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Protein kinase B (AKT) plays a pivotal in regulating cell migration, proliferation, apoptosis, and survival, making it a prominent target for anticancer therapy. While the kinase activity of AKT has been extensively explored, its dephosphorylation have largely remained uncharted. Herein, we aimed to unravel the molecular mechanisms governing AKT dephosphorylation, with a specific emphasis on dual-specificity phosphatases DUSP22. Our investigation sought to shed light on the potential of DUSP22 as a potential therapeutic target for non-small cell lung cancer (NSCLC). To determine the expression level of DUSP22 in NSCLC cell lines, the gene expression profiling interactive analysis (GEPIA) and Oncomine database were searched. Additionally, the effect of DUSP22 on patient survival was analyzed with Kaplan-Meier database. Antitumor effects of DUSP22 were tested in A549 and H1299 cell lines. Experiments are based on: (1) cell viability determined by the cell counting kit-8 assay and colony-formation assay; (2) cell migratory ability assessed through the scratch assay and the transwell migration assay; (3) the mechanism behind the antitumor effects of DUSP22 dissected with co-immunoprecipitation (Co-IP) and in vitro kinase assays. Our study revealed a significant downregulation of DUSP22 in both NSCLC cell lines and tissues. Meanwhile, survival rate analysis results demonstrated that reduced DUSP22 expression was correlated with poorer overall survival in lung cancer patients. Moreover, DUSP22 exhibited an inhibitory effect on the cell viability and migratory capacity of A549 and H1299 cells. This inhibition was accompanied by the decrease in the phosphorylation of AKT and p38. Mechanistically, the phosphatase domain of DUSP22 interacted with AKT, resulting in the inhibition of AKT phosphorylation. This inhibitory effect was contingent upon the phosphatase activity of DUSP22. These findings provide compelling evidence that DUSP22 directly interacted with AKT, leading to the dephosphorylation of AKT at S473 and T308 residues, ultimately curbing the proliferation and migration of lung cancer cells. Additionally, our results also highlight a preclinical rationale for utilizing DUSP22 as a prognostic marker in NSCLC.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Fosfatases de Especificidade Dupla/genética , Fosfatases de Especificidade Dupla/metabolismo , Neoplasias Pulmonares/patologia , Fosfatases da Proteína Quinase Ativada por Mitógeno/genética , Fosfatases da Proteína Quinase Ativada por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
BACKGROUND: The impact of antidepressants on Inflammatory bowel diseases (IBD) has been extensively studied. However, the biological effects and molecular mechanisms of antidepressants in alleviating colitis remain unclear. METHODS: We systematically assessed how antidepressants (fluoxetine, fluvoxamine and venlafaxine) affected IBD and chose fluoxetine, the most effective one, for mechanism studies. We treated the C56BL/6 mice of the IBD model with fluoxetine and their controls. We initially assessed the severity of intestinal inflammation in mice by body weight loss, disease Activity Index scores and the length of the colon. The H&E staining and immunohistochemical staining of MUC2 of colon sections were performed to observe the pathological changes. RT-qPCR and western blot were conducted to assess the expression level of the barrier and inflammation-associated genes. Then, single-cell RNA sequencing was performed on mouse intestinal mucosa. Seurat was used to visualize the data. Uniform Manifold Approximation and Projection (UMAP) was used to perform the dimensionality reduction. Cell Chat package was used to perform cell-cell communication analysis. Monocle was used to conduct developmental pseudotime analysis. Last, RT-qPCR, western blot and immunofluorescence staining were conducted to test the phenomenon discovered by single-cell RNA sequencing in vitro. RESULTS: We found that fluoxetine treatment significantly alleviated colon inflammation. Notably, single-cell RNA sequencing analysis revealed that fluoxetine affected the distribution of different cell clusters, cell-cell communication and KEGG pathway enrichment. Under the treatment of fluoxetine, enterocytes, Goblet cells and stem cells became the dominating cells. The pseudotime analysis showed that there was a trend for M1 macrophages to differentiate into M2 macrophages. Lastly, we tested this phenomenon in vitro, which exhibited anti-inflammatory effects on enterocytes. CONCLUSIONS: Fluoxetine exhibited anti-inflammatory effects on intestinal mucosa via remodeling of the intestinal cells and macrophages, which reveals that fluoxetine is a promising therapeutic drug for the treatment of IBD and psychiatric comorbidities.
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Colite , Doenças Inflamatórias Intestinais , Animais , Camundongos , Fluoxetina/metabolismo , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Citocinas/metabolismo , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/patologia , Inflamação/metabolismo , Mucosa Intestinal/metabolismo , Antidepressivos/metabolismo , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Anti-Inflamatórios/farmacologia , Camundongos Endogâmicos C57BLRESUMO
Colorectal cancer (CRC) is related to gut microbiota dysbiosis, especially butyrate-producing bacteria reduction. Our previous study suggested that administration of Clostridium butyricum, a butyrate-producing bacterium, exerts a crucial effect against CRC, however the potential mechanism is not clear. We first found that methyltransferase-like 3 (METTL3) showed a positive correlation with proliferation, epithelial-mesenchymal transition (EMT), DNA repair, metastasis, and invasion in a database analysis. The expression of METTL3 gradually increased from human normal colon tissue, to adenoma, and carcinoma, and was positively correlated with E-cadherin and CD34 levels. Overexpression of METTL3 promoted the proliferation, migration, and invasion of CRC cells and induced vasculogenic mimicry (VM) formation. Clostridium butyricum could downregulate METTL3 expression in CRC cells and decrease the expression of vimentin and vascular endothelial growth factor receptor 2 to reduce EMT and VM formation. Clostridium butyricum alleviated the pro-oncogenic effect of METTL3 overexpressing plasmid in CRC cells. The anti-EMT effect on METTL3 reduction of C. butyricum could be blunted by knocking down G-protein coupled receptor 43. Moreover, C. butyricum prevented EMT and VM and inhibited tumor metastasis in nude mice. Accordingly, C. butyricum could inhibit EMT and VM formation of intestinal carcinogenesis through downregulating METTL3. These findings broaden our understanding of probiotics supplement in CRC prevention and treatment.
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Clostridium butyricum , Neoplasias Colorretais , Animais , Camundongos , Humanos , Transição Epitelial-Mesenquimal/genética , Fator A de Crescimento do Endotélio Vascular , Camundongos Nus , Butiratos , Carcinogênese/genética , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Movimento Celular , Metiltransferases/genéticaRESUMO
Carbon dots (C-Dots), with unique properties from tunable photoluminescence to biocompatibility, show wide applications in biotechnology, optoelectronic device and catalysis. Chiral C-Dots are expected to have strongly chirality-dependent biological and catalytic properties. For chiral C-Dots, a clear structure and quantitative structure-property relationship need to be clarified. Here, chiral C-Dots were fabricated by electrooxidation polymerization from serine enantiomers. The oxidized serine has a reversed chiral configuration to serine, which leads to the chiral C-Dots possessing inverse handedness compared with their raw materials. Electron circular dichroism spectrum, together with other diverse characterization techniques and theoretical calculations, confirmed that these chiral C-Dots (2-7 nm) have a well-defined primary structure of polycyclic dipeptide and possess a spatial structure with a c-axis of hexagonal symmetry and two cyclic dipeptides as the spatial structural unit. These chiral C-Dots also show enantioselective catalytic activity on DOPA enantiomers oxidation.
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Carbono , Serina , Carbono/química , Catálise , Dicroísmo Circular , EstereoisomerismoRESUMO
A high-fat diet (HFD) leads to long-term exposure to gut microbial metabolite secondary bile acids, such as deoxycholic acid (DCA), in the intestine, which is closely linked to colorectal cancer (CRC). Evidence reveals that vasculogenic mimicry (VM) is a critical event for the malignant transformation of cancer. Therefore, this study investigated the crucial roles of DCA in the regulation of VM and the progression of intestinal carcinogenesis. The effects of an HFD on VM formation and epithelial-mesenchymal transition (EMT) in human CRC tissues were investigated. The fecal DCA level was detected in HFD-treated Apcmin/+ mice. Then the effects of DCA on VM formation, EMT, and vascular endothelial growth factor receptor 2 (VEGFR2) signaling were evaluated in vitro and in vivo. Here we demonstrated that compared with a normal diet, an HFD exacerbated VM formation and EMT in CRC patients. An HFD could alter the composition of the gut microbiota and significantly increase the fecal DCA level in Apcmin/+ mice. More importantly, DCA promoted tumor cell proliferation, induced EMT, increased VM formation, and activated VEGFR2, which led to intestinal carcinogenesis. In addition, DCA enhanced the proliferation and migration of HCT-116 cells, and induced EMT process and vitro tube formation. Furthermore, the silence of VEGFR2 reduced DCA-induced EMT, VM formation, and migration. Collectively, our results indicated that microbial metabolite DCA promoted VM formation and EMT through VEGFR2 activation, which further exacerbated intestinal carcinogenesis.
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Carcinogênese/patologia , Ácido Desoxicólico/metabolismo , Mucosa Intestinal/patologia , Neovascularização Patológica/patologia , Adulto , Idoso , Animais , Apoptose , Ácidos e Sais Biliares/análise , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Dieta Hiperlipídica/efeitos adversos , Transição Epitelial-Mesenquimal , Fezes/química , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal , Células HCT116 , Humanos , Mucosa Intestinal/microbiologia , Masculino , Camundongos , Pessoa de Meia-Idade , Neovascularização Patológica/etiologia , Neovascularização Patológica/microbiologia , Transdução de Sinais , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
Limited research has been conducted on the heavy metal (loid) (HM) exchanges among seawater, sediments and cultured mussels in mariculture areas. To determine the impacts of mussel mariculture on the transfer and risks of HMs in coastal environments, samples of seawater, sediments and cultured mussels from a typical mariculture area in the South China Sea were analysed. The logarithmic partition coefficients of sediment/water indicated that HMs were preferentially retained by sediments. There were relatively low ecological risks in mussel raft mariculture areas. Principal component analysis and correlation analysis revealed the influences of terrestrial input and ocean circulation on the HMs in seawater, and the bioaccumulation factors reflected the possible accumulation of HMs in seawater by cultured mussels. Mussel farming was the indirect source of HMs in sediments, and the biochemical processes of cultured mussels promoted the transfer and accumulation of HMs into sediments. Health risk assessment revealed that children were more susceptible than adults, and Cd, As and Cr were among the threatening elements. Nonetheless, the health risks that were possibly caused by the daily consumption of farmed mussels were still within safe limits. Thus, the potential pollution remediation and biomonitoring functions of mussel aquaculture in coastal water environments will be further studied in the future.
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Bivalves , Metais Pesados , Poluentes Químicos da Água , Animais , Criança , China , Monitoramento Ambiental , Sedimentos Geológicos/análise , Humanos , Metais Pesados/análise , Metais Pesados/toxicidade , Medição de Risco , Água/análise , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidadeRESUMO
An outbreak of a macrozooplankton Creseis acicula occurred in the summer of 2020 nearby the Daya Bay Nuclear Power Plant located on the coast of the Daya Bay in the South China Sea. The outbreaks of C. acicula often threaten human health, the marine environment, and other human activities including the safe operation of coastal nuclear power plants. Seawater temperature has been suggested as an important factor influencing such outbreaks. However, the underlying mechanisms through which temperature influences C. acicula remains unknown. Here, we studied the effects of temperature on the ingestion and assimilation of algal food by feeding radiocarbon-labeled algae Chlorella sp. at simulated field temperatures (19-31 °C) to C. acicula collected during the outbreak in the Daya Bay. We also quantified the allocation of the food carbon to dissolved organic carbon (DOC), CO2, and fecal pellets. The results showed that the zooplankton during the same feeding time ingested doubled or tripled algal food at higher temperatures, and it produced and released significantly more DOC, CO2, and fecal pellets with more ingested food carbon. Meanwhile, the assimilation efficiency for the ingested food carbon slightly increased from 48% to 54% with rising temperature. As a result, higher assimilation rates indicating faster growth of C. acicula were observed at higher temperatures. In addition, the high activation energy of 0.908 eV indicated that the assimilation rate was very sensitive to temperature rising. Our results show that relatively rising temperature can enhance C. acicula's ingestion and assimilation rates for algal food, benefit its growth and metabolism, and contribute to its outbreak. This study provides a mechanistic interpretation for the relationship between rising temperature and the outbreaks of C. acicula and suggests that such outbreaks may occur more frequently and widely in the warming ocean.
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Chlorella , Gastrópodes , Animais , Baías , Carbono , Dióxido de Carbono , China , Surtos de Doenças , Humanos , Centrais Nucleares , Água do Mar , TemperaturaRESUMO
The master oscillator power amplifier structure has been widely employed to realize high-power and narrow-linewidth output in fiber lasers. However, the stimulated Raman scattering (SRS) effect would appear in high-power operation and even become an important limitation on further power scaling, especially when the seed lasers are based on a fiber Bragg grating (FBG) pair. In order to improve SRS suppressing ability, a composite cavity structure was demonstrated by employing an additional wide-bandwidth low-reflectivity FBG outside the conventional oscillator. After passing through a piece of 50 m SMF-28e fiber, thanks to the improved temporal stability of the composite oscillator, the proportion of Raman Stokes light dropped dramatically compared with the proportion in a conventional fiber oscillator. This composite cavity design could provide a simple and compact approach for SRS suppression in a high-power narrow-linewidth fiber laser system.
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PURPOSE: Microbial dysbiosis is considered as a hallmark of colorectal cancer (CRC). Trimethylamine-N-oxide (TMAO) as a gut microbiota-dependent metabolite has recently been implicated in CRC development. Nevertheless, evidence relating TMAO to intestinal carcinogenesis remains largely unexplored. Herein, we aimed to examine the crucial role of TMAO in CRC progression. METHODS: Apcmin/+ mice were treated with TMAO or sterile PBS for 14 weeks. Intestinal tissues were isolated to evaluate the effects of TMAO on the malignant transformation of intestinal adenoma. The gut microbiota of mouse feces was detected by 16S rRNA sequencing analysis. HCT-116 cells were used to provide further evidence of TMAO on the progression of CRC. RESULTS: TMAO administration increased tumor cell and stem cell proliferation, and decreased apoptosis, accompanied by DNA damage and gut barrier impairment. Gut microbiota analysis revealed that TMAO induced changes in the intestinal microbial community structure, manifested as reduced beneficial bacteria. Mechanistically, TMAO bound to farnesoid X receptor (FXR), thereby inhibiting the FXR-fibroblast growth factor 15 (FGF15) axis and activating the Wnt/ß-catenin signaling pathway, whereas the FXR agonist GW4064 could blunt TMAO-induced Wnt/ß-catenin pathway activation. CONCLUSION: The microbial metabolite TMAO can enhance intestinal carcinogenesis by inhibiting the FXR-FGF15 pathway.
Assuntos
Carcinogênese , Microbioma Gastrointestinal , Metilaminas , Receptores Citoplasmáticos e Nucleares , Transdução de Sinais , Via de Sinalização Wnt , Metilaminas/metabolismo , Metilaminas/farmacologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Humanos , Microbioma Gastrointestinal/efeitos dos fármacos , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Carcinogênese/patologia , Camundongos , Transdução de Sinais/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Células HCT116 , Proliferação de Células/efeitos dos fármacos , Neoplasias Intestinais/metabolismo , Neoplasias Intestinais/patologia , Neoplasias Intestinais/induzido quimicamente , Neoplasias Intestinais/microbiologia , Masculino , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais/microbiologia , Neoplasias Colorretais/induzido quimicamente , Apoptose/efeitos dos fármacos , Fatores de Crescimento de Fibroblastos/metabolismoRESUMO
This study aimed to predict the 5-year overall survival (OS) benefit of pola-R-CHP versus R-CHOP in the POLARIX trial based on the 2-year event-free survival (EFS) and progression-free survival (PFS) rates in diffuse large B-cell lymphoma (DLBCL). We identified randomized controlled trials (RCT) published before 31 May 2023. The correlation between the logarithmic (log) hazard ratio (HR) for EFS (HREFS) or PFS (HRPFS) and the HR for OS (HROS) was estimated at the trial-level. Correlation analysis was performed between 2-year PFS or EFS and 5-year OS rates at the treatment arm-level. Linear regression models were used to calculate the 5-year OS of pola-R-CHP and R-CHOP. In the included 20 RCTs, a linear correlation between HREFS (r = 0.765) or HRPFS (r = 0.534) and HROS was observed at the trial- level. Two-year EFS (r = 0.918) or 2-year PFS (r = 0.865) correlated linearly with 5-year OS. Linear regression analysis between 2-year EFS/PFS and 5-year OS gave estimated 5-year OS rates between pola-R-CHP and R-CHOP of 6.4% and 6.3%, respectively. Two-year EFS and PFS are feasible early endpoints in patients with DLBCL treated primarily with immunochemotherapy. The pola-R-CHP regimen is expected to improve 5-year OS.
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Protocolos de Quimioterapia Combinada Antineoplásica , Ciclofosfamida , Doxorrubicina , Linfoma Difuso de Grandes Células B , Prednisona , Intervalo Livre de Progressão , Ensaios Clínicos Controlados Aleatórios como Assunto , Rituximab , Vincristina , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Rituximab/uso terapêutico , Ciclofosfamida/uso terapêutico , Prednisona/uso terapêutico , Vincristina/uso terapêutico , Doxorrubicina/uso terapêutico , Feminino , Masculino , Pessoa de Meia-Idade , Citarabina/uso terapêutico , Anticorpos Monoclonais , ImunoconjugadosRESUMO
Contamination and risk assessments generally ignore the potential bias in results caused by the variation of background values at different spatial scales due to the spatial heterogeneity of sediments. This study aims to perform quantitative source-ecological risk assessment via establishing geochemical baselines values (GBVs) of heavy metal(loid)s (HMs) in Daya Bay, China. Cumulative frequency distribution (CFD) curves determined the GBVs of 12.44 (Cu), 30.88 (Pb), 69.89 (Zn), 0.06 (Cd), 47.85 (Cr), 6.80 (As), and 0.056 mg kg-1 (Hg), which were comparable to the background values of Guangdong Province surface soils, and implied a potential terrestrial origin of the coastal sediments. Principal component analysis (PCA) and positive matrix factorization (PMF) identified three sources (F1: natural processes; F2: anthropogenic impacts; F3: specific sources) with contributions of 51.7%, 29.2%, and 19.1%, respectively. The source-specific risk assessment revealed an ecological risk contribution potential of 73.8% for the mixed anthropogenic sources (F2 + F3) and only 26.2% for natural processes. Cd and Hg were the priority management of metallic elements, occupying 63.5% and 72.5% of the contribution weights of F2 and F3, respectively, which showed multi-level pollution potentials and ecological risk levels. The spatial distribution patterns demonstrated the hotspot features of HM pollution, and priority concerns should be given to the management of marine traffic and industrial point source pollution in Daya Bay. The results of the study provide a scientific approach and perspective for pollution treatment and risk management in the coastal environment.
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Mercúrio , Metais Pesados , Cádmio/análise , Monitoramento Ambiental , Metais Pesados/análise , Mercúrio/análise , Medição de Risco , China , Sedimentos GeológicosRESUMO
Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death worldwide. It involves the complex interactions between genetic factors, environmental exposure, and gut microbiota. Specific changes in the gut microbiome and metabolome have been described in CRC, supporting the critical role of gut microbiota dysbiosis and microbiota-related metabolites in the tumorigenesis process. Short-chain fatty acids (SCFAs), the principal metabolites generated from the gut microbial fermentation of insoluble dietary fiber, can directly activate G-protein-coupled receptors (GPCRs), inhibit histone deacetylases (HDACs), and serve as energy substrates to connect dietary patterns and gut microbiota, thereby improving the intestinal health. A significantly lower abundance of SCFAs and SCFA-producing bacteria has been demonstrated in CRC, and the supplementation of SCFA-producing probiotics can inhibit intestinal tumor development. SCFAs-guided modulation in both mouse and human CRC models augmented their responses to chemotherapy and immunotherapy. This review briefly summarizes the complex crosstalk between SCFAs and CRC, which might inspire new approaches for the diagnosis, treatment and prevention of CRC on the basis of gut microbiota-derived metabolites SCFAs.
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Neoplasias Colorretais/genética , Ácidos Graxos Voláteis/metabolismo , Microbioma Gastrointestinal/genética , Animais , Humanos , CamundongosRESUMO
The human body harbors a vast array of microbiota that modulates host pathophysiological processes and modifies the risk of diseases including cancer. With the advent of metagenomic sequencing studies, the intratumoural microbiota has been found as a component of the tumor microenvironment, imperceptibly affecting the tumor progression and response to current antitumor treatments. The underlying carcinogenic mechanisms of intratumoural microbiota, mainly including inducing DNA damages, activating oncogenic signaling pathways and suppressing the immune response, differ significantly in varied organs and are not fully understood. Some native or genetically engineered microbial species can specifically accumulate and replicate within tumors to initiate antitumor immunity, which will be conducive to pursue precise cancer therapies. In this review, we summarized the community characteristics and therapeutic potential of intratumoural microbiota across diverse tumor types. It may provide new insights for a better understanding of tumor biology and hint at the significance of manipulating intratumoural microbiota.
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Microbiota/imunologia , Neoplasias/imunologia , Microambiente Tumoral/imunologia , HumanosRESUMO
A novel polyhedral oligomeric siloxane (POSS)-based zwitterionic monolithic capillary column was prepared via one-pot polymerization in ionic liquid porogen, using N,N-dimethyl-N-methacryloxyethyl-N-(3-sulfopropyl)ammonium betaine (DMMSA) and methacrylic ethyl trimethylammonium chloride (META) as binary functional monomers, and methacryl substituted POSS as cross-linker. The pore structure, permeability and homogeneity were well tuned by optimizing the polymerization conditions. The resultant monolith was characterized by scanning electron microscopy, nitrogen adsorption/desorption isotherm and Fourier transform infrared spectroscopy. The incorporation of zwitterionic ligand (DMMSA), quaternary amine group (META) and rigid POSS skeleton endows the hybrid organic-silica monolith with high hydrophilicity, electrostatic interaction and good mechanical stability, as well as a tunable electroosmotic flow over wide pH range. A close investigation of capillary electrochromatographic separations of different types of polar compounds such as bases, nucleosides and benzoic acids on such stationary phase exhibited a retention independent column efficiency up to 118,000 plates/m (thiourea), as well as a mixed-mode hydrophilic interaction chromatography (HILIC) retention mechanism including weak electrostatic interaction, hydrophobic interaction and anion exchange.
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Eletrocromatografia Capilar , Líquidos Iônicos , Interações Hidrofóbicas e Hidrofílicas , Polimerização , SiloxanasRESUMO
As a class of the commonly used drugs in clinical practice, non-steroidal anti-inflammatory drugs (NSAIDs) can cause a series of adverse events including gastrointestinal injuries. Besides upper gastrointestinal injuries, NSAID enteropathy also attracts attention with the introduction of capsule endoscopy and double balloon enteroscopy. However, the pathogenesis of NSAID enteropathy remains to be entirely clarified. Growing evidence from basic and clinical studies presents that gut microbiota is a critical factor in NSAID enteropathy progress. We have reviewed the recent data about the interplay between gut microbiota dysbiosis and NSAID enteropathy. The chronic medication of NSAIDs could change the composition of the intestinal bacteria and aggravate bile acids cytotoxicity. Meanwhile, NSAIDs impair the intestinal barrier by inhibiting cyclooxygenase and destroying mitochondria. Subsequently, intestinal bacteria translocate into the mucosa, and then lipopolysaccharide released from gut microbiota combines to Toll-like receptor 4 and induce excessive production of nitric oxide and pro-inflammatory cytokines. Intestinal injuries present in the condition of intestinal inflammation and oxidative stress. In this paper, we also have reviewed the possible strategies of regulating gut microbiota for the management of NSAID enteropathy, including antibiotics, probiotics, prebiotics, mucosal protective agents, and fecal microbiota transplant, and we emphasized the adverse effects of proton pump inhibitors on NSAID enteropathy. Therefore, this review will provide new insights into a better understanding of gut microbiota in NSAID enteropathy.
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Microbioma Gastrointestinal , Enteropatias , Microbiota , Probióticos , Anti-Inflamatórios não Esteroides/efeitos adversos , Humanos , Enteropatias/induzido quimicamente , Mucosa IntestinalRESUMO
Obesity is a worldwide epidemic metabolic disease. Gut microbiota dysbiosis and bile acids (BAs) metabolism disorder are closely related to obesity. Farnesoid X-activated receptor (FXR), served as a link between gut microbiota and BAs, is involved in maintaining metabolic homeostasis and regulating glucose and lipid metabolism. We previously reported that diammonium glycyrrhizinate (DG) could alter gut microbiota and prevent non-alcoholic fatty liver disease. However, it remains ambiguous how DG affects the gut microbiota to regulate host metabolism. In this present study, 16S rRNA Illumina NovaSeq and metabolomic analysis revealed that DG treatment suppressed microbes associated with bile-salt hydrolase (BSH) activity, which, in turn, increased the levels of taurine-conjugated BAs accompanied by inhibition of ileal FXR-FGF15 signaling. As a result, several obesity-related metabolism were improved, like lower serum glucose and insulin levels, increased insulin sensitivity, few hepatic steatosis and resistance to weight gain. Additionally, decreased level of serum lipopolysaccharide was observed, which contributed to a strengthened intestinal barrier. The effect of DG on weight loss was slightly enhanced in the antibiotics-treated obese mice. Collectively, the efficacy of DG in the treatment of obesity might depend on gut microbiota-conjugated BAs-FXR axis. Hence, it will provide a potential novel approach for the treatment of obesity.
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Accumulating evidence from studies in humans and animal models has elucidated that gut microbiota, acting as a complex ecosystem, contributes critically to colorectal cancer (CRC). The potential mechanisms often reported emphasize the vital role of carcinogenic activities of specific pathogens, but in fact, a series of metabolites produced from exogenous dietary substrates or endogenous host compounds occupy a decisive position similarly. Detrimental gut microbiota-derived metabolites such as trimethylamine-N-oxide, secondary bile acids, hydrogen sulfide and N-nitroso compounds could reconstruct the ecological composition and metabolic activity of intestinal microorganisms and formulate a microenvironment that opens susceptibility to carcinogenic stimuli. They are implicated in the occurrence, progression and metastasis of CRC through different mechanisms, including inducing inflammation and DNA damage, activating tumorigenic signaling pathways and regulating tumor immunity. In this review, we mainly summarized the intimate relationship between detrimental gut microbiota-derived metabolites and CRC, and updated the current knowledge about detrimental metabolites in CRC pathogenesis. Then, multiple interventions targeting these metabolites for CRC management were critically reviewed, including diet modulation, probiotics/prebiotics, fecal microbiota transplantation, as well as more precise measures such as engineered bacteria, phage therapy and chemopreventive drugs. A better understanding of the interplay between detrimental microbial metabolites and CRC would hold great promise against CRC.
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Inflammaging refers to chronic, low-grade inflammation during aging, which contributes to the pathogenesis of age-related diseases. Studies have shown that probiotic intervention in the aging stage could delay aging-related disorders. However, whether the application of probiotics in early life could have antiaging effects on offspring was unknown. Here, we investigated the effects of Lactobacillus rhamnosus GG (LGG) colonization in early life on inflammaging of offspring. Pregnant mice with the same conception time were given LGG live bacteria (LC group) or LGG fixed bacteria (NC group) from the 18th day after pregnancy until natural birth. The progeny mice were treated with 107 cfu of live or fixed LGG for 0-5 days after birth, respectively. LGG colonization could be detected in the feces of 3-week offspring. The 16S rRNA sequencing analysis of 3-week-old offspring showed that colonization of LGG in early life could alter the composition and diversity of gut microbiota. Interestingly, the beneficial effects of LGG colonization in early life on the microbiota lasted to 8 months old. The abundance of longevity-related bacteria (Lactobacillus, Bifidobacterium, and Akkermansia muciniphila) increased significantly in the LGG colonization group. In addition, LGG colonization increased the abundance of short-chain fatty acid- (SCFA-) producing bacteria and the production of cecal SCFAs. LGG colonization in early life protected the intestinal barrier, enhanced antioxidant defense, attenuated epithelial cell DNA damage, and inhibited intestinal low-grade inflammation in 8-month-old progeny mice. Mechanically, LGG could upregulate Sirtuin1 (SIRT1)/Adenosine 5'-monophosphate-activated protein kinase (AMPK)/Peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) pathway and repress activation of nuclear factor-kappa B (NF-κB), while the protective effect of LGG was blunted after SIRT1 gene silencing. Together, LGG colonization in early life could ameliorate inflammaging of offspring, which would provide a new strategy for the prevention of age-related diseases.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/prevenção & controle , Lacticaseibacillus rhamnosus/fisiologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Probióticos/administração & dosagem , Sirtuína 1/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Animais , Animais Recém-Nascidos , Feminino , Microbioma Gastrointestinal , Inflamação/microbiologia , Inflamação/patologia , Intestinos/efeitos dos fármacos , Intestinos/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/genética , NF-kappa B/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Gravidez , Sirtuína 1/genéticaRESUMO
PURPOSE: This study assessed the correlation between Epstein-Barr virus (EBV) biomarkers and the eighth American Joint Committee on Cancer staging system and the prognostic values of IgG antibodies against replication and transcription activator (Rta-IgG), IgA antibodies against Epstein-Barr nuclear antigen 1, and BamH1 Z transactivator (Zta-IgA) in locoregionally advanced nasopharyngeal carcinoma (NPC) patients. MATERIALS AND METHODS: Serum EBV antibody levels were measured by enzyme-linked immunosorbent assay in 435 newly diagnosed stage III-IVA NPC patients administered intensity-modulated radiation therapy±chemotherapy. The primary endpoint was progression-free survival (PFS). RESULTS: Rta-IgG and Zta-IgA levels were positively correlated with the N category and clinical stage. Patients with high Rta-IgG levels (> 29.07 U/mL) showed a significantly inferior prognosis as indicated by PFS (77% vs. 89.8%, p=0.004), distant metastasis-free survival (DMFS) (88.3% vs. 95.8%, p=0.021), and local recurrence-free survival (LRFS) (91.2% vs. 98.3%, p=0.009). High Rta-IgG levels were also significantly associated with inferior PFS and LRFS in multivariable analyses. In the low-level EBV DNA group (≤ 1,500 copies/mL), patients with high Rta-IgG levels had significantly inferior PFS and DMFS (both p < 0.05). However, in the high-level EBV DNA group, Rta-IgG levels were not significantly associated with PFS, DMFS, and LRFS. In the advanced T category (T3-4) subgroup, high Rta-IgG levels were also significantly associated with inferior PFS, DMFS, and LRFS (both p < 0.05). CONCLUSION: Rta-IgG and Zta-IgA levels were strongly correlated with the TNM classification. Rta-IgG level was a negative prognostic factor in locoregionally advanced NPC patients, especially those with advanced T category or low EBV DNA level.
Assuntos
Anticorpos Antivirais/sangue , Biomarcadores Tumorais/sangue , Quimiorradioterapia/mortalidade , Infecções por Vírus Epstein-Barr/complicações , Carcinoma Nasofaríngeo/patologia , Recidiva Local de Neoplasia/patologia , Radioterapia de Intensidade Modulada/mortalidade , Infecções por Vírus Epstein-Barr/sangue , Infecções por Vírus Epstein-Barr/virologia , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Feminino , Seguimentos , Herpesvirus Humano 4/imunologia , Herpesvirus Humano 4/isolamento & purificação , Humanos , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/sangue , Carcinoma Nasofaríngeo/terapia , Carcinoma Nasofaríngeo/virologia , Neoplasias Nasofaríngeas/sangue , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/terapia , Neoplasias Nasofaríngeas/virologia , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/terapia , Recidiva Local de Neoplasia/virologia , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease throughout the world. The relationship between gut microbiota and NAFLD has been extensively investigated. The gut microbiota is involved in the regulation of NAFLD by participating in the fermentation of indigestible food, interacting with the intestinal mucosal immune system, and influencing the intestinal barrier function, leading to signaling alteration. Meanwhile, the microbial metabolites not only affect the signal transduction pathway in the gut but also reach the liver far away from gut. In this review, we focus on the effects of certain key microbial metabolites such as short-chain fatty acids, trimethylamine-N-oxide, bile acids, and endogenous ethanol and indole in NAFLD, and also summarize several potential therapies targeting the gut-liver axis and modulation of gut microbiota metabolites including antibiotics, prebiotics, probiotics, bile acid regulation, and fecal microbiota transplantation. Understanding the complex interactions between microbial metabolites and NAFLD may provide crucial insight into the pathogenesis and treatment of NAFLD.