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Roasted-rice leachate fermentation, a distinctive local tobacco fermentation method in Sichuan, imparts a mellow flavor and glossy texture to tobacco leaves, along with a roasted rice aroma. In order to find out the impact of roasted-rice leachate on cigar tobacco leaves, the physicochemical properties, volatile flavor profile, and microbial community were investigated. The content of protein significantly decreased after fermentation. The volatile flavor compounds increased following roasted-rice leachate fermentation, including aldehydes, alcohols, acids, and esters. High-throughput sequencing identified Staphylococcus, Pseudomonas, Pantoea, Oceanobacillus, Delftia, Corynebacterium, Sphingomonas, Aspergillus, Weissella, and Debaryomyces as the primary genera. Network and correlation analysis showed Debaryomyces played a crucial role in roasted-rice leachate fermentation, due to its numerous connections with other microbes and positive relationships with linoelaidic acid, aromandendrene, and benzaldehyde. This study is useful for gaining insight into the relationship between flavor compounds and microorganisms and provides references regarding the effect of extra nutrients on traditional fermentation products. KEY POINTS: ⢠Volatile flavor compounds increased following roasted-rice leachate fermentation ⢠Staphylococcus was the primary genera in fermented cigar ⢠Debaryomyces may improve the quality of tobacco leaves.
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Bactérias , Fermentação , Aromatizantes , Oryza , Compostos Orgânicos Voláteis , Compostos Orgânicos Voláteis/metabolismo , Compostos Orgânicos Voláteis/análise , Aromatizantes/metabolismo , Oryza/microbiologia , Bactérias/metabolismo , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Folhas de Planta/microbiologia , Produtos do Tabaco , Paladar , Nicotiana/microbiologia , Microbiota , Odorantes/análiseRESUMO
So far, few literature studies have been reported on niobium-lead binary intermetallic compounds, which are expected to have very different properties compared to existing niobium-carbon binary compounds, due to the distinct electronic properties of lead when compared to other carbon-group elements. Herein, we carry out a global structure search for the Nb-Pb system based on the evolutionary algorithm and density functional theory. Based on the dynamical and mechanical stability analyses, we unveiled five new phases, P4/m-Nb9Pb, Cmcm-Nb3Pb, I4/mmm-Nb2Pb, Pmm2-Nb5Pb3, and I4/mmm-NbPb2, that are promising candidates for experimental synthesis. Moreover, the superconducting transitions of all Nb-Pb binary intermetallic compounds are performed with electron-phonon calculations. As Nb9Pb exhibited the maximum Tc in the Nb-Pb intermetallics, greater than 3.0 K at 20 GPa, the phonon band structures, partial phonon density of states (PHDOS), the corresponding Eliashberg spectral functions α2F(ω), and integral electron-phonon coupling (EPC) parameters λ as a function of frequency of Nb9Pb were also studied. This work filled the gap in the pressure-tuned Nb-Pb phase transitions from a systematic first principles study for the first time.
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The natural fermentation of cigar tobacco leaves usually utilizes natural temperature and humidity for fermentation. Cigars produced in China are often fermented in winter, and the low environmental temperatures can lead to slow heating of the tobacco stack, affecting the cigar tobacco leaves quality. This study aimed to determine the minimum chamber temperature required to initiate the process of fermentation for cigar tobacco leaves and to explore the impact of temperature on the microbial community of tobacco leaves. Here, the cigar variety "Dexue 1" were subjected to stacking fermentation under three temperature parameters (20 â, 27 â, 34 â). With an increase in environmental temperature, the temperature inside the stack of cigar leaves increased significantly, the protein, total sugar, starch, and total alkaloid content in fermented tobacco leaves decreased, and the aroma components and amino acid content increased. Microbial richness and community diversity associated with fermented tobacco were highest at chamber temperatures of above 27 â. The relative abundance of Chryseobacterium and Rhodococcus was significantly negatively correlated with protein, alkaloids, total sugar, and starch, and positively correlated with amino acids and aroma components. Chryseobacterium and Rhodococcus may be responsible for the degradation of macromolecular substances and the conversion of favorable aromatic substances, thus improving the tobacco leaves quality. This study demonstrated that increasing the fermentation chamber temperature above 27 â was conductive to raising the inner-stack temperature, increased microbial diversity and aromatic quality, reduced the strength and irritation, and extremely enhanced the overall quality of fermented cigar tobacco leaves. KEY POINTS: ⢠The environmental temperature of the fermentation chamber has a significant impact on the quality of tobacco ⢠Temperature > 27 â can initiate the process of cigar tobacco leaves fermentation and increase inner-stack temperature and microbial diversity and abundance ⢠Chryseobacterium and Rhodococcus may be related to the degradation of macromolecular substances and the transformation of aromatic substances, thereby improving the quality of tobacco leaves.
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Nicotiana , Produtos do Tabaco , Nicotiana/microbiologia , Temperatura , Fermentação , Substâncias Macromoleculares , Amido , AçúcaresRESUMO
Noncentrosymmetric superconductors are strong candidates for exploring intrinsic topological superconductivity. Here, we predict two new noncentrosymmetric superconductors SnVSe2 and PbVSe2 by a systematic first-principles study. These two compounds show good thermal and dynamic stabilities. Moreover, the band topology of both compounds is predicted to be nontrivial via Z2 calculation and slab models. We also investigate the electron-phonon interactions in SnVSe2 and PbVSe2, indicating the Tc of SnVSe2 and PbVSe2 without external pressure are predicted to be â¼1.18 K and â¼0.22 K, respectively. Furthermore, the results on pressure engineering in PbVSe2 imply that the Tc of PbVSe2 can be tuned to 2.39 K for enhanced contributions from Pb layers under pressure up to 6.4 GPa. This work may provide new platforms for probing spin-triplet paring and may help with designing and developing new metal-intercalated transition metal dichalcogenides.
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Prolyl hydroxylase 3 (PHD3) has initially been reported to hydroxylase hypoxia-inducible factor α (HIFα) and mediate HIFα degradation. More recent studies have shown that, in addition to HIFα, PHD3 has also other substrates. Moreover, pHD3 is believed to act as a tumor suppressor, but the underlying mechanism remains to be elucidated. Here, we demonstrate that PHD3 stabilizes p53 in a hydroxylase-independent manner. We found that PHD3 overexpression increases and PHD3 knockdown decreases p53 levels. Mechanistically, PHD3 bound MDM2 proto-oncogene (MDM2) and prevented MDM2 from interacting with p53, thereby inhibiting MDM2-mediated p53 degradation. Interestingly, we found that PHD3 overexpression could enhance p53 in the presence of the prolyl hydroxylase inhibitor dimethyloxalylglycine, and the prolyl hydroxylase activity-deficient variant PHD3-H196A also inhibited the p53-MDM2 interaction and stabilized p53. Genetic ablation of PHD3 decreased p53 protein levels in mice intestinal epithelial cells, but a genetic knockin of PHD3-H196A did not affect p53 protein levels in vivo These results suggest that the prolyl hydroxylase activity of PHD3 is dispensable for its ability to stabilize p53. We found that both PHD3 and PHD3-H196A suppress the expression of the stem cell-associated gene NANOG and inhibited the properties of colon cancer stem cells through p53. Our results reveal an additional critical mechanism underlying the regulation of p53 expression and highlight that PHD3 plays a role in the suppression of colon cancer cell stemness in a hydroxylase-independent manner.
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Neoplasias do Colo/patologia , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Células-Tronco Neoplásicas/patologia , Pró-Colágeno-Prolina Dioxigenase/fisiologia , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/química , Animais , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Humanos , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células-Tronco Neoplásicas/metabolismo , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-mdm2/genética , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , UbiquitinaçãoRESUMO
BACKGROUND: To explore the optimum fermentation conditions for tobacco leaves and also screen the microbiota and metabolites that are beneficial for fermentation. METHODS: Tobacco leaves were fermented at 25 °C, 35 °C, and 45 °C for 2, 4, and 6 weeks, respectively. For identification of the best fermentation temperature, physicochemical properties and sensory quality of fermented tobacco were investigated. Subsequently, based on the appropriate temperature, 16 s rRNA sequencing and metabolomics analysis of tobacco were performed to monitor the change of microbes and metabolites during fermentation process (from 2 to 6 weeks). RESULTS: Sensory quality analysis indicated that fermentation at 45 °C for 6 weeks represented the optimum condition. Metabolomics analysis showed that a total of 415 metabolites were annotated. The increase of fermentation period led to significant changes of metabolites. Results revealed an increase in concentration of L-phenylalanine and sphingosine as well as decreased concentration of betaine and phytosphingosine with the prolongation of fermentation period (2 to 6 weeks). Distinct changes in the microbiota were also observed with prolongation of the fermentation time. Results revealed that Pseudomonas, Pantoea, and Burkholderia were dominant bacteria in fermentation at 45 °C for 6 weeks. With the extension of the fermentation time, the abundance of Pseudomonas increased, while that of Sphingomonas and Methylobacterium decreased. Furthermore, microbiota profiles were tightly relevant to the altered metabolites, especially compounds involved in the sphingolipid metabolism. CONCLUSION: Suitable fermentation conditions were 45 °C for 6 weeks; phytosphingosine and sphingosine might affect tobacco fermentation via the sphingolipid metabolism pathway. This study provides a theoretical basis for guiding tobacco fermentation and gives insights into reducing harmful substances during tobacco fermentation.
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Microbiota , Nicotiana/microbiologia , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Bactérias/metabolismo , Fermentação , Folhas de Planta/microbiologia , RNA Ribossômico 16S/genética , Sensação , Esfingolipídeos/metabolismo , Temperatura , Fatores de TempoRESUMO
Previous work has confirmed that the chronic hypoxia-hypercapnia (CHH) associated with chronic obstructive pulmonary disease contributes to the development of skeletal muscle atrophy. Neuromuscular Electrical Stimulation (NMES) has shown some efficacy when used as a treatment to reduce skeletal muscle atrophy. The present study focuses on the MicroRNA-486/PTEN/FoxO1 pathway with the goal of identifying its physiological role in skeletal muscle atrophy induced by CHH as well as its role during NMES treatment. To test this, 32 male Sprague Dawley rats were randomly divided into four groups. After completion of the disease modeling, gastrocnemius muscles were collected from all animals and cross-sectional areas of muscular fiber were observed and analyzed via H&E staining. MiR-486 expression was further assessed by qRT-PCR, and protein levels of TNF-α, PTEN, p-Akt, Akt, FoxO1, atrogin-1 and MuRF1 were measured by immunohistochemistry and western blotting. CSA, miR-486, and the ratio p-Akt/Akt were significantly reduced in the CHH group, while the levels of TNF-α, PTEN, FoxO1, atrogin-1, and MuRF1 were markedly increased. Importantly, these findings were reversed as a result of NMES. Thus, the MicroRNA-486/PTEN/FoxO1 pathway functions in muscle protein synthesis and degradation. NEW & NOTEWORTHY: Our research provides a theoretical basis for the application of NMES as a means of improving muscle atrophy. Moreover, these therapeutic targets provide possible clues relevant to the treatment of amyotrophic diseases.
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Estimulação Elétrica , Hipercapnia/complicações , Hipóxia/complicações , MicroRNAs/metabolismo , Atrofia Muscular/terapia , Proteínas do Tecido Nervoso/metabolismo , Animais , Hipercapnia/fisiopatologia , Hipóxia/fisiopatologia , Proteínas Musculares/biossíntese , Proteínas Musculares/metabolismo , Atrofia Muscular/etiologia , PTEN Fosfo-Hidrolase/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Prolyl hydroxylases (PHD1-3) hydroxylate hypoxia inducible factor α (HIFα), leading to HIFα ubiquitination and degradation. Recent studies indicated that administration of generic inhibitors of PHDs improved mice colitis, suggesting that suppression of PHD activity by these inhibitors may be a potential strategy for the treatment of inflammatory bowel diseases. However, the exact role of each member of PHD family in homeostasis of intestinal epithelium remains elusive. The aim of this work is to study the possible role of PHD2 by using mice with genetic ablation of Phd2 in intestinal epithelial cells (IECs). We found that deletion of PHD2 in IECs did not lead to spontaneous enteritis or colitis in mice. Deletion of PHD2 in IECs did not confer upon mice higher susceptibility to dextran sodium sulfate-induced colitis. Furthermore, in a colitis-associated colon cancer model, the PHD2-conditional knockout mice had similar susceptibility to azoxymethane (AOM)-induced colonic tumorigenesis as control mice did. Our results suggest that PHD2 is dispensable for maintenance of intestinal epithelium homeostasis in mice.
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Células Epiteliais/metabolismo , Homeostase/genética , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , Mucosa Intestinal/metabolismo , Animais , Azoximetano , Linhagem Celular , Linhagem Celular Tumoral , Colite/induzido quimicamente , Colite/genética , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/genética , Sulfato de Dextrana , Humanos , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Camundongos Knockout , Camundongos TransgênicosRESUMO
Prolyl hydroxylase domain proteins (PHDs) control cellular adaptation to hypoxia. PHDs are found involved in inflammatory bowel disease (IBD); however, the exact role of PHD3, a member of the PHD family, in IBD remains unknown. We show here that PHD3 plays a critical role in maintaining intestinal epithelial barrier function. We found that genetic ablation of Phd3 in intestinal epithelial cells led to spontaneous colitis in mice. Deletion of PHD3 decreases the level of tight junction protein occludin, leading to a failure of intestinal epithelial barrier function. Further studies indicate that PHD3 stabilizes occludin by preventing the interaction between the E3 ligase Itch and occludin, in a hydroxylase-independent manner. Examination of biopsy of human ulcerative colitis patients indicates that PHD3 is decreased with disease severity, indicating that PHD3 down-regulation is associated with progression of this disease. We show that PHD3 protects intestinal epithelial barrier function and reveal a hydroxylase-independent function of PHD3 in stabilizing occludin. These findings may help open avenues for developing a therapeutic strategy for IBD.
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Mucosa Intestinal/fisiologia , Ocludina/fisiologia , Pró-Colágeno-Prolina Dioxigenase/fisiologia , Animais , Colite/genética , Colite/prevenção & controle , Deleção de Genes , Células HEK293 , Humanos , Camundongos , Camundongos TransgênicosRESUMO
Here we evaluate the immunomodulatory function of two potential probiotic strains, Lactobacillus salivarius CICC 23174 and Lactobacillus plantarum CGMCC 1.557. Mice were fed with each Lactobacillus strain at different doses for several consecutive days. The effects of the two probiotic strains on immune organs, immune cells and immune molecules were investigated on days 10 and 20. Both Lactobacillus strains increased the spleen index, improved the spleen lymphocyte transformation rate, enhanced sIgA production and improved the number of CD11c(+) CD80(+) double-positive cells. L. plantarum CGMCC 1.557 was the more active strain in enhancing the phagocytic activity of macrophages, while, L. salivarius CICC 23174 was the more effective strain at maintaining the Th1/Th2 balance. This study suggests that these two Lactobacillus strains have beneficial effects on regulation of immune responses, which has promising implications for the development of ecological agents and functional foods.
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Fatores Imunológicos/administração & dosagem , Lactobacillus/crescimento & desenvolvimento , Lactobacillus/imunologia , Probióticos/administração & dosagem , Imunidade Adaptativa , Animais , Feminino , Imunoglobulina A Secretora/sangue , Linfócitos/imunologia , Macrófagos/imunologia , Camundongos Endogâmicos BALB C , FagocitoseRESUMO
This study aims to evaluate the functional and probiotic characteristics of eight indigenous Lactobacillus strains in vitro. The selected lactobacilli include strains of Lactobacillus casei subsp. casei, Lactobacillus salivarius subsp. salicinius, Lactobacillus fermentum, Lactobacillus plantarum, Lactobacillus delbrueckii subsp. lactis, Lactobacillus delbrueckii subsp. bulgaricus, and Lactobacillus rhamnosus. All strains tolerated both pH 2 for 3 h and 1% bile salt for 24 h. The strains CICC 23174 and CGMCC 1.557 were the most adhesive strains producing the highest quantity of EPS. Although a wide variation in the ability of the eight strains to deplete cholesterol and nitrite, antagonize pathogens, scavenge free radical, and stimulate innate immune response were observed, the strains CICC 23174 and CGMCC 1.557 showed the widest range of these useful traits. Taken together, the strains CICC 23174 and CGMCC 1.557 exhibited the best probiotic properties with the potential for use in the production of probiotic fermented foods.
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Microbiologia de Alimentos , Intestinos/microbiologia , Lactobacillus/isolamento & purificação , Lactobacillus/fisiologia , Probióticos/isolamento & purificação , Ácidos/metabolismo , Antibiose , Aderência Bacteriana , Ácidos e Sais Biliares/metabolismo , Colesterol/metabolismo , Detergentes/toxicidade , Radicais Livres/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Imunidade Inata , Lactobacillus/classificação , Lactobacillus/imunologia , Viabilidade Microbiana , Nitritos/metabolismo , Polissacarídeos Bacterianos/metabolismo , Fatores de TempoRESUMO
Manipulating the structural and kinetic dissociation processes of water at the catalyst-electrolyte interface is vital for alkaline hydrogen evolution reactions (HER) at industrial current density. This is seldom actualized due to the intricacies of the electrochemical reaction interface. Herein, this work introduces a rapid, nonequilibrium cooling technique for synthesizing ternary Turing catalysts with short-range ordered structures (denoted as FeNiRu/C). These advanced structures empower the FeNiRu/C to exhibit excellent HER performance in 1 m KOH with an ultralow overpotential of 6.5 and 166.2 mV at 10 and 1000 mA cm-2, respectively, and a specific activity 7.3 times higher than that of Pt/C. Comprehensive mechanistic analyses reveal that abundant atomic species form asymmetric atomic electric fields on the catalyst surface inducing a directed evolution and the dissociation process of interfacial H2O molecules. In addition, the locally topologized structure effectively mitigates the high hydrogen coverage of the active site induced by the high current density. The establishment of the relationship between free water population and HER activity provides a new paradigm for the design of industrially relevant high performance alkaline HER catalysts.
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Ensuring the consumption rate of noble metals while guaranteeing satisfactory hydrogen evolution reaction (HER) performance at different pH values is imperative to the development of Ru-based catalysts. Herein, we design a Mott-Schottky electrocatalyst (Ru/CeO2) with a built-in electric field (BEF) based on density functional theory (DFT). The Ru/CeO2 achieves the criterion current density of 10 mA cm-2 at overpotentials of 55 mV, 80 mV, and 120 mV in alkaline, acidic and neutral media, respectively. Both theoretical calculations and experimental analysis confirm that the improved HER activity in the Ru/CeO2 catalyst could be due to the successful construction of BEF at the interface between the prepared Ru clusters and CeO2. Under the action of BEF, the electron-deficient Ru atoms can optimize the adsorption energy of H* and H2O and thus promote HER kinetics. Furthermore, the Ru/CeO2 catalyst delivers a power density of approximately 94.5 mW cm-2 in alkaline-acidic Zn-H2O cell applications while maintaining good H2 production stability. In this work, we optimize the electrocatalytic performance of the Ru/CeO2 catalyst through examination of the interfacial BEF electrical charge, which combines hydrogen production with power generation and provides a promising method for sustainable energy conversion.
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Designing transition metal-oxide-based bifunctional electrocatalysts with excellent activity and stability for OER/HER to achieve efficient water splitting is of great importance for renewable energy technologies. Herein, a highly efficient bifunctional catalysts with oxygen-rich vacancies of nickel-decorated RuO2 (NiRuO2-x) prepared by a unique one-pot glucose-blowing approach were investigated. Remarkably, the NiRuO2-x catalysts exhibited excellent HER and OER activity at 10 mA cm-2 in alkaline solution with only a minimum overpotential of 51 mV and 245 mV, respectively. Furthermore, the NiRuO2-x overall water splitting exhibited an ultra-low voltage of 1.6 V to obtain 10 mA cm-2 and stability for more than 10 h. XPS measurement and theoretical calculations demonstrated that the introduction of Ni-dopant and oxygen vacancies make the d-band center to lie close to the Fermi energy level, the chemical bonds between the active site and the adsorbed oxygen intermediate state are enhanced, thereby lowering the reaction activation barriers of HER and OER. The assembly of solar-driven alkaline electrolyzers facilitate the application of the NiRuO2-x bifunctional catalysts.
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Staphylococcus aureus is an opportunistic pathogen that can colonize human and animal intestinal tracts, causing certain gastrointestinal diseases. The adherence of enteric pathogens to host intestinal epithelial cells is important for their pathogenesis. In the present study, Lactobacillus salivarius and Lactobacillus plantarum were investigated in vitro to examine their ability to competitively exclude S. aureus. Various factors involved in attachment, including bacterial status and cell concentration, growth phase, competition patterns, and surface-layer protein extracts, were also investigated. Live lactobacilli in the mid-log growth phase exhibited maximum inhibitory activity when lactobacilli were pre- or co-incubated with S. aureus. However, the inhibitory activity was significantly reduced when the lactobacilli were inactivated by heating or treated with LiCl. Furthermore, both lactobacilli possessed certain cell surface properties, such as hydrophobicity, autoaggregation, and coaggregation ability. L. salivarius and L. plantarum strongly inhibited S. aureus adherence to Caco-2 cells and their inhibition activity was significantly influenced by several factors that affect adhesion inhibition.
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Antibiose , Aderência Bacteriana , Lactobacillus/fisiologia , Staphylococcus aureus/patogenicidade , Células CACO-2 , Parede Celular/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Propriedades de SuperfícieRESUMO
Cigar is made of a typical fermented tobacco where the microbiota inhabits within an alkaline environment. Our current understanding on cigar fermentation is far from thorough. This work employed both high-throughput sequencing and chromatography-mass spectrometric technologies to provide new scientific reference for this specific fermented system. Typical cigar samples from different regions (the Caribbeans, South America, East Asia, and Southeast Asia) were investigated. The results show that Firmicutes, Actinobacteria, Proteobacteria, Ascomycota, and Basidiomycota were the predominant phyla in the cigar samples. Rather than the fungal community, it was the bacterial community structures that played vital roles to differentiate the cigar from different regions: Staphylococcus was the dominant genus in the Americas; Bacillus was the dominant genus in Southeast Asia; while in East Asia, there was no dominant genus. Such differences in community structure then affected the microflora metabolism. The correlation between microbiota and metabolites revealed that Aspergillaceae, Cercospora, and Staphylococcus were significantly correlated with sclareolide; Bacillus were positively associated with isophorone. Alcaligenaceae was significantly and positively correlated with L-nicotine and hexadecanoic acid, methyl ester. GRAPHICAL ABSTRACT.
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During injury, monocytes are recruited from the circulation to inflamed tissues and differentiate locally into mature macrophages, with prior reports showing that cavity macrophages of the peritoneum and pericardium invade deeply into the respective organs to promote repair. Here we report a dual recombinase-mediated genetic system designed to trace cavity macrophages in vivo by intersectional detection of two characteristic markers. Lineage tracing with this method shows accumulation of cavity macrophages during lung and liver injury on the surface of visceral organs without penetration into the parenchyma. Additional data suggest that these peritoneal or pleural cavity macrophages do not contribute to tissue repair and regeneration. Our in vivo genetic targeting approach thus provides a reliable method to identify and characterize cavity macrophages during their development and in tissue repair and regeneration, and distinguishes these cells from other lineages.
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Fígado/fisiopatologia , Lesão Pulmonar/fisiopatologia , Macrófagos/fisiologia , Monócitos/fisiologia , Cavidade Peritoneal/fisiologia , Cavidade Pleural/fisiologia , Animais , Linhagem da Célula/genética , Células Cultivadas , Fígado/lesões , Ativação de Macrófagos/fisiologia , Macrófagos/citologia , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Microscopia de Fluorescência/métodos , Monócitos/citologia , Monócitos/metabolismo , Cavidade Peritoneal/citologia , Fagocitose/fisiologia , Cavidade Pleural/citologiaRESUMO
Two-dimensional transition metal carbides and nitrides (MXenes) have attracted intensive attention since 2011, and surface groups have been determined to show a key role in MXene properties. Recently, an emerging functional group of chlorine was realized in MXenes, such as in Ti3C2Cl2 and Ti2CCl2. In order to understand and apply MXenes terminated by this type functional group, the structural, mechanical and electronic properties of M2X2Cl2 and M3X2Cl2 (M = Sc, Ti, V, Cr, Zr, Nb, Mo, Hf, Ta, W; X = C, N) are investigated in this work from first-principles theory. For M2X2Cl2, the chlorine groups are all stabilized on the top-sites of the bottom M atoms on both sides. In M3X2Cl2, the surface groups of most configurations are functionalized on the top-sites of the middle M atoms. Regarding to the mechanical properties, the elastic constants vary significantly with the types of M and X elements. The highest Young modulus of 208.3 GPa is determined in Ta3C2Cl2. The mechanical, dynamical and thermodynamic stabilities are further tested. Thirteen members.ie. M2CCl2 (M = Sc, Ti, Zr, Nb, Hf), M2NCl2 (M = Sc, Zr), M3C2Cl2 (M = Ti, Zr, Hf) and M3N2Cl2 (M = Sc, Ti, Zr) are determined to be stable. In addition, Ta2CCl2, Hf2NCl2, M3C2Cl2 (M = Sc, Nb, Ta) and Hf3N2Cl2 could be metestable. For these stable and metastable configurations, the electronic structures and work functions are studied. Most configurations are metallic, except for Sc2CCl2, Zr3N2Cl2 and Hf3N2Cl2. These three members are indirect band gap semiconductors, with their band gap values of 1.65, 0.135 and 0.246 eV, respectively. All the structures show high work functions, and the smallest value is approximate to 3.97 eV determined in Ti2CCl2. Our work implies that the chlorine-functionalized MXenes could be utilized in semiconductors and metallic films.
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Drug resistance is a big problem in cancer treatment and one of the most prominent mechanisms underlain is overexpression of ATP-binding cassette (ABC) transporters, particularly ABCB1, ABCC1 and ABCG2. Inhibition of ABC transporters is an important approach to overcome drug resistance. The inositol-requiring enzyme 1α (IRE1α), an arm of unfolded protein response (UPR), splices XBP1 mRNA to generate an active transcription factor XBP1s. UPR is implicated in drug resistance. However, the underlying mechanism is unclear. We found that the anticancer drugs such as 5-fluorouracil (5-FU) activated the IRE1α-XBP1 pathway to induce the expression of ABCB1, ABCC1 and ABCG2 in colon cancer cells. Inhibition of IRE1α RNase activity with small molecule 4µ8c suppressed the drug-induced expression of these ABC transporters and sensitized 5-FU-resistant colon cancer cells to drug treatment. In vivo xenograft assay indicates that administration of 4µ8C substantially enhanced the efficacy of 5-FU chemotherapy on 5-FU-resistant colon cancer cells. These results suggest that IRE1α-targeting might be a strategy to cope with drug resistance of colon cancer.
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Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Neoplasias do Colo/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Endorribonucleases/antagonistas & inibidores , Fluoruracila/farmacologia , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Antimetabólitos Antineoplásicos/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Resistência a Múltiplos Medicamentos , Endorribonucleases/genética , Endorribonucleases/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Intestinal epithelia self-renew constantly and generate differentiated cells such as secretary goblet cells. The intestine goblet cells secrete gel-forming mucins that form mucus to create a barrier of defense. We reported previously that loss of prolyl hydroxylase (PHD) 3 led to disruption of the intestinal epithelial barrier function. However, the underlying mechanism remains elusive. Here, we demonstrate that PHD3 controls the generation of intestine goblet cell. We found that genetic ablation of Phd3 in mice intestine epithelial cells reduced the amount of goblet cells. Mechanistically, PHD3 bounds the E3 ubiquitin ligase HUWE1 and prevented HUWE1 from mediating ubiquitination and degradation of ATOH1, an essential driver for goblet cell differentiation. The prolyl hydroxylase activity-deficient variant PHD3(H196A) also prevented ATOH1 destruction. A genetic intestine epithelial PHD3(H196A)-knockin had no effect on ATOH1 expression or goblet cell amount in mice, suggesting that the PHD3 prolyl hydroxylase activity is dispensable for its ability to control ATOH1 expression and goblet cell generation. In dextran sulfate sodium (DSS)-induced experimental colitis, PHD3-knockout rather than PHD3(H196A)-knockin sensitized the mice to DSS treatment. Our results reveal an additional critical mechanism underlying the regulation of ATOH1 expression and goblet cell generation and highlight that PHD3 plays a role in controlling intestine goblet cell generation in a hydroxylase-independent manner.