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1.
J Biochem Mol Toxicol ; 38(7): e23760, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38953502

RESUMO

Cyclophosphamide (CP) is an antineoplastic drug widely used in chemotherapy. Curcumin (CUR) and piperine (PP) show a protective effect on neurodegenerative and neurological diseases. This research was designed to measure several biochemical parameters in the brain tissue of CP-applied rats to investigate the impact of combined CUR-PP administration. The study evaluated six groups of eight rats: Group 1 was the control; Groups 2 and 3 were administered 200 or 300 mg/kg CUR-PP via oral gavage; Group 4 received only 200 mg/kg CP on day 1; Groups 5 and 6 received CP + CUR-PP for 7 days. Data from all parameters indicated that CP caused brain damage. Phosphorylated TAU (pTAU), amyloid-beta peptide 1-42 (Aß1-42), glutamate (GLU), and gamma amino butyric acid (GABA) parameters were the same in Groups 4, 5, and 6. On the other hand, 8-hydroxy-2-deoxyguanosine (8-OHdG), nitric oxide (NO), interleukin-6 (IL-6), nuclear factor kappa beta (NF-kß), malondialdehyde (MDA), and tumor necrosis factor-alpha (TNF-α) levels in the CP + CUR-PP groups were lower than those in the CP group (p < 0.05). However, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and reduced glutathione (GSH) parameters were higher in the CP + CUR-PP groups compared to the CP group (p < 0.05). It is thought that the similarity of Groups 5 and 6 with Group 4 in Aß1-42, pTAU, GLU, and GABA parameters hinder the determination of treatment protection however, they might have a therapeutic effect if the applied dose or study duration were changed. This study attempted to evaluate the effects of a CUR-PP combination on CP-induced brain damage in rats by measuring biochemical parameters and performing histopathological examinations. Based on the findings, this CUR-PP combination could be considered an alternative medicine option in cases with conditions similar to those evaluated in this study.


Assuntos
Alcaloides , Benzodioxóis , Lesões Encefálicas , Curcumina , Ciclofosfamida , Piperidinas , Alcamidas Poli-Insaturadas , Animais , Alcamidas Poli-Insaturadas/farmacologia , Benzodioxóis/farmacologia , Curcumina/farmacologia , Piperidinas/farmacologia , Alcaloides/farmacologia , Ratos , Ciclofosfamida/toxicidade , Ciclofosfamida/efeitos adversos , Masculino , Lesões Encefálicas/induzido quimicamente , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Lesões Encefálicas/prevenção & controle , Ratos Wistar , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Estresse Oxidativo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia
2.
Cancer Imaging ; 24(1): 95, 2024 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-39026377

RESUMO

BACKGROUND: Radiotherapy is a major therapeutic approach in patients with brain tumors. However, it leads to cognitive impairments. To improve the management of radiation-induced brain sequalae, deformation-based morphometry (DBM) could be relevant. Here, we analyzed the significance of DBM using Jacobian determinants (JD) obtained by non-linear registration of MRI images to detect local vulnerability of healthy cerebral tissue in an animal model of brain irradiation. METHODS: Rats were exposed to fractionated whole-brain irradiation (WBI, 30 Gy). A multiparametric MRI (anatomical, diffusion and vascular) study was conducted longitudinally from 1 month up to 6 months after WBI. From the registration of MRI images, macroscopic changes were analyzed by DBM and microscopic changes at the cellular and vascular levels were evaluated by quantification of cerebral blood volume (CBV) and diffusion metrics including mean diffusivity (MD). Voxel-wise comparisons were performed on the entire brain and in specific brain areas identified by DBM. Immunohistology analyses were undertaken to visualize the vessels and astrocytes. RESULTS: DBM analysis evidenced time-course of local macrostructural changes; some of which were transient and some were long lasting after WBI. DBM revealed two vulnerable brain areas, namely the corpus callosum and the cortex. DBM changes were spatially associated to microstructural alterations as revealed by both diffusion metrics and CBV changes, and confirmed by immunohistology analyses. Finally, matrix correlations demonstrated correlations between JD/MD in the early phase after WBI and JD/CBV in the late phase both in the corpus callosum and the cortex. CONCLUSIONS: Brain irradiation induces local macrostructural changes detected by DBM which could be relevant to identify brain structures prone to radiation-induced tissue changes. The translation of these data in patients could represent an added value in imaging studies on brain radiotoxicity.


Assuntos
Lesões Encefálicas , Animais , Ratos , Masculino , Lesões Encefálicas/etiologia , Lesões Encefálicas/diagnóstico por imagem , Lesões Encefálicas/patologia , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Lesões por Radiação/diagnóstico por imagem , Lesões por Radiação/patologia , Lesões por Radiação/etiologia , Encéfalo/efeitos da radiação , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Imageamento por Ressonância Magnética/métodos , Lesões Experimentais por Radiação/diagnóstico por imagem , Lesões Experimentais por Radiação/patologia , Lesões Experimentais por Radiação/etiologia , Imageamento por Ressonância Magnética Multiparamétrica/métodos
3.
Int J Biol Macromol ; 273(Pt 1): 132887, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38851621

RESUMO

Acute alcohol intoxication is a harmful clinical condition characterized by behavioral and neurological symptoms, for which few effective therapies are available at present. Dysfunction of microglial BV-2 cells has been reported to be associated with acute alcohol-induced brain injuries. In the present study, the protective effects of Eucommia ulmoides Oliv. leaves polysaccharides (EULP) on acute alcoholic brain injury and microglial dysfunction were investigated. 14-day pretreatment of EULP significantly attenuated neurobehavioral deficit and neurotransmitter damage in the brain tissue of mice caused by acute alcohol exposure. Additionally, EULP regulated the metabolic disorder of brain tissue. Consistently, it was shown that EULP pretreatment significantly improved alcohol-induced phagocytosis decrease, oxidative stress and inflammation in BV-2 cells. Therefore, EULP may be proposed and employed as a potential therapeutic agent for alcohol-induced brain damage.


Assuntos
Eucommiaceae , Microglia , Estresse Oxidativo , Folhas de Planta , Polissacarídeos , Animais , Polissacarídeos/farmacologia , Polissacarídeos/química , Microglia/efeitos dos fármacos , Microglia/metabolismo , Camundongos , Eucommiaceae/química , Folhas de Planta/química , Estresse Oxidativo/efeitos dos fármacos , Masculino , Etanol , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/induzido quimicamente , Lesões Encefálicas/metabolismo , Lesões Encefálicas/etiologia , Lesões Encefálicas/patologia , Linhagem Celular , Fagocitose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Extratos Vegetais/farmacologia , Extratos Vegetais/química
4.
Bratisl Lek Listy ; 125(7): 414-418, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38943501

RESUMO

OBJECTIVE: Astrocytes undergo morphological and molecular changes in response to numerous pathological conditions. BACKROUND: Increased expression of glial fibrillary acidic protein (GFAP) has been reported as a characteristic feature of reactive astrocytes. However, GFAP-positive cells occur rarely in adult human brain cultures. These cultures are mostly composed of flat GFAP-negative "glia-like" cells, which remain poorly characterized in relation to reactive astrogliosis. METHODS: We examined the cultures from macroscopically injured and normal brain tissue from patients with brain trauma, gliomas, or brain metastases. Immunofluorescence and immunohistochemical methods were used for reactive astrocytes detection. RESULTS: The intensity of GFAP-positive staining was higher in reactive astrocytes in the brain tissue surrounding gliomas or metastases and lower in brain tissue damaged by traumatic injury. We did not observe any correlation between GFAP-positive reactive astrocytes in cultures and brain tissue. However, we found rapidly proliferating spindle-shaped cells in cultures prepared from injured brain tissue. CONCLUSION: Present data demonstrate the unexplained phenomenon of disparate cell morphologies in cultures when prepared either from macroscopically normal or injured human brain tissue. While normal cultures are mainly comprised of flat cells, the cultures from severely damaged brain tissue may be entirely composed of spindle-shaped cells usually classified as fibroblasts. We suggest that this spindle-shaped cellular morphology is not specific for fibroblasts, but it rather can be interpreted as the most favorable shape for rapid cell proliferation under culture conditions. After brain trauma, unknown processes may be triggered, such as induced cell proliferation which can be revealed under culture condition. Accordingly, we conclude that spindle-shaped cells are activated precursors of glial cells (Fig. 3, Ref. 15).


Assuntos
Astrócitos , Fibroblastos , Proteína Glial Fibrilar Ácida , Humanos , Fibroblastos/patologia , Fibroblastos/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Astrócitos/patologia , Astrócitos/metabolismo , Lesões Encefálicas/patologia , Lesões Encefálicas/metabolismo , Feminino , Pessoa de Meia-Idade , Masculino , Adulto , Células Cultivadas , Idoso , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/metabolismo , Encéfalo/patologia , Encéfalo/citologia , Glioma/patologia , Glioma/metabolismo , Neuroglia/patologia , Neuroglia/metabolismo
6.
J Cell Mol Med ; 28(11): e18366, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38856956

RESUMO

Ischemic stroke is one of the main causes of disability and death. However, recanalization of occluded cerebral arteries is effective only within a very narrow time window. Therefore, it is particularly important to find neuroprotective biological targets for cerebral artery recanalization. Here, gene expression profiles of datasets GSE160500 and GSE97537 were downloaded from the GEO database, which were related to ischemic stroke in rats. Olfactory receptor 78 (Olfr78) was screened, and which highly associated with Calcium signalling pathway and MAPK pathway. Interacting protein of Olfr78, Prkaca, was predicted by STRING, and their interaction was validated by Co-IP analysis. Then, a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R) and a neuronal cell model stimulated by oxygen-glucose deprivation/reoxygenation (OGD/R) were constructed, and the results showed that expression of Olfr78 and Prkaca was downregulated in MCAO rats and OGD/R-stimulated neurons. Overexpression of Olfr78 or Prkaca inhibited the secretion of inflammatory factors, Ca2+ overload, and OGD/R-induced neuronal apoptosis. Moreover, Overexpression of Prkaca increased protein levels of cAMP, PKA and phosphorylated p38 in OGD/R-stimulated neurons, while SB203580, a p38 inhibitor, treatment inhibited activation of the cAMP/PKA-MAPK pathway and counteracted the effect of Olfr78 overexpression on improvement of neuronal functions. Meanwhile, overexpression of Olfr78 or Prkaca markedly inhibited neuronal apoptosis and improved brain injury in MCAO/R rats. In conclusion, overexpression of Olfr78 inhibited Ca2+ overload and reduced neuronal apoptosis in MCAO/R rats by promoting Prkaca-mediated activation of the cAMP/PKA-MAPK pathway, thereby improving brain injury in cerebral ischaemia-reperfusion.


Assuntos
Apoptose , AMP Cíclico , Ratos Sprague-Dawley , Receptores Odorantes , Traumatismo por Reperfusão , Animais , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/genética , Ratos , Masculino , AMP Cíclico/metabolismo , Receptores Odorantes/metabolismo , Receptores Odorantes/genética , Isquemia Encefálica/metabolismo , Isquemia Encefálica/genética , Isquemia Encefálica/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Lesões Encefálicas/metabolismo , Lesões Encefálicas/etiologia , Lesões Encefálicas/patologia , Neurônios/metabolismo , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/metabolismo , Transdução de Sinais
7.
Methods Cell Biol ; 188: 237-254, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38880526

RESUMO

The prevalence of central nervous system (CNS) dysfunction as a result of disease or trauma remains a clinically unsolved problem which is raising increased awareness in our aging society. Human Dental Pulp Stem Cells (hDPSCs) are excellent candidates to be used in tissue engineering and regenerative therapies of the CNS due to their neural differentiation ability and lack of tumorigenicity. Accordingly, they have been successfully used in animal models of spinal cord injury, stroke and peripheral neuropathies. The ideal therapy in brain injury should combine strategies aiming to protect the damaged lesion and, at the same time, accelerate brain tissue regeneration, thus promoting fast recovery while minimizing side or long-term effects. The use of bioresorbable nanopatterned poly(lactide-co-ɛ-caprolactone) (PLCL) polymeric scaffolds as hDPCSs carriers can represent an advantage for tissue regeneration. In this chapter, we describe the surgical procedures to implant functionalized bioresorbable scaffolds loaded with hDPSCs to improve the brain lesion microenvironment in an intracranial stab wound injury model severing the rostral migratory stream (RMS) that connects the brain subventricular zone (SVZ) and the olfactory bulb in nude mice. Additionally, we also describe the technical steps after animal sacrifice for histological tissue observation and characterization.


Assuntos
Polpa Dentária , Modelos Animais de Doenças , Camundongos Nus , Células-Tronco , Alicerces Teciduais , Polpa Dentária/citologia , Animais , Humanos , Alicerces Teciduais/química , Camundongos , Células-Tronco/citologia , Transplante de Células-Tronco/métodos , Ferimentos Perfurantes/terapia , Implantes Absorvíveis , Lesões Encefálicas/terapia , Lesões Encefálicas/patologia , Engenharia Tecidual/métodos
8.
Neuropathol Appl Neurobiol ; 50(3): e12992, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38831600

RESUMO

PURPOSE: Radiation-induced brain injury, one of the side effects of cranial radiotherapy in tumour patients, usually results in durable and serious cognitive disorders. Microglia are important innate immune-effector cells in the central nervous system. However, the interaction between microglia and neurons in radiation-induced brain injury remains uncharacterised. METHODS AND MATERIALS: We established a microglia-neuron indirect co-culture model to assess the interaction between them. Microglia exposed to radiation were examined for pyroptosis using lactate dehydrogenase (LDH) release, Annexin V/PI staining, SYTOX staining and western blot. The role of nucleotide-binding oligomerisation domain-like receptor family pyrin domain containing 3 (NLRP3) was investigated in microglia exposed to radiation and in mouse radiation brain injury model through siRNA or inhibitor. Mini-mental state examination and cytokines in blood were performed in 23 patients who had experienced cranial irradiation. RESULTS: Microglia exerted neurotoxic features after radiation in the co-culture model. NLRP3 was up-regulated in microglia exposed to radiation, and then caspase-1 was activated. Thus, the gasdermin D protein was cleaved, and it triggered pyroptosis in microglia, which released inflammatory cytokines. Meanwhile, treatment with siRNA NLRP3 in vitro and NLRP3 inhibitor in vivo attenuated the damaged neuron cell and cognitive impairment, respectively. What is more, we found that the patients after radiation with higher IL-6 were observed to have a decreased MMSE score. CONCLUSIONS: These findings indicate that radiation-induced pyroptosis in microglia may promote radiation-induced brain injury via the secretion of neurotoxic cytokines. NLRP3 was evaluated as an important mediator in radiation-induced pyroptosis and a promising therapeutic target for radiation-induced brain injury.


Assuntos
Lesões Encefálicas , Microglia , Proteína 3 que Contém Domínio de Pirina da Família NLR , Piroptose , Piroptose/efeitos da radiação , Piroptose/fisiologia , Microglia/metabolismo , Microglia/efeitos da radiação , Microglia/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Camundongos , Humanos , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Lesões Encefálicas/etiologia , Masculino , Neurônios/metabolismo , Neurônios/patologia , Neurônios/efeitos da radiação , Técnicas de Cocultura , Lesões por Radiação/patologia , Lesões por Radiação/metabolismo , Feminino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade
9.
Cells ; 13(11)2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38891060

RESUMO

Mitochondrial aldehyde dehydrogenase-2 (ALDH2) metabolizes acetaldehyde to acetate. People with ALDH2 deficiency and Aldh2-knockout (KO) mice are more susceptible to alcohol-induced tissue damage. However, the underlying mechanisms behind ALDH2-related gut-associated brain damage remain unclear. Age-matched young female Aldh2-KO and C57BL/6J wild-type (WT) mice were gavaged with binge alcohol (4 g/kg/dose, three doses) or dextrose (control) at 12 h intervals. Tissues and sera were collected 1 h after the last ethanol dose and evaluated by histological and biochemical analyses of the gut and hippocampus and their extracts. For the mechanistic study, mouse neuroblast Neuro2A cells were exposed to ethanol with or without an Aldh2 inhibitor (Daidzin). Binge alcohol decreased intestinal tight/adherens junction proteins but increased oxidative stress-mediated post-translational modifications (PTMs) and enterocyte apoptosis, leading to elevated gut leakiness and endotoxemia in Aldh2-KO mice compared to corresponding WT mice. Alcohol-exposed Aldh2-KO mice also showed higher levels of hippocampal brain injury, oxidative stress-related PTMs, and neuronal apoptosis than the WT mice. Additionally, alcohol exposure reduced Neuro2A cell viability with elevated oxidative stress-related PTMs and apoptosis, all of which were exacerbated by Aldh2 inhibition. Our results show for the first time that ALDH2 plays a protective role in binge alcohol-induced brain injury partly through the gut-brain axis, suggesting that ALDH2 is a potential target for attenuating alcohol-induced tissue injury.


Assuntos
Aldeído-Desidrogenase Mitocondrial , Consumo Excessivo de Bebidas Alcoólicas , Lesões Encefálicas , Trato Gastrointestinal , Animais , Feminino , Camundongos , Aldeído-Desidrogenase Mitocondrial/metabolismo , Aldeído-Desidrogenase Mitocondrial/genética , Apoptose/efeitos dos fármacos , Consumo Excessivo de Bebidas Alcoólicas/patologia , Lesões Encefálicas/patologia , Lesões Encefálicas/metabolismo , Etanol/farmacologia , Etanol/toxicidade , Hipocampo/patologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Trato Gastrointestinal/lesões , Trato Gastrointestinal/metabolismo
10.
Med Eng Phys ; 127: 104163, 2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38692763

RESUMO

Explosions in the battlefield can result in brain damage. Research on the effects of shock waves on brain tissue mainly focuses on the effects of single-orientation blast waves, while there have been few studies on the dynamic response of the human brain to directional explosions in different planes, multi-point explosions and repetitive explosions. Therefore, the brain tissue response and the intracranial pressure (ICP) caused by different blast loadings were numerically simulated using the CONWEP method. In the study of the blast in different directions, the lateral explosion blast wave was found to cause greater ICP than did blasts from other directions. When multi-point explosions occurred in the sagittal plane simultaneously, the ICP in the temporal lobe increased by 37.8 % and the ICP in the parietal lobe decreased by 17.6 %. When multi-point explosions occurred in the horizontal plane, the ICP in the frontal lobe increased by 61.8 % and the ICP in the temporal lobe increased by 12.2 %. In a study of repetitive explosions, the maximum ICP of the second blast increased by 40.6 % over that of the first blast, and that of the third blast increased by 61.2 % over that of the second blast. The ICP on the brain tissue from repetitive blasts can exceed 200 % of that of a single explosion blast wave.


Assuntos
Traumatismos por Explosões , Lesões Encefálicas , Explosões , Pressão Intracraniana , Humanos , Lesões Encefálicas/fisiopatologia , Lesões Encefálicas/patologia , Traumatismos por Explosões/fisiopatologia , Traumatismos por Explosões/patologia , Encéfalo/fisiopatologia , Encéfalo/patologia
11.
Cell Rep Med ; 5(5): 101522, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38701781

RESUMO

Neuroinflammation plays a significant role in ischemic injury, which can be promoted by oxidized mitochondrial DNA (Ox-mtDNA). Cytidine/uridine monophosphate kinase 2 (CMPK2) regulates mtDNA replication, but its role in neuroinflammation and ischemic injury remains unknown. Here, we report that CMPK2 expression is upregulated in monocytes/macrophages and microglia post-stroke in humans and mice, respectively. Microglia/macrophage CMPK2 knockdown using the Cre recombination-dependent adeno-associated virus suppresses the inflammatory responses in the brain, reduces infarcts, and improves neurological outcomes in ischemic CX3CR1Cre/ERT2 mice. Mechanistically, CMPK2 knockdown limits newly synthesized mtDNA and Ox-mtDNA formation and subsequently blocks NLRP3 inflammasome activation in microglia/macrophages. Nordihydroguaiaretic acid (NDGA), as a CMPK2 inhibitor, is discovered to reduce neuroinflammation and ischemic injury in mice and prevent the inflammatory responses in primary human monocytes from ischemic patients. Thus, these findings identify CMPK2 as a promising therapeutic target for ischemic stroke and other brain disorders associated with neuroinflammation.


Assuntos
AVC Isquêmico , Microglia , Doenças Neuroinflamatórias , Animais , Humanos , Masculino , Camundongos , Lesões Encefálicas/patologia , Lesões Encefálicas/metabolismo , Lesões Encefálicas/genética , Isquemia Encefálica/patologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/genética , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Inflamassomos/metabolismo , AVC Isquêmico/patologia , AVC Isquêmico/metabolismo , AVC Isquêmico/genética , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Microglia/patologia , Monócitos/metabolismo , Monócitos/efeitos dos fármacos , Doenças Neuroinflamatórias/patologia , Doenças Neuroinflamatórias/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética
12.
Neurosci Biobehav Rev ; 162: 105720, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38754714

RESUMO

Limb apraxia is a motor disorder frequently observed following a stroke. Apraxic deficits are classically assessed with four tasks: tool use, pantomime of tool use, imitation, and gesture understanding. These tasks are supported by several cognitive processes represented in a left-lateralized brain network including inferior frontal gyrus, inferior parietal lobe (IPL), and lateral occipito-temporal cortex (LOTC). For the past twenty years, voxel-wise lesion symptom mapping (VLSM) studies have been used to unravel the neural correlates associated with apraxia, but none of them has proposed a comprehensive view of the topic. In the present work, we proposed to fill this gap by performing a systematic Anatomic Likelihood Estimation meta-analysis of VLSM studies which included tasks traditionally used to assess apraxia. We found that the IPL was crucial for all the tasks. Moreover, lesions within the LOTC were more associated with imitation deficits than tool use or pantomime, confirming its important role in higher visual processing. Our results questioned traditional neurocognitive models on apraxia and may have important clinical implications.


Assuntos
Apraxias , Humanos , Apraxias/fisiopatologia , Apraxias/diagnóstico por imagem , Apraxias/etiologia , Apraxias/patologia , Mapeamento Encefálico , Encéfalo/fisiopatologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Funções Verossimilhança , Lesões Encefálicas/fisiopatologia , Lesões Encefálicas/patologia , Lesões Encefálicas/diagnóstico por imagem , Acidente Vascular Cerebral/fisiopatologia , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/complicações
14.
Proc Natl Acad Sci U S A ; 121(22): e2400648121, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38781210

RESUMO

After central nervous system injury, a rapid cellular and molecular response is induced. This response can be both beneficial and detrimental to neuronal survival in the first few days and increases the risk for neurodegeneration if persistent. Semaphorin4B (Sema4B), a transmembrane protein primarily expressed by cortical astrocytes, has been shown to play a role in neuronal cell death following injury. Our study shows that after cortical stab wound injury, cytokine expression is attenuated in Sema4B-/- mice, and microglia/macrophage reactivity is altered. In vitro, Sema4B enhances the reactivity of microglia following injury, suggesting astrocytic Sema4B functions as a ligand. Moreover, injury-induced microglia reactivity is attenuated in the presence of Sema4B-/- astrocytes compared to Sema4B+/- astrocytes. In vitro experiments indicate that Plexin-B2 is the Sema4B receptor on microglia. Consistent with this, in microglia/macrophage-specific Plexin-B2-/- mice, similar to Sema4B-/- mice, microglial/macrophage reactivity and neuronal cell death are attenuated after cortical injury. Finally, in Sema4B/Plexin-B2 double heterozygous mice, microglial/macrophage reactivity is also reduced after injury, supporting the idea that both Sema4B and Plexin-B2 are part of the same signaling pathway. Taken together, we propose a model in which following injury, astrocytic Sema4B enhances the response of microglia/macrophages via Plexin-B2, leading to increased reactivity.


Assuntos
Astrócitos , Camundongos Knockout , Microglia , Proteínas do Tecido Nervoso , Semaforinas , Animais , Camundongos , Astrócitos/metabolismo , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Lesões Encefálicas/genética , Comunicação Celular , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Microglia/patologia , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/genética , Semaforinas/metabolismo , Semaforinas/genética
15.
Free Radic Biol Med ; 220: 271-287, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38734267

RESUMO

Bilirubin-induced brain damage is a serious clinical consequence of hyperbilirubinemia, yet the underlying molecular mechanisms remain largely unknown. Ferroptosis, an iron-dependent cell death, is characterized by iron overload and lipid peroxidation. Here, we report a novel regulatory mechanism of demethylase AlkB homolog 5 (ALKBH5) in acyl-coenzyme A synthetase long-chain family member 4 (ACSL4)-mediated ferroptosis in hyperbilirubinemia. Hyperdifferential PC12 cells and newborn Sprague-Dawley rats were used to establish in vitro and in vivo hyperbilirubinemia models, respectively. Proteomics, coupled with bioinformatics analysis, first suggested the important role of ferroptosis in hyperbilirubinemia-induced brain damage. In vitro experiments showed that ferroptosis is activated in hyperbilirubinemia, and ferroptosis inhibitors (desferrioxamine and ferrostatin-1) treatment effectively alleviates hyperbilirubinemia-induced oxidative damage. Notably, we observed that the ferroptosis in hyperbilirubinemia was regulated by m6A modification through the downregulation of ALKBH5 expression. MeRIP-seq and RIP-seq showed that ALKBH5 may trigger hyperbilirubinemia ferroptosis by stabilizing ACSL4 mRNA via m6A modification. Further, hyperbilirubinemia-induced oxidative damage was alleviated through ACSL4 genetic knockdown or rosiglitazone-mediated chemical repression but was exacerbated by ACSL4 overexpression. Mechanistically, ALKBH5 promotes ACSL4 mRNA stability and ferroptosis by combining the 669 and 2015 m6A modified sites within 3' UTR of ACSL4 mRNA. Our findings unveil a novel molecular mechanism of ferroptosis and suggest that m6A-dependent ferroptosis could be an underlying clinical target for the therapy of hyperbilirubinemia.


Assuntos
Homólogo AlkB 5 da RNA Desmetilase , Coenzima A Ligases , Ferroptose , Estabilidade de RNA , Ratos Sprague-Dawley , Animais , Ferroptose/genética , Ratos , Coenzima A Ligases/genética , Coenzima A Ligases/metabolismo , Homólogo AlkB 5 da RNA Desmetilase/metabolismo , Homólogo AlkB 5 da RNA Desmetilase/genética , Células PC12 , Cicloexilaminas/farmacologia , Humanos , Desferroxamina/farmacologia , Estresse Oxidativo , Lesões Encefálicas/metabolismo , Lesões Encefálicas/genética , Lesões Encefálicas/patologia , Lesões Encefálicas/etiologia , Fenilenodiaminas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Masculino , Modelos Animais de Doenças , Peroxidação de Lipídeos
16.
J Neuroinflammation ; 21(1): 116, 2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38702778

RESUMO

BACKGROUND: Subarachnoid hemorrhage (SAH), a severe subtype of stroke, is characterized by notably high mortality and morbidity, largely due to the lack of effective therapeutic options. Although the neuroprotective potential of PPARg and Nrf2 has been recognized, investigative efforts into oroxin A (OA), remain limited in preclinical studies. METHODS: SAH was modeled in vivo through filament perforation in male C57BL/6 mice and in vitro by exposing HT22 cells to hemin to induce neuronal damage. Following the administration of OA, a series of methods were employed to assess neurological behaviors, brain water content, neuronal damage, cell ferroptosis, and the extent of neuroinflammation. RESULTS: The findings indicated that OA treatment markedly improved survival rates, enhanced neurological functions, mitigated neuronal death and brain edema, and attenuated the inflammatory response. These effects of OA were linked to the suppression of microglial activation. Moreover, OA administration was found to diminish ferroptosis in neuronal cells, a critical factor in early brain injury (EBI) following SAH. Further mechanistic investigations uncovered that OA facilitated the translocation of nuclear factor erythroid 2-related factor 2 (Nrf-2) from the cytoplasm to the nucleus, thereby activating the Nrf2/GPX4 pathway. Importantly, OA also upregulated the expression of FSP1, suggesting a significant and parallel protective effect against ferroptosis in EBI following SAH in synergy with GPX4. CONCLUSION: In summary, this research indicated that the PPARg activator OA augmented the neurological results in rodent models and diminished neuronal death. This neuroprotection was achieved primarily by suppressing neuronal ferroptosis. The underlying mechanism was associated with the alleviation of cellular death through the Nrf2/GPX4 and FSP1/CoQ10 pathways.


Assuntos
Ferroptose , Camundongos Endogâmicos C57BL , Doenças Neuroinflamatórias , Hemorragia Subaracnóidea , Animais , Hemorragia Subaracnóidea/metabolismo , Hemorragia Subaracnóidea/patologia , Hemorragia Subaracnóidea/complicações , Ferroptose/efeitos dos fármacos , Ferroptose/fisiologia , Camundongos , Masculino , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/etiologia , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Lesões Encefálicas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/patologia
17.
J Neurosci Res ; 102(5): e25356, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38773875

RESUMO

From the blood brain barrier to the synaptic space, astrocytes provide structural, metabolic, ionic, and extracellular matrix (ECM) support across the brain. Astrocytes include a vast array of subtypes, their phenotypes and functions varying both regionally and temporally. Astrocytes' metabolic and regulatory functions poise them to be quick and sensitive responders to injury and disease in the brain as revealed by single cell sequencing. Far less is known about the influence of the local healthy and aging microenvironments on these astrocyte activation states. In this forward-looking review, we describe the known relationship between astrocytes and their local microenvironment, the remodeling of the microenvironment during disease and injury, and postulate how they may drive astrocyte activation. We suggest technology development to better understand the dynamic diversity of astrocyte activation states, and how basal and activation states depend on the ECM microenvironment. A deeper understanding of astrocyte response to stimuli in ECM-specific contexts (brain region, age, and sex of individual), paves the way to revolutionize how the field considers astrocyte-ECM interactions in brain injury and disease and opens routes to return astrocytes to a healthy quiescent state.


Assuntos
Astrócitos , Encéfalo , Matriz Extracelular , Astrócitos/fisiologia , Astrócitos/metabolismo , Matriz Extracelular/metabolismo , Matriz Extracelular/fisiologia , Humanos , Animais , Encéfalo/metabolismo , Lesões Encefálicas/patologia , Lesões Encefálicas/metabolismo
18.
Int Immunopharmacol ; 135: 112311, 2024 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-38781607

RESUMO

OBJECTIVE: Obstructive Sleep Apnea (OSA) during pregnancy is characterized by intermittent hypoxia (IH) during sleep and will lead to the rise of oxidative stress in the fetal body. Pyroptosis, a type of inflammatory and programmable cell death mediated by Gasdermin D (GSDMD), plays a substantial role in oxygen deprivation's contribution to neural system damage. Existing research shows that Nicotinamide Adenine Dinucleotide Phosphate (NADPH) plays a protective role in alleviating brain tissue pyroptosis. We speculate that exogenous NADPH may play a protective role in OSA during pregnancy. METHODS: A model of GIH group was established to simulate the pathophysiological mechanisms of OSA during pregnant and AIR group was established by giving the same frequency. Sham group was established by injecting NS and the NADPH group was established and given exogenous NADPH. We utilized the Morris Water Maze to assess cognitive function impairment, Luxol Fast Blue (LBF) staining to confirm myelin sheath formation, TUNEL staining to examine cell death in fetal mice brain tissue, and Western blotting to detect pertinent protein expressions. RESULTS: The GIH group offspring exhibited decreases in spatial learning and memory abilities, reduced numbers of oligodendrocytes and formed myelin, as well as increased expression of pyroptosis-related proteins. The NADPH group offspring showed restoration in spatial learning and memory abilities increased counts of oligodendrocytes and formed myelin sheaths, in addition to decreased expression of pyroptosis-related. CONCLUSIONS: This study demonstrates that early injection of exogenous NADPH can alleviate the damage to fetal brain development caused by gestational intermittent hypoxia (GIH).


Assuntos
NADP , Piroptose , Animais , Gravidez , Feminino , Camundongos , NADP/metabolismo , Lesões Encefálicas/patologia , Lesões Encefálicas/metabolismo , Hipóxia/metabolismo , Encéfalo/patologia , Encéfalo/metabolismo , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos C57BL , Efeitos Tardios da Exposição Pré-Natal
19.
J Neuroinflammation ; 21(1): 83, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38581043

RESUMO

BACKGROUND: It is well established that traumatic brain injury (TBI) causes acute and chronic alterations in systemic immune function and that systemic immune changes contribute to posttraumatic neuroinflammation and neurodegeneration. However, how TBI affects bone marrow (BM) hematopoietic stem/progenitor cells chronically and to what extent such changes may negatively impact innate immunity and neurological function has not been examined. METHODS: To further understand the role of BM cell derivatives on TBI outcome, we generated BM chimeric mice by transplanting BM from chronically injured or sham (i.e., 90 days post-surgery) congenic donor mice into otherwise healthy, age-matched, irradiated CD45.2 C57BL/6 (WT) hosts. Immune changes were evaluated by flow cytometry, multiplex ELISA, and NanoString technology. Moderate-to-severe TBI was induced by controlled cortical impact injury and neurological function was measured using a battery of behavioral tests. RESULTS: TBI induced chronic alterations in the transcriptome of BM lineage-c-Kit+Sca1+ (LSK+) cells in C57BL/6 mice, including modified epigenetic and senescence pathways. After 8 weeks of reconstitution, peripheral myeloid cells from TBI→WT mice showed significantly higher oxidative stress levels and reduced phagocytic activity. At eight months after reconstitution, TBI→WT chimeric mice were leukopenic, with continued alterations in phagocytosis and oxidative stress responses, as well as persistent neurological deficits. Gene expression analysis revealed BM-driven changes in neuroinflammation and neuropathology after 8 weeks and 8 months of reconstitution, respectively. Chimeric mice subjected to TBI at 8 weeks and 8 months post-reconstitution showed that longer reconstitution periods (i.e., time post-injury) were associated with increased microgliosis and leukocyte infiltration. Pre-treatment with a senolytic agent, ABT-263, significantly improved behavioral performance of aged C57BL/6 mice at baseline, although it did not attenuate neuroinflammation in the acutely injured brain. CONCLUSIONS: TBI causes chronic activation and progressive dysfunction of the BM stem/progenitor cell pool, which drives long-term deficits in hematopoiesis, innate immunity, and neurological function, as well as altered sensitivity to subsequent brain injury.


Assuntos
Lesões Encefálicas Traumáticas , Lesões Encefálicas , Camundongos , Animais , Doenças Neuroinflamatórias , Camundongos Endogâmicos C57BL , Lesões Encefálicas Traumáticas/patologia , Lesões Encefálicas/patologia , Encéfalo/metabolismo
20.
Neuroreport ; 35(8): 536-541, 2024 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-38597261

RESUMO

Transfer RNAs (tRNAs) can regulate cell behavior and are associated with neurological disorders. Here, we aimed to investigate the expression levels of tRNAs in oligodendrocyte precursor cells (OPCs) and their possible roles in the regulation of brain white matter injury (WMI). Newborn Sprague-Dawley rats (postnatal day 5) were used to establish a model that mimicked neonatal brain WMI. RNA-array analysis was performed to examine the expression of tRNAs in OPCs. psRNAtarget software was used to predict target mRNAs of significantly altered tRNAs. Gene ontology (GO) and KEGG were used to analyze the pathways for target mRNAs. Eighty-nine tRNAs were changed after WMI (fold change absolute ≥1.5, P  < 0.01), with 31 downregulated and 58 upregulated. Among them, three significantly changed tRNAs were identified, with two being significantly increased (chr10.trna1314-ProTGG and chr2.trna2771-ProAGG) and one significantly decreased (chr10.trna11264-GlyTCC). Further, target mRNA prediction and GO/KEGG pathway analysis indicated that the target mRNAs of these tRNAs are mainly involved in G-protein coupled receptor signaling pathways and beta-alanine metabolism, which are both related to myelin formation. In summary, the expression of tRNAs in OPCs was significantly altered after brain WMI, suggesting that tRNAs may play important roles in regulating WMI. This improves the knowledge about WMI pathophysiology and may provide novel treatment targets for WMI.


Assuntos
RNA de Transferência , Ratos Sprague-Dawley , Substância Branca , Animais , RNA de Transferência/metabolismo , RNA de Transferência/genética , Substância Branca/metabolismo , Substância Branca/patologia , Ratos , Animais Recém-Nascidos , Células Precursoras de Oligodendrócitos/metabolismo , Lesões Encefálicas/metabolismo , Lesões Encefálicas/genética , Lesões Encefálicas/patologia , RNA Mensageiro/metabolismo
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