RESUMEN
With the rapidly aging human population, age-related cognitive decline and dementia are becoming increasingly prevalent worldwide. Aging is considered the main risk factor for cognitive decline and acts through alterations in the composition of the gut microbiota, microbial metabolites, and the functions of astrocytes. The microbiota-gut-brain axis has been the focus of multiple studies and is closely associated with cognitive function. This article provides a comprehensive review of the specific changes that occur in the composition of the gut microbiota and microbial metabolites in older individuals and discusses how the aging of astrocytes and reactive astrocytosis are closely related to age-related cognitive decline and neurodegenerative diseases. This article also summarizes the gut microbiota components that affect astrocyte function, mainly through the vagus nerve, immune responses, circadian rhythms, and microbial metabolites. Finally, this article summarizes the mechanism by which the gut microbiota-astrocyte axis plays a role in Alzheimer's and Parkinson's diseases. Our findings have revealed the critical role of the microbiota-astrocyte axis in age-related cognitive decline, aiding in a deeper understanding of potential gut microbiome-based adjuvant therapy strategies for this condition.
RESUMEN
JOURNAL/nrgr/04.03/01300535-202502000-00029/figure1/v/2024-05-28T214302Z/r/image-tiff Cerebral edema caused by blood-brain barrier injury after intracerebral hemorrhage is an important factor leading to poor prognosis. Human-induced pluripotent stem cell-derived neural stem cell exosomes (hiPSC-NSC-Exos) have shown potential for brain injury repair in central nervous system diseases. In this study, we explored the impact of hiPSC-NSC-Exos on blood-brain barrier preservation and the underlying mechanism. Our results indicated that intranasal delivery of hiPSC-NSC-Exos mitigated neurological deficits, enhanced blood-brain barrier integrity, and reduced leukocyte infiltration in a mouse model of intracerebral hemorrhage. Additionally, hiPSC-NSC-Exos decreased immune cell infiltration, activated astrocytes, and decreased the secretion of inflammatory cytokines like monocyte chemoattractant protein-1, macrophage inflammatory protein-1α, and tumor necrosis factor-α post-intracerebral hemorrhage, thereby improving the inflammatory microenvironment. RNA sequencing indicated that hiPSC-NSC-Exo activated the PI3K/AKT signaling pathway in astrocytes and decreased monocyte chemoattractant protein-1 secretion, thereby improving blood-brain barrier integrity. Treatment with the PI3K/AKT inhibitor LY294002 or the monocyte chemoattractant protein-1 neutralizing agent C1142 abolished these effects. In summary, our findings suggest that hiPSC-NSC-Exos maintains blood-brain barrier integrity, in part by downregulating monocyte chemoattractant protein-1 secretion through activation of the PI3K/AKT signaling pathway in astrocytes.
RESUMEN
PURPOSE: To investigate the effects of different surface treatments and thicknesses on the color, transparency, and surface roughness of ultra-transparent zirconia. METHODS: A total of 120 Katana ultra-translucent multi-layered zirconia specimens were divided into 12 groups according to the thickness (0.3, 0.5, and 0.7 mm) and surface treatment (control, airborne particle abrasion [APA], lithium disilicate coating, and glaze on). Color difference (ΔE00) and relative translucency parameter (RTP00) were calculated using a digital spectrophotometer. The surface roughness (Ra, Rq, Sa, and Sq) was measured using a non-contact profile scanner. The surface morphologies and microstructures of the samples were observed using a tungsten filament scanning electron microscope. Statistical analyses were performed by one-way and two-way analysis of variance (ANOVA) followed by post hoc multiple comparisons and Pearson's correlation (α = 0.05). RESULTS: The results showed that the surface treatment, ceramic thickness, and their interactions had significant effects on ΔE00 and RTP00 (p < 0.001). The surface treatment significantly altered the micromorphology and increased the surface roughness of the ceramic samples. APA exhibited the lowest transparency, largest color difference, and highest surface roughness. Zirconia with 0.3 mm and 0.7 mm thicknesses showed strong negative correlations between Sa and RTP00. CONCLUSIONS: The three internal surface treatments significantly altered the surface roughness, color difference, and transparency of ultra-transparent zirconia. As the thickness increased, the influence of the inner surface treatment on the color difference and transparency of zirconia decreased. CLINICAL IMPLICATIONS: For new zirconia internal surface treatment technologies, in addition to considering the enhancement effect on the bonding properties, the potential effects on the color and translucency of high-transparency zirconia should also be considered. Appropriately increasing the thickness of zirconia restorations helps minimize the effect of surface treatment on the optical properties.
Asunto(s)
Color , Ensayo de Materiales , Microscopía Electrónica de Rastreo , Espectrofotometría , Propiedades de Superficie , Circonio , Circonio/química , Porcelana Dental/química , Materiales Dentales/química , Recubrimiento Dental Adhesivo/métodosRESUMEN
AIM: To prevent neovascularization in diabetic retinopathy (DR) patients and partially control disease progression. METHODS: Hypoxia-related differentially expressed genes (DEGs) were identified from the GSE60436 and GSE102485 datasets, followed by gene ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Potential candidate drugs were screened using the CMap database. Subsequently, a protein-protein interaction (PPI) network was constructed to identify hypoxia-related hub genes. A nomogram was generated using the rms R package, and the correlation of hub genes was analyzed using the Hmisc R package. The clinical significance of hub genes was validated by comparing their expression levels between disease and normal groups and constructing receiver operating characteristic curve (ROC) curves. Finally, a hypoxia-related miRNA-transcription factor (TF)-Hub gene network was constructed using the NetworkAnalyst online tool. RESULTS: Totally 48 hypoxia-related DEGs and screened 10 potential candidate drugs with interaction relationships to upregulated hypoxia-related genes were identified, such as ruxolitinib, meprylcaine, and deferiprone. In addition, 8 hub genes were also identified: glycogen phosphorylase muscle associated (PYGM), glyceraldehyde-3-phosphate dehydrogenase spermatogenic (GAPDHS), enolase 3 (ENO3), aldolase fructose-bisphosphate C (ALDOC), phosphoglucomutase 2 (PGM2), enolase 2 (ENO2), phosphoglycerate mutase 2 (PGAM2), and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3). Based on hub gene predictions, the miRNA-TF-Hub gene network revealed complex interactions between 163 miRNAs, 77 TFs, and hub genes. The results of ROC showed that the except for GAPDHS, the area under curve (AUC) values of the other 7 hub genes were greater than 0.758, indicating their favorable diagnostic performance. CONCLUSION: PYGM, GAPDHS, ENO3, ALDOC, PGM2, ENO2, PGAM2, and PFKFB3 are hub genes in DR, and hypoxia-related hub genes exhibited favorable diagnostic performance.
RESUMEN
BACKGROUND: There is a close relationship between obesity and the occurrence of asthma.The weight-adjusted waist index (WWI) is a relatively novel anthropometric parameter that reflects obesity. OBJECTIVE: We aimed to explore the association between WWI and mortality in the asthma population. METHODS: We included adult with asthma from NHANES 1999-2018. WWI = Waist circumference (cm)/square root of body weight (kg). Current asthma was determined by the participant's responses in standardized questionnaires. All-cause, cardiovascular disease (CVD), cancer, and respiratory disease mortality information was obtained by prospectively matching these data to the National Death Index. Multivariate-adjusted Cox proportional hazards regression analyses, Kaplan Meier survival analyses, restricted cubic spline (RCS) analyses, stratified analyses, and sensitivity analyses were used to clarify these associations. RESULTS: A total of 101,316 participants were included in the study, and 3223 were diagnosed with asthma.WWI was independently and positively associated with all-cause and all factor-specific mortality in asthma. In fully adjusted models, each unit increase in WWI was associated with 43 % (hazard ratio [HR] and 95 % confidence interval [CI] = 1.43 [1.25,1.64], p < 0.0001), 58 % (1.58 [1.25, 1.99], p < 0.001), 50 % (1.50 [1.19, 1.90], p < 0.001), and 79 % (1.79 [1.34, 2.39], p < 0.0001) increased all-cause, CVD, cancer, and respiratory disease mortality, respectively. RCS analyses showed largely linear associations between WWI and all mortality risks. Stratified analyses indicated that these associations were influenced by multiple factors, and that age was consistently the effect modifier across all associations. CONCLUSIONS: WWI is an independent predictor of all-cause, CVD, cancer, and respiratory-related mortality in the adult asthma population. These findings highlight that WWI may have novel prognostic value as a simple and easily accessible obesity parameter in asthma patients.
RESUMEN
This study aimed to investigate the association between serum chloride levels and all-cause mortality in critically ill patients with chronic obstructive pulmonary disease (COPD). Data from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database were extracted for analysis. Demographic information, laboratory results, medical histories, vital signs, and prognosis-related data were collected. Cox proportional hazard models were used to assess the relationship between serum chloride levels and 90-day and 365-day mortality. Subgroup analyses were conducted to explore potential interactions between serum chloride levels and various factors. The study included patients with a median age of 72.00 years, of whom 52.39% were male. Higher quartiles of serum chloride levels were associated with significantly lower levels of weight, RBC, platelet, hemoglobin, and other variables (P < 0.05), accompanied by lower 90-day and 365-day mortality (P < 0.05). Cox proportional hazard model indicated that the risk of death was significantly lower in the fourth quartile of serum chloride levels compared with the first quartile after adjusting for confounders (90-day HR = 0.54, 365-day HR = 0.52, both P < 0.05). An L-shape relationship was observed, with risks of death decreasing as serum chloride levels increased, although the magnitude decreased when levels reached 102 mmol/L. This study demonstrated an independent L-shaped association between serum chloride levels and all-cause mortality in critically ill patients with COPD. This finding helps us to understand the prognostic value of serum chloride levels in critically ill patients with COPD.
Asunto(s)
Cloruros , Enfermedad Crítica , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Masculino , Femenino , Enfermedad Pulmonar Obstructiva Crónica/sangre , Enfermedad Pulmonar Obstructiva Crónica/mortalidad , Enfermedad Crítica/mortalidad , Anciano , Estudios Retrospectivos , Cloruros/sangre , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Anciano de 80 o más AñosRESUMEN
In previous studies, we have demonstrated that stress response-induced high glucocorticoid levels could be the underlying cause of traumatic heterotopic ossification (HO), and we have developed a glucocorticoid-induced ectopic mineralization (EM) mouse model by systemic administration of a high dose of dexamethasone (DEX) to animals with muscle injury induced by cardiotoxin injection. In this model, dystrophic calcification (DC) developed into HO in a cell autonomous manner. However, it is not clear how DC is formed after DEX treatment. Therefore, in this study, we aimed to explore how glucocorticoids initiate muscle EM at a cellular and molecular level. We showed that DEX treatment inhibited inflammatory cell infiltration into injured muscle but inflammatory cytokine production in the muscle was significantly increased, suggesting that other non-inflammatory muscle cell types may regulate the inflammatory response and the muscle repair process. Accompanying this phenotype, transforming growth factor ß1 (TGF-ß1) expression in fibro-adipogenic progenitors (FAPs) was greatly downregulated. Since TGF-ß1 is a strong immune suppressor and FAP's regulatory role has a large impact on muscle repair, we hypothesized that downregulation of TGF-ß1 in FAPs after DEX treatment resulted in this hyperinflammatory state and subsequent failed muscle repair and EM formation. To test our hypothesis, we utilized a transgenic mouse model to specifically knockout Tgfb1 gene in PDGFRα-positive FAPs to investigate if the transgenic mice could recapitulate the phenotype that was induced by DEX treatment. Our results showed that the transgenic mice completely phenocopied this hyperinflammatory state and spontaneously developed EM following muscle injury. On the contrary, therapeutics that enhanced TGF-ß1 signaling in FAPs inhibited the inflammatory response and attenuated muscle EM. In summary, these results indicate that FAPs-derived TGF-ß1 is a key molecule in regulating muscle inflammatory response and subsequent EM, and that glucocorticoids exert their effect via downregulating TGF-ß1 in FAPs.
Heterotopic ossification (HO) is abnormal bone formation in soft tissue. Glucocorticoids, which have strong anti-inflammatory properties, have usually been used as HO therapeutics. However, our findings suggest that glucocorticoids can also promote HO formation. In this study, we tried to explain the underlying reason for these seemingly contradictory observations. We showed that glucocorticoids, in addition to exerting an anti-inflammatory effect on inflammatory cells, can also target another type of muscle cell to exert a proinflammatory effect. These cells are called fibro-adipogenic progenitors (FAPs), and we demonstrated that FAPs played a master regulatory role in the muscle inflammatory response by modulating the expression of transforming growth factor ß1 (TGF-ß1), a well-known immune suppressor. In summary, our findings highlighted the importance of FAP TGF-ß1 levels in affecting the progression and regression of muscle HO and provided new treatment options for HO based on their ability to elevate TGF-ß1 levels in FAPs.
Asunto(s)
Dexametasona , Regulación hacia Abajo , Células Madre , Factor de Crecimiento Transformador beta1 , Animales , Factor de Crecimiento Transformador beta1/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Ratones , Dexametasona/farmacología , Células Madre/metabolismo , Células Madre/efectos de los fármacos , Adipogénesis/efectos de los fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Músculo Esquelético/efectos de los fármacosRESUMEN
BACKGROUND: Parkinson's disease (PD) is a prevalent neurodegenerative disorder, marked by the degeneration of dopamine (DA) neurons in the substantia nigra (SN). Current evidence strongly suggests that neuroinflammation, primarily mediated by microglia, contributes to PD pathogenesis. Triggering receptor expressed on myeloid cells 2 (TREM2) might serve as a promising therapeutic target for PD due to its ability to suppress neuroinflammation. Dihydroquercetin (DHQ) is an important natural dihydroflavone and confers apparent anti-inflammatory, antioxidant and anti-fibrotic effects. Recently, DHQ-mediated neuroprotection was exhibited. However, the specific mechanisms of its neuroprotective effects remain incompletely elucidated. METHODS: In this study, rat models were utilized to induce damage to DA neurons using lipopolysaccharide (LPS) and 6-hydroxydopamine (6-OHDA) to assess the impacts of DHQ on the loss of DA neurons. Furthermore, DA neuronal MN9D cells and microglial BV2 cells were employed to investigate the function of TREM2 in DHQ-mediated DA neuroprotection. Finally, TREM2 knockout mice were used to investigate whether the neuroprotective effects mediated by DHQ through a mechanism dependent on TREM2. RESULTS: The main findings demonstrated that DHQ effectively protected DA neurons against neurotoxicity induced by LPS and 6-OHDA and inhibited microglia-elicited neuroinflammation. Meanwhile, DHQ promoted microglial TREM2 signaling activation. Notably, DHQ failed to reduce inflammatory cytokines release and further present neuroprotection from DA neurotoxicity upon TREM2 silencing. Similarly, DHQ didn't exert DA neuroprotection in TREM2 knockout mice. CONCLUSIONS: These findings suggest that DHQ exerted DA neuroprotection by regulating microglia TREM2 activation.
Asunto(s)
Neuronas Dopaminérgicas , Glicoproteínas de Membrana , Microglía , Fármacos Neuroprotectores , Quercetina , Receptores Inmunológicos , Animales , Masculino , Ratones , Ratas , Línea Celular , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Lipopolisacáridos , Glicoproteínas de Membrana/metabolismo , Ratones Noqueados , Microglía/efectos de los fármacos , Microglía/metabolismo , Fármacos Neuroprotectores/farmacología , Oxidopamina , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Quercetina/farmacología , Quercetina/análogos & derivados , Ratas Sprague-Dawley , Receptores Inmunológicos/metabolismo , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Vascular dementia (VaD), the second most prevalent type of dementia, lacks a well-defined cause and effective treatment. Our objective was to utilize bioinformatics analysis to discover the fundamental disease-causing genes and pathological mechanisms in individuals diagnosed with VaD. METHODS: To identify potential pathogenic genes associated with VaD, we conducted weighted gene co-expression network analysis (WGCNA), differential expression analysis, and protein-protein interaction (PPI) analysis. The exploration of potential biological mechanisms involved the utilization of Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis. Moreover, a bilateral common carotid artery stenosis (BCAS) mouse model of VaD was established, and the expression of the hub gene, its relationship with cognitive function and its potential pathogenic mechanism were verified by cognitive behavior tests, cerebral blood flow measurement, Western blotting, and immunofluorescence experiments. RESULTS: This study identified 293 DEGs from the brain cortex of VaD patients and healthy controls, among these genes, the Toll-like receptor 2 (TLR2) gene was identified as hub gene, and it was associated with the apoptosis-related pathway PI3K/AKT.The BCAS model demonstrated that the use of TLR2 inhibitors greatly enhanced the cognitive function of the mice (p < 0.05). Additionally, there was a notable decrease in the number of apoptotic cells in the brain cortex of the mice (p < 0.01). Moreover, significant alterations in the levels of proteins related to the PI3K/AKT pathway and cleaved-caspase3 proteins were detected (p < 0.05). CONCLUSIONS: TLR2 plays a role in the pathophysiology of VaD by enhancing the neuronal apoptotic pathway, suggesting it could be a promising therapeutic target.
Asunto(s)
Apoptosis , Biología Computacional , Demencia Vascular , Modelos Animales de Enfermedad , Neuronas , Receptor Toll-Like 2 , Demencia Vascular/metabolismo , Demencia Vascular/genética , Demencia Vascular/patología , Animales , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 2/genética , Humanos , Ratones , Masculino , Neuronas/metabolismo , Mapas de Interacción de Proteínas , Ratones Endogámicos C57BL , Redes Reguladoras de Genes , Femenino , Estenosis Carotídea/metabolismo , Estenosis Carotídea/patología , Anciano , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
BACKGROUND: Cell cycle protein-dependent kinase inhibitor protein 3 (CDKN3), as a member of the protein kinase family, has been demonstrated to exhibit oncogenic properties in several tumors. However, there are no pan-carcinogenic analyses for CDKN3. METHODS: Using bioinformatics tools such as The Cancer Genome Atlas (TCGA) and the UCSC Xena database, a comprehensive pan-cancer analysis of CDKN3 was conducted. The inverstigation encompassed the examination of CDKN3 function actoss 33 different kinds of tumors, as well as the exploration of gene expressions, survival prognosis status, clinical significance, DNA methylation, immune infiltration, and associated signal pathways. RESULTS: CDKN3 was significantly upregulated in most of tumors and correlated with overall survival (OS) of patients. Methylation levels of CDKN3 differed significantly between tumors and normal tissues. In addition, infiltration of CD4 + T cells, cancer-associated fibroblasts, macrophages, and endothelial cells were associated with CDKN3 expression in various tumors. Mechanistically, CDKN3 was associated with P53, PI3K-AKT, cell cycle checkpoints, mitotic spindle checkpoint, and chromosome maintenance. CONCLUSION: Our pan-cancer analysis conducted in the study provides a comprehensive understanding of the involvement of CDKN3 gene in tumorigenesis. The findings suggest that targeting CDKN3 may potentially lead to novel therapeutic strategies for the treatment of tumors.
Asunto(s)
Biomarcadores de Tumor , Proteínas Inhibidoras de las Quinasas Dependientes de la Ciclina , Neoplasias , Humanos , Neoplasias/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Proteínas Inhibidoras de las Quinasas Dependientes de la Ciclina/genética , Proteínas Inhibidoras de las Quinasas Dependientes de la Ciclina/metabolismo , Pronóstico , Regulación Neoplásica de la Expresión Génica , Metilación de ADN , Biología Computacional/métodos , Fosfatasas de Especificidad DualRESUMEN
Yang-deficiency constitution (YADC) is linked to a higher vulnerability to various diseases, such as cold coagulation and blood stasis (CCBS) syndrome and infertility. Endometrial hyperplastic processes (EHPs) are a leading cause of infertility in women and are characterized by CCBS. However, it remains unclear whether YADC is related to the development of EHPs. METHODS: We recruited 202 EHPs patients including 147 with YADC (YEH group) and 55 with non-YADC (NYEH group). Fecal samples were collected from 8 YEH patients and 3 NYEH patients and analyzed using 16S rRNA V3-V4 sequencing for gut microbiota analysis. We obtained constitution survey data and a differential gut microbiota dataset from the literature for further analysis. Bioinformatics analysis was conducted using gut microbiota-related genes from public databases. RESULTS: YADC was significantly more prevalent in EHPs than non-YADC (P < 0.001), suggesting it as a potential risk factor for EHPs occurrence (ORpopulation survey = 13.471; ORhealthy women = 5.173). The YEH group had higher levels of inflammation, estrogen, and tamoxifen-related flora compared to NYEH and healthy YADC groups. There was an interaction between inflammation, estrogen, differential flora, and EHPs-related genes, particularly the TNF gene (related to inflammation) and the EGFR gene (related to estrogen), which may play a crucial role in EHPs development. CONCLUSION: YEH individuals exhibit significant changes in their gut microbiota compared to NYEH and healthy YADC. The interaction between specific microbiota and host genes is believed to play a critical role in the progression of EHPs.
RESUMEN
Purpose: The objective of this study was to provide theoretically feasible strategies by understanding the relationship between the immune microenvironment and the diagnosis and prognosis of AML patients. To this end, we built a ceRNA network with lncRNAs as the core and analyzed the related lncRNAs in the immune microenvironment by bioinformatics analysis. Methods: AML transcriptome expression data and immune-related gene sets were obtained from TCGA and ImmPort. Utilizing Pearson correlation analysis, differentially expressed immune-related lncRNAs were identified. Then, the LASSO-Cox regression analysis was performed to generate a risk signature consisting immune-related lncRNAs. Accuracy of signature in predicting patient survival was evaluated using univariate and multivariate analysis. Next, GO and KEGG gene enrichment and ssGSEA were carried out for pathway enrichment analysis of 183 differentially expressed genes, followed by drug sensitivity and immune infiltration analysis with pRRophetic and CIBERSORT, respectively. Cytoscape was used to construct the ceRNA network for these lncRNAs. Results: 816 common lncRNAs were selected to acquire the components related to prognosis. The final risk signature established by multivariate Cox and stepwise regression analysis contained 12 lncRNAs engaged in tumor apoptotic and metastatic processes: LINC02595, HCP5, AC020934.2, AC008770.3, LINC01770, AC092718.4, AL589863.1, AC131097.4, AC012368.1, C1RL-AS1, STARD4-AS1, and AC243960.1. Based on this predictive model, high-risk patients exhibited lower overall survival rates than low-risk patients. Signature lncRNAs showed significant correlation with tumor-infiltrating immune cells. In addition, significant differences in PD-1/PD-L1 expression and bleomycin/paclitaxel sensitivity were observed between risk groups. Conclusion: LncRNAs related to immune microenvironment were prospective prognostic and therapeutic options for AML.
RESUMEN
Previous studies have revealed that abnormal expressions of membrane transporters were associated with colorectal cancer (CRC). We herein performed a comprehensive bioinformatics analysis to identify the key transporter protein-related genes involved in CRC and potential mechanisms. Differentially expressed transporter protein-related genes (DE-TPRGs) were identified from CRC and normal samples using The Cancer Genome Atlas database. SLC38A3 expression was validated by immunohistochemistry and RT-qPCR, and the potential mechanism was explored. A total of 63 DE-TPRGs (29 up-regulated and 34 down-regulated) were screened. Inside, ABCC2, ABCG2, SLC4A4, SLC9A3, SLC15A1, and SLC38A3 were identified as hub genes. SLC38A3 is indeed upregulated in colorectal cancer patients. Furthermore, we found that knockdown of SLC38A3 inhibited the proliferation and migration of HCT116 cells, and Hsp70 ATPase activator could rescue it. Overall, SLC38A3 is a novel potential biomarker involved in CRC progression and promotes the proliferation and migration of tumor cells by positively regulating the function of Hsp70.
RESUMEN
Microglia play a pivotal role in the neuroinflammatory response after brain injury, and their proliferation is dependent on colony-stimulating factors. In the present study, we investigated the effect of inhibiting microglia proliferation on neurological damage post intracerebral hemorrhage (ICH) in a mouse model, an aspect that has never been studied before. Using a colony-stimulating factor-1 receptor antagonist (GW2580), we observed that inhibition of microglia proliferation significantly ameliorated neurobehavioral deficits, attenuated cerebral edema, and reduced hematoma volume after ICH. This intervention was associated with a decrease in pro-inflammatory factors in microglia and an increased infiltration of peripheral regulatory CD8 + CD122+ T cells into the injured brain tissue. The CXCR3/CXCL10 axis is the mechanism of brain homing of regulatory CD8 + CD122+ T cells, and the high expression of IL-10 is the hallmark of their synergistic anti-inflammatory effect with microglia. And activated astrocytes around the insult site are a prominent source of CXCL10. Thus, inhibition of microglial proliferation offers a new perspective for clinical translation. The cross-talk between multiple cells involved in the regulation of the inflammatory response highlights the comprehensive nature of neuroimmunomodulation.
Asunto(s)
Encéfalo , Linfocitos T CD8-positivos , Hemorragia Cerebral , Microglía , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos , Animales , Masculino , Ratones , Anisoles , Encéfalo/patología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Hemorragia Cerebral/tratamiento farmacológico , Hemorragia Cerebral/inmunología , Quimiocina CXCL10/metabolismo , Modelos Animales de Enfermedad , Interleucina-10/metabolismo , Subunidad beta del Receptor de Interleucina-2/metabolismo , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Pirimidinas , Receptores CXCR3/metabolismo , Receptores CXCR3/antagonistas & inhibidores , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismoRESUMEN
Gut microbial homeostasis is crucial for the health of cognition in elderly. Previous study revealed that polysorbate 80 (P80) as a widely used emulsifier in food industries and pharmaceutical formulations could directly alter the human gut microbiota compositions. However, whether long-term exposure to P80 could accelerate age-related cognitive decline via gut-brain axis is still unknown. Accordingly, in this study, we used the senescence accelerated mouse prone 8 (SAMP8) mouse model to investigate the effects of the emulsifier P80 intake (1 % P80 in drinking water for 12 weeks) on gut microbiota and cognitive function. Our results indicated that P80 intake significantly exacerbated cognitive decline in SAMP8 mice, along with increased brain pathological proteins deposition, disruption of the blood-brain barrier and activation of microglia and neurotoxic astrocytes. Besides, P80 intake could also induce gut microbiota dysbiosis, especially the increased abundance of secondary bile acids producing bacteria, such as Ruminococcaceae, Lachnospiraceae, and Clostridium scindens. Moreover, fecal microbiota transplantation from P80 mice into 16-week-old SAMP8 mice could also exacerbated cognitive decline, microglia activation and intestinal barrier impairment. Intriguingly, the alterations of gut microbial composition significantly affected bile acid metabolism profiles after P80 exposure, with markedly elevated levels of deoxycholic acid (DCA) in serum and brain tissue. Mechanically, DCA could activate microglial and promote senescence-associated secretory phenotype production through adenosine triphosphate-binding cassette transporter A1 (ABCA1) importing lysosomal cholesterol. Altogether, the emulsifier P80 accelerated cognitive decline of aging mice by inducing gut dysbiosis, bile acid metabolism alteration, intestinal barrier and blood brain barrier disruption as well as neuroinflammation. This study provides strong evidence that dietary-induced gut microbiota dysbiosis may be a risk factor for age-related cognitive decline.
Asunto(s)
Barrera Hematoencefálica , Disfunción Cognitiva , Disbiosis , Emulsionantes , Microbioma Gastrointestinal , Polisorbatos , Animales , Ratones , Microbioma Gastrointestinal/efectos de los fármacos , Polisorbatos/farmacología , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/inducido químicamente , Emulsionantes/metabolismo , Emulsionantes/farmacología , Disbiosis/metabolismo , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Envejecimiento/metabolismo , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Masculino , Microglía/metabolismo , Microglía/efectos de los fármacos , Eje Cerebro-Intestino/efectos de los fármacos , Cognición/efectos de los fármacos , Ácidos y Sales Biliares/metabolismoRESUMEN
The precise recognition and sensing of steroids, a type of vital biomolecules, hold immense practical value across various domains. In this study, we introduced corral[4]BINOLs (C[4]BINOLs), a pair of enantiomeric conjugated deep-cavity hosts, as novel synthetic receptors for binding steroids. Due to the strong hydrophobic effect of their deep nonpolar, chiral cavities, the two enantiomers of C[4]BINOLs demonstrated exceptionally high recognition affinities (up to 1012â M-1) for 16 important steroidal compounds as well as good enantioselectiviy (up to 15.5) in aqueous solutions, establishing them as the most potent known steroid receptors. Harnessing their ultrahigh affinity, remarkable enantioselectivity, and fluorescence emission properties, the two C[4]BINOL enantiomers were employed to compose a fluorescent sensor array which achieved discrimination and sensing of 16 structurally similar steroids at low concentrations.
Asunto(s)
Naftoles , Esteroides , Estereoisomerismo , Esteroides/química , Esteroides/análisis , Naftoles/química , Estructura MolecularRESUMEN
Research on the microbiota associated with marine invertebrates is important for understanding host physiology and the relationship between the host and the environment. In this study, the microbiota of the green mussel Perna viridis was characterized at the tissue scale using 16S rRNA gene high-throughput sequencing and compared with the microbiota of the surrounding environment. Different mussel tissues were sampled, along with two environmental samples (the mussel's attachment substratum and seawater). The results showed that the phyla Proteobacteria, Bacteroidetes, and Spirochaetae were dominant in mussel tissues. The bacterial community composition at the family level varied among the tissues of P. viridis. Although the microbiota of P. viridis clearly differed from that of the surrounding seawater, the composition and diversity of the microbial community of the foot and outer shell surface were similar to those of the substratum, indicating their close relationship with the substratum. KEGG prediction analysis indicated that the bacteria harbored by P. viridis were enriched in the degradation of aromatic compounds, osmoregulation, and carbohydrate oxidation and fermentation, processes that may be important in P. viridis physiology. Our study provides new insights into the tissue-scale characteristics of mussel microbiomes and the intricate connection between mussels and their environment.
RESUMEN
Several genes involved in the pathogenesis have been identified, with the human leukocyte antigen (HLA) system playing an essential role. However, the relationship between HLA and a cluster of hematological diseases has received little attention in China. Blood samples (n = 123913) from 43568 patients and 80345 individuals without known pathology were genotyped for HLA class I and II using sequencing-based typing. We discovered that HLA-A*11:01, B*40:01, C*01:02, DQB1*03:01, and DRB1*09:01 were prevalent in China. Furthermore, three high-frequency alleles (DQB1*03:01, DQB1*06:02, and DRB1*15:01) were found to be hazardous in malignant hematologic diseases when compared to controls. In addition, for benign hematologic disorders, 7 high-frequency risk alleles (A*01:01, B*46:01, C*01:02, DQB1*03:03, DQB1*05:02, DRB1*09:01, and DRB1*14:54) and 8 high-frequency susceptible genotypes (A*11:01-A*11:01, B*46:01-B*58:01, B*46:01-B*46:01, C*01:02-C*03:04, DQB1*03:01-DQB1*05:02, DQB1*03:03-DQB1*06:01, DRB1*09:01-DRB1*15:01, and DRB1*14:54-DRB1*15:01) were observed. To summarize, our findings indicate the association between HLA alleles/genotypes and a variety of hematological disorders, which is critical for disease surveillance.
Asunto(s)
Enfermedades Hematológicas , Antígenos de Histocompatibilidad Clase I , Humanos , Frecuencia de los Genes , Alelos , Cadenas beta de HLA-DQ/genética , Cadenas HLA-DRB1/genética , Genotipo , Antígenos de Histocompatibilidad Clase I/genética , Enfermedades Hematológicas/genética , Haplotipos , Predisposición Genética a la EnfermedadRESUMEN
Chronic pain is the key manifestations of rheumatoid arthritis. Neuroinflammation in the spinal cord drives central sensitization and chronic pain. Ferroptosis has potentially important roles in the occurrence of neuroinflammation and chronic pain. In the current study, mouse model of collagen-induced arthritis was established by intradermal injection of type II collagen in complete Freund's adjuvant (CFA) solution. CFA inducement resulted in swollen paw and ankle, mechanical and spontaneous pain, and impaired motor coordination. The spinal inflammation was triggered, astrocytes were activated, and increased NLRP3-mediated inflammatory signal was found in CFA spinal cord. Oxidative stress and ferroptosis in the spinal cord were manifested. Meanwhile, enhancive spinal GSK-3ß activity and abnormal phosphorylated Drp1 were observed. To investigate the potential therapeutic options for arthritic pain, mice were intraperitoneally injected with AB4 for three consecutive days. AB4 treatment reduced pain sensitivity and increased the motor coordination. In the spinal cord, AB4 treatment inhibited NLRP3 inflammasome-mediated inflammatory response, increased antioxidation, decreased mitochondrial reactive oxygen species and ferroptosis. Furthermore, AB4 decreased GSK-3ß activity by binding with GSK-3ß through five electrovalent bonds. Our findings indicated that AB treatment relieves arthritis pain by inhibiting GSK-3ß activation, increasing antioxidant capability, reducing Drp1-mediated mitochondrial dysfunction and suppressing neuroinflammation.
Asunto(s)
Artritis Reumatoide , Dolor Crónico , Ferroptosis , Saponinas , Ratones , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Dolor Crónico/metabolismo , Enfermedades Neuroinflamatorias , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Artritis Reumatoide/tratamiento farmacológico , Médula Espinal/metabolismoRESUMEN
BACKGROUND: Hyperproliferation, inflammation, and mitochondrial abnormalities in pulmonary artery smooth muscle cells (PASMCs) underlie the pathological mechanisms of vascular remodeling in pulmonary arterial hypertension (PAH). Cytoplasmic mtDNA activates the cGAS-STING-NFκB pathway and secretes pro-inflammatory cytokines that may be involved in the pathogenesis of PAH. Calcitonin gene-related peptide (CGRP) acts as a vasodilator to regulate patterns of cellular energy metabolism and has vasodilatory and anti-inflammatory effects. METHODS: The role of the cGAS-STING-NFκB signaling pathway in PAH vascular remodeling and the regulation of CGRP in the cGAS-STING-NFκB signaling pathway were investigated by echocardiography, morphology, histology, enzyme immunoassay, and fluorometry. RESULTS: Monocrotaline (MCT) could promote right heart hypertrophy, pulmonary artery intima thickening, and inflammatory cell infiltration in rats. Cinnamaldehyde (CA)-induced CGRP release alleviates MCT-induced vascular remodeling in PAH. CGRP reduces PDGF-BB-induced proliferation, and migration, and downregulates smooth muscle cell phenotypic proteins. In vivo and in vitro experiments confirm that the mitochondria of PASMCs were damaged during PAH, and the superoxide and mtDNA produced by injured mitochondria activate the cGAS-STING-NFκB pathway to promote PAH process, while CGRP could play an anti-PAH role by protecting the mitochondria and inhibiting the cGAS-STING-NFκB pathway through PKA. CONCLUSION: This study identifies that CGRP attenuates cGAS-STING-NFκB axis-mediated vascular remodeling in PAH through PKA.