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Adipose tissue group 2 innate lymphoid cells (ILC2s) help maintain metabolic homeostasis by sustaining type 2 immunity and promoting adipose beiging. Although impairment of the ILC2 compartment contributes to obesity-associated insulin resistance, the underlying mechanisms have not been elucidated. Here, we found that ILC2s in obese mice and humans exhibited impaired liver kinase B1 (LKB1) activation. Genetic ablation of LKB1 disrupted ILC2 mitochondrial metabolism and suppressed ILC2 responses, resulting in exacerbated insulin resistance. Mechanistically, LKB1 deficiency induced aberrant PD-1 expression through activation of NFAT, which in turn enhanced mitophagy by suppressing Bcl-xL expression. Blockade of PD-1 restored the normal functions of ILC2s and reversed obesity-induced insulin resistance in mice. Collectively, these data present the LKB1-PD-1 axis as a promising therapeutic target for the treatment of metabolic disease.
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Tecido Adiposo , Homeostase , Resistência à Insulina , Linfócitos , Mitocôndrias , Obesidade , Receptor de Morte Celular Programada 1 , Proteínas Serina-Treonina Quinases , Animais , Resistência à Insulina/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Camundongos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Mitocôndrias/metabolismo , Humanos , Tecido Adiposo/metabolismo , Tecido Adiposo/imunologia , Obesidade/imunologia , Obesidade/metabolismo , Linfócitos/imunologia , Linfócitos/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Imunidade Inata , Masculino , Mitofagia/imunologia , Quinases Proteína-Quinases Ativadas por AMPRESUMO
Innate lymphoid cells (ILCs) lack antigen-specific receptors and are considered the innate arm of the immune system, phenotypically and functionally mirroring CD4+ helper T cells. ILCs are categorized into groups 1, 2, and 3 based on transcription factors and cytokine expression. ILCs predominantly reside in mucosal tissues and play important roles in regional immune responses. The development and function of ILC subsets are controlled by both transcriptional and epigenetic mechanisms, which have been extensively studied in recent years. Epigenetic regulation refers to inheritable changes in gene expression that occur without affecting DNA sequences. This mainly includes chromatin status, histone modifications, and DNA methylation. In this review, we summarize recent discoveries on epigenetic mechanisms regulating ILC development and function, and how these regulations affect disease progression under pathological conditions. Although the ablation of specific epigenetic regulators can cause global changes in corresponding epigenetic modifications to the chromatin, only partial genes with altered epigenetic modifications change their mRNA expression, resulting in specific outcomes in cell differentiation and function. Therefore, elucidating epigenetic mechanisms underlying the regulation of ILCs will provide potential targets for the diagnosis and treatment of inflammatory diseases.
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Pigmented potato tubers are abundant in chlorogenic acids (CGAs), a metabolite with pharmacological activity. This article comprehensively analyzed the transcriptome and metabolome of pigmented potato Huaxingyangyu and Jianchuanhong at four altitudes of 1800 m, 2300 m, 2800 m, and 3300 m. A total of 20 CGAs and intermediate CGA compounds were identified, including 3-o-caffeoylquinic acid, 4-o-caffeoylquinic acid, and 5-o-caffeoylquinic acid. CGA contents in Huaxinyangyu and Jianchuanhong reached its maximum at an altitude of 2800 m and slightly decreased at 3300 m. 48 candidate genes related to the biosynthesis pathway of CGAs were screened through transcriptome analysis. Weighted gene co-expression network analysis (WGCNA) identified that the structural genes of phenylalanine deaminase (PAL), coumarate-3 hydroxylase (C3H), cinnamic acid 4-hydroxylase (C4H) and the transcription factors of MYB and bHLH co-regulate CGA biosynthesis. The results of this study provide valuable information to reveal the changes in CGA components in pigmented potato at different altitudes.
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MYB transcription factors play an extremely important regulatory role in plant responses to stress and anthocyanin synthesis. Cloning of potato StMYB-related genes can provide a theoretical basis for the genetic improvement of pigmented potatoes. In this study, two MYB transcription factors, StMYB113 and StMYB308, possibly related to anthocyanin synthesis, were screened under low-temperature conditions based on the low-temperature-responsive potato StMYB genes family analysis obtained by transcriptome sequencing. By analyzed the protein properties and promoters of StMYB113 and StMYB308 and their relative expression levels at different low-temperature treatment periods, it is speculated that StMYB113 and StMYB308 can be expressed in response to low temperature and can promote anthocyanin synthesis. The overexpression vectors of StMYB113 and StMYB308 were constructed for transient transformation tobacco. Color changes were observed, and the expression levels of the structural genes of tobacco anthocyanin synthesis were determined. The results showed that StMYB113 lacking the complete MYB domain could not promote the accumulation of tobacco anthocyanins, while StMYB308 could significantly promote the accumulation involved in tobacco anthocyanins. This study provides a theoretical reference for further study of the mechanism of StMYB113 and StMYB308 transcription factors in potato anthocyanin synthesis.
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Solanum tuberosum , Fatores de Transcrição , Fatores de Transcrição/metabolismo , Solanum tuberosum/genética , Solanum tuberosum/metabolismo , Antocianinas , Temperatura , Proteínas de Plantas/metabolismo , Regulação da Expressão Gênica de Plantas , Plantas Geneticamente Modificadas/genéticaRESUMO
Glucagon-like peptide-1 receptor agonists (GLP-1RAs), which are drugs used for treating type 2 diabetes, have been reported to exert anti-inflammatory effects on inflammatory bowel disease (IBD), the mechanism of which remains elusive. Here, we report that GLP-1RAs ameliorate dextran sulfate sodium (DSS)-induced colitis in both wild-type and T/B-cell-deficient mice through modulating group 3 innate lymphoid cells (ILC3s), a subset of innate lymphoid cells that regulate intestinal immunity. GLP-1RAs promote IL-22 production by ILC3, and the protective effect of GLP-1RAs on DSS-induced colitis was abrogated in ILC3-deficient RORgtgfp/gfp mice. Furthermore, the treatment effect of GLP-RAs on colitis, as well as the generation of IL-22-producing ILC3s by GLP-RAs, is dependent on the gut microbiota. GLP-1RAs increase the abundance of Firmicutes and Proteobacteria in the gut, particularly beneficial bacteria such as Lactobacillus reuteri, and decrease the abundance of enteropathogenic Staphylococcus bacteria. The untargeted gas chromatography (GC)/liquid chromatography (LC)-mass spectrometry (MS) of faecal metabolites further revealed enrichment of N,N-dimethylsphingosine (DMS), an endogenous metabolite derived from sphingosine, in the GLP-1RA-treated group. Strikingly, DMS ameliorates colitis while promoting intestinal IL-22-producing ILC3s. Taken together, our findings show that GLP-1RAs exert a therapeutic effect on colitis possibly by regulating the microbiota-DMS-IL-22+ILC3 axis, highlighting the potential beneficial role of GLP-RAs in inflammatory intestinal disorders with diabetes complications.
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Colite , Sulfato de Dextrana , Microbioma Gastrointestinal , Receptor do Peptídeo Semelhante ao Glucagon 1 , Imunidade Inata , Interleucina 22 , Linfócitos , Animais , Microbioma Gastrointestinal/imunologia , Microbioma Gastrointestinal/efeitos dos fármacos , Colite/imunologia , Colite/tratamento farmacológico , Colite/metabolismo , Colite/induzido quimicamente , Camundongos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Imunidade Inata/efeitos dos fármacos , Linfócitos/imunologia , Linfócitos/metabolismo , Linfócitos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Interleucinas/metabolismo , Camundongos Knockout , Colo/imunologia , Colo/microbiologia , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Liraglutida/farmacologia , Liraglutida/uso terapêutico , Agonistas do Receptor do Peptídeo 1 Semelhante ao GlucagonRESUMO
Two clinically important subspecies, Francisella tularensis subsp. tularensis (type A) and F. tularensis subsp. holarctica (type B) are responsible for most tularaemia cases, but these isolates typically form a weak biofilm under in vitro conditions. Phase variation of the F. tularensis lipopolysaccharide (LPS) has been reported in these subspecies, but the role of variation is unclear as LPS is crucial for virulence. We previously demonstrated that a subpopulation of LPS variants can constitutively form a robust biofilm in vitro, but it is unclear whether virulence was affected. In this study, we show that biofilm-forming variants of both fully virulent F. tularensis subspecies were highly attenuated in the murine tularaemia model by multiple challenge routes. Genomic sequencing was performed on these strains, which revealed that all biofilm-forming variants contained a lesion within the wbtJ gene, a formyltransferase involved in O-antigen synthesis. A ΔwbtJ deletion mutant recapitulated the biofilm, O-antigen and virulence phenotypes observed in natural variants and could be rescued through complementation with a functional wbtJ gene. Since the spontaneously derived biofilm-forming isolates in this study were a subpopulation of natural variants, reversion events to the wbtJ gene were detected that eliminated the phenotypes associated with biofilm variants and restored virulence. These results demonstrate a role for WbtJ in biofilm formation, LPS variation and virulence of F. tularensis.
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Francisella tularensis , Francisella , Hidroximetil e Formil Transferases , Tularemia , Animais , Camundongos , Francisella tularensis/genética , Antígenos O/genética , Lipopolissacarídeos , Hidroximetil e Formil Transferases/genética , Variação de Fase , MutaçãoRESUMO
Dechlorination of chloropyridines can eliminate their detrimental environmental effects. However, traditional dechlorination technology cannot efficiently break the C-Cl bond of chloropyridines, which is restricted by the uncontrollable nonselective species. Hence, we propose the carbonate species-activated hydrogen peroxide (carbonate species/H2O2) process wherein the selective oxidant (peroxymonocarbonate ion, HCO4-) and selective reductant (hydroperoxide anion, HO2-) controllably coexist by manipulation of reaction pH. Taking 2-chloropyridine (Cl-Py) as an example, HCO4- first induces Cl-Py into pyridine N-oxidation intermediates, which then suffer from the nucleophilic dechlorination by HO2-. The obtained dechlorination efficiencies in the carbonate species/H2O2 process (32.5-84.5%) based on the cooperation of HCO4- and HO2- are significantly higher than those in the HO2--mediated sodium hydroxide/hydrogen peroxide process (0-43.8%). Theoretical calculations confirm that pyridine N-oxidation of Cl-Py can effectively lower the energy barrier of the dechlorination process. Moreover, the carbonate species/H2O2 process exhibits superior anti-interference performance and low electric energy consumption. Furthermore, Cl-Py is completely detoxified via the carbonate species/H2O2 process. More importantly, the carbonate species/H2O2 process is applicable for efficient dehalogenation of halogenated pyridines and pyrazines. This work offers a simple and useful strategy to enhance the dehalogenation efficiency of halogenated organics and sheds new insights into the application of the carbonate species/H2O2 process in practical environmental remediation.
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Peróxido de Hidrogênio , Piridinas , Peróxido de Hidrogênio/química , Oxirredução , CarbonatosRESUMO
There is a paucity of evidence on exercise interventions for frail older adults with diabetes. This scoping review aims to identify the scope of the current literature on the characteristics and effects of exercise interventions for frail older adults with diabetes. A search without time limitation was conducted in eight databases. 14 studies were finally included. Resistance exercise and multicomponent exercise were the most common types of exercise. There was considerable variation in the frequency, duration and intensity of exercise interventions. Studies reported improvements in frailty status, physical function, blood glucose and lipid levels and economic effectiveness. The most frequent combined interventions involved nutrition and education. Although evidence was limited, the potential benefits of exercise interventions for frail older adults with diabetes were substantial. Further high-quality studies are needed to explore the most effective and cost-saving exercise interventions for frail older adults with diabetes.
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Diabetes Mellitus , Terapia por Exercício , Idoso Fragilizado , Humanos , Idoso , Terapia por Exercício/métodos , Diabetes Mellitus/terapia , Exercício FísicoRESUMO
With a millennium-long history, traditional Chinese cereal vinegar (CCV) is a significant part of China's cultural heritage. The unique flavor of CCV is derived from the use of cereal and its bran as raw materials and solid-state fermentation as a brewing technique. This paper systemically summarized recent research progress on the aroma compounds in CCV, the biochemical generation of aroma compounds during the brewing process, and the association between sensory perception and the primary aroma compounds. Furthermore, a complete CCV lexicon and sensory wheel prototype were constructed. This study aims to lay a foundation for future CCV aroma research, quality improvement, and industrialization.
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The aim of this study was to assess the advantages of an industry-scale microfluidizer system (ISMS) to prepare whole-grain highland barley pulp (WHBP) compared with colloid milling. Storage stability was evaluated by particle size, gravity separation stability, and rheological properties, as well as the microstructure observation by scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLMS). The results showed that colloid milling failed to effectively homogenize the material, while ISMS sample surfaces were compact and smooth at higher pressures according to visual observation and SEM. The Turbiscan stability index of WHBP by ISMS was much lower as a result of colloid milling, demonstrating ISMS can improve WHBP stability. WHBP by colloid milling displayed a three-peak particle size distribution pattern, while a single-peak pattern was evident after ISMS treatment. A higher shear rate decreased the apparent viscosity, suggesting that WHBP was a shear-thinning fluid. According to CLMS, ISMS can successfully improve homogenization by disrupting the structures of oil bodies, proteins, and starches. The WHBP prepared by ISMS exhibited a higher ß-glucan level than that prepared by colloid milling, and showed a significant increase in ß-glucan level with ISMS pressure. These findings indicate that using ISMS to produce WHBP is viable for enhancing its storage stability and nutritional value.
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Myeloid-derived suppressor cells (MDSCs) occupy a pivotal role in the intricate pathogenesis of the autoimmune disorder, Type 1 diabetes mellitus (T1DM). Since our previous work demonstrated that trichosanthin (TCS), an active compound of Chinese herb medicine Tian Hua Fen, regulated immune response, we aimed to clarify the efficacy and molecular mechanism of TCS in the treatment of T1DM. To this end, T1DM mouse model was established by streptozotocin (STZ) induction. The mice were randomly divided into normal control group (Ctl), T1DM group (STZ), TCS treated diabetic group (STZ + TCS) and insulin-treated diabetic group (STZ + insulin). Our comprehensive evaluation encompassed variables such as blood glucose, glycosylated hemoglobin, body weight, pertinent biochemical markers, pancreatic histopathology, and the distribution of immune cell populations. Furthermore, we meticulously isolated MDSCs from the bone marrow of T1DM mice, probing into the expressions of genes pertaining to the advanced glycation end product receptor (RAGE)/NF-κB signaling pathway through RT-qPCR. Evidently, TCS exhibited a substantial capacity to effectively counteract the T1DM-induced elevation in random blood glucose, glycosylated hemoglobin, and IL-6 levels in plasma. Pathological scrutiny underscored the ability of TCS to mitigate the damage incurred by islets. Intriguingly, TCS interventions engendered a reduction in the proportion of MDSCs within the bone marrow, particularly within the IL-6+ MDSC subset. In contrast, IL-10+ MDSCs exhibited an elevation following TCS treatment. Moreover, we observed a significant down-regulation of relative mRNA of pro-inflammatory genes, including arginase 1 (Arg1), inducible nitric oxide synthase (iNOS), RAGE and NF-κB, within MDSCs due to the influence of TCS. It decreases total MDSCs and regulates the balance between IL-6+ and IL-10+ MDSCs thus alleviating the symptoms of T1DM. TCS also down-regulates the RAGE/NF-κB signaling pathway, making it a promising alternative therapeutic treatment for T1DM. Collectively, our study offered novel insights into the underlying mechanism by which TCS serves as a promising therapeutic intervention for T1DM.
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The effects of ethanol on the physicochemical, structural and in vitro digestive properties of Tartary buckwheat starch-quercetin/rutin complexes (e-TBSQ and e-TBSR) were investigated. Ethanol restricted the gelatinization of Tartary buckwheat starch (TBS), which resulted an increase in ∆H, G' and G" as well as a decrease in apparent viscosity of e-TBSQ and e-TBSR. The particle size, scanning electron microscopy and X-ray diffraction results showed that ethanol influenced the morphological structure of TBS granules and the starch crystalline structure in e-TBSQ and e-TBSR changed from B-type to V-type when the ethanol concentration was 25%. Saturation transfer difference-nuclear magnetic resonance results revealed that ethanol weakened the binding ability of quercetin/rutin to TBS in e-TBSQ and e-TBSR, leading to a change in the binding site on the quercetin structural unit. The residual ungelatinized TBS granules in e-TBSQ and e-TBSR induced a high slowly digestible starch content, and thus displayed a "resistant-to-digestion".
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Digestão , Etanol , Fagopyrum , Quercetina , Rutina , Amido , Fagopyrum/química , Amido/química , Quercetina/química , Etanol/química , Viscosidade , Rutina/química , Tamanho da Partícula , Extratos Vegetais/química , Modelos Biológicos , Difração de Raios XRESUMO
Group 2 innate lymphoid cells (ILC2s) play crucial roles in mediating allergic inflammation. Recent studies also indicate their involvement in regulating tumor immunity. The tumor suppressor liver kinase B1 (LKB1) inactivating mutations are associated with a variety of human cancers; however, the role of LKB1 in ILC2 function and ILC2-mediated tumor immunity remains unknown. Here, we show that ablation of LKB1 in ILC2s results in an exhausted-like phenotype, which promotes the development of lung melanoma metastasis. Mechanistically, LKB1 deficiency leads to a marked increase in the expression of programmed cell death protein-1 (PD-1) in ILC2s through the activation of the nuclear factor of activated T cell pathway. Blockade of PD-1 can restore the effector functions of LKB1-deficient ILC2s, leading to enhanced antitumor immune responses in vivo. Together, our results reveal that LKB1 acts to restrain the exhausted state of ILC2 to maintain immune homeostasis and antitumor immunity.
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Proteínas Quinases Ativadas por AMP , Imunidade Inata , Linfócitos , Camundongos Endogâmicos C57BL , Proteínas Serina-Treonina Quinases , Animais , Proteínas Serina-Treonina Quinases/metabolismo , Camundongos , Linfócitos/imunologia , Linfócitos/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Receptor de Morte Celular Programada 1/metabolismo , Humanos , Linhagem Celular Tumoral , Melanoma/imunologia , Melanoma/patologiaRESUMO
Introduction: Basal cell carcinoma (BCC) is the most common skin cancer, lacking reliable biomarkers or therapeutic targets for effective treatment. Genome-wide association studies (GWAS) can aid in identifying drug targets, repurposing existing drugs, predicting clinical trial side effects, and reclassifying patients in clinical utility. Hence, the present study investigates the association between plasma proteins and skin cancer to identify effective biomarkers and therapeutic targets for BCC. Methods: Proteome-wide mendelian randomization was performed using inverse-variance-weight and Wald Ratio methods, leveraging 1 Mb cis protein quantitative trait loci (cis-pQTLs) in the UK Biobank Pharma Proteomics Project (UKB-PPP) and the deCODE Health Study, to determine the causal relationship between plasma proteins and skin cancer and its subtypes in the FinnGen R10 study and the SAIGE database of Lee lab. Significant association with skin cancer and its subtypes was defined as a false discovery rate (FDR) < 0.05. pQTL to GWAS colocalization analysis was executed using a Bayesian model to evaluate five exclusive hypotheses. Strong colocalization evidence was defined as a posterior probability for shared causal variants (PP.H4) of ≥0.85. Mendelian randomization-Phenome-wide association studies (MR-PheWAS) were used to evaluate potential biomarkers and therapeutic targets for skin cancer and its subtypes within a phenome-wide human disease category. Results: PTGES2, RNASET2, SF3B4, STX8, ENO2, and HS3ST3B1 (besides RNASET2, five other plasma proteins were previously unknown in expression quantitative trait loci (eQTL) and methylation quantitative trait loci (mQTL)) were significantly associated with BCC after FDR correction in the UKB-PPP and deCODE studies. Reverse MR showed no association between BCC and these proteins. PTGES2 and RNASET2 exhibited strong evidence of colocalization with BCC based on a posterior probability PP.H4 >0.92. Furthermore, MR-PheWAS analysis showed that BCC was the most significant phenotype associated with PTGES2 and RNASET2 among 2,408 phenotypes in the FinnGen R10 study. Therefore, PTGES2 and RNASET2 are highlighted as effective biomarkers and therapeutic targets for BCC within the phenome-wide human disease category. Conclusion: The study identifies PTGES2 and RNASET2 plasma proteins as novel, reliable biomarkers and therapeutic targets for BCC, suggesting more effective clinical application strategies for patients.
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Microplastics (MPs) are environmental pollutants and can be inhaled by humans to threaten health. The lung tissue, responsible for the gas exchange between the body and the environment, is vulnerable to MPs exposure. However, from the perspective of cellular senescence, the effect of MPs on lung cells and tissues has not yet been deeply dissected. In this study, we reported that all the four typical MPs exhibited the significant biological effects in term of inducing senescence of human lung derived cells A549 and BEAS-2B in vitro. We further found that polyvinyl chloride (PVC) increased the reactive oxygen species (ROS) level in A549 cells and that PVC-induced senescent characteristics could be largely reversed by antioxidant treatment. Importantly, intratracheal instillation of PVC MPs in mice could effectively impair their physical function, induce the increased systemic inflammation level, cause the accumulation of senescent cells. Our study demonstrates that MPs induce senescence in human lung epithelial cells and mouse lungs by activating ROS signaling, and provides new insight into the potential pathogenesis of MPs on lung diseases.
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Microplásticos , Poluentes Químicos da Água , Humanos , Animais , Camundongos , Plásticos , Espécies Reativas de Oxigênio , Células Epiteliais , PulmãoRESUMO
Gut microbiota is linked to human metabolic diseases. The previous work showed that leucine deprivation improved metabolic dysfunction, but whether leucine deprivation alters certain specific species of bacterium that brings these benefits remains unclear. Here, this work finds that leucine deprivation alters gut microbiota composition, which is sufficient and necessary for the metabolic improvements induced by leucine deprivation. Among all the affected bacteria, B. coccoides is markedly increased in the feces of leucine-deprived mice. Moreover, gavage with B. coccoides improves insulin sensitivity and reduces body fat in high-fat diet (HFD) mice, and singly colonization of B. coccoides increases insulin sensitivity in gnotobiotic mice. The effects of B. coccoides are mediated by metabolizing tryptophan into indole-3-acetic acid (I3AA) that activates the aryl hydrocarbon receptor (AhR) in the liver. Finally, this work reveals that reduced fecal B. coccoides and I3AA levels are associated with the clinical metabolic syndrome. These findings suggest that B. coccoides is a newly identified bacterium increased by leucine deprivation, which improves metabolic disorders via metabolizing tryptophan into I3AA.
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Modelos Animais de Doenças , Microbioma Gastrointestinal , Leucina , Camundongos Endogâmicos C57BL , Animais , Camundongos , Leucina/metabolismo , Microbioma Gastrointestinal/fisiologia , Microbioma Gastrointestinal/genética , Masculino , Doenças Metabólicas/metabolismo , Doenças Metabólicas/microbiologia , Dieta Hiperlipídica , Resistência à Insulina/fisiologia , Triptofano/metabolismo , Ácidos Indolacéticos/metabolismo , Fezes/microbiologia , Clostridiales/metabolismo , Clostridiales/genética , HumanosRESUMO
Background: Yersinia pestis is the etiological agent of plague, which can manifest as bubonic, septicemic, and/or pneumonic disease. Plague is a severe and rapidly progressing illness that can only be successfully treated with antibiotics initiated early after infection. There are no FDA-approved vaccines for plague, and some vaccine candidates may be less effective against pneumonic plague than bubonic plague. Y. pestis is not known to impact males and females differently in mechanisms of pathogenesis or severity of infection. However, one previous study reported sex-biased vaccine effectiveness after intranasal Y. pestis challenge. As part of developing a safe and effective vaccine, it is essential that potential sex differences are characterized. Methods: In this study we evaluated novel vaccines in male and female BALB/c mice using a heterologous prime-boost approach and monitored survival, bacterial load in organs, and immunological correlates. Our vaccine strategy consisted of two subcutaneous immunizations, followed by challenge with aerosolized virulent nonencapsulated Y. pestis. Mice were immunized with a combination of live Y. pestis pgm- pPst-Δcaf1, live Y. pestis pgm- pPst-Δcaf1/ΔyopD, or recombinant F1-V (rF1-V) combined with adjuvants. Results: The most effective vaccine regimen was initial priming with rF1-V, followed by boost with either of the live attenuated strains. However, this and other strategies were more protective in female mice. Males had higher bacterial burden and differing patterns of cytokine expression and serum antibody titers. Male mice did not demonstrate synergy between vaccination and antibiotic treatment as repeatedly observed in female mice. Conclusions: This study provides new knowledge about heterologous vaccine strategies, sex differences in plague-vaccine efficacy, and the immunological factors that differ between male and female mice.
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Camundongos Endogâmicos BALB C , Vacina contra a Peste , Peste , Yersinia pestis , Animais , Feminino , Peste/prevenção & controle , Peste/imunologia , Masculino , Yersinia pestis/imunologia , Vacina contra a Peste/imunologia , Vacina contra a Peste/administração & dosagem , Camundongos , Anticorpos Antibacterianos/sangue , Caracteres Sexuais , Fatores Sexuais , Modelos Animais de Doenças , Eficácia de VacinasRESUMO
The intestine constantly encounters and adapts to the external environment shaped by diverse dietary nutrients. However, whether and how gut adaptability to dietary challenges is compromised in ulcerative colitis is incompletely understood. Here, we show that a transient high-fat diet exacerbates colitis owing to inflammation-compromised bile acid tolerance. Mechanistically, excessive tumor necrosis factor (TNF) produced at the onset of colitis interferes with bile-acid detoxification through the receptor-interacting serine/threonine-protein kinase 1/extracellular signal-regulated kinase pathway in intestinal epithelial cells, leading to bile acid overload in the endoplasmic reticulum and consequent apoptosis. In line with the synergy of bile acids and TNF in promoting gut epithelial damage, high intestinal bile acids correlate with poor infliximab response, and bile acid clearance improves infliximab efficacy in experimental colitis. This study identifies bile acids as an "opportunistic pathogenic factor" in the gut that would represent a promising target and stratification criterion for ulcerative colitis prevention/therapy.
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The correlation between liver disease and the progression of ulcerative colitis (UC) has remained elusive. In this study, it demonstrates that liver injury is intricately linked to the heightened severity of UC in patients, and causes more profound intestinal damage during DSS-induced colitis in mice. Metabolomics analysis of plasma from liver cirrhosis patients shows liver injury compromising nicotinamide supply for NAD+ biosynthesis in the intestine. Subsequent investigation identifies intestinal group 2 innate lymphoid cells (ILC2s) are responsible for liver injury-exacerbated colitis. Reconstitution of ILC2s or the restoration of NAD+ metabolism proves effective in relieving liver injury-aggravated experimental colitis. Mechanistically, the NAD+ salvage pathway regulates gut ILC2s in a cell-intrinsic manner by supporting the generation of succinate, which fuels the electron transport chain to sustaining ILC2s function. This research deepens the understanding of cellular and molecular mechanisms in liver disease-UC interplay, identifying a metabolic target for innovative treatments in liver injury-complicated colitis.
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Anaplasma and Ehrlichia are tick-borne bacterial pathogens that cause anaplasmoses and ehrlichioses in humans and animals. In this study, we examined the prevalence of Anaplasma and Ehrlichia species in ticks and domesticated animals in Suizhou County, Hubei Province in the central China. We used PCR amplification and DNA sequencing of the 16S rRNA, groEL, and gltA genes to analyze. We collected 1900 ticks, including 1981 Haemaphysalis longicornis and 9 Rhipicephalus microplus, 159 blood samples of goats (n = 152), cattle (n = 4), and dogs (n = 3) from May to August of 2023. PCR products demonstrated that Anaplasma bovis, Anaplasma capra, and an Ehrlichia species were detected in the H. longicornis with the minimum infection rates (MIR) of 1.11%, 1.32%, and 0.05%, respectively; A. bovis, A. capra, and unnamed Anaplasma sp. were detected in goats with an infection rate of 26.31%, 1.31% and 1.97%, respectively. Anaplasma and Ehrlichia species were not detected from cattle, dogs and R. microplus ticks. The genetic differences in the groEL gene sequences of the Anaplasma in the current study were large, whereas the 16S rRNA and gltA gene sequences were less disparate. This study shows that ticks and goats in Suizhou County, Hubei Province carry multiple Anaplasma species and an Ehrlichia species, with relatively higher infection rate of A. bovis in goats. Our study indicates that multiple Anaplasma and Ehrlichia species exist in ticks and goats in the central China with potential to cause human infection.