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Dysregulation of iron metabolism in brain following TBI can result in the accumulation of redoxactive ferrous iron in various brain cells.This is possibly due to alterations in the expressionfunction of regulatory proteins such as ferroportin and ferritin, which fail to export iron from cells and thereby increase the labile iron pool.Although ferritin plays a vital role in iron metabolism by storing excess cellular iron, its precise function in the brain and whether it involves melatonins neuroprotection remain unexplored.It is noted that autophagy is activated to degrade ferritin, which is mediated by the cargo receptor NCOA, thereby increasing iron levels and leading to oxidative injury.The fate of excess iron in the absence of ferritin H in astrocytes and microglia remains elusive.Lipid peroxidation is regarded as the driving force of ferroptosis.Although the role of ferroptosis in the pathophysiological process of TBI has been illustrated, future research is required to investigate whether ferroptosis could serve as an intervention target for TBI.Considering distinct mechanisms of ferroptosis inhibition exist, the action of its inhibitors appear to act through different mechanisms.The characterization of new inhibitors should be accompanied by an evaluation of ironchelating or antioxidant activity.For example, melatonin exhibits antioxidant activity, which is probably based on their ability to inhibit ferroptosis.Thus, our findings underscore the protective role of melatonin in inhibiting ferroptosis, supporting the notion that melatonin is an excellent inhibitor of ferroptosis.In conclusion, we report that melatonin produces cerebroprotection in a mouse TBI model, via inhibiting neurological outcome in wildtype mice.Third, loss of neuronal ferritin increases the susceptibility to ferroptosis via an increase in lipid ROS and iron metabolism dysfunction following TBI.The present study sheds new light on the understanding of the diverse biological functions of melatonin, and provides a path for investigating the antiferroptosis actions of melatonin following TBI.Considering the antiferroptosis potential of melatonin, it could be a potential therapeutic target for treating TBI.AUTHOR CONTRIBUTIONS CL, LT, FW, and TR designed the experiments.TR, HW, QL, YC, YG, XM, GC, CG, CW, ZG, SS, JZ, ZW, TW, MZ and CL performed the research.XC, JM, LT, FW and CL provided intellectual contributions throughout the project.FW, XF and JZ contributed essential reagents or tools.CL and TR wrote the manuscript.All authors have read and approved the final manuscript.Estimating the global incidence of purchase Lenalidomide traumatic brain injury.Balancing acts: molecular control of mammalian iron metabolism.Systemic and cerebral iron homeostasis in ferritin knockout mice.Conditional deletion of ferritin H in mice induces loss of iron storage and liver damage.Shortterm effects of melatonin and pinealectomy on serotonergic neuronal activity across the lightdark cycle.Melatonin ameliorates neural function by promoting endogenous neurogenesis through the MT melatonin receptor in ischemicstroke mice.Regulation of ferroptotic cancer cell death by GPX.Ablation of ferroptosis regulator glutathione peroxidase in forebrain neurons promotes reasch Lenalidomide cognitive impairment and neurodegeneration.Preferential formation of MTMT melatonin receptor heterodimers with distinct ligand interaction properties compared with MT homodimers.The presence and role of iron in mild traumatic brain injury: an imaging perspective.Ferroptosis is an autophagic cell death process.Acute phase response after fatal traumatic brain injury.Mice were sacrificed at the indicated time points after TBI.
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Dysregulation of iron metabolism in brain following TBI can result in the accumulation of redoxactive ferrous iron in various brain cells.This is possibly due to alterations in the expressionfunction of regulatory proteins such as ferroportin and ferritin, which fail to export iron from cells and thereby increase the labile iron pool.Although ferritin plays a vital role in iron metabolism by storing excess cellular iron, its precise function in the brain and whether it involves melatonins neuroprotection remain unexplored.It is noted that autophagy is activated to degrade ferritin, which is mediated by the cargo receptor NCOA, thereby increasing iron levels and reasch Azelastine hydrochloride leading to oxidative injury.The fate of excess iron in the absence of ferritin H in astrocytes and microglia remains elusive.Lipid peroxidation is regarded as the driving force of ferroptosis.Although the role of ferroptosis in the pathophysiological process of TBI has been illustrated, future research is required to investigate whether ferroptosis could serve as an intervention target for TBI.Considering distinct mechanisms of ferroptosis inhibition exist, the action of its inhibitors appear to act through different mechanisms.The characterization of new inhibitors should be accompanied by an evaluation of ironchelating or antioxidant activity.For example, melatonin exhibits antioxidant activity, which is purchase Agomelatine probably based on their ability to inhibit ferroptosis.Thus, our findings underscore the protective role of melatonin in inhibiting ferroptosis, supporting the notion that melatonin is an excellent inhibitor of ferroptosis.In conclusion, we report that melatonin produces cerebroprotection in a mouse TBI model, via inhibiting neurological outcome in wildtype mice.Third, loss of neuronal ferritin increases the susceptibility to ferroptosis via an increase in lipid ROS and iron metabolism dysfunction following TBI.The present study sheds new light on the understanding of the diverse biological functions of melatonin, and provides a path for investigating the antiferroptosis actions of melatonin following TBI.Considering the antiferroptosis potential of melatonin, it could be a potential therapeutic target for treating TBI.AUTHOR CONTRIBUTIONS CL, LT, FW, and TR designed the experiments.TR, HW, QL, YC, YG, XM, GC, CG, CW, ZG, SS, JZ, ZW, TW, MZ and CL performed the research.XC, JM, LT, FW and CL provided intellectual contributions throughout the project.FW, XF and JZ contributed essential reagents or tools.CL and TR wrote the manuscript.All authors have read and approved the final manuscript.Estimating the global incidence of traumatic brain injury.Balancing acts: molecular control of mammalian iron metabolism.Systemic and cerebral iron homeostasis in ferritin knockout mice.Conditional deletion of ferritin H in mice induces loss of iron storage and liver damage.Shortterm effects of melatonin and pinealectomy on serotonergic neuronal activity across the lightdark cycle.Melatonin ameliorates neural function by promoting endogenous neurogenesis through the MT melatonin receptor in ischemicstroke mice.Regulation of ferroptotic cancer cell death by GPX.Ablation of ferroptosis regulator glutathione peroxidase in forebrain neurons promotes cognitive impairment and neurodegeneration.Preferential formation of MTMT melatonin receptor heterodimers with distinct ligand interaction properties compared with MT homodimers.The presence and role of iron in mild traumatic brain injury: an imaging perspective.Ferroptosis is an autophagic cell death process.Acute phase response after fatal traumatic brain injury.Mice were sacrificed at the indicated time points after TBI.
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[10]]][“E Metabolism”

Enrichment analysis identied overrepresentation of functions related to neuronal development and differentiation, as well as terms and pathways related to cell proliferation, in ischemic microglia compared with eYFP cells of PA ischemic WT mice. Gene set enrichment analysis also identied overrepresentation in microglia of genes involved in the cell division cycle, including GM checkpoint, mitotic spindle assembly, cell cyclerelated targets of EF transcription factors, and genes associated with spermatogenesis. Bars show mean SEM and symbols show individual values per each mouse.We then studied the identity of peripheral eYFP cells inltrating the ischemic brain tissue of WT PA mice by phenotyping DC subsets by ow cytometry.Notably, ischemia induced mRNA expression of chemokines binding those DC receptors at different time points. We isolated microglia, astrocytes, and endothelial cells from control brain tissue and days postischemia to identify which brain cells express these chemokines.To nd out whether microglia contributed to DC inltration to the ischemic brain tissue, we used a pharmacological strategy to deplete microglia.Given that microglial cell viability is CSFR dependent, chronic treatment with the CSFR inhibitor PLX provided in the diet causes strong microglial depletion. Of note, cDC showed a stronger reduction than the other DC subsets after microglia depletion. After weeks we studied the brain of each pair, or we induced brain ischemia in the WT mouse of each pair and studied the brain days later and after ischemia. At steady state, the number of eYFP cells. The representation includes natural clusters found by unsupervised clustering: subclusters PA were upregulated in PA samples, and subcluster mG was upregulated in microglia.Subclusters contained, and genes, respectively.To test this possibility, we blocked CCR by systemic to WT mice. The neurological score and the sizes of the lesion were not different between groups before treatment, as buy Benzethonium chloride assessed by MRI and behavioral tests hpostischemia, prior to drug administration.Drug treatment did not modify the size of the lesion versus the vehicle days postischemia. Batf mice showed larger infarctions and worse neurological decits than WT mice. The population of microglial cells is heterogeneous and shows phenotypic and functional diversity. Necrotic cell death induced by ischemia generates dangerassociated molecular patterns. ACKR, a scavenger of CXCL, was previously found in microglia in which expression increased under inammatory stimuli. Accordingly, microglia depletion reduced ischemiainduced expression of chemokines in brain and attenuated DC inltration, particularly of cDC.After days of treatment, ischemia was induced, and brain was studied days later using ow cytometry.Bars show group mean SEM and points are values per mouse.We monitored the brain lesion using MRI and assessed the neurological function with a neuroscore. Brain tissue was studied at day using ow cytometry.OXL binds OX on T cells to stimulate clonal expansion of effector and memory T cells. Notably, in the ischemic brain, OXL was expressed by cDC cells and not by other inltrating DC populations or microglia.Moreover, cDC regulate complex innate immune responses that may contribute to their effect on stroke outcome.Phenotypic differences dened and direct ex vivo antigen presentation to myelin basic proteinreactive CD T cells compared.Science.
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This article is protected by copyright.Meanwhile, TBI induces the decrease of GSH and the increase of intracellular lipid ROS generated by excess iron, thereby inducing lipid peroxidation and ferroptosis in wildtype mice.In addition, no significant difference in expression of melatonin receptors was observed between control and KO mice subjected to TBI. Notably, the neuroprotection by exogenous melatonin was mostly lost in FthKO mice, indicating that melatonin produces cerebroprotection following TBI, at least partly via inhibiting neuronal Fth mediated ferroptosis.All rights reserved jpif.tif Thisarticleisprotectedbycopyright.Allrightsreserved jpif.tif Thisarticleisprotectedbycopyright.Allrightsreserved jpif.tif Thisarticleisprotectedbycopyright.Allrightsreserved jpif.tif Thisarticleisprotectedbycopyright.Allrightsreserved jpif.tif Thisarticleisprotectedbycopyright.Allrightsreserved jpif.tif Thisarticleisprotectedbycopyright.Allrightsreserved jpif.tif Thisarticleisprotectedbycopyright.Allrightsreserved jpif.tif Thisarticleisprotectedbycopyright.Allrightsreserved jpif.tif Thisarticleisprotectedbycopyright.Allrightsreserved Microglia attract different DC subsets via chemokines, especially cDC that exert benecial functions in cerebral ischemia.These regions comprise the leptomeninges, ventricles, choroid plexus, circumventricular organs, and rostral migratory pathway. However, their presence increases in the aged brain and under neuroinammatory and neuropathological conditions, including infection, cancer, autoimmunity, seizures, neurodegenerative diseases, and stroke. Furthermore, eYFP cells were seen in the proximity of reactive astrocytes surrounding the ischemic core. Itgax mRNA expression was induced from to hafter IL treatment, in agreement with a previous study. In the ischemic tissue, some, but not all, eYFP cells shared with microglia several morphological features, common markers, and proliferative capacity. For comparative purposes, we also obtained reference control microglia of nonischemic mice.Comparative RNA sequencing showed that eYFP cells of the ischemic brain display a gene expression prole distinct from microglia, both ischemic and control, and from spleen eYFP cells. After ischemia, eYFP cells increase in the parenchyma.versus control,n mice per time point.Fltg mRNA in microglia, astroglia, and endothelial cells sorted from control and ischemic brains. Values are expressed as fold increase versus control microglia.We found pathways enriched in eYFP cells compared with microglia but only pathways enriched in microglia compared with eYFP cells.The fact that only a few pathways were enriched in microglia versus eYFP cells suggested that microglial genes could be expressed in the eYFP population too.Functional annotation clustering highlighted functions overrepresented in eYFP cells versus microglia, such as antigen presentation and immune responses. Then we compared the expression of those sets of genes in our samples. Furthermore, expression of typical microglial markers was comparatively lower in the eYFP cells.The selected group of genes clearly separated microglia genes from DC genes, as illustrated in the volcano plot. To this end, we used OTII transgenic mice with CD T cells specic for ovalbumin peptide.After weeks of parabiosis, we detected a few eYFP cells located mainly in the leptomeningeal zone and choroid plexus, while being absent from the brain parenchyma. In other groups of PA mice, we induced cerebral ischemia in the WT mouse of each PA pair. Four days postischemia, we detected eYFP cells in the ischemic brain parenchyma of the PA WT mice.Flow cytometry conrmed the very small number of eYFP cells in the brain of the PA WT mice in steady state and the increased number following ischemia. Principal component analysis separated inltrating cells. A wide repertoire of pattern recognition receptors, DECTIN were overrepresented in inltrating PA eYFP cells versus microglia, whose expression is high in brain tissue.
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Enrichment analysis identied overrepresentation of functions related to neuronal development and differentiation, as well as terms and pathways related to cell proliferation, in ischemic microglia compared with eYFP cells of PA ischemic WT mice. Gene set enrichment analysis also identied overrepresentation in microglia of genes involved in the cell division cycle, including GM checkpoint, mitotic spindle assembly, cell cyclerelated targets of EF transcription factors, and genes associated with spermatogenesis. Bars show mean SEM and symbols show individual values per each mouse.We then studied the identity of peripheral eYFP cells inltrating the ischemic brain tissue of WT PA mice by phenotyping DC subsets by ow cytometry.Notably, ischemia induced mRNA expression of chemokines binding those DC receptors at different time points. We isolated microglia, astrocytes, and endothelial cells from control brain tissue and days postischemia to identify which brain cells express these chemokines.To nd out whether microglia contributed to DC inltration to the ischemic brain tissue, we used a pharmacological strategy to deplete microglia.Given that microglial cell viability is CSFR dependent, chronic treatment with the CSFR inhibitor PLX provided in the diet causes strong microglial depletion. Of note, cDC showed a stronger reduction than the other DC subsets after microglia depletion. After weeks we studied the brain of each pair, or we induced brain ischemia in the WT mouse of each pair and studied the brain days later and after ischemia. At steady state, the number of eYFP cells. The representation includes natural clusters found by unsupervised clustering: subclusters PA were upregulated in PA samples, and subcluster mG was upregulated in microglia.Subclusters contained, and genes, respectively.To test this possibility, we blocked CCR by systemic to WT mice. The neurological score and the sizes of the lesion were not different between groups before treatment, as assessed by MRI and behavioral tests hpostischemia, prior to drug administration.Drug treatment did not modify the size of the lesion versus the vehicle days postischemia. Batf mice showed larger infarctions and worse neurological decits than WT mice. The population of microglial cells is heterogeneous and shows phenotypic and functional diversity. Necrotic cell death induced by ischemia generates dangerassociated molecular patterns. ACKR, a scavenger of CXCL, was previously found in microglia in which expression increased under inammatory stimuli. Accordingly, microglia depletion reduced ischemiainduced expression of chemokines in brain and attenuated DC inltration, particularly of cDC.After days of treatment, ischemia was induced, and brain was studied days later using ow cytometry.Bars show group mean SEM and points are values per mouse.We monitored the brain lesion using MRI and assessed the neurological function with a neuroscore. Brain tissue was studied at day using ow cytometry.OXL binds OX on T cells to stimulate clonal expansion of effector and memory T cells. Notably, in the ischemic brain, OXL was expressed by cDC cells and not by other inltrating DC populations or microglia.Moreover, cDC regulate complex innate immune responses that may contribute to their effect on stroke outcome.Phenotypic differences dened and direct ex vivo antigen presentation to myelin basic proteinreactive CD T cells compared.Science.
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Immunofluorescence staining showed that both MT and MT expressed in HT cells subjected to mechanical scratch injury or not. Most of the studies evaluated the effects of melatonin on cellular, histopathological and behavioral outcomes following TBI, including but are not limited to: markers of oxidative stress, inflammatory cytokines, edema, lesion size, and cognitive impairment.Although melatonin exerts multiple protective effects on treating TBI, including antiapoptotic, antioxidative, and antiinflammatory properties, there is no information regarding the effects of melatonin on ferroptosis after TBI.As a novel form of cell death, ferroptosis plays an important role in various pathological conditions, including TBI.Similarly, baicalein attenuated ferroptosis signaling and cognitive outcome after TBI.Together, the previous reports indicated that ferroptosis is involved in the pathogenesis of TBI.However, the underlying mechanisms of ferroptosis following TBI, and the antiferroptosis actions of melatonin have still not been clarified.Considering the halflife of melatonin is short, the animals received melatonin hour after TBI and once a day until sacrifice in this study.The effects of melatonin are observable both after a single administration. Numerous studies have suggested that endogenous glutathione exerts a neuroprotective effect against TBI.Cortical GSH content is significantly reduced following TBI in rats and mice.Inhibition of xc depletes GSH levels and impairs glutathione peroxidase activity, thereby increasing lipid peroxidation.Certain membrane lipids have been found to be oxidized during ferroptosis.In addition, we found the expression of MT and MT reduced in a timedependent fashion after TBI, while melatonin inhibited the MT and MT deficiency following TBI.However, there is no report about how melatonin treatment prevents a decrease in MT and MT expression after insults.More research work needs to address this in the future.We speculate that the dosage of luzindole matters or heterodimerization of melatonin receptors may affect the agonist response of luzindole.Moreover, inhibition of MAPKERK activation is correlated with antiferroptotic mechanisms in a renal ischemiareperfusion injury model.To our knowledge, this study is the first study directly investigating the effects of melatonin on ferroptosis after TBI.These findings indicate that a strategy using melatonin aimed at attenuating lipid peroxidation may be a viable approach to mitigate ferroptosis and the subsequent long term physical, cognitive, and emotional deficiencies caused by TBI.Another characteristic of ferroptosis is iron accumulation.Iron homeostasis appears to play an important role in the pathobiology of TBI.As a crucial micromineral required for all living beings, iron serves as a cofactor in heme and the ironsulfur cluster. However, abnormal iron deposition in specific regions of the brain is directly involved in the poor cognitive outcome, since nonheme bound iron accumulates in deep gray matter areas of the brain and may contribute to secondary pathological injury following TBI.These findings underscore the importance of maintaining iron homeostasis in the brain.In mammals, the uptake, transport, and storage of iron are tightly coordinated by various proteins and pathways to maintain iron homeostasis at both the cellular and systemic levels.In the central nervous system, cells including neurons, have evolved highly regulated mechanisms for controlling cellular iron levels, including the iron storage protein ferritin, iron importer transferrin receptor. Ferritin has regarded as the endpoint protein to store and remove excess iron to reduce cellular damage and stress.
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If a mouse failed to reach the platform within s, it was guided to the platform and allowed to stay for s.Swimming escape latency was automatically recorded and analyzed with a videocompute system. An open field test was conducted to explore the presence of anxiety or disinhibition in CCI injured mice at days after TBI.The open field test was performed, as previously described.Before each behavioral session, the apparatus was cleaned by the solution of ethanol.Animals were removed from their home cage and placed in an open field test arena. Behaviors and parameters were recorded and analyzed by an buy Spermine automated behavioral tracking system. Ambulatory activity was recorded for min and analyzed.Briefly, the brains were fixed in paraformaldehyde for h, then cut into serial coronal sections with a cryostat.A random sampling scheme was used to yield five total sections, by estimating every tenth section from rostral to caudal.Transfections were performed as per the manufacturers instructions. Melatonin was then added hours before the scratch injury.Cell viability was assessed using the cell counting kit. Finally, cells were used for protein extraction, cellular reactive oxygen species detection, and BODIRY C staining.The ROS generation by the cells was measured with a cellular ROS detection assay kit. Harvested cells were washed with serumfree culture medium at C for min.GSH plays an important role in ferroptosis, and reduced GSH levels can trigger ferroptosis.Perls blue staining showed that the number of ironpositive cells was significantly increased at days after TBI and continued to increase gradually afterward. Compared with the sham group, the cell bodies of injured neurons exhibited cytoplasmic shrinkage or nuclear pyknosis at days following TBI.To elucidate whether the protective eect of melatonin is dependent on its receptors following TBI, we first. Our results were consistent with the previous report that both MT and MT levels were reduced in a time pointdependent manner, although the expression of MT and MT was evaluated during the acute period postTBI.Furthermore, melatonin significantly ameliorated MT and MT loss in the brains of melatonintreated TBI mice at h. Taken together, the effect of melatonin was blocked by MT and MT receptors antagonists.In the MWM test, animals that find the platform more quickly are regarded as having better learning and memory function.An open field test was then conducted to explore the presence of anxiety or disinhibition on days after TBI.Animals in the vehicle TBI group traveled markedly shorter total distance than that in the sham group.In parallel, significantly shorter distance moved were observed in the vehicletreated TBI group than that in the sham group.CCK assay was used to assess cell survival rate for choosing the time course of the damage and the dose of melatonin.The results showed that the general trend of cell survival rate was decreased and reached the buy Panthenol bottom with at hafter injury, then increased gradually afterwards. Given lipid peroxidation is a hallmark of ferroptosis, we assessed the cytosolic ROS using dichlorodihydrofluorescien diacetate and BODIRY C as convenient proxies.Resistance to ferroptosis correlated with suppression of BODIRYC oxidation.Similar to the above ROS results, we found mechanical scratch injury significantly promoted lipid peroxide formation with red fluorescence of the BODIPY shifted to green fluorescence, indicating that scratch cell injury rises to lipid peroxidation.
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This article is protected by copyright.Meanwhile, TBI induces the decrease of GSH and the increase of intracellular lipid ROS generated by excess iron, thereby inducing lipid peroxidation and ferroptosis in wildtype mice.In addition, no significant difference in expression of melatonin receptors was observed between control and KO mice subjected to TBI.Notably, the neuroprotection by exogenous melatonin was mostly lost in FthKO mice, indicating that melatonin produces cerebroprotection following TBI, at least partly via inhibiting neuronal Fth mediated ferroptosis.All rights reserved jpif.tif Thisarticleisprotectedbycopyright.Allrightsreserved jpif.tif Thisarticleisprotectedbycopyright.Allrightsreserved jpif.tif Thisarticleisprotectedbycopyright.Allrightsreserved jpif.tif Thisarticleisprotectedbycopyright.Allrightsreserved jpif.tif Thisarticleisprotectedbycopyright.Allrightsreserved jpif.tif Thisarticleisprotectedbycopyright.Allrightsreserved jpif.tif Thisarticleisprotectedbycopyright.Allrightsreserved jpif.tif Thisarticleisprotectedbycopyright.Allrightsreserved jpif.tif Thisarticleisprotectedbycopyright.Allrightsreserved Microglia attract different DC subsets via chemokines, especially cDC that exert benecial functions in cerebral ischemia.These regions comprise the leptomeninges, ventricles, choroid plexus, circumventricular organs, and rostral migratory pathway. However, their presence increases in the aged brain and under neuroinammatory and neuropathological conditions, purchase Azathioprine including infection, cancer, autoimmunity, seizures, neurodegenerative diseases, and stroke. Furthermore, eYFP cells were seen in the proximity of reactive astrocytes surrounding the ischemic core. Itgax mRNA expression was induced from to hafter IL treatment, in agreement with a previous study. In the ischemic tissue, some, but not all, eYFP cells shared with microglia several morphological features, common markers, and proliferative capacity. For comparative purposes, we also obtained reference control microglia of nonischemic mice.Comparative RNA sequencing showed that eYFP cells of the ischemic brain display a gene expression prole distinct from microglia, both ischemic and control, and from spleen eYFP cells. After ischemia, eYFP cells increase in the parenchyma.versus control,n mice per time point.Fltg mRNA in microglia, astroglia, and endothelial cells sorted from control and ischemic brains. Values are expressed as fold increase versus control microglia.We found pathways enriched in eYFP cells compared with microglia but only pathways enriched in microglia compared with eYFP cells.The fact that only a few pathways were enriched in microglia versus eYFP cells suggested that microglial genes could be expressed in the eYFP population too.Functional annotation clustering highlighted functions overrepresented in eYFP cells versus microglia, such as antigen presentation and immune responses. Then we compared the expression of those sets of genes in our samples. Furthermore, expression of typical microglial markers was comparatively lower in the eYFP cells.The selected group of genes clearly separated microglia genes from DC genes, as illustrated in the volcano plot. To this end, we used OTII transgenic mice with CD T cells specic for ovalbumin peptide.After weeks of parabiosis, we detected a few eYFP cells located mainly in the leptomeningeal zone and choroid plexus, while being absent from the brain parenchyma. In other groups of PA mice, we induced cerebral ischemia in the WT mouse of each PA pair. Four days postischemia, we detected eYFP cells in the ischemic brain parenchyma of the PA WT mice.Flow cytometry conrmed the very small number of eYFP cells in the brain of the PA WT mice in steady state and the increased number following ischemia. Principal component analysis separated inltrating cells. A wide repertoire of pattern recognition receptors, DECTIN were overrepresented in inltrating PA eYFP cells versus microglia, whose expression is high in brain tissue.
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Metabolism Jelent├ęse

These findings revealed that, curcumin reverse myocardial infarction and heart attack via its antioxidant, antiinflammatory and antiapoptotic properties.In animal study, curcumin administration reported to possess antiatherosclerotic activity by downregulating the expression of lipocalin in apolipoprotein E knockout mice. It oxidized LDL and lowered lipid levels in the serum of hypercholesterolemic rabbits. A clinical study demonstrated that turmeric attenuated hematuria, proteinuria and systolic blood pressure associated with refractory or relapsing nephritis in patients without any adverse events. In animal study, curcumin administration downregulated the expression angiotensin I receptor in vascular smooth muscle cells.In addition, it decreased the level of circulating angiotensin converting Targetmol’s Guanosine enzyme and induced vascular relaxation in hypertensive rats.Further, curcumin administration upregulated eNOS expression, decreased superoxide enzyme level and downregulated pphox NADPH oxidase expression in vascular tissues, which is known to be responsible for kidneyclip induced hypertension in rats. In another study, curcumin treatment increased the expression of eNOS, decreased oxidative stress, restored glutathione redox ratio in aortic tissues along with decrease in plasma protein carbonyls, MDA and urinary nitrate nitrite levels in cadmium intoxicated mice resulting in antihypertensive effect. In conclusion, curcumin supplementation effectively reduce hypertension via blocking angiotensin I receptor, reducing circulating angiotensinconverting enzyme, inducing vasodilation and mediating nephroprotection.In experimental study, clinicopathological evidence indicates that, curcumin treatment reduces cardiac dysrhythmias, ventricular fibrillation and tachycardia by attenuating oxidative stress in mesenteric vessels of rats during ischemiareperfusion injury. In in vitro study, curcumin administration inhibited human etheragogorelated gene potassium channels, resulting in cardiac repolarization prolongation, which might associated with the observed antiarrhythmic effects. Paradoxically, clinical report represented that curcumin treatment for one month causes complete atrioventricular block and after withdrawal of curcumin no further cardiac disturbances was observed. Further, curcumin administration reduced oxidative stress, inflammation and apoptosis in spinal cord as well as reversed locomotor deficit in rats. Curcumin administration increased the SOD activity in cerebral cortex and corpus striatum, inhibited brain LPO and reversed motor dysfunction in rats. Curcumin treatment diminished mortality, reduced infarct volume and cerebral damage, reduced the brain water content, downregulated iNOS expression and ameliorated neurological deficit as well as prevented bloodbrain barrier damage in focal cerebral ischemic rats. Mechanistically, curcumin administration reduced oxidative stress, inflammation, apoptosis, mitochondrial dysfunction, cerebral infract size and volume thereby ameliorates neurogenesis and behavioral performance in experimental stroke models.Therefore, curcumin may be a promising supplementary phytoconstituent for stroke in the future.A recent metaanalysis revealed that, curcumin or combined curcuminoids supplementation effectively lowered the level of fasting blood glucose in individuals with some degree of dysglycemia.In animal study, curcumin administration is reported to reduce glucose intolerance through induction of glucagonlike peptide secretion in CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION rats. In addition, curcumin administration is known to reduce insulin resistance by downregulating phosphorylation of IRS serine residue and upregulating phosphorylation of IRS tyrosine in the skeletal muscle of rats fed with high fructose.Curcumin treatment also reduced glucose intolerance, hyperinsulinemia and homeostasis model assessmentinsulin resistance level.Additionally, curcumin significantly downregulated extracellular kinase and p protein expressions in skeletal muscle.A recent study demonstrated that, curcumin administration attenuated splenic damage and improved immunity in streptozotocininduced diabetic rats via antioxidant, antiinflammatory and antiapoptotic mechanisms.
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Dysregulation of iron metabolism in brain following TBI can result in the accumulation of redoxactive ferrous iron in various brain cells.This is possibly due to alterations in the expressionfunction of regulatory proteins such as ferroportin and ferritin, which fail to export iron from cells and thereby increase the labile iron pool.Although ferritin plays a vital role in iron metabolism by storing excess cellular iron, its precise function in the brain and whether it involves melatonins neuroprotection remain unexplored.It is noted that autophagy is activated to degrade ferritin, which is mediated by the cargo receptor NCOA, thereby increasing iron levels and leading to oxidative injury.The fate of excess iron in the absence of ferritin H in astrocytes and microglia remains elusive.Lipid peroxidation is regarded as the driving force of ferroptosis.Although the role of ferroptosis in the pathophysiological process of TBI has been illustrated, future research is required to investigate whether ferroptosis could serve as an intervention target for TBI.Considering distinct mechanisms of ferroptosis inhibition exist, the action of its inhibitors appear to act through different mechanisms.The characterization of new inhibitors should be accompanied by an evaluation of ironchelating or antioxidant activity.For example, melatonin exhibits antioxidant activity, which is probably based on their ability to inhibit ferroptosis.Thus, our findings underscore the protective role of melatonin in inhibiting ferroptosis, supporting the notion that melatonin is an excellent inhibitor of ferroptosis.In conclusion, we report that melatonin produces cerebroprotection in a mouse TBI model, via inhibiting neurological outcome in wildtype mice.Third, loss of neuronal ferritin increases the susceptibility to ferroptosis via an increase in lipid ROS and iron metabolism dysfunction following TBI.The Targetmol’s Aniracetam present study sheds new light on the understanding of the diverse biological functions of melatonin, and provides a path for investigating the antiferroptosis actions of melatonin following TBI.Considering the antiferroptosis potential of melatonin, it could be a potential therapeutic target for treating TBI.AUTHOR CONTRIBUTIONS CL, LT, FW, and TR designed the experiments.TR, HW, QL, YC, YG, XM, GC, CG, CW, ZG, SS, JZ, ZW, TW, MZ and CL performed the research.XC, JM, LT, FW and CL provided intellectual contributions throughout the project.FW, XF and JZ contributed essential reagents or tools.CL and TR wrote the manuscript.All authors have read and approved the final manuscript.Estimating the global incidence of traumatic brain injury.Balancing acts: molecular control of mammalian iron metabolism.Systemic and cerebral iron homeostasis in ferritin knockout mice.Conditional deletion of ferritin H in mice induces loss of iron storage and liver damage.Shortterm effects of melatonin and pinealectomy on serotonergic neuronal activity across the lightdark cycle.Melatonin ameliorates neural function by promoting endogenous neurogenesis through the MT melatonin receptor in ischemicstroke mice.Regulation of ferroptotic cancer cell death by GPX.Ablation of ferroptosis regulator glutathione peroxidase in forebrain neurons promotes cognitive impairment and neurodegeneration.Preferential formation of MTMT melatonin receptor heterodimers with distinct ligand interaction properties compared with MT homodimers.The presence and role of iron in mild traumatic brain injury: an imaging perspective.Ferroptosis is an autophagic cell death process.Acute phase response after fatal traumatic brain injury.Mice were sacrificed at the indicated time points after TBI.