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1.
Cell ; 150(4): 685-96, 2012 Aug 17.
Artículo en Inglés | MEDLINE | ID: mdl-22901803

RESUMEN

Tumor-specific pyruvate kinase M2 (PKM2) is essential for the Warburg effect. In addition to its well-established role in aerobic glycolysis, PKM2 directly regulates gene transcription. However, the mechanism underlying this nonmetabolic function of PKM2 remains elusive. We show here that PKM2 directly binds to histone H3 and phosphorylates histone H3 at T11 upon EGF receptor activation. This phosphorylation is required for the dissociation of HDAC3 from the CCND1 and MYC promoter regions and subsequent acetylation of histone H3 at K9. PKM2-dependent histone H3 modifications are instrumental in EGF-induced expression of cyclin D1 and c-Myc, tumor cell proliferation, cell-cycle progression, and brain tumorigenesis. In addition, levels of histone H3 T11 phosphorylation correlate with nuclear PKM2 expression levels, glioma malignancy grades, and prognosis. These findings highlight the role of PKM2 as a protein kinase in its nonmetabolic functions of histone modification, which is essential for its epigenetic regulation of gene expression and tumorigenesis.


Asunto(s)
Astrocitoma/metabolismo , Proteínas Portadoras/metabolismo , Transformación Celular Neoplásica , Regulación Neoplásica de la Expresión Génica , Glioblastoma/metabolismo , Histonas/metabolismo , Proteínas de la Membrana/metabolismo , Hormonas Tiroideas/metabolismo , Animales , Astrocitoma/genética , Línea Celular , Línea Celular Tumoral , Ciclina D1/genética , Ciclina D1/metabolismo , Factor de Crecimiento Epidérmico/metabolismo , Epigénesis Genética , Femenino , Glioblastoma/genética , Humanos , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Proteínas Proto-Oncogénicas c-myc/genética , Transcripción Genética , Trasplante Heterólogo , Proteínas de Unión a Hormona Tiroide
2.
Mol Cell ; 76(1): 148-162.e7, 2019 10 03.
Artículo en Inglés | MEDLINE | ID: mdl-31447391

RESUMEN

The rapid proliferation of cancer cells and dysregulated vasculature within the tumor leads to limited nutrient accessibility. Cancer cells often rewire their metabolic pathways for adaption to nutrient stress, and the underlying mechanism remains largely unknown. Glutamate dehydrogenase 1 (GDH1) is a key enzyme in glutaminolysis that converts glutamate to α-ketoglutarate (α-KG). Here, we show that, under low glucose, GDH1 is phosphorylated at serine (S) 384 and interacts with RelA and IKKß. GDH1-produced α-KG directly binds to and activates IKKß and nuclear factor κB (NF-κB) signaling, which promotes glucose uptake and tumor cell survival by upregulating GLUT1, thereby accelerating gliomagenesis. In addition, GDH1 S384 phosphorylation correlates with the malignancy and prognosis of human glioblastoma. Our finding reveals a unique role of α-KG to directly regulate signal pathway, uncovers a distinct mechanism of metabolite-mediated NF-κB activation, and also establishes the critical role of α-KG-activated NF-κB in brain tumor development.


Asunto(s)
Neoplasias Encefálicas/metabolismo , Proliferación Celular , Metabolismo Energético , Glioblastoma/metabolismo , Glucosa/metabolismo , Glutamato Deshidrogenasa/metabolismo , Ácidos Cetoglutáricos/metabolismo , FN-kappa B/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Supervivencia Celular , Niño , Femenino , Regulación Neoplásica de la Expresión Génica , Glioblastoma/genética , Glioblastoma/patología , Glucosa/deficiencia , Transportador de Glucosa de Tipo 1/genética , Transportador de Glucosa de Tipo 1/metabolismo , Glutamato Deshidrogenasa/genética , Células HEK293 , Humanos , Quinasa I-kappa B/genética , Quinasa I-kappa B/metabolismo , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , FN-kappa B/genética , Clasificación del Tumor , Fosforilación , Transducción de Señal , Factor de Transcripción ReIA/genética , Factor de Transcripción ReIA/metabolismo , Adulto Joven
3.
Mol Cell ; 71(2): 201-215.e7, 2018 07 19.
Artículo en Inglés | MEDLINE | ID: mdl-30029001

RESUMEN

Macrophages are a dominant leukocyte population in the tumor microenvironment and actively promote cancer progression. However, the molecular mechanism underlying the role of macrophages remains poorly understood. Here we show that polarized M2 macrophages enhance 3-phosphoinositide-dependent protein kinase 1 (PDPK1)-mediated phosphoglycerate kinase 1 (PGK1) threonine (T) 243 phosphorylation in tumor cells by secreting interleukin-6 (IL-6). This phosphorylation facilitates a PGK1-catalyzed reaction toward glycolysis by altering substrate affinity. Inhibition of PGK1 T243 phosphorylation or PDPK1 in tumor cells or neutralization of macrophage-derived IL-6 abrogates macrophage-promoted glycolysis, proliferation, and tumorigenesis. In addition, PGK1 T243 phosphorylation correlates with PDPK1 activation, IL-6 expression, and macrophage infiltration in human glioblastoma multiforme (GBM). Moreover, PGK1 T243 phosphorylation also correlates with malignance and prognosis of human GBM. Our findings demonstrate a novel mechanism of macrophage-promoted tumor growth by regulating tumor cell metabolism, implicating the therapeutic potential to disrupt the connection between macrophages and tumor cells by inhibiting PGK1 phosphorylation.


Asunto(s)
Macrófagos/metabolismo , Fosfoglicerato Quinasa/genética , Fosfoglicerato Quinasa/metabolismo , Proteínas Quinasas Dependientes de 3-Fosfoinosítido/genética , Proteínas Quinasas Dependientes de 3-Fosfoinosítido/metabolismo , Animales , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Carcinogénesis/metabolismo , Línea Celular Tumoral , Proliferación Celular , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Femenino , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patología , Glucólisis , Humanos , Macrófagos/patología , Ratones , Ratones Desnudos , Mieloma Múltiple/genética , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , Fosforilación , Pronóstico , Microambiente Tumoral
4.
Nature ; 571(7763): 127-131, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31243371

RESUMEN

Cancer metastasis is the primary cause of morbidity and mortality, and accounts for up to 95% of cancer-related deaths1. Cancer cells often reprogram their metabolism to efficiently support cell proliferation and survival2,3. However, whether and how those metabolic alterations contribute to the migration of tumour cells remain largely unknown. UDP-glucose 6-dehydrogenase (UGDH) is a key enzyme in the uronic acid pathway, and converts UDP-glucose to UDP-glucuronic acid4. Here we show that, after activation of EGFR, UGDH is phosphorylated at tyrosine 473 in human lung cancer cells. Phosphorylated UGDH interacts with Hu antigen R (HuR) and converts UDP-glucose to UDP-glucuronic acid, which attenuates the UDP-glucose-mediated inhibition of the association of HuR with SNAI1 mRNA and therefore enhances the stability of SNAI1 mRNA. Increased production of SNAIL initiates the epithelial-mesenchymal transition, thus promoting the migration of tumour cells and lung cancer metastasis. In addition, phosphorylation of UGDH at tyrosine 473 correlates with metastatic recurrence and poor prognosis of patients with lung cancer. Our findings reveal a tumour-suppressive role of UDP-glucose in lung cancer metastasis and uncover a mechanism by which UGDH promotes tumour metastasis by increasing the stability of SNAI1 mRNA.


Asunto(s)
Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/prevención & control , Estabilidad del ARN , Factores de Transcripción de la Familia Snail/genética , Uridina Difosfato Glucosa/metabolismo , Animales , Línea Celular Tumoral , Movimiento Celular , Proteína 1 Similar a ELAV/deficiencia , Proteína 1 Similar a ELAV/genética , Proteína 1 Similar a ELAV/metabolismo , Transición Epitelial-Mesenquimal , Femenino , Humanos , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/metabolismo , Ratones , Ratones Desnudos , Fosfotirosina/metabolismo , Pronóstico , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Neoplásico/genética , ARN Neoplásico/metabolismo , Factores de Transcripción de la Familia Snail/biosíntesis , Uridina Difosfato Glucosa Deshidrogenasa/química , Uridina Difosfato Glucosa Deshidrogenasa/genética , Uridina Difosfato Glucosa Deshidrogenasa/metabolismo , Uridina Difosfato Ácido Glucurónico/metabolismo
5.
Cancer Immunol Immunother ; 73(5): 92, 2024 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-38564022

RESUMEN

Current immune checkpoint inhibiters (ICIs) have contrasting clinical results in poorly immunogenic cancers such as microsatellite-stable colorectal cancer (MSS-CRC). Therefore, understanding and developing the combinational therapeutics for ICI-unresponsive cancers is critical. Here, we demonstrated that the novel topoisomerase I inhibitor TLC388 can reshape the tumor immune landscape, corroborating their antitumor effects combined with radiotherapy as well as immunotherapy. We found that TLC388 significantly triggered cytosolic single-stranded DNA (ssDNA) accumulation for STING activation, leading to type I interferons (IFN-Is) production for increased cancer immunogenicity to enhance antitumor immunity. TLC388-treated tumors were infiltrated by a vast number of dendritic cells, immune cells, and costimulatory molecules, contributing to the favorable antitumor immune response within the tumor microenvironment. The infiltration of cytotoxic T and NK cells were more profoundly existed within tumors in combination with radiotherapy and ICIs, leading to superior therapeutic efficacy in poorly immunogenic MSS-CRC. Taken together, these results showed that the novel topoisomerase I inhibitor TLC388 increased cancer immunogenicity by ssDNA/STING-mediated IFN-I production, enhancing antitumor immunity for better therapeutic efficacy in combination with radiotherapy and ICIs for poorly immunogenic cancer.


Asunto(s)
Camptotecina/análogos & derivados , Neoplasias Colorrectales , Inhibidores de Topoisomerasa I , Humanos , Inhibidores de Topoisomerasa I/farmacología , Inhibidores de Topoisomerasa I/uso terapéutico , Neoplasias Colorrectales/terapia , Citosol , Microambiente Tumoral
6.
Small ; : e2402055, 2024 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-38805743

RESUMEN

Zn ion batteries (ZIBs) are a promising candidate in safe and low-cost large-scale energy storage applications. However, significantly deteriorated cycling stability of Zn anode in high depth of charge or after long-term quiescence impedes the practical application of ZIBs. Aiming at the above issue, a spontaneous solid electrolyte interphase (SEI) formation of Zn4(OH)6SO4·xH2O (ZHS) on Zn powder is achieved in pure ZnSO4 electrolyte by facile and rational interface design. The stable and ultrathin ZHS SEI plays a crucial part in insulating water molecules and conducting Zn2+ ions, intrinsically suppressing the severe hydrogen evolution and dendrite formation on the Zn powder anode. The ZHS-Zn anode delivers a stable cycling at a high DOD of 50% for over 500 h, as well as a lifespan of over 200 h after 40-days of resting at a DOD of 25%. Benefiting from the high utilization of Zn anode, the energy density of the Zn-MnxV2O5 full cell is up to 118 Wh Kg-1. This facile method can fabricate the ZHS-Zn anode as long as 1 m, revealing its feasibility in large-scale production and commercialization.

7.
J Med Virol ; 96(3): e29543, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38528839

RESUMEN

Amidst the COVID-19 pandemic, uncertainty persists among caregivers regarding the vaccination of pediatric liver transplant recipients (PLTRs). This study evaluates the immunogenicity and safety of COVID-19 vaccination in this vulnerable population. A cohort of 30 PLTRs underwent sequential vaccinations with an inactivated SARS-CoV-2 vaccine followed by an Ad5-nCoV booster. We collected and analyzed blood samples pre-vaccination and four weeks post-vaccination to quantify antibody and IGRA (IFN-γ Release Assay) levels. We also documented any adverse reactions occurring within seven days post-vaccination and monitored participants for infections over six months post-vaccination, culminating in a comprehensive statistical analysis. The Ad5-nCoV booster substantially elevated IgG (T1: 18.01, 20%; T2: 66.61, 55%) and nAb (T1: 119.29, 8%; T2: 3799.75, 80%) levels, as well as T-cell responses, in comparison to the initial dose. The first dose was associated with some common adverse reactions, such as injection site pain (13.3%) and fever (16.6%), but a low rate of systemic reactions (16.0%). There was no significant difference in Omicron infection rates or RTPCR conversion times between vaccinated and unvaccinated groups. Notably, following Omicron infection, vaccinated individuals exhibited significantly higher SARS-CoV-2 IgG and nAb titers (average IgG: 231.21 vs. 62.09 S/CO, p = 0.0003; nAb: 5246.11 vs. 2592.07 IU/mL, p = 0.0002). The use of inactivated vaccines followed by an Ad5-nCoV booster in PLTRs is generally safe and elicits a robust humoral response, albeit with limited T-cell responses.


Asunto(s)
COVID-19 , Trasplante de Hígado , Humanos , Niño , Vacunas contra la COVID-19/efectos adversos , COVID-19/prevención & control , Pandemias , SARS-CoV-2 , Anticuerpos Antivirales , Inmunoglobulina G , Vacunas de Productos Inactivados/efectos adversos , Anticuerpos Neutralizantes , Vacunación
8.
Fish Shellfish Immunol ; 146: 109418, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38301811

RESUMEN

The rice fish system represents an innovative and sustainable approach to integrated farming, combining rice cultivation with fish rearing in the same ecosystem. However, one of the major challenges in this system is the pesticidal pollution resulting from various sources, which poses risks to fish health and overall ecosystem balance. In recent years, dietary polyphenols have emerged as promising bioactive compounds with potential chemo-preventive and therapeutic properties. These polyphenols, derived from various plant sources, have shown great potential in reducing the toxicity of pesticides and improving the health of fish within the rice fish system. This review aims to explore the novel aspects of using dietary polyphenols to mitigate pesticidal toxicity and enhance fish health in the rice fish system. It provides comprehensive insights into the mechanisms of action of dietary polyphenols and their beneficial effects on fish health, including antioxidant, anti-inflammatory, and detoxification properties. Furthermore, the review discusses the potential application methods of dietary polyphenols, such as direct supplementation in fish diets or through incorporation into the rice fields. By understanding the interplay between dietary polyphenols and pesticides in the rice fish system, researchers can develop innovative and sustainable strategies to promote fish health, minimize pesticide impacts, and ensure the long-term viability of this integrated farming approach. The information presented in this review will be valuable for scientists, aqua-culturists, and policymakers aiming to implement eco-friendly and health-enhancing practices in the rice fish system.


Asunto(s)
Oryza , Plaguicidas , Animales , Ecosistema , Agricultura/métodos , Plaguicidas/toxicidad , Plaguicidas/análisis , Peces , Polifenoles/farmacología
10.
Neurol Sci ; 45(6): 2681-2696, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38265536

RESUMEN

BACKGROUND: Parkinson's disease (PD) ranks as the second most prevalent neurodegenerative disorder globally, and its incidence is rapidly rising. The diagnosis of PD relies on clinical characteristics. Although current treatments aim to alleviate symptoms, they do not effectively halt the disease's progression. Early detection and intervention hold immense importance. This study aimed to establish a new PD diagnostic model. METHODS: Data from a public database were adopted for the construction and validation of a PD diagnostic model with random forest and artificial neural network models. The CIBERSORT platform was applied for the evaluation of immune cell infiltration in PD. Quantitative real-time PCR was performed to verify the accuracy and reliability of the bioinformatics analysis results. RESULTS: Leveraging existing gene expression data from the Gene Expression Omnibus (GEO) database, we sifted through differentially expressed genes (DEGs) in PD and identified 30 crucial genes through a random forest classifier. Furthermore, we successfully designed a novel PD diagnostic model using an artificial neural network and verified its diagnostic efficacy using publicly available datasets. Our research also suggests that mast cells may play a significant role in the onset and progression of PD. CONCLUSION: This work developed a new PD diagnostic model with machine learning techniques and suggested the immune cells as a potential target for PD therapy.


Asunto(s)
Redes Neurales de la Computación , Enfermedad de Parkinson , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/inmunología , Enfermedad de Parkinson/diagnóstico , Humanos , Aprendizaje Automático , Transcriptoma , Biología Computacional , Perfilación de la Expresión Génica , Mastocitos/inmunología , Bosques Aleatorios
11.
Ren Fail ; 46(1): 2313176, 2024 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38482886

RESUMEN

OBJECTIVE: This study was designed to observe the effect of toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) pathway activity on sepsis-associated acute kidney injury (SA-AKI), thereby providing new considerations for the prevention and treatment of SA-AKI. METHODS: The rats were divided into Sham, cecal ligation and puncture (CLP), CLP + vehicle, and CLP + TAK-242 groups. Except the Sham group, a model of CLP-induced sepsis was established in other groups. After 24 h, the indicators related to kidney injury in blood samples were detected. The pathological changes in the kidneys were observed by hematoxylin-eosin staining, and tubular damage was scored. Oxidative stress-related factors, mitochondrial dysfunction-related indicators in each group were measured; the levels of inflammatory factors in serum and kidney tissue of rats were examined. Finally, the expression of proteins related to the TLR4/NF-κB signaling pathway was observed by western blot. RESULTS: Compared with the CLP + vehicle and CLP + TAK-242 groups, the CLP + TAK-242 group reduced blood urea nitrogen (BUN), creatinine (Cr), cystatin-C (Cys-C), reactive oxygen species (ROS), malondialdehyde (MDA), and inflammatory factors levels (p < 0.01), as well as increased superoxide dismutase (SOD) activity of CLP rats (p < 0.01). Additionally, TAK-242 treatment improved the condition of CLP rats that had glomerular and tubular injuries and mitochondrial disorders (p < 0.01). Further mechanism research revealed that TAK-242 can inhibit the TLR4/NF-κB signaling pathway activated by CLP (p < 0.01). Above indicators after TAK-242 treatment were close to those of the Sham group. CONCLUSION: TAK-242 can improve oxidative stress, mitochondrial dysfunction, and inflammatory response by inhibiting the activity of TLR4/NF-κB signaling pathway, thereby preventing rats from SA-AKI.


Asunto(s)
Lesión Renal Aguda , Enfermedades Mitocondriales , Sepsis , Sulfonamidas , Ratas , Animales , FN-kappa B/metabolismo , Receptor Toll-Like 4/metabolismo , Transducción de Señal , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/etiología , Lesión Renal Aguda/prevención & control , Sepsis/complicaciones , Sepsis/tratamiento farmacológico , Sepsis/metabolismo
12.
J Clin Nurs ; 33(3): 1209-1218, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38284439

RESUMEN

AIMS AND OBJECTIVES: This study aims to propose a self-management clusters classification method to determine the self-management ability of elderly patients with mild cognitive impairment (MCI) associated with diabetes mellitus (DM). BACKGROUND: MCI associated with DM is a common chronic disease in old adults. Self-management affects the disease progression of patients to a large extent. However, the comorbidity and patients' self-management ability are heterogeneous. DESIGN: A cross-sectional study based on cluster analysis is designed in this paper. METHOD: The study included 235 participants. The diabetes self-management scale is used to evaluate the self-management ability of patients. SPSS 21.0 was used to analyse the data, including descriptive statistics, agglomerative hierarchical clustering with Ward's method before k-means clustering, k-means clustering analysis, analysis of variance and chi-square test. RESULTS: Three clusters of self-management styles were classified as follows: Disease neglect type, life oriented type and medical dependence type. Among all participants, the percentages of the three clusters above are 9.78%, 32.77% and 57.45%, respectively. The difference between the six dimensions of each cluster is statistically significant. CONCLUSION(S): This study classified three groups of self-management styles, and each group has its own self-management characteristics. The characteristics of the three clusters may help to provide personalized self-management strategies and delay the disease progression of MCI associated with DM patients. RELEVANCE TO CLINICAL PRACTICE: Typological methods can be used to discover the characteristics of patient clusters and provide personalized care to improve the efficiency of patient self-management to delay the progress of the disease. PATIENT OR PUBLIC CONTRIBUTION: In our study, we invited patients and members of the public to participate in the research survey and conducted data collection.


Asunto(s)
Disfunción Cognitiva , Diabetes Mellitus , Automanejo , Adulto , Humanos , Anciano , Estudios Transversales , Diabetes Mellitus/terapia , Disfunción Cognitiva/complicaciones , Progresión de la Enfermedad
13.
Nano Lett ; 23(22): 10571-10578, 2023 Nov 22.
Artículo en Inglés | MEDLINE | ID: mdl-37929933

RESUMEN

Two-dimensional (2D) carbon nitride (CN) materials have received tremendous attention as photocatalysts for clean energy and environmental treatment. However, the photocatalytic efficiency of CN is constrained by the high exciton binding energy and sluggish charge kinetics due to weak dielectric screening, impeding the overall process. Herein, localized flexo-/piezoelectric polarization is introduced via strain engineering, boosting exciton dissociation and promoting charge separation to enhance the multielectron photocatalytic process. Consequently, the exciton binding energy of polarized CN is reduced from 52 to 34 meV, and the hydrogen evolution yield increased by 2.9 times compared to that of the pristine CN. For other photocatalytic reactions (e.g., H2O2 production), the polarized CN also maintained a 2.1-fold increase compared to the pristine CN. This strategy of inducing localized polarization via strain engineering provides new insights for boosting photocatalytic reactions involving electrons.

14.
Zhongguo Dang Dai Er Ke Za Zhi ; 26(5): 499-505, 2024 May 15.
Artículo en Zh | MEDLINE | ID: mdl-38802911

RESUMEN

OBJECTIVES: To summarize the clinical data of 7 children with activated phosphoinositide 3-kinase delta syndrome (APDS) and enhance understanding of the disease. METHODS: A retrospective analysis was conducted on clinical data of 7 APDS children admitted to Hunan Provincial People's Hospital from January 2019 to August 2023. RESULTS: Among the 7 children (4 males, 3 females), the median age of onset was 30 months, and the median age at diagnosis was 101 months. Recurrent respiratory tract infections, hepatosplenomegaly, and multiple lymphadenopathy were observed in all 7 cases. Sepsis was observed in 5 cases, otitis media and multiple caries were observed in 3 cases, and diarrhea and joint pain were observed in 2 cases. Lymphoma and systemic lupus erythematosus were observed in 1 case each. Fiberoptic bronchoscopy was performed in 4 cases, revealing scattered nodular protrusions in the bronchial lumen. The most common respiratory pathogen was Streptococcus pneumoniae (4 cases). Six patients had a p.E1021K missense mutation, and one had a p.434-475del splice site mutation. CONCLUSIONS: p.E1021K is the most common mutation site in APDS children. Children who present with one or more of the following symptoms: recurrent respiratory tract infections, hepatosplenomegaly, multiple lymphadenopathy, otitis media, and caries, and exhibit scattered nodular protrusions on fiberoptic bronchoscopy, should be vigilant for APDS. Citation:Chinese Journal of Contemporary Pediatrics, 2024, 26(5): 499-505.


Asunto(s)
Fosfatidilinositol 3-Quinasa Clase I , Humanos , Femenino , Masculino , Preescolar , Niño , Fosfatidilinositol 3-Quinasa Clase I/genética , Estudios Retrospectivos , Infecciones del Sistema Respiratorio , Mutación , Enfermedades de Inmunodeficiencia Primaria/genética , Lactante
15.
Cancer Immunol Immunother ; 72(7): 2283-2297, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-36881132

RESUMEN

The CD39-CD73-adenosinergic pathway converts adenosine triphosphate (ATP) to adenosine for inhibiting anti-tumor immune responses. Therefore, targeting CD73 to reinvigorate anti-tumor immunity is considered the novel cancer immunotherapy to eradicate tumor cells. To fully understand the critical role of CD39/CD73 in colon adenocarcinoma (COAD), this study aims to comprehensive investigate the prognostic significance of CD39 and CD73 in stage I-IV COAD. Our data demonstrated that CD73 staining strongly marked malignant epithelial cells and CD39 was highly expressed in stromal cells. Attractively, tumor CD73 expression was significantly associated with tumor stage and the risk of distant metastasis, which suggested CD73 was as an independent factor for colon adenocarcinoma patients in univariate COX analysis [HR = 1.465, 95%CI = 1.084-1.978, p = 0.013]; however, high stromal CD39 in COAD patients was more likely to have favorable survival outcome [HR = 1.458, p = 1.103-1.927, p = 0.008]. Notably, high CD73 expression in COAD patients showed poor response to adjuvant chemotherapy and high risk of distant metastasis. High CD73 expression was inversely associated with less infiltration of CD45+ and CD8+ immune cells. However, administration with anti-CD73 antibodies significantly increased the response to oxaliplatin (OXP). Blockade of CD73 signaling synergistically enhanced OXP-induced ATP release, which is a marker of immunogenic cell death (ICD), promotes dendritic cell maturation and immune cell infiltration. Moreover, the risk of colorectal cancer lung metastasis was also decreased. Taken together, the present study revealed tumor CD73 expression inhibited the recruitment of immune cells and correlated with a poor prognosis in COAD patients, especially patients received adjuvant chemotherapy. Targeting CD73 to markedly increased the therapeutic response to chemotherapy and inhibited lung metastasis. Therefore, tumor CD73 may be an independent prognostic factor as well as the potential of therapeutic target for immunotherapy to benefit colon adenocarcinoma patients.


Asunto(s)
Adenocarcinoma , Neoplasias del Colon , Neoplasias Pulmonares , Humanos , Adenocarcinoma/patología , Neoplasias del Colon/tratamiento farmacológico , Adenosina Trifosfato/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Oxaliplatino/uso terapéutico , Células Dendríticas/metabolismo
16.
Neurochem Res ; 48(11): 3457-3471, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37470906

RESUMEN

The objective of this research was to investigate the role of lncRNA MALAT1 and HSP90 in the regulation of neuronal necroptosis in mice with cerebral ischemia-reperfusion (CIR). We used male C57BL/6J mice to establish a middle cerebral artery occlusion (MCAO) model and conducted in vitro experiments using the HT-22 mouse hippocampal neuron cell line. The cellular localization of NeuN and MLKL, as well as the expression levels of neuronal necroptosis factors, MALAT1, and HSP90 were analyzed. Cell viability and necroptosis were assessed, and we also investigated the relationship between MALAT1 and HSP90. The results showed that MALAT1 expression increased after MCAO and oxygen-glucose deprivation/re-oxygenation (OGD/R) treatment in both cerebral tissues and cells compared with the control group. The levels of neuronal necroptosis factors and the co-localization of NeuN and MLKL were also increased in MCAO mice compared with the Sham group. MALAT1 was found to interact with HSP90, and inhibition of HSP90 expression led to decreased phosphorylation levels of neuronal necroptosis factors. Inhibition of MALAT1 expression resulted in decreased co-localization levels of NeuN and MLKL, decreased phosphorylation levels of neuronal necroptosis factors, and reduced necroptosis rate in cerebral tissues. Furthermore, inhibiting MALAT1 expression also led to a shorter half-life of HSP90, increased ubiquitination level, and decreased phosphorylation levels of neuronal necroptosis factors in cells. In conclusion, this study demonstrated that lncRNA MALAT1 promotes neuronal necroptosis in CIR mice by stabilizing HSP90.


Asunto(s)
Isquemia Encefálica , Proteínas HSP90 de Choque Térmico , ARN Largo no Codificante , Daño por Reperfusión , Animales , Masculino , Ratones , Apoptosis/genética , Isquemia Encefálica/metabolismo , Glucosa/metabolismo , Infarto de la Arteria Cerebral Media/metabolismo , Ratones Endogámicos C57BL , MicroARNs/metabolismo , Necroptosis , Neuronas/metabolismo , Reperfusión , Daño por Reperfusión/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Proteínas HSP90 de Choque Térmico/metabolismo
17.
BMC Endocr Disord ; 23(1): 240, 2023 Nov 02.
Artículo en Inglés | MEDLINE | ID: mdl-37919711

RESUMEN

BACKGROUND: Mild cognitive impairment (MCI) associated with diabetes mellitus (DM) is common among older adults, and self-management is critical to controlling disease progression. However, both MCI and DM are heterogeneous diseases, and existing integrated self-management interventions do not consider patient differences. Grouping patients by disease characteristics could help to individualize disease management and improve the use of available resources. The current study sought to explore the feasibility and effectiveness of a stratified support model for DM-MCI patients. METHODS: Eighty-four DM-MCI patients will be randomly divided into an intervention group and a control group in a 1:1 ratio. The intervention group will receive a self-management intervention using the stratified support pattern-based internet-assisted therapy (SISMT), while the control group will receive the health manual intervention (HMI). The study recruiter will be blinded to the group allocation and unable to foresee which group the next participant will be assigned to. At the same time, the allocation will be also hidden from the research evaluators and participants. After 12 weeks and 24 weeks, cognitive function, blood glucose, self-management ability, psychological status, health literacy, and self-management behavior of patients in both groups will be measured and compared. DISCUSSION: This study developed a stratified support pattern-based internet-assisted to provide self-management intervention for patients with DM-MCI. The impact of different models and forms of self-management intervention on cognitive function, blood glucose management, and psychological status health literacy and self-management behavior of patients will be assessed. The results of this study will inform related intervention research on the stratified support pattern-based internet-assisted self-management therapy, and help to slow the decline of cognitive function in patients with DM-MCI. TRIAL REGISTRATION: ChiCTR2200061991. Registered 16 July 2022.


Asunto(s)
Disfunción Cognitiva , Diabetes Mellitus , Automanejo , Humanos , Anciano , Glucemia , Disfunción Cognitiva/terapia , Disfunción Cognitiva/psicología , Internet , Ensayos Clínicos Controlados Aleatorios como Asunto
18.
Nature ; 550(7674): 142, 2017 09 20.
Artículo en Inglés | MEDLINE | ID: mdl-28953868

RESUMEN

This corrects the article DOI: 10.1038/nature10598.

19.
J Cell Physiol ; 237(3): 1845-1856, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-34881818

RESUMEN

Abdominal irradiation (IR) may destroy the intestinal mucosal barrier, leading to severe intestinal infection and multiple organ dysfunction syndromes. The role of intestinal microbiota in the development of IR-induced intestinal injury remains largely unknown. Herein, we reported that abdominal IR altered the composition of the microbiota and reduced the abundance and diversity of the gut microbiome. Alterations of bacteria, in particular reduction of Lactobacillus, played a critical role in IR-induced intestinal injury. Fecal microbiota transplant (FMT) from normal mice or administration of Lactobacillus plantarum to intestinal microbiota-eliminated mice substantially reduced IR-induced intestinal damage and prevented mice from IR-induced death. We further characterized that L. plantarum activated the farnesoid X receptor (FXR) - fibroblast growth factor 15 (FGF15) signaling in intestinal epithelial cells and hence promoted DNA-damage repair. Application of GW4064, an activator of FXR, to microbiota eliminated mice markedly mitigated IR-induced intestinal damage, reduced intestinal epithelial cell death and promoted the survival of IR mice. In contrast, suppression of FXR with Gly-ß-MCA, a bile acid and an intestine-selective and high-affinity FXR inhibitor, abrogated L. Plantarum-mediated protection on the ileum of IR mice. Taken together, our findings not only provide new insights into the role of intestinal flora in radiation-induced intestinal injury but also shed new light on the application of probiotics for the protection of radiation-damaged individuals.


Asunto(s)
Microbioma Gastrointestinal , Lactobacillus plantarum , Animales , Ácidos y Sales Biliares , Microbioma Gastrointestinal/fisiología , Mucosa Intestinal/metabolismo , Intestinos , Ratones , Ratones Endogámicos C57BL
20.
Opt Express ; 30(19): 34510-34518, 2022 Sep 12.
Artículo en Inglés | MEDLINE | ID: mdl-36242461

RESUMEN

In the rapidly changing moisture air, conventional relative humidity (RH) sensors are often difficult to respond in time and accurately due to the limitation of flow rate and non-uniform airflow distribution. In this study, we numerically demonstrate that humidity changes on micro-zones can be monitored in real time using a Bloch surface wave (BSW) ubiquitous in one-dimensional photonic crystals (1DPC). This phenomenon can be observed by leakage radiation microscope (LRM). After theoretically deriving the angular resolution limit of LRM, we obtained the minimum BSW angular change on a practical scheme that can be observed in the momentum space to complete the detection, and realized the dynamic real-time monitoring of small-scale humidity change in experiment for the first time. This monitoring method has extremely high figure of merit (FOM) without hysteresis, which can be used in humidity sensing and refractive index sensing as well as the research on turbulence.

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