RESUMO
Interferon-α (IFNα) signaling is essential for antiviral response via induction of IFN-stimulated genes (ISGs). Through a non-biased high-throughput RNAi screening of 711 known epigenetic modifiers in cellular models of IFNα-mediated inhibition of HBV replication, we identified methyltransferase SETD2 as a critical amplifier of IFNα-mediated antiviral immunity. Conditional knockout mice with hepatocyte-specific deletion of Setd2 exhibit enhanced HBV infection. Mechanistically, SETD2 directly mediates STAT1 methylation on lysine 525 via its methyltransferase activity, which reinforces IFN-activated STAT1 phosphorylation and antiviral cellular response. In addition, SETD2 selectively catalyzes the tri-methylation of H3K36 on promoters of some ISGs such as ISG15, leading to gene activation. Our study identifies STAT1 methylation on K525 catalyzed by the methyltransferase SETD2 as an essential signaling event for IFNα-dependent antiviral immunity and indicates potential of SETD2 in controlling viral infections.
Assuntos
Vírus da Hepatite B/fisiologia , Hepatite B Crônica/imunologia , Histona-Lisina N-Metiltransferase/metabolismo , Interferon-alfa/imunologia , Fator de Transcrição STAT1/genética , Animais , Linhagem Celular , Linhagem Celular Tumoral , Epigênese Genética , Hepatite B Crônica/virologia , Hepatócitos/metabolismo , Histonas/metabolismo , Humanos , Camundongos , Fosforilação , Domínios Proteicos , Interferência de RNA , Transcrição Gênica , Replicação ViralRESUMO
CCR7 chemokine receptor stimulation induces rapid but transient dendritic cell (DC) migration toward draining lymph nodes, which is critical for the initiation of protective immunity and maintenance of immune homeostasis. The mechanisms for terminating CCR7-mediated DC migration remain incompletely understood. Here we have identified a long non-coding RNA lnc-Dpf3 whose feedback restrained CCR7-mediated DC migration. CCR7 stimulation upregulated lnc-Dpf3 via removing N6-methyladenosine (m6A) modification to prevent RNA degradation. DC-specific lnc-Dpf3 deficiency increased CCR7-mediated DC migration, leading to exaggerated adaptive immune responses and inflammatory injuries. Mechanistically, CCR7 stimulation activated the HIF-1α transcription factor pathway in DCs, leading to metabolic reprogramming toward glycolysis for DC migration. lnc-Dpf3 directly bound to HIF-1α and suppressed HIF-1α-dependent transcription of the glycolytic gene Ldha, thus inhibiting DC glycolytic metabolism and migratory capacity. We demonstrate a critical role for CCR7-inducible lnc-Dpf3 in coupling epigenetic and metabolic pathways to feedback-control DC migration and inflammatory responses.
Assuntos
Movimento Celular/genética , Proteínas de Ligação a DNA/genética , Glicólise/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Receptores CCR7/genética , Fatores de Transcrição/genética , Imunidade Adaptativa/genética , Animais , Linhagem Celular , Células Dendríticas/patologia , Epigênese Genética/genética , Regulação da Expressão Gênica/genética , Células HEK293 , Humanos , Inflamação/genética , Inflamação/patologia , Linfonodos/patologia , Redes e Vias Metabólicas/genética , Camundongos , Camundongos Endogâmicos C57BL , Transcrição Gênica/genética , Regulação para Cima/genéticaRESUMO
Tissue-resident mast cells are associated with many inflammatory and physiological processes. Although mast cells arise from the yolk sac, the exact ontogeny of adult mast cells remains unclear. Here we have investigated the hematopoietic origin of mast cells using fate-mapping systems. We have shown that early erythro-myeloid progenitors (EMPs), late EMPs, and definitive hematopoietic stem cells (HSCs) each gave rise to mast cells in succession via an intermediate integrin ß7+ progenitor. From late embryogenesis to adult, early EMP-derived mast cells were largely replaced by late EMP-derived cells in most connective tissues except adipose and pleural cavity. Thus, mast cells with distinct origin displayed tissue-location preferences: early EMP-derived cells were limited to adipose and pleural cavity and late EMP-derived cells dominated most connective tissues, while HSC-derived cells were a main group in mucosa. Therefore, embryonic origin shapes the heterogeneity of adult mast cells, with diverse functions in immunity and development.
Assuntos
Células Eritroides/imunologia , Mastócitos/imunologia , Células Progenitoras Mieloides/imunologia , Animais , Linhagem da Célula/imunologia , Células Cultivadas , Tecido Conjuntivo/imunologia , Tecido Conjuntivo/metabolismo , Embrião de Mamíferos/citologia , Embrião de Mamíferos/embriologia , Embrião de Mamíferos/imunologia , Células Eritroides/citologia , Células Eritroides/metabolismo , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/imunologia , Células-Tronco Hematopoéticas/metabolismo , Cadeias beta de Integrinas/imunologia , Cadeias beta de Integrinas/metabolismo , Mastócitos/citologia , Mastócitos/metabolismo , Camundongos Transgênicos , Células Progenitoras Mieloides/citologia , Células Progenitoras Mieloides/metabolismoRESUMO
Excessive activation of dendritic cells (DCs) leads to the development of autoimmune and inflammatory diseases, which has prompted a search for regulators of DC activation. Here we report that Rhbdd3, a member of the rhomboid family of proteases, suppressed the activation of DCs and production of interleukin 6 (IL-6) triggered by Toll-like receptors (TLRs). Rhbdd3-deficient mice spontaneously developed autoimmune diseases characterized by an increased abundance of the TH17 subset of helper T cells and decreased number of regulatory T cells due to the increase in IL-6 from DCs. Rhbdd3 directly bound to Lys27 (K27)-linked polyubiquitin chains on Lys302 of the modulator NEMO (IKKγ) via the ubiquitin-binding-association (UBA) domain in endosomes. Rhbdd3 further recruited the deubiquitinase A20 via K27-linked polyubiquitin chains on Lys268 to inhibit K63-linked polyubiquitination of NEMO and thus suppressed activation of the transcription factor NF-κB in DCs. Our data identify Rhbdd3 as a critical regulator of DC activation and indicate K27-linked polyubiquitination is a potent ubiquitin-linked pattern involved in the control of autoimmunity.
Assuntos
Proteínas Reguladoras de Apoptose/fisiologia , Autoimunidade , Células Dendríticas/imunologia , Interleucina-6/biossíntese , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Ubiquitinação , Animais , Interleucina-6/antagonistas & inibidores , Lisina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/fisiologia , Estrutura Terciária de Proteína , Linfócitos T/imunologia , Receptores Toll-Like/fisiologiaRESUMO
Gene-encoded aldehyde tag technology has been widely utilized in protein bioorthogonal chemistry and biotechnological application. Herein, we report utilization of the promiscuous rSAM cyclophane synthase SjiB involved in triceptide biosynthesis as a dedicated and highly efficient formylglycine synthase. The new aldehyde tag sequence in this system, YQSSI, is biosynthetically orthogonal to the known aldehyde tag (C/S)x(P/A)xR. The potential use of SjiB/YQSSI aldehyde tag system was further validated in fluorescent labelling of model proteins.
Assuntos
Aldeídos , Ciclofanos , ProteínasRESUMO
Metabolic reprogramming plays a pivotal role in the differentiation and function of immune cells including dendritic cells (DCs). Regulatory DCs can be generated in regional tissue niches like splenic stroma and act as an important part of stromal control of immune response for the maintenance of immune tolerance. However, the metabolic alterations during splenic stroma-driven regulatory DCs differentiation and the metabolic enzyme involved in regulatory DCs function remain poorly understood. By combining metabolomic, transcriptomic, and functional investigations of mature DCs (maDCs) and diffDCs (regulatory DCs differentiated from activated mature DCs through coculturing with splenic stroma), here we identified succinate-CoA ligase subunit beta Suclg2 as a key metabolic enzyme that reprograms the proinflammatory status of mature DCs into a tolerogenic phenotype via preventing NF-κB signaling activation. diffDCs downregulate succinic acid levels and increase the Suclg2 expression along with their differentiation from mature DCs. Suclg2-interference impaired the tolerogenic function of diffDCs in inducing T cell apoptosis and enhanced activation of NF-κB signaling and expression of inflammatory genes CD40, Ccl5, and Il12b in diffDCs. Furthermore, we identified Lactb as a new positive regulator of NF-κB signaling in diffDCs whose succinylation at the lysine 288 residue was inhibited by Suclg2. Our study reveals that the metabolic enzyme Suclg2 is required to maintain the immunoregulatory function of diffDCs, adding mechanistic insights into the metabolic regulation of DC-based immunity and tolerance.
Assuntos
Células Dendríticas , NF-kappa B , Diferenciação Celular , Células Dendríticas/imunologia , Regulação da Expressão Gênica , Tolerância Imunológica , NF-kappa B/metabolismo , Transdução de Sinais , Succinato-CoA Ligases/imunologia , beta-Lactamases/imunologiaRESUMO
BACKGROUND: There is currently a lack of effective treatments for non-small cell lung cancer (NSCLC) patients harboring HER2 mutations. We examined the efficacy and safety of, and potential resistance mechanism to, pyrotinib, a pan-HER inhibitor, in advanced NSCLC carrying HER2 mutations. METHODS: In this multicenter, single-arm, phase II trial, stage IIIB-IV NSCLC patients harboring HER2 mutations, as determined using next-generation sequencing, were enrolled and treated with pyrotinib at a dose of 400 mg/day. The primary endpoint was 6-month progression-free survival (PFS) rate, and secondary endpoints were objective response rate (ORR), PFS, overall survival (OS), disease control rate (DCR), and safety. The impact of different HER2 mutation types on sensitivity to pyrotinib and the potential of utilizing mutational profile derived from circulating tumor DNA (ctDNA) to predict disease progression were also explored. RESULTS: Seventy-eight patients were enrolled for efficacy and safety analysis. The 6-month PFS rate was 49.5% (95% confidence interval [CI], 39.2-60.8). Pyrotinib produced an ORR of 19.2% (95% CI, 11.2-30.0), with median PFS of 5.6 months (95% CI, 2.8-8.4), and median OS of 10.5 months (95% CI, 8.7-12.3). The median duration of response was 9.9 months (95% CI, 6.2-13.6). All treatment-related adverse events (TRAEs) were grade 1-3 (all, 91.0%; grade 3, 20.5%), and the most common TRAE was diarrhea (all, 85.9%; grade 3, 16.7%). Patients with exon 20 and non-exon 20 HER2 mutations had ORRs of 17.7% and 25.0%, respectively. Brain metastases at baseline and prior exposure to afatinib were not associated with ORR, PFS, or OS. Loss of HER2 mutations and appearance of amplification in HER2 and EGFR were detected upon disease progression. CONCLUSIONS: Pyrotinib exhibited promising efficacy and acceptable safety in NSCLC patients carrying exon 20 and non-exon 20 HER2 mutations and is worth further investigation. TRIAL REGISTRATION: Chinese Clinical Trial Registry Identifier: ChiCTR1800020262.
Assuntos
Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Acrilamidas/efeitos adversos , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Aminoquinolinas/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Genes erbB-2/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , MutaçãoRESUMO
Histone modifications play important roles in multiple physiological processes by regulating gene expression. However, the roles of histone modifications in immunity remain poorly understood. Here we report that Ash1l, a H3K4 methyltransferase, suppressed interleukin-6 (IL-6), and tumor necrosis factor (TNF) production in Toll-like receptor (TLR)-triggered macrophages, protecting mice from sepsis. Ash1l-silenced mice were more susceptible to autoimmune disease as a result of enhanced IL-6 production. Ash1l enhanced A20 expression through induction of H3K4 modification at the Tnfaip3 promoter via H3K4 methyltransferase activity of Ash1l SET (Su[var]3-9, E[z] and trithorax) domain. Ash1l suppressed NF-κB, mitogen-activated protein kinase (MAPK) pathways, and subsequent IL-6 production via facilitating A20-mediated NF-κB signal modulator NEMO and transducer TRAF6 deubiquitination. Therefore, Ash1l-mediated H3K4 methylation at the Tnfaip3 promoter is required for controlling innate IL-6 production and suppressing inflammatory autoimmune diseases, providing mechanistic insight into epigenetic modulation of immune responses and inflammation.
Assuntos
Doenças Autoimunes/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Proteínas de Ligação a DNA/metabolismo , Interleucina-6/biossíntese , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Células Cultivadas , Cisteína Endopeptidases , Proteínas de Ligação a DNA/biossíntese , Histonas/metabolismo , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Inflamação , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Macrófagos , Camundongos , Camundongos Knockout , NF-kappa B/metabolismo , Regiões Promotoras Genéticas , Interferência de RNA , RNA Interferente Pequeno , Sepse/imunologia , Sepse/prevenção & controle , Transdução de Sinais , Fator 6 Associado a Receptor de TNF/metabolismo , Receptores Toll-Like/metabolismo , Proteína 3 Induzida por Fator de Necrose Tumoral alfa , Fatores de Necrose Tumoral/biossíntese , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/biossínteseRESUMO
Unbalanced production of proinflammatory cytokines and type I interferons in immune responses may lead to immunopathology; thus, the mechanisms that ensure the beneficial production of proinflammatory cytokines and type I interferons are of particular importance. Here we demonstrate that the phosphatase SHP-1 negatively regulated Toll-like receptor-mediated production of proinflammatory cytokines by inhibiting activation of the transcription factor NF-kappaB and mitogen-activated protein kinase. Simultaneously, SHP-1 increased the production of type I interferon mediated by Toll-like receptors and the helicase RIG-I by directly binding to and inhibiting activation of the kinase IRAK1. Our data demonstrate that SHP-1 contributes to immune homeostasis by balancing the production of proinflammatory cytokines and type I interferons in the innate immune response.
Assuntos
Interferon Tipo I/biossíntese , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Receptores Toll-Like/metabolismo , Animais , Domínio Catalítico/fisiologia , Citocinas/biossíntese , Homeostase/imunologia , Imunidade Inata , Fator Regulador 1 de Interferon/metabolismo , Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Quinases Associadas a Receptores de Interleucina-1/química , Macrófagos Peritoneais , Proteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Proteínas do Tecido Nervoso/imunologia , Ligação Proteica , Proteína Tirosina Fosfatase não Receptora Tipo 6/imunologia , Receptores de Superfície Celular , Transdução de Sinais , Receptores Toll-Like/imunologiaRESUMO
Bilberry (Vaccinium myrtillus L.) juice was fermented with Torulaspora delbrueckii (TD291 and TD70526) and Schizosaccharomyces pombe (SP3796 and SP70572) in pure fermentation as well as in sequential and simultaneous inoculations with Saccharomyces cerevisiae 1116 (SC1116). Altogether, 56 volatile compounds were identified and semi-quantified with HS-SPME-GC/MS in bilberry products. Yeast fermentation prominently enhanced the aroma complexity of bilberry with a sharp increase in alcohols, esters, aldehydes, and acetals. Compared to S. cerevisiae, T. delbrueckii produced less ethanol but more fusel alcohols that potentially enhance "alcohol" and "nail polish" odors in TD70526 and less "fruity" esters in TD291. SP70572 resulted in high productions of undesirable compounds of acetoin and acetaldehyde but a low content of higher alcohols and esters, SP3796 produced a high content of fatty acid ethyl esters and acetoin. In comparison with monoculture of non-Saccharomyces yeast, sequential and simultaneous cultures of S. pombe and S. cerevisiae significantly decreased the content of acetoin while increased the relative level of esters; sequential cultures of T. delbrueckii and S. cerevisiae remarkably increased the concentration of acetaldehyde; simultaneous inoculations of S. cerevisiae with TD70526 and TD291 significantly decreased the content of fusel alcohols and increased the content of esters, respectively. The findings suggested that non-Saccharomyces yeasts possess the potential to affect and modulate the aromatic profile of fermented bilberry products. Sequential and simultaneous inoculations with S. pombe strains and S. cerevisiae as well as simultaneous fermentation using T. delbrueckii strains and S. cerevisiae are optimal strategies to positively influence the aroma profile of bilberry wines.
Assuntos
Saccharomyces cerevisiae/metabolismo , Schizosaccharomyces/metabolismo , Torulaspora/metabolismo , Vaccinium myrtillus/metabolismo , Compostos Orgânicos Voláteis/análise , Vinho/análise , Antocianinas/metabolismo , Técnicas de Cocultura , Fermentação , Cinética , Extratos Vegetais , Vinho/microbiologiaRESUMO
This study aimed to investigate the effect of Lactobacillus plantarum strains on quality improvement of bog bilberry juice. Bog bilberry juice with different pH conditions was fermented by Lactobacillus B7 or C8-1 strain. Physicochemical index, amino acids, phenolic compounds, and volatiles of these fermented juices were compared. Results indicated that Lactobacillus plantarum strains preferred to metabolize malic acid and reducing sugar in non-pH-adjusted juice (NJ, pH 2.65), whereas quinic and citric acids were largely consumed in pH-adjusted juice (AJ, pH 3.50). Shikimic acid and aromatic amino acids were significantly accumulated in pH-adjusted juice, and phenolic compounds in both juices were significantly reduced. These strains enhanced the composition and concentration of volatiles compounds in non-pH-adjusted juice and improved the floral and fruity flavors. However, concentration and complexity of volatiles were reduced in pH-adjusted juices.
RESUMO
Rhomboid domain-containing protein 3 (Rhbdd3), which belongs to a family of proteins with rhomboid domain, is widely expressed in immune cells; however, the roles of the Rhbdd members, including Rhbdd3, in immunity remain unknown. Natural killer (NK) cells are critical for host immune defense and also can mediate inflammatory diseases such as hepatitis. Although much is known about how NK cells are activated, the detailed mechanisms for negative regulation of NK cell activation remain to be fully understood. Using Rhbdd3-deficient mice, we reveal that Rhbdd3, selectively up-regulated in NK cells upon Toll-like receptor 3 (TLR3) stimulation, negatively regulates TLR3-mediated NK cell activation in a feedback manner. Rhbdd3 inhibits TLR3-triggered IFN-γ and granzyme B expression of NK cells in cell-cell contact dependence of accessory cells such as dendritic cells and Kupffer cells. Rhbdd3 interacts with DNAX activation protein of 12 kDa and promotes its degradation, inhibiting MAPK activation in TLR3-triggered NK cells. Furthermore, Rhbdd3 plays a critical role in attenuating TLR3-triggered acute inflammation by controlling NK cell activation and accumulation in liver and disrupting NK cell-Kupffer cell interaction. Therefore, Rhbdd3 is a feedback inhibitor of TLR3-triggered NK cell activation. Our study outlines a mechanism for the negative regulation of NK cell activation and also provides clues for the function of the rhomboid proteins in immunity.
Assuntos
Proteínas Reguladoras de Apoptose/fisiologia , Regulação da Expressão Gênica , Células Matadoras Naturais/metabolismo , Ativação Linfocitária , Receptor 3 Toll-Like/metabolismo , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Comunicação Celular , Células Dendríticas/citologia , Ensaio de Imunoadsorção Enzimática , Células de Kupffer/citologia , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Poli I-C/metabolismo , Interferência de RNA , Regulação para CimaRESUMO
Phenolic compounds determine the color quality of fruit wines. In this study, the phenolic compound content and composition, color characteristics and changes during 6 months of bottle aging were studied in wines fermented with bog bilberry syrup under three different pHs. The total anthocyanins and total phenols were around 15.12-16.23 mg/L and 475.82 to 486.50 mg GAE/L in fresh wines and declined 22%-31% and about 11% in bottle aged wines, respectively. In fresh wines, eight anthocyanins, six phenolic aids and 14 flavonols, but no flavon-3-ols were identified; Malvidin-3-O-glucoside, petunidin-3-O-glucoside and delphinium-3-O-glucoside were the predominant pigments; Chlorogentic acid was the most abundant phenolic acid, and quercetin-3-O-galactoside and myricetin-3-O-galactoside accounted for nearly 90% of the total flavonols. During 6 months of bottle storage, the amounts of all the monomeric anthocyanins and phenolic acids were reduced dramatically, while the glycosidyl flavonols remained constant or were less reduced and their corresponding aglycones increased a lot. The effects of aging on blueberry wine color were described as the loss of color intensity with a dramatic change in color hue, from initial red-purple up to final red-brick nuances, while the pH of the fermentation matrix was negatively related to the color stability of aged wine.
Assuntos
Polifenóis/química , Vaccinium myrtillus/química , Vinho/análise , Antocianinas/química , Fermentação , Flavonóis/química , Concentração de Íons de Hidrogênio , Hidroxibenzoatos/química , Fenóis/química , Pigmentos Biológicos/análiseRESUMO
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with an unknown etiology. It is associated with various factors and causes great inconvenience to the patient's life. The gut-brain axis (GBA), which serves as a bidirectional information channel for exchanging information between the gut microbiota and the brain, is vital in studying many neurodegenerative diseases. Dietary flavonoids provide anti-inflammatory and antioxidant benefits, as well as regulating the structure and function of the gut microbiota. The occurrence and development of ASD are associated with dysbiosis of the gut microbiota. Modulation of gut microbiota can effectively improve the severity of ASD. This paper reviews the links between gut microbiota, flavonoids, and ASD, focusing on the mechanism of dietary flavonoids in regulating ASD through the GBA.
Assuntos
Transtorno do Espectro Autista , Eixo Encéfalo-Intestino , Flavonoides , Microbioma Gastrointestinal , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Transtorno do Espectro Autista/microbiologia , Transtorno do Espectro Autista/metabolismo , Transtorno do Espectro Autista/dietoterapia , Flavonoides/farmacologia , Dieta , Disbiose , Encéfalo/metabolismo , Animais , Antioxidantes/farmacologiaRESUMO
This study focused on isolating and characterising autochthonous lactic acid bacteria (LAB) from spontaneously fermented Chinese bayberry (CB) and their potential application in CB wine fermentation in co-inoculation with yeast starter cultures. Numerous LAB, including Lactiplantibacillus (Lp.) plantarum (9), Limosilactobacillus (Lb.) fermentum (6), Lactococcus (Lc.) lactis (3), Enterococcus (Ec.) hirae (1), Leuconostoc (Le.) mesenteroides (1), and Weissella (Ws.) cibaria (1), were isolated and identified. The isolated strains Lp. plantarum ZFM710 and ZFM715, together with Lb. fermentum ZFM720 and ZFM722, adapted well to unfavourable fermentation environment, including ethanol, osmolality, and acidity stresses, were selected for producing CB wine by co-inoculation with Saccharomyces cerevisiae. During fermentation, the presence of LAB promoted the development of S. cerevisiae, while the population dynamics of LAB in different groups at different stages showed strain-specific differences. Fermentation trials involving LAB yielded a lower ethanol concentration except for Lp. plantarum ZFM715. Compared to the pure S. cerevisiae fermented sample, the addition of LAB led to a clear modulation in organic acid composition. Lb. fermentum strains in co-fermentation led to significant decreases in each classified group of aroma compounds, while Lp. plantarum ZFM715 significantly increased the complexity and intensity of aroma compounds, as well as the intensities of fruity and floral notes. The study selects interesting strains for the design of starter cultures for use in CB wine production, underlining the interest in the selection of autochthonous LAB in fruit wines, with the aim of improving the adaptation of bacteria to specific environmental conditions and shaping the unique traits of the finished products.
Assuntos
Lactobacillales , Myrica , Vinho , Vinho/análise , Saccharomyces cerevisiae , Microbiologia de Alimentos , Etanol/análise , ChinaRESUMO
Background: Platinum-based chemotherapy combined with immune checkpoint inhibitors (ICIs) is now becoming the standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-negative advanced gastric cancer (AGC). In China, paclitaxel has shown good efficacy and tolerability in AGC as an alternative for first-line therapy. Combining ICIs with paclitaxel-based chemotherapy may lead to improved tumor immune microenvironment, but evidence in paclitaxel combing with ICIs as first-line regimen is lacking. This multicenter, retrospective research aims to compare effectiveness and tolerability of paclitaxel-based chemotherapy combined with ICIs versus chemotherapy alone as a first-line treatment of HER2-negative AGC in a real-world setting. Methods: Eighty-six patients with HER2-negative AGC were included from 2017 to 2022. Among them, 57 patients received paclitaxel-based chemotherapy plus ICIs, and 29 patients received paclitaxel-based chemotherapy alone. We compared the efficacy and incidence of adverse events between the two therapy options. Results: Significant improvements in median progression-free survival (PFS) (8.77 versus 7.47 months; P=0.04) and median overall survival (OS) (15.70 versus 14.33 months; P=0.04) were observed in the ICIs combined with paclitaxel-based chemotherapy group. The use of ICIs also significantly prolonged the duration of response (DOR) (7.47 versus 4.59 months; P=0.02). Meanwhile, the ICIs plus chemotherapy group demonstrated significantly improved objective response rate (ORR) (50.9% vs. 27.6%; P=0.03) and disease control rate (DCR) (98.3% vs. 82.8%; P=0.01), and the side effects were tolerable. Conclusions: In summary, for HER2-negative AGC, ICIs plus paclitaxel-based chemotherapy is effective with mild toxicities, which should be considered as an alternative first-line therapy regimen.
RESUMO
The effects of Saccharomyces cerevisiae and Torulaspora delbrueckii on phenolic composition and sensory quality were characterized in the production of alcoholic beverages from selected pear cultivars with diverse biochemical characteristics. The fermentation process generally affected the phenolic composition by increasing the contents of hydroxycinnamic acids and flavan-3-ols and reducing the levels of hydroxybenzoic acids, procyanidins, and flavonols. Although the phenolic compositions and sensory properties of pear beverages depended primarily on pear cultivar selection, the applied yeast strains also played important roles in beverage quality. Fermentation with T. delbrueckii resulted in higher caffeoylquinic acid and quercetin-3-O-glucoside contents, higher rated intensities of 'cooked pear' and 'floral' odors and a sweeter taste than fermentation with S. cerevisiae. Moreover, higher concentrations of hydroxybenzoic acids, hydroxycinnamic acids, and flavonols correlated closely with astringency perception. Applying T. delbrueckii strains and breeding novel pear cultivars are important approaches to produce fermented beverages of high quality.
Assuntos
Pyrus , Torulaspora , Vinho , Saccharomyces cerevisiae , Vinho/análise , Melhoramento Vegetal , Fenóis , Fermentação , HidroxibenzoatosRESUMO
CCR7-triggered DC migration toward draining lymph nodes is critical for the initiation of protective immunity and maintenance of immune tolerance. How to promote CCR7-mediated DC migration to determine T cell responses under inflammatory and homeostatic conditions remains poorly understood. Here we demonstrate that the Extl1 (Exostosin like glycosyltransferase 1) promotes CCR7-triggered DC migration in a heparan sulfate proteoglycans (HSPG)-dependent manner. Mechanistically, Extl1 mediates HSPG production via its glycosyltransferase domain to inhibit C1q expression. Extl1/HSPG axis relieves C1q-mediated restriction of CCR7 surface expression and internalization, and thus enhances CCR7-dependent migratory signaling activation. Consequently, Extl1 is required for DC-mediated Th1 and Th17 responses in immune defense against bacterial infection and for Treg cell development in the prevention of autoimmunity. Our study adds mechanistic insights to the regulation of CCR7-triggered DC migration in immunity and tolerance and provides a potential target for the treatment of infectious and autoimmune diseases.
Assuntos
Doenças Autoimunes , Células Dendríticas , Humanos , Receptores CCR7/metabolismo , Células Dendríticas/metabolismo , Autoimunidade , Complemento C1q/metabolismo , Proteoglicanas de Heparan Sulfato/metabolismo , Doenças Autoimunes/metabolismo , Movimento CelularRESUMO
Wine is a highly complex mixture of components with different chemical natures. These components largely define wine's appearance, aroma, taste, and mouthfeel properties. Among them, aroma is among the most important indicators of wine's sensory characteristics. The essence of winemaking ecosystem is the process of metabolic activities of diverse microbes including yeasts, lactic acid bacteria, and molds, which result in wines with complicated and diversified aromas. A better understanding of how these microbes affect wine's aroma is a crucial step to producing premium quality wine. This study illustrates existing knowledge on the diversity and classification of wine aroma compounds and their microbial origin. Their contributions to wine characteristics are discussed, as well. Furthermore, we review the relationship between these microbes and wine aroma characteristics. This review broadens the discussion of wine aroma compounds to include more modern microbiological concepts, and it provides relevant background and suggests new directions for future research.
Assuntos
Odorantes , Vinho , Odorantes/análise , Ecossistema , Fermentação , Vinho/análise , Leveduras/metabolismoRESUMO
A balance of inhibitory and activating signals determines the function of dendritic cells (DCs) in the immune response, which may be regulatory or stimulatory. Defects of inhibitory receptor FcγRIIb are involved in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE), in which high levels of circulating immune complexes (IC) exist. Our previous study showed that IC/Ig can suppress TLR4-triggered inflammatory responses in macrophages via FcγRIIb. This led us to question whether IC/Ig can polarize FcγRIIb-overexpressing DCs (DC-FcγRIIb) to be tolerogenic, thus attenuating lupus progression once infused in vivo. First, we found that IC/Ig markedly inhibited LPS- or CpG-induced DC maturation, enhanced tolerogenicity of DCs via FcγRIIb, and induced massive prostaglandin E2 (PGE2) secretion from DCs, both contributing to T-cell hyporesponsiveness. Endogenous Ig and lupus-derived IC also exhibited the same effect. DC-FcγRIIb, transfected with recombinant adenovirus encoding FcγRIIb, displayed enhanced tolerogenic function and produced more PGE2 in the presence of IC, thus further inhibiting T-cell responses. Importantly, in vivo infusion with DC-FcγRIIb significantly reduced kidney damage and prolonged the survival of lupus-prone MRL/lpr mice either before or after the onset of clinic lupus. Therefore, administration of DC-FcγRIIb may be a new approach to attenuate lupus progression.