bims-mistre 2025-02-02 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2025–02–02
thirty-two papers selected by
Ellen Siobhan Mitchell, MitoQ

Recent advancements in the understanding of the alterations in mitochondrial biogenesis in Alzheimer's disease.
VDAC1: A Key Player in the Mitochondrial Landscape of Neurodegeneration.
Interplay between energy metabolism and NADPH oxidase-mediated pathophysiology in cardiovascular diseases.
Oxidative Stress and the Central Nervous System.
Mitochondria as a Therapeutic Target: Focusing on Traumatic Brain Injury.
Mitochondrial dysfunction in Alzheimer's disease: a key frontier for future targeted therapies.
Neuroprotective Effects of Myrtle Berry By-Product Extracts on 6-OHDA-Induced Cytotoxicity in PC12 Cells.
Effects of Astragaloside IV and Formononetin on Oxidative Stress and Mitochondrial Biogenesis in Hepatocytes.
Reactive Oxygen Species, a Potential Therapeutic Target for Vascular Dementia.
Molecular Symphony of Mitophagy: Ubiquitin-Specific Protease-30 as a Maestro for Precision Management of Neurodegenerative Diseases.
Navigating the dichotomy of reactive oxygen, nitrogen, and sulfur species: detection strategies and therapeutic interventions.
Unraveling the AMPK-SIRT1-FOXO Pathway: The In-Depth Analysis and Breakthrough Prospects of Oxidative Stress-Induced Diseases.
NPT100-18A rescues mitochondrial oxidative stress and neuronal degeneration in human iPSC-based Parkinson's model.
Oxyglutamate Carrier Alleviates Cerebral Ischaemia-Reperfusion Injury by Regulating Mitochondrial Function.
Mitochondrial dynamics: molecular mechanism and implications in endometriosis.
Oxidative Stress and Cardiovascular Complications in Type 2 Diabetes: From Pathophysiology to Lifestyle Modifications.
The Potential Application of Nanocarriers in Delivering Topical Antioxidants.
Mutations of the Electron Transport Chain Affect Lifespan and ROS Levels in C. elegans.
Uncovering the intricacies of IGF-1 in Alzheimer's disease: new insights from regulation to therapeutic targeting.
Multivalent Neuroprotective Activity of Elettaria cardamomum (Cardamom) and Foeniculum vulgare (Fennel) in H2O2-Induced Oxidative Stress in SH-SY5Y Cells and Acellular Assays.
Ellagic Acid: A Green Multi-Target Weapon That Reduces Oxidative Stress and Inflammation to Prevent and Improve the Condition of Alzheimer's Disease.
Repurposing Mitochondria-Targeted Therapeutics for Kidney Diseases.
A randomized double-blind clinical trial investigating the effects of ellagic acid on glycemic status, liver enzymes, and oxidative stress in patients with non-alcoholic fatty liver disease.
Blocking the mineralocorticoid receptor prevents cardiac and mitochondrial dysfunction through the activation of NOX-4 in female hormone deprivation rats.
Mitochondria Express Functional Signaling Ligand-Binding Receptors that Regulate their Biological Responses - the Novel Role of Mitochondria as Stress-Response Sentinels.
Strategic Mutations in Designer Native Peptides Combat NLRP3 Inflammasome Activation in Neurodegenerative Disorders.
Redox Metabolism and Autonomic Regulation During Aging: Can Heart Rate Variability Be Used to Monitor Healthy Longevity?
Production of Amyloid-β in the Aβ-Protein-Precursor Proteolytic Pathway Is Discontinued or Severely Suppressed in Alzheimer's Disease-Affected Neurons: Contesting the 'Obvious'.
Exploring the application of dietary antioxidant index for disease risk assessment: a comprehensive review.
Oral prodrug of a novel glutathione surrogate reverses metabolic dysregulation and attenuates neurodegenerative process in APP/PS1 mice.
Current Status of Plant-Based Bioactive Compounds as Therapeutics in Alzheimer's Diseases.
In Vitro and In Vivo Antioxidant and Immune Stimulation Activity of Wheat Product Extracts.

Mol Biol Rep. 2025 Jan 29. 52(1): 173

Recent advancements in the understanding of the alterations in mitochondrial biogenesis in Alzheimer's disease.

Shreya Singh, Rakesh Kumar Singh.

  Alzheimer's disease (AD) is a common neurodegenerative disease characterized by progressive memory loss and cognitive decline. The processes underlying the pathophysiology of AD are still not fully understood despite a great deal of research. Since mitochondrial dysfunction affects cellular energy metabolism, oxidative stress, and neuronal survival, it is becoming increasingly clear that it plays a major role in the development of AD. This review summarizes the recent developments of mitochondrial dysfunction in AD, emphasizing mitochondrial biogenesis, dynamics, axonal transport, interactions between endoplasmic reticulum and mitochondria, mitophagy, and mitochondrial proteostasis. It emphasizes how tau and amyloid-beta (Aβ) proteins worsen mitochondrial and synaptic dysfunction by impairing adenosine triphosphate (ATP) synthesis, causing oxidative stress, and upsetting equilibrium. Additionally, important processes controlling mitochondrial activity and their correlation to the brain health are also discussed. One of the promising therapeutic approaches to lessen neurodegeneration and cognitive decline in AD is to improve mitochondrial activity. This study highlights possible directions for creating focused therapies to impede the advancement of AD through incorporating knowledge of mitochondrial biogenesis and its related mechanisms.

Keywords:  Alzheimer’s disease; Dementia; Mitochondrial biogenesis; Mitophagy

DOI:  https://doi.org/10.1007/s11033-025-10297-6
Biomolecules. 2024 Dec 30. pii: 33. [Epub ahead of print]15(1):

VDAC1: A Key Player in the Mitochondrial Landscape of Neurodegeneration.

Shirel Argueti-Ostrovsky, Shir Barel, Joy Kahn, Adrian Israelson.

  Voltage-Dependent Anion Channel 1 (VDAC1) is a mitochondrial outer membrane protein that plays a crucial role in regulating cellular energy metabolism and apoptosis by mediating the exchange of ions and metabolites between mitochondria and the cytosol. Mitochondrial dysfunction and oxidative stress are central features of neurodegenerative diseases. The pivotal functions of VDAC1 in controlling mitochondrial membrane permeability, regulating calcium balance, and facilitating programmed cell death pathways, position it as a key determinant in the delicate balance between neuronal viability and degeneration. Accordingly, increasing evidence suggests that VDAC1 is implicated in the pathophysiology of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and others. This review summarizes the current findings on the contribution of VDAC1 to neurodegeneration, focusing on its interactions with disease-specific proteins, such as amyloid-β, α-synuclein, and mutant SOD1. By unraveling the complex involvement of VDAC1 in neurodegenerative processes, this review highlights potential avenues for future research and drug development aimed at alleviating mitochondrial-related neurodegeneration.

Keywords:  ALS; Alzheimer’s disease; Parkinson’s disease; VDAC1; neurodegenerative diseases

DOI:  https://doi.org/10.3390/biom15010033
Front Pharmacol. 2024 ;15 1503824

Interplay between energy metabolism and NADPH oxidase-mediated pathophysiology in cardiovascular diseases.

Haipeng Jie, Jingjing Zhang, Shuzhen Wu, Luyao Yu, Shengnan Li, Bo Dong, Feng Yan.

  Sustained production of reactive oxygen species (ROS) and an imbalance in the antioxidant system have been implicated in the development of cardiovascular diseases (CVD), especially when combined with diabetes, hypercholesterolemia, and other metabolic disorders. Among them, NADPH oxidases (NOX), including NOX1-5, are major sources of ROS that mediate redox signaling in both physiological and pathological processes, including fibrosis, hypertrophy, and remodeling. Recent studies have demonstrated that mitochondria produce more proteins and energy in response to adverse stress, corresponding with an increase in superoxide radical anions. Novel NOX4-mediated modulatory mechanisms are considered crucial for maintaining energy metabolism homeostasis during pathological states. In this review, we integrate the latest data to elaborate on the interactions between oxidative stress and energy metabolism in various CVD, aiming to elucidate the higher incidence of CVD in individuals with metabolic disorders. Furthermore, the correlations between NOX and ferroptosis, based on energy metabolism, are preliminarily discussed. Further discoveries of these mechanisms might promote the development of novel therapeutic drugs targeting NOX and their crosstalk with energy metabolism, potentially offering efficient management strategies for CVD.

Keywords:  NADPH oxidases; cardiovascular diseases; energy metabolism; ferroptosis; oxidative stress

DOI:  https://doi.org/10.3389/fphar.2024.1503824
Antioxidants (Basel). 2025 Jan 19. pii: 110. [Epub ahead of print]14(1):

Oxidative Stress and the Central Nervous System.

Marcello D'Ascenzo, Claudia Colussi.

Reactive oxygen and nitrogen species (ROS; RNS) are natural bioproducts of cellular metabolism, particularly produced within the mitochondria during energy production [...].

DOI: https://doi.org/10.3390/antiox14010110
J Integr Neurosci. 2025 Jan 21. 24(1): 25292

Mitochondria as a Therapeutic Target: Focusing on Traumatic Brain Injury.

Randhall Bruce Carteri.

  Mitochondria are organelles of eukaryotic cells delimited by two membranes and cristae that consume oxygen to produce adenosine triphosphate (ATP), and are involved in the synthesis of vital metabolites, calcium homeostasis, and cell death mechanisms. Strikingly, normal mitochondria function as an integration center between multiple conditions that determine neural cell homeostasis, whereas lesions that lead to mitochondrial dysfunction can desynchronize cellular functions, thus contributing to the pathophysiology of traumatic brain injury (TBI). In addition, TBI leads to impaired coupling of the mitochondrial electron transport system with oxidative phosphorylation that provides most of the energy needed to maintain vital functions, ionic homeostasis, and membrane potentials. Furthermore, mitochondrial metabolism produces signaling molecules such as reactive oxygen species (ROS), regulating calcium levels and controlling the expression profile of intrinsic pro-apoptotic effectors influenced by TBI. Hence, the set of these functions is widely referred to as 'mitochondrial function', although the complexity of the relationship between such components limits such a definition. In this review, we present mitochondria as a therapeutic target, focus on TBI, and discuss aspects of mitochondrial structure and function.

Keywords:  head injury; metabolism; neurodegeneration

DOI:  https://doi.org/10.31083/JIN25292
Front Immunol. 2024 ;15 1484373

Mitochondrial dysfunction in Alzheimer's disease: a key frontier for future targeted therapies.

Shuguang Wang, Zuning Liao, Qiying Zhang, Xinyuan Han, Changqing Liu, Jin Wang.

  Alzheimer's disease (AD) is the most common neurodegenerative disorder, accounting for approximately 70% of dementia cases worldwide. Patients gradually exhibit cognitive decline, such as memory loss, aphasia, and changes in personality and behavior. Research has shown that mitochondrial dysfunction plays a critical role in the onset and progression of AD. Mitochondrial dysfunction primarily leads to increased oxidative stress, imbalances in mitochondrial dynamics, impaired mitophagy, and mitochondrial genome abnormalities. These mitochondrial abnormalities are closely associated with amyloid-beta and tau protein pathology, collectively accelerating the neurodegenerative process. This review summarizes the role of mitochondria in the development of AD, the latest research progress, and explores the potential of mitochondria-targeted therapeutic strategies for AD. Targeting mitochondria-related pathways may significantly improve the quality of life for AD patients in the future.

Keywords:  AD; dysfunction; mechanisms; mitochondria; therapeutic targets

DOI:  https://doi.org/10.3389/fimmu.2024.1484373
Antioxidants (Basel). 2025 Jan 13. pii: 88. [Epub ahead of print]14(1):

Neuroprotective Effects of Myrtle Berry By-Product Extracts on 6-OHDA-Induced Cytotoxicity in PC12 Cells.

Debora Dessì, Giacomo Fais, Paolo Follesa, Giorgia Sarais.

  The rising global focus on healthy lifestyles and environmental sustainability has prompted interest in repurposing plant-based by-products for health benefits. With increasing life expectancy, the incidence of neurodegenerative diseases-characterized by complex, multifactorial mechanisms such as abnormal protein aggregation, mitochondrial dysfunction, oxidative stress, and inflammation-continues to grow. Medicinal plants, with their diverse bioactive compounds, offer promising therapeutic avenues for such conditions. Myrtus communis L., a Mediterranean plant primarily used in liquor production, generates significant waste rich in antioxidant and anti-inflammatory properties. This study explores the neuroprotective potential of Myrtus berry by-products in a cellular model of neurodegeneration. Using PC12 cells exposed to 6-hydroxydopamine (6-OHDA), we assessed cell viability via MTT assay and measured reactive oxygen species (ROS) production using DCFDA fluorescence. Additionally, we analyzed the expression of genes linked to oxidative stress and neuronal function, including AChE, PON2, Grin1, Gabrd, and c-fos, by RT-PCR. Our findings reveal that Myrtus extract significantly protects against 6-OHDA-induced cytotoxicity, reduces ROS levels, and modulates the expression of key stress-related genes, underscoring its potential as a neuroprotective agent. These results highlight the therapeutic promise of Myrtus extracts in mitigating neurodegenerative processes, paving the way for future interventions.

Keywords:  Parkinson’s disease; antioxidants; myrtle berries; neurodegenerative diseases; neuroprotection; oxidative stress

DOI:  https://doi.org/10.3390/antiox14010088
Int J Mol Sci. 2025 Jan 17. pii: 774. [Epub ahead of print]26(2):

Effects of Astragaloside IV and Formononetin on Oxidative Stress and Mitochondrial Biogenesis in Hepatocytes.

Quoc-Anh Tran, Grant Van Tran, Sanel Velic, Hou-Mai Xiong, Jaspreet Kaur, Zuhurr Moosavi, Phuong Nguyen, Nhi Duong, Vy Tran Luu, Gurjot Singh, Tram Bui, Melanie Rose, Linh Ho.

  Over-accumulation of reactive oxygen species (ROS) causes hepatocyte dysfunction and apoptosis that might lead to the progression of liver damage. Sirtuin-3 (SIRT3), the main NAD+-dependent deacetylase located in mitochondria, has a critical role in regulation of mitochondrial function and ROS production as well as in the mitochondrial antioxidant mechanism. This study explores the roles of astragaloside IV (AST-IV) and formononetin (FMR) in connection with SIRT3 for potential antioxidative effects. It was shown that the condition of combined pre- and post-treatment with AST-IV or FMR at all concentrations statistically increased and rescued cell proliferation. ROS levels were not affected by pre-or post-treatment individually with AST-IV or pre-treatment with FMR; however, post-treatment with FMR resulted in significant increases in ROS in all groups. Significant decreases in ROS levels were seen when pre- and post-treatment with AST-IV were combined at 5 and 10 μM, or FMR at 5 and 20 μM. In the condition of combined pre- and post-treatment with 10 μM AST-IV, there was a significant increase in SOD activity, and the transcriptional levels of Sod2, Cat, and GPX1 in all treatment groups, which is indicative of reactive oxygen species detoxification. Furthermore, AST-IV and FMR activated PGC-1α and AMPK as well as SIRT3 expression in AML12 hepatocytes exposed to t-BHP-induced oxidative stress, especially at high concentrations of FMR. This study presents a novel mechanism whereby AST-IV and FMR yield an antioxidant effect through induction of SIRT3 protein expression and activation of an antioxidant mechanism as well as mitochondrial biogenesis and mitochondrial content and potential. The findings suggest these agents can be used as SIRT3 modulators in treating oxidative-injury hepatocytes.

Keywords:  SIRT3; SIRT3 modulators; astragaloside; formononetin; mitochondrial sirtuins; oxidative injury; oxidative stress; tert-butyl hydrogen peroxide (t-BHP)

DOI:  https://doi.org/10.3390/ijms26020774
Biomolecules. 2024 Dec 25. pii: 6. [Epub ahead of print]15(1):

Reactive Oxygen Species, a Potential Therapeutic Target for Vascular Dementia.

Amanda Louise White, Grant M Talkington, Blake Ouvrier, Saifudeen Ismael, Rebecca J Solch-Ottaiano, Gregory Bix.

  Vascular dementia (VaD) is a progressive neurodegenerative condition prevalent among elderly adults marked by cognitive decline resulting from injured and/or improperly functioning cerebrovasculature with resultant disruptions in cerebral blood flow. Currently, VaD has no specific therapeutics and the exact pathobiology is still being investigated. VaD has been shown to develop when reactive oxygen species (ROS) form from damaged targets at different levels of organization-mitochondria, endothelial cells, or cerebrovasculature. In this review, we highlight how specific ROS molecules may be important in the development of VaD and how they can be targeted as a potential therapeutic for VaD.

Keywords:  Alzheimer’s disease; antioxidants; reactive oxygen species; therapeutic; vascular dementia

DOI:  https://doi.org/10.3390/biom15010006
CNS Neurosci Ther. 2025 Jan;31(1): e70192

Molecular Symphony of Mitophagy: Ubiquitin-Specific Protease-30 as a Maestro for Precision Management of Neurodegenerative Diseases.

Ankit Siwach, Harit Patel, Amit Khairnar, Pathik Parekh.

   INTRODUCTION: Mitochondrial dysfunction stands as a pivotal feature in neurodegenerative disorders, spurring the quest for targeted therapeutic interventions. This review examines Ubiquitin-Specific Protease 30 (USP30) as a master regulator of mitophagy with therapeutic promise in Alzheimer's disease (AD) and Parkinson's disease (PD). USP30's orchestration of mitophagy pathways, encompassing PINK1-dependent and PINK1-independent mechanisms, forms the crux of this exploration.
METHOD: A systematic literature search was conducted in PubMed, Scopus, and Web of Science, selecting studies that investigated USP's function, inhibitor design, or therapeutic efficacy in AD and PD. Inclusion criteria encompassed mechanistic and preclinical/clinical data, while irrelevant or duplicate references were excluded. Extracted findings were synthesized narratively.
RESULTS: USP30 modulates interactions with translocase of outer mitochondrial membrane (TOM) 20, mitochondrial E3 ubiquitin protein ligase 1 (MUL1), and Parkin, thus harmonizing mitochondrial quality control. Emerging novel USP30 inhibitors, racemic phenylalanine derivatives, N-cyano pyrrolidine, and notably, benzosulphonamide class compounds, restore mitophagy, and reduce neurodegenerative phenotypes across diverse models with minimal off-target effects. Modulation of other USPs also influences neurodegenerative disease pathways, offering additional therapeutic avenues.
CONCLUSIONS: In highlighting the nuanced regulation of mitophagy by USP30, this work heralds a shift toward more precise and effective treatments, paving the way for a new era in the clinical management of neurodegenerative disorders.

Keywords:  Alzheimer's disease; Parkinson's disease; USP13 inhibitors; USP14 inhibitors; USP30 inhibitors; deubiquitinating enzymes; mitophagy; ubiquitin‐specific protease

DOI:  https://doi.org/10.1111/cns.70192
RSC Chem Biol. 2025 Jan 17.

Navigating the dichotomy of reactive oxygen, nitrogen, and sulfur species: detection strategies and therapeutic interventions.

Prayasee Baruah, Dikshaa Padhi, Hariharan Moorthy, Madhu Ramesh, Thimmaiah Govindaraju.

Reactive oxygen, nitrogen and sulfur species (RONSS) collectively encompasses a variety of energetically dynamic entities that emerge as inherent characteristics of aerobic life. This broad category includes reactive oxygen species (ROS), reactive nitrogen species (RNS), and reactive sulfur species (RSS). A conundrum arises from the indispensable role of RONSS in redox signalling, while its overproduction in the mitochondria poses deleterious effects. This imbalance leads to biomolecular damage and contributes to neurodegenerative disorders, cancer, cardiovascular diseases and inflammation. Notably, the differential roles of RONSS across various diseases can be strategically exploited for therapeutic interventions. Timely, precise, and sensitive detection methods are indispensable for elucidating the spatiotemporal dynamics of RONSS and evaluating disease pathogenesis and progression. By monitoring RONSS levels, we can discern early markers of disease onset, enabling proactive intervention strategies for effective disease management. Therapeutic interventions targeting oxidative/nitrosative stress in disease pathologies have proven to be effective treatment routes in the mitigation of different diseases. This review aims to offer a comprehensive overview of the functional implications and delicate balance of RONSS in disease conditions, and advances made in detection strategies over the years while offering therapeutic strategies to tackle their adverse effects. A special emphasis is focussed on neurodegenerative disorders and cancer with case studies using RONSS-targeted chemical probes and prodrugs.

DOI: https://doi.org/10.1039/d5cb00006h
Antioxidants (Basel). 2025 Jan 09. pii: 70. [Epub ahead of print]14(1):

Unraveling the AMPK-SIRT1-FOXO Pathway: The In-Depth Analysis and Breakthrough Prospects of Oxidative Stress-Induced Diseases.

Guangqi Guan, Yaoxing Chen, Yulan Dong.

  Oxidative stress (OS) refers to the production of a substantial amount of reactive oxygen species (ROS), leading to cellular and organ damage. This imbalance between oxidant and antioxidant activity contributes to various diseases, including cancer, cardiovascular disease, diabetes, and neurodegenerative conditions. The body's antioxidant system, mediated by various signaling pathways, includes the AMPK-SIRT1-FOXO pathway. In oxidative stress conditions, AMPK, an energy sensor, activates SIRT1, which in turn stimulates the FOXO transcription factor. This cascade enhances mitochondrial function, reduces mitochondrial damage, and mitigates OS-induced cellular injury. This review provides a comprehensive analysis of the biological roles, regulatory mechanisms, and functions of the AMPK-SIRT1-FOXO pathway in diseases influenced by OS, offering new insights and methods for understanding OS pathogenesis and its therapeutic approaches.

Keywords:  AMPK-SIRT1-FOXO pathway; antioxidant mechanism; oxidative stress; reactive oxygen species

DOI:  https://doi.org/10.3390/antiox14010070
BMC Neurosci. 2025 Jan 28. 26(1): 8

NPT100-18A rescues mitochondrial oxidative stress and neuronal degeneration in human iPSC-based Parkinson's model.

Julian E Alecu, Veronika Sigutova, Razvan-Marius Brazdis, Sandra Lörentz, Marios Evangelos Bogiongko, Anara Nursaitova, Martin Regensburger, Laurent Roybon, Kerstin M Galler, Wolfgang Wrasidlo, Beate Winner, Iryna Prots.

   BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder characterized by protein aggregates mostly consisting of misfolded alpha-synuclein (αSyn). Progressive degeneration of midbrain dopaminergic neurons (mDANs) and nigrostriatal projections results in severe motor symptoms. While the preferential loss of mDANs has not been fully understood yet, the cell type-specific vulnerability has been linked to a unique intracellular milieu, influenced by dopamine metabolism, high demand for mitochondrial activity, and increased level of oxidative stress (OS). These factors have been shown to adversely impact αSyn aggregation. Reciprocally, αSyn aggregates, in particular oligomers, can impair mitochondrial functions and exacerbate OS. Recent drug-discovery studies have identified a series of small molecules, including NPT100-18A, which reduce αSyn oligomerization by preventing misfolding and dimerization. NPT100-18A and structurally similar compounds (such as NPT200-11/UCB0599, currently being assessed in clinical studies) point towards a promising new approach for disease-modification.
METHODS: Induced pluripotent stem cell (iPSC)-derived mDANs from PD patients with a monoallelic SNCA locus duplication and unaffected controls were treated with NPT100-18A. αSyn aggregation was evaluated biochemically and reactive oxygen species (ROS) levels were assessed in living mDANs using fluorescent dyes. Adenosine triphosphate (ATP) levels were measured using a luminescence-based assay, and neuronal cell death was evaluated by immunocytochemistry.
RESULTS: Compared to controls, patient-derived mDANs exhibited higher cytoplasmic and mitochondrial ROS probe levels, reduced ATP-related signals, and increased activation of caspase-3, reflecting early neuronal cell death. NPT100-18A-treatment rescued cleaved caspase-3 levels to control levels and, importantly, attenuated mitochondrial oxidative stress probe levels in a compartment-specific manner and, at higher concentrations, increased ATP signals.
CONCLUSIONS: Our findings demonstrate that NPT100-18A limits neuronal degeneration in a human in vitro model of PD. In addition, we provide first mechanistic insights into how a compartment-specific antioxidant effect in mitochondria might contribute to the neuroprotective effects of NPT100-18A.

Keywords:  Aggregation; Alpha-synuclein; Dopaminergic neurons; Mitochondria; NPT100-18A; Oxidative stress; Parkinson’s disease; ROS; iPSC

DOI:  https://doi.org/10.1186/s12868-025-00926-y
Eur J Neurosci. 2025 Jan;61(1): e16659

Oxyglutamate Carrier Alleviates Cerebral Ischaemia-Reperfusion Injury by Regulating Mitochondrial Function.

Wenhao Liu, Xin Liu, Min Liu, Rui Zhao, Zhiyuan Zhao, Jingrui Xiao, Dongdong Wan, Qi Wan, Rui Xu.

  Mitochondrial dysfunction has been reported to participate in the pathophysiological processes of cerebral ischaemia-reperfusion injury, which include reduced energy homeostasis, increased generation of oxidative stress species (ROS) and the release of apoptotic factors. Oxyglutamate carrier (OGC) is an important carrier protein on the inner mitochondrial membrane that can transport metabolites from the cytoplasm to the mitochondria. The role of OGC in cerebral ischaemia-reperfusion injury (I/R) remains unknown. In this study, we found that the expression of OGC was significantly upregulated after cerebral ischaemia-reperfusion injury. Inhibiting OGC with phenylsuccinic acid (PSA) increased neuronal death after oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro. Mechanistically, OGC was localized in mitochondria and could facilitate the transport of glutathione from the cytoplasm to the mitochondria to reduce ROS levels and increase ATP production after OGD/R. In addition, in vivo inhibition of OGC exacerbated brain infarction, and GSH supplementation alleviated brain infarction resulting from OGC inhibition. This study revealed the role of OGC in alleviating brain damage by regulating mitochondrial GSH transport to alleviate mitochondrial function after cerebral ischaemia-reperfusion injury, which may provide a target for alleviating ischaemic brain injury.

Keywords:  OGC; ROS; ischaemia–reperfusion injury; mitochondria; neuron

DOI:  https://doi.org/10.1111/ejn.16659
Biochimie. 2025 Jan 28. pii: S0300-9084(25)00023-9. [Epub ahead of print]

Mitochondrial dynamics: molecular mechanism and implications in endometriosis.

Ylenia Marino, Francesca Inferrera, Tiziana Genovese, Salvatore Cuzzocrea, Roberta Fusco, Rosanna Di Paola.

  Endometriosis affects about 10% of women of reproductive age, leading to a disabling gynecologic condition. Chronic pain, inflammation, and oxidative stress have been identified as the molecular pathways involved in the progression of this disease, although its precise etiology remains uncertain. Although mitochondria are considered crucial organelles for cellular activity, their dysfunction has been linked to the development of this disease. The purpose of this review is to examine the functioning of the mitochondrion in endometriosis: in particular, we focused on the mitochondrial dynamics of biogenesis, fusion, and fission. Since excessive mitochondrial activity is reported to affect cell proliferation, we also considered mitophagy as a mechanism involved in limiting disease development. To better understand mitochondrial activity, we also considered alterations in circadian rhythms, the gut microbiome, and estrogen receptors: indeed, these mechanisms are also involved in the development of endometriosis. In addition, we focused on recent research about the impact of numerous substances on mitochondrial activity; some of them may offer a future breakthrough in endometriosis treatment by acting on mitochondria and inhibiting cell proliferation.

Keywords:  Endometriosis; Inflammation; Mitochondria; Mitochondrial Dysfunction; Oxidative stress

DOI:  https://doi.org/10.1016/j.biochi.2025.01.012
Antioxidants (Basel). 2025 Jan 09. pii: 72. [Epub ahead of print]14(1):

Oxidative Stress and Cardiovascular Complications in Type 2 Diabetes: From Pathophysiology to Lifestyle Modifications.

Alfredo Caturano, Maria Rocco, Giuseppina Tagliaferri, Alessia Piacevole, Davide Nilo, Giovanni Di Lorenzo, Ilaria Iadicicco, Mariarosaria Donnarumma, Raffaele Galiero, Carlo Acierno, Celestino Sardu, Vincenzo Russo, Erica Vetrano, Caterina Conte, Raffaele Marfella, Luca Rinaldi, Ferdinando Carlo Sasso.

  Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder that significantly increases the risk of cardiovascular disease, which is the leading cause of morbidity and mortality among diabetic patients. A central pathophysiological mechanism linking T2DM to cardiovascular complications is oxidative stress, defined as an imbalance between reactive oxygen species (ROS) production and the body's antioxidant defenses. Hyperglycemia in T2DM promotes oxidative stress through various pathways, including the formation of advanced glycation end products, the activation of protein kinase C, mitochondrial dysfunction, and the polyol pathway. These processes enhance ROS generation, leading to endothelial dysfunction, vascular inflammation, and the exacerbation of cardiovascular damage. Additionally, oxidative stress disrupts nitric oxide signaling, impairing vasodilation and promoting vasoconstriction, which contributes to vascular complications. This review explores the molecular mechanisms by which oxidative stress contributes to the pathogenesis of cardiovascular disease in T2DM. It also examines the potential of lifestyle modifications, such as dietary changes and physical activity, in reducing oxidative stress and mitigating cardiovascular risks in this high-risk population. Understanding these mechanisms is critical for developing targeted therapeutic strategies to improve cardiovascular outcomes in diabetic patients.

Keywords:  Mediterranean diet; cardiovascular complications; lifestyle interventions; oxidative stress; pathophysiology; type 2 diabetes mellitus

DOI:  https://doi.org/10.3390/antiox14010072
Pharmaceuticals (Basel). 2025 Jan 06. pii: 56. [Epub ahead of print]18(1):

The Potential Application of Nanocarriers in Delivering Topical Antioxidants.

Zulfan Zazuli, Rika Hartati, Cornelia Rosasepti Rowa, Sukmadjaja Asyarie, Satrialdi.

  The imbalance in the production of reactive oxygen species (ROS) with endogenous antioxidant capacity leads to oxidative stress, which drives many disorders, especially in the skin. In such conditions, supplementing exogenous antioxidants may help the body prevent the negative effect of ROS. However, the skin, as the outermost barrier of the body, provides a perfect barricade, making the antioxidant delivery complicated. Several strategies have been developed to enhance the penetration of antioxidants through the skin, one of which is nanotechnology. This review focuses on utilizing several nanocarrier systems, including nanoemulsions, liposomes, solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), and polymeric nanoparticles, for transporting antioxidants into the skin. We also reveal ROS formation in the skin and the role of antioxidant therapy, as well as the natural sources of antioxidants. Furthermore, we discuss the clinical application of topical antioxidant therapy concomitantly with the current status of using nanotechnology to deliver topical antioxidants. This review will accelerate the advancement of topical antioxidant therapy.

Keywords:  antioxidants; nanocarriers; natural antioxidants; topical

DOI:  https://doi.org/10.3390/ph18010056
Antioxidants (Basel). 2025 Jan 10. pii: 76. [Epub ahead of print]14(1):

Mutations of the Electron Transport Chain Affect Lifespan and ROS Levels in C. elegans.

Fanni Ősz, Aamir Nazir, Krisztina Takács-Vellai, Zsolt Farkas.

  Mutations in highly conserved genes encoding components of the electron transport chain (ETC) provide valuable insights into the mechanisms of oxidative stress and mitochondrial ROS (mtROS) in a wide range of diseases, including cancer, neurodegenerative disorders, and aging. This review explores the structure and function of the ETC in the context of its role in mtROS generation and regulation, emphasizing its dual roles in cellular damage and signaling. Using Caenorhabditis elegans as a model organism, we discuss how ETC mutations manifest as developmental abnormalities, lifespan alterations, and changes in mtROS levels. We highlight the utility of redox sensors in C. elegans for in vivo studies of reactive oxygen species, offering both quantitative and qualitative insights. Finally, we examine the potential of C. elegans as a platform for testing ETC-targeting drug candidates, including OXPHOS inhibitors, which represent promising avenues in cancer therapeutics. This review underscores the translational relevance of ETC research in C. elegans, bridging fundamental biology and therapeutic innovation.

Keywords:  C. elegans; ETC; ROS; SDH; cancer; electron transport chain; healthspan; lifespan; reactive oxygen species; succinate dehydrogenase

DOI:  https://doi.org/10.3390/antiox14010076
Inflammopharmacology. 2025 Jan 30.

Uncovering the intricacies of IGF-1 in Alzheimer's disease: new insights from regulation to therapeutic targeting.

Navpreet Kaur, Khadga Raj Aran.

  Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β plaques and tau tangles, leading to cognitive decline and dementia. Insulin-like Growth Factor-1 (IGF-1) is similar in structure to insulin and is crucial for cell growth, differentiation, and regulating oxidative stress, synaptic plasticity, and mitochondrial function. IGF-1 exerts its physiological effects by binding to the IGF-1 receptor (IGF-1R) and activating PI3K/Akt pathway. In addition to the physiological activities in the brain, numerous studies point to a potential protective role of the IGF-1 pathway in the pathogenesis of neurodegenerative diseases, such as AD. Interestingly, patients with AD often exhibit altered insulin and IGF-1 levels, along with an inadequate insulin response. Dysregulation of IGF-1 signaling contributes to hyperphosphorylation of tau, NFT accumulation, increased β- and γ-secretase activity, elevated Aβ production, and impaired Aβ clearance, highlighting the need to explore the role of this signaling for potential therapeutic targets of AD. This review explores the role of IGF signaling in AD pathology, highlighting IGF-1 as a promising therapeutic target due to its significant involvement in disease mechanisms. Modulating IGF-1 activity could help mitigate neurodegeneration and preserve cognitive function in AD. A comprehensive understanding of the mechanisms underlying IGF-1 dysregulation is crucial for developing targeted therapeutic strategies to address the complex and multifaceted nature of AD.

Keywords:  Acetylcholine; Alzheimer’s disease; BACE-1; GSK-3β; IGF-1; NFTs

DOI:  https://doi.org/10.1007/s10787-025-01641-0
Pharmaceuticals (Basel). 2024 Dec 24. pii: 2. [Epub ahead of print]18(1):

Multivalent Neuroprotective Activity of Elettaria cardamomum (Cardamom) and Foeniculum vulgare (Fennel) in H2O2-Induced Oxidative Stress in SH-SY5Y Cells and Acellular Assays.

Himadri Sharma, Hyewon Yang, Niti Sharma, Seong Soo A An.

   BACKGROUND: Elettaria cardamomum (Cardamom) and Foeniculum vulgare (Fennel) are well-known spices and are also used as natural mouth fresheners. This study was performed to evaluate their neuroprotective ability based on certain acellular and cellular assays.
METHODS: Hexane and ethyl acetate extracts were prepared using cardamom and fennel seeds. GC/MS was performed for the identification of important bioactive compounds. Cell-based assays were performed using SH-SY5Y cells. Hydrogen peroxide was used for the induction of oxidative stress, and evaluation was done based on neuroprotection, reduced reactive oxygen species, and restoration of mitochondrial membrane potential (MMP). Additionally, anti-Aβ fibrillization/oligomerization activities were also analyzed along with anti-acetylcholinesterase activity.
RESULTS: α-Terpinyl acetate and anethol were identified as major phytocompounds in cardamom and fennel, respectively. Cardamom extracts and α-terpinyl acetate were more potent acetylcholinesterase (AChE) inhibitors than fennel extracts and anethol [IC50 cardamom extracts, 130-150 μg/mL; α-terpinyl acetate, 61.87 μg/mL; anethol, 374.2 μg/mL; fennel extracts, >1 mg/mL] and showed mixed-type inhibition. Only the extracts displayed potent anti-Aβ fibrilization activity (>50%). Anethol showed potent anti-Aβ oligomerization activity (>50%), followed by α-terpinyl acetate and fennel-H (~36%). The neuroprotective potential of the spice extracts/phytochemicals was evaluated in SH-SY5Y cells by using H2O2-induced oxidative stress. Cardamom-EA displayed the best neuroprotection (0.01 to 30 μg/mL). No neuroprotection was observed by α-terpinyl acetate and anethol. Cardamom extracts and fennel-H restored the normal reactive oxygen species (ROS) levels at 30 µg/mL and 1 µg/mL, respectively.
CONCLUSION: Overall, the extracts provided better neuroprotection than the pure compounds in cellular assays and displayed strong anti-Aβ fibrilization activity.

Keywords:  anethol; anti-Aβ fibrillization/oligomerization; anti-acetylcholine esterase activity; cardamom; fennel; neuroprotection; oxidative stress; α-terpinyl acetate

DOI:  https://doi.org/10.3390/ph18010002
Int J Mol Sci. 2025 Jan 20. pii: 844. [Epub ahead of print]26(2):

Ellagic Acid: A Green Multi-Target Weapon That Reduces Oxidative Stress and Inflammation to Prevent and Improve the Condition of Alzheimer's Disease.

Silvana Alfei, Guendalina Zuccari.

  Oxidative stress (OS), generated by the overrun of reactive species of oxygen and nitrogen (RONS), is the key cause of several human diseases. With inflammation, OS is responsible for the onset and development of clinical signs and the pathological hallmarks of Alzheimer's disease (AD). AD is a multifactorial chronic neurodegenerative syndrome indicated by a form of progressive dementia associated with aging. While one-target drugs only soften its symptoms while generating drug resistance, multi-target polyphenols from fruits and vegetables, such as ellagitannins (ETs), ellagic acid (EA), and urolithins (UROs), having potent antioxidant and radical scavenging effects capable of counteracting OS, could be new green options to treat human degenerative diseases, thus representing hopeful alternatives and/or adjuvants to one-target drugs to ameliorate AD. Unfortunately, in vivo ETs are not absorbed, while providing mainly ellagic acid (EA), which, due to its trivial water-solubility and first-pass effect, metabolizes in the intestine to yield UROs, or irreversible binding to cellular DNA and proteins, which have very low bioavailability, thus failing as a therapeutic in vivo. Currently, only UROs have confirmed the beneficial effect demonstrated in vitro by reaching tissues to the extent necessary for therapeutic outcomes. Unfortunately, upon the administration of food rich in ETs or ETs and EA, URO formation is affected by extreme interindividual variability that renders them unreliable as novel clinically usable drugs. Significant attention has therefore been paid specifically to multitarget EA, which is incessantly investigated as such or nanotechnologically manipulated to be a potential "lead compound" with protective action toward AD. An overview of the multi-factorial and multi-target aspects that characterize AD and polyphenol activity, respectively, as well as the traditional and/or innovative clinical treatments available to treat AD, constitutes the opening of this work. Upon focus on the pathophysiology of OS and on EA's chemical features and mechanisms leading to its antioxidant activity, an all-around updated analysis of the current EA-rich foods and EA involvement in the field of AD is provided. The possible clinical usage of EA to treat AD is discussed, reporting results of its applications in vitro, in vivo, and during clinical trials. A critical view of the need for more extensive use of the most rapid diagnostic methods to detect AD from its early symptoms is also included in this work.

Keywords:  AD diagnosis; Alzheimer’s disease (AD); antioxidants; ellagic acid (EA); ellagitannins (ETs); in vitro and in vivo EA applications; multi-target drugs; one-target drugs; oxidative stress (OS); radical scavenging activity; reactive nitrogen species; reactive oxygen species; urolithins (UROs)

DOI:  https://doi.org/10.3390/ijms26020844
Kidney Int. 2025 Jan 22. pii: S0085-2538(25)00071-7. [Epub ahead of print]

Repurposing Mitochondria-Targeted Therapeutics for Kidney Diseases.

Austin D Thompson, S Paul Victor, Natalie E Scholpa, Rick G Schnellmann.

  The kidney is one of the most metabolically demanding organs in the human body and requires a large amount of energy, in the form of adenosine triphosphate (ATP), to perform and maintain normal renal functions. To meet this energy demand, proximal tubule cells within the nephron segments of the renal cortex are mitochondrially dense with high oxygen consumption rates. Mitochondria are complex organelles involved in diverse cellular and molecular functions, including the production of ATP, calcium homeostasis, and phospholipid regulation. Mitochondrial dysfunction is critical in the onset and progression of kidney disease. Dysfunctional renal mitochondria have been linked with alterations in redox homeostasis, impaired bioenergetics, oxidative stress, and inflammation, all of which result in renal cell injury and death, as well as fibrotic accumulation in kidney injury and disease. As such, interest in the development and/or repurposing of mitochondria-targeted therapeutics for the potential treatment of kidney diseases has recently surged. While novel therapeutics and promising new drug targets have been identified, drug repurposing for kidney diseases offers numerous advantages over traditional drug discovery initiatives, including reduced cost, time of therapeutic development, and preclinical testing, in addition to known pharmacokinetics/pharmacodynamics and safety profiles. Here, we provide an overview of mitochondrial dysfunction in the context of kidney injury and disease and shed light on promising mitochondria-targeted therapeutic agents that display repurposing potential for the restoration of renal function and/or acceleration of renal recovery.

Keywords:  Drug Repurposing; Kidney Disease; Mitochondrial Dysfunction; Mitochondrial Therapeutics

DOI:  https://doi.org/10.1016/j.kint.2024.12.020
BMC Complement Med Ther. 2025 Jan 30. 25(1): 33

A randomized double-blind clinical trial investigating the effects of ellagic acid on glycemic status, liver enzymes, and oxidative stress in patients with non-alcoholic fatty liver disease.

Sara Mighani, Rasoul Samimi, Mohamadreza Rashidi Nooshabadi, Seyed Amir Farzam, Hossein Khadem Haghighian, Maryam Javadi.

   BACKGROUND: It seems that oxidative stress is involved in the occurrence and progression of non-alcoholic fatty liver disease (NAFLD). Considering the antioxidant features of Ellagic acid (EA), this study was designed to assess the effect of EA on some biochemical factors in patients with NAFLD.
METHODS: In this clinical trial, 44 patients were selected based on including criteria and randomly received 180 mg of EA per day (n = 22) or placebo (n = 22) for 8 weeks. At the beginning and end of the study, glycemic indices, lipid profiles, liver enzymes, oxidative stress markers, and inflammatory factors were measured.
RESULTS: At the end of the study, the mean of insulin, insulin resistance (IR), triglycerides (TG), low-density lipoprotein (LDL), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), malondialdehyde (MDA), and C-reactive protein (CRP) were significantly decreased in the intervention group (P < 0.05). Also, a significant increase in the mean of total antioxidant capacity (TAC) was observed in the EA group (P < 0.05). However, changes in high-density lipoprotein (HDL), total cholesterol (TC), and fasting blood sugar (FBS) were not significant in any of the groups (P > 0.05).
CONCLUSIONS: Based on the results, the present study provided evidence that EA can be used as a supplemental therapy alongside current treatment plans to reduce the complications of NAFLD due to its antioxidant and anti-inflammatory properties.
TRIAL REGISTRATION: This study was prospectively registered at the Iranian Registry of Clinical Trials on the 23th of January 2022 (ID: IRCT20141025019669N21).

Keywords:  Ellagic acid; Glycemic status; Lipid profile; Liver enzymes; Non-alcoholic fatty liver disease; Oxidative stress

DOI:  https://doi.org/10.1186/s12906-025-04759-4
Acta Physiol (Oxf). 2025 Mar;241(3): e70007

Blocking the mineralocorticoid receptor prevents cardiac and mitochondrial dysfunction through the activation of NOX-4 in female hormone deprivation rats.

Samya Mere L Rodrigues, Carolina F Ximenes, Nathália Rodrigues, Karoline Ronconi, Anna Karolina Nascimento Costa, Livia Barroca Vieira, Maria Luiza Yago da Silva, Katyana K S Ferreira, Marcos Eliezeck, Sergio Scalzo, André Monteiro, Bruno Sanches, Thiago Spalenza, Aurélia Araújo Fernandes, Silvia Guatimosim, Kurt J Varner, Eduardo Hertel Ribeiro, Ivanita Stefanon.

   AIM: Young women exhibit lower rates of cardiovascular disease (CVD) than age-matched men, a protective effect often attributed to estrogen's influence on cardiac and mitochondrial function. The risk of CVD increases in post-menopausal women, likely due to estrogen deficiency and aldosterone's negative effects, including those on mitochondria and other cellular targets. This study aimed to explore the link between estrogen deficiency and mitochondrial dysfunction in cardiac health. We hypothesized that in estrogen-deprived conditions, aldosterone could stimulate NADPH oxidase, leading to mitochondrial dysfunction, and reduced cardiac contractility.
METHODS: Wistar rats were divided into four groups: Sham, Ovariectomy-induced hormone deprivation (Ovx), Ovx with apocynin treatment, and Ovx with spironolactone treatment for 60 days.
RESULTS: Both apocynin and spironolactone countered the adverse effects of hormone deprivation by preserving myocardial contractility, improving cellular responses to calcium and isoproterenol, and normalizing the expression of key mitochondrial proteins. These compounds also attenuated the increase in reactive oxygen species (ROS) and maintained mitochondrial respiration rates.
CONCLUSION: We concluded that estrogen deficiency contributes to cardiac oxidative stress via the NADPH oxidase and mitochondrial pathways. Apocynin and spironolactone offer significant protective effects, opening new avenues for treating cardiac issues related to estrogen deficiency.

Keywords:  aldosterone; female hormone deficiency; mitochondria; myocardial contractility; oxidative stress; reactivity oxygen species

DOI:  https://doi.org/10.1111/apha.70007
Stem Cell Rev Rep. 2025 Jan 31.

Mitochondria Express Functional Signaling Ligand-Binding Receptors that Regulate their Biological Responses - the Novel Role of Mitochondria as Stress-Response Sentinels.

Katarzyna Brzezniakiewicz-Janus, Justyna Jarczak, Adrian Konopko, Janina Ratajczak, Magdalena Kucia, Mariusz Z Ratajczak.

  Evidence accumulated mitochondria, as the "powerplants of the cell," express several functional receptors for external ligands that modify their function and regulate cell biology. This review sheds new light on the role of these organelles in sensing external stimuli to facilitate energy production for cellular needs. This is possible because mitochondria express some receptors on their membranes that are responsible for their autonomous responses. This is not surprising given the widely accepted hypothesis that these intracellular organelles originated from prokaryotic ancestors that fused with eukaryotic cells during early evolution. It has been reported that mitochondria express functional estrogen, androgen, glucocorticoid, 5-hydroxytryptamine, melatonin, and cannabinoid receptors. What is intriguing is recent evidence showing that mitochondria could also be directly regulated by active mediators of intracellular complement (complosome) and intrinsic mediators of purinergic signaling. Accordingly, they express receptors for intracellular complement cleavage fragments (C5a and C3a) as well as for adenosine triphosphate (ATP), which, besides its crucial role in transferring energy in the cells, is also an important signaling molecule interacting with P2X7 receptor expressed not only on the cell surface but also on the mitochondria membrane. Based on this, intrinsic complosome and purinergic signaling mediators emerge as important cooperating regulators of reactive oxygen species (ROS) release from mitochondria and activators of intracellular pattern recognition receptor Nlrp3 inflammasome. This activation within the beneficial "hormetic zone response" regulates cell metabolism, proliferation, migration, and adaptation to the surrounding challenges of the microenvironment in a favorable way.

Keywords:  C3aR; C5aR; Complement; Complosome; Mitochondrial receptors; Nlrp3 inflammasome; P2X7; Purinergic signaling; ROS

DOI:  https://doi.org/10.1007/s12015-025-10847-2
J Med Chem. 2025 Jan 28.

Strategic Mutations in Designer Native Peptides Combat NLRP3 Inflammasome Activation in Neurodegenerative Disorders.

Sabyasachi Mandal, Madhu Ramesh, Thimmaiah Govindaraju.

Nucleotide-binding oligomerization domain (NOD)-, leucine-rich repeat (LRR)-, and pyrin domain (PYD)-containing protein 3 (NLRP3) form an inflammasome by assembling with apoptosis-associated speck-like protein containing a CARD (ASC) and procaspase-1 that plays a pivotal role in various neurodegenerative diseases such as Alzheimer's and Parkinson diseases. We designed native peptides derived from the PYDs of NLRP3 and ASC based on their interfacial interaction to inhibit NLRP3 inflammasome formation. Screening revealed that NP3, derived from NLRP3, inhibits inflammasome activation. Furthermore, a strategic mutation (F → L) in native peptide NP3 results in MNP2 that selectively binds to PYD of ASC with nanomolar affinity, inhibiting NLRP3 inflammasome formation, interleukin-1β (IL-1β) release, and caspase-1 maturation. MNP2 also reduced potassium (K) and chloride (Cl) ion efflux, key signals in NLRP3 activation, and prevented mitochondrial damage and reactive oxygen species (ROS) production. MNP2 significantly reduced NLRP3 inflammasome formation in neurodegenerative conditions triggered by amyloid-β (Aβ), Tau, and α-Synuclein (α-Syn), suggesting a promising therapeutic strategy for NLRP3-related inflammatory diseases, including neurodegenerative disorders.

DOI: https://doi.org/10.1021/acs.jmedchem.4c02158
Biomedicines. 2025 Jan 10. pii: 161. [Epub ahead of print]13(1):

Redox Metabolism and Autonomic Regulation During Aging: Can Heart Rate Variability Be Used to Monitor Healthy Longevity?

Olha Yelisyeyeva, Danylo Kaminskyy, Marta Semen, Ilona Chelpanova, Khrystyna O Semen.

  The functionality of redox metabolism is frequently named as an important contributor to the processes of aging and anti-aging. Excessive activation of free radical reactions accompanied by the inability of the antioxidant defense (AOD) mechanisms to control the flow of the reactive oxygen species (ROS) leads to the persistence of oxidative stress, hypoxia, impaired mitochondrial energy function and reduced ATP potential. From a long-term perspective, such changes contribute to the development of chronic diseases and facilitate aging. In turn, preconditioning of a biosystem with small doses of stressful stimuli might cause mobilization of the mechanisms of AOD and control an excessive flow of ROS, which supports optimal functioning of the redox reactions. Those mechanisms are of crucial importance for anti-aging and are also known as a eustress or hormetic response. To ensure continuous support of mild pro-oxidant activity in a metabolic system, close monitoring and timely corrections preventing the development of excessive ROS production are required. The paper introduces the potential of heart rate variability (HRV) as a biomarker of functional and metabolic reserves and a tool to measure stress resilience during aging. The practical approaches to interpretation of HRV are provided based on total power, changes in total power in response to an orthostatic test and activities of all spectral components. It is suggested that the complex of those parameters can reflect the depth of oxidative stress and may be used to guide lifestyle interventions and promote active longevity.

Keywords:  aging; anti-aging; heart rate variability; hormetic response

DOI:  https://doi.org/10.3390/biomedicines13010161
Genes (Basel). 2025 Jan 02. pii: 46. [Epub ahead of print]16(1):

Production of Amyloid-β in the Aβ-Protein-Precursor Proteolytic Pathway Is Discontinued or Severely Suppressed in Alzheimer's Disease-Affected Neurons: Contesting the 'Obvious'.

Vladimir Volloch, Sophia Rits-Volloch.

  A notion of the continuous production of amyloid-β (Aβ) via the proteolysis of Aβ-protein-precursor (AβPP) in Alzheimer's disease (AD)-affected neurons constitutes both a cornerstone and an article of faith in the Alzheimer's research field. The present Perspective challenges this assumption. It analyses the relevant empirical data and reaches an unexpected conclusion, namely that in AD-afflicted neurons, the production of AβPP-derived Aβ is either discontinued or severely suppressed, a concept that, if proven, would fundamentally change our understanding of the disease. This suppression, effectively self-suppression, occurs in the context of the global inhibition of the cellular cap-dependent protein synthesis as a consequence of the neuronal integrated stress response (ISR) elicited by AβPP-derived intraneuronal Aβ (iAβ; hence self-suppression) upon reaching certain levels. Concurrently with the suppression of the AβPP proteolytic pathway, the neuronal ISR activates in human neurons, but not in mouse neurons, the powerful AD-driving pathway generating the C99 fragment of AβPP independently of AβPP. The present study describes molecular mechanisms potentially involved in these phenomena, propounds novel approaches to generate transgenic animal models of AD, advocates for the utilization of human neuronal cells-based models of the disease, makes verifiable predictions, suggests experiments designed to validate the proposed concept, and considers its potential research and therapeutic implications. Remarkably, it opens up the possibility that the conventional production of AβPP, BACE enzymes, and γ-secretase components is also suppressed under the neuronal ISR conditions in AD-affected neurons, resulting in the dyshomeostasis of AβPP. It follows that whereas conventional AD is triggered by AβPP-derived iAβ accumulated to the ISR-eliciting levels, the disease, in its both conventional and unconventional (triggered by the neuronal ISR-eliciting stressors distinct from iAβ) forms, is driven not (or not only) by iAβ produced in the AβPP-independent pathway, as we proposed previously, but mainly, possibly exclusively, by the C99 fragment generated independently of AβPP and not cleaved at the γ-site due to the neuronal ISR-caused deficiency of γ-secretase (apparently, the AD-driving "substance X" predicted in our previous study), a paradigm consistent with a dictum by George Perry that Aβ is "central but not causative" in AD. The proposed therapeutic strategies would not only deplete the driver of the disease and abrogate the AβPP-independent production of C99 but also reverse the neuronal ISR and ameliorate the AβPP dyshomeostasis, a potentially significant contributor to AD pathology.

Keywords:  AD as the disease of the neuronal ISR; Amyloid Cascade Hypothesis 2.0 (ACH2.0); AβPP-independent generation of the C99 fragment; C99 as the driver of AD; ISR-mediated suppression of the AβPP proteolytic pathway and dyshomeostasis of AβPP in AD-affected neurons; RNA-dependent amplification of human AβPP mRNA; concurrent inhibition of the ISR and activation of BACE1 and BACE2 as composite AD therapy; conventional and unconventional Alzheimer’s disease (AD); design of AD models; neuronal integrated stress response (ISR)

DOI:  https://doi.org/10.3390/genes16010046
Front Nutr. 2024 ;11 1497364

Exploring the application of dietary antioxidant index for disease risk assessment: a comprehensive review.

Hossein Pourmontaseri, Sina Bazmi, Matin Sepehrinia, Ayda Mostafavi, Reza Arefnezhad, Reza Homayounfar, Farhad Vahid.

  Oxidative stress contributes to the development of cardiometabolic diseases and cancers. Numerous studies have highlighted the adverse effects of high reactive oxygen species (ROS) levels in the progression of chronic noncommunicable diseases and also during infections. On the other hand, antioxidants play a crucial role in preventing oxidative stress or postponing cell damage via the direct scavenging of free radicals or indirectly via the Keap1/Nrf2/ARE pathway, among others. Dietary antioxidants can be obtained from various sources, mainly through a plant-based diet, including fruits and vegetables. The dietary antioxidant index (DAI) has been developed to assess total antioxidant intake from diet. This review delineated the performance of DAI in the risk assessment of different diseases. It is suggested that a high DAI score prevents obesity-related diseases, including diabetes mellitus, hyperuricemia, dyslipidemia, and metabolic (dysfunction)-associated steatotic liver disease (MASLD). Additionally, DAI is negatively associated with Helicobacter pylori and Human papillomavirus infection, thus reducing the risk of gastric and cervical cancer. Also, a high intake of antioxidants prevents the development of osteoporosis, miscarriage, infertility, and mental illnesses. However, further prospective observations and clinical trials are warranted to confirm the application of DAI in preventing diseases that have been studied.

Keywords:  cancer; cardiovascular diseases; infertility; mental disorders; metabolic disease; obesity; osteoporosis

DOI:  https://doi.org/10.3389/fnut.2024.1497364
bioRxiv. 2025 Jan 17. pii: 2025.01.15.633247. [Epub ahead of print]

Oral prodrug of a novel glutathione surrogate reverses metabolic dysregulation and attenuates neurodegenerative process in APP/PS1 mice.

Swetha Pavani Rao, Aminat O Imam-Fulani, Wei Xie, Samuel Phillip, Krishna Chennavajula, Erin B Lind, Ying Zhang, Robert Vince, Michael K Lee, Swati S More.

Glycation-induced oxidative stress underlies the numerous metabolic ravages of Alzheimer's disease (AD). Reduced glutathione levels in AD lead to increased oxidative stress, including glycation-induced pathology. Previously, we showed that the accumulation of reactive 1,2-dicarbonyls such as methylglyoxal, the major precursor of non-enzymatic glycation products, was reduced by the increased function of GSH-dependent glyoxalase-1 enzyme in the brain. In this two-pronged study, we evaluate the therapeutic efficacy of an orally bioavailable prodrug of our lead glyoxalase substrate, pro-ψ-GSH, for the first time in a transgenic Alzheimer's disease mouse model. This prodrug delivers pharmacodynamically relevant brain concentrations of ψ-GSH upon oral delivery. Chronic oral dosing of pro-ψ-GSH effectively reverses the cognitive decline observed in the APP/PS1 mouse model. The prodrug successfully mirrors the robust effects of the parent drug i.e., reducing amyloid pathology, glycation stress, neuroinflammation, and the resultant neurodegeneration in these mice. We also report the first metabolomics study of such a treatment, which yields key biomarkers linked to the reversal of AD-related metabolic dysregulation. Collectively, this study establishes pro-ψ-GSH as a viable, disease-modifying therapy for AD and paves the way for further preclinical advancement of such therapeutics. Metabolomic signatures identified could prove beneficial in the development of treatment-specific clinically translatable biomarkers.
ABSTRACT GRAPHIC:

DOI: https://doi.org/10.1101/2025.01.15.633247
J Integr Neurosci. 2025 Jan 20. 24(1): 23090

Current Status of Plant-Based Bioactive Compounds as Therapeutics in Alzheimer's Diseases.

Dan Chen, Yun Sun.

  Alzheimer's disease (AD) is a common central neurodegenerative disease disorder characterized primarily by cognitive impairment and non-cognitive neuropsychiatric symptoms that significantly impact patients' daily lives and behavioral functioning. The pathogenesis of AD remains unclear and current Western medicines treatment are purely symptomatic, with a singular pathway, limited efficacy, and substantial toxicity and side effects. In recent years, as research into AD has deepened, there has been a gradual increase in the exploration and application of medicinal plants for the treatment of AD. Numerous studies have shown that medicinal plants and their active ingredients can potentially mitigate AD by regulating various molecular mechanisms, including the production and aggregation of pathological proteins, oxidative stress, neuroinflammation, apoptosis, mitochondrial dysfunction, neurogenesis, neurotransmission, and the brain-gut microbiota axis. In this review, we analyzed the pathogenesis of AD and comprehensively summarized recent advancements in research on medicinal plants for the treatment of AD, along with their underlying mechanisms and clinical evidence. Ultimately, we aimed to provide a reference for further investigation into the specific mechanisms through which medicinal plants prevent and treat AD, as well as for the identification of efficacious active ingredients derived from medicinal plants.

Keywords:  Alzheimer’s disease; cognitive function; medicinal plants; neuroinflammation; neuroprotection

DOI:  https://doi.org/10.31083/JIN23090
Nutrients. 2025 Jan 16. pii: 302. [Epub ahead of print]17(2):

In Vitro and In Vivo Antioxidant and Immune Stimulation Activity of Wheat Product Extracts.

Beatrice Mengoni, Federica Armeli, Emily Schifano, Sabrina Antonia Prencipe, Laura Pompa, Fabio Sciubba, Elisa Brasili, Ottavia Giampaoli, Francesco Mura, Massimo Reverberi, Marzia Beccaccioli, Alessandro Pinto, Maria De Giusti, Daniela Uccelletti, Rita Businaro, Giuliana Vinci.

   BACKGROUND/OBJECTIVES: Inflammation and oxidative stress are the main pathogenetic pathways involved in the development of several chronic degenerative diseases. Our study is aimed at assessing the antioxidant and anti-inflammatory activity of hydroalcoholic extracts obtained from wheat and its derivatives.
METHODS: The content of total phenolic and total flavonoid compounds and antioxidant activity were carried out by ABTS and DPPH assays. The ability of wheat extracts to promote microglia polarization towards an anti-inflammatory phenotype was evaluated analyzing the increased expression of anti-inflammatory markers by real-time qPCR and immunofluorescence assays. Antioxidant activity of all the extracts was evaluated in C. elegans by analyzing ROS levels and the expression of the antioxidant enzymes GST-4 and SOD-3 by real-time qPCR and fluorescence experiments. The expression of key genes involved in the innate immune response and stress resistance pathways-daf-16, sek-1, and pmk-1-was evaluated by real-time qPCR.
RESULTS: Wheat extracts showed the ability to polarize microglia cells towards an anti-inflammatory phenotype, even after the addition of LPS. An antioxidant response was detected both in microglia and in Caenorhabditis elegans nematode, where the extracts also implemented an anti-stress resilience response and stimulated the innate immunity.
CONCLUSIONS: The present study shows that wheat seeds, flour, chaff, and pasta present anti-inflammatory as well as antioxidant activities and may be considered as prospective positive health agents for the preparation of functional foods. Moreover, the valorization of by-products from agricultural and agro-industrial activities would also have significant implications in terms of circular economy.

Keywords:  C. elegans; functional foods; inflammation; innate immune response; microglia polarization; oxidative stress; wheat

DOI:  https://doi.org/10.3390/nu17020302