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BACKGROUND: This study aimed to investigate the association of high-sensitivity C-reactive protein (hs-CRP) with incident frailty as well as its effects on pre-frailty progression and regression among middle-aged and older adults. METHODS: Based on the frailty index (FI) calculated with 41 items, 6890 eligible participants without frailty at baseline from China Health and Retirement Longitudinal Study (CHARLS) were categorized into health, pre-frailty, and frailty groups. Logistic regression models were used to estimate the longitudinal association between baseline hs-CRP and incident frailty. Furthermore, a series of genetic approaches were conducted to confirm the causal relationship between CRP and frailty, including Linkage disequilibrium score regression (LDSC), pleiotropic analysis, and Mendelian randomization (MR). Finally, we evaluated the association of hs-CRP with pre-frailty progression and regression. RESULTS: The risk of developing frailty was 1.18 times (95% CI: 1.03-1.34) higher in participants with high levels of hs-CRP at baseline than low levels of hs-CRP participants during the 3-year follow-up. MR analysis suggested that genetically determined hs-CRP was potentially positively associated with the risk of frailty (OR: 1.06, 95% CI: 1.03-1.08). Among 5241 participants with pre-frailty at baseline, we found pre-frailty participants with high levels of hs-CRP exhibit increased odds of progression to frailty (OR: 1.39, 95% CI: 1.09-1.79) and decreased odds of regression to health (OR: 0.84, 95% CI: 0.72-0.98) when compared with participants with low levels of hs-CRP. CONCLUSIONS: Our results suggest that reducing systemic inflammation is significant for developing strategies for frailty prevention and pre-frailty reversion in the middle-aged and elderly population.
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Proteína C-Reactiva , Fragilidad , Anciano , Humanos , Persona de Mediana Edad , Estudios Longitudinales , Proteína C-Reactiva/genética , Fragilidad/diagnóstico , Fragilidad/epidemiología , Fragilidad/genética , Estudios de Cohortes , InflamaciónRESUMEN
The Y-STR landscape of Coastal Southeastern Han (CSEH) living in Chinese southeast areas (including Guangdong, Fujian, and Zhejiang provinces) is still unclear. We investigated 62 Y-STR markers in a reasonably large number of 1021 unrelated males and 1027 DNA-confirmed father-son pairs to broaden the genetic backgrounds of CSEH. In total, 85 null alleles, 121 off-ladder alleles, and 95 copy number variants were observed, and 1012 distinct haplotypes were determined with the overall HD and DC values of 0.999974 and 0.9912. We observed 369 mutations in 76 099 meiotic transfers, and the average estimated Y-STR mutation rate was 4.85 × 10-3 (95% CI, 4.4 × 10-3 -5.4 × 10-3 ). The Spearman correlation analyses indicated that GD values (R2 = 0.6548) and average allele sizes (R2 = 0.5989) have positive correlations with Y-STR mutation rates. Our RM Y-STR set including 8 candidate RM Y-STRs, of which DYS534, DYS630, and DYS713 are new candidates in CSEH, distinguished 18.52% of father-son pairs. This study also clarified the population structures of CSEH which isolated in population-mixed South China relatively. The strategy, SM Y-STRs for familial searching and RM Y-STRs for individual identification regionally, could be applicable based on enough knowledge of the Y-STR mutability of different populations.
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Tasa de Mutación , China , Cromosomas Humanos Y/genética , Genética Forense , Genética de Población , Haplotipos , Humanos , Masculino , Repeticiones de Microsatélite/genética , MutaciónRESUMEN
Uniparental disomy (UPD) has attracted more attention recently in paternity testing, though it is an infrequent genetic event. Although short tandem repeat (STR) profiling has been widely used in paternity testing, it is not sufficient to use STR only to judge the genetic relationship, because the existence of UPD will inevitably affect the results of genotyping. Compared with complete UPD, segmental UPD is more difficult to detect because it does not affect all genotypes on the same chromosome. It is necessary to determine the type of UPD with multiple methods because a single method is not sufficient. Therefore, it is advisable to detect UPD in paternity testing with multiple methods. In this study, after autosomal STR profiling was used, we found that there were several gene loci on the same chromosome that did not conform to Mendelian genetic law, thus we highly suspected the existence of UPD and performed X-STR profiling immediately. Then whole-genome single nucleotide polymorphism (SNP) array analysis was performed to identify the type, and the results provided straightforward evidence for distinguishing complete from segmental UPD. Lastly, we used deletion insertion polymorphism (DIP)-SNP SNaPshot assay and Miseq FGx sequencing (for SNP and STR) to determine whether the mutation source is maternal uniparental disomy (mUPD) or paternal uniparental disomy (pUPD). To avoid false exclusion of kinship, it is vital to determine the type of UPD in paternity testing and effective strategies based on multiple methods to detect the type of UPD are provided in this study.
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Dermatoglifia del ADN/métodos , Pruebas Genéticas/métodos , Técnicas de Diagnóstico Molecular , Paternidad , Disomía Uniparental/diagnóstico , Disomía Uniparental/genética , Adulto , Niño , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Mutación INDEL , Masculino , Repeticiones de Microsatélite , Polimorfismo de Nucleótido SimpleRESUMEN
Autophagy is a self-proteolytic process that degrades intracellular material to maintain cellular homeostasis. Transcription factor EB (TFEB) is the master activator that regulates the transcription of genes involved in autophagy and lysosomal biogenesis. However, the cotranscriptional factors of TFEB are rarely identified. Here, we found that Yin Yang 1 (YY1) regulated autophagy and lysosome biogenesis in melanoma cells. YY1 cooperates with TFEB to regulate autophagy through controlling the transcription of autophagy and lysosome biogenesis related genes. Moreover, suppression of YY1 enhanced the antitumor efficiency of vemurafenib both in vitro and in vivo. Collectively, these studies identify YY1 as a novel cotranscription factor of TFEB in regulating autophagy and lysosomal functions and suggest YY1 could be a therapeutic target in cancer treatment.
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Autofagia/genética , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Melanoma/genética , Factor de Transcripción YY1/genética , Animales , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Xenoinjertos , Humanos , Lisosomas/genética , Melanoma/patología , Ratones , Plásmidos/genéticaRESUMEN
In order to analyze the influence of different segmentation techniques on hepatocellular carcinoma (HCC) CT (Computed Tomography) imaging histological feature extraction, Grow Cut method and Graph Cut method are used to segment hepatocellular carcinoma from arterial CT images of HCC patients, and the stability and repeatability of imaging histological features are studied. Meanwhile, hierarchical clustering method is used to reduce the redundancy of features. The results show that the repeatability and redundancy mainly depend on the method of tumor segmentation. Semi-automatic segmentation method can improve the repeatability of image features, and hierarchical clustering can reduce the redundancy of features. Different segmentation techniques have different effects on the extraction of histological features of CT images of HCC.
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Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/patología , Procesamiento de Imagen Asistido por Computador/métodos , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/patología , Tomografía Computarizada por Rayos X/métodos , Algoritmos , HumanosRESUMEN
Vascular calcification is a notable risk factor for cardiovascular system. High phosphate can induce calcification in vascular smooth muscle cells (VSMCs), but the detail mechanism underlying this process remains unclear. In the present study, we determined the relationship between high phosphate and bone morphogenetic protein 9 (BMP9) in VSMCs, the effect of BMP9 on calcification in VSMCs and the effect of COX-2 on BMP9 induced calcification in VSMCs, as well as the possible mechanism underlying this biological process. We found that high phosphate obviously up-regulates the expression of BMP9 in VSMCs. Over-expression of BMP9 decreases the level of alpha-smooth muscle cell actin (α-SMA) apparently, but increases the level of Runx-2, Dlx-5, and ALP in VSMCs. Meanwhile, BMP9 increases the level of OPN and OCN, promotes mineralization in VSMCs and induces calcification in thoracic aorta. High phosphate and over-expression of BMP9 increases the level of COX-2. Over-expression of COX-2 enhances the inhibitory effect of BMP9 on α-SAM and increases the level of OPN and OCN induced by BMP9. However, inhibition of COX-2 decreases the BMP9-induced calcification in VSMCs and thoracic aorta. For mechanism, we found that high phosphate or BMP9 increases the level of ß-catenin and p-GSK3ß in VSMCs, but no substantial effect on GSK3ß. However, COX-2 inhibitor decreases the expression of ß-catenin induced by BMP9. Our findings indicated that BMP9 is involved in the phosphate-induced calcification in VSMCs and COX-2 partly mediates the BMP9-induced calcification in VSMCs through activating Wnt/ß-catenin pathway.
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Calcinosis/metabolismo , Ciclooxigenasa 2/biosíntesis , Factor 2 de Diferenciación de Crecimiento/biosíntesis , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Fosfatos/efectos adversos , Vía de Señalización Wnt/efectos de los fármacos , Animales , Calcinosis/inducido químicamente , Calcinosis/patología , Células Cultivadas , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/patología , Fosfatos/farmacología , Ratas , beta Catenina/metabolismoRESUMEN
Mutation analysis of 42 Y chromosomal short tandem repeats (Y-STRs) loci was performed using a sample of 1160 father-son pairs from the Chinese Han population in Eastern China. The results showed that the average mutation rate across the 42 Y-STR loci was 0.0041 (95% CI 0.0036-0.0047) per locus per generation. The locus-specific mutation rates varied from 0.000 to 0.0190. No mutation was found at DYS388, DYS437, DYS448, DYS531, and GATA_H4. DYS627, DYS570, DYS576, and DYS449 could be classified as rapidly mutating Y-STRs, with mutation rates higher than 1.0 × 10-2. DYS458, DYS630, and DYS518 were moderately mutating Y-STRs, with mutation rates ranging from 8 × 10-3 to 1 × 10-2. Although the characteristics of the Y-STR mutations were consistent with those in previous studies, mutation rate differences between our data and previous published data were found at some rapidly mutating Y-STRs. The single-copy loci located on the short arm of the Y chromosome (Yp) showed relatively higher mutation rates more frequently than the multi-copy loci. These results will not only extend the data for Y-STR mutations but also be important for kinship analysis, paternal lineage identification, and family relationship reconstruction in forensic Y-STR analysis.
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Cromosomas Humanos Y/genética , Genética de Población , Repeticiones de Microsatélite , Tasa de Mutación , China , Haplotipos , Humanos , Masculino , MutaciónRESUMEN
The adult intestinal homeostasis is tightly controlled by proper proliferation and differentiation of intestinal stem cells. The JAK/STAT (Janus Kinase/Signal Transducer and Activator of Transcription) signaling pathway is essential for the regulation of adult stem cell activities and maintenance of intestinal homeostasis. Currently, it remains largely unknown how JAK/STAT signaling activities are regulated in these processes. Here we have identified windpipe (wdp) as a novel component of the JAK/STAT pathway. We demonstrate that Wdp is positively regulated by JAK/STAT signaling in Drosophila adult intestines. Loss of wdp activity results in the disruption of midgut homeostasis under normal and regenerative conditions. Conversely, ectopic expression of Wdp inhibits JAK/STAT signaling activity. Importantly, we show that Wdp interacts with the receptor Domeless (Dome), and promotes its internalization for subsequent lysosomal degradation. Together, these data led us to propose that Wdp acts as a novel negative feedback regulator of the JAK/STAT pathway in regulating intestinal homeostasis.
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Diferenciación Celular/genética , Proteínas de Drosophila/genética , Mucosa Intestinal/metabolismo , Quinasas Janus/genética , Proteínas de la Membrana/genética , Receptores de Interleucina/genética , Animales , Proliferación Celular , Proteínas de Drosophila/metabolismo , Drosophila melanogaster , Endocitosis/genética , Regulación del Desarrollo de la Expresión Génica , Homeostasis/genética , Intestinos/crecimiento & desarrollo , Quinasas Janus/metabolismo , Lisosomas/genética , Lisosomas/metabolismo , Proteínas de la Membrana/metabolismo , Receptores de Interleucina/metabolismo , Factores de Transcripción STAT/genética , Factores de Transcripción STAT/metabolismo , Transducción de Señal , Células MadreRESUMEN
The highly conserved janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is a well-known signaling system that is involved in many biological processes. In Drosophila, this signaling cascade is activated by ligands of the Unpaired (Upd) family. Therefore, the regulation of Upd distribution is one of the key issues in controlling the JAK/STAT signaling activity and function. Heparan sulfate proteoglycans (HSPGs) are macromolecules that regulate the distribution of many ligand proteins including Wingless, Hedgehog and Decapentaplegic (Dpp). Here we show that during Drosophila eye development, HSPGs are also required in normal Upd distribution and JAK/STAT signaling activity. Loss of HSPG biosynthesis enzyme Brother of tout-velu (Botv), Sulfateless (Sfl), or glypicans Division abnormally delayed (Dally) and Dally-like protein (Dlp) led to reduced levels of extracellular Upd and reduction in JAK/STAT signaling activity. Overexpression of dally resulted in the accumulation of Upd and up-regulation of the signaling activity. Luciferase assay also showed that Dally promotes JAK/STAT signaling activity, and is dependent on its heparin sulfate chains. These data suggest that Dally and Dlp are essential for Upd distribution and JAK/STAT signaling activity.
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Proteínas de Drosophila/metabolismo , Drosophila/metabolismo , Discos Imaginales/metabolismo , Quinasas Janus/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteoglicanos/metabolismo , Factores de Transcripción STAT/metabolismo , Factores de Transcripción/metabolismo , Animales , Células Cultivadas , Drosophila/genética , Drosophila/crecimiento & desarrollo , Proteínas de Drosophila/biosíntesis , Proteínas de Drosophila/genética , Ojo/crecimiento & desarrollo , Ojo/metabolismo , Técnica del Anticuerpo Fluorescente , Regulación del Desarrollo de la Expresión Génica , Proteoglicanos de Heparán Sulfato/metabolismo , Quinasas Janus/genética , Glicoproteínas de Membrana/genética , N-Acetilglucosaminiltransferasas/biosíntesis , N-Acetilglucosaminiltransferasas/genética , Proteoglicanos/genética , Interferencia de ARN , ARN Interferente Pequeño , Factores de Transcripción STAT/genética , Transducción de Señal , Sulfotransferasas/biosíntesis , Sulfotransferasas/genética , Factores de Transcripción/genéticaRESUMEN
BACKGROUND: Acute pancreatitis (AP) is a severe condition with complications that can impact multiple organ systems throughout the body. Specifically, the diffusion of peripancreatic effusion to the pleural cavity is a significant phenomenon in AP. However, its pathways and implications for disease severity are not fully understood. OBJECTIVE: This study aims to investigate the anatomical routes of peripancreatic effusion diffusion into the pleural cavity in patients with AP and to analyze the correlation between the severity of pleural effusion (PE) and the computed tomography severity index (CTSI) and acute physiology and chronic health evaluation II (APACHE II) scoring system. METHODS: 119 patients with AP admitted to our institution were enrolled in this study (mean age 50 years, 74 male and 45 female). Abdominal CT was performed, and the CTSI and APACHE II index were used to evaluate the severity of the AP, Meanwhile, the prevalence and semiquantitative of PE were also mentioned. The anatomical pathways of peripancreatic effusion draining to pleural were analyzed. Finally, the correlation relationship between the severity of AP and the PE was analyzed. RESULTS: In 119 patients with AP, 74.8% of patients had PE on CT. The anatomic pathways of peripancreatic effusion draining to pleural included esophageal hiatus in 33.7% of patients, aortic hiatus in 6.7% of patients and inferior vena cava hiatus in 3.37% of patients. The rating of PE on CT was correlated with CTSI scores (r= 0.449, P= 0.000) and was slightly correlated with the APACHE II scores (r= 0.197, P= 0.016). CONCLUSION: PE is a common complication of AP, which can be caused by anatomic pathways such as diaphragmatic hiatus. Due to its correlation with the CTSI score, the PE may be a supplementary indicator in determining the severity of AP.
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Pancreatitis , Derrame Pleural , Índice de Severidad de la Enfermedad , Humanos , Masculino , Femenino , Persona de Mediana Edad , Derrame Pleural/diagnóstico por imagen , Derrame Pleural/epidemiología , Pancreatitis/diagnóstico por imagen , Pancreatitis/complicaciones , Adulto , Anciano , APACHE , Tomografía Computarizada por Rayos X/métodos , Enfermedad Aguda , Tomografía Computarizada Multidetector/métodosRESUMEN
BACKGROUND: This study aimed to investigate the effect of systemic inflammation, assessed by high sensitivity C-reactive protein (hs-CRP) levels, on prediabetes progression and regression in middle-aged and older adults based on the China Health and Retirement Longitudinal Study (CHARLS). METHODS: Participants with prediabetes from CHARLS were followed up 4 years later with blood samples collected for measuring fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c). The level of hs-CRP was assessed at baseline and categorized into tertiles (low, middle, and high groups). Prediabetes at baseline and follow-up was defined primarily according to the American Diabetes Association (ADA) criteria. Logistic regression models were used to estimate the odds ratios (ORs) and confidence intervals (CIs). We also performed stratified analyses according to age, gender, BMI, the presence of hypertension, and the disease history of heart disease and dyslipidemia and sensitivity analyses excluding a subset of participants with incomplete data. RESULTS: Of the 2,874 prediabetes included at baseline, 834 participants remained as having prediabetes, 146 progressed to diabetes, and 1,894 regressed to normoglycemia based on ADA criteria with a 4 year follow-up. After multivariate logistics regression analysis, prediabetes with middle (0.67-1.62 mg/L) and high (>1.62 mg/L) hs-CRP levels had an increased incidence of progressing to diabetes compared with prediabetes with low hs-CRP levels (<0.67 mg/L; OR = 1.846, 95%CI: 1.129-3.018; and OR = 1.632, 95%CI: 0.985-2.703, respectively), and the incidence of regressing to normoglycemia decreased (OR = 0.793, 95%CI: 0.645-0.975; and OR = 0.769, 95%CI: 0.623-0.978, respectively). Stratified analyses and sensitivity analyses showed consistent results. CONCLUSIONS: Low levels of hs-CRP are associated with a high incidence of regression from prediabetes to normoglycemia and reduced odds of progression to diabetes.
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Estado Prediabético , Persona de Mediana Edad , Humanos , Anciano , Proteína C-Reactiva/metabolismo , Glucemia/análisis , Estudios Longitudinales , Estudios Prospectivos , Factores de RiesgoRESUMEN
The physicochemical properties of Nemipterus virgatus surimi gel were investigated, with tremella powder (TP) at concentrations ranging from 0 to 0.5% (w/w) combined with continuous microwave heating (CMH) using water-bath heating (WBH) as control. Results showed that TP addition (0.1%-0.3%, w/w) could significantly enhance the water holding capacity and reduce whiteness and cooking loss, attributed to the changed lateral relaxation time of water distribution. Notably, at 0.3% TP and 80 °C, the gel strength significantly increased by 96.84%, and the hardness, chewiness, and adhesiveness improved, but the quality of surimi decreased above 0.3% TP. The gel network structure was influenced by protein secondary structure composition, especially for increasing ß-sheet in Raman spectra, thus promoting the gel microstructure density and uniform protein distribution. These findings offer insights for enhancing surimi gel quality and broadening tremella application in product processing.
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The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has decreased the efficacy of SARS-CoV-2 vaccines in containing coronavirus disease 2019 (COVID-19) over time, and booster vaccination strategies are urgently necessitated to achieve sufficient protection. Intranasal immunization can improve mucosal immunity, offering protection against the infection and sustaining the spread of SARS-CoV-2. In this study, an intranasal booster of the RBD-HR vaccine after two doses of the mRNA vaccine significantly increased the levels of specific binding antibodies in serum, nasal lavage fluid, and bronchoalveolar lavage fluid compared with only two doses of mRNA vaccine. After intranasal boosting with the RBD-HR vaccine, the levels of serum neutralizing antibodies against prototype and variant strains of SARS-CoV-2 pseudoviruses were markedly higher than those in mice receiving mRNA vaccine alone, and intranasal boosting with the RBD-HR vaccine also inhibited the binding of RBD to hACE2 receptors. Furthermore, the heterologous intranasal immunization regimen promoted extensive memory T cell responses and activated CD103+ dendritic cells in the respiratory mucosa, and potently enhanced the formation of T follicular helper cells and germinal center B cells in vital immune organs, including mediastinal lymph nodes, inguinal lymph nodes, and spleen. Collectively, these data infer that heterologous intranasal boosting with the RBD-HR vaccine elicited broad protective immunity against SARS-CoV-2 both locally and systemically.
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Previous observational studies on the relationship between sleep characteristics and fracture have yielded contradictory results. The goal of this study was to replicate the findings in a large longitudinal cohort and then conduct a Mendelian randomization (MR) analysis to infer the causality between sleep behaviors and fracture risk. Based on data from the China Health and Retirement Longitudinal Study (CHARLS) including 17,708 participants, we found that individuals with short sleep duration (<5 h) (OR [odds ratio] = 1.62, 95% CI: 1.07-2.44) or restless sleep (OR = 1.55, 95% CI: 1.10-2.19) have a higher risk of hip fracture. A U-shaped relationship between nighttime sleep duration and hip fracture risk (p-nonlinear = 0.01) was observed using restricted cubic spline regression analysis. Through joint effect analysis, we found that participants with short sleep duration (<5 h) combined with midday napping could significantly decrease hip fracture incidence. We further inferred the causal relationship between self-reported sleep behaviors and hip fracture using the MR approach. Among four sleep phenotypic parameters (sleep duration, daytime napping, chronotype, and insomnia), we found a modest causal relationship between sleep duration and fracture (OR = 0.69, 95% CI: 0.48 to 0.99, p = 0.04). However, no causal relationship was observed for other sleep traits. In conclusion, our findings suggest that short sleep duration has a potential detrimental effect on hip fracture. Improving sleep patterns is of significance for developing hip fracture preventive strategies in the middle-aged and the elderly populations.
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Osteosarcoma is the most common primary malignant bone tumour in children and adolescents. Chemoresistance leads to poor responses to conventional therapy in patients with osteosarcoma. The discovery of novel effective therapeutic targets and drugs is still the main focus of osteosarcoma research. Nuclear receptors (NRs) have shown substantial promise as novel therapeutic targets for various cancers. In the present study, we performed a drug screen using 29 chemicals that specifically target 17 NRs in several different human osteosarcoma and osteoblast cell lines. The retinoic acid receptor beta (RARb) antagonist LE135, peroxisome proliferator activated receptor gamma (PPARg) antagonist T0070907, liver X receptor (LXR) agonist T0901317 and Rev-Erba agonist SR9011 significantly inhibited the proliferation of malignant osteosarcoma cells (U2OS, HOS-MNNG and Saos-2 cells) but did not inhibit the growth of normal osteoblasts. The effects of these NR modulators on osteosarcoma cells occurred in a dose-dependent manner and were not observed in NR-knockout osteosarcoma cells. These NR modulators also significantly inhibited osteosarcoma growth in vivo and enhanced the antitumour effect of doxorubicin (DOX). Transcriptomic and immunoblotting results showed that these NR modulators may inhibit the growth of osteosarcoma cells by regulating the PI3K/AKT/mTOR and ERK/mTOR pathways. DDIT4, which blocks mTOR activation, was identified as one of the common downstream target genes of these NRs. DDIT4 knockout significantly attenuated the inhibitory effects of these NR modulators on osteosarcoma cell growth. Together, our results revealed that modulators of RARb, PPARg, LXRs and Rev-Erba inhibit osteosarcoma growth both in vitro and in vivo through the mTOR signaling pathway, suggesting that treatment with these NR modulators is a novel potential therapeutic strategy.
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Neoplasias Óseas , Osteosarcoma , Adolescente , Niño , Humanos , Fosfatidilinositol 3-Quinasas/metabolismo , PPAR gamma , Proteínas Proto-Oncogénicas c-akt/metabolismo , Línea Celular Tumoral , Transducción de Señal , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/genética , Osteosarcoma/metabolismo , Proliferación Celular/genética , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , ApoptosisRESUMEN
BACKGROUND: Mitochondrial transcription factor A (TFAM) is a transcription factor that maintains mitochondrial DNA (mtDNA) stabilization and initiates mtDNA replication. However, little is known about the immune regulation function and TFAM expression in immune cells in the tumors. METHODS: Mouse tumor models were applied to analyze the effect of TFAM deficiency in myeloid cell lineage on tumor progression and tumor microenvironment (TME) modification. In vitro, primary mouse bone marrow-derived dendritic cells (BMDCs) were used in the investigation of the altered function and the activated pathway. OVA was used as the model antigen to validate the activation of immune responses in vivo. STING inhibitors were used to confirm the STING activation provoked by Tfam deficient in DCs. RESULTS: The deletion of TFAM in DCs led to mitochondrial dysfunction and mtDNA cytosolic leakage resulting in the cGAS-STING pathway activation in DCs, which contributed to the enhanced antigen presentation. The deletion of TFAM in DCs has interestingly reversed the immune suppressive TME and inhibited tumor growth and metastasis in tumor models. CONCLUSIONS: We have revealed that TFAM knockout in DCs ameliorated immune-suppressive microenvironment in tumors through STING pathway. Our work suggests that specific TFAM knockout in DCs might be a compelling strategy for designing novel immunotherapy methods in the future.
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Proteínas de Unión al ADN , Células Dendríticas , Proteínas del Grupo de Alta Movilidad , Mitocondrias , Neoplasias , Animales , Ratones , Presentación de Antígeno , Modelos Animales de Enfermedad , ADN Mitocondrial , Proteínas de Unión al ADN/genética , Proteínas del Grupo de Alta Movilidad/genética , Mitocondrias/patología , Neoplasias/patologíaRESUMEN
BA.4 and BA.5 (BA.4/5), the subvariants of Omicron, are more transmissible than BA.1 with more robust immune evasion capability because of its unique spike protein mutations. In light of such situation, the vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is in desperate need of the third booster. It has been reported that heterologous boosters might produce more effective immunity against wild-type SARS-CoV-2 and the variants. Additionally, the third heterologous protein subunit booster should be considered potentially. In the present study, we prepared a Delta full-length spike protein sequence-based mRNA vaccine as the "priming" shot and developed a recombinant trimeric receptor-binding domain (RBD) protein vaccine referred to as RBD-HR/trimer as a third heterologous booster. Compared to the homologous mRNA group, the heterologous group (RBD-HR/trimer vaccine primed with two mRNA vaccines) induced higher neutralizing antibody titers against BA.4/5-included SARS-CoV-2 variants. In addition, heterologous vaccination exhibited stronger cellular immune response and long-lasting memory response than the homologous mRNA vaccine. In conclusion, a third heterologous boosting with RBD-HR/trimer following two-dose mRNA priming vaccination should be a superior strategy than a third homologous mRNA vaccine. The RBD-HR/trimer vaccine becomes an appropriate candidate for a booster immune injection.
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Mucosal immunity plays a significant role in the first-line defense against viruses transmitted and infected through the respiratory system, such as SARS-CoV-2. However, the lack of effective and safe adjuvants currently limits the development of COVID-19 mucosal vaccines. In the current study, we prepare an intranasal vaccine containing cationic crosslinked carbon dots (CCD) and a SARS-CoV-2 antigen, RBD-HR with spontaneous antigen particlization. Intranasal immunization with CCD/RBD-HR induces high levels of antibodies with broad-spectrum neutralization against authentic viruses/pseudoviruses of Omicron-included variants and protects immunized female BALB/c mice from Omicron infection. Despite strong systemic cellular immune response stimulation, the intranasal CCD/RBD-HR vaccine also induces potent mucosal immunity as determined by the generation of tissue-resident T cells in the lungs and airway. Moreover, CCD/RBD-HR not only activates professional antigen-presenting cells (APCs), dendritic cells, but also effectively targets nasal epithelial cells, promotes antigen binding via sialic acid, and surprisingly provokes the antigen-presenting of nasal epithelial cells. We demonstrate that CCD is a promising intranasal vaccine adjuvant for provoking strong mucosal immunity and might be a candidate adjuvant for intranasal vaccine development for many types of infectious diseases, including COVID-19.
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COVID-19 , Vacunas , Femenino , Animales , Ratones , Humanos , SARS-CoV-2 , COVID-19/prevención & control , Adyuvantes Inmunológicos , Vacunas contra la COVID-19 , Carbono , CationesRESUMEN
For coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), 15-30% of patients are likely to develop COVID-19-related acute respiratory distress syndrome (ARDS). There are still few effective and well-understood therapies available. Novel variants and short-lasting immunity are posing challenges to vaccine efficacy, so finding antiviral and antiinflammatory treatments remains crucial. Here, tripterin (TP), a traditional Chinese medicine, was encapsulated into liposome (TP lipo) to investigate its antiviral and antiinflammatory effects in severe COVID-19. By using two severe COVID-19 models in human ACE2-transgenic (hACE2) mice, an analysis of TP lipo's effects on pulmonary immune responses was conducted. Pulmonary pathological alterations and viral burden were reduced by TP lipo treatment. TP lipo inhibits SARS-CoV-2 replication and hyperinflammation in infected cells and mice, two crucial events in severe COVID-19 pathophysiology, it is a promising drug candidate to treat SARS-CoV-2-induced ARDS.
Asunto(s)
COVID-19 , Síndrome de Dificultad Respiratoria , Humanos , Animales , Ratones , SARS-CoV-2 , Liposomas , Tratamiento Farmacológico de COVID-19 , Antivirales/farmacología , Síndrome de Dificultad Respiratoria/tratamiento farmacológicoRESUMEN
The outbreak of coronavirus disease 2019 (COVID-19) has posed great threats to global health and economy. Several effective vaccines are available now, but additional booster immunization is required to retain or increase the immune responses owing to waning immunity and the emergency of new variant strains. The deficiency of intramuscularly delivered vaccines to induce mucosal immunity urged the development of mucosal vaccines. Here, we developed an adjuvanted intranasal RBD vaccine and monitored its long-term immunogenicity against both wild-type and mutant strains of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), including Omicron variants, in mice. Three-dose intranasal immunization with this vaccine induced and maintained high levels of neutralizing IgG antibodies in the sera for at least 1 year. Strong mucosal immunity was also provoked, including mucosal secretory IgA and lung-resident memory T cells (TRM). We also demonstrated that the long-term persistence of lung TRM cells is a consequence of local T-cell proliferation, rather than T-cell migration from lymph nodes. Our data suggested that the adjuvanted intranasal RBD vaccine is a promising vaccine candidate to establish robust, long-lasting, and broad protective immunity against SARS-CoV-2 both systemically and locally.