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Anaerobic microbiologically influenced corrosion (MIC) of Fe (0) metals causes great harm to the environment and economy, which depends on the key electron transfer process between anaerobic microorganisms and Fe (0) metals. However, the key electron transfer process in microbiota dominating MIC remains unclear, especially for methanogenic microbiota wildly distributed in the environment. Herein, three different methanogenic microbiota (Methanothrix, Methanospirillum, and Methanobacterium) were acclimated to systematically investigate electron transfer pathways on corroding Q235A steel coupons. Results indicated that microbiota dominated by Methanothrix, Methanospirillum, or Methanobacterium accelerated the steel corrosion mainly through direct electron transfer (DET) pathway, H2 mediated electron transfer (HMET) pathway, and combined DET and HMET pathways, respectively. Compared with Methanospirillum dominant microbiota, Methanothrix or Methanobacterium dominant microbiota caused more methane production, higher weight loss, corrosion pits with larger areas, higher corrosion depth, and smaller corrosion pits density. Such results reflected that the DET process between microbiota and Fe (0) metals decided the biocorrosion degree and behavior of Fe (0) metals. This study insightfully elucidates the mechanisms of methanogenic microbiota on corroding steels, in turn providing new insights for anti-corrosion motives.
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BACKGROUND/AIMS: Anti-programmed cell death protein 1 (PD-1) treatment has exhibited clinical benefits in colorectal cancer (CRC). However, the low response rate of CRC to immunotherapy is an urgent problem that needs to be solved. MATERIALS AND METHODS: MC-38 tumor cells was challenged subcutaneously in the flank of 7-week-old male C57BL/6 mice. The mice were randomly divided into 3 groups, and 200µg/mouse anti-PD-1 antibody and 100 mg/kg RAS-Seletive Lethal 3 (RSL) or phosphate buffer saline (PBS) were intraperitoneally injected every 2 days. The expression of oxidative stress and ferroptosis-related genes was measured by Western blotting, real-time reverse transcription-polymerase chain reaction, Prussian blue staining, and enzyme-linked immunosorbent assay. RESULTS: Anti-PD-1 treatment-unresponsive tumors showed stronger immunosuppression than responsive tumors. Notably, the responsive tumors showed higher levels of H2O2 and reactive oxygen species, both of which could impair the antitumor effect of cytotoxic CD8+ T cells. The anti-PD-1 treatment-responsive tumors showed a higher expression of pro-ferroptosis genes and Fe2+ accumulation than those of anti-PD-1 nonresponsive tumors, indicating the potential role of ferroptosis in the efficacy of anti-PD-1 treatment. In MC-38 syngeneic tumor model, (1S, 3R)-RSL3 (RSL), a glutathione peroxidase 4 inhibitor, effectively promoted the antitumor effect of anti-PD-1 treatment in vivo. However, anti-PD-1 treatment did not affect the levels of ferroptosis-related genes in tumor model. Mechanistically, RSL treatment significantly upregulated the frequency of proliferating (ki67+) and cytotoxic (GZMB+) CD8+ T cells. Furthermore, the frequency of tumor neoantigen-specific interferon (IFN)-γ CD8+ T cells showed a significant increase after RSL plus anti-PD-1 treatment. CONCLUSION: RSL may be a promising drug for potentiating the antitumor efficiency of anti-PD-1 treatment in CRC.
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Neoplasias Colorretais , Ferroptose , Camundongos Endogâmicos C57BL , Receptor de Morte Celular Programada 1 , Animais , Ferroptose/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Masculino , Camundongos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linhagem Celular Tumoral , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Espécies Reativas de Oxigênio/metabolismo , Modelos Animais de Doenças , Imunoterapia/métodos , CarbolinasRESUMO
Bioactive peptides (BPs) are protein fragments with beneficial effects on metabolism, physiology, and diseases. This review focuses on proteolytic BPs, which are produced by the action of gut microbiota on proteins in food and have demonstrated to influence the composition of gut microbes. And gut microbiota are candidate targets of BPs to alleviate oxidative stress, enhance immunity, and control diseases, including diabetes, hypertension, obesity, cancer, and immune and neurodegenerative diseases. Despite promising results, further research is needed to understand the mechanisms underlying the interactions between BPs and gut microbes, and to identify and screen more BPs for industrial applications. Overall, BPs offer potential as therapeutic agents for various diseases through their interactions with gut microbes, highlighting the importance of continued research in this area.
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PURPOSE: To develop a combined radiomics and deep learning (DL) model in predicting radiation esophagitis (RE) of a grade ≥ 2 for patients with esophageal cancer (EC) underwent volumetric modulated arc therapy (VMAT) based on computed tomography (CT) and radiation dose (RD) distribution images. MATERIALS AND METHODS: A total of 273 EC patients underwent VMAT were retrospectively reviewed and enrolled from two centers and divided into training (n = 152), internal validation (n = 66), and external validation (n = 55) cohorts, respectively. Radiomic and dosiomic features along with DL features using convolutional neural networks were extracted and screened from CT and RD images to predict RE. The performance of these models was evaluated and compared using the area under curve (AUC) of the receiver operating characteristic curves (ROC). RESULTS: There were 5 and 10 radiomic and dosiomic features were screened, respectively. XGBoost achieved a best AUC of 0.703, 0.694 and 0.801, 0.729 with radiomic and dosiomic features in the internal and external validation cohorts, respectively. ResNet34 achieved a best prediction AUC of 0.642, 0.657 and 0.762, 0.737 for radiomics based DL model (DLR) and RD based DL model (DLD) in the internal and external validation cohorts, respectively. Combined model of DLD + Dosiomics + clinical factors achieved a best AUC of 0.913, 0.821 and 0.805 in the training, internal, and external validation cohorts, respectively. CONCLUSION: Although the dose was not responsible for the prediction accuracy, the combination of various feature extraction methods was a factor in improving the RE prediction accuracy. Combining DLD with dosiomic features was promising in the pretreatment prediction of RE for EC patients underwent VMAT.
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Egg white protein ovomucin and its hydrolysates were previously reported to exhibit anti-inflammatory and anti-adhesive activities. However, their potential to regulate pathogen colonization and disease severity has not been fully characterized. To investigate the effects of ovomucin (OVM) and its hydrolysates including ovomucin-Protex 26L (OP) and -pepsin/pancreatin (OPP) on host resistance to pathogen infection, a well-documented colitis model in mice for attaching and effacing E. coli pathogens, Citrobacter rodentium, was used in the current study. C57Bl/6J female mice were fed on a basal diet supplemented with OVM or its hydrolysates for 3 weeks prior to the C. rodentium challenge, with the dietary treatments continued for seven days. Body weight was not affected throughout the experimental period. OP supplementation resulted in lower (P < 0.05) pathogen loads at 7 dpi. Attenuated colitis severity was observed in mice that received OVM and OP, as indicated by reduced colonic pathological scores and pro-inflammatory responses compared with the infected control group. In contrast, OPP consumption resulted in enhanced C. rodentium colonization and disease severity. Notably, reduced microbial diversity indices of the gut microbiota were observed in the OPP-supplemented mice compared with the OVM- and OP-supplemented groups. This study showed the potential of OVM and OP to alleviate the severity of colitis induced by infection while also suggesting the opposite outcome of OPP in mitigating enteric infection.
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Citrobacter rodentium , Colite , Infecções por Enterobacteriaceae , Camundongos Endogâmicos C57BL , Ovomucina , Animais , Camundongos , Feminino , Colite/induzido quimicamente , Colite/microbiologia , Infecções por Enterobacteriaceae/microbiologia , Microbioma Gastrointestinal , Modelos Animais de Doenças , Colo/microbiologia , Colo/patologia , Colo/metabolismo , Hidrolisados de Proteína/farmacologiaRESUMO
The Pseudomonas aeruginosa lipase PaL catalyzes the stereoselective hydrolysis of menthyl propionate to produce L-menthol. The lack of a three-dimensional structure of PaL has so far prevented a detailed understanding of its stereoselective reaction mechanism. Here, the crystal structure of PaL was determined at a resolution of 1.80 Å by single-wavelength anomalous diffraction. In the apo-PaL structure, the catalytic His302 is located in a long loop on the surface that is solvent exposed. His302 is distant from the other two catalytic residues, Asp274 and Ser164. This configuration of catalytic residues is unusual for lipases. Using metadynamics simulations, we observed that the enzyme undergoes a significant conformational change upon ligand binding. We also explored the catalytic and stereoselectivity mechanisms of PaL by all-atom molecular dynamics simulations. These findings could guide the engineering of PaL with an improved diastereoselectivity for L-menthol production.
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The present study aimed to explore the underlying mechanism of bile reflux-inducing chronic atrophic gastritis (CAG) with colonic mucosal lesion. The rat model of CAG with colonic mucosal lesion was induced by free-drinking 20 mmol/L sodium deoxycholate to simulate bile reflux and 2% cold sodium salicylate for 12 weeks. In comparison to the control group, the model rats had increased abundances of Bacteroidetes and Firmicutes but had decreased abundances of Proteobacteria and Fusobacterium. Several gut bacteria with bile acids transformation ability were enriched in the model group, such as Blautia, Phascolarctobacter, and Enterococcus. The cytotoxic deoxycholic acid and lithocholic acid were significantly increased in the model group. Transcriptome analysis of colonic tissues presented that the down-regulated genes enriched in T cell receptor signaling pathway, antigen processing and presentation, Th17 cell differentiation, Th1 and Th2 cell differentiation, and intestinal immune network for IgA production in the model group. These results suggest that bile reflux-inducing CAG with colonic mucosal lesion accompanied by gut dysbacteriosis, mucosal immunocompromise, and increased gene expressions related to repair of intestinal mucosal injury.
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Colo , Ácido Desoxicólico , Gastrite Atrófica , Microbioma Gastrointestinal , Mucosa Intestinal , Animais , Gastrite Atrófica/microbiologia , Gastrite Atrófica/imunologia , Gastrite Atrófica/patologia , Gastrite Atrófica/induzido quimicamente , Ratos , Mucosa Intestinal/patologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/efeitos dos fármacos , Masculino , Colo/patologia , Colo/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Modelos Animais de Doenças , Imunidade nas Mucosas/efeitos dos fármacos , Ratos Sprague-Dawley , Doença CrônicaRESUMO
Egg white hydrolysates (EWH) and ovotransferrin-derived peptides have distinct beneficial effects on glucose metabolism. This research aims to investigate whether ovalbumin hydrolysates (OVAHs), without ovotransferrin can improve insulin signaling pathway in high-fat diet (HFD)-fed mice. Two types of ovalbumin hydrolysates were produced, either using thermoase (OVAT), or thermoase + pepsin (OVATP). Both OVAHs-supplemented groups exhibited lower body weight gain (P < 0.001) and enhanced oral glucose tolerance (P < 0.05) compared with HFD. Moreover, diet supplementation with either hydrolysate increased the insulin-stimulated activation of protein kinase B (AKT) and insulin receptor ß (IRß) (P < 0.0001) in skeletal muscle. In conclusion, OVAHs improved glucose tolerance and insulin-dependent signaling pathway in HFD-fed mice.
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Dieta Hiperlipídica , Insulina , Camundongos Endogâmicos C57BL , Músculo Esquelético , Ovalbumina , Hidrolisados de Proteína , Transdução de Sinais , Animais , Dieta Hiperlipídica/efeitos adversos , Insulina/metabolismo , Camundongos , Transdução de Sinais/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/efeitos dos fármacos , Masculino , Hidrolisados de Proteína/química , Hidrolisados de Proteína/administração & dosagem , Hidrolisados de Proteína/metabolismo , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Resistência à Insulina , Receptor de Insulina/metabolismo , Receptor de Insulina/genéticaRESUMO
Telangiectasias are the most frequent type of sequelae of infantile hemangiomas after involution. Few studies have reported the treatment of telangiectasias with 595-nm pulsed dye lasers. Therefore, the objective of this study was to assess the efficacy and safety of a 595-nm pulsed dye laser for treating residual telangiectasias following hemangioma involution. This is a retrospective case series that analyzes the medical records and reviews the charts of 22 patients who had undergone 595-nm pulsed dye laser treatment for residual telangiectasias. Pre- and post-treatment digital images were independently assessed, and the changes were scored to ascertain the efficacy of the treatment (0 = no change, 4 = complete improvement). Of the 22 patients, 59.1% experienced complete resolution of telangiectasias following treatment. No serious complications or side effects were reported. The observations indicate that the 595-nm pulsed dye laser is effective and safe for treating residual telangiectasias following hemangioma involution.
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Hemangioma , Lasers de Corante , Telangiectasia , Humanos , Estudos Retrospectivos , Lasers de Corante/uso terapêutico , Telangiectasia/radioterapia , Telangiectasia/cirurgia , Feminino , Masculino , Lactente , Hemangioma/radioterapia , Resultado do Tratamento , Pré-Escolar , Terapia com Luz de Baixa Intensidade/métodosRESUMO
BACKGROUND: To integrate radiomics and dosiomics features from multiple regions in the radiation pneumonia (RP grade ≥ 2) prediction for esophageal cancer (EC) patients underwent radiotherapy (RT). METHODS: Total of 143 EC patients in the authors' hospital (training and internal validation: 70%:30%) and 32 EC patients from another hospital (external validation) underwent RT from 2015 to 2022 were retrospectively reviewed and analyzed. Patients were dichotomized as positive (RP+) or negative (RP-) according to CTCAE V5.0. Models with radiomics and dosiomics features extracted from single region of interest (ROI), multiple ROIs and combined models were constructed and evaluated. A nomogram integrating radiomics score (Rad_score), dosiomics score (Dos_score), clinical factors, dose-volume histogram (DVH) factors, and mean lung dose (MLD) was also constructed and validated. RESULTS: Models with Rad_score_Lung&Overlap and Dos_score_Lung&Overlap achieved a better area under curve (AUC) of 0.818 and 0.844 in the external validation in comparison with radiomics and dosiomics models with features extracted from single ROI. Combining four radiomics and dosiomics models using support vector machine (SVM) improved the AUC to 0.854 in the external validation. Nomogram integrating Rad_score, and Dos_score with clinical factors, DVH factors, and MLD further improved the RP prediction AUC to 0.937 and 0.912 in the internal and external validation, respectively. CONCLUSION: CT-based RP prediction model integrating radiomics and dosiomics features from multiple ROIs outperformed those with features from a single ROI with increased reliability for EC patients who underwent RT.
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Neoplasias Esofágicas , Nomogramas , Pneumonite por Radiação , Humanos , Neoplasias Esofágicas/radioterapia , Pneumonite por Radiação/etiologia , Feminino , Masculino , Estudos Retrospectivos , Pessoa de Meia-Idade , Idoso , Dosagem Radioterapêutica , Prognóstico , Idoso de 80 Anos ou mais , Tomografia Computadorizada por Raios X , RadiômicaRESUMO
BACKGROUND AND OBJECTIVE: To evaluate the feasibility and accuracy of radiomics, dosiomics, and deep learning (DL) in predicting Radiation Pneumonitis (RP) in lung cancer patients underwent volumetric modulated arc therapy (VMAT) to improve radiotherapy safety and management. METHODS: Total of 318 and 31 lung cancer patients underwent VMAT from First Affiliated Hospital of Wenzhou Medical University (WMU) and Quzhou Affiliated Hospital of WMU were enrolled for training and external validation, respectively. Models based on radiomics (R), dosiomics (D), and combined radiomics and dosiomics features (R+D) were constructed and validated using three machine learning (ML) methods. DL models trained with CT (DLR), dose distribution (DLD), and combined CT and dose distribution (DL(R+D)) images were constructed. DL features were then extracted from the fully connected layers of the best-performing DL model to combine with features of the ML model with the best performance to construct models of R+DLR, D+DLD, R+D+DL(R+D)) for RP prediction. RESULTS: The R+D model achieved a best area under curve (AUC) of 0.84, 0.73, and 0.73 in the internal validation cohorts with Support Vector Machine (SVM), XGBoost, and Logistic Regression (LR), respectively. The DL(R+D) model achieved a best AUC of 0.89 and 0.86 using ResNet-34 in training and internal validation cohorts, respectively. The R+D+DL(R+D) model achieved a best performance in the external validation cohorts with an AUC, accuracy, sensitivity, and specificity of 0.81(0.62-0.99), 0.81, 0.84, and 0.67, respectively. CONCLUSIONS: The integration of radiomics, dosiomics, and DL features is feasible and accurate for the RP prediction to improve the management of lung cancer patients underwent VMAT.
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Aprendizado Profundo , Neoplasias Pulmonares , Pneumonite por Radiação , Radioterapia de Intensidade Modulada , Humanos , Pneumonite por Radiação/diagnóstico por imagem , Pneumonite por Radiação/etiologia , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/diagnóstico por imagem , Masculino , Radioterapia de Intensidade Modulada/métodos , Radioterapia de Intensidade Modulada/efeitos adversos , Feminino , Pessoa de Meia-Idade , Idoso , Tomografia Computadorizada por Raios X , Dosagem Radioterapêutica , MultiômicaRESUMO
Lipases play a vital role in various biological processes, from lipid metabolism to industrial applications. However, the ever-evolving challenges and diverse substrates necessitate the continual exploration of novel high-performance lipases. In this study, we employed an in silico mining approach to search for lipases with potential high sn-1,3 selectivity and catalytic activity. The identified novel lipase, PLL, from Paenibacillus larvae subsp. larvae B-3650 exhibited a specific activity of 111.2 ± 5.5â¯U/mg towards the substrate p-nitrophenyl palmitate (pNPP) and 6.9 ± 0.8â¯U/mg towards the substrate olive oil when expressed in Escherichia coli (E. coli). Computational design of cysteine mutations was employed to enhance the catalytic performance of PLL. Superior stability was achieved with the mutant K7C/A386C/H159C/K108C (2M3/2M4), showing an increase in melting temperature (Tm) by 1.9°C, a 2.05-fold prolonged half-life at 45°C, and no decrease in enzyme activity. Another mutant, K7C/A386C/A174C/A243C (2M1/2M3), showed a 4.9-fold enhancement in specific activity without compromising stability. Molecular dynamics simulations were conducted to explore the mechanisms of these two mutants. Mutant 2M3/2M4 forms putative disulfide bonds in the loop region, connecting the N- and C-termini of PLL, thus enhancing overall structural rigidity without impacting catalytic activity. The cysteines introduced in mutant 2M1/2M3 not only form new intramolecular hydrogen bonds but also alter the polarity and volume of the substrate-binding pocket, facilitating the entry of large substrate pNPP. These results highlight an efficient in silico exploration approach for novel lipases, offering a rapid and efficient method for enhancing catalytic performance through rational protein design.
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Proteínas de Bactérias , Estabilidade Enzimática , Lipase , Paenibacillus , Lipase/genética , Lipase/metabolismo , Lipase/química , Paenibacillus/enzimologia , Paenibacillus/genética , Especificidade por Substrato , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/química , Simulação por Computador , Engenharia de Proteínas , Escherichia coli/genética , Escherichia coli/metabolismo , Escherichia coli/enzimologia , Cinética , Simulação de Dinâmica Molecular , Azeite de Oliva/metabolismo , Azeite de Oliva/química , Mutagênese Sítio-Dirigida , Biocatálise , PalmitatosRESUMO
Lipase from Rhizopus oryzae (ROL) exhibits remarkable sn-1,3 stereoselectivity and catalytic activity, but its poor thermostability limits its applications in the production of 1,3-dioleoyl-2-palmitoyl glycerol (OPO, a high-quality substitute for human milk fat). In this work, a semirational method was proposed to engineer the thermostability and catalytic activity of 4M (ROL mutant in our previous study). First, a computer-aided design is performed using 4M as a template, and N-glycosylation mutants are then recombinantly expressed and screened in Pichia pastoris, the optimal mutant N227 exhibited a half-life of 298.8 h at 45 °C, which is 7.23-folds longer than that of 4M. Its catalytic activity also reached 1043.80 ± 61.98 U/mg, representing a 29.2% increase compared to 4M (808.02 ± 47.02 U/mg). Molecular dynamics simulations of N227 suggested that the introduction of glycan enhanced the protein rigidity, while the strong hydrogen bonds formed between the glycan and the protein stabilized the lipase structure, thereby improving its thermostability. The acidolysis reaction between oleic acid (OA) and glycerol tripalmitate (PPP) was successfully carried out using immobilized N227, achieving a molar conversion rate of 90.2% for PPP. This engineering strategy guides the modification of lipases, while the glycomutants obtained in this study have potential applications in the biosynthesis of OPO.
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Biocatálise , Estabilidade Enzimática , Proteínas Fúngicas , Lipase , Rhizopus oryzae , Lipase/química , Lipase/genética , Lipase/metabolismo , Glicosilação , Proteínas Fúngicas/genética , Proteínas Fúngicas/química , Proteínas Fúngicas/metabolismo , Rhizopus oryzae/enzimologia , Rhizopus oryzae/genética , Rhizopus oryzae/química , Rhizopus oryzae/metabolismo , Temperatura Alta , Cinética , Rhizopus/enzimologia , Rhizopus/genéticaRESUMO
Global change factors are known to strongly affect soil microbial community function and composition. However, as of yet, the effects of warming and increased anthropogenic nitrogen deposition on soil microbial network complexity and stability are still unclear. Here, we examined the effects of experimental warming (3°C above ambient soil temperature) and nitrogen addition (5 g N m-2 year-1) on the complexity and stability of the soil microbial network in a subtropical primary forest. Compared to the control, warming increased |negative cohesion|:positive cohesion by 7% and decreased network vulnerability by 5%; nitrogen addition decreased |negative cohesion|:positive cohesion by 10% and increased network vulnerability by 11%. Warming and decreased soil moisture acted as strong filtering factors that led to higher bacterial network stability. Nitrogen addition reduced bacterial network stability by inhibiting soil respiration and increasing resource availability. Neither warming nor nitrogen addition changed fungal network complexity and stability. These findings suggest that the fungal community is more tolerant than the bacterial community to climate warming and nitrogen addition. The link between bacterial network stability and microbial community functional potential was significantly impacted by nitrogen addition and warming, while the response of soil microbial network stability to climate warming and nitrogen deposition may be independent of its complexity. Our findings demonstrate that changes in microbial network structure are crucial to ecosystem management and to predict the ecological consequences of global change in the future. IMPORTANCE: Soil microbes play a very important role in maintaining the function and health of forest ecosystems. Unfortunately, global change factors are profoundly affecting soil microbial structure and function. In this study, we found that climate warming promoted bacterial network stability and nitrogen deposition decreased bacterial network stability. Changes in bacterial network stability had strong effects on bacterial community functional potentials linked to metabolism, nitrogen cycling, and carbon cycling, which would change the biogeochemical cycle in primary forests.
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Bactérias , Florestas , Fungos , Microbiota , Nitrogênio , Microbiologia do Solo , Nitrogênio/metabolismo , Bactérias/metabolismo , Fungos/metabolismo , Solo/química , Aquecimento Global , Mudança ClimáticaRESUMO
Angiotensin-converting enzyme 2 (ACE2) is a key enzyme in the renin-angiotensin system (RAS), also serving as an amino acid transporter and a receptor for certain coronaviruses. Its primary role is to protect the cardiovascular system via the ACE2/Ang (1-7)/MasR cascade. Given the critical roles of ACE2 in regulating numerous physiological functions, molecules that can upregulate or activate ACE2 show vast therapeutic value. There are only a few ACE2 activators that have been reported, a wide range of molecules, including food-derived compounds, have been reported as ACE2 up-regulators. Effective doses of bioactive peptides range from 10 to 50 mg/kg body weight (BW)/day when orally administered for 1 to 7 weeks. Protein hydrolysates require higher doses at 1000 mg/kg BW/day for 20 days. Phytochemicals and vitamins are effective at doses typically ranging from 10 to 200 mg/kg BW/day for 3 days to 6 months, while Traditional Chinese Medicine requires doses of 1.25 to 12.96 g/kg BW/day for 4 to 8 weeks. ACE2 activation is linked to its hinge-bending region, while upregulation involves various signaling pathways, transcription factors, and epigenetic modulators. Future studies are expected to explore novel roles of ACE2 activators or up-regulators in disease treatments and translate the discovery to bedside applications.
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Enzima de Conversão de Angiotensina 2 , Regulação para Cima , Enzima de Conversão de Angiotensina 2/metabolismo , Enzima de Conversão de Angiotensina 2/genética , Humanos , Animais , Regulação para Cima/efeitos dos fármacos , Sistema Renina-Angiotensina/efeitos dos fármacos , Peptidil Dipeptidase A/metabolismo , Peptidil Dipeptidase A/genética , Compostos Fitoquímicos/metabolismo , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologiaRESUMO
Optically pure 1,2,3,4-tetrahydroquinolines (THQs) represent a class of important motifs in many natural products and pharmaceutical agents. While recent advances on redox biocatalysis have demonstrated the great potential of amine oxidases, all the transformations focused on 2-substituted THQs. The corresponding biocatalytic method for the preparation of chiral 4-substituted THQs is still challenging due to the poor activity and stereoselectivity of the available enzyme. Herein, we developed a biocatalytic kinetic resolution approach for enantiodivergent synthesis of 4-phenyl- or alkyl-substituted THQs. Through structure-guided protein engineering of cyclohexylamine oxidase derived from Brevibacterium oxidans IH-35 A (CHAO), the variant of CHAO (Y215H/Y214S) displayed improved specific activity toward model substrate 4-phenyl substituted THQ (0.14 U/mg, 13-fold higher than wild-type CHAO) with superior (R)-stereoselectivity (E > 200). Molecular dynamics simulations show that CHAO Y215H/Y214S allows a suitable substrate positioning in the expanded binding pocket to be facilely accessed, enabling enhanced activity and stereoselectivity. Furthermore, a series of 4-alkyl-substituted THQs can be transformed by CHAO Y215H/Y214S, affording R-isomers with good yields (up to 50 %) and excellent enantioselectivity (up to ee > 99 %). Interestingly, the monoamine oxidase from Pseudomonas fluorescens Pf0-1 (PfMAO1) with opposite enantioselectivity was also mined. Together, this system enriches the kinetic resolution methods for the synthesis of chiral THQs.
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Quinolinas , Cinética , Estereoisomerismo , Quinolinas/química , Biocatálise , Brevibacterium/enzimologia , Especificidade por Substrato , Simulação de Dinâmica Molecular , Monoaminoxidase/metabolismo , Monoaminoxidase/químicaRESUMO
The potential threshold for dietary energy intake (DEI) that might prevent protein-energy wasting (PEW) in chronic kidney disease (CKD) is uncertain. The subjects were non-dialysis CKD patients aged ≥ 14 years who were hospitalised from September 2019 to July 2022. PEW was measured by subjective global assessment. DEI and dietary protein intake (DPI) were obtained by 3-d diet recalls. Patients were divided into adequate DEI group and inadequate DEI group according to DEI ≥ 30 or < 30 kcal/kg/d. Logistic regression analysis and restricted cubic spline were used in this study. We enrolled 409 patients, with 53·8 % had hypertension and 18·6 % had diabetes. The DEI and DPI were 27·63 (sd 5·79) kcal/kg/d and 1·00 (0·90, 1·20) g/kg/d, respectively. 69·2 % of participants are in the inadequate DEI group. Malnutrition occurred in 18·6 % of patients. Comparing with patients in the adequate DEI group, those in the inadequate DEI group had significantly lower total lymphocyte count, serum cholesterol and LDL-cholesterol and a higher prevalence of PEW. For every 1 kcal/kg/d increase in DEI, the incidence of PEW was reduced by 12·0 % (OR: 0·880, 95 % CI: 0·830, 0·933, P < 0·001). There was a nonlinear curve relationship between DEI and PEW (overall P < 0·001), and DEI ≥ 27·6 kcal/kg/d may have a preventive effect on PEW in CKD. Low DPI was also significantly associated with malnutrition, but not when DEI was adequate. Decreased energy intake may be a more important factor of PEW in CKD than protein intake.
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The global market for plant-based meat alternatives (PBMAs) is expanding quickly. In this narrative review, analysis of the most recent scientific literature was achieved to understand the nutritional profile, health implications, and the challenges faced by PBMAs. On the positive side, most PBMAs are good sources of dietary fiber, contain phytochemicals, have comparable levels of iron, and are lower in calories, saturated fat, and cholesterol than meat. However, PBMAs frequently contain anti-nutrients, have less protein, iron, and vitamin B12, are lower in protein quality, and also have higher amounts of sodium. Substituting PBMAs for meats may cause iron, vitamin B12, and less likely protein deficiency for these vulnerable population such as women, older adults, and individuals with disorders. PBMAs fall into the category of ultra-processed foods, indicating a need to develop minimally processed, clean-label products. Replacing red meat with healthy plant-based foods is associated with lower risks of cardiovascular diseases, type 2 diabetes, and total mortality. There is a lack of robust, long-term evidence on the role of PBMAs consumption in health. As the nutrient contents of PBMAs can vary, consumers must read nutrition facts labels and ingredient lists to select a product that best fits their nutritional and health objectives.