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1.
Cell ; 148(1-2): 259-72, 2012 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-22225612

RESUMEN

Identification of the factors critical to the tumor-initiating cell (TIC) state may open new avenues in cancer therapy. Here we show that the metabolic enzyme glycine decarboxylase (GLDC) is critical for TICs in non-small cell lung cancer (NSCLC). TICs from primary NSCLC tumors express high levels of the oncogenic stem cell factor LIN28B and GLDC, which are both required for TIC growth and tumorigenesis. Overexpression of GLDC and other glycine/serine enzymes, but not catalytically inactive GLDC, promotes cellular transformation and tumorigenesis. We found that GLDC induces dramatic changes in glycolysis and glycine/serine metabolism, leading to changes in pyrimidine metabolism to regulate cancer cell proliferation. In the clinic, aberrant activation of GLDC correlates with poorer survival in lung cancer patients, and aberrant GLDC expression is observed in multiple cancer types. This link between glycine metabolism and tumorigenesis may provide novel targets for advancing anticancer therapy.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/enzimología , Transformación Celular Neoplásica , Glicina-Deshidrogenasa (Descarboxilante)/metabolismo , Neoplasias Pulmonares/metabolismo , Secuencia de Aminoácidos , Antígenos CD/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Moléculas de Adhesión Celular Neuronal/metabolismo , Línea Celular Tumoral , Proteínas de Unión al ADN/metabolismo , Proteínas Fetales/metabolismo , Glicina/metabolismo , Humanos , Datos de Secuencia Molecular , Neoplasias/enzimología , Neoplasias/genética , Proteínas de Unión al ARN , Alineación de Secuencia , Serina/metabolismo , Thermus thermophilus/enzimología , Trasplante Heterólogo
2.
Yeast ; 41(3): 108-127, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38450805

RESUMEN

Schizosaccharomyces japonicus Yukawa et Maki (1931) and Schizosaccharomyces versatilis Wickerham et Duprat (1945) have been treated as varieties of S. japonicus or as conspecific, based on various approaches including mating trials and nDNA/nDNA optical reassociation studies. However, the type strains of S. japonicus and S. versatilis differ by five substitutions (99.15% identity) and one 1-bp indel in the sequences of the D1/D2 domain of the 26S rRNA gene, and 23 substitutions (96.3% identity) and 31-bp indels in the sequences of internal transcribed spacer (ITS) of rRNA, suggesting that they may not be conspecific. To reassess their taxonomic status, we conducted mating trials and whole-genome analyses. Mating trials using the type strains showed a strong but incomplete prezygotic sterility barrier, yielding interspecies mating products at two orders of magnitude lower efficiency than intraspecies matings. These mating products, which were exclusively allodiploid hybrids, were unable to undergo the haplontic life cycle of the parents. We generated chromosome-level gap-less genome assemblies for both type strains. Whole genome sequences yielded an average nucleotide identity (ANI) of 86.4%, indicating clear separation of S. japonicus and S. versatilis. Based on these findings, we propose the reinstatement of S. versatilis as a distinct species (holotype strain: CBS 103T and ex-types: NRRL Y-1026, NBRC 1607, ATCC 9987, PYCC 7100; Mycobank no.: 847838).


Asunto(s)
Schizosaccharomyces , Schizosaccharomyces/genética , Filogenia , Análisis de Secuencia de ADN
3.
Cell Commun Signal ; 22(1): 438, 2024 Sep 11.
Artículo en Inglés | MEDLINE | ID: mdl-39261825

RESUMEN

Pathological cardiac hypertrophy is the primary cause of heart failure, yet its underlying mechanisms remain incompletely understood. Transmembrane protein 100 (TMEM100) plays a role in various disorders, such as nervous system disease, pain and tumorigenesis, but its function in pathological cardiac hypertrophy is still unknown. In this study, we observed that TMEM100 is upregulated in cardiac hypertrophy. Functional investigations have shown that adeno-associated virus 9 (AAV9) mediated-TMEM100 overexpression mice attenuates transverse aortic constriction (TAC)-induced cardiac hypertrophy, including cardiomyocyte enlargement, cardiac fibrosis, and impaired heart structure and function. We subsequently demonstrated that adenoviral TMEM100 (AdTMEM100) mitigates phenylephrine (PE)-induced cardiomyocyte hypertrophy and downregulates the expression of cardiac hypertrophic markers in vitro, whereas TMEM100 knockdown exacerbates cardiomyocyte hypertrophy. The RNA sequences of the AdTMEM100 group and control group revealed that TMEM100 was involved in oxidative stress and the MAPK signaling pathway after PE stimulation. Mechanistically, we revealed that the transmembrane domain of TMEM100 (amino acids 53-75 and 85-107) directly interacts with the C-terminal region of TAK1 (amino acids 1-300) and inhibits the phosphorylation of TAK1 and its downstream molecules JNK and p38. TAK1-binding-defective TMEM100 failed to inhibit the activation of the TAK1-JNK/p38 pathway. Finally, the application of a TAK1 inhibitor (iTAK1) revealed that TAK1 is necessary for TMEM100-mediated cardiac hypertrophy. In summary, TMEM100 protects against pathological cardiac hypertrophy through the TAK1-JNK/p38 pathway and may serve as a promising target for the treatment of cardiac hypertrophy.


Asunto(s)
Cardiomegalia , Quinasas Quinasa Quinasa PAM , Proteínas de la Membrana , Miocitos Cardíacos , Animales , Cardiomegalia/genética , Cardiomegalia/metabolismo , Cardiomegalia/patología , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Quinasas Quinasa Quinasa PAM/metabolismo , Quinasas Quinasa Quinasa PAM/genética , Ratones , Ratones Endogámicos C57BL , Masculino , Progresión de la Enfermedad , Humanos , Fenilefrina/farmacología , Sistema de Señalización de MAP Quinasas , Estrés Oxidativo
4.
Br J Cancer ; 128(9): 1647-1664, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36810913

RESUMEN

BACKGROUND: Lung cancer cells overexpress mucin 1 (MUC1) and active subunit MUC1-CT. Although a peptide blocks MUC1 signalling, metabolites targeting MUC1 are not well studied. AICAR is a purine biosynthesis intermediate. METHODS: Cell viability and apoptosis were measured in AICAR-treated EGFR-mutant and wild-type lung cells. AICAR-binding proteins were evaluated by in silico and thermal stability assays. Protein-protein interactions were visualised by dual-immunofluorescence staining and proximity ligation assay. AICAR-induced whole transcriptomic profile was determined by RNA sequencing. EGFR-TL transgenic mice-derived lung tissues were analysed for MUC1 expression. Organoids and tumours from patients and transgenic mice were treated with AICAR alone or in combination with JAK and EGFR inhibitors to evaluate treatment effects. RESULTS: AICAR reduced EGFR-mutant tumour cell growth by inducing DNA damage and apoptosis. MUC1 was one of the leading AICAR-binding and degrading proteins. AICAR negatively regulated JAK signalling and JAK1-MUC1-CT interaction. Activated EGFR upregulated MUC1-CT expression in EGFR-TL-induced lung tumour tissues. AICAR reduced EGFR-mutant cell line-derived tumour formation in vivo. Co-treating patient and transgenic mouse lung-tissue-derived tumour organoids with AICAR and JAK1 and EGFR inhibitors reduced their growth. CONCLUSIONS: AICAR represses the MUC1 activity in EGFR-mutant lung cancer, disrupting protein-protein interactions between MUC1-CT and JAK1 and EGFR.


Asunto(s)
Receptores ErbB , Neoplasias Pulmonares , Ratones , Animales , Receptores ErbB/genética , Receptores ErbB/metabolismo , Mucina-1/genética , Mucina-1/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Pulmón/metabolismo , Ratones Transgénicos , Proteínas Oncogénicas , Purinas , Línea Celular Tumoral
5.
J Neuroinflammation ; 18(1): 64, 2021 Mar 02.
Artículo en Inglés | MEDLINE | ID: mdl-33653377

RESUMEN

BACKGROUND: Immune cell infiltration and neuroinflammation are heavily associated with spinal cord injury (SCI). C-C motif chemokine ligand 2/C-C chemokine receptor type 2 (CCL2/CCR2) axis has been identified as a critical role player during the invasion of immune cells to lesions in many diseases. γδ T cells, a subgroup of T cells, manage the course of inflammation response in various diseases; however, it remains unknown whether γδ T cells are recruited to injury site through CCL2/CCR2 signaling and exert the regulation effect on neuroinflammation after SCI. METHODS: Basso Mouse Scale (BMS), regularity index, cadence, max contact area, and motor-evoked potential testing (MEP) were measured to determine the neurological function recovery after spinal cord injury. Nissl staining was performed to identify the number of surviving motor neurons at lesion epicenter. Immunofluorescence, Western blot, enzyme-linked immunosorbent assays (ELISA), and quantitative real-time polymerase chain reaction (QRT-PCR) also were employed to evaluate the expression of associated proteins and genes. RESULTS: In this study, we demonstrated that TCRδ-/- mice present improved neurological recovery after SCI. γδ T cell recruitment to the SCI site was significantly reduced and motor functional improvement enhanced in CCL2-/- and CCR2-/- mouse strains. Furthermore, reconstitution of TCRδ-/- mice with γδ T cells extracted from CCR2-/- mice also showed similar results to CCL2 and CCR2 deficient mice. CONCLUSIONS: In conclusion, γδ T cell recruitment to SCI site promotes inflammatory response and exacerbates neurological impairment. CCL2/CCR2 signaling is a vital recruitment mechanism of γδ T cells to the SCI site, and it may be taken as a novel therapeutic target for future SCI.


Asunto(s)
Quimiocina CCL2/inmunología , Receptores CCR2/inmunología , Transducción de Señal/inmunología , Traumatismos de la Médula Espinal/inmunología , Linfocitos T/inmunología , Animales , Quimiocina CCL2/metabolismo , Quimiotaxis de Leucocito/inmunología , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Receptores CCR2/metabolismo , Traumatismos de la Médula Espinal/patología , Linfocitos T/metabolismo
6.
Nutr Cancer ; 73(2): 215-220, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-32336142

RESUMEN

Background: Preoperative assessment of patients is meaningful to predict survival in patients with malignant tumors. The prognostic nutritional index (PNI) is one of the most significant factors related to the prognosis in various types of cancer; however, its role in esophageal cancer is still inconclusive. The aim of this study was to identify the prognostic value of PNI in predicting overall survival (OS) in esophageal squamous cell carcinoma (ESCC).Methods: This retrospective study included 4146 ESCC patients, 3812 who underwent esophagectomy for ESCC. Other 334 had no surgery. The Preoperative PNI was measured before any therapies and calculated as 10 × serum albumin (g/dL) + 0.005 × total lymphocyte count (per mm3). We classified the patients into three categories according to the PNI, >50, 45-50, and <45.Results: Our study showed that PNI was associated with age (P<0.0001), gender(P<0.001),tumor length (P<0.0001), T grade (P = 0.001), N staging (P = 0.017),and M staging (P<0.0001). Multivariate analysis showed that PNI was a significant predictor of overall survival Lower PNI vs. Higher PNI group had significantly increased the hazard ratio of ESCC survival (OR = 1.2, 95% CI= 1.05-1.5, p = 0.01). The Kaplan-Meier curve suggested that high PNI group will significantly increase the OS in both surgical and non-surgical group.Conclusion: PNI is a useful predictive factor for long-term survival in ESCC. The survival rate of ESCC can be discriminated between three groups, PNI, >50, 45-50, and <45. The prognostic value of PNI can be applied for both surgical and non-surgical ESCC patients.


Asunto(s)
Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Neoplasias de Cabeza y Cuello , Neoplasias Esofágicas/cirugía , Carcinoma de Células Escamosas de Esófago/cirugía , Humanos , Evaluación Nutricional , Estado Nutricional , Pronóstico , Estudios Retrospectivos
7.
Int J Mol Sci ; 21(8)2020 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-32316322

RESUMEN

Lung cancer is one of the deadliest forms of cancer affecting society today. Non-coding RNAs, such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), through the transcriptional, post-transcriptional, and epigenetic changes they impose, have been found to be dysregulated to affect lung cancer tumorigenesis and metastasis. This review will briefly summarize hallmarks involved in lung cancer initiation and progression. For initiation, these hallmarks include tumor initiating cells, immortalization, activation of oncogenes and inactivation of tumor suppressors. Hallmarks involved in lung cancer progression include metastasis and drug tolerance and resistance. The targeting of these hallmarks with non-coding RNAs can affect vital metabolic and cell signaling pathways, which as a result can potentially have a role in cancerous and pathological processes. By further understanding non-coding RNAs, researchers can work towards diagnoses and treatments to improve early detection and clinical response.


Asunto(s)
Neoplasias Pulmonares/patología , ARN Largo no Codificante/metabolismo , Ácidos Nucleicos Libres de Células/metabolismo , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , MicroARNs/metabolismo , Metástasis de la Neoplasia , Células Madre Neoplásicas/citología , Células Madre Neoplásicas/metabolismo , ARN Circular/metabolismo
8.
Int J Mol Sci ; 20(23)2019 Dec 03.
Artículo en Inglés | MEDLINE | ID: mdl-31816897

RESUMEN

Relapsed disease following first-line therapy remains one of the central problems in cancer management, including chemotherapy, radiotherapy, growth factor receptor-based targeted therapy, and immune checkpoint-based immunotherapy. Cancer cells develop therapeutic resistance through both intrinsic and extrinsic mechanisms including cellular heterogeneity, drug tolerance, bypassing alternative signaling pathways, as well as the acquisition of new genetic mutations. Reactive oxygen species (ROSs) are byproducts originated from cellular oxidative metabolism. Recent discoveries have shown that a disabled antioxidant program leads to therapeutic resistance in several types of cancers. ROSs are finely tuned by dysregulated microRNAs, and vice versa. However, mechanisms of a crosstalk between ROSs and microRNAs in regulating therapeutic resistance are not clear. Here, we summarize how the microRNA-ROS network modulates cancer therapeutic tolerance and resistance and direct new vulnerable targets against drug tolerance and resistance for future applications.


Asunto(s)
Resistencia a Antineoplásicos , MicroARNs/metabolismo , Neoplasias/patología , Neoplasias/terapia , Estrés Oxidativo , Animales , Resistencia a Antineoplásicos/genética , Epigénesis Genética , Humanos , MicroARNs/genética , Neoplasias/genética , Neoplasias/metabolismo , Estrés Oxidativo/genética , Especies Reactivas de Oxígeno/metabolismo
9.
Anal Chem ; 90(17): 10279-10285, 2018 09 04.
Artículo en Inglés | MEDLINE | ID: mdl-30106558

RESUMEN

MicroRNAs (miRNA) are short, noncoding RNAs that have been implicated in many diseases, including cancers. Because miRNAs are dysregulated in disease, miRNAs show promise as highly stable biomarkers. Formalin-fixed, paraffin-embedded (FFPE) tissue is a valuable sample type to assay for biomolecules because it is a convenient storage method and is often used by pathologists for histological staining. However, extracting biomolecules from FFPE tissue is challenging because of the presence of cellular and extracellular proteins, formaldehyde cross-links, and paraffin. Moreover, most protocols to measure miRNA in FFPE tissue are time-consuming and laborious. Here, we report a simple protocol to directly measure miRNA from formalin-fixed cells, FFPE tissue sections after paraffin is removed, and FFPE tissue sections using encoded hydrogel microparticles fabricated using stop flow lithography. Measurements by these particles show agreement between formalin-fixed cells and fresh cells, and measurement of FFPE tissue with paraffin is 10% less than FFPE tissue when paraffin is removed before the assay. When normal and tumor FFPE tissue are compared using this microparticle assay, we observe differential miRNA signal for oncogenic miRNAs and tumor suppressing miRNAs. This approach reduces assay times, reduces the use of hazardous chemicals to remove paraffin, and provides a sensitive, quantitative, and multiplexed measurement of miRNA in FFPE tissue.


Asunto(s)
Formaldehído/química , Hidrogeles , MicroARNs/química , Adhesión en Parafina , Animales , Carcinoma de Pulmón de Células no Pequeñas/genética , Línea Celular Tumoral , Femenino , Humanos , Pulmón/metabolismo , Neoplasias Pulmonares/genética , Ratones , Ratones Desnudos , Tamaño de la Partícula
10.
Cell Physiol Biochem ; 38(6): 2438-51, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27287545

RESUMEN

BACKGROUND/AIMS: Myeloid-derived suppressor cells (MDSCs) are increased in inflammatory and autoimmune disorders. This study aims to evaluate the significance of MDSCs in dilated cardiomyopathy (DCM) patients. METHODS: In total, 42 newly hospitalized DCM patients and 39 healthy controls were enrolled in the study. The frequencies of circulating CD14+HLA-DR-/low MDSCs were determined by flow cytometry. Then, the functional properties of MDSCs in suppressing T cell proliferation and interferon-gamma (IFN-x03B3;) production were measured in a co-culture model. Then, mRNA expression levels of various important molecules in peripheral blood mononuclear cells were measured by real time polymerase chain reaction. Furthermore, correlation analyses between MDSC frequencies and cardiac function parameters were also performed. RESULTS: The frequencies of circulating CD14+HLA-DR-/low MDSCs were significantly elevated in DCM patients compared with healthy controls. It showed that MDSCs from DCM patients more effectively suppressed T cell proliferation and IFN-x03B3; production compared with those from healthy controls, which was partially mediated by arginase-1 (Arg-1). In addition, the correlation analysis suggested that MDSC frequencies were negatively correlated with left ventricular ejection fraction (LVEF), while positively with N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with DCM. CONCLUSIONS: Circulating activated MDSCs might play significant immunomodulatory roles in the pathogenesis of DCM.


Asunto(s)
Cardiomiopatía Dilatada/patología , Inflamación/patología , Células Supresoras de Origen Mieloide/patología , Cardiomiopatía Dilatada/complicaciones , Cardiomiopatía Dilatada/inmunología , Femenino , Antígenos HLA-DR/análisis , Antígenos HLA-DR/inmunología , Humanos , Tolerancia Inmunológica , Inflamación/complicaciones , Inflamación/inmunología , Receptores de Lipopolisacáridos/análisis , Receptores de Lipopolisacáridos/inmunología , Masculino , Persona de Mediana Edad , Células Supresoras de Origen Mieloide/inmunología , Miocardio/inmunología , Miocardio/patología , Linfocitos T/inmunología , Linfocitos T/patología
11.
Cell Physiol Biochem ; 35(1): 292-304, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25591771

RESUMEN

AIM: The aim of this study was to explore whether the circulating frequency and function of myeloid-derived suppressor cells (MDSCs) are altered in patients with acute coronary syndrome (ACS). METHODS: The frequency of MDSCs in peripheral blood was determined by flow cytometry, and mRNA expression in purified MDSCs was analyzed by real-time reverse transcription polymerase chain reaction (RT-PCR). The suppressive function of MDSCs isolated from different groups was also determined. The plasma levels of certain cytokines were determined using Bio-Plex Pro™ Human Cytokine Assays. RESULTS: The frequency of circulating CD14(+)HLA-DR(-/low) MDSCs; arginase-1 (Arg-1) expression; and plasma levels of interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α, and IL-33 were markedly increased in ACS patients compared to stable angina (SA) or control patients. Furthermore, MDSCs from ACS patients were more potent suppressors of T-cell proliferation and IFN-γ production than those from the SA or control groups at ratios of 1:4 and 1:2; this effect was partially mediated by Arg-1. In addition, the frequency of MDSCs was positively correlated with plasma levels of IL-6, IL-33, and TNF-α. CONCLUSIONS: We observed an increased frequency and suppressive function of MDSCs in ACS patients, a result that may provide insights into the mechanisms involved in ACS.


Asunto(s)
Síndrome Coronario Agudo/patología , Células Mieloides/metabolismo , Síndrome Coronario Agudo/metabolismo , Angina Estable/metabolismo , Angina Estable/patología , Arginasa/genética , Arginasa/metabolismo , Proliferación Celular , Células Cultivadas , Electrocardiografía , Femenino , Antígenos HLA-DR/metabolismo , Humanos , Interferón gamma/metabolismo , Interleucina-1beta/sangre , Interleucina-33 , Interleucina-6/sangre , Interleucinas/sangre , Leucocitos Mononucleares/citología , Receptores de Lipopolisacáridos/metabolismo , Masculino , Persona de Mediana Edad , Células Mieloides/citología , ARN Mensajero/metabolismo , Linfocitos T/citología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Factor de Necrosis Tumoral alfa/sangre
12.
J Huazhong Univ Sci Technolog Med Sci ; 35(1): 16-20, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25673187

RESUMEN

This study investigated the relationship between IL-33/ST2 signal pathway gene polymorphisms and myocardial infarction (MI) in Han Chinese. A case-control association analysis was performed on a total of 490 MI patients (MI group) and 929 normal subjects (NC group). Sequenom Mass Array and Taqman genotyping technique were used to analyze the tag single nucleotide polymorphisms (SNPs) in the genes encoding IL-33, ST2, and IL-1RaP (rs11792633, rs1041973 and rs4624606). The results showed that the frequencies of rs4624606 genotypes AA, TT, AT were 0.031, 0.647, 0.322 in MI group and 0.026, 0.712, 0.263 in NC group, and the allele frequencies of A and T were 0.192, 0.808 in MI group and 0.157, 0.843 in NC group. There were significant differences in rs4624606 genotypes and allele frequencies between MI group and NC group (P<0.05). For rs11792633, the allele frequencies of C and T were 0.45, 0.55 in MI group and 0.454, 0.546 in NC group with no significant differences found between the two groups. Compared with genotype CC+TC, rs11792633 genotype TT had an increased risk of hypertension (P<0.05). However, there were no significant differences in the frequencies of rs11792633 genotypes between the two groups. No significant differences were noted in the frequencies of rs1041973 genotype and allele between the two groups. Logistic regression analysis showed that rs4624606 genotypes AT and AA+AT were both significantly associated with MI (AT: OR=1.325, P=0.029, 95% CI=1.03-1.705; AA+AT: OR=1.316, P=0.028, 95% CI=1.03-1.681) after factors such as age, gender, smoking, drinking, body mass index (BMI), triglyceride (TG) and cholesterol were adjusted. Those carrying rs4624606 genotype AT or AA+AT had an increased risk of MI. No associations were found between the polymorphisms of the other two loci with MI. It was concluded that, in the IL33/ST2 signal pathway, the A allele of rs4624606 polymorphism of IL-1RaP gene is a potential independent risk factor for MI, and the genotypes AA+AT and AT are associated with the incidence of MI.


Asunto(s)
Etnicidad/genética , Interleucinas/genética , Infarto del Miocardio/genética , Receptores de Superficie Celular/genética , Transducción de Señal/genética , China , Femenino , Humanos , Proteína 1 Similar al Receptor de Interleucina-1 , Interleucina-33 , Interleucinas/metabolismo , Masculino , Receptores de Superficie Celular/metabolismo
13.
Biochemistry ; 53(5): 947-56, 2014 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-24467211

RESUMEN

Glycine decarboxylase (GLDC) is a metabolic oncogene that links glycine metabolism with tumorigenesis. In humans, GLDC is part of a multienzyme complex (which includes the lipoyl-containing H-protein) that couples the decarboxylation of glycine to the biosynthesis of serine. Details of the GLDC-catalyzed glycine decarboxylation reaction are critical to drug development but remain elusive. This is the first report on the mechanism of the GLDC-catalyzed reaction and shows that GLDC is an unusual PLP-containing α-amino acid decarboxylase that removes carbon dioxide from the glycine substrate without releasing the expected amine (methylamine, a metabolic precursor of toxic formaldehyde) as a product. In an unusual decarboxylation mechanism, the resulting aminomethyl moiety is instead transferred to an accessory H-protein. This study defines the role of H-protein in GLDC-catalyzed glycine decarboxylation. (1) H-Protein is not required for glycine decarboxylation but, instead, is required for the release of the aminomethyl moiety from the quinonoid adduct. (2) Glycine decarboxylation is reversible and presumably proceeds through a stable quinonoid intermediate. (3) The physiological product of glycine decarboxylation is H-protein-S-aminomethyl dihydrolipoyllysine and not methylamine (in the absence of H-protein, the aminomethyl moiety remains as a quinonoid adduct). Mechanistic insights obtained from this study will inform future efforts for targeted anticancer therapeutic development.


Asunto(s)
Carcinogénesis/metabolismo , Glicina-Deshidrogenasa (Descarboxilante)/química , Catálisis , Glicina/química , Proteína H del Complejo de la Glicina Descarboxilasa/química , Proteína H del Complejo de la Glicina Descarboxilasa/metabolismo , Glicina-Deshidrogenasa (Descarboxilante)/metabolismo , Humanos , Cinética
14.
Cancer Cell Int ; 14(1): 101, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25317078

RESUMEN

BACKGROUND: Side population (SP) assay identifies cells with dye/drug extrusion ability, a characteristic of stem cells. Here, we determined if SP cells exist in a verified cell line originating from recurrent nasopharyngeal carcinoma (NPC) and a xenograft established from recurrent metastatic NPC. These cells were evaluated for stem-like properties via functional assays as well as for tumourigenicity. METHODS: We used Hoechst 33342 to identify the SP from non-SP (NSP) cells in HK1 NPC cell line and xeno-284 NPC xenograft. The cells were assayed for in vitro characteristics of cancer stem cells (CSC), gene expression and tumourigenicity ability. Student's t test was used to test for significance. RESULTS: Five to ten percent and less than 0.5% of HK1 and xeno-284 NPC cells, respectively, were SP cells. Fumitremorgin C (FTC), as opposed to verapamil, was effective in causing the cells to retain Hoechst 33342 dye. HK1 SP cells formed more holoclones, had more aldehyde dehydrogenase (ALDH) activity, divided asymmetrically and contained slow-proliferating cells. ABCG2, SOX2, TERT, MYC, Hedgehog, Notch, TGFß and Wnt signalling pathway genes were significantly upregulated in the SP cells. However, despite these differences in vitro, both HK1 SP and NSP cells had an overall similar tumourigenic potential in vivo. CONCLUSIONS: HK1 SP cells were ABCG2-specific as confirmed by FTC inhibition and gene expression data. Despite data from in vitro and gene expression experiments suggesting stem-like features, there was no significant difference in tumourigenic potential between SP and NSP cells. We conclude that SP assay alone is not sufficient to identify CSCs in HK1 cells. Our work also suggests the presence of a stem-cell like population among NPC cells which do not display increased tumourigenicity.

15.
Mediators Inflamm ; 2014: 869148, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24987196

RESUMEN

OBJECTIVE: To investigate the role of CD4(+)CD25(+) T cells (Tregs) in protecting fine particulate matter (PM-) induced inflammatory responses, and its potential mechanisms. METHODS: Human umbilical vein endothelial cells (HUVECs) were treated with graded concentrations (2, 5, 10, 20, and 40 µg/cm(2)) of suspension of fine particles for 24h. For coculture experiment, HUVECs were incubated alone, with CD4(+)CD25(-) T cells (Teff), or with Tregs in the presence of anti-CD3 monoclonal antibodies for 48 hours, and then were stimulated with or without suspension of fine particles for 24 hours. The expression of adhesion molecules and inflammatory cytokines was examined. RESULTS: Adhesion molecules, including vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), and inflammatory cytokines, such as interleukin (IL-) 6 and IL-8, were increased in a concentration-dependent manner. Moreover, the adhesion of human acute monocytic leukemia cells (THP-1) to endothelial cells was increased and NF- κ B activity was upregulated in HUVECs after treatment with fine particles. However, after Tregs treatment, fine particles-induced inflammatory responses and NF- κ B activation were significantly alleviated. Transwell experiments showed that Treg-mediated suppression of HUVECs inflammatory responses impaired by fine particles required cell contact and soluble factors. CONCLUSIONS: Tregs could attenuate fine particles-induced inflammatory responses and NF- κ B activation in HUVECs.


Asunto(s)
Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/inmunología , Inflamación/inmunología , Inflamación/metabolismo , Material Particulado/toxicidad , Linfocitos T Reguladores/metabolismo , Humanos , Molécula 1 de Adhesión Intercelular/sangre , Interleucina-8/sangre , FN-kappa B/sangre , Molécula 1 de Adhesión Celular Vascular/sangre
16.
Food Sci Nutr ; 12(6): 4110-4121, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38873490

RESUMEN

Among middle-aged and older people, balanced and nutritious diets are the foundation for maintaining bone health and preventing osteoporosis. This study is aimed at investigating the link between dietary folic acid intake and the risk of osteoporosis among middle-aged and older people. A total of 20,686 people from the National Health and Nutritional Examination Survey (NHANES) 2007-2010 are screened and included, and 5312 people aged ≥45 years with integral data are ultimately enrolled in evaluation. Demographics and dietary intake-related data are gathered and analyzed, and the odds ratio (OR) and 95% confidence interval (CI) of each tertile category of dietary folic acid intake and each unit increase in folic acid are assessed via multivariate logistic regression models. On this basis, the receiver operating characteristic (ROC) curve is used to identify the optimal cutoff value of dietary folic acid intake for indicating the risk of osteoporosis. Of 5312 people with a mean age of 62.4 ± 11.0 years old, a total of 513 people with osteoporosis are screened, and the dietary folic acid intake amount of the osteoporosis group is significantly lower than that of the non-osteoporosis group (p < .001). The lowest tertile category is then used to act as a reference category, and a higher dietary folic acid intake amount is observed to be positively related to lower odds for risk of osteoporosis. This trend is also not changed in adjustments for combinations of different covariates (p all < .05). Based on this, a dietary folic acid intake of 475.5 µg/day is identified as an optimal cutoff value for revealing osteoporosis. Collectively, this nationwide population-based study reveals that a higher daily dietary folic acid intake has potential protective effects on osteoporosis in middle-aged and older people.

17.
Cell Chem Biol ; 31(4): 776-791.e7, 2024 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-37751743

RESUMEN

The tumor microenvironment (TME) is a heterogeneous ecosystem containing cancer cells, immune cells, stromal cells, cytokines, and chemokines which together govern tumor progression and response to immunotherapies. Methyltransferase-like 3 (METTL3), a core catalytic subunit for RNA N6-methyladenosine (m6A) modification, plays a crucial role in regulating various physiological and pathological processes. Whether and how METTL3 regulates the TME and anti-tumor immunity in non-small-cell lung cancer (NSCLC) remain poorly understood. Here, we report that METTL3 elevates expression of pro-tumorigenic chemokines including CXCL1, CXCL5, and CCL20, and destabilizes PD-L1 mRNA in an m6A-dependent manner, thereby shaping a non-inflamed TME. Thus, inhibiting METTL3 reprograms a more inflamed TME that renders anti-PD-1 therapy more effective in several murine lung tumor models. Clinically, NSCLC patients who exhibit low-METTL3 expression have a better prognosis when receiving anti-PD-1 therapy. Collectively, our study highlights targeting METTL3 as a promising strategy to improve immunotherapy in NSCLC patients.

18.
J Biol Chem ; 287(41): 34157-66, 2012 Oct 05.
Artículo en Inglés | MEDLINE | ID: mdl-22872639

RESUMEN

Regulatory T (Treg) cells play a protective role against the development of atherosclerosis. Previous studies have revealed Treg cell defects in patients with non-ST elevation acute coronary syndrome (NSTACS), but the mechanisms underlying these defects remain unclear. In this study, we found that the numbers of peripheral blood CD4(+)CD25(+)CD127(low) Treg cells and CD4(+)CD25(+)CD127(low)CD45RA(+)CD45RO(-) naive Treg cells were lower in the NSTACS patients than in the chronic stable angina (CSA) and the chest pain syndrome (CPS) patients. However, the number of CD4(+)CD25(+)CD127(low)CD45RA(-)CD45RO(+) memory Treg cells was comparable in all of the groups. The frequency of CD4(+)CD25(+)CD127(low)CD45RO(-)CD45RA(+)CD31(+) recent thymic emigrant Treg cells and the T cell receptor excision circle content of purified Treg cells were lower in the NSTACS patients than in the CSA patients and the CPS controls. The spontaneous apoptosis of Treg cells (defined as CD4(+)CD25(+)CD127(low)annexin V(+)7-AAD(-)) was increased in the NSTACS patients compared with the CSA and CPS groups. Furthermore, oxidized LDL could induce Treg cell apoptosis, and the oxidized LDL levels were significantly higher in the NSTACS patients than in the CSA and CPS groups. In accordance with the altered Treg cell levels, the concentration of TNF-α was increased in the NSTACS patients, resulting in a decreased IL-10/TNF-α ratio. These findings indicate that the impaired thymic output of Treg cells and their enhanced susceptibility to apoptosis in the periphery were responsible for Treg cell defects observed in the NSTACS patients.


Asunto(s)
Síndrome Coronario Agudo/sangre , Apoptosis , Linfocitos T Reguladores/metabolismo , Timo/metabolismo , Síndrome Coronario Agudo/genética , Síndrome Coronario Agudo/inmunología , Anciano , Antígenos CD/sangre , Antígenos CD/inmunología , Transporte Biológico/inmunología , Femenino , Humanos , Interleucina-11/sangre , Interleucina-11/inmunología , Lipoproteínas LDL/sangre , Lipoproteínas LDL/inmunología , Masculino , Persona de Mediana Edad , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patología , Timo/inmunología , Timo/patología , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/inmunología
19.
Int J Neuropsychopharmacol ; 16(4): 849-56, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-22827928

RESUMEN

Placebo analgesia is one of the most robust and best-studied placebo effects. Recent researches suggest that placebo analgesia activated the µ-opioid receptor signalling in the human brain. However, whether other opioid receptors are involved in the placebo analgesia remains unclear. We have previously evoked placebo responses in mice (Guo et al. 2010, 2011) and these mice may serve as a model for investigating placebo analgesia. In the present study, we tried to explore the site of action and types of opioid receptors involved in placebo response. Male Sprague-Dawley rats were trained with 10 mg/kg morphine for 4 d to establish the placebo analgesia model. This placebo analgesia can be blocked by injection of 5 mg/kg dose naloxone or by microinjection with naloxone (1, 3 or 10 µg/rat) into rostral anterior cingulate cortex (rACC). Then, animals were tested after intra-rACC microinjection of D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) (CTOP, a selective µ-opioid receptor antagonist) or naltrindole (NTI, a highly selective δ-opioid receptor antagonist) or nor-binaltorphimine (nor-BNI, a highly selective κ-opioid receptor antagonist). Our results showed that CTOP, but not NTI or nor-BNI, could reduce the pain threshold in placebo analgesia rats. It may be concluded that rACC is the key brain region involved in placebo analgesia and the opioid placebo analgesia is mediated exclusively through µ-opioid receptor in rat.


Asunto(s)
Analgesia/métodos , Umbral del Dolor/efectos de los fármacos , Umbral del Dolor/fisiología , Receptores Opioides mu/fisiología , Analgésicos Opioides/administración & dosificación , Animales , Giro del Cíngulo/efectos de los fármacos , Giro del Cíngulo/fisiología , Masculino , Microinyecciones , Naltrexona/administración & dosificación , Antagonistas de Narcóticos/administración & dosificación , Efecto Placebo , Ratas , Ratas Sprague-Dawley , Receptores Opioides mu/agonistas , Receptores Opioides mu/antagonistas & inhibidores
20.
Cancer Res Commun ; 3(6): 1013-1025, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37377607

RESUMEN

Recent preclinical studies have linked antidepressants (AD) to their potential anticancer effects in multiple cancers, but the impact on lung cancer remains unclear. This meta-analysis examined the associations between ADs and lung cancer incidence and survival. The Web of Science, Medline, CINAHL, and PsycINFO databases were searched to identify eligible studies published by June 2022. We conducted a meta-analysis using a random-effects model to compare the pooled risk ratio (RR) and 95% confidence interval (CI) in those treated with or without ADs. Heterogeneity was examined using Cochran Q test and inconsistency I2 statistics. The methodologic quality of the selected studies was assessed using the Newcastle-Ottawa Scale for observational studies. Our analysis, including 11 publications involving 1,200,885 participants, showed that AD use increased lung cancer risk by 11% (RR = 1.11; 95% CI = 1.02-1.20; I2 = 65.03%; n = 6) but was not associated with overall survival (RR = 1.04; 95% CI = 0.75-1.45; I2 = 83.40%; n = 4). One study examined cancer-specific survival. Subgroup analysis showed that serotonin and norepinephrine reuptake inhibitors (SNRIs) were associated with an increased lung cancer risk by 38% (RR = 1.38; 95% CI = 1.07-1.78; n = 2). The quality of selected studies was good (n = 5) to fair (n = 6). Our data analysis suggests that SNRIs were associated with an elevated risk of lung cancer, raising concerns regarding the use of AD treatment in patients vulnerable to lung cancer. The effects of ADs-particularly SNRIs-and their interplay with cigarette use and lung cancer risk in vulnerable patients merits further study. Significance: In this meta-analysis of 11 observational studies, we found evidence of a statistically significant association between the use of certain ADs and lung cancer risk. This effect merits further study, particularly as it relates to known environmental and behavioral drivers of lung cancer risk, such as air pollution and cigarette smoke.


Asunto(s)
Neoplasias Pulmonares , Inhibidores de Captación de Serotonina y Norepinefrina , Humanos , Antidepresivos/efectos adversos , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos , Neoplasias Pulmonares/epidemiología , Estudios Observacionales como Asunto
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