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Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis are characterized by progressive destruction of neurons and cognitive impairment, and thorough studies have provided evidence that these pathologies have a close relationship to the failure of the blood-brain barrier (BBB). Nattokinase (NK), a protease found in fermented soybeans, has been extensively studied because it displays powerful neuroprotective abilities, which is why current research was reviewed in the present article. It was concluded that there is enough evidence in preclinical studies using experimental animals that NK supplementation can alleviate the condition related to BBB dysfunction, reduce brain inflammation, and improve cognitive ability. Furthermore, the study of NK on the cardiovascular system leads to certain assumptions, which include the impact on vasculature function and the ability to manage blood flow, which is the key feature of BBB integrity. Such assumed mechanisms are fibrinolytic action, anti-inflammatory and antioxidant action, and endothelium function modulation. There are many positive research findings, and it seems that NK may serve as an effective opponent for BBB breakdown; however, a new research level should be taken to disclose the application and therapeutic use of NK in brain neurodegenerative disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Dual leucine zipper kinase (DLK), expressed primarily in neuronal cells, is a regulator of neuronal degeneration in response to cellular stress from chronic disease or neuronal injury. This makes it an attractive target for the treatment of neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, and neuronal injury, such as chemotherapy-induced peripheral neuropathy. Here, we describe the discovery of a potent, selective, brain-penetrant DLK inhibitor, KAI-11101 ( 59 ). Throughout the program's progression, medicinal chemistry challenges such as potency, hERG inhibition, CNS penetration, CYP3A time-dependent inhibition, and kinase selectivity were overcome through the implementation of cutting-edge in silico tools. KAI-11101 displayed an excellent in vitro safety profile and showed neuroprotective properties in an ex vivo axon fragmentation assay as well as dose-dependent activity in a mouse PD model.

14-3-3 proteins play a crucial role in the regulation of protein-protein interactions, impacting various cellular processes and disease mechanisms. Recent advancements have led to the development of stabilizers that enhance the binding of 14-3-3 proteins to clients, presenting promising therapeutic potentials. This perspective provides an updated overview of the latest developments in the field of 14-3-3 stabilizers, with a focus on their design, synthesis, and biological evaluation. We discuss the structural basis for the interaction between 14-3-3 proteins and their ligands, highlighting key modifications that enhance binding affinity and selectivity. Additionally, we explore the therapeutic applications of 14-3-3 stabilizers across major therapeutic areas such as cancer, metabolic disorders, and neurodegenerative diseases. By summarizing recent research findings and technological advancements, this perspective aims to shed light on the current state of 14-3-3 stabilizer developments and outline future directions for optimizing these compounds as effective therapeutic agents.

Nucleotide-binding oligomerization domain (NOD)-, leucine-rich repeat (LRR)-, and pyrin domain (PYD)-containing protein 3 (NLRP3) form an inflammasome by assembling with apoptosis-associated speck-like protein containing a CARD (ASC) and procaspase-1 that plays a pivotal role in various neurodegenerative diseases such as Alzheimer's and Parkinson diseases. We designed native peptides derived from the PYDs of NLRP3 and ASC based on their interfacial interaction to inhibit NLRP3 inflammasome formation. Screening revealed that NP3 , derived from NLRP3, inhibits inflammasome activation. Furthermore, a strategic mutation (F → L) in native peptide NP3 results in MNP2 that selectively binds to PYD of ASC with nanomolar affinity, inhibiting NLRP3 inflammasome formation, interleukin-1β (IL-1β) release, and caspase-1 maturation. MNP2 also reduced potassium (K) and chloride (Cl) ion efflux, key signals in NLRP3 activation, and prevented mitochondrial damage and reactive oxygen species (ROS) production. MNP2 significantly reduced NLRP3 inflammasome formation in neurodegenerative conditions triggered by amyloid-β (Aβ), Tau, and α-Synuclein (α-Syn), suggesting a promising therapeutic strategy for NLRP3-related inflammatory diseases, including neurodegenerative disorders.

Molecular mechanisms of chaperone-mediated autophagy (CMA) constitute essential regulatory elements in cellular homeostasis, encompassing protein quality control, metabolic regulation, cellular signaling cascades, and immunological functions. Perturbations in CMA functionality have been causally associated with various pathological conditions, including neurodegenerative pathologies and neoplastic diseases. Recent advances in targeted protein degradation (TPD) methodologies have demonstrated that engineered degraders incorporating KFERQ-like motifs can facilitate lysosomal translocation and subsequent proteolysis of noncanonical substrates, offering novel therapeutic interventions for both oncological and neurodegenerative disorders. This comprehensive review elucidates the molecular mechanisms, physiological significance, and pathological implications of CMA pathways. Additionally, it provides a critical analysis of contemporary developments in CMA-based degrader technologies, with particular emphasis on their structural determinants, mechanistic principles, and therapeutic applications. The discourse extends to current technical limitations in CMA investigation and identifies key obstacles that must be addressed to advance the development of CMA-targeting therapeutic agents.

Background: Neurodegenerative diseases (NDs) are conditions characterized by irreversible progressive degeneration to the nervous tissue and are usually associated with cognitive decline and functional deficits, especially in elderly. Acetylcholinesterase inhibitors (AChEIs) like donepezil, rivastigmine, and galantamine are commonly prescribed to alleviate cognitive symptoms associated with NDs. However, their long-term impact on slowing structural brain degeneration, particularly hippocampal atrophy, remains unclear., Objective: This systematic review and meta-analysis assess the efficacy of AChEIs in reducing hippocampal atrophy in patients with NDs or clinical syndromes that lead to cognitive decline., Methods: A systematic search of PubMed, Scopus, Web of Science, and Cochrane databases, since inception till 20th August 2024, identified randomized controlled trials (RCTs) and comparative studies that measured hippocampal volume changes in elderly patients with NDs and other clinical syndromes. Random effect model was employed to estimate the pooled atrophy rates. Subgroup analysis was conducted by disease, dosage, and side of the measurement., Results: From 5,943 initially screened studies, nine were included in the review, and six were analyzed in the meta-analysis, encompassing a total of 2,179 participants. The meta-analysis showed that donepezil at a 10 mg dose significantly reduced hippocampal atrophy compared to placebo (SMD = 0.44, 95% CI [0.08 to 0.81], p = 0.01), whereas the 5 mg dose showed no significant effect on hippocampal volume. Overall, pooled results favored donepezil in reducing hippocampal atrophy (SMD = 0.33, p = 0.04), indicating that higher doses are more effective. Among patients with mild cognitive impairment (MCI), both donepezil and vitamin E were associated with a significant reduction in hippocampal atrophy compared to placebo (SMD = 0.27, p = 0.01). In contrast, galantamine did not significantly reduce hippocampal atrophy in the overall analysis, but it was associated with reduced whole brain atrophy in APOE ε4 carriers. Further analysis revealed no significant difference in the reduction of right or left hippocampal atrophy in donepezil-treated patients. These findings suggest that donepezil, particularly at higher doses, may have a protective effect against hippocampal atrophy in patients with AD and MCI, while galantamine's effect may be more limited, especially in certain genetic subgroups., Conclusion: Higher doses of donepezil (10 mg) significantly reduce hippocampal atrophy in Alzheimer's disease and mild cognitive impairment, suggesting potential neuroprotective effects. In contrast, lower doses (5 mg) and galantamine showed no significant impact on hippocampal volume, though galantamine reduced whole brain atrophy in APOE ε4 carriers. Dosage and genetic factors are crucial in determining the efficacy of acetylcholinesterase inhibitors in slowing neurodegeneration., Competing Interests: Declarations. Ethical approval and consent to Participate: For this type of study formal consent is not required. This article does not contain any studies with human participants performed by any of the authors. Consent for publication: Not Applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Reactive oxygen species (ROS) play essential roles in both physiological and pathological processes. Under physiological conditions, appropriate amounts of ROS play an important role in signaling and regulation in cells. However, too much ROS can lead to many health problems, including inflammation, cancer, delayed wound healing, neurodegenerative diseases (such as Parkinson's disease and Alzheimer's disease), and autoimmune diseases, and oxidative stress from excess ROS is also one of the most critical factors in the pathogenesis of cardiovascular and metabolic diseases such as atherosclerosis. Hydrogen gas effectively removes ROS from the body due to its good antioxidant properties, and hydrogen therapy has become a promising gas therapy strategy due to its inherent safety and stability. The combination of nanomaterials can achieve targeted delivery and effective accumulation of hydrogen, and has some ameliorating effects on diseases. Herein, we summarize the use of hydrogen-producing nanomaterials for the treatment of ROS-related diseases and talk about the prospects for the treatment of other ROS-induced disease models, such as acute kidney injury.

Today, herbal drugs are prominent in the pharmaceutical industry due to their well-known therapeutic and side effects. Plant-based compounds often face limitations such as poor solubility, low bioavailability, and instability in physiological environments, restricting their therapeutic efficacy and delivery. Nanotechnology-based solutions, including nanoparticle formulations and advanced delivery systems like liposomes and transfersomes, address these issues by enhancing solubility, stability, bioavailability, and targeted delivery, thereby optimizing the therapeutic potential of phytoactive compounds. Neuroinflammation can be a cause of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, or amyotrophic lateral sclerosis. Consequently, there is a need for the optimal delivery of a pharmacological anti-inflammatory agents to the CNS. Thus, the non-invasive administration of a stable compound at a therapeutic concentration is needed to assure molecule crossing through the blood-brain barrier. Natural resources have more structural diversity and novelty than synthetic compounds, e.g. plant-derived drug products have higher molecular weights, incorporate more oxygen atoms, and are more complex. As a result, plant-derived products have unique features which can be used to effectively modulate neuroinflammation. Therefore, this review aims to identify herbal molecules capable of targeting neuroinflammation and present novel strategies for their efficient delivery., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests. Ethical approval: Not applicable. Consent to participate: Not applicable. Consent to publish: Not applicable., (© 2025. The Author(s), under exclusive licence to Springer Nature B.V.)

Neurodegenerative diseases are a group of disorders characterized by progressive degeneration of discrete groups of neurons causing severe disability. The main risk factor is age, hence their incidence is rapidly increasing worldwide due to the rise in life expectancy. Although the causes of the disease are not identified in about 90% of the cases, in the last decades there has been great progress in understanding the basis for neurodegeneration. Different pathological mechanisms including oxidative stress, mitochondrial dysfunction, alteration in proteostasis and inflammation have been addressed as important contributors to neuronal death. Despite our better understanding of the pathophysiology of these diseases, there is still no cure and available therapies only provide symptomatic relief. In an effort to discover new therapeutic approaches, natural products have aroused interest among researchers given their structural diversity and wide range of biological activities. In this review, we focus on three plant-derived compounds with promising neuroprotective potential that have been traditionally used by folk medicine: the flavonoid quercetin (QCT), the phytocannabinoid cannabidiol (CBD)and the tryptamine N,N-dimethyltryptamine (DMT). These compounds exert neuroprotective effects through different mechanisms of action, some overlapping, but each demonstrating a principal biological activity: QCT as an antioxidant, CBD as an anti-inflammatory, and DMT as a promoter of neuroplasticity. This review summarizes current knowledge on these activities, potential therapeutic benefits of these compounds and their limitations as candidates for neuroprotective therapies. We envision that treatments with QCT, CBD, and DMT could be effective either when combined or when targeting different stages of these diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

Xanthohumol (XN), a bioactive plant flavonoid, is an antioxidant, and as such, it exhibits numerous beneficial properties, including anti-inflammatory, antimicrobial, and antioxidative effects. The main dietary source of XN is beer, where it is introduced through hops. Although the concentration of XN in beer is low, the large quantities of hop-related post-production waste present an opportunity to extract XN residues for technological or pharmaceutical purposes. The presented study focuses on the role of XN in the prevention of neurodegenerative diseases, analyzing its effect at a molecular level and including its signal transduction and metabolism. The paper brings up XN's mechanism of action, potential effects, and experimental and clinical studies on Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Additionally, challenges and future research directions on XN, including its bioavailability, safety, and tolerance, have been discussed.

The cholinergic anti-inflammatory pathway (CAP) is comprised of the vagus nerve, acetylcholine, nicotinic acetylcholine receptors, the spleen, and the splenic nerve. It represents a sophisticated neuroimmune axis that critically regulates the crosstalk between the nervous system and the immune response via the vagus nerve. Here, we provided a nuanced exploration of the CAP's role in curbing inflammatory processes and its broad therapeutic potential across a spectrum of diseases. We meticulously dissect the intricate mechanisms by which the CAP modulates key signaling cascades, including the NF-κB, JAK2/STAT3, MAPK/ERK, PI3K/AKT, COX2/PGE2, and NRF2/HO-1 pathways, which are quintessential in the pathogenesis of various conditions. Additionally, we also summarized the CAP's profound implications in the management of inflammatory diseases, neurodegenerative disorders, metabolic syndromes, and oncological malignancies, elucidating its capacity to mitigate disease severity and progression through sophisticated immune modulation. The modulation of the CAP is suggested as a novel strategy that could potentially transform treatment approaches for a variety of conditions. However, the precise cellular and molecular underpinnings of the CAP's effects, as well as its translatability to clinical settings, remain subjects of ongoing investigation. The review calls for further research to demystify the mechanisms of the CAP and to harness its therapeutic potential fully, with the aim of developing innovative and efficacious treatment modalities that exploit the pathway's unique attributes., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Nature B.V.)

Objective: The study was aimed at the synthesis and pharmacological investigation of (4Z)-4-(2-hydroxybenzylidine)-5-methyl-2-(pyridine-3-ylcarbonyl)-2, 4-dihydro-3H-pyrazole-3-one (IIc) in mice model of scopolamine-induced neurodegeneration and cognition impairment., Methods: The behavioural studies included Y-Maze Test, Water Morris Test, and Novel Object Recognition Test in Albino mice (20-25 g). Scopalamine was used as an inducing agent. The acetylcholinesterase (AChE) inhibitory assay was used to assess the role of the test compounds in vitro. The Crystal Violet Staining (Nissl staining) was used to assess the neuroprotective and antiapoptotic effect through quantifying the number of neurons and viability. The expression of the anti-inflammatory enzyme cyclooxygenase-2 (COX-2), cytokine tumour necrotic factor (TNF-α), key transcription factor producing pro-inflammatory signals nuclear factor kappa B (P-NFkB), and apoptosis marker p-JNK was validated through enzyme-linked immunosorbent assay (ELISA) and immunohistochemical (IHC) analysis. The tested compound reverted cognitive and behavioural impairment through inhibiting scopolamine-induced inflammation and oxidative stress., Key Findings: We found that the compound IIc improved the short-term memory and learning behaviour of the experimental animals. Further investigation into molecular mechanisms showed that this effect was the manifestation of immunomodulatory, antioxidant, and consequently, of downsizing of inflammatory cytokines. These results were further validated through docking analysis., Conclusion: Finally, we conclude that the pyrazolone-nicotinic acid derivative IIc reversed the scopolamine-induced cognitive and behavioural deficits, attributed to acetylcholinesterase inhibition, neuronal recovery, antioxidant potential, and through downregulating the neuroinflammatory mediators p-NF-kB, cytokine TNF-α, and anti-inflammatory enzyme COX-2., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Wogonin, an O-methylated flavonoid extracted from Scutellaria baicalensis, has demonstrated profound neuroprotective effects in a range of central nervous system (CNS) diseases. This review elucidates the pharmacological mechanisms underlying the protective effects of wogonin in CNS diseases, including ischemic stroke, hemorrhagic stroke, traumatic brain injury, epilepsy, anxiety, neurodegenerative diseases, and CNS infections. Wogonin modulates key signaling pathways, such as the MAPK, NF-κB, and ROS pathways, contributing to its anti-inflammatory, antioxidant, and antiapoptotic properties. In ischemic stroke models, wogonin reduces infarct size and enhances neurological outcomes by mitigating inflammation and oxidative stress. For patients with hemorrhagic stroke and traumatic brain injury, it accelerates hematoma regression, mitigates secondary brain damage, and promotes neurogenesis, making it an entirely new treatment option for patients with limited access to this type of therapy. Its anticonvulsant and anxiolytic effects are mediated through GABA-A receptor modulation. Moreover, wogonin shows promise in treating neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease by promoting autophagy and reducing neuroinflammation. Additionally, it exhibits antiviral properties, offering potential benefits against CNS infections. Despite extensive preclinical evidence, further clinical studies are warranted to confirm its efficacy and safety in humans. This review highlights the great therapeutic potential of wogonin in terms of CNS protection. However, despite the substantial preclinical evidence, further large-scale clinical studies are necessary. Future researchers need to further explore the long-term efficacy and safety of wogonin in clinical trials and translate it for early application in the clinical treatment of true CNS disorders., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Hydrogen sulfide has been known to humans for about 300 years and the previous studies emphasize only on its toxic side effects. In the last two decennium, researchers have varied their perspectives and insights towards H 2 S biology based on experimental findings. It has been found that H 2 S is an endogenic gaseous signaling molecule in many organisms and plays a crucial role in many systems and diseases. Early reports suggest that H 2 S as a neuromodulator influences calcium levels within the brain cells which ultimately control memory, learning, and cognition. It has also been observed that some complications in the pathogenesis of neurodegenerative diseases are due to anomalies in the biosynthesis and metabolism of H 2 S. This review focuses on the role of H 2 S in the pathophysiology of major neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and Vascular dementia. H 2 S was observed to have a protective role in the above-mentioned neurological conditions and the H 2 S donor therapy may help in disease management. The H 2 S gas displays a neuroprotective role and protects against cellular damage thereby declining the neurological conditions. Some studies have revealed that treatment with H 2 S donors has improved neuronal damage, restored memory and cognition in animal models. In this review, we have discussed the role of H 2 S donors as neuroprotective agents with examples of some of the natural and synthetic H 2 S donors, and also briefly enumerated the molecules used to detect H 2 S in neurodegenerative diseases., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Glycolysis, present in most organisms, is evolutionarily one of the oldest metabolic pathways. It has great relevance at a physiological level because it is responsible for generating ATP in the cell through the conversion of glucose into pyruvate and reducing nicotinamide adenine dinucleotide (NADH) (that may be fed into the electron chain in the mitochondria to produce additional ATP by oxidative phosphorylation), as well as for producing intermediates that can serve as substrates for other metabolic processes. Glycolysis takes place through 10 consecutive chemical reactions, each of which is catalysed by a specific enzyme. Although energy transduction by glucose metabolism is the main function of this pathway, involvement in virulence, growth, pathogen-host interactions, immunomodulation and adaptation to environmental conditions are other functions attributed to this metabolic pathway. In humans, where glycolysis occurs mainly in the cytosol, the mislocalization of some glycolytic enzymes in various other subcellular locations, as well as alterations in their expression and regulation, has been associated with the development and progression of various diseases. In this review, we describe the role of glycolytic enzymes in the pathogenesis of diseases of clinical interest. In addition, the potential role of these enzymes as targets for drug development and their potential for use as diagnostic and prognostic markers of some pathologies are also discussed.

Neurodegenerative diseases pose significant challenges to healthcare systems globally due to their complex etiology and relentless progression, often rendering conventional treatments ineffective. Recent advances have spotlighted excitatory amino acids, particularly D-amino acids, once considered as products of metabolism of the microbiota or deriving from food intake. This review explores the role of D-amino acids in mitigating excitotoxicity-a process characterized by excessive calcium influx through aberrant N-methyl-D-aspartate receptor (NMDAR) activation, which is implicated in the pathogenesis of diseases like Alzheimer's disease. By providing alternative pathways for neuronal signaling and protecting against excitotoxic damage, D-amino acids offer a novel approach to reversing neurodegenerative trajectories. Future research should focus on elucidating the detailed mechanisms of action of these compounds, evaluating their therapeutic potential through rigorous preclinical and clinical trials, and developing effective delivery systems to optimize their neuroprotective effects. This emerging field holds promise for developing innovative treatment strategies that could significantly improve outcomes for patients with neurodegenerative disorders., Competing Interests: Declarations: All authors read and approved the manuscript, and the manuscript has not been submitted elsewhere nor published in whole or in part. Ethical approval: Not applicable. Human and animal rights: Not applicable. Informed consent: Not applicable. Conflict of interests: The authors have no relevant financial or non-financial interests to disclose. Competing interests: The authors declare no conflict of interest., (© 2024. Fondazione Società Italiana di Neurologia.)

Neurodegenerative diseases are now significant chronic progressive neurological conditions that affect individuals' physical health. Oxidative stress is crucial in the development of these diseases. Among the various neurodegenerative diseases, mitochondrial damage has become a major factor in oxidative stress and disease advancement. During this process, oxidative stress and mitophagy plays an important role. In this paper, we introduced the role of mitophagy and oxidative stress in detail, and expounded the relationship between them. In addition, we summarized the pathogenesis of some neurodegenerative diseases and the mechanism of three antioxidants. The former includes AD, PD, HD and ALS, while the latter includes carnosine, adiponectin and resveratrol. Provide goals and directions for further research and treatment of neurodegenerative diseases. This review summarizes the impact of oxidative stress on neurodegenerative diseases by regulating mitophagy, provides a deeper understanding of their pathological mechanisms, and suggests potential new therapeutic targets., Competing Interests: Conflict of interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Urolithin A, an active precursor derived from the metabolism of ellagitanins in rats and humans, is known for its potential health benefits, including stimulating mitophagy and promoting muscular skeletal function. While experimental studies have demonstrated Urolithin A's potential to enhance cellular health, the detailed molecular interactions through which Urolithin A exerts its effects are not fully elucidated. In this study, we investigated the anti-inflammatory, antioxidation and neuroprotective abilities of Urolithin A in selected targets using molecular docking and molecular dynamics simulation methods. Molecular docking studies revealed the strong affinity for receptors involved in inflammation activities, including human p38 MAP kinase (4DLI) with -10.1 kcal/mol interacting with SER252, LYS249, and ASP294 residues. The binding energy in the 5KIR target was -8.6 kcal/mol, interacting with GLN203 through hydrogen bond, and lastly, 1A9U with an affinity of -6.8 with no hydrogen bond formed with Urolithin A and interacts with van der Waals interactions. In oxidant targets, the influence of Urolithin was observed in 1OG5 with -7.9 kcal/mol interacting with GLN185, PHE447. For the 1M17 target, the binding affinity was -7.7 kcal/mol interacting with THR95 residue and 1ZXM target at -7.4 kcal/mol interacting with TYR36, TYR216, and LEU234 residues. The neuroprotective ability of urolithin A was observed in selected targets for acetylcholinesterase; the binding energy was -9.7 kcal/mol interacting with van der Waals and π interactions; for the 1GQR target, the binding energy was -9.9 kcal/mol interacting with van der Waals and π interactions and for β-amylase (1iyt) the binding energy was -5.5 forming hydrogen bond with SER8, GLN15 residues. Molecular Dynamics simulations at 100 ns of Urolithin A compared with reference 4DLI. The Urolithin A-4DLI complex exhibited greater stability than the reference receptor, as confirmed by RMSD, RMSF, Radius of Gyration, Hydrogen bond, and SASA analyses., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a neurodegenerative pathology caused by accumulation of mutant neuroserpin (NS) polymers inside the endoplasmic reticulum (ER) of neurons, leading to cellular toxicity and neuronal death. To date, there is no cure for FENIB, and only palliative care is available for FENIB patients, underlining the urgency to develop therapeutic strategies. The purpose of this work was to create a cellular system designed for testing small molecules able to reduce the formation of NS polymers. Our results show the generation and characterisation of a novel cell culture model for FENIB based on neural stem progenitor cells (NPCs) with inducible expression of either wild type (WT) or G392E NS, a variant that causes severe FENIB. We also report the use of these novel cell lines to explore the effects of four different proteolysis targeting chimaera (PROTAC) compounds, small bivalent molecules engineered to bind to the E3 ubiquitin ligase cereblon, and to NS through a recruiting motif based on the small molecule embelin. This approach aims to enhance the degradation of mutant NS after retro-translocation to the cytosol by facilitating its targeting to the proteasome. Our results show little toxicity and no variation in NS levels with any of the compounds tested. In conclusion, this work sets the basis for future attempts to identify molecules able to prevent NS accumulation inside the ER of cultured cells., (© 2024 The Author(s). Drug Development Research published by Wiley Periodicals LLC.)

Ethnopharmacological Relevance: Research suggests that traditional Chinese medicine (TCM) holds promise in offering innovative approaches to tackle neurodegenerative disorders. In our endeavor, we conducted a comprehensive bibliometric analysis to delve into the landscape of TCM research within the realm of neurodegenerative diseases, aiming to uncover the present scenario, breadth, and trends in this field. This analysis presents potentially valuable insights for the clinical application of traditional Chinese medicine and provides compelling evidence supporting its efficacy in the treatment of neurodegenerative conditions., Aim of the Study: The incidence of neurodegenerative diseases is on the rise, yet effective treatments are still lacking. Research indicates that TCM could offer novel perspectives for addressing neurodegenerative conditions. Nonetheless, the literature on this topic is intricate and multifaceted, with existing reviews offering only limited coverage. To gain a thorough understanding of TCM research in neurodegenerative diseases, we undertook a bibliometric analysis to explore the current status, scope, and trends in this area., Materials and Methods: A literature search was carried out on April 1, 2024, utilizing the Web of Science Core Collection (WoSCC). Visualization and quantitative analyses were then performed with the assistance of CiteSpace, VOSviewer, and R software., Results: A total of 6856 articles were retrieved in the search. Research on TCM for neurodegenerative diseases commenced in 1989 and has exhibited a notable overall growth since then. Main research contributors include East Asian countries like China, as well as the United States. Through our analysis, we identified 15 highly productive authors, 10 top-tier journals, 13 citation clusters, 11 influential articles, and observed a progression in keyword evolution across 4 distinct categories. In 2020, there was a significant upsurge in the knowledge base, collaboration efforts, and publication output within the field. This field is interdisciplinary: network pharmacology emerges as the cutting-edge paradigm in TCM research, while Alzheimer's disease remains a prominent focus among neurodegenerative conditions due to its evolving etiology. A burst detection analysis unveils that in 2024, the focal points of research convergence between TCM and neurodegenerative diseases lie in two key biological processes or mechanisms: autophagy and microbiota., Conclusions: For the first time, this study quantitatively and visually captures the evolution of TCM in addressing neurodegenerative diseases, showcasing a notable acceleration in recent years. Our findings underscore the pivotal role of interdisciplinary collaboration and the necessity for increased global partnerships. Network pharmacology, leveraging the advancements of the big data era, embraces a holistic and systematic approach as a novel paradigm in exploring traditional Chinese medicine and unraveling their fundamental mechanisms. Three ethnomedical plants-Tianma, Renshen, and Wuweizi-demonstrate the promise of their bioactive compounds in treating neurodegenerative disorders, bolstered by their extensive historical usage for such ailments. Moreover, our intricate analysis of the evolutionary trajectories of key themes such as targets and biomarkers substantially enriches our comprehension of the underlying mechanisms involved., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Celastrol is one of the main active ingredients extracted from the plant Tripterygium wilfordii Hook F. A growing number of studies have shown that celastrol has various pharmacological effects, including anti-inflammation, anti-rheumatism, treatment of neurodegenerative diseases, and anti-tumor. This article systematically summarized the mechanism and role of celastrol in lipid metabolism and obesity, rheumatoid arthritis (RA), osteoarthritis (OA), gouty arthritis, inflammatory bowel disease, neurodegenerative diseases, and cancer and other diseases (such as diabetes, respiratory-related diseases, atherosclerosis, psoriasis, hearing loss, etc.). The celastrol played roles in inflammation response, cell apoptosis, autophagy, ferroptosis, and lipid metabolism mainly by acting on chondrocytes, macrophages, mitochondria, and endoplasmic reticulum (ER) through NF-κB, STAT, MAPK, TLR, PI3K-AKT-mTOR, and other signal pathways. This review could provide a reference for the clinical application and further development and utilization of celastrol., Competing Interests: Declarations. Conflict of interest: The authors declare no conflict of interest., (© 2025. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

This review explores the intricate connections between Drosophila models and the human blood-brain barrier (BBB) with nanoparticle-based approaches for neurological treatment. Drosophila serves as a powerful model organism due to its evolutionary conservation of key biological processes, particularly in the context of the BBB, which is formed by glial cells that share structural and functional similarities with mammalian endothelial cells. Recent advancements in nanoparticle technology have highlighted their potential for effective drug delivery across the BBB, utilizing mechanisms such as passive diffusion, receptor-mediated transcytosis, and carrier-mediated transport. The ability to engineer nanoparticles with specific physicochemical properties-such as size, surface charge, and functionalization-enhances their targeting capabilities, particularly towards astrocytes, which play a crucial role in maintaining BBB integrity and responding to neuroinflammation. Insights gained from Drosophila studies have informed the design of personalized nanomedicine strategies aimed at treating neurodegenerative diseases, including Alzheimer's, Parkinson's disease etc. As research progresses, the integration of findings from Drosophila models with emerging humanized BBB systems will pave the way for innovative therapeutic approaches that improve drug delivery and patient outcomes in neurological disorders., Competing Interests: Declarations. Competing Interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Neurodegenerative disorders are characterized by a progressive decline of specific neuronal populations in the brain and spinal cord, typically containing aggregates of one or more proteins. They can result in behavioral alterations, memory loss and a decline in cognitive and motor abilities. Various pathways and mechanisms have been outlined for the potential treatment of these diseases, where redox regulation is considered as one of the most common druggable targets. For example, in amyotrophic lateral sclerosis (ALS) with superoxide dismutase-1 (SOD1) pathology, there is a downregulation of the antioxidant response nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. TDP-43 proteinopathy in ALS is associated with elevated levels of reactive oxygen species and mitochondrial dyshomeostasis. In ALS with mutant FUS, poly ADP ribose polymerase-dependent X ray repair cross complementing 1/DNA-ligase recruitment to the sites of oxidative DNA damage is affected, thereby causing defects in DNA damage repair. Oxidative stress in Huntington's disease (HD) with mutant huntingtin accumulation manifests as protein oxidation, metabolic energetics dysfunction, metal ion dyshomeostasis, DNA damage and mitochondrial dysfunction. The impact of oxidative stress in the progression of these diseases further warrants studies into the role of antioxidants in their treatment. While an antioxidant, edaravone, has been approved for therapeutics of ALS, numerous antioxidant molecules failed to pass the clinical trials despite promising initial studies. In this review, we summarize the oxidative stress pathways and redox modulators that are investigated in ALS and HD using various models., Competing Interests: Declaration of competing interest All authors declare that there are no conflicts of interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The ubiquitin-proteasome system (UPS) is an important type of protein post-translational modification that affects the quantity and quality of various proteins and influences cellular processes such as the cell cycle, transcription, oxidative stress, and autophagy. Nanomaterials (NMs), which exhibit excellent physicochemical properties, can directly interact with the UPS and act as molecular-targeted drugs to induce changes in biological processes. This review provides an overview of the influence of NMs on the UPS of misfolded proteins and key proteins, which are related to cancer, neurodegenerative diseases and oxidative stress. This review also summarizes the role of modification processes involved in ubiquitination the biological effects of NMs and the mechanism of such effects of NMs through regulation of the UPS. This review deepens our understanding of the influence of NMs on the protein degradation process and provides new potential therapeutic targets for disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Neurodegenerative diseases (NDs) are caused by the gradual decline of neuronal structure and function, which presents significant challenges in treatment. Cellular stress responses significantly impact the pathophysiology of these disorders, often exacerbating neuronal damage. Plant-derived flavonoids have demonstrated potential as neuroprotective agents due to their potent anti-inflammatory, anti-apoptotic, and antioxidant properties. This review provides an in-depth analysis of the molecular processes and clinical insights that cause the neuroprotective properties of flavonoids in NDs. By controlling essential signaling pathways such as Nrf2/ARE, MAPK, and PI3K/Akt, flavonoids can lower cellular stress and improve neuronal survival. The study discusses the challenges of implementing these discoveries in clinical practice and emphasizes the therapeutic potential of specific flavonoids and their derivatives. Flavonoids are identified as potential therapeutic agents for NDs, potentially slowing progression by regulating cellular stress and improving neuroprotection despite their potential medicinal uses and clinical challenges. The study designed a strategy to identify literature published in prestigious journals, utilizing search results from PubMed, Scopus, and WOS. We selected and investigated original studies, review articles, and research reports published until 2024. It suggests future research and therapeutic approaches to effectively utilize the neuroprotective properties of flavonoids., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

NMDAR antagonists, such as memantine and ketamine, have shown efficacy in treating neurodegenerative diseases and major depression. The mechanism by which these drugs correct the aforementioned diseases is still unknown. Our study reveals that these antagonists significantly enhance 20S proteasome activity, crucial for degrading intrinsically disordered, oxidatively damaged, or misfolded proteins, factors pivotal in neurodegenerative diseases like Alzheimer's and Parkinson's. In our mouse model experiment, ketamine administration notably altered brain synaptic protein profiles within two hours, significantly downregulating proteins strongly associated with Alzheimer's and Parkinson's diseases. Furthermore, the altered proteins exhibited enrichment in terms related to plasticity and potentiation, including retrograde endocannabinoid signaling-a pivotal pathway in both short- and long-term plasticity that may elucidate the long-lasting effects of ketamine in major depression. Via the ubiquitin-independent 20S proteasome pathway (UIPS), these drugs maintain cellular protein homeostasis, which is crucial as proteasome activity declines with age, leading to protein aggregation and disease symptoms. Therefore, these findings hold promise for new treatment options not only for brain diseases but also for other systemic conditions associated with unfolded or misfolded proteins., Competing Interests: Declarations. Competing interests: FS is the inventor of the “Enhancing Proteasome Activity by NMDAR Antagonists Explains Their Therapeutic Effect in Neurodegenerative and Mental Diseases” mentioned in this publication. The patent application was filed by FS. The other authors do not have any competing interests., (© 2025. The Author(s).)

In recent decades, the scientific community has faced a major challenge in the search for new therapies that can slow down or alleviate the process of neuronal death that accompanies neurodegenerative diseases. This study aimed to identify an effective therapy using neurotrophic factors to delay the rapid and aggressive cerebellar degeneration experienced by the Purkinje Cell Degeneration (PCD) mouse, a model of childhood-onset neurodegeneration with cerebellar atrophy (CONDCA). Initially, we analyzed the changes in the expression of several neurotrophic factors related to the degenerative process itself, identifying changes in insulin-like growth factor 1 (IGF-1) and Vascular Endothelial Growth Factor B (VEGF-B) in the affected animals. Then, we administered pharmacological treatments using human recombinant IGF-1 (rhIGF-1) or VEGF-B (rhVEGF-B) proteins, considering their temporal variations during the degenerative process. The effects of these treatments on motor, cognitive, and social behavior, as well as on cerebellar destructuration were analyzed. Whereas treatment with rhIGF-1 did not demonstrate any neuroprotective effect, rhVEGF-B administration at moderate dosages stopped the process of neuronal death and restored motor, cognitive, and social functions altered in PCD mice (and CONDCA patients). However, increasing the frequency of rhVEGF-B administration had a detrimental effect on Purkinje cell survival, suggesting an inverted U-shaped dose-response curve of this substance. Additionally, we demonstrate that this neuroprotective effect was achieved through a partial inhibition or delay of apoptosis. These findings provide strong evidence supporting the use of rhVEGF-B as a pharmacological agent to limit severe cerebellar neurodegenerative processes.

The incidence of neurodegenerative diseases (NDs) has increased recently. However, most of the current governance strategies are palliative and lack effective therapeutic drugs. Therefore, elucidating the pathological mechanism of NDs is the key to the development of targeted drugs. As a member of the tyrosine phosphatase family, the role of Shp2 has been studied in tumors, but the research in the nervous system is still in a sporadic state. It can be phosphorylated by tyrosine kinases and then positively regulate tyrosine kinase-dependent signaling pathways. It could also be used as an adaptor protein to mediate downstream signaling pathways. Most of the existing studies have shown that Shp2 may be a potential molecular "checkpoint" against NDs, but its role in promoting degenerative lesions is difficult to ignore as well, and its two-way effect of both activation and inhibition is very distinctive. Shp2 is closely related to NDs-related pathogenic factors such as oxidative stress, mitochondrial dysfunction, excitatory toxicity, immune inflammation, apoptosis, and autophagy. Its bidirectional effects interfere with these pathogenic factors, making it a core component of the feedback and crosstalk network between multiple signaling pathways. Therefore, this article reviews the molecular mechanism of Shp2 regulation in NDs and its regulatory role in various pathogenic factors, providing evidence for the treatment of NDs by targeting Shp2 and the development of molecular targeted drugs., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Cells orchestrate their processes through complex interactions, precisely organizing biomolecules in space and time. Recent discoveries have highlighted the crucial role of biomolecular condensates-membrane-less assemblies formed through the condensation of proteins, nucleic acids, and other molecules-in driving efficient and dynamic cellular processes. These condensates are integral to various physiological functions, such as gene expression and intracellular signal transduction, enabling rapid and finely tuned cellular responses. Their ability to regulate cellular signaling pathways is particularly significant, as it requires a careful balance between flexibility and precision. Disruption of this balance can lead to pathological conditions, including neurodegenerative diseases, cancer, and viral infections. Consequently, biomolecular condensates have emerged as promising therapeutic targets, with the potential to offer novel approaches to disease treatment. In this review, we present the recent insights into the regulatory mechanisms by which biomolecular condensates influence intracellular signaling pathways, their roles in health and disease, and potential strategies for modulating condensate dynamics as a therapeutic approach. Understanding these emerging principles may provide valuable directions for developing effective treatments targeting the aberrant behavior of biomolecular condensates in various diseases., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Oxidative stress and neuroinflammation are recognized as key factors in the development of neurodegenerative diseases, yet effective interventions and biomarkers to address oxidative stress and neuroinflammation in these conditions are limited. Uric acid (UA), traditionally associated with gout, is now gaining prominence as a potential target in neurodegenerative diseases. Soluble UA stands out as one of the most vital antioxidant compounds produced by the human body, accounting for up to 55% of the extracellular capacity to neutralize free radicals. While there is increasing evidence supporting the neuroprotective properties of UA in Parkinson's disease and Alzheimer's disease, gaps in knowledge still exist regarding the underlying mechanisms and how to effectively translate these benefits into clinical practice. Moreover, the current UA elevation therapy exhibits unstable antioxidant properties, individual variability, and even adverse effects, limiting its potential clinical applications. This review consolidates recent advancements in understanding how UA exerts neuroprotective effects on neurodegenerative diseases and emphasizes the dual roles of UA in managing oxidative stress and neuroinflammation. Additionally, the review elucidates the mechanisms through which UA confers neuroprotection. Based on this, the review underscores the significance of UA as a potential biomarker and aims to provide a comprehensive understanding of its potential as a therapeutic target, while also addressing possible challenges to clinical implementation., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Current FDA-approved drugs for neurodegenerative diseases primarily aim to reduce pathological protein aggregation or alleviate symptoms by enhancing neurotransmitter signaling. However, outcomes remain suboptimal and often fail to modify the course of neurodegenerative diseases. Acute neurologic injury that occurs in stroke and traumatic brain injury (TBI) also suffer from inadequate therapies to prevent neuronal cell death, resulting from both the acute insult and the subsequent reperfusion injury following recanalization of the occlusion in stroke. Approaches to prevent neuronal loss in neurodegenerative disease and acute neurologic injury hold significant therapeutic promise. Parthanatos is a cell death pathway that is activated and plays an integral role in these neurologic disorders. Parthanatos-associated apoptosis-inducing factor nuclease (PAAN), also known as macrophage migration inhibitory factor (MIF) nuclease, is the final executioner in the parthanatic cell death cascade. We posit that inhibiting parthanatos by blocking MIF nuclease activity offers a promising and precise strategy to prevent neuronal cell death in both chronic neurodegenerative disease and acute neurologic injury. In this chapter, we discuss the role of MIF's nuclease activity - distinct from its other enzymatic activities - in driving cell death that occurs in various neurological diseases. We also delve into the discovery, screening, structure, and function of MIF nuclease inhibitors, which have demonstrated neuroprotection in Parkinson's disease (PD) cell and mouse models. This analysis includes essential future research directions and queries that need to be considered to advance the clinical development of MIF nuclease inhibitors. Ultimately, our discussion aims to inspire drug development centered around inhibiting MIF's nuclease activity, potentially resulting in transformative, disease-modifying therapeutics., Competing Interests: Conflict of interest statement T.M.D. and V.L.D. have filed patents on MIF nuclease inhibitors to treat neurologic disorders and disorders characterized by activation of parthanatos., (Copyright © 2025. Published by Elsevier Inc.)

The multifaceted nature of the neurodegenerative diseases, as Alzheimer's disease (AD) and Parkinson's disease (PD) with several interconnected etiologies, and the absence of effective drugs, led herein to the development and study of a series of multi-target directed ligands (MTDLs). The developed RIV-IND hybrids, derived from the conjugation of an approved anti-AD drug, rivastigmine (RIV), with melatonin analogues, namely indole (IND) derivatives, revealed multifunctional properties, by associating the cholinesterase inhibition of the RIV drug with antioxidant activity, biometal (Cu(II), Zn(II), Fe(III)) chelation properties, inhibition of amyloid-β (Aβ) aggregation (self- and Cu-induced) and of monoamine oxidases (MAOs), as well as neuroprotection capacity in cell models of AD and PD. In particular, two hybrids with hydroxyl-substituted indoles (5a2 and 5a3) could be promising multifunctional compounds that inspire further development of novel anti-neurodegenerative drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Oxidative stress, or the chronic generation of reactive oxygen species (ROS), is thought to contribute to the progression of aging and aging related diseases. However, low degree of ROS generation has repeatedly been shown to be associated with beneficial outcomes via activation of protective signaling pathways. Berberine, a natural alkaloid isolated from Rhizomacoptidis, has a long history of medicinal use in both Ayurvedic and traditional Chinese medicine, which possesses anti-cancer, anti-inflammatory and anti-neurodegenerative properties. In this study, we utilize Caenorhabditis elegans to examine the mechanisms by which berberine influences healthspan and neurodegenerative diseases. We find that 10 μM berberine significantly extends healthy lifespan in wild type C. elegans. We further show that berberine generates ROS, which is followed by activation of PMK-1/SKN-1 to extend healthspan. Intriguingly, berberine also delays neurodegenerative diseases such as Alzheimer's and polyglutamine diseases in a PMK-1/SKN-1dependent manner. Our work suggests that berberine may be a viable candidate for the prevention and treatment of aging and aging related diseases., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Acute nerve agent exposure can kill a person within minutes or produce multiple neurotoxic effects and subsequent brain damage with potential long-term adverse outcomes. Recent abuse of nerve-agents on Syrian civilians, during Japan terrorist attacks, and personal assassinations in the UK, and Malaysia indicate their potential threat to world population. Existing nerve agent antidotes offer only incomplete protection especially, if the treatment is delayed. To develop the effective drugs, it is advantageous to elucidate the underlying mechanisms of nerve agent-induced multiple neurological impairments. This study aimed to investigate the molecular basis of neuroinflammation during nerve agent toxicity with focus on inflammasome-associated proteins and neurodegeneration. In rats, NOD-like receptor family pyrin domain containing 3 (NLRP3), and glial fibrillary acidic protein (GFAP) immunoreactivity levels were considerably increased in the hippocampus, piriform cortex, and amygdala areas after single subcutaneous soman exposure (90 µg/kg -1 ). Western analysis indicated a notable increase in the neuroinflammatory indicator proteins, high mobility group box 1 (HMGB1) and inducible nitric oxide synthase (iNOS) levels. The presence of fluorojade-C-stained degenerating neurons in distinct rat brain areas is indicating the neurodegeneration during nerve agent toxicity. Pre-treatment with galantamine (3 mg/kg, - 30 min) followed by post-treatment of atropine (10 mg/kg, i.m.) and midazolam (5 mg/kg, i.m.), has completely protected animals from death induced by supra-lethal dose of soman (2XLD 50 ) and reduced the neuroinflammatory and neurodegenerative changes. Results highlight that this new prophylactic and therapeutic drug combination might be an effective treatment option for soldiers deployed in conflict areas and first responders dealing with accidental/deliberate release of nerve agents., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics Approval: Animals used in this study were treated as per all animal protocols were approved by the Institutional Animals Ethics Committee (No.37/1999/CPCSEA) in accordance with the PCA Acts of 1960 and 1998. The care and maintenance of animals were in accordance the Committee for the Purpose of Control of Experimental Animals (CPCSEA, India) guidelines, which are in line with the international criteria of the National Research Council’s Guide for the Care and Use of Laboratory Animals. Consent for Publication: All authors gave consent to the manuscript for submission/publication., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Uncaria tomentosa is a traditional medicinal herb renowned for its anti-inflammatory, antioxidant, and immune-enhancing properties. In the realm of neurodegenerative diseases (NDDS), CLASP proteins, responsible for regulating microtubule dynamics in neurons, have emerged as critical players. Dysregulation of CLASP proteins is associated with NDDS, such as Alzheimer's, Parkinson's, and Huntington's diseases. Consequently, comprehending the role of CLASP proteins in NDDS holds promise for the development of innovative therapeutic interventions., Objectives: The objectives of the research were to identify phytoconstituents in the hydroalcoholic extract of Uncaria tomentosa (HEUT), to evaluate its antioxidant potential through in vitro free radical scavenging assays and to explore its potential interaction with CLASP using in silico molecular docking studies., Methods: HPLC and LC-MS techniques were used to identify and quantify phytochemicals in HEUT. The antioxidant potential was assessed through DPPH, ferric reducing antioxidant power (FRAP), nitric oxide (NO) and superoxide (SO) free radical scavenging methods. Interactions between conventional quinovic acid, chlorogenic acid, epicatechin, corynoxeine, rhynchophylline and syringic acid and CLASP were studied through in silico molecular docking using Auto Dock 4.2., Results: The HEUT extract demonstrated the highest concentration of quinovic acid derivatives. HEUT exhibited strong free radical-scavenging activity with IC 50 values of 0.113 μg/ml (DPPH) and 9.51 μM (FRAP). It also suppressed NO production by 47.1 ± 0.37% at 40 μg/ml and inhibited 77.3 ± 0.69% of SO generation. Additionally, molecular docking revealed the potential interaction of quinovic acid with CLASP for NDDS., Conclusion: The strong antioxidant potential of HEUT and the interaction of quinovic acid with CLASP protein suggest a promising role in treating NDDS linked to CLASP protein dysregulation., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, pose significant health challenges and economic burdens worldwide. Recent studies have emphasized the potential therapeutic value of activating silent information regulator-1 (SIRT1) in treating these conditions. Resveratrol, a compound known for its ability to potently activate SIRT1, has demonstrated promising neuroprotective effects by targeting the underlying mechanisms of neurodegeneration. In this review, we delve into the crucial role of resveratrol-mediated SIRT1 upregulation in improving neurodegenerative diseases. The role of the activation of SIRT1 by resveratrol was reviewed. Moreover, network pharmacology was used to elucidate the possible mechanisms of resveratrol in these diseases. Activation of SIRT1 by resveratrol had positive effects on neuronal function and survival and alleviated the hallmark features of these diseases, such as protein aggregation, oxidative stress, neuroinflammation, and mitochondrial dysfunction. In terms of network pharmacology, the signaling pathways by which resveratrol protects against different neurodegenerative diseases were slightly different. Although the precise mechanisms underlying the neuroprotective effects of resveratrol and SIRT1 activation remain under investigation, these findings offer valuable insights into potential therapeutic strategies for neurodegenerative diseases., Competing Interests: Declarations. Ethical approval: Not applicable. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Neuronal survival depends on neurotrophins and their receptors. There are two types of neurotrophin receptors: a nonenzymatic, trans-membrane protein of the tumor necrosis factor receptor (TNFR) family-p75 receptor and the tyrosine kinase receptors (TrkR) A, B, and C. Activation of the TrkBR by brain-derived neurotrophic factor (BDNF) or neurotrophin 4/5 (NT-4/5) promotes neuronal survival, differentiation, and synaptic function. It is shown that in the pathogenesis of several neurodegenerative conditions (Alzheimer's disease, Parkinson's disease, Huntington's disease) the BDNF/TrkBR signaling pathway is impaired. Since it is known that GPCRs and TrkR are regulating several cell functions by interacting with each other and generating a cross-communication in this review we have focused on the interaction between different GPCRs and their ligands on BDNF/TrkBR signaling pathway., (© 2024 Wiley Periodicals LLC.)

Introduction: Mitochondrial dysfunction stands as a pivotal feature in neurodegenerative disorders, spurring the quest for targeted therapeutic interventions. This review examines Ubiquitin-Specific Protease 30 (USP30) as a master regulator of mitophagy with therapeutic promise in Alzheimer's disease (AD) and Parkinson's disease (PD). USP30's orchestration of mitophagy pathways, encompassing PINK1-dependent and PINK1-independent mechanisms, forms the crux of this exploration., Method: A systematic literature search was conducted in PubMed, Scopus, and Web of Science, selecting studies that investigated USP's function, inhibitor design, or therapeutic efficacy in AD and PD. Inclusion criteria encompassed mechanistic and preclinical/clinical data, while irrelevant or duplicate references were excluded. Extracted findings were synthesized narratively., Results: USP30 modulates interactions with translocase of outer mitochondrial membrane (TOM) 20, mitochondrial E3 ubiquitin protein ligase 1 (MUL1), and Parkin, thus harmonizing mitochondrial quality control. Emerging novel USP30 inhibitors, racemic phenylalanine derivatives, N-cyano pyrrolidine, and notably, benzosulphonamide class compounds, restore mitophagy, and reduce neurodegenerative phenotypes across diverse models with minimal off-target effects. Modulation of other USPs also influences neurodegenerative disease pathways, offering additional therapeutic avenues., Conclusions: In highlighting the nuanced regulation of mitophagy by USP30, this work heralds a shift toward more precise and effective treatments, paving the way for a new era in the clinical management of neurodegenerative disorders., (© 2025 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Peptide-based therapies have attracted considerable interest in the treatment of cancer, diabetes, bacterial infections, and neurodegenerative diseases due to their promising therapeutic properties and enhanced safety profiles. This review provides a comprehensive overview of the major trends in peptide drug discovery and development, emphasizing preclinical strategies aimed at improving peptide stability, specificity, and pharmacokinetic properties. It assesses the current applications and challenges of peptide-based drugs in these diseases, illustrating the pharmaceutical areas where peptide-based drugs demonstrate significant potential. Furthermore, this review analyzes the obstacles that must be overcome in the future, aiming to provide valuable insights and references for the continued advancement of peptide-based drugs., (Copyright © 2025 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

The anti-aging effects of alpha-lipoic acid (αLA), a natural antioxidant synthesized in human tissues, have attracted a growing interest in recent years. αLA is a short- -chain sulfur-containing fatty acid occurring in the mitochondria of all kinds of eukaryotic cells. Both the oxidized disulfide of αLA and its reduced form (dihydrolipoic acid, DHLA) exhibit prominent antioxidant function. The amount of αLA inside the human body gradually decreases with age resulting in various health disorders. Its lack can be compensated by supplying from external sources such as dietary supplements or medicinal dosage forms. The primary objectives of this study were the analysis of updated information on the latest two-decade research regarding the use of αLA from an anti-aging perspective. The information was collected from PubMed, Wiley Online Library, Scopus, ScienceDirect, SpringerLink, Google Scholar, and clinicaltrials.gov. Numerous in silico, in vitro, in vivo , and clinical studies revealed that αLA shows a protective role in biological systems by direct or indirect reactive oxygen/nitrogen species quenching. αLA demonstrated beneficial properties in the prevention and treatment of many age-related disorders such as neurodegeneration, metabolic disorders, different cancers, nephropathy, infertility, and skin senescence. Its preventive effects in case of Alzheimer's and Parkinson's diseases are of particular interest. Further mechanistic and clinical studies are highly recommended to evaluate the wide spectrum of αLA therapeutic potential that could optimize its dietary intake for prevention and alleviation disorders related to aging., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Neurological conditions encompassing a wide range of disorders pose significant challenges globally. The complex interactions among signaling pathways and molecular elements play pivotal roles in the initiation and progression of neurodegenerative diseases. Isoflavones have emerged as a promising candidate to fight against neurodegenerative diseases. Daidzein, a 7-hydroxy-3-(4-hydroxyphenyl)-chromen-4-one, belongs to the isoflavone class and exhibits a diverse pharmacological profile. It is found primarily in soybeans and soy products, as well as in some other legumes and herbs. Investigations into daidzein have revealed that it confers neuroprotection by inhibiting oxidative stress, inflammation, and apoptosis, which are key contributors to neuronal damage and degeneration. Activating pathways like PI3K/Akt/mTOR and promoting neurotrophic factors like BDNF by daidzein underscore its potential in supporting neuronal function and combating neurodegeneration. Daidzein's effects on dopamine provide further avenues for intervention in conditions like Parkinson's disease. Additionally, the modulation of inflammatory and NRF-2-antioxidant signaling by daidzein reinforces its neuroprotective role. Moreover, daidzein's interaction with receptors and cellular processes like ER-β, GPR30, MAO, VEGF, and GnRH highlights its multifaceted effects across multiple pathways involved in neuroprotection and neuronal function. This review article delves into the mechanistic interplay of various mediators in mediating the neuroprotective effects of daidzein. The review article consolidates and analyzes research published over nearly two decades (2005-2024) from various databases, including PubMed, Scopus, ScienceDirect, and Web of Science, to provide a comprehensive understanding of daidzein's effects and mechanisms in neuroprotection., Competing Interests: Declarations. Ethical approval: This article does not contain any studies with human participants or animals performed by any of the authors. Informed consent: Not applicable. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Ziziphora clinopodioides Lam. (Z. clinopodioides) is a traditional Chinese and ethnic medicine in Xinjiang, China with various therapeutic effects. It is primarily used for conditions such as heart disease, fever with chills, palpitations, and insomnia. Flavonoids are the main medicinal components of Z. clinopodioides, Interestingly, current research has increasingly focused on its neuroprotective effects. This study provides a comprehensive overview of the potential therapeutic applications of Z. clinopodioides and its constituents in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and cerebral ischemia-reperfusion injury. At present, about 25 flavonoids have been isolated and identified from various organs of Z. clinopodioides, including linarin, acacetin, hyperoside, quercetin, apigenin, luteolin, chrysin, kaempferol, baicalein, rutin and others. Modern pharmacological studies have revealed that Z. clinopodioides and its constituents exhibits neuroprotective effects in vitro and in vivo, and the mechanism of action is related to anti-apoptosis, anti-inflammatory, antioxidant, autophagy, endoplasmic reticulum stress and so on. Currently, there is limited research on the extracts of Z. clinopodioides and their potential mechanisms of action in these neurological disorders. It is also important to prioritize research on biosynthetic pathways and chemical modification approaches to fully explore and improve the neuroprotective potential of Z. clinopodioides and its flavonoids and establish a strong foundation for its clinical applications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Neurodegenerative diseases pose a significant health challenge for the elderly. The escalating presence of toxic metals and chemicals in the environment is a potential contributor to central nervous system dysfunction and the onset of neurodegenerative conditions. Transition metals play a crucial role in various pathophysiological mechanisms associated with prevalent neurodegenerative diseases such as Alzheimer's and Parkinson's. Given the ubiquitous exposure to metals from diverse sources in everyday life, the workplace, and the environment, most of the population faces regular contact with different forms of these metals. Disturbances in the levels and homeostasis of certain transition metals are closely linked to the manifestation of neurodegenerative disorders. Oxidative damage further exacerbates the progression of neurological consequences. Presently, there exists no curative therapy for individuals afflicted by neurodegenerative diseases, with treatment approaches primarily focusing on alleviating pathological symptoms. Within the realm of biologically active compounds derived from plants, flavonoids and curcuminoids stand out for their extensively documented antioxidant, antiplatelet, and neuroprotective properties. The utilization of these compounds holds the potential to formulate highly effective therapeutic strategies for managing neurodegenerative diseases. This review provides a comprehensive overview of the impact of abnormal metal levels, particularly copper, iron, and zinc, on the initiation and progression of neurodegenerative diseases. Additionally, it aims to elucidate the potential of fisetin and curcumin to inhibit or decelerate the neurodegenerative process., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics Approval: Not applicable. Consent to Participate: Not applicable. Consent for Publication: Not applicable. Conflict of Interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aim: The purpose of the current study was to explore the virtual library for the screening against Monoamine oxidase (MAO) isoforms. An in-house library of natural based ligands was docked within the active sites of MAO isoforms and their in vitro study was also conducted., Objective: The prime objective of the current study was to screen and validate the natural-based derivatives for MAO inhibitory action with the least adverse effects and get molecular aspects about further structural modifications on the most active leads., Background: The importance of MAOs in controlling the activity of the central nervous system has been extensively studied. Our goal in this work is to identify a prospective natural lead molecule that has a stronger affinity for the MAO enzyme in order to produce a more effective natural candidate for a neurological agent., Methods and Results: In order to get insight into how different categories of natural compounds interact with the targeted protein, we virtually screened the numerous natural compound categories in the current study. Rhamnetin, quercetin, piperine, eugenol, and umbelliferone showed the highest dock scores in the case of MAO-B, with scores of -10.57, -9.938, -9.445, and 7.821, respectively. For MAO-A, umbelliferone, curcumin, caffeic acid, and quercetin, the corresponding dock scores were -8.001, -7.941, -7.357, and -6.658. Additionally, an in vitro MAO inhibitory experiment was utilized to assess the top-ranked compounds with the best docking scores. The most potent Human Monoamine oxidase (hMAO-A) inhibitor, with an IC 50 of 10.98±0.006 M and a selectivity index (SI) of 0.607, was discovered to be the compound umbelliferone. Rhamnetin, the lead chemical, has demonstrated hMAO-B activity with a value of 10.32±0.044 M (SI value of 3.096)., Conclusion: These natural potential ligands have been found remarkable to the standard compounds against MAO-A and MAO-B, and they could be used as a lead chemical in the development of novel therapeutic candidates. The in silico screening results and in vitro hMAO inhibitory efficacy exhibited strong correlations., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Neurodegenerative diseases were mostly perceived as diseases of ageing populations, but now-a-days, these diseases pose a threat to populations of all age groups despite significant improvements in quality of life. Almost all essential oils (EOs) have been reported to have some neuroprotective abilities and have been used as supplements for good mental health over the centuries. This review highlights the therapeutic potential of one such monoterpene phenolic EO, carvacrol (CV), that has the potential to be used as a main therapeutic intervention for neurodegenerative disorders. Three libraries, Google Scholar, PubMed, and ScienceDirect, were explored for research studies related to the neuroprotective roles of CV. All the research articles from these libraries were sorted out, with the first article tracing back to 2009, and the latest article was published in 2024. The positive effects of CV in the treatment of Alzheimer's and Parkinson's Diseases, multiple sclerosis, ischemia, and behavioural disorders have been supported with evidence. This review not only focused on study designs and the pharmacological pathways taken by CV for neuroprotection but also focused on demographics, illustrating the trend of CV research studies in certain countries and the preferences for the use of in vitro or in vivo models in studies. Our review provides useful evidence about the neuroprotective potential of CV; however, a lack of studies was observed regarding CV encapsulation in proper dosage forms, in particular nanoparticles, which could be further explored for CV delivery to the central nervous system.

Disorders, including cancer, metabolic disorders, and neurodegenerative diseases, can threaten human health; therefore, disease prevention is essential. Naringenin, a phytochemical with low toxicity, has been used in various disease prevention studies. This study aimed to comprehensively review the effects of naringenin on human health. First, we introduced the general characteristics of naringenin and its pharmacokinetic features when absorbed in the body. Next, we summarized the inhibitory effects of naringenin on colorectal, gastric, lung, breast, ovarian, cervical, prostate, bladder, liver, pancreatic, and skin cancers in preclinical studies. Lastly, we investigated the inhibitory effects of naringenin on metabolic disorders, including diabetes, obesity, hyperlipidemia, hypertension, cardiac toxicity, hypertrophy, steatosis, liver disease, and arteriosclerosis, as well as on neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. In conclusion, naringenin may serve as a significant natural compound that benefits human health.

Flavonoids are naturally occurring polyphenolic compounds known for their extensive range of biological activities. This review focuses on the inhibitory effects of flavonoids on acetylcholinesterase (AChE) and their potential as therapeutic agents for cognitive dysfunction. AChE, a serine hydrolase that plays a crucial role in cholinergic neurotransmission, is a key target in the treatment of cognitive impairments due to its function in acetylcholine hydrolysis. Natural polyphenolic compounds, particularly flavonoids, have demonstrated significant inhibition of AChE, positioning them as promising alternatives or adjuncts in neuropharmacology. This study specifically examines flavonoids such as quercetin, apigenin, kaempferol, and naringenin, investigating their inhibitory efficacy, binding mechanisms, and additional neuroprotective properties, including their antioxidant and anti-inflammatory effects. In vitro, in vivo, and in silico analyses reveal that these flavonoids effectively interact with both the active and peripheral anionic sites of AChE, resulting in increased acetylcholine levels and the stabilization of cholinergic signaling. Their mechanisms of action extend beyond mere enzymatic inhibition, as they also exhibit antioxidant and anti-amyloidogenic properties, thereby offering a multifaceted approach to neuroprotection. Given these findings, flavonoids hold considerable therapeutic potential as modulators of AChE, with implications for enhancing cognitive function and treating neurodegenerative diseases. Future studies should prioritize the enhancement of flavonoid bioavailability, evaluate their efficacy in clinical settings, and explore their potential synergistic effects when combined with established therapies to fully harness their potential as neurotherapeutic agents.

Chronic diseases, including cardiovascular and neurodegenerative diseases and cancer, are significant global health challenges. Oxidative stress, characterized by an imbalance between reactive oxygen species (ROS) production and antioxidant defenses, is a critical factor in the progression of these pathologies. Lactoferrin (Lf), a multifunctional iron-binding glycoprotein, has emerged as a promising therapeutic agent due to its potent antioxidant, anti-inflammatory, and iron-regulating properties. Lf plays a pivotal role in iron homeostasis by chelating iron, modulating its cellular uptake, and reducing ROS production, thereby mitigating oxidative stress-related tissue damage. Lf also demonstrates neuroprotective potential in diseases like Parkinson's and Alzheimer's, where it alleviates oxidative damage, regulates iron metabolism, and enhances antioxidant defenses. Furthermore, its ability to enhance endogenous antioxidant mechanisms, such as superoxide dismutase and glutathione peroxidase, underscores its systemic protective effects. Lf's anti-inflammatory and antimicrobial activities also contribute to its broad-spectrum protective role in chronic diseases. This review consolidates evidence of Lf's mechanisms in mitigating oxidative stress and highlights its therapeutic potential as a versatile molecule for preventing and managing chronic conditions linked to oxidative damage., Competing Interests: The authors declare no conflicts of interest.

Curcumin is among the most well-studied natural substances, known for its biological actions within the central nervous system, its antioxidant and anti-inflammatory properties, and human health benefits. However, challenges persist in effectively utilising curcumin, addressing its metabolism and passage through the blood-brain barrier (BBB) in therapies targeting cerebrovascular diseases. Current challenges in curcumin's applications revolve around its effects within neoplastic tissues alongside the development of intelligent formulations to enhance its bioavailability. Formulations have been discovered including curcumin's complexes with brain-derived phospholipids and proteins, or its liposomal encapsulation. These novel strategies aim to improve curcumin's bioavailability and stability, and its capability to cross the BBB, thereby potentially enhancing its efficacy in treating cerebrovascular diseases. In summary, this review provides a comprehensive overview of molecular pathways involved in interactions of curcumin and its metabolites, and brain vascular homeostasis. This review explores cellular and molecular current aspects, of curcumin-based effects with an emphasis on curcumin's metabolism and its impact on pathological conditions, such as neurodegenerative diseases, schizophrenia, and cerebral angiopathy. It also highlights the limitations posed by curcumin's poor bioavailability and discusses ongoing efforts to surpass these impediments to harness the full therapeutic potential of curcumin in neurological disorders.

As the proportion of the aging population globally is surging year by year, age-associated diseases, including neurodegenerative, metabolic, and cardiovascular diseases, have recently attracted widespread attention of food scientists and nutritionists. Polymethoxyflavonoids (PMFs), a type of dietary flavonoids, have emerged as potential antiaging candidates owing to their diverse bioactivities, encompassing antioxidant, anti-inflammatory, neuroprotective, and metabolic regulatory effects. Herein, this comprehensive updated review has summarized and discussed the effects of PMFs on aging, and the possible mechanisms that link PMFs-mediated modulation and the prevention or treatment of various aging-related diseases have been elaborated in detail. Furthermore, the biological fate of PMFs have been discussed elaborately from their absorption, distribution, metabolism, and excretion in vivo. Special attention is given to the bioavailability-bioactivity relationship of PMFs, as PMF's biological activity is significantly hampered by poor bioavailability. Overall, all of these conclusions may help in providing a perspective for further study of PMFs on aging.