RESUMEN
Bivalent Smac mimetics have been shown to possess binding affinity and pro-apoptotic activity similar to or more potent than that of native Smac, a protein dimer able to neutralize the anti-apoptotic activity of an inhibitor of caspase enzymes, XIAP, which endows cancer cells with resistance to anticancer drugs. We design five new bivalent Smac mimetics, which are formed by various linkers tethering two diazabicyclic cores being the IAP binding motifs. We built in silico models of the five mimetics by the TwistDock workflow and evaluated their conformational tendency, which suggests that compound 3, whose linker is n-hexylene, possess the highest binding potency among the five. After synthesis of these compounds, their ability in tumour cell growth inhibition and apoptosis induction displayed in experiments with SK-OV-3 and MDA-MB-231 cancer cell lines confirms our prediction. Among the five mimetics, compound 3 displays promising pro-apoptotic activity and deserves further optimization.
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Antineoplásicos , Neoplasias , Humanos , Proteínas Inhibidoras de la Apoptosis/metabolismo , Proteínas Inhibidoras de la Apoptosis/farmacología , Proteína Inhibidora de la Apoptosis Ligada a X/metabolismo , Proteína Inhibidora de la Apoptosis Ligada a X/farmacología , Antineoplásicos/farmacología , Antineoplásicos/química , Conformación Molecular , Apoptosis , Línea Celular TumoralRESUMEN
To establish accurate detection methods of process-specific Escherichia coli residual host cell protein (HCP) and residual host cell DNA (rcDNA) in recombinant biological preparations. Taking the purification process of GLP expressed by E. coli as a specific-process model, the HCP of empty E. coli was intercepted to immunize mice and rabbits. Using IgG from immunized rabbits as the coating antibody and mouse immune serum as the second sandwich antibody, a process-specific enzyme-linked immunosorbent assay (ELISA) for E. coli HCP was established. Targeting the 16S gene of E. coli, ddPCR was used to obtain the absolute copies of rcDNA in samples. Non-process-specific commercial ELISA kit and the process-specific ELISA established in this study were used to detect the HCP in GLP preparation. About 62% of HCPs, which should be process-specific HCPs, could not be detected by the non-process-specific commercial ELISA kit. The sensitivity of established ELISA can reach 338 pg/mL. The rcDNA could be absolutely quantitated by ddPCR, for the copies of rcDNA in three multiple diluted samples showed a reduced gradient. While the copies of rcDNA in three multiple diluted samples could not be distinguished by the qPCR. Process-specific ELISA has high sensitivity in detecting process-specific E. coli HCP. The absolutely quantitative ddPCR has much higher accuracy than the relatively quantitative qPCR, it is a nucleic acid quantitative method that is expected to replace qPCR in the future.
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Anticuerpos , Escherichia coli , Conejos , Animales , Ratones , Escherichia coli/genética , Escherichia coli/metabolismo , ADN/metabolismo , Ensayo de Inmunoadsorción Enzimática/métodosRESUMEN
To explore the effect of ultra-strong static magnetic field on gut microbiota, 16 T static magnetic field was used to study the changes in the structure and composition of human and mouse gut microbiota in this environment. In the mouse gut microbiota, at the genus level, the magnetic field significantly decreased the relative abundances of Escherichia-Shigella, Lactobacillus, Enterococcus, Burkholderia-Caballeronia-Paraburkholderia, Parasutterella, and Ralstonia and significantly increased those of Parabacteroides, Alloprevotella, Alistipes, Odoribacter, Bacteroides, Mucispirillum, Sutterella, and Prevotellaceae_UCG-001. Similarly, at the genus level, the relative abundances of Bacteroides, Parabacteroides, Romboutsia, and Streptococcus significantly decreased in the human gut microbiota. Contrary to the changing trend of the abundance in the mouse gut, the abundances of Bacteroides and Parabacteroides in the human gut were significantly reduced under magnetic field. The BugBase phenotypic prediction analysis showed that the relative abundances of five phenotypes, including anaerobism, mobile elements, potential pathogenicity, stress-tolerant, and biofilm formation, changed significantly in the mouse gut microbiota, while the relative abundances of two phenotypes, including Gram-positive and Gram-negative phenotypes, changed significantly in the human gut microbiota. The 16 T magnetic field could differently affect the composition, structure, and phenotypes of gut microbiota in human and mice, suggesting the importance of model selection in studying the biological effects of magnetic field.
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Microbioma Gastrointestinal , Humanos , Animales , Ratones , Microbioma Gastrointestinal/genética , Bacterias/genéticaRESUMEN
The current pandemic of coronavirus disease 2019 (COVID-19) has affected >160â million individuals to date, and has caused millions of deaths worldwide, at least in part due to the unclarified pathophysiology of this disease. Identifying the underlying molecular mechanisms of COVID-19 is critical to overcome this pandemic. Metabolites mirror the disease progression of an individual and can provide extensive insights into their pathophysiological significance at each stage of disease. We provide a comprehensive view of metabolic characterisation of sera from COVID-19 patients at all stages using untargeted and targeted metabolomic analysis. As compared with the healthy controls, we observed different alteration patterns of circulating metabolites from the mild, severe and recovery stages, in both the discovery cohort and the validation cohort, which suggests that metabolic reprogramming of glucose metabolism and the urea cycle are potential pathological mechanisms for COVID-19 progression. Our findings suggest that targeting glucose metabolism and the urea cycle may be a viable approach to fight COVID-19 at various stages along the disease course.
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COVID-19 , Estudios de Cohortes , Humanos , Metabolómica , Pandemias , SARS-CoV-2RESUMEN
The present study was conducted to investigate the influence of microgravity on human gut microbiota using 16S rRNA gene sequencing in vitro. The diamagnetic material magnetic levitation method was used to simulate weightless environment. The human gut microbiota was cultured under two different conditions: normal gravity (1 g), and simulated microgravity (0 g), which showed that both the richness (P = 0.04) and diversity (P = 0.0002) of human gut microbiota were significantly altered. As compared to the normal gravity, the simulated microgravity significantly reduced abundance of bacteria related to anti-inflammatory effects, such as Subdoligranulum, Faecalibacterium, Fusicatenibacter, Butyricicoccus, and Lachnospiraceae-NK4A136-0 group (P < 0.05), while significantly increased that of Alistipes and Eubacterium-Ventriosum-group (P < 0.05). Moreover, the Spearman's correlation analysis showed that there were more significantly correlated species (|r|≥ 0.5, P < 0.05) in normal gravity than that in the simulated microgravity. KEGG pathway analysis revealed that the microgravity significantly (P < 0.05) affected the metabolism of gut microbiota, such as the metabolism of pyrimidine, fatty acids, glyoxylate and dicarboxylate, peptidoglycan biosynthesis, and carbon fixation in photosynthetic organisms. These results suggested that the exposure to a microgravity environment might induce disturbances in human gut microbiota. KEY POINTS: ⢠Using 16sRNA gene sequencing technology, it was found that magnetic levitation-simulated microgravity had varying degrees of influence on the abundance, diversity, species correlation, and KEGG pathways of human intestinal microbes. ⢠Digital PCR can improve the detection rate of microorganisms with low abundance.
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Microbioma Gastrointestinal , Ingravidez , Bacterias/genética , Clostridiales/genética , Microbioma Gastrointestinal/genética , Humanos , ARN Ribosómico 16S/genéticaRESUMEN
OBJECTIVE: To examine whether a modified endometriosis fertility index (EFI) can better predict the rate of pregnancy without assisted reproductive technologies (ART) after laparoscopic surgery in infertile Chinese women with endometriosis. METHODS: 564 infertile women undergoing laparoscopy for endometriosis were retrospectively collected from January 2014 to December 2018. 472 patients were used to modify the EFI based on new, optimal cutoffs for its predictor variables. The predictive accuracy of the modified EFI was examined in the other 92 patients. RESULTS: Among the patients for the EFI modification, the multivariable Cox regression results showed that historical factors made more contribution in predicting non-ART pregnancy rate than surgical factors both in modified EFI (C-index: historical factors 0.617 vs surgical factors 0.558) and original EFI (C-index: historical factors 0.600 vs surgical factors 0.549). No significant relationship between the prior pregnancy and post-operative non-ART pregnancy rates was detected by both modified EFI and original EFI (p = 0.530 and 0.802, respectively). To assess the predictive effect of modified EFI, the two versions of modified EFI not only had higher predictive accuracy (C-index: 0.627 and 0.632) for non-ART pregnancy rates than that of the original EFI (C-index: 0.602) in the patients undergoing surgery during 2014-2017, but also higher than that of the original EFI (C-index: 0.638 and 0.612 vs 0.560) in the externally validated population in 2018. CONCLUSIONS: A modified EFI based on population-specific optimal cutoffs and weights might be more suitable for estimating the rate of non-ART pregnancy after laparoscopic surgery in infertile women with endometriosis.
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Endometriosis/cirugía , Fertilidad/fisiología , Índice de Embarazo/tendencias , Adulto , China , Estudios de Cohortes , Femenino , Humanos , EmbarazoRESUMEN
This study revealed that iturin A-like lipopeptides produced by Bacillus subtillis induced both paraptosis and apoptosis in heterogeneous human epithelial colorectal adenocarcinoma (Caco-2) cells. Autophagy was simultaneously induced in Caco-2 cells treated with iturin A-like lipopeptides at the early stage and inhibited at the later stage. A western blot analysis showed that the lipopeptides induced apoptosis in Caco-2 cells via a mitochondrial-dependent pathway, as indicated by upregulated expression of the apoptotic genes bax and bad and downregulated expression of the antiapoptotic gene bcl-2. The induction of paraptosis in Caco-2 cells was indicated by the occurrence of many cytoplasmic vacuoles accompanied by endoplasmic reticulum (ER) dilatation and mitochondrial swelling and dysfunction. ER stress also occurred with significant increases in reactive oxygen species and Ca2+ levels in cells. Autophagy was detected by a transmission electron microscopy analysis and by upregulated expression of LC3-II and downregulated expression of LC3-I. The inhibition of autophagy at the later stage was shown by upregulated expression of p62. This study revealed the capability of iturin A-like B. subtilis lipopeptides to simultaneously execute antitumor potential via multiple pathways.
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Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Neoplasias Colorrectales , Péptidos Cíclicos/farmacología , Bacillus subtilis , Células CACO-2 , HumanosRESUMEN
Extracellular vesicles (EVs) are nano vesicular structures that are secreted by almost all kinds of cells. Exosomes are small EVs derived from endosomes, with a diameter between 30-100nm. Tumour-derived exosomes carry many molecules and factors from tumour cells. These exosomes are recognized and taken up by immunocytes. However, tumour-derived exosomes can not only suppress immune cell functions but also help tumours escape immune surveillance in the tumour microenvironment. The present work investigated the effect of exosomes derived from genetical modified K562 cells (GMK cells), which express IL-15, IL-18 and 4-1BBL (TNFSF9) on their surface. The results showed that these GME exosomes, carrying IL-15, IL-18 and 4-1BBL proteins similar to their host cells, could activate NK cells, increase the cytotoxicity of NK cells on some tumour cells in a short treatment (4h) and promote NK cells proliferation. However, with an extended treatment time (48h), these exosomes could inhibite the cytotoxicity of NK cells by inhibiting activated receptor expression on NK cells. These results indicated the bifacial effects of GMK exosomes on NK cells, which will be helpful to explore the possibility of using transformed exosomes as an anti-tumour immune vaccine or a therapeutic tool in future.
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Ingeniería Celular , Citotoxicidad Inmunológica/inmunología , Exosomas/metabolismo , Vesículas Extracelulares/metabolismo , Células Asesinas Naturales/inmunología , Ingeniería Celular/métodos , Proliferación Celular/fisiología , Humanos , Células K562 , Transducción de Señal/fisiología , Microambiente Tumoral/fisiologíaRESUMEN
Candida albicans is a fungal pathogen that is difficult to cure clinically. The current clinic C. albicans-inhibiting drugs are very harmful to humans. This study revealed the potential of iturin fractions from Bacillus subtilis to inhibit C. albicans in free status (MIC = 32 µg/mL) and natural biofilm in vitro. The inhibition mechanism was identified as an apoptosis pathway via the decrease of mitochondrial membrane potential, the increase of the reactive oxygen species (ROS) accumulation, and the induction of nuclear condensation. For in vivo experiments, the C. albicans infection model was constructed via intraperitoneal injection of 1 × 108C. albicans cells into mice. One day after the infection, iturin was used to treat infected mice at different concentrations alone and in combination with amphotericin B (AmB) by intraperitoneal injection. The treatment with AmB alone could cause the death of infected mice, whereas treatment with 15 mg/kg iturin per day alone led to the survival of all infected mice throughout the study. After continuously treated for 6 days, all mice were sacrificed and analyzed. As results, the combination of 15 mg/kg iturin and AmB at a ratio of 2:1 had the most efficient effect to remove the fungal burden in the kidney and cure the infected mice by reversing the symptoms caused by C. albicans infection, such as the loss of body weight, change of immunology cells in blood and cytokines in serum, and damage of organ structure and functions. Overall, iturin had potential in the development of efficient and safe drugs to cure C. albicans infection.
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Antifúngicos/farmacología , Bacillus subtilis/metabolismo , Candida albicans/efectos de los fármacos , Péptidos Cíclicos/farmacología , Animales , Antifúngicos/aislamiento & purificación , Antifúngicos/uso terapéutico , Biopelículas/efectos de los fármacos , Candidiasis/tratamiento farmacológico , Modelos Animales de Enfermedad , Ratones , Pruebas de Sensibilidad Microbiana , Viabilidad Microbiana/efectos de los fármacos , Péptidos Cíclicos/aislamiento & purificación , Péptidos Cíclicos/uso terapéutico , Resultado del TratamientoRESUMEN
PURPOSE: This paper aims to summarize recent developments regarding the synthesis, application and challenges of fungal AgNPs. Possible methods to overcome the challenge of synthesis and reduce the toxicity of AgNPs have been discussed. MATERIALS AND METHODS: This review consults and summary a large number of papers. RESULTS: Silver nanoparticles (AgNPs) have great potential in many areas, as they possess multiple novel characteristics. Conventional methods for AgNPs biosynthesis involve chemical agents, causing environmental toxicity and high energy consumption. Fungal bioconversion is a simple, low-cost and energy-efficient biological method, which could successfully be used for AgNPs synthesis. Fungi can produce enzymes that act as both reducing and capping agents, to form stable and shape-controlled AgNPs. CONCLUSIONS: AgNPs have great potential in the medical and food industries, due to their antimicrobial, anticancer, anti-HIV, and catalytic activities. However, the observed in vitro and in vivo toxicity poses considerable challenges in the synthesis and application of AgNPs.
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Antiinfecciosos , Hongos/metabolismo , Nanopartículas del Metal , Plata , Animales , Antiinfecciosos/química , Antiinfecciosos/toxicidad , Humanos , Nanopartículas del Metal/química , Nanopartículas del Metal/toxicidad , Plata/química , Plata/metabolismo , Plata/toxicidadRESUMEN
Extracellular vesicles (EVs) are phospholipid membrane-enclosed entities containing specific proteins, RNA, miRNA, and lncRNA. EVs are released by various cells and play a vital role in cell communication by transferring their contents from the host cells to the recipient cells. The role of EVs has been characterized in a wide range of physiological and pathophysiological processes. In this context, we highlight recent advances in our understanding of the regulatory effects of EVs, with a focus on bone metabolism and the bone microenvironment. The roles of EVs in cell communication among bone-related cells, stem cells, tumor cells, and other cells under physiological or pathological conditions are also discussed. In addition, promising applications for EVs in treating bone-related diseases are proposed.
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Huesos/metabolismo , Microambiente Celular , Vesículas Extracelulares/metabolismo , Animales , Enfermedades Óseas/patología , Humanos , Modelos Biológicos , Células Madre/metabolismoRESUMEN
Cancer is one of the most common causes of death worldwide. Extensive research has been conducted on cancer; regardless, the link between cancer and diet remains undetermined. Recent studies have emphasized the importance of miRNAs in cancer-associated pathways from the perspective of dietary modulation. We highlighted the recent data on dietary modulation of gut microbiota and miRNAs related to cancer on the basis of recently published results. The targets of miRNAs are oncogenes or tumor suppressors that mediate the progression and initiation of carcinogenesis. Different miRNAs display complex expression profiles in response to dietary manipulation. Various dietary components, such as fatty acids, resveratrol, isothiocyanate, and curcumin, have been effectively used in cancer prevention and treatment. This potency is attributed to the capability of these components to alter miRNA expression, thereby modulating the vital pathways involved in metastasis, invasion, apoptosis, tumor growth, and cell proliferation.
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Dieta , Microbioma Gastrointestinal/fisiología , MicroARNs/análisis , Neoplasias/microbiología , HumanosRESUMEN
Endophytes are microorganisms that colonize the interior of host plants without causing apparent disease. They have been widely studied for their ability to modulate relationships between plants and biotic/abiotic stresses, often producing valuable secondary metabolites that can affect host physiology. Owing to the advantages of microbial fermentation over plant/cell cultivation and chemical synthesis, endophytic fungi have received significant attention as a mean for secondary metabolite production. This article summarizes currently reported results on plant-endophyte interaction hypotheses and highlights the biotechnological applications of endophytic fungi and their metabolites in agriculture, environment, biomedicine, energy, and biocatalysts. Current bottlenecks in industrial development and commercial applications as well as possible solutions are also discussed.
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Biotecnología/tendencias , Endófitos/metabolismo , Hongos/metabolismo , Plantas/microbiología , FermentaciónRESUMEN
Lactic acid bacteria are associated with the human gastrointestinal tract. They are important for maintaining the balance of microflora in the human gut. An increasing number of published research reports in recent years have denoted the importance of producing interferon-gamma and IgA for treatment of disease. These agents can enhance the specific and nonspecific immune systems that are dependent on specific bacterial strains. The mechanisms of these effects were revealed in this investigation, where the cell walls of these bacteria were modulated by the cytokine pathways, while the whole bacterial cell mediated the host cell immune system and regulated the production of tumor necrosis factors and interleukins. A supplement of highly active lactic acid bacteria strains provided significant potential to enhance host's immunity, offering prevention from many diseases including some cancers. This review summarizes the current understanding of the function of lactic acid bacteria immunity enhancement and cancer prevention.
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Inmunidad Innata , Lactobacillales/inmunología , Neoplasias/prevención & control , HumanosRESUMEN
The effects of weightlessness on enteric microorganisms have been extensively studied, but have mainly been focused on pathogens. As a major component of the microbiome of the human intestinal tract, probiotics are important to keep the host healthy. Accordingly, understanding their changes under weightlessness conditions has substantial value. This study was carried out to investigate the characteristics of Lactobacillus acidophilus, a typical probiotic for humans, under simulated microgravity (SMG) conditions. The results revealed that SMG had no significant impact on the morphology of L. acidophilus, but markedly shortened its lag phase, enhanced its growth rate, acid tolerance ability up to pH < 2.5, and the bile resistance at the bile concentration of <0.05%. SMG also decreased the sensitivity of L. acidophilus to cefalexin, sulfur gentamicin, and sodium penicillin. No obvious effect of SMG was observed on the adhesion ability of L. acidophilus to Caco-2 cells. Moreover, after SMG treatment, both the culture of L. acidophilus and its liquid phase exhibited higher antibacterial activity against S. typhimurium and S. aureus in a time-dependent manner. The SMG treatment also increased the in vitro cholesterol-lowering ability of L. acidophilus by regulating the expression of the key cholesterol metabolism genes CYP7A1, ABCB11, LDLR, and HMGCR in the HepG2 cell line. Thus, the SMG treatment did have considerable influence on some biological activities and characteristics of L. acidophilus related to human health. These findings provided valuable information for understanding the influence of probiotics on human health under simulated microgravity conditions, at least.
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Lactobacillus acidophilus/crecimiento & desarrollo , Lactobacillus acidophilus/fisiología , Simulación de Ingravidez , Ingravidez , Antibacterianos/farmacología , Adhesión Bacteriana , Ácidos y Sales Biliares/farmacología , Células CACO-2 , Colesterol/genética , Colesterol/metabolismo , Humanos , Concentración de Iones de Hidrógeno , Intestinos/efectos de los fármacos , Lactobacillus acidophilus/efectos de los fármacos , Probióticos/metabolismo , Staphylococcus aureus/efectos de los fármacosRESUMEN
The lipopeptides of Bacillus are small metabolites that contain a cyclic structure formed by 7-10 amino acids (including 2-4 D-amino acids) and a beta-hydroxy fatty acid with 13-19 C atoms. These lipopeptides exhibit a variety of biological activities, including interactions with biofilms, and anti-fungal, anti-inflammatory, anti-tumor, anti-virus, and anti-platelet properties. The multiple activities of lipopeptides have stimulated significant interest in the exploitation of these lipopeptides for use as antibiotics, feed additives, anti-tumor agents, urgent thrombolytic therapeutic agents, and drug delivery systems. Understanding the natural function of these structurally diverse lipopeptides in Bacillus provides insight into microbial regulatory programs and is required for efficient development of more effective products. Currently, there is still insufficient knowledge of the direct target of these lipopeptides, and continued efforts are needed to enhance their biosynthesis efficiency for industrial applications.
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Bacillus subtilis/metabolismo , Proteínas Bacterianas/metabolismo , Lipopéptidos/química , Lipopéptidos/metabolismo , Antibacterianos/farmacología , Antifúngicos , Biopelículas , Lipopéptidos/aislamiento & purificación , Lipopéptidos/farmacología , Péptidos Cíclicos/metabolismoRESUMEN
In this article, we present COMSAT, a hybrid framework for residue contact prediction of transmembrane (TM) proteins, integrating a support vector machine (SVM) method and a mixed integer linear programming (MILP) method. COMSAT consists of two modules: COMSAT_SVM which is trained mainly on position-specific scoring matrix features, and COMSAT_MILP which is an ab initio method based on optimization models. Contacts predicted by the SVM model are ranked by SVM confidence scores, and a threshold is trained to improve the reliability of the predicted contacts. For TM proteins with no contacts above the threshold, COMSAT_MILP is used. The proposed hybrid contact prediction scheme was tested on two independent TM protein sets based on the contact definition of 14 Å between Cα-Cα atoms. First, using a rigorous leave-one-protein-out cross validation on the training set of 90 TM proteins, an accuracy of 66.8%, a coverage of 12.3%, a specificity of 99.3% and a Matthews' correlation coefficient (MCC) of 0.184 were obtained for residue pairs that are at least six amino acids apart. Second, when tested on a test set of 87 TM proteins, the proposed method showed a prediction accuracy of 64.5%, a coverage of 5.3%, a specificity of 99.4% and a MCC of 0.106. COMSAT shows satisfactory results when compared with 12 other state-of-the-art predictors, and is more robust in terms of prediction accuracy as the length and complexity of TM protein increase. COMSAT is freely accessible at http://hpcc.siat.ac.cn/COMSAT/.
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Simulación por Computador , Proteínas de la Membrana/química , Modelos Moleculares , Programación Lineal , Algoritmos , Reconocimiento de Normas Patrones Automatizadas , Posición Específica de Matrices de Puntuación , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Reproducibilidad de los Resultados , Alineación de Secuencia , Análisis de Secuencia de Proteína , Homología Estructural de Proteína , Máquina de Vectores de SoporteRESUMEN
Trans-resveratrol (trans-3,5,4'-trihydroxystilbene) is one of the most promising stilbenes, a type of natural phenol that is produced naturally by some plant species in response to stress. Resveratrol exhibits multiple bioactivities and is used in the agriculture, medical, food, and cosmetic industries due to its antitumor, anti-inflammatory, cardioprotective, and antioxidant properties. Due to the increasing demand, an active area of investigation is the use of plant cell culture and metabolic engineering techniques to produce large quantities of active resveratrol. However, most recent studies have focused on the efficiency of synthesizing resveratrol in vitro, but have not investigated the contributions of the transcriptional activities of the genes encoding the related enzymes in the biosynthesis pathway. This article reviews recently developed methods for the biosynthesis of resveratrol and comprehensively reviews the current state of knowledge of the function of the key pathway enzymes in resveratrol synthesis. Approaches for enhancing resveratrol production, such as introducing non-pathway genes and co-localizing enzymes are described in detail.
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Ingeniería Metabólica/métodos , Células Vegetales/metabolismo , Plantas/metabolismo , Estilbenos/síntesis química , Estilbenos/metabolismo , Antiinflamatorios/metabolismo , Antioxidantes/metabolismo , Técnicas de Cultivo de Célula , Escherichia coli/genética , Escherichia coli/metabolismo , Resveratrol , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismoRESUMEN
Heat shock protein 90 (Hsp90) is a ubiquitously expressed ATP-dependent molecular chaperone across all species that helps to the correct the folding of many proteins related to important signaling pathways. Tumor cells expressing Hsp90 have more ATP-binding affinity than normal cells. Many correlative inhibitors have been developed to promising anti-tumor strategies and have been evaluated in clinical trials. However, the effect of Hsp90 inhibitors on immunocytes cannot be ignored. Natural killer (NK) cells are key components of the innate immune system that play a pivotal role in tumor surveillance. The present study has investigated the potential effect of four Hsp90 inhibitors (NVP-AUY922, BIIB021, 17-DMAG, and SNX-2112) on human primary NK cells. The viability, cytotoxicity, apoptosis, phenotype, and cytokine secretion of NK cells after inhibitor treatment were assessed. The results of this study demonstrated that the inhibitors had negative effects on NK cell activity in a dose-dependent manner. The four inhibitors significantly reduced the cytotoxicity of the NK cells by decreasing viability, inducing apoptosis and down-regulating the expression of cytokines and functional receptors. These findings suggest that more attention should be given to the effect of Hsp90 inhibitors on NK cell function during clinical trials and also represent a potential immunosuppressant strategy.
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Adenina/análogos & derivados , Benzoquinonas/farmacología , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Isoxazoles/farmacología , Células Asesinas Naturales/metabolismo , Lactamas Macrocíclicas/farmacología , Piridinas/farmacología , Resorcinoles/farmacología , Adenina/farmacología , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Citocinas/metabolismo , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo/efectos de los fármacos , Femenino , Humanos , MasculinoRESUMEN
BACKGROUND: Telomerase reverse transcriptase (TERT) rs2735940 polymorphism was found to be associated with increased cancer risk. However, recent studies reported controversial results. The aim of our study was to detect its relationship with cancer risk. MATERIAL AND METHODS: EMBASE and PubMed databases were searched for all publications until October 2014. ORs and 95% CIs were applied to investigate the association in the random-effects model. RESULTS: Thirteen case-control studies with 19385 cases and 17558 controls were included in this study. We found a significant association between cancer risk and TERT rs2735940 polymorphism (OR=1.06, 95% CI 1.02-1.11, P=0.005). In the subgroup analysis by ethnicity, a marginal association was found in Caucasians (OR=1.05, 95% CI 1.00-1.10, P=0.05), but not in Asians (OR=1.01, 95% CI 0.82-1.24, P=0.93). In the subgroup analysis by cancer site, this polymorphism was significantly associated with lung cancer risk (OR=1.08, 95% CI 1.02-1.13, P=0.004). CONCLUSIONS: TERT rs2735940 polymorphism was significantly associated with cancer risk, especially lung cancer.