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Telomerase plays a pivotal role in tumorigenesis by both telomere-dependent and telomere-independent activities, although the underlying mechanisms are not completely understood. Using single-sample gene set enrichment analysis (ssGSEA) across 9,264 tumour samples, we observe that expression of telomerase reverse transcriptase (TERT) is closely associated with immunosuppressive signatures. We demonstrate that TERT can activate a subclass of endogenous retroviruses (ERVs) independent of its telomerase activity to form double-stranded RNAs (dsRNAs), which are sensed by the RIG-1/MDA5-MAVS signalling pathway and trigger interferon signalling in cancer cells. Furthermore, we show that TERT-induced ERV/interferon signalling stimulates the expression of chemokines, including CXCL10, which induces the infiltration of suppressive T-cell populations with increased percentage of CD4+ and FOXP3+ cells. These data reveal an unanticipated role for telomerase as a transcriptional activator of ERVs and provide strong evidence that TERT-mediated ERV/interferon signalling contributes to immune suppression in tumours.
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Retrovirus Endógenos , Neoplasias , Telomerase , Microambiente Tumoral , RNA Polimerases Dirigidas por DNA/metabolismo , Retrovirus Endógenos/genética , Humanos , Neoplasias/imunologia , Neoplasias/virologia , Telomerase/genética , Telomerase/metabolismo , Telômero/metabolismo , Microambiente Tumoral/genéticaRESUMO
Solar-powered photocatalytic conversion of CO2 to hydrocarbon fuels represents an emerging approach to solving the greenhouse effect. However, low charge separation efficiency, deficiency of surface catalytic active sites, and sluggish charge-transfer kinetics, together with the complicated reaction pathway, concurrently hinder the CO2 reduction. Herein, we show the rational construction of transition metal chalcogenides (TMCs) heterostructure CO2 reduction photosystems, wherein the TMC substrate is tightly integrated with amorphous oxygen-containing cobalt sulfide (CoSOH) by a solid non-conjugated polymer, i.e., poly(vinyl alcohol) (PVA), to customize the unidirectional charge-transfer pathway. In this well-defined multilayered nanoarchitecture, the PVA interim layer intercalated between TMCs and CoSOH acts as a hole-relaying mediator and meanwhile boosts CO2 adsorption capacity, while CoSOH functions as a terminal hole-collecting reservoir, stimulating the charge transport kinetics and boosting the charge separation over TMCs. This peculiar interface configuration and charge transport characteristics endow TMC/PVA/CoSOH heterostructures with significantly enhanced visible-light-driven photoactivity and CO2 conversion. Based on the intermediates probed during the photocatalytic CO2 reduction reaction, the photocatalytic mechanism was determined. Our work would inspire sparkling ideas to mediate the charge transfer over semiconductor for solar carbon neutral conversion.
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OBJECTIVE: To analyze and explore the risk factors for neurological symptoms in patients with purely hepatic Wilson's disease (WD) at diagnosis. METHODS: This retrospective study was conducted at the First Affiliated Hospital of the Guangdong Pharmaceutical University on 68 patients with purely hepatic WD aged 20.6 ± 7.2 years. The physical examinations, laboratory tests, color Doppler ultrasound of the liver and spleen, and magnetic resonance imaging (MRI) of the brain were performed. RESULTS: The elevated alanine transaminase (ALT) and aspartate transaminase (AST) levels and 24-h urinary copper level were higher in the purely hepatic WD who developed neurological symptoms (NH-WD) group than those in the purely hepatic WD (H-WD) group. Adherence to low-copper diet, and daily oral doses of penicillamine (PCA) and zinc gluconate (ZG) were lower in the NH-WD group than those in the H-WD group. Logistic regression analysis showed that insufficient doses of PCA and ZG were associated with the development of neurological symptoms in patients with purely hepatic WD at diagnosis. CONCLUSION: The development of neurological symptoms in patients with purely hepatic WD was closely associated with insufficient doses of PCA and ZG, and the inferior efficacy of copper-chelating agents. During the course of anti-copper treatment, the patient's medical status and the efficacy of copper excretion should be closely monitored.
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Degeneração Hepatolenticular , Humanos , Encéfalo , Cobre , Degeneração Hepatolenticular/complicações , Degeneração Hepatolenticular/tratamento farmacológico , Penicilamina/uso terapêutico , Estudos Retrospectivos , Fatores de Risco , Zinco/uso terapêuticoRESUMO
Shear stress is an important index to evaluate the rheological behavior of magnetorheological fluids (MRFs), which is not only related to the properties of ferromagnetic particles, but also the viscosity of the carrier. However, the research related to the carrier viscosity is quite lacking, and the mechanism of its effect on shear stress is still unclear. In this work, the carrier viscosity effect on the microstructure of MRFs under shearing was investigated via numerical simulations, and the relationship between chain inclination and carrier viscosity was presented for the first time. It was found that the deflection angle of the chain increases with the increase of carrier viscosity. Based on the simulation results, the relationship between the shear resistance induced by the magnetic field and the deflection angle of the chain was studied. Finally, a constitutive model incorporating the mechanism of the viscosity effect on shear stress was proposed, and the calculated results agreed well with the experimental data. This work provides new insights into the effect of carrier viscosity and can help us to better understand the corresponding microscopic mechanism.
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[This corrects the article DOI: 10.7150/ijms.26954.].
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Glycine has been shown to protect against ischemic stroke through various mechanisms. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) which antagonize Akt-dependent cell survival has been linked to neuronal damage. However, whether glycine has a neuroprotective property in intracerebral hemorrhage (ICH) was unknown. This study aimed to determine the protective effect of glycine in rats ICH. Adult male Sprague-Dawley (SD) rats were subjected to left striatum infusion of autologous blood. ICH animals received glycine (0.2-3â¯mg/kg, icv) at 1â¯h after ICH with or without pre-injection of Akt Inhibitor IV (100⯵M, 2⯵l, icv) 0.5â¯h prior to glycine treatment. Our results showed that in the perihematomal area PTEN was up-regulated in the early stage after ICH. However, glycine treatment decreased PTEN protein level and increased the phosphorylation level of AKT (p-AKT) in the perihematomal area. With the administration of glycine, neuronal death was significantly reduced and Evans blue leakage was alleviated as well as the brain edema after ICH. Moreover, hematoma volume was decreased and neurobehavioral outcome was improved. Nevertheless, Akt Inhibitor IV abolished the neuroprotective effects of glycine after ICH. Together, our findings demonstrate, for the first time, the protective role of glycine on ICH rats, and suggest that the neuroprotective effect of glycine was mediated through PTEN/Akt signal pathway.
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Hemorragia Cerebral/tratamento farmacológico , Hemorragia Cerebral/metabolismo , Glicina/farmacologia , Neuroproteção/efeitos dos fármacos , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Benzimidazóis/farmacologia , Benzotiazóis/farmacologia , Edema Encefálico/tratamento farmacológico , Edema Encefálico/metabolismo , Edema Encefálico/patologia , Morte Celular/efeitos dos fármacos , Hemorragia Cerebral/patologia , Modelos Animais de Doenças , Masculino , Neurônios/efeitos dos fármacos , Neurônios/patologia , Fármacos Neuroprotetores/farmacologia , PTEN Fosfo-Hidrolase/antagonistas & inibidores , Fosforilação , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacosRESUMO
Bisperoxovanadium (pyridine-2-carboxyl) [bpV(pic)] is a commercially available PTEN inhibitor. Previous studies from us and others have shown that bpV(pic) confers neuroprotection in cerebral ischemia injury. We set up to determine whether ERK 1/2 activation plays a role in bpV(pic)-induced neuroprotective effect in cerebral ischemia injury. We found that the phosphorylation levels of Akt (p-AKT) and ERK1/2 (p-ERK 1/2) were down-regulated after cerebral ischemia-reperfusion injury. The injection of bpV(pic) after injury not only increased the level of p-AKT but also the level of p-ERK 1/2. While the inhibition of PTEN mediated the up-regulatation of p-AKT and p-ERK 1/2 by bpV(pic). Interestingly, the ERK 1/2 activation induced by bpV(pic) was also independent of the inhibition of PTEN. Our results indicate that bpV(pic) protects against OGD-induced neuronal death and promotes the functional recovery of stroke animals through PTEN inhibition and ERK 1/2 activation, respectively. This study suggests that the effect of bpV(pic) on ERK 1/2 signaling should be considered while using bpV(pic) as a PTEN inhibitor.
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Lesões Encefálicas/tratamento farmacológico , Isquemia Encefálica/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Compostos de Vanádio/farmacologia , Animais , Modelos Animais de Doenças , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/efeitos dos fármacosRESUMO
Renal tubule cell apoptosis plays a pivotal role in the progression of chronic renal diseases. The previous study indicates that Sirolimus is effective on unilateral ureteral obstruction (UUO)-induced renal fibrosis. However, the role of Sirolimus in renal tubular apoptosis induced by UUO has not yet been addressed. The aim of this study was to determine the role of Sirolimus in renal tubular apoptosis induced by UUO. Male Sprague-Dawley rats were divided into three groups, sham-operated rats, and after which unilateral ureteral obstruction (UUO) was performed: non-treated and sirolimus-treated (1mg/kg). After 4, 7 and 14 d, animals were sacrificed and blood, kidney tissue samples were collected for analyses. Histologic changes and interstitial collagen were determined microscopically following HE and Masson's trichrome staining. The expression of PCNA was investigated using immunohistochemistry and the expression of Bcl-2, Bax, caspase-9, and caspase-3 were investigated using Western blot in each group. Tubular apoptotic cell deaths were assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay. Sirolimus administration resulted in a significant reduction in tubulointerstitial fibrosis scores. After UUO, there was an increase in tubular and interstitial apoptosis in untreated controls as compared to Sirolimus treatment rats (P<0.05). In addition, the expression of PCNA, Bcl-2, Bax, caspase-9, and caspase-3 in obstructed kidney was characterized by immunohistochemistry and Western blot analyses demonstrating that sirolimus treatment significantly reduced PCNA, Bax, caspase-9 and cleaved caspase-3 expression compared to those observed in controls (P<0.05), whereas, Bcl-2 in the obstructed kidney were decreased in untreated controls compared to Sirolimus treatment rats subjected to the same time course of obstruction (P<0.05). We demonstrated a marked renoprotective effect of sirolimus by inhibition of UUO-induced renal tubular apoptosis in vivo.
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Sirolimo/uso terapêutico , Obstrução Ureteral/tratamento farmacológico , Obstrução Ureteral/metabolismo , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 9/metabolismo , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Antígeno Nuclear de Célula em Proliferação/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RatosRESUMO
This study aimed to examine the impact of trivalent, divalent, or monovalent cations dissolving into water and being mixed with maize starch to influence its retrogradation, gelatinization, and gel characteristics. The result of the analysis using a differential scanning calorimeter showed that all cations raised the peak of gelatinization temperature of maize starch, especially Al3+ or Fe3+, while trivalent cations reduced the enthalpy. The result of the analysis using a rapid viscosity analyzer showed that trivalent cation caused lower trough viscosity, final viscosity, and pasting temperature but higher breakdown viscosity of maize starch than monovalent or divalent cations. Confocal laser scanning microscopy showed that the cation promoted the destruction of gelatinized maize starch granules, especially Zn2+, Fe3+, or Al3+. Additionally, trivalent Fe3+ or Al3+ caused higher gel strength of maize starch. Generally, the cation with higher valence changed more retrogradation, gelatinization, and gel characteristics of maize starch.
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Cátions , Géis , Amido , Zea mays , Zea mays/química , Amido/química , Géis/química , Cátions/química , Viscosidade , Temperatura , Gelatina/químicaRESUMO
Pyruvate kinase M2 (PKM2) is a key metabolic enzyme. Yet, its role in cerebral ischemia injury remains unclear. In this study we demonstrated that PKM2 expression was increased in the microglia after mouse cerebral ischemia-reperfusion (I/R) injury. We found that microglial polarization-mediated pro-inflammatory effect was mediated by PKM2 after cerebral I/R. Mechanistically, our results revealed that nuclear PKM2 mediated ischemia-induced microglial polarization through association with acetyl-H3K9. Hif-1α mediated the effect of nuclear PKM2/histone H3 on microglial polarization. PKM2-dependent Histone H3/Hif-1α modifications contributed the expression of CCL2 and induced up-regulation of microglial polarization in peri-infarct, resulting in neuroinflammation. Inhibiting nuclear translocation of microglial PKM2 reduced ischemia-induced pro-inflammation and promoted neuronal survival. Together, this study identifies nucleus PKM2 as a crucial mediator for regulating ischemia-induced neuroinflammation, suggesting PKM2 as a potential therapeutic target in ischemic stroke.
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Cations can combine with starch and alter its physicochemical characteristics. The addition of cations may influence the in vitro digestion of potato starch. Scanning electron microscopy, X-ray diffraction, low-field nuclear magnetic resonance, and Fourier transform infrared spectroscopy were used to measure the microstructure, relative crystallinity, water distribution, and interaction of potato starch with cations and characterize its digestibility. The results showed that all cations decreased rapidly digestible starch (RDS) at a low concentration but increased the RDS with the addition of cations, especially trivalent cations. However, the resistant starch (RS) had the opposite trend. All cations increased the relative crystallinity of potato starch, except Ca2+. Fe3+, and Al3+ markedly decreased the mobility and hydrogen bonds in potato starch. In general, the addition of cations influenced the retrogradation of potato starch, resulting in a change in its digestibility.
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Solanum tuberosum , Espectroscopia de Infravermelho com Transformada de Fourier , Solanum tuberosum/química , Raios X , Amido/química , Difração de Raios X , Espectroscopia de Ressonância MagnéticaRESUMO
The objective of this study was to investigate effects of anthocyanins (AC) and microbial transglutaminase (MTGase) on the physicochemical properties of surimi gels from silver carp. The addition of AC and MTGase significantly increased gel strength and water holding capacity (WHC) of surimi gels, but the effect of MTGase was much stronger (p < .05). There were the highest gel strength, storage modulus (G') and WHC with 0.1 g/100 g AC and 0.4 g/100 g MTGase, while they were higher than that with AC or MTGase alone. AC promoted the cross-linking mainly by covalent and non-covalent bonds in surimi gels, while MTGase did mainly through covalent bonds. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) confirmed the results of gel strength, WHC, chemical interactions and G' of surimi gel or paste with AC and MTGase. In general, AC and MTGase could synergistically improve the physicochemical properties of surimi gels and potentially enhance the quality of surimi-based product from silver carp.
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Antocianinas , Carpas , Animais , Transglutaminases/química , Géis/química , ÁguaRESUMO
The present study aimed to investigate effects of pH and monovalent (Na+ and K+)/divalent (Ca2+ and Mg2+) cations on the structural and physicochemical properties of myofibrillar protein (MP) from silver carp. MP treated with divalent cation had lesser change for the structure than that treated with monovalent cation. Ca2+-ATPase activity of MP treated with monovalent cation was increased firstly and then decreased, while that treated with divalent cation was decreased with increasing ionic strength. Surface hydrophobicity and Z-average of MP treated with divalent cations was lower than that with monovalent cations, while they decreased and then increased with the pH shifting from 3.0 to 9.0. Zeta potential of MP was increased and then decreased with increasing the pH but decreased and then increased with increasing ionic strength. In general, the pH and monovalent/divalent cations could cause various hydrophobic and electrostatic interactions, resulting in changes of the physicochemical properties of MP.
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Carpas , Animais , Cátions Monovalentes/química , Cátions Bivalentes/química , Carpas/metabolismo , Sódio/metabolismo , Concentração de Íons de Hidrogênio , CátionsRESUMO
Severe microenvironmental changes after spinal cord injury (SCI) present serious challenges in neural regeneration and tissue repair. Gelatin (GL)- and hyaluronic acid (HA)-based hydrogels are attractive scaffolds because they are major components of the extracellular matrix and can provide a favorable adjustable microenvironment for neurogenesis and motor function recovery. In this study, three-dimensional hybrid GL/HA hydrogel scaffolds were prepared and optimized. The hybrid hydrogels could undergoin situgelation and fit the defects perfectly via visible light-induced crosslinking in the complete SCI rats. We found that the transplantation of the hybrid hydrogel scaffold significantly reduced the inflammatory responses and suppressed glial scar formation in an HA concentration-dependent manner. Moreover, the hybrid hydrogel with GL/HA ratios less than 8/2 effectively promoted endogenous neural stem cell migration and neurogenesis, as well as improved neuron maturation and axonal regeneration. The results showed locomotor function improved 60 days after transplantation, thus suggesting that GL/HA hydrogels can be considered as a promising scaffold for complete SCI repair.
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Gelatina/química , Ácido Hialurônico , Traumatismos da Medula Espinal/metabolismo , Regeneração da Medula Espinal/efeitos dos fármacos , Alicerces Teciduais/química , Animais , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Reagentes de Ligações Cruzadas/química , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Feminino , Ácido Hialurônico/química , Ácido Hialurônico/farmacologia , Neurogênese/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
Acute lung injury (ALI) is the leading cause of bacterial sepsis-related death because of disrupted pulmonary endothelial barrier, resulting in protein-rich pulmonary oedema, an influx of pro-inflammatory cells and refractory hypoxaemia. Several studies have reported that C3a levels are significantly higher in organs with sepsis and their peripheral organs and are closely associated with organ dysfunction and poor prognosis in sepsis. However, the role of the C3a complement in sepsis ALI remains unclear. Therefore, this study aimed to investigate the important role and mechanism of C3a in preventing the occurrence of pyroptosis (a pro-inflammatory form of cell death) to protect the lung endothelial cells (ECs) in sepsis-induced ALI. A septic mouse model was established with cecal ligation and puncture (CLP), which demonstrated that C3a mediated EC pyroptosis through its C3aR receptor. Furthermore, inhibition of the C3a-C3aR axis could block both NLRP3/caspase-1 and caspase-11 pathways, thus preventing pulmonary EC from pyroptosis. These results indicate that inhibition of the C3A-C3AR complement axis can inhibit pulmonary vascular EC pyroptosis, a potential target for the treatment of ALI.
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Lesão Pulmonar Aguda , Sepse , Lesão Pulmonar Aguda/metabolismo , Animais , Caspases/metabolismo , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Piroptose , Sepse/complicações , Sepse/metabolismoRESUMO
Background: We and others have previously demonstrated that glycine is neuroprotective in cerebral ischemia-reperfusion injury. But glycine has low permeability to the blood-brain barrier (BBB). To deliver glycine into the ischemic brain to confer neuroprotection, we designed a novel glycine-containing and BBB-permeable tripeptide, the H-glycine-cysteine-phenylalanine-OH (GCF). Methods: For the synthesis of GCF, phenylalanine was included to increase the BBB permeability of the tripeptide. Cysteine was conjugated with glycine to enable the release of glycine from GCF. With the use of immunofluorescence labeling and HPLC assays, we measured the distribution and level of GCF. We used TTC labeling, LDH release, and MTT assays to evaluate the neuroprotective effect of GCF. Results: Following intravenous injection in a rat model of cerebral ischemia-reperfusion injury, GCF was intensively distributed in the ischemic neurons. Intravenous injection of GCF, but not the non-cleavable acetyl-GCF, resulted in the elevation of glycine in the ischemic brain. GCF but not acetyl-GC conferred neuroprotection in ischemic stroke animals. Conclusion: GCF protects against cerebral ischemia-reperfusion injury in the rat. In contrast to peptide drugs that exert therapeutic effect by interfering with signaling interaction, GCF acts as a BBB shuttle and prodrug to deliver glycine to confer neuroprotection, representing a novel therapeutic strategy for acute ischemic stroke.
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OBJECTIVE: To observe the protective effect of AC-YVAD-CMK on sepsis-induced acute kidney injury in mice and to explore its possible mechanisms primarily. METHODS: Eighteen male C57BL/6 mice were randomly divided into sham-operated group (Control), cecal ligation and puncture group (CLP), and CLP model treated with AC-YVAD-CMK group (AC-YVAD-CMK) (n = 6 in each group). Mice were sacrificed at 24 h after operation, and blood and kidney tissue samples were collected for analyses. Histologic changes were determined microscopically following HE staining. The expression of Ly-6B and CD68 was investigated using immunohistochemistry. Serum concentrations of creatinine (sCR) and blood urea nitrogen (BUN) were measured. Serum levels of interleukin-1ß (IL-1ß), interleukin-18 (IL-18), TNF-α, and interleukin-6 (IL-6) were determined by ELISA. The expressions of Caspas-1, NLRP-1, IL-1ß, and IL-18 in renal tissues were investigated using Western blot. Immunofluorescence staining was used to detect the expression of GSDMD protein in renal tissues. RESULTS: AC-YVAD-CMK treatment significantly alleviates sepsis-induced acute kidney injury, with decreased histological injury in renal tissues, suppresses the accumulation of neutrophils and macrophages in renal tissues, and decreased sCR and BUN level (P < 0.05). Attenuation of sepsis-induced acute kidney injury was due to the prohibited production of inflammatory cytokines and decrease expression of Caspas-1, NLRP-1, IL-1ß, and IL-18 in renal tissues. In addition, AC-YVAD-CMK treatment significantly reduced the expression of GSDMD in renal tissues compared to those observed in controls (P < 0.05). CONCLUSIONS: We demonstrated a marked renoprotective effect of caspase-1-inhibitor AC-YVAD-CMK in a rat model of sepsis by inhibition of pyroptosis.
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Injúria Renal Aguda/tratamento farmacológico , Clorometilcetonas de Aminoácidos/farmacologia , Caspase 1/metabolismo , Inibidores de Caspase/farmacologia , Piroptose/efeitos dos fármacos , Sepse/tratamento farmacológico , Injúria Renal Aguda/metabolismo , Animais , Antígenos CD/biossíntese , Antígenos de Diferenciação Mielomonocítica/biossíntese , Nitrogênio da Ureia Sanguínea , Creatinina , Citocinas/metabolismo , Interleucina-18/biossíntese , Interleucina-1beta/biossíntese , Interleucina-6/biossíntese , Rim/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/metabolismo , Sepse/metabolismoRESUMO
Neuroinflammation is a secondary response following ischemia stroke. Arginine is a non-essential amino acid that has been shown to inhibit acute inflammatory reaction. In this study we show that arginine treatment decreases neuronal death after rat cerebral ischemia/reperfusion (I/R) injury and improves functional recovery of stroke animals. We also show that arginine suppresses inflammatory response in the ischemic brain tissue and in the cultured microglia after OGD insult. We further provide evidence that the levels of HIF-1α and LDHA are increased after rat I/R injury and that arginine treatment prevents the elevation of HIF-1α and LDHA after I/R injury. Arginine inhibits inflammatory response through suppression of HIF-1α and LDHA in the rat ischemic brain tissue and in the cultured microglia following OGD insult, and protects against ischemic neuron death after rat I/R injury by attenuating HIF-1α/LDHA-mediated inflammatory response. Together, these results indicate a possibility that arginine-induced neuroprotective effect may be through the suppression of HIF-1α/LDHA-mediated inflammatory response in microglia after cerebral ischemia injury.
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Arginina/uso terapêutico , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Inflamação/patologia , Fármacos Neuroprotetores/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Arginina/farmacologia , Morte Celular , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/patologia , L-Lactato Desidrogenase/metabolismo , Masculino , Microglia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Neuroproteção , Fármacos Neuroprotetores/farmacologia , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Transdução de Sinais/efeitos dos fármacosRESUMO
l-lysine is a basic amino acid that has been shown to exert neuroprotective effect. However, the underlying mechanism remains to be elucidated. In this study, we investigate how l-lysine exerts its neuroprotective effect in hemin-insulted mouse cortical neurons in vitro and the mouse model of intracerebral hemorrhage (ICH) in vivo. We demonstrate that l-lysine treatment promotes M2 microglial polarization and reduces inflammatory response both in vitro and in vivo, suggesting that l-lysine may play a neuroprotective role in ICH injury. Indeed, we show that l-lysine treatment reduces cortical neuronal death after hemin insult in vitro and decrease the number of degenerating neurons after ICH in vivo. l-lysine also improves the functional recovery of ICH animals in neurobehavioral tests. Consistent with the role of PTEN in regulating inflammatory response, we find that PTEN inhibition promotes M2 microglial polarization and suppresses pro-inflammatory response in mouse ICH injury, which contribute to the neuroprotective effect of l-lysine. Moreover, our results reveal that microRNA-575 directly suppressed PTEN to promote M2 microglial polarization and mediate the neuroprotective effect of l-lysine in ICH injury. Together, our results suggest that l-lysine confers neuroprotection after ICH injury through enhancing M2 microglial polarization and reducing inflammatory response, which is mediated by microRNA-575 upregulation and subsequent PTEN downregulation.
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Hemorragia Cerebral/metabolismo , Inflamação/tratamento farmacológico , Lisina/farmacologia , MicroRNAs/metabolismo , Fármacos Neuroprotetores/farmacologia , PTEN Fosfo-Hidrolase/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Polaridade Celular/efeitos dos fármacos , Hemorragia Cerebral/complicações , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Inflamação/etiologia , Inflamação/metabolismo , Lisina/uso terapêutico , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Regulação para Cima/efeitos dos fármacosRESUMO
A batch culture experiment was conducted to study the interactive effects of ocean acidification (OA) and solar ultraviolet radiation (UVR, 280-400 nm) on the harmful dinoflagellate Karenia mikimotoi. Cells were incubated in 7-days trials under four treatments. Physiological (growth, pigments, UVabc) and toxicity (hemolytic activity and its toxicity to zebrafish embryos) response variables were measured in four treatments, representing two factorial combinations of CO2 (400 and 1000 µatm) and solar irradiance (with or without UVR). Toxic species K. mikimotoi showed sustained growth in all treatments, and there was not statistically significant difference among four treatments. Cell pigment content decreased, but UVabc and hemolytic activity increased in all HC treatments and PAB conditions. The toxicity to zebrafish embryos of K. mikimotoi was not significantly different among four treatments. All HC and UVR conditions and the combinations of HC*UVR (HC-PAB) positively affected the UVabc, hemolytic activity in comparison to the LC*P (LC-P) treatment, and negatively affected the pigments. Ocean acidification (OA) was probably the main factor that affected the chlorophyll-a (Chl-a) and UVabc, but UVR was the main factor that affected the carotenoid (Caro) and hemolytic activity. There were no significant interactive effects of OA*UVR on growth, toxicity to zebrafish embryos. If these results are extrapolated to the natural environment, it can be hypothesized that this strain (DP-C32) of K. mikimotoi cells have the efficient mechanisms to endure the combination of ocean acidification and solar UVR. It is assumed that this toxic strain could form harmful bloom and enlarge the threatening to coastal communities, marine animals, even human health under future conditions.