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Objective: Alcohol use disorder (AUD) is a common mental disorder characterized by repeated withdrawal episodes. Negative emotions during withdrawal are the primary factors affecting successful abstinence. Oxytocin is a critical modulator of emotions. OXTR, the oxytocin receptor, may also be a promising candidate for treating alcohol withdrawal symptoms. Previous studies indicated that people with different genotypes of OXTR rs2254298 were reported to suffer from more significant depressive or heightened anxiety symptoms when experiencing early adversity. The present study aims to explore the modulatory role of the polymorphism OXTR rs2254298 on mood disorders during alcohol withdrawal and to help researchers better understand and develop effective relapse prevention and interventions for alcohol use disorders. Methods: We recruited 265 adult Chinese Han men with AUD. Anxiety and depressive symptoms were measured using the Self-Rating Anxiety Scale and Self-Rating Depression Scale. Alcohol dependence levels were measured using Michigan Alcoholism Screening Test. Genomic DNA extraction and genotyping from participants' peripheral blood samples. Result: First, a multiple linear regression was used to set the alcohol dependence level, OXTR.rs2254298, interaction terms as the primary predictor variable, and depression or anxiety as an outcome; age and educational years were covariates. There was a significant interaction between OXTR rs2254298 and alcohol dependence level on anxiety (B = 0.23, 95% confidence interval [CI]: 0.01-0.45) but not on depression (B = -0.06, 95% CI: -0.30 - 0.18). The significance region test showed that alcohol-dependent men who are GG homozygous were more likely to experience anxiety symptoms than subjects with the A allele (A allele: ß = 0.27, p < 0.001; GG homozygote: ß = 0.50, p < 0.001). Finally, re-parameterized regression analysis demonstrated that this gene-environment interaction of OXTR rs2254298 and alcohol dependence on anxiety fits the weak differential susceptibility model (R2 = 0.17, F (5,259) = 13.46, p < 0.001). Conclusion: This study reveals a gene-environment interactive effect between OXTR rs2254298 and alcohol withdrawal on anxiety but not depression. From the perspective of gene-environment interactions, this interaction fits the differential susceptibility model; OXTR rs2254298 GG homozygote carriers are susceptible to the environment and are likely to experience anxiety symptoms of alcohol withdrawal.
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Nanoparticle technologies offer a non-invasive means to deliver basic fibroblast growth factor (bFGF) for the treatment of spinal cord injury (SCI). However, the inability of bFGF to accumulate at the injury site and inefficient penetration across the blood-spinal cord barrier (BSCB) remain challenges. The present study describes a dual-targeting liposome (bFGF@Lip-Cp&Rp) with injury lesion targeting and BSCB-penetrating capability to deliver bFGF for SCI treatment. The CAQK peptide (Cp) with injury lesion targeting ability and R2KC peptide (Rp) with BSCB-penetrating capability were grafted onto the liposomes for a flexible and non-invasive drug delivery systems preparation. Results exhibit that the dual-targeted liposomes could significantly cross the BSCB and accumulate at the injury site. During the early stage of SCI, bFGF@Lip-Cp&Rp promotes repair of BSCB and facilitates M2-polarization of macrophages. Regular delivery of bFGF@Lip-Cp&Rp increase HUVECs tube formation and angiogenesis, ameliorate the microenvironment of lesion site, suppress the neuronal apoptosis and axonal atrophy in SCI rats. Importantly, continuous treatment of bFGF@Lip-Cp&Rp supports the restoration of limb motor function in SCI rats. In summary, this research implies that the injury site-targeting and BSCB-penetrating liposomes could be a promising therapeutic approach for the treatment of SCI.
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BACKGROUND: Although attentional bias modification training (ABM) and cognitive behavioural therapy (CBT) are two effective methods to decrease the symptoms of generalized anxiety disorders (GAD), to date, no randomized controlled trials have yet evaluated the effectiveness of an intervention combining internet-based cognitive behavioural therapy (ICBT) and ABM for adults with GAD. AIMS: This study aimed to investigate the effectiveness of an intervention combining ICBT and ABM for adults with GAD. METHOD: Sixty-three participants diagnosed with GAD were randomly assigned to the treatment group (ICBT with ABM; 31 participants) or the control group (ICBT with ABM placebo; 32 participants), and received 8 weeks of treatment and three evaluations. The CBT, ABM and ABM-placebo training were conducted via the internet. The evaluations were conducted at baseline, 8 weeks later, and 1 month later, respectively. RESULTS: Both the treatment and control groups reported significantly reduced anxiety symptoms and attentional bias, with no clear superiority of either intervention. However, the treatment group showed a greater reduction in negative automatic thoughts than the control group after treatment and at 1-month follow-up (η2 = 0.123). CONCLUSION: The results suggest that although not differing in therapeutic efficacy, the intervention combining ICBT and ABM is superior to the intervention combining ICBT and ABM-placebo in the reduction of negative automatic thoughts. ABM may be a useful augmentation of ICBT on reducing anxiety symptoms.
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Trastornos de Ansiedad , Terapia Cognitivo-Conductual , Humanos , Trastornos de Ansiedad/terapiaRESUMEN
BACKGROUND AND AIMS: Nicotine dependence (ND)-induced anxiety might be modulated by genetic polymorphisms. The gene-by-environment interaction can be fitted into the diathesis-stress and differential susceptibility models. Nevertheless, knowledge of the interaction between adiponectin (ADPN) polymorphisms and ND on the incident mental disorder is currently scarce. This study aims to understand the role of ADPN rs266729 on anxiety in patients with ND while elucidating the psychology model and the various reactions across genotypes. METHODS: We included 315 Chinese males with confirmed ND, measured using the Fagerstrom test for nicotine dependence (FTND). Anxiety was assessed using the Self-rating Anxiety Scale. Genomic DNA was extracted and genotyped from peripheral blood. Hierarchical regression models were used to test the interactions. RESULTS: There was a significant interaction between ADPN rs266729 and ND (ß = -0.19, p < 0.05). The CC homozygote was more likely to be affected by ND-induced anxiety (ß = 0.14, t = 4.43, p < 0.01). Re-parameterized regression models revealed that the interaction between ADPN rs266729 and ND could fit the strong differential susceptibility model (R2 = 0.05, p < 0.001). CONCLUSIONS: ADPN rs266729 was correlated with susceptibility to anxiety symptoms among male adults with ND and could fit the differential susceptibility model. The CC homozygote of rs266729 was a plasticity factor that increased anxiety symptoms in individuals with ND.
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Adiponectina , Tabaquismo , Adulto , Humanos , Masculino , Adiponectina/genética , Tabaquismo/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Ansiedad/genéticaRESUMEN
OBJECTIVE: The study aimed to investigate the relationship between cerebrospinal fluid (CSF) metal ions and anxiety, depression, and insomnia among cigarette smokers. METHODS: We measured CSF levels of various metal ions from 178 Chinese male subjects. Apart from sociodemographic and clinical characteristics data, the Fagerstrom Test for Nicotine Dependence (FTND), Beck Depression Inventory (BDI), Self-Rating Anxiety Scale (SAS), and Pittsburgh Sleep Quality Index (PSQI) were applied. RESULTS: BDI and PSQI scores (all p < 0.001) were significantly higher in active smokers than nonsmokers. Active smokers have significantly higher CSF levels of magnesium, zinc, iron, lead, lithium, and aluminum (all p ≤ 0.002). Some metal ions, including zinc, iron, lead, and aluminum, were found to have a significant correlation with BDI scores, whereas metal ions, including zinc and lead, were found to have a significant correlation with PSQI scores in the general group. More interesting, mediation analysis showed that aluminum mediated the relationship between smoking and depression. CONCLUSIONS: Cigarette smoking was indeed associated with depression and insomnia. Active smokers had significantly higher CSF levels of magnesium, zinc, iron, lead, lithium, and aluminum. Furthermore, CSF aluminum played a mediating role in the relationship between smoking and depression, which further confirmed its neurotoxicity.
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Trastornos del Inicio y del Mantenimiento del Sueño , Productos de Tabaco , Masculino , Humanos , Fumadores , Depresión , Aluminio , Magnesio , Litio , Ansiedad , Iones , Zinc , HierroRESUMEN
BACKGROUND: Impulsivity is more commonly reported in subjects with mental disorders compared to healthy subjects, suggesting a potential application of impulsivity in predicting impulsivity-related mental disorders. However, no biomarker of impulsivity available so far. This study explored the association between cerebrospinal fluid (CSF) fibroblast growth factor 21 (FGF21), a key hormonal mediator of the stress response, and impulsivity in healthy subjects. METHODS: A total of 126 healthy persons subjected to surgery of anterior cruciate ligament were recruited in the present study. The impulsiveness of the subjects was evaluated by the Chinese version of the Barratt Impulsiveness Scale (BIS)-11 before surgery. CSF and blood samples of the subjects were collected before spinal anesthesia for surgery. The levels of FGF21, serotonin and dopamine in CSF and the level of FGF21 in blood of the subjects were measured by ELISA using commercial kits. RESULTS: Negative correlations were found between BIS-11 total score and either FGF21, serotonin or dopamine in CSF. However, BIS-11 total score was not correlated with FGF21 in blood. In addition, FGF21 was positively correlated with serotonin and dopamine in CSF, respectively. Multivariable linear regression models indicated that the decrease of FGF21 level associating with the decrease of serotonin and dopamine level in CSF contributed to the higher impulsivity. Furthermore, receiver operating characteristic curve (ROC) analysis indicated an important role of CSF FGF21 predicting high impulsivity. CONCLUSIONS: FGF21, serotonin and dopamine in CSF associate with impulsivity in opposite directions. The decrease of CSF FGF21 is related to higher impulsivity, and indicate that CSF FGF21 may predict impulsivity in healthy subjects.
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Dopamina/metabolismo , Factores de Crecimiento de Fibroblastos/metabolismo , Conducta Impulsiva/fisiología , Serotonina/metabolismo , Adolescente , Adulto , Biomarcadores/análisis , Femenino , Voluntarios Sanos/estadística & datos numéricos , Humanos , Masculino , Trastornos Mentales/fisiopatología , Persona de Mediana Edad , Escalas de Valoración Psiquiátrica/estadística & datos numéricos , Adulto JovenRESUMEN
Alcohol dependence (AD) is characterized by compulsive alcohol consumption, which involves behavioral impairments such as aggression. Members of fibroblast growth factor (FGF) 19 superfamily, including FGF19, FGF21, and FGF23, are major endocrine mediators that play an important role in alcohol metabolism and alcohol related disorders. The objective of the present study is to explore the possible associations among the interaction of single nucleotide polymorphisms (SNPs) of the FGF 19 superfamily, AD occurrence, and aggression in patients with AD. A total of 956 subjects were enrolled in this study, including 482 AD patients and 474 healthy controls (HCs). Michigan alcoholism screening test (MAST) was used to measure the level of AD, a Chinese version of the Buss-Perry Aggression Questionnaire was used to evaluate the aggressive behavior of subjects, and MassARRAY@ system was used to genotype rs948992 of FGF19, rs11665841 and rs11665896 of FGF21, rs7955866 and rs11063118 of FGF23. The results showed that AD patients presented a significantly higher level of aggression compared to HCs, and MAST scores were significantly positively associated Buss-Perry aggression scores (r = 0.402, p < 0.001) in AD patients. The interaction of FGF19 rs948992 TC × FGF21 rs11665896 GG presented the high-risk genotype combination predicting the high level of AD. In addition, the interaction of FGF19 rs948992 TC × FGF21 rs11665896 TG × FGF23 rs11063118 TT presented the high-risk genotype combination predicting the high level of aggression in AD patients. Our results added evidence linking the combination of rs948992 TC × rs11665896 TG × rs11063118 TT to aggressive behavior in AD patients and pointed out the potential usefulness of the SNPs of FGF19 superfamily as a predictor for the aggression in AD patients.
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Traumatic brain injury (TBI) is one of the most serious public health problems in the world. TBI causes neurological deficits by triggering secondary injuries. Hydrogen sulfide (H2S), a gaseous mediator, has been reported to exert neuroprotective effects in central nervous system diseases, such as TBI. However, the molecular mechanisms involved in this effect are still unclear. The present study was designed to explore the ability of NaHS, a H2S donor, to provide neuroprotection in a mouse model of TBI and to discover the associated molecular mechanisms of these protective effects. Here, we found that administration of NaHS not only maintained the integrity of the blood brain barrier (BBB), protected neurons from apoptosis, and promoted remyelination and axonal reparation but also protected mitochondrial function. In addition, we found that autophagy was inhibited after treatment with NaHS following TBI, an effect that was induced by activation of the PI3K/AKT/mTOR signalling pathway. Our study indicated that H2S treatment is beneficial for TBI, pointing to H2S as a potential therapeutic target for treating TBI.
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Autofagia/efectos de los fármacos , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Mitocondrias/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Sulfuros/farmacología , Animales , Barrera Hematoencefálica/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Humanos , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Neuronas/citología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Sprague-Dawley , Sulfuros/uso terapéutico , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Spinal cord injury (SCI) is a severe nervous system disease that may lead to lifelong disability. Studies have shown that autophagy plays a key role in various diseases; however, the mechanisms regulating cross-talk between autophagy, inflammation, and endoplasmic reticulum (ER) stress during SCI recovery remain unclear. This study was designed to investigate the mechanism by which chloroquine (CQ) inhibits autophagy-associated inflammation and ER stress in rats during their recovery from acute SCI. We evaluated the locomotor function, level of autophagy, and levels of inflammatory cytokines and ER-stress-associated proteins and examined the degradation of the key regulator of inflammation inhibitor of kappa B alpha (I-κBα) through autophagy by analyzing the colocalization of I-κBα, p62, and microtubule-associated protein 1 light chain 3-II. In addition, overexpression of the p62 and activating transcription factor 4 (ATF4) silencing plasmids was used to verify the important roles for autophagic degradation and ER stress. In this study, locomotor function is improved, and autophagy and inflammation are significantly inhibited by, CQ treatment in the model rats. In addition, CQ significantly inhibits the degradation of ubiquitinated I-κBα and blocks the nuclear translocation of nuclear factor kappa B p65 and expression of inflammatory factors. Overexpression of p62 increases I-κBα degradation and improves inflammatory responses. Moreover, CQ treatment also inhibits the activation of ER stress in the rat SCI model, and the ATF4 signaling pathway is required for ER-stress-induced activation of autophagy. These findings reveal a novel mechanism underlying the beneficial effects of CQ on the recovery of SCI, particularly the mechanisms regulating cross-talk between autophagy, inflammation, and ER stress.
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Cloroquina/farmacología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Inflamación/patología , Fármacos Neuroprotectores/farmacología , Traumatismos de la Médula Espinal/patología , Animales , Autofagia/efectos de los fármacos , Femenino , Inflamación/metabolismo , Inflamación/fisiopatología , Ratas , Ratas Sprague-Dawley , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/fisiopatologíaRESUMEN
Fibroblast growth factor 13 (FGF13), a nonsecretory protein of the FGF family, plays a crucial role in developing cortical neurons by stabilizing the microtubule. In previous studies, we showed that regulation of microtubule dynamics was instrumental for both growth cone initiation and for promoting regrowth of injured axon. However, the expression and effect of FGF13 in spinal cord or after spinal cord injury (SCI) remains undefined. Here, we demonstrated a role of FGF13 in regulating microtubule dynamics and in enhancing axon regeneration after SCI. Administration of FGF13 not only promoted neuronal polarization, axon formation, and growth cone initiation in vitro, but it also facilitated functional recovery following SCI. In addition, we found that upregulation of FGF13 in primary cortical neurons was accompanied by enhanced mitochondrial function, which is essential for axon regeneration. Our study has defined a novel mechanism underlying the beneficial effect of FGF13 on axon regeneration, pointing out that FGF13 may serve as a potential candidate for treating SCI or other central nervous system (CNS) injury.
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Factores de Crecimiento de Fibroblastos/metabolismo , Microtúbulos/fisiología , Mitocondrias/fisiología , Traumatismos de la Médula Espinal/patología , Regeneración de la Medula Espinal/fisiología , Animales , Axones/fisiología , Femenino , Vectores Genéticos , Lentivirus , Ratas , Ratas Sprague-Dawley , Recuperación de la Función , Traumatismos de la Médula Espinal/metabolismoRESUMEN
After spinal cord injury (SCI), the destruction of blood-spinal cord barrier (BSCB) is shown to accelerate gathering of noxious blood-derived components in the nervous system, leading to secondary neurodegenerative damages. SCI activates endoplasmic reticulum stress (ER stress), which is considered to evoke secondary damages of neurons and glia. Recent evidence indicates that Dl-3-n-butylphthalide (NBP) has the neuroprotective effect in ischaemic brain injury, but whether it has protective effects on SCI or not is largely unclear. Here, we show that NBP prevented BSCB disruption after SCI via inhibition of ER stress. Following a moderate contusion injury of the T9 level of spinal cord, NBP was administered by oral gavage and further treated once a day. NBP significantly attenuated BSCB permeability and breakdown of adherens junction (AJ) and tight junction (TJ) proteins, then improved locomotion recovery following SCI. The protective role of NBP on BSCB disruption is associated with the restrain of ER stress caused by SCI. Furthermore, NBP considerably constrained the expression of ER stress-associated proteins and degradation of TJ and AJ in human brain microvascular endothelial cells (HBMECs) treated with TG. In conclusion, our results indicate that ER stress is associated with the disruption of BSCB integrity after injury, NBP attenuates BSCB disruption via inhibiting ER stress and improve functional recovery following SCI.
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Benzofuranos/farmacología , Barrera Hematoencefálica/efectos de los fármacos , Traumatismos de la Médula Espinal/fisiopatología , Médula Espinal/efectos de los fármacos , Uniones Adherentes/efectos de los fármacos , Animales , Células Cultivadas , Estrés del Retículo Endoplásmico/efectos de los fármacos , Femenino , Humanos , Locomoción/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Recuperación de la Función , Uniones Estrechas/efectos de los fármacosRESUMEN
Cerebrovascular disease such as stroke is one of the most common diseases in the aging population, and neural stem cells (NSCs) transplantation may provide an alternative therapy for cerebral ischemia. However, a hostile microenvironment in the ischemic brain offers is challenging for the survival of the transplanted cells. Considering the neuroprotective role of basic fibroblast growth factor (bFGF), the present study investigated whether bFGF gene-modified NSCs could improve the neurological function deficit after transient middle cerebral artery occlusion (MCAO) in adult male Sprague-Dawley rats. These rats were intravenously injected with modified NSCs (5×106/200 µL) or vehicle 24 h after MCAO. Histological analysis was performed on days 7 and 28 after tMCAO. The survival, migration, proliferation, and differentiation of the transplanted modified C17.2 cells in the brain were improved. In addition, the intravenous infusion of NSCs and bFGF gene-modified C17.2 cells improved the functional recovery as compared to the control. Furthermore, bFGF promoted the C17.2 cell growth, survival, and differentiation into mature neurons within the infarct region. These data suggested that bFGF gene-modified NSCs have the potential to be a therapeutic agent in brain ischemia.
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Colorectal cancer (CRC) is the third most widespread cancer in the world. Although many advances have been made in molecular biology, novel approaches are still required to reveal molecular mechanisms for the diagnosis and therapy of colon cancer. In this study, we aimed to determine and analyse the hub genes of CRC. First, we explored the mRNA and microRNA (miRNA) expression profiles of colon carcinoma, then we screened target genes of differentially expressed miRNAs and obtained the intersection between differently expressed genes and target genes. Gene Ontology (GO) classification and KEGG pathway analysis of differently expressed genes were performed, and gene-miRNA and TF-gene-miRNA networks were constructed to identify hub genes, miRNAs, and TFs. In total, 3436 significant differentially expressed genes (1709 upregulated and 1727 downregulated) and 216 differentially expressed miRNAs (99 upregulated and 117 downregulated) were identified in colon cancer. These differentially expressed genes were significantly enriched in GO terms and KEGG pathways, such as cell proliferation, cell adhesion, and cytokine-cytokine receptor interaction signalling pathways. GCNT4, EDN2, and so on were located in the central hub of the co-expression network. MYC, WT1, mir-34a, and LEF1 were located in the central hub of the network of TF-gene-miRNA. These findings increase our understanding of the molecular mechanisms of colon cancer and will aid in identifying potential targets for diagnostic and therapeutic usage.
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The blood-spinal cord barrier (BSCB) plays significance roles in recovery following spinal cord injury (SCI), and diabetes mellitus (DM) impairs endothelial cell function and integrity of BSCS. Endoplasmic reticulum (ER) stress occurs in the early stages of SCI and affects prognosis and cell survival. However, the relationship between ER stress and the integrity of BSCB in diabetic rats after SCI remains unclear. Here we observed that diabetic rats showed increased extravasation of Evans Blue (EB) dye, and loss of endothelial cells and pericytes 1 day after SCI compared to non-diabetic rats. Diabetes was also shown to induce activation of ER stress. Similar effects were observed in human brain microvascular endothelial cells. 4-phenylbutyric acid (4-PBA), an ER stress inhibitor lowered the adverse effect of diabetes on SCI, reduced EB dye extravasation, and limited the loss of endothelial cells and pericytes. Moreover, 4-PBA treatment partially reversed the degradation of tight junction and adherens junction both in vivo and in vitro. In conclusion, diabetes exacerbates the disruption of BSCB after SCI via inducing ER stress, and inhibition of ER stress by 4-PBA may play a beneficial role on the integrity of BSCB in diabetic SCI rats, leading to improved prognosis.
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Barrera Hematoencefálica/metabolismo , Estrés del Retículo Endoplásmico , Traumatismos de la Médula Espinal/etiología , Traumatismos de la Médula Espinal/metabolismo , Uniones Adherentes/metabolismo , Animales , Barrera Hematoencefálica/efectos de los fármacos , Butilaminas/farmacología , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/diagnóstico , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Estrés del Retículo Endoplásmico/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Femenino , Peróxido de Hidrógeno/metabolismo , Microvasos/efectos de los fármacos , Microvasos/patología , Pericitos/efectos de los fármacos , Pericitos/metabolismo , Pericitos/patología , Proteolisis , Ratas , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/patología , Uniones Estrechas/metabolismoRESUMEN
In this study, we examined the neuroprotective effects and anti-inflammatory properties of Dl-3-n-butylphthalide (NBP) in Sprague-Dawley (SD) rats following traumatic spinal cord injury (SCI) as well as microglia activation and inflammatory response both in vivo and in vitro. Our results showed that NBP improved the locomotor recovery of SD rats after SCI an significantly diminished the lesion cavity area of the spinal cord, apoptotic activity in neurons, and the number of TUNEL-positive cells at 7 days post-injury. NBP inhibited activation of microglia, diminished the release of inflammatory mediators, and reduced the upregulation of microglial TLR4/NF-κB expression at 1 day post-injury. In a co-culture system with BV-2 cells and PC12 cells, NBP significantly reduced the cytotoxicity of BV-2 cells following lipopolysaccharide (LPS) stimulation. In addition, NBP reduced the activation of BV-2 cells, diminished the release of inflammatory mediators, and inhibited microglial TLR4/NF-κB expression in BV-2 cells. Our findings demonstrate that NBP may have neuroprotective and anti-inflammatory properties in the treatment of SCI by inhibiting the activation of microglia via TLR4/NF-κB signalling.
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Antiinflamatorios/farmacología , Benzofuranos/farmacología , Microglía/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Traumatismos de la Médula Espinal/tratamiento farmacológico , Animales , Línea Celular , Técnicas de Cocultivo , Femenino , Regulación de la Expresión Génica , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Microglía/citología , Microglía/metabolismo , FN-kappa B/antagonistas & inhibidores , FN-kappa B/genética , FN-kappa B/inmunología , Células PC12 , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Médula Espinal/efectos de los fármacos , Médula Espinal/inmunología , Médula Espinal/metabolismo , Médula Espinal/patología , Traumatismos de la Médula Espinal/genética , Traumatismos de la Médula Espinal/inmunología , Traumatismos de la Médula Espinal/patología , Receptor Toll-Like 4/antagonistas & inhibidores , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/inmunologíaRESUMEN
The blood-brain barrier (BBB) plays important roles in the recovery of traumatic brain injury (TBI) which is a major factor contributing to cerebral edema. Acid fibroblast growth factor (aFGF) contributes to maintain vascular integrity and restores nerve function. However, whether aFGF protects BBB following TBI remains unknown. The purpose of this study was to determine whether exogenous aFGF preserves BBB integrity by activating the PI3K-Akt-Rac1 pathway and inhibiting RhoA after TBI. BBB permeability was assessed using evans blue dye and fluorescein isothiocyanate dextran fluorescence. Neurofunctional tests, such as the garcia test, were conducted in a blinded fashion, and protein expression was evaluated via western blotting and immunofluorescence staining. Our results showed that aFGF improved neurofunctional deficits, preserved BBB integrity, and up-regulated tight junction proteins and adherens junction proteins 24 h after experimental TBI. However, the PI3K/Akt inhibitor LY294002 reversed the protective effects of aFGF on neurofunctional deficits and junction protein expression and significantly suppressed p-Akt and GTP-Rac1 activity. Furthermore, aFGF administration significantly decreased GTP-RhoA expression in the treated group compared with the vehicle group, while PI3K/Akt inhibition increased GTP-RhoA expression. Similar results were observed in vitro, as aFGF exerted protective effects on endothelial cell integrity by up-regulating junction proteins and PI3K-Akt-Rac1 pathway and down-regulating RhoA expression under oxygen-glucose deprivation/reoxygenation (OGD) conditions. These data suggest that exogenous aFGF reduces RhoA activity in part by activating the PI3K-Akt-Rac1 signaling pathway, thus improving neurofunctional deficits and preserving BBB integrity after TBI.
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Endoplasmic reticulum (ER) stress-induced apoptosis occurs in the spinal cord following traumatic spinal cord injury (SCI). Dl-3-n-butylphthalide (NBP) exerts an neuroprotective effects against both ischemic brain injury and neurodegenerative diseases; however, the relationship between ER stress-induced apoptosis and the therapeutic effect of NBP in SCI remains unclear. In this study, moderate spinal cord injuries were induced in Sprague-Dawley (SD) rats with a vascular clip. NBP was administered by oral (80 mg/kg/d) gavage 2 h before injury and then once daily for 28 d thereafter. Neurological recovery was assessed using the Basso, Beattie, and Bresnahan (BBB) locomotion rating scale, the inclined plane test, and the footprint analysis. Neuronal cell death was examined by TUNEL staining at 7 days post-injury. ER stress and apoptosis-related proteins were quantified by immunofluorescence staining and western blotting both in vivo and in vitro. Our results showed that NBP significantly decreased spinal cord lesion cavity area and improved locomotor recovery in SD rats after SCI. NBP also decreased neuronal apoptosis and inhibited activation of the caspase 3 cascade. Upregulation of ER stress-related proteins, such as GRP78, ATF-6, ATF-4, PDI, XBP-1, and CHOP, was reversed by NBP treatment in SD rats with SCI. Similarly, NBP effectively ameliorated ER stress and apoptosis-related protein expression induced by incubation with thapsigargin (TG) in PC12 cells. Our findings demonstrate that NBP treatment alleviates secondary SCI by inhibiting ER stress-induced apoptosis, thereby promoting neurological and locomoter functional recovery.
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Endoplasmic reticulum (ER) stress-induced apoptosis plays an important role in a range of neurological disorders, such as neurodegenerative diseases, spinal cord injury, and diabetic neuropathy. Valproate (VPA), a typical antiepileptic drug, is commonly used in the treatment of bipolar disorder and epilepsy. Recently, VPA has been reported to exert neurotrophic effects and promote neurite outgrowth, but its molecular mechanism is still unclear. In the present study, we investigated whether VPA inhibited ER stress and promoted neuroprotection and neuronal restoration in SH-SY5Y cells and in primary rat cortical neurons, respectively, upon exposure to thapsigargin (TG). In SH-SY5Y cells, cell viability was detected by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, and the expression of ER stress-related apoptotic proteins such as glucoseregulated protein (GRP78), C/EBP homologous protein (CHOP), and cleaved caspase-12/-3 were analyzed with Western blot analyses and immunofluorescence assays. To explore the pathway involved in VPA-induced cell proliferation, we also examined p-AKT, GSK3ß, p-JNK and MMP-9. Moreover, to detect the effect of VPA in primary cortical neurons, immunofluorescence staining of ß-III tubulin and Anti-NeuN was analyzed in primary cultured neurons exposed to TG. Our results demonstrated that VPA administration improved cell viability in cells exposed to TG. In addition, VPA increased the levels of GRP78 and p-AKT and decreased the levels of ATF6, XBP-1, GSK3ß, p-JNK and MMP-9. Furthermore, the levels of the ER stress-induced apoptosis response proteins CHOP, cleaved caspase-12 and cleaved caspase-3 were inhibited by VPA treatment. Meanwhile, VPA administration also increased the ratio of Bcl-2/Bax. Moreover, VPA can maintain neurite outgrowth of primary cortical neurons. Collectively, the neurotrophic effect of VPA is related to the inhibition of ER stress-induced apoptosis in SH-SY5Y cells and the maintenance of neuronal growth. Collectively, our results suggested a new approach for the therapeutic function of VPA in neurological disorders and neuroprotection.