscopy showed that Cr-SPs efficiently bind with α-Syn and delay the conversion of α-helical intermediate into β-sheet rich structures. Cr-SPs are also effective even if onset of α-Syn fibrillation has already started and they also have the ability to dissolve pre-formed fibrils. Thus, the current work has substantial therapeutic implications towards unlocking the immense potential of algal products to function as alternative therapeutic agents against PD and other protein aggregation related disorders.

Triphala (Trl) is an ayurvedic formulation used for treating disorders of the digestive, respiratory, and nervous systems. Its anticancer properties have also been documented. We studied effects of Trl on tubulin, a target protein for several anticancer drugs, and systematically elucidated a possible antiproliferative mechanism of action of Trl. Trl inhibited proliferation of HeLa (cervical adenocarcinoma), PANC-1 (pancreatic adenocarcinoma), and MDA-MB-231 (triple-negative breast carcinoma) cells in microgram quantities and strongly suppressed the clonogenicity of HeLa cells. The formulation disrupted secondary conformation of tubulin and inhibited anilino naphthalene sulfonate binding to tubulin. In cells, Trl-tubulin interactions were manifested as a perturbed microtubule network. Acetylation pattern of Trl-treated cellular microtubules indicated persistent stabilization of microtubule dynamics. In addition, Trl interfered with reassembly of the microtubules. Cells treated with Trl eventually underwent programmed cell death as evidenced by annexin-V staining. Our study shows that the effect of aqueous extract of Trl is potent enough to interfere with the assembly dynamics of microtubules, and that Trl can be investigated further for its antitumor potential., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

We report here interesting synergistic effects of proline and sorbitol, two well-known chemical chaperones, in the inhibition of fibrillation of two proteins, insulin and lysozyme. A combination of many biophysical techniques has been used to understand the structural morphology and modes of interaction of the chaperones with the proteins during fibrillation. Both the chaperones establish stronger polar interactions in the elongation and saturation stages of fibrillation compared to that in the native stage. However, when presented as a mixture, we also see contribution of hydrophobic interactions. Thus, a co-operative adjustment of polar and hydrophobic interactions between the chaperones and the protein surface seems to drive the synergistic effects in the fibrillation process. In insulin, this synergy is quantitatively similar in all the stages of the fibrillation process. These observations would have significant implications for understanding protein folding concepts, in general, and for designing combination therapies against protein fibrillation, in particular., Competing Interests: The authors have declared that no competing interests exist.