Accumulating evidence suggests that deposition of neurotoxic α-synuclein
aggregates in the brain during the development of neurodegenerative diseases like
Parkinson’s disease can be curbed by anti-aggregation strategies that
either disrupt or eliminate toxic aggregates. Curcumin, a dietary polyphenol
exhibits anti-amyloid activity but the use of this polyphenol is limited owing to
its instability. As chemical modifications in curcumin confiscate this limitation,
such efforts are intensively performed to discover molecules with similar but
enhanced stability and superior properties. This study focuses on the inhibitory
effect of two stable analogs of curcumin viz. curcumin pyrazole and curcumin
isoxazole and their derivatives against α-synuclein aggregation,
fibrillization and toxicity. Employing biochemical, biophysical and cell based
assays we discovered that curcumin pyrazole (3) and its derivative
N-(3-Nitrophenylpyrazole) curcumin (15) exhibit remarkable potency in not only
arresting fibrillization and disrupting preformed fibrils but also preventing
formation of A11 conformation in the protein that imparts toxic effects. Compounds 3
and 15 also decreased neurotoxicity associated with fast aggregating A53T mutant
form of α-synuclein. These two analogues of curcumin described here may
therefore be useful therapeutic inhibitors for the treatment of
α-synuclein amyloidosis and toxicity in Parkinson’s disease
and other synucleinopathies.
Inhibition of amyloid formation along with modulation of toxicity employing small molecules is emerging as a potential therapeutic approach for protein misfolding disorders which includes Parkinson's disease, Alzheimer's disease and Multiple System Atrophy etc. Countless current interventional strategies for treating α-synucleinopathies consider using peptidic and non-peptidic inhibitors for arresting fibrillisation, disrupting existing fibrils and reducing associated toxicity. One group of molecules less exploited in this regard are triphenylmethane dyes. Herein we tested the inhibitory effect of two routinely used protein staining dyes viz Coomassie Brilliant blue G (CBBG) and Coomassie Brilliant blue R (CBBR) employing several biophysical and cell based methods. Our results showed that both the dyes not only efficiently inhibit fibrillisation but also disrupt existing fibrils. Nonetheless, only CBBR prevented the appearance of A11 epitopes which are marker of toxicity. Moreover, CBBR was also able to stall fibrillisation of A53T mutant α-synuclein and reduce associated neurotoxicity. This study thus reports the potential of CBBR as a therapeutic molecule.
The pathophysiology of coronavirus disease-19 (COVID-19) is characterized by worsened inflammation because of weakened immunity, causing the infiltration of immune cells, followed by necrosis. Consequently, these pathophysiological changes may lead to a life-threatening decline in perfusion due to hyperplasia of the lungs, instigating severe pneumonia, and causing fatalities. Additionally, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can cause mortality due to viral septic shock, resulting from unrestrained and backfiring immune reactions to the pathogen. Sepsis can cause premature organ failure in COVID-19 patients, as well. Notably, vitamin D and its derivatives and minerals, such as zinc and magnesium, have been reported to improve the immune system against respiratory illnesses. This comprehensive review aims to provide updated mechanistic details of vitamin D and zinc as immunomodulators. Additionally, this review also focuses on their role in respiratory illnesses, while specifically delineating the plausibility of employing them as a preventive and therapeutic agent against current and future pandemics from an immunological perspective. Furthermore, this comprehensive review will attract the attention of health professionals, nutritionists, pharmaceuticals, and scientific communities, as it encourages the use of such micronutrients for therapeutic purposes, as well as promoting their health benefits for a healthy lifestyle and wellbeing.
Integration of optical technologies in biomedical sciences permitted light manipulation at smaller time-length scales for specific detection and imaging of biological entities. Similarly, advances in consumer electronics and wireless telecommunications strengthened the development of affordable and portable point-of-care (POC) optical devices, circumventing the necessity of conventional clinical analyses by trained personnel. However, many of the POC optical technologies translated from bench to bedside require industrial support for their commercialization and dissemination to the population. This review aims to demonstrate the intriguing progress and challenges of emerging POC devices utilizing optics for clinical imaging (depth-resolved and perfusion imaging) and screening (infections, cancer, cardiac health, and haematologic disorders) with a focus on research studies over the previous 3 years. Special attention is given to POC optical devices that can be utilized in resource-constrained environments.
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