Dissecting the contributions of membrane affinity and bivalency of the spider venom protein DkTx to its sustained mode of TRPV1 activation.

The spider venom protein, double-knot toxin (DkTx), partitions into the cellular membrane and binds bivalently to the pain-sensing ion channel, TRPV1, triggering long-lasting channel activation. In contrast, its monovalent single knots membrane partition poorly and invoke rapidly reversible TRPV1 activation. To discern the contributions of the bivalency and membrane affinity of DkTx to its sustained mode of action, here, we developed diverse toxin variants including those containing truncated linkers between individual knots, precluding bivalent binding. Additionally, by appending the single-knot domains to the Kv2.1 channel-targeting toxin, SGTx, we created monovalent double-knot proteins that demonstrated higher membrane affinity and more sustained TRPV1 activation than the single-knots. We also produced hyper-membrane affinity-possessing tetra-knot proteins, (DkTx)2 and DkTx-(SGTx)2, that demonstrated longer-lasting TRPV1 activation than DkTx, establishing the central role of the membrane affinity of DkTx in endowing it with its sustained TRPV1 activation properties. These results suggest that high membrane affinity-possessing TRPV1 agonists can potentially serve as long-acting analgesics.

Mitigating neuroinflammation in Parkinson's disease: Exploring the role of proinflammatory cytokines and the potential of phytochemicals as natural therapeutics.

Parkinson's disease (PD) is one of the most prevalent neuroinflammatory illnesses, characterized by the progressive loss of neurons in the brain. Proinflammatory cytokines play a key role in initiating and perpetuating neuroinflammation, which can lead to the activation of glial cells and the deregulation of inflammatory pathways, ultimately leading to permanent brain damage. Currently, available drugs for PD mostly alleviate symptoms but do not target underlying inflammatory processes. There is a growing interest in exploring the potential of phytochemicals to mitigate neuroinflammation. Phytochemicals such as resveratrol, apigenin, catechin, anthocyanins, amentoflavone, quercetin, berberine, and genistein have been studied for their ability to scavenge free radicals and reduce proinflammatory cytokine levels in the brain. These plant-derived compounds offer a natural and potentially safe alternative to conventional drugs for managing neuroinflammation in PD and other neurodegenerative diseases. However, further research is necessary to elucidate their underlying mechanisms of action and clinical effectiveness. So, this review delves into the pathophysiology of PD and its intricate relationship with proinflammatory cytokines, and explores how their insidious contributions fuel the disease's initiation and progression via cytokine-dependent signaling pathways. Additionally, we tried to give an account of PD management using existing drugs along with their limitations. Furthermore, our aim is to provide a thorough overview of the diverse groups of phytochemicals, their plentiful sources, and the current understanding of their anti-neuroinflammatory properties. Through this exploration, we posit the innovative idea that consuming nutrient-rich phytochemicals could be an effective approach to preventing and treating PD.