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Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-beta plaques and neurofibrillary tangles, leading to neuronal loss. Curcumin, a polyphenolic compound derived from Curcuma longa, has shown potential neuroprotective effects due to its anti-inflammatory and antioxidant properties. This review aims to synthesize current preclinical data on the anti-neuroinflammatory mechanisms of curcumin in the context of AD, addressing its pharmacokinetics, bioavailability, and potential as a therapeutic adjunct. An exhaustive literature search was conducted, focusing on recent studies within the last 10 years related to curcumin's impact on neuroinflammation and its neuroprotective role in AD. The review methodology included sourcing articles from specialized databases using specific medical subject headings terms to ensure precision and relevance. Curcumin demonstrates significant neuroprotective properties by modulating neuroinflammatory pathways, scavenging reactive oxygen species, and inhibiting the production of pro-inflammatory cytokines. Despite its potential, challenges remain regarding its limited bioavailability and the scarcity of comprehensive human clinical trials. Curcumin emerges as a promising therapeutic adjunct in AD due to its multimodal neuroprotective benefits. However, further research is required to overcome challenges related to bioavailability and to establish effective dosing regimens in human subjects. Developing novel delivery systems and formulations may enhance curcumin's therapeutic potential in AD treatment., (© 2024 John Wiley & Sons Ltd.)

Brain inflammation, characterized by increased microglia and astrocyte activation, increases during aging and is a key feature of neurodegenerative diseases, such as Alzheimer's disease (AD). In AD, neuronal death and synaptic impairment, induced by amyloid-β (Aβ) peptide, are at least in part mediated by microglia and astrocyte activation. Glial activation results in the sustained production of proinflammatory cytokines and reactive oxygen species, giving rise to a chronic inflammatory process. Astrocytes are the most abundant glial cells in the central nervous system and are involved in the neuroinflammation. Astrocytes can be activated by numerous factors, including free saturated fatty acids, pathogens, lipopolysaccharide, and oxidative stress. Activation of astrocytes produces inflammatory cytokines and the enzyme cyclooxygenase-2, enhancing the production of Aβ. Furthermore, the role of the receptor for advanced glycation end products/nuclear factor-κB (NF-κB) axis in neuroinflammation is in line with the nonenzymatic glycosylation theory of aging, suggesting a central role of the advanced glycation end products in the age-related cognitive and a possible role of nutraceuticals in the prevention of neuroinflammation and AD. However, modulation of P-glycoprotein, rather than antioxidant and anti-inflammatory effects, could be the major mechanism of polyphenolic compounds, including flavonoids. Curcumin, resvertrol, piperine, and other polyphenols have been explored as novel therapeutic and preventive agents for AD. The aim of this review is to critically analyze and discuss the mechanisms involved in neuroinflammation and the possible role of nutraceuticals in the prevention and therapy of AD by targeting neuroinflammation., (© 2017 Elsevier Inc. All rights reserved.)

S100 calcium-binding protein B (S100B) is highly expressed in glioma cells and promotes cancer cell survival via inhibition of the p53 protein. In melanoma cells, this S100B-p53 interaction is known to be inhibited by pentamidine isethionate, an antiprotozoal agent. Thus, the aim of the present study was to evaluate the effect of pentamidine on rat C6 glioma cell proliferation, migration and apoptosis in vitro . The change in C6 cell proliferation following treatment with pentamidine was determined by performing a 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide-formazan assay. Significant dose-dependent decreases in proliferation were observed at pentamidine concentrations of 0.05 µM (58.5±5%; P<0.05), 0.5 µM (40.6±7%; P<0.01) and 5 µM (13±4%; P<0.001) compared with the control (100% viability). Furthermore, treatment with 0.05, 0.5 and 5 µM pentamidine was associated with a significant increase in apoptosis versus the untreated cells, as determined by DNA fragmentation assays, immunofluorescence analysis of C6 chromatin using Hoechst staining, and immunoblot analysis of B-cell lymphoma-2 (Bcl-2)-associated X protein (100%, P<0.05; 453%, P<0.01; and 1000%, P<0.001, respectively) and Bcl-2 (-60%, P<0.001; -80.13%, P<0.001; -95%, P<0.001, respectively). In addition, the administration of 0.05, 0.5 and 5 µM pentamidine significantly upregulated the protein expression levels of p53 (681±87.5%, P<0.05; 1244±94.3%, P<0.01; and 2244±111%, P<0.001, respectively), and significantly downregulated the expression levels of matrix metalloproteinase-2 (42±2.3%, P<0.05; 71±2.5%, P<0.01; and 95.8±3.3%, P<0.001, respectively) and aquaporin 4 (38±2.5%, P<0.05; 69±2.6%, P<0.01; and 88±3.0%, P<0.001, respectively), compared with the untreated cells. The wound healing assay demonstrated that cell migration was significantly impaired by treatment with 0.05, 0.5 and 5 µM pentamidine compared with untreated cells (88±4.2%, P<0.05; 64±2%, P<0.01; and 42±3.1%, P<0.001, respectively). Although additional in vivo studies are required to clarify the current in vitro data, the present study indicates that pentamidine and S100B-p53 inhibitors may represent a novel approach for the treatment of glioma.

Background/Objectives. Obesity, type 2 diabetes (T2D), and Alzheimer's disease (AD) are pathologies that affect millions of people worldwide. They have no effective therapy and are difficult to prevent and control when they develop. It has been known for many years that these diseases have many pathogenic aspects in common. We highlight in this review that neuroglial cells (astroglia, oligodendroglia, and microglia) play a vital role in the origin, clinical–pathological development, and course of brain neurodegeneration. Moreover, we include the new results of a T2D-AD mouse model (APP+PS1 mice on a high-calorie diet) that we are investigating. Methods. Critical bibliographic revision and biochemical neuropathological study of neuroglia in a T2D-AD model. Results. T2D and AD are not only "connected" by producing complex pathologies in the same individual (obesity, T2D, and AD), but they also have many common pathogenic mechanisms. These include insulin resistance, hyperinsulinemia, hyperglycemia, oxidative stress, mitochondrial dysfunction, and inflammation (both peripheral and central—or neuroinflammation). Cognitive impairment and AD are the maximum exponents of brain neurodegeneration in these pathological processes. both due to the dysfunctions induced by metabolic changes in peripheral tissues and inadequate neurotoxic responses to changes in the brain. In this review, we first analyze the common pathogenic mechanisms of obesity, T2D, and AD (and/or cerebral vascular dementia) that induce transcendental changes and responses in neuroglia. The relationships between T2D and AD discussed mainly focus on neuroglial responses. Next, we present neuroglial changes within their neuropathological context in diverse scenarios: (a) aging involution and neurodegenerative disorders, (b) human obesity and diabetes and obesity/diabetes models, (c) human AD and in AD models, and (d) human AD-T2D and AD-T2D models. An important part of the data presented comes from our own studies on humans and experimental models over the past few years. In the T2D-AD section, we included the results of a T2D-AD mouse model (APP+PS1 mice on a high-calorie diet) that we investigated, which showed that neuroglial dysfunctions (astrocytosis and microgliosis) manifest before the appearance of amyloid neuropathology, and that the amyloid pathology is greater than that presented by mice fed a normal, non-high-caloric diet A broad review is finally included on pharmacological, cellular, genic, and non-pharmacological (especially diet and lifestyle) neuroglial-related treatments, as well as clinical trials in a comparative way between T2D and AD. These neuroglial treatments need to be included in the multimodal/integral treatments of T2D and AD to achieve greater therapeutic efficacy in many millions of patients. Conclusions. Neuroglial alterations (especially in astroglia and microglia, cornerstones of neuroinflammation) are markedly defining brain neurodegeneration in T2D and A, although there are some not significant differences between each of the studied pathologies. Neuroglial therapies are a very important and p. promising tool that are being developed to prevent and/or treat brain dysfunction in T2D-AD. The need for further research in two very different directions is evident: (a) characterization of the phenotypic changes of astrocytes and microglial cells in each region of the brain and in each phase of development of each isolated and associated pathology (single-cell studies are mandatory) to better understand the pathologies and define new therapeutic targets; (b) studying new therapeutic avenues to normalize the function of neuroglial cells (preventing neurotoxic responses and/or reversing them) in these pathologies, as well as the phenotypic characteristics in each moment of the course and place of the neurodegenerative process. [ABSTRACT FROM AUTHOR]

Background: Brain tissue in Alzheimer's patients is exposed to oxidative stress. Silymarin is an adjunct drug that has anti-inflammatory and antioxidant properties. Objective: This study aimed to evaluate the effect of silymarin on biomarkers of oxidative stress, inflammation, and disease severity in Alzheimer's patients. Methods: This randomized, single-blind clinical trial study was performed on 33 patients with Alzheimer's disease (AD) whose disease was confirmed by DSM-5 criteria and by brain imaging. Patients in the case group received three 250 mg silymarin capsules daily (each containing 150 mg silymarin), as an adjunctive medication in addition to the routine medication regimen. In the placebo group (control), patients received the same amount of placebo. All patients underwent Mini Mental State Exam (MMSE) and a panel of blood tests including malondialdehyde, neopterin, catalase, paraoxonase-1, total oxidative status, and total antioxidant capacity to reevaluate the changes pre/postintervention at the end of the trimester. Results: The catalase and MDA serum levels after the adjunctive silymarin treatment decreased significantly (Catalasebefore silymarin = 9.29 ± 7.02 vs Catalaseafter silymarin = 5.32 ± 2.97, p = 0.007 and MDAbefore silymarin = 4.29 ± 1.90 vs MDAafter silymarin = 1.66 ± 0.84, p < 0.001) while MMSE increased notably (MMSEbefore silymarin = 10.39 ± 6.42 vs MMSEafter silymarin = 13.37 ± 6.81, p < 0.001). Conclusion: Silymarin can be effective as an adjunct drug and a powerful antioxidant in reducing oxidative stress and improving the course of AD. [ABSTRACT FROM AUTHOR]

The effective components and key targets of Shan Zhuyu (Cornus officinalis Sieb.et Zucc, SZY)-ShanYao (Dioscorea opposita Thunb, SY) (SS) in the treatment of Alzheimer's disease (AD, neurodegenerative disease) were screened by network pharmacology (NP) and molecular docking (MD) technology in this study. We obtained 25 potential bioactive ingredients, 88 putative targets of SS and 4893 related-AD targets. Traditional Chinese Medicine of SS has 77 common targets with AD disease.The network of drug-disease was fabricated 7 key pharmacodynamic components. Interaction network construction and topological analysis yielded, 8 anti-AD targets of SS were filtered. MD investigations showed that bioactive compounds (Hydroxygenkwanin and hancinone C) could stably bind to the key target proteins. 13 pathways related to AD were revealed signaling pathway and functional enrichment analysis. Among them, identified a statistically high significance of the calcium signaling pathway and a variety of calcium channels have been shown to be altered in AD. Our studies confirmed multiple active ingredients, potential targets about pathways of SS, by regulating the active components combined with relevant target proteins in the calcium signaling pathway, which are crucial in the accumulation of neurofbrillary tangles (NFTs) and amyloid-β (Aβ) plaques. Thereby, this furnishes a robust foundation for subsequent experimental studies. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is a critical global health issue, marked by a progressive decline in kidney function and significant associated morbidity and mortality. Central to the pathogenesis of CKD is oxidative stress, characterized by an imbalance between the production of reactive oxygen species (ROS) and the body's antioxidant defenses. This review provides an integrative insight into the roles of oxidative stress and antioxidants in CKD progression. It synthesizes current research, highlighting the pathogenic mechanisms through which oxidative stress exacerbates kidney damage - principally through inducing apoptosis and inflammation - and discusses the therapeutic potential of natural antioxidants. Our comprehensive literature search covered key databases including PubMed/MedLine, Science Direct, and Google Scholar, focusing on studies that elucidate the interplay between oxidative stress and antioxidants in CKD pathophysiology. While emerging evidence from preclinical studies suggests that antioxidants can play a protective role by neutralizing ROS, clinical trials remain insufficient to justify widespread adoption of antioxidant therapy in CKD treatment protocols. The review underscores the urgent need for more rigorous clinical studies to establish the efficacy and safety of antioxidant interventions in CKD patients. Future research should prioritize identifying effective antioxidant therapies and elucidating their mechanisms of action within the CKD context. [ABSTRACT FROM AUTHOR]

Aging-related disorders pose significant challenges due to their complex interplay of physiological and metabolic factors, including inflammation, oxidative stress, and mitochondrial dysfunction. Curcumin, a natural compound with potent antioxidant and anti-inflammatory properties, has emerged as a promising candidate for mitigating these age-related processes. However, gaps in understanding the precise mechanisms of curcumin's effects and the optimal dosages for different conditions necessitate further investigation. This systematic review synthesizes current evidence on curcumin's potential in addressing age-related disorders, emphasizing its impact on cognitive function, neurodegeneration, and muscle health in older adults. By evaluating the safety, efficacy, and mechanisms of action of curcumin supplementation, this review aims to provide insights into its therapeutic potential for promoting healthy aging. A systematic search across three databases using specific keywords yielded 2256 documents, leading to the selection of 15 clinical trials for synthesis. Here, we highlight the promising potential of curcumin as a multifaceted therapeutic agent in combating age-related disorders. The findings of this review suggest that curcumin could offer a natural and effective approach to enhancing the quality of life of aging individuals. Further research and well-designed clinical trials are essential to validate these findings and optimize the use of curcumin in personalized medicine approaches for age-related conditions. [ABSTRACT FROM AUTHOR]

Acmella oleracea L. (Asteraceae), commonly known as the toothache plant, is a tropical herb with significant therapeutic potential. Traditionally, it has been used for its analgesic and sialagogue properties, and it is known for its distinctive yellow flower crest. This review addresses current gaps in the understanding of its pharmacological properties and aims to provide a comprehensive analysis of its therapeutic potential. A thorough literature review was conducted using databases such as Google Scholar, ScienceDirect, and PubMed/MedLine. The findings indicate that A. oleracea contains a variety of phytochemicals, including spilanthol, which exhibit diverse pharmacological activities such as antioxidant, anti-inflammatory, immunomodulatory, antinociceptive, pronociceptive, antibacterial, antifungal, antidiabetic, diuretic, and vasorelaxant effects. The results highlight the significant medicinal potential of A. oleracea while also identifying areas for further research, particularly regarding its toxicological impacts on humans and animals. This review aims to guide future studies on the health benefits and safety of this plant.Article Highlights: Acmella oleracea exhibits significant pain-relieving properties, interacting with pain receptors effectively. The plant's extracts show strong antimicrobial effects, useful against various bacterial infections. Acmella oleracea demonstrates potent antioxidant and antifungal activities, promoting health and disease prevention. [ABSTRACT FROM AUTHOR]

The most prevalent rare genetic disease affecting young individuals is spinal muscular atrophy (SMA), which is caused by a loss-of-function mutation in the telomeric gene survival motor neuron (SMN) 1. The high heterogeneity of the SMA pathophysiology is determined by the number of copies of SMN2, a separate centromeric gene that can transcribe for the same protein, although it is expressed at a slower rate. SMA affects motor neurons. However, a variety of different tissues and organs may also be affected depending on the severity of the condition. Novel pharmacological treatments, such as Spinraza, Onasemnogene abeparvovec-xioi, and Evrysdi, are considered to be disease modifiers because their use can change the phenotypes of the patients. Since oxidative stress has been reported in SMA-affected cells, we studied the impact of antioxidant therapy on neural stem cells (NSCs) that have the potential to differentiate into motor neurons. Antioxidants can act through various pathways; for example, some of them exert their function through nuclear factor (erythroid-derived 2)-like 2 (NRF2). We found that curcumin is able to induce positive effects in healthy and SMA-affected NSCs by activating the nuclear translocation of NRF2, which may use a different mechanism than canonical redox regulation through the antioxidant-response elements and the production of antioxidant molecules. [ABSTRACT FROM AUTHOR]

Introduction: Memory impairment is a critical challenge in neurodegenerative disorders, particularly in Alzheimer's disease, Parkinson's disease, and age-related cognitive decline. This research explores the molecular mechanisms by which curcumin, a polyphenolic compound derived from Curcuma longa, exerts neuroprotective effects that may ameliorate cognitive deficits associated with these conditions., Results and Conclusion: Evidence from both preclinical studies and emerging clinical trials indicates that curcumin enhances neuronal signaling and synaptic plasticity, primarily through the modulation of pathways such as NF-κB and PI3K/Akt. Specifically, curcumin has been shown to reduce neuroinflammation and oxidative stress, thereby promoting synaptic integrity and function. For instance, studies demonstrate that curcumin treatment increases the density of dendritic spines in the hippocampus, which correlates with improved spatial learning and memory performance in animal models. Despite promising findings, significant gaps remain in our understanding of curcumin's efficacy in humans. Most existing research is derived from animal studies, with limited large-scale clinical trials to substantiate its therapeutic potential. Furthermore, challenges such as curcumin's low bioavailability and inconsistencies in dosing complicate its clinical application. This review underscores the need for future research focused on enhancing curcumin's bioavailability, establishing optimal dosages, and conducting comprehensive human trials to validate its effectiveness. By addressing these issues, we aim to clarify curcumin's role as a potential therapeutic agent for memory impairment in neurodegenerative disorders, paving the way for innovative treatment strategies., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests. Ethical approval: Not applicable (this paper was provided based on researching in global databases)., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Alzheimer's disease (AD) is considered one of the most common neurological conditions associated with memory and cognitive impairment and mainly affects people aged 65 or above. Even with tremendous progress in modern neuroscience, a permanent remedy or cure for this crippling disease is still unattainable. Polyphenols are a group of naturally occurring potent compounds that can modulate the neurodegenerative processes typical of AD. The present comprehensive study has been conducted to find out the preclinical and clinical potential of polyphenols and elucidate their possible mechanisms in managing AD. Additionally, we have reviewed different clinical studies investigating polyphenols as single compounds or cotherapies, including those currently recruiting, completed, terminated, withdrawn, or suspended in AD treatment. Natural polyphenols were systematically screened and identified through electronic databases including Google Scholar, PubMed, and Scopus based on in vitro cell line studies and preclinical data demonstrating their potential for neuroprotection. A total of 63 significant polyphenols were identified. A multimechanistic pathway for polyphenol's mode of action has been proposed in the study. Out of 63, four potent polyphenols have been identified as promising potential candidates, based on their reported clinical efficacy. Polyphenols hold tremendous scope for the development of a future drug molecule as a phytopharmaceutical that may be incorporated as an adjuvant to the therapeutic regime. However, more high-quality studies with novel delivery methods and combinatorial approaches are required to overcome obstacles such as bioavailability and blood-brain barrier crossing to underscore the therapeutic potential of these compounds in AD management., (© 2024 John Wiley & Sons Ltd.)

Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disease and clinically manifests with cognitive decline and behavioral disabilities. Over the past years, mounting studies have demonstrated that the inflammatory response plays a key role in the onset and development of AD, and neuroinflammation has been proposed as the third major pathological driving factor of AD, ranking after the two well-known core pathologies, amyloid β (Aβ) deposits and neurofibrillary tangles (NFTs). Epigenetic mechanisms, referring to heritable changes in gene expression independent of DNA sequence alterations, are crucial regulators of neuroinflammation which have emerged as potential therapeutic targets for AD. Upon regulation of transcriptional repression or activation, epigenetic modification profiles are closely involved in inflammatory gene expression and signaling pathways of neuronal differentiation and cognitive function in central nervous system disorders. In this review, we summarize the current knowledge about epigenetic control mechanisms with a focus on DNA and histone modifications involved in the regulation of inflammatory genes and signaling pathways in AD, and the inhibitors under clinical assessment are also discussed. [ABSTRACT FROM AUTHOR]

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Neurodegenerative disorders, such as Alzheimer's disease (AD), negatively affect the economic and psychological system. For AD, there is still a lack of disease-altering treatments and promising cures due to its complex pathophysiology. In this study, we computationally screened the natural database of fungal metabolites against three known therapeutic target proteins of AD. Initially, a pharmacophore-based, drug-likeness category was employed for screening, and it filtered the 14 (A–N) best hits out of 17,544 fungal metabolites. The 14 best hits were docked individually against GSK-3β, the NMDA receptor, and BACE-1 to investigate the potential of finding a multitarget inhibitor. We found that compounds B, F, and L were immuno-toxic, whereas E, H, I, and J had a higher LD50 dose (5000 mg/kg). Among the examined metabolites, the Bisacremine-C (compound I) was found to be the most active molecule against GSK-3β (ΔG: −8.7 ± 0.2 Kcal/mol, Ki: 2.4 × 106 M−1), NMDA (ΔG: −9.5 ± 0.1 Kcal/mol, Ki: 9.2 × 106 M−1), and BACE-1 (ΔG: −9.1 ± 0.2 Kcal/mol, Ki: 4.7 × 106 M−1). It showed a 25-fold higher affinity with GSK-3β, 6.3-fold higher affinity with NMDA, and 9.04-fold higher affinity with BACE-1 than their native ligands, respectively. Molecular dynamic simulation parameters, such as RMSD, RMSF, Rg, and SASA, all confirmed that the overall structures of the targeted enzymes did not change significantly after binding with Bisacremine-C, and the ligand remained inside the binding cavity in a stable conformation for most of the simulation time. The most significant hydrophobic contacts for the GSK-3β-Bisacremine-C complex are with ILE62, VAL70, ALA83, and LEU188, whereas GLN185 is significant for H-bonds. In terms of hydrophobic contacts, TYR184 and PHE246 are the most important, while SER180 is vital for H-bonds in NMDA-Bisacremine-C. THR232 is the most crucial for H-bonds in BACE-1-Bisacremine-C and ILE110-produced hydrophobic contacts. This study laid a foundation for further experimental validation and clinical trials regarding the biopotency of Bisacremine-C. [ABSTRACT FROM AUTHOR]

We evaluated the therapeutic potentials of Khudari fruit pulp, a functional food and cultivar of Phoenix dactylifera, against neurological disorders. Our results demonstrate a good amount of phytochemicals (total phenolic content: 17.77 ± 8.21 µg GA/mg extract) with a high antioxidant potential of aqueous extract (DPPH assay IC50 = 235.84 ± 11.65 µg/mL) and FRAP value: 331.81 ± 4.56 µmol. Furthermore, the aqueous extract showed the marked inhibition of cell-free acetylcholinesterase (electric eel) with an IC50 value of 48.25 ± 2.04 µg/mL, and an enzyme inhibition kinetics study revealed that it exhibits mixed inhibition. Thereafter, we listed the 18 best-matched phytochemical compounds present in aqueous extract through LC/MS analysis. The computational study revealed that five out of eighteen predicted compounds can cross the BBB and exert considerable aqueous solubility. where 2-{5-[(1E)-3-methylbuta-1,3-dien-1-yl]-1H-indol-3-yl}ethanol (MDIE) indicates an acceptable LD50. value. A molecular docking study exhibited that the compounds occupied the key residues of acetylcholinesterase with ΔG range between −6.91 and −9.49 kcal/mol, where MDIE has ∆G: −8.67 kcal/mol, which was better than that of tacrine, ∆G: −8.25 kcal/mol. Molecular dynamics analyses of 100 ns supported the stability of the protein–ligand complexes analyzed through RMSD, RMSF, Rg, and SASA parameters. TRP_84 and GLY_442 are the most critical hydrophobic contacts for the complex, although GLU_199 is important for H-bonds. Prime/MM-GBSA showed that the protein–ligand complex formed a stable confirmation. These findings suggest that the aqueous extract of Khudari fruit pulp has significant antioxidant and acetylcholinesterase inhibition potentials, and its compound, MDIE, forms stably with confirmation with the target protein, though this fruit of Khudari dates can be a better functional food for the treatment of Alzheimer's disease. Further investigations are needed to fully understand the therapeutic role of this plant-based compound via in vivo study. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) constitutes a multifactorial neurodegenerative pathology characterized by cognitive deterioration, personality alterations, and behavioral shifts. The ongoing brain impairment process poses significant challenges for therapeutic interventions due to activating multiple neurotoxic pathways. Current pharmacological interventions have shown limited efficacy and are associated with significant side effects. Approaches focusing on the early interference with disease pathways, before activation of broad neurotoxic processes, could be promising to slow down symptomatic progression of the disease. Curcumin-an integral component of traditional medicine in numerous cultures worldwide-has garnered interest as a promising AD treatment. Current research indicates that curcumin may exhibit therapeutic potential in neurodegenerative pathologies, attributed to its potent anti-inflammatory and antioxidant properties. Additionally, curcumin and its derivatives have demonstrated an ability to modulate cellular pathways via epigenetic mechanisms. This article aims to raise awareness of the neuroprotective properties of curcuminoids that could provide therapeutic benefits in AD. The paper provides a comprehensive overview of the neuroprotective efficacy of curcumin against signaling pathways that could be involved in AD and summarizes recent evidence of the biological efficiency of curcumins in vivo., (© 2024 The Authors. BioFactors published by Wiley Periodicals LLC on behalf of International Union of Biochemistry and Molecular Biology.)

BACKGROUND: The therapeutic properties of Hippophae rhamnoides L. were known in Ancient Greece and in Tibetan and Mongolian medicine, which commonly used it for the treatment of heart ailments, rheumatism, and brain disorders. Modern studies have indicated that Hippophae rhamnoides L. polysaccharide (HRP) can improve cognitive impairment in mice with Alzheimer's disease (AD) but the specific mechanisms of the protective effect of HRP have not been elucidated fully. RESULTS: Our results showed that Hippophae rhamnoides L. polysaccharide I (HRPI) improved pathological behaviors related to memory and cognition, and reduced 1Beta‐amyloid (Aβ) peptide deposition and neuronal cell necrosis. Pretreatment with Hippophae rhamnoides L. polysaccharide I (HRPI) also decreased the level of Toll‐like receptor 4 (TLR4) and Myeloid differentiation factor 88 (MyD88), and reduced the release of inflammatory factors Tumor necrosis factor alpha (TNFα) and interleukin 6 (IL‐6) in the brains of mice with AD. Treatment with HRPI also suppressed the expression level of Recombinant Kelch Like ECH Associated Protein 1 (KEAP1), and increased the levels of Nuclear factor erythroid 2‐Related Factor 2 (Nrf2), antioxidant enzymes Superoxide dismutase (SOD) and Glutathione peroxidase (GSH‐Px) in the brains of AD mice. CONCLUSIONS: On the whole, these findings revealed that HRPI could improve the learning and memory ability and attenuate pathologic impairment in AD mice, and the underlying mechanisms may involve mediating oxidative stress and inflammation, possibly through the regulation of the Keap1/Nrf2 and TLR4/MyD88 signaling pathways. © 2023 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

The Australian rainforest is a rich source of medicinal plants that have evolved in the face of dramatic environmental challenges over a million years due to its prolonged geographical isolation from other continents. The rainforest consists of an inherent richness of plant secondary metabolites that are the most intense in the rainforest. The search for more potent and more bioavailable compounds from other plant sources is ongoing, and our short review will outline the pathways from the discovery of bioactive plants to the structural identification of active compounds, testing for potency, and then neuroprotection in a triculture system, and finally, the validation in an appropriate neuro-inflammatory mouse model, using some examples from our current research. We will focus on neuroinflammation as a potential treatment target for neurodegenerative diseases including multiple sclerosis (MS), Parkinson's (PD), and Alzheimer's disease (AD) for these plant-derived, anti-inflammatory molecules and highlight cytokine suppressive anti-inflammatory drugs (CSAIDs) as a better alternative to conventional nonsteroidal anti-inflammatory drugs (NSAIDs) to treat neuroinflammatory disorders. [ABSTRACT FROM AUTHOR]

Most patients who die of cancer do so from its metastasis to other organs. The calcium-binding protein S100A4 can induce cell migration/invasion and metastasis in experimental animals and is overexpressed in most human metastatic cancers. Here, we report that a novel inhibitor of S100A4 can specifically block its increase in cell migration in rat (IC50, 46 µM) and human (56 µM) triple negative breast cancer (TNBC) cells without affecting Western-blotted levels of S100A4. The moderately-weak S100A4-inhibitory compound, US-10113 has been chemically attached to thalidomide to stimulate the proteasomal machinery of a cell. This proteolysis targeting chimera (PROTAC) RGC specifically eliminates S100A4 in the rat (IC50, 8 nM) and human TNBC (IC50, 3.2 nM) cell lines with a near 20,000-fold increase in efficiency over US-10113 at inhibiting cell migration (IC50, 1.6 nM and 3.5 nM, respectively). Knockdown of S100A4 in human TNBC cells abolishes this effect. When PROTAC RGC is injected with mouse TNBC cells into syngeneic Balb/c mice, the incidence of experimental lung metastases or local primary tumour invasion and spontaneous lung metastasis is reduced in the 10–100 nM concentration range (Fisher's Exact test, p ≤ 0.024). In conclusion, we have established proof of principle that destructive targeting of S100A4 provides the first realistic chemotherapeutic approach to selectively inhibiting metastasis. [ABSTRACT FROM AUTHOR]

This study investigates the role of autophagy regulation in modulating neuroinflammation and cognitive function in an Alzheimer's disease (AD) mouse model with chronic cerebral hypoperfusion (CCH). Using the APP23/PS1 mice plus CCH model, we examined the impact of autophagy regulation on cognitive function, neuroinflammation, and autophagic activity. Our results demonstrate significant cognitive impairments in AD mice, exacerbated by CCH, but mitigated by treatment with the autophagy inhibitor 3-methyladenine (3-MA). Dysregulation of autophagy-related proteins, accentuated by CCH, underscores the intricate relationship between cerebral blood flow and autophagy dysfunction in AD pathology. While 3-MA restored autophagic balance, rapamycin (RAPA) treatment did not induce significant changes, suggesting alternative therapeutic approaches are necessary. Dysregulated microglial polarization and neuroinflammation in AD+CCH were linked to cognitive decline, with 3-MA attenuating neuroinflammation. Furthermore, alterations in M2 microglial polarization and the levels of inflammatory markers NLRP3 and MCP1 were observed, with 3-MA treatment exhibiting potential anti-inflammatory effects. Our findings shed light on the crosstalk between autophagy and neuroinflammation in AD+CCH and suggest targeting autophagy as a promising strategy for mitigating neuroinflammation and cognitive decline in AD+CCH., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Curcumin and omega-3 polyunsaturated fatty acids (ω-3 PUFA) are multifunctional compounds which play an important role in Alzheimer's disease (AD) and little has been addressed about the role of these two compounds together in the progression of the disease. There is evidence of the beneficial effect of combined administration of ω-3 PUFA and other dietary supplements such as vitamins and polyphenols in the prevention of AD, although much remains to be understood about their possible complementary or synergistic activity. Therefore, the objective of this work is to review the research focused on studying the effect and mechanisms of action of curcumin, ω-3 PUFA, and the combination of these nutraceutical compounds, particularly on AD, and to integrate the possible ways in which these compounds can potentiate their effect. The most important pathophysiologies that manifest in AD will be addressed, in order to have a better understanding of the mechanisms of action through which these bioactive compounds exert a neuroprotective effect., (© 2024 Japanese Psychogeriatric Society.)

Background: Toll-like receptor 3 (TLR3) plays an important role in the immune/inflammatory response in the nervous system and is a main pathological feature of Alzheimer's disease (AD). This study investigates the role of early activation of TLR3 in the pathophysiological process of AD. Methods: In the experiment, the agonist of TLR3, Poly(I:C), was intraperitoneally injected into the APP/PS1 mouse model of AD and wild-type control mice starting from the age of 4 to 9 months. At the age of 14 months, behavioral tests were conducted. Western blot and immunohistochemistry staining were used to evaluate the level of amyloid β-protein (Aβ), the activation of inflammatory cells, and neuron loss. In addition, the levels of inflammatory cytokines were measured using a quantitative polymerase chain reaction. Results: The results demonstrated that the early activation of TLR3 attenuated neuronal loss and neurobehavioral dysfunction. Moreover, the early activation of TLR3 reduced Aβ deposition, inhibited the activation of microglia and astrocytes, and decreased the transcription of pro-inflammatory factors in the hippocampus. Conclusions: The results indicated that the activation of TLR3 by Poly (I:C) in the early stage of development of AD in a mouse model attenuated neuron loss and improved neurobehavioral functions. The underlying mechanisms could be attributed to its role in Aβ clearance, the inhibition of glial cells, and the regulation of neuroinflammation in the hippocampus. [ABSTRACT FROM AUTHOR]

Alzheimer's disease is characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. However, emerging evidence suggests that neuroinflammation, mediated notably by activated neuroglial cells, neutrophils, and macrophages, also plays an important role in the pathogenesis of Alzheimer's disease. Therefore, understanding the interplay between the nervous and immune systems might be the key to the prevention or delay of Alzheimer's disease progression. One of the most important mechanisms determining gliogenic cell fate is the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway that is influenced by the overactivation of microglia and astrocytes. The JAK/STAT signaling pathway is one of the critical factors that promote neuroinflammation in neurodegenerative diseases such as Alzheimer's disease by initiating innate immunity, orchestrating adaptive immune mechanisms, and finally, constraining neuroinflammatory response. Since a chronic neuroinflammatory environment in the brain is a hallmark of Alzheimer's disease, understanding the process would allow establishing the underlying role of neuroinflammation, then estimating the prognosis of Alzheimer's disease development and finding a new potential treatment target. In this review, we highlight the recent advances in the potential role of JAK/STAT signaling in neurological diseases with a focus on discussing future research directions regarding novel therapeutic approaches and predictive biomarkers for Alzheimer's disease. [ABSTRACT FROM AUTHOR]

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Alzheimer's disease (AD) is a neurological illness that causes memory loss over time. Currently, available pharmaceutical medicines and products are limited, and they have side effects at a higher price. Researchers and scientists have observed significant effects of nutraceuticals. Various preclinical and clinical studies were investigated for the Anti‐Alzheimer's activity of nutraceuticals. The increasing ability of the pathogenesis of AD has led to the analysis of novel therapeutic targets, including the pathophysiological mechanisms and distinct cascades. So, current improvement will show the most adequate and prominent nutraceuticals and suggested concise mechanisms involving autophagy regulation, anti‐inflammatory, antioxidant, mitochondrial homeostasis, and others. The effects of nutraceuticals cannot be ignored; it is important to investigate high‐quality clinical trials. Given the potential of nutraceuticals to battle AD as multi‐targeted therapies, it's vital to evaluate them as viable lead compounds for drug discovery and development. To the best of the authors 'knowledge, modification of blood–brain barrier permeability, bioavailability, and aspects of randomized clinical trials should be considered in prospective investigations. Practical applications: Advancements in molecular diagnostic and fundamentals have implemented particular usefulness for drug evaluation. An excess of experimental knowledge occurs regarding the effect of nutraceuticals on AD. There are various preclinical and clinical studies that have been done on nutraceuticals. In addition, various substitute inhibit and enhance some pathophysiological levels associated with AD. Nutraceuticals are easily available and have fewer side effects with cost‐effective advantages. However, further investigations and clinical trials are required to encourage its effect on disease. [ABSTRACT FROM AUTHOR]

Since the original description of Alzheimer´s disease (AD), research into this condition has mainly focused on assessing the alterations to neurons associated with dementia, and those to the circuits in which they are involved. In most of the studies on human brains and in many models of AD, the glial cells accompanying these neurons undergo concomitant alterations that aggravate the course of neurodegeneration. As a result, these changes to neuroglial cells are now included in all the "pathogenic cascades" described in AD. Accordingly, astrogliosis and microgliosis, the main components of neuroinflammation, have been integrated into all the pathogenic theories of this disease, as discussed in this part of the two-part monograph that follows an accompanying article on gliopathogenesis and glioprotection. This initial reflection verified the implication of alterations to the neuroglia in AD, suggesting that these cells may also represent therapeutic targets to prevent neurodegeneration. In this second part of the monograph, we will analyze the possibilities of acting on glial cells to prevent or treat the neurodegeneration that is the hallmark of AD and other pathologies. Evidence of the potential of different pharmacological, non-pharmacological, cell and gene therapies (widely treated) to prevent or treat this disease is now forthcoming, in most cases as adjuncts to other therapies. A comprehensive AD multimodal therapy is proposed in which neuronal and neuroglial pharmacological treatments are jointly considered, as well as the use of new cell and gene therapies and non-pharmacological therapies that tend to slow down the progress of dementia. [ABSTRACT FROM AUTHOR]

Background: The aberrant accumulation of β-amyloid peptides (Aβ), reactive astrocytes and glucose metabolism deficit are typical features in the early Alzheimer's disease (AD) pathology. Previous studies have demonstrated that astrocytes process glucose mainly by glycolysis to generate lactate. However, the changes of glycolytic metabolism of reactive astrocytes in AD are still unknown. The present study aims to explore the effect of Aβ on the astrocytic activation and glycolytic metabolism, as well as the role of glycolysis in the activation of astrocytes. Methods and Results: The primary astrocytes were cultured and treated with Aβ oligomers, Aβ-activated microglia conditioned medium (aMCM) or the glycogen phosphorylase inhibitor (DAB) for 12 h. Then ECAR was used to detect the glycolysis function of reactive astrocytes. The phenotypes of reactive astrocytes were evaluated by detecting the mRNA expression of Gfap (pan-reactive marker), and Ugt1a, Ggta1 (A1-phenotypes markers), and S100a10, Emp1 (A2-phenotypes markers) using qRT-PCR. The levels of GFAP, the marker protein of pan-reactive astrocytes, was also quantified by immunofluorescence and western-blot in Aβ, aMCM or DAB-treated astrocytes. In this study, we found that Aβ oligomers could not directly activate astrocytes or promote the glycolysis. However, Aβ oligomers could induce the activation of neurotoxic A1 astrocytes and up-regulate the glycolysis function via aMCM. Reactivity of A1-astrocytes were inhibited when the glycolytic metabolism was blocked by DAB. Conclusions: The results revealed that Aβ could indirectly activate A1 astrocytes by Aβ-activated microglia, which depended on the up-regulation of the glycolysis of astrocytes. The glycolysis was crucial for the activation of the neurotoxic A1 astrocytes and inhibiting the glycolysis of neurotoxic A1 astrocytes might be a new therapeutic strategy for AD. [ABSTRACT FROM AUTHOR]

Traditional Chinese medicine suggests that Ginseng and Astragalus Decoction (GAD) may effectively treat postmenopausal osteoporosis (PMO). However, the exact mechanism of action for GAD remains unclear. This study aims to utilize network pharmacology and molecular docking technology to explore the potential mechanism of GAD in treating PMO. The main chemical components of GAD were identified by consulting literature and traditional Chinese medicine systems pharmacology database. GeneCards and online mendelian inheritance in man were used to identify PMO disease targets, and Cytoscape 3.8.2 software was used to construct a herb-disease-gene-target network. The intersection of drug targets and disease targets was introduced into the search tool for the retrieval of interacting genes platform to construct a protein-protein interaction network. Additionally, we further conducted gene ontology and Kyoto encyclopedia of genes and genomes enrichment analyses, followed by molecular docking between active ingredients and core protein targets. We have identified 59 potential targets related to the treatment of PMO by GAD, along with 33 effective components. Quercetin and kaempferol are the compounds with higher degree. In the protein-protein interaction network, IL6, AKT1, and IL1B are proteins with high degree. The enrichment analysis of gene ontology and KEEG revealed that biological processes involved in treating PMO with GAD mainly include response to hormones, positive regulation of phosphorylation, and regulation of protein homodimerization activity. The signal pathways primarily include Pathways in cancer, PI3K-Akt signaling pathway, and AGE-RAGE signaling pathway. Molecular docking results indicate that kaempferol and quercetin have a high affinity for IL6, AKT1, and IL1B. Our research predicts that IL6, AKT1, and IL1B are highly likely to be potential targets for treating PMO with GAD. PI3K/AKT pathway and AGE-ARGE pathway may play an important role in PMO., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Despite ongoing advancements in research, the inability of therapeutics to cross the blood-brain barrier (BBB) makes the treatment of neurological disorders (NDs) a challenging task, offering only partial symptomatic relief. Various adverse effects associated with existing approaches are another significant barrier that prompts the usage of structurally diverse phytochemicals as preventive/therapeutic lead against NDs in preclinical and clinical settings. Despite numerous beneficial properties, phytochemicals suffer from poor pharmacokinetic profile which limits their pharmacological activity and necessitates the utility of nanotechnology for efficient drug delivery. Nanocarriers have been shown to be proficient carriers that can enhance drug delivery, bioavailability, biocompatibility, and stability of phytochemicals. We, thus, conducted a meticulous literature survey using several electronic databases to gather relevant studies in order to provide a comprehensive summary about the use of nanocarriers in delivering phytochemicals as a treatment approach for NDs. Additionally, the review highlights the mechanisms of drug transport of nanocarriers across the BBB and explores their potential future applications in this emerging field., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Alzheimer's disease (AD) causes dementia and memory loss in the elderly. Deposits of beta-amyloid peptide and hyperphosphorylated tau protein are present in a brain with AD. A filtrate of Helicobacter pylori's culture was previously found to induce hyperphosphorylation of tau in vivo, suggesting that bacterial exotoxins could permeate the blood–brain barrier and directly induce tau's phosphorylation. H. pylori, which infects ~60% of the world population and causes gastritis and gastric cancer, produces a pro-inflammatory urease (HPU). Here, the neurotoxic potential of HPU was investigated in cultured cells and in rats. SH-SY5Y neuroblastoma cells exposed to HPU (50–300 nM) produced reactive oxygen species (ROS) and had an increased [Ca2+]i. HPU-treated BV-2 microglial cells produced ROS, cytokines IL-1β and TNF-α, and showed reduced viability. Rats received daily i.p., HPU (5 µg) for 7 days. Hyperphosphorylation of tau at Ser199, Thr205 and Ser396 sites, with no alterations in total tau or GSK-3β levels, and overexpression of Iba1, a marker of microglial activation, were seen in hippocampal homogenates. HPU was not detected in the brain homogenates. Behavioral tests were performed to assess cognitive impairments. Our findings support previous data suggesting an association between infection by H. pylori and tauopathies such as AD, possibly mediated by its urease. [ABSTRACT FROM AUTHOR]

Objectives: Neuroinflammation is a complex inflammatory process in the central nervous system (CNS) where microglia may play a critical role. GPETAFLR is a peptide isolated from Lupinus angustifolius L. protein hydrolysates with functional activity in mononuclear phagocytes. However, it is unknown whether GPETAFLR has neuroprotective effects. Methods: We analysed the potential anti-neuroinflammatory activity of GPETAFLR by using two different models of neuroinflammation: BV-2 microglial cells and mice with high-fat diet (HFD)-induced obesity. Results: GPETAFLR hampered LPS-induced upregulation of pro-inflammatory and M1 marker genes in BV-2 cells. This effect was accompanied by an unchanged expression of anti-inflammatory IL-10 gene and by an increased expression of M2 marker genes. GPETAFLR also increased the transcriptional activity of M2 marker genes, while the microglia population remained unchanged in number and M1/M2 status in brain of mice with high-fat diet (HFD)-induced obesity. Furthermore, GPETAFLR counteracted HFD-induced downregulation of IL-10 and upregulation of pro-inflammatory markers in the mouse brain, both at gene and protein levels. Discussion: This is the first report describing that a peptide from plant origin robustly restrained the pro-inflammatory activation of microglial cells in cultures and in brain. Our data suggest that GPETAFLR might be instrumental in maintaining CNS homeostasis by inhibiting neuroinflammation. [ABSTRACT FROM AUTHOR]

Inflammation is a defensive reaction for external stimuli to the human body and generally accompanied by immune responses, which is associated with multiple diseases such as atherosclerosis, type 2 diabetes, Alzheimer's disease, psoriasis, asthma, chronic lung diseases, inflammatory bowel disease, and multiple virus-associated diseases. Epigenetic mechanisms have been demonstrated to play a key role in the regulation of inflammation. Common epigenetic regulations are DNA methylation, histone modifications, and non-coding RNA expression; among these, histone modifications embrace various post-modifications including acetylation, methylation, phosphorylation, ubiquitination, and ADP ribosylation. This review focuses on the significant role of histone modifications in the progression of inflammatory diseases, providing the potential target for clinical therapy of inflammation-associated diseases. [ABSTRACT FROM AUTHOR]

A nutraceutical is a food-derived molecule that provides medical or health benefits beyond its basic nutritional role, including the prevention and treatment of disease and its symptoms. In the peripheral nervous system, satellite glial cells are found in close relationship with neurons, mainly in peripheral sensory ganglia, but, compared with other glial cells, the relationship between these cells and nutraceuticals has received little attention. After describing satellite glial cells and their role and changes in physiology and pathology, we review the studies on the effects of nutraceuticals as modulators of their functions. Maybe due to the difficulties in selectively labeling these cells, only a few studies, performed mainly in rodent models, have analyzed nutraceutical effects, showing that N-acetylcysteine, curcumin, quercetin, osthole and resveratrol may palliate neuropathic pain through satellite glial cells-dependent pathways, namely antioxidant mechanisms and/or interference with purinergic signaling. Neither other conditions in which satellite glial cells are involved (visceral pain, nerve regeneration) nor other nutraceuticals or mechanisms of action have been studied. Although more preclinical and clinical research is needed, the available reports support the general notion that nutraceuticals may become interesting alternatives in the prevention and/or treatment of peripheral gliopathies and their associated conditions, including those affecting the satellite glial cells. [ABSTRACT FROM AUTHOR]

Cadmium (Cd) is a potent neurotoxic metal present in the environment and food. In this study, CdCl2 (2 or 4 μM) induced cytotoxicity and neurotoxicity in PC12 cells, causing decreases in cell viability and NEP protein expression and increase in p‐tau protein expression. For the first time, CdCl2‐initiated injury was found to result from the induction of not only apoptosis but also ferroptosis, as evidenced by the increased iron content, ROS production, and mitochondrial membrane potential along with changes in the expressions of iron death‐related genes (FTH1, GPX4, ASCL4, PTGS2, and NOX1) and levels of caspase9, Bax, and Bcl‐2 proteins. The molecular mechanisms leading to apoptosis and ferroptosis at least included the participation of the miR‐34a‐5p/Sirt1 axis, in which miR‐34a‐5p promoted CdCl2‐induced neurotoxicity through targeting Sirt1. Knocking out miR‐34a‐5p attenuated CdCl2‐induced damage of PC12 cells, cytotoxicity and neurotoxicity. This research provides the underlying molecular mechanisms of CdCl2‐induced damage and asserts the role of miRNAs as critical regulators. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a major contributor of dementia leading to the degeneration of neurons in the brain with major symptoms like loss of memory and learning. Many evidences suggest the involvement of neuroinflammation in the pathology of AD. Cytokines including TNF-α and IL-6 are also found increasing the BACE1 activity and expression of NFκB resulting in generation of Aβ in AD brain. Following the interaction of Aβ with microglia and astrocytes, other inflammatory molecules also get translocated to the site of inflammation by chemotaxis and exaggerate neuroinflammation. Various pathways like NFκB, p38 MAPK, Akt/mTOR, caspase, nitric oxide and COX trigger microglia to release inflammatory cytokines. PPARγ agonists like pioglitazone increases the phagocytosis of Aβ and reduces inflammatory cytokine IL-1β. Celecoxib and roficoxib like selective COX-2 inhibitors also ameliorate neuroinflammation. Non-selective COX inhibitor indomethacin is also potent inhibitor of inflammatory mediators released from microglia. Mitophagy process is considered quite helpful in reducing inflammation due to microglia as it promotes the phagocytosis of over activated microglial cells and other inflammatory cells. Mitophagy induction is also beneficial in the removal of damaged mitochondria and reduction of infiltration of inflammatory molecules at the site of accumulation of the damaged mitochondria. Targeting these pathways and eventually ameliorating the activation of microglia can mitigate neuroinflammation and come out as a better therapeutic option for the treatment of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

It was already shown that microdoses of lithium carbonate (Li2CO3) promoted memory stabilization in humans and mice. Prolonged treatment also reduced neuronal loss and increased the density of the neurotrophin BDNF in transgenic mice for Alzheimer's disease. The aim of this study was to evaluate whether lithium ions affect inflammatory profiles and neuronal integrity in an animal model of accelerated senescence (SAMP-8). Organotypic hippocampal cultures obtained from 11 to 12-month-old SAMP-8 mice were treated with 2 µM, 20 µM and 200 µM Li2CO3. 2 µM Li2CO3 promoted a significant reduction in propidium iodide uptake in the CA2 area of hippocampus, whereas 20 µM promoted neuroprotection in the CA3 and GrDG areas. 200 µM caused an increase in cellular death, showing toxicity. Measured with quantitative PCR, IL-1α, IL-6 and MIP-1B/CCL-4 gene expression was significantly reduced with 20 µM Li2CO3, whereas IL-10 gene expression was significantly increased with the same concentration. In addition, 2 µM and 20 µM Li2CO3 were also effective in reducing the activation of NFkB and inflammatory cytokines densities, as evaluated by ELISA. It is concluded that very low doses of Li2CO3 can play an important role in neuroprotection as it can reduce neuronal loss and neuroinflammation in older individuals. [ABSTRACT FROM AUTHOR]

Background: The therapeutic properties of Hippophae rhamnoides L. were known in Ancient Greece and in Tibetan and Mongolian medicine, which commonly used it for the treatment of heart ailments, rheumatism, and brain disorders. Modern studies have indicated that Hippophae rhamnoides L. polysaccharide (HRP) can improve cognitive impairment in mice with Alzheimer's disease (AD) but the specific mechanisms of the protective effect of HRP have not been elucidated fully., Results: Our results showed that Hippophae rhamnoides L. polysaccharide I (HRPI) improved pathological behaviors related to memory and cognition, and reduced 1 Beta-amyloid (Aβ) peptide deposition and neuronal cell necrosis. Pretreatment with Hippophae rhamnoides L. polysaccharide I (HRPI) also decreased the level of Toll-like receptor 4 (TLR4) and Myeloid differentiation factor 88 (MyD88), and reduced the release of inflammatory factors Tumor necrosis factor alpha (TNFα) and interleukin 6 (IL-6) in the brains of mice with AD. Treatment with HRPI also suppressed the expression level of Recombinant Kelch Like ECH Associated Protein 1 (KEAP1), and increased the levels of Nuclear factor erythroid 2-Related Factor 2 (Nrf2), antioxidant enzymes Superoxide dismutase (SOD) and Glutathione peroxidase (GSH-Px) in the brains of AD mice., Conclusions: On the whole, these findings revealed that HRPI could improve the learning and memory ability and attenuate pathologic impairment in AD mice, and the underlying mechanisms may involve mediating oxidative stress and inflammation, possibly through the regulation of the Keap1/Nrf2 and TLR4/MyD88 signaling pathways. © 2023 Society of Chemical Industry., (© 2023 Society of Chemical Industry.)

Formyl peptide receptors (FPRs) are a group of G protein-coupled cell surface receptors that play important roles in host defense and inflammation. Owing to the ubiquitous expression of FPRs throughout different cell types and since they interact with structurally diverse chemotactic agonists, they have a dual function in inflammatory processes, depending on binding with different ligands so that accelerate or inhibit key intracellular kinase-based regulatory pathways. Neuroinflammation is closely associated with the pathogenesis of neurodegenerative diseases, neurogenic tumors and cerebrovascular diseases. From recent studies, it is clear that FPRs are important biomarkers for neurological diseases as they regulate inflammatory responses by monitoring glial activation, accelerating neural differentiation, regulating angiogenesis, and controlling blood brain barrier (BBB) permeability, thereby affecting neurological disease progression. Given the complex mechanisms of neurological diseases and the difficulty of healing, we are eager to find new and effective therapeutic targets. Here, we review recent research about various mechanisms of the effects generated after FPR binding to different ligands, role of FPRs in neuroinflammation as well as the development and prognosis of neurological diseases. We summarize that the FPR family has dual inflammatory functional properties in central nervous system. Emphasizing that FPR2 acts as a key molecule that mediates the active resolution of inflammation, which binds with corresponding receptors to reduce the expression and activation of pro-inflammatory composition, govern the transport of immune cells to inflammatory tissues, and restore the integrity of the BBB. Concurrently, FPR1 is essentially related to angiogenesis, cell proliferation and neurogenesis. Thus, treatment with FPRs-modulation may be effective for neurological diseases. [ABSTRACT FROM AUTHOR]

Neuroinflammation-induced neurodegeneration and immune cell infiltration are two features of Alzheimer disease (AD). This study aimed to identify potential peripheral biomarkers that interact with cerebrospinal fluid (CSF) and infiltrating immune cells in AD. Blood and CSF data were downloaded from the Alzheimer's disease Neuroimaging Initiative database. We identified differentially expressed genes (DEGs) in AD and assessed infiltrating immune cells using the Immune Cell Abundance Identifier (ImmuCellAI) algorithm. Blood-brain barrier (BBB) and immune-related genes were identified from medical databases, and common genes were used to construct a protein-protein interaction network (PPI). Potential biomarkers reflecting the clinical features of AD were screened using Pearson correlations and logistic regression analysis. We identified 210 DEGs in the AD group. ImmuCellAI indicated that blood samples from patients with AD had a higher abundance of exhausted T (Tex; 0.196 vs. 0.132) and induced regulatory T (iTreg; 0.180 vs. 0.137) cells than controls. Thirty-two genes overlapped between the BBB and immune-related genes, and 27 genes in the PPI network were associated with eight pathways, including the cytokine-cytokine receptor interaction pathway (hsa04060) and the chemokine signaling pathway (hsa04062). Pearson correlations showed that five genes were associated with the CSF biomarkers, Aβ, total, and phosphorylated tau. Logistics analysis showed that the B cell-associated genes, CXCL12 and TNFRSF13C, were independent risk factors for AD diagnosis. Peripheral CXCL12 and TNFRSF13C genes that correlated with immune cell infiltration in AD might serve as easily accessible biomarkers for the early diagnosis of AD. [ABSTRACT FROM AUTHOR]

Introduction: Alzheimer's disease (AD) is a progressive neurodegenerative disease accompanying memory deficits. The available pharmaceutical care has some limitations mostly entailing side effects, shelf-life, and patient's compliance. The momentous implications of nutraceuticals in AD have attracted scientists. Several preclinical studies for the investigation of nutraceuticals have been conducted. Areas covered: This review focuses on the potential use of a nutraceuticals-based therapeutic approach to treat and prevent AD. Increasing knowledge of AD pathogenesis has led to the discovery of new therapeutic targets including pathophysiological mechanisms and various cascades. Hence, the present contribution will attend to the most popular and effective nutraceuticals with proposed brief mechanisms entailing antioxidant, anti-inflammatory, autophagy regulation, mitochondrial homeostasis, and more. Therefore, even though the effectiveness of nutraceuticals cannot be dismissed, it is essential to do further high-quality randomized clinical trials. Expert opinion: According to the potential of nutraceuticals to combat AD as multi-target directed drugs, there is critical importance to assess them as feasible lead compounds for drug discovery and development. To the best of the authors' knowledge, modification of blood–brain barrier permeability, bioavailability, and features of randomized clinical trials should be considered in prospective studies. [ABSTRACT FROM AUTHOR]

Clinical studies have found that some Alzheimer's disease (AD) patients suffer from Cushing's syndrome (CS). CS is caused by the long-term release of excess glucocorticoids (GCs) from the adrenal gland, which in turn, impair brain function and induce dementia. Thus, we investigated the mechanism of the effect of corticosterone (CORT) on the development and progression of AD in a preclinical model. Specifically, the plasma CORT levels of 9-month-old APP/PS1 Tg mice were abnormally increased, suggesting an association between GCs and AD. Long-term administration of CORT accelerated cognitive dysfunction by increasing the production and deposition of β-amyloid (Aβ). The mechanism of action of CORT treatment involved stimulation of the expression of BACE-1 and presenilin (PS) 1 in in vitro and in vivo. This observation was confirmed in mice with adrenalectomy (ADX), which had lower levels of GCs. Moreover, the glucocorticoid receptor (GR) mediated the effects of CORT on the stimulation of the expression of BACE-1 and PS1 via the PKA and CREB pathways in neuroblastoma N2a cells. In addition to these mechanisms, CORT can induce a cognitive decline in APP/PS1 Tg mice by inducing apoptosis and decreasing the differentiation of neurons. [ABSTRACT FROM AUTHOR]

Grafting of neural stem cells (NSCs) derived from human induced pluripotent stem cells (hiPSCs) has shown promise for brain repair after injury or disease, but safety issues have hindered their clinical application. Employing nano-sized extracellular vesicles (EVs) derived from hiPSC-NSCs appears to be a safer alternative because they likely have similar neuroreparative properties as NSCs and are amenable for non-invasive administration as an autologous or allogeneic off-the-shelf product. However, reliable methods for isolation, characterization and testing the biological properties of EVs are critically needed for translation. We investigated signatures of miRNAs and proteins and the biological activity of EVs, isolated from hiPSC-NSCs through a combination of anion-exchange chromatography (AEC) and size-exclusion chromatography (SEC). AEC and SEC facilitated the isolation of EVs with intact ultrastructure and expressing CD9, CD63, CD81, ALIX and TSG 101. Small RNA sequencing, proteomic analysis, pathway analysis and validation of select miRNAs and proteins revealed that EVs were enriched with miRNAs and proteins involved in neuroprotective, anti-apoptotic, antioxidant, anti-inflammatory, blood-brain barrier repairing, neurogenic and Aβ reducing activities. Besides, EVs comprised miRNAs and/or proteins capable of promoting synaptogenesis, synaptic plasticity and better cognitive function. Investigations using an in vitro macrophage assay and a mouse model of status epilepticus confirmed the anti-inflammatory activity of EVs. Furthermore, the intranasal administration of EVs resulted in the incorporation of EVs by neurons, microglia and astrocytes in virtually all adult rat and mouse brain regions, and enhancement of hippocampal neurogenesis. Thus, biologically active EVs containing miRNAs and proteins relevant to brain repair could be isolated from hiPSC-NSC cultures, making them a suitable biologic for treating neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Drug compounds including memantine moieties are an important group of biologically active agents for different pathologies, including the Alzheimer's disease. In the present study, a series of memantine derivatives incorporating amino acid residues have been synthesized and their neuroprotective in vitro evaluation in respect of the Alzheimer's disease, involving the effects on the resistance to Aβ toxicity, excitotoxicity, oxidative stress, hypoxia, and neuroinflammation has been studied. The cytotoxicities of the compounds were detected by CPE assay. TC50 and IC50 were determined using Reed and Muench method. Solubility and distribution were measured using a shake-flask method. Permeability of the compounds was studied using Franz diffusion cell and Permeapad™ barrier. These compounds displayed apparent multi-neuroprotective effects against copper-triggered Aβ toxicity, glutamate-induced excitotoxicity, and oxidative and hypoxic injuries. They also showed the ability to inhibit the inflammatory cytokine release from the activated microglia and potential anti-neuroinflammatory effects. Especially, two most promising compounds H-4-F-Phe-memantine and H-Tyr-memantine demonstrated the equivalent functional bioactivities in comparison with the positive control memantine hydrochloride. Higher solubility in muriatic buffer than in phosphate buffer was detected. The distribution coefficients showed the optimal lipophilicity for compounds. The presented results propose new class of memantine derivatives as potential drug compounds. Based on the experimental results, the correlations have been obtained between the biological, physicochemical parameters and structural descriptors. The correlation equations have been proposed to predict the properties of new memantine derivatives knowing only the structural formula. [ABSTRACT FROM AUTHOR]

Oxidative stress has a significant impact on neurodegenerative diseases. The present paper reviewed the role of oxidative stress in disease progression of Alzheimer's disease (AD) and measurement of the oxidative stress markers in cerebrospinal fluid (CSF) in AD in vivo. Oxidative stress measurement in CSF in AD provides knowledge of underlying pathophysiology, to be a counterpart of oxidative stress neuroimaging, and to help differentiating AD from other neurodegenerative diseases. In addition, these findings warrant future studies to see whether antioxidant intervention might help preventing progression of neurodegenerative diseases including AD. [ABSTRACT FROM AUTHOR]