Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder for which current treatments provide only symptomatic relief, primarily through cholinesterase (ChE) inhibition and N-methyl-d-aspartate receptor (NMDAR) antagonism. To improve therapeutic efficacy and safety, we designed and synthesized 16 novel tacrine derivatives modified at position 7 with various (hetero)aryl groups or deuterium substitution. Initially, in silico screening predicted favorable CNS permeability and oral bioavailability. Subsequent in vitro evaluations demonstrated significant inhibitory potency against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with derivatives 5i and 5m displaying particularly promising profiles. Metabolic stability assessed using human liver microsomes revealed enhanced stability for compound 5e, whereas 5i and 5m underwent rapid metabolism. Notably, compound 7 showed improved metabolic stability attributed to deuterium incorporation. The newly synthesized compounds were further tested for antagonistic activity on the GluN1/GluN2B subtype of NMDAR, with compound 5m exhibiting the most potent and voltage-independent inhibition. The ability of these compounds to permeate the blood-brain barrier (BBB) was confirmed through in vitro PAMPA assays. In preliminary hepatotoxicity screening (HepG2 cells), most derivatives exhibited higher cytotoxicity than tacrine, emphasizing the ongoing challenge in hepatotoxicity management. Based on its overall favorable profile, compound 5m advanced to in vivo pharmacokinetic studies in mice, demonstrating efficient CNS penetration, with brain concentrations exceeding plasma levels (brain-to-plasma ratio 2.36), indicating active transport across the BBB. These findings highlight compound 5m as a promising tacrine-based multi-target-directed ligand, supporting further preclinical development as a potential therapeutic candidate for AD.

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition marked by difficulties in social communication, languages, and repetitive behaviors. Its rising prevalence has made it a critical global public health issue. ASD is believed to arise from a combination of genetic and environmental influences. While some gene mutations associated with ASD have been identified, most cases lack clear genetic explanations. Evidence increasingly points to early-life environmental factors as key contributors to ASD, including advanced parental age, maternal diabetes during pregnancy, infections, hormonal imbalances, certain medications, and exposure to air pollution. Currently, ASD diagnosis relies on behavioral assessments, but the absence of specific molecular biomarkers poses significant obstacles to early detection and targeted therapies. Encouragingly, research has identified potential biomarkers, such as neuroimaging classifiers, electroencephalography patterns, eye-tracking data, digital analytics, gene expression profiles, inflammatory and chemokine markers, proteomic and metabolomic profiles, and gut microbiota characteristics. Potential therapeutical strategies under investigation include digital therapies, non-invasive brain stimulation, antioxidants, oxytocin, AVPR1a antagonists, PPAR agonists, and mTOR inhibitors. This review explores ASD across five areas: epidemiological trends, genetic mechanisms, early-life environmental factors and their potential roles, diagnostic biomarkers, and therapeutic approaches.

Gamma radiation is known to induce several detrimental effects on the nervous system. The hippocampus region, specifically the dentate gyrus (DG) and subventricular zone (SVZ), have been identified as a radiation-sensitive neurogenic niche. Radiation alters the endogenous redox status of neural stem cells (NSCs) and other proliferative cells, especially in the hippocampus region, leading to oxidative stress, neuroinflammation, and cell death. Planned (i.e., radiotherapy of brain tumor patients) or unplanned radiation exposure (i.e., accidental radiation exposure) can induce nonspecific damage to neuronal tissues, resulting in chronic or acute radiation syndrome. Although anatomical alterations in the neuronal tissues have been reported at higher doses of gamma radiation, biochemical and molecular perturbations may be evident even at much lower radiation doses. They may manifest in the form of neuronal deficits and cognitive impairment. In the present review, several molecular events and signaling pathways, such as oxidative stress, neuroinflammation, apoptosis, cognition, neuroplasticity, and neurotoxicity induced in neuronal cells upon ionizing radiation exposure, are reviewed. Furthermore, brain-specific radioprotectors and mitigators that protect normal neuronal cells and tissues against ionizing radiation during radiotherapy of cancer patients or nuclear emergencies are also discussed.

Epilepsy is often marked by paroxysmal seizures that disrupt the brain's sensory, motor, and psychosocial functions. The underlying pathology is generally believed to involve an imbalance between excitatory and inhibitory neurotransmission. However, a less explored but significant contributor to epilepsy is the collapse of the brain's metabolic and bioenergetic systems. The breakdown of the brain's bioenergetic system leads to the activation of various detrimental downstream signaling cascades that ultimately result in oxidative stress, neuroinflammation, and reduced autophagic flux, all of which impair neuronal-glial communication and precipitate epileptic attacks. This highlights the pressing need for a therapeutic agent to address these complex challenges. Researchers have identified adenosine monophosphate kinase (AMPK) as a potential solution. AMPK acts as the body's primary stress sensor, activated in response to the deficiency of growth factors and nutrient starvation to restore energy homeostasis. AMPK activation also maintains the intricate communication between neurons and glial cells, preserving synaptic plasticity integrity, mitigating mitochondrial damage, and dampening inflammatory signaling cascades. Despite demonstrating significant efficacy in managing a range of peripheral and neurological disorders, the role of AMPK in neurotransmission and epilepsy remains unexplored. This review explores the multifaceted molecular roles of AMPK beyond its traditional metabolic regulatory functions, suggesting that targeting AMPK could provide a novel avenue for drug development in epilepsy treatment.

Fibromyalgia (FM) is a chronic disorder that lacks both well-defined underlying causes and effective treatments. Mito-TEMPO (MIT) is a mitochondrial-specific antioxidant that has demonstrated benefits in many cancerous, renal, cardiovascular, and neurodegenerative disorders. However, the therapeutic effect of MIT on FM remains ambiguous. The objective of the current work is to illuminate the use of MIT for FM and its prospective mechanisms. Here, we used the FM rat model induced by three days of subcutaneous reserpine injection (1 mg/kg) and examined the role of MIT on SIRT1 activation and other implicated molecular pathways. Behavioral tests showed that MIT (0.7 mg/kg) can effectively alleviate the locomotor, nociceptive, and depressive-like behaviors in reserpinized rats, an effect that simultaneously reconciles the balance of monoamines in the rat brain. Western blot analysis showed that MIT up-regulates SIRT1 and improves the expression of mitochondrial dynamics proteins (DRP1 and OPA1) and the endoplasmic reticulum protein (CHOP). Furthermore, MIT treatment significantly enhanced the SOD and CAT activities and decreased the brain contents of NF-κB, TNF-α, and BAX, but significantly enriching the Bcl-2 content. Lastly, MIT treatment significantly reduced the genetic expression of miRNA-320 following RES treatment. All the measured parameters showed a significant correlation with SIRT1 expression. Our results suggest that MIT provides antioxidant, anti-apoptotic, and anti-inflammatory impacts on the FM rat model, with proposed mechanisms involved activating the SIRT1 pathway to regulate mitochondrial dynamics, endoplasmic reticulum stress, as well as miRNA-320. Thus, MIT has the potential to be an effectual drug candidate for FM treatment.

Alzheimer's disease (AD) is the main cause of dementia in the elderly, and is becoming one of the most expensive and deadly diseases. Deficiency of neurotrophic factors signaling is an important cause of this disease. Therefore, we investigated whether neuritin as a neurotrophic factor can have a neuroprotective effect against streptozotocin (STZ)-induced rat model of AD. The animals were bilaterally injected with intra hippocampal-STZ (3 mg/kg). Different concentrations of neuritin (0.5, 1, 1.5 µg/rat) were administrated 15 min before STZ injection. After 14 days, the rats were evaluated for cognitive performance using novel object recognition (NOR), open field and Morris water maze (MWM) tests and then sacrificed for biochemical analysis (by real-time PCR and western blot examinations). The results demonstrated that the STZ- induced learning and memory impairments were significantly prevented by 1.5 µg neuritin. Moreover, the increased levels of inflammatory factors (NF-κb, TNF-α and IL-1β) and apoptotic parameters (cytochrome c and caspase‑3) in STZ- treated rats were also significantly decreased by neuritin. In addition, hippocampal neuritin gene expression was downregulated by STZ injection, which was reversed by intra hippocampal neuritin injection. In conclusion, the present study suggests that neuritin prevents cognitive defects in AD rat model and its expression level is associated with cognitive resilience.

Neurodegenerative diseases are chronic progressive disorders that impair memory, cognition, and motor functions, leading to conditions such as dementia, muscle weakness, and speech difficulties. Aging disrupts the stringent balance between pro- and anti-inflammatory cytokines, increasing neuroinflammation, which contributes to neurodegenerative diseases. The aging brain is particularly vulnerable to infections due to a weakened and compromised immune response and impaired integrity of the blood-brain barrier, allowing pathogens like viruses to trigger neurodegeneration. Coronaviruses have been linked to both acute and long-term neurological complications, including cognitive impairments, psychiatric disorders, and neuroinflammation. The virus can induce a cytokine storm, damaging the central nervous system (CNS) and worsening existing neurological conditions. Though its exact mechanism of neuroinvasion remains elusive, evidence suggests it disrupts the blood-brain barrier and triggers immune dysregulation, leading to persistent neurological sequelae in elderly individuals. This review aims to understand the interaction between the peripheral immune system and CNS glial cells in aged individuals, which is imperative in addressing coronavirus-induced neuroinflammation and concomitant neurodegeneration.

Motor dysfunction constitutes a prominent characteristic of Parkinson's disease (PD), a neurodegenerative disorder associated with compromised mitochondrial activity, perturbed gut microbial composition, and neuronal loss. In this study, we examined the regulatory mechanisms of Lactiplantibacillus plantarum SG5 (SG5) on mitochondrial function in PD mouse models, with a particular emphasis on its interaction with the GLP-1/PGC-1α pathway. Findings revealed that MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, MPTP) induced (male 6-8 weeks C57BL/6 mice) motor impairments and damage to dopaminergic (DA) neurons in PD mice, resulting in mitochondrial dysfunction, decreased mitochondrial biogenesis, disrupted dynamics, and autophagy, while promoting fission and apoptosis. Additionally, MPTP modified gut microbial diversity and community structure. Nevertheless, supplementation with SG5 alleviated motor deficits and DA neurons damage in PD mice, enhancing mitochondrial quality by elevating PGC-1α expression and restoring biogenesis, dynamics, and autophagy levels. Mechanistic investigations demonstrated that SG5 increased colonic GLP-1 expression, suggesting that GLP-1 might regulate mitochondrial function via the GLP-1R-mediated PGC-1α. Furthermore, SG5 counteracted MPTP-induced gut dysbiosis. Notably, both GLP-1R antagonists and PGC-1α inhibitors attenuated the protective effects of SG5 in PD mice. In conclusion, L. plantarum SG5 may enhance mitochondrial function in the substantia nigra (SN) of PD mice through the GLP-1/PGC-1α pathway, potentially delaying neurodegeneration. Its mechanism is closely related to the regulation of the gut microenvironment and GLP-1 levels, presenting novel microbiota-based therapeutic targets for PD.

In normal conditions, neuroinflammation induces microglia and astrocyte activation to maintain brain homeostasis. However, excessive or prolonged neuroinflammation can inflict harmful damage on brain tissue. Numerous factors can trigger chronic neuroinflammation, ultimately leading to neurodegeneration. In this context, considering the pressing need for novel, natural approaches to mitigate neuroinflammatory damage, attention has turned to unconventional sources such as agricultural by-products. Citrus fruits are widely consumed globally, producing substantial waste, including peels, seeds, and pulp. Traditionally regarded as agricultural waste, these by-products are now recognized as valuable reservoirs of bioactive compounds, including flavonoids, carotenoids, terpenoids, and limonoids. Among these, citrus polyphenols-particularly flavanones like hesperidin, naringenin, and eriocitrin-have emerged as potent modulators of neuroinflammatory pathways through their multifaceted interactions with cellular antioxidant systems, pro-inflammatory signaling cascades, neurovascular integrity, and gut-brain axis dynamics. This review aims to characterize the key molecules present in citrus waste and synthesizes preclinical and clinical evidence to elucidate the biochemical mechanisms underlying neuroinflammation in neurodegenerative disorders.

Purpose: Glyphosate and glyphosate-based herbicides (GBHs) are widely used across the globe. Experimental research indicates that these herbicides may elevate oxidative stress and impair mitochondrial function. However, the relationship between glyphosate exposure, oxidative stress, and mitochondrial function remains poorly characterized in epidemiological studies. In particular, the role of oxidative stress and mitochondrial function biomarkers in mediating the mortality risk associated with glyphosate exposure in nationally representative populations is not well understood. Approach and Results: In this study, we utilized data from the 2013-2014 National Health and Nutrition Examination Survey (NHANES), encompassing 1464 participants aged 18 years and older. This dataset was linked to mortality records from the National Center for Health Statistics (NCHS), with follow-up data extending through 2019. The primary objective was to examine the associations between urinary glyphosate levels and biomarkers of oxidative stress and mitochondrial function-specifically pyrazino-s-triazine derivative of 4-α-hydroxy-5-methyl-tetrahydrofolate (MeFox) and methylmalonic acid (MMA)-and to evaluate the role of these biomarkers in influencing glyphosate-related mortality outcomes. Results: Urinary glyphosate levels were positively associated with serum MMA and MeFox in weighted multiple linear regression models. For MMA, glyphosate showed significant positive associations in both adjusted models (Model 2: β = 0.061, p = 0.001). Similarly, urinary glyphosate was strongly associated with MeFox in all models (Model 2: β = 0.215, p < 0.001). During a median follow-up of 69.57 months, 116 deaths occurred, including 44 from cardiovascular causes. Glyphosate was not significantly associated with all-cause or cardiovascular mortality in the overall population. However, subgroup analysis revealed significant associations in individuals with higher MeFox levels (≥50th percentile) for all-cause mortality (HR = 1.395, p = 0.027) and borderline associations for cardiovascular mortality (HR = 1.367, p = 0.051). When adjusted for MMA, glyphosate was significantly associated with increased all-cause mortality in participants with MMA levels below the 50th percentile (HR = 2.679, p = 0.001), with a significant interaction between glyphosate and MMA for all-cause (p = 0.002) and cardiovascular mortality (p = 0.038). Conclusions: In this comprehensive analysis of NHANES data, urinary glyphosate levels were associated with biomarkers of oxidative stress and mitochondrial function. While no overall mortality associations were observed, glyphosate exposure was linked to increased all-cause mortality in subgroups with lower MMA or higher MeFox levels. These findings highlight the role of oxidative stress and mitochondrial function in glyphosate-related health risks and the need for further research to identify vulnerable populations.

The inhibition of acetylcholinesterase (AChE), an enzyme responsible for the inactivation and decrease in acetylcholine in the cholinergic pathway, has been considered an attractive target for small-molecule drug discovery in Alzheimer's disease (AD) therapy. In the present study, a series of TZD derivatives were designed, synthesized, and studied for drug likeness, blood-brain barrier (BBB) permeability, and adsorption, distribution, metabolism, excretion, and toxicity (ADMET). Additionally, docking studies of the designed compounds were performed on AChE. Additionally, all the TZD derivatives (CHT1-5) showed an acceptable affinity for AChE inhibition, and the results showed convincing binding modes in the active site of AChE. Among them, 5-(4-methoxybenzylidene) thiazolidine-2,4-dione (CHT1) was identified as the most potent AChE inhibitor (IC50 of 165.93 nM) with the highest antioxidant activity. Following the exposure of PC12 cells to Aβ1-42 (100 μM), a marked reduction in cell survival was observed. Pretreatment of PC12 cells with TZD derivatives had a neuroprotective effect and significantly enhanced cell survival in response to Aβ-induced toxicity. Western blotting analysis revealed that CHT1 (5 and 8 μM) downregulated p-Tau and HSP70 expression levels. The results indicate that CHT1 is a promising and effective AchE-I that could be utilized as a powerful candidate against AD.

Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by progressive cognitive decline and distinct neuropathological features. The absence of a definitive cure presents a significant challenge in neurology and neuroscience. Early clinical manifestations, such as memory retrieval deficits and apathy, underscore the need for a deeper understanding of the disease's underlying mechanisms. While amyloid-β plaques and tau neurofibrillary tangles have dominated research efforts, accumulating evidence highlights mitochondrial dysfunction as a central factor in AD pathogenesis. Mitochondria, essential cellular organelles responsible for energy production necessary for neuronal function become impaired in AD, triggering several cellular consequences. Factors such as oxidative stress, disturbances in energy metabolism, failures in the mitochondrial quality control system, and dysregulation of calcium release are associated with mitochondrial dysfunction. These abnormalities are closely linked to the neurodegenerative processes driving AD development and progression. This review explores the intricate relationship between mitochondrial dysfunction and AD pathogenesis, emphasizing its role in disease onset and progression, while also considering its potential as a biomarker and a therapeutic target.

Cerebral ischemia-reperfusion (CIR) injury results in significant secondary brain damage after ischemic stroke due to oxidative stress, mitochondrial dysfunction, and neuroinflammation. Transchalcone (TCH), a polyphenolic compound, exhibits antioxidant and anti-inflammatory properties that may contribute to neuroprotection. The present study investigated the potential protective effects of TCH in a rat model of CIR, focusing on its impact on the activation of AMP-activated protein kinase (AMPK) pathway, mitochondrial function, and inflammatory mediators. Sixty adult Sprague-Dawley rats were randomly divided into five groups of Control, CIR (ischemia-reperfusion only), CIR+TCH (CIR with TCH), CIR+CC (CIR with compound C), and CIR+CC+TCH (CIR with compound C plus TCH). TCH (100 μg/kg b.w per day) was given intraperitoneally over 7 days before CIR injury to animals. Middle cerebral artery occlusion was performed for 60 min to induce cerebral ischemia, and then blood flow was restored (reperfusion) for 24 h. Neuromotor function was assessed using neurological scoring, rotarod, and grid tests. The infarct volumes were determined using 2,3,5-triphenyltetrazolium chloride staining. Mitochondrial function was evaluated using fluorometric and calorimetric methods. Oxidative stress and inflammatory mediators were measured by enzyme-linked immunosorbent assay. Protein expression was analyzed using Western blotting. CIR significantly impaired neuromotor function, increased infarct volume, elevated mitochondrial reactive oxygen species (ROS) levels, and disrupted adenosine triphosphate (ATP) synthesis and manganese superoxide dismutase (Mn-SOD) activity. It also heightened pro-inflammatory cytokines interleukin-1β (IL-1β), tumor necrosis factor-alpha, and nuclear factor kappa B levels while reducing the anti-inflammatory IL-10 level. TCH treatment significantly attenuated CIR outcomes by promoting AMPK phosphorylation, upregulating peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) and nuclear factor erythroid 2-related factor 2 (NRF2) expression, reducing mitochondrial ROS, improving ATP production and Mn-SOD activity, and suppressing pro-inflammatory cytokine mediators while increasing IL-10. Co-treatment with compound C (a selective AMPK inhibitor) significantly diminished the protective effects of TCH, confirming the contribution of AMPK signaling in its neuroprotective mechanism. TCH provides significant neuroprotection against CIR injury by activating AMPK/PGC-1α and AMPK/NRF2 signaling, preserving mitochondrial function, and modulating inflammation. These findings highlight the therapeutic potential of TCH for ischemic stroke management.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by multiple dysfunctions in behavior, the nervous system, and the immune system. Increasing evidence suggests that mitochondrial DNA (mtDNA) plays a crucial role in the pathology of ASD. In clinical practice, altered mtDNA levels have been observed in various tissues of individuals with ASD. Mutation or oxidation of mtDNA is also closely related to the immune response associated with the pathology of autism. With mtDNA identified as a causal factor, much interest has focused on how its production affects neurodevelopment and neurophysiology. Here, we review how mtDNA leads to dysfunction of cellular mitochondria and immune response. We also illustrate the relationship between mtDNA alterations and the pathology of autism. Finally, we discuss the existing evidence on cell-free mtDNA associated with ASD and look forward to its application in clinical diagnosis and treatment.

Mitochondria, as the primary energy factories of cells, play a pivotal role in maintaining nervous system function and regulating inflammatory responses. The balance of mitochondrial quality control is critical for neuronal health, and disruptions in this balance are often implicated in the pathogenesis of various neurological disorders. Mitochondrial dysfunction not only exacerbates energy deficits but also triggers neuroinflammation through the release of damage-associated molecular patterns (DAMPs), such as mitochondrial DNA (mtDNA) and reactive oxygen species (ROS). This review examines the mechanisms and recent advancements in mitochondrial quality control in neurological diseases, focusing on processes such as mitochondrial fusion and fission, mitophagy, biogenesis, and protein expression regulation. It further explores the role of mitochondrial dysfunction and subsequent inflammatory cascades in conditions such as ischemic and hemorrhagic stroke, neurodegenerative diseases and brain tumors. Additionally, emerging research highlights the significance of mitochondrial transfer mechanisms, particularly intercellular transfer between neurons and glial cells, as a potential strategy for mitigating inflammation and promoting cellular repair. This review provides insights into the molecular underpinnings of neuroinflammatory pathologies while underscoring the translational potential of targeting mitochondrial quality control for therapeutic development.

There has been a recent expansion in our understanding of DNA-sensing mechanisms. Mitochondrial dysfunction, oxidative and proteostatic stresses, instability and impaired disposal of nucleoids cause the release of mitochondrial DNA (mtDNA) from the mitochondria in several human diseases, as well as in cell culture and animal models. Mitochondrial DNA mislocalized to the cytosol and/or the extracellular compartments can trigger innate immune and inflammation responses by binding DNA-sensing receptors (DSRs). Here, we define the features that make mtDNA highly immunogenic and the mechanisms of its release from the mitochondria into the cytosol and the extracellular compartments. We describe the major DSRs that bind mtDNA such as cyclic guanosine-monophosphate-adenosine-monophosphate synthase (cGAS), Z-DNA-binding protein 1 (ZBP1), NOD-, LRR-, and PYD- domain-containing protein 3 receptor (NLRP3), absent in melanoma 2 (AIM2) and toll-like receptor 9 (TLR9), and their downstream signaling cascades. We summarize the key findings, novelties, and gaps of mislocalized mtDNA as a driving signal of immune responses in vascular, metabolic, kidney, lung, and neurodegenerative diseases, as well as viral and bacterial infections. Finally, we define common strategies to induce or inhibit mtDNA release and propose challenges to advance the field.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the gradual loss of dopamine-producing neurons. Oxidative stress, mitochondrial dysfunction, detrimental immune response, and neuroinflammation are mainly responsible for the injury and degeneration of dopaminergic neurons in the brains of patients suffering from PD. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have emerged as a promising therapeutic approach for treating PD due to their ability to suppress the activation of inflammatory immune cells and enhance the viability and function of dopamine-producing neurons. MSC-EVs can easily bypass the blood-brain barrier and deliver their cargo (neuroprotective factors, immunosuppressive proteins, and microRNAs) to injured dopamine-producing neurons and brain-infiltrated inflammatory immune cells. A large number of recently published experimental studies demonstrated that MSC-EVs efficiently alleviated PD-related motor and behavioral deficits in animal models, indicating that MSC-EVs should be considered as potentially new therapeutic agents for the treatment of PD. Accordingly, in this review article, we summarized current knowledge about the therapeutic potential of MSCs-EVs in the treatment of PD, paving the way for their future clinical use in the treatment of neurodegenerative and neuroinflammatory disorders.

The importance of fatty acids in human health and their potential in treating various brain diseases is increasingly acknowledged. Research indicates that ultra-long-chain fatty acids adversely affect dietary habits, while omega (ω)-3 polyunsaturated fatty acids confer health benefits. Eicosapentaenoic acid (EPA), an ω-3 polyunsaturated fatty acid, manifests diverse protective activities, including anti-oxidative effects and the attenuation of brain diseases. Previous studies have suggested that EPA can alleviate oxidative stress and forestall diseases stemming from oxidative damage. Nevertheless, EPA's precise antioxidant mechanism and signaling pathway in human astrocytes remain elusive. To address this knowledge gap, we established an H2O2-induced oxidative damage model in Gibco® Human Astrocytes (GHA cells) and elucidated the underlying mechanisms and signaling pathways.

Our assessments included cell viability through the CCK-8 assay, morphological examination via microscopy, ROS quantification using the DCFH-DA fluorescent probe, GSH content evaluation with the CMF-DA fluorescent probe, and protein expression analysis for antioxidant and apoptotic markers through Western blotting. The results showed that pretreatment with 3 µM of EPA countered the cytotoxicity, ROS production, and GSH depletion caused by H2O2 (250 µM) in GHA cells. Additionally, EPA pretreatment effectively reduced the cytotoxicity and oxidative stress resulting from H2O2 by modulating the Nrf2/HO-1/NQO1 and Bax/Bcl-2/caspase-9/caspase-3 signaling pathways in GHA cells.

These findings enhance our understanding of EPA's antioxidant mechanisms in the oxidative stress model of human astrocytes, illuminate the interplay between antioxidant and apoptotic signals, and offer promise for exploring potential preventive and therapeutic interventions for brain diseases.

Background/Objectives: This review has been prepared to promote interest in the interdisciplinary study of mitochondrial dysfunction (MD) and atherosclerosis. This review aims to describe the state of this problem and indicate the direction for further implementation of this knowledge in clinical medicine. Methods: Extensive research of the literature was implemented to elucidate the role of the molecular mechanisms of MD in the pathogenesis of atherosclerosis. Results: A view on the pathogenesis of atherosclerosis through the prism of knowledge about MD is presented. MD is the cause and primary mechanism of the onset and progression of atherosclerosis. It is proposed that this problem be considered in the context of a continuum. Conclusions: MD and atherosclerosis are united by common molecular mechanisms of pathogenesis. Knowledge of MD should be used to argue for a healthy lifestyle as the primary way to prevent atherosclerosis. The development of new approaches to diagnosing and treating MD in atherosclerosis is an urgent task and challenge for modern science.

This narrative review presents the role of antioxidants in regulating the gut microbiota and the impact on the gut-brain axis, with a particular focus on neurodegenerative diseases, such as Alzheimer's (AD) and Parkinson's disease (PD). These diseases are characterised by cognitive decline, motor dysfunction, and neuroinflammation, all of which are significantly exacerbated by oxidative stress. This review elucidates the contribution of oxidative damage to disease progression and explores the potential of antioxidants to mitigate these pathological processes through modulation of the gut microbiota and associated pathways. Based on recent studies retrieved from reputable databases, including PubMed, Web of Science, and Scopus, this article outlines the mechanisms by which antioxidants influence gut health and exert neuroprotective effects. Specifically, it discusses how antioxidants, including polyphenols, vitamins, and flavonoids, contribute to the reduction in reactive oxygen species (ROS) production and neuroinflammation, thereby promoting neuronal survival and minimising oxidative damage in the brain. In addition, the article explores the role of antioxidants in modulating key molecular pathways involved in oxidative stress and neuroinflammation, such as the NF-κB, Nrf2, MAPK, and PI3K/AKT pathways, which regulate ROS generation, inflammatory cytokine expression, and antioxidant responses essential for maintaining cellular homeostasis in both the gut and the central nervous system. In addition, this review explores the complex relationship between gut-derived metabolites, oxidative stress, and neurodegenerative diseases, highlighting how dysbiosis-an imbalance in the gut microbiota-can exacerbate oxidative stress and contribute to neuroinflammation, thereby accelerating the progression of such diseases as AD and PD. The review also examines the role of short-chain fatty acids (SCFAs) produced by beneficial gut bacteria in modulating these pathways to attenuate neuroinflammation and oxidative damage. Furthermore, the article explores the therapeutic potential of microbiota-targeted interventions, including antioxidant delivery by probiotics and prebiotics, as innovative strategies to restore microbial homeostasis and support brain health. By synthesising current knowledge on the interplay between antioxidants, the gut-brain axis, and the molecular mechanisms underlying neurodegeneration, this review highlights the therapeutic promise of antioxidant-based interventions in mitigating oxidative stress and neurodegenerative disease progression. It also highlights the need for further research into antioxidant-rich dietary strategies and microbiota-focused therapies as promising avenues for the prevention and treatment of neurodegenerative diseases.

Neuroinflammation is a hallmark of various neurodegenerative disorders, yet effective treatments remain limited. This study investigates the neuroprotective potential of a cannabidiol (CBD)-Rich Cannabis sativa L. (CS) extract in a lipopolysaccharide (LPS)-induced neuroinflammation mouse model. The effects on anxiety-like behavior, cognitive function, and locomotor activity were assessed using behavioral tests (open field, elevated plus maze, novel object recognition, and Morris water maze). Antioxidant activity was measured by assaying glutathione (GSH) levels and lipid peroxidation by-products (TBARs). Anti-inflammatory properties were evaluated using quantitative reverse transcription polymerase chain reaction (QRt-PCR) for proinflammatory cytokines (IL-6 and TNF-α), glial fibrillary acidic protein (GFAP), and cannabinoid receptor 1 (CB1) mRNAs in the prefrontal cortex (PFC). Astrocytic bioenergetics were analyzed using extracellular flux assays. Additionally, computational inference with a deep learning approach was conducted to evaluate the synergistic interactions among CS phytocompounds on the CB1 receptors. Compared with synthetic CBD, the CS extract (20.0 mg/kg) demonstrated superior efficacy in mitigating LPS-induced anxiety-like behavior, cognitive deficits, and locomotor impairments. It also significantly mitigated oxidative stress (increased GSH, reduced TBARs) and suppressed proinflammatory cytokines and GFAP mRNAs, indicating potent anti-inflammatory properties. The extract modulated CB1 receptor expression and preserved metabolic homeostasis in cortical astrocytes, preventing their shift from glycolysis to oxidative phosphorylation under neuroinflammatory conditions. Computational modeling highlighted conformational changes in CB1 receptor residues induced by Delta-9-THC that enhanced CBD binding. These findings underscore the potential of CS extract as a therapeutic candidate for managing neuroinflammation and its associated neurodegenerative consequences, warranting further clinical exploration.

Morchella esculenta (L.) Pers. is considered a precious edible and medicinal fungus due to its strict growth environment requirements, difficult to cultivate, resulted in expensive in the market. A polysaccharide (MMP-L) was isolated from the mycelia of Morchella esculenta, with molecular weight of 3.02 × 103 kDa. MMP-L was composed of galactose, glucose, and mannose in a molar ratio of 1.00: 12.89: 0.29. Structural characterization showed that MMP-L had a backbone mainly consisting of →4)-α-D-Glcp-(1→, →6)-α-D-Glcp-(1→, →4,6)-α-D-Glcp-(1→, →2)-α-D-Galp-(1→, →3)-α-D-Manp-(1→, and →4,6)-α-D-Manp-(1→, and branched chains incorporating of α-D-Glcp(1→. The antioxidant activity test results indicated that MMP-L has effective scavenging ability against 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2'2-Azinobis-(3-ethylbenzthiazoline-6-sulphonate) (ABTS), and hydroxyl radicals. Within the range of concentration (0.05-3.20 mg/mL), MMP-L increased the enzyme activity of superoxide dismutase (SOD) and glutathione (GSH) in H2O2-induced PC12 cells in a dose-dependent manner, while inhibiting the content of lactate dehydrogenase (LDH) and malondialdehyde (MDA). Furthermore, the decrease in reactive oxygen species (ROS) and apoptosis in PC12 cells may be attributed to the activation of the PI3K/Akt signaling pathway and downstream mitochondrial apoptosis-related protein Bcl-2/BAX/Caspase-3 signaling pathways. In summary, MMP-L might serve as a potential functional components for the future prevention and treatment of neurodegenerative disorders caused by oxidative damage.

This comprehensive review navigates the landscape of genetic mutations in kinases, offering a thorough examination of both marketed inhibitors and unexplored targets in the context of Parkinson's Disease (PD). Although existing treatments for PD primarily center on symptom management, progress in comprehending the molecular foundations of the disease has opened avenues for targeted therapeutic approaches. This review encompasses an in-depth analysis of four key kinases-PINK1, LRRK2, GAK, and PRKRA-revealing that LRRK2 has garnered the most attention with a plethora of marketed inhibitors. However, the study underscores notable gaps in the exploration of inhibitors for PINK1, GAK, and a complete absence for PRKRA. The observed scarcity of inhibitors for these kinases emphasizes a significant area of untapped potential in PD therapeutics. By drawing attention to these unexplored targets, the review highlights the urgent need for focused research and drug development efforts to diversify the therapeutic landscape, potentially providing novel interventions for halting or slowing the progression of PD.

Chronic inflammation is a common hallmark of many chronic diseases. Although exercise holds paramount importance in preventing and managing chronic diseases, adherence to exercise programs can be challenging for some patients. Consequently, there is a pressing need to explore alternative strategies to emulate the anti-inflammatory effects of exercise for chronic diseases.

This review explores the emerging role of green tea bioactive components as potential mitigators of chronic inflammation, offering insights into their capacity to mimic the beneficial effects of exercise. We propose that bioactive components in green tea are promising agents for suppressing chronic inflammation, suggesting their unique capability to replicate the health benefits of exercise.

This review focuses on several key concepts, including chronic inflammation and its role in chronic diseases, the anti-inflammatory effects of regular exercise, and bioactive components in green tea responsible for its health benefits. It elaborates on scientific evidence supporting the anti-inflammatory properties of green tea bioactive components, such as epigallocatechin gallate (EGCG), and theorizes how these bioactive components might replicate the effects of exercise at a molecular level. Through a comprehensive analysis of current research, this review proposes a novel perspective on the application of green tea as a potential intervention strategy to suppress chronic inflammation, thereby extending the benefits akin to those achieved through exercise.

Background/Objectives: Amyloid-β (Aβ) plaque accumulation, oxidative stress, and cholinergic dysfunction are hallmarks of Alzheimer's disease (AD), a neurodegenerative disability that progresses over time, ultimately resulting in the loss of neurons. The side effects and limitations of current synthetic drugs have shifted attention toward natural alternatives. This study investigates the ethanolic extract of Aegle marmelos (L.) Corrêa fruits for their antioxidant, AChE-inhibitory, and anti-amyloidogenic properties, as well as their neuroprotective effects against amyloid beta-peptide (Aβ1-42). Methods: Phytochemical constituents were identified through HR-LCMS analysis and their antioxidant (DPPH, FRAP) and neuroprotective activities (AChE inhibition, ThT binding, MTT assay, ROS reduction, MMP restoration, and AD-related gene expression via qRT-PCR) were assessed using SHSY-5Y neuroblastoma cells. Results: The extract revealed the existence of flavonoids, phenols, and other bioactive substances. In vitro assays demonstrated strong antioxidant and AChE-inhibitory activities, while the ThT binding assay showed protection against amyloid-β aggregation. The extract exhibited no cytotoxicity in SHSY-5Y cells, even at a concentration of 500 μg/mL, whereas Aβ1-42 at 20 μM induced significant cytotoxicity. Co-treatment with Aβ1-42 (10 μM and 20 μM) and the extract improved cell viability (˃50%) and reduced ROS levels. Additionally, the extract restored mitochondrial membrane potential in Aβ1-42 treated cells, highlighting its role in preserving mitochondrial function. Conclusions: These findings suggest that A. marmelos fruits serve as a powerful source of natural antioxidants, AChE inhibitors, and anti-amyloidogenic agents, positioning them as a compelling option for AD treatment.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial inflammation and progressive joint destruction. Existing evidence indicates that hypoxia potentially contributes to the pathology of RA, though the specific mechanism remains unidentified. In this study, we explored the molecular mechanism through which the hypoxia-inducible factor (HIF-1α) contributed to the pathological process of RA. Our preliminary results suggested that hypoxia stimulates the activation of fibroblast-like synoviocytes (FLS) by inducing mitochondrial damage to activate cGAS-STING signaling, which can be effectively inhibited by silencing HIF-1α. In line with this, HIF-1α deficiency significantly alleviated the symptoms of collagen-induced arthritis (CIA) mice. RNA-Seq and CUT-Tag analysis revealed that HIF-1α down-regulated the expression of AlkB homologue 7 (ALKBH7) by acting on the ALKBH7 promoter site on chromosome 19 6372400-6372578. Using dual luciferase reporter analysis, we identified that ACCGTGGC as the motif to which HIF-1α bound directly. Subsequently, we demonstrated that knockdown of ALKBH7 induces mitochondrial damage and activates cGAS-STING signaling by downregulating the expression of UQCRC2. Conversely, overexpression of ALKBH7 could resist hypoxia-induced mitochondrial damage and FLS activation. In conclusion, HIF-1α triggers mitochondrial damage by downregulating the expression of ALKBH7 thereby promoting FLS activation, which may be the molecular mechanism by which hypoxia is involved in the pathological process of RA. Hypoxia promotes the activation of FLS through the induction of mitochondrial damage, which subsequently activates cGAS-STING signaling. Mechanistically, HIF-1α triggers mitochondrial damage by downregulating the expression of ALKBH7 in a target manner. Furthermore, the deletion of ALKBH7 leads to mitochondrial damage under hypoxic conditions, primarily through the downregulation of UQCRC2, as opposed to other complexes.

Neurodegenerative diseases (NDs) like Alzheimer's, Parkinson's, and ALS rank among the most challenging global health issues, marked by substantial obstacles in early diagnosis and effective treatment. Current diagnostic techniques frequently demonstrate inadequate sensitivity and specificity, whilst conventional treatment strategies encounter challenges related to restricted bioavailability and insufficient blood-brain barrier (BBB) permeability. Recently, exosomes-nanoscale vesicles packed with proteins, RNAs, and lipids-have emerged as promising agents with the potential to reshape diagnostic and therapeutic approaches to these diseases. Unlike conventional drug carriers, they naturally traverse the BBB and can deliver bioactive molecules to affected neural cells. Their molecular cargo can influence cell signaling, reduce neuroinflammation, and potentially slow neurodegenerative progression. Moreover, exosomes serve as non-invasive biomarkers, enabling early and precise diagnosis while allowing real-time disease monitoring. Additionally, engineered exosomes, loaded with therapeutic molecules, enhance this capability by targeting diseased neurons and overcoming conventional treatment barriers. By offering enhanced specificity, reduced immunogenicity, and an ability to bypass physiological limitations, exosome-based strategies present a transformative advantage over existing diagnostic and therapeutic approaches. This review examines the multifaceted role of exosomes in NDDs, emphasizing their diagnostic capabilities, intrinsic therapeutic functions, and transformative potential as advanced treatment vehicles.

The association between insulin resistance (IR), type 2 diabetes mellitus (T2DM), and cancer is increasingly recognized and poses an escalating global health challenge, as the incidence of these conditions continues to rise. Studies indicate that individuals with T2DM have a 10-20% increased risk of developing various solid tumors, including colorectal, breast, pancreatic, and liver cancers. The relative risk (RR) varies depending on cancer type, with pancreatic and liver cancers showing a particularly strong association (RR 2.0-2.5), while colorectal and breast cancers demonstrate a moderate increase (RR 1.2-1.5). Understanding these epidemiological trends is crucial for developing integrated management strategies. Given the global rise in T2DM and cancer cases, exploring the complex relationship between these conditions is critical. IR contributes to hyperglycemia, chronic inflammation, and altered lipid metabolism. Together, these factors create a pro-tumorigenic environment conducive to cancer development and progression. In individuals with IR, hyperinsulinemia triggers the insulin-insulin-like growth factor (IGF1R) signaling pathway, activating cancer-associated pathways such as mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PIK3CA), which promote cell proliferation and survival, thereby supporting tumor growth. Both IR and T2DM are linked to increased morbidity and mortality in patients with cancer. By providing an in-depth analysis of the molecular links between insulin resistance and cancer, this review offers valuable insights into the role of metabolic dysfunction in tumor progression. Addressing insulin resistance as a co-morbidity may open new avenues for risk assessment, early intervention, and the development of integrated treatment strategies to improve patient outcomes.

Mitochondria are versatile eukaryotic organelles that play a crucial role in the body's stress response. Prolonged stress exposure can cause structural and functional alterations, leading to mitochondrial DNA (mtDNA) damage and subsequent release of mtDNA into the circulation. Cell-free circulating mtDNA (ccf-mtDNA) is a potential biomarker indicating cellular damage and stress. In this study we investigated the applicability of ccf-mtDNA and cf-nDNA as biomarkers of chronic stress in healthy subjects.

We developed a quantitative polymerase chain reaction (qPCR) assay to directly measure ccf-mtDNA in human blood plasma samples, addressing numerous challenges specifically related to ccf-mtDNA quantification. We validated our 68 bp target assay based on the FDA, International Organization for Standardization (ISO) and Clinical & Laboratory Standards Institute (CLSI) guidelines for assay development, including parameters such as limit of blank (LOB), limit of detection (LOD) and limit of quantification (LOQ). Furthermore, we implemented incurred samples analysis and inter-plate samples to ensure reliability and reproducibility of the assay. In addition, we evaluated the effects of centrifugation forces on ccf-mtDNA and cf-nDNA concentrations in native plasma samples and showed that mainly ccf-mtDNA is strongly affected by centrifugation forces. We found a significant negative correlation between ccf-mtDNA levels and chronic stress. In contrast, cf-nDNA levels were not affected in response to chronic stress.

ccf-mtDNA can directly and reliably quantified in unpurified plasma samples. However, the ccf-mtDNA levels in plasma samples of healthy subjects are close the LOQ, showing that the assay is not yet suitable for all conditions.

Extracellular vesicles (EVs) convey complex signals between cells that can be used to promote neuronal plasticity and neurological recovery in brain disease models. These EV signals are multimodal and context-dependent, making them unique therapeutic principles. This review analyzes how EVs released from various cell sources control neuronal metabolic function, neuronal survival and plasticity. Preferential sites of EV communication in the brain are interfaces between pre- and postsynaptic neurons at synapses, between astrocytes and neurons at plasma membranes or tripartite synapses, between oligodendrocytes and neurons at axons, between microglial cells/macrophages and neurons, and between cerebral microvascular cells and neurons. At each of these interfaces, EVs support mitochondrial function and cell metabolism under physiological conditions and orchestrate neuronal survival and plasticity in response to brain injury. In the injured brain, the promotion of neuronal survival and plasticity by EVs is tightly linked with EV actions on mitochondrial function, cell metabolism, oxidative stress and immune responses. Via the stabilization of cell metabolism and immune balance, neuronal plasticity responses are activated and functional neurological recovery is induced. As such, EV lay the ground for neuronal plasticity.

Cerebral ischemia-reperfusion injury (CIRI) causes significant neuronal damage through oxidative stress, inflammation, and mitochondrial dysfunction. The G-protein-coupled receptor kinase 4 (GRK4) has been implicated in regulating stress responses in various tissues, but its role in ischemic brain injury remains unclear. In this study, we investigated the role of GRK4 in oxidative stress, inflammation, and mitophagy during CIRI using both in vivo and in vitro models. For the in vivo experiments, we employed the bilateral common carotid artery occlusion (BCCAO) model to induce ischemia-reperfusion injury. Our finding demonstrated that ischemic reperfusion significantly upregulated GRK4 expression in the brain, correlating with elevated levels of inflammatory cytokines and oxidative stress markers. In cultured cerebellar neurons subjected to oxygen-glucose deprivation (OGD), over-expression of GRK4 decreased cell viability, while GRK4 inhibition enhanced neuronal survival, suggesting that GRK4 exacerbates neuronal damage in ischemic conditions. Furthermore, GRK4 overexpression impaired mitophagy, as indicated by altered expression of key mitophagy-related proteins (Beclin-1, PINK1, and p62), which led to mitochondrial dysfunction and increased oxidative stress. In contrast, GRK4 inhibition promoted more efficient mitophagy and improved mitochondrial quality control. These results highlight the detrimental role of GRK4 in ischemic brain injury and suggest that targeting GRK4 could offer a novel therapeutic strategy to mitigate neuronal damage by balancing oxidative stress, inflammation, and mitochondrial dynamics. Further studies are needed to elucidate the precise molecular mechanisms underlying GRK4-mediated neuroinflammation and mitochondrial dysfunction in ischemic stroke.

Alzheimer's disease (AD) is a leading cause of dementia in the elderly, with late-onset AD (LOAD) accounting for 95% of the cases. The etiology underlying LOAD, however, remains unclear. Using a humanized mouse model, we showed previously that exposure to ozone (O3), a potential environment risk factor, in a cyclic exposure protocol that mimics a human exposure scenario, accelerated AD-like neuropathophysiology in old humanized male ApoE3 (E3) but not ApoE4 (E4) mice. Using RNA sequencing (RNA-seq) techniques, we further demonstrate here that the ApoE genotype has the greatest influence on transcriptional changes, followed by age and O3 exposure. Notably, AD-related genes were expressed even at baseline and in young mice, but the differences in the expression levels are obvious in old age. Importantly, although both E3 and E4 mice exhibited some AD-related transcriptomic alterations, old E3 mice exposed to O3, which showed memory impairment, experienced more pronounced disruptions in the expression of genes related to redox balance, neurogenesis, neuroinflammation, and cellular senescence in the hippocampus, compared with O3-exposed old E4 mice. These results provide new insights into the molecular mechanisms underlying memory loss in O3-exposed old E3 male mice and emphasize the complexity of interactions between gene, environment, and aging in AD pathophysiology.

Septic Encephalopathy (SE) is a frequent and severe complication of sepsis, characterized by a range of neurocognitive impairments from mild confusion to deep coma. The underlying pathophysiology of SE involves systemic inflammation, neuroinflammation, blood-brain barrier (BBB) disruption, and mitochondrial dysfunction. Among these factors, mitochondrial dysfunction plays a pivotal role, contributing to impaired ATP production, increased reactive oxygen species (ROS) generation, and activation of apoptotic pathways, all of which exacerbate neuronal damage and cognitive deficits. Diagnosis of SE relies on clinical evaluation, neuroimaging, electroencephalography (EEG), and laboratory tests, though specific diagnostic markers are still lacking. Epidemiological data show SE is prevalent in intensive care unit (ICU) patients, especially those with severe sepsis or septic shock, with incidence rates varying widely depending on the population and diagnostic criteria used. Recent research highlights the importance of mitochondrial dynamics, including biogenesis, fission, and fusion, in the development of SE. Mitophagy, a selective form of autophagy that degrades damaged mitochondria, plays a critical role in maintaining mitochondrial health and protecting against dysfunction. Targeting mitochondrial pathways and enhancing mitophagy offers a promising therapeutic strategy to mitigate the effects of SE, reduce oxidative stress, prevent apoptosis, and support the resolution of neuroinflammation. Further research is essential to elucidate the mechanisms of mitochondrial dysfunction and mitophagy in SE and develop effective interventions to improve patient outcomes.

Age-related oxidative stress is a critical factor in vascular dysfunction, contributing to hypertension and atherosclerosis. Smooth muscle cells and endothelial cells are particularly susceptible to oxidative damage, which exacerbates vascular aging through cellular senescence, chronic inflammation, and arterial stiffness. Gasotransmitters-hydrogen sulfide (H2S), nitric oxide (NO), and carbon monoxide (CO)-are emerging as promising therapeutic agents for counteracting these processes. This review synthesizes findings from recent studies focusing on the mechanisms by which H2S, NO, and CO influence vascular smooth muscle and endothelial cell function. Therapeutic strategies involving exogenous gasotransmitter delivery systems and combination therapies were analyzed. H2S enhances mitochondrial bioenergetics, scavenges ROS, and activates antioxidant pathways. NO improves endothelial function, promotes vasodilation, and inhibits platelet aggregation. CO exhibits cytoprotective and anti-inflammatory effects by modulating heme oxygenase activity and ROS production. In preclinical studies, gasotransmitter-releasing molecules (e.g., NaHS, SNAP, CORMs) and targeted delivery systems show significant promise. Synergistic effects with lifestyle modifications and antioxidant therapies further enhance their therapeutic potential. In conclusion, gasotransmitters hold significant promise as therapeutic agents to combat age-related oxidative stress in vascular cells. Their multifaceted mechanisms and innovative delivery approaches make them potential candidates for treating vascular dysfunction and promoting healthy vascular aging. Further research is needed to translate these findings into clinical applications.

To explore the molecular mechanism of aerobic exercise to improve heart failure and to provide a theoretical basis and experimental reference for the treatment of heart failure. Nine-week-old male mice were used to establish a left ventricular pressure overload-induced heart failure model by transverse aortic constriction (TAC). The mice were randomly divided into four groups: a sham group (SHAM), heart failure group (HF), heart failure + SKQ1 group (HS) and heart failure + aerobic exercise group (HE). The mice in the HE group were subjected to moderate-intensity aerobic exercise interventions. The mitochondrion-targeting antioxidant (SKQ1) contains the lipophilic cation TPP, which targets scavenging mitochondrial ROS. The HS group was subjected to SKQ1 (100 nmol/kg/d) interventions, which were initiated 1 week after the surgery, and the interventions lasted 8 weeks. Cardiac function was assessed by ultrasound, cardiomyocyte size by H&E and WGA staining, myocardial fibrosis by Masson's staining, and myocardial tissue oxidative stress and apoptosis by DHE and TUNEL fluorescence staining, respectively. Western blotting was used to detect the expression of mitochondrial quality control, inflammation, and apoptosis-related proteins. In the cellular level, an in vitro cellular model was established by isolating primary cardiomyocytes from neonatal mice (2-3 days) and intervening with Ang II (1 μM) to mimic heart failure. Oxidative stress and mitochondrial membrane potential were determined in the cardiomyocytes of each group by DHE and JC-1 staining, respectively. Myocardial fibrosis was increased significantly and cardiac function was reduced significantly in the heart failure mice. Aerobic exercise and SKQ1 intervention improved cardiac function and reduced myocardial hypertrophy and myocardial fibrosis in the heart failure mice significantly. Meanwhile, aerobic exercise and SKQ1 intervention reduced the number of DHE-positive particles (p < 0.01) and inhibited myocardial oxidative stress in the heart failure mice significantly. Aerobic exercise also reduced DRP1, Parkin, and BNIP3 protein expression (p < 0.05, p < 0.01), and increased OPA1 and PINK1 protein expression (p < 0.05, p < 0.01) significantly. Moreover, aerobic exercise and SKQ1 intervention decreased the number of TUNEL-positive particles and the expression of inflammation- and apoptosis-related proteins NLRP3, TXNIP, Caspase-1, IL-1β, BAX, BAK, and p53 significantly (p < 0.05, p < 0.01). In addition, the AMPK agonist AICAR and the mitochondria-targeted ROS scavenger (SKQ1) ameliorated AngII-induced mitochondrial fragmentation and decreased mitochondrial membrane potential in cardiomyocytes significantly. It was shown that inhibition of mitochondrial ROS by aerobic exercise, which in turn inhibits mitochondrial damage, improves mitochondrial quality control, and reduces myocardial inflammatory and apoptosis, may be an important molecular mechanism by which aerobic exercise exerts endogenous antioxidant protective effects to improve cardiac function.

Hypermobile Ehlers-Danlos Syndrome (hEDS) is a hereditary connective tissue disorder characterized by joint hypermobility, skin hyperextensibility, and systemic manifestations such as chronic fatigue, gastrointestinal dysfunction, and neurological symptoms. Unlike other EDS subtypes with known genetic mutations, hEDS lacks definitive markers, suggesting a multifactorial etiology involving both mitochondrial dysfunction and non-mitochondrial pathways. This scoping review, conducted in accordance with the PRISMA-ScR guidelines, highlights mitochondrial dysfunction as a potential unifying mechanism in hEDS pathophysiology. Impaired oxidative phosphorylation (OXPHOS), elevated reactive oxygen species (ROS) levels, and calcium dysregulation disrupt cellular energetics and extracellular matrix (ECM) homeostasis, contributing to the hallmark features of hEDS. We reviewed candidate genes associated with ECM remodeling, signaling pathways, and immune regulation. Protein-protein interaction (PPI) network analyses revealed interconnected pathways linking mitochondrial dysfunction with these candidate genes. Comparative insights from Fabry disease and fragile X premutation carriers underscore shared mechanisms such as RNA toxicity, matrix metalloproteinases (MMP) activation, and ECM degradation. These findings may suggest that mitochondrial dysfunction amplifies systemic manifestations through its interplay with non-mitochondrial molecular pathways. By integrating these perspectives, this review provides a potential framework for understanding hEDS pathogenesis while highlighting latent avenues for future research into its molecular basis. Understanding the potential role of mitochondrial dysfunction in hEDS not only sheds light on its complex molecular etiology but also opens new paths for targeted interventions.

This study examines the intricacies of Alzheimer's disease (AD), its origins, and the potential advantages of various herbal extracts and natural compounds for enhancing memory and cognitive performance. Future studies into AD treatments are encouraged by the review's demonstration of the effectiveness of phytoconstituents that were extracted from a number of plants. In addition to having many beneficial effects, such as improved cholinergic and cognitive function, herbal medicines are also much less harmful, more readily available, and easier to use than other treatments. They also pass without difficulty through the blood-brain barrier (BBB). This study focused on natural substances and their effects on AD by using academic databases to identify peer-reviewed studies published between 2015 and 2024. According to the literature review, 66 phytoconstituents that were isolated from 21 distinct plants have shown efficacy, which could be encouraging for future research on AD therapies. Since most clinical trials produce contradictory results, the study suggests that larger-scale studies with longer treatment durations are necessary to validate or refute the therapeutic efficacy of herbal AD treatments.

Neurodegenerative diseases (NDDs) are one of the prevailing conditions characterized by progressive neuronal loss. Polyadenylation (PA) and alternative polyadenylation (APA) are the two main post-transcriptional events that regulate neuronal gene expression and protein production. This systematic review analyzed the available literature on the role of PA and APA in NDDs, with an emphasis on their contributions to disease development. A comprehensive literature search was performed using the PubMed, Scopus, Cochrane, Google Scholar, Embase, Web of Science, and ProQuest databases. The search strategy was developed based on the framework introduced by Arksey and O'Malley and supplemented by the inclusion and exclusion criteria. The study selection was performed by two independent reviewers. Extraction and data organization were performed in accordance with the predefined variables. Subsequently, quantitative and qualitative analyses were performed. Forty-seven studies were included, related to a variety of NDDs, namely Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Disease induction was performed using different models, including human tissues, animal models, and cultured cells. Most investigations were related to PA, although some were related to APA or both. Amyloid precursor protein (APP), Tau, SNCA, and STMN2 were the major genes identified; most of the altered PA patterns were related to mRNA stability and translation efficiency. This review particularly underscores the key roles of PA and APA in the pathogenesis of NDDs through their mechanisms that contribute to gene expression dysregulation, protein aggregation, and neuronal dysfunction. Insights into these mechanisms may lead to new therapeutic strategies focused on the modulation of PA and APA activities. Further research is required to investigate the translational potential of targeting these pathways for NDD treatment.

Postoperative neurocognitive dysfunction (PND) is a prevalent and debilitating complication in elderly surgical patients, characterized by persistent cognitive decline that negatively affects recovery and quality of life. As the aging population grows, the rising number of elderly surgical patients has made PND an urgent clinical challenge. Despite increasing research efforts, the pathophysiological mechanisms underlying PND remain inadequately characterized, underscoring the need for a more integrated framework to guide targeted interventions. To better understand the molecular mechanisms and therapeutic targets of PND, this narrative review synthesized evidence from peer-reviewed studies, identified through comprehensive searches of PubMed, Embase, Cochrane Library, and Web of Science. Key findings highlight neuroinflammation, oxidative stress, mitochondrial dysfunction, neurotransmitter imbalances, microvascular changes, and white matter lesions as central to PND pathophysiology, with particular parallels to encephalocele- and sepsis-associated cognitive impairments. Among these, neuroinflammation, mediated by pathways such as the NLRP3 inflammasome and blood-brain barrier disruption, emerges as a pivotal driver, triggering cascades that exacerbate neuronal injury. Oxidative stress and mitochondrial dysfunction synergistically amplify these effects, while neurotransmitter imbalances and microvascular alterations, including white matter lesions, contribute to synaptic dysfunction and cognitive decline. Anesthetic agents modulate these interconnected pathways, exhibiting both protective and detrimental effects. Propofol and dexmedetomidine demonstrate neuroprotective properties by suppressing neuroinflammation and microglial activation, whereas inhalational anesthetics like sevoflurane intensify oxidative stress and inflammatory responses. Ketamine, with its anti-inflammatory potential, offers promise but requires further evaluation to determine its long-term safety and efficacy. By bridging molecular insights with clinical practice, this review highlights the critical role of personalized anesthetic strategies in mitigating PND and improving cognitive recovery in elderly surgical patients. It aims to inform future research and clinical decision-making to address this multifaceted challenge.

The objective of this study was to examine the impact of "Tianyu" Pairing on oxidative stress in the development of Rheumatoid arthritis (RA) and approach its potential mechanism using cell experiments.

A cell model of RA was developed by stimulating rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) with tumor necrosis factor-α (TNF-α). This model aimed to assess the impact of serum containing Rhodiola rosea-Euonymus alatus drug pair (TYP) on inflammation and oxidative stress in the development of RA, specifically through the Keap1/Nrf2/HO-1 pathway.

The findings from the in vitro experiment demonstrated that the presence of TYP in the serum effectively suppressed the proliferation of RA-FLS induced by TNF-α. Additionally, TYP facilitated the apoptosis of afflicted cells, attenuated the migratory and invasive capabilities of diseased cells, and decreased the levels of Kelch ECH associating protein 1 (Keap1), reactive oxygen species (ROS), glutathione peroxidase (GSH-Px), catalase (CAT), and malondialdehyde (MDA) (p < 0.01). The influence of inflammation and oxidative stress in RA-FLS cells was reduced by increasing the nuclear-cytoplasmic ratio of Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) and levels of phosphorylated Nrf2, Heme Oxygenase 1 (HO-1), and Superoxide Dismutase (SOD) (p < 0.01).

TYP can regulate inflammation and oxidative stress in RA-FLS cells by activating the Keap1/Nrf2/HO-1 pathway.

Neurodegenerative diseases encompass a spectrum of conditions characterized by the gradual deterioration of neurons in the central and peripheral nervous system. While their origins are multifaceted, emerging data underscore the pivotal role of impaired mitochondrial functions and endolysosomal homeostasis to the onset and progression of pathology. This article explores whether mitochondrial dysfunctions act as causal factors or are intricately linked to the decline in endolysosomal function. As research delves deeper into the genetics of neurodegenerative diseases, an increasing number of risk loci and genes associated with the regulation of endolysosomal and autophagy functions are being identified, arguing for a downstream impact on mitochondrial health. Our hypothesis centers on the notion that disturbances in endolysosomal processes may propagate to other organelles, including mitochondria, through disrupted inter-organellar communication. We discuss these views in the context of major neurodegenerative diseases including Alzheimer's and Parkinson's diseases, and their relevance to potential therapeutic avenues.