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The timely degradation of proteins that regulate the cell cycle is essential for oocyte maturation. Oocytes are equipped to degrade proteins via the ubiquitin-proteasome system. In meiosis, anaphase promoting complex/cyclosome (APC/C), an E3 ubiquitin-ligase, is responsible for the degradation of proteins. Ubiquitin-conjugating enzyme E2 S (UBE2S), an E2 ubiquitin-conjugating enzyme, delivers ubiquitin to APC/C. APC/C has been extensively studied, but the functions of UBE2S in oocyte maturation and mouse fertility are not clear. In this study, we used Ube2s knockout mice to explore the role of UBE2S in mouse oocytes. Ube2s-deleted oocytes were characterized by meiosis I arrest with normal spindle assembly and spindle assembly checkpoint dynamics. However, the absence of UBE2S affected the activity of APC/C. Cyclin B1 and securin are two substrates of APC/C, and their levels were consistently high, resulting in the failure of homologous chromosome separation. Unexpectedly, the oocytes arrested in meiosis I could be fertilized and the embryos could become implanted normally, but died before embryonic day 10.5. In conclusion, our findings reveal an indispensable regulatory role of UBE2S in mouse oocyte meiosis and female fertility.
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Puntos de Control de la Fase M del Ciclo Celular , Meiosis , Animales , Femenino , Ratones , Ciclosoma-Complejo Promotor de la Anafase/genética , Ciclosoma-Complejo Promotor de la Anafase/metabolismo , Oocitos/metabolismo , Ubiquitinas/metabolismoRESUMEN
Excessive accumulation of reduced nicotinamide adenine dinucleotide (NADH) within biological organisms is closely associated with many diseases. It remains a challenge to efficiently convert superfluous and detrimental NADH to NAD+. NADH oxidase (NOX) is a crucial oxidoreductase that catalyzes the oxidation of NADH to NAD+. Herein, M1M2 (Mi=V/Mn/Fe/Co/Cu/Mo/Rh/Ru/Pd, i = 1 or 2) mated-atom nanozymes (MANs) are designed by mimicking natural enzymes with polymetallic active centers. Excitingly, RhCo MAN possesses excellent and sustainable NOX-like activity, with Km-NADH (16.11 µM) being lower than that of NOX-mimics reported so far. Thus, RhCo MAN can significantly promote the regeneration of NAD+ and regulate macrophage polarization toward the M2 phenotype through down-regulation of TLR4 expression, which may help to recover skin regeneration. However, RhRu MAN with peroxidase-like activity and RhMn MAN with superoxide dismutase-like activity exhibit little modulating effects on eczema. This work provides a new strategy to inhibit skin inflammation and promote skin regeneration.
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Mounting evidence has highlighted the multifunctional characteristics of glutamine metabolism (GM) in cancer initiation, progression and therapeutic regimens. However, the overall role of GM in the tumour microenvironment (TME), clinical stratification and therapeutic efficacy in patients with ovarian cancer (OC) has not been fully elucidated. Here, three distinct GM clusters were identified and exhibited different prognostic values, biological functions and immune infiltration in TME. Subsequently, glutamine metabolism prognostic index (GMPI) was constructed as a new scoring model to quantify the GM subtypes and was verified as an independent predictor of OC. Patients with low-GMPI exhibited favourable survival outcomes, lower enrichment of several oncogenic pathways, less immunosuppressive cell infiltration and better immunotherapy responses. Single-cell sequencing analysis revealed a unique evolutionary trajectory of OC cells from high-GMPI to low-GMPI, and OC cells with different GMPI might communicate with distinct cell populations through ligand-receptor interactions. Critically, the therapeutic efficacy of several drug candidates was validated based on patient-derived organoids (PDOs). The proposed GMPI could serve as a reliable signature for predicting patient prognosis and contribute to optimising therapeutic strategies for OC.
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Glutamina , Neoplasias Ováricas , Humanos , Femenino , Pronóstico , Microambiente Tumoral , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , CogniciónRESUMEN
BACKGROUND: Harmonia axyridis is an effective natural enemy insect to a variety of phloem-sucking pests and Lepidopteran larvae, such as aphids, scabies, and phylloxera, while its industrial production is limited due to unmature artificial diet. Insect intestinal microbiota affect host development and reproduction. The aim of this study is to understand intestinal microbiota composition of H. axyridis and screen effective probiotics on artificial diet. Considering the role of the components and composition of the diet on the structure and composition of the intestinal microbiome, four kinds of diets were set up: (1) aphid; (2) basic diet; (3) basic diet + glucose; (4) basic diet + trehalose. The gut microbiota of H. axyridis was detected after feeding on different diets. RESULTS: Results showed that the gut microbiota between artificial diet group and aphid groups were far apart, while the basic and glucose groups were clearly clustered. Besides, the glucose group and trehalose group had one unique phylum, Cryptophyta and Candidatus Saccharibacteria, respectively. The highest abundance of Proteobacteria was found in the aphid diet. The highest abundance of Firmicutes was found in the basic diet. However, the addition of glucose or trehalose alleviated the change. In addition, the relative abundance of Enterobacter, Klebsiella, Enterobacteriaceae_unclassified, Enterobacteriales_unclassified and Serratia in the aphid group was higher than other groups. Moreover, the function of gut genes in each group also showed clear differences. CONCLUSION: These results have offered a strong link between artificial diets and gut microbes, and also have provided a theoretical basis for the screening of synergistic probiotics in artificial diet.
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Áfidos , Escarabajos , Microbioma Gastrointestinal , Animales , Trehalosa , Insectos , Dieta , Enterobacter , GlucosaRESUMEN
Ultrasmall Au25(MPA)18 clusters show great potential in biocatalysts and bioimaging due to their well-defined, tunable structure and properties. Hence, in vivo pharmacokinetics and toxicity of Au nanoclusters (Au NCs) are very important for clinical translation, especially at high dosages. Herein, the in vivo hematological, tissue, and neurological effects following exposure to Au NCs (300 and 500 mg kg-1) were investigated, in which the concentration is 10 times higher than in therapeutic use. The biochemical and hematological parameters of the injected Au NCs were within normal limits, even at the ultrahigh level of 500 mg kg-1. Meanwhile, no histopathological changes were observed in the Au NC group, and immunofluorescence staining showed no obvious lesions in the major organs. Furthermore, real-time near-infrared-II (NIR-II) imaging showed that most of the Au25(MPA)18 and Au24Zn1(MPA)18 can be metabolized via the kidney. The results demonstrated that Au NCs exhibit good biosafety by evaluating the manifestation of toxic effects on major organs at ultrahigh doses, providing reliable data for their application in biomedicine.
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Oro , Nanopartículas del Metal , Oro/toxicidad , Oro/química , Nanopartículas del Metal/toxicidad , Nanopartículas del Metal/químicaRESUMEN
This study aimed to evaluate a novel albumin-binding strategy for addressing the challenge of insufficient tumor retention of fibroblast activation protein inhibitors (FAPIs). Maleimide, a molecule capable of covalent binding to free thiol groups, was modified to conjugate with FAPI-04 in order to enhance its binding to endogenous albumin, resulting in an extended blood circulation half-life and increased tumor uptake. DOTA-FAPI-maleimide was prepared and radiolabeled with Ga-68 and Lu-177, followed by cellular assays, pharmacokinetic analysis, PET/CT, and SPECT/CT imaging to assess the probe distribution in various tumor-bearing models. Radiolabeling of the modified probe was successfully achieved with a radiochemical yield of over 99% and remained stable for 144 h. Cellular assays showed that the ligand concentration required for 50% inhibition of the probe was 1.20 ± 0.31 nM, and the Kd was 0.70 ± 0.07 nM with a Bmax of 7.94 ± 0.16 fmol/cell, indicative of higher specificity and affinity of DOTA-FAPI-maleimide compared to other FAPI-04 variants. In addition, DOTA-FAPI-maleimide exhibited a persistent blood clearance half-life of 7.11 ± 0.34 h. PET/CT images showed a tumor uptake of 2.20 ± 0.44%ID/g at 0.5 h p.i., with a tumor/muscle ratio of 5.64 in HT-1080-FAP tumor-bearing models. SPECT/CT images demonstrated long-lasting tumor retention. At 24 h p.i., the tumor uptake of [177Lu]Lu-DOTA-FAPI-maleimide reached 5.04 ± 1.67%ID/g, with stable tumor retention of 3.40 ± 1.95%ID/g after 4 days p.i. In conclusion, we developed and evaluated the thiol group-attaching strategy, which significantly extended the circulation and tumor retention of the adapted FAPI tracer. We envision its potential application for clinical cancer theranostics.
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BACKGROUND: Invasive pulmonary aspergillosis (IPA) is a deep fungal infection caused by invasion of Aspergillus mycelium into the lung parenchyma resulting in tissue destruction and necrosis, which occurs more often in im-munosuppressed populations. The severity of the disease and the rapid progression of the lung lesions puts pa¬tients at high risk of death and poor prognosis if the correct therapeutic intervention is not given as early as possible. METHODS: Here we report a case of IPA, which was initially diagnosed as community-acquired pneumonia in a local hospital. The symptoms did not improve after receiving anti-infective treatment. The patient was diagnosed with IPA after completing a chest CT examination and an electronic bronchoscopy, as well as pathogenetic examination of the bronchoalveolar lavage fluid and pathological examination of the left bronchial mass in the respiratory department of our hospital, which was finally diagnosed as IPA. After one week of administration of voriconazole for anti-fungal infection treatment, the patient's symptoms improved significantly, and a repeat chest CT suggested that the lung lesions were better than before. In order to raise clinicians' awareness of this disease, we also conducted a literature analysis. RESULTS: The final diagnosis of IPA was made by analyzing the patient's history, symptoms, signs, and relevant findings. CONCLUSIONS: When the patient's clinical symptoms and imaging manifestations are consistent with IPA, electronic bronchoscopy and pathogenetic and pathological examinations may be appropriately performed to clarify the na-ture of the lesion. More consideration should be given to the possibility of disease diagnosis to avoid misdiagnosis and underdiagnosis. Appropriate treatment should be given at an early stage.
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Antifúngicos , Aspergilosis Pulmonar Invasiva , Tomografía Computarizada por Rayos X , Voriconazol , Humanos , Aspergilosis Pulmonar Invasiva/diagnóstico , Aspergilosis Pulmonar Invasiva/tratamiento farmacológico , Aspergilosis Pulmonar Invasiva/microbiología , Antifúngicos/uso terapéutico , Voriconazol/uso terapéutico , Broncoscopía , Masculino , Líquido del Lavado Bronquioalveolar/microbiología , Persona de Mediana Edad , Pulmón/diagnóstico por imagen , Pulmón/microbiología , Pulmón/patologíaRESUMEN
BACKGROUND: IgG4-related disease (IgG4-RD) is an immune-mediated systemic inflammatory fibrotic disease, which is a relatively rare and novel disease that can involve multiple organs or tissues, with variable clinical manifestations, and for which pulmonary involvement has been reported relatively infrequently. METHODS: Here we report a case of pulmonary infection that was initially suspected and received anti-inflammatory treatment, but the symptoms did not improve. CT examination indicated progression of the pulmonary lesion, and the nature of the lesion could not be determined by tracheoscopy and bronchoalveolar lavage. The diagnosis of IgG4 related lung disease (IgG4-RLD) was confirmed by percutaneous lung biopsy. A joint literature analysis was conducted to improve clinicians' understanding of this disease. RESULTS: The patient's history, symptoms, signs and relevant examination results were analyzed. The final diagnosis was IgG4-RLD. CONCLUSIONS: When the clinical symptoms and imaging manifestations of the patients are consistent with IgG4-RLD, pathological examination can be appropriately performed to clarify the nature of the lesions. More consideration should be given to the possibility of disease diagnosis to avoid misdiagnosis and underdiagnosis, and proper treatment should be given at an early stage.
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Enfermedad Relacionada con Inmunoglobulina G4 , Inmunoglobulina G , Enfermedades Pulmonares , Tomografía Computarizada por Rayos X , Humanos , Enfermedad Relacionada con Inmunoglobulina G4/diagnóstico , Enfermedad Relacionada con Inmunoglobulina G4/inmunología , Enfermedades Pulmonares/diagnóstico , Enfermedades Pulmonares/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Masculino , Pulmón/diagnóstico por imagen , Pulmón/patología , Pulmón/inmunología , Persona de Mediana Edad , BiopsiaRESUMEN
BACKGROUND: Coronavirus disease 2019 (COVID-19) is an acute respiratory infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). With the normalization of COVID-19 globally, it is crucial to construct a prediction model that enables clinicians to identify patients at risk for ProLOS based on demographics and serum inflammatory biomarkers. METHODS: The study included hospitalized patients with a confirmed diagnosis of COVID-19. These patients were randomly grouped into a training (80%) and a test (20%) cohort. The LASSO regression and ten-fold cross-validation method were applied to filter variables. The training cohort utilized multifactorial logistic regression analyses to identify the independent factors of ProLOS in COVID-19 patients. A 4-variable nomogram was created for clinical use. ROC curves were plotted, and the area under the curve (AUC) was calculated to evaluate the model's discrimination; calibration analysis was planned to assess the validity of the nomogram, and decision curve analysis (DCA) was used to evaluate the clinical usefulness of the model. RESULTS: The results showed that among 310 patients with COVID-19, 80 had extended hospitalization (80/310). Four independent risk factors for COVID-19 patients were identified: age, coexisting chronic respiratory diseases, white blood cell count (WBC), and serum albumin (ALB). A nomogram based on these variables was created. The AUC in the training cohort was 0.808 (95% CI: 0.75 - 0.8671), and the AUC in the test cohort was 0.815 (95% CI: 0.7031 - 0.9282). The model demonstrates good calibration and can be used with threshold probabilities ranging from 0% to 100% to obtain clinical net benefits. CONCLUSIONS: A predictive model has been created to accurately predict whether the hospitalization duration of COVID-19 patients will be prolonged. This model incorporates serum WBC, ALB levels, age, and the presence of chronic respiratory system diseases.
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COVID-19 , Tiempo de Internación , Nomogramas , Humanos , COVID-19/diagnóstico , COVID-19/sangre , COVID-19/epidemiología , COVID-19/complicaciones , Femenino , Masculino , Persona de Mediana Edad , Anciano , Tiempo de Internación/estadística & datos numéricos , Factores de Riesgo , SARS-CoV-2 , Adulto , Curva ROC , Hospitalización , Estudios RetrospectivosRESUMEN
BACKGROUND: Organizing pneumonia (OP) is a pathologic diagnosis with clinical and imaging manifestations that often resemble other diseases, such as infections and cancers, which can lead to delays in diagnosis and inappropriate management of the underlying disease. In this article, we present a case of organized pneumonia that resembles lung cancer. METHODS: We report a case of initial suspicion of pulmonary malignancy, treated with anti-inflammatory medication and then reviewed with CT suggesting no improvement, and finally confirmed to be OP by pathological biopsy taken via transbronchoscopy. A joint literature analysis was performed to raise clinicians' awareness of the diagnosis and treatment of OP. RESULTS: Initially, because of the atypical auxiliary findings, we thought that the disease turned out to be a lung tumor, which was eventually confirmed as OP by pathological diagnosis. CONCLUSIONS: The diagnosis and treatment of OP requires a combination of clinical information and radiological expertise, as well as biopsy to obtain histopathological evidence. That is, clinical-imaging-pathological tripartite cooperation and comprehensive analysis.
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Neoplasias Pulmonares , Tomografía Computarizada por Rayos X , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/diagnóstico por imagen , Diagnóstico Diferencial , Neumonía en Organización Criptogénica/diagnóstico , Neumonía en Organización Criptogénica/patología , Neumonía en Organización Criptogénica/diagnóstico por imagen , Biopsia , Masculino , Anciano , Persona de Mediana Edad , Pulmón/patología , Pulmón/diagnóstico por imagen , Broncoscopía , Neumonía OrganizadaRESUMEN
BACKGROUND: Carcinoembryonic antigen (CEA) is a polysaccharide complex that is found in the human respiratory system. It is of significant use in disease surveillance of lung cancer; however, serum CEA can occasionally only offer little assistance. We present a case of recurring infection initially diagnosed as carcinoembryonic antigen-negative in a patient with a history of hypersensitivity pneumonitis infection, which finally led to the diagnosis of lung adenocarcinoma following percutaneous lung puncture. METHODS: Appropriate laboratory tests, chest CT, bronchoscopy, percutaneous lung puncture, and pathologic examination were performed to explore the cause of the disease. RESULTS: Because CEA was negative and a chest CT showed interstitial changes in both lungs with numerous hyperdense shadows, coupled with the patient's history of hypersensitivity pneumonitis, we initially believed that the infection was relapsing. However, a percutaneous lung puncture eventually revealed that the patient had lung adenocarcinoma. CONCLUSIONS: Vigilance needs to be increased in clinical work for patients with interstitial lung disease, low tumor markers such as CEA, and imaging suggestive of inflammatory progression, which in fact turns into lung cancer. When the treatment is ineffective after standardized application of hormone and anti-infection, lung tissue should be obtained for pathological examination in time to obtain pathological evidence.
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Adenocarcinoma del Pulmón , Adenocarcinoma , Alveolitis Alérgica Extrínseca , Neoplasias Pulmonares , Humanos , Antígeno Carcinoembrionario , Recurrencia Local de Neoplasia , Adenocarcinoma del Pulmón/diagnóstico , Neoplasias Pulmonares/patología , Biomarcadores de Tumor , BiopsiaRESUMEN
BACKGROUND: Patients with tuberculous empyema (TE) can have a serious impact on lung function as their disease progresses, and, if left untreated, can cause damage to other parts of the body such as the thorax and spine, causing pain and inconvenience to the patient. Early diagnosis and the search for appropriate treatment are key to improving the survival rate of the disease. METHODS: We report a case of a young patient with an unexpected finding of right pleural effusion on physical examination, who was eventually diagnosed with TE using next-generation sequencing of pleural tissue. We analyzed the literature to improve clinicians' understanding of TE and how to properly diagnose and treat the disease. RESULTS: Laboratory results of the pleural effusion suggested a possible Mycobacterium tuberculosis infection, but pathogen-related tests were negative, and the diagnosis was eventually successfully confirmed by thoracoscopic pleural biopsy. CONCLUSIONS: The diagnosis of TE should be considered in young patients with pleural thickening of the empyema. Adenosine deaminase may provide diagnostic direction in patients with unexplained thorax abscess. Pleural biopsy, although an invasive procedure, is an essential diagnostic tool in some cases.
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Empiema Tuberculoso , Derrame Pleural , Tuberculosis Pleural , Humanos , Empiema Tuberculoso/diagnóstico , Empiema Tuberculoso/complicaciones , Tuberculosis Pleural/diagnóstico , Tuberculosis Pleural/patología , Derrame Pleural/etiología , Pleura/patología , Biopsia , Adenosina DesaminasaRESUMEN
BACKGROUND: Pulmonary tuberculosis (PTB) is an important infectious disease that threatens the health and life of human beings. In the diagnosis of PTB, imaging plays a dominant role, but due to the increasing drug resistance of Mycobacterium tuberculosis, atypical clinical manifestations, "different images with the same disease" or "different diseases with the same image" in chest imaging, and the low positivity rate of routine sputum bacteriology, which leads to a high rate of misdiagnosis of PTB. We report a case of pulmonary tuberculosis that was misdiagnosed on imaging. We report a case of pulmonary tuberculosis that resembled sarcoidosis on imaging and was negative for antacid staining on sputum smear and alveolar lavage fluid, and was later diagnosed by microbial next-generation sequencing (NGS). The case was initially misdiagnosed as sarcoidosis. METHODS: Alveolar lavage fluid NGS, chest CT, bronchoscopy. RESULTS: Chest CT showed multiple inflammatory lesions in both lungs, multiple nodular foci in both lungs, and multiple enlarged lymph nodes in the mediastinum and hilar region on both sides. Fiberoptic bronchoscopy was performed in the basal segment of the left lower lobe of the lungs to carry out bronchoalveolar lavage, and the lavage fluid was sent to the NGS test and returned the following results: Mycobacterium tuberculosis complex group detected in the number of sequences of 293. Based on the results of the NGS test, the diagnosis of pulmonary tuberculosis could be confirmed. CONCLUSIONS: The diagnosis of pulmonary tuberculosis cannot be easily excluded in patients with "different images with the same disease" or "different diseases with the same image" on chest imaging without the support of sputum positivity. The goal was to improve the alertness of medical personnel to the misdiagnosis of tuberculosis and the application of NGS technology.
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Mycobacterium tuberculosis , Sarcoidosis , Tuberculosis Pulmonar , Humanos , Tuberculosis Pulmonar/diagnóstico , Tuberculosis Pulmonar/microbiología , Mycobacterium tuberculosis/genética , Líquido del Lavado Bronquioalveolar/microbiología , Sarcoidosis/diagnóstico , Esputo/microbiología , Errores Diagnósticos , Secuenciación de Nucleótidos de Alto Rendimiento , Sensibilidad y EspecificidadRESUMEN
Cancer stem cells (CSCs) represent both a key driving force and therapeutic target of tumoral carcinogenesis, tumor evolution, progression, and recurrence. CSC-guided tumor diagnosis, treatment, and surveillance are strategically significant in improving cancer patients' overall survival. Due to the heterogeneity and plasticity of CSCs, high sensitivity, specificity, and outstanding targeting are demanded for CSC detection and targeting. Nanobiotechnologies, including biosensors, nano-probes, contrast enhancers, and drug delivery systems, share identical features required. Implementing these techniques may facilitate the overall performance of CSC detection and targeting. In this review, we focus on some of the most recent advances in how nanobiotechnologies leverage the characteristics of CSC to optimize cancer diagnosis and treatment in liquid biopsy, clinical imaging, and CSC-guided nano-treatment. Specifically, how nanobiotechnologies leverage the attributes of CSC to maximize the detection of circulating tumor DNA, circulating tumor cells, and exosomes, to improve positron emission computed tomography and magnetic resonance imaging, and to enhance the therapeutic effects of cytotoxic therapy, photodynamic therapy, immunotherapy therapy, and radioimmunotherapy are reviewed.
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Inmunoterapia , Células Neoplásicas Circulantes , Humanos , Biopsia Líquida , Tomografía de Emisión de Positrones , Células Madre NeoplásicasRESUMEN
PURPOSE: Lymph node status is a determinant of survival in patients with early-stage cervical cancer. However, the relationship between obesity and lymph node status remains unclear. Therefore, this systematic review aims to evaluate the correlation between body mass index (BMI) and lymph node metastasis in cervical cancer. METHODS: Cohort studies through six databases were reviewed until December 2021. Odds ratios (ORs) for lymphatic metastasis were estimated using random-effects models and network meta-analysis. BMI groups for lymph node metastasis were ranked. Heterogeneities were assessed using I2. Subgroup analyses were performed to determine possible sources of heterogeneity. RESULTS: No significant difference was found between obese (BMI ≥ 25) and non-obese patients (BMI < 25) (OR = 1.01; 95% CI 0.69-1.47; P = 0.97). In subgroup analyses, obesity was associated with higher risk among the Americans and advanced-stage patients. The grouping analysis based on BMI and the rankogram values revealed that the '35 ≤ BMI' group had the highest risk of lymph node metastasis. CONCLUSION: Although there were no significant differences in lymph node metastasis between obese and non-obese cervical cancer patients in overall analysis, patients with BMI ≥ 35 were at significantly higher risk of lymph node metastasis.
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BACKGROUND: RNA splicing plays significant roles in fundamental biological activities. However, our knowledge about the roles of alternative splicing and underlying mechanisms during spermatogenesis is limited. RESULTS: Here, we report that Serine/arginine-rich splicing factor 2 (SRSF2), also known as SC35, plays critical roles in alternative splicing and male reproduction. Male germ cell-specific deletion of Srsf2 by Stra8-Cre caused complete infertility and defective spermatogenesis. Further analyses revealed that deletion of Srsf2 disrupted differentiation and meiosis initiation of spermatogonia. Mechanistically, by combining RNA-seq data with LACE-seq data, we showed that SRSF2 regulatory networks play critical roles in several major events including reproductive development, spermatogenesis, meiotic cell cycle, synapse organization, DNA recombination, chromosome segregation, and male sex differentiation. Furthermore, SRSF2 affected expression and alternative splicing of Stra8, Stag3 and Atr encoding critical factors for spermatogenesis in a direct manner. CONCLUSIONS: Taken together, our results demonstrate that SRSF2 has important functions in spermatogenesis and male fertility by regulating alternative splicing.
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Empalme del ARN , Espermatogénesis , Masculino , Humanos , Espermatogénesis/genética , Proteínas de Unión al ARN/genética , Empalme Alternativo , Meiosis/genética , ARN MensajeroRESUMEN
Cisplatin nephrotoxicity is an etiological factor for acute kidney injury (AKI). MicroRNA (miRNA) expression is dysregulated in cisplatin-induced AKI (cAKI) although the underlying mechanisms are unclear. A cAKI model was established by intraperitoneally injecting cisplatin, and key miRNAs were screened using high-throughput miRNA sequencing. The functions of key miRNAs were determined using the cell viability, live/dead, reactive oxygen species (ROS), and 5-ethynyl-2'-deoxyuridine (EdU) proliferation assays. Additionally, the macrophage membrane was wrapped around a metal-organic framework (MOF) loaded with miRNA agomir to develop a novel composite material, macrophage/MOF/miRNA agomir nanoparticles (MMA NPs). High-throughput miRNA sequencing revealed that miR-30e-5p is a key miRNA that is downregulated in cAKI. The results of in vitro experiments demonstrated that miR-30e-5p overexpression partially suppressed the cisplatin-induced or lipopolysaccharide (LPS)-induced downregulation of cell viability, proliferation, upregulation of ROS production, and cell death. Meanwhile, the results of in vivo and in vitro experiments demonstrated that MMA NPs alleviated cAKI by exerting anti-inflammatory effects. Mechanistically, cisplatin downregulates the expression of miR-30e-5p, and the downregulated miR-30e-5p can target Galnt3 to activate the adenosine 5'-monophosphate activated protein kinase (AMPK) signaling pathway, which promotes the progression of AKI. Our study found that miR-30e-5p is a key downregulated miRNA in cAKI. The downregulated miR-30e-5p promotes AKI progression by targeting Galnt3 to activate the AMPK signaling pathway. The newly developed MMA NPs were found to have protective effects on cAKI, suggesting a potential novel strategy for preventing cAKI.
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Lesión Renal Aguda , MicroARNs , Humanos , Cisplatino/farmacología , Proteínas Quinasas Activadas por AMP/metabolismo , Especies Reactivas de Oxígeno , MicroARNs/genética , Transducción de Señal , Lesión Renal Aguda/genética , Apoptosis/genéticaRESUMEN
Selenium (Se) and tellurium (Te) nanomaterials with novel chain-like structures have attracted widespread interest owing to their intriguing properties. Unfortunately, the still-unclear catalytic mechanisms have severely limited the development of biocatalytic performance. In this work, we developed chitosan-coated Se nanozymes with a 23-fold higher antioxidative activity than Trolox and bovine serum albumin coated Te nanozymes with stronger prooxidative biocatalytic effects. Based on density functional theory calculations, we first propose that the Se nanozyme with Se/Se2- active centers favored reactive oxygen species (ROS) clearance via a LUMO-mediated mechanism, while the Te nanozyme with Te/Te4+ active centers promoted ROS production through a HOMO-mediated mechanism. Furthermore, biological experiments confirmed that the survival rate of γ-irritated mice treated with the Se nanozyme was maintained at 100% for 30 days by inhibiting oxidation. However, the Te nanozyme had the opposite biological effect via promoting radiation oxidation. The present work provides a new strategy for improving the catalytic activities of Se and Te nanozymes.
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Biocatálisis , Telurio/química , Selenio/química , Especies Reactivas de Oxígeno/química , Nanopartículas/química , Antioxidantes/química , Animales , Ratones , Oxidación-ReducciónRESUMEN
Clinical observation indicates that exercise capacity, an important determinant of survival in patients with congenital heart disease (CHD), is most decreased in children with reduced pulmonary blood flow (RPF). However, the underlying mechanism remains unclear. Here, we obtained human RPF lung samples from children with tetralogy of Fallot as well as piglet and rat RPF lung samples from animals with pulmonary artery banding surgery. We observed impaired alveolarization and vascularization, the main characteristics of pulmonary dysplasia, in the lungs of RPF infants, piglets, and rats. RPF caused smaller lungs, cyanosis, and body weight loss in neonatal rats and reduced the number of alveolar type 2 cells. RNA sequencing demonstrated that RPF induced the downregulation of metabolism and migration, a key biological process of late alveolar development, and the upregulation of immune response, which was confirmed by flow cytometry and cytokine detection. In addition, the immunosuppressant cyclosporine A rescued pulmonary dysplasia and increased the expression of the Wnt signaling pathway, which is the driver of postnatal lung development. We concluded that RPF results in pulmonary dysplasia, which may account for the reduced exercise capacity of patients with CHD with RPF. The underlying mechanism is associated with immune response activation, and immunosuppressants have a therapeutic effect in CHD-associated pulmonary dysplasia.
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Cardiopatías Congénitas , Alveolos Pulmonares , Lactante , Niño , Animales , Humanos , Ratas , Porcinos , Alveolos Pulmonares/metabolismo , Pulmón/metabolismo , Cardiopatías Congénitas/complicaciones , Cardiopatías Congénitas/metabolismo , Cardiopatías Congénitas/patología , Circulación Pulmonar , Hiperplasia/metabolismo , Hiperplasia/patología , Animales Recién NacidosRESUMEN
Better biomarkers are needed to improve the efficacy of immune checkpoint inhibitors in lung adenocarcinoma (LUAD) treatment. We investigated the plasma extracellular vesicle (EV)-derived long RNAs (exLRs) in unresectable/advanced LUAD to explore biomarkers for immunochemotherapy. Seventy-four LUAD patients without targetable mutations receiving first-line anti-programmed cell death 1 (PD-1) immunochemotherapy were enrolled. Their exLRs were profiled through plasma EV transcriptome sequencing. Biomarkers were analyzed against response rate and survival using pre- and post-treatment samples in the retrospective cohort (n = 36) and prospective cohort (n = 38). The results showed that LUAD patients demonstrated a distinct exLR profile from the healthy individuals (n = 56), and T-cell activation-related pathways were enriched in responders. Among T-cell activation exLRs, CD160 exhibited a strong correlation with survival. In the retrospective cohort, the high baseline EV-derived CD160 level correlated with prolonged progression-free survival (PFS) (P < 0.001) and overall survival (OS) (P = 0.005), with an area under the curve (AUC) of 0.784 for differentiating responders from non-responders. In the prospective cohort, the CD160-high patients also showed prolonged PFS (P = 0.003) and OS (P = 0.014) and a promising AUC of 0.648. The predictive value of CD160 expression was validated by real-time quantitative PCR. We also identified the dynamics of EV-derived CD160 for monitoring therapeutic response. The elevated baseline CD160 reflected a higher abundance of circulating NK cells and CD8+ -naïve T cells, suggesting more active host immunity. In addition, increased CD160 levels of tumors also correlated with a favorable prognosis in LUAD patients. Together, plasma EV transcriptome analysis revealed the role of the baseline CD160 level and early post-treatment CD160 dynamics for predicting the response to anti-PD-1 immunochemotherapy in LUAD patients.