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Introduction: Oxidative stress has been identified as a major contributor to the pathogenesis of DR, and many diagnostic and therapeutic strategies have been developed to target oxidative stress. Our aim was to understand the contribution of the country of origin of the publication, the institution, the authors, and the collaborative relationship between them. Methods: We performed a bibliometric analysis to summarize and explore the research hotspots and trends of oxidative stress in the DR. Results: We observe an upward trend in the number of posts on related topics from year to year. Expanding on this, Queens University Belfast is the most influential research institution. Current research hotspots and trends focus on the mechanism of autophagy and NLRP3 inflammasome's role in oxidative stress in DR. Discussion: We conducted a multi-dimensional analysis of the research status of oxidative stress in diabetic retinopathy through bibliometric analysis, and proposed possible future research trends and hotspots.
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Retinopatía Diabética , Estrés Oxidativo , Estrés Oxidativo/fisiología , Humanos , Retinopatía Diabética/metabolismo , Retinopatía Diabética/epidemiología , Bibliometría , Investigación Biomédica/tendenciasRESUMEN
BACKGROUND: Intracranial aneurysm (IA) is a severe cerebrovascular disease, and effective gene therapy and drug interventions for its treatment are still lacking. Oxidative stress (OS) is closely associated with the IA, but the key regulatory genes involved are still unclear. Through multiomics analysis and experimental validation, we identified two diagnostic markers for IA associated with OS. METHODS: In this study, we first analyzed the IA dataset GSE75436 and conducted a joint analysis of oxidative stress-related genes (ORGs). Differential analysis, functional enrichment analysis, immune infiltration, WGCNA, PPI, LASSO, and other methods were used to identify IA diagnostic markers related to OS. Next, the functions of TLR4 and ALOX5 expression in IA and their potential targeted therapeutic drugs were analyzed. We also performed single-cell sequencing of patient IA and control (superficial temporal artery, STA) tissues. 23,342 cells were captured from 2 IA and 3 STA samples obtained from our center. Cell clustering and annotation were conducted using R software to observe the distribution of TLR4 and ALOX5 expression in IAs. Finally, the expression of TLR4 and ALOX5 were validated in IA patients and in an elastase-induced mouse IA model using experiments such as WB and immunofluorescence. RESULTS: Through bioinformatics analysis, we identified 16 key ORGs associated with IA pathogenesis. Further screening revealed that ALOX5 and TLR4 were highly expressed to activate a series of inflammatory responses and reduce the production of myocytes. Methotrexate (MTX) may be a potential targeted drug. Single-cell analysis revealed a notable increase in immune cells in the IA group, with ALOX5 and TLR4 primarily localized to monocytes/macrophages. Validation through patient samples and mouse models confirmed high expression of ALOX5 and TLR4 in IAs. CONCLUSIONS: Bioinformatics analysis indicated that ALOX5 and TLR4 are the most significant ORGs associated with the pathogenesis of IA. Single-cell sequencing and experiments revealed that the high expression of ALOX5 and TLR4 are closely related to IA. These two genes are promising new targets for IA therapy.
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Araquidonato 5-Lipooxigenasa , Biomarcadores , Aneurisma Intracraneal , Estrés Oxidativo , Receptor Toll-Like 4 , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 4/genética , Aneurisma Intracraneal/metabolismo , Aneurisma Intracraneal/genética , Animales , Ratones , Humanos , Estrés Oxidativo/fisiología , Araquidonato 5-Lipooxigenasa/metabolismo , Araquidonato 5-Lipooxigenasa/genética , Araquidonato 5-Lipooxigenasa/biosíntesis , Biomarcadores/metabolismo , Masculino , Ratones Endogámicos C57BL , Femenino , MultiómicaRESUMEN
AIMS: We aimed to resolve the uncertainty as to whether betulin exerted neuroprotection on early brain injury (EBI) caused by subarachnoid hemorrhage (SAH), and to investigate the related molecular mechanisms. METHODS: Bioinformatic analysis was performed to pre-study the differently expressed genes (DEGs) and the possible signaling pathways. Rat and cellular model of SAH were introduced in this study, and betulin, an activator of DJ-1 protein, was administered to reveal the effect. Gross assessment regarding mortality, neurofunctions, SAH grade, brain water content (BWC) along with multiple cellular and molecular studies in vivo or/and in vitro such as immunofluorescence (IF) staining, western blot (WB), reactive oxygen species (ROS) assay, and flow cytometry (FCM) were all conducted after SAH induction to verify the protective effect and the relevant mechanisms of DJ-1 in diverse levels. In addition, MK2206 (selective inhibitor of Akt) and iRNADj-1 (interfering RNA to Dj-1) were utilized to confirm the mechanisms of the effect. RESULTS: The data from our study showed that DJ-1 protein was moderately expressed in neurons, microglia, and astrocytes; its level in brain tissue elevated and peaked at 24-72 h after SAH induction. Betulin could efficaciously induce the expression of DJ-1 which in turn activated Akt and Bcl-2, and anti-oxidative enzymes SOD2 and HO-1, functioning to reduce the activation of cleaved caspase-3 (c-Casp-3) and reactive oxygen species (ROS). The induced DJ-1 could upregulate the expression of Nrf2. However, Akt seemed no direct effect on elevating the expression of Nrf2. DJ-1 alone could as well activate Akt-independent antiapoptotic pathway via suppressing the activation of caspase-8 (Casp-8). CONCLUSIONS: Betulin which was a potent agonist of DJ-1 had the ability to induce its expression in brain tissue. DJ-1 had neuroprotective effect on EBI through comprehensive mechanisms, including facilitating intrinsic and extrinsic antiapoptotic pathway, and reducing oxidative injury by upregulating the expression of redox proteins. Betulin as an inexpensive drug showed the potential for SAH treatment.
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Apoptosis , Factor 2 Relacionado con NF-E2 , Neuronas , Estrés Oxidativo , Proteína Desglicasa DJ-1 , Proteínas Proto-Oncogénicas c-akt , Ratas Sprague-Dawley , Transducción de Señal , Hemorragia Subaracnoidea , Triterpenos , Hemorragia Subaracnoidea/metabolismo , Hemorragia Subaracnoidea/tratamiento farmacológico , Hemorragia Subaracnoidea/patología , Animales , Proteína Desglicasa DJ-1/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Ratas , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Apoptosis/efectos de los fármacos , Triterpenos/farmacología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Masculino , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fármacos Neuroprotectores/farmacología , Especies Reactivas de Oxígeno/metabolismo , Ácido BetulínicoRESUMEN
Context Sires differ in their ability to produce viable blastocysts, yet our understanding of the cellular mechanisms regulated by the sire during early embryo development is limited. Aims The first aim was to characterise autophagy and reactive oxygen species (ROS) in embryos produced by high and low performing sires under normal and stress culture conditions. The second aim was to evaluate DNA damage and lipid peroxidation as mechanisms that may be impacted by increased cellular stress, specifically oxidative stress. Methods Embryos were produced using four high and four low performing sires based on their ability to produce embryos. Autophagy and ROS were measured throughout development. To evaluate oxidative stress response, autophagy, and ROS were measured in 2-6 cell embryos exposed to heat stress. To understand how cellular stress impacts development, DNA damage and lipid peroxidation were assessed. Key results Under normal conditions, embryos from low performing sires had increased ROS and autophagy. Under heat stress, embryos from low performing sires had increased ROS, yet those from high performing sires had increased autophagy. There was no difference in DNA damage or lipid peroxidation. Conclusions Results suggest that embryos from low performing sires may begin development under increased cellular stress, and autophagy potentially increases to mitigate the impacts of stress. Implications There is potential for improving embryonic competence through selection of sires with lower stress-related markers.
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Autofagia , Daño del ADN , Desarrollo Embrionario , Peroxidación de Lípido , Estrés Oxidativo , Especies Reactivas de Oxígeno , Animales , Bovinos , Especies Reactivas de Oxígeno/metabolismo , Estrés Oxidativo/fisiología , Peroxidación de Lípido/fisiología , Autofagia/fisiología , Desarrollo Embrionario/fisiología , Femenino , Masculino , Blastocisto/metabolismo , Técnicas de Cultivo de Embriones/veterinaria , Fertilización In Vitro/veterinaria , Embarazo , Estrés Fisiológico/fisiologíaRESUMEN
Xi-Kun Yuan Pin-Shi Ni Zhen-Hao Yan Zhi Yu Zhuang-Zhi Wang Chen-Kai Zhang Fang-Hui Li Xiao-Ming Yu 1Sports Department, Nanjing University of Science and Technology ZiJin College, Nanjing, China, 2School of Sport Sciences, Nanjing Normal University, Nanjing, China, 3Shanghai Seventh People's Hospital, Shanghai, China To investigate the effects of life-long exercise (LLE) on age-related inflammatory cytokines, apoptosis, oxidative stress, ferroptosis markers, and the NRF2/KAEP 1/Klotho pathway in rats. Eight-month-old female Sprague-Dawley rats were divided into four groups: 1) LLE: 18-month LLE training starting at 8 months of age, 2) Old moderate-intensity continuous training (OMICT): 8 months of moderate-intensity continuous training starting at 18 months of age, 3) Adult sedentary (ASED): 8 month-old adult sedentary control group, and 4) Old sedentary (OSED): a 26-month-old sedentary control group. Hematoxylin eosin staining was performed to observe the pathological changes of kidney tissue injury in rats; Masson's staining to observe the deposition of collagen fibers in rat kidney tissues; and western blotting to detect the expression levels of IL-6, IL 1beta, p53, p21, TNF-alpha, GPX4, KAEP 1, NRF2, SLC7A11, and other proteins in kidney tissues. Results: Compared with the ASED group, the OSED group showed significant morphological changes in renal tubules and glomeruli, which were swollen and deformed, with a small number of inflammatory cells infiltrated in the tubules. Compared with the OSED group, the expression levels of inflammation-related proteins such as IL-1beta, IL-6, TNF alpha, and MMP3 were significantly lower in the LLE group. Quantitative immunofluorescence analysis and western blotting revealed that compared with the ASED group, KAEP 1 protein fluorescence intensity and protein expression levels were significantly enhanced, while Klotho and NRF2 protein fluorescence intensity and protein expression levels were reduced in the OSED group. Compared with the OSED group, KAEP 1 protein fluorescence intensity and protein expression levels were reduced in the LLE and OMICT groups. Klotho and KAEP 1 protein expression levels and immunofluorescence intensity were higher in the LLE group than in the OSED group. The expression levels of GPX4 and SLC7A11, two negative marker proteins associated with ferroptosis, were significantly higher in the LLE group than in the OSED group, while the expression of p53 a cellular senescence-associated protein that negatively regulates SLC7A11, and the downstream protein p21 were significantly decreased. LLE may ameliorated aging-induced oxidative stress, inflammatory response, apoptosis, and ferroptosis by regulating Klotho and synergistically activating the NRF2/KAEP 1 pathway. Keywords: Life-long exercise, Moderate intensity continuous training, Aging, Kidney tissue, Ferroptosis.
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Apoptosis , Ferroptosis , Riñón , Proteínas Klotho , Factor 2 Relacionado con NF-E2 , Estrés Oxidativo , Condicionamiento Físico Animal , Ratas Sprague-Dawley , Animales , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/fisiología , Femenino , Apoptosis/fisiología , Ratas , Ferroptosis/fisiología , Riñón/metabolismo , Riñón/patología , Condicionamiento Físico Animal/fisiología , Envejecimiento/metabolismo , Envejecimiento/patología , Inflamación/metabolismo , Inflamación/patología , Transducción de Señal/fisiología , Glucuronidasa/metabolismo , Biomarcadores/metabolismoRESUMEN
BACKGROUND: The relationship between neurotransmitters and oxidative stress in Major Depressive Disorder (MDD) patients, considering HPA axis activity and psychological and cognitive states, is unclear. This study examines changes in neurotransmitters (GABA, Glx) and antioxidants (GSH) in the dorsal anterior cingulate cortex (dACC) of MDD patients under varying levels of ACTH, and their relationship with psychological and cognitive conditions. METHODS: Forty-five MDD patients were divided into high-ACTH (>65 pg/mL; n = 16) and normal-ACTH (7-65 pg/mL; n = 29) groups based on blood ACTH levels, along with 12 healthy controls (HC). All participants underwent HAM-D, HAM-A assessments, and most completed MMSE and MoCA tests. GABA+, Glx, and GSH levels in the dACC were measured using the MEGA-PRESS sequence. Intergroup differences and correlations between clinical factors, HPA axis activity, and metabolites were analyzed. RESULTS: Compared to HC, the normal ACTH group showed higher Glx and lower GSH levels. Glx and GSH were negatively correlated with MDD severity. In the high-ACTH MDD group, Glx positively correlated with delayed memory, and GSH positively correlated with abstraction. Factors influencing GABA included ACTH levels, depression duration, and negative events. Predictive factors for HAM-D scores were GSH and GABA. LIMITATIONS: The sample size is small. CONCLUSION: MDD patients exhibit neurochemical differences in the brain related to HPA axis levels, MDD severity, and cognitive function. Clinical factors, neurotransmitters, and neuroendocrine levels significantly influence depression severity.
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Hormona Adrenocorticotrópica , Antioxidantes , Trastorno Depresivo Mayor , Giro del Cíngulo , Neurotransmisores , Ácido gamma-Aminobutírico , Humanos , Trastorno Depresivo Mayor/sangre , Trastorno Depresivo Mayor/metabolismo , Trastorno Depresivo Mayor/fisiopatología , Hormona Adrenocorticotrópica/sangre , Femenino , Masculino , Adulto , Antioxidantes/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Ácido gamma-Aminobutírico/sangre , Persona de Mediana Edad , Neurotransmisores/sangre , Neurotransmisores/metabolismo , Giro del Cíngulo/metabolismo , Glutatión/sangre , Glutatión/metabolismo , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipotálamo-Hipofisario/fisiopatología , Sistema Hipófiso-Suprarrenal/metabolismo , Sistema Hipófiso-Suprarrenal/fisiopatología , Estrés Oxidativo/fisiología , Estudios de Casos y ControlesRESUMEN
Autism spectrum disorders (ASD) are highly heterogeneous neurodevelopmental diseases. Epidemiological data report that males have been diagnosed with autism more frequently than females. However, recent studies hypothesize that females' low incidence might be underestimated due to standard clinical measures of ASD behavioural symptoms, mostly derived from males. Indeed, up to now, ASD mouse models focused mainly on males, considering the prevalence of the diagnosis in that sex. Regarding ASD aetiopathogenesis, it has been recently reported that oxidative stress might be implicated in its onset and development, suggesting an association with ASD typical repetitive behaviours that still need to be disentangled. Here, we investigated possible behavioural and molecular sex-related differences by using the BTBR mouse model of idiopathic ASD. To this aim, animals were exposed to behavioural tests related to different ASD core symptoms and comorbidities, i.e. stereotyped repertoire, social dysfunctions, hyperlocomotion and risk-taking behaviours. Moreover, we analyzed hippocampal levels of pro-oxidant and anti-oxidant enzymes, together with biomarkers of oxidative stress and lipid peroxidation. Our results showed that BTBR females did not display the same patterns for repetitive behaviours as the male counterpart. From a biomolecular point of view, we found an increase in oxidative stress and pro-oxidant enzymes, accompanied by deficient enzymatic anti-oxidant response, only in BTBR males compared to C57BL/6 male mice, while no differences were retrieved in females. Overall, our study suggests that in females there is an urgent need to depict the distinct ASD symptomatology, accompanied by the identification of sex-specific pharmacological targets.
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Trastorno del Espectro Autista , Modelos Animales de Enfermedad , Hipocampo , Estrés Oxidativo , Caracteres Sexuales , Animales , Trastorno del Espectro Autista/metabolismo , Hipocampo/metabolismo , Femenino , Masculino , Ratones , Estrés Oxidativo/fisiología , Conducta Estereotipada/fisiología , Conducta Estereotipada/efectos de los fármacos , Oxidación-Reducción , Conducta Animal/fisiología , Ratones Endogámicos C57BL , Peroxidación de Lípido/fisiología , Asunción de RiesgosRESUMEN
Glutathione peroxidase-1 (GPx1) and cAMP/Ca2+ responsive element (CRE)-binding protein (CREB) regulate neuronal viability by maintaining the redox homeostasis. Since GPx1 and CREB reciprocally regulate each other, it is likely that GPx1-CREB interaction may play a neuroprotective role against oxidative stress, which are largely unknown. Thus, we investigated the underlying mechanisms of the reciprocal regulation between GPx1 and CREB in the male rat hippocampus. Under physiological condition, L-buthionine sulfoximine (BSO)-induced oxidative stress increased GPx1 expression, extracellular signal-regulated kinase 1/2 (ERK1/2) activity and CREB serine (S) 133 phosphorylation in CA1 neurons, but not dentate granule cells (DGC), which were diminished by GPx1 siRNA, U0126 or CREB knockdown. GPx1 knockdown inhibited ERK1/2 and CREB activations induced by BSO. CREB knockdown also decreased the efficacy of BSO on ERK1/2 activation. BSO facilitated dynamin-related protein 1 (DRP1)-mediated mitochondrial fission in CA1 neurons, which abrogated by GPx1 knockdown and U0126. CREB knockdown blunted BSO-induced DRP1 upregulation without affecting DRP1 S616 phosphorylation ratio. Following status epilepticus (SE), GPx1 expression was reduced in CA1 neurons and DGC. SE also decreased CREB activity CA1 neurons, but not DGC. SE degenerated CA1 neurons, but not DGC, accompanied by mitochondrial elongation. These post-SE events were ameliorated by N-acetylcysteine (NAC, an antioxidant), but deteriorated by GPx1 knockdown. These findings indicate that a transient GPx1-ERK1/2-CREB activation may be a defense mechanism to protect hippocampal neurons against oxidative stress via maintenance of proper mitochondrial dynamics.
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Proteína de Unión a Elemento de Respuesta al AMP Cíclico , Glutatión Peroxidasa GPX1 , Glutatión Peroxidasa , Hipocampo , Sistema de Señalización de MAP Quinasas , Dinámicas Mitocondriales , Neuronas , Estrés Oxidativo , Ratas Sprague-Dawley , Estado Epiléptico , Animales , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Masculino , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Glutatión Peroxidasa/metabolismo , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/patología , Dinámicas Mitocondriales/efectos de los fármacos , Dinámicas Mitocondriales/fisiología , Estado Epiléptico/inducido químicamente , Estado Epiléptico/metabolismo , Estado Epiléptico/patología , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Ratas , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/fisiologíaRESUMEN
Alzheimer's disease (AD) is a degenerative brain disease that affects millions of people worldwide. It is caused by abnormalities in cholinergic neurons, oxidative stress, and inflammatory cascades. The illness is accompanied by personality changes, memory issues, and dementia. Metabolic signaling pathways help with fundamental processes like DNA replication and RNA transcription. Being adaptable is essential for both surviving and treating illness. The body's metabolic signaling depends on adipokines, including adiponectin (APN) and other adipokines secreted by adipose tissues. Energy homeostasis is balanced by adipokines, and nutrients. Overconsumption of nutrients messes with irregular signaling of adipokines, such as APN in both peripheral and brain which leads to neurodegeneration, such as AD. Despite the failure of traditional treatments like memantine and cholinesterase inhibitors, natural plant bioactive substances like Osmotin (OSM) have been given a focus as potential therapeutics due to their antioxidant properties, better blood brain barrier (BBB) permeability, excellent cell viability, and especially nanoparticle approaches. The review highlights the published preclinical literature regarding the role of OSM in AD pathology while there is a need for more research to investigate the hidden therapeutic potential of OSM which may open a new gateway and further strengthen its healing role in the pathogenesis of neurodegeneration, especially AD.
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Adiponectina , Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Animales , Adiponectina/metabolismo , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiologíaRESUMEN
Diabetic encephalopathy (DE), a significant micro-complication of diabetes, manifests as neurochemical, structural, behavioral, and cognitive alterations. This condition is especially dangerous for the elderly because aging raises the risk of neurodegenerative disorders and cognitive impairment, both of which can be made worse by diabetes. Despite its severity, diagnosis of this disease is challenging, and there is a paucity of information on its pathogenesis. The pivotal roles of various cellular pathways, activated or influenced by hyperglycemia, insulin sensitivity, amyloid accumulation, tau hyperphosphorylation, brain vasculopathy, neuroinflammation, and oxidative stress, are widely recognized for contributing to the potential causes of diabetic encephalopathy. We also reviewed current pharmacological strategies for DE encompassing a comprehensive approach targeting metabolic dysregulations and neurological manifestations. Antioxidant-based therapies hold promise in mitigating oxidative stress-induced neuronal damage, while anti-diabetic drugs offer neuroprotective effects through diverse mechanisms, including modulation of insulin signaling pathways and neuroinflammation. Additionally, tissue engineering and nanomedicine-based approaches present innovative strategies for targeted drug delivery and regenerative therapies for DE. Despite significant progress, challenges remain in translating these therapeutic interventions into clinical practice, including long-term safety, scalability, and regulatory approval. Further research is warranted to optimize these approaches and address remaining gaps in the management of DE and associated neurodegenerative disorders.
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Hipoglucemiantes , Humanos , Animales , Hipoglucemiantes/uso terapéutico , Complicaciones de la Diabetes/terapia , Complicaciones de la Diabetes/metabolismo , Estrés Oxidativo/fisiología , Encefalopatías/terapia , Encefalopatías/etiología , Encefalopatías/metabolismoRESUMEN
Globally, marine heatwave frequency, intensity, and duration are on the rise, posing a significant threat to plankton communities, the foundational elements of the marine food web. This study investigates the ecological and physiological responses of a temperate plankton community in the Thau lagoon, north-western Mediterranean, to a simulated +3°C ten-day heatwave followed by a ten-day post-heatwave period in in-situ mesocosms. Our analyses encompassed zooplankton grazing, production, community composition in water and sediment traps, as well as oxidative stress and anti-oxidant biomarkers. The results revealed increased abundances of harpacticoid copepods and polychaete larvae during the simulated heatwave and post-heatwave event. Sediment trap data indicated elevated mortality, particularly dominated by polychaete larvae during the post-heatwave period. Oxidative stress biomarker (lipid peroxidation LPX) levels in the plankton community correlated with temperature, signaling cellular damage during the heatwave. LPX increased and proteins decreased with increasing salinity during the experiment. Offspring production peaked during the post-heatwave phase. Notably, the calanoid copepod Acartia clausi exhibited a preference for ciliates as its primary prey, constituting 20% of the overall available prey. Our findings suggest a potential shift in coastal zooplankton communities during future marine heatwaves, transitioning from calanoid mesozooplankton dominance to a system featuring meroplankton and/or harpacticoid copepods. Although species preying on microzooplankton may gain advantages in such conditions, the study underscores the damaging impact of heatwaves on organismal lipids, with potential consequences for reproduction, growth, and survival within marine ecosystems.
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Estrés Oxidativo , Zooplancton , Animales , Zooplancton/fisiología , Mar Mediterráneo , Estrés Oxidativo/fisiología , Copépodos/fisiología , Cadena Alimentaria , Ecosistema , Peroxidación de Lípido , Biomarcadores , Calor ExtremoRESUMEN
Traumatic brain injuries are extremely common, and although most patients recover from their injuries many TBI patients suffer prolonged symptoms and remain at a higher risk for developing cardiovascular disease and neurodegeneration. Moreover, it remains challenging to identify predictors of poor long-term outcomes. Here, we tested the hypothesis that preexisting cerebrovascular impairment exacerbates metabolic and vascular dysfunction and leads to worse outcomes after TBI. Male mice underwent a mild surgical reduction in cerebral blood flow using a model of bilateral carotid artery stenosis (BCAS) wherein steel microcoils were implanted around the carotid arteries. Then, 30 days post coil implantation, mice underwent TBI or sham surgery. Gene expression profiles, cerebral blood flow, metabolic function, oxidative damage, vascular health and angiogenesis were assessed. Single nuclei RNA sequencing of endothelial cells isolated from mice after TBI showed differential gene expression profiles after TBI and BCAS, that were further altered when mice underwent both challenges. TBI but not BCAS increased mitochondrial oxidative metabolism. Both BCAS and TBI decreased cerebrovascular responses to repeated whisker stimulation. BCAS induced oxidative damage and inflammation in the vasculature as well as loss of vascular density, and reduced the numbers of angiogenic tip cells. Finally, intravascular protein accumulation was increased among mice that experienced both BCAS and TBI. Overall, our findings reveal that a prior vascular impairment significantly alters the profile of vascular health and function of the cerebrovasculature, and when combined with TBI may result in worsened outcomes.
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Lesiones Traumáticas del Encéfalo , Circulación Cerebrovascular , Ratones Endogámicos C57BL , Animales , Ratones , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/patología , Lesiones Traumáticas del Encéfalo/fisiopatología , Masculino , Circulación Cerebrovascular/fisiología , Estenosis Carotídea/complicaciones , Estrés Oxidativo/fisiologíaRESUMEN
PURPOSE: The epithelial-mesenchymal transition of human lens epithelial cells plays a role in posterior capsule opacification, a fibrotic process that leads to a common type of cataract. Hyaluronic acid has been implicated in this fibrosis. Studies have investigated the role of transforming growth factor (TGF)-ß2 in epithelial-mesenchymal transition. However, the role of TGF-ß2 in hyaluronic acid-mediated fibrosis of lens epithelial cell remains unknown. We here examined the role of TGF-ß2 in the hyaluronic acid-mediated epithelial-mesenchymal transition of lens epithelial cells. METHODS: Cultured human lens epithelial cells (HLEB3) were infected with CD44-siRNA by using the Lipofectamine 3000 transfection reagent. The CCK-8 kit was used to measure cell viability, and the scratch assay was used to determine cell migration. Cell oxidative stress was analyzed in a dichloro-dihydro-fluorescein diacetate assay and by using a flow cytometer. The TGF-ß2 level in HLEB3 cells was examined through immunohistochemical staining. The TGF-ß2 protein level was determined through western blotting. mRNA expression levels were determined through quantitative real-time polymerase chain reaction. RESULTS: Treatment with hyaluronic acid (1.0 µM, 24 h) increased the epithelial-mesenchymal transition of HLEB3 cells. The increase in TGF-ß2 levels corresponded to an increase in CD44 levels in the culture medium. However, blocking the CD44 function significantly reduced the TGF-ß2-mediated epithelial-mesenchymal transition response of HLEB3 cells. CONCLUSIONS: Our study showed that both CD44 and TGF-ß2 are critical contributors to the hyaluronic acid-mediated epithelial-mesenchymal transition of lens epithelial cells, and that TGF-ß2 in epithelial-mesenchymal transition is regulated by CD44. These results suggest that CD44 could be used as a target for preventing hyaluronic acid-induced posterior capsule opacification. Our findings suggest that CD44/TGF-ß2 is crucial for the hyaluronic acid-induced epithelial-mesenchymal transition of lens epithelial cells.
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Movimiento Celular , Células Epiteliales , Transición Epitelial-Mesenquimal , Receptores de Hialuranos , Ácido Hialurónico , Cristalino , Factor de Crecimiento Transformador beta2 , Humanos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/fisiología , Ácido Hialurónico/farmacología , Receptores de Hialuranos/metabolismo , Factor de Crecimiento Transformador beta2/farmacología , Factor de Crecimiento Transformador beta2/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Cristalino/citología , Cristalino/efectos de los fármacos , Cristalino/metabolismo , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Western Blotting , Opacificación Capsular/metabolismo , Opacificación Capsular/patología , Reacción en Cadena en Tiempo Real de la Polimerasa , Citometría de Flujo , Inmunohistoquímica , Células CultivadasRESUMEN
BACKGROUND: Status epilepticus is a common and potentially life-threatening neurological emergency with a high risk for cognitive and neurobiological impairment. Our aim was to evaluate the neuroprotective effects of centrally administered irisin and acute exhausting exercise against oxidative brain injury and memory dysfunction due to a pentylenetetrazole (PTZ)-induced single seizure. Male Sprague Dawley rats with intracerebroventricular (icv) cannulas were randomly divided into intraperitoneally (ip) saline-injected control and PTZ-injected (45 mg/kg) seizure groups. Both the control and PTZ groups were then treated with irisin (7.5 µg/kg, 2 µl, icv), saline (2 µl, icv) or were forced to an acute bout of strenuous exercise before the ip injection of saline (control) or PTZ. Seizures were evaluated using the Racine score. To evaluate memory performance, a passive avoidance test was performed before and after PTZ injection. Following euthanasia at the 24th hour of seizure induction, brain tissues were removed for histopathological examination and for evaluating oxidative damage, antioxidant capacity, and neurotransmitter levels. RESULTS: Glutamate/GABA imbalance observed in PTZ rats was corrected by irisin administration (p < 0.001/p < 0.01), while irisin prevented the generation of reactive oxygen species and lipid peroxidation (p < 0.05 - 0.001) and replenished the antioxidant catalase and glutathione levels (p < 0.01-0.01) in the cerebral tissue, and reduced the histologically evident neuronal injury due to a single seizure (p < 0.05 - 0.01). Irisin also delayed the onset of seizures (p < 0.05) and improved memory dysfunction (p < 0.05), but did not affect the severity of seizures. The acute exhaustive swimming exercise completed before PTZ-seizure depressed glutamate level (p < 0.001), maintained the oxidant/antioxidant balance, alleviated neuronal injury (p < 0.05 - 0.01) and upregulated cerebral BDNF expression (p < 0.05). CONCLUSION: In conclusion, acute high-intensity exercise or exogenously administered irisin provides neuroprotection by maintaining the balance of excitatory/inhibitory neurotransmitters and oxidant/antioxidant systems.
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Fibronectinas , Trastornos de la Memoria , Pentilenotetrazol , Condicionamiento Físico Animal , Ratas Sprague-Dawley , Convulsiones , Animales , Masculino , Trastornos de la Memoria/etiología , Condicionamiento Físico Animal/fisiología , Condicionamiento Físico Animal/métodos , Fibronectinas/metabolismo , Fibronectinas/administración & dosificación , Ratas , Enfermedades Neuroinflamatorias , Epilepsia , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/administración & dosificación , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiologíaRESUMEN
Varicocele can reduce male fertility potential through various oxidative stress mechanisms. Excessive production of reactive oxygen species may overwhelm the sperm's defenses against oxidative stress, damaging the sperm chromatin. Sperm DNA fragmentation, in the form of DNA strand breaks, is recognized as a consequence of the oxidative stress cascade and is commonly found in the ejaculates of men with varicocele and fertility issues. This paper reviews the current knowledge regarding the association between varicocele, oxidative stress, sperm DNA fragmentation, and male infertility, and examines the role of varicocele repair in alleviating oxidative-sperm DNA fragmentation in these patients. Additionally, we highlight areas for further research to address knowledge gaps relevant to clinical practice.
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Fragmentación del ADN , Infertilidad Masculina , Estrés Oxidativo , Espermatozoides , Varicocele , Humanos , Masculino , Varicocele/fisiopatología , Varicocele/complicaciones , Estrés Oxidativo/fisiología , Infertilidad Masculina/etiología , Infertilidad Masculina/genética , Infertilidad Masculina/fisiopatología , Infertilidad Masculina/metabolismo , Espermatozoides/fisiología , Espermatozoides/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Neurodegenerative diseases (NDDs) are an increasing group of chronic and progressive neurological disorders that ultimately lead to neuronal cell failure and death. Despite all efforts throughout decades, their burden on individuals and society still casts one of the most massive socioeconomic problems worldwide. The neuronal failure observed in NDDs results from an intricacy of events, mirroring disease complexity, ranging from protein aggregation, oxidative stress, (neuro)inflammation, and even blood-brain barrier (BBB) dysfunction, ultimately leading to cognitive and motor symptoms in patients. As a result of such complex pathobiology, to date, there are still no effective treatments to treat/halt NDDs progression. Fortunately, interest in the bioavailable low molecular weight (LMW) phenolic metabolites derived from the metabolism of dietary (poly)phenols has been rising due to their multitargeted potential in attenuating multiple NDDs hallmarks. Even if not highly BBB permeant, their relatively high concentrations in the bloodstream arising from the intake of (poly)phenol-rich diets make them ideal candidates to act within the vasculature and particularly at the level of BBB. In this review, we highlight the most recent - though still scarce - studies demonstrating LMW phenolic metabolites' ability to modulate BBB homeostasis, including the improvement of tight and adherens junctional proteins, as well as their power to decrease pro-inflammatory cytokine secretion and oxidative stress levels in vitro and in vivo. Specific BBB-permeant LMW phenolic metabolites, such as simple phenolic sulfates, have been emerging as strong BBB properties boosters, pleiotropic compounds capable of improving cell fitness under oxidative and pro-inflammatory conditions. Nevertheless, further studies should be pursued to obtain a holistic overview of the promising role of LMW phenolic metabolites in NDDs prevention and management to fully harness their true therapeutic potential.
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Barrera Hematoencefálica , Polifenoles , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Humanos , Animales , Polifenoles/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/tratamiento farmacológico , Peso Molecular , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/metabolismo , Fenoles/metabolismo , Fenoles/farmacología , Estrés Oxidativo/fisiología , Estrés Oxidativo/efectos de los fármacosRESUMEN
Transthyretin (ATTR) amyloidosis constitutes a spectrum of debilitating neurodegenerative diseases instigated by systemic extracellular deposition of partially unfolded/aggregated aberrant transthyretin. The homotetrameric protein, TTR, is abundant in the plasma, and to a lesser extent the cerebrospinal fluid. Rate-limiting tetramer dissociation of the native protein is regarded as the critical step in the formation of morphologically heterogenous toxic aggregates and the onset of clinical manifestations such as polyneuropathy, cardiomyopathy, disturbances in motor and autonomic functions. Over the past few decades there has been increasing evidence suggesting that in addition to destabilization in TTR tetramer structure, oxidative stress may also play an important role in the pathogenesis of ATTR amyloidosis. In this review, an update on the impact of oxidative stress in TTR amyloidogenesis as well as TTR aggregate-mediated pathologies is discussed. The counteracting effects of antioxidants and nutraceutical agents explored in the treatment of ATTR amyloidosis based on recent evidence is also critically examined. The insights unveiled could further strengthen current understanding of the mechanisms underlying ATTR amyloidosis as well as extend the range of strategies for effective management of ATTR amyloidoses.
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Neuropatías Amiloides Familiares , Antioxidantes , Suplementos Dietéticos , Estrés Oxidativo , Prealbúmina , Humanos , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Antioxidantes/uso terapéutico , Antioxidantes/farmacología , Neuropatías Amiloides Familiares/tratamiento farmacológico , Neuropatías Amiloides Familiares/metabolismo , Prealbúmina/metabolismo , AnimalesRESUMEN
Fluorosis is a global public health concern. Prolonged exposure to excessive fluoride causes fluoride accumulation in the hippocampus, resulting in cognitive dysfunction. Cell death is necessary for maintaining tissue function and morphology, and changes in the external morphology of nerve cells and the function of many internal organelles are typical features of cell death; however, it is also a typical feature of cognitive impairment caused by fluorosis. However, the pathogenesis of cognitive impairment caused by different degrees of fluoride exposure varies. Herein, we provide an overview of cognitive impairment caused by excessive fluoride exposure in different age groups, and the underlying mechanisms for cognitive impairment in various model organisms. The mechanisms underlying these impairments include oxidative stress, synaptic and neurotransmission dysfunction, disruption of mitochondrial and energy metabolism, and calcium channel dysregulation. This study aims to provide potential insights that serve as a reference for subsequent research on the cognitive function caused by excessive fluoride.
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Disfunción Cognitiva , Fluoruros , Animales , Humanos , Fluoruros/toxicidad , Fluoruros/efectos adversos , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/metabolismo , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiologíaRESUMEN
Intermittent hypoxia (IH) in patients with obstructive sleep apnea (OSA) syndrome elicited neuron injury (especially in the hippocampus and cortex), contributing to cognitive dysfunction. This study investigated the effects and clarified the mechanisms of ETS domain-containing protein Elk-4 (ELK4) on the cognitive function and neuroinflammation of mice with IH. Mouse microglia BV2 cells were induced with IH by exposure to fluctuating O2 concentrations (alternating from 5â¯% to 21â¯% every 30â¯min), and mice with OSA were developed and subjected to lentivirus-mediated gene intervention. ELK4 expression was significantly reduced in IH-induced microglia and brain tissues of mice with OSA. Overexpression of ELK4 attenuated oxidative stress, decreased the pro-inflammatory factors IL-1ß, IL-6, and TNF-α, and increased the level of the anti-inflammatory factors IL-10 and TGF-ß1, as well as the neuroprotective factor BDNF. ELK4 promoted the transcription of fibronectin type III domain-containing protein 5 (FNDC5) by binding to the promoter of FNDC5. Knockdown of FNDC5 in IH-induced microglia and animals reversed the protective effects of ELK4 on OSA-associated neuroinflammation and cognitive dysfunction. Overall, the results demonstrated that ELK4 overexpression repressed microglial activation by inducing the transcription of FNDC5, thus attenuating neuroinflammation and cognitive dysfunction induced by OSA.