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Early and precise diagnosis of α-synucleinopathies is challenging but critical. In this study, we developed a molecular beacon-based assay to evaluate microRNA-containing extracellular vesicles (EVs) in plasma. We recruited 1203 participants including healthy controls (HCs) and patients with isolated REM sleep behavior disorder (iRBD), α-synucleinopathies, or non-α-synucleinopathies from eight centers across China. Plasma miR-44438-containing EV levels were significantly increased in α-synucleinopathies, including those in the prodromal stage (e.g., iRBD), compared to both non-α-synucleinopathy patients and HCs. However, there are no significant differences between Parkinson's disease (PD) and multiple system atrophy. The miR-44438-containing EV levels negatively correlated with age and the Hoehn and Yahr stage of PD patients, suggesting a potential association with disease progression. Furthermore, a longitudinal analysis over 16.3 months demonstrated a significant decline in miR-44438-containing EV levels in patients with PD. These results highlight the potential of plasma miR-44438-containing EV as a biomarker for early detection and progress monitoring of α-synucleinopathies.
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Biomarcadores , MicroRNA Circulante , Vesículas Extracelulares , Doença de Parkinson , Sinucleinopatias , Humanos , Vesículas Extracelulares/metabolismo , Masculino , Biomarcadores/sangue , Feminino , Pessoa de Meia-Idade , MicroRNA Circulante/sangue , Doença de Parkinson/sangue , Doença de Parkinson/diagnóstico , Idoso , Sinucleinopatias/sangue , Sinucleinopatias/diagnóstico , alfa-Sinucleína/sangue , Estudos de Casos e Controles , MicroRNAs/sangue , Atrofia de Múltiplos Sistemas/sangue , Atrofia de Múltiplos Sistemas/diagnósticoRESUMO
Cells use signaling pathways to sense and respond to their environments. The transforming growth factor-ß (TGF-ß) pathway produces context-specific responses. Here, we combined modeling and experimental analysis to study the dependence of the output of the TGF-ß pathway on the abundance of signaling molecules in the pathway. We showed that the TGF-ß pathway processes the variation of TGF-ß receptor abundance using Liebig's law of the minimum, meaning that the output-modifying factor is the signaling protein that is most limited, to determine signaling responses across cell types and in single cells. We found that the abundance of either the type I (TGFBR1) or type II (TGFBR2) TGF-ß receptor determined the responses of cancer cell lines, such that the receptor with relatively low abundance dictates the response. Furthermore, nuclear SMAD2 signaling correlated with the abundance of TGF-ß receptor in single cells depending on the relative expression levels of TGFBR1 and TGFBR2. A similar control principle could govern the heterogeneity of signaling responses in other signaling pathways.
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Transdução de Sinais , Fator de Crescimento Transformador beta , Fator de Crescimento Transformador beta/metabolismo , Humanos , Receptor do Fator de Crescimento Transformador beta Tipo II/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Proteína Smad2/metabolismo , Biologia Computacional , Modelos Biológicos , Linhagem Celular Tumoral , Proteínas Smad/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismoRESUMO
Overexpression of vesicular stomatitis virus G protein (VSV-G) elevates the secretion of EVs known as gectosomes, which contain VSV-G. Such vesicles can be engineered to deliver therapeutic macromolecules. We investigated viral glycoproteins from several viruses for their potential in gectosome production and intracellular cargo delivery. Expression of the viral glycoprotein (viral glycoprotein from the Chandipura virus [CNV-G]) from the human neurotropic pathogen Chandipura virus in 293T cells significantly augments the production of CNV-G-containing gectosomes. In comparison with VSV-G gectosomes, CNV-G gectosomes exhibit heightened selectivity toward specific cell types, including primary cells and tumor cell lines. Consistent with the differential tropism between CNV-G and VSV-G gectosomes, cellular entry of CNV-G gectosome is independent of the Low-density lipoprotein receptor, which is essential for VSV-G entry, and shows varying sensitivity to pharmacological modulators. CNV-G gectosomes efficiently deliver diverse intracellular cargos for genomic modification or responses to stimuli in vitro and in the brain of mice in vivo utilizing a split GFP and chemical-induced dimerization system. Pharmacokinetics and biodistribution analyses support CNV-G gectosomes as a versatile platform for delivering macromolecular therapeutics intracellularly.
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Vesiculovirus , Animais , Humanos , Camundongos , Vesiculovirus/genética , Vesiculovirus/metabolismo , Vesículas Extracelulares/metabolismo , Proteínas do Envelope Viral/metabolismo , Proteínas do Envelope Viral/genética , Glicoproteínas/metabolismo , Glicoproteínas/genética , Células HEK293 , Proteínas Virais/metabolismo , Proteínas Virais/genética , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Sistemas de Liberação de Medicamentos/métodos , Linhagem Celular TumoralRESUMO
Livingstone's turaco, Tauraco livingstonii, belongs to the family Musophagidae. In this study, we obtained the complete mitochondrial genome sequence of Livingstone's turaco by high-throughput sequencing technology and constructed a phylogenetic tree. It was found that the mitochondria of this species are 19,015 bp in length and contain a total of 37 genes, comprising 13 protein-coding genes, 22 tRNA genes, and 2 rRNA genes. The base composition of the mitochondrial genome is 31.61% A, 24.22% T, 30.64% C, and 13.52% G, with a GC content of 44%. Notably, an intriguing phenomenon of mitochondrial genome rearrangements was observed, characterized by the duplication of the tRNA Glu-L-CR gene order. In addition, the results of the phylogenetic tree analysis shed light on the taxonomic position of Livingstone's turaco and supported the taxonomy of Otidimorphae. The study provides a basis for future phylogenetic and taxonomic investigations of Musophagiformes.
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Background: Multiple system atrophy (MSA) is a disease with diverse symptoms and the commonly used classifications, MSA-P and MSA-C, do not cover all the different symptoms seen in MSA patients. Additionally, these classifications do not provide information about how the disease progresses over time or the expected outcome for patients. Objective: To explore clinical subtypes of MSA with a natural disease course through a data-driven approach to assist in the diagnosis and treatment of MSA. Methods: We followed 122 cases of MSA collected from 3 hospitals for 3 years. Demographic characteristics, age of onset, clinical signs, scale assessment scores, and auxiliary examination were collected. Age at onset; time from onset to assisted ambulation; and UMSARS I, II, and IV, COMPASS-31, ICARS, and UPDRS III scores were selected as clustering elements. K-means, partitioning around medoids, and self-organizing maps were used to analyze the clusters. Results: The results of all three clustering methods supported the classification of three MSA subtypes: The aggressive progression subtype (MSA-AP), characterized by mid-to-late onset, rapid progression and severe clinical symptoms; the typical subtype (MSA-T), characterized by mid-to-late onset, moderate progression and moderate severity of clinical symptoms; and the early-onset slow progression subtype (MSA-ESP), characterized by early-to-mid onset, slow progression and mild clinical symptoms. Conclusions: We divided MSA into three subtypes and summarized the characteristics of each subtype. According to the clustering results, MSA patients were divided into three completely different types according to the severity of symptoms, the speed of disease progression, and the age of onset.
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Progressão da Doença , Atrofia de Múltiplos Sistemas , Humanos , Atrofia de Múltiplos Sistemas/classificação , Atrofia de Múltiplos Sistemas/diagnóstico , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Análise por Conglomerados , Idade de Início , Índice de Gravidade de DoençaRESUMO
Objective: This study investigates the application of metagenomic next-generation sequencing (mNGS) in the diagnosis of neurobrucellosis (NB). Methods: We retrospectively analyzed patients diagnosed with NB who underwent cerebrospinal fluid (CSF) mNGS testing in Xijing Hospital from 2015 to 2021. Results: Among the 20 individuals included in the study, the serum rose bengal test was positive in 11 out of 16 cases, serum agglutination test was positive in 13 out of 16 cases, CSF culture was positive in 6 out of 11 cases, and CSF mNGS tests were positive in 18 out of 20 cases. Conclusion: CSF mNGS demonstrates superior sensitivity; therefore, it is recommended to collect CSF for mNGS testing prior to antibiotic therapy when NB is suspected.
Neurobrucellosis (NB) is a disease of the nervous system caused by a type of bacteria called Brucella. It is rare, serious and manifests inconsistently, making it hard to diagnose. Metagenomic next-generation sequencing (mNGS) is a new way to detect disease-causing bacteria by looking at their genetic material. mNGS is fast, accurate and covers a wide range of disease-causing bacteria. We looked back at patients diagnosed with NB at Xijing Hospital between 2015 and 2021 and tested samples of the fluid surrounding the brain and the spinal cord, called cerebrospinal fluid (CSF), by mNGS. A total of 20 patients were included in the study. Compared with the traditional methods, mNGS of CSF samples showed advantages in diagnosing NB. However, antibiotics may affect the results.
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Brucelose , Sequenciamento de Nucleotídeos em Larga Escala , Metagenômica , Humanos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Estudos Retrospectivos , Metagenômica/métodos , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Brucelose/diagnóstico , Brucelose/microbiologia , Brucelose/líquido cefalorraquidiano , Idoso , Adulto Jovem , Sensibilidade e Especificidade , AdolescenteRESUMO
Purpose: To investigate the clinical value of serum lysophosphatidylcholine (LPC) as a predictive biomarker for determining disease severity and mortality risk in hospitalized elderly patients with community-acquired pneumonia (CAP). Methods: This prospective, single-center study enrolled 208 elderly patients, including 67 patients with severe CAP (SCAP) and 141 with non-SCAP between November 1st, 2020, and November 30th, 2021 at the Qingdao Municipal Hospital, Shandong Province, China. The demographic and clinical parameters were recorded for all the included patients. Serum LPC levels were measured on day 1 and 6 after admission using ELISA. Propensity score matching (PSM) was used to balance the baseline variables between SCAP and non-SCAP patient groups. Receiver operative characteristic (ROC) curve analysis was used to compare the predictive performances of LPC and other clinical parameters in discriminating between SCAP and non-SCAP patients and determining the 30-day mortality risk of the hospitalized CAP patients. Univariate and multivariate logistic regression analyses were performed to identify the independent risk factors associated with SCAP. Cox proportional hazard regression analysis was used to determine if serum LPC was an independent risk factor for the 30-day mortality of CAP patients. Results: The serum LPC levels at admission were significantly higher in the non-SCAP patients than in the SCAP patients (P = 0.011). Serum LPC level <24.36 ng/mL, and PSI score were independent risk factors for the 30-day mortality in the elderly patients with CAP. The risk of 30-day mortality in the elderly CAP patients with low serum LPC levels (< 24.36ng/mL) was >5-fold higher than in the patients with high serum LPC levels (≥ 24.36ng/mL). Conclusion: Low serum LPC levels were associated with significantly higher disease severity and 30-day mortality in the elderly patients with CAP. Therefore, serum LPC is a promising predictive biomarker for the early identification of elderly CAP patients with poor prognosis.
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Infecções Comunitárias Adquiridas , Pneumonia , Humanos , Idoso , Lisofosfatidilcolinas , Estudos Prospectivos , Prognóstico , Biomarcadores , Índice de Gravidade de Doença , Gravidade do Paciente , Estudos RetrospectivosRESUMO
The PTEN-induced kinase 1 (PINK1)-Parkin pathway plays a vital role in maintaining a healthy pool of mitochondria in higher eukaryotic cells. While the downstream components of this pathway are well understood, the upstream triggers remain less explored. In this study, we conducted an extensive analysis of inhibitors targeting various mitochondrial electron transport chain (ETC) complexes to investigate their potential as activators of the PINK1-Parkin pathway. We identified cloflucarban, an antibacterial compound, as a novel pathway activator that simultaneously inhibits mitochondrial complexes III and V, and V. RNA interference (RNAi) confirmed that the dual inhibition of these complexes activates the PINK1-Parkin pathway. Intriguingly, we discovered that albumin, specifically bovine serum albumin (BSA) and human serum albumin (HSA) commonly present in culture media, can hinder carbonyl cyanide m-chlorophenyl hydrazone (CCCP)-induced pathway activation. However, cloflucarban's efficacy remains unaffected by albumin, highlighting its reliability for studying the PINK1-Parkin pathway. This study provides insights into the activation of the upstream PINK1-Parkin pathway and underscores the influence of culture conditions on research outcomes. Cloflucarban emerges as a promising tool for investigating mitochondrial quality control and neurodegenerative diseases.
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Carbanilidas , Proteínas Quinases , Ubiquitina-Proteína Ligases , Humanos , Proteínas Quinases/metabolismo , Reprodutibilidade dos Testes , Ubiquitina-Proteína Ligases/metabolismo , Mitocôndrias/metabolismo , Albuminas/metabolismoRESUMO
As the crucial part of a transmission assembly, the monitoring of the status of the crankshaft is essential for the normal working of a reciprocating machinery system. In consideration of the interaction between crankshaft system components, the fault vibration feature is typically non-stationary and nonlinear, and the single-scale feature extraction method cannot adequately assess the fault features, therefore a novel impact feature extraction method based on genetic algorithms to optimize multi-scale permutation entropy is proposed. Compared with other traditional feature extraction methods, the proposed method illustrates good robustness and high adaptability in the signal processing of crankshaft vibrations. Firstly, the improved complete ensemble empirical mode decomposition with adaptive noise (ICEEMDAN) method is developed on the signal to obtain several intrinsic mode function (IMF) components, and the IMF components with a large kurtosis are selected for array reorganization. Then, the parameters of multi-scale permutation entropy (MPE) are optimized based on genetic algorithm (GA), the multi-scale permutation entropy is calculated and the feature vector set is constructed. The feature vector set is input into the support vector machine (SVM) and optimized by a particle swarm optimization (PSO) model for training and final pattern recognition, where the Variational Mode Decomposition(VMD)-GA-MPE with a PSO-SVM recognition model and the ICEEMDAN-MPE with PSO-SVM recognition model without GA optimization are constructed for a comparison with the proposed method. The research result illustrates that the proposed method, which inputs the genetic algorithm optimized multi-scale permutation entropy extracted from the ICEEMDAN decomposition into the PSO-SVM, performs well in impact feature extraction and the pattern recognition of crankshaft vibrations.
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Background: Data about eosinophil-to-lymphocyte ratio (ELR) and eosinophil-to-monocyte ratio (EMR) in patients with community-acquired pneumonia (CAP) are rare. We aimed to evaluate the role of EMR and ELR in predicting disease severity and mortality in patients with CAP. Methods: A total of 454 patients (76 with severe CAP (SCAP), 378 with non-SCAP) were enrolled from November 18, 2020, and November 21, 2021. Laboratory examination on day 1 after admission was measured. The ELR and EMR values were calculated for patients. Propensity score matching (PSM) was performed to balance potential confounding factors. Binary logistic regression model was fitted to identify the potential risk factors for disease severity and Cox proportional hazards regression model analysis for mortality in CAP. Receiver operating characteristic (ROC) analysis was performed to distinguish disease severity and mortality. Results: EMR and ELR at admission were significantly lower in SCAP patients than in non-SCAP patients (P<0.001). EMR < 0.018 ([OR] = 12.104, 95% CI: 4.970-29.479), neutrophil (NEU) ([OR]=1.098, 95% CI:1.005-1.199), and age ([OR]=1.091, 95% CI:1.054-1.130) were independent risk factors for disease severity of CAP. EMR < 0.032 ([HR] = 5.816, 95% CI: 1.704-9.848) was an independent predictor of in-hospital mortality. Combining EMR or ELR with CRB-65 improved the overall accuracy of disease severity prediction (AUC from 0.894 to 0.937), the same as CURB-65. The area under the curve of EMR (AUC=0.704; 95% CI: 0.582-0.827) to predict in-hospital mortality was higher than that of CURB-65 (AUC=0.619; 95% CI: 0.484-0.754). Otherwise, EMR combined with CRB-65 (AUC=0.721; 95% CI: 0.592-0.851) had significantly higher diagnostic accuracy for in-hospital mortality than that of CURB-65 alone. Conclusion: EMR combined with CRB-65 was superior to CURB-65 in predicting mortality in patients with CAP. This new combination was simpler and easier to obtain for physicians in clinics or admission, and it was more convenient for early recognition of patients with poor prognoses.
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Chronic Pseudomonas aeruginosa (PA) infection significantly contributes to morbidity and mortality in bronchiectasis patients. Initiating antibiotics early may lead to the eradication of PA. Here we outline the design of a trial (ERASE; NCT06093191) assessing the efficacy and safety of inhaled tobramycin, alone or with oral ciprofloxacin, in bronchiectasis patients with a new isolation of PA. This multicentre, 2×2 factorial randomised, double-blind, placebo-controlled, parallel-group trial includes a 2-week screening period, a 12-week treatment phase (with a combination of ciprofloxacin or a placebo at initial 2â weeks) and a 24-week follow-up. 364 adults with bronchiectasis and a new PA isolation will be randomly assigned to one of four groups: placebo (inhaled saline and ciprofloxacin placebo twice daily), ciprofloxacin alone (750â mg ciprofloxacin and inhaled saline twice daily), inhaled tobramycin alone (inhaled 300â mg tobramycin and ciprofloxacin placebo twice daily) or a combination of both drugs (inhaled 300â mg tobramycin and 750â mg ciprofloxacin twice daily). The primary objective of this study is to assess the proportion of patients successfully eradicating PA in each group by the end of the study. Efficacy will be evaluated based on the eradication rate of PA at other time points (12, 24 and 36â weeks), the occurrence of exacerbations and hospitalisations, time to first pulmonary exacerbations, patient-reported outcomes, symptom measures, pulmonary function tests and the cost of hospitalisations. To date no randomised trial has evaluated the benefit of different PA eradication strategies in bronchiectasis patients. The ERASE trial will therefore generate crucial data to inform future clinical guidelines.
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AcrAB-TolC is a multidrug RND-type efflux pump that is widespread in Gram-negative bacteria. As the substrate-binding subunit, AcrB was shown to modulate antimicrobial resistance in Escherichia coli, but the influence of AcrB mutation on Klebsiella pneumoniae, a major clinical pathogen, has not been well-studied. The finding of an R716L mutation in AcrB in a clinical tigecycline-nonsusceptible K. pneumoniae S1 strain inspired us to probe the role of AcrB residue 716 in antimicrobial resistance. This residue was subsequently subjected to saturation mutagenesis, followed by antibiotic susceptibility tests, survival assays, and antibiotic accumulation assays, showing strong influences of AcrB mutation on antimicrobial resistance. In particular, resistance levels to azithromycin, tetracycline, tigecycline, and cefoxitin were significantly changed by AcrB mutation at residue 716. Mutations to charged residues, polar residues, and residues that disrupt secondary structures have particularly reduced the antimicrobial susceptibility of bacteria, except for azithromycin, and the impact is not due to the abolishment of the efflux function of the pump. Therefore, it is concluded that residue 716 is an important residue that significantly influences antimicrobial resistance in K. pneumoniae, adding to our understanding of antimicrobial resistance mechanisms in this key clinical pathogen.
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Proteínas de Escherichia coli , Minociclina , Tigeciclina/farmacologia , Tigeciclina/metabolismo , Minociclina/farmacologia , Minociclina/metabolismo , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/metabolismo , Azitromicina , Aminoácidos , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Antibacterianos/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas de Escherichia coli/metabolismoAssuntos
Infecções Comunitárias Adquiridas , Pneumopatias , Pneumonia , Doença Pulmonar Obstrutiva Crônica , Humanos , Idoso , Pneumonia/tratamento farmacológico , Corticosteroides/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Administração por Inalação , Infecções Comunitárias Adquiridas/tratamento farmacológicoRESUMO
Purpose: The aim of this study was to investigate the level of serum tumor suppressor factor (Oncostatin-M, OSM) in patients with community-acquired pneumonia (CAP) and evaluate its predictive value for the severity and prognosis of pneumonia, so as to improve the ability to identify the risk of death in CAP patients. Patients and Methods: A total of 110 patients with CAP admitted to the hospital from November 2020 to November 2021 were enrolled in this prospective study. Clinical data of all patients were collected. According to the 2016 edition of "Guidelines for the Diagnosis and Treatment of Community-acquired Pneumonia in Chinese Adults", the patients were divided into non-severe CAP (NSCAP)(n=55) and severe CAP (SCAP)(n=55). At the same time, they were divided into a survival group (n=96) and a death group (n=14) by tracking the survival of patients in the hospital. The OSM concentration of CAP patients on the first day after admission was determined by enzyme-linked immunosorbent assay. All clinical data were statistically and graphed using SPSS V23.0 and Grahpad Prim 8. Results: Compared with NSCAP, patients with SCAP had higher serum OSM concentration on the day of admission, which was negatively correlated with LYM and positively correlated with WBC, NEU, CRP, IL-6, IL-8, IL-10, CURB-65 score, and PSI score. The level of OSM in the dead patient group was significantly higher than that in the surviving patient group. OSM and PSI scores were independent risk factors for in-hospital mortality in CAP patients. Kaplan-Meier survival curve showed that OSM≥76pg/mL was more advantageous in predicting mortality in patients with CAP. Conclusion: The level of the OSM is closely related to the severity and prognosis of CAP and may be a new biomarker for the prognosis of CAP patients.
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ABSTRACTPyrolysis is an effective way for the harmless treatment of oily sludge. The composition, physicochemical properties, and pyrolysis of oily sludge were experimentally studied in the present study. The Starink and Coats-Redfern methods were used to analyze the pyrolysis kinetics of oily sludge. Pyrolysis of oily sludge is divided into four stages: water evaporation stage, light component evaporation stage, heavy component pyrolysis stage, and final pyrolysis stage. The light component evaporation and heavy component pyrolysis stages are the main stages of medium-temperature pyrolysis. The pyrolysis characteristic parameters under heating rates of 10, 20, 30, and 40â K/min were obtained, and the effects of heating rates on the pyrolysis characteristics of oily sludge were discussed. The results show that with the increase in heating rate, the temperature range of each stage expands, and the temperature of the pyrolysis peaks also increases, with an average increase of 14.88%. The activation energies of the main pyrolysis stages obtained by the Starink method and Coats-Redfern method are consistent. In the light component evaporation stage, the activation energies obtained by the two methods are 61.93kJ/mol and 68.6kJ/mol, while the activation energies are 294.88kJ/mol and 367kJ/mol in the heavy component pyrolysis stage. The pyrolysis mechanism functions are obtained, and the pyrolysis kinetic equations under 10, 20, 30, and 40â K/min were constructed and validated by comparison with the results of the calculated properties and experimental measurement. This study can provide a better insight into the heat and mass transfer processes of oily sludge in pyrolysis reactors for further development and optimization.
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MicroRNAs (miRNAs) play a crucial role in maintaining the balance between the rapid growth and suppression of tumorigenesis during antler regeneration. This study investigated the role of a novel miRNA, PC-3p-2869 (miR-PC-2869), in antler growth and its therapeutic potential in human osteosarcoma and chondrosarcoma. Stem-loop RT-qPCR showed that miR-PC-2869 was expressed extensively in diverse layers of antler tissues. Overexpression of miR-PC-2869 suppressed the proliferation and migration of antler cartilage cells. Similarly, heterologous expression of miR-PC-2869 reduced the proliferation, colony formation, and migration of osteosarcoma cell line MG63 and U2OS and chondrosarcoma cell line SW1353. Moreover, 18 functional target genes of miR-PC-2869 in humans were identified based on the screening of the reporter library. Among them, 15 target genes, including CDK8, EEF1A1, and NTN1, possess conserved miR-PC-2869-binding sites between humans and red deer (Cervus elaphus). In line with this, miR-PC-2869 overexpression decreased the expression levels of CDK8, EEF1A1, and NTN1 in MG63, SW1353, and antler cartilage cells. As expected, the knockdown of CDK8, EEF1A1, or NTN1 inhibited the proliferation and migration of MG63, SW1353, and antler cartilage cells, demonstrating similar suppressive effects as miR-PC-2869 overexpression. Furthermore, we observed that CDK8, EEF1A1, and NTN1 mediated the regulation of c-myc and cyclin D1 by miR-PC-2869 in MG63, SW1353, and antler cartilage cells. Overall, our work uncovered the cellular functions and underlying molecular mechanism of antler-derived miR-PC-2869, highlighting its potential as a therapeutic candidate for bone cancer.
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Chifres de Veado , Neoplasias Ósseas , Condrossarcoma , Cervos , MicroRNAs , Osteossarcoma , Humanos , Animais , MicroRNAs/genética , MicroRNAs/metabolismo , Chifres de Veado/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Movimento Celular/genética , Cervos/genética , Osteossarcoma/genética , Osteossarcoma/metabolismo , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Condrossarcoma/genética , Regulação Neoplásica da Expressão Gênica , Fator 1 de Elongação de Peptídeos/genética , Quinase 8 Dependente de Ciclina/genéticaRESUMO
The capability of microRNAs (miRNAs) to regulate gene expression across species has opened new avenues for miRNA-based therapeutics. Here, we investigated the potential of PC-5p-1090 (miR-PC-1090), a miRNA found in deer antlers, to control the malignant phenotypes of hepatocellular carcinoma (HCC) cells. Using Cell Counting Kit-8 and transwell assays, we found that heterologous expression of miR-PC-1090 inhibited HCC cell proliferation, migration, and invasion. Bioinformatics analysis indicated that predicted miR-PC-1090 targets, including MARCKS, SMARCAD1, and SOX9, were significantly elevated in HCC tissues, and their high expressions were associated with poor overall survival of HCC patients. Moreover, mechanistic investigations revealed that miR-PC-1090 promoted the degradation of MARCKS and SMARCAD1 mRNAs and hindered the translation of SOX9 mRNA by recognizing their 3' untranslated regions. Subsequent loss-of-function and rescue experiments confirmed the involvement of MARCKS, SMARCAD1, and SOX9 in miR-PC-1090-suppressed HCC cell proliferation, migration, and invasion. Notably, MARCKS knockdown induced the downregulation of phosphorylated MARCKS and a corresponding upregulation of phosphorylated AKT in HCC. Conversely, miR-PC-1090 repressed MARCKS phosphorylation and effectively circumvented the activation of the PI3K/AKT pathway. Furthermore, miR-PC-1090 regulates the Wnt/ß-catenin pathway through SMARCAD1- and SOX9-mediated reduction of ß-catenin expression. Overall, our results illustrate the tumor-suppressive activity and molecular mechanism of antler-derived miR-PC-1090 in HCC cells, indicating its potential as a multiple-target agent for HCC treatment.
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Chifres de Veado , Carcinoma Hepatocelular , Cervos , Neoplasias Hepáticas , MicroRNAs , Animais , beta Catenina/genética , beta Catenina/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Cervos/genética , Cervos/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Humanos , Fatores de Transcrição SOX9RESUMO
This prospective, single-center study evaluated the clinical utility of annenxin (Anx)A1 level as a biomarker for determining the severity of illness and predicting the risk of death in hospitalized patients with community-acquired pneumonia (CAP). A total of 105 patients (53 with severe [S]CAP, 52 with non-SCAP) were enrolled from December 2020 to June 2021. Demographic and clinical data were recorded. Serum AnxA1 concentration on days one and six after admission was measured by enzyme-linked immunosorbent assay. AnxA1 level at admission was significantly higher in SCAP patients than in non-SCAP patients (p < 0.001) irrespective of CAP etiology and was positively correlated with Pneumonia Severity Index and Confusion, Uremia, Respiratory Rate, Blood Pressure, and Age ≥ 65 Years score. AnxA1 level was significantly lower on day six after treatment than on day one (p = 0.01). Disease severity was significantly higher in patents with AnxA1 level ≥254.13 ng/mL than in those with a level <254.13 ng/mL (p < 0.001). Kaplan-Meier analysis of 30-day mortality showed that AnxA1 level ≤670.84 ng/mL was associated with a significantly higher survival rate than a level >670.84 ng/mL. These results indicate that AnxA1 is a useful biomarker for early diagnosis and prognostic assessment of CAP.