Free Radical Biology and Medicine最新文献

{"title":"A critical role for microglia in regulating metabolic homeostasis and neural repair after spinal cord injury","authors":"","doi":"10.1016/j.freeradbiomed.2024.10.288","DOIUrl":"10.1016/j.freeradbiomed.2024.10.288","url":null,"abstract":"<div><div>Traumatic spinal cord injury (SCI) often results in severe immune and metabolic disorders, aggravating neurological damage and inhibiting locomotor functional recovery. Microglia, as resident immune cells of the spinal cord, play crucial roles in maintaining neural homeostasis under physiological conditions. However, the precise role of microglia in regulating immune and metabolic functions in SCI is still unclear and is easily confused with that of macrophages. In this study, we pharmacologically depleted microglia to explore the role of microglia after SCI. We found that microglia are beneficial for the recovery of locomotor function. Depleting microglia disrupted glial scar formation, reducing neurogenesis and angiogenesis. Using liquid chromatography tandem mass spectrometry (LC‒MS/MS), we discovered that depleting microglia significantly inhibits lipid metabolism processes such as fatty acid degradation, unsaturated fatty acid biosynthesis, glycophospholipid metabolism, and sphingolipid metabolism, accompanied by the accumulation of multiple organic acids. Subsequent studies demonstrated that microglial depletion increased the inhibition of FASN after SCI. FASN inhibition exacerbated malonyl-CoA accumulation and significantly impeded the activity of mTORC1. Moreover, microglial depletion exacerbated the oxidative stress of neurons. In summary, our results indicate that microglia alleviate neural damage and metabolic disorders after SCI, which is beneficial for achieving optimal neuroprotection and neural repair.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CREBRF regulates apoptosis and estradiol via ISG15/ISGylation in pig granulosa cells","authors":"","doi":"10.1016/j.freeradbiomed.2024.10.287","DOIUrl":"10.1016/j.freeradbiomed.2024.10.287","url":null,"abstract":"<div><div>Granulosa cells play a crucial role in the reproductive processes of female animals, as their proliferation, apoptosis, and hormonal secretion are vital for follicular development and ovulation. Although the role and mechanisms of CREBRF in the reproductive system have been partly reported, its functions in ovarian granulosa cells have not been fully explored. In this study, the results indicated that the expression of CREBRF in the ovaries at 30 days after birth was significantly higher than that during puberty and sexual maturity. Studies on the function of CREBRF found that CREBRF could enhance the synthesis of estradiol and had no effect on progesterone synthesis in pig granulosa cells. At the same time, CREBRF could suppress apoptosis through the Bax/caspase3/caspase9 pathway and modulation of ISG15/ISGylation in pig granulosa cells. During this process, the expression of many genes changed in granulosa cells. Several genes (CMPK2, MX1, MX2, ZBP1, PML, CHAC1, and BAX) which were promoted apoptosis, were upregulated after CREBRF knockdown with siRNA. ISG15-protein conjugation genes (HERC5, UBA7, UBE2L6, ISG15) were also were upregulated. On the contrary, the expression of anti-apoptotic (RFK, SNAP23) genes decreased. In conclusion, CREBRF could enhance the synthesis of estradiol and acted as anti-apoptosis role in pig granulosa cells. This discovery can provide novel insights for further elucidating the molecular mechanisms of granulosa cells in the ovary and potentially identifies CREBRF as a molecular target for improving fertility.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nox4 is involved in acute kidney injury associated to intravascular hemolysis","authors":"","doi":"10.1016/j.freeradbiomed.2024.10.283","DOIUrl":"10.1016/j.freeradbiomed.2024.10.283","url":null,"abstract":"<div><div>Massive intravascular hemolysis occurs not unfrequently in many clinical conditions. Breakdown of erythrocytes promotes the accumulation of heme-derivates in the kidney, increasing oxidative stress and cell death, thus promoting acute kidney injury (AKI). NADPH oxidase 4 (Nox4) is a major source of reactive oxygen species (ROS) in the kidney, however it is unknown the role of Nox4 in hemolysis and whether inhibition of this enzyme may protect from heme-mediated injury. To answer these questions, we elicited intravascular hemolysis in <em>wild type</em> and Nox4 <em>knockout</em> mice. We also evaluated whether nephrotoxic effects of heme may be reduced by using Nox4 siRNA and pharmacologic inhibition with GKT137831, a Nox4 inhibitor, both <em>in vivo</em> and in cultured renal cells. Our results showed that induction of massive hemolysis elicited AKI characterized by loss of renal function, morphological alterations of the tubular epithelium and podocytes, oxidative stress, inflammation, mitochondrial dysfunction, blockade of autophagy and cell death. These pathological effects were significantly prevented in Nox4-deficient mice and in animals treated with GKT137831. <em>In vitro</em> studies showed that Nox4 disruption by specific siRNAs or Nox4 inhibitors declined heme-mediated ROS production and cell death. Our data identify Nox4 as a key enzyme involved in intravascular hemolysis-induced AKI. Thus, Nox4 inhibition may be a potential therapeutic approach to prevent renal damage in patients with severe hemolytic crisis.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"Redox regulation of cytokine-mediated inhibition of myelin gene expression in human primary oligodendrocytes\" [Free Radic. Biol. Med. 39 (2005) 823-831].","authors":"Malabendu Jana, Kalipada Pahan","doi":"10.1016/j.freeradbiomed.2024.10.276","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2024.10.276","url":null,"abstract":"","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Astrocytic lactoferrin deficiency augments MPTP-induced dopaminergic neuron loss by disturbing glutamate/calcium and ER-mitochondria signaling","authors":"","doi":"10.1016/j.freeradbiomed.2024.10.284","DOIUrl":"10.1016/j.freeradbiomed.2024.10.284","url":null,"abstract":"<div><div>Increased levels of lactoferrin (Lf) are present in the aged brain and in the lesions of various neurodegenerative diseases, including Parkinson's disease (PD), and may contribute to the cascade of events involved in neurodevelopment and neuroprotection. However, whether Lf originates from astrocytes and functions within either the normal or pathological brain are unknown. Here, we employed mice with specific knockout of the astrocyte <em>lactoferrin</em> gene (named <em>Lf</em>-cKO) to explore its specific roles in the pathological process of PD. We observed a decrease in tyrosine hydroxylase-positive cells, mitochondrial dysfunction of residual dopaminergic neurons, and motor deficits in <em>Lf</em>-cKO mice, which were significantly aggravated after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. To further explore how astrocytic <em>lactoferrin</em> deficiency exacerbated PD-like manifestation in MPTP-treated mice, the critical molecules involved in endoplasmic reticulum (ER)-mitochondria contacts and signaling pathways were investigated. In <em>vitro</em> and in vivo models, we found an aberrant level of effects implicated in glutamate and calcium homeostasis, mitochondrial morphology and functions, mitochondrial dynamics, and mitochondria-associated ER membranes, accompanied by signs of oxidative stress and ER stress, which increase the fragility of dopaminergic neurons. These findings confirm the existence of astrocytic Lf and its influence on the fate of dopaminergic neurons by regulating glutamate/calcium metabolism and ER-mitochondria signaling. Our findings may be a promising target for the treatment of PD.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142445767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antioxidant mito-TEMPO prevents the increase in tropomyosin oxidation and mitochondrial calcium accumulation under 7-day rat hindlimb suspension","authors":"","doi":"10.1016/j.freeradbiomed.2024.10.285","DOIUrl":"10.1016/j.freeradbiomed.2024.10.285","url":null,"abstract":"<div><div>After the first day of muscle disuse (unloading) mitochondria-derived ROS accumulate in the postural-tonic soleus muscle. It is known that excess of ROS can lead to the accumulation of intramitochondrial calcium and overload of mitochondria with calcium, can negatively affect mitochondrial function and fatigue resistance of soleus muscle.</div><div>We assumed that the use of mitochondrial ROS scavenger mito-TEMPO will be able to prevent the unloading-induced disruption of mitochondrial functions and will help maintain soleus muscle fatigue resistance.</div><div>To test this hypothesis, male rats were divided into 3 groups (n = 16 in each): vivarium control with placebo (C), 7-day hindlimb suspension with placebo (7HS) and 7-day hindlimb suspension with intraperitoneal administration of the mimetic superoxide dismutase mito-TEMPO at a dose of 1 mg/kg (7HSM). In the 7HS group, increased fatigue of the soleus muscle was found in the <em>ex vivo</em> test, accompanied with increased activity of ETC complex I and “leak” respiration, as well as a twofold increased content of oxidized tropomyosin (a marker of ROS level in tissues) and increase in intramitochondrial calcium compared to C. In 7HSM, the activity of ETC complex I and “leak” respiration had no significant differences from the control group, and the increase in intramitochondrial calcium and the content of oxidized tropomyosin was partially prevented, however, muscle fatigue was also significantly higher than in the control group. Thus, mitochondrial ROS under 7-day muscle unloading contribute to the accumulation of intramitochondrial calcium and oxidation of tropomyosin, but do not have a significant effect on soleus muscle function.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142441058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The tolerable upper intake level of manganese alleviates Parkinson-like motor performance and neuronal loss by activating mitophagy","authors":"","doi":"10.1016/j.freeradbiomed.2024.10.281","DOIUrl":"10.1016/j.freeradbiomed.2024.10.281","url":null,"abstract":"<div><div>Manganese (Mn²⁺) is among the indispensable trace elements required by the human body, but high-dose Mn²⁺ exposure can lead to Mn poisoning. Therefore, the tolerable upper intake level (UL) for Mn²⁺ has been established for normal individuals in different countries. However, whether the UL of Mn²⁺ is suitable for the patients of Parkinson's disease (PD) is unclear.</div><div>Here, we found unexpectedly that the dietary UL of Mn²⁺ supplement enhanced mitophagy through the PINK1/Parkin-mediated ubiquitin-dependent pathway in MPTP- induced mice and cells. Mn²⁺ promoted mitochondrial biogenesis and dynamics, thereby increased the activity of the mitochondrial respiratory chain with restored mitochondrial function. Additionally, Mn²⁺ directly elevated the activity of mitochondrial superoxide dismutase (MnSOD), which contributed to the clearance of reactive oxygen species (ROS), restored dopaminergic and motor functions in the MPTP-induced PD mouse model. Similar results were also observed in SH-SY5Y cells, whereas knockdown parkin using siRNA or application of mitophagy inhibitors (Mdivi-1 or Cyclosporine A), abolished the neuroprotective effects of Mn²⁺.</div><div>These findings demonstrate that the dietary UL of Mn²⁺ is protective for the MPTP-induced Parkinson-like lesions with the mechanisms involving the activation of mitophagy, suggesting potential intervention of PD by moderately increasing dietary Mn²⁺ intake.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of low and high dietary nitrate intake on human saliva, plasma and skeletal muscle nitrate and nitrite concentrations and their functional consequences.","authors":"Matthew I Black, Lee J Wylie, Stefan Kadach, Barbora Piknova, Ji W Park, Zdravko Stoyanov, Joanna E L'Heureux, Alan N Schechter, Anni Vanhatalo, Andrew M Jones","doi":"10.1016/j.freeradbiomed.2024.10.282","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2024.10.282","url":null,"abstract":"<p><p>Dietary nitrate (NO₃^-) supplementation has been shown to reduce blood pressure (BP), improve exercise performance, and alter the oral microbiome. Following a \"control\" diet (CON), we manipulated dietary NO₃^- intake to examine the effect of a short-term (7-day) low NO₃^- diet (LOW) followed by a 3-day high NO₃^- diet (HIGH), compared to a 7-day standard (STD) NO₃^- diet followed by HIGH, on saliva, plasma, and muscle [NO₃^-] and nitrite [NO₂^-], BP, and cycling exercise performance in healthy young adults. We also examined the effect of LOW on the oral microbiome. Saliva [NO₃^-] and [NO₂^-], and plasma [NO₃^-] were significantly lower than CON following LOW (all P<0.05) but there was no change in plasma [NO₂^-] or muscle [NO₃^-] and [NO₂^-] (all P>0.05). Following HIGH, saliva and plasma [NO₃^-] and [NO₂^-], and muscle [NO₃^-], were significantly elevated above CON, LOW and STD (all P<0.05), but there was no difference between CON-LOW-HIGH and CON-STD-HIGH (P<0.05). BP and exercise performance were not altered following LOW (P>0.05). HIGH significantly reduced systolic and diastolic BP compared to CON when preceded by STD (both P<0.05) but not when preceded by LOW (P>0.05). Peak (+4%) and mean (+3%) power output during sprint cycling was significantly improved following HIGH (both P<0.05), with no differences between CON-LOW-HIGH and CON-STD-HIGH (both P>0.05). LOW altered the oral microbiome composition, including decreases in relative abundances of phylum Proteobacteria and genus Neisseria. The findings indicate that a short-term low NO₃^- diet lowers plasma but not skeletal muscle [NO₃^-]. The maintenance of plasma [NO₂^-] and muscle [NO₃^-] and [NO₂^-] following LOW may be indicative of their importance to biological functions, including BP regulation and exercise performance.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Melatonin ameliorates chronic sleep deprivation against memory encoding vulnerability: Involvement of synapse regulation via the mitochondrial-dependent redox homeostasis-induced autophagy inhibition","authors":"","doi":"10.1016/j.freeradbiomed.2024.10.279","DOIUrl":"10.1016/j.freeradbiomed.2024.10.279","url":null,"abstract":"<div><div>Voluntary sleep curtailment is increasingly more rampant in modern society and compromises healthy cognition, including memory, to varying degrees. However, whether memory encoding is impaired after chronic sleep deprivation (CSD) and the underlying molecular mechanisms involved remain unclear. Here, using the mice, we tested the impact of CSD on the encoding abilities of social recognition-dependent memory and object recognition-dependent memory. We found that memory encoding was indeed vulnerable to CSD, while memory retrieval remained unaffected. The hippocampal neurons of mice with memory encoding deficits exhibited significant synapse damage and hyperactive autophagy, which dissipates during regular sleep cycles. This excessive autophagy appeared to be triggered by damage to mitochondrial DNA (mtDNA), resulting from oxidative stress within the mitochondria. The relief at the behavioral and molecular biological levels can be achieved with intraperitoneal injections of the antioxidant compound melatonin. Moreover, our <em>in vitro</em> experiments using HT-22 cells demonstrated that oxidative stress induced by hydrogen peroxide led to oxidative damage, including mtDNA damage, and activation of autophagy. Melatonin treatment effectively countered these effects, restoring redox homeostasis and reducing excessive autophagic activity. Notably, this protective effect was not observed when melatonin was administered as a pre-treatment. Together, our findings reveal the vulnerability of memory encoding during chronic sleep curtailment, which is caused by oxidative stress and consequent enhancement of autophagy, suggest a potential therapeutic strategy for addressing these effects following prolonged wakefulness through melatonin intervention, and reiterate the significance of adequate sleep for memory formation and retention.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142445648","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Connexin30-deficient mice increase susceptibility to noise via redox and lactate imbalances","authors":"","doi":"10.1016/j.freeradbiomed.2024.10.280","DOIUrl":"10.1016/j.freeradbiomed.2024.10.280","url":null,"abstract":"<div><div>Noise significantly contributes to one-third of the global burden of hearing loss. The intricate interplay of genetic and environmental factors impacts various molecular and cellular processes that lead to noise-induced hearing loss (NIHL). Defective connexin 26 (Cx26) and connexin 30 (Cx30), encoded by <em>Gjb2/Cx26</em> and <em>Gjb6/Cx30</em>, respectively, are prevalent causes of hereditary deafness. However, the role of Cx30 in the pathogenesis of NIHL remains unclear. Herein, we observed that homozygous <em>Cx30</em> knockout (<em>Cx30</em> KO) mice exhibited poorer hearing recovery after noise exposure (97 dB mean sound pressure level for 2 h) and increased susceptibility to noise. In addition to the exacerbation of noise-induced damage to hair cells and synapses, <em>Cx30</em> KO mice exposed to noise exhibited increased oxidative stress. The 2-(N-(7-nitrobenz-2-oxa-1,3-dia-zol-4-yl) amino)-2-deoxyglucose assay showed a reduction in glucose levels associated with a decrease in gap junctions as well as a reduction in adenosine triphosphate release. Glucose metabolomics analysis further revealed that <em>Cx30</em> KO mice had elevated lactate and NAD ⁺ levels after noise exposure, thus worsening anaerobic oxidation from glycolysis. Our study emphasizes that Cx30-deficient mice increase susceptibility to noise via redox and lactate imbalances in the cochlea.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}