Aging is the major risk factor for many human diseases. In vitro studies have demonstrated that cellular reprogramming to pluripotency reverses cellular age, but alteration of the aging process ...through reprogramming has not been directly demonstrated in vivo. Here, we report that partial reprogramming by short-term cyclic expression of Oct4, Sox2, Klf4, and c-Myc (OSKM) ameliorates cellular and physiological hallmarks of aging and prolongs lifespan in a mouse model of premature aging. Similarly, expression of OSKM in vivo improves recovery from metabolic disease and muscle injury in older wild-type mice. The amelioration of age-associated phenotypes by epigenetic remodeling during cellular reprogramming highlights the role of epigenetic dysregulation as a driver of mammalian aging. Establishing in vivo platforms to modulate age-associated epigenetic marks may provide further insights into the biology of aging.
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•Partial reprogramming erases cellular markers of aging in mouse and human cells•Induction of OSKM in progeria mice ameliorates signs of aging and extends lifespan•In vivo reprogramming improves regeneration in 12-month-old wild-type mice
Cellular reprogramming by transient expression of Yamanaka factors ameliorates age-associated symptoms, prolongs lifespan in progeroid mice, and improves tissue homeostasis in older mice.
Effects of gut microbiota on systemic immunity
Abstract
The mammalian intestine is colonized by trillions of microorganisms that have co-evolved with the host in a symbiotic relationship. Although ...the influence of the gut microbiota on intestinal physiology and immunity is well known, mounting evidence suggests a key role for intestinal symbionts in controlling immune cell responses and development outside the gut. Although the underlying mechanisms by which the gut symbionts influence systemic immune responses remain poorly understood, there is evidence for both direct and indirect effects. In addition, the gut microbiota can contribute to immune responses associated with diseases outside the intestine. Understanding the complex interactions between the gut microbiota and the host is thus of fundamental importance to understand both immunity and human health.
Despite the accepted health benefits of consuming dietary fiber, little is known about the mechanisms by which fiber deprivation impacts the gut microbiota and alters disease risk. Using a ...gnotobiotic mouse model, in which animals were colonized with a synthetic human gut microbiota composed of fully sequenced commensal bacteria, we elucidated the functional interactions between dietary fiber, the gut microbiota, and the colonic mucus barrier, which serves as a primary defense against enteric pathogens. We show that during chronic or intermittent dietary fiber deficiency, the gut microbiota resorts to host-secreted mucus glycoproteins as a nutrient source, leading to erosion of the colonic mucus barrier. Dietary fiber deprivation, together with a fiber-deprived, mucus-eroding microbiota, promotes greater epithelial access and lethal colitis by the mucosal pathogen, Citrobacter rodentium. Our work reveals intricate pathways linking diet, the gut microbiome, and intestinal barrier dysfunction, which could be exploited to improve health using dietary therapeutics.
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•Characterized synthetic bacterial communities enable functional insights in vivo•Low-fiber diet promotes expansion and activity of colonic mucus-degrading bacteria•Purified prebiotic fibers do not alleviate degradation of the mucus layer•Fiber-deprived gut microbiota promotes aggressive colitis by an enteric pathogen
Regular consumption of dietary fiber helps prevent erosion of the intestinal mucus barrier by the gut microbiome, blunting pathogen infection and reducing the incidence of colitis.
Necroptosis is a physiological cell suicide mechanism initiated by receptor-interacting protein kinase-3 (RIPK3) phosphorylation of mixed-lineage kinase domain-like protein (MLKL), which results in ...disruption of the plasma membrane. Necroptotic cell lysis, and resultant release of proinflammatory mediators, is thought to cause inflammation in necroptotic disease models. However, we previously showed that MLKL signaling can also promote inflammation by activating the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome to recruit the adaptor protein apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) and trigger caspase-1 processing of the proinflammatory cytokine IL-1β. Here, we provide evidence that MLKL-induced activation of NLRP3 requires (i) the death effector four-helical bundle of MLKL, (ii) oligomerization and association of MLKL with cellular membranes, and (iii) a reduction in intracellular potassium concentration. Although genetic or pharmacological targeting of NLRP3 or caspase-1 prevented MLKL-induced IL-1β secretion, they did not prevent necroptotic cell death. Gasdermin D (GSDMD), the pore-forming caspase-1 substrate required for efficient NLRP3-triggered pyroptosis and IL-1β release, was not essential for MLKL-dependent death or IL-1β secretion. Imaging of MLKL-dependent ASC speck formation demonstrated that necroptotic stimuli activate NLRP3 cell-intrinsically, indicating that MLKL-induced NLRP3 inflammasome formation and IL-1β cleavage occur before cell lysis. Furthermore, we show that necroptotic activation of NLRP3, but not necroptotic cell death alone, is necessary for the activation of NF-κB in healthy bystander cells. Collectively, these results demonstrate the potential importance of NLRP3 inflammasome activity as a driving force for inflammation in MLKL-dependent diseases.
Intestinal Th17 cells are induced and accumulate in response to colonization with a subgroup of intestinal microbes such as segmented filamentous bacteria (SFB) and certain extracellular pathogens. ...Here, we show that adhesion of microbes to intestinal epithelial cells (ECs) is a critical cue for Th17 induction. Upon monocolonization of germ-free mice or rats with SFB indigenous to mice (M-SFB) or rats (R-SFB), M-SFB and R-SFB showed host-specific adhesion to small intestinal ECs, accompanied by host-specific induction of Th17 cells. Citrobacter rodentium and Escherichia coli O157 triggered similar Th17 responses, whereas adhesion-defective mutants of these microbes failed to do so. Moreover, a mixture of 20 bacterial strains, which were selected and isolated from fecal samples of a patient with ulcerative colitis on the basis of their ability to cause a robust induction of Th17 cells in the mouse colon, also exhibited EC-adhesive characteristics.
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•A strong correlation between epithelial adhesion and Th17 induction by SFB and EHEC•Twenty Th17-inducing strains isolated from human feces show epithelial-adhesive property•Bacterial adhesion elicits a Th17-inducing gene-expression program in epithelium
The adhesion of specific members of the gut microbiome to intestinal epithelial cells is found to be essential for the induction of Th17 cells, thus highlighting location as an additional layer of regulation for the adaptive immune system.
The NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome is a cytoplasmic supramolecular complex that is activated in response to cellular perturbations triggered by infection and ...sterile injury. Assembly of the NLRP3 inflammasome leads to activation of caspase-1, which induces the maturation and release of interleukin-1β (IL-1β) and IL-18, as well as cleavage of gasdermin D (GSDMD), which promotes a lytic form of cell death. Production of IL-1β via NLRP3 can contribute to the pathogenesis of inflammatory disease, whereas aberrant IL-1β secretion through inherited NLRP3 mutations causes autoinflammatory disorders. In this review, we discuss recent developments in the structure of the NLRP3 inflammasome, and the cellular processes and signaling events controlling its assembly and activation.
The NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, a critical component of the host innate immune system, has an important role in microbial infection, but its aberrant activation causes inherited disorders and contributes to sporadic inflammatory diseases.At steady state, the structure of NLRP3 is oligomeric and kept in an inactive form through interactions among the C-terminal LRR domains. In response to specific stimuli, NLRP3 forms a supramolecular complex, called the inflammasome, which activates caspase-1, leading to the release of interleukin (IL)-1β and IL-18.The NLRP3 inflammasome senses the disturbance of intracellular homeostasis induced by an array of stimuli that converge on K+ efflux, which is critical for NLRP3 activation.Localization of NLRP3 to the dispersed trans-Golgi network has been suggested to have an important role in NLRP3 activation.Post-translational modifications regulate the NLRP3 inflammasome at both the priming and activation steps.
Iron is a central micronutrient needed by all living organisms. Competition for iron in the intestinal tract is essential for the maintenance of indigenous microbial populations and for host health. ...How symbiotic relationships between hosts and native microbes persist during times of iron limitation is unclear. Here, we demonstrate that indigenous bacteria possess an iron-dependent mechanism that inhibits host iron transport and storage. Using a high-throughput screen of microbial metabolites, we found that gut microbiota produce metabolites that suppress hypoxia-inducible factor 2α (HIF-2α) a master transcription factor of intestinal iron absorption and increase the iron-storage protein ferritin, resulting in decreased intestinal iron absorption by the host. We identified 1,3-diaminopropane (DAP) and reuterin as inhibitors of HIF-2α via inhibition of heterodimerization. DAP and reuterin effectively ameliorated systemic iron overload. This work provides evidence of intestine-microbiota metabolic crosstalk that is essential for systemic iron homeostasis.
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•Lactobacillus species sense intestinal iron levels and attenuate host iron absorption•Microbial metabolites DAP and reuterin are novel HIF-2α inhibitors•Gut microbial metabolites regulate intestinal iron storage via ferritin regulation•Gut microbiota can be therapeutically targeted for iron-related disorders
Das et al. show that gut microbiota regulate host iron metabolism. Lactobacillus species are the major bacterial players involved in sensing intestinal iron levels and attenuating host iron absorption. The authors further show that mammalian iron disorders can be therapeutically targeted by modulating microbial species or their metabolites.
In this research work, we report for the first time the green synthesis of silver nanoparticles (AgNPs), using two varieties of a natural extract of dark (D) or white (Wh) Salvia hispanica L. seeds, ...commonly named chia (Ch), as a reducing-stabilizing agent. Similarly, it was carried out a study on the effect of the variation of different physicochemical parameters, like aging time and storage temperature of the natural extract of dark Ch seeds, in the morphology, size and polydispersity of the prepared AgNPs. We found that the ideal conditions to do the green synthesis of AgNPs, are to use the Ch extract one day after it have been prepared and stored at 5 °C (1D C). The AgNPs were characterized by UV–Vis, FT-IR, FE-SEM-EDS and TEM. The TEM images of the synthesized AgNPs showed spherical morphology with an average nanoparticle size of 7 nm, at optimum conditions (AgNPs/D Ch (1D C)). Additionally, we studied the antimicrobial activity of the green synthesized AgNPs with both types of Ch seeds, against bacteria gram-positive and gram-negative, using as the bacterial model E. coli and S. aureus, respectively. We determined that the synthesized AgNPs/D Ch have more antimicrobial activity against both bacteria, in comparation with AgNPs/W Ch (ZOI against E. coli, 18.5 mm; S. aureus, 14.9 mm).
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•We report a green chemistry method for silver nanoparticles (Ag-NPs) synthesis with Salvia hispanica seed aqueous extract.•We study the effect of the type of Salvia hispanica seed on the silver nanoparticles (Ag-NPs) synthesis.•The silver nanoparticles (Ag-NPs) characterization were done by Uv-vis, SEM-EDS, and TEM.•The nanoparticles obtained are spherical in shape and between 1 and 27 nm in size.
Members of the nucleotide-binding domain and leucine-rich repeat (LRR)-containing (NLR) family and the pyrin and HIN domain (PYHIN) family can form multiprotein complexes termed ‘inflammasomes’. The ...biochemical function of inflammasomes is to activate caspase-1, which leads to the maturation of interleukin 1 beta (IL-1β) and IL-18 and the induction of pyroptosis, a form of cell death. Unlike other inflammasomes, the NLRP3 inflammasome can be activated by diverse stimuli. The importance of the NLRP3 inflammasome in immunity and human diseases has been well documented, but the mechanism and regulation of its activation remain unclear. In this review we summarize current understanding of the mechanism and regulation of NLRP3 inflammasome activation as well as recent advances in the noncanonical and alternative inflammasome pathways.
The NLRP3 inflammasome is an essential mediator of host immune responses through the activation of caspase-1 and interleukin 1 beta (IL-1β)/IL-18.
The NLRP3 inflammasome is thought to sense the disturbance of cellular homeostasis rather than directly recognizing a common motif present in its activators, and multiple cellular signals have been proposed to trigger its activation, including K+ efflux, Ca2+ signaling, mitochondrial dysfunction, and lysosomal rupture.
Noncanonical and alternative inflammasome pathways were recently shown to activate the NLRP3 inflammasome.
Nek7 has emerged as an essential regulator of NLRP3 inflammasome activation.
The nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (Nlrp3) inflammasome plays an important role in inflammation by controlling the maturation and secretion of the ...cytokines IL-1β and IL-18 in response to multiple stimuli including pore-forming toxins, particulate matter, and ATP. Although the pathways activated by the latter stimuli lead to a decrease in intracellular K(+) concentration, which is required for inflammasome activation, the mechanism by which microbial RNA activates Nlrp3, remains poorly understood. In this study, we found that cytosolic poly(I:C), but not total RNA from healthy macrophages, macrophages undergoing pyroptosis, or mitochondrial RNA, induces caspase-1 activation and IL-1β release through the Nlrp3 inflammasome. Experiments with macrophages deficient in Tlr3, Myd88, or Trif, indicate that poly(I:C) induces Nlrp3 activation independently of TLR signaling. Further analyses revealed that the cytosolic sensors Rig-I and melanoma differentiation-associated gene 5 act redundantly via the common adaptor mitochondrial antiviral signaling (Mavs) to induce Nlrp3 activation in response to poly(I:C), but not ATP or nigericin. Mechanistically, Mavs triggered membrane permeabilization and K(+) efflux independently of the inflammasome which were required for poly(I:C)-induced Nlrp3 activation. We conclude that poly (I:C) activates the inflammasome through an Mavs-dependent surveillance pathway that converges into a common K(+) lowering step in the cytosol that is essential for the induction of Nlrp3 activation.
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