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Ischemic stroke is characterized by high morbidity and mortality and a lack of effective therapeutic interventions. Leptin plays an important role in regulating oxidative stress, angiogenesis, hematopoiesis, etc. Although recent studies have found a neuroprotective effect of leptin, little is known about its role in cerebral ischemia. This study explores the possible roles and potential preventative mechanisms of leptin in cerebral ischemia-reperfusion injury (CIRI). An in vivo middle cerebral artery occlusion/reperfusion (MCAO/R) mouse model was used to replicate the CIRI model, low (0.5 mg/kg), medium (1 mg/kg) and high (2 mg/kg) concentrations of leptin were injected intraperitoneally immediately after inserting the embolic line. After 1.5 h of ischemia and 24 h of reperfusion, we examined the neural function of the mice, collected brain tissue for histological examination, and screened for the optimal concentrations of leptin intervention. On this basis, we observed the changes of cortical apoptosis injury, intracellular calcium fluorescence intensity and astrocyte glial fibrillary acidic protein (GFAP) expression and morphological changes. In addition, we also tested the expression of transporters and metabolism-related enzymes (VGLUT-1, VGLUT-2, GLAST, GLT-1, GS, ATP1α1), the expression of inflammatory factors and the content of glutamate (Glu). Compared with the I/R group, we found that leptin improved neurological deficits, reduced the area of infarcts, maintained the normal morphology of astrocytes (AST), downregulated the expression of VGLUT-1, and upregulates the expression of GLT-1 and GLAST, thereby reducing the content of Glu in the synaptic cleft. Our studies suggest that leptin may have a neuroprotective effect by decreasing the excitotoxicity of glutamate.
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The number of applications for National Virtual Simulation Experimental Teaching Projects (NVSETPs) in China has seen a significant increase. Consequently, the influence of contextual factors and their potential personal connections on the evaluation results, whether for national or non-national NVSETPs, has become a prominent concern. In this study, we employed a modified back-chaining method using logistic regression to examine whether contextual factors in NVSETP applications could explain the evaluation outcomes. Our analysis was based on data available on the open platform of China's Ministry of Education (MOE). We identified several significant influencing factors, including the score on a five-point rating system, the number of clicks on the application page, school quality, school region, and the gender, title, and position of the applicants. Our results shed light on the impact of contextual factors on the evaluation results of NVSETPs in the fields of biology and medicine, using a modified back-chaining method. We conclude that enhancing the transparency of the assessment process and implementing standardized, detailed scoring guidelines for NVSETPs would mitigate the negative influence of contextual factors.
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Biología , Evaluación de Programas y Proyectos de Salud , Humanos , China , Evaluación de Programas y Proyectos de Salud/métodos , Biología/educación , Entrenamiento Simulado/organización & administración , Entrenamiento Simulado/métodos , Masculino , Educación Médica/organización & administración , Educación Médica/métodos , FemeninoRESUMEN
The majority of advanced breast cancers exhibit strong aggressiveness, heterogeneity, and drug resistance, and currently, the lack of effective treatment strategies is one of the main challenges that cancer research must face. Therefore, developing a feasible preclinical model to explore tailored treatments for refractory breast cancer is urgently needed. We established organoid biobanks from 17 patients with breast cancer and characterized them by immunohistochemistry (IHC) and next generation sequencing (NGS). In addition, we in the first combination of patient-derived organoids (PDOs) with mini-patient-derived xenografts (Mini-PDXs) for the rapid and precise screening of drug sensitivity. We confirmed that breast cancer organoids are a high-fidelity three-dimension (3D) model in vitro that recapitulates the original tumour's histological and genetic features. In addition, for a heavily pretreated patient with advanced drug-resistant breast cancer, we combined PDO and Mini-PDX models to identify potentially effective combinations of therapeutic agents for this patient who were alpelisib + fulvestrant. In the drug sensitivity experiment of organoids, we observed changes in the PI3K/AKT/mTOR signalling axis and oestrogen receptor (ER) protein expression levels, which further verified the reliability of the screening results. Our study demonstrates that the PDO combined with mini-PDX model offers a rapid and precise drug screening platform that holds promise for personalized medicine, improving patient outcomes and addressing the urgent need for effective therapies in advanced breast cancer.
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Neoplasias de la Mama , Organoides , Medicina de Precisión , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Femenino , Organoides/efectos de los fármacos , Organoides/patología , Organoides/metabolismo , Medicina de Precisión/métodos , Animales , Ensayos Antitumor por Modelo de Xenoinjerto , Ratones , Resistencia a Antineoplásicos/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales/métodos , Persona de Mediana EdadRESUMEN
Background: Urticaria places a significant burden on individuals and society due to its widespread nature. The aim of this study was to evaluate the burden of urticaria in different regions and nations by analysing data from the Global Burden of Disease study 2019 (GBD 2019), with the goal of providing information to health care policymakers. Methods: By utilising data from the GBD 2019 database, this study analysed metrics such as incidence, prevalence, disability-adjusted life years (DALYs), age-standardised rate (ASR), and estimated annual percentage changes (EAPC) globally and across 204 countries and regions. The data was further stratified by age, sex, and sociodemographic index (SDI). Results: In 2019, global incidence cases, prevalence cases, and overall disease burden as measured by DALYs all increased. The distribution of the burden exhibited marked geographical heterogeneity. At the regional level, the burden is highest in Central and Eastern Europe and Central Asia, with the strongest growth in South Asia, compared with a decline in the high-income Asia Pacific. At the country level, Nepal reports the highest burden of urticaria, while Portugal has the lowest. Gender and age analyses showed that the burden of urticaria is higher in females than in males, with urticaria cases declining with age, especially in children, and picking up among the elderly. The study also finds a correlation between the burden of urticaria and the SDI, with the central part of the SDI showing a consistent increasing trend. Conclusion: This study found that the global burden of urticaria has risen from 1990 to 2019. Factors like geographic location, gender, and SDI influenced the urticaria burden. Overall, these results offer a resource to guide public health strategies seeking to reduce the burden of urticaria.
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Costo de Enfermedad , Carga Global de Enfermedades , Salud Global , Urticaria , Humanos , Carga Global de Enfermedades/tendencias , Masculino , Femenino , Salud Global/estadística & datos numéricos , Urticaria/epidemiología , Adulto , Niño , Adulto Joven , Adolescente , Persona de Mediana Edad , Preescolar , Anciano , Incidencia , Lactante , Años de Vida Ajustados por Discapacidad/tendencias , Prevalencia , Recién NacidoRESUMEN
The interaction between tumor fatty acid metabolism and immune microenvironment is a novel topic in oncology research, and the relationship of lipid-derived factors with immune editing in tumor is unclear. The breast cancer samples from the TCGA database were used as the training set, and samples from GSE42568 were employed as the validation set for constructing a model to identify a signature associated with fatty acid metabolism through Lasso Cox regression. And the changes in immune related signatures and risk score before and after anti-PD-1 monotherapy were caught by the differential analysis in GSE225078. A 14-gene prognostic risk scoring model identifying by fatty acid metabolism relevant signature was conducted, and the high risk group had shorter overall survival and progression free survival than low risk group. Many metabolism-related pathways were enriched in the high risk group, and many immune-related pathways were enriched in low risk group. The crucial differentially expressed genes between the high/low risk groups, CYP4F8 and CD52, were found to be strongly associated with SUCLA2 and ACOT4 of 14-gene model, and strongly related to immune infiltration. Immune related signatures, fatty acid metabolism-risk score and the expression level of ALDH1A1 (in 14-gene-model) changed after anti-PD-1 monotherapy. And the mice model results also showed anti-PD-1 mAb could significantly reduce the expression level of ALDH1A1 (p < 0.01). These results brought up the crosstalk between immune components and fatty acid metabolism in breast cancer microenvironment, which provided a new possibility of targeting fatty acid metabolism for combination therapy in breast cancer immunotherapy.
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BACKGROUND: Six transmembrane epithelial antigen 1 (STEAP1) is aberrantly expressed in cancers and could therefore be a potential biomarker. This study examined the connection between STEAP1 expression and clinical features/prognosis in cancer patients. METHODS: Several databases were comprehensively searched for related published studies. The combination of hazard ratios (HRs), odd ratios (ORs), and 95% confidence intervals (95% CIs) was used to assess the role of STEAP1. The Cancer Genome Atlas (TCGA) dataset was used to estimate the prognostic value of STEAP1 in multiple cancer types, and several biological behaviors related to STEAP1 were evaluated by CancerSEA. RESULTS: Searches of electronic databases revealed 7 relevant trials with 765 patients. A significant connection was found between high STEAP1 expression and worse overall survival amongst cancer patients (HR = 1.87, 95% CI: 1.49-2.34, p < 0.001). In addition, a strong correlation was found between high STEAP1 expression and the occurrence of lymph node metastases (OR = 3.19, 95% CI: 1.26-8.09, p < 0.001). Analysis of TCGA datasets verified that a higher level of STEAP1 expression is linked with reduced survival in many kinds of cancer. At the single cell level, STEAP1 expression was correlated with some tumor biological behaviors, such as angiogenesis, quiescence, and stemness. CONCLUSIONS: STEAP1 could regulate various biological functions in tumors and predict prognosis as a novel biomarker in a number of cancer types.
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Carcinoma , Neoplasias , Humanos , Antígenos de Neoplasias/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinoma/diagnóstico , Carcinoma/genética , Neoplasias/diagnóstico , Neoplasias/genética , Oxidorreductasas/metabolismo , PronósticoRESUMEN
Background: The respiratory system is intensely damaged by acute lung injury (ALI). The anti-inflammatory effects of tetramethylpyrazine (TMP) against ALI have been confirmed, but it exhibits a short half-life. miR-194-5p could directly target Rac1, but the internalization rate of miRNA cells was low. Purpose: To explore the potential of the soft mesoporous organic silica nanoplatform (NPs) as carriers for delivery of TMP and miR-194-5p through the tail vein. Methods: NPs@TMP and NPs@PEI@miR-194-5p were added to the HUVEC cell-lines, in vitro, to observe the cell uptake and cytotoxic effects. In vivo experiments were conducted by injecting fluorescently labeled NPs through the tail vein and tracking distribution. Therapeutic and toxic side-effects were analyzed systemically. Results: In vitro study exhibited that NPs have no toxic effect on HUVECs within the experimental parameters and have excellent cellular uptake. The IVIS Spectrum Imaging System shows that NPs accumulate mainly in the lungs. NPs@TMP treatment can improved oxidative stress and inflammation levels in ALI mice and inhibited the TLR4/NLRP3/caspase 1 pathway. NPs@PEI@miR-194-5p can inhibit the Rac1/ZO-1/occludin pathway and improved endothelial cell permeability in ALI mice. The co-treatment of NPs@TMP and NPs@PEI@miR-194-5p can significantly improved the survival rates of the mice, reduced pulmonary capillary permeability and improved pathological injury in ALI mice. Innovation: This study combined traditional Chinese medicine, bioinformatics, cellular molecular biology and nanobiomedicine to study the pathogenesis and treatment of ALI. The rate of cellular internalization was improved by changing the shape and hardness of nanoparticles. NPs@TMP and NPs@PEI@miR-194-5p combined application can significantly improve the survival condition and pathological injury of mice. Conclusion: NPs loaded with TMP and miR-194-5p showed a greater therapeutic effect in ALI mice.
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Lesión Pulmonar Aguda , MicroARNs , Compuestos de Organosilicio , Pirazinas , Animales , Humanos , Ratones , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/tratamiento farmacológico , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Lipopolisacáridos , Pulmón/patología , MicroARNs/farmacología , Compuestos de Organosilicio/farmacología , Pirazinas/farmacologíaRESUMEN
Residual antibiotics in nature are an important cause of antimicrobial drug resistance, and how to deal with residual ß-lactam antibiotics in aqueous environments has become an urgent issue. In this work, magnetic zeolitic imidazolate frameworks-8 (ZIF-8) for immobilizing metallo-ß-lactamases (MBLs), or Fe3O4@ZIF-8@MBLs, were successfully synthesized using the one-pot method in aqueous solution. The morphology and chemical structure of Fe3O4@ZIF-8@MBLs were characterized by scanning electron microscopy, energy dispersive spectra, X-ray diffraction, infrared spectra, physical adsorption, and zeta potential. Further, the degradation performance of Fe3O4@ZIF-8@MBLs for ß-lactam antibiotics (penicillin G, cefoperazone, meropenem) in an aqueous environment was investigated by UV-visible absorption spectrophotometry. The results indicated that Fe3O4@ZIF-8@MBLs, compared to control ZIF-8, exhibited superior degradation ability, excellent reusability, and better stability under several harsh conditions. The strategy of combining ZIF-8 and MBLs to form magnetic porous polymers may be suitable for removing ß-lactam antibiotics from an aqueous environment. This work provided an original insight into future studies on the degradation of ß-lactam antibiotics employing MBLs immobilized by magnetic metal-organic frameworks.
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Glioblastoma (GBM) is a highly malignant brain cancer with a poor prognosis despite standard treatments. This investigation aimed to explore the feasibility of PTPN6 to combat GBM with immunotherapy. Our study employed a comprehensive analysis of publicly available datasets and functional experiments to assess PTPN6 gene expression, prognostic value, and related immune characteristics in glioma. We evaluated the influence of PTPN6 expression on CD8+ T cell exhaustion, immune suppression, and tumor growth in human GBM samples and mouse models. Our findings demonstrated that PTPN6 overexpression played an oncogenic role in GBM and was associated with advanced tumor grades and unfavorable clinical outcomes. In human GBM samples, PTPN6 upregulation showed a strong association with immunosuppressive formation and CD8+ T cell dysfunction, whereas, in mice, it hindered CD8+ T cell infiltration. Moreover, PTPN6 facilitated cell cycle progression, inhibited apoptosis, and promoted glioma cell proliferation, tumor growth, and colony formation in mice. The outcomes of our study indicate that PTPN6 is a promising immunotherapeutic target for the treatment of GBM. Inhibition of PTPN6 could enhance CD8+ T cell infiltration and improve antitumor immune response, thus leading to better clinical outcomes for GBM patients.
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Neoplasias Encefálicas , Glioblastoma , Glioma , Humanos , Animales , Ratones , Glioblastoma/patología , Glioma/genética , Neoplasias Encefálicas/patología , Pronóstico , Proliferación Celular/genética , Línea Celular Tumoral , Proteína Tirosina Fosfatasa no Receptora Tipo 6RESUMEN
Background and Objective: Previous studies have demonstrated that cyclin-dependent kinase 4/6 (CDK4/6) inhibitors combined with endocrine therapy are able to effectively improve the prognosis of hormone receptor positive (HR+), human epidermal growth factor receptor 2 (HER2) negative advanced breast cancer (ABC). Five CDK4/6 inhibitors, palbociclib, ribociclib, abemaciclib, dalpiciclib, and trilaciclib have been approved for the treatment of this breast cancer subset at present. The efficacy and safety profile of adding these CDK4/6 inhibitors to endocrine therapies in HR+ breast cancer has been proved in a number of clinical trials. Besides, extending the application of CDK4/6 inhibitors to HER2+ or triple negative breast cancers (TNBCs) has also led to some clinical benefits. Methods: A comprehensive, non-systematic review of the latest literature about CDK4/6 inhibitors resistance in breast cancer was conducted. The examined database was PubMed/MEDLINE, and the last search was run on October 1, 2022. Key Content and Findings: In this review, the generation of CDK4/6 inhibitors resistance is related to gene alteration, pathway dysregulation, and tumor microenvironment change. With a deeper insight in the mechanisms of CDK4/6 inhibitor resistance, some biomarkers have presented the potential to predict drug resistance and showed prognostic value. Furthermore, in preclinical studies, some modified treatment strategies based on CDK4/6 inhibitors exhibited effectiveness on drug-resistant tumors, suggesting a preventable or reversible drug-resistant status. Conclusions: This review clarified the current knowledge about mechanisms, the biomarkers to overcome the drug resistance of CDK4/6 inhibitors, and the latest clinical progresses about CDK4/6 inhibitors. Possible approaches to overcome CDK4/6 inhibitors resistance were further discussed. For example, using another CDK4/6 inhibitor, PI3K inhibitor, mTOR inhibitor, or a novel drug.
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[This corrects the article DOI: 10.3389/fimmu.2022.805184.].
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TP53 is the most frequently mutated gene in lung adenocarcinoma (LUAD). The tumor immune microenvironment (TIM) is considered a vital factor that influences tumor progression and survival rate. The influence of TP53 mutation on TIM in LUAD has not been fully studied. Here we systematically investigated the relationship and potential mechanisms between TP53 mutation status and immune response in LUAD. We constructed an immune prognostic model (IPM) using immune associated genes, which were expressed differentially between the TP53 mutant and wild type LUAD patients. We discovered that TP53 mutations were significantly associated with 5 immune related biological processes. Thirty-six immune genes were expressed differentially between TP53 mutant and wild type LUAD patients. An IPM was constructed using 3 immune genes to differentiate the prognostic survival in LUAD. The high-risk LUAD group displayed significantly higher proportions of dendritic cell resting, T cell CD4 memory resting and mast cell resting, and significantly low proportions of dendritic cell activated, T cell CD4 memory activated, and mast cell activated. Moreover, IPM was found to be an independent clinical feature and can be used to predict immunotherapy responses. In summary, we constructed and validated an IPM using 3 immune related genes, which provides a better understanding of the mechanism from an immunological perspectives.
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Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Adenocarcinoma del Pulmón/patología , Humanos , Neoplasias Pulmonares/patología , Mutación , Pronóstico , Tasa de Supervivencia , Microambiente Tumoral/genética , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Breast cancer is characterized by some types of heterogeneity, high aggressive behaviour, and low immunotherapeutic efficiency. Detailed immune stratification is a prerequisite for interpreting resistance to treatment and escape from immune control. Hence, the immune landscape of breast cancer needs further understanding. We systematically clustered breast cancer into six immune subtypes based on the mRNA expression patterns of immune signatures and comprehensively depicted their characteristics. The immunotherapeutic benefit score (ITBscore) was validated to be a superior predictor of the response to immunotherapy in cohorts from various datasets. Six distinct immune subtypes related to divergences in biological functions, signatures of immune or stromal cells, extent of the adaptive immune response, genomic events, and clinical prognostication were identified. These six subtypes were characterized as immunologically quiet, chemokine dominant, lymphocyte depleted, wounding dominant, innate immune dominant, and IFN-γ dominant and exhibited features of the tumor microenvironment (TME). The high ITBscore subgroup, characterized by a high proportion of M1 macrophages:M2 macrophages, an activated inflammatory response, and increased mutational burden (such as mutations in TP53, CDH1 and CENPE), indicated better immunotherapeutic benefits. A low proportion of tumor-infiltrating lymphocytes (TILs) and an inadequate response to immune treatment were associated with the low ITBscore subgroup, which was also associated with poor survival. Analyses of four cohorts treated with immune checkpoint inhibitors (ICIs) suggested that patients with a high ITBscore received significant therapeutic advantages and clinical benefits. Our work may facilitate the understanding of immune phenotypes in shaping different TME landscapes and guide precision immuno-oncology and immunotherapy strategies.
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Neoplasias de la Mama/genética , Neoplasias de la Mama/inmunología , Inmunoterapia , Transcriptoma , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Biomarcadores de Tumor/genética , Neoplasias de la Mama/terapia , Estudios de Cohortes , Femenino , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Genoma , Humanos , Inmunofenotipificación , Linfocitos Infiltrantes de Tumor/inmunología , Mutación , PronósticoRESUMEN
Acute lung injury (ALI) is a respiratory disorder characterized by severe inflammation of the alveoli and lung parenchyma. Tetramethylpyrazine (TMP), the main active compound in Ligusticum chuanxiong Hort (LC), can protect against lipopolysaccharide (LPS)-induced ALI. Our study aimed to investigate how TMP protects the endothelial cell barrier in pulmonary capillaries. We administered TMP intraperitoneally at different doses and found that acute lung injury in mice was improved, but not in a dose-dependent manner. TMP toxicity was tested in vitro. We observed that LPS-induced cytoskeletal remodeling was inhibited by TMP. Murine ALI was induced as follows: For the 1st hit, LPS (2 mg/kg) was injected intraperitoneally; after 16 h, for the 2nd hit, LPS (4 mg/kg) was instilled intratracheally. The mice in treatment groups had TMP or dexamethasone administered intraperitoneally 30 min prior to the 1st hit and 30 min past the 2nd hit. Mice were euthanized 24 h after the last injecting. We measured protein and mRNA levels using enzyme-linked immunosorbent assay (ELISA) and reverse transcriptase real-time PCR (RT-qPCR), respectively. The ultrastructural analysis was performed with transmission electron microscopy (TEM) and the cytoskeleton was observed by immunofluorescence. Immunohistochemistry and Western blotting were used to detect protein expression in the Rac1/LIMK1/ZO-1/occludin signal pathway. The results showed that TMP treatment decreased inflammatory cell infiltration and alleviated LPS-induced damage in lung tissue. Also, TMP significantly inhibited the Rac1/LIMK1/ZO-1/occludin signaling pathway. Our findings show that using TMP during sepsis can protect the pulmonary microvascular endothelial cell barrier and suppress inflammation. Therefore, TMP may have a promising therapeutic role in preventing acute lung injury from sepsis.
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BACKGROUND: A novel and improved methodology is still required for the diagnosis of diabetic kidney disease (DKD). The aim of the present study was to identify novel biomarkers using extracellular vesicle (EV)-derived mRNA based on kidney tissue microarray data. METHODS: Candidate genes were identified by intersecting the differentially expressed genes (DEGs) and eGFR-correlated genes using the GEO datasets GSE30528 and GSE96804, followed by clinical parameter correlation and diagnostic efficacy assessment. RESULTS: Fifteen intersecting genes, including 8 positively correlated genes, B3GALT2, CDH10, MIR3916, NELL1, OCLM, PRKAR2B, TREM1 and USP46, and 7 negatively correlated genes, AEBP1, CDH6, HSD17B2, LUM, MS4A4A, PTN and RASSF9, were confirmed. The expression level assessment results revealed significantly increased levels of AEBP1 in DKD-derived EVs compared to those in T2DM and control EVs. Correlation analysis revealed that AEBP1 levels were positively correlated with Cr, 24-h urine protein and serum CYC and negatively correlated with eGFR and LDL, and good diagnostic efficacy for DKD was also found using AEBP1 levels to differentiate DKD patients from T2DM patients or controls. CONCLUSIONS: Our results confirmed that the AEBP1 level from plasma EVs could differentiate DKD patients from T2DM patients and control subjects and was a good indication of the function of multiple critical clinical parameters. The AEBP1 level of EVs may serve as a novel and efficacious biomarker for DKD diagnosis.
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Diabetes Mellitus , Nefropatías Diabéticas , Vesículas Extracelulares , Biomarcadores , Carboxipeptidasas , Nefropatías Diabéticas/diagnóstico , Nefropatías Diabéticas/genética , Tasa de Filtración Glomerular , Humanos , ARN Mensajero/genética , Proteínas RepresorasRESUMEN
OBJECTIVE: To investigate the role of the pannexin-1 (Panx1) protein in the invasion and migration of testicular cancer Tcam-2 cells and its possible action mechanism. METHODS: Tcam-2 cells were treated with carbenoxolone (CBX) at 100 µmol/L and probenecid (PBN) 200 µmol/L. Then the intercellular fluorescence transmission was assessed by real-time fluorescence assay, the extracellular ATP concentration measured by chemi-luminescence immunoassay, the invasive and migratory abilities of the Tcam-2 cells detected by Transwell assay, and the expressions of the proteins Panx1, p-ERK1/2, ERK1/2, vimentin, MMP-9 and E-cadherin in the TM3 Leydig cells and testicular cancer Tcam-2 cells determined by Western blot. RESULTS: Western blot showed that the expression of the Panx1 protein was significantly higher in the testicular cancer Tcam-2 cells than in the TM3 Leydig cells (2.79 ± 0.17 vs 1.00 ± 0.06, P<0.05). The rates of intercellular fluorescence transmission in the Tcam-2 cells treated with CBX and PBN were markedly decreased as compared with the blank control group (ï¼»61.54 ± 3.30ï¼½% and ï¼»68.06 ± 4.03ï¼½% vs ï¼»99.50 ± 3.12ï¼½%, P<0.01), and so were the extracellular ATP concentrations (ï¼»57.06 ± 5.80ï¼½% and ï¼»56.42 ± 7.70ï¼½% vs ï¼»110 ± 8.16ï¼½%, P<0.01). The numbers of migrated Tcam-2 cells in the CBX and PBN groups were significantly reduced in comparison with that in the control (11.5 ± 1.11 and 8.25 ± 1.23 vs 331.00 ± 30.80, P<0.05), and so were those of the invaded ones (11.75 ± 3.77 and 11.5 ± 3.5 vs 89.00 ± 13.09, P<0.01). CBX and PBN significantly down-regulated the expression of p-ERK1/2 as compared with that in the blank control group (0.538 ± 0.05 and 0.476 ± 0.02 vs 0.98 ± 0.03, P<0.05), as well as those of vimentin (0.541 ± 0.09 and 0.705 ± 0.07, P<0.01) and MMP-9 (0.439 ± 0.08 and 0.557 ± 0.065, P<0.01) but up-regulated that of E-cadherin (3.896 ± 0.06 and 3.551 ± 0.04, P<0.01). CONCLUSIONS: The Panx1 protein is highly expressed in testicular cancer Tcam-2 cells. CBX and PBN can inhibit the function of the panneixn1 channel and reduce the invasive and migratory abilities of the Tcam-2 cells, which is associated with the decreased expression of the p-ERK1/2 protein.
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Movimiento Celular , Conexinas/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Neoplasias Testiculares/patología , Carbenoxolona/farmacología , Línea Celular Tumoral , Humanos , Sistema de Señalización de MAP Quinasas , Masculino , Metaloproteinasa 9 de la Matriz , Probenecid/farmacologíaRESUMEN
Diabetic encephalopathy is a severe diabetes-related complication in the central nervous system (CNS) that is characterized by the impairment of neurochemical and structural changes leading to cognitive dysfunction. Its cellular and molecular mechanisms are still unclear and clinical approaches are still lacking of promising therapies. In this study, we have investigated the changes of different hippocampal neurons during diabetic encephalopathy in mouse models of diabetes by simultaneously analyzing the activities and synaptic transmission of glutamatergic neurons and GABAergic neurons in brain slices. Compared with the data from a group of control, diabetic encephalopathy permanently impairs the excitability of GABAergic neurons and synaptic transmission mediated by γ-aminobutyric acid (GABA). However, glutamatergic neurons appear to be more excited. Our findings highlight the critical role of the dysfunction of GABAergic neurons and glutamatergic neurons during diabetic encephalopathy in hippocampus to neural impairment as well as a strategy to prevent the function of progress of diabetic encephalopathy by protecting central neurons.
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Encefalopatías/fisiopatología , Neuronas GABAérgicas/fisiología , Neuronas/fisiología , Potenciales de Acción/fisiología , Animales , Encefalopatías/metabolismo , Diabetes Mellitus Experimental/metabolismo , Fármacos actuantes sobre Aminoácidos Excitadores/metabolismo , Fármacos actuantes sobre Aminoácidos Excitadores/farmacología , Ácido Glutámico/fisiología , Hipocampo/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Inhibición Neural/fisiología , Técnicas de Placa-Clamp , Estreptozocina/farmacología , Transmisión Sináptica/fisiologíaRESUMEN
Nanosized polymeric vesicles (polymersomes) assembled from ABA triblock copolymers of poly(N-vinylcaprolactam)-poly(dimethylsiloxane)-poly(N-vinylcaprolactam) (PVCL-PDMS-PVCL) are a promising platform for biomedical applications, as the temperature-responsiveness of the PVCL blocks enables reversible vesicle shrinkage and permeability of the polymersome shell at elevated temperatures. Herein, we explore the effects of molecular weight, polymer block weight ratios, and temperature on the structure of these polymersomes via electron microscopy, dynamic light scattering, small angle neutron scattering (SANS), and all-atom molecular dynamic methods. We show that the shell structure and overall size of the polymersome can be tuned by varying the hydrophilic (PVCL) weight fraction of the polymer: at room temperature, polymers of smaller hydrophilic ratios form larger vesicles that have thinner shells, whereas polymers with higher PVCL content exhibit interchain aggregation of PVCL blocks within the polymersome shell above 50 °C. Model fitting and model-free analysis of the SANS data reveals that increasing the mass ratio of PVCL to the total copolymer weight from 0.3 to 0.56 reduces the temperature-induced change in vesicle diameter by a factor of 3 while simultaneously increasing the change in shell thickness by a factor of 1.5. Finally, by analysis of the shell structures and overall size of polymersomes with various PVCL weight ratios and those without temperature-dependent polymer components, we bring into focus the mechanism of temperature-triggered drug release reported in a previous study. This work provides new fundamental perspectives on temperature-responsive polymersomes and elucidates important structure-property relationships of their constituent polymers.
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BACKGROUND: MicroRNAs (miRNAs) are small non-coding molecules that exhibit important regulatory roles in various biological or cellular functions, including tumor metastasis. However, the detailed mechanisms of the expression and functions of miRNAs in hepatocellular carcinoma (HCC) have not yet been completely investigated. METHODS: In this study, the levels of miR-148b in HCC cells and patient specimens were determined using qPCR assays. MiR-148b-overexpressing HCC cells were used to investigate the effect of miR-148b in vitro and in vivo. The relationship between the expression of miR-148b and colony stimulating factor-1 (CSF1) in HCC patients and the infiltration of macrophages into the tumor microenvironment were assessed by immunohistochemical staining. RESULTS: MiR-148b expression was decreased in metastatic HCC cells. A positive association between downregulated miR-148b expression and several clinical parameters, including recurrence, metastasis, and poor prognosis, was observed in patients with HCC. The results of bio-functional experiments indicated that the biological characteristics of HCC cells were not affected by miR-148b deficiency in vitro. However, miR-148b deficiency significantly enhanced the progression and metastasis of HCC in nude mice. By analyzing the gene expression profiles, we demonstrated that CSF1 was regulated by miR-148b and that miR-148b deficiency promoted HCC growth and metastasis through CSF1/CSF1 receptor (CSF1R)-mediated tumor-associated macrophage (TAM) infiltration. These results were supported by the negative relationship between miR-148b and CSF1 expression and TAM infiltration in HCC patients. Moreover, HCC patients with low miR-148b levels and high TAM infiltration were associated with poorer prognosis. CONCLUSION: MiR-148b-CSF1 signaling-induced TAM infiltration promotes HCC metastasis. Therefore, miR-148b plays a suppressor role in HCC and might be a potential prognostic factor and therapeutic candidate for HCC.
Asunto(s)
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Factor Estimulante de Colonias de Macrófagos/metabolismo , Macrófagos/fisiología , MicroARNs/metabolismo , Aminopiridinas/farmacología , Animales , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/fisiología , Humanos , Masculino , Ratones , Ratones Desnudos , MicroARNs/genética , Metástasis de la Neoplasia , Neoplasias Experimentales , Pirroles/farmacología , Transducción de SeñalRESUMEN
Blocking the PD-L1/PD-1 pathway to prevent the immune evasion of tumor cells is a powerful approach for treating multiple cancers, including hepatocellular carcinoma (HCC). Previous studies have shown that baicalein and baicalin are directly cytotoxic to some tumors, here we demonstrate that in addition to direct cytotoxicity, these two flavonoids stimulate the T cell mediated immune response against tumors through reduction of PD-L1 expression in cancer cells. Interestingly, more significant tumor regression was observed in BALB/c mice than in BALB/c-nu/nu mice after baicalein and baicalin treatment. PD-L1 upregulation induced by interferon-γ (IFN-γ) was significantly inhibited by these two flavonoids in vitro. Both baicalein and baicalin enhanced the cytotoxicity of T cells to eliminate tumor cells, which was abrogated after HCC cells were transfected with a PD-L1 overexpression plasmid or after T cells were pretreated with an anti-PD-1 blocking antibody. Further mechanistic research indicated that the IFN-γ-induced expression and promoter activity of PD-L1 were suppressed by these two flavonoids, and these effects were mediated by STAT3 activity inhibition. Therefore, baicalein and baicalin decreased STAT3 activity, further downregulated IFN-γ-induced PD-L1 expression and subsequently restored T cell sensitivity to kill tumor cells. Our findings provide novel insight into the anticancer effects of baicalein and baicalin through which tumor growth is inhibited by PD-L1 expression downregulation and suggest that these flavonoids have great potential for clinical treatment.