RESUMO
Gastric cancer is the fifth most common malignancy worldwide having the fourth highest mortality rate. Energy metabolism is key and closely linked to tumour development. Most important in the reprogramming of cancer metabolism is the Warburg effect, which suggests that tumour cells will utilise glycolysis even with normal oxygen levels. Various molecules exert their effects by acting on enzymes in the glycolytic pathway, integral to glycolysis. Second, mitochondrial abnormalities in the reprogramming of energy metabolism, with consequences for glutamine metabolism, the tricarboxylic acid cycle and oxidative phosphorylation, abnormal fatty acid oxidation and plasma lipoprotein metabolism are important components of tumour metabolism. Third, inflammation-induced oxidative stress is a danger signal for cancer. Fourth, patterns of signalling pathways involve all aspects of metabolic transduction, and many clinical drugs exert their anticancer effects through energy metabolic signalling. This review summarises research on energy metabolism genes, enzymes and proteins and transduction pathways associated with gastric cancer, and discusses the mechanisms affecting their effects on postoperative treatment resistance and prognoses of gastric cancer. We believe that an in-depth understanding of energy metabolism reprogramming will aid the diagnosis and subsequent treatment of gastric cancer.
Assuntos
Neoplasias , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamento farmacológico , Metabolismo Energético/fisiologia , Neoplasias/patologia , Glicólise/genética , Ciclo do Ácido Cítrico , Fosforilação OxidativaRESUMO
Pancreatic cancer is one of the deadliest types of cancer, with a death rate nearly equal to the incidence. The P2X7 receptor (P2X7R) is a kind of extracellular adenosine triphosphate (ATP)-gated ion channel with special permeability, which exists in most tissues of human body and mediates inflammation-related signaling pathways and immune signal transduction after activation. P2X7R is also present on the surface of several tumor cells and is involved in tumor growth and progression. P2X7R expression in pancreatic cancer has also been identified in recent studies. Activation of P2X7R in pancreatic cancer can support the proliferation of pancreatic stellate cells, participate in protein interactions, and mediate ERK1/2, IL-6/STAT3, hCAP-18/LL-37, PI3K/AKT signaling pathways to promote pancreatic cancer progression. Inhibitors targeting P2X7R can inhibit the development of pancreatic cancer and are expected to be used in clinical therapy. Therefore, P2X7R is promising as a potential therapeutic target for pancreatic cancer. This article reviews the progress of research on P2X7R in pancreatic cancer.
Assuntos
Neoplasias Pancreáticas , Receptores Purinérgicos P2X7 , Humanos , Receptores Purinérgicos P2X7/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias Pancreáticas/patologia , Transdução de Sinais/fisiologia , Neoplasias PancreáticasRESUMO
The activation of heme oxygenase 1 (HO-1)/carbon monoxide (CO) inhibits chronic inflammatory pain, but its role in the central nervous system (CNS) is not entirely known. We evaluated whether the treatment with an HO-1 inducer, cobalt protoporphyrin IX (CoPP), or a CO-releasing molecule, tricarbonyldichlororuthenium(II)dimer (CORM-2), modulates the nociceptive, apoptotic and/or oxidative responses provoked by persistent inflammatory pain in the CNS. In C57BL/6 male mice with peripheral inflammation caused by complete Freund's adjuvant (CFA), we assessed the effects of CORM-2 and CoPP on the expression of protein kinase B (Akt), the apoptotic protein BAX, and the antioxidant enzymes HO-1 and NADPH quinone oxidoreductase 1 (NQO1) in the periaqueductal gray matter (PAG), amygdala (AMG), ventral hippocampus (VHPC) and medial septal area (MSA). Our results showed that the increased expression of p-Akt caused by peripheral inflammation in the four analyzed brain areas was reversed by CORM-2 and CoPP therapies. Both treatments also normalized the upregulation of BAX induced by CFA on the VHPC and MSA. Oxidative stress, demonstrated with the decreased expression of HO-1 on the PAG and AMG, was normalized in CORM-2 and CoPP treated animals. CoPP also increased the expression of HO-1 on VHPC, and both treatments up-regulated the NQO1 levels on the PAG of CFA-injected animals. In conclusion, both CORM-2 and CoPP treatments inhibited the nociceptive and apoptotic responses generated by peripheral inflammation and/or potentiated the antioxidant responses in several brain areas revealing the new modulatory effects of these treatments in the CNS of animals with chronic inflammatory pain.
Assuntos
Dor Crônica , Compostos Organometálicos , Animais , Antioxidantes/metabolismo , Monóxido de Carbono/metabolismo , Sistema Nervoso Central/metabolismo , Dor Crônica/metabolismo , Heme Oxigenase-1/metabolismo , Inflamação/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nociceptividade , Compostos Organometálicos/metabolismo , Compostos Organometálicos/farmacologia , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína X Associada a bcl-2/metabolismoRESUMO
This study aimed to estimate the incidence of central nervous system (CNS) metastases in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) treated with trastuzumab. Studies were identified through a literature search of electronic databases. Random-effects meta-analyses were performed to estimate the incidence rate of CNS metastases, trastuzumab therapy duration, and time from trastuzumab therapy to CNS metastasis diagnosis. A meta-analysis of odds ratios was performed to evaluate the significance of a difference in CNS metastasis incidence between patients with and without trastuzumab treatment. Thirty studies (8121 trastuzumab-treated and 3972 control patients) were included. The follow-up duration was 18.9 months (95% confidence interval [CI]: 13.8, 24.1). The trastuzumab treatment duration was 9.0 months (95% CI: 7.0, 11.0). The median interval between the start of trastuzumab therapy and CNS metastasis diagnosis was 12.2 months (95% CI: 9.5, 14.7). The incidence of CNS metastasis after the start of trastuzumab therapy was 22% (95% CI: 16, 27). The incidence of CNS metastases was significantly higher in trastuzumab-treated than in non-trastuzumab-treated patients (odds ratio: 1.39 [95% CI: 1.06, 1.82], p=0.02). The survival time from the start of the study was 23.4 months (95% CI: 19.7, 27.1) in trastuzumab-treated patients and 18.4 months (95% CI: 12.7, 24.1) in patients treated with control regimens. The survival time after the development of CNS metastases in trastuzumab-treated patients was 19.2 months (95% CI: 15.6, 25.9). Approximately 22% of patients with HER2-positive MBC who were treated with trastuzumab developed CNS metastases. However, trastuzumab-treated patients had a longer survival than patients who were not treated with trastuzumab.
Assuntos
Neoplasias da Mama , Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Sistema Nervoso Central , Feminino , Humanos , Incidência , Receptor ErbB-2 , Trastuzumab/uso terapêuticoRESUMO
This study aimed to estimate the incidence of central nervous system (CNS) metastases in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) treated with trastuzumab. Studies were identified through a literature search of electronic databases. Random-effects meta-analyses were performed to estimate the incidence rate of CNS metastases, trastuzumab therapy duration, and time from trastuzumab therapy to CNS metastasis diagnosis. A meta-analysis of odds ratios was performed to evaluate the significance of a difference in CNS metastasis incidence between patients with and without trastuzumab treatment. Thirty studies (8121 trastuzumab-treated and 3972 control patients) were included. The follow-up duration was 18.9 months (95% confidence interval [CI]: 13.8, 24.1). The trastuzumab treatment duration was 9.0 months (95% CI: 7.0, 11.0). The median interval between the start of trastuzumab therapy and CNS metastasis diagnosis was 12.2 months (95% CI: 9.5, 14.7). The incidence of CNS metastasis after the start of trastuzumab therapy was 22% (95% CI: 16, 27). The incidence of CNS metastases was significantly higher in trastuzumab-treated than in non-trastuzumab-treated patients (odds ratio: 1.39 [95% CI: 1.06, 1.82], p=0.02). The survival time from the start of the study was 23.4 months (95% CI: 19.7, 27.1) in trastuzumab-treated patients and 18.4 months (95% CI: 12.7, 24.1) in patients treated with control regimens. The survival time after the development of CNS metastases in trastuzumab-treated patients was 19.2 months (95% CI: 15.6, 25.9). Approximately 22% of patients with HER2-positive MBC who were treated with trastuzumab developed CNS metastases. However, trastuzumab-treated patients had a longer survival than patients who were not treated with trastuzumab.
Assuntos
Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Sistema Nervoso Central , Incidência , Receptor ErbB-2 , Anticorpos Monoclonais Humanizados/uso terapêutico , Trastuzumab/uso terapêuticoRESUMO
BACKGROUND: Inflorescence architecture is denoted by the spatial arrangement of various lateral branches and florets formed on them, which is shaped by a complex of regulators. Unveiling of the regulatory mechanisms underlying inflorescence architecture is pivotal for improving crop yield potential. Quinoa (Chenopodium quinoa Willd), a pseudo cereal originated from Andean region of South America, has been widely recognized as a functional super food due to its excellent nutritional elements. Increasing worldwide consumption of this crop urgently calls for its yield improvement. However, dissection of the regulatory networks underlying quinoa inflorescence patterning is lacking. RESULTS: In this study, we performed RNA-seq analysis on quinoa inflorescence samples collected from six developmental stages, yielding a total of 138.8 GB data. We screened 21,610 differentially expressed genes (DEGs) among all the stages through comparative analysis. Weighted Gene Co-Expression Network Analysis (WGCNA) was performed to categorize the DEGs into ten different modules. Subsequently, we placed emphasis on investigating the modules associated with none branched and branched inflorescence samples. We manually refined the coexpression networks with stringent edge weight cutoffs, and generated core networks using transcription factors and key inflorescence architecture related genes as seed nodes. The core networks were visualized and analyzed by Cytoscape to obtain hub genes in each network. Our finding indicates that the specific occurrence of B3, TALE, WOX, LSH, LFY, GRAS, bHLH, EIL, DOF, G2-like and YABBY family members in early reproductive stage modules, and of TFL, ERF, bZIP, HD-ZIP, C2H2, LBD, NAC, C3H, Nin-like and FAR1 family members in late reproductive stage modules, as well as the several different MADS subfamily members identified in both stages may account for shaping quinoa inflorescence architecture. CONCLUSION: In this study we carried out comparative transcriptome analysis of six different stages quinoa inflorescences, and using WGCNA we obtained the most highly potential central hubs for shaping inflorescence. The data obtained from this study will enhance our understanding of the gene network regulating quinoa inflorescence architecture, as well will supply with valuable genetic resources for high-yield elite breeding in the future.
Assuntos
Chenopodium quinoa/genética , Regulação da Expressão Gênica de Plantas , Inflorescência/genética , Chenopodium quinoa/anatomia & histologia , Chenopodium quinoa/metabolismo , Grão Comestível/genética , Redes Reguladoras de Genes/fisiologia , Inflorescência/anatomia & histologia , Inflorescência/metabolismo , Proteínas de Domínio MADS/genética , Proteínas de Domínio MADS/metabolismo , RNA-Seq , América do Sul , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
BACKGROUND: Common buckwheat (Fagopyrum esculentum) is an important staple food crop in southwest China, where drought stress is one of the largest limiting factors that lead to decreased crop production. To reveal the molecular mechanism of common buckwheat in response to drought stress, we performed a comprehensive transcriptomics study to evaluate gene expression profiles of common buckwheat during PEG-mediated drought treatment. RESULTS: In total, 45 million clean reads were assembled into 53,404 unigenes with an average length of 749 bp and N50 length of 1296 bp. A total of 1329 differentially expressed genes (DEGs) were identified by comparing wellwatered and drought-treated plants, out of which 666 were upregulated and 663 were downregulated. Furthermore, we defined the functional characteristics of DEGs using GO and KEGG classifications. GO enrichment analysis showed that the DEGs were significantly overrepresented in four categories, namely, "oxidoreductase activity," "oxidationreduction process," "xyloglucan:xyloglucosyl transferase activity," and "apoplast." Using KEGG pathway analysis, a large number of annotated genes were overrepresented in terms such as "plant hormone signal transduction," "phenylpropanoid biosynthesis," "photosynthesis," and "carbon metabolism." Conclusions: These results can be further exploited to investigate the molecular mechanism of common buckwheat in response to drought treatment and could supply with valuable molecular sources for abiotic-tolerant elite breeding programs in the future.
Assuntos
Estresse Fisiológico/genética , Fagopyrum/genética , Fatores de Transcrição , Transferases , Transdução de Sinais , Expressão Gênica , Análise de Sequência de RNA , Secas , Proteínas de Ligação à Clorofila , Reação em Cadeia da Polimerase em Tempo Real , TranscriptomaRESUMO
Tetrameric assembly of channel subunits in the endoplasmic reticulum (ER) is essential for surface expression and function of K+ channels, but the molecular mechanism underlying this process remains unclear. In this study, we found through genetic screening that ER-located J-domain-containing chaperone proteins (J-proteins) are critical for the biogenesis and physiological function of ether-a-go-go-related gene (ERG) K+ channels in both Caenorhabditis elegans and human cells. Human J-proteins DNAJB12 and DNAJB14 promoted tetrameric assembly of ERG (and Kv4.2) K+ channel subunits through a heat shock protein (HSP) 70-independent mechanism, whereas a mutated DNAJB12 that did not undergo oligomerization itself failed to assemble ERG channel subunits into tetramers in vitro and in C. elegans. Overexpressing DNAJB14 significantly rescued the defective function of human ether-a-go-go-related gene (hERG) mutant channels associated with long QT syndrome (LQTS), a condition that predisposes to life-threatening arrhythmia, by stabilizing the mutated proteins. Thus, chaperone proteins are required for subunit stability and assembly of K+ channels.
Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Canal de Potássio ERG1/metabolismo , Retículo Endoplasmático/metabolismo , Proteínas de Choque Térmico HSP40/metabolismo , Proteínas de Choque Térmico HSP47/metabolismo , Canais de Potássio/metabolismo , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/química , Proteínas de Caenorhabditis elegans/genética , Linhagem Celular Tumoral , Canal de Potássio ERG1/química , Canal de Potássio ERG1/genética , Células HEK293 , Proteínas de Choque Térmico HSP40/química , Proteínas de Choque Térmico HSP40/genética , Proteínas de Choque Térmico HSP47/química , Proteínas de Choque Térmico HSP47/genética , Proteínas de Choque Térmico HSP70/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Síndrome do QT Longo/genética , Síndrome do QT Longo/metabolismo , Potenciais da Membrana , Chaperonas Moleculares , Mutação , Miócitos Cardíacos/metabolismo , Canais de Potássio/química , Canais de Potássio/genética , Multimerização Proteica , Estabilidade Proteica , Estrutura Quaternária de Proteína , Interferência de RNA , Canais de Potássio Shal/genética , Canais de Potássio Shal/metabolismo , Fatores de Tempo , TransfecçãoRESUMO
OBJECTIVE: Silent brain infarctions are the silent cerebrovascular events that are distinguished from symptomatic lacunar infarctions by their 'silence'; the origin of these infarctions is still unclear. This study analyzed the characteristics of silent and symptomatic lacunar infarctions and sought to explore the mechanism of this 'silence'. METHODS: In total, 156 patients with only silent brain infarctions, 90 with only symptomatic lacunar infarctions, 160 with both silent and symptomatic lacunar infarctions, and 115 without any infarctions were recruited. Vascular risk factors, leukoaraiosis, and vascular assessment results were compared. The National Institutes of Health Stroke Scale scores were compared between patients with only symptomatic lacunar infarctions and patients with two types of infarctions. The locations of all of the infarctions were evaluated. The evolution of the two types of infarctions was retrospectively studied by comparing the infarcts on the magnetic resonance images of 63 patients obtained at different times. RESULTS: The main risk factors for silent brain infarctions were hypertension, age, and advanced leukoaraiosis; the main factors for symptomatic lacunar infarctions were hypertension, atrial fibrillation, and atherosclerosis of relevant arteries. The neurological deficits of patients with only symptomatic lacunar infarctions were more severe than those of patients with both types of infarctions. More silent brain infarctions were located in the corona radiata and basal ganglia; these locations were different from those of the symptomatic lacunar infarctions. The initial sizes of the symptomatic lacunar infarctions were larger than the silent brain infarctions, whereas the final sizes were almost equal between the two groups. CONCLUSIONS: Chronic ischemic preconditioning and nonstrategic locations may be the main reasons for the 'silence' of silent brain infarctions.
Assuntos
Infarto Encefálico/etiologia , Isquemia Encefálica/complicações , Acidente Vascular Cerebral Lacunar/etiologia , Idoso , Infarto Encefálico/patologia , Infarto Encefálico/fisiopatologia , Estudos de Casos e Controles , Doença Crônica , Feminino , Humanos , Angiografia por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral Lacunar/patologia , Acidente Vascular Cerebral Lacunar/fisiopatologiaRESUMO
OBJECTIVE: Silent brain infarctions are the silent cerebrovascular events that are distinguished from symptomatic lacunar infarctions by their 'silence'; the origin of these infarctions is still unclear. This study analyzed the characteristics of silent and symptomatic lacunar infarctions and sought to explore the mechanism of this 'silence'. METHODS: In total, 156 patients with only silent brain infarctions, 90 with only symptomatic lacunar infarctions, 160 with both silent and symptomatic lacunar infarctions, and 115 without any infarctions were recruited. Vascular risk factors, leukoaraiosis, and vascular assessment results were compared. The National Institutes of Health Stroke Scale scores were compared between patients with only symptomatic lacunar infarctions and patients with two types of infarctions. The locations of all of the infarctions were evaluated. The evolution of the two types of infarctions was retrospectively studied by comparing the infarcts on the magnetic resonance images of 63 patients obtained at different times. RESULTS: The main risk factors for silent brain infarctions were hypertension, age, and advanced leukoaraiosis; the main factors for symptomatic lacunar infarctions were hypertension, atrial fibrillation, and atherosclerosis of relevant arteries. The neurological deficits of patients with only symptomatic lacunar infarctions were more severe than those of patients with both types of infarctions. More silent brain infarctions were located in the corona radiata and basal ganglia; these locations were different from those of the symptomatic lacunar infarctions. The initial sizes of the symptomatic lacunar infarctions were larger than the silent brain infarctions, whereas the final sizes were almost equal between the two groups. CONCLUSIONS: Chronic ischemic preconditioning and nonstrategic locations may be the main reasons for the 'silence' of silent brain infarctions.