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The interplay between circadian rhythms and epilepsy has gained increasing attention. The suprachiasmatic nucleus (SCN), which acts as the master circadian pacemaker, regulates physiological and behavioral rhythms through its complex neural networks. However, the exact role of the SCN and its Bmal1 gene in the development of epilepsy remains unclear. In this study, we utilized a lithium-pilocarpine model to induce epilepsy in mice and simulated circadian disturbances by creating lesions in the SCN and specifically knocking out the Bmal1 gene in the SCN neurons. We observed that the pilocarpine-induced epileptic mice experienced increased daytime seizure frequency, irregular oscillations in core body temperature, and circadian gene alterations in both the SCN and the hippocampus. Additionally, there was enhanced activation of GABAergic projections from the SCN to the hippocampus. Notably, SCN lesions intensified seizure activity, concomitant with hippocampal neuronal damage and GABAergic signaling impairment. Further analyses using the Gene Expression Omnibus database and gene set enrichment analysis indicated reduced Bmal1 expression in patients with medial temporal lobe epilepsy, potentially affecting GABA receptor pathways. Targeted deletion of Bmal1 in SCN neurons exacerbated seizures and pathology in epilepsy, as well as diminished hippocampal GABAergic efficacy. These results underscore the crucial role of the SCN in modulating circadian rhythms and GABAergic function in the hippocampus, aggravating the severity of seizures. This study provides significant insights into how circadian rhythm disturbances can influence neuronal dysfunction and epilepsy, highlighting the therapeutic potential of targeting SCN and the Bmal1 gene within it in epilepsy management.
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Ritmo Circadiano , Hipocampo , Ratones Endogámicos C57BL , Núcleo Supraquiasmático , Animales , Núcleo Supraquiasmático/metabolismo , Ratones , Hipocampo/metabolismo , Factores de Transcripción ARNTL/genética , Factores de Transcripción ARNTL/metabolismo , Masculino , Epilepsia/inducido químicamente , Epilepsia/metabolismo , Epilepsia/genética , Pilocarpina , Convulsiones/metabolismo , Convulsiones/inducido químicamente , Convulsiones/genética , Convulsiones/fisiopatología , Ratones Noqueados , Neuronas GABAérgicas/metabolismoRESUMEN
This study aimed to explore the mediation effects of one-carbon metabolism (OCM) related nutrients on the association between MTHFR rs1801133 polymorphism and gestational diabetes mellitus (GDM). Folate, vitamin B12 and homocysteine (Hcy) were measured in the serum of 1254 pregnant women. Linear and logistic regressions were used to estimate the associations of OCM nutrients and MTHFR rs1801133 polymorphism with blood glucose levels and GDM risk. Mediation analysis was applied to test the mediation effects of folate, vitamin B12 and Hcy on the association of MTHFR rs1801133 polymorphism with blood glucose concentrations and GDM. Pregnant women with MTHFR rs1801133 CC genotype had higher serum folate (10·75 v. 8·90 and 9·40 ng/ml) and lower serum Hcy (4·84 v. 4·93 and 5·20 µmol/l) than those with CT and TT genotypes. Folate concentrations were positively associated with fasting plasma glucose (FPG), 1-h plasma glucose (1-h PG), 2-h plasma glucose (2-h PG) and GDM risk. Vitamin B12 levels were negatively correlated with FPG and GDM. Although no direct association was found between MTHFR rs1801133 genotypes and GDM, there were significant indirect effects of MTHFR rs1801133 CC genotype on FPG (ß: 0·005; 95 % CI: 0·001, 0·013), 1-h PG (ß: 0·006; 95 % CI: 0·001, 0·014), 2-h PG (ß: 0·007; 95 % CI: 0·001, 0·015) and GDM (ß: 0·006; 95 % CI: 0·001, 0·014) via folate. In conclusion, serum folate mediates the effect of MTHFR rs1801133 on blood glucose levels and GDM. Our findings potentially provide a feasible GDM prevention strategy via individualised folate supplementation according to the MTHFR genotypes.
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Diabetes Gestacional , Ácido Fólico , Femenino , Humanos , Embarazo , Glucemia/análisis , Diabetes Gestacional/sangre , Diabetes Gestacional/genética , Pueblos del Este de Asia , Ácido Fólico/genética , Genotipo , Homocisteína , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Vitamina B 12 , VitaminasRESUMEN
BACKGROUND: Single nucleotide polymorphisms (SNPs) in N6AMT1 and AS3MT are associated with arsenic (As) metabolism, and efficient As methylation capacity has been associated with diabetes. However, little is known about the gene-As interaction on gestational diabetes mellitus (GDM). OBJECTIVE: This study aimed to explore the individual and combined effects of N6AMT1 and AS3MT SNPs with As metabolism on GDM. METHODS: A cross-sectional study was performed among 385 Chinese pregnant women (86 GDM and 299 Non-GDM). Four SNPs in N6AMT1 (rs1997605 and rs1003671) and AS3MT (rs1046778 and rs11191453) were genotyped. Urinary inorganic arsenic (iAs), monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) were determined, and the percentages of As species (iAs%, MMA%, and DMA%) were calculated to assess the efficiency of As metabolism. RESULTS: Pregnant women with N6AMT1 rs1997605 AA genotype had lower iAs% (B: 2.11; 95% CI: 4.08, -0.13) and MMA% (B: 0.21; 95% CI: 0.39, -0.04) than pregnant women with GG genotype. The AS3MT rs1046778 and rs11191453 C alleles were negatively associated with iAs% and MMA% but positively associated with DMA%. Higher urinary MMA% was significantly associated with a lower risk of GDM (OR: 0.54; 95% CI: 0.30, 0.97). The A allele in N6AMT1 rs1997605 (OR: 0.46; 95% CI: 0.26, 0.79) was associated with a decreased risk of GDM. The additive interactions between N6AMT1 rs1997605 GG genotypes and lower iAs% (AP: 0.50; 95% CI: 0.01, 0.99) or higher DMA% (AP: 0.52; 95% CI: 0.04, 0.99) were statistically significant. Similar additive interactions were also found between N6AMT1 rs1003671 GG genotypes and lower iAs% or higher DMA%. CONCLUSIONS: Genetic variants in N6AMT1 and efficient As metabolism (indicated by lower iAs% and higher DMA%) can interact to influence GDM occurrence synergistically in Chinese pregnant women.
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Arsénico , Diabetes Gestacional , Humanos , Femenino , Embarazo , Arsénico/metabolismo , Polimorfismo de Nucleótido Simple , Diabetes Gestacional/genética , Mujeres Embarazadas , Metiltransferasas/genética , Metiltransferasas/metabolismo , Estudios Transversales , Pueblos del Este de Asia , Ácido Cacodílico , Metiltransferasa de ADN de Sitio Específico (Adenina Especifica)/genética , Metiltransferasa de ADN de Sitio Específico (Adenina Especifica)/metabolismoRESUMEN
BACKGROUND: Post-stroke depression (PSD), the most frequent psychiatric complication following stroke, could have a negative impact on the recuperation of stroke patients. Hyperhomocysteinemia (HHCY) has been reported to be a modifiable risk factor of stroke. OBJECTIVE: The study tries to explore the effect of HHCY on PSD and the role of N-methyl-d-aspartate receptors (NMDARs)-mediated synaptic alterations. METHODS: Forty-five adult male Sprague-Dawley rats were randomly allocated into five groups: sham operation group, middle cerebral artery occlusion group (MCAO), HCY-treated MCAO group HCY and MK-801 co-treated MCAO group and MK-801-treated MCAO group. 1.6â mg/kg/d D, L-HCY was administered by tail vein injection for 28 d prior to SHAM or MCAO operationand up to 14 d after surgery. The MK-801 (3â mg/kg) was administered by intraperitoneal injection 15â min prior to MCAO operation. RESULTS: HCY treatment aggravated depressive-like disorders of post-stroke rats by the open field test and sucrose preference test. Further, HCY significantly decreased central monoamines levels in the MCAO rats by HPLC. The transmission electron microscopy results showed that the number of synapses and the area of postsynaptic density decreased in the hippocampus of the HCY-treated MCAO rats. Additionally, HCY augmented ischemia-induced up-regulation of NMDARs, decreased the levels of synaptic structure-related marker PSD-95and the synaptic transmission-associated synaptic proteins (VGLUT1, SNAP-25 and Complexin Ι/ΙΙ). These effects of HCY were partly reversed by the NMDA antagonist MK-801. CONCLUSIONS: The current study suggested that NMDARs-mediated synaptic plasticity may be involved in the adverse effect of HCY on PSD.
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Infarto de la Arteria Cerebral Media , Accidente Cerebrovascular , Ratas , Animales , Masculino , Ratas Sprague-Dawley , Infarto de la Arteria Cerebral Media/complicaciones , Receptores de N-Metil-D-Aspartato , Maleato de Dizocilpina/farmacología , Accidente Cerebrovascular/complicaciones , Reperfusión , HomocisteínaRESUMEN
Brain aging is a complex biological process often associated with a decline in cognitive functions and motility. Astaxanthin (AST) is a strong antioxidant capable of crossing the blood-brain barrier. The effect of AST on brain aging and its physiological and molecular mechanism are still unclear. The study aimed to investigate whether AST from AstaReal A1010 improved brain aging by inducing autophagy in SAMP10 mice. Different concentrations of AstaReal A1010 were intragastrically administered to 6-month-old SAMP10 mice for 3 months. The results demonstrated that AST delayed age-related cognitive decline, motor ability and neurodegeneration, upregulated the expression levels of autophagy-related genes beclin-1 and LC3 in the brain. It may induce autophagy by regulating IGF-1/Akt/mTOR and IGF-1/Akt/FoxO3a signaling. Treatment with autophagy inhibitor 3-methyladenine (3MA) partly reversed the anti-aging effect of AST. In conclusion, our findings suggest that AST may induce autophagy by regulating IGF-1/Akt/mTOR and IGF-1/Akt/FoxO3a signaling, thereby delaying age-related neurodegeneration and cognitive decline in SAMP10 mice.
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Factor I del Crecimiento Similar a la Insulina , Proteínas Proto-Oncogénicas c-akt , Ratones , Animales , Factor I del Crecimiento Similar a la Insulina/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Envejecimiento/fisiología , Encéfalo/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Serina-Treonina Quinasas TOR/farmacología , AutofagiaRESUMEN
Microbial reduction of sulfate and metal were simultaneously enhanced in the presence of graphene oxide (GO)-like nanomaterials, however, the mechanism remained unclear. In this study, bio-reduction of Cr was compared between free-living bacterium BY7 and immobilized BY7 (BY-rGO) on reduced GO particles. The role of extracellular polymeric substances (EPS) and rGO material on reduction of sulfate and Cr was investigated. Cr(VI) was reduced to Cr(III) and elemental Cr by BY-rGO particles up to 51% and 28%, respectively. EPS produced by the bacterium BY7 mainly consisted of proteins, polysaccharides, nucleic acids and humic substances. Concentration of EPS was sharply increased (about 54%) with the addition of graphene oxide, while the composition of EPS components was strongly affected by the exposure to Cr. By removing surface EPS without breaking the cells, reduction activities of sulfate and chromium by both BY-rGO particles and free-living BY7 cells were decreased. In contrast, reduction of sulfate and Cr by the free-living BY7 cells was enhanced with external addition of extracted EPS. Based on electrochemical analysis, the reduction peak indicating enhanced electron transfer was lost after removing EPS. Moreover, the contribution of each EPS fractions on sulfate and Cr reduction followed an order of polysaccharides > proteins > humic substances. Therefore, microbial sulfate and Cr reduction processes in the presence of BY-rGO particles were enhanced by the increasing amounts of EPS, which likely mediated electron transfer during sulfate and Cr reduction, and relieved bacteria from metal toxicity. Nevertheless, the presence of rGO was crucially important for elemental Cr production under sulfate-reducing condition, which might contribute to lowering electric potential or reducing activation energy for Cr(III) reduction. This work provided direct evidences for enhancing sulfate and Cr reduction activities by supplement of EPS as an additive to increase treatment efficiency in environmental bioremediation.
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Cromo , Grafito , Matriz Extracelular de Sustancias Poliméricas , SulfatosRESUMEN
Purpose: In this study, we sought to test the hypothesis that oxidative stress injury in ischemic brains and H2O2-treated mouse neuroblastoma Neuro-2a cells (N2a) was related to STAT3 activation.Materials and methods: Rat middle cerebral artery occlusion (MCAO) model and H2O2-treated mouse neuroblastoma Neuro-2a cells (N2a) were used to investigate the relationship between oxidative stress injury and STAT3 activation.Results: 8-Hydroxy-2'-deoxyguanosine (8-OHdG) content and STAT3 protein phosphorylation level were significantly increased after cerebral ischemia-reperfusion. H2O2 treatment inhibited the cell viability, induced the apoptosis, and further raised pSTAT3 protein level in N2a cells. Moreover, the addition of AG490, the protein inhibitor of JAK2, significantly alleviated cerebral ischemic damage in vivo and H2O2-induced injury in vitro, and JAK2 siRNA also alleviated H2O2-induced injury in N2a cell.Conclusions: JAK2/STAT3 pathway may play a crucial role in mediating reactive oxidative species (ROS)-induced cell injury in rat middle cerebral artery occlusion (MCAO) model and N2a cells. ROS scavenging and down-regulation of STAT3 activation might be a candidate design of therapeutic strategies against oxidative stress-related neurological diseases.
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Apoptosis , Inhibidores Enzimáticos/farmacología , Peróxido de Hidrógeno/farmacología , Infarto de la Arteria Cerebral Media/metabolismo , Janus Quinasa 2/metabolismo , Neuroblastoma , Oxidantes/farmacología , Estrés Oxidativo , Daño por Reperfusión/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , 8-Hidroxi-2'-Desoxicoguanosina/metabolismo , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 2/efectos de los fármacos , Ratones , Estrés Oxidativo/efectos de los fármacos , Ratas , Factor de Transcripción STAT3/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Tirfostinos/farmacologíaRESUMEN
OBJECTIVE: To investigate the effects of electrolytic drinking water on the hyperuricemia and the potential mechanism. METHODS: The 6-week-old SD rats were induced as the animal model with hyperuricemia by yeast extract(10 g/kg) and adenine(100 g/kg) gavage(twice per day) combined with oxygen oxazine acid potassium(300 mg/kg, the 1~(st), 5~(th) and 10~(th )day) i. p. Then the rats were supplied electrolytic drinking water in different dosages(1 mL, 2 mL and 3 mL) by gavage for 7 days. Weight was measured at regular intervals. The 24-hour urine was sampled by metabolic cage for the measurements of uric acid, creatinine and urea nitrogen levels. The parameters for the uric acid clearance were calculated. The serum was sampled after execution for the determination of serum uric acid, creatinine. The activities of xanthine oxidase and adenine dehydrogenase were detected. The morphological measurements of stomach and kidney were completed. RESULTS: The hyperuricemia model was successfully induced by this method. In the intervention, the pH of urine was significantly elevated along with the electrolytic drinking water intake(P<0. 01). The excretion of uric acid in the rats with hyperuricemia was significantly increased while administrated with electrolytic drinking water. The effects of improving uric acid excretion were enhanced along with the intake of electrolytic drinking water. The levels of serum uric acid(group Model, Model+Treatment 1, Model+Treatment 2 and Model+Treatment 3: 693. 7 µmol/L, 668. 1 µmol/L, 642. 5 µmol/L, 633. 1 µmol/L), urine uric acid(5740. 0 µmol/L, 5894. 1 µmol/L, 5562. 3 µmol/L, 5083. 2 µmol/L) and urea nitrogen(11. 40 mmol/L, 10. 47 mmol/L, 9. 54 mmol/L, 8. 93 mmol/L) were significantly decreased in the model rats with high dose intervention(P<0. 05). Clearance of uric acid was obviously increased(9. 27%, 10. 40%, 10. 44%, 11. 13%, P<0. 05). However, no pathological change was observed among the three groups with intervention. CONCLUSION: The electrolytic drinking water intake is benefit for the excretion of uric acid of hyperuricemia rat. Enhancing alkalization of urine is considered as the important mechanism of the beneficial effects.
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Agua Potable , Hiperuricemia , Animales , Creatinina , Hiperuricemia/inducido químicamente , Ratas , Ratas Sprague-Dawley , Ácido ÚricoRESUMEN
Several studies have investigated the relationship between vitamin D (VD) and its receptors (VDR) and the risk of cervical cancer. However, the underlying mechanisms that underpin these associations remain incompletely comprehended. In this review, we analyzed the impacts of VD and VDR on cervical cancer and related mechanisms, and discussed the effects of VD, calcium, and other vitamins on cervical cancer. Our literature research found that VD, VDR and their related signaling pathways played indispensable roles in the occurrence and progression of cervical cancer. Epidemiological studies have established associations between VD, VDR, and cervical cancer susceptibility. Current studies have shown that the inhibitory effect of VD and VDR on cervical cancer may be attributed to a variety of molecules and pathways, such as the EAG potassium channel, HCCR-1, estrogen and its receptor, p53, pRb, TNF-α, the PI3K/Akt pathway, and the Wnt/ß-catenin pathway. This review also briefly discussed the association between VDR gene polymorphisms and cervical cancer, albeit a comprehensive elucidation of this relationship remains an ongoing research endeavor. Additionally, the potential ramifications of VD, calcium, and other vitamins on cervical cancer has been elucidated, yet further exploration into the precise mechanistic underpinnings of these potential effects is warranted. Therefore, we suggest that further studies should focus on explorations into the intricate interplay among diverse molecular pathways and entities, elucidation of the mechanistic underpinnings of VDR polymorphic loci changes in the context of HPV infection and VD, inquiries into the mechanisms of VD in conjunction with calcium and other vitamins, as well as investigations of the efficacy of VD supplementation or VDR agonists as part of cervical cancer treatment strategies in the clinical trials.
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Inflammatory myofibroblastic tumors (IMTs) of the heart are rarely observed in the eldly. We report a case involving an elderly woman with an IMT situated on the right atrial wall. The tumor was fully excised. The patient had a smooth recovery post-surgery and remained free of recurrence for three years.
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Fibrilación Atrial , Neoplasias Cardíacas , Femenino , Humanos , Anciano , Fibrilación Atrial/cirugía , Corazón , Neoplasias Cardíacas/diagnóstico por imagen , Neoplasias Cardíacas/cirugíaRESUMEN
Ozone pollution has become one of the most concerned environmental issue. Developing low-cost and efficient catalysts is a promising alternative for ozone decomposition. This work presents a creative strategy that using α-Fe2O3-supported Co3O4 nanoparticles for constructing interfacial oxygen vacancies (Vo) to remove ozone. The efficiency of Co3O4/α-Fe2O3 was superior to that of pure α-Fe2O3 by nearly two times for 200-ppm ozone removal after 6-h reaction at 25 °C, which is ascribed to the highly active interfacial Vo. X-ray photoelectron spectroscopy (XPS) and Raman spectroscopy suggest that the Fe3+-Vo-Co2+ was formed when Co3O4 was loaded in α-Fe2O3. Furthermore, the density functional theory (DFT) calculations reveal the desorption and electron transfer ability of intermediate peroxide (O22-) on Fe3+-Vo-Co2+ are higher than the Vo from other regions. In situ diffuse reflectance Fourier transform (DRIFT) spectroscopy also demonstrate the higher conversion rate of O22- on Co3O4/α-Fe2O3. Base on the intermediates detected, we propose a recycle mechanism of interfacial Vo for ozone removal: O22- is quickly converted to O2- and transformed into O2 on interfacial Vo. Moreover, O2-temperature-programmed desorption (TPD), H2-temperature-programmed reduction (TPR), and electrochemical impedance spectroscopy (EIS) reveal that the oxygen mobility, reducibility, and conductivity of Co3O4/α-Fe2O3 are greatly superior to those of α-Fe2O3, which is contributed to the conversion of O22-. Consequently, our proposed strategy effectively enhances the activity and stability of the bimetallic transition oxides for ozone decomposition.
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Nanopartículas , Ozono , Ozono/química , Especies Reactivas de Oxígeno , Oxígeno/químicaRESUMEN
Folic acid, a water-soluble B-vitamin, has been demonstrated to decrease the risk of first stroke and improve its poor prognosis. However, the molecular mechanisms responsible for the beneficial effect of folic acid on recovery from ischemic insult remain largely unknown. Excessive activation of the N-methyl-d-aspartate receptors (NMDARs) has been shown to trigger synaptic dysfunction and excitotoxic neuronal death in ischemic brains. Here, we hypothesized that the effects of folic acid on cognitive impairment may involve the changes in synapse loss and NMDAR expression and function following cerebral ischemia/reperfusion injury. The ischemic stroke models were established by middle cerebral artery occlusion/reperfusion (MCAO/R) and by oxygen-glucose deprivation and reperfusion (OGD/R)-treated primary neurons. The results showed that folic acid supplemented diets (8.0 mg/kg for 28 days) improved cognitive performances of rats after MCAO/R. Folic acid also caused a reduction in the number of neuronal death, an increase in the number of synapses and the expressions of synapse-related proteins including SNAP25, Syn, GAP-43 and PSD95, and a decrease in p-CAMKII expression in ischemic brains. Similar changes in synaptic functions were observed in folic acid (32 µM)-treated OGD/R neurons. Furthermore, NMDA treatment reduced folic acid-induced upregulations of synapse-associated proteins and Ca2+ influx, whereas downregulations of NMDARs by NR1 or both NR2A and NR2B siRNA further enhanced the expressions of synapse-related proteins raised by folic acid in OGD/R neurons. Our findings suggest that folic acid improves cognitive dysfunctions and ameliorates ischemic brain injury by strengthening synaptic functions via the NMDARs.
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Isquemia Encefálica , Daño por Reperfusión , Accidente Cerebrovascular , Ratas , Animales , Receptores de N-Metil-D-Aspartato/genética , Ácido Fólico/farmacología , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Daño por Reperfusión/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/tratamiento farmacológicoRESUMEN
AIM: To demonstrate the role of IL-6 and pSTAT3 in the inflammatory response to cerebral ischemia/reperfusion following folic acid deficiency (FD). METHODS: The middle cerebral artery occlusion/reperfusion (MCAO/R) model was established in adult male Sprague-Dawley rats in vivo, and cultured primary astrocytes were exposed to oxygen-glucose deprivation/reoxygenation (OGD/R) to emulate ischemia/reperfusion injury in vitro. RESULTS: Glial fibrillary acidic protein (GFAP) expression significantly increased in astrocytes of the brain cortex in the MCAO group compared to the SHAM group. Nevertheless, FD did not further promote GFAP expression in astrocytes of rat brain tissue after MCAO. This result was further confirmed in the OGD/R cellular model. In addition, FD did not promote the expressions of TNF-α and IL-1ß but raised IL-6 (Peak at 12 h after MCAO) and pSTAT3 (Peak at 24 h after MCAO) levels in the affected cortices of MCAO rats. In the in vitro model, the levels of IL-6 and pSTAT3 in astrocytes were significantly reduced by treatment with Filgotinib (JAK-1 inhibitor) but not AG490 (JAK-2 inhibitor). Moreover, the suppression of IL-6 expression reduced FD-induced increases in pSTAT3 and pJAK-1. In turn, inhibited pSTAT3 expression also depressed the FD-mediated increase in IL-6 expression. CONCLUSIONS: FD led to the overproduction of IL-6 and subsequently increased pSTAT3 levels via JAK-1 but not JAK-2, which further promoted increased IL-6 expression, thereby exacerbating the inflammatory response of primary astrocytes.
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Isquemia Encefálica , Deficiencia de Ácido Fólico , Daño por Reperfusión , Animales , Masculino , Ratas , Astrocitos/metabolismo , Isquemia Encefálica/metabolismo , Deficiencia de Ácido Fólico/metabolismo , Infarto de la Arteria Cerebral Media/metabolismo , Interleucina-6/metabolismo , Ratas Sprague-Dawley , Reperfusión , Daño por Reperfusión/metabolismoRESUMEN
Saikosaponin-a (SSa) exhibits antiepileptic effects. However, its poor water solubility and inability to pass through the blood-brain barrier greatly limit its clinical development and application. In this study, SSa-loaded Methoxy poly (ethylene glycol)-poly(ε-caprolactone) (MePEG-SSa-PCL) NPs were successfully prepared and characterized. Our objective was to further investigate the effect of this composite on acute seizure in mice. First, we confirmed the particle size and surface potential of the composite (51.00 ± 0.25 nm and - 33.77 ± 2.04 mV, respectively). Further, we compared the effects of various MePEG-SSa-PCL doses (low, medium, and high) with those of free SSa, valproic acid (VPA - positive control), and saline only (model group) on acute seizure using three different acute epilepsy mouse models. We observed that compared with the model group, the three MePEG-SSa-PCL treatments showed significantly lowered seizure frequency in mice belonging to the maximum electroconvulsive model group. In the pentylenetetrazol and kainic acid (KA) acute epilepsy models, MePEG-SSa-PCL increased both clonic and convulsion latency periods and shortened convulsion duration more effectively than equivalent SSa-only doses. Furthermore, hematoxylin-eosin and Nissl staining revealed considerably less neuronal damage in the hippocampal CA3 area of KA mice in the SSa, VPA, and three MePEG-SSa-PCL groups relative to mice in the model group. Hippocampal gamma-aminobutyric acid-A (GABA-A) receptor and cleaved caspase-3 expression levels in KA mice were significantly higher and lower, respectively, in the three MePEG-SSa-PCL treatment groups than in the model group. Thus, MePEG-SSa-PCL exhibited a more potent antiepileptic effect than SSa in acute mouse epilepsy models and could alleviate neuronal damage in the hippocampus following epileptic seizures, possibly via GABA-A receptor expression upregulation.
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Epilepsy is one of the most common neurological disorders. The pro-epileptic and antiepileptic roles of microglia have recently garnered significant attention. Interleukin-1 receptor-associated kinase (IRAK)-M, an important kinase in the innate immune response, is mainly expressed in microglia and acts as a negative regulator of the TLR4 signaling pathway that mediates the anti-inflammatory effect. However, whether IRAK-M exerts a protective role in epileptogenesis as well as the molecular and cellular mechanisms underlying these processes are yet to be elucidated. An epilepsy mouse model induced by pilocarpine was used in this study. Real-time quantitative polymerase chain reaction and western blot analysis were used to analyze mRNA and protein expression levels, respectively. Whole-cell voltage-clamp recordings were employed to evaluate the glutamatergic synaptic transmission in hippocampal neurons. Immunofluorescence was utilized to show the glial cell activation and neuronal loss. Furthermore, the proportion of microglia was analyzed using flow cytometry. Seizure dynamics influenced the expression of IRAK-M. Its knockout dramatically exacerbated the seizures and the pathology in epilepsy and increased the N-methyl-d-aspartate receptor (NMDAR) expression, thereby enhancing glutamatergic synaptic transmission in hippocampal CA1 pyramidal neurons in mice. Furthermore, IRAK-M deficiency augmented hippocampal neuronal loss via a possible mechanism of NMDAR-mediated excitotoxicity. IRAK-M deletion promotes microglia toward the M1 phenotype, which resulted in high levels of proinflammatory cytokines and was accompanied by a visible increase in the expressions of key microglial polarization-related proteins, including p-STAT1, TRAF6, and SOCS1. The findings demonstrate that IRAK-M dysfunction contributes to the progression of epilepsy by increasing M1 microglial polarization and glutamatergic synaptic transmission. This is possibly related to NMDARs, particularly Grin2A and Grin2B, which suggests that IRAK-M could serve as a novel therapeutic target for the direct alleviation of epilepsy.
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Epilepsia , Estado Epiléptico , Ratones , Animales , Microglía/metabolismo , Enfermedades Neuroinflamatorias , Quinasas Asociadas a Receptores de Interleucina-1/metabolismo , Estado Epiléptico/metabolismo , Convulsiones/metabolismo , Epilepsia/metabolismoRESUMEN
In this work, mesoporous poorly crystalline hematite (α-Fe2O3) was prepared using mesoporous silica (KIT-6) functionalized with 3-[(2-aminoethyl)amino]propyltrimethoxysilane as a hard template (SMPC-α-Fe2O3). The disordered atomic arrangement structure of SMPC-α-Fe2O3 promoted the formation of oxygen vacancies, which was confirmed using X-ray photoelectron spectroscopy (XPS), O2-temperature-programmed desorption (TPD), H2-temperature-programmed reduction (TPR), and in situ diffuse reflectance infrared Fourier transform (DRIFT) analyses. Density functional theory calculations (DFT) also proved that reducing the crystallinity of α-Fe2O3 decreased the formation energy of oxygen vacancies. TPD and in situ DRIFT analyses of NH3 adsorption suggested that the surface acidity of SMPC-α-Fe2O3 was considerably higher than those of mesoporous poorly crystalline α-Fe2O3 (MPC-α-Fe2O3) and highly crystalline α-Fe2O3 (HC-α-Fe2O3). The oxygen vacancies and acid sites formed on α-Fe2O3 surface are beneficial for ozone (O3) decomposition. Compared with MPC-α-Fe2O3 and HC-α-Fe2O3, SMPC-α-Fe2O3 exhibited a higher removal efficiency for 200-ppm O3 at a space velocity of 720 L g-1 h-1 at 25 ± 2 °C under dry conditions. Additionally, in situ DRIFT and XPS results suggested that the accumulation of peroxide (O22-) and the conversion of O22- to lattice oxygen over the oxygen vacancies caused catalyst deactivation. However, O22- could be desorbed completely by continuous N2 purging at approximately 350 °C. This study provides significant insights for developing highly active α-Fe2O3 catalysts for O3 decomposition.
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Ozono , Adsorción , Catálisis , Oxígeno , PeróxidosRESUMEN
Water vapor is very common in contaminated streams, which has a great influence on the adsorption of low-concentration volatile organic compounds (VOCs) due to the competition between water and VOCs. Understanding adsorption mechanisms and predicting adsorption of VOCs under different relative humidity (RH) are of great importance to design effective adsorption unit. In this study, we comprehensively investigated the effects of RH on the surface properties of hyper-cross-linked polymeric resin (HPR) and adsorption of 18 VOCs at low concentration on HPR under five levels of RH using inverse gas chromatography (IGC). Further, a promising RH-dependent poly-parameter linear free energy relationships (PP-LFERs) model was developed. It was found that water vapor caused the decrease of surface free energy (γst) of HPR due to the occupation of active sites by water molecules, resulting in the decrease of adsorption partition coefficients (K). Moreover, the γst could accurately quantify the effects of RH on the surface properties of HPR. Therefore, the RH-dependent PP-LFERs model was established by correlating RH and γst. The developed model overcame the limited predictive ability of existing models only under a specific RH level, and excellently predicted the lnK values of VOCs (R2 = 0.944, RMSEt = 0.36 and RMSEv = 0.47) under various RH.
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Compuestos Orgánicos Volátiles , Adsorción , Cromatografía de Gases , Humedad , PolímerosRESUMEN
Ischemic stroke represents a major cause of mortality worldwide. An elevated level of homocysteine (Hcy) is recognized as a powerful risk factor of ischemic stroke. We previously reported that Hcy induces cytotoxicity and proliferation inhibition in neural stem cells (NSCs) derived from the neonatal rat hippocampus in vitro. However, the toxic potential of Hcy on NSCs and its underlying mechanisms are not entirely clear in ischemic brain. Since DNA methylation is critical for establishing the diverse cell fates in the central nervous system, we hypothesized that negative effect of Hcy (an intermediate in the one-carbon metabolism) on neurogenesis might be link to DNA methylation in ischemic stroke. In our study, the rats in Hcy intervention group were intraperitoneally injected with 2% Hcy solution (5 mL/kg/d) for 7 consecutive days before MCAO surgery until they were sacrificed. Our study indicated that Hcy inhibited NSCs self-renewal capacity, which was exhibited by lowering the number of DCX+/BrdU+ and NeuN+/BrdU+ in ischemic brain hippocampus. A reduction in the activity of the DNA methyltransferases (DNMTs), total methylation level and the number of 5mC+/NeuN+ and DCX+/5mC+ cells was observed in Hcy-treated ischemic brains. Additionally, Hcy also induced an increase in S-adenosylhomocysteine (SAH), and a decrease in the ratio of S-adenosylmethionine (SAM) to SAH. These results suggest that the alterations in DNA methylation may be an important mechanism by which Hcy inhibits neurogenesis after stroke. Hcy-induced DNA hypomethylation may be mainly caused by a reduction in the DNMT activity which is regulated by the concentrations of SAM and SAH. Maintaining normal DNA methylation by lowering Hcy level may possess therapeutic potential for promoting neurological recovery and reconstruction after stroke.
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Isquemia Encefálica/tratamiento farmacológico , Metilación de ADN/efectos de los fármacos , Hipocampo/efectos de los fármacos , Homocisteína/farmacología , Animales , Hipocampo/metabolismo , Masculino , Células-Madre Neurales/efectos de los fármacos , Células-Madre Neurales/metabolismo , Neurogénesis/efectos de los fármacos , Ratas Sprague-Dawley , Accidente Cerebrovascular/tratamiento farmacológicoRESUMEN
Aging is the leading cause of human morbidity and death worldwide. Pyrroloquinoline quinone (PQQ) is a water-soluble vitamin-like compound that has strong anti-oxidant capacity. Beneficial effects of PQQ on lifespan have been discovered in the model organism Caenorhabditis elegans (C. elegans), yet the underlying mechanisms remain unclear. In the current study, we hypothesized that the longevity-extending effect of PQQ may be linked to autophagy and insulin/IGF1 signaling (IIS) in C. elegans. Our data demonstrate that PQQ at a concentration of 1 mM maximally extended the mean life of C. elegans by 33.1%. PQQ increased locomotion and anti-stress ability, and reduced fat accumulation and reactive oxygen species (ROS) levels. There was no significant lifespan extension in PQQ-treated daf-16, daf-2, and bec-1 mutants, suggesting that these IIS- and autophagy-related genes may mediate the anti-aging effects of the PQQ. Furthermore, PQQ raised mRNA expression and the nuclear localization of the pivotal transcription factor daf-16, and then activated its downstream targets sod-3, clt-1, and hsp16.2. Enhanced activity of the autophagy pathway was also observed in PQQ-fed C. elegans, as evidenced by increased expression of the key autophagy genes including lgg-1, and bec-1, and also by an increase in the GFP::LGG-1 puncta. Inactivation of the IIS pathway-related genes daf-2 or daf-16 by RNAi partially blocked the increase in autophagy activity caused by PQQ treatment, suggesting that autophagy may be regulated by IIS. This study demonstrates that anti-aging properties of PQQ, in the C. elegans model, may be mediated via the IIS pathway and autophagy.
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Autofagia/efectos de los fármacos , Caenorhabditis elegans , Insulina/metabolismo , Longevidad/efectos de los fármacos , Cofactor PQQ/farmacología , Animales , Caenorhabditis elegans/efectos de los fármacos , Caenorhabditis elegans/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Ischemic stroke remains one of the most common causes of death and disability worldwide. The stroke patients with an inadequate intake of folic acid tend to have increased brain injury and poorer prognosis. However, the precise mechanisms underlying the harmful effects of folic acid deficiency (FD) in ischemic stroke is still elusive. Here, we aimed to test the hypothesis that mitochondrial localized STAT3 (mitoSTAT3) expression may be involved in the process of neuronal damage induced by FD in in vivo and in vitro models of ischemic stroke. Our results exhibited that FD increased infarct size and aggravated the damage of mitochondrial ultrastructure in ischemic brains. Meanwhile, FD upregulated the phosphorylation levels of mitoSTAT3 at Tyr705 (Y705) and Ser727 (S727) sites in the rat middle cerebral artery occlusion/reperfusion (MCAO/R) model and oxygen-glucose deprivation followed by reperfusion (OGD/R) N2a cells. Furthermore, the inhibition of JAK2 by AG490 led to a significant decrease in FD-induced phosphorylation of Y705, while S727 phosphorylation was unaffected. Conversely, U0126 and LY294002, which respectively inhibited phosphorylation of ERK1/2 and Akt, partially prevented S727 phosphorylation, but had limited effects on the level of pY705, suggesting that phosphorylation of Y705 and S727 is regulated via independent mechanisms in FD-treated brains.