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Chemotherapy-induced neurodegeneration represents a significant challenge in cancer survivorship, manifesting in cognitive impairments that severely affect patients' quality of life. Emerging neuroregenerative therapies offer promise in mitigating these adverse effects, with miRNA-124 playing a pivotal role due to its critical functions in neural differentiation, neurogenesis, and neuroprotection. This review article delves into the innovative approach of using miRNA-124-loaded extracellular vesicles (EVs) encapsulated within hydrogel matrices as a targeted strategy for combating chemotherapy-induced neurodegeneration. We explore the biological underpinnings of miR-124 in neuroregeneration, detailing its mechanisms of action and therapeutic potential. The article further examines the roles and advantages of EVs as natural delivery systems for miRNAs and the application of hydrogel matrices in creating a sustained release environment conducive to neural tissue regeneration. By integrating these advanced materials and biological agents, we highlight a synergistic therapeutic strategy that leverages the bioactive properties of miR-124, the targeting capabilities of EVs, and the supportive framework of hydrogels. Preclinical studies and potential pathways to clinical translation are discussed, alongside the challenges, ethical considerations, and future directions in the field. This comprehensive review underscores the transformative potential of miR-124-loaded EVs in hydrogel matrices, offering insights into their development as a novel and integrative approach for addressing the complexities of chemotherapy-induced neurodegeneration., 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.)

The neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and Spinocerebellar ataxias (SCAs), present an enormous medical, social, financial and scientific problem. Despite intense research into the causes of these disorders, only marginal progress has been made in the clinic and no cures exist for any of them. Most of the scientific effort has been focused on identification of the major causes of these diseases and on developing ways to target them, such as targeting amyloid accumulation for AD or targeting expression of mutant Huntingtin for HD. Calcium (Ca 2+ ) signaling has long been proposed to play an important role in the pathogenesis of neurodegenerative disorders, but blockers of Ca 2+ channels and Ca 2+ signaling proteins have not been translated to clinic primarily due to side effects related to the important roles of target molecules for these compounds at the peripheral tissues. In this review article, we would like to discuss an idea that recently identified positive allosteric modulators (PAMs) of the sarco-endoplasmic reticulum calcium (SERCA) pump may provide a promising approach to develop therapeutic compounds for treatment of these disorders. This hypothesis is supported by the preclinical data obtained with animal models of AD and PD. The first critical test of this idea will be an imminent phase I study that will offer an opportunity to evaluate potential side effects of this class of compounds in humans., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: R.D. is an inventor of the patents US11,730,729, US11,821,626, US10,772,881, and WO2022/020261 “Quinolines that modulate SERCA and their use for treating disease” that describe all of the compounds disclosed herein and are assigned to Neurodon Corporation. Part of the cost of this research was paid for by Neurodon. R.D. is an employee of Neurodon. I.B. is a member of Neurodon SAB. R.D. and I.B. hold Neurodon stock or stock options, (Copyright © 2024 Elsevier Inc. All rights reserved.)

Propionic and methylmalonic acidemias (PAcidemia and MMAcidemia, respectively) are genetic disorders characterized by acute metabolic decompensation and neurological complications. L-carnitine (LC) is effective in reducing toxic metabolites that are related to the pathophysiology of these diseases. Therefore we investigated biomarkers of inflammation (cytokines and C-reactive protein (CRP)), neurodegeneration (BDNF, NCAM-1 and cathepsin-D) and biomolecules oxidation (sulfhydryl content and thiobarbituric acid-reactive species (TBARS)), as well as carnitine concentrations in untreated patients with PAcidemia and MMAcidemia, in patients under treatment with LC and a protein-restricted diet for until 2 years and in patients under the same treatment for more than 2 years. It was verified an increase of CRP, IL-6, IL-8, TNF-α, IL-10, NCAM-1 and cathepsin-D in untreated patients compared to controls. On the other hand, reduced levels of TNF-α, CRP, IL-10, NCAM-1 and cathepsin-D were found in plasma from treated patients, as well as increased concentrations of LC. Furthermore, oxidative biomarkers were increased in untreated patients and were normalized with the prolonged treatment with LC. In conclusion, this work shows, for the first time, that inflammatory and neurodegenerative peripheral biomarkers are increased in patients with PAcidemia and MMAcidemia and that treatment with LC is effective to protect against these alterations., Competing Interests: Declarations Ethics approval This study was approved by the Ethics Committee of Hospital de Clínicas de Porto Alegre, RS, Brazil, and the informed consent was obtained according to the guidelines of the committee (Project number 20230157). All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Consent to participate Informed consent was obtained from all patients for being included in the study. Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Depression is a complex neurological disease that holds many theories on its aetiology and pathophysiology. The monoamine strategy of treating depression with medications to increase levels of monoamines in the (extra)synapse, primarily through the inhibition of monoamine transporters, does not always work, as seen in patients that lack a response to multiple anti-depressant exposures, as well as a lack of depressive symptoms in healthy volunteers exposed to monoamine reduction. Depression is increasingly being understood not as a single condition, but as a complex interplay of adaptations in various systems, including inflammatory responses and neurotransmission pathways in the brain. This understanding has led to the development of the neurodegenerative hypothesis of depression. This hypothesis, which is gaining widespread acceptance posits that both oxidative stress and inflammation play significant roles in the pathophysiology of depression. This article is a review of the literature focused on neuroinflammation in depression, as well as summarised studies of anti-inflammatory and antioxidant effects of antidepressants., Competing Interests: Declaration of competing interest We confirm that the paper has been seen and reviewed by co-authors, approved the submission to the journal. We confirm that there are no conflicts of interest in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The development of durable photosensitizers is pivotal for advancing phototherapeutic applications in biomedicine. Here, we introduce a core-shell azobenzene-spiropyran structure on gold nanoparticles, engineered to enhance singlet oxygen generation. These nano-photosensitizers exhibit increased structural stability and thermal resistance, as demonstrated by slowed O-N-C bond recombination dynamics via in-situ Raman spectroscopy. Notably, the in-situ formation of merocyanine and a light-induced compact shell arrangement extend its half-life from 47 minutes to over 154 hours, significantly boosting singlet oxygen output. The nano-photosensitizer also shows high biocompatibility and notably inhibits tau protein aggregation in neural cells, even with phosphatase inhibitors. Further, it promotes dendritic growth in neuro cells, doubling typical lengths. This work not only advances chemical nanotechnology but also sets a foundation for developing long-lasting phototherapy agents for treating neurodegenerative diseases., (© 2024 Wiley-VCH GmbH.)

Alzheimer's disease (AD) and Parkinson's disease (PD) are multifactorial, chronic diseases involving neurodegeneration. According to recent studies, it is hypothesized that the intraneuronal and postsynaptic accumulation of misfolded proteins such as α-synuclein (α-syn) and tau, responsible for Lewy bodies (LB) and tangles, respectively, disrupts neuron functions. Considering the co-occurrence of α-syn and tau inclusions in the brains of patients afflicted with subtypes of dementia and LB disorders, the discovery and development of small molecules for the inhibition of α-syn and tau aggregation can be a potentially effective strategy to delay neurodegeneration. Urea is a chaotropic agent that alters protein solubilization and hydrophobic interactions and inhibits protein aggregation and precipitation. The presence of three hetero atoms (O/S and N) in proximity can coordinate with neutral, mono, or dianionic groups to form stable complexes in the biological system. Therefore, in this study, we evaluated urea and thiourea linkers with various substitutions on either side of the carbamide or thiocarbamide functionality to compare the aggregation inhibition of α-syn and tau. A thioflavin-T (ThT) fluorescence assay was used to evaluate the level of fibril formation and monitor the anti-aggregation effect of the different compounds. We opted for transmission electron microscopy (TEM) as a direct means to confirm the anti-fibrillar effect. The oligomer formation was monitored via the photoinduced cross-linking of unmodified proteins (PICUP). The anti-inclusion and anti-seeding activities of the best compounds were evaluated using M17D intracellular inclusion and biosensor cell-based assays, respectively. Disaggregation experiments were performed with amyloid plaques extracted from AD brains. The analogues with indole, benzothiazole, or N , N -dimethylphenyl on one side with halo-substituted aromatic moieties had shown less than 15% cutoff fluorescence obtained with the ThT assay. Our lead molecules 6T and 14T reduced α-syn oligomerization dose-dependently based on the PICUP assays but failed at inhibiting tau oligomer formation. The anti-inclusion effect of our lead compounds was confirmed using the M17D neuroblastoma cell model. Compounds 6T and 14T exhibited an anti-seeding effect on tau using biosensor cells. In contrast to the control, disaggregation experiments showed fewer Aβ plaques with our lead molecules (compounds 6T and 14T ). Pharmacokinetics (PK) mice studies demonstrated that these two thiourea-based small molecules have the potential to cross the blood-brain barrier in rodents. Urea and thiourea linkers could be further improved for their PK parameters and studied for the anti-inclusion, anti-seeding, and disaggregation effects using transgenic mice models of neurodegenerative diseases.

Central neurodegenerative disorders (e.g. Alzheimer's disease (AD) and Parkinson's disease (PD)) are tightly associated with extensive neuron loss. Current therapeutic interventions merely mitigate the symptoms of these diseases, falling short of addressing the fundamental issue of neuron loss. Cell reprogramming, involving the transition of a cell from one gene expression profile to another, has made significant strides in the conversion between diverse somatic cell types. This advancement has been facilitated by gene editing techniques or the synergistic application of small molecules, enabling the conversion of glial cells into functional neurons. Despite this progress, the potential for in situ reprogramming of astrocytes in treating neurodegenerative disorders faces challenges such as immune rejection and genotoxicity. A novel avenue emerges through chemical reprogramming of astrocytes utilizing small molecules, circumventing genotoxic effects and unlocking substantial clinical utility. Recent studies have successfully demonstrated the in situ conversion of astrocytes into neurons using small molecules. Nonetheless, these findings have sparked debates, encompassing queries regarding the origin of newborn neurons, pivotal molecular targets, and alterations in metabolic pathways. This review succinctly delineates the background of astrocytes reprogramming, meticulously surveys the principal classes of small molecule combinations employed thus far, and examines the complex signaling pathways they activate. Finally, this article delves into the potential vistas awaiting exploration in the realm of astrocytes chemical reprogramming, heralding a promising future for advancing our understanding and treatment of neurodegenerative diseases., Competing Interests: Declaration of Competing interest All authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Acute inflammation is elicited by lipid and protein mediators in defense of the host following sterile or pathogen-driven injury. A common refrain is that chronic inflammation is a result of incomplete resolution of acute inflammation and behind the etiology of all chronic diseases, including cancer. However, mediators that participate in inflammation are also essential in homeostasis and developmental biology but without eliciting the clinical symptoms of inflammation. This non-inflammatory physiological activity of the so called 'inflammatory' mediators, apparently under the functional balance with anti-inflammatory mediators, is defined as unalamation ( un-ala-mation ). Inflammation in the absence of injury is a result of perturbance in unalamation due to a decrease in the anti-inflammatory mediators rather than an increase in the inflammatory mediators and leads to chronic inflammation. This concept on the etiology of chronic inflammation suggests that treatment of chronic diseases is better achieved by stimulating the endogenous anti-inflammatory mediators instead of inhibiting the 'inflammatory' mediator biosynthesis with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). Furthermore, both 'inflammatory' and anti-inflammatory mediators are present at higher concentrations in the tumor microenvironment compared to normal tissue environments. Since cancer is a proliferative disorder rather than a degenerative disease, it is proposed that heightened unalamation , rather than chronic inflammation, drives tumor growth. This understanding helps explain the inefficacy of NSAIDs as anticancer agents. Finally, inhibition of anti-inflammatory mediator biosynthesis in tumor tissues could imbalance unalamation toward local acute inflammation triggering an immune response to restore homeostasis and away from tumor growth., Competing Interests: The author declares 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 © 2024 Maddipati.)

Phosphodiesterase type 5 (PDE5) is an enzyme primarily found in the smooth muscle of the corpus cavernosum and also highly expressed in the substantia nigra, cerebellum, caudate, hippocampal regions and cerebellar purkinje cells, responsible for selectively breaking down cyclic guanosine monophosphate (cGMP) into 5'-GMP and regulate intracellular cGMP levels. As a second messenger, cyclic GMP enhances signals at postsynaptic receptors and triggers downstream effector molecules, leading to changes in gene expression and neuronal responses. Additionally, cGMP signaling transduction cascade, present in the brain, is also essential for learning and memory processes. Mechanistically, PDE5 inhibitors share structural similarities with cGMP, competitively binding to PDE5 and inhibiting cGMP hydrolysis. This action enhances the effects of nitric oxide, resulting in anti-inflammatory and neuroprotective effects. Neurodegenerative disorders entail the progressive loss of neuron structure, culminating in neuronal cell death, with currently available drugs providing only limited symptomatic relief, rendering neurodegeneration considered incurable. PDE5 inhibitors have recently emerged as a potential therapeutic approach for neurodegeneration, neuroinflammation, and diseases involving cognitive impairment. This review elucidates the principal roles of 3',5'-cyclic adenosine monophosphate (cAMP) and cGMP signaling pathways in neuronal functions, believed to play pivotal roles in the pathogenesis of various neurodegenerative disorders. It provides an updated assessment of PDE5 inhibitors as disease-modifying agents for conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, cerebral ischemia, Huntington's disease, and neuroinflammation. The paper aims to review the current understanding of PDE5 inhibitors, which concurrently regulate both cAMP and cGMP signaling pathways, positing that they may exert complementary and synergistic effects in modifying neurodegeneration, thus presenting a novel direction in therapeutic discovery. Moreover, the review provides critical about biological functions, therapeutic potentials, limitations, challenges, and emerging applications of selective PDE5 inhibitors. This comprehensive overview aims to guide future academic and industrial endeavors in this field., (© 2024 Wiley Periodicals LLC.)

Mitophagy, the selective degradation of mitochondria, is impaired in many neurodegenerative diseases (NDs), resulting in an accumulation of dysfunctional mitochondria and neuronal damage. Although enhancing mitophagy shows promise as a therapeutic strategy, the clinical significance of mitophagy activators remains uncertain due to limited understanding and poor representation of mitophagy in the central nervous system (CNS). This review explores recent insights into which mitophagy pathways to target and the extent of modulation necessary to be therapeutic towards NDs. We also highlight the complexities of mitophagy in the CNS, highlighting the need for disease-relevant models. Last, we outline crucial aspects of in vitro models to consider during drug discovery, aiming to bridge the gap between preclinical research and clinical applications in treating NDs through mitophagy modulation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The incidence of type 2 diabetes mellitus (T2DM) has increased in our society in recent decades as the population ages, and this trend is not expected to revert. This is the same for the incidence of the main neurodegenerative disorders, including the two most common ones, which are, Alzheimer's and Parkinson's disease. Currently, no pharmacological therapies have been developed to revert or cure any of these pathologies. Interestingly, in recent years, an increased number of studies have shown a high co-morbidity between T2DM and neurodegeneration, as well as some common molecular pathways that are affected in both types of diseases. For example, while the etiopathology of T2DM and neurodegenerative disorders is highly complex, mitochondrial dysfunction has been broadly described in the early steps of both diseases; accordingly, this dysfunction has emerged as a plausible molecular link between them. In fact, the prominent role played by mitochondria in the mammalian metabolism of glucose places the physiology of the organelle in a central position to regulate many cellular processes that are affected in both T2DM and neurodegenerative disorders. In this collaborative review, we critically describe the relationship between T2DM and neurodegeneration; making a special emphasis on the mitochondrial mechanisms that could link these diseases. A better understanding of the role of mitochondria on the etiopathology of T2DM and neurodegeneration could pave the way for the development of new pharmacological therapies focused on the regulation of the physiology of the organelle. These therapies could, ultimately, contribute to increase healthspan., Competing Interests: Declaration of Competing Interest Nothing to declare, (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Millions of people worldwide are affected by neurodegenerative diseases and cognitive impairment, which includes dementia, while there are only symptomatic treatments available for this syndrome at present. However, several important prospective drug targets have been identified in recent years that can potentially arrest or even reverse the progression of neurodegenerative diseases. Their natural or synthetic ligands are currently in the experimental stage of drug development. In vitro and preclinical (e.g. using animal models) studies confirm their therapeutic potential, but clinical trials often fail or produce conflicting results. Here, we first review the complexity and typology of dementia, followed by the discussion of currently available treatments, and, finally, some novel molecular and cellular approaches to this problem., (© 2024 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.)

Flavonoids, a commonly consumed natural product, elicit health-benefits such as antioxidant, anti-inflammatory, antiviral, anti-allergic, hepatoprotective, anti-carcinogenic and neuroprotective activities. Several studies have reported the beneficial role of flavonoids in improving memory, learning, and cognition in clinical settings. Their mechanism of action is mediated through the modulation of multiple signalling cascades. This polypharmacology makes them an attractive natural scaffold for designing and developing new effective therapeutics for complex neurological disorders like Alzheimer's disease and Parkinson's disease. Flavonoids are shown to inhibit crucial targets related to neurodegenerative disorders (NDDs), including acetylcholinesterase, butyrylcholinesterase, β-secretase, γ-secretase, α-synuclein, Aβ protein aggregation and neurofibrillary tangles formation. Conserved neuro-signalling pathways related to neurotransmitter biogenesis and inactivation, ease of genetic manipulation and tractability, cost-effectiveness, and their short lifespan make Caenorhabditis elegans one of the most frequently used models in neuroscience research and high-throughput drug screening for neurodegenerative disorders. Here, we critically appraise the neuroprotective activities of different flavonoids based on clinical trials and epidemiological data. This review provides critical insights into the absorption, metabolism, and tissue distribution of various classes of flavonoids, as well as detailed mechanisms of the observed neuroprotective activities at the molecular level, to rationalize the clinical data. We further extend the review to critically evaluate the scope of flavonoids in the disease management of neurodegenerative disorders and review the suitability of C. elegans as a model organism to study the neuroprotective efficacy of flavonoids and natural products., 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 Ltd. All rights reserved.)

Mitochondria functionally degrade as neurons age. Degenerative changes cause inefficient oxidative phosphorylation (OXPHOS) and elevated electron leakage from the electron transport chain (ETC) promoting increased intramitochondrial generation of damaging reactive oxygen and reactive nitrogen species (ROS and RNS). The associated progressive accumulation of molecular damage causes an increasingly rapid decline in mitochondrial physiology contributing to aging. Melatonin, a multifunctional free radical scavenger and indirect antioxidant, is synthesized in the mitochondrial matrix of neurons. Melatonin reduces electron leakage from the ETC and elevates ATP production; it also detoxifies ROS/RNS and via the SIRT3/FOXO pathway it upregulates activities of superoxide dismutase 2 and glutathione peroxidase. Melatonin also influences glucose processing by neurons. In neurogenerative diseases, neurons often adopt Warburg-type metabolism which excludes pyruvate from the mitochondria causing reduced intramitochondrial acetyl coenzyme A production. Acetyl coenzyme A supports the citric acid cycle and OXPHOS. Additionally, acetyl coenzyme A is a required co-substrate for arylalkylamine-N-acetyl transferase, which rate limits melatonin synthesis; therefore, melatonin production is diminished in cells that experience Warburg-type metabolism making mitochondria more vulnerable to oxidative stress. Moreover, endogenously produced melatonin diminishes during aging, further increasing oxidative damage to mitochondrial components. More normal mitochondrial physiology is preserved in aging neurons with melatonin supplementation., 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 B.V. All rights reserved.)

Neurotrophins, such as nerve growth factor and brain-derived neurotrophic factor, play an essential role in the survival of neurons. However, incorporating better features can increase their therapeutic efficacy in neurodegenerative diseases (NDs). Peptidomimetics, which mimic these neurotrophins, show potential for treating NDs. This study emphasizes the use of peptidomimetics from neurotrophins for treating NDs and their benefits. By improving bioavailability and stability, these molecules can completely transform the therapy for NDs. This in-depth review guides researchers and pharmaceutical developers, providing insight into the changing field of neurodegenerative medicine., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Exosomes, extracellular vesicles secreted by various cells, actively participate in intercellular communication by facilitating the exchange of crucial molecular information such as DNA, RNA, and lipids. Within this intricate network, microRNAs, endogenous non-coding small RNAs, emerge as pivotal regulators of post-transcriptional gene expression, significantly influencing the development of neurodegenerative diseases. The historical prominence of traditional Chinese medicine (TCM) in clinical practice in China underscores its enduring significance. Notably, TCM monomers, serving as active constituents within herbal medicine, assume a critical role in the treatment of neurodegenerative diseases, particularly in mitigating oxidative stress, inhibiting apoptosis, and reducing inflammation. This comprehensive review aims to delineate the specific involvement of exosomal microRNAs in various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke, and amyotrophic lateral sclerosis. Furthermore, the exploration extends to the application of TCM monomers, elucidating their efficacy as therapeutic agents in these conditions. Additionally, the review examines the utilization of exosomes as drug delivery carriers in the context of neurodegenerative diseases, providing a nuanced understanding of the potential synergies between TCM and modern therapeutic approaches. This synthesis of knowledge aims to contribute to the advancement of our comprehension of the intricate molecular mechanisms underlying neurodegeneration and the potential therapeutic avenues offered by TCcom interventions., (© 2024 John Wiley & Sons Ltd.)

Neurodegenerative disorders are generally characterized by progressive neuronal loss and cognitive decline, with underlying mechanisms involving oxidative stress, protein aggregation, neuroinflammation, and synaptic dysfunction. Currently, the available treatment options only improve the symptoms of the disease but do not stop disease progression; neurodegeneration. This underscores the urgent need for novel therapeutic strategies targeting multiple neurodegenerative pathways alongside the conventional therapeutic strategies available. Emerging evidence demonstrates that flavones a subgroup of flavonoids found abundantly in various dietary sources, have surfaced as promising candidates for neuroprotection due to their multifaceted pharmacological properties. Flavones possess the potency to modulate these pathophysiological processes through their antioxidant, anti-inflammatory, and neurotrophic activities. Additionally, flavones have been shown to interact with various cellular targets, including receptors and enzymes, to confer neuroprotection. Though there are ample evidence available, the nutraceutical and neuroprotective pharmacodynamics of flavones have not been very well established. Hence, the current review aims to explores the therapeutic potential of flavones as nutraceuticals with neuroprotective effects, focusing on their ability to modulate key pathways implicated in neurodegenerative diseases. The current article also aims to actuate supplementary research into flavones as potential agents for alleviating neurodegeneration and improving patient outcomes in neurodegenerative disorders globally., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The cell cycle is the sequence of events orchestrated by a complex network of cell cycle proteins. Unlike normal cells, mature neurons subsist in a quiescent state of the cell cycle, and aberrant cell cycle activation triggers neuronal death accompanied by neurodegeneration. The periodicity of cell cycle events is choreographed by various mechanisms, including DNA damage repair, oxidative stress, neurotrophin activity, and ubiquitin-mediated degradation. Given the relevance of cell cycle processes in cancer and neurodegeneration, this review delineates the overlapping cell cycle events, signaling pathways, and mechanisms associated with cell cycle aberrations in cancer and the major neurodegenerative disorders. We suggest that dysregulation of some common fundamental signaling processes triggers anomalous cell cycle activation in cancer cells and neurons. We discussed the possible use of cell cycle inhibitors for neurodegenerative disorders and described the associated challenges. We propose that a greater understanding of the common mechanisms driving cell cycle aberrations in cancer and neurodegenerative disorders will open a new avenue for the development of repurposed drugs., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Nanoparticles (NPs) that target multiple transport mechanisms facilitate targeted delivery of active therapeutic agents to the central nervous system (CNS) and improve therapeutic transport and efficacy across the blood-brain barrier (BBB). CNS nanotherapeutics mostly target neurons and endothelial cells, however, microglial immune cells are the first line of defense against neuronal damage and brain infections. Through triggering release of inflammatory cytokines, chemokines and proteases, microglia can however precipitate neurological damage-a significant factor in neurodegenerative diseases. Thus, microglial inhibitory agents are attracting much attention among those researching and developing novel treatments for neurodegenerative disorders. The most established inhibitors of microglia investigated to date are resveratrol, curcumin, quercetin, and minocycline. Thus, there is great interest in developing novel agents that can bypass or easily cross the BBB. One such approach is the use of modified-nanocarriers as, or for, delivery of, therapeutic agents to the brain and wider CNS. For microglial inhibition, polymeric NPs are the preferred vehicles for choice. Here, we summarize the immunologic and neuroinflammatory role of microglia, established microglia inhibitor agents, challenges of CNS drug delivery, and the nanotherapeutics explored for microglia inhibition to date. We also discuss applications of the currently considered "most useful" polymeric NPs for microglial-inhibitor drug delivery in CNS-related diseases., (© 2024 Wiley Periodicals LLC.)

Aberrant Ca 2+ signaling is an early hallmark of multiple neurodegenerative syndromes including Alzheimer's and Parkinson's disease (AD and PD) as well as classes of rare genetic disorders such as Spinocebellar Ataxias. Therapeutic strategies that target aberrant Ca 2+ signals whilst allowing normal neuronal Ca 2+ signals have been a challenge. In a recent study Princen et al., performed a screen in the tauP301L cell model of AD for drugs that could specifically ameliorate the excess Ca 2+ entry observed. They identified a class of compounds referred to as ReS19-T that interact with Septins, previously identified as regulators of the Store-operated Ca 2+ entry channel Orai. Drug treatment of the cellular model, a mouse model and human iPSC derived neurons alleviate cellular and systemic deficits associated with tauP301L. Comparison of Septin filament architecture in disease conditions with and without the drug treatment indicate that excess Ca 2+ entry is a consequence of abnormal Septin filament architecture resulting in aberrant ER-PM contacts. The importance of membrane contacts for maintaining precise cellular signaling has been recognized previously. However, the molecular mechanism by which Septin filaments organize the ER-PM junctions to regulate Ca 2+ entry through Orai remains to be fully understood., Competing Interests: Declaration of competing interest The author declares no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

We investigated whether soticlestat (TAK-935), a newly discovered cholesterol 24-hydroxylase (CH24H) inhibitor now in phase 3 clinical trials for Dravet and Lennox-Gastaut syndromes, has effects on neurodegeneration in both chronic and acute animal models associated with glutamate hyperexcitation. Soticlestat was administered at doses that approximately halve 24S-hydroxycholesterol in both experiments. In the kainic acid (KA)-induced acute hippocampal degeneration model, soticlestat ameliorated inflammatory cytokine expression, hippocampal degeneration, and memory impairment. We ruled out the possibility that soticlestat directly interferes with KA binding to the KA receptor, or that 24S-hydroxycholesterol modulates KA receptor signaling, by conducting receptor binding and cell death assays. In the PS19 chronic degeneration model of tauopathy, treatment effects were observed in neurodegeneration markers. Notably, there was a significant correlation between the levels of brain 24S-hydroxycholesterol and a proinflammatory cytokine, tumor necrosis factor-α, which is implicated in cognitive decline and lowering of seizure threshold. This is the first study demonstrating that CH24H inhibition can alleviate neurodegeneration concomitant with neuroinflammation. Herein, we discuss the interplay among 24S-hydroxycholesterol production, neuroinflammation, and excitotoxicity. Effects on neurodegeneration and neuroinflammation demonstrated in two preclinical models suggest that soticlestat is effective in ameliorating seizures and addressing cognitive dysfunction in seizure disorders., Competing Interests: Declaration of Competing Interest All authors were employees of Takeda Pharmaceutical Company Limited, Fujisawa, Japan at the time of the study., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Autophagy is an evolutionarily conserved turnover process for intracellular substances in eukaryotes, relying on lysosomal (in animals) or vacuolar (in yeast and plants) mechanisms. In the past two decades, emerging evidence suggests that, under specific conditions, autophagy can target particular macromolecules or organelles for degradation, a process termed selective autophagy. Recently, accumulating studies have demonstrated that the abnormality of selective autophagy is closely associated with the occurrence and progression of many human diseases, including neurodegenerative diseases, cancers, metabolic diseases, and cardiovascular diseases., Aim of Review: This review aims at systematically and comprehensively introducing selective autophagy and its role in various diseases, while unravelling the molecular mechanisms of selective autophagy. By providing a theoretical basis for the development of related small-molecule drugs as well as treating related human diseases, this review seeks to contribute to the understanding of selective autophagy and its therapeutic potential., Key Scientific Concepts of Review: In this review, we systematically introduce and dissect the major categories of selective autophagy that have been discovered. We also focus on recent advances in understanding the molecular mechanisms underlying both classical and non-classical selective autophagy. Moreover, the current situation of small-molecule drugs targeting different types of selective autophagy is further summarized, providing valuable insights into the discovery of more candidate small-molecule drugs targeting selective autophagy in the future. On the other hand, we also reveal clinically relevant implementations that are potentially related to selective autophagy, such as predictive approaches and treatments tailored to individual patients., 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. Production and hosting by Elsevier B.V.)

In view of the increasing risk of neurodegenerative diseases, epigenetics plays a fundamental role in the field of neuroscience. Several modifications have been studied including DNA methylation, histone acetylation, histone phosphorylation, etc. Histone acetylation and deacetylation regulate gene expression, and the regular activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs) provides regulatory stages for gene expression and cell cycle. Imbalanced homeostasis in these enzymes causes a detrimental effect on neurophysiological function. Intriguingly, epigenetic remodelling via histone acetylation in certain brain areas has been found to play a key role in the neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. It has been demonstrated that a number of HATs have a role in crucial brain processes such regulating neuronal plasticity and memory formation. The most recent therapeutic methods involve the use of small molecules known as histone deacetylase (HDAC) inhibitors that antagonize HDAC activity thereby increase acetylation levels in order to prevent the loss of HAT function in neurodegenerative disorders. The target specificity of the HDAC inhibitors now in use raises concerns about their applicability, despite the fact that this strategy has demonstrated promising therapeutic outcomes. The aim of this review is to summarize the cross-linking between histone modification and its regulation in the pathogenesis of neurological disorders. Furthermore, these findings also support the notion of new pharmacotherapies that target particular areas of the brain using histone deacetylase inhibitors., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Sleep is a fundamental process essential for reparatory and restorative mechanisms in all organisms. Recent research has linked sleep to various pathological conditions, including cancer and neurodegeneration, which are associated with various molecular changes in different cellular environments. Despite the potential significance of various molecules, the HSPA1A or Hsp70 protein, which has possible connections with sleep and different neuropsychological and pathological disorders, has been explored the least. This paper explores the potential for manipulating and discovering drugs related to the Hsp70 protein to alleviate sleep problems and improve the prognosis for various other health issues. This paper discusses the critical role of Hsp70 in cancer, neurodegeneration, apoptosis, sleep, and its regulation at the structural level through allosteric mechanisms and different substrates. The significant impact of Hsp70's connection to various conditions suggests that existing sleep medicine could be used to improve such conditions, leading to improved outcomes, minimized research costs, and a new direction for current research. Overall, this paper highlights the potential of Hsp70 protein as a key therapeutic target for developing new drugs for the treatment of sleep disorders, cancer, neurodegeneration, and other related pathological conditions. Further research into the molecular mechanisms of Hsp70 regulation and its interactions with other cellular pathways is necessary to develop targeted treatments for these conditions.Communicated by Ramaswamy H. Sarma.

Ginsenosides are the primary component discernible from ginseng, including Rb1, Rb2, Rd, Rg1, Rg2, and compound K, and so forth. They have been shown to have multiple pharmacological activities. In recent years, more and more studies have been devoted to the neuroprotection of various ginsenosides against neurological diseases and their potential mechanisms. This paper comprehensively summarizes and reviews the neuroprotective effects of various ginsenosides on neurological diseases, especially acute and chronic neurodegenerative diseases, and their mechanisms, as well as their potential therapeutic applications to promote neuroprotection in disease prevention, treatment, and prognosis. Briefly, ginsenosides exert effective neuroprotective effects on neurological conditions, including stroke, Alzheimer's disease, Parkinson's disease, and brain/spinal cord injuries through a variety of molecular mechanisms, including anti-inflammatory, antioxidant, and anti-apoptotic. Among them, some signaling pathways play important roles in related processes, such as PI3K/Akt, TLR4/NF-κB, ROS/TXNIP/NLRP3, HO-1/Nrf2, Wnt/β-catenin, and Ca 2+ pathway. In conclusion, the present study reviews the research progress on the neuroprotective effects of ginsenosides in the last decade, with the aim of furnishing essential theoretical underpinning and effective references for further research and exploration of the multiple medicinal values of Chinese herbal medicines and their small molecule compounds, including ginseng and panax ginseng. Because there is less evidence in the existing clinical studies, future research should be focused on clinical trials in order to truly reflect the clinical value of various ginsenosides for the benefit of patients., (© 2024 The Author(s). IUBMB Life published by Wiley Periodicals LLC on behalf of International Union of Biochemistry and Molecular Biology.)

As the uncontrolled entry of calcium ions (Ca 2+ ) through plasmalemmal calcium channels is a cell death trigger, the conjecture is here raised that mitigating such an excess of Ca 2+ entry should rescue from death the vulnerable neurons in neurodegenerative diseases (NDDs). However, this supposition has failed in some clinical trials (CTs). Thus, a recent CT tested whether isradipine, a blocker of the Cav1 subtype of voltage-operated calcium channels (VOCCs), exerted a benefit in patients with Parkinson's disease (PD); however, outcomes were negative. This is one more of the hundreds of CTs done under the principle of one-drug-one-target, that have failed in Alzheimer's disease (AD) and other NDDs during the last three decades. As there are myriad calcium channels to let Ca 2+ ions gain the cell cytosol, it seems reasonable to predict that blockade of Ca 2+ entry through a single channel may not be capable of preventing the Ca 2+ flood of cells by the uncontrolled Ca 2+ entry. Furthermore, as Ca 2+ signaling is involved in the regulation of myriad functions in different cell types, it seems also reasonable to guess that a therapy should be more efficient by targeting different cells with various drugs. Here, we propose to mitigate Ca 2+ entry by the simultaneous partial blockade of three quite different subtypes of plasmalemmal calcium channels that is, the Cav1 subtype of VOCCs, the Orai1 store-operated calcium channel (SOCC), and the purinergic P2X7 calcium channel. All three channels are expressed in both microglia and neurons. Thus, by targeting the three channels with a combination of three drug blockers we expect favorable changes in some of the pathogenic features of NDDs, namely (i) to mitigate Ca 2+ entry into microglia; (ii) to decrease the Ca 2+ -dependent microglia activation; (iii) to decrease the sustained neuroinflammation; (iv) to decrease the uncontrolled Ca 2+ entry into neurons; (v) to rescue vulnerable neurons from death; and (vi) to delay disease progression. In this review we discuss the arguments underlying our triad hypothesis in the sense that the combination of three repositioned medicines targeting Cav1, Orai1, and P2X7 calcium channels could boost neuroprotection and delay the progression of AD and other NDDs., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Neuroinflammation, characterised by the activation of immune cells in the central nervous system (CNS), plays a dual role in both protecting against and contributing to the progression of neurodegenerative diseases, such as Alzheimer's disease (AD) and multiple sclerosis (MS). This review explores the role of phosphoinositide 3-kinase (PI3K), a key enzyme involved in cellular survival, proliferation, and inflammatory responses, within the context of neuroinflammation. Two PI3K isoforms of interest, PI3Kγ and PI3Kδ, are specific to the regulation of CNS cells, such as microglia, astrocytes, neurons, and oligodendrocytes, influencing pathways, such as Akt, mTOR, and NF-κB, that control cytokine production, immune cell activation, and neuroprotection. The dysregulation of PI3K signalling is implicated in chronic neuroinflammation, contributing to the exacerbation of neurodegenerative diseases. Preclinical studies show promise in targeting neuronal disorders using PI3K inhibitors, such as AS605240 (PI3Kγ) and idelalisib (PI3Kδ), which have reduced inflammation, microglial activation, and neuronal death in in vivo models of AD. However, the clinical translation of these inhibitors faces challenges, including blood-brain barrier (BBB) permeability, isoform specificity, and long-term safety concerns. This review highlights the therapeutic potential of PI3K modulation in neuroinflammatory diseases, identifying key gaps in the current research, particularly in the need for brain-penetrating and isoform-specific inhibitors. These findings underscore the importance of future research to develop targeted therapies that can effectively modulate PI3K activity and provide neuroprotection in chronic neurodegenerative disorders.

Eugenol, a phenylpropanoid compound, is found in various dietary resources and medicinal plants. From a historical perspective, eugenol is widely employed as a flavoring agent in the food and fragrance industries. Here, this review mainly focuses on recent advances in eugenol with respect to its versatile physiological roles in health and disease and discusses the mechanisms. Emerging evidence has highlighted that eugenol exhibits multiple biological activities in cancer, diabetes, obesity, cardiovascular diseases, and neurodegenerative diseases. It also has analgesic, anti-inflammatory, and antioxidant qualities and has lethal or inhibiting effects on various viruses, bacteria, fungi, and parasites. The manuscript also contains some patents that have been filed thus far regarding the production and application of eugenol. Overall, these benefits make eugenol a promising nutritional supplement which fulfils its historical function as a flavoring agent, opening up new possibilities for the creation of therapeutic agents for the treatment of disease.

Nanobodies (Nbs) are antibody fragments derived from heavy-chain-only IgG antibodies found in the Camelidae family as well as cartilaginous fish. Their unique structural and functional properties, such as their small size, the ability to be engineered for high antigen-binding affinity, stability under extreme conditions, and ease of production, have made them promising tools for diagnostics and therapeutics. This potential was realized in 2018 with the approval of caplacizumab, the world's first Nb-based drug. Currently, Nbs are being investigated in clinical trials for a broad range of treatments, including targeted therapies against PDL1 and Epidermal Growth Factor Receptor (EGFR), cardiovascular diseases, inflammatory conditions, and neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. They are also being studied for their potential for detecting and imaging autoimmune conditions and infectious diseases such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A variety of methods are now available to generate target-specific Nbs quickly and efficiently at low costs, increasing their accessibility. This article examines these diverse applications of Nbs and their promising roles. Only the most recent articles published in the last five years have been used to summarize the most advanced developments in the field., (© 2024. The Author(s).)

Moringa oleifera , which is known as a drumstick tree in different areas of the world, is well-known for many health benefits, which are attributed to the abundance of flavonoids, phenolic chemicals, and thiocyanates it contains. This review focuses on M. oleifera 's potential for neuroprotection, emphasizing its anti-inflammatory, antioxidant, and neurotransmitter-modulating qualities. Different parts of M. oleifera include leaves, roots, bark, and gum. Flowers, seeds, and seed oil are used for many health purposes, most notably in the treatment of neurological diseases. Neurodegeneration, which is characterized by the progressive death of nerve cells, is a major concern with an aging population, leading to disorders such as dementia and movement disorders. M. oleifera bioactive compounds improve the antioxidant defense activities of the brain, reduce inflammation, and improve neurotransmitter levels, showing potential therapeutic applications for neurodegenerative disorders. This review emphasizes the importance of further research, especially clinical trials, to fully understand and utilize M. oleifera 's neuroprotective capabilities., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Beniam Worku and Nafyad Tolossa.)

The neurotoxicant trimethyltin (TMT) triggers cognitive impairment and hippocampal neurodegeneration. TMT is a useful research tool for the study of Alzheimer's disease (AD) pathogenesis and treatment. Although the antidiabetic agent metformin has shown promising neuroprotective effects, however, its precise modes of action in neurodegenerative disorders need to be further elucidated. In this study, we investigated whether metformin can mitigate TMT cognition impairment and hippocampal neurodegeneration. To induce an AD-like phenotype, TMT was injected i.p. (8 mg/kg) and metformin was administered daily p.o. for 3 weeks at 200 mg/kg. Our results showed that metformin administration to the TMT group mitigated learning and memory impairment in Barnes maze, novel object recognition (NOR) task, and Y maze, attenuated hippocampal oxidative, inflammatory, and cell death/pyroptotic factors, and also reversed neurodegeneration-related proteins such as presenilin 1 and p-Tau. Hippocampal level of AMP-activated protein kinase (AMPK) as a key regulator of energy homeostasis was also improved following metformin treatment. Additionally, metformin reduced hippocampal acetylcholinesterase (AChE) activity, glial fibrillary acidic protein (GFAP)-positive reactivity, and prevented the loss of CA1 pyramidal neurons. This study showed that metformin mitigated TMT-induced neurodegeneration and this may pave the way to develop new therapeutics to combat against cognitive deficits under neurotoxic conditions., (© 2024. The Author(s).)

The present study investigated the neural health benefit of beta-sitosterol (BSS) against trimethyltin (TMT)-induced neurodegeneration in mice. Forty male Institute of Cancer Research (ICR) mice were randomly divided into Sham-veh, TMT-veh, TMT-BSS50, and TMT-BSS100. A one-time intraperitoneal injection of 2.6 mg/kg of TMT was given to mice in TMT groups. Vehicle (veh), BSS 50 mg/kg or BSS 100 mg/kg were orally given for 2 weeks. Spatial learning and memory were evaluated. Brain oxidative status, hippocampal neuropathology, and reactive astrocytes were done. White matter pathology was also evaluated. The results indicated the massy effect of TMT on induced motor ability and spatial memory deficits in accordance with increased neuronal degeneration in Cornus ammonis (CA) 1, CA3, and dentate gyrus (DG) and internal capsule white matter damage. TMT also induced the reduction of reactive astrocytes in CA1 and DG. Brain's catalase activity was significantly reduced by TMT, but not in mice with BSS treatments. Both doses of BSS treatment exhibited improvement in motor ability and spatial memory deficits in accordance with the activation of reactive astrocytes in CA1, CA3, and DG. However, they successfully prevented the increase of neuronal degeneration in CA1 found only with the BSS dose of 100 mg/kg, and it was indicated as the effective dose for neuroprotection in the vulnerable brain area. This study demonstrated mitigative effects of BSS against motor ability and memory deficits with neural health benefits, including a protective effect against CA1 neurodegeneration and a nurturing effect on hippocampal reactive astrocytes.

Currently, the age structure of the world population is changing due to declining birth rates and increasing life expectancy. As a result, physicians worldwide have to treat an increasing number of age-related diseases, of which neurological disorders represent a significant part. In this context, there is an urgent need to discover new therapeutic approaches to counteract the effects of neurodegeneration on human health, and computational science can be of pivotal importance for more effective neurodrug discovery. The knowledge of the molecular structure of the receptors and other biomolecules involved in neurological pathogenesis facilitates the design of new molecules as potential drugs to be used in the fight against diseases of high social relevance such as dementia, Alzheimer's disease (AD) and Parkinson's disease (PD), to cite only a few. However, the absence of comprehensive guidelines regarding the strengths and weaknesses of alternative approaches creates a fragmented and disconnected field, resulting in missed opportunities to enhance performance and achieve successful applications. This review aims to summarize some of the most innovative strategies based on computational methods used for neurodrug development. In particular, recent applications and the state-of-the-art of molecular docking and artificial intelligence for ligand- and target-based approaches in novel drug design were reviewed, highlighting the crucial role of in silico methods in the context of neurodrug discovery for neurodegenerative diseases.

As the global population ages, the incidence of neurodegenerative diseases such as Alzheimer's and Parkinson's is rapidly rising. These diseases present a significant public health challenge, as they severely impair cognitive and motor functions, ultimately leading to a substantial reduction in quality of life and placing a heavy burden on healthcare systems worldwide. Although several therapeutic agents have been developed to manage the symptoms of these diseases, their effectiveness is often limited, and there remains an urgent need for preventive strategies. Growing evidence indicates that bioactive compounds from natural products possess neuroprotective properties through antioxidant and anti-inflammatory effects, modulating key pathways such as phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) and brain-derived neurotrophic factor-tropomyosin receptor kinase B-cAMP response element-binding protein (BDNF-TrkB-CREB), which are crucial for neuronal survival. These compounds may also reduce amyloid-beta and tau pathology, as well as enhance cholinergic neurotransmission by inhibiting acetylcholinesterase activity. By targeting oxidative stress, neuroinflammation, and neurodegeneration, natural products offer a promising approach for both prevention and treatment. These findings suggest that natural products may be promising for preventing and treating neurodegenerative diseases. This review aims to explore the pathogenesis of neurodegenerative diseases, the limitations of current therapies, and the potential role of natural products as therapeutic agents.

In recent decades, nanotechnology has significantly advanced drug delivery systems, particularly in targeting subcellular organelles, thus opening new avenues for disease treatment. Mitochondria, critical for cellular energy and health, when dysfunctional, contribute to cancer, neurodegenerative diseases, and metabolic disorders. This has propelled the development of nanomedicines aimed at precise mitochondrial targeting to modulate their function, marking a research hotspot. This review delves into the recent advancements in mitochondrial-targeted nanotherapeutics, with a comprehensive focus on targeting strategies, nanocarrier designs, and their therapeutic applications. It emphasizes nanotechnology's role in enhancing drug delivery by overcoming biological barriers and optimizing drug design for specific mitochondrial targeting. Strategies exploiting mitochondrial membrane potential differences and specific targeting ligands improve the delivery and mitochondrial accumulation of nanomedicines. The use of diverse nanocarriers, including liposomes, polymer nanoparticles, and inorganic nanoparticles, tailored for effective mitochondrial targeting, shows promise in anti-tumor and neurodegenerative treatments. The review addresses the challenges and future directions in mitochondrial targeting nanotherapy, highlighting the need for precision, reduced toxicity, and clinical validation. Mitochondrial targeting nanotherapy stands at the forefront of therapeutic strategies, offering innovative treatment perspectives. Ongoing innovation and research are crucial for developing more precise and effective treatment modalities., Competing Interests: 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 © 2024 Li, Li, Wei and Ye.)

Aging, an inevitable physiological process leading to a progressive decline in bodily functions, has been an abundantly researched domain with studies attempting to slow it down and reduce its debilitating effects. Investigations into the cellular and molecular pathways associated with aging have allowed the formulation of therapeutic strategies. Of these, caloric restriction (CR) has been implicated for its role in promoting healthy aging by modulating key molecular targets like Insulin/IGF-1, mTOR, and sirtuins. However, CR requires dedication and commitment to a strict regimen which poses a difficulty in maintaining consistency. To maneuver around cumbersome diets, Caloric Restriction Mimetics (CRMs) have emerged as promising alternatives by mimicking the beneficial effects of CR. This review elucidates the molecular foundations enabling CRMs like rapamycin, metformin, resveratrol, spermidine, and many more to function as suitable anti-aging molecules. Moreover, it explores clinical trials (retrieved from the clinicaltrials.gov database) aimed at demonstrating the efficacy of CRMs as effective candidates against age-related neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease., (© 2024. The Author(s).)

α -Synuclein ( α -Syn) aggregation in Lewy bodies and Lewy neurites has emerged as a key pathogenetic feature in Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Various factors, including posttranslational modifications (PTMs), can influence the propensity of α -Syn to misfold and aggregate. PTMs are biochemical modifications of a protein that occur during or after translation and are typically mediated by enzymes. PTMs modulate several characteristics of proteins including their structure, activity, localization, and stability. α -Syn undergoes various posttranslational modifications, including phosphorylation, ubiquitination, SUMOylation, acetylation, glycation, O-GlcNAcylation, nitration, oxidation, polyamination, arginylation, and truncation. Different PTMs of a protein can physically interact with one another or work together to influence a particular physiological or pathological feature in a process known as PTMs crosstalk. The development of detection techniques for the cooccurrence of PTMs in recent years has uncovered previously unappreciated mechanisms of their crosstalk. This has led to the emergence of evidence supporting an association between α -Syn PTMs crosstalk and synucleinopathies. In this review, we provide a comprehensive evaluation of α -Syn PTMs, their impact on misfolding and pathogenicity, the pharmacological means of targeting them, and their potential as biomarkers of disease. We also highlight the importance of the crosstalk between these PTMs in α -Syn function and aggregation. Insight into these PTMS and the complexities of their crosstalk can improve our understanding of the pathogenesis of synucleinopathies and identify novel targets of therapeutic potential. SIGNIFICANCE STATEMENT: α -Synuclein is a key pathogenic protein in Parkinson's disease and other synucleinopathies, making it a leading therapeutic target for disease modification. Multiple posttranslational modifications occur at various sites in α -Synuclein and alter its biophysical and pathological properties, some interacting with one another to add to the complexity of the pathogenicity of this protein. This review details these modifications, their implications in disease, and potential therapeutic opportunities., (Copyright © 2024 by The Author(s).)

Silymarin, a bioflavonoid derived from the Silybum marianum plant, was discovered in 1960. It contains C 25 and has been extensively used as a therapeutic agent against liver-related diseases caused by alcohol addiction, acute viral hepatitis, and toxins-inducing liver failure. Its efficacy stems from its role as a potent anti-oxidant and scavenger of free radicals, employed through various mechanisms. Additionally, silymarin or silybin possesses immunomodulatory characteristics, impacting immune-enhancing and immune-suppressive functions. Recently, silymarin has been recognized as a potential neuroprotective therapy for various neurological conditions, including Parkinson's and Alzheimer's diseases, along with conditions related to cerebral ischemia. Its hepatoprotective qualities, primarily due to its anti-oxidant and tissue-regenerating properties, are well-established. Silymarin also enhances health by modifying processes such as inflammation, β-amyloid accumulation, cellular estrogenic receptor mediation, and apoptotic machinery. While believed to reduce oxidative stress and support neuroprotective mechanisms, these effects represent just one aspect of the compound's multifaceted protective action. This review article further delves into the possibilities of potential therapeutic advancement of silymarin and silibinin for the management of neurodegenerative disorders via mechanics modules., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Neurodegenerative diseases are linked to the process of neurodegeneration. This can be caused by several mechanisms, including inflammation and accumulation of reactive oxygen species. Despite their high incidence, there is still no effective treatment or cure for these diseases. Cyanobacteria have been seen as a possible source for new compounds with anti-inflammatory and antioxidant potential, such as polysaccharides (sacran), phycobiliproteins (phycocyanin) and lipopeptides (honaucins and malyngamides), which can be interesting to combat neurodegeneration. As a promising case of success, Arthrospira (formerly Spirulina ) has revealed a high potential for preventing neurodegeneration. Additionally, advantageous culture conditions and sustainable production of cyanobacteria, which are allied to the development of genetic, metabolic, and biochemical engineering, are promising. The aim of this review is to compile and highlight research on the anti-inflammatory and antioxidant potential of cyanobacteria with focus on the application as neuroprotective agents. Also, a major goal is to address essential features that brand cyanobacteria as an ecoefficient and economically viable option, linking health to sustainability.

Indole derivatives have become an important class of compounds in medicinal chemistry, recognized for their wide-ranging biological activities and therapeutic potential. This review provides a comprehensive overview of recent advances in the evaluation of indole-based compounds in the last five years, highlighting their roles in cancer treatment, infectious disease management, anti-inflammatory therapies, metabolic disorder interventions, and neurodegenerative disease management. Indole derivatives have shown significant efficacy in targeting diverse biological pathways, making them valuable scaffolds in designing new drugs. Notably, these compounds have demonstrated the ability to combat drug-resistant cancer cells and pathogens, a significant breakthrough in the field, and offer promising therapeutic options for chronic diseases such as diabetes and hypertension. By summarizing recent key findings and exploring the underlying biological mechanisms, this review underscores the potential of indole derivatives in addressing major healthcare challenges, thereby instilling hope and optimism in the field of modern medicine.

Cyclodextrins (CDs) are ubiquitous excipients, constituted of cyclic glucopyranose units, and possess a unique dual nature, that of a hydrophobic interior and a hydrophilic exterior. This enables their interaction with lipid-affinitive compounds and hydrophilic compounds, thereby augmenting their application in pharmaceutical formulations as agents for improving solubility, as well as fundamental elements of advanced drug delivery systems. Additionally, CDs, upon suitable modification, can strategically participate in the interaction with cellular components and physical barriers, such as the blood-brain barrier, where their intricate and multifunctional engagement leads to various biological impacts. This review consolidates the crucial features of CDs and their derivatives, and summarizes the applications of them as drug delivery systems in neurodegenerative disorders, emphasizing their notable potentials.

Ferroptosis, distinct from apoptosis, necrosis, and autophagy, is a unique type of cell death driven by iron-dependent phospholipid peroxidation. Since ferroptosis was defined in 2012, it has received widespread attention from researchers worldwide. From a biochemical perspective, the regulation of ferroptosis is strongly associated with cellular metabolism, primarily including iron metabolism, lipid metabolism, and redox metabolism. The distinctive regulatory mechanism of ferroptosis holds great potential for overcoming drug resistance-a major challenge in treating cancer. The considerable role of nanobiotechnology in disease treatment has been widely reported, but further and more systematic discussion on how nanobiotechnology enhances the therapeutic efficacy on ferroptosis-associated diseases still needs to be improved. Moreover, while the exciting therapeutic potential of ferroptosis in cancer has been relatively well summarized, its applications in other diseases, such as neurodegenerative diseases, cardiovascular and cerebrovascular diseases, and kidney disease, remain underreported. Consequently, it is necessary to fill these gaps to further complete the applications of nanobiotechnology in ferroptosis. In this review, we provide an extensive introduction to the background of ferroptosis and elaborate its regulatory network. Subsequently, we discuss the various advantages of combining nanobiotechnology with ferroptosis to enhance therapeutic efficacy and reduce the side effects of ferroptosis-associated diseases. Finally, we analyze and discuss the feasibility of nanobiotechnology and ferroptosis in improving clinical treatment outcomes based on clinical needs, as well as the current limitations and future directions of nanobiotechnology in the applications of ferroptosis, which will not only provide significant guidance for the clinical applications of ferroptosis and nanobiotechnology but also accelerate their clinical translations., (© 2024. The Author(s).)

The G protein-coupled receptor 40 (GPR40) is known to exert a significant influence on neurogenesis and neurodevelopment within the central nervous system of both humans and rodents. Research findings indicate that the activation of GPR40 by an agonist has been observed to promote the proliferation and viability of hypothalamus cells in the human body. The objective of the present study is to discover new agonist compounds for the GPR40 protein through the utilization of machine learning and pharmacophore-based screening techniques, in conjunction with other computational methodologies such as docking, molecular dynamics simulations, free energy calculations, and investigations of the free energy landscape. In the course of our investigation, we successfully identified five unreported agonist compounds that exhibit robust docking score, displayed stability in ligand RMSD and consistent hydrogen bonding with the receptor in the MD trajectories. Free energy calculations were observed to be higher than control molecule. The measured binding affinities of compounds namely 1, 3, 4, 6 and 10 were -13.9, -13.5, -13.4, -12.9, and -12.1 Kcal/mol, respectively. The identified molecular agonist that has been found can be assessed in terms of its therapeutic efficacy in the treatment of neurological diseases., Competing Interests: The authors declare they have no competing financial interests., (Copyright: © 2024 Siddiqui et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Caspase-8, a renowned cysteine-aspartic protease within its enzyme family, initially garnered attention for its regulatory role in extrinsic apoptosis. With advancing research, a growing body of evidence has substantiated its involvement in other cell death processes, such as pyroptosis and necroptosis, as well as its modulatory effects on inflammasomes and proinflammatory cytokines. PANoptosis, an emerging concept of cell death, encompasses pyroptosis, apoptosis, and necroptosis, providing insight into the often overlapping cellular mortality observed during disease progression. The activation or deficiency of caspase-8 enzymatic activity is closely linked to PANoptosis, positioning caspase-8 as a key regulator of cell survival or death across various physiological and pathological processes. Aberrant expression of caspase-8 is closely associated with the development and progression of a range of inflammatory diseases, including immune system disorders, neurodegenerative diseases (NDDs), sepsis, and cancer. This paper delves into the regulatory role and impact of caspase-8 in these conditions, aiming to elucidate potential therapeutic strategies for the future intervention., (© 2024. The Author(s).)

Over three decades ago, two independent groups of investigators identified free D-aspartic and later D-serine in specific brain nuclei and endocrine glands. This finding revealed a novel, non-proteinogenic role of these molecules. Moreover, the finding that aged proteins from the human eye crystallin, teeth, bone, blood vessels or the brain incorporate D-aspartic acids to specific primary protein sequences fostered the hypothesis that aging might be related to D-amino acid isomerization of body proteins. The experimental confirmation that schizophrenia and neurodegenerative diseases modify plasma free D-amino acids or tissue levelsnurtured the opportunity of using D-amino acids as therapeutic agents for several disease treatments, a strategy that prompted the successful current application of D-amino acids to human medicine., (© 2024 The Chemical Society of Japan and Wiley-VCH GmbH.)

For over forty years, a sugar of rare configuration known as trehalose (two molecules of glucose linked at their 1-carbons), has been recognised for more than just its roles as a storage compound. The ability of trehalose to protect an extensive range of biological materials, for instance cell lines, tissues, proteins and DNA, has sparked considerable interest in the biotechnology and pharmaceutical industries. Currently, trehalose is now being investigated as a promising therapeutic candidate for human use, as it has shown potential to reduce disease severity in various experimental models. Despite its diverse biological effects, the precise mechanism underlying this observation remain unclear. Therefore, this review delves into the significance of trehalose biosynthesis pathway in the development of novel drug, investigates the inhibitors of trehalose synthesis and evaluates the binding efficiency of T6P with TPS1. Additionally, it also emphasizes the knowledge about the protective effect of trehalose on modulation of autophagy, combating viral infections, addressing the conditions like cancer and neurodegenerative diseases based on the recent advancement. Furthermore, review also highlight the trehalose's emerging role as a surfactant in delivering monoclonal antibodies that will further broadening its potential application in biomedicines., Competing Interests: Declaration of competing interest • The author declares there are no conflicts of interest to disclose. • The authors also 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.)

Introduction: c-Jun N-terminal kinase (JNK) regulates various biological processes through the phosphorylation cascade and is closely associated with numerous diseases, including inflammation, cardiovascular diseases, and neurological disorders. Therefore, JNKs have emerged as potential targets for disease treatment., Areas Covered: This review compiles the patents and literatures concerning JNK inhibitors through retrieving relevant information from the SciFinder, Google Patents databases, and PubMed from 2015 to the present. It summarizes the structure-activity relationship (SAR) and biological activity profiles of JNK inhibitors, offering valuable perspectives on their potential therapeutic applications., Expert Opinion: The JNK kinase serves as a novel target for the treatment of neurodegenerative disorders, pulmonary fibrosis, and other illnesses. A variety of small-molecule inhibitors targeting JNKs have demonstrated promising therapeutic potential in preclinical studies, which act upon JNK kinases via distinct mechanisms, encompassing traditional ATP competitive inhibition, covalent inhibition, and bidentate inhibition. Among them, several JNK inhibitors from PregLem SA, Celegene SA, and Xigen SA have accomplished the early stage of clinical trials, and their results will guide the development and indications of future JNK inhibitors.

Introduction: Caspases are a family of protease enzymes that play a crucial role in apoptosis. Dysregulation of caspase activity has been implicated in various pathological conditions, making caspases an important focus of research in understanding cell death mechanisms and developing therapeutic strategies for diseases associated with abnormal apoptosis., Areas Covered: It is a comprehensive review of caspase inhibitors that have been comprising recently granted patents from 2016 to 2023. It includes peptide and non-peptide caspase inhibitors with their application for different diseases., Expert Opinion: This review categorizes and analyses recently patented caspase inhibitors on various diseases. Diseases linked to caspase dysregulation, including neurodegenerative disorders, and autoimmune conditions, are highlighted to accentuate the therapeutic relevance of the patented caspase inhibitors. This paper serves as a valuable resource for researchers, clinicians, and pharmaceutical developers seeking an up-to-date understanding of recently patented caspase inhibitors. The integration of recent patented compounds, structural insights, and mechanistic details provides a holistic view of the progress in caspase inhibitor research and its potential impact on addressing various diseases.

Mammalian flavoenzyme Monoamine oxidase (MAO) resides on the outer mitochondrial membrane (OMM) and it is involved in the metabolism of different monoamine neurotransmitters in brain. During MAO mediated oxidative deamination of relevant substrates, H 2 O 2 is released as a catalytic by-product, thus serving as a major source of reactive oxygen species (ROS). Under normal conditions, MAO mediated ROS is reported to propel the functioning of mitochondrial electron transport chain and phasic dopamine release. However, due to its localization onto mitochondria, sudden elevation in its enzymatic activity could directly impact the form and function of the organelle. For instance, in the case of Parkinson's disease (PD) patients who are on l-dopa therapy, the enzyme could be a concurrent source of extensive ROS production in the presence of uncontrolled substrate (dopamine) availability, thus further impacting the health of surviving neurons. It is worth mentioning that the expression of the enzyme in different brain compartments increases with age. Moreover, the involvement of MAO in the progression of neurological disorders such as PD, Alzheimer's disease and depression has been extensively studied in recent times. Although the usage of available synthetic MAO inhibitors has been instrumental in managing these conditions, the associated complications have raised significant concerns lately. Natural products have served as a major source of lead molecules in modern-day drug discovery; however, there is still no FDA-approved MAO inhibitor which is derived from natural sources. In this review, we have provided a comprehensive overview of MAO and how the enzyme system is involved in the pathogenesis of different age-associated neuropathologic conditions. We further discussed the applications and drawbacks of the long-term usage of presently available synthetic MAO inhibitors. Additionally, we have highlighted the prospect and worth of natural product derived molecules in addressing MAO associated complications., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Ferroptosis is a form of cell death that is induced by iron-mediated accumulation of lipid peroxidation. The involvement of ferroptosis in different pathophysiological conditions has offered new perspectives on potential therapeutic interventions. Natural products, which are widely recognized for their significance in drug discovery and repurposing, have shown great promise in regulating ferroptosis by targeting various ferroptosis players. In this review, we discuss the regulatory mechanisms of ferroptosis and its implications in different pathological conditions. We dissect the interactions between natural products and ferroptosis in cancer, ischemia/reperfusion, neurodegenerative diseases, acute kidney injury, liver injury, and cardiomyopathy, with an emphasis on the relevance of ferroptosis players to disease targetability., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)