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Amyloid fibrils of tau are increasingly accepted as a cause of neuronal death and brain atrophy in Alzheimer's disease (AD). Diminishing tau aggregation is a promising strategy in the search for efficacious AD therapeutics. Previously, our laboratory designed a six-residue, nonnatural amino acid inhibitor D-TLKIVW peptide (6-DP), which can prevent tau aggregation in vitro. However, it cannot block cell-to-cell transmission of tau aggregation. Here, we find D-TLKIVWC (7-DP), a d-cysteine extension of 6-DP, not only prevents tau aggregation but also fragments tau fibrils extracted from AD brains to neutralize their seeding ability and protect neuronal cells from tau-induced toxicity. To facilitate the transport of 7-DP across the blood-brain barrier, we conjugated it to magnetic nanoparticles (MNPs). The MNPs-DP complex retains the inhibition and fragmentation properties of 7-DP alone. Ten weeks of MNPs-DP treatment appear to reverse neurological deficits in the PS19 mouse model of AD. This work offers a direction for development of therapies to target tau fibrils.

The substantia nigra is generally considered to show significant cell loss not only in Parkinson's but also in Alzheimer's disease, conditions that share several neuropathological traits. An interesting feature of this nucleus is that the pars compacta dopaminergic neurons contain acetylcholinesterase (AChE). Independent of its enzymatic role, this protein is released from pars reticulata dendrites, with effects that have been observed in vitro, ex vivo and in vivo. The part of the molecule responsible for these actions has been identified as a 14-mer peptide, T14, cleaved from the AChE C-terminus and acting at an allosteric site on alpha-7 nicotinic receptors, with consequences implicated in neurodegeneration. Here, we show that free T14 is co-localized with tyrosine hydroxylase in rodent pars compacta neurons. In brains with Alzheimer's pathology, the T14 immunoreactivity in these neurons increases in density as their number decreases with the progression of the disease. To explore the functional implications of raised T14 levels in the substantia nigra, the effect of exogenous peptide on electrically evoked neuronal activation was tested in rat brain slices using optical imaging with a voltage-sensitive dye (Di-4-ANEPPS). A significant reduction in the activation response was observed; this was blocked by the cyclized variant of T14, NBP14. In contrast, no such effect of the peptide was seen in the striatum, a region lacking the T14 target, alpha-7 receptors. These findings add to the accumulating evidence that T14 is a key signaling molecule in neurodegenerative disorders and that its antagonist NBP14 has therapeutic potential.

Introduction: The neuronal mechanism driving Alzheimer's disease (AD) is incompletely understood., Methods: Immunohistochemistry, pharmacology, biochemistry, and behavioral testing are employed in two pathological contexts-AD and a transgenic mouse model-to investigate T14, a 14mer peptide, as a key signaling molecule in the neuropathology., Results: T14 increases in AD brains as the disease progresses and is conspicuous in 5XFAD mice, where its immunoreactivity corresponds to that seen in AD: neurons immunoreactive for T14 in proximity to T14-immunoreactive plaques. NBP14 is a cyclized version of T14, which dose-dependently displaces binding of its linear counterpart to alpha-7 nicotinic receptors in AD brains. In 5XFAD mice, intranasal NBP14 for 14 weeks decreases brain amyloid and restores novel object recognition to that in wild-types., Discussion: These findings indicate that the T14 system, for which the signaling pathway is described here, contributes to the neuropathological process and that NBP14 warrants consideration for its therapeutic potential., Competing Interests: Susan Greenfield is the founder and CEO of Neuro‐Bio Limited and holds shares in the Company. She is the inventor in all Neuro‐Bio patents. Neuro‐Bio has a patent portfolio that currently includes 15 patent families (granted patents in Australia ( AU), China (CN), Europe (EP), Japan (JP), Mexico (MX), and United States of America (USA)). The bulk of this patent protection is in the field of neurodegeneration and, in particular, Alzheimer's disease. Of these, there are granted patents (in AU x2, CN, EP, JP, MX, and USA) and pending patent applications (in Brazil (BR), Canada (CA), India (IN), Republic of Korea (KR), New Zeland (NZ), and South Africa (ZA)) all based on WO2015/004430 (use of cyclic peptides from the C‐terminus of AChE for the diagnosis, prevention and treatment of neurodegeneration). In addition, Neuro‐Bio has a published international patent application with 12 corresponding national phases at different stages of prosecution based on each of WO2016/083809 (Novel linear peptides for treating neurodegeneration); WO2018/033724 (Peptidomimetics for treating Alzheimer's disease); and WO2016/156803 (Antibody that recognizes the T14 peptide of AChE). Neuro‐Bio also has published international patent application based on WO2018/178665 (Quantitative predictive biomarker for predicting cognitive decline) with national phases proceeding in the USA and EP. Neuro‐Bio additionally has an unpublished UK patent application drawn to Braak staging and positron emision tomography (PET) scanning for diagnosing Alzheimer's disease, and an unpublished international patent cooperation treaty (PCT) application protecting an in vivo animal model of Alzheimer's disease for testing novel therapies. In addition to Neuro‐Bio's core focus of detection and therapy of neurodegenerative disorders (in particular, Alzheimer's disease), it has two patent families concerning cancer and metastasis, that is, WO2017/130003 (diagnosing cancer) and WO2015/054068 (treating cancer with cyclic peptides), both of which have 12 national phases currently pending. All are owned by Neuro‐Bio with no encumbrance. Recent inventions have led to patent applications relating to various skin conditions. Neuro‐Bio has also recently filed a United Kingdom (UK) patent application for the treatment of Down's syndrome. Susan Greenfield is a member of the House of Lords in the United Kingdom's Parliament; this is a non‐stipendiary appointment. Clive Coen holds shares in the company and sits on the Neuro‐Bio Science Advisory Board (non‐stipendiary). He is Editor of Neuroendocrinology and the Chair of the Rationalist Association [UK]; neither of these entities has made payments to him or his institution. His research has been supported by the Biotechnology and Biological Sciences Research Council. Sara Garcia‐Ratés, Paul Morrill, Owen Hollings, Matthew Passmore, and Sibah Hasan are employees of Neuro‐Bio. Gregory Cole and his colleagues at University of California, Los Angeles (UCLA) (Sally Fraustchy, Ram P Singh, and Marisa Mekkittikul), have received partial support for consumables from Neuro‐Bio. Nikisha Carty, Silvia Bison, Laura Piccoli, Renzo Carletti, Stephano Tacconi, Anna Chalidou, Matthew Pedercini, Tim Kroecher, Hubert Astner, and Philip Gerrard are employees of Evotec. Evotec, a provider of scientific expertise to the global health care industry and academia, was contracted by Neuro‐Bio to undertake the behavioral part of the project and the immunohistochemical studies on amyloid. In the past 36 months, Gregory Cole has received grants and contracts: Veterans administration (VA) Merit BX004332, 2019‐2023 (Cole Principal Investigator (PI)): Tauopathy in mice and humans: surrogate plasma biomarkers for brain trauma‐initiated neurodegenerative disease. Akros/Japan Tobacco Contract, 2018‐2020 (Cole PI): Enhancing pyruvate dehydrogenase activity. NIH NIA R01AG057658, 2017‐2022 (Cole Co‐PI): Treating Alzheimer's disease by reducing brain insulin resistance with incretin receptor agonists. AstraZeneca NCR‐19‐14517, 2019‐2020 (Ajit Divakaruni PI; Cole Co‐I): Determining the role of brain nutrient preference in cognitive impairment and AD. National Neurological Aids Bank 3U24MH100929‐08S1, 2021‐2023 (Elyse Singer PI; Cole Co‐I): Alzheimer's related biomarker neuropathology in HIV post‐mortem brains. NIH/NIA R21 AG069100‐01, 2020 (Qiulan Ma PI; Cole Co‐I): Modulation of TGF‐beta signaling by omega‐6 polyunsaturated fatty acids for treating Alzheimer's disease. NIH NINR R01NR017190‐03, 2020‐2021 (Sarah Choi & Rajesh Kumar MPI; Cole Co‐I): Relationships between brain tissue integrity and self‐care abilities in adults with type 2 diabetes administrative supplement. Michael J Fox Foundation, 2021 (David Eisenberg PI; Cole Co‐I): Completion of pre‐clinical study of a safe and effective image‐based biomarker for Parkinson's disease. Michael J Fox Foundation, 2021‐2022 (Sally Frautschy PI; Cole Co‐I): Liganded nanoparticles to inhibit alpha‐synuclein aggregate deficits in endosomal/lysosomal/autophagy. In the past 36 months, Gregory Cole has received royalties or licenses from a curcumin formulation patent and Ram Singh has received consulting fees from UCLA., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Introduction: Retinal imaging is a non-invasive tool to study both retinal vasculature and neurodegeneration. In this exploratory retinal curcumin-fluorescence imaging (RFI) study, we sought to determine whether retinal vascular features combined with retinal amyloid burden correlate with the neurocognitive status., Methods: We used quantitative RFI in a cohort of patients with cognitive impairment to automatically compute retinal amyloid burden. Retinal blood vessels were segmented, and the vessel tortuosity index (VTI), inflection index, and branching angle were quantified. We assessed the correlations between retinal vascular and amyloid parameters, and cognitive domain Z-scores using linear regression models., Results: Thirty-four subjects were enrolled and twenty-nine (55% female, mean age 64 ± 6 years) were included in the combined retinal amyloid and vascular analysis. Eleven subjects had normal cognition and 18 had impaired cognition. Retinal VTI was discriminated among cognitive scores. The combined proximal mid-periphery amyloid count and venous VTI index exhibited significant differences between cognitively impaired and cognitively normal subjects (0.49 ± 1.1 vs. 0.91 ± 1.4, p = 0.006), and correlated with both the Wechsler Memory Scale-IV and SF-36 mental component score Z-scores ( p < 0.05)., Conclusion: This pilot study showed that retinal venular VTI combined with the proximal mid-periphery amyloid count could predict verbal memory loss. Future research is needed to finesse the clinical application of this retinal imaging-based technology.

Subcortical white matter ischemic lesions are increasingly recognized to have pathologic overlap in individuals with Alzheimer's disease (AD). The interaction of white matter ischemic lesions with amyloid pathology seen in AD is poorly characterized. We designed a novel mouse model of subcortical white matter ischemic stroke and AD that can inform our understanding of the cellular and molecular mechanisms of mixed vascular and AD dementia. Subcortical white matter ischemic stroke underlying forelimb motor cortex was induced by local stereotactic injection of an irreversible eNOS inhibitor. Subcortical white matter ischemic stroke or sham procedures were performed on human ApoE4-targeted-replacement (TR):5XFAD mice at 8 weeks of age. Behavioral tests were done at 7, 10, 15, and 20 weeks. A subset of animals underwent 18 FDG-PET/CT. At 20 weeks of age, brain tissue was examined for amyloid plaque accumulation and cellular changes. Compared with sham E4-TR:5XFAD mice, those with an early subcortical ischemic stroke showed a significant reduction in amyloid plaque burden in the region of cortex overlying the subcortical stroke. Cognitive performance was improved in E4-TR:5XFAD mice with stroke compared with sham E4-TR:5XFAD animals. Iba-1+ microglial cells in the region of cortex overlying the subcortical stroke were increased in number and morphologic complexity compared with sham E4-TR:5XFAD mice, suggesting that amyloid clearance may be promoted by an interaction between activated microglia and cortical neurons in response to subcortical stroke. This novel approach to modeling mixed vascular and AD dementia provides a valuable tool for dissecting the molecular interactions between these two common pathologies.

Introduction: Despite advances in imaging retinal amyloidosis, a quantitative and topographical investigation of retinal amyloid beta burden in patients with cognitive decline has never been reported., Methods: We used the specific amyloid-binding fluorophore curcumin and laser ophthalmoscopy to assess retinal amyloid imaging (RAI) in 34 patients with cognitive decline. We automatically quantified retinal amyloid count (RAC) and area in the superotemporal retinal sub-regions and performed correlation analyses with cognitive and brain volumetric parameters., Results: RAC significantly and inversely correlated with hippocampal volume (HV; r = -0.39, P  = .04). The proximal mid-periphery (PMP) RAC and RA areas were significantly greater in patients with Montreal Cognitive Assessment (MOCA) score < 26 ( P  = .01; Cohen d = 0.83 and 0.81, respectively). PMP showed significantly more RAC and area in subjects with amnestic mild cognitive impairment (MCI) and Alzheimer's disease (AD) compared to cognitively normal ( P  = .04; Cohen d = 0.83)., Conclusion: Quantitative RAI is a feasible technique and PMP RAC may predict HV. Future larger studies should determine RAI's potential as a biomarker of early AD., Competing Interests: Keith L. Black, Steven Verdooner, Yosef Koronyo, and Maya Koronyo‐Hamaoui are co‐founding members of NeuroVision Imaging Inc. Keith L. Black, Steven Verdooner, and Czeszynski Alan D are in leading roles in NeuroVision Imaging Inc. Keith L. Black, Steven Verdooner, Yosef Koronyo, and Maya Koronyo‐Hamaoui are co‐inventors of US patents related to retinal imaging and Alzheimer's disease. Sally Frautschy is co‐inventor on US patent US9192644B2 for a curcumin formulation and is a co‐founding member of Optimized Curcumin Longvida. Other authors declare no conflict., (© 2020 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Phagocytosis plays diverse roles in biology, but our understanding of the purpose, interplay, and cell signaling mechanisms associated with different modes of phagocytosis is limited, without being able to capture and visualize each step in this rapid process from the beginning to end. A new study by Walbaum et al. uses stunning time-lapse 3D imaging of the engulfment of erythrocytes by macrophages via sinking, ruffling, and cup formation, unequivocally confirming a visionary 44-year-old theory derived from still electron microscopy photos that phagocytosis mediated by complement receptor CR3 occurs via a sinking mechanism and antibodymediated phagocytosis occurs via phagocytic cup formation. The article also challenges the dogma, showing that phagocytic cup formation is not unique to antibody receptor phagocytosis, rather CR3 plays a complex role in different modes of phagocytosis. For example, inhibition of antibody-mediated phagocytosis leads to a compensatory upregulation of CR3-mediated sinking phagocytosis. These findings animate, in vivid colors, processes previously only captured as stills, exposing interactions between different phagocytic mechanisms and altering our basic understanding of this important process. [ABSTRACT FROM AUTHOR]

Gene therapy has made substantial progress in the treatment of the genetic diseases, focussing on the reduction of characteristics of recessive/dominant disorders, as well as various cancers. Extensive research has been conducted in the past few decades to investigate the application of nanotechnology and CRISPR/Cas technology in gene therapy. Nanotechnology due to attributes such has targeted drug delivery, controlled release, scalability and low toxicity has gained attention of the medical world. CRISPR/Cas9 system is considered as an impactful genome editing tool in the area of next-generation therapeutics and molecular diagnostics. CRISPR technology emphasises on gene editing, gene regulation modulation, and formulation of defined genetic changes. Its applications in treatment of the genetic disorders are extended beyond traditional therapies. These techniques are being explored as treatment of several genetic disorders including Duchenne muscular dystrophy, cystic fibrosis, Alzheimer's disease, Parkinson's disease, and Huntington disease. Despite considerable therapeutic potential of gene therapy, several obstacles must be addressed before it can be widely adopted in clinical practice, particularly in terms of ensuring safety and effectiveness. As research advances in this captivating field, these therapies will become the primary treatments and will have significant beneficial effects on the lives of patients with genetic disorders., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Psychiatric disorders cause long-lasting disabilities across different age groups. While various medications are available for mental disorders, some patients do not fully benefit from them or experience treatment resistance. The pathogenesis of psychiatric disorders involves multiple mechanisms, including an increase in the inflammatory response. Targeting inflammatory mechanisms has shown promise as a therapeutic approach for these disorders. Curcumin, known for its anti-inflammatory properties and potential neuroprotective effects, has been the subject of studies investigating its potential as a treatment option for psychiatric disorders. This review comprehensively examines the potential therapeutic role of curcumin and its nanoformulations in psychiatric conditions, including major depressive disorder (MDD), bipolar disorder, schizophrenia, and anxiety disorders. There is lack of robust clinical trials across all the studied psychiatric disorders, particularly bipolar disorder and schizophrenia. More studies have focused on MDD. Studies on depression indicate that curcumin may be effective as an antidepressant agent, either alone or as an adjunct therapy. However, inconsistencies exist among study findings, highlighting the need for further research with improved blinding, optimized dosages, and treatment durations. Limited evidence supports the use of curcumin for bipolar disorder, making its therapeutic application challenging. Well-designed clinical trials are warranted to explore its potential therapeutic benefits. Exploring various formulations and delivery strategies, such as utilizing liposomes and nanoparticles, presents intriguing avenues for future research. More extensive clinical trials are needed to assess the efficacy of curcumin as a standalone or adjunctive treatment for psychiatric disorders, focusing on optimal dosages, formulations, and treatment durations., (© 2024 John Wiley & Sons Ltd.)

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.)

Background: Noninvasive detection of Alzheimer's disease (AD) with high specificity and sensitivity can greatly facilitate identification of at-risk populations for earlier, more effective intervention. AD patients exhibit a myriad of retinal pathologies, including hallmark amyloid β-protein (Aβ) deposits., Methods: Burden, distribution, cellular layer, and structure of retinal Aβ plaques were analyzed in flat mounts and cross sections of definite AD patients and controls (n = 37). In a proof-of-concept retinal imaging trial (n = 16), amyloid probe curcumin formulation was determined and protocol was established for retinal amyloid imaging in live patients., Results: Histological examination uncovered classical and neuritic-like Aβ deposits with increased retinal Aβ42 plaques (4.7-fold; P = 0.0063) and neuronal loss (P = 0.0023) in AD patients versus matched controls. Retinal Aβ plaque mirrored brain pathology, especially in the primary visual cortex (P = 0.0097 to P = 0.0018; Pearson's r = 0.84-0.91). Retinal deposits often associated with blood vessels and occurred in hot spot peripheral regions of the superior quadrant and innermost retinal layers. Transmission electron microscopy revealed retinal Aβ assembled into protofibrils and fibrils. Moreover, the ability to image retinal amyloid deposits with solid-lipid curcumin and a modified scanning laser ophthalmoscope was demonstrated in live patients. A fully automated calculation of the retinal amyloid index (RAI), a quantitative measure of increased curcumin fluorescence, was constructed. Analysis of RAI scores showed a 2.1-fold increase in AD patients versus controls (P = 0.0031)., Conclusion: The geometric distribution and increased burden of retinal amyloid pathology in AD, together with the feasibility to noninvasively detect discrete retinal amyloid deposits in living patients, may lead to a practical approach for large-scale AD diagnosis and monitoring., Funding: National Institute on Aging award (AG044897) and The Saban and The Marciano Family Foundations.

Alzheimer's disease (AD) is a form of brain degeneration that gradually impairs a person's memory and cognitive skills, eventually making it harder for them to perform everyday activities. Its pathophysiology has been attributed to the deposition of amyloid β (Aβ), neurofibrillary tangles (NFT), and α-synuclein (A-s) in some cases. Presently, 4 drugs have been approved for the treatment. They are Donepezil, Rivastigmine, Galantamine and Memantine. The first three are acetylcholinesterase inhibitors, while memantine is an NMDA receptor antagonist. Even though these medications are successful in treating mild to moderate Alzheimer's disease, they have not been able to reverse the disease or even slow its progression completely. Hence, natural products are gaining more popularity due to the advantage of the multitarget intervention effect. The most investigated spice, Curcuma longa 's bioactive component, curcumin, has demonstrated anti-amyloid, anti-NFT, and anti-Lewy body properties and substantial antiinflammatory, antioxidant, and antiapoptotic properties. However, its proven neuroprotective activity is hampered by many factors, such as poor water solubility and bioavailability. Therefore, many novel formulations have been designed to improve its bioavailability with methods such as 1) Micellar Solubilization, 2) Cyclodextrin Complexation, 3) Crystal Modification, and 4) Particle Size Reduction, etc. The current chapter aims to summarize various novel formulations of curcumin and their effectiveness in treating AD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

High-density lipoprotein (HDL) is protective against cardiovascular disease. Exercise can increase HDL concentration, and some evidence suggests that this effect occurs more strongly in women than in men. Both HDL and exercise are associated with inflammation. We hypothesized a sex-by-exercise interaction on HDL level, whereby women would benefit from exercise more strongly than men, and tumor necrosis factor alpha and serum soluble tumor necrosis factor receptor-2 would mediate this relationship. This study included 2,957 older adult participants (1,520 women; 41% Black, 59% White; 73.6-years-old) from the Health, Aging, and Body Composition study. Regression models revealed a positive exercise-HDL relationship in women only (sex-by-exercise interaction: β = 0.09, p =.013; exercise on HDL in women: β = 0.07, p =.015), mediated by TNFα (axb = 0.15; CI: 0.01, 0.30), suggesting that exercise may increase HDL levels in women through reduced inflammation. Given that vascular risk contributes to Alzheimer's disease risk, findings have implications for sex differences in AD risk factors. [ABSTRACT FROM AUTHOR]

Recent years have seen significant advances in diagnostic testing of central nervous system (CNS) function and disease. However, there remain challenges in developing a comprehensive suite of non- or minimally invasive assays of neural health and disease progression. Due to the direct connection with the CNS, structural changes in the neural retina, retinal vasculature and morphological changes in retinal immune cells can occur in parallel with disease conditions in the brain. The retina can also, uniquely, be assessed directly and non-invasively. For these reasons, the retina may prove to be an important "window" for revealing and understanding brain disease. In this review, we discuss the gross anatomy of the eye, focusing on the sensory and non-sensory cells of the retina, especially microglia, that lend themselves to diagnosing brain disease by imaging the retina. We include a history of ocular imaging to describe the different imaging approaches undertaken in the past and outline current and emerging technologies including retinal autofluorescence imaging, Raman spectroscopy, and artificial intelligence image analysis. These new technologies show promising potential for retinal imaging to be used as a tool for the diagnosis of brain disorders such as Alzheimer's disease and others and the assessment of treatment success. [ABSTRACT FROM AUTHOR]

In recent years, researchers have highly observed that neurological disorders (NSDs) with the aging of the population are a global health burden whose prevalence is increasing every year. Previous evidence suggested that the occurrence of neurological disorders is correlated with predisposing factors such as inflammation, aging, and injury. Particularly, the neuronal cells are susceptible to oxidative stress, leading to lesions caused by high oxygen-consuming properties. Oxidative stress (OS) is a state of peroxidation, which occurs as a result of the disruption of the balance between oxidizing and antioxidizing substances. The oxidative intermediates such as free radicals, hydrogen peroxide (H2O2), and superoxide anion (O2-) produced by OS promote disease progression. Curcumin, a natural diketone derived from turmeric, is a natural antioxidant with a wide range of neuroprotective, anti-inflammatory, anti-tumor, anti-aging, and antioxidant effects. Fortunately, curcumin is recognized for its potent antioxidant properties and is considered a promising candidate for the prevention and treatment of neurological diseases. Consequently, this review elucidates the mechanisms by which curcumin mitigates oxidative stress and emphasizes the potential in treating nervous system disorders, including depression, Alzheimer's disease, Parkinson's disease, epilepsy, subarachnoid hemorrhage, and glioblastoma. We aim to provide a new therapeutic option for the management of neurological diseases. [ABSTRACT FROM AUTHOR]

As current treatments for Alzheimer's disease (AD) lack disease‐modifying interventions, novel therapies capable of restraining AD progression and maintaining better brain function have great significance. Anti‐inflammatory extracellular vesicles (EVs) derived from human induced pluripotent stem cell (hiPSC)‐derived neural stem cells (NSCs) hold promise as a disease‐modifying biologic for AD. This study directly addressed this issue by examining the effects of intranasal (IN) administrations of hiPSC‐NSC‐EVs in 3‐month‐old 5xFAD mice. IN administered hiPSC‐NSC‐EVs incorporated into microglia, including plaque‐associated microglia, and encountered astrocyte soma and processes in the brain. Single‐cell RNA sequencing revealed transcriptomic changes indicative of diminished activation of microglia and astrocytes. Multiple genes linked to disease‐associated microglia, NOD‐, LRR‐, and pyrin domain‐containing protein 3 (NLRP3)‐inflammasome and interferon‐1 (IFN‐1) signalling displayed reduced expression in microglia. Adding hiPSC‐NSC‐EVs to cultured human microglia challenged with amyloid‐beta oligomers resulted in similar effects. Astrocytes also displayed reduced expression of genes linked to IFN‐1 and interleukin‐6 signalling. Furthermore, the modulatory effects of hiPSC‐NSC‐EVs on microglia in the hippocampus persisted 2 months post‐EV treatment without impacting their phagocytosis function. Such effects were evidenced by reductions in microglial clusters and inflammasome complexes, concentrations of mediators, and end products of NLRP3 inflammasome activation, the expression of genes and/or proteins involved in the activation of p38/mitogen‐activated protein kinase and IFN‐1 signalling, and unaltered phagocytosis function. The extent of astrocyte hypertrophy, amyloid‐beta plaques, and p‐tau were also reduced in the hippocampus. Such modulatory effects of hiPSC‐NSC‐EVs also led to better cognitive and mood function. Thus, early hiPSC‐NSC‐EV intervention in AD can maintain better brain function by reducing adverse neuroinflammatory signalling cascades, amyloid‐beta plaque load, and p‐tau. These results reflect the first demonstration of the efficacy of hiPSC‐NSC‐EVs to restrain neuroinflammatory signalling cascades in an AD model by inducing transcriptomic changes in activated microglia and reactive astrocytes. [ABSTRACT FROM AUTHOR]

Xenorhabdus and Photorhabdus bacteria, which live in mutualistic symbiosis with entomopathogenic nematodes, are currently recognised as an important source of bioactive compounds. During their extraordinary life cycle, these bacteria are capable of fine regulation of mutualism and pathogenesis towards two different hosts, a nematode and a wide range of insect species, respectively. Consequently, survival in a specific ecological niche favours the richness of biosynthetic gene clusters and respective metabolites with a specific structure and function, providing templates for uncovering new agrochemicals and therapeutics. To date, numerous studies have been published on the genetic ability of Xenorhabdus and Photorhabdus bacteria to produce biosynthetic novelty as well as distinctive classes of their metabolites with their activity and mechanism of action. Research shows diverse techniques and approaches that can lead to the discovery of new natural products, such as extract-based analysis, genetic engineering, and genomics linked with metabolomics. Importantly, the exploration of members of the Xenorhabdus and Photorhabdus genera has led to encouraging developments in compounds that exhibit pharmaceutically important properties, including antibiotics that act against Gram- bacteria, which are extremely difficult to find. This article focuses on recent advances in the discovery of natural products derived from these nematophilic bacteria, with special attention paid to new valuable leads for therapeutics. [ABSTRACT FROM AUTHOR]

The total number of Japanese populations is 124.34 million in 2023, and the population of older than 100 years old is 92,139 (about 0.07% of total population). Japan is called as the super aging society. Possibly, it is easily understood that the aging society is widely spread in the world. We have to work out countermeasures for preventing onset of several severe diseases, e.g., dementia, cerebrovascular disease, frailty, etc., seen in the elderly persons. In this review, we focused on the effects of oroxylin A and curcumin on the age-related memory impairment and frailty. Oroxylin A is an extract of Oroxylum indicum and is a natural flavone with anti-inflammatory, neuroprotective and anti-oxidant properties. It has been reported that oroxylin A increases the brain derived neurotrophic factor expression and significantly increased the Complex-I activity in the cortex and other regions. Moreover, it has been documented that oroxylin A dose-dependently inhibited the beta-secretase expressions and activities in PS-70 cells. These results suggest that oroxylin A is a proper supplement to use to reduce the severity of Alzheimer !s disease. Moreover, Curcuma longa has been well documented in the 细 urveda India as for the treatment of diabetes, respiratory disorders, liver disease, inflammatory conditions. Curcumin C3 complex® is a standardized extract from Curcuma longa for 95% curcuminoids. The effects of Curcumin C3 complex® on dementia and osteoarthritis have been well estimated. In conclusion, co-administration of oroxylin A and curcumin is for the prevention of specific diseases in elderly persons. And such novel supplement can contribute the development of acting health in the super aging society. [ABSTRACT FROM AUTHOR]

While Alzheimer's disease and other neurodegenerative diseases have traditionally been viewed as brain disorders, there is growing evidence indicating their manifestation in the eyes as well. The retina, being a developmental extension of the brain, represents the only part of the central nervous system that can be noninvasively imaged at a high spatial resolution. The discovery of the specific pathological hallmarks of Alzheimer's disease in the retina of patients holds great promise for disease diagnosis and monitoring, particularly in the early stages where disease progression can potentially be slowed. Among various retinal imaging methods, hyperspectral imaging has garnered significant attention in this field. It offers a label-free approach to detect disease biomarkers, making it especially valuable for large-scale population screening efforts. In this review, we discuss recent advances in the field and outline the current bottlenecks and enabling technologies that could propel this field toward clinical translation. [ABSTRACT FROM AUTHOR]

Microglia, the resident immune cells of the central nervous system, play a crucial role in regulating adult neurogenesis and contribute significantly to the pathogenesis of Alzheimer's disease (AD). Under physiological conditions, microglia support and modulate neurogenesis through the secretion of neurotrophic factors, phagocytosis of apoptotic cells, and synaptic pruning, thereby promoting the proliferation, differentiation, and survival of neural progenitor cells (NPCs). However, in AD, microglial function becomes dysregulated, leading to chronic neuroinflammation and impaired neurogenesis. This review explores the intricate interplay between microglia and adult neurogenesis in health and AD, synthesizing recent findings to provide a comprehensive overview of the current understanding of microglia-mediated regulation of adult neurogenesis. Furthermore, it highlights the potential of microglia-targeted therapies to modulate neurogenesis and offers insights into potential avenues for developing novel therapeutic interventions. [ABSTRACT FROM AUTHOR]

Leading neurodegenerative diseases Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by the impairment of memory and motor functions, respectively. Despite several breakthroughs, there exists a lack of disease-modifying treatment strategies for these diseases, as the available drugs provide symptomatic relief and bring along side effects. Bioactive compounds are reported to bear neuroprotective properties with minimal toxicity, however, a detailed elucidation of their modes of neuroprotection is lacking. The review elucidates the neuroprotective mechanism(s) of some of the major phyto-compounds in pre-clinical and clinical studies of AD and PD to understand their potential in combating these diseases. Curcumin, eugenol, resveratrol, baicalein, sesamol and so on have proved efficient in countering the pathological hallmarks of AD and PD. Curcumin, resveratrol, caffeine and so on have reached the clinical phases of these diseases, while aromadendrin, delphinidin, cyanidin and xanthohumol are yet to be extensively explored in pre-clinical phases. The review highlights the need for extensive investigation of these compounds in the clinical stages of these diseases so as to utilize their disease-modifying abilities in the real field of treatment. Moreover, poor pharmacokinetic properties of natural compounds are constraints to their therapeutic yields and this review suggests a plausible contribution of nanotechnology in overcoming these limitations., (© 2023 John Wiley & Sons Ltd.)

Limonoids are important constituents of citrus that have a significant impact on promoting human health. Therefore, the primary focus of this research was to assess the overall limonoid content and isolate limonoids from Adalia lemon (Citrus limon L.) peels for their potential use as antioxidants and anti-diabetic agents. The levels of limonoid aglycones in the C. limon peel extract were quantified through a colorimetric assay, revealing a concentration of 16.53 ± 0.93 mg/L limonin equivalent. Furthermore, the total concentration of limonoid glucosides was determined to be 54.38 ± 1.02 mg/L. The study successfully identified five isolated limonoids, namely limonin, deacetylnomilin, nomilin, obacunone 17-O-β-D-glucopyranoside, and limonin 17-O-β-D-glucopyranoside, along with their respective yields. The efficacy of the limonoids-rich extract and the five isolated compounds was evaluated at three different concentrations (50, 100, and 200 µg/mL). It was found that both obacunone 17-O-β-D-glucopyranoside and limonin 17-O-β-D-glucopyranoside possessed the highest antioxidant, free radical scavenging, and anti-diabetic activities, followed by deacetylnomilin, and then the limonoids-rich extract. The molecular dynamic simulations were conducted to predict the behavior of the isolated compounds upon binding to the protein's active site, as well as their interaction and stability. The results revealed that limonin 17-O-β-D-glucopyranoside bound to the protein complex system exhibited a relatively more stable conformation than the Apo system. The analysis of Solvent Accessible Surface Area (SASA), in conjunction with the data obtained from Root-Mean-Square Deviation (RMSD), Root-Mean-Square Fluctuation (RMSF), and Radius of Gyration (ROG) computations, provided further evidence that the limonin 17-O-β-D-glucopyranoside complex system remained stable within the catalytic domain binding site of the human pancreatic alpha-amylase (HPA)-receptor. The research findings suggest that the limonoids found in Adalia lemon peels have the potential to be used as effective natural substances in creating innovative therapeutic treatments for conditions related to oxidative stress and disorders in carbohydrate metabolism. [ABSTRACT FROM AUTHOR]

Aging is the result of the accumulation of a wide variety of molecular and cellular damages over time, meaning that "the more damage we accumulate, the higher the possibility to develop age-related diseases". Therefore, to reduce the incidence of such diseases and improve human health, it becomes important to find ways to combat such damage. In this sense, geroprotectors have been suggested as molecules that could slow down or prevent age-related diseases. On the other hand, nutraceuticals are another set of compounds that align with the need to prevent diseases and promote health since they are biologically active molecules (occurring naturally in food) that, apart from having a nutritional role, have preventive properties, such as antioxidant, anti-inflammatory and antitumoral, just to mention a few. Therefore, in the present review using the specialized databases Scopus and PubMed we collected information from articles published from 2010 to 2023 in order to describe the role of nutraceuticals during the aging process and, given their role in targeting the hallmarks of aging, we suggest that they are potential geroprotectors that could be consumed as part of our regular diet or administered additionally as nutritional supplements. [ABSTRACT FROM AUTHOR]

The main pathological features of Alzheimer’s disease (AD) include the cytotoxic extracellular accumulation of the amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles. The Aβ plaques are responsible for cholinergic dysfunction and dementia in AD patients. Immunoglobulin G (IgG) and Aβ form an immune complex that activates neuroglia, clearing Aβ from the brain. Various Aβ-based therapeutic strategies have been proposed to reduce Aβ production, inhibit Aβ aggregation, and increase Aβ clearance. New medicines, such as aducanumab and donanemab, which are human IgG1 monoclonal antibodies, reduce cognitive impairment in patients with AD by decreasing the amount of Aβ plaques. Despite the considerable advantages of these agents, some disadvantages have also been reported, including Aβ-related imaging abnormalities, anaphylaxis, high cost, and contradictory results. Moreover, donanemab has delivered contradictory outcomes in improving recognition and performance in AD. However, although not fully proven yet, fewer side effects are reported for donanemab compared to aducanumab. Therefore, this review aims to explore the research background, compare the mechanism of action, and understand the advantages and disadvantages of aducanumab and donanemab. As a result, these medicines with maximum effectiveness and safety, yet fewer side effects, could be developed for future treatment and references. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) accounts for most dementia cases, but we lack a complete understanding of the mechanisms responsible for the core pathology associated with the disease (e.g., amyloid plaque and neurofibrillary tangles). Inflammation has been identified as a key contributor of AD pathology, with recent evidence pointing towards Reelin dysregulation as being associated with inflammation. Here we describe Reelin signaling and outline existing research involving Reelin signaling in AD and inflammation. Research is described pertaining to the inflammatory and immunological functions of Reelin before we propose a mechanism through which inflammation renders Reelin susceptible to dysregulation resulting in the induction and exacerbation of AD pathology. Based on this hypothesis, it is predicted that disorders of both inflammation (including peripheral inflammation and neuroinflammation) and Reelin dysregulation (including disorders associated with upregulated Reelin expression and disorders of Reelin downregulation) have elevated risk of developing AD. We conclude with a description of AD risk in various disorders involving Reelin dysregulation and inflammation. [ABSTRACT FROM AUTHOR]

Purpose: Type 2 diabetes mellitus (T2DM) is associated with multiple neuropsychiatric impairments, including cognitive dysfunction, and melatonin (MLT) plays a crucial role in maintaining normal neuropsychiatric functions. This study is aimed at investigating the change in plasma MLT levels and its association with neuropsychiatric impairments in T2DM patients. Methods: One hundred twenty‐six T2DM patients were recruited, and their demographics and clinical data were collected. Apart from the plasma glycated hemoglobin (HbA1c) levels and other routine metabolic indicators, the plasma concentrations of MLT, C‐reactive protein (CRP), Interleukin 6 (IL‐6), soluble myeloid triggered receptor 1 (sTREM 1), and receptor 2 (sTREM 2) were measured. Moreover, the executive function and depressive tendency were evaluated via the Behavior Rating Inventory of Executive Function‐Adult Version (BRIEF‐A) and the Epidemiological Research Center Depression Scale (CES‐D), respectively. Result: Compared with the low HbA1c group, the T2DM patients in the high HbA1c group presented lower plasma MLT levels but higher plasma concentrations of inflammatory biomarker levels, together with higher scores in the BRIEF‐A and CES‐D scales. Moreover, results of the Pearson correlation test showed that the plasma MLT levels were negatively correlated with the BRIEF‐A and CES‐D scores, as well as plasma concentrations of HbA1c and inflammatory indications, indicating that MLT may mediate their neuroinflammation and neuropsychiatric impairments. Furthermore, the ROC curve results indicated that plasma MLT levels have a predictive effect on executive impairment and depressive status in T2DM patients. Conclusion: MLT levels decreased in patients with T2DM and were associated with neuropsychiatric impairments and inflammatory status, and MLT might be developed as a therapeutic agent and predictive indicator for T2DM‐associated executive impairment and depression status. [ABSTRACT FROM AUTHOR]

Background. Neutrophil–lymphocyte ratio (NLR) is a noninvasive, inexpensive, and easily applicable marker of inflammation. Since immune dysregulation leading to inflammation is regarded as a hallmark of dementia, in particular Alzheimer's disease (AD), we decided to investigate the potentials of NLR as a diagnostic and predictive biomarker in this clinical setting. Materials and Methods. NLR was measured in the blood of patients with AD (n = 103), amnestic type mild cognitive impairment (aMCI, n = 212), vascular dementia (VAD, n = 34), and cognitively healthy Controls (n = 61). One hundred twelve MCI patients underwent a regular clinical follow‐up. Over a 36‐months median follow‐up, 80 remained stable, while 32 progressed to overt dementia. Results. NLR was higher in patients with aMCI or dementia compared to Controls; however, the difference was statistically significant only for aMCI (+13%, p = 0.04) and AD (+20%, p = 0.03). These results were confirmed by multivariate logistic analysis, which showed that high NLR was associated with an increase in the likelihood of receiving a diagnosis of aMCI (odd ratio (OR): 2.58, 95% confidence interval (CI): 1.36–4.89) or AD (OR: 3.13, 95%CI: 1.47–6.70), but not of VAD. NLR did not differ when comparing stable vs. progressing aMCI. Conclusions. This is the first report showing that NLR is significantly increased in MCI and AD but not in VAD. We also found that NLR was unable to predict the conversion from aMCI to AD. Further research on larger cohorts is warranted to definitely ascertain the application of NLR as a possible marker for aMCI and AD. [ABSTRACT FROM AUTHOR]

Mild traumatic brain injury (mTBI) resulting from low-intensity blast (LIB) exposure in military and civilian individuals is linked to enduring behavioral and cognitive abnormalities. These injuries can serve as confounding risk factors for the development of neurodegenerative disorders, including Alzheimer's disease-related dementias (ADRD). Recent animal studies have demonstrated LIB-induced brain damage at the molecular and nanoscale levels. Nevertheless, the mechanisms linking these damages to cognitive abnormalities are unresolved. Challenges preventing the translation of preclinical studies into meaningful findings in "real-world clinics" encompass the heterogeneity observed between different species and strains, variable time durations of the tests, quantification of dosing effects and differing approaches to data analysis. Moreover, while behavioral tests in most pre-clinical studies are conducted at the group level, clinical tests are predominantly assessed on an individual basis. In this investigation, we advanced a high-resolution and sensitive method utilizing the CognitionWall test system and applying reversal learning data to the Boltzmann fitting curves. A flow chart was developed that enable categorizing individual mouse to different levels of learning deficits and patterns. In this study, rTg4510 mice, which represent a neuropathology model due to elevated levels of tau P301L, together with the non-carrier genotype were exposed to LIB. Results revealed distinct and intricate patterns of learning deficits and patterns within each group and in relation to blast exposure. With the current findings, it is possible to establish connections between mice with specific cognitive deficits to molecular changes. This approach can enhance the translational value of preclinical findings and also allow for future development of a precision clinical treatment plan for ameliorating neurologic damage of individuals with mTBI. [ABSTRACT FROM AUTHOR]

Secondary metabolites, bioactive compounds produced by living organisms, can unveil symbiotic relationships in nature. In this study, soilborne entomopathogenic nematodes associated with symbiotic bacteria (Xenorhabdus stockiae and Photorhabdus luminescens) were extracted from solvent supernatant containing secondary metabolites, demonstrating significant inhibitory effects against E. coli, S. aureus, B. subtilus, P. mirabilis, E. faecalis, and P. stutzeri. The characterization of these secondary metabolites by Fourier transforms infrared spectroscopy revealed amine groups of proteins, hydroxyl and carboxyl groups of polyphenols, hydroxyl groups of polysaccharides, and carboxyl groups of organic acids. Furthermore, the obtained crude extracts were analyzed by high-performance liquid chromatography for the basic identification of potential bioactive peptides. Gas chromatography–mass spectrometry analysis of ethyl acetate extracts from Xenorhabdus stockiae identified major compounds including nonanoic acid derivatives, proline, paromycin, octodecanal derivatives, trioxa-5-aza-1-silabicyclo, 4-octadecenal, methyl ester, oleic acid, and 1,2-benzenedicarboxylicacid. Additional extraction from Photorhabdus luminescens yielded functional compounds such as indole-3-acetic acid, phthalic acid, 1-tetradecanol, nemorosonol, 1-eicosanol, and unsaturated fatty acids. These findings support the potential development of novel natural antimicrobial agents for future pathogen suppression. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disease with no effective treatments, not least due to the lack of authentic animal models. Typically, rodent models recapitulate the effects but not causes of AD, such as cholinergic neuron loss: lesioning of cholinergic neurons mimics the cognitive decline reminiscent of AD but not its neuropathology. Alternative models rely on the overexpression of genes associated with familial AD, such as amyloid precursor protein, or have genetically amplified expression of mutant tau. Yet transgenic rodent models poorly replicate the neuropathogenesis and protein overexpression patterns of sporadic AD. Seeding rodents with amyloid or tau facilitates the formation of these pathologies but cannot account for their initial accumulation. Intracerebral infusion of proinflammatory agents offer an alternative model, but these fail to replicate the cause of AD. A novel model is therefore needed, perhaps similar to those used for Parkinson's disease, namely adult wildtype rodents with neuron-specific (dopaminergic) lesions within the same vulnerable brainstem nuclei, 'the isodendritic core', which are the first to degenerate in AD. Site-selective targeting of these nuclei in adult rodents may recapitulate the initial neurodegenerative processes in AD to faithfully mimic its pathogenesis and progression, ultimately leading to presymptomatic biomarkers and preventative therapies. [ABSTRACT FROM AUTHOR]

This Research determines the factors influencing American consumers' willingness to purchase turmeric products, amidst the spice's rising popularity for its potential health benefits, particularly those linked to its bioactive component, curcumin. Through a comprehensive analysis of a Qualtrics online survey with 1,020 national respondents in the U.S., we employed advanced choice experiment mixed logit models to elucidate consumer preferences regarding product form, origin, sustainability certification, curcumin content, and price. Contrary to the initial hypothesis that curcumin potency would be a primary driver, our results indicate that the place of origin and price significantly shape purchasing decisions, with a clear preference for inland domestically grown, organically certified turmeric products. These insights offer valuable guidance for producers, manufacturers, and marketers in the natural products industry, suggesting a focus on emphasizing local, sustainable sourcing and clear communication of organic credentials to align with consumer expectations. Our findings not only provide a detailed understanding of current consumer attitudes toward turmeric but also highlight potential markets for turmeric-based product development and effective marketing to cater to the evolving demand for health-beneficial natural products. [ABSTRACT FROM AUTHOR]

Neurotoxic microglia‐provoked neuroinflammation is implicated in cognitive decline in Alzheimer's disease (AD). Supplementation with Ginkgo biloba, phosphatidylserine, Curcuma longa, and propolis is reported to improve the cognitive functions of elderly people; however, the underlying mechanisms of this combination of natural ingredients are unknown. We investigated the effects of a mixture of extracts from propolis, Coffea arabica, Gotu kola, phosphatidylserine, Ginkgo biloba, and Curcuma longa (mixture) on microglia polarization after exposure to amyloid β1‐42 (Aβ1‐42, 1 μM) and lipopolysaccharide from Porphyromonas gingivalis (PgLPS, 1 μg/mL), using MG6 and BV2 microglial cells. Exposure to Aβ1‐42 and PgLPS (AL) raised the mRNA expression of IL‐1β, TNF‐α, and IL‐6, nuclear translocation of p65 NF‐κB in MG6 cells and BV2 cells, and mitochondrial reactive oxygen species (ROS) production in MG6 cells. The mixture dramatically suppressed the mRNA expression of IL‐1β, TNF‐α, and IL‐6, but significantly promoted that of IL‐10, TGFβ1, and BDNF in AL‐exposed MG6 and BV2 cells. Furthermore, the mixture significantly suppressed the nuclear translocation of p65 NF‐κB but significantly promoted that of NF‐E2‐related factor 2 (Nrf2) in AL‐exposed MG6 and BV2 cells. Furthermore, the mixture significantly ameliorated mitochondrial ROS production but increased mitochondrial membrane potential in MG6 cells. These observations strongly suggest that the mixture demotes the neuropathic polarization of microglia by modulating NF‐κB/Nrf2 activation and improving mitochondrial functions. This study supplies the potential mechanisms of the efficacy of a combination of natural ingredients that can be applied in the prevention of cognitive decline in AD and aging by targeting microglia‐mediated neuroinflammation. [ABSTRACT FROM AUTHOR]

Curcumin is a biologically active phytochemical which manifests therapeutic activities in numerous health conditions, including cancer. Several curcuminoids obtained naturally and synthesized artificially also showcase anti-cancer and anti-tumorigenic effects. However, its water insolubility poses difficulties in its application to biological systems, lowering its availability in living tissues, which can be overcome by using various micro-encapsulation and nano-formulations of curcumin. When used in combination with other chemotherapeutic drugs, curcumin enhances the anti-carcinogen potential and reduces the side effects induced via chemotherapy. Structural modelling of basic pharmacophores of curcumin can enhance its biological and pharmacokinetic properties, as revealed by structure-activity relationship studies of curcumin. Various clinical trials of curcumin have proven its worth as an anti-neoplastic agent in humans, with minimal side effects. Its mechanism of action involves blockage of cell-signalling pathways and cellular enzymes, promotion of immunomodulatory effects and induction of programmed cell death in cancerous cells. Curcumin is an interesting molecule with diverse effects on various diseases, but its absolute potential has yet to be reached. Hence, more in-depth studies and clinical trials are needed. This review outlines curcumin's chemical properties and summarizes its anti-cancer and pharmacokinetic potential. [ABSTRACT FROM AUTHOR]

Alzheimer's disease is the leading cause of dementia in the world. It affects 6 million people in the United States and 50 million people worldwide. Alzheimer's disease is characterized by the accumulation of amyloid-β plaques (Aβ), an increase in tau protein neurofibrillary tangles, and a loss of synapses. Since the 1990s, removing and reducing Aβ has been the focus of Alzheimer's treatment and prevention research. The accumulation of Aβ can lead to oxidative stress, inflammation, neurotoxicity, and eventually apoptosis. These insults impair signaling systems in the brain, potentially leading to memory loss and cognitive decline. Aniracetam is a safe, effective, cognitive-enhancing drug that improves memory in both human and animal studies. Aniracetam may prevent the production and accumulation of Aβ by increasing α-secretase activity through two distinct pathways: 1) increasing brain derived neurotrophic factor expression and 2) positively modulating metabotropic glutamate receptors. This is the first paper to propose an evidence-based model for aniracetam reducing the accumulation and production of Aβ. [ABSTRACT FROM AUTHOR]

Many people around the world suffer from neurodegenerative diseases associated with cognitive impairment. As life expectancy increases, this number is steadily rising. Therefore, it is extremely important to search for new treatment strategies and to discover new substances with potential neuroprotective and/or cognition-enhancing effects. This study focuses on investigating the potential of astragaloside IV (AIV), a triterpenoid saponin with proven acetylcholinesterase (AChE)-inhibiting activity naturally occurring in the root of Astragalus mongholicus, to attenuate memory impairment. Scopolamine (SCOP), an antagonist of muscarinic cholinergic receptors, and lipopolysaccharide (LPS), a trigger of neuroinflammation, were used to impair memory processes in the passive avoidance (PA) test in mice. This memory impairment in SCOP-treated mice was attenuated by prior intraperitoneal (ip) administration of AIV at a dose of 25 mg/kg. The attenuation of memory impairment by LPS was not observed. It can therefore be assumed that AIV does not reverse memory impairment by anti-inflammatory mechanisms, although this needs to be further verified. All doses of AIV tested did not affect baseline locomotor activity in mice. In the post mortem analysis by mass spectrometry of the body tissue of the mice, the highest content of AIV was found in the kidneys, then in the spleen and liver, and the lowest in the brain. [ABSTRACT FROM AUTHOR]

Cognitive decline and spinal pain (back pain [BP] and neck pain [NP]) represent a major public health challenge, yet the potential relationship between them remains elusive. A retrospective analysis of the Longitudinal Study of Ageing Danish Twins was performed to determine any potential relationships between BP/NP and cognitive function adjusting for age, sex, educational and socioeconomic status. A total of 4731 adults (2788 females/1943 males) aged 78 ± 6 (SD) years were included in the analysis. We observed a 1‐month prevalence of 25% with BP, 21% with NP and 11% for combined BP/NP. While there were no differences in cognition scores for males and females reporting combined BP/NP, compared to those without combined BP/NP (34.38 points [95% confidence interval (CI) = 31.88, 36.88] vs. 35.72 points [95% CI = 35.19, 36.26]; P = 0.180; and 35.72 points [95% CI = 35.19, 36.26] vs. 35.85 points [95% CI = 35.39, 36.31]; P = 0.327; for male and females, respectively), an adjusted analysis revealed that males with combined BP/NP presented with lower cognitive scores compared to males without combined BP/NP (81.26 points [95% CI = 73.80, 88.72] vs. 79.48 points [95% CI = 70.31, 88.66]; P = 0.043). The findings of this hypothesis‐generating study may highlight a potential sex‐specific association between spinal pain and later‐life neurodegeneration. What is the central question of this study?Do adults reporting spinal pain (neck pain and/or low back pain) exhibit lower cognitive function compared to pain‐free controls, and to what extent does this relationship differ as a function of biological sex?What is the main finding and its importance?In elderly males reporting spinal pain, cognitive function was selectively lower compared to females following adjustment for age, sex, educational and socioeconomic status. These findings identify spinal pain as a potential modifiable risk factor for latent neurodegeneration. [ABSTRACT FROM AUTHOR]

Background: We hypothesize that Alzheimer's disease (AD)-related pathology may accelerate cognitive decline in patients with cardiovascular diseases. Objective: To investigate the association between blood-based biomarkers of AD, astrocyte activation, and neurodegeneration and cognitive decline. Methods: From the multi-center Heart-Brain study, we included 412 patients with heart failure, carotid occlusive disease or vascular cognitive impairment (age:68.6±9.0) and 128 reference participants (65.7±7.5). Baseline amyloid-β42/40 (Aβ42/40), phosphorylated-tau181 (pTau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) were determined using SiMoA (Quanterix). Memory, attention, language, and executive functioning were evaluated (follow-up:2.1±0.3 years). We applied linear mixed models with terms for biomarker, time and biomarker*time interactions, adjusted for age, sex, education, and site, to assess associations between biomarkers and cognitive decline. Results: Among patients, Aβ42/40 was not associated with cognitive performance at baseline. However, lower Aβ42/40 was associated with steeper decline in global cognition (β±SE:0.04±0.02). Higher pTau181 was associated with worse baseline performance on global cognition (–0.14±0.04) and memory (–0.31±0.09) and with steeper decline in global cognition (–0.07±0.02), memory (–0.09±0.04), attention (–0.05±0.02), and language (–0.10±0.03). Higher GFAP was associated with worse baseline performance on global cognition (–0.22±0.05), memory (–0.43±0.10), attention (–0.14±0.06), language (–0.15±0.05), and executive functioning (–0.15±0.05) and steeper decline in global cognition (–0.05±0.01). Higher NfL was associated with worse baseline performance on global cognition (–0.16±0.04), memory (–0.28±0.09), attention (–0.20±0.06), and executive functioning (-0.10±0.04), but was not associated with performance over time. In reference participants, no associations were found. Conclusions: Our findings suggest that blood-based biomarkers of AD-related pathology predict cognitive decline in patients with cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Skin wound healing is a complex biological process in which the replacement of dead tissue by a vital one takes place. The aim of this study was to assess the clinical and histopathological modalities of Curcumin nanoparticles and (Platelet-rich plasma) application on excisional skin wound healing activity. Under complete aseptic conditions full-thickness (10 mm) artificial uniform skin wounds were created on the back of twenty anaesthetized male rats (divided into four groups; Control (Group A), Curcumin treatment (Group B), Platelet-rich plasma treatment (Group C), and Curcumin - Platelet-rich plasma treatment (Group D). Tissue sections were stained by hematoxylin and eosin, PAS, and Crossman trichrome for histopathological evaluation of the wound healing properties following the curcumin and PRP topical treatment. Significant skin regeneration including wound closure and histopathological healing was better in Curcumin nanoparticles and PRP treated groups compared to the control untreated one through better reepithelization and coaptation between the epidermis and dermal layers, more vascular angiogenesis, less inflammatory reactions, healthy granulation tissue and better collagen fibers density in the dermal layer. The obtained results proved an effective external therapeutic use of both Curcumin and PRP on cutaneous wound healing progression. [ABSTRACT FROM AUTHOR]

Curcuma longa, often known as turmeric, is a highly regarded and extensively utilised medicinal plant native to India. It belongs to the Zingiberaceae family. Curcumin, Demethoxycurcumin (DMC) and Bisdemethoxycurcumin (BDMC) are the chemical components found in turmeric and are together referred to as curcuminoids. Curcumin, also known as Diferuloylmethane, is a compound that is widely recognised for its diverse range of biological effects. This document presents a discussion on several clinical trials and their corresponding observations related to these activities. Curcumin is a chemical that exists in two different forms depending on the solvent it is in. In organic solvents, it exists in the enolic form, while in water, it exists in the keto form. This review article provides a comprehensive overview of the several functions and activities of Curcumin. [ABSTRACT FROM AUTHOR]

Ischemia/reperfusion (I/R) injury is a term used to describe phenomena connected to the dysfunction of various tissue damage due to reperfusion after ischemic injury. While I/R may result in systemic inflammatory response syndrome or multiple organ dysfunction syndrome, there is still a long way to improve therapeutic outcomes. A number of cellular metabolic and ultrastructural alterations occur by prolonged ischemia. Ischemia increases the expression of proinflammatory gene products and bioactive substances within the endothelium, such as cytokines, leukocytes, and adhesion molecules, even as suppressing the expression of other "protective" gene products and substances, such as thrombomodulin and constitutive nitric oxide synthase (e.g., prostacyclin, nitric oxide [NO]). Curcumin is the primary phenolic pigment derived from turmeric, the powdered rhizome of Curcuma longa. Numerous studies have shown that curcumin has strong antiinflammatory and antioxidant characteristics. It also prevents lipid peroxidation and scavenges free radicals like superoxide anion, singlet oxygen, NO, and hydroxyl. In our study, we highlight the mechanisms of protective effects of curcumin against I/R injury in various organs., (© 2022 John Wiley & Sons Ltd.)

Converging translational and clinical research strongly indicates that altered immune and inflammatory homeostasis (neuroinflammation) plays a critical pathophysiological role in Alzheimer's disease (AD), across the clinical continuum. A dualistic role of neuroinflammation may account for a complex biological phenomenon, representing a potential pharmacological target. Emerging blood-based pathophysiological biomarkers, such as cytokines (Cyt) and interleukins (ILs), have been studied as indicators of neuroinflammation in AD. However, inconsistent results have been reported probably due to a lack of standardization of assays with methodological and analytical differences. We used machine-learning and a cross-validation-based statical workflow to explore and analyze the potential impact of key biological factors, such as age, sex, and apolipoprotein-E (APOE) genotype (the major genetic risk factor for late-onset AD) on Cyt. A set of Cyt was selected based on previous literature, and we investigated any potential association in a pooled cohort of cognitively healthy, mild cognitive impairment (MCI), and AD-like dementia patients. We also performed explorative analyses to extrapolate preliminary clinical insights. We found a robust sex effect on IL12 and an APOE-related difference in IL10, with the latter being also related to the presence of advanced cognitive decline. IL1β was the variable most significantly associated with MCI-to-dementia conversion over a 2.5 year-clinical follow-up. Although preliminary, our data support further clinical research to understand whether plasma Cyt may represent reliable and noninvasive tools serving the investigation of neuroimmune and inflammatory dynamics in AD and to foster biomarker-guided pathway-based therapeutic approaches, within the precision medicine development framework., (© 2022 International Society for Neurochemistry.)

Curcumin, isolated from turmeric (Curcuma longa L.) is one of the broadly studied phytomolecule owing to its strong antioxidant and anti-inflammatory potential and has been considered a promising therapeutic candidate in a wide range of disorders. Considering, its low bioavailability, different curcumin analogs have been developed to afford desired pharmacokinetic profile and therapeutic outcome in varied pathological states. Several preclinical and clinical studies have indicated that curcumin ameliorates mitochondrial dysfunction, inflammation, oxidative stress apoptosis-mediated neural cell degeneration and could effectively be utilized in the treatment of different neurodegenerative diseases. Hence, in this review, we have summarized key findings of experimental and clinical studies conducted on curcumin and its analogues with special emphasis on molecular pathways, viz. NF-kB, Nrf2-ARE, glial activation, apoptosis, angiogenesis, SOCS/JAK/STAT, PI3K/Akt, ERK1/2 /MyD88 /p38 MAPK, JNK, iNOS/NO, and MMP pathways involved in imparting ameliorative effects in the therapy of neurodegenerative disorders and associated conditions., (© 2022 John Wiley & Sons Ltd.)

Stressful life events and glucocorticoid (stress) hormones appear to increase the risk of Alzheimer's disease and hasten its progression, but the reasons for this remain unclear. One potential explanation is that when amyloid β (Aβ) pathology is accumulating in the preclinical disease stage, glucocorticoid receptor signalling during stressful events exacerbates cellular dysfunction caused by Aβ. Alternatively, Aβ may disrupt glucocorticoid receptor signalling. To explore these possibilities, we investigated whether the synthetic glucocorticoid dexamethasone and Aβ have overlapping effects on the cellular proteome and whether Aβ influences canonical glucocorticoid receptor function. Human olfactory neurosphere-derived (ONS) cells, collected from the olfactory mucosa of six adult donors, were treated with soluble Aβ40 or Aβ42 followed by dexamethasone. Proteins were quantified by mass spectrometry. After 32 h treatment, Aβ40 and Aβ42 both induced profound changes in innate immunity-related proteins. After 72 h, Aβ42 formed widespread aggregates and induced few proteomic changes, whereas Aβ40 remained soluble and altered expression of mitochondrial and innate immunity-related proteins. ONS cells revealed overlapping impacts of Aβ40 and dexamethasone, with 23 proteins altered by both treatments. For 16 proteins (including eight mitochondrial proteins) dexamethasone counteracted the effects of Aβ40. For example, caspase 4 and methylmalonate-semialdehyde dehydrogenase were increased by Aβ40 and decreased by dexamethasone. Consistent with this finding, Aβ40 increased, but dexamethasone decreased, ONS cell proliferation. For seven proteins, including superoxide dismutase [Mn] mitochondrial, dexamethasone exacerbated the effects of Aβ40. For some proteins, including complement C3, the effects of dexamethasone differed depending on whether Aβ40 was present or absent. Neither Aβ species influenced glucocorticoid receptor nuclear translocation. Overall, this study revealed that glucocorticoid receptor signalling modifies the intracellular effects of Aß40, counteracting some effects and exacerbating others. It suggests that cellular mechanisms through which glucocorticoid receptor signalling influences Alzheimer's disease risk/progression are complex and determined by the balance of beneficial and detrimental glucocorticoid effects., (© 2024 International Society for Neurochemistry.)

Background and Purpose: The CAPEOX (combination of oxaliplatin and capecitabine) chemotherapy protocol is widely used for colorectal cancer treatment, but it can lead to chemotherapy-induced adverse effects (CRAEs)., Experimental Approach: To uncover the mechanisms and potential biomarkers for CRAE susceptibility, we performed whole-genome sequencing on normal colorectal tissue (CRT) before adjuvant chemotherapy. This is followed by in vivo and in vitro verifications for selected gene and CRAE pair., Key Results: Our analysis revealed specific germline mutations linked to Grade 2 (or higher) chemotherapy-induced thrombocytopenia (CIT) and nausea/vomiting (CINV). Notably, both CRAEs were associated with mutations in the DLG5 gene. We found that DLG5 mutations related to CIT were associated with increased gene expression, while those associated with CINV were linked to suppressed gene expression, as indicated by the Genotype-Tissue Expression (GTEX) database. In megakaryocytes, overexpression of human DLG5 suppressed the hippo signalling pathway and induced YAP expression. In zebrafish, overexpression of human DLG5 not only reduced platelet production but also inhibited thrombus formation. Subsequent qPCR analysis revealed that DLG5 overexpression affected genes involved in cytoskeleton formation and alpha-granule formation, which could impact the normal generation of proplatelets., Conclusion and Implications: We identified a series of germline mutations associated with susceptibility to CIT and CINV. Of particular interest, we demonstrated that induced and suppressed DLG5 expression is respectively related to CIT and CINV. These findings shed light on the involvement of the hippo signalling pathway and DLG5 in the development of CRAEs, providing valuable insights into potential targets for therapeutic interventions., (© 2024 British Pharmacological Society.)