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The increasing comorbidity of alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD) associated with traumatic brain injury (TBI) is a serious medical, economic, and social issue. However, the molecular toxicology and pathophysiological mechanisms of comorbid AUD and PTSD are not well understood and the identification of the comorbidity state markers is significantly challenging. This review summarizes the main characteristics of comorbidity between AUD and PTSD (AUD/PTSD) and highlights the significance of a comprehensive understanding of the molecular toxicology and pathophysiological mechanisms of AUD/PTSD, particularly following TBI, with a focus on the role of metabolomics, inflammation, neuroendocrine, signal transduction pathways, and genetic regulation. Instead of a separate disease state, a comprehensive examination of comorbid AUD and PTSD is emphasized by considering additive and synergistic interactions between the two diseases. Finally, we propose several hypotheses of molecular mechanisms for AUD/PTSD and discuss potential future research directions that may provide new insights and translational application opportunities.
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Alcoholismo , Lesiones Traumáticas del Encéfalo , Trastornos por Estrés Postraumático , Humanos , Alcoholismo/complicaciones , Alcoholismo/epidemiología , Alcoholismo/metabolismo , Comorbilidad , Consumo de Bebidas Alcohólicas , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/epidemiologíaRESUMEN
Although traumatic brain injury (TBI) is a common cause of death and disability worldwide, there is currently a lack of effective therapeutic drugs and targets. To reveal the complex pathophysiologic mechanisms of TBI, we performed transcriptome analysis of the mouse cerebral cortex and immunohistochemical analysis of human cerebral tissues. The genes Mt1, Mt2, Il33, and Fth1 were upregulated post-TBI and enriched in pathways associated with the inflammatory response, oxidative phosphorylation, and ferroptosis. As an agonist of MT1/2, melatonin (MLT) confers anti-oxidant, anti-inflammatory, and anti-ferroptosis effects after TBI. However, whether these upregulated genes and their corresponding pathways are involved in the neuroprotective effect of MLT remains unclear. In this study, interventions to inhibit MT1/2, IL-33, and ferroptosis (i.e., ferritin H (Fth)-KO) were applied post-TBI. The results showed that MLT attenuated TBI-induced cerebral edema and neurological outcomes by inhibiting inflammation and ferroptosis. Mechanistically, MLT mainly suppressed inflammatory responses and ferroptosis via the activation of MT2 and IL-33 pathways. Building on the previous finding that Fth deletion increases susceptibility to ferroptosis post-TBI, we demonstrated that Fth depletion remarkably exacerbated the post-TBI inflammatory response, and abolished the anti-inflammatory effects of MLT both in vivo and in vitro. Furthermore, the post-TBI anti-inflammatory effect of MLT, which occurs by promoting the polarization of CD206+ macrophages, was dependent on Fth. Taken together, these results clarified that MLT alleviates inflammation- and ferroptosis-mediated brain edema and neurological deficits by activating the MT2/IL-33/Fth pathway, which provides a novel target and theoretical basis for MLT to treat TBI patients.
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Edema Encefálico , Lesiones Traumáticas del Encéfalo , Melatonina , Animales , Humanos , Ratones , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Lesiones Traumáticas del Encéfalo/genética , Lesiones Traumáticas del Encéfalo/complicaciones , Inflamación/tratamiento farmacológico , Inflamación/complicaciones , Interleucina-33/genética , Melatonina/farmacología , Enfermedades Neuroinflamatorias , Ferritinas/metabolismoRESUMEN
Ferroptosis is a form of regulated cell death that is mainly triggered by iron-dependent lipid peroxidation. A growing body of evidence suggests that ferroptosis is involved in the pathophysiology of traumatic brain injury (TBI), and tropomyosin-related kinase B (TrkB) deficiency would mediate TBI pathologies. As an agonist of TrkB and an immediate precursor of melatonin, N-acetyl serotonin (NAS) exerts several beneficial effects on TBI, but there is no information regarding the role of NAS in ferroptosis after TBI. Here, we examined the effect of NAS treatment on TBI-induced functional outcomes and ferroptosis. Remarkably, the administration of NAS alleviated TBI-induced neurobehavioral deficits, lesion volume, and neurodegeneration. NAS also rescued TBI-induced mitochondrial shrinkage, the changes in ferroptosis-related molecule expression, and iron accumulation in the ipsilateral cortex. Similar results were obtained with a well-established ferroptosis inhibitor, liproxstatin-1. Furthermore, NAS activated the TrkB/PI3K/Akt/Nrf2 pathway in the mouse model of TBI, while inhibition of PI3K and Nrf2 weakened the protection of NAS against ferroptosis both in vitro and in vivo, suggesting that a possible pathway linking NAS to the action of anti-ferroptosis was TrkB/PI3K/Akt/Nrf2. Given that ferritin H (Fth) is a known transcription target of Nrf2, we then investigated the effects of NAS on neuron-specific Fth knockout (Fth-KO) mice. Strikingly, Fth deletion almost abolished the protective effects of NAS against TBI-induced ferroptosis and synaptic damage, although Fth deletion-induced susceptibility toward ferroptosis after TBI was reversed by an iron chelator, deferoxamine. Taken together, these data indicate that the TrkB agonist NAS treatment appears to improve brain function after TBI by suppressing ferroptosis, at least in part, through activation of the PI3K/Akt/Nrf2/Fth pathway, providing evidence that NAS is likely to be a promising anti-ferroptosis agent for further treatment for TBI.
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Lesiones Traumáticas del Encéfalo , Proteínas Proto-Oncogénicas c-akt , Ratones , Animales , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Ferritinas , Serotonina , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Lesiones Traumáticas del Encéfalo/genética , Lesiones Traumáticas del Encéfalo/metabolismo , Hierro/metabolismoRESUMEN
OBJECTIVE: We aim to explore the detailed molecular mechanisms of membrane nephropathy (MN) related genes by bioinformatics analysis. METHODS: Two microarray datasets (GSE108109 and GSE104948) with glomerular gene expression data from 65 MN patients and 9 healthy donors were obtained from the Gene Expression Omnibus (GEO) database. After processing the raw data, DEGs screening was conducted using the LIMMA (linear model for microarray data) package and Gene set enrichment analysis (GSEA) was performed with GSEA software (v. 3.0), followed by gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. The protein-protein interaction (PPI) network analysis was carried out to determine the hub genes, by applying the maximal clique centrality (MCC) method, which was visualized by Cytoscape. Finally, utilizing the Nephroseq v5 online platform, we analyzed subgroups associated with hub genes. The findings were further validated by immunohistochemistry (IHC) staining in renal tissues from MN or control patients. RESULTS: A sum of 370 DEGs (188 up-regulated genes, 182 down-regulated genes) and 20 hub genes were ascertained. GO and KEGG enrichment analysis demonstrated that DEGs of MN were preponderantly associated with cell damage and complement cascade-related immune responses. Combined with literature data and hub gene-related MN subset analysis, CTSS, ITGB2, and HCK may play important roles in the pathological process of MN. CONCLUSION: This study identified novel hub genes in MN using bioinformatics. We found that some hub genes such as CTSS, ITGB2, and HCK might contribute to MN immunopathological process, providing new insights for further study of the molecular mechanisms underlying glomerular injury of MN.
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PURPOSE: This study aimed to investigate the association between chronic kidney disease (CKD) and different types of cancer and the effect of CKD on mortality among types of cancer. METHODS: 30559 participants from NHANES 1999-2014 were included in our analysis, which had 2824 participants with cancer. Subgroups were grouped by cancer location. The association of different types of cancer with CKD was assessed using logistic regression models. Kaplan-Meier estimates and Cox proportional hazards models were used to evaluate the correlation between CKD and all-cause mortality in different cancer groups. RESULTS: Age, gender, race, education level, income level, hypertension, diabetes, smoking status, alcohol consumption, TG, HDL-C, UA and eGFR were significantly different between the cancer and non-cancer group. The three cancers with highest prevalence of CKD were kidney cancer (72.3%), bladder cancer (54.7%), and colon cancer (43.0%) in this study. The prevalence of CKD was higher in cancer patients compared to non-cancer ones. Only genitourinary cancer showed a positive association with CKD (OR=1.23, 95% CI: 1.05-1.44) after adjusting for confounding factors. However, CKD was an independent risk factor for mortality from cancer regardless of the type of cancer. CONCLUSION: CKD is significantly associated only with genitourinary cancer among different types of cancer. CKD is an independent risk factor for survival in cancer patients, regardless of the type of cancer. Monitoring and maintaining the renal function of cancer patients is essential for prolonging their life.
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Background: Chronic kidney disease (CKD) in women is often accompanied by hormone disorders such as sex hormones, and most women with CKD are in the post-menopausal age group. Due to the close relationship between menopause and sex hormones, we aimed to explore the association between early menopause and CKD in post-menopausal women, and the influence of early menopause on longevity in the CKD population. Methods: Information regarding 4,945 post-menopausal women was extracted from the database of the National Health and Nutrition Examination Survey (NHANES) 1999-2014, and then divided into 4 groups according to the type of menopause (natural or surgical) and early menopause (menopause at age <45) or not. The association between early menopause and CKD prevalence was examined using multivariable logistic regression, while we used multivariable Cox proportional hazards models to investigate the possible relationship between early menopause and all-cause mortality in CKD and non-CKD populations. The differences in the levels of sex hormones between women with and without CKD were also explored. Results: Compared with women with natural menopause at age ≥45, women experiencing early natural menopause had a higher risk of CKD [OR = 1.26 (1.01-1.56)]. Similarly, as compared to women with surgical menopause at age ≥ 45, women in the early surgical menopause group were more likely to have CKD [OR = 1.38 (1.05-1.81)]. In addition, early surgical menopause was associated with higher mortality in the non-CKD group [HR = 1.62 (1.06-2.49)], but not in the CKD group. Women with CKD had a higher level of luteinizing hormone and follicle-stimulating hormone, combined with a lower level of testosterone and estradiol than the non-CKD women. Conclusion: Both early natural and surgical menopause were associated with a higher risk of CKD. Early surgical menopause was a hazard factor for survival in the non-CKD group, but not in the CKD group. Further research is required to understand the mechanisms.
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OBJECTIVE: The long-term safety of consuming low-carbohydrate diets (LCDs) remains controversial. As high protein and high fat might accelerate chronic kidney disease (CKD) progression, the impact of LCD on mortality might be different in subjects with CKD and subjects without CKD. Therefore, the objective of this study was to assess the association of LCD with mortality among individuals with and without CKD. METHODS: Data from 1158 subjects with CKD and 9523 subjects without CKD in the Third National Health and Nutrition Examination Survey were analyzed. The LCD score was calculated based on a 24-hour dietary recall interview. Mortality was from baseline until 31 December 2015. Cox proportional hazards regression models were fitted to estimate multivariable-adjusted hazard ratios and 95% confidence intervals. RESULTS: During the median follow-up of 24 years, 751 (65%) deaths and 2624 (28%) deaths were recorded in the CKD group and the non-CKD group, respectively. The multivariable-adjusted hazard ratio for all-cause mortality comparing the highest versus lowest quarters of LCD score was 1.51 (95% confidence interval, 1.01-2.25, P for trend = 0.045) in the CKD group. However, there were no association between the LCD score and all-cause mortality in the non-CKD group. CONCLUSIONS: The LCD scores were found significantly positively associated with all-cause mortality in adults with CKD, but not in adults without CKD.
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Dieta Baja en Carbohidratos , Insuficiencia Renal Crónica , Adulto , Carbohidratos , Dieta Baja en Carbohidratos/métodos , Femenino , Humanos , Masculino , Encuestas Nutricionales , Encuestas y CuestionariosRESUMEN
Based on accumulating evidence, patients recovering from mild and moderate traumatic brain injury (TBI) often experience increased sensitivity to stressful events. However, few studies have assessed on the effects and pathophysiological mechanisms of stress on TBI. In the current study, using a mouse model of moderate TBI, we investigated whether restraint stress (RS) regulates secondary neurodegeneration and neuronal cell death, which are commonly associated with neurological dysfunctions. Our data showed that RS significantly reduced body weight recovery, delayed the recovery of neurological functions (motor function, cognitive function and anxiety-like behavior) and exacerbated the brain lesion volume after moderate TBI. Immunofluorescence results indicated that moderate TBI-induced cell insults and blood-brain barrier leakage were aggravated by RS. Further Western blotting experiments showed that RS activated endoplasmic reticulum (ER) stress excessively after moderate TBI and decreased the number of NeuN-positive cells, but increased the number of CHOP/NeuN-co-positive cells by performing immunostaining in the injured cortex after moderate TBI. Moreover, RS increased the ratios of CHOP/Aß and CHOP/p-Tau co-positive cells in the injured cortex after moderate TBI. However, blocking ER stress with the classic ER stress inhibitor salubrinal remarkably decreased apoptosis and the levels of autophagy-related proteins in the mouse model of moderate TBI plus RS. Collectively, RS delays the recovery of neurological function and deteriorates morphological damage by excessively activating ER stress-mediated neurodegeneration, apoptosis and autophagy after moderate TBI. Thus, monitoring stress levels in patients recovering from non-severe TBI may merit consideration in the future.
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Lesiones Traumáticas del Encéfalo , Estrés del Retículo Endoplásmico , Apoptosis , Autofagia , Lesiones Traumáticas del Encéfalo/patología , Corteza Cerebral/patología , HumanosRESUMEN
BACKGROUND: The relationship between marital status and CKD is rarely studied. We aimed to explore the effect of marital status on the depression and mortality of patients with CKD. METHODS: The data sources came from the NHANES database during 2005-2014 and 3,865 participants were included in this study. We used logistic regression models to examine the relationship between marital status and depression of CKD patients. The Cox proportional hazard models were used to evaluate the association between marital status and mortality of CKD patients. RESULTS: In terms of depression in CKD patients, unmarried patients had a worse situation than married patients. Meanwhile, after adjusting the covariables, unmarried patients had increased risk of depression (OR = 1.26, 95% CI: 1.01-1.57) compared with married CKD patients, especially in males (OR = 1.45, 95% CI: 1.02-2.06) and patients with more than college education level (OR = 12.4, 95% CI: 3.75-41.02). There was a significant relationship between marital status and mortality of general CKD patients (HR = 1.36, 95% CI: 1.17-1.58). Moreover, marriage showed a protective effect against death among male patients, patients with school graduate or less and more than college educational level, patients with high income, and patients in different estimated glomerular filtration rate groups. CONCLUSIONS: The use of large numbers of participants has revealed the effect of marital status on CKD patients. Unmarried ones had a higher risk of depression than married ones among CKD patients. Meanwhile, the risk of death was higher in unmarried ones than married ones among CKD patients in this study.
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Autophagy is a self-phagocytic and highly evolutionarily conserved intracellular lysosomal catabolic system, which plays a vital role in a variety of trauma models, including skin wound healing (SWH). However, the roles and potential mechanisms of autophagy in SWH are still controversial. We firstly investigated the role of autophagy in SWH-induced wound closure rate, inflammatory response, and histopathology, utilizing an inhibitor of autophagy 3-methyladenine (3-MA) and its agonist rapamycin (RAP). As expected, we found 3-MA treatment remarkably increased the wound closure rate, combated inflammation response, and mitigated histopathological changes, while RAP delivery aggravated SWH-induced pathological damage. To further exploit the underlying mechanism of autophagy regulating inflammation, the specific inhibitors of yes-associated protein (YAP), Verteporfin, and Anti-IL-33 were applied. Herein, treating with 3-MA markedly suppressed the expression of tumor necrosis factor-α (TNF-α), IL-1ß, and IL-6, promoted that of IL-10, IL-33, and ST2, while RAP administration reverted SWH-induced the up-regulation of these inflammatory cytokines mentioned above. Importantly, Verteporfin administration not only down-regulated the expression levels of YAP, TNF-α, and IL-6 but also up-regulated that of IL-33 and IL-10. Unexpectedly, 3-MA or RAP retreatment did not have any impact on the changes in IL-33 among these inflammatory indicators. Furthermore, elevated expression of IL-33 promoted wound closure and alleviated the pathological damage, whereas, its antagonist Anti-IL-33 treatment overtly reversed the above-mentioned effects of IL-33. Moreover, 3-MA in combination with anti-IL-33 treatment reversed the role of 3-MA alone in mitigated pathological changes, but they failed to revert the effect of anti-IL-33 alone on worsening pathological damage. In sum, emerging data support the novel contribution of the YAP/IL-33 pathway in autophagy inhibition against SWH-induced pathological damage, and highlight that the autophagy/YAP/IL-33 signal axis is expected to become a new therapeutic target for SWH.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Autofagia , Interleucina-33/metabolismo , Transducción de Señal , Piel/metabolismo , Cicatrización de Heridas , Adenina/análogos & derivados , Adenina/farmacología , Animales , Autofagia/efectos de los fármacos , Modelos Animales de Enfermedad , Inflamación/metabolismo , Masculino , Ratones , Ratones Endogámicos ICR , Sirolimus/farmacología , Cicatrización de Heridas/efectos de los fármacos , Proteínas Señalizadoras YAPRESUMEN
Background: Tertiary lymphoid organs (TLOs) occur after multiple chronic kidney injuries. interleukin-17A (IL-17A) has been reported to associate with the development of TLOs in inflammatory diseases. However, regulation of the renal TLOs and its clinical significance to the pathogenesis of chronic kidney injury are unknown. Methods: To evaluate the clinical significance and regulation of renal TLOs, we analyzed the progression of patients with kidney damage based on the existence and absence of TLOs in a larger multicenter cohort. We also blocked the recruitment of lymphocyte cells into the kidney by FTY720 (fingolimod) in vivo. Besides, we used aged IL-17A genetic knocked out mice and IL-17A-neutralizing antibody to explore the role of IL-17A in renal TLOs formation. Results: We demonstrated that renal TLOs of IgA nephropathy patients were associated with disease severity and were independent risk factors for renal progression after adjustment for age, sex, mean arterial pressure, proteinuria and, baseline eGFR and MEST-C score, especially in the early stage. Plasma levels of TLO-related chemokines CXCL13, CCL19, and CCL21 were higher in patients with renal TLOs. Inhibiting the formation of renal TLOs by FTY720 could reduce the intrarenal inflammation and fibrosis, and early intervention was found to be more effective. IL-17A was increased in renal TLOs models, and genetic depletion of IL-17A or treatment with anti-IL-17A antibody resulted in a marked reduction of the TLOs formation as well as alleviation of renal inflammation and fibrosis. Conclusion: These results indicate that TLOs are associated with the progression of kidney damage and regulated by IL-17A and may be effective targets for the treatment of kidney damage.
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Interleucina-17/genética , Riñón/patología , Insuficiencia Renal Crónica/patología , Estructuras Linfoides Terciarias/patología , Adulto , Animales , Progresión de la Enfermedad , Femenino , Clorhidrato de Fingolimod/farmacología , Glomerulonefritis por IGA/inmunología , Glomerulonefritis por IGA/patología , Glomerulonefritis Membranosa/inmunología , Glomerulonefritis Membranosa/patología , Humanos , Inmunosupresores/farmacología , Riñón/efectos de los fármacos , Riñón/inmunología , Nefritis Lúpica/inmunología , Nefritis Lúpica/patología , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Nefrosis Lipoidea/inmunología , Nefrosis Lipoidea/patología , Insuficiencia Renal Crónica/inmunología , Estructuras Linfoides Terciarias/genética , Estructuras Linfoides Terciarias/inmunologíaRESUMEN
BACKGROUND: Tertiary lymphoid organs play an essential role in the inflammation of the kidney. The clinical association between TLOs and membranous nephropathy (MN) is not clear yet. METHODS: Consecutive patients with the histologically confirmed membranous nephropathy in Tongji Hospital from July 19, 2012, to September 26, 2019, were included in this study. TLOs in renal biopsy tissues were detected by periodic acid-Schiff-stained and immunohistochemistry. Logistic regression was performed to evaluate the correlations of TLOs and clinical features of patients with MN. Kaplan-Meier analysis was utilized to examine the relationship between TLOs and remission of proteinuria. RESULTS: A total of 442 patients with MN were included in this study, of which the average age was 46.4 years old, and 58.8% were male. Moreover, 33% of patients with MN had TLOs in this study. The median value of proteinuria among patients with MN with TLOs was 4.9 g/24 h, which was much greater than no-TLOs ones (3.2 g/24 h, p < 0.001). Moreover, the patients with TLOs had higher serum creatinine and lower serum albumin. The severity of clinical features among the patients with MN aggravated with the increase in the grade of TLOs. In addition, the patients who had TLOs were more likely to be positive of anti-phospholipase A2 receptor autoantibodies. Meanwhile, the patients without TLOs showed significantly higher complete remission and total remission of proteinuria. CONCLUSION: In this study, we demonstrated that TLOs were common among patients with MN. Moreover, the patients with MN with TLOs showed a worse clinical manifestation and an outcome compared with the patients without TLOs.
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Accumulating evidence demonstrates that ferroptosis may be important in the pathophysiological process of traumatic brain injury (TBI). As a major hormone of the pineal gland, melatonin exerts many beneficial effects on TBI, but there is no information regarding the effects of melatonin on ferroptosis after TBI. As expected, TBI resulted in the time-course changes of ferroptosis-related molecules expression and iron accumulation in the ipsilateral cortex. Importantly, we found that treating with melatonin potently rescued TBI induced the changes mentioned above and improved functional deficits versus vehicle. Similar results were obtained with a ferroptosis inhibitor, liproxstatin-1. Moreover, the protective effect of melatonin is likely dependent on melatonin receptor 1B (MT2). Although ferritin plays a vital role in iron metabolism by storing excess cellular iron, its precise function in the brain, and whether it involves melatonin's neuroprotection remain unexplored. Considering ferritin H (Fth) is expressed predominantly in the neurons and global loss of Fth in mice induces early embryonic lethality, we then generated neuron-specific Fth conditional knockout (Fth-KO) mice, which are viable and fertile but have altered iron metabolism. In addition, Fth-KO mice were more susceptible to ferroptosis after TBI, and the neuroprotection by melatonin was largely abolished in Fth-KO mice. In vitro siFth experiments further confirmed the results mentioned above. Taken together, these data indicate that melatonin produces cerebroprotection, at least partly by inhibiting neuronal Fth-mediated ferroptosis following TBI, supporting the notion that melatonin is an excellent ferroptosis inhibitor and its anti-ferroptosis provides a potential therapeutic target for treating TBI.
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Apoferritinas/metabolismo , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Lesiones Traumáticas del Encéfalo/metabolismo , Melatonina/uso terapéutico , Animales , Apoferritinas/genética , Western Blotting , Ferroptosis/efectos de los fármacos , Inmunohistoquímica , Hierro/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Alcohol use disorder (AUD) is an enormous public health problem that poses significant social, medical, and economic burdens. Under AUD, the liver is one of the most adversely affected organs. As current therapies and protective drugs for AUD-mediated liver injury are very limited, the prevention and therapy of alcoholic liver disease are urgently needed. The present study aims to investigate the beneficial effects of tartary buckwheat extract (TBE), the important component of Maopu tartary buckwheat liquor, on both alcoholic-induced acute and chronic liver injuries. We show that the TBE administration, similar to curcumin, significantly reduces the elevated serum aspartate aminotransferase and alanine aminotransferase levels, improves liver index, alleviates the elevated contents of hepatic malondialdehye, and restores the decreased contents of hepatic glutathione both in acute and chronic liver injuries in alcohol-exposed rats. Furthermore, histopathological analyses show that a medium dose of TBE (16.70 ml/kg body weight) alleviates hepatocyte morphology changes in both acute and chronic alcohol exposure models. We also show the protective effects of TBE on the cell death rates of alcohol-exposed primary cultured hepatocytes, HepG2 hepatoma, and Huh 7 hepatoma cells. Furthermore, we demonstrate that TBE exerts hepatoprotection partly through inhibiting the mitochondrial cell death pathway by reducing cytochrome c release, caspase-9 and -3 activities, and the number of TUNEL-positive cells. These effects of TBE were accompanied by enhanced levels of Bcl-2 and Bcl-xL and autophagic cell death pathway by reducing Beclin-1 expression, as well as through promoting its anti-oxidant capacity by suppressing reactive oxygen species production. This study demonstrates, for the first time, the protective effect of TBE against alcohol-induced acute and chronic liver injury in vivo and in vitro. Given the dietary nature of tartary buckwheat, pueraria, lycium barbarum, and hawthorn, the oral intake of TBE or liquor contained TBE, e.g., Maopu Tartary buckwheat liquor, compared with pure liquor consumption alone, may have the potential to alleviate alcoholic-induced liver injuries.
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Neuroinflammation accompanied by microglial activation triggers multiple cell death after traumatic brain injury (TBI). The secondary injury caused by inflammation may persist for a long time. Recently, platelet C-type lectin-like 2 receptor (CLEC-2) has been shown to regulate inflammation in certain diseases. However, its possible effects on TBI remain poorly understood. Here, we aimed to investigate the role of platelet CLEC-2 in the pathological process of neuroinflammation after TBI. In this study, mice were subjected to sham or controlled cortical impact injury, and arbitrarily received recombinant platelet CLEC-2. In parallel, BV2 cells were treated with lipopolysaccharide (LPS) to mimic microglial activation after TBI. Primary endothelial cells were also subjected to LPS in order to replicate the inflammatory damage caused by TBI. We used western blot analysis, reverse transcription polymerase chain reaction (RT-PCR), and immunostaining to evaluate the role of platelet CLEC-2 in TBI. In conditional knock out platelet CLEC-2 mice, trauma worsened the integrity of the blood-brain barrier and amplified the release of inflammatory cytokines. In wild type mice subjected to controlled cortical impact injury, recombinant platelet CLEC-2 administration altered the secretion of inflammatory cytokines, reduced brain edema, and improved neurological function. In vitro, the polarization phenotype of microglia induced by LPS was transformed by recombinant platelet CLEC-2, and this conversion depended on the mammalian target of rapamycin (mTOR) pathway. Endothelial cell injury by LPS was ameliorated when microglia expressed mostly M2 phenotype markers. In conclusion, platelet CLEC-2 regulates trauma-induced neuroinflammation and restores blood-brain barrier integrity.
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Plaquetas/metabolismo , Barrera Hematoencefálica/patología , Lesiones Traumáticas del Encéfalo/patología , Inflamación/patología , Lectinas Tipo C/metabolismo , Animales , Lesiones Traumáticas del Encéfalo/metabolismo , Modelos Animales de Enfermedad , Inflamación/metabolismo , Masculino , Ratones , Ratones Endogámicos ICR , Ratones NoqueadosRESUMEN
Tropomyosin-related kinase B (TrkB) has emerged as a key mediator in the pathophysiology of traumatic brain injury (TBI). However, it is not known whether TrkB's agonist N-acetyl serotonin (NAS) involves in neuronal damage and brain dysfunction caused by TBI that is known as one of the most important causes of disability and death worldwide. Here, we investigated the effects of NAS on brain edema, blood-brain barrier (BBB), apoptosis activation and autophagy dysfunction after experimental TBI. A mouse TBI model was applied, NAS and ANA-12 (an antagonist of TrkB) were administered. Here, we first found that NAS administration ameliorated TBI-induced brain edema, blood-brain barrier (BBB) disruption, increase of matrix metalloproteinase-9 (MMP-9) expression and decrease of claudin-5 expression. NAS treatment decreased TBI-induced cell death and apoptosis activation (detected by propidium iodide labeling, TUNEL staining, blots for Bcl-2, Bax and caspase-3). In addition, NAS treatment decreased the expression of Beclin-1 and LC3, along with ratio of Beclin-1/Bcl-2, but increased p62 expression following TBI. NAS also enhanced the activation of the TrkB/Akt pathway following TBI. Whereas, the above protective effect of NAS following TBI was blocked by ANA-12 addition. Thus, we conclude that NAS-initiating the TrkB/Akt signaling cascade provides neuroprotection after experimental TBI in mice, which at least in part through inhibiting apoptosis activation and autophagic dysfunction.
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Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Lesiones Traumáticas del Encéfalo/prevención & control , Glicoproteínas de Membrana/agonistas , Fármacos Neuroprotectores/uso terapéutico , Serotonina/análogos & derivados , Animales , Apoptosis/fisiología , Autofagia/fisiología , Lesiones Traumáticas del Encéfalo/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Endogámicos ICR , Fármacos Neuroprotectores/farmacología , Proteínas Tirosina Quinasas/metabolismo , Serotonina/farmacología , Serotonina/uso terapéuticoRESUMEN
Growing evidences have shown that patients recovering from stroke experience high and unremitting stress. Chronic restraint stress (CRS) has been found to exacerbate neurological impairments in an experimental focal cortical ischemia model. However, there have been no studies reporting the effect and mechanism of CRS on intracerebral hemorrhage (ICH). This study aimed to evaluate the effect of CRS on a mouse ICH model. Adult male C57BL mice were subjected to infusion of collagenase IV (to induce ICH) or saline (for sham) into the left striatum. After ICH, animals were stressed with application of CRS protocol for 21 days. Our results showed that CRS significantly exacerbated neurological deficits (Garcia test, corner turn test, and wire grip test) and the ipsilateral brain atrophy and reduced body weight gain after ICH. Immunofluorescence staining indicated that CRS exerted significant suppressive effects on neuron, astrocyte, vascular endothelial cell and pericyte and excessively activated microglia post ICH. All of the key cellular components mentioned above are involved in the neurovascular unit (NVU) remodeling in the peri-hemorrhagic region after ICH. Western blot results showed that matrix metalloproteinase (MMP)-9 and tight junction (TJ) proteins including zonula occludens-1, occludin and claudin-5 were increased after ICH, but MMP-9 protein was further up-regulated and TJ-related proteins were down-regulated by CRS. In addition, ICH-induced activation of endoplasmic reticulum stress and apoptosis were further strengthened by CRS. Collectively, CRS exacerbates neurological deficits and disrupts the remodeling of the peri-hemorrhagic NVU after ICH, which may be associated with TJ proteins degradation and excessive activation of MMP-9 and endoplasmic reticulum stress-apoptosis.LAY SUMMARYCRS exacerbates neurological deficits and disrupts the remodeling of the NVU in the recovery stage after ICH, which suggest that monitoring chronic stress levels in patients recovering from ICH may merit consideration in the future.
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Hemorragia Cerebral , Estrés Psicológico , Animales , Modelos Animales de Enfermedad , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , NeuronasRESUMEN
Traumatic brain injury (TBI) is a complex injury that can cause severe disabilities and even death. TBI can induce secondary injury cascades, including but not limited to endoplasmic reticulum (ER) stress, apoptosis and autophagy. Although the investigators has previously shown that salubrinal, the selective phosphatase inhibitor of p-eIF2α, ameliorated neurologic deficits in murine TBI model, the neuroprotective mechanisms of salubrinal need further research to warrant the preclinical value. This study was undertaken to characterize the effects of salubrinal on cell death and neurological outcomes following TBI in mice and the potential mechanisms. In the current study, ER stress-related proteins including p-eIF2α, GRP78 and CHOP showed peak expressions both in the cortex and hippocampus from day 2 to day 3 after TBI, indicating ER stress was activated in our TBI model. Immunofluorescence staining showed that CHOP co-located NeuN-positive neuron, GFAP-positive astrocyte, Iba-1-positive microglia, CD31-positive vascular endothelial cell and PDGFR-ß-positive pericyte in the cortex on day 2 after TBI, and these cells mentioned above constitute the neurovascular unit (NVU). We also found TBI-induced plasmalemma permeability, motor dysfunction, spatial learning and memory deficits and brain lesion volume were alleviated by continuous intraperitoneal administration of salubrinal post TBI. To investigate the underlying mechanisms further, we determined that salubrinal suppressed the expression of ER stress, autophagy and apoptosis related proteins on day 2 after TBI. In addition, salubrinal administration decreased the number of CHOP+/TUNEL+ and CHOP+/LC3+ cells on day 2 after TBI, detected by immunofluorescence. In conclusion, these data imply that salubrinal treatment improves morphological and functional outcomes caused by TBI in mice and these neuroprotective effects may be associated with inhibiting apoptosis, at least in part by suppressing ER stress-autophagy pathway.
Asunto(s)
Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Cinamatos/farmacología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Tiourea/análogos & derivados , Animales , Modelos Animales de Enfermedad , Chaperón BiP del Retículo Endoplásmico , Masculino , Ratones , Ratones Endogámicos ICR , Tiourea/farmacologíaRESUMEN
Interleukin-33 (IL-33) is a member of the interleukin-1 (IL-1) cytokine family and an extracellular ligand for the orphan IL-1 receptor ST2. Accumulated evidence shows that the IL-33/ST2 axis plays a crucial role in the pathogenesis of central nervous system (CNS) diseases and injury, including traumatic brain injury (TBI). However, the roles and molecular mechanisms of the IL-33/ST2 axis after TBI remain poorly understood. In this study, we investigated the role of IL-33/ST2 signaling in mouse TBI-induced brain edema and neurobehavioral deficits, and further exploited underlying mechanisms, using salubrinal (SAL), the endoplasmic reticulum (ER) stress inhibitor and anti-ST2L. The increase in IL-33 level and the decrease in ST2L level at injured cortex were first observed at 24 h post-TBI. By immunofluorescent double-labeled staining, IL-33 co-localized in GFAP-positive astrocytes, and Olig-2-positive oligodendrocytes, and predominantly presented in their nucleus. Additionally, TBI-induced brain water content, motor function outcome, and spatial learning and memory deficits were alleviated by IL-33 treatment. Moreover, IL-33 and SAL alone, or their combination prevented TBI-induced the increase of IL-1ß and TNF-α levels, suppressed the up-regulation of ER stress, apoptosis and autophagy after TBI. However, anti-ST2L treatment could significantly invert the above effects of IL-33. Together, these data demonstrate that IL-33/ST2 signaling mitigates TBI-induced brain edema, motor function outcome, spatial learning and memory deficits, at least in part, by a mechanism involving suppressing autophagy, ER stress, apoptosis and neuroinflammation.
RESUMEN
The exposure time of carcasses in insect succession studies are generally not consistent and more than 40% studies start in the morning. How such an arrangement affects the succession of insects is worth evaluating. In this study, six piglet carcasses (15-17 kg) were exposed at 6 time points during the day: 11:00, 15:00, 19:00, 23:00, 03:00 and 07:00 on July 20th-July 21st 2006 in Guangzhou, China to investigate the potential effects of the time of day of carcass exposure on body decomposition and insect succession, and also to provide fundamental data on insect succession in summer for this area. The results showed that there were negligible differences in the decay process among the carcasses. We found the carcasses synchronized their decay stage after entering the bloated stage on July 21st. All 6 carcasses entered the remains stage on August 3rd (approximately 14 d after carcass placement). The carcasses yielded 30 species of arthropods, representing 3 orders and 12 families, and no obvious differences were found in species composition between the carcasses. However, we found that there were significant differences in the arrival and colonization of Calliphoridae. We found two batches of Chrysomya megacephala (Fabricius) larvae with significant differences in body length and instar on the carcasses placed at the site at 11:00, 15:00 and 19:00. By contrast, there was only one batch of C. megacephala larvae having similar body length and instar on the carcasses placed at the site at 23:00, 03:00 and 07:00. These observations have potential use for estimating the postmortem interval in forensic entomology.