Amyotrophic Lateral Sclerosis Pathoetiology and Pathophysiology: Roles of Astrocytes, Gut Microbiome, and Muscle Interactions via the Mitochondrial Melatonergic Pathway, with Disruption by Glyphosate-Based Herbicides

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 24(1), P. 587 - 587

Published: Dec. 29, 2022

The pathoetiology and pathophysiology of motor neuron loss in amyotrophic lateral sclerosis (ALS) are still to be determined, with only a small percentage ALS patients having known genetic risk factor. article looks integrate wider bodies data on the biological underpinnings ALS, highlighting integrative role alterations mitochondrial melatonergic pathways systemic factors regulating this pathway across number crucial hubs pathophysiology, namely glia, gut, muscle/neuromuscular junction. It is proposed that suppression underpins changes muscle brain-derived neurotrophic factor, its mimic, N-acetylserotonin, leading lack metabolic trophic support at neuromuscular attenuation astrocytes prevents activation toll-like receptor agonists-induced pro-inflammatory transcription factors, NF-kB, yin yang 1, from built-in limitation inflammatory induction arises their synchronized melatonin release. Such maintained astrocyte activation, coupled heightened microglia reactivity, an important driver susceptibility ALS. Two gut dysbiosis/permeability pineal mediate many beneficial effects via capacity upregulate central cells. may seen as core aspect cellular function, increasing reactive oxygen species (ROS), ROS-induced microRNAs, thereby altering patterning genes induced. increased occupational farmers, gardeners, sportsmen women intimately linked exposure, whilst being physically active, widely used glyphosate-based herbicides. This has numerous research treatment implications.

Language: Английский

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BACE1 regulates expression of Clusterin in astrocytes for enhancing clearance of β-amyloid peptides

Molecular Neurodegeneration, Journal Year: 2023, Volume and Issue: 18(1)

Published: May 4, 2023

Abstract Background Abnormal accumulation of amyloid beta peptide (Aβ) in the brain induces a cascade pathological changes Alzheimer’s disease (AD), and inhibiting BACE1, which is required for Aβ generation, therefore being explored treatment AD by reducing accumulation. As Bace1 knockout mice exhibit increased number reactive astrocytes brains have that surround plaques, we investigated role BACE1 determined whether regulates astrocytic functions. Methods We conducted unbiased single cell RNA-seq (scRNA-seq) using purified from KO wild type control littermates. Similar scRNA-seq was also with conditional deletion adult stage ( 5xFAD;Bace1 fl/fl ;UBC-creER compared to controls). transcriptomes astrocyte clusters identified several differentially expressed genes, were further validated cultures. Mice astrocyte-specific 5xFAD background used compare deposition. Mechanistic studies cultured identify substrates gene expression signaling activity. Results Among altered Clusterin Clu ) Cxcl14 significantly upregulated measuring protein levels. Moreover, deficiency enhanced both uptake degradation, this effect attenuated siRNA knockdown . study suggests abolishes cleavage insulin receptors (IR), may enhance Acutely isolated ;Gfap-cre show similar increases CLU IR. Furthermore, resulted significant attenuation cortical plaque load through clearance. Conclusion Together, our , likely via receptor pathway, inhibition potential alternative strategy enhancing

Language: Английский

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Application of biomarker-derived fluorescent probes for the detection of Alzheimer's disease

TrAC Trends in Analytical Chemistry, Journal Year: 2023, Volume and Issue: 169, P. 117369 - 117369

Published: Oct. 12, 2023

Language: Английский

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Microglial Dyshomeostasis: A Common Substrate in Neurodevelopmental and Neurodegenerative Diseases

Neuroglia, Journal Year: 2024, Volume and Issue: 5(2), P. 119 - 128

Published: May 12, 2024

Neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention-deficit hyperactivity (ADHD) are clinically distinct, yet share synaptic dysfunction a common brain pathophysiology. Neurodegenerative diseases Huntington’s disease (HD) entail neuroinflammatory cascade of molecular cellular events which can contribute to the death neurons. Emerging roles for supportive glial cells microglia astrocytes in ongoing regulation neural synapses excitability raise possibility that some pathology and/or inflammatory could be direct consequence malfunctioning cells. Focusing on microglia, we cross-examined 12 recently published studies microglial was induced/identified cell-autonomous manner its functional development, volume, connectivity, response were evaluated; many cases, onset symptoms relevant all three neurodevelopmental assessed behaviorally. Challenging classic notion activation an neuropathology, our compilation clarifies dyshomeostasis itself consequently disrupt homeostasis, leading neuropathology symptom onset. This further warranted defining signatures context-specific human diseases.

Language: Английский

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Virtual screening, ADMET prediction, molecular docking, and dynamic simulation studies of natural products as BACE1 inhibitors for the management of Alzheimer’s disease

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Nov. 2, 2024

Alzheimer's disease (AD) is a degenerative neurological disorder that chronically and irreversibly affects memory, cognitive function, learning ability, organizational skills. Numerous studies have demonstrated BACE1 as critical therapeutic target for AD, emphasizing the need specific inhibition of to develop effective therapeutics. However, current inhibitors certain limitations. Therefore, aim this study was identify potential novel candidates derived from natural products can be utilized treatment AD. To achieve this, 80,617 compounds ZINC database were subjected virtual screening subsequently filtered according rule five (RO5), leading identification 1,200 compounds. Subsequently, underwent molecular docking against receptor, utilizing high-throughput (HTVS), standard precision (SP), extra (XP) techniques high-affinity ligands. Of 50 ligands exhibited highest G-Scores in HTVS, further analysis conducted using SP scoring methods. This led seven with enhanced binding affinities, which then additional via XP scoring. Finally, stability most promising ligand relation assessed through dynamics (MD) simulations. The computational energy values enzymes ranged between − 6.096 7.626 kcal/mol. Among these, 2 (L2) best at -7.626 kcal/mol BACE1. MD simulations confirmed BACE1-L2 complex, formation robust interaction L2 enzymes. Additionally, pharmacokinetic drug-likeness evaluations indicated non-carcinogenic able permeate blood-brain barrier (BBB). findings will contribute narrowing down selection subsequent vitro vivo testing.

Language: Английский

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Polydopamine/Ruthenium Nanoparticle Systems as Photothermal Therapy Reagents and Reactive Oxygen Species Scavengers for Alzheimer’s Disease Treatment

ACS Applied Nano Materials, Journal Year: 2023, Volume and Issue: 6(7), P. 5384 - 5393

Published: April 5, 2023

The important causes of microglial dysfunction include continuous accumulation amyloid beta (Aβ) fibrils, elevated reactive oxygen species (ROS), and hypoxia. They may be the key pathogenic mechanism Alzheimer's disease (AD). Photothermal therapy (PTT) is considered an innovative noninvasive alternative due to its huge potential, which modulated decomposition mature Aβ fibrils. Here, we report a polydopamine-ruthenium nanosystem (PDA-Ru) that simultaneously used as near-infrared PTT reagent, ROS scavenger, hydrogen peroxide catalyst. photothermal conversion performance catalase activity PDA were improved by anchoring Ru nanoparticles small size. In vivo studies demonstrate PDA-Ru + NIR decreases deposition successfully, thereby restoring neuroregulatory function microglia. Ultimately, it ameliorates neuroinflammation memory deficits in AD mice. conclusion, work illustrates versatile nanomaterial can rescue neuronal damage modulate It could serve potential strategy for treatment other neurodegenerative diseases.

Language: Английский

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Systems Pharmacology Approach and Experiment Evaluation Reveal Pterocarpus Mildbraedii (Fabaceae) Intervention for Counteracting Behavioral Changes and Neuroinflammatory and Oxidative Stress Markers Against Lps-Induced Alzheimer's Disease in Rats

Published: Jan. 1, 2025

Ethnopharmacological relevance: Pterocarpus mildbraedii was believed to have multiple benefits, including antioxidant, antipyretic, antalgic, anti-convulsant, and anxiolytic effects. Previous studies reported that water extract (Pm) contained secondary metabolites able cross the BBB. However, Pm's systemic mechanism targets for neuroinflammation remain largely unexplored.Aim of study: This research used a systems pharmacology approach experiment evaluation reveal potential protective effects Pm against neuroinflammation, oxidative stress, behavioral changes in an LPS-induced Alzheimer's disease (AD) rat model.Materials methods: integrated network analysis experimental verification evaluate pharmacological PM AD systematically. Swiss Target Prediction, GeneCards, STRING databases were employed identify targets. The interaction between active components hub confirmed via molecular docking. GO KEGG pathway analyses also carried out. Further, vitro bioassays explore anti-inflammatory antioxidant activities and, finally, vivo neuroinflammatory stress markers.Results: Network docking revealed primarily regulates signaling pathways such as ESR1, ESR2, BACE1, MAPK1, TLR4, IL6, GSK3B through like liquiritigenin pterocarptriol. identified significant action AD, nitrogen metabolism VEGF pathway. In vitro, demonstrated their properties, along with inhibitory on AchE BchE. Behavioral tests showed LPS exposure impaired exploratory behavior, spatial learning, increased anxiety rats, correlating brain, marked by elevated MDA NO levels, decreased CAT, SOD, GSH levels. raised TNF-α IL-6 levels while reducing dopamine, serotonin, AChE activity. Notably, treatment significantly mitigated improved activity, restored neurotransmitter animals.Conclusion: paper established P. could inhibit its components, targets, pathways. milbraedii may be candidate treatment.

Language: Английский

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Pharmacological effects of herbal ingredients of Manasamitra vatakam in the treatment of Alzheimer's disease: A review

Journal of Ayurveda and Integrative Medicine, Journal Year: 2025, Volume and Issue: 16(1), P. 101041 - 101041

Published: Jan. 1, 2025

Multi-targeted drug therapy has received substantial attention for the treatment of diseases multi-factorial origin, including neurodegenerative and autoimmune diseases. It seems reasonable to argue that complex pathology (ND) cannot be reduced a single target modulate broad range cellular signaling, associated pathologies, symptoms. is this idea brought scientific world towards phytochemicals traditional drugs are notoriously multi-targeted. A systematic study these formulations establishing molecular pathways individual molecules can lead standardized multi-component product activities on different targets ND. This could provide an accessible affordable solution significant disease burden With in mind, review was carried out Ayurvedic Manasamitra Vatakam (MMV), known neuroprotective formulation highly effective against Alzheimer's disease. MMV source phytomolecules treating The multifactorial nature makes them suitable candidates testing due inherent multitargeting capabilities compounds. primary objective comprehensive understanding from responsible its multitargeted effect From reported literature, it clear many phytoconstituents extracts herbal ingredients have demonstrated their efficacy AD models. However, combination models never been tested. Scientific studies should done explore bioactive compounds druggability identified evaluated using experimental methods.

Language: Английский

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Innate and adaptive immunity in neurodegenerative disease

Cellular and Molecular Life Sciences, Journal Year: 2025, Volume and Issue: 82(1)

Published: Feb. 2, 2025

Neurodegenerative diseases (NDs) are a group of neurological disorders characterized by the progressive loss selected neurons. Alzheimer's disease (AD) and Parkinson's (PD) most common NDs. Pathologically, NDs failure neural interactions aberrant protein fibril aggregation deposition, which lead to neuron cognitive behavioral impairments. Great efforts have been made delineate underlying mechanism However, very first trigger these state illness still vague. Existing therapeutic strategies can relieve symptoms but cannot cure diseases. The human immune system is complex intricate network comprising various components that work together protect body against pathogens maintain overall health. They be broadly divided into two main types: innate immunity, line defense pathogens, acts nonspecifically, adaptive follows process more specifically targeted. significance brain immunity in maintaining homeostatic environment brain, its direct implications NDs, has increasingly come focus. Some beneficial regulatory effects, whereas others may detrimental effects on interplay mechanisms remain an area active research. This review focuses both AD PD, offering comprehensive understanding initiation regulation as well between influencing progression

Language: Английский

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Inositol Phosphates and Synthesizing Enzymes: Implications in Neurodegenerative Disorders

Biomolecules, Journal Year: 2025, Volume and Issue: 15(2), P. 225 - 225

Published: Feb. 4, 2025

Inositol is a vital sugar molecule involved in numerous signaling pathways required for cellular homeostasis and cell survival. Myo-inositol its phospho-derivatives, inositol phosphates (IPs), are the most prevalent forms of found living cells. They regulating ion channels, metabolic flux, stress response, other key biological processes. While emerging research has highlighted significant roles immunity, cancer, diseases, there lack comprehensive reviews on their psychiatric neurological disorders. This review aims to fill that gap by analyzing existing literature importance severe conditions such as Parkinson’s disease, Alzheimer’s bipolar disorder, amyotrophic lateral sclerosis, schizophrenia, Huntington’s underscoring potential pave way new treatment regimens these debilitating disorders targeting pathways.

Language: Английский

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