Search Results (3,753)

Aging, a progressive and time-dependent decline in physiological functions, is driven by interconnected hallmarks, among which mitochondrial dysfunction plays a central role. Mitochondria not only regulate energy production but also play key roles in other cellular processes, including ROS generation, apoptosis, and metabolic signaling—all of which decline with aging. Polyphenols are a diverse group of natural compounds found in fruits, vegetables, tea, and wine; they emerged as promising anti-aging agents due to their ability to modulate several hallmarks of aging, particularly mitochondrial dysfunction. This review explores how various polyphenolic classes influence mitochondrial function and mitigate aging-related decline. These natural compounds have been shown to reduce oxidative stress, increase energy production, and help maintain normal mitochondrial structure. Moreover, in vitro and in vivo studies suggest that polyphenols can delay signs of aging and improve physical and cognitive functions. Overall, polyphenols show great potential to promote healthy aging and even delay the decline in physiological functions by protecting and enhancing mitochondrial health. Full article

Eriobotrya japonica (Thunb.) Lindl. leaves are rich in polyphenolic compounds, yet their toxicological effects in aquatic models remain poorly understood. This study evaluated the impact of a hydroethanolic E. japonica leaf extract on zebrafish embryos through the use of morphological, behavioral, and biochemical parameters. The 96 h LC₅₀ was determined as 189.8 ± 4.5 mg/L, classifying the extract as practically non-toxic, according to OECD guidelines. Thereby, embryos were exposed for 90 h to 75 and 150 mg/L concentrations of the E. japonica leaf extract. While no significant effects were noted at the lowest concentration of 150 mg/L, significant developmental effects were observed, including reduced survival, delayed hatching, underdevelopment of the swim bladder, and retention of the yolk sac. These malformations were accompanied by marked behavioral impairments. Biochemical analysis revealed a concentration-dependent increase in superoxide dismutase (SOD) and catalase (CAT) activity, suggesting the activation of antioxidant defenses, despite no significant change in reactive oxygen species (ROS) levels. This indicates a potential compensatory redox response to a pro-oxidant signal. Additionally, the acetylcholinesterase (AChE) activity was significantly reduced at the highest concentration, which may have contributed to the observed neurobehavioral changes. While AChE inhibition is commonly associated with neurotoxicity, it is also a known therapeutic target in neurodegenerative diseases, suggesting concentration-dependent dual effects. In summary, the E. japonica leaf extract induced concentration-dependent developmental and behavioral effects in zebrafish embryos, while activating antioxidant responses without triggering oxidative damage. These findings highlight the extract’s potential bioactivity and underscore the need for further studies to explore its safety and therapeutic relevance. Full article

Oxybenzone (OBZ), an organic ultraviolet filter, is an emerging contaminant posing severe threats to ecosystem health. Using tobacco (Nicotiana tabacum) as a model plant, this study investigated the alleviation mechanisms of exogenous silicon (Na₂SiO₃, Si) and bamboo-based biochar (Bc) under OBZ stress. We systematically analyzed physiological and biochemical responses, including phenotypic parameters, reactive oxygen species metabolism, photosynthetic function, chlorophyll synthesis, and endogenous hormone levels. Results reveal that OBZ significantly inhibited tobacco growth and triggered a reactive oxygen species (ROS) burst. Additionally, OBZ disrupted antioxidant enzyme activities and hormonal balance. Exogenous Bc mitigated OBZ toxicity by adsorbing OBZ, directly scavenging ROS, and restoring the ascorbate-glutathione (AsA-GSH) cycle, thereby enhancing photosynthetic efficiency, while Si alleviated stress via cell wall silicification, preferential regulation of root development and hormonal signaling, and repair of chlorophyll biosynthesis precursor metabolism and PSII function. The mechanisms of the two stress mitigators were complementary, Bc primarily relied on physical adsorption and ROS scavenging, whereas Si emphasized metabolic regulation and structural reinforcement. These findings provide practical strategies for simultaneously mitigating organic UV filter pollution and enhancing plant resilience in contaminated soils. Full article

Sepsis is a clinical syndrome characterized by a dysregulated host response to infection, frequently resulting in septic shock and multi-organ failure. Emerging evidence highlights the critical role of neutrophil extracellular traps (NETs) in the pathophysiology of sepsis. NETs are extracellular structures composed of chromatin DNA, histones, and granular proteins released by neutrophils through a specialized form of cell death known as NETosis. While NETs contribute to the containment of pathogens, their excessive or dysregulated production in sepsis is associated with endothelial damage, immunothrombosis, and organ dysfunction. Several NET-associated biomarkers have been identified, including circulating cell-free DNA (cfDNA), histones, MPO-DNA complexes, and neutrophil elastase–DNA complexes, which correlate with the disease severity and prognosis. Therapeutic strategies targeting NETs are currently under investigation. Inhibition of NET formation using PAD4 inhibitors or ROS scavengers has shown protective effects in preclinical models. Conversely, DNase I therapy facilitates the degradation of extracellular DNA, reducing the NET-related cytotoxicity and thrombotic potential. Additionally, heparin and its derivatives have demonstrated the ability to neutralize NET-associated histones and mitigate coagulopathy. Novel approaches include targeting upstream signaling pathways, such as TLR9 and IL-8/CXCR2, offering further therapeutic promise. Full article

Fine particulate matter (PM_2.5) exposure has been linked to increased lung damage due to compromised vascular barrier function, while 3-deoxysappanchalcone (3-DSC), a chalcone derived from Caesalpinia sappan, is known for its pharmacological benefits such as anti-cancer, anti-inflammatory, and antioxidant effects; however, its potential role in mitigating PM_2.5-induced pulmonary damage remains unexplored. To confirm the inhibitory effects of 3-DSC on PM_2.5-induced pulmonary injury, this research focused on evaluating how 3-DSC influences PM_2.5-induced disruption of the barrier of the endothelial cells (ECs) in the lungs and the resulting pulmonary inflammation. Permeability, leukocyte migration, proinflammatory protein activation, reactive oxygen species (ROS) generation, and histology were assessed in PM_2.5-treated ECs and mice. This study demonstrated that 3-DSC effectively neutralized the reactive oxygen species (ROS) generated by PM_2.5 exposure in the lung endothelial cells, suppressing ROS-triggered p38 MAPK activation while enhancing Akt signaling pathways critical to preserving vascular barrier function. In animal models, 3-DSC administration markedly decreased vascular permeability, attenuated the influx of immune cells into the lung tissue, and lowered inflammatory mediators like cytokines in the airways of PM_2.5-exposed mice. These data suggest that 3-DSC might exert protective effects on PM_2.5-induced inflammatory lung injury and vascular hyperpermeability. Full article

Powdery mildew (PM), caused by Sphaerotheca phaseoli, severely threatens mungbean (Vigna radiata) productivity and quality, yet the molecular basis of resistance remains poorly defined. This study employed transcriptome profiling to compare defense responses in a resistant genotype, SUPER5, and a susceptible variety, CN84-1, following pathogen infection. A total of 1755 differentially expressed genes (DEGs) were identified, with SUPER5 exhibiting strong upregulation of genes encoding pathogenesis-related (PR) proteins, disease resistance proteins, and key transcription factors. Notably, genes involved in phenylpropanoid and flavonoid biosynthesis, pathways associated with antimicrobial compound and lignin production, were markedly induced in SUPER5. In contrast, CN84-1 showed limited activation of defense genes and downregulation of essential regulators such as MYB14. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses highlighted the involvement of plant–pathogen interaction pathways, MAPK signaling, and reactive oxygen species (ROS) detoxification in the resistant response. Quantitative real-time PCR validated 11 candidate genes, including PAL3, PR2, GSO1, MLO12, and P21, which function in pathogen recognition, signaling, the biosynthesis of antimicrobial metabolites, the production of defense proteins, defense regulation, and the reinforcement of the cell wall. Co-expression network analysis revealed three major gene modules linked to flavonoid metabolism, chitinase activity, and responses to both abiotic and biotic stresses. These findings offer valuable molecular insights for breeding PM-resistant mungbean varieties. Full article

Activation of macrophages plays a key role in both inflammation and oxidative stress, key features of many chronic diseases. Pro-inflammatory M1-like macrophages, in particular, contribute to pro-oxidative environments and are a frequent focus of immunological research. This research examined the effects of kiwifruit allergen Act d 1, in comparison to LPS, on THP-1 macrophages in vitro differentiated under optimized conditions, both in the presence and in the absence of selected vanilloids. THP-1 monocyte differentiation was optimized by varying PMA exposure and resting time. Act d 1 induced M1-like phenotypic changes comparable to LPS, including upregulation of CD80, IL-1β and IL-6 secretion, gene expression of iNOS and NF-κB activation, in addition to increased reactive oxygen species (ROS) and catalase activity. Treatment with specific vanilloids mitigated these responses, primarily through reduced oxidative stress and NF-κB activation. Notably, vanillin (VN) was the most effective, also reducing CD80 expression and IL-1β levels. These results suggest that vanilloids can affect pro-inflammatory signaling and oxidative stress in THP-1 macrophages and highlight their potential to alter inflammatory conditions characterized by similar immune responses. Full article

Low-temperature stress severely limits plant growth and reduces agricultural productivity. Calmodulin-like (CML) proteins are crucial calcium sensors in plant cold responses. Transcriptome analysis of cold-stressed Saussurea involucrata identified seven differentially expressed CML genes. qRT-PCR confirmed that SiCML6 was strongly induced at 4 °C and −2 °C. Bioinformatics analysis showed that SiCML6 encodes a transmembrane protein containing an EF-hand domain. This protein carries a signal peptide and shows the closest phylogenetic relationship to Helianthus annuus CML3. Its promoter contains ABA, methyl jasmonate (MeJA), and cold-response elements. Arabidopsis plants overexpressing SiCML6 showed significantly higher survival rates at −2 °C than wild-type plants. Under freezing stress, SiCML6-overexpressing lines exhibited reduced malondialdehyde content, relative electrolyte leakage, and ROS accumulation (H₂O₂ and O₂⁻), along with increased proline, soluble sugars, soluble proteins, and total antioxidant capacity (T-AOC). SiCML6 elevated the expression of cold-responsive genes CBF3 and COR15a under normal conditions and further upregulated CBF1/2/3 and COR15a at 4 °C. Thus, low temperatures induced SiCML6 expression, which was potentially regulated by ABA/MeJA. SiCML6 enhances freezing tolerance by mitigating oxidative damage through boosted T-AOC and osmoprotectant accumulation while activating the CBF-COR signaling pathway. This gene is a novel target for improving crop cold resistance. Full article

Alzheimer’s disease (AD) is increasingly recognized as a multifactorial disorder driven by a combination of disruptions in proteostasis and organelle communication. The 2020 Lancet commission reported that approximately 10 million people worldwide were affected by AD in the mid-20th century. AD is the most prevalent cause of dementia. By early 2030, the global cost of dementia is projected to rise by USD 2 trillion per year, with up to 85% of that cost attributed to daily patient care. Several factors have been implicated in the progression of neurodegeneration, including increased oxidative stress, the accumulation of misfolded proteins, the formation of amyloid plaques and aggregates, the unfolded protein response (UPR), and mitochondrial–endoplasmic reticulum (ER) calcium homeostasis. However, the exact triggers that initiate these pathological processes remain unclear, in part because clinical symptoms often emerge gradually and subtly, complicating early diagnosis. Among the early hallmarks of neurodegeneration, elevated levels of reactive oxygen species (ROS) and the buildup of misfolded proteins are believed to play pivotal roles in disrupting proteostasis, leading to cognitive deficits and neuronal cell death. The accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles is a characteristic feature of AD. These features contribute to chronic neuroinflammation, which is marked by the release of pro-inflammatory cytokines and chemokines that exacerbate oxidative stress. Given these interconnected mechanisms, targeting stress-related signaling pathways, such as oxidative stress (ROS) generated in the mitochondria and ER, ER stress, UPR, and cytosolic chaperones, represents a promising strategy for therapeutic intervention. This review focuses on the relationship between stress chaperone responses and organelle function, particularly the interaction between mitochondria and the ER, in the development of new therapies for AD and related neurodegenerative disorders. Full article

This paper presents a method for optimizing the inertia constants and damping coefficients of interconnected virtual synchronous generators (VSGs) using a genetic algorithm. The goal of optimization is to find a balance between minimizing the rate of change of frequency (RoCoF) and enhancing controllability. Five controllability-based metrics are tested: the minimum eigenvalue, the sum of the two smallest eigenvalues, the maximum eigenvalue, the trace, and the determinant of the controllability Gramian matrix. The approach includes the oscillatory modes’ damping ratio constraints to ensure the small-signal stability of the entire system. The results of optimization on the IEEE 9-bus system with three VSGs show that the proposed method improves controllability, reduces RoCoF, and maintains the desired oscillation damping. The proposed approach was tested through time-domain simulations. Full article

Background: Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) hold transformative potential for cardiovascular regenerative medicine, yet their clinical application is hindered by suboptimal mitochondrial maturation and metabolic inefficiencies. This systematic review evaluates targeted strategies for optimizing mitochondrial function, integrating metabolic preconditioning, substrate selection, and pathway modulation to enhance energy production and cellular resilience. Additionally, we examine the role of extracellular matrix stiffness and mechanical stimulation in mitochondrial adaptation, given their influence on metabolism and maturation. Methods: A comprehensive analysis of recent advancements in iPSC-CM maturation was conducted, focusing on metabolic interventions that enhance mitochondrial structure and function. Studies employing metabolic preconditioning, lipid and amino acid supplementation, and modulation of key signaling pathways, including PGC-1α, AMPK, and mTOR, were reviewed. Computational modeling approaches predicting optimal metabolic shifts were assessed, alongside insights into reactive oxygen species (ROS) signaling, calcium handling, and the impact of electrical pacing on energy metabolism. Results: Evidence indicates that metabolic preconditioning with fatty acids and oxidative phosphorylation enhancers improves mitochondrial architecture, cristae density, and ATP production. Substrate manipulation fosters a shift toward adult-like metabolism, while pathway modulation refines mitochondrial biogenesis. Computational models enhance precision, predicting interventions that best align iPSC-CM metabolism with native cardiomyocytes. The synergy between metabolic and biomechanical cues offers new avenues for accelerating maturation, bridging the gap between in vitro models and functional cardiac tissues. Conclusions: Strategic metabolic optimization is essential for overcoming mitochondrial immaturity in iPSC-CMs. By integrating biochemical engineering, predictive modeling, and biomechanical conditioning, a robust framework emerges for advancing iPSC-CM applications in regenerative therapy and disease modeling. These findings pave the way for more physiologically relevant cell models, addressing key translational challenges in cardiovascular medicine. Full article

Reactive oxygen species (ROS) play a dual role as both essential signaling molecules and harmful mediators of damage. Imbalances in the redox state of the liver can overwhelm antioxidant defenses and promote mitochondrial dysfunction, oxidative damage, and inflammation. Complex feedback loops between ROS and immune signaling pathways are a hallmark of pathological liver conditions, such as hepatic ischemia–reperfusion injury (IRI). This is a major cause of liver transplant failure and is of increasing significance due to the increased use of marginally discarded livers for transplantation. This review outlines the major enzymatic and metabolic sources of ROS in hepatic IRI, including mitochondrial reverse electron transport, NADPH oxidases, cytochrome P450 enzymes, and endoplasmic reticulum stress. Hepatocyte injury activates redox feedback loops that initiate immune cascades through DAMP release, toll-like receptor signaling, and cytokine production. Emerging regulatory mechanisms, such as succinate accumulation and cytosolic calcium–CAMKII signaling, further shape oxidative dynamics. Pharmacological therapies and the use of antioxidant and immunomodulatory approaches, including nanoparticles and redox-sensitive therapeutics, are discussed as protective strategies. A deeper understanding of how redox and immune feedback loops interact is an exciting and active area of research that warrants further clinical investigation. Full article

Background/Objectives: An important new consideration when studying autism spectrum disorder (ASD) is the bioenergetic mechanisms underlying the relatively recent rapid evolutionary expansion of the human brain, which pose fundamental risks for mitochondrial dysfunction and calcium signaling abnormalities and their potential role in ASD, as recently highlighted by insights from the BTBR mouse model of ASD. The rapid brain expansion taking place as Homo sapiens evolved, particularly in the parietal lobe, led to increased energy demands, making the brain vulnerable to such metabolic disruptions as are seen in ASD. Methods: Mitochondrial dysfunction in ASD is characterized by impaired oxidative phosphorylation, elevated lactate and alanine levels, carnitine deficiency, abnormal reactive oxygen species (ROS), and altered calcium homeostasis. These dysfunctions are primarily functional, rather than being due to mitochondrial DNA mutations. Calcium signaling plays a crucial role in neuronal ATP production, with disruptions in inositol 1,4,5-trisphosphate receptor (ITPR)-mediated endoplasmic reticulum (ER) calcium release being observed in ASD patient-derived cells. Results: This impaired signaling affects the ER–mitochondrial calcium axis, leading to mitochondrial energy deficiency, particularly in high-energy regions of the developing brain. The BTBR mouse model, with its unique Itpr3 gene mutation, exhibits core autism-like behaviors and metabolic syndromes, providing valuable insights into ASD pathophysiology. Conclusions: Various interventions have been tested in BTBR mice, as in ASD, but none have directly targeted the Itpr3 mutation or its calcium signaling pathway. This review presents current genetic, biochemical, and neurological findings in ASD and its model systems, highlighting the need for further research into metabolic resilience and calcium signaling as potential diagnostic and therapeutic targets for ASD. Full article

Background: Aicardi-Goutières Syndrome (AGS) is a rare neuroinflammatory condition characterized by early-onset symptoms that extend outside the nervous system. Due to the rarity of the disease, the pathogenesis is not well understood, and its diagnosis and treatment remain elusive. We recently demonstrated mitochondrial abnormalities and increased reactive oxygen species (ROS) levels in lymphoblastoid cell lines (LCLs) derived from RNASEH2B- and RNASEH2A-mutated AGS patients. On this background, we turned our attention to metformin, the first-choice drug for type 2 diabetes, as a possible treatment acting on oxidative stress in RNASEH2-mutant AGS cells. Methods and Results: By means of flow cytometry, we found that metformin treatment significantly decreases ROS production in RNASEH2B- and RNASEH2A-mutated AGS LCLs. Of note, metformin treatment reduces the green JC-1 monomeric signal and, concurrently, increases the red JC-1 signal in both mutated LCLs, accounting for restoration of the mitochondrial membrane potential. Immunofluorescence staining shows a decrease in 8-oxoG levels only in RNASEH2B- mutated AGS LCLs. Finally, the significant upregulation of Forkhead Box O3 (FOXO3), cytochrome C somatic (CYCS), and superoxide dismutase 2 (SOD2) mRNA levels in RNASEH2B-mutated AGS LCLs after metformin treatment points to FOXO3 signaling as a possible mechanism to reduce oxidative stress. Conclusions: In conclusion, even if these pilot results need to be confirmed on a larger cohort, we shed light on metformin treatment as a valid approach to ameliorate oxidative stress-related inflammation in AGS patients. Full article

Natural compounds, particularly flavonoids, have emerged as promising anticancer agents due to their various biological activities and no or negligible toxicity towards healthy tissues. Among these, isorhamnetin, a methylated flavonoid, has gained significant attention for its potential to target multiple cancer hallmarks. This review comprehensively explores the mechanisms by which isorhamnetin exerts its anticancer effects, including cell cycle regulation, apoptosis, suppression of metastasis and angiogenesis, and modulation of oxidative stress and inflammation. Notably, isorhamnetin arrests cancer cell proliferation by regulating cyclins, and CDKs induce apoptosis via caspase activation and mitochondrial dysfunction. It inhibits metastatic progression by downregulating MMPs, VEGF, and epithelial–mesenchymal transition (EMT) markers. Furthermore, its antioxidant and anti-inflammatory properties mitigate reactive oxygen species (ROS) and pro-inflammatory cytokines, restricting cancer progression and modulating tumor microenvironments. Combining isorhamnetin with other treatments was also discussed to overcome multidrug resistance. Importantly, this review integrates the recent literature (2022–2024) and highlights isorhamnetin’s roles in modulating cancer-specific signaling pathways, immune evasion, tumor microenvironment dynamics, and combination therapies. We also discuss nanoformulation-based strategies that significantly enhance isorhamnetin’s delivery and bioavailability. This positions isorhamnetin as a promising adjunct in modern oncology, capable of improving therapeutic outcomes when used alone or in synergy with conventional treatments. The future perspectives and potential research directions were also summarized. By consolidating current knowledge and identifying critical research gaps, this review positions Isorhamnetin as a potent and versatile candidate in modern oncology, offering a pathway toward safer and more effective cancer treatment strategies. Full article