Mitochondrial Oxidative Stress Research Articles

Mitochondrial oxidant stress promotes α-synuclein aggregation and spreading in mice with mutated glucocerebrosidase

In this study, heterozygous expression of a common Parkinson-associated GBA1 variant, the L444P mutation, was found to exacerbate α-synuclein aggregation and spreading in a mouse model of Parkinson-like pathology targeting neurons of the medullary vagal system. These neurons were also shown to become more vulnerable to oxidative and nitrative stress after L444P expression. The latter paralleled neuronal formation of reactive oxygen species and led to a pronounced accumulation of nitrated α-synuclein. A causal relationship linked mutation-induced oxidative/nitrative stress to enhanced α-synuclein aggregation and spreading that could indeed be rescued by neuronal overexpression of mitochondrial superoxide dismutase 2. Further evidence supported a key involvement of mitochondria as sources of reactive oxygen species as well as targets of oxidative and nitrative damage within L444P-expressing neurons. These findings support the conclusion that enhanced vulnerability to mitochondrial oxidative stress should be considered an important mechanism predisposing to pathology conversion in carriers of GBA1 mutations.

In Vitro Protective Effects of a Standardized Extract of Opuntia ficus-indica (L.) Mill. Cladodes and Olea europaea L. Leaves Against Indomethacin-Induced Intestinal Epithelial Cell Injury

Nonsteroidal anti-inflammatory drugs (NSAIDs) can induce serious adverse effects in gastrointestinal (GI) mucosa, increasing intestinal permeability and leading to mitochondrial dysfunction, oxidative stress, apoptosis and inflammation. As proton pump inhibitors are effective in protecting against NSAID-induced gastropathy but not NSAID-induced enteropathy, current research is focused on natural products as protective substances for therapy and prevention of intestinal injury. Herein, through the use of an in vitro model based on intestinal epithelial cell (Caco-2) damage caused by indomethacin (INDO), we examined the protective activity of a commercially available standardized extract (OFI+OE) from Opuntia ficus-indica (L.) Mill. cladodes and Olea europaea L. leaves. Pre-treatment with OFI+OE prevented INDO-induced intestinal epithelial barrier damage, as demonstrated by TEER measurement, fluorescein permeability, and tight junction protein expression. The extract showed positive effects against INDO-induced oxidative stress and correlated activation of apoptosis, decreasing pro-apoptotic markers BAX and Caspase-3 and increasing anti-apoptotic factor Bcl-2. Moreover, the extract inhibited the NF-κB pathway and pro-inflammatory cascade. In conclusion, these data support the use of OFI+OE extract as a natural strategy for therapy and prevention of intestinal mucosal damage, demonstrating its beneficial effects against INDO-induced intestinal damage, through modulation of oxidative, apoptotic, and inflammatory pathways.

Inflammatory Signaling Induces Mitochondrial Dysfunction and Neuronal Death in Traumatic Brain Injury via Downregulation of OXPHOS Genes.

Traumatic brain injury (TBI) is a major cause of neurological dysfunction and disability. This study aimed to investigate the transcriptomic changes and the functional consequences in TBI, focusing on the interplay between inflammation and mitochondrial impairment. Brain tissue samples from TBI patients and healthy controls were subjected to RNA-sequencing analysis. Mouse hippocampal HT-22 cells were treated with inflammatory cytokine and the PGC-1α activator ZLN005. Mitochondrial function, oxidative stress, and apoptosis were assessed using Seahorse respirometry, electron microscopy, flow cytometry, and molecular assays. A TBI mouse model was established to evaluate the therapeutic effects of ZLN005. Transcriptome profiling revealed downregulation of mitochondrial oxidative phosphorylation (OXPHOS) genes, particularly those encoded by the mitochondrial genome, along with enrichment of neurodegenerative pathways in TBI patients. Concomitantly, pro-inflammatory signaling pathways showed upregulation. In vitro studies demonstrated that inflammatory cytokine TNF-α treatment impaired mitochondrial respiration, induced oxidative stress and apoptosis in HT-22 cells, which could be rescued by ZLN005-mediated PGC-1α activation and restoration of OXPHOS gene expression. Administration of ZLN005 in the TBI mouse model alleviated neuronal cell death, preserved mitochondrial integrity, normalized OXPHOS gene levels in brain tissues, and improved cognitive function. This study uncovers a mechanistic link between inflammation-induced downregulation of mitochondrial OXPHOS genes and neuronal damage in TBI. Targeting this pathway by activating PGC-1α represents a potential therapeutic strategy for TBI.

DEHP impairs the oxidative stress response and disrupts trace element and mineral metabolism within the mitochondria of detoxification organs.

Di(2-ethylhexyl) phthalate (DEHP), a widely utilized plasticizer in various consumer products, is classified as an endocrine disruptor and has been implicated in numerous adverse health effects, including oxidative stress, inflammation, and metabolic disturbances. Despite the growing body of literature addressing the systemic effects of DEHP, the specific influence of DEHP-induced oxidative stress on mitochondrial function within detoxification organs, particularly the liver and kidneys, remains largely unexplored. This study evaluated the effects of DEHP exposure (0, 100, 200, and 400mg/kg/day) on mitochondrial oxidative stress, trace elements, and mineral metabolism associated with signaling pathways in the liver and kidneys of rats. Altered mitochondrial oxidative stress status was indicated by impaired glucose 6-phosphate dehydrogenase (G6PD), 6-phosphoglucerate dehydrogenase (6-PGD), glutathione reductase (GR), glutathione s-transferase (GST), and glutathione peroxidase (GPx) activities, along with significant disruptions in essential minerals and trace elements, including Na, Mg, Cu, Zn, and Fe. Key oxidative stress signaling pathways, such as NF-κB, Akt, STAT3, and CREB, glucose, and tissue homeostasis, displayed dose-dependent responses to DEHP, indicating complex regulatory mechanisms. This study represents the first comprehensive investigation into DEHP-induced mitochondrial dysfunction, highlighting its effects on oxidative stress metabolism, trace element homeostasis, and cellular signaling pathways in detoxification organs. These findings provide novel insights into the mitochondrial mechanisms underlying DEHP toxicity and underscores the need for further research into the implications of plasticizer exposure on human health.

Innovative formulations for the ocular delivery of coenzyme Q10.

Coenzyme Q10 (CoQ10) is a lipophilic antioxidant agent that plays a crucial role in the mitochondrial electron transport chain. The neuroprotective role of CoQ10, countering mitochondrial dysfunction and oxidative stress, suggests its potential as an adjuvant for ocular neurodegenerative diseases linked to retinal cell loss. However, despite its promising properties, ocular barriers pose challenges for effective delivery. Therefore, the present work aimed to identify new ocular delivery strategies to improve the therapeutic potential of CoQ10 by increasing its ocular bioavailability at the posterior segment and supporting its controlled release. Polymeric micelles of D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) were selected as carriers for the loading of CoQ10, increasing its solubility and promoting its penetration through ocular tissues. After their characterization by dynamic light scattering (DLS) and small-angle X-ray scattering (SAXS), loaded micelles were applied to porcine sclera and choroid to confirm their ex vivo retention and permeation capacity. To ensure a controlled release, they were then loaded into a crosslinked polymer film, which was characterized in terms of mechanical properties, swelling degree and release profiles of TPGS and CoQ10. The biocompatibility of this platform was tested by the HET-CAM assay, and ex vivo studies confirmed its ocular potential.

The Effect of Physical Exercise on Post-COVID-19 Survivors: A Scoping Review

Background: Post-COVID-19 survivors or patients show deterioration in respiratory function, physical symptoms, musculoskeletal strength, quality of life (QoL), and psychological problems due to persistent symptoms. These symptoms are associated with mitochondrial dysfunction, reduced antioxidants, and oxidative stress. Physical exercise has been proven to positively affect general and psychological health.Objective: This study intended to explore physical exercise's effect on post-COVID-19 survivors.Methods: Literature in this scoping review was searched from seven databases, including Embase, PubMed, CINAHL, Cochrane, Scopus, Ovid-MEDLINE, and Web of Science. A manual search from Google Scholar and citations from previous meta-analyses were also performed. The keywords are “physical exercise” OR “physical activity” AND “post-COVID” OR “Long COVID.” Studies were included if involving patients with post-COVID diagnosis. However, studies that did not focus on post-COVID-19 focused on respiratory rehabilitation and had no complete data were excluded from this review.Results: 33 studies from 1.909 were included (30 from databases and three citations from previous meta-analyses). Physical activity for post-COVID survivors can improve lung function, exercise capacity, functional capacity, physical symptoms (for instance, pain, fatigue), psychological or QoL, and also biochemical and hematological variables (for example, platelets, red blood cells, white blood cells, hemoglobin, hematocrit, creatinine, and urea).Conclusion: Physical activity programs may represent an important supportive therapy for post-COVID-19 survivors. Therefore, health workers are encouraged to closely monitor respiratory parameters or post-COVID-19 patient symptoms and motivate patients to perform physical exercise.

Suppression of PINK1 autophosphorylation attenuates pilocarpine-induced seizures and neuronal injury in rats

PTEN-induced kinase 1 (PINK1) autophosphorylation triggers the PINK1/Parkin pathway, which is the main mitophagic pathway in the mammalian nervous system. In the present study, we aimed to mechanistically explore the role of PINK1 in pilocarpine-induced status epilepticus (SE) in Sprague-Dawley rats. Evidence from immunohistochemistry, western blotting, biochemical assays, and behavioral testing showed that pilocarpine-induced SE led to increased levels of PINK1 phosphorylation, mitophagy, mitochondrial oxidative stress, neuronal damage and learning and memory deficits. Using shRNA interference to suppress the expression of translocase outer mitochondrial membrane 7, a positive regulator of PINK1 autophosphorylation, lowered the increased levels of phosphorylated PINK1 following pilocarpine administration. It also reduced the levels of mitophagy, mitochondrial oxidative stress and neuronal damage, and attenuated seizure severity and cognitive deficits. In contrast, suppressing the expression of overlapping with the m-AAA protease 1 homolog, a negative regulator of PINK1 autophosphorylation, led to higher levels of phosphorylated PINK1 following pilocarpine administration. It also led to more serious mitophagy, neuronal damage, as well as worsened seizure severity and cognitive deficits. Our results indicate that PINK1 autophosphorylation plays a vital role in epileptic seizures and neuronal injury by mediating mitophagy. Regulating PINK1 autophosphorylation may change the adverse consequences of epilepsy, and may be an effective neuroprotective strategy.

Dapagliflozin has protective effects on palmitate-induced renal tubular epithelial cells by enhancing mitochondrial function and reducing oxidative stress.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors, commonly utilized for diabetic nephropathy, have demonstrated benefits beyond glucose control, including organ protection. This study investigated the protective effects of the SGLT2 inhibitor, dapagliflozin (DAPA), on palmitate-induced renal tubular epithelial cell (HK-2) injury, particularly concentrating on mitochondrial function and oxidative stress. HK-2 cells were treated with 150μmol/L palmitate to induce mitochondrial dysfunction and oxidative stress, and they were co-treated with 2μmol/L DAPA for 24h. DAPA significantly increased cell viability (P<0.05), reduced reactive oxygen species (ROS) levels (P<0.001), and restored mitochondrial membrane potential (P<0.05). It also lowered malondialdehyde (MDA) level (P<0.001) and increased superoxide dismutase (SOD) expression level (P<0.001). Western blot analysis revealed that DAPA reversed palmitate-induced upregulation of apoptosis-related proteins, including Bax and Cytochrome C. DAPA also mitigated the overactivation of autophagy-related proteins, such as LC3 and Beclin-1, indicating its role in modulating autophagy under diabetic nephropathy. Electron microscopy confirmed improvements in mitochondrial morphology, accompanying by reduced swelling and restored cristae structure. These findings highlight the potential of DAPA, as an SGLT2 inhibitor, to mitigate renal injury by enhancing mitochondrial function and reducing oxidative stress, providing novel insights into its therapeutic value for diabetic nephropathy management.

Nepetin limits NLRP3 inflammasome activation and alleviates NLRP3-driven inflammatory diseases via PINK1-dependent mitophagy.

The NLRP3 inflammasome plays a pivotal role in the progression of inflammatory diseases. Mitochondrial damage, oxidative stress and mitochondrial DNA (mtDNA) leak are the key upstream factors for NLRP3 inflammasome activation. Nepetin (Nep), a naturally occurring flavonoid found with anti-inflammatory properties; however, whether it can affect the NLRP3 inflammasome activation and its precise anti-inflammatory mechanism remains unclear. In this study, we demonstrated that Nep enhances PINK1-mediated ubiquitin phosphorylation, which promotes mitophagy and subsequently inhibits NLRP3 inflammasome activation and pyroptosis in macrophages. The administration of Nep to macrophages alleviated of mitochondrial damage, reduced mitochondrial superoxide production, restored mitochondrial membrane potential and prevented the mtDNA leakage. These findings provide compelling evidence for the antioxidant effect of Nep. Furthermore, the pivotal function of mitophagy in the NLRP3 inflammasome inhibitory impact of Nep was substantiated through the utilisation of mitophagy inhibitors and siRNA techniques. Notably, Nep increased survival and reduced organ damage in mice with systemic inflammation by inhibiting NLRP3 inflammasome activation. In addition, Nep suppressed NLRP3 inflammasome activation in obese mice, which led to reduced white adipose and liver inflammation, thereby ameliorating insulin resistance. In conclusion, our findings suggest that Nep is a potent NLRP3 inflammasome inhibitor and a promising candidate for the development of anti-inflammatory therapies.

Nobiletin protects against alcohol-induced mitochondrial dysfunction and liver injury by regulating the hepatic NRF1-TFAM signaling pathway.

Alcohol and its metabolites, such as acetaldehyde, induced hepatic mitochondrial dysfunction play a pathological role in the development of alcohol-related liver disease (ALD). In this study, we investigated the potential of nobiletin (NOB), a polymethoxylated flavone, to counter alcohol-induced mitochondrial dysfunction and liver injury. Our findings demonstrate that NOB administration markedly attenuated alcohol-induced hepatic steatosis, endoplasmic reticulum stress, inflammation, and tissue damage in mice. NOB reversed hepatic mitochondrial dysfunction and oxidative stress in both alcohol-fed mice and acetaldehyde-treated hepatocytes. Mechanistically, NOB restored the reduction of hepatic mitochondrial transcription factor A (TFAM) at both mRNA and protein levels. Notably, the protective effects of NOB against acetaldehyde-induced mitochondrial dysfunction and cell death were abolished in hepatocytes lacking Tfam. Furthermore, NOB administration reinstated the levels of hepatocellular NRF1, a key transcriptional regulator of TFAM, which were decreased by alcohol and acetaldehyde exposure. Consistent with these findings, hepatocyte-specific overexpression of Nrf1 protected against alcohol-induced hepatic Tfam reduction, mitochondrial dysfunction, oxidative stress, and liver injury. Our study elucidates the involvement of the NRF1-TFAM signaling pathway in the protective mechanism of NOB against chronic-plus-binge alcohol consumption-induced mitochondrial dysfunction and liver injury, suggesting NOB supplementation as a potential therapeutic strategy for ALD.

Curcumin Derivatives Linked to a Reduction of Oxidative Stress in Mental Dysfunctions and Inflammatory Disorders.

Stress is a critical factor in the etiology of inflammation and neurodegeneration. The risk factor for the majority of psychiatric disorders is oxidative stress-induced depression. Mitochondrial damage and oxidative stress are associated with the development of neurodegenerative disorders. During aging, the brain and associated regions become more susceptible due to oxidative stress. The leading cause of oxidative stress is the continuous generation of ROS (reactive oxygen species) and RNS (Reactive nitrogen species) endogenously or exogenously. In this review, discussion on a potent antioxidant natural constituent "curcumin" has been made to alleviate many pathological and neurological disorders. A focused compilation of vast and informative research on the potential of curcumin as a magical moiety used therapeutically has been done in search of its role in controlling the neurological and similar disorders induced by oxidative stress.

Mitigating mitochondrial dysfunction and neuroinflammation by hematoma aspiration in a new surgical model for severe intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is associated with a large hematoma that causes compression, increased intracranial pressure (IICP), midline shift, and brain herniation, and may ultimately lead to death. Urgent surgical removal of the large hematoma can ameliorate these injuries, which would be life-saving, but has not improved clinical outcome. A suitable animal model that mimics the clinically relevant human severe ICH injury requiring surgical hematoma evacuation is urgently needed. Here, we established a novel model of severe ICH in rats allowing aspiration of the hematoma and studying the effects of mitochondrial dysfunction in ICH. Severe ICH was induced by intra-striatal injection of 0.6 U of collagenase in 3 μl sterile saline over 15 min. Aspiration of approximately 75 % of the total hematoma was performed 6 h after induction of severe ICH. The effects of hematoma aspiration on hematoma volume, mortality, oxidative stress, ATP levels, mitochondrial dysfunction, and neurological function were measured in rats. Severe ICH induction increased hematoma volume, neurological deficits, and mortality. Hematoma aspiration abolished mortality and significantly reduced hematoma volume, and neurological deficits. In addition, hematoma aspiration ameliorated the pronounced mitochondrial dysfunction responsible for the failure of energy production and excessive oxidative stress associated with severe hemorrhagic injury. Hematoma aspiration also modulated mitochondrial biogenesis and mitophagy, thereby promoting mitochondrial homeostasis. Markers of neuroinflammation, including iNOS, MMP9, and MPO, were elevated in severe ICH but attenuated by hematoma aspiration. This study established an animal model of severe ICH and provides valuable insights into the complex pathogenesis of severe ICH. The results showed that hematoma aspiration effectively ameliorates mitochondrial dysfunction, oxidative stress, and neuroinflammation, highlighting its potential as a therapeutic intervention.

Biological function of EPHB4 in the aging process of vascular endothelial cells: mtDNA molecular mechanism and MAPK/PGC-1/TFAM signaling pathway.

Previous studies have shown that EPHB4 is also involved in regulating the proliferation, migration, and apoptosis of endothelial cells. In this study, we found a close relationship between EPHB4 and aging. Therefore, in-depth research on the relationship between EPHB4 and aging can help reveal the molecular mechanisms of aging and provide new ideas and methods for developing anti-aging drugs and treating vascular aging-related diseases. In addition, in our current study, we found a close relationship between EPHB4, cellular senescence, and CM-AVM. The MAPK/PGC-1/TFAM signaling axis mediated by EPHB4 may also be involved in the process of CM-AVM, laying a solid foundation for future in-depth studies on the relationship between EPHB4 and CM-AVM. Our findings revealed a decrease in mitochondrial membrane potential associated with EPHB4 deficiency, suggesting that EPHB4 loss may contribute to mitochondrial dysfunction. Additionally, EPHB4 deficiency led to an elevation in mitochondrial ROS levels, which was confirmed using mitochondrial-specific fluorescent probes. Furthermore, EPHB4 deficiency resulted in down-regulated expression of NRF1 and SOD2, which could be a significant contributor to mitochondrial oxidative stress. To validate this hypothesis, we conducted rescue experiments by restoring PGC-1 expression. The results showed a partial recovery of mitochondrial membrane potential and a reduction in cell senescence. These findings suggest that EPHB4 regulates mitochondrial functional integrity through the MAPK/PGC-1/TFAM signaling axis.

Reactive oxygen species in skeletal muscle injury, fatigue, regeneration and ageing: In memory of John Faulkner

One of the most critical factors impacting healthspan in the elderly is the loss of muscle mass and function, clinically referred to as sarcopenia. Muscle atrophy and weakness lead to loss of mobility, increased risk of injury, metabolic changes and loss of independence. Thus, defining the underlying mechanisms of sarcopenia is imperative to enable the development of effective interventions to preserve muscle function and quality in the elderly and improve healthspan. Over the past few decades, understanding the roles of mitochondrial dysfunction and oxidative stress has been a major focus of studies seeking to reveal critical molecular pathways impacted during aging. In this review, we will highlight how oxidative stress might contribute to sarcopenia by discussing the impact of oxidative stress on the loss of innervation and alteration in the neuromuscular junction (NMJ), on muscle mitochondrial function and atrophy pathways, and finally on muscle contractile function.

Cadmium exposure triggers alveolar epithelial cell pyroptosis by inducing mitochondrial oxidative stress and activating the cGAS-STING pathway

BackgroundCadmium is a ubiquitous toxic metal and environmental pollutant. More and more studies have shown that cadmium exposure can damage lung function. Alveolar epithelial cells (AECs) are structural cells that maintain the stability of lung function. The injury of AECs is an essential determinant of many lung diseases. In the lung, cadmium accumulation can cause damage to AECs. However, the specific mechanism is still unclear. This study aimed to explore the key mechanism underlying the injury of AECs caused by cadmium exposure.MethodsThe main modes of death of AECs induced by cadmium exposure were evaluated in vivo and in vitro. Transcriptomic changes of AECs induced by cadmium exposure were analyzed using RNA-sequence. Mitochondrial ROS scavengers (mitoQ), voltage-dependent anion channel 1 (VDAC1) oligomer inhibitor (VBIT4), and cyclic GMP-AMP synthase (cGAS) inhibitor (RU.521) were used to assess whether cadmium exposure triggered pyroptosis of AECs by inducing mitochondrial stress to activate the cGAS-STING-NLRP3 axis.ResultsIn this study, the expression of pyroptosis-related proteins was significantly up-regulated in the cadmium-exposed AECs, while the expression of apoptosis, necroptosis, and ferroptosis-related proteins had no significant up-regulated. The pan-caspase inhibitor ZVAD-FMK significantly reduced cell death. Thus, our research indicates that pyroptosis is the primary type of AEC death exported to cadmium. Mechanistically, RNA-seq and Western Blot results showed that cadmium exposure activated the cGAS-STING pathway in AECs and promoted pyroptosis by activating the NLRP3 inflammasome. Further investigation of the mechanism found that cadmium exposure caused mitochondrial oxidative stress, which led to mtDNA leakage into the cytoplasm and activated the cGAS-STING pathway. In addition, inhibition of the cGAS-STING pathway significantly alleviated lung injury induced by cadmium exposure in mice.ConclusionOur study confirmed that pyroptosis of AECs was a vital mechanism of lung injury after cadmium exposure in a cGAS-STING-dependent manner, which may provide a new target for the treatment of lung diseases induced by cadmium exposure.

Oxidative/Nitrosative Stress and Brain Involvement in Sepsis: A Relationship Supported by Immunohistochemistry

Background and Objectives: A large amount of recent evidence suggests that cellular inability to consume oxygen could play a notable part in promoting sepsis as a consequence of mitochondrial dysfunction and oxidative stress. The latter could, in fact, represent a fundamental stage in the evolution of the “natural history” of sepsis. Following a study previously conducted by the same working group on heart samples, the present research project aims to evaluate, through an immunohistochemical study, the existence and/or extent of oxidative stress in the brains of subjects who died due to sepsis and define, after reviewing the literature, its contribution to the septic process to support the use of medications aimed at correcting redox anomalies in the management of septic patients. Materials and Methods: 10 cases of subjects who died in healthcare facilities with ante-mortem clinical-laboratory signs that allowed the diagnosis of septic shock were selected as case studies, and 1 case of a subject who died immediately following a road traffic accident was used as a negative control. Samples of the cerebral cortex were then taken, fixed in formalin, and subjected to sections on which an immunohistochemical study was performed using anti-NOX-2, NT, iNOS, and 8-OHdG antibodies. Results: The results emerging from the present study demonstrate that despite a variable expressivity for the NT, iNOS, and NOX2 markers, the brain samples demonstrated univocal and high positivity for the 8-OHdG marker. Conclusions: This would allow us to hypothesize how, regardless of the mechanism of production of ROS and NOS (iNOS or NOX2 mediated) and the pathophysiological mechanisms that are triggered during sepsis, oxidative damage to DNA represents the event to which this whole process leads and, in fact, in the literature, is directly correlated to sepsis-dependent mortality. Neurons, conversely, appear to be more sensitive to oxidative stress because of a low number of protective or scavenger molecules (catalase, glutathione peroxidase, GSH, or vitamin E). Therefore, despite reduced production, the manifestation of the damage remains high. This evidence, together with that of the previous study, can only support the introduction of substances with an antioxidant function in the guidelines for the treatment of sepsis.

Comparative mitochondrial proteomic: PGAM5-mediated necroptosis through excessive mitophagy in sheep livers under molybdenum and cadmium co-exposure

Accumulation of excessive molybdenum (Mo) and cadmium (Cd) in the environment poses detrimental effects on organisms. The precise mechanisms of hepatotoxicity that are involved with mitochondria, resulting from the co-exposure to Mo and Cd, remain poorly understood and elusive. To fill the gap, a total of 24 sheep were stratified into two groups: control group and Mo + Cd group (45 mg Mo·kg⁻¹·B.W. and 1 mg Cd·kg⁻¹·B.W.). Results showed that exposure to Mo and Cd adversely co-induced the liver function related biochemical marker alterations in serum, histopathological abnormalities, mitochondrial ultrastructure damage and oxidative stress in the livers of sheep. Sequencing results from isolated mitochondria indicated that a total of approximately 4788 mitochondria-localized proteins were identified, of which 360 exhibited significant differential expression. GO and KEGG database analysis demonstrated excessive Mo and Cd primarily induced hepatotoxicity by affecting mitochondria-mediated oxidation-reduction processes, single-organism metabolic processes, and enhancing the TNF signaling pathway. Mo and Cd co-exposure increased the levels of mitophagy- and necroptosis- related factors regulated by PGAM5 in the livers. Consistently, our findings highlight the co-exposure of Mo and Cd induced necroptosis triggered by PGAM5-mediated mitophagy, which offers valuable insights into the toxicological mechanisms underlying the combined effects of Mo and Cd.

Phytochemical analysis, antioxidant activity and modulatory effect of aqueous leaf extract of Pistacia lentiscus L on oxaliplatin-induced oxidative stress in isolated rat liver mitochondria

This study evaluates the antioxidant effects of aqueous leaf extract of Pistacia lentiscus (ALEPL) and its potential to counteract oxaliplatin (OXA)-induced mitochondrial oxidative stress in rat livers, a common side effect of chemotherapy in cancer treatment. Bioactive compounds were identified using High-Performance Liquid Chromatography coupled with Tandem Mass Spectrometry (HPLC-MS and MS), with Fourier-Transform Infrared Spectroscopy (FTIR) and Atomic Absorption Spectrophotometry (AAS) for chemical and mineral analysis. ALEPL showed notable antioxidant activity, with IC50 values of 4.30 ± 0.27 μg/mL for DPPH (2,2-Diphenyl-1-picrylhydrazyl) scavenging, 13.64 ± 0.51 μg/mL for reducing power, 32.62 ± 5.32 μg/mL for hydroxyl radical scavenging, and 205.08 ± 25.77 μg/mL for superoxide anion radical scavenging. In ex vivo experiments, mitochondria isolated from Wistar rat livers were treated with OXA and ALEPL in a dose-dependent manner. ALEPL pretreatment effectively restored mitochondrial antioxidant enzyme activities, increased glutathione (GSH) levels, and reduced lipid peroxidation (MDA) caused by OXA. These findings suggest that ALEPL has the potential to act as a natural antioxidant to support cancer treatment by mitigating chemotherapy-induced oxidative stress. Future studies could explore its application as an adjuvant in clinical settings to enhance the efficacy of chemotherapy while reducing its side effects.

Myricetin Alleviates Silica-Mediated Lung Fibrosis via PPARγ-PGC-1α Loop and Suppressing Mitochondrial Senescence in Epithelial Cells.

Long-term inhalation of silica dust particles leads to lung tissue fibrosis, resulting in impaired gas exchange and increased mortality. Silica inhalation triggers the aging of epithelial cells (AECs), which is a key contributor to the development of pulmonary fibrosis. Myricetin, a flavonoid compound extracted from Myrica genus plants, possesses various biological activities, including antioxidant and immunomodulatory effects. However, the mechanisms underlying myricetin's ability to counter senescence and fibrosis need to be further studied. In vivo, the antifibrotic and anti-senescence effects of myricetin were evaluated using a silica-induced pulmonary fibrosis mouse model. To further elucidate the mechanisms by which myricetin counteracts silica-induced senescence, in vitro experiments were conducted using AECs. Our studies revealed that myricetin treatment alleviated silica-induced mortality, improved lung function, and reduced the severity of pulmonary fibrosis in mice. Immunofluorescence analysis suggests its potential in mitigating senescence of AECs. Under laboratory conditions, myricetin intervened in the cellular senescence pathway induced by silica dust by modulating mitochondrial function. It acted through the PPARγ-PGC1α axis, effectively reducing silica-induced mitochondrial oxidative stress in AECs, promoting mitophagy, and maintaining mitochondrial dynamics. However, the efficacy of myricetin was reversed under PPARγ siRNA intervention. Additionally, myricetin exhibited an enhancing effect on PPARγ and autophagy in animal models. Treatment with PPARγ and PGC-1α siRNA elucidated the role of myricetin in promoting the formation of a positive feedback loop between PPARγ and PGC-1α. Additionally, the PPARγ inhibitor GW9662 verified the in vivo effects of myricetin. Myricetin activates PPARγ, forming a PPARγ-PGC-1α loop, which promotes mitophagy and maintains mitochondrial dynamics. This alleviates epithelial cell senescence induced by silica exposure, consequently mitigating silica-induced pulmonary fibrosis in mice.

The Neural Palette of Heme: Altered Heme Homeostasis Underlies Defective Neurotransmission, Increased Oxidative Stress, and Disease Pathogenesis

Heme, a complex iron-containing molecule, is traditionally recognized for its pivotal role in oxygen transport and cellular respiration. However, emerging research has illuminated its multifaceted functions in the nervous system, extending beyond its canonical roles. This review delves into the diverse roles of heme in the nervous system, highlighting its involvement in neural development, neurotransmission, and neuroprotection. We discuss the molecular mechanisms by which heme modulates neuronal activity and synaptic plasticity, emphasizing its influence on ion channels and neurotransmitter receptors. Additionally, the review explores the potential neuroprotective properties of heme, examining its role in mitigating oxidative stress, including mitochondrial oxidative stress, and its implications in neurodegenerative diseases. Furthermore, we address the pathological consequences of heme dysregulation, linking it to conditions such as Alzheimer’s disease, Parkinson’s disease, and traumatic brain injuries. By providing a comprehensive overview of heme’s multifunctional roles in the nervous system, this review underscores its significance as a potential therapeutic target and diagnostic biomarker for various neurological disorders.