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1.
Bioorg Chem ; 116: 105291, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34438122

RESUMO

In this study, twenty novel cinnamic acid magnolol derivatives were synthesized, and screened for their anti-hyperglycemic potential. All synthesized compounds exhibited good to moderate α-glucosidase and α-amylase inhibitory activities with IC50 values: 5.11 ± 1.46-90.26 ± 1.85 µM and 4.27 ± 1.51-49.28 ± 2.54 µM as compared to the standard acarbose (IC50: 255.44 ± 1.89 µM and 80.33 ± 2.95 µM, respectively). Compound 6j showed the strongest inhibitory activity against α-glucosidase (IC50 = 5.11 ± 1.46 µM) and α-amylase (IC50 = 4.27 ± 1.51 µM). Kinetic study indicated that compound 6j was reversible and a mixed type inhibitor against α-glucosidase and α-amylase. In silico studies revealed the binding interaction between 6j and two enzymes, respectively. Finally, cells cytotoxicity assay revealed that compound 6j showed low toxicity against 3 T3-L1 cells and HepG2 cells.

2.
BMC Infect Dis ; 21(1): 629, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34210287

RESUMO

BACKGROUND: Along with the medical development, organ transplant patients increase dramatically. Since these transplant patients take immunosuppressants for a long term, their immune functions are in a suppressed state, prone to all kinds of opportunistic infections and cancer. However, it is rarely reported that the kidney transplant recipients (KTRs) have pulmonary tuberculosis and lung cancer simultaneously. CASE PRESENTATION: A 60-year-old male was admitted because of persistent lung shadow for 2 years without any obvious symptom 8 years after renal transplant. T-SPOT test was positive but other etiological examinations for Mycobacterium tuberculosis were negative. Chest CT scan revealed two pulmonary lesions in the right upper and lower lobe respectively. 18F-fluorodesoxyglucose positron-emission tomography (FDG-PET) CT found FDG intake increased in both pulmonary consolidation lesions. CT-guided percutaneous transthoracic needle biopsy revealed lung adenocarcinoma and tuberculosis. The video-assisted thoracoscopic surgery was operated to resect the malignancy lesions. The patient received specific anti-tuberculosis therapy and was discharged. At the follow-up of 6 months post drug withdrawal, the patient was recovered very well. CONCLUSIONS: We for the first time reported co-existence of smear-negative pulmonary TB and lung adenocarcinoma in a KTR, which highlighted the clinical awareness of co-occurrence of TB and malignancy after renal transplant and emphasized the value of biopsy and 18F-FDG-PET in early diagnosis of TB and cancer.


Assuntos
Adenocarcinoma/complicações , Transplante de Rim , Neoplasias Pulmonares/complicações , Tuberculose Pulmonar/complicações , Adenocarcinoma/cirurgia , China/epidemiologia , Etambutol/uso terapêutico , Fluordesoxiglucose F18 , Humanos , Biópsia Guiada por Imagem , Isoniazida/uso terapêutico , Pulmão/diagnóstico por imagem , Pulmão/patologia , Pulmão/cirurgia , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Moxifloxacina/uso terapêutico , Mycobacterium tuberculosis/isolamento & purificação , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Cirurgia Torácica Vídeoassistida , Resultado do Tratamento , Tuberculose Pulmonar/tratamento farmacológico
3.
Quant Imaging Med Surg ; 11(4): 1651-1667, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33816198

RESUMO

Tuberculosis is a serious public health challenge facing mankind and one of the top ten causes of death. Diagnostic imaging plays an important role, particularly for the diagnosis and treatment planning of tuberculosis patients with negative microbiology results. This article illustrates a number of atypical computed tomography (CT) appearances of pulmonary tuberculosis (PTB), including (I) clustered micronodules (CMNs) sign; (II) reversed halo sign (RHS); (III) tuberculous pneumatocele; (IV) hematogenously disseminated PTB with predominantly diffuse ground glass opacity manifestation; (V) hematogenously disseminated PTB with randomly distributed non-miliary nodules; (VI) PTB changes occur on the background of emphysema or honeycomb changes of interstitial pneumonia; and (VII) PTB manifesting as organizing pneumonia. While the overall incidence of PTB is decreasing globally, the incidence of atypical manifestations of tuberculosis is increasing. A good understanding of the atypical CT imaging changes of active PTB shall help the diagnosis and differential diagnosis of PTB in clinical practice.

4.
Sci Transl Med ; 13(583)2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33658352

RESUMO

The members of the interleukin-17 (IL-17) cytokine family and their receptors were identified decades ago. Unlike IL-17 receptor A (IL-17RA), which heterodimerizes with IL-17RB, IL-17RC, and IL-17RD and mediates proinflammatory gene expression, IL-17RB plays a distinct role in promoting tumor growth and metastasis upon stimulation with IL-17B. However, the molecular basis by which IL-17RB promotes oncogenesis is unknown. Here, we report that IL-17RB forms a homodimer and recruits mixed-lineage kinase 4 (MLK4), a dual kinase, to phosphorylate it at tyrosine-447 upon treatment with IL-17B in vitro. Higher amounts of phosphorylated IL-17RB in tumor specimens obtained from patients with pancreatic cancer correlated with worse prognosis. Phosphorylated IL-17RB recruits the ubiquitin ligase tripartite motif containing 56 to add lysine-63-linked ubiquitin chains to lysine-470 of IL-17RB, which further assembles NF-κB activator 1 (ACT1) and other factors to propagate downstream oncogenic signaling. Consequentially, IL-17RB mutants with substitution at either tyrosine-447 or lysine-470 lose their oncogenic activity. Treatment with a peptide consisting of amino acids 403 to 416 of IL-17RB blocks MLK4 binding, tyrosine-477 phosphorylation, and lysine-470 ubiquitination in vivo, thereby inhibiting tumorigenesis and metastasis and prolonging the life span of mice bearing pancreatic tumors. These results establish a clear pathway of how proximal signaling of IL-17RB occurs and provides insight into how this pathway provides a therapeutic target for pancreatic cancer.


Assuntos
Neoplasias Pancreáticas , Receptores de Interleucina-17 , Animais , Carcinogênese , Humanos , Camundongos , NF-kappa B/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Transdução de Sinais
5.
Free Radic Biol Med ; 165: 368-384, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33460768

RESUMO

Emerging evidences implicate the contribution of ROS to T cell activation and signaling. The tyrosine kinase, ζ-chain-associated protein of 70 kDa (ZAP70), is essential for T cell development and activation. However, it remains elusive whether a direct redox regulation affects ZAP70 activity upon TCR stimulation. Here, we show that deficiency of non-selenocysteine containing phospholipid hydroperoxide glutathione peroxidase (NPGPx), a redox sensor, results in T cell hyperproliferation and elevated cytokine productions. T cell-specific NPGPx-knockout mice reveal enhanced T-dependent humoral responses and are susceptible to experimental autoimmune encephalomyelitis (EAE). Through proteomic approaches, ZAP70 is identified as the key interacting protein of NPGPx through disulfide bonding. NPGPx is activated by ROS generated from TCR stimulation, and modulates ZAP70 activity through redox switching to reduce ZAP70 recruitment to TCR/CD3 complex in membrane lipid raft, therefore subduing TCR responses. These results reveal a delicate redox mechanism that NPGPx serves as a modulator to curb ZAP70 functions in maintaining T cell homeostasis.


Assuntos
Proteômica , Linfócitos T , Animais , Homeostase , Camundongos , Oxirredução , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Linfócitos T/metabolismo
6.
Infect Dis Poverty ; 9(1): 66, 2020 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-32517798

RESUMO

BACKGROUND: Tuberculosis (TB) is a great mimicker and diagnostic chameleon, and prone to be diagnosed as malignancy. Even though many reports have described the differences between pulmonary TB and lung cancer, the atypical systemic hematogenous disseminated TB (HDTB) is very rare and more confusing in clinical practice. CASE PRESENTATION: A 73-year-old man, HIV-negative, was hospitalized to the local county hospital because of chest pain, low-grade fever, asthenia, anorexia and weight loss for the pasting two months. The CT findings of the two lungs showed multiple round or round-like nodules of different sizes, with clear boundaries and partial fusion. The level of serum CA19-9 was significantly higher than normal, and progressively increased. There were multiple enlarged lymph nodes in the neck, mediastinum, abdominal cavity and pelvic cavity. The symptoms were diagnosed as hematogenous spread of gastrointestinal tumor in the local county hospital. However, when transferred to our provincial hospital, through comprehensive dynamic analysis, this patient was diagnosed as atypical systemic HDTB, no cancer at all. Through routine anti-TB therapy for one year, the patient was recovered very well at the follow-up of half year after withdrawal. CONCLUSIONS: In the past, most TB misdiagnosis cases involved in single organ and were finally confirmed through invasive examination. This case enriched clinical experiences in the diagnosis of atypical HDTB. We encouraged clinicians to establish a dynamic thinking for diagnosis and treatment and emphasized the value of biopsy and 18F-FDG-PET in distinguishing TB and cancer.


Assuntos
Neoplasias Gastrointestinais/patologia , Neoplasias Pulmonares/diagnóstico , Tuberculose Pulmonar/diagnóstico , Idoso , China , Erros de Diagnóstico , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/secundário , Masculino , Metástase Neoplásica , Tomografia Computadorizada por Raios X , Tuberculose Pulmonar/diagnóstico por imagem , Tuberculose Pulmonar/patologia
7.
J Bone Miner Metab ; 38(5): 742-743, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32514735

RESUMO

In the original publication of the article, some of the pictures were misplaced in the Fig. 6 and published incorrectly. The correct Fig. 6 is provided in this version.

8.
J Biochem Mol Toxicol ; 34(5): e22462, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32045083

RESUMO

Heart failure (HF) is a medical condition inability of the heart to pump sufficient blood to meet the metabolic demand of the body to take place. The number of hospitalized patients with cardiovascular diseases is estimated to be more than 1 million each year, of which 80% to 90% of patients ultimately progress to decompensated HF. Digitalis glycosides exert modest inotropic actions when administered to patients with decompensated HF. Although its efficacy in patients with HF and atrial fibrillation is clear, its value in patients with HF and sinus rhythm has often been questioned. A series of recent studies have cast serious doubt on the benefit of digoxin when added to contemporary HF treatment. We are hypothesizing the role and mechanism of exosome and its biological constituents responsible for worsening the disease state and mortality in decompensated HF patients on digitalis.


Assuntos
Antiarrítmicos/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Cardiotônicos/uso terapêutico , Digitalis/química , Digoxina/uso terapêutico , Exossomos/efeitos dos fármacos , Insuficiência Cardíaca/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Antiarrítmicos/farmacologia , Cardiotônicos/farmacologia , Digoxina/farmacologia , Humanos , Extratos Vegetais/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos
9.
Am J Cancer Res ; 10(1): 12-37, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32064151

RESUMO

Small extracellular vesicles (sEVs) mediate the interaction between tumor and tumor-associated macrophages (TAMs). This study aims to demonstrate that the pancreatic ductal adenocarcinoma (PDAC)-derived sEV Ezrin (sEV-EZR) could modulate macrophage polarization and promote PDAC metastasis. We isolated PDAC-derived sEVs and plasma sEVs from PDAC patients. Human blood mononuclear cell (PBMC)-derived macrophages were treated with PDAC-derived sEVs or the counterpart depleted Ezrin (EZR) with shRNA-mediated knockdown. We used enzyme-linked immunosorbent assays and flow cytometry to monitor macrophages polarization. NOD/SCID/IL2Rγnull mice were treated with sEVs to study PDAC liver metastasis. The plasma sEV-EZR levels of 165 PDAC patients and 151 high-risk controls were analyzed. The EZR levels are higher in sEVs derived from PDAC cells and PDAC-patient plasma than that of the normal controls. PDAC-derived sEVs modulate the polarization of macrophages to M2 phenotype, while PDAC-shEZR-derived sEVs polarize macrophages into M1 phenotype. We found an increase in M1 TAMs and a decrease in M2 TAMs in orthotropic tumors treated with PDAC-shEZR-derived sEVs. The amount of liver metastasis in PDAC-shEZR-derived sEVs-treated mice was observed to be smaller than that of controls. The mean plasma sEV-EZR levels from PDAC patients were significantly higher than those from the controls (32.43±20.78 vs. 21.88±11.43 pg/ml; P<0.0001). The overall survival in the high-plasma sEV-EZR patients was significantly shorter than that in the low-EZR group (6.94±15.25 vs. 9.63±15.11 months; P=0.0418). sEV-EZR could modulate macrophage polarization and promote metastasis in PDAC. Targeting sEV-EZR can be considered a promising therapeutic strategy to inhibit PDAC metastasis.

10.
EMBO Mol Med ; 12(1): e9386, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31782617

RESUMO

Human caspase-4 and its mouse homolog caspase-11 are receptors for cytoplasmic lipopolysaccharide. Activation of the caspase-4/11-dependent NLRP3 inflammasome is required for innate defense and endotoxic shock, but how caspase-4/11 is modulated remains unclear. Here, we show that mice lacking the oxidative stress sensor glutathione peroxidase 8 (GPx8) are more susceptible to colitis and endotoxic shock, and exhibit reduced richness and diversity of the gut microbiome. C57BL/6 mice that underwent adoptive cell transfer of GPx8-deficient macrophages displayed a similar phenotype of enhanced colitis, indicating a critical role of GPx8 in macrophages. GPx8 binds covalently to caspase-4/11 via disulfide bonding between cysteine 79 of GPx8 and cysteine 118 of caspase-4 and thus restrains caspase-4/11 activation, while GPx8 deficiency leads to caspase-4/11-induced inflammation during colitis and septic shock. Inhibition of caspase-4/11 activation with small molecules reduces the severity of colitis in GPx8-deficient mice. Notably, colonic tissues from patients with ulcerative colitis display low levels of Gpx8 and high caspase-4 expression. In conclusion, these results suggest that GPx8 protects against colitis by negatively regulating caspase-4/11 activity.

11.
Cell Rep ; 29(8): 2134-2143.e7, 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31747588

RESUMO

Amyotrophic lateral sclerosis (ALS), the most common motor neuron disease, usually occurs in middle-aged people. However, the molecular basis of age-related cumulative stress in ALS pathogenesis remains elusive. Here, we found that mice deficient in NPGPx (GPx7), an oxidative stress sensor, develop ALS-like phenotypes, including paralysis, muscle denervation, and motor neurons loss. Unlike normal spinal motor neurons that exhibit elevated O-GlcNAcylation against age-dependent oxidative stress, NPGPx-deficient spinal motor neurons fail to boost O-GlcNAcylation and exacerbate ROS accumulation, leading to cell death. Mechanistically, stress-activated NPGPx inhibits O-GlcNAcase (OGA) through disulfide bonding to fine-tune global O-GlcNAcylation. Pharmacological inhibition of OGA rescues spinal motor neuron loss in aged NPGPx-deficient mice. Furthermore, expression of NPGPx in ALS patients is significantly lower than in unaffected adults. These results suggest that NPGPx modulates O-GlcNAcylation by inhibiting OGA to cope with age-dependent oxidative stress and protect motor neurons from degeneration, providing a potential therapeutic axis for ALS.


Assuntos
Neurônios Motores/metabolismo , Estresse Oxidativo/fisiologia , beta-N-Acetil-Hexosaminidases/metabolismo , Envelhecimento/fisiologia , Esclerose Amiotrófica Lateral/metabolismo , Animais , Feminino , Humanos , Camundongos , Camundongos Mutantes , Denervação Muscular , Estresse Oxidativo/genética , Paralisia/metabolismo
12.
Infect Drug Resist ; 12: 1265-1276, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31190914

RESUMO

Purpose: Multidrug-resistant tuberculosis (MDR-TB) remains a challenge of global TB control, with difficulty in early detection of drug-sensitive tuberculosis (DS-TB). We investigate the diagnostic significance of IDO as a potential biomarker to discriminate MDR patients among the TB patients. Patients and methods: Plasma indoleamine 2,3-dioxygenase (IDO) was measured by the ratio of kynurenine (Kyn) to tryptophan (Trp) concentrations, using high performance liquid chromatography-mass spectrometry (LC-MS/MS). Chest computed tomography (CT) imaging signs from TB patients were collected and analyzed in 18 DS-TB patients, 16 MDR-TB patients, 6 lung cancer (LC) patients, and 11 healthy individuals. Lung imaging signs from TB patients were collected and analyzed. Results: We found that plasma IDO activity was significantly higher in the MDR-TB patients than in the DS-TB patients (p=0.012) and in the LC patients (p=0.003). We evaluated the diagnostic significance of plasma IDO activity in discriminating the MDR-TB group from the DS-TB group using a receiver operating characteristic (ROC) curve. With a cutoff level of 46.58 uM/mM, the diagnostic sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for IDO activity were 87.50%, 72.22%, 73.68%, and 86.67%, respectively. Plasma IDO activity was higher in cavity cases than in non-cavity cases (p=0.042), proving a positive correlation between lung cavity number and cavity size (p<0.05, separately) among all the TB patients studied. Conclusion: Our findings confirmed that plasma IDO activity might have an auxiliary diagnosis value for early discrimination of MDR-TB patients from DS-TB patients. Among the TB patients with cavitary lung lesions, higher plasma IDO activity can indicate a higher risk of MDR-TB.

13.
Biomed Res Int ; 2019: 2965035, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31073524

RESUMO

The type 2C protein which belongs to the major group of protein phosphatases (PP2C) plays a vital role in abscisic acid (ABA) signaling and signal transductions processes. In the present study, 131 PP2C genes were identified in total in Brassica rapa and categorized into thirteen subgroups based on their phylogenetic relationships. These B. rapa PP2C are structurally conserved based on amino acid sequence alignment, phylogenetic analysis, and conserved domains. Moreover, we utilized previously reported RNA-sequence data on various tissues (root, stem, leaf, flower, and silique), which suggests overlapping expression pattern in 29 paralogous gene pairs. The qRT-PCR validation of 15 paralogous gene pairs depicts distinct expression patterns in response to various abiotic stresses, such as heat, cold, ABA, and drought. Interestingly, stress-responsive BraPP2C candidate genes were also identified, suggesting their significance in stress-tolerance mechanism in B. rapa. The evolutionary analysis for 15 paralogous gene pairs suggested that only three pairs have the positive selection and remaining were purifying in nature. The presented results of this study hasten our understanding of the molecular evolution of the PP2C gene family in B. rapa. Thus, it will be ultimately helping in future research for facilitating the functional characterization of BraPP2C genes in developing the abiotic stress tolerant plants.


Assuntos
Brassica rapa/genética , Evolução Molecular , Filogenia , Proteína Fosfatase 2C/genética , Sequência de Aminoácidos/genética , Cromossomos de Plantas/genética , Flores/genética , Regulação da Expressão Gênica de Plantas , Genoma de Planta/genética , Família Multigênica/genética , Proteína Fosfatase 2C/classificação
14.
Cell Metab ; 29(6): 1334-1349.e10, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-30853214

RESUMO

KRAS mutations are the earliest events found in approximately 90% of pancreatic ductal adenocarcinomas (PDACs). However, little is known as to why KRAS mutations preferentially occur in PDACs and what processes/factors generate these mutations. While abnormal carbohydrate metabolism is associated with a high risk of pancreatic cancer, it remains elusive whether a direct relationship between KRAS mutations and sugar metabolism exists. Here, we show that under high-glucose conditions, cellular O-GlcNAcylation is significantly elevated in pancreatic cells that exhibit lower phosphofructokinase (PFK) activity than other cell types. This post-translational modification specifically compromises the ribonucleotide reductase (RNR) activity, leading to deficiency in dNTP pools, genomic DNA alterations with KRAS mutations, and cellular transformation. These results establish a mechanistic link between a perturbed sugar metabolism and genomic instability that induces de novo oncogenic KRAS mutations preferentially in pancreatic cells.


Assuntos
Acetilglucosamina/metabolismo , Transformação Celular Neoplásica/induzido quimicamente , Enzimas/metabolismo , Glucose/farmacologia , Nucleotídeos/metabolismo , Pâncreas/efeitos dos fármacos , Proteínas Proto-Oncogênicas p21(ras)/genética , Acetilação/efeitos dos fármacos , Acetiltransferases/metabolismo , Adulto , Idoso , Animais , Carcinoma Ductal Pancreático/induzido quimicamente , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Células Cultivadas , Dano ao DNA/genética , Relação Dose-Resposta a Droga , Enzimas/genética , Feminino , Glucose/efeitos adversos , Células HEK293 , Humanos , Recém-Nascido , Masculino , Redes e Vias Metabólicas/efeitos dos fármacos , Redes e Vias Metabólicas/genética , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Mutagênese/efeitos dos fármacos , Mutação/efeitos dos fármacos , Pâncreas/metabolismo , Neoplasias Pancreáticas/induzido quimicamente , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Adulto Jovem
15.
FASEB J ; 33(2): 2017-2025, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30199284

RESUMO

Cellular supply of deoxythymidine triphosphate (dTTP) is crucial for DNA replication and repair. Thymidylate kinase (TMPK) catalyzes the conversion of thymidine monophosphate to thymidine diphosphate, which is an essential step for dTTP synthesis. Despite their major cellular localization in cytosol, TMPK and ribonucleotide reductase (RNR) are detected at DNA damage sites for local dNDP formation. Because deoxyuridine diphosphate is synthesized by RNR, the simultaneous recruitment of TMPK and RNR to DNA damage sites is critical for preventing deoxyuridine triphosphate-mediated toxic repair. This study investigates the mechanism responsible for the recruitment of TMPK to DNA damage sites. Our data demonstrate the requirement of ataxia telangiectasia mutated (ATM) kinase activity for TMPK recruitment to DNA lesion sites. Moreover, we find that TMPK is able to form the complex with histone acetyltransferase Tip60 and RNR. Inhibition of ATM kinase reduces the complex formation and TMPK phosphorylation. Our analysis further shows the presence of TMPK phosphorylation at serine 88, which is an ATM kinase consensus site. A phosphorylation-defective mutation at this site suppresses TMPK recruitment to DNA damage sites and the complex formation with Tip60. Finally, we provide evidence that this site is critical for the function of TMPK in DNA repair but not for catalytic activity. Together, these findings suggest that Tip60-ATM signaling has a functional contribution to the recruitment of TMPK to DNA damage sites, thereby increasing local dTTP synthesis for DNA repair.-Hu, C.-M., Tsao, N., Wang, Y.-T., Chen, Y.-J., Chang, Z.-F. Thymidylate kinase is critical for DNA repair via ATM-dependent Tip60 complex formation.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Dano ao DNA , Reparo do DNA , Lisina Acetiltransferase 5/metabolismo , Complexos Multienzimáticos/metabolismo , Núcleosídeo-Fosfato Quinase/metabolismo , Proteínas Mutadas de Ataxia Telangiectasia/genética , Células HEK293 , Células HeLa , Humanos , Lisina Acetiltransferase 5/genética , Complexos Multienzimáticos/genética , Núcleosídeo-Fosfato Quinase/genética , Fosforilação/genética , Ribonucleotídeo Redutases/genética , Ribonucleotídeo Redutases/metabolismo
16.
J Bone Miner Metab ; 37(4): 594-606, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30470957

RESUMO

Osteosarcoma (OS) is a prevalent cancer that plagues people worldwide. Identifying prognostic markers would be useful in treating human OS. In this study, we aimed to explore the functions of Ras-related protein Rab-31 (RAB31) in OS-cell proliferation, migration, and invasion as well as its roles in the Hedgehog signaling pathway for better understanding of the mechanism. To assess the detailed regulatory mechanism of RAB31 silencing on OS, both RT-qPCR and Western blot analysis were employed to evaluate the expressions of RAB31 as well as the Hedgehog signaling pathway-related genes. Besides, we also investigated the effects of silenced RAB31 both in vitro and in vivo. First, we found that in OS tissues, both mRNA and protein expressions of RAB31 and PCNA had a significant increase. Second, the Hedgehog signaling pathway was detected to play an integral role in OS progression. Finally, after transfection of RAB31-siRNA to reduce the expression of RAB31, the Hedgehog signaling pathway was suppressed, along with cell proliferation, invasion, and migration. Therefore, we conclude that RAB31 plays an important role in OS development and its silencing delays the OS progression via suppression of the Hedgehog signaling pathway.


Assuntos
Movimento Celular , Inativação Gênica , Proteínas Hedgehog/metabolismo , Osteossarcoma/genética , Osteossarcoma/patologia , Transdução de Sinais , Proteínas rab de Ligação ao GTP/genética , Adenoviridae/metabolismo , Adolescente , Adulto , Apoptose , Neoplasias Ósseas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células , Criança , Progressão da Doença , Feminino , Vetores Genéticos/metabolismo , Humanos , Masculino , Invasividade Neoplásica , RNA Mensageiro/genética , Adulto Jovem
17.
Ann Surg Oncol ; 26(3): 807-814, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30569296

RESUMO

BACKGROUND: Thrombospondin-2 (TSP-2) has been reported as an early diagnostic marker for pancreatic ductal adenocarcinoma (PDAC) in Caucasian populations. This study was designed to validateTSP-2 as a diagnostic marker in a large Taiwan cohort and to investigate the association of TSP-2 with the clinical outcomes of PDAC patients. METHODS: The serum TSP-2 levels in 263 PDAC patients and 230 high-risk individuals (HRIs) were measured via an enzyme-linked immunosorbent assay. The sensitivity, specificity, and accuracy of TSP-2 as a diagnostic marker to discriminating PDAC patients from HRIs and correlations between TSP-2 levels and prognosis of PDAC patients were analyzed. RESULTS: Serum TSP-2 levels were significantly higher in patients with PDAC (44.90 ± 40.70 ng/ml) than in the HRIs (17.52 ± 6.23 ng/ml). At a level of ≥ 29.8 ng/ml, TSP-2 exhibited 100% specificity, 55.9% sensitivity, 100% positive predictive value (PPV), and 66.5% negative predictive value (NPV) for discriminating PDAC patients from HRIs. The Cox regression analysis showed that higher serum TSP-2 levels were significantly associated with poor outcomes in PDAC patients (hazard ratio = 1.54, 95% confidence interval = 1.143-2.086, P = 0.005). Combining the carbohydrate antigen 19-9 (CA19-9) (cutoff value of 62.0 U/ml) and TSP-2 (cutoff value of 29.8 ng/ml) levels yielded 98.7% specificity, 90.5% sensitivity, 98.8% PPV, and 90.1% NPV for discriminating patients with PDAC from HRIs. CONCLUSIONS: TSP-2 is a highly specific diagnostic marker and an independent prognostic marker in patients with PDAC. A combined biomarker panel, including TSP-2 and CA19-9, may facilitate future PDAC screening.


Assuntos
Biomarcadores Tumorais/sangue , Carcinoma Ductal Pancreático/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Trombospondinas/sangue , Carcinoma Ductal Pancreático/sangue , Carcinoma Ductal Pancreático/terapia , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/terapia , Prognóstico , Taxa de Sobrevida
18.
Sci Rep ; 8(1): 16265, 2018 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-30389998

RESUMO

Homeobox (HB) genes are crucial for plant growth and development processes. They encode transcription factors and responses to various stresses, as reported by recent emerging evidence. In this study, a total of 113 BraHB genes were identified in Brassica rapa. On the basis of domain organization and phylogenetic analysis, the BraHBs were grouped into nine subclasses, in which homeobox leucine-zipper (HB LZP-III) showed the highest number of genes (28) compared to other subclasses. The BraHBs exhibited similarities in exon-intron organization and motif composition among the members of the same subclasses. The analysis revealed that HB-Knotted was more preferentially retained than any other subclass of BraHB. Furthermore, we evaluated the impact of whole-genome triplication on the evolution of BraHBs. In order to analyze the subgenomes of B. rapa, we identified 39 paralogous pairs for which synonymous substitution values were lower than 1.00 for further purifying selection. Finally, the expression patterns of BraHBs across six tissues expressed dynamic variations combined with their responses against multiple stresses. The current study provides brief information on the homeobox gene family in B. rapa. Our findings can serve as a reference for further functional analysis of BraHBs.


Assuntos
Brassica rapa/genética , Regulação da Expressão Gênica de Plantas , Genes Homeobox/genética , Proteínas de Plantas/genética , Estresse Fisiológico/genética , Mapeamento Cromossômico , Éxons/genética , Duplicação Gênica , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Genes de Plantas , Íntrons/genética , Zíper de Leucina/genética , Filogenia
19.
J Cell Biochem ; 119(11): 9591-9603, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30191602

RESUMO

BACKGROUND: Patients with metastatic spine tumors may suffer from pain or neurologic deficit, and the disease may be detected in patients with a known malignancy. Sonic hedgehog (SHH) has received special attention due to its role in cancers. Therefore, this study investigated the effects of epigenetic silencing of SHH on antitumor immune response and tumor growth by regulating the hedgehog (Hh) signaling pathway in metastatic spine tumors. METHODS: Rat models of metastatic spine tumors were successfully established. We first calculated the tumor volume and the inhibition rate of tumor growth to investigate the effect of SHH on tumor growth. Afterwards, immunohistochemistry was used to determine whether proliferation was delayed by SHH depletion, and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was conducted to test the changes in the lymphocyte transformation rate in the spleen triggered by SHH silencing. Then, the influence of SHH depletion on immune function was investigated. Later, quantitative reverse transcription polymerase chain reaction and Western blot assay were performed to explore the Hh signaling pathway-related factors. Finally, we added the Hh signaling pathway inhibitor, GDC-0449, to confirm the role of the pathway in tumor progression. RESULTS: Initially, we observed that SHH depletion was a negative factor for tumor growth. Afterwards, it was revealed that epigenetic silencing of SHH served as an inhibitor factor for the function of spleen lymphocyte transformation and inflammation while promoting antitumor immune function. CONCLUSION: Our preliminary results indicate that epigenetic silencing of SHH elicits an antitumor immune response and suppresses tumor growth by inhibiting the Hh signaling pathway in metastatic spine tumors.


Assuntos
Proteínas Hedgehog/metabolismo , Neoplasias da Coluna Vertebral/genética , Neoplasias da Coluna Vertebral/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Proliferação de Células/fisiologia , Epigênese Genética/genética , Epigênese Genética/fisiologia , Feminino , Inativação Gênica/fisiologia , Proteínas Hedgehog/genética , Imuno-Histoquímica , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
20.
Biomed Res Int ; 2018: 5206758, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30225257

RESUMO

To understand ubiquitination mechanism, E2s (ubiquitin conjugating enzymes) have crucial part as they play a major role in regulating many biological processes in plants. Meanwhile, Brassica rapa is an important leafy vegetable crop and therefore its characterization along with the expression pattern of E2s under various stresses is imperative. In this study, a total of 83 genes were identified in B. rapa and were classified into four different classes based on domain information. Here, we analyzed phylogenetic relationships, collinear correlation, gene duplication, interacting network, and expression patterns of E2 genes in B. rapa. Furthermore, RT-PCR analysis for 8 multiple abiotic and hormone treatments (namely, ABA, GA, JA, BR, PEG, NaCl, and heat and cold stress) illustrated striking expression pattern under one or more treatments, speculating that these might be stress-responsive genes. The cis-elements and interaction network analyses implicate valuable clues of important function of E2 genes in development and multiple stress responses in B. rapa. This study will further facilitate functional analysis of E2s for improving stress resistance mechanism in B. rapa.


Assuntos
Brassica rapa/genética , Proteínas de Plantas/metabolismo , Brassica rapa/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Filogenia , Reguladores de Crescimento de Plantas , Estresse Fisiológico
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