Inflammasomes are multimeric protein complexes that typically comprise a sensor, an adaptor and the zymogen procaspase-1. An inflammasome assembles in response to a diverse range of ...pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage, which further induces maturation of interleukins 1β and 18 (IL-1β and IL-18) through proteolytic cleavage of pro-IL-1β and pro-IL-18. Activated caspase-1 also cleaves gasdermin D, which leads to a particular form of cell death called pyroptosis. Mutations in genes that encode inflammasome components are associated with many inflammatory disorders, and studies in the past decade have highlighted the importance of appropriate activation of the inflammasome in homeostasis and disease pathogenesis. Therefore, much attention is being paid to uncover the modulators and regulators of inflammasome assembly and pyroptosis. This Cell Science at a Glance article and accompanying poster outlines the concepts in the activation of inflammasome sensors and assembly of the inflammasome platform. We also discuss recent insights into the mechanisms of regulation of inflammasome activity and the induction of cell death by pyroptosis.
Inflammatory bowel diseases (IBD) increase risk for colorectal cancer. Mutations in the Mediterranean fever gene (MEFV or pyrin) are associated with hereditary autoinflammatory disease and severe ...IBD. Expression of MEFV, a sensor protein that the initiates assembly of the inflammasome complex, is increased in colon biopsies from patients with IBD. We investigated the role of pyrin in intestinal homeostasis in mice.
Mefv–/– mice and C57/BL6 mice (controls) were given azoxymethane followed by multiple rounds of dextran sodium sulfate (DSS) to induce colitis and tumorigenesis. In some experiments, Mefv–/– mice were given injections of recombinant interleukin 18 (rIL18) or saline (control) during DSS administration. Colon tissues were collected at different time points during colitis development and analyzed by histology, immunohistochemistry, immunoblots, or ELISAs (to measure cytokines). Spleen and mesenteric lymph node were collected, processed, and analyzed by flow cytometry. Colon epithelial permeability was measured in mice with colitis by gavage of fluorescent dextran and quantification of serum levels.
MEFV was expressed in colons of control mice and expression increased during chronic and acute inflammation; high levels were detected in colon tumor and adjacent non-tumor tissues. Mefv–/– mice developed more severe colitis than control mice, with a greater extent of epithelial hyperplasia and a larger tumor burden. Levels of inflammatory cytokines (IL6) and chemokines were significantly higher in colons of Mefv–/– mice than control mice following colitis induction, whereas the level IL18, which depends on the inflammasome for maturation and release, was significantly lower in colons of Mefv–/– mice. Mefv–/– mice had increased epithelial permeability following administration of DSS than control mice, and loss of the tight junction proteins occludin and claudin-2 from intercellular junctions. STAT3 was activated (phosphorylated) in inflamed colon tissues from Mefv–/–, which also had increased expression of stem cell markers (OLFM4, BMI1, and MSI1) compared with colons from control mice. Administration of rIL18 to Mefv–/– mice reduced epithelial permeability, intestinal inflammation, the severity of colitis, and colon tumorigenesis.
In studies with DSS-induced colitis, we found that pyrin (MEFV) is required for inflammasome activation and IL18 maturation, which promote intestinal barrier integrity and prevent colon inflammation and tumorigenesis. Strategies to increase activity of MEFV or IL18 might be developed for the treatment of IBD and prevention of colitis-associated tumorigenesis.
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Fungi represent a significant proportion of the gut microbiota. Aberrant immune responses to fungi are frequently observed in inflammatory bowel diseases (IBD) and colorectal cancer (CRC), and ...mutations in the fungal-sensing pathways are associated with the pathogenesis of IBD. Fungal recognition receptors trigger downstream signaling via the common adaptor protein CARD9 and the kinase SYK. Here we found that commensal gut fungi promoted inflammasome activation during AOM-DSS-induced colitis. Myeloid cell-specific deletion of Card9 or Syk reduced inflammasome activation and interleukin (IL)-18 maturation and increased susceptibility to colitis and CRC. IL-18 promoted epithelial barrier restitution and interferon-γ production by intestinal CD8+ T cells. Supplementation of IL-18 or transfer of wild-type myeloid cells reduced tumor burden in AOM-DSS-treated Card9−/− and Sykfl/flLysMCre/+ mice, whereas treatment with anti-fungal agents exacerbated colitis and CRC. CARD9 deletion changes the gut microbial landscape, suggesting that SYK-CARD9 signaling maintains a microbial ecology that promotes inflammasome activation and thereby restrains colitis and colon tumorigenesis.
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•Commensal gut fungi contribute to inflammasome activation during experimental colitis•Microbial landscape is altered in Card9−/− mice•Defective inflammasome activation, IL-18 maturation in myeloid cells lacking CARD9 or SYK•Metronidazole treatment protects Card9−/− and SykLysM mice from colon tumorigenesis
Fungi represent a significant proportion of the gut microbiota, but how anti-fungal immunity contributes to tumor-promoting inflammatory responses is unclear. Malik et al. find that recognition of commensal gut fungi, sensed via the Card9-Syk signaling axis, is protective in the context of inflammation-associated cancer. IL-18 maturation downstream of inflammasome activation promotes epithelial barrier restitution and IFN-γ production by intestinal CD8+ T cells.
Colorectal cancer is a leading cause of cancer-related deaths. Mutations in the innate immune sensor AIM2 are frequently identified in patients with colorectal cancer, but how AIM2 modulates colonic ...tumorigenesis is unknown. Here, we found that Aim2-deficient mice were hypersusceptible to colonic tumor development. Production of inflammasome-associated cytokines and other inflammatory mediators was largely intact in Aim2-deficient mice; however, intestinal stem cells were prone to uncontrolled proliferation. Aberrant Wnt signaling expanded a population of tumor-initiating stem cells in the absence of AIM2. Susceptibility of Aim2-deficient mice to colorectal tumorigenesis was enhanced by a dysbiotic gut microbiota, which was reduced by reciprocal exchange of gut microbiota with healthy wild-type mice. These findings uncover a synergy between a specific host genetic factor and gut microbiota in determining the susceptibility to colorectal cancer. Therapeutic modulation of AIM2 expression and microbiota has the potential to prevent colorectal cancer.
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•AIM2 is required to mediate protection against colorectal cancer•AIM2 suppresses overt proliferation in enterocytes•AIM2 inhibits expansion of the intestinal stem cell population•Transfer of healthy microbiota dampens tumor development in Aim2-deficient mice
The cytosolic DNA sensor AIM2 regulates stem cell proliferation in the intestinal mucosa in an inflammasome-independent fashion, contributing to a decrease in the likelihood of colorectal cancer development.
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This research work aims to fabricate cetuximab (CTX) decorated cabazitaxel (CBZ) loaded redox-sensitive D-alpha-tocopheryl-polyethyleneglycol-1000-succinate (TPGS-SS) nanoparticles ...(NPs) for epidermal growth factor receptor (EGFR)-targeted lung tumor therapy.The NPs were prepared using a dialysis bag diffusion method to produce, non-redox sensitive non targeted (TPGS-CBZ-NPs), redox-sensitive nontargeted (TPGS-SS-CBZ-NPs), and targeted redox-sensitive NPs (CTX-TPGS-SS-CBZ-NPs). Developed NPs were characterized for particle sizes, polydispersity, surface charge, surface morphologies, and entrapment efficiency. Moreover, additional in vitro studies have been conducted, including in vitro drug release, cytotoxicity, and cellular uptake studies.The particle size and charge over the surface were found to be in the range of 145.6 to 308.06 nm and −15 to –23 mV respectively. The IC50 values of CBZ clinical injection (Jevtana®), TPGS-CBZ-NPs, TPGS-SS-CBZ-NPs, and CTX-TPGS-SS-NPs were found to be 17.54 ± 3.58, 12.8 ± 2.45, 9.28 ± 1.13 and 4.013 ± 1.05 µg/ml, suggesting the 1.37, 1.89 and 4.37-folds respectively, enhancement of cytotoxicity as compared to CBZ clinical injection, demonstrating a significant augmentation in cytotoxicity. In addition, the in-vitro cellular uptake investigation showed that CTX-TPGS-SS-CMN6-NPs accumulated significantly compared to pure CMN6, TPGS-CMN6-NPs, and TPGS-SS-CMN6-NPs in the A549 cells. Furthermore, the targeting efficiency of developed NPs were analysed by ultrasound/photoacoustic and IVIS imaging.
Death due to sepsis remains a persistent threat to critically ill patients confined to the intensive care unit and is characterized by colonization with multi-drug-resistant healthcare-associated ...pathogens. Here we report that sepsis in mice caused by a defined four-member pathogen community isolated from a patient with lethal sepsis is associated with the systemic suppression of key elements of the host transcriptome required for pathogen clearance and decreased butyrate expression. More specifically, these pathogens directly suppress interferon regulatory factor 3. Fecal microbiota transplant (FMT) reverses the course of otherwise lethal sepsis by enhancing pathogen clearance via the restoration of host immunity in an interferon regulatory factor 3-dependent manner. This protective effect is linked to the expansion of butyrate-producing Bacteroidetes. Taken together these results suggest that fecal microbiota transplantation may be a treatment option in sepsis associated with immunosuppression.
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•The current status of antimicrobial resistance development and its impact in the future has been presented.•Various sampling strategies for antimicrobial waste sampling from ...environmental matrices have been briefly presented.•Cartridges used for the solid phase extraction have been tabulated with brief specifications.•More than 48 liquid chromatographic analytical methods for antibiotics from environmental waste samples have been covered.
Antibiotics are life-saving drugs, projecting their pivotal role in preventing and mitigating infectious diseases from the time of their evolution. The mass production of antibiotics was started in the twentieth century, primarily of semisynthetic derivatives of naturally occurring antimicrobial molecules and a few purely synthetic compounds. As a result, the whole bacterial populations were subjected to unprecedented antibiotic evolutionary pressures, leading to the accelerated development of antimicrobial resistance (AMR) among many infectious microorganisms that we encounter today. Consistent disposal and perseverance of antibiotics in ecosystems have been recognized as evolving environmental health hazards. Conventional techniques for removing antibiotics, such as wastewater treatment plants, have been proved to be inefficient. In addition, antibiotics should be proactively removed from environmental matrices. For setting the standard guideline by authorities for antibiotics disposal in the environment and their confinements, it is essential to develop highly efficient analytical methods for the qualification and quantification of antibiotic residues in the environmental matrices. Generally, antibiotics in the environmental matrices are complex and below the nanogram or picogram range; hence, sample purification and enrichment are quite essential prior to analysis. This review presents an overview of sampling techniques for antibiotics from environmental matrices, their purification and enrichment by liquid–liquid extraction, solid phase extraction, lyophilization and rotary evaporation. The review highlighted various qualification and quantification of extracted antibiotics that have been carried out by using high performance liquid chromatography (HPLC), ultra-high performance liquid chromatography (UPLC) and liquid chromatography tandem mass spectroscopy (LC-MS/MS).
Campylobacter jejuni is a leading cause of gastroenteritis that has been causally linked with development of the autoimmune peripheral neuropathy Guillain Barré Syndrome (GBS). Previously, we showed ...that C. jejuni isolates from human enteritis patients induced Type1/17-cytokine dependent colitis in interleukin-10 (IL-10)
−/−
mice, while isolates from GBS patients colonized these mice without colitis but instead induced autoantibodies that cross-reacted with the sialylated oligosaccharide motifs on the LOS of GBS-associated C. jejuni and the peripheral nerve gangliosides. We show here that infection of IL-10
−/−
mice with the GBS but not the colitis isolate led to sciatic nerve inflammation and abnormal gait and hind limb movements, with character and timing consistent with this syndrome in humans. Autoantibody responses and associated nerve histologic changes were dependent on IL-4 production by CD4 T cells. We further show that Siglec-1 served as a central antigen presenting cell receptor mediating the uptake of the GBS isolates via interaction with the sialylated oligosaccharide motifs found specifically on the LOS of GBS-associated C. jejuni, and the ensuing T cell differentiation and autoantibody elicitation. Sialylated oligosaccharide motifs on the LOS of GBS-associated C. jejuni therefore acted as both the Siglec-1-ligand for phagocytosis, as well as the epitope for autoimmunity. Overall, we present a mouse model of an autoimmune disease induced directly by a bacterium that is dependent upon Siglec-1 and IL-4. We also demonstrate the negative regulatory role of IL-10 in C. jejuni induced autoimmunity and provide IL-4 and Siglec-1 blockade as potential therapeutic interventions against GBS.
The miniaturization of electronics has been following Moore's Law for decades and has resulted in the development of sequentially evolutionized multifunctional nanoengineered devices. The ...conventional electronic devices are processed over planar hierarchically nanopatterned substrates having mechanical rigidity and stiffness which limit the degree of utility due to its inability to interface with soft curvilinear morphology, brittle nature, and inferior optical transparency. However, flexible substrates assembled over polymeric framework would, therefore, play a key role by offering light weighted thin film architecture, wearability, improved optical transparency, and morphological configuration to curvilinearity. The flexibility of substrate is defined when the material is processed such that individual component complies to a comparable degree of bending without deterioration of electronic/optoelectronic performance. Since the fabricated structure is pliable, the mechanical integrity of the structure governs the electromechanical performance of flexible electronic devices. The structure may undergo delamination, which occurs due to the stress field gradient developed due to the coefficient of thermal expansion, thereby generating a built-in strain potentially capable of breaking the adhering bonds. This article provides a consolidated review of numerous processing techniques to fabricate flexible electronics ranging from printing, sol-gel, chemical vapor deposition to chemical synthesis route, etc. and their applications in thin-film transistors, solar cells, sensors, health monitoring e-skins, optical devices, etc. along with a theoretical mechanical two layer film substrate model.
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