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Throughout a 24-h period, the small intestine (SI) is exposed to diurnally varying food- and microbiome-derived antigenic burdens but maintains a strict immune homeostasis, which when perturbed in genetically susceptible individuals, may lead to Crohn disease. Herein, we demonstrate that dietary content and rhythmicity regulate the diurnally shifting SI epithelial cell (SIEC) transcriptional landscape through modulation of the SI microbiome. We exemplify this concept with SIEC major histocompatibility complex (MHC) class II, which is diurnally modulated by distinct mucosal-adherent SI commensals, while supporting downstream diurnal activity of intra-epithelial IL-10+ lymphocytes regulating the SI barrier function. Disruption of this diurnally regulated diet-microbiome-MHC class II-IL-10-epithelial barrier axis by circadian clock disarrangement, alterations in feeding time or content, or epithelial-specific MHC class II depletion leads to an extensive microbial product influx, driving Crohn-like enteritis. Collectively, we highlight nutritional features that modulate SI microbiome, immunity, and barrier function and identify dietary, epithelial, and immune checkpoints along this axis to be potentially exploitable in future Crohn disease interventions.
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Enfermedad de Crohn/microbiología , Células Epiteliales/metabolismo , Microbioma Gastrointestinal , Antígenos de Histocompatibilidad Clase II/metabolismo , Intestino Delgado/inmunología , Intestino Delgado/microbiología , Transcriptoma/genética , Animales , Antibacterianos/farmacología , Relojes Circadianos/fisiología , Enfermedad de Crohn/inmunología , Enfermedad de Crohn/metabolismo , Dieta , Células Epiteliales/citología , Células Epiteliales/inmunología , Citometría de Flujo , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/genética , Perfilación de la Expresión Génica , Antígenos de Histocompatibilidad Clase II/genética , Homeostasis , Hibridación Fluorescente in Situ , Interleucina-10/metabolismo , Interleucina-10/farmacología , Intestino Delgado/fisiología , Linfocitos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Periodicidad , Linfocitos T/inmunología , Transcriptoma/fisiologíaRESUMEN
Paneth cells are the primary source of C-type lysozyme, a ß-1,4-N-acetylmuramoylhydrolase that enzymatically processes bacterial cell walls. Paneth cells are normally present in human cecum and ascending colon, but are rarely found in descending colon and rectum; Paneth cell metaplasia in this region and aberrant lysozyme production are hallmarks of inflammatory bowel disease (IBD) pathology. Here, we examined the impact of aberrant lysozyme production in colonic inflammation. Targeted disruption of Paneth cell lysozyme (Lyz1) protected mice from experimental colitis. Lyz1-deficiency diminished intestinal immune responses to bacterial molecular patterns and resulted in the expansion of lysozyme-sensitive mucolytic bacteria, including Ruminococcus gnavus, a Crohn's disease-associated pathobiont. Ectopic lysozyme production in colonic epithelium suppressed lysozyme-sensitive bacteria and exacerbated colitis. Transfer of R. gnavus into Lyz1-/- hosts elicited a type 2 immune response, causing epithelial reprograming and enhanced anti-colitogenic capacity. In contrast, in lysozyme-intact hosts, processed R. gnavus drove pro-inflammatory responses. Thus, Paneth cell lysozyme balances intestinal anti- and pro-inflammatory responses, with implications for IBD.
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Clostridiales/inmunología , Colitis Ulcerosa/patología , Muramidasa/genética , Muramidasa/metabolismo , Células de Paneth/metabolismo , Animales , Clostridiales/genética , Colitis Ulcerosa/microbiología , Enfermedad de Crohn/patología , Femenino , Microbioma Gastrointestinal/genética , Células Caliciformes/citología , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Factor de Transcripción STAT6/genéticaRESUMEN
Paneth cells (PCs), a specialized secretory cell type in the small intestine, are increasingly recognized as having an essential role in host responses to microbiome and environmental stresses. Whether and how commensal and pathogenic microbes modify PC composition to modulate inflammation remain unclear. Using newly developed PC-reporter mice under conventional and gnotobiotic conditions, we determined PC transcriptomic heterogeneity in response to commensal and invasive microbes at single cell level. Infection expands the pool of CD74+ PCs, whose number correlates with auto or allogeneic inflammatory disease progressions in mice. Similar correlation was found in human inflammatory disease tissues. Infection-stimulated cytokines increase production of reactive oxygen species (ROS) and expression of a PC-specific mucosal pentraxin (Mptx2) in activated PCs. A PC-specific ablation of MyD88 reduced CD74+ PC population, thus ameliorating pathogen-induced systemic disease. A similar phenotype was also observed in mice lacking Mptx2. Thus, infection stimulates expansion of a PC subset that influences disease progression.
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Microbiota , Células de Paneth , Humanos , Animales , Ratones , Células de Paneth/metabolismo , Células de Paneth/patología , Intestino Delgado , Inflamación/patología , Citocinas/metabolismoRESUMEN
DNA methylation functions as a repressive epigenetic mark that can be reversed by the Ten-eleven translocation (TET) family of DNA dioxygenases that sequentially oxidize 5-methylcytosine into 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). Both 5fC and 5caC can be excised by DNA base-excision repair factors leading to unmodified cytosines. TET enzymes were recently implicated as potential risk factors for inflammatory bowel disease (IBD), but the contribution of TET-mediated DNA oxidation to intestinal homeostasis and response to environmental stressors are unknown. Here, we show prominent roles of TET3 in regulating mouse intestinal epithelial differentiation and response to luminal stressors. Compared with wild-type littermates, mice with intestinal epithelial cell-specific ablation of Tet3 (Tet3ΔIEC) demonstrated a decreased transcriptome involved in innate immune response, Paneth cell differentiation, and epithelial regeneration. Tet3IEC mice exhibited an elevated susceptibility to enteric pathogen infection that is correlated with a decreased epithelial 5hmC abundance. Infection of human enterocytes or mice with the pathogenic bacteria acutely increased 5hmC abundance. Genome-wide 5hmC profiling revealed a shift of genomic enrichment of 5hmC toward genes involved in activating Notch, Wnt, and autophagy pathways. Furthermore, chemical stressor dextran sulfate sodium (DSS) represses epithelial 5hmC abundance in a temporal fashion, and Tet3IEC mice exhibited increased susceptibility to DSS experimental colitis with reduced regenerative capacity. TET3 is a critical regulator of gut epithelial DNA methylome and transcriptome, especially in response to luminal stressors, for the maintenance of tissue homeostasis.
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Colitis , Dioxigenasas , Animales , Humanos , Ratones , ADN , Enterocitos , Oxidación-Reducción , Células de PanethRESUMEN
Lysozyme is a ß-1,4-glycosidase that hydrolyzes the polysaccharide backbone of bacterial cell walls. With an additional bactericidal function mediated by a separate protein domain, lysozyme is considered a uniquely important antimicrobial molecule contributing to the host's innate immune response to infection. Elevated lysozyme production is found in various inflammatory conditions while patients with genetic risks for inflammatory bowel diseases demonstrate abnormal lysozyme expression, granule packaging, and secretion in Paneth cells. However, it remains unclear how a gain- or loss-of-function in host lysozyme may impact the host inflammatory responses to pathogenic infection. We challenged Lyz1-/- and ectopic Lyz1-expressing (Villin-Lyz1TG) mice with S. Typhimurium and then comprehensively assessed the inflammatory disease progression. We conducted proteomics analysis to identify molecules derived from human lysozyme-mediated processing of live Salmonella. We examined the barrier-impairing effects of these identified molecules in human intestinal epithelial cell monolayer and enteroids. Lyz1-/- mice are protected from infection in terms of morbidity, mortality, and barrier integrity, whereas Villin-Lyz1TG mice demonstrate exacerbated infection and inflammation. The growth and invasion of Salmonella in vitro are not affected by human or chicken lysozyme, whereas lysozyme encountering of live Salmonella stimulates the release of barrier-disrupting factors, InvE-sipC and Lpp1, which directly or indirectly impair the tight junctions. The direct engagement of host intestinal lysozyme with an enteric pathogen such as Salmonella promotes the release of virulence factors that are barrier-impairing and pro-inflammatory. Controlling lysozyme function may help alleviate the inflammatory progression.
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Muramidasa , Salmonella typhimurium , Muramidasa/metabolismo , Animales , Salmonella typhimurium/metabolismo , Salmonella typhimurium/patogenicidad , Ratones , Humanos , Infecciones por Salmonella/microbiología , Infecciones por Salmonella/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Ratones Noqueados , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Proteínas de MicrofilamentosRESUMEN
BACKGROUND: Ruminococcus gnavus is a mucolytic commensal bacterium whose increased gut colonization has been associated with chronic inflammatory and metabolic diseases in humans. Whether R. gnavus metabolites can modulate host intestinal physiology remains largely understudied. METHODS: We performed untargeted metabolomic and bulk RNA sequencing analyses using R. gnavus mono-colonization in germ free mice. Based on transcriptome-metabolome correlations, we tested the impact of specific arginine metabolites on intestinal epithelial production of nitric oxide (NO) and examined the effect of NO on the growth of various strains of R. gnavus in vitro and in Nos2-deficient mice. RESULTS: R. gnavus produces specific arginine, tryptophan and tyrosine metabolites, some of which are regulated by the environmental richness of sialic acid and mucin. R. gnavus colonization promotes expression of amino acid transporters and enzymes involved in metabolic flux of arginine and associated metabolites into NO. R. gnavus induced elevated levels of Nitric Oxide Synthase 2 (NOS2) while Nos2 ablation resulted in R. gnavus expansion in vivo. The growth of various R. gnavus strains can be inhibited by NO. Specific R. gnavus metabolites modulate intestinal epithelial cell NOS2 abundance and reduce epithelial barrier function at higher concentrations. CONCLUSIONS: Intestinal colonization and interaction with R. gnavus are partially regulated by an arginine-NO metabolic pathway, whereby a balanced control by the gut epithelium may restrain R. gnavus growth in healthy individuals. Disruption in this arginine metabolic regulation will contribute to the expansion and blooming of R. gnavus.
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Although Wnt signaling is clearly important for the intestinal epithelial homeostasis, the relevance of various sources of Wnt ligands themselves remains incompletely understood. Blocking the release of Wnt in distinct stromal cell types suggests obligatory functions of several stromal cell sources and yields different observations. The physiological contribution of epithelial Wnt to tissue homeostasis remains unclear. We show here that blocking epithelial Wnts affects colonic Reg4+ epithelial cell differentiation and impairs colonic epithelial regeneration after injury in mice. Single-cell RNA analysis of intestinal stroma showed that the majority of Wnt-producing cells were contained in transgelin (Tagln+) and smooth muscle actin α2 (Acta2+) expressing populations. We genetically attenuated Wnt production from these stromal cells using Tagln-Cre and Acta2-CreER drivers, and found that blockage of Wnt release from either epithelium or Tagln+ and Acta2+ stromal cells impaired colonic epithelial healing after chemical-induced injury. Aggregated blockage of Wnt release from both epithelium and Tagln+ or Acta2+ stromal cells drastically diminished epithelial repair, increasing morbidity and mortality. These results from two uncharacterized stromal populations suggested that colonic recovery from colitis-like injury depends on multiple Wnt-producing sources.
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Actinas/metabolismo , Colitis Ulcerosa/metabolismo , Mucosa Intestinal/metabolismo , Proteínas de Microfilamentos/metabolismo , Proteínas Musculares/metabolismo , Proteína Wnt3A/metabolismo , Cicatrización de Heridas , Actinas/genética , Animales , Células Cultivadas , Colon/citología , Colon/metabolismo , Colon/fisiología , Mucosa Intestinal/citología , Ratones , Ratones Endogámicos C57BL , Proteínas de Microfilamentos/genética , Proteínas Musculares/genética , Proteínas Asociadas a Pancreatitis/genética , Proteínas Asociadas a Pancreatitis/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Células Madre/metabolismo , Proteína Wnt3A/genéticaRESUMEN
Light and temperature are 2 major environmental factors that affect the growth and development of plants during their life cycle. Plants have evolved complex mechanisms to adapt to varying external environments. Here, we show that JASMONATE ZIM-domain protein 3 (JAZ3), a jasmonic acid signaling component, acts as a factor to integrate light and temperature in regulating seedling morphogenesis. JAZ3 overexpression transgenic lines display short hypocotyls under red, far-red, and blue light and warm temperature (28â °C) conditions compared to the wild type in Arabidopsis (Arabidopsis thaliana). We show that JAZ3 interacts with the transcription factor PHYTOCHROME-INTERACTING FACTOR4 (PIF4). Interestingly, JAZ3 spontaneously undergoes liquid-liquid phase separation (LLPS) in vitro and in vivo and promotes LLPS formation of PIF4. Moreover, transcriptomic analyses indicate that JAZ3 regulates the expression of genes involved in many biological processes, such as response to auxin, auxin-activated signaling pathway, regulation of growth, and response to red light. Finally, JAZ3 inhibits the transcriptional activation activity and binding ability of PIF4. Collectively, our study reveals a function and molecular mechanism of JAZ3 in regulating plant growth in response to environmental factors such as light and temperature.
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Proteínas de Arabidopsis , Arabidopsis , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Regulación de la Expresión Génica de las Plantas , Luz , Arabidopsis/genética , Arabidopsis/crecimiento & desarrollo , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Temperatura , Plantas Modificadas Genéticamente , Oxilipinas/metabolismo , Ciclopentanos/metabolismo , Hipocótilo/crecimiento & desarrollo , Hipocótilo/genética , Hipocótilo/metabolismo , Transducción de Señal , Plantones/crecimiento & desarrollo , Plantones/genética , Plantones/metabolismo , Plantones/efectos de la radiación , Morfogénesis/efectos de la radiación , Morfogénesis/genética , VernalizaciónRESUMEN
When human cord blood-derived CD34+ cells are induced to differentiate, they undergo rapid and dynamic morphological and molecular transformations that are critical for fate commitment. In particular, the cells pass through a transitory phase known as "multilineage-primed" state. These cells are characterized by a mixed gene expression profile, different in each cell, with the coexpression of many genes characteristic for concurrent cell lineages. The aim of our study is to understand the mechanisms of the establishment and the exit from this transitory state. We investigated this issue using single-cell RNA sequencing and ATAC-seq. Two phases were detected. The first phase is a rapid and global chromatin decompaction that makes most of the gene promoters in the genome accessible for transcription. It results 24 h later in enhanced and pervasive transcription of the genome leading to the concomitant increase in the cell-to-cell variability of transcriptional profiles. The second phase is the exit from the multilineage-primed phase marked by a slow chromatin closure and a subsequent overall down-regulation of gene transcription. This process is selective and results in the emergence of coherent expression profiles corresponding to distinct cell subpopulations. The typical time scale of these events spans 48 to 72 h. These observations suggest that the nonspecificity of genome decompaction is the condition for the generation of a highly variable multilineage expression profile. The nonspecific phase is followed by specific regulatory actions that stabilize and maintain the activity of key genes, while the rest of the genome becomes repressed again by the chromatin recompaction. Thus, the initiation of differentiation is reminiscent of a constrained optimization process that associates the spontaneous generation of gene expression diversity to subsequent regulatory actions that maintain the activity of some genes, while the rest of the genome sinks back to the repressive closed chromatin state.
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Cromatina , Genoma , Humanos , Cromatina/genética , Linaje de la Célula/genética , Diferenciación Celular/genética , Expresión GénicaRESUMEN
RAB11 small GTPases and associated recycling endosome have been localized to mitotic spindles and implicated in regulating mitosis. However, the physiological significance of such regulation has not been observed in mammalian tissues. We have used newly engineered mouse models to investigate intestinal epithelial renewal in the absence of single or double isoforms of RAB11 family members: Rab11a and Rab11b. Comparing with single knockouts, mice with compound ablation demonstrate a defective cell cycle entry and robust mitotic arrest followed by apoptosis, leading to a total penetrance of lethality within 3 days of gene ablation. Upon Rab11 deletion ex vivo, enteroids show abnormal mitotic spindle formation and cell death. Untargeted proteomic profiling of Rab11a and Rab11b immunoprecipitates has uncovered a shared interactome containing mitotic spindle microtubule regulators. Disrupting Rab11 alters kinesin motor KIF11 function and impairs bipolar spindle formation and cell division. These data demonstrate that RAB11A and RAB11B redundantly control mitotic spindle function and intestinal progenitor cell division, a mechanism that may be utilized to govern the homeostasis and renewal of other mammalian tissues.
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Proteómica , Proteínas de Unión al GTP rab , Animales , Ratones , Mamíferos/metabolismo , Mitosis , Proteínas de Unión al GTP rab/metabolismo , Huso Acromático/metabolismo , Células Madre/metabolismoRESUMEN
The increasing prevalence of multidrug-resistant bacterial infections necessitates the exploration of novel paradigms for anti-infective therapy. Antimicrobial peptides (AMPs), also known as host defense peptides (HDPs), have garnered extensive recognition as immunomodulatory molecules that leverage natural host mechanisms to enhance therapeutic benefits. The unique immune mechanism exhibited by certain HDPs that involves self-assembly into supramolecular nanonets capable of inducing bacterial agglutination and entrapping is significantly important. This process effectively prevents microbial invasion and subsequent dissemination and significantly mitigates selective pressure for the evolution of microbial resistance, highlighting the potential of HDP-based antimicrobial therapy. Recent advancements in this field have focused on developing bio-responsive materials in the form of supramolecular nanonets. A comprehensive overview of the immunomodulatory and bacteria-agglutinating activities of HDPs, along with a discussion on optimization strategies for synthetic derivatives, is presented in this article. These optimized derivatives exhibit improved biological properties and therapeutic potential, making them suitable for future clinical applications as effective anti-infective therapeutics.
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Antiinfecciosos , Infecciones Bacterianas , Humanos , Péptidos Catiónicos Antimicrobianos/farmacología , Péptidos Catiónicos Antimicrobianos/uso terapéutico , Antiinfecciosos/farmacología , Antiinfecciosos/uso terapéutico , Bacterias , Infecciones Bacterianas/tratamiento farmacológico , Farmacorresistencia Bacteriana MúltipleRESUMEN
Dual-ion batteries (DIBs) are becoming an important technology for energy storage. To overcome the disadvantages of traditional electrodes and electrolytes, here we assemble a dual-carbon DIB with nanodiamond (ND)-modified crimped graphene (DCG) and electrolyte. The DCG anode and cathode realize high capacities of 1121 mA h g-1 and 149 mA h g-1, respectively, at 0.1 A g-1. The corresponding DCG//DCG full cells present a high capacity of 143 mA h g-1 at 1 A g-1 after 3300 cycles, which is superior to most reported results. Achieving these record performances is strongly dependent on the formed DCG electrodes with expanded interlayer spacing and abundant active sites, and NDs dispersed in DCG and electrolytes are very helpful for enhancing the storage of both cations and anions, effectively suppressing the irreversible decomposition of electrolytes. This work breaks through the bottleneck of graphitic-based DIBs, paving the way for realizing high-performance DIBs applied in industry.
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Antiferromagnets (AFMs) are ideal materials to boost neuromorphic computing toward the ultrahigh speed and ultracompact integration regime. However, developing a suitable AFM neuromorphic memory remains an aspirational but challenging goal. In this work, we construct such a memory based on the CoO/Pt heterostructure, in which the collinear insulating AFM CoO shows a strong perpendicular anisotropy facilitating its electrical readout and writing. Utilizing the unique nonlinear response and bipolar fading memory properties of the device, we demonstrate a multidimensional reservoir computing beyond the traditional binary paradigm. These results are expected to pave the way toward next-generation fast and massive neuromorphic computing.
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The molecular links between tissue-level morphogenesis and the differentiation of cell lineages in the pancreas remain elusive despite a decade of studies. We previously showed that in pancreas both processes depend on proper lumenogenesis. The Rab GTPase Rab11 is essential for epithelial lumen formation in vitro, however few studies have addressed its functions in vivo and none have tested its requirement in pancreas. Here, we show that Rab11 is critical for proper pancreas development. Co-deletion of the Rab11 isoforms Rab11A and Rab11B in the developing pancreatic epithelium (Rab11pancDKO) results in â¼50% neonatal lethality and surviving adult Rab11pancDKO mice exhibit defective endocrine function. Loss of both Rab11A and Rab11B in the embryonic pancreas results in morphogenetic defects of the epithelium, including defective lumen formation and lumen interconnection. In contrast to wildtype cells, Rab11pancDKO cells initiate the formation of multiple ectopic lumens, resulting in a failure to coordinate a single apical membrane initiation site (AMIS) between groups of cells. This results in an inability to form ducts with continuous lumens. Here, we show that these defects are due to failures in vesicle trafficking, as apical and junctional components remain trapped within Rab11pancDKO cells. Together, these observations suggest that Rab11 directly regulates epithelial lumen formation and morphogenesis. Our report links intracellular trafficking to organ morphogenesis in vivo and presents a novel framework for decoding pancreatic development.
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Páncreas , Proteínas de Unión al GTP rab , Ratones , Animales , Epitelio/metabolismo , Membrana Celular/metabolismo , Isoformas de Proteínas/metabolismo , Páncreas/metabolismo , Morfogénesis , Proteínas de Unión al GTP rab/genética , Proteínas de Unión al GTP rab/metabolismoRESUMEN
Human enterocytes are primary targets of infection by invasive bacterium Salmonella Typhimurium, and studies using nonintestinal epithelial cells established that S. Typhimurium activates Rho family GTPases, primarily CDC42, to modulate the actin cytoskeletal network for invasion. The host intracellular protein network that engages CDC42 and influences the pathogen's invasive capacity are relatively unclear. Here, proteomic analyses of canonical and variant CDC42 interactomes identified a poorly characterized CDC42 interacting protein, CDC42EP1, whose intracellular localization is rapidly redistributed and aggregated around the invading bacteria. CDC42EP1 associates with SEPTIN-7 and Villin, and its relocalization and bacterial engagement depend on host CDC42 and S. Typhimurium's capability of activating CDC42. Unlike CDC42, CDC42EP1 is not required for S. Typhimurium's initial cellular entry but is found to associate with Salmonella-containing vacuoles after long-term infections, indicating a contribution to the pathogen's intracellular growth and replication. These results uncover a new host regulator of enteric Salmonella infections, which may be targeted to restrict bacterial load at the primary site of infection to prevent systemic spread.
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Proteínas del Citoesqueleto , Salmonella typhimurium , Proteínas de Unión al GTP rho , Humanos , Actinas/metabolismo , Proteína de Unión al GTP cdc42/genética , Proteína de Unión al GTP cdc42/metabolismo , Citoesqueleto/metabolismo , Proteínas de Unión al GTP rho/genética , Proteínas de Unión al GTP rho/metabolismo , Salmonella typhimurium/patogenicidad , Proteínas del Citoesqueleto/genética , Proteínas del Citoesqueleto/metabolismoRESUMEN
Modulating the electronic structure of metal nanoparticles via metal-support interaction has attracted intense interest in the field of catalytic science. However, the roles of supporting substrates in regulating the catalytic properties of electrochemiluminescence (ECL) remain elusive. Here, we find that the use of graphdiyne (GDY) as the substrate for electroless deposition of Pd nanoparticles (Pd/GDY) produces the most pronounced anodic signal enhancement in luminol-dissolved oxygen (O2) ECL system as co-reactant accelerator over other carbon-based Pd composite nanomaterials. Pd/GDY exhibits electrocatalytic activity for the reduction of O2 through a four-electron pathway at approximately -0.059 V (vs Ag/AgCl) in neutral solution forming reactive oxygen species (ROS) as intermediates. The study shows that the interaction of Pd and GDY increases the amount and stability of ROS on the Pd/GDY electrode surface and promotes the reaction of ROS and luminol anion radical to generate excited luminol, which significantly boosts the luminol anodic ECL emission. Based on quenching of luminol ECL through the consumption of ROS by antioxidants, we develop a platform for the detection of intracellular antioxidants. This study provides an avenue for the development of efficient luminol ECL systems in neutral media and expands the biological application of ECL systems.
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Intestinal microbiota confers susceptibility to diet-induced obesity, yet many probiotic species that synthesize tryptophan (trp) actually attenuate this effect, although the underlying mechanisms are unclear. We monocolonized germ-free mice with a widely consumed probiotic Lacticaseibacillus rhamnosus GG (LGG) under trp-free or -sufficient dietary conditions. We obtained untargeted metabolomics from the mouse feces and serum using liquid chromatography-mass spectrometry and obtained intestinal transcriptomic profiles via bulk-RNA sequencing. When comparing LGG-monocolonized mice with germ-free mice, we found a synergy between LGG and dietary trp in markedly promoting the transcriptome of fatty acid metabolism and ß-oxidation. Upregulation was specific and was not observed in transcriptomes of trp-fed conventional mice and mice monocolonized with Ruminococcus gnavus. Metabolomics showed that fecal and serum metabolites were also modified by LGG-host-trp interaction. We developed an R-Script-based MEtabolome-TRanscriptome Correlation Analysis algorithm and uncovered LGG- and trp-dependent metabolites that were positively or negatively correlated with fatty acid metabolism and ß-oxidation gene networks. This high-throughput metabolome-transcriptome correlation strategy can be used in similar investigations to reveal potential interactions between specific metabolites and functional or disease-related transcriptomic networks.
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Microbioma Gastrointestinal , Lacticaseibacillus rhamnosus , Ratones , Animales , Intestinos , Microbioma Gastrointestinal/genética , Perfilación de la Expresión Génica , Ácidos GrasosRESUMEN
Smad4, a critical mediator of TGF-ß signaling, plays a pivotal role in regulating various cellular functions, including immune responses. In this study, we investigated the impact of Smad4 knockout specifically in macrophages on anti-tumor immunity, focusing on lung metastasis of B16 melanoma cells. Using a mouse model with Smad4 knockout in macrophages established via Lyz2-cre mice and Smad4 flox/flox mice, we demonstrated a significant inhibition of B16 metastasis in the lungs. Interestingly, the inhibition of tumor growth was found to be independent of adaptive immunity, as no significant changes were observed in the numbers or activities of T cells, B cells, or NK cells. Instead, Smad4 knockout led to the emergence of an MCHIIlow CD206high subset of lung interstitial macrophages, characterized by enhanced phagocytosis function. Our findings highlight the crucial role of Smad4 in modulating the innate immune response against tumors and provide insights into potential therapeutic strategies targeting lung interstitial macrophages to enhance anti-tumor immunity.
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Neoplasias Pulmonares , Melanoma Experimental , Fagocitosis , Proteína Smad4 , Animales , Ratones , Línea Celular Tumoral , Pulmón/patología , Pulmón/inmunología , Pulmón/metabolismo , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/inmunología , Macrófagos Alveolares/patología , Melanoma Experimental/patología , Melanoma Experimental/inmunología , Ratones Endogámicos C57BL , Ratones Noqueados , Fagocitosis/genética , Proteína Smad4/deficiencia , Proteína Smad4/genética , Proteína Smad4/metabolismoRESUMEN
Designing materials with low exciton binding energy is an efficient way of improving the hydrogen production performance of COFsï¼Covalent Organic Frameworks. Here, it is demonstrated that the strategy of decorating bromine atoms on Pyene-based COFs can achieve elevated photocatalytic H2 evolution rates (HER = 13.61 mmol g-1h-1). Low-temperature fluorescence and time-resolved fluorescence spectroscopy (TRPL) indicate that the introduction of bromine atoms can significantly suppress charge recombination. DFT (Density Functional Theory) calculation clarified that the C atoms adjacent to Br are the active sites with a reduced energy barrier in the process of formatting H intermediate species (H*). The modification strategy of Br atoms in COF furnishes a new medium for exploiting exquisite photocatalysts.
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Nowadays, oral medications are the primary method of treating disease due to their convenience, low cost, and safety, without the need for complex medical procedures. To maximize treatment effectiveness, almost all oral medications utilize drug carriers, such as capsules, liposomes, and sugar coatings. However, these carriers rely on dissolution or fragmentation to achieve drug release, which leads to drugs and carriers coabsorption in the body, causing unnecessary adverse drug reactions, such as nausea, vomiting, abdominal pain, and even death caused by allergy. Therefore, the ideal oral drug carrier should avoid degradation and absorption and be totally excreted after drug release at the desired location. Herein, a gastrointestinally stable oral drug carrier based on porous aromatic framework-1 (PAF-1) is constructed, and it is modified with famotidine (a well-known gastric drug) and mesalazine (a well-known ulcerative colitis drug) to verify the excellent potential of PAF-1. The results demonstrate that PAF-1 can accurately release famotidine in stomach, mesalazine in the intestine, and finally be completely excreted from the body without any residue after 12 h. The use of PAF materials for the construction of oral drug carriers with no residue in the gastrointestinal tract provides a new approach for efficient disease treatment.