RESUMO
The ring-shaped Cohesin complex, consisting of core subunits Smc1, Smc3, Scc1, and SA2 (or its paralog SA1), topologically entraps two duplicated sister DNA molecules to establish sister chromatid cohesion in S-phase. It remains largely elusive how the Cohesin release factor Wapl binds the Cohesin complex, thereby inducing Cohesin disassociation from mitotic chromosomes to allow proper resolution and separation of sister chromatids. Here, we show that Wapl uses two structural modules containing the FGF motif and the YNARHWN motif, respectively, to simultaneously bind distinct pockets in the extensive composite interface between Scc1 and SA2. Strikingly, only when both docking modules are mutated, Wapl completely loses the ability to bind the Scc1-SA2 interface and release Cohesin, leading to erroneous chromosome segregation in mitosis. Surprisingly, Sororin, which contains a conserved FGF motif and functions as a master antagonist of Wapl in S-phase and G2-phase, does not bind the Scc1-SA2 interface. Moreover, Sgo1, the major protector of Cohesin at mitotic centromeres, can only compete with the FGF motif but not the YNARHWN motif of Wapl for binding Scc1-SA2 interface. Our data uncover the molecular mechanism by which Wapl binds Cohesin to ensure precise chromosome segregation.
Assuntos
Proteínas de Ciclo Celular , Proteínas Cromossômicas não Histona , Segregação de Cromossomos , Coesinas , Proteínas Cromossômicas não Histona/metabolismo , Proteínas Cromossômicas não Histona/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Humanos , Ligação Proteica , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Motivos de Aminoácidos , Mitose , Cromátides/metabolismo , Proteínas de Transporte , Proteínas Proto-OncogênicasRESUMO
PURPOSE: White matter hyperintensity (WMH) is a common feature of brain aging, often linked with cognitive decline and dementia. This study aimed to employ deep learning and radiomics to develop models for detecting cognitive impairment in WMH patients and to analyze the causal relationships among cognitive impairment and related factors. MATERIALS AND METHODS: A total of 79 WMH patients from hospital 1 were randomly divided into a training set (62 patients) and a testing set (17 patients). Additionally, 29 patients from hospital 2 were included as an independent testing set. All participants underwent formal neuropsychological assessments to determine cognitive status. Automated identification and segmentation of WMH were conducted using VB-net, with extraction of radiomics features from cortex, white matter, and nuclei. Four machine learning classifiers were trained on the training set and validated on the testing set to detect cognitive impairment. Model performances were evaluated and compared. Causal analyses were conducted among cortex, white matter, nuclei alterations, and cognitive impairment. RESULTS: Among the models, the logistic regression (LR) model based on white matter features demonstrated the highest performance, achieving an AUC of 0.819 in the external test dataset. Causal analyses indicated that age, education level, alterations in cortex, white matter, and nuclei were causal factors of cognitive impairment. CONCLUSION: The LR model based on white matter features exhibited high accuracy in detecting cognitive impairment in WMH patients. Furthermore, the possible causal relationships among alterations in cortex, white matter, nuclei, and cognitive impairment were elucidated.
Assuntos
Disfunção Cognitiva , Imageamento por Ressonância Magnética , Substância Branca , Humanos , Disfunção Cognitiva/diagnóstico por imagem , Feminino , Masculino , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Imageamento por Ressonância Magnética/métodos , Idoso , Pessoa de Meia-Idade , Inteligência Artificial , Idoso de 80 Anos ou mais , Aprendizado Profundo , Interpretação de Imagem Assistida por Computador/métodosRESUMO
Background: To observe the basic metabolic characteristics of obese patients with polycystic ovarian syndrome (PCOS), and observe and compare the effect of laparoscopic sleeve gastrectomy and metformin treatment after 3 months. Methods: In January to December 2018, the Second Hospital of Hebei Medical University selected 104 women who were classified as obese with a body mass index (BMI) of 28 kg/cm2 or higher and had PCOS. They were divided into obese PCOS group (53 cases) and obese non-PCOS group (51 cases). Results: 1. There was no significant difference in waist circumference and WHR between patients who are obese with PCOS and patients who are obese without PCOS (P > 0.05). Obese PCOS patients were significantly higher in anti-Müllerian hormone (AMH), LH/FSH, T, FAI, homa-ir, triglyceride (TG), low density lipoprotein (LDL), Apo-B and uric acid than the group of non-PCOS patients who were obese. (P<0.05). The SHBG levels of obese patients with PCOS were obviously lower when contrasted with the levels in obese patients without PCOS (P < 0.05). 2. Body weight, BMI, INS, homa-ir and TG of obese PCOS patients were significantly decreased 3 months after laparoscopic sleeve gastrectomy compared with that before surgery (P < 0.05). After three months of medical treatment with metformin, the patients' homeostatic model assessment of insulin resistance (HOMA-IR) was obviously reduced when contrasted with the pre-treatment HOMA-IR levels (P < 0.05), and there was no significant difference in the improvement degree of homa-ir between the two groups (P > 0.05). Conclusions: 1. Obese patients with PCOS demonstrated higher expression of AMH, LH/FSH, T, SHBG, and FAI when contrasted with the control group. Additionally, they experienced more severe insulin resistance and lipid metabolism disorders. 2. The weight and BMI of obese PCOS patients were significantly decreased after weight loss, while IR and blood lipid were significantly improved, while IR was improved in metformin group, and no significant discrepancy was observed in the degree of improvement of insulin resistance between both groups.
RESUMO
The 16-subunit Constitutive Centromere-associated Network (CCAN)-based inner kinetochore is well-known for connecting centromeric chromatin to the spindle-binding outer kinetochore. Here, we report a non-canonical role for the inner kinetochore in directly regulating sister-chromatid cohesion at centromeres. We provide biochemical, X-ray crystal structure, and intracellular ectopic localization evidence that the inner kinetochore directly binds cohesin, a ring-shaped multi-subunit complex that holds sister chromatids together from S-phase until anaphase onset. This interaction is mediated by binding of the 5-subunit CENP-OPQUR sub-complex of CCAN to the Scc1-SA2 sub-complex of cohesin. Mutation in the CENP-U subunit of the CENP-OPQUR complex that abolishes its binding to the composite interface between Scc1 and SA2 weakens centromeric cohesion, leading to premature separation of sister chromatids during delayed metaphase. We further show that CENP-U competes with the cohesin release factor Wapl for binding the interface of Scc1-SA2, and that the cohesion-protecting role for CENP-U can be bypassed by depleting Wapl. Taken together, this study reveals an inner kinetochore-bound pool of cohesin, which strengthens centromeric sister-chromatid cohesion to resist metaphase spindle pulling forces.
Assuntos
Proteínas de Ciclo Celular , Centrômero , Cromátides , Proteínas Cromossômicas não Histona , Cinetocoros , Cinetocoros/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Proteínas Cromossômicas não Histona/genética , Humanos , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Cromátides/metabolismo , Cromátides/genética , Centrômero/metabolismo , Coesinas , Células HeLa , Ligação Proteica , Cristalografia por Raios XRESUMO
Small extracellular vesicles (sEVs) secreted by human umbilical cord have therapeutic effects on various degenerative diseases. However, the characteristics and potential functions of human umbilical cord mesenchymal stem cells (huMSCs)-derived sEVs, especially the role of premature ovarian failure (POF), are poorly understood. Here, we isolated and characterized huMSCs and their sEVs. huMSCs highly expressed CD73, CD90, and CD105. huMSC-sEVs showed typical exosomal features, highly expressing CD9, TSG101, and CD63. It was shown that huMSC-sEVs could be taken up by granulosa cells (GCs) and damaged ovarian tissue, which increased the levels of hormone secretion and reduced GCs apoptosis. We further confirmed that the levels of follicle-stimulating hormone in rat serum decreased dramatically, while the levels of estrogen (E2ï¼and anti-mullerian hormone (AMH) increased significantly with the treatment of huMSC-sEVs. Meanwhile, huMSC-sEVs treatment greatly reduced cell apoptosis and autophagy, while increased the phosphorylation levels of p-PI3K and p-Akt. Therefore, treatment with huMSC-sEVs significantly inhibited GCs apoptosis, improved ovarian morphology, promoted follicular development, inhibited follicular over-atresia, and improved ovarian reserve capacity in POF rats. Our study verified that activation of PI3K/Akt signaling pathway and regulation of cellular autophagy, thus reducing GCs death, are the mechanisms by which huMSC-sEVs restore ovarian tissue function.
Assuntos
Apoptose , Cisplatino , Vesículas Extracelulares , Células da Granulosa , Células-Tronco Mesenquimais , Ovário , Insuficiência Ovariana Primária , Cordão Umbilical , Feminino , Células-Tronco Mesenquimais/efeitos dos fármacos , Animais , Vesículas Extracelulares/efeitos dos fármacos , Vesículas Extracelulares/metabolismo , Humanos , Cordão Umbilical/citologia , Insuficiência Ovariana Primária/induzido quimicamente , Cisplatino/toxicidade , Apoptose/efeitos dos fármacos , Ratos , Ovário/efeitos dos fármacos , Ovário/patologia , Células da Granulosa/efeitos dos fármacos , Ratos Sprague-Dawley , Antineoplásicos/toxicidadeRESUMO
The Qinling Mountains in East Asia serve as the geographical boundary between the north and south of China and are also indicative of climatic differences, resulting in rich ecological and species diversity. However, few studies have focused on the responses of plants to geological and climatic changes in the Qinling Mountains and adjacent regions. Therefore, we investigated the evolutionary origins and phylogenetic relationships of three Pedicularis species in there to provide molecular evidence for the origin and evolution of plant species. Ecological niche modeling was used to predict the geographic distributions of three Pedicularis species during the last interglacial period, the last glacial maximum period, and current and future periods, respectively. Furthermore, the distribution patterns of climate fluctuations and the niche dynamics framework were used to assess the equivalence or difference of niches among three Pedicularis species. The results revealed that the divergence of three Pedicularis species took place in the Miocene and Holocene periods, which was significantly associated with the large-scale uplifts of the Qinling Mountains and adjacent regions. In addition, the geographic distributions of three Pedicularis species have undergone a northward migration from the past to the future. The most important environmental variables affecting the geographic distributions of species were the mean diurnal range and annual mean temperature range. The niche divergence analysis suggested that the three Pedicularis species have similar ecological niches. Among them, P. giraldiana showed the highest niche breadth, covering nearly all of the climatic niche spaces of P. dissecta and P. bicolor. In summary, this study provides novel insights into the divergence and origins of three Pedicularis species and their responses to climate and geological changes in the Qinling Mountains and adjacent regions. The findings have also provided new perspectives for the conservation and management of Pedicularis species.
RESUMO
As an output effector of the Hippo signaling pathway, the TEAD transcription factor and co-activator YAP play crucial functions in promoting cell proliferation and organ size. The tumor suppressor NF2 has been shown to activate LATS1/2 kinases and interplay with the Hippo pathway to suppress the YAP-TEAD complex. However, whether and how NF2 could directly regulate TEAD remains unknown. We identified a direct link and physical interaction between NF2 and TEAD4. NF2 interacted with TEAD4 through its FERM domain and C-terminal tail and decreased the protein stability of TEAD4 independently of LATS1/2 and YAP. Furthermore, NF2 inhibited TEAD4 palmitoylation and induced the cytoplasmic translocation of TEAD4, resulting in ubiquitination and dysfunction of TEAD4. Moreover, the interaction with TEAD4 is required for NF2 function to suppress cell proliferation. These findings reveal an unanticipated role of NF2 as a binding partner and inhibitor of the transcription factor TEAD, shedding light on an alternative mechanism of how NF2 functions as a tumor suppressor through the Hippo signaling cascade.
Assuntos
Via de Sinalização Hippo , Neurofibromina 2 , Proteínas Serina-Treonina Quinases , Transdução de Sinais , Fatores de Transcrição de Domínio TEA , Humanos , Proliferação de Células , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Células HEK293 , Lipoilação , Neurofibromina 2/metabolismo , Neurofibromina 2/genética , Ligação Proteica , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Estabilidade Proteica , Fatores de Transcrição de Domínio TEA/metabolismo , Proteínas Supressoras de Tumor , UbiquitinaçãoRESUMO
Bacterial extracellular vesicles (BEVs) are nano-size particles secreted by bacteria that carry various bioactive components. These vesicles are thought to provide a new window into the mechanisms by which bacteria affect their hosts, but their fundamental proprieties within human remain poorly understood. Here, we developed a single-vesicle analytical platform that enabled BEV detection in complex biological samples of host. Using this platform, we found the presence of BEVs in the host circulation and they were mainly derived from gut microbes. We showed that the levels of circulating BEVs in humans significantly increased with aging due to an age-related increase in intestinal permeability. Significantly different levels of BEVs in blood were also found in patients with colorectal cancer and colitis. Together, our study provides new insights into circulating BEV biology and reveals their potential as a new class of biomarkers.
Assuntos
Vesículas Extracelulares , Humanos , BactériasRESUMO
BACKGROUND: The aim of this meta-analysis was to assess the performance of magnetic resonance elastography (MRE) in detecting gastroesophageal varices (GEV) in patients with chronic liver disease (CLD). METHODS: A literature search in English and Chinese databases such as PubMed, EMBASE, Cochrane Library, Web of Science, and China National Knowledge Infrastructure was conducted. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the curve (AUC) of the summary receiver-operating characteristic (SROC) curve with a 95% CI were calculated. A quality analysis of the included study was conducted using the QUADAS-2 tool, and a meta-analysis was performed using Stata16. The clinical practical value of MRE in detecting GEV was evaluated using the Fagan plot. Heterogeneity across studies was explored through meta-regression and subgroup analyses. RESULTS: A total of nine relevant articles that compared liver stiffness (LS) or spleen stiffness (SS) using MRE with esophagogastroduodenoscopy (EGD) to detect the existence of GEV were identified. The pooled summary sensitivity, specificity, PLR, NLR, and DOR of LS or SS for the detection of GEV were 81% (95% CI: 74%, 87%), 72% (95% CI: 62%, 80%), 2.89 (95% CI: 2.12, 3.94), 0.26 (95% CI: 0.19, 0.36), and 10.91 (95% CI: 6.53, 18.24), respectively. The year of publication, study design, and MR equipment are the sources of heterogeneity. There was no significant difference in the publication bias (p > 0.05). CONCLUSIONS: Based on these findings, MRE demonstrates good diagnostic accuracy for detecting GEV in patients with CLD.
RESUMO
PURPOSE: The Ki67 index and the Gleason grade group (GGG) are vital prognostic indicators of prostate cancer (PCa). This study investigated the value of biparametric magnetic resonance imaging (bpMRI) radiomics feature-based machine learning (ML) models in predicting the Ki67 index and GGG of PCa. METHODS: A total of 122 patients with pathologically proven PCa who had undergone preoperative MRI were retrospectively included. Radiomics features were extracted from T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI), and apparent diffusion coefficient (ADC) maps. Then, recursive feature elimination (RFE) was applied to remove redundant features. ML models for predicting Ki67 expression and GGG were constructed based on bpMRI and different algorithms, including logistic regression (LR), support vector machine (SVM), random forest (RF), and K-nearest neighbor (KNN). The performances of different models were evaluated with receiver operating characteristic (ROC) analysis. In addition, a joint analysis of Ki67 expression and GGG was performed by assessing their Spearman correlation and calculating the diagnostic accuracy for both indices. RESULTS: The ML model based on LR and ADC + T2 (LR_ADC + T2, AUC = 0.8882) performed best in predicting Ki67 expression, and ADC_wavelet-LHH_firstorder_Maximum had the highest feature weighting. The SVM_DWI + T2 (AUC = 0.9248) performed best in predicting GGG, and DWI_wavelet HLL_glcm_SumAverage had the highest feature weighting. The Ki67 and GGG exhibited a weak positive correlation (r = 0.382, p < 0.001), and LR_ADC + DWI had the highest diagnostic accuracy in predicting both (0.6230). CONCLUSION: The proposed ML models are suitable for predicting both Ki67 expression and GGG in PCa. This algorithm could be used to identify indolent or invasive PCa with a noninvasive, repeatable, and accurate diagnostic method.
RESUMO
PURPOSE: To characterize the magnetic resonance imaging features of primary intrahepatic lymphoepithelioma-like cholangiocarcinoma (LELCC). MATERIALS AND METHODS: Thirty-four patients with 38 histologically confirmed LELCCs were enrolled retrospectively from January 2014 to August 2022. We evaluated the clinical features, histologic findings, and imaging manifestations on dynamic enhanced MRI. RESULTS: 74% (25/34) of the cases were associated with EBV infection. Moreover, patients infected with EBV exhibited a lower level of Ki-67 proliferation. The serum CA199 level was elevated in 10 patients. The median tumor diameter was 2.8 cm (range, 1.1-8.7 cm). Most tumors were well-defined with a smooth or lobulated margin and showed peripheral hyperintensity and central hypointensity on T2-weighted imaging (T2WI). T2 hyperintense foci were recognized in 8 patients. In the dynamic enhanced MRI, 21 tumors demonstrated Type A enhancement pattern (rim enhancement), 10 demonstrated Type B (rapid wash-in and wash-out), and seven demonstrated Type C (rapid wash-in without wash-out). Capsular enhancement in PVP or DP was found in 22 tumors. A few patients had satellite lesions, portal vein thrombosis, bile duct dilatation, and distal metastasis. Lymph node metastases were discovered pathologically in 11 patients. CONCLUSIONS: MRI findings of LELCC vary and are non-specific. While a majority of LELCCs exhibit typical features of intrahepatic cholangiocarcinoma (iCCA), unique findings like T2 hyperintense foci or capsular enhancement could suggest LELCC. EBV infection and elevated tumor markers can aid in differentiation. However, given the mimics of some cases of liver hypervascular lesions, histological examination remains essential for definitive diagnosis.
RESUMO
Given the targeted binding ability and cleavage activity of the emerging CRISPR/Cas12a assay which transduces the target into its cleavage activity exhibited broadly prospective applications in integrated sensing and actuating system. Here, we elaborated a universal approach to quickly activate CRISPR/Cas12a for low-abundance biomarker detection based on the amplification strategy of a target-induced spherical nucleic acid enzyme (SNAzyme) network that could accelerate the output of activators. Specifically, multifunctional Y-shaped probes and hairpin probes (HPs, which contained the specific sequence of the activators of CRISPR/Cas12a and the substrate chain of DNAzyme) were rationally designed to construct SNAzyme. Target recognition induced disassembly of the Y-shaped probes, which released DNAzyme strands to active DNAzyme and accompanied by SNAzyme self-assembly into SNAzyme network. Interestingly, compared with randomly dispersed SNAzyme, the reaction kinetics of the SNAzyme network enhanced 1.6 times in response to Α-methyl acyl-CoA racemase (AMACR, a biomarker for prostate cancer), which was attributed to the promoted catalytic efficiency of DNAzyme by the confined SNAzyme network. Benefiting from these, the prepared biosensor based on electrochemiluminescence (ECL) platform by loading AuAg nanoclusters (AuAgNCs) into metal-organic framework-5 (MOF-5) exhibited satisfying detection performance for AMACR with a wide linear range (0.001 µg/mL to 100 µg/mL) and a low detection limit (1.0 × 10-4 µg/mL, which exhibited significant potential in clinical diagnoses.
Assuntos
Técnicas Biossensoriais , DNA Catalítico , Masculino , Humanos , Bioensaio , CatáliseRESUMO
Lung ischemia-reperfusion injury (LIRI) is a complex "aseptic" inflammatory response, macrophage play a pivotal role in the pathogenesis of LIRI. Galectin-3 (Gal3), a lectin implicated inflammation, has received limited attention in LIRI. Studies have reported Gal3 as a ligand for triggering receptor expressed on myeloid cell 2 (TREM2) in macrophages in Alzheimer's disease. Hence, we established LIRI C57BL/6 mice model and hypoxia/glucose deprivation and reoxygenation (OGD/R) model to investigate the relationship among Gal3, TREM2, and macrophage polarization. Our result demonstrated inhibition of Gal3 significantly reduced M1-type macrophage polarization while markedly increased M2-type in LIRI. In addition, we observed colocalization of Gal3 and TREM2 in macrophages, inhibition of Gal3 could recover the downregulation of TREM2 induced by LIRI while promoting TREM2 expression could attenuate lung injury in LIRI. In summary, our findings suggest Gal3 as an upstream factor of TREM2, play a crucial role in LIRI by regulating macrophage polarization.
RESUMO
RATIONALE AND OBJECTIVES: To develop and evaluate a peritumoral radiomic-based machine learning model to differentiate low-Gleason grade group (L-GGG) and high-GGG (H-GGG) prostate lesions. MATERIALS AND METHODS: In this retrospective study, a total of 175 patients with prostate cancer (PCa) confirmed by puncture biopsy were recruited and included 59 patients with L-GGG and 116 patients with H-GGG. The original PCa regions of interest (ROIs) were delineated on T2-weighted (T2WI), diffusion-weighted imaging (DWI), and apparent diffusion coefficient (ADC) maps, and then centra-tumoral and peritumoral ROIs were defined. Features were meticulously extracted from each ROI to establish radiomics models, employing distinct sequence datasets. Peritumoral radiomics models were specifically developed for both the peripheral zone (PZ) and transitional zone (TZ), utilizing dedicated PZ and TZ datasets, respectively. The performances of the models were evaluated by using the receiver operating characteristic (ROC) curve and precision-recall curve. RESULTS: The classification model with combined peritumoral features based on T2 + DWI + ADC sequence dataset demonstrated superior performance compared to the original tumor and centra-tumoral classification models. It achieved an area under the ROC curve (AUC) of 0.850 [95% confidence interval, 0.849, 0.860] and an average accuracy of 0.950. The combined peritumoral model outperformed the regional peritumoral models with AUC of 0.85 versus 0.75 for PZ lesions and 0.88 versus 0.69 for TZ lesions, respectively. The peritumoral classification models exhibit greater efficacy in predicting PZ lesions as opposed to TZ lesions. CONCLUSION: The peritumoral radiomics features showed excellent performance in predicting GGG in PCa patients and might be a valuable addition to the non-invasive assessment of PCa aggressiveness.
Assuntos
Neoplasias da Próstata , Masculino , Humanos , Estudos Retrospectivos , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Imageamento por Ressonância Magnética/métodos , Imagem de Difusão por Ressonância Magnética/métodos , Aprendizado de MáquinaRESUMO
Introduction: Dexamethasone (DEX), as an important enduring-effect glucocorticoid (GC), holds great promise in the field of lung ischemia-reperfusion injury (LIRI) comprehensive therapy owing to its immunomodulatory properties, such as inducing apoptosis and cell cycle distribution. However, its potent anti-inflammatory application is still restricted because of multiple internal physiologic barriers. Methods: Herein, we developed upconversion nanoparticles (UCNPs) coated with photosensitizer/capping agent/fluorescent probe-modified mesoporous silica (UCNPs@mSiO2[DEX]-Py/ß-CD/FITC, USDPFs) for precise DEX release synergistic LIRI comprehensive therapy. The UCNPs were designed by covering an inert YOF:Yb shell on the YOF:Yb, Tm core to achieve high-intensity blue and red upconversion emission upon Near-Infrared (NIR) laser irradiation. Results: Under suitable compatibility conditions, the molecular structure of photosensitizer can be damaged along with capping agent shedding, which endowed USDPFs with an outstanding capability to carry out DEX release controlling and fluorescent indicator targeting. Furthermore, the hybrid encapsulating of DEX significantly increased utilization of nano-drugs, improving the water solubility and bioavailability, which was conducive to developing the anti-inflammatory performance of USDPFs in the complex clinical environment. Discussion: The response-controlled release of DEX in the intrapulmonary microenvironment can reduce normal cell damage, which can effectively avoid the side effects of nano-drugs in anti-inflammatory application. Meanwhile, the multi-wavelength of UCNPs endowed nano-drugs with the fluorescence emission imaging capacity in an intrapulmonary microenvironment, providing precise guidance for LIRI.
RESUMO
Objective To investigate the protective effect of artesunate on hypoxic-ischemic brain damage (HIBD) and its mechanism in neonatal rats. Methods 7-day-old neonatal SD rats were randomly divided into sham operation group, model group, artesunate 5 mg/kg group, artesunate 10 mg/kg group, artesunate 20 mg/kg group and dexamethasone 6 mg/kg group, with 18 rats in each group. HIBD models were established in groups except for the sham operation group. The sham operation group only needed to separate the left common carotid artery without ligation and nitrogen-oxygen mixed gas ventilation. Each group was injected with drug intraperitoneally right after surgery and the rats in the sham operation group and the model group were injected with an equal volume of normal saline (once a day for a total of 5 times). One hour after the last injection, the rats in each group were scored for neurological defects. After the rats were sacrificed, the brain water content was measured and the pathological changes of the brain tissues of rats were observed. Terminal-deoxynucleotidyl transferase mediated nick end labeling (TUNEL) was used to detect the neuronal cell apoptosis, and ELISA was applied to detect the levels of IL-1ß, IL-6 and TNF-α in brain tissues and peripheral blood of each group of rats. Western blot analysis was adopted to detect the protein expression levels of NLR family pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein containing CARD (ASC) and caspase-1 in the rats brain tissues of each group. Results Compared with the model group, the neurological deficit score was decreased; the pathological damage of brain tissues was relieved; the brain water content was significantly reduced; the apoptosis number of hippocampal neurons was decreased significantly; the levels of IL-1ß, IL-6 and TNF-α in brain tissues and peripheral blood were significantly reduced; the protein expression levels of NLRP3, ASC and caspase-1 were significantly lowered in the middle-dose and high-dose artesunate groups and the dexamethasone group. Conclusion Artesunate can improve the neurological function, relieve the brain damage, and alleviate the brain edema in neonatal rats with HIBD. It can protect the HIBD, which may be related to the inhibition of NLRP3 inflammasome activation and reduction of inflammatory cytokine secretion.
Assuntos
Hipóxia-Isquemia Encefálica , Inflamassomos , Animais , Ratos , Animais Recém-Nascidos , Artesunato/farmacologia , Encéfalo/metabolismo , Caspases/metabolismo , Dexametasona , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Hipóxia-Isquemia Encefálica/metabolismo , Hipóxia-Isquemia Encefálica/patologia , Interleucina-6/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo , Água/metabolismoRESUMO
The replication of HBV in hepatocytes can be effectively inhibited by lifelong antiviral therapy. Because of the long-term presence of HBV reservoirs, the virus rebound frequently occurs once the treatment is stopped, which poses a considerable obstacle to the complete removal of the virus. In terms of gene composition, regulation of B cell action and function, CXCR5+ CD8+ T cells are similar to CXCR5+ CD4+ T follicular helper cells, while these cells are characterized by elevated programmed cell death 1 and cytotoxic-related proteins. CXCR5+ CD8+ T cells are strongly associated with progression in inflammatory and autoimmune diseases. In addition, CXCR5 expression on the surface of CD8+ T cells is mostly an indicator of memory stem cell-like failure in progenitor cells in cancer that are more responsive to immune checkpoint blocking therapy. Furthermore, the phenomena have also been demonstrated in some viral infections, highlighting the duality of the cellular immune response of CXCR5+ CD8+ T cells. This mini-review will focus on the function of CXCR5+ CD8+ T cells in HBV infection and discuss the function of these CD8+ T cells and the potential of associated co-stimulators or cytokines in HBV therapeutic strategies.
Assuntos
Vírus da Hepatite B , Hepatite B , Humanos , Linfócitos T CD8-Positivos , Citocinas/metabolismo , Linfócitos B , Hepatite B/complicações , Receptores CXCR5/genética , Receptores CXCR5/metabolismoRESUMO
Background: To construct and validate a simple and easily administered scoring tool for the prediction of short-term prognostic survival in adult patients with sepsis. Methods: This study is a retrospective and prospective cohort study. A total of 382 patients with sepsis. 274 sepsis patients from January 2020 to December 2020 were collected as the modeling group and 54 sepsis patients from January 2021 to December 2021 and April to May 2022 in the hospital were randomly collected as the validation group. They were divided into survival and non-survival groups according to the outcome. The receiver operating characteristic (ROC) curves were plotted with subgroup analysis. The resulting models were tested using the Hosmer-Lemeshow test. The prognostic value of the variables on prognosis was expressed using the area under the receiver operating characteristic curve (AUC). A scoring tool was constructed and tested for the prognostic value of this score in the validation group. Results: The model had an AUC of 0.880 [95% CI (0.838-0.922), P < 0.001], model sensitivity of 81.15%, and specificity of 80.26% for predicting short-term prognosis in patients with sepsis. Further simplifying the model scoring rules and adding the lactate variable, the AUCs was 0.876 [95% CI (0.833-0.918)], P < 0.001], sensitivity was 78.69%, specificity was 82.89%, and scoring criteria were established. the AUCs of the internally validated model in 2021 and 2022 were 0.968 [95% CI (0.916 to 1.000), P < 0.001] and 0.943 [95% CI (0.873 to 1.000), P < 0.001], indicating that the constructed scoring tool has a good predictive value for short-term survival outcomes in patients with sepsis. Conclusions: Age, shock, lactate, lactate/albumin ratio (L/A), and interleukin-6 (IL-6) are five risk factors for adult sepsis prognosis in an early emergency. This scoring tool is developed to quickly assess the short-term survival outcome in adult sepsis patients. It is straightforward and easy to administer. It also has a high prognostic predictive value.The Chinese Clinical Trial Registry (ChiCTR2200058375).
RESUMO
The enrichment of histone H3 variant CENP-A is the epigenetic mark of centromere and initiates the assembly of the kinetochore at centromere. The kinetochore is a multi-subunit complex that ensures accurate attachment of microtubule centromere and faithful segregation of sister chromatids during mitosis. As a subunit of kinetochore, CENP-I localization at centromere also depends on CENP-A. However, whether and how CENP-I regulates CENP-A deposition and centromere identity remains unclear. Here, we identified that CENP-I directly interacts with the centromeric DNA and preferentially recognizes AT-rich elements of DNA via a consecutive DNA-binding surface formed by conserved charged residues at the end of N-terminal HEAT repeats. The DNA binding-deficient mutants of CENP-I retained the interaction with CENP-H/K and CENP-M, but significantly diminished the centromeric localization of CENP-I and chromosome alignment in mitosis. Moreover, the DNA binding of CENP-I is required for the centromeric loading of newly synthesized CENP-A. CENP-I stabilizes CENP-A nucleosomes upon binding to nucleosomal DNA instead of histones. These findings unveiled the molecular mechanism of how CENP-I promotes and stabilizes CENP-A deposition and would be insightful for understanding the dynamic interplay of centromere and kinetochore during cell cycle.
Assuntos
Centrômero , Proteínas Cromossômicas não Histona , Proteína Centromérica A/genética , Proteína Centromérica A/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Centrômero/genética , Centrômero/metabolismo , Histonas/genética , Histonas/metabolismo , Nucleossomos/genética , DNA/genética , Mitose , Autoantígenos/metabolismoRESUMO
Obesity, defined as a disorder of lipid metabolism caused by white fat accumulation, is closely related to the gut microbiota. Akkermansia muciniphila (Akk), one of the most common gut commensals, can reduce fat storage and promote the browning of white adipocytes, alleviating disorders of lipid metabolism. However, which components of Akk produce the effect remain unclear, limiting the application of Akk in the treatment of obesity. Here, we found that the membrane protein Amuc_1100 of Akk decreased formation of lipid droplets and fat accumulation during the differentiation process and stimulated browning in vivo and in vitro. Transcriptomics revealed that Amuc_1100 accelerated lipolysis through upregulation of the AC3/PKA/HSL pathway in 3T3-L1 preadipocytes. Quantitative PCR (qPCR) and Western blotting showed that Amuc_1100 intervention promotes steatolysis and browning of preadipocytes by increasing lipolysis-related genes (AC3/PKA/HSL) and brown adipocyte marker genes (PPARγ, UCP1, and PGC1α) at both the mRNA and protein levels. These findings introduce new insight into the effects of beneficial bacteria and provide new avenues for the treatment of obesity. IMPORTANCE An important intestinal bacterial strain Akkermansia muciniphila contributes to improving carbohydrate and lipid metabolism, thus alleviating obesity symptoms. Here, we find that the Akk membrane protein Amuc_1100 regulates lipid metabolism in 3T3-L1 preadipocytes. Amuc_1100 inhibits lipid adipogenesis and accumulation during the differentiation process of preadipocytes, upregulates the browning-related genes of preadipocytes, and promotes thermogenesis through activation of uncoupling protein-1 (UCP-1), including Acox1 involved in lipid oxidation. Amuc_1100 accelerates lipolysis via the AC3/PKA/HSL pathway, phosphorylating HSL at Ser 660. The experiments illustrated here identify the specific molecules and functional mechanisms of Akk. Therapeutic approaches with Amuc_1100 derived from Akk may help alleviate obesity and metabolic disorders.