Molecular Mechanisms of Neuroprotection by Ketone Bodies and Ketogenic Diet in Cerebral Ischemia and Neurodegenerative Diseases

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 25(1), P. 124 - 124

Published: Dec. 21, 2023

Ketone bodies (KBs), such as acetoacetate and β-hydroxybutyrate, serve crucial alternative energy sources during glucose deficiency. KBs, generated through ketogenesis in the liver, are metabolized into acetyl-CoA extrahepatic tissues, entering tricarboxylic acid cycle electron transport chain for ATP production. Reduced metabolism mitochondrial dysfunction correlate with increased neuronal death brain damage cerebral ischemia neurodegeneration. Both KBs ketogenic diet (KD) demonstrate neuroprotective effects by orchestrating various cellular processes metabolic signaling functions. They enhance function, mitigate oxidative stress apoptosis, regulate epigenetic post-translational modifications of histones non-histone proteins. Additionally, KD contribute to reducing neuroinflammation modulating autophagy, neurotransmission systems, gut microbiome. This review aims explore current understanding molecular mechanisms underpinning against neurodegenerative diseases, including Alzheimer’s disease Parkinson’s disease.

Language: Английский

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Tauroursodeoxycholic acid: a bile acid that may be used for the prevention and treatment of Alzheimer’s disease

Frontiers in Neuroscience, Journal Year: 2024, Volume and Issue: 18

Published: Feb. 19, 2024

Alzheimer’s disease (AD) is a prevalent neurodegenerative that has become one of the main factors affecting human health. It serious impacts on individuals, families, and society. With development population aging, incidence AD will further increase worldwide. Emerging evidence suggests many physiological metabolic processes, such as lipid metabolism, are implicated in pathogenesis AD. Bile acids, undertakers play an important role occurrence disease. Tauroursodeoxycholic acid, endogenous bile been proven to possess therapeutic effects different diseases, including This review tries find relationship between acid metabolism AD, well explore potential taurocursodeoxycholic for this The mechanisms may include reducing deposition Amyloid-β protein, regulating apoptotic pathways, preventing tau hyperphosphorylation aggregation, protecting neuronal synapses, exhibiting anti-inflammatory properties, improving disorders. objective study shed light use tauroursodeoxycholic preparations prevention treatment with aim identifying effective targets clarifying various involved

Language: Английский

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Pantothenate-encapsulated liposomes combined with exercise for effective inhibition of CRM1-mediated PKM2 translocation in Alzheimer's therapy

Journal of Controlled Release, Journal Year: 2024, Volume and Issue: 373, P. 336 - 357

Published: July 24, 2024

Alzheimer's disease (AD) is a complex neurodegenerative condition characterized by metabolic imbalances and neuroinflammation, posing formidable challenge in medicine due to the lack of effective treatments. Despite considerable research efforts, cure for AD remains elusive, with current therapies primarily focused on symptom management rather than addressing disease's underlying causes. This study initially discerned, through Mendelian randomization analysis that elevating pantothenate levels significantly contributes prophylaxis disease. We explore therapeutic potential encapsulated liposomes (Pan@TRF@Liposome NPs), targeting modulation CRM1-mediated PKM2 nuclear translocation, critical mechanism pathology. Additionally, we investigate synergistic effects exercise, proposing combined approach treatment. Exercise-induced alterations share significant similarities those associated dementia, suggesting complementary effect. The Pan@TRF@Liposome NPs exhibit notable biocompatibility, showing no liver or kidney toxicity vivo, while demonstrating stability effectiveness modulating thereby reducing neuroinflammation neuronal apoptosis. treatment exercise NP administration an animal model leads improved neurofunctional outcomes cognitive performance. These findings highlight nanoparticles' role as modulators implications mitigating Together this dual-modality could offer new avenues enhancing performance AD, marking promising step forward developing strategies challenging disorder.

Language: Английский

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Mitochondrial DNA (mtDNA) as fluid biomarker in neurodegenerative disorders: A systematic review

European Journal of Neurology, Journal Year: 2025, Volume and Issue: 32(1)

Published: Jan. 1, 2025

Abstract Background Several studies evaluated peripheral and cerebrospinal fluid (CSF) mtDNA as a putative biomarker in neurodegenerative diseases, often yielding inconsistent findings. We systematically reviewed the current evidence assessing blood CSF levels variant burden Parkinson's disease (PD), Alzheimer's (AD) amyotrophic lateral sclerosis (ALS). Multiple (MS) was also included paradigm of chronic neuroinflammation‐driven neurodegeneration. Methods Medline, Embase, Scopus Web Science were searched for articles published from inception until October 2023. Studies focused on haplogroups or hereditary pathogenic variants excluded. Critical appraisal performed using Quality Assessment Diagnostic Accuracy criteria. Results Fifty‐nine original met our priori‐defined inclusion The majority CSF‐focused showed (i) decreased PD AD; (ii) increased MS compared to controls. No ALS. cell‐free intracellular contradictory, even within evaluating same disease. This poor reproducibility is likely due lack consideration many factors known affect levels. damage methylation reduced patients controls, respectively. A few investigated correlation between severity, with conflicting results. Conclusions Additional well‐designed are needed evaluate profiles biomarkers diseases. identification “mitochondrial subtypes” may enable novel precision medicine strategies counteract

Language: Английский

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Alzheimer’s Disease: Exploring Pathophysiological Hypotheses and the Role of Machine Learning in Drug Discovery

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(3), P. 1004 - 1004

Published: Jan. 24, 2025

Alzheimer’s disease (AD) is a major neurodegenerative dementia, with its complex pathophysiology challenging current treatments. Recent advancements have shifted the focus from traditionally dominant amyloid hypothesis toward multifactorial understanding of disease. Emerging evidence suggests that while amyloid-beta (Aβ) accumulation central to AD, it may not be primary driver but rather part broader pathogenic process. Novel hypotheses been proposed, including role tau protein abnormalities, mitochondrial dysfunction, and chronic neuroinflammation. Additionally, gut–brain axis epigenetic modifications gained attention as potential contributors AD progression. The limitations existing therapies underscore need for innovative strategies. This study explores integration machine learning (ML) in drug discovery accelerate identification novel targets candidates. ML offers ability navigate AD’s complexity, enabling rapid analysis extensive datasets optimizing clinical trial design. synergy between these themes presents promising future more effective

Language: Английский

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Mitochondrial Dysfunction in Diabetes: Shedding Light on a Widespread Oversight

Pathophysiology, Journal Year: 2025, Volume and Issue: 32(1), P. 9 - 9

Published: Feb. 13, 2025

Diabetes mellitus represents a complicated metabolic condition marked by ongoing hyperglycemia arising from impaired insulin secretion, inadequate action, or combination of both. Mitochondrial dysfunction has emerged as significant contributor to the aetiology diabetes, affecting various processes critical for glucose homeostasis. This review aims elucidate complex link between mitochondrial and covering spectrum diabetes types, role mitochondria in resistance, highlighting pathophysiological mechanisms, DNA damage, altered biogenesis dynamics. Additionally, it discusses clinical implications complications its complications, diagnostic approaches assessing function diabetics, therapeutic strategies, future directions, research opportunities.

Language: Английский

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Mitochondria targeted nanoparticles for the treatment of mitochondrial dysfunction-associated brain disorders

Frontiers in Bioengineering and Biotechnology, Journal Year: 2025, Volume and Issue: 13

Published: March 12, 2025

Mitochondria play a significant role in several cellular activities and their function health disease has become an important area of research. Since the brain is high-energy-demanding organ, it particularly vulnerable to mitochondrial dysfunction. This been implicated disorders including neurodegenerative, psychiatric neurological disorders, e.g., Parkinson’s schizophrenia. Significant efforts are underway develop mitochondria-targeting pharmaceutical interventions. However, complex membrane network restricts entry therapeutic compounds into matrix. Nanoparticles (NPs) present novel solution this limitation, while also increasing stability moieties improving bioavailability. article provides detailed overview studies that have investigated treatment dysfunction using either targeted or non-targeted NPs as drug delivery systems. All showed improved functioning reduction reactive oxygen species (ROS) production, improvement overall respiration reversal toxin-induced damage. mitochondrial-targeted advantage over they were able improve rescue dynamics biogenesis, required lower concentration vivo dosage load show effect. Consequently, mitochondria-targeted promising approach. Future should exploit advances nanotechnology, neuroscience chemistry design can cross blood-brain barrier selectively target dysfunctional mitochondria, outcomes.

Language: Английский

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Excitotoxicity, Oxytosis/Ferroptosis, and Neurodegeneration: Emerging Insights into Mitochondrial Mechanisms

Aging and Disease, Journal Year: 2024, Volume and Issue: unknown, P. 0 - 0

Published: Jan. 1, 2024

Mitochondrial dysfunction plays a pivotal role in the development of age-related diseases, particularly neurodegenerative disorders. The etiology mitochondrial involves multitude factors that remain elusive. This review centers on elucidating role(s) excitotoxicity, oxytosis/ferroptosis and neurodegeneration within context bioenergetics, biogenesis, mitophagy oxidative stress explores their intricate interplay pathogenesis diseases. effective coordination turnover processes, notably is assumed to be critically important for cellular resilience longevity. However, age-associated decrease impedes elimination dysfunctional mitochondria, consequently impairing biogenesis. deleterious cascade results accumulation damaged mitochondria deterioration functions. Both excitotoxicity have been demonstrated contribute significantly pathophysiology including Alzheimer's disease (AD), Parkinson's (PD), Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS) Multiple (MS). Excitotoxicity, characterized by excessive glutamate signaling, initiates events involving calcium dysregulation, energy depletion, intricately linked dysfunction. Furthermore, emerging concepts surrounding underscore importance iron-dependent lipid peroxidation engagement neurodegeneration. not only discusses individual contributions ferroptosis but also emphasizes convergence with dysfunction, key driver Understanding crosstalk between oxytosis/ferroptosis, holds potential pave way mitochondrion-targeted therapeutic strategies. Such strategies, focus mitophagy, stress, emerge as promising avenues intervention.

Language: Английский

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A More Holistic Perspective of Alzheimer's Disease: Roles of Gut Microbiome, Adipocytes, HPA Axis, Melatonergic Pathway and Astrocyte Mitochondria in the Emergence of Autoimmunity

Frontiers in Bioscience-Landmark, Journal Year: 2023, Volume and Issue: 28(12), P. 355 - 355

Published: Dec. 28, 2023

Alzheimer's disease is widely regarded as poorly treated due to poor conceptualization. For 40 years, pathophysiology has focused on two culprits, amyloid-β induced plaques and hyperphosphorylated tau associated tangles, with no significant treatment advance. This confounded by data showing be an endogenous antimicrobial that increased in a wide array of diverse medical conditions heightened inflammation. article reviews the wider bodies pertaining pathophysiology, highlighting role suppressed astrocyte mitochondrial function melatonergic pathway core hub driving neuronal loss dementia. It proposed over aging becomes dysregulated, at least partly mediated systemic processes involving 10-fold decrease pineal melatonin leading attenuated capacity night-time dampen residual daytime Suppressed also attenuates melatonin's inhibition glucocorticoid receptor nuclear translocation, thereby changing not only stress/hypothalamus-pituitary-adrenal (HPA) axis consequences but cortisol awakening response, which 'primes body for coming day'. Gut microbiome-derived butyrate inhibits well inducing pathway. prevents autocrine paracrine effects limiting levels effects. production induction lactate, decreasing metabolism The lactate melatonin, coupled suppression decreases mitophagy, major histocompatibility complex (MHC)-1. MHC-1 initiates chemoattraction CD8+ t cells, destruction being driven 'autoimmune'/'immune-mediated' processes. may therefore conceptualized initiated act astrocytes hub, leaving neurons deplete appropriate metabolic substrates co-ordinated antioxidants. culminates 'immune-mediated' cell death. Future research treatment/prevention implications are indicated.

Language: Английский

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From Plaques to Pathways in Alzheimer’s Disease: The Mitochondrial-Neurovascular-Metabolic Hypothesis

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(21), P. 11720 - 11720

Published: Oct. 31, 2024

Alzheimer's disease (AD) presents a public health challenge due to its progressive neurodegeneration, cognitive decline, and memory loss. The amyloid cascade hypothesis, which postulates that the accumulation of amyloid-beta (Aβ) peptides initiates leading AD, has dominated research therapeutic strategies. failure recent Aβ-targeted therapies yield conclusive benefits necessitates further exploration AD pathology. This review proposes Mitochondrial-Neurovascular-Metabolic (MNM) integrates mitochondrial dysfunction, impaired neurovascular regulation, systemic metabolic disturbances as interrelated contributors pathogenesis. Mitochondrial hallmark leads oxidative stress bioenergetic failure. Concurrently, breakdown blood-brain barrier (BBB) cerebral blood flow, characterize dysregulation, accelerate neurodegeneration. Metabolic such glucose hypometabolism insulin resistance impair neuronal function survival. hypothesis highlights interconnectedness these pathways suggests strategies targeting health, integrity, regulation may offer more effective interventions. MNM addresses multifaceted aspects providing comprehensive framework for understanding progression developing novel approaches. approach paves way innovative could significantly improve outcomes millions affected worldwide.

Language: Английский

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