RESUMEN
Bone marrow mesenchymal stem cells (BMSCs) are indispensable cells constituting the bone marrow microenvironment that are generally recognized as being involved in the development and progression of osteosarcoma (OS). To explore whether mTORC2 signaling inhibition in BMSCs suppressed OS growth and tumor-caused bone destruction, 3-month-old littermates genotyped Rictorflox/flox or Prx1-cre; Rictorflox/flox (with same gender) were injected with K7M2 cells in the proximal tibia. After 40 days, bone destruction was alleviated in Prx1-cre; Rictorflox/flox mice, as observed on X-ray and micro-CT. This was accompanied by decreased serum N-terminal propeptide of procollagen type I (PINP) levels and reduced tumor bone formation in vivo. Interactions between K7M2 and BMSCs were studied in vitro. Rictor-deficient BMSCs, which were cultured in tumor-conditioned medium (TCM), caused reduced bone proliferation and suppressed osteogenic differentiation. Moreover, compared with the control group, K7M2 cells cultured in BCM (culture medium extracted from Rictor-deficient BMSCs) displayed less proliferation, migration, and invasion, and attenuated osteogenic activity. Forty types of cytokines were then analyzed by mouse cytokine array and decreased levels CCL2/3/5 and interleukin-16 were detected in Rictor-deficient BMSCs. These results suggested that inhibition of mTORC2 (Rictor) signaling pathway in BMSCs exerted anti-OS effects through 2 mechanisms: (1) by suppressing the proliferation and osteogenic differentiation of BMSCs induced by OS to alleviate bone destruction; (2) by reducing the secretion of cytokines by BMSCs, which are closely related to OS cell growth, migration, invasion, and tumorigenic osteogenesis.
Asunto(s)
Neoplasias Óseas , Células Madre Mesenquimatosas , Osteosarcoma , Ratones , Animales , Osteogénesis , Células Madre Mesenquimatosas/metabolismo , Diferenciación Celular , Células de la Médula Ósea , Diana Mecanicista del Complejo 2 de la Rapamicina/metabolismo , Citocinas/metabolismo , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Células Cultivadas , Osteosarcoma/metabolismo , Microambiente TumoralRESUMEN
In this article, o-carborane has a high boron content, high hydrophobicity, and good chemical stability. It has been widely used in the fields of biology and medicine, especially in the application of boron neutron capture therapy (BNCT). However, o-carborane is a fat-soluble compound, its hydrophobicity is too strong, and its bioavailability is poor. This project aims to improve the water solubility of o-carborane drugs, so that the drugs can reach specific sites. For this reason, this article provides a one-pot reaction for the synthesis of water-soluble boron-containing drugs. 2-Chloro-1-(difluoroboranyl)-5-((4-ethyl-3,5-dimethyl-2H-pyrrol-2-ylidene)(phenyl) methyl)-1H-pyrrole and ethylenediamine are used as raw materials to synthesize fluorescent molecular probe BODIPY-NH2, and the fluorescent molecular probe is reacted with P-CBMA (poly(carboxybetaine methacrylate)) to produce a water-soluble gel polymer. Water-soluble o-carborane polymers were synthesized by hydrogen bonding of the polymers with bis(4-azaspiro[3.4]octan-4-ium)-nido-ortho-carborane and bis(5-azaspiro[4.5]decan-5-ium)-nido-ortho-caborane. The two polymers were characterized and the results showed that the maximum UV absorption wavelength of the two boron polymers in different polar solutions was 530-540 nm. In the fluorescence spectrum, the maximum emission wavelengths of the two boron polymers are concentrated between 550 and 560 nm. Through electron microscopy imaging, the fluoroboron pyrrole polymers wrap the boron clusters to form a spherical stacked. Through fluorescent cell imaging, both boron polymers can enter target cells.
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Terapia por Captura de Neutrón de Boro , Nanopartículas , Compuestos de Boro/química , Terapia por Captura de Neutrón de Boro/métodos , Nanopartículas/química , Agua/químicaRESUMEN
BACKGROUND: Defective mismatch repair (dMMR) and microsatellite instability (MSI) correlate with gastric cancer (GC) outcome. We hypothesized that MMR genetic polymorphisms that have low-penetrant effects but may cause heterogeneous MMR capability among individuals also affect GC outcome. METHODS: The polymorphisms rs1800734 in MLH1, rs2303428 and rs3732183 in MSH2, rs735943 in EXO1, and rs11797 in TREX1 were selected and analyzed in independent discovery and validation sets that included 167 and 593 patients, respectively. MSI was determined. RESULTS: In both the discovery and validation sets, the rs2303428 TC + CC genotype correlated with poor overall survival (OS) in non-cardia (P < 0.05) but not in cardia GC. Multivariate models showed that for OS of patients with non-cardia GC, the rs2303428 TC + CC genotype was an independent predictor in the validation set (HR 1.54; 95% CI 1.02-2.32; P = 0.040) and had a trend to be an independent predictor in the discovery set (HR 1.70; 95% CI 0.96-3.01; P = 0.067). Furthermore, in both patient sets, fluoropyrimidines-based adjuvant chemotherapy improved OS for non-cardia patients with the rs2303428 TC + CC genotype (HR 0.14; 95% CI 0.04-0.57; P = 0.006; and HR 0.29; 95% CI 0.15-0.58; P < 0.001, respectively) but not for those with the TT genotype. The rs2303428 genotypes were not associated with MSI frequency. The rs2303428 TC + CC genotype correlated with reduced expressions for thymidylate synthetase, P-glycoprotein and ERCC1 (P < 0.05) in non-cardia GC. CONCLUSIONS: The rs2303428 genotypes may predict prognosis and adjuvant chemotherapy benefit in non-cardia GC patients.
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Reparación de la Incompatibilidad de ADN , Inestabilidad de Microsatélites , Neoplasias Gástricas/terapia , Anciano , Cardias/patología , Quimioterapia Adyuvante , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Pronóstico , Estudios Prospectivos , Estudios Retrospectivos , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Tasa de SupervivenciaRESUMEN
Noncanonical NF-κB pathway is essential for the B cell activation and antibody production, which centralize the critical role of B cells in regulating the pathogenesis of systemic lupus erythematosus (SLE). We have previously demonstrated that Pellino1 (Peli1) negatively regulates noncanonical NF-κB activation and lupus autoimmunity. Here, we showed that poly IC is a potent inducer of Peli1 protein in mouse splenic B cells in dose- and time-dependent manners, and poly IC-induced Peli1 protein dramatically suppressed the activation of noncanonical NF-κB pathway. In addition, poly IC-pretreated B cells failed to induce lupus-like disease in BM12 CD4+ T cell-immunized mice. Accordingly, the induction of antibody-producing plasma cells and germinal center B cells, as well as the production of autoantibodies were significantly impaired in immunized µMT mice that were transferred with poly IC-pretreated B cells. Our findings demonstrate that poly IC-induced Peli1 negatively regulates the noncanonical NF-κB pathway in the context of restraining the pathogenesis of lupus-like disease.
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Autoinmunidad/efectos de los fármacos , Linfocitos B/efectos de los fármacos , Lupus Eritematoso Sistémico/prevención & control , Proteínas Nucleares/inmunología , Poli I-C/farmacología , Ubiquitina-Proteína Ligasas/inmunología , Animales , Autoanticuerpos/inmunología , Autoanticuerpos/metabolismo , Autoinmunidad/genética , Autoinmunidad/inmunología , Linfocitos B/inmunología , Linfocitos B/metabolismo , Línea Celular Tumoral , Humanos , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/metabolismo , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , FN-kappa B/inmunología , FN-kappa B/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Recent studies have shown that sulforaphane (SFN) selectively inhibits the growth of ALDH⺠breast cancer stem-like cells.Herein, a series of SFN analogues were synthesized and evaluated against breast cancer cell lines MCF-7 and SUM-159, and the leukemia stem cell-like cell line KG-1a. These SFN analogues were characterized by the replacement of the methyl group with heterocyclic moieties, and the replacement of the sulfoxide group with sulfide or sulfone. A growth inhibitory assay indicated that the tetrazole analogs 3d, 8d and 9d were significantly more potent than SFN against the three cancer cell lines. Compound 14c, the water soluble derivative of tetrazole sulfide 3d, demonstrated higher potency against KG-1a cell line than 3d. SFN, 3d and 14c significantly induced the activation of caspase-3, and reduced the ALDH⺠subpopulation in the SUM159 cell line, while the marketed drug doxrubicin(DOX) increased the ALDH⺠subpopulation.
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Ácidos Heterocíclicos/síntesis química , Ácidos Heterocíclicos/farmacología , Anticarcinógenos/síntesis química , Anticarcinógenos/farmacología , Ácidos Heterocíclicos/química , Aldehído Deshidrogenasa/metabolismo , Anticarcinógenos/química , Caspasa 3/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Isotiocianatos/química , Células MCF-7 , SulfóxidosRESUMEN
Detection of cytoplasmic DNA is an essential biological mechanism that elicits IFN-dependent and immune-related responses. A better understanding of the mechanisms regulating cytoplasmic DNA sensing in tumor cells could help identify immunotherapeutic strategies to improve cancer treatment. Here we identified abundant cytoplasmic DNA accumulated in lung squamous cell carcinoma (LUSC) cells. DNA-PK, but not cGAS, functioned as a specific cytoplasmic DNA sensor to activate downstream ZAK/AKT/mTOR signaling, thereby enhancing the viability, motility, and chemoresistance of LUSC cells. DNA-PK-mediated cytoplasmic DNA sensing boosted glycolysis in LUSC cells, and blocking glycolysis abolished the tumor-promoting activity of cytoplasmic DNA. Elevated DNA-PK-mediated cytoplasmic DNA sensing was positively correlated with poor prognosis of human patients with LUSC. Targeting signaling activated by cytoplasmic DNA sensing with the ZAK inhibitor iZAK2 alone or in combination with STING agonist or anti-PD-1 antibody suppressed the tumor growth and improved the survival of mouse lung cancer models and human LUSC patient-derived xenografts model. Overall, these findings established DNA-PK-mediated cytoplasmic DNA sensing as a mechanism that supports LUSC malignancy and highlight the potential of targeting this pathway for treating LUSC. SIGNIFICANCE: DNA-PK is a cytoplasmic DNA sensor that activates ZAK/AKT/mTOR signaling and boosts glycolysis to enhance malignancy and chemoresistance of lung squamous cell carcinoma.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Animales , Ratones , Humanos , Resistencia a Antineoplásicos , Proteínas Proto-Oncogénicas c-akt , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/genética , Proteína Quinasa Activada por ADN , Glucólisis , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Pulmón , Serina-Treonina Quinasas TOR , PronósticoRESUMEN
Tumor recurrence after chemoradiotherapy is challenging to overcome, and approaches to predict the recurrence remain elusive. Here, human cervical cancer tissues before and after concurrent chemoradiotherapy (CCRT) analyzed by single-cell RNA sequencing reveal that CCRT specifically promotes CD8+ T cell senescence, driven by atypical chemokine receptor 2 (ACKR2)+ CCRT-resistant tumor cells. Mechanistically, ACKR2 expression is increased in response to CCRT and is also upregulated through the ligation of CC chemokines that are produced by activated myeloid and T cells. Subsequently, ACKR2+ tumor cells are induced to produce transforming growth factor ß to drive CD8+ T cell senescence, thereby compromising antitumor immunity. Moreover, retrospective analysis reveals that ACKR2 expression and CD8+ T cell senescence are enhanced in patients with cervical cancer who experienced recurrence after CCRT, indicating poor prognosis. Overall, we identify a subpopulation of CCRT-resistant ACKR2+ tumor cells driving CD8+ T cell senescence and tumor recurrence and highlight the prognostic value of ACKR2 and CD8+ T cell senescence for chemoradiotherapy recurrence.
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Linfocitos T CD8-positivos , Senescencia Celular , Quimioradioterapia , Recurrencia Local de Neoplasia , Neoplasias del Cuello Uterino , Humanos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Femenino , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/terapia , Neoplasias del Cuello Uterino/inmunología , Neoplasias del Cuello Uterino/tratamiento farmacológico , Quimioradioterapia/métodos , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/genética , Animales , Ratones , Línea Celular Tumoral , Pronóstico , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica , Factor de Crecimiento Transformador beta/metabolismo , Senescencia de Células TRESUMEN
Background: To evaluate the efficacy and safety of allogenic CD8 + natural killer T (CD8+ NKT) immunotherapy combined with gefitinib in the treatment of advanced or metastatic EGFR mutant non-small cell lung cancer (NSCLC). Methods: This study is prospective. The NSCLC patients with exon 19 (Ex19del) or exon 21 L858R point mutations, and response to gefitinib treatment were enrolled into the trial to be randomly assigned into the gefitinib arm and the gefitinib/NKT arm. Allogenic CD8+ NKT cells were cultured in vitro and adaptive transferred into the patients via vein in the gefitinib/NKT arm. The primary endpoint was progression-free survival (PFS). Secondary endpoint analysis included time to disease progression (TTP), overall survival (OS), levels of serum tumour markers for carcinoembryonic antigen (CEA) and alanine aminotransferase (ALT) in the blood, the response rate and safety. From July 2017 to June 2021, 19 patients were randomly assigned to the gefitinib arm (n = 8) and the gefitinib/NKT arm (n = 11). Results: The estimated median survival PFS in the gefitinib/NKT arm was significantly longer than that of the gefitinib arm (12 months vs 7 months). Similar results were also observed for the median TTP. Moreover, the gefitinib/NKT arm had better CEA control than the gefitinib arm. Clinical grade 3 adverse reactions occurred in 64% and 39% of patients in the gefitinib/NKT arm and the gefitinib arm, respectively. The most common grade 3 adverse events in the gefitinib/NKT arm included abnormal liver function in 8 cases (73%) and diarrhoea in 1 case (9%), both of which resolved after drug intervention. Conclusion: The PFS of EGFR-mutated advanced NSCLC treated with allogenic CD8+ NKT cells combined with gefitinib was longer than that of gefitinib alone. No obvious serious adverse reactions occurred, and the patients compliance and survival status were good.
Asunto(s)
Receptores ErbB , Neoplasias Pulmonares , Mutación , Células T Asesinas Naturales , Humanos , Femenino , Receptores ErbB/genética , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/mortalidad , Persona de Mediana Edad , Masculino , Anciano , Células T Asesinas Naturales/inmunología , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Gefitinib/uso terapéutico , Terapia Combinada , Linfocitos T CD8-positivos/inmunología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Estudios Prospectivos , Inmunoterapia/métodos , Resultado del Tratamiento , Estadificación de NeoplasiasRESUMEN
Helicobacter pylori (H. pylori) is a human gastric pathogen that colonizes the stomach in more than 50 % of the world's human population. Infection with this bacterium can induce several gastric diseases ranging from gastritis to peptic ulcer and gastric cancer. Virulent H. pylori isolates harboring the cag pathogenicity island (cag PAI), which encodes a Type IV Secretion System (T4SS), form a pilus for the injection of its major virulence protein CagA into gastric cells. Several cag PAI genes have been identified as homologues of T4SS genes from Agrobacterium tumefaciens, while the other members in cag PAI still have no known function. We studied one of such proteins with unknown function, CagM, which was predicted to have a putative N-terminal signal sequence and at least three transmembrane helices. To determine the subcellular localization of CagM, we performed a cell fractionation procedure and produced rabbit anti-CagM polyclonal antibodies for immunoblotting assays. Furthermore, we generated an isogenic ΔcagM mutant to investigate the ability of CagA translocation compared with the wild-type NCTC 11637 strain using GES-1 and MKN-45 cell infection experiments. Our results indicated that CagM was mainly located in the bacterial membrane, partially located in the periplasm, and essential for CagA translocation both in GES-1 and MKN-45 cells, which suggested that CagM was one of the core members of Cag T4SS and localized in the transmembrane channel.
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Proteínas Bacterianas/metabolismo , Membrana Celular/metabolismo , Helicobacter pylori/metabolismo , Canales Iónicos/metabolismo , Proteínas Bacterianas/genética , Línea Celular , Expresión Génica , Helicobacter pylori/genética , Humanos , Canales Iónicos/genética , Mutación , Periplasma/metabolismo , Transporte de ProteínasRESUMEN
OBJECTIVE: To determine the relationship between estimated glomerular filtration rate (eGFR) and proteinuria with cardiovascular events in subjects aged 80 years or older. METHODS: Data for this retrospective prognostic study were drawn from the patient database for routine checkup in Beijing hospital between January 2001 to December 2001. Baseline eGFR and proteinuria were evaluated in 340 subjects [mean age: (85.6 ± 4.0) years]. eGFR was calculated using the modified abbreviated MDRD equations based on the Chinese chronic kidney disease patients. The subjects were divided into normal renal function group and reduced renal function group (eGFR <60 ml·min(-1)·1.73 m(-2)). The subjects were divided into subjects without proteinuria and subjects with proteinuria group. Cardiovascular events included cardiovascular death, nonfatal myocardial infarction, nonfatal stroke. RESULTS: The proportion of reduced renal function was 36.8% (125/340). The proportion of proteinuria was 10.3% (35/340). The proportion of reduced renal function or proteinuria was 41.8% (142/340). Follow-up time was 79 months (40-114 months). Cardiovascular events rate was significantly higher in reduced renal function group than in normal renal function group [37.6% (47/125) vs. 26.2% (55/210), P < 0.05 ] and in proteinuria group than in without proteinuria group [50.0% (17/34) vs. 28.2% (85/301), P < 0.01 ]. Cox multivariate analysis revealed that both eGFR (HR = 0.978, 95%CI:0.961-0.994, P < 0.05 ) and proteinuria (HR = 2.049, 95%CI:1.132-3.709, P < 0.05) were independent risk factors for cardiovascular events after adjusting for age, gender, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, uric acid, hypertension, coronary heart disease, diabetes mellitus. CONCLUSIONS: Reduced eGFR and presence of proteinuria are independent risk factors for cardiovascular event in subjects aged 80 years or older. eGFR and proteinuria can thus be used for cardiovascular event risk stratification in subjects aged 80 years or older.
Asunto(s)
Enfermedades Cardiovasculares/complicaciones , Enfermedades Cardiovasculares/fisiopatología , Tasa de Filtración Glomerular , Proteinuria , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Análisis Multivariante , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Increased interleukin-17 (IL-17)-producing Th (Th17) cells have been described in a variety of human carcinoma cases, however, the mechanism of Th17 cells' accumulation in a tumor microenvironment remains elusive. This study was designed to investigate whether Th17 cells were involved in the development of esophageal cancer. We found that the proportion of Th17 cells increased within the peripheral blood and tumor tissues of esophageal cancer patients. Furthermore, the proportion of circulating Th17 cells was higher in advanced esophageal cancer patients than that in early esophageal cancer patients. In addition, the Th17 cells differentiation-related cytokines (IL-23, IL-1ß, and IL-6) and accumulation-related chemokines (CCL22 and CCL20) were present in a tumor microenvironment. Therefore, the findings may partly explain the cause for the increased proportion of Th17 cells and indicate a potential prognostic marker of Th17 cells in esophageal cancer.
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Linfocitos T CD4-Positivos/inmunología , Movimiento Celular/inmunología , Neoplasias Esofágicas/inmunología , Interleucina-17/biosíntesis , Interleucina-17/inmunología , Células Th17/inmunología , Adulto , Anciano , Linfocitos T CD4-Positivos/metabolismo , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Movimiento Celular/genética , Quimiocina CCL20/metabolismo , Quimiocina CCL22/metabolismo , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patología , Femenino , Humanos , Interleucina-17/metabolismo , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/metabolismo , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias/métodos , Receptores CCR4/metabolismo , Receptores CCR6/metabolismo , Células Th17/metabolismo , Microambiente Tumoral/genética , Microambiente Tumoral/inmunologíaRESUMEN
Coronavirus is a family of viruses that can cause diseases such as the common cold, severe acute respiratory syndrome (SARS), and Middle East respiratory syndrome (MERS). The universal outbreak of coronavirus disease 2019 (COVID-19) caused by SARS coronaviruses 2 (SARS-CoV-2) has become a global pandemic. The ß-Coronaviruses, which caused SARS-CoV-2 (COVID-19), have spread in more than 213 countries, infected over 81 million people, and caused more than 1.79 million deaths. COVID-19 symptoms vary from mild fever, flu to severe pneumonia in severely ill patients. Difficult breathing, acute respiratory distress syndrome (ARDS), acute kidney disease, liver damage, and multi-organ failure ultimately lead to death. Researchers are working on different pre-clinical and clinical trials to prevent this deadly pandemic by developing new vaccines. Along with vaccines, therapeutic intervention is an integral part of healthcare response to address the ongoing threat posed by COVID-19. Despite the global efforts to understand and fight against COVID-19, many challenges need to be addressed. This article summarizes the current pandemic, different strains of SARS-CoV-2, etiology, complexities, surviving medications of COVID-19, and so far, vaccination for the treatment of COVID-19.
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Vacunas contra la COVID-19/administración & dosificación , COVID-19/genética , Variación Genética/genética , SARS-CoV-2/genética , Vacunación/tendencias , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/genética , Antivirales/administración & dosificación , COVID-19/prevención & control , Vacunas contra la COVID-19/genética , Brotes de Enfermedades/prevención & control , Humanos , Medicina Tradicional China/tendencias , Vacunación/métodos , Tratamiento Farmacológico de COVID-19RESUMEN
The low sensitivity of radiotherapy is the main cause of tumor tolerance against ionizing radiation (IR). However, the molecular mechanisms by which radiosensitivity is controlled remain elusive. Here, we observed that high expression of pellino E3 ubiquitin protein ligase 1 (PELI1) was correlated with improved prognosis in human esophageal squamous cell carcinoma stage III patients that received adjuvant radiotherapy. Moreover, we found PELI1-mediated IR-induced tumor cell apoptosis in vivo and in vitro. Mechanistically, PELI1 mediated the lysine 48 (Lys48)-linked polyubiquitination and degradation of NF-κB-inducing kinase (NIK; also known as MAP3K14), the master kinase of the noncanonical NF-κB pathway, thereby inhibiting IR-induced activation of the noncanonical NF-κB signaling pathway during radiotherapy. As a consequence, PELI1 inhibited the noncanonical NF-κB-induced expression of the anti-apoptotic gene BCL2 like 1 (Bclxl; also known as BCL2L1), leading to an enhancement of the IR-induced apoptosis signaling pathway and ultimately promoting IR-induced apoptosis in tumor cells. Therefore, Bclxl or NIK knockdown abolished the apoptosis-resistant effect in PELI1-knockdown tumor cells after radiotherapy. These findings establish PELI1 as a critical tumor intrinsic regulator in controlling the sensitivity of tumor cells to radiotherapy through modulating IR-induced noncanonical NF-κB expression.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Proteínas Nucleares , Ubiquitina-Proteína Ligasas , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/radioterapia , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/radioterapia , Humanos , Ligasas , FN-kappa B/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Tolerancia a Radiación , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
T follicular helper (Tfh) cells are crucial for regulating autoimmune inflammation and protective immunity against viral infection. However, the molecular mechanism controlling Tfh cell differentiation is poorly understood. Here, through two mixed bone marrow chimeric experiments, we identified Peli1, a T cell-enriched E3 ubiquitin ligase, as an intrinsic regulator that inhibits Tfh cell differentiation. Peli1 deficiency significantly promoted c-Rel-mediated inducible T-cell costimulator (ICOS) expression, and PELI1 mRNA expression was negatively associated with ICOS expression on human CD4+ T cells. Mechanistically, increased ICOS expression on Peli1-KO CD4+ T cells enhanced the activation of PI3K-AKT signaling and thus suppressed the expression of Klf2, a transcription factor that inhibits Tfh differentiation. Therefore, reconstitution of Klf2 abolished the differences in Tfh differentiation and germinal center reaction between WT and Peli1-KO cells. As a consequence, Peli1-deficient CD4+ T cells promoted lupus-like autoimmunity but protected against H1N1 influenza virus infection in mouse models. Collectively, our findings established Peli1 as a critical negative regulator of Tfh differentiation and indicated that targeting Peli1 may have beneficial therapeutic effects in Tfh-related autoimmunity or infectious diseases.
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Autoinmunidad , Proteína Coestimuladora de Linfocitos T Inducibles/metabolismo , Lupus Eritematoso Sistémico/patología , Activación de Linfocitos/inmunología , Proteínas Nucleares/fisiología , Infecciones por Orthomyxoviridae/prevención & control , Células T Auxiliares Foliculares/inmunología , Ubiquitina-Proteína Ligasas/fisiología , Animales , Diferenciación Celular , Femenino , Regulación de la Expresión Génica , Humanos , Proteína Coestimuladora de Linfocitos T Inducibles/genética , Subtipo H1N1 del Virus de la Influenza A/inmunología , Lupus Eritematoso Sistémico/etiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Infecciones por Orthomyxoviridae/inmunologíaRESUMEN
Resveratrol (RV) is a well-known polyphenolic compound in various plants, including grape, peanut, and berry fruits, which is quite famous for its association with several health benefits such as anti-obesity, cardioprotective neuroprotective, antitumor, antidiabetic, antioxidants, anti-age effects, and glucose metabolism. Significantly, promising therapeutic properties have been reported in various cancer, neurodegeneration, and atherosclerosis and are regulated by several synergistic pathways that control oxidative stress, cell death, and inflammation. Similarly, RV possesses a strong anti-adipogenic effect by inhibiting fat accumulation processes and activating oxidative and lipolytic pathways, exhibiting their cardioprotective effects by inhibiting platelet aggregation. The RV also shows significant antibacterial effects against various food-borne pathogens (Listeria, Campylobacter, Staphylococcus aureus, and E. coli) by inhibiting an electron transport chain (ETC) and F0F1-ATPase, which decreases the production of cellular energy that leads to the spread of pathogens. After collecting and analyzing scientific literature, it may be concluded that RV is well tolerated and favorably affects cardiovascular, neurological, and diabetic disorders. As such, it is possible that RV can be considered the best nutritional additive and a complementary drug, especially a therapeutic candidate. Therefore, this review would increase knowledge about the blend of RV as well as inspire researchers around the world to consider RV as a pharmaceutical drug to combat future health crises against various inhumane diseases. In the future, this article will be aware of discoveries about the potential of this promising natural compound as the best nutraceuticals and therapeutic drugs in medicine.
Asunto(s)
Suplementos Dietéticos , Fitoquímicos/uso terapéutico , Resveratrol/uso terapéutico , Animales , Suplementos Dietéticos/efectos adversos , Humanos , Seguridad del Paciente , Fitoquímicos/efectos adversos , Fitoquímicos/farmacocinética , Resveratrol/efectos adversos , Resveratrol/farmacocinética , Medición de RiesgoRESUMEN
TGFß is essential for the generation of anti-tumor Th9 cells; on the other hand, it causes resistance against anti-tumor immunity. Despite recent progress, the underlying mechanism reconciling the double-edged effect of TGFß signaling in Th9-mediated cancer immunotherapy remains elusive. Here, we find that TGFß-induced down-regulation of bifunctional apoptosis regulator (BFAR) represents the key mechanism preventing the sustained activation of TGFß signaling and thus impairing Th9 inducibility. Mechanistically, BFAR mediates K63-linked ubiquitination of TGFßR1 at K268, which is critical to activate TGFß signaling. Thus, BFAR deficiency or K268R knock-in mutation suppresses TGFßR1 ubiquitination and Th9 differentiation, thereby inhibiting Th9-mediated cancer immunotherapy. More interestingly, BFAR-overexpressed Th9 cells exhibit promising therapeutic efficacy to curtail tumor growth and metastasis and promote the sensitivity of anti-PD-1-mediated checkpoint immunotherapy. Thus, our findings establish BFAR as a key TGFß-regulated gene to fine-tune TGFß signaling that causes Th9 induction insensitivity, and they highlight the translational potential of BFAR in promoting Th9-mediated cancer immunotherapy.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/inmunología , Proteínas Reguladoras de la Apoptosis/inmunología , Proteínas de la Membrana/inmunología , Neoplasias/inmunología , Neoplasias/terapia , Transducción de Señal/inmunología , Factor de Crecimiento Transformador beta/inmunología , Animales , Diferenciación Celular/inmunología , Regulación hacia Abajo/inmunología , Humanos , Inmunoterapia/métodos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Linfocitos T Colaboradores-Inductores/inmunologíaRESUMEN
Chronic neuroinflammation is known to contributes to the toxicity of neurodegeneration of Parkinson's disease (PD). However, the molecular and cellular mechanisms controlling inflammatory responses in the central nervous system remain poorly understood. Here we found that a E3 ubiquitin ligase Peli1 is dramatically induced only in the substantia nigra (SN) of the human and mouse PD brains. The ablation of Peli1 significantly suppressed LPS-induced production of neurotoxic mediators and proinflammatory cytokines in SN and in primary microglia, whereas Peli1 is dispensable for the inflammatory responses in astrocyte. Accordingly, Peli1 deficiency markedly inhibited neuron death induced by the conditioned medium from LPS-stimulated microglia. Mechanistical study suggested that Peli1 acts as a positive regulator of inflammatory response in microglia through activation of NF-κB and MAP kinase. Our results established Peli1 as a critical mediator in the regulation of microglial activation and neuroinflammation-induced death of dopaminergic neurons during PD pathogenesis, suggesting that targeting Peli1 may have therapeutic effect in neuroinflammation.
Asunto(s)
Neuronas Dopaminérgicas/patología , Microglía/inmunología , Proteínas Nucleares/metabolismo , Enfermedad de Parkinson/inmunología , Sustancia Negra/patología , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Apoptosis/inmunología , Línea Celular Tumoral , Medios de Cultivo Condicionados/metabolismo , Citocinas/metabolismo , Conjuntos de Datos como Asunto , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Humanos , Mediadores de Inflamación/metabolismo , Lipopolisacáridos/inmunología , Sistema de Señalización de MAP Quinasas/inmunología , Masculino , Ratones , Ratones Noqueados , Microglía/metabolismo , FN-kappa B/metabolismo , Proteínas Nucleares/genética , Enfermedad de Parkinson/patología , Cultivo Primario de Células , Técnicas Estereotáxicas , Sustancia Negra/citología , Sustancia Negra/inmunología , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
Purpose: The effect of microsatellite instability (MSI) on the response to radiotherapy remains unknown. The aim of this study was to investigate the association between the MSI status and the outcomes of gastric cancer (GC) treated by surgical resection with or without postoperative adjuvant chemoradiotherapy. Methods: The records of patients who underwent surgical resection of stage IB-III GC with or without postoperative adjuvant chemoradiotherapy were retrospectively retrieved from the Affiliated Hospital of Jiangsu University (n = 89), The Cancer Genome Atlas (n = 202), and the Asian Cancer Research Group (n = 138). The primary endpoint was overall survival (OS). Results: The MSI status had no significant influence on OS in all cohorts. Compared with surgery alone, adjuvant chemoradiotherapy improved or tended to improve OS of patients with stage III disease, irrespective of the MSI status, in all cohorts. Among patients with stage Ib/II disease, only those with microsatellite stability (MSS) benefited from chemoradiotherapy in terms of OS, whereas those with MSI showed no improvement in OS. A comparison of gene expression profiles between MSI stage Ib/II GC and MSS stage Ib/II GC revealed that MSI correlated with the overexpression of thymidylate synthetase, a marker of fluoropyrimidine resistance. Furthermore, tumor hypoxia scoring for stage Ib/II lesions showed significantly greater hypoxia in MSI tumors than in MSS tumors. Conclusions: The findings of this study suggest that postoperative adjuvant chemoradiotherapy is effective for stage III GC, regardless of the MSI status. However, MSI may predict a poor response to postoperative adjuvant chemoradiotherapy in patients with stage Ib/II GC.
RESUMEN
Stat6 is known to drive macrophage M2 polarization. However, how macrophage polarization is fine-tuned by Stat6 is poorly understood. Here, we find that Lys383 of Stat6 is acetylated by the acetyltransferase CREB-binding protein (CBP) during macrophage activation to suppress macrophage M2 polarization. Mechanistically, Trim24, a CBP-associated E3 ligase, promotes Stat6 acetylation by catalyzing CBP ubiquitination at Lys119 to facilitate the recruitment of CBP to Stat6. Loss of Trim24 inhibits Stat6 acetylation and thus promotes M2 polarization in both mouse and human macrophages, potentially compromising antitumor immune responses. By contrast, Stat6 mediates the suppression of TRIM24 expression in M2 macrophages to contribute to the induction of an immunosuppressive tumor niche. Taken together, our findings establish Stat6 acetylation as an essential negative regulatory mechanism that curtails macrophage M2 polarization.
Asunto(s)
Activación de Macrófagos , Macrófagos/metabolismo , Neoplasias Experimentales/metabolismo , Proteínas Nucleares/metabolismo , Factor de Transcripción STAT6/metabolismo , Factores de Transcripción/metabolismo , Acetilación , Animales , Línea Celular Tumoral , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Regulación de la Expresión Génica , Células HEK293 , Humanos , Lisina/genética , Lisina/metabolismo , Macrófagos/clasificación , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Neoplasias Experimentales/genética , Neoplasias Experimentales/patología , Proteínas Nucleares/genética , Factor de Transcripción STAT6/genética , Factores de Transcripción/genéticaRESUMEN
Dysregulation of micro (mi)RNA-let-7 has been associated with the development and prognosis of multiple cancer types. Lin28, a RNA-binding protein, plays a conserved role in regulating the maturation of let-7 family proteins. However, few studies have focused on the effects of Lin28/let-7 on Wnt-activated esophageal squamous cell carcinoma (ESCC). Analysis of the expression of let-7a, let-7b and let-7c in clinical tissues revealed that lower let-7a expression was correlated with higher tumor node metastasis staging and recurrence in patients with ESCC. Furthermore, it was demonstrated that let-7a was inversely correlated with the migration and invasion of ESCC cells. In addition, epithelial-mesenchymal transition, and the expression of VEGF-C and MMP9 were effectively decreased by let-7a-mimic or siRNA-Lin28 pretreatment. Mechanistically, Lin28 functioned as the key factor in signal transduction, which regulated the expression of let-7a and the downstream genes along the Wnt signaling pathway. Taken together, these findings identified a biochemical and functional association between Lin28/let-7a, and the Wnt pathway in ESCC cells.